tbuckley/cabot-search huggingface dataset:
New vascular insights into premature aging
Authors: Charles J. Lowenstein, J. Allen Bennett
Journal: Journal of Clinical Investigation (2018)

Hutchinson-Gilford progeria syndrome (HGPS) is a fatal disease characterized by premature aging in which young children fail to thrive and adolescents die from myocardial infarction or stroke. The pathogenesis of HGPS is studied intensively because the mechanisms of premature aging may lead to a better understanding of normal aging. In this issue of the JCI, Osmanagic-Myers and colleagues identify the cellular mechanisms that lead to vascular abnormalities and death in children with HGPS.
The Predictive Value of Intracellular Imatinib Levels in Chronic Myeloid Leukemia
Authors: Nicholas L Jackson Chornenki, Christopher M. Hillis, Isabelle Bence-Bruckler, Lambert Busque, Caroline Hamm, Wanda Hasegawa, Jeffrey H. Lipton, Lynn Savoie, Robert Turner, Anargyros Xenocostas, Suzanne Kamel-Reid, Brian Leber
Journal: Blood (2018)
Efficacy and Safety of P-Bcma-101 CAR-T Cells in Patients with Relapsed/Refractory (r/r) Multiple Myeloma (MM)
Authors: Tara Gregory, Adam D. Cohen, Caitlin L. Costello, Syed Abbas Ali, Jesus G. Berdeja, Eric M Ostertag, Christopher Martin, Devon J Shedlock, Michelle Lynn Resler, Matthew A. Spear, Robert Z. Orlowski, Krina K. Patel
Journal: Blood (2018)
Chemotherapy-Free Combination of Obinutuzumab and Ibrutinib in First LINE Treatment of Follicular Lymphoma. the Alternative Study By the German Low Grade Lymphoma Study Group (GLSG)
Authors: Christian Schmidt, Anna-Katharina Zoellner, Vindi Jurinovic, Martin Sökler, Roswitha Forstpointner, Sascha Haubner, Christian Buske, Andreas Viardot, Ulrich Keller, Christiane Pott, Ullrich Graeven, Reinhard Marks, Mathias Hänel, Ruediger Liersch, Jan Dürig, Eva Hoster, Michael Unterhalt, Wolfgang Hiddemann
Journal: Blood (2018)
Dissecting the antitumor immune response upon PARP inhibition in homologous recombination repair (HRR)-deficient tumors
Authors: B. Pellegrino, A. Llop-Guevara, C. Cruz, M. Castroviejo, A. Cedro-Tanda, R. Fasani, P.G. Nuciforo, A. Gros, J. Balmaña, M.J. O'Connor, V. Serra Elizalde
Journal: Annals of Oncology (2018)

Background: HRR-deficient tumors are sensitive to PARP inhibitors (PARPi) and exhibit high levels of cytosolic DNA that can result in the activation of innate immune signaling as well as upregulation of PD-L1, which has the potential to suppress the immune response. We aimed to study if PARPi-induced PD-L1 upregulation limits the antitumor activity of PARPi by inhibiting the antitumor immune response, and if this is counteracted by anti-PD-L1 treatment. Methods: 30 Patient-Derived breast (BrC) and ovarian cancer (OvC) Xenografts (PDXs) were implanted in NMRI mice and tested for the PARPi olaparib sensitivity (5 BRCA2-, 23 BRCA1-, 2 PALB2-mutated). Their response was categorized according to the modified RECIST criteria as Complete (CR), Partial (PR) Response, Stable (SD) or Progressive (PD) Disease. RNASeq analyses were performed in PDX samples. We quantified PD-L1, CD45 (leucocyte marker), CD56 (NK cell marker) and CD11b (myeloid cell marker) positive cells by IHC in PDXs and clinical samples. Patient-derived tumor cell models (PDCs) were established (n = 17). Results: 7 PDXs were classified as responders (CR/PR) and 23 as non-responders (SD/PD) to PARPi. At baseline, non-responder tumors expressed several pro-inflammatory genes (TNF, IL1A, IL33 and CXCL11) and exhibited a negative regulation of genes related to leukocyte proliferation by RNASeq compared to responders. In PARPi-sensitive tumors, olaparib treatment significantly increased infiltration of non-NK/non-myeloid-CD45+ immune cells, while in non-responders there was a marked increase in PD-L1 expression. Ex vivo cultures and PDXs recapitulated the patient's PARPi response and PD-L1 expression, and are being prospectively used to investigate whether the PARPi-induced PD-L1 activation sensitizes to anti-PD-L1 therapy by enhancing the antitumor immune response. Conclusions: In experimental models, olaparib elicits an antitumor immune response in PARPi-sensitive tumors that is not observed in PARPi-resistant tumors, which upregulate PD-L1. In these cases, the combination with anti-PDL1 therapy could enhance PARPi response. Legal entity responsible for the study: Vall d'Hebron Institute of Oncology. Funding: AstraZeneca. Disclosure: J. Balmaña: Advisory board member: Clovis, Tesaro, Medivation; Speaker bureau honoraria: AstraZeneca. M.J. O'Connor: Employee of AstraZeneca. V. Serra Elizalde: Non-commercial research agreement: AstraZeneca. All other authors have declared no conflicts of interest.
PARP1 Inhibitors Eliminated Imatinib-Refractory Chronic Myeloid Leukemia Cells in Bone Marrow Microenvironment Conditions
Authors: Margaret Nieborowska-Skorska, Paulina Podszywalow-Bartnicka, Silvia Maifrede, Bac Viet Le, Monika Toma, Peter Valent, Tomasz Sliwinski, Wayne Childers, Katarzyna Piwocka, Alexei Tulin, Tomasz Skorski
Journal: Blood (2018)
Interventions to Improve Medication Adherence
Authors: Vinay Kini, P. Michael Ho
Journal: JAMA (2018)

Among adults with chronic illness, 30% to 50% of medications are not taken as prescribed. In the United States, it is estimated that medication nonadherence is associated with 125 000 deaths, 10% of hospitalizations, and $100 billion in health care services annually.PubMed was searched from January 1, 2000, to September 6, 2018, for English-language randomized clinical trials of interventions to improve medication adherence. Trials of patients younger than 18 years, trials that used self-report as the primary adherence outcome, and trials with follow-up periods less than 6 months were excluded; 49 trials were included. The most common methods of identifying patients at risk for nonadherence were patient self-report, electronic drug monitors (pill bottles), or pharmacy claims data to measure gaps in supply. Patient self-report is the most practical method of identifying nonadherent patients in the context of clinical care but may overestimate adherence compared with objective methods such as electronic drug monitors and pharmacy claims data. Six categories of interventions, and characteristics of successful interventions within each category, were identified: patient education (eg, recurrent and personalized telephone counseling sessions with health educators); medication regimen management (using combination pills to reduce the number of pills patients take daily); clinical pharmacist consultation for chronic disease co-management (including education, increased frequency of disease monitoring via telephone or in-person follow-up visits, and refill reminders); cognitive behavioral therapies (such as motivational interviewing by trained counselors); medication-taking reminders (such as refill reminder calls or use of electronic drug monitors for real-time monitoring and reminding); and incentives to promote adherence (such as reducing co-payments and paying patients and clinicians for achieving disease management goals). The choice of intervention to promote adherence will depend on feasibility and availability within a practice or health system. Successful interventions that are also clinically practical include using combination pills to reduce daily pill burden, clinical pharmacist consultation for disease co-management, and medication-taking reminders such as telephone calls to prompt refills (maximum observed absolute improvements in adherence of 10%, 15%, and 33%, respectively).Adherence can be assessed and improved within the context of usual clinical care, but more intensive and costly interventions that have demonstrated success will require additional investments by health systems.
Challenges of Non–Intention-to-Treat Analyses
Authors: David L. DeMets, Thomas Cook
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
Non-covalent hitchhiking on endogenous carriers as a protraction mechanism for antiviral macromolecular prodrugs
Authors: Camilla Kaas Frich, Franziska Krüger, Raoul Walther, Cecilie Domar, Anna H.F. Andersen, Anne Tvilum, Frederik Dagnæs-Hansen, Paul W. Denton, Martin Tolstrup, Søren R. Paludan, Jan Münch, Alexander N. Zelikin
Journal: Journal of Controlled Release (2018)
The transcription factor POU3F2 regulates a gene coexpression network in brain tissue from patients with psychiatric disorders
Authors: Chao Chen, Qingtuan Meng, Yan Xia, Chaodong Ding, Le Wang, Rujia Dai, Lijun Cheng, Preethi Gunaratne, Richard A. Gibbs, Shishi Min, Cristian Coarfa, Jeffrey G. Reid, Chunling Zhang, Chuan Jiao, Yi Jiang, Gina Giase, Amber Thomas, Dominic Fitzgerald, Tonya Brunetti, Annie Shieh, Cuihua Xia, Yongjun Wang, Yunpeng Wang, Judith A. Badner, Elliot S. Gershon, Kevin P. White, Chunyu Liu
Journal: Science Translational Medicine (2018)

POU3F2 regulates expression of key genes in postmortem brain tissue from patients with schizophrenia or bipolar disorder.
Ulnar Artery Occlusion and Severity Markers of Vasculopathy in Systemic Sclerosis: A Multicenter Cross‐Sectional Study
Authors: Alain Lescoat, Cécile Marie Yelnik, Guillaume Coiffier, Matthieu Wargny, Christophe Lamotte, Claire Cazalets, Nicolas Belhomme, Alice Ballerie, Pierre-Yves Hatron, David Launay, Aleth Perdriger, Vincent Sobanski, Eric Hachulla, Patrick Jégo
Journal: Arthritis & Rheumatology (2018)

To evaluate the association of ulnar artery occlusion (UAO) assessed using Doppler ultrasound (DUS) with the severity markers of systemic sclerosis (SSc).Two hundred four unselected patients fulfilling the American College of Rheumatology/European League Against Rheumatism 2013 classification criteria for SSc were included in this cross-sectional multicenter study. All patients underwent bilateral hand DUS to evaluate the presence of UAO and clinical/paraclinical visceral evaluation according to current guidelines. Univariable and multivariable ordinal regression models were applied, grading the severity of UAO as "no UAO," "only one UAO," and "UAO on both hands," and assessing its association with clinical features of SSc. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.UAO was found in 76 patients (37.3%) and was bilateral in 49 patients (24%). UAO as an ordinal event was significantly associated with disease duration, history of fingertip ulcers, telangiectasia, higher modified Rodnan skin thickness score (MRSS), worse diffusing capacity for carbon monoxide (DLco) values, higher tricuspid jet velocity, late capillaroscopic pattern, and positivity for anticentromere antibodies (ACAs) (univariable analysis). In the adjusted multivariable ordinal model, UAO was less frequent in women (OR 0.35 [95% CI 0.15-0.83], P = 0.017) and in patients receiving steroids (OR 0.24 [95% CI 0.09-0.62], P = 0.0034). In multivariable analyses, significant association with UAO was retained for history of fingertip ulcers (OR 2.55 [95% CI 1.24-5.21], P = 0.011), higher MRSS (OR 1.65 [95% CI 1.06-2.56], P =0.025), lower DLco values (OR 0.85 [95% CI 0.78-0.94], P = 0.0015), and ACA positivity (OR 2.89 [95% CI 1.36-6.11], P = 0.0056).UAO may represent a relevant severity marker of vasculopathy in SSc. Its predictive value for the onset of severe vascular manifestations such as pulmonary arterial hypertension, and its association with mortality, remain to be determined in longitudinal studies.
P077 miR-338-3p Promotes the Resistance of Non-Small Cell Lung Cancers To EGFR-TKI By Targeting PTPN12
Authors: Q. Wu, F. Guo, Y. Li, W. Li, G. Ma, Y. Deng, W. Luo, Y. Zhao, F. Xu, Q. Zhou
Journal: Journal of Thoracic Oncology (2018)
Synaptic Vesicle Protein 2 and Vesicular Monoamine Transporter 1 and 2 Are Expressed in Neuroblastoma
Authors: Kleopatra Georgantzi, Apostolos V. Tsolakis, Åke Jakobson, Rolf Christofferson, Eva Tiensuu Janson, Lars Grimelius
Journal: Endocrine Pathology (2019)

Neuroblastoma (NB), the most common extracranial cancer in childhood, exhibits neuroendocrine (NE) differentiation. Two well-established NE markers, chromogranin A (CgA) and synaptophysin (syn), are used in the histopathological diagnostics. Our aims were to explore if the NE markers synaptic vesicle protein 2 (SV2) and vesicular monoamine transporter 1 (VMAT1) and 2 (VMAT2) also are expressed in human NB and if so, evaluate their usefulness in NB histopathological diagnostics. Tumor specimens from 21 NB patients, before and/or after chemotherapy, were immunostained for CgA, syn, SV2, VMAT1, and VMAT2. Clinical data was extracted from patients' records. SV2 was highly expressed in NB, as was CgA while syn was less frequently expressed compared to the other two. Both VMATs were expressed in several NB, VMAT2 in more cases than VMAT1 and its expression was similar to syn. Chemotherapy did not affect the immunoreactivity in an obvious way. SV2 was highly expressed in NB and can thus be useful marker in NB diagnostics. VMAT1 and VMAT2 were also expressed in NB but similar to syn less reliable as tumor markers.
On the origin of proteins in human drusen: The meet, greet and stick hypothesis
Authors: Arthur A. Bergen, Swati Arya, Céline Koster, Matthew G. Pilgrim, Dagmara Wiatrek-Moumoulidis, Peter J. van der Spek, Stefanie M. Hauck, Camiel J.F. Boon, Eszter Emri, Alan J. Stewart, Imre Lengyel
Journal: Progress in Retinal and Eye Research (2018)
Clinical and Genetic Determinants of Varicose Veins
Authors: Eri Fukaya, Alyssa M. Flores, Daniel Lindholm, Stefan Gustafsson, Daniela Zanetti, Erik Ingelsson, Nicholas J. Leeper
Journal: Circulation (2018)

Background: Varicose veins are a common problem with no approved medical therapies. Although it is believed that varicose vein pathogenesis is multifactorial, there is limited understanding of the genetic and environmental factors that contribute to their formation. Large-scale studies of risk factors for varicose veins may highlight important aspects of pathophysiology and identify groups at increased risk for disease. Methods: We applied machine learning to agnostically search for risk factors of varicose veins in 493 519 individuals in the UK Biobank. Predictors were further studied with univariable and multivariable Cox regression analyses (2441 incident events). A genome-wide association study of varicose veins was also performed among 337 536 unrelated individuals (9577 cases) of white British descent, followed by expression quantitative loci and pathway analyses. Because height emerged as a new candidate risk factor, we performed mendelian randomization analyses to assess a potential causal role for height in varicose vein development. Results: Machine learning confirmed several known (age, sex, obesity, pregnancy, history of deep vein thrombosis) and identified several new risk factors for varicose vein disease, including height. After adjustment for traditional risk factors in Cox regression, greater height remained independently associated with varicose veins (hazard ratio for upper versus lower quartile, 1.74; 95% CI, 1.51–2.01; P &lt;0.0001). A genome-wide association study identified 30 new genome-wide significant loci, identifying pathways involved in vascular development and skeletal/limb biology. Mendelian randomization analysis provided evidence that increased height is causally related to varicose veins (inverse-variance weighted: odds ratio, 1.26; P =2.07×10 −16 ). Conclusions: Using data from nearly a half-million individuals, we present a comprehensive genetic and epidemiological study of varicose veins. We identified novel clinical and genetic risk factors that provide pathophysiological insights and could help future improvements of treatment of varicose vein disease.
Tissue transglutaminase prevents thapsigargin-induced cell death through cross-linking of caspase-3 in Bax-deficient HCT116 cells
Authors: Hirohito Yamaguchi, Hong-Gang Wang
Journal: Cancer Research (2006)

720  We have reported previously that thapsigargin (THG), an inhibitor of the endoplasmic reticulum Ca2+-ATPase, induces caspase-3 activation and apoptosis in HCT116 cells through a DR5-initiated and Bax-dependent pathway. In Bax-deficient HCT116 cells, THG treatment generates high-molecular-weight inactive species of caspase-3 that are highly resistant to SDS and 2-mercaptoethanol through an unknown mechanism. Here, we show that the Ca2+-dependent protein cross-linking enzyme tissue transglutaminase (tTGase) catalyzes caspase-3 cross-linking reactions, thereby inactivating caspase-3 and blocking apoptosis in HCT116 cells in response to THG. A prolonged exposure of Bax-deficient cells to THG caused cell rounding and reduced clonogenic cells but did not induce caspase-3 activation and cell membrane permeabilization. Concurrently, two additional species of caspase-3, termed p40 and p64, with molecular mass approximately 40 and 64 kDa, respectively, were observed. However, this formation of p40 and p64 species was inhibited by the tTGase inhibitor monodansylcadaverine. Overexpression of tTGase increased p40 and p64 in THG-treated Bax-deficient cells and purified tTGase catalyzed caspase-3 cross-linking in vitro. In contrast, knockdown of tTGase by shRNA in Bax-deficient cells reduced the cross-linked species p40 and p64 and restored caspase-3 activation in response to THG treatment. Moreover, the protein levels of XIAP and cIAP-1were decreased after a prolonged exposure to THG, but the protein levels and enzymatic activity of tTGase were subsequently upregulated. Expression of cytosolic Smac sensitized Bax-deficient cells to THG-induced apoptosis, while this effect was diminished by co-expression of tTGase. Taken together, these results suggest that tTGase serves as an inhibitor of apoptosis by cross-linking caspase-3 in THG-treated cells.
Smoking and Urinary Cotinine Levels Are Predictors of Increased Risk for Gastric Intestinal Metaplasia
Authors: Kyungeun Kim, Yoosoo Chang, Jiin Ahn, Hyo-Joon Yang, Ju Young Jung, Seokkyun Kim, Chong Il Sohn, Seungho Ryu
Journal: Cancer Research (2018)

Studies on a longitudinal relationship between smoking status and intestinal metaplasia (IM), a premalignant lesion of stomach cancer, are limited. Here we examined the association of smoking status and urinary cotinine levels, an objective measure of smoking, with the development of endoscopic IM. This cohort study included 199,235 Korean adults free of endoscopic IM who underwent upper endoscopy at baseline and subsequent visits and who were followed for up to 6.8 years (median, 3.7 years). Former and current smoking status and pack-years based on self-reports were associated with an increased risk of new-onset IM in men but not in women. However, urinary cotinine levels were positively associated with incident IM in a dose-response manner in both men and women. For men, the multivariable-adjusted HR [95% confidence interval (CI)] for incident IM comparing the urinary cotinine levels of 50 to 99 ng/mL, 100 to 499 ng/mL, and ≥500 ng/mL with <50 ng/mL were 1.20 (0.94-1.55), 1.26 (1.14-1.40), and 1.54 (1.44-1.64), respectively, whereas for women, corresponding HR (95% CI) were 0.75 (0.19-2.99), 1.86 (1.20-2.88), and 1.57 (1.07-2.30), respectively. These associations were observed when changes in smoking status and other confounders were updated during follow-up as time-varying covariates. In this large cohort of young and middle-aged men and women, urinary cotinine levels were independently associated with an increased incidence of endoscopic IM in a dose-response manner. Collectively, these data confirm smoking as an independent risk factor for the development of gastric IM, a precursor lesion of stomach cancer. SIGNIFICANCE: A large-scale cohort study of nearly 200,000 adults associates smoking with increased risk for gastric intestinal metaplasia, a precursor lesion of stomach cancer.
Author Correction: Predicting the clinical impact of human mutation with deep neural networks
Authors: Laksshman Sundaram, Hong Gao, Samskruthi Reddy Padigepati, Jeremy F. McRae, Yanjun Li, Jack A. Kosmicki, Nondas Fritzilas, Jörg Hakenberg, Anindita Dutta, John Shon, Jinbo Xu, Serafim Batzoglou, Xiaolin Li, Kyle Kai-How Farh
Journal: Nature Genetics (2018)
Abstract 16474: Pregnancy Outcomes in Patients With Congenital Heart Disease: The POPS Study
Authors: Anita Saraf, Kirsten Gibbs-Nieto, Ijeoma Ananaba, Iram Hasan, Mary Kay Benton, Dhaval R Parekh, Wayne J Franklin
Journal: Circulation (2011)

Objectives: Maternal and fetal pregnancy outcomes were investigated at a single tertiary center. We investigated incidence of spontaneous abortions, elective terminations, and maternal and fetal co...
Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial
Authors: Arun Sanyal, Edgar D Charles, Brent A Neuschwander-Tetri, Rohit Loomba, Stephen A Harrison, Manal F Abdelmalek, Eric J Lawitz, Dina Halegoua-DeMarzio, Sudeep Kundu, Stephanie Noviello, Yi Luo, Rose Christian
Journal: The Lancet (2018)