tbuckley/cabot-search huggingface dataset:
Individual‐ and hospital‐level factors associated with epidermal necrolysis mortality: a nationwide multilevel study, France, 2012–2016
Authors: C. Traikia, C. Hua, L. Le Cleach, N. Prost, F. Hemery, T. Bettuzzi, O. Chosidow, P. Wolkenstein, S. Ingen‐Housz‐Oro, E. Sbidian
Journal: British Journal of Dermatology (2019)

Epidermal necrolysis (EN) is a rare and life‐threatening condition. To assess whether admitting hospital characteristics and interhospital transfer are associated with mortality due to EN. We studied the French nationwide hospital discharge database (retrospective national cohort). All patients admitted during 2012–2016 with a code for EN in the International Classification of Diseases, 10th Revision, were eligible. We extracted data on the patients (age, sex, intensive care unit admission, comorbidities) and hospitals (private proprietary vs. public, nonteaching or teaching; and number of admissions for EN as a proxy for experience). Multivariable analysis was used to identify independent predictors of in‐hospital mortality with mixed logistic regression. We identified 991 patients (467 male; mean age 52·7 ± 23 years). They were admitted to 300 different hospitals, including teaching hospitals (25% of hospitals) for around half of the patients. Overall, 597 patients (60%) had a diagnosis of Stevens–Johnson syndrome (SJS), 171 (17%) had SJS/toxic epidermal necrolysis (TEN) overlap and 223 (23%) had TEN. In total, 109 (11%) patients died: nine (2%) with SJS, 26 (15%) with SJS/TEN overlap and 74 (33%) with TEN. The in‐hospital mortality rate was lower in centres with vs. without substantial EN experience – odds ratio for one supplemental EN admission in a department 0·5 (95% confidence interval 0·3–1·0); P = 0·05 – even after adjusting for potentially relevant individual risk factors. We found no significant association between mortality and interhospital transfer. Our findings highlight increased survival of patients with EN in centres with a high volume of EN procedures. If confirmed in other settings, these findings reinforce the importance of expertise in early diagnosis and management of this condition. What's already known about this topic? Epidermal necrolysis (EN) is a rare and life‐threatening condition. At the individual level, risk factors for in‐hospital mortality have been identified. Few studies have examined the association between hospital characteristics and EN mortality, with special attention to referral hospitals. What does this study add? Short‐term mortality rates were lower for patients in centres with EN experience than in centres without EN experience, after adjusting for known risk factors. We found no association between interhospital transfer and survival. If confirmed in other settings, these findings support the early transfer of patients with suspected or diagnosed EN to centres with experience, where a multidisciplinary approach can be implemented by experienced healthcare professionals, to maximize short‐term survival.
Abstract 1160: Endoplasmic reticulum stress disrupts stemness-related transcriptional regulatory network: Implication for therapy response in cancer
Authors: Appolinaire Olou, Kamiya Mehla, Pankaj Singh
Journal: Cancer Research (2019)

Abstract Pancreatic cancer is the third leading cause of cancer-associated deaths in the United States. We have recently demonstrated that endoplasmic reticulum (ER) stress correlates with improved survival in human pancreatic cancer patients on gemcitabine therapy. Cancer cell stemness is a significant contributor of poor response to therapy and disease recurrence. We also observed that inducing ER stress can diminish stemness in cancer cells. Hence, to investigate the mechanism of ER stress-mediated alterations in diminishing cancer stemness, we investigated the impact of ER stress on transcriptomic alterations by performing RNAseq studies. We subjected cancer cells to treatment with thapsigargin and the harvested mRNA was utilized for RNAseq analysis. We observed significant alterations in mRNA expression levels of the stemness-associated gene set, which also showed significant enrichment in Ingenuity pathway analysis. Hence, our studies demonstrate that ER stress regulates stemness at the transcriptional level. Our ongoing and future studies will target individual genes/pathways to identify their relative contributions to ER stress-mediated regulation of stemness. Considering the role of stemness in disease recurrence, our studies will provide novel mechanistic insights that may lead to novel therapies for targeting disease recurrence in pancreatic cancer. Citation Format: Appolinaire Olou, Kamiya Mehla, Pankaj Singh. Endoplasmic reticulum stress disrupts stemness-related transcriptional regulatory network: Implication for therapy response in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1160.
Abstract 5275: Cancer specific caloric restriction using novel small molecule improves the therapeutic regime for triple negative breast cancer
Authors: Dhanir Tailor, Angel Resendez, Vineet Kumar, Catherine Going, Sharon Pitteri, Sanjay Malhotra
Journal: Cancer Research (2019)

Abstract Hyperglycemic and hyper insulin condition are the signature symptoms for type two diabetes which is the most favorable condition for the development of cancer. Women having a type two diabetes has 20-27% high risk to develop breast cancer including triple negative breast cancer (TNBC). Microenvironment including hyperglycemic, hyper insulin condition leads to the therapy resistance. According to ‘Warburg’s effect’ cancer cells consume a high amount of glucose in comparison to normal cells via aerobic glycolysis process. To take care of this condition currently, several clinical studies are going on for the combination therapy of type 2 diabetes and chemotherapy drugs together including erlotinib and metformin. The major drawback of this kind of type 2 diabetes drugs is that they won't affect cancer cells under hyperglycemic and hyper insulin conditions. These drugs including metformin work via AMP-activated protein kinase (AMPK) activation to switch aerobic glycolysis to oxidative phosphorylation. We have developed a novel AMPK activator (SU-18) who selectively induces an oxidative phosphorylation in TNBC cells and glycolysis in normal cells. We found that SU-18 induces G2/M phase arrest, mitochondrial stress and apoptosis in TNBC cells as same as metformin but at 1000 fold less concentration. It selectively reduces the glucose consumption, lactate and ATP production in TNBC cells where normal cells act opposite to this. SU-18 activity is through AMPK activation which got abolished in presence of AMPK inhibitor (Compound c). During mouse xenograft studies, it inhibits the tumor growth and progression. It also improves the blood glucose level in hyperglycemic mice. Comparative studies with metformin suggest that SU-18 works irrespective of hyperglycemia and insulin conditions, whereas metformin, is ineffective in this condition. FDG-PET scan analysis also supported to our in vitro glucose consumption data that treatment with SU-18 reduces the FDG accumulation in tumor cells. This study advocates the clinical candidature of SU-18 for TNBC patients. Citation Format: Dhanir Tailor, Angel Resendez, Vineet Kumar, Catherine Going, Sharon Pitteri, Sanjay Malhotra. Cancer specific caloric restriction using novel small molecule improves the therapeutic regime for triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5275.
Abstract 15647: Mental Stress-Induced Reductions in Left Ventricular Ejection Fraction Predict Future Heart Failure Exacerbation
Authors: Amy Newhouse, Stephen H Boyle, Julia Sun, Samad Zainab, Michael A Babyak, Jennifer Wilson, Cynthia Kuhn, Richard C Becker, Thomas L Ortel, Redford Williams, Joseph G Rogers, Christoper M O'Connor, Eric J Velazquez, Wei Jiang
Journal: Circulation (2015)

Background: Mental stress-induced myocardial ischemia (MSIMI) is common in patients with ischemic heart disease (IHD) and has been associated with an elevated risk of mortality and adverse cardiac events. Microcirculation dysfunction may have a critical mechanistic role as MSIMI has been associated with microvascular constriction but not epicardial coronary stenotic burden. This may also play a role in the etiology of heart failure and other cardiovascular (CV) events. We explored the relationship of MSIMI to heart failure exacerbations and other categories of CV events using data from the REMIT trial. Methods: Patients with stable IHD (N=310) underwent mental and exercise tress testing; 44% had mental stress induced myocardial ischemia (by echocardiographic wall motion abnormality, left ventricular ejection fraction (LVEF) reduction of &gt; 8%, and/or ischemic ST-change on ECG). Patients were followed for up to 6 years (median 4 yrs) for all-cause mortality and CV events resulting in hospitalization. Cox proportional hazard models, controlling for age, sex, and resting LVEF, were used to examine the associations of MSIMI indices with each CV category. Results: MSIMI, as a dichotomous variable, was not significantly associated with any CV category. Continuous mental stress-induced LVEF change scores were linearly associated with risk of being hospitalized for a heart failure exacerbation (HR = 2.35, 95%CI = 1.30 - 4.25,p=.005) (Table). This association did not significantly change after controlling for exercise-induced LVEF changes (HR = 2.35, 95%CI = 1.24 - 4.47,p=.009). Conclusion: In patients with stable IHD, every incremental 5% reduction in LVEF change induced by mental stress was associated with a 2.35 times greater risk of experiencing a hospitalization for heart failure exacerbation over an average 4-year period. This is independent of the risk conferred by traditional exercise testing.
Characterization of Transcriptional Regulatory Networks that Promote and Restrict Identities and Functions of Intestinal Innate Lymphoid Cells
Authors: Maria Pokrovskii, Jason A. Hall, David E. Ochayon, Ren Yi, Natalia S. Chaimowitz, Harsha Seelamneni, Nicholas Carriero, Aaron Watters, Stephen N. Waggoner, Dan R. Littman, Richard Bonneau, Emily R. Miraldi
Journal: Immunity (2019)
Diagnostic Imaging in Pregnant Patients With Suspected Appendicitis
Authors: Steven J. Schwulst, Moeun Son
Journal: JAMA (2019)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Abstract 18473: Oxidative Stress Improves Coronary Endothelial Function Through Activation of the Pro-Survival Kinase AMPK
Authors: Ehtesham Shafique, Wing Choy, yuhong Liu, Jun Feng, Cesario Bianchi, Laura E Benjamin, Frank W Sellke, Ruhul Abid
Journal: Circulation (2013)

Introduction: Failure of several multi-center clinical trials using antioxidants to improve outcomes in patients with cardiovascular disease, and the recent findings showing paradoxical role for NADPH oxidase-derived reactive oxygen species (ROS) in endothelial function challenge a long-held notion that higher ROS levels are harmful for vascular function. Hypothesis: We examined the hypothesis that endothelium-specific conditional increase in NADPH oxidase-derived ROS will induce stress-signal-mediated activation of eNOS and thus improve coronary endothelial function. Methods: We have generated a novel binary (Tet-ON/OFF) conditional transgenic mouse (Tet-Nox2:VE-Cad-tTA) that induces endothelial cell (EC)-specific overexpression of Nox2/gp91 (NADPH oxidase) and 1.8±0.42-fold increase in EC-ROS upon tetracycline withdrawal (Tet-OFF). We examined the effects of increased ROS on EC signaling and coronary endothelial function using eight animals in each group (Tet-ON and Tet-OFF). Results: First, we demonstrate that endothelium-dependent coronary vasodilation was significantly improved in Tet-OFF Nox2 compared to Tet-ON (control) littermates. Using EC isolated from mouse heart (MHEC), we demonstrate that Nox2-derived ROS increased eNOS activation and nitric oxide (NO) synthesis through activation of the survival kinase AMPK. We also show that endothelium-dependent coronary vasodilation in Tet-OFF Nox2 animals was CaMKKβ-AMPK-dependent. Finally, we demonstrate that AMPK activation induced autophagy and thus, protected ECs from oxidant-induced cell death in these animals. Together, these results suggest that activation of AMPK plays an important role in EC survival and endothelial function during oxidative stress. Conclusion: These findings suggest that increased ROS levels, often associated with pathophysiological conditions, play a protective role in endothelial homeostasis by inducing AMPK-eNOS axis.
The Prognostic and Predictive Value of IKZF1 and IKZF3 Expression in T-Cells in Patients with Multiple Myeloma
Authors: Mohamed H.S. Awwad, Katharina Kriegsmann, Julian Plaumann, Michael Benn, Jens Hillengass, Marc-Steffen S Raab, Uta Bertsch, Markus Munder, Katja C. Weisel, Hans Jürgen Salwender, Mathias Hänel, Roland Fenk, Jan Dürig, Carsten Müller-Tidow, Hartmut Goldschmidt, Michael Hundemer
Journal: Blood (2017)
Abstract 16473: Cadmium Zinc Telluride SPECT/CT Imaging Detects Regional Differences in Resting Skeletal Muscle Perfusion Between Patients With Type II Diabetes and Healthy Volunteers
Authors: Jessica L Alvelo, Stephanie Thorn, Albert J Sinusas, Mitchel R Stacy
Journal: Circulation (2017)

Introduction: No standard non-invasive imaging tool exists for quantitative functional assessment of lower extremity physiology. In this study, we utilize a high-resolution, high-sensitivity single...
Abstract 2254: Solid tumor activity with a selective PI3Kdelta inhibitor as a single agent and in combination with anti-PD-1
Authors: Joey L. Methot, Hua Zhou, Meredith A. McGowan, Benjamin W. Trotter, Michael Altman, Xavier Fradera, Charles Lesburg, Chaomin Li, Stephen Alves, Craig P. Chappell, Renu Jain, Ruban Mangado, Elaine Pinheiro, Sybil M. Williams, Peter Goldenblatt, Armetta D. Hill, Lynsey Shaffer, Dapeng Chen, Robbie L. McLeod, Hyun-Hee Lee, Sanjiv Shah, Jason D. Katz
Journal: Cancer Research (2019)

Abstract Inhibitors of PI3Kdelta are approved as monotherapy for the treatment of hematologic malignancies such as follicular B-cell non-Hodgkin lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma. Recent reports suggest that inhibition of PI3Kdelta in mice is effective against solid cancers as well. Mechanistic studies by several groups have suggested a possible adaptive immune-mediated anti-tumor response involving immunosuppressive Tregs and/or MDSCs in the tumor microenvironment. Our structure-guided discovery program led to the identification of a novel heterocycloalkyl purine inhibitor class with excellent isoform and kinome selectivity, as well as good solubility. Optimization included potency enhancements, addressing metabolism and increasing half-life in preclinical species to provide a PI3Kdelta inhibitor with a low once-daily predicted human dose. In FoxP3 reporter mice harboring MC38 tumors treated with inhibitor, we observed reduced peripheral Treg function and an increased ratio of CD8 to Treg in both spleen and tumor-infiltrating lymphocytes. In three-week efficacy studies, modest tumor growth inhibition was found in 4T1, MC38 and CT26 syngeneic tumor models when our inhibitor was dosed as a single agent and we demonstrated a trend towards better efficacy when our inhibitor was dosed in combination with an anti-mPD-1 antibody in CT26 tumor-bearing mice as compared to anti-mPD-1 alone. These preliminary studies confirm the impact of PI3Kdelta inhibition on T-cell subpopulations, and support continued exploration of PI3Kdelta inhibitors for the treatment of solid tumors, either as monotherapy or in combination with other agents. Citation Format: Joey L. Methot, Hua Zhou, Meredith A. McGowan, Benjamin W. Trotter, Michael Altman, Xavier Fradera, Charles Lesburg, Chaomin Li, Stephen Alves, Craig P. Chappell, Renu Jain, Ruban Mangado, Elaine Pinheiro, Sybil M. Williams, Peter Goldenblatt, Armetta D. Hill, Lynsey Shaffer, Dapeng Chen, Robbie L. McLeod, Hyun-Hee Lee, Sanjiv Shah, Jason D. Katz. Solid tumor activity with a selective PI3Kdelta inhibitor as a single agent and in combination with anti-PD-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2254.
Abstract 340: Development of high affinity anti-CLDN18.2 antibody to treat gastric cancers
Authors: Zhenhao Zhou
Journal: Cancer Research (2019)

Abstract Claudins are tight junction proteins that regulate epithelial-cell barrier function and polarity. Gastric lineage-specific isoform 2 of CLDN18 (CLDN18.2) has been proposed as therapy target in primary/metastatic gastric cancers and CLDN18.2-ectopically-activated cancers, such as pancreatic, esophageal and lung adenocarcinomas. As demonstrated by Zolbetuximab, a monoclonal chimeric antibody directing CLDN18.2, the median overall survival was prolonged to 16.7 months when treated with Zolbetuximab+EOX (OS of EOX group: 9.0 months) in pre-screened CLDN18.2 highly expressing patients (2+/3+ staining in ≥70% tumor cells). Expression of CLDN18.2 in gastric tumors in Chinese population, however, showed diverse levels of frequency with low-frequency expression in a significant portion of tumor cells. Antibody of high affinity is expected to have advantage in targeting antigen of low-frequency, thus clearing tiny lesions clinically. We developed a high affinity anti-CLDN18.2 antibody, GB7004-09. GB7004-09 binded to human/mouse CLDN18.2 while sparing CLDN18.1. It displayed significantly better binding/ADCC/CDC potency against CLDN18.2 expressing tumor cells comparing to leading clinical drug entity. And its in vitro superiority translated to greater in vivo efficacy. Humanization version of GB7004-09, GB7004-09hu15, has been put into preliminary toxicity and PK study. As we are observing safety, stability and activity of GB7004-09hu15, GB7004-09hu15 is a promising agent for extended clinical exploration in cancer indications mention above Citation Format: Zhenhao Zhou. Development of high affinity anti-CLDN18.2 antibody to treat gastric cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 340.
Abstract LB-312: Interleukin 6 transsignaling is a candidate mechanism to drive progression of human DCCs during periods of clinical latency
Authors: Melanie Werner-Klein, Ana Grujovic, Milan Obradovic, Martin Hoffmann, Xin Lu, Stefan Kirsch, Steffi Treitschke, Cäcilia Köstler, Kathrin Weidele, Christoph Irlbeck, Catherine Botteron, Christian Werno, Bernhard Polzer, Miodrag Guzvic, Stefan Buchholz, Petra Rümmele, Norbert Heine, Stefan Rose-John, Christoph A. Klein
Journal: Cancer Research (2019)

Abstract While thousands of breast cancer cells disseminate and home to bone marrow (BM) until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. Signals and mechanisms determining failure or success of disseminated cancer cells (DCCs) are largely unknown and there is no in vivo model available to study the spontaneous progression and genomic evolution from early bone marrow infiltration to manifestation of bone metastasis, as spontaneous or transgenic mouse models do not generate bone metastases. We therefore profiled DCCs from BM of breast cancer patients long before manifestation of metastasis by RNAseq to identify signals supporting survival or outgrowth of DCCs and identified IL6/PTEN/PI3K signaling as candidate pathway for DCC activation. Since early DCCs often display close-to-normal genomes we used mammary epithelial cells ex vivo isolated from reduction mammoplasties and immortalized pre-malignant breast cancer cell lines as model for functional testing in vitro. Using specific activators and inhibitors of IL6 signaling revealed that IL6 trans, but not classical signaling, regulates stemness of mammary epithelial cells. Moreover, knock-down of PTEN revealed that PI3K/PTEN pathway activation renders cells independent of IL6 trans-signaling. Interestingly, gp130 expression, a pre-requisite for IL6 trans-signaling was found to be down-regulated by bone marrow stromal and endosteal, but not vascular niche cells, and as a consequence the number of cells with stem-like ability was significantly reduced. Consistent with a bottleneck function of microenvironmental DCC control, we found PIK3CA mutations highly associated with late-stage metastatic DCCs and CTCs while generally absent in early DCCs. Our data suggest that the initial steps of metastasis formation depend on microenvironmental signals and are not cancer cell-autonomous. Citation Format: Melanie Werner-Klein, Ana Grujovic, Milan Obradovic, Martin Hoffmann, Xin Lu, Stefan Kirsch, Steffi Treitschke, Cäcilia Köstler, Kathrin Weidele, Christoph Irlbeck, Catherine Botteron, Christian Werno, Bernhard Polzer, Miodrag Guzvic, Stefan Buchholz, Petra Rümmele, Norbert Heine, Stefan Rose-John, Christoph A. Klein. Interleukin 6 transsignaling is a candidate mechanism to drive progression of human DCCs during periods of clinical latency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-312.
Insulin: still a miracle after all these years
Authors: Fabrizio Barbetti, Simeon I. Taylor
Journal: Journal of Clinical Investigation (2019)

The discovery of insulin almost 100 years ago has resulted in a remarkable increase in lifespan and quality of life for patients with type 1 diabetes. The Joslin Medalist Study has allowed researchers to access and study patients (Medalists) with type 1 diabetes who have been insulin dependent for 50 years or more. In this issue of the JCI, Yu et al. evaluated HLA variants, autoantibody status, β cell function, C-peptide release, and monogenetic diabetes genes in a cohort of Medalists. Postmortem analysis of pancreata from Medalists revealed the presence of insulin-positive β cells in these patients. Moreover, some patients were still able to respond to metabolic stimuli despite long-term insulin dependence. Overall, the Medalist cohort was highly heterogenous, and genetic testing suggested that several patients would fall into categories other than type 1 diabetes on the basis of REVEL (rare exome variant ensemble learner) classification and may be able to transfer to other therapy options.