tbuckley/cabot-search huggingface dataset:
Role of ER stress and caspase 4 activation in bladder cancer cell death following exposure to Ad-IFNα
Authors: Zhibo Yang, William Benedict
Journal: Cancer Research (2008)

1387  Adenoviruses encoding interferon (Ad-IFNα) show a significant potential for treatment of superficial bladder cancer based on our preclinical findings (Benedict et al. Mol. Ther. 10: 525-532, 2004). These findings have resulted in a Phase l study now underway for superficial bladder cancer using Ad-IFN. Cancer cells transfected with Ad-IFN show high perinuclear cytoplasmic IFN expression and lead to our examination of whether endoplasmic reticulum (ER) stress and cleavage of caspase 4 could play a major role in the direct effect of Ad-IFN produced cell death. Further knowledge may help optimize the therapeutic use of Ad-IFNα and provide markers of efficacy. Since the cancer cells in this study,namely UC9, are resistant to high concentrations of IFNα protein , this mechanism of Ad-IFN produced cell death was excluded (Zhang et al, Cancer Gene Ther. 14(3):241-50, 2007). The UC9 bladder cancer line was examined by Western blotting and immunofluorescent confocal microscopy to investigate the role of ER stress and cleavage of caspase 4 in the direct cell death following Ad-IFNα transfection. We found caspase 4 was cleaved following Ad-IFNα transfection but not treatment with Intron A by Western blot analysis. In addition confocal microscopy showed both enhanced signals of the cleaved caspase 4 form p10 and enhanced staining of ER tracker in the perinuclear areas following Ad-IFNα transfection, indicating the involvement of the ER stress-mediated apoptotic pathway in the cell killing caused by Ad-IFNα. Interestingly, Ad-IFNα also induced upregulation of procaspase 4 expression in these cells. In conclusion ER stress and activation of caspase 4 could be an important mechanism involved in the cell death induced by Ad-IFNα.
Abstract 12624: Relationship Between the Duration of Hypertension and Cerebral and Cardiovascular Disease in the Adult Korean Population: From the Korean National Health and Nutritional Examination Survey 2007-2014
Authors: Seung Woon Rha, Byoung Geol Choi, Se Yeon Choi, Jae Kyeong Byun, Jinah Cha, Yoonjee Park, Dong Oh Kang, Won-Young Jang, Woohyeun Kim, Ja Yeon Choi, Jin Oh Na, Cheol Ung Choi, Chang Gyu Park, Hong Seog Seo
Journal: Circulation (2019)

Background: Although advances in medical technology and health care have led to increased life expectancy, the prevalence of chronic diseases such as hypertension, diabetes, stroke and cardiovascul...
The Diagnostic, Prognostic, and Therapeutic Potential of Adaptive Immune Receptor Repertoire Profiling in Cancer
Authors: Lindsay G. Cowell
Journal: Cancer Research (2019)

Abstract Lymphocytes play a critical role in antitumor immune responses. They are directly targeted by some therapies, and the composition and spatial organization of intratumor T-cell populations is prognostic in some cancer types. A better understanding of lymphocyte population dynamics over the course of disease and in response to therapy is urgently needed to guide therapy decisions and to develop new therapy targets. Deep sequencing of the repertoire of antigen receptor–encoding genes expressed in a lymphocyte population has become a widely used approach for profiling the population's immune status. Lymphocyte antigen receptor repertoire deep sequencing data can be used to assess the clonal richness and diversity of lymphocyte populations; to track clone members over time, between tissues, and across lymphocyte subsets; to detect clonal expansion; and to detect the recruitment of new clones into a tissue. Repertoire sequencing is thus a critical complement to other methods of lymphocyte and immune profiling in cancer. This review describes the current state of knowledge based on repertoire sequencing studies conducted on human cancer patients, with a focus on studies of the T-cell receptor beta chain locus. The review then outlines important questions left unanswered and suggests future directions for the field.
Time to dissect the autoimmune etiology of cancer antibody immunotherapy
Authors: Michael Dougan, Massimo Pietropaolo
Journal: Journal of Clinical Investigation (2020)

Immunotherapy has transformed the treatment landscape for a wide range of human cancers. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that block the immune-regulatory "checkpoint" receptors CTLA-4, PD-1, or its ligand PD-L1, can produce durable responses in some patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs) that can affect any organ system and can be treatment-limiting and life-threatening, such as diabetic ketoacidosis, which appears to be more frequent than initially described. The majority of irAEs from checkpoint blockade involve either barrier tissues (e.g., gastrointestinal mucosa or skin) or endocrine organs, although any organ system can be affected. Often, irAEs resemble spontaneous autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid disease, type 1 diabetes mellitus (T1D), and autoimmune pancreatitis. Yet whether similar molecular or pathologic mechanisms underlie these apparent autoimmune adverse events and classical autoimmune diseases is presently unknown. Interestingly, evidence links HLA alleles associated with high risk for autoimmune disease with ICI-induced T1D and colitis. Understanding the genetic risks and immunologic mechanisms driving ICI-mediated inflammatory toxicities may not only identify therapeutic targets useful for managing irAEs, but may also provide new insights into the pathoetiology and treatment of autoimmune diseases.
Association Between Automotive Assembly Plant Closures and Opioid Overdose Mortality in the United States
Authors: Atheendar S. Venkataramani, Elizabeth F. Bair, Rourke L. O’Brien, Alexander C. Tsai
Journal: JAMA Internal Medicine (2019)

Fading economic opportunity has been hypothesized to be an important factor associated with the US opioid overdose crisis. Automotive assembly plant closures are culturally significant events that substantially erode local economic opportunities.To estimate the extent to which automotive assembly plant closures were associated with increasing opioid overdose mortality rates among working-age adults.A county-level difference-in-differences study was conducted among adults aged 18 to 65 years in 112 manufacturing counties located in 30 commuting zones (primarily in the US South and Midwest) with at least 1 operational automotive assembly plant as of 1999. The study analyzed county-level changes from January 1, 1999, to December 31, 2016, in age-adjusted, county-level opioid overdose mortality rates before vs after automotive assembly plant closures in manufacturing counties affected by plant closures compared with changes in manufacturing counties unaffected by plant closures. Data analyses were performed between April 1, 2018, and July 20, 2019.Closure of automotive assembly plants in the commuting zone of residence.The primary outcome was the county-level age-adjusted opioid overdose mortality rate. Secondary outcomes included the overall drug overdose mortality rate and prescription vs illicit drug overdose mortality rates.During the study period, 29 manufacturing counties in 10 commuting zones were exposed to an automotive assembly plant closure, while 83 manufacturing counties in 20 commuting zones remained unexposed. Mean (SD) baseline opioid overdose rates per 100 000 were similar in exposed (0.9 [1.4]) and unexposed (1.0 [2.1]) counties. Automotive assembly plant closures were associated with statistically significant increases in opioid overdose mortality. Five years after a plant closure, mortality rates had increased by 8.6 opioid overdose deaths per 100 000 individuals (95% CI, 2.6-14.6; P = .006) in exposed counties compared with unexposed counties, an 85% higher increase relative to the mortality rate that would have been expected had exposed counties followed the same outcome trends as unexposed counties. In analyses stratified by age, sex, and race/ethnicity, the largest increases in opioid overdose mortality were observed among non-Hispanic white men aged 18 to 34 years (20.1 deaths per 100 000; 95% CI, 8.8-31.3; P = .001) and aged 35 to 65 years (12.8 deaths per 100 000; 95% CI, 5.7-20.0; P = .001). We observed similar patterns of prescription vs illicit drug overdose mortality. Estimates for opioid overdose mortality in nonmanufacturing counties were not statistically significant.From 1999 to 2016, automotive assembly plant closures were associated with increases in opioid overdose mortality. These findings highlight the potential importance of eroding economic opportunity as a factor in the US opioid overdose crisis.
Intensification with dipeptidyl peptidase-4 inhibitor, insulin, or thiazolidinediones and risks of all-cause mortality, cardiovascular diseases, and severe hypoglycemia in patients on metformin-sulfonylurea dual therapy: A retrospective cohort study
Authors: Carlos K. H. Wong, Kenneth K. C. Man, Margaret Shi, Esther W. Chan, Chu Wa Ho, Emily T. Y. Tse, Ian C. K. Wong, Cindy L. K. Lam
Journal: PLoS Medicine (2019)

Background Although patients with type 2 diabetes mellitus (T2DM) may fail to achieve adequate hemoglobin A1c (HbA1c) control despite metformin-sulfonylurea (Met-SU) dual therapy, a third-line glucose-lowering medication—including dipeptidyl peptidase-4 inhibitor (DPP4i), insulin, or thiazolidinedione (TZD)—can be added to achieve this. However, treatment effects of intensification with the medications on the risk of severe hypoglycemia (SH), cardiovascular disease (CVD), and all-cause mortality are uncertain. Study aim was to compare the risks of all-cause mortality, CVD, and SH among patients with T2DM on Met-SU dual therapy intensified with DPP4i, insulin, or TZD. Methods and findings We analyzed a retrospective cohort data of 17,293 patients with T2DM who were free from CVD and on Met-SU dual therapy and who were intensified with DPP4i (n = 8,248), insulin (n = 6,395), or TZD (n = 2,650) from 2006 to 2017. Propensity-score weighting was used to balance out baseline covariates across groups. Hazard ratios (HRs) for all-cause mortality, CVD, and SH were assessed using Cox proportional hazard models. Mean age of all patients was 58.56 ± 11.41 years. All baseline covariates achieved a balance across the 3 groups. Over a mean follow-up period of 34 months with 49,299 person-years, cumulative incidences of all-cause mortality, SH, and CVD were 0.061, 0.119, and 0.074, respectively. Patients intensified with insulin had higher risk of all-cause mortality (HR = 2.648, 95% confidence interval [CI] 2.367–2.963, p < 0.001; 2.352, 95% CI 2.123–2.605, p < 0.001) than those intensified with TZD and DPP4i, respectively. Insulin users had the greatest risk of SH (HR = 1.198, 95% CI 1.071–1.340, p = 0.002; 1.496, 95% CI 1.342–1.668, p < 0.001) compared with TZD and DPP4i users, respectively. Comparing between TZDs and DPP4i, TZDs were associated with a higher risk of SH (HR = 1.249, 95% CI 1.099–1.419, p < 0.001) but not all-cause mortality (HR = 0.888, 95% CI 0.776–1.016, p = 0.084) or CVD (HR = 1.005, 95% CI 0.915–1.104, p = 0.925). Limitations of this study included the lack of data regarding lifestyle, drug adherence, time-varying factors, patients' motivation, and cost considerations. A limited duration of patients intensifying with TZD might also weaken the strength of study results. Conclusions Our results indicated that, for patients with T2DM who are on Met-SU dual therapy, the addition of DPP4i was a preferred third-line medication among 3 options, with the lowest risks of mortality and SH and posing no increased risk for CVD events when compared to insulin and TZD. Intensification with insulin had the greatest risk of mortality and SH events.
A phase IIIb, open-label study of afatinib in EGFR TKI-naïve patients with EGFR mutation-positive NSCLC: A biomarker analysis
Authors: R. Rosell, A. Poltoratskiy, M. Hochmair, K.K. Laktionov, R. Ramlau, M. Alonso Garcìa, J. Skrickova, P.L. Piovano, S. Rizzato, P. Bidoli, D. Kowalski, L. Clementi, A. Cseh, F. De Marinis
Journal: Annals of Oncology (2019)
Abstract 175: Cerebral and Myocardial Mitochondrial Injury Differ in a Rat Model of Cardiac Arrest
Authors: Xianfei Ji, Jennifer Bradley, Guanghui Zheng, Weiwei Ge, Jing Xu, Fenglian He, Mary Ann A Peberdy, Joseph P Ornato, Qun Chen, Edward J Lesnefsky, Wanchun Tang
Journal: Circulation (2019)

Introduction: Neurologic and myocardial dysfunction after successful resuscitation is prominent and mitochondrial dysfunction is predicted to be a key determinant of poor outcomes. Mitochondria contribute a critical role as effectors and targets of reperfusion injury. However, the onset and severity of mitochondrial dysfunction during cardiac arrest (CA) is not fully understood. The present study was done to explore whether changes in cerebral and myocardial mitochondria differ after cardiac arrest and cardiopulmonary resuscitation (CPR). Hypothesis: Mitochondrial injury is more severe in the brain compared to the heart during and following cardiac arrest and CPR. Methods: Sprague-Dawley rats weighing between 450 - 550 g were randomized into 4 groups (n=6): 1) sham (surgery, no ventricular fibrillation (VF) or CPR), 2) VF (VF 8 mins, no CPR); 3) VF and CPR (VF 8 mins and CPR 8 mins, no defibrillation); ROSC 1 h (VF 8 mins, CPR 8 mins, defibrillation, and observe 1 h after ROSC). VF was induced through a guide wire advanced from the right jugular vein into the right ventricle. Brain and heart mitochondria were extracted by differential centrifugation and used to measure oxidative phosphorylation and calcium retention capacity (CRC). Results: Compared with sham, brain mitochondrial CRC in VF, VF+CPR and ROSC 1 h were decreased (110±11 vs. 70±13, 62±24, 50±6 nmol Ca 2+ /mg protein, p&lt;0.05). However, the CRC of the heart mitochondria was decreased only 1 h after ROSC compared to sham (1000±150 vs. 1000±84, 993±78, 600±76 nmol Ca 2+ /mg protein). Brain mitochondrial oxidative phosphorylation with complex I substrate glutamate in VF, VF+CPR and ROSC 1 h were all decreased compared to sham (127 + 8 vs 92±17, 84±12, and 92±15, p&lt;0.05). This contrasted myocardial mitochondria oxidative phosphorylation which had no impairment (324±3 vs 338±46, 379±29, and 323±45). Conclusions: Mitochondria in the brain are more sensitive to injury during CA and CPR compared to heart mitochondria. With markedly decreased CRC, mitochondria are likely to contribute to cerebral reperfusion injury during CPR and ROSC. Preservation of cerebral mitochondrial activity and mitochondrial function during cardiac arrest may improve post-resuscitation neurological function.
Myocardial slices come to age: an intermediate complexity in vitro cardiac model for translational research
Authors: Fotios G Pitoulis, Samuel A Watson, Filippo Perbellini, Cesare M Terracciano
Journal: Cardiovascular Research (2019)

Abstract Although past decades have witnessed significant reductions in mortality of heart failure together with advances in our understanding of its cellular, molecular, and whole-heart features, a lot of basic cardiac research still fails to translate into clinical practice. In this review we examine myocardial slices, a novel model in the translational arena. Myocardial slices are living ultra-thin sections of heart tissue. Slices maintain the myocardium’s native function (contractility, electrophysiology) and structure (multicellularity, extracellular matrix) and can be prepared from animal and human tissue. The discussion begins with the history and current advances in the model, the different interlaboratory methods of preparation and their potential impact on results. We then contextualize slices’ advantages and limitations by comparing it with other cardiac models. Recently, sophisticated methods have enabled slices to be cultured chronically in vitro while preserving the functional and structural phenotype. This is more timely now than ever where chronic physiologically relevant in vitro platforms for assessment of therapeutic strategies are urgently needed. We interrogate the technological developments that have permitted this, their limitations, and future directions. Finally, we look into the general obstacles faced by the translational field, and how implementation of research systems utilizing slices could help in resolving these.
Orbital floor repair using patient specific osteoinductive implant made by stereolithography
Authors: Olivier Guillaume, Mike A. Geven, Viktor Varjas, Peter Varga, Dominic Gehweiler, Vincent A. Stadelmann, Tanja Smidt, Stephan Zeiter, Christoph Sprecher, Ruud R.M. Bos, Dirk W. Grijpma, Mauro Alini, Huipin Yuan, Geoff R. Richards, Tingting Tang, Ling Qin, Lai Yuxiao, Peng Jiang, David Eglin
Journal: Biomaterials (2019)
Recurrence After Resection of Pancreatic Ductal Adenocarcinoma—Reply
Authors: John P. Neoptolemos, Robert P. Jones, Markus W. Büchler
Journal: JAMA Surgery (2020)

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 Surgery 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 Surgery journal
Prognostic Value of Baseline Total Metabolic Tumor Volume Measured on FDG PET in Patients With Richter Syndrome
Authors: Clémence Pontoizeau, Antoine Girard, Habiba Mesbah, Laure-Anne Haumont, Anne Devillers, Adrian Tempescul, Pierre-Yves Salaün, Thierry Lamy, Florence Le Jeune, Xavier Palard-Novello
Journal: Clinical Nuclear Medicine (2019)

Purpose We evaluated the prognostic value of baseline total metabolic tumor volume (TMTV) measured using pretreatment FDG PET for patients with transformation of chronic lymphocytic leukemia (CLL) into diffuse large B-cell lymphoma (DLBCL). Methods A total of 28 patients with transformation of CLL into DLBCL who had undergone FDG PET before treatment were retrospectively reviewed. Univariate and multivariate analysis of conventional clinicopathologic variables (sex, age, World Health Organization performance status score, International Prognostic Index score, Binet stage, lactate dehydrogenase serum level [LDH], platelet count, presence or not of prior therapies for CLL, the time from CLL to Richter syndrome, Ann Arbor stage, Bulky or not) and metabolic parameters (SUV max , SUV mean , TMTV, and total lesion glycolysis) at the time of the transformation of CLL into DLBCL were tested for overall survival (OS). Results Of the 28 patients, 14 patients (50%) died during the follow-up period. Low platelet count, World Health Organization performance status score &gt;1, high LDH, and high TMTV were found to be significant prognostic factors for OS on univariate analysis. The 5-year estimates of OS were 63% in the low metabolic burden group (TMTV ≤1200 cm 3 ) and 0% in the high metabolic burden group (TMTV &gt;1200 cm 3 ). Multivariate analysis revealed that only high LDH was a significant predictor after adjustment for other variables of OS. Conclusions TMTV extracted from FDG PET at the time of the transformation of CLL into DLBCL is a predictor of OS.
Evening and overnight closed-loop control versus 24/7 continuous closed-loop control for type 1 diabetes: a randomised crossover trial
Authors: Boris P Kovatchev, Laura Kollar, Stacey M Anderson, Charlotte Barnett, Marc D Breton, Kelly Carr, Rachel Gildersleeve, Mary C Oliveri, Christian A Wakeman, Sue A Brown
Journal: The Lancet Digital Health (2020)

Automated closed-loop control (CLC), known as the "artificial pancreas" is emerging as a treatment option for Type 1 Diabetes (T1D), generally superior to sensor-augmented insulin pump (SAP) treatment. It is postulated that evening-night (E-N) CLC may account for most of the benefits of 24-7 CLC; however, a direct comparison has not been done.
Is Gefitinib Combined With Platinum-Doublet Chemotherapy a Counterpart to Osimertinib Monotherapy in Advanced <i>EGFR</i>-Mutated Non–Small-Cell Lung Cancer in the First-Line Setting?
Authors: Tomohiro Tanaka, Hiroto Ishiki, Emi Kubo, Sayuri Yokota, Masaki Shimizu, Daisuke Kiuchi, Eriko Satomi
Journal: Journal of Clinical Oncology (2020)
The Importance of Describing as Well as Defining Usual Care
Authors: Stuart G. Nicholls, Merrick Zwarenstein, Monica Taljaard
Journal: The American Journal of Bioethics (2020)

In their article “Misrepresenting ‘Usual Care’ in Research: An Ethical and Scientific Error” Macklin and Natanson (2020) use three exemplar randomized controlled trials (RCTs) to argue that—far fro...
Targeting downstream subcellular YAP activity as a function of matrix stiffness with Verteporfin-encapsulated chitosan microsphere attenuates osteoarthritis
Authors: Xianzhu Zhang, Dandan Cai, Feifei Zhou, Jie Yu, Xinyu Wu, Dongsheng Yu, Yiwei Zou, Yi Hong, Chunhui Yuan, Yishan Chen, Zongyou Pan, Varitsara Bunpetch, Heng Sun, Chengrui An, Toh Yi-Chin, Hongwei Ouyang, Shufang Zhang
Journal: Biomaterials (2019)
PATH-13. SEX-LINKED TUMORAL MGMT STATUS AND OUTCOMES IN NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Addison Barnett, Anas Saeed Bamashmos, Assad Ali, Hong Li, David Bosler, Justin Lathia, Gabrielle Yeaney, Soumya Sagar, Jennifer Yu, Erin Murphy, Samuel Chao, John Suh, Alireza Mohammadi, Glen Stevens, Lilyana Angelov, David Peereboom, Gene Barnett, Manmeet Ahluwalia
Journal: Neuro-Oncology (2019)

Abstract INTRO/OBJECTIVE Glioblastoma (GBM) and MGMT have been reported to have sexual dimorphism. The primary objective of this study was to analyze the impact and association between sex and MGMT status on progression-free survival (PFS) and overall survival (OS) in patients with newly diagnosed GBM. METHODS 582 patients with newly diagnosed GBM who underwent first surgical intervention at a single tertiary care institution between 2012 and 2018 were reviewed. Adults with documented methylated (≥ 12) and un-methylated (≤ 7) MGMT status were included. A Kaplan-Meier and Cox proportional hazard models were used to analyze the association between sex and MGMT status on PFS and OS. RESULTS 464 adult patients (median age 63.4, 36.6% female) had documented MGMT status. Overall rate of MGMT methylated patients was 42.5%, while females were more often methylated than males (52.1% vs 37.4%, p=0.004). MGMT methylated compared to un-methylated females (median: 12.8 vs 7.4 months; 1-yr: 53% vs 27%) had a greater PFS benefit than males (median: 9.6 vs 6.8 months; 1-yr: 44% vs 23%). OS was significantly improved in MGMT methylated compared to un-methylated patients among females (p=0.001) but not among males (p=0.22). Among MGMT methylated patients, females had significantly better OS compared to males (median: 18.7 vs 12.4 months; 2-yr OS: 36.8% vs 24.3%, p=0.03). Although statistically not significant, a similar pattern was observed on PFS (median: 12.8 vs 9.6 months; 1-yr PFS: 52.6% vs 44.4%). Compared to MGMT methylated females, MGMT methylated males had a PFS HR=1.22 (95% CI=0.80 – 1.85, p=0.36), and an OS HR=1.45 (95% CI=1.03 – 2.04, p=0.032). CONCLUSION MGMT methylation is more common in females and methylation had a larger impact on both PFS and OS in females compared to males. These analyses highlight the need to further investigate sex differences that can inform clinical management of GBM.