Podcasts about STAT3

In this research paper, researchers demonstrate a promising new treatment option for refractory metastatic gastrointestinal cancers using a combination of two FDA-approved drugs. Researchers Jun Zhang, Lanlan Zhou, Shuai Zhao, and Wafik S. El-Deiry from Fox Chase Cancer Center and Brown University explore the potential of combining TAS102 (trifluridine/tipiracil) and regorafenib as a treatment option for gastrointestinal (GI) cancers. Their research paper, published in Oncotarget's Volume 15 on July 2, 2024, is entitled, “Regorafenib synergizes with TAS102 against multiple gastrointestinal cancers and overcomes cancer stemness, trifluridine-induced angiogenesis, ERK1/2 and STAT3 signaling regardless of KRAS or BRAF mutational status.” The Study The combination of two FDA-approved drugs, TAS102 and regorafenib, has shown promising results in preclinical studies. TAS102 is an oral formulation consisting of trifluridine (FTD) and tipiracil hydrochloride (TPI). It has been approved by the US FDA for the treatment of refractory metastatic colorectal cancer and metastatic gastric cancer. Regorafenib is a multi-target tyrosine kinase inhibitor that inhibits tumor angiogenesis and cell proliferation and is approved for the treatment of gastrointestinal cancers. Recent studies have shown that TAS102, in combination with regorafenib, can lead to improved survival and restrict tumor progression. The combination therapy has been found effective in multiple gastrointestinal cancer cell lines, including colorectal, gastric, and pancreatic cancers. Full blog - https://www.oncotarget.org/2024/08/09/combining-regorafenib-and-tas102-to-target-gastrointestinal-cancers-and-overcome-cancer-stemness/ Paper DOI - https://doi.org/10.18632/oncotarget.28602 Correspondence to - Wafik S. El-Deiry - wafik@brown.edu Video short - https://www.youtube.com/watch?v=tuEmJTkyyGQ Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28602 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, TAS102, regorafenib, ERK1/2, angiogenesis, microvessel density 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

Join ASGCT and the Molecular Therapy family of journals for a conversation between Drs. Paloma Giangrande and Marcin Kortylewski. They discuss a recent article published in Molecular Therapy Nucleic Acids by Dr. Kortylewski and colleagues titled "Oligo-PROTAC strategy for cell-selective and targeted degradation of activated STAT3." If you enjoy today's conversation, you'll also enjoy the upcoming ASGCT Policy Summit in Washington, DC, September 23-24.  This can't-miss event brings together policymakers and gene and cell therapy experts, including FDA leaders Julie Tierney and Dr. Nicole Verdun, to discuss the latest policies impacting this rapidly evolving field.  Register now at https://www.asgct.org/PolicySummit for invaluable insights on navigating the regulatory landscape.  In This Episode: Dr. Paloma GiangrandeEditor-in-Chief of Molecular Therapy Nucleic Acids and Chief Technology Officer at Eleven Therapeutics Dr. Marcin KortylewskiProfessor, Department of Immuno-Oncology at City of Hope 'Electric Dreams' by Scott Buckley - released under CC-BY 4.0.www.scottbuckley.com.auShow your support for ASGCT!: https://asgct.org/membership/donateSee omnystudio.com/listener for privacy information.

BUFFALO, NY- July 8, 2024 – A new research paper was published in Oncotarget's Volume 15 on July 2, 2024, entitled, “Regorafenib synergizes with TAS102 against multiple gastrointestinal cancers and overcomes cancer stemness, trifluridine-induced angiogenesis, ERK1/2 and STAT3 signaling regardless of KRAS or BRAF mutational status.” Single-agent TAS102 (trifluridine/tipiracil) and regorafenib are FDA-approved treatments for metastatic colorectal cancer (mCRC). Researchers previously reported that regorafenib combined with a fluoropyrimidine can delay disease progression in clinical case reports of multidrug-resistant mCRC patients. In this new study, researchers Jun Zhang, Lanlan Zhou, Shuai Zhao, and Wafik S. El-Deiry from Fox Chase Cancer Center and Brown University hypothesized that the combination of TAS102 and regorafenib may be active in CRC and other gastrointestinal (GI) cancers and may in the future provide a treatment option for patients with advanced GI cancer. “We investigated the therapeutic effect of TAS102 in combination with regorafenib in preclinical studies employing cell culture, colonosphere assays that enrich for cancer stem cells, and in vivo.” TAS102 in combination with regorafenib has synergistic activity against multiple GI cancers in vitro including colorectal and gastric cancer, but not liver cancer cells. TAS102 inhibits colonosphere formation and this effect is potentiated by regorafenib. In vivo anti-tumor effects of TAS102 plus regorafenib appear to be due to anti-proliferative effects, necrosis and angiogenesis inhibition. Growth inhibition by TAS102 plus regorafenib occurs in xenografted tumors regardless of p53, KRAS or BRAF mutations, although more potent tumor suppression was observed with wild-type p53. Regorafenib significantly inhibits TAS102-induced angiogenesis and microvessel density in xenografted tumors, as well inhibits TAS102-induced ERK1/2 activation regardless of RAS or BRAF status in vivo. TAS102 plus regorafenib is a synergistic drug combination in preclinical models of GI cancer, with regorafenib suppressing TAS102-induced increase in microvessel density and p-ERK as contributing mechanisms. “The TAS102 plus regorafenib drug combination may be further tested in gastric and other GI cancers.” DOI - https://doi.org/10.18632/oncotarget.28602 Correspondence to - Wafik S. El-Deiry - wafik@brown.edu Video short - https://www.youtube.com/watch?v=tuEmJTkyyGQ Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28602 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, TAS102, regorafenib, ERK1/2, angiogenesis, microvessel density 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

BUFFALO, NY- May 22, 2024 – A new research paper was published in Oncotarget's Volume 15 on May 17, 2024, entitled, “GZ17-6.02 kills PDX isolates of uveal melanoma.” In this new study, researchers Laurence Booth, Jane L. Roberts, Ivan Spasojevic, Kaitlyn C. Baker, Andrew Poklepovic, Cameron West, John M. Kirkwood, and Paul Dent from Virginia Commonwealth University, Duke University School of Medicine, Genzada Pharmaceuticals, Texas Tech University Health Sciences Center, and University of Pittsburgh Cancer Institute defined the biology of GZ17-6.02 in UM cells and in parallel determined its interaction with irreversible ERBB inhibitors (afatinib, neratinib) and with the cytotoxic agent doxorubicin. “GZ17-6.02 is a novel compound, containing the synthetically manufactured components: curcumin, harmine and isovanillin and has undergone phase I safety evaluation in cancer patients (NCT03775525).” GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15% reduction in tumor mass for 5 months at this dose. Studies in this manuscript have defined the biology of GZ17-6.02 in PDX isolates of uveal melanoma cells. GZ17-6.02 killed uveal melanoma cells through multiple convergent signals including enhanced ATM-AMPK-mTORC1 activity, inactivation of YAP/TAZ and inactivation of eIF2α. GZ17-6.02 significantly enhanced the expression of BAP1, predictive to reduce metastasis, and reduced the levels of ERBB family RTKs, predicted to reduce growth. GZ17-6.02 interacted with doxorubicin or ERBB family inhibitors to significantly enhance tumor cell killing which was associated with greater levels of autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5 or eIF2α were more protective than knock down of ATM, AMPKα, CD95 or FADD, however, over-expression of FLIP-s provided greater protection compared to knock down of CD95 or FADD. Expression of activated forms of mTOR and STAT3 significantly reduced tumor cell killing. GZ17-6.02 reduced the expression of PD-L1 in uveal melanoma cells to a similar extent as observed in cutaneous melanoma cells whereas it was less effective at enhancing the levels of MHCA. The components of GZ17-6.02 were detected in tumors using a syngeneic tumor model. “Our data support future testing GZ17-6.02 in uveal melanoma as a single agent, in combination with ERBB family inhibitors, in combination with cytotoxic drugs, or with an anti-PD1 immunotherapy.” DOI - https://doi.org/10.18632/oncotarget.28586 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.28586 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, autophagy, ER stress, GZ17-6.02, doxorubicin, afatinib, neratinib 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

BUFFALO, NY- October 9, 2023 – A new editorial perspective was published in Oncotarget's Volume 14 on October 4, 2023, entitled, “STAT3 as a biologically relevant target in H3K27M-mutant diffuse midline glioma.” Pediatric H3K27M-mutant diffuse midline gliomas (DMGs), including those formerly classified as diffuse intrinsic pontine gliomas (DIPG), are uniformly lethal central nervous system malignancies. Children diagnosed with these tumors have an extremely poor prognosis, with a median survival of approximately 12 months. The current standard of care for DMG includes possible biopsy for diagnostic confirmation and a 6-week course of palliative radiation. Despite enormous effort toward the development of novel therapeutics in DMG, chemotherapy remains ineffective in this disease. “Indeed, over 100 clinical trials for chemotherapeutics in DMG have failed to show therapeutic benefit [5].” In their new editorial perspective, researchers Jacob B. Anderson, Samantha M. Bouchal, Liang Zhang, and David J. Daniels from the Mayo Clinic discussed the currently available literature and their recent study on the Signal Transducer and Activator of Transcription (STAT) as a biologically relevant therapeutic target in H3K27M-mutant DMGs. In their recently published manuscript, the lab performed a screen of drugs currently in clinical use or clinical trials for efficacy against a library of H3K27Mmutant and H3-wildtype patient-derived cell lines. The results of this drug screen identified the STAT3 signaling pathway as a novel target in DMG. “Until recently, however, STAT3 was not a druggable target.” DOI - https://doi.org/10.18632/oncotarget.28516 Correspondence to - David J. Daniels - daniels.david@mayo.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28516 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, H3K27M, DMG, DIPG, midline glioma, STAT3 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: SoundCloud - https://soundcloud.com/oncotarget 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/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

References Cells. 2022 Mar; 11(6): 997. Nat Cell Biol. 2019 Mar; 21(3): 397–407. Rheumatology (Oxford). 2023 Jul; 62(7):2611–2620 --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support

Drs. Vamsi Velcheti, Taofeek Owonikoko, and Janakiraman Subramanian discuss their experiences navigating the cancer drug shortage in the United States, the impact on patients and clinical trial enrollment, lessons learned, and proactive strategies to mitigate future crises. TRANSCRIPT  Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I'm a professor of medicine and director of thoracic oncology at the Perlmutter Cancer Center at NYU Langone. On today's episode, we'll be discussing the impact of the shortage of cancer chemotherapy drugs across the United States. This has been affecting several thousands of patients with adult and pediatric cancers and hampering enrollment in clinical trials. Among the shortages are very commonly used drugs like cisplatin, carboplatin, methotrexate, and fludarabine. Some of these shortages have persisted since the time of the pandemic in 2020.   So today, to discuss this really troubling scenario, I have two outstanding colleagues, Dr. Janakiraman Subramanian, the director of thoracic oncology at Inova Schar Cancer Institute in Virginia, and Dr. Taofeek Owonikoko, a professor of medicine and the chief of the Division of Hematology and Oncology at the University of Pittsburgh Hillman Cancer Center in Pittsburgh.   Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available at asco.org/DNpod.  So, a recent survey by the NCCN found that 90% of the nation's largest cancer centers have experienced a shortage in carboplatin, and 70% of the centers have reported a shortage in cisplatin. These are platinum-based chemotherapies we use frequently in patients with cancer, and these are often curative intent treatments for several cancers, and these are used in several tumor types, both solid tumors and hematologic malignancies. So, the scale of the problem is immense.   Dr. Owonikoko, I'd like to hear your take on this situation and how are you dealing with this at the UPMC Cancer Center.  Dr. Taofeek Owonikoko: Yeah, thank you, Dr. Velcheti, and happy to be part of this panel. As you rightly surmised, the chemotherapy drug shortage is what we've all experienced across the length and breadth of the United States. Our cancer center here in Pittsburgh is not an exception. We've had to be proactive as well as think outside the box to be able to manage the challenge. Just like every other cancer center across the country, maybe to varying degrees, we've had to look at patients in need of chemotherapy with these standard-of-care agents such as cisplatin or carboplatin, and to some degree docetaxel, during this past episode of drug shortage that we all went through. And while we did not have to, fortunately, cancel any patient treatment, we all went through it with bated breath; not sure of where the next batch of chemotherapy drugs will come through, but I would say in the past couple of weeks, we've actually seen some improvement in drug availability.   But before then, we've had to have contingency plans where, on a weekly basis, we review our patient list and the drug regimens that they're going to need, and must make sure that we have enough drug on hand for those patients. And in situations where we thought we might not have enough drug; we also had a plan to use alternative regimens. We were proactive in having guiding principles that are consistent with ASCO's recommendations in terms of quality care delivery for cancer patients. So, I'm sure that this is more or less the same approach adopted by other leading cancer centers across the country.   Dr. Vamsi Velcheti: Thank you, Dr. Owonikoko. And Dr. Subramanian, you're in a community setting, a large cancer center that serves a lot of patients in the state of Virginia. So, what is the scale of the problem at your institution and how are you handling it?   Dr. Janakiraman Subramanian: First of all, Dr. Velcheti, thanks for having me here on this panel. And as you rightly said, this is a significant problem, and it is across the country like Dr. Owonikoko said. And as medical oncologists, we are not always thinking of drug shortages. Our focus is on taking care of our patients. So, this is one more issue that we need to keep in mind now as we manage our patients with cancer. When this shortage started, the biggest problem, as you know, was when we became aware of this was primarily in cisplatin and we had some of our patients who were getting curative treatment and we had to make a decision - can they get cisplatin or can they get carboplatin. And one of the things we did was to have an ethics committee that will review each patient that is being planned to receive cisplatin-based chemotherapy and come to a decision on how best we can support them.   The template for some of this was based upon some of the triage mechanisms we used during COVID, as well as the ASCO guideline document for managing this chemotherapy shortage, which was one of the blueprints we used. And they have reviewed all cases, all patients that are being planned for cisplatin or carboplatin for that matter, and we come to a decision based on that. And we also have another committee that constantly monitors drug availability on a weekly basis and tries to forecast where the next problem would be as we take care of our patients.   And particularly as a lung cancer doctor, we've had situations where we had to use carboplatin instead of cisplatin and even we also have carboplatin shortage. And so, the committee usually approves two cycles at a time, but thankfully so far we have not had a situation where we could not offer our patients the chemotherapy treatment. But we are very carefully monitoring the situation, hoping that this will improve.   The other aspect of the shortage has been in 5FU. A lot of our GI colleagues; I treat esophageal cancer patients as well, where we've had to forego the bolus 5FU and have a 10% reduction on all 5FU infusions. And we've been using some of that dose reduction to ensure that we can have 5FU available for all our patients. And that's how we've been trying to manage this shortage situation here at Inova Schar.   Dr. Vamsi Velcheti: Dr. Subramanian and Dr. Owonikoko, we are oncologists, we are treating patients, and the toughest part really is telling a patient that we don't have access to certain drugs and we have to switch treatments to perhaps another treatment regimen that may be suboptimal. And it's always a very anxiety-provoking discussion, and especially for patients with metastatic cancer, they're already under a lot of stress and it's a really difficult conversation. How do you handle that, Dr. Owonikoko?  Dr. Taofeek Owonikoko: That's a conversation we all hope we don't have to have. And fortunately, with this current crisis, I've actually not had such misfortune of having to inform a patient that we don't have drugs to treat them or that we have to switch to something inferior. But conceptually, it's possible that could have happened and that would have been very difficult. But the one thing that we did, though, as part of our mitigation strategy was actually to inform the patient ahead of time because the way we handled this was to look at our inventory on a week-by-week basis. And if there are patients where we felt maybe they will be coming in towards the end of the week and we may not have enough drugs for them, to let them know the possibility exists that we might have to switch them to something different. While we did not have to do that for any patient, yes, there are patients that we had to give that heads up to, to say, “We're having this shortage. We're doing everything we can to make sure it's available. But just in case it's not available…” I think what is most important for most patients is to be aware of that decision ahead of time, to be able to process it, and to be transparent.   The other challenge that we face was, if you have to choose between patients, what should be your guiding principles as to who gets the drug and who doesn't get it? I think it's very easy for all of us to say, “Oh, if it's curative intent, we do it. If it's not curative intent, we don't do it.” It's a little more complicated than that because if we put the equity hat on, curative intent doesn't actually mean that that life is more valuable than somebody who cannot be cured. And this is where really, I think having people with expertise in ethics of care delivery and disaster management will be very important for us to proactively anticipate that, should this become a recurrent problem in the future that we actually have a well-vetted approach, just like we did during COVID where you have to ration resources that we have those people with expertise to help us as oncologists because not all of us, at least personally I can speak for myself, that is not my area of expertise and comfort.  Dr. Vamsi Velcheti: Excellent points. Dr. Subramanian, anything to add?  Dr. Janakiraman Subramanian: Oh, absolutely. I echo what Dr. Owonikoko said. These are conversations that we would like to hopefully never have with our patients. But this is a crisis that we are facing now. And personally, I can tell you two situations where we ran into this problem. But overall, though, we never had to stop a treatment or cancel a treatment for our patient. In the first situation, we had a young man with a rare germ cell tumor in the hospital for whom cisplatin was key. He was already in the ICU and sometimes the treatment start dates are not perfect, unlike what we do in the outpatient setting, depending on how well he's doing or the treatment start dates might move by a day or so. So we basically had to hold a certain dose of cisplatin for him.   This brings the next question, which is how do we decide who gets cisplatin versus who can go for an alternative option? And I think Dr. Owonikoko made a great point where, just because it is a curative disease does not mean their life is more valuable. This is where I think trying to make that decision at an individual level, as an individual treating physician can be extremely hard. And that's why at our institution we have this ethics committee where we have oncologists, pharmacists, and ethicists that review these chemotherapy orders, particularly for cisplatin, and try to use some guiding principles that we learned from COVID as well as ASCO's guidance to decide how we assign our resources. That's one option, one way we have done it.    And then in another situation that was faced by one of my GI oncology colleagues was a patient that was originally planned to go on a clinical trial where the chemotherapy backbone was FOLFOX and because we had the 5FU shortage, we could not offer that patient clinical trial enrollment. And that was a tough conversation where they had to tell them that they could not go on a clinical trial that they were looking forward to. And this then brings the next question, which is by foregoing the bolus 5FU and by the 10% reduction in the infusional 5FU, are we providing them inferior treatment? And it's a conversation that's had at a very individual level. I don't envy my colleague who had to have that conversation. It's a challenge and we try to do our best to communicate to our patients that we are trying to provide care without trying to compromise the effectiveness of treatment for them.  Dr. Vamsi Velcheti: Thank you so much both of you. And we had the same issues here at NYU in New York City as well. It appears, you know, the degree of shortage and the drugs that are in shortage has been somewhat different at different locations across the United States. But the theme has been that we are having to ration treatments for our patients. And of course, there are some tumor types where there's really no adequate substitution, for example, GU cancers. I mean, you can't really not give them cisplatin. A lot of these are situations which have curative intent and young patients. So, it's really troubling.   And I think one of the things that really came out of this is there's been a lot of push from professional societies that actually ASCO has been spearheading and some intense discussions with CMS and legislators to kind of provide more long-term fix for these things. And I think all of us have to be more engaged in those discussions with our professional societies like ASCO to kind of help promote awareness. So if you kind of think about it, these drugs are not that expensive. These are generic drugs that we've all been using for such a long time. And the fact that we can't provide these drugs for various reasons is kind of really concerning. We spend so much money on research and more expensive drugs and not being able to manufacture these drugs within the country and kind of having to rely on complex supply chains is troubling, and I hope the situation improves very soon.    So, I know both of you are at large cancer centers that enroll patients on clinical trials. Of course, these drugs, especially carboplatin, for lung cancer, especially, are like core treatments that are used in managing cancer patients with lung cancer. So how is this affecting your clinical trial accrual? Are you prioritizing patients on clinical trials for these drugs? Have you had to make any decisions to hold clinical trial accrual for certain trials? Kind of curious to hear.  Dr. Taofeek Owonikoko: Yeah, so I can maybe weigh in a little bit on that in terms of what we've had to do for patients receiving treatment as standard of care versus those going on clinical trials. As we all recognize that when a patient goes on a clinical trial, even if they are going to receive a standard-of-care regimen as part of that trial, it still has to be administered in line with the protocol. So, during the extreme period of shortage anxiety, we actually had consideration for perhaps not putting patients on trial if we're not sure that they will be able to continue to receive the protocol-mandated treatment, whether it's a control intervention or the experimental intervention.   The good thing to come out of this is at least here at UPMC, we actually did not have any instance where we had to deny a patient clinical trial participation. But there were anxious periods when we already had patients enrolled and they were scheduled to receive a platinum-containing regimen and we were not sure whether or not we were going to have adequate supply of the drug for them while on trial. I think this really raises an important consideration going forward as we come out of this current shortage. I don't by any stretch of the imagination assume that this is going to be the last one we experience, but I think the lessons learned here, we have to also carry that forward both in the design of the trial as well as in the regulatory environment surrounding clinical trial conduct, to say, should another incidence of drug shortage are to happen, how do we actually operationalize that with respect to patients on trial, whether starting or already on trial?   I think it's much more challenging when the patient is already on the trial, they've already started. It's less challenging if you just have to make a decision about somebody starting newly on the trial. But equally important is that by not allowing new patients to go on trial is denying something that potentially could be of benefit to them, albeit it is still a trial, it's not an established treatment option yet.  Dr. Janakiraman Subramanian : I completely agree with Dr. Owonikoko. Those were very key points and issues that we face as well. In terms of my patients with lung cancer, we haven't had a problem in getting them on clinical trials. Even though we have had carboplatin shortage patients who are already on treatment, they were able to get the carboplatin. For new patients, we were still able to provide them carboplatin as well. The biggest problem for clinical trials has been primarily with my GI colleagues who have to use 5FU. And there, as I said before, we are unable to give bolus 5FU and there is a 10% reduction of the infusional 5FU. So, we can't have any of these patients go on clinical trials.    And as a result, anything that has to do with 5FU has come to a screeching halt in terms of clinical trials for our patients. And I think I echo the point of Dr. Owonikoko that by no means this is the last drug shortage we're going to be dealing with and we are here today discussing this, also because this shortage has not ended. It's been ongoing. It's one of the longest drug shortages in my memory as a medical oncologist, and that's concerning. We still see that there is some improvement, but we haven't gotten past it yet.     And therefore, as we develop clinical trials and we need to have methods to address drug shortages and how we manage patient enrollment as well as how do we manage existing patients who are already on a clinical trial and, if possible, what might be their options in that situation. We may not have all the answers, but it is definitely an issue that we need to think about in the future as we develop and implement newer clinical trials for our patients.  Dr. Vamsi Velcheti: I completely agree and great points, both of you. And we've had the same issues with clinical trials at NYU Langone as well due to the shortage. It's been a challenge, and I think this is a problem that's so complex because of supply chain issues and the way the drugs are priced and incentives for manufacturing these drugs in the United States are not lucrative enough to actually onshore a lot of the production of these drugs.   I think at the end of the day, I think we have to come up with some creative, innovative, reimbursement structures for these generic chemotherapy drugs. I think this would require a very complex economic solution that perhaps ASCO and other organizations should kind of really foster an environment of innovation to kind of help facilitate onshoring some of the manufacturing of these key drugs within the United States. I think ASCO is already trying to do that, trying to collaborate with all the stakeholders to kind of address this problem is very critical, and I think all of us have to be engaged in some of the advocacy efforts that are ongoing to kind of address these drug shortages. And this is not a short-term problem.  So, Dr. Owonikoko and Dr. Subramanian, any final thoughts before we wrap up the podcast today?  Dr. Janakiraman Subramanian: So, Vamsi, you mentioned the whole complex supply chain and the fact that we rely primarily on overseas manufacturers to get these drugs that are off-patent but still a key backbone of our cancer treatment. I think those are all key issues that policymakers and leaders in the field have to keep in mind. As an institution at Inova, one of the key mechanisms that have helped us to sort of stay ahead of the shortage was to have this inventory management team that monitors the inventory out there. And in fact, the inventory management team does have access to what the inventory is in some of their main suppliers in terms of the drugs. And they also have an idea of how many patients are going through treatment, what is the weekly usage of a specific drug like carboplatin. And they try to forecast what is coming down the road and try to prepare for it.   And as we try to look for solutions, maybe a forecasting mechanism in a larger scale like either spearheaded by ASCO or by policymakers level that can, for the overall country, try to see where some of the inventory is for some of these critical drugs and try to prepare for it ahead of time, rather than wait till we hit the shortage and then try to find alternative suppliers to get the drug, which obviously doesn't happen quick enough. It takes months or even longer to catch up and get the inventory back to the level where we can comfortably take care of our patients.  I think that is something we should be advocating for that as well as the professional societies should take a handle on that and see if they can support something like that as well as letting the institutions know ahead of time what's coming might be very helpful.  Dr. Vamsi Velcheti: Yeah, very good point, Janakiraman, and I think that's a key takeaway here. I think we have to learn from other industries and try to– I mean this is not unique to healthcare by any means. I mean these chronic shortages due to supply chain issues, inventory management, there might be some learnings from other industries here that we probably should also focus on inventory management and improve supply chain logistics.   Dr. Owonikoko, any closing thoughts?   Dr. Taofeek Owonikoko: Yeah, I agree as well with all the points made by Dr. Subramanian and yourself. This is a chronic problem that requires a long-term strategy. I think it's both an economic problem as well as a regulatory problem. As we all know, part of the reason why we went through this current crisis is the regulatory decision by the FDA regarding safety of one of the manufacturers. So being proactive in terms of how these audits are conducted and giving people lead time I think will help avoid similar situations in the future.    It's an economic problem. There's a reason why a lot of the big pharma companies are not producing these drugs. And if the cost of production is such that the amount of money you get paid is enough to cover your price, I think there is an economic issue there to be addressed. That is unfortunately not within the scope of what any one of us can do individually, but as advocates in terms of the structure of incentivizing new drug versus old drug, some of these newer drugs are quite expensive, but oftentimes they are used along with standard drugs that are not as expensive. So, where do we strike that balance where we do not stifle innovation but at the same time, we don't create a perverse incentive system where everybody just wants to come up with the newest, most expensive drug and nobody is interested in really producing the backbone chemotherapy and other agents that will make those new drugs work well.   So, I think we have to pay attention. We have to advocate for our patients through our different institutions and organizations, and I hope that society as a whole that we've learned a lot of lessons from this crisis and that will help us craft some long-term strategies.   Dr. Vamsi Velcheti: Thank you both Dr. Owonikoko and Dr. Subramanian for your time today to speak with me and our listeners and for sharing your insights with us on the ASCO Daily News podcast.   Dr. Taofeek Owonikoko: Thank you.   Dr. Janakiraman Subramanian: Thank you.  Dr. Vamsi Velcheti: And thank you to our listeners for your time today. If you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you so much.  Disclaimer: 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.  ASCO Resources Related to Drug Shortages are available here.     Follow today's speakers:    Dr. Vamsidhar Velcheti    @VamsiVelcheti    Dr. Janakiraman Subramanian  @RamSubraMD  Dr. Taofeek Owonikoko  @teekayowo    Follow ASCO on social media:     @ASCO on X (formerly Twitter)    ASCO on Facebook    ASCO on LinkedIn      Disclosures:     Dr. Vamsidhar Velcheti:     Honoraria: ITeos Therapeutics    Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus    Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline      Dr. Janakiraman Subramanian:  Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Daichi, G1 Therapeutics, Jazz Pharmaceuticals, Janssen Oncology, Lilly, Blueprint Medicines, Axcess, BeiGene, Cardinal Health, Takeda, OncoCyte  Speakers' Bureau: AstraZeneca, Boehringer Ingelheim, G1 Therapeutics, Jazz Pharmaceuticals, Janssen Oncology  Research Funding (Inst.): G1 Therapeutics, Tesaro/GSK, Novartis, Genentech, Novocure, Merck   Dr. Taofeek Owonikoko:  Stocks and Other Ownership Interests: Cambium Oncology, GenCart, Coherus Biosciences  Consulting or Advisory Role: Novartis, Celgene, Abbvie, Eisai, GI Therapeutics, Takeda, Bristol-Myers Squibb, MedImmune, BerGenBio, Lilly, Amgen, AstraZeneca, PharmaMar, Boehringer Ingelheim, EMD Serono, Xcovery, Bayer, Merck, Jazz Pharmaceuticals, Zentalis, Wells Fargo, Ipsen, Roche/Genentech, Janssen, Exelixis, BeiGene, Triptych Health Partners, Daichi, Coherus Biosciences  Speakers Bureau: Abbvie  Research Funding (Inst.): Novartis, Astellas Pharma, Bayer, Regeneron, AstraZenece/MedImmune, Abbvie, G1Therapeutics, Bristol-Myers Squibb, United Therapeutics, Amgen, Loxo/Lilly, Fujifilm, Pfizer, Aeglea Biotherapeutics, Incyte, Merck, Oncorus, Ispen, GlaxoSmithKline, Calithera Biosciences, Eisai, WindMIL, Turning Point Therapeutics, Roche/Genentech, Mersana, Meryx, Boehringer Ingelheim  Patents, Royalties, Other Intellectual Property (Inst.):   Overcoming Acquired Resistance to Chemotherapy Treatments Through Suppression of STAT3  Selective Chemotherapy Treatments and Diagnostic Methods Related Thereto  DR4 Modulation and Its Implications in EGFR-Target Cancer Therapy Ref: 18089 PROV (CSP) United States Patent Application No. 62/670,210 June 26, 2018 (Co-Inventor)  Soluble FAS ligand as a biomarker of recurrence in thyroid cancer; provisional patent 61/727,519 (Inventor)  Other Relationship: Roche/Genentech, EMD Serono, Novartis  Uncompensated Relationships: Reflexion Medical           

Dr. Ralph W. Moss and son Ben discuss the benefits and dangers of mushrooms in the prevention and healing of cancer. For more information on the healing properties of mushrooms and other cancer-fighting foods, please visit our website: www.themossreport.com  Program Notes: Real Mushrooms 5 Defenders Immune Strength [Affiliate Link] Real Mushrooms Organic Reishi Mushroom Capsules [Affiliate Link] Medicinal Mushrooms Section of  www.themossreport.com Ralph's Mushroom Soup Recipe Ralph W. Moss, PhD Discusses Medicinal Mushrooms with Mike Shirota c.1992 DIY Blood tests Four Studies Current Advancements in Antitumor Properties and Mechanisms of Medicinal Components in Edible Mushrooms Correlation between efficacy of PSK postoperative adjuvant immunochemotherapy for gastric cancer and expression of MHC class I Ganoderma lucidum extract (GLE) impairs breast cancer stem cells by targeting the STAT3 pathway Trametes versicolor (Synn. Coriolus versicolor) Polysaccharides in Cancer Therapy: Targets and Efficacy

A new research paper was published in Oncotarget's Volume 14 on April 24, 2023, entitled, “Differential silencing of STAT3 isoforms leads to changes in STAT3 activation.” Signal transducer and activator of transcription 3 (STAT3) is a transcription factor involved in multiple fundamental biological processes and a key player in cancer development and progression. STAT3 is activated upon tyrosine phosphorylation and is constitutively active in various malignancies; therefore, the expression of phospho-STAT3 (pSTAT3) has been recognized as a predictor of poor survival. STAT3 encodes two alternatively-spliced STAT3 isoforms: the full-length STAT3α isoform and the truncated STAT3β isoform. These isoforms have been suggested as the reason for the occasionally observed opposing roles of STAT3 in cancer: an oncogene, on one hand, and a tumor suppressor on the other. In this new study, researchers Inbal Shamir, Ilan Tsarfaty, Gidi Paret, and Yael Nevo-Caspi from Sheba Medical Center and Tel Aviv University investigated the roles of STAT3α and STAT3β in aggressive breast cancer. They manipulated endogenous STAT3 isoform expression and measured outcomes to mimic physiological changes more accurately. “In this study we examined the roles of STAT3 isoforms using specific siRNAs that target either STAT3α or STAT3β. We used the MDA-MB-231 cell line which represents an aggressive and mortal subtype of breast cancer, in which STAT3 is overexpressed and constitutively activated [14].” The team separately silenced each isoform in the MDA-MB-231 cell line and found that they affect each other's activation, impacting cell viability, cytokine expression, and migration. Their results show that each of the isoforms affects the activation (i.e., phosphorylation) of the other isoform and leads to changes in the outcome of the cells. They conclude that both STAT3α and STAT3β play a crucial role in the function of STAT3. Distinguishing between the two isoforms and their active forms is crucial for STAT3-related cancer diagnosis and therapy. “Referring to STAT3 as a single protein can lead to wrong conclusions, as they have different functions. Current STAT3 inhibitors target both isoforms, but this approach should be revised for better patient care. We present an endogenous mechanism that can shift the balance in a favorable direction, and we suggest developing treatments that mimic this mechanism could lead to new avenues for cancer therapy.” DOI: https://doi.org/10.18632/oncotarget.28412 Correspondence to - Yael Nevo-Caspi - yael.caspi@sheba.health.gov.il Keywords - STAT3: Signal transducer and activator of transcription 3, ER: endoplasmic reticulum, TAD: transactivation domain, SH2: Src homology 2, RQ: Relative quantitative Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28412 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ 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

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.18.533289v1?rss=1 Authors: Deng, Y., Zhao, Z., Sheldon, M., Zhao, Y., Teng, H., Martinez, C., Zhang, J., Lin, C., Sun, Y., Yao, F., Zhu, H., Ma, L. Abstract: The molecular links between tissue repair and tumorigenesis remain elusive. Here, we report that loss of the liver tumor suppressor Lifr in mouse hepatocytes impairs the recruitment and activity of reparative neutrophils, resulting in the inhibition of liver regeneration after partial hepatectomy or toxic injuries. On the other hand, overexpression of LIFR promotes liver repair and regeneration after injury. Interestingly, LIFR deficiency or overexpression does not affect hepatocyte proliferation ex vivo or in vitro. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of the neutrophil chemoattractant CXCL1 (which binds CXCR2 to recruit neutrophils) and cholesterol in a STAT3-dependent manner. Cholesterol, in turn, acts on the recruited neutrophils to secrete hepatocyte growth factor (HGF) to accelerate hepatocyte proliferation and regeneration. Altogether, our findings reveal a LIFR-STAT3-CXCL1-CXCR2 axis and a LIFR-STAT3-cholesterol-HGF axis that mediate hepatic damage-induced crosstalk between hepatocytes and neutrophils to repair and regenerate the liver. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

A new research paper was published in Oncotarget's Volume 14 on February 2, 2023, entitled, “Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC).” TP53 mutant head and neck squamous cell carcinoma (HNSCC) patients exhibit poor clinical outcomes with 50–60% recurrence rates in advanced stage patients. In a recent phase II clinical trial, adjuvant therapy with everolimus (mTOR inhibitor) significantly increased 2-year progression-free survival in p53 mutated patients. TP53-driven mTOR activation in solid malignancies causes upregulation of HIF-1α and its target, downstream effector VEGF, by activating STAT3 cell signaling pathway. In this recent study, researchers Md Maksudul Alam, Janmaris Marin Fermin, Mark Knackstedt, Mackenzie J. Noonan, Taylor Powell, Landon Goodreau, Emily K. Daniel, Xiaohua Rong, Tara Moore-Medlin, Alok R. Khandelwal, and Cherie-Ann O. Nathan from LSU-Health Sciences Center investigated the effects of everolimus on the STAT3/HIF-1α/VEGF pathway in TP53 mutant cell lines and xenograft models. “The role of mTOR inhibitors (mTORi) as potent growth inhibitory and antiangiogenic/anti-lymphangiogenic agents in HNSCC is well established [18]. Moreover, mTORi significantly suppressed baseline invasiveness of endothelial and HNSCC tumor cells [19]. However, the underlying molecular mechanisms for mutant p53 protein-mediated activation of the mTOR pathway which drive the oncologic processes in HNSCC are yet to be elucidated.” Treatment with everolimus significantly inhibited cell growth in vitro and effectively reduced the growth of TP53 mutant xenografts in a minimal residual disease (MRD) model in nude mice. Everolimus treatment was associated with significant downregulation of STAT3/HIF-1α/VEGF pathway in both models. Further, treatment with everolimus was associated with attenuation in tumor angiogenesis and lymphangiogenesis as indicated by decreased microvessel density of vascular and lymphatic vessels in HN31 and FaDu xenografts. Everolimus downregulated the STAT3/HIF-1α/VEGF pathway to inhibit growth and in vitro tube formation of HMEC-1 (endothelial) and HMEC-1A (lymphatic endothelial) cell lines. “Our studies demonstrated that everolimus inhibits the growth of TP53 mutant tumors by inhibiting angiogenesis and lymphangiogenesis through the downregulation of STAT3/HIF-1α/VEGF signaling.” DOI: https://doi.org/10.18632/oncotarget.28355 Correspondence to: Cherie-Ann O. Nathan - cherieann.nathan@lsuhs.edu Keywords: TP53 mutant, HNSCC, angiogenesis, everolimus, mTOR 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

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.30.522316v1?rss=1 Authors: Nakamura, Y., Nakano, T., Park, J.-H., Tanaka, M., Li, W., Esposito, E., Ahn, B.-J., Duran-Laforet, V., Desai, R., Sencan, I., Sakadzic, S., Lo, E., Snyder, E., Tabaka, M., Hayakawa, K. Abstract: The neural crest (NC) is a transient structure in vertebrate embryogenesis comprising highly migratory multipotent stem cells that give rise to a diverse array of cell types in organs throughout the body, including initiating neurovascular patterning. It is assumed that neural crest stem cells (NCSCs) disappear after development. Unexpectedly, using single-nucleus RNA-sequencing, we discovered residual quiescent NCSCs in the adult mouse meninges which are activated by injury and contribute to homeostatic response in the brain. RNA velocity, pathway, and transcription factor analyses in a murine stroke model combined with in vivo imaging show that these adult NCSCs migrate towards the perivascular spaces of the infarct and undergo a perivascular stromal cell transition that is regulated by Ptp1b, Ghr, and Stat3. Loss- and gain-of-function experiments show that these vestigial NCSCs are required for restoring vascular endothelial barrier function via {beta}-catenin and Stat3 signaling. These findings suggest that, in the adult, an unexpected reservoir of cells, once pivotal to embryogenesis and vascular morphogenesis, are re-invoked for neurovascular repair. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

A new research paper was published in Oncotarget's Volume 13 on December 6, 2022, entitled, “Expression of p-STAT3 and c-Myc correlates with P2-HNF4α expression in nonalcoholic fatty liver disease (NAFLD).” Nonalcoholic fatty liver disease (NAFLD) is associated with the metabolic syndrome and is rapidly becoming one of the major causes of hepatic cirrhosis and hepatocellular carcinoma (HCC), although some cases of HCC have developed in non-cirrhotic livers [1–8]. Although the percentage of patients with NAFLD who ultimately progress to fibrosis and later to HCC is relatively small, the number is significant because of the sheer number of patients who have NAFLD. Because there are no reliable biomarkers to predict the risk of HCC in patients with NAFLD, designing effective and cost-effective surveillance programs aimed at prevention and early detection of HCC is difficult, if not impossible. Therefore, there is an urgent need to identify such biomarkers and especially those that may appear at different stages of progression toward HCC. In the current study, researchers Mamoun Younes, Lin Zhang, Baharan Fekry, and Kristin Eckel-Mahan from George Washington University School of Medicine and Health Sciences and McGovern Medical School at the University of Texas Health Science Center (UTHealth) studied the expression of two hepatocyte nuclear factor 4 alpha (HNF4α) isoforms, p-STAT3. and c-Myc in 49 consecutive liver biopsies with nonalcoholic fatty liver disease (NAFLD) using immunohistochemistry. “The aim of this study was to determine the relationships between p-STAT3, c-Myc and P2-HNF4α expression in biopsies from livers with NAFLD as potential biomarkers of HCC risk.” All 49 biopsies (100%) were positive for nuclear expression of P1-HNF4α. Twenty-eight (57%) cases were positive for P2-HNF4α, 6 (12%) were positive for p-STAT3 and 5 (10%) were positive for c-Myc. All 6 (100%) p-STAT3-positive cases were also positive for P2-HNF4α (p = 0.03). p-STAT3-positive cases were more likely to be positive for c-Myc (67% vs. 2%, p = 0.0003). Four cases were positive for P2-HNF4α, p-STAT3 and c-Myc. p-STAT3 expression was associated with hypertension (p = 0.037). All c-Myc positive biopsies were from patients with obesity, diabetes and hypertension. Only c-Myc expression was associated with advanced fibrosis; three (60%) of the c-Myc positive cases were associated with advanced fibrosis in contrast to 7 (10%) of the 44 c-Myc negative cases (p = 0.011). “Based on these results, we hypothesize with the following sequence of events with progression of NAFLD: P2-HNF4α expression is followed by expression of p-STAT3 which in turn is followed by the expression of c-Myc. Additional larger studies are needed to confirm these findings.” DOI: https://doi.org/10.18632/oncotarget.28324 Correspondence to: Mamoun Younes - myounes@mfa.gwu.edu Video: https://www.youtube.com/watch?v=LVR29K6P5I4 Keywords: hepatocyte nuclear factor four alpha, steatohepatitis, immunohistochemistry, hepatocellular carcinoma, isoform 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

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.20.517270v1?rss=1 Authors: Sengstack, J., Zheng, J., Mobaraki, M., Lin, J., Deng, C., Li, H. Abstract: Rejuvenation, long a quixotic dream, recently became a possibility through exciting new approaches to counteract aging. For example, parabiosis and partial reprogramming through overexpressing four stem cell transcription factors (Yamanaka factors) both rejuvenate organisms and cells. We hypothesize there are many other genetic solutions to human cell rejuvenation, and some solutions may be safer and more potent than current gene targets. We set out to develop a systematic approach to identify novel genes that, when overexpressed or repressed, reprogram the global gene expression of a cell back to a younger state. Using the Hayflick model of human cell replicative aging, we performed a Perturb-seq screen of 200 transcription factors (TFs) selected through a combination of bioinformatic analysis and literature search. We identified dozens of potentially rejuvenating TFs, those that when overexpressed or repressed in late passage cells reprogrammed global gene expression patterns back to an earlier passage state. We further validated four top TF perturbations through molecular phenotyping of various aging hallmarks. Late passage cells either overexpressing EZH2 or E2F3 or repressing STAT3 or ZFX had more cell division, less senescence, improved proteostasis, and enhanced mitochondrial function. These TF perturbations led to similar downstream gene expression programs. In addition, the rejuvenating effects of these TFs were independent of telomeres. We believe our general approach for identifying rejuvenating factors can be applied to other model systems, and some of the top TF perturbations we discovered will lead to future research in novel, safer rejuvenation therapies. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

VIDEOS: The Cost of Denial Clip (17:33) Hang On, Bill Gates and Dr. Fauci just did WHAT? | Redacted with Clayton Morris (21:43) There is nothing constructive about the pot calling the kettle black. – Clare Daly  (1:17) Clinical trial for nicotinamide riboside: Vitamin safely boosts levels of important cell metabolite linked to multiple health benefits University of Iowa Health Care, October 10, 2022 In a clinical trial of nicotinamide riboside (NR), a newly discovered form of Vitamin B3, researchers have shown that the compound is safe for humans and increases levels of a cell metabolite that is critical for cellular energy production and protection against stress and DNA damage. Studies in mice have shown that boosting the levels of this cell metabolite — known as NAD+ — can produce multiple health benefits, including resistance to weight gain, improved control of blood sugar and cholesterol, reduced nerve damage, and longer lifespan. Levels of NAD+ diminish with age, and it has been suggested that loss of this metabolite may play a role in age-related health decline. These findings in animal studies have spurred people to take commercially available NR supplements designed to boost NAD+. However, these over-the-counter supplements have not undergone many clinical trials to see if they work in people. The new research, reported in the journal Nature Communications, was led by Charles Brenner, PhD, professor and Roy J. Carver Chair of Biochemistry at the University of Iowa Carver College of Medicine The human trial involved six men and six women, all healthy. Each participant received single oral doses of 100 mg, 300 mg, or 1,000 mg of NR in a different sequence with a seven-day gap between doses. After each dose, blood and urine samples were collected and analyzed to measure various NAD+ metabolites in a process called metabolomics. The trial showed that the NR vitamin increased NAD+ metabolism by amounts directly related to the dose, and there were no serious side effects with any of the doses. “This trial shows that oral NR safely boosts human NAD+ metabolism,” Brenner says. “We are excited because everything we are learning from animal systems indicates that the effectiveness of NR depends on preserving and/or boosting NAD+ and related compounds in the face of metabolic stresses. Because the levels of supplementation in mice that produce beneficial effects are achievable in people, it appears than health benefits of NR will be translatable to humans safely.” Consumption of a bioactive compound from Neem plant could significantly suppress development of prostate cancer National University of Singapore, September 29, 2022 Oral administration of nimbolide, over 12 weeks shows reduction of prostate tumor size by up to 70 per cent and decrease in tumor metastasis by up to 50 per cent A team of international researchers led by Associate Professor Gautam Sethi from the Department of Pharmacology at the Yong Loo Lin School of Medicine at the National University of Singapore (NUS) has found that nimbolide, a bioactive terpenoid compound derived from Azadirachta indica or more commonly known as the neem plant or curry leaf common in throughout Indian cuisine, could reduce the size of prostate tumor by up to 70 per cent and suppress its spread or metastasis by half. In this research, we have demonstrated that nimbolide can inhibit tumor cell viability — a cellular process that directly affects the ability of a cell to proliferate, grow, divide, or repair damaged cell components — and induce programmed cell death in prostate cancer cells,” said Assoc Prof Sethi. The researchers observed that upon the 12 weeks of administering nimbolide, the size of prostate cancer tumor was reduced by as much as 70 per cent and its metastasis decreased by about 50 per cent, without exhibiting any significant adverse effects. “This is possible because a direct target of nimbolide in prostate cancer is glutathione reductase, an enzyme which is responsible for maintaining the antioxidant system that regulates the STAT3 gene in the body. The activation of the STAT3 gene has been reported to contribute to prostate tumor growth and metastasis,” explained Assoc Prof Sethi. “We have found that nimbolide can substantially inhibit STAT3 activation and thereby abrogating the growth and metastasis of prostate tumor,” he added. Mindfulness training provides a natural high, study finds University of Utah, October 20, 2022 New research from the University of Utah finds that a mindfulness meditation practice can produce a healthy altered state of consciousness in the treatment of individuals with addictive behaviors. Not unlike what one might experience under the influence of psychedelic drugs—achieving this altered state through mindful meditation has the potential lifesaving benefit of decreasing one's addictive behaviors by promoting healthy changes to the brain. The findings come from the largest neuroscience study to date on mindfulness as a treatment for addiction. The study, published in the journal Science Advances, provides new insight into the neurobiological mechanisms by which mindfulness treats addiction. Study findings provide a promising, safe and accessible treatment option for the more than 9 million Americans misusing opioids. Eric Garland is the lead author of the paper and is a distinguished professor and directs the University of Utah's Center on Mindfulness and Integrative Health Intervention Development. Garland's study builds on previous research measuring the positive effects of theta waves in the human brain. Researchers have found that individuals with low theta waves tend to experience a wandering mind, trouble concentrating or they ruminate on thoughts about themselves. Low theta waves result in a loss of self-control as the brain slips into its default mode of automatic habits. In contrast, when a person is focused, present and fully absorbed in a task, EEG scans will show increased frontal midline theta wave activity. “With high theta activity, your mind becomes very quiet, you focus less on yourself and become so deeply absorbed in what you are doing that the boundary between yourself and the thing you are focusing on starts to fade away. You lose yourself in what you are doing,” said Garland. Garland's new study showed it is in this mindful, theta wave state that people begin to experience feelings of self-transcendence and bliss, and the brain changes in ways that actually reduce one's addictive behaviors. Garland's research team recruited 165 adults with long-term opioid use for the study. Participants were randomly placed into either the control group that participated in supportive group psychotherapy or the experimental group taught to incorporate Mindfulness-Oriented Recovery Enhancement (MORE) into their daily lives. Participants showed more than twice as much frontal midline theta brain activity following treatment with MORE, whereas those in supportive therapy showed no increase in theta. Participants in MORE who showed the biggest increases in theta waves reported more intense experiences of self-transcendence during meditation, including the sense of one's ego fading away, a sense of oneness with the universe or feelings of blissful energy and love. MORE also led to significant decreases in opioid misuse through the nine-month follow-up. These reductions in opioid misuse were caused in part by the increases in frontal midline theta brain waves. Garland explained that by achieving “tastes of self-transcendence” through meditation, mindfulness therapy boosted theta waves in the frontal lobes of the brain to help participants gain self-control over their addictive behaviors. Free radicals blamed for toxic buildup in Alzheimer's brains Rutgers University, October 11, 2022. A study reported in Cell Death & Disease revealed a previously unknown mechanism that may contribute to traumatic brain injury and Alzheimer's disease. While a buildup of the protein amyloid-beta has been hypothesized to be the major driver of Alzheimer's disease, the study suggests that another protein, after undergoing oxidation by free radicals, could be a causative factor. “Indeed, scientists have known for a long time that during aging or in neurodegenerative disease cells produce free radicals,” explained lead researcher Federico Sesti, who is a professor of neuroscience and cell biology at Rutgers Robert Wood Johnson Medical School. “Free radicals are toxic molecules that can cause a reaction that results in lost electrons in important cellular components, including the channels.” Dr Sesti and colleagues determined that oxidation of a potassium channel known as KCNB1 results in a toxic buildup of this protein, leading to increased amyloid-beta production and damage to brain function. “The discovery of KCNB1's oxidation/build-up was found through observation of both mouse and human brains, which is significant as most scientific studies do not usually go beyond observing animals,” Dr Sesti reported. “Further, KCBB1 channels may not only contribute to Alzheimer's but also to other conditions of stress as it was found in a recent study that they are formed following brain trauma.” Study: Maternal, paternal exercise affects metabolic health in offspring Ohio State University, October 19, 2022 A mouse study by Kristin Stanford, with The Ohio State University College of Medicine at the Wexner Medical Center, provides new ways to determine how maternal and paternal exercise improve metabolic health of offspring. This study used mice to evaluate how their lifestyles—eating fatty foods vs. healthy and exercising vs. not—affected the metabolites of their offspring. Metabolites are substances made or used when the body breaks down food, drugs or chemicals, or its own fat or muscle tissue. This process, called metabolism, makes energy and the materials needed for growth, reproduction and maintaining health. Metabolites can serve as disease markers, particularly for type 2 diabetes and cardiovascular disease. “Tissue metabolites contribute to overall metabolism, including glucose or fatty acid metabolism, and thus systemic metabolism. We have previously shown that maternal and paternal exercise improve health of offspring. Tissue and serum metabolites play a fundamental role in the health of an organism, but how parental exercise affects offspring tissue and serum metabolites has not yet been investigated. This new data contributes to how maternal or paternal exercise could improve metabolism in offspring,” Stanford said. This study found that all forms of parental exercise improved whole-body glucose metabolism in offspring as adults, and metabolomics profiling of offspring serum, muscle, and liver reveal that parental exercise results in extensive effects across all classes of metabolites in all of these offspring tissues. Regular consumption of fried food before pregnancy increases risk of developing gestational diabetes Kennedy Shriver National Institute of Child Health and Human Development, October 10, 2022 New research published in Diabetologia (the journal of the European Association for the Study of Diabetes) shows that women who eat fried food regularly before conceiving are at increased risk of developing gestational diabetes during pregnancy. Gestational diabetes (GDM) is a complication that can arise during pregnancy, and is characterised by abnormally high blood glucose during the pregnancy (especially in the final 3 months). It can lead to increased birthweight of the child, as well jaundice and other complications. When left untreated, it can cause complications or stillbirth. Women who have GDM are more likely to later develop full blown type 2 diabetes. The authors included 21,079 singleton pregnancies from 15,027 women in the Nurses' Health Study II (NHS II) cohort. NHS II is an ongoing prospective cohort study of 116,671 female nurses in the USA aged 25-44 years at the start of study. For fried food consumption, participants were asked “how often do you eat fried food away from home (e.g. French fries, fried chicken, fried fish)?” and “how often do you eat food that is fried at home?” Both questions had four possible frequency responses: less than once per week, 1-3 times per week, 4-6 times per week, or daily. The researchers analysed fried food consumption at home and away from home separately, as well as total fried food consumption. In addition, they asked the participants what kind of frying fat/oils they usually used at home, with the possible responses as follows: real butter, margarine, vegetable oil, vegetable shortening, or lard. The association persisted after further adjustments were made for varying body-mass index (BMI). After this, the risk ratios of GDM among women who consumed total fried foods 1-3, 4-6, and 7 or more times per week, compared with those who consumed less than once per week, were 1.06, 1.14, and 1.88 respectively (thus an 88% increased risk for 7 or more times per week compared with less than once per week). The authors say: “The potential detrimental effects of fried food consumption on GDM risk may result from the modification of foods and frying medium and generation of harmful by-products during the frying process. Frying deteriorates oils through the processes of oxidation and hydrogenation, leading to an increase in the absorption of oil degradation products by the foods being fried, and also a loss of unsaturated fatty acids such as linoleic and linolenic acids and an increase in the corresponding trans fatty acids such as trans-linoleic acids and trans-linolenic acids.” They add: “Frying also results in significantly higher levels of dietary advanced glycation end products (AGEs), the derivatives of glucose-protein or glucose-lipid interactions. Recently, AGEs have been implicated in insulin resistance, pancreatic beta-cell damage, and diabetes, partly because they promote oxidative stress and inflammation. Moreover, intervention studies with a diet low in AGEs have shown significantly improved insulin sensitivity, reduced oxidant stress, and alleviated inflammation.” When analysed separately, the authors found that there was a statistically significant association of GDM with fried food consumption away from home, but not with fried food consumption at home. The authors say: “Deterioration of oils during frying is more profound when the oils are reused, a practice more common away from home than at home. This may partly explain why we observed a stronger association of GDM risk with fried foods consumed away from home than fried foods consumed at home.”

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.09.507263v1?rss=1 Authors: PARASAR, P., Kaur, N., Poisson, L., Singh, J. Abstract: ABSTRACT Objective: The role of astrocytes largely remains to be explored in X-linked adrenoleukodystrophy (X-ALD). Due to limited study models and inaccessibility to patient-tissue samples, we differentiated astrocytes from patient fibroblast-derived induced pluripotent stem cell (iPSCs) which provided a unique system to investigate molecular and etiopathogenetic mechanisms, identify targets, and develop therapeutic agents for X-ALD. Methods: We reprogrammed fibroblasts from adrenomyeloneuropathy (AMN) and cerebral adrenoleukodystrophy (cALD) patients carrying ABCD1 with pathogenic variants and a control patient to generate iPSCs. We differentiated iPSCs into astrocytes and performed transmission electron microscopy, gene expression, immunoblotting, enzyme-linked immunosorbent assay, miRNA-Seq, and lipidomics to characterize phenotypic and molecular features of patient-derived astrocytes. Results: These differentiated astrocytes exhibit diseased phenotypes and replicate biochemical and molecular changes found in patients. We confirmed the deletion of ABCD1 gene-encoded ALD protein and identified ABCD1 variant-driven very long chain fatty acid deposition in AMN and cALD astrocytes. Especially, cALD astrocytes showed increased glycolysis, increased signal transducer and transcription activator (STAT)3 activation, higher miR-9 expression in miRNA-Seq analysis, and reduced expression of anti-inflammatory cytokines such as arginase-1 and mannose receptor C-type-1. Consequently, Toll-like receptor-signaling via myeloid differentiation primary response gene 88 (MyD88) and nuclear factor-kappa B (NF-{kappa}B; p52 and p65) induced STAT3 and an altered miR-9 expression is a potential contributor to inflammatory milieu in cALD while interleukin-6 -induced anti-inflammatory cytokine production and increased chemotactic CCL-2 (MCP-1) production in AMN potentially favors microglial recruitment protecting its further progression. Interpretation: We demonstrate for the first time that patient iPSC-derived astrocytes mimic and recapitulate neuroinflammatory and biochemical defects of X-ALD and provide an in vitro cellular system to study X-ALD. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.07.506981v1?rss=1 Authors: Parks, S. Z., Rutter, G. A., Leclerc, I. Abstract: Background: Soluble Resistance Related Calcium Binding Protein (sorcin) is a calcium (Ca2+) binding protein which has been shown to play a role in maintaining intracellular endoplasmic reticulum (ER) Ca2+ stores and lowering ER stress. Recently, our lab has demonstrated that sorcin expression was downregulated in the islets of Langerhans of mice fed a high-fat diet or in human islets incubated with the saturated fatty acid palmitate. We also showed that overexpression of sorcin under control of the rat insulin promoter (RIP7) in C57BL/6J mice, or whole body sorcin deletion in 129S1/SvImJ mice, improves or impairs insulin secretion and pancreatic {beta}-cell function respectively. The mechanisms behind this beneficial role of sorcin in the pancreatic {beta}-cell might depend on protection against lipotoxic endoplasmic reticulum (ER) stress through improved ER Ca2+ dynamics and activation of the Activating Transcription Factor 6 (ATF6) branch of the unfolded protein response (UPR). Whether sorcin is also implicated in hypothalamic ER stress during the progression of obesity is unknown. This could potentially contribute to the diminished satiety typically observed in overweight individuals. Aim: To investigate a potential role of sorcin in hypothalamic ER stress, leptin resistance, hyperphagia and obesity. Methods: Whole-body sorcin null mice, backcrossed onto the C57BL/6J genetic background, were used. Body weight, food intake and EchoMRI body composition were measured in vivo whereas qRT-PCR analysis of sorcin and ER stress markers expression were performed on the arcuate nucleus of the hypothalamus. Leptin signalling through STAT3 phosphorylation was measured by Western blots on sorcin-null HEK293 cells, engineered by CRISPR/Cas9, and transfected with leptin receptor (LepRb). Results: Sorcin expression was not influenced in the arcuate nucleus (ARC) of the hypothalamus by diet-induced obesity. Whole-body sorcin ablation did not cause ARC ER stress nor changes in body weight, body composition or food intake in C57BL/6 male mice exposed to a high-fat, high-sugar diet. STAT3 phosphorylation (Y705) in response to leptin was not impaired in sorcin-null HEK293 cells. Conclusion: In our model, whole body sorcin ablation did not increase hypothalamic ER stress nor influenced food intake or body weight. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.23.504918v1?rss=1 Authors: Pons-Espinal, M., Blasco-Agell, L., Fernandez-Carasa, I., di Domenico, A., Richaud, Y., Mosquera, J. L., Marruecos, L., Espinosa, L., Garrido, A., Tolosa, E., Edel, M. J., Juan Otero, M., Ferrer, I., Raya, A., Consiglio, A. Abstract: Parkinson's disease (PD) is associated with premature death of dopamine-producing neurons in the brain. Previous studies have shown that astrocytes of PD patients may contribute to neuronal degeneration by mechanisms involving both direct cell-to-cell contact and transfer of soluble molecules. Since it has been proposed that PD patients exhibit an overall pro-inflammatory state, and since astrocytes are key mediators of the inflammation response in the brain, here we sought to address whether astrocyte-mediated inflammatory signaling could contribute to PD neuropathology. For this purpose, we generated astrocytes from induced pluripotent stem cells (iPSCs) representing PD patients and healthy controls. Transcriptomic analyses identified a unique inflammatory gene expression signature in PD astrocytes compared to controls. In particular, the pro-inflammatory cytokine IL-6 was found to be highly expressed and released by PD astrocytes, and to induce toxicity in dopamine neurons. Mechanistically, neuronal cell death was mediated by IL-6 signaling via IL-6 receptor (IL-6R) expressed in human PD neurons, leading to downstream activation of STAT3. Importantly, astrocyte-induced cell death in PD disease midbrain neurons could be prevented by blocking IL6R-mediated signaling using clinically available antibodies. Moreover, examination of postmortem tissue brain of early-stage PD patients uncovered increased numbers of dopamine neurons overexpressing IL-6R and of reactive astrocytes overexpressing IL-6, compared to healthy brains. Our findings highlight the potential role of astrocyte-mediated inflammatory signaling in neuronal loss in PD, and open the way for new therapies based on IL-6 immunomodulation for preventing PD pathogenesis. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Dr. Dae Joon Kim and Liza Morales from the Department of Biomedical Sciences, School of Medicine, University of Texas Rio Grande Valley, Edinburg, TX, detail a priority research paper they co-authored that was published by Oncotarget in Volume 8, Issue 53, entitled, “UVB-induced nuclear translocation of TC-PTP by AKT/14-3-3σ axis inhibits keratinocyte survival and proliferation.” DOI - https://doi.org/10.18632/oncotarget.21794 Correspondence to - Dae Joon Kim - dae.kim@utrgv.edu Abstract Understanding protein subcellular localization is important to determining the functional role of specific proteins. T-cell protein tyrosine phosphatase (TC-PTP) contains bipartite nuclear localization signals (NLSI and NLSII) in its C-terminus. We previously have demonstrated that the nuclear form of TC-PTP (TC45) is mainly localized to the cytoplasm in keratinocytes and it is translocated to the nucleus following UVB irradiation. Here, we report that TC45 is translocated by an AKT/14-3-3σ-mediated mechanism in response to UVB exposure, resulting in increased apoptosis and decreased keratinocyte proliferation. We demonstrate that UVB irradiation increased phosphorylation of AKT and induced nuclear translocation of 14-3-3σ and TC45. However, inhibition of AKT blocked nuclear translocation of TC45 and 14-3-3σ. Site-directed mutagenesis of 14-3-3σ binding sites within TC45 showed that a substitution at Threonine 179 (TC45/T179A) effectively blocked UVB-induced nuclear translocation of ectopic TC45 due to the disruption of the direct binding between TC45 and 14-3-3σ. Overexpression of TC45/T179A in keratinocytes resulted in a decrease of UVB-induced apoptosis which corresponded to an increase in nuclear phosphorylated STAT3, and cell proliferation was higher in TC45/T179A-overexpressing keratinocytes compared to control keratinocytes following UVB irradiation. Furthermore, deletion of TC45 NLSII blocked its UVB-induced nuclear translocation, indicating that both T179 and NLSII are required. Taken together, our findings suggest that AKT and 14-3-3σ cooperatively regulate TC45 nuclear translocation in a critical step of an early protective mechanism against UVB exposure that signals the deactivation of STAT3 in order to promote keratinocyte cell death and inhibit keratinocyte proliferation. Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.21794 Keywords - TC-PTP, nuclear translocation, AKT, 14-3-3σ, keratinocytes About Oncotarget Oncotarget is a peer-reviewed, open access biomedical journal covering research on all aspects of oncology. 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/c/OncotargetYouTube/ LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC: https://www.ImpactJournals.com Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Oncotarget published "Reversing oncogenic transformation with iron chelation" which reported that cancer cells accumulate iron to supplement their aberrant growth and metabolism. Depleting cells of iron by iron chelators has been shown to be selectively cytotoxic to cancer cells in vitro and in vivo. A plethora of studies have shown iron chelators can reverse some of the major hallmarks and enabling characteristics of cancer. Iron chelators inhibit signalling pathways that drive proliferation, migration and metastasis as well as return tumour suppressive signalling. Iron chelators target cancer cell metabolism, attenuating oxidative phosphorylation and glycolysis. Dr. Gina Abdelaal from The Northumbria University said, "Iron is vital for normal cell growth and survival." Cancer is an evolutionary maverick, which exploits its trademark genomic instability to drain environmental resources. As an enzyme cofactor, iron is responsible for many cellular processes including mitochondrial metabolism and DNA synthesis. As iron can drive cellular proliferation, cancer cells have an adapted iron metabolism allowing increased iron accumulation. The thiosemicarbazone class is a later stage of iron chelator evolution which manifested in 1992. Unlike their predecessor DFO, thiosemicarbazone chelators are capable of inducing reactive oxygen species. Triapine is a thiosemicarbazone; its primary mode of action is thought to be ribonucleotide reductase inhibition with a higher potency than commonly used ribonucleotide reductase inhibitor, hydroxyurea. This approach is predicted to protect healthy tissues from the cytotoxic effects as the timing and place of the drug release can be controlled. Encapsulating Dp44mT in PLGA nanoparticles enhanced its ability to induce apoptosis and improved its selectivity towards cancer cells. At present many more classes of iron chelators are being taken into consideration as potential cancer therapy candidates. The Abdelaal Research Team concluded in their Oncotarget Research Output that based on the data presented in this review iron chelators could potentially reverse many of the key hallmarks of cancer. Stripping the cells of iron impacts many cellular targets with some targets still undiscovered. NDRG1 has been proven to be the common link between the ability of iron chelators to reverse many of the hallmarks of cancer as overexpression of NDRG1 mimics the impact of iron chelation on several signalling pathways. There are still many unanswered questions about the mechanism of action of iron chelators. A consensus must be reached on the impact of iron chelation on angiogenesis through in vivo studies. As STAT3 is essential for VEGF gene expression and iron chelation attenuates STAT3 dimerisation and nuclear localisation. The cleaved isoform is only present in cancer cells and could potentially be oncogenic. Although many mechanistic studies have been undertaken iron chelators, the complexity of cell signalling remains a hurdle preventing the discovery of all cellular targets of iron chelation. A potential way of discovering new targets is combining iron chelators with well-characterised cancer therapeutics. DOI - https://doi.org/10.18632/oncotarget.27866 Full text - https://www.oncotarget.com/article/27866/text/ Correspondence to - Gina Abdelaal - gina.abdelaal@northumbria.ac.uk Keywords - iron chelator, oncogenesis, selective cytotoxicity, hallmarks of cancer, NDRG1 About Oncotarget Oncotarget is a biweekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/

Oncotarget published "Reversing oncogenic transformation with iron chelation" which reported that cancer cells accumulate iron to supplement their aberrant growth and metabolism. Depleting cells of iron by iron chelators has been shown to be selectively cytotoxic to cancer cells in vitro and in vivo. A plethora of studies have shown iron chelators can reverse some of the major hallmarks and enabling characteristics of cancer. Iron chelators inhibit signalling pathways that drive proliferation, migration and metastasis as well as return tumour suppressive signalling. Iron chelators target cancer cell metabolism, attenuating oxidative phosphorylation and glycolysis. Dr. Gina Abdelaal from The Northumbria University said, "Iron is vital for normal cell growth and survival." Cancer is an evolutionary maverick, which exploits its trademark genomic instability to drain environmental resources. As an enzyme cofactor, iron is responsible for many cellular processes including mitochondrial metabolism and DNA synthesis. As iron can drive cellular proliferation, cancer cells have an adapted iron metabolism allowing increased iron accumulation. The thiosemicarbazone class is a later stage of iron chelator evolution which manifested in 1992. Unlike their predecessor DFO, thiosemicarbazone chelators are capable of inducing reactive oxygen species. Triapine is a thiosemicarbazone; its primary mode of action is thought to be ribonucleotide reductase inhibition with a higher potency than commonly used ribonucleotide reductase inhibitor, hydroxyurea. This approach is predicted to protect healthy tissues from the cytotoxic effects as the timing and place of the drug release can be controlled. Encapsulating Dp44mT in PLGA nanoparticles enhanced its ability to induce apoptosis and improved its selectivity towards cancer cells. At present many more classes of iron chelators are being taken into consideration as potential cancer therapy candidates. The Abdelaal Research Team concluded in their Oncotarget Research Output that based on the data presented in this review iron chelators could potentially reverse many of the key hallmarks of cancer. Stripping the cells of iron impacts many cellular targets with some targets still undiscovered. NDRG1 has been proven to be the common link between the ability of iron chelators to reverse many of the hallmarks of cancer as overexpression of NDRG1 mimics the impact of iron chelation on several signalling pathways. There are still many unanswered questions about the mechanism of action of iron chelators. A consensus must be reached on the impact of iron chelation on angiogenesis through in vivo studies. As STAT3 is essential for VEGF gene expression and iron chelation attenuates STAT3 dimerisation and nuclear localisation. The cleaved isoform is only present in cancer cells and could potentially be oncogenic. Although many mechanistic studies have been undertaken iron chelators, the complexity of cell signalling remains a hurdle preventing the discovery of all cellular targets of iron chelation. A potential way of discovering new targets is combining iron chelators with well-characterised cancer therapeutics. DOI - https://doi.org/10.18632/oncotarget.27866 Full text - https://www.oncotarget.com/article/27866/text/ Correspondence to - Gina Abdelaal - gina.abdelaal@northumbria.ac.uk Keywords - iron chelator, oncogenesis, selective cytotoxicity, hallmarks of cancer, NDRG1 About Oncotarget Oncotarget is a biweekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/

Eating leafy greens could help prevent macular degeneration Westmead Institute for Medical Research (Australia), October 13, 2021    A new study has shown that eating vegetable nitrates, found mainly in green leafy vegetables and beetroot, could help reduce your risk of developing early-stage age-related macular degeneration (AMD). Researchers at the Westmead Institute for Medical Research interviewed more than 2,000 Australian adults aged over 49 and followed them over a 15-year period. The research showed that people who ate between 100 to 142 mgs of vegetable nitrates each day had a 35% lower risk of developing early AMD than people who ate less than 69mgs of vegetable nitrates each day. Lead Researcher Associate Professor Bamini Gopinath from the Westmead Institute and the University of Sydney said the link between vegetable nitrates and macular degeneration could have important implications. "This is the first time the effects of dietary nitrates on macular degeneration risk has been measured. "Essentially we found that people who ate 100 to 142 mgs of vegetable nitrates every day had a reduced risk of developing early signs of macular degeneration compared with people who ate fewer nitrates. "If our findings are confirmed, incorporating a range of foods rich in dietary nitrates - like green leafy vegetables and beetroot - could be a simple strategy to reduce the risk of early macular degeneration," Associate Professor Gopinath said. Spinach has approximately 20mg of nitrate per 100g, while beetroot has nearly 15mg of nitrate per 100g. The research did not show any additional benefits for people who exceeded 142mgs of dietary nitrate each day. It also did not show any significant connections between vegetable nitrates and late stage AMD, or between non-vegetable nitrates and AMD risk. One in seven Australians over 50 have some signs of macular degeneration. Age is the strongest known risk factor and the disease is more likely to occur after the age of 50. There is currently no cure for the disease. The research compiled data from the Blue Mountains Eye Study, a benchmark population-based study that started in 1992. It is one of the world's largest epidemiology studies, measuring diet and lifestyle factors against health outcomes and a range of chronic diseases. "Our research aims to understand why eye diseases occur, as well as the genetic and environmental conditions that may threaten vision," Associate Professor Gopinath concluded.     Research review shows intermittent fasting works for weight loss, health changes University of Illinois Chicago, October 13, 2021 Intermittent fasting can produce clinically significant weight loss as well as improve metabolic health in individuals with obesity, according to a new study review led by University of Illinois Chicago researchers. "We noted that intermittent fasting is not better than regular dieting; both produce the same amount of weight loss and similar changes in blood pressure, cholesterol and inflammation," said Krista Varady, professor of nutrition at the UIC College of Applied Health Sciences and author of "Cardiometabolic Benefits of Intermittent Fasting."  According to the analysis published in the Annual Review of Nutrition, all forms of fasting reviewed produced mild to moderate weight loss, 1 percent to 8 percent from baseline weight, which represents results that are similar to that of more traditional, calorie-restrictive diets. Intermittent fasting regimens may also benefit health by decreasing blood pressure and insulin resistance, and in some cases, cholesterol and triglyceride levels are also lowered. Other health benefits, such as improved appetite regulation and positive changes in the gut microbiome, have also been demonstrated.  The review looked at over 25 research studies involving three types of intermittent fasting:  Alternate day fasting, which typically involves a feast day alternated with a fast day where 500 calories are consumed in one meal.  5:2 diet, a modified version of alternate day fasting that involves five feast days and two fast days per week.  Time-restricted eating, which confines eating to a specified number of hours per day, usually four to 10 hours, with no calorie restrictions during the eating period.  Various studies of time-restricted eating show participants with obesity losing an average of 3 percent of their body weight, regardless of the time of the eating window.  Studies showed alternate day fasting resulted in weight loss of 3 percent to 8 percent of body weight over three to eight weeks, with results peaking at 12 weeks. Individuals on alternate day fasting typically do not overeat or binge on feast days, which results in mild to moderate weight loss, according to the review.  Studies for the 5:2 diet showed similar results to alternate day fasting, which surprised the study's reviewers. The subjects who participate in the 5:2 diet fast much less frequently than alternate-day fasting participants do, but the weight loss results are similar.  Weight loss with alternate day and 5:2 fasting are comparable to more traditional daily calorie-restrictive diets. And, both fasting diets showed individuals were able to maintain an average of 7 percent weight loss for a year.  "You're fooling your body into eating a little bit less and that's why people are losing weight," Varady said.  Varady added the review set out to debunk some myths regarding intermittent fasting. Intermittent fasting does not negatively affect metabolism, nor does it cause disordered eating, according to the studies reviewed.  "Fasting people are worried about feeling lethargic and not being able to concentrate. Even though you are not eating, it won't affect your energy," Varady said. "A lot of people experience a boost of energy on fasting days. Don't worry, you won't feel crappy. You may even feel better."  The study review includes a summary of practical considerations for those who may want to try intermittent fasting. Among the considerations are:  Adjustment time—Side effects such as headaches, dizziness and constipation subside after one to two weeks of fasting. Increased water intake can help alleviate headaches caused by dehydration during this time.  Exercise—Moderate to high-intensity endurance or resistance training during food abstention can be done, and some study participants reported having more energy on fast days. However, studies recommend those following alternate day fasting eat their fasting day meal after exercise.  Diet during fasting—There are no specific recommendations for food consumption during intermittent fasting, but eating fruits, vegetables and whole grains can help boost fiber intake and help relieve constipation that sometimes accompanies fasting.  Alcohol and caffeine—For those using an alternate day or 5:2 fasting plan, alcohol is not recommended on fast days as the limited calories should be used on healthy foods that provide nutrition.  There are several groups who should not intermittent fast, according to the studies. Those individuals include:  Those who are pregnant or lactating.  Children under 12.  Those with a history of disordered eating.  Those with a body mass index, or BMI, less than 18.5. Shift workers. Studies have shown they may struggle with fasting regimens because of shifting work schedules.  Those who need to take medication with food at regimented times.  "People love intermittent fasting because it's easy. People need to find diets that they can stick to long term. It's definitely effective for weight loss and it's gained popularity because there are no special foods or apps necessary. You can also combine it with other diets, like Keto," Varady said.  Varady has recently been awarded a National Institutes of Health grant to study time-restricted eating for 12 months to see if it works long term.   Antioxidants to prevent Alzheimer's disease A balanced intake of antioxidants could prevent the development of Alzheimer's disease. Institut National de la Recherche Scientifique (France), October 13, 2021 Research conducted by the Ph.D student Mohamed Raâfet Ben Khedher and the postdoctoral researcher Mohamed Haddad of the Institut national de la recherche scientifique (INRS) has shown that an oxidation-antioxidant imbalance in the blood is an early indicator of Alzheimer's disease, rather than a consequence. This breakthrough made by researchers under the supervision of the Professor Charles Ramassamy provides an avenue for preventive intervention: the antioxidants intake.  The research team showed that oxidative markers, known to be involved in Alzheimer's disease, show an increase up to five years before the onset of the disease. The results of this study, published in the Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring (DADM) journal, suggest that oxidation may be an early marker of this disease that affects more than 500,000 Canadians. “Given that there is an increase in oxidative stress in people who develop the disease, we may regulate the antioxidant systems. For example, we could modulate the antioxidant systems, such as apolipoproteins J and D, which transport lipids and cholesterol in the blood and play an important role in brain function and Alzheimer's disease. Another avenue would be to increase the intake of antioxidants through nutrition”, says Professor Ramassamy.  Accessible biomarkers Unlike the current set of invasive and expensive tests used to diagnose Alzheimer's disease, the oxidative markers discovered by Professor Ramassamy's research team can be detected by a blood test. These markers are found in plasma extracellular vesicles, which are pockets released by all cells in the body, including those in the brain.     The research team focused specifically on the "sporadic" Alzheimer's disease, the most common form of the disease which results primarily from the presence of the APOE4 susceptibility gene. This same form of the disease had been studied by the team for other early markers. “By identifying oxidative markers in the blood of individuals at risk five years before the onset of the disease, we could make recommendations to slow the onset of the disease and limit the risks”, scientists noted. This breakthrough brings new hope to Alzheimer's research. Once the disease is symptomatic, it is difficult, if not impossible, to reverse it.         Meditation training reduces long-term stress, according to hair analysis Max Planck Institute for Human Cognitive and Brain Sciences (Germany), October 11, 2021 Mental training that promotes skills such as mindfulness, gratitude or compassion reduces the concentration of the stress hormone cortisol in hair. This is what scientists from the Max Planck Institute for Human Cognitive and Brain Sciences in Leipzig and the Social Neuroscience Research Group of the Max Planck Society in Berlin have found out. The amount of cortisol in hair provides information about how much a person is burdened by persistent stress. Earlier positive training effects had been shown in acutely stressful situations or on individual days—or were based on study participants' self-reports. According to a study by the Techniker Krankenkasse, 23 percent of people in Germany frequently suffer from stress. This condition not only puts a strain on the well-being of those affected, but it is also linked to a number of physiological diseases, including diabetes, cardiovascular diseases and psychological disorders such as depression, one of the world's leading causes of disease burden (Global Burden of Disease Study, 2017). Therefore, effective methods are being sought to reduce everyday stress in the long term. One promising option is mindfulness training, in which participants train their cognitive and social skills, including attention, gratitude and compassion, through various meditation and behavioral exercises. Various studies have already shown that even healthy people feel less stressed after a typical eight-week training program. Until now, however, it has been unclear how much the training actually contributes to reducing the constant burden of everyday stress. The problem with many previous studies on chronic stress is that the study participants were usually asked to self-assess their stress levels after the training. However, this self-reporting by means of questionnaires could have distorted the effects and made the results appear more positive than they actually were. The reason for such a bias: The participants knew they were training their mindfulness, and a reduction in stress levels was a desired effect of this training. This awareness alone has an impact on subsequent information. "If you are asked whether you are stressed after a training session that is declared as stress-reducing, even addressing this question can distort the statements," explains Lara Puhlmann, doctoral student at the Max Planck Institute for Human Cognitive and Brain Sciences and first author of the underlying publication, which has now appeared in the journal Psychosomatic Medicine. Factors such as social desirability and placebo effects played a role here. Unlike pharmacological studies, for example, in which the study participants do not know whether they have actually received the active substance or not, so-called blinded studies are not possible in mental training. "The participants know that they are ingesting the 'antidote,'" says Puhlmann. "In mindfulness research, we are therefore increasingly using more objective, i.e. physiological, methods to measure the stress-reducing effect more precisely." The concentration of cortisol in hair is considered a suitable measure of exposure to prolonged stress. Cortisol is a hormone that is released when we are confronted with an overwhelming challenge, for example. In that particular situation, it helps put our body on alert and mobilize energy to overcome the challenge. The longer the stress lasts, the longer an increased concentration of cortisol circulates around our body—and the more it accumulates in our hair. On average, hair grows one centimeter per month. To measure the study participants' stress levels during the 9-month training, the researchers, in cooperation with the working group of Clemens Kirschbaum at the University of Dresden, analyzed the amount of cortisol every three months in the first three centimeters of hair, starting at the scalp. The mental training itself was developed as part of a large-scale longitudinal study on the effects of mental training, the ReSource project, led by Tania Singer, scientific director of the Social Neuroscience Research Group. This 9-month mental training program consisted of three 3-month sessions, each designed to train a specific skill area using Western and Far Eastern mental exercises. The focus was either on the factors of attention and mindfulness, on socio-affective skills such as compassion and gratitude, or on so-called socio-cognitive skills, in particular the ability to take perspective on one's own and others' thoughts. Three groups of about 80 participants each completed the training modules in different order. The training lasted up to nine months, 30 minutes a day, six days a week. Less stress, less cortisol And it really showed: After six months of training, the amount of cortisol in the subjects' hair had decreased significantly, on average by 25 percent. In the first three months, slight effects were seen at first, which increased over the following three months. In the last third, the concentration remained at a low level. The researchers therefore assume that only sufficiently long training leads to the desired stress-reducing effects. The effect did not seem to depend on the content of the training. It is therefore possible that several of the mental approaches studied are similarly effective in improving the way people deal with chronic everyday stress. In an earlier study from the ReSource project with the same sample, the researchers had investigated the effects of training on dealing with acute stressful situations. In this study, the participants were placed in a stressful job interview and had to solve difficult maths problems under observation. The results showed that people who had undergone socio-cognitive or socio-affective training released up to 51 percent less cortisol under stress than those who had not been trained. In this case, they did not measure the amount of cortisol in the subjects' hair, but instead acute cortisolsurges in their saliva. Overall, the researchers conclude that training can improve the handling of acute particularly stressful social situations as well as chronic everyday stress. "We assume that different training aspects are particularly helpful for these different forms of stress," says Veronika Engert, head of the research group "Social Stress and Family Health" at the Max Planck Institute for Human Cognitive and Brain Sciences. "There are many diseases worldwide, including depression, that are directly or indirectly related to long-term stress," explains Puhlmann. "We need to work on counteracting the effects of chronic stress in a preventive way. Our study uses physiological measurements to prove that meditation-based training interventions can alleviate general stress levels even in healthy individuals."   Study: Moderate carbohydrate intake is a cardiovascular benefit for women Monash University (Australia), October 13, 2021 Women's heart health has been the focus of a recent study by Monash University, with researchers finding that proportional carbohydrate intake and not saturated fat was significantly associated with cardiovascular disease benefit in Australian women. Cardiovascular disease (CVD) is the leading cause of death in women. Poor diet is recognized as both an independent CVD risk factor and a contributor to other CVD risk factors, such as obesity, diabetes mellitus (DM), hypertension, and dyslipidaemia. The research found that in middle-aged Australian women, increasing the percentage of carbohydrate intake was significantly associated with reduced odds of CVD, hypertension, diabetes mellitus, and obesity. Furthermore, a moderate carbohydrate intake between 41.0 percent—44.3 percent of total energy intake was associated with the lowest risk of CVD compared to women who consumed less than 37 percent energy as carbohydrates. No significant relationship was demonstrated between proportional carbohydrate intake and all-cause mortality. In addition, increasing proportional saturated fat intake was not associated with cardiovascular disease or mortality in women; rather, increasing saturated fat intakecorrelated with lower odds of developing diabetes mellitus, hypertension, and obesity. The findings are now published in the British Medical Journal. The results contradict much of the historical epidemiological research that supported a link between saturated fat and CVD. Instead, the results mirror contemporary meta-analysis of prospective cohort studies where saturated fat was found to have no significant relationship with total mortality or CVD. While the cause of this inconsistency in the literature is unclear, it has been suggested that historical studies neglected to adjust for fiber, which is known to help prevent plaque from forming in the arteries. "Controversy still exists surrounding the best diet to prevent CVD," said Sarah Zaman, a former Monash University professor who is now an associate professor at the University of Sydney. "A low-fat diet has historically been the mainstay of primary prevention guidelines, but the major issue within our dietary guidelines is that many dietary trials have predominately involved male participants or lacked sex-specific analyses." She adds: "Further research is needed to tailor our dietary guidelines according to sex." The study's first author Sarah Gribbin, a Doctor of Medicine and BMedSc (Hons) student, says: "As an observational study, our findings only show association and not causation. Our research is purely hypothesis-generating. We are hoping that our findings will spark future research into sex-specific dietary research." The Heart Foundation, which is one of the study's funders, welcomed the focus on women and CVD, which has historically been under-researched. Heart Foundation manager, food and nutrition, Eithne Cahill, cautioned that "not all carbohydrates are created equal." "We know that quality carbohydrate foods such as vegetables and whole grains—including whole grain bread, cereals, and pasta—are beneficial for heart health, whereas poor quality carbohydrates such as white bread, biscuits, cakes, and pastries can increase risk," she said. "Similarly, different fats have different effects on heart health. That is why the Heart Foundation focuses on healthy eating patterns—that is, a combination of foods, chosen regularly over time—rather than a single nutrient or food. Include plenty of vegetables, fruit, and whole grains, and heart-healthy fat choices such as nuts, seeds, avocados, olives and their oils for cooking and a variety of healthy proteins especially seafood, beans and lentils, eggs and dairy."   Anti-cancer effects found in natural compound derived from onions   Kumamoto University (Japan), October 18, 2021   Research from Kumamoto University, Japan has found that a natural compound isolated from onions, onionin A (ONA), has several anti-ovarian cancer properties. This discovery is a result of research on the effects of ONA on a preclinical model of epithelial ovarian cancer (EOC) both in vivo and in vitro. This research comes from the same group that found ONA suppressed pro-tumor activation of host myeloid cells.   According to a 2014 review of cancer medicines from the World Health Organization, EOC is the most common type of ovarian cancer and has a 5-year survival rate of approximately 40%. It has a relatively low lifetime risk that is less than 1%, but that can increase up to 40% if there is a family history of the disease. A majority of patients (80%) experience a relapse after their initial treatment with chemotherapy, therefore a more effective line of treatment is needed.   Kumamoto University researchers found that ONA has several effects on EOC. The group's in vitro experiments showed that EOCs, which usually proliferate in the presence of pro-tumor M2 macrophages, showed inhibited growth after introduction of ONA. This was thought to be due to ONAs influence on STAT3, a transcription factor known to be involved in both M2 polarization and cancer cell proliferation. Furthermore, the team found that ONA inhibited the pro-tumor functions of myeloid derived suppressor cells (MDSC), which are closely associated with the suppression of the anti-tumor immune response of host lymphocytes, by using preclinical sarcoma model. ONA was also found to enhance the effects of anti-cancer drugs by strengthening their anti-proliferation capabilities. Moreover, experiments on an ovarian cancer murine model that investigated the effects of orally administered ONA resulted in longer lifespans and inhibited ovarian cancer tumor development. This was considered to be a result of ONA's suppression of M2 polarized macrophages.   The research shows that ONA reduces the progression of malignant ovarian cancer tumors by interfering with the pro-tumor function of myeloid cells. ONA appears to activate anti-tumor immune responses by nullifying the immunosuppressive function of myeloid cells. ONA has the potential to enhance existing anti-cancer drugs while also having little to no cytotoxic effects on normal cells. Additionally, side effects in animals have not been seen. With a little more testing, an oral ONA supplement should greatly benefit cancer patients.     Risk of chronic diseases caused by exogenous chemical residues Dalian Institute of Chemical Physics (China), October 13, 2021 Chronic diseases are main killers affecting the health of human. The morbidities of major chronic diseases such as obesity, hypertension, diabetes, hyperuricemia and dyslipidemia are as high as 10% to 30%, showing a gradually upward trend as well. More and more studies have shown that environmental pollution is a major health risk factor that cannot be ignored. However, the evidence for their relationship is equivocal and the underlying mechanisms is unclear. Recently, a research group led by Prof. Xu Guowang from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences (CAS) discovered the risk of chronic diseases caused by exogenous chemical residues through metabolome-wide association study. Their findings were published in Environment International on Oct. 8. Researchers from National Institute for Nutrition and Health of the Chinese Center for Disease Control and Prevention, and Tongji Medical College of Huazhong University of Science and Technology were also involved in this study. The researchers discovered positive associations of serum perfluoroalkyl substances (PFASs) with hyperuricemia, and revealed the mechanism of the relationship between the exogenous chemical residues in the serum and the risk of chronic diseases at the metabolic level. The researchers investigated the relationship between 106 exogenous chemical residues and five chronic diseases in 496 serum samples. They revealed the metabolic perturbations related to exogenous chemical residues and chronic diseases by the metabolome-wide association study combined with meeting-in-the-middle approach and mediation analysis, and investigated the further potential underlying mechanism at the metabolic level. "PFASs were the risk factor for hyperuricemia," said Prof. Xu. Lipid species including glycerophospholipids and glycerides presented the strongest correlation with exposure and disease, which were not only positively related to PFASs exposure but also the risk factor for hyperuricemia. "We also found that key mediation metabolites mediated 25% to 68% of the exposure-disease risk relationship," Prof. Xu added. This study provides in-depth etiological understanding for the occurrence and development of diseases, which may be helpful for the early detection of the disease and the identification of early warning markers.

Can low temperature-aged garlic enhance exercise performance? Korea Univesity & National Institute of Agricultural Sciences (South Korea), October 8, 2021 Scientists from South Korea's National Institute of Agricultural Sciences and Korea University looked at aged garlic to see whether it could help reduce fatigue. To do this, they conducted a study on mice fed with a special low-temperature-aged garlic (LTAG). Their findings were published in the Journal of Medicinal Food. Testing the fatigue-fighting effects of low temperature-aged garlic The researchers chose to use LTAG because it lacked the pungent odor and spicy flavor of regular garlic, making it easier to use for animal testing. To create the LTAG, the researchers stored garlic in a sealed container, aging at 60 C for 60 days. The resulting LTAG was then peeled and pulverized, before being added to 200 milliliters of 70 percent ethanol (EtOH), which was then subjected to ultrasonic extraction three times. This 70 percent EtOH and LTAG extract was then concentrated under a vacuum at 45 C and then lyophilized to create a dry LTAG residue. After the creation of the LTAG, the researchers then separated mice into six groups. The first group was given a low dose of LTAG extract; the second was fed a high dose of LTAG extract; the third was given a low dose of garlic extract; and the fourth was given a high dose of garlic extract. The fifth and sixth groups consisted of normal mice that were given phosphate-buffered saline (PBS) instead of garlic. One of these control groups was made to exercise while the other group was not. The mice in the five groups were forced to run on a treadmill for four weeks. With each passing week, the amount of exercise the mice would have to do on the treadmills would increase. This was done by increasing both the speed that the mice had to run, and the amount of time they had to spend running. (Related: How to alleviate fatigue with herbal medicine.) After 28 days of treatment, five mice from each group were subjected to a final, exhaustive treadmill test. This test increased the treadmill speed from 15 meters per minute (m/min) to 40 m/min every 3 minutes. During this test, the running time was monitored until each mouse failed to follow the increase in speed on three consecutive occasions and lag occurred. At this point, the mouse's total running time was recorded. The effect of the LTAG on the levels of glucose, lactate dehydrogenase (LDH), free fatty acid (FFA) and lactate in the mice's blood. Following the final exercise, the mice were killed and blood samples were collected from them. In addition, the mice's gastrocnemius muscles were also isolated and frozen in liquid nitrogen for testing. LTAG treated mice demonstrated less fatigue Following the exhaustive running tests, the researchers found that the mice treated with LTAG extract were able to run for much longer than the control mice. Meanwhile, looking at the blood tests, they noted that the mice treated with LTAG extract exhibited lower levels of glucose, LDH, FFA and lactate. More importantly, the LTAG treated mice had increased amounts of glycogen and creatine kinase (CK) in their muscles. Glycogen storage is an important source of energy during exercise. It serves a central role in maintaining the body's glucose homeostasis by supplementing blood glucose. Because of this, glycogen is seen as an accurate marker for fatigue, with increased glycogel levels closely associated with improved endurance and anti-fatigue effects. CK, on the other hand, is known to be an accurate indicator of muscle damage. During muscle degeneration, muscle cells are dissolved and their contents enter the bloodstream. As a result, when muscle damage occurs, muscle CK comes out into the blood. As such, fatigue tends to lead to lower muscle CK levels and higher blood CK levels. Higher levels of glycogen and muscle CK in the LTAG treated mice indicated that they experienced less fatigue than the other groups. Based on these findings, the researchers believe that LTAG has potential for use as an anti-fatigue agent.       Mindfulness meditation helps preterm-born adolescents University of Geneva (Switzerland), October 7, 2021 Adolescents born prematurely present a high risk of developing executive, behavioral and socio-emotional difficulties. Now, researchers from Geneva University Hospitals (HUG) and the University of Geneva (UNIGE) have revealed that practicing mindfulness may help improve these various skills. The study, published in the journal Scientific Reports, suggests using mindfulness as a means of clinical intervention with adolescents, whether prematurely born or not. Several studies have already shown that very preterm (VPT) children and adolescents are at higher risk of exhibiting cognitive and socio-emotional problems that may persist into adulthood. To help them overcome the difficulties they face, researchers from the HUG and UNIGE have set up an intervention based on mindfulness, a technique known to have beneficial effects in these areas. Mindfulness consists in training the mind to focus on the present moment, concentrating on physical sensations, on breathing, on the weight of one's body, and even on one's feelings and thoughts, completely judgment-free. The mindfulness-based interventions generally take place in a group with an instructor along with invitations to practice individually at home. To accurately assess the effects of mindfulness, a randomized controlled trial was performed with young adolescents aged 10 to 14, born before 32 weeks gestational weeks. Scientists quickly found that mindfulness improves the regulation of cognitive, social and emotional functions, in other worlds, our brain's ability to interact with our environment. Indeed, it increases the ability to focus on the present—on thoughts, emotions and physical sensations, with curiosity and non-judgment. Thanks to this practice, adolescents improve their executive functions, i.e. the mental processes that enable us to control our behavior to successfully achieve a goal. As a result, young people find it easier to focus, manage and regulate their behavior and emotions in everyday life. For eight weeks, the young teens spent an hour and a half each week with two mindfulness instructors. They were further encouraged to practice mindfulness daily at home. Parents were also involved in this study. They were asked to observe their child's executive functions, for example the ability to regulate their emotions and attentional control, their relationships with others and their behavior. The adolescents also underwent a series of computerized tasks to assess their reactions to events. A comparison of their test results with a control group that did not practice mindfulness shows a positive impact of the intervention on the adolescents' everyday life and on their ability to react to new events. "Each teenager is unique, with their own strenghts and difficulties. Through their involvement in this study, our volunteers have contributed to show that mindfulness can help many young people to feel better, to refocus and to face the world, whether they were born preterm born or not," agree Dr. Russia Hà-Vinh Leuchter, a consultant in the Division of Development and Growth, Department of Paediatrics, Gynaecology and Obstetrics at Geneva University Hospitals, and Dr. Vanessa Siffredi, a researcher at the Child Development Laboratory at the Department of Paediatrics, Gynaecology and Obstetrics at the UNIGE Faculty of Medicine, two of the authors of this work. "However, while the practice of meditation can be a useful resource, it is important to be accompanied by well-trained instructors", they specify. The adolescents who took part in the program are now between 14 and 18 years. Scientists are currently evaluating the long-term effects of mindfulness-based intervention on their daily attention and stress. Furthermore, to validate their clinical data with neurobiological measurements, researchers are currently studying the effects of mindfulness on the brain using magnetic resonance imaging (MRI).   Iron deficiency in middle age is linked with higher risk of developing heart disease University Heart and Vasculature Centre Hamburg (Germany) 6 October 2021 Approximately 10% of new coronary heart disease cases occurring within a decade of middle age could be avoided by preventing iron deficiency, suggests a study published today in ESC Heart Failure, a journal of the European Society of Cardiology (ESC).1 “This was an observational study and we cannot conclude that iron deficiency causes heart disease,” said study author Dr. Benedikt Schrage of the University Heart and Vasculature Centre Hamburg, Germany. “However, evidence is growing that there is a link and these findings provide the basis for further research to confirm the results.” Previous studies have shown that in patients with cardiovascular diseases such as heart failure, iron deficiency was linked to worse outcomes including hospitalisations and death. Treatment with intravenous iron improved symptoms, functional capacity, and quality of life in patients with heart failure and iron deficiency enrolled in the FAIR-HF trial.2 Based on these results, the FAIR-HF 2 trial is investigating the impact of intravenous iron supplementation on the risk of death in patients with heart failure. The current study aimed to examine whether the association between iron deficiency and outcomes was also observed in the general population. The study included 12,164 individuals from three European population-based cohorts. The median age was 59 years and 55% were women. During the baseline study visit, cardiovascular risk factors and comorbidities such as smoking, obesity, diabetes and cholesterol were assessed via a thorough clinical assessment including blood samples. Participants were classified as iron deficient or not according to two definitions: 1) absolute iron deficiency, which only includes stored iron (ferritin); and 2) functional iron deficiency, which includes iron in storage (ferritin) and iron in circulation for use by the body (transferrin). Dr. Schrage explained: “Absolute iron deficiency is the traditional way of assessing iron status but it misses circulating iron. The functional definition is more accurate as it includes both measures and picks up those with sufficient stores but not enough in circulation for the body to work properly.” Participants were followed up for incident coronary heart disease and stroke, death due to cardiovascular disease, and all-cause death. The researchers analysed the association between iron deficiency and incident coronary heart disease, stroke, cardiovascular mortality, and all-cause mortality after adjustments for age, sex, smoking, cholesterol, blood pressure, diabetes, body mass index, and inflammation. Participants with a history of coronary heart disease or stroke at baseline were excluded from the incident disease analyses. At baseline, 60% of participants had absolute iron deficiency and 64% had functional iron deficiency. During a median follow-up of 13.3 years there were 2,212 (18.2%) deaths. Of these, a total of 573 individuals (4.7%) died from a cardiovascular cause. Incidence coronary heart disease and stroke were diagnosed in 1,033 (8.5%) and 766 (6.3%) participants, respectively. Functional iron deficiency was associated with a 24% higher risk of coronary heart disease, 26% raised risk of cardiovascular mortality, and 12% increased risk of all-cause mortality compared with no functional iron deficiency. Absolute iron deficiency was associated with a 20% raised risk of coronary heart disease compared with no absolute iron deficiency, but was not linked with mortality. There were no associations between iron status and incident stroke. The researchers calculated the population attributable fraction, which estimates the proportion of events in 10 years that would have been avoided if all individuals had the risk of those without iron deficiency at baseline. The models were adjusted for age, sex, smoking, cholesterol, blood pressure, diabetes, body mass index, and inflammation. Within a 10-year period, 5.4% of all deaths, 11.7% of cardiovascular deaths, and 10.7% of new coronary heart disease diagnoses were attributable to functional iron deficiency. “This analysis suggests that if iron deficiency had been absent at baseline, about 5% of deaths, 12% of cardiovascular deaths, and 11% of new coronary heart disease diagnoses would not have occurred in the following decade,” said Dr. Schrage. “The study showed that iron deficiency was highly prevalent in this middle-aged population, with nearly two-thirds having functional iron deficiency,” said Dr. Schrage. “These individuals were more likely to develop heart disease and were also more likely to die during the next 13 years.” Dr. Schrage noted that future studies should examine these associations in younger and non-European cohorts. He said: “If the relationships are confirmed, the next step would be a randomised trial investigating the effect of treating iron deficiency in the general population.”     Consumption of a bioactive compound from Neem plant could significantly suppress development of prostate cancer National University of Singapore, September 29, 2021   Oral administration of nimbolide, over 12 weeks shows reduction of prostate tumor size by up to 70 per cent and decrease in tumor metastasis by up to 50 per cent   A team of international researchers led by Associate Professor Gautam Sethi from the Department of Pharmacology at the Yong Loo Lin School of Medicine at the National University of Singapore (NUS) has found that nimbolide, a bioactive terpenoid compound derived from Azadirachta indica or more commonly known as the neem plant, could reduce the size of prostate tumor by up to 70 per cent and suppress its spread or metastasis by half.   Prostate cancer is one of the most commonly diagnosed cancers worldwide. However, currently available therapies for metastatic prostate cancer are only marginally effective. Hence, there is a need for more novel treatment alternatives and options.   "Although the diverse anti-cancer effects of nimbolide have been reported in different cancer types, its potential effects on prostate cancer initiation and progression have not been demonstrated in scientific studies. In this research, we have demonstrated that nimbolide can inhibit tumor cell viability -- a cellular process that directly affects the ability of a cell to proliferate, grow, divide, or repair damaged cell components -- and induce programmed cell death in prostate cancer cells," said Assoc Prof Sethi.   Nimbolide: promising effects on prostate cancer   Cell invasion and migration are key steps during tumor metastasis. The NUS-led study revealed that nimbolide can significantly suppress cell invasion and migration of prostate cancer cells, suggesting its ability to reduce tumor metastasis. The researchers observed that upon the 12 weeks of administering nimbolide, the size of prostate cancer tumor was reduced by as much as 70 per cent and its metastasis decreased by about 50 per cent, without exhibiting any significant adverse effects.   "This is possible because a direct target of nimbolide in prostate cancer is glutathione reductase, an enzyme which is responsible for maintaining the antioxidant system that regulates the STAT3 gene in the body. The activation of the STAT3 gene has been reported to contribute to prostate tumor growth and metastasis," explained Assoc Prof Sethi. "We have found that nimbolide can substantially inhibit STAT3 activation and thereby abrogating the growth and metastasis of prostate tumor," he added.   The findings of the study were published in the April 2016 issue of the scientific journal Antioxidants & Redox Signaling. This work was carried out in collaboration with Professor Goh Boon Cher of Cancer Science Institute of Singapore at NUS, Professor Hui Kam Man of National Cancer Centre Singapore and Professor Ahn Kwang Seok of Kyung Hee University.   The neem plant belongs to the mahogany tree family that is originally native to India and the Indian sub-continent. It has been part of traditional Asian medicine for centuries and is typically used in Indian Ayurvedic medicine. Today, neem leaves and bark have been incorporated into many personal care products such as soaps, toothpaste, skincare and even dietary supplements.       Review looks at the efficacy of acupuncture in treating insulin resistance Guangzhou University of Chinese Medicine (China), October 8, 2021 In their report, researcherss from Guangzhou University of Chinese Medicine in China explored the role of acupuncture in treating insulin resistance. The study was published in the journal Complementary Therapies in Clinical Practice. Earlier studies have reported the effectiveness of acupuncture in treating insulin resistance and related conditions. The review looked at acupuncture and its effects on clinical outcomes. The researchers searched the following databases for randomized controlled trials involving insulin resistance patients treated with acupuncture: Cochrane Central Register of Controlled Trials Embase Medline (via OVID) China National Knowledge Infrastructure (CNKI) Wan Fang and China Science and Technology Journal Database (VIP) The studies show that homeostasis model assessment of insulin resistance significantly decreased with acupuncture treatment. Other significant decreases include fasting blood glucose, postprandial blood glucose and fasting insulin. Acupuncture increased insulin sensitivity with very few adverse effects. In sum, acupuncture is a safe and effective alternative treatment for insulin resistance.     Blueberries may improve attention in children following double-blind trial University of Reading (UK), October 10, 2021  Primary school children could show better attention by consuming flavonoid-rich blueberries, following a study conducted by the University of Reading. In a paper published in Food & Function, a group of 7-10 year olds who consumed a drink containing wild blueberries or a matched placebo and were tested on their speed and accuracy in completing an executive task function on a computer. The double blind trial found that the children who consumed the flavonoid-rich blueberry drink had 9% quicker reaction times on the test without any sacrifice of accuracy. In particular, the effect was more noticeable as the tests got harder. Professor Claire Williams, a neuroscience professor at the University of Reading said: "This is the first time that we have seen the positive impact that flavonoids can have on the executive function of children. We designed this double blind trial especially to test how flavonoids would impact on attention in young people as it's an area of cognitive performance that hasn't been measured before. "We used wild blueberries as they are rich in flavonoids, which are compounds found naturally in foods such as fruits and their juices, vegetables and tea. They have been associated with a range of health benefits including antioxidant and anti-inflammatory effects, and our latest findings continue to show that there is a beneficial cognitive effect of consuming fruit and vegetables, tea, coffee and even dark chocolate which all contain flavonoids." The children were then asked to pay attention to an array of arrows shown on a PC screen and press a key corresponding to the direction that the central arrow was facing. The task was repeated over a number of trials, where cognitive demand was manipulated by varying how quickly the arrows appeared, whether there were additional arrows appearing either side of the central arrow, and whether the flanking arrows were pointing in the same/different direction as the central arrow. Previous Reading research has shown that consuming wild blueberries can improve mood in children and young people, simple memory recall in primary school children, and that other flavonoid rich drinks such as orange juice, can also improve memory and concentration. The Wild Blueberry Association of North America provided a freeze-dried powder made from wild blueberries which was used in the study but did not provide any additional financial support and did not play a role in the design of the study. Wild blueberries are grown and harvested in North America, and are smaller than regular blueberries, and are higher in flavonoids compared to regular varieties. The double-blind trial used a flavonoid-rich wild blueberry drink, with a matched placebo contained 8.9g of fructose, 7.99g of glucose and 4 mg of vitamin C matching the levels of nutrients found in the blueberry drink. The amount of fructose is akin to levels found in a standard pear. This was an executive function task- requiring participants to pay attention to stimuli appearing on screen and responding correctly. The task was a simple one- responding to the direction of an arrow in the middle of a screen (by pressing left/right arrow key) but we then varied how quickly the stimuli appeared, whether there was additional arrows appearing either side of the stimuli and whether those flanking arrows were pointing in the same/different direction as they direction you had to respond. There are 6 main classes of flavonoids: Anthocyanins – found in berry fruits such as the blueberries used in this study and also in red wine. Flavonols - found in onions, leeks, and broccoli Flavones - found in parsley and celery, Isoflavones - found in soy and soy products, Flavanones - found in citrus fruit and tomatoes Flavanols—found in green tea, red wine, and chocolate     Nocebo effect: Does a drug's high price tag cause its own side effects? University Medical Center Hamburg (Germany), October 5, 2021  Pricey drugs may make people more vulnerable to perceiving side effects, a new study suggests—and the phenomenon is not just "in their heads." The study delved into the so-called "nocebo effect." It's the negative version of the well-known placebo effect, where people feel better after receiving a therapy because they expected good things. With the nocebo effect, patients' worries over treatment side effects make them feel sick. In this study, researchers found that people were more likely to report painful side effects from a fake drug when told it was expensive. But it wasn't just something people were "making up." Using brain imaging, the researchers traced the phenomenon to specific activity patterns in the brain and spine. "These findings are a strong argument against the perception of placebo and nocebo effects as being only 'fake' effects—created purely by imagination or delusions of the patient," said lead researcher Alexandra Tinnermann. She is with the University Medical Center Hamburg-Eppendorf, in Germany. Dr. Luana Colloca, a researcher at the University of Maryland in Baltimore, agreed. "This is not merely a reflection of people's biases," said Colloca, who wrote an editorial published with the study. "Expectations do modulate symptoms and patients' responses to treatment," she said. For the study, Tinnermann's team recruited 49 healthy volunteers and randomly assigned them to test one of two itch-relieving "medical creams." In reality, both creams were identical and contained no active ingredients. However, people in both groups were told that the products could have the side effect of making the skin more sensitive to pain. There was only one apparent difference between the two phony creams: One came in fancy packing with a high price tag; the other was cheap. After participants applied the creams to their forearms, the researchers had them undergo a standard test that measured their tolerance for heat-induced pain. It turned out that people who'd used the expensive cream were more sensitive to pain during the tests. On average, their pain rating hovered around a 15—within the "mild" pain range—whereas people using the cheap cream barely registered any discomfort. It's likely, Tinnermann said, that people expect a pricey medication to be potent—which could also make them expect more side effects. Colloca agreed. We are all "vulnerable" to such outside influences, she said, be it a drug's price or how it's given (by IV versus mouth, for instance). However, we are not just imagining those placebo or nocebo effects, both researchers noted. Using functional MRI brain scans, Tinnermann's team found specific patterns of nervous system activity in people who had a nocebo response to the pricey cream. That included a change in "communication" between certain brain structures and the spinal cord, Tinnermann said. According to Colloca, research like this can have practical uses. Doctors could, for instance, inform patients that drug prices or other factors can sway their expectations about a treatment's benefits and risks—and that, in turn, can influence whether they feel better or develop side effects. There is, however, no research into whether that kind of knowledge helps prevent patients from the nocebo effect, Tinnermann said. But, she added, health professionals can be aware that patients' expectations "play a huge role in medicine"—and be mindful of how they talk about a medication and its possible side effects. It's an important matter, Colloca said, because the nocebo effect can cause people to stop taking needed medications. Colloca pointed to the example of cholesterol-lowering statins. The potential for those medications to cause muscle pain has been widely reported. And one recent study found evidence that this knowledge can make statin users more likely to report muscle pain side effects. Other research, Colloca said, has shown that when people stop taking their statins, their risk of heart attack and stroke rises.

This week's episode features author Philippe Gabriel Steg and editorialist Gregg Stone as they discuss the article "International Observational Analysis of Evolution and Outcomes of Chronic Stable Angina: The Multinational Observational CLARIFY Study." TRANSCRIPT BELOW Dr. Carolyn Lam: Welcome to Circulation 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 here with my other co-host, a little bird that you can hear I think in the background and then my real co-host, Greg. Dr. Greg Hundley: Thanks so much, Carolyn. Yes, I'm Dr. Greg Hundley. I'm not the bird this week. Associate editor, director of the Pauley Heart Center in Richmond, Virginia. Carolyn, so this week, our feature discussion is really going to be on the importance of stable angina and what that means prognostically. But before we get to that, how about we grab a cup of coffee, talk to our other bird friends and then we jump in and talk about the other papers in the issue. Would you like to go first? Dr. Carolyn Lam: Love it, Greg. Thank you so much. This first paper, very important question. We know that while the 99th percentile is the recommended diagnostic threshold for myocardial infarction, some guidelines also advocate the use of higher troponin thresholds to rule in myocardial infarction at presentation. It's still unclear whether the magnitude or change in troponin concentration can differentiate causes of myocardial injury and infarction in practice. And so today's paper is really important from Dr. Mills from the University Center for Cardiovascular Science Royal Infirmary of Edinburgh in the University of Edinburgh and colleagues. Dr. Carolyn Lam: What they did was a secondary analysis of the high stakes trial of more than 46,000 consecutive patients with suspected acute coronary syndrome. They evaluated the performance of the 99th percentile rule in threshold and thresholds of 64 ng/L and five times the upper reference limit for the diagnosis of type 1 myocardial infarction. They found that troponin concentrations at presentation have a low, positive predictive value for type 1 myocardial infarction and a threshold of 50 times the upper reference limit is required to achieve a positive predictive value of more than 70%. A change in troponin on serial testing only marginally improved positive predictive value for type 1 myocardial infarction over the presenting troponin alone. Dr. Greg Hundley: Interesting, Carolyn. Very important data. What's our take home message here. Dr. Carolyn Lam: Well, troponin concentrations at presentation are insufficient to distinguish type 1 myocardial infarction from other causes of myocardial injury or infarction and should not be used in isolation to guide management decisions in patients with suspected ACS. Consideration of other important clinical factors may be more helpful than any particular rule in threshold to guide initial triage and management. Dr. Greg Hundley: Wow, Carolyn, so really great new data and more data on the utility of these troponin concentrations. Dr. Greg Hundley: Well, my next paper comes from the world of preclinical science and it's from Professor Vladimir Kalinichenko from Cincinnati Children's Hospital Medical Center. Carolyn, as we know, pulmonary hypertension is a common complication in patients with alveolar capillary dysplasia with misalignment of pulmonary veins, a severe congenital disorder associated with mutations in the Foxf1 gene. Now, while the loss of alveolar microvasculature causes pulmonary hypertension in, and we're going to abbreviate this ACDMPV patients, it is unknown whether increasing neonatal lung angiogenesis could prevent pulmonary hypertension and right ventricular hypertrophy in these subjects. Dr. Carolyn Lam: Wow. Wow. Okay. Let's repeat that. ACDMPV stands for alveolar capillary dysplasia and misalignment of pulmonary veins. Really cool stuff. What did they find, Greg? This sounds like a first of its kind study. Dr. Greg Hundley: Right, Carolyn. Thanks. The Foxf1 wild type, S52 mice developed pulmonary hypertension and RV hypertrophy after birth. The severity of pulmonary hypertension in these mice directly correlated with mortality, low body weight, pulmonary artery muscularization and increased collagen deposition in the lung tissue. Second, increased fibrotic remodeling was found in the human ACDMPV lungs. Third, the mouse endothelial cells carrying the S52F Fox1 mutation were used to produce chimeras via blastocyst complementation and to demonstrate that the Foxf1 wild type S52F endothelial cells have a propensity to differentiate into pulmonary myofibroblasts. And then finally, intravascular delivery of nanoparticles carrying Stat3 copy DNA protected the Foxf1 wild type S52F mice from RV hypertrophy and pulmonary hypertension, improved their survival and decreased that fibrotic lung remodeling. Carolyn, nanoparticle therapies increasing neonatal pulmonary angiogenesis may be considered to prevent pulmonary hypertension in alveolar capillary dysplasia with misalignment of pulmonary veins. Dr. Carolyn Lam: Wow, thank you, Greg. Such incredibly hopeful papers here. The next paper identified a key role of a particular amino acid in cardiac aging. Dr. Greg Hundley: Ah, Carolyn, so you didn't ask me the quiz but I guess it's implied here. Okay, I give up. Which amino acid is it? Dr. Carolyn Lam: Spot on, Greg. Well, the answer is phenylalanine. This is an essential amino acid whose levels are regulated by the tetrahydrobiopterin or BH4 dependent rate limiting enzyme, phenylalanine hydroxylase and whose expression is physiologically restricted to the liver and the kidney. Well, co-corresponding authors Dr. Czibik and Derumeaux from Paris, France, hypothesized that phenylalanine plays a causal role in promoting cardiac senescence and dysfunction based on prior evidence from human metabolomics that shed light on a link between amino acids, aging and heart failure, as well as data showing that plasma levels of phenylalanine increase with age and inversely correlate with leukocyte telomere length. In addition, increased serum phenylalanine levels are associated with heart failure. Here, the authors tested their hypothesis in a series of elegant mouse experiments and showed for the first time that a decline in hepatic phenylalanine catabolism was a causal contributor to a rise in systemic levels, leading to cardiac ectopic phenylalanine hydroxylase activity and resultant cardiac aging. Dr. Carolyn Lam: They demonstrated that phenylalanine administration induced a remarkable premature cardiac deterioration in young mice, closely mimicking that of aged mice and leading to cellular senescence in vitro. They identified hepatic phenylalanine catabolism to decline with age in a p21 dependent manner, while demonstrating that p21 deficiency prevented age related cardiac dysfunction. Administration of phenylalanine hydroxylase cofactor BH4 or dietary phenylalanine restriction, both abrogated the age related rise in the plasma levels and reversed age associated cardiac alterations. This study really identifies phenylalanine and its hydroxylase modulation as a potential therapeutic strategy to promote cardiac health and prevent age related cardiac impairment. Amazing, isn't it? Dr. Greg Hundley: Yeah, Carolyn. Really interesting about phenylalanine and while it may impact cardiovascular health and the aging process. Dr. Greg Hundley: Well, I know we've got some other articles in this issue, so how about I'll go and dip into the mailbag first? The first is from Professors Wong and Finn and they're exchanging letters regarding the prior publication entitled, Microthrombi as a Major Cause of Cardiac Injury in COVID-19 and it's a pathologic study. There's a nice Research Letter from Dr. Zhu entitled, “Catheter Based Adrenal Ablation Remits Primary Aldosteronism: A Randomized Medication Control Trial.” There's a Perspective piece from Dr. Stehlik entitled, “The Long and Winding Road to an Effective Left Ventricular Assist Device: The Demise of Medtronic's HVAD.” And then finally a report from Dr. Mehta and colleagues, really Carolyn, thinking about clinicians' wellbeing and addressing global needs for improvements in the healthcare field. And it's a Joint Opinion representing the American College of Cardiology, the American Heart Association, the European Society of Cardiology and the World Heart Federation. Really a nice report on really addressing physician stress in the workplace. Dr. Carolyn Lam: Nice. Well, there's also an ECG Challenge by Dr. Shi entitled, “An Acutely Breathless Patient with Inferior St-Segment Elevation: A Diagnostic Trap.” In Cardiology News, Bridget Kuehn describe studies detailing heart risks for firefighters. Wow, what an interesting issue, but let's go on now to the feature discussion shall we, Greg? Dr. Greg Hundley: You bet. Dr. Greg Hundley: Welcome listeners to our feature discussion. And today we have with us Dr. Gabriel Steg from Paris, France, Universite de Paris. And also Dr. Gregg Stone, an editorialist from Mount Sinai in New York. Welcome gentlemen. And Gabriel, we'll start with you first. Could you describe for us some of the background related to your study and what was the hypothesis that you wanted to test? Dr. Gabriel Steg: Thank you, Greg. As you know, there have been tremendous changes in cardiology over the past 25 years with the advent of effective anti-anginal therapy, with the advent of myocardial revascularization and the dramatic changes produced by widespread availability of percutaneous coronary intervention and finally the availability of evidence based secondary prevention therapies. And there has been really a sea change in the presentation and treatment, management and outcomes of patients with coronary artery disease. And when we started off, we asked ourselves, is angina pectoris really prognostic in patients with stable coronary artery disease? Is the symptom of angina really prognostic? That was the question we tried to address. Dr. Greg Hundley: And Gabriel, what was your study population and your study design? Dr. Gabriel Steg: It was a very simple descriptive design. We use a large international registry of patients with stable coronary artery disease called the CLARIFY registry, which enrolled almost 35,000 patients with stable coronary artery disease and followed them up for five years. Now, how was stable coronary artery disease defined? It was defined as any of the following conditions, a prior MI, more than three months before enrollment, a prior PCI or a CBG, angina pectoris was a demonstration of myocardial ischemia on noninvasive stress testing or finally the presence of a fixed stenosis of the coronary arteries on an angiogram. And you could get any of these criteria. Of course you could have more than one at the same time. And the design was to describe the anginal status at baseline and every year based on investigator reports, not a formal angina questionnaire, as there are several, including the Seattle angina questionnaire. We had a very simple assessment of angina and angina severity based on presence or absence and then Canadian class of angina. Dr. Greg Hundley: Did you follow these individuals too? Did they experience specific events? Dr. Gabriel Steg: Yes. We collected all the cardiovascular hospitalizations events, revascularizations. We followed the medications and we collected the biological results, although there was no core lab but we collected the results of the tests that were done. We essentially aimed was that registry to describe the population, their management and their outcomes over five years. And this is over 40 plus countries. And fortunately does not include any patient from the United States but has a substantial contribution from Canada and Mexico. Dr. Greg Hundley: Very nice. And so what did you find, Gabriel? Dr. Gabriel Steg: Well, the first observation is the prevalence of angina at baseline and it's 22%. We found that in a patient population selected for having stable coronary artery disease, approximately a fifth to a quarter will have anginal symptoms. I don't think that's a major surprise but what was a big surprise to us is that angina resolved very, very substantially, 40% of the patients who had angina at baseline had no longer angina by one year. And what was even more surprising is what caused the resolution of angina. And it was rarely changes in anginal medications, rarely revascularization. It was largely spontaneous. Almost 80% of the patients had spontaneous resolution of angina. And so, yes, it's been known that angina can regress but we did not expect that it would regress that often and that much spontaneously without intervention or need for increasing medications. Dr. Gabriel Steg: And the other aspect is then we looked at what happened for those patients who had angina resolution at one year and what were the subsequent outcomes? And we found they were indistinguishable from those who had no angina at baseline. And then we looked at those patients who had persistent angina at one year or occurrence of angina at one year, despite not having angina at baseline. And again, we found that having angina at one year was detrimental to the longterm prognosis. It's really good that you either not have angina or that your angina resolve. That's really important. Dr. Greg Hundley: Did you find any differences, Gabriel, between men and women? Dr. Gabriel Steg: No. We looked at a variety of subgroups. We looked by criteria for enrollment. We looked across geographic locales. We looked according to the presence or absence of diabetes and sex and other variables and there were really no major differences. The results were remarkably consistent. Dr. Greg Hundley: Very nice. Well listeners, one of the advantages of some of the publications that we pursue at Circulation is the ability to bring in an editorialist. And with us today, we have Dr. Gregg Stone from Mount Sinai in New York. And Gregg, we want to turn to you. How do we put the results of this study in perspective with other studies that have been involved in this sphere of research? Dr. Gregg Stone: Well, thank you, Greg. First off, I'd like to congratulate Gabriel and his colleagues for a tremendous study and thank you and Circulation for offering David Waters and I, the chance to provide our perspectives. I think this study raises a lot of important issues. Angina is kind of like the common cold to cardiologists. We're always dealing with it but it can be very difficult to diagnose. There's typical angina, atypical angina, anginal equivalent disease, non-anginal chest pain, et cetera. And we've learned in the last several years or decade that the etiology of angina can be very complex. It's not just epicardial coronary disease. There can be microvascular disease, macro or microvascular spasm and other causes. I think that we have to, when we're thinking of angina, we have to try to understand the mechanism and know whether or not it's really due to at least epicardial coronary artery disease, which is the type of disease that may respond to revascularization. Dr. Gregg Stone: In this regard, both David and I were struck with the fact that the CLARIFY even though a very large population, is a very mature population of patients with coronary disease, who I believe were diagnosed at least approximately seven years ago, most had undergone a prior revascularization therapy, about 50% ahead of myocardial infarct and the minority interestingly had inducible ischemia. We wondered is this real angina? Is this true angina that these patients are having? Because they've been effectively revascularized. In contrast, I was one of the co-principal investigators of the ISCHEMIA trial, which was a very different population because we took only with exercise induced moderate or severe ischemia. And while we excluded most patients with class three or four angina because we know those patients basically don't tolerate medical therapy without frequent crossovers. We found that in our trial, angina was more persistent and was substantially reduced by revascularization, by an interventional approach. Much more so than in the medical therapy arm. I think that it really does depend on the patient population and the likelihood of which the angina is due to true inducible ischemia that may respond to a revascularization approach. Dr. Greg Hundley: Very nice. And so Gabriel, want to turn back to you, what do you think is the next study that really needs to be performed in this space? Dr. Gabriel Steg: Well, I think it's really in line with Dr. Stone's comments. I think that what we need to do is to have a much more formal prospective assessment of a broader population of patients with angina using formalized questionnaire, such as the Seattle angina questionnaire, which allow a much better and thorough characterization of the presence, type and severity of symptoms and to look across the whole spectrum of patients with and without myocardial ischemia and look at the prognostic importance of the symptoms. I think that teasing out the relationship between the anginal symptoms, their severity, myocardial ischemia and outcomes is really critical to our interpretation of the series of recent trials, the last of which being ISCHEMIA, which have revolutionized our thinking regarding management of coronary artery disease. And we're still somewhat in the dark as to how to incorporate that information relative to the symptoms and outcomes of our patients. And I think we still have a lot of work to do in that respect. Dr. Greg Hundley: Very Good. And Gregg, do you have anything to add to that? Dr. Gregg Stone: Yeah. I would certainly echo Gabriel's comments. In addition, I think we have to think of angina as a collection of different diseases. And we have to do a better job at trying to understand the mechanisms underlying angina. First, we have to be able to determine whether it's really cardiac in origin versus non-cardiac. And then second, we have to understand again, whether it's coming from epicardial coronary disease, microvascular disease or other mechanisms. We've just been struck in even many of our simple stent studies, how often patients redevelop angina after treatment with no re-stenosis whatsoever, suggesting that many of them may have other etiologies of angina. I think these studies to me are very important because they really highlight, yes how much we've learned but how much more work there still is to do for us to be able to effectively diagnose and treat these patients. Dr. Greg Hundley: Well listeners, we want to thank both Dr. Gabriel Steg, the author of this paper and also Dr. Gregg Stone, who provided his editorial expertise, in bringing us information from these 32,000 plus individuals from the CLARIFY registry, of patients with stable coronary artery disease and helping us answer really two questions regarding the presence of angina. One, both that angina may resolve spontaneously and then second, persistent angina is associated with future cardiovascular events. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, I want to thank our speakers and then also wish everyone a great week and we will catch you next week on the run. 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.  

1. The Ugly Truth About Lockdowns Pt1  - 14 mins    Lycopene found to inhibit pathway involved in Helicobacter pylori-induced gastric cancer Yonsei University (South Korea), April 6, 2021 In this study, researchers at Yonsei University in South Korea evaluated the effects of lycopene on hyperproliferation induced by Helicobacter pylori infection. They reported their findings in an article published in the journal Nutrition Research. H. pylori is known to colonize the human stomach and is linked to an increased risk of gastric diseases, including gastric cancer. According to studies, H. pylori increases the generation of reactive oxygen species (ROS), which activate Janus-activator kinase 1 (Jak1)/signal transducers and activators of transcription 3 (Stat3) in gastric epithelial cells. ROS also mediate hyperproliferation — a hallmark of carcinogenesis — by activating Wnt/B-catenin signaling in various cells. The researchers hypothesized that lycopene, a potent antioxidant with anti-cancer properties, may be able to suppress hyperproliferation by inhibiting the ROS-mediated activation of Jak1/Stat3 and Wnt/B-catenin signaling, as well as the expression of B-catenin target genes. To test their hypothesis, they measured the ROS levels and viability of H. pylori-infected gastric epithelial AGS cells before and after lycopene treatment. The Jak1/Stat3 inhibitor AG490 served as the control treatment. They also measured the protein levels of the following: Total and phosphorylated Jak1/Stat3 Wnt/B-catenin signaling molecules Wnt-1 Lipoprotein-related protein 5 B-catenin target oncogenes (c-Myc and cyclin E) The researchers found that lycopene, like AG490, reduced ROS levels and inhibited the activation of Jak1/Stat3, alterations in the levels of Wnt/B-catenin multiprotein complex molecules, the expression of c-Myc and cyclin E and the proliferation of H. pylori-infected gastric epithelial AGS cells. Lycopene and AG490 also inhibited the increase in Wnt-1 and lipoprotein-related protein 5 expression caused by H. pylori infection. Based on these findings, the researchers concluded that lycopene can be used to prevent H. pylori-associated gastric diseases, thanks to its inhibitory effects on gastric cell hyperproliferation.   Less sugar, please! New studies show low glucose levels might assist muscle repair Skeletal muscle satellite cells found to grow better with less glucose in vitro Tokyo Metropolitan University, April 3, 2021 Researchers from Tokyo Metropolitan University have shown that skeletal muscle satellite cells, key players in muscle repair, proliferate better in low glucose environments. This is contrary to conventional wisdom that says mammalian cells fare better when there is more sugar to fuel their activities. Because ultra-low glucose environments do not allow other cell types to proliferate, the team could produce pure cultures of satellite cells, potentially a significant boost for biomedical research. Healthy muscles are an important part of a healthy life. With the wear and tear of everyday use, our muscles continuously repair themselves to keep them in top condition. In recent years, scientists have begun to understand how muscle repair works at the cellular level. Skeletal muscle satellite cells have been found to be particularly important, a special type of stem cell that resides between the two layers of sheathing, the sarcolemma and basal lamina, that envelopes myofiber cells in individual muscle fibers. When myofiber cells get damaged, the satellite cells go into overdrive, multiplying and finally fusing with myofiber cells. This not only helps repair damage, but also maintains muscle mass. To understand how we lose muscles due to illness, inactivity, or age, getting to grips with the specific mechanisms involved is a key challenge for medical science. A team of scientists from Tokyo Metropolitan University led by Assistant Professor Yasuro Furuichi, Associate Professor Yasuko Manabe and Professor Nobuharu L Fujii have been studying how skeletal muscle satellite cells multiply outside the body. Looking at cells multiplying in petri dishes in a growth medium, they noticed that higher levels of glucose had an adverse effect on the rate at which they grew. This is counterintuitive; glucose is considered to be essential for cellular growth. It is converted into ATP, the fuel that drives a lot of cellular activity. Yet, the team confirmed that lower glucose media led to a larger number of cells, with all the biochemical markers expected for greater degrees of cell proliferation. They also confirmed that this doesn't apply to all cells, something they successfully managed to use to their advantage. In experiments in high glucose media, cultures of satellite cells always ended up as a mixture, simply due to other cell types in the original sample also multiplying. By keeping the glucose levels low, they were able to create a situation where satellite cells could proliferate, but other cell types could not, giving a very pure culture of skeletal muscle satellite cells. This is a key prerequisite for studying these cells in a variety of settings, including regenerative medicine. So, was the amount of glucose in their original experiment somehow "just right"? The team added glucose oxidase, a glucose digesting enzyme, to get to even lower levels of glucose, and grew the satellite cells in this glucose-depleted medium. Shockingly, the cells seemed to fare just fine, and proliferated normally. The conclusion is that these particular stem cells seem to derive their energy from a completely different source. Work is ongoing to try to pin down what this is. The team notes that the sugar levels used in previous experiments matched those found in diabetics. This might explain why loss of muscle mass is seen in diabetic patients, and may have significant implications for how we might keep our muscles healthier for longer.   Higher plasma glutathione levels associated with decreased risk of Alzheimer disease Kapodistrian University (Greece), March 31, 2021 According to news reporting originating in Athens, Greece,research stated, “Potential links between oxidative stress and the pathophysiology of Alzheimer’s disease (AD) have been reported in the existing literature. Biological markers of oxidative stress, such as the reduced form of glutathione (GSH), may have a potential role as predictive biomarkers for AD development.” Funders for this research include Alzheimer’s Association, ESPA-EU program Excellence Grant (ARISTEIA), Ministry for Health and Social Solidarity (Greece). The news reporters obtained a quote from the research from the National and Kapodistrian University of Athens, “The aim of the present study was to explore the longitudinal associations between plasma GSH and the risk of developing AD or cognitive decline, in a sample of community-dwelling, non-demented older adults. Participants from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) were included in the present prospective study. The sample used in the analyses consisted of 391 non-demented individuals over the age of 64 (mean age = 73.85 years; SD = 5.06), with available baseline GSH measurements and longitudinal follow-up. Plasma GSH was treated both as a continuous variable and as tertiles in our analyses. Cox proportional hazards models were used to evaluate the hazard ratio (HR) for AD incidence as a function of baseline plasma GSH. Generalized estimating equations (GEE) models were deployed to explore the associations between baseline plasma GSH and the rate of change of performance scores on individual cognitive domains over time. Models were adjusted for age, years of education and sex. Supplementary exploratory models were also adjusted for mild cognitive impairment (MCI) at baseline, risk for malnutrition, physical activity and adherence to the Mediter-ranean dietary pattern. A total of 24 incident AD cases occurred during a mean (SD) of 2.99 (0.92) years of follow-up. Individuals in the highest GSH tertile group (highest baseline plasma GSH values) had a 70.1% lower risk for development of AD, compared to those in the lowest one [HR = 0.299 (0.093-0.959); p = 0.042], and also demonstrated a slower rate of decline of their executive functioning over time (5.2% of a standard deviation less decline in the executive composite score for each additional year of follow-up; p = 0.028). The test for trend was also significant suggesting a potential dose-response relationship.” According to the news reporters, the research concluded: “In the present study, higher baseline plasma GSH levels were associated with a decreased risk of developing AD and with a better preservation of executive functioning longitudinally.” This research has been peer-reviewed.     Citrus fruit found to decrease risk of stroke University of East Anglia (UK),  March 31, 2021    We’ve all heard how good citrus fruit is for us due to its vitamin C content and immune system-boosting properties. Now research is showing that citrus fruit can also help to reduce stroke risk.   A study conducted at the University of East Anglia in Norwich, UK reveals that eating citrus fruit, especially oranges, lowers the risk of ischemic stroke significantly. The researchers compared the health of women who ate both oranges and grapefruit regularly versus those who did not.   Compounds in citrus fruit improve circulation and blood flow, reducing stroke risk   The study looked at the flavonoid content of citrus fruits and how they impacted blood vessel health. Previous studies have found that specific orange phytochemicals are protective against intracerebral hemorrhage and considerably improve blood flow in the brain.   Researchers reviewed around 14 years of Nurse’s Health Study data tracking the health and diets of about 70,000 women. Correlations between six flavonoid sub-classes from citrus fruits were assessed related to risks of hemorrhagic, ischemic or complete stroke.   Women who consumed the highest amounts of orange and grapefruit as well as juices from these fruits had much better blood circulation, as well as a 19 percent lowered risk of stroke related to blood clotting as compared with women who didn’t eat much citrus fruit.   Why an orange alongside that apple – each day – is a powerful combination   The women who favored citrus fruit showed a substantially reduced risk of stroke and associated risks. Indeed, if an apple a day keeps the doctor away, an orange a day can keep strokes away.   Other studies of flavonoids in fruit substantiate these results regarding a reduction in stroke risk. Higher intake of all kinds of fruit has a positive impact on stroke risk as well as many other areas of health.   A 2011 study by Western University in London, Ontario found that an additional benefit of flavonoid intake was the prevention of weight gain. A tangerine flavonoid called Nobiletin was shown to reduce the risk of both type 2 diabetes and obesity in mice. The mice given the Nobiletin flavonoid avoided these issues, while those that did not became obese, developed type 2 diabetes, and had atherosclerosis and fatty liver issues.   A 2012 Japanese study found the pulp and juice from satsuma mandarin oranges inhibited tumor growth in cancers of the colon, lung and tongue. Vitamin C is a potent antioxidant known for inhibiting free radical damage in the cells. The Nobiletin in citrus fruit has also been linked with apoptosis, or programmed cell death of cancer cells.   Oregon Health & Science University researchers found a connection between eye health and the vitamin C found in citrus fruit. Retinal nerve cells benefited from the compound, and it’s likely brain and nervous system health are positively impacted as well. While fruit juice packs a potent nutritional punch, there are advantages to eating whole oranges, grapefruits and other fruits instead. Whole fruits tend to be richer in vitamins and nutrients, lower in sugar, and higher in fiber.     For older patients, focusing on what matters is often the best medicine Yale University, April 4, 2021 A woman in her 80s wanted to play with her great-grandchildren when they came to visit, but knee pain made it difficult for her. A man in his late 70s said he enjoyed going out to dinner, but was constrained by the meal preparation guidelines that he needed to follow because of his diabetes. Both people have multiple chronic conditions. They also have life goals, things they want to do to live their lives fully, like playing with grandchildren and going out to eat. Understanding these goals and barriers to them, helps doctors align care with what matters most to their patients while eliminating unwanted health care, said the authors of a report that was published March 24 in JAMA Network Open. The report, the first systematic description of older adults' health care priorities, describes a structured process called Patient Health Priorities that health care providers can follow to identify the life goals of older adults with multiple chronic conditions as well as their health care preferences. "There is growing awareness of the need to transition health care, particularly for people with multiple chronic conditions, from treating single diseases in isolation to health care that is aligned with patients' priorities," said Mary Tinetti, MD, the principal investigator of the Patient Priorities Care study, and the Gladys Phillips Crofoot Professor of Medicine (Geriatrics) at Yale School of Medicine (YSM). During the study, health care providers asked 163 patients who were 65 and older and have multiple chronic conditions to identify what they value most in life such as connecting with family, being productive, or remaining independent. They then asked what specific and realistic activities they most wanted to be able to do that reflected their values. The participants also were asked to describe the barriers that prevented them from achieving their goals, such as unnecessary doctors' visits, taking too many medications, or health concerns such as fatigue and shortness of breath. "The medications, health care visits, testing, procedures, and self-management tasks entailed in treating multiple chronic conditions require investments of time and effort that may be burdensome and conflict with what patients are willing and able to do," Tinetti said. The study was conducted among patients of 10 primary care doctors from a multi-site practice in Connecticut who invited patients to participate during routine visits. Participants had to be 65 or older and have at least three chronic health conditions that were treated with at least 10 prescription medications. They also had to be under the care of two or more specialists, or have visited the emergency room at least two times, or had been hospitalized once, during the past year. Of the 236 patients at the practice, 163 agreed to participate. Most participants were white, female, about 78 years old, and had four chronic conditions. Nearly half had high school-level or less education. Participants were asked to identify their values with questions such as, "What does enjoying life mean to you?" and "When you have a good day, what happens?" Their health care providers then worked with them to make sure their care was focused on achieving those goals. Participants also were asked what health issues most interfered with their goals, and what aspects of their health care they found helpful and which they felt were unhelpful to too burdensome. The 163 participants identified 459 outcome goals, the most common of which were sharing meals with friends and family (7.8%); visiting with grandchildren (16.3%); going shopping (6.1%), and exercising (4.6%). Twenty participants (4.4%) said they wanted to be able to stay in their homes and live independently. Common barriers to their goals were pain (41%); fatigue, lack of energy or poor sleep (14.4%); unsteadiness (13.5%); and shortness of breath and dizziness (6.1%). Thirty-two participants (19.8%) felt they were taking too many medications, while 57 (35.0%) reported having bothersome symptoms from their medications but did not mention specific drugs. Also, 43 (26%) participants said that visits to their primary care physicians and specialists were helpful, although 15 (9%) said they have too many visits or doctors. "I'm tired of going to so many doctors." Understanding what's important to patients can help with patient-doctor communication and decision-making, Tinetti said. "If a patient's outcome goals are not achievable or realistic given their health status, a conversation might include, "I worry that you might not be able to continue driving your friends to the theater. I wonder if there are other ways to fulfill your desire to see shows and connect with your friends that could be more achievable." Participants were drawn from a single practice with a homogeneous patient population; results may not generalize to other populations, and identifying the priorities of diverse groups is essential, the report's authors noted. "While further research is needed, the study suggests the feasibility of asking people about their goals and preferences, and getting responses that can inform decision-making," Tinetti said. A newly launched website, MyHealthPriorities.org, grew out of the Patient Priorities Care initiative. People can use the website to identify their priorities so they can discuss them with their health care team. "When there isn't a healthcare provider available to do the health priorities identification, there is now this option of the self-directed website," said Jessica Esterson, MPH, project director in the Section of Geriatrics at YSM. "We want to spread this capability to as many older adults as possible. By providing the website directly to individuals we greatly expand its reach and potential." The website walks people through the Patient Priorities Care health priorities identification process. At the end they will have a summary to bring to their doctors that outlines their health priorities—the activities they want their health care to help them achieve based on what they are willing and able to do. Tinetti encourages people of all ages, particularly older adults with multiple health conditions, to use MyHealthPriorities.org. "It will help you think about things you haven't thought about before, and better understand what matters most to you about your health and health care," Tinetti said. "It's important to you, your family, and your doctors."   Paleopharmaceuticals from Baltic amber might fight drug-resistant infections University of Minnesota, April 5, 2021 For centuries, people in Baltic nations have used ancient amber for medicinal purposes. Even today, infants are given amber necklaces that they chew to relieve teething pain, and people put pulverized amber in elixirs and ointments for its purported anti-inflammatory and anti-infective properties. Now, scientists have pinpointed compounds that help explain Baltic amber's therapeutic effects and that could lead to new medicines to combat antibiotic-resistant infections. The researchers will present their results today at the spring meeting of the American Chemical Society (ACS). ACS Spring 2021 is being held online April 5-30. Live sessions will be hosted April 5-16, and on-demand and networking content will continue through April 30. The meeting features nearly 9,000 presentations on a wide range of science topics.  Each year in the U.S., at least 2.8 million people get antibiotic-resistant infections, leading to 35,000 deaths, according to the U.S. Centers for Disease Control and Prevention. "We knew from previous research that there were substances in Baltic amber that might lead to new antibiotics, but they had not been systematically explored," says Elizabeth Ambrose, Ph.D., who is the principal investigator of the project. "We have now extracted and identified several compounds in Baltic amber that show activity against gram-positive, antibiotic-resistant bacteria." Ambrose's interest originally stemmed from her Baltic heritage. While visiting family in Lithuania, she collected amber samples and heard stories about their medicinal uses. The Baltic Sea region contains the world's largest deposit of the material, which is fossilized resin formed about 44 million years ago. The resin oozed from now-extinct pines in the Sciadopityaceae family and acted as a defense against microorganisms such as bacteria and fungi, as well as herbivorous insects that would become trapped in the resin. Ambrose and graduate student Connor McDermott, who are at the University of Minnesota, analyzed commercially available Baltic amber samples, in addition to some that Ambrose had collected. "One major challenge was preparing a homogeneous fine powder from the amber pebbles that could be extracted with solvents," McDermott explains. He used a tabletop jar rolling mill, in which the jar is filled with ceramic beads and amber pebbles and rotated on its side. Through trial and error, he determined the correct ratio of beads to pebbles to yield a semi-fine powder. Then, using various combinations of solvents and techniques, he filtered, concentrated and analyzed the amber powder extracts by gas chromatography-mass spectrometry (GC-MS). Dozens of compounds were identified from the GC-MS spectra. The most interesting were abietic acid, dehydroabietic acid and palustric acid -- 20-carbon, three-ringed organic compounds with known biological activity. Because these compounds are difficult to purify, the researchers bought pure samples and sent them to a company that tested their activity against nine bacterial species, some of which are known to be antibiotic resistant. "The most important finding is that these compounds are active against gram-positive bacteria, such as certain Staphylococcus aureus strains, but not gram-negative bacteria," McDermott says. Gram-positive bacteria have a less complex cell wall than gram-negative bacteria. "This implies that the composition of the bacterial membrane is important for the activity of the compounds," he says. McDermott also obtained a Japanese umbrella pine, the closest living species to the trees that produced the resin that became Baltic amber. He extracted resin from the needles and stem and identified sclarene, a molecule present in the extracts that could theoretically undergo chemical transformations to produce the bioactive compounds the researchers found in Baltic amber samples. "We are excited to move forward with these results," Ambrose says. "Abietic acids and their derivatives are potentially an untapped source of new medicines, especially for treating infections caused by gram-positive bacteria, which are increasingly becoming resistant to known antibiotics."     Complementary effects of pine bark extract supplementation on inattention, impulsivity, and antioxidative status in children with ADHD Taipei Medical University (Taiwan), April 1, 2021 The purpose of this study was to investigate the complementary effects of polyphenolic compounds from pine bark extract (PE) as a strong antioxidative substrate on the symptoms of inattention and impulsivity in children with attention‐deficit hyperactivity disorder (ADHD). This was a randomized, double‐blind, crossover, placebo‐controlled study that included two experimental units (4 weeks with PE supplementation and 4 weeks with placebo supplementation) separated by a 2‐week washout period. ADHD participants were supplemented with 25 mg or 50 mg PE. We recruited 20 participants (17 boys and 3 girls) with a mean age of 10.0 ± 2.1 years. PE supplementation caused a significant reduction in the inattention and hyperactivity‐impulsivity items of SNAP‐IV. During the period of PE supplementation, the item of commissions in the Continuous Performance Test III (CPT III) significantly decreased, which was used to evaluate the symptoms of inattention and impulsivity. In addition, the erythrocytic reduced glutathione/oxidized glutathione ratio significantly increased, and the plasma TBARs level significantly decreased after 4 weeks of PE supplementation. However, there was no significant correlation between CPT III (commission) and antioxidative status indictors. PE supplementation may have potential effects of ameliorating inattention and impulsivity, and elevating the antioxidative status in children with ADHD.

Listen to short summaries of the latest oncology-focused research literature published in this week's issue of Oncotarget Volume 12, Issue 5. Click here for the complete issue: https://www.oncotarget.com/archive/v12/i5/ Oncotarget Volume 12, Issue 5 features: Cover Paper: "The cancer testis antigens CABYR-a/b and CABYR-c are expressed in a subset of colorectal cancers and hold promise as targets for specific immunotherapy." https://doi.org/10.18632/oncotarget.27897 Research Perspective: "Tumor mutational burden as a predictor of immunotherapy response in breast cancer." https://doi.org/10.18632/oncotarget.27877 Research Paper: "STAT3 induces the expression of GLI1 in chronic lymphocytic leukemia cells." https://doi.org/10.18632/oncotarget.27884 Research Paper: "Multi-modal effects of 1B3, a novel synthetic miR-193a-3p mimic, support strong potential for therapeutic intervention in oncology." https://doi.org/10.18632/oncotarget.27894 Research Paper: "Mutational profile of skin lesions in hepatocellular carcinoma patients under tyrosine kinase inhibition: a repercussion of a wide-spectrum activity." https://doi.org/10.18632/oncotarget.27891 Research Paper: "Development of a ghrelin receptor inverse agonist for positron emission tomography." https://doi.org/10.18632/oncotarget.27895 Research Paper: "Global DNA hypermethylation pattern and unique gene expression signature in liver cancer from patients with Indigenous American ancestry." https://doi.org/10.18632/oncotarget.27890 Research Paper: "Fine–mapping of two differentiated thyroid carcinoma susceptibility loci at 2q35 and 8p12 in Europeans, Melanesians and Polynesians." https://doi.org/10.18632/oncotarget.27888 Research Paper: "Quantitative proteome profiling stratifies fibroepithelial lesions of the breast." https://doi.org/10.18632/oncotarget.27889 About Oncotarget: Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit www.oncotarget.com or follow us: SoundCloud - @oncotarget Facebook - www.facebook.com/Oncotarget/ Twitter - twitter.com/oncotarget LinkedIn - www.linkedin.com/company/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/OncotargetYouTube Pinterest - www.pinterest.com/oncotarget/ Reddit - www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC please visit www.ImpactJournals.com or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957x105

The anti-inflammatory IL-10 pathway in the CNS can lead to Glioblastoma which is a disease presented 3-4 fold higher in people ≥65 years old, and with a mortality rate for the same age group some 7 fold higher. Activation of the IL-10 Receptor bound ligand induces the JAK1 signal transducer and activator of transcription 3 (STAT3) pathway in APCs. This results in the subsequent translocation of STAT3 homodimers into the nucleus. This STAT3 homodimer binds to STAT-binding elements which promotes the expression of the suppressor of cytokine signaling 3 (SOCS-3) and IL-1 receptor antagonist (IL-1RN). IL-10 reduces the production of pro-inflammatory cytokines (IL-1β, IL-6, tumor necrosis factor alpha) and diminished expression of both major histocompatibility complex II. The anti-inflammatory MiDAS phenotype can also induce heart failure in the aging population. References: Front Pharmacol. 2019; 10: 200 Aging Cell. 2018 Oct;17(5) Int Heart J. 2018 Jul 31;59(4):837-844 Front. Immunol., 19 March 2018 Neuro Oncol . 2020 Mar 5;22(3):333-344 --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

Episode 347 is an updated guide to somatropic hormone and GOD did I go crazy on this one! I honestly want to know more about growth hormone than anyone alive and thus, begins this string of GH based guides! I DID finally discuss the MoA for how GH causes localized fat loss which really had me excited since no one in our industry has EVER talked about this so that definitely was an interesting avenue to go down! Below I am going to reference a lot of the literature for this hormone that I was read through over the past few years on this topic so please DO NOT TAKE MY WORD FOR THIS - READ THESE YOURSELF! Keep in mind this is a brief snippet of every bit of literature on the topic however. REFERENCES   Daughaday WH, Rotwein P. Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev. 1989;10:68–91. [PubMed] [Google Scholar] Jones JI, Clemmons DR. 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Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.02.364356v1?rss=1 Authors: Mirabella, F., Desiato, G., Mancinelli, S., Fossati, G., Rasile, M., Morini, R., Markicevic, M., Grimm, C., amegandjin, C., Termanini, A., Peano, C., Kunderfranco, P., DiCristo, G., Zerbi, V., Lodato, S., Menna, E., Matteoli, M., Pozzi, D. Abstract: Early prenatal inflammatory conditions are thought to represent a risk factor for different neurodevelopmental disorders, with long-term consequences on adult brain connectivity. Here we show that a transient IL-6 elevation, occurring at vulnerable stages of early neurodevelopment, directly impacts brain developmental trajectories through the aberrant enhancement of glutamatergic synapses and overall brain hyper-connectivity. The IL6-mediated boost of excitatory synapse density results from the neuronautonomous, genomic effect of the transcription factor STAT3 and causally involves the activation of RGS4 gene as a candidate downstream target. The STAT3/RGS4 pathway is also activated in neonatal brains as a consequence of maternal immune activation protocols mimicking a viral infection during pregnancy. By demonstrating that prenatal IL-6 elevations result in aberrant synaptic and brain connectivity through the molecular players identified, we provide a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.14.286765v1?rss=1 Authors: Han, J.-K., Kwon, S.-H., Kim, Y. G., Choi, J., Kim, J.-I., Lee, Y.-S., Ye, S.-K., Kim, S. J. Abstract: Emotional memory processing, such as fear memory, engages a large neuronal network of brain regions including the cerebellum. However, the molecular and cellular mechanisms of the cerebellar cortex modulating the fear memory network is largely unknown. Here, we illustrate a novel mechanism by which synaptic signaling in cerebellar Purkinje cells (PCs) via STAT3 regulates long-term fear memory. Firstly, we generated PC-specific STAT3 knockout (STAT3PKO) mice. Transcriptome analyses revealed that STAT3 deletion results in transcriptional changes that lead to an increase in the expression of glutamate receptors. The amplitude of AMPA receptor-mediated excitatory postsynaptic currents at parallel fiber to PC synapses was larger in STAT3PKO mice than in wild-type littermates. Conditioning at the parallel fiber induced long-term depression of parallel fiber-PC synapses in STAT3PKO mice while the same manipulation induced long-term potentiation in wild-type littermates. Interestingly, STAT3PKO mice showed an aberrantly enhanced long-term fear memory. Neuronal activity in fear-related regions increased in fear-conditioned STAT3PKO mice. Our data suggest that STAT3-dependent molecular regulation in PCs is indispensable for proper expression of fear memory processing. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.01.274753v1?rss=1 Authors: Sobolev, V., Soboleva, A., Svitich, O., Dvoriankova, E., Piruzyan, A., Mildzikhova, D., Korsunskaya, I., Nesterova, A. Abstract: Interactions of genes in intersecting signaling pathways, as well as environmental influences, are required for the development of psoriasis. Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) is a nuclear receptor and transcription factor which inhibits the expression of many proinflammatory genes. We tested the hypothesis that low levels of PPAR{gamma} expression promote the development of psoriatic lesions. We combined experimental results and network functional analysis to reconstruct the model of PPAR{gamma} downregulated signaling in psoriasis. We found that the expression of PPAR{gamma} maybe be slightly downregulated in human psoriatic skin and laser treatment may facilitate it. We tested the reconstructed model and found that at least on mRNA level the expression of IL17, STAT3, FOXP3, and RORC and FOSL1 genes in psoriatic skin before and after laser treatment were correlated with the level of PPAR{gamma} mRNA expression suggesting that genes belong to the same signaling pathway that may regulate the development of psoriasis lesion. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.17.254888v1?rss=1 Authors: Mohammed, S., Nicklas, E. H., Thadathil, N., Selvarani, R., Royce, G. H., Richardson, A., Deepa, S. S. Abstract: Mice deficient in the antioxidant enzyme Cu/Zn-superoxide dismutase (Sod1-/- or Sod1KO mice) develop spontaneous hepatocellular carcinoma (HCC) with age. Similar to humans, HCC development in Sod1KO mice progresses from fatty liver disease to non-alcoholic steatohepatitis (NASH) with fibrosis, which eventually progresses to HCC. Because liver inflammation is the main mechanism that drives the disease progression in chronic liver disease (CLD) and because necroptosis is a major source of inflammation, we tested the hypothesis that increased necroptosis in the liver plays a role in increased inflammation and progression to fibrosis and HCC in Sod1KO mice. Phosphorylation of MLKL (P-MLKL), a well-accepted marker of necroptosis, and expression of MLKL protein were significantly increased in the livers of Sod1KO mice compared to WT mice indicating increased necroptosis. Similarly, phosphorylation of RIPK3 and RIPK3 protein levels were also significantly increased. Markers of pro-inflammatory M1 macrophages, NLRP3 inflammasome, and transcript levels of pro-inflammatory cytokines and chemokines, e.g., TNF, IL-6, IL-1{beta}, and Ccl2 that are associated with human NASH and HCC, were significantly increased. Markers of fibrosis and oncogenic transcription factor STAT3 were also upregulated in the livers of Sod1KO mice. Short term treatment of Sod1KO mice with necrostatin-1s (Nec-1s), a necroptosis inhibitor, significantly reduced necroptosis, pro-inflammatory cytokines, fibrosis markers and STAT3 activation. Our data show for the first time that necroptosis-mediated inflammation contributes to fibrosis and HCC progression in Sod1KO mice, a mouse model of accelerated aging and progressive HCC development. These findings suggest that necroptosis might be a target for treating NASH and HCC. Copy rights belong to original authors. Visit the link for more info

En este episodio comentamos el efecto de la vitamina D en la incidencia de cáncer y enfermedades cardiovasculares. También un estudio en el que se investiga el repertorio de anticuerpos que la madre transfiere al feto durante el embarazo. Esta inmunidad pasiva permitirá al recién nacido defenderse de las infecciones hasta que desarrolle su propio sistema inmune. El tercer artículo que discutimos se ha publicado en Nature y aporta nuevos datos para entender por qué muchos tumores dan lugar a metástasis en el hígado: según parece, las células del hígado activan un programa de señales moleculares, mediadas por STAT3 e interleucina 6, que facilita la adhesión de las células metastásicas. Nuestros estudiantes colaboradores nos traen (bio)noticias frescas y, como broche de oro, entrevistamos al filósofo de la ciencia Antonio J. Diéguez, autor del libro “Transhumanismo”, una necesaria reflexión sobre el futuro de la especie humana en el contexto actual de vertiginosos avances en dos poderosas tecnologías: la biología sintética y la inteligencia artificial.

Giovanna Tosato explains how a cytokine subunit activates inflammatory signaling inside endothelial cells.

Lois Smith and Ye Sun explain why SOCS3 activity in neural and glial cells of the retina prevents pathological retinal neovascularization.

Keqiang Ye discusses a small molecule inhibitor of the kinase JAK2 that blocks proliferation of glioblastoma cells.

Jedes Jahr erleiden weltweit circa 22 Menschen pro eine Million Einwohner eine Querschnittslähmung, die bei den Betroffenen zu dauerhaften Behinderungen und erheblichen Einschränkungen im Alltag führt. Die schwerwiegenden Defizite nach einer Querschnittslähmung, darunter Lähmungen und chronischer Schmerz, sind darauf zurückzuführen, dass geschädigte Axone im Rückenmark kaum regenerieren und es auch nur in geringem Ausmaß zur funktionellen Reorganisation der noch erhaltenen Nervenverbindungen kommt. Im Unterschied zum peripheren Nervensystem, wo zerstörte Nervenfasern erfolgreich regenerieren, ist die axonale Regenerationskapazität des zentralen Nervensystems (ZNS) spärlich ausgeprägt. Zwar konnte durch intensive Forschung im Verlauf der letzten Jahrzehnte eine Anzahl von „extrinsischen“ wachstumshemmenden Molekülen von Gliazellen und der extrazellulären Matrix des ZNS identifiziert werden. Es gibt jedoch zunehmend Hinweise darauf, dass zahlreiche dieser „extrinsischen“ Signale letztlich in „intrinsische“ Signalwege der Neuronen selbst einmünden um schließlich die Transkription neuronaler Gene zu verändern. Einer der interessantesten intrinsischen Regulatoren axonaler Regeneration ist der Transkriptionsfaktor ´Signal transducer and activator of transcription 3´ (STAT3). In dieser Arbeit habe ich mithilfe moderner In-vivo-Mikroskopie sowie viraler Gentherapie in Spinalganglien genetisch veränderter Mäuse zum ersten Mal die entscheidende Rolle von STAT3 in der intrinsischen Regulation axonaler Regeneration in vivo identifizieren können. So konnte nachgewiesen werden, dass die nur rudimentär ausgeprägte Regeneration der zentralen Fortsätze der Neuronen in den Spinalganglien mit einer fehlenden Induktion von STAT3 in den entsprechenden Ganglien einhergeht. Durch Überexpression von STAT3 mittels rekombinanter Adeno-assoziierter Viren in zervikalen Spinalganglien konnte zwei Tage nach Läsion das Auswachsen von Axonen sowie das Aussprießen von Kollateralen um mehr als das Vierfache gesteigert werden. Darüber hinaus konnte mittels repetitiver Multiphotonenmikroskopie einzelner fluoreszenzmarkierter Axone gezeigt werden, dass die Überexpression von STAT3 nur in der Frühphase (2-4 Tage) die axonale Wachstumsgeschwindigkeit erhöhen konnte, nicht aber zu einem späteren Zeitpunkt (4-10 Tage) nach Läsion. Um die Hypothese zu überprüfen, dass die fehlende Aufrechterhaltung des axonalen Wachstums durch Kontakt der aussprossenden Axone mit einem zunehmend inhibitorischen ZNS-Milieu bedingt ist, wurde die Überexpression von STAT3 zusätzlich mit der Applikation von Chondroitinase ABC, einem Enzym, das die inhibitorischen Moleküle der glialen Narbe neutralisieren kann, kombiniert. Dabei konnte ich zeigen, dass das durchschnittliche Wachstum von Axonen um mehr als das Zweifache gesteigert werden konnte. Aus den Ergebnissen meiner Versuche konnte ich mehrere Schlussfolgerungen ziehen: Erstens konnte ich STAT3 als effektiven Initiator axonalen Wachstums nach Rückenmarksläsion identifizieren. Zweitens wurde nachgewiesen, dass STAT3 selektiv Wachstum in der frühen Phase reguliert, nicht jedoch zu späteren Zeitpunkten. Daraus folgt, dass das axonale Regenerationsprogramm aus mindestens zwei verschiedenen, molekular distinkten Phasen besteht. Mit STAT3 wurde zum ersten Mal ein phasenspezifischer Regulator der axonalen Regeneration entdeckt. Abschließend konnte gezeigt werden, dass synergistische Therapien - wie hier durch die Kombination von STAT3 und Chondroitinase ABC belegt wurde - axonales Wachstum zusätzlich verbessern. Die gewonnenen Einblicke in die Mechanismen axonaler Regeneration geben Grund zur Hoffnung, dass in der Zukunft effektive Kombinationstherapien für Querschnittsgelähmte entwickelt werden können.

Background: The FHIT tumor suppressor gene is arguably the most commonly altered gene in cancer since it is inactivated in about 60% of human tumors. The Fhit protein is a member of the ubiquitous histidine triad proteins which hydrolyze dinucleoside polyphosphates such as Ap(3)A. Despite the fact that Fhit functions as a tumor suppressor, the pathway through which Fhit inhibits growth of cancer cells remains largely unknown. Phosphorylation by Src tyrosine kinases provides a linkage between Fhit and growth factor signaling. Since many G proteins can regulate cell proliferation through multiple signaling components including Src, we explored the relationship between G alpha subunits and Fhit. Results: Several members of the G alpha(q) subfamily (G alpha(16), G alpha(14), and G alpha(q)) were found to co-immunoprecipitate with Fhit in their GTP-bound active state in HEK293 cells. The binding of activated G alpha(q) members to Fhit appeared to be direct and was detectable in native DLD-1 colon carcinoma cells. The use of G alpha(16/z) chimeras further enabled the mapping of the Fhit-interacting domain to the alpha 2-beta 4 region of G alpha(16). However, G alpha(q)/Fhit did not affect either Ap(3)A binding and hydrolysis by Fhit, or the ability of G alpha(q/16) to regulate downstream effectors including phospholipase C beta, Ras, ERK, STAT3, and IKK. Functional mutants of Fhit including the H96D, Y114F, L25W and L25W/I10W showed comparable abilities to associate with G alpha(q). Despite the lack of functional regulation of G(q) signaling by Fhit, stimulation of G(q)-coupled receptors in HEK293 and H1299 cells stably overexpressing Fhit led to reduced cell proliferation, as opposed to an enhanced cell proliferation typically seen with parental cells. Conclusions: Activated G alpha(q) members interact with Fhit through their alpha 2-beta 4 region which may result in enhancement of the growth inhibitory effect of Fhit, thus providing a possible avenue for G protein-coupled receptors to modulate tumor suppression.

Haiyan Li

Haiyan Li

Das autosomal-dominante Hyper-IgE-Syndrom (AD-HIES) gehört zu den angeborenen Immundefekten und wird durch Ekzem, erhöhtes Serum-IgE, Eosinophilie, rezidivierende Abszesse und Lungeninfektionen sowie assoziierte Skelett- und Bindegewebssymptome charakterisiert. Durch die Assoziation von Mutationen im Gen STAT3 bei Patienten mit AD-HIES gelang es 2007 die ätiologische Ursache dieses Krankheitsbildes aufzuklären, wodurch die Diagnose heute molekulargenetisch bestätigt werden kann (Holland et al. 2007; Minegishi et al. 2007). Ziel der vorgelegten Arbeit war es, den klassischen AD-HIES-Phänotyp mit dem STAT3-Genotyp zu korrelieren und die bestmöglichen Kriterien zu definieren, die Patienten mit STAT3-HIES charakterisieren und eine Abgrenzung zu ähnlichen Erkrankungen (z.B. atopische Dermatitis) sowie eine frühzeitige Diagnose ermöglichen. Hierfür wurden 78 Patienten mit unterschiedlich ausgeprägtem HIES-Phänotyp auf eine Mutation in STAT3 untersucht. Der Phänotyp der Patienten wurde anhand des NIH-Scores quantitativ beurteilt, der die Wahrscheinlichkeit für ein HIES bestimmt (≥40 Punkte entsprechen der klinischen Diagnose HIES) (Grimbacher et al. 1999b). Bei 48 der untersuchten Patienten konnte eine heterozygote Mutation in STAT3 identifiziert werden. Es handelte sich um 24 verschiedene Mutationen, darunter 19 Erstbeschreibungen, die in drei funktionellen Domänen des STAT3 Proteins auftraten. Alle Mutationen erlauben die Expression eines veränderten STAT3 Proteins, das einen dominant-negativen Effekt auf die STAT3 Funktion ausübt (Minegishi et al. 2007; Renner et al. 2008). 96% der Patienten mit STAT3 Mutation (STAT3-mut Patienten) hatten ≥40 Punkte im NIH-Score und dementsprechend die klinisch-gesicherte Diagnose eines HIES. Bei 30 Patienten wurde auf genomischer DNA-Ebene keine Mutation in STAT3 gefunden (STAT3-wt Patienten); 90% gehörten der Gruppe der „Verdacht auf HIES“-Patienten an (85% Spezifität): Organabszesse, schwere Infektionen (Sepsis, Meningitis, Osteomyelitis), Pneumatozelen, Frakturen ohne adäquates Trauma, Skoliose und Nagel/mukokutane Candidiasis. Funktionell spielt STAT3 eine wichtige Rolle bei der Differenzierung von IL-17 produzierenden CD4+-T-Zellen (TH17-Zellen), die bei der Abwehr von extrazellulären Bakterien und Pilzen beteiligt sind (Yang et al. 2007; Ochs et al. 2009). Diese Arbeit konnte bestätigen, dass STAT3-mut Patienten signifikant erniedrigte TH17-Zellen im Vergleich zu STAT3-wt Patienten und normalen Kontrollen haben. Zum einen kann hiermit die Abwehrschwäche gegenüber Staphylococcus aureus und Candida albicans erklärt werden, zum anderen stellen die TH17-Zellen einen sehr sensitiven und spezifischen diagnostischen Marker für ein STAT3-HIES dar. Aus der Literatur ist außerdem bekannt, dass STAT3-Signalwege eine wichtige Rolle bei der Differenzierung von Osteoblasten und Osteoklasten spielen, und für die Aufrechterhaltung der Knochenhomöostase von Bedeutung sind (O'Brien et al. 1999; Itoh et al. 2006). Daraus ergibt sich eine mögliche Erklärung für die Skelett- und Bindegewebsanomalien bei STAT3-HIES Patienten, die aufgrund einer verminderten STAT3-Proteinfunktion entstehen können. Basierend auf den klinischen und immunologischen Korrelationsanalysen wurde der NIH-Score in den vereinfachten 5-Punkt-Score weiter entwickelt, der keine qualitative Wertung der Ausprägung und Häufigkeit der Symptome enthält (vergl. Tabelle 12). Die retrospektive Erhebung des 5-Punkt-Scores erzielte in dieser Studie eine vergleichbar hohe Korrelationsrate wie der NIH-Score (vergl. Tabelle 13). Zusammen mit der TH17-Zellzahlbestimmung stellt der 5-Punkt-Score ein diagnostisches Hilfsmittel für STAT3-HIES dar, ohne dem NIH-Score überlegen zu sein. Die Erkenntnisse dieser Studie liefern einen wichtigen Beitrag zur klinisch-genetischen Definition des STAT3-assoziierten HIES und stellen wesentliche Kriterien, die zur Diagnosefindung und Abgrenzung klinisch ähnlicher Erkrankungen führen, dar. Durch eine frühzeitige Diagnosestellung wird schließlich die Einleitung einer adäquaten Therapie ermöglicht, durch die Komplikationen vermieden und die Lebensqualität sowie Prognose der Patienten deutlich verbessert werden können. Weitere Untersuchungen von Zusammenhängen zwischen STAT3-Mutationen, der STAT3-Proteinfunktion und der Entstehung der einzelnen Symptome können in Zukunft neue Therapieansätze generieren und wichtige Erkenntnisse über die Entstehung von eigenständigen Erkrankungen wie der Osteoporose, der idiopathischen Skoliose oder Erkrankungen aus dem atopischen Formenkreis liefern.

The pleiotropic cytokine interleukin-6 (IL-6) is one of the major growth factors for multiple myeloma cells. It was previously shown that IL-6 induces the activation of Src family kinases Hck, Lyn and Fyn and that Hck is associated with the IL-6-receptor beta chain (gp130) via an acidic domain in gp130. In the first part of this thesis the acidic domain is narrowed down from 41 to 18 amino acids by a peptide-based functional screening assay. A derivative of the acidic domain, an 18mer lipopeptide, peptide 18AD, is characterised on the cellular and molecular level. IL-6-dependent growth of human and murine myeloma cells is inhibited with an IC50 of 25-30 µM by the addition of peptide 18AD to the growth medium. These cells remain unaffected by treatment with a control peptide with scrambled sequence (18sc). Furthermore, growth of IL-6-independent myeloma cells is not inhibited by peptide 18AD. In IL-6-dependent cells, peptide 18AD causes the same degree of apoptosis induction as IL-6 deprivation. On the molecular level it is shown by peptide competition assays that the association of Hck and gp130 is inhibited by peptide 18AD in a concentration dependent way. Peptide 18AD blocked the IL-6-induced activity of the Src family kinases Hck, Lyn and Fyn. Results from different factor-dependent cell lines demonstrate a common mechanism of the molecular peptide effects on Src family kinase activity, but the involved pathways downstream of the kinases appear to differ among species and cell lines tested. Treatment of human IL-6-dependent myeloma cells with peptide 18AD reduced the activating tyrosine phosphorylation of the signal transducer and activator of transcription 3 (STAT3), while STAT3 activation remains unaffected in murine cells. The Co-immunoprecipitations from different overexpressed receptor-deletionmutants and Hck confirms that the association is mainly due to the interaction between the kinase and a 9 amino acids spanning region within the acidic domain which carries the highest accumulation of acidic residues. Apparently, a sequence of 8-9 amino acids within gp130 with the prevalence of acidic side chains resembles a potential pseudosubstrate domain of tyrosine kinases and is responsible for localisation and activation of Src family kinases in response to receptor stimulation. The identification of sequence motives similar to the acidic domain of gp130 in other cytokine receptors, receptor tyrosine kinases and adapter proteins by an in silicio motive scan might suggest a general role of such motives. This could be the efficient recruitment of cytoplasmic kinases to signalling complexes at the time of ligand stimulation. Here, the importance of the acidic domain-kinase interaction for the IL-6-signaling pathway is shown by the growth-inhibiting effect of peptide 18AD on myeloma cells. In the second part, a novel sequence and celltype-specific anti-myeloma agent, peptide 1A, is characterised. It was initially designed as the negative control for a "reverse alanine scan" to define the role of the acidic residues within the sequence of peptide 18AD. Unexpectedly it turned out to be at least a 25-fold more potent growth inhibitor of myeloma cells than peptide 18AD. Similar molecular bases of the observed effects of peptide 18AD and peptide 1A are very unlikely, because in contrast to peptide 18AD, peptide 1A efficiently kills IL-6-independent myeloma cells as well. Moreover, an excess of IL-6 fails to rescue the cells from peptide 1A-induced cell death. Peptide 1A shows, as tested so far, no effects on cells derived from non-tumor tissue or tumor cells of various origins other than multiple myeloma. Peptide 1A specifically kills myeloma cells by the induction of apoptosis and severely disturbs cell cycle progression. Apoptotic cell death induction by peptide 1A is shown by peptide 1A-induced caspase-3 activation and the cleavage of PARP, a substrate of effector caspases. Peptide-induced cell death can partly be inhibited by co-treatment with the pan-caspase inhibitor ZVAD-fmk. Major survival pathways like the STAT3, PI3K/Akt and the MAPK pathway are inhibited in peptide 1A treated cells. If a biotinylated version of the peptide is added to the growth medium, it is incorporated into human myeloma cells and localised in defined regions of the cytoplasm of myeloma cells. Here some of the molecular mechanisms of peptide 1A-induced cell death are elucidated. However, the direct molecular target(s) are still unknown. Despite the potential difference in the molecular mechanisms, both peptides 18AD and 1A are expected to prove useful for developing derivatives with possible applications for the treatment of multiple myeloma.

Traditionally, Crohn's disease has been associated with a Th1 cytokine profile, while Th2 cytokines are modulators of ulcerative colitis. This concept has been challenged by the description of tolerising regulatory T cells (Treg) and by proinflammatory Th17 cells, a novel T cell population characterised by the master transcription factor RORtextgreekgt, the surface markers IL23R and CCR6, and by production of the proinflammatory cytokines IL17A, IL17F, IL21, IL22 and IL26, and the chemokine CCL20. Th17 cells differentiate under the influence of IL1textgreekb, IL6, IL21 and IL23. Recent studies indicate that TGFtextgreekb is essential not only for the development of murine Th17 cells but also for differentiation of human Th17 cells. TGFtextgreekb reciprocally regulates the differentiation of inflammatory Th17 cells and suppressive Treg subsets, with the concomitant presence of proinflammatory cytokines favouring Th17 cell differentiation. Several studies demonstrated an important role of Th17 cells in intestinal inflammation, particularly in Crohn's disease. Genome-wide association studies indicate that IL23R and five additional genes involved in Th17 differentiation (IL12B, JAK2, STAT3, CCR6 and TNFSF15) are associated with susceptibility to Crohn's disease and partly also to ulcerative colitis. Taken together, both Th1 and Th17 cells are important mediators of inflammation in Crohn's disease, although activities previously ascribed to IL12 may be mediated by IL23. Anti-IL12/IL23p40 antibody therapy, which targets both Th1 and Th17 cells, is effective in Crohn's disease. However, the complex relationship between Th1 and Th17 cells has not been completely analysed. This will be of great importance to delineate the specific contributions of these cells to Crohn's disease and other autoimmune diseases.

In den vergangenen Jahren ist es gelungen mittels verbesserter Fahrzeugtechniken, verkürzten Rettungszeiten und verbesserten Primärversorgungskonzepten, sowie standardisiertem Schockraum-Management und kontinuierlich optimierter intensivmedizinischer Behandlung, etc. die frühe Mortalität nach schwerem Polytrauma zu senken. Immer weniger Patienten versterben somit an den direkten Traumafolgen. Im weiteren Verlauf jedoch versterben noch immer bis zu 30 % an den Folgen eines posttraumatischen MOF. Somit stellt dieses immunologische Phänomen die schwerwiegendste Komplikation nach Polytrauma dar. In diesem Zusammenhang haben verschiedene Autoren versucht, jene Faktoren und Mechanismen zu identifizieren, die den Organismus dazu bewegen, seine eigenen, von dem initialen Trauma nicht betroffenen Organe zu zerstören. Jüngste Veröffentlichungen geben starke Hinweise darauf, dass der gefürchteten Ausbildung einer posttraumatischen Immunsystemdysfunktion mit konsekutivem Organversagen die Fehlfunktion immunkompetenter Zellen (Monozyten, Granulozyten) vorausgeht. Ferner sind intrazelluläre Netzwerke zahlreicher pro- und antiinflammatorischer Mediatoren, die in komplexen Verkettungen miteinander interagieren, daran beteiligt. Die intrazellulären Steuerungsmechanismen, die diese Fehlfunktion induzieren und regulieren, sind bislang jedoch weitgehend unerforscht. Zahlreiche Studien belegen, dass insbesondere Zytokine und ihre Signaltransduktionskaskaden an der Immunantwort beteiligt sind. Deren initiierende Steuerung ist jedoch weitgehend unbekannt. Von besonderer Bedeutung sind in diesem Zusammenhang die Transkriptionsfaktoren, da diese über die Expression von Reporter- und Effektorgenen entscheiden und sowohl hemmende als auch aktivierende Effekte ausüben können. Zahlreiche Untersuchungen weisen auf die Bedeutung der Signal Transducer and Activator of Transcription (STAT) Proteine in Inflammationsreaktionen hin. Bislang liegen jedoch noch keine Daten über die Aktivierung von STAT1 und STAT3 in immunkompetenten Zellen polytraumatisierter Patienten vor. Kenntnisse dieser Aktivität wären jedoch klinisch von essentieller Bedeutung für das Verständnis der posttraumatischen Immunreaktion und für die Entwicklung potentieller innovativer Therapiestrategien. Ziel der vorliegenden Arbeit war es daher, die DNA-Bindungsaktivität dieser Transkriptionsfaktoren in Monozyten und Granulozyten von Normalprobanden und schwerst verletzten Patienten in der initialen Phase nach Polytrauma zu analysieren und die Ergebnisse mit den klinischen Parametern wie Überleben, Verletzungsschwere und erhaltener Massentransfusion zu vergleichen. Zu diesem Zweck wurden polytraumatisierte Patienten mit einem Injury Severity Score größer 16 Punkten eingeschlossen. Die Blutabnahmen erfolgten zu festgelegten Abnahmezeitpunkten, nämlich initial nach Trauma und nach 6, 12, 24, 48 und 72h. Wobei die Initialabnahme innerhalb der ersten 90min nach Trauma erfolgte. Zur Zellisolation wurden aus dem entnommenen EDTA-Vollblut mittels positiven cell-sortings durch magnetische AK-Markierung CD-14 positive Monozyten und CD 15 positive Granulozyten isoliert. Das nukleäre Protein aus diesen wurde radioaktiv markiert und mittels EMSA elektrophoretisch aufgetrennt um so die DNA-Bindungsaktivität von STAT3 und STAT1 quantitativ nachzuweisen. Zusätzlich wurden Monozyten und Granulozyten gesunder Normalprobanden als Negativkontrolle bzw. mit LPS stimuliert als Positivkontrolle untersucht. Die Ergebnisse zeigen die DNA Bindungsaktivität von STAT1 und STAT3 in den Normalprobanden signifikant erhöht nach LPS Stimulation. Bei den Patienten konnte in beiden Zellpopulationen eine erhöhte Aktivität von STAT1 und STAT3 im Vergleich zur Nativkontrolle detektierte werden. Die Aufteilung des Kollektivs hinsichtlich klinischer Parameter wie outcome, Verletzungsschwere und erhaltener Massentransfusion zeigt, dass Patienten mit einem schlechteren klinischen Verlauf eine Reduktion der Aktivität von STAT1 und STAT3 in beiden Zellpopulationen aufweisen. Die vorgelegten Ergebnisse sind eine erstmalige Analyse der intranukleären DNA-Bindungsaktivität von STAT1 und STAT3 in polytraumatisierten Patienten in der direkt posttraumatischen Phase. Die frühe Induktion der Bindungsaktivität in Monozyten und Granulozyten im gesamten Kollektiv weist auf die beginnende systemische Entzündungsreaktion hin, und die Reduktion in massentransfundierten bzw. verstorbenen Patienten auf die bereits postulierte Unfähigkeit des Immunsystems, nach schwererer Verletzung adäquat zu reagieren. Die Daten sind Grundlage weiterer Folgeuntersuchungen wobei insbesondere die Frage nach der biologischen Relevanz mittels Reportergenexpression untersucht werden sollte.

Background/aim: Interleukin 31 (IL31), primarily expressed in activated lymphocytes, signals through a heterodimeric receptor complex consisting of the IL31 receptor alpha (IL31Rtextgreeka) and the oncostatin M receptor (OSMR). The aim of this study was to analyse IL31 receptor expression, signal transduction, and specific biological functions of this cytokine system in intestinal inflammation.Methods: Expression studies were performed by RT-PCR, quantitative PCR, western blotting, and immunohistochemistry. Signal transduction was analysed by western blotting. Cell proliferation was measured by MTS assays, cell migration by restitution assays.Results: Colorectal cancer derived intestinal epithelial cell (IEC) lines express both IL31 receptor subunits, while their expression in unstimulated primary murine IEC was low. LPS and the proinflammatory cytokines TNF-textgreeka, IL1textgreekb, IFN-textgreekg, and sodium butyrate stimulation increased IL31, IL31Rtextgreeka, and OSMR mRNA expression, while IL31 itself enhanced IL8 expression in IEC. IL31 mediates ERK-1/2, Akt, STAT1, and STAT3 activation in IEC resulting in enhanced IEC migration. However, at low cell density, IL31 had significant antiproliferative capacities (p

Die akute Pankreatitis beginnt in den Azinuszellen, allerdings bestimmen die sich anschließenden außerazinären, immunologischen Geschehnisse den Schweregrad der Erkrankung. Diese immunologische Reaktion wird über Zytokine vermittelt, die hauptsächlich von Immunzellen, zusätzlich aber auch von Pankreasazinuszellen selbst sezerniert werden. In dieser Arbeit wurde untersucht, ob Pankreasazinuszellen in der Lage sind, auf autokrin oder parakrin freigesetzte Zytokine zu reagieren. Der JAK/STAT-Signaltransduktionsweg, eine Phosphorylierungskaskade, die von Oberflächenrezeptoren initiierte Signale in den Zellkern weiterleitet, stellt den Haupteffektor der meisten Zytokine dar. Wir konnten mittels Immunopräzipitation und Western-Blot die meisten JAK und STAT Proteine in Pankreasazinuszellen nachweisen (JAK1, JAK2 und TYK2 sowie STAT1, STAT2, STAT3, STAT5 und STAT6). Darüber hinaus konnten wir zeigen, dass einige dieser Proteine in Pankreasazinustellen durch physiologische (Zytokine), aber auch unphysiologische (Stress) Stimuli phosphoryliert und damit aktiviert werden. Dies belegt neben der Expression zusätzlich eine Regulation dieser Proteine und damit eine funktionelle Rolle des JAK/STATSignaltransduktionsweges im Pankreas. Exemplarisch wurde mitttels Immunhistochemie gezeigt, dass IFN-

In der vorliegenden Arbeit wurden Effekte von IL-10 auf monocytäre Lipidrezeptoren und -Transporter untersucht, die zusätzlich zu den anti-inflammatorischen Wirkungen von IL-10 für dessen anti-atherosklerotische Wirkung von Bedeutung sein könnten. Es konnte gezeigt werden, dass IL-10 die Expression des quantitativ wichtigsten Scavenger Rezeptors, CD36, in Monocyten/Makrophagen sowohl auf RNA- als auch auf Proteinebene hemmt. Diese Hemmung ging einher mit einer verringerten zellulären Aufnahme von oxidiertem LDL. Durch PPARgamma-FACS und -Western Blot in Cytosol-Kern-Fraktionen sowie Koinkubationen mit IL-10 und den PPARgamma-Agonisten 15d-PGJ2 (15-deoxy-Δ12,14-Prostaglandin J2) und Indomethacin konnte gezeigt werden, dass die IL-10 Hemmung von CD36 über die Hemmung des Transkriptionsfaktors PPARgamma vermittelt wird. Im Gegensatz dazu stimulierte IL-10 den Cholesterinexporter ABCA1 und dessen wichtigsten Transkriptionsfaktor LXRalpha auf RNA- und Proteinebene. Die Induktion von ABCA1 hatte funktionell einen verstärkten zellulären Cholesterinefflux zur Folge, welcher die Monocyten und Makrophagen vor Lipidakkumulationen schützte und das vermehrte Einschleusen von Cholesterin in den reversen Cholesterintransport ermöglicht. IL-10 stimulierte ABCA1 dabei trotz der Hemmung des Transkriptionsfaktor PPARgamma. Die IL-10 Stimulation von ABCA1 war durch Piceatannol, einem Inhibitor der proximalen, STAT3-vermittelten Signalübertragung des IL-10 Rezeptors, hemmbar. Mittels LXRalpha "knock down" Zellen konnte weiter gezeigt werden, dass für die IL-10-stimulierte ABCA1 Expression ein intakter LXRalpha-Signaltransduktionsweg nötig ist. Koinkubationen mit Fenofibrat, 9-cis RA (9-cis retinoic acid) und 22-OHC (22-Hydroxycholesterol) ergaben, dass IL-10 auch die Induktion von ABCA1 durch die beiden Transkriptionsfaktoren, PPARalpha und LXRalpha, verstärkte. Durch Hemmung der Proteinkinase A (PKA) und Messung der zellulären cAMP-Spiegel konnte des Weiteren ein distaler cross-talk des IL-10-Signalweges mit dem cAMP/PKA-Weg für die ABCA1 Stimulation nachgewiesen werden. Dagegen hatte IL-10 keinen anhaltenden Einfluss auf die Transkription von SR-BI. Der Scavenger Rezeptor BI (SR-BI) kann je nach Konzentrationsgradient sowohl die zelluläre Cholesterinaufnahme wie die Cholesterinabgabe vermitteln. Des Weiteren reduzierte IL-10 die LPS-induzierte ICAM-1 Expression, was auf die Attenuierung der NFkappaB- und PPARgamma-vermittelten ICAM-1 Expression zurückgeführt werden konnte. Insgesamt befördert IL-10 somit den ABCA1-initiierten peripheren Cholesterinabtransport aus Monocyten/Makrophagen durch HDL. Die gezeigten Effekte von IL-10 erklären tierexperimentelle Befunde eines deutlich reduzierten Lipidgehalts in atherosklerotischen Plaques unter IL-10 Behandlung. Sie erklären auch die niedrigen HDL-Spiegel bei IL-10 knock out (IL-10-/-) Mäusen, die durch exogene IL-10 Substitution korrigiert werden können. Demnach sollte IL-10 nicht nur durch seine anti-inflammatorischen Mechanismen, sondern auch durch seine Effekte auf das Cholesterinhandling von Monocyten/Makrophagen in der Gefäßwand die Entstehung und Progression atherosklerotischer Plaques reduzieren.

Thu, 7 Oct 2004 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/2709/ https://edoc.ub.uni-muenchen.de/2709/1/Pau_Michael.pdf P