tbuckley/cabot-search huggingface dataset:
Tracking Vibrio cholerae Cell-Cell Interactions during Infection Reveals Bacterial Population Dynamics within Intestinal Microenvironments
Authors: Yang Fu, Brian T. Ho, John J. Mekalanos
Journal: Cell Host & Microbe (2018)

Highlights•DNA conjugation can be used to track bacterial cell-cell contacts during infection•Sites of in vivo cell-cell contact correspond to sites of T6SS-mediated killing•V. cholerae T6SS contributes to colonization of the middle small intestine•DNA conjugation among V. cholerae occurs more efficiently in vivo than in vitroSummaryVibrio cholerae is the causative agent of the diarrheal disease cholera. Although many V. cholerae virulence factors have been studied, the role of interbacterial interactions within the host gut and their influence on colonization are poorly understood. Here, we utilized the conjugative properties of a Vibrio-specific plasmid to serve as a quantifiable genetic marker for direct contact among V. cholerae cells in the infant rabbit model for cholera. In conjunction, we also quantified contact-dependent type 6 secretion system (T6SS)-mediated killing of co-infecting V. cholerae strains. Tracking these interbacterial interactions revealed that most contact-dependent cell-cell interactions among V. cholerae occur in specific intestinal microenvironments, notably the distal small intestine and cecum, and that the T6SS confers a competitive advantage within the middle small intestine. These results support a model for V. cholerae gut colonization, which includes microenvironments where critical microbial-host and bacterial-bacterial interactions occur to facilitate colonization by this pathogen.Graphical abstract
Protein Kinase 2β Is Expressed in Neural Crest-Derived Urinary Pacemaker Cells and Required for Pyeloureteric Contraction
Authors: Samir M. Iskander, Meghan M. Feeney, Kirby Yee, Norman D. Rosenblum
Journal: Journal of the American Society of Nephrology (2018)

Nonobstructive hydronephrosis, defined as dilatation of the renal pelvis with or without dilatation of the ureter, is the most common antenatal abnormality detected by fetal ultrasound. Yet, the etiology of nonobstructive hydronephrosis is poorly defined. We previously demonstrated that defective development of urinary tract pacemaker cells (utPMCs) expressing hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) and the stem cell marker cKIT causes abnormal ureteric peristalsis and nonobstructive hydronephrosis. However, further investigation of utPMC development and function is limited by lack of knowledge regarding the embryonic derivation, development, and molecular apparatus of these cells. Here, we used lineage tracing in mice to identify cells that give rise to utPMCs. Neural crest cells (NCCs) indelibly labeled with tdTomato expressed HCN3 and cKIT. Furthermore, purified HCN3+ and cKIT+ utPMCs were enriched in Sox10 and Tfap-2α , markers of NCCs. Sequencing of purified RNA from HCN3+ cells revealed enrichment of a small subset of RNAs, including RNA encoding protein kinase 2 β (PTK2 β ), a Ca 2+ -dependent tyrosine kinase that regulates ion channel activity in neurons. Immunofluorescence analysis in situ revealed PTK2 β expression in NCCs as early as embryonic day 12.5 and in HCN3+ and cKIT+ utPMCs as early as embryonic day 15.5, with sustained expression in HCN3+ utPMCs until postnatal week 8. Pharmacologic inhibition of PTK2 β in murine pyeloureteral tissue explants inhibited contraction frequency. Together, these results demonstrate that utPMCs are derived from NCCs, identify new markers of utPMCs, and demonstrate a functional contribution of PTK2 β to utPMC function.
Tamoxifen Metabolism and Efficacy in Breast Cancer: A Prospective Multicenter Trial
Authors: Patrick Neven, Lynn Jongen, Anneleen Lintermans, Kathleen Van Asten, Chantal Blomme, Diether Lambrechts, An Poppe, Hans Wildiers, Anne-Sophie Dieudonné, Olivier Brouckaert, Jan Decloedt, Patrick Berteloot, Didier Verhoeven, Markus Joerger, Peter Vuylsteke, Wim Wynendaele, Minne Casteels, Sabine Van Huffel, Willem Lybaert, Johan Van Ginderachter, Robert Paridaens, Ignace Vergote, Vincent Olaf Dezentjé, Ben Van Calster, Henk-Jan Guchelaar
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Levels of endoxifen, the most active metabolite of tamoxifen, vary by the highly polymorphic cytochrome P450 (CYP) 2D6 enzyme. We prospectively investigated tamoxifen efficacy by serum endoxifen levels and the tamoxifen activity score (TAS). Experimental Design: A prospective observational multicenter study included postmenopausal women with an estrogen receptor–positive breast cancer receiving first-line tamoxifen, 20 mg daily in the neoadjuvant or metastatic setting, recruited between February 2009 and May 2014. The primary endpoint was the objective response rate (ORR) using RECIST criteria 1.0. Secondary endpoints were clinical benefit (CB), progression-free survival (PFS), and tolerability of tamoxifen. The main analysis used logistic regression to relate ORR to serum endoxifen levels after 3 months. Endpoints were also related to other tamoxifen metabolites and to TAS. Results: Endoxifen levels were available for 247 of all 297 patients (83%), of which 209 with target lesions (85%). Median follow-up time for PFS was 32.5 months, and 62% progressed. ORR and CB were 45% and 84%, respectively. ORR was not related to endoxifen, and the OR of ORR was 1.008 per μg/L increase in endoxifen (95% confidence interval, 0.971–1.046; P = 0.56). In general, none of the endpoints was associated with endoxifen levels, tamoxifen metabolites, or TAS. Conclusions: Under the prespecified assumptions, the results from this prospective clinical trial do not suggest therapeutic drug monitoring of endoxifen to be of clinical value in postmenopausal women treated with tamoxifen for breast cancer in the neoadjuvant or metastatic setting. Clin Cancer Res; 24(10); 2312–8. ©2018 AACR.
Intranuclear delivery of the transcription modulation domain of Tbet-improved lupus nephritis in (NZB/NZW) F1 lupus-prone mice
Authors: Jae-Seung Moon, Chin Hee Mun, Jung-Ho Kim, Jen-Young Cho, Sung-Dong Park, Tae-Yoon Park, Jin-Su Shin, Chun-Chang Ho, Yong-Beom Park, Sankar Ghosh, Alfred L.M. Bothwell, Sang-Won Lee, Sang-Kyou Lee
Journal: Kidney International (2018)
A Prevalent Variant in PPP1R3A Impairs Glycogen Synthesis and Reduces Muscle Glycogen Content in Humans and Mice (vol 5, pg e27, 2008)
Authors: D B Savage, L Zhai, B Ravikumar, C S Choi, J E Snaar, A C McGuire, Wou S-E., G Medina-Gomez, S Kim, C B Bock, D M Segvich, B Solanky, D Deelchand, A Vidal-Puig, N J Wareham, G I Shulman, F Karpe, R Taylor, B A Pederson, P J Roach, S O'Rahilly, A A DePaoli-Roach
Journal: PLoS Medicine (2008)
Virtual-reality-based cognitive behavioural therapy versus waiting list control for paranoid ideation and social avoidance in patients with psychotic disorders: a single-blind randomised controlled trial
Authors: Roos M C A Pot-Kolder, Chris N W Geraets, Wim Veling, Marije van Beilen, Anton B P Staring, Harm J Gijsman, Philippe A E G Delespaul, Mark van der Gaag
Journal: The Lancet Psychiatry (2018)
Abstract 20903: A Novel Approach to Arrhythmia Risk Stratification in Patients With Non-ischemic Cardiomyopathy
Authors: Plamen Nikolov, Adityo Prakosa, Hermenegild J Arevalo, Katherine C Wu, Natalia Trayanova
Journal: Circulation (2016)

Introduction: We have recently developed a novel non-invasive and accurate test for arrhythmia risk stratification in ischemic cardiomyopathy patients, termed Virtual Arrhythmia Risk Prediction (VA...
Long non-coding RNA implicated in the invasion and metastasis of head and neck cancer: possible function and mechanisms
Authors: Xiaobo Luo, Yan Qiu, Yuchen Jiang, Fangman Chen, Lu Jiang, Yu Zhou, Hongxia Dan, Xin Zeng, Yu L. Lei, Qianming Chen
Journal: Molecular Cancer (2018)

Head and neck cancer (HNC) ranks as the 6th most common malignancy across the world. Metastasis is a hallmark of cancer, primarily contributing to the relapse and poor prognosis of HNC. Recently, long noncoding RNAs (lncRNAs), previously considered as non-functional, are increasingly appreciated by scholars to play crucial roles in mediating HNC metastasis. LncRNAs, which are located in the nucleus and cytoplasm, mainly exert their function via epigenetic modification, transcriptional control and translational regulation. As several lncRNAs are presently demonstrated to participate in HNC metastasis, we make a summary of the functions and mechanisms regarding these lncRNAs. As shown in the literature, most lncRNAs appear to promote the metastasis of HNC. Hence, we primarily discuss the lncRNAs involved in enhancing metastasis. Additionally, more studies are needed to understand those lncRNAs without clear mechanisms. Furthermore, we introduced the upstream regulator for the aberrant expression of lncRNAs in HNC. Finally, we concisely addressed future research prospects of lncRNAs, particularly the interplay between lncRNAs and tumor immunity as well as lncRNA-targeted therapeutic techniques, and we introduced clustered regularly interspaced short palindromic repeats (CRISPR)-Display as a possibly transformative tool to study lncRNAs. Although lncRNA research is still in the initial stage, it holds great promise to be applied as a prognosticator of HNC and a therapeutic target to inhibit HNC metastasis, which could significantly enhance the outcome of HNC patients.
Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction
Authors: Eleanor M. Dunican, Brett M. Elicker, David S. Gierada, Scott K. Nagle, Mark L. Schiebler, John D. Newell, Wilfred W. Raymond, Marrah E. Lachowicz-Scroggins, Selena Di Maio, Eric A. Hoffman, Mario Castro, Sean B. Fain, Nizar N. Jarjour, Elliot Israel, Bruce D. Levy, Serpil C. Erzurum, Sally E. Wenzel, Deborah A. Meyers, Eugene R. Bleecker, Brenda R. Phillips, David T. Mauger, Erin D. Gordon, Prescott G. Woodruff, Michael C. Peters, John V. Fahy
Journal: Journal of Clinical Investigation (2018)

BACKGROUND. The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown.
Implementing lung cancer screening: baseline results from a community-based ‘Lung Health Check’ pilot in deprived areas of Manchester
Authors: Phil A Crosbie, Haval Balata, Matthew Evison, Melanie Atack, Val Bayliss-Brideaux, Denis Colligan, Rebecca Duerden, Josephine Eaglesfield, Timothy Edwards, Peter Elton, Julie Foster, Melanie Greaves, Graham Hayler, Coral Higgins, John Howells, Klaus Irion, Devinda Karunaratne, Jodie Kelly, Zoe King, Sarah Manson, Stuart Mellor, Donna Miller, Amanda Myerscough, Tom Newton, Michelle O’Leary, Rachel Pearson, Julie Pickford, Richard Sawyer, Nick J Screaton, Anna Sharman, Maggi Simmons, Elaine Smith, Ben Taylor, Sarah Taylor, Anna Walsham, Angela Watts, James Whittaker, Laura Yarnell, Anthony Threlfall, Phil V Barber, Janet Tonge, Richard Booton
Journal: Thorax (2018)

We report baseline results of a community-based, targeted, low-dose CT (LDCT) lung cancer screening pilot in deprived areas of Manchester. Ever smokers, aged 55-74 years, were invited to 'lung health checks' (LHCs) next to local shopping centres, with immediate access to LDCT for those at high risk (6-year risk ≥1.51%, PLCO
New closure method for a mucosal defect after endoscopic submucosal dissection: the clip-on-clip closure method
Authors: Tatsuma Nomura, Akira Kamei, Shinya Sugimoto, Jun Oyamada
Journal: Endoscopy (2018)

Endoscopic submucosal dissection (ESD) is an effective method that enables simultaneous resection of early malignant tumors. However, postoperative bleeding and perforation are often problematic. Therefore, various postoperative mucosal defect closure methods have been reported. The 8-ring and endoscopic slipknot clip suturing methods are closure methods that require additional devices, as well as regular clips [1] [2]. Recently, a useful mucosa – submucosa clip closure method using only clips has been reported [3]. However, these methods may require a special device or damage the muscular layer of the mucosal defect. We developed a new, simple method, named the clip-on-clip closure method (CCCM), which is described below.
Blood will out: vascular contributions to Alzheimer’s disease
Authors: Sidney Strickland
Journal: Journal of Clinical Investigation (2018)

The fundamental pathology in Alzheimer’s disease (AD) is neuronal dysfunction leading to cognitive impairment. The amyloid-β peptide (Aβ), derived from amyloid precursor protein, is one driver of AD, but how it leads to neuronal dysfunction is not established. In this Review, I discuss the complexity of AD and possible cause-and-effect relationships between Aβ and the vascular and hemostatic systems. AD can be considered a multifactorial syndrome with various contributing pathological mechanisms. Therefore, as is routinely done with cancer, it will be important to classify patients with respect to their disease signature so that specific pathologies, including vascular pathways, can be therapeutically targeted.
Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience
Authors: Susan O’Brien, Richard R. Furman, Steven Coutre, Ian W. Flinn, Jan A. Burger, Kristie Blum, Jeff Sharman, William Wierda, Jeffrey Jones, Weiqiang Zhao, Nyla A. Heerema, Amy J. Johnson, Ying Luan, Danelle F. James, Alvina D. Chu, John C. Byrd
Journal: Blood (2018)
Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging
Authors: Gregory W. Albers, Michael P. Marks, Stephanie Kemp, Soren Christensen, Jenny P. Tsai, Santiago Ortega-Gutierrez, Ryan A. McTaggart, Michel T. Torbey, May Kim-Tenser, Thabele Leslie-Mazwi, Amrou Sarraj, Scott E. Kasner, Sameer A. Ansari, Sharon D. Yeatts, Scott Hamilton, Michael Mlynash, Jeremy J. Heit, Greg Zaharchuk, Sun Kim, Janice Carrozzella, Yuko Y. Palesch, Andrew M. Demchuk, Roland Bammer, Philip W. Lavori, Joseph P. Broderick, Maarten G. Lansberg
Journal: New England Journal of Medicine (2018)

Thrombectomy is currently recommended for eligible patients with stroke who are treated within 6 hours after the onset of symptoms.We conducted a multicenter, randomized, open-label trial, with blinded outcome assessment, of thrombectomy in patients 6 to 16 hours after they were last known to be well and who had remaining ischemic brain tissue that was not yet infarcted. Patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion, an initial infarct size of less than 70 ml, and a ratio of the volume of ischemic tissue on perfusion imaging to infarct volume of 1.8 or more were randomly assigned to endovascular therapy (thrombectomy) plus standard medical therapy (endovascular-therapy group) or standard medical therapy alone (medical-therapy group). The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability) at day 90.The trial was conducted at 38 U.S. centers and terminated early for efficacy after 182 patients had undergone randomization (92 to the endovascular-therapy group and 90 to the medical-therapy group). Endovascular therapy plus medical therapy, as compared with medical therapy alone, was associated with a favorable shift in the distribution of functional outcomes on the modified Rankin scale at 90 days (odds ratio, 2.77; P<0.001) and a higher percentage of patients who were functionally independent, defined as a score on the modified Rankin scale of 0 to 2 (45% vs. 17%, P<0.001). The 90-day mortality rate was 14% in the endovascular-therapy group and 26% in the medical-therapy group (P=0.05), and there was no significant between-group difference in the frequency of symptomatic intracranial hemorrhage (7% and 4%, respectively; P=0.75) or of serious adverse events (43% and 53%, respectively; P=0.18).Endovascular thrombectomy for ischemic stroke 6 to 16 hours after a patient was last known to be well plus standard medical therapy resulted in better functional outcomes than standard medical therapy alone among patients with proximal middle-cerebral-artery or internal-carotid-artery occlusion and a region of tissue that was ischemic but not yet infarcted. (Funded by the National Institute of Neurological Disorders and Stroke; DEFUSE 3 ClinicalTrials.gov number, NCT02586415 .).
Cost-effectiveness of Population-Based BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2 Mutation Testing in Unselected General Population Women
Authors: Ranjit Manchanda, Shreeya Patel, Vladimir S Gordeev, Antonis C Antoniou, Shantel Smith, Andrew Lee, John L Hopper, Robert J MacInnis, Clare Turnbull, Susan J Ramus, Simon A Gayther, Paul D P Pharoah, Usha Menon, Ian Jacobs, Rosa Legood
Journal: JNCI Journal of the National Cancer Institute (2017)

The cost-effectiveness of population-based panel testing for high- and moderate-penetrance ovarian cancer (OC)/breast cancer (BC) gene mutations is unknown. We evaluate the cost-effectiveness of population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 mutation testing compared with clinical criteria/family history (FH) testing in unselected general population women. A decision-analytic model comparing lifetime costs and effects of criteria/FH-based BRCA1/BRCA2 testing is compared with BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing in those fulfilling clinical criteria/strong FH of cancer (≥10% BRCA1/BRCA2 probability) and all women age 30 years or older. Analyses are presented for UK and US populations. Identified carriers undergo risk-reducing salpingo-oophorectomy. BRCA1/BRCA2/PALB2 carriers can opt for magnetic resonance imaging/mammography, chemoprevention, or risk-reducing mastectomy. One-way and probabilistic sensitivity analysis (PSA) enabled model uncertainty evaluation. Outcomes include OC, BC, and additional heart disease deaths. Quality-adjusted life-years (QALYs), OC incidence, BC incidence, and incremental cost-effectiveness ratio (ICER) were calculated. The time horizon is lifetime and perspective is payer. Compared with clinical criteria/FH-based BRCA1/BRCA2 testing, clinical criteria/FH-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is cost-effective (ICER = £7629.65/QALY or $49 282.19/QALY; 0.04 days' life-expectancy gained). Population-based testing for BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 mutations is the most cost-effective strategy compared with current policy: ICER = £21 599.96/QALY or $54 769.78/QALY (9.34 or 7.57 days' life-expectancy gained). At £30 000/QALY and $100 000/QALY willingness-to-pay thresholds, population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 panel testing is the preferred strategy in 83.7% and 92.7% of PSA simulations; criteria/FH-based panel testing is preferred in 16.2% and 5.8% of simulations, respectively. Population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing can prevent 1.86%/1.91% of BC and 3.2%/4.88% of OC in UK/US women: 657/655 OC cases and 2420/2386 BC cases prevented per million. Population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is more cost-effective than any clinical criteria/FH-based strategy. Clinical criteria/FH-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is more cost-effective than BRCA1/BRCA2 testing alone.
Determinants of tuberculosis trends in six Indigenous populations of the USA, Canada, and Greenland from 1960 to 2014: a population-based study
Authors: Kianoush Dehghani, Zhiyi Lan, Peizhi Li, Sascha Wilk Michelsen, Sean Waites, Andrea Benedetti, Pierre Lejeune, Jill Torrie, Elizabeth Robinson, Berenica Vejvoda, Muhammad Mullah, Diana Redwood, Michael Cooper, Anne Fanning, Wadieh Yacoub, Gonzalo G Alvarez, Bolette Søborg, Richard Long, Dick Menzies
Journal: The Lancet Public Health (2018)

Tuberculosis continues to disproportionately affect many Indigenous populations in the USA, Canada, and Greenland. We aimed to investigate whether population-based tuberculosis-specific interventions or changes in general health and socioeconomic indicators, or a combination of these factors, were associated with changes in tuberculosis incidence in these Indigenous populations.
Epidemiology, clinical characteristics, and associations for symptom-based Rome IV functional dyspepsia in adults in the USA, Canada, and the UK: a cross-sectional population-based study
Authors: Imran Aziz, Olafur S Palsson, Hans Törnblom, Ami D Sperber, William E Whitehead, Magnus Simrén
Journal: The Lancet. Gastroenterology & hepatology (2018)
Molecular Markers Increase Precision of the European Association of Urology Non–Muscle-Invasive Bladder Cancer Progression Risk Groups
Authors: Kim E.M. van Kessel, Kirstin A. van der Keur, Lars Dyrskjøt, Ferran Algaba, Naeromy Y.C. Welvaart, Willemien Beukers, Ulrika Segersten, Bastian Keck, Tobias Maurer, Tatjana Simic, Marcus Horstmann, Marc-Oliver Grimm, Gregers G. Hermann, Karin Mogensen, Arndt Hartmann, Niels Harving, Astrid C. Petersen, Jørgen B. Jensen, Kerstin Junker, Joost L. Boormans, Francisco X. Real, Núria Malats, Per-Uno Malmström, Torben F. Ørntoft, Ellen C. Zwarthoff
Journal: Clinical Cancer Research (2018)

Purpose: The European Association of Urology (EAU) guidelines for non-muscle-invasive bladder cancer (NMIBC) recommend risk stratification based on clinicopathologic parameters. Our aim was to investigate the added value of biomarkers to improve risk stratification of NMIBC.Experimental Design: We prospectively included 1,239 patients in follow-up for NMIBC in six European countries. Fresh-frozen tumor samples were analyzed for GATA2, TBX2, TBX3, and ZIC4 methylation and FGFR3, TERT, PIK3CA, and RAS mutation status. Cox regression analyses identified markers that were significantly associated with progression to muscle-invasive disease. The progression incidence rate (PIR = rate of progression per 100 patient-years) was calculated for subgroups.Results: In our cohort, 276 patients had a low, 273 an intermediate, and 555 a high risk of tumor progression based on the EAU NMIBC guideline. Fifty-seven patients (4.6%) progressed to muscle-invasive disease. The limited number of progressors in this large cohort compared with older studies is likely due to improved treatment in the past two decades. Overall, wild-type FGFR3 and methylation of GATA2 and TBX3 were significantly associated with progression (HR = 0.34, 2.53, and 2.64, respectively). The PIR for EAU high-risk patients was 4.25. On the basis of FGFR3 mutation status and methylation of GATA2, this cohort could be reclassified into a good class (PIR = 0.86, 26.2% of patients), a moderate class (PIR = 4.32, 49.7%), and a poor class (PIR = 7.66, 24.0%).Conclusions: We conclude that the addition of selected biomarkers to the EAU risk stratification increases its accuracy and identifies a subset of NMIBC patients with a very high risk of progression. Clin Cancer Res; 24(7); 1586-93. ©2018 AACR.