tbuckley/cabot-search huggingface dataset:
CEA expression patterns determine response and resistance to the CEA-TCB bispecific immunotherapy antibody in colorectal cancer patient derived organoids.
Authors: Reyes Gonzalez Exposito, Maria Semmianikova, Beatrice Griffiths, Khurum Hayat Khan, Louise J Barber, Andrew Woolston, Georgia Spain, Katharina von Loga, Amanda Swain, Janet Thomas, Annette Bryant, David Mansfield, Sheela Rao, David J. Watkins, Ian Chau, Naureen Starling, Nik Matthews, Fredrik Wallberg, David Cunningham, Marco Gerlinger
Journal: Journal of Clinical Oncology (2019)

535 Background: The bispecific antibody CEA-TCB binds Carcino-Embryonic Antigen (CEA) on cancer cells and CD3 on T cells. This triggers T cell killing of colorectal cancer cell lines expressing moderate to high levels of CEA at the cell surface (Bacac, Clin Cancer Res 2016). Patient derived organoids (PDOs) may more accurately represent patient tumors than established cell lines. Yet, determinants of CEA-TCB resistance have not been studied in PDOs. Methods: PDOs were established from biopsies of eight multidrug-resistant metastatic CRCs, GFP labelled and adapted to 2D culture. Allogenic CD8 T cells and CEA-TCB or a non-targeting control antibody were added and cancer cell killing and growth were monitored for 10 days. CEA expression of PDOs was determined by FACS. Results: CRC PDOs could be categorized into three groups based on CEA cell-surface expression: CEAhigh (n = 3), CEAlow (n = 2), and CEA heterogeneous PDOs (n = 3) that stably maintained populations of both CEAhigh and CEAlow cells, which has not previously been described in CRC cell lines. Heterogeneity of cell-surface CEA expression is common in CRC cells in patients, supporting that PDOs may better represent these tumors than established cell lines. CEAhigh cells were sensitive whereas CEAlow cells showed resistance to CEA-TCB. All PDOs with heterogeneous CEA expression were resistant to CEA-TCB, suggesting that CEA-negative cells maintain cancer cell growth. Culture of FACS sorted CEAhigh and CEAlow cells from PDOs with heterogeneous CEA expression demonstrated high plasticity of CEA expression which may contribute to rapid resistance acquisition through CEA antigen loss. Conclusions: These results suggest that cell-surface CEA expression is a major determinant of CEA-TCB sensitivity and resistance in PDOs. In addition, we identified heterogeneous CEA expression in several PDOs and demonstrated that this could confer CEA-TCB resistance in vitro. These PDO models are likely to provide insights into the mechanism of CEA loss and may inform therapeutic opportunities to counter CEA-TCB resistance. RNA-sequencing and functional experiments are ongoing to investigate this and will be presented.
Outcomes of Myeloma Patients with Deletion 1p Receiving Lenalidomide, Bortezomib, and Dexamethasone (RVD) Therapy
Authors: Levani Odikadze, Nisha Joseph, Timothy M. Schmidt, Leonard Heffner, Craig C Hofmeister, Madhav V Dhodapkar, Vikas A. Gupta, Lawrence H. Boise, David L. Jaye, Sagar Lonial, Ajay K Nooka, Jonathan L Kaufman
Journal: Blood (2018)
Joint ESM-EVBO meetings: past, present, and future
Authors: Judith C Sluimer, Alfons J H M Houben
Journal: Cardiovascular Research (2019)

to 18 of this year, we are pleased to host the third joint meeting of the European Society for Microcirculation (ESM) 1 and the European Vascular Biology Organization (EVBO) 2 in Maastricht (Figure 1A).The conference draws research scientists, investigators in basic and applied research, clinicians, post-doctoral fellows, and graduate students actively engaged in the growing fields of microcirculation and vascular biology.The conference objective is to advance research and education in the many areas of microcirculation and vascular biology.
Clinical and Molecular Characteristics of Acute Myeloid Leukemia (AML) Patients with TP53 Mutations and TP73 Mutations
Authors: Alice S. Mims, Jessica Kohlschmidt, Ann-Kathrin Eisfeld, Krzysztof Mrózek, James S. Blachly, Shelley Orwick, Dimitrios Papaioannou, Deedra Nicolet, Deepa Sampath, Richard M. Stone, Bayard L. Powell, Jonathan E. Kolitz, John C. Byrd, Clara D. Bloomfield
Journal: Blood (2018)
Asthma as a comorbidity in adult patients receiving treatment in an emergency department, ambulatory surgery and inpatient for back pain in a large, inner city, municipal New York hospital.
Authors: Nneoma Obiejemba, Obinna Obiejemba, Sairaman Nagarajan, Roshni Naik, Rauno Joks
Journal: Journal of Allergy and Clinical Immunology (2019)
Metachronous Neoplasias Arise in a Higher Proportion of Colon Segments From Which Large Polyps Were Previously Removed, and Can be Used to Estimate Incomplete Resection of 10–20 mm Colorectal Polyps
Authors: Jeffrey Adler, Dana Toy, Joseph C. Anderson, Douglas J. Robertson, Heiko Pohl
Journal: Clinical Gastroenterology and Hepatology (2019)
How Would You Treat This Patient With Gallstone Pancreatitis?
Authors: Anjala Tess, Steven D. Freedman, Tara Kent, Howard Libman
Journal: Annals of Internal Medicine (2019)

Acute pancreatitis, a common cause of hospitalization in the United States, is often the result of biliary tract disease. In 2016, the American Gastroenterological Association released a guideline that addresses the practical considerations in managing acute pancreatitis within the first 72 hours after the patient presents. The guideline specifically recommends goal-directed hydration therapy, early enteral feeding, judicious use of endoscopic retrograde cholangiopancreatography (ERCP), and gallbladder surgery during the index admission for patients with mild pancreatitis. The authors discuss their approach to these interventions in the context of a patient with recurrent acute pancreatitis who chooses to delay surgery until after hospital discharge. They address hydration and timing of surgery, as well as how they would manage the patient's preferences in the face of existing guidelines.
THE EFFECT OF DRUG–ELUTING STENTS ON CLINICAL AND ANGIOGRAPHIC OUTCOMES IN DIABETIC PATIENTS, THREE–YEAR RESULT: MULTICENTER REGISTRY IN ASIA
Authors: Sunao Nakamura, Hisao Ogawa, Hans Yeo, Wasan Udayachalerm, Damras Tresukosol, Sudaratana Tansuphaswadikul
Journal: Journal of the American College of Cardiology (2013)
Abstract LB-332: A novel TIMP-2-mediated cytoplasmic mechanism for the regulation of receptor tyrosine kinase, VEGFR-2
Authors: Renuka Sivendran, Hongmei Li, Dong-Wan Seo, Tere Diaz, Beiyang Wei, William G. Stetler-Stevenson
Journal: Cancer Research (2008)

Abstract The vascular endothelial growth factors (VEGFs) and their receptors (receptor tyrosine kinases) are critical for angiogenesis. The binding of VEGF-A induces dimerization and autophosphorylation of its receptor, VEGFR-2. This initiates a signaling cascade that results in increased cell proliferation, migration, and permeability. The introduction of tissue inhibitor of metalloproteinase-2 (TIMP-2) protein or a dominant negative mutant that has no MMP inhibitory activity (Ala+TIMP-2) intercepts this signaling cascade and affects these cellular functions. To elucidate the mechanisms of this disruption in VEGFR-2 signaling, we explored direct (competition binding, substrate affinity, total binding capacity) and indirect (receptor degradation, receptor dimerization by cross-linking, and FRET) mechanisms that could facilitate the inhibition of growth factor signaling by TIMP-2. Our studies showed that TIMP-2 did not directly compete for binding to VEGFR-2 as previously reported for TIMP-3 (Qi JH. Nature Medicine 2003;9:407-15). Further, TIMP-2 did not increase the internalization and degradation of VEGFR-2, nor did it decrease the affinity of the VEGF-A ligand. In contrast, TIMP-2 decreased the total cellular binding capacity for VEGF-A. These data suggest a novel mechanism by which TIMP-2 may regulate the binding conformation or state of VEGFR-2 dimerization, thereby influencing the cell sensitivity to VEGF-A stimulation. To study the conformation or state of VEGFR-2 dimerization, we conducted cross-linking analysis of VEGFR-2, and the results showed that TIMP-2 pretreatment prior to VEGF-A treatment significantly decreased VEGFR-2 dimer formation. In order to study this quantitatively, we designed a fluorescence resonance energy transfer (FRET) system that would detect the intracellular dimers of VEGFR-2. We fused Cerulean or Venus to the C-terminus of human VEGFR-2, transfected porcine aortic endothelial (PAE) cells, and selected stable cells expressing the constructs. Sensitized emission FRET analysis of the transfected PAE cells showed that Ala+TIMP-2 pretreatment prior to VEGF-A treatment decreased the VEGFR-2 dimerization to basal levels. This demonstrated that TIMP-2 regulates the binding capacity of VEGFR-2 by modulating the monomer-dimer equilibrium of VEGFR-2. This is the first demonstration of a cytoplasmic signaling mechanism influencing the monomer-dimer equilibrium of a receptor tyrosine kinase. This may potentially be a common mechanism for cellular regulation of growth factor sensitivity for this class of receptor tyrosine kinases.
Probiotic Safety—Reasonable Certainty of No Harm—Reply
Authors: Pieter A. Cohen
Journal: JAMA Internal Medicine (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 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
Hepatitis B infection in hemodialysis centers from Santa Catarina State, southern Brazil: predictive risk factors for infection and molecular epidemiology
Authors: Flair Jose Carrilho, Cleusa R. de Moraes, João R. Pinho, Regina Moreira, Denis Bertolini, Isabel M. Mello, Isabel Gatura, Leda Bassit, Rita A. Cardoso, Luiz C. da Silva, Antônio Atílio Laudanna
Journal: Hepatology (2001)
Vascular E-Selectin Acts As a Gatekeeper Inducing Commitment and Loss of Self-Renewal in HSC Transmigrating through the Marrow Vasculature
Authors: Ingrid G Winkler, Valerie Barbier, Jessica Lowe, Joshua Tay, John L Magnani, Paula Marlton, Anthony K Mills, Andrew Perkins, Corrine E Fiveash, Johanna M Erbani, Jean-Pierre Levesque
Journal: Blood (2018)
Effect of Haplotype Matching on Outcomes after Adult Single Cord Blood Transplantation
Authors: Junya Kanda, Takakazu Kawase, Hidenori Tanaka, Naoyuki Uchida, Koji Nagafuji, Yoshiko Matsuhashi, Yuji Ohno, Makoto Onizuka, Junji Tanaka, Tatsuo Ichinohe, Yoshiko Atsuta
Journal: Blood (2018)
Abstract 13856: Circulating microRNA Differentiates HFpEF and HFrEF Patients
Authors: Min Lu, Xuguang Hu, John G Cleland, Rachel Nicholls, Andrew L Clark, Aarif Khakoo, Fitzpatrick Dan, Xiaozhen Wang
Journal: Circulation (2016)

Introduction: Circulating microRNAs (miRNAs) might reflect altered regulation of key pathways that determine the progression of heart failure (HF) and therefore provide therapeutic targets. We explored the feasibility of serum miRNA profiling in patients with HF and whether miRNA profiles are different in i) non-HF control vs. HF and ii) HF with preserved ejection fraction (HFpEF) vs HF with reduced ejection fraction (HFrEF). Methods: Serum samples from 124 subjects were obtained from non-HF controls (n=61), patients with HFpEF (n=51), and patients with HFrEF (n=12). miRNAs were isolated, and levels of 84 miRNAs known to exhibit altered expression in cardiovascular disease were assessed using real-time quantitative PCR. Data analyses were carried out using R limma package. Multiple testing was adjusted by Benjamini-Hochberg’s approach. Results: 57 out of 84 miRNAs had detectable expression in the serum (Ct mean&lt;35), in which 3 miRNAs (miR-122, miR-142, and miR-143) differed significantly between HF and control subjects (adjusted p-value&lt;0.01, absolute fold change &gt;2). These miRNAs negatively regulate expression of pathogenic genes in cardiovascular diseases. Specifically, miR-142 targets acetyltransferase p300 and gp130, key regulators of growth and STAT3-mediated survival signals. miR-143, together with miR-145 (adjusted p-value=0.1, absolute fold change=1.9) are highly expressed in vascular smooth muscle cells (VSMCs). They are required for the transition from proliferative to contractile VSMCs via targeting known repressor genes of the contractile VSMC phenotype such as KLF4, KLF5, and ACE. One miRNA, miR-140 differed between HFpEF and HFrEF (non-adjusted p=0.03, absolute fold change&gt;3). miR-140 targets SUMRF1, an E3 ligase for bone morphogenetic protein receptor II (BMPR2). Mutations of BMPR2 cause pulmonary arterial hypertension and cardiomyopathy in human. Conclusions: Circulating miRNA profiles exhibit distinct patterns in control and HF that are plausibly associated with specific pathogenetic pathways in HF which may be useful biomarkers or therapeutic targets.
Acral Involvement of Lymphoblastic Lymphoma Revealed on FDG PET/CT
Authors: Zhe Wen, Hongming Zhuang
Journal: Clinical Nuclear Medicine (2019)

Lymphoma rarely involves hand or foot. We presented the FDG PET/CT findings of lymphoblastic lymphoma in a 28-year-old man who had recurrent disease in many bones, including those of the hand and foot without any lymph node involvement 17 years after initial diagnosis.
IL-23 favours outgrowth of spondyloarthritis-associated pathobionts and suppresses host support for homeostatic microbiota
Authors: Linda M Rehaume, Nicholas Matigian, Ahmed M Mehdi, Nancy Lachner, Kate L Bowerman, Joshua Daly, Kim-Anh Lê Cao, Philip Hugenholtz, Ranjeny Thomas
Journal: Annals of the Rheumatic Diseases (2019)

Objectives Certain gut bacterial families, including Bacteroidaceae, Porphyromonadaceae and Prevotellaceae, are increased in people suffering from spondyloarthropathy (SpA), a disease group associated with IL23R signalling variants. To understand the relationship between host interleukin (IL)-23 signalling and gut bacterial dysbiosis in SpA, we inhibited IL-23 in dysbiotic ZAP-70-mutant SKG mice that develop IL-23-dependent SpA-like arthritis, psoriasis-like skin inflammation and Crohn’s-like ileitis in response to microbial beta 1,3-glucan (curdlan). Methods We treated SKG mice weekly with anti-IL-23 or isotype mAb for 3 weeks, rested them for 3 weeks, then administered curdlan or saline. We collected faecal samples longitudinally, assessed arthritis, spondylitis, psoriasis and ileitis histologically, and analysed the microbiota community profiles using next-generation sequencing. We used multivariate sparse partial least squares discriminant analysis to identify operational taxonomic unit (OTU) signatures best classifying treatment groups and linear regression to develop a predictive model of disease severity. Results IL-23p19 inhibition in naïve SKG mice decreased Bacteroidaceae, Porphyromonadaceae and Prevotellaceae. Abundance of Clostridiaceae and Lachnospiraceae families concomitantly increased, and curdlan-mediated SpA development decreased. Abundance of Enterobacteriaceae and Porphyromonadaceae family and reduction in Lachnospiraceae Dorea genus OTUs early in disease course were associated with disease severity in affected tissues. Conclusions Dysbiosis in SKG mice reflects human SpA and is IL-23p19 dependent. In genetically susceptible hosts, IL-23p19 favours outgrowth of SpA-associated pathobionts and reduces support for homeostatic-inducing microbiota. The relative abundance of specific pathobionts is associated with disease severity.
Abstract 14960: Left Ventricular Native T1 Time and the Risk of Arial fibrillation Recurrence After Pulmonary Vein Isolation in Patients With Paroxysmal Atrial Fibrillation
Authors: Shingo Kato, Sébastien Roujol, Tamer Basha, Sophie Berg, Kraig V Kissinger, Beth Goddu, Warren J Manning, Reza Nezafat
Journal: Circulation (2015)

Introduction: Native T1 mapping has emerged as a noninvasive non-contrast magnetic resonance imaging (MRI) method to assess for diffuse myocardial fibrosis. However, LV native T1 time in atrial fibrillation (AF) patients and its clinical relevance are unclear. Hypothesis: We hypothesized that native T1 time is elevated in AF patients and elevated native T1 time is associated with higher rate of AF recurrence after pulmonary vein isolation (PVI). Methods: Fifty paroxysmal AF patients referred for PVI (60±8 years, 37 male) and 13 healthy control subjects (57±8 years, 10 male) were studied. All patients were in sinus rhythm during the MRI scan. Native T1 mapping images were acquired using a Modified Look-Locker imaging (MOLLI) sequence in 3 short-axis planes (basal, mid and apical slices) using an electrocardiogram triggered single-shot acquisition with a balanced steady-state free precession readout. Results: LV ejection fraction was similar between groups (AF: 61±6%; controls: 60±5%, p=0.31). No LV myocardial scar was observed in any patient on LGE. Myocardial native T1 time was greater in AF patients (1099±52 vs 1047±26 msec, p=0.001). During a mean follow-up period of 233 days, 7 of 50 (14%) patients experienced recurrence of AF. Kaplan Meier curve demonstrated significant difference in AF recurrence between patients with elevated LV native T1 time and patients with non-elevated LV native T1 time (p=0.032 by Log-rank test, elevated native LV T1 time was defined as &gt;2SD of controls: 1099msec). Cox proportional hazard analysis identified native T1 time as an independent predictor of recurrence of AF (HR: 1.21, 95% CI: 1.05-1.40, p=0.009). Conclusions: There are differences in the native LV myocardial T1 time between AF patients with preserved LV function referred for PVI and normal controls. Native T1 time is an independent predictor of recurrence of AF after PVI in patients with paroxysmal AF.
Abstract P292: Cardiovascular Risk Factors in U.S. Men With and Without History of Prostate Cancer: NHANES 1999-2014
Authors: Ahmed A Hassoon, Lawrence Appel, Hsin-Chieh Yeh
Journal: Circulation (2018)

In 2017 161,000 new cases of prostate cancer diagnosed in the U.S. With improved survival from prostate cancer, cardiovascular disease has emerged as competing cause of morbidity and mortality. However, few studies have assessed CVD risk factors among prostate cancer survivors. We analyzed National Health and Nutrition Examination Survey (NHANES) from 1999-2014 to assess CVD risk factors, as defined by AHA/ACC, in adult men with and without a history of prostate cancer. A total of 602 men, age 50 years and older, with prostate cancer history and 8,226 men without cancer history were included in the analysis. Among men with prostate cancer history, the mean (SE) age at survey was 72.3(0.4); 41% of the survivors had their diagnoses less than 5 years ago, while 31% survived more than 10 years after diagnosis. Compared to men without cancer, prostate cancer survivors were older (mean age 72 (0.4) vs 62y (0.1)), but with similar education level ( p =0.41). For CVD risk factors, prostate cancer survivors were less likely to be current smokers (6.5% vs 20.3%), but more likely to have hypertension and on anti-hypertensive medication (95.6% vs 88.9%) with age-adjusted prevalence odds ratio of 1.53 ([95% CI, 1.2 - 1.9]; p =0.001) and 1.78 ([95% CI, 1.1 - 2.9]; p =0.024), respectively. There were no differences in lipids profiles between men with and without prostate cancer. In stratified analysis, non-Hispanic blacks’ survivors have almost two times the prevalence of hypertension compared to non-Hispanic blacks free of cancer, with age-adjusted prevalence odds ratio of 1.9 ([95% CI, 1.2 - 2.96]; p=0.005). In conclusion, CVD risk factors were prevalent in prostate cancer survivors. Improving cardiovascular health through lifestyle change and preventive strategies is a public health priority, particularly among non-Hispanic Blacks.
Idarucizumab for Dabigatran-Related Gastrointestinal Bleeds
Authors: Deborah M. Siegal, Stuart J. Connolly
Journal: Circulation (2019)

Article, see p 748 T he introduction of direct oral anticoagulants (DOACs), including the oral direct thrombin inhibitor dabigatran etexilate, ushered in a new era for chronic thrombotic disease management.Despite evidence of DOAC safety, there are valid concerns regarding an anticoagulant effect in the setting of uncontrolled bleeding.Unlike the coagulation defect induced by vitamin K antagonists, which is correctable with vitamin K and coagulation factor replacement, there were no agents to reverse DOAC anticoagulant effect until recently.Idarucizumab is a monoclonal antibody fragment that binds to dabigatran with high affinity, and andexanet alfa is a form of deactivated factor Xa that acts as a decoy to bind factor Xa inhibitor molecules. 1,2These reversal agents rapidly correct the coagulopathy induced by the respective DOACs and should improve clinical outcomes.In the multicenter, open-label, single-cohort REVERSE-AD study (Reversal Effects of Idarucizumab on Active Dabigatran), idarucizumab corrected laboratory indices of anticoagulation and reduced the level of active drug in dabigatran-treated individuals with uncontrolled bleeding or the need for urgent surgery. 3Gastrointestinal bleeding accounted for 46% (137/301) of bleeding events in REVERSE-AD, the characteristics and outcomes of which are reported by van der Wall et al 4 in this issue of Circulation.Gastrointestinal bleeding represents about 40% of major oral anticoagulant (OAC)-related bleeds. 5,6[9][10] Although the morbidity and mortality of acute gastrointestinal bleeding is lower than intracranial hemorrhage, it frequently necessitates hospitalization and procedures (eg, endoscopy, embolization) and is associated with significant healthcare costs. 11,12Over the next 50 years, the number of patients with atrial fibrillation (the most common indication for OACs) is expected to increase 2.5-fold, making atrial fibrillation and its complications a growing major health problem. 13EVERSE-AD included 137 dabigatran-treated patients with gastrointestinal bleeds judged by treating clinicians as uncontrollable and which were subsequently classified as minor (16%), major (60%), or life-threatening (22%).Idarucizumab (given as two 2.5-g intravenous boluses) rapidly reversed the anticoagulant effect of dabigatran in 98% of patients, an effect that persisted for up to 24 hours in most patients (59%).Given the methodological limitations of an open-label singlecohort study design, the contribution of idarucizumab to promoting and maintaining hemostasis remains uncertain.In the absence of a control group, it is unclear whether idarucizumab (in addition to supportive measures) leads to improved clinical outcomes.Furthermore, there are inherent clinical and methodological challenges in determining the timing of gastrointestinal bleed cessation, in particular, by treating clinicians, as was done in this study.
CPSF1-Mediated Acute Myeloid Leukemia Fusion 3'UTR Alternation Is a Potential Therapeutic Target
Authors: Takahiro Shima, Amanda G Davis, Daniel T Johnson, Yu Kochi, Sayuri Miyauchi, Samuel A Stoner, Junichiro Yuda, Toshihiro Miyamoto, Jie-Hua Zhou, Edward D. Ball, Koichi Akashi, Dong-Er Zhang
Journal: Blood (2018)