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Michael K. Skinner - One of the best experts on this subject based on the ideXlab platform.
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Vinclozolin induced epigenetic transgenerational inheritance of pathologies and sperm epimutation biomarkers for specific Diseases.
PloS one, 2018Co-Authors: Eric E. Nilsson, Stephanie E. King, Margaux Mcbirney, Daniel Beck, Ingrid Sadler-riggleman, Michelle Pappalardo, Deepika Kubsad, Michael K. SkinnerAbstract:Exposure to vinclozolin has been shown to induce the epigenetic transgenerational inheritance of increased susceptibility to Disease, and to induce transgenerational changes to the epigenome. In the current study, gestating F0 generation rats were exposed to vinclozolin, and the subsequent F1, F2 and transgenerational F3 generations were evaluated for Diseases and pathologies. F1 and F2 generation rats exhibited few abnormalities. However, F3 generation rats showed transgenerational increases in testis, Prostate, and kidney Disease, changes in the age of puberty onset in males, and an increased obesity rate in females. Overall there was an increase in the rate of animals with Disease, and in the incidence of animals with multiple Diseases. The objective of the current study was to analyze the sperm epigenome of F3 generation rats with specific abnormalities and compare them to rats without those abnormalities, in an effort to find epigenetic biomarkers of transgenerational Disease. Unique signatures of differential DNA methylation regions (DMRs) in sperm were found that associated with testis Disease, Prostate Disease and kidney Disease. Confounding factors identified were the presence of multiple Diseases in the analysis and the limited number of animals without Disease. These results further our understanding of the mechanisms governing epigenetic transgenerational inheritance, and may lead in the future to the use of epigenetic biomarkers that will help predict an individual’s susceptibility for specific Diseases.
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ancestral dichlorodiphenyltrichloroethane ddt exposure promotes epigenetic transgenerational inheritance of obesity
BMC Medicine, 2013Co-Authors: Michael K. Skinner, Mohan Manikkam, Rebecca Tracey, Carlos Guerrerobosagna, Muksitul Haque, Eric E. NilssonAbstract:Ancestral environmental exposures to a variety of environmental factors and toxicants have been shown to promote the epigenetic transgenerational inheritance of adult onset Disease. The present work examined the potential transgenerational actions of the insecticide dichlorodiphenyltrichloroethane (DDT) on obesity and associated Disease. Outbred gestating female rats were transiently exposed to a vehicle control or DDT and the F1 generation offspring bred to generate the F2 generation and F2 generation bred to generate the F3 generation. The F1 and F3 generation control and DDT lineage rats were aged and various pathologies investigated. The F3 generation male sperm were collected to investigate methylation between the control and DDT lineage male sperm. The F1 generation offspring (directly exposed as a fetus) derived from the F0 generation exposed gestating female rats were not found to develop obesity. The F1 generation DDT lineage animals did develop kidney Disease, Prostate Disease, ovary Disease and tumor development as adults. Interestingly, the F3 generation (great grand-offspring) had over 50% of males and females develop obesity. Several transgenerational Diseases previously shown to be associated with metabolic syndrome and obesity were observed in the testis, ovary and kidney. The transgenerational transmission of Disease was through both female (egg) and male (sperm) germlines. F3 generation sperm epimutations, differential DNA methylation regions (DMR), induced by DDT were identified. A number of the genes associated with the DMR have previously been shown to be associated with obesity. Observations indicate ancestral exposure to DDT can promote obesity and associated Disease transgenerationally. The etiology of Disease such as obesity may be in part due to environmentally induced epigenetic transgenerational inheritance.
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plastics derived endocrine disruptors bpa dehp and dbp induce epigenetic transgenerational inheritance of obesity reproductive Disease and sperm epimutations
PLOS ONE, 2013Co-Authors: Mohan Manikkam, Rebecca Tracey, Carlos Guerrerobosagna, Michael K. SkinnerAbstract:Environmental compounds are known to promote epigenetic transgenerational inheritance of adult onset Disease in subsequent generations (F1–F3) following ancestral exposure during fetal gonadal sex determination. The current study was designed to determine if a mixture of plastic derived endocrine disruptor compounds bisphenol-A (BPA), bis(2-ethylhexyl)phthalate (DEHP) and dibutyl phthalate (DBP) at two different doses promoted epigenetic transgenerational inheritance of adult onset Disease and associated DNA methylation epimutations in sperm. Gestating F0 generation females were exposed to either the “plastics” or “lower dose plastics” mixture during embryonic days 8 to 14 of gonadal sex determination and the incidence of adult onset Disease was evaluated in F1 and F3 generation rats. There were significant increases in the incidence of total Disease/abnormalities in F1 and F3 generation male and female animals from plastics lineages. Pubertal abnormalities, testis Disease, obesity, and ovarian Disease (primary ovarian insufficiency and polycystic ovaries) were increased in the F3 generation animals. Kidney and Prostate Disease were only observed in the direct fetally exposed F1 generation plastic lineage animals. Analysis of the plastics lineage F3 generation sperm epigenome previously identified 197 differential DNA methylation regions (DMR) in gene promoters, termed epimutations. A number of these transgenerational DMR form a unique direct connection gene network and have previously been shown to correlate with the pathologies identified. Observations demonstrate that a mixture of plastic derived compounds, BPA and phthalates, can promote epigenetic transgenerational inheritance of adult onset Disease. The sperm DMR provide potential epigenetic biomarkers for transgenerational Disease and/or ancestral environmental exposures.
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epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome
PLOS ONE, 2010Co-Authors: Carlos Guerrerobosagna, Matthew L Settles, Ben F Lucker, Michael K. SkinnerAbstract:Previous observations have demonstrated that embryonic exposure to the endocrine disruptor vinclozolin during gonadal sex determination promotes transgenerational adult onset Disease such as male infertility, kidney Disease, Prostate Disease, immune abnormalities and tumor development. The current study investigates genome-wide promoter DNA methylation alterations in the sperm of F3 generation rats whose F0 generation mother was exposed to vinclozolin. A methylated DNA immunoprecipitation with methyl-cytosine antibody followed by a promoter tilling microarray (MeDIP-Chip) procedure was used to identify 52 different regions with statistically significant altered methylation in the sperm promoter epigenome. Mass spectrometry bisulfite analysis was used to map the CpG DNA methylation and 16 differential DNA methylation regions were confirmed, while the remainder could not be analyzed due to bisulfite technical limitations. Analysis of these validated regions identified a consensus DNA sequence (motif) that associated with 75% of the promoters. Interestingly, only 16.8% of a random set of 125 promoters contained this motif. One candidate promoter (Fam111a) was found to be due to a copy number variation (CNV) and not a methylation change, suggesting initial alterations in the germline epigenome may promote genetic abnormalities such as induced CNV in later generations. This study identifies differential DNA methylation sites in promoter regions three generations after the initial exposure and identifies common genome features present in these regions. In addition to primary epimutations, a potential indirect genetic abnormality was identified, and both are postulated to be involved in the epigenetic transgenerational inheritance observed. This study confirms that an environmental agent has the ability to induce epigenetic transgenerational changes in the sperm epigenome.
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epigenetic programming of the germ line effects of endocrine disruptors on the development of transgenerational Disease
Reproductive Biomedicine Online, 2008Co-Authors: Matthew D. Anway, Michael K. SkinnerAbstract:Epigenetic programming of the germ line occurs during embryonic development in a sex-specific manner. The male germ line becomes imprinted following sex determination. Environmental influences can alter this epigenetic programming and affect not only the developing offspring, but also potentially subsequent generations. Exposure to an endocrine disruptor (i.e. vinclozolin) during embryonic gonadal sex determination can alter the male germ-line epigenetics (e.g. DNA methylation). The epigenetic mechanism involves the alteration of DNA methylation in the germ line that appears to transmit transgenerational adult onset Disease, including spermatogenic defects, Prostate Disease, kidney Disease and cancer.
Judd W Moul - One of the best experts on this subject based on the ideXlab platform.
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optimized Prostate biopsy via a statistical atlas of cancer spatial distribution
Medical Image Analysis, 2004Co-Authors: Dinggang Shen, Jianchao Zeng, Wei Zhang, Isabel A Sesterhenn, Judd W Moul, Edward H Herskovits, Gabor Fichtinger, Christos DavatzikosAbstract:A methodology is presented for constructing a statistical atlas of spatial distribution of Prostate cancer from a large patient cohort, and it is used for optimizing needle biopsy. An adaptive-focus deformable model is used for the spatial normalization and registration of 100 Prostate histological samples, which were provided by the Center for Prostate Disease Research of the US Department of Defense, resulting in a statistical atlas of spatial distribution of Prostate cancer. Based on this atlas, a statistical predictive model was developed to optimize the needle biopsy sites, by maximizing the probability of detecting cancer. Experimental results using cross-validation show that the proposed method can detect cancer with a 99% success rate using seven needles, in these samples.
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early versus delayed hormonal therapy for Prostate specific antigen only recurrence of Prostate cancer after radical Prostatectomy
The Journal of Urology, 2004Co-Authors: David G. Mcleod, Christopher L Amling, Judd W Moul, Leon Sun, Leo Kusuda, Timothy R Donahue, Wade J Sexton, Keith J Oreilly, Javier HernandezAbstract:AbstractPurpose: Hormonal therapy (HT) is the current mainstay of systemic treatment for Prostate specific antigen (PSA) only recurrence (PSAR), however, there is virtually no published literature comparing HT to observation in the clinical setting. The goal of this study was to examine the Department of Defense Center for Prostate Disease Research observational database to compare clinical outcomes in men who experienced PSAR after radical Prostatectomy by early versus delayed use of HT and by a risk stratified approach.Materials and Methods: Of 5,382 men in the database who underwent primary radical Prostatectomy (RP), 4,967 patients were treated in the PSA-era between 1988 and December 2002. Of those patients 1,352 men who had PSAR (PSA after surgery greater than 0.2 ng/ml) and had postoperative followup greater than 6 months were used as the study cohort. These patients were further divided into an early HT group in which patients (355) received HT after PSA only recurrence but before clinical metasta...
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factors associated with blood loss during radical Prostatectomy for localized Prostate cancer in the Prostate specific antigen psa era an overview of the department of defense dod center for Prostate Disease research cpdr national database
Urologic Oncology-seminars and Original Investigations, 2003Co-Authors: David G. Mcleod, Christopher L Amling, Judd W Moul, Leon Sun, Raymond S Lance, John P FoleyAbstract:Radical Prostatectomy (RP) has been traditionally associated with significant operative blood loss and high risk of transfusion. However, over the last few years, centers of excellence have reported less bleeding and transfusion. To verify and document changes in the epidemiology of bleeding and transfusion of men electing RP, we undertook an analysis of such cases in the Department of Defense (DoD) Center for Prostate Disease Research (CPDR) Multicenter Research Database. Using the Department of Defense Center for Prostate Disease Research (CPDR) Multicenter National Research Database, a query of all RPs performed between January 1, 1985 and December 31, 2000 was conducted revealing 2918 cases with blood-loss data available for analysis from nine hospital sites. These cases were analyzed over time (calendar year) and changes in the characteristics of the patients, Disease severity, and surgical results were compared with estimated blood loss (EBL) and transfusion data. Among the 2918 evaluable men, 2399 (82%) underwent a retropubic RP, 97% had clinical T1-2 Disease, and 77% had a PSA level > or =10.0 ng/mL. Overall median operation time was 3.8 h, and EBL was 1000 cc. Examining trends over time, there was a dramatic decline in median operative time, EBL, and transfusion rate. In multiple linear regression analysis, operative time, operative approach, surgery year, lymphadenectomy status, and neoadjuvant hormonal therapy were significant predictor of EBL. Blood loss difference between retropubic and perineal RP became insignificant in the latter years. Radical Prostatectomy is being performed more commonly on men with earlier stage Disease in the PSA-Era. The operation is now performed more rapidly with less blood loss and fewer transfusion requirements. In a broad practice experience represented here, autologous blood donation would appear to be unnecessary for the majority of men and the blood loss advantage traditionally associated with perineal RP is no longer evident.
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improved Prostate cancer specific survival and other Disease parameters impact of Prostate specific antigen testing
Urology, 2002Co-Authors: Edmond L Paquette, David G. Mcleod, Judd W Moul, Roger R Connelly, Laurence R PaquetteAbstract:OBJECTIVES: To determine how the implementation of Prostate-specific antigen (PSA) testing has affected Disease-specific survival and other characteristics of Prostate cancer. METHODS: Data were collected on all patients with Prostate cancer diagnosed between 1988 and 1998 and registered in the Center for Prostate Disease Research Database at Walter Reed Army Medical Center. Statistical analyses were used to summarize trends over time in survival, mortality, and clinical stage. RESULTS: Between 1988 and 1998, a total of 2042 patients with Prostate cancer were registered at Walter Reed Army Medical Center. The 5-year Disease-specific survival rate was 86.9% and 93.7% for patients diagnosed in the respective year groups of 1988 to 1991 and 1992 to 1994, with follow-up through December 1, 2000 (P < 0.001). Prostate cancer was the cause of death for 37.5% of the patients in 1988 to 1989 versus 15.4% in 1999 to 2000. Marked stage migration has occurred; from 1988 to 1998, the percentage of patients presenting with metastatic Disease decreased from 14.1% to 3.3% (P < 0.001). CONCLUSIONS: A statistically significant improved 5-year Disease-specific survival and a decreased chance of dying from Prostate cancer has occurred after the widespread implementation of PSA. We suspect that PSA testing has resulted in fewer patients presenting with metastatic Disease and more patients presenting with localized Disease amenable to curative treatment. This portends well for the use of PSA screening to improve outcomes for Prostate cancer. However, randomized trials are needed to confirm the improvements in survival and mortality.
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epidemiology of radical Prostatectomy for localized Prostate cancer in the era of Prostate specific antigen an overview of the department of defense center for Prostate Disease research national database
Surgery, 2002Co-Authors: Judd W Moul, David G. Mcleod, Christopher L Amling, Leon Sun, Leo Kusuda, Raymond S Lance, John P Foley, Hongyu Wu, Timothy R Donahue, Andrew ChungAbstract:Abstract Background. Because of public awareness and screening, the incidence of clinically localized Prostate cancer has increased dramatically in the last 15 years. The Department of Defense Center for Prostate Disease Research (CPDR) was established by the US Congress in 1991 to study Prostate cancer in the US military health care system. A key component of CPDR is a multicenter prospective and retrospective Prostate research database that collects comprehensive standardized data on all consenting patients. To verify and document changes in the epidemiology of men electing radical Prostatectomy (RP) as primary treatment for their localized Prostate cancer, we undertook an analysis of such cases when the PSA screening test became widely available and used. Methods. The CPDR database consists of standardized data collection forms for each episode of care completed prospectively, and in some cases, retrospectively, on men with Prostate cancer and those undergoing a Prostate biopsy for presumed cancer at participating medical centers. In July 2001, a query of all RPs performed between January 1, 1991, and December 31, 2000, was conducted, revealing 3681 cases for analysis from 9 hospital sites. These cases were analyzed over time (calendar year), and changes in the characteristics of the patients, Disease severity, and surgical results were compared. Results. There was a significant shift to younger men undergoing RP with the median age declining to 62.3 years old by 2000, and more than 40% of the men were less than 60 years old. There was an increase in African-Americans undergoing RP and a large increase in clinical stage T1 Disease candidates of both races representing 56.5% of men by 2000. There was a large increase in patients having pretreatment PSA levels between 4 and 10 ng/mL (59.2% by 2000). Retropubic approach was predominant (over 80%) and was associated with a much lower blood loss by 2000 (approximately 800 mL). There was an increase in use of nerve-sparing procedures, and operative time declined significantly to a median of 3.5 hours by 2000. Finally, there was a marked surgical stage migration with a higher proportion of men with organ-confined Disease and negative surgical margins; by 2000, 63.4% had pT2 Disease. The early outcomes improved with a 1-year Disease-free survival in excess of 93%. Conclusions. RP is being performed more commonly on younger men with earlier stage Disease in the PSA era. The operation is now performed more rapidly with less blood loss, and the surgical pathology outcome end points and early Disease-free survival are improved. These results portend well for improved long-term outcomes of surgical therapy. (Surgery 2002;132:213-9.) Surgery 2002;132:213-9.
David G. Mcleod - One of the best experts on this subject based on the ideXlab platform.
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long term overall survival and metastasis free survival for men with Prostate specific antigen recurrent Prostate cancer after Prostatectomy analysis of the center for Prostate Disease research national database
BJUI, 2011Co-Authors: Emmanuel S. Antonarakis, Yongmei Chen, Mario A. Eisenberger, Sally I. Elsamanoudi, Stephen A. Brassell, Mario V. Da Rocha, David G. McleodAbstract:OBJECTIVE To describe metastasis-free survival (MFS) and overall survival (OS) among men with Prostate-specific antigen (PSA)-recurrent Prostate cancer after radical Prostatectomy who did not receive additional therapy until metastasis, using a multicentre database capturing a wide ethnic mix. PATIENTS AND METHODS A retrospective analysis of the Center for Prostate Disease Research National Database (comprised of five US military hospitals and one civilian centre) was performed for patients with PSA relapse (≥0.2 ng/mL) after radical Prostatectomy who had no additional therapy until the time of radiographic metastatic Disease. We investigated factors influencing metastasis and all-cause mortality using univariate and multivariate Cox regression analysis. RESULTS There were a total of 346 men who underwent radical Prostatectomy between May 1983 and November 2008 and fulfilled the entry criteria. All patients had information on survival and 190 men had information on metastasis. Among patients with survival data (n = 346), 10-year OS was 79% after a median follow-up of 8.6 years from biochemical recurrence. Among men with metastasis data (n = 190), 10-year MFS was 46% after a median follow-up of 7.5 years. In Cox regressions, four clinical factors (Gleason score, pathological stage, time to PSA relapse and PSA doubling time), as well as age, were predictive of OS and/or MFS in univariate analysis, although only PSA doubling time (≥9 vs 3–8.9 vs <3 months) remained independently predictive of these outcomes in multivariate analysis (P < 0.001). CONCLUSIONS This multicentre multi-ethnic dataset shows that OS and MFS can be extensive for men with PSA-recurrent Prostate cancer, even in the absence of further therapy before metastasis. This unique patient cohort, the second largest of its type after the Johns Hopkins cohort, confirms that PSA doubling time is the strongest determinant of OS and MFS in men with PSA-recurrent Disease. Longer follow-up and more events will be required to determine whether other variables may also contribute to these outcomes. Keywords: metastasis-free survival, natural history, overall survival, Prostate cancer, PSA recurrence INTRODUCTION Prostate cancer is the most prevalent malignancy in men worldwide, and accounts for over 200 000 new cases in the USA each year [1]. Although radical Prostatectomy is curative for most patients with localized Prostate cancer, ≈20–40% will experience Disease recurrence by 10 years after surgery [2]. As a result of the universal availability and high sensitivity of PSA testing, most patients with Disease relapse after Prostatectomy present with a rising PSA in the absence of detectable local or distant recurrence. Once PSA progression has occurred, the condition is often incurable, although the clinical course of the Disease may be extensive. There is currently no consensus on the optimal management of non-metastatic PSA-recurrent Prostate cancer [3,4]. Treatment options include continuous androgen deprivation therapy (ADT) initiated at the time of PSA recurrence [5,6], deferred ADT reserved until after the development of metastases [7,8], intermittent ADT [9,10] or enrollment in clinical trials [11]. A subset of patients with PSA-recurrent Disease may be candidates for salvage pelvic irradiation [12]. An understanding of the factors that predict metastatic progression and death is crucial when choosing optimal risk-based therapies for these patients. To help inform treatment decisions for such patients, investigators from Johns Hopkins previously described the natural history of a cohort of patients with PSA-recurrent Disease after Prostatectomy who did not receive additional therapies (such as ADT) until the development of metastases. This unique cohort has been used to estimate metastasis-free survival (MFS) [13,14], Prostate cancer-specific survival [15] and overall survival (OS) [16] in this patient population. In addition, clinical factors influencing these outcomes have been described and can be used to risk-stratify patients. These factors include the surgical Gleason score, the PSA doubling time (PSADT) after biochemical recurrence, and possibly the time from surgery to biochemical recurrence. However, these findings represent data from a single institution and have not been validated elsewhere, primarily because most men with PSA relapse were historically treated with immediate ADT (thus precluding a study of the natural history of these patients). Furthermore, the number of men in the Johns Hopkins cohort that were non-white was very small (≈10%) [14,15], and this may not reflect the true racial mix of Prostate cancer patients. In an effort to confirm and validate the Johns Hopkins natural history data, the present study aimed to describe MFS and OS in a similar population of men with hormone-naive PSA-recurrent Prostate cancer after radical Prostatectomy using information from the Center for Prostate Disease Research (CPDR) National Database [17]. This repository contains patient information from five US military hospitals and one civilian centre, and it includes a larger proportion of non-white men (28%). In addition, the present study aimed to identify risk factors for metastasis and all-cause mortality using this patient population. The ultimate goal was to identify those patients with PSA-recurrent Prostate cancer who may benefit from early systemic therapy and to distinguish them from those in whom a conservative approach may be reasonable.
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early versus delayed hormonal therapy for Prostate specific antigen only recurrence of Prostate cancer after radical Prostatectomy
The Journal of Urology, 2004Co-Authors: David G. Mcleod, Christopher L Amling, Judd W Moul, Leon Sun, Leo Kusuda, Timothy R Donahue, Wade J Sexton, Keith J Oreilly, Javier HernandezAbstract:AbstractPurpose: Hormonal therapy (HT) is the current mainstay of systemic treatment for Prostate specific antigen (PSA) only recurrence (PSAR), however, there is virtually no published literature comparing HT to observation in the clinical setting. The goal of this study was to examine the Department of Defense Center for Prostate Disease Research observational database to compare clinical outcomes in men who experienced PSAR after radical Prostatectomy by early versus delayed use of HT and by a risk stratified approach.Materials and Methods: Of 5,382 men in the database who underwent primary radical Prostatectomy (RP), 4,967 patients were treated in the PSA-era between 1988 and December 2002. Of those patients 1,352 men who had PSAR (PSA after surgery greater than 0.2 ng/ml) and had postoperative followup greater than 6 months were used as the study cohort. These patients were further divided into an early HT group in which patients (355) received HT after PSA only recurrence but before clinical metasta...
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factors associated with blood loss during radical Prostatectomy for localized Prostate cancer in the Prostate specific antigen psa era an overview of the department of defense dod center for Prostate Disease research cpdr national database
Urologic Oncology-seminars and Original Investigations, 2003Co-Authors: David G. Mcleod, Christopher L Amling, Judd W Moul, Leon Sun, Raymond S Lance, John P FoleyAbstract:Radical Prostatectomy (RP) has been traditionally associated with significant operative blood loss and high risk of transfusion. However, over the last few years, centers of excellence have reported less bleeding and transfusion. To verify and document changes in the epidemiology of bleeding and transfusion of men electing RP, we undertook an analysis of such cases in the Department of Defense (DoD) Center for Prostate Disease Research (CPDR) Multicenter Research Database. Using the Department of Defense Center for Prostate Disease Research (CPDR) Multicenter National Research Database, a query of all RPs performed between January 1, 1985 and December 31, 2000 was conducted revealing 2918 cases with blood-loss data available for analysis from nine hospital sites. These cases were analyzed over time (calendar year) and changes in the characteristics of the patients, Disease severity, and surgical results were compared with estimated blood loss (EBL) and transfusion data. Among the 2918 evaluable men, 2399 (82%) underwent a retropubic RP, 97% had clinical T1-2 Disease, and 77% had a PSA level > or =10.0 ng/mL. Overall median operation time was 3.8 h, and EBL was 1000 cc. Examining trends over time, there was a dramatic decline in median operative time, EBL, and transfusion rate. In multiple linear regression analysis, operative time, operative approach, surgery year, lymphadenectomy status, and neoadjuvant hormonal therapy were significant predictor of EBL. Blood loss difference between retropubic and perineal RP became insignificant in the latter years. Radical Prostatectomy is being performed more commonly on men with earlier stage Disease in the PSA-Era. The operation is now performed more rapidly with less blood loss and fewer transfusion requirements. In a broad practice experience represented here, autologous blood donation would appear to be unnecessary for the majority of men and the blood loss advantage traditionally associated with perineal RP is no longer evident.
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improved Prostate cancer specific survival and other Disease parameters impact of Prostate specific antigen testing
Urology, 2002Co-Authors: Edmond L Paquette, David G. Mcleod, Judd W Moul, Roger R Connelly, Laurence R PaquetteAbstract:OBJECTIVES: To determine how the implementation of Prostate-specific antigen (PSA) testing has affected Disease-specific survival and other characteristics of Prostate cancer. METHODS: Data were collected on all patients with Prostate cancer diagnosed between 1988 and 1998 and registered in the Center for Prostate Disease Research Database at Walter Reed Army Medical Center. Statistical analyses were used to summarize trends over time in survival, mortality, and clinical stage. RESULTS: Between 1988 and 1998, a total of 2042 patients with Prostate cancer were registered at Walter Reed Army Medical Center. The 5-year Disease-specific survival rate was 86.9% and 93.7% for patients diagnosed in the respective year groups of 1988 to 1991 and 1992 to 1994, with follow-up through December 1, 2000 (P < 0.001). Prostate cancer was the cause of death for 37.5% of the patients in 1988 to 1989 versus 15.4% in 1999 to 2000. Marked stage migration has occurred; from 1988 to 1998, the percentage of patients presenting with metastatic Disease decreased from 14.1% to 3.3% (P < 0.001). CONCLUSIONS: A statistically significant improved 5-year Disease-specific survival and a decreased chance of dying from Prostate cancer has occurred after the widespread implementation of PSA. We suspect that PSA testing has resulted in fewer patients presenting with metastatic Disease and more patients presenting with localized Disease amenable to curative treatment. This portends well for the use of PSA screening to improve outcomes for Prostate cancer. However, randomized trials are needed to confirm the improvements in survival and mortality.
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epidemiology of radical Prostatectomy for localized Prostate cancer in the era of Prostate specific antigen an overview of the department of defense center for Prostate Disease research national database
Surgery, 2002Co-Authors: Judd W Moul, David G. Mcleod, Christopher L Amling, Leon Sun, Leo Kusuda, Raymond S Lance, John P Foley, Hongyu Wu, Timothy R Donahue, Andrew ChungAbstract:Abstract Background. Because of public awareness and screening, the incidence of clinically localized Prostate cancer has increased dramatically in the last 15 years. The Department of Defense Center for Prostate Disease Research (CPDR) was established by the US Congress in 1991 to study Prostate cancer in the US military health care system. A key component of CPDR is a multicenter prospective and retrospective Prostate research database that collects comprehensive standardized data on all consenting patients. To verify and document changes in the epidemiology of men electing radical Prostatectomy (RP) as primary treatment for their localized Prostate cancer, we undertook an analysis of such cases when the PSA screening test became widely available and used. Methods. The CPDR database consists of standardized data collection forms for each episode of care completed prospectively, and in some cases, retrospectively, on men with Prostate cancer and those undergoing a Prostate biopsy for presumed cancer at participating medical centers. In July 2001, a query of all RPs performed between January 1, 1991, and December 31, 2000, was conducted, revealing 3681 cases for analysis from 9 hospital sites. These cases were analyzed over time (calendar year), and changes in the characteristics of the patients, Disease severity, and surgical results were compared. Results. There was a significant shift to younger men undergoing RP with the median age declining to 62.3 years old by 2000, and more than 40% of the men were less than 60 years old. There was an increase in African-Americans undergoing RP and a large increase in clinical stage T1 Disease candidates of both races representing 56.5% of men by 2000. There was a large increase in patients having pretreatment PSA levels between 4 and 10 ng/mL (59.2% by 2000). Retropubic approach was predominant (over 80%) and was associated with a much lower blood loss by 2000 (approximately 800 mL). There was an increase in use of nerve-sparing procedures, and operative time declined significantly to a median of 3.5 hours by 2000. Finally, there was a marked surgical stage migration with a higher proportion of men with organ-confined Disease and negative surgical margins; by 2000, 63.4% had pT2 Disease. The early outcomes improved with a 1-year Disease-free survival in excess of 93%. Conclusions. RP is being performed more commonly on younger men with earlier stage Disease in the PSA era. The operation is now performed more rapidly with less blood loss, and the surgical pathology outcome end points and early Disease-free survival are improved. These results portend well for improved long-term outcomes of surgical therapy. (Surgery 2002;132:213-9.) Surgery 2002;132:213-9.
Matthew D. Anway - One of the best experts on this subject based on the ideXlab platform.
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Transgenerational effects of the endocrine disruptor vinclozolin on the Prostate transcriptome and adult onset Disease.
The Prostate, 2008Co-Authors: Matthew D. AnwayAbstract:PURPOSE The ability of an endocrine disruptor exposure during gonadal sex determination to promote a transgenerational Prostate Disease phenotype was investigated in the current study. METHODS Exposure of an F0 gestating female rat to the endocrine disruptor vinclozolin during F1 embryo gonadal sex determination promoted a transgenerational adult onset Prostate Disease phenotype. The Prostate Disease phenotype and physiological parameters were determined for males from F1 to F4 generations and the Prostate transcriptome was assessed in the F3 generation. RESULTS Although the Prostate in prepubertal animals develops normally, abnormalities involving epithelial cell atrophy, glandular dysgenesis, prostatitis, and hyperplasia of the ventral Prostate develop in older animals. The ventral Prostate phenotype was transmitted for four generations (F1–F4). Analysis of the ventral Prostate transcriptome demonstrated 954 genes had significantly altered expression between control and vinclozolin F3 generation animals. Analysis of isolated ventral Prostate epithelial cells identified 259 genes with significantly altered expression between control and vinclozolin F3 generation animals. Characterization of regulated genes demonstrated several cellular pathways were influenced, including calcium and WNT. A number of genes identified have been shown to be associated with Prostate Disease and cancer, including beta-microseminoprotein (Msp) and tumor necrosis factor receptor superfamily 6 (Fadd). CONCLUSIONS The ability of an endocrine disruptor to promote transgenerational Prostate abnormalities appears to involve an epigenetic transgenerational alteration in the Prostate transcriptome and male germ-line. Potential epigenetic transgenerational alteration of Prostate gene expression by environmental compounds may be important to consider in the etiology of adult onset Prostate Disease. Prostate 68: 517–529, 2008. © 2008 Wiley-Liss, Inc.
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epigenetic programming of the germ line effects of endocrine disruptors on the development of transgenerational Disease
Reproductive Biomedicine Online, 2008Co-Authors: Matthew D. Anway, Michael K. SkinnerAbstract:Epigenetic programming of the germ line occurs during embryonic development in a sex-specific manner. The male germ line becomes imprinted following sex determination. Environmental influences can alter this epigenetic programming and affect not only the developing offspring, but also potentially subsequent generations. Exposure to an endocrine disruptor (i.e. vinclozolin) during embryonic gonadal sex determination can alter the male germ-line epigenetics (e.g. DNA methylation). The epigenetic mechanism involves the alteration of DNA methylation in the germ line that appears to transmit transgenerational adult onset Disease, including spermatogenic defects, Prostate Disease, kidney Disease and cancer.
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epigenetic transgenerational actions of vinclozolin on the development of Disease and cancer
Critical Reviews in Oncogenesis, 2007Co-Authors: Michael K. Skinner, Matthew D. AnwayAbstract:Exposure to an environmental endocrine disruptor (e.g., vinclozolin) dur- ing embryonic gonadal sex determination appears to alter the male germ line epigenome and subsequently promotes transgenerational adult onset Disease. The epigenetic mecha- nism involves the induction of new imprinted-like genes/DNA sequences in the germ line that appear to transmit Disease phenotypes. The Disease phenotypes include testis abnor- malities, Prostate Disease, kidney Disease, immune abnormalities, and tumor development. This epigenetic transgenerational Disease mechanism provides a unique perspective from which to view inheritable adult onset Disease states, such as cancer, and ultimately offers new insights into novel diagnostic and therapeutic strategies.
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endocrine disruptor vinclozolin induced epigenetic transgenerational adult onset Disease
Endocrinology, 2006Co-Authors: Matthew D. Anway, Charles W LeathersAbstract:The fetal basis of adult Disease is poorly understood on a molecular level and cannot be solely attributed to genetic mutations or a single etiology. Embryonic exposure to environmental compounds has been shown to promote various Disease states or lesions in the first generation (F1). The current study used the endocrine disruptor vinclozolin (antiandrogenic compound) in a transient embryonic exposure at the time of gonadal sex determination in rats. Adult animals from the F1 generation and all subsequent generations examined (F1–F4) developed a number of Disease states or tissue abnormalities including Prostate Disease, kidney Disease, immune system abnormalities, testis abnormalities, and tumor development (e.g. breast). In addition, a number of blood abnormalities developed including hypercholesterolemia. The incidence or prevalence of these transgenerational Disease states was high and consistent across all generations (F1–F4) and, based on data from a previous study, appears to be due in part to epig...
David J Handelsman - One of the best experts on this subject based on the ideXlab platform.
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determinants of male reproductive health disorders the men in australia telephone survey mates
BMC Public Health, 2010Co-Authors: Carol A Holden, Robert I Mclachlan, Marian Pitts, Robert G Cumming, G Wittert, D M De Kretser, Johnathon P Ehsani, David J HandelsmanAbstract:The relationship between reproductive health disorders and lifestyle factors in middle-aged and older men is not clear. The aim of this study is to describe lifestyle and biomedical associations as possible causes of erectile dysfunction (ED), Prostate Disease (PD), lower urinary tract symptoms (LUTS) and perceived symptoms of androgen deficiency (pAD) in a representative population of middle-aged and older men, using the Men in Australia Telephone Survey (MATeS). A representative sample (n = 5990) of men aged 40+ years, stratified by age and State, was contacted by random selection of households, with an individual response rate of 78%. All men participated in a 20-minute computer-assisted telephone interview exploring general and reproductive health. Associations between male reproductive health disorders and lifestyle and biomedical factors were analysed using multivariate logistic regression (odds ratio [95% confidence interval]). Variables studied included age, body mass index, waist circumference, smoking, alcohol consumption, physical activity, co-morbid Disease and medication use for hypertension, high cholesterol and symptoms of depression. Controlling for age and a range of lifestyle and co-morbid exposures, sedentary lifestyle and being underweight was associated with an increased likelihood of ED (1.4 [1.1-1.8]; 2.9 [1.5-5.8], respectively) and pAD (1.3 [1.1-1.7]; 2.7 [1.4-5.0], respectively. Diabetes and cardiovascular Disease were both associated with ED, with hypertension strongly associated with LUTS and pAD. Current smoking (inverse association) and depressive symptomatology were the only variables independently associated with PD. All reproductive disorders showed consistent associations with depression (measured either by depressive symptomatology or medication use) in both age-adjusted and multivariate analyses. A range of lifestyle factors, more often associated with chronic Disease, were significantly associated with male reproductive health disorders. Education strategies directed to improving general health may also confer benefits to male reproductive health.
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men in australia telephone survey mates a national survey of the reproductive health and concerns of middle aged and older australian men
The Lancet, 2005Co-Authors: Carol A Holden, Robert I Mclachlan, Marian Pitts, Robert G Cumming, G Wittert, Paul A Agius, David J Handelsman, D M De KretserAbstract:Summary Background The Men in Australia Telephone Survey (MATeS) describes the prevalence of self-reported reproductive health disorders as well as related concerns and health behaviours among middle-aged and older Australian men. Methods A representative sample population (n=5990) of Australian men (≥40 years) was obtained by contacting a random selection of households with unbiased sampling, stratified by age and state. A 20-min computer-assisted telephone interview was done to assess reproductive health and related knowledge and beliefs, sociodemographic factors, general health, and lifestyle factors. Findings A response rate of 78% (5990/7636) was achieved. 34% (1627/4737) of men surveyed reported one or more reproductive health disorder, all of which were most common in the oldest age group. Age-standardised prevalence of significant lower urinary tract symptoms was 16%, erectile dysfunction was 21%, and Prostate Disease was 14%. About 50% of participants reported having had a Prostate cancer test whereas only 30% (300/1012) of men with erectile dysfunction sought medical help. Willingness to seek medical help for erectile dysfunction was related to age and ethnic origin. Although men aged 40–69 years expressed a moderate or high level of concern about Prostate cancer and loss of erectile function, concern about reproductive health was less in the oldest age group (≥70 years). Interpretation The high prevalence of reproductive health disorders and associated concerns in middle-aged and older Australian men draws attention to the need to develop appropriate services and education strategies specifically directed to improving reproductive health in these men.
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Effects of androgen deficiency and replacement on Prostate zonal volumes.
Clinical endocrinology, 2001Co-Authors: B. Jin, Ann J. Conway, David J HandelsmanAbstract:BACKGROUND AND OBJECTIVES Androgens play a key role in Prostate development and Disease. However the effects of androgen deficiency and replacement on the Prostate during mid-life are not well understood, and there is no information on their effects on Prostate zonal volumes. This study aimed to define the effects of androgen deficiency and androgen replacement therapy on Prostate zonal volumes (central, peripheral & total) using planimetric Prostate ultrasound with particular emphasis on the central zone of the Prostate, the most hormonally sensitive and fastest growing region of the Prostate and the zone where nodular benign Prostate hyperplasia originates. PATIENTS AND MEASUREMENTS Central and total Prostate volume were measured directly, and peripheral Prostate volume calculated, by a single observer using transrectal ultrasound in 71 hypogonadal men (aged 40 +/- 2, range 18-78 years) who were compared with individually age-matched health controls without Prostate or gonadal Disease. Among the men with androgen deficiency, 17 men had untreated androgen deficiency (never treated or no treatment for at least 6 months) and 54 men were receiving long-term androgen replacement therapy (median 32 months, 93% > or = 6 months) with testosterone implants (n = 27), testosterone ester injections (n = 24) or other testosterone treatment (n = 3). RESULTS Compared with individually age-matched controls, untreated androgen deficient men (n = 17) had reduced central (4.0 +/- 0.5 vs. 6.2 +/- 0.5 ml, P < 0.001) and total (23.4 +/- 2.6 vs. 29.2 +/- 1.6 ml, P < 0.001) Prostate volumes whereas the reduction in peripheral Prostate volume (19.4 +/- 2.1 vs. 23.0 +/- 1.3 ml, P = 0.15) was not statistically significant. Men with treated androgen deficiency (n = 54) also still had significantly reduced central (4.8 +/- 0.4 vs. 6.8 +/- 0.4, P < 0.001), peripheral Prostate volume (19.6 +/- 0.8 vs. 21.6 +/- 0.7 ml, P = 0.06) and total (24.4 +/- 1.1 vs. 28.4 +/- 1.0 ml, P = 0.008) despite prolonged restoration of physiological testosterone concentrations. Neither modality of testosterone treatment nor type of hypogonadism influenced Prostate zonal volumes before or after treatment. In contrast, central, peripheral and total Prostate volume increased with age among healthy controls and men with androgen deficiency regardless of androgen replacement therapy. Plasma PSA concentrations were reduced in men with untreated androgen deficiency and were similar to age-matched controls in men with treated androgen deficiency. CONCLUSIONS We conclude that, during mid-life, chronic androgen deficiency due to hypogonadism is associated with reduced central, peripheral and total Prostate volumes. Reduced Prostate volumes persist even during long-term maintenance of effective androgen replacement therapy with physiological testosterone concentrations until the fourth decade of life. After that, Prostate volumes increase with age regardless of androgen deficiency or replacement. These findings suggest that, during mid-life, age is a more important determinant of Prostate growth than ambient testosterone concentrations maintained in the physiological range. The persistently subnormal Prostate volumes despite adequate androgen replacement therapy may explain the apparent paucity of cases of overt Prostate Disease among testosterone-treated androgen deficient men who retain protection against Prostate Disease despite physiological androgen replacement therapy.
