tbuckley/cabot-search huggingface dataset:
p53-Reactive T Cells Are Associated with Clinical Benefit in Patients with Platinum-Resistant Epithelial Ovarian Cancer After Treatment with a p53 Vaccine and Gemcitabine Chemotherapy
Authors: Nicola R. Hardwick, Paul Frankel, Christopher Ruel, Julie Kilpatrick, Weimin Tsai, Ferdynand Kos, Teodora Kaltcheva, Lucille Leong, Robert Morgan, Vincent Chung, Raechelle Tinsley, Melissa Eng, Sharon Wilczynski, Joshua D.I. Ellenhorn, Don J. Diamond, Mihaela Cristea
Journal: Clinical Cancer Research (2018)

Purpose: To conduct a phase I trial of a Modified Vaccinia Ankara vaccine delivering wild-type human p53 (p53MVA) in combination with gemcitabine chemotherapy in patients with platinum-resistant ovarian cancer.Experimental Design: Patients received gemcitabine on days 1 and 8 and p53MVA vaccine on day 15, during the first 3 cycles of chemotherapy. Toxicity was classified using the NCI Common Toxicity Criteria and clinical response assessed by CT scan. Peripheral blood samples were collected for immunophenotyping and monitoring of anti-p53 immune responses.Results: Eleven patients were evaluated for p53MVA/gemcitabine toxicity, clinical outcome, and immunologic response.there were no DLTs, but 3 of 11 patients came off study early due to gemcitabine-attributed adverse events (AE). Minimal AEs were attributed to p53MVA vaccination. Immunologic and clinical response: enhanced in vitro recognition of p53 peptides was detectable after immunization in both the CD4+ and CD8+ T-cell compartments in 5 of 11 and 6 of 11 patients, respectively. Changes in peripheral T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSC) did not correlate significantly with vaccine response or progression-free survival (PFS). Patients with the greatest expansion of p53-reactive T cells had significantly longer PFS than patients with lower p53-reactivity after therapy. Tumor shrinkage or disease stabilization occurred in 4 patients.Conclusions: p53MVA was well tolerated, but gemcitabine without steroid pretreatment was intolerable in some patients. However, elevated p53-reactive CD4+ and CD8+ T-cell responses after therapy correlated with longer PFS. Therefore, if responses to p53MVA can be enhanced with alternative agents, superior clinical responses may be achievable. Clin Cancer Res; 24(6); 1315-25. ©2018 AACR.
Clinical Impact of ITCA 650, a Novel Drug-Device GLP-1 Receptor Agonist, in Uncontrolled Type 2 Diabetes and Very High Baseline HbA1c: The FREEDOM-1 HBL (High Baseline) Study
Authors: Robert R. Henry, Julio Rosenstock, Douglas S. Denham, Prakash Prabhakar, Lise Kjems, Michelle A. Baron
Journal: Diabetes Care (2018)

OBJECTIVE ITCA 650 is a subdermal osmotic mini-pump that continuously delivers exenatide subcutaneously for 3–6 months. The efficacy, safety, and tolerability of ITCA 650 added to diet and exercise alone or combined with metformin, sulfonylurea, or thiazolidinedione monotherapy or a combination of these drugs was evaluated in poorly controlled patients with type 2 diabetes (T2D) who were ineligible for participation in a placebo-controlled study (FREEDOM-1) because of severe hyperglycemia (HbA1c &amp;gt;10% [86 mmol/mol]). RESEARCH DESIGN AND METHODS This 39-week, open-label, phase 3 trial enrolled patients aged 18–80 years with HbA1c &amp;gt;10% to ≤12% (86–108 mmol/mol) and BMI 25–45 kg/m2. Patients received ITCA 650 20 μg/day for 13 weeks, then 60 μg/day for 26 weeks. The primary end point was change in HbA1c at week 39. RESULTS Sixty patients were enrolled. At baseline, mean HbA1c was 10.8% (94.7 mmol/mol) and mean (± SD) duration of diabetes was 8.6 (± 5.3) years. At week 39, there was a mean reduction in HbA1c of −2.8% (−30.3 mmol/mol; P &amp;lt; 0.001 vs. baseline) and in body weight of −1.2 kg (P = 0.105), and 25% of patients achieved HbA1c &amp;lt;7% (53 mmol/mol). A reduction in HbA1c of ≥1% (≥10.9 mmol/mol) occurred in 90% of patients. The most common adverse events were nausea, vomiting, diarrhea, and headache. Gastrointestinal adverse events were generally transient and subsided over time; only 4 patients (6.7%) discontinued for gastrointestinal events. CONCLUSIONS Treatment with ITCA 650, the first injection-free glucagon-like peptide 1 receptor agonist, resulted in significant improvements in glycemic control in poorly controlled long-standing T2D patients with a high baseline HbA1c &amp;gt;10%.
Precision therapy for acute myeloid leukemia
Authors: Xue Yang, Jianxiang Wang
Journal: Journal of Hematology & Oncology (2018)

Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous disease. Despite advances in understanding the pathogenesis of AML, the standard therapy remained nearly unchanged over the past three decades. With the poor survival for older patients and high relapse rate, multiple studies are ongoing to address this important issue. Novel therapies for AML, including the refinements of conventional cytotoxic chemotherapies and genetic and epigenetic targeted drugs, as well as immunotherapies, have been developed in recent years. Here, we present a mechanism-based review of some promising new drugs with clinical efficacy, focus on targeted drugs that are most potential to pave the road to success, and put forward the major challenges in promoting the precision therapy for AML.
AODTU-003 Sustained change in colonoscopy practice 3 years after introduction of quality in colonoscopy (qic) bundle
Authors: LJ Neilson, JE East, P Rajasekhar, S Dunn, R Bevan, S Paremal, S Esmaily, CJ Rees
Journal: Gut (2017)

Introduction  Adenoma detection rate (ADR) is the most widely used contemporaneous measure of colonoscopy quality. Low ADRs are associated with higher post colonoscopy colorectal cancer rates and poorer patient outcomes. 1  A study implementing a “bundle” of evidence-based interventions demonstrated practice change and ADR improvement driven by improvements amongst the poorest performing colonoscopists. 2  Interventions were: withdrawal time ≥6 min; hyoscine butylbromide use; position change; rectal retroflexion. We assessed whether practice change and ADR improvements were sustained 3 years following intervention.  Method  Data were collected from the original study sites, including ADR and hyoscine butylbromide use (marker of bundle uptake). Comparisons were made with baseline data collected for 3 months prior to bundle implementation and for a duration of 9 months following completion. Sustainability data were collected for 6 months, 3 years following implementation. Data were compared globally, by endoscopy unit and by quartile, where colonoscopists were ranked by baseline ADR. Multilevel logistic regression analyses were undertaken.  Results  12 endoscopy units housed within 8 UK NHS Trusts participated. Global analyses included data from a total of 184 colonoscopists and 28 615 procedures. Quartile analyses included data from 50 colonoscopists and 14 435 procedures. Hyoscine butylbromide use rose and was sustained above baseline globally in all units and quartiles. A sustained ADR increase (18.2%) was observed globally. Quartile analyses demonstrated that improvement was most marked in the lowest colonoscopist quartile (Table 1).  Conclusion  A simple, evidence-based intervention changed colonoscopy practice and improved ADR. These effects were sustained 3 years following implementation, suggesting this approach is a feasible and durable means of improving ADR with minimal resources.  References  . Corley DA, et al. N Engl J Med2014;370(14):1298–306.  . Rajasekhar PT, et al. Endoscopy2015;47(3):217–24.  Disclosure of Interest  None Declared
Pisa Syndrome in a Child With Subacute Sclerosing Panencephalitis
Authors: Sanjay Pandey, Laxmikant Ramkumarsingh Tomar, Priyanka Tater
Journal: JAMA Neurology (2018)

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 Neurology 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 Neurology journal
Maintenance of murine platelet homeostasis by the kinase Csk and phosphatase CD148
Authors: Jun Mori, Zoltan Nagy, Giada Di Nunzio, Christopher W. Smith, Mitchell J. Geer, Rashid Al Ghaithi, Johanna P. van Geffen, Silke Heising, Luke Boothman, Bibian M. E. Tullemans, Joao N. Correia, Louise Tee, Marijke J. E. Kuijpers, Paul Harrison, Johan W. M. Heemskerk, Gavin E. Jarvis, Alexander Tarakhovsky, Arthur Weiss, Alexandra Mazharian, Yotis A. Senis
Journal: Blood (2018)
Structural brain abnormalities and cardiac dysfunction in patients with chronic heart failure
Authors: Hideaki Suzuki, Yasuharu Matsumoto, Hideki Ota, Koichiro Sugimura, Jun Takahashi, Kenta Ito, Satoshi Miyata, Yoshihiro Fukumoto, Yasuyuki Taki, Hiroaki Shimokawa
Journal: European Journal of Heart Failure (2018)
Deletion of the von Hippel-Lindau Gene in Hemangioblasts Causes Hemangioblastoma-like Lesions in Murine Retina
Authors: Herui Wang, Matthew J. Shepard, Chao Zhang, Lijin Dong, Dyvon Walker, Liliana Guedez, Stanley Park, Yujuan Wang, Shida Chen, Ying Pang, Qi Zhang, Chun Gao, Wai T. Wong, Henry Wiley, Karel Pacak, Emily Y. Chew, Zhengping Zhuang, Chi-Chao Chan
Journal: Cancer Research (2018)

von Hippel-Lindau (VHL) disease is an autosomal-dominant tumor predisposition syndrome characterized by the development of highly vascularized tumors and cysts. LOH of the
A Clear-eyed View of Restasis and Chronic Dry Eye Disease
Authors: Lisa M. Schwartz, Steven Woloshin
Journal: JAMA Internal Medicine (2018)

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
ERS/ATS workshop report on respiratory health effects of household air pollution
Authors: Akshay Sood, Nour A. Assad, Peter J. Barnes, Andrew Churg, Stephen B. Gordon, Kevin S. Harrod, Hammad Irshad, Om P. Kurmi, William J. Martin, Paula Meek, Kevin Mortimer, Curtis W. Noonan, Rogelio Perez-Padilla, Kirk R. Smith, Yohannes Tesfaigzi, Tony Ward, John Balmes
Journal: European Respiratory Journal (2018)

Exposure to household air pollution (HAP) from solid fuel combustion affects almost half of the world population. Adverse respiratory outcomes such as respiratory infections, impaired lung growth and chronic obstructive pulmonary disease have been linked to HAP exposure. Solid fuel smoke is a heterogeneous mixture of various gases and particulates. Cell culture and animal studies with controlled exposure conditions and genetic homogeneity provide important insights into HAP mechanisms. Impaired bacterial phagocytosis in exposed human alveolar macrophages possibly mediates several HAP-related health effects. Lung pathological findings in HAP-exposed individuals demonstrate greater small airways fibrosis and less emphysema compared with cigarette smokers. Field studies using questionnaires, air pollution monitoring and/or biomarkers are needed to better establish human risks. Some, but not all, studies suggest that improving cookstove efficiency or venting emissions may be associated with reduced respiratory symptoms, lung function decline in women and severe pneumonia in children. Current studies focus on fuel switching, stove technology replacements or upgrades and air filter devices. Several governments have initiated major programmes to accelerate the upgrade from solid fuels to clean fuels, particularly liquid petroleum gas, which provides research opportunities for the respiratory health community.
Potentiating Tissue-Resident Type 2 Innate Lymphoid Cells by IL-33 to Prevent Renal Ischemia-Reperfusion Injury
Authors: Qi Cao, Yiping Wang, Zhiguo Niu, Chengshi Wang, Ruifeng Wang, Zhiqiang Zhang, Titi Chen, Xin Maggie Wang, Qing Li, Vincent W.S. Lee, Qingsong Huang, Jing Tan, Minghao Guo, Yuan Min Wang, Guoping Zheng, Di Yu, Stephen I. Alexander, Hui Wang, David C.H. Harris
Journal: Journal of the American Society of Nephrology (2018)

The IL-33-type 2 innate lymphoid cell (ILC2) axis has an important role in tissue homeostasis, inflammation, and wound healing. However, the relative importance of this innate immune pathway for immunotherapy against inflammation and tissue damage remains unclear. Here, we show that treatment with recombinant mouse IL-33 prevented renal structural and functional injury and reduced mortality in mice subjected to ischemia-reperfusion injury (IRI). Compared with control-treated IRI mice, IL-33–treated IRI mice had increased levels of IL-4 and IL-13 in serum and kidney and more ILC2, regulatory T cells (Tregs), and anti-inflammatory (M2) macrophages. Depletion of ILC2, but not Tregs, substantially abolished the protective effect of IL-33 on renal IRI. Adoptive transfer of ex vivo –expanded ILC2 prevented renal injury in mice subjected to IRI. This protective effect associated with induction of M2 macrophages in kidney and required ILC2 production of amphiregulin. Treatment of mice with IL-33 or ILC2 after IRI was also renoprotective. Furthermore, in a humanized mouse model of renal IRI, treatment with human IL-33 or transfer of ex vivo –expanded human ILC2 ameliorated renal IRI. This study has uncovered a major protective role of the IL-33–ILC2 axis in renal IRI that could be potentiated as a therapeutic strategy.
The Big Five: consensus considerations before a muscle injury registry revolution - stating the (not so) obvious
Authors: Fionn C Büttner, Eamonn Delahunt, Mark Roe
Journal: British Journal of Sports Medicine (2018)

The topic of international data sharing recently enlivened the ‘Twittersphere’ following a thought-provoking editorial by van Dyk and colleagues.1 They recommended that sporting federations, research institutions and clinicians collaborate to develop an international muscle injury registry. The proposal gained further momentum at the Second World Congress of Sports Physical Therapy, following a keynote presentation by Dr Rod Whiteley. In table 1, we outline the rationale for the creation of a muscle injury registry. An international muscle injury registry would present a novel opportunity to analyse large samples of individual patient data, which researchers aggregate in meta-research, rather than summary data from individual studies. We support the creation of a muscle injury registry, and present five important considerations.

View this table:

Table 1 
Rationale for the creation of a muscle injury registry



Public reporting, clinical observations and research findings contribute to patient registries, creating a ‘shared information environment’.2 A collaborative muscle injury registry compiling individual patient data would facilitate in-depth analysis of large sample sizes, enabling recommendations to be made about specific subcohorts to inform patient-centred …
Whole genome sequencing options for bacterial strain typing and epidemiologic analysis based on single nucleotide polymorphism versus gene-by-gene–based approaches
Authors: A.C. Schürch, S. Arredondo-Alonso, R.J.L. Willems, R.V. Goering
Journal: Clinical Microbiology and Infection (2018)

BackgroundWhole genome sequence (WGS)-based strain typing finds increasing use in the epidemiologic analysis of bacterial pathogens in both public health as well as more localized infection control settings.AimsThis minireview describes methodologic approaches that have been explored for WGS-based epidemiologic analysis and considers the challenges and pitfalls of data interpretation.SourcesPersonal collection of relevant publications.ContentWhen applying WGS to study the molecular epidemiology of bacterial pathogens, genomic variability between strains is translated into measures of distance by determining single nucleotide polymorphisms in core genome alignments or by indexing allelic variation in hundreds to thousands of core genes, assigning types to unique allelic profiles. Interpreting isolate relatedness from these distances is highly organism specific, and attempts to establish species-specific cutoffs are unlikely to be generally applicable. In cases where single nucleotide polymorphism or core gene typing do not provide the resolution necessary for accurate assessment of the epidemiology of bacterial pathogens, inclusion of accessory gene or plasmid sequences may provide the additional required discrimination.ImplicationsAs with all epidemiologic analysis, realizing the full potential of the revolutionary advances in WGS-based approaches requires understanding and dealing with issues related to the fundamental steps of data generation and interpretation.
Abstract 18460: Nuclear Translocation of Calmodulin, Which Dissociated From Cardiac Ryanodine Receptor, Promotes the Pathological Cardiac Hypertrophy
Authors: Tetsuro Oda, Takeshi Yamamoto, Takayoshi Kato, Shigehiko Nishimura, Go Fukui, Shinichi Okuda, Shigeki Kobayashi, Donald Bers, Masafumi Yano
Journal: Circulation (2016)

Calmodulin (CaM) is a ubiquitous Ca binding protein, and ~20% of cardiac myocyte CaM binds to and regulates cardiac ryanodine receptor (RyR2) channel function. CaM binding to RyR2 (CaM-RyR2) inhibi...
The Paradigm of Escalation of Commitment in Treatment Decisions Near the End of Life
Authors: Maxwell T. Vergo, Amelia M. Cullinan, Matthew Wilson
Journal: JAMA Oncology (2018)

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 Oncology 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 Oncology journal
Digital Pill Gains Approval
Authors: Rebecca Voelker
Journal: JAMA (2018)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Autophagy Is Required for Sortilin-Mediated Degradation of Apolipoprotein B100
Authors: Jaume Amengual, Liang Guo, Alanna Strong, Julio Madrigal-Matute, Haizhen Wang, Susmita Kaushik, Jeffrey L. Brodsky, Daniel J. Rader, Ana Maria Cuervo, Edward A. Fisher
Journal: Circulation Research (2018)

Rationale: Genome-wide association studies identified single-nucleotide polymorphisms near the SORT1 locus strongly associated with decreased plasma LDL-C (low-density lipoprotein cholesterol) levels and protection from atherosclerotic cardiovascular disease and myocardial infarction. The minor allele of the causal SORT1 single-nucleotide polymorphism locus creates a putative C/EBPα (CCAAT/enhancer-binding protein α)-binding site in the SORT1 promoter, thereby increasing in homozygotes sortilin expression by 12-fold in liver, which is rich in this transcription factor. Our previous studies in mice have showed reductions in plasma LDL-C and its principal protein component, apoB (apolipoprotein B) with increased SORT1 expression, and in vitro studies suggested that sortilin promoted the presecretory lysosomal degradation of apoB associated with the LDL precursor, VLDL (very-low-density lipoprotein). Objective: To determine directly that SORT1 overexpression results in apoB degradation and to identify the mechanisms by which this reduces apoB and VLDL secretion by the liver, thereby contributing to understanding the clinical phenotype of lower LDL-C levels. Methods and Results: Pulse-chase studies directly established that SORT1 overexpression results in apoB degradation. As noted above, previous work implicated a role for lysosomes in this degradation. Through in vitro and in vivo studies, we now demonstrate that the sortilin-mediated route of apoB to lysosomes is unconventional and intersects with autophagy. Increased expression of sortilin diverts more apoB away from secretion, with both proteins trafficking to the endosomal compartment in vesicles that fuse with autophagosomes to form amphisomes. The amphisomes then merge with lysosomes. Furthermore, we show that sortilin itself is a regulator of autophagy and that its activity is scaled to the level of apoB synthesis. Conclusions: These results strongly suggest that an unconventional lysosomal targeting process dependent on autophagy degrades apoB that was diverted from the secretory pathway by sortilin and provides a mechanism contributing to the reduced LDL-C found in individuals with SORT1 overexpression.