tbuckley/cabot-search huggingface dataset:
New role for azathioprine in case of switching anti-TNFs in IBD
Authors: Konstantinos Papamichael, Adam S Cheifetz, Peter M Irving
Journal: Gut (2020)

Antitumour necrosis factor (anti-TNF) therapy has revolutionised the treatment of moderate to severe inflammatory bowel disease (IBD). However, up to 30% of patients with Crohn’s disease (CD) and ulcerative colitis (UC) do not respond to anti-TNF therapy, often referred to as primary non-responders. Additionally, almost 50% of patients who initially respond to anti-TNF lose response over time, a phenomenon known as secondary loss of response (SLR).1 Both of these negative outcomes are most commonly caused by pharmacokinetic issues characterised by undetectable or low drug concentrations due to increased clearance with or without the presence of antidrug antibodies (ADA), so-called immunogenicity.2 The recent prospective The Personalised Anti-TNF therapy in Crohn’s Disease Study (PANTS) study showed that for both infliximab and adalimumab, suboptimal week 14 drug concentrations predicted immunogenicity, and the development of ADA predicted subsequent low drug concentrations.3 Immunogenicity may account for at least 20% of SLR in patients with IBD.2 

The addition of an immunomodulator (IMM), such as a thiopurine or methotrexate, has been shown to improve the pharmacokinetic profile of anti-TNF agents both by attenuating immunogenicity and increasing drug concentrations.3–5 These factors consequently lead to better long-term clinical outcomes and less SLR.3–5 A post hoc analysis of the Study of Biologic and Immunomodulator naive Patients in Crohn’s Disease (SONIC) randomised controlled trial (RCT) showed that combination therapy with azathioprine appears to …
Mesenchymal stem cells suppress leukemia via macrophage-mediated functional restoration of bone marrow microenvironment
Authors: Chengxiang Xia, Tongjie Wang, Hui Cheng, Yong Dong, Qitong Weng, Guohuan Sun, Peiqing Zhou, Kaitao Wang, Xiaofei Liu, Yang Geng, Shihui Ma, Sha Hao, Ling Xu, Yuxian Guan, Juan Du, Xin Du, Yangqiu Li, Xiaofan Zhu, Yufang Shi, Sheng Xu, Demin Wang, Tao Cheng, Jinyong Wang
Journal: Leukemia (2020)
Recapitulating and Deciphering Tumor Microenvironment by Using 3D Printed Plastic Brick–Like Microfluidic Cell Patterning
Authors: Yang Liu, Yingying Liu, Xiaonan Zheng, Liang Zhao, Xueji Zhang
Journal: Advanced Healthcare Materials (2020)

Abstract Within the body, tumor cells are surrounded by neighboring counterparts, such as extracellular matrix, vasculature, and host stroma, which is also known as the tumor microenvironment. To understand tumorigenesis, it is essential to reconstitute the incorporative tumor niche with quantitative measurements in vitro. Here, a 3D printed plastic brick–like microfluidic gadget is developed for spatially patterning tumors and fibroblasts, enabling the recapitulation of tumor microenvironment with minimized microfluidic expertise and compatibility of standard pipetting. This method facilitates heterotypic coculturing, quantitative phenotype decoding, and downstream molecular assays with a small number of cells (less than 100). Phenotypic and gene/protein expression‐based analysis of cell–cell interactions between fibrosarcoma cells and fibroblasts on this device reveals that the tumor and its counterparts show reciprocal synergism mainly by upregulation of proinflammatory cytokines. Notably, at the whole transcriptional landscape (RNA‐seq), fibroblasts display a transition from normal to cancer‐associated fibroblast (CAF)‐like phase, and tumor cells exhibit a hyperactive ribosome biogenesis. The mouse xenograft model is also involved to validate the in vitro analysis. Given its easy‐to‐use feature, full compatibility with molecular analysis, and open‐source accessibility, this approach provides an in vitro experimental system to advance knowledge of tumorigenesis and the corresponding tumor microenvironment.
Detection of Nonreciprocal/Reciprocal ALK Translocation as Poor Predictive Marker in Patients With First-Line Crizotinib-Treated ALK-Rearranged NSCLC
Authors: Yongchang Zhang, Liang Zeng, Chunhua Zhou, Yizhi Li, Lin Wu, Chen Xia, Wenjuan Jiang, Yijuan Hu, Dehua Liao, Lili Xiao, Li Liu, Haiyan Yang, Yi Xiong, Rui Guan, Analyn Lizaso, Aaron S. Mansfield, Nong Yang
Journal: Journal of Thoracic Oncology (2020)
Cost-effectiveness of upfront therapeutic options in low-volume <i>de novo</i> metastatic hormone-sensitive prostate cancer.
Authors: Neil Rohit Parikh, Eric M. Chang, Nicholas George Nickols, Matthew Rettig, Ann C. Raldow, Michael L. Steinberg, Bridget F. Koontz, Neha Vapiwala, Curtiland Deville, Felix Y Feng, Daniel Eidelberg Spratt, Robert Evan Reiter, Ryan Phillips, Phuoc T. Tran, Amar Upadhyaya Kishan
Journal: Journal of Clinical Oncology (2020)

211 Background: Low-volume de novo metastatic hormone-sensitive prostate cancer (mHSPC) has historically been treated with lifelong androgen deprivation therapy (ADT). Recently, however, the addition of several advanced therapeutic options – radiation therapy (RT) to the primary, advanced hormonal therapy agents such as abiraterone acetate/prednisone (AAP), and chemotherapy – to ADT have been shown to improve survival in low-volume mHSPC. The objective of this study was to compare the cost-effectiveness of treating low-volume mHSPC patients upfront with RT+ADT, AAP+ADT, or docetaxel+ADT. Methods: A Markov-based cost-effectiveness analysis was constructed comparing three treatment strategies for low-volume mHSPC patients: (1) upfront RT+ADT --&gt; salvage AAP+ADT --&gt; salvage docetaxel+ADT; (2) upfront AAP+ADT --&gt; salvage docetaxel+ADT, and (3) upfront docetaxel+ADT --&gt; salvage AAP+ADT. Transition probabilities were calculated using data from STAMPEDE arms C/G/H, COU-AA-301, COU-AA-302, and TAX-327. RT was delivered via five-fraction stereotactic body radiation therapy. The analysis utilized a 10-year time horizon, and a $100,000/quality adjusted life year (QALY) willingness-to-pay threshold. Utilities were extracted from the literature; costs were taken from Medicare fee schedules and VA oral drug contracts. Results: At 10 years, total cost was $140K, $259K, and $189K, with total QALYs of 4.66, 5.03, and 3.72 for strategies (1) upfront RT+ADT, (2) upfront AAP+ADT, and (3) upfront docetaxel+ADT, respectively. Compared to upfront RT+ADT, upfront AAP+ADT was not cost-effective (ICER: $321K/QALY). This result remained unchanged even after modification of various model inputs in 1-way sensitivity analysis. Upfront docetaxel+ADT was both more costly and less effective than upfront RT+ADT (ICER: -$53K/QALY). Conclusions: At 10 years, RT+ADT is cost-effective compared to other advanced systemic therapy options alone, and should be considered as a viable treatment strategy in all patients with a low-burden of metastatic disease. Additional studies are needed to determine whether any benefit exists in combining RT to the primary with upfront advanced systemic therapy.
Albumin in decompensated cirrhosis: new concepts and perspectives
Authors: Mauro Bernardi, Paolo Angeli, Joan Claria, Richard Moreau, Pere Gines, Rajiv Jalan, Paolo Caraceni, Javier Fernandez, Alexander L Gerbes, Alastair J O'Brien, Jonel Trebicka, Thierry Thevenot, Vicente Arroyo
Journal: Gut (2020)

The pathophysiological background of decompensated cirrhosis is characterised by a systemic proinflammatory and pro-oxidant milieu that plays a major role in the development of multiorgan dysfunction. Such abnormality is mainly due to the systemic spread of bacteria and/or bacterial products from the gut and danger-associated molecular patterns from the diseased liver triggering the release of proinflammatory mediators by activating immune cells. The exacerbation of these processes underlies the development of acute-on-chronic liver failure. A further mechanism promoting multiorgan dysfunction and failure likely consists with a mitochondrial oxidative phosphorylation dysfunction responsible for systemic cellular energy crisis. The systemic proinflammatory and pro-oxidant state of patients with decompensated cirrhosis is also responsible for structural and functional changes in the albumin molecule, which spoil its pleiotropic non-oncotic properties such as antioxidant, scavenging, immune-modulating and endothelium protective functions. The knowledge of these abnormalities provides novel targets for mechanistic treatments. In this respect, the oncotic and non-oncotic properties of albumin make it a potential multitarget agent. This would expand the well-established indications to the use of albumin in decompensated cirrhosis, which mainly aim at improving effective volaemia or preventing its deterioration. Evidence has been recently provided that long-term albumin administration to patients with cirrhosis and ascites improves survival, prevents complications, eases the management of ascites and reduces hospitalisations. However, variant results indicate that further investigations are needed, aiming at confirming the beneficial effects of albumin, clarifying its optimal dosage and administration schedule and identify patients who would benefit most from long-term albumin administration.
Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series
Authors: Xiao-Wei Xu, Xiao-Xin Wu, Xian-Gao Jiang, Kai-Jin Xu, Ling-Jun Ying, Chun-Lian Ma, Shi-Bo Li, Hua-Ying Wang, Sheng Zhang, Hai-Nv Gao, Ji-Fang Sheng, Hong-Liu Cai, Yun-Qing Qiu, Lan-Juan Li
Journal: BMJ (2020)

Abstract Objective To study the clinical characteristics of patients in Zhejiang province, China, infected with the 2019 severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) responsible for coronavirus disease 2019 (covid-2019). Design Retrospective case series. Setting Seven hospitals in Zhejiang province, China. Participants 62 patients admitted to hospital with laboratory confirmed SARS-Cov-2 infection. Data were collected from 10 January 2020 to 26 January 2020. Main outcome measures Clinical data, collected using a standardised case report form, such as temperature, history of exposure, incubation period. If information was not clear, the working group in Hangzhou contacted the doctor responsible for treating the patient for clarification. Results Of the 62 patients studied (median age 41 years), only one was admitted to an intensive care unit, and no patients died during the study. According to research, none of the infected patients in Zhejiang province were ever exposed to the Huanan seafood market, the original source of the virus; all studied cases were infected by human to human transmission. The most common symptoms at onset of illness were fever in 48 (77%) patients, cough in 50 (81%), expectoration in 35 (56%), headache in 21 (34%), myalgia or fatigue in 32 (52%), diarrhoea in 3 (8%), and haemoptysis in 2 (3%). Only two patients (3%) developed shortness of breath on admission. The median time from exposure to onset of illness was 4 days (interquartile range 3-5 days), and from onset of symptoms to first hospital admission was 2 (1-4) days. Conclusion As of early February 2020, compared with patients initially infected with SARS-Cov-2 in Wuhan, the symptoms of patients in Zhejiang province are relatively mild.
Dupilumab Reduces Blood, Urine, and Nasal Biomarkers of Type 2 Inflammation in Patients With Chronic Rhinosinusitis With Nasal Polyps in the Phase 3 SINUS-52 Trial
Authors: Claus Bachert, Seong Cho, Tanya Laidlaw, Brian Swanson, Sivan Harel, Leda Mannent, Nikhil Amin, Alexandre Jagerschmidt
Journal: Journal of Allergy and Clinical Immunology (2020)
Sixty seconds on . . . canals
Authors: Abi Rimmer
Journal: BMJ (2020)

Nope—we’re talking about canals, the former waterways of British industry. There are plans afoot that may see them used for heating hospitals in the future.

A new, carbon smart energy grid called GreenSCIES (Green Smart Community Integrated Energy System) has been launched in London and the West Midlands by London South …
Rediscovery of the Second β-Cell Hormone: Co-replacement With Pramlintide and Insulin in Type 1 Diabetes
Authors: Matthew C. Riddle
Journal: Diabetes Care (2020)

Insulin is always deficient relative to need in diabetes. Injected insulin is essential to replace the complete lack of insulin in type 1 diabetes and to supplement endogenous insulin for many people with type 2 diabetes. Unfortunately, despite advances in insulin formulation and delivery and the effects of other glucose-lowering therapies instead of or in combination with insulin, the goals of therapy are seldom completely met. People using insulin (especially prandial insulin) are at risk for hypoglycemia and weight gain, and their postprandial glucose levels are rarely well controlled. Surprisingly, an obvious contributor to this dilemma has received little attention—a concurrent deficiency of the hormone amylin in all people with diabetes.

Amylin was isolated and characterized three decades ago (1,2), about 70 years after insulin therapy became available, and “co-replacement therapy” with insulin and amylin was soon proposed for type 1 diabetes (3). Delay in characterization of amylin was partly due to its tendency to self-aggregate and cling to glass or plastic surfaces. In some species, notably cats and humans, amylin aggregates as “amyloid” in the endocrine pancreas and may contribute to injury of β-cells (4). Studies have been further hampered by difficulties in assaying amylin levels in blood, where significant proportions are modified and likely inactive (5). Even so, much has been learned about amylin’s distribution, regulation, and physiologic functions in animal and human studies (6). It is a 37–amino acid peptide that is produced in the pancreatic β-cell and secreted in parallel with insulin, and thus it is lacking in type 1 diabetes (6,7). Although present in other parts of the body, amylin is released into the blood only by β-cells. The actions of secreted amylin are mediated through parts of the brain that are outside the blood-brain barrier, and effects elsewhere depend on …
Characterizing Racial Differences in Particulate Air Pollution Exposure within a Multi-site Longitudinal Cohort of Food-allergic Children
Authors: Christopher Warren, Amal Assa'ad, Ruchi Gupta, Tesfaye Mersha, Mary Tobin, Hemant Sharma, Jacqueline Pongracic, Jialing Jiang, Pamela Newmark, Jamie Fierstein, Mahboobeh Mahdavinia, Susan Fox, Iman Abdikarim, Lucy Bilaver, Alexandria Bozen, Aame Andy-Nweye, Annika Chura, Perry Catlin, Olivia Negris, Adam Robinson
Journal: Journal of Allergy and Clinical Immunology (2020)
Urine exosome gene expression assay net benefit analysis in a large pooled cohort.
Authors: James M. McKiernan, Ronald F. Tutrone, Michael Joseph Donovan, Phillipp Torkler, Mikkel Noerholm, Jason Alter, Johan Skog
Journal: Journal of Clinical Oncology (2020)

287 Background: Over-diagnosis of indolent prostate cancer (PCa), supports the need for non-invasive tools that can differentiate low-grade (≤ Gleason score 6, GS 6) from high-grade (≥ GS 7). We examined the clinical benefit of ExoDx™ Prostate (IntelliScore) (EPI) results in a pooled cohort over a range of probabilities using net benefit analysis. Methods: A pooled dataset of two prior validation cohorts and additional cases from a large group practice provided a large data set (N=1,212) for net benefit analysis. The pooled population consisted of men &gt; 50 years, scheduled for initial biopsy and with a PSA measurement. Urine specimens were collected at enrollment using a provided urine collection device and the EPI tests were run at a CLIA-certified central laboratory at Exosome Diagnostics, Waltham, MA. The clinical decision value of the urine exosome gene expression assay (EPI) was assessed using net benefit analysis and compared EPI results with standard of care information across a range of probabilities for which a patient might decide on a prostate biopsy. The net benefit is determined by adding the true positive results and subtracting the false negatives across different biopsy probability thresholds. Results: The ExoDx IntelliScore or EPI assay (green) demonstrated superior clinical benefit when compared to the Prostate Cancer Prevention Trial (PCPT) prostate cancer risk calculator or PSA. Conclusions: In this new analysis of a large pooled cohort, the EPI exosome gene expression assay had the highest clinical net benefit across the 10% - 50% decision threshold compared to decision support methods currently used in the clinic.
Novel, genetically induced mouse model that recapitulates the histological morphology and immunosuppressive tumor microenvironment of metastatic peritoneal carcinomatosis
Authors: Ssu-Hsueh Tseng, Sung-Taek Park, Brandon Lam, Ya-Chea Tsai, Max A Cheng, Emily Farmer, Deyin Xing, Chien-Fu Hung
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Peritoneal carcinomatosis is a hallmark of advanced peritoneal tumor progression, particularly for tubal/ovarian high-grade serous carcinomas (HGSCs). Patients with peritoneal carcinomatosis have poor survival rates and are difficult to treat clinically due to widespread tumor dissemination in the peritoneal cavity. Methods We developed a clinically relevant, genetically induced, peritoneal carcinomatosis model that recapitulates the histological morphology and immunosuppressive state of the tumor microenvironment of metastatic peritoneal HGSCs by intraperitoneally injecting shp53, AKT, c-Myc, luciferase and sleeping beauty transposase, followed by electroporation (EP) in the peritoneal cavity of immunocompetent mice (intraperitoneal (IP)/EP mice). Results Similar to the spread of human ovarian cancers, IP/EP mice displayed multiple tumor nodules attached to the surface of the abdomen. Histopathological analysis indicated that these tumors were epithelial in origin. These IP/EP mice also displayed a loss of CD3 + T cell infiltration in tumors, highly expressed inhibitory checkpoint molecules in tumor-infiltrating and global CD4 + and CD8 + T cells, and increased levels of transforming growth factor-β in the ascites, all of which contribute to the promotion of tumor growth. Conclusions Overall, our tumor model recapitulates clinical peritoneal HGSC metastasis, which makes it ideal for preclinical drug screening, testing of immunotherapy-based therapeutics and studying of the tumor biology of peritoneal carcinomatosis.
Next-generation sequencing of FFPE solid tumor specimens for clinical use.
Authors: Roman Yelensky, Kai Wang, Snjezana Dogan, Laetitia Borsu, Garrett Frampton, Doron Lipson, Philip Stephens, Boris Bastian, David Klimstra, Marc Ladanyi, Maureen T. Cronin, Cyrus Hedvat, Michael F. Berger
Journal: Journal of Clinical Oncology (2012)

10524 Background: As more therapies targeting genomic alterations become available, genotyping (e.g., by Sequenom) is increasingly performed in tumor types where mutational status may drive treatment choice. Next-generation sequencing (NGS) technology can expand on genotyping of individual base pairs because it can detect mutations across entire exons, copy changes and fusion genes. However, for NGS to be clinically viable, it must be made compatible with FFPE tissues and shown concordant with best current diagnostic methods. Methods: To explore a potential clinical role for NGS, we selected 120 FFPE specimens (68 NSCLC, 32 CRC, 20 melanoma) previously tested for 97 oncogenic mutations in 8 oncogenes by Sequenom, and sequenced all exons of 182 cancer genes. Genotyping and sequencing were both performed in CLIA compliant labs. DNA was extracted from 4x 10μ unstained sections from the diagnostic FFPE block, followed by library construction and hybridization capture of 3230 exons and 37 commonly rearranged introns. Average coverage of &gt;900X uniquely-mapping reads was obtained. Sequence data were analyzed for all genomic alterations and examined for potentially actionable mutations. Results: High concordance was noted between Sequenom and NGS: 103 and 105 mutations were called by the two technologies, respectively, at mutually tested sites, with 97 mutation calls in common. Notably, mutant allele frequencies in concordant calls ranged as low as 2% by NGS, highlighting the sensitivity of detection enabled by both approaches. Furthermore, in 45/120 (38%) specimens, NGS revealed additional alterations that may confer sensitivity or resistance to approved or experimental targeted therapies and thus plausibly influence treatment decisions. These included 39 copy changes or loss-of-function variants best assayed by an NGS approach. Conclusions: Our results demonstrate technical feasibility and highlight potential benefits of comprehensive cancer gene characterization through next-generation sequencing of clinical FFPE specimens. As NGS is the most practical means to detect all classes of somatic alteration in a small, clinically relevant sample, we suggest that this type of testing will become an essential component of patient care.
Robustness and applicability of transcription factor and pathway analysis tools on single-cell RNA-seq data
Authors: Christian H. Holland, Jovan Tanevski, Javier Perales-Patón, Jan Gleixner, Manu P. Kumar, Elisabetta Mereu, Brian A. Joughin, Oliver Stegle, Douglas A. Lauffenburger, Holger Heyn, Bence Szalai, Julio Saez-Rodriguez
Journal: Genome biology (2020)

Abstract Background Many functional analysis tools have been developed to extract functional and mechanistic insight from bulk transcriptome data. With the advent of single-cell RNA sequencing (scRNA-seq), it is in principle possible to do such an analysis for single cells. However, scRNA-seq data has characteristics such as drop-out events and low library sizes. It is thus not clear if functional TF and pathway analysis tools established for bulk sequencing can be applied to scRNA-seq in a meaningful way. Results To address this question, we perform benchmark studies on simulated and real scRNA-seq data. We include the bulk-RNA tools PROGENy, GO enrichment, and DoRothEA that estimate pathway and transcription factor (TF) activities, respectively, and compare them against the tools SCENIC/AUCell and metaVIPER, designed for scRNA-seq. For the in silico study, we simulate single cells from TF/pathway perturbation bulk RNA-seq experiments. We complement the simulated data with real scRNA-seq data upon CRISPR-mediated knock-out. Our benchmarks on simulated and real data reveal comparable performance to the original bulk data. Additionally, we show that the TF and pathway activities preserve cell type-specific variability by analyzing a mixture sample sequenced with 13 scRNA-seq protocols. We also provide the benchmark data for further use by the community. Conclusions Our analyses suggest that bulk-based functional analysis tools that use manually curated footprint gene sets can be applied to scRNA-seq data, partially outperforming dedicated single-cell tools. Furthermore, we find that the performance of functional analysis tools is more sensitive to the gene sets than to the statistic used.