tbuckley/cabot-search huggingface dataset:
Phenotypic Consequences of a Genetic Predisposition to Enhanced Nitric Oxide Signaling
Authors: Connor A. Emdin, Amit V. Khera, Derek Klarin, Pradeep Natarajan, Seyedeh M. Zekavat, Akihiro Nomura, Mary Haas, Krishna Aragam, Diego Ardissino, James G. Wilson, Heribert Schunkert, Ruth McPherson, Hugh Watkins, Roberto Elosua, Matthew J. Bown, Nilesh J. Samani, Usman Baber, Jeanette Erdmann, Padhraig Gormley, Aarno Palotie, Nathan O. Stitziel, Namrata Gupta, John Danesh, Danish Saleheen, Stacey Gabriel, Sekar Kathiresan
Journal: Circulation (2017)

Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on risk for cardiovascular diseases, thus informing the potential utility of pharmacological stimulation of the nitric oxide pathway as a therapeutic strategy.We analyzed the association of common and rare genetic variants in 2 genes that mediate nitric oxide signaling (Nitric Oxide Synthase 3 [NOS3] and Guanylate Cyclase 1, Soluble, Alpha 3 [GUCY1A3]) with a range of human phenotypes. We selected 2 common variants (rs3918226 in NOS3 and rs7692387 in GUCY1A3) known to associate with increased NOS3 and GUCY1A3 expression and reduced mean arterial pressure, combined them into a genetic score, and standardized this exposure to a 5 mm Hg reduction in mean arterial pressure. Using individual-level data from 335 464 participants in the UK Biobank and summary association results from 7 large-scale genome-wide association studies, we examined the effect of this nitric oxide signaling score on cardiometabolic and other diseases. We also examined whether rare loss-of-function mutations in NOS3 and GUCY1A3 were associated with coronary heart disease using gene sequencing data from the Myocardial Infarction Genetics Consortium (n=27 815).A genetic predisposition to enhanced nitric oxide signaling was associated with reduced risks of coronary heart disease (odds ratio, 0.37; 95% confidence interval [CI], 0.31-0.45; P=5.5*10-26], peripheral arterial disease (odds ratio 0.42; 95% CI, 0.26-0.68; P=0.0005), and stroke (odds ratio, 0.53; 95% CI, 0.37-0.76; P=0.0006). In a mediation analysis, the effect of the genetic score on decreased coronary heart disease risk extended beyond its effect on blood pressure. Conversely, rare variants that inactivate the NOS3 or GUCY1A3 genes were associated with a 23 mm Hg higher systolic blood pressure (95% CI, 12-34; P=5.6*10-5) and a 3-fold higher risk of coronary heart disease (odds ratio, 3.03; 95% CI, 1.29-7.12; P=0.01).A genetic predisposition to enhanced nitric oxide signaling is associated with reduced risks of coronary heart disease, peripheral arterial disease, and stroke. Pharmacological stimulation of nitric oxide signaling may prove useful in the prevention or treatment of cardiovascular disease.
Mumps outbreak among the military in Luxembourg in 2008: epidemiology and evaluation of control measures
Authors: J Mossong, Ch Bonert, P Weicherding, M Opp, P Reichert, J Even, F Schneider
Journal: Eurosurveillance (2009)

In the last quarter of 2008, an outbreak of mumps occurred in Luxembourg affecting initially 10 young adults at a military centre. Following a mass vaccination campaign, no further clinical cases were observed. 90% of 136 vaccine recipients were IgG positive one month after vaccination compared to 54% before vaccination. Until 31 December 2008, 19 mumps cases were also reported from the community. The outbreak strain belonged to genogroup G.
Evaluation of BRCA1/2 mutation status among women with triple-negative breast cancer.
Authors: Axel Muendlein, Bettina Rhode, Klaus Gasser, Elena Kinz, Heinz Drexel, Wera Hofmann, Verena Schindler, Rita Kapoor, Thomas Decker, Alois Lang
Journal: Journal of Clinical Oncology (2014)

1119 Background: Testing for BRCA1 and BRCA2 mutations in breast cancer patients is used to identify risk of second primary cancers and risk of cancer in the patients’ family. A high proportion of BRCA1 mutation positive patients have triple-negative breast cancer (TNBC). TNBC shows a poor prognosis and no effective treatment strategies against TNBC are available to date. However, BRCA-related cancers are sensitive to platinum chemotherapy as well as to drugs targeting poly (ADP-ribose) polymerase enzymes, which are under development so far. Women with TNBC are thought to be more likely to be BRCA mutation carriers, but there have only been limited numbers of studies investigating BRCA1- and BRCA2-mutation status among Caucasian patients with TNBC. Methods: We determined the prevalence of BRCA1 and BRCA2 mutations within a cohort of 88 unselected TNBC cases including patients from Germany and Austria. Double-stranded Sanger sequencing of all exons of BRCA1 and BRCA2, respectively, was performed. Results: We identified a total of 14 deleterious mutations in BRCA1 and of 4 deleterious mutations in BRCA2, including 10 frame shift, five missense and two nonsense mutations as well as one splice mutation. One of our patients carried two deleterious BRCA1 mutations. The total rate of deleterious BRCA1/2 mutation carriers was 19.3% in our cohort. Furthermore, six mutations with biological significance, but unclear clinical impact, have been found. In total, 15 novel mutations have been identified, which have not been described in public BRCA mutation databases (NCBI, BIC, LOVD, and UMD, respectively) so far. Conclusions: We conclude that women with TNBC frequently show BRCA1 as well as BRCA2 mutations. TNBC patients may therefore benefit from BRCA genetic testing to identify those with a masked family history of breast cancer or to indentify candidates who may profit from BRCA-related therapies.
Moonshot Acceleration Factor: Medical Imaging
Authors: Eva M. Sevick-Muraca, Richard A. Frank, Maryellen L. Giger, James L. Mulshine
Journal: Cancer Research (2017)

Medical imaging is essential to screening, early diagnosis, and monitoring responses to cancer treatments and, when used with other diagnostics, provides guidance for clinicians in choosing the most effective patient management plan that maximizes survivorship and quality of life. At a gathering of agency officials, patient advocacy organizations, industry/professional stakeholder groups, and clinical/basic science academicians, recommendations were made on why and how one should build a "cancer knowledge network" that includes imaging. Steps to accelerate the translation and clinical adoption of cancer discoveries to meet the goals of the Cancer Moonshot include harnessing computational power and architectures, developing data sharing policies, and standardizing medical imaging and in vitro diagnostics. Cancer Res; 77(21); 5717-20. ©2017 AACR.
Abstract 15797: Fibrotic Remodeling and Stiffening of Mitral Valve Leaflets After Undersizing Ring Annuloplasty to Correct Ischemic Mitral Regurgitation
Authors: Alicja Sielicka, Eric L Sarin, Weiwei Shi, Daniella Espiritu, Vinod H Thourani, Robert A Guyton, Muralidhar Padala
Journal: Circulation (2016)

Introduction: Systolic leaflet coaptation after undersizing ring annuloplasty (URA) to repair ischemic mitral regurgitation (IMR) is highly non-physiological, with a hyper-extending anterior leafle...
Characterization of complete responses (CRs) in patients with advanced melanoma (MEL) who received the combination of nivolumab (NIVO) and ipilimumab (IPI), NIVO or IPI alone
Authors: C. Robert, J. Larkin, P.A. Ascierto, G.V. Long, J.C. Hassel, D. Schadendorf, F.S. Hodi, C. Lebbé, J.-J. Grob, K. Grossmann, J. Wagstaff, J. Chesney, D. Hogg, O. Bechter, I. Márquez-Rodas, A.C. Pavlick, D. Walker, R. Bhore, M.A. Postow, J.D. Wolchok
Journal: Annals of Oncology (2017)
Genomic instability is associated with increased immune infiltration and PDL1 expression in epithelial ovarian cancer
Authors: A. Leary, C. Genestie, Y. Boursin, J. Adam, A. Leformal-Ensarguex, S. Gouy, P. Morice, E. Bentivegna, P. Pautier, J. Michels, B. Job, M. Deloger, S. Mesnage, A. Auguste
Journal: Annals of Oncology (2017)
Indirect comparison of abiraterone acetate and docetaxel for treatment of metastatic “hormone-sensitive” prostate cancer
Authors: S. Feyerabend, F. Saad, T. Li, T. Ito, J. Diels, S. Van Sanden, P. De Porre, J. Roïz, S. Abogunrin, K. Fizazi
Journal: Annals of Oncology (2017)
Lung Cancer Patients with Germline Mutations Detected by Next-Generation Sequencing and/or Liquid Biopsy
Authors: Takehito Shukuya, Sandipkumar Patel, Kate Shane-Carson, Kai He, Erin M. Bertino, Konstantin Shilo, Gregory A. Otterson, David P. Carbone
Journal: Journal of Thoracic Oncology (2017)
Poor early response to methotrexate portends inadequate long-term outcomes in patients with moderate-to-severe psoriasis: Evidence from 2 phase 3 clinical trials
Authors: Kenneth B. Gordon, Keith A. Betts, Murali Sundaram, James E. Signorovitch, Junlong Li, Meng Xie, Eric Q. Wu, Martin M. Okun
Journal: Journal of the American Academy of Dermatology (2017)
Top-line data from the randomized phase 2 IMPULSE study in small-cell lung cancer (SCLC): Immunotherapeutic maintenance treatment with lefitolimod
Authors: M. Thomas, S. Ponce-Aix, A. Navarro Mendivil, J. Riera Knorrenschild, M. Schmidt, M. Krikow, E. Wiegert, M. Domine Gomez, J. Kollmeier, P. Sadjadian, K.P. Fröhling, R.M. Huber, M. Wolf
Journal: Annals of Oncology (2017)
Reply to Ege Can Serefoglu, Gregory C. Mitchell, and Wayne J.G. Hellstrom’s Letter to the Editor re: Hartmut Porst, Edward D. Kim, Adolfo R. Casabé, et al., for the LVHJ study team. Efficacy and Safety of Tadalafil Once Daily in the Treatment of Men With Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia: Results of an International Randomized, Double-Blind, Placebo-Controlled Trial. Eur Urol 2011;60:1105–13
Authors: Hartmut Porst, Edward D. Kim, Adolfo R. Casabé, Vincenzo Mirone, Roberta J. Secrest, Lei Xu, David P. Sundin, Lars Viktrup
Journal: European Urology (2012)
Radiologist shortage leaves patient care at risk, warns royal college
Authors: Abi Rimmer
Journal: BMJ (2017)

The UK does not have enough radiologists to meet imaging and diagnostic demands in the NHS, the Royal College of Radiologists has warned.

Nearly all radiology departments in the UK (97%) said that they had been unable to meet their diagnostic reporting requirements in 2016 within their radiology staff’s contracted hours, the college’s 2016 census report found.1 “This points to an insufficient number of radiologists to meet the increasing demand for imaging and diagnostic services,” it said.

The census received …
Efficacy and safety of olaparib combined with eribulin in patients with advanced or metastatic triple negative breast cancer (TNBC) previously treated with anthracyclines and taxanes: The final analysis of a Japanese phase I/II trial
Authors: K. Aogi, K. Yonemori, M. Takahashi, N. Masuda, Y. Naito, S. Shimizu, R. Nakamura, H. Yamamoto, A. Hamada, H. Michimae, K. Tamura, T. Sukigara, R. Nagasaka, Y. Fujiwara
Journal: Annals of Oncology (2017)
Integrated molecular signatures of TERT promoter deregulation predict disease outcomes in non-muscle invasive bladder cancer
Authors: R. Leão, D. Lee, A. Figueiredo, M. Komosa, C. Zhang, J. Apolónio, N.M. Nunes, T. Hermanns, P. Wild, C. Poyet, R.J. Hamilton, P. Castelo-Branco, U. Tabori
Journal: Annals of Oncology (2017)
Whole-exome sequencing of matched germline and plasma cell-free DNA portrays the somatic mutation landscape of refractory metastatic colorectal cancer and identifies mutated KDR/VEGFR2 as new cause of therapy resistance
Authors: R.A. Toledo, E. Garralda, T. Pons, J. Monsech, E. Vega, R. Alvarez, A. Cubillo, C. Blanco-Aparicio, O. Dominguez, J.L. Martinez, M. Hidalgo
Journal: Annals of Oncology (2017)
Is there a clinical benefit of anti-PD-1 in patients older than 75 years with previously treated solid tumour?
Authors: Thierry Landre, Cherifa Taleb, Patrick Nicolas, Gaetan Des Guetz
Journal: Journal of Clinical Oncology (2016)

3070 Background: The immune system undergoes profound transformations with age, and response patterns to immune challenges are therefore highly age dependent. Nivolumab, an anti-PD-1 immune checkpoint inhibitor, showed promising activity and tolerability in several solid tumours. However, in our knowledge, few data are available in patients older than 75 years. Methods: We performed an age subgroup analysis of published randomized control trials concerning nivolumab versus standard therapy in previously treated patients with advanced solid tumours. Overall Survival (OS) among the elderly ( ≥ 75 years) was compared with that of younger patients ( ≥ 65 to < 75 years). Hazard ratios (HRs) with their 95 % confidence interval (CI) were collected from the studies and pooled. A fixed-effect model was used. Results: Few studies have been published corresponding to our inclusion criteria. Two studies (CheckMate 017 for Squamous and CheckMate 057 for Non-Squamous) assessed nivolumab versus docetaxel in Non-Small Cell Lung Cancer (NSCLC) and one study (CheckMate 025) assessed nivolumab versus everolimus in Renal-Cell Carcinoma (RCC). Our pooled-analysis included 146 patients older than 75 years (72 NSCLC, 74 RCC) and 541 patients between 65 and 75 years (291 NSCLC and 250 RCC). All patients were mostly men (68%), with good Performance Status (0 or 1). For patients ≥75 years, OS of the nivolumab arm was inferior to that of the control arm (HR = 1.22; 95% CI 0.80-1.85; p = 0.36). Conversely, among younger patients (≥65 to < 75 years), a statistically significant OS benefit was seen with nivolumab (HR = 0.62; 95 % CI 0.50-0.77; p < 0.0001). Similar trends were observed for PFS in patients with NSCLC (HR = 1.24; 95 % CI 0.73-2.09; p = 0.43 for patients ≥75 years and HR = 0.78; 95 % CI 0.60-1.01; p = 0.06 for patients ≥65 to < 75 years). Conclusions: Nivolumab survival benefit in patients older than 75 years appears uncertain. Several significant changes in the elderly individuals in regulatory elements of CD4+ and CD8+ T cells could explain the lack of effectiveness of nivolumab.These results should be interpreted with caution due to the small number of patients. Further studies are warranted to evaluate anti-PD-1 efficacy in elderly.
Adding abiraterone acetate plus prednisolone (AAP) or docetaxel for patients (pts) with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Directly randomised data from STAMPEDE (NCT00268476)
Authors: M.R. Sydes, M.D. Mason, M.R. Spears, N.W. Clarke, D. Dearnaley, A.W.S. Ritchie, M. Russell, C. Gilson, R. Jones, J. de Bono, S. Gillessen, R. Millman, S. Tolan, J. Wagstaff, S. Chowdhury, J. Lester, D. Sheehan, J. Gale, M.K. Parmar, N.D. James
Journal: Annals of Oncology (2017)
The elderly left behind—changes in survival trends of primary central nervous system lymphoma over the past 4 decades
Authors: Joe S Mendez, Quinn T Ostrom, Haley Gittleman, Carol Kruchko, Lisa M DeAngelis, Jill S Barnholtz-Sloan, Christian Grommes
Journal: Neuro-Oncology (2017)

There has been significant improvement in treatment outcomes of primary central nervous system lymphoma (PCNSL) at specialized centers over the past several decades; however, it is unclear if these changes have translated to benefits in the general population. In this study, we utilized 2 national databases to examine survival trends over time for PCNSL: the Central Brain Tumor Registry of the United States (CBTRUS, 2000–2013) and 18 registries from the Surveillance, Epidemiology, and End Results program (SEER, 1973–2013). The annual incidence of PCNSL in 2013 was 0.4 per 100000 population (CBTRUS/SEER). Incidence increased from 0.1 per 100000 in the 1970s to 0.4 per 100000 in the 1980s, correlating with an increase in the diagnosis of patients ≥70 years (1973: 0.2 vs 2013: 2.1 [SEER]). Incidence rates differed greatly between young and elderly patients (age 20–29 y: 0.08 vs 70–79 y: 4.32 [CBTRUS]). Even though the median overall survival of all patients doubled from 12.5 months in the 1970s to 26 months in the 2010s, this survival benefit was limited to patients <70 years. Survival in the elderly population has not changed in the last 40 years (6 mo in the 1970s vs 7 mo in the 2010s, P = 0.1). The poor outcome seen in the particularly vulnerable elderly patient population highlights the need for clinical trials targeting the elderly in hopes of improving treatment strategies and survival.
Reversion of epithelial–mesenchymal transition (EMT) as a mechanism of action of cabazitazel in castration-resistant prostate cancer
Authors: N. Jiménez, M. Marín-Aguilera, O. Reig, P.L. Fernández, S. García-Recio, M.V. Pereira, A. Prat, B. Mellado Gonzalez
Journal: Annals of Oncology (2017)
Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer)
Authors: H. Nokihara, S. Lu, T.S.K. Mok, K. Nakagawa, N. Yamamoto, Y.K. Shi, L. Zhang, R.A. Soo, J.C. Yang, S. Sugawara, M. Nishio, T. Takahashi, K. Goto, J. Chang, M. Maemondo, Y. Ichinose, Y. Cheng, W.T. Lim, S. Morita, T. Tamura
Journal: Annals of Oncology (2017)

BackgroundChemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC.Patients and methodsPatients with advanced NSCLC previously treated with ≥1 platinum-based therapy were randomized 1 : 1 to docetaxel (60 mg/m2 in Japan, 75 mg/m2 at all other study sites; day 1 in a 3-week cycle) or S-1 (80–120 mg/day, depending on body surface area; days 1–28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2.ResultsA total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms, respectively [HR 0.945; 95% confidence interval (CI) 0.833–1.073; P = 0.3818]. The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913–1.168; P = 0.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm.ConclusionS-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC.Clinical trial numberJapan Pharmaceutical Information Center, JapicCTI-101155.
Abstract 15641: Profiling the Altered Cellular and Secreted Proteome of Cardiac Fibroblasts in Hypoxia Through Label-free Quantitation
Authors: Jake Cosme, Hongbo Guo, Andrew Emili, Anthony Gramolini
Journal: Circulation (2016)

Introduction:  Cardiac fibroblasts (CF) are key contributers to pathophysiology of the heart after ischemic injury and disease progression, such as fibrosis, which ultimately lead to heart failure Cardiomyocyte (CM) and CF intercellular communication can occur through paracrine interactions and modulate to myocyte stress response. In addition to soluble factors, cardiac cells secrete exosomes (EXO), with evidence suggesting CF EXO modulate pathophysiology  in vitro . Detailed proteomic analysis of the fibroblast secretome in normal and stressed conditions will offer insights into the role of CF in heart disease.   Methods:  Primary mouse CF were cultured for 24h in 21% (normoxic) or 2% (hypoxic) O 2  for 24h in serum-free media. Conditioned media was differentially centrifuged and ultracentrifuged to obtain EXO and EXO-depleted secretome (SEC) fractions. Successful EXO isolation was verified biochemically and via electron microscopy. 6-step MuDPIT was performed on four biological replicates in duplicate. Whole cell lysate data (WCL) was also generated to provide subcelluar context to the CF secretome. Data was searched using multi-search algorithm platform. Protein relative abundance was compared using QSpec.   Results:  Proteomic analysis identified 6163 unique proteins in total, with 5655, 1752, and 715 in normoxic WCL, EXO, and SEC, respectively and 5158, 1616, and 1042 in hypoxic WCL, EXO, and SEC, respectively. QSpec analysis identified 494 proteins differentially expressed between normoxic fractions, 430 proteins between hypoxic fractions, 122 proteins between normoxic and hypoxic SEC, and 144 proteins between normoxic and hypoxic EXO. Gene Ontology revealed hypoxic conditions increase expression of ECM and signalling annotations, suggesting an activated secretory phenotype. Proteins enriched in EXO and in SEC were associated with cytoskeleton and glycoprotein annotations, respectively. For functional assessment, we subjected cardiomyocytes pretreated with either CF EXO or SEC for 24h, to 60 μM H 2 O 2  for 24h to mimic oxidative stress. Viability assays suggest reduced viability due to CF-derived secreted factors.   Conclusions:  CF secretome proteomics reveal differential expression based on mode of secretion and oxygen-levels  in vitro .
Vigilancia de enfermedades de transmisión sexual por redes de laboratorios en Francia
Authors: V Goulet, P Sednaoui
Journal: Eurosurveillance (1998)

En Francia, casi todos los casos de enfermedades de transmision sexual (ETS) los diagnostican facultativos del sector privado (medicos generales, ginecologos, dermatologos especializados en enfermedades venereas y urologos), pero hay dispensarios antivenereos (DAV) en todo el pais que atienden gratuitamente a pacientes con algunas ETS (gonorrea, sifilis). La reorganizacion del sistema de declaracion obligatoria, que se llevo a cabo en 1985, limito el numero de enfermedades de declaracion obligatoria y no incluyo las ETS. Los facultativos del sector privado ya no declaran estas enfermedades y, desde 1995, los servicios de estadistica del ministerio de sanidad no recogen los casos de ETS diagnosticados en los DAV.