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Veronica Höiom Hanna Eriksson Charlotta All‐Ericsson Rainer Tuominen Ivayla Ivanova Joakim Lundeberg Olof Emanuelsson Johan Hansson 《Genes, chromosomes & cancer》2013,52(4):378-384
Melanoma of the eye is a rare and distinct subtype of melanoma, which only rarely are familial. However, cases of uveal melanoma (UM) have been found in families with mixed cancer syndromes. Here, we describe a comprehensive search for inherited genetic variation in a family with multiple cases of UM but no aggregation of other cancer diagnoses. The proband is a woman diagnosed with UM at 16 years who within 6 months developed liver metastases. We also identified two older paternal relatives of the proband who had died from UM. We performed exome sequencing of germline DNA from members of the affected family. Exome‐wide analysis identified a novel loss‐of‐function mutation in the BAP1 gene, previously suggested as a tumor suppressor. The mutation segregated with the UM phenotype in this family, and we detected a loss of the wild‐type allele in the UM tumor of the proband, strongly supporting a causative association with UM. Screening of BAP1 germline mutations in families predisposed for UM may be used to identify individuals at increased risk of disease. Such individuals may then be enrolled in preventive programs and regular screenings to facilitate early detection and thereby improve prognosis. © 2013 Wiley Periodicals, Inc. 相似文献
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Background
Minimization as an adaptive allocation technique has been recommended in the literature for use in randomized clinical trials. However, it remains uncommonly used due in part to a lack of easily accessible implementation tools.Objective
To provide clinical trialists with a robust, flexible, and readily accessible tool for implementing covariate-adaptive biased-coin randomization.Methods
We developed a Web-based random allocation system, MinimRan, that applies Pocock–Simon (for trials with 2 or more arms) and 2-way (currently limited to 2-arm trials) minimization methods for trials using only categorical prognostic factors or the symmetric Kullback–Leibler divergence minimization method for trials (currently limited to 2-arm trials) using continuous prognostic factors with or without categorical factors, in covariate-adaptive biased-coin randomization.Results
In this paper, we describe the system’s essential statistical and computer programming features and provide as an example the randomization results generated by it in a recently completed trial. The system can be used in single- and double-blind trials as well as single-center and multicenter trials.Conclusions
We expect the system to facilitate the translation of the 3 validated random allocation methods into broad, efficient clinical research practice. 相似文献95.
Nielsen CF Reisen WK Armijos MV Maclachlan NJ Scott TW 《The American journal of tropical medicine and hygiene》2008,78(1):45-52
Although horse cases frequently are reported during West Nile virus (WNV) outbreaks, few investigations have focused on the epidemiology of this transmission. From April to October 2003 to 2005, mosquito abundance and infection were monitored 3 days per week at an equine research facility at the University of California, Davis. Thirty-two nonvaccinated horses enrolled as controls in a vaccine study were bled monthly, and their serum was tested for evidence of WNV infection by plaque reduction neutralization test (PRNT). In 2004, one positive Culex pipiens pool was associated with a single horse that presented with confirmed WNV disease in late September. The annual incidence of clinical and subclinical WNV infection in the nonvaccinated horses was 16%, with an apparent to inapparent ratio of 1:4 among infected horses. In 2005, two Culex tarsalis and two Cx. pipiens WNV-positive pools were associated with an equine infection incidence of 62%, with an apparent to inapparent ratio of 1:17. The majority (79%) of 70 blood-engorged Cx. pipiens fed on birds and the remaining on equines (21%). Conversely, Cx. tarsalis fed primarily on equines (n = 23, 74%), followed by birds (n = 7, 23%) and 1 (3%) fed on a lagomorph. These data indicated that nonvaccinated horses were a sensitive indicator of WNV activity and that their risk of infection was associated with the presence of infection in Cx. pipiens and Cx. tarsalis, which served as both enzootic and bridge vectors amplifying WNV among birds and transmitting WNV to horses. 相似文献
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Luca Masotti Grazia Panigada Giancarlo Landini Filippo Pieralli Francesco Corradi Salvatore Lenti Rino Migliacci Stefano Arrigucci Anna Frullini Maria Chiara Bertieri Stefano Tatini Alberto Fortini Irene Cascinelli Nicola Mumoli Stefano Giuntoli Alessandro De Palma Veronica De Crescenzo Michele Piacentini Giancarlo Tintori Alba Dainelli Giuseppa Levantino Plinio Fabiani Filippo Risaliti Roberta Mastriforti Michele Voglino Valentina Carli Simone Meini 《Journal of thrombosis and thrombolysis》2016,41(4):606-612
Prognostic stratification of acute pulmonary embolism (PE) remains a challenge in clinical practice. Simplified PESI (sPESI) score is a practical validated score aimed to stratify 30-day mortality risk in acute PE. Whether prognostic value of sPESI score differs according to sex has not been previously investigated. Therefore the aim of our study was to provide information about it. Data records of 452 patients, 180 males (39.8 %) and 272 females (60.2 %) discharged for acute PE from Internal Medicine wards of Tuscany (Italy) were analysed. sPESI was retrospectively calculated. Variables enclosed in sPESI score, all cause in-hospital mortality and overall bleedings were compared between sexes. Moreover, predictive ability of sPESI score as prognosticator of all cause in-hospital mortality was tested and compared between sexes. sPESI score 0 (low risk) was found in 17.7 % of males and 13.6 % of females (p = 0.2323). We didn’t find significant difference in sPESI scoring distribution. Age ≥80 years (51.4 vs. 33.8 %, p = 0.0003) and heart rate ≥110 bpm (23.5 vs. 14.4 %, p = 0.0219) were found significantly more prevalent in females, whereas active cancer (23.8 vs. 39.4 %, p = 0.0004) and cardio-respiratory diseases (19.8 vs. 27.7 %, p = 0.0416) were in males. All cause in-hospital mortality was 0 % in both genders for sPESI score 0, whereas it was 5.4 % in females and 13.6 % in males with sPESI score 1–2 (p = 0.0208) and 22 % in females and 19.3 % in males with sPESI score ≥3 (p = 0.7776). Overall bleedings were significantly more frequent in females compared with males (4.77 vs. 0.55 %, p = 0.0189). In females overall bleedings ranged from 2.7 % in sPESI score 0 to 6 % in sPESI score ≥3. Predictive ability of sPESI score as prognosticator of all cause in-hospital mortality was higher in females compared to males (AUC 0.72 vs. 0.67, respectively). In real life different co-morbidity burdens in females compared to males. Females seems to be at lower risk of all cause in-hospital mortality for sPESI score ≤2 but at higher risk of bleeding, irrespective from sPESI scoring. Predictive ability of sPESI score seems better in females. 相似文献
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Gisela G. Slaats Joshua C. Saldivar Julien Bacal Michelle K. Zeman Andrew C. Kile Ann Marie Hynes Shalabh Srivastava Jekaterina Nazmutdinova Krista den Ouden Miriam S. Zagers Veronica Foletto Marianne C. Verhaar Colin Miles John A. Sayer Karlene A. Cimprich Rachel H. Giles 《The Journal of clinical investigation》2015,125(9):3657-3666
Juvenile ciliopathy syndromes that are associated with renal cysts and premature renal failure are commonly the result of mutations in the gene encoding centrosomal protein CEP290. In addition to centrosomes and the transition zone at the base of the primary cilium, CEP290 also localizes to the nucleus; however, the nuclear function of CEP290 is unknown. Here, we demonstrate that reduction of cellular CEP290 in primary human and mouse kidney cells as well as in zebrafish embryos leads to enhanced DNA damage signaling and accumulation of DNA breaks ex vivo and in vivo. Compared with those from WT mice, primary kidney cells from Cep290-deficient mice exhibited supernumerary centrioles, decreased replication fork velocity, fork asymmetry, and increased levels of cyclin-dependent kinases (CDKs). Treatment of Cep290-deficient cells with CDK inhibitors rescued DNA damage and centriole number. Moreover, the loss of primary cilia that results from CEP290 dysfunction was rescued in 3D cell culture spheroids of primary murine kidney cells after exposure to CDK inhibitors. Together, our results provide a link between CEP290 and DNA replication stress and suggest CDK inhibition as a potential treatment strategy for a wide range of ciliopathy syndromes. 相似文献