tbuckley/cabot-search huggingface dataset:
NICE asks care home visitors to look for signs of neglect
Authors: Ingrid Torjesen
Journal: BMJ (2020)

People who spend time in care homes, whether visiting residents or in a professional capacity, are being asked by the UK National Institute for Health and Care Excellence to look out for signs of neglect and abuse and to report them if they spot them.1

NICE’s draft guideline on safeguarding adults in care homes says that care home staff and all types of visitors, be they NHS or social care professionals, or family and friends of the residents, can play an important role in identifying and halting neglect and abuse. It outlines potential signs of neglect and abuse, differentiating between signs and physical and emotional behaviours displayed by residents that may be possible indicators of abuse or neglect that may require investigation and those stronger signals that should prompt immediate action.

For signs where there may be another plausible …
Toward a unified genetic map of higher plants, transcending the monocot-dicot divergence. [Erratum: Mar 1997, v. 15 (3), p. 322.]
Authors: A.H. Patterson, T.H. Lan, K.P. Reischmann, C. Chang, Y.R. Lin, S.C. Liu, Burow, S.P. Kowalski, C.S. Katsar, T.A. DelMonte
Journal: Nature Genetics (1996)
Hepatitis B virus persistence and reactivation
Authors: Yu Shi, Min Zheng
Journal: BMJ (2020)

Hepatitis B virus (HBV) infection causes chronic hepatitis and has long term complications. Individuals ever infected with HBV are at risk of viral reactivation under certain circumstances. This review summarizes studies on HBV persistence and reactivation with a focus on the definitions and mechanisms. Emphasis is placed on the interplay between HBV replication and host immunity as this interplay determines the patterns of persistence following viral acquisition. Chronic infections exhibit as overt persistence when a defective immune response fails to control the viral replication. The HBV genome persists despite an immune response in the form of covalently closed circular DNA (cccDNA) and integrated DNA, rendering an occult state of viral persistence in individuals whose infection appears to have been resolved. We have described HBV reactivation that occurs because of changes in the virus or the immune system. This review aims to raise the awareness of HBV reactivation and to understand how HBV persists, and discusses the risks of HBV reactivation in a variety of clinical settings.
Celastrol induces ROS-mediated apoptosis via directly targeting peroxiredoxin-2 in gastric cancer cells
Authors: Xi Chen, Ying Zhao, Wu Luo, Sian Chen, Feng Lin, Xi Zhang, Shijie Fan, Xian Shen, Yi Wang, Guang Liang
Journal: Theranostics (2020)

Background: Oxidative stress from elevated reactive oxygen species (ROS) has been reported to induce cell apoptosis and may provide a means to target cancer cells. Celastrol is a natural bioactive compound that was recently shown to increase ROS levels and cause apoptosis in cancer cells. However, the underlying mechanism for this cytotoxic action remains unclear and direct molecular targets of Celastrol have not been identified. Methods: Proteome microarray, surface plasmon resonance, isothermal titration calorimetry and molecular simulation were used to identify the molecular target of Celastrol. Binding and activity assays were used to validate the interaction of Celastrol with target protein in cell-free and gastric cancer cell lysates. We then assessed target transcript levels in in biopsy specimens obtained from patients with gastric cancer. Gastric cancer growth-limiting and cytotoxic activity of Celastrol was evaluated in BALB/c nu/nu mice. Results: Our data show that Celastrol directly binds to an antioxidant enzyme, peroxiredoxin-2 (Prdx2), which then inhibits its enzyme activity at both molecular and cellular level. Inhibition of Prdx2 by Celastrol increased cellular ROS levels and led to ROS-dependent endoplasmic reticulum stress, mitochondrial dysfunction, and apoptosis in gastric cancer cells. Functional tests demonstrated that Celastrol limits gastric cancer cells, at least in part, through targeting Prdx2. Celastrol treatment of mice implanted with gastric cancer cells also inhibited tumor growth, associated with Prdx2 inhibition and increased ROS. Analysis of human gastric cancer also showed increased Prdx2 levels and correlation with survival. Conclusion: Our studies have uncovered a potential Celastrol-interacting protein Prdx2 and a ROS-dependent mechanism of its action. The findings also highlight Prdx2 as a potential target for the treatment of gastric cancer.
Abstract 4595: SERGE- the development of an optical sensor for the detection glioblastoma recurrence
Authors: Igor Fischer, Daniel Hänggi, Ulf Dietrich Kahlert
Journal: Cancer Research (2020)

Abstract Objective: Total gross resection is the clinical most positive prognostic treatment of brain cancer. Tumor recurrence is a frequent event in patients undergone neurosurgical removal of the primary cancer. Current surveillance of the disease requires cost-intensive and infrastructural sophisticated means and is applied in an infrequent manner. Better tools to monitor the therapy success in order to increase the chances of total gross resection of the recurrent lesion are of high clinical need. Concept and Results: Photodynamic diagnosis (PDD) is a clinical applied procedure that exploits metabolic alterations in brain tumor cells to discriminate of cancerous tissue from healthy brain parenchyma. This project aims to develop an implant-prototype that enables the surveillance of any tumor recurrence at the primary tumor resection cavity by applying the principles of PDD. We present initial electro-engineering details and the study design to probe its functionality in vitro and in vivo. Supported by the Volkswagen Foundation the project aims to create evidences for the technological feasibility and therapeutic benefit of SERGE as a future class III medical device. Citation Format: Igor Fischer, Daniel Hänggi, Ulf Dietrich Kahlert. SERGE- the development of an optical sensor for the detection glioblastoma recurrence [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4595.
Salidroside can target both P4HB-mediated inflammation and melanogenesis of the skin
Authors: Xiu-Juan Ding, Zhi-Yuan Zhang, Jing Jin, Jing-Xia Han, Yan Wang, Kai Yang, Yu-Yan Yang, Hong-Qi Wang, Xin-Tong Dai, Cheng Yao, Tao Sun, Cai-Bin Zhu, Hui-Juan Liu
Journal: Theranostics (2020)

Many external factors can induce the melanogenesis and inflammation of the skin. Salidroside (SAL) is the main active ingredient of
Abstract 242: Identification of biomarkers predicting sensitivity to GLS1 inhibition using a CRISPR screen
Authors: Christophe Henry, Karine Berthelot, Christophe Lanneau, Cécile Orsini, Dimitri Gorge-Bernat, Isabelle Meaux, Dorine Chassin, Jürgen Moll, Berangere Thiers, David Machnik, Laurent Debussche
Journal: Cancer Research (2020)

Abstract The conditional essential amino acid glutamine is utilized by tumors to sustain bioenergetic requirements in a nutrient-poor microenvironment. Based on this specific tumor need, efforts have been made to target the glutamine metabolism using glutaminase inhibitors. This approach has demonstrated activity in preclinical models and in a range of phase I studies. It was shown that a subset of models/patients are benefiting from glutaminase inhibition, however, biomarkers predicting sensitivity to GLS1 inhibitors are lacking. The objective of this study is to identify molecular predictors of the sensitivity towards GLS1 inhibition. Using the cBioportal, we analyzed the most prevalent genetic deficiencies in Triple Negative Breast cancers, Kidney cancers, Acute Myeloid Leukemia and Multiple Myeloma. From this analysis, a library of CRISPR gRNA including the most disease relevant LOF linked-genes was created. Individual cell lines stably expressing Cas9 were used for a focused CRISPR screen in the presence of suboptimal doses of GLS1 inhibitor. The sgRNA library mimicking the major genetic deficiencies identified from the cBioportal datamining was delivered in pool lentiviral particles. Genes deficiencies associated with increased GLS1 sensitivity were identified with sgRNA targeted NGS sequencing of the remaining cell population at treatment completion. We present the setup and validation of an innovative experimental design for the identification of biomarkers predictive to GLS1 inhibition with the aim to identify gene deficiencies associated with increased sensitivity to GLS1 inhibitors that could be used as predictive biomarkers in the clinic. Citation Format: Christophe Henry, Karine Berthelot, Christophe Lanneau, Cécile Orsini, Dimitri Gorge-Bernat, Isabelle Meaux, Dorine Chassin, Jürgen Moll, Berangere Thiers, David Machnik, Laurent Debussche. Identification of biomarkers predicting sensitivity to GLS1 inhibition using a CRISPR screen [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 242.
Increasing proportion of vancomycin resistance among enterococcal bacteraemias in Switzerland: a 6-year nation-wide surveillance, 2013 to 2018
Authors: Vanja Piezzi, Michael Gasser, Andrew Atkinson, Andreas Kronenberg, Danielle Vuichard-Gysin, Stephan Harbarth, Jonas Marschall, Niccolò Buetti
Journal: Eurosurveillance (2020)

Background Vancomycin-resistant enterococci (VRE), mostly Enterococcus faecium , are multidrug-resistant microorganisms that can cause nosocomial infections. VRE has increased throughout many European countries, but data from Switzerland are scarce. Aim The aim of this work was to characterise the epidemiology of enterococcal bacteraemias in Switzerland with a focus on VRE. Methods In this observational study, we retrospectively investigated bacteraemias from 81 healthcare institutions from January 2013 to December 2018 using data from the Swiss Centre for Antibiotic Resistance. Only the first blood isolate with E. faecalis or E. faecium from an individual patient was considered. We analysed the annual incidences of enterococcal bacteraemias and determined the proportion of VRE over time. We also assessed epidemiological factors potentially associated with VRE bacteraemia. Results We identified 5,369 enterococcal bacteraemias, of which 3,196 (59.5%) were due to E. faecalis and 2,173 (40.5%) to E. faecium . The incidence of enterococcal bacteraemias increased by 3.2% per year (95% confidential interval (CI): 1.6–4.8%), predominantly due to a substantial increase in E. faecalis bacteraemic episodes. Vancomycin resistance affected 30 (1.4%) E. faecium and one E. faecalis bacteraemic episodes. Among all E. faecium bacteraemias, the proportion of vancomycin-resistant isolates increased steadily from 2013 to 2018 (2% per year; 95% CI: 1.5–2.9%). No independent epidemiological factor for higher prevalence of vancomycin-resistant E. faecium bacteraemias was identified. Conclusions Vancomycin-resistant E. faecium bacteraemias remain infrequent in Switzerland. However, an important increase was observed between 2013 and 2018, highlighting the need for implementing active surveillance and targeted prevention strategies in the country.
Evaluation of a new point-of-care test to determine prior dengue infection for potential use in pre-vaccination screening
Authors: Jedas Veronica Daag, Michelle Ylade, Cameron Adams, Ramesh Jadi, Maria Vinna Crisostomo, Riacarl Alpay, Emma Teresa Carmela Aportadera, In-Kyu Yoon, Laura White, Jacqueline Deen, Aravinda M. de Silva, Anna Lena Lopez
Journal: Clinical Microbiology and Infection (2020)

ObjectiveVaccination with the first licensed dengue vaccine is recommended only for those who have had previous infection with dengue virus (DENV). A point-of-care test with the desired sensitivity of 95% and specificity of 98% could facilitate pre-vaccination screening. We evaluated a newly developed, automated dengue immunoglobulin fluorescence immunoassay for determining dengue serostatus.MethodsWe used serum samples collected just prior to a mass dengue vaccination in Cebu, Philippines. Healthy children residing in Bogo and Balamban who would be 9–14 years old at the time of the mass dengue vaccination were eligible to participate. We evaluated the ichroma™ II dengue fluorescence immunoassay (Boditech Med Incorporated, Gang-won-do, Republic of Korea) using a neutralization test (NT) as the reference assay.ResultsWe enrolled 2996 children (mean age 10.39 years, 51.7% female) in the cohort and included a subsample of 1000 (mean age 10.56 years, 54.4% female) in this study. Of the 1000 children, 86/1000 (8.6%) tested seronegative and 914/1000 (91.4%) seropositive for DENV antibodies by neutralization testing. Compared with the NT, the dengue IgG fluorescence immunoassay had an overall specificity of 90.7% (95%CI: 82.5–95.9%) and a sensitivity of 91.8% (95%CI: 89.8–93.5%) for determining dengue seropositivity. The sensitivity declined to 51.2% (42.3–61.0%) for the detection of the subset with a monotypic dengue profile.ConclusionThe insufficient specificity and sensitivity (particularly in the detection of a previous monotypic dengue infection) would render the test, in its current state, inadequate for pre-vaccination screening. Considering its user-friendly interphase and possibility of point-of-care use, the test could be further developed and validated to improve its performance characteristics.
Results of a phase 2 trial of an oral CXCR4 antagonist, mavorixafor, for treatment of WHIM syndrome
Authors: David C. Dale, Frank Firkin, Audrey Anna Bolyard, Merideth Kelley, Vahagn Makaryan, Kenneth J. Gorelick, Tarek Ebrahim, Varun Garg, Weihua Tang, Honghua Jiang, Renato Skerlj, Sarah Beaussant Cohen
Journal: Blood (2020)
Abstract 5714: Targeting serine metabolism impairs tumor growth in preclinical models of Ewing sarcoma
Authors: Sameer Issaq, Arnulfo Mendoza, Tracy Rosales, Christine Heske, Craig Thomas, Ralph DeBerardinis, Lee Helman
Journal: Cancer Research (2020)

Abstract Despite a growing body of knowledge about the genomic landscape of Ewing sarcoma (ES), translation of basic discoveries into targeted therapies and significant clinical gains has remained elusive. Recent insights have revealed that the oncogenic transcription factor EWS-FLI1 can impact ES cellular metabolism, raising the possibility of targeting metabolic dependencies as a novel therapeutic strategy. Here, we show that 3-phosphoglycerate dehydrogenase (PHGDH), the first enzyme in de novo serine synthesis, is highly expressed in human ES cells and that EWS-FLI1 regulates PHGDH expression and de novo serine synthesis. PHGDH knockdown resulted in decreased ES cell proliferation, especially under serine limitation, and significantly inhibited xenograft tumorigenesis in preclinical orthotopic models of ES. Additionally, the PHGDH inhibitor NCT-503 caused a dose-dependent decrease in cellular proliferation. Moreover, we report a novel drug combination in which nicotinamide phosphoribosyltransferase (NAMPT) inhibition, which blocks production of the PHGDH substrate NAD+, synergized with NCT-503 to abolish ES cellular proliferation and tumor growth. Furthermore, we show that serine deprivation inhibited ES cell proliferation and tumorigenesis, indicating that ES cells depend on exogenous serine in addition to de novo serine synthesis. Our findings suggest that serine metabolism is critical for ES tumorigenesis, and that targeting serine metabolism should be further investigated as a potential therapeutic strategy for ES. Citation Format: Sameer Issaq, Arnulfo Mendoza, Tracy Rosales, Christine Heske, Craig Thomas, Ralph DeBerardinis, Lee Helman. Targeting serine metabolism impairs tumor growth in preclinical models of Ewing sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5714.
Single-cell RNA-Seq reveals the transcriptional landscape and heterogeneity of skin macrophages in Vsir<sup>-/-</sup> murine psoriasis
Authors: Chenxin Qie, Jingwei Jiang, Wanmei Liu, Xinlei Hu, Wenting Chen, Xiaoxue Xie, Jun Liu
Journal: Theranostics (2020)

V-domain immunoglobulin suppressor of T cell activation (VISTA) is a novel inhibitory immune checkpoint molecule. Vsir
Histone deacetylase inhibitors promote epithelial-mesenchymal transition in Hepatocellular Carcinoma <i>via</i> AMPK-FOXO1-ULK1 signaling axis-mediated autophagy
Authors: Qiang Xiao, Hao Liu, Hong-Sheng Wang, Meng-Ting Cao, Xiao-Jun Meng, Ya-Li Xiang, Ya-Qin Zhang, Feng Shu, Qiu-Gui Zhang, Hong Shan, Guan-Min Jiang
Journal: Theranostics (2020)

Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related deaths globally because of high metastasis and recurrence rates. Elucidating the molecular mechanisms of HCC recurrence and metastasis and developing effective targeted therapies are expected to improve patient survival. The promising anti-cancer agents for the treatment of hematological malignancies, histone deacetylase inhibitors (HDIs), have limited effects against epithelial cell-derived cancers, including HCC, the mechanisms involved have not been elucidated. Herein, we studied the molecular mechanisms underlying HDI-induced epithelial-mesenchymal transition (EMT) involving FOXO1-mediated autophagy. Methods: The biological functions of HDIs in combination with autophagy inhibitors were examined both in vitro and in vivo. Cell autophagy was assessed using the generation of mRFP-GFP-LC3-expressing cells and fluorescent LC3 puncta analysis, Western blotting, and electron microscopy. An orthotopic hepatoma model was established in mice for the in vivo experiments. Results: Our study provided novel mechanistic insights into HDI-induced EMT mediated by the autophagy AMPK-FOXO1-ULK1-Snail signaling axis. We demonstrated that autophagy served as a pro-metastasis mechanism in HDI-treated hepatoma cells. HDIs induced autophagy via a FOXO1-dependent pathway, and FOXO1 inhibition promoted HDI-mediated apoptosis in hepatoma cells. Thus, our findings provided novel insights into the molecular mechanisms underlying HDI-induced EMT involving FOXO1-mediated autophagy and demonstrated that a FOXO1 inhibitor exerted a synergistic effect with an HDI to inhibit cell growth and metastasis in vitro and in vivo. Conclusion: We demonstrated that HDIs triggers FOXO1-dependent autophagy, which ultimately promotes EMT, limiting the clinical outcome of HDI-based therapies. Our study suggests that the combination of an HDI and a FOXO1 inhibitor is an effective therapeutic strategy for the treatment of HCC.
Abstract 1313: Genomic and transcriptomic profiles of primary prostate cancer identify unique targets for therapeutic intervention
Authors: Dimple Chakravarty, Zichen Wang, Michael Rossi, Parita Ratnani, Boris Reva, Dmitry Rykunov, Kamala Bhatt, Vinayak Wagaskar, Rachel Weil, Kristin Beaumont, Michael Beaumont, Avi Maayan, Robert Sebra, Nina Bhardwaj, Sujit S. Nair, Ashutosh K. Tewari
Journal: Cancer Research (2020)

Abstract The tumor microenvironment and genomic landscape of intermediate and high-risk primary localized prostate cancers are clinically heterogeneous and result in variable treatment response in individuals. Cancer-specific alterations at DNA and RNA level is a critical driver of intra-tumoral heterogeneity that significantly impacts the molecular processes which influence the path of disease progression and outcome. In this study, we have performed genomic and transcriptomic analysis of 267 primary prostate cancer. Our analysis revealed actionable alterations and gene signatures for risk stratification and decision support. Clinically significant variants were detected in DNA repair (HR and Mismatch pathway), PI3/AKT, and TP53 signaling pathways with a strong association with disease progression. Further, single-cell analysis (scRNA-seq) of prostate cancer that progressed to metastasis post-therapy identified the unique tumor and immune cell-clusters. Functional annotation of these clusters and drug repurposing studies revealed novel targets for therapeutic intervention that was validated using organoid cultures. Our studies show that an Integrated analysis using genomic, clinical, and pathological features has the potential to define prostate cancer subtypes or phenotypes associated with poor prognosis. Our approach can advance prostate cancer treatment in patients with adverse clinical features by providing treatment options beyond the standard of care (surgery or radiation) and with better therapeutic benefit. Citation Format: Dimple Chakravarty, Zichen Wang, Michael Rossi, Parita Ratnani, Boris Reva, Dmitry Rykunov, Kamala Bhatt, Vinayak Wagaskar, Rachel Weil, Kristin Beaumont, Michael Beaumont, Avi Maayan, Robert Sebra, Nina Bhardwaj, Sujit S. Nair, Ashutosh K. Tewari. Genomic and transcriptomic profiles of primary prostate cancer identify unique targets for therapeutic intervention [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1313.
Timothy George Frankau
Authors: Jude Frankau, Caroline Frankau
Journal: BMJ (2020)

Timothy George Frankau (“Tim”) served as a GP in Dursley, Gloucestershire, between 1978 and 2010. Although somewhat reserved, Tim was an excellent family doctor, respected by and endeared to colleagues, patients, and the local community.

Born in Newmarket in 1950, Tim was the younger son of an officer in the Royal Engineers. Although he was not the first medic in the family, the focus of Tim’s medical career would be somewhat different from those of his great uncle, Sir Claude Frankau (past president of the Association of Surgeons of Great Britain and Ireland, as well as of the Surgical Section of the …
Abstract 14425: Plasma Biomarkers Reflecting High Oxidative Stress Predicts Myocardial Injury Related to Anthracycline Chemotherapy in the CECCY Trial
Authors: WanderleyMauro R, Mônica S Avila, Miguel M Fernandes-Silva, Edecio Cunha-Neto, Fatima d Cruz, Sara M Gonçalves Brandão, Vagner O Rigaud, Ludhmila A Hajjar, Roberto Kalil Filho, Edimar A Bocchi, Silvia M Ayub-Ferreira
Journal: Circulation (2018)

Introduction: Anthracycline (ATN) chemotherapy in women with breast cancer can lead to cardiotoxicity (CTX). In CECCY trial carvedilol attenuated Troponin I (TnI) after ANT chemotherapy, suggesting...