Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26
Filtrar
1.
Sci Rep ; 13(1): 353, 2023 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-36611126

RESUMO

Head and neck cancer is the sixth most common malignancy, and there is an urgent need to identify physiological processes contributing to tumorigenesis. Extracellular acidification caused by aerobic glycolysis within tumor microenvironments can stimulate proton-sensing receptors. GPR68, or ovarian cancer G protein-coupled receptor 1, responds to extracellular acidity and is highly expressed in head and neck squamous cell carcinoma (HNSCC) as well as normal esophageal tissue. To study the role of GPR68 in oral dysplasia, wild-type and GPR68-/- mice were treated with 4-Nitroquinoline N-oxide (4NQO) in drinking water for 11-13 weeks, followed by normal water for 11-12 weeks. 4NQO treatment resulted in 45 percent of GPR68-/- mice developing severe dysplasia or squamous cell carcinoma compared to only 10.5 percent of GPR68+/+ mice. This correlated with increased frequencies of regulatory T cells in the spleens of male GPR68-/- mice. Dysplastic regions of the tongue had increased CD31 staining compared to normal regions in both GPR68-/- and GPR68+/+ mice, suggesting that angiogenesis was GPR68-independent. RNA knockdown studies using HNSCC cell lines demonstrated no direct effect of GPR68 on survival or growth. Overall, we demonstrate that GPR68-deficiency worsens the severity of chemical-induced oral dysplasia, suggesting a protective role for this gene in tumorigenesis.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Masculino , Camundongos , Animais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Carcinoma de Células Escamosas/patologia , Carcinogênese/patologia , 4-Nitroquinolina-1-Óxido/toxicidade , Transformação Celular Neoplásica , Neoplasias de Cabeça e Pescoço/induzido quimicamente , Neoplasias de Cabeça e Pescoço/genética , Hiperplasia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Microambiente Tumoral
2.
Occup Environ Med ; 79(2): 102-108, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34417337

RESUMO

OBJECTIVES: Radon is carcinogenic, but more studies are needed to understand relationships with lung cancer and extrathoracic cancers at low exposures. There are few studies evaluating associations with cancer incidence or assessing the modifying effects of smoking. METHODS: We conducted a case-cohort study with 16 434 underground uranium miners in the Czech Republic with cancer incidence follow-up 1977-1996. Associations between radon exposure and lung cancer, and extrathoracic cancer, were estimated with linear excess relative rate (ERR) models. We examined potential modifying effects of smoking, time since exposure and exposure rate. RESULTS: Under a simple ERR model, assuming a 5-year exposure lag, the estimated ERR of lung cancer per 100 working level months (WLM) was 0.54 (95% CI 0.33 to 0.83) and the estimated ERR of extrathoracic cancer per 100 WLM was 0.07 (95% CI -0.17 to 0.72). Most lung cancer cases were observed among smokers (82%), and the estimated ERR of lung cancer per 100 WLM was larger among smokers (ERR/100 WLM=1.35; 95% CI 0.84 to 2.15) than among never smokers (ERR/100 WLM=0.12; 95% CI -0.05 to 0.49). Among smokers, the estimated ERR of lung cancer per 100 WLM decreased with time since exposure from 3.07 (95% CI -0.04 to 10.32) in the period 5-14 years after exposure to 1.05 (95% CI 0.49 to 1.87) in the period 25+ years after exposure. CONCLUSIONS: We observed positive associations between cumulative radon exposure and lung cancer, consistent with prior studies. We observed a positive association between cumulative radon exposure and extrathoracic cancers, although the estimates were small. There was evidence that the association between radon and lung cancer was modified by smoking in a multiplicative or super-multiplicative fashion.


Assuntos
Neoplasias Pulmonares/epidemiologia , Neoplasias/epidemiologia , Exposição Ocupacional/efeitos adversos , Radônio/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , República Tcheca/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Mineradores/estatística & dados numéricos , Neoplasias Induzidas por Radiação/epidemiologia , Produtos de Decaimento de Radônio/efeitos adversos , Fumar/efeitos adversos , Urânio
3.
Am J Case Rep ; 22: e933847, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34716288

RESUMO

BACKGROUND Several cases of herpes simplex virus type 1 meningoencephalitis (HSVE) have been reported in patients receiving steroids, but the exact contribution of steroids to the disorder remains unclear because other risk factors, such as chemotherapy, brain radiation, or surgery, were present in almost all cases. CASE REPORT We report the case of a 76-year-old man who developed HSVE following the administration of pulse-dose steroids. The patient had occupational asbestos exposure and a chronic interstitial lung disease of unclear etiology (sarcoidosis versus hypersensitivity pneumonitis) and was admitted for acute-on-chronic respiratory failure requiring mechanical ventilation. After a negative infectious workup and several days of antibiotics without improvement, pulse-dose steroids were administered. In the following days, the patient developed a fever and worsening encephalopathy. A lumbar puncture showed elevated nucleated cells and positive polymerase chain reaction for herpes simplex virus 1 in the cerebrospinal fluid, confirming the diagnosis of HSVE. Acyclovir treatment was initiated, but the patient later died as a result of persistent severe encephalopathy and respiratory failure with an inability to wean mechanical ventilation. CONCLUSIONS Clinicians should keep in mind that HSVE is a potential complication of steroids and carefully consider the benefit/risk ratio of pulse-dose steroids, taking into account associated factors of immunosuppression. A high level of awareness should be especially maintained in critically ill patients because of associated risk factors (critical illness immune paralysis) and because neurological signs of HSVE may be missed in mechanically ventilated, sedated patients.


Assuntos
Encefalite por Herpes Simples , Herpesvirus Humano 1 , Meningoencefalite , Aciclovir/efeitos adversos , Idoso , Encefalite por Herpes Simples/diagnóstico , Encefalite por Herpes Simples/tratamento farmacológico , Humanos , Masculino , Meningoencefalite/induzido quimicamente , Meningoencefalite/diagnóstico , Metilprednisolona/efeitos adversos
4.
Am J Ind Med ; 63(10): 859-867, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33448434

RESUMO

BACKGROUND: This study aims to estimate the association between radon and site-specific cancer mortality among a large contemporary cohort of male uranium miners. METHODS: Annual occupational radon exposure was estimated based on a worker's duration of underground mining in a year and estimates of potential alpha energy of radon progeny in their location of work. Cancer mortality over the period 1977-1992 was ascertained for a cohort of 16 434 male underground uranium miners employed in the Czech Republic between 1946 and 1992. Poisson regression was used to estimate relationships between cumulative radiation exposure (in working level months [WLM]) and site-specific cancer mortality. RESULTS: Radon is positively associated with lung cancer mortality (excess relative rate [ERR] per 100 WLM = 0.2; 95% confidence interval [CI]: 0.10, 0.37). The best fit of the dose-response relationship between radon and lung cancer mortality was linear and estimates of radon-lung cancer associations varied by windows of time-since-exposure. Positive associations between radon and several types of cancer other than lung cancer were identified, notably chronic lymphocytic leukemia (CLL) (ERR/100 WLM = 0.24; 95% CI: [not determined [ND], 5.10]) and extrathoracic cancer (ERR/100 WLM = 0.12; 95% CI: [ND, 0.69]). We observed no associations between radon and stomach cancer, nor between radon and several hematopoietic cancer subtypes. CONCLUSIONS: This study confirms the established radon-lung cancer association and suggests that radon may also be associated with other types of cancer mortality. Further investigations of extrathoracic and CLL cancer, with the aim of obtaining more precise estimates, are warranted to understand associations between radon and cancers other than lung.


Assuntos
Mineração , Neoplasias Induzidas por Radiação/mortalidade , Doenças Profissionais/mortalidade , Radônio/toxicidade , Urânio , República Tcheca , Humanos , Leucemia Linfocítica Crônica de Células B/etiologia , Leucemia Linfocítica Crônica de Células B/mortalidade , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/mortalidade , Masculino , Doenças Profissionais/etiologia , Exposição Ocupacional/efeitos adversos , Distribuição de Poisson
5.
Occup Environ Med ; 76(8): 511-518, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31167952

RESUMO

OBJECTIVES: Uranium miners in Príbram, Czech Republic were exposed to low and moderate levels of radon gas and other hazards. It is unknown whether these hazards increase the risk of mortality or cancer incidence when compared with the general Czech population. METHODS: A cohort of 16 434 male underground miners employed underground for at least 1 year between 1946 and 1976, and alive and residing in the Czech Republic in 1977, were followed for mortality and cancer incidence through 1992. We compared observed deaths and cancer incidence to expectation based on Czech rates. Standardised mortality ratios (SMRs), standardised incidence ratios (SIRs) and causal mortality ratios were calculated. RESULTS: Underground workers in the Príbram mines had higher rates of death than expected due to all causes (SMR=1.23, 95% CI 1.20 to 1.27), all cancers (SMR=1.52, 95% CI 1.44 to 1.60), lung cancer (SMR=2.12, 95% CI 1.96 to 2.28) and extrathoracic cancer (SMR=1.41, 95% CI 1.15 to 1.77). Similar excess was observed in cancer incidence analyses, with the addition of stomach cancer (SIR=1.37, 95% CI 1.11 to 1.63), liver cancer (SIR=1.70, 95% CI 1.16 to 2.25) and rectal cancer (SIR=1.41, 95% CI 1.16 to 1.66). The SIR was elevated for all leukaemias (SIR=1.51, 95% CI 1.08 to 2.07) and for lymphatic and haematopoietic cancers combined (SIR=1.31, 95% CI 1.05 to 1.61), but results for specific subtypes were imprecise. Deaths due to hazardous mining conditions resulted in 0.33 person-years of life lost per miner. CONCLUSIONS: Occupational exposure to the Príbram mines resulted in excess cancers at several sites, including sites previously linked to radon and uranium exposure. Incidence analyses showed relative excess of several additional cancer subtypes.


Assuntos
Mineradores , Neoplasias Induzidas por Radiação/epidemiologia , Neoplasias Induzidas por Radiação/mortalidade , Exposição Ocupacional/efeitos adversos , Adulto , Idoso , Causas de Morte , Estudos de Coortes , República Tcheca/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Radônio/efeitos adversos , Urânio/efeitos adversos
6.
Nat Commun ; 10(1): 2535, 2019 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182712

RESUMO

Rif1 is involved in telomere homeostasis, DNA replication timing, and DNA double-strand break (DSB) repair pathway choice from yeast to human. The molecular mechanisms that enable Rif1 to fulfill its diverse roles remain to be determined. Here, we demonstrate that Rif1 is S-acylated within its conserved N-terminal domain at cysteine residues C466 and C473 by the DHHC family palmitoyl acyltransferase Pfa4. Rif1 S-acylation facilitates the accumulation of Rif1 at DSBs, the attenuation of DNA end-resection, and DSB repair by non-homologous end-joining (NHEJ). These findings identify S-acylation as a posttranslational modification regulating DNA repair. S-acylated Rif1 mounts a localized DNA-damage response proximal to the inner nuclear membrane, revealing a mechanism of compartmentalized DSB repair pathway choice by sequestration of a fatty acylated repair factor at the inner nuclear membrane.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , Proteínas Repressoras/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Proteínas de Ligação a Telômeros/genética , Acilação , Reparo do DNA , Membrana Nuclear/metabolismo , Proteínas Repressoras/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Ligação a Telômeros/metabolismo
7.
Urol Case Rep ; 25: 100891, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31049289

RESUMO

Renal schwannomas are an extremely rare renal tumor with possibility for malignant conversion. Although reports are scant, most reports have been presented from academic institutions. We report on a case of a renal schwannoma that was removed via robotic assisted laparoscopic nephrectomy in a community-based specialty practice under the suspicion of a renal malignancy.

8.
Environ Health Perspect ; 125(12): 127003, 2017 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-29373861

RESUMO

BACKGROUND: The Sister Study was designed to address gaps in the study of environment and breast cancer by taking advantage of more frequent breast cancer diagnoses among women with a sister history of breast cancer and the presumed enrichment of shared environmental and genetic exposures. OBJECTIVE: The Sister Study sought a large cohort of women never diagnosed with breast cancer but who had a sister (full or half) diagnosed with breast cancer. METHODS: A multifaceted national effort employed novel strategies to recruit a diverse cohort, and collected biological and environmental samples and extensive data on potential breast cancer risk factors. RESULTS: The Sister Study enrolled 50,884 U.S. and Puerto Rican women 35-74y of age (median 56 y). Although the majority were non-Hispanic white, well educated, and economically well off, substantial numbers of harder-to-recruit women also enrolled (race/ethnicity other than non-Hispanic white: 16%; no college degree: 35%; household income <$50,000: 26%). Although all had a biologic sister with breast cancer, 16.5% had average or lower risk of breast cancer according to the Breast Cancer Risk Assessment Tool (Gail score). Most were postmenopausal (66%), parous with a first full-term pregnancy <30y of age (79%), never-smokers (56%) with body mass indexes (BMIs) of <29.9 kg/m2 (70%). Few (5%) reported any cancer prior to enrollment. CONCLUSIONS: The Sister Study is a unique cohort designed to efficiently study environmental and genetic risk factors for breast cancer. Extensive exposure data over the life-course and baseline specimens provide important opportunities for studying breast cancer and other health outcomes in women. Collaborations are welcome. https://doi.org/10.1289/EHP1923.


Assuntos
Neoplasias da Mama/epidemiologia , Irmãos , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Porto Rico/epidemiologia , Fatores de Risco , Estados Unidos/epidemiologia
9.
BMC Cancer ; 15: 960, 2015 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-26673874

RESUMO

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit several pathways in experimental models of breast carcinogenesis, but epidemiological evidence remains insufficient to support their use for breast cancer prevention. We examined the association between use of NSAIDs and breast cancer risk in a prospective cohort. METHODS: The Sister Study is a prospective cohort study of women who had a sister(s) with breast cancer. As of December 2013, 2118 incident breast cancers were ascertained from 50,884 women enrolled between 2003 and 2009. Lifetime history of NSAID use was estimated from self-reported data in pill-years, with 1 pill per week for a year equivalent to 1 pill-year. Cox regression models were used to estimate hazard ratios (HRs) of breast cancer in relation to pill-years of use for different NSAIDs, with adjustment for potential confounders. RESULTS: In the full cohort, although there was some evidence that use of non-aspirin, non-COXib NSAIDs was associated with lower breast cancer risk, there was little evidence of overall association for most categories of NSAID use. Among postmenopausal women NSAID use was not associated with reduced risk of breast cancer. However, among premenopausal women there was significantly reduced risk for any NSAID (HR4vs1=0.66, 95% CI: 0.50-0.87) and specifically for aspirin (HR4vs1=0.57, 95% CI: 0.33-0.98), with small, but non-significant reductions in risk for other drug classes. CONCLUSION: Women with a sister with breast cancer are themselves at increased risk and might benefit the most from chemoprevention. Although there was little evidence of protective effect from NSAIDs in the overall cohort of women or among the subset who are postmenopausal, there is intriguing evidence that NSAID use, particularly aspirin, may reduce risk among premenopausal women.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Neoplasias da Mama/epidemiologia , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Linhagem , Pós-Menopausa , Pré-Menopausa , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Irmãos , Inquéritos e Questionários
10.
Carcinogenesis ; 35(2): 333-8, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24130171

RESUMO

Global decrease in DNA methylation is a common feature of cancer and is associated with genomic and chromosomal instability. Retrospective case-control studies have reported that cancer patients have lower global methylation levels in blood DNA than do controls. We used prospectively collected samples and a case-cohort study design to examine global DNA methylation and incident breast cancer in 294 cases and a sample of 646 non-cases in the Sister Study, a study of 50 884 women aged 35-74 years who had not been diagnosed with breast cancer at the time of blood draw. Global methylation in DNA from peripheral blood was assessed by pyrosequencing of the LINE-1 repetitive element. Quartiles of LINE-1 methylation levels were associated with the risk of breast cancer in a dose-dependent fashion (P, trend = 0.002), with an increased risk observed among women in the lowest quartile compared with those in the highest quartile (hazard ratio = 1.75; 95% confidence interval 1.19, 2.59). We also examined 22 polymorphisms in 10 one-carbon metabolism genes in relation to both LINE-1 methylation levels and breast cancer. We found three single-nucleotide polymorphisms in those genes associated with LINE-1 methylation: SLC19A1 (rs1051266); MTRR (rs10380) and MTHFR (rs1537514), one of which was also associated with breast cancer risk: MTHFR (rs1537514). PON1 (rs757158) was associated with breast cancer but not methylation.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Carbono/metabolismo , Metilação de DNA , Genoma Humano , Elementos Nucleotídeos Longos e Dispersos/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Fatores de Risco
11.
J Endourol ; 27(4): 475-9, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23030764

RESUMO

BACKGROUND AND PURPOSE: Numerous holmium:yttrium-aluminum-garnet laser fibers are available for flexible ureteroscopy. Performance and durability of fibers can vary widely among different manufacturers and their product lines with differences within a single product line have been reported. We sought to evaluate a newly developed nontapered, single-use 240-µm fiber, Flexiva™ 200 (Boston Scientific, Natick, MA), during clinical use and in a bench-testing model. MATERIALS AND METHODS: A total of 100 new fibers were tested after their use in 100 consecutive flexible ureteroscopic lithotripsy procedures by a single surgeon (B.K.). Prospectively recorded clinical parameters were laser pulse energy and frequency settings, total energy delivered and fibers failure. Subsequently, each fiber was bench-tested using an established protocol. Parameters evaluated for were fibers true diameter, flexibility, tip degradation, energy transmission in straight and 180° bend configuration and fibers failure threshold with stress testing. RESULTS: The mean total energy delivered was 2.20 kJ (range 0-18.24 kJ) and most common laser settings used were 0.8 J at 8 Hz, 0.2 J at 50 Hz, and 1.0 J at 10 Hz, respectively. No fiber fractured during clinical procedures. The true fiber diameter was 450 µm. Fiber tips burnt back an average of 1.664 mm, but were highly variable. With laser setting of 400 mJ at 5 Hz, the mean energy transmitted was 451 and 441 mJ in straight and 180° bend configuration, respectively. Thirteen percent of fibers fractured at the bend radius of 0.5 cm with a positive correlation to the total energy transmitted during clinical use identified. CONCLUSION: Fiber performance was consistent in terms of energy transmission and resistance to fracture when activated in bent configuration. Fiber failure during stress testing showed significant correlation with the total energy delivered during the clinical procedure. The lack of fiber fracture during clinical use may reduce the risk of flexible endoscope damage due to fiber failure.


Assuntos
Estudos de Avaliação como Assunto , Lasers de Estado Sólido , Fibras Ópticas , Ureteroscópios , Ureteroscopia/instrumentação , Desenho de Equipamento , Humanos , Maleabilidade
12.
J Am Coll Cardiol ; 60(12): 1094-102, 2012 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-22974693

RESUMO

OBJECTIVES: This study investigated whether cardiac magnetic resonance (CMR) and echocardiography (echo) can replace catheterization (cath) for routine evaluation prior to Fontan and under what circumstances CMR and cath are used together. BACKGROUND: Routine cath prior to Fontan has been utilized for years; noninvasive methods, however, may be sufficient. METHODS: This study reviews clinical data in 119 consecutive patients investigating 3 groups: those who underwent CMR alone (MR; n = 41), cath alone (C; n = 41), or both cath and CMR (C+M; n = 37) prior to Fontan. RESULTS: No clinically significant differences were noted in patient characteristics, hemodynamics, or clinical status prior to or after surgery between the C and MR groups. CMR added information in 82%. There were no discrepant findings between CMR and cath data in the C+M group. Diagnostic success was ≥95% in all groups. Of those undergoing Fontan completion, the C+M group had similar outcomes to C and MR; C and CMR were utilized in combination to assess aortopulmonary collaterals or the need for an intervention or evaluate its success. Echo could not delineate pulmonary arterial anatomy in 46% to 53% of patients. The C+M and C groups were exposed to 6.8 ± 4.1 mSv of radiation. CONCLUSIONS: Single ventricle patients not requiring an intervention can undergo successful Fontan completion with CMR and echo alone with similar short-term outcomes to C, which was used as a control, preventing an invasive test and exposure to radiation. CMR can add information in a significant number of patients. Cath and CMR are utilized together for interventions and assessment of aortopulmonary collaterals.


Assuntos
Cateterismo Cardíaco/normas , Técnica de Fontan , Ventrículos do Coração/anormalidades , Imagem Cinética por Ressonância Magnética/normas , Cuidados Pré-Operatórios/normas , Cateterismo Cardíaco/métodos , Pré-Escolar , Feminino , Técnica de Fontan/métodos , Ventrículos do Coração/patologia , Humanos , Lactente , Recém-Nascido , Imagem Cinética por Ressonância Magnética/métodos , Masculino , Cuidados Pré-Operatórios/métodos
13.
Curr Opin Cell Biol ; 21(6): 855-63, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19796927

RESUMO

Ribosomes provide the basis for protein production and this drives cell growth. Recent studies, both in yeast and in higher eukaryotes, are beginning to reveal new mechanisms underlying the elaborate control of ribosome biogenesis, which requires coordinate regulation of all three RNA polymerases. Transcription of ribosomal RNA is finely tuned to cellular energy status and linked to the production of ribosomal proteins. Several autoregulatory mechanisms controlling various aspects of ribosome biogenesis have been uncovered and reveal new connections to cell-cycle and cell-size control. Ribosome biogenesis has now been clearly linked to disease, particularly to cancer and anemia, and also to aging. A challenge for future studies will be to elucidate further the molecular mechanisms underlying these connections.


Assuntos
Ribossomos/metabolismo , Animais , Ciclo Celular , DNA Ribossômico/metabolismo , Eucariotos/metabolismo , Crescimento/fisiologia , Humanos , Modelos Biológicos , Biogênese de Organelas , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Transcrição Gênica
14.
PLoS Genet ; 4(6): e1000101, 2008 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-18566672

RESUMO

Invasive aspergillosis (IA) is a common and life-threatening infection in immunocompromised individuals. A number of environmental and epidemiologic risk factors for developing IA have been identified. However, genetic factors that affect risk for developing IA have not been clearly identified. We report that host genetic differences influence outcome following establishment of pulmonary aspergillosis in an exogenously immune suppressed mouse model. Computational haplotype-based genetic analysis indicated that genetic variation within the biologically plausible positional candidate gene plasminogen (Plg; Gene ID 18855) correlated with murine outcome. There was a single nonsynonymous coding change (Gly110Ser) where the minor allele was found in all of the susceptible strains, but not in the resistant strains. A nonsynonymous single nucleotide polymorphism (Asp472Asn) was also identified in the human homolog (PLG; Gene ID 5340). An association study within a cohort of 236 allogeneic hematopoietic stem cell transplant (HSCT) recipients revealed that alleles at this SNP significantly affected the risk of developing IA after HSCT. Furthermore, we demonstrated that plasminogen directly binds to Aspergillus fumigatus. We propose that genetic variation within the plasminogen pathway influences the pathogenesis of this invasive fungal infection.


Assuntos
Alelos , Aspergilose/genética , Aspergilose/microbiologia , Predisposição Genética para Doença , Pneumopatias Fúngicas/genética , Pneumopatias Fúngicas/microbiologia , Plasminogênio/genética , Transdução de Sinais/genética , Animais , Aspergilose/mortalidade , Aspergilose/patologia , Aspergillus fumigatus/imunologia , Aspergillus fumigatus/patogenicidade , Feminino , Humanos , Pneumopatias Fúngicas/imunologia , Pneumopatias Fúngicas/mortalidade , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos AKR , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Endogâmicos MRL lpr , Camundongos Endogâmicos NZB , Camundongos Knockout , Plasminogênio/fisiologia
15.
J Endourol ; 21(11): 1277-80, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18042014

RESUMO

PURPOSE: Although the use of stents after ureteroscopy has been studied extensively, relatively little has been published about stent placement before complicated ureteroscopic procedures. In this study, we examined our experience with stent placement before ureteroscopic management of renal and ureteral stone disease. PATIENTS AND METHODS: A total of 90 patients underwent ureteroscopic surgery on 115 renal units by a single surgeon from 2001 to 2006. All patients had documented follow-up with imaging either by CT or intravenous urography (IVU) with tomography. Patients were classified into two groups depending on whether they had a stent placed before ureteroscopy. Baseline characteristics, operative indications for stent placement, stone-free rates, and complications were compared between groups. RESULTS: Baseline characteristics were similar between the groups. The majority of patients received stents before stone management because of technical considerations during surgery (17/36, 47%) or infection (13/36, 37%). Strict stone-free rates after ureteroscopic treatment were 47% in the 79 procedures without previous stents, compared with 67% in the 36 procedures with prestenting (P < 0.05). Including small fragments (2 mm or smaller), stone-free rates improved to 54% v 78%, respectively (P < 0.02). Complications were not significantly different in the two groups (P = 0.70). CONCLUSION: Although routine stent placement is not necessary before all ureteroscopic procedures, we demonstrate that it is associated with good stone-free rates and few complications. In this retrospective cohort, prestenting was associated with significantly higher stone-free rates. Prestenting should be considered in challenging cases.


Assuntos
Cálculos Renais/cirurgia , Stents , Cálculos Ureterais/cirurgia , Ureteroscopia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
16.
Am J Epidemiol ; 166(4): 447-55, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17556763

RESUMO

Targeting the first-degree relatives of people with a particular complex disease can offer a powerful approach to building a risk-based cohort for prospective studies of etiologic factors. Such a cohort provides both a sizable increase in the rate of accrual of newly incident cases, enriching for risk factors that are known or even unknown, and a high level of motivation among participants. A nationwide study of breast cancer in the United States and Puerto Rico, the Sister Study, made up of women who are each the sister of a woman with breast cancer, exemplifies this approach. In this paper, the authors provide power calculations to aid in the design of such studies and quantify their benefits for detecting both genetic variants related to risk and interactive effects of genetic and environmental factors. While the risk-based cohort can have markedly increased prevalences of rare causative alleles, most of the power advantages for this design is due to the increased rate of accrual of newly incident cases rather than the increase in any one individual allele.


Assuntos
Estudos de Coortes , Exposição Ambiental/efeitos adversos , Projetos de Pesquisa Epidemiológica , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Neoplasias da Mama/genética , Suscetibilidade a Doenças , Determinação de Ponto Final , Feminino , Frequência do Gene , Variação Genética , Genótipo , Humanos , Prevalência , Estudos Prospectivos , Risco , Irmãos
17.
Environ Health Perspect ; 114(6): 818-22, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16759978

RESUMO

OBJECTIVE: Uranium miners are chronically exposed to low levels of radon and its progeny. We investigated whether radon exposure is associated with increased incidence of leukemia, lymphoma, or multiple myeloma in this population. DESIGN: We conducted a retrospective case-cohort study in 23,043 uranium miners and identified a total of 177 incident cases of leukemia, lymphoma, and myeloma. Detailed information on occupational radon exposure was obtained for the cases and a randomly selected subcohort of 2,393 subjects. We used the proportional hazards model with power relative risk (RR) function to estimate and test the effects of cumulative radon exposures on incidence rates. RESULTS: Incidence of all leukemia combined and chronic lymphocytic leukemia (CLL) alone was positively associated with cumulative radon exposure. The RR comparing high radon exposure [110 working level months (WLM) ; 80th percentile] to low radon exposure (3 WLM ; 20th percentile) was 1.75 [95% confidence interval (CI) , 1.10-2.78 ; p = 0.014] for all leukemia combined and 1.98 (95% CI, 1.10-3.59 ; p = 0.016) for CLL. Myeloid leukemia and Hodgkin lymphoma were also associated with radon, but RRs were not statistically significant. There was no apparent association of radon with either non-Hodgkin lymphoma or multiple myeloma. Exposure to radon and its progeny was associated with an increased risk of developing leukemia in underground uranium miners. CLL, not previously believed to be radiogenic, was linked to radon exposure.


Assuntos
Leucemia/epidemiologia , Linfoma/epidemiologia , Mineração , Mieloma Múltiplo/epidemiologia , Urânio/toxicidade , Estudos de Casos e Controles , República Tcheca/epidemiologia , Humanos , Incidência , Estudos Retrospectivos
18.
J Toxicol Environ Health A ; 69(7): 633-54, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16608830

RESUMO

Radon is a well-established cause of lung cancer in miners. Residents of homes with high levels of radon are potentially also at risk. Although most individual studies of indoor radon have failed to demonstrate significant risks, results have generally been consistent with estimates from studies of miners. We studied 1474 incident lung cancer cases aged 40-79 yr in Connecticut, Utah, and southern Idaho. Population controls (n = 1811) were identified by random telephone screening and from lists of Medicare recipients, and were selected to be similar to cases on age, gender, and smoking 10 yr before diagnosis/interview using randomized recruitment. Complete residential histories and information on known lung cancer risk factors were obtained by in-person and telephone interviews. Radon was measured on multiple levels of past and current homes using 12-mo alpha-track etch detectors. Missing data were imputed using mean radon concentrations for informative subgroups of controls. Average radon exposures were lower than anticipated, with median values of 23 Bq/m3 in Connecticut and 45 Bq/m3 in Utah/southern Idaho. Overall, there was little association between time-weighted average radon exposures 5 to 25 yr prior to diagnosis/interview and lung cancer risk. The excess relative risk (ERR) associated with a 100-Bq/m3 increase in radon level was 0.002 (95% CI -0.21, 0.21) in the overall population, 0.134 (95% CI -0.23, 0.50) in Connecticut, and -0.112 (95% CI -0.34, 0.11) in Utah/Idaho. ERRs were higher for some subgroups less prone to misclassification, but there was no group with a statistically significant linear increase in risk. While results were consistent with the estimates from studies of miners, this study provides no evidence of an increased risk for lung cancer at the exposure levels observed.


Assuntos
Poluentes Radioativos do Ar/efeitos adversos , Poluição do Ar em Ambientes Fechados/efeitos adversos , Carcinógenos Ambientais/efeitos adversos , Exposição Ambiental/efeitos adversos , Neoplasias Pulmonares/etiologia , Neoplasias Induzidas por Radiação/etiologia , Radônio/efeitos adversos , Adulto , Idoso , Estudos de Casos e Controles , Connecticut/epidemiologia , Relação Dose-Resposta à Radiação , Feminino , Habitação , Humanos , Entrevistas como Assunto , Neoplasias Pulmonares/epidemiologia , Masculino , Medicare , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/epidemiologia , Medição de Risco , Utah/epidemiologia
19.
Leuk Res ; 29(10): 1117-30, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16111530

RESUMO

Occupational and industrial exposures have been implicated in the etiology of leukemia, yet uncertainty remains regarding potential high risk occupations. We examined the associations between self-reported occupations and hobbies and acute leukemia risk using data from 811 cases and 637 controls participating in a case-control study in the U.S. and Canada. We found that several occupations may increase the risk of acute leukemia, particularly occupations related to petroleum products, rubber, nuclear energy, munitions, plastics, and electronics manufacturing. Differences were noted according to histological type. Other occupations and hobbies were not clearly associated with risk.


Assuntos
Passatempos , Leucemia Mieloide/epidemiologia , Exposição Ocupacional , Ocupações , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Doença Aguda , Adulto , Idoso , Canadá/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Leucemia Mieloide/etiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Fatores de Risco , Estados Unidos/epidemiologia
20.
Leuk Res ; 28(12): 1263-5, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15475066

RESUMO

In a case-control study of adult acute leukemia we defined alcohol intake as either non-regular (<1 drink per week), light (1-5 drinks per week), moderate (6-8 drinks per week) or heavy (>8 drinks per week). An inverse association was found for light and moderate beer intake (RR = 0.58; 95% CI: 0.44, 0.76). In contrast, a positive association was found for moderate and heavy wine intake (RR = 2.1; 95% CI: 1.2, 3.8). Divergent results might reflect the effect of different nutrients in beer and wine, unmeasured confounding, or differing impacts of selection bias on these associations.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Leucemia/induzido quimicamente , Doença Aguda , Adulto , Idoso , Cerveja/efeitos adversos , Estudos de Casos e Controles , Feminino , Humanos , Incidência , Leucemia/etiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , América do Norte , Risco , Vinho/efeitos adversos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA