tbuckley/cabot-search huggingface dataset:
Myelodysplastic syndromes: 2018 update on diagnosis, risk‐stratification and management
Authors: Guillermo Montalban‐Bravo, Guillermo Garcia‐Manero
Journal: American Journal of Hematology (2017)

Abstract Disease overview The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older males and in individuals with prior exposure to cytotoxic therapy. Diagnosis Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry or molecular genetics is usually complementary and may help refine diagnosis. Risk‐stratification Prognosis of patients with MDS can be calculated using a number of scoring systems. In general, all these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the bone marrow and cytogenetic characteristics. The most commonly used system is probably the International Prognostic Scoring System (IPSS). IPSS is now replaced by the revised IPSS‐R score. Although not systematically incorporated into new validated prognostic systems, somatic mutations can help define prognosis and should be considered as new prognostic factors. Risk‐adapted therapy Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts and cytogenetic and mutational profiles. Goals of therapy are different in lower risk patients than in higher risk. In lower risk, the goal is to decrease transfusion needs and transformation to higher risk disease or AML, as well as to improve survival. In higher risk, the goal is to prolong survival. Current available therapies include growth factor support, lenalidomide, hypomethylating agents, intensive chemotherapy and allogeneic stem cell transplantation. The use of lenalidomide has significant clinical activity in patients with lower risk disease, anemia and a chromosome 5 alteration. 5‐azacitidine and decitabine have activity in both lower and higher‐risk MDS. 5‐azacitidine has been shown to improve survival in higher risk MDS. A number of new molecular lesions have been described in MDS that may serve as new therapeutic targets or aid in the selection of currently available agents. Additional supportive care measures may include the use of prophylactic antibiotics and iron chelation. Management of progressive or refractory disease At the present time there are no approved interventions for patients with progressive or refractory disease particularly after hypomethylating based therapy. Options include participation in a clinical trial or cytarabine based therapy and stem cell transplantation.
Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome
Authors: Elizabeth M. Berry-Kravis, Lothar Lindemann, Aia E. Jønch, George Apostol, Mark F. Bear, Randall L. Carpenter, Jacqueline N. Crawley, Aurore Curie, Vincent Des Portes, Farah Hossain, Fabrizio Gasparini, Baltazar Gomez-Mancilla, David Hessl, Eva Loth, Sebastian H. Scharf, Paul P. Wang, Florian Von Raison, Randi Hagerman, Will Spooren, Sébastien Jacquemont
Journal: Nature Reviews Drug Discovery (2017)
Checkpoint modulation in chronic hepatitis B: From hypothesis to approval
Authors: Georgios Germanidis, Prodromos Hytiroglou, Themistoklis Vassiliadis, Matthaios Speletas
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. TO THE EDITOR: We read with great interest the article by A.S. Lok et al.,1 and we would like to address some issues regarding possible future use of checkpoint modulation in chronic hepatitis B (CHB). Recently, it was described that the proliferative burst after PD‐1 blockade comes almost exclusively from a specific CD8+ T‐cell subset, expressing the transcription factor, TCF1.2 Germline heterozygous mutations of CTLA‐4 in subjects with severe immune dysregulation from four unrelated families were identified.3 Human CTLA‐4 haploinsufficiency caused dysregulation of FoxP3+ regulatory T (Treg) cells, hyperactivation of effector T cells, severe immunoregulatory disorder, and autoimmune lymphocytic infiltration of target organs. Affected patients had reduced CTLA‐4 protein (similarly as to use a neutralizing CTLA‐4 antibody) and mRNA expression in sorted Treg cells relative to healthy donors; this reduction persisted after activation.3 These results demonstrate the complex spectrum of clinical complications that can be anticipated from CTLA‐4–blocking drugs. In the HBeAg‐negative CHB disease model, most patients in current clinical practice are maintained on continuous antiviral treatment in a long‐term remission state. In this most common clinical case scenario, we have found that the expression of FOXP3, IL10, TGFB1, PD1, PDL1, FASL, and CD8 was significantly down‐regulated in the remission state.4 Moreover, FOXP3, PD1, PDL1, and CD8 transcripts were positively correlated with the intensity of liver inflammation. However, it is still uncertain whether the expression of PDL1 on hepatocytes truly contributes to the development of T‐cell exhaustion or whether it is a homoeostatic mechanism that dampens the inflammatory reaction.4 Therefore, the targeting of Tregs and/or PD1/PDL1 pathway in the acute, or the early chronic HBV infection setting, may trigger autoimmune phenomena or increase immune‐mediated liver damage. These findings provide a better understanding of the mechanisms that regulate CD8+ T‐cell responses during CHB and may have implications for the optimization of CTLA‐4/PD‐1‐directed immunotherapy in the future that could restore function in exhausted CD8+ T cells. Such therapy needs to be delivered in the proper phase of the disease, when the liver expression of the molecules is high, and can target a specific cell subset, such as the TCF1‐expressing CD8+ T‐cells, avoiding at the same time disruption of the immune regulation by FoxP3+ Treg cells, that might promote autoimmunity.
Genomic risk prediction of aromatase inhibitor-related arthralgias (AIA) in breast cancer (BC) patients using a novel analytical algorithm (NAA).
Authors: Raquel E. Reinbolt, Stephen T. Sonis, Cynthia Dawn Timmers, Juan Luis Fernández-Martínez, Enrique J. deAndrés-Galiana, Sepehr Hashemi, Karin Miller, Bhuvaneswari Ramaswamy, Robert Wesolowski, Anne M. Noonan, Shabana Jaynul Dewani, Nicole Olivia Williams, Sagar D. Sardesai, Robert Pilarski, Maryam B. Lustberg
Journal: Journal of Clinical Oncology (2017)

10102 Background: Many BC patients treated with aromatase inhibitors (AIs) develop AIA; 20% have symptoms severe enough to effect treatment compliance. Results of candidate gene studies to identify AIA risk are limited in scope. In this case-controlled study, we evaluated the potential of a NAA to predict AIA using germline single nucleotide polymorphism (SNP) data obtained prior to treatment initiation. Methods: Systematic chart review of 700 AI-treated patients with stage I-III BC between 2003-2012 identified asymptomatic patients (n = 39) and those with clinically significant AIA resulting in AI termination or therapy switch (n = 123). Germline DNA was obtained from peripheral blood cells and SNP genotyping performed using the Affymetrix UK BioBank Axiom Array to yield 695,277 SNPs. The identity of the cluster of SNPs that most closely defined AIA risk was discovered using an NAA that sequentially combined statistical filtering and a machine learning algorithm. NCBI PhenGenI and Ensemble databases were used to define gene attribution of the 200 most discriminating SNPs. Phenotype, pathway, and ontologic analyses assessed functional and mechanistic validity. Results: Cases and controls were similar in demographic characteristics. A cluster of 70 SNPs, correlated to 57 genes (accounting for linkage disequilibrium), was identified. This SNP group predicted AIA occurrence with a maximum accuracy of 75.93%. Strong associations with arthralgia, breast cancer, and estrogen phenotypes were seen in 19/57 genes (33%) and were functionally and ontologically consistent. Conclusions: Using a NAA, we identified a 70 SNP cluster that predicted AIA risk with fair accuracy. Phenotype, functional, and pathway analysis of attributed genes was consistent with clinical phenotypes. This study is the first to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias. An ongoing prospective companion study will be used to validate and to expand upon results.
Organ-specific lymphatic vasculature: From development to pathophysiology
Authors: Tatiana V. Petrova, Gou Young Koh
Journal: The Journal of Experimental Medicine (2017)

Recent discoveries of novel functions and diverse origins of lymphatic vessels have drastically changed our view of lymphatic vasculature. Traditionally regarded as passive conduits for fluid and immune cells, lymphatic vessels now emerge as active, tissue-specific players in major physiological and pathophysiological processes. Lymphatic vessels show remarkable plasticity and heterogeneity, reflecting their functional specialization to control the tissue microenvironment. Moreover, alternative developmental origins of lymphatic endothelial cells in some organs may contribute to the diversity of their functions in adult tissues. This review aims to summarize the most recent findings of organotypic differentiation of lymphatic endothelial cells in terms of their distinct (patho)physiological functions in skin, lymph nodes, small intestine, brain, and eye. We discuss recent advances in our understanding of the heterogeneity of lymphatic vessels with respect to the organ-specific functional and molecular specialization of lymphatic endothelium, such as the hybrid blood-lymphatic identity of Schlemm’s canal, functions of intestinal lymphatics in dietary fat uptake, and discovery of meningeal lymphatic vasculature and perivascular brain lymphatic endothelial cells.
Benefits, Limitations, and Value of Abuse-Deterrent Opioids
Authors: Gregory D. Curfman, Leo Beletsky, Ameet Sarpatwari
Journal: JAMA Internal Medicine (2017)

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
The EUROSKI biomarker study: Analyzing the mechanisms of treatment-free remission in chronic myeloid leukemia
Authors: R. Sébastien, C. Sticht, M. Pfirrmann, D. Nowak, A. Fabarius, W. Seifarth, B. Spiess, P. Panayiotidis, M. Pagoni, M. Dimou, J. Dengler, C.F. Waller, T.H. Brümmendorf, A. Burchert, G. Freunek, W-K. Hofmann, F-X. Mahon, S. Saussele
Journal: Annals of Oncology (2017)
Merkel Cell Carcinoma Patients Presenting Without a Primary Lesion Have Elevated Markers of Immunity, Higher Tumor Mutation Burden, and Improved Survival
Authors: Natalie Vandeven, Christopher W. Lewis, Vladimir Makarov, Nadeem Riaz, Kelly G. Paulson, Daniel Hippe, Amy Bestick, Ryan Doumani, Tessa Marx, Seesha Takagishi, Timothy A. Chan, Jaehyuk Choi, Paul Nghiem
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Patients presenting with nodal Merkel cell carcinoma without an identifiable (unknown) primary lesion (MCC-UP) are nearly twice as likely to survive compared with similarly staged patients with known primary lesions (MCC-KP). The basis of this previously reported finding is unclear. Experimental Design: Survival analyses and markers of immunity were evaluated in 123 patients with advanced MCC. Whole-exome sequence data were analyzed from 16 tumors. Results: As in prior studies, patients with nodal MCC-UP had strikingly improved MCC-specific survival as compared with MCC-KP patients (HR, 0.297; P &amp;lt; 0.001). Surprisingly, patients presenting with distant metastatic MCC-UP also had significantly improved survival (HR, 0.296; P = 0.038). None of the 72 patients with MCC-UP were immunosuppressed as compared to 12 of the 51 (24%) patients with MCC-KP (P &amp;lt; 0.001). Merkel polyomavirus oncoprotein antibody median titer was higher in MCC-UP patients (26,229) than MCC-KP patients (3,492; P &amp;lt; 0.001). In addition, the median number of nonsynonymous exome mutations in MCC-UP tumors (688 mutations) was markedly higher than MCC-KP tumors (10 mutations, P = 0.016). Conclusions: This is the first study to our knowledge to explore potential underlying immune-mediated mechanisms of MCC-UP presentation. In this cohort, MCC-UP patients were never immune suppressed, had higher oncoprotein antibody titers, and higher tumor mutational burdens. In addition, we show that nodal tumors identified in MCC-UP patients did indeed arise from primary skin lesions as they contained abundant UV-signature mutations. These findings suggest that stronger underlying immunity against MCC contributes to primary lesion elimination and improved survival. Clin Cancer Res; 24(4); 963–71. ©2017 AACR.
A Rapid Irregular Rhythm in a Healthy, Young Patient
Authors: Arvind Nishtala, Salman Rahman, Nora Goldschlager
Journal: JAMA Internal Medicine (2017)

A healthy woman in her 20s presented to the emergency department with palpitations, a heart rate of 200 beats per minute, and normal heart sounds with no murmurs, rubs, or gallops after completing a run.
Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma
Authors: Alex F. Herrera, Alison J. Moskowitz, Nancy L. Bartlett, Julie M. Vose, Radhakrishnan Ramchandren, Tatyana A. Feldman, Ann S. LaCasce, Stephen M. Ansell, Craig H. Moskowitz, Keenan Fenton, Carol Anne Ogden, David Taft, Qu Zhang, Kazunobu Kato, Mary Campbell, Ranjana H. Advani
Journal: Blood (2017)
Immunological Serum Protein Profiles for Noninvasive Detection of Acute Cellular Rejection After Heart Transplantation
Authors: Ihdina Sukma Dewi, Olof Gidlöf, Zsuzsanna Hollander, Karen K. Lam, Mark D. Benson, Oscar O. Braun, Johan Nilsson, Scott J. Tebbutt, Raymond T. Ng, Jenny Öhman, Bruce M. McManus, J. Gustav Smith
Journal: Journal of the American College of Cardiology (2017)
A model including sarcopenia surpasses the MELD score in predicting waiting list mortality in cirrhotic liver transplant candidates: A competing risk analysis in a national cohort
Authors: Jeroen Laurens Ad van Vugt, Louise Johanna Maria Alferink, Stefan Buettner, Marcia Patricia Gaspersz, Daphne Bot, Sarwa Darwish Murad, Shirin Feshtali, Peter Martinus Adranius van Ooijen, Wojciech Grzegorz Polak, Robert Jack Porte, Bart van Hoek, Aad Pieter van den Berg, Herold J Metselaar, Jan Nicolaas Maria IJzermans
Journal: Journal of Hepatology (2017)
“It takes two to know one” – Tongue protrusion-retraction is only one small facet of early intersubjectivity
Authors: Kenneth J. Aitken
Journal: Behavioral and Brain Sciences (2017)

Abstract Tongue protrusion-retraction is critical to early nutrition but is also a gustatory-olfactory aspect of early infant social behaviour that is, in part, reliant on pre-natal exposure and learning. Most early development is necessarily dyadic and intrinsically associated with other aspects of social functioning.
Hypoxia-induced upregulation of BMX kinase mediates therapeutic resistance in acute myeloid leukemia
Authors: Jolieke G. van Oosterwijk, Daelynn R. Buelow, Christina D. Drenberg, Aksana Vasilyeva, Lie Li, Lei Shi, Yong-Dong Wang, David Finkelstein, Sheila A. Shurtleff, Laura J. Janke, Stanley Pounds, Jeffrey E. Rubnitz, Hiroto Inaba, Navjotsingh Pabla, Sharyn D. Baker
Journal: Journal of Clinical Investigation (2017)

Oncogenic addiction to the Fms-like tyrosine kinase 3 (FLT3) is a hallmark of acute myeloid leukemia (AML) that harbors the FLT3–internal tandem duplication (FLT3-ITD) mutation. While FLT3 inhibitors like sorafenib show initial therapeutic efficacy, resistance rapidly develops through mechanisms that are incompletely understood. Here, we used RNA-Seq–based analysis of patient leukemic cells and found that upregulation of the Tec family kinase BMX occurs during sorafenib resistance. This upregulation was recapitulated in an in vivo murine FLT3-ITD–positive (FLT3-ITD+) model of sorafenib resistance. Mechanistically, the antiangiogenic effects of sorafenib led to increased bone marrow hypoxia, which contributed to HIF-dependent BMX upregulation. In in vitro experiments, hypoxia-dependent BMX upregulation was observed in both AML and non-AML cell lines. Functional studies in human FLT3-ITD+ cell lines showed that BMX is part of a compensatory signaling mechanism that promotes AML cell survival during FLT3 inhibition. Taken together, our results demonstrate that hypoxia-dependent upregulation of BMX contributes to therapeutic resistance through a compensatory prosurvival signaling mechanism. These results also reveal the role of off-target drug effects on tumor microenvironment and development of acquired drug resistance. We propose that the bone marrow niche can be altered by anticancer therapeutics, resulting in drug resistance through cell-nonautonomous microenvironment-dependent effects.
Functional Metabolomics Characterizes a Key Role for <i>N</i> -Acetylneuraminic Acid in Coronary Artery Diseases
Authors: Lei Zhang, Ting-Ting Wei, Yong Li, Jing Li, Yong Fan, Feng-Qing Huang, Yuan-Yuan Cai, Gaoxiang Ma, Jin-Feng Liu, Qian-Qian Chen, Shi-Lei Wang, Honglin Li, Raphael N. Alolga, Baolin Liu, Dong-Sheng Zhao, Jian-Hua Shen, Xiang-Ming Wang, Wei Zhu, Ping Li, Lian-Wen Qi
Journal: Circulation (2017)

Background: As new biomarkers of coronary artery diseases (CAD) emerge via metabolomics, the underlying functional mechanisms remain to be elucidated. Functional metabolomics aims to translate metabolomics-derived biomarkers to disease mechanisms. Methods: A cohort of 2324 patients who underwent coronary angiography from 4 independent centers was studied. A combination of ultra–performance liquid chromatography and quadrupole time-of-flight mass spectrometry in the negative ion mode was used for untargeted analysis of metabolites in plasma. Significant differential metabolites were identified by cross-comparisons with and within CAD types, including normal coronary artery, nonobstructvie coronary atherosclerosis, stable angina, unstable angina, and acute myocardial infarction. A tandem liquid chromatography-mass spectrometry–based approach using isotope-labeled standard addition was subsequently performed for targeted analysis of the metabolic marker N -acetylneuraminic acid (Neu5Ac). A functional metabolomics strategy was proposed to investigate the role of Neu5Ac in the progression of CAD by using in vitro and in vivo models. Results: We identified a total of 36 differential metabolites, 35 of which were confirmed with reference compounds. Elevation of Neu5Ac was observed in plasma during CAD progression in center 1 ( P =4.0e-64, n=2019) and replicated in 3 independent centers (n=305). The increased level of Neu5Ac in plasma was confirmed by accurate targeted quantification. Mechanistically, Neu5Ac was able to trigger myocardial injury in vitro and in vivo by activation of the Rho/Rho-associated coiled-coil containing protein kinase signaling pathway through binding to RhoA and Cdc42, but not Rac1. Silencing neuraminidase-1, the enzyme that regulates Neu5Ac generation, ameliorated oxygen-glucose deprivation–induced injury in cardiomyocytes and ligation/isoprenaline-induced myocardial ischemia injury in rats. Pharmacological inhibition of neuraminidase by anti-influenza drugs, oseltamivir and zanamivir, also protected cardiomyocytes and the heart from myocardial injury. Conclusions: Functional metabolomics identified a key role for Neu5Ac in acute myocardial infarction, and targeting neuraminidase-1 may represent an unrecognized therapeutic intervention for CAD.
Abstract 15338: A Novel Approach to Tailor Heparin Dosage During Ablation of Atrial Fibrillation: An Assessment of Sensitivity to Unfractionated Heparin
Authors: Akinori Sairaku, Yukiko Nakano, Yasuki Kihara
Journal: Circulation (2016)

Background:  Heparinization during ablation of atrial fibrillation (AF) is not necessarily easy due to individual variations in the sensitivity to heparin. We aimed to develop an approach for determining heparin requirements quickly during AF ablation.   Methods and Results:  Patients skipped the last dose of novel anticoagulants (NOACs) before AF ablation (dabigatran 150 mg BID, N=110; apixaban 5 mg BID, N=92; rivaroxaban 15 mg QD, N=75), and were given an overnight unfractionated heparin bridging at an administration rate of 10000 U/24h. The ACT was measured just before the initial heparin injection (baseline ACT) and thereafter every 10 minutes. A bolus of heparin was infused based on each measurement result. No intergroup differences were noted in the baseline ACT, time to achieve a target ACT (300 msec), and total heparin requirement. We created a multiple logistic model to determine the ACT measured after an initial heparin injection (2 nd  ACT), in which the baseline ACT (β=0.7; P  2 =0.6). The 2 nd  ACT within ±50 sec of the target ACT was achieved in 82.0% of the patients by applying an inverse prediction with this logistic model.   Conclusion:  The interpatient variation in the baseline ACT may reflect the sensitivity to unfractionated heparin in each individual. Measuring the ACT after an overnight heparin bridging thus may be helpful to determine the initial heparin dosage.
Primary Biliary Cirrhosis
Authors: Stephen P. James
Journal: New England Journal of Medicine (1985)

Primary biliary cirrhosis has been a challenge to physicians since its initial description over 100 years ago. Over the years many observations have been published that have defined the disease more precisely, medical management of symptoms has improved, and hepatic transplantation now offers the hope of long-term survival to patients who would otherwise die from end-stage liver disease. However, the fundamental challenge has not changed: the origin and pathogenesis of the disease are still unknown, and no medical treatment is available that prolongs survival.Primary biliary cirrhosis is a syndrome that usually has an insidious onset in middle-aged women who . . .