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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
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.08.548192v1?rss=1 Authors: Aguilan, J., Pedrosa, E., Dolstra, H., Nur Baykara, R., Barnes, J., Zhang, J., Sidoli, S., Lachman, H. Abstract: Background: Jansen de Vries Syndrome (JdVS) is a rare neurodevelopmental disorder (NDD) caused by gain-of-function (GOF) truncating mutations in PPM1D exons 5 or 6. PPM1D is a serine/threonine phosphatase that plays an important role in the DNA damage response (DDR) by negatively regulating TP53 (P53). JdVS-associated mutations lead to the formation of a truncated PPM1D protein that retains catalytic activity and has a GOF effect because of reduced degradation. Somatic PPM1D exons 5 and 6 truncating mutations are well-established factors in a number of cancers, due to excessive dephosphorylation and reduced function of P53 and other substrates involved in DDR. Children with JdVS have a variety of neurodevelopmental, psychiatric, and physical problems. In addition, a small fraction has acute neuropsychiatric decompensation apparently triggered by infection or severe non-infectious environmental stress factors. Methods: To understand the molecular basis of JdVS, we developed an induced pluripotent stem cell (iPSC) model system. iPSCs heterozygous for the truncating variant (PPM1D+/tr), were made from a patient, and control lines engineered using CRISPR-Cas9 gene editing. Proteomics and phosphoprotemics analyses were carried out on iPSC-derived glutamatergic neurons and microglia from three control and three PPM1D+/tr iPSC lines. We also analyzed the effect of the TLR4 agonist, lipopolysaccharide, to understand how activation of the innate immune system in microglia could account for acute behavioral decompensation. Results: One of the major findings was the downregulation of POGZ in unstimulated microglia. Since loss-of-function variants in the POGZ gene are well-known causes of autism spectrum disorder, the decrease in PPM1D+/tr microglia suggests this plays a role in the neurodevelopmental aspects of JdVS. In addition, neurons, baseline, and LPS-stimulated microglia show marked alterations in the expression of several E3 ubiquitin ligases, most notably UBR4, and regulators of innate immunity, chromatin structure, ErbB signaling, and splicing. In addition, pathway analysis points to overlap with neurodegenerative disorders. Limitations: Owing to the cost and labor-intensive nature of iPSC research, the sample size was small. Conclusions: Our findings provide insight into the molecular basis of JdVS and can be extrapolated to understand neuropsychiatric decompensation that occurs in subgroups of patients with ASD and other NDDs. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.03.522525v1?rss=1 Authors: Hu, X., Zhu, Q., Lou, T., Hu, Q., Niu, X., He, L., Huang, H., Xu, Y., Qiu, M., Shen, Y., Jia, J.-M., Tao, Y. Abstract: White matter abnormalities are an emerging feature of schizophrenia, yet the underlying pathophysiological mechanisms are largely unknown. Disruption of ErbB signaling that is essential for peripheral myelination has been genetically associated with schizophrenia and white matter lesions in schizophrenic patients. However, the roles of ErbB signaling in oligodendrocytes remain elusive. Here, we used a pan-ErbB inhibition strategy and demonstrated the synergistic functions of endogenous ErbB receptors in oligodendrocytes. Through analyses of the cellular, histological, biochemical, behavioral, and electrophysiological differences in mice with manipulation of ErbB activities in oligodendrocytes at different differentiation stages, we found that ErbB signaling regulates myelination and aerobic glycolysis in oligodendrocytes, and both functions are required for working memory. ErbB inhibition in oligodendrocytes at early differentiation stages induces hypomyelination by suppressing the differentiation of newly-formed oligodendrocytes. In contrast, ErbB inhibition in mature oligodendrocytes alters neither myelination nor oligodendrocyte numbers, but accelerates axonal conduction decline under energy stress. Mechanistically, mature oligodendrocytes with ErbB inhibition reduce the expression of lactate dehydrogenase A, failing to provide lactate to electrically active axons. Supplementation of L-lactate restores axonal conduction and working memory capacity that are suppressed by ErbB inhibition in mature oligodendrocytes. These findings reveal the indispensable roles of ErbB signaling in white matter integrity and function, and provide insights into the multifaceted contributions of white matter abnormalities to cognitive impairment. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
CME credits: 1.00 Valid until: 17-08-2023 Claim your CME credit at https://reachmd.com/programs/cme/what-are-nrg1-gene-fusions-and-the-rationale-for-targeting-erbb/14338/ tbd
Two American Cancer Society grantees—one with a recent publication on the early mechanisms of lung cancer initiation, the other with a new study out on the development of melanoma resistance during the earliest phases of treatment—joined the podcast for a conversation about catching the problem early. This conversation is geared for a scientific audience, until the last few minutes. Sabrina Spencer, PhD, is Associate Professor of Biochemistry at University of Colorado, Boulder. She recently published a study in Nature Communications on “Melanoma subpopulations that rapidly escape MAPK pathway inhibition incur DNA damage and rely on stress signaling:” https://www.nature.com/articles/s41467-021-21549-x?elqTrackId=2842c2f36cc243139afc4151f4f48ee6. Xaralabos (Bob) Varelas, PhD, is Associate Professor of Biochemistry at Boston University School of Medicine. He recently published work in Proceedings of the National Academy of Sciences of the United States of America titled, “Aberrant epithelial polarity cues drive the development of precancerous airway lesions:” https://www.pnas.org/content/118/18/e2019282118. 1:08 – Dr. Varelas on his recent study, which offered insights into mechanisms that drive the onset of lung squamous cell carcinomas 4:20 – Dr. Spencer asks clarifying questions about how they disrupted the polarity… 5:08 – …and whether the Crumbs3 mutation occurs in patients or was a way to initiate the system 7:56 – A provocative question from Dr. Spencer: “would that mean that a precancerous lesion would be a candidate for treatment with some of these clinically approved drugs?” 9:25 – “Can you connect increased ERBB signaling to actual increased cell cycling?” 10:48 – Dr. Spencer talks about her interest in the origin of drug resistance in cancer and her recent paper, which focused on melanoma 20:15 – Dr. Varelas asks how broadly applicable these findings are to other cancers 22:10 – “Why do you think some of the cells escape? Is there an underlying difference in the cells to begin with? Or are some cells randomly taking on some kind of adaptive mechanism?” 28:11 – The impact of American Cancer Society funding on their research
Investor Ideas Potcasts #600: (CSE: BRAX) (OTC: BRAXF) (OTC: ERBB) (OTCQX: AVCNF) (NASDAQ: GNLN)
Investor Ideas Potcasts #600: (CSE: BRAX) (OTC: BRAXF) (OTC: ERBB) (OTCQX: AVCNF) (NASDAQ: GNLN)
Investor Ideas Potcasts #600: (CSE: BRAX) (OTC: BRAXF) (OTC: ERBB) (OTCQX: AVCNF) (NASDAQ: GNLN)
Investor Ideas Potcasts #593, Cannabis News and Stocks on the Move: (TSX: WEED) (NASDAQ: CGC), (TSX: VLNS) (OTCQX: VLNCF), (OTC: LRSV) and (OTC: ERBB)
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.10.377226v1?rss=1 Authors: Hu, X., Xiao, G., He, L., Niu, X., Li, H., Xu, Q., Wei, Z., Qiu, M., Tanaka, K. F., Shen, Y., Tao, Y. Abstract: Oligodendrocytes are vulnerable to genetic and environmental insults and its injury leads to demyelinating diseases. The roles of ErbB receptors in the CNS myelin integrity are largely unknown. Here we overactivate ErbB receptors that mediate signaling of either neuregulin or EGF family growth factors and found their synergistic activation caused deleterious outcomes in white matter. Sustained ErbB activation induced by the tetracycline-dependent mouse tool Plp-tTA resulted in demyelination, axonal degeneration, oligodendrocyte precursor cell (OPC) proliferation, astrogliosis, and microgliosis in white matter. Moreover, there was hypermyelination prior to these pathological events. In contrast, sustained ErbB activation induced by another tetracycline-dependent mouse tool Sox10+/rtTA caused hypomyelination in the corpus callosum and optic nerve, which appeared to be a developmental deficit and did not associate with OPC regeneration, astrogliosis, or microgliosis. By analyzing the differentiation states of cells that were pulse-labeled with a viral reporter, we found that, during juvenile to adolescent development, Plp-tTA targeted mainly mature oligodendrocytes (MOs), while Sox10+/rtTA targeted OPCs and newly-formed oligodendrocytes. The distinct phenotypes of mice with ErbB overactivation induced by Plp-tTA and Sox10+/rtTA supported the reporter pulse-labeling results, and consolidated their non-overlapping targeting preferences in the oligodendrocyte lineage after early development. These features enabled us to demonstrate that ErbB overactivation in MOs induced necroptosis that caused pathological demyelination, whereas in OPCs induced apoptosis that caused developmental hypomyelination. These results established an upstream pathogenic role of ErbB overactivation in oligodendrocytes, providing molecular and cellular insights into the primary oligodendropathy in demyelinating diseases. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.09.289223v1?rss=1 Authors: Hu, X., Xiao, G., He, L., Zhu, Q., Niu, X., Li, H., Xu, Q., Wei, Z., Huang, H., Luan, Y., Qiu, M., Tanaka, K. F., Shen, Y., Tao, Y. Abstract: White matter abnormalities are an emerging pathological feature of schizophrenia. However, their attributions to the disease remain largely elusive. ErbB receptors and their ligands, some of which are essential for peripheral myelination, confer susceptibility to schizophrenia. By synergistically manipulating ErbB receptor activities in a oligodendrocyte-stage-specific manner in mice after early development, we demonstrate the distinct effects of ErbB signaling on oligodendrocytes at various differentiation states. ErbB overactivation, in mature oligodendrocytes, induces necroptosis causing demyelination, whereas in oligodendrocyte precursor cells, induces apoptosis causing hypomyelination. In contrast, ErbB inhibition increases oligodendrocyte precursor cell proliferation but induces hypomyelination by suppressing the myelinating capabilities of newly-formed oligodendrocytes. Remarkably, ErbB inhibition in mature oligodendrocytes diminishes axonal conduction under energy stress and impairs working memory capacity independently of myelin pathology. This study reveals the etiological implications of oligodendrocyte vulnerability induced by ErbB dysregulation, and elucidates the pathogenetic mechanisms for variable structural and functional white matter abnormalities. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.23.167833v1?rss=1 Authors: Meng, X., Borges, B. C., Long, P., Kanold, P. O., Corfas, G. Abstract: Myelination of central nervous system axons increases the conduction speed of neural impulses and contributes to the function and maintenance of neural circuits. Accordingly, loss of myelin leads to axonal loss and to severe brain dysfunction. In contrast, much less is known about the functional consequences of mild hypomyelination on central network connectivity. To address this gap in knowledge, we studied mice that have mild hypomyelination due to loss of oligodendrocyte ErbB receptor signaling. We focused on the primary auditory cortex (A1) due to the crucial role that temporal precision plays in the processing of auditory information. We find that loss of oligodendrocyte ErbB receptor signaling causes reduction in myelin in A1. We mapped and quantified the intracortical inputs to L2/3 neurons using laser-scanning photostimulation combined with patch clamp recordings. We found that hypomyelination reduces inhibitory connections to L2/3 neurons without affecting excitatory inputs, thus altering excitatory/inhibitory balance. Remarkably, these effects are not associated with changes in the expression of GABAergic and glutamatergic synaptic components, but with a reduction of parvalbumin (PV) neuron density and PV mRNA levels. These results demonstrate that mild hypomyelination can impact cortical neuronal networks and cause a network shift towards excitation. Copy rights belong to original authors. Visit the link for more info
Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 427 (TSXV: NUMI) (CSE: IPOT) (TSXV: RTI) (OTC: ERBB)
Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 427 (TSXV: NUMI) (CSE: IPOT) (TSXV: RTI) (OTC: ERBB)
Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 427 (TSXV: NUMI) (CSE: IPOT) (TSXV: RTI) (OTC: ERBB)
Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 418 (OTC: CSUI) (TSX: TGOD) (NYSE: APHA) (TSX: LABS) (OTC: ERBB)
Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 418 (OTC: CSUI) (TSX: TGOD) (NYSE: APHA) (TSX: LABS) (OTC: ERBB)
Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 418 (OTC: CSUI) (TSX: TGOD) (NYSE: APHA) (TSX: LABS) (OTC: ERBB)
Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 413 (OTC: CSUI) (OTC: ERBB) (NASDAQ: NEPT) (NYSE: CGC) (CSE: CRFT) (TSXV: NDVA)
Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 413 (OTC: CSUI) (OTC: ERBB) (NASDAQ: NEPT) (NYSE: CGC) (CSE: CRFT) (TSXV: NDVA)
Investor Ideas Potcasts, Cannabis News and Stocks on the Move; Episode 413 (OTC: CSUI) (OTC: ERBB) (NASDAQ: NEPT) (NYSE: CGC) (CSE: CRFT) (TSXV: NDVA)
Featuring perspectives from Dr Shirish M Gadgeel on the later-line management of metastatic squamous cell carcinoma of the lung. Recent advances in the management of advanced non-small cell lung cancer (NSCLC) (0:00) Case: A woman in her early 70s with metastatic squamous cell carcinoma (SCC) of the lung receives carboplatin/paclitaxel and pembrolizumab as first-line therapy on the KEYNOTE-021 trial (02:25) Response to pembrolizumab and chemotherapy in advanced SCC of the lung (04:34) Efficacy of pembrolizumab alone or in combination with chemotherapy for advanced NSCLC (07:41) Choice of immune checkpoint inhibitor/chemotherapy regimen as first-line therapy for metastatic SCC of the lung (12:22) Results of the Phase III CheckMate 227 trial evaluating nivolumab alone, with ipilimumab or with chemotherapy as first-line therapy for metastatic NSCLC (15:43) Interim overall survival analysis of the Phase III IMpower110 study investigating atezolizumab versus platinum-based chemotherapy for metastatic NSCLC in the first-line setting (18:32) Cancer site and adverse events induced by immune checkpoint inhibitors (20:05) Genetic alterations in patients with SCC of the lung; rationale for targeting the ERBB signaling pathway (22:18) Results of the Phase III LUX-Lung 8 trial of afatinib versus erlotinib as second-line treatment for advanced SCC of the lung (25:53) Secondary analysis of LUX-Lung 8: Association of ERBB mutations with clinical outcomes among patients with afatinib- or erlotinib-treated SCC of the lung (28:04) Role of HER2 mutations and HER2 amplification in patients with NSCLC; incidence of HER2 alterations in patients with SCC of the lung (30:14) Targeting HER2 alterations with the tyrosine kinase inhibitors afatinib and dacomitinib in patients with NSCLC (34:15) Efficacy of the antibody-drug conjugate trastuzumab deruxtecan (DS-8201) in patients with NSCLC and HER2 alterations (36:11) Activity of T-DM1 in patients with NSCLC and HER2 mutations (38:04) Management of gastrointestinal side effects associated with afatinib (40:22) Activity of afatinib in heavily pretreated ERBB2 mutation-positive advanced NSCLC (43:01) Afatinib in patients with metastatic or recurrent lung cancer with HER2 mutations (45:15) Case: A man in his early 80s develops metastases to the liver during treatment with durvalumab after chemoradiation therapy for Stage III SCC of the lung and is found to have FGFR1 amplification (47:15) FGFR signaling as a target for NSCLC therapy; outcomes with the FGFR inhibitor AZD4547 in patients with metastatic SCC of the lung and FGFR alterations (51:04) SWOG-S1400 Lung Cancer Master Protocol (Lung-MAP) — Biomarker-targeted therapy for patients with previously treated Stage IV SCC of the lung (56:02) Case: A woman in her early 50s with ALK-rearranged metastatic lung adenocarcinoma experiences a dramatic response to crizotinib on the PROFILE 1014 study (1:02:39) Response to ALK inhibitors for ALK-rearranged metastatic NSCLC (1:06:54) CME information and select publications
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. We're your co-hosts, I'm Dr Carolyn Lam, associate editor from The National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Greg Hundley, associate editor for Circulation and director of The Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam: Guess what Greg? Right after this we have a double feature discussion. It is all about dapagliflozin with some really, really important self-analyses from the DECLARED-TIMI 58 trial and about heart failure in Type 2 Diabetes with dapagliflozin. But, all of that coming right up only after we have our chat. So Greg, what do you have for us today? Dr Greg Hundley: My first article is going to be from Dr Mintu Turakhia at the VA Palo Alto healthcare system at Stanford University and is going to discuss the practice variation in anticoagulation prescription and outcomes after device-detected atrial fibrillation. It's a study that has insights from the VA Health Administration. This study evaluated the relationship between oral anticoagulant prescription practice variation in response to new device detected atrial fibrillation and the association to outcomes. As you know Carolyn, there are no clearly defined thresholds of AF burden, for which to initiate oral anticoagulation. Dr Carolyn Lam: Interesting, so what did they find, how did they do this? Dr Greg Hundley: Carolyn, the investigators performed a retrospective cohort analysis using data from the Veterans Health Administration linked to remote monitoring data that included day level AF burden. They included patients with cardiac implantable electronic devices and remote monitoring from the years 2011 through 2014. A CHA2DS2-VASc score of greater or equal to 2, and no prior stroke or oral anticoagulant receipt in the preceding 2 years. They determined the proportion of patients prescribed oral anticoagulants within 90 days following new device-detected AFib across a range of AFib thresholds. Greater than or equal to 6 minutes, all the way up to greater than 24 hours. And they examined sight variation in oral anticoagulation prescription. Dr Carolyn Lam: And so? What did they find? Dr Greg Hundley: Well, you ask among 10,212 patients with defibrillators, proportion receiving oral anticoagulation varied based on device detected AF burden. For example, for those greater than or equal to 6 minutes, it was roughly 13% of individuals, for those greater than 24 hours, 27% of individuals received oral anticoagulants. Importantly, there was a substantial sight variation in oral anticoagulation prescription after device-detected atrial fibrillation, for example, greater than one hour. The median was 16%, but it ranged from as low as 3% up to highs of 67%. And so, in adjusted models, oral anticoagulant prescription after device-detected AFib of greater than 24 hours was associated with reduced stroke risk and has a ratio of 0.28, p-value's 0.02, although, the propensity adjusted model was significant when AFib lasted at least 6 minutes. So, in conclusion, among veterans with implanted devices, device-detected atrial fibrillation is common. There is large practice variation in 90-day oral anticoagulation initiation after new device-detected AFib with low rates of treatment overall, even for episodes greater than 24 hours. Remember, we said that rate was 27%. The strongest association of oral anti-coagulation with reduction in stroke was observed after device-detected Afib of greater than 24 hours. And what this study shows, is that randomized trials are needed to perform these observational findings. So, Carolyn, how about your next study? Dr Carolyn Lam: Well, from anti-coagulants to anti-hypertensives. I'm going to tell you about the 6-month results if the RADIANCE Hypertension Solo Trial. Dr Greg Hundley: Oh, so, what was the RADIANCE Hypertension Solo Trial? Can you remind us? Dr Carolyn Lam: Glad you asked. So the trial was the one that demonstrated a greater reduction in daytime ambulatory systolic blood pressure at 2 months by endovascular ultrasound renal denervation compared with a sham procedure among patients who were not treated with anti-hypertensive medications. So the current paper, led by Michel Azizi from Université Paris-Descartes and colleagues, now report the 6-month results following the addition of a recommended, standardized, stepped-care anti-hypertensive treatment to the randomized endovascular procedure under continued blinding to the initial treatment. Now, remember these were patients with uncontrolled combined systolic and diastolic hypertension who were initially off medications for two months following randomization. Now, between two and five months, if the monthly measured home blood pressure was more than 135/85, the stepped-care antihypertensive treatment approach was recommended and consisted of sequential addition of, for example, amlodipine 5mg a day, then a standard dose of an angiotensin-converting-enzyme inhibitor, or an ARB, and hydrochlorothiazide at 12.5mg a day, followed by sequential uptitration of the hydrochlorothiazide and amlodipine. So, what did they find? At 6 months, 65% of the patients in the original renal denervation group were being treated by this stepped-care approach, versus 84.5 in the sham group. And the average number of antihypertension medications and defined-daily doses were all less in the renal denervation group than the sham group. Now, despite less intensive antihypertensive treatment, the renal denervation group had reduced daytime ambulatory systolic blood pressure to a great extent than the sham group. Importantly, there were no major adverse events in either group through 6 months. The blood pressure lowering effect of endovascular ultrasound renal denervation was maintained at 6 months with less prescribed antihypertension medications compared with the sham control. And what this means is if safety is maintained in larger studies with longer follow-up, renal denervation could be a promising adjunct therapy for patients with hypertension. Dr Greg Hundley: Wow, so we're getting back toward renal denervation? How about that? Carolyn, my next paper jumps into the world of basic science. This is a study from Kari Alitalo at the University of Helsinki, and it involves endothelial cells and how they regulate physiological cardiomyocyte growth versus VEGFR2 mediated paracrine signaling. The study evaluates the role of bidirectional endothelial cells and cardiomyocyte cross-talk via cardiokine and angiocrine signaling as it pertains to the regulation of cardiac growth and homeostasis in pathological cardiac hypertrophy. The expansion of the cardiac vasculature to maintain adequate supply of oxygen and nutrients is a key determinant of whether the heart grows in a physiological compensated manner, or a pathological decompensated manner. Understanding how an excess of angiogenesis induces cardiac hypertrophy and how endothelial cells regulate cardiomyocyte homeostasis, could provide novel therapeutic targets for heart failure. Dr Carolyn Lam: Ah, this is something very close to my heart. So Greg tell us, how did they establish the link between the endothelial cells and cardiomyocytes? Dr Greg Hundley: The investigators demonstrated that both endothelial cell deletion of vascular endothelial growth factor receptor 1 and AAV-mediated delivery of the VEGFR1's specific ligands, VEGF-B or BGIF, into the myocardium increased the coronary vasculature and induced cardiomyocyte hypertrophy in adult mice. The resulting cardiac hypertrophy was a physiological as indicated by preserved cardiac function and exercise capacity and lack and pathological gene activation. Also, the investigators demonstrated that the reported changes were mediated by increased VEGF signaling via endothelial VEGFR2 and found that the notch and ERBb pathways are involved in transducing signals for endothelial cell cardiomyocyte cross-talk in response to angiogenesis. So clinically, the relevance of the findings are highlighted nicely in an editorial by professor Issei Komuro at the University of Tokyo Hospital. First, he emphasizes that cross-talk between the endothelial cell VEGFR2 and cardiomyocyte ErbB signaling pathways coordinates cardiomyocyte hypertrophy with angiogenesis and contributes to physiological cardiac growth. And understanding whether factors could modify this process may impact the treatment down the road of pathologic hypertrophy. Dr Carolyn Lam: Oh interesting! Well you know what, Greg, I've got a preclinical one for you too, and this time looking at the role of inflammation in atherosclerosis and specifically at the role of the adaptive immune response and T-cells. So, Greg, let me remind you that when we looked at CANTOS and Canakinumab we were actually looking at the role of the innate immune response. And here is where I had planned this very nice, complicated quiz for you, Greg, about the innate versus the adaptive immune response in the various cells. Would you like to take the quiz? Dr Greg Hundley: You know what? I think I'm going to pledge that I'm already going to get a D or an F, so why don't you enlighten us? Dr Carolyn Lam: Now alright, remember that the CD4 T-cells are assumed to be activated by our antigens derived from modified proteins such as oxidized LDL, and these are presented via MHC class II molecules in the context of cytokine signaling, remember those? What I didn't realize is that it hadn't been assumed that atherosclerosis involves a loss of tolerance against these modified self-antigens, generated in response to hypercholesterolemia and that presentation of such antigens on these MHC class II cells, then lead to activation of proatherogenic Th1 cells. So, that was the assumptions, but this was really studied in detail by the authors, Dr Wigren from Scania University Hospital and Lund University in Sweden and their colleagues, who addressed the role of CD4 T-cells in a real novel, unconventional way. And they did this by crossing MHC class ii deficient mice with atherosclerosis-prone ApoE-deficient mice. Now the result of these double deficient mice was almost complete void of CD4 T-cells. However, despite the lack of these T-cells and inflammation, these mice developed larger atherosclerotic lesions in the aortic root area of the heart than their ApoE-deficient counterparts. Cell transfer and blocking antibody studies also, then supported these findings and suggested that loss of regulatory T-cells is the most important cause of aggravated atherosclerosis in the double-deficient mice. So, overall these observations demonstrate that deficiency of activation of the adaptive immune responses through MHC class ii is associated with increased development of atherosclerosis, and the findings have important implications for our understanding the possible risks and benefits of immunosuppressive therapy in patients with cardiovascular disease. Now this is discussed in a beautiful editorial by Dr Slütter and Kuiper and they are from Leiden, the Netherlands. So, Greg, interesting stuff, huh? Dr Greg Hundley: You bet! Let's go on and here a little bit more about diabetes. Dr Carolyn Lam: And dapagliflozin coming right up. Today's feature discussion is all about SGLT2 inhibitors both in heart failure and atherosclerotic disease. A huge discussion because we have two papers, and they're all coming from the DECLARE-TIMI 58 trial. I am so pleased to have the corresponding author, Dr Stephen Wiviott from the TIMI study group at Brigham Women's hospital in Boston, Massachusetts, as well as the first author of one of the papers, and that is Dr Eri Kato, who was at the TIMI study group and is now at Kyoto University, as well as the editorialist for these two papers, Dr Subodh Verma from University of Toronto, and our deputy editor, Dr Darren McGuire from UT Southwestern. All-star cast, all-star papers. So, Steve, could you start by telling us about the DECLARE-TIMI 58 trial, just to set the background please? Dr Stephen Wiviott: So DECLARE, for people who don't know, was a large, randomized trial of 17,000+ patients with diabetes, comparing the SGLT2 inhibitor dapagliflozin to placebo. And the patients could be enrolled if the patients had either an established cardiovascular disease, meaning secondary prevention, or simply risk factors for cardiovascular disease with primary prevention. Patients that were treated with dapagliflozin or placebo were followed for a period of just over 4 years and there were co-primary endpoints. Those were cardiovascular death and hospitalization for heart failure, and the second co-primary endpoint was MACE, major adverse cardiovascular events, a combination of cardiovascular death, MI, or stroke. And what we saw, initially, this was a safety trial to demonstrate the safety of this diabetes agent according to worldwide guidelines. We saw that there was certainly non-inferiority for MACE, so it was safe with regard to MACE, but we did see a statistically significant reduction in cardiovascular death and hospitalization for heart failure driven predominantly by a large reduction in hospitalization for heart failure, and we also saw consistent with the other SGLT2 inhibitors, a significant reduction in the progression of renal disease. And so we had the opportunity to follow up with a couple of important papers that were published in circulation. Dr Carolyn Lam: Thanks, Steve. And at this point I would love to invite Eri to tell us, because we just heard that the heart failure hospitalization signal is very strong. What did you do in your analysis? Dr Eri Kato: So previously, SGLT2 inhibitors including dapagliflozin have shown to reduce hospitalization for heart failure, now we wanted to take a step further and explore those who are at high risk. So, the aim of our study was to evaluate whether the clinical benefit of dapagliflozin is greater in patients with HFrEF, heart failure with reduced ejection fraction, compared with patients without HFrEF. So, we used data from the DECLARE-TIMI 58, which you just heard, which included a broad spectrum of patients with Type 2 diabetes, and was also unique that it is the only SGLT trial to date that has detailed the information of these ejection fractions. So, for this study, for our study trying to find patients by the presence or absence of HFrEF, which was defined as having ejection fraction less than 45%, which is pre-specified ejection fraction couplings, and the key outcome in each was cardiovascular death or hospitalization for heart failure, its components, and of course, mortality. But we also additionally looked at MACE and renal composite endpoints. There are several interesting findings. First, is that dapagliflozin reduced the risk of hospitalization for heart failure regardless of ejection fraction, including those with preserved ejection fraction. Second, is we have observed lower rates of cardiovascular death in all-cause mortality with dapagliflozin in patients with HFrEF, but not in those without HFrEF. So, in patients with HFrEF, there was a significant 45% reduction in cardiovascular death, and 41% reduction in all all-cause mortality with dapagliflozin. And I'd like to highlight that these were achieved on top of high-proportional use of conventional evidence-based heart failure therapies, and that it did not increase any adverse events. And third, and finally, there were lower rates of renal composite endpoints with dapagliflozin regardless rejection fraction, and once again, it improves patients with preserved rejection fraction. So, to summarize, our results showed a robust mortality benefit in patients with HFrEF, but also showed that dapagliflozin is beneficial in full spectrum patients with diabetes, regardless of ejection fraction. Dr Carolyn Lam: Thank you Eri, that's beautifully summarized, but could I just clarify? These were patients not just with a reduced ejection fraction, but with heart failure? And how was that determined? Dr Eri Kato: We collected data at the baseline and the heart failure was collected based on the medical record. Dr Carolyn Lam: So, I just wanted to clarify that it wasn't just rEF, but HFrEF, but the HF part was a medical record. So, Darren, I know you thought a lot about this stuff, so what do you think? Is there still equipoise for these heart failure trials, or how do you think this adds? Dr Darren McGuire: First, as deputy editor of Circulation, I'm thrilled that were attracting these excellent diabetes-related publications, we've had a track record of several years now of capturing many of the key analyses and certainly these two papers we're talking about today qualify among the very best we've had, and I've also had the privilege of working with these investigators on the executive committee at DECLARE. And to the investigators and the credit of the sponsor, we observed these heart failure signals in other trials as DECLARE was ongoing, and we actually made a modification during the trial to begin to collect as much as we could pre-randomization ejection fraction data. And we were able to capture on roughly one-third of the patients, pre-trial EF data and we took any way it was measured and any time of when it was measured, and there are some limitations to that, but this now represents the largest data set where we can stratify the outcomes by some measure of ejection fraction. And I have to say I was really surprised by these results; that the cardiovascular death benefits were amplified in patients with heart failure with reduced ejection fraction, but not in those with heart failure with preserved ejection fraction, as these medications are relatively modest, diuretic agents I anticipated the opposite, honestly, that heart failure would preserve ejection fraction that is much more volume-sensitive may have incremental benefits from these medications. So, I was surprised by this, it was a little bit upside-down from what I expected. I know Subodh and Carolyn you've both thought a lot about this as well, I'd be interested in your opinions. Did you expect that heart failure with reduced ejection fraction would drive these clinical results? Dr Carolyn Lam: Subodh, I'm going to let you go first. Dr Subodh Verma: First and foremost, I appreciate the opportunity the circulation gave both myself and Professor McMurray to write the editorial to these very important pre-specified analyses from DECLARE. I actually see the results not only as interesting and tantalizing as you already discussed, but I actually see a lot of consistency between the two phenotypes, if I may, in that there is a heart failure signal or reduction in heart failure hospitalizations that appears to be consistent between the two groups, right? People with an EF of less than 45 with or without heart failure and then on the other side, people without reduced ejection fraction. They're both responsive in terms of reductions in heart failure hospitalization, so it brings into question that is this differences that we're seeing with respect to mortality, a reflection of a difference in phenotypic responsiveness to an SGLT2 inhibitor, or is this simply a reflection of increasing placebo event rates and a response based on baseline of entry in one group versus the other. So, as has been nicely outlined by the authors, the placebo event rate for CB death and heart failure and the placebo group would have pass, if I may, was about 5 times lower than those with heart failure with reduced ejection fraction. And it might be that as we go up the pyramid of risk, whether that risk is defined based on a TIMI risk score, whether it's based on a post-MI versus stable CAV risk score, or whether it's defined based on GFR, or whether, finally, it's defined based on the event rates for CV death and heart failure, that the higher the event rate, the higher the probability of demonstrating a CV death benefit, but that old strategies are actually demonstrating a consistent benefit on the overall driver of that outcome, which in this case, is a reduction in heart failure. So, that's what we sort of said in the editorial as well that we think that it may be a bit premature at this point to reach a conclusion that one group is responsive, and the other group is not responsive. But, as you rightfully said, Darren, it is entirely feasible through these analyses to hypothesize that one of the alternative hypotheses could be that there is a greater responsiveness in HFrEF compared to HFpEF. I actually don't understand the mechanisms of it, if that was the pieces I would have a difficult time explaining it based on the overall biology and sort of current understanding of these agents. But, I would say let’s wait: dapa heart failure is just around the corner. That trial will enroll people with documented heart failure with reduced ejection fraction. I think 4,774 patients that are being randomized on top of base, on top of RNA, on top of MRA, etc. who still have heart failure and who have a BP that's elevated so the definitive proof for this, at least from a rough standpoint, will be forthcoming. And then there are numerous HFpEF studies that are ongoing. There's Emperor Preserve and there's Deliver, and they have characterized the HFpEF population with a little bit more granularity and clarity. And I think we will be able to then look at, specifically, is there a HFpEF group that has the same event rate for CV death and heart failure, and compare that population to a HFrEF group at the same level of risk and whether there is differences in the responsiveness to be definitive about whether this is a matter of risk, threshold, or whether this is a true representation phenotypically. Dr Carolyn Lam: Subodh is a hard act to follow. So, I will answer your question directly, but maybe not with so many words, because it's already been said, Darren. And I'll just say I expected this benefit to be in both, I wouldn't have said one versus the other, but because we do know that in trials and with prospective studies that HFpEF outcomes are lower, especially mortality is lower, compared to HFrEF. I do wonder if it's a power issue, but the most important message--and this is coming from me also being on the steering on the committee of both DELIVER and EMPEROR Preserve--that please, this doesn't mean that we don't need the trials. I really really think that there's equipoise there still and we need to look at the DEDICATED HFpEF trials. But, moving on from the concept of risk stratification, I would like to go on and talk about the next paper. About the DECLARE sub-study of those with a prior MI. So, Steve, could you tell us, why did you do this, and what did you find? Dr Stephen Wiviott: I think that what we've seen as a pattern across the three SGLT2 inhibitor trials including CANVAS, EMPEROR, Outcome, and DECLARE, was that there seems to be, as Subodh has said, reductions that are relatively consistent in heart failure and renal outcomes. But there was what appears to be ischemic outcomes, the MACE outcomes, cardiovascular death, MI and stroke. In fact, in a meta-analysis that we published at the same time as the primary paper for DECLARE, we demonstrated that there was an interaction between the primary prevention in the population, those without established cardiovascular disease, and the secondary prevention population as it relates to MACE, where the benefits for MACE seem to be in the secondary prevention population. So, this was seen in DECLARE as well, and so we hypothesized that the population of patients who had myocardial infarction as their entering condition may be particularly at high risk for MACE and it may potentially be that that was driving the benefit. And so, what we did was we stratified the patients based on history of prior myocardial infarction versus none, turned out that there was about 3,500 patients in the trial who had had a prior myocardial infarction. As would be expected from what's known about the conditions, the event rates for those patients in the placebo arm were much higher, about 2.5 times higher than patients without myocardial infarction for MACE, also true for CV death and hospitalization for heart failure. And then what we saw when we looked at the treatment outcomes was that there tended to be a greater reduction in MACE for patients with prior myocardial infarction. In fact, for the MACE outcome, we saw about a 16% reduction in MACE with patients with prior MI compared to reduction with patients without prior MI. And so, the combination of this higher risk, also a tendency towards a greater relative benefit lead to a much greater absolute benefit, where, in fact, we saw about a 2.5% reduction in MACE over the four-year period for patients with prior MI, compared to a 0% reduction for patients without prior MI. And, in fact, when we broke this down to three groups: patients with prior MI, patients with atherosclerotic cardiovascular disease without prior MI, and then patients with no atherosclerotic vascular disease, essentially, we saw the same thing, which is that patients with MI were the ones who had the greatest benefit in terms of MACE. And this was almost entirely driven by reductions in myocardial infarction. Now, I would say in contradistinction, as we look at heart failure reductions, the relative benefits for heart failure were similar among these groups, but because the risk was higher in the patients with prior MI, and of course the absolute benefits were greater in the MI population, and similar for renal outcome. So, I think that this sort of extends what we have previously known that patients with atherosclerotic cardiovascular disease were at higher risk intended to have greater benefit with the SGLT2 inhibitors on MACE events that the core of that appears to be those patients with myocardial infarction. Dr Carolyn Lam: Thanks, Steve, that was just so clearly explained. Darren, in the last couple of minutes could I ask you to give us the take-home messages from these two studies, and maybe just, what next? Dr Darren McGuire: I think the take-home message from these two studies in the context of the overall field of SGLT2 inhibitor data, I think the picture's becoming relatively clear and Subodh stated in eloquently before and is reviewed in the editorial is that I think across the board, and independent of how you define higher versus lower risk subsets, this class of medications in general and dapagliflozin, and these studies appear to have augmented benefit, the greater the risk. Whether that greater risk is defined by prior myocardial infarction, or heart failure with reduced ejection fraction, or decreased EGFR, these are all states where various sub studies have consistently shown across the three compounds where we have outcomes data that the treatment benefits are amplified in the higher risk patients. And it's not just an absolute risk reduction that's augmented based on baseline risk, but there appears to be an interaction where the relative risk reduction is also amplified. And so, it's really a remarkable field and it's providing therapeutic options in these really high-risk subsets of patients where we've really been handicapped up until now with these antihyperglycemic therapies for type ii diabetes. Dr Carolyn Lam: Thank you everybody for joining us today. This was truly a bonanza feature discussion, didn't I tell you? You've been listening to Circulation on the Run, thank you for listening today and don't forget to tune in again next week. This program is copyright American Heart Association 2019
Dr Jean-Pascal Machiels of Cliniques Universitaires Saint-Luc, Brussels, Belgium talks to ecancertv at ESMO 2014 in Madrid Spain. He presents results from a phase III trial on the tyrosine kinase inhibitor, afatinib and the significant improvements it has shown in progression-free survival for patients with recurrent or metastatic squamous cell carcinoma of the head and neck after failure of platinum-based chemotherapy. Afatinib is a compound that irreversibly blocks the ErbB family of cell surface receptors, which includes epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), HER3 and HER4.
You have to be aware of these speculative bubbled frenzies and paid-promotion scams even if you're just an average Joe investor. I personally have received dozens of thank you's from readers who listened to my advice to stay away from these lousy investments and themselves saved millions of dollars in unnecessary losses. Remember my simple rule: don't ever buy a penny stock. Here's an audacious real-life, real-time example of how this penny stock promotion game works. Indeed, this is the most brazen stock promotion game I've ever seen, and I've seen them all. This company gets paid $17,500 dollars by BreedIT, a lousy penny stock trading at 19 cents per share, to write an article touting the BreedIT stock which they then pay to get sent out over the newswire services and which then even gets picked up on Marketwatch's Newswire feeds. This in particular article is all the more outrageous as it quotes yours truly and cites Marketwatch to try to gain some semblance of credibility: "As noted by Marketwatch contributor and major Scutify shareholder Cody Willard, Aegion items like 'water and wastewater, Brinderson, corrosion engineering and cathodic protection' will be in direct demand. It's notable that Willard is adamant about only investing in blue chip plays. Monsanto and billionaire investor George Soros have gotten their hands dirty and pushed to get into the marijuana business." Ironically, the article they're citing that I wrote for Marketwatch is all about avoiding penny stocks like BreedIT. Here's a better, more apropos quote from me in that same article where I mentioned Aegion as a great long-term marijuana play: "I’ll give you one more public service announcement that penny stocks up 1,000% on hype will take you to the poorhouse. Do you think I’m wrong that these penny pot stocks like $PHOT, $CBIS, $HEMP and $MJNA are going to leave retail investors with big losses when it’s all said and done? Comment below or come join the discussion on this stuff over on my Scutify page." You can click on any of those symbols and you'll see my track record and historical analysis for each one. In fact, every single one of those four pot penny stocks I mentioned in that article are down 60%-90% since I wrote that. Just in the last couple days, I've added 150% to my performance on Scutify Sentiment rankings as two pot penny stocks and one other penny stock Bearish Sentiment Views expired. Meanwhile, Aegion is up about 10% since I wrote that article. But back to BreedIT -- BreedIT has generated some $6,000 in revenues each of the last two years (you read that right, six thousand dollars in sales in 2012 and 2013) and would need to grow that number 30,000% to get to sales to 1x market cap. And the kicker is that up until the recently popped marijuana penny stock bubble got started, this BreedIT company which currently says it's in the business of "develops, licenses, and markets agro-breeding solutions for plant breeders and researchers" was actually called ProGaming and touted itself as "an online gaming platform for multiplayer skill game competitions on the internet." So let me be clear since this company and it's hypester shills have tried to associate my name with it -- I predict that BRDT will be right back down to its 52-week low of 3 cents per share and that it's headed much lower than that over the next few years. I don't think it has any product for "agro-breeding solutions for plant breeders" that will ever sell enough to make this company worth $1 million, much less the current $17 million market cap it has. After I mention how much money I have saved warning retail investors about pot penny stocks, the attacks commence immediately. Insiders and hypesters are sensitive about people calling out their scams. My favorite attack from the hypsters recently is the guy on Twitter who calls me an idiot for having nailed an 80% crash in ERBB. Now the hypesters are deleting their tweets to me cuz I made them look stupid by calling out their scams. Sigh. Forget penny stocks. The key is to have a strategy for finding the best revolutionary stocks on the planet and navigating the broader market swings with them. I covered much of this recently on a panel I sat on with Bill Harris of Personal Capital, Jim Hurd of Green Science Exchange, talking about how "disruption from drones, robots, wearables, nanotech, and cleantech is coming our way." Sticking with the best revolutionary stocks that I've outlined for years such as Apple, Google, Facebook while avoiding penny stocks and other scams will put you far ahead of most retail investors. It still won't be easy and it will be stressful, but a good game plan for the long-term is what it's all about. I don't know when the ongoing bubble-blowing bull market will pop or what will actually cause it to pop. I am doing my best to look out over the next year or two and get a feel for where the economy, earnings and stocks and other financial assets are headed, but when it comes to investing, I want to just slowly scale into the most revolutionary stocks on the planet and use tranche-trading to maximize my gains and minimize my risks over the next decade or two. If and when the markets do crash, which could be another 3 or 5 years out for all I know, I expect I will have navigated it by having lots of cash on the sides to continue building my favorite revolutionary stocks. Longer-term I think we'll have 10x our money on another Google or another Apple kind of 100x gain in some of our stocks, and that's the reason I risk my hard-earned capital to begin with. In the meantime, there are also great pitches being thrown at all traders as the markets bubble and swing. I've recently been focusing some on finding great bubbled up tech shorting opportunities, and there are a plethora of them in this bubble-blowing bull market.
This week on #PotStockRadio Eric @EbizDizzle Ry @ryanmodfrey and Trace @supergravy will talk to Tranzbyte COO Stephen Shearin @American_Green about all of the @Tranzbyte companies including American Green and One Bode. We'll ask him about Avon, Colorado on April 12th and the direction the what we all know in the pot stock world as ERBB! We'll also be talking about the week that was with the #wolfpack and @WolfofWeedST as well as what's happening at WolfOfWeedStreet.com. Don't forget that when the pack's advice pays off to spread the good #karma and #payitforward but donating to your favorite charity. Than take a picture of your donation and put it up on Twitter and tag it with #wolfpack. We apprecite the support and any questions or feedback about the show can be directed to eric@potstockradio.com
Douglas Lauffenburger discusses how amplification of the receptor tyrosine kinase AXL promotes migration of triple negative breast cancer cells.
Mathematical modeling of signaling pathways can be used to identify candidate targets for cancer therapies.
Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 01/06
In dieser Arbeit wurde die biologische Funktion der PTP-Meg2 in der zellulären Signaltransduktion untersucht. Analysen mittels c-DNA-Filter, „Real Time PCR” und Immunblot zeigen eine ubiquitäre Expression der PTP-Meg2 auf ähnlichem, jedoch geringem Niveau in fast allen untersuchten Krebszelllinien unterschiedlicher Gewebeherkunft, wobei die Expressions-stärke nicht in direktem Zusammenhang mit krebsrelevanten Eigenschaften wie Invasivität und Metastasierung steht. Die induzierte Differenzierung von MCF 7-Zellen durch Natriumbutyrat steigert die Meg2-Expression um das 5-fache, wogegen die Differenzierung von SW948- und SK-N- SH-Zellen mit TPA bzw. Retinolsäure die Meg2-Expression reprimiert. Zellfraktionierung und Immunfluoreszenz zeigen eine primär zytosolische, aber partiell auch vesikuläre bzw. strukturierte Lokalisation der PTP-Meg2, für welche die CRALBP-Domäne der PTP-Meg2 mitverantwortlich ist. Untersuchungen der endogenen Meg2-Aktivität nach Immunpräzipitation und in vitro Phosphatasetests zeigen eine erhöhte Phosphataseaktivität nach Stimulation von Zellen mit FCS, EGF und LPA, wogegen TPA stark inhibierenden wirkt. Aktivitätsstudien mit GST-Meg2-Fusionsproteinen zeigen, dass die CRALBP-Domäne die Meg2-Phosphataseaktivität negativ reguliert. Im Protein-Lipid-Overlay interagiert PTP-Meg2 mit PI(3)P, PI(4)P, PI(5)P und Phosphatidylserin. Eine Interaktion mit PI(4)P führt zu einer erhöhten Meg2 Aktivität. Pervanadat-Stimulation von Zellen führt zu einer Tyrosinphosphorylierung sowie einer Mobilitätsänderung der PTP-Meg2, was auch mit einer katalytisch inaktiven Meg2-Mutante beobachtet wurde. PTP-Meg2 interagiert in vitro und in Koexpressionsstudien mit dem EGF-Rezeptor in Abhängigkeit von dessen Aktivierung. Eine physiologische Relevanz konnte nicht gezeigt werden. Die Depletion der PTP-Meg2 durch spezifische siRNA führt zu einer erhöhten Tyrosinphosphorylierung einiger, noch zu identifizierender Proteine. PTP-Meg2 vermindert, die inaktive PTP-Meg2CS-Mutante erhöht die durch v-ErbB und EGF-Rezeptor, nicht aber die durch HER2 und v-Ki-Ras induzierte Transformation von NIH3T3-Zellen im Focusbildungstest. Zudem bewirkt PTP-Meg2CS, mit Ausnahme der v-Ki-Ras infizierten Zellen, eine leicht erhöhte ERK1/2-Aktivität. Ferner stimuliert PTP-Meg2 die Migration von NIH3T3-Zellen im Wundheilungsexperiment. Ein Einfluss auf die basale und durch Stimuli induzierte Proliferation von Zellen in Wachstumstests wurde nicht beobachtet. Ein durch siRNA-vermittelter Meg2- „knockdown“ führte zur Induktion bzw. Repression der Expression von Genen, wie z.B. einiger Liganden, Caveolin-2, Nck und Rock, was auf eine Beteiligung der PTP-Meg2 an der Regulation von Signalwegen kleiner GTPasen bzw. von endo- sowie exocytotischen Prozessen schließen lässt.
Concentrations of soluble c-erbB-2 were determined in the sera of 64 patients with distant metastasis from advanced breast cancer receiving second-line hormone or chemotherapy in comparison to 35 breast cancer patients without detectable recurrent disease and 17 healthy blood donors. The sera of non-metastatic breast cancer patients contained s-erbB-2 concentrations similar to those of healthy blood donors. Patients with distant metastasis from advanced breast cancer had significantly higher values of s-erbB-2 in comparison to patients with non-disseminated disease (mean: 59.6 vs. 11.6 U/ml; p = 0.022). A significant correlation was observed between s-erbB-2 serum levels and serum LDH concentrations (p < 0.001), levels of alkaline phosphatase (p < 0.001), and the presence of hepatic metastasis (p = 0.001). Time to tumor progression was significantly shorter in patients with s-erbB-2 levels above 40 U/ml (mean: 23.4 vs. 56.7 months; p = 0.002). Furthermore, breast cancer patients with hepatic metastasis and those with elevated s-erbB-2 serum levels above 40 U/ml had limited response to hormone or chemotherapy. Non-responders had significantly higher s-erbB-2 levels (mean: 270.3, range: 42-500 U/ml;) compared with the responder group (mean: 23.1, range: 0-149 U/ml; p < 0.001). Logistic regression analysis indicated that elevated s-erbB-2 serum levels above 40 U/ml independently predicted an unfavorable response to second-line hormone or chemotherapy in patients with advanced metastatic breast cancer. Copyright (C) 2002 S. KargerAG, Basel.
A human yeast artificial chromosome (YAC) library was screened by polymerase chain reaction with oligonucleotide primers defined for DNA sequences of the BCR gene and the protooncogenes c-raf-1, c-fms, and c-erB-2. Alu-PCR-generated human DNA sequences were obtained from the respective YAC clones and used for fluorescence in situ hybridization experiments under suppression conditions. After chromosomal in situ suppression hybridization to GTG-banded human prometaphase chromosomes, seven of nine initially isolated YAC clones yielded strong signals exclusively in the chromosome bands containing the respective genes. Two clones yielded additional signals on other chromosomes and were excluded from further tests. The band-specific YACs were successfully applied to visualize specific structural chromosome aberrations in peripheral blood cells from patients with myelodysplasia exhibiting del(5)(q13q34), chronic myeloid leukemia and acute lymphocytic leukemia with t(9;22)(q34;q11), acute promyelocytic leukemia (M3) with t(15;17)(q22;q21), and in a cell line established from a proband with the constitutional translocation t(3;8)(p14.2;q24). In addition to the analysis of metaphase spreads, we demonstrate the particular usefulness of these YAC clones in combination with whole chromosome painting to analyze specific chromosome aberrations directly in the interphase nucleus.
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