tbuckley/cabot-search huggingface dataset:
Caveolae-localized L-type Ca2+ channels do not contribute to function or hypertrophic signalling in the mouse heart
Authors: Robert N. Correll, Catherine A. Makarewich, Hongyu Zhang, Chen Zhang, Michelle A. Sargent, Allen J. York, Remus M. Berretta, Xiongwen Chen, Steven R. Houser, Jeffery D. Molkentin
Journal: Cardiovascular Research (2017)

L-type Ca2+ channels (LTCCs) in adult cardiomyocytes are localized to t-tubules where they initiate excitation-contraction coupling. Our recent work has shown that a subpopulation of LTCCs found at the surface sarcolemma in caveolae of adult feline cardiomyocytes can also generate a Ca2+ microdomain that activates nuclear factor of activated T-cells signaling and cardiac hypertrophy, although the relevance of this paradigm to hypertrophy regulation in vivo has not been examined.Here we generated heart-specific transgenic mice with a putative caveolae-targeted LTCC activator protein that was ineffective in initiating or enhancing cardiac hypertrophy in vivo. We also generated transgenic mice with cardiac-specific overexpression of a putative caveolae-targeted inhibitor of LTCCs, and while this protein inhibited caveolae-localized LTCCs without effects on global Ca2+ handling, it similarly had no effect on cardiac hypertrophy in vivo. Cardiac hypertrophy was elicited by pressure overload for 2 or 12 weeks or with neurohumoral agonist infusion. Caveolae-specific LTCC activator or inhibitor transgenic mice showed no greater change in nuclear factor of activated T-cells activity after 2 weeks of pressure overload stimulation compared with control mice.Our results indicate that LTCCs in the caveolae microdomain do not affect cardiac function and are not necessary for the regulation of hypertrophic signaling in the adult mouse heart.
Extracellular Matrix/Integrin Signaling Promotes Resistance to Combined Inhibition of HER2 and PI3K in HER2+ Breast Cancer
Authors: Ariella B. Hanker, Mónica Valeria Estrada, Giampaolo Bianchini, Preston D. Moore, Junfei Zhao, Feixiong Cheng, James P. Koch, Luca Gianni, Darren R. Tyson, Violeta Sánchez, Brent N. Rexer, Melinda E. Sanders, Zhongming Zhao, Thomas P. Stricker, Carlos L. Arteaga
Journal: Cancer Research (2017)

Abstract PIK3CA mutations are associated with resistance to HER2-targeted therapies. We previously showed that HER2+/PIK3CAH1047R transgenic mammary tumors are resistant to the HER2 antibodies trastuzumab and pertuzumab but respond to PI3K inhibitor buparlisib (TPB). In this study, we identified mechanisms of resistance to combined inhibition of HER2 and PI3K. TPB-resistant tumors were generated by treating HER2+/PIK3CAH1047R tumor-bearing mice long term with the drug combination. RNA sequencing of TPB-resistant tumors revealed that extracellular matrix and cell adhesion genes, including collagen II (Col2a1), were markedly upregulated, accompanied by activation of integrin β1/Src. Cells derived from drug-resistant tumors were sensitive to TBP when grown in vitro, but exhibited resistance when plated on collagen or when reintroduced into mice. Drug resistance was partially reversed by the collagen synthesis inhibitor ethyl-3,4-dihydroxybenzoate. Inhibition of integrin β1/Src blocked collagen-induced resistance to TPB and inhibited growth of drug-resistant tumors. High collagen II expression was associated with significantly lower clinical response to neoadjuvant anti-HER2 therapy in HER2+ breast cancer patients. Overall, these data suggest that upregulation of collagen/integrin/Src signaling contributes to resistance to combinatorial HER2 and PI3K inhibition. Cancer Res; 77(12); 3280–92. ©2017 AACR.
Decreased thromboembolic stroke but not atherosclerosis or vascular remodelling in mice with ROCK2-deficient platelets
Authors: Nikola Sladojevic, Goo Taeg Oh, Hyung-Hwan Kim, Lea M. Beaulieu, Hervé Falet, Karol Kamiński, Jane E. Freedman, James K. Liao
Journal: Cardiovascular Research (2017)

Rho-associated coiled-coil containing kinase (ROCK)-2 is an important mediator of the actin cytoskeleton. Because changes in the actin cytoskeleton are critical for platelet function, we hypothesized that ROCK2 in platelets will play important role in thrombosis and can be potentially a target for therapeutic intervention in thromboembolic stroke.We generated platelet-specific ROCK2-deficient mice (ROCK2Plt-/-) from conditional ROCK2fl°x/fl°x and platelet factor (PF)-4-Cre transgenic mice. Platelets from ROCK2Plt-/- mice were less responsive to thrombin stimulation in terms of pseudopodia formation, collagen adhesion, and in the formation of homotypic and heterotypic aggregates. This corresponded to prolonged bleeding time and delayed vascular occlusion following vessel injury. To determine whether these changes in platelet function could affect thrombotic disease, we utilized a clot-embolic model of ischaemic stroke. When pre-formed clots from ROCK2Plt-/- mice were injected into the middle cerebral artery of control mice, cerebral blood flow recovery occurred more rapidly, leading to decreased cerebral injury and neurological deficits, compared to pre-formed clots from control mice. Interestingly, pre-formed clots from control mice produced similar degree of cerebral injury when injected into control or ROCK2Plt-/- mice, suggesting that platelet ROCK2 deficiency affects clot formation but not propagation. Indeed, in a non-thrombotic intra-filament MCA occlusion model of stroke, platelet ROCK2 deletion was not protective. Furthermore, ROCK2Plt-/- mice exhibit similar atherosclerosis severity and vascular remodeling as control mice.These findings indicate that platelet ROCK2 plays important role in platelet function and thrombosis, but does not contribute to the pathogenesis of atherosclerosis and vascular remodeling.
Microparticles: Compartmentalized Spherical Collagen Microparticles for Anisotropic Cell Culture Microenvironments (Adv. Healthcare Mater. 8/2017)
Authors: Satoru Yoshida, Masahiro Takinoue, Hiroaki Onoe
Journal: Advanced Healthcare Materials (2017)

A new fabrication method for obtaining anisotropic hydrogel microparticles (approximately 100 μm in diameter) with different types of ECM hemispheres is proposed by Hiroaki Onoe and co-workers in article number 1601463 to mimic the microenvironments observed in in vivo. This fabrication method enables gaining control of the hemispherical volume, density, and type of ECM. The proposed microparticles can be utilized for cell culture in anisotropic microenvironments.
Experience with MRD Testing in B- ALL By Flow Cytometry Does Not Prevent Interpretative Discordance
Authors: Michael Keeney, Brent L. Wood, Benjamin Hedley, Joseph A. DiGiuseppe, Maryalice Stetler-Stevenson, Elisabeth Paietta, Gerard Lozanski, Adam C. Seegmiller, Bruce W Greig, Aaron C. Shaver, Lata Mukundan, Howard R. Higley, Caroline C Sigman, Gary Kelloff, John Milburn Jessup, Michael J Borowitz
Journal: Blood (2016)
Projected health effects of realistic dietary changes to address freshwater constraints in India: a modelling study
Authors: James Milner, Edward J M Joy, Rosemary Green, Francesca Harris, Lukasz Aleksandrowicz, Sutapa Agrawal, Pete Smith, Andy Haines, Alan D Dangour
Journal: The Lancet Planetary Health (2017)

BackgroundThe availability of freshwater for irrigation in the Indian agricultural sector is expected to decline over the coming decades. This might have implications for food production in India, with subsequent effects on diets and health. We identify realistic and healthy dietary changes that could enhance the resilience of the Indian food system to future decreases in water availability.MethodsIn this modelling study, we optimised typical dietary patterns in an Indian population sample to meet projected decreases in the availability of water per person for irrigation (blue water footprint) due to population growth (to 2025 and 2050). The optimised diets met nutritional guidelines and minimised deviation from existing patterns. Resulting changes in life-years lost due to coronary heart disease, stroke, diabetes, and cancers were modelled using life tables, and changes in greenhouse gas emissions associated with the production of diets were estimated. The primary outcomes of the model were changes in life-years per 100 000 total population over 40 years (to 2050).FindingsThe optimised diets had up to 30% lower blue water footprints and generally contained lower amounts of wheat, dairy, and poultry, and increased amounts of legumes. In the 2050 scenario, adoption of these diets would on average result in 6800 life-years gained per 100 000 total population (95% CI 1600–13 100) over 40 years. The dietary changes were accompanied by reductions in greenhouse gas emissions. The magnitude of the health and environmental effects varied between dietary patterns.InterpretationModest changes in diets could help to address projected reductions in the availability of freshwater for irrigation in India. These dietary changes could also simultaneously reduce diet-related greenhouse gas emissions and improve diet-related health outcomes.FundingWellcome Trust.
Early Glycemic Control and Magnitude of HbA1c Reduction Predict Cardiovascular Events and Mortality: Population-Based Cohort Study of 24,752 Metformin Initiators
Authors: Elisabeth Svensson, Lisbeth M. Baggesen, Søren P. Johnsen, Lars Pedersen, Helene Nørrelund, Esben S. Buhl, Christiane L. Haase, Reimar W. Thomsen
Journal: Diabetes Care (2017)

We investigated the association of early achieved HbA1c level and magnitude of HbA1c reduction with subsequent risk of cardiovascular events or death in patients with type 2 diabetes who initiate metformin.This was a population-based cohort study including all metformin initiators with HbA1c tests in Northern Denmark, 2000-2012. Six months after metformin initiation, we classified patients by HbA1c achieved (<6.5% or higher) and by magnitude of HbA1c change from the pretreatment baseline. We used Cox regression to examine subsequent rates of acute myocardial infarction, stroke, or death, controlling for baseline HbA1c and other confounding factors.We included 24,752 metformin initiators (median age 62.5 years, 55% males) with a median follow-up of 2.6 years. The risk of a combined outcome event gradually increased with rising levels of HbA1c achieved compared with a target HbA1c of <6.5%: adjusted hazard ratio (HR) 1.18 (95% CI 1.07-1.30) for 6.5-6.99%, HR 1.23 (1.09-1.40) for 7.0-7.49%, HR 1.34 (1.14-1.57) for 7.5-7.99%, and HR 1.59 (1.37-1.84) for ≥8%. Results were consistent for individual outcome events and robust by age-group and other patient characteristics. A large absolute HbA1c reduction from baseline also predicted outcome: adjusted HR 0.80 (0.65-0.97) for Δ = -4, HR 0.98 (0.80-1.20) for Δ = -3, HR 0.92 (0.78-1.08) for Δ = -2, and HR 0.99 (0.89-1.10) for Δ = -1 compared with no HbA1c change (Δ = 0).A large initial HbA1c reduction and achievement of low HbA1c levels within 6 months after metformin initiation are associated with a lower risk of cardiovascular events and death in patients with type 2 diabetes.
Overcoming the Interference of Daratumumab with Immunofixation Electrophoresis (IFE) Using an Industry-Developed Dira Test : Hydrashift 2/4 Daratumumab
Authors: Helene Caillon, Alix Irimia, Jason S. Simon, Amy Axel, Kate Sasser, Matthew James Scullion, Thierry Ligneel, Georges Nouadje, Philippe Moreau, Thomas Dejoie
Journal: Blood (2016)
Long-term Survival in Glioblastoma with Cytomegalovirus pp65-Targeted Vaccination
Authors: Kristen A. Batich, Elizabeth A. Reap, Gary E. Archer, Luis Sanchez-Perez, Smita K. Nair, Robert J. Schmittling, Pam Norberg, Weihua Xie, James E. Herndon, Patrick Healy, Roger E. McLendon, Allan H. Friedman, Henry S. Friedman, Darell Bigner, Gordana Vlahovic, Duane A. Mitchell, John H. Sampson
Journal: Clinical Cancer Research (2017)

Purpose: Patients with glioblastoma have less than 15-month median survival despite surgical resection, high-dose radiation, and chemotherapy with temozolomide. We previously demonstrated that targeting cytomegalovirus pp65 using dendritic cells (DC) can extend survival and, in a separate study, that dose-intensified temozolomide (DI-TMZ) and adjuvant granulocyte macrophage colony-stimulating factor (GM-CSF) potentiate tumor-specific immune responses in patients with glioblastoma. Here, we evaluated pp65-specific cellular responses following DI-TMZ with pp65-DCs and determined the effects on long-term progression-free survival (PFS) and overall survival (OS).Experimental Design: Following standard-of-care, 11 patients with newly diagnosed glioblastoma received DI-TMZ (100 mg/m2/d × 21 days per cycle) with at least three vaccines of pp65 lysosome-associated membrane glycoprotein mRNA-pulsed DCs admixed with GM-CSF on day 23 ± 1 of each cycle. Thereafter, monthly DI-TMZ cycles and pp65-DCs were continued if patients had not progressed.Results: Following DI-TMZ cycle 1 and three doses of pp65-DCs, pp65 cellular responses significantly increased. After DI-TMZ, both the proportion and proliferation of regulatory T cells (Tregs) increased and remained elevated with serial DI-TMZ cycles. Median PFS and OS were 25.3 months [95% confidence interval (CI), 11.0-∞] and 41.1 months (95% CI, 21.6-∞), exceeding survival using recursive partitioning analysis and matched historical controls. Four patients remained progression-free at 59 to 64 months from diagnosis. No known prognostic factors [age, Karnofsky performance status (KPS), IDH-1/2 mutation, and MGMT promoter methylation] predicted more favorable outcomes for the patients in this cohort.Conclusions: Despite increased Treg proportions following DI-TMZ, patients receiving pp65-DCs showed long-term PFS and OS, confirming prior studies targeting cytomegalovirus in glioblastoma. Clin Cancer Res; 23(8); 1898-909. ©2017 AACR.
Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2
Authors: Andrea B. Moffitt, Sarah L. Ondrejka, Matthew McKinney, Rachel E. Rempel, John R. Goodlad, Chun Huat Teh, Sirpa Leppa, Susanna Mannisto, Panu E. Kovanen, Eric Tse, Rex K.H. Au-Yeung, Yok-Lam Kwong, Gopesh Srivastava, Javeed Iqbal, Jiayu Yu, Kikkeri Naresh, Diego Villa, Randy D. Gascoyne, Jonathan Said, Magdalena B. Czader, Amy Chadburn, Kristy L. Richards, Deepthi Rajagopalan, Nicholas S. Davis, Eileen C. Smith, Brooke C. Palus, Tiffany J. Tzeng, Jane A. Healy, Patricia L. Lugar, Jyotishka Datta, Cassandra Love, Shawn Levy, David B. Dunson, Yuan Zhuang, Eric D. Hsi, Sandeep S. Dave
Journal: The Journal of Experimental Medicine (2017)

Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1, JAK3, STAT3, and SOCS1. We also identified mutations in KRAS, TP53, and TERT. Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell–specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes.
JetValve: Rapid manufacturing of biohybrid scaffolds for biomimetic heart valve replacement
Authors: Andrew K. Capulli, Maximillian Y. Emmert, Francesco S. Pasqualini, Debora Kehl, Etem Caliskan, Johan U. Lind, Sean P. Sheehy, Sung Jin Park, Seungkuk Ahn, Benedikt Weber, Josue A. Goss, Simon P. Hoerstrup, Kevin Kit Parker
Journal: Biomaterials (2017)
Motoring through: the role of kinesin superfamily proteins in female meiosis
Authors: Nicole J. Camlin, Eileen A. McLaughlin, Janet E. Holt
Journal: Human Reproduction Update (2017)

The kinesin motor protein family consists of 14 distinct subclasses and 45 kinesin proteins in humans. A large number of these proteins, or their orthologues, have been shown to possess essential function(s) in both the mitotic and the meiotic cell cycle. Kinesins have important roles in chromosome separation, microtubule dynamics, spindle formation, cytokinesis and cell cycle progression. This article contains a review of the literature with respect to the role of kinesin motor proteins in female meiosis in model species. Throughout, we discuss the function of each class of kinesin proteins during oocyte meiosis, and where such data are not available their role in mitosis is considered. Finally, the review highlights the potential clinical importance of this family of proteins for human oocyte quality.To examine the role of kinesin motor proteins in oocyte meiosis.A search was performed on the Pubmed database for journal articles published between January 1970 and February 2017. Search terms included 'oocyte kinesin' and 'meiosis kinesin' in addition to individual kinesin names with the terms oocyte or meiosis.Within human cells 45 kinesin motor proteins have been discovered, with the role of only 13 of these proteins, or their orthologues, investigated in female meiosis. Furthermore, of these kinesins only half have been examined in mammalian oocytes, despite alterations occurring in gene transcripts or protein expression with maternal ageing, cryopreservation or behavioral conditions, such as binge drinking, for many of them.Kinesin motor proteins have distinct and important roles throughout oocyte meiosis in many non-mammalian model species. However, the functions these proteins have in mammalian meiosis, particularly in humans, are less clear owing to lack of research. This review brings to light the need for more experimental investigation of kinesin motor proteins, particularly those associated with maternal ageing, cryopreservation or exposure to environmental toxicants.
Speaking out about gender imbalance in invited speakers improves diversity
Authors: Robyn S Klein, Rhonda Voskuhl, Benjamin M Segal, Bonnie N Dittel, Thomas E Lane, John R Bethea, Monica J Carson, Carol Colton, Susanna Rosi, Aileen Anderson, Laura Piccio, Joan M Goverman, Etty N Benveniste, Melissa A Brown, Seema Kaushalya Tiwari-Woodruff, Tajie H Harris, Anne H Cross
Journal: Nature Immunology (2017)
Dedicated Barrett's surveillance sessions managed by trained endoscopists improve dysplasia detection rate
Authors: Joanne Ooi, Patrick Wilson, Giles Walker, Paul Blaker, Sabina DeMartino, John O’Donohue, David Reffitt, Effie Lanaspre, Fuju Chang, John Meenan, Jason Dunn
Journal: Endoscopy (2017)

Abstract Background and study aim Barrett’s esophagus (BE)-associated dysplasia is an important marker for risk of progression to esophageal adenocarcinoma (EAC) and an indication for endoscopic therapy. However, BE surveillance technique is variable. The aim of this study was to assess the effect of dedicated BE surveillance lists on dysplasia detection rate (DDR). Patients and methods This was a prospective study of patients undergoing BE surveillance at two hospitals – community (UHL) and upper gastrointestinal center (GSTT). Four endoscopists (Group A) were trained in Prague classification, Seattle protocol biopsy technique, and lesion detection prior to performing BE surveillance endoscopies at both sites, with dedicated time slots or lists. The DDR was then compared with historical data from 47 different endoscopists at GSTT and 24 at UHL (Group B) who had undertaken Barrett’s surveillance over the preceding 5-year period. Results A total of 729 patients with BE underwent surveillance endoscopy between 2007 and 2012. There was no significant difference in patient age, sex, or length of BE between the two groups. There was a significant difference in detection rate of confirmed indefinite or low grade dysplasia and high grade dysplasia (HGD)/EAC between the two groups: 18 % (26 /142) Group A vs. 8 % (45/587) in Group B (P &lt; 0.001). Documentation of Prague criteria and adherence to the Seattle protocol was significantly higher in Group A. Conclusion This study demonstrated that a group of trained endoscopists undertaking Barrett’s surveillance on dedicated lists had significantly higher DDR than a nonspecialist cohort. These findings support the introduction of dedicated Barrett’s surveillance lists.
The nexus between periodontics and oral pathology
Authors: Alison M. Rich, Benedict Seo, Venkata Parachuru, Haizal M. Hussaini
Journal: Periodontology 2000 (2017)

Abstract A wide variety of lesions may arise from the oral mucosa, fibrous connective tissue, bone and cementum of the periodontium. The commonest pathology occurs as a result of bacterial infection and is very well known to dentists and periodontists, but rarer conditions present as gingival pathology. The pathogenesis of these conditions ranges from genetic to traumatic to immunological to neoplastic, and includes benign, malignant and metastatic lesions. This paper outlines some of these conditions and describes how the periodontist and oral pathologist can work together using a framework, and how with careful consideration of the clinical features and the use of appropriate special tests, including obtaining an adequate tissue specimen, a timely and accurate diagnosis can be obtained.
Phenotyping sleep apnea using polysomnography: upper airway collapsibility and responsiveness
Authors: S. A. Sands, B. A. Edwards, P. Terrill, L. Taranto Montemurro, A. Azarbarzin, M. Marques, S. Loring, J. P. Butler, D. P. White, A. Wellman
Journal: American Journal of Respiratory and Critical Care Medicine (2016)
TCTAP A-067 Treatment of Chronic Total Occlusions in Native Coronary Arteries by Drug-coated Balloons Without Stenting
Authors: Philine Jascha Koeln, Bruno Scheller, Houng Bang Liew, Tuomas Rissanen, Wan Azman Wan Ahmad, Amin Ariff Nuruddin, Hee Hwa Ho, Antonia Schulz, Franz X. Kleber
Journal: Journal of the American College of Cardiology (2017)
Treat addictions with evidence, not ideology
Authors: Fiona Godlee
Journal: BMJ (2017)

The war on drugs is failing. This was the conclusion The BMJ reached at the end of last year, leading us to call for reform of drug policy (doi:10.1136/bmj.i6067). Evidence now supports decriminalisation of non-violent drug use, as do a growing number of health and human rights organisations. And the debate is moving cautiously towards support for legalised but heavily regulated drug markets.

Adding their voices to calls for drug legalisation are parents of young people who have died as a result of taking drugs. As …
Environmental Exposure To Nox And No2 And Respiratory Function In Schoolchildren From Mothers Who Participated In A Randomized Clinical Trial During Pregnancy
Authors: A. Barraza-Villarreal, M. C. Escamilla-Nunez, L. Hernandez-Cadena, P. D. Sly, U. Ramakrishnan, I. Romieu
Journal: American Journal of Respiratory and Critical Care Medicine (2016)