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1.
J Pediatr ; 272: 114089, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38734133

RESUMEN

OBJECTIVE: To assess cognitive, behavioral, and adaptive functions in children and young adults with hemophilia treated according to contemporary standards of care. STUDY DESIGN: Evolving Treatment of Hemophilia's Impact on Neurodevelopment, Intelligence, and Other Cognitive Functions (eTHINK) is a US-based, prospective, cross-sectional, observational study (September 2018 through October 2019). Males (aged 1-21 years) with hemophilia A or B of any severity, with or without inhibitors, were eligible. Participants underwent neurologic examinations and age-appropriate neuropsychological assessments, including standardized tests/ratings scales of early development, cognition, emotional/behavioral adjustment, and adaptive skills. RESULTS: Five hundred and fifty-one males with hemophilia A (n = 433) or B (n = 101) were enrolled. Performance on cognitive tests was largely comparable with that of age-matched US population norms, although participants in certain age groups (4-5 and 10-21 years) performed worse on measures of attention and processing speed. Furthermore, adolescents and young adults and those with comorbid attention-deficit/hyperactivity disorder (ADHD; n = 64) reported more adaptive and executive function problems in daily life. Incidence of ADHD in adolescents (21%) was higher than expected in the general population. CONCLUSIONS: In general, males with hemophilia demonstrated age-appropriate intellectual, behavioral, and adaptive development. However, specific patient/age groups showed poorer attention performance and concerns for executive and adaptive development. This study established a normative data set for monitoring neurodevelopment in individuals with hemophilia and highlight the importance of screening and intervention for challenges with cognitive and adaptive skills in this population. CLINICAL TRIAL REGISTRATION: Evolving Treatment of Hemophilia's Impact on Neurodevelopment, Intelligence, and Other Cognitive Functions (eTHINK); NCT03660774; https://clinicaltrials.gov/ct2/show/NCT03660774.


Asunto(s)
Hemofilia A , Humanos , Hemofilia A/complicaciones , Masculino , Adolescente , Niño , Estudios Transversales , Estudios Prospectivos , Adulto Joven , Preescolar , Lactante , Cognición , Pruebas Neuropsicológicas , Hemofilia B/complicaciones , Trastorno por Déficit de Atención con Hiperactividad , Función Ejecutiva , Adaptación Psicológica
2.
Diabetologia ; 65(1): 55-64, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34704120

RESUMEN

AIMS/HYPOTHESIS: Hypoglycaemia is a common side effect of insulin and some other antihyperglycaemic agents used to treat diabetes. Severe hypoglycaemia has been associated with adverse cardiovascular events in trials of intensive glycaemic control in type 2 diabetes. The relationship between non-severe hypoglycaemic episodes (NSHEs) and severe hypoglycaemia in type 2 diabetes has been documented. However, an association between more frequent NSHEs and cardiovascular events has not been verified. This post hoc analysis of the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial aimed to confirm whether there is an association between NSHEs and severe hypoglycaemic episodes in individuals with type 2 diabetes. In addition, the possible association between NSHEs and major adverse cardiac events (MACE), cardiovascular death and all-cause mortality was investigated. METHODS: LEADER was a double-blind, multicentre, placebo-controlled trial that found that liraglutide significantly reduced the risk of MACE compared with the placebo. In this post hoc analysis, we explored, in all LEADER participants, whether the annual rate of NSHEs (defined as self-measured plasma glucose <3.1 mmol/l [56 mg/dl]) was associated with time to first severe hypoglycaemic episode (defined as an episode requiring the assistance of another person), time to first MACE, time to cardiovascular death and time to all-cause mortality. Participants with <2 NSHEs per year were used as reference for HR estimates. Cox regression with a time-varying covariate was used. RESULTS: We demonstrate that there is an association between NSHEs (2-11 NSHEs per year and ≥12 NSHEs per year) and severe hypoglycaemic episodes (unadjusted HRs 1.98 [95% CI 1.43, 2.75] and 5.01 [95% CI 2.84, 8.84], respectively), which was consistent when baseline characteristics were accounted for. Additionally, while no association was found between participants with 2-11 NSHEs per year and adverse cardiovascular outcomes, higher rates of NSHEs (≥12 episodes per year) were associated with higher risk of MACE (HR 1.50 [95% CI 1.01, 2.23]), cardiovascular death (HR 2.08 [95% CI 1.17, 3.70]) and overall death (HR 1.80 [95% CI 1.11, 2.92]). CONCLUSIONS/INTERPRETATION: The analysis of data from the LEADER trial demonstrated that higher rates of NSHEs were associated with both a higher risk of severe hypoglycaemia and adverse cardiovascular outcomes in individuals with type 2 diabetes. Therefore, irrespective of the cause of this association, it is important that individuals with high rates of hypoglycaemia are identified so that the potentially increased risk of cardiovascular events can be managed and steps can be taken to reduce NSHEs. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01179048).


Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Hipoglucemia , Enfermedades Cardiovasculares/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Hipoglucemiantes/efectos adversos , Insulina/uso terapéutico
3.
Prostate ; 81(10): 683-693, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33956343

RESUMEN

BACKGROUND: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer). METHODS: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer. A dense-module-searching method identified modules enriched with significant genes from a genome-wide association study (GWAS) study in a discovery data set, Physicians' Health Study and Health Professionals Follow-up Study (PHS/HPFS). The top 48 candidate single nucleotide polymorphisms (SNPs) from the dense-module-searching method were then assessed in an independent prostate cancer cohort and the one SNP reproducibly associated with lethality was tested in a third cohort. Logistic regression models evaluated the association between each SNP and lethal prostate cancer. The candidate SNP was assessed for association with lethal prostate cancer in 6 of 28 studies in the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) Consortium where there was some medical record review for death ascertainment which also had SNP data from the ONCOARRAY platform. All men self-identified as Caucasian. RESULTS: The rs1910301 SNP which was reproducibly associated with lethal disease was nominally associated with lethal disease (odds ratio [OR] = 1.40; p = .02) in the discovery cohort and the minor allele was also associated with lethal disease in two independent cohorts (OR = 1.35; p = .04 and OR = 1.35; p = .07). Fixed effects meta-analysis of all three cohorts found an association: OR = 1.37 (95% confidence interval [CI]: 1.15-1.62, p = .0003). This SNP is in the promoter region of FRAS1, a gene involved in epidermal-basement membrane adhesion and is present at a higher frequency in men with African ancestry. No association was found in the subset of studies from the PRACTICAL consortium studies which had a total of 106 deaths out total of 3263 patients and a median follow-up of 4.4 years. CONCLUSIONS: Through its connection with the NFκB pathway, a candidate SNP with a higher frequency in men of African ancestry without cancer was found to be associated with lethal prostate cancer across three well-annotated independent cohorts of Caucasian men.


Asunto(s)
Proteínas de la Matriz Extracelular/genética , Estudios de Asociación Genética/métodos , Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , Neoplasias de la Próstata/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/diagnóstico
4.
BMC Med Inform Decis Mak ; 21(1): 164, 2021 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-34016120

RESUMEN

BACKGROUND: Robust identification of surrogate endpoints can help accelerate the development of pharmacotherapies for diseases traditionally evaluated using true endpoints associated with prolonged follow-up. The meta-analysis-based surrogate endpoint evaluation (SEE) integrates data from multiple, usually smaller, trials to statistically confirm a surrogate endpoint as a robust proxy for the true endpoint. To test the applicability of SEE when only a single, larger trial is available, we analysed the cardiovascular (CV) survival endpoint from the large multinational trial LEADER (9340 subjects) that confirmed the CV safety of a diabetes drug (liraglutide). We evaluated if using country as a trial unit adequately facilitated the meta-analysis and calculation of R2 by country group. METHODS: Data were grouped by country, ensuring at least 30 CV deaths (497 in total) in each of the nine resulting by-country groups. In a two-step SEE on the grouped dataset, we first fitted the group-specific Cox proportional hazard models; next, on the trial-level, we regressed the estimated hazard ratio (HR; liraglutide vs placebo) of the true endpoints (CV death: 497 events, or all-cause death: 828 events) on the HR of the surrogate endpoint (major CV adverse event [MACE]: 1302 events) and derived the group-specific R2 and its 95% confidence interval (CI). RESULTS: Group-level surrogacy of MACE was supported for CV death but not for all-cause death, with [Formula: see text] values of 0.85 [0.63;1.00]95% CI and 0.23 [0.00;0.67]95% CI, respectively. Sensitivity analyses using different grouping approaches (e.g. grouping by region) corroborated the robustness of the conclusions as well as the appropriateness of the data-grouping approaches. CONCLUSIONS: We derived a specific grouping approach to successfully apply SEE on data from a single trial. This may allow for the statistically robust identification and validation of surrogate endpoints based on the abundance of large monolithic outcome trials conducted as part of drug development programmes in, for example, diabetes.


Asunto(s)
Biometría , Hipoglucemiantes , Biomarcadores , Humanos , Modelos de Riesgos Proporcionales , Ensayos Clínicos Controlados Aleatorios como Asunto
5.
Diabetes Obes Metab ; 22(9): 1537-1547, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32314525

RESUMEN

AIMS: To validate the clusters of Swedish individuals with recent-onset diabetes at differential risk of complications, which were identified in a previous study, in three global populations with long-standing type 2 diabetes (T2D) who were at high cardiovascular risk, and to test for differences in the risk of major diabetes complications and survival endpoints. MATERIALS AND METHODS: We assigned participants from recent global outcomes trials (DEVOTE [n = 7637], LEADER [n = 9340] and SUSTAIN-6 [n = 3297]) to the previously defined clusters according to age at diabetes diagnosis, baseline glycated haemoglobin (HbA1c) and body mass index (BMI). Outcomes were assessed using Kaplan-Meier analysis and log-rank tests. RESULTS: The T2D clusters were consistently replicated across the three trial cohorts. The risk of major adverse cardiovascular events and cardiovascular death differed significantly, in all trials, across clusters over a median follow-up duration of 2.0, 3.8 and 2.1 years, respectively, and was highest for the cluster of participants with high HbA1c and low BMI (P < 0.05 in DEVOTE and LEADER). In LEADER and SUSTAIN-6, the risk of nephropathy differed across clusters (P < 0.0001 and P = 0.003, respectively). The risk of severe hypoglycaemia differed in DEVOTE (P = 0.006). CONCLUSIONS: Previously identified clusters can be replicated in three geographically diverse cohorts of long-standing T2D and are associated with cluster-specific risk profiles for additional clinical and survival outcomes, providing further validation of the clustering methodology. The external validity and stability of clusters across cohorts provides a premise for future work to optimize the clustering approach to yield T2D subgroups with maximum predictive validity who may benefit from subtype-specific treatment paradigms.


Asunto(s)
Complicaciones de la Diabetes , Diabetes Mellitus Tipo 2 , Hipoglucemia , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Hemoglobina Glucada , Humanos , Hipoglucemiantes
6.
Eur J Nutr ; 59(7): 2929-2937, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31705265

RESUMEN

PURPOSE: The evidence from the literature regarding the association of dietary factors and risk of prostate cancer is inconclusive. METHODS: A nutrient-wide association study was conducted to systematically and comprehensively evaluate the associations between 92 foods or nutrients and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox proportional hazard regression models adjusted for total energy intake, smoking status, body mass index, physical activity, diabetes and education were used to estimate hazard ratios and 95% confidence intervals for standardized dietary intakes. As in genome-wide association studies, correction for multiple comparisons was applied using the false discovery rate (FDR < 5%) method and suggested results were replicated in an independent cohort, the Netherlands Cohort Study (NLCS). RESULTS: A total of 5916 and 3842 incident cases of prostate cancer were diagnosed during a mean follow-up of 14 and 20 years in EPIC and NLCS, respectively. None of the dietary factors was associated with the risk of total prostate cancer in EPIC (minimum FDR-corrected P, 0.37). Null associations were also observed by disease stage, grade and fatality, except for positive associations observed for intake of dry cakes/biscuits with low-grade and butter with aggressive prostate cancer, respectively, out of which the intake of dry cakes/biscuits was replicated in the NLCS. CONCLUSIONS: Our findings provide little support for an association for the majority of the 92 examined dietary factors and risk of prostate cancer. The association of dry cakes/biscuits with low-grade prostate cancer warrants further replication given the scarcity in the literature.


Asunto(s)
Estudio de Asociación del Genoma Completo , Neoplasias de la Próstata , Estudios de Cohortes , Dieta , Europa (Continente)/epidemiología , Humanos , Masculino , Países Bajos/epidemiología , Nutrientes , Estudios Prospectivos , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/etiología , Factores de Riesgo
7.
Genomics ; 111(1): 10-16, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-26902887

RESUMEN

This study examined whether differential DNA methylation is associated with clinical features of more aggressive disease at diagnosis and prostate cancer recurrence in African American men, who are more likely to die from prostate cancer than other populations. Tumor tissues from 76 African Americans diagnosed with prostate cancer who had radical prostatectomy as their primary treatment were profiled for epigenome-wide DNA methylation levels. Long-term follow-up identified 19 patients with prostate cancer recurrence. Twenty-three CpGs were differentially methylated (FDR q≤0.25, mean methylation difference≥0.10) in patients with vs. without recurrence, including CpGs in GCK, CDKL2, PRDM13, and ZFR2. Methylation differences were also observed between men with metastatic-lethal prostate cancer vs. no recurrence (five CpGs), regional vs. local pathological stage (two CpGs), and higher vs. lower tumor aggressiveness (one CpG). These results indicate that differentially methylated CpG sites identified in tumor tissues of African American men may contribute to prostate cancer aggressiveness.


Asunto(s)
Negro o Afroamericano , Metilación de ADN , Progresión de la Enfermedad , Neoplasias de la Próstata/etnología , Neoplasias de la Próstata/genética , Adulto , Anciano , Islas de CpG , Epigenómica , Perfil Genético , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Supervivencia sin Progresión , Prostatectomía , Neoplasias de la Próstata/terapia
8.
Hum Mol Genet ; 25(24): 5490-5499, 2016 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-27798103

RESUMEN

Molecular and epidemiological differences have been described between TMPRSS2:ERG fusion-positive and fusion-negative prostate cancer (PrCa). Assuming two molecularly distinct subtypes, we have examined 27 common PrCa risk variants, previously identified in genome-wide association studies, for subtype specific associations in a total of 1221 TMPRSS2:ERG phenotyped PrCa cases. In meta-analyses of a discovery set of 552 cases with TMPRSS2:ERG data and 7650 unaffected men from five centers we have found support for the hypothesis that several common risk variants are associated with one particular subtype rather than with PrCa in general. Risk variants were analyzed in case-case comparisons (296 TMPRSS2:ERG fusion-positive versus 256 fusion-negative cases) and an independent set of 669 cases with TMPRSS2:ERG data was established to replicate the top five candidates. Significant differences (P < 0.00185) between the two subtypes were observed for rs16901979 (8q24) and rs1859962 (17q24), which were enriched in TMPRSS2:ERG fusion-negative (OR = 0.53, P = 0.0007) and TMPRSS2:ERG fusion-positive PrCa (OR = 1.30, P = 0.0016), respectively. Expression quantitative trait locus analysis was performed to investigate mechanistic links between risk variants, fusion status and target gene mRNA levels. For rs1859962 at 17q24, genotype dependent expression was observed for the candidate target gene SOX9 in TMPRSS2:ERG fusion-positive PrCa, which was not evident in TMPRSS2:ERG negative tumors. The present study established evidence for the first two common PrCa risk variants differentially associated with TMPRSS2:ERG fusion status. TMPRSS2:ERG phenotyping of larger studies is required to determine comprehensive sets of variants with subtype-specific roles in PrCa.


Asunto(s)
Proteínas de Fusión Oncogénica/genética , Neoplasias de la Próstata/genética , Serina Endopeptidasas/genética , Regulación Neoplásica de la Expresión Génica/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Hibridación Fluorescente in Situ , Masculino , Neoplasias de la Próstata/patología , Sitios de Carácter Cuantitativo/genética , Regulador Transcripcional ERG/genética
9.
Prostate ; 2018 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-29956356

RESUMEN

BACKGROUND: Prognostic biomarkers for localized prostate cancer (PCa) could improve personalized medicine. Our group previously identified a panel of differentially methylated CpGs in primary tumor tissue that predict disease aggressiveness, and here we further validate these biomarkers. METHODS: Pyrosequencing was used to assess CpG methylation of eight biomarkers previously identified using the HumanMethylation450 array; CpGs with strongly correlated (r >0.70) results were considered technically validated. Logistic regression incorporating the validated CpGs and Gleason sum was used to define and lock a final model to stratify men with metastatic-lethal versus non-recurrent PCa in a training dataset. Coefficients from the final model were then used to construct a DNA methylation score, which was evaluated by logistic regression and Receiver Operating Characteristic (ROC) curve analyses in an independent testing dataset. RESULTS: Five CpGs were technically validated and all were retained (P < 0.05) in the final model. The 5-CpG and Gleason sum coefficients were used to calculate a methylation score, which was higher in men with metastatic-lethal progression (P = 6.8 × 10-6 ) in the testing dataset. For each unit increase in the score there was a four-fold increase in risk of metastatic-lethal events (odds ratio, OR = 4.0, 95%CI = 1.8-14.3). At 95% specificity, sensitivity was 74% for the score compared to 53% for Gleason sum alone. The score demonstrated better prediction performance (AUC = 0.91; pAUC = 0.037) compared to Gleason sum alone (AUC = 0.87; pAUC = 0.025). CONCLUSIONS: The DNA methylation score improved upon Gleason sum for predicting metastatic-lethal progression and holds promise for risk stratification of men with aggressive tumors. This prognostic score warrants further evaluation as a tool for improving patient outcomes.

10.
Int J Cancer ; 140(2): 322-328, 2017 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-27741566

RESUMEN

Coffee consumption has been shown in some studies to be associated with lower risk of prostate cancer. However, it is unclear if this association is causal or due to confounding or reverse causality. We conducted a Mendelian randomisation analysis to investigate the causal effects of coffee consumption on prostate cancer risk and progression. We used two genetic variants robustly associated with caffeine intake (rs4410790 and rs2472297) as proxies for coffee consumption in a sample of 46,687 men of European ancestry from 25 studies in the PRACTICAL consortium. Associations between genetic variants and prostate cancer case status, stage and grade were assessed by logistic regression and with all-cause and prostate cancer-specific mortality using Cox proportional hazards regression. There was no clear evidence that a genetic risk score combining rs4410790 and rs2472297 was associated with prostate cancer risk (OR per additional coffee increasing allele: 1.01, 95% CI: 0.98,1.03) or having high-grade compared to low-grade disease (OR: 1.01, 95% CI: 0.97,1.04). There was some evidence that the genetic risk score was associated with higher odds of having nonlocalised compared to localised stage disease (OR: 1.03, 95% CI: 1.01, 1.06). Amongst men with prostate cancer, there was no clear association between the genetic risk score and all-cause mortality (HR: 1.00, 95% CI: 0.97,1.04) or prostate cancer-specific mortality (HR: 1.03, 95% CI: 0.98,1.08). These results, which should have less bias from confounding than observational estimates, are not consistent with a substantial effect of coffee consumption on reducing prostate cancer incidence or progression.


Asunto(s)
Café/efectos adversos , Neoplasias de la Próstata/etiología , Anciano , Alelos , Progresión de la Enfermedad , Variación Genética/genética , Humanos , Masculino , Análisis de la Aleatorización Mendeliana/métodos , Persona de Mediana Edad , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Factores de Riesgo
11.
Prostate ; 77(3): 282-290, 2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27753122

RESUMEN

BACKGROUND: Calcium channel blockers (CCBs) may affect prostate cancer (PCa) growth by various mechanisms including those related to androgens. The fusion of the androgen-regulated gene TMPRSS2 and the oncogene ERG (TMPRSS2:ERG or T2E) is common in PCa, and prostate tumors that harbor the gene fusion are believed to represent a distinct disease subtype. We studied the association of CCB use with the risk of PCa, and molecular subtypes of PCa defined by T2E status. METHODS: Participants were residents of King County, Washington, recruited for population-based case-control studies (1993-1996 or 2002-2005). Tumor T2E status was determined by fluorescence in situ hybridization using tumor tissue specimens from radical prostatectomy. Detailed information on use of CCBs and other variables was obtained through in-person interviews. Binomial and polytomous logistic regression were used to generate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The study included 1,747 PCa patients and 1,635 age-matched controls. A subset of 563 patients treated with radical prostatectomy had T2E status determined, of which 295 were T2E positive (52%). Use of CCBs (ever vs. never) was not associated with overall PCa risk. However, among European-American men, users had a reduced risk of higher-grade PCa (Gleason scores ≥7: adjusted OR = 0.64; 95% CI: 0.44-0.95). Further, use of CCBs was associated with a reduced risk of T2E positive PCa (adjusted OR = 0.38; 95% CI: 0.19-0.78), but was not associated with T2E negative PCa. CONCLUSIONS: This study found suggestive evidence that use of CCBs is associated with reduced relative risks for higher Gleason score and T2E positive PCa. Future studies of PCa etiology should consider etiologic heterogeneity as PCa subtypes may develop through different causal pathways. Prostate 77:282-290, 2017. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Fusión Génica/genética , Vigilancia de la Población , Neoplasias de la Próstata/genética , Serina Endopeptidasas/genética , Anciano , Bloqueadores de los Canales de Calcio/farmacología , Estudios de Casos y Controles , Fusión Génica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Vigilancia de la Población/métodos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Factores de Riesgo , Serina Endopeptidasas/metabolismo , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismo
12.
Cancer ; 122(14): 2168-77, 2016 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-27142338

RESUMEN

BACKGROUND: DNA methylation has been hypothesized as a mechanism for explaining the association between smoking and adverse prostate cancer (PCa) outcomes. This study was aimed at assessing whether smoking is associated with prostate tumor DNA methylation and whether these alterations may explain in part the association of smoking with PCa recurrence and mortality. METHODS: A total of 523 men had radical prostatectomy as their primary treatment, detailed smoking history data, long-term follow-up for PCa outcomes, and tumor tissue profiled for DNA methylation. Ninety percent of the men also had matched tumor gene expression data. A methylome-wide analysis was conducted to identify differentially methylated regions (DMRs) by smoking status. To select potential functionally relevant DMRs, their correlation with the messenger RNA (mRNA) expression of corresponding genes was evaluated. Finally, a smoking-related methylation score based on the top-ranked DMRs was created to assess its association with PCa outcomes. RESULTS: Forty DMRs were associated with smoking status, and 10 of these were strongly correlated with mRNA expression (aldehyde oxidase 1 [AOX1], claudin 5 [CLDN5], early B-cell factor 1 [EBF1], homeobox A7 [HOXA7], lectin galactoside-binding soluble 3 [LGALS3], microtubule-associated protein τ [MAPT], protocadherin γ A [PCDHGA]/protocadherin γ B [PCDHGB], paraoxonase 3 [PON3], synaptonemal complex protein 2 like [SYCP2L], and zinc finger and SCAN domain containing 12 [ZSCAN12]). Men who were in the highest tertile for the smoking-methylation score derived from these DMRs had a higher risk of recurrence (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.42-3.72) and lethal disease (OR, 4.21; 95% CI, 1.65-11.78) in comparison with men in the lower 2 tertiles. CONCLUSIONS: This integrative molecular epidemiology study supports the hypothesis that smoking-associated tumor DNA methylation changes may explain at least part of the association between smoking and adverse PCa outcomes. Future studies are warranted to confirm these findings and understand the implications for improving patient outcomes. Cancer 2016;122:2168-77. © 2016 American Cancer Society.


Asunto(s)
Metilación de ADN , Neoplasias de la Próstata/etiología , Neoplasias de la Próstata/mortalidad , Fumar , Adulto , Anciano , Islas de CpG , Epigénesis Genética , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Mortalidad , Clasificación del Tumor , Recurrencia Local de Neoplasia , Oportunidad Relativa , Evaluación del Resultado de la Atención al Paciente , Pronóstico , Prostatectomía , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/cirugía , Fumar/efectos adversos
13.
Prostate ; 75(16): 1941-50, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26383847

RESUMEN

BACKGROUND: Aberrant DNA methylation may promote prostate carcinogenesis. We investigated epigenome-wide DNA methylation profiles in prostate cancer (PCa) compared to adjacent benign tissue to identify differentially methylated CpG sites. METHODS: The study included paired PCa and adjacent benign tissue samples from 20 radical prostatectomy patients. Epigenetic profiling was done using the Infinium HumanMethylation450 BeadChip. Linear models that accounted for the paired study design and False Discovery Rate Q-values were used to evaluate differential CpG methylation. mRNA expression levels of the genes with the most differentially methylated CpG sites were analyzed. RESULTS: In total, 2,040 differentially methylated CpG sites were identified in PCa versus adjacent benign tissue (Q-value < 0.001), the majority of which were hypermethylated (n = 1,946; 95%). DNA methylation profiles accurately distinguished between PCa and benign tissue samples. Twenty-seven top-ranked hypermethylated CpGs had a mean methylation difference of at least 40% between tissue types, which included 25 CpGs in 17 genes. Furthermore, for 10 genes over 50% of promoter region CpGs were hypermethylated in PCa versus benign tissue. The top-ranked differentially methylated genes included three genes that were associated with both promoter hypermethylation and reduced gene expression: SCGB3A1, HIF3A, and AOX1. Analysis of The Cancer Genome Atlas (TCGA) data provided confirmatory evidence for our findings. CONCLUSIONS: This study of PCa versus adjacent benign tissue showed many differentially methylated CpGs and regions in and outside gene promoter regions, which may potentially be used for the development of future epigenetic-based diagnostic tests or as therapeutic targets.


Asunto(s)
Metilación de ADN , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Próstata/metabolismo , Neoplasias de la Próstata/genética , Islas de CpG , Epigenómica , Humanos , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología
14.
Am J Epidemiol ; 177(12): 1388-98, 2013 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-23722011

RESUMEN

Flavonoids are natural antioxidants found in various foods, and a major source is black tea. Some experimental evidence indicates that flavonoids could prevent prostate cancer. We investigated the associations between flavonoid intake, black tea consumption, and prostate cancer risk in the Netherlands Cohort study, which includes 58,279 men who provided detailed baseline information on several cancer risk factors. From 1986 to 2003, 3,362 prostate cancers were identified, including 1,164 advanced (stage III/IV) cancers. Cox proportional hazards regression using the case-cohort approach was used to estimate hazard ratios and 95% confidence intervals. Intake of total catechin, epicatechin, kaempferol, and myricetin and consumption of black tea were associated with a decreased risk of stage III/IV or stage IV prostate cancer. Hazard ratios of stage III/IV and stage IV prostate cancer for the highest versus the lowest category of black tea consumption (≥5 versus ≤1 cups/day) were 0.75 (95% confidence interval: 0.59, 0.97) and 0.67 (95% confidence interval: 0.50, 0.91), respectively. No associations were observed for overall and nonadvanced prostate cancer. In conclusion, dietary flavonoid intake and black tea consumption were associated with a decreased risk of advanced stage prostate cancer.


Asunto(s)
Antioxidantes/administración & dosificación , Flavonoides/administración & dosificación , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/prevención & control , Anciano , Índice de Masa Corporal , Catequina/administración & dosificación , Estudios de Cohortes , Dieta , Ejercicio Físico , Humanos , Incidencia , Quempferoles/administración & dosificación , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Países Bajos , Modelos de Riesgos Proporcionales , Antígeno Prostático Específico/efectos de los fármacos , Factores de Riesgo , Factores Socioeconómicos ,
15.
Prostate ; 73(11): 1214-22, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23633265

RESUMEN

BACKGROUND: We investigated associations between statin use begun before prostate cancer (PCa) diagnosis and PCa recurrence/progression and PCa-specific mortality (PCSM) in a prospective, population-based cohort study. METHODS: The analysis included 1,001 PCa patients diagnosed in 2002-2005 in King County, Washington. Statin use was assessed at the time of diagnosis using a detailed in-person interview. Prostate cancer recurrence/progression events and cause-specific survival were ascertained from a follow-up survey and the SEER registry. Multivariable competing risk and Cox proportional hazards regression models were used to assess the risk of PCa outcomes according to categories of statin use. RESULTS: Of the 1,001 PCa patients in our study, 289 men were ever users of statin drugs. During follow-up, we identified 151 PCa recurrence/progression events and 123 total deaths, including 39 PCa-specific deaths. In unadjusted analysis, the risk of PCSM was significantly lower for statin users compared to non-users (1% vs. 5% at 10 years; P < 0.01). In multivariable analysis, the adjusted hazard ratio of PCSM for statin users versus non-users was 0.19 (95% CI: 0.06, 0.56). Statin use was not associated with overall PCa recurrence/progression and other-cause mortality. CONCLUSIONS: Statin use begun before PCa diagnosis was unrelated to PCa recurrence/progression but was associated with a decrease in risk of PCSM.


Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Vigilancia de la Población , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/mortalidad , Adulto , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Vigilancia de la Población/métodos , Estudios Prospectivos , Sistema de Registros , Resultado del Tratamiento
16.
Prostate ; 73(7): 734-42, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23143801

RESUMEN

BACKGROUND: While several studies showed that selenium may prevent prostate cancer (PCa), few studies have evaluated variation in selenoenzyme genes in relation to PCa risk and survival. METHODS: We studied common variants in seven selenoenzymes genes in relation to risk of PCa and PCa-specific mortality (PCSM). In a population-based case-control study of men of European ancestry (1,309 cases, 1,266 controls), we evaluated 35 common, tagging single nucleotide polymorphisms (SNPs) in GPX1 (n = 2), GPX2 (n = 4), GPX3 (n = 6), GPX4 (n = 6), SEP15 (n = 4), SEPP1 (n = 6), and TXNRD1 (n = 7) in relation to PCa risk, and among cases, associations between these variants and risk of PCSM. We used logistic regression and Cox proportional hazards regression to estimate the relative risk of PCa and PCSM, respectively. RESULTS: Of the SNPs examined, only GPX1 rs3448 was associated with overall PCa risk with an odds ratio of 0.62 for TT versus CC (95% confidence interval, 0.44-0.88). SNPs in GPX2, GPX3, GPX4, SEP15, and SEPP1 had different risk estimates for PCa in subgroups based on stage and grade. We observed associations between SNPs in GPX4, and TXNRD1 and risk of PCSM. None of these associations, however, remained significant after adjustment for multiple comparisons. CONCLUSIONS: We found evidence that genetic variation in a subset of selenoenzyme genes may alter risk of PCa and PCSM. These results need validation in additional subsets.


Asunto(s)
Glutatión Peroxidasa/genética , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/mortalidad , Selenio/metabolismo , Adulto , Anciano , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Factores de Riesgo
17.
Cancer Causes Control ; 24(5): 941-8, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23412806

RESUMEN

PURPOSE: Tea and coffee contain bioactive compounds and both beverages have recently been associated with a reduced risk of prostate cancer (PCa). METHODS: We studied associations of tea and coffee consumption with PCa risk in a population-based case-control study from King County, Washington, USA. Prostate cancer cases were diagnosed in 2002-2005 and matched to controls by 5-year age groups. Logistic regression was used to generate odds ratios (ORs) and 95 % confidence intervals (CIs). RESULTS: Among controls, 19 and 58 % consumed at least one cup per day of tea and coffee, respectively. The analysis of tea included 892 cases and 863 controls, and tea consumption was associated with a reduced overall PCa risk with an adjusted OR of 0.63 (95 % CI: 0.45, 0.90; P for trend = 0.02) for men in the highest compared to lowest category of tea intake (≥2 cups/day vs. ≤1 cup/week). Risk estimates did not vary substantially by Gleason grade or disease stage. Coffee consumption was not associated with risk of overall PCa or PCa in subgroups defined by tumor grade or stage. CONCLUSIONS: Our results contribute further evidence that tea consumption may be a modifiable exposure that reduces PCa risk.


Asunto(s)
Café/efectos adversos , Neoplasias de la Próstata/epidemiología , Té/efectos adversos , Adulto , Anciano , Cafeína/farmacología , Estudios de Casos y Controles , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Neoplasias de la Próstata/etiología , Factores de Riesgo , Estados Unidos/epidemiología
18.
Cancer Causes Control ; 24(11): 1947-54, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23907772

RESUMEN

BACKGROUND: Bioactive compounds found in coffee and tea may delay the progression of prostate cancer. METHODS: We investigated associations of pre-diagnostic coffee and tea consumption with risk of prostate cancer recurrence/progression. Study participants were men diagnosed with prostate cancer in 2002-2005 in King County, Washington, USA. We assessed the usual pattern of coffee and tea consumption two years before diagnosis date. Prostate cancer-specific outcome events were identified using a detailed follow-up survey. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). RESULTS: The analysis of coffee intake in relation to prostate cancer recurrence/progression included 630 patients with a median follow-up of 6.4 years, during which 140 prostate cancer recurrence/progression events were recorded. Approximately 61 % of patients consumed at least one cup of coffee per day. Coffee consumption was associated with a reduced risk of prostate cancer recurrence/progression; the adjusted HR for ≥4 cups/day versus ≤1 cup/week was 0.41 (95 % CI: 0.20, 0.81; p for trend = 0.01). Approximately 14 % of patients consumed one or more cups of tea per day, and tea consumption was unrelated to prostate cancer recurrence/progression. CONCLUSION: Results indicate that higher pre-diagnostic coffee consumption is associated with a lower risk of prostate cancer recurrence/progression. This finding will require replication in larger studies.


Asunto(s)
Café , Conducta Alimentaria , Neoplasias de la Próstata/diagnóstico , , Adulto , Anciano , Estudios de Casos y Controles , Progresión de la Enfermedad , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia , Pronóstico , Modelos de Riesgos Proporcionales , Neoplasias de la Próstata/epidemiología , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Factores de Riesgo , Programa de VERF/estadística & datos numéricos , Encuestas y Cuestionarios , Washingtón/epidemiología
19.
Metabolism ; 145: 155616, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37302695

RESUMEN

BACKGROUND: Fibroblast growth factor 21 (FGF21) has demonstrated efficacy for reducing liver fat and reversing non-alcoholic steatohepatitis in phase 2 clinical trials. It is also postulated to have anti-fibrotic effects and therefore may be amenable to repurposing for the prevention and treatment of chronic kidney disease (CKD). METHODS: We leverage a missense genetic variant, rs739320 in the FGF21 gene, that associates with magnetic resonance imaging-derived liver fat as a clinically validated and biologically plausible instrumental variable for studying the effects of FGF21 analogs. Performing Mendelian randomization, we ascertain associations between instrumented FGF21 and kidney phenotypes, cardiometabolic disease risk factors, as well as the circulating proteome (Somalogic, 4907 aptamers) and metabolome (Nightingale platform, 249 metabolites). RESULTS: We report consistent renoprotective associations of genetically proxied FGF21 effect, including higher glomerular filtration rates (p = 1.9 × 10-4), higher urinary sodium excretion (p = 5.1 × 10-11), and lower urine albumin-creatinine ratio (p = 3.6 × 10-5). These favorable effects translated to lower CKD risk (odds ratio per rs739320 C-allele, 0.96; 95%CI, 0.94-0.98; p = 3.2 × 10-4). Genetically proxied FGF21 effect was also associated with lower fasting insulin, waist-to-hip ratio, blood pressure (systolic and diastolic BP, p < 1.0 × 10-07) and blood lipid (low-density lipoprotein cholesterol, triglycerides and apolipoprotein B, p < 6.5 × 10-24) profiles. The latter associations are replicated in our metabolome-wide association study. Proteomic perturbations associated with genetically predicted FGF21 effect were consistent with fibrosis reduction. CONCLUSION: This study highlights the pleiotropic effects of genetically proxied FGF21 and supports a re-purposing opportunity for the treatment and prevention of kidney disease specifically. Further work is required to triangulate these findings, towards possible clinical development of FGF21 towards the treatment and prevention of kidney disease.


Asunto(s)
Proteoma , Insuficiencia Renal Crónica , Humanos , Proteoma/genética , Análisis de la Aleatorización Mendeliana , Proteómica , Factores de Crecimiento de Fibroblastos/genética , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/prevención & control , Estudio de Asociación del Genoma Completo
20.
J Thromb Haemost ; 18 Suppl 1: 5-14, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32544297

RESUMEN

BACKGROUND: N8-GP (turoctocog alfa pegol; Esperoct® , Novo Nordisk A/S, Bagsvaerd, Denmark) is a glycoPEGylated human recombinant factor VIII with a half-life of ~1.6-fold of standard FVIII products. pathfinder2 (NCT01480180) was a multi-national, open-label trial of N8-GP in previously treated adolescent and adult patients with severe hemophilia A. OBJECTIVE: We report end-of-trial efficacy and safety of N8-GP from pathfinder2. METHODS: pathfinder2 main phase and extension phase part 1 results have been previously reported. During extension phase part 2, patients could switch from N8-GP prophylaxis 50 IU/kg every fourth day (Q4D) or 75 IU/kg once weekly (Q7D), depending on bleeding status. Extension phase part 2 collected long-term safety and efficacy data for all regimens until trial end (first patient in main phase, 30 January 2012; trial end, 10 December 2018). RESULTS: Overall, 186 patients were exposed to N8-GP for up to 6.6 years (median 5.4 years). The estimated annualized bleeding rate (ABR) was 2.14 (median 0.84) for the Q4D prophylaxis arm and 1.31 (median 1.67) for the Q7D prophylaxis arm. Nearly 30% of patients experienced zero bleeds throughout the entire duration of the trial, the hemostatic response was 83.2% across all treatment arms, and patient-reported outcomes were maintained or slightly improved. No safety concerns were detected. CONCLUSION: Data from the completed pathfinder2 trial, one of the largest and longest-running clinical trials to investigate treatment of severe hemophilia A, demonstrate the efficacy and safety of N8-GP in previously treated adolescent and adult patients.


Asunto(s)
Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Hemorragia/inducido químicamente , Adolescente , Adulto , Factor VIII/efectos adversos , Factor VIIa , Semivida , Hemofilia A/diagnóstico , Hemorragia/epidemiología , Hemostasis , Humanos , Medición de Resultados Informados por el Paciente , Resultado del Tratamiento
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