tbuckley/cabot-search huggingface dataset:
The association of patient fatigue and outcomes in advanced cancer: An analysis of four SWOG treatment trials.
Authors: Julia Mo, Amy Darke, Katherine A Guthrie, Jeff A. Sloan, Joseph M. Unger, Dawn L. Hershman, Mark Allen O'Rourke, Marie Bakitas, Robert S. Krouse
Journal: Journal of Clinical Oncology (2020)

140 Background: Prior studies have suggested that patient-reported outcomes may be associated with cancer outcomes. We evaluated the association between clinically significant fatigue (CSF) and adverse events (AEs), quality of life (QOL), and overall survival (OS) during cancer treatment. Methods: Four phase II or III chemotherapy trials, two each in advanced non-small cell lung cancer (NSCLC) and advanced hormone-refractory prostate cancer (HRPC), were used to compare patients with or without baseline CSF. Baseline CSF was defined as a rating of 2 or greater on the FACT fatigue survey question or an EORTC QLQ-C30 fatigue symptom score of 50% or greater. Change in QOL from baseline, AE rates, and survival were compared according to baseline CSF with linear regression models, equality of proportions chi-squared tests, and Kaplan-Meier survival estimates and Cox regression models, respectively, separately for each trial. Results: Of 1,994 participants, 1,907 had complete baseline QOL survey data, with 52% reporting CSF at baseline. Baseline CSF was associated with an increased incidence of grade 3-5 constitutional (16.5% vs 9.4%, p = 0.002 and 13.9% vs 6.3%, p = 0.002) and neurological (11.7% vs 6.1%, p = 0.006 and 9.0% vs 3.9%, p = 0.01) AEs, respectively, in two studies of advanced HRPC. Overall, patients with baseline CSF had significantly lower baseline QOL across all four domains (p &lt; 0.01). Across all four studies, baseline CSF was associated with higher mortality rates, with adjusted hazard ratios (95% confidence interval, p-value): 1.34 (1.14, 1.57, p &lt; .001) and 1.30 (1.02, 1.66, p = 0.03) in NSCLC studies, 1.49 (0.95, 2.35, p = 0.09) and 1.53 (1.12, 2.11, p = 0.008) in HRPC studies. Conclusions: Oncology trial participants with baseline CSF had significantly lower baseline QOL, experienced more adverse events and had poorer survival compared to participants without CSF. We have confirmed previous work indicating that fatigue is an important baseline stratification factor that should be considered in all oncology treatment trials. Consistent with other research, our results indicate that fatigue should be measured and ameliorated wherever possible among advanced cancer patients.
Analysis of the molecular nature associated with microsatellite status in colon cancer identifies clinical implications for immunotherapy
Authors: Xuanwen Bao, Hangyu Zhang, Wei Wu, Shaobing Cheng, Xiaomeng Dai, Xudong Zhu, Qihan Fu, Zhou Tong, Lulu Liu, Yi Zheng, Peng Zhao, Weijia Fang, Fanglong Liu
Journal: Journal for ImmunoTherapy of Cancer (2020)

Microsatellite instability in colon cancer implies favorable therapeutic outcomes after checkpoint blockade immunotherapy. However, the molecular nature of microsatellite instability is not well elucidated. We examined the immune microenvironment of colon cancer using assessments of the bulk transcriptome and the single-cell transcriptome focusing on molecular nature of microsatellite stability (MSS) and microsatellite instability (MSI) in colorectal cancer from a public database. The association of the mutation pattern and microsatellite status was analyzed by a random forest algorithm in The Cancer Genome Atlas (TCGA) and validated by our in-house dataset (39 tumor mutational burden (TMB)-low MSS colon cancer, 10 TMB-high MSS colon cancer, 15 MSI colon cancer). A prognostic model was constructed to predict the survival potential and stratify microsatellite status by a neural network. Despite the hostile CD8+ cytotoxic T lymphocyte (CTL)/Th1 microenvironment in MSI colon cancer, a high percentage of exhausted CD8+ T cells and upregulated expression of immune checkpoints were identified in MSI colon cancer at the single-cell level, indicating the potential neutralizing effect of cytotoxic T-cell activity by exhausted T-cell status. A more homogeneous highly expressed pattern of PD1 was observed in CD8+ T cells from MSI colon cancer; however, a small subgroup of CD8+ T cells with high expression of checkpoint molecules was identified in MSS patients. A random forest algorithm predicted important mutations that were associated with MSI status in the TCGA colon cancer cohort, and our in-house cohort validated higher frequencies of BRAF, ARID1A, RNF43, and KM2B mutations in MSI colon cancer. A robust microsatellite status-related gene signature was built to predict the prognosis and differentiate between MSI and MSS tumors. A neural network using the expression profile of the microsatellite status-related gene signature was constructed. A receiver operating characteristic curve was used to evaluate the accuracy rate of neural network, reaching 100%. Our analysis unraveled the difference in the molecular nature and genomic variance in MSI and MSS colon cancer. The microsatellite status-related gene signature is better at predicting the prognosis of patients with colon cancer and response to the combination of immune checkpoint inhibitor-based immunotherapy and anti-VEGF therapy.
US congressional leaders attack high pharma company prices
Authors: Paul D Thacker
Journal: BMJ (2020)

Congressional leaders in the US are challenging the high prices Americans pay for pharmaceuticals. Last week, the House Oversight Committee held two days of hearings, each beginning with the release of a congressional report containing drug company internal emails and strategy documents on pricing, followed by livestreamed forums with corporate executives forced to testify before the public.

“These companies sell drugs that are critical to our health and wellbeing, but their skyrocketing prices are unsustainable,” said chairwoman Carolyn B Maloney. Committee investigators spent almost two years examining more than a million pages of company internal documents that were requested in January 2019. Their reports provide new details about how and why company executives keep charging more.

On the first day of …
A computational approach to identify apossible SARS-CoV-2 vaccine from receptor bindingdomain peptide sequence on spike glycoproteins
Authors: Majid Al-Zahrani
Journal: Clinical Cancer Research (2020)

The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a pathogenic virus responsible for thecoronavirus disease 2019 (COVID-19) outbreak  The virus has rapidly spread worldwide and caused serious globalhealth and economic issues  The World Health Organization has declared COVID-19 a pandemic and suggestedthat all countries should take extreme countermeasures to stop it from spreading  SARS-CoV-2 targets theangiotensin-converting enzyme 2 (ACE2) receptor on human lung cells through receptor binding domain on thespike proteins (S-RBD) via N487, Y489, and G496 residues as previously reported  The virus uses ACE2 toinoculate mRNA and to replicate inside the cells, which results in a severe respiratory syndrome  Patients mightexperience serious symptoms including fever, cough, inability to taste, shortness of breath, and sometimesrespiratory failure  Therefore, developing a vaccine is highly necessary to control the outbreak, which led to our goalin this study to identify antigenic peptide sequences on the S-RBD domain that may induce the immune response toprovide protection from the virus  We virtually analyzed S-RBD protein structure by multiple sequence alignment(MSA) via CLUSTAL OMEGA to study the homology of the S-RBD domain in both strains (SARS-CoV and SARS-CoV-2), and the results showed 76% identical shared amino acids  Moreover, the S-RBD sequence for SARS-CoV-2was blasted against the sequence “486-FNCYFPLQSYGFQ-498” on Drugbank database with a penalty of -1 foreach indel, -3 for the mismatch, and with an expected value of 8 to screen for potential molecules that might interact with the target sequence  The blast results showed a possible alignment with complement component 4A (C4-A) protein, a protein involved in autoimmunity and antibody signaling, on the residues F490, C488, P491, Y495, G496, F497, and Q498  Lastly, a molecular docking analysis was performed by ClusPro 2 0 docking system to analyze thebinding affinity of C4-A protein to the S-RBD-protein, and the results of the docking analysis showed 30 differentbindings with different weighted energy coefficient scores  The top 10 binding conformations were chosen based onthe coefficient score values between -856 2 to -985 4  The highest binding affinity of C4-A protein was observed onthe target sequence, which might be a therapeutic approach for a possible COVID-19 vaccine  Further experimentsare required to synthesize recombinant peptides for S-RBD protein and test it on animal models to check if it willinduce C4-A production in response to recombinant S-RBD peptide and antibodies signaling to counter SARS-CoV-2 virus and, hopefully, competing with ACE2 binding to S-protein
Single‐cell molecular profiling provides a high‐resolution map of basophil and mast cell development
Authors: Fiona K. Hamey, Winnie W.Y. Lau, Iwo Kucinski, Xiaonan Wang, Evangelia Diamanti, Nicola K. Wilson, Berthold Göttgens, Joakim S. Dahlin
Journal: Allergy (2020)

Abstract Background Basophils and mast cells contribute to the development of allergic reactions. Whereas these mature effector cells are extensively studied, the differentiation trajectories from hematopoietic progenitors to basophils and mast cells are largely uncharted at the single‐cell level. Methods We performed multicolor flow cytometry, high‐coverage single‐cell RNA sequencing analyses, and cell fate assays to chart basophil and mast cell differentiation at single‐cell resolution in mouse. Results Analysis of flow cytometry data reconstructed a detailed map of basophil and mast cell differentiation, including a bifurcation of progenitors into two specific trajectories. Molecular profiling and pseudotime ordering of the single cells revealed gene expression changes during differentiation. Cell fate assays showed that multicolor flow cytometry and transcriptional profiling successfully predict the bipotent phenotype of a previously uncharacterized population of peritoneal basophil‐mast cell progenitors. Conclusions A combination of molecular and functional profiling of bone marrow and peritoneal cells provided a detailed road map of basophil and mast cell development. An interactive web resource was created to enable the wider research community to explore the expression dynamics for any gene of interest.
Covid-19, Ebola, and HIV — Leveraging Lessons to Maximize Impact
Authors: Connie Celum, Ruanne Barnabas, Myron S. Cohen, Ann Collier, Wafaa El-Sadr, King K. Holmes, Christine Johnston, Peter Piot
Journal: New England Journal of Medicine (2020)

Covid-19, Ebola, and HIV Our response to the Covid-19 pandemic should build on lessons from the HIV and Ebola epidemics, including the importance of basing interventions on sound science and of inv...
The Role of Market Forces in U.S. Health Care
Authors: Michael E. Chernew
Journal: New England Journal of Medicine (2020)

Interview with Dr. Michael Chernew on the role of markets in improving the efficiency of health care delivery. (12:18)Download The weaknesses associated with market-based health care systems are severe, but that does not mean the market should be abandoned. Relatively incremental actions could improve market functioning with a relatively light touch.
Facile engineering of silk fibroin capped AuPt bimetallic nanozyme responsive to tumor microenvironmental factors for enhanced nanocatalytic therapy
Authors: Ruihao Yang, Shiyan Fu, Ruidong Li, Lei Zhang, Zhigang Xu, Yang Cao, Hongjuan Cui, Yuejun Kang, Peng Xue
Journal: Theranostics (2020)

Background: Reactive oxygen species (ROS), as a category of highly reactive molecules, are attractive for eliminating tumor cells in situ.However, the intrinsic tumor microenvironment (TME) always compromises treatment efficacy.In another aspect, silk fibroin (SF), as a category of natural biomacromolecules, is highly promising for synthesis of metallic nanocrystals via biomineralization.Methods: As a proof-of-concept study, AuPt bimetallic nanozyme derived from bioinspired crystallization of chloroauric acid and chloroplatinic acid was facilely developed in the presence of silk fibroin (SF).Antitumor effects caused by the as-synthesized AuPt@SF (APS) nanozyme were demonstrated in 4T1 tumor cells in vitro and xenograft tumor models in vivo.Results: APS nanozyme can decompose glucose to constantly supply H2O2 and deplete intracellular glutathione (GSH).APS nanozyme can simultaneously convert adsorbed O2 and endogenic H2O2 into superoxide radicals ( • O2 -) and hydroxyl radical ( • OH), respectively, upon highly efficient catalytic reaction.Subsequently, these cytotoxic ROS cause irreversible damage to the cell membrane, nucleic acid and mitochondria of tumors.Upon fluorescence/photoacoustic (FL/PA)-imaging guidance, remarkable tumor damage based on the current nanoplatform was confirmed in vivo. Conclusion:The objective of our investigation is to supply more useful insights on the development of SF-based nanocatalysts, which are specifically responsive to TME for extremely efficient tumor theranostics.
A Bayesian Mutation–Selection Framework for Detecting Site-Specific Adaptive Evolution in Protein-Coding Genes
Authors: Nicolas Rodrigue, Thibault Latrille, Nicolas Lartillot
Journal: Molecular Biology and Evolution (2020)

In recent years, codon substitution models based on the mutation-selection principle have been extended for the purpose of detecting signatures of adaptive evolution in protein-coding genes. However, the approaches used to date have either focused on detecting global signals of adaptive regimes-across the entire gene-or on contexts where experimentally derived, site-specific amino acid fitness profiles are available. Here, we present a Bayesian site-heterogeneous mutation-selection framework for site-specific detection of adaptive substitution regimes given a protein-coding DNA alignment. We offer implementations, briefly present simulation results, and apply the approach on a few real data sets. Our analyses suggest that the new approach shows greater sensitivity than traditional methods. However, more study is required to assess the impact of potential model violations on the method, and gain a greater empirical sense its behavior on a broader range of real data sets. We propose an outline of such a research program.
Antibody dynamics to SARS‐CoV‐2 in asymptomatic COVID‐19 infections
Authors: Qing Lei, Yang Li, Hong‐yan Hou, Feng Wang, Zhu‐qing Ouyang, Yandi Zhang, Dan‐yun Lai, Jo‐Lewis Banga Ndzouboukou, Zhao‐wei Xu, Bo Zhang, Hong Chen, Jun‐biao Xue, Xiao‐song Lin, Yun‐xiao Zheng, Zong‐jie Yao, Xue‐ning Wang, Cai‐zheng Yu, He‐wei Jiang, Hai‐nan Zhang, Huan Qi, Shu‐juan Guo, Sheng‐hai Huang, Zi‐yong Sun, Sheng‐ce Tao, Xiong‐lin Fan
Journal: Allergy (2020)

Abstract Background The missing asymptomatic COVID‐19 infections have been overlooked because of the imperfect sensitivity of the nucleic acid testing (NAT). Globally understanding the humoral immunity in asymptomatic carriers will provide scientific knowledge for developing serological tests, improving early identification, and implementing more rational control strategies against the pandemic. Measure Utilizing both NAT and commercial kits for serum IgM and IgG antibodies, we extensively screened 11 766 epidemiologically suspected individuals on enrollment and 63 asymptomatic individuals were detected and recruited. Sixty‐three healthy individuals and 51 mild patients without any preexisting conditions were set as controls. Serum IgM and IgG profiles were further probed using a SARS‐CoV‐2 proteome microarray, and neutralizing antibody was detected by a pseudotyped virus neutralization assay system. The dynamics of antibodies were analyzed with exposure time or symptoms onset. Results A combination test of NAT and serological testing for IgM antibody discovered 55.5% of the total of 63 asymptomatic infections, which significantly raises the detection sensitivity when compared with the NAT alone (19%). Serum proteome microarray analysis demonstrated that asymptomatics mainly produced IgM and IgG antibodies against S1 and N proteins out of 20 proteins of SARS‐CoV‐2. Different from strong and persistent N‐specific antibodies, S1‐specific IgM responses, which evolved in asymptomatic individuals as early as the seventh day after exposure, peaked on days from 17 days to 25 days, and then disappeared in two months, might be used as an early diagnostic biomarker. 11.8% (6/51) mild patients and 38.1% (24/63) asymptomatic individuals did not produce neutralizing antibody. In particular, neutralizing antibody in asymptomatics gradually vanished in two months. Conclusion Our findings might have important implications for the definition of asymptomatic COVID‐19 infections, diagnosis, serological survey, public health, and immunization strategies.
Advanced hydrogels for the repair of cartilage defects and regeneration
Authors: Wei Wei, Yuanzhu Ma, Xudong Yao, Wenyan Zhou, Xiaozhao Wang, Chenglin Li, Junxin Lin, Qiulin He, Sebastian Leptihn, Hongwei Ouyang
Journal: Bioactive Materials (2020)

Cartilage defects are one of the most common symptoms of osteoarthritis (OA), a degenerative disease that affects millions of people world-wide and places a significant socio-economic burden on society. Hydrogels, which are a class of biomaterials that are elastic, and display smooth surfaces while exhibiting high water content, are promising candidates for cartilage regeneration. In recent years, various kinds of hydrogels have been developed and applied for the repair of cartilage defects in vitro or in vivo, some of which are hopeful to enter clinical trials. In this review, recent research findings and developments of hydrogels for cartilage defects repair are summarized. We discuss the principle of cartilage regeneration, and outline the requirements that have to be fulfilled for the deployment of hydrogels for medical applications. We also highlight the development of advanced hydrogels with tailored properties for different kinds of cartilage defects to meet the requirements of cartilage tissue engineering and precision medicine.
Inhibition of aquaporin-1 prevents myocardial remodeling by blocking the transmembrane transport of hydrogen peroxide
Authors: Virginie Montiel, Ramona Bella, Lauriane Y. M. Michel, Hrag Esfahani, Delphine De Mulder, Emma L. Robinson, Jean-Philippe Deglasse, Malte Tiburcy, Pak Hin Chow, Jean-Christophe Jonas, Patrick Gilon, Benjamin Steinhorn, Thomas Michel, Christophe Beauloye, Luc Bertrand, Charlotte Farah, Flavia Dei Zotti, Huguette Debaix, Caroline Bouzin, Davide Brusa, Sandrine Horman, Jean-Louis Vanoverschelde, Olaf Bergmann, Dimitri Gilis, Marianne Rooman, Alessandra Ghigo, Simonetta Geninatti-Crich, Andrea Yool, Wolfram H. Zimmermann, H. Llewelyn Roderick, Olivier Devuyst, Jean-Luc Balligand
Journal: Science Translational Medicine (2020)

Pharmacological inhibition of AQP1 prevents H 2 O 2 transport and hypertrophy of cardiac myocytes.
THU0052 Heparin affin regulatory peptide (harp) in acute and chronic articular diseases
Authors: M Héroult, F Lioté, R Champy, D Barritault, J Courty
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Heparin affin regulatory peptide (HARP), also known as pleiotrophin (PTN) is a potent mitogen for various cell types and an angiogenic polypeptide implicated in tumour development.<sup>1–4</sup> <h3>Objectives</h3> Since the progression of the pannus is associated with angiogenic processes and synovial membrane hypertrophy,<sup>5,6</sup> the involvement of HARP in comparison with two other growth factors including MK and VEGF in rheumatoid pathologies was investigated. <h3>Methods</h3> Presence of HARP in human synovial fluids and sera from patients was investigated by immunoassay. The distribution of HARP mRNA and protein was studied by <i>in situ</i> hybridization and immunohistochemistry respectively. <h3>Results</h3> Comparative analysis showed that HARP as well as MK concentrations were significantly higher (p &lt; 0.001) in synovial fluids from patients with inflammatory arthritis including rheumatoid arthritis (n = 14), ankylosing spondylitis (n = 8), chondrocalcinosis (n = 7) and gout (n = 11) than from patients with osteoarthritis (n = 29). In contrast, no significant difference was observed between inflammatory and non inflammatory diseases for VEGF. In addition, serum HARP and MK concentrations were significantly higher in patients with arthritis (n = 37) than in normal subjects (n = 18) (p &lt; 0.001). Immunohistological studies demonstrated HARP within the synovial lining cells, endothelial cells of new capillaries, and macrophages of inflammatory synovial tissue. <i>In situ</i> hybridization studies revealed that synovial lining cells and vascular endothelial cells expressed high levels of HARP mRNA. <h3>Conclusion</h3> These results suggest that HARP, in concert with other cytokines and growth factors, may play a role in the pathophysiology of acute and chronic synovitis in conditions such as crystal-induced arthritis and rheumatoid arthritis, respectively. <h3>References</h3> Li YS, Milner PG, Chauhan AK, Watson MA, Hoffman RM, Kodner CM, Milbrandt J, Deuel TF. Science 1990;250:1690–4 Courty J, Dauchel MC, Caruelle D, Pederiset M, Barritault D. <i>Biochem Biophy Res Commun</i>. 1991;180:145–51 Bernard-Pierrot I, Delbé J, Caruelle D, Barritault D, Courty J. <i>J Biol Chem</i>. in press Choudhuri R, Zhang HT, Donnini S, Ziche M, Bicknell R. Cancer Res. 1997;57:1814–19 Peacok DJ, Banquerigo ML, Brahn E. J Exp Med. 1992;175:1135–8 Koch AE. Ann Rheu Dis. 2000;59(Suppl 1):I65–71