tbuckley/cabot-search huggingface dataset:
Abstract P2-08-02: Novel tumor suppressor regulating the PI3K/AKT pathway in breast cancer
Authors: S Chan, MD Cardamone, V Perissi
Journal: Cancer Research (2018)

Abstract Breast cancer affects approximately 1 in 8 women over the course of their lifetime. Of the many genes and pathways deregulated by this heterogeneous disease, alterations of members in the PI3K/AKT pathway are present in approximately 20% of all cases, making it one of the more frequently mutated pathways in breast cancer. The PI3K/AKT pathway is well known to be involved in essential cellular processes necessary for cancer development and progression, including altered proliferation, metabolism, and cell survival. Previous studies have made it well known that the activation of AKT is regulated through its phosphorylation, but recent studies have also shown that AKT can also be regulated via ubiquitination, leading to AKT hyperactivation. However, the mechanism and players involved in this process are not well understood. Better understanding of these pathways could inform on better potential therapeutics to target this disease. Recent work in our lab has identified GPS2, a member of the NCoR/SMRT complex, as a regulator of the insulin-signaling pathway through the inhibition of AKT ubiquitination by Ubc13. As many human cancers frequently have an increase in activated AKT, here we explore the potential of GPS2 as a tumor suppressor in the context of breast cancer and hope to elucidate the mechanism by which AKT ubiquitination regulates its activation. Citation Format: Chan S, Cardamone MD, Perissi V. Novel tumor suppressor regulating the PI3K/AKT pathway in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-08-02.
Specific Activation of the Alternative Cardiac Promoter of <i>Cacna1c</i> by the Mineralocorticoid Receptor
Authors: Thassio R. Mesquita, Gaëlle Auguste, Débora Falcón, Gema Ruiz-Hurtado, Rogelio Salazar-Enciso, Jessica Sabourin, Florence Lefebvre, Say Viengchareun, Hussein Kobeissy, Patrick Lechène, Valérie Nicolas, Amaya Fernandez-Celis, Susana Gómez, Sandra Lauton Santos, Eric Morel, Angelica Rueda, Natalia López-Andrés, Ana Maria Gómez, Marc Lombès, Jean-Pierre Benitah
Journal: Circulation Research (2018)

The MR (mineralocorticoid receptor) antagonists belong to the current therapeutic armamentarium for the management of cardiovascular diseases, but the mechanisms conferring their beneficial effects are poorly understood. Part of the cardiovascular effects of MR is because of the regulation of L-type Cav1.2 Ca2+ channel expression, which is generated by tissue-specific alternative promoters as a long cardiac or short vascular N-terminal transcripts.To analyze the molecular mechanisms by which aldosterone, through MR, modulates Cav1.2 expression and function in a tissue-specific manner.In primary cultures of neonatal rat ventricular myocytes, aldosterone exposure for 24 hours increased in a concentration-dependent manner long cardiac Cav1.2 N-terminal transcripts expression at both mRNA and protein levels, correlating with enhanced concentration-, time-, and MR-dependent P1-promoter activity. In silico analysis and mutagenesis identified MR interaction with both specific activating and repressing DNA-binding elements on the P1-promoter. The relevance of this regulation is confirmed both ex and in vivo in transgenic mice harboring the luciferase reporter gene under the control of the cardiac P1-promoter. Moreover, we show that this cis-regulatory mechanism is not limited to the heart. Indeed, in smooth muscle cells from different vascular beds, in which the short vascular Cav1.2 N-terminal transcripts is normally the major isoform, we found that MR signaling activates long cardiac Cav1.2 N-terminal transcripts expression through P1-promoter activation, leading to vascular contractile dysfunction. These results were further corroborated in hypertensive aldosterone/salt rodent models, showing notably a positive correlation between blood pressure and cardiac P1-promoter activity in aorta. This new vascular long cardiac Cav1.2 N-terminal transcripts molecular signature reduced sensitivity to the Ca2+ channel blocker, nifedipine, in aldosterone-treated vessels.Our results reveal that MR acts as a transcription factor to translate aldosterone signal into specific cardiac P1-promoter activation that might influence the therapeutic outcome of cardiovascular diseases.
Smartwatch Algorithm for Automated Detection of Atrial Fibrillation
Authors: Joseph M. Bumgarner, Cameron T. Lambert, Ayman A. Hussein, Daniel J. Cantillon, Bryan Baranowski, Kathy Wolski, Bruce D. Lindsay, Oussama M. Wazni, Khaldoun G. Tarakji
Journal: Journal of the American College of Cardiology (2018)
Therapeutic checkpoint targets: Evaluation of co-expression profiles in individual tumor and immune cells in the tumor microenvironment of FFPE tissue.
Authors: Annelies Laeremans, Na Li, Jeff Kim, Xiao-Jun Ma, Emily Park
Journal: Journal of Clinical Oncology (2018)

176 Background: Interactions between tumor and immune cells in the tumor microenvironment (TME) play a key role in tumor progression and treatment response with accumulating evidence indicating a crucial role for tumor infiltrating immune cells. Although infiltrating cytotoxic T lymphocytes (CTLs) have been correlated with improved clinical outcome, they are ineffective in eradicating tumors due to their inhibition by immune checkpoint molecules. Immune checkpoint inhibitors have demonstrated therapeutic efficacy and durable response for several tumor types including non-small cell lung cancer (NSCLC). However, the majority of patients are resistant or relapse after initial response. Characterizing the TME for checkpoint expression with single-cell and spatial resolution can provide critical insight into new immunotherapeutic strategies and identify new predictive biomarkers for stratifying and identifying patients most likely to benefit from immunotherapy including PD-1/PD-L1 immune checkpoint blockade. Methods: Using RNAscope in situ hybridization, we evaluated in situ co-expression profiles of therapeutic checkpoint targets at single-cell level in the TME of 56 archived NSCLC FFPE tissues. Results: Checkpoint molecules including PD1, PD-L1, PD-L2, TIM3, LAG3, CTLA-4 and GITR were visualized in a highly specific and sensitive manner in individual cells within tissue morphological context. Multiple checkpoint molecules were detected in the same immune environment, especially in highly inflamed tumors. In addition to PD-L1, tumor cell-intrinsic expression of PD1, TIM3, LAG3, and PD-L2 was observed in a subset of samples. Furthermore, co-expression of therapeutic checkpoint targets including PD1, LAG3, and TIM3 was observed in infiltrating immune cells and tumor cells. Conclusions: Single-cell co-expression profiles of checkpoint molecules could shed light on how cancer cells evade the host immune surveillance and develop resistance against checkpoint blockades. Also, they could reveal valuable insights into combinatorial therapies for checkpoint markers co-expressed by the patient’s immune cells in the TME.
SEX-RELATED DIFFERENCES IN MORTALITY AND LEFT VENTRICULAR REMODELING AFTER TRANSCATHETER AORTIC VALVE IMPLANTATION
Authors: Koki Shishido, Futoshi Yamanaka, Tomoki Ochiai, Yutaka Tanaka, Tsuyosi Yamabe, Kenichiro Noguchi, Norio Tada, Toru Naganuma, Motoharu Araki, Shinichi Shirai, Hiroshi Ueno, Kazuki Mizutani, Minoru Tabata, Akihiro Higashimori, Kensuke Takagi, Yusuke Watanabe, Yamamoto Masanori, Shigeru Saito, Kentaro Hayashida
Journal: Journal of the American College of Cardiology (2018)
NHS trust is voted second best employer of lesbian, gay, and bisexual staff in Britain
Authors: Abi Rimmer
Journal: BMJ (2014)

Nottinghamshire Healthcare NHS Trust has been named the second most gay friendly employer in Britain by the charity Stonewall.

A further eight health service employers appeared in the charity’s list of the top 100 employers for lesbian, gay, and bisexual staff in 2014.

To gain a place on the list employers submitted written responses and supporting evidence that the charity then assessed and rated. In addition to the written evidence, Stonewall interviewed …
Race/Ethnicity and Age Distribution of Breast Cancer Diagnosis in the United States
Authors: Sahael M. Stapleton, Tawakalitu O. Oseni, Yanik J. Bababekov, Ya-Ching Hung, David C. Chang
Journal: JAMA Surgery (2018)

The US Preventive Services Task Force (USPSTF) currently recommends initiating breast cancer screening at 50 years of age in patients at average risk. 1 However, we hypothesize that these guidelines may not be sensitive to racial differences and may be inappropriately extrapolating data from largely white populations for use in racially diverse populations.This process could result in underscreening of nonwhite female patients.These concerns are similar to broader discussions regarding sex bias in the clinical research process, leading to recent policy changes at the National Institutes of Health and the US Food and Drug Administration. 2 The goal of this study is to assess the age distribution of breast cancer diagnosis across race/ethnicity in the United States.Methods | We analyzed the Surveillance, Epidemiology, and End Results (SEER) Program database from January 1, 1973, through December 31, 2010.Female patients aged 40 to 75 years with malignant breast neoplasms were included.The primary end point was age and stage at breast cancer diagnosis across racial groups.
Loss of Caspase 8 in liver parenchymal cells protects against experimental obstructive cholestasis
Authors: Francisco. Javier. Cubero, Gang. Zhao, Christian. Trautwein, Maximilian. Hatting, Johanna. Reissing, Christian. Liedtke, Ricardo. Macias-Rodriguez, Astrid. Ruiz-Margain, Miguel. Eugenio. Zoubek, Jin. Peng, Henning. W. Zimmermann, Tom. Luedde, Niko. Laus. Gassler
Journal: Hepatology (2015)
10-Year Resource Utilization and Costs for Cardiovascular Care
Authors: Leslee J. Shaw, Abhinav Goyal, Christina Mehta, Joe Xie, Lawrence Phillips, Anita Kelkar, Joseph Knapper, Daniel S. Berman, Khurram Nasir, Emir Veledar, Michael J. Blaha, Roger Blumenthal, James K. Min, Reza Fazel, Peter W.F. Wilson, Matthew J. Budoff
Journal: Journal of the American College of Cardiology (2018)
Immunogenicity of Fractional-Dose Vaccine during a Yellow Fever Outbreak — Final Report
Authors: Rebecca M. Casey, Jennifer B. Harris, Steve Ahuka-Mundeke, Meredith G. Dixon, Gabriel M. Kizito, Pierre M. Nsele, Grace Umutesi, Janeen Laven, Olga Kosoy, Gilson Paluku, Abdou S. Gueye, Terri B. Hyde, Raimi Ewetola, Guylain K.M. Sheria, Jean-Jacques Muyembe-Tamfum, J. Erin Staples
Journal: New England Journal of Medicine (2018)

In 2016, the response to a yellow fever outbreak in Angola and the Democratic Republic of Congo led to a global shortage of yellow fever vaccine. As a result, a fractional dose of the 17DD yellow fever vaccine (containing one fifth [0.1 ml] of the standard dose) was offered to 7.6 million children 2 years of age or older and nonpregnant adults in a preemptive campaign in Kinshasa. The goal of this study was to assess the immune response to the fractional dose in a large-scale campaign.We recruited participants in four age strata at six vaccination sites. We assessed neutralizing antibody titers against yellow fever virus in blood samples obtained before vaccination and at 1 month and 1 year after vaccination, using a plaque reduction neutralization test with a 50% cutoff (PRNT50). Participants with a PRNT50 titer of 10 or higher were considered to be seropositive. Those with a baseline titer of less than 10 who became seropositive at follow-up were classified as having undergone seroconversion. Participants who were seropositive at baseline and who had an increase in the titer by a factor of 4 or more at follow-up were classified as having an immune response.Among 716 participants who completed the 1-month follow-up, 705 (98%; 95% confidence interval [CI], 97 to 99) were seropositive after vaccination. Among 493 participants who were seronegative at baseline, 482 (98%; 95% CI, 96 to 99) underwent seroconversion. Among 223 participants who were seropositive at baseline, 148 (66%; 95% CI, 60 to 72) had an immune response. Lower baseline titers were associated with a higher probability of having an immune response (P<0.001). Among 684 participants who completed the 1-year follow-up, 666 (97%; 95% CI, 96 to 98) were seropositive for yellow fever antibody. The distribution of titers among the participants who were seronegative for yellow fever antibody at baseline varied significantly among age groups at 1 month and at 1 year (P<0.001 for both comparisons).A fractional dose of the 17DD yellow fever vaccine was effective at inducing seroconversion in participants who were seronegative at baseline. Titers remained above the threshold for seropositivity at 1 year after vaccination in nearly all participants who were seropositive at 1 month after vaccination. These findings support the use of fractional-dose vaccination for outbreak control. (Funded by the U.S. Agency for International Development and the Centers for Disease Control and Prevention.).
Cardiomyocyte binucleation is associated with aberrant mitotic microtubule distribution, mislocalization of RhoA and IQGAP3, as well as defective actomyosin ring anchorage and cleavage furrow ingression
Authors: Marina Leone, Gentian Musa, Felix Benedikt Engel
Journal: Cardiovascular Research (2018)

After birth mammalian cardiomyocytes initiate a last cell cycle which results in binucleation due to cytokinesis failure. Despite its importance for cardiac regenerative therapies, this process is poorly understood. Here, we aimed at a better understanding of the difference between cardiomyocyte proliferation and binucleation and providing a new tool to distinguish these two processes.Monitoring of cell division by time-lapse imaging revealed that rat cardiomyocyte binucleation stems from a failure to properly ingress the cleavage furrow. Astral microtubule required for actomyosin ring anchorage and thus furrow ingression were not symmetrically distributed at the periphery of the equatorial region during anaphase in binucleating cardiomyocytes. Consequently, RhoA, the master regulator of actomyosin ring formation and constriction, non-muscle myosin IIB, a central component of the actomyosin ring, as well as IQGAP3 were abnormally localized during cytokinesis. In agreement with improper furrow ingression, binucleation in vitro and in vivo was associated with a failure of RhoA and IQGAP3 to localize to the stembody of the midbody.Taken together, these results indicate that naturally occurring cytokinesis failure in primary cardiomyocytes is due to an aberrant mitotic microtubule apparatus resulting in inefficient anchorage of the actomyosin ring to the plasma cell membrane. Thus, cardiomyocyte binucleation and division can be discriminated by the analysis of RhoA as well as IQGAP3 localization.
ECGs for A&E
Authors: Gillian Kelly
Journal: BMJ (2009)

All doctors working in an acute setting. The website advertises the course as most suitable for foundation year one doctors to specialist trainee year 3 doctors, but anyone who looks at electrocardiograms (ECGs) will benefit, and there are usually a few emergency department consultants (who keep their job title very quiet) on each course.

I did the course in my first year as an emergency medicine specialist registrar.

I went into emergency medicine from a surgical background and had thought I was confident in ECG analysis. As a middle grade in the emergency department I found I was frequently being asked questions about ECGs by juniors and peers to which I couldn’t respond with a level of confidence with which I …
The Decreasing Prevalence of Nonrefractive Visual Impairment in Older Europeans
Authors: Cécile Delcourt, Mélanie Le Goff, Therese von Hanno, Alireza Mirshahi, Anthony P. Khawaja, Virginie J.M. Verhoeven, Ruth E. Hogg, Eleftherios Anastosopoulos, Maria Luz Cachulo, René Höhn, Christian Wolfram, Alain Bron, Stefania Miotto, Isabelle Carrière, Johanna M. Colijn, Gabriëlle H.S. Buitendijk, Jennifer Evans, Dorothea Nitsch, Panayiota Founti, Jennifer L.Y. Yip, Norbert Pfeiffer, Catherine Creuzot-Garcher, Rufino Silva, Stefano Piermarocchi, Fotis Topouzis, Geir Bertelsen, Paul J. Foster, Astrid Fletcher, Caroline C.W. Klaver, Jean-François Korobelnik, Niyazi Acar, Eleftherios Anastosopoulos, Augusto Azuara-Blanco, Tos Berendschot, Arthur Bergen, Geir Bertelsen, Christine Binquet, Alan Bird, Martin Bobak, Camiel Boon, Lionel Brétillon, Rebecca Broe, Alain Bron, Gabrielle Buitendijk, Maria Luz Cachulo, Vittorio Capuano, Isabelle Carrière, Usha Chakravarthy, Michelle Chan, Petrus Chang, Johanna Colijn, Audrey Cougnard-Grégoire, Angela Cree, Catherine Creuzot-Garcher, Phillippa Cumberland, José Cunha-Vaz, Vincent Daien, Eiko De Jong, Gabor Deak, Cécile Delcourt, Marie-Noëlle Delyfer, Anneke den Hollander, Martha Dietzel, Maja Gran Erke, Pedro Faria, Claudia Farinha, Sascha Fauser, Robert Finger, Astrid Fletcher, Paul Foster, Panayiota Founti, Theo Gorgels, Jakob Grauslund, Franz Grus, Christopher Hammond, Morten Hansen, Catherine Helmer, Hans-Werner Hense, Manuel Hermann, René Hoehn, Ruth Hogg, Frank Holz, Carel Hoyng, Nomdo Jansonius, Sarah Janssen, Eveline Kersten, Anthony Khawaja, Caroline Klaver, Jean-François Korobelnik, Julia Lamparter, Mélanie Le Goff, Yara Lechanteur, Terho Lehtimäki, Irene Leung, Andrew Lotery, Matthias Mauschitz, Magda Meester, Bénédicte Merle, Verena Meyer zu Westrup, Edoardo Midena, Stefania Miotto, Alireza Mirshahi, Sadek Mohan-Saïd, Michael Mueller, Alyson Muldrew, Joaquim Murta, Stefan Nickels, Sandrina Nunes, Christopher Owen, Tunde Peto, Norbert Pfeiffer, Stefano Piermarocchi, Elena Prokofyeva, Jugnoo Rahi, Olli Raitakari, Franziska Rauscher, Luisa Ribeiro, Marie-Bénédicte Rougier, Alicja Rudnicka, José Sahel, Aggeliki Salonikiou, Clarisa Sanchez, Steffen Schmitz-Valckenberg, Johannes Schouten, Alexander Schuster, Cédric Schweitzer, Tatiana Segato, Jasmin Shehata, Rufino Silva, Giuliana Silvestri, Christian Simader, Eric Souied, Martynas Speckauskas, Henriet Springelkamp, Robyn Tapp, Fotis Topouzis, Elisa van Leeuwen, Virginie Verhoeven, Timo Verzijden, Therese Von Hanno, Stela Vujosevic, Peter Wiedemann, Katie Williams, Christian Wolfram, Jennifer Yip, Jennyfer Zerbib
Journal: Ophthalmology (2018)
Objective assessment of physical activity during chemotherapy for breast cancer.
Authors: Michelle E. Melisko, Edward Kenji Hadeler, Sandahl H Nelson, Audrey Lunde, Irene Acerbi, Hope S. Rugo, Melanie Catherine Majure, Amy Jo Chien, Laura Esserman, Sheri J. Hartman
Journal: Journal of Clinical Oncology (2017)

TPS6626 Background: Exercise can alleviate side effects of chemotherapy, improve quality of life (QOL), and positively impact disease specific and overall survival. Despite the benefits of physical activity (PA), many patients’ activity levels decrease during chemotherapy. Wearable devices, such as the Fitbit, can provide insight into patterns of activity, and help encourage behavior change. The aims of this study are: 1) determine the feasibility/acceptability of using a Fitbit to measure PA and sleep throughout chemotherapy for breast cancer; 2) describe patterns of PA, sedentary time, and sleep during chemotherapy; 3) explore associations of activity and sleep with QOL. Methods: Non-metastatic breast cancer patients from UCSF and UCSD will be enrolled prior to starting chemotherapy. Eligibility criteria include ability to speak/read English, walk unassisted, and access to internet or Fitbit compatible smart phone. Patients sign informed consent, receive a Fitbit Charge HR and guidance on how to use the device. Patients are instructed to wear the Fitbit throughout their adjuvant or neoadjuvant chemotherapy and 6 months post therapy and to sync the Fitbit at least weekly. Patients complete surveys at start, midpoint, end, and 6 months post chemotherapy. Questionnaires include PROMIS anxiety, depression, physical function, fatigue, cognitive function, social roles, comfort with technology and usefulness of the Fitbit. Fitabase database collects minute level activity, sleep, and heart rate. To assess feasibility, we will evaluate if a participant wears FitBit for at least 10 hour per day for ≥ 80% of the days during chemotherapy. We will use mixed effects regression models to assess patterns of PA and associations between activity and QOL. All models will include activity time and Fitbit wear time and will control for the potential confounding effects of age and other demographic or clinical variables. As of February 6 2017, 48 out of a planned 80 patients are enrolled. Acknowledgment: Athena Breast Health Network investigators and patients; support at UCSD by NCI (U54 CA155435-01) and by gift from Carol Vassiliadis and family; NCI grant K07CA181323 to SH; UCSF M Zion Health Fund Award, GBCTB unrestricted funding and TriValley SOCKS to MM. Clinical trial information: NCT03041545.
Three fluoropyrimidine-based regimens in second-line therapy following nab-paclitaxel plus gemcitabine in metastatic pancreatic cancer: Efficacy and tolerance in clinical practice.
Authors: Anne Laure Pointet, David Tougeron, Simon Pernot, Astrid Pozet, Dominique Bechade, Isabelle Trouilloud, Nelson Lourenco, Vincent Hautefeuille, Christophe Locher, Nicolas Williet, Jérôme Desrame, Anne Thirot Bidault, Denis Pezet, Julien Taieb
Journal: Journal of Clinical Oncology (2018)

370 Background: Combination of nab-paclitaxel plus gemcitabine (N+G) has recently become a valid first-line treatment (1L) in metastatic pancreatic adenocarcinoma (MPA) in patients (pts) with performance status (PS) of 0,1 or 2, but there is currently no standard second-line treatment (2L) after this new 1L option. We evaluated survival outcomes and tolerability of three usual fluoropyrimidine-based regimens: FOLFOX, FOLFIRI or FOLFIRI.3 (FOLFIRI1/3), and FOLFIRINOX after N+G failure in MPA pts. Methods: We prospectively identified 138 pts from 11 French centers who received 1L N+G for unresectable pancreatic adenocarcinoma. After disease progression or unacceptable toxicity, we excluded pts with locally advanced cancer, or who underwent secondary resection/chemoradiotherapy. Three subgroups of 2L chemotherapy were identified: FOLFOX, FOLFIRI1/3 and FOLFIRINOX regimens. Response was evaluated by RECIST criteria, progression-free survivals (PFS1, PFS2), and overall survival (OS1, OS2) were calculated using Kaplan-Meier method and compared with the Log-rank test. Results: 61 pts with MPA received a 2L. Persistent neuropathy was present in 27% of pts. Median age was 71.7 years [41-83]. PS was 0, 1 or 2. Median 1L duration, number of metastatic sites, PS, CA19.9, albumin, and bilirubin levels, and persistent neuropathy grade were statistically comparable between the 3 subgroups. Median OS for all 2L pts was 6.0 months [4-8]. Third line regimen was used in 32.8% of 2L pts without statistical significance between the subgroups. Main grade 3/4 adverse events reported were thrombocytopenia (18%), anemia (7.7%), neutropenia (21.4%) and nausea (5.4%). No toxic deaths occurred. Conclusions: This study suggests a clinical benefit and a manageable toxicity profile of 2L fluoropyrimidine-based regimens after N+G failure in patients with MPA, in particularly combined with irinotecan.[Table: see text]