tbuckley/cabot-search huggingface dataset:
FTO Inhibition Enhances the Antitumor Effect of Temozolomide by Targeting MYC-miR-155/23a Cluster-MXI1 Feedback Circuit in Glioma
Authors: Li Xiao, Xiaodi Li, Zekun Mu, Jianwen Zhou, Peng Zhou, Chen Xie, Songshan Jiang
Journal: Cancer Research (2020)

Abstract Malignant glioma constitutes one of the fatal primary brain tumors in adults. Such poor prognosis calls for a better understanding of cancer-related signaling pathways of this disease. Here we elucidate a MYC-miRNA-MXI1 feedback loop that regulates proliferation and tumorigenesis in glioma. MYC suppressed MXI1 expression via microRNA-155 (miR-155) and the microRNA-23a∼27a∼24-2 cluster (miR-23a cluster), whereas MXI1, in turn, inhibited MYC expression by binding to its promoter. Overexpression of miR-155 and the miR-23a cluster promoted tumorigenesis in U87 glioma cells. Furthermore, fat mass and obesity-associated protein (FTO), an N6-methyladenosine (m6A) RNA demethylase, regulated the loop by targeting MYC. The ethyl ester form of meclofenamic acid (MA2) inhibited FTO and enhanced the effect of the chemotherapy drug temozolomide on suppressing proliferation of glioma cells and negatively regulated the loop. These data collectively highlight a key regulatory circuit in glioma and provide potential targets for clinical treatment. Significance: These findings elucidate a novel feedback loop that regulates proliferation in glioma and can be targeted via inhibition of FTO to enhance the efficacy of temozolomide.
Periodontal disease, tooth loss, and risk of oesophageal and gastric adenocarcinoma: a prospective study
Authors: Chun-Han Lo, Sohee Kwon, Liang Wang, Georgios Polychronidis, Markus D Knudsen, Rong Zhong, Yin Cao, Kana Wu, Shuji Ogino, Edward L Giovannucci, Andrew T Chan, Mingyang Song
Journal: Gut (2020)

We read with great interest the study by Coker et al 1 that provided supportive evidence for the role of oral microbiota in gastric cancer. A few studies also highlighted the possible link with oesophageal cancer.2–4 However, there is a lack of robust epidemiologic data on whether periodontal disease and tooth loss, indicators of oral microbial dysbiosis, are associated with these two cancers.

Here, we prospectively examined the association of history of periodontal disease and tooth loss with the risk of oesophageal and gastric adenocarcinoma in 98 459 women from the Nurses’ Health Study (1992–2014) and 49 685 men from the Health Professionals Follow-up Study (1988–2016). Dental measures, demographics, lifestyle, and diet were assessed using validated follow-up questionnaires. Self-reported cancer diagnosis was confirmed by review of medical records. We used Cox proportional hazards models to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). We also examined the independent association of history of periodontal disease and tooth loss in a joint analysis.

Over 22–28 years of follow-up, we documented 199 cases of oesophageal adenocarcinoma and 238 cases of gastric adenocarcinoma. History of periodontal disease was associated with a 43% and 52% increased risk of oesophageal adenocarcinoma (multivariable-adjusted HR (aHR) 1.43, 95% CI 1.05 to 1.96) and gastric adenocarcinoma (aHR 1.52, 95% CI 1.13 to 2.04) (table …
Dexamethasone for COVID-19: data needed from randomised clinical trials in Africa
Authors: Helen Brotherton, Effua Usuf, Behzad Nadjm, Karen Forrest, Kalifa Bojang, Ahmadou Lamin Samateh, Mustapha Bittaye, Charles AP Roberts, Umberto d'Alessandro, Anna Roca
Journal: The Lancet Global Health (2020)
Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects
Authors: Chunxiao Li, Ping Jiang, Shuhua Wei, Xiaofei Xu, Junjie Wang
Journal: Molecular Cancer (2020)

Abstract Regulatory T cells (Tregs) characterized by the expression of the master transcription factor forkhead box protein p3 (Foxp3) suppress anticancer immunity, thereby hindering protective immunosurveillance of tumours and hampering effective antitumour immune responses in tumour-bearing hosts, constitute a current research hotspot in the field. However, Tregs are also essential for the maintenance of the immune tolerance of the body and share many molecular signalling pathways with conventional T cells, including cytotoxic T cells, the primary mediators of tumour immunity. Hence, the inability to specifically target and neutralize Tregs in the tumour microenvironment without globally compromising self-tolerance poses a significant challenge. Here, we review recent advances in characterizing tumour-infiltrating Tregs with a focus on the functional roles of costimulatory and inhibitory receptors in Tregs, evaluate their potential as clinical targets, and systematically summarize their roles in potential treatment strategies. Also, we propose modalities to integrate our increasing knowledge on Tregs phenotype and function for the rational design of checkpoint inhibitor-based combination therapies. Finally, we propose possible treatment strategies that can be used to develop Treg-targeted therapies.
Hydroxyethyl Starch vs Saline for Volume Expansion After Abdominal Surgery
Authors: Daniel De Backer, Gregoire Michiels
Journal: JAMA (2020)

To the Editor Dr Futier and colleagues reported the effects of HES vs saline in high-risk surgical patients.1 This placebo-controlled trial found no significant difference in the primary end point, a composite of death and preselected major postoperative complications.
Busulfan Fludarabine (BU-FLU) Compared to Thiotepa Busulfan Fludarabine (TBF) for Allogeneic Transplants in Acute Myeloid Leukemia (AML) or Refractory Anemia with Excess Blasts (RAEB) in Remission
Authors: Federica Sora, Simona Sica, Carmen Di Grazia, Patrizia Chiusolo, Luca Laurenti, Nicola Mordini, Attilio Olivieri, Anna Paola Iori, Emanuele Angelucci, Andrea Bacigalupo
Journal: Blood (2017)
Combinatorial ETS1-Dependent Control of Oncogenic NOTCH1 Enhancers in T-cell Leukemia
Authors: Anna C. McCarter, Giusy Della Gatta, Ashley Melnick, Erin Kim, Cher Sha, Qing Wang, Jahnavi K. Nalamolu, Yiran Liu, Theresa M. Keeley, Ran Yan, Mengxi Sun, Rohan Kodgule, Nicholas Kunnath, Alberto Ambesi-Impiombato, Rork Kuick, Arvind Rao, Russell J.H. Ryan, Barbara L. Kee, Linda C. Samuelson, Michael C. Ostrowski, Adolfo A. Ferrando, Mark Y. Chiang
Journal: Blood Cancer Discovery (2020)

Abstract Notch activation is highly prevalent among cancers, in particular T-cell acute lymphoblastic leukemia (T-ALL). However, the use of pan-Notch inhibitors to treat cancers has been hampered by adverse effects, particularly intestinal toxicities. To circumvent this barrier in T-ALL, we aimed to inhibit ETS1, a developmentally important T-cell transcription factor previously shown to cobind Notch response elements. Using complementary genetic approaches in mouse models, we show that ablation of Ets1 leads to strong Notch-mediated suppressive effects on T-cell development and leukemogenesis but milder intestinal effects than pan-Notch inhibitors. Mechanistically, genome-wide chromatin profiling studies demonstrate that Ets1 inactivation impairs recruitment of multiple Notch-associated factors and Notch-dependent activation of transcriptional elements controlling major Notch-driven oncogenic effector pathways. These results uncover previously unrecognized hierarchical heterogeneity of Notch-controlled genes and point to Ets1-mediated enucleation of Notch–Rbpj transcriptional complexes as a target for developing specific anti-Notch therapies in T-ALL that circumvent the barriers of pan-Notch inhibition. Significance: Notch signaling controls developmentally important and tissue-specific activities, raising barriers for developing anti-Notch therapies. Pivoting away from pan-Notch inhibitors, we show antileukemic but less toxic effects of targeting ETS1, a T-cell NOTCH1 cofactor. These results demonstrate the feasibility of context-dependent suppression of NOTCH1 programs for the treatment of T-ALL. This article is highlighted in the In This Issue feature, p. 127
Dystopian Diary of a Medical Resident
Authors: Allison Sarah Vise
Journal: JAMA Internal Medicine (2020)

Dystopian Diary of a Medical ResidentI love dystopian fiction.All the better when it has a "coming of age" bent.From early childhood favorites like The Giver to more recent indulgences like The Handmaid's Tale, I marvel at the heroines, the moral dilemmas, and the fantasy of it all.I feel fondness for those characters-while maintaining distance between them and myself.How bad could it really get?As a resident physician, I am starting to see those dystopian fables as prophecies more than fiction.When the coronavirus disease 2019 (COVID-19) pandemic began, I often caught sight of young people on my way to work, throwing frisbees in some act of defiance against sheltering at home.Today, my commute is eerily quiet-scenes of people clad in scrubs or hard hats, and face masks.When the occasional nonessential worker walks by, they briskly cross the street, seeking far greater than a 6-foot berth.Maybe my role as a healthcare worker is disquieting.An almost militant order of business has overtaken the hospital.I flash my ID badge to the security officer standing guard like a bouncer at the entrance."Thanks, Doc," he says.I pass through the first set of doors, where a redeployed, masked employee sprays my hands with sanitizer.The next staffer issues my surgical mask for the day.A third waves me through after I display my cell phone; on the screen is a completed survey attesting to my lack of COVID-19 symptoms.Another person allows me onto the escalator.Other employees limit access to the elevators; 4 at a time, 6 feet apart.A single-file line of workers snakes down the hospital corridor-the same hallway ordinarily filled with the bustle of patients, their families, and staff.I have found a rhythm to dancing through these restrictions.Admittedly, I have more routine than many of my peers outside of medicine.I go to work.I see colleagues.And, I am seeing a very different reality unfold.Our hospital floors are now intensive care units.Patients with COVID-19 usurp the usual delivery ward.I remember joining a friend there last year as she was bringing life into the world.Now, I wipe down my desk and chair with bleach-soaked wipes, and wait for loss.The smell of lavender hand cream from the nurse whose desk I occupy still lingers.There are pamphlets on the cubicle wall about insurance coverage, and pictures of
Retrospective Multicenter Cohort Study Shows Early Interferon Therapy Is Associated with Favorable Clinical Responses in COVID-19 Patients
Authors: Nan Wang, Yan Zhan, Linyu Zhu, Zhibing Hou, Feng Liu, Pinhong Song, Feng Qiu, Xiaolin Wang, Xiafei Zou, Deyun Wan, Xiaosong Qian, Shanshan Wang, Yabi Guo, Hao Yu, Miao Cui, Gangling Tong, Yunsheng Xu, Zhihua Zheng, Yingying Lu, Peng Hong
Journal: Cell Host & Microbe (2020)
The Structural and Social Determinants of the Racial/Ethnic Disparities in the U.S. COVID-19 Pandemic. What’s Our Role?
Authors: Neeta Thakur, Stephanie Lovinsky-Desir, Christian Bime, Juan P. Wisnivesky, Juan C. Celedón
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Author(s): Thakur, Neeta; Lovinsky-Desir, Stephanie; Bime, Christian; Wisnivesky, Juan P; Celedon, Juan C
Frequency of Opioid Prescription at Emergency Department Discharge in Patients with Inflammatory Bowel Disease: A Nationwide Analysis
Authors: Tarun Chhibba, Leonardo Guizzetti, Cynthia H. Seow, Cathy Lu, Kerri L. Novak, Ashwin N. Ananthakrishnan, Charles N. Bernstein, Gilaad G. Kaplan, Remo Panaccione, Christopher Ma
Journal: Clinical Gastroenterology and Hepatology (2020)
THU0011 Bsm-1 polymorphism and bone mineral density in polymyalgia rheumatica
Authors: A Daroszewska, W Taylor, JL Usher, RC Bucknall, RJ Moots, RN Thompson, EJ Tunn, WD Fraser
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> VDR gene polymorphism has been associated with variations in bone mineral density (BMD) in normal populations, most studies linking the presence of the Bsm-1 restriction site (b) with higher BMD as compared to absence of Bsm-1 restriction site (B). We found that in steroid induced osteoporosis in PMR patients there is an overrepresentation of bb and that in normal controls, higher BMD is found in Bb heterozygotes (FA Gidden: data submitted). <h3>Objectives</h3> To investigate the VDR gene polymorphism frequency and association with BMD in newly diagnosed patients with PMR, prior to treatment with corticosteroids. <h3>Methods</h3> Thirty patients with active PMR (fulfilling Bird’s criteria), consecutively referred by GP’s to the PMR clinic, underwent lumbar spine and hip BMD scanning on a Hologic dual X-ray absorptiometer (DXA). 5 ml EDTA blood was obtained from each patient and used for DNA extraction. Polymerase chain reaction (PCR) and agarose gel electrophoresis were used for Bsm-1 site typing. <h3>Results</h3> The VDR genotype distribution was: BB in 6 patients (20%), Bb in 10 patients (33.3%) and bb in 14 patients (46.7%). Mean BMD of lumbar spine (L1-L4) expressed as Z-score was in BB group 0.32 (95% CI: -0.47–1.11), in Bb group 1.37 (95% CI: 0.31–2.41) and in bb group 0.46 (95% CI: -0.25–1.18). Mean BMD of femoral neck (Z-score) was in BB group -0.05 (95% CI: -1.5–1.39), in Bb group 0.49 (95% CI: -0.24–1.23) and in bb group 0.13 (95% CI: -0.39–0.65). Mean age of patients was 73.6, SD 7.6. There was no statistically significant difference between groups with regard to age, disease duration and disease activity (measured by ESR, CRP, Pain Visual Analogue Score, Global Disease Activity Score and Health Assessment Questionnaire). <h3>Conclusion</h3> There is an overrepresentation of bb in PMR patients (as compared to UK VDR frequencies: BB 20.5%, Bb 49.7%, bb 29.8%)<sup>1</sup> which may reflect VDR polymorphism role in susceptibility to inflammatory conditions e.g. PMR. Heterozygotes Bb have highest BMD. Bb genotype may be bone protective for steroid induced osteoporosis. <h3>Reference</h3> Houston LA, <i>et al</i>. Bone 1996;18(3):249–52
Efficacy of Modern Diabetes Treatments DPP-4i, SGLT-2i, and GLP-1RA in White and Asian Patients With Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials
Authors: Sushrima Gan, Adem Y. Dawed, Louise A. Donnelly, Anand T.N. Nair, Colin N.A. Palmer, Viswanathan Mohan, Ewan R. Pearson
Journal: Diabetes Care (2020)

The pathophysiology of type 2 diabetes differs markedly by ethnicity.A systematic review and meta-analysis was conducted to assess the impact of ethnicity on the glucose-lowering efficacy of the newer oral agents, sodium-glucose cotransporter 2 inhibitors (SGLT-2i), glucagon-like peptide 1 receptor agonists (GLP-1RA), and dipeptidyl peptidase 4 inhibitors (DPP-4i), using evidence from randomized clinical trials (RCTs).A literature search was conducted in PubMed of all randomized, placebo-controlled trials of DPP-4i, SGLT-2i, and GLP-1RA. The search strategy was developed based on Medical Subject Headings (MeSH) terms and keywords.A total of 64 studies that qualified for meta-analysis after full-text review based on predefined inclusion and exclusion criteria-RCTs with at least 50 patients in each arm, >70% of population from Asian or white group, duration ≥24 weeks, and publication up to March 2019-were selected for systematic review and meta-analysis.Data extraction was done for aggregated study-level data by two independent researchers. Absolute changes in HbA1c (%) from baseline to 24 weeks between the drug and placebo were considered as the primary end point of the study.Change in HbA1c was evaluated by computing mean differences and 95% CIs between treatment and placebo arms.The study is based on summarized data and could not be separated based on East Asians and South Asians.The glucose-lowering efficacy of SGLT-2i, and to a lesser extent DPP-4i, was greater in studies of predominantly Asian ethnicity compared with studies of predominantly white ethnicity. There was no difference seen by ethnicity for GLP-1RA.
Pulmonary Angiopathy in Severe COVID-19: Physiologic, Imaging, and Hematologic Observations
Authors: Brijesh V. Patel, Deepa J. Arachchillage, Carole A. Ridge, Paolo Bianchi, James F. Doyle, Benjamin Garfield, Stephane Ledot, Cliff Morgan, Maurizio Passariello, Susanna Price, Suveer Singh, Louit Thakuria, Sarah Trenfield, Richard Trimlett, Christine Weaver, S. John Wort, Tina Xu, Simon P. G. Padley, Anand Devaraj, Sujal R. Desai
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Clinical and epidemiologic data in coronavirus disease (COVID-19) have accrued rapidly since the outbreak, but few address the underlying pathophysiology.Objectives: To ascertain the physiologic, hematologic, and imaging basis of lung injury in severe COVID-19 pneumonia.Methods: Clinical, physiologic, and laboratory data were collated. Radiologic (computed tomography (CT) pulmonary angiography [n = 39] and dual-energy CT [DECT, n = 20]) studies were evaluated: observers quantified CT patterns (including the extent of abnormal lung and the presence and extent of dilated peripheral vessels) and perfusion defects on DECT. Coagulation status was assessed using thromboelastography.Measurements and Results: In 39 consecutive patients (male:female, 32:7; mean age, 53 ± 10 yr [range, 29–79 yr]; Black and minority ethnic, n = 25 [64%]), there was a significant vascular perfusion abnormality and increased physiologic dead space (dynamic compliance, 33.7 ± 14.7 ml/cm H2O; Murray lung injury score, 3.14 ± 0.53; mean ventilatory ratios, 2.6 ± 0.8) with evidence of hypercoagulability and fibrinolytic "shutdown". The mean CT extent (±SD) of normally aerated lung, ground-glass opacification, and dense parenchymal opacification were 23.5 ± 16.7%, 36.3 ± 24.7%, and 42.7 ± 27.1%, respectively. Dilated peripheral vessels were present in 21/33 (63.6%) patients with at least two assessable lobes (including 10/21 [47.6%] with no evidence of acute pulmonary emboli). Perfusion defects on DECT (assessable in 18/20 [90%]) were present in all patients (wedge-shaped, n = 3; mottled, n = 9; mixed pattern, n = 6).Conclusions: Physiologic, hematologic, and imaging data show not only the presence of a hypercoagulable phenotype in severe COVID-19 pneumonia but also markedly impaired pulmonary perfusion likely caused by pulmonary angiopathy and thrombosis.
Socioeconomic correlates of SARS-CoV-2 and influenza H1N1 outbreaks
Authors: Jan Christian Kaiser, Georgios T. Stathopoulos
Journal: European Respiratory Journal (2020)

<b>Geographic disease patterns of the SARS-CoV-2 and the H1N1 influenza pandemics are cross-examined with socioeconomic indices, revealing that the two outbreaks are fundamentally different and that SARS-CoV-2 spread is linked with economic output</b>https://bit.ly/3fqkiyp
Abstract B52: Ewing sarcoma: A case study of clonal aneuploidy and DNA damage repair in pediatric cancer
Authors: Xiaofeng A. Su, Duanduan Ma, James V. Parsons, John M. Replogle, James F. Amatruda, Charles A. Whittaker, Kimberly Stegmaier, Angelika Amon
Journal: Cancer Research (2020)

Abstract Many tumor types harbor specific chromosome gains or losses. In Ewing sarcoma (ES) chromosome 8 gain is extremely common, indicating that this trisomy drives tumorigenesis. However, in primary cells, whole chromosome gains and losses are universally detrimental. We hypothesize that gain of chromosome 8 suppresses cellular stresses associated with oncogenic transformation in ES. In this study, we induced expression of EWS-FLI1 fusion oncogene, which drives ES, in various primary human mesenchymal progenitor and fibroblast cells. We showed that expression of EWS-FLI1 results in a strong cell cycle-dependent replication stress in euploid mesenchymal progenitor cells and fibroblast cells. As a consequence, proliferation is impaired when EWS-FLI1 is expressed in these cells. However, primary fibroblast cells carrying an extra copy of chromosome 8 (trisomy 8) exhibit much less replication stress, and the impairment of proliferation was also not seen in these cells. The levels of replication-associated DNA damage are lower in the trisomy 8 cells than in the euploid cells in the presence of EWS-FLI1. Then, we applied weighted co-expression network analysis (WGCNA) to RNA sequencing data obtained from ES patient tumor tissues in combination of mouse synteny analysis. We identified multiple potential genes and regions on chromosome 8, which are beneficial to ES oncogenesis when gain of extra copies. Above all, we demonstrate that gain of chromosome 8 in Ewing sarcoma facilitates the primary mesenchymal-lineage cells to overcome certain oncogenic stresses and reduces DNA damage associated with tumorigenic processes, which is achieved by cooperative upregulation of multiple gene expression on chromosome 8. Citation Format: Xiaofeng A. Su, Duanduan Ma, James V. Parsons, John M. Replogle, James F. Amatruda, Charles A. Whittaker, Kimberly Stegmaier, Angelika Amon. Ewing sarcoma: A case study of clonal aneuploidy and DNA damage repair in pediatric cancer [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B52.
Hematopoietic lineage-converted T cells carrying tumor-associated antigen-recognizing TCRs effectively kill tumor cells
Authors: Fangxiao Hu, Dehao Huang, Yuxuan Luo, Peiqing Zhou, Cui Lv, Kaitao Wang, Qitong Weng, Xiaofei Liu, Yuxian Guan, Yang Geng, Juan Du, Jiekai Chen, Jinyong Wang, Hongling Wu
Journal: Journal for ImmunoTherapy of Cancer (2020)

Tumor-associated antigen (TAA) T-cell receptor (TCR) gene-engineered T cells exhibit great potential in antitumor immunotherapy. Considering the high costs and low availability of patient-derived peripheral blood T cells, substantial efforts have been made to explore alternatives to natural T cells. We previously reported that enforced expression of Hoxb5 converted B cells into induced T (iT) cells in vivo . Here, we successfully regenerated naive OT1 (major histocompatibility complex I restricted ovalbumin antigen) iT cells (OT1-iT) in vivo by expressing Hoxb5 in pro-pre-B cells in the OT1 transgenic mouse. The OT1-iT cells can be activated and expanded in vitro in the presence of tumor cells. Particularly, these regenerated OT1-iT cells effectively eradicated tumor cells expressing the TAA (ovalbumin) both in vitro and in vivo . This study provides insights into the translational applications of blood lineage-transdifferentiated T cells in immunotherapy.
関連マラリア寄生系統の共伝播は宿主内寄生生物多様性を形成する【JST・京大機械翻訳】
Authors: C Nkhoma Standwell, G Trevino Simon, M Gorena Karla, Nair Shalini, Khoswe Stanley, Jett Catherine, Garcia Roy, Daniel Benjamin, Dia Aliou, J Terlouw Dianne, A Ward Stephen, J C Anderson Timothy, H Cheeseman Ian
Journal: Cell Host & Microbe (2020)