tbuckley/cabot-search huggingface dataset:
Abstract 11403: T-Wave Area as an Additional Predictor of Volumetric and Clinical Response to Cardiac Resynchronization Therapy
Authors: Elien B Engels, Eszter M Vegh, Caroline J van Deursen, Kevin Vernooy, Jagmeet P Singh, Frits W Prinzen
Journal: Circulation (2014)

Purpose: Chronic heart failure (HF) patients with a left ventricular (LV) conduction delay, mostly due to left bundle branch block (LBBB), derive benefit from cardiac resynchronization therapy (CRT). However, approximately 30% of patients do not improve clinically after CRT. We investigated whether T-wave analysis can improve patient selection. Methods: The study population comprised 335 CRT recipients with baseline 12-lead electrocardiogram recordings. Echocardiographic response after 6-months CRT was defined as a ≥ 5% increase in LV ejection fraction (LVEF). Patients were assessed for HF hospitalization and death separately, as well as both combined with heart transplantation and LVAD implantation (HTLD) at 3 years follow-up. T-wave area was determined in vectorcardiograms (VCGs), constructed from digital 12-lead ECGs using an adapted Kors method. Results: Logistic regression models indicated repolarization variables as good predictors of CRT response. The VCG-derived T-wave area predicted CRT response (odds ratio (OR) per 10 μVs increase 1.172 (p &lt; 0.001)), even better than QRS-wave area (OR = 1.116 (p = 0.001)). T-wave area had especially predictive value in LBBB patients (OR = 2.77 in LBBB vs. 1.09 in non-LBBB). This predictive value persisted after adjustment for multiple covariates, such as gender, ischemia, age, hypertension, coronary artery bypass graft, and the usage of diuretics and beta-blockers. The table depicts that patients with large T-wave area showed a larger increase in LVEF and a lower occurrence of the end-points HF hospitalization, death and HTLD, as compared to those with a small T-wave area, the difference being significant for LBBB patients. Conclusions: In patients with LBBB morphology of the QRS complex, a larger baseline T-wave area is an important additional predictor of both volumetric and long-term clinical response following CRT.
Abstract 45: Cardiomyocytes Undergo Division Postnatally to Generate New Cardiomyocytes in Mouse Models of Aging and Cardiac Injury
Authors: Shah R Ali, Lily S Saadat, Simon Hippenmeyer, Liqun Luo, Irving L Weissman, Reza Ardehali
Journal: Circulation Research (2012)

The dogma of the adult mammalian heart as a post-mitotic organ has recently come under question. Radiolabeled isotope studies have demonstrated that the human heart exhibits a low rate of renewal of cardiomyocytes throughout one’s lifespan. Furthermore, a neonatal mouse can regenerate its ventricle if the apex is resected within the first week of birth. However, the field has yet to clonally address whether cardiomyocytes divide symmetrically upon birth, or if a resident progenitor differentiates into cardiomyocytes. Rather than rely on proxies for cell division (e.g. BrdU incorporation studies), we use genetic mouse models in which cell division results in asymmetric, indelible labeling of the daughter cells (“Mosaic analysis of double markers” (MADM)) to identify which cell type(s) generate cardiomyocytes. We made two triple-transgenic mouse strains: actinCreER;MADMGT/TG and Myh6CreERT2;MADMGT/TG. The former model allows us to identify postnatal cardiogenesis from any cell type, whereas with the latter model we identify postnatal cardiomyocytes that arise from existing alpha-myosin heavy chain-expressing cardiomyocytes. Our studies demonstrate limited symmetric division of cardiomyocytes during normal aging up to six weeks, with a significantly high rate of cardiomyocyte division during the first postnatal week, in both models. The rate of generation of cardiomycoytes is very similar in both models, suggesting that the postnatal cardiomyocyte division accounts for all postnatal cardiomyocyte birth. In the injury model, we provide evidence for cell division in the infarcted heart of a myocardial infarction model, but this rate of division is not greater than in the sham animal, suggesting that the inflammatory environment following an MI does not provide additional pro-mitotic signals. Our data suggests that, as in teleost fish such as zebrafish that demonstrate robust myocardial regeneration even in adulthood, the cell of origin for mammalian postnatal cardiogenesis is a differentiated cell - the cardiomyocyte - rather than a multipotent progenitor cell. It remains to be explored whether all cardiomyocyte are able to divide postnatally or whether this phenomenon is restricted to a subpopulation of cardiomyocytes.
Letter by Balligand and Michel Regarding Article, “Adrenergic Receptors in Individual Ventricular Myocytes: the Beta-1 and Alpha-1B Are in All Cells, the Alpha-1A Is in a Subpopulation, and the Beta-2 and Beta-3 Are Mostly Absent”
Authors: Jean-Luc Balligand, Lauriane Y.M. Michel
Journal: Circulation Research (2017)
Inhibition of EGF-like ligand activity disrupts the MAPK-driven EGFR autocrine loop affecting survival and proliferation of lung cancer cell lines
Authors: Justin Balko, Esther Black
Journal: Clinical Cancer Research (2007)

B42  Lung cancer cell lines sensitive to inhibition by EGFR tyrosine kinase inhibitors (TKI) demonstrate sensitivity to inhibitors of MAP kinase (MEK1). Inhibition of MAP kinase activity results in decreased expression of epidermal growth factor (EGF)-like ligands. Thus, lung cancers might employ overexpression of EGFR and/or constitutive expression of EGF-like ligands, such as transforming growth factor α (TGFα), heparin-binding EGF-like ligand (HB-EGF), or EGF, to achieve survival and proliferation. TGFα and HB-EGF are both highly- and constitutively-expressed in lung cancer cell lines sensitive to chemical inhibitors of the EGFR and MAPK cascades. Thus, we hypothesized that inhibition of EGFR ligand production and/or activity disrupts the EGFR autocrine loop and may circumvent resistance to EGFR TKI in non-small cell lung cancers, regardless of mutational status of EGFR. Cell lines sensitive to inhibitors of either EGFR or MAPK demonstrate a reduction in expression of the EGF-like ligands prior to induction of cell death. We have explored inhibition of activity of EGF-like ligands by RNAi toward TGFα and HB-EGF and blocking EGFR with antibody in lung cancer cell lines. Here we report the effect on EGFR receptor dimerization, activity of downstream signaling cascades, and cell survival. Not only could these findings identify new therapeutic strategies for treatment of epithelial malignancies, , but monitoring intra-tumoral expression and secretion of EGFR ligands could be a mechanism to identify patients who will demonstrate benefit from EGFR and or MAPK pathway inhibition.
Understanding the American healthcare reform debate
Authors: Donald M Berwick
Journal: BMJ (2017)

If you don’t understand American healthcare, join the crowd. Donald M Berwick explains US government attempts to repeal and replace the Affordable Care Act Debates over the US healthcare reform law—the Affordable Care Act (ACA) or “Obamacare”—have raged for almost a decade, with new fury now in the “repeal and replace” initiatives of the Trump administration. The act is complex, the more so because its provisions build on an already tortuous non-system of financing and delivering care to the people of the United States. Here I present a quick tour of that non-system, an explanation of the basics of the ACA, and an analysis of the present attempts to undo it. Although I have tried to be technically correct, I make no claim to be non-partisan. I was President Obama’s appointee as administrator of the US Centers for Medicare and Medicaid Services between July 2010 and December 2011, which provides insurance at a cost above $820bn (£640bn; €730bn) to over 100 million Americans and which was and is responsible for implementing and managing more than 70% of the provisions of the ACA. I am a fan of the ACA, and I strongly oppose its repeal. Understanding the ACA and its critics requires an understanding of how the US funds its healthcare. There are seven main routes of funding (box 1). #### Box 1: How the US funds healthcare
Chemotherapy (CT) for isolated locoregional recurrence (ILRR) of breast cancer in ER-positive (ER+) and ER-negative (ER-) cohorts: Final analysis of the CALOR trial.
Authors: Irene Wapnir, Karen N. Price, Stewart J. Anderson, Andre Robidoux, Miguel Martin, J. W.R. Nortier, Alexander H. G. Paterson, Mothaffar F. Rimawi, Istvan Lang, José Manuel Baena Cañada, Beat J. K. Thurlimann, Eleftherios P. Mamounas, Charles E. Geyer, Shari I. Gelber, Alan S. Coates, Richard D. Gelber, Priya Rastogi, Meredith M. Regan, Norman Wolmark, Stefan Paul Aebi
Journal: Journal of Clinical Oncology (2017)

513 Background: ILRR is associated with a high risk of developing breast cancer distant metastases and death. The CALOR trial (NCT00074152) investigated the effectiveness of CT following local therapy for ILRR. Previously reported results at 5-yrs median follow-up (MFU) showed significant benefit of CT for ER- ILRR, but further follow-up was required in ER+ ILRR. This report presents results at 8.8 yrs MFU within ER status cohorts. Methods: CALOR is an open-label, randomized trial for patients with completely excised ILRR after unilateral breast cancer. Eligible patients were randomized to CT (selected by the investigator; multidrug for at least 3 months recommended) or No-CT, and stratified by prior CT, hormone-receptor (ER, PR) status, and location of ILRR. Patients with ER and/or PR positive ILRR received adjuvant endocrine therapy. Radiation therapy was mandated for patients with microscopically involved margins, and anti-HER2 therapy was optional. Endpoints are disease-free survival (DFS), overall survival (OS) and breast cancer-free interval (BCFI). Results: From August 2003 to January 2010, 162 patients were enrolled: 104 ER+ and 58 ER-. The results at 8.8 years MFU in ER status cohorts are summarized in the Table (40 and 27 DFS events, respectively). The reduction in the hazard of an event associated with CT for the ER- ILRR cohort was sustained, but no benefit was observed for the ER+ cohort; interactions were significant for DFS and BCFI. The reduction in the hazard of an event seen in the ER- cohort was not apparent in ER+, with significant interactions for DFS and BCFI. Results for the 3 endpoints were consistent in multi-variable analyses adjusting for location of ILRR, prior chemotherapy, and interval from primary surgery. Conclusions: The final analysis of CALOR confirms that CT benefits patients with resected ER- ILRR. Long-term CALOR trial results do not support the use of CT for ER+ ILRR. Clinical trial information: NCT00074152. [Table: see text]
Interaction Between Neuronal Nitric Oxide Synthase Signaling and Temperature Influences Sarcoplasmic Reticulum Calcium Leak
Authors: Raul A. Dulce, Vera Mayo, Erika B. Rangel, Wayne Balkan, Joshua M. Hare
Journal: Circulation Research (2014)

Although nitric oxide (NO) signaling modulates cardiac function and excitation-contraction coupling, opposing results because of inconsistent experimental conditions, particularly with respect to temperature, confound the ability to elucidate NO signaling pathways. Here, we show that temperature significantly modulates NO effects.
Use of Angiotensin System Inhibitors Is Associated with Immune Activation and Longer Survival in Nonmetastatic Pancreatic Ductal Adenocarcinoma
Authors: Hao Liu, Kamila Naxerova, Matthias Pinter, Joao Incio, Hang Lee, Kohei Shigeta, William W. Ho, Jonathan A. Crain, Alex Jacobson, Theodoros Michelakos, Daniella Dias-Santos, Andrea Zanconato, Theodore S. Hong, Jeffrey W. Clark, Janet E. Murphy, David P. Ryan, Vikram Deshpande, Keith D. Lillemoe, Carlos Fernandez-del Castillo, Michael Downes, Ronald M. Evans, James Michaelson, Cristina R. Ferrone, Yves Boucher, Rakesh K. Jain
Journal: Clinical Cancer Research (2017)

Purpose: Angiotensin system inhibitors (ASI) can improve prognosis in multiple cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, no study has examined the effect of ASIs alone or combined with adjuvant chemotherapy in resected PDAC patients.Experimental Design: We performed an analysis of the records of ASI users and nonuser patients with PDAC seen at Massachusetts General Hospital (Boston, MA) between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA sequencing (RNA-Seq) of resected primary lesions.Results: A total of 794 consecutive patients were included. In 299 resected patients, ASI users experienced longer overall survival (OS) in both univariate (median OS, 36.3 vs. 19.3 months, P = 0.011) and adjusted multivariate [HR, 0.505; 95% confidence interval (CI), 0.339-0.750; P = 0.001] analyses. Propensity score-adjusted analysis also showed a longer median OS for chronic ASI users. In unresected patients, the beneficial effect of ASIs was significant in patients with locally advanced disease, but not in metastatic patients. RNA-Seq analysis revealed in tumors of ASI users (lisinopril) a normalized extracellular matrix, a reduced expression of genes involved in PDAC progression (e.g., WNT and Notch signaling), and an increased expression of genes linked with the activity of T cells and antigen-presenting cells. Finally, chronic use of ASI was associated with a gene expression signature that is predictive of survival in independent validation cohorts.Conclusions: In patients with nonmetastatic PDAC, chronic ASI use is associated with longer OS independently of chemotherapy. Our RNA-Seq analysis suggests that ASIs reduce the malignant potential of cancer cells and stimulate the immune microenvironment in primary PDAC. Clin Cancer Res; 23(19); 5959-69. ©2017 AACR.
Long-term outcomes with postoperative chemotherapy in appendicular carcinoma.
Authors: Tulasi Gummadi, Chitra Ganesan, Ryan Shanley, Edward Greeno, Anne Hudson Blaes
Journal: Journal of Clinical Oncology (2014)

e15182 Background: Appendicular carcinoma is a very rare malignant neoplasm of the vermiform appendix. Cytoreduction with hyperthermic intraperitoneal chemotherapy ( HIPEC) continues to be the standard of care. The utility of post-operative chemotherapy is not clear. Methods: A retrospective analysis of 55 patients with appendicular adenocarcinoma treated at University of Minnesota Masonic Cancer Center from January 2006 to June 2012 was conducted. Patients with biopsy proven appendicular adenocarcinoma were eligible. Kaplan-Meier survival was estimated for 40 patients for whom dates of diagnosis and last follow-up could be obtained. Survival and recurrence outcomes were analyzed on the basis of receiving standard of care or post-operative chemotherapy. Results: The median age was 57 years. There were 36 (65%) women and 19 (35%) men. Thirty (55%) were stage IV, 7 (13%) were stage III, 2 (4%) were stage II, and 16 (29%) were unknown. Twenty-eight (51%) received cytoreduction and HIPEC. Post-operative chemotherapy with a fluoropyrimidine regimen, either Xeloda or 5-FU or FOLFOX, was administered in 21 (38%) patients. The median follow up time among survivors was 801 days (minimum 65 days). Even though 55% of the patients were stage IV, 5-year overall survival was estimated to be 72% (95% CI: 48-87). Among patients who received the standard cytroreduction and HIPEC, 5 year overall survival was 88% in patients who received post-operative chemotherapy and 89% in those who did not (p=0.91). Recurrence percentages were 60% and 50%, respectively (p=0.70) Conclusions: Although chemotherapy after standard cytoreduction and HIPEC is being routinely used in practice by many oncologists, it might not add substantial benefit to overall survival or recurrence. However, there might be selection bias as patients with worse disease were more likey to get post-operative chemotherapy, masking its benefit.
Extension of ustekinumab maintenance dosing interval in moderate-to-severe psoriasis: results of a phase IIIb, randomized, double-blinded, active-controlled, multicentre study (PSTELLAR)
Authors: A. Blauvelt, L.K. Ferris, P.S. Yamauchi, A. Qureshi, C.L. Leonardi, K. Farahi, S. Fakharzadeh, M.-C. Hsu, S. Li, M. Chevrier, K. Smith, K. Goyal, Y. Chen, E.J. Muñoz-Elías, K. Callis Duffin
Journal: British Journal of Dermatology (2017)

Phase III studies showed that some patients maintained response for ≥ 6 months following ustekinumab discontinuation. To assess clinical responses with extended ustekinumab maintenance dosing intervals. Adults with moderate-to-severe plaque psoriasis received ustekinumab at weeks 0, 4 and 16 during open-label treatment. Patients achieving a week-28 Physician's Global Assessment (PGA) score of cleared/minimal (PGA = 0/1) were randomized 1 : 4 to group 1 [approved every 12 weeks (q12 wk) maintenance] or group 2 (q12-24 wk; response-based dosing determined by time to loss of PGA = 0/1). Key end points included the number of visits with PGA = 0/1 (primary end point) and ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) between weeks 88 and 112, and PGA/PASI responses between weeks 28 and 112. Overall, 378 patients achieved PGA = 0/1 at week 28 and were randomized to group 1 (n = 76) or group 2 (n = 302). Patients in group 1 had numerically greater mean numbers of visits with PGA = 0/1 than group 2 and also with PASI 75 from week 88 to 112. A higher proportion of patients in group 1 (55%) than group 2 (39%) had PGA = 0/1 at all seven visits from week 88 to 112. Maintenance of response was observed with dose-interval extension beyond q12 wk in a subset of patients. Extending the dosing interval did not affect antibody development or safety. Efficacy was better maintained among week-28 PGA responders randomized to continue q12 wk ustekinumab vs. extending maintenance dosing based on clinical response, although some patients maintained high levels of efficacy with up to q24 wk dosing.
Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women
Authors: Enrico Carmina, Didier Dewailly, Héctor F. Escobar-Morreale, Fahrettin Kelestimur, Carlos Moran, Sharon Oberfield, Selma F. Witchel, Ricardo Azziz
Journal: Human Reproduction Update (2017)

Non-classic congenital hyperplasia (NCAH) due to 21-hydroxylase deficiency is a common autosomal recessive disorder characterized by androgen excess.We conducted a systematic review and critical assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of NCAH. A meta-analysis of epidemiological data was also performed.Peer-reviewed studies evaluating NCAH published up to October 2016 were reviewed. Multiple databases were searched including MEDLINE, EMBASE, Cochrane, ERIC, EBSCO, dissertation abstracts, and current contents.The worldwide prevalence of NCAH amongst women presenting with signs and symptoms of androgen excess is 4.2% (95% confidence interval: 3.2-5.4%). The clinical consequences of NCAH expand from infancy, i.e. accelerated growth, to adolescence and adulthood, i.e. premature pubarche, cutaneous symptoms and oligo-ovulation in a polycystic ovary syndrome (PCOS)-like clinical picture. The diagnosis of NCAH relies on serum 17-hydroxyprogesterone (17-OHP) concentrations. A basal 17-OHP concentration ≥2 ng/ml (6 nmol/l) should be used for screening if more appropriate in-house cut-off values are not available. Definitive diagnosis requires a 17-OHP concentration ≥10 ng/ml (30 nmol/l), either basally or after cosyntropin-stimulation. Molecular genetic analysis of the CYP21A2 gene, which is responsible for 21-hydroxylase activity, may be used for confirmation purposes and should be offered to all patients with NCAH along with genetic counseling because these patients frequently carry alleles that may result in classic CAH, the more severe form of the disease, in their progeny. Treatment must be individualized. Glucocorticoid replacement therapy may benefit pediatric patients with accelerated growth or advanced bone age or adult women seeking fertility, whereas adequate control of menstrual irregularity, hirsutism and other cutaneous symptoms is best served by the use of oral contraceptive pills and/or anti-androgens. Some women may need ovulation induction or assisted reproductive technology to achieve pregnancy. Patients with NCAH have a higher risk of miscarriage and may benefit from glucocorticoid treatment during pregnancy.Evidence-based diagnostic and treatment strategies are essential for the proper management of women with NCAH, especially considering that these patients may need different therapeutic strategies at different stages during their follow-up and that appropriate genetic counseling may prevent the occurrence of CAH in their children.
Working Towards an Appropriate Use of Ibuprofen in Children: An Evidence-Based Appraisal
Authors: Maurizio de Martino, Alberto Chiarugi, Attilio Boner, Giovanni Montini, Gianluigi L. de’ Angelis
Journal: Drugs (2017)

Ibuprofen is the most widely used non-steroidal anti-inflammatory drug (NSAID) for the treatment of inflammation, mild-to-moderate pain and fever in children, and is the only NSAID approved for use in children aged ≥3 months. Its efficacy and safety profile have led to its increasing use in paediatric care, even without medical prescription. However, an increase of suspected adverse reactions to ibuprofen has been noted in concomitance with the raised, often medically unsupervised, consumption of the drug. The purpose of this work was a critical review of the paediatric literature over the last 15 years on side effects and adverse events associated with ibuprofen, in order to highlight circumstances associated with higher risks and to promote safe and appropriate use of this drug. The literature from 2000 to date demonstrates that gastrointestinal events are rare, but (when they occur) include both upper and lower digestive tract lesions. Dehydration plays an important role in triggering renal damage, so ibuprofen should not be given to patients with diarrhoea and vomiting, with or without fever. Likewise, ibuprofen should never be administered to patients who are sensitive to it or to other NSAIDs. It is contraindicated in neonates and in children with wheezing and persistent asthma and/or during varicella. Most of the analysed studies reported adverse events when ibuprofen was being used for fever symptoms or flu-like syndrome. Ibuprofen should not be used as an antipyretic, except in rare cases. Ibuprofen remains the drug of first choice in the treatment of inflammatory pain in children.
GP vows to keep up pressure over Brexiteers’ use of NHS logo
Authors: Matthew Limb
Journal: BMJ (2017)

A GP is to fight on to establish whether the government did enough to prevent the public being misled in the EU referendum campaign by Brexiteers’ use of the NHS logo.

Paul Thornton said that he would ask the UK information commissioner to overturn a ruling by the Department of Health for England that documents—including correspondence between the department’s legal advisers and the Vote Leave campaign—should not be disclosed.

Thornton, from Nuneaton, has been making requests under freedom of information legislation for nearly a year about the use of the trademarked NHS logo by Vote Leave ahead of the UK referendum on membership of the European Union on 23 June 2016.

He obtained emails that showed that the Department of Health’s brand and identity team had issued warnings to the campaign in February 2016 …