tbuckley/cabot-search huggingface dataset:
Farnesoid X Receptor Is Required for the Redifferentiation of Bipotential Progenitor Cells During Biliary‐Mediated Zebrafish Liver Regeneration
Authors: Pengcheng Cai, Xiaoyu Mao, Jieqiong Zhao, Li Nie, Yan Jiang, Qifen Yang, Rui Ni, Jianbo He, Lingfei Luo
Journal: Hepatology (2021)

Liver regeneration after extreme hepatocyte loss occurs through transdifferentiation of biliary epithelial cells (BECs), which includes dedifferentiation of BECs into bipotential progenitor cells (BPPCs) and subsequent redifferentiation into nascent hepatocytes and BECs. Although multiple molecules and signaling pathways have been implicated to play roles in the BEC-mediated liver regeneration, mechanisms underlying the dedifferentiation-redifferentiation transition and the early phase of BPPC redifferentiation that is pivotal for both hepatocyte and BEC directions remain largely unknown.The zebrafish extreme liver damage model, genetic mutation, pharmacological inhibition, transgenic lines, whole-mount and fluorescent in situ hybridizations and antibody staining, single-cell RNA sequencing, quantitative real-time PCR, and heat shock-inducible overexpression were used to investigate roles and mechanisms of farnesoid X receptor (FXR; encoded by nuclear receptor subfamily 1, group H, member 4 [nr1h4]) in regulating BPPC redifferentiation. The nr1h4 expression was significantly up-regulated in response to extreme liver injury. Genetic mutation or pharmacological inhibition of FXR was ineffective to BEC-to-BPPC dedifferentiation but blocked the redifferentiation of BPPCs to both hepatocytes and BECs, leading to accumulation of undifferentiated or less-differentiated BPPCs. Mechanistically, induced overexpression of extracellular signal-related kinase (ERK) 1 (encoded by mitogen-activated protein kinase 3) rescued the defective BPPC-to-hepatocyte redifferentiation in the nr1h4 mutant, and ERK1 itself was necessary for the BPPC-to-hepatocyte redifferentiation. The Notch activities in the regenerating liver of nr1h4 mutant attenuated, and induced Notch activation rescued the defective BPPC-to-BEC redifferentiation in the nr1h4 mutant.FXR regulates BPPC-to-hepatocyte and BPPC-to-BEC redifferentiations through ERK1 and Notch, respectively. Given recent applications of FXR agonists in the clinical trials for liver diseases, this study proposes potential underpinning mechanisms by characterizing roles of FXR in the stimulation of dedifferentiation-redifferentiation transition and BPPC redifferentiation.
Ligase 1 is a predictor of platinum resistance and its blockade is synthetically lethal in XRCC1 deficient epithelial ovarian cancers
Authors: Reem Ali, Muslim Alabdullah, Mashael Algethami, Adel Alblihy, Islam Miligy, Ahmed Shoqafi, Katia A. Mesquita, Tarek Abdel-Fatah, Stephen YT Chan, Pei Wen Chiang, Nigel P Mongan, Emad A Rakha, Alan E Tomkinson, Srinivasan Madhusudan
Journal: Theranostics (2021)

The human ligases (LIG1, LIG3 and LIG4) are essential for the maintenance of genomic integrity by catalysing the formation of phosphodiester bonds between adjacent 5'-phosphoryl and 3'-hydroxyl termini at single and double strand breaks in duplex DNA molecules generated either directly by DNA damage or during replication, recombination, and DNA repair. Whether LIG1, LIG3 and LIG4 can influence ovarian cancer pathogenesis and therapeutics is largely unknown.
Baseline Evaluation of Cancer Mortality in US States that Expanded Medicaid vs Nonexpansion States
Authors: Michelle C. Salazar, Michael F. Kaminski, Maureen E. Canavan, Richard C. Maduka, Andrew X. Li, Theresa Ermer, Daniel J. Boffa
Journal: JAMA Oncology (2021)

This cohort study examines baseline differences in cancer mortality between Medicaid expansion and nonexpansion states.
Comparison of CSF biomarkers in Down syndrome and autosomal dominant Alzheimer's disease: a cross-sectional study
Authors: Anne M Fagan, Rachel L Henson, Yan Li, Anna H Boerwinkle, Chengjie Xiong, Randall J Bateman, Alison Goate, Beau M Ances, Eric Doran, Bradley T Christian, Florence Lai, H Diana Rosas, Nicole Schupf, Sharon Krinsky-McHale, Wayne Silverman, Joseph H Lee, William E Klunk, Benjamin L Handen, Ricardo F Allegri, Jasmeer P Chhatwal, Gregory S Day, Neill R Graff-Radford, Mathias Jucker, Johannes Levin, Ralph N Martins, Colin L Masters, Hiroshi Mori, Catherine J Mummery, Yoshiki Niimi, John M Ringman, Stephen Salloway, Peter R Schofield, Mikio Shoji, Ira T Lott
Journal: The Lancet Neurology (2021)
MHRA to shed a fifth of its workforce in post-Brexit cost cutting drive
Authors: Gareth Iacobucci
Journal: BMJ (2021)

The UK’s drug and medical devices regulator is to lose a substantial number of staff as part of a post-Brexit restructure, The BMJ has learned.

The Medicines and Healthcare Products Regulatory Agency (MHRA), which employs around 1200 people in England, could cut its workforce by as much as 20% as part of a transformation programme that will radically reshape how the agency operates, leaked documents seen by The BMJ show. The agency is targeting savings after losing a substantial amount of funding from the European regulatory system after the UK’s exit from the European Union.

The documents reveal details of a voluntary exit scheme that MHRA is offering to staff from its divisions on vigilance and risk management of medicines, licensing, devices, inspection enforcement and standards, as well as its committee secretariat.

A document marked “official sensitive,” seen by The BMJ, said that the MHRA’s income is expected to reduce by 15-20% in next financial year and beyond, while …
P-254 Role of neutrophil-lymphocyte ratio in the prognosis of stomach carcinoma undergoing curative resection
Authors: S. Ambre, D. Muduly, M. Imaduddin, L. Colney, P. Kumar CG, M. Sultania, J. Swain, G. Chhabra, M. Kar
Journal: Annals of Oncology (2021)
Reply to: Rectally shed SARS-CoV-2 lacks infectivity: time to rethink faecal–oral transmission?
Authors: Meng Guo, Wanyin Tao, Richard A. Flavell, Shu Zhu
Journal: Nature Reviews Gastroenterology & Hepatology (2021)

1 , on the potential faecaloral transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).A com prehensive list of reasons to sub stantiate that such a transmission route is probable was presented, including the well-documented shedding of viral RNA in faeces, epidemiological reports, and laboratory and animal tests.Viral debris and RNA are often found in large quantities in faeces from patients with COVID-19 as most of the viral material produced in the airways is cleared through swallowing.Furthermore, as argued by Guo et al. 1 , studies indicate that intestinal infection by SARS-CoV-2 might contribute to the viral material shed in faeces.In either case, it is important to emphasize that for the rectally shed virus to transmit to other humans it must retain its infectivity when it leaves the body.Proof in support of this property is obtained by successful isolation of the virus; that is, successful propagation of the sampled virus in laboratory cell culture.Guo et al. 1 refer to four studies in support of infectious virus particles being successfully isolated from patient's faeces 2-5 .However, three of these studies base their conclusion of successful propagation of SARS-CoV-2 on microscopy observations alone 2-4 , which is inadequate as it requires additional substantiation by quantitative analysis (such as reverse transcription PCR, RT-PCR) to conclude that virions have increased in number upon culturing 6,7 .All three papers use electron microscopy to show what appears to be intact SARS-CoV-2 particles in culture supernatants [2][3][4] , but identifying SARS-CoV-2 in complex specimens in this way is difficult and error prone 8,9 , and, even if visually intact virions are identified, it does not provide evidence for infectious capacity.Notably, only Zhou et al. confirmed viral propagation by RT-PCR 5 ; a result that was obtained for a single faecal sample 5 and is, to the best of our knowledge, the only valid evidence reported in
Mutational Frequency in Hispanic and Non-Hispanic Patients with Acute Myeloid Leukemia (AML): Updated Analysis of 227 Patients
Authors: Terrence J Bradley, Jorge Monge, Chetasi Talati, Sandra Dannielle Algaze, Christine Angela Vaupel, Jennifer R Chapman, Francisco Vega, Jeff Hall, Jeffrey E. Lancet, Eric Padron, Ronan T. Swords, Justin M Watts
Journal: Blood (2017)
Targeting intracellular WT1 in AML with a novel RMF-peptide-MHC-specific T-cell bispecific antibody
Authors: Christian Augsberger, Gerulf Hänel, Wei Xu, Vesna Pulko, Lydia Jasmin Hanisch, Angelique Augustin, John Challier, Katharina Hunt, Binje Vick, Pier Eduardo Rovatti, Christina Krupka, Maurine Rothe, Anne Schönle, Johannes Sam, Emmanuelle Lezan, Axel Ducret, Daniela Ortiz-Franyuti, Antje-Christine Walz, Jörg Benz, Alexander Bujotzek, Felix S. Lichtenegger, Christian Gassner, Alejandro Carpy, Victor Lyamichev, Jigar Patel, Nikola Konstandin, Antje Tunger, Marc Schmitz, Michael von Bergwelt-Baildon, Karsten Spiekermann, Luca Vago, Irmela Jeremias, Estelle Marrer-Berger, Pablo Umaña, Christian Klein, Marion Subklewe
Journal: Blood (2021)
Metabolic-associated fatty liver disease is associated with length of stay but not worse survival post COVID-19
Authors: K. C. Perdikis, A. Balaphas, K. Gkoufa, N. Colucci, S. Carballo, C. Gaudet-Blavignac, C. Lovis, F. Negro, C. Toso, N. Goossens
Journal: Journal of Hepatology (2021)
Clinical utility of circulating genetically anormal cells in stage I small-cell lung cancer diagnosis.
Authors: Hui Wang, Ziqi Wang, Xiaoxuan Zheng, Jiayuan Sun, Xiaoju Zhang, Xin Ye, Yanci Chen, Meng Huang, Juncheng Zhang, Xiaozheg Yang, Chunxue Bai
Journal: Journal of Clinical Oncology (2021)

e20581 Background: Small-cell lung cancer (SCLC) is an aggressive disease with rapid progression rate and high metastatic potential that accounts for 15% of all lung cancers. Early-stage SCLC is usually asymptomatic; therefore, the majority of the SCLC patients were diagnosed in advanced stages. Although some radiological features were reported with advanced stages SCLC by CT scans, diagnosis of early stages SCLC from CT images has remained challenging since the radiological features are not distinct. Neuron-specific enolase (NSE) is commonly used in the clinical setting as a biomarker for SCLC, but the sensitivity of the test did not meet the needs. Here, we proposed a study using Circulating Genetically Abnormal Cells (CAC) to improve the diagnosis rate of SCLC in the early stages. Methods: A series of 26 stage I SCLC patients were enrolled from October 2019 to October 2020. All participants were having newly discovered pulmonary nodules ≤ 30mm when enrolled in the study, with no previous cancer history. Before the histopathological examination, 10 ml of peripheral blood were collected from each patient for CAC test, by using a 4 color FISH–based assay to detect the genetic abnormalities of 3p22.1, 3q29, 10q22.3, and CEP10 in the chromosome. Besides, NSE was performed on all participants. Both tests were intended to evaluate the malignant risk of lung nodules. Results: Confirmed by histopathological exam, 69% patients were diagnosed with SCLC located on the central part of the lung, and 31% patients were found to have peripheral-type SCLC. 88% of the patients in the overall cohort were smokers or past smokers, and only 12% participants had a family history of cancer. For Immunohistochemistry tests, the numbers of participants with positive CD56, TTF-1, CgA, CK, Syn and Ki-67 ≥ 60% are 65%, 58%, 12%, 42%, 50% and 69%, respectively. For diagnostic performance, the sensitivity of CAC in the over-all cohort is 73.08% (95%CI: 52.21%-88.43%), compared with 50.00% (95%CI: 29.93%- 70.07%) for NSE. CAC has achieved 77.78% (95%CI: 52.36% - 93.59%) and 62.5% (95%CI：24.49% - 91.48%) sensitivity in the centra and peripheral group. For NSE, the sensitivity of these two groups were 55.56% (95%CI: 30.76% - 78.47%) and 37.5% (95%CI: 8.52% - 75.51%). Conclusions: Compared with NSE, CAC is more sensitive to stage I SCLC, especially for SCLC that arising in central locations. This non-invasive method can be a complementary diagnostic tool with LDCT for smokers aged ≥65 with newly discovered pulmonary nodules. Clinical trial information: ChiCTR1900026233.
Abstract 16736: Risk Stratification With Treadmill Exercise Stress Testing in Patients With Long QT Syndrome
Authors: Ram K Rohatgi, Johan M Bos, Alan Sugrue, Michael J Ackerman
Journal: Circulation (2017)

Introduction: The treadmill exercise stress test (TEST) has a diagnostic (unmask patients with concealed long QT syndrome, LQTS) and therapeutic impact (assess degree of beta blockade) for patients...
scDPN for High-Throughput Single-Cell CNV Detection to Uncover Clonal Evolution During HCC Recurrence
Authors: Liang Wu, Miaomiao Jiang, Yuzhou Wang, Biaofeng Zhou, Yunfan Sun, Kaiqian Zhou, Jiarui Xie, Yu Zhong, Zhikun Zhao, Michael Dean, Yong Hou, Shiping Liu
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract Single-cell genomics provides substantial resources for dissecting cellular heterogeneity and cancer evolution. Unfortunately, classical DNA amplification-based methods have low throughput and introduce coverage bias during sample preamplification. We developed a single-cell DNA library preparation method without preamplification in nanolitre scale (scDPN) to address these issues. The method achieved a throughput of up to 1800 cells per run for copy number variation (CNV) detection. Also, our approach demonstrated a lower level of amplification bias and noise than the multiple displacement amplification (MDA) method and showed high sensitivity and accuracy for cell line and tumor tissue evaluation. We used this approach to profile the tumor clones in paired primary and relapsed tumor samples of hepatocellular carcinoma (HCC). We identified three clonal subpopulations with a multitude of aneuploid alterations across the genome. Furthermore, we observed that a minor clone of the primary tumor containing additional alterations in chromosomes 1q, 10q, and 14q developed into the dominant clone in the recurrent tumor, indicating clonal selection during recurrence in HCC. Overall, this approach provides a comprehensive and scalable solution to understand genome heterogeneity and evolution
An artificial intelligence framework integrating longitudinal electronic health records with real-world data enables continuous pan-cancer prognostication
Authors: Olivier Morin, Martin Vallières, Steve Braunstein, Jorge Barrios Ginart, Taman Upadhaya, Henry C. Woodruff, Alex Zwanenburg, Avishek Chatterjee, Javier E. Villanueva-Meyer, Gilmer Valdes, William Chen, Julian C. Hong, Sue S. Yom, Timothy D. Solberg, Steffen Löck, Jan Seuntjens, Catherine Park, Philippe Lambin
Journal: Nature Cancer (2021)
Revised Neuroblastoma Risk Classification System: A Report From the Children's Oncology Group
Authors: Meredith S. Irwin, Arlene Naranjo, Fan F. Zhang, Susan L. Cohn, Wendy B. London, Julie M. Gastier-Foster, Nilsa C. Ramirez, Ruthann Pfau, Shalini Reshmi, Elizabeth Wagner, Jed Nuchtern, Shahab Asgharzadeh, Hiroyuki Shimada, John M. Maris, Rochelle Bagatell, Julie R. Park, Michael D. Hogarty
Journal: Journal of Clinical Oncology (2021)

Treatment planning for children with neuroblastoma requires accurate assessment of prognosis. The most recent Children's Oncology Group (COG) risk classification system used tumor stage as defined by the International Neuroblastoma Staging System. Here, we validate a revised classifier using the International Neuroblastoma Risk Group Staging System (INRGSS) and incorporate segmental chromosome aberrations (SCA) as an additional genomic biomarker.
Phase 1/2 TRIDENT-1 Study of Repotrectinib in Patients with ROS1 or NTRK plus Advanced Solid Tumors
Authors: BC Cho, RC Doebele, J Lin, M Nagasaka, C Baik, A Van der Wekken, V Velcheti, KH Lee, S Liu, B Solomon, S Kao, MG Krebs, V Zhu, S Stopatschinskaja, R Camidge, A Drilon
Journal: Journal of Thoracic Oncology (2021)
Abstract 9146: Antithrombotic Use and Outcomes in Patients with Atrial Fibrillation Complicating Acute Coronary Syndromes
Authors: Renato D Lopes, Jennifer A White, Dan Atar, Matyas Keltai, Neal S Kleiman, Harvey D White, Petr Widimsky, Uwe Zeymer, Kevin Jackson, Robert P Giugliano, Pierluigi Tricoci, Eugene Braunwald, C. M Gibson, Christoph Bode, E. M Ohman, Paul W Armstrong, Frans Van de Werf, Robert A Harrington, L. K Newby
Journal: Circulation (2011)

Background: Little is known about the use of oral anticoagulant and antiplatelet agents in patients with atrial fibrillation (AF) complicating non-ST-segment elevation (NSTE) ACS. Methods: We examined the occurrence and timing of AF and use of antithrombotic therapy in 9242 high-risk NSTE ACS patients randomized in EARLY ACS to early eptifibatide vs. delayed provisional use at PCI for whom AF information was available. Logistic regression with a landmark approach examined the association of AF within 7 days after ACS with death at 30 days. Adjusted models considered important clinical variables available prior to the 7-day landmark period. Results: Overall, 550 patients (6.0%) had AF as an in-hospital complication. AF events occurred at a median of 4 (2, 8) days after ACS, and 395 (72%) AF events occurred within 7 days. AF patients were older (median age 72 vs. 67 years), had worse renal function (median eCrCl 66 vs. 74 ml/min), more frequently had elevated troponin at baseline (90 vs. 83%), and more often had diabetes (34 vs. 30%), HTN (74 vs. 71%), or history of heart failure (15 vs. 12%) compared with patients without AF. The table shows rates of discharge antiplatelet and antithrombotic therapy. Among AF patients, 87% received aspirin at discharge, 48% received clopidogrel, and 19% received warfarin. Triple therapy (combination of aspirin, clopidogrel, and warfarin) was used in only 5.7%. After adjusting for clinical variables, in-hospital AF within 7 days post ACS was associated with nearly 5-fold higher risk for death between 7 and 30 days (HR 4.83, 95% CI 3.06-7.62). Conclusions: AF complicated 6% of post-ACS patients and was associated with substantially greater risk for death at 30 days. The majority of AF patients did not receive oral anticoagulation with antiplatelet agents at discharge, highlighting unmet needs to better optimize antithrombotic therapy at hospital discharge in these patients.
Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicenter, phase II trial
Authors: B.G.M. Hughes, E. Munoz-Couselo, L. Mortier, Å. Bratland, R. Gutzmer, O. Roshdy, R. González Mendoza, J. Schachter, A. Arance, F. Grange, N. Meyer, A. Joshi, S. Billan, P. Zhang, B. Gumuscu, R.F. Swaby, J.-J. Grob
Journal: Annals of Oncology (2021)

Pembrolizumab demonstrated clinically meaningful and durable antitumor activity with a manageable safety profile in recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC).KEYNOTE-629 was a global, open-label, nonrandomized, phase II trial of patients with locally advanced (LA) or R/M cSCC conducted at 59 centers. Eligible patients received intravenous pembrolizumab 200 mg every 3 weeks for up to 35 cycles. Primary endpoint was objective response rate (ORR), defined as the percentage of patients with a complete (CR) or partial response (PR), by blinded independent central review as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included duration of response (DOR), disease control rate, progression-free survival, overall survival, and safety and tolerability. Efficacy and safety were analyzed in patients who were treated with at least one dose of pembrolizumab.Between 29 November 2017 and 25 September 2019, 159 patients were enrolled and treated with pembrolizumab (LA cohort, n = 54; R/M cohort, n = 105). The median time from the first dose to data cut-off date (29 July 2020) was 14.9 [interquartile range (IQR), 12.6-17.2] months for the LA cohort and 27.2 (IQR, 25.6-29.2) months for the R/M cohort. In the LA cohort, ORR was 50.0% [95% confidence interval (CI), 36.1% to 63.9%], including 16.7% of patients with a CR and 33.3% with a PR. In the R/M cohort, ORR was 35.2% (95% CI, 26.2% to 45.2%), including 10.5% of patients with a CR and 24.8% with a PR. Median DOR was not reached in either cohort. Grade 3-5 treatment-related adverse events occurred in 11.9% of patients.The robust antitumor activity of pembrolizumab in both LA and R/M cSCC was confirmed and demonstrated to be durable without unexpected safety signals. Our findings establish pembrolizumab as a promising treatment option for cSCC.
Exploring the choroidal vascular labyrinth and its molecular and structural roles in health and disease
Authors: J. Brinks, E.H.C. van Dijk, I. Klaassen, R.O. Schlingemann, S.M. Kielbasa, E. Emri, P.H.A. Quax, A.A. Bergen, O.C. Meijer, C.J.F. Boon
Journal: Progress in Retinal and Eye Research (2021)

The choroid is a key player in maintaining ocular homeostasis and plays a role in a variety of chorioretinal diseases, many of which are poorly understood. Recent advances in the field of single-cell RNA sequencing have yielded valuable insights into the properties of choroidal endothelial cells (CECs). Here, we review the role of the choroid in various physiological and pathophysiological mechanisms, focusing on the role of CECs. We also discuss new insights regarding the phenotypic properties of CECs, CEC subpopulations, and the value of measuring transcriptomics in primary CEC cultures derived from post-mortem eyes. In addition, we discuss key phenotypic, structural, and functional differences that distinguish CECs from other endothelial cells such as retinal vascular endothelial cells. Understanding the specific clinical and molecular properties of the choroid will shed new light on the pathogenesis of the broad clinical range of chorioretinal diseases such as age-related macular degeneration, central serous chorioretinopathy and other diseases within the pachychoroid spectrum, uveitis, and diabetic choroidopathy. Although our knowledge is still relatively limited with respect to the clinical features and molecular pathways that underlie these chorioretinal diseases, we summarise new approaches and discuss future directions for gaining new insights into these sight-threatening diseases and highlight new therapeutic strategies such as pluripotent stem cell‒based technologies and gene therapy.
Resistant starch, microbiome, and precision modulation
Authors: Peter A. Dobranowski, Alain Stintzi
Journal: Gut Microbes (2021)

Resistant starch, microbiome, and precision modulation. Mounting evidence has positioned the gut microbiome as a nexus of health. Modulating its phylogenetic composition and function has become an attractive therapeutic prospect. Resistant starches (granular amylase-resistant α-glycans) are available as physicochemically and morphologically distinguishable products. Attempts to leverage resistant starch as microbiome-modifying interventions in clinical studies have yielded remarkable inter-individual variation. Consequently, their utility as a potential therapy likely depends predominantly on the selected resistant starch and the subject's baseline microbiome. The purpose of this review is to detail i) the heterogeneity of resistant starches, ii) how resistant starch is sequentially degraded and fermented by specialized gut microbes, and iii) how resistant starch interventions yield variable effects on the gut microbiome.