tbuckley/cabot-search huggingface dataset:
Aspirin, NSAID, and Acetaminophen Use and the Risk of Endometrial Cancer
Authors: Akila N. Viswanathan, Diane Feskanich, Eva S. Schernhammer, Susan E. Hankinson
Journal: Cancer Research (2008)

Abstract To date, no prospective studies have explored the relationship between the use of aspirin, other nonsteroidal anti-inflammatory medications (NSAID), and acetaminophen and endometrial adenocarcinoma. Of the 82,971 women enrolled in a prospective cohort study, 747 developed medical record–confirmed invasive endometrial cancer over a 24-year period. Use of aspirin was ascertained from 1980 to 2004, and for other NSAIDs and acetaminophen, from 1990 to 2004. Cox regression models calculated multivariate relative risks (MV RR), controlling for body mass index (BMI), postmenopausal hormone (PMH) use, and other endometrial cancer risk factors. Currency, duration, and quantity of aspirin were not associated with endometrial cancer risk overall [current use: MV RR, 1.03; 95% confidence interval (CI) 0.83–1.27; &amp;gt;10 years of use: MV RR, 1.01; 95% CI, 0.78–1.30; and cumulative average &amp;gt;7 tablets per week: (MV RR, 1.10; 95% CI, 0.84–1.44)]. However, stratified analyses showed that a lower risk of endometrial cancer among obese (BMI, ≥30 kg/m2) women was seen with current aspirin use (MV RR, 0.66; 95% CI, 0.46–0.95). The greatest risk reduction for current aspirin users was seen in postmenopausal obese women who had never used PMH (MV RR, 0.43; 95% CI, 0.26–0.73). The use of other NSAIDs or acetaminophen was not associated with endometrial cancer. Our data suggest that use of aspirin or other NSAIDs does not play an important role in endometrial cancer risk overall. However, risk was significantly lower for current aspirin users who were obese or who were postmenopausal and had never used PMHs; these subgroup findings require further confirmation. [Cancer Res 2008;68(7):2507–13]
Evaluation of the Stage IB Designation of the American Joint Committee on Cancer Staging System in Breast Cancer
Authors: Elizabeth A. Mittendorf, Karla V. Ballman, Linda M. McCall, Min Yi, Aysegul A. Sahin, Isabelle Bedrosian, Nora Hansen, Sheryl Gabram, Thelma Hurd, Armando E. Giuliano, Kelly K. Hunt
Journal: Journal of Clinical Oncology (2014)

Purpose The seventh edition of the American Joint Committee on Cancer (AJCC) staging system for breast cancer differentiates patients with T1 tumors and lymph node micrometastases (stage IB) from patients with T1 tumors and negative nodes (stage IA). This study was undertaken to determine the utility of the stage IB designation. Patients and Methods The following two cohorts of patients with breast cancer were identified: 3,474 patients treated at The University of Texas MD Anderson Cancer Center from 1993 to 2007 and 4,590 patients from the American College of Surgeons Oncology Group (ACOSOG) Z0010 trial. Clinicopathologic and outcomes data were recorded, and disease was staged according to the seventh edition AJCC staging system. Recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) were determined using the Kaplan-Meier method and compared using the log-rank test. Results Median follow-up times were 6.1 years and 9.0 years for the MD Anderson Cancer Center and ACOSOG cohorts, respectively. In both cohorts, there were no significant differences between patients with stage IA and stage IB disease in 5- or 10-year RFS, DSS, or OS. Estrogen receptor (ER) status and grade significantly stratified patients with stage I disease with respect to RFS, DSS, and OS. Conclusion Among patients with T1 breast cancer, individuals with micrometastases and those with negative nodes have similar survival outcomes. ER status and grade are better discriminants of survival than the presence of small-volume nodal metastases. In preparing the next edition of the AJCC staging system, consideration should be given to eliminating the stage IB designation and incorporating biologic factors.
cGMP Formation in Rat Atrial Slices Is Ligand and Endothelin Receptor Subtype Specific
Authors: Zurit Shraga-Levine, Mordechai Sokolovsky
Journal: Circulation Research (1996)

Abstract Involvement of a cGMP pathway in signal transduction stimulated by endothelins (ETs) and sarafotoxins (SRTXs) was examined in rat atrial slices. These peptides activated different receptor-binding sites (ET-1 and SRTX-b reacted with the picomolar binding sites of the ET A receptor, and ET-3 and SRTX-c reacted with the nanomolar binding sites of the ET B receptor) to produce cGMP. ET-1 and SRTX-b stimulated an increase in cGMP levels via a Ca 2+ -dependent NO pathway involving a pertussis toxin–insensitive G protein, whereas ET-3 and SRTX-c elevated cGMP levels via a Ca 2+ -independent CO pathway involving a pertussis toxin–sensitive G protein. These results can best be explained in terms of formation of different ligand-receptor–G-protein complexes. The ligands had no effect on ventricular slices, indicating that these signal transduction mechanisms are unique to the atria.
Phase II Study of Erlotinib in Recurrent or Metastatic Endometrial Cancer: NCIC IND-148
Authors: Amit M. Oza, Elizabeth A. Eisenhauer, Laurie Elit, Jean-Claude Cutz, Akira Sakurada, Ming S. Tsao, Paul J. Hoskins, Jim Biagi, Prafull Ghatage, John Mazurka, Diane Provencher, Naomi Dore, Janet Dancey, Anthony Fyles
Journal: Journal of Clinical Oncology (2008)

Epidermal growth factor receptor (EGFR) overexpression is common in endometrial cancers and may have a major role in tumor growth and progression. Erlotinib is an orally active, selective inhibitor of EGFR tyrosine kinase activity.A multinomial design two-stage phase II study was performed to evaluate single-agent activity of erlotinib in women with advanced endometrial cancer with recurrent or metastatic disease who were chemotherapy naïve and had received up to one line of prior hormonal therapy. Erlotinib was administered at daily dose of 150 mg. Archival tumor tissue was analyzed for EGFR expression by immunohistochemistry (IHC) and gene amplification by fluorescent in situ hybridization (FISH). Mutational status of EGFR was determined in responders.Thirty-two of 34 entered patients are assessable for response. Treatment was well tolerated and severe toxicity infrequent, with the only grade 4 toxicity being an elevation of transaminases (AST). There were four confirmed partial responses (PRs; 12.5%; 95% CI, 3.5% to 29%) lasting 2 to 36 months. Fifteen patients had stable disease (SD), with median duration of 3.7 months (range, 2 to 12 months). EGFR expression was analyzed in thirty patients; 19 were positive, nine were negative, and two were not assessable. Of the 19 patients who were EGFR positive, three had PR (16%), seven SD, and eight progressive disease, and one was not assessable. No mutations were identified in responders. FISH showed no correlation of response with gene amplification.Erlotinib is well tolerated with an overall objective response rate of 12.5%. Molecular analysis did not identify EGFR mutations in responders or correlation of response with gene amplification.
Serum Albumin (SA) as a Predictor of Response to Chemotherapy in Patients with Locally Advanced (LA) Esophageal Cancer
Authors: Ruiz-Garcia Erika, Rivera-Salcedo Daniel, Calderillo German, Ñamendys Silva Sylvio, Zamora Moreno Jesus, Diaz Consuelo, Lopez-Yañez Alicia, Meneses-Garcia Abelardo, Astudillo-de la Vega Horacio
Journal: Annals of Oncology (2014)
Carotid Plaque Echolucency Increases the Risk of Stroke in Carotid Stenting
Authors: Giorgio M. Biasi, Alberto Froio, Edward B. Diethrich, Gaetano Deleo, Stefania Galimberti, Paolo Mingazzini, Andrew N. Nicolaides, Maura Griffin, Dieter Raithel, Donald B. Reid, Maria Grazia Valsecchi
Journal: Circulation (2004)

Carotid artery stenting (CAS) has recently emerged as a potential alternative to carotid endarterectomy. Cerebral embolization is the most devastating complication of CAS, and the echogenicity of carotid plaque has been indicated as one of the risk factors involved. This is the first study to analyze the role of a computer-assisted highly reproducible index of echogenicity, namely the gray-scale median (GSM), on the risk of stroke during CAS.The Imaging in Carotid Angioplasty and Risk of Stroke (ICAROS) registry included 418 cases of CAS collected from 11 international centers. An echographic evaluation of carotid plaque with GSM measurement was made preprocedurally. The onset of neurological deficits during the procedure and the postprocedural period was recorded. The overall rate of neurological complications was 3.6%: minor strokes, 2.2%, and major stroke, 1.4%. There were 11 of 155 strokes (7.1%) in patients with GSM < or =25 and 4 of 263 (1.5%) in patients with GSM >25 (P=0.005). Patients with severe stenosis (> or =85%) had a higher rate of stroke (P=0.03). The effectiveness of brain protection devices was confirmed in those with GSM >25 (P=0.01) but not in those with GSM < or =25. Multivariate analysis revealed that GSM (OR, 7.11; P=0.002) and rate of stenosis (OR, 5.76; P=0.010) are independent predictors of stroke.Carotid plaque echolucency, as measured by GSM < or =25, increases the risk of stroke in CAS. The inclusion of echolucency measured as GSM in the planning of any endovascular procedure of carotid lesions allows stratification of patients at different risks of complications in CAS.
Proinflammatory Stimuli Engage Brahma Related Gene 1 and Brahma in Endothelial Injury
Authors: Fei Fang, Dewei Chen, Liming Yu, Xin Dai, Yuyu Yang, Wenfang Tian, Xian Cheng, Huihui Xu, Xinyu Weng, Mingming Fang, Jiliang Zhou, Yuqi Gao, Qi Chen, Yong Xu
Journal: Circulation Research (2013)

Rationale: Endothelial dysfunction inflicted by inflammation is found in a host of cardiovascular pathologies. One hallmark event in this process is the aggregation and adhesion of leukocyte to the vessel wall mediated by the upregulation of adhesion molecules (CAM) in endothelial cells at the transcriptional level. The epigenetic modulator(s) of CAM transactivation and its underlying pathophysiological relevance remain poorly defined. Objective: Our goal was to determine the involvement of Brahma related gene 1 (Brg1) and Brahma (Brm) in CAM transactivation and its relevance in the pathogenesis of atherosclerosis. Methods and Results: In the present study, we report that proinflammatory stimuli augmented the expression of Brg1 and Brm in vitro in cultured endothelial cells and in vivo in arteries isolated from rodents. Overexpression of Brg1 and Brm promoted while knockdown of Brg1 and Brm abrogated transactivation of adhesion molecules and leukocyte adhesion induced by inflammatory signals. Brg1 and Brm interacted with and were recruited to the CAM promoters by nuclear factor κB/p65. Conversely, depletion of Brg1 and Brm disrupted the kinetics of p65 binding on CAM promoters and crippled CAM activation. Silencing of Brg1 and Brm also altered key epigenetic changes associated with CAM transactivation. Of intrigue, 17β-estradiol antagonized both the expression and activity of Brg1/Brm. Most importantly, endothelial-targeted elimination of Brg1/Brm conferred atheroprotective effects to Apoe -/- mice on a Western diet. Conclusions: Our data suggest that Brg1 and Brm integrate various proinflammatory cues into CAM transactivation and endothelial malfunction and, as such, may serve as potential therapeutic targets in treating inflammation-related cardiovascular diseases.
Undetermined impact of patient decision support interventions on healthcare costs and savings: systematic review
Authors: T. Walsh, P. J. Barr, R. Thompson, E. Ozanne, C. O'Neill, G. Elwyn
Journal: BMJ (2014)

To perform a systematic review of studies that assessed the potential of patient decision support interventions (decision aids) to generate savings.Systematic review.After registration with PROSPERO, we searched 12 databases, from inception to 15 March 2013, using relevant MeSH terms and text words. Included studies were assessed with Cochrane's risk of bias method and Drummond's quality checklist for economic studies. Per patient costs and projected savings associated with introducing patient decision support interventions were calculated, as well as absolute changes in treatment rates after implementation.Studies were included if they contained quantitative economic data, including savings, spending, costs, cost effectiveness analysis, cost benefit analysis, or resource utilization. We excluded studies that lacked quantitative data on savings, costs, monetary value, and/or resource utilization.After reviewing 1508 citations, we included seven studies with eight analyses. Of these seven studies, four analyses predicted system-wide savings, with two analyses from the same study. The predicted savings range from $8 (£5, €6) to $3068 (£1868, €2243) per patient. Larger savings accompanied reductions in treatment utilization rates. The impact on utilization rates was mixed. Authors used heterogeneous methods to allocate costs and calculate savings. Quality scores were low to moderate (median 4.5, range 0-8 out of 10), and risk of bias across the studies was moderate to high (3.5, range 3-6 out of 6), with studies predicting the most savings having the highest risk of bias. The range of issues identified in the studies included the relative absence of sensitivity analyses, the absence of incremental cost effectiveness ratios, and short time periods.Although there is evidence to show that patients choose more conservative approaches when they become better informed, there is insufficient evidence, as yet, to be confident that the implementation of patient decision support interventions leads to system-wide savings. Further work-with sensitivity analyses, longer time horizons, and more contexts-is required to avoid premature or unrealistic expectations that could jeopardize implementation and lead to the loss of already proved benefits.PROSPERO registration CRD42012003421.
Absence of Type VI Collagen Paradoxically Improves Cardiac Function, Structure, and Remodeling After Myocardial Infarction
Authors: Daniel J. Luther, Charles K. Thodeti, Patricia E. Shamhart, Ravi K. Adapala, Cheryl Hodnichak, Dorothee Weihrauch, Paolo Bonaldo, William M. Chilian, J. Gary Meszaros
Journal: Circulation Research (2012)

We previously reported that type VI collagen deposition increases in the infarcted myocardium in vivo. To date, a specific role for this nonfibrillar collagen has not been explored in the setting of myocardial infarction (MI).To determine whether deletion of type VI collagen in an in vivo model of post-MI wound healing would alter cardiac function and remodeling in the days to weeks after injury.Wild-type and Col6a1(-/-) mice were subjected to MI, followed by serial echocardiographic and histological assessments. At 8 weeks after MI, infarct size was significantly reduced, ejection fraction was significantly preserved (43.9% ± 3.3% versus 29.1% ± 4.3% for wild-type), and left ventricular chamber dilation was attenuated in the Col6a1(-/-) MI group (25.8% ± 7.9% increase versus 62.6% ± 16.5% for wild-type). The improvement in cardiac remodeling was evident as early as 10 days after MI in the Col6a1(-/-) mice. Myocyte apoptosis within the infarcted zones was initially greater in the Col6a1(-/-) group 3 days after MI, but by day 14 this was significantly reduced. Collagen deposition also was reduced in the infarcted and remote areas of the Col6a1(-/-) hearts. The reductions in chronic myocyte apoptosis and fibrosis are critical events leading to improved long-term remodeling and functional outcomes.These unexpected results demonstrate for the first time that deletion of type VI collagen in this knockout model plays a critical protective role after MI by limiting infarct size, chronic apoptosis, aberrant remodeling, and fibrosis, leading to preservation of cardiac function.
Functional Consequence of Serotonin/5-HT <sub>2B</sub> Receptor Signaling in Heart
Authors: Canan G. Nebigil, Luc Maroteaux
Journal: Circulation (2003)

P ara-and/or autocrine factors that interact with receptors coupled to G proteins of the Gq/11 families are implicated in the development of myocardial hypertrophy and apoptosis.Whether hypertrophy renders cardiac myocytes more sensitive or resistant to apoptosis is still controversial.A delicate balance may exist among hypertrophy, apoptosis, and heart failure.However, the factors involved in the transition from compensatory hypertrophy to heart failure have not been elucidated yet in the context of Gq-coupled pathways.Overexpressing serotonin Gq-coupled 5-HT 2B receptor in the mouse heart induces mitochondrial proliferation associated with hypertrophy, whereas ablation of this receptor leads to mitochondrial structural and functional impairments associated with myofibrillar breakdown and dilated cardiomyopathy.In this review, we discuss a novel role of mitochondria in the transition from hypertrophic to dilated cardiomyopathy that involves the Gq-coupled 5-HT 2B R signaling pathway.
Epsilon protein kinase C as a potential therapeutic target for the ischemic heart
Authors: K INAGAKI, E CHURCHILL, D MOCHLYROSEN
Journal: Cardiovascular Research (2006)

Ischemic heart disease is the leading cause of morbidity and mortality in the western world. Ischemic damage can occur by acute myocardial infarction, stable angina, cardiac stunning, and myocardial hibernation. In addition, 'scheduled' ischemic events, occurring during cardiac surgery, heart transplantation, and elective angioplasty, can also result in cardiac damage. Ischemic or pharmacological preconditioning can decrease the extent of damage to the myocardium. Although the mechanism of preconditioning-mediated cardioprotection is not fully understood, epsilonPKC has been implicated as a critical mediator of this process in animal studies. The use of isozyme-specific pharmacological tools has permitted a better elucidation of the upstream stimuli and the downstream transducers of epsilonPKC in the pathways leading to cardioprotection. While little is known about the role of epsilonPKC in these pathways in humans, animal studies suggest a potential therapeutic role of epsilonPKC. This review will focus on the role of epsilonPKC in cardiac protection and on the signal transduction cascades that have been implicated in this protection.
Impact of Physical Activity on Glycemic Control and Prevalence of Cardiovascular Risk Factors in Adults With Type 1 Diabetes: A Cross-sectional Multicenter Study of 18,028 Patients
Authors: Barbara Bohn, Antje Herbst, Martin Pfeifer, Dietmar Krakow, Stefan Zimny, Florian Kopp, Andreas Melmer, Jürgen M. Steinacker, Reinhard W. Holl
Journal: Diabetes Care (2015)

Physical activity (PA) can improve cardiovascular risk in the general population and in patients with type 2 diabetes. Studies also indicate an HbA(1c)-lowering effect in patients with type 2 diabetes. Since reports in patients with type 1 diabetes are scarce, this analysis aimed to investigate whether there is an association between PA and glycemic control or cardiovascular risk in subjects with type 1 diabetes.A total of 18,028 adults (≥18 to <80 years of age) from Germany and Austria with type 1 diabetes from the Diabetes-Patienten-Verlaufsdokumentation (DPV) database were included. Patients were stratified according to their self-reported frequency of PA (PA0, inactive; PA1, one to two times per week; PA2, more than two times per week). Multivariable regression models were applied for glycemic control, diabetes-related comorbidities, and cardiovascular risk factors. Data were adjusted for sex, age, and diabetes duration. P values for trend were given. SAS 9.4 was used for statistical analysis.An inverse association between PA and HbA(1c), diabetic ketoacidosis, BMI, dyslipidemia (all P < 0.0001), and hypertension (P = 0.0150), as well as between PA and retinopathy or microalbuminuria (both P < 0.0001), was present. Severe hypoglycemia (assistance required) did not differ in PA groups (P = 0.8989), whereas severe hypoglycemia with coma was inversely associated with PA (P < 0.0001).PA seemed to be beneficial with respect to glycemic control, diabetes-related comorbidities, and cardiovascular risk factors without an increase of adverse events. Hence, our data underscore the recommendation for subjects with type 1 diabetes to perform regular PA.
Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy–Resistant Breast Cancer
Authors: Suzanne E. Wardell, Matthew J. Ellis, Holly M. Alley, Koleen Eisele, Todd VanArsdale, Stephen G. Dann, Kim T. Arndt, Tina Primeau, Elizabeth Griffin, Jieya Shao, Robert Crowder, Jin-Ping Lai, John D. Norris, Donald P. McDonnell, Shunqiang Li
Journal: Clinical Cancer Research (2015)

Endocrine therapy, using tamoxifen or an aromatase inhibitor, remains first-line therapy for the management of estrogen receptor (ESR1)-positive breast cancer. However, ESR1 mutations or other ligand-independent ESR1 activation mechanisms limit the duration of response. The clinical efficacy of fulvestrant, a selective estrogen receptor downregulator (SERD) that competitively inhibits agonist binding to ESR1 and triggers receptor downregulation, has confirmed that ESR1 frequently remains engaged in endocrine therapy-resistant cancers. We evaluated the activity of a new class of selective estrogen receptor modulators (SERM)/SERD hybrids (SSH) that downregulate ESR1 in relevant models of endocrine-resistant breast cancer. Building on the observation that concurrent inhibition of ESR1 and the cyclin-dependent kinases 4 and 6 (CDK4/6) significantly increased progression-free survival in advanced patients, we explored the activity of different SERD- or SSH-CDK4/6 inhibitor combinations in models of endocrine therapy-resistant ESR1(+) breast cancer.SERDs, SSHs, and the CDK4/6 inhibitor palbociclib were evaluated as single agents or in combination in established cellular and animal models of endocrine therapy-resistant ESR1(+) breast cancer.The combination of palbociclib with a SERD or an SSH was shown to effectively inhibit the growth of MCF7 cell or ESR1-mutant patient-derived tumor xenografts. In tamoxifen-resistant MCF7 xenografts, the palbociclib/SERD or SSH combination resulted in an increased duration of response as compared with either drug alone.A SERD- or SSH-palbociclib combination has therapeutic potential in breast tumors resistant to endocrine therapies or those expressing ESR1 mutations. See related commentary by DeMichele and Chodosh, p. 4999.
International Association of Diabetes and Pregnancy Study Groups Recommendations on the Diagnosis and Classification of Hyperglycemia in Pregnancy
Authors: Letícia S. Weinert
Journal: Diabetes Care (2010)

Lack of international uniformity for the diagnosis of gestational diabetes mellitus (GDM) has been a clinical problem. The International Association of Diabetes and Pregnancy Study Groups (IADPSG) suggested new criteria for diagnosis and classification of diabetes in pregnancy (1) based on the association of maternal glycemia with perinatal outcomes reported in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study (2).

Clinical outcomes are the best way to define diagnostic thresholds, and this approach to GDM diagnosis has already been reported in the Brazilian population. The study by Schmidt et al. (3) merits mentioning since it is one of the few large studies of unselected pregnant women universally evaluated with the …