Podcasts about hdac

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Best podcasts about hdac

Latest podcast episodes about hdac

JCO Precision Oncology Conversations
JCO PO Article Insights: Exceptional Responders with Abexinostat and Pazopanib

JCO Precision Oncology Conversations

Play Episode Listen Later Apr 30, 2025 6:44


In this JCO PO Article Insights episode, host Harold Tan summarizes Low Kynurenine Levels Among Exceptional Responders on Phase Ib Trial of the HDAC Inhibitor Abexinostat with Pazopanib by Tsang et al, published November 07, 2024. Transcript Harold Nathan Tan: Welcome to JCO Precision Oncology Article Insights, where we explore cutting-edge discoveries in the world of cancer treatment and research. I'm Harold Nathan Tan, your host, and today we're taking a focused look at a compelling phase Ib trial led by Dr. Tsang, which investigates a combination of abexinostat, a histone deacetylase inhibitor, with pazopanib, a VEGF-targeting tyrosine kinase inhibitor, in patients with advanced solid tumors. VEGF inhibition has long been an established therapeutic strategy across a wide range of tumor types, including colorectal, ovarian, sarcoma, and renal cell carcinoma. These agents function by disrupting tumor angiogenesis, effectively limiting oxygen and nutrient delivery to malignant cells and contributing to improved survival outcomes. However, over time, acquired resistance remains a significant challenge. A key mechanism implicated in this resistance involves the upregulation of hypoxia-inducible factor 1-alpha, or HIF-1-alpha for short, a master regulator of angiogenesis that restores VEGF signaling under hypoxic conditions. Interestingly, HIF-1-alpha overexpression is mediated by histone deacetylases, especially HDAC2. Preclinical studies suggest that HDAC2 inhibition can suppress tumor cell migration and downregulate HIF-1-alpha activity, effectively disabling a critical escape pathway used by tumors under VEGF pressure. Moreover, combining HDAC inhibition with VEGF blockade has demonstrated synergy in pazopanib-resistant tumor models, forming a compelling rationale for this dual approach. The phase Ib trial by Tsang et al. was designed to evaluate the safety, tolerability, and preliminary efficacy of this dual-targeted approach in patients with heavily pretreated advanced solid tumors. A dose-expansion cohort focused on individuals with renal cell carcinoma, allowing for more detailed evaluation in this population. A central component of this study was the incorporation of biomarker analysis, particularly regarding HDAC2 expression levels. The results were noteworthy. Patients with high HDAC2 expression achieved a progression-free survival of 7.7 months compared to only 3.5 months in those with low expression. Even more compelling, overall survival reached 32.3 months for those with a high HDAC2 expression versus just 9.2 months for those with low expression. This suggests the potential role for HDAC2 as a predictive biomarker for response to combination HDAC and VEGF-targeted therapy. The authors also explored the metabolic landscape of these patients, conducting metabolomic analysis focused on kynurenine, a key tryptophan catabolite known to contribute to the immune suppression in the tumor microenvironment. Its reduction is driven by HIF-1-alpha and inflammatory cytokines, including interleukin-6 and tumor necrosis factor-alpha. What they found was striking. Exceptional responders, defined as patients with treatment responses lasting more than 3 years, had consistently lower levels of kynurenine both before and after treatment. This finding introduces kynurenine as a potential metabolic biomarker. It suggests that patients with lower kynurenine levels may have a less immunosuppressive microenvironment, making them more responsive to the combined effects of HDAC inhibition and VEGF blockade. Of note, VEGF levels themselves did not significantly differ between responders and nonresponders, highlighting that the treatment benefit is not purely VEGF-mediated but likely driven by epigenetic and metabolic modulation. On the safety front, the combination of abexinostat and pazopanib was generally well tolerated. However, this study did report a correlation between higher plasma concentrations of abexinostat and an increased incidence of thrombocytopenia, a class effect associated with HDAC inhibitors. This trial introduces several key considerations for future research. First, it calls for validation of HDAC2 as a predictive biomarker. If confirmed in larger cohorts, HDAC2 expression could be used to select patients most likely to benefit from HDAC inhibitor-based regimens, transforming how we approach trial enrollment and treatment planning. Second, the link between low kynurenine and exceptional response supports further investigation into how metabolic pathways can influence treatment response to combined HDAC and VEGF inhibition. Overall, HDAC inhibitors hold significant promise in precision oncology. Realizing their full therapeutic potential requires a deeper understanding of HDAC biology, refined combination strategies, and thorough preclinical and clinical evaluations tailored to individual patient profiles. This study exemplifies the potential of epigenetic-metabolic crosstalk as a therapeutic vulnerability and underscores the importance of precision stratification in clinical trial design. As research in this space progresses, the integration of molecular, epigenetic, and metabolic profiling will be essential in optimizing the use of HDAC inhibitors and expanding their role within precision oncology. Thank you for tuning into JCO Precision Oncology Article Insights. Don't forget to subscribe and join us next time as we explore more groundbreaking research shaping the future of oncology. Until then, stay informed and stay inspired.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Oncotarget
Novel Triple-Drug Combination to Fight Pancreatic Cancer

Oncotarget

Play Episode Listen Later Jul 25, 2024 8:10


In the ever-evolving quest for effective cancer treatments, researchers are continuously exploring innovative combinatorial approaches that exploit the vulnerabilities of malignant cells. In a new study, researchers Benigno C. Valdez, Apostolia M. Tsimberidou, Bin Yuan, Yago Nieto, Mehmet A. Baysal, Abhijit Chakraborty, Clark R. Andersen, and Borje S. Andersson from The University of Texas MD Anderson Cancer Center unveiled a promising synergistic strategy for combating pancreatic cancer (a cancer known for its resistance to conventional therapies). On June 3, 2024, their research paper was published in Oncotarget's Volume 15, entitled, “Synergistic cytotoxicity of histone deacetylase and poly-ADP ribose polymerase inhibitors and decitabine in pancreatic cancer cells: Implications for novel therapy.” Full blog - https://www.oncotarget.org/2024/07/25/novel-triple-drug-combination-to-fight-pancreatic-cancer/ Research paper DOI - https://doi.org/10.18632/oncotarget.28588 Correspondence to - Apostolia M. Tsimberidou - atsimber@mdanderson.org Video short - https://www.youtube.com/watch?v=zwZVrAsdgE8 Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28588 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, decitabine, HDAC inhibitors, pancreatic cancer, PARP inhibitors, synergistic cytotoxicity About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Oncotarget
Synergistic Cytotoxicity of HDAC and PARP Inhibitors and Decitabine in Pancreatic Cancer Cells

Oncotarget

Play Episode Listen Later Jun 5, 2024 3:38


BUFFALO, NY- June 5, 2024 – A new research paper was published in Oncotarget's Volume 15 on June 3, 2024, entitled, “Synergistic cytotoxicity of histone deacetylase and poly-ADP ribose polymerase inhibitors and decitabine in pancreatic cancer cells: Implications for novel therapy.” Histone deacetylase inhibitors (HDACi) can modulate the acetylation status of proteins, influencing the genomic instability exhibited by cancer cells. Poly (ADP ribose) polymerase (PARP) inhibitors (PARPi) have a direct effect on protein poly (ADP-ribosyl)ation, which is important for DNA repair. Decitabine is a nucleoside cytidine analogue, which when phosphorylated gets incorporated into the growing DNA strand, inhibiting methylation and inducing DNA damage by inactivating and trapping DNA methyltransferase on the DNA, thereby activating transcriptionally silenced DNA loci. In this new study, researchers Benigno C. Valdez, Apostolia M. Tsimberidou, Bin Yuan, Yago Nieto, Mehmet A. Baysal, Abhijit Chakraborty, Clark R. Andersen, and Borje S. Andersson from The University of Texas MD Anderson Cancer Center explored various combinations of HDACi and PARPi +/− decitabine (hypomethylating agent) in pancreatic cancer cell lines BxPC-3 and PL45 (wild-type BRCA1 and BRCA2) and Capan-1 (mutated BRCA2). “[...] we explored various combinations of HDACis and PARPis, with or without decitabine, in pancreatic cancer cell lines.” The combination of HDACi (panobinostat or vorinostat) with PARPi (talazoparib or olaparib) resulted in synergistic cytotoxicity in all cell lines tested. The addition of decitabine further increased the synergistic cytotoxicity noted with HDACi and PARPi, triggering apoptosis (evidenced by increased cleavage of caspase 3 and PARP1). The 3-drug combination treatments (vorinostat, talazoparib, and decitabine; vorinostat, olaparib, and decitabine; panobinostat, talazoparib, and decitabine; panobinostat, olaparib, and decitabine) induced more DNA damage (increased phosphorylation of histone 2AX) than the individual drugs and impaired the DNA repair pathways (decreased levels of ATM, BRCA1, and ATRX proteins). The 3-drug combinations also altered the epigenetic regulation of gene expression (NuRD complex subunits, reduced levels). “This is the first study to demonstrate synergistic interactions between the aforementioned agents in pancreatic cancer cell lines and provides preclinical data to design individualized therapeutic approaches with the potential to improve pancreatic cancer treatment outcomes.” DOI - https://doi.org/10.18632/oncotarget.28588 Correspondence to - Apostolia M. Tsimberidou - atsimber@mdanderson.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28588 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Journal of Clinical Oncology (JCO) Podcast
JCO Article Insights: Final Analysis of the Ro-CHOP Trial

Journal of Clinical Oncology (JCO) Podcast

Play Episode Listen Later May 27, 2024 8:49


In this JCO Article Insights episode, Alexandra Rojek provides a summary on "Romidepsin Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Versus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Previously Untreated Peripheral T-Cell Lymphoma: Final Analysis of the Ro-CHOP Trial" by Camus et al published February 16th, 2024 and the associated editorial written by Dr. Mehta-Shah and Dr. Horwitz. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Alexandra Rojek: Hello and welcome to JCO Article Insights. I'm your host, Alexandra Rojek, and today we will be discussing a clinical trial update published in the May 10th issue of JCO addressing the long term follow up of the addition of romidepsin to CHOP chemotherapy for previously untreated peripheral T-cell lymphoma, or PTCL. This report by Camus et al discusses a five-year follow up of the original Ro-CHOP trial, which did not meet its primary endpoint of progression free survival. The original Ro-CHOP study, conducted by the LYSA group, was published in 2021 in JCO and was conducted as a one-to-one randomized phase III study of Ro-CHOP versus CHOP for patients aged 18 to 80 years with PTCL. 98 international centers were included, and the study enrolled patients between 2013 and ‘17. Nodal follicular helper T-cell, or TFH lymphoma was defined in this study follow-up as a PTCL expressing at least two of five TFH markers according to the latest classifications. The study's primary endpoint was PFS with secondary endpoints of OS and duration of response, or DOR. Five year follow up was reached in December 2022. In the original study report, the addition of romidepsin to CHOP did result in a reduction of dose intensity of chemotherapy. However, in this updated follow up, there were no new safety signals reported. A total of 421 patients were enrolled in the trial with a median age of 65 years. Notably, those who were randomized to the Ro-CHOP arm had a higher proportion of IPI 4-5 scores at 33%, versus 24% of those who were assigned to CHOP alone despite randomization. Nearly half of patients carried a histologic diagnosis of angioimmunoblastic T-cell lymphoma. 30% were characterized as PTCL NOS, not otherwise specified, 10% ALK negative anaplastic large cell lymphoma, leaving 13% reported as other. Over 60% of patients had stage four disease at enrollment, with nearly half having more than two sites of extranodal involvement. Median follow up was six years with a median PFS of 12 months for Ro-CHOP and 10.2 months for CHOP, which did not reach statistical significance as reported in the original study publication. Estimated five year OS available as a part of this clinical trial update was 50% for Ro-CHOP and 43% for CHOP alone, and also did not reach significance. There was, however, a longer duration of response observed in the Ro-CHOP arm at 52 months versus 24 months for CHOP, which is a new finding in this extended follow up of the study. In an effort to better understand whether there are subgroups which may benefit from romidepsin despite the overall negative outcome of this study, the authors are able to provide new insights from this Ro-CHOP study in line with our current and updated understanding of PTCL. When the authors evaluated the study population for subgroups which may benefit from addition of romidepsin, TFH lymphomas, which included angioimmunoblastic, follicular, and NOS subtypes, were noted to have an improved response to the addition of this HDAC inhibitor. This subgroup, numbering 201 patients, experienced a mean PFS of over 19 months with Ro-CHOP versus over 10 months for those who received CHOP, and this difference achieved statistical significance. Similarly, there was a higher complete response rate and longer duration of response for those in the TFH subgroup who received romidepsin. The authors also make note that those patients in this subgroup with high IPI appeared to particularly benefit. However, those in the PTCL NOS group who did not fit the TFH subtype experienced poor outcomes with shorter PFS and OS as compared to other histologic subtypes, which is in line with other reported data in the field. The authors in this update also report on treatments and outcomes after first progression or relapse of disease, which includes a total of 274 patients, of whom 251 received second line therapy. The median PFS in OS after progression or relapse was only 3.3 months and 11.5 months, respectively, and again, patients with the TFH subtype experienced a longer median OS than other included histologies. Only 8% of patients proceeded to undergo autologous stem cell transplantation overall, and 5% underwent allogeneic stem cell transplantation. While the authors note that they did not observe any notable outcome differences between various included second line therapies, they do note of a possible benefit of the antibody drug conjugate brentuximab vedotin or BV in combination with chemotherapy backbones. Those who received a BV containing regimen in the second line experienced a better CR rate and a longer PFS, too. However, the OS too was not significantly different. Again, the authors note that most of the benefit of the addition of BV to chemotherapy in the second line appeared focused on this TFH lymphoma subgroup. Of note, CD30 status was not recorded as a part of the study for included patients and could not be further reported on. The findings of the authors present in this subgroup analysis of the negative Ro-CHOP study seek to find benefit in future lessons for patients with these rare lymphomas who do not have a multitude of effective treatments available to them. The subgroup benefit in this clinical trial update based on the TFH phenotype fits our evolving understanding of PTCL in the modern era. Mutations characteristic of the TFH subgroup, in this case often involved in chromatin modification and the tumor microenvironment, have been linked to improved responses when treating with epigenetic targeting drugs such as romidepsin, thus making the findings of TFH lymphoma in the Ro-CHOP trial confirmatory of what we would expect from correlative studies. Despite the benefit of Ro-CHOP for those with TFH lymphoma, this updated analysis of a major frontline study of PTCL highlights the critical need in the T-cell lymphoma field to, first of all, better understand and separate what we have come to recognize as the heterogeneous diseases historically lumped together as PTCL. This historic classification, based on a lack of deeper molecular understanding of disease biology is unlikely to represent the true biologic diversity of its component subtypes, including the focus on TFH lymphoma presented here. The second critical unmet need, which this subgroup analysis highlights, is the need to investigate the benefit of new therapeutic agents in these distinct subgroups of PTCL, where the need for improved survival outcomes is sorely needed when examining historical outcomes with currently available therapies, both in the frontline setting as well as those in the relapsed refractory group. The associated editorial, written by Dr. Mehta-Shah and Dr. Horwitz, elegantly discusses the challenges of designing studies in rare diseases such as PTCL, which are both biologically informed as well as appropriately powered. As the authors discuss, it is rare to get a second chance for a drug, as is the case for romidepsin, where these negative results led to its voluntary withdrawal in PTCL, affecting availability of the drug for patients in the relapsed setting, as well as future clinical trials, which could have had potential for success. Additionally, better understanding of the biological underpinnings of PTCL needs to lead to better designed and appropriately powered clinical trials, as these subsets of patients are in great need of therapeutic advances. While none of these tasks is easy nor straightforward, this clinical trial update of the RoCHOP study suggests a path forward from learning from prior, promising yet failed attempts at moving the standard of care for frontline therapy of T-cell lymphoma forward. This is Alexandra Rojek thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at ascp.org/podcasts. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

NeurologyLive Mind Moments
Special Episode: FDA Approval of Givinostat for Duchenne Muscular Dystrophy

NeurologyLive Mind Moments

Play Episode Listen Later Mar 29, 2024 12:52


Welcome to this special episode of the NeurologyLive® Mind Moments® podcast. Tune in to hear leaders in neurology sound off on topics that impact your clinical practice. For major FDA decisions in the field of neurology, we release short special episodes to offer a snapshot of the news, including the main takeaways for the clinical community, as well as highlights of the efficacy and safety profile of the agent in question. In this episode, we're covering the recent approval of givinostat (Duvyzat; Italfarmaco) for the treatment of Duchenne muscular dystrophy (DMD). The therapy, a proprietary histone deacetylase (HDAC) inhibitor, was approved as the first nonsteroidal drug for patients with all genetic variants of DMD. The supporting data for the approval of givinostat comes from the phase 3 EPIDYS trial (NCT02851797). EPIDYS, a randomized, double-blind, placebo-controlled, multicenter study, included 179 ambulant male individuals who were randomly assigned 2:1 to either oral givinostat or placebo for an 18-month treatment period. Following the approval, Sharon Hesterlee, PhD, executive vice president and chief research officer of the Muscular Dystrophy Association, sat down to discuss the significance of the approval and how it changes the care for patients with DMD. She spoke specifically about the mechanism of action of the therapy, its safety profile, and how it may be used with other agents. In addition, she discussed other related topics on gene therapy and unmet needs for this patient population.  For more of NeurologyLive's coverage of givinostat's approval, head here: FDA Approves Italfarmaco's Givinostat for Duchenne Muscular Dystrophy Episode Breakdown: 0:30 – Givinostat approved for Duchenne muscular dystrophy 2:00 – Sharon Hesterlee, PhD, on the approval's implications 3:35 – Positive downstream effects of the approval 4:50 – Hersterlee on the safety profile of givinostat 5:40 – Promising outlook of the DMD field 6:45 – Overcoming roadblocks involved with gene therapy  8:55 – Remaining unmet needs for patients with Duchenne 10:15 – Closing thoughts on the approval  Thanks for listening to the NeurologyLive Mind Moments podcast. To support the show, be sure to rate, review, and subscribe wherever you listen to podcasts. For more neurology news and expert-driven content, visit neurologylive.com.

New FDA Approvals
Nexletol and Nexlizet for LDL Lowering and CV Risk, Iclusig for ALL, Elahere for Ovarian Cancer, Duvyzat for DMD, Spevigo for Psoriasis, Tryvio for Hypertension, Opsynvi for PAH, Lenmeldy for Juvenile Metachromatic Leukodystrophy

New FDA Approvals

Play Episode Listen Later Mar 25, 2024 13:43


Nascentmc.com for medical writing assistance for your company. Visit nascentmc.com/podcast for full show notes Visit learnAMAstyle.com for free downloads regarding editing and the AMA Manual of Style tip sheet.  Nexletol and Nexlizet for LDL Lowering and CV Risk: The FDA approved bempedoic acid (Nexletol) and its combination with ezetimibe (Nexlizet) for reducing cardiovascular risk and treating primary hyperlipidemia. Bempedoic acid inhibits a cholesterol synthesis enzyme, while ezetimibe blocks cholesterol absorption, both lowering LDL-C levels. The approval, for high-risk patients not yet having cardiovascular events, was based on the CLEAR Outcomes trial. Iclusig for ALL: The FDA granted accelerated approval to ponatinib (Iclusig) with chemotherapy for treating previously untreated Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Ponatinib, a tyrosine kinase inhibitor, is the first targeted agent for this leukemia type in combination with chemotherapy, based on the PhALLCON trial results. Further confirmatory data may be required to verify its clinical benefit. Elahere for Ovarian Cancer: Mirvetuximab soravtansine-gynx (Elahere) received FDA approval for treating folate receptor alpha-positive, platinum-resistant ovarian cancer, marking it as the first antibody-drug conjugate in the U.S. for this condition. The treatment targets cancer cells by binding to the folate receptor alpha, delivering a cytotoxic agent. Approval was based on the Phase 3 MIRASOL trial. Duvyzat for DMD: The FDA approved givinostat (Duvyzat) for patients 6 years or older with Duchenne muscular dystrophy (DMD), a rare neuromuscular condition. Givinostat is an HDAC inhibitor that mitigates muscle damage and slows disease progression. Approval was based on the EPIDYS trial results, granted to Italfarmaco S.p.A. Spevigo for Psoriasis: Spesolimab-sbzo (Spevigo) received FDA approval for treating generalized pustular psoriasis (GPP) in adults and pediatric patients, expanding its indication from initial approval for GPP flares. As the first targeted therapy for GPP, it acts as an IL-36 receptor antagonist. The expanded approval was based on the Effisayil 2 trial, showing significant reduction in GPP flares. Tryvio for Hypertension: The FDA approved aprocitentan (Tryvio) in combination with other antihypertensive drugs for adults not adequately controlled on other medications, marking it as the first new oral antihypertensive therapy pathway in nearly 40 years. Based on the PRECISION trial, aprocitentan was shown to be effective in patients with resistant hypertension. Opsynvi for PAH: Macitentan and tadalafil (Opsynvi) was approved by the FDA for adults with pulmonary arterial hypertension (PAH) and WHO functional class II-III, as the first once-daily single-tablet combination therapy for PAH. The approval was based on the A DUE study, demonstrating greater reduction in pulmonary vascular resistance compared to monotherapies. Lenmeldy for Juvenile Metachromatic Leukodystrophy: The FDA approved Lenmeldy (atidarsagene autotemcel) gene therapy for children with metachromatic leukodystrophy (MLD), a rare genetic disease affecting the brain and nervous system. The therapy uses the patient's own genetically modified stem cells to produce the missing enzyme. Approval was based on significant improvements in survival, mobility, and cognitive functions observed in clinical trials and an expanded access program.

Oncotarget
GZ17-6.02 With Proteasome Inhibitors Kills Multiple Myeloma Cells

Oncotarget

Play Episode Listen Later Mar 6, 2024 3:38


BUFFALO, NY- March 6, 2024 – A new #researchpaper was #published in Oncotarget's Volume 15 on March 5, 2024, entitled, “GZ17-6.02 interacts with proteasome inhibitors to kill multiple myeloma cells.” In this new study, researchers Laurence Booth, Jane L. Roberts, Cameron West, and Paul Dent from Virginia Commonwealth University and Genzada Pharmaceuticals investigated GZ17-6.02, a synthetically manufactured compound containing isovanillin, harmine and curcumin, in multiple myeloma cells. GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525) with a recommended phase 2 dose (RP2D) of 375 mg PO BID. GZ17-6.02 was more efficacious as a single agent at killing multiple myeloma cells than had previously been observed in solid tumor cell types. “GZ17-6.02 interacted with proteasome inhibitors in a greater than additive fashion to kill myeloma cells and alone it killed inhibitor-resistant cells to a similar extent.” The drug combination of GZ17-6.02 and bortezomib activated ATM, the AMPK and PERK and inactivated ULK1, mTORC1, eIF2α, NFκB and the Hippo pathway. The combination increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM, and reduced the levels of BCL-XL and MCL1. GZ17-6.02 interacted with bortezomib to enhance autophagosome formation and autophagic flux, and knock down of ATM, AMPKα, ULK1, Beclin1 or ATG5 significantly reduced both autophagy and tumor cell killing. Knock down of BAK and BIM significantly reduced tumor cell killing. The expression of HDACs1/2/3 was significantly reduced beyond that previously observed in solid tumor cells and required autophagy. This was associated with increased acetylation and methylation of histone H3. Combined knock down of HDACs1/2/3 caused activation of ATM and the AMPK and caused inactivation of ULK1, mTORC1, NFκB and the Hippo pathway. HDAC knock down also enhanced ATG13 phosphorylation, increased BAK levels and reduced those of BCL-XL. “Collectively, our present studies support performing additional in vivo studies with multiple myeloma cells.” DOI - https://doi.org/10.18632/oncotarget.28558 Correspondence to - Paul Dent - paul.dent@vcuhealth.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28558 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, autophagy, ER stress, GZ17-6.02, bortezomib, proteasome inhibitor About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

First In Human By Vial
EP 49: Jeffrey Bacha (Chairman, Rakovina Therapeutics)

First In Human By Vial

Play Episode Listen Later Dec 19, 2023 21:55 Transcription Available


Join Jeffrey Bacha, a pioneer in the fight against cancer and the creative force behind Rakovina Therapeutics. For 25 years, Jeffrey has been reshaping the industry landscape, and today, he gives us a peek into his world of innovation. We venture into Rakovina's research and development of oncology drugs. exploring their groundbreaking technique combining PARP and HDAC inhibitors into a single molecule, a game-changer in enhancing synergy and reducing toxicity. First In Human is a biotech-focused podcast that interviews industry leaders and investors to learn about their journey to in-human clinical trials. Presented by Vial, a tech-enabled CRO, hosted by Simon Burns, CEO & Co-Founder. Episodes launch weekly on Tuesdays. To view the full transcript of this episode, click here.Interested in being featured as a guest on First In Human? Please reach out to catie@vial.com.

Blood Podcast
Gut microbiota diversity and mortality in pediatric allo-HSCT; C5 inhibition in atypical HUS; and pembrolizumab plus vorinostat in PD-1-refractory Hodgkin lymphoma

Blood Podcast

Play Episode Listen Later Oct 19, 2023 19:30


In this week's episode, we'll learn how the diversity of gut microbiota predicts mortality and acute graft-versus-host disease in pediatric allogeneic transplant recipients. Then we'll discuss complement inhibition in patients with complement-mediated atypical hemolytic uremic syndrome. Finally we'll learn how PD-1 plus HDAC equals responses in previously treated Hodgkin lymphoma, specifically that response rates were encouraging in a heavily pretreated cohort, even among patients with PD-1 refractory disease.  

This Week in Startups
Next Unicorns: The Path to Reaching Net Zero with Avnos CEO Will Kain | E1810

This Week in Startups

Play Episode Listen Later Sep 15, 2023 62:56


This Week in Startups is brought to you by… LinkedIn Jobs. A business is only as strong as its people, and every hire matters. Go to http://linkedin.com/unicorn to post your first job for free. Terms and conditions apply. Fount. Do you want access to the performance protocols that pro athletes and special ops use? With Fount, an elite military operator supercharges your focus, sleep, recovery, and longevity, all powered by your unique data. Want a true edge in work and life? Go to fount.bio/TWIST for $500 off. Catalog. Stop wasting time and money with expensive design firms and unreliable freelancers! Get fast, 3-day turnarounds for a flat monthly fee with Catalog! Get $1200 off right now at https://trycatalog.com/twist * Today's show: Avnos CEO Will Kain joins Jason to discuss the importance of direct air capture technology for our planet (4:07), CO2's relationship to climate change (11:02), the path to reaching net zero (36:45), and much more! * Time stamps: (0:00) Avnos CEO Will Kain joins Jason (4:07) What carbon capture is and what makes it important (6:15) The high levels of CO2 in the atmosphere (9:46) LinkedIn Jobs - Post your first job for free at https://linkedin.com/unicorn (11:02) CO2's relationship to climate change (19:05) Fount - Get $500 off at https://fount.bio/twist (20:36) Direct air capture (DAC) technology developments and the cost of carbon capture (26:17) What is takes to power a DAC system, resource efficiency, and Avnos' unique HDAC (32:33) Environmental conditions for DAC (35:16) Catalog - Get $1200 off right now at https://trycatalog.com/twist (36:45) The path to reaching net zero (38:49) Monetization strategies (42:46) The section 45Q tax credit legislation and the VC angle (50:48) Avnos' number one goal (55:44) Mastering natural systems (59:36) AI's impact on DAC technology * Check out Avnos: https://www.avnos.com * Read LAUNCH Fund 4 Deal Memo: https://www.launch.co/four Apply for Funding: https://www.launch.co/apply Buy ANGEL: https://www.angelthebook.com Great recent interviews: Steve Huffman, Brian Chesky, Aaron Levie, Sophia Amoruso, Reid Hoffman, Frank Slootman, Billy McFarland, PrayingForExits, Jenny Lefcourt Check out Jason's suite of newsletters: https://substack.com/@calacanis * Follow Jason: Twitter: https://twitter.com/jason Instagram: https://www.instagram.com/jason LinkedIn: https://www.linkedin.com/in/jasoncalacanis * Follow TWiST: Substack: https://twistartups.substack.com Twitter: https://twitter.com/TWiStartups YouTube: https://www.youtube.com/thisweekin * Subscribe to the Founder University Podcast: https://www.founder.university/podcast

Oncotarget
Targeting Cellular Respiration as a Therapeutic Strategy in Glioblastoma

Oncotarget

Play Episode Listen Later May 19, 2023 3:13


A new research perspective was published in Oncotarget's Volume 14 on May 4, 2023, entitled, “Targeting cellular respiration as a therapeutic strategy in glioblastoma.” While glycolysis is abundant in malignancies, mitochondrial metabolism is significant as well. Mitochondria harbor the enzymes relevant for cellular respiration, which is a critical pathway for both regeneration of reduction equivalents and energy production in the form of ATP. In this research perspective, researchers Enyuan Shang, Trang Thi Thu Nguyen, Mike-Andrew Westhoff, Georg Karpel-Massler, and Markus D. Siegelin from Columbia University Medical Center, City University of New York and Ulm University Medical Center discuss their recent finding that FDA-approved HDAC-inhibitors may have a profound impact on energy metabolism in solid tumor cells, including glioblastoma (GBM). “Because of the impact of HDAC-inhibitors on metabolism we hypothesized that imipridones, which suppress cellular respiration, might synergize with these compounds to significantly enhance killing of GBM cells [38]. Indeed, we found that imipridones reversed HDAC-inhibitor induced activation of cellular respiration and in turn the combination treatment facilitated induction of intrinsic apoptosis in a manner that was partially reliant on the anti-apoptotic Bcl-2 family members.” The oxidation of NADH2 and FADH2 are fundamental since NAD and FAD are the key components of the TCA-cycle that is critical to entertain biosynthesis in cancer cells. The TCA-cycle itself is predominantly fueled through carbons from glucose, glutamine, fatty acids and lactate. Targeting mitochondrial energy metabolism appears feasible through several drug compounds that activate the CLPP protein or interfere with NADH-dehydrogenase, pyruvate-dehydrogenase, enzymes of the TCA-cycle and mitochondrial matrix chaperones. While these compounds have demonstrated anti-cancer effects in vivo, recent research suggests which patients most likely benefit from such treatments. “In summary, targeting tumor cell metabolism is relevant and future research needs to identify patient populations that particularly benefit from such treatments. Moreover, while most studies related to metabolism still rest predominantly on the tumor cells it is critical to extend such observations to the microenvironment of the tumors, especially with regards to the immune system [41, 42].” DOI - https://doi.org/10.18632/oncotarget.28424 Correspondence to - Markus D. Siegelin - ms4169@cumc.columbia.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28424 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - glioblastoma, metabolism, lactate, carbon tracing, central carbon metabolism About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

PaperPlayer biorxiv neuroscience
HDAC-6 inhibition ameliorates the early neuropathology in a mouse model of Krabbe disease

PaperPlayer biorxiv neuroscience

Play Episode Listen Later May 1, 2023


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.05.01.538924v1?rss=1 Authors: Braz, S. O., Morgado, M. M., Pereira, M. I., Monteiro, A. C., Jarpe, M., Brites, P., Sousa, M. M., Nogueira-Rodrigues, J. Abstract: Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Aging-US
Characterization of the HDAC/PI3K Inhibitor CUDC-907 as a Novel Senolytic

Aging-US

Play Episode Listen Later Apr 26, 2023 3:27


A new research paper was published in Aging (Aging-US) Volume 15, Issue 7, entitled, “Characterization of the HDAC/PI3K inhibitor CUDC-907 as a novel senolytic.” The accumulation of senescent cells has an important role in the phenotypical changes observed in aging and in many age-related pathologies. Thus, the strategies designed to prevent these effects, collectively known as senotherapies, have a strong clinical potential. Senolytics are a type of senotherapy aimed at specifically eliminating senescent cells from tissues. Several small molecule compounds with senolytic properties have already been identified, but their specificity and range of action are variable. Because of this, potential novel senolytics are being actively investigated. Given the involvement of HDACs and the PI3K pathway in senescence, researchers Fares Al-Mansour, Abdullah Alraddadi, Buwei He, Anes Saleh, Marta Poblocka, Wael Alzahrani, Shaun Cowley, and Salvador Macip from the University of Leicester, Najran University and Universitat Oberta de Catalunya hypothesized that the dual inhibitor CUDC-907, a drug already in clinical trials for its antineoplastic effects, could have senolytic effects. “Here, we show that CUDC-907 was indeed able to selectively induce apoptosis in cells driven to senesce by p53 expression, but not when senescence happened in the absence of p53.” Consistent with this, CUDC-907 showed senolytic properties in different models of stress-induced senescence. Their results also indicate that the senolytic functions of CUDC-907 depend on the inhibitory effects of both HDACs and PI3K, which leads to an increase in p53 and a reduction in BH3 pro-survival proteins. Taken together, their results show that CUDC-907 has the potential to be a clinically relevant senolytic in pathological conditions in which stress-induced senescence is involved. “According to our results, CUDC-907 could be an interesting drug to be used as a senolytic, alone or as part of a targeted approach.” DOI: https://doi.org/10.18632/aging.204616 Corresponding author - Salvador Macip - sm460@le.ac.uk Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204616 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, senescence, senolytics, HDAC, PI3K, CUDC-907 About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

PaperPlayer biorxiv neuroscience
A shared pathogenic mechanism for valproic acid and SHROOM3 knockout in a brain organoid model of neural tube defects

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Apr 11, 2023


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.11.536245v1?rss=1 Authors: Takla, T. N., Luo, J., Sudyk, R., Huang, J., Walker, J. C., Vora, N. L., Sexton, J. Z., Parent, J. M., Tidball, A. M. Abstract: Neural tube defects (NTDs) including anencephaly and spina bifida are common major malformations of fetal development resulting from incomplete closure of the neural tube. These conditions lead to either universal death (anencephaly) or life-long severe complications (spina bifida). Despite hundreds of genetic mouse models having neural tube defect phenotypes, the genetics of human NTDs are poorly understood. Furthermore, pharmaceuticals such as antiseizure medications have been found clinically to increase the risk of NTDs when administered during pregnancy. Therefore, a model that recapitulates human neurodevelopment would be of immense benefit to understand the genetics underlying NTDs and identify teratogenic mechanisms. Using our self-organizing single rosette spheroid (SOSRS) brain organoid system, we have developed a high-throughput image analysis pipeline for evaluating SOSRS structure for NTD-like phenotypes. Similar to small molecule inhibition of apical constriction, the antiseizure medication valproic acid (VPA), a known cause of NTDs, increases the apical lumen size and apical cell surface area in a dose-responsive manner. This expansion was mimicked by GSK3-{beta} and HDAC inhibitors; however, RNA sequencing suggests VPA does not inhibit GSK3-{beta} at these concentrations. Knockout of SHROOM3, a well-known NTD-related gene, also caused expansion of the lumen as well as reduced f-actin polarization. The increased lumen sizes were caused by reduced cell apical constriction suggesting that impingement of this process is a shared mechanism for VPA treatment and SHROOM3-KO, two well-known causes of NTDs. Our system allows the rapid identification of NTD-like phenotypes for both compounds and genetic variants and should prove useful for understanding specific NTD mechanisms and predicting drug teratogenicity. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

PaperPlayer biorxiv neuroscience
Plasticity of gene expression in the nervous system by exposure to environmental odorants that inhibit HDACs

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Feb 21, 2023


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.21.529339v1?rss=1 Authors: Haga-Yamanaka, S., Nunez-Flores, R., Scott, C. A., Perry, S., Chen, S. T., Pontrello, C., Nair, M. G., Ray, A. Abstract: Eukaryotes are often exposed to microbes and respond to their secreted metabolites, such as the microbiome in animals or commensal bacteria in roots. Little is known about the effects of long-term exposure to volatile chemicals emitted by microbes, or other volatiles that we are exposed to over a long duration. Using the model system Drosophila melanogaster we evaluate a yeast emitted volatile, diacetyl, found in high levels around fermenting fruits where they spend long periods of time. We find that exposure to just the headspace containing the volatile molecules can alter gene expression in the antenna. Experiments showed that diacetyl and structurally related volatile compounds inhibited human histone-deacetylases (HDACs), increased histone-H3K9 acetylation in human cells, and caused wide changes in gene expression in both Drosophila and mice. Diacetyl crosses the blood-brain barrier and exposure causes modulation of gene expression in the brain, therefore has potential as a therapeutic. Using two separate disease models known to be responsive to HDAC-inhibitors, we evaluated physiological effects of volatile exposure. First, we find that the HDAC inhibitor also halts proliferation of a neuroblastoma cell line in culture as predicted. Next, exposure to vapors slows progression of neurodegeneration in a Drosophila model for Huntington's disease. These changes strongly suggest that unbeknown to us, certain volatiles in the surroundings can have profound effects on histone acetylation, gene expression and physiology in animals. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

The Gary Null Show
The Gary Null Show - 12.27.22

The Gary Null Show

Play Episode Listen Later Dec 27, 2022 58:38


Study links nutrients in blood to better brain connectivity, cognition in older adults University of Illinois, December 20, 2022 A new study links higher levels of several key nutrients in the blood with more efficient brain connectivity and performance on cognitive tests in older adults. The study, reported in the journal NeuroImage, looked at 32 key nutrients in the Mediterranean diet, which previous research has shown is associated with better brain function in aging. It included 116 healthy adults 65-75 years of age. "We wanted to investigate whether diet and nutrition predict cognitive performance in healthy older adults," said University of Illinois postdoctoral researcher Christopher Zwilling, who led the study with U. of I. psychology professor Aron Barbey in the Beckman Institute for Advanced Science and Technology. The analysis linked specific patterns of a handful of nutrient biomarkers in the blood to better brain health and cognition. The nutrient patterns included omega-3 fatty acids, which are abundant in fish, walnuts and Brussels sprouts; omega-6 fatty acids, found in flaxseed, pumpkin seeds, pine nuts and pistachios; lycopene, a vivid red pigment in tomatoes, watermelon and a few other fruits and vegetables; alpha- and beta-carotenoids, which give sweet potatoes and carrots their characteristic orange color; and vitamins B and D. The researchers relied on some of the most rigorous methods available for examining nutrient intake and brain health, Barbey said. Rather than asking participants to answer food-intake surveys, which require the accurate recall of what and how much participants ate, the team looked for patterns of nutrient "biomarkers" in the blood. The team also used functional magnetic resonance imaging to carefully evaluate the efficiency with which various brain networks performed. The analysis found a robust link between higher levels of several nutrient biomarkers in the blood and enhanced performance on specific cognitive tests. These nutrients, which appeared to work synergistically, included omega-3 and omega-6 fatty acids, carotenoids, lycopene, riboflavin, folate, vitamin B12 and vitamin D. The analysis also revealed that a pattern of omega-3s, omega-6s and carotene was linked to better functional brain network efficiency. Different nutrient patterns appeared to moderate the efficiency in different brain networks. For example, higher levels of omega-3 fatty acids paralleled the positive relationship between a healthy frontoparietal network and general intelligence. The frontoparietal network supports the ability to focus attention and engage in goal-directed behavior. "Our study suggests that diet and nutrition moderate the association between network efficiency and cognitive performance," Barbey said. "This means that the strength of the association between functional brain network efficiency and cognitive performance is associated with the level of the nutrients." (NEXT) Sunlight offers surprise benefit -- it energizes infection fighting T cells Georgetown University Medical Center, December 20, 2022 Sunlight allows us to make vitamin D, credited with healthier living, but a surprise research finding could reveal another powerful benefit of getting some sun. Georgetown University Medical Center researchers have found that sunlight, through a mechanism separate than vitamin D production, energizes T cells that play a central role in human immunity. Their findings, published in Scientific Reports, suggest how the skin, the body's largest organ, stays alert to the many microbes that can nest there. "We all know sunlight provides vitamin D, which is suggested to have an impact on immunity, among other things. But what we found is a completely separate role of sunlight on immunity," says the study's senior investigator, Gerard Ahern, PhD, associate professor in the Georgetown's Department of Pharmacology and Physiology. "Some of the roles attributed to vitamin D on immunity may be due to this new mechanism." They specifically found that low levels of blue light, found in sun rays, makes T cells move faster -- marking the first reported human cell responding to sunlight by speeding its pace. "T cells, whether they are helper or killer, need to move to do their work, which is to get to the site of an infection and orchestrate a response," Ahern says. "This study shows that sunlight directly activates key immune cells by increasing their movement." Ahern also added that while production of vitamin D required UV light, which can promote skin cancer and melanoma, blue light from the sun, as well as from special lamps, is safer. And while the human and T cells they studied in the laboratory were not specifically skin T cells -- they were isolated from mouse cell culture and from human blood -- the skin has a large share of T cells in humans, he says, approximately twice the number circulating in the blood. What drove the motility response in T cells was synthesis of hydrogen peroxide, which then activated a signaling pathway that increases T cell movement. Hydrogen peroxide is a compound that white blood cells release when they sense an infection in order to kill bacteria and to "call" T cells and other immune cells to mount an immune response. "We found that sunlight makes hydrogen peroxide in T cells, which makes the cells move. And we know that an immune response also uses hydrogen peroxide to make T cells move to the damage," Ahern says. "This all fits together." (NEXT)  Capsaicin molecule inhibits growth of breast cancer cells Centre of Genomics, Ruhr-Universität Bochum (Germany), December 22, 2022  Capsaicin, an active ingredient of pungent substances such as chilli or pepper, inhibits the growth of breast cancer cells. This was reported by a team headed by the Bochum-based scent researcher Prof Dr Dr Dr habil Hanns Hatt and Dr Lea Weber, following experiments in cultivated tumour cells. The experiments were carried out with the SUM149PT cell culture, a model system for a particularly aggressive type of breast cancer, i.e. the triple-negative type. Chemotherapy is currently the only available treatment for this type of cancer. In the cultivated cells, the team detected a number of typical olfactory receptors. One receptor occurred very frequently; it is usually found in the fifth cranial nerve, i.e. the trigeminal nerve. It belongs to the so-called Transient Receptor Potential Channels and is named TRPV1. That receptor is activated by the spicy molecule capsaicin as well as by helional – a scent of fresh sea breeze. In collaboration with Dr Gabriele Bonatz from the Augusta clinics in Bochum (Brustzentrum), Hatt's team confirmed the existence of TRPV1 in tumour cells in nine different samples from patients suffering from breast cancer. The researchers activated the TRPV1 receptor in the cell culture with capsaicin or helional, by adding the substances to the culture for a period of several hours or days. As a result, the cancer cells divide more slowly. Moreover, the treatment caused tumour cells to die in larger numbers. The surviving cells were no longer able to move as quickly as heretofore; this implies that their ability to form metastases in the body was impeded. Earlier studies had demonstrated that the chemical arvanil – with a chemical make-up similar to that of the spicy molecule capsaicin – was effective against brain tumours in mice; it reduces tumour growth in the animals. Due to its side effects, however, this substance is not approved for humans. In addition to capsaicin and helional, the endovanilloids, produced naturally in the body, also activate the TRPV1 receptor. (NEXT)  Losing body fat could be facilitated by light evening exercise and fasting Baylor College of Medicine, December 20, 2022 Making muscles burn more fat and less glucose can increase exercise endurance, but could simultaneously cause diabetes, says a team of scientists from Baylor College of Medicine and other institutions. Mouse muscles use glucose (carbohydrate) as fuel when the animals are awake and active and switch to fat (lipid) when they are asleep. The team discovered that disrupting this natural cycle may lead to diabetes but, surprisingly, can also enhance exercise endurance. The switch is controlled by a molecule called histone deacetylase 3, or HDAC3. This finding opens the possibility of selecting the right time to exercise for losing body fat but also raises the concern of using HDAC inhibitors as doping drugs for endurance exercise. The study appears in Nature Medicine. Skeletal muscles, the voluntary muscles, are important in the control of blood glucose in the body. They consume most of the glucose, and if they develop insulin resistance and consequently are not able to use glucose, then diabetes likely will develop. To study the role of HDAC3 in mouse skeletal muscle, Sun and colleagues genetically engineered laboratory mice to deplete HDAC3 only in the skeletal muscles. Then they compared these knocked out mice with normal mice regarding how their muscles burn fuel. When normal mice eat, their blood sugar increases and insulin is released, which stimulates muscles to take in and use glucose as fuel. "When the knocked out mice ate, their blood sugar increased and insulin was released just fine, but their muscles refused to take in and use glucose," said Sun. "Lacking HDAC3 made the mice insulin resistant and more prone to develop diabetes." Yet, when the HDAC3-knocked out mice ran on a treadmill, they showed superior endurance, "which was intriguing because diabetes is usually associated with poor muscle performance," said Sun. "Glucose is the main fuel of muscle, so if a condition limits the use of glucose, the expectation is low performance in endurance exercises. That's the surprise." The researchers then studied what fueled the HDAC3-knocked out mice's stellar performance using metabolomics approaches and found that their muscles break down more amino acids. This changed the muscles' preference from glucose to lipids and allowed them to burn lipid very efficiently. This explains the high endurance, because the body carries a much larger energy reservoir in the form of lipid than carbohydrate. The team performed a number of functional genomics studies that established the link between HDAC3 and the circadian clock. "In normal mice, when the mouse is awake, the clock in the muscle anticipates a feeding cycle and uses HDAC3 to turn off many metabolic genes. This leads the muscles to use more carbohydrate," said Sun. "When the animal is about to go to sleep and anticipates a fasting cycle, the clock removes HDAC3. This leads the muscles to use more lipid." Although these studies were done in mice, the researchers speculate that human muscles most likely will follow the same cycle. The study opens the possibility of promoting body fat burning by increasing exercise activity during the periods in which muscles use lipid, which is at night for people. "Losing body fat would be easier by exercising lightly and fasting at night," said Sun. "It's not a bad idea to take a walk after dinner." (NEXT)  Employees who are open about religion are happier, study suggests Kansas State University, December 17, 2022 It may be beneficial for employers to not only encourage office Christmas parties but also celebrate holidays and festivals from a variety of religions, according to a Kansas State University researcher. Sooyeol Kim was involved in a collaborative study that found that employees who openly discuss their religious beliefs at work are often happier and have higher job satisfaction than those employees who do not. "For many people, religion is the core of their lives," Kim said. "Being able to express important aspects of one's life can influence work-related issues, such as job satisfaction, work performance or engagement. It can be beneficial for organizations to have a climate that is welcoming to every religion and culture." Kim said employers might even want to consider a religion-friendly policy or find ways to encourage religious expression. For example, organizations could have an office Christmas party, but also could celebrate and recognize other religious holidays and dates, such as Hanukkah, Ramadan or Buddhist holidays. For the cross-cultural study, the researchers surveyed nearly 600 working adults from a variety of industries -- including education and finance -- in the U.S. and South Korea. The surveyed employees were all Christian, but identified with a variety of denominations, including Presbyterian, Baptist and Methodist, among others. Results showed that employees who valued religion as a core part of their lives were more likely to disclose their religion in the workplace. Employees who felt pressure to assimilate in the workplace were less likely to disclose their religious identity, Kim said. But most significantly, the researchers found that the employees who disclosed their religion in the workplace had several positive outcomes, including higher job satisfaction and higher perceived well-being. "Disclosing your religion can be beneficial for employees and individual well-being," Kim said. "When you try to hide your identity, you have to pretend or you have to lie to others, which can be stressful and negatively impact how you build relationships with co-workers." Kim said the research on religion in the workplace plays a part into work-life balance. Research continues to show that individual characteristics -- such as family and religion -- can influence work-related issues. (NEXT) New Cannabis Capsule Is So Powerful It's Going To Completely Replace All Pain Killers University of Pennsylvania, December 19, 2022    In places where medical marijuana is legal, opioid abuse and addiction has fallen by 25%, but the government maintain they are stumped as to why Opioid abuse and addiction is a massive problem all over the US, hence why people are eager to find natural alternatives. The health benefits of cannabis are become more and more accepted in mainstream society, as more studies which support cannaboid use are published. This doesn't sit well with big pharma, who are desperate to hold on to the monopoly they control. In the U.S. states where medical marijuana is legal to use, deaths from opioid overdoses have decreased by almost 25 percent, according to a new data. The study was done by Bachhuber, of the Philadelphia Veterans Affairs Medical Center and the University of Pennsylvania, and his colleagues who used state-level death certificate data for all 50 states. According to JAMA Medicine, in states with a medical marijuana law, overdose deaths from opioids like morphine, oxycodone and heroin decreased by an average of 20 percent after just one year. After two years, they continued to decrease to 25 percent. In the mean time, opioid overdose deaths across the country skyrocketed. The cannabis capsules are made from the extract of cannabis flower. The active ingredients are processed without microbials and then packaged with a specific mix of 60 mg of THC (tetrahydrocannabinol) and 10 mg of CBD (cannabidiol). The combination together creates the perfect effect to relieve pain. The THC helps send happy feelings to the brain, while the CBD helps promote relaxation of the muscles. This helps reduce muscle spasms as well as inflammation.

PaperPlayer biorxiv neuroscience
High-Contrast PET imaging with -NT160, a Class-IIa Histone Deacetylase (Class-IIa HDAC) Probe for In Vivo Imaging of Epigenetic Machinery in the Central Nervous System

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Nov 13, 2022


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.12.516260v1?rss=1 Authors: Turkman, N., Xu, S., Huang, C.-H., Eyermann, C., Salino, J., Khan, P. Abstract: We utilized positron emission tomography (PET) imaging in vivo to map the spatiotemporal biodistribution/expression (protein density) of class-IIa histone deacetylases (class-IIa HDACs) in the brain. Herein, we report an improved radiosynthesis of [18F]-NT160 using 4-hydroxy-TEMPO which led to a significant improvement in radiochemical yield and molar activity. PET imaging with [18F]-NT160, a highly potent class-IIa HDAC inhibitor with sub-nM affinity for HDAC4 and 5 isoforms, led to high-quality and high-contrast images among various brain regions. [18F]-NT160 displayed excellent pharmacokinetic and imaging characteristics: brain uptake is high in gray matter regions, leading to high-quality PET images; tissue kinetics are appropriate for an 18F tracer and specific binding for class-IIa HDACs is demonstrated by self-blockade. Higher uptake with [18F]-NT160 was observed in the hippocampus, thalamus, and cortex while there was relatively lower uptake in the cerebellum and striatum. Overall, our current studies with [18F]-NT160 will likely facilitate the development and clinical translation of class-IIa HDACs of the next generation of PET tracers for imaging and targeted therapy of cancer and the diseases of the central nervous system (CNS). Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Oncotarget
Synergy of HDACi, PARPi and Chemotherapeutics Against Blood Cancer

Oncotarget

Play Episode Listen Later Oct 19, 2022 8:07


Listen to a blog summary of a recently published research paper in Volume 13 of Oncotarget, entitled, "HDAC inhibitors suppress protein poly(ADP-ribosyl)ation and DNA repair protein levels and phosphorylation status in hematologic cancer cells: implications for their use in combination with PARP inhibitors and chemotherapeutic drugs." _______________________________________ Chromatin constitutes chromosomes in eukaryotic cells and comprises DNA and proteins. Chromosomes produce proteins and enzymes that are essential for cellular function and maintenance, including DNA repair. A critical process for DNA repair is poly(ADP-ribosyl)ation, or PARylation. PARylation is triggered by poly(ADP ribose) polymerase (PARP) enzymes. When DNA becomes damaged, PARP enzymes bind to the damaged location in the cell. In cancer cells, however, this natural process can be counterproductive in respect to cancer treatment. PARylation can produce DNA repair mechanisms in cancer cells that can lead to the evasion of cell death, and even drug resistance. Inhibiting PARylation may be a viable therapeutic strategy for cancer treatment. Histones, the main proteins that constitute chromatin, undergo post-translational modifications that regulate gene expression. Histone acetylation is an important epigenetic process that affects gene expression by relaxing the chromatin structure, making chromatin remodeling more feasible. Histone deacetylases (HDACs) are enzymes that can have the opposite effect. Histone deacetylation makes the chromatin more compact and difficult to remodel. The overexpression of HDAC has also been associated with tumorigenesis. Histone deacetylase inhibitors (HDACi) are a class of therapeutics that have shown promise in the treatment of hematologic malignancies (blood cancer) and solid tumors. In a new study, researchers Benigno C. Valdez, Yago Nieto, Bin Yuan, David Murray, and Borje S. Andersson from the Department of Stem Cell Transplantation and Cellular Therapy at the University of Texas MD Anderson Cancer Center and the Cross Cancer Institute's Department of Experimental Oncology at the University of Alberta investigate the efficacy of HDACi in combination with PARP inhibitors (PARPi) and chemotherapeutic drugs to treat hematologic cancer. On October 14, 2022, their research paper was published in Volume 13 of Oncotarget, entitled, “HDAC inhibitors suppress protein poly(ADP-ribosyl)ation and DNA repair protein levels and phosphorylation status in hematologic cancer cells: implications for their use in combination with PARP inhibitors and chemotherapeutic drugs.” Full blog - https://www.oncotarget.org/2022/10/19/synergy-of-hdaci-parpi-and-chemotherapeutics-against-blood-cancer/ DOI - https://doi.org/10.18632/oncotarget.28278 Correspondence to - Benigno C. Valdez - bvaldez@mdanderson.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28278 Keywords - poly(ADP-ribosyl)ation, HDAC inhibitors, PARP inhibitors, chemotherapy, hematologic malignancy About Oncotarget Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/OncotargetYouTube LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

PaperPlayer biorxiv neuroscience
Dysregulation of The Chromatin Environment Leads to Differential Alternative Splicing as A Mechanism Of Disease In a Human Model of Autism Spectrum Disorders

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Sep 9, 2022


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.08.507162v1?rss=1 Authors: Leung, C. S., Rosenzweig, S., Yoon, B., Marinelli, N. A., Hollingsworth, E. W., Maguire, A. M., Cowen, M. M., Schmidt, M., Imitola, J., Uzun, E. D. G., Lizarraga, S. B. Abstract: Autism spectrum disorder (ASD) affects 1 in 44 children. Chromatin regulatory proteins are overrepresented among genes that contain high risk variants in ASD. Disruption of the chromatin environment leads to widespread dysregulation of gene expression, which is traditionally thought as a mechanism of disease pathogenesis associated with ASD. Alternatively, alterations in chromatin dynamics could also lead to dysregulation of alternative splicing, which is understudied as a mechanism of ASD pathogenesis. The anticonvulsant valproic acid (VPA) is a well-known environmental risk factor for ASD that acts as a class I histone deacetylase (HDAC) inhibitor. However, the precise molecular mechanisms underlying defects in human neuronal development associated with exposure to VPA are understudied. To dissect how VPA exposure and subsequent chromatin hyperacetylation influence molecular signatures involved in ASD pathogenesis, we conducted RNA sequencing (RNA-seq) in human cortical neurons that were treated with VPA. We observed that differentially expressed genes (DEGs) were enriched for mRNA splicing, mRNA processing, histone modification, and metabolism related gene sets. Furthermore, we observed widespread increase in the number and the type of alternative splicing events. Analysis of differential transcript usage (DTU) showed that exposure to VPA induces extensive alterations in transcript isoform usage across neurodevelopmentally important genes. Finally, we find that DEGs and genes that display DTU overlap with known ASD-risk genes. Together, these findings suggest that, in addition to differential gene expression, changes in alternative splicing correlated with alterations in the chromatin environment could act as an additional mechanism of disease in ASD. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Oncotarget
Press Release: CUDC907 Promotes Apoptosis Of NF2 Schwannoma Cells

Oncotarget

Play Episode Listen Later Jul 26, 2022 5:33


A new research paper was published in Oncotarget on July 19, 2022, entitled, “CUDC907, a dual phosphoinositide-3 kinase/histone deacetylase inhibitor, promotes apoptosis of NF2 Schwannoma cells.” Neurofibromatosis Type 2 (NF2) is a rare tumor disorder caused by pathogenic variants of the merlin tumor suppressor encoded by NF2. Patients develop vestibular schwannomas (VS), peripheral schwannomas, meningiomas, and ependymomas. There are no approved drug therapies for NF2. Previous work identified phosphoinositide-3 kinase (PI3K) as a druggable target. Researchers Julianne Huegel, Christine T. Dinh, Maria Martinelli, Olena Bracho, Rosa Rosario, Haley Hardin, Michael Estivill, Anthony Griswold, Sakir Gultekin, Xue-Zhong Liu, and Cristina Fernandez-Valle, from the University of Central Florida and the University of Miami Miller School of Medicine, conducted an unbiased chemical compound screen of the Library of Pharmacologically Active Compounds (LOPAC) as a pilot high-throughput screen to identify NF2 schwannoma targets for inhibition. “Here we screened PI3K pathway inhibitors for efficacy in reducing viability of human schwannoma cells.” The lead compound, CUDC907, a dual histone deacetylase (HDAC)/PI3K inhibitor, was further evaluated for its effects on isolated and nerve-grafted schwannoma model cells, and primary VS cells. CUDC907 (3 nM IG50) reduced human merlin deficient Schwann cell (MD-SC) viability and was 5–100 fold selective for MD over WT-SCs. CUDC907 (10 nM) promoted cell cycle arrest and caspase-3/7 activation within 24 hours in human MD-SCs. Western blots confirmed a dose-dependent increase in acetylated lysine and decreases in pAKT and YAP. In a 14-day treatment regimen, CUDC907 decreased tumor growth rate by 44%, modulated phospho-target levels, and decreased YAP levels. In five primary VS, CUDC907 decreased viability, induced caspase-3/7 cleavage, and reduced YAP levels. Its efficacy correlated with basal phospho-HDAC2 levels. CUDC907 has cytotoxic activity in NF2 schwannoma models and primary VS cells and is a candidate for clinical trials. “In summary, we demonstrated that CUDC907 reduced the activity of three major signaling pathways in NF2 schwannomas (HDAC, PI3K, and YAP) and consistently reduced viability and induced apoptosis in several schwannoma cell models and in all five genetically unique primary VS studied. These consistent results offer the possibility that CUDC907 will promote schwannoma regression in patients with diverse NF2 mutations and support clinical evaluation of CUDC907 for NF2-associated schwannomas and potentially other cancers driven by NF2 pathogenic variants [45]. Current use of this drug in clinical trials for other indications reveals clinical interest in multi-modal drugs over monotherapies.” DOI: https://doi.org/10.18632/oncotarget.28254 Correspondence to: Cristina Fernandez-Valle – Email: cfv@ucf.edu Keywords: fimepinostat, Schwann cell, vestibular schwanomma, merlin, nerve allograft About Oncotarget: Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, visit Oncotarget.com and connect with us on social media: Twitter – https://twitter.com/Oncotarget Facebook – https://www.facebook.com/Oncotarget YouTube – www.youtube.com/c/OncotargetYouTube Instagram – https://www.instagram.com/oncotargetjrnl/ LinkedIn – https://www.linkedin.com/company/oncotarget/ Pinterest – https://www.pinterest.com/oncotarget/ LabTube – https://www.labtube.tv/channel/MTY5OA SoundCloud – https://soundcloud.com/oncotarget For media inquiries, please contact: media@impactjournals.com.

Circulation on the Run
Circulation February 8, 2022

Circulation on the Run

Play Episode Listen Later Feb 7, 2022 20:53


Please join author David Webb and Editorialist Steven Smith as they discuss the original research article “Regular Acetaminophen Use and Blood Pressure in People With Hypertension: The PATH-BP Trial" and the editorial "Acetaminophen-Induced Hypertension: Where Have All the "Safe" Analgesics Gone?" Dr. Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm your host today, Dr. Carolyn Lam, associate editor from The National Heart Center in Duke National University of Singapore. And I'm so missing my co-host Dr. Greg Hundley, who can't make it today, but will be back next week. Now, I have the privilege of telling you all about the exciting papers in today's issue, but before I even get there, I need to let you know that coming right up is a discussion you are not going to want to miss. It deals with an issue that we encounter very commonly and perhaps should have questioned many times, but haven't yet. What is it? Well, regular acetaminophen use and its blood pressure effect. Acetaminophen, what we commonly call paracetamol or Tylenol depending where you're coming from, but have we ever stopped to really ask, does this impact blood pressure? We're going to find out more in the path BP trial coming right up, but first here are your summaries. Dr. Carolyn Lam: The first original paper I'd like to tell you about is a study representing additional four years a follow up from the Danish trial. Now recall that Danish was a trial that found that primary prevention ICD implantation was not associated with an overall survival benefit in patients with non-ischemic systolic heart failure, doing a median follow-up of 5.6 years. Although, there was a beneficial effect on all-cause mortality in patients aged 70 years or younger. Now, the current study led by Dr. Lars Køber from Copenhagen University Hospital and colleagues showed that during a median follow up of now 9.5 years, ICD implantation did not provide an overall survival benefit in patients with non-ischemic systolic heart failure. In patients age 70 years or younger, however, ICD implantation was associated with a lower incidence of all-cause mortality, cardiovascular death, and sudden cardiovascular death. Dr. Carolyn Lam: The next original paper reports on pre-specified analyses from the FIGARO-DKD trial assessing the impact of finerenone known on clinically important heart failure outcomes. Now recall that FIDELIO-DKD and FIGARO-DKD, in those trials finerenone, which is a selective nonsteroidal mineralocorticoid receptor antagonist, improved cardiovascular outcomes in patients with albuminuric chronic kidney disease and type two diabetes. In the current study, Dr. Filippatos from Attikon University Hospital in Athens, Greece and colleagues presented the pre-specified analyses of FIGARO-DKD describing novel heart failure related outcomes, which were not previously published in finerenone studies, and these included new onset heart failure. Different outcomes containing first or total hospitalization for heart failure events in the overall population. The results indicated that in patients with chronic kidney disease and type two diabetes on a maximum tolerated dose of renin-angiotensin system inhibitor therapy, fenerenone reduced new onset heart failure and improved heart failure related outcomes irrespective of history of heart failure. This is the first indication that a nonsteroidal mineralocorticoid receptor antagonist may provide benefit in a population with chronic kidney disease and type two diabetes, in which patients with heart failure with reduced dejection fraction or symptomatic NYHA 2-4 were excluded, thus indicating that patients with type two diabetes and chronic kidney disease at risk of heart failure or with early stage heart failure may indeed benefit from fenerenone treatment. Dr. Carolyn Lam: The next original paper shows for the first time, a role of the nuclear receptor Rev-Erb, a key component of the circadian clock in obesity. So, co-corresponding authors, Dr. Song from Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China, as well as Doctors Zheng Sun, both from Baylor College of Medicine, and their colleagues used mice with cardiomyocyte specific Rev-Erb deletion that manifested contractile dysfunction, cardiac dilatation, and heart failure. And using these models, authors showed that there was a temporal coordination between clock mediated anticipation and nutrient induced response in myocardial metabolism at multiomic levels. Obesity, together with insulin resistance via a high fat diet, paradoxically improved dysfunction and fatty acid availability from edibles lipolysis in the disrupted circadian mouse model that Rev-Erb knockout. These elegant studies reveal a punitive link between circadian regulation and nutrient induced responses in the heart, potentially helping to explain the obesity paradox. Cardiac molecular chronotropes may, therefore, be involved in human dilated cardiomyopathy. And the implication is that myocardial bioenergetics downstream of Rev-Erb may be a chronotherapy target in treating patients with heart failure. Now, all of this is discussed in an editorial by Dr. Inna Rabinovich-Nikitin and Dr. Lorrie Kirshenbaum from Manitoba, Canada. Dr. Carolyn Lam: The final original paper in today's issue is an important translational paper, in which ZEB2, which is a master regulator of epithelial to mesenchymal transition and is associated with many cancers, has for the first time been identified as a new coronary artery disease associated gene. This was first identified by human Genome-wide Association studies, following which the authors Dr. Quertermous from Cardiovascular Institute Stanford and colleagues used smooth muscle cell specific deletion of ZEB2 in mice, coupled with single cell transcriptomic and epigenetic profiling of smooth muscle cells specific [inaudible 00:07:31] cells, and showed that ZEB2 dramatically alters cell state trajectories of the smooth muscle cells through epigenetic regulation of TGF-β and notch signaling. Lower ZEB2 in smooth muscle cells resulted in atherosclerotic plaques with high risk features. So what are the clinical implications? Well, therapies that specifically regulate smooth muscle behavior can potentially alter the risk of plaque rupture, and may be used to further reduce the risk of myocardial infarction. Existing chemotherapies and additional drugs in development that modulate the epigenetic silencing, such as HDAC inhibitors or hypomethylating agents, may, on the other hand, increase the risk of myocardial infarction. Dr. Carolyn Lam: So very interesting paper. Wraps it up for our original papers, and now onto what else there is in today's issue. There's an On My Mind paper by Dr. Messerli on [entitled] “Why Are We Still Prescribing ACE Inhibitors?” and a Research Letter by Dr. Simon on one-year major cardiovascular events after restrictive versus liberal blood transfusion strategy in patients with AMI and anemia from the reality randomized trial. Well, that's it for the summaries. Thanks for joining. And please hang on tight for this next exciting feature discussion. Dr. Carolyn Lam: For today's feature paper, we are talking about a very familiar medication. Believe it or not, it's just paracetamol, or acetaminophen in its generic term. What we also call Tylenol in the US. And I'm sure this is something that everybody recognizes as one of the first line therapies that we take for chronic pain. It's even over the counter. It's perceived as extremely safe, and in particular, is as having little or no effect on blood pressure. But is that correct? Ah, this paper, I have to tell you audience, really sent chills up my spine. I learned so much from it and I am so, so pleased to have with us the corresponding author, Dr. David Webb from Queens Medical Research Institute in Edinburgh, as well as our editorialists Dr. Steven Smith from University of Florida in United States to discuss this very, very important paper. David, if you don't mind if I start with you, what made you look at this question? It's strikingly important, but seemingly strikingly ignored until your study, so please tell us about that. Dr. David Webb: So paracetamol, or acetaminophen, has a really long history going back to the 1800s, and it replaced a drug that was removed called phenacetin that caused significant toxicity. It didn't really grow in use until about the 1980s, but from then on, it really took off and now it's the most widely used and prescribed analgesic in the world. There have been observational studies, large ones, and small clinical trials that suggested an increase in blood pressure. We undertook a systematic review in 2013 that suggested this really needed to be a topic for a further study, and so we undertook a randomized control trial to answer the question of whether, in hypertensive subjects, paracetamol would increase blood pressure. Dr. Carolyn Lam: Well, thank you for that background. I have to admit, I didn't even know about the origins and that very first paper you talked about, and this is really beautifully summarized as well in, Steve, your beautiful editorial. But before we go there, David, could you tell us about this path BP trial, what you did and what you found? Dr. David Webb: So we were funded by the British Heart Foundation, and we under took a randomized placebo controlled blinded study of one gram of paracetamol given four times a day versus match placebo. And we looked primarily at the gold standard ambulatory blood pressure in patients with hypertension, a third off treatment, and two thirds on treatment, and about a hundred, more than a hundred patients took part in this study. It was a crossover study with washout, and we saw that ambulatory blood pressure compared to placebo treatment increased by five millimeters of mercury, which is substantial. It's very similar to what we see with the nonsteroidal anti-inflammatory drugs, the NSAIDs, which also have effects mediated through prostaglandin metabolism, and that increase of five millimeters of mercury would amount to an increased cardiovascular risk, if sustained, of around 20%. Our study was only for two weeks for practical reasons, but we have no reason to think the effect would not last longer. Dr. Carolyn Lam: And David, just before we carry on, could you clarify a few things? So, these patients did not have pain to enter, and did they have hypertension, and were they on other medications for hypertension? Dr. David Webb: Yeah, so they were patients with hypertension. They had to have an entry average ambulatory blood pressure daytime of more than 135 over 85, but less than 150 over 95, so this is mild to moderate hypertension. A third of them were not treated at the time of the study, but went on to treatment, and two thirds were already on treatment and stayed on their existing treatment. So this is a study in both treated and untreated hypertension, and we saw, although it wasn't powered to look at differences, we saw similar effects in those who were treated and untreated. Dr. Carolyn Lam: So an incredibly important question and Dr. Smith, Steve if I may, you wrote very nicely how the fact that this is individuals with hypertension, but not having an indication of pain and so on. It's really something we needed to look at this question because pain can confound, I suppose, the measurement of blood pressure and so on. So could you tell us a little bit more of why this study is so important and what do you think its impact of the findings will be? Dr. Steven Smith: Sure. Thank you, Carolyn. And first of all, I just say, I appreciate you having me on and getting to discuss this really interesting study by Dr. Webb and his team. I think it's a really interesting study. As you may know now, acetaminophen has been associated with blood pressure increases going back almost half a century now and there have been a number of studies, not all have been particularly strong studies and there's a number of limitations to that literature, and I think I was really fascinated by Dr. Webb's study because they really just asked a simple question and did a well designed, robust study to try to address that question and I think it provided some pretty definitive results. Dr. Steven Smith: As I mentioned in the editorial, despite the fact that acetaminophen has been associated with blood pressure increases in the past, if you go look at Google or whatever, your favorite search engine of choices, you'll find a number of articles right at the top that seem to imply or directly state that acetaminophen is perfectly safe for patients with high blood pressure. And I think that's a concerning thing that the medical information out there is implying or directly stating that acetaminophen is perfectly fine for these patients and so, I'm appreciative with the work that Dr. Webb is doing to try to bring to light some of the risks of acetaminophen Dr. Carolyn Lam: Indeed. And I think it raises a lot of questions that you also so nicely put in your editorial, and maybe this is the chance to ask David directly. For example, what do you think are the implications, in terms of generalizability, in chronic uses of acetaminophen in lower or higher doses in people without hypertension? I mean, this is a big and important issue. What do you think, David? Dr. David Webb: Sorry, Carolyn. Maybe I could start by just sticking to the subjects of the study itself. I think what this tells us, and it's important to recognize that there is very little evidence that paracetamol provides benefit in chronic pain. It's not of any value in low back pain. There seems to be no evidence that it's particularly useful in cancer pain and in a wide range of other forms of pain. The evidence for benefit is very limited, so harms really matter where the benefit is small, and probably most patients with chronic pain are not benefiting from the paracetamol in terms of its analgesic effect. So cautiously trying to withdraw treatment in these patients may well be a benefit in terms of reducing cardiovascular risk. So that's for what patients with hypertension. So beyond hypertension, that's a bit more difficult because we didn't study that, but we looked at a range of blood pressures. Dr. David Webb: And whilst we weren't powered to address this specifically, it looks as though the effects are there for lower blood pressures and for higher blood pressures. So, it would be nice to do the direct study, but it looks as though this might be slightly more general I support. We didn't look at people with chronic pain for practical reasons, but as I say, there's very little evidence that paracetamol is providing a benefit. I always thought that paracetamol was a safe drug. I use it in my hypertension clinic. And I think in my head, this is safer than using a nonsteroidal, but they're less effective and they may be no safer. So I think one needs to inform clinicians and their patients about the relative safety of paracetamol when considering treatment for chronic pain. You asked one other question. In the UK four grams a day as a common dose. It is in many parts of the world as a maximum dose. In the US, FDA has advised reducing to three grams a day as the maximum dose. You can still give four grams a day, but I think that's a helpful recommendation because this is very likely to be a dose dependent effect. So the lower maximum dose will to some extent protect subjects. Dr. Carolyn Lam: And Steve, would you agree with that? What would your take-home message to the audience be, or what do you think are the most important unanswered questions? Dr. Steven Smith: Yeah, it's a great question. If I could piggyback on David's answer, I think one of the really interesting findings from this study is that we see these blood pressure changes even after only two weeks of therapy, so this is not something that requires some chronic, very high dose of acetaminophen to start experiencing these blood pressure changes. Obviously a lot of people are on acetaminophen, as David mentioned all over the world. Many of those patients, of course, are on it for chronic therapy, for example, for osteoarthritis, but a lot take it much more sporadically or for short term use. And I think it's telling that we see these blood pressure changes pretty rapidly after starting therapy. Dr. Steven Smith: As far as unanswered questions go, I think Dr. Webb summarized some of those already, but I guess what I would add is we still lack some clarity on what the ultimate outcomes of these blood pressure changes are. Obviously we know that blood pressure is highly correlated with adverse cardiovascular outcomes, as well as other outcomes, but the data showing an increased cardiovascular risk with acetaminophen is a little bit more murky. And so I do think there's still some question as to how this translates to increased cardiovascular risk, and I totally agree with David that the evidence supporting efficacy of acetaminophen is so weak at this point for most things, it may be a moot point. We may want to just move on from acetaminophen to the extent that we can, because it seems to have some risks, or at least some concern for risks, without a lot of evidence. Dr. Carolyn Lam: Wow. Thank you so much, gentlemen, for this. It's just amazing discussion, but even more so for publishing such an important study and such an elegant editorial in our journal. I think this is one that not only may change practice, but changes my personal perception and things that I'm going to do immediately. Dr. Carolyn Lam: Thank you very much audience. I'm sure you agree. This was incredible. Do tune in again next week for another episode of Circulation On The Run. Dr. Greg Hundley: This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit ahajournals.org.

Pushing The Limits
Cancer Treatments: Starve Cancer, Be Free From It with Jane McLelland

Pushing The Limits

Play Episode Listen Later Jan 6, 2022 78:22


Cancer treatments in modern medicine often have long-lasting and harmful side effects. While modern treatments like chemotherapy can be useful in some cases, not all cancer patients need to — or should — resort to it.  When cancers aggressively develop, patients are often told how many weeks they have left to live. Why is this the case when there is still hope to be free from cancer?  Research and clinical studies have found natural therapies and dieting are possible cancer treatments. The truth is, you can starve cancer cells without harming your body! In this episode, Jane McLelland, author of How to Starve Cancer, discusses how cancer develops in the body and what causes dysfunctional mitochondria. She shares the importance of starving cancer cells and why cancer treatments should vary based on the type you have. Don't lose hope; you can beat cancer. Understand how it works metabolically and you'll soon be on the path to recovery.   If you want to learn more about beating cancer by starving it, then this episode is for you! Here are three reasons why you should listen to the full episode: Understand how cancer develops in our bodies and why mRNA can help us detect early cancer.  Learn why there is no one correct approach to cancer treatment. Instead, focus on understanding the principle of starving cancer by blocking specific pathways.  Discover Jane's recommendations on what to focus on for cancer treatment.  Get Customised Guidance for Your Genetic Make-Up For our epigenetics health programme, all about optimising your fitness, lifestyle, nutrition and mind performance to your particular genes, go to  https://www.lisatamati.com/page/epigenetics-and-health-coaching/. Customised Online Coaching for Runners CUSTOMISED RUN COACHING PLANS — How to Run Faster, Be Stronger, Run Longer  Without Burnout & Injuries Have you struggled to fit in training in your busy life? Maybe you don't know where to start, or perhaps you have done a few races but keep having motivation or injury troubles? Do you want to beat last year's time or finish at the front of the pack? Want to run your first 5-km or run a 100-miler? ​​Do you want a holistic programme that is personalised & customised to your ability, goals, and lifestyle?  Go to www.runninghotcoaching.com for our online run training coaching. Health Optimisation and Life Coaching Are you struggling with a health issue and need people who look outside the square and are connected to some of the greatest science and health minds in the world? Then reach out to us at support@lisatamati.com, we can jump on a call to see if we are a good fit for you. If you have a big challenge ahead, are dealing with adversity or want to take your performance to the next level and want to learn how to increase your mental toughness, emotional resilience, foundational health, and more, contact us at support@lisatamati.com. Order My Books My latest book Relentless chronicles the inspiring journey about how my mother and I defied the odds after an aneurysm left my mum Isobel with massive brain damage at age 74. The medical professionals told me there was absolutely no hope of any quality of life again. Still, I used every mindset tool, years of research and incredible tenacity to prove them wrong and bring my mother back to full health within three years. Get your copy here: https://shop.lisatamati.com/collections/books/products/relentless. For my other two best-selling books Running Hot and Running to Extremes, chronicling my ultrarunning adventures and expeditions all around the world, go to https://shop.lisatamati.com/collections/books. Lisa's Anti-Ageing and Longevity Supplements  NMN: Nicotinamide Mononucleotide, an NAD+ precursor Feel Healthier and Younger* Researchers have found that Nicotinamide Adenine Dinucleotide or NAD+, a master regulator of metabolism and a molecule essential for the functionality of all human cells, is being dramatically decreased over time. What is NMN? NMN Bio offers a cutting edge Vitamin B3 derivative named NMN (beta Nicotinamide Mononucleotide) that can boost the levels of NAD+ in muscle tissue and liver. Take charge of your energy levels, focus, metabolism and overall health so you can live a happy, fulfilling life. Founded by scientists, NMN Bio offers supplements of the highest purity and rigorously tested by an independent, third-party lab. Start your cellular rejuvenation journey today. Support Your Healthy Ageing We offer powerful third-party tested NAD+ boosting supplements so you can start your healthy ageing journey today. Shop now: https://nmnbio.nz/collections/all NMN (beta Nicotinamide Mononucleotide) 250mg | 30 capsules NMN (beta Nicotinamide Mononucleotide) 500mg | 30 capsules 6 Bottles | NMN (beta Nicotinamide Mononucleotide) 250mg | 30 Capsules 6 Bottles | NMN (beta Nicotinamide Mononucleotide) 500mg | 30 Capsules Quality You Can Trust — NMN Our premium range of anti-ageing nutraceuticals (supplements that combine Mother Nature with cutting edge science) combats the effects of aging while designed to boost NAD+ levels. Manufactured in an ISO9001 certified facility Boost Your NAD+ Levels — Healthy Ageing: Redefined Cellular Health Energy & Focus Bone Density Skin Elasticity DNA Repair Cardiovascular Health Brain Health  Metabolic Health My  ‘Fierce' Sports Jewellery Collection For my gorgeous and inspiring sports jewellery collection, 'Fierce', go to https://shop.lisatamati.com/collections/lisa-tamati-bespoke-jewellery-collection. Resources Gain exclusive access and bonuses to Pushing the Limits Podcast by becoming a patron!  How to Starve Cancer by Jane McLelland Learn Jane's four pillars to help you recover from cancer with the How to Starve Cancer Online Course  Episode 227: Fighting Cancer and Other Diseases Using the Ketogenic Diet with Dr Dominic D'Agostino  Boulder Longevity Institute  PubMed  Australian Integrative Medicine Association  Learn from Dr Elizabeth Yurth on the function of our mitochondria:  Episode 196: Rethinking the Function of Mitochondria for Our Health  Episode 187: Back to Basics: Slow Down Ageing and Promote Longevity    Connect with Jane: Website I Twitter I LinkedIn I Email (info@howtostarvecancer.com)  Episode Highlights [04:40] Why Jane Wrote ‘How to Starve Cancer' Jane shares that she was first diagnosed with cancer when she was 30. Her cancer developed to an advanced stage over a prolonged screening. Her mother had stage-IV breast cancer and passed away a few years later.  As her cancer developed further, Jane felt that the medical industry wasn't helping her enough.  There was already research on how glucose serves as a fuel for cancer. However, Jane found out that cancer can also metabolise glutamine and protein — even lipids.  Jane wrote her book to help people starve cancer without starving themselves. Starving cancer is about being blocking the different chemical pathways that cancer uses.  [13:10] How Cancer Develops In 1924, Warburg found that cancer cells use sugar up to 20 times more than normal cells; this an indication that cancer is a metabolic disease.  Jane argues that cancer is linked to the microenvironment and often develops when a patient has inflammation.    Inflammation can develop due to obesity, exposure to carcinogens, and more. Hormonal influences can also promote cancer growth. These influences include exposure to xenoestrogen, plastics, microwaves, and microplastics.  These influences can change mRNA to trigger changes in the mitochondrial DNA, leading to cancer development.  [19:25] How to Detect Early Cancer You can prevent cancer as long as you understand what's causing it.  Dysfunctional mitochondria are a symptom and not the cause.  It's critical to look at changes in the mRNA to detect early cancer.   [20:47] Learn to be Careful about what You Take There isn't a lot of data regarding mRNA-based COVID-19 vaccines and their long-term effects on the human immune system. We need to be careful about what we're putting in our bodies and their potential consequences.  For example, high doses of Vitamin E and NAC may be inappropriate for specific cancers.  Jane shares that small doses of NAC can be beneficial when you're trying to kill cancer and improve immunity post-chemotherapy. Stopping glutamine transport is also helpful to block fuel transport to cancer cells.     [25:45] There's no One Solution for Cancer Cancers work differently and can have different fuel sources. No single approach will beat all cancer types.  For example, B cell lymphoma is responsive to ferroptosis. However, you need to ensure that this method kills only the cancer cells and does not affect the brain.  HDAC inhibitors are also viable cancer treatments.   [30:31] How Homocysteine can Help or Worsen Your Condition Jane recommends having low to normal homocysteine levels by sometimes taking vitamin B. Cysteine can help provide backup replenishment for cells.  When you're trying to induce ferroptosis and have high homocysteine, the cancer cells may utilise the homocysteine instead.  This is why your homocysteine levels should be low before starting ferroptosis for cancer treatment.  [32:08] There are Better Cancer Treatments Most medical practitioners are often not updated with the latest clinical studies and tend to dismiss them.  For example, high doses of Vitamin C can be used as a pharmaceutical, and not an antioxidant. There are ways to treat terminal illnesses even when medical professionals tell you otherwise.   [43:50] Don't Focus on Only One Phase of Cancer Jane's book is a simplified discussion of cancer metabolism and how cancer develops.  Current cancer treatments often don't focus on earlier phases of cancer development. You need to tackle every phase of cancer and stop the tumour environment that helps cancer grow. Diet can make a huge difference.   Ketones and hydroxybutyrate are also HDAC inhibitors and can help with ferroptosis. Hyperbaric oxygen therapy can also help since cancer cells can't thrive with high oxygen levels.  [49:18] Cancer Treatment is Different Per Phase Lisa shares that her mother is currently following the Riordan Protocol. They use a blend of Vitamin C, hyperbaric oxygen therapy, and ketones. Fenugreek can help stimulate the production of free radicals, but you need to avoid antioxidants like luteolin and green tea.  You need to ensure you're getting the desired effect in the right phase. The kill phase tends to be more specific.  In the full episode, Jane discusses how berberine and metformin can help lower cancer markers.  [54:29] Jane's Recommendations Jane recommends being careful with taking DCA since some brands can cause inflammation.  Deoxy glucose is like fake glucose that the body recognises as glucose, but cancer cells don't.  Melatonin can block glycolysis pathways.  Jane recommends being selective when taking her course. You don't need to learn about every single pathway. She recommends focusing on glycolysis, glutamine, fats, and lipids.  Jane shares what she did to block her cancer pathways in the full episode.     [1:01:55] Remember, It's about the Metabolic Pathway Over the years, starving cancer has become the critical key to curing cancer.  Remember that cancer is about the metabolic pathway. You need to have the right combination of supplements and cancer treatments. 7 Powerful Quotes [01:51] "...if you're at all affected by cancer in your family, if you have high-risk factors, one in six of us is going to get cancer at some stage in our lives, and you need to know this stuff."   [09:11] "...the trick was trying to find ways that would actually starve the cancer without having to go on starving yourself."   [16:44] "I think a lot of people stop the estrogen, and I think it's a good idea, in many cases, to reduce or your estrogen exposure. That can be plastics, it can be cooking in the microwave, just all sorts of, you know. Now, it's just about everywhere. We've got tiny bits of microplastic in the air as well now. It's just pervasive."   [18:29] "There are these viruses that can cause cancer, and I think it's a combination of the influence of kind of like these things acting a bit like a parasite."   [23:38] "People should have the choice of doing that [going unvaccinated] if they want to run that risk. But the problem is it's putting other people at risk, and you get slated."   [27:03] "You have to tailor your approach a little bit. Is it feeding more on glutamine? Is it feeding more —? What are the mutations?"   [35:50] "...you have to fight for your rights. You really do. When it comes to this, they don't have the answer for cancer."   [53:10] "But it's all about getting the correct effect..you've got to be a little bit careful that what you're doing with one thing doesn't counteract something else. "   About Jane Jane McLelland trained as a Chartered Physiotherapist and was able to win the Sarah Leeson Memorial Award as a promising student. She then worked in the NHS and private practice for 12 years, specialising in orthopaedics and neurology. From 1994 to 2004, Jane battled two aggressive terminal cancers. For that reason, she put together a cancer-starving formula using natural therapies, exercise, and diet to save herself. After her recovery, Jane advocated for off label drugs for cancer therapy and wrote the book How to Starve Cancer. In 2019, she won the title of "Amazing Women Global" from the Lifetime Achievement Award.  Interested in Jane's work? Check out her website.  You can also connect with her on Twitter, LinkedIn, and email (info@howtostarvecancer.com). 

Circulation on the Run
Circulation May 11, 2021 Issue

Circulation on the Run

Play Episode Listen Later May 10, 2021 31:55


This week is a Double Feature Circulation on the Run. Please join authors Alexander Benz and Lars Wallentin as they discuss their article "Biomarker-Based Risk Prediction With The ABC-AF Scores in Patients With Atrial Fibrillation Not Receiving Oral Anticoagulation." Then, please join author Timothy McKinsey, editorialist Thomas Gillette and Associate Editor Sergio Lavandero as they discuss the article "HDAC Inhibition Reverses Preexisting Diastolic Dysfunction and Blocks Covert Extracellular Matrix Remodeling" and the editorial "HDAC Inhibition in the Heart: Erasing Hidden Fibrosis." TRANSCRIPT BELOW Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, I cannot get enough of our double features, and this one's really nice because it's a clinical feature and a preclinical feature, and both are just phenomenally interesting. The first is about the ABC-AF scores. In case you don't recognize it, well, then you just have to listen. Very, very important information on biomarker-based risk prediction in patients with atrial fibrillation, not receiving oral anticoagulation. Then we've got a really interesting paper talking about HDAC inhibition and diastolic dysfunction. Interested? Well, listen up. Dr. Carolyn Lam: First, let's talk about some of the papers in today's issue, shall we? I want to start, Greg. You grab your coffee. I need to talk about this first one, which really provides the first extensive genetic and phenotypic landscape of a very important condition, peripartum cardiomyopathy. This is from Dr. Arany and colleagues from Perlman School of Medicine, University of Pennsylvania. What they did is studied 469 women with peripartum cardiomyopathy, who were identified from several US and international academic centers. They acquired clinical information and DNA samples. Next-generation sequencing was performed on 67 genes and evaluated for the burden of truncating and missense variance. Dr. Carolyn Lam: What they found was that women with peripartum cardiomyopathy bear a significantly high burden of loss of function variants in a number of genes, including familiar ones like TTN, FLNC, DSP, and BAG3. The identity and relative abundance of these variants were remarkably similar to that seen in idiopathic dilated cardiomyopathy, indicating that the genetic predisposition to peripartum cardiomyopathy and dilated cardiomyopathy may be one in the same. Now, while peripartum cardiomyopathy patients with the TTN truncating variants presented with lower ejection fraction. No significant differences in the rates of recovery were seen. Dr. Greg Hundley: Really interesting, Carolyn. Clinically, what are the implications today as we see these patients? Dr. Carolyn Lam: Well, I think the most important one is that genetic counseling and testing should, perhaps, be considered for women with peripartum cardiomyopathy, following the guidelines for dilated cardiomyopathy. What about you, Greg? Dr. Greg Hundley: Very nice, Carolyn. Well, my paper evaluates the role of inflammation and outcomes in patients that sustain out-of-hospital cardiac arrest. It comes to us from Dr. Martin Meyer from Rigshospitalet. Carolyn, out-of-hospital cardiac arrest patients who remain comatose after initial resuscitation are at high risk of morbidity and mortality due to the ensuing post-cardiac arrest syndrome. Now, systemic inflammation constitutes a major component of the post-cardiac arrest syndrome and interleukin 6 levels are associated with this severity. The IL-6 receptor antagonists tocilizumab could potentially dampen inflammation after post-cardiac arrest. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after out-of-hospital cardiac arrest, A presumed cardiac cause, and thereby potentially mitigate organ injury. Dr. Carolyn Lam: Oh, wow. Interesting, Greg. what did they find? Dr. Greg Hundley: Carolyn, they had 80 comatose out-of-hospital cardiac arrest patients and they were randomized 1:1 in a double-blind, placebo-controlled trial to a single infusion of tocilizumab or placebo, in addition to standard of care, including targeted temperature management. The primary endpoint of the study was reduction of CRP response. This was achieved by tocilizumab, as there was a significant treatment-by-time interaction. Systemic inflammation was reduced by treatment with tocilizumab, as both CRP and leukocyte levels were markedly reduced. Now, myocardial injury was also reduced, documented by reductions in CK-MB and troponin T. However, there were no differences, Carolyn, in survival or neurological outcome. So Carolyn, it looks like for those that survive an out-of-hospital cardiac arrest and do experience neurological recovery, there could be cardiac benefits. Dr. Carolyn Lam: Wow, very interesting. I cannot imagine how difficult it must've been to perform such a trial. Thanks, Greg. Well, the next paper demonstrates a new mechanism underlying diastolic dysfunction, and provides theoretical and experimental evidence to explain, perhaps, the ineffectiveness of conventional nitric oxide enhancement trials for HFpEF. And you know, that's my favorite topic. Dr. Greg Hundley: Wow, Carolyn, really interesting. Can you summarize it for us? Dr. Carolyn Lam: Sure. Well, first of all, this comes from Doctors Eom and Kook from Chonnam National University Biomedical Research Center in Korea. These authors used two animal models of diastolic dysfunction, the salty drinking water, unilateral nephrectomy with aldosterone, or SAUNA, model, and a mild transverse aortic constriction model. They also looked at human heart samples from patients with left ventricular hypertrophy. Dr. Carolyn Lam: Together, in very, very elegant experiments, they showed that neuronal nitric oxide synthase was upregulated in diastolic dysfunction, which increases S-nitrosylation and cardiomyocytes, and its pharmacologic inhibition, as well as genetic ablation, alleviated diastolic dysfunction. Now, specifically, protein S-nitrosylation of histone deacetylase 2, or HDAC2, played a critical role in the development of diastolic dysfunction and nitric oxide reduction and the following protein denitrosylation may provide a novel therapeutic strategy for HFpEF. Dr. Greg Hundley: Very nice, Carolyn. Well, my next paper comes from Dr. William Pu from Boston Children's Hospital and looks at reactive oxygen species-mediated CaM kinase 2 activation, and how that contributes to calcium handling abnormalities and impaired contraction in the Barth syndrome. Carolyn, mutations in tafazzin, a gene required for biogenesis of cardiolipin, the signature phospholipid of the inner mitochondrial membrane, causes Barth syndrome. Carolyn, remember that Barth syndrome occurs primarily in males, is associated with cardiomyopathy, a low white count, and recurrent infections, and also skeletal muscle myopathy and short stature. Cardiomyopathy and the risk of sudden cardiac death are prominent features of the Barth syndrome, but the mechanisms by which impaired cardiolipin biogenesis causes cardiac muscle weakness and these arrhythmias are poorly understood. Dr. Carolyn Lam: Oh, Greg, thanks so much for not quizzing me on that one. I was trying to remember what Barth syndrome is, and thanks for the review. Okay, so what did they find? Dr. Greg Hundley: Right, Carolyn. The investigators identified a molecular pathway that links tafazzin mutation to abnormal calcium handling and decreased cardiomyocyte contractility. This pathway may offer therapeutic opportunities to treat Barth syndrome, and potentially other diseases with elevated mitochondrial reactive oxygen species production. Dr. Carolyn Lam: Thanks, Greg. Nicely summarized. Well, let's go through what else there is in today's issue. There is a Perspective piece by Dr. Singh, entitled The Morbidly Obese Patients with Symptomatic Atrial Fibrillation: Why are we Holding Back on Bariatric Surgery? There's an On My Mind piece by Dr. Wenger on the incremental change versus disruptive transformation: COVID-19 and the cardiovascular community. There's also a research letter by Dr. Phillip on cardiovascular evaluation after COVID-19 in 137 collegiate athletes, and it's the results of an algorithm-guided screening. A very interesting piece. Dr. Greg Hundley: Very nice, Carolyn. Well, Carolyn, in the mailbag, I've got an exchange of letters regarding the article Anti-Inflammatory Actions of Soluble Ninjurin-1 and the Amelioration of Atherosclerosis with Dr. Zheng, Jianmin, and Oh. Then finally, Dr. Rob Califf has an On My Mind piece, entitled Avoiding the Coming Tsunami of Common Chronic Disease: What the Lessons of the COVID-19 Pandemic Can Teach Us. Well, Carolyn, I'm really excited. Another double feature Tuesday. How about we turn our attention and move toward those articles? Dr. Carolyn Lam: Yep. Something for everyone in this one. Let's go. Today's feature discussion will sound somewhat familiar if we're talking about the ABC scores. Now, remember that stands for age, biomarkers, clinical history scores, and they're the scores that we use in patients with atrial fibrillation receiving oral anticoagulation, or at least that's the data we have so far. But, what are the utilities of these ABC scores in patients not receiving oral anticoagulation? Dr. Carolyn Lam: Well, guess what? That's what today's feature paper is all about. I'm so pleased to have with us today, the first author, Dr. Alexander Benz, from Population Health Research Institute, McMaster University in Canada, as well as Dr. Lars Wallentin, he's a senior author from Uppsala University in Sweden. Welcome, gentlemen. Alex, if I could start with you, please. A very interesting question and not so easy to answer, could you please tell us a little bit about the background to your study, what you did, and what you found? Dr. Alexander Benz: Sure. Thanks for the opportunity to speak here. The ABC scores have now been shown to outperform clinical risk scores in the setting of patients with AFib receiving oral anticoagulant therapy. But so far, nobody has ever looked at the performance of these scores in patients who are not treated with oral anticoagulant therapy. So here we validated the ABC stroke, bleeding, and death scores in patients with AFib who were not receiving oral anticoagulant therapy. We chose the ACTIVE A and AVERROES trials, where patients were randomized to receive antiplatelet therapy, so aspirin or aspirin plus clopidogrel, for the validation study. We ended up studying the scores and over 4,300 patients who were receiving either aspirin, which were over 3,195 patients, or aspirin plus clopidogrel in about 1100 patients, in these studies. Dr. Alexander Benz: Now, we found that the ABC stroke score was superior to the CHA2DS2–VASc score, yielding a C-index of 0.7. The ABC bleeding score was also better than the currently recommended HAS-BLED score for the assessment of the risk of bleeding, yielding an overall C-index of 0.73. And finally, the ABC-AF death score yielded a C-index of 0.78, which I think is remarkable. Dr. Alexander Benz: Now, as these scores were derived from patients receiving oral anticoagulant therapy, we're not surprised to see that the ABC stroke score underestimated the risk of stroke in this population. And very similarly, the ABC bleeding score overestimated the risk of bleeding in these patients receiving antiplatelet therapy. So these scores, the ABC stroke and bleeding scores, were recalibrated for our prediction of absolute event rates in the absence of oral anticoagulant therapy. Dr. Carolyn Lam: Thanks, Alex. That was a beautiful summary. Now, Lars, if I could ask you, please, could you really highlight to all of us, what is the key thing about validating these scores in patients with atrial fibrillation, but not receiving oral anticoagulation? Dr. Lars Wallentin: I think what people like to have is an estimate of the risk of stroke and the risk of bleeding. If you start them on oral anticoagulation and that has been difficult, we only knew this based on the risk scores on patients that were on treatment. But if we now are using this score, which are also well-calibrated, we can really estimate the absolute risk of a stroke. Let's say, 3% without oral anticoagulation, then how much is it lowered by oral anticoagulation down to 1%? And we can do this on an individual level, because there is a variability between patients and we can identify the risk for an individual patient without treatment, and the risk on treatment, and that can be balanced then against the risk for bleeding on treatment and without the treatment. And thereby, you can get the precise estimate on the risk-benefit ratio for the individual patients. Dr. Lars Wallentin: This is a precision medicine approach, which we think will provide a better treatment with better outcomes for the patients than we have had before. Also, death can be, of course, involved at the final net benefit, with and without treatment. Therefore, we think this is a great step forward, and this cannot be implemented in the real life because we have used biomarkers that now can be available in the routine laboratories. These are NTproBNP and troponin, which are available in all hospitals, and a new marker, GDF-15, a marker that's related to the bleeding risk and that is currently launched by Roche Diagnostics as a new tool. So I think this is a realistic future to improve treatments. Dr. Carolyn Lam: Dr. Lars, I have to tell you, all us editors fully agreed as well, that this is a great contribution, filling an important gap in the literature so far in a very clinically important question when we face the patient who hasn't started anticoagulation. So really, again, thank you both for this study and for publishing with us. A couple of questions, though. It does require these extra biomarkers that come with some, what can I say, cost of needing to measure them if they're not already measured. Could you give us some idea of how much the scores add to what we're used to, the CHA2DS2–VASc and the HAS-BLED score? I don't know, maybe Alex? Dr. Alexander Benz: Sure. I think one downside of the widely-accepted and also often useD clinical scores is that they rely on Arbitrary categorization and dichotomization of clinical variables, and with biomarkers, we have the great advantage of having a continuous tool to assess the risk of outcomes here. And as Lars mentioned, these are mainly the cardiac biomarkers NTproBNP and cardiac troponin, as well as the GDF-15, or growth differentiation factor 15. We think that biomarkers reflect a powerful tool to also reflect underlying subclinical disease, which is very important, I think, in this stratification, and this is probably where much of the superiority of the biomarker-based tool stems from. Dr. Carolyn Lam: Right, thanks. Back to what Lars had said about more precision, which is exactly what the whole of cardiology is, I think, moving towards as well, but it was very, very clever to look for the studies ACTIVE and AVERROES. Hard to think of the population in which you tested this. But weren't the blood samples in these studies very old? Did you then have to remeasure those biomarkers? Were they reliable? Dr. Lars Wallentin: Yes. These were old samples that were taken at entry into the ACTIVE and AVERROES trial. The investigators in Canada were really very clever to save the sample, but the samples have been saved for a decade or more since then. But fortunately, these assays are very stable over time, so all of them, and therefore the results are reliable. The levels are very similar to the ones we get in the real-life setting for samples as the one we have in ARISTOTLE and RE-LY, where the scores were derived. So this seems to be, I think, also an advantage that this can be used for stored samples, and fresh samples. Dr. Carolyn Lam: Thank you for addressing that so nicely. We're running out of time sadly, but I would love to hear, maybe as final remarks, what you think are the overall clinical implications and perhaps the next steps for important studies that need to be done. Maybe I could ask Alex to start first and then Lars can finish? Dr. Alexander Benz: Well, I think the next steps in the ABC score program will depend on potential integration or a combination of scores, which then may guide physicians in whom to treat or even whom not to treat. Withholding anti-platelet therapy in certain very low-risk patients, that's what comes to mind. I know that Lars and his colleagues are performing a randomized controlled trial in Sweden where they're testing the ABC scores in clinical practice against the usual care with the clinical scores. Maybe, Lars, you want to elaborate on this. Dr. Lars Wallentin: Yeah, I think the final step is, of course, a prospective randomized trial showing which are the real benefits. We are randomizing 6,000 patients to conventional care versus precision medicine-based care using the ABC risk scores. Outcomes are death and stroke and bleeding. I hope that we will find usefulness of this also in a prospective trial, which will be the final piece of evidence, of course. Dr. Carolyn Lam: Wow, Lars, that is amazing. Thank you so much for sharing that with us. First time on Circulation on the Run. Well, audience, I'm sure you enjoyed that. Thank you so much, Lars and Alex. Now, hold on tight, we're going on to our next feature discussion. Dr. Carolyn Lam: Oh, I can't wait to get onto this feature discussion. You see, it's actually going to reveal a potential new way to target diastolic dysfunction. My absolute favorite topic. It's a basic science paper. It is incredible. You're going to hear all about its clinical translational potential and significance, and from none other than the corresponding author, Dr. Timothy McKinsey from University of Colorado School of Medicine, and editorialist of a beautiful accompanying editorial, Dr. Thomas Gillette from UT Southwestern, and Dr. Sergio Lavandero, our Associate Editor from University of Chile, San Diego. Thank you so much for being here. Tim, could I get you started off? Recognizing there are a lot of clinicians listening out there, this is an incredible paper. HDAC, I think for some, it will be the first time you've been hearing such a word. Please, please, could you break it down for us what you did and what you found? Dr. Timothy McKinsey: Sure. Thanks, Carolyn, and thanks for inviting me to do this. It's really a pleasure. HDAC, that stands for a class of enzymes called histone deacetylases, and those are also known as erasers of acetyl marks on chromatin. So they're really famous for the regulation of epigenetics or gene expression. But we found that HDACs do a lot of other things in the heart too, by deacetylating both histone and non-histone proteins, and we're just really interested in the therapeutic potential of inhibiting HDAC enzymes for the treatment of heart failure. And, in so doing, we assess their ability to reverse existing diastolic dysfunction in a mouse model of kidney disease and hypertension. Dr. Carolyn Lam: You know what, Tim, I really liked the way you very carefully said that. A mouse model of diastolic dysfunction with preserved ejection fraction, that I think, previously, a lot of people with just very loosely used the word HFpEF for such a model, but I really, really appreciate how carefully you worded that. Could you tell us a little bit about the model and what you found? Dr. Timothy McKinsey: Sure. Yeah, we've been really careful not to call it a model of HFpEF, because it isn't a model of heart failure. It really is a model of isolated diastolic dysfunction and preserved ejection fraction. It's a model that's been used in the literature in the past, where you perform a uninephrectomy in mice, so remove one kidney, and then implant something called DOCA, which is an aldosterone memetic. And over time, these animals develop systemic hypertension that results in cardiac hypertrophy and diastolic dysfunction. Dr. Timothy McKinsey: We were perplexed because we couldn't see any fibrosis in the model. But when we did a deep dive into fibrosis using more sensitive methods than are traditionally used, we did uncover what we're calling hidden fibrosis. We believe that HDAC inhibitors, our data suggests that HDAC inhibitors, can actually block the formation of hidden fibrosis that leads to diastolic dysfunction. Dr. Carolyn Lam: Very nice. If you could just give us a one-line on how will you find this hidden fibrosis? Dr. Timothy McKinsey: We got stuck on that for years, because we did all the traditional assays to measure cardiac fibrosis, mainly picrosirius red stain, and we didn't see anything. But we were fortunate to team up with some really talented collaborators, including Maggie Lam here at the University of Colorado, who is an expert at using mass spectrometry to study cardiac remodeling, and also Luisa Mestroni and Brisa Peña who use atomic force microscopy to look at tissue stiffness. When we teamed up with those investigators, first with Maggie we found that, sure enough, when we used her sensitive mass spec assay to look at extracellular matrix protein expression in the heart, there was really a profound increase in ECM protein expression in this mouse model, even though the staining for fibrosis was negative. That told us that there was this underlying hidden fibrosis. Dr. Carolyn Lam: Oh, that is really interesting. And so it is that form of fibrosis that was actually reversed, perhaps, by the HDAC inhibition, and that's what you showed. Would that be accurate to say? Dr. Timothy McKinsey: Yeah. So the HDAC inhibitor really had this profound ability to block that ECM remodeling, the hidden fibrosis, to the point where initially we thought it was an artifact. We thought maybe there was a mix-up of samples. It wasn't a mix up. It's just that the compound, this inhibitor of HDAC enzymatic activity, really has this amazing ability to block the formation of hidden fibrosis. Dr. Carolyn Lam: Oh, wow. Wow, Tom, I really, really loved your editorial where you put all of this in context and talked a little bit about the translational and clinical potential. Could you maybe share your thoughts here? I love the title by the way, Erasing Hidden Fibrosis. Dr. Thomas Gillette: Thanks. Thanks for that. Yeah, first of all, Tim, it was a really great piece of work, and it's actually really exciting because when we think of this diastolic dysfunction, and really it's the development of HFpEF, I think, that a lot of people are... It's the single most critical unmet need in cardiovascular medicine, is the treatment for HFpEF. That diastolic dysfunction, it's really that stiffness that Tim was measuring with his atomic force microscopy and those changes in ECM that really seemed to be critical, at least in that model. Dr. Thomas Gillette: And we know from other models as well that these underlying changes in fibrosis and stiffness, perhaps in the ECM, play a really important role, not only in the diastolic dysfunction, but also if you think about in strain as well, because I know in our models of HFpEF and this mouse model of HFpEF, we have the two-hit model published that Gabrielle, a Allie developed with Dr. Hale in Nature. It's that strain that we could measure that really seems to correlate well with the heart failure phenotype. And so it begs the question, has he caught a very early change in the ECM that's really critical to the development of this pathology? And is there a way that we could detect it early on in patients? Is there a way we could measure that in patients and really get a sense of who's progressing and how they're progressing? Dr. Thomas Gillette: Then there's a second point, and I mentioned a little bit in the editorial, I didn't go into it too deeply, and that is, it's really intriguing what this might mean for the development of the disease, because the matrix not only is involved in stiffness, but it's also a reservoir for growth factors, it helps recruit inflammatory cells, and inflammation plays a huge role in HFpEF. And so it begs the question, how many of those changes may proceed a lot of that pathology as well? Dr. Carolyn Lam: Wow, Tom, I really couldn't agree more. I made a big deal earlier about agreeing with Tim, calling this a diastolic dysfunction model rather than HFpEF, but I completely agree with you that the implications are for the development of HFpEF, and it needed the begs, the question of how many patients actually have this hidden fibrosis? And we know that in patients with HFpEF, there is a stage of advanced fibrosis where we feel patients don't respond to treatment as well. So have we caught an early phase that may be clinically applicable? I really loved the way you worded that. But finally, with Sergio, could you put it all together and what the editors thought of this paper? Why you invited Tom to write this editorial? And perhaps what next steps are? Dr. Sergio Lavandero: Okay, Tim, this is really a fascinating work. I have a long road, because in Italy, you develop the most important new concept. The new concept, the hidden fibrosis. The second important, originally, most of the HDAC inhibitors were developed for other diseases, originally for cancer. So now we have more data that, probably, this compound can apply to other diseases like cardiovascular disease. It was difficult to convince at the beginning some reviewers about the concept of hidden fibrosis, because it's not traditional. But finally, we asked to another expert to, "Okay, why don't you explain, please, this new technique?" For the future, Tim, what do you think? How can we evaluate hidden fibrosis in patients? Dr. Timothy McKinsey: Ideally, and you would have a non-invasive approach to assessing hidden fibrosis in patients. Obviously I know myocardial biopsies could be analyzed using the mass spec approach and atomic force microscopy, but not everyone is going to want to get a myocardial biopsy. So ultimately, we would like to correlate data that we obtain with biopsies, with circulating factors to see if there is a non-invasive surrogate circulating factor that correlates with the existence of hidden fibrosis. I think that would be very powerful clinically. Dr. Sergio Lavandero: What do you think the specificity of this research, because maybe it's too broad? What do you think? Dr. Timothy McKinsey: Yeah, that's a great point. There's a negative impression of general HDAC inhibition, because people just can't believe that you could inhibit a large number of HDAC enzymes throughout the body and not kill someone. But you can. And in our models you can use pretty low doses of these HDAC inhibitors and see efficacy. But obviously, the holy grail in this field would be to identify specific HDAC isoforms that regulate specific disease processes. So we have an active area of investigation where we're trying to tease apart the roles of different HDACs in the heart, with the ultimate goal of finding the HDAC or a subset of HDACs that regulate in fibrosis. Then you could selectively inhibit those and perhaps have a safer drug than a general HDAC inhibitor. Dr. Carolyn Lam: Thank you, once again. This is an amazing discussion and really, really an example of just the kind of papers we love publishing at Circulation. So novel and with such translational potential. Thank you, Tim, again, and Tom and Sergio. Thank you, audience, for joining us today. From Greg and I, you've been listening to Circulation on the Run. Don't forget to tune in again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

Oncotarget
Oncotarget - ATM Inhibition Overcomes Resistance To Histone Deacetylase Inhibitor

Oncotarget

Play Episode Listen Later Sep 16, 2020 4:31


The cover for issue 37 of Oncotarget features Figure 7, "The combination of romidepsin and KU60019 is synergistic in a xenograft model of MCL," by Scotto, et al. which reported that the antiproliferative effect induced by histone deactylase inhibitors is associated with the up-regulated expression of the cyclin-dependent kinase inhibitor p21. Paradoxically, the increased expression of p21 correlates with a reduced cell killing to the drug. HDAC inhibitors appear to activate p21 expression via ataxia telangiectasia mutated activity. The Oncotarget authors explored the potential synergistic interaction of the ATM inhibitor with romidepsin, given the potential complementary impact around p21. A synergistic cytotoxic effect was observed in all lymphoma cell lines examined when the HDACi was combined with KU60019. The increase in apoptosis correlates with decreased expression of p21 due to the ATM inhibitor. KU60019 decreased expression of the cyclin-dependent kinase inhibitor at the transcriptional level, compromising the ability of HDACi to induce p21 and cell cycle arrest and ultimately facilitating a shift toward the apoptotic phase. Central to the increased apoptosis observed when romidepsin is combined with KU60019 is the reduced expression of p21 and the absence of a G2/M cell cycle arrest that would be exploited by the tumor cells to evade the cytotoxic effect of the HDAC inhibitor. Dr. Owen A. O'Connor from The Columbia University Medical Center said, "HDAC inhibitors (HDACi) have emerged as valuable drugs in the treatment of select lymphomas and synergize with a diverse range of pharmacological and biological agents." The observation leads to the following hypothesis: if induction of p21 compromises the efficacy of HDAC inhibitors, then strategies to mitigate HDAC inhibitor induced p21 expression could lead to promising synergistic combinations. Induction of p21 by HDAC inhibitors is compromised in A-T cells given that ATM activity is essential for HDAC inhibitor-induced p21 expression. Collectively, these observations have led to the following hypothesis: If ATM activity is necessary for HDAC inhibitor mediated p21 induction, then selective ATM inhibitors could mitigate the HDAC induced p21 expression and potentiate its cytotoxic effect. The ATM inhibitor nullifies HDAC induction of p21 expression resulting in a synergistic interaction. KU60019 reduces p21 expression at the transcriptional level and antagonizes romidepsin transcriptional induction of p21. In both instances, the result is a markedly down-regulation of p21 expression at the protein level. The O'Connor Research Team concluded in their Oncotarget Research Paper that it is intuitive that pleotropic drugs like HDACi are likely to have both favorable and unfavorable effects on cell growth and survival. Strategies directed toward understanding how to mitigate the unfavorable influences of the class can lead to improved efficacy in rational combinations. Many examples of drug synergy with HDAC inhibitors have been driven by random efforts in mixing and matching in order to identify possible complementary partners. Obviously, a clear understanding of the molecular pharmacologic features of pleotropic drug classes like HDAC inhibitors can afford unique opportunities to think about logical combinations. Ultimately, these approaches need to be translated to the clinic in order to establish therapeutic merit in the clinic. Sign up for free Altmetric alerts about this article DOI - https://doi.org/10.18632/oncotarget.27723 Full text - https://www.oncotarget.com/article/27723/text/ Correspondence to - Owen A. O'Connor - owenaoconnor@gmail.com Keywords - lymphoma, HDAC inhibitor, ATM inhibitor, p21, cell cycle About Oncotarget Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com

PaperPlayer biorxiv neuroscience
Septal HDAC1 facilitates long-lasting extinction of social fear in male mice

PaperPlayer biorxiv neuroscience

Play Episode Listen Later Sep 5, 2020


Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.05.284406v1?rss=1 Authors: Bludau, A., Paul, A., Neumann, I. D., Menon, R. Abstract: Social anxiety disorder (SAD) is primarily caused by traumatic social events and is characterized by intense fear and avoidance of socially enriched contexts. Formation of such intense social aversion requires learning of the association between trauma and originally neutral social stimuli. Acetylation of histones in response to learning is critical for long-term memory formation. Class I histone deacetylases (HDACs) have emerged as powerful negative regulators of long-term memory formation. However, the lack of clarity in isoform and spatial specificity in HDAC function exists. Utilizing the social fear conditioning (SFC) as well as cued fear conditioning (CFC) paradigms, we aimed to functionally characterize the role of class I HDACs, especially HDAC1, in the regulation of aversive memories in social versus non-social contexts. Using cFos expression as a marker of cellular activity, we revealed that the lateral septum (LS) was specifically activated post-acquisition in socially fear conditioned (SFC+) mice. We further measured an increase in activity-inducing HDAC1 phosphorylation at serine residues within the septum of SFC+ mice during extinction of social fear. Pharmacological inhibition of HDAC1 within the LS facilitated, while viral overexpression of septal HDAC1 impaired extinction of social fear. Finally, we found that the abovementioned facilitation of extinction memory by HDAC1 inhibition was long-lasting and persists even after 30 days of extinction. Our results show that LS-HDAC1 is a key regulator of long-lasting social fear extinction, which points towards HDAC1 as a potential therapeutic target for SAD. Copy rights belong to original authors. Visit the link for more info

MCAT Modules - Review
5:2. DNA and Chromatin Regulation

MCAT Modules - Review

Play Episode Listen Later Jul 18, 2020 17:38


Discusses HAT and HDAC enzymes to uncoil/coil DNA (uncoil = activate for transcription) then transitioned into DNA methylation as it relates to CpG Islands and MBB's.

あたらしい経済ニュース(幻冬舎のブロックチェーン・仮想通貨ニュース)
米半導体AMDとConsenSysがBCデータセンター立ち上げなどのブロックチェーン・仮想通貨ニュース解説

あたらしい経済ニュース(幻冬舎のブロックチェーン・仮想通貨ニュース)

Play Episode Listen Later Jun 29, 2020 12:59


仮想通貨・ブロックチェーンに特化した幻冬舎のメディア「あたらしい経済 https://www.neweconomy.jp/ 」がおくる、ラジオ番組です。毎日最新ニュース解説とコラムをお届けします。 ・米半導体大手AMDとConsenSys(コンセンシス)がブロックチェーンデータセンター「W3BCLOUD,」の立ち上げ ・SBIが日本初の暗号資産ファンドの立ち上げの計画を発表 ・Vanguard(ヴァンガード)のブロックチェーンベースの外国為替取引システムが2020年第3四半期にローンチか ・レシカと千葉大医学部附属病院がブロックチェーンを活用した医療データ共有プラットフォームを開発 ・韓国ヒュンダイ技術部門の子会社Hdacが3件のブロックチェーン関連特許を出願 ニュースの詳細や、アーカイブやその他の記事はこちらから https://www.neweconomy.jp/

Mike Satoshi
News Flash 11.03.2020 Tether drukuje, Chainlink i partnerstwo HDAC, Binance RPA, Rosja chce blokować Telegram - NewsFlash

Mike Satoshi

Play Episode Listen Later Mar 11, 2020 23:54


Wszystkie dobre podcasty o kryptowalutach https://darmowekrypto.org.pl/podcasty————————————NewsFlash 09.03.2020 100k TPS na ETH, Brave 4M userów, Tiffany Hayden odeszła z XRP, Jack Dorsey dalej CEONa świecie szaleje epidemie, ale świat kryptowalut nie zwalnia tempa. Zapraszam Was na kolejny odcinek wypakowany do pełni wiadomościami. Niezbędnik każdego fana kryptowalut.Dzisiaj zaczynamy od odwołania imprezy w Białymstoku, czyli Kryptostoku. Wszystko ze względu na epidemię i w trosce o Wasze bezpieczeństwo. Zobaczymy się, mam nadzieję, w kwietniu.Giełda Binance chce na ostro wejść na rynek południowoafrykański, a więc dodaje do platformy lokalną walutę fiat, a także inwestuje 1M USD w edukację blockchainową. Druga z kolei giełda - Bithumb zaczyna używać narzędzie od Chainalysis, aby tropić podejrzane transakcje.Poza tym pojawi się nowy coin prywatny, który ma być lepszy od Monero i Zcash, a jego nazwa to DAPS.Spis treści:- Tether wyemitował dodatkowe 60 milionów USDT - https://bitcoinpl.org/tether-wyemitowal-dodatkowe-60-milionow-usdt/- Karolina Południowa uznaje blockchain za krytyczną technologię - https://cointelegraph.com/news/south-carolina-senate-recognizes-blockchain-as-critical-emerging-tech- Chainlink i HDAC ramie w ramie - https://cointelegraph.com/news/chainlink-to-partners-with-hyundai-ceo-founded-firm-for-oracle-problem- Senat USA rozmawia o cyberbezpieczeństwie - https://cointelegraph.com/news/us-senate-looks-at-new-cybersecurity-measures-for-new-era-in-homeland-security- Nowa prywatna kryptowaluta - DAPS - https://cointelegraph.com/news/new-privacy-coin-says-it-solves-problem-with-monero-and-zcash- Ubezpieczenia kryptowalut - https://cointelegraph.com/news/retail-crypto-insurance-protecting-crypto-holdings-becoming-mainstream- Co to jest krypto lending? - https://cointelegraph.com/explained/crypto-lending-explained- Rosja chce zablokować darknet i Telegram - https://www.coindesk.com/russia-seeks-to-block-darknet-technologies-including-telegrams-blockchain- Scamy bardzie niebezpieczne niż oszustwa - https://www.coindesk.com/crypto-scams-pose-more-risk-than-payments-fraud-report-suggests- 2 osoby, które kupiły NEMy z Coinchecka aresztowane - https://www.coindesk.com/2-arrested-in-japan-for-obtaining-crypto-linked-to-coinchecks-530-million-hack- Sieć IOTA znowu działa - https://bitcoinpl.org/siec-iota-zostala-wznowiona/- Paradigm Labs nietrafiło w DeFi - https://www.coindesk.com/paradigm-labs-shuts-down-says-it-was-too-early-for-defi-boom- Edward Snowden ostrzega przed nową ustawą w Kongresie USA - https://coinnounce.com/edward-snowden-warns-about-a-bill-that-threatens-digital-security/- Bithumb zaczyna używać narzędzia od Chainalysis - https://coinfomania.com/bithumb-integrates-chainalysis-tool-reactor/- Binance chce wejść do RPA - https://coinfomania.com/binance-donates-1-million-south-africa/- Australiska skarbówka tropi podatników - https://coinfomania.com/australian-taxation-office-cryptocurrency-traders/- Kolejny scam używa wizerunków Elona Muska i Daniela Craiga, uwaga na Bitcoin Era - https://dailyhodl.com/2020/03/11/elon-musk-and-daniel-craig-featured-in-cryptocurrency-scam-promising-massive-returns/- YouTube cenzuruje kanały kryptowalutowe i usuwa filmy - https://www.coindesk.com/youtube-temporarily-bans-two-popular-crypto-channels-claiming-policy-breach-----------------------------------------OFICJALNY SKLEP Z GADŻETAMI KANAŁU MIKE SATOSHI http://kryptonarod.store/ZOSTAŃ PATRONEM KANAŁU MIKE SATOSHI https://patronite.pl/mike-satoshi-----------------------------------------Jeżeli chciałbyś wesprzeć rozwój i działania kanału, możesz przekazać dotację: https://tipanddonation.com/mikesatoshi lub PayPal: paypal.me/mikesatoshi Portfele do dotacji krypto są tutaj: https://cryptokoks.wixsite.com/mikesatoshi/dotacje ----------------------------------------- Mój kanał na YouTube: https://www.youtube.com/channel/UCEX4iDKLfxtIJY6IVgMSqCQE-mail do kontaktu: cryptokoks@gmail.com Oficjalny Twitter: https://twitter.com/Mikey_Satoshi Kanał na DTube: https://d.tube/#!/c/mikesatoshi Grupa KryptoNaród na FB: https://www.facebook.com/groups/230649241027530/ Grupa KryptoNaród na Discord: https://discord.gg/CPTSa43 Airdropy i inne sposoby na darmowe kryptowaluty: https://darmowekrypto.org.pl -----------------------------------------

Podcast Notes Playlist: Fitness
Episode 100: Peter Attia gives an update on his views regarding longevity and health span

Podcast Notes Playlist: Fitness

Play Episode Listen Later Dec 17, 2019 63:21


Podcast Notes Key Takeaways The five drivers of longevity:Nutritional biochemistryExercise physiologySleep physiologyEverything that goes into improving emotional health (techniques for increasing distress tolerance, enhancing mindfulness, etc.)Exogenous moleculesThe best longevity-based lab tests (and data):Continuous glucose monitor (CGM) dataLong-term average glucose & its standard deviation (the latter gives insight into insulin secretion)ApoB or LDL-P (LDL particle number)Lactate levels at a specific level of exertionOverall inflammation levels Any tests related to liver function (particularly one’s uric acid levels)In regards to lab tests, what constitutes “normal” is based on an unhealthy general population“There’s a strong association between lower insulin and lower glucose and improved metabolic health, and therefore risk reduction of atherosclerotic disease, neurodegenerative disease, and cancer” – Peter Attia There’s no longevity “magic bullet”—focusing on exercise, nutrition and sleep will give 95%+ of the benefitsRead the full notes @ podcastnotes.orgToday’s episode marks the 100th episode of STEM-Talk and the return of guest Peter Attia, who Ken and Dawn interviewed for episode one of STEM-Talk back in 2016. Peter is the founder of Attia Medical, a medical practice with offices in San Diego and New York City that focuses on the applied science of longevity. Peter emphasizes nutritional biochemistry, exercise physiology, sleep physiology, lipidology, pharmacology and four-system endocrinology to help people increase their lifespan and health span. Peter is the host of the podcast The Drive. He earned his M.D. from Stanford University and holds a B.S. in mechanical engineering and applied mathematics. Show notes: [00:04:44] Dawn opens the interview welcoming Peter back to the show. Dawn mentions that a lot has happened since she and Ken last interviewed Peter and points out that Peter is in the process of writing a book. [00:05:51] Ken asks Peter if it’s true that he does his best writing on long flights. [00:06:21] Dawn mentions that in 2014 Peter created Attia Medical, which is a practice with offices in San Diego and New York City, where he focuses on the applied science of longevity and optimal performance. Peter gives an overview of his practice and how he works to improve people’s healthspan and lifespan. [00:07:29] Ken asks Peter to explain the difference between a strategy and a tactic in the domain of optimization of performance and healthspan. [00:10:35] Dawn mentions that back on episode one of STEM-Talk that Peter talked about his eight drivers of longevity. Dawn asks Peter if his thinking over the past three years has changed in terms of the eight drivers. [00:12:30] Dawn asks what are some of the best lab tests in terms of longevity that people should request from their primary care physician. [00:14:25] Ken asks how Peter goes about determining optimal reference ranges to target in his patients, noting that the guidelines constituting normal are based on a sick overall population. [00:17:26] Dawn talks about how every year a new secret to longevity comes out with the force of hype behind it, but that rarely does the new so-called secret deliver. In contrast, she mentions how Peter encourages people to keep things simple and focus on nutrition, exercise and sleep. Peter explains how these three things can have the biggest impact on a person’s physical health. [00:19:35] Dawn explains that optimizing health span can be expensive, often costing upwards of $100,000 a year in tests and devices and off-label medications. She asks if Peter has any thoughts on if there is becoming a class divide in the world of healthspan and lifespan. [00:21:10] Ken explains that a primary inhibitor of BDNF is HDAC, and BHB is a powerful inhibitor of HDAC, which leads one to think that one of the mechanisms of exercise to increase BDNF is the elevation of BHB. [00:22:21] Ken mentions that the area under the curve for insulin is one of Peter’s favorite longevity markers, and asks him to talk about the concept of insulin area under the curve.  In addition to blood tests and glucose monitoring, Ken asks Peter what would be the next item of greatest interest in terms of longevity markers. [00:24:28] Dawn mentions that Peter wears an Oura Ring to monitor his sleep, and a glucose monitor to measure his blood sugar in real time. Dawn asks Peter to talk about the benefits of continuous monitoring versus short-term use for the purpose of building future behavior. [00:25:54] Dawn asks if Peter uses any other wearables besides the ones she just mentioned. [00:27:45] Dawn points out that Peter traveled to Easter Island with some friends, including David Sabatini, a guest on episode 70 of STEM-Talk. Dawn asks Peter to talk about the trip which was set up to explore first-hand the place where a group of Canadian researchers first discovered rapamycin. [00:29:13] Ken mentions that Peter is on record saying,

Podcast Notes Playlist: Nutrition
Episode 100: Peter Attia gives an update on his views regarding longevity and health span

Podcast Notes Playlist: Nutrition

Play Episode Listen Later Dec 17, 2019 63:21


Podcast Notes Key Takeaways The five drivers of longevity:Nutritional biochemistryExercise physiologySleep physiologyEverything that goes into improving emotional health (techniques for increasing distress tolerance, enhancing mindfulness, etc.)Exogenous moleculesThe best longevity-based lab tests (and data):Continuous glucose monitor (CGM) dataLong-term average glucose & its standard deviation (the latter gives insight into insulin secretion)ApoB or LDL-P (LDL particle number)Lactate levels at a specific level of exertionOverall inflammation levels Any tests related to liver function (particularly one’s uric acid levels)In regards to lab tests, what constitutes “normal” is based on an unhealthy general population“There’s a strong association between lower insulin and lower glucose and improved metabolic health, and therefore risk reduction of atherosclerotic disease, neurodegenerative disease, and cancer” – Peter Attia There’s no longevity “magic bullet”—focusing on exercise, nutrition and sleep will give 95%+ of the benefitsRead the full notes @ podcastnotes.orgToday’s episode marks the 100th episode of STEM-Talk and the return of guest Peter Attia, who Ken and Dawn interviewed for episode one of STEM-Talk back in 2016. Peter is the founder of Attia Medical, a medical practice with offices in San Diego and New York City that focuses on the applied science of longevity. Peter emphasizes nutritional biochemistry, exercise physiology, sleep physiology, lipidology, pharmacology and four-system endocrinology to help people increase their lifespan and health span. Peter is the host of the podcast The Drive. He earned his M.D. from Stanford University and holds a B.S. in mechanical engineering and applied mathematics. Show notes: [00:04:44] Dawn opens the interview welcoming Peter back to the show. Dawn mentions that a lot has happened since she and Ken last interviewed Peter and points out that Peter is in the process of writing a book. [00:05:51] Ken asks Peter if it’s true that he does his best writing on long flights. [00:06:21] Dawn mentions that in 2014 Peter created Attia Medical, which is a practice with offices in San Diego and New York City, where he focuses on the applied science of longevity and optimal performance. Peter gives an overview of his practice and how he works to improve people’s healthspan and lifespan. [00:07:29] Ken asks Peter to explain the difference between a strategy and a tactic in the domain of optimization of performance and healthspan. [00:10:35] Dawn mentions that back on episode one of STEM-Talk that Peter talked about his eight drivers of longevity. Dawn asks Peter if his thinking over the past three years has changed in terms of the eight drivers. [00:12:30] Dawn asks what are some of the best lab tests in terms of longevity that people should request from their primary care physician. [00:14:25] Ken asks how Peter goes about determining optimal reference ranges to target in his patients, noting that the guidelines constituting normal are based on a sick overall population. [00:17:26] Dawn talks about how every year a new secret to longevity comes out with the force of hype behind it, but that rarely does the new so-called secret deliver. In contrast, she mentions how Peter encourages people to keep things simple and focus on nutrition, exercise and sleep. Peter explains how these three things can have the biggest impact on a person’s physical health. [00:19:35] Dawn explains that optimizing health span can be expensive, often costing upwards of $100,000 a year in tests and devices and off-label medications. She asks if Peter has any thoughts on if there is becoming a class divide in the world of healthspan and lifespan. [00:21:10] Ken explains that a primary inhibitor of BDNF is HDAC, and BHB is a powerful inhibitor of HDAC, which leads one to think that one of the mechanisms of exercise to increase BDNF is the elevation of BHB. [00:22:21] Ken mentions that the area under the curve for insulin is one of Peter’s favorite longevity markers, and asks him to talk about the concept of insulin area under the curve.  In addition to blood tests and glucose monitoring, Ken asks Peter what would be the next item of greatest interest in terms of longevity markers. [00:24:28] Dawn mentions that Peter wears an Oura Ring to monitor his sleep, and a glucose monitor to measure his blood sugar in real time. Dawn asks Peter to talk about the benefits of continuous monitoring versus short-term use for the purpose of building future behavior. [00:25:54] Dawn asks if Peter uses any other wearables besides the ones she just mentioned. [00:27:45] Dawn points out that Peter traveled to Easter Island with some friends, including David Sabatini, a guest on episode 70 of STEM-Talk. Dawn asks Peter to talk about the trip which was set up to explore first-hand the place where a group of Canadian researchers first discovered rapamycin. [00:29:13] Ken mentions that Peter is on record saying,

STEM-Talk
Episode 100: Peter Attia gives an update on his views regarding longevity and health span

STEM-Talk

Play Episode Listen Later Dec 17, 2019 63:21


Today’s episode marks the 100th episode of STEM-Talk and the return of guest Peter Attia, who Ken and Dawn interviewed for episode one of STEM-Talk back in 2016. Peter is the founder of Attia Medical, a medical practice with offices in San Diego and New York City that focuses on the applied science of longevity. Peter emphasizes nutritional biochemistry, exercise physiology, sleep physiology, lipidology, pharmacology and four-system endocrinology to help people increase their lifespan and health span. Peter is the host of the podcast The Drive. He earned his M.D. from Stanford University and holds a B.S. in mechanical engineering and applied mathematics. Show notes: [00:04:44] Dawn opens the interview welcoming Peter back to the show. Dawn mentions that a lot has happened since she and Ken last interviewed Peter and points out that Peter is in the process of writing a book. [00:05:51] Ken asks Peter if it’s true that he does his best writing on long flights. [00:06:21] Dawn mentions that in 2014 Peter created Attia Medical, which is a practice with offices in San Diego and New York City, where he focuses on the applied science of longevity and optimal performance. Peter gives an overview of his practice and how he works to improve people’s healthspan and lifespan. [00:07:29] Ken asks Peter to explain the difference between a strategy and a tactic in the domain of optimization of performance and healthspan. [00:10:35] Dawn mentions that back on episode one of STEM-Talk that Peter talked about his eight drivers of longevity. Dawn asks Peter if his thinking over the past three years has changed in terms of the eight drivers. [00:12:30] Dawn asks what are some of the best lab tests in terms of longevity that people should request from their primary care physician. [00:14:25] Ken asks how Peter goes about determining optimal reference ranges to target in his patients, noting that the guidelines constituting normal are based on a sick overall population. [00:17:26] Dawn talks about how every year a new secret to longevity comes out with the force of hype behind it, but that rarely does the new so-called secret deliver. In contrast, she mentions how Peter encourages people to keep things simple and focus on nutrition, exercise and sleep. Peter explains how these three things can have the biggest impact on a person’s physical health. [00:19:35] Dawn explains that optimizing health span can be expensive, often costing upwards of $100,000 a year in tests and devices and off-label medications. She asks if Peter has any thoughts on if there is becoming a class divide in the world of healthspan and lifespan. [00:21:10] Ken explains that a primary inhibitor of BDNF is HDAC, and BHB is a powerful inhibitor of HDAC, which leads one to think that one of the mechanisms of exercise to increase BDNF is the elevation of BHB. [00:22:21] Ken mentions that the area under the curve for insulin is one of Peter’s favorite longevity markers, and asks him to talk about the concept of insulin area under the curve.  In addition to blood tests and glucose monitoring, Ken asks Peter what would be the next item of greatest interest in terms of longevity markers. [00:24:28] Dawn mentions that Peter wears an Oura Ring to monitor his sleep, and a glucose monitor to measure his blood sugar in real time. Dawn asks Peter to talk about the benefits of continuous monitoring versus short-term use for the purpose of building future behavior. [00:25:54] Dawn asks if Peter uses any other wearables besides the ones she just mentioned. [00:27:45] Dawn points out that Peter traveled to Easter Island with some friends, including David Sabatini, a guest on episode 70 of STEM-Talk. Dawn asks Peter to talk about the trip which was set up to explore first-hand the place where a group of Canadian researchers first discovered rapamycin. [00:29:13] Ken mentions that Peter is on record saying,

区块链与比特币-币须知道
10-9|Telegram首次正式将区块链网络TON公布于世

区块链与比特币-币须知道

Play Episode Listen Later Oct 9, 2019 9:11


主要内容:V神:以太坊2.0不是一个“骗局” 未来一周或写有关研究文章;Telegram首次正式将区块链网络TON公布于世;乌克兰政府拟制定加密货币税收规则 并计划在两到三年内使挖矿合法化;瑞士国家银行将在国际清算银行创新中心研究CBDC蜜蜂查24小时行情早报(10-9 8:00)BTC现价:$8196.08,24小时涨跌 -0.25%,交易量$139.19亿 ETH现价:$181.04,24小时涨跌 0.21%,交易量$71.47亿V神:以太坊2.0不是一个“骗局” 未来一周或写有关研究文章针对于此前关于以太坊2.0的报道,以太坊创始人V神发推表示,这篇报道很不公平。在标题中暗示以太坊2.0可能是一个“骗局”,不尊重几十个人多年的辛勤工作,特别是距离第0阶段还有几个月。他随后表示,对于如何从以太坊1.0迁移到以太坊2.0,“没有明确的计划”是不对的。大纲很清楚:将以太坊1.0状态根放入以太坊2.0中,让以太坊1.0作为执行环境继续存在于以太坊2.0中。现有的以太坊1.X工作已经使我们朝着这一目标迈进。V神还称,他可能会在接下来的一周写一些关于他觉得人们有误解的事情(包括以太坊1.0与2.0转换、DeFi可组合性、过渡)的研究文章。Telegram首次正式将区块链网络TON公布于世周二,Telegram官网在其代币的钱包应用程序的服务条款(ToS)中首次提及TON及其gram代币。据ToS称,Telegram将把钱包整合到公司的旗舰消息传递应用程序中,并将其作为独立产品提供。该文件写道:“我们无法控制TON区块链网络,因此无法确保您通过服务提交的任何交易详细信息都会在TON区块链上得到验证和确认。”根据ToS,Telegram不会保留其用户的个人信息或公钥和私钥。Telegram发布Grams Wallet使用条款10月8日,Telegram发布了其原生加密货币钱包Grams Wallet的使用条款。这是为其原生加密货币Gram(GRM)设计的钱包,该规则适用于独立应用程序或与Telegram Messenger应用程序结合使用。Telegram在声明中强调,在任何适用法律、法规或规则禁止其服务的司法管辖区(包括禁运、受制裁的国家和受制裁的个人)均不得使用Grams Wallet。 Telegram还强调,其客户应负责确定使用Gram服务应缴纳的税款。加密货币分析员:Tether正在缓慢迁移到以太坊网络据AmbCrypto报道,加密货币分析员Mark Prestwood表示,在过去几个月中Tether正在缓慢迁移到以太坊网络。Tether在ETH区块链上积累了巨大的空间,促进了ETH网络上价值41.7万美元的交易,堵塞了第二大区块链的网络。Bitfinex:在上诉期间不应该为纽约总检察长办公室收集文件据CoinDesk 10月8日消息,Bitfinex、Tether和其他关联公司的律师周二致信纽约州最高法院,称NYAG办公室有关姐妹公司Bitfinex和Tether之间9,000亿美元贷款的请求应被拒绝。Bitfinex的律师称,NYAG的办公室没有援引任何支持其要求的权威,进一步表明州检察官似乎认为“收集负担毫无意义”。话虽如此,信中承认,仅仅是收集文件就需要一大笔费用。这封信还驳斥了有关该交易所正在拖延法庭下达的文件制作要求的指控。John McAfee:SEC将对我的加密交易所进行严厉打击,但不会使其关闭加密货币爱好者、杀毒软件之父John McAfee今日在推特发文称,对于我在加密世界中创建的加密交易所而言,SEC将对其进行严厉打击,但不会使其关闭。其存在于区块链智能合约上,McAfeedex.com 只是进入其中的一个窗口,而且其开源的。乌克兰政府拟制定加密货币税收规则 并计划在两到三年内使挖矿合法化乌克兰数字转型部(Digital Transformation Ministry)计划在两到三年内使该国的加密货币挖矿合法化。根据该部新闻部门于10月7日发布的一份声明,在与该国的区块链社区会面之后,政府希望制定税收规则来处理加密货币,并批准有关在2020年夏季之前打击洗钱的国际建议,以最大程度地减少加密货币合法化的负面影响。该部还计划在上述时期内将区块链技术引入国家注册机构,鼓励国际加密货币交易所进入乌克兰,并欢迎外国公司和投资者,以提升乌克兰在全球虚拟资产市场上的竞争力。(Unian)现代旗下区块链部门将设立1000万美元的主网启动资金Hdac Technology是韩国最大的汽车制造商现代汽车集团(Hyundai Motor Group)旗下区块链子公司,该公司计划在2019年设立一只1000万美元的区块链投资基金。据韩国媒体报道,Hdac将用这笔资金启动其主网,并开发分散的应用程序,支持新的行业初创企业,创建一个“加密货币补偿系统”的生态系统。现代代币(Hdac)的发行人Hdac计划在2020年第一季度发布其主网,测试网计划在2019年11月发布。(cointelegraph)瑞士国家银行将在国际清算银行创新中心研究CBDC根据10月8日的官方新闻稿,国际清算银行的首批三个创新中心将在瑞士、香港和新加坡建立。瑞士国家银行(SNB)和国际清算银行(BIS)已签署一项协议,在国际清算银行位于瑞士的创新中心进行合作。该文件指出,瑞士中心最初将专注于两个研究项目,将中央银行数字货币(CBDC)集成到分布式分类帐技术的基础结构中,并分析央行对跟踪快速节奏的电子市场的不断增长的需求。瑞士国家银行与瑞士主要金融服务提供商SIX Group合作,将以概念验证的形式进行第一个项目。此外,该新闻稿称,基于区块链的CBDC将“旨在促进金融机构之间代币化资产的结算”。福布斯董事长:比特币面临的挑战是成为像黄金一样值得信赖的货币据Cointelegraph报道,福布斯媒体集团董事长史蒂夫·福布斯(Steve Forbes)近日在节目上表示,他相信比特币可以帮助对抗专制政府。他将比特币称为“高科技解救”,称比特币可以“摆脱那些想控制你,饿死和伤害你的政府”,原因是人们对传统货币缺乏信任。他同时指出比特币面临的挑战在于成为像黄金一样值得信赖的货币。联合国机构推出比特币以太坊加密基金UNICEF据Forbes消息,联合国儿童基金会创新办公室创始人Chris Fabian、区块链创始人Christina Lomazzo和她的国际团队今天宣布了UNICEF加密基金,该机构可以接受比特币和以太币捐赠并直接投资于区块链初创企业。除了将加密货币投资于与儿童合作的早期开放源代码公司之外,该基金还代表联合国任何机构,无论是去年获得了67亿美元收入的联合国机构,还是第一次能够接受比特币和以太坊捐款的加密基金。土耳其政府冻结超过300万个银行帐户,该国加密货币普及率达20%据土耳其当地媒体Sözcü Gazetesi报道,在土耳其有将近250万的纳税人无法偿还债务,另外还有80万家公司与个人积欠社会保障开支,而这些人从上周开始收到取消抵押品赎回权与银行帐户被冻结的通知。当地税务专家内迪姆.土库曼(Nedim Türkmen)推估,土国政府发出的电子断赎通知总计超过330 万份,这也代表着在土耳其,有330 万位债务人在土耳其的银行帐户都受到影响。先是去年的货币危机、高度通膨,再到今年帐户突然被冻结,这让土耳其当地人民很难继续对国家货币抱持信任。而去中心化、不会被政府操弄的加密货币在某种程度上就成了他们的避风港,从2018 年起,加密货币的受欢迎程度呈指数级增长。今年6月发布的统计资料显示,在参与调查的土耳其人中有5分之1的人表示他们曾经或是正在持有加密货币。这相当于受访者中有20%的人民持有加密货币,此比例目前排名世界第一。杭州综保区:利用区块链技术提高贸易便利化水平10月8日,人民网刊文《杭州综保区“一个优化三个创新”为跨境电商高水平发展创造良好条件》。文章指出,杭州综保区将联合杭州互联网法院利用区块链技术打通关、汇、税、运、付五大环节。通过去中心化的区块链技术,增信各方数据,实现数据互通和监管过程中的信息不对称、不信任问题,进一步创新监管方式,提高贸易便利化水平。国家邮政局局长马军胜:重点推动大数据、区块链等技术和邮政业深度融合据新京报消息,10月9日,国家邮政局局长马军胜在2019年世界邮政日表示,针对我国邮政业的发展不足,在“智慧邮政”方面,要聚焦提质效育动能,进一步增强邮政业的发展后劲。加快推进“两进一出”工程,推动“快递进厂”、“快递进村”、“快递出海”;大力实施“科技兴邮”战略,加快落实“邮政业大数据发展”行动计划,重点推动云计算、大数据、物联网、区块链、人工智能和邮政业深度融合,提高全要素生产率和运行效率,加快“智慧邮政”建设等。四维图新:在2018年加入工信部区块链重点实验室 是副主任单位据新浪财经报道,四维图新在董秘回答投资者提问时表示,公司在2018年加入工信部区块链重点实验室,是副主任单位,公司区块链实验室分别是汽车研究小组、数据研究小组成员,公司已经就自动驾驶时代全球数据安全与协作治理在实验室进行立项研究。

STEM-Talk
Episode 94: John Newman discusses how the ketogenic diet and fasting regulate the genes and pathways that control aging

STEM-Talk

Play Episode Listen Later Aug 27, 2019 88:52


Our guest today is Dr. John Newman, a geriatrician and researcher who is well-known for a 2017 study that found a ketogenic diet reduced the mid-life mortality of aging mice while also improving their memory and healthspan. John is an assistant professor at the Buck Institute for Research on Aging and a geriatrician in the Division of Geriatrics at the University of California, San Francisco. He also is a physician who works with older adults in the San Francisco VA Medical Center. At Buck, John studies the molecular details of how diet and fasting regulate the genes and pathways that control aging. He particularly focuses on the ketone body beta-hydroxybutyrate and how its molecular signaling activities involving epigenetics and inflammation regulate aging and memory in mice. Show notes: [00:02:51] Dawn opens the interview asking John what it was like growing up in Long Island. [00:04:20] Dawn mentions that John was described as a pretty geeky kid growing up, and asks him about his childhood. [00:05:40] Ken asks John if being the type of kid who would do all the homework in his textbooks in the first couple of months annoyed his classmates. [00:07:34] Dawn asks why John decided to go to Yale University. [00:08:45] Mentioning that Yale doesn’t have a pre-med program, Dawn asks what John decided to major in. [00:10:15] John explains how he met his wife at Yale. [00:11:28] Dawn asks John why he traveled across the country to the University of Washington after graduating from Yale. [00:12:26] Dawn asks why John decided to focus his graduate work on the progeroid Cockayne syndrome. [00:14:15] John discusses his decision to go to the University of California, San Francisco for his residency. [00:16:05] Dawn asks if John immediately joined the faculty at San Francisco after his residency. [00:17:03] Ken asks John about his work to improve the care of older adults and help them maintain their independence as they age. Ken asks for an overview of the work John and his colleagues do in this area at the Buck Institute [00:18:39] Ken mentions that a lot of John’s work focuses on the molecular details of how diet and fasting regulate the genes and pathways that control aging. Ken asks John to elaborate on this work. [00:20:04] Dawn asks what specifically attracted John to the idea of studying the ketogenic diet as an intervention in mid to later life as opposed to a diet consumed habitually throughout life. [00:23:12] Dawn mentions that John and Eric Verdin, who recruited John to the Buck institute, share an interest in looking at ketone bodies as signaling metabolites, a topic they have written about. [00:26:21] Ken talks about a conference he and Dawn attended on CBD and seizures, where Ken made the point that ketones are a metabolite of THC. [00:27:52] Ken asks John to go into more detail about how ketone bodies may link environmental cues such as diet to the regulation of aging. [00:29:08] Ken talks about how it seems clear that ketone bodies are emerging as crucial regulators of metabolic health and longevity via their ability to regulate HDAC (histone deacetylases) activity and thereby epigenetic gene regulation. He asks John to discuss how beta hydroxybutyrate may be an increasingly useful and important signaling molecule as we age. [00:34:24] Dawn mentions that John and his colleagues published paper in 2017 in Cell Metabolism titled “Ketogenic Diet Reduces Midlife Mortality and Improves Aging in Mice.” Dawn asks why John chose a cyclical rather than continuous ketogenic diet for this study. [00:37:56] Dawn asks why John decided to conduct the test of physiological function while the ketogenic diet group was off the diet, and on a standard high-carbohydrate diet. [00:40:02] Dawn mentions that Megan Roberts and her colleagues at theUniversity of California Davis were also conducting studies on the effects of a ketogenic diet on mice around the same time as John...

Circulation on the Run
Circulation August 13, 2019 Issue

Circulation on the Run

Play Episode Listen Later Aug 12, 2019 23:09


Dr Carolyn Lam:                Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your cohosts. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, associate editor from the Poly Heart Center at VCU health in Richmond, Virginia. Carolyn, oh, this is going to be an exciting featured article today, and we're going to discuss the combination of agents or their administration et al that are best suited for managing both anticoagulation and antiplatelet therapy and those with coronary disease, peripheral arterial disease and heart failure. And, we'll speak with Dr Kelley Branch from the University of Washington. Dr Carolyn Lam:                And me! Dr Greg Hundley:             Yes. How am I going to interview you? And, we'll discuss the utility of Rivaroxaban with or without aspirin in patients with heart failure or peripheral arterial disease from the compass trial. Dr Carolyn Lam:                Well, I'm not going to let you get there until I tell you about this first basic paper I've chosen because it focuses on the unfolded protein response. Dr Greg Hundley:             What's that? Dr Carolyn Lam:                Well, Greg, I was really hoping you'd ask. The unfolded protein response is a cellular adaptive process to cope with protein folding stress. Now, approximately 40% of human proteins are predicted to be either transmembrane or secretory. The synthesis, the folding, the cellular transportation and location of these proteins rely on proper functioning of this secretory pathway. Numerous studies have established that the unfolded protein response plays versatile roles during development and under physiologic and pathophysiologic conditions. However, the role of this unfolded protein response in the regulation of cardiomyocyte growth is unclear. Dr Greg Hundley:             That's fantastic, Carolyn. I've already learned something here. So, what did this paper show? Dr Carolyn Lam:                This is from Dr Wang and colleagues from UT Southwestern, and basically, they use both gain and loss of function approaches to genetically manipulate spliced X-box binding protein one or XBP1, which is the most conserved signaling branch of the unfolded protein response in the heart. In addition, primary cardiomyocyte cultures were employed to address the role of XBP1S in cell growth in a cell autonomous manner. They found that XBP1S expression was reduced in both human and Rhode and cardiac tissues with heart failure deficiency of XBP1S lead to decompensation and exacerbation of heart failure progression under pressure overload. On the other hand, cardiac restricted over expression of XBP1S prevented the development of cardiac dysfunction. Mechanistically, they found that XBP1S stimulated adaptive cardiac growth, your activation of mechanistic target of rapamycin or MTOR signaling which is mediated via the FK-506 binding protein 11, which is a novel transcriptional target of XBP1S. So in conclusion, this study really showed a critical role of the XBP1S FKB or FK-506 binding protein 11 and MTOR axis in coupling the unfolded protein response and cardiac cell growth regulation. Dr Greg Hundley:             Boy Carolyn, you explained that so well, and I learned a lot from that. I hope I can do as well with this next article from Professor Johann Backs from the University of Heidelberg. Now paradoxically, some glucose lowering drugs have been shown to worsen heart failure, raising the question of how glucose mediates protective versus detrimental cardiac signaling, and this study from his group focused on one of the class two histone deacetylases or HDAC's namely HDAC-4, which functions as an important epigenetic regulator by responding to upstream stress signals, and linking them to downstream gene regulatory programs involved in among other things, metabolic regulation. Dr Carolyn Lam:                Very interesting. So what did they find? Dr Greg Hundley:             What they found is that HDAC4 acts as an important maintenance factor of cardiac function in diabetes and O-glycine-N0acetylglucosamine of HDAC4 at searing 642 induces the production of cardio-protective HDAC F-end terminal fragment and attenuates cardio detrimental Cam kinase two mediated phosphorylation of HDAC4 at searing 632. Vice versa, Cam kinase two mediated phosphorylation of HDAC4 at searing 632 attenuates HDAC-4 n terminal production. Thus, these findings lay the ground for the development of novel therapeutic strategies for diabetic patients with heart failure by inhibiting Cam kinase phosphorylation at CIHR 632 or enhancing o-glycine and escalation at searing 642. Dr Carolyn Lam:                Fascinating, Greg. Well, my next paper is a subgroup analysis of EUCLID and is the first to assess acute limb ischemia in the context of a large-scale clinical trial studying a primary peripheral artery disease population. Dr Greg Hundley:             So Carolyn, reminded us what was the EUCLID trial. Dr Carolyn Lam:                Okay, so EUCLID stands for Examining Use of Ticagrelor in Peripheral Artery Disease, and this was a randomized clinical trial that included acute limb ischemia as an adjudicated outcome in a primary peripheral artery disease population randomized to ticagrelor versus clopidogrel. Now in EUCLID ticagrelor was not superior to Clopidogrel for the prevention of cardiovascular events in patients with stable peripheral artery disease. However, a EUCLID subgroup analysis of patients with and without prior limb revascularization demonstrated significantly higher risk for acute limb ischemia hospitalization in patients with prior low extremity revascularization. Dr Greg Hundley:             So Carolyn, that's interesting. So, what did they find related in this study that focused on the acute limb ischemia? Dr Carolyn Lam:                Right. So, today's paper is from Dr Hess and colleagues at University of Colorado School of Medicine and CPC, clinical research in Aurora, Colorado. And, they found that acute limb ischemia occurred in 1.7% of almost 13,900 randomized patients with a median time to hospitalization for acute limb Ischemia of 320 days after randomization. In this population, prior lower extremity revascularization, atrial fibrillation and lower ankle brachial index identified patients at higher risk for acute limb ischemia. Hospitalization for acute limb ischemia was associated with subsequent cardiovascular and limb ischemic events. So, the take home message is providers should monitor for signs and symptoms of acute limb ischemia in patients with stable symptomatic peripheral artery disease, particularly those with prior lower extremity revascularization, atrial fibrillation, and lower ankle brachial index. Dr Greg Hundley:             That's very instructive, Carolyn. Fantastic message. So, I'm going to ask you if you could select one lipid biomarker to forecast future adverse cardiovascular events, which would you select? Total cholesterol, HTLC, non-HTLC, direct and calculated LDLC, APO-A1, or APO-B? Dr Carolyn Lam:                Well, I'm traditional. I would have chosen LDL. Dr Greg Hundley:             Okay. Well, the authors of this study led by Dr Paul Welsh at the University of Glasgow attempted to answer this question by studying participants from the UK Biobank without baseline cardiovascular disease and not taking statins with relevant lipid measurements. They had 346,686 participants. An incident fatal or nonfatal cardiovascular event occurred in 6,200 participants of which 1,656 were fatal, and they occurred over a median time of 8.9 years. So, the associations of non-fasting lipid measurements, total cholesterol, HDLC, non HDLC, direct and calculated LDLC, APO-a1, and APO-B with cardiovascular disease were compared using Cox models, adjusting for classical risk factors and predictive utility was determined by the C-index and net reclassification index. Also, prediction was tested in 68,649 participants taking a statin with or without baseline cardiovascular disease, and that group experienced 3,515 cardiovascular events. Dr Carolyn Lam:                Okay, so drum roll. What did they find? Dr Greg Hundley:             So, measurement of total cholesterol and HDLC in the non-fasted state is sufficient or was sufficient to capture the lipid associated risk in the cardiovascular disease prediction with no meaningful improvement from addition of APO lipoproteins, direct or calculated LDLC. And, similar findings were reproduced in those taking a statin at baseline.                                                 As such, the authors feel like calls for widespread use of APO lipoproteins are not warranted given the negligible difference in risk prediction beyond total cholesterol in HDLC. And, direct LDLC is also not required for risk prediction. Non HDLC is a cheaper or equivalent predictor of risk on and off statins without the requirement of one of us being fasting. This is an excellent article for our listeners to review or download. Dr Carolyn Lam:                Wow, that is so cool. So, from one excellent paper to another excellent paper in our feature discussion. Let's go, shall we? Dr Greg Hundley:             Welcome everyone to discussion of our featured article. We have Dr Kelley Branch from the University of Washington and our own Carolyn Lam, and they're going to be discussing the compass trial. So Kelley, could you tell us a little bit about the rationale for compass as opposed to the previously published commander study? Dr Kelley Branch:              So, in order to understand compass and compare it to commanders, we're going to have to go back a little bit in time here. And recall, you know well over 20 years ago that when we used anticoagulants in coronary artery disease, that was actually shown to be more beneficial than aspirin alone, but because of the excess bleeding risk, warfarin or vitamin K antagonists not used, and aspirin won. Fast forward a number of years, and now we have the non-vitamin K anticoagulants, and the was potentially that we could find the goldilocks, if you will, the good balance of benefit as well as less bleeding maybe used to these new agents. So, the compass trial was really born from an atlas ACS one and Atlas ACS two, which found that a low dose of, in this case, Rivaroxaban 2.5 milligrams VAB as well as five milligrams VAB were shown to be beneficial in patients after acute coronary syndrome.                                                 And then, it was thought what happens if we treat these patients with now chronic coronary disease as well as arterial disease? And from this 27,000 patients, 47,395 patients were tested, and our study very specifically looked at patients with a baseline or a history of heart failure when they answered compass. Compass were shown to be beneficial with specifically the use of aspirin plus Rivaroxaban, 2.5 milligrams BAD. And, our idea was to test this in patients with this baseline or history of heart failure. Now, this is in real contradistinction to what the commander tried to do. And the reason why encompass, we actually excluded patients with severe heart failure. This was defined as a New York Heart Association class three or four or an ejection fraction less than 30%. Now if you looked at patients with commander, these patients had ejection fraction less than 40%. That was a criteria to get in. And of course, these patients had to have a recent hospitalization for heart failure. So, these are very different patient populations. Well, both of them, yes, they did have coronary artery disease, but really very different patient populations. Dr Greg Hundley:             Very good. So Kelley, tell us specifically, what were your treatment group assignments and the doses and the outcomes that you were going to follow, and then lead us into what did you find? What were the outcomes of your study? Dr Kelley Branch:              Sure, so compass was actually developed as a partial three by two factorial. The arm that we're going to be talking about is the rivaroxaban arm. There was also another arm that tested the use of Proton pump inhibitors, and that actually was shown to not be as beneficial as we thought to decreased bleeding. But specifically for rivaroxaban, the baseline was aspirin, and this was on top of guideline based medical therapy. And then patients were randomized to either aspirin alone plus placebo or Rivaroxaban, five milligrams BAD, plus placebo. So, no aspirin at all or aspirin, a hundred milligrams daily, plus Rivaroxaban, 2.5 milligrams BAD. Those were really the three treatments. Patients were going to be followed for about three to four years. That's what we expected to get our 2200 events , an event-driven trial. But, because of the overwhelming benefits at 23 months median follow up, this trial was actually stopped early, so we only had a little over 1300 events at that time.                                                 And with that we saw substantial reduction in major adverse cardiovascular events, about 24% mortality was reduced 18%, and there was a bleeding risk along with this, major bleeding, little different way of actually measuring major bleeding, but that was increased by about 70%, and that was the overall trial results. So, looking at the patients with heart failure, though, there was actually a relatively large proportion of patients, so 5,902 patients, about 22% of patients, actually had either baseline heart failure or had a history of heart failure coming in. Now, this was defined specifically by the PI's. These were not rigorously defined as compared to say commander, but these were patients where the PI said this patient has history or has chronic heart failure. So, with these 5,902 patients, we looked specifically at the outcomes of major adverse cardiovascular events similar to what we saw with compass and that is cardiovascular death, myocardial infarction, or any stroke, that combination. And then, looked at some others exploratory analysis like mortality.                                                 And, what we found is that in patients with heart failure, the baseline rate was substantially higher for a mate's. Not too surprising because this tends to be a higher risk patient population. But, what we found is that the hazard ratio was about 0.68, so pretty similar to what we've seen the 24% relative risk. In this case, this was a 32% relative risk reduction in those patients with heart failure. Now, if we looked at a patients without heart failure, the hazard ratio is 0.79, so fairly similar and the [conference intervals 00:16:33] overlap. No statistical heterogeneity or no difference between those, but what we did see if we looked at the absolute risk reduction, was an absolute risk reduction in heart failure of 2.4% reduction. That means a number needed to treat of about 42. If you look at the absolute risk reduction for those patients without heart failure, that was 0.9 to 1.0 depending on what the rounding was. We took 1.0 so that means the number needed to treat of 103. So, these were slightly different relative risks, but overall, what we saw is that the hazard ratio is very consistent with the overall effect of compass in the same direction.                                                 Interestingly, and actually I think even for me it was surprisingly, we actually looked at the hazard ratios for bleeding, and when we looked at the hazard ratios for bleeding, we fully expected that because it's the higher risk patient population, we actually expected that to go up. What we saw is that the bleeding actually was no difference at all, and if anything in the heart failure population was slightly lower. And, this was fairly surprising to us because we thought that the patients with heart failure, the bleeding would actually trend up because this was a higher risk patient population. So it looks like it's something can be used and really no substantial increase in bleeding. Dr Greg Hundley:             Very good. Well Carolyn, as someone that's managing patients with heart failure, what do you see are the clinical implications of this study? Dr Carolyn Lam:                That is a beautifully simple, direct question but is not as easy to answer as I may have thought. And, that's because the commander trial that Kelley did describe a bit earlier was neutral on its primary outcome. And, the commander trial is what we would traditionally think of as a heart failure trial. And why? Because those were patients that we rigorously define heart failure, including a naturally acid peptide inclusion criteria. And, because we really wanted these to be severe heart failure patients, we recruited them very close to their hospitalization or decompensation event. So, I just want to reiterate what Kelley has already so beautifully described that commander was neutral, whereas this heart failure subset of compass showed very impressive results that were consistent with the very impressive positive results of the overall compass trial.                                                 So, how do we reconcile all of it? Well, first of all, I have to humbly remind myself that this heart failure subset of compass, the entire subset was actually bigger in numbers than the entire of the commander trials. So, this is not a small little subgroup analysis. This is a huge subgroup analysis. And that's why a paper like this, we're so proud to be publishing in circulation.                                                 So, how do I apply it? Well, when I have a compass like patient, which means it's a stable coronary artery disease or peripheral artery disease patient who happens to have some mild heart failure. I think of this patient as a compass patient and I think that the combination of aspirin and low dose Rivaroxaban has been shown to be effective in these patients. So, in such a patient, I continue the aspirin rivaroxaban combination. However, if I have a new patient coming in with decompensated heart failure, a very low ejection fraction and has some coronary artery disease, by the way, I see that as a commander patient, and I just want to make sure that in such a patient I'm not trying to reduce their overall mortality by treating them with a combination of aspirin Rivaroxaban because commander has shown that I don't impact their overall survival with this combination, even though we may still have beneficial effects on their thromboembolic thrombotic events.                                                 Kelley, would you agree? Dr Kelley Branch:              I would completely agree. That was actually born out very, very well by Barry Greenberg who had a really a wonderful sub analysis which he looked at the thrombotic events published in Jama cardiology and really showing that yes, you can affect the thrombotic events, but I mean really what it comes down to is we want to save lives. We want people to be better. There's just an overwhelming risk for these patients with heart failure that is really non thrombotic, primarily. And so, you're really not going to move the needle very much. You may prevent a stroke here, you may prevent some cardiovascular death from a thrombotic problem, but overwhelmingly pump failure, arrhythmia, et cetera. Those are really going to be the drivers for the commander like population. Dr Carolyn Lam:                But Kelley, this comes up a lot when we've chatted, but if you have a compass patient who has heart failure and then gets admitted with heart failure, what would you do then? Dr Kelley Branch:              That's a really interesting question, right? It depends on what the overall goal is. So, if the patient gets admitted for heart failure, now has it decreased ejection fraction sick. So has an MI, now decreased the ejection fraction. What's the end game? Right? Well you know, you may not be affecting mortality in this case because there's now competing events. However, if the goal was to decrease stroke, we've seen that. Still this goal is to decrease MI to some extent than we see that also. So, it would be reasonable to continue in order to prevent those events. But, just knowing full well that there's many other medications which actually do much better for the patients with decreased ejection fraction. And, those would probably be considered first line, but it's reasonable to continue. But, I would never start it. Dr Carolyn Lam:                Kelley, I couldn't agree more. And here I think the, your data showing that the bleeding risk is not significantly increased in this patient matters a lot. So, if I had a patient, a compass patient who was already on the combination and then gets admitted with heart failure, I too, if there's no additional bleeding risk, I would continue the combination as well. Dr Kelley Branch:              Couldn't agree more. Dr Greg Hundley:             Well listeners, this was a fantastic discussion, and we look forward to seeing you next week. Have a great week. Dr Carolyn Lam:                This program is copyright American Heart Association 2019.  

Nourish Balance Thrive
Nutritional Ketosis and Guided Behavior Change to Reverse Type 2 Diabetes

Nourish Balance Thrive

Play Episode Listen Later Aug 12, 2019 70:08


James McCarter, MD, PhD. is a researcher and author of over 60 scientific publications and patents. He recently led research and clinical operations for San Francisco-based Virta Health, a nationwide medical provider that delivers the first clinically-proven treatment to safely and sustainably reverse type 2 diabetes without medications or surgery. Dr. McCarter recently directed the Virta - Indiana University Health clinical trial demonstrating reversal of diabetes using nutritional ketosis and guided behavior change. This trial has resulted in changes to the American Diabetes Association Standards of Care and consensus statement on nutrition in 2019, reflecting the benefit of low-carbohydrate diets.  In this podcast, James discusses the results that have emerged from this research and the incredible outcomes Virta is demonstrating in helping people reverse their type-2 diabetes and improve cardiac risk markers. He also talks about the five facets of treatment behind Virta’s success, and the business model they employ to make treatment more widely available.  Dr McCarter recently spoke at the AACE (American Association of Clinical Endocrinology) meeting in Kansas City on ketosis for T2D. These slides provide nice visuals for all of the Virta-IUH trial outcomes as well as background information. Here’s the outline of this interview with Jim McCarter: [00:00:19] Two-year clinical trial: Athinarayanan, Shaminie J., et al. "Long-Term Effects of a Novel Continuous Remote Care Intervention Including Nutritional Ketosis for the Management of Type 2 Diabetes: A 2-year Non-randomized Clinical Trial." Frontiers in endocrinology 10 (2019): 348. [00:00:23] Virta Health. [00:01:09] Type 2 Diabetes (T2D) affects 30 million people in the US, 400 million worldwide. [00:02:24] Long term complications of T2D. [00:04:16] Ketogenic diet: Getting people off the glucose rollercoaster. [00:08:47] Setting up the clinical trial; Sarah Hallberg, DO, MS, Virta Medical Director. [00:10:13] Nine papers published by Virta so far: 7 on the trial and 2 reviews: 1, 2, 3, 4, 5, 6, 7, 8, 9, plus whitepaper on cardiovascular benefits of Virta treatment. [00:10:46] 5 facets to treatment: In-house medication management, health coaching, nutrition behavior change education, biometric feedback, online community. [00:16:05] Podcasts with Doug Hilbert: How Busy Realtors Can Avoid Anxiety and Depression Without Prescriptions or the Help of a Doctor, and Ancestral Health Symposium ‘18 Recap. [00:16:54] Doug Hilbert’s AHS talk 2018: AHS18 Douglas Hilbert - Virta 1 Year Clinical Trial Results/Patient Outcomes. [00:18:13] Adherence to the program: 74% of patients completed 2 years of the trial. [00:18:26] Blog post: Top 10 Keto Myths Debunked After 150,000 Days of Patient Care. [00:20:30] Jeff Volek, PhD, RD & Stephen Phinney, MD, PhD. [00:21:20] Ketone metabolism: beta-hydroxybutyrate, acetoacetate and acetone. [00:23:05] Beta-hydroxybutyrate as an histone deacetylase (HDAC) inhibitor; Study: Shimazu, Tadahiro, et al. "Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor." Science 339.6116 (2013): 211-214. [00:24:10] Higher levels of ketones correlate with greater reductions of hemoglobin A1c and greater weight loss. [00:24:29] Ken Ford, Podcast: Optimal Diet and Movement for Healthspan, Amplified Intelligence and More with Ken Ford (ketone signaling is discussed at minute 54:20). [00:25:58] Kaiser study on diabetes remission rates: Karter, Andrew J., et al. "Incidence of remission in adults with type 2 diabetes: the diabetes & aging study." Diabetes Care 37.12 (2014): 3188-3195. [00:29:09] Readout: creating less invasive ways for measuring metabolic markers. [00:29:28] Dan Ariely; Shapa scale and app. [00:31:55] Non-scale victories (NSV). [00:32:56] Ashley Mason podcasts: Paleo Psychology with Ashley Mason PhD and Mindfulness and Cognitive Behavioral Strategies for Diabetes and Sleep Problems. [00:33:22] Elimination of drugs that cause hypoglycemia (e.g., sulphonylureas). [00:34:13] Common pitfalls: Electrolytes. [00:37:46] Myth: Keto causes diabetic ketoacidosis. [00:38:50] Improvements in cardio risk markers; Study: Bhanpuri, Nasir H., et al. "Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study." Cardiovascular diabetology 17.1 (2018): 56. [00:44:25] Dave Feldman on The Fat Emperor Podcast with Ivor Cummins: LDL and All-Cause Mortality  - Does Cholestesterol Kill You?; Related NBT podcasts: How to Drop Your Cholesterol, with Dave Feldman, and How Not to Die of Cardiovascular Disease, with Ivor Cummins. [00:49:15] American Diabetes Association (ADA) changed their Standards of Care and consensus statement on nutrition in 2019. [00:51:04] Virta's value-based business model. [00:54:13] Navigating difficult food environments. [00:55:52] Robb Wolf; Chickasaw Nation. [01:01:43] Cardiovascular effects of GLP-1 agonist and SGLT2 inhibitor drugs; Studies: Busch, Robert S., and Michael P. Kane. "Combination SGLT2 inhibitor and GLP-1 receptor agonist therapy: a complementary approach to the treatment of type 2 diabetes." Postgraduate medicine 129.7 (2017): 686-697, and DeFronzo, Ralph A. "Combination therapy with GLP‐1 receptor agonist and SGLT2 inhibitor." Diabetes, Obesity and Metabolism 19.10 (2017): 1353-1362. [01:02:13] Podcast: Nudge Tactics for Performance and Health, with Simon Marshall, PhD. [01:04:50] Find James on Twitter, Medium and LinkedIn.

Authentic Biochemistry
HDAC 4 is a positive player in ALS muscle since it is not a functional histone deacetylase: The complexity of motor neuron disease reveals not-so-subtle differences in protein function

Authentic Biochemistry

Play Episode Listen Later Apr 16, 2019 27:12


Because HDAC4 closely resembles the structural component of the superfamily of histone deacetylases, in might be assumed it functions to catalyze the removal of LYS bound acetate. But since HDAC4 does not contain the catalytically necessary TYR-OH but rather an HIS-imidizole it has no deacetylase enzymatic activity. However HDAC4 does interact with other proteins and the net result is protective of skeletal muscle atrophy and motor neuron degeneration in a murine mutant human SOD1 model of Amyotrophic Lateral Sclerosis (ALS). This Authentic Biochemistry podcast episode reveals once again that specificity in time and space with coordinated expression of biochemical species will be more complicated than previously reported once a sharper lens is used to examine the disease pathology at the biochemical/molecular level. --- Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

Circulation: Arrhythmia and Electrophysiology On the Beat
Circulation: Arrhythmia and Electrophysiology March 2019 Issue

Circulation: Arrhythmia and Electrophysiology On the Beat

Play Episode Listen Later Mar 25, 2019 15:22


Dr Paul Wang:                   Welcome to the monthly podcast "On the Beat" for Circulation: Arrhythmia, and Electrophysiology. I'm Dr Paul Wang, Editor-in Chief, with some of the key highlights from this month's issue.                                                 In our first manuscript, Marie Bayer Elming and associates, examined whether the right ventricular ejection fraction can identify patients with non-ischemic systolic heart failure, more likely to benefit from ICD implantation. The Danish study, to assess the efficacy of ICDs in patients with non-ischemic systolic heart failure, on mortality, the Danish study, randomized patients with non-ischemic systolic heart failure to ICD our control. In 239 patients with interpretable cardiovascular magnetic resonance images, the right ventricular volume and ejection fraction was measured. Right ventricular ejection fraction was an independent predictor of all-cause mortality, with a hazard ration 1.34 per 10% absolute decrease in our right ventricular ejection fraction. P=0.02. There is statistically significant interaction between right ventricular ejection fraction and the effect of ICD implantation. P=0.001. ICD implantation significantly reduced all-cause mortality in patients with right ventricular systolic dysfunction. Hazard ratio 0.41, but not in patients without right ventricular systolic dysfunction.                                                 Thus, in this post-hoc analysis of the Danish trial, ICD therapy was associated with survival benefit in patients with bi-ventricular heart failure.                                                 In our next paper, Dawn Pedrotty and Volodymyr Kuzmenko and associates, have proposed a concept of using a stretchable, flexible, bio patch, with conductive properties, to attempt to restore conduction across regions in which activation is disrupted. They use carbon nanotube patches, composed of nanofibrillated cellulose, in single wall carbon nanotube ink, 3-D printed in conductive patterns onto bacterial nanocellulose.                                                 Electro anatomic mapping was performed on normal epicardium and repeated over surgically disruptive epicardium, and finally with the patch applied passively. The patch resulted in restored conduction based on mapping.                                                 In our next paper, Ayman Hussein and colleagues developed a fully automated platform to collect patient reported outcomes in a prospective cohort of atrial fibrillation ablation. Two thousand one hundred and seventy-five patients were eligible to receive 10,903 patient reported outcome assessment invitations. More follow up assessments were obtained with automated patient reported outcomes in routine follow-up, compared with routine follow up alone, P > 0.001, which allowed for longer duration of follow up, 378 vs 217 days. By automated patient reported outcomes, a large number of disease specific variables were collected and showed improvement in quality of life. Baseline median AF symptom severity score of 12 and ranged between 2 and 3 on subsequent assessments, P > 0.0001. This improvement was also true for each of the atrial fibrillation symptom severity score components. In patient reported outcomes, there was a significant reduction in atrial fibrillation burden, such as frequency and duration episodes and associated healthcare utilization including emergency visits and hospitalizations after the ablation procedures.                                                 In our next paper, Nicolas Johner, Dipen Shah, and associates, examined the role of post pacing intervals shorter than tachycardia cycling during entrainment mapping. The author studied 24 non-cavotricuspid isthmus dependent macro oriented atrial flutters in 19 consecutive patients. High density electro anatomic activation maps were acquired with a 64-electrode basket catheter of 102 entrainment mapping sites. Post pacing interval difference less than 30 was observed at 72 sites on complete maps of 24 atypical atrial flutters compared to sites with the difference in post pacing intervals 0 to 30, with 45 sites difference in the post pacing interval less than 0 at 27 were more commonly located within isthmuses less than 15mm wide and more frequently located in within 5mm of the leading wave front. It also exhibited slower local conduction, lower voltages in more frequently fractioned electrograms. The authors concluded that in atrial flutter, sites with differences with the post pacing interval are markers of limited width critical isthmuses with slower conduction velocity, while sites with difference in post pacing interval 0 to 30ms are often not in close proximity to the reentrance circuit. Virtual electrode simultaneous down and up stream, antidromic capture of a confined isthmus of slow conduction can explain a difference in the post pacing interval less than 0.                                                 In the next paper, José Manuel Alfonso-Almazán, and associates studied the safety and efficacy parameters associated with catheter-based radiofrequency delivery at the root of the aorta and pulmonary artery. The author studied 34 pigs undergoing in vivo catheter based ablation using continuous contact force and lesion index monitoring during 60 second radiofrequency delivery with an open, irrigated tip catheter. Twenty-eight animals were allocated to groups receiving 40 watts, 50 watts, or 60 watts and acute, chronic arterial damage was quantified by multi photon microscopy in ex vivo samples. Adjacent microlesion were quantified in parallel samples. The remaining 8 pigs, these were used to validate safety and efficacy parameters. Acute collagen elastic alterations were significantly associated with radiofrequency power, although chronic assessment revealed vascular wall recovery in patients without [steam pop 00:06:56]. The main parameters associated with steam pops were median peak temperature greater than 42C, and impedance falls greater than 23 ohms. Unlike other parameters, lesion index values of 9.1 units were associated with the presence of adjacent myocardial lesions in both univariate and multivariate analyses. In the validation group, lesion index values using 40 watts over a range of contact forces correlated with the size of radiofrequency lesions. Lesion index values obtained during 40 watts radiofrequency application reliably monitor safe and effective lesion creation at the root of the great arteries.                                                 In our next paper, Eiichiro Oka and associates examine the prevalence and significance of the early repolarization electrocardiographic pattern and its mechanistic insight based on cardiac magnetic resonance findings in patients with acute myocarditis. The author studied 30 patients with the diagnosis of acute myocarditis. Nine had an early repolarization electrocardiographical pattern, which was defined as a terminal QRS notching or slurring with an amplitude of greater than zero-point millivolts in at least two inferior and/or lateral leads. The early repolarization group, while the remaining 21 cases had broad ST elevation or pathological QAs.                                                 The non-early repolarization group. The cardiac prepotency level was significantly higher in the non-early repolarization group than the early repolarization group. The ECD changes returned to baseline, along with a normalization of the cardiac biomarkers. Nine of the 21 non-early repolarization group patients, but none of the 9 early repolarization groups developed fulminant course of lethal ventricular arrhythmias. T2-weighted cardiac magnetic resonance imaging showed high intensity signals over the entire transmittal left vertical in the non-early repolarization group, where as they were localized to the left ventricle epicardium in early repolarization group. The early repolarization pattern in acute myocarditis was transient and reversible, and was not associated with a worse prognosis. Inflammation or swelling localized to the left ventricular epicardium, due to myocarditis, may provide a mechanistic insight into the early repolarization pattern.                                                 In our next paper, Beatrix Scholz and Jan Sebastian Schulte and associates analyzed whether the histone deacetylase class I and II inhibitor valproic acid is able to attenuate atrial remodeling in CREM-IbΔCx (TG) transgenic mice. A mouse model of extensive atrial remodeling with age dependent progression from spontaneous atrial ectopy to paroxysmal and finally long lasting atrial fibrillation. Valproic acid was administered for 7 or 25 weeks to transgenic and control mice. Valproic acid attenuated many components of atrial remodeling that were present in the transgenic mice.                                                 Valproic acid significantly reduced atrial dilation, cardiomyocyte enlargement, atrial fibrosis, and the disorganization of myocytes ultrastructure. It significantly reduced the occurrence of atrial thrombi, reversed action potential alterations, and finally delayed the onset of atrial fibrillation by 4 to 8 weeks. Increased histone H4 acetylation in atria from valproic acid treated transgenic mice verified effective in in vivo histone deacetylase inhibition. Cardiomyocyte specific genetic inactivation of histone deacetylase HDAC 2 in transgenic mice attenuated the ultrastructural disorganization of myocytes compared to valproic acid. The author suggests that valproic acid, clinically available, well tolerated, and prescribed to many patients for years, has a therapeutic potential to delay the development of atrial remodeling in the onset of atrial fibrillation in patients at risk.                                                 In our next paper, Bence Hegyi and associates measure the major inward currents in their calcium channel and beta-adrenergic dependence under physiologic action potential clamp in rabbit ventricular myocytes in chronic pressure volume overload induced heart failure versus age matched controls. They found that CAM kinase II dependent up regulation of late sodium current in heart failure significantly contributes to the action potential prolongation in increased short-term variability of action potential repolarization, which may lead to increased arrhythmia propensity and is further exacerbated by adrenergic stress.                                                 In a research letter, Arnaud Bisson and associates examined mitral regurgitation in 838, or 10%, of 8675 patients with atrial fibrillation. A total 135, or 16%, had severe mitral regurgitation. During mean follow-up with 2.5 years, 688 ischemic stroke or thromboembolic events were recorded. mitral regurgitation was associated with a non-significant higher risk of these embolic events. After adjustment for anticoagulant and antiplatelet use, CHA2DS2-VASc and HAS-BLED scores, patients with mitral regurgitation tended to have a higher all cause or cardiovascular mortality but had similar risks of ischemic stroke or thromboembolic events, when compared to patients with no mitral regurgitation. Severe mitral regurgitation was also associated with similar risk for ischemic stroke and thromboembolic events when compared with other atrial fibrillation patients. However, our findings indicate that in patients with atrial fibrillation, neither mitral regurgitation nor severe mitral regurgitation, appears to independently be associated with a different risk of ischemic stroke or thromboembolic events. The perceived protective effect of mitral regurgitation against the risk of thromboembolic events is not relevant in atrial fibrillation when using a contemporary risk score scheme, the CHA2DS2-VASc score.                                                 In our final research paper, Jack Z. Li and associates noted that in 2017, an aggregate of four manufacturers of devices yielded 89.6% with the DF-4 ICD implants. While DF-4 and DF-1 leads generally have comparable performance, several concerns over reduced versatility of the DF-4 have been raised. First, to downgrade an ICD with a DF-4 lead to a pacemaker, a generator change, a new right ventricular pace sense lead must be implanted. The DF-4 pin is incompatible with the IS-1 port and there is no straightforward way to bridge this gap. In contrast, the DF-1 IS-1 lead requires only capping of the DF-1 pin. Second, if an ICD with DF-4 lead has either a distal coil or a right ventricular pacing malfunction, a new lead must be implanted. Third, if a ICD with DF-4 lead has a high defibrillation threshold, management requires either a new DF-1 IS-1 lead with an adapter for a subcutaneous array, or an adapter that inserts into the DF-4 port and receives both the DF-4 lead and the DF-1 pin of the subcutaneous lead. Physicians should have the foresight to select DF-1 leads at the time of initial implant in selected circumstances, such as high possibility for elevated defibrillation threshold requiring a subcutaneous lead or array.                                                 That's it for this month! We hope that you'll find the journal to be the go-to place for everyone interested in the field. See ya next time.                                                 This program is copyright American Heart Association 2019.

Cancer.Net Podcasts
Leukemia Highlights from the 2018 American Society of Hematology, with Guillermo Garcia-Manero, MD

Cancer.Net Podcasts

Play Episode Listen Later Feb 19, 2019 15:53


ASCO: You’re listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world’s leading professional organization for doctors who care for people with cancer. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. In this podcast, Cancer.Net Associate Editor Dr. Guillermo Garcia-Manero will discuss some of the new research in leukemia and myelodysplastic syndromes, or MDS, that was presented at the 2018 American Society of Hematology Annual Meeting, held December first through fourth in San Diego, California. Dr. Garcia-Manero is the Deputy Chair of Translational Research and Professor, Department of Leukemia, at The University of Texas MD Anderson Cancer Center in Houston, Texas. He is also the Chief of the Section of Myelodysplastic Syndromes at MD Anderson Cancer Center. ASCO would like to thank Dr. Garcia-Manero for discussing this topic. Dr. Garcia-Manero: Hello, I'm Guillermo Garcia-Manero. I am 1 of the leukemia physicians at the University of Texas MD Anderson Cancer Center, where I also serve as the chief of the section of myelodysplastic syndromes. I'm happy to do this podcast today, trying to highlight a few of the studies that were presented at ASH this past December 2018. I have to start saying that this is basically mission impossible because the good news is there were so many important presentations, with active meaning for our patients, with new drugs, and that makes the selection of these 4 presentations extremely difficult. I'm going to mainly focus on presentations on myeloid malignancies, mainly MDS and AML. And I'm going to start with the first presentation. It's a very important phase III trial that was conducted all over the world, known as the MEDALIST trial. This study was, again, a phase III trial, was presented by Dr. List from the Moffitt Cancer Center, but it was a large effort, basically, countries all over the world. And the idea here was to test the activity of a compound known as luspatercept. This is a brand-new drug. This is an antibody that basically has the capacity to affect signaling of TGF-beta pathway in MDS. And the hypothesis is that by doing so, it may promote the capacity of the bone marrow to produce red cells and therefore improve or ameliorate anemia. As all of you know, anemia is a major complication of multiple disorders, in particular, myelodysplastic syndrome. So the study was a randomized study. The patient population was for a specific subset of patients with myelodysplastic syndrome that are known as patients with refractory anemia with ring sideroblasts. And these patients had received already prior therapy, mainly with a growth factor, drugs like erythropoietin. The study had what they call a 2:1 randomization, meaning that for each 3 patients, 2 got into the investigational compound, luspatercept, and 1 into placebo. This drug has already been tested on prior phase I, phase II studies and is extremely safe, and we know that we can administer this compound every 21 days. The major endpoints of the study were basically to see what was the rate of transfusion independency, and that actually is measured every 8 weeks. This is criteria that investigators in the field pick. And there were other endpoints, like 12 weeks, and then also measuring increases in hemoglobin and, importantly, of course, duration of response. This data was quite significant, and it's probably one of the first phase III trials for patients with myelodysplastic syndromes that is positive in many years. The primary endpoint, again, that was transfusion independency in the first 8 weeks, was met. So patients on the luspatercept arm had an improvement in their transfusions. The [inaudible] was close to 38% versus 13% for those patients who were on placebo, and this was highly significant. Most importantly, when the investigators looked at the duration of response, this was also significantly in favor for those patients that received luspatercept. So, in other words, not only was there higher response rate with this new agent, the response is also longer. So that is very important. And then, as I mentioned earlier, in general, these compounds are extremely well tolerated without a major, significant toxicity issue. So we are excited about these results because it may be—of course, this drug is not yet approved by the FDA. But the expectation will be that this would be an excellent compound for this first subset of patients with myelodysplastic syndrome. But there is already an ongoing phase III trial for patients with MDS, low risk, that have not received any prior therapy. So we're moving into front line with this particular compound. And there was also some very interesting data in patients with thalassemia, that was also positive. So it has implications beyond myelodysplastic syndrome. I am not sure what the future development of this compound will be, but I think it's going to have multiple applications in solid tumor malignancies, potentially as an adjunct in patients receiving induction chemotherapy for acute leukemia. And there are also some ongoing clinical trials in myelofibrosis. So that was very exciting. The second study that I would like to highlight is a study known as TELESTO, and this is basically a clinical trial where patients with low-risk MDS were randomized to received iron chelation with a drug known as deferasirox or not. Why this is important is because, over a decade ago, this compound, deferasirox, was approved for patients with a number of disorders, including myelodysplastic syndrome, that had evidence of iron overload. So in myelodysplastic syndrome, because of the need for red cell transfusions, it is not uncommon that patients will accumulate iron. And that in itself can result in complications for the patients, such as liver damage, heart damage, etc. So, despite the fact that this drug was approved, the way it was approved was on non-randomized clinical trials. So we never actually knew for a decade whether there was true benefit to this compound or intervention in patients with lower risk disease and anemia with iron overload. And why this is important to know is because this drug, although it's an oral compound, it can have some side effects that can be significant, and there's also a cost issue with this approach for our patients. The study was actually designed many years ago. I was part of the group that designed this clinical trial. And originally, it was designed to test whether iron chelation was going to result or not only in improvement in overall survival. And the original design was going to involve, I believe, over 800 patients. When the study was opened, it became clear that this was not going to be feasible because this drug had already been kind of embraced by the community as a standard of care. So the study actually was then modified with the advice of the authorities, mainly the FDA, and it became this study where the main endpoint was event-free survival. Similar to the study that I discussed earlier, this had 2:1 randomization, and patients were randomized into deferasirox or placebo. And because these are tablets, that was quite easy to do. Again, the main objective was to evaluate event-free survival, but we were also interested in looking at overall survival and other biomarkers like ferritin levels, [inflammatory?] responses, and some of the comorbidities that are associated with iron chelation. The study, again, was positive. And what these investigators—and this data was presented by Dr. Angelucci, who is from Italy—clearly indicated that there was a longer event-free survival for those patients that were treated with the iron chelation drug deferasirox compared to those that do not. And, indeed, actually, the risk reduction was almost 37%. So this data is important because it establishes a potential role for iron chelation in our patients. Now, there is a major limitation, of course, of this drug. That is, unfortunately, we cannot really measure or state that the overall survival benefit was clearly achieved by this compound. That said, actually, there was an improvement also in overall survival for patients treated with this compound, but the hazard ratio was significantly higher than that for event-free survival. And again, this study is likely not powerful enough to really clearly demonstrate an improvement in survival, although it clearly demonstrated this other event-free survival improvement. The other limitation of the trial is that we don't know why the event-free survival is better. That is something that is not clear from this data analysis. But the reality is that, in my mind, this is the only and probably will never be repeated randomized phase III trial of iron chelation. And I think it shows that this is associated with a clinical benefit for our patients. The next study that I would like to present is a study for patients with acute myelogenous leukemia, and this was a study presented by Dr. Maiti from Houston. And it's one of the multiple studies that looked at the addition of venetoclax to drugs like decitabine or azacitidine for patients with acute myelogenous leukemia. As many of you know, during the meeting, this new agent venetoclax, or ABT-199, was approved for patients with AML. And this was based on a number of clinical trials that had been done at multiple centers. So there were multiple presentations, but I can tell you that this was one of the most exciting topics of the ASH meeting, the addition of ABT-199, or venetoclax, to either decitabine or azacitidine for patients with AML. So venetoclax, or ABT-199, is a drug that modifies apoptosis. Basically, the idea is that enhances cell death in these leukemia cells. And data from Dr. Konopleva and other investigators have indicated that there is synergism between venetoclax and the hypomethylating agent, either azacitidine or decitabine. And there are a number of studies showing actually very high response rate with these compounds. But I highlighted this study because it looks like a different alternative schedule. Here, the investigators gave 10 days of decitabine with venetoclax for basically every day of the month, and they reported an overall response rate that was over 90%. And what I think is striking, that half of these patients with acute myelogenous leukemia achieved what we call minimal residual disease status. So they were MRD-negative with this therapy, indicating that there was eradication of the leukemia clone. The follow-up on this study was short, but the survival actually was close to over 95%. So we all believe that this very exciting data, whether you administer this with 10 days of decitabine or 5 days of decitabine or with azacitidine. And it's likely now becoming the standard of care for most patients that are receiving a hypomethylating agent for acute myelogenous leukemia. So this is extremely good news for our patients, and it will open up to multiple other combinations. And to finish, I will bring one of the last presentations in myelodysplastic syndrome. But I think that this is a topic that has also implications for other myeloid malignancies. So this is Abstract Number 465, and I had the opportunity to present this poster. So this is a study performed mostly in Houston, where we combined azacitidine with drugs that are known as immune checkpoint inhibitors, drugs like nivolumab or ipilimumab. The hypothesis for this is that it turns out that the leukemia cell or the MDS cell express molecules like PD-1, CTLA-4 on their surface. And similar to what you see in solid tumors, where these compounds are extremely effective, for instance, for melanoma and other solid tumors, it is possible that these compounds could also have activity in these myeloid diseases. So we have tested these in a clinical trial, combining these immune checkpoint inhibitors with azacitidine. And we have tested this in patients with high-risk MDS that have not received prior therapy or in patients with relapsed refractory disease that already have failed a hypomethylating agent like azacitidine. The study actually has accrued almost 100 patients, and we believe that this data is very important. So what we first found was that the combination in the front line of immune checkpoint inhibitor, such as nivo or ipilimumab with azacitidine, is associated with a very high response rate. So the overall response rate, for instance, with azacitidine-nivolumab was over 70%, and it was over 60% with AZA-ipilimumab. But that's not what I think is important from this presentation. What was important was that the duration of response, particularly in the combination of azacitidine and ipilimumab with a follow-up on this clinical trial of around 20 months—this is quite a long number—had not been reached. And we have not had data like these in any of the prior studies that we have done with doublets, for instance, with HDAC inhibitors or other compounds. Now, there is a limitation of this, that the incorporation of this immune checkpoint can be toxic. This is something that solid tumor oncologists are familiar with, but it's a little bit new for us. It can cause things like pneumonitis—this is lung inflammation—colitis, skin rash. These sometimes are difficult to treat, so this is not ready for standard-of-care type of approach. But I think it's going to be an important part of the armamentarium for our patients with myelodysplastic syndrome. So with that, I would like to conclude, perhaps, do a very quick summary. I presented to you 4, what I think, very important presentations. The first one was a new drug for MDS called luspatercept. This may be very important to treat anemia, and we are excited about future development of these compounds. The second presentation was about iron chelation in MDS. This has been an area of huge debate in our field, and this data I think supports further the use of these types of compounds for our patients with iron accumulation. Third, the data with ABT-199, or venetoclax, with decitabine in AML is really important. And I think it's now established as the standard of care for those patients not fit for chemotherapy. And finally, this data with immune checkpoint inhibitors indicates that there may be an important role for these compounds also in MDS, and other presentations at the ASH meeting in AML suggested kind of the same. And with that, I want to thank you for this opportunity and your time. ASCO: Thank you, Dr. Garcia-Manero. Learn more about leukemia and MDS at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show on Apple Podcasts or Google Play. Cancer.Net is supported by ASCO’s Conquer Cancer Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/support.

Crypto Waves: The Crypto Lark Podcast
205 Crypto Waves 291 - IOT blockchain of the future HDAC ICO Review_pd_05162018

Crypto Waves: The Crypto Lark Podcast

Play Episode Listen Later May 23, 2018 16:55


SOCIAL MEDIA LINKSTWITTER https://twitter.com/TheCryptoLark FACEBOOK https://www.facebook.com/TheCryptoLark/ TELEGRAM https://t.me/thecryptolark MINDS https://www.minds.com/register?referr... STEEMIT https://steemit.com/@larksongbird CONTACTE-mail thecryptolark@gmail.com with business or event enquiries. DISCLAIMEREverything expressed here is my opinion and not official investment advice - please do your own research before risking your own money. Thanks for watching; please like, subscribe, and share if you found this useful!

crypto waves hdac iot blockchain
FoundMyFitness
#040 Dr. Eric Verdin on Ketogenic Diet Longevity, Beta-Hydroxybutyrate & HDAC Inhibitors

FoundMyFitness

Play Episode Listen Later Dec 13, 2017 63:26


Eric M. Verdin Eric M. Verdin, M.D. is the fifth president and chief executive officer of the Buck Institute for Research on Aging and is a professor of Medicine at UCSF. Dr. Verdin's laboratory focuses on the role of epigenetic regulators in the aging process, the role of metabolism and diet in aging and on the chronic diseases of aging, including Alzheimer's, proteins that play a central role in linking caloric restriction to increased healthspan, and more recently a topic near and dear to many of you, ketogenesis. He's held faculty positions at the University of Brussels, the NIH and the Picower Institute for Medical Research.  In this episode, you'll discover: The effects of a low protein, cyclic ketogenic diet beginning in midlife (12 months of age) in male mice. The result? Increased healthspan and improved memory. Dr. Verdin explains how the cyclic ketogenic diet decreased insulin, IGF-1, and mTOR signaling and decreased fatty acid synthesis, and increased PPAR-alpha (which promotes beta-oxidation and mitochondrial biogenesis in muscle). How this diet is somewhat qualitatively similar to fasting. Some of the possible reasons why the cyclic ketogenic diet created such a striking improvement in memory even when compared to younger mice. How beta-hydroxybutyrate, which is the major circulating ketone body during fasting and nutritional ketosis, may, in addition to being an energy source, regulate inflammation and gene expression by acting as a signaling molecule by inhibiting what are known as class 1 histone deacetylases (HDACs). How this inhibition of class 1 HDACs leads to the increased expression of notorious longevity gene Foxo3, which may help explain why mice given an exogenous beta-hydroxybutyrate ester had lower markers of inflammation and oxidative damage, which are physiological contributors to the aging process. The role of the nicotinamide adenine dinucleotide (NAD+) in the aging process and how replacing declining levels (or preventing them from declining in the first place) may prove to be an important anti-aging strategy. Some of the reasons why NAD+ might be declining with age, its role in DNA damage repair via an enzyme known as PARP, and what the literature says about the NAD+ precursor nicotinamide riboside. How a special class of enzymes called sirtuins, also known to be activated by caloric restriction and caloric restriction mimetic resveratrol, is tightly correlated with the level of NAD+ and how this "energetic currency" rises in response to fasting. The role of the sirtuin enzymes in regulating mitochondrial function, neuronal functions, stem cell rejuvenation and why they may be important in delaying the aging process.   If you're interested in learning more, you can read the full show notes here: https://www.foundmyfitness.com/episodes/69 Join over 300,000 people and get the latest distilled information on ketogenic diet & longevity straight to your inbox weekly: https://www.foundmyfitness.com/newsletter Become a FoundMyFitness premium member to get access to exclusive episodes, emails, live Q+A's with Rhonda and more: https://www.foundmyfitness.com/crowdsponsor

FoundMyFitness
Dr. Eric Verdin on Ketogenic Diet Longevity, Beta-Hydroxybutyrate & HDAC Inhibitors

FoundMyFitness

Play Episode Listen Later Dec 13, 2017 63:26


Eric M. Verdin, M.D. is the fifth president and chief executive officer of the Buck Institute for Research on Aging and is a professor of Medicine at UCSF. Dr. Verdin's laboratory focuses on the role of epigenetic regulators in the aging process, the role of metabolism and diet in aging and on the chronic diseases of aging, including Alzheimer’s, proteins that play a central role in linking caloric restriction to increased healthspan, and more recently a topic near and dear to many of you, ketogenesis. He's held faculty positions at the University of Brussels, the NIH and the Picower Institute for Medical Research. In this episode, we discuss... The effects of a low protein, cyclic ketogenic diet beginning in midlife (12 months of age) in male mice. The result? Increased healthspan and improved memory. Dr. Verdin explains how the cyclic ketogenic diet decreased insulin, IGF-1, and mTOR signaling and decreased fatty acid synthesis, and increased PPAR-alpha (which promotes beta-oxidation and mitochondrial biogenesis in muscle). How this diet is somewhat qualitatively similar to fasting. Some of the possible reasons why the cyclic ketogenic diet created such a striking improvement in memory even when compared to younger mice. How beta-hydroxybutyrate, which is the major circulating ketone body during fasting and nutritional ketosis, may, in addition to being an energy source, regulate inflammation and gene expression by acting as a signaling molecule by inhibiting what are known as class 1 histone deacetylases (HDACs). How this inhibition of class 1 HDACs leads to the increased expression of notorious longevity gene Foxo3, which may help explain why mice given an exogenous beta-hydroxybutyrate ester had lower markers of inflammation and oxidative damage, which are physiological contributors to the aging process. The role of the nicotinamide adenine dinucleotide (NAD+) in the aging process and how replacing declining levels (or preventing them from declining in the first place) may prove to be an important anti-aging strategy. Some of the reasons why NAD+ might be declining with age, its role in DNA damage repair via an enzyme known as PARP, and what the literature says about the NAD+ precursor nicotinamide riboside. How a special class of enzymes called sirtuins, also known to be activated by caloric restriction and caloric restriction mimetic resveratrol, is tightly correlated with the level of NAD+ and how this "energetic currency" rises in response to fasting. The role of the sirtuin enzymes in regulating mitochondrial function, neuronal functions, stem cell rejuvenation and why they may be important in delaying the aging process. Grab the full show notes, timeline & glossary from the episode page now. Did you enjoy this podcast? It was brought to you by people like you! Click here to visit our crowdsponsor page where you can learn more about how you can support the podcast for as little or as much as you like.

Nourish Balance Thrive
A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice

Nourish Balance Thrive

Play Episode Listen Later Oct 27, 2017 56:10


Our Scientific Director Megan Hall (née Roberts) recently had some of the work from her Master’s degree published in the journal Cell Metabolism, which is seriously impressive. The paper appeared on Science Daily, and generally caused a bit of a stir in the low carb community. As we have direct access to the horse’s mouth, I’ve asked Megan to join me in this episode of the podcast to summarise the findings and give some thoughts on how it might relate to human health. Here’s the outline of this interview with Megan Hall: [00:00:55] Mastermind Talks. [00:01:47] The lead up to the study. [00:02:17] Time-restricted feeding. [00:02:38] Are they eating longer because of a less crappy diet? [00:04:21] Calorie restriction was the focus of Megan's lab. [00:05:27] Stephen Phinney, MD, PhD and Jon Ramsey, PhD. [00:06:13] Study design. [00:07:36] High-fat diets in rodents. [00:08:39] Two arms: longevity and healthspan. [00:10:55] Grip strength in a rodent. [00:11:40] Novel object test. [00:12:55] fMRI for body composition using the EchoMRI. [00:13:13] The results. Study: Roberts, Megan N., et al. "A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice." Cell Metabolism 26.3 (2017): 539-546. [00:15:40] Valter Longo, PhD and USC Longevity Institute. Studies: Brandhorst, Sebastian, et al. "A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan." Cell metabolism 22.1 (2015): 86-99 and Wei, Min, et al. "Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease." Science translational medicine 9.377 (2017): eaai8700. [00:16:27] Study: Sleiman, Sama F., et al. "Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate." Elife 5 (2016): e15092. [00:17:34] Motor function and coordination. [00:18:58] The importance of preserving type IIA muscle fibers. Podcast: The Most Reliable Way to Lose Weight with Dr Tommy Wood and The High-Performance Athlete with Drs Tommy Wood and Andy Galpin. [00:19:18] Study: Zou, Xiaoting, et al. "Acetoacetate accelerates muscle regeneration and ameliorates muscular dystrophy in mice." Journal of Biological Chemistry291.5 (2016): 2181-2195. [00:20:04] Exercise performance. [00:21:13] Physiologic insulin resistance. [00:22:06] Podcast: Real Food for Gestational Diabetes with Lily Nichols. [00:24:21] Keto vs low-carb. [00:27:05] Studies: β-Hydroxybutyrate: A Signaling Metabolite and Ketone bodies as signalling metabolites. [00:27:49] YouTube: Histone deacetylation and inhibition. [00:29:19] I mentioned the Khan Academy, but in the end Megan liked these videos on HDAC inhibitors and cancer and Histone deacetylation and inhibition (also mentions p53!). [00:30:49] FOXO proteins. [00:31:30] Lysine residues. [00:31:48] Mn SOD. [00:32:10] mTOR, Dr. Ron Rosedale. [00:34:04] REDD1 protein. [00:34:32] P53 protein, metformin. [00:35:30] Less cancer in KD mice. [00:36:00] Warburg Effect. [00:36:21] Replicability. [00:36:57] Study: Newman, John C., et al. "Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice." Cell Metabolism 26.3 (2017): 547-557. [00:38:28] Press coverage of the study, “Eat Fat, Live Longer” at Sciencedaily.com. [00:41:01] Soybean oil in rodent diets. [00:41:34] Sex-dependent differences. [00:43:23] Takeaways. [00:44:21] Dogma displacement inertia. [00:45:19] Exogenous ketones. Study: Stubbs, Brianna Jane, et al. "On the metabolism of exogenous ketones in humans." Frontiers in Physiology 8 (2017): 848. [00:46:34] What does this mean for humans? [00:47:42] Weightloss. [00:48:36] Micromanaging the details. [00:50:33] Who are you and what are your goals -- Robb Wolf. Podcast: Wired to Eat with Robb Wolf. [00:51:55] Nourish Balance Thrive Highlights Series sign up. [00:53:11] Megan's purpose. [00:53:39] Book: Find Your Why: A Practical Guide for Discovering Purpose for You and Your Team by Simon Sinek and David Mead.

WIN 2017
Synthetic lethality as a basis to select drug combinations

WIN 2017

Play Episode Listen Later Jul 31, 2017 8:32


Prof Bernards speaks with ecancer at WIN 2017 about a staggered '1-2 punch' treatment schedule of cancer therapies, built on synthetic lethality. In the case of BRAF melanoma, he describes the acquired MEK-resistance of tumour cells following initial treatments exposes vulnerability to histone deacetylases (HDAC) which generate a toxic level of reactive oxygen species (ROS) in cancer cells. Prof Bernards outlines how intermittent dosing cycles with short HDAC therapies 'chasers' may prevent further resistance development and extend patient survival. He goes on to explain the best treatment window for selectively targeting cancer cells follows an induced senescence, with animal models currently in development.

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 06/06
The role of FKBP5 in transcriptional regulation and in shaping cellular pathways of psychopharmaca action

Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 06/06

Play Episode Listen Later Mar 10, 2016


FK506 binding protein 5 (FKBP5) has been linked to stress related diseases and treatment response in depression (Binder et al., 2004). The corresponding protein FKBP51 was first identified as co-chaperone of HSP90 in a complex with steroid hormone receptors, where it diminishes hormone affinity and nuclear translocation efficiency of the receptors (Pratt and Toft, 1997; Wochnik et al., 2005). With FKBP5 transcription being induced by glucocorticoid signalling, an ultra-short feedback loop is provided for regulation and termination of GR activity. Dysregulation of this ultra-short feedback loop interferes with the stress hormone regulation and likely contributes to the association of FKBP5 with stress-related psychiatric disorders. Recently, important actions of FKBP51 beyond glucocorticoid signalling have been characterised in shaping the posttranslational regulation of certain molecular pathways in response to treatment with particular psychopharmaca (Gassen et al., 2014, 2015). As a contribution to elucidating the role of FKBP5 in stress related diseases, a two-sided approach was taken in this study by analysing the role of FKBP5 in regulation of transcription and in calibrating the responsiveness of these pathways to psychopharmacological treatment. To elucidate the transcriptional effects of FKBP5 in an unbiased approach, the expression profile of mice with deleted FKBP5 and their litter mates with functional FKBP5 were compared. A marked difference in glyoxalase-1 (GLO1) transcription was observed with higher GLO1 transcription in mice with deleted FKBP5, which was reflected by about two-fold more GLO1 protein in these mice. The efforts in deciphering the role of FKBP5 in elevation of GLO1 expression led to the identification of a duplication of the GLO1 gene inherent to mice with deleted FKBP5; this likely explains the enhanced GLO1 expression in these mice. This observation exemplifies the flanking gene problem and is a note of caution for interpreting data from conventionally generated knock-out mice. Overall, deletion of FKBP5 did not markedly change gene expression. In the second part of this thesis, the molecular effects of psychopharmacologic drugs were profiled for their dependency on FKBP51 function to modulate intracellular pathways relevant for treatment outcome in a cellular FKBP5 knockout model. For this purpose, psychopharmaca from the classes of SSRIs, SSNRIs, TCAs, atypical antidepressants, mood stabilisers, and NMDA receptor antagonists were analysed. In addition to GSK3β and AKT, which were reported to interact with and be targeted by FKBP51 recently (Gassen et al., 2015; Pei et al., 2009), ERK was identified as a novel kinase interacting with and being targeted by FKBP51 in this work. With GSK3β, AKT, and ERK, three major kinases were observed to be regulated by psychopharmaca. The effects were not homogeneous across all psychopharmaca and only loosely followed drug classes. Moreover, regulation of these kinases as well as their downstream targets was non-uniformly influenced by FKBP51. With FKBP51 being a stress induced gene, this transcriptional mechanism efficiently links the stress response to the regulation of the targets analysed in this work. Moreover, markers of autophagy, a cellular degradation process which has been linked to neurotransmission, were detected to be regulated by valproic acid (VPA), a mood stabiliser with HDAC inhibitory activity. VPA, as well as a second HDAC inhibitor butyric acid (BUT) enhanced the transcription of late and delayed autophagy markers controlled by FOXO3 signalling. Considering the versatile action of FKBP51 on targets analysed in this work, the list of proteins modulated by FKBP5 seems by far not complete. The diversity of effects evoked by different psychopharmaca hints to superimposed molecular effects underlying treatment outcome. Better understanding of pathway responsiveness could yield molecular markers for personalised medication that could be utilised to improve treatment outcome in stress related psychiatric diseases.

2016 Genitourinary Cancers Symposium
Entinostat and high-dose Interleukin 2 in renal cell carcinoma patients

2016 Genitourinary Cancers Symposium

Play Episode Listen Later Jan 28, 2016 3:44


Prof Pili talks to ecancertv at ASCO GU 2016, about the results from the phase II study CTEP#7870: treating renal cell carcinoma patients with entinostat and high-dose interleukin 2 (IL-2). Immunosuppressive factors such as regulatory T cells and myeloid-derived suppressive cells limit the efficacy of immunotherapies. Histone deacetylase (HDAC) inhibitors have been shown to have immunomodulatory effects which can be harnessed to improve treatment efficacy. The results from this phase I/II suggest that entinostat may increase the therapeutic effect of high dose IL-2 by modulating immunosuppressive cells.

15th International Myeloma Workshop
What is the potential for using monoclonal antibodies in multiple myeloma?

15th International Myeloma Workshop

Play Episode Listen Later Nov 1, 2015 17:59


Prof Lonial (Emory University, Atlanta, USA) chairs a discussion for ecancertv at the 15th International Myeloma Workshop with Prof Sonneveld (University Hospital Rotterdam, Rotterdam, Netherlands) and Prof San Miguel (University Hospital, Salamanca, Spain) about the interesting data on the use of monoclonal antibodies in combination with lenalidomide or bortezomib and their possible role in maintenance therapy for multiple myeloma. They start by talking about the use of monoclonal antibodies as single agent therapy before looking at their use in combination with other treatments and some of the practicalities of using them clinically. During the discussion they also look at the potential and pitfalls for proteasome inhibitors, such as carflizomib and newer oral agents including ixazomib, and comment on the histone deacetylase (HDAC) inhibitors’ potential in relapsed and refractory disease. They also provide comment on the use of genomics and minimal residual disease (MRD) assessment. MRD could be important for prognosis, Prof Sonneveld suggests. Finally they talk about the new definition and revised international staging system for multiple myeloma.

This Week in Microbiology
TWiM #71: Colon cancer’s little shop of horrors

This Week in Microbiology

Play Episode Listen Later Jan 22, 2014 78:38


Vincent, Michael, and Michele explain how the gut microbiome modulates colon tumorigenesis, and regulation of intestinal macrophage function by the microbial metabolite butyrate.

Myeloma Crowd Radio
HealthTree Podcast for Multiple Myeloma: Dr. Shaji Kumar, Mayo Clinic

Myeloma Crowd Radio

Play Episode Listen Later Sep 27, 2013 62:00


Listen to Dr. Shaji Kumar, MD of the Mayo Clinic in Rochester as he describes how all myeloma was once MGUS, how new inhibitors (like CDK and HDAC) work, and his study of how cytogenetics impacts disease progression. 

Myeloma Crowd Radio
mPatient Myeloma Radio: Dr. Shaji Kumar, Mayo Clinic

Myeloma Crowd Radio

Play Episode Listen Later Sep 27, 2013 62:00


Listen to Dr. Shaji Kumar, MD of the Mayo Clinic in Rochester as he describes how all myeloma was once MGUS, how new inhibitors (like CDK and HDAC) work, and his study of how cytogenetics impacts disease progression. 

2012 San Antonio Breast Cancer Symposium (SABCS)
HDAC inhibition sensitises breast cancer cells to PARP inhibition: Dr Kapil Bhalla - University of Kansas Cancer Center

2012 San Antonio Breast Cancer Symposium (SABCS)

Play Episode Listen Later Dec 18, 2012 6:27


Exposure to histone deacetylase (HDAC) inhibitors sensitise triple-negative breast cancer cells to treatment with a PARP inhibitor and cisplatin, according to preclinical research presented at the 35th San Antonio Breast Cancer Symposium. Dr Kapil Bhalla explains how HDAC inhibition indirectly causes DNA damage and impairs the cells ability to repair damaged DNA. These effects mimic those in BRCA1 mutated breast cancer cells and cause cells to become more susceptible to PARP inhibitor and cisplatin therapy.

2012 San Antonio Breast Cancer Symposium (SABCS)
HDAC inhibitors sensitise triple-negative breast cancer cells to PARP inhibition and cisplatin treatment: Dr Kapil Bhalla

2012 San Antonio Breast Cancer Symposium (SABCS)

Play Episode Listen Later Dec 18, 2012 4:32


In-vitro exposure to an HDAC inhibitor indirectly impaired the ability of triple-negative breast cancer cells to repair damaged DNA and sensitised the cells to treatment with two therapies that have clinical activity in some patients with breast cancer — a PARP inhibitor and cisplatin, according to data presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium.

Molecular and Cellular Biology
S. Sonda - A single HDAC regulates gene expression and stage differentiation in the minimized protozoan Giardia lamblia

Molecular and Cellular Biology

Play Episode Listen Later Mar 19, 2010 38:35


Sabrina Sonda, Institute of Parasitology, University of Zurich, Zurich, SWITZERLAND speaks on "A single HDAC regulates gene expression and stage differentiation in the minimized protozoan Giardia lamblia". This seminar has been recorded by ICGEB Trieste

KUCI: Bio Frontiers
Interview with Dr. Marcelo Wood

KUCI: Bio Frontiers

Play Episode Listen Later Sep 3, 2007


Dr. Marcelo Wood, from the Department of Neurobiology and Behavior, will share his research on how HDAC inhibitors can enhance memory and potentially treat things such as Rubinstein-Taybi Syndrome and Huntingon's disease.