tbuckley/cabot-search huggingface dataset:
Dynamic analysis of human small intestinal microbiota after an ingestion of fermented milk by small-intestinal fluid perfusion using an endoscopic retrograde bowel insertion technique
Authors: Toshihiko Takada, Daisuke Chinda, Tatsuya Mikami, Kensuke Shimizu, Kosuke Oana, Shiro Hayamizu, Kuniaki Miyazawa, Tetsu Arai, Miyuki Katto, Yusuke Nagara, Hiroshi Makino, Akira Kushiro, Kenji Oishi, Shinsaku Fukuda
Journal: Gut Microbes (2020)

Probiotic products have been shown to have beneficial effects on human hosts, but what happens in the gastrointestinal tract after its ingestion remains unclear. Our aim was to investigate the changes within the small intestines after a single intake of a fermented milk product containing a probiotic. We have periodically collected the small-intestinal fluids from the terminal ileum of seven healthy subjects for up to 7 h after ingestion by small-intestinal fluid perfusion using an endoscopic retrograde bowel insertion technique. The bacterial composition of the terminal ileum clearly revealed that the ingested probiotics (Lactobacillus casei strain Shirota: LcS and Bifidobacterium breve strain Yakult: BbrY) occupied the ileal microbiota for several hours, temporarily representing over 90% of the ileal microbiota in several subjects. Cultivation of ileal fluids showed that under a dramatic pH changes before reaching the terminal ileum, a certain number of the ingested bacteria survived (8.2 ± 6.4% of LcS, 7.8 ± 11.0% of BbrY). This means that more than 1 billion LcS and BbrY cells reached the terminal ileum with their colony-forming ability intact. These results indicate that there is adequate opportunity for the ingested probiotics to continuously stimulate the host cells in the small intestines. Our data suggest that probiotic fermented milk intake affects intestinal microbes and the host, explaining part of the process from the intake of probiotics to the exertion of their beneficial effects on the host.
Potential role of memantine in the prevention and treatment of COVID-19: its antagonism of nicotinic acetylcholine receptors and beyond
Authors: Senad Hasanagic, Fadila Serdarevic
Journal: European Respiratory Journal (2020)

<b>Memantine, as an antagonist of α7-nAChR and NMDA receptors, may decrease ACE2 receptor expression and reduce oxidative stress and inflammation. Hence, memantine may potentially reduce SARS-CoV-2 virulence.</b>https://bit.ly/2AZHiVg
Infographic. Keep it cool and beat the heat: cooling strategies for exercise in hot and humid conditions
Authors: Coen C W G Bongers, Johannus Q de Korte, Thijs Eijsvogels
Journal: British Journal of Sports Medicine (2020)

Environmental conditions for the upcoming Tokyo Summer Olympics (32th Olympiad) are expected to be extremely challenging for athletes.1 The high ambient temperature, radiant temperature and absolute humidity, in combination with the urbanisation and heat storage in crowded stadiums, will limit the capability of athletes to dissipate the exercise-induced heat production. Significant elevations of core temperature may occur, leading to an increased risk to develop heat-related disorders and a substantial deterioration of exercise performance. Therefore, application of cooling strategies prior to (precooling) or during exercise (percooling) is highly recommended. In this infographic, we will summarise the latest scientific insights on the effectiveness of cooling strategies.

Cooling strategies are known to improve exercise performance in the heat, such as time trial performance, time to exhaustion and intermittent sprint exercise,2 due to reductions in thermal strain …
Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics
Authors: Sateesh Maddirevula, Hiroyuki Kuwahara, Nour Ewida, Hanan E. Shamseldin, Nisha Patel, Fatema Alzahrani, Tarfa AlSheddi, Eman AlObeid, Mona Alenazi, Hessa S. Alsaif, Maha Alqahtani, Maha AlAli, Hatoon Al Ali, Rana Helaby, Niema Ibrahim, Firdous Abdulwahab, Mais Hashem, Nadine Hanna, Dorota Monies, Nada Derar, Afaf Alsagheir, Amal Alhashem, Badr Alsaleem, Hamoud Alhebbi, Sami Wali, Ramzan Umarov, Xin Gao, Fowzan S. Alkuraya
Journal: Genome biology (2020)

Abstract Background At least 50% of patients with suspected Mendelian disorders remain undiagnosed after whole-exome sequencing (WES), and the extent to which non-coding variants that are not captured by WES contribute to this fraction is unclear. Whole transcriptome sequencing is a promising supplement to WES, although empirical data on the contribution of RNA analysis to the diagnosis of Mendelian diseases on a large scale are scarce. Results Here, we describe our experience with transcript-deleterious variants (TDVs) based on a cohort of 5647 families with suspected Mendelian diseases. We first interrogate all families for which the respective Mendelian phenotype could be mapped to a single locus to obtain an unbiased estimate of the contribution of TDVs at 18.9%. We examine the entire cohort and find that TDVs account for 15% of all “solved” cases. We compare the results of RT-PCR to in silico prediction. Definitive results from RT-PCR are obtained from blood-derived RNA for the overwhelming majority of variants (84.1%), and only a small minority (2.6%) fail analysis on all available RNA sources (blood-, skin fibroblast-, and urine renal epithelial cells-derived), which has important implications for the clinical application of RNA-seq. We also show that RNA analysis can establish the diagnosis in 13.5% of 155 patients who had received “negative” clinical WES reports. Finally, our data suggest a role for TDVs in modulating penetrance even in otherwise highly penetrant Mendelian disorders. Conclusions Our results provide much needed empirical data for the impending implementation of diagnostic RNA-seq in conjunction with genome sequencing.
ATF3 Coordinates Antitumor Synergy between Epigenetic Drugs and Protein Disulfide Isomerase Inhibitors
Authors: Ravyn M. Duncan, Leticia Reyes, Katelyn Moats, Reeder M. Robinson, Sara A. Murphy, Balveen Kaur, Holly A.F. Stessman, Nathan G. Dolloff
Journal: Cancer Research (2020)

Abstract Histone deacetylase inhibitors (HDACi) are largely ineffective in the treatment of solid tumors. In this study, we describe a new class of protein disulfide isomerase (PDI) inhibitors that significantly and synergistically enhance the antitumor activity of HDACi in glioblastoma and pancreatic cancer preclinical models. RNA-sequencing screening coupled with gene silencing studies identified ATF3 as the driver of this antitumor synergy. ATF3 was highly induced by combined PDI and HDACi treatment as a result of increased acetylation of key histone lysine residues (acetylated histone 3 lysine 27 and histone 3 lysine 18) flanking the ATF3 promoter region. These chromatin marks were associated with increased RNA polymerase II recruitment to the ATF3 promoter, a synergistic upregulation of ATF3, and a subsequent apoptotic response in cancer cells. The HSP40/HSP70 family genes DNAJB1 and HSPA6 were found to be critical ATF3-dependent genes that elicited the antitumor response after PDI and HDAC inhibition. In summary, this study presents a synergistic antitumor combination of PDI and HDAC inhibitors and demonstrates a mechanistic and tumor suppressive role of ATF3. Combined treatment with PDI and HDACi offers a dual therapeutic strategy in solid tumors and the opportunity to achieve previously unrealized activity of HDACi in oncology. Significance: This study uses a first-in-class PDI inhibitor entering clinical development to enhance the effects of epigenetic drugs in some of the deadliest forms of cancer.
Grading Changes for USMLE Step 1 — A Golden Opportunity to Recalibrate Medical Education Priorities
Authors: Charles G. Prober
Journal: New England Journal of Medicine (2020)

Interview with Dr. Debra Weinstein on the announcement that scores for Step 1 of the U.S. Medical Licensing Examination will be reported as pass or fail. (11:38)Download Without the USMLE Step 1 exam exerting undue influence on our curricula, we have the opportunity to work as a community to redefine what it takes to train scientifically grounded and exemplary caregivers in today's world. Such collaborative action is overdue.
Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma
Authors: Liana Nobre, Michal Zapotocky, Sara Khan, Kohei Fukuoka, Adriana Fonseca, Tara McKeown, David Sumerauer, Ales Vicha, Wieslawa A. Grajkowska, Joanna Trubicka, Kay Ka Wai Li, Ho-Keung Ng, Luca Massimi, Ji Yeoun Lee, Seung-Ki Kim, Shayna Zelcer, Alexandre Vasiljevic, Cécile Faure-Conter, Peter Hauser, Boleslaw Lach, Marie-Lise van Veelen-Vincent, Pim J. French, Erwin G. Van Meir, William A. Weiss, Nalin Gupta, Ian F. Pollack, Ronald L. Hamilton, Amulya A. Nageswara Rao, Caterina Giannini, Joshua B. Rubin, Andrew S. Moore, Lola B. Chambless, Rajeev Vibhakar, Young Shin Ra, Maura Massimino, Roger E. McLendon, Helen Wheeler, Massimo Zollo, Veronica Ferruci, Toshihiro Kumabe, Claudia C. Faria, Jaroslav Sterba, Shin Jung, Enrique López-Aguilar, Jaume Mora, Carlos G. Carlotti, James M. Olson, Sarah Leary, Jason Cain, Lenka Krskova, Josef Zamecnik, Cynthia E. Hawkins, Uri Tabori, Annie Huang, Ute Bartels, Paul A. Northcott, Michael D. Taylor, Stephen Yip, Jordan R. Hansford, Eric Bouffet, Vijay Ramaswamy
Journal: Cell Reports Medicine (2020)

Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763–0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.
Abstract PR02: Epigenetic biomarkers in cell-free DNA for early detection of high-grade serous ovarian carcinoma
Authors: Ben Yi Tew, Gerald Gooden, David N. Buckley, Heather Miller, Monique Spillman, Lynda Roman, Bodour Salhia
Journal: Clinical Cancer Research (2020)

Abstract Background: High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy, with a 5-year survival rate of 40% or less when diagnosed with late-stage disease. There is a dramatic benefit to early diagnosis of HGSOC with a 5-year survival rate of nearly 90% for stage I disease. Unfortunately, the majority of HGSOC is diagnosed as late-stage disease and there are no reliable early screening or diagnostic tests. The objective of this study is to identify tumor-specific aberrant DNA methylation alterations detectable in circulation in order to develop a biomarker to detect early-stage HGSOC. Methods: We performed reduced representation bisulfite sequencing (RRBS) on 33 stage 1 HGSOC tissues and 10 normal fallopian tube tissue samples from contralateral ovaries of patients with ovarian cancer. We selected the top 82 regions from RRBS for validation by targeted bisulfite amplicon sequencing in plasma. We successfully designed assays for 35 out of 82 regions. Targeted bisulfite amplicon sequencing was performed on these top 35 regions in a separate cohort of circulating tumor DNA extracted from 27 stage 1 HGSOC and 11 benign ovarian masses. We constructed a novel classifier model that we used to differentiate between patients with HGSOC and those with benign ovarian lesions. Results: We identified 10,972 statistically significant differentially methylated regions between stage 1 HGSOC and normal fallopian tube tissues using RRBS. We then applied the classifier model on the top 35 regions determined by targeted bisulfite amplicon sequencing data on an independent cohort of plasma samples. This demonstrated that 13 of the 35 regions were able to discriminate stage 1 HGSOC from benign tumors with a high sensitivity and specificity (Area Under Curve = 0.909). Conclusions: These novel, noninvasive biomarkers show promise as an early detection test for high-grade serous ovarian cancer. This abstract is also being presented as Poster A08. Citation Format: Ben Yi Tew, Gerald Gooden, David N. Buckley, Heather Miller, Monique Spillman, Lynda Roman, Bodour Salhia. Epigenetic biomarkers in cell-free DNA for early detection of high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr PR02.
Long-term developmental effect of withholding parenteral nutrition in paediatric intensive care units: a 4-year follow-up of the PEPaNIC randomised controlled trial
Authors: An Jacobs, Karolijn Dulfer, Renate D Eveleens, José Hordijk, Hanna Van Cleemput, Ines Verlinden, Pieter J Wouters, Liese Mebis, Gonzalo Garcia Guerra, Koen Joosten, Sascha C Verbruggen, Fabian Güiza, Ilse Vanhorebeek, Greet Van den Berghe
Journal: The Lancet Child & Adolescent Health (2020)
Abstract B34: The number of tumorspheres cultured from peripheral blood is directly related to presence of metastasis in breast cancer patients
Authors: Monika Pizon, Dorothea Schott, Ulrich Pachmann, Katharina Pachmann
Journal: Clinical Cancer Research (2020)

Abstract Background: Cancer stem cells (CSCs) are the critical subpopulation of cancer cells involved in tumor formation, progression, metastasis, and drug resistance. CSCs also have been considered the main cause of cancer recurrence, and the identification of targets and biomarkers is still under development. In this study, primary cultures from peripheral blood were established, using sphere-forming assays for CSC enrichment, and correlated with clinicopathologic features. Methods: Circulating cancer stem cells were cultured under conditions favoring growth of tumorspheres from 72 patients with breast cancer, including a subpopulation of 23 patients with metastatic disease. Cell viability, stem cell marker expression, and ALDH 1 activity were evaluated by fluorescence scanning microscope (Olympus Scan®R). Results: Sphere formation was observed in 79% of patients with breast cancer. In the current study we found that the number of tumorspheres depended on stage of disease. Patients with metastatic disease had statistically significantly more tumorspheres compared to patients without metastasis (median 30 vs. 10; p=0.002). Furthermore, patients with multiple metastases had more tumorspheres as compared to patients with single metastasis (median 30 vs. 60; p&amp;lt;0.05). Analysis of surface marker expression profile of tumorspheres cultured from peripheral blood showed that spheres had typical phenotype of cancer stem cells with a high enzymatic activity for ALDH 1. There was no sphere formation in a control group with 20 healthy donors. Conclusion: Identifying the circulating cancer stem cell may provide more clinically useful prognostic information and can be the basis for developing novel therapies. Citation Format: Monika Pizon, Dorothea Schott, Ulrich Pachmann, Katharina Pachmann. The number of tumorspheres cultured from peripheral blood is directly related to presence of metastasis in breast cancer patients [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr B34.
Bendamustine Monotherapy for Primary Cutaneous Gamma-Delta T-Cell Lymphoma
Authors: Alexander Kreuter, Bijan Koushk-Jalali, Georgios Mitrakos, Frank Oellig, Chalid Assaf, Lorenzo Cerroni, Christian Tigges
Journal: JAMA Dermatology (2020)

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Soil and Seed: Coconspirators in Therapy-Induced Myeloid Neoplasms
Authors: Kevin Shannon, Daniel C. Link
Journal: Blood Cancer Discovery (2020)

Abstract Summary: In this issue of Blood Cancer Discovery, Stoddart and colleagues describe cooperative effects of exposing both the bone marrow microenvironment of recipient mice and donor hematopoietic stem and progenitor cells (HSPC) to an alkylating agent in a genetically accurate model of therapy-induced myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) characterized by chromosome 5q deletions. The authors further implicate senescence of alkylator-treated mesenchymal stem cells (MSC) as contributing to the microenvironmental damage and subsequent therapy-induced myeloid neoplasms (tMN). Loss of Trp53 function and somatic mutations in other DNA damage response (DDR) genes were associated with overt AML in this model. Together, these studies shed new light on the complex pathogenesis of tMN and establish a robust model for biologic and preclinical investigation. See related article by Stoddart et al., p. 32.
3M-052, a synthetic TLR-7/8 agonist, induces durable HIV-1 envelope–specific plasma cells and humoral immunity in nonhuman primates
Authors: Sudhir Pai Kasturi, Mohammed Ata Ur Rasheed, Colin Havenar-Daughton, Mathew Pham, Traci Legere, Zarpheen Jinnah Sher, Yevgeny Kovalenkov, Sanjeev Gumber, Jessica Y. Huang, Raphael Gottardo, William Fulp, Alicia Sato, Sheetal Sawant, Sherry Stanfield-Oakley, Nicole Yates, Celia LaBranche, S. Munir Alam, Georgia Tomaras, Guido Ferrari, David Montefiori, Jens Wrammert, Francois Villinger, Mark Tomai, John Vasilakos, Christopher B. Fox, Steven G. Reed, Barton F. Haynes, Shane Crotty, Rafi Ahmed, Bali Pulendran
Journal: Science Immunology (2020)

Our study describes robust and durable induction of HIV-1–specific antibody as well as germinal center and plasma cellular responses in rhesus macaques.
Randomized Trial Comparing Double Versus Triple Bortezomib-Based Regimen in Patients With Multiple Myeloma and Acute Kidney Injury Due to Cast Nephropathy
Authors: Frank Bridoux, Bertrand Arnulf, Lionel Karlin, Nicolas Blin, Nolwenn Rabot, Margaret Macro, Vincent Audard, Karim Belhadj, Brigitte Pegourie, Pierre Gobert, Emilie Cornec Le Gall, Bertrand Joly, Alexandre Karras, Arnaud Jaccard, Karine Augeul-Meunier, Salomon Manier, Bruno Royer, Denis Caillot, Mourad Tiab, Sébastien Delbes, Felipe Suarez, Cécile Vigneau, Sophie Caillard, Nina Arakelyan-Laboure, Damien Roos-Weil, Sylvie Chevret, Jean Paul Fermand
Journal: Journal of Clinical Oncology (2020)

We report a multicenter controlled trial comparing renal recovery and tolerance profile of doublet versus triplet bortezomib-based regimens in patients with initial myeloma cast nephropathy (CN) and acute kidney injury (AKI) without need for dialysis.After symptomatic measures and high-dose dexamethasone, patients were randomly assigned to receive bortezomib plus dexamethasone (BD), or BD plus cyclophosphamide (C-BD). In patients with < 50% reduction of serum free light chains (sFLCs) after 3 cycles, chemotherapy was reinforced with either cyclophosphamide (BD group) or thalidomide (C-BD group).Ninety-two patients were enrolled in each group. At random assignment, characteristics of the 2 groups were similar, including median age (68 years) and serum creatinine level (305.5 and 273.5 µmol/L in BD and C-BD group, respectively). At 3 months, renal response rate (primary end point) was not different (41 v 47 responders in the BD and C-BD groups, respectively; relative risk [RR], 0.87; P = .46). Very good partial response (free light chain reduction ≥ 90%) or more was achieved in 36 and 47 patients, respectively (RR, 0.76; P = .10). After 1 cycle of chemotherapy, 69 in the BD group and 67 patients in the C-BD group had achieved sFLC level ≤ 500 mg/L. Serious adverse events were recorded in 30 and 40 patients, respectively. At 12 months, 19 patients had died (9 in the BD group v 10 in the C-BD group), including 10 (6 in the BD group and 4 in the C-BD group) from myeloma progression and 3 (0 in the BD group and 3 in the C-BD group) from infection. Within median follow-up of 27 months, 43 and 42 patients switched to new therapy, respectively. Overall, 50 patients (24 in the BD group and 26 in the C-BD group) had died.This randomized study did not show any benefit of C-BD compared with BD on renal recovery of patients with initial CN not requiring dialysis. Adding cyclophosphamide did not sufficiently improve the efficacy-toxicity balance. Patients with myeloma with AKI are fragile, and indication for doublet or triplet regimen should be adapted to frailty.
Epithelial Vasopressin Type-2 Receptors Regulate Myofibroblasts by a YAP-CCN2–Dependent Mechanism in Polycystic Kidney Disease
Authors: Nidhi Dwivedi, Shixin Tao, Abeda Jamadar, Sonali Sinha, Christianna Howard, Darren P. Wallace, Timothy A. Fields, Andrew Leask, James P. Calvet, Reena Rao
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement In autosomal dominant polycystic kidney disease (ADPKD), progressive fibrosis contributes to renal failure, leading to ESKD. The vasopressin type-2 receptor (V2R) helps to regulate renal water homeostasis and stimulates cyst expansion in ADPKD. We discovered a novel pathogenic pathway behind V2R regulation of fibrosis in ADPKD kidneys. Epithelial V2R stimulation activates interstitial myofibroblasts, in a paracrine manner, in Pkd1 gene knockout (KO) mice. Pharmacologic inhibition and gene knockout studies indicated that V2R regulates myofibroblast activation by a yes-associated protein (YAP)– and connective tissue growth factor (CCN2)–dependent mechanism. The V2R-YAP-CCN2 molecular axis may present novel pharmacologic targets for control of fibrosis in ADPKD. Background Fibrosis is a major cause of loss of renal function in autosomal dominant polycystic kidney disease (ADPKD). In this study, we examined whether vasopressin type-2 receptor (V2R) activity in cystic epithelial cells can stimulate interstitial myofibroblasts and fibrosis in ADPKD kidneys. Methods We treated Pkd1 gene knockout ( Pkd1 KO) mice with dDAVP, a V2R agonist, for 3 days and evaluated the effect on myofibroblast deposition of extracellular matrix (ECM). We also analyzed the effects of conditioned media from primary cultures of human ADPKD cystic epithelial cells on myofibroblast activation. Because secretion of the profibrotic connective tissue growth factor (CCN2) increased significantly in dDAVP-treated Pkd1 KO mouse kidneys, we examined its role in V2R-dependent fibrosis in ADPKD as well as that of yes-associated protein (YAP). Results V2R stimulation using dDAVP increased the renal interstitial myofibroblast population and ECM deposition. Similarly, conditioned media from human ADPKD cystic epithelial cells increased myofibroblast activation in vitro , suggesting a paracrine mechanism. Renal collecting duct–specific gene deletion of CCN2 significantly reduced cyst growth and myofibroblasts in Pkd1 KO mouse kidneys. We found that YAP regulates CCN2 , and YAP inhibition or gene deletion reduces renal fibrosis in Pkd1 KO mouse kidneys. Importantly, YAP inactivation blocks the dDAVP-induced increase in myofibroblasts in Pkd1 KO kidneys. Further in vitro studies showed that V2R regulates YAP by an ERK1/2-dependent mechanism in human ADPKD cystic epithelial cells. Conclusions Our results demonstrate a novel mechanism by which cystic epithelial cells stimulate myofibroblasts in the pericystic microenvironment, leading to fibrosis in ADPKD. The V2R-YAP-CCN2 cell signaling pathway may present a potential therapeutic target for fibrosis in ADPKD.