tbuckley/cabot-search huggingface dataset:
Role of clinical and histologic factors in decision making on adjuvant therapy of small HER2-positive breast cancer.
Authors: Faisal Azam, Saif Yousif, Aarifah Aaseem, Eliyaz Ahmed
Journal: Journal of Clinical Oncology (2012)

e11053 Background: With increased use of screening mammography for breast cancer (BC), the incidence of small (T1a, b), node negative BC has increased. These cancers are considered low-risk and hence not offered adjuvant (adj) chemotherapy (CT). However, increasing retrospective studies suggest that outcomes in small node negative HER-2 positive BC might be worse than the HER-2 negative tumours of similar size . Current guidelines generally do not recommend adj CT and Trastuzumab (T) for small (T1 a, b) HER-2 positive tumours. As a part of our ongoing audit on the outcome of small HER -2 positive BC, we wished to determine the factors that oncologists consider in decision making on adj treatment of these tumours in the absence of clear guidelines. Methods: Patients (pts) with a diagnosis of node negative T1a, b, HER-2 positive BC treated across our cancer network, between Jan 2008 and Dec 2011, were identified from our electronic database. Results: A total 230 pts had stage T1, HER 2 +ve BC. Out of those 41(17%) pts had tumour size of &lt; 1cm (13, 31%pts were T1a and 28, 74%pts wereT1b) and node negative disease. Median age was 55 years (29-84yrs). 33 Pts had BCS and 8 pts had mastectomy. All pts with BCS received adj radiotherapy and all pts who were ER positive received adj endocrine therapy. 21(51%) out of 41pts received adjuvant CT and T. All pts had anthracycline based CT. The clinical and pathological characteristics of pts who received adj CT and T were as follows; Median age- 50 (33-64years), grade 1- 1(4%), grade 2 – 9(43%), grade 3- 11(53%), LVI present- 2(9%), LVI absent- 7(34%), LVI unknown – 12(57%), ER positive- 16(76%), ER negative – 5(24%). None of the pts had recurred or died at the time of analysis of the data and longer follow up is needed for survival analysis. Conclusions: In the absence of clear guidelines on adj CT and T in node negative small HER-2 positive BC, the oncologists relied on the traditional factors such as grade, ER status in risk stratification and decision on adj therapy. Tumour grade was the most important factor but age and ER status were not discriminating factors in this study. Prospective randomised trials needed to clearly define the role of adj systemic therapy in this group of pts.
1,25-Dihydroxyvitamin D3 Increases In Vitro Vascular Calcification by Modulating Secretion of Endogenous Parathyroid Hormone–Related Peptide
Authors: ShuichiJono, YoshikiNishizawa, AtsushiShioi, HirotoshiMorii
Journal: Circulation (1998)

Background—A significant association between vascular calcification and osteoporosis has been noted, suggesting that calcium homeostasis is important in vascular calcification as well as in osteoporosis. Moreover, results of our previous studies suggest that calcium-regulating hormones such as parathyroid hormone–related peptide (PTHrP) may modulate vascular calcification. Therefore, we hypothesized that 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] may have a direct impact on the calcium-regulating system of vascular smooth muscle cells, resulting in deposition of calcium in vascular wall. Methods and Results—We investigated the effect of 1,25(OH)2D3 on in vitro calcification by bovine vascular smooth muscle cells (BVSMCs). 1,25(OH)2D3 dose dependently increased BVSMC calcification and alkaline phosphatase activity. 1,25(OH)2D3 also decreased secretion of PTHrP by BVSMCs in a dose-dependent manner and depressed its gene expression. Furthermore, exogenous PTHrP (fragment 1-34) antagonized the stimulatory effect...
Unusual and Diffuse Hypermetabolism in Routine 18F-FDG PET/CT of the Supra-aortic Vessels in Biopsy-Positive Giant Cell Arteritis
Authors: Anthime Flaus, Denise Granjon, Vincent Habouzit, Jean-Baptiste Gaultier, Nathalie Prevot-Bitot
Journal: Clinical Nuclear Medicine (2018)

Abstract 18 F-FDG PET-CT used to lack of resolution to detect vasculitis in the superficial cranial and cervical arteries. Very few cases, for which some of these arteries were visualized, are published, and the images were acquired using a dedicated PET protocol. We present a case, acquired using a routine whole-body protocol, with increased tracer uptake detected in vertebral arteries, internal and external carotid arteries, superficial temporal arteries, occipital arteries, maxillary arteries, facial arteries, and lingual arteries. It underlines the potential for newer-generation PET-CT system to assess vasculitis. 18 F-FDG PET-CT may have an important role to detect and follow vasculitis in the future.
Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease
Authors: Na Zhu, Carrie L. Welch, Jiayao Wang, Philip M. Allen, Claudia Gonzaga-Jauregui, Lijiang Ma, Alejandra K. King, Usha Krishnan, Erika B. Rosenzweig, D. Dunbar Ivy, Eric D. Austin, Rizwan Hamid, Michael W. Pauciulo, Katie A. Lutz, William C. Nichols, Jeffrey G. Reid, John D. Overton, Aris Baras, Frederick E. Dewey, Yufeng Shen, Wendy K. Chung
Journal: Genome Medicine (2018)

Pulmonary arterial hypertension (PAH) is a rare disease characterized by distinctive changes in pulmonary arterioles that lead to progressive pulmonary arterial pressures, right-sided heart failure, and a high mortality rate. Up to 30% of adult and 75% of pediatric PAH cases are associated with congenital heart disease (PAH-CHD), and the underlying etiology is largely unknown. There are no known major risk genes for PAH-CHD.
Primary Extragastrointestinal Stromal Tumor on FDG PET/CT
Authors: Yanyan Zhang, Annan Zhang, Le Song, Xinxin Li, Weifang Zhang
Journal: Clinical Nuclear Medicine (2018)

Primary extragastrointestinal stromal tumor is very rare. We report a case of cervical paravertebral extragastrointestinal stromal tumor involving adjacent bones revealed by FDG PET/CT in a 66-year-old man without any gastrointestinal involvement.
Exchange protein activated by cyclic-adenosine monophosphate (Epac) regulates atrial fibroblast function and controls cardiac remodelling
Authors: Sirirat Surinkaew, Mona Aflaki, Abhijit Takawale, Yu Chen, Xiao-Yan Qi, Marc-Antoine Gillis, Yan-Fen Shi, Jean-Claude Tardif, Nipon Chattipakorn, Stanley Nattel
Journal: Cardiovascular Research (2018)

Heart failure (HF) produces left atrial (LA)-selective fibrosis and promotes atrial fibrillation. HF also causes adrenergic activation, which contributes to remodelling via a variety of signalling molecules, including the exchange protein activated by cAMP (Epac). Here, we evaluate the effects of Epac1-signalling on LA fibroblast (FB) function and its potential role in HF-related atrial remodelling.HF was induced in adult male mongrel dogs by ventricular tachypacing (VTP). Epac1-expression decreased in LA-FBs within 12 h (-3.9-fold) of VTP onset. The selective Epac activator, 8-pCPT (50 µM) reduced, whereas the Epac blocker ESI-09 (1 µM) enhanced, collagen expression in LA-FBs. Norepinephrine (1 µM) decreased Epac1-expression, an effect blocked by prazosin, and increased FB collagen production. The β-adrenoceptor (AR) agonist isoproterenol increased Epac1 expression, an effect antagonized by ICI (β2-AR-blocker), but not by CGP (β1-AR-blocker). β-AR-activation with isoproterenol decreased collagen expression, an effect mimicked by the β2-AR-agonist salbutamol and blocked by the Epac1-antagonist ESI-09. Transforming growth factor-β1, known to be activated in HF, suppressed Epac1 expression, an effect blocked by the Smad3-inhibitor SIS3. To evaluate effects on atrial fibrosis in vivo, mice subjected to myocardial infarction (MI) received the Epac-activator Sp-8-pCPT or vehicle for 2 weeks post-MI; Sp-8-pCPT diminished LA fibrosis and attenuated cardiac dysfunction.HF reduces LA-FB Epac1 expression. Adrenergic activation has complex effects on FBs, with α-AR-activation suppressing Epac1-expression and increasing collagen expression, and β2-AR-activation having opposite effects. Epac1-activation reduces cardiac dysfunction and LA fibrosis post-MI. Thus, Epac1 signalling may be a novel target for the prevention of profibrillatory cardiac remodelling.
The Association Between Diabetes and Age-Related Macular Degeneration Among the Elderly in Taiwan
Authors: Ming-Shan He, Fang-Ling Chang, Hong-Zin Lin, Jung-Lun Wu, Tsung-Cheng Hsieh, Yuan-Chieh Lee
Journal: Diabetes Care (2018)

OBJECTIVE To investigate the relationship between diabetes and future development of age-related macular degeneration (AMD). RESEARCH DESIGN AND METHODS Longitudinal, retrospective cohort study data for the period between 1997 and 2012 were obtained from the Longitudinal Health Insurance Database (LHID) of Taiwan. The final available 71,904 patients with diabetes and 270,213 patients without diabetes ≥50 years of age were further matched by age, sex, and Charlson comorbidity index. In the end, 54,616 study subjects in each of the diabetes and nondiabetes groups were recruited. The stratified populations of patients with diabetes with diabetic retinopathy (DR) (n = 7,119) versus those with diabetes who do not have DR (n = 7,119) and populations of patients with proliferative DR (PDR) (n = 2,134) versus those with nonproliferative DR (NPDR) (n = 2,134) were also obtained. Competing risk regression models were used to assess the adjusted hazard ratio (HR) and 99% CI. The main outcome measures were the first-ever diagnosis of AMD during the observational period. RESULTS The incidences of nonexudative AMD (HR 1.23; P = 0.108) and exudative AMD (HR 1.37; P = 0.023) were not significantly associated with cohorts of persons with diabetes compared with cohorts without diabetes. The stratified analysis showed that nonexudative AMD (HR 3.89; P = 0.001) and exudative AMD (HR 3.42; P &amp;lt; 0.001) were significantly correlated to diabetes with DR cohorts, compared with diabetes without DR cohorts. The incidences of nonexudative AMD (HR 0.53; P = 0.277) and exudative AMD (HR 2.27; P = 0.058) were not significantly different between PDR cohorts compared with NPDR cohorts. CONCLUSIONS This study provides large-scale, population-based evidence that diabetes with retinopathy is independently associated with an increased risk of subsequent AMD development.
The neoantigen landscape underlying clinical response to ipilimumab.
Authors: Alexandra Snyder Charen, Vladimir Makarov, Taha Merghoub, Logan Walsh, Jianda Yuan, Martin Miller, Kasthuri Kannan, Michael Andrew Postow, Ceyhan Elipenahli, Cailian Liu, Jedd D. Wolchok, Timothy Anthony Chan
Journal: Journal of Clinical Oncology (2014)

3003 Background: Ipilimumab, an antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), prolongs overall survival and can produce durable tumor regression in patients with advanced melanoma. Ipilimumab activates cytotoxic T-lymphocytes and enables them to destroy tumor cells. However, the molecular determinants of response to ipilimumab are unknown. Methods: Fresh frozen tumor DNA (and matching blood) from 25 melanoma patients treated with ipilimumab was subjected to whole exome sequencing. Exon capture was performed using the SureSelect Human All Exon 50MB kit (Agilent). Enriched exome libraries were sequenced on the HiSeq 2000 platform (Illumina) to a mean coverage of 103X. Somatic mutations and candidate somatic neoantigens generated from these mutations were identified and characterized. Results: Our cohort included complete responders (CR) and nonresponders (NR). Mutational burden ranged from 1-1121 mutations per tumor. Mutational load was significantly associated with clinical response (p=0.028, CR vs. NR, Fisher’s Exact Test), but alone was not sufficient to predict response. Using genome-wide somatic neoepitope analysis, we defined candidate tumor neoantigens and identified a neoantigen landscape that is specifically present in tumors with complete responses to ipilimumab. These somatic neoepitopes share consensus sequences with experimentally validated antigens from a variety of pathogens. Furthermore, in four of six CR patients, a mutation led to the generation of a consensus amino acid sequence previously identified as necessary for T-cell recognition of melanoma antigen recognized by T-cells (MART-1). Conclusions: Somatic mutations and concomitant generation of neoepitopes in melanoma tumors confers enhanced antigenicity and response to the immune checkpoint modulator ipilimumab. Our study defines the neoantigen landscape in responders to ipilimumab, provides a rationale for examining the exomes of patients for whom ipilimumab is being considered, and builds a foundation for understanding the molecular determinants of response to cancer immunotherapy.
Effect of Repetitive Intra-Arterial Infusion of Bone Marrow Mononuclear Cells in Patients With No-Option Limb Ischemia
Authors: Martin Teraa, Ralf W. Sprengers, Roger E.G. Schutgens, Ineke C.M. Slaper-Cortenbach, Yolanda van der Graaf, Ale Algra, Ingeborg van der Tweel, Pieter A. Doevendans, Willem P.Th.M. Mali, Frans L. Moll, Marianne C. Verhaar
Journal: Circulation (2015)

Background— Patients with severe limb ischemia may not be eligible for conventional therapeutic interventions. Pioneering clinical trials suggest that bone marrow–derived cell therapy enhances neovascularization, improves tissue perfusion, and prevents amputation. The objective of this trial was to determine whether repetitive intra-arterial infusion of bone marrow mononuclear cells (BMMNCs) in patients with severe, nonrevascularizable limb ischemia can prevent major amputation. Methods and Results— The Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial is a randomized, double-blind, placebo-controlled clinical trial in 160 patients with severe, nonrevascularizable limb ischemia. Patients were randomly assigned to repetitive (3 times; 3-week interval) intra-arterial infusion of BMMNC or placebo. No significant differences were observed for the primary outcome, ie, major amputation at 6 months, with major amputation rates of 19% in the BMMNC versus 13% in the placebo group (relative risk, 1.46; 95% confidence interval, 0.62–3.42). The safety outcome (all-cause mortality, occurrence of malignancy, or hospitalization due to infection) was not significantly different between the groups (relative risk, 1.46; 95% confidence interval, 0.63–3.38), neither was all-cause mortality at 6 months with 5% versus 6% (relative risk, 0.78; 95% confidence interval, 0.22–2.80). Secondary outcomes quality of life, rest pain, ankle-brachial index, and transcutaneous oxygen pressure improved during follow-up, but there were no significant differences between the groups. Conclusions— Repetitive intra-arterial infusion of autologous BMMNCs into the common femoral artery did not reduce major amputation rates in patients with severe, nonrevascularizable limb ischemia in comparison with placebo. The general improvement in secondary outcomes during follow-up in both the BMMNC and the placebo group, as well, underlines the essential role for placebo-controlled design of future trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00371371.
Re: Fabio Conforti, Laura Pala, Vincenzo Bagnardi, et al. Cancer Immunotherapy Efficacy and Patients’ Sex: A Systematic Review and Meta-analysis. Lancet Oncol 2018;19:737–46
Authors: Jeffrey Graham, Omar Abdel-Rahman, Toni K. Choueiri, Daniel Y.C. Heng
Journal: European Urology (2018)
Abstract 1501: Do Low Dose Statins Affect Cognition? Results of the UCSD Statin Study
Authors: Beatrice A Golomb, Joel E Dimsdale, Halbert L White, Michael H Criqui
Journal: Circulation (2006)

Subjects: 1016 subjects (692 men over age 20 and 324 postmenopausal women), without cardiovascular disease or diabetes, with LDL 115–190mg/dl.  Design: Six month double blind RCT with equal allocation to simvastatin 20mg, pravastatin 40mg or placebo; statins chosen for similar lipid reduction at the extremes of lipophilicity.  Primary endpoints: Change from baseline for four primary cognitive indices (see Table).  Analysis: Primary analysis: T-test of difference in mean comparing statin vs placebo; or regression to adjust for baseline characteristics if baseline disparities between statin and placebo. Secondary analyses stratified effects by sex and statin; and assessed a prespecified hypothesis that mitochondrial vulnerability (using proxies of age and blood pressure) would identify a vulnerable subset.  Result: Baseline characteristics were comparable across treatment arms. Mean cholesterol reductions (mg/dl) were −2.1±26 placebo; −57±29 simvastatin; and −47±29 pravastatin. Cognitive variances were high, compatible with broad inclusion criteria. Cognitive endpoints (total sample) showed no significant effect with statins. However stratified analyses suggested possible effect modification, with trends toward harm significant on one-sided analysis for six groups. Additionally, the hypothesis of vulnerable subsets was provisionally supported, with consistent trends toward harm in the mitochondrial subgroup, despite the smaller sample (N=97).  Conclusion: Findings provide reassurance that low dose statins confer little average cognitive impact with short term use in a generally healthy population, regardless of lipophilicity. However possible effect modification was provisionally supported. Future studies should evaluate subgroups with potential for differential statin effects; and should assess the higher doses of statins increasingly used in lipid therapy.
Mitofusin 2 Regulates Axonal Transport of Calpastatin to Prevent Neuromuscular Synaptic Elimination in Skeletal Muscles
Authors: Luwen Wang, Ju Gao, Jingyi Liu, Sandra L. Siedlak, Sandy Torres, Hisashi Fujioka, Mikayla L. Huntley, Yinfei Jiang, Haiyan Ji, Tingxiang Yan, Micah Harland, Pichet Termsarasab, Sophia Zeng, Zhen Jiang, Jingjing Liang, George Perry, Charles Hoppel, Cheng Zhang, Hu Li, Xinglong Wang
Journal: Cell Metabolism (2018)
Sudden vs Pressure Wean From Nasal Continuous Positive Airway Pressure in Infants Born Before 32 Weeks of Gestation
Authors: Christina Friis Jensen, Anna Sellmer, Finn Ebbesen, Rasa Cipliene, Anders Johansen, Rikke Monrad Hansen, Jens Peter Nielsen, Olga Hogreffe Nikitina, Jesper Padkær Petersen, Tine Brink Henriksen
Journal: JAMA Pediatrics (2018)

<h3>Importance</h3> Nasal continuous positive airway pressure (nCPAP) is a well-established treatment of respiratory distress syndrome in preterm infants. Suboptimal weaning from nCPAP may be associated with lung injury, pulmonary morbidity, and infant weight gain. To our knowledge, the best weaning strategy from nCPAP is unknown. <h3>Objective</h3> To compare the effect of sudden wean and pressure wean from nCPAP in very preterm infants. <h3>Design, Setting, and Participants</h3> A randomized, clinical, open-label, multicenter trial was conducted at 6 neonatal intensive care units in Denmark from September 2012 to December 2016 and included infants born before 32 weeks of gestation. <h3>Interventions</h3> Sudden wean with discontinuation of nCPAP without a prior reduction in pressure. Pressure wean with gradual pressure reduction prior to the discontinuation of nCPAP. <h3>Main Outcome and Measures</h3> The primary outcome was weight gain velocity from randomization to postmenstrual age 40 weeks. Secondary outcomes included other measures of growth, nCPAP and the duration of oxygen supplementation, postmenstrual age at successful wean and at discharge, successful wean at the first attempt, the number of attempts to wean, and the length of the hospital stay. Prespecified subgroup analyses by gestational age were performed. <h3>Results</h3> Of the 372 randomized infants, 185 (49.7%) were randomized to sudden wean and 187 infants (50.3%) to pressure wean. A total of 177 infants in both groups completed the trial (median gestational age for sudden and pressure wean, 30 weeks [interquartile range, 29-31]; male: sudden wean, 89 [50%]; pressure wean, 96 [54%]). There was no difference in mean [SD] weight gain velocity from randomization to 40 weeks postmenstrual age between the 2 groups (22 [6] g/kg/day). No difference was found in any of the secondary outcomes. More infants born before 28 weeks of gestation were successfully weaned from nCPAP during the first attempt in the pressure wean group compared with the sudden wean group (risk difference, 31%; 95% CI, 13%-50%), but there was no difference in the duration of nCPAP and oxygen supplementation. <h3>Conclusions and Relevance</h3> Overall, we found no difference in weight gain velocity or any of the secondary outcomes between very preterm infants who were randomized to sudden wean or pressure wean from nCPAP. However, among infants born before 28 weeks' gestation, infants from the pressure wean group were more often successfully weaned during the first attempt without a longer total duration of nCPAP treatment. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01721629
Diabetes and aortic aneurysm: current state of the art
Authors: Juliette Raffort, Fabien Lareyre, Marc Clément, Réda Hassen-Khodja, Giulia Chinetti, Ziad Mallat
Journal: Cardiovascular Research (2018)

Aortic aneurysm is a life-threatening disease due to the risk of aortic rupture. The only curative treatment available relies on surgical approaches; drug-based therapies are lacking, highlighting an unmet need for clinical practice. Abdominal aortic aneurysm (AAA) is frequently associated with atherosclerosis and cardiovascular risk factors including male sex, age, smoking, hypertension, and dyslipidaemia. Thoracic aortic aneurysm (TAA) is more often linked to genetic disorders of the extracellular matrix and the contractile apparatus but also share similar cardiovascular risk factors. Intriguingly, a large body of evidence points to an inverse association between diabetes and both AAA and TAA. A better understanding of the mechanisms underlying the negative association between diabetes and aortic aneurysm could help the development of innovative diagnostic and therapeutic approaches to tackle the disease. Here, we summarize current knowledge on the relationship between glycaemic parameters, diabetes, and the development of aortic aneurysm. Cellular and molecular pathways that underlie the protective effect of diabetes itself and its treatment are reviewed and discussed, along with their potential implications for clinical translation.
Efficacy and Safety of Ezetimibe Coadministered With Atorvastatin or Simvastatin in Patients With Homozygous Familial Hypercholesterolemia
Authors: ClaudeGagné, DanielGaudet, EricBruckert
Journal: Circulation (2002)

Background— Patients with homozygous familial hypercholesterolemia (HoFH) have a high incidence of cardiovascular morbidity and mortality from premature atherosclerosis, and the efficacy of pharmacological therapy has been limited. We evaluated the efficacy, safety, and tolerability of ezetimibe, a novel cholesterol absorption inhibitor, in a multicenter, double-blind, randomized trial of HoFH patients receiving atorvastatin or simvastatin. Methods and Results— Fifty patients with a diagnosis of HoFH on the National Cholesterol Education Program Step 1 or stricter diet and taking open-label atorvastatin 40 mg/d or simvastatin 40 mg/d (statin-40) with (n=25) or without (n=25) concomitant LDL apheresis were randomized to 1 of 3 double-blind treatments: atorvastatin or simvastatin 80 mg/d (statin-80, n=17); ezetimibe 10 mg/d plus atorvastatin or simvastatin 40 mg/d (n=16); or ezetimibe 10 mg/d plus atorvastatin or simvastatin 80 mg/d (n=17) for 12 weeks. The primary end point was mean percentage change in LD...