tbuckley/cabot-search huggingface dataset:
Gut Reactions: Breaking Down Xenobiotic–Microbiome Interactions
Authors: Gerard Clarke, Kiran V. Sandhu, Brendan T. Griffin, Timothy G. Dinan, John F. Cryan, Niall P. Hyland
Journal: Pharmacological Reviews (2019)

The microbiome plays a key role in health and disease, and there has been considerable interest in therapeutic targeting of the microbiome as well as mining this rich resource in drug discovery efforts. However, a growing body of evidence suggests that the gut microbiota can itself influence the actions of a range of xenobiotics, in both beneficial and potentially harmful ways. Traditionally, clinical studies evaluating the pharmacokinetics of new drugs have mostly ignored the important direct and indirect effects of the gut microbiome on drug metabolism and efficacy. Despite some important observations from xenobiotic metabolism in general, there is only an incomplete understanding of the scope of influence of the microbiome specifically on drug metabolism and absorption, and how this might influence systemic concentrations of parent compounds and toxic metabolites. The significance of both microbial metabolism of xenobiotics and the impact of the gut microbiome on host hepatic enzyme systems is nonetheless gaining traction and presents a further challenge in drug discovery efforts, with implications for improving treatment outcomes or counteracting adverse drug reactions. Microbial factors must now be considered when determining drug pharmacokinetics and the impact that an evolving and dynamic microbiome could have in this regard. In this review, we aim to integrate the contribution of the gut microbiome in health and disease to xenobiotic metabolism focusing on therapeutic interventions, pharmacological drug action, and chemical biotransformations that collectively will have implications for the future practice of precision medicine.
Simulating exploration versus exploitation in agent foraging under different environment uncertainties
Authors: Nader Chmait, David L. Dowe, David G. Green, Yuan-Fang Li
Journal: Behavioral and Brain Sciences (2019)

Abstract For artificial agents trading off exploration (food seeking) versus (short-term) exploitation (or consumption), our experiments suggest that uncertainty (interpreted information, theoretically) magnifies food seeking. In more uncertain environments, with food distributed uniformly randomly, exploration appears to be beneficial. In contrast, in biassed (less uncertain) environments, with food concentrated in only one part, exploitation appears to be more advantageous. Agents also appear to do better in biassed environments.
Expenses disclosure at BMA sparks review
Authors: Melanie Newman
Journal: BMJ (2019)

The BMA has come under fire from members of its governing council after it emerged that until the practice was stopped earlier this year many senior officers had been taking spouses with them on trips abroad and reclaiming the costs as expenses, even though the BMA had no formal policy to permit it.

During this period the only senior officer officially allowed to be accompanied by his or her partner to some events and to claim for the associated costs was the BMA president. However, it recently became apparent that other senior officers were also reimbursed for spousal travel expenses in this way.

Chaand Nagpaul, who has been chair of the BMA’s ruling council since 2017, instituted a ban on such expense claims after he became aware of them this January. He is now planning a wider review of the BMA’s governance.

The scale of the payouts is not yet clear. The BMJ has been told that none of the current chief …
QIM19-121: Improving Testing for Hepatitis B Before Treatment With Rituximab Through Automated Electronic Health Record Alert System: A Single Institutional Retrospective Review and Quality Improvement Project
Authors: Sowmya Boddhula, Satish Kumar Boddhula, Bishesh Shrestha, Kelly Morris, Rosana Gnanajothy
Journal: Journal of the National Comprehensive Cancer Network (2019)

Introduction: Individuals with chronic hepatitis B virus infection (HBV) or previous infection with HBV are at increased risk of HBV exacerbation or reactivation when they receive treatment with anti-CD20 monoclonal antibodies like rituximab (RTX). HBV screening and appropriate use of prophylactic antiviral therapy is recommended to prevent reactivation. A software program named Beacon Oncology was integrated into Epic, which creates an automated alert for HBV screening before starting first dose of chemotherapy with RTX and results the previously resulted HBV test results. Retrospective data analysis for screening was done after implementation of the software and its impact was assessed. Methods: We conducted retrospective chart review on screening for HBV before starting treatment with RTX before and after implementation of the electronic health record (EHR) alert system. Results: A baseline review (before software introduction) of 165 patients showed that only 40 (24%) had screening tests for HBV (hepatitis B surface antigen [HBsAg] and hepatitis B core antibody [anti-HBcAb]) before receiving rituximab. Following introduction of the automated electronic alert system, chart review for HBV testing rates among patients being initiated onto rituximab was performed. There was a marked increase in pre-rituximab testing for HBsAg from 24% to 88% and for anti-HBcAb from 24% to 76%. The remainder cases also had the HBV screening done but after the first dose of the RTX chemotherapy between 1.3 to 7.5 days. There was one patient identified as anti-HBcAb-positive after the implementation of the protocol. Conclusions: This retrospective single-institution study clearly indicates that simple strategies can markedly improve appropriate HBV screening. There was a more than 3-fold increase in HBV testing before the first dose of HBV after implementation of the EHR alert system. There has been increased use of EHR alert systems recently to improve implementation of clinical guidelines, and they have been shown to improve patient outcomes. In conclusion, an automated EHR alert directed toward screening for HBV before initiating RTX effectively increased the number of HBV screening tests completed, and similar protocols could be implemented to identify other at-risk patient groups.
FLT PET/CT imaging of metastatic prostate cancer patients treated with pTVG-HP DNA vaccine and pembrolizumab
Authors: Matthew Scarpelli, Christopher Zahm, Scott Perlman, Douglas G. McNeel, Robert Jeraj, Glenn Liu
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Immunotherapy has demonstrated remarkable success in treating different cancers. Nonetheless, a large number of patients do not respond, many respond without immediate changes detectable with conventional imaging, and many have unusual immune-related adverse events that cannot be predicted in advance. In this exploratory study, we investigate how 3′-Deoxy-3'-<sup>18</sup>F-fluorothymidine (FLT) positron emission tomography (PET) measurements of tumor and immune cell proliferation might be utilized as biomarkers in immunotherapy. <h3>Methods</h3> Seventeen patients with metastatic castrate resistant prostate cancer were treated with combination pTVG-HP DNA vaccine and pembrolizumab. Patients underwent baseline and 12-week FLT PET/CT scans. FLT PET standardized uptake values (SUVs) were extracted from tumors, non-metastatic lymph nodes, spleen, bone marrow, pancreas, and thyroid to quantify cell proliferation in these tissues. Regional immune cell responses to pTVG-HP DNA vaccine were assessed by comparing FLT uptake changes in vaccine draining and non-draining lymph nodes. Cox proportional hazards regression was utilized to relate FLT uptake and other clinical markers (PSA and tumor size) to progression-free survival. Area under receiver operating characteristic (AUC) curves and concordance indices were used to assess the predictive capabilities of FLT uptake. <h3>Results</h3> Changes in FLT uptake in vaccine draining lymph nodes were significantly greater than changes in non-draining lymph nodes (<i>P</i> = 0.02), suggesting a regional immune response to vaccination. However, the changes in FLT uptake in lymph nodes were not significantly predictive of progression-free survival. Increases in tumor FLT uptake were significantly predictive of shorter progression-free survival (concordance index = 0.83, <i>P</i> &lt; 0.01). Baseline FLT uptake in the thyroid was significantly predictive of whether or not a patient would subsequently experience a thyroid-related adverse event (AUC = 0.97, <i>P</i> &lt; 0.01). <h3>Conclusions</h3> FLT PET uptake was significantly predictive of progression-free survival and the occurrence of adverse events relating to thyroid function. The results suggest FLT PET imaging has potential as a biomarker in immunotherapy, providing a marker of tumor and immune responses, and as a possible means of anticipating specific immune-related adverse events. <h3>Trial registration</h3> NCT02499835.
<i>miR-26a</i> Limits Muscle Wasting and Cardiac Fibrosis through Exosome-Mediated microRNA Transfer in Chronic Kidney Disease
Authors: Bin Wang, Aiqing Zhang, Haidong Wang, Janet D. Klein, Lin Tan, Ze-Mu Wang, Jie Du, Nawazish Naqvi, Bi-Cheng Liu, Xiaonan H. Wang
Journal: Theranostics (2019)

Uremic cardiomyopathy and muscle atrophy are associated with insulin resistance and contribute to chronic kidney disease (CKD)-induced morbidity and mortality. We hypothesized that restoration of miR-26a levels would enhance exosome-mediated microRNA transfer to improve muscle wasting and cardiomyopathy that occur in CKD. Methods: Using next generation sequencing and qPCR, we found that CKD mice had a decreased level of miR-26a in heart and skeletal muscle. We engineered an exosome vector that contained Lamp2b, an exosomal membrane protein gene fused with a muscle-specific surface peptide that targets muscle delivery. We transfected this vector into muscle satellite cells and then transduced these cells with adenovirus that expresses miR-26a to produce exosomes encapsulated miR-26a (Exo/miR-26a). Exo/miR-26a was injected once per week for 8 weeks into the tibialis anterior (TA) muscle of 5/6 nephrectomized CKD mice. Results: Treatment with Exo/miR-26a resulted in increased expression of miR-26a in skeletal muscle and heart. Overexpression of miR-26a increased the skeletal muscle cross-sectional area, decreased the upregulation of FBXO32/atrogin-1 and TRIM63/MuRF1 and depressed cardiac fibrosis lesions. In the hearts of CKD mice, FoxO1 was activated, and connective tissue growth factor, fibronectin and collagen type I alpha 1 were increased. These responses were blunted by injection of Exo/miR-26a. Echocardiograms showed that cardiac function was improved in CKD mice treated with Exo/miR-26a. Conclusion: Overexpression of miR-26a in muscle prevented CKD-induced muscle wasting and attenuated cardiomyopathy via exosome-mediated miR-26a transfer. These results suggest possible therapeutic strategies for using exosome delivery of miR-26a to treat complications of CKD.
Genomic and transcriptional heterogeneity of multifocal hepatocellular carcinoma
Authors: L.X. Xu, M.H. He, Z.H. Dai, J. Yu, J.G. Wang, X.C. Li, B.B. Jiang, Z.F. Ke, T.H. Su, Z.W. Peng, Y. Guo, Z.B. Chen, S.L. Chen, S. Peng, M. Kuang
Journal: Annals of Oncology (2019)

BackgroundHepatocellular carcinoma (HCC) often presents with multiple nodules within the liver, with limited effective interventions. The high genetic heterogeneity of HCC might be the major cause of treatment failure. We aimed to characterize genomic heterogeneity, infer clonal evolution, investigate RNA expression pattern and explore tumour immune microenvironment profile of multifocal HCC.Patients and methodsWhole-exome sequencing and RNA sequencing were carried out in 34 tumours and 6 adjacent normal liver tissue samples from 6 multifocal HCC patients. Protein expression of Ki67, AFP, P53, Survivin and CD8 was detected by immunohistochemistry. Fluorescence in situ hybridization was carried out to validate the amplification status of sorafenib-targeted genes.ResultsWe deciphered genomic and transcriptional heterogeneity among tumours in each multifocal HCC patient including mutational profiles, copy number alterations, tumour evolutionary trajectory and tumour immune microenvironment profiles. Of note, sorafenib-targeted alterations were identified in the trunk of phylogenetic tree in only one out of the six patients, which may explain the relative low treatment response rate to sorafenib in clinical practice. Moreover, we demonstrated RNA expression patterns and tumour immune microenvironment profiles of all nodules. We found that RNA expression pattern was associated with Edmondson–Steiner grading. Based on the differential expression of 66 reported immune markers, unsupervised hierarchical clustering analysis of 34 nodules identified immune subsets: one low expression cluster with seven nodules and one high expression cluster with 11 nodules. CD8+ T cells were more enriched in nodules of the high expression cluster.ConclusionsOur study provided a detailed view of genomic and transcriptional heterogeneity, clonal evolution and immune infiltration of multifocal HCC. The heterogeneity of druggable targets and immune landscape might help interpret the clinical responsiveness to targeted drugs and immunotherapy for multifocal HCC patients.
Comparison of vascularity measures from PET and MRI for improved breast tumor characterization and therapeutic response evaluation
Authors: S. C. Partridge, P. R. Eby, R. K. Doot, S. W. White, B. F. Kurland, E. K. Schubert, L. K. Dunnwald, C. D. Lehman, D. A. Mankoff
Journal: Journal of Clinical Oncology (2007)

589 Background: Dynamic contrast-enhanced MRI (DCE-MRI) and positron emission tomography (PET) are two imaging modalities previously shown to be predictive of response to neoadjuvant therapy in breast cancer. As the two techniques are functionally very different, the extent of their agreement or discordance for tumor characterization is not well understood. The purpose of this study was therefore to investigate the association between quantitative DCE-MRI enhancement kinetics and 15 O-water PET/ 18 F-FDG PET blood flow and metabolic measures of breast tumors. Methods: We retrospectively evaluated exams for 20 patients with locally advanced breast cancer (LABC) who underwent both 15 O-water/ 18 F-FDG PET and DCE-MRI. PET measures included 15 O-water blood flow, 18 F-FDG transport rate constant from blood to tissue (K 1 ), and FDG metabolic rate. DCE-MRI measures included functional tumor volume, initial peak enhancement (PE), and a delayed signal enhancement ratio (SER) assessing washout. Pearson’s correlations and multivariate stepwise regression analyses were performed; p&lt;0.05 was considered significant. Results: PET 15 O-water blood flow correlated significantly with DCE-MRI peak SER (r=0.8) and tumor volume (r=0.7). PET K 1 measures correlated significantly with DCE-MRI peak PE (r=0.7), peak SER (r=0.6) and tumor volume (r=0.6). By multivariate analysis, SER was the strongest independent MRI correlate of PET blood flow, and PE the strongest MRI correlate for K 1 . No significant correlations were observed between 18 F-FDG PET metabolic rate and the DCE-MRI kinetic parameters. Also, while blood flow and K 1 were strongly correlated (r=0.9, p=0.0001), blood flow and metabolic rate were not (r=0.4, p=0.12). Conclusions: The associations between PET and MRI measures may lead to a better understanding of angiogenesis, vascular permeability, and glucose transport in LABC. A lack of correlation of metabolic rate with blood flow and DCE MRI kinetics suggests that 18 F-FDG PET provides complimentary metabolic information independent of vascular factors. The combination of MRI and PET may be helpful in understanding tumor pharmacodynamics in response to novel therapy. No significant financial relationships to disclose.
Complement C4 Prevents Viral Infection through Capsid Inactivation
Authors: Maria Bottermann, Stian Foss, Sarah L. Caddy, Dean Clift, Laurens M. van Tienen, Marina Vaysburd, James Cruickshank, Kevin O’Connell, Jessica Clark, Keith Mayes, Katie Higginson, Heidrun E. Lode, Martin B. McAdam, Inger Sandlie, Jan Terje Andersen, Leo C. James
Journal: Cell Host & Microbe (2019)
Fully Automated, Label-Free Isolation of Extracellular Vesicles from Whole Blood for Cancer Diagnosis and Monitoring
Authors: Vijaya Sunkara, Chi-Ju Kim, Juhee Park, Hyun-Kyung Woo, Dongyoung Kim, Hong Koo Ha, Mi-Hyun Kim, Youlim Son, Jae-Ryong Kim, Yoon-Kyoung Cho
Journal: Theranostics (2019)

Extracellular vesicles (EVs) that circulate in body fluids possess significant potential for disease diagnosis.Their use in clinical settings, however, has been limited owing to lack of simple and robust isolation methods.To rectify this problem, a centrifugal device for automatic, fast, and efficient isolation of EVs from whole-blood, called Exodisc-B is presented in this paper.Methods: The device comprises a built-in chamber to facilitate plasma separation and two nanoporous filters-one for removing larger particles and the other for enriching EVs.The performance of the device in comparison to ultracentrifugation (UC) was evaluated by analyzing the yield, purity, protein and RNA content of the isolated EVs.Additionally, the EV protein marker expressions were measured by ELISA and statistically analyzed to differentiate prostate cancer patients from healthy donors.Results: Compared with the UC technique, the proposed device is capable of isolating at least an order of magnitude higher number of EVs with about 30-fold higher mRNA count within 40 min.Sandwich ELISA of EV-specific membrane proteins-CD9-CD81-confirmed that Exodisc-B can isolate EVs from a volume of whole blood as low as 30 µL with a capture efficiency exceeding 75%.The device also facilitates temporal monitoring of tumor progression within live mouse xenograft models over a period of 13 weeks while using minimal volumes of weekly collected blood samples.Further, in ELISA analyses of multiple cancer-related proteins, such as prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), epithelial cell adhesion molecule (EpCAM), epidermal growth factor receptor 1 (EGFR1), and heat shock protein 90 (HSP90), extracted from EVs isolated from human plasma, 43 patients were differentiated from 30 healthy donors. Conclusion:The results demonstrated the ability of Exodisc-B to provide a rapid, sensitive, and point-of-care-type method for extracting intact EVs from small volumes of clinical blood samples for disease diagnosis and monitoring.
BTNL2‐Ig Protein Attenuates Type 1 Diabetes in Non‐Obese Diabetic (NOD) Mice
Authors: Xiaohong Tian, Yujun Lin, Cheng Cui, Min Su, Laijun Lai
Journal: Advanced Healthcare Materials (2019)

Abstract Type 1 diabetes (T1D) is a T cell‐mediated autoimmune disease in which insulin‐producing β ‐cells are destroyed. Although butyrophilin‐like 2 (BTNL2) has been shown to be a negative T cell regulator in vitro, its ability to inhibit T cell responses in vivo has not been determined. In this study, the effect of a recombinant BTNL2‐IgG2a Fc (rBTNL2‐Ig) fusion protein on T1D development in vivo is determined. It is shown here that in vivo administration of rBTNL2‐Ig ameliorates T1D in non‐obese diabetic (NOD) mice. This is associated with the ability of rBTNL2‐Ig to inhibit the proliferation, activation, and inflammatory cytokine production from autoreactive T cells in vivo. In addition, rBTNL2‐Ig treatment increases the generation of regulatory T cells. The results suggest that targeting the BTNL2 pathway has the potential to be used in the prevention and treatment of patients with T1D.
The role of SOX family members in solid tumours and metastasis
Authors: Daniela Grimm, Johann Bauer, Petra Wise, Marcus Krüger, Ulf Simonsen, Markus Wehland, Manfred Infanger, Thomas J. Corydon
Journal: Seminars in Cancer Biology (2019)

Cancer is a heavy burden for humans across the world with high morbidity and mortality. Transcription factors including sex determining region Y (SRY)-related high-mobility group (HMG) box (SOX) proteins are thought to be involved in the regulation of specific biological processes. The deregulation of gene expression programs can lead to cancer development. Here, we review the role of the SOX family in breast cancer, prostate cancer, renal cell carcinoma, thyroid cancer, brain tumours, gastrointestinal and lung tumours as well as the entailing therapeutic implications. The SOX family consists of more than 20 members that mediate DNA binding by the HMG domain and have regulatory functions in development, cell-fate decision, and differentiation. SOX2, SOX4, SOX5, SOX8, SOX9, and SOX18 are up-regulated in different cancer types and have been found to be associated with poor prognosis, while the up-regulation of SOX11 and SOX30 appears to be favourable for the outcome in other cancer types. SOX2, SOX4, SOX5 and other SOX members are involved in tumorigenesis, e.g. SOX2 is markedly up-regulated in chemotherapy resistant cells. The SoxF family (SOX7, SOX17, SOX18) plays an important role in angio- and lymphangiogenesis, with SOX18 seemingly being an attractive target for anti-angiogenic therapy and the treatment of metastatic disease in cancer. In summary, SOX transcription factors play an important role in cancer progression, including tumorigenesis, changes in the tumour microenvironment, and metastasis. Certain SOX proteins are potential molecular markers for cancer prognosis and putative potential therapeutic targets, but further investigations are required to understand their physiological functions.
Impact of mastectomy on quality of life in female patients with breast cancer in the Gaza Strip: a cross-sectional study
Authors: Enas Alaloul, Mohamedraed Elshami, Esraa Khader, Huda Abu Nemer, Alaa Alhelu, Israa Awad, Heba Baraka, Bettina Böttcher, Khamis Elessi
Journal: The Lancet (2019)
Hyperprogression—Immunotherapy-Related Phenomenon vs Intrinsic Natural History of Cancer—In Reply
Authors: Roberto Ferrara, Caroline Caramella, Benjamin Besse
Journal: JAMA Oncology (2019)

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Animal models of arrhythmia: classic electrophysiology to genetically modified large animals
Authors: Sebastian Clauss, Christina Bleyer, Dominik Schüttler, Philipp Tomsits, Simone Renner, Nikolai Klymiuk, Reza Wakili, Steffen Massberg, Eckhard Wolf, Stefan Kääb
Journal: Nature Reviews Cardiology (2019)
Preliminary Safety Profile of the CD19-Directed Defined Composition CAR T Cell Product JCAR017 in Relapsed/Refractory Aggressive B-NHL Patients: Potential for Outpatient Administration
Authors: David G. Maloney, Jeremy S. Abramson, Maria Lia Palomba, Leo I. Gordon, Matthew A. Lunning, Jon E. Arnason, Michael Wang, Andres Forero, Tina Albertson, Jacob Garcia, Daniel Li, Benhuai Xie, Tanya Siddiqi
Journal: Blood (2017)