tbuckley/cabot-search huggingface dataset:
Use of multidimensional composite scores in rheumatology: parsimony versus subtlety
Authors: Robert B M Landewé, Désirée van der Heijde
Journal: Annals of the Rheumatic Diseases (2020)

Rheumatic and musculoskeletal diseases (RMDs) form a diverse group of diseases. Proper disease assessment is pivotal, for instance to make treatment choices and for optimising outcome in general. RMDs are multidimensional diseases, entrenching many, sometimes very different aspects. Composite outcome measures (‘composites’) have become very popular to assess RMDs, because of their claim to catch all relevant dimensions of the disease into one convenient measure. In this article we discuss dimensionality of RMDs in the context of the most popular conceptual framework of RMDs, being an inflammatory process leading to some sort of damage over time. We will argue that multidimensionality not only refers to heterogeneity in disease manifestations, but also to heterogeneity in possible outcomes. Unlike most unidimensional measures, multidimensional composites may include several disease manifestations as well as several outcome dimensions into one index. We will discuss fundamental problems of multidimensional composites in light of modern strategies such as treat-to-target and personalised medicine. Finally, we will disentangle the use of multidimensional composites in clinical trials versus their use in clinical practice, and propose simple solutions in order to overcome problems of multidimensionality and to avoid harm to our patients due to overtreatment.
New possible silver lining for pancreatic cancer therapy: Hydrogen sulfide and its donors
Authors: Xu Hu, Yan Xiao, Jianan Sun, Bao Ji, Shanshan Luo, Bo Wu, Chao Zheng, Peng Wang, Fanxing Xu, Keguang Cheng, Huiming Hua, Dahong Li
Journal: Acta Pharmaceutica Sinica B (2020)

As one of the most lethal diseases, pancreatic cancer shows a dismal overall prognosis and high resistance to most treatment modalities. Furthermore, pancreatic cancer escapes early detection during the curable period because early symptoms rarely emerge and specific markers for this disease have not been found. Although combinations of new drugs, multimodal therapies, and adjuvants prolong survival, most patients still relapse after surgery and eventually die. Consequently, the search for more effective treatments for pancreatic cancer is highly relevant and justified. As a newly re-discovered mediator of gasotransmission, hydrogen sulfide (H2S) undertakes essential functions, encompassing various signaling complexes that occupy key processes in human biology. Accumulating evidence indicates that H2S exhibits bimodal modulation of cancer development. Thus, endogenous or low levels of exogenous H2S are thought to promote cancer, whereas high doses of exogenous H2S suppress tumor proliferation. Similarly, inhibition of endogenous H2S production also suppresses tumor proliferation. Accordingly, H2S biosynthesis inhibitors and H2S supplementation (H2S donors) are two distinct strategies for the treatment of cancer. Unfortunately, modulation of endogenous H2S on pancreatic cancer has not been studied so far. However, H2S donors and their derivatives have been extensively studied as potential therapeutic agents for pancreatic cancer therapy by inhibiting cell proliferation, inducing apoptosis, arresting cell cycle, and suppressing invasion and migration through exploiting multiple signaling pathways. As far as we know, there is no review of the effects of H2S donors on pancreatic cancer. Based on these concerns, the therapeutic effects of some H2S donors and NO-H2S dual donors on pancreatic cancer were summarized in this paper. Exogenous H2S donors may be promising compounds for pancreatic cancer treatment.
Tazemetostat Is Associated with Lower Risk for Safety Outcomes Versus the PI3-Kinases Idelalisib, Duvelisib and Copanlisib, in Patients with Relapsed/Refractory Follicular Lymphoma Who Have Received at Least 2 Prior Systemic Treatments: A Matching-Adjusted Indirect Comparison of Single-Arm Trials
Authors: David Proudman, Dave Nellesen, Deepshekhar Gupta, Deyaa Adib, Jay Yang, Michael Keith, Khalid Mamlouk
Journal: Blood (2020)
Mutant Kras co-opts a proto-oncogenic enhancer network in inflammation-induced metaplastic progenitor cells to initiate pancreatic cancer
Authors: Yong Li, Yi He, Junya Peng, Zhendong Su, Zeyao Li, Bingjie Zhang, Jing Ma, Meilian Zhuo, Di Zou, Xinde Liu, Xinhong Liu, Wenze Wang, Dan Huang, Mengyue Xu, Jianbin Wang, Haiteng Deng, Jing Xue, Wei Xie, Xun Lan, Mo Chen, Yupei Zhao, Wenming Wu, Charles J. David
Journal: Nature Cancer (2020)
Efficacy and Safety of Idecabtagene Vicleucel (ide-cel, bb2121) in Elderly Patients with Relapsed and Refractory Multiple Myeloma: KarMMa Subgroup Analysis
Authors: Jesus G. Berdeja, Noopur S. Raje, David S. Siegel, Yi Lin, Larry D. Anderson, Paula Rodriguez-Otero, Salomon Manier, Hermann Einsele, Michele Cavo, Anna Truppel-Hartmann, Everton Rowe, Jill Sanford, Julie Wang, Timothy B. Campbell, Sundar Jagannath
Journal: Blood (2020)
Efficacy of Circulating Tumor Cell Count–Driven vs Clinician-Driven First-line Therapy Choice in Hormone Receptor–Positive, ERBB2-Negative Metastatic Breast Cancer
Authors: François-Clément Bidard, William Jacot, Nicolas Kiavue, Sylvain Dureau, Amir Kadi, Etienne Brain, Thomas Bachelot, Hugues Bourgeois, Anthony Gonçalves, Sylvain Ladoire, Hervé Naman, Florence Dalenc, Joseph Gligorov, Marc Espié, George Emile, Jean-Marc Ferrero, Delphine Loirat, Sophie Frank, Luc Cabel, Véronique Diéras, Laure Cayrefourcq, Cécile Simondi, Frédérique Berger, Catherine Alix-Panabières, Jean-Yves Pierga
Journal: JAMA Oncology (2020)

The choice between chemotherapy and endocrine therapy as first-line treatment for hormone receptor-positive, ERBB2 (also known as HER2)-negative metastatic breast cancer is usually based on the presence of clinical features associated with a poor prognosis. In this setting, a high circulating tumor cell (CTC) count (≥5 CTCs/7.5 mL) is a strong adverse prognostic factor for overall survival and progression-free survival (PFS).To compare the efficacy of a clinician-driven treatment choice vs a CTC-driven choice for first-line treatment.In the CTC arm, patients received chemotherapy or endocrine therapy according to the CTC count (chemotherapy if ≥5 CTCs/7.5 mL; endocrine therapy if <5 CTCs/7.5 mL), whereas in the control arm, the choice was left to the investigator.In the STIC CTC randomized, open-label, noninferiority phase 3 trial, participants were randomized to a clinician-driven choice of first-line treatment or a CTC count-driven first-line treatment choice. Eligible participants were premenopausal and postmenopausal women 18 years or older diagnosed with hormone receptor-positive, ERBB2-negative metastatic breast cancer. Data were collected at 17 French cancer centers from February 1, 2012, to July 28, 2016, and analyzed June 2019 to October 2019.The primary end point was the investigator-assessed PFS in the per-protocol population, with a noninferiority margin of 1.25 for the 90% CI of the hazard ratio.Among the 755 women in the per-protocol population, the median (range) age was 63 (30-88) years [64 (30-88) years for the 377 patients allocated to the CTC arm and 63 (31-87) years for the 378 patients allocated to the standard arm]; 138 (37%) and 103 (27%) received chemotherapy, respectively. Median PFS was 15.5 months (95% CI, 12.7-17.3) in the CTC arm and 13.9 months (95% CI, 12.2-16.3) in the standard arm. The primary end point was met, with a hazard ratio of 0.94 (90% CI, 0.81-1.09).This randomized clinical trial found that the CTC count may be a reliable biomarker method for guiding the choice between chemotherapy and endocrine therapy as the first-line treatment in hormone receptor-positive, ERBB2-negative metastatic breast cancer.ClinicalTrials.gov Identifier: NCT01710605.
Ultra-Deep Targeted Sequencing Reveals Cancer-Associated, Prognostically Significant Mutations in Circulating Cell-Free DNA in Treatment-Naive Patients with Follicular Lymphoma
Authors: Tevfik Hatipoğlu, Esra Esmeray, Xiaozhou Hu, Hongling Yuan, Ayça Erşen Danyeli, Ahmet Şeyhanlı, Tuğba Önal Süzek, Weiwei Zhang, Aybüke Olgun, Burcu Akman, Sermin Özkal, Hua You, ¡nci Alacacıoğlu, Mehmet Ali Özcan, Can Kucuk
Journal: Blood (2020)
Covid-19: Hospital discharges during pandemic were often chaotic, says watchdog
Authors: David Oliver
Journal: BMJ (2020)

Many patients discharged from hospitals in England in the past six months under new arrangements to free up beds did not get the follow-up support they needed, concludes a report from HealthWatch, which represents patients' interests in England. 1 Department of Health and Social Care.Coronavirus (covid-19): hospital discharge service requirements.
Paleo-polyploidization in Lycophytes
Authors: Jinpeng Wang, Jigao Yu, Pengchuan Sun, Chao Li, Xiaoming Song, Tianyu Lei, Yuxian Li, Jiaqing Yuan, Sangrong Sun, Hongling Ding, Xueqian Duan, Shaoqi Shen, Yanshuang Shen, Jing Li, Fanbo Meng, Yangqin Xie, Jianyu Wang, Yue Hou, Jin Zhang, Xianchun Zhang, Xiu-Qing Li, Andrew H. Paterson, Xiyin Wang
Journal: Genomics Proteomics & Bioinformatics (2020)

Abstract Lycophytes and seed plants constitute the typical vascular plants. Lycophytes have been thought to have no paleo-polyploidization although the event is known to be critical for the fast expansion of seed plants. Here, genomic analyses including the homologous gene dot plot analysis detected multiple paleo-polyploidization events, with one occurring approximately 13–15 million years ago (MYA) and another about 125–142 MYA, during the evolution of the genome of Selaginella moellendorffii, a model lycophyte. In addition, comparative analysis of reconstructed ancestral genomes of lycophytes and angiosperms suggested that lycophytes were affected by more paleo-polyploidization events than seed plants. Results from the present genomic analyses indicate that paleo-polyploidization has contributed to the successful establishment of both lineages—lycophytes and seed plants—of vascular plants.
Assay Interference By Emicizumab in Aptt and Chromogenic Based FVIII:C and Inhibitor Assays
Authors: Brian F Poirier, Mary Robinson, Stefan Tiefenbacher, Erin McEwan, Caroline Cogswell, Roxy Gode, Emily Burger, Tyler Allison, Jennifer Littlefield, Amanda Pikas, Andrea Schmoker
Journal: Blood (2020)
Response to Collinson et al. Comment
Authors: Miriam Belmonte, Nina F. Øbro, David G. Kent
Journal: HemaSphere (2020)

In response to our recent paper which identified GRO-α, EGF and Eotaxin as potential biomarkers in chronic phase myeloproliferative neoplasms,1 Collinson et al explored one of the possible cellular sources of these molecules by measuring levels of transcripts produced (and stored) within platelet granules.2 Mutant megakaryocytes and platelets have been previously implicated in MPN pathogenesis, including in the fibrotic processes which is associated with poor prognosis.3,4 In line with our data, high EGF transcript levels were observed in platelets from essential thrombocythemia (ET) and polycythemia vera (PV) patients. On the other hand, GRO-α transcript levels in platelets were highest in myelofibrosis (MF) patients whereas our study reported that high GRO-α was present in chronic phase patients who eventually transformed to MF in samples taken prior to treatment initiation. Assuming that the Collinson et al. samples were also collected prior to treatment, there are several possible explanations for this discrepancy. First, it could be due to transcript levels not mirroring protein levels, as has been described previously in hematopoietic cells.5 Second, while the relative amounts of transcript might be highest in platelets, it is possible that the bulk of GRO-α is produced by other cell types, thereby minimizing the impact of relative changes in one cellular fraction. Finally, as suggested by the authors, platelet “exhaustion” or failed production in MF patients could contribute to differences. Irrespective of the underlying reason, the Collinson et al report emphasizes the importance of characterizing the sources of GRO-α in order to identify the arbiters of the inflammatory cytokine phenotype observed in numerous MPNs. Antibody stains in tissue sections, spatial transcriptomic analysis,6 or further proteomic profiling might help resolve the cellular drivers of disease. Overall, this study extends our examination of the cellular drivers responsible for different cytokine levels across MPN subtypes, surveying platelets as a potential mediator of these differences. It is exciting to see additional research in this space which reaches beyond the simple identification of potential biomarkers to try and understand the cellular sources of disease modulators. Such studies could reveal distinct mechanisms of pathogenesis across different disease subtypes or throughout disease progression. It is already clear that cytokines are diverse across patients and there is accumulating evidence that they clarify some aspects of the disease heterogeneity that cannot be explained by genetic mutations alone.
OX40 Agonist BMS-986178 Alone or in Combination With Nivolumab and/or Ipilimumab in Patients With Advanced Solid Tumors
Authors: Martin Gutierrez, Victor Moreno, Kimberley M. Heinhuis, Anthony J. Olszanski, Anna Spreafico, Michael Ong, Quincy Chu, Richard D. Carvajal, José Trigo, Maria Ochoa de Olza, Mariano Provencio, Filip Yves De Vos, Filippo De Braud, Stephen Leong, Deanne Lathers, Rui Wang, Palani Ravindran, Yan Feng, Praveen Aanur, Ignacio Melero
Journal: Clinical Cancer Research (2020)

This phase I/IIa study (NCT02737475) evaluated the safety and activity of BMS-986178, a fully human OX40 agonist IgG1 mAb, ± nivolumab and/or ipilimumab in patients with advanced solid tumors.Patients (with non-small cell lung, renal cell, bladder, other advanced cancers) received BMS-986178 (20-320 mg) ± nivolumab (240-480 mg) and/or ipilimumab (1-3 mg/kg). The primary endpoint was safety. Additional endpoints included immunogenicity, pharmacodynamics, pharmacokinetics, and antitumor activity per RECIST version 1.1.Twenty patients received BMS-986178 monotherapy, and 145 received combination therapy in various regimens (including two patients receiving nivolumab monotherapy). With a follow-up of 1.1 to 103.6 weeks, the most common (≥5%) treatment-related adverse events (TRAEs) included fatigue, pruritus, rash, pyrexia, diarrhea, and infusion-related reactions. Overall, grade 3-4 TRAEs occurred in one of 20 patients (5%) receiving BMS-986178 monotherapy, six of 79 (8%) receiving BMS-986178 plus nivolumab, zero of two receiving nivolumab monotherapy, six of 41 (15%) receiving BMS-986178 plus ipilimumab, and three of 23 (13%) receiving BMS-986178 plus nivolumab plus ipilimumab. No deaths occurred. No dose-limiting toxicities were observed with monotherapy, and the MTD was not reached in either the monotherapy or the combination escalation cohorts. No objective responses were seen with BMS-986178 alone; objective response rates ranged from 0% to 13% across combination therapy cohorts.In this study, BMS-986178 ± nivolumab and/or ipilimumab appeared to have a manageable safety profile, but no clear efficacy signal was observed above that expected for nivolumab and/or ipilimumab.
The Molecular Characteristics and Clinical Relevance of <i>NUP98</i>-Other Translocations in Pediatric Acute Myeloid Leukemia
Authors: Eline J.M. Bertrums, Jenny L. Smith, Rhonda E. Ries, Todd A. Alonzo, Fabiana Ostronoff, Gertjan J.L. Kaspers, Henrik Hasle, Christian M. Zwaan, Betsy A Hirsch, Susana C. Raimondi, Todd M. Cooper, Richard Aplenc, Alan S. Gamis, Edward A. Kolb, Bianca F. Goemans, Soheil Meshinchi
Journal: Blood (2020)
Efficient Gene Editing of CART Cells with CRISPR-Cas12a for Enhanced Antitumor Efficacy
Authors: Elizabeth L. Siegler, Brandon W Simone, Reona Sakemura, Erin E. Tapper, Paulina Horvei, Michelle J. Cox, Mehrdad Hefazi, Claudia Manriquez Roman, Ismail Can, Kendall J. Schick, Michael W. Ruff, Stephen C Ekker, Saad S. Kenderian
Journal: Blood (2020)
THU0241 Behcet’s disease: does lack of knowledge result in underdiagnosis?
Authors: Y Yazici, D Erkan, G Nesher, E Kural, N Seyahi, A Ince
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Prevalence of Behcet's disease has been estimated at 8–38/10,000 in Turkey and 1–2/30,000 in the USA. Pathergy test positivity is a major criterion for making the diagnosis of Behcet's disease. <h3>Objectives</h3> To determine the knowledge among internal medicine (IM) residents from 2 different Mediterranean regions and 2 different regions in the USA regarding general rheumatology (GR), Behcet's disease, pathergy test and PPD test for tuberculosis. <h3>Methods</h3> A 26-item questionnaire was developed including both closed and open-ended items, testing knowledge of GR, Behcet's disease, pathergy test, and PPD test. It was given to IM residents from 4 university centres (St. Louis University Health Sciences Centre (A) and Weill Medical College of Cornell University (B) in the USA, Shaare-Zedak Medical Centre (C) in Israel, and Cerrahpasa Medical Faculty (D) in Turkey). In a single session, residents were asked 10 questions each about GR and Behcet's disease and 3 questions each about pathergy test and PPD. Rates of correct responses between IM residents from the USA and IM residents from Israel/Turkey were compared using Fischer's Exact test. <h3>Results</h3> 69 residents participated in this study (A: 26, B: 13, C: 10, D: 20). The Table 1 shows the proportion of correct answers given for each category of questions. There was a statistically significant difference between the rate of correct responses among IM residents in the USA compared to those in Israel/Turkey with respect to the categories of GR, Behcet's disease, and pathergy test. This difference was more pronounced in the questions regarding Behcet's disease and pathergy test. <h3>Conclusion</h3> Knowledge of Behcet's disease, and especially pathergy test among IM residents tested is significantly lower in the USA than among those in Israel/Turkey. The difference in the prevalence of Behcet's disease in these two regions of the world may partly explain this disparity. Contrarily, lack of GR and Behcet's disease knowledge may contribute to decreased recognition and thus underdiagnosis of Behcet's disease resulting in the reported low prevalence in the US. Only by improving the education of internists with respect to Behcet's disease will the true prevalence of this condition be realised.
Abstract 288: Distribution of Pathological Features and Inflammatory Cells in Patients With Giant Cell Myocarditis
Authors: LIU SHANGYU, Yao Yan
Journal: Circulation Research (2020)

Background: Giant-cell myocarditis (GCM) is a rare disease with a poor prognosis. The typical pathological features of GCM include an infiltration of multinucleated giant cells accompanied by numerous inflammatory immune cells. However, the etiology and pathophysiology of GCM remain largely unclear. Methods: Eight patients with pathological diagnoses with GCM underwent heart transplantation at our center. Hematoxylin- eosin (H-E) and Masson’s tri-chrome staining were performed on biopsies of the free walls of the right and left ventricles and interventricular septa of the original hearts to determine the characteristic distribution of cardiac lesions and the composition of infiltrating immune cells. A multiplex immunohistochemistry and multispectral imaging analysis were applied to further classify the specific types of inflammatory immune cells. Results: Inflammation found in a descending frequency gradually from the epicardium to the endocardium in the free wall of the left ventricle, but concentrated on the surface of right ventricular septum. Typical inflammatory infiltration and pathological changes were observed in the right-sided ventricular septum samples from all 8 patients. Numerous inflammatory immune cells, particularly CD4 + T cells, were detected in the lesion, which surrounded the emerging multinucleated giant cells. CD8 + T cells and a small number of regulatory T cells were scattered in the periphery. Conclusions: In GCM, cardiac lesions appear to concentrate particularly beneath the epicardium of the left ventricular free wall and the right side of the ventricular septum. These findings provide a rationale for the diagnostic use of conventional endocardial biopsy. The findings further suggest that myocardial injury is mediated by a variety of lymphocytes, especially CD4 + T cells.
Bayesian Network Modelling As a New Tool in Predicting of the Early Progression of Disease in Follicular Lymphoma Patients
Authors: Vít K Procházka, Štěpánka Matuštíková, Tomáš Fürst, David Belada, Andrea Janíková, Kateřina Benešová, Heidi Mociková, Juraj Ďuraš, Jan Pirnos, Kateřina Kopečková, Vít Campr, Jozef Michalka, Robert Pytlík, Tomáš Papajík, Marek Trněný
Journal: Blood (2020)
Abstract 291: <i>In Vitro</i> Matured Human Embryonic Stem Cell-derived Cardiomyocytes Form Grafts With Enhanced Structure and Improved Electromechanical Integration in Injured Hearts
Authors: Wahiba Dhahri, Tamilla Sadikov Valdman, Beiping Qiang, Hassan Masoudpour, Eylul Ceylan, Fanny Wulkan, Michael A Laflamme
Journal: Circulation Research (2020)

Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) have tremendous promise for application in cardiac repair, but their immature phenotype greatly limits their translational potential. The present study was designed to two hypotheses: 1) that previously reported methods to promote the maturation of hESC-CMs by culture on soft polydimethylsiloxane (PDMS) substrates can be upscaled to the quantities required for transplantation studies; and 2) that PDMS-matured hESC-CMs will stably engraft in injured hearts and form graft myocardium with enhanced structural and functional properties. First, we cultured hESC-CMs on either PDMS or tissue culture plastic (TCP) for 20 and 40 days, then phenotyped the resultant populations. All hESC-CMs were engineered to express the fluorescent voltage-sensitive protein ASAP1 to facilitate in vitro and in vivo electrophysiological studies. Relative to their counterparts on TCP, hESC-CMs on PDMS at both time-points exhibited increased cardiac gene expression as well as a more mature structural and electrophysiological phenotype in vitro. Single-cell transcriptomics confirmed enrichment of cardiac maturation markers including gene pathways involved in cardiac contraction, extracellular matrix organization, sarcomerogenesis, and adult heart development in PDMS versus TCP cultures. Next, we transplanted day 20 or 40 TCP vs PDMS ASAP1+ hESC-CMs into injured guinea pig hearts. Recipient hearts were later analyzed by ex vivo optical voltage mapping studies and histology. While CMs from both substrates showed similar capacity for engraftment, grafts formed with PDMS-matured myocytes had more mature structural properties including enhanced alignment, sarcomere lengths and maturation marker expression. Most importantly, graft formed with PDMS-matured myocytes showed improved electrophysiological properties including better host-graft electromechanical integration and more rapid and uniform propagation. We conclude that large quantities of matured hESC-CMs can indeed be economically produced by these methods. Moreover, PDMS-matured myocytes form large intramyocardial grafts with enhanced cardiac structure and electrical function, thereby establishing that maturation prior to transplantation meaningfully improves outcomes in vivo.