tbuckley/cabot-search huggingface dataset:
Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy
Authors: Xi Fang, Julius Bogomolovas, Tongbin Wu, Wei Zhang, Canzhao Liu, Jennifer Veevers, Matthew J. Stroud, Zhiyuan Zhang, Xiaolong Ma, Yongxin Mu, Dieu-Hung Lao, Nancy D. Dalton, Yusu Gu, Celine Wang, Michael Wang, Yan Liang, Stephan Lange, Kunfu Ouyang, Kirk L. Peterson, Sylvia M. Evans, Ju Chen
Journal: Journal of Clinical Investigation (2017)

Defective protein quality control (PQC) systems are implicated in multiple diseases. Molecular chaperones and co-chaperones play a central role in functioning PQC. Constant mechanical and metabolic stress in cardiomyocytes places great demand on the PQC system. Mutation and downregulation of the co-chaperone protein BCL-2-associated athanogene 3 (BAG3) are associated with cardiac myopathy and heart failure, and a BAG3 E455K mutation leads to dilated cardiomyopathy (DCM). However, the role of BAG3 in the heart and the mechanisms by which the E455K mutation leads to DCM remain obscure. Here, we found that cardiac-specific Bag3-KO and E455K-knockin mice developed DCM. Comparable phenotypes in the 2 mutants demonstrated that the E455K mutation resulted in loss of function. Further experiments revealed that the E455K mutation disrupted the interaction between BAG3 and HSP70. In both mutants, decreased levels of small heat shock proteins (sHSPs) were observed, and a subset of proteins required for cardiomyocyte function was enriched in the insoluble fraction. Together, these observations suggest that interaction between BAG3 and HSP70 is essential for BAG3 to stabilize sHSPs and maintain cardiomyocyte protein homeostasis. Our results provide insight into heart failure caused by defects in BAG3 pathways and suggest that increasing BAG3 protein levels may be of therapeutic benefit in heart failure.
Predictive role of PD-L1 expression in the response of renal Medullary carcinoma to PD-1 inhibition
Authors: Quaovi Sodji, Kandy Klein, Kavuri Sravan, Jigarkumar Parikh
Journal: Journal for ImmunoTherapy of Cancer (2017)

<h3>Background</h3> Renal medullary carcinoma is one of the rarest malignancies arising from the kidney. Despite various aggressive therapeutic regimens, mortality remains significantly high (95%) with a median overall survival of 5&nbsp;months. Furthermore, the scarcity of this malignancy renders randomized clinical trials impossible. We examined the expression of programmed death ligand 1 (PD-L1) in two new renal medullary carcinoma cases, investigated their responses to the PD-L1 inhibitor nivolumab and explored the predictive role of the rate of PD-L1 expression in such response. <h3>Case presentation</h3> Two African-American patients (male and female) with sickle cell trait who presented to our center with hematuria and flank pain were diagnosed with metastatic renal medullary carcinoma. PD-L1 was expressed at rate of 25% and 60% in patient 1 and 2 respectively. Following nephrectomy, they were started on nivolumab. Patient 1 initially responded to the treatment with regression of metastatic lesions. However, following this early response, patient 1 who has been receiving nivolumab for more than 15&nbsp;months, was noted to have a disease progression. Patient 2 had disease progression after 3&nbsp;months of nivolumab therapy. <h3>Conclusions</h3> Although PD-L1 is expressed in these patients with renal medullary carcinoma, response to nivolumab was only observed in patient 1 whose tumor has the lowest rate of PD-L1 expression. This may suggest that in RMC, response to PD-L1 inhibition therapy may not correlate with the rate of PD-L1 expression.
Near absence of IL-15R-alpha T-cells in EBV-associated Hodgkin lymphoma patients
Authors: O. C. Baiocchi, L. Lin, J. Yang, M. V. Lemas, L. Post, N. Mueller, R. F. Ambinder
Journal: Journal of Clinical Oncology (2007)

8087 Background: Epstein-Barr virus (EBV) (+) Hodgkin's lymphoma (HL) has been linked to acute infectious mononucleosis (AIM). EBV-associated AIM was recently reported (Sauce et al, Blood 2006, 108: 11) to be associated with a long lasting immunologic scar (near complete absence of IL-15 receptor alpha (IL-15Ra expression on T cells in peripheral blood mononuclear cells (PBMC)). We sought to confirm the scar observation and to determine whether such a scar might also be characteristic of EBV (+) HL patients. Methods: PBMCs from 5 donors with history of AIM (3 months to 4 years before), 10 EBV-seropositive donors without history of AIM, 10 EBV-seronegative donors, 22 HL patients with EBV (+) tumors and 29 HL patients with EBV (-) tumors were assayed to determine IL-15Ra expression on CD3/CD8+ cells using a FACScalibur flow cytometer. Results: IL-15Ra expression in healthy donors with history of AIM [mean: 2.9% (1.5–6.5%)] was much lower than in those without history of AIM [mean: 83% (65–98%)] (p = 0.001). Expression did not differ between healthy EBV-seropositive donors without history of AIM [mean: 82% (65–95%)] and healthy EBV-seronegative donors [mean: 89% (82–98%)] (p = 0.32). Expression was markedly different between EBV (-) HL [mean: 82% (72–99%)] and EBV (+) HL patients [mean: 3.2% (1.1–7.1%)] [p = 0.001, 95% CI(10.3–32.1)]. No difference was found when age, time blood was drawn (pre or post-treatment), disease stage and histological subtype were compared. This IL- 15Ra deficit was seen in patients before and more than one year after standard therapy. Conclusions: This study confirms the virtual absence of IL-15Ra expression in lymphocytes from patients with history of AIM. That observation is now extended to include patients with EBV (+) HL at presentation and in remission. Whether this deficit contributes to the pathogenesis of EBV (+) associated HL remains to be determined. No significant financial relationships to disclose.
Same-day HIV testing with initiation of antiretroviral therapy versus standard care for persons living with HIV: A randomized unblinded trial
Authors: Serena P. Koenig, Nancy Dorvil, Jessy G. Dévieux, Bethany L. Hedt-Gauthier, Cynthia Riviere, Mikerlyne Faustin, Kerlyne Lavoile, Christian Perodin, Alexandra Apollon, Limathe Duverger, Margaret L. McNairy, Kelly A. Hennessey, Ariadne Souroutzidis, Pierre-Yves Cremieux, Patrice Severe, Jean W. Pape
Journal: PLoS Medicine (2017)

Background Attrition during the period from HIV testing to antiretroviral therapy (ART) initiation is high worldwide. We assessed whether same-day HIV testing and ART initiation improves retention and virologic suppression. Methods and findings We conducted an unblinded, randomized trial of standard ART initiation versus same-day HIV testing and ART initiation among eligible adults ≥18 years old with World Health Organization Stage 1 or 2 disease and CD4 count ≤500 cells/mm3. The study was conducted among outpatients at the Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic infections (GHESKIO) Clinic in Port-au-Prince, Haiti. Participants were randomly assigned (1:1) to standard ART initiation or same-day HIV testing and ART initiation. The standard group initiated ART 3 weeks after HIV testing, and the same-day group initiated ART on the day of testing. The primary study endpoint was retention in care 12 months after HIV testing with HIV-1 RNA <50 copies/ml. We assessed the impact of treatment arm with a modified intention-to-treat analysis, using multivariable logistic regression controlling for potential confounders. Between August 2013 and October 2015, 762 participants were enrolled; 59 participants transferred to other clinics during the study period, and were excluded as per protocol, leaving 356 in the standard and 347 in the same-day ART groups. In the standard ART group, 156 (44%) participants were retained in care with 12-month HIV-1 RNA <50 copies, and 184 (52%) had <1,000 copies/ml; 20 participants (6%) died. In the same-day ART group, 184 (53%) participants were retained with HIV-1 RNA <50 copies/ml, and 212 (61%) had <1,000 copies/ml; 10 (3%) participants died. The unadjusted risk ratio (RR) of being retained at 12 months with HIV-1 RNA <50 copies/ml was 1.21 (95% CI: 1.04, 1.38; p = 0.015) for the same-day ART group compared to the standard ART group, and the unadjusted RR for being retained with HIV-1 RNA <1,000 copies was 1.18 (95% CI: 1.04, 1.31; p = 0.012). The main limitation of this study is that it was conducted at a single urban clinic, and the generalizability to other settings is uncertain. Conclusions Same-day HIV testing and ART initiation is feasible and beneficial in this setting, as it improves retention in care with virologic suppression among patients with early clinical HIV disease. Trial registration This study is registered with ClinicalTrials.gov number NCT01900080
Abstract 234: Defining Domains In The Transcription Factor Grainyhead-like 3 Required For Protective Functions In The Endothelium
Authors: Sabrina Farrokh, Niloofar Ale-Agha, Judith Haendeler, Joachim Altschmied
Journal: Circulation Research (2013)

Important aspects during aging of human endothelial cells (EC) are an increased apoptosis level and a reduced migratory capacity. In a screening for anti-apoptotic genes we have identified the transcription factor Grainyhead-like 3 (GRHL3) and demonstrated its anti-apoptotic and pro-migratory effects after overexpression and knockdown in EC. To define the domains in GRHL3 responsible for these - potentially also extranuclear - functions we have cloned large scale deletion mutants and mutants with deletions of putative nuclear localization signals (NLS) and analyzed them for their intracellular localization and functional properties. Immunostaining of transfected EC were used to examine the subcellular distribution. Two mutants with deletions in a bioinformatically predicted bipartite NLS were localized predominantly in the cytoplasm. To corroborate these data, lysates of the cells were fractionated biochemically. Western blotting confirmed the immunostaining data, indicating that we have identified the major NLS in GRHL3. To analyze the transcriptional properties of these mutants, we constructed a GRHL3-specific luciferase reporter containing a tandem GRHL3 binding sites in front of a minimal promoter and cotransfected it with expression vectors for the GRHL3 deletion mutants. Besides the previously described activation domain we identified another region required for transcriptional upregulation of target genes in the N-terminal half of the protein. We will now use these mutants to further dissect the regions in GRHL3 necessary for its pro-migratory and anti-apoptotic activities in endothelial cells. This will also allow us to investigate if all of these functions are mediated solely by the activation of target genes or by other mechanisms coupled to a non-nuclear function of GRHL3.
MET amplification (amp) as a resistance mechanism to osimertinib.
Authors: Zofia Piotrowska, Kenneth Stephen Thress, Meghan Mooradian, Rebecca Suk Heist, Christopher G. Azzoli, Jennifer S. Temel, Coleen Rizzo, Rebecca J Nagy, Richard B. Lanman, Scott N. Gettinger, Tracey L. Evans, Aaron N. Hata, Alice Tsang Shaw, Lecia V. Sequist
Journal: Journal of Clinical Oncology (2017)

9020 Background: Osimertinib (osi) is an EGFR T790M inhibitor. Mechanisms (mech) of acquired resistance (AR) are under study. We report a cohort of osi-AR pts with extensive pre/post-osi tissue and plasma. Methods: We analyzed 23 pts with AR to osi. Tumor biopsies (bx) underwent NGS (SNaPshot, MGH) and FISH for EGFR, MET amp (target:CEP7 &gt; 2.2.) Plasma underwent ctDNA NGS (Guardant360). Results: Of the 23 osi-treated EGFR-mutants (13 with EGFR del19, 10 L858R), 2 had de novo T790M, 21 acquired T790M. 13 had prior 3 rd gen EGFR TKIs before osi - rociletinib(11), ASP8273(1), EGF816(1). Median time on osi was 12 mo (range 2-25), med total time on 3 rd -gen EGFR TKIs was 18 mo. Bx types were tissue (16), plasma (18), and both (11, med interval 31d). All pts retained their founder EGFR mutation, but 15/23 (65%) “lost” T790M post-osi, suggesting AR arose from a T790wt subclone (Table). Common AR mech were MET amp (7/23; 30%) and EGFR C797S (5/23; 22%). 1 pt each had SCLC transformation, PIK3CA E545K/PIK3CA amp and FGFR1 D60N/FGFR1 amp. 2 pts had 2 distinct post-osi tissue bx showing heterogeneity. Pt 8 had plasma and a lung nodule with C797S/T790M while a mediastinal LN was wt at both loci. Pt 22 had MET-amp in pleural fluid but no MET amp on lung bx. Plasma identified AR mech not seen in tissue in 2/11 pts with both bx types. Among 7 pts with MET amp, 3 received combo EGFR/ MET TKI; all 3 had a RECIST PR. Conclusions: In this osi-resistant cohort, we commonly saw MET amp (30%) and C797S (22%). MET amp seems more common post-osi than after 1 st -line TKIs, and 3/3 pts responded to EGFR+MET TKIs. AR heterogeneity was seen in 2 pts with matched tissue/plasma and 2 with &gt;1 tissue bx, underscoring the complementary roles of plasma and tissue. [Table: see text]
Gastric Function of Dogs after Stimulation with Acetyl-β-Methylcholine Chloride and Histamine Diphosphate
Authors: Helen M. Dyer, Margaret G. Kelly
Journal: JNCI Journal of the National Cancer Institute (1944)

Journal Article Gastric Function of Dogs after Stimulation with Acetyl-β-Methylcholine Chloride and Histamine Diphosphate Get access Helen M. Dyer, Helen M. Dyer research fellow National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Margaret G. Kelly Margaret G. Kelly junior biochemist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 5, Issue 3, December 1944, Pages 227–232, https://doi.org/10.1093/jnci/5.3.227 Published: 01 December 1944
World Health Organisation to develop global action plan to promote physical activity: time for action
Authors: Charlie Foster, Trevor Shilton, Lucy Westerman, Justin Varney, Fiona Bull
Journal: British Journal of Sports Medicine (2017)

Coinciding with the WHO’s 70th World Health Assembly in Geneva (22–31 May), the WHO launched the process to develop a new Global Action Plan to promote physical activity.1 This development could not come at a more critical time for global health.

The Assembly heard that progress on reducing the burden of non-communicable diseases (NCDs) is significantly off track, and the target to reduce physical inactivity, a key risk factor for NCDs, is far from being achieved. With physical inactivity a rising global concern from Europe, North and South America, to Asia, Australasia and increasingly Africa,2 the development of a new Global Action Plan should be welcomed by physical activity advocates, practitioners, policy makers and scientists everywhere. The Global Action Plan is a new opportunity to enable a step change in the approach to using evidence-based policy across geographies, environments and communities and different populations.

This moment matters to the physical activity and health community. It reflects years of advocacy and campaigning and is a testament to an increase in volume and quality of research into basic, clinical …
Patient reported distress and survival after palliative radiotherapy.
Authors: Jacob Habboush, Robert P. Shannon, Laeticia Hollant, Megan Paige Single, Katherine Gaines, Bridget Smart, Steven J. Buskirk, Laura Vallow, Katherine S. Tzou, Stephen Ko, Jennifer Layton Peterson, Heather Biers, Atiya Day, Byron C. May, Robert Clell Miller
Journal: Journal of Clinical Oncology (2016)

e18084 Background: Patient reported distress (PRD) is well recognized in cancer patients receiving treatment; regrettably, it is not always assessed in clinical practice. The failure to assess PRD might affect treatment, decrease patient’s quality of life (QoL), increase burden of suffering, and increases health care costs. Patients receiving palliative RT usually have a severe disease that requires an intervention to help ease symptom burden, especially pain. Methods: All RT patients in our clinic are asked to complete a PRD survey during treatment course. PRD forms consist of 30 categorical questions that assess distress subscales. Patients have the option to rate each question from 1 (low distress) to 5 (high distress). The survey also includes the National Comprehensive Cancer Network distress thermometer, which allows patients to rate overall distress level from 0 (no distress) to 10 (extreme distress). Patients’ records were retrospectively reviewed to abstract the needed information to assess survivorship. Results: 270 patients were included from March 2012-May 2015. Overall PRD was analyzed as a continuous and a categorical variable (low: 0-3, moderate: 4-6, high: 7-10). A correlation was noted in moderate distress category (RR: 1.51, P = 0.034), however, this was not noted in high distress category (RR: 1.25, P = 0.33). Age (P: 0.079) and primary site (P = 0.022) had the strongest correlation with survival. However, when combining patients with a moderate or high distress level, we observed a significantly increased risk of death compared to patients with low distress in single variable analysis (RR: 1.45, P = 0.046). This finding weakened slightly in multivariable analysis and was no longer quite significant (RR: 1.43, P = 0.066). Conclusions: This study suggests that 64% of patients receiving palliative RT were under moderate to severe distress that affected their QoL The results provide evidence that patients who have a score of 4 or higher on the patient reported distress level questionnaire have poorer survival after palliative RT. This finding was statistically significant without adjustment for potentially confounding variables, however was no longer quite significant after such multivariable adjustment.
Stable XIAP knockdown clones of HCT116 colon cancer cells are more sensitive to taxanes and irradiation in vitro
Authors: Kate Connolly, Richard Mitter, Morwenna Muir, Duncan Jodrell, Sylvie Guichard
Journal: Cancer Research (2007)

3610  X-linked inhibitor of apoptosis (XIAP) is the most potent endogenous caspase inhibitor preventing cell death via caspase-9, -7 and -3 (inhibitor and executioner caspase pathways). Using short hairpin RNA (shRNA) against XIAP stably expressed in a parent HCT116 human colon cancer cell line, a series of clones have been developed, as described previously (Connolly et al, Clin Can Res, Dec 2005, Vol 11, No 24, Pt 2, pp 9104-5s, C23). The 4 XIAP knockdown (X) clonal cell lines showed 83-93% reduction in XIAP mRNA when compared to the luciferase (L) control cell lines. Immunoblot analysis showed a 63-89% reduction in XIAP protein in X cell lines compared to L cell lines.  Gene expression analysis using microarray has now been undertaken using an Affymetrix HG_U133 plus 2.0 oligonucleotide array and has confirmed significant XIAP knockdown (6 out of 7 probe sets) at early passage: mean fold change -4.3 ± 1.9. Knockdown was maintained for at least 4 passages. There was good correlation between microarray and quantitative RT-PCR data for all members of the IAP family investigated and no compensatory upregulation was observed. XIAP downregulation did not modify the expression of Bcl2 family members, genes linked to the extrinsic pathway and other genes reported to be associated with XIAP.  The differential sensitivity of L and X cell lines was evaluated against gamma irradiation and different cytotoxic agents (taxanes, camptothecin, 5FU, oxaliplatin, cisplatin, doxorubicin). XIAP knockdown cell lines showed a 20% increase in sensitivity to a single fraction of gamma radiation, the mean dose for 50% survival was 10.5 ± 0.93 Gy for X cell lines compared to 13.4 ± 0.88 Gy for L cell lines (t-test p  These cell lines demonstrate that XIAP downregulation induces sensitisation to taxanes and radiation in vitro. They have also been established in vivo and will be useful for the evaluation of combination treatment protocols.
Sharing Knowledge for Health Care
Authors: Tammy Hoffmann, Sharon Straus
Journal: JAMA Internal Medicine (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Abstract P023: HDAC Inhibition Promotes Cardiogenesis and the Survival of Embryonic Stem Cells Through Proteasome-Dependent Pathway
Authors: Ting C Zhao, Hongping Chen, Megan DeNicola, Yu Zhao, Xin Qin, Ling Zhang, Shugang Zhuang, Paul Liu, Julio Ma
Journal: Circulation Research (2011)

Objectives: Histone deacetylase (HDAC) inhibition plays a crucial role in mediating cardiogenesis and myocardial protection, whereas HDAC degradation has recently attracted attention in mediating the biological function of HDACs. However, it remains unknown whether HDAC inhibition modulates cardiogenesis and embryonic stem cell (ESC) survival through the proteasome pathway. Methods and Results: Using the well-established mouse CGR8 mouse ESC culture, we evaluated the impact of HDAC inhibition and proteasome pathway on the cell death, viability and apoptosis in ESCs in response to oxidant stress (100μ mol/L hydrogen peroxides). We demonstrated that HDAC inhibitors, both TSA (50 nmol/L) and sodium butyrate (200 μ mol/L) that causes the pronounced reduction of HDAC4 activity, decreased cell death and increased viability of ESCs. HDAC inhibition reduced the cleaved caspase 3, 6, 9, PARP and TUNE-positive ESCs, which were abrogated with MG132 (0.5 μ mol/L), a specific proteasome inhibitor. Furthermore, we employed in vitro “hanging drop” methods to carry out two weeks of embryoid bodies (EB) culture to assess the effect of HDAC inhibition and proteasome pathway on cardiogenesis. HDAC inhibition stimulates the growth of EB, which is associated with faster spontaneous rhythmic contraction. HDAC inhibition increased the up-regulation of GATA4, MEF2, NKX2.5, cardiac actin, and α-SMA mRNA and protein levels that were abrogated by MG132. Immunostaining analysis demonstrates that trichostatin A and sodium butyrate resulted in a significant increase in cardiac lineage commitments that were blocked by the proteasome inhibition. Notably, HDAC inhibitors led to noticeable HDAC4 degradation, which was effectively prevented by MG132. Luciferase assay demonstrates an activation of MEF2 cardiac transcriptional factor by HDAC inhibition, which was repressed by MG132, revealing that the degradation of HDAC4 allows the activation of MEF2. Conclusions: Taken together, our study is the first to demonstrate that HDAC inhibition through proteasome pathway forms a novel signaling to determine the cardiac lineage commitment and elicit the survival pathway, which is dependent on specific HDAC4 degradation and subsequent MEF2 activation of ESCs.