tbuckley/cabot-search huggingface dataset:
Phase I/II study of tirabrutinib, a second-generation Bruton’s tyrosine kinase inhibitor, in relapsed/refractory primary central nervous system lymphoma
Authors: Yoshitaka Narita, Motoo Nagane, Kazuhiko Mishima, Yasuhito Terui, Yoshiki Arakawa, Hajime Yonezawa, Katsunori Asai, Noriko Fukuhara, Kazuhiko Sugiyama, Naoki Shinojima, Junsaku Kitagawa, Arata Aoi, Ryo Nishikawa
Journal: Neuro-Oncology (2020)

Abstract Background The safety, tolerability, efficacy, and pharmacokinetics of tirabrutinib, a second-generation, highly selective oral Bruton’s tyrosine kinase inhibitor, were evaluated for relapsed/refractory primary central nervous system lymphoma (PCNSL). Methods Patients with relapsed/refractory PCNSL, Karnofsky performance status ≥70, and normal end-organ function received tirabrutinib 320 and 480 mg once daily (q.d.) in phase I to evaluate dose-limiting toxicity (DLT) within 28 days using a 3 + 3 dose escalation design and with 480 mg q.d. under fasted conditions in phase II. Results Forty-four patients were enrolled; 20, 7, and 17 received tirabrutinib at 320, 480, and 480 mg under fasted conditions, respectively. No DLTs were observed, and the maximum tolerated dose was not reached at 480 mg. Common grade ≥3 adverse events (AEs) were neutropenia (9.1%), lymphopenia, leukopenia, and erythema multiforme (6.8% each). One patient with 480 mg q.d. had grade 5 AEs (pneumocystis jirovecii pneumonia and interstitial lung disease). Independent review committee assessed overall response rate (ORR) at 64%: 60% with 5 complete responses (CR)/unconfirmed complete responses (CRu) at 320 mg, 100% with 4 CR/CRu at 480 mg, and 53% with 6 CR/CRu at 480 mg under fasted conditions. Median progression-free survival was 2.9 months: 2.1, 11.1, and 5.8 months at 320, 480, and 480 mg under fasted conditions, respectively. Median overall survival was not reached. ORR was similar among patients harboring CARD11, MYD88, and CD79B mutations, and corresponding wild types. Conclusion These data indicate favorable efficacy of tirabrutinib in patients with relapsed/refractory PCNSL. Trial registration JapicCTI-173646.
Single-operator cholangioscopy: more good numbers, with a few caveats
Authors: Christopher Khor
Journal: Endoscopy (2020)

The finding of an indeterminate biliary stricture (IDBS) is not uncommon; it is often defined as a stricture for which definitive diagnosis remains elusive following standard evaluation with transabdominal imaging and endoscopic retrograde cholangiopancreatography (ERCP) with brush cytology. The yield of ERCP techniques for detecting malignancy remains low; in a recent meta-analysis, the pooled sensitivities of brush cytology and forceps biopsy were 45 % and 48.1 %, respectively. Combining the two methods increased sensitivity modestly, to 59.4 % [1]. Mischaracterization of IDBSs can have a significant impact on patient outcomes by leading to unnecessary surgery or delays in oncological therapy. Peroral cholangioscopy (POCS) affords direct visualization of biliary strictures and facilitates tissue sampling guided by endoscopic views.
Allele-specific DNA methylation is increased in cancers and its dense mapping in normal plus neoplastic cells increases the yield of disease-associated regulatory SNPs
Authors: Catherine Do, Emmanuel L. P. Dumont, Martha Salas, Angelica Castano, Huthayfa Mujahed, Leonel Maldonado, Arunjot Singh, Sonia C. DaSilva-Arnold, Govind Bhagat, Soren Lehman, Angela M. Christiano, Subha Madhavan, Peter L. Nagy, Peter H. R. Green, Rena Feinman, Cornelia Trimble, Nicholas P. Illsley, Karen Marder, Lawrence Honig, Catherine Monk, Andre Goy, Kar Chow, Samuel Goldlust, George Kaptain, David Siegel, Benjamin Tycko
Journal: Genome biology (2020)

Mapping of allele-specific DNA methylation (ASM) can be a post-GWAS strategy for localizing regulatory sequence polymorphisms (rSNPs). The advantages of this approach, and the mechanisms underlying ASM in normal and neoplastic cells, remain to be clarified.
Therapeutic Effect of Adipose Derived Mesenchymal Stem Cell Transplantation in Reducing Restenosis in a Murine Angioplasty Model
Authors: Chuanqi Cai, Sreenivasulu Kilari, Chenglei Zhao, Michael L. Simeon, Avanish Misra, Yiqing Li, Andre J. van Wijnen, Debabrata Mukhopadhyay, Sanjay Misra
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement The arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis, but several studies have shown that the primary patency rate at 1 year is approximately 60%. Percutaneous transluminal angioplasty (PTA) is the first line of treatment for AVF stenosis. However, the rate of restenosis after angioplasty is high and the primary patency rate after PTA treatment in AVFs at 6, 12, and 24 months is 61%, 42%, and 35%, respectively. Currently, no durable therapies prolong patency after angioplasty. This paper describes the use of adipose-derived mesenchymal stem cells to reduce stenosis after PTA treatment in a murine AVF model and provides rationale for potential clinical use. Background Percutaneous transluminal angioplasty (PTA) is the first line of treatment for stenosis in the arteriovenous fistula (AVF) created to provide access for hemodialysis, but resenosis still occurs. Transplants of adipose-derived mesenchymal stem cells (AMSCs) labeled with green fluorescent protein (GFP) to the adventitia could reduce pro-inflammatory gene expression, possibly restoring patency in a murine model of PTA for venous stenosis. Methods Partial nephrectomy of male C57BL/6J mice induced CKD. Placement of the AVF was 28 days later and, 14 days after that, PTA of the stenotic outflow vein was performed with delivery of either vehicle control or AMSCs (5×10 5 ) to the adventitia of the vein. Mice were euthanized 3 days later and gene expression for interleukin-1 beta (IL-1 β ) and tumor necrosis factor-alpha TNF- α ) analyzed, and histopathologic analysis performed on day 14 and 28. GFP (+) AMSCs were tracked after transplantation for up to 28 days and Doppler ultrasound performed weekly after AVF creation. Results Gene and protein expression of IL-1 β and TNF- α, fibrosis, proliferation, apoptosis and smooth muscle actin decreased, and the proportions of macrophage types (M2/M1) shifted in a manner consistent with less inflammation in AMSC-transplanted vessels compared to controls. After PTA, AMSC-treated vessels had significantly higher wall shear stress, average peak, and mean velocity, with increased lumen vessel area and decreased neointima/media area ratio compared to the control group. At 28 days after delivery, GFP (+) AMSC were present in the adventitia of the outflow vein. Conclusions AMSC-treated vessels had improved vascular remodeling with decreased proinflammatory gene expression, inflammation, and fibrotic staining compared to untreated vessels.
Is artificial intelligence a superior diagnostician in ulcerative colitis?
Authors: Shuhei Fukunaga, Yoshio Kusaba, Akihiro Ohuchi, Tsutomu Nagata, Keiichi Mitsuyama, Osamu Tsuruta, Takuji Torimura
Journal: Endoscopy (2020)

A 46-year-old woman with a 26-year history of pancolitis visited our hospital regularly. She had remained in remission for the past 5 years and was taking oral mesalamine. Annual endoscopy examination showed a slightly elevated reddish lesion (5 mm) in the lower rectum ([Fig. 1]). Endocytoscopy (CF-H290ECI; Olympus, Tokyo, Japan) with narrow-band imaging revealed surface microvessels of uniform caliber and arrangement ([Video 1]). An artificial intelligence-based system (EndoBRAIN; Cybernet Systems, Tokyo, Japan) diagnosed the lesion as a neoplasm. On the basis of biopsy findings, we diagnosed the lesion as being high grade dysplasia ([Fig. 2]) and performed endoscopic submucosal dissection. After treatment, she was discharged on postoperative day 7, without any complications.
Sex-specific maternal calcium requirements for the prevention of nonalcoholic fatty liver disease by altering the intestinal microbiota and lipid metabolism in the high-fat-diet-fed offspring mice
Authors: Ping Li, Kesong Yan, Xuelian Chang, Xiaoyu Chen, Rui Wang, Xiuqin Fan, Tiantian Tang, Dawei Zhan, Kemin Qi
Journal: Gut Microbes (2020)

The significance of maternal appropriate calcium intakes for energy metabolism in the offspring has been recognized. Nonalcoholic fatty liver disease (NAFLD) is considered as the hepatic manifestation of metabolic syndrome. So in this study, we proposed that there were long-term effects of maternal calcium status on the progress of NAFLD by altering the intestinal microbiota and lipid metabolism with attention to potential sex differences among the mouse offspring. Thirty-four-week female C57BL/6 J mice were subjected to obtain low, normal and high calcium reproductive diets throughout the gestation and lactation. After weaning, both the male and female mouse offspring were fed with the high-fat diet for 16 weeks, with the normal diet as control. Biochemical indicators in the plasma and hepatic tissue were measured using ELISA or enzymatic methods. The expression of lipid metabolism, inflammatory and fibrosis related genes was determined by RT-PCR. The intestinal microbiota was analyzed by 16S rRNA high-throughput sequencing. Maternal normal and low calcium intake could, respectively, inhibit the progress of high-fat diet induced NAFLD in the male and female mouse offspring, which was characterized by the least lipid droplets, inflammatory infiltration and fibrosis, the lowest concentrations of free fatty acids and triglyceridethe lowest expression of genes involving in de novo lipogenesis and the highest expression of genes related to lipid oxidation and hydrolysis, inflammatory, and fibrosis. Pyrosequencing of 16S rRNA genes revealed that the male mouse offspring with maternal normal calcium intake and the female mouse offspring with maternal low calcium intake, after the high-fat diet feeding, had distinct intestinal microbiota, which was closer to thosein mice with the normal diet feeding. Analysis of the functional features for the different microbiota was compatible with the expression of genes associated with lipogenesis, lipid oxidation and hydrolysis. Thus, there is a sex-specific manner for maternal calcium requirement to inhibit the progress of offspring NAFLD, that might be less for the female offspring and more for the male offspring.
Characteristics of Adult Outpatients and Inpatients with COVID-19 — 11 Academic Medical Centers, United States, March–May 2020
Authors: Mark W. Tenforde, Erica Billig Rose, Christopher J. Lindsell, Nathan I. Shapiro, D. Clark Files, Kevin W. Gibbs, Matthew E. Prekker, Jay S. Steingrub, Howard A. Smithline, Michelle N. Gong, Michael S. Aboodi, Matthew C. Exline, Daniel J. Henning, Jennifer G. Wilson, Akram Khan, Nida Qadir, William B. Stubblefield, Manish M. Patel, Wesley H. Self, Leora R. Feldstein, Ahmed M. Kassem, Courtney N. Sciarratta, Nicole Dzuris, Paula L. Marcet, Akshita Siddula, Eric P. Griggs, Emily R. Smith, Constance E. Ogokeh, Michael Wu, Sara S. Kim
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Descriptions of coronavirus disease 2019 (COVID-19) in the United States have focused primarily on hospitalized patients. Reports documenting exposures to SARS-CoV-2, the virus that causes COVID-19, have generally been described within congregate settings, such as meat and poultry processing plants (1) and long-term care facilities (2). Understanding individual behaviors and demographic characteristics of patients with COVID-19 and risks for severe illness requiring hospitalization can inform efforts to reduce transmission. During April 15-May 24, 2020, telephone interviews were conducted with a random sample of adults aged ≥18 years who had positive reverse transcription-polymerase chain reaction (RT-PCR) test results for SARS-CoV-2 in outpatient and inpatient settings at 11 U.S. academic medical centers in nine states. Respondents were contacted 14-21 days after SARS-CoV-2 testing and asked about their demographic characteristics, underlying chronic conditions, symptoms experienced on the date of testing, and potential exposures to SARS-CoV-2 during the 2 weeks before illness onset (or the date of testing among those who did not report symptoms at the time of testing). Among 350 interviewed patients (271 [77%] outpatients and 79 [23%] inpatients), inpatients were older, more likely to be Hispanic and to report dyspnea than outpatients. Fewer inpatients (39%, 20 of 51) reported a return to baseline level of health at 14-21 days than did outpatients (64%, 150 of 233) (p = 0.001). Overall, approximately one half (46%) of patients reported known close contact with someone with COVID-19 during the preceding 2 weeks. This was most commonly a family member (45%) or a work colleague (34%). Approximately two thirds (64%, 212 of 333) of participants were employed; only 35 of 209 (17%) were able to telework. These findings highlight the need for screening, case investigation, contact tracing, and isolation of infected persons to control transmission of SARS-CoV-2 infection during periods of community transmission. The need for enhanced measures to ensure workplace safety, including ensuring social distancing and more widespread use of cloth face coverings, are warranted (3).
Potential contribution of increased soluble IL-2R to lymphopenia in COVID-19 patients
Authors: Yaguang Zhang, Xiaojing Wang, Xuezhen Li, Dong Xi, Ruizhi Mao, Xiaohui Wu, Shipeng Cheng, Xiaoyu Sun, Chunyan Yi, Zhiyang Ling, Liyan Ma, Qin Ning, Yiru Fang, Bing Sun, Di Wu
Journal: Cellular and Molecular Immunology (2020)
Cisplatin-induced peripheral neuropathy is associated with neuronal senescence-like response
Authors: Aina Calls, Abel Torres-Espin, Xavier Navarro, Victor J Yuste, Esther Udina, Jordi Bruna
Journal: Neuro-Oncology (2020)

Cisplatin-induced peripheral neuropathy (CIPN) is a frequent serious dose-dependent adverse event that can determine dosage limitations for cancer treatment. CIPN severity correlates with the amount of platinum detected in sensory neurons of the dorsal root ganglia (DRG). However, the exact pathophysiology of CIPN is poorly understood, so the chance of developing neuroprotective treatment is reduced. The aim of this study was to determine the exact mechanisms involved in CIPN development.
Efficacy and Safety of Vandetanib in Progressive and Symptomatic Medullary Thyroid Cancer: Post Hoc Analysis From the ZETA Trial
Authors: Michael C. Kreissl, Lars Bastholt, Rossella Elisei, Robert Haddad, Ole Hauch, Barbara Jarząb, Bruce Robinson, Raffaella Colzani, Meredith Foster, Richard Weiss, Martin Schlumberger
Journal: Journal of Clinical Oncology (2020)

We conducted a post hoc analysis of the vandetanib phase III trial involving patients with advanced medullary thyroid cancer (MTC) to assess the efficacy and safety of vandetanib in patients with progressive and symptomatic MTC. The primary objective of the analysis was to determine progression-free survival (PFS) of these patients.Eligible patients from the ZETA trial were divided into 4 disease severity subgroups: progression and symptoms, symptoms only, progression only, and no progression and no symptoms assessed at baseline. PFS, determined from objective tumor measurements performed by the local investigator, overall survival (OS), time to worsening of pain (TWP), and objective response rate (ORR) were evaluated.Of the 331 patients in this trial, 184 had symptomatic and progressive disease at baseline. In this subgroup, results were similar in magnitude to those observed in the overall trial for PFS (hazard ratio [HR], 0.43; 95% CI, 0.28 to 0.64; P < .0001), OS (HR, 1.08; 95% CI, 0.72 to 1.61; P = .71), and TWP (HR, 0.67; 95% CI, 0.43 to 1.04; P = .07), and the observed adverse events were consistent with the known safety profile of vandetanib. In this subgroup, the ORR was 37% in the treatment arm versus 2% in the placebo arm.Vandetanib demonstrated clinical benefit-specifically, increased PFS-in patients with symptomatic and progressive MTC.
Initial dose of oncolytic myxoma virus programs durable antitumor immunity independent of in vivo viral replication
Authors: Erica B Flores, Bulent A Aksoy, Eric Bartee
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Oncolytic therapy uses live-replicating viruses to improve the immunological status of treated tumors. Critically, while these viruses are known to self-amplify in vivo, clinical oncolytic therapies still appear to display a strong dose dependence and the mechanisms mediating this dose dependence are not well understood. Methods To explore this apparent contradiction, we investigated how the initial dose of oncolytic myxoma virus affected the subsequent ability of treatment to alter the immunological status of tumors as well as synergize with programmed cell death protein 1 (PD1) blockade. Results Our results indicate that, due to viral self-amplification in vivo, the overall load of myxoma virus rapidly normalizes within treated tumors despite up to 3-log differences in inoculating dose. Because of this, therapeutic efficacy in the absence of checkpoint blockade is largely dose independent. Despite this rapid normalization, however, treatment with high or low doses of myxoma virus induces distinct immunological changes within treated tumors. Critically, these changes appear to be durably programmed based on the initial oncolytic dose with low-dose treatment failing to induce immunological improvements despite rapidly achieving equivalent viral burdens. Finally, due to the distinct immunological profiles induced by high and low myxoma virus doses, oncolytic efficacy resulting from combination with PD1 blockade therapy displays a strong dose dependence. Conclusions Taken together, these data suggest that the ability of oncolytic myxoma virus to immunologically reprogram treated tumors is dependent on initial viral dose. Additionally, this work could provide a possible mechanistic explanation for clinical results observed with other oncolytic viruses.
Patient-derived tumor-like cell clusters for drug testing in cancer therapy
Authors: Shenyi Yin, Ruibin Xi, Aiwen Wu, Shu Wang, Yingjie Li, Chaobin Wang, Lei Tang, Yuchao Xia, Di Yang, Juan Li, Buqing Ye, Ying Yu, Junyi Wang, Hanshuo Zhang, Fei Ren, Yuanyuan Zhang, Danhua Shen, Lin Wang, Xiangji Ying, Zhongwu Li, Zhaode Bu, Xin Ji, Xiangyu Gao, Yongning Jia, Ziyu Jia, Nan Li, Ziyu Li, Jia-Fu Ji, Jianzhong Jeff Xi
Journal: Science Translational Medicine (2020)

Patient-derived tumor-like cell clusters may be able to prospectively guide personalized therapeutic selection.
Siamon Gordon: A half-century fascination with macrophages
Authors: Stephanie Houston
Journal: The Journal of Experimental Medicine (2020)

Siamon Gordon is a Glaxo Wellcome Professor Emeritus of Cellular Pathology at the University of Oxford and a fellow of the Royal Society. Throughout his career, Siamon has focused on macrophages, and his work led to the identification of the pan-macrophage marker F4/80 and the description of a role for Dectin-1 in the innate recognition of β-glucans. I caught up with Siamon to discuss his career path and his thoughts on macrophages.
Go slow to go fast: a plea for sustained scientific rigour in air pollution research during the COVID-19 pandemic
Authors: Dick J.J. Heederik, Lidwien A.M. Smit, Roel C.H. Vermeulen
Journal: European Respiratory Journal (2020)

Researchers in the air pollution field are well aware that indoor and outdoor air pollution is associated with multiple disorders, including an increase in respiratory infection-related morbidity and mortality [1, 2]. Investigating associations linking air pollution and coronavirus disease 2019 (COVID-19) spread and prognosis of respiratory disease in COVID-19 patients is therefore timely, relevant and plausible. Over a 10-day period, three papers involving original research associating COVID-19 mortality and air pollution were published [3–5]. These publications attracted considerable attention from international news outlets and on social media [6, 7]. Present studies on the role of air pollution and COVID-19 spread, and the prognosis in patients, do not fulfil quality criteria and are not sufficiently informative <https://bit.ly/3hGjd73> We thank Calvin Ge for proof reading and editing the editorial and Marc Chadeau-Hyam for his critical and constructive comments.
Investigation of genetically regulated gene expression and response to treatment in rheumatoid arthritis highlights an association between <i>IL18RAP</i> expression and treatment response
Authors: Svetlana Cherlin, Myles J Lewis, Darren Plant, Nisha Nair, Katriona Goldmann, Evan Tzanis, Michael R Barnes, Paul McKeigue, Jennifer H Barrett, Costantino Pitzalis, Anne Barton, Heather J Cordell
Journal: Annals of the Rheumatic Diseases (2020)

Objectives In this study, we sought to investigate whether there was any association between genetically regulated gene expression (as predicted using various reference panels) and anti-tumour necrosis factor (anti-TNF) treatment response (change in erythrocyte sedimentation rate (ESR)) using 3158 European ancestry patients with rheumatoid arthritis. Methods The genetically regulated portion of gene expression was estimated in the full cohort of 3158 subjects (as well as within a subcohort consisting of 1575 UK patients) using the PrediXcan software package with three different reference panels. Estimated expression was tested for association with anti-TNF treatment response. As a replication/validation experiment, we also investigated the correlation between change in ESR with measured gene expression at the Interleukin 18 Receptor Accessory Protein ( IL18RAP ) gene in whole blood and synovial tissue, using an independent replication data set of patients receiving conventional synthetic disease modifying anti-rheumatic drugs, with directly measured (via RNA sequencing) gene expression. Results We found that predicted expression of IL18RAP showed a consistent signal of association with treatment response across the reference panels. In our independent replication data set, IL18RAP expression in whole blood showed correlation with the change in ESR between baseline and follow-up ( r = − 0.35, p=0.0091). Change in ESR was also correlated with the expression of IL18RAP in synovial tissue ( r = − 0.28, p=0.02). Conclusion Our results suggest that IL18RAP expression is worthy of further investigation as a potential predictor of treatment response in rheumatoid arthritis that is not specific to a particular drug type.