tbuckley/cabot-search huggingface dataset:
Hypoplastic Myelodysplastic Syndrome: Clinical, Histopathological and Molecular Characterization
Authors: Elisa Bono, Donal McLornan, Erica Travaglino, Shreyans Gandhi, Anna Gallì, Alesia Abigael Khan, Austin G. Kulasekararaj, Emanuela Boveri, Kavita Raj, Chiara Elena, Robin M. Ireland, Antonio Bianchessi, Jie Jiang, Gabriele Todisco, Luca Malcovati, Judith Marsh, Mario Cazzola, Ghulam Mufti
Journal: Blood (2017)
Realizing highly chemoselective detection of H2S in vitro and in vivo with fluorescent probes inside core-shell silica nanoparticles
Authors: Feiyi Wang, Ge Xu, Xianfeng Gu, Zhijun Wang, Zhiqiang Wang, Ben Shi, Cuifen Lu, Xueqing Gong, Chunchang Zhao
Journal: Biomaterials (2018)
A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia
Authors: Amy Y. Wang, Howard Weiner, Margaret Green, Hua Chang, Noreen Fulton, Richard A. Larson, Olatoyosi Odenike, Andrew S. Artz, Michael R. Bishop, Lucy A. Godley, Michael J. Thirman, Satyajit Kosuri, Jane E. Churpek, Emily Curran, Kristen Pettit, Wendy Stock, Hongtao Liu
Journal: Journal of Hematology & Oncology (2018)

Novel therapies for patients with acute myeloid leukemia (AML) are imperative, particularly for those with high-risk features. Selinexor, an exportin 1 (XPO1/CRM1) inhibitor, has demonstrated anti-leukemia activity as a single agent, as well as in combination with anthracyclines and/or DNA-damaging agents. We report the findings of a phase I dose escalation trial with cohort expansion in 20 patients with newly diagnosed or relapsed/refractory AML that combined selinexor with age-adjusted high-dose cytarabine and mitoxantrone (HiDAC/Mito). Three (15%) patients received the initial dose of 60 mg of selinexor (~ 35 mg/m2), and 17 (85%) received the target level of 80 mg (~ 50 mg/m2). No dose-limiting toxicities were observed. Common adverse events included febrile neutropenia (70%), diarrhea (40%), anorexia (30%), electrolyte abnormalities (30%), bacteremia (25%), cardiac toxicities (25%), fatigue (25%), and nausea/vomiting (25%). None were unexpected given the HiDAC/Mito regimen. Serious adverse events occurred in 6 (30%) patients; one was fatal. Ten (50%) patients achieved a complete remission (CR), 3 (15%) achieved CR with incomplete recovery (CRi), 1 (5%) achieved partial remission (PR), and 6 (30%) had progressive disease for an overall response rate (ORR) of 70%. Eight of 14 (57%) responders proceeded to allogeneic stem cell transplantation. Correlative studies of WT1 levels showed persistently detectable levels in patients who either did not respond or relapsed quickly after induction. The selinexor/HiDAC/Mito regimen is feasible and tolerable at selinexor doses of 80 mg/day (~ 50 mg/m2/day) twice weekly. The recommended phase II dose is 80 mg and warrants further study in this combination. ClinicalTrials.gov , NCT02573363 . Registered October 5, 2015
Endothelial–mesenchymal transition in atherosclerosis
Authors: Celine Souilhol, Martin C Harmsen, Paul C Evans, Guido Krenning
Journal: Cardiovascular Research (2018)

Atherosclerosis is an inflammatory disease resulting in the hardening and thickening of the wall of arteries and the formation of plaques, which comprise immune cells, mesenchymal cells, lipids, and extracellular matrix. The source of mesenchymal cells in the atherosclerotic plaques has been under scrutiny for years. Current endothelial-lineage tracing studies indicate that the endothelium is a source for plaque-associated mesenchymal cells. Endothelial cells can acquire a mesenchymal phenotype through endothelial-mesenchymal transition (EndMT), wherein the expression of endothelial markers and functions is lost and the expression of mesenchymal cell marker and functions acquired. Furthermore, EndMT can result in delamination and migration of endothelial cell-derived mesenchymal cells into the underlying tissue. Here, we review the contribution of EndMT in vascular disease focusing on atherosclerosis and describe the major biochemical and biomechanical signalling pathways in EndMT during atherosclerosis progression. Furthermore, we address how the well-established systemic atherosclerosis risk factors might facilitate EndMT during atherosclerosis.
A dose-escalation study of imipridone ONC201 administered every one (QW) or three weeks (Q3W) in advanced solid tumors and multiple myeloma.
Authors: Anthony J. Olszanski, Efrat Dotan, Michael J. Hall, Margaret vonMehren, Eric A. Ross, Amanda M Viereck, Crystal Shereen Denlinger
Journal: Journal of Clinical Oncology (2017)

2592 Background: ONC201 is an orally active, first-in-class small molecule activator of the integrated stress response that selectively upregulates ATF4 to trigger tumor cell death. A phase I study of ONC201 exploring different dosing regimens and drug exposure was conducted to determine the maximum tolerated dose (MTD), and recommended phase II dose (RP2D). Methods: A modified accelerated-titration dose escalation design was employed to enroll patients onto 2 sequential dose-escalation arms: ONC201 Q3W and QW. Dose escalation proceeded with the following order: 125, 250, 500, and 625mg (Q3W) and 250, 375, 500 and 625 (QW). Dose exposure ranged from 125 mg/6 wks to 1875 mg/3 wks. Key eligibility: advance/refractory solid tumor or myeloma, ECOG 0/1, and no active CNS disease. Adverse events, SAEs, laboratory values, physical exam findings, EKGs and bio-samples (for PK/PD) are collected. Pre and post ONC201 dose biopsies are being obtained from the 500mg weekly cohort and above. Results: 17 pts (12F:5M) with treatment-refractory tumors have been enrolled to date. Dose/#pts Q3W: 125/6, 250/1, 500/1, and 625/1; QW: 250/4, 375/4. Two patients have been enrolled at 500mg QW after database lock and not included in this assessment. Median (range) age: 57 yrs (27-72). ECOG 0/1: 2/15. MTD has not been reached. No DLTs observed. Tumor types: 8 CRC, 3 pancreatic, 2 sarcoma and 1 each cervical, endometrial, NSCLC (adeno) and small bowel. Of 17 pts, 10 (59%) had ≥1 tx-related adverse events (TRAEs), possibly related. Most common TRAEs (≥15% pts): fatigue (9,53%), anorexia (5,29%), nausea (4,24%), vomiting (4,24%), abdominal pain (3,18%), and arthralgias (2,12%). Grade ≥ 3 TRAEs were observed in 3 pts (18%). Pharmacokinetic and pharmacodynamic analysis is ongoing. Fresh frozen and paraffin-embedded biopsies (baseline and week 2) are being assessed for tumor markers implicated in the mechanism of action. No objective responses by RECIST have been seen. Final cohort is enrolling. Conclusions: ONC201 was well tolerated throughout the Q3W dosing and weekly dosing has been well tolerated to date without an apparent increase in AEs. Final enrollment summary, AEs and PK/PD data will be presented. Clinical trial information: NCT02609230.
A Population-Based Study of Chronic Myeloid Leukemia Treated with Imatinib in First Line
Authors: Fausto Castagnetti, Francesco Di Raimondo, Antonio de Vivo, Antonio Spitaleri, Gabriele Gugliotta, Francesco Fabbiano, Isabella Capodanno, Donato Mannina, Marzia Salvucci, Agostino Antolino, Roberto Marasca, Maurizio Musso, Monica Crugnola, Stefana Impera, Elena Trabacchi, Caterina Musolino, Francesco Cavazzini, Giuseppe Mineo, Patrizia Tosi, Carmela Anna Maria Tomaselli, Michele Rizzo, Sergio Siragusa, Miriam Fogli, Riccardo Ragionieri, Alessandro Zironi, Simona Soverini, Giovanni Martinelli, Michele Cavo, Paolo Vigneri, Fabio Stagno, Gianantonio Rosti, Michele Baccarani
Journal: Blood (2016)
Risk of Anaphylaxis during an Oral Food Challenge Increases with Increasing Specific IgE Levels
Authors: Noriyuki Yanagida, Sakura Sato, Kyohei Takahashi, Kenichi Nagakura, Tomoyuki Asaumi, Kiyotake Ogura, Motohiro Ebisawa
Journal: Journal of Allergy and Clinical Immunology (2018)
Response by Trachtenberg and Hare to Letter Regarding the Article, “Inflammatory Cardiomyopathic Syndromes”
Authors: Barry Trachtenberg, Joshua Hare
Journal: Circulation Research (2018)

Thank you Bestetti et al for your interest in our article 1 and for your important letter.Indeed, although antiparasital therapy is clearly recommended for acute Chagas disease and is not recommended for chronic Chagas associated with cardiomyopathy, antiparasital therapy for those with the indeterminate form is controversial.This is largely because of a lack of large, randomized trials in this population.As Bestetti et al point out, most patients have the indeterminate form, and more than one third of these will eventually develop cardiomyopathy.Studies of patients with indeterminate Chagas and no overt cardiomyopathy have detected changes in myocardial perfusion and right ventricular systolic function, for example, at a much higher frequency than would be expected for conversion to the chronic form. 2,3Thus, this suggests that many patients with indeterminate form are at a higher risk for developing cardiac manifestations than appreciated by traditional diagnostic methods.Data from small studies suggest that treated patients with indeterminate Chagas are less likely to develop cardiac manifestations that control. 4ecause of the risk of developing clinical cardiac manifestations, many societies, including the Brazilian Society of Cardiology (Sociedade Brasileira de Cardiologia), have endorsed antiparasital treatment of patients, especially children, with the indeterminate form.Importantly, studies have shown that this approach is cost effective. 5owever, we concur with the authors that guidelines for patients with indeterminate form are not based on large randomized trials.We also share the concerns on the lack of clear evidence on the benefit of therapy and of the potential harmful side effects in attempting to treat all patients in this phase.Hopefully, better tools to predict who may respond to therapy and targeted therapies with less toxicities will be available in the years to come.Thank you for the opportunity to clarify the recommendations.
Childhood malignant diseases associated with neurofibromatosis Type 1: Hacettepe experience.
Authors: M. Tezer Kutluk, Ali Varan, Hilal Susam Sen, Burca Aydin, Bilgehan Yalcin, Canan Akyuz
Journal: Journal of Clinical Oncology (2015)

e21015 Background: To evaluate clinical characteristics and prognosis of patients with NF 1 and malignancy excluding optic glioma. Methods: Between 1975 and 2013, 92 of 473 patients (19%) with NF 1 who were followed up at our center were found to have malignant disease. 67 (14%) of them had optic glioma and in 25 (5%) of them there were other malignant disorders. Files of these 25 patients were analyzed retrospectively in terms of clinical features and treatment results. Results: The male to female ratio of these 25 patients was 16/9. The age of diagnosis of NF 1 was between 3 months-16 years (median 5.5 years) and diagnosis of malignancy at age between was 1.5 - 33 years (median 8), respectively. Sixteen patients were diagnosed with NF1 and malignancy simultaneously. Histological subtypes were 12 soft tissue tumors (6 malignant peripheral nerve sheath tumor (MPNST), five rhabdomyosarcoma and one malignant fibrous histiocytoma), 10 brain tumors (three grade 3-4 astrocytoma or glioblastoma, four astrocytoma, two medulloblastoma and one cervical pilocytic astrocytoma), two neuroblastoma and one non-Hodgkin's lymphoma. Disease was located in the posterior fossa in three patients with brain tumors. Three patients with high grade glioma, onewith non-Hodgkin’s lymphoma, one with medulloblastoma, two with rhabdomyosarcoma, and one with astrocytoma have died with disease progression despite treatment. Five of 6 patients with a diagnosis of MPNST died with disease, one patient diagnosed at age 1.5 years is being followed up in remission during 32 months. Twelve out of 25 patients are still alive. Conclusions: Five percent of the patients with NF1 have developed malignant diseases. The prognosis is poor despite the treatment. Close and regular follow-up is crucial for early detection of malignancy for NF 1.
Abstract 15807: The Changing Epidemiology of Myocardial Infarction in the Population, 1995-2012
Authors: Yariv Gerber, Susan A Weston, Ruoxiang Jiang, Veronique L Roger
Journal: Circulation (2014)

Background: Contemporary data on the epidemiology of myocardial infarction (MI) in the population are limited and derived primarily from cohorts of hospitalized MI patients. We assessed temporal tr...
Abstract 16364: Physician Documentation Behaviors in Electronic Health Records as a Potential Source of Noise for Early Detection of Heart Failure
Authors: Yajuan Wang, Kenney Ng, Jianying Hu, Roy J Byrd, Steven R Steinhubl, Christopher deFilippi, Walter F Stewart
Journal: Circulation (2015)

Introduction: Electronic health records (EHRs) are a potentially rich source of data for developing predictive models for early detection of heart failure (HF). But, EHR documentation can vary both because of patient health and variation in clinical practice and behavior among physicians. Hypothesis: The “noise” contributed by variable physician behaviors, such as differences in the frequency and detail of documentation, could potentially confound predictive models for detection of HF. In this study, we characterized the documentation behaviors of primary care physicians (PCPs) in an effort to better understand this potential source of noise. Methods: We used longitudinal EHR data of a stratified random sample of 5,187 patients who were: 1) ≥50 years of age, and without a history of HF. PCPs (n=144) were identified and paired with the patients that they had treated for a minimum of 6 months. We derived 28 measures to characterize PCP behaviors - documentation frequencies of assertions and denials of selected Framingham HF signs and symptoms (FHFSS) in office visit encounter notes adjusted for patient comorbidities. Hierarchical clustering analyses (HCA) were performed on PCP documentation behaviors. Results: Based on HCA analyses, PCPs were clustered into 3 groups with distinct documentation behaviors. Group 1 PCPs (n=63) documented 10 out of 15 assertions, and 11 out of 13 denials of FHFSS significantly more frequently than Group 3 (n=20); while Group 2 PCPs (n=61) have significantly more frequent denial documentation behaviors than the other two (see Figure 1). No significant differences were found among patients’ chronic, episodic and cardio metabolic chronic disease counts (comorbidities) in each of the groups (p&lt;0.05). Conclusions: This study identified PCP groups with distinct documentation behaviors unrelated to patient complexity. This source of noise and potential confounder should be taken into account for predictive modeling.
Effects of Direct Oral Anticoagulants at the Peak Phase, Trough Phase, and After Vascular Injury
Authors: Sou Otuki, Daisuke Izumi, Masayoshi Suda, Akinori Sato, Yuki Hasegawa, Nobue Yagihara, Kenichi Iijima, Masaomi Chinushi, Ichiro Fuse, Tohru Minamino
Journal: Journal of the American College of Cardiology (2018)
Erratum: Corrigendum: Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance
Authors: Maria Secrier, Xiaodun Li, Nadeera de Silva, Matthew D Eldridge, Gianmarco Contino, Jan Bornschein, Shona MacRae, Nicola Grehan, Maria O'Donovan, Ahmad Miremadi, Tsun-Po Yang, Lawrence Bower, Hamza Chettouh, Jason Crawte, Núria Galeano-Dalmau, Anna Grabowska, John Saunders, Tim Underwood, Nicola Waddell, Andrew P Barbour, Barbara Nutzinger, Achilleas Achilleos, Paul A W Edwards, Andy G Lynch, Simon Tavaré, Rebecca C Fitzgerald
Journal: Nature Genetics (2017)
Loss-of-function mutations in ADCY3 cause monogenic severe obesity
Authors: Sadia Saeed, Amélie Bonnefond, Filippo Tamanini, Muhammad Usman Mirza, Jaida Manzoor, Qasim M. Janjua, Sadia M. Din, Julien Gaitan, Alexandra Milochau, Emmanuelle Durand, Emmanuel Vaillant, Attiya Haseeb, Franck De Graeve, Iandry Rabearivelo, Olivier Sand, Gurvan Queniat, Raphaël Boutry, Dina A. Schott, Hina Ayesha, Muhammad Ali, Waqas I. Khan, Taeed A. Butt, Tuula Rinne, Connie Stumpel, Amar Abderrahmani, Jochen Lang, Muhammad Arslan, Philippe Froguel
Journal: Nature Genetics (2018)
Abstract 15039: ROCK2-Mediated Fibroblast Growth Factor-2 Expression in Cardiac Fibroblasts is Critical for Inducing Cardiac Hypertrophy and Fibrosis
Authors: Toru Shimizu, James K Liao
Journal: Circulation (2016)

Introduction:  Cardiac hypertrophy and fibrosis can often lead to heart failure. Presently, the pathophysiological mechanism underlying the development of cardiac fibrosis is not known. We hypothesized that Rho-associated coiled-coil containing kinase (ROCK)-2 in cardiac fibroblasts (CFs) may be involved in the pathogenesis of cardiac hypertrophy and fibrosis.   Methods and Results:  We developed CF-specific ROCK2-deficient (ROCK2 Postn-/- ) and CF-specific constitutively active ROCK knockin (caROCK Postn-/- ) mice by using fibroblast-specific promoter (Postn) with the Cre/loxP system. Despite comparable increases in systemic blood pressure, angiotensin II (Ang II) infusion (1000ng/kg/min, 28d)-induced cardiac hypertrophy and fibrosis were substantially reduced in ROCK2 Postn-/-  mice and were enhanced in caROCK Postn-/-  mice compared to littermate controls (n=5-10, P Postn-/-  mice and were developed in caROCK Postn-/-  mice compared to littermate controls (n=8-10, P Postn-/-  mice was substantially decreased compared to littermate controls (n=5 each, P   Conclusions:  These findings indicate that ROCK2 in CF is an important mediator of cardiac hypertrophy and fibrosis through the upregulation of CTGF and FGF2. Inhibition of ROCK2 may prevent the deleterious cardiac remodeling associated with elevated Ang II and TGF-β1 levels.
Linking FOXO3, NCOA3, and TCF7L2 to Ras pathway phenotypes through a genome-wide forward genetic screen in human colorectal cancer cells
Authors: Snehangshu Kundu, Muhammad Akhtar Ali, Niklas Handin, Narendra Padhan, Jimmy Larsson, Maria Karoutsou, Kenneth Ban, Jacek R Wiśniewski, Per Artursson, Liqun He, Mats Hellström, Tobias Sjöblom
Journal: Genome Medicine (2018)

The Ras pathway genes KRAS, BRAF, or ERBBs have somatic mutations in ~ 60% of human colorectal carcinomas. At present, it is unknown whether the remaining cases lack mutations activating the Ras pathway or whether they have acquired mutations in genes hitherto unknown to belong to the pathway. To address the second possibility and extend the compendium of Ras pathway genes, we used genome-wide transposon mutagenesis of two human colorectal cancer cell systems deprived of their activating KRAS or BRAF allele to identify genes enabling growth in low glucose, a Ras pathway phenotype, when targeted. Of the 163 recurrently targeted genes in the two different genetic backgrounds, one-third were known cancer genes and one-fifth had links to the EGFR/Ras/MAPK pathway. When compared to cancer genome sequencing datasets, nine genes also mutated in human colorectal cancers were identified. Among these, stable knockdown of FOXO3, NCOA3, and TCF7L2 restored growth in low glucose but reduced MEK/MAPK phosphorylation, reduced anchorage-independent growth, and modulated expressions of GLUT1 and Ras pathway related proteins. Knockdown of NCOA3 and FOXO3 significantly decreased the sensitivity to cetuximab of KRAS mutant but not wild-type cells. This work establishes a proof-of-concept that human cell-based genome-wide forward genetic screens can assign genes to pathways with clinical importance in human colorectal cancer.
AJP at 175: Remembering Our Past as We Envision Our Future
Authors: Robert Freedman
Journal: American Journal of Psychiatry (2018)

This issue initiates our 175th year of continuous of publication.The American Journal of Insanity began publication in 1844 to facilitate sharing of information among superintendents of state mental hospitals.From the first issue, psychiatrists wrote about the numbers of patients they were seeing, interesting brain pathology they had observed, and the latest discussions from Europe on the emerging interest in diagnosis.They regularly discussed problems in the funding of their work by their state legislatures.In 1921 the name of our association was changed to the American Psychiatric Association and the journal was retitled the American Journal of Psychiatry, with a sense of optimism that psychiatry was now better integrated into the general care of the mental problems of people in American communities.These themes-diagnosis and treatment, funding, and integration-continue to be major concerns for psychiatrists and for the Journal in its 175th year.The Editorial Board and I decided that looking at our past, fascinating though it can be, should not be the focus of our 175th year commemoration.We thought instead that the 175th year should look forward to what the next 25 years might accomplish.To that end, we have solicited Review and Overview articles for this year's issues that provide perspective on what has been learned and where it might take us in the understanding and treatment of mental disorders.The first in this series, by Patrick Sullivan and his colleagues of the Psychiatric Genomics Collaboration (1), indeed provides their view of what has been accomplished and their vision of the impact that it can have in the future.Review articles in subsequent issues will focus on a variety of issues, ranging from childhood behavioral problems to cognitive problems in the elderly.We do not entirely neglect our history, however, and the series will include an accounting of the reaction to Kraepelin's ideas on diagnosis during his lifetime, both in Europe and in the United States, covering issues still relevant to diagnosis today.Each "AJP at 175" Review will have a special logo and will highlight a citation to an earlier Journal article, to allow readers to see the continuity to what was learned in the past.Although we have Reviews coming from many of the major areas within our field, it would be impossible to cover every mental illness from each of its many perspectives.Colleagues worldwide in all fields and
Direct Comparison of Anti-CD33 and Anti-CD123 Chimeric Antigen Receptor T Cells with CD28 or 41BB Co-Stimulatory Domains for Treatment of Acute Myeloid Leukemia
Authors: Samiksha Tarun, Haiying Qin, Lila Yang, Christopher Daniel Chien, Mark Eric Kohler, Terry J. Fry
Journal: Blood (2017)
Role of thiopurines as disease-modifying agents in Crohn’s disease
Authors: Jonathan Blackwell, Sonia Saxena, Richard C Pollok
Journal: Gut (2018)

We agree with Danese et al 1 that prospective studies to evaluate the disease-modifying action of antitumour necrosis factor (anti-TNF) drugs are overdue. As a counterpoint to this informative review, we would like to highlight some additional evidence for the role of thiopurines as disease-modifying agents in Crohn’s disease. A cohort study by Magro et al 2 supports a role for thiopurines in delaying phenotype progression from an inflammatory (B1) to a stricturing/penetrating (B2/B3) disease (HR 0.15, 95% CI 0.11 to 0.19). A meta-analysis of 10 …
Management of Sentinel-Node Metastasis in Melanoma
Authors: Lisa Caulley, Charles M. Balch, Merrick I. Ross, Caroline Robert
Journal: New England Journal of Medicine (2018)

This interactive feature about melanoma with sentinel lymph-node metastasis offers a case vignette accompanied by essays that support either recommending or not recommending completion lymph-node dissection to improve disease control and provide precise staging.
APTO-253 Interaction with G-Quadruplex DNA Is Linked to Inhibition of c-Myc Expression, Induction of DNA Damage, and Generation of Synthetic Lethality in Cells with BRCA1/2 Impairment
Authors: Andrea Local, Hongying Zhang, Khalid Benbatoul, Peter Folger, Susan Sheng, Cheng-Yu Tsai, Stephen Howell, William Rice
Journal: Blood (2017)