Androgen deprivation therapy and cardiovascular risk in patients with prostate cancer

International Nuclear Information System (INIS)

Khan, M.Y.; Haider, N.; Rasul, S.; Mahmood, A.; Nadeem, M.S.

2017-01-01

The objective of this study was to investigate the effects of androgen deprivation therapy (ADT) on risk of subsequent cardiovascular morbidity in men with prostate cancer. Study Design: Quasi experimental study. Place and Duration of Study: Department of oncology Combined Military Hospital Rawalpindi, from Sep 2014 to May 2015. Patients and Methods: Thirty consecutive patients fulfilling inclusion criteria were enrolled. All patients were subjected to medical castration/ androgen deprivation therapy (ADT) with monthly 3.75 mg leuprorelin acetate intramuscular injection until castrate levels of testosterone (<50ng/dL) were achieved. We used Framingham's score for assessment of 10 years cardiovascular risk of individual patient before initiation and after completion of 6 months ADT. Serum lipid profile (fasting), systolic blood pressure, history of smoking, diabetes and antihypertensive medication were recorded. Proforma was designed to get clinical information. A p-value of <0.05 was considered significant. A paired-samples t-test was conducted to compare Framingham cardiovascular risk scores before initiation and after completion of 6 months ADT. Results: We enrolled 30 men with high/intermediate risk localized prostate cancer. Mean age was 63.47 +- 7.32 years. All patients received 6 months ADT with monthly 3.75mg leuprorelin acetate intramuscular injection. There was a significant difference in Framingham cardiovascular risk scores before (mean +- sd; 20.95 +- 7.98) and after (mean +- sd; 25.72 +- 6.15) 6 months ADT; t (29) =-4.54, p<0.01, two-tailed. Hence ADT resulted in a significant increase (mean +- sd; 25.7 +- 6.15) in 10 years cardiovascular morbidity risk t (29) =-4.54, p<0.01, two tailed. Subset analyses revealed significant increase in fasting serum total cholesterol, triglycerides and Low density lipoprotein (LDL) levels after 6 months ADT (p<0.01, <0.01 and <0.01 respectively) however high density lipoprotein (HDL) remained un-changed (p=0.043) in

Lack of benefit from a short course of androgen deprivation for unfavorable prostate cancer patients treated with an accelerated hypofractionated regime

International Nuclear Information System (INIS)

Martinez, Alvaro A.; Demanes, D. Jeffrey; Galalae, Razvan; Vargas, Carlos; Bertermann, Hagen; Rodriguez, Rodney; Gustafson, Gary; Altieri, Gillian; Gonzalez, Jose

2005-01-01

biochemical control among the three institutions. The corresponding 8-year rates with and without androgen deprivation therapy were biochemical control 85% and 81%; overall survival 83% and 78%; cause-specific survival 89% and 94%; and metastatic rates of 16.6% and 7.3%. A multivariate analysis revealed androgen deprivation therapy did not predict for biochemical failure for either the entire group or the subset of 177 patients harboring all three poor prognostic factors. Moreover, adding androgen deprivation therapy strongly correlated with higher rates of both metastasis (p = 0.09; hazard ratio, 2.08) and cancer-related deaths (p = 0.02, hazard ratio 3.25). These negative results for the most unfavorable group led us to question if androgen deprivation therapy might have a deleterious impact through delay in delivery of the potentially curative radiation or whether there may be a biologic basis by fixing the cycling cells in G 0 . Conclusions: Accelerated hypofractionated pelvic EBRT integrated with TRUS-guided conformally modulated HDR administered to 1,260 patients in three institutions was an excellent method of delivering very high radiation dose to the prostate in 5 weeks. Similar high overall, cause-specific, and biochemical no evidence of disease survival rates achieved show that prostate HDR can be successfully delivered in academic and community settings. At 8 years, the addition of a course of ≤6 months of neoadjuvant/concurrent androgen deprivation therapy to a very high radiation dose did not confer a therapeutic advantage but added side effects and cost. Furthermore, for the most unfavorable group, there was a higher rate of distant metastasis and more prostate cancer-related deaths. We question the value of a short course of androgen deprivation therapy when used with high-dose radiation

Prostate Cancer Metastases to Bone: Role of High Bone Turnover Induced by Androgen Deprivation

National Research Council Canada - National Science Library

Padalecki, Susan

2002-01-01

.... Treatment with androgen deprivation therapy leads to an increase in bone turnover as indicated by the loss of bone mineral density and the increase in markers of bone turnover in patients on treatment...

Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

Energy Technology Data Exchange (ETDEWEB)

Ragnum, Harald Bull [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Røe, Kathrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Holm, Ruth; Vlatkovic, Ljiljana [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Nesland, Jahn Marthin [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Aarnes, Eva-Katrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Ree, Anne Hansen [Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Flatmark, Kjersti [Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Department of Gastrointestinal Surgery, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Seierstad, Therese [Department of Radiology and Nuclear Medicine, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Faculty of Health Sciences, Buskerud University College, Drammen (Norway); Lilleby, Wolfgang [Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Lyng, Heidi, E-mail: heidi.lyng@rr-research.no [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway)

2013-11-15

Purpose: We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Methods and Materials: Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry. Results: A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). Conclusions: AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to

Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

International Nuclear Information System (INIS)

Ragnum, Harald Bull; Røe, Kathrine; Holm, Ruth; Vlatkovic, Ljiljana; Nesland, Jahn Marthin; Aarnes, Eva-Katrine; Ree, Anne Hansen; Flatmark, Kjersti; Seierstad, Therese; Lilleby, Wolfgang; Lyng, Heidi

2013-01-01

Purpose: We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Methods and Materials: Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry. Results: A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). Conclusions: AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to

Football training in men with prostate cancer undergoing androgen deprivation therapy

DEFF Research Database (Denmark)

Uth, Jacob; Hornstrup, Therese; Christensen, Jesper F

2016-01-01

) and density, BTMs and postural balance. RESULTS: In the last part of the 12 weeks, FTG performed 194 ± 41 accelerations and 296 ± 65 decelerations at >0.6 m/s/s and covered a distance of 905 ± 297 m at speeds >6 km/h and 2646 ± 705 m per training session. Analysis of baseline-to-12-week change scores showed......PURPOSE: To investigate the activity profile of football training and its short-term effects on bone mass, bone turnover markers (BTMs) and postural balance in men with prostate cancer (PCa) undergoing androgen deprivation therapy (ADT). METHODS: This was a randomised 12-week study in which men...

Practice Patterns Compared with Evidence-based Strategies for the Management of Androgen Deprivation Therapy-Induced Side Effects in Prostate Cancer Patients: Results of a European Web-based Survey

NARCIS (Netherlands)

Bultijnck, R.; Surcel, C.; Ploussard, G.; Briganti, A.; Visschere, P. De; Futterer, J.J.; Ghadjar, P.; Giannarini, G.; Isbarn, H.; Massard, C.; Sooriakumaran, P.; Valerio, M.; Bergh, R. van den; Ost, P.

2016-01-01

BACKGROUND: Evidence-based recommendations are available for the management of androgen deprivation therapy (ADT)-induced side effects; however, there are no data on the implementation of the recommendations into daily practice patterns. OBJECTIVE: To compare practice patterns in the management of

Riscos cardiovasculares do bloqueio androgênico Riesgos cardiovasculares del bloqueo androgénico Cardiovascular risks of androgen deprivation therapy

Directory of Open Access Journals (Sweden)

Adriano Freitas Ribeiro

2010-09-01

bien conocidas. Recientemente, una serie de complicaciones metabólicas fue descripta como aumento de la circunferencia abdominal, resistencia a la insulina, hiperglicemia, diabetes, dislipidemia y síndrome metabólico con consecuente aumento del riesgo de eventos coronarios y mortalidad cardiovascular en esa población específica. Este artículo de actualización presenta una revisión bibliográfica realizada en el MEDLINE de toda literatura publicada en inglés en el período de 1966 hasta junio de 2009, con las siguientes palabras-clave: androgen deprivation therapy, androgen supression therapy, hormone treatment, prostate cancer, metabolic syndrome y cardiovascular disease, con el propósito de analizar cuales serían los reales riesgos cardiovasculares de la terapia de deprivación androgénica, también llamada bloqueo androgénico, en los pacientes con cáncer de próstata.Prostate adenocarcinoma is the most common cancer type in the male sex after skin cancer. Among the several types of treatment for prostate cancer, the androgen deprivation therapy has been highly recommended in patients with metastatic or locally advanced disease, which probably results in increased survival. However, the androgen deprivation is the cause of several adverse effects. Complications such as osteoporosis, sexual dysfunction, gynecomastia, anemia and body composition alterations are well-known effects of the therapy. Recently, a number of metabolic complications have been described, such as increase in the abdominal circumference, insulin resistance, hyperglycemia, diabetes, dyslipidemia and metabolic syndrome, with a consequent increase in the risk of coronary events and cardiovascular mortality in this specific population. This update article presents a literature review carried out at MEDLINE database of all literature published in English from 1966 to June 2009, using the following key words: androgen deprivation therapy, androgen suppression therapy, hormone treatment

Psychological effects of androgen-deprivation therapy on men with prostate cancer and their partners.

Science.gov (United States)

Donovan, Kristine A; Walker, Lauren M; Wassersug, Richard J; Thompson, Lora M A; Robinson, John W

2015-12-15

The clinical benefits of androgen-deprivation therapy (ADT) for men with prostate cancer (PC) have been well documented and include living free from the symptoms of metastases for longer periods and improved quality of life. However, ADT comes with a host of its own serious side effects. There is considerable evidence of the adverse cardiovascular, metabolic, and musculoskeletal effects of ADT. Far less has been written about the psychological effects of ADT. This review highlights several adverse psychological effects of ADT. The authors provide evidence for the effect of ADT on men's sexual function, their partner, and their sexual relationship. Evidence of increased emotional lability and depressed mood in men who receive ADT is also presented, and the risk of depression in the patient's partner is discussed. The evidence for adverse cognitive effects with ADT is still emerging but suggests that ADT is associated with impairment in multiple cognitive domains. Finally, the available literature is reviewed on interventions to mitigate the psychological effects of ADT. Across the array of adverse effects, physical exercise appears to have the greatest potential to address the psychological effects of ADT both in men who are receiving ADT and in their partners. © 2015 American Cancer Society.

Nutrition therapy with high intensity interval training to improve prostate cancer-related fatigue in men on androgen deprivation therapy: a study protocol.

Science.gov (United States)

Baguley, Brenton J; Skinner, Tina L; Leveritt, Michael D; Wright, Olivia R L

2017-01-03

Cancer-related fatigue is one of the most prevalent, prolonged and distressing side effects of prostate cancer treatment with androgen deprivation therapy. Preliminary evidence suggests natural therapies such as nutrition therapy and structured exercise prescription can reduce symptoms of cancer-related fatigue. Men appear to change their habitual dietary patterns after prostate cancer diagnosis, yet prostate-specific dietary guidelines provide limited support for managing adverse side effects of treatment. The exercise literature has shown high intensity interval training can improve various aspects of health that are typically impaired with androgen deprivation therapy; however exercise at this intensity is yet to be conducted in men with prostate cancer. The purpose of this study is to examine the effects of nutrition therapy beyond the current healthy eating guidelines with high intensity interval training for managing cancer-related fatigue in men with prostate cancer treated with androgen deprivation therapy. This is a two-arm randomized control trial of 116 men with prostate cancer and survivors treated with androgen deprivation therapy. Participants will be randomized to either the intervention group i.e. nutrition therapy and high intensity interval training, or usual care. The intervention group will receive 20 weeks of individualized nutrition therapy from an Accredited Practising Dietitian, and high intensity interval training (from weeks 12-20 of the intervention) from an Accredited Exercise Physiologist. The usual care group will maintain their standard treatment regimen over the 20 weeks. Both groups will undertake primary and secondary outcome testing at baseline, week 8, 12, and 20; testing includes questionnaires of fatigue and quality of life, objective measures of body composition, muscular strength, cardiorespiratory fitness, biomarkers for disease progression, as well as dietary analysis. The primary outcomes for this trial are measures of

Gene Polymorphism-related Individual and Interracial Differences in the Outcomes of Androgen Deprivation Therapy for Prostate Cancer.

Science.gov (United States)

Fujimoto, Naohiro; Shiota, Masaki; Tomisaki, Ikko; Minato, Akinori

2017-06-01

Among patients with prostate cancer, the prognosis after androgen deprivation therapy differs significantly among individuals and among races; however, the reasons underlying these differences are poorly understood. Several single nucleotide polymorphisms in genes associated with prostate cancer progression or castration resistance might serve as the host factor that influences prognosis and, thus, accounts for these individual and racial gaps in treatment outcomes. Accordingly, single nucleotide polymorphisms associated with treatment outcomes could be used as predictive and/or prognostic biomarkers for patient stratification and to identify personalized treatment and follow-up protocols. The present review has summarized the genetic polymorphisms that have been reported to associate with androgen deprivation therapy outcomes among patients with prostate cancer and compared the allele frequencies among different ethnic groups. Copyright © 2017 Elsevier Inc. All rights reserved.

The effect of androgen deprivation on the early changes in prostate volume following transperineal ultrasound guided interstitial therapy for localized carcinoma of the prostate

Energy Technology Data Exchange (ETDEWEB)

Whittington, Richard; Broderick, Gregory A; Arger, Peter; Malkowicz, S Bruce; Epperson, Robert D; Arjomandy, Bijan; Kassaee, Alireza

1999-07-15

Purpose: To determine the change in volume of the prostate as a result of neoadjuvant androgen deprivation prior to prostate implant and in the early postimplant period following transperineal ultrasound guided palladium-103 brachytherapy for early-stage prostate cancer. Methods and Materials: Sixty-nine men received 3 to 6 months of androgen deprivation therapy followed by treatment planning ultrasound followed 4 to 8 weeks later by palladium-103 implant of the prostate. All patients had clinical and radiographic stage T1c-T2b adenocarcinoma of the prostate. A second ultrasound study was carried out 11 to 13 days following the implant to determine the change in volume of the prostate as a result of the implant. The prehormonal and preimplant volumes were compared to the postimplant volume to determine the effect of hormones and brachytherapy on prostate volume. Results: The median decrease in prostate volume as a result of androgen deprivation was 33% among the 54 patients with prostate volume determinations prior to hormonal therapy. The reduction in volume was greatest in the quartile of men with the largest initial gland volume (59%) and least in the quartile of men with smallest glands (10%). The median reduction in prostate volume between the treatment planning ultrasound and the follow-up study after implant was 3%, but 23 (33%) patients had an increase in prostate volume, including 16 (23%) who had an increase in volume >20%; 11 of these patients (16%) had an increase in volume >30%. The time course of development and resolution of this edema is not known. The severity of the edema was not related to initial or preimplant prostate volume or duration of hormonal therapy. Conclusions: Prostate edema may significantly affect the dose delivered to the prostate following transperineal ultrasound guided brachytherapy. The effect on the actual delivered dose will be greater when shorter lived isotopes are used. It remains to be observed whether this edema will

Effects of Androgen Blockade on Cognitive Function and Quality of Life in Men with Prostate Cancer

National Research Council Canada - National Science Library

Grigaby, James

2003-01-01

The purpose of this project is to examine the nature and severity of cognitive impairments experienced by men undergoing continuous androgen deprivation or intermittent androgen deprivation treatment...

Effects of Androgen Blockade on Cognitive Function and Quality of Life in Men with Prostate Cancer

National Research Council Canada - National Science Library

Grigsby, James

2004-01-01

The purpose of this project is to examine the nature and severity of cognitive impairments experienced by men undergoing continuous androgen deprivation or intermittent androgen deprivation treatment...

To Die or to Survive, a Fatal Question for the Destiny of Prostate Cancer Cells after Androgen Deprivation Therapy

International Nuclear Information System (INIS)

Zhang, Kai-Xin; Firus, Jessica; Prieur, Brenda; Jia, William; Rennie, Paul S.

2011-01-01

Prostate cancer is the most frequently diagnosed non-skin cancer in adult males in North America and is the second leading cause of cancer-related mortality. For locally advanced or metastatic disease, androgen deprivation, through medical or surgical castration, is the primary treatment to induce prostate cancer cell death and extend patient survival. However, the vast majority of cancers progress to a castration-resistant/androgen-independent state where the cell death processes are no longer active. This review describes the main cell death processes, apoptosis, autophagy, necrosis and necroptosis, which may be activated in prostate cancers after androgen deprivation therapy as well as the molecular mechanisms through which the cancers progress to become castration resistant. In particular, the central role of persistent androgen receptor (AR)-mediated signaling and AR crosstalk with other critical cell signaling pathways, including (i) the PI3K/Akt pathway, (ii) receptor tyrosine kinases, (iii) the p38 MAPK pathway, and (iv) the Wnt/β-catenin pathway, as well as reactivation of AR by de novo synthesized androgen are discussed in this context. Understanding the molecular changes that subvert normal cell death mechanisms and thereby compromise the survival of prostate cancer patients continues to be a major challenge

To Die or to Survive, a Fatal Question for the Destiny of Prostate Cancer Cells after Androgen Deprivation Therapy

Energy Technology Data Exchange (ETDEWEB)

Zhang, Kai-Xin; Firus, Jessica; Prieur, Brenda [The Vancouver Prostate Centre, 2660 Oak St., Vancouver, BC V6H 3Z6 (Canada); Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada); Jia, William [Department of Surgery and Brain Research Centre, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada); Rennie, Paul S., E-mail: prennie@interchange.ubc.ca [The Vancouver Prostate Centre, 2660 Oak St., Vancouver, BC V6H 3Z6 (Canada); Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada)

2011-03-24

Prostate cancer is the most frequently diagnosed non-skin cancer in adult males in North America and is the second leading cause of cancer-related mortality. For locally advanced or metastatic disease, androgen deprivation, through medical or surgical castration, is the primary treatment to induce prostate cancer cell death and extend patient survival. However, the vast majority of cancers progress to a castration-resistant/androgen-independent state where the cell death processes are no longer active. This review describes the main cell death processes, apoptosis, autophagy, necrosis and necroptosis, which may be activated in prostate cancers after androgen deprivation therapy as well as the molecular mechanisms through which the cancers progress to become castration resistant. In particular, the central role of persistent androgen receptor (AR)-mediated signaling and AR crosstalk with other critical cell signaling pathways, including (i) the PI3K/Akt pathway, (ii) receptor tyrosine kinases, (iii) the p38 MAPK pathway, and (iv) the Wnt/β-catenin pathway, as well as reactivation of AR by de novo synthesized androgen are discussed in this context. Understanding the molecular changes that subvert normal cell death mechanisms and thereby compromise the survival of prostate cancer patients continues to be a major challenge.

To Die or to Survive, a Fatal Question for the Destiny of Prostate Cancer Cells after Androgen Deprivation Therapy

Directory of Open Access Journals (Sweden)

Paul S. Rennie

2011-03-01

Full Text Available Prostate cancer is the most frequently diagnosed non-skin cancer in adult males in North America and is the second leading cause of cancer-related mortality. For locally advanced or metastatic disease, androgen deprivation, through medical or surgical castration, is the primary treatment to induce prostate cancer cell death and extend patient survival. However, the vast majority of cancers progress to a castration-resistant/androgen-independent state where the cell death processes are no longer active. This review describes the main cell death processes, apoptosis, autophagy, necrosis and necroptosis, which may be activated in prostate cancers after androgen deprivation therapy as well as the molecular mechanisms through which the cancers progress to become castration resistant. In particular, the central role of persistent androgen receptor (AR-mediated signaling and AR crosstalk with other critical cell signaling pathways, including (i the PI3K/Akt pathway, (ii receptor tyrosine kinases, (iii the p38 MAPK pathway, and (iv the Wnt/β-catenin pathway, as well as reactivation of AR by de novo synthesized androgen are discussed in this context. Understanding the molecular changes that subvert normal cell death mechanisms and thereby compromise the survival of prostate cancer patients continues to be a major challenge.

Effects of Androgen Blockade on Cognitive Function and Quality of Life in Men with Prostate Cancer

National Research Council Canada - National Science Library

Grigsby, James P; Brega, Angela G

2006-01-01

The purpose of this project was to examine the nature and severity of cognitive impairments experienced by men undergoing continuous androgen deprivation or intermittent androgen deprivation treatment (ADT...

[Clinical Study of 2014 ISUP New Grade Group Classification for Prostate Cancer Patients Treated by Androgen Deprivation Therapy].

Science.gov (United States)

Uno, Masahiro; Kawase, Makoto; Kato, Daiki; Ishida, Takashi; Kato, Seiichi; Fujimoto, Yoshinori

2018-01-01

The 2014 International Society of Urological Pathology (ISUP) has proposed a new grade group (GG) classification for Gleason scores (GS). The usefulness of the new GG classification was investigated with 518 prostate cancer patients who underwent androgen deprivation therapy. According to the new GG classification, Stages B‒D and the new GG classification relapse-free rate for each stage were calculated using the Kaplan‒Meier method. The new GG classification revealed a significant difference for the relapse-free rate only between some groups. Analysis using the Cox proportional hazards model indicated that the risk of relapse was higher in GGs 4 and 5 than in GG 1. The usefulness about the relapse-free rate in androgen deprivation therapy of the 2014 ISUP new grade group classification a waits future examination.

PSA bounces after neoadjuvant androgen deprivation and external beam radiation: Impact on definitions of failure

International Nuclear Information System (INIS)

Zietman, Anthony L.; Christodouleas, John P.; Shipley, William U.

2005-01-01

Purpose: To determine the characteristics of prostate specific antigen (PSA) bounces after external beam radiation therapy (EBRT) with neoadjuvant androgen deprivation and their impact on definitions of biochemical failure. Methods and Materials: Characteristics of bounce were calculated for all patients treated by EBRT with neoadjuvant androgen deprivation at our institution between 1992 and 1998 (preexclusion analysis). Calculations were repeated for the subgroup that satisfied additional inclusion/exclusion criteria (postexclusion analysis). The percentage of bounces scoring as false positives according to the ASTRO definition of biochemical failure was compared with those for three alternative definitions (Vancouver, Nadir-plus-two, and Nadir-plus-three) using McNemar's tests. Results: Thirty-nine percent (preexclusion cohort) and 56% (postexclusion cohort) of patients demonstrated a PSA bounce. Twenty percent (preexclusion analysis) and 25% (postexclusion analysis) of these bounces scored as biochemical failure according to the ASTRO definition. The Nadir-plus-three definition scored the smallest percentage of bounces as failure, but the difference between this definition and the ASTRO definition reached statistical significance in neither preexclusion nor postexclusion analyses (p ≥ 0.070). Conclusions: A substantial proportion of patients treated by EBRT with neoadjuvant deprivation experienced a PSA bounce. A large percentage of these bounces scored as biochemical failure according to the ASTRO definition. The Nadir-plus-three definition is less vulnerable to this bias

Endurance training improves insulin sensitivity and body composition in prostate cancer patients treated with androgen deprivation therapy

DEFF Research Database (Denmark)

Hvid, Thine; Winding, Kamilla; Rinnov, Anders

2013-01-01

Insulin resistance and changes in body composition are side effects of androgen deprivation therapy (ADT) given to prostate cancer patients. The present study investigated whether endurance training improves insulin sensitivity and body composition in ADT-treated prostate cancer patients. Nine me...... and magnetic resonance imaging). The secondary endpoint was systemic inflammation. Statistical analysis was carried out using two-way ANOVA. Endurance training increased VO2max (ml(O2)/min per kg) by 11 and 13% in the patients and controls respectively (P...

External beam radiation therapy for clinically localized prostate cancer: when and how we optimize with concurrent hormonal deprivation.

Science.gov (United States)

Koontz, Bridget F; Lee, W Robert

2011-10-01

Androgen deprivation plays a major role in the treatment of prostate cancer.Preclinical studies have shown that androgen deprivation provides both an independent cytotoxic effect and radiosensitization on prostate tumors. For men with non-metastatic prostate cancer, the addition of androgen deprivation to radiotherapy has been shown to improve survival for intermediate and high risk disease compared to radiation alone.This review discusses the clinical trial data regarding combination of androgen deprivation and radiation and provides recommendations for its use in men undergoing radiotherapy for localized prostate cancer.

Functional and structural changes in internal pudendal arteries underlie erectile dysfunction induced by androgen deprivation

Directory of Open Access Journals (Sweden)

Rhéure Alves-Lopes

2017-01-01

Full Text Available Androgen deficiency is strongly associated with erectile dysfunction (ED. Inadequate penile arterial blood flow is one of the major causes of ED. The blood flow to the corpus cavernosum is mainly derived from the internal pudendal arteries (IPAs; however, no study has evaluated the effects of androgen deprivation on IPA′s function. We hypothesized that castration impairs IPAs reactivity and structure, contributing to ED. In our study, Wistar male rats, 8-week-old, were castrated and studied 30 days after orchiectomy. Functional and structural properties of rat IPAs were determined using wire and pressure myograph systems, respectively. Protein expression was determined by Western blot and immunohistochemistry. Plasma testosterone levels were determined using the IMMULITE 1000 Immunoassay System. Castrated rats exhibited impaired erectile function, represented by decreased intracavernosal pressure/mean arterial pressure ratio. IPAs from castrated rats exhibited decreased phenylephrine- and electrical field stimulation (EFS-induced contraction and decreased acetylcholine- and EFS-induced vasodilatation. IPAs from castrated rats exhibited decreased internal diameter, external diameter, thickness of the arterial wall, and cross-sectional area. Castration decreased nNOS and α-actin expression and increased collagen expression, p38 (Thr180/Tyr182 phosphorylation, as well as caspase 3 cleavage. In conclusion, androgen deficiency is associated with impairment of IPA reactivity and structure and increased apoptosis signaling markers. Our findings suggest that androgen deficiency-induced vascular dysfunction is an event involving hypotrophic vascular remodeling of IPAs.

Optimal duration of androgen deprivation therapy following radiation therapy in intermediate- or high-risk non-metastatic prostate cancer: a systematic review and meta-analysis

Energy Technology Data Exchange (ETDEWEB)

Leal, Frederico; Figueiredo, Maximiliano Augusto Novis de; Sasse, Andre Deeke, E-mail: sasse@cevon.com.br [Universidade Estadual de Campinas (UNICAMP), SP (Brazil)

2015-05-15

Objectives: to investigate current evidence on the optimal duration of adjuvant hormone deprivation for prostate cancer treated with radiation therapy with curative intent. Materials and Methods: A systematic search was performed in electronic databases. Data from randomized trials comparing different durations of hormone blockade was collected for pooled analysis. Overall survival, disease-free survival, disease-specific survival and toxicity were the outcomes of interest. Meta-analyses were performed using random-effects model. Results: Six studies met the eligibility criteria. For overall survival, the pooled data from the studies demonstrated a statistically significant benefit for longer hormone deprivation (Hazard Ratio 0.84; 95% CI 0.74 - 0.96). A statistically significant benefit was also found for disease-free survival (Hazard Ratio 0.74; 95% CI 0.62 - 0.89), and disease-specific survival (Hazard Ratio 0.73; 95% CI 0.62 - 0.85). Studies with longer blockade duration arm demonstrated greater benefit. Toxicity was low, with no increase in cardiovascular events. Conclusions: Longer duration of androgen deprivation combined to radiotherapy prolongs OS, DFS and DSS in patients with intermediate and high-risk non-metastatic prostate cancer. However, this evidence is based on trials using older radiation techniques, and further research of combination of androgen deprivation and new RT technologies may be warranted. (author)

Androgen deprivation therapy and fracture risk in Chinese patients with prostate carcinoma.

Directory of Open Access Journals (Sweden)

Chi-Ho Lee

Full Text Available Androgen deprivation therapy (ADT increases fracture risk in men with carcinoma of the prostate, but little is known about the fracture risk for different types of ADT. We studied the fracture risk amongst Chinese patients with carcinoma of the prostate prescribed different ADT regimens.This was a single-centered observational study that involved 741 patients with carcinoma of the prostate from January 2001 to December 2011.After a median follow-up of 5 years, 71.7% of the study cohort received ADT and the incidence rate of fracture was 8.1%. Multivariable Cox regression analysis revealed that use of ADT was significantly associated with risk of incident fracture (Hazard Ratio [HR] 3.60; 95% Confidence Interval [95% CI] 1.41-9.23; p = 0.008, together with aged >75 years and type 2 diabetes. Compared with no ADT, all three types of ADT were independently associated with the risk of incident fracture: anti-androgen monotherapy (HR 4.47; 95% CI 1.47-13.7; p = 0.009, bilateral orchiectomy ± anti-androgens (HR 4.01; 95% CI 1.46-11.1; p = 0.007 and luteinizing hormone-releasing hormone agonists ± anti-androgens (HR 3.16; 95% CI 1.18-8.43; p = 0.022. However, there was no significant difference in the relative risks among the three types of ADT.Fracture risk increases among all types of ADT. Clinicians should take into account the risk-benefit ratio when prescribing ADT, especially in elderly patients with type 2 diabetes.

Can exercise ameliorate treatment toxicity during the initial phase of testosterone deprivation in prostate cancer patients? Is this more effective than delayed rehabilitation?

Directory of Open Access Journals (Sweden)

Newton Robert U

2012-09-01

Full Text Available Abstract Background There has been substantial increase in use of androgen deprivation therapy as adjuvant management of prostate cancer. However, this leads to a range of musculoskeletal toxicities including reduced bone mass and increased skeletal fractures compounded with rapid metabolic alterations, including increased body fat, reduced lean mass, insulin resistance and negative lipoprotein profile, increased incidence of cardiovascular and metabolic morbidity, greater distress and reduced quality of life. Numerous research studies have demonstrated certain exercise prescriptions to be effective at preventing or even reversing these treatment toxicities. However, all interventions to date have been of rehabilitative intent being implemented after a minimum of 3 months since initiation of androgen deprivation, by which time considerable physical and psychological health problems have manifested. The pressing question is whether it is more efficacious to commence exercise therapy at the same time as initiating androgen deprivation, so treatment induced adverse effects can be immediately attenuated or indeed prevented. Methods/design We are proposing a multi-site randomized controlled trial with partial crossover to examine the effects of timing of exercise implementation (immediate or delayed on preserving long-term skeletal health, reversing short- and long-term metabolic and cardiovascular risk factors, and supporting mental health in men receiving androgen deprivation therapy. 124 men who are about to initiate androgen deprivation for prostate cancer will be randomized to immediate or delayed groups. Immediate will commence a 6-month exercise program within 7–10 days of their first dose. Delayed will receive usual care for 6 months and then commence the exercise program for 6 months (partial cross-over. Immediate will be free to adopt the lifestyle of their choosing following the initial 6-month intervention. Measurements for primary and

Can exercise ameliorate treatment toxicity during the initial phase of testosterone deprivation in prostate cancer patients? Is this more effective than delayed rehabilitation?

International Nuclear Information System (INIS)

Newton, Robert U; Taaffe, Dennis R; Spry, Nigel; Cormie, Prue; Chambers, Suzanne K; Gardiner, Robert A; Shum, David HK; Joseph, David; Galvão, Daniel A

2012-01-01

There has been substantial increase in use of androgen deprivation therapy as adjuvant management of prostate cancer. However, this leads to a range of musculoskeletal toxicities including reduced bone mass and increased skeletal fractures compounded with rapid metabolic alterations, including increased body fat, reduced lean mass, insulin resistance and negative lipoprotein profile, increased incidence of cardiovascular and metabolic morbidity, greater distress and reduced quality of life. Numerous research studies have demonstrated certain exercise prescriptions to be effective at preventing or even reversing these treatment toxicities. However, all interventions to date have been of rehabilitative intent being implemented after a minimum of 3 months since initiation of androgen deprivation, by which time considerable physical and psychological health problems have manifested. The pressing question is whether it is more efficacious to commence exercise therapy at the same time as initiating androgen deprivation, so treatment induced adverse effects can be immediately attenuated or indeed prevented. We are proposing a multi-site randomized controlled trial with partial crossover to examine the effects of timing of exercise implementation (immediate or delayed) on preserving long-term skeletal health, reversing short- and long-term metabolic and cardiovascular risk factors, and supporting mental health in men receiving androgen deprivation therapy. 124 men who are about to initiate androgen deprivation for prostate cancer will be randomized to immediate or delayed groups. Immediate will commence a 6-month exercise program within 7–10 days of their first dose. Delayed will receive usual care for 6 months and then commence the exercise program for 6 months (partial cross-over). Immediate will be free to adopt the lifestyle of their choosing following the initial 6-month intervention. Measurements for primary and secondary endpoints will take place at baseline, 6

Maintaining intimacy for prostate cancer patients on androgen deprivation therapy.

Science.gov (United States)

Wassersug, Richard J

2016-03-01

Androgen deprivation therapy (ADT) causes erectile dysfunction and increases patients' emotionality while diminishing their sexual interest. ADT has been linked to erosion of spousal bonds; however, this is not an invariant outcome. Understanding the factors that lead to these various outcomes may help couples deal with ADT. A subset of couples report that they became closer as a result of the patients going on ADT. Recent data suggest that what helps couples most is preemptive awareness of ADT's side-effects and congruence in how patients and their partners understand and accept the psychosexual impact of ADT. Sex therapy for prostate cancer patients divides along gendered lines, with distinctly 'male' (recovery of erections) and 'female' (promoting sexual practices that are not erection dependent) approaches. Unfortunately, neither is very effective for couples when the patient is on ADT. Options beyond the standard gendered framework, such as use of an external penile prosthesis, may be worth offering to ADT patients trying to find a 'new normal' that is sexually rewarding for them. Intimacy is sharing something with someone that one shares with no one else. Exploring novel sexual practices can help couples stay intimate, even when the patient is on ADT.

Atmospheric Pressure Photoionization Tandem Mass Spectrometry of Androgens in Prostate Cancer

Science.gov (United States)

Lih, Fred Bjørn; Titus, Mark A.; Mohler, James L.; Tomer, Kenneth B.

2010-01-01

Androgen deprivation therapy is the most common treatment option for advanced prostate cancer. Almost all prostate cancers recur during androgen deprivation therapy, and new evidence suggests that androgen receptor activation persists despite castrate levels of circulating androgens. Quantitation of tissue levels of androgens is critical to understanding the mechanism of recurrence of prostate cancer during androgen deprivation therapy. A liquid chromatography atmospheric pressure photoionization tandem mass spectrometric method was developed for quantitation of tissue levels of androgens. Quantitation of the saturated keto-steroids dihydrotestosterone and 5-α-androstanedione required detection of a novel parent ion, [M + 15]+. The nature of this parent ion was explored and the method applied to prostate tissue and cell culture with comparison to results achieved using electrospray ionization. PMID:20560527

Combined curative radiotherapy including HDR brachytherapy and androgen deprivation in localized prostate cancer: A prospective assessment of acute and late treatment toxicity

International Nuclear Information System (INIS)

Wahlgren, Thomas; Nilsson, Sten; Ryberg, Marianne; Brandberg, Yvonne; Lennernaes, Bo

2005-01-01

Self-reported symptoms including urinary, bowel and sexual side effects were investigated prospectively at multiple assessment points before and after combined radiotherapy of prostate cancer including HDR brachytherapy and neoadjuvant androgen deprivation therapy. Between April 2000 and June 2003, patients with predominantly advanced localized prostate tumours subjected to this treatment were asked before treatment and on follow-up visits to complete a questionnaire covering urinary, bowel and sexual problems. The mainly descriptive analyses included 525 patients, responding to at least one questionnaire before or during the period 2-34 months after radiotherapy. Adding androgen deprivation before radiotherapy significantly worsened sexual function. During radiotherapy, urinary, bowel and sexual problems increased and were reported at higher levels up to 34 months, although there seemed to be a general tendency to less pronounced irritative bowel and urinary tract symptoms over time. No side effects requiring surgery were reported. Classic late irradiation effects such as mucosal bleeding were demonstrated mainly during the second year after therapy, but appear less pronounced in comparison with dose escalated EBRT series. In conclusion, despite the high radiation dose given, the toxicity seemed comparable with that of other series but long term (5-10 years) symptom outcome has to be determined

Effects of Different Exercise Modalities on Fatigue in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: A Year-long Randomised Controlled Trial.

Science.gov (United States)

Taaffe, Dennis R; Newton, Robert U; Spry, Nigel; Joseph, David; Chambers, Suzanne K; Gardiner, Robert A; Wall, Brad A; Cormie, Prue; Bolam, Kate A; Galvão, Daniel A

2017-08-01

Physical exercise mitigates fatigue during androgen deprivation therapy (ADT); however, the effects of different exercise prescriptions are unknown. To determine the long-term effects of different exercise modes on fatigue in prostate cancer patients undergoing ADT. Between 2009 and 2012, 163 prostate cancer patients aged 43-90 y on ADT were randomised to exercise targeting the musculoskeletal system (impact loading+resistance training; ILRT; n=58), the cardiovascular and muscular systems (aerobic+resistance training; ART; n=54), or to usual care/delayed exercise (DEL; n=51) for 12 mo across university-affiliated exercise clinics in Australia. Supervised ILRT for 12 mo, supervised ART for 6 mo followed by a 6-mo home program, and DEL received a printed booklet on exercise information for 6 mo followed by 6-mo stationary cycling exercise. Fatigue was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 36 and vitality using the Short Form-36. Analysis of variance was used to compare outcomes for groups at 6 mo and 12 mo. Fatigue was reduced (p=0.005) in ILRT at 6 mo and 12 mo (∼5 points), and in ART (p=0.005) and DEL (p=0.022) at 12 mo. Similarly, vitality increased for all groups (p≤0.001) at 12 mo (∼4 points). Those with the highest levels of fatigue and lowest vitality improved the most with exercise (p trend fatigue and enhancing vitality during ADT. Patients with the highest levels of fatigue and lowest vitality had the greatest benefits. We compared the effects of different exercise modes on fatigue in men on androgen deprivation therapy. All exercise programs reduced fatigue and enhanced vitality. We conclude that undertaking some form of exercise will help reduce fatigue, especially in those who are the most fatigued. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Androgens as therapy for androgen receptor-positive castration-resistant prostate cancer

Directory of Open Access Journals (Sweden)

Lin Hui-Ping

2011-08-01

Full Text Available Abstract Prostate cancer is the most frequently diagnosed non-cutaneous tumor of men in Western countries. While surgery is often successful for organ-confined prostate cancer, androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, this therapy is associated with several undesired side-effects, including increased risk of cardiovascular diseases. Shortening the period of androgen ablation therapy may benefit prostate cancer patients. Intermittent Androgen Deprivation therapy improves quality of life, reduces toxicity and medical costs, and delays disease progression in some patients. Cell culture and xenograft studies using androgen receptor (AR-positive castration-resistant human prostate cancers cells (LNCaP, ARCaP, and PC-3 cells over-expressing AR suggest that androgens may suppress the growth of AR-rich prostate cancer cells. Androgens cause growth inhibition and G1 cell cycle arrest in these cells by regulating c-Myc, Skp2, and p27Kip via AR. Higher dosages of testosterone cause greater growth inhibition of relapsed tumors. Manipulating androgen/AR signaling may therefore be a potential therapy for AR-positive advanced prostate cancer.

A phase II RCT and economic analysis of three exercise delivery methods in men with prostate cancer on androgen deprivation therapy

OpenAIRE

Alibhai, Shabbir MH; Santa Mina, Daniel; Ritvo, Paul; Sabiston, Catherine; Krahn, Murray; Tomlinson, George; Matthew, Andrew; Segal, Roanne; Warde, Padraig; Durbano, Sara; O?Neill, Meagan; Culos-Reed, Nicole

2015-01-01

Background Androgen deprivation therapy is commonly used to treat prostate cancer, the most common visceral cancer in men. However, various side effects often worsen physical functioning and reduce well-being among men on this treatment. Based on existing evidence, both resistance and aerobic training provide benefits for this population yet adherence rates are often low. The method of exercise delivery (supervised in-center or home-based) may be important, yet few studies have compared diffe...

Prognostic Value of Abnormal p53 Expression in Locally Advanced Prostate Cancer Treated With Androgen Deprivation and Radiotherapy: A Study Based on RTOG 9202

International Nuclear Information System (INIS)

Che Mingxin; DeSilvio, Michelle; Pollack, Alan; Grignon, David J.; Venkatesan, Varagur Mohan; Hanks, Gerald E.; Sandler, Howard M.

2007-01-01

Purpose: The goal of this study was to verify the significance of p53 as a prognostic factor in Radiation Therapy Oncology Group 9202, which compared short-term androgen deprivation (STAD) with radiation therapy (RT) to long-term androgen deprivation + RT in men with locally advanced prostate cancer (Pca). Methods and Materials: Tumor tissue was sufficient for p53 analysis in 777 cases. p53 status was determined by immunohistochemistry. Abnormal p53 expression was defined as 20% or more tumor cells with positive nuclei. Univariate and multivariate Cox proportional hazards models were used to evaluate the relationships of p53 status to patient outcomes. Results: Abnormal p53 was detected in 168 of 777 (21.6%) cases, and was significantly associated with cause-specific mortality (adjusted hazard ratio [HR] = 1.89; 95% confidence interval (CI) 1.14 - 3.14; p = 0.014) and distant metastasis (adjusted HR = 1.72; 95% CI 1.13-2.62; p = 0.013). When patients were divided into subgroups according to assigned treatment, only the subgroup of patients who underwent STAD + RT showed significant correlation between p53 status and cause-specific mortality (adjusted HR = 2.43; 95% CI = 1.32-4.49; p = 0.0044). When patients were divided into subgroups according to p53 status, only the subgroup of patients with abnormal p53 showed significant association between assigned treatment and cause-specific mortality (adjusted HR = 3.81; 95% CI 1.40-10.37; p = 0.0087). Conclusions: Abnormal p53 is a significant prognostic factor for patients with prostate cancer who undergo short-term androgen deprivation and radiotherapy. Long-term androgen deprivation may significantly improve the cause-specific survival for those with abnormal p53

Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival.

Directory of Open Access Journals (Sweden)

Audrey Dayon

Full Text Available BACKGROUND: Sphingosine kinase-1 (SphK1 is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival. METHODOLOGY/PRINCIPAL FINDINGS: Short-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway--by negatively impacting SphK1 activity--could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity. CONCLUSIONS/SIGNIFICANCE: We report the first evidence that androgen deprivation induces a differential effect on SphK1 activity in hormone-sensitive prostate cancer cell models. These results also suggest that SphK1 activation upon chronic androgen deprivation may serve as a

Effects of Androgen Blockade on Cognitive Function and Quality of Life in Men with Prostate Cancer

National Research Council Canada - National Science Library

Grigsby, James

2004-01-01

.... Our major hypothesis is the patients undergoing androgen deprivation therapy will experience impairments in those cognitive abilities reported in the research literature to be related to androgen levels (e.g...

Effects of Androgen Blockade on Cognitive Function and Quality of Life in Men with Prostate Cancer

National Research Council Canada - National Science Library

Grigaby, James

2003-01-01

.... Our major hypothesis is that patients undergoing androgen deprivation therapy will experience impairments in those cognitive abilities reported in the research literature to be related to androgen levels (e.g...

Football training improves lean body mass in men with prostate cancer undergoing androgen deprivation therapy

DEFF Research Database (Denmark)

Uth, J; Hornstrup, Therese; Schmidt, Jakob Friis

2014-01-01

Androgen deprivation therapy (ADT) remains a cornerstone in the management of patients with prostate cancer (PCa) despite adverse effects on body composition and functional parameters. We compared the effects of football training with standard care in PCa patients managed with ADT (> 6 months......). Fifty-seven men aged 67 (range: 43-74) were randomly assigned to a football group (FG, n = 29) or a usual care control group (CON, n = 28). The primary outcome was change in lean body mass (LBM) assessed by dual-energy X-ray absorptiometry scanning. Secondary outcomes included changes in knee.......7%; 95%CI 1.3-0.0; P = 0.06), but these changes were not significantly different from CON. In conclusion, football training over 12 weeks improved LBM and muscle strength compared with usual care in men with prostate cancer receiving ADT....

Androgen-deprivation therapy does not impact cause-specific or overall survival after permanent prostate brachytherapy

International Nuclear Information System (INIS)

Merrick, Gregory S.; Butler, Wayne M.; Wallner, Kent E.; Galbreath, Robert W.; Allen, Zachariah A. M.S.; Adamovich, Edward

2006-01-01

Purpose: To determine if androgen-deprivation therapy (ADT) has an impact on cause-specific, biochemical progression-free, or overall survival after prostate brachytherapy. Methods and Materials: From April 1995 through June 2002, 938 consecutive patients underwent brachytherapy for clinical Stage T1b to T3a (2002 AJCC) prostate cancer. All patients underwent brachytherapy more than 3 years before analysis. A total of 382 patients (40.7%) received ADT with a duration of 6 months or less in 277 and more than 6 months in 105. The median follow-up was 5.4 years. Multiple clinical, treatment, and dosimetric parameters were evaluated as predictors of cause-specific, biochemical progression-free, and overall survival. Results: The 10-year cause-specific, biochemical progression-free, and overall survival rates for the entire cohort were 96.4%, 95.9%, and 78.1%, respectively. Except for biochemical progression-free survival in high-risk patients, ADT did not statistically impact any of the three survival categories. A Cox linear-regression analysis demonstrated that Gleason score was the best predictor of cause-specific survival, whereas percent-positive biopsies, prostate volume, and risk group predicted for biochemical progression-free survival. Patient age and tobacco use were the strongest predictors of overall survival. One hundred two patients have died, with 80 of the deaths a result of cardiovascular disease (54) and second malignancies (26). To date, only 12 patients have died of metastatic prostate cancer. Conclusions: After brachytherapy, androgen-deprivation therapy did not have an impact on cause-specific or overall survival for any risk group; however, ADT had a beneficial effect on biochemical progression-free survival in high-risk patients. Cardiovascular disease and second malignancies far outweighed prostate cancer as competing causes of death

[Osteoporosis fracture in a male patient secondary to hypogonadism due to androgen deprivation treatment for prostate cancer].

Science.gov (United States)

Verdú Solans, J; Roig Grau, I; Almirall Banqué, C

2014-01-01

A 84 year-old patient, in therapy with androgen deprivation during the last 5 years due a prostate cancer, is presented with a osteoporotic fracture of the first lumbar vertebra. The pivotal role of the primary care physician, in the prevention of the osteoporosis secondary to the hypogonadism in these patients, is highlighted. Copyright © 2012 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España. All rights reserved.

Neoadjuvant androgen deprivation and prostate gland shrinkage during conformal radiotherapy

International Nuclear Information System (INIS)

Sanguineti, Giuseppe; Marcenaro, Michela; Franzone, Paola; Foppiano, Franca; Vitale, Vito

2003-01-01

Purpose: The shrinking effect of 3-month neoadjuvant androgen deprivation (NAD) on preradiotherapy prostate gland volume is well documented. However, recently, it has been shown that the cancerous prostate gland keeps shrinking up to 12 months after NAD start. Thus, if such a reduction is not taken into account, a larger than planned portion of the surrounding normal tissues might shift in the high-dose region during conformal radiotherapy (3DCRT) course. The present study was undertaken to quantify this issue. Materials and Methods: Prostate gland volume reduction between planning CT (plCT) and the last week of 3DCRT (tmtCT) was prospectively assessed in 33 consecutive patients with localized prostate carcinoma. The median time interval between plCT and tmtCT was 2.5 months (2.1-2.7 months). A single observer was asked to draw on each slice prostate gland volume as appropriate. The observer was 'blind' to the timing of CT (plCT vs. tmtCT). In order to estimate intra-observer variability, prostate gland delineation was repeated twice for each data set. Mean prostate gland change, plCT and tmtCT cumulative dose volume histogram (DVH) calculations for the rectum were analyzed for each patient. Results were correlated to AD status and its duration before plCT. Means were compared by non-parametric rank tests. Results: Based on an internal protocol, 14 patients (42%) did not receive AD, while 19 patients (58%) had undergone neoadjuvant and concomitant AD. The median duration of AD before plCT ranged from 0.2 to 6 months (median: 2.9 months). Although individual data were highly variable, compared to plCT volume, mean prostate gland volume change at the end of 3DCRT was similar for patients receiving (-7.3%) or not (-7%) androgen deprivation (P=0.77). However, within the group of patients treated with hormones, patients starting AD within 3 months from plCT had a significantly larger reduction in prostate volume (-14.2%) than patients with longer NAD duration (-1.1%, P

Acceptability of short term neo-adjuvant androgen deprivation in patients with locally advanced prostate cancer

International Nuclear Information System (INIS)

Lamb, David S.; Denham, James W.; Mameghan, Hedy; Joseph, David; Turner, Sandra; Matthews, John; Franklin, Ian; Atkinson, Chris; North, John; Poulsen, Michael; Kovacev, Olga; Robertson, Randall; Francis, Lynne; Christie, David; Spry, Nigel A.; Tai, K.-H.; Wynne, Chris; Duchesne, Gillian

2003-01-01

Purpose: To determine the acceptability of short term neo-adjuvant maximal androgen deprivation (MAD) to patients treated with external beam radiation for locally advanced prostate cancer. Methods: Between 1996 and 2000, 818 patients with locally advanced, but non-metastatic, prostate cancer were entered into a randomised clinical trial (TROG 96.01), which compared radiation treatment alone with the same radiation treatment and 3 or 6 months neo-adjuvant MAD with goserelin and flutamide. Relevant symptoms, and how troublesome they were to the patient, were scored using a self-assessment questionnaire. This was completed by the patient at registration, and at specified times during and after treatment. Patients taking flutamide had liver function tests checked at regular intervals. Results: All patients have completed at least 12 months follow-up after treatment. Nearly all patients completed planned treatment with goserelin, but 27% of patients in the 6-month MAD treatment arm, and 20% in the 3-month arm, had to stop flutamide early. This was mainly due to altered liver function (up to 17% patients) and bowel side effects (up to 8% patients). However, although flutamide resulted in more bowel symptoms for patients on MAD, there was significant reduction in some urinary symptoms on this treatment. Acute bowel and urinary side effects at the end of radiation treatment were similar in all treatment arms. Side effect severity was unrelated to radiation target volume size, which was reduced by MAD, but symptomatology prior to any treatment was a powerful predictor. Of the 36% of patients who were sexually active before any treatment, the majority became inactive whilst on MAD. However, sexual activity at 12 months after radiation treatment was similar in all treatment arms, indicating that the effects of short term MAD on sexual function are reversible. Conclusion: Despite temporary effects on sexual activity, and compliance difficulties with flutamide, short-term neo

Orphan nuclear receptor TLX contributes to androgen insensitivity in castration-resistant prostate cancer via its repression of androgen receptor transcription.

Science.gov (United States)

Jia, Lin; Wu, Dinglan; Wang, Yuliang; You, Wenxing; Wang, Zhu; Xiao, Lijia; Cai, Ganhui; Xu, Zhenyu; Zou, Chang; Wang, Fei; Teoh, Jeremy Yuen-Chun; Ng, Chi-Fai; Yu, Shan; Chan, Franky L

2018-03-20

The metastatic castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer, in which the expression of androgen receptor (AR) is highly heterogeneous. Indeed, lower AR expression and attenuated AR signature activity is shown in CRPC tissues, especially in the subset of neuroendocrine prostate cancer (NEPC) and prostate cancer stem-like cells (PCSCs). However, the significance of AR downregulation in androgen insensitivity and de-differentiation of tumor cells in CRPC is poorly understood and much neglected. Our previous study shows that the orphan nuclear receptor TLX (NR2E1), which is upregulated in prostate cancer, plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence. In the present study, we further established that TLX exhibited an increased expression in metastatic CRPC. Further analyses showed that overexpression of TLX could confer resistance to androgen deprivation and anti-androgen in androgen-dependent prostate cancer cells in vitro and in vivo, whereas knockdown of endogenous TLX could potentiate the sensitivity to androgen deprivation and anti-androgen in prostate cancer cells. Our study revealed that the TLX-induced resistance to androgen deprivation and anti-androgen was mediated through its direct suppression of AR gene transcription and signaling in both androgen-stimulated and -unstimulated prostate cancer cells. We also characterized that TLX could bind directly to AR promoter and repress AR transcription by recruitment of histone modifiers, including HDAC1, HDAC3, and LSD1. Together, our present study shows, for the first time, that TLX can contribute to androgen insensitivity in CRPC via repression of AR gene transcription and signaling, and also implicates that targeting the druggable TLX may have a potential therapeutic significance in CRPC management, particularly in NEPC and PCSCs.

Testosterone Responders to Continuous Androgen Deprivation Therapy Show Considerable Variations in Testosterone Levels on Followup: Implications for Clinical Practice.

Science.gov (United States)

Sayyid, Rashid K; Sayyid, Abdallah K; Klaassen, Zachary; Fadaak, Kamel; Goldberg, Hanan; Chandrasekar, Thenappan; Ahmad, Ardalanejaz; Leao, Ricardo; Perlis, Nathan; Chadwick, Karen; Hamilton, Robert J; Kulkarni, Girish S; Finelli, Antonio; Zlotta, Alexandre R; Fleshner, Neil E

2018-01-01

We determined whether men on continuous androgen deprivation therapy who achieve testosterone less than 0.7 nmol/l demonstrate subsequent testosterone elevations during followup and whether such events predict worse oncologic outcomes. We evaluated a random, retrospective sample of 514 patients with prostate cancer treated with continuous androgen deprivation therapy in whom serum testosterone was less than 0.7 nmol/l at University Health Network between 2007 and 2016. Patients were followed from the date of the first testosterone measurement of less than 0.7 nmol/l to progression to castrate resistance, death or study period end. Study outcomes were the development of testosterone elevations greater than 0.7, greater than 1.1 and greater than 1.7 nmol/l, and progression to a castrate resistant state. Survival curves were constructed to determine the rate of testosterone elevations. Multivariate Cox regression analysis was done to assess whether elevations predicted progression to castrate resistance. Median patient age was 74 years and median followup was 20.3 months. Within 5 years of followup 82%, 45% and 18% of patients had subsequent testosterone levels greater than 0.7, greater than 1.1 and greater than 1.7 nmol/l, respectively. In 96% to 100% of these patients levels less than 0.7 nmol/l were subsequently reestablished within 5 years. No patient baseline characteristic was associated with elevations and elevations were not a significant predictor of progression to a castrate resistant state. Men on continuous androgen deprivation therapy in whom initial testosterone is less than 0.7 nmol/l frequently show subsequent elevations in serum testosterone. Such a development should not trigger an immediate response from physicians as these events are prognostically insignificant with regard to oncologic outcomes. Levels are eventually reestablished at less than 0.7 nmol/l. Copyright © 2018 American Urological Association Education and Research, Inc. Published by

Significance of pretreatment cardiovascular morbidity as a risk factor during treatment with parenteral oestrogen or combined androgen deprivation of 915 patients with metastasized prostate cancer

DEFF Research Database (Denmark)

Johansson, Robert; Damber, Jan Erik; Hagerman, Inger

2011-01-01

This study aimed to evaluate prognostic risk factors for cardiovascular events during treatment of metastatic prostate cancer patients with high-dose parenteral polyoestradiol phosphate (PEP, Estradurin®) or combined androgen deprivation (CAD) with special emphasis on pretreatment cardiovascular...

Health-related quality of life for immediate versus delayed androgen-deprivation therapy in patients with asymptomatic, non-curable prostate cancer (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial.

Science.gov (United States)

Duchesne, Gillian M; Woo, Henry H; King, Madeleine; Bowe, Steven J; Stockler, Martin R; Ames, Alice; D'Este, Catherine; Frydenberg, Mark; Loblaw, Andrew; Malone, Shawn; Millar, Jeremy; Tai, Keen Hun; Turner, Sandra

2017-09-01

Androgen-deprivation therapy in patients with prostate cancer who have relapsed with rising prostate-specific antigen concentration only (PSA-only relapse), or with non-curable but asymptomatic disease at diagnosis, could adversely affect quality of life at a time when the disease itself does not. We aimed to compare the effect of immediate versus delayed androgen-deprivation therapy on health-related quality of life over 5 years in men enrolled in the TOAD (Timing of Androgen Deprivation) trial. This randomised, multicentre, open-label, phase 3 trial done in 29 public and private cancer centres across Australia, New Zealand, and Canada compared immediate with delayed androgen-deprivation therapy in men with PSA-only relapse after definitive treatment, or de-novo non-curable disease. Patients were randomly assigned (1:1) with a database-embedded, dynamically balanced algorithm to immediate androgen-deprivation therapy (immediate therapy group) or to delayed androgen-deprivation therapy (delayed therapy group). Any type of androgen-deprivation therapy was permitted, as were intermittent or continuous schedules. The European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaires QLQ-C30 and PR25 were completed before randomisation, every 6 months for 2 years, and annually for a further 3 years. The primary outcome of the trial, reported previously, was overall survival, with global health-related quality of life at 2 years as a secondary endpoint. Here we report prespecified secondary objectives of the quality-of-life endpoint. Analysis was by intention to treat. Statistical significance was set at p=0·0036. The trial was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12606000301561, and ClinicalTrials.gov, number NCT00110162. Between Sept 3, 2004, and July 13, 2012, 293 men were recruited and randomly assigned; 151 to the delayed therapy group and 142 to the immediate therapy group. There was no

National survey addressing the information needs of primary care physicians: Side effect management of patients on androgen deprivation therapy.

Science.gov (United States)

Soeyonggo, Tony; Locke, Jennifer; Giudice, Maria Elizabeth Del; Alibhai, Shabbir; Fleshner, Neil Eric; Warde, Padraig

2014-03-01

Androgen deprivation therapy (ADT) is a common treatment for prostate cancer with numerous side effects. We assess primary care physicians' (PCPs) knowledge of ADT side effects and their interest in increasing their knowledge in this area. A list of active Canadian PCPs was obtained using the Canadian Medical Directory. A cross-sectional survey was distributed to 600 randomly selected physicians. We collected PCPs' demographic information, experience with ADT management, knowledge regarding ADT side effects and desired sources for obtaining knowledge on ADT management. In total, we received 103 completed questionnaires. Of these, 89% of PCPs had patients on ADT. One-third of respondents prescribed ADT and over half of them administered ADT annually. Thirty-eight percent felt their knowledge of ADT side effects was inadequate and 50% felt uncomfortable counselling patients on ADT. Many PCPs were less familiar with the incidence of functional side effects of ADT (i.e., hot flashes, fatigue and erectile dysfunction) compared to life-threatening side effects (i.e., cardiovascular events, metabolic syndrome, fractures). In terms of increasing their knowledge of ADT side effects, 82% of PCPs would use educational resources if they were available (52% and 32% preferred continued medical education [CME] events and educational pamphlets, respectively). PCPs play an important role in managing ADT side effects. There is poor awareness of the prevalence of ADT side effects, and many are uncomfortable in managing these side effects. These areas may be addressed through CME programs and educational pamphlets.

Vascular responses to radiotherapy and androgen-deprivation therapy in experimental prostate cancer

International Nuclear Information System (INIS)

Røe, Kathrine; Mikalsen, Lars TG; Kogel, Albert J van der; Bussink, Johan; Lyng, Heidi; Ree, Anne H; Marignol, Laure; Olsen, Dag R

2012-01-01

Radiotherapy (RT) and androgen-deprivation therapy (ADT) are standard treatments for advanced prostate cancer (PC). Tumor vascularization is recognized as an important physiological feature likely to impact on both RT and ADT response, and this study therefore aimed to characterize the vascular responses to RT and ADT in experimental PC. Using mice implanted with CWR22 PC xenografts, vascular responses to RT and ADT by castration were visualized in vivo by DCE MRI, before contrast-enhancement curves were analyzed both semi-quantitatively and by pharmacokinetic modeling. Extracted image parameters were correlated to the results from ex vivo quantitative fluorescent immunohistochemical analysis (qIHC) of tumor vascularization (9 F1), perfusion (Hoechst 33342), and hypoxia (pimonidazole), performed on tissue sections made from tumors excised directly after DCE MRI. Compared to untreated (Ctrl) tumors, an improved and highly functional vascularization was detected in androgen-deprived (AD) tumors, reflected by increases in DCE MRI parameters and by increased number of vessels (VN), vessel density (VD), and vessel area fraction (VF) from qIHC. Although total hypoxic fractions (HF) did not change, estimated acute hypoxia scores (AHS) – the proportion of hypoxia staining within 50 μm from perfusion staining – were increased in AD tumors compared to in Ctrl tumors. Five to six months after ADT renewed castration-resistant (CR) tumor growth appeared with an even further enhanced tumor vascularization. Compared to the large vascular changes induced by ADT, RT induced minor vascular changes. Correlating DCE MRI and qIHC parameters unveiled the semi-quantitative parameters area under curve (AUC) from initial time-points to strongly correlate with VD and VF, whereas estimation of vessel size (VS) by DCE MRI required pharmacokinetic modeling. HF was not correlated to any DCE MRI parameter, however, AHS may be estimated after pharmacokinetic modeling. Interestingly, such

Effects of Hormone Deprivation, 2-Methoxyestradiol Combination Therapy on Hormone-Dependent Prostate Cancer In Vivo

Directory of Open Access Journals (Sweden)

Fuminori Sato

2005-09-01

Full Text Available 2-Methoxyestradiol (2-ME has potent anti proliferative effects on cancer cells. Its utility alone or in combination with other therapies for treating prostate cancer, however, has not been fully explored. Androgendependent, independent human prostate cancer cells were examined in vivo for their response to combination therapy. Efficacy was assessed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay, measuring microvessel density (MVD in excised tumors. Animals harboring hormonedependent tumors treated with 2-ME alone, androgen deprivation therapy alone, or the combination of the two had a 3.1-fold, 5.3-fold, 10.1-fold increase in apoptosis, respectively. For hormone-independent tumors, treatment with 2-ME resulted in a 2.43-fold increase in apoptosis, a 73% decrease in MVD. 2-ME was most effective against hormone-dependent tumors in vivo, combination therapy resulted in a significant increase in efficacy compared to no treatment controls, trended toward greater efficacy than either 2-ME or androgen deprivation alone. Combination therapy should be investigated further as an additional therapeutic option for early prostate cancer.

Plumbagin improves the efficacy of androgen deprivation therapy in prostate cancer: A pre-clinical study.

Science.gov (United States)

Abedinpour, Parisa; Baron, Véronique T; Chrastina, Adrian; Rondeau, Gaelle; Pelayo, Jennifer; Welsh, John; Borgström, Per

2017-12-01

Plumbagin is a candidate drug for the treatment of prostate cancer. Previous observations indicated that it may improve the efficacy of androgen deprivation therapy (ADT). This study evaluates the effectiveness of treatment with combinations of plumbagin and alternative strategies for ADT in mouse models of prostate cancer to support its clinical use. Plumbagin was administered per oral in a new sesame oil formulation. Standard toxicology studies were performed in rats. For tumor growth studies, mouse prostate cancer cell spheroids were placed on top of grafted prostate tissue in a dorsal chamber and allowed to form tumors. Mice were separated in various treatment groups and tumor size was measured over time by intra-vital microscopy. Survival studies were done in mice after injection of prostate cancer cells in the prostate of male animals. Androgen receptor (AR) levels were analyzed by Western blot from prostate cancer cells treated with plumbagin. Plumbagin caused a decrease in AR levels in vitro. In mice, plumbagin at 1 mg/kg in sesame oil displayed low toxicity and caused a 50% tumor regression when combined with castration. The combination of plumbagin with various forms of chemical ADT including treatment with a GnRH receptor agonist, a GnRH receptor antagonist, or CYP17A1 inhibitors, outperformed ADT alone, increasing mouse survival compared to the standard regimen of castration alone. In contrast, the combination of plumbagin with AR antagonists, such as bicalutamide and enzalutamide, showed no improvement over AR antagonists alone. Thus, plumbagin is effective in combination with drugs that prevent the synthesis of testosterone or its conversion to dihydrotestosterone, but not with drugs that bind to AR. Plumbagin significantly improves the effect of ADT drugs currently used in the clinic, with few side effects in mice. © 2017 Wiley Periodicals, Inc.

Androgen Receptor Signaling in Bladder Cancer

Science.gov (United States)

Li, Peng; Chen, Jinbo; Miyamoto, Hiroshi

2017-01-01

Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific differences in bladder cancer. This review summarizes and discusses the available data, suggesting the involvement of androgens and/or the androgen receptor pathways in urothelial carcinogenesis as well as tumor growth. While the precise mechanisms of the functions of the androgen receptor in urothelial cells remain far from being fully understood, current evidence may offer chemopreventive or therapeutic options, using androgen deprivation therapy, in patients with bladder cancer. PMID:28241422

Androgen Receptor Signaling in Bladder Cancer

Directory of Open Access Journals (Sweden)

Peng Li

2017-02-01

Full Text Available Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific differences in bladder cancer. This review summarizes and discusses the available data, suggesting the involvement of androgens and/or the androgen receptor pathways in urothelial carcinogenesis as well as tumor growth. While the precise mechanisms of the functions of the androgen receptor in urothelial cells remain far from being fully understood, current evidence may offer chemopreventive or therapeutic options, using androgen deprivation therapy, in patients with bladder cancer.

Sunitinib Plus Androgen Deprivation and Radiation Therapy for Patients With Localized High-Risk Prostate Cancer: Results From a Multi-institutional Phase 1 Study

International Nuclear Information System (INIS)

Corn, Paul G.; Song, Danny Y.; Heath, Elisabeth; Maier, Jordan; Meyn, Raymond; Kuban, Deborah; DePetrillo, Thomas A.; Mathew, Paul

2013-01-01

Purpose: To evaluate the feasibility of administering sunitinib in combination with androgen deprivation therapy and external-beam intensity modulated radiation therapy (XRT) in patients with localized high-risk prostate cancer. Methods and Materials: Seventeen men with localized adenocarcinoma of the prostate with cT2c-cT4 or Gleason 8-10 or prostate-specific antigen >20 ng/mL received initial androgen deprivation (leuprolide 22.5 mg every 12 weeks plus oral bicalutamide 50 mg daily) for 4-8 weeks before oral sunitinib 12.5, 25, or 37.5 mg daily for 4 weeks as lead-in, then concurrently with and 4 weeks after XRT (75.6 Gy in 42 fractions to prostate and seminal vesicles). A 3+3 sequential dose-escalation design was used to assess the frequency of dose-limiting toxicity (DLT) and establish a maximal tolerated dose of sunitinib. Results: Sunitinib at 12.5- and 25-mg dose levels was well tolerated. The first 4 patients enrolled at 37.5 mg experienced a DLT during lead-in, and a drug interaction between sunitinib and bicalutamide was suspected. The protocol was revised and concurrent bicalutamide omitted. Of the next 3 patients enrolled at 37.5 mg, 2 of 3 receiving concurrent therapy experienced DLTs during radiation: grade 3 diarrhea and grade 3 proctitis, respectively. Only 1 of 7 patients completed sunitinib at 37.5 mg daily, whereas 3 of 3 patients (25 mg as starting dose) and 3 of 4 patients (25 mg as reduced dose) completed therapy. Conclusions: The feasibility of combined vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitor therapy, androgen deprivation, and radiation therapy for prostate cancer was established. Using a daily dosing regimen with lead-in, concurrent, and post-XRT therapy, the recommended phase 2 dose of sunitinib is 25 mg daily

Sunitinib Plus Androgen Deprivation and Radiation Therapy for Patients With Localized High-Risk Prostate Cancer: Results From a Multi-institutional Phase 1 Study

Energy Technology Data Exchange (ETDEWEB)

Corn, Paul G., E-mail: pcorn@mdanderson.org [Department of Genitourinary Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Song, Danny Y. [Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland (United States); Heath, Elisabeth; Maier, Jordan [Karmanos Cancer Institute, Wayne State University, Detroit, Michigan (United States); Meyn, Raymond [Department of Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Kuban, Deborah [Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); DePetrillo, Thomas A. [Department of Radiation Oncology, Tufts Medical Center, Boston, Massachusetts (United States); Mathew, Paul, E-mail: pmathew@tuftsmedicalcenter.org [Department of Hematology-Oncology, Tufts Medical Center, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States)

2013-07-01

Purpose: To evaluate the feasibility of administering sunitinib in combination with androgen deprivation therapy and external-beam intensity modulated radiation therapy (XRT) in patients with localized high-risk prostate cancer. Methods and Materials: Seventeen men with localized adenocarcinoma of the prostate with cT2c-cT4 or Gleason 8-10 or prostate-specific antigen >20 ng/mL received initial androgen deprivation (leuprolide 22.5 mg every 12 weeks plus oral bicalutamide 50 mg daily) for 4-8 weeks before oral sunitinib 12.5, 25, or 37.5 mg daily for 4 weeks as lead-in, then concurrently with and 4 weeks after XRT (75.6 Gy in 42 fractions to prostate and seminal vesicles). A 3+3 sequential dose-escalation design was used to assess the frequency of dose-limiting toxicity (DLT) and establish a maximal tolerated dose of sunitinib. Results: Sunitinib at 12.5- and 25-mg dose levels was well tolerated. The first 4 patients enrolled at 37.5 mg experienced a DLT during lead-in, and a drug interaction between sunitinib and bicalutamide was suspected. The protocol was revised and concurrent bicalutamide omitted. Of the next 3 patients enrolled at 37.5 mg, 2 of 3 receiving concurrent therapy experienced DLTs during radiation: grade 3 diarrhea and grade 3 proctitis, respectively. Only 1 of 7 patients completed sunitinib at 37.5 mg daily, whereas 3 of 3 patients (25 mg as starting dose) and 3 of 4 patients (25 mg as reduced dose) completed therapy. Conclusions: The feasibility of combined vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitor therapy, androgen deprivation, and radiation therapy for prostate cancer was established. Using a daily dosing regimen with lead-in, concurrent, and post-XRT therapy, the recommended phase 2 dose of sunitinib is 25 mg daily.

Antisense-MDM2 Sensitizes LNCaP Prostate Cancer Cells to Androgen Deprivation, Radiation, and the Combination In Vivo

International Nuclear Information System (INIS)

Stoyanova, Radka; Hachem, Paul; Hensley, Harvey; Khor, L.-Y.; Mu Zhaomei; Hammond, M. Elizabeth H.; Agrawal, Sudhir; Pollack, Alan

2007-01-01

Purpose: To test the effects of antisense (AS)-MDM2 alone and with androgen deprivation (AD), radiotherapy (RT), and AD + RT on wild-type LNCaP cells in an orthotopic in vivo model. Methods: Androgen-sensitive LNCaP cells were grown in the prostates of nude mice. Magnetic resonance imaging-based tumor volume and serum prostate-specific antigen (PSA) measurements were used to assess effects on tumor response. Tumor response was measured by biochemical and tumor volume failure definitions and doubling time estimates from fitted PSA and tumor volume growth curves. Expression of MDM2, p53, p21, and Ki-67 was quantified using immunohistochemical staining and image analysis of formalin-fixed tissue, analogous to methods used clinically. Results: Antisense-MDM2 significantly inhibited the growth of LNCaP tumors over the mismatch controls. The most significant increase in tumor growth delay and tumor doubling time was from AS-MDM2 + AD + RT, although the effect of AS-MDM2 + AD was substantial. Expression of MDM2 was significantly reduced by AS-MDM2 in the setting of RT. Conclusions: This is the first in vivo investigation of the effects of AS-MDM2 in an orthotopic model and the first to demonstrate incremental sensitization when added to AD and AD + RT. The results with AD underscore the potential to affect micrometastatic disease, which is probably responsible for treatment failure in 30-40% of men with high-risk disease

Evaluating Intermittent Androgen-Deprivation Therapy Phase III Clinical Trials: The Devil Is in the Details.

Science.gov (United States)

Hussain, Maha; Tangen, Catherine; Higano, Celestia; Vogelzang, Nicholas; Thompson, Ian

2016-01-20

Intermittent androgen deprivation (IAD) has been widely tested in prostate cancer. However, phase III trials testing continuous androgen deprivation (CAD) versus IAD have reached inconclusive and seemingly contradictory results. Different design and conduct issues must be critically evaluated to better interpret the results. Seven published phase III trials were examined for prespecified design and outcomes. Treatment specifications; primary end point; superiority versus noninferiority design assumptions, including magnitude of assumed versus observed noninferiority margin (NIM); duration of follow-up; and quality-of-life (QOL) outcomes were considered in terms of the results and conclusions reported. Five trials had a superiority and three had a noninferiority primary hypothesis. Only three trials had a uniform population and overall survival (OS) end point. All trials observed better outcomes in terms of OS and progression-free survival (PFS) than assumed at time of study design, translating into prespecified NIMs or hazard ratios that reflected larger absolute differences in OS or PFS between arms. Lower-than-expected event rates also reduced statistical power for the trials. Other factors, including length of follow-up, cause of death, QOL, and primary end point, and their impact on trial interpretation are discussed. No trial to date has demonstrated survival superiority of IAD compared with CAD. Trials concluding IAD is noninferior to CAD were based on wide NIMs that included clinically important survival differences, not likely to be considered comparable by physicians or patients. Interim analyses relying on short follow-up and including a majority of non-prostate cancer deaths will favor a noninferiority conclusion and should be interpreted cautiously. Adequate follow-up is required to ensure capture of prostate cancer deaths in both superiority and noninferiority trials. © 2015 by American Society of Clinical Oncology.

Prostate cancer: assessing the effects of androgen-deprivation therapy using quantitative diffusion-weighted and dynamic contrast-enhanced MRI

International Nuclear Information System (INIS)

Hoetker, Andreas M.; Mazaheri, Yousef; Zheng, Junting; Moskowitz, Chaya S.; Berkowitz, Joshua; Pei, Xin; Zelefsky, Michael J.; Lantos, Joshua E.; Hricak, Hedvig; Akin, Oguz

2015-01-01

To investigate the effects of androgen-deprivation therapy (ADT) on MRI parameters and evaluate their associations with treatment response measures. The study included 30 men with histopathologically confirmed prostate cancer who underwent MRI before and after initiation of ADT. Thirty-four tumours were volumetrically assessed on DW-MRI (n = 32) and DCE-MRI (n = 18), along with regions of interest in benign prostatic tissue, to calculate apparent diffusion coefficient (ADC) and transfer constant (K trans ) values. Changes in MRI parameters and correlations with clinical parameters (change in prostate-specific antigen [PSA], treatment duration, PSA nadir) were assessed. Prostate volume and PSA values decreased significantly with therapy (p < 0.001). ADC values increased significantly in tumours and decreased in benign prostatic tissue (p < 0.05). Relative changes in ADC and absolute post-therapeutic ADC values differed significantly between tumour and benign tissue (p < 0.001). K trans decreased significantly only in tumours (p < 0.001); relative K trans changes and post-therapeutic values were not significantly different between tumour and benign tissue. The relative change in tumour ADC correlated significantly with PSA decrease. No changes were associated with treatment duration or PSA nadir. Multi-parametric MRI shows significant measurable changes in tumour and benign prostate caused by ADT and may help in monitoring treatment response. (orig.)

Unraveling the Complexities of Androgen Receptor Signaling in Prostate Cancer Cells

OpenAIRE

Heemers, Hannelore V.; Tindall, Donald J.

2009-01-01

Androgen signaling is critical for proliferation of prostate cancer cells but cannot be fully inhibited by current androgen deprivation therapies. A study by Xu et al. in this issue of Cancer Cell provides insights into the complexities of androgen signaling in prostate cancer and suggests avenues to target a subset of androgen-sensitive genes.

Patterns of Declining Use and the Adverse Effect of Primary Androgen Deprivation on All-cause Mortality in Elderly Men with Prostate Cancer.

Science.gov (United States)

Sammon, Jesse D; Abdollah, Firas; Reznor, Gally; Pucheril, Daniel; Choueiri, Toni K; Hu, Jim C; Kim, Simon P; Schmid, Marianne; Sood, Akshay; Sun, Maxine; Kibel, Adam S; Nguyen, Paul L; Menon, Mani; Trinh, Quoc-Dien

2015-07-01

Primary androgen deprivation therapy (pADT) is commonly used to treat elderly men diagnosed with localized prostate cancer (CaP), despite the lack of evidence supporting its use. To examine the effect of pADT on mortality and to assess contemporary trends of pADT use in elderly men with CaP. Men older than 65 yr residing in Surveillance, Epidemiology, and End Results (SEER) registry areas diagnosed with localized or locally advanced CaP between 1992 and 2009 and not receiving definitive therapy. Propensity score (PS)-weighted Cox proportional hazards models were used to estimate the effect of pADT use on overall survival among patients receiving pADT. The interaction between comorbidity-adjusted life expectancy (LE) and pADT use was assessed within the Cox and PS-weighted models. Contemporary (2004-2009) trends for pADT use were analyzed by linear regression. The primary cohort included 46 376 men, of whom 17 873 received pADT (39%). Patients with >10 yr LE had lower pADT utilization rates than patients with short LE. Between 2004 and 2009, the use of pADT in men with localized CaP decreased by 14% (from 36% to 22%). Relative to observation, pADT was associated with a survival disadvantage, with a hazard ratio for all-cause mortality of 1.37 (95% confidence interval 1.20-1.56). Limitations included biases not accounted for by the PS-weighted model, changes in CaP staging over the study period, the absence of prostate-specific antigen (PSA) data prior to 2004, and the limits of retrospective analysis to demonstrate causality. The use of pADT in elderly men with localized CaP has decreased over time. For men forgoing primary definitive therapy, the use of pADT is not associated with a survival benefit compared to observation, and denies men an opportunity for cure with definitive therapy. The deleterious effect of pADT is most pronounced in men with prolonged LE. In this report, we assessed the effect of primary androgen deprivation (pADT) on prostate cancer

Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer: part 2. Final evaluation of the Scandinavian Prostatic Cancer Group (SPCG) Study No. 5

DEFF Research Database (Denmark)

Hedlund, P.O.; Damber, J.E.; Hagerman, I.

2008-01-01

To compare parenteral estrogen therapy in the form of high-dose polyestradiol phosphate (PEP; Estradurin) with combined androgen deprivation (CAD) in the treatment of prostate cancer patients with skeletal metastases. The aim of the study was to compare anticancer efficacy and adverse events...

Androgen Deprivation and Thromboembolic Events in Men with Prostate Cancer

Science.gov (United States)

Ehdaie, Behfar; Atoria, Coral L.; Gupta, Amit; Feifer, Andrew; Lowrance, William T.; Morris, Michael J.; Scardino, Peter T.; Eastham, James A.; Elkin, Elena B.

2011-01-01

Background Androgen deprivation therapy (ADT) improves prostate cancer outcomes in specific clinical settings, but is associated with adverse effects, including cardiac complications and possibly thromboembolic complications. Our objective was to estimate the impact of ADT on thromboembolic events (TEs) in a population-based cohort. Methods In the linked Surveillance, Epidemiology and End Results (SEER)-Medicare database, we identified men aged over 65 diagnosed with non-metastatic prostate cancer between 1999 and 2005. Medical or surgical ADT was identified by Medicare claims for gonadotropin-releasing hormone agonists or bilateral orchiectomy at any time following diagnosis. TEs included deep venous thrombosis, pulmonary embolism, and arterial embolism. We estimated ADT’s impact on the risk of any TE and on total number of events, controlling for patient and tumor characteristics. Results Of 154,611 prostate cancer patients, 58,466 (38%) received ADT. During a median follow-up of 52 months, 15,950 men had at least one TE, including 8,829 (55%) who had ADT and 7,121 (45%) with no ADT. ADT was associated with increased risk of a TE (adjusted hazard ratio 1.56, 95% CI: 1.50 to 1.61, P < 0.0001), and duration of ADT was associated with the total number of events (P < 0.0001). Conclusion In this population-based cohort, ADT was associated with increased risk of a TE, and longer durations of ADT were associated with more TEs. Men with intermediate- and low-risk prostate cancer should be assessed for TE risk factors before starting ADT and counseled regarding the risks and benefits of this therapy. PMID:22072494

Risk of fracture in men with prostate cancer on androgen deprivation therapy: a population-based cohort study in New Zealand

International Nuclear Information System (INIS)

Wang, Alice; Obertová, Zuzana; Brown, Charis; Karunasinghe, Nishi; Bishop, Karen; Ferguson, Lynnette; Lawrenson, Ross

2015-01-01

Androgen deprivation therapy (ADT) administered as a prostate cancer treatment is known to exert multiple side effects including bone deterioration leading to bone fracture. The current analysis is to evaluate the burden of fracture risk in the New Zealand prostate cancer (PCa) population treated with ADT, and to understand the subsequent risk of mortality after a fracture. Using datasets created through linking records from the New Zealand Cancer Registry, National Minimal Dataset, Pharmaceutical Collection and Mortality Collection, we studied 25,544 men (aged ≥40 years) diagnosed with PCa between 2004 and 2012. ADT was categorised into the following groups: gonadotropin-releasing hormone (GnRH) agonists, anti-androgens, combined androgen blockade (GnRH agonists plus anti-androgens), bilateral orchiectomy, and bilateral orchiectomy plus pharmacologic ADT (anti-androgens and/or GnRH agonists). Among patients receiving ADT, 10.8 % had a fracture compared to 3.2 % of those not receiving ADT (p < 0.0001). After controlling for age and ethnicity, the use of ADT was associated with a significantly increased risk of any fracture (OR = 2.83; 95 % CI 2.52–3.17) and of hip fracture requiring hospitalisation (OR = 1.82; 95 % CI 1.44–2.30). Those who received combined androgen blockade (OR = 3.48; 95 % CI 3.07–3.96) and bilateral orchiectomy with pharmacologic ADT (OR = 4.32; 95 % CI 3.34–5.58) had the greatest risk of fracture. The fracture risk following different types of ADT was confounded by pathologic fractures and spinal cord compression (SCC). ADT recipients with fractures had a 1.83-fold (95 % CI 1.68–1.99) higher mortality risk than those without a fracture. However, after the exclusion of pathologic fractures and SCC, there was no increased risk of mortality. ADT was significantly associated with an increased risk of any fracture and hip fracture requiring hospitalisation. The excess risk was partly driven by pathologic fractures and SCC which are

Prostate cancer: assessing the effects of androgen-deprivation therapy using quantitative diffusion-weighted and dynamic contrast-enhanced MRI

Energy Technology Data Exchange (ETDEWEB)

Hoetker, Andreas M. [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States); Universitaetsmedizin Mainz, Department of Diagnostic and Interventional Radiology, Mainz (Germany); Mazaheri, Yousef [Memorial Sloan-Kettering Cancer Center, Department of Medical Physics, New York, NY (United States); Zheng, Junting; Moskowitz, Chaya S. [Memorial Sloan-Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY (United States); Berkowitz, Joshua; Pei, Xin; Zelefsky, Michael J. [Memorial Sloan-Kettering Cancer Center, Department of Radiation Oncology, New York, NY (United States); Lantos, Joshua E.; Hricak, Hedvig; Akin, Oguz [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States)

2015-09-15

To investigate the effects of androgen-deprivation therapy (ADT) on MRI parameters and evaluate their associations with treatment response measures. The study included 30 men with histopathologically confirmed prostate cancer who underwent MRI before and after initiation of ADT. Thirty-four tumours were volumetrically assessed on DW-MRI (n = 32) and DCE-MRI (n = 18), along with regions of interest in benign prostatic tissue, to calculate apparent diffusion coefficient (ADC) and transfer constant (K{sup trans}) values. Changes in MRI parameters and correlations with clinical parameters (change in prostate-specific antigen [PSA], treatment duration, PSA nadir) were assessed. Prostate volume and PSA values decreased significantly with therapy (p < 0.001). ADC values increased significantly in tumours and decreased in benign prostatic tissue (p < 0.05). Relative changes in ADC and absolute post-therapeutic ADC values differed significantly between tumour and benign tissue (p < 0.001). K{sup trans} decreased significantly only in tumours (p < 0.001); relative K{sup trans} changes and post-therapeutic values were not significantly different between tumour and benign tissue. The relative change in tumour ADC correlated significantly with PSA decrease. No changes were associated with treatment duration or PSA nadir. Multi-parametric MRI shows significant measurable changes in tumour and benign prostate caused by ADT and may help in monitoring treatment response. (orig.)

Computerized cognitive training in prostate cancer patients on androgen deprivation therapy: a pilot study.

Science.gov (United States)

Wu, Lisa M; Amidi, Ali; Tanenbaum, Molly L; Winkel, Gary; Gordon, Wayne A; Hall, Simon J; Bovbjerg, Katrin; Diefenbach, Michael A

2018-06-01

Prostate cancer patients who have undergone androgen deprivation therapy (ADT) may experience cognitive impairment, yet there is an unmet need for nonpharmacological interventions to address cognitive impairment in this population. This study examines the feasibility, acceptability, and preliminary efficacy of a home-based computerized cognitive training (CCT) program to treat cancer-related cognitive impairment. Sixty men who had received ≥ 3 months of ADT were screened for at least mild cognitive or neurobehavioral impairment and randomized to 8 weeks of CCT or usual care. Follow-up assessments occurred immediately post-intervention or equivalent (T2) and 8 weeks later (T3). The acceptability of CCT was also assessed. Feasibility:A priori feasibility thresholds were partially met (i.e., randomization rate > 50%, retention rate > 70% excluding CCT drop-outs, but cognitive functioning, neurobehavioral functioning, nor quality of life. This study provides tentative support for the feasibility and acceptability of CCT to treat mild cognitive impairment in ADT patients. CCT had a beneficial effect on reaction time, but temporarily suppressed memory. CCT's benefits may be limited to a narrow area of functioning. Larger-scale studies are needed.

Lifestyle guidelines for managing adverse effects on bone health and body composition in men treated with androgen deprivation therapy for prostate cancer: an update.

Science.gov (United States)

Owen, P J; Daly, R M; Livingston, P M; Fraser, S F

2017-06-01

Men treated with androgen deprivation therapy (ADT) for prostate cancer are prone to multiple treatment-induced adverse effects, particularly with regard to a deterioration in bone health and altered body composition including decreased lean tissue mass and increased fat mass. These alterations may partially explain the marked increased risk in osteoporosis, falls, fracture and cardiometabolic risk that has been observed in this population. A review was conducted that assessed standard clinical guidelines for the management of ADT-induced adverse effects on bone health and body composition in men with prostate cancer. Currently, standard clinical guidelines exist for the management of various bone and metabolic ADT-induced adverse effects in men with prostate cancer. However, an evaluation of the effectiveness of these guidelines into routine practice revealed that men continued to experience increased central adiposity, and, unless pharmacotherapy was instituted, accelerated bone loss and worsening glycaemia occurred. This review discusses the current guidelines and some of the limitations, and proposes new recommendations based on emerging evidence regarding the efficacy of lifestyle interventions, particularly with regard to exercise and nutritional factors, to manage ADT-related adverse effects on bone health and body composition in men with prostate cancer.

The Interactions between Insulin and Androgens in Progression to Castrate-Resistant Prostate Cancer

Directory of Open Access Journals (Sweden)

Jennifer H. Gunter

2012-01-01

Full Text Available An association between the metabolic syndrome and reduced testosterone levels has been identified, and a specific inverse relationship between insulin and testosterone levels suggests that an important metabolic crosstalk exists between these two hormonal axes; however, the mechanisms by which insulin and androgens may be reciprocally regulated are not well described. Androgen-dependant gene pathways regulate the growth and maintenance of both normal and malignant prostate tissue, and androgen-deprivation therapy (ADT in patients exploits this dependence when used to treat recurrent and metastatic prostate cancer resulting in tumour regression. A major systemic side effect of ADT includes induction of key features of the metabolic syndrome and the consistent feature of hyperinsulinaemia. Recent studies have specifically identified a correlation between elevated insulin and high-grade PCa and more rapid progression to castrate resistant disease. This paper examines the relationship between insulin and androgens in the context of prostate cancer progression. Prostate cancer patients present a promising cohort for the exploration of insulin stabilising agents as adjunct treatments for hormone deprivation or enhancers of chemosensitivity for treatment of advanced prostate cancer.

The Interactions between Insulin and Androgens in Progression to Castrate-Resistant Prostate Cancer

Science.gov (United States)

Gunter, Jennifer H.; Lubik, Amy A.; McKenzie, Ian; Pollak, Michael; Nelson, Colleen C.

2012-01-01

An association between the metabolic syndrome and reduced testosterone levels has been identified, and a specific inverse relationship between insulin and testosterone levels suggests that an important metabolic crosstalk exists between these two hormonal axes; however, the mechanisms by which insulin and androgens may be reciprocally regulated are not well described. Androgen-dependant gene pathways regulate the growth and maintenance of both normal and malignant prostate tissue, and androgen-deprivation therapy (ADT) in patients exploits this dependence when used to treat recurrent and metastatic prostate cancer resulting in tumour regression. A major systemic side effect of ADT includes induction of key features of the metabolic syndrome and the consistent feature of hyperinsulinaemia. Recent studies have specifically identified a correlation between elevated insulin and high-grade PCa and more rapid progression to castrate resistant disease. This paper examines the relationship between insulin and androgens in the context of prostate cancer progression. Prostate cancer patients present a promising cohort for the exploration of insulin stabilising agents as adjunct treatments for hormone deprivation or enhancers of chemosensitivity for treatment of advanced prostate cancer. PMID:22548055

Endurance training improves insulin sensitivity and body composition in prostate cancer patients treated with androgen deprivation therapy.

Science.gov (United States)

Hvid, Thine; Winding, Kamilla; Rinnov, Anders; Dejgaard, Thomas; Thomsen, Carsten; Iversen, Peter; Brasso, Klaus; Mikines, Kari J; van Hall, Gerrit; Lindegaard, Birgitte; Solomon, Thomas P J; Pedersen, Bente K

2013-10-01

Insulin resistance and changes in body composition are side effects of androgen deprivation therapy (ADT) given to prostate cancer patients. The present study investigated whether endurance training improves insulin sensitivity and body composition in ADT-treated prostate cancer patients. Nine men undergoing ADT for prostate cancer and ten healthy men with normal testosterone levels underwent 12 weeks of endurance training. Primary endpoints were insulin sensitivity (euglycemic-hyperinsulinemic clamps with concomitant glucose-tracer infusion) and body composition (dual-energy X-ray absorptiometry and magnetic resonance imaging). The secondary endpoint was systemic inflammation. Statistical analysis was carried out using two-way ANOVA. Endurance training increased VO2max (ml(O2)/min per kg) by 11 and 13% in the patients and controls respectively (PBody weight (Pbody fat mass (FM) (Pbody mass (P=0.99) was unchanged. Additionally, reductions were observed in abdominal (Pcancer patients exhibited improved insulin sensitivity and body composition to a similar degree as eugonadal men.

Group-based exercise in daily clinical practice to improve physical fitness in men with prostate cancer undergoing androgen deprivation therapy

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Østergren, Peter; Ragle, Anne-Mette; Jakobsen, Henrik

2016-01-01

. This article describes the design of an ongoing prospective observational study to evaluate the potential benefits of exercise in daily clinical practice. METHODS AND ANALYSIS: Men diagnosed with prostate cancer starting or already receiving ADT at our facility are invited to participate in a 12-week exercise......INTRODUCTION: Level 1 evidence supports the use of supervised exercise to mitigate the adverse effects of androgen deprivation therapy (ADT) in men with prostate cancer. The data, however, have been generated in controlled research settings and might not be transferable to daily clinical practice...... programme implemented as the standard of care. Exclusion criteria are opioid-demanding treatment for skeletal pain, an Eastern Cooperative Oncology Group (ECOG) performance status above 2 or the inability to perform floor and machine exercises independently. The intervention consists of an initial...

Network analysis of an in vitro model of androgen-resistance in prostate cancer

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Detchokul, Sujitra; Elangovan, Aparna; Crampin, Edmund J.; Davis, Melissa J.; Frauman, Albert G.

2015-01-01

The development of androgen resistance is a major limitation to androgen deprivation treatment in prostate cancer. We have developed an in vitro model of androgen-resistance to characterise molecular changes occurring as androgen resistance evolves over time. Our aim is to understand biological network profiles of transcriptomic changes occurring during the transition to androgen-resistance and to validate these changes between our in vitro model and clinical datasets (paired samples before and after androgen-deprivation therapy of patients with advanced prostate cancer). We established an androgen-independent subline from LNCaP cells by prolonged exposure to androgen-deprivation. We examined phenotypic profiles and performed RNA-sequencing. The reads generated were compared to human clinical samples and were analysed using differential expression, pathway analysis and protein-protein interaction networks. After 24 weeks of androgen-deprivation, LNCaP cells had increased proliferative and invasive behaviour compared to parental LNCaP, and its growth was no longer responsive to androgen. We identified key genes and pathways that overlap between our cell line and clinical RNA sequencing datasets and analysed the overlapping protein-protein interaction network that shared the same pattern of behaviour in both datasets. Mechanisms bypassing androgen receptor signalling pathways are significantly enriched. Several steroid hormone receptors are differentially expressed in both datasets. In particular, the progesterone receptor is significantly differentially expressed and is part of the interaction network disrupted in both datasets. Other signalling pathways commonly altered in prostate cancer, MAPK and PI3K-Akt pathways, are significantly enriched in both datasets. The overlap between the human and cell-line differential expression profiles and protein networks was statistically significant showing that the cell-line model reproduces molecular patterns observed in

Androgen receptor and immune inflammation in benign prostatic hyperplasia and prostate cancer

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Izumi, Kouji; Li, Lei; Chang, Chawnshang

2014-01-01

Both benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are frequent diseases in middle-aged to elderly men worldwide. While both diseases are linked to abnormal growth of the prostate, the epidemiological and pathological features of these two prostate diseases are different. BPH nodules typically arise from the transitional zone, and, in contrast, PCa arises from the peripheral zone. Androgen deprivation therapy alone may not be sufficient to cure these two prostatic diseases due to its undesirable side effects. The alteration of androgen receptor-mediated inflammatory signals from infiltrating immune cells and prostate stromal/epithelial cells may play key roles in those unwanted events. Herein, this review will focus on the roles of androgen/androgen receptor signals in the inflammation-induced progression of BPH and PCa. PMID:26594314

Cardiovascular Adaptations to Recreational Football Training in Men with Type 2 Diabetes, Untrained Elderly Men and in Men with Prostate Cancer Receiving Androgen Deprivation Therapy

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Schmidt, Jakob Friis

Numerous people in the general population are not suffuciently physically active and the use of new exercise training modalities which could promote physically active lifestyles are important. The present PhD thesis includes studies , which investigated the effect of recreational football training...... in middle-aged men with type 2 diabetes, 65-75-year-old untrained men, men with prostate cancer receiving androgen deprivation therapy and the effect of life-long participation in football training in veteran football players. The primary purpose was to evaluate the structure and function of the heart...... by ultrasound (echocardiography) and in three studies football training was shown to have marked positive effects on the heart function. In addition cardiorespiratory fitness, blood pressure, resting heart rate and peripheral microvascular function was evaluated and in men with type 2 diabetes, elderly...

Planning magnetic resonance imaging for prostate cancer intensity-modulated radiation therapy: Impact on target volumes, radiotherapy dose and androgen deprivation administration.

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Horsley, Patrick J; Aherne, Noel J; Edwards, Grace V; Benjamin, Linus C; Wilcox, Shea W; McLachlan, Craig S; Assareh, Hassan; Welshman, Richard; McKay, Michael J; Shakespeare, Thomas P

2015-03-01

Magnetic resonance imaging (MRI) scans are increasingly utilized for radiotherapy planning to contour the primary tumors of patients undergoing intensity-modulated radiation therapy (IMRT). These scans may also demonstrate cancer extent and may affect the treatment plan. We assessed the impact of planning MRI detection of extracapsular extension, seminal vesicle invasion, or adjacent organ invasion on the staging, target volume delineation, doses, and hormonal therapy of patients with prostate cancer undergoing IMRT. The records of 509 consecutive patients with planning MRI scans being treated with IMRT for prostate cancer between January 2010 and July 2012 were retrospectively reviewed. Tumor staging and treatment plans before and after MRI were compared. Of the 509 patients, 103 (20%) were upstaged and 44 (9%) were migrated to a higher risk category as a result of findings at MRI. In 94 of 509 patients (18%), the MRI findings altered management. Ninety-four of 509 patients (18%) had a change to their clinical target volume (CTV) or treatment technique, and in 41 of 509 patients (8%) the duration of hormone therapy was changed because of MRI findings. The use of radiotherapy planning MRI altered CTV design, dose and/or duration of androgen deprivation in 18% of patients in this large, single institution series of men planned for dose-escalated prostate IMRT. This has substantial implications for radiotherapy target volumes and doses, as well as duration of androgen deprivation. Further research is required to investigate whether newer MRI techniques can simultaneously fulfill staging and radiotherapy contouring roles. © 2014 Wiley Publishing Asia Pty Ltd.

Dissecting the roles of the androgen receptor in prostate cancer from molecular perspectives.

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Hu, Jieping; Wang, Gongxian; Sun, Ting

2017-05-01

Androgen receptor plays a pivotal role in prostate cancer progression, and androgen deprivation therapy to intercept androgen receptor signal pathway is an indispensable treatment for most advanced prostate cancer patients to delay cancer progression. However, the emerging of castration-resistant prostate cancer reminds us the alteration of androgen receptor, which includes androgen receptor mutation, the formation of androgen receptor variants, and androgen receptor distribution in cancer cells. In this review, we introduce the process of androgen receptor and also its variants' formation, translocation, and function alteration by protein modification or interaction with other pathways. We dissect the roles of androgen receptor in prostate cancer from molecular perspective to provide clues for battling prostate cancer, especially castration-resistant prostate cancer.

Intratumoral conversion of adrenal androgen precursors drives androgen receptor-activated cell growth in prostate cancer more potently than de novo steroidogenesis.

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Kumagai, Jinpei; Hofland, Johannes; Erkens-Schulze, Sigrun; Dits, Natasja F J; Steenbergen, Jacobie; Jenster, Guido; Homma, Yukio; de Jong, Frank H; van Weerden, Wytske M

2013-11-01

Despite an initial response to hormonal therapy, patients with advanced prostate cancer (PC) almost always progress to castration-resistant disease (CRPC). Although serum testosterone (T) is reduced by androgen deprivation therapy, intratumoral T levels in CRPC are comparable to those in prostate tissue of eugonadal men. These levels could originate from intratumoral conversion of adrenal androgens and/or from de novo steroid synthesis. However, the relative contribution of de novo steroidogenesis to AR-driven cell growth is unknown. The relative contribution of androgen biosynthetic pathways to activate androgen receptor (AR)-regulated cell growth and expression of PSA, FKBP5, and TMPRSS2 was studied at physiologically relevant levels of adrenal androgen precursors and intermediates of de novo androgen biosynthesis in human prostate cancer cell lines, PC346C, VCaP, and LNCaP. In PC346C and VCaP, responses to pregnenolone and progesterone were absent or minimal, while large effects of adrenal androgen precursors were found. VCaP CRPC clones overexpressing CYP17A1 did not acquire an increased ability to use pregnenolone or progesterone to activate AR. In contrast, all precursors stimulated growth and gene expression in LNCaP cells, presumably resulting from the mutated AR in these cells. Our data indicate that at physiological levels of T precursors PC cells can generally convert adrenal androgens, while de novo steroidogenesis is not generally possible in PC cells and is not able to support AR transactivation and PC growth. © 2013 Wiley Periodicals, Inc.

Androgen deprivation results in time-dependent hypoxia in LNCaP prostate tumours: informed scheduling of the bioreductive drug AQ4N improves treatment response.

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Ming, Louise; Byrne, Niall M; Camac, Sarah Nicole; Mitchell, Christopher A; Ward, Claire; Waugh, David J; McKeown, Stephanie R; Worthington, Jenny

2013-03-15

Androgen withdrawal induces hypoxia in androgen-sensitive tissue; this is important as in the tumour microenvironment, hypoxia is known to drive malignant progression. Our study examined the time-dependent effect of androgen deprivation therapy (ADT) on tumour oxygenation and investigated the role of ADT-induced hypoxia on malignant progression in prostate tumours. LNCaP xenografted tumours were treated with anti-androgens and tumour oxygenation measured. Dorsal skin fold (DSF) chambers were used to image tumour vasculature in vivo. Quantitative PCR (QPCR) identified differential gene expression following treatment with bicalutamide. Bicalutamide-treated and vehicle-only-treated tumours were re-established in vitro, and invasion and sensitivity to docetaxel were measured. Tumour growth delay was calculated following treatment with bicalutamide combined with the bioreductive drug AQ4N. Tumour oxygenation measurements showed a precipitate decrease following initiation of ADT. A clinically relevant dose of bicalutamide (2 mg/kg/day) decreased tumour oxygenation by 45% within 24 hr, reaching a nadir of 0.09% oxygen (0.67 ± 0.06 mmHg) by Day 7; this persisted until Day 14 when it increased up to Day 28. Using DSF chambers, LNCaP tumours treated with bicalutamide showed loss of small vessels at Days 7 and 14 with revascularisation occurring by Day 21. QPCR showed changes in gene expression consistent with the vascular changes and malignant progression. Cells from bicalutamide-treated tumours were more malignant than vehicle-treated controls. Combining bicalutamide with AQ4N (50 mg/kg, single dose) caused greater tumour growth delay than bicalutamide alone. Our study shows that bicalutamide-induced hypoxia selects for cells that show malignant progression; targeting hypoxic cells may provide greater clinical benefit. Copyright © 2012 UICC.

Clinical evaluation of internal iliac artery anticancer drug infusion for the treatment of androgen-independent prostate cancer

International Nuclear Information System (INIS)

Cao Ye; Wang Jin; Nie Yong; Chen Hua; Huang Xinjie

2008-01-01

Objective: To evaluate the clinical efficacy of bilateral internal iliac artery chemotherapy infusion for the treatment of androgen-independent prostate cancer (ALPC). Methods: Thirty eight eases of confirmed AIPC were randomly divided into treatment group and control group. The patients in treatment group (23 cases) were treated with androgen deprivation therapy and regular internal iliac artery chemotherapy, while patients in control group (15 cases) were only received androgen deprivation therapy. The therapeutic efficacies of the two groups were compared and analyzed after completion of the treatment. Results: The clinical symptoms and maximum urine flow rates of' treatment group were improved rapidly 6 months later. After 2 years follow-up, the total efficacies of treatment group and control group were 65.2% and 26.7% respectively, showing a significant statistical difference (P<0.05). Conclusions: The treatment of AlPC with bilateral internal iliac artery chemotherapy is effective, providing melioration the quality of life and alleviation of the symptoms. (authors)

Evolving perspectives of the role of novel agents in androgen-independent prostate cancer

Directory of Open Access Journals (Sweden)

Sujith Kalmadi

2008-01-01

Full Text Available Metastatic androgen-independent prostate cancer presents an intriguing clinical challenge, with a subtle interaction between hormone-responsive and refractory tumor cell elements. The treatment of advanced prostate carcinoma, which had remained stagnant for several decades following the understanding of the link between androgenic stimulation and carcinogenesis, has now started to make steady headway with chemotherapy and targeted approaches. Metastatic prostate cancer is almost always treated with initial androgen deprivation, in various forms. However, despite such treatment androgen-independent prostate cancer cells eventually emerge and progress to threaten life. The therapeutic objectives for treatment of metastatic prostate cancer are to maintain the quality of life and prolong survival. The out-dated nihilistic dogma of deferring chemotherapy until the most advanced stages in advanced prostate cancer is now falling by the wayside with the development of newer effective, tolerable agents.

LncRNA HOTAIR Enhances the Androgen-Receptor-Mediated Transcriptional Program and Drives Castration-Resistant Prostate Cancer

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Ali Zhang

2015-10-01

Full Text Available Understanding the mechanisms of androgen receptor (AR activation in the milieu of low androgen is critical to effective treatment of castration-resistant prostate cancer (CRPC. Here, we report HOTAIR as an androgen-repressed lncRNA, and, as such, it is markedly upregulated following androgen deprivation therapies and in CRPC. We further demonstrate a distinct mode of lncRNA-mediated gene regulation, wherein HOTAIR binds to the AR protein to block its interaction with the E3 ubiquitin ligase MDM2, thereby preventing AR ubiquitination and protein degradation. Consequently, HOTAIR expression is sufficient to induce androgen-independent AR activation and drive the AR-mediated transcriptional program in the absence of androgen. Functionally, HOTAIR overexpression increases, whereas HOTAIR knockdown decreases, prostate cancer cell growth and invasion. Taken together, our results provide compelling evidence of lncRNAs as drivers of androgen-independent AR activity and CRPC progression, and they support the potential of lncRNAs as therapeutic targets.

Prospective study of exercise intervention in prostate cancer patients on androgen deprivation therapy

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Beydoun, Nadine; Bucci, Joseph A.; Chin, Yaw S.; Spry, Nigel; Newton, Robert; Galvão, Daniel A.

2014-01-01

Androgen deprivation therapy (ADT) is an important component of modern prostate cancer treatment. Survival benefits from neo-adjuvant and adjuvant hormones may take years to manifest, and balancing this with potential morbidity of therapy can be challenging. This study aimed to assess whether education and short-term combined aerobic and resistance exercises could help to ameliorate the adverse side effects of ADT. Eight hundred fifty-nine patients with relapsed or metastatic prostate cancer on leuprorelin acetate were allocated to three interventional streams based on patient preference and medical fitness: supervised group (Face-to-Face) exercise sessions, home-based (At Home) exercise or a support programme for those incapable of exercising (Support). Patients enrolled onto Face to Face underwent measurement of body composition and cardiorespiratory fitness variables at baseline and programme completion. Patients in the exercise streams were surveyed to determine the programme's impact on physical fitness and well-being. Statistically significant improvements (p<0.001) were seen in all measured cardiorespiratory fitness and strength variables. Programme attrition rates were low (75/859; 8.7%), the primary reason for withdrawal being discontinuation of hormones (70%). Programme satisfaction was high, with 98% of surveyed patients reporting a positive impact on fitness and 97% planning to continue exercising after programme completion. At 6 months, improved physical and emotional well-being was reported by 93 and 79% of patients, respectively. A short-term structured exercise intervention results in high compliance and significant improvements in muscle strength and cardiorespiratory fitness in prostate cancer patients on ADT.

Depressive symptomatology in men receiving androgen deprivation therapy for prostate cancer: a controlled comparison.

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Lee, Morgan; Jim, Heather S; Fishman, Mayer; Zachariah, Babu; Heysek, Randy; Biagioli, Matthew; Jacobsen, Paul B

2015-04-01

Prostate cancer patients who receive androgen deprivation therapy (ADT) often experience many physical and psychological side effects. ADT may be associated with increased risk for depression, but the relationship between ADT and depression is not fully understood. This study used a longitudinal design to assess depressive symptomatology in patients receiving ADT compared with two groups of matched controls. Participants were men initiating ADT treatment (ADT+ group; n = 61) and their matched controls: prostate cancer patients treated with radical prostatectomy (ADT- group; n = 61), and no-cancer controls (CA- group; n = 61). Depressive symptomatology was assessed using the Center for Epidemiological Studies Depression Scale at ADT initiation and again 6 months later. Differences in depressive symptomatology and rates of clinically significant depressive symptomatology were analyzed between groups at each time point and within groups over time. Between baseline and follow-up, ADT+ participants demonstrated increased depressive symptomatology and increased rates of clinically significant depressive symptomatology (ps depressive symptomatology than both control groups at follow-up (ps depressive symptomatology were higher in the ADT+ group than the ADT- and CA- groups at both time points (baseline: 28%, 5%, 12%; follow-up: 39%, 9%, 11%). Findings support the hypothesis that ADT administration yields increases in depression and suggest that the mechanism behind ADT's association with depression should be explored and that prostate cancer patients treated with ADT should receive particular focus in depression screening and intervention. Copyright © 2014 John Wiley & Sons, Ltd.

Influence of androgen deprivation therapy on the uptake of PSMA-targeted agents: Emerging opportunities challenges

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Bakht, Martin K.; Oh, So Won; Youn, Hye Won; Cheon, Gi Jeong; Kwak, Cheol; Kang, Keon Wook [Seoul National University College of Medicine, Seoul (Korea, Republic of)

2017-09-15

Prostate-specific membrane antigen (PSMA) is an attractive target for both diagnosis and therapy because of its high expression in the vast majority of prostate cancers. Development of small molecules for targeting PSMA is important for molecular imaging and radionuclide therapy of prostate cancer. Recent evidence implies that androgen-deprivation therapy increase PSMA-ligand uptake in some cases. The reported upregulations in PSMA-ligand uptake after exposure to second-generation antiandrogens such as enzalutamide and abiraterone might disturb PSMA-targeted imaging for staging and response monitoring of patients undergoing treatment with antiandrogen-based drugs. On the other hand, second-generation antiandrogens are emerging as potential endoradio-/chemosensitizers. Therefore, the enhancement of the therapeutic efficiency of PSMA-targeted theranostic methods can be listed as a new capability of antiandrogens. In this manuscript, we will present what is currently known about the mechanism of increasing PSMA uptake following exposure to antiandrogens. In addition, we will discuss whether these above-mentioned antiandrogens could play the role of endoradio-/chemosensitizers in combination with the well-established PSMA-targeted methods for pre-targeting of prostate cancer.

Influence of androgen deprivation therapy on the uptake of PSMA-targeted agents: Emerging opportunities challenges

International Nuclear Information System (INIS)

Bakht, Martin K.; Oh, So Won; Youn, Hye Won; Cheon, Gi Jeong; Kwak, Cheol; Kang, Keon Wook

2017-01-01

Prostate-specific membrane antigen (PSMA) is an attractive target for both diagnosis and therapy because of its high expression in the vast majority of prostate cancers. Development of small molecules for targeting PSMA is important for molecular imaging and radionuclide therapy of prostate cancer. Recent evidence implies that androgen-deprivation therapy increase PSMA-ligand uptake in some cases. The reported upregulations in PSMA-ligand uptake after exposure to second-generation antiandrogens such as enzalutamide and abiraterone might disturb PSMA-targeted imaging for staging and response monitoring of patients undergoing treatment with antiandrogen-based drugs. On the other hand, second-generation antiandrogens are emerging as potential endoradio-/chemosensitizers. Therefore, the enhancement of the therapeutic efficiency of PSMA-targeted theranostic methods can be listed as a new capability of antiandrogens. In this manuscript, we will present what is currently known about the mechanism of increasing PSMA uptake following exposure to antiandrogens. In addition, we will discuss whether these above-mentioned antiandrogens could play the role of endoradio-/chemosensitizers in combination with the well-established PSMA-targeted methods for pre-targeting of prostate cancer

Muscle function, physical performance and body composition changes in men with prostate cancer undergoing androgen deprivation therapy

Institute of Scientific and Technical Information of China (English)

Thomas W Storer; Renee Miciek; Thomas G Travison

2012-01-01

Prostate cancer (PCa) is the most common visceral malignancy in men with androgen deprivation therapy (ADT) the preferred therapy to suppress testosterone production and hence tumor growth.Despite its effectiveness in lowering testosterone,ADT is associated with side effects including loss of muscle mass,diminished muscle strength,decrements in physical performance,earlier fatigue and declining quality of life.This review reports a survey of the literature with a focus on changes in muscle strength,physical function and body composition,due to short-term and long-term ADT.Studies in these areas are sparse,especially well-controlled,prospective randomized trials.Cross-sectional and longitudinal data (up to 2 years) for men with PCa treated with ADT as well as patients with PCa not receiving ADT and age-matched healthy men are presented when available.Based on limited longitudinal data,the adverse effects of ADT on muscle function,physical performance and body composition occur shortly after the onset of ADT andtend to persist and worsen over time.Exercise training is a safe and effective intervention for mitigating these changes and initial guidelines for exercise program design for men with PCa have been published by the American College of Sports Medicine.Disparities in study duration,typos of studies and other patient-specific variables such as time since diagnosis,cancer stage and comorbidities may all affect an understanding of the influence of ADT on health,physical performance and mortality.

Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

Directory of Open Access Journals (Sweden)

Shakespeare TP

2016-03-01

Full Text Available Thomas P Shakespeare,1,2 Shea W Wilcox,1 Noel J Aherne1,2 1Department of Radiation Oncology, North Coast Cancer Institute, 2Faculty of Medicine, Rural Clinical School, The University of New South Wales, Coffs Harbour, New South Wales, Australia Background: Both dose-escalated external beam radiotherapy (DE-EBRT and androgen deprivation therapy (ADT improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. Findings: In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. Conclusion: There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered. Keywords: radiotherapy, IMRT, dose, dose escalation, dose de-escalation, androgen deprivation therapy

Neoadjuvant androgen deprivation plus prostatectomy for stage T3 disease: lack of PSA-based benefit even among patients with negative lymphadenectomy

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Hyslop, T; Corn, B; Werner-Wasik, M; Gomella, L

1995-07-01

Objective: Urologists have attempted to treat stage T3 prostate cancer by neoadjuvant total androgen deprivation (TAD) and prostatectomy. This approach has been disappointing because of the inability of ultrasonography to predict pathological disease status and frequent upstaging due to nodal positivity. Moreover, no reports give PSA-based outcome data among patients treated with TAD and prostatectomy. We therefore instituted a pilot study for T3 disease based on non-invasive staging (endorectal coil MRI), mandatory negative laparoscopic nodal dissections prior to hormonal manipulation, and prostatectomy followed by pathological and PSA-based outcome determinations. Materials and Methods: Twenty-one patients had negative laparoscopic lymphadenectomy followed by 4 months of neoadjuvant hormonal treatment (Lupron, Flutamide) prior to radical prostatectomy. Endorectal coil MRI was performed at the time of diagnosis and following hormonal treatment. Serum PSA was determined at 3 month intervals. Prostatectomy specimens were evaluated by 3 mm whole mount step sections. Results: Median age was 63 (range: 51-68). Karnofsky performance status was 90-100 in all patients. The median number of nodes sampled was 10 (range: 2-60). Prior to prostatectomy, downsizing was observed by MRI in 57% and biochemical response was documented in all patients. However, pathological downstaging to a lower state ({<=}T2c) was achieved in only 48%. The actuarial 3 year freedom from biochemical relapse was only 24%. Conclusion: Neither serum PSA response nor MRI downsizing predicted pathological disease status after pre-operative androgen deprivation. Even in the setting of pathologically negative lymph nodes, TAD decreased the pathological stage of disease in the minority of patients. The present approach appeared to offer no advantage when compared with PSA-based benchmarks achieved with conformal irradiation (Urology 45: 484, 1995) or TAD followed by external beam treatment (IJROBP 27: 246

Neoadjuvant androgen deprivation plus prostatectomy for stage T3 disease: lack of PSA-based benefit even among patients with negative lymphadenectomy

International Nuclear Information System (INIS)

Hyslop, T.; Corn, B.; Werner-Wasik, M.; Gomella, L.

1995-01-01

Objective: Urologists have attempted to treat stage T3 prostate cancer by neoadjuvant total androgen deprivation (TAD) and prostatectomy. This approach has been disappointing because of the inability of ultrasonography to predict pathological disease status and frequent upstaging due to nodal positivity. Moreover, no reports give PSA-based outcome data among patients treated with TAD and prostatectomy. We therefore instituted a pilot study for T3 disease based on non-invasive staging (endorectal coil MRI), mandatory negative laparoscopic nodal dissections prior to hormonal manipulation, and prostatectomy followed by pathological and PSA-based outcome determinations. Materials and Methods: Twenty-one patients had negative laparoscopic lymphadenectomy followed by 4 months of neoadjuvant hormonal treatment (Lupron, Flutamide) prior to radical prostatectomy. Endorectal coil MRI was performed at the time of diagnosis and following hormonal treatment. Serum PSA was determined at 3 month intervals. Prostatectomy specimens were evaluated by 3 mm whole mount step sections. Results: Median age was 63 (range: 51-68). Karnofsky performance status was 90-100 in all patients. The median number of nodes sampled was 10 (range: 2-60). Prior to prostatectomy, downsizing was observed by MRI in 57% and biochemical response was documented in all patients. However, pathological downstaging to a lower state (≤T2c) was achieved in only 48%. The actuarial 3 year freedom from biochemical relapse was only 24%. Conclusion: Neither serum PSA response nor MRI downsizing predicted pathological disease status after pre-operative androgen deprivation. Even in the setting of pathologically negative lymph nodes, TAD decreased the pathological stage of disease in the minority of patients. The present approach appeared to offer no advantage when compared with PSA-based benchmarks achieved with conformal irradiation (Urology 45: 484, 1995) or TAD followed by external beam treatment (IJROBP 27: 246

Effects of androgens on insulin action in women: is androgen excess a component of female metabolic syndrome?

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Corbould, A

2008-10-01

Hyperinsulinemia as a consequence of insulin resistance causes hyperandrogenemia in women. The objective was to review evidence for the converse situation, i.e. whether androgens adversely influence insulin action. Androgen excess could potentially contribute to the pathogenesis of insulin resistance in women with polycystic ovary syndrome (PCOS), metabolic syndrome/type 2 diabetes, and in obese peripubertal girls. An Entrez-PubMed search was conducted to identify studies addressing the relationship of androgens with metabolic syndrome/type 2 diabetes in women. Studies reporting outcomes of androgen administration, interventions to reduce androgen effects in hyperandrogenemic women, and basic studies investigating androgen effects on insulin target tissues were reviewed. Multiple studies showed associations between serum testosterone and insulin resistance or metabolic syndrome/type 2 diabetes risk in women, but their cross-sectional nature did not allow conclusions about causality. Androgen administration to healthy women was associated with development of insulin resistance. Intervention studies in women with hyperandrogenism were limited by small subject numbers and use of indirect methods for assessing insulin sensitivity. However, in three of the seven studies using euglycemic hyperinsulinemic clamps, reduction of androgen levels or blockade of androgen action improved insulin sensitivity. Testosterone administration to female rats caused skeletal muscle insulin resistance. Testosterone induced insulin resistance in adipocytes of women in vitro. In conclusion, the metabolic consequences of androgen excess in women have been under-researched. Studies of long-term interventions that lower androgen levels or block androgen effects in young women with hyperandrogenism are needed to determine whether these might protect against metabolic syndrome/type 2 diabetes in later life. Copyright (c) 2008 John Wiley & Sons, Ltd.

Associations between statin use and progression in men with prostate cancer treated with primary androgen deprivation therapy

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Mikkelsen, Marta Kramer; Thomsen, Frederik Birkebæk; Berg, Kasper Drimer

2017-01-01

between statin use and risk of progression, HR 0.98 (95% CI: 0.72-1.32). In competing risk analyses the 5-year cumulative incidence of progression was 55% (95% CI: 46-64%) for statin users and 62% (95% CI: 57-67%) for non-statin users, p = 0.11. CONCLUSION: In the current study, statin use at time of PCa......INTRODUCTION: In several observational studies, statin use has been associated with reduced risk of progression and mortality in men with prostate cancer (PCa). The study aim was to investigate the association between statin use at time of PCa diagnosis and time to PCa progression in men...... with advanced or metastatic PCa receiving androgen deprivation therapy (ADT) as primary treatment. PATIENTS AND METHODS: The study population consisted of all men receiving ADT as primary therapy at two Danish Urological Departments in 2007-2013. The primary outcome was time to progression defined as castration...

Evaluation of primary androgen deprivation therapy in prostate cancer patients using the J-CAPRA risk score

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Akaza, Hideyuki; Hinotsu, Shiro; Usami, Michiyuki; Ogawa, Osamu; Kitamura, Tadaichi; Suzuki, Kazuhiro; Tsukamoto, Taiji; Naito, Seiji; Namiki, Mikio; Hirao, Yoshihiko; Murai, Masaru

2013-01-01

Purpose: To determine the influence of maximal androgen blockade (MAB) and non-MAB hormonal therapy with an luteinizing hormone releasing hormone (LHRH) analog on overall survival of prostate cancer patients in the Japan Study Group of Prostate Cancer (J-CaP) registry according to risk, as assessed using the novel J-CAPRA risk instrument. To undertake a multivariate analysis combining J-CAPRA risk score, type of hormonal therapy and comorbidities, in order to assess their impact on overall survival. Methods: The J-CaP database includes men in Japan diagnosed with any stage of prostate cancer between 2001 and 2003 and treated with primary androgen deprivation therapy (PADT), as monotherapy or in combination. A total of 26,272 men were enrolled and of these 19,265 were treated with PADT. This analysis was undertaken using the latest data set (30 April, 2010) including a total of 15,727 patients who received PADT and had follow-up data for periods ranging from 0 to 9.2 years. Results: MAB for prostate cancer patients with intermediate- or high-risk disease has a significant benefit in terms of overall survival compared with LHRH analog monotherapy or surgical castration alone. Better results may be achieved in older (≥75 years) patients. Patient comorbidities are an important factor in determining overall survival, notably in older patients, and should be considered when selecting therapy. Conclusions: Based on large-scale registry data, this report is the first to analyze the outcomes of MAB therapy in patients with prostate cancer at a wide range of disease stages. MAB therapy may provide significant survival benefits in intermediate- and high-risk patients. PMID:24223407

Metabolic syndrome in patients with prostate cancer undergoing intermittent androgen-deprivation therapy.

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Rezaei, Mohammadali Mohammadzadeh; Rezaei, Mohammadhadi Mohammadzadeh; Ghoreifi, Alireza; Kerigh, Behzad Feyzzadeh

2016-01-01

The presence of metabolic syndrome in men with prostate cancer (PCa) undergoing androgen-deprivation therapy (ADT), especially intermittent type, has not been completely evaluated. The aim of this study is to evaluate metabolic syndrome in men with PCa undergoing intermittent ADT. In this longitudinal study, we studied the prevalence of metabolic syndrome and its components in 190 patients who were undergoing intermittent ADT. The metabolic syndrome was defined according to the Adult Treatment Panel III criteria. All metabolic parameters, including lipid profile, blood glucose, blood pressures, and waist circumferences of the patients were measured six and 12 months after treatment. Mean age of the patients was 67.5 ± 6.74 years. The incidence of metabolic syndrome after six and 12 months was 6.8% and 14.7%, respectively. Analysis of various components of the metabolic syndrome revealed that patients had significantly higher overall prevalence of hyperglycemia, abdominal obesity, and hypertriglyceridemia in their six- and 12-month followups, but blood pressure has not been changed in the same period except for diastolic blood pressure after six months. Although there was an increased risk of metabolic syndrome in patients receiving intermittent ADT, it was lower than other studies that treated the same patients with continuous ADT. Also it seems that intermittent ADT has less metabolic complications than continuous ADT and could be used as a safe alternative in patients with advanced and metastatic PCa.

Androgen deprivation therapy impact on quality of life and cardiovascular health, monitoring therapeutic replacement.

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Trost, Landon W; Serefoglu, Ege; Gokce, Ahmet; Linder, Brian J; Sartor, Alton O; Hellstrom, Wayne J G

2013-02-01

Androgen deprivation therapy (ADT) is commonly utilized in the management of both localized and advanced adenocarcinoma of the prostate. The use of ADT is associated with several adverse events, physical changes, and development of medical comorbidities/mortality. The current article reviews known adverse events associated with ADT as well as treatment options, where available. Current recommendations and guidelines are cited for ongoing monitoring of patients receiving ADT. A PubMed search of topics relating to ADT and adverse outcomes was performed, with select articles highlighted and reviewed based on level of evidence and overall contribution. Reported outcomes of studies detailing adverse effects of ADT were reviewed and discussed. Where available, randomized trials and meta-analyses were reported. ADT may result in several adverse events including decreased libido, erectile dysfunction, vasomotor symptoms, cognitive, psychological and quality of life impairments, weight gain, sarcopenia, increased adiposity, gynecomastia, reduced penile/testicular size, hair changes, periodontal disease, osteoporosis, increased fracture risk, diabetes and insulin resistance, hyperlipidemia, and anemia. The definitive impact of ADT on lipid profiles, cardiovascular morbidity/mortality, and all-cause mortality is currently unknown with available data. Treatment options to reduce ADT-related adverse events include changing to an intermittent treatment schedule, biophysical therapy, counseling, and pharmacotherapy. Patients treated with ADT are at increased risk of several adverse events and should be routinely monitored for the development of potentially significant morbidity/mortality. Where appropriate, physicians should reduce known risk factors and counsel patients as to known risks and benefits of therapy. © 2013 International Society for Sexual Medicine.

Re: Final Report of the Intergroup Randomized Study of Combined AndrogenDeprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer

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Malcolm D. Mason

2015-06-01

Full Text Available No certain treatment recommendations were given for locally advanced or high-risk prostate cancer in the European Association of Urology (EAU guidelines (1. In the guidelines, studies supporting surgery or radiotherapy (RT were listed, and the readers were left alone to make their own decisions. In the present study, Mason et al. reported the impact of adding RT to androgen deprivation therapy (ADT. One thousand two hundred and five patients with T3- 4, N0/Nx, M0 prostate cancer or T1-2 disease with either PSA more than 40 μg/L or PSA 20 to 40 μg/L plus Gleason score of 8 to 10 were randomized to ADT alone (n=602 or to ADT+RT (n=603. A lower dose radiation 64 to 69 Gy was used for RT. Overall survival (OS risk reduction was 30% for ADT+RT group (P<0.001 at a median follow-up of 8 years. Cancer-specific survival (CSS was significantly improved by the addition of RT to ADT (HR: 0.46, 95% CI: 0.34 to 0.61; p<0.001. Patients on ADT+RT reported a higher frequency of adverse events related to bowel toxicity. However, reported frequency of ADT-related toxicities (impotence, hot flushes, urinary frequency, ischemia, and hypertension were similar for both arms. The present study provided results of high-risk patients in a longer median follow-up time than SPCG-7 study (2. Because the study took place between 1995 and 2005, less than 70 Gy was used for RT. Even at lower radiation doses, the authors confirmed that adding RT to ADT improved both OS and cancer-specific survival (CSS with minimal general toxicity. In the modern era, improved RT techniques may help achieve better outcomes with much higher radiation doses without increased morbidity in this group of patients

Context dependent regulatory patterns of the androgen receptor and androgen receptor target genes

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Olsen, Jan Roger; Azeem, Waqas; Hellem, Margrete Reime; Marvyin, Kristo; Hua, Yaping; Qu, Yi; Li, Lisha; Lin, Biaoyang; Ke, XI- Song; Øyan, Anne Margrete; Kalland, Karl- Henning

2016-01-01

Expression of the androgen receptor (AR) is associated with androgen-dependent proliferation arrest and terminal differentiation of normal prostate epithelial cells. Additionally, activation of the AR is required for survival of benign luminal epithelial cells and primary cancer cells, thus androgen deprivation therapy (ADT) leads to apoptosis in both benign and cancerous tissue. Escape from ADT is known as castration-resistant prostate cancer (CRPC). In the course of CRPC development the AR typically switches from being a cell-intrinsic inhibitor of normal prostate epithelial cell proliferation to becoming an oncogene that is critical for prostate cancer cell proliferation. A clearer understanding of the context dependent activation of the AR and its target genes is therefore desirable. Immortalized human prostate basal epithelial EP156T cells and progeny cells that underwent epithelial to mesenchymal transition (EMT), primary prostate epithelial cells (PrECs) and prostate cancer cell lines LNCaP, VCaP and 22Rv1 were used to examine context dependent restriction and activation of the AR and classical target genes, such as KLK3. Genome-wide gene expression analyses and single cell protein analyses were applied to study the effect of different contexts. A variety of growth conditions were tested and found unable to activate AR expression and transcription of classical androgen-dependent AR target genes, such as KLK3, in prostate epithelial cells with basal cell features or in mesenchymal type prostate cells. The restriction of androgen- and AR-dependent transcription of classical target genes in prostate basal epithelial cells was at the level of AR expression. Exogenous AR expression was sufficient for androgen-dependent transcription of AR target genes in prostate basal epithelial cells, but did not exert a positive feedback on endogenous AR expression. Treatment of basal prostate epithelial cells with inhibitors of epigenetic gene silencing was not efficient in

Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer

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Rosenberg JE

2012-01-01

Full Text Available Yasser Rehman1, Jonathan E Rosenberg21Division of Hospital Medicine, UMass Memorial Healthcare, Worcester, MA, USA; 2Lank Center for Genitourinary Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USAAbstract: Prostate cancer is the second leading cause of cancer death in men in the US and Europe. The treatment of advanced-stage prostate cancer has been androgen deprivation. Medical castration leads to decreased production of testosterone and dihydrotestosterone by the testes, but adrenal glands and even prostate cancer tissue continue to produce androgens, which eventually leads to continued prostate cancer growth despite castrate level of androgens. This stage is known as castrate-resistant prostate cancer (CRPC, which continues to be a challenge to treat. Addition of androgen antagonists to hormonal deprivation has been successful in lowering the prostate-specific antigen levels further, but has not actually translated into life-prolonging options. The results of several contemporary studies have continued to demonstrate activation of the androgen receptor as being the key factor in the continued growth of prostate cancer. Blockade of androgen production by nongonadal sources has led to clinical benefit in this setting. One such agent is abiraterone acetate, which significantly reduces androgen production by blocking the enzyme, cytochrome P450 17 alpha-hydroxylase (CYP17. This has provided physicians with another treatment option for patients with CRPC. The landscape for prostate cancer treatment has changed with the approval of cabazitaxel, sipuleucel-T and abiraterone. Here we provide an overview of abiraterone acetate, its mechanism of action, and its potential place for therapy in CRPC.Keywords: CRPC, abiraterone, CYP17, inhibitors, androgens, castration resistant prostate cancer

[Histopathological changes due to transurethural microwave thermotherapy associated with androgen deprivation therapy in patients with localized prostate cancer].

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Jujo, Yutaka; Koshiba, Ken; Suzuki, Ryuta; Hoshiai, Osamu; Endo, Tadao; Aihara, Masahiro; Katsuta, Masayuki; Nakajo, Hirotaka

2006-03-01

The 2nd generation transurethral microwave thermotherapy (TUMT), equipped with high energy microwave generator and urethral cooling device is widely accepted as an less invasive effective modality to treat benign prostatic hyperplasia. For prostatic cancer, however, it is generally estimated as insufficient because of limitation in penetration of microwave into deep prostatic tissue. In this study, we examined histopathologic changes after androgen deprivation theraphy (ADT) and TUMT. Ten patients with localized prostate cancer underwent ADT for 3 months, and then TUMT was proceeded using Urowave (Dornier MedTech GmbH). Additional 3 months after TUMT and continued ADT, TURP in radical fashion was performed in all the patients, and all the resected chips were submitted for pathological study. Significant reduction in prostate volume was noted after NHT for 3 months from 37.4 +/- 9.6 ml to 22.0 +/- 5.6 ml. The pathological study of resected chips revealed progressive fibrotic changes without viable cancer cells in 9 of 10 patients. In 1 patient, however, some remnant of carcinomatous foci were noted in a resected chip from the middle lobe of the prostate. Although the number of patient is limited and longer follow-up is needed, the results in present series was interested and worth considering.

Abiraterone acetate/androgen deprivation therapy combination versus docetaxel/androgen deprivation therapy combination in advanced hormone-sensitive prostate cancer: a network meta-analysis on safety and efficacy.

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Kassem, Loay; Shohdy, Kyrillus S; Abdel-Rahman, Omar

2018-05-01

A major, yet precisely studied, shift has occurred in the treatment of advanced hormone-sensitive prostate cancer (HSPC) by the addition of docetaxel to androgen deprivation therapy (ADT) in the first line. Recently, two landmark trials showed that abiraterone acetate (AA) can be an effective alternative along with ADT in the same setting. We implemented a network meta-analysis to compare the safety and efficacy of the two combinations. PubMed database, ASCO and ESMO meeting library databases of all results published until June 2017 were searched using the keywords: "prostate cancer" AND "docetaxel" OR "abiraterone acetate". Efficacy endpoints including progression-free survival (PFS) and overall survival (OS), and safety endpoints (including treatment related deaths and selected adverse events) were assessed. Twenty relevant studies were retrieved and assessed for eligibility. Of those trials, eight were found potentially eligible. Inconsistent reporting of efficacy outcomes limited our analysis to M1 HSPC. The pooled hazard ratios (HRs) of OS and PFS of the direct comparison of abiraterone acetate plus ADT versus ADT were 0.63 (95% CI: 0.545-0.717) and 0.38 (95% CI: 0.34-0.43), respectively. Meanwhile, in the trials of docetaxel plus ADT the pooled HRs of OS and PFS were 0.75 (95% CI: 0.65-0.86) and 0.634 (95% CI: 0.57-0.70), respectively. The indirect comparison showed that the HRs of OS and PFS in DOC + ADT in comparison to AA + ADT were 1.2 (95% CI: 0.98-1.46) and 1.65 (1.40-1.94), respectively. The pooled RR of treatment-related mortality in docetaxel + ADT versus AA + ADT was 1.438 (95% CI: 0.508-4.075). Patients with metastatic HSPC (mHSPC) who received abiraterone acetate with ADT had better PFS and less toxicity compared to those receiving docetaxel with ADT. A trend towards superior OS and fewer treatment-related deaths was also observed, but was statistically non-significant. In view of lacking clear OS advantage, the choice between

Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

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Shakespeare TP

2016-05-01

Full Text Available Thomas P Shakespeare,1,2 Shea W Wilcox,1 Noel J Aherne1,2 1Department of Radiation Oncology, North Coast Cancer Institute, 2Rural Clinical School, Faculty of Medicine, University of New South Wales, Coffs Harbour, NSW, Australia Aim: Both dose-escalated external beam radiotherapy (DE-EBRT and androgen deprivation therapy (ADT improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients and methods: Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3–6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. Results: In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. Conclusion: There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered. Keywords: radiotherapy, IMRT, dose

First off-time treatment prostate-specific antigen kinetics predicts survival in intermittent androgen deprivation for prostate cancer.

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Sanchez-Salas, Rafael; Olivier, Fabien; Prapotnich, Dominique; Dancausa, José; Fhima, Mehdi; David, Stéphane; Secin, Fernando P; Ingels, Alexandre; Barret, Eric; Galiano, Marc; Rozet, François; Cathelineau, Xavier

2016-01-01

Prostate-specific antigen (PSA) doubling time is relying on an exponential kinetic pattern. This pattern has never been validated in the setting of intermittent androgen deprivation (IAD). Objective is to analyze the prognostic significance for PCa of recurrent patterns in PSA kinetics in patients undergoing IAD. A retrospective study was conducted on 377 patients treated with IAD. On-treatment period (ONTP) consisted of gonadotropin-releasing hormone agonist injections combined with oral androgen receptor antagonist. Off-treatment period (OFTP) began when PSA was lower than 4 ng/ml. ONTP resumed when PSA was higher than 20 ng/ml. PSA values of each OFTP were fitted with three basic patterns: exponential (PSA(t) = λ.e(αt)), linear (PSA(t) = a.t), and power law (PSA(t) = a.t(c)). Univariate and multivariate Cox regression model analyzed predictive factors for oncologic outcomes. Only 45% of the analyzed OFTPs were exponential. Linear and power law PSA kinetics represented 7.5% and 7.7%, respectively. Remaining fraction of analyzed OFTPs (40%) exhibited complex kinetics. Exponential PSA kinetics during the first OFTP was significantly associated with worse oncologic outcome. The estimated 10-year cancer-specific survival (CSS) was 46% for exponential versus 80% for nonexponential PSA kinetics patterns. The corresponding 10-year probability of castration-resistant prostate cancer (CRPC) was 69% and 31% for the two patterns, respectively. Limitations include retrospective design and mixed indications for IAD. PSA kinetic fitted with exponential pattern in approximately half of the OFTPs. First OFTP exponential PSA kinetic was associated with a shorter time to CRPC and worse CSS. © 2015 Wiley Periodicals, Inc.

High-Dose Adjuvant Radiotherapy After Radical Prostatectomy With or Without Androgen Deprivation Therapy

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Ost, Piet; Cozzarini, Cesare; De Meerleer, Gert; Fiorino, Claudio; De Potter, Bruno; Briganti, Alberto; Nagler, Evi V.T.; Montorsi, Francesco; Fonteyne, Valérie; Di Muzio, Nadia

2012-01-01

Purpose: To retrospectively evaluate the outcome and toxicity in patients receiving high-dose (>69 Gy) adjuvant radiotherapy (HD-ART) and the impact of androgen deprivation therapy (ADT). Methods and Materials: Between 1999 and 2008, 225 node-negative patients were referred for HD-ART with or without ADT to two large academic institutions. Indications for HD-ART were extracapsular extension, seminal vesicle invasion (SVI), and/or positive surgical margins at radical prostatectomy (RP). A dose of at least 69.1 Gy was prescribed to the prostate bed and seminal vesicle bed. The ADT consisted of a luteinizing hormone–releasing hormone analog. The duration and indication of ADT was left at the discretion of the treating physician. The effect of HD-ART and ADT on biochemical (bRFS) and clinical (cRFS) relapse-free survival was examined through univariate and multivariate analysis, with correction for known patient- and treatment-related variables. Interaction terms were introduced to evaluate effect modification. Results: After a median follow-up time of 5 years, the 7-year bRFS and cRFS were 84% and 88%, respectively. On multivariate analysis, the addition of ADT was independently associated with an improved bRFS (hazard ratio [HR] 0.4, p = 0.02) and cRFS (HR 0.2, p = 0.008). Higher Gleason scores and SVI were associated with decreased bRFS and cRFS. A lymphadenectomy at the time of RP independently improved cRFS (HR 0.09, p = 0.009). The 7-year probability of late Grade 2–3 toxicity was 29% and 5% for genitourinary (GU) and gastrointestinal (GI) symptoms, respectively. The absolute incidence of Grade 3 toxicity was <1% and 10% for GI and GU symptoms, respectively. The study is limited by its retrospective design and the lack of a standardized use of ADT. Conclusions: This retrospective study shows significantly improved bRFS and cRFS rates with the addition of ADT to HD-ART, with low Grade 3 gastrointestinal toxicity and 10% Grade 3 genitourinary toxicity.

Multimodal therapy for locally advanced prostate cancer: the roles of radiotherapy, androgen deprivation therapy, and their combination

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Lee, Sung Uk; Cho, Kwan Ho [The Proton Therapy Center, Research Institute and Hospital, National Cancer Center, Goyang (Korea, Republic of)

2017-09-15

Locally advanced prostate cancer (LAPC) is defined as histologically proven T3–4 prostatic adenocarcinoma. In this review, we define the individual roles of radiotherapy (RT), short-term (ST-) and long-term (LT-) androgen deprivation therapy (ADT), and their combination in multimodal therapy for LAPC. Despite limitations in comparing the clinical outcomes among published papers, in the present study, a trend of 10-year clinical outcomes was roughly estimated by calculating the average rates weighted by the cohort number. With RT alone, the following rates were estimated: 87% biochemical failure, 34% local failure (LF), 48% distant metastasis (DM), 38% overall survival (OS), and 27% disease-specific mortality (DSM). Those associated with ADT alone were 74% BCF, 54% OS, and 25% DSM, which appeared to be better than those of RT alone. The addition of ADT to RT produced a notable local and systemic effect, regardless of ST- or LT-ADT. The LF rate decreased from 34% with RT alone to 21% with ST-ADT and further to 15% with LT-ADT. The DM and DSM rates also showed a similar trend among RT alone, RT+ST-ADT, and RT+LT-ADT. The combination of RT+LT-ADT resulted in the best long-term clinical outcomes, indicating that both RT and ADT are important parts of multimodal therapy.

Multimodal therapy for locally advanced prostate cancer: the roles of radiotherapy, androgen deprivation therapy, and their combination

International Nuclear Information System (INIS)

Lee, Sung Uk; Cho, Kwan Ho

2017-01-01

Locally advanced prostate cancer (LAPC) is defined as histologically proven T3–4 prostatic adenocarcinoma. In this review, we define the individual roles of radiotherapy (RT), short-term (ST-) and long-term (LT-) androgen deprivation therapy (ADT), and their combination in multimodal therapy for LAPC. Despite limitations in comparing the clinical outcomes among published papers, in the present study, a trend of 10-year clinical outcomes was roughly estimated by calculating the average rates weighted by the cohort number. With RT alone, the following rates were estimated: 87% biochemical failure, 34% local failure (LF), 48% distant metastasis (DM), 38% overall survival (OS), and 27% disease-specific mortality (DSM). Those associated with ADT alone were 74% BCF, 54% OS, and 25% DSM, which appeared to be better than those of RT alone. The addition of ADT to RT produced a notable local and systemic effect, regardless of ST- or LT-ADT. The LF rate decreased from 34% with RT alone to 21% with ST-ADT and further to 15% with LT-ADT. The DM and DSM rates also showed a similar trend among RT alone, RT+ST-ADT, and RT+LT-ADT. The combination of RT+LT-ADT resulted in the best long-term clinical outcomes, indicating that both RT and ADT are important parts of multimodal therapy

Androgen deprivation therapy for volume reduction, lower urinary tract symptom relief and quality of life improvement in patients with prostate cancer

DEFF Research Database (Denmark)

Axcrona, Karol; Aaltomaa, Sirpa; da Silva, Carlos Martins

2012-01-01

Study Type--Therapy (RCT) Level of Evidence 1b. What's known on the subject? and What does the study add? Androgen deprivation therapy (ADT) is commonly used as a primary treatment for patients with prostate cancer (PCa) who are not eligible for radical treatment options. ADT is also used...... in patients with PCa as neo-adjuvant hormone therapy to reduce prostate volume and down-stage the disease before radiotherapy with curative intent. The present study showed that ADT with the gonadotropin hormone-releasing hormone (GhRH) antagonist degarelix is non-inferior to combined treatment with the LHRH...... agonist goserelin and bicalutamide in terms of reducing prostate volume during the treatment period of 3 months. Degarelix treatment evokes, however, significantly better relief of lower urinary tract symptoms in patients having moderate and severe voiding problems....

Decision analytic cost-effectiveness model to compare prostate cryotherapy to androgen deprivation therapy for treatment of radiation recurrent prostate cancer

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Boyd, Kathleen A; Jones, Rob J; Paul, Jim; Birrell, Fiona; Briggs, Andrew H; Leung, Hing Y

2015-01-01

Objective To determine the cost-effectiveness of salvage cryotherapy (SC) in men with radiation recurrent prostate cancer (RRPC). Design Cost-utility analysis using decision analytic modelling by a Markov model. Setting and methods Compared SC and androgen deprivation therapy (ADT) in a cohort of patients with RRPC (biopsy proven local recurrence, no evidence of metastatic disease). A literature review captured published data to inform the decision model, and resource use data were from the Scottish Prostate Cryotherapy Service. The model was run in monthly cycles for RRPC men, mean age of 70 years. The model was run over the patient lifetime, to assess changes in patient health states and the associated quality of life, survival and cost impacts. Results are reported in terms of the discounted incremental costs and discounted incremental quality-adjusted life years (QALYs) gained between the 2 alternative interventions. Probabilistic sensitivity analysis used a 10 000 iteration Monte Carlo simulation. Results SC has a high upfront treatment cost, but delays the ongoing monthly cost of ADT. SC is the dominant strategy over the patient lifetime; it is more effective with an incremental 0.56 QALY gain (95% CI 0.28 to 0.87), and less costly with a reduced lifetime cost of £29 719 (€37 619) (95% CI −51 985 to −9243). For a ceiling ratio of £30 000, SC has a 100% probability to be cost-effective. The cost neutral point was at 3.5 years, when the upfront cost of SC (plus any subsequent cumulative cost of side effects and ADT) equates the cumulative cost in the ADT arm. Limitations of our model may arise from its insensitivity to parameter or structural uncertainty. Conclusions The platform for SC versus ADT cost-effective analysis can be employed to evaluate other treatment modalities or strategies in RRPC. SC is the dominant strategy, costing less over a patient's lifetime with improvements in QALYs. Trial registration number This economic analysis

Effects of recreational soccer in men with prostate cancer undergoing androgen deprivation therapy: study protocol for the ‘FC Prostate’ randomized controlled trial

International Nuclear Information System (INIS)

Uth, Jacob; Brasso, Klaus; Rørth, Mikael; Krustrup, Peter; Midtgaard, Julie; Schmidt, Jakob Friis; Christensen, Jesper Frank; Hornstrup, Therese; Andersen, Lars Juel; Hansen, Peter Riis; Christensen, Karl Bang; Andersen, Lars Louis; Helge, Eva Wulff

2013-01-01

Androgen deprivation therapy (ADT) is a cornerstone in the treatment of advanced prostate cancer. Adverse musculoskeletal and cardiovascular effects of ADT are widely reported and investigations into the potential of exercise to ameliorate the effects of treatment are warranted. The ‘Football Club (FC) Prostate’ study is a randomized trial comparing the effects of soccer training with standard treatment approaches on body composition, cardiovascular function, physical function parameters, glucose tolerance, bone health, and patient-reported outcomes in men undergoing ADT for prostate cancer. Using a single-center randomized controlled design, 80 men with histologically confirmed locally advanced or disseminated prostate cancer undergoing ADT for 6 months or more at The Copenhagen University Hospital will be enrolled on this trial. After baseline assessments eligible participants will be randomly assigned to a soccer training group or a control group receiving usual care. The soccer intervention will consist of 12 weeks of training 2–3 times/week for 45–60 min after which the assessment protocol will be repeated. Soccer training will then continue bi-weekly for an additional 20 weeks at the end of which all measures will be repeated to allow for additional analyses of long-term effects. The primary endpoint is changes in lean body mass from baseline to 12 weeks assessed by dual X-ray absorptiometry scan. Secondary endpoints include changes of cardiovascular, metabolic, and physical function parameters, as well as markers of bone metabolism and patient-reported outcomes. The FC Prostate trial will assess the safety and efficacy of a novel soccer-training approach to cancer rehabilitation on a number of clinically important health outcomes in men with advanced prostate cancer during ADT. The results may pave the way for innovative, community-based interventions in the approach to treating prostate cancer. ClinicalTrials.gov: http

Androgen deprivation therapy for prostate cancer and the risk of hospitalisation for community-acquired pneumonia.

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Hicks, Blánaid M; Yin, Hui; Bladou, Franck; Ernst, Pierre; Azoulay, Laurent

2017-07-01

Androgens have been shown to influence both the immune system and lung tissue, raising the hypothesis that androgen deprivation therapy (ADT) for prostate cancer may increase the risk of pneumonia. Thus, the aim of this study was to determine whether ADT is associated with an increased risk of hospitalisation for community-acquired pneumonia in patients with prostate cancer. This was a population-based cohort study using the United Kingdom Clinical Practice Research Datalink linked to the Hospital Episode Statistics repository. The cohort consisted of 20 310 men newly diagnosed with non-metastatic prostate cancer between 1 April 1998 and 31 March 2015. Time-dependent Cox proportional hazards models were used to estimate adjusted HRs and 95% CIs for hospitalisation for community-acquired pneumonia associated with current and past use of ADT compared with non-use. During a mean follow-up of 4.3 years, there were 621 incident hospitalisations for community-acquired pneumonia (incidence rate: 7.2/1000 person-years). Current ADT use was associated with an 81% increased risk of hospitalisation for community-acquired pneumonia (12.1 vs 3.8 per 1000 person-years, respectively; HR 1.81, 95% CI 1.47 to 2.23). The association was observed within the first six months of use (HR 1.73, 95% CI 1.23 to 2.42) and remained elevated with increasing durations of use (≥25 months; HR 1.79, 95% CI 1.39 to 2.30). In contrast, past ADT use was not associated with an increased risk (HR 1.23, 95% CI 0.95 to 1.60). The use of ADT is associated with an increased risk of hospitalisation for community-acquired pneumonia in men with prostate cancer. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

The Effects of Sleep Deprivation on Pain

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Bernd Kundermann

2004-01-01

Full Text Available Chronic pain syndromes are associated with alterations in sleep continuity and sleep architecture. One perspective of this relationship, which has not received much attention to date, is that disturbances of sleep affect pain. To fathom this direction of cause, experimental human and animal studies on the effects of sleep deprivation on pain processing were reviewed. According to the majority of the studies, sleep deprivation produces hyperalgesic changes. Furthermore, sleep deprivation can counteract analgesic effects of pharmacological treatments involving opioidergic and serotoninergic mechanisms of action. The heterogeneity of the human data and the exclusive interest in rapid eye movement sleep deprivation in animals so far do not allow us to draw firm conclusions as to whether the hyperalgesic effects are due to the deprivation of specific sleep stages or whether they result from a generalized disruption of sleep continuity. The significance of opioidergic and serotoninergic processes as mediating mechanisms of the hyperalgesic changes produced by sleep deprivation are discussed.

Inherited Variants in Wnt Pathway Genes Influence Outcomes of Prostate Cancer Patients Receiving Androgen Deprivation Therapy

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Jiun-Hung Geng

2016-11-01

Full Text Available Aberrant Wnt signaling has been associated with many types of cancer. However, the association of inherited Wnt pathway variants with clinical outcomes in prostate cancer patients receiving androgen deprivation therapy (ADT has not been determined. Here, we comprehensively studied the contribution of common single nucleotide polymorphisms (SNPs in Wnt pathway genes to the clinical outcomes of 465 advanced prostate cancer patients treated with ADT. Two SNPs, adenomatous polyposis coli (APC rs2707765 and rs497844, were significantly (p ≤ 0.009 and q ≤ 0.043 associated with both prostate cancer progression and all-cause mortality, even after multivariate analyses and multiple testing correction. Patients with a greater number of favorable alleles had a longer time to disease progression and better overall survival during ADT (p for trend ≤ 0.003. Additional, cDNA array and in silico analyses of prostate cancer tissue suggested that rs2707765 affects APC expression, which in turn is correlated with tumor aggressiveness and patient prognosis. This study identifies the influence of inherited variants in the Wnt pathway on the efficacy of ADT and highlights a preclinical rationale for using APC as a prognostic marker in advanced prostate cancer.

Obesity and the Odds of Weight Gain following Androgen Deprivation Therapy for Prostate Cancer

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Lior Z. Braunstein

2014-01-01

Full Text Available Background. Increasing body mass index (BMI is associated with increased risk of mortality; however, quantifying weight gain in men undergoing androgen deprivation therapy (ADT for prostate cancer (PC remains unexplored. Methods. Between 1995 and 2001, 206 men were enrolled in a randomized trial evaluating the survival difference of adding 6 months of ADT to radiation therapy (RT. BMI measurements were available in 171 men comprising the study cohort. The primary endpoint was weight gain of ≥10 lbs by 6-month followup. Logistic regression analysis was performed to assess whether baseline BMI or treatment received was associated with this endpoint adjusting for known prognostic factors. Results. By the 6-month followup, 12 men gained ≥10 lbs, of which 10 (83% received RT + ADT and, of these, 7 (70% were obese at randomization. Men treated with RT as compared to RT + ADT were less likely to gain ≥10 lbs (adjusted odds ratio (AOR: 0.18 [95% CI: 0.04–0.89]; P=0.04, whereas this risk increased with increasing BMI (AOR: 1.15 [95% CI: 1.01–1.31]; P=0.04. Conclusions. Consideration should be given to avoid ADT in obese men with low- or favorable-intermediate risk PC where improved cancer control has not been observed, but shortened life expectancy from weight gain is expected.

Is modern external beam radiotherapy with androgen deprivation therapy still a viable alternative for prostate cancer in an era of robotic surgery and brachytherapy: a comparison of Australian series.

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Wilcox, Shea William; Aherne, Noel J; McLachlan, Craig Steven; McKay, Michael J; Last, Andrew J; Shakespeare, Thomas P

2015-02-01

We compare the results of modern external-beam radiotherapy (EBRT), using combined androgen deprivation and dose-escalated intensity-modulated radiotherapy with MRI-CT fusion and daily image guidance with fiducial markers (DE-IG-IMRT), with recently published Australian series of brachytherapy and surgery. Five-year actuarial biochemical disease-free survival (bDFS), metastasis-free survival (MFS) and prostate cancer-specific survival (PCaSS) were calculated for 675 patients treated with DE-IG-IMRT and androgen deprivation therapy (ADT). Patients had intermediate-risk (IR) and high-risk (HR) disease. A search was conducted identifying Australian reports from 2005 onwards of IR and HR patients treated with surgery or brachytherapy, reporting actuarial outcomes at 3 years or later. With a median follow-up of 59 months, our 5-year bDFS was 93.3% overall: 95.5% for IR and 91.3% for HR disease. MFS was 96.9% overall (99.0% IR, 94.9% HR), and PCaSS was 98.8% overall (100% IR, 97.7% HR). Prevalence of Grade 2 genitourinary and gastrointestinal toxicity at 5 years was 1.3% and 1.6%, with 0.3% Grade 3 genitourinary toxicity and no Grade 3 gastrointestinal toxicity. Eight reports of brachytherapy and surgery were identified. The HDR brachytherapy series' median 5-year bDFS was 82.5%, MFS 90.0% and PCaSS 97.9%. One surgical series reported 5-year bDFS of 65.5% for HR patients. One LDR series reported 5-year bDFS of 85% for IR patients. Modern EBRT is at least as effective as modern Australian surgical and brachytherapy techniques. All patients considering treatment for localised prostate cancer should be referred to a radiation oncologist to discuss EBRT as an equivalent option. © 2015 The Royal Australian and New Zealand College of Radiologists.

Is modern external beam radiotherapy with androgen deprivation therapy still a viable alternative for prostate cancer in an era of robotic surgery and brachytherapy: a comparison of Australian series

International Nuclear Information System (INIS)

Wilcox, Shea W.; Last, Andrew J.; Aherne, Noel J.; McLachlan, Craig S.; McKay, Michael J.; Shakespeare, Thomas P.

2015-01-01

We compare the results of modern external-beam radiotherapy (EBRT), using combined androgen deprivation and dose-escalated intensity-modulated radiotherapy with MRI-CT fusion and daily image guidance with fiducial markers (DE-IG-IMRT), with recently published Australian series of brachytherapy and surgery. Five-year actuarial biochemical disease-free survival (bDFS), metastasis-free survival (MFS) and prostate cancer-specific survival (PCaSS) were calculated for 675 patients treated with DE-IG-IMRT and androgen deprivation therapy (ADT). Patients had intermediate-risk (IR) and high-risk (HR) disease. A search was conducted identifying Australian reports from 2005 onwards of IR and HR patients treated with surgery or brachytherapy, reporting actuarial outcomes at 3 years or later. With a median follow-up of 59 months, our 5-year bDFS was 93.3% overall: 95.5% for IR and 91.3% for HR disease. MFS was 96.9% overall (99.0% IR, 94.9% HR), and PCaSS was 98.8% overall (100% IR, 97.7% HR). Prevalence of Grade 2 genitourinary and gastrointestinal toxicity at 5 years was 1.3% and 1.6%, with 0.3% Grade 3 genitourinary toxicity and no Grade 3 gastrointestinal toxicity. Eight reports of brachytherapy and surgery were identified. The HDR brachytherapy series' median 5-year bDFS was 82.5%, MFS 90.0% and PCaSS 97.9%. One surgical series reported 5-year bDFS of 65.5% for HR patients. One LDR series reported 5-year bDFS of 85% for IR patients. Modern EBRT is at least as effective as modern Australian surgical and brachytherapy techniques. All patients considering treatment for localised prostate cancer should be referred to a radiation oncologist to discuss EBRT as an equivalent option.

A novel selective androgen receptor modulator (SARM) MK-4541 exerts anti-androgenic activity in the prostate cancer xenograft R-3327G and anabolic activity on skeletal muscle mass & function in castrated mice.

Science.gov (United States)

Chisamore, Michael J; Gentile, Michael A; Dillon, Gregory Michael; Baran, Matthew; Gambone, Carlo; Riley, Sean; Schmidt, Azriel; Flores, Osvaldo; Wilkinson, Hilary; Alves, Stephen E

2016-10-01

The androgen receptor (AR) is a member of the nuclear hormone receptor super family of transcription factors. Androgens play an essential role in the development, growth, and maintenance of male sex organs, as well as the musculoskeletal and central nervous systems. Yet with advancing age, androgens can drive the onset of prostate cancer, the second leading cause of cancer death in males within the United States. Androgen deprivation therapy (ADT) by pharmacologic and/or surgical castration induces apoptosis of prostate cells and subsequent shrinkage of the prostate and prostate tumors. However, ADT is associated with significant musculoskeletal and behavioral adverse effects. The unique pharmacological activity of selective androgen receptor modulator (SARM) MK-4541 recently has been reported as an AR antagonist with 5α-reductase inhibitor function. The molecule inhibits proliferation and induces apoptosis in AR positive, androgen dependent prostate cancer cells. Importantly, MK-4541 inhibited androgen-dependent prostate growth in male rats yet maintained lean body mass and bone formation following ovariectomy in female rats. In the present study, we evaluated the effects of SARM MK-4541 in the androgen-dependent Dunning R3327-G prostate carcinoma xenograft mouse model as well as on skeletal muscle mass and function, and AR-regulated behavior in mice. MK-4541 significantly inhibited the growth of R3327-G prostate tumors, exhibited anti-androgen effects on the seminal vesicles, reduced plasma testosterone concentrations in intact males, and inhibited Ki67 expression. MK-4541 treated xenografts appeared similar to xenografts in castrated mice. Importantly, we demonstrate that MK-4541 exhibited anabolic activity in androgen deficient conditions, increasing lean body mass and muscle function in adult castrated mice. Moreover, MK-4541 treatment restored general activity levels in castrated mice. Thus, MK-4541 exhibits an optimum profile as an adjuvant therapy to ADT

Effect of propofol on androgen receptor activity in prostate cancer cells.

Science.gov (United States)

Tatsumi, Kenichiro; Hirotsu, Akiko; Daijo, Hiroki; Matsuyama, Tomonori; Terada, Naoki; Tanaka, Tomoharu

2017-08-15

Androgen receptor is a nuclear receptor and transcription factor activated by androgenic hormones. Androgen receptor activity plays a pivotal role in the development and progression of prostate cancer. Although accumulating evidence suggests that general anesthetics, including opioids, affect cancer cell growth and impact patient prognosis, the effect of those drugs on androgen receptor in prostate cancer is not clear. The purpose of this study was to investigate the effect of the general anesthetic propofol on androgen receptor activity in prostate cancer cells. An androgen-dependent human prostate cancer cell line (LNCaP) was stimulated with dihydrotestosterone (DHT) and exposed to propofol. The induction of androgen receptor target genes was investigated using real-time reverse transcription polymerase chain reaction, and androgen receptor protein levels and localization patterns were analyzed using immunoblotting and immunofluorescence assays. The effect of propofol on the proliferation of LNCaP cells was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Propofol significantly inhibited DHT-induced expression of androgen receptor target genes in a dose- and time-dependent manner, and immunoblotting and immunofluorescence assays indicated that propofol suppressed nuclear levels of androgen receptor proteins. Exposure to propofol for 24h suppressed the proliferation of LNCaP cells, whereas 4h of exposure did not exert significant effects. Together, our results indicate that propofol suppresses nuclear androgen receptor protein levels, and inhibits androgen receptor transcriptional activity and proliferation in LNCaP cells. Copyright © 2017 Elsevier B.V. All rights reserved.

Concept and viability of androgen annihilation for advanced prostate cancer.

Science.gov (United States)

Mohler, James L

2014-09-01

There remains no standard of care for patients with a rising prostate-specific antigen level after radical prostatectomy or radiotherapy but who have no radiographic metastases, even though this is the second largest group of patients with prostate cancer (CaP) in the United States. Androgen deprivation therapy (ADT) may cure some men with advanced CaP based on single-institution series and a randomized clinical trial of immediate versus delayed ADT for men found to have pelvic lymph node metastasis at the time of radical prostatectomy. ADT may be more effective when initiated for minimal disease burden, which can be detected using PSA after radical prostatectomy or radiotherapy, and if more complete disruption of the androgen axis using newer agents decreases the chance that androgen-sensitive cells survive to adapt to a low-androgen environment. Androgens may be "annihilated" simultaneously using a luteinizing hormone-releasing hormone antagonist or agonist to inhibit testicular production of testosterone, a P45017A1 (CYP17A1) inhibitor to diminish metabolism of testosterone via the adrenal pathway and dihydrotestosterone (DHT) via the backdoor pathway, a 5α-reductase (SRD5A) inhibitor to diminish testosterone reduction to DHT and backdoor metabolism of progesterone substrates to DHT, and a newer antiandrogen to compete better with DHT for the androgen receptor ligand-binding domain. Early initiation of androgen annihilation for induction as part of planned intermittent ADT should be safe, may reduce tumor burden below a threshold that allows eradication by the immune system, and may cure many men who have failed definitive local therapy. © 2014 American Cancer Society.

Exercise Improves V˙O2max and Body Composition in Androgen Deprivation Therapy-treated Prostate Cancer Patients.

Science.gov (United States)

Wall, Bradley A; GALVãO, Daniel A; Fatehee, Naeem; Taaffe, Dennis R; Spry, Nigel; Joseph, David; Hebert, Jeffrey J; Newton, Robert U

2017-08-01

Prostate cancer is the most common cancer in men, and patients treated with androgen deprivation therapy (ADT) experience unfavorable changes in body composition and associated metabolic complications, which can increase the risk of cardiovascular disease. We examined the effect of a 6-month program of aerobic and resistance exercise aimed at improving body composition and cardiorespiratory health in this population. Ninety-seven men (43-90 yr) with localized prostate cancer receiving ADT were randomized to either exercise (EX, n = 50) or usual care (CON, n = 47). Supervised exercise was undertaken twice weekly at moderate to high intensity. Measures of cardiorespiratory capacity (V˙O2max), resting metabolic rate, central blood pressure, hemodynamic variables, blood markers, and body composition were assessed. There was a significant group-time interaction present for V˙O2max (P = 0.033) with a treatment effect for EX of 0.11 L·min (95% confidence interval [CI] = 0.04-0.19) (relative to body mass = 1.3 mL·kg·min, 95% CI = 0.3-2.3) and fat oxidation (P = 0.037) of 12.0 mg·min (95% CI = 2.3-21.7). Similarly, there was a significant improvement in glucose (P Body composition was enhanced for EX with adjusted mean differences in lean mass (P = 0.015) of 0.8 kg (95% CI = 0.3-1.3), total fat mass (P = 0.020) of -1.1 kg (95% CI = -1.8 to -0.5), and trunk fat mass (P body composition despite the adverse effects of hormone suppression. Combined aerobic and resistance training should be considered a key adjuvant component in men undergoing ADT for the treatment of prostate cancer.

The effect of short term neo-adjuvant androgen deprivation on erectile function in patients treated with external beam radiotherapy for localised prostate cancer: an analysis of the 4- versus 8-month randomised trial (Irish Clinical Oncology Research Group 97-01).

LENUS (Irish Health Repository)

Daly, Patricia E

2012-07-01

Erectile dysfunction is a common consequence of external beam radiotherapy (EBRT) for prostate cancer. The addition of neo-adjuvant androgen deprivation (NAD) has an indeterminate additive effect. We examined the long-term effect on erectile function (EF) of two durations (4 months: arm 1 and 8 months: arm 2) of NAD prior to radiation (RT) for patients with localised prostate cancer from the Irish Clinical Oncology Research Group (ICORG 97-01) 4- versus 8-month trial. In this study we aimed to (1) analyse the overall effect on EF of NAD in an EBRT population, (2) compare the probability of retained EF over time in an EBRT population treated with either 4 or 8 months of NAD and (3) identify any variables such as risk group and age which may have an additive detrimental effect. This analysis provides unique long term follow up data.

Maximal exercise testing of men with prostate cancer being treated with androgen deprivation therapy.

Science.gov (United States)

Wall, Bradley A; Galvão, Daniel A; Fatehee, Naeem; Taaffe, Dennis R; Spry, Nigel; Joseph, David; Newton, Robert U

2014-12-01

Exercise is being increasingly established as a key adjuvant therapy in clinical oncology. As research has demonstrated the beneficial effect of exercise for cancer management, a growing number of patients with cancer are undertaking structured exercise programs. This study aimed to determine the safety and feasibility of formal exercise testing in clinical settings as it is becoming increasingly used as a screening tool and for exercise prescription purposes. One hundred and twelve patients with prostate cancer undergoing androgen deprivation therapy (ADT) took part in a physician-supervised multistage maximal stress test (Bruce protocol). Sixty patients had been on ADT for 3 months (chronic). Of these men, 85% were able to meet the criteria for the attainment of V˙O2max, whereas three positive tests (3.2%) were observed. The three participants who recorded a positive stress test underwent further medical examination and were subsequently cleared of clinically significant cardiovascular disease. Apart from the relatively low V˙O2max (24.7 ± 6.0 mL·kg·min, 10th-15th percentile), compared with normative data in healthy age-matched controls, the cardiovascular response to exercise was similar in this cancer population. Moreover, treatment duration did not seem to influence cardiovascular responses to exercise. This early evidence suggests that risk of adverse events during maximal exercise testing is relatively low in this population and certainly no higher than that in ages-matched, apparently healthy individuals. Maximal exercise testing was demonstrated to be feasible and safe, providing a direct assessment of V˙O2max. The relatively low number of positive tests in this study suggests that the risk of adverse events is relatively low in this population and certainly no higher than that in age-matched, apparently healthy individuals.

Changes in microfilament and focal adhesion distribution with loss of androgen responsiveness in cultured mammary tumor cells

DEFF Research Database (Denmark)

Couchman, J R; Yates, J; King, R J

1981-01-01

of the cells to grow in suspension culture. All these parameters were documented for androgen-responsive and -unresponsive cells grown in culture, as well as the transition of androgen-responsive to -unresponsive cells when deprived of androgen. The androgen-unresponsive cells had extensive and prominent...... microfilament bundles together with focal adhesions on the lower cell surface and also showed strict anchorage dependence for growth. In contrast, microfilament bundles and focal adhesions were absent from androgen-responsive cells, which furthermore had the ability to grow in suspension culture. Differences......, characteristics of both cell types were visible in the cell populations. However, at the stage where all androgen-responsive characteristics were lost, the cells were no longer androgen sensitive. The loss of androgen responsiveness in Shionogi 115 mouse mammary tumor cells is correlated with changes at the cell...

Survival benefit associated with adjuvant androgen deprivation therapy combined with radiotherapy for high- and low-risk patients with nonmetastatic prostate cancer

International Nuclear Information System (INIS)

Zeliadt, Steven B.; Potosky, Arnold L.; Penson, David F.; Etzioni, Ruth

2006-01-01

Background: The use of adjuvant androgen deprivation therapy (ADT) combined with radiotherapy has become common in low-risk patients, although clinical trials have focused primarily on high-risk patients. This study examines the effectiveness of adjuvant ADT combined with radiotherapy for a wide range of patients treated in the 1990s. Methods and Materials: Prostate cancer survival was examined in a population based cohort of 31,643 patients aged 65 to 85 years who were diagnosed with nonmetastatic prostate cancer and treated with external beam radiotherapy and/or brachytherapy. Instrumental variable analysis methods were used to control for selection bias. Results: Patients with stage T3/T4 disease who received adjuvant ADT experienced improved 5-year and 8-year survival. No survival advantage was observed for men with T1/T2 disease during this interval. Conclusion: High-risk patients who receive primary radiotherapy have benefited from adjuvant ADT, whereas low-risk patients with disease confined to the prostate have not yet benefited from adjuvant therapy within the first 8 years after treatment. These findings are consistent with practice guidelines, which recommend adjuvant ADT for patients with high-risk disease

Sleep deprivation: cardiovascular effects for anesthesiologists

Directory of Open Access Journals (Sweden)

Ali Dabbagh

2016-03-01

Full Text Available Sleep and anesthesia have some common or "overlapping" neural pathways. Both involve wakefulness; while they are not the same; anesthesia is an iatrogenic, reversible, pharmacologic-based coma; which could affect the CNS neural pathways at many levels. In the current era of modern anesthesiology, the practice and science of anesthesia is composed of 4 basic elements; (1: 1. hypnosis (i.e. iatrogenic pharmacologicinduced coma 2. amnesia (not to remember the events of the operation 3. analgesia (being painless 4. akinesia (lack of movements to stimuli The first two ingredients of anesthesia could have common points with sleep. Thalamic nuclei are involved both in sleep and anesthesia (2, 3; though, they are not the same phenomena (4. However, could there be any clinical concern if some of our patients have abnormalities in sleep? In fact, the effects of sleep deprivation have long been studied in patients undergoing anesthesia for surgical operations (4, 5. Sleep deprivation causes altered neurohumoral activity, neuroendocrine dysregulations, abnormalities in the immune system and impairments in cardiac autonomic function (6, 7. Sleep deprivation may affect the clinical effects of the anesthetics or it may create unpredicted changes in the clinical response to a determined dose of anesthetic drugs (8. In this volume of the Journal, Choopani et al have published their results regarding sleep deprivation; they have demonstrated that in rats, if sleep deprivation is induced prior to an ischemia/reperfusion event, it can increase the chance for ventricular tachycardia and ventricular fibrillation; also, they have shown that this untoward effect could be eliminated using chemical sympathectomy (9. In clinical practice, the main message from this study could be that when anesthesiologists perform anesthesia for their patients, they should be aware of effects of acute or chronic sleep deprivation. Undoubtedly, sleep deprivation could occur during the

Epigenetic Machinery Regulates Alternative Splicing of Androgen Receptor (AR) Gene in Castration Resistant Prostate Cancer

Science.gov (United States)

2017-09-01

resistant prostate cancer PRINCIPAL INVESTIGATOR: Zhi-Ping Liu CONTRACTING ORGANIZATION: UT Southwestern Medical Center Dallas, TX 75390 REPORT DATE...NUMBER gene in castration-resistant prostate cancer 5b. GRANT NUMBER W81XWH-16-1-0531 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Zhi-Ping Liu 5d...NOTES 14. ABSTRACT Androgen deprivation therapy (ADT) is the primary treatment for metastatic prostate cancer (PCa) since PCa depends on androgen for

Effect of Whole Pelvic Radiotherapy for Patients With Locally Advanced Prostate Cancer Treated With Radiotherapy and Long-Term Androgen Deprivation Therapy

International Nuclear Information System (INIS)

Mantini, Giovanna; Tagliaferri, Luca; Mattiucci, Gian Carlo; Balducci, Mario; Frascino, Vincenzo; Dinapoli, Nicola; Di Gesù, Cinzia; Ippolito, Edy; Morganti, Alessio G.; Cellini, Numa

2011-01-01

Purpose: To evaluate the effect of whole pelvic radiotherapy (WPRT) in prostate cancer patients treated with RT and long-term (>1 year) androgen deprivation therapy (ADT). Methods and materials: Prostate cancer patients with high-risk features (Stage T3-T4 and/or Gleason score ≥7 and/or prostate-specific antigen level ≥20 ng/mL) who had undergone RT and long-term ADT were included in the present analysis. Patients with bowel inflammatory disease, colon diverticula, and colon diverticulitis were excluded from WPRT and treated with prostate-only radiotherapy (PORT). Patients were grouped according to nodal risk involvement as assessed by the Roach formula using different cutoff levels (15%, 20%, 25%, and 30%). Biochemical disease-free survival (bDFS) was analyzed in each group according to the RT type (WPRT or PORT). Results: A total of 358 patients treated between 1994 and 2007 were included in the analysis (46.9% with WPRT and 53.1% with PORT). The median duration of ADT was 24 months (range, 12–38). With a median follow-up of 52 months (range, 20–150), the overall 4-year bDFS rate was 90.5%. The 4-year bDFS rate was similar between the patients who had undergone WPRT or PORT (90.4% vs. 90.5%; p = NS). However, in the group of patients with the greatest nodal risk (>30%), a significant bDFS improvement was recorded for the patients who had undergone WPRT (p = .03). No differences were seen in acute toxicity among the patients treated with WPRT or PORT. The late gastrointestinal toxicity was similar in patients treated with PORT or WPRT (p = NS). Conclusions: Our analysis has supported the use of WPRT in association with long-term ADT for patients with high-risk nodal involvement (>30%), although a definitive recommendation should be confirmed by a randomized trial.

Long-term outcomes from dose-escalated image-guided intensity-modulated radiotherapy with androgen deprivation: encouraging results for intermediate- and high-risk prostate cancer.

Science.gov (United States)

Wilcox, Shea W; Aherne, Noel J; Benjamin, Linus C; Wu, Bosco; de Campos Silva, Thomaz; McLachlan, Craig S; McKay, Michael J; Last, Andrew J; Shakespeare, Thomas P

2014-01-01

Dose-escalated (DE) radiotherapy in the setting of localized prostate cancer has been shown to improve biochemical disease-free survival (bDFS) in several studies. In the same group of patients, androgen deprivation therapy (ADT) has been shown to confer a survival benefit when combined with radiotherapy doses of up to 70 Gy; however, there is currently little long-term data on patients who have received high-dose intensity-modulated radiotherapy (IMRT) with ADT. We report the long-term outcomes in a large cohort of patients treated with the combination of DE image-guided IMRT (IG-IMRT) and ADT. Patients with localized prostate cancer were identified from a centralized database across an integrated cancer center. All patients received DE IG-IMRT, combined with ADT, and had a minimum follow up of 12 months post-radiotherapy. All relapse and toxicity data were collected prospectively. Actuarial bDFS, metastasis-free survival, prostate cancer-specific survival, and multivariate analyses were calculated using the SPSS v20.0 statistical package. Seven hundred and eighty-two eligible patients were identified with a median follow up of 46 months. Overall, 4.3% of patients relapsed, 2.0% developed distant metastases, and 0.6% died from metastatic prostate cancer. At 5-years, bDFS was 88%, metastasis-free survival was 95%, and prostate cancer-specific survival was 98%. Five-year grade 2 genitourinary and gastrointestinal toxicity was 2.1% and 3.4%, respectively. No grade 3 or 4 late toxicities were reported. Pretreatment prostate specific antigen (P=0.001) and Gleason score (P=0.03) were significant in predicting biochemical failure on multivariate analysis. There is a high probability of tumor control with DE IG-IMRT combined with androgen deprivation, and this is a technique with a low probability of significant late toxicity. Our long term results corroborate the safety and efficacy of treating with IG-IMRT to high doses and compares favorably with published series for

Cardiometabolic and Skeletal Risk Factors in Black Men with Prostate Cancer Starting Androgen Deprivation Therapy

Energy Technology Data Exchange (ETDEWEB)

Gunnarsson, Orvar, E-mail: orvar.gunnarsson@uphs.upenn.edu [Department of Medicine, Division of Hematology and Oncology, Hospital of the University of Pennsylvania, 3400 Spruce Street, 16 Penn Tower, Philadelphia, PA 19104 (United States); Basaria, Shehzad [Department of Medicine, Section of Men’s Health, Aging and Metabolism, Brigham and Women’s Hospital, Boston, MA 02115 (United States); Gignac, Gretchen A. [Department of Medicine, Section of Hematology and Oncology, Boston University School of Medicine, Boston, MA 02118 (United States)

2015-04-22

Background: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with multiple metabolic complications, previously predominantly evaluated in the white population. Methods: A chart-based retrospective review was conducted on black patients with PCa, considered for ADT, from September 2007 to July 2010. Baseline data were collected on body mass index (BMI), vitamin-D status, bone mineral density (BMD), dyslipidemia and diabetes. Overweight and obesity were classified as BMI ≥ 25 and BMI ≥ 30, respectively. Vitamin-D sufficiency was defined as levels ≥30 ng/mL, insufficiency as <30 ng/mL and deficiency as ≤20 ng/mL. Osteopenia was defined as T scores between −1 to −2.5 and osteoporosis when T scores ≤−2.5. Results: Of the initial cohort of 130 black men, 111 (85.4%) patients underwent ADT. At baseline, average BMI was 28.1 ± 5.9 with 43.3% of men being overweight and 30.8% obese. More than one-third of the patients had pre-existing dyslipidemia while 28.8% were diabetics. 50% were vitamin-D deficient while 41% had low bone mass. Conclusions: Black men with PCa presenting for consideration of ADT have a high prevalence of existing metabolic risk factors. Close monitoring of this patient population is needed during ADT to prevent and treat metabolic complications.

Cardiometabolic and Skeletal Risk Factors in Black Men with Prostate Cancer Starting Androgen Deprivation Therapy

International Nuclear Information System (INIS)

Gunnarsson, Orvar; Basaria, Shehzad; Gignac, Gretchen A.

2015-01-01

Background: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with multiple metabolic complications, previously predominantly evaluated in the white population. Methods: A chart-based retrospective review was conducted on black patients with PCa, considered for ADT, from September 2007 to July 2010. Baseline data were collected on body mass index (BMI), vitamin-D status, bone mineral density (BMD), dyslipidemia and diabetes. Overweight and obesity were classified as BMI ≥ 25 and BMI ≥ 30, respectively. Vitamin-D sufficiency was defined as levels ≥30 ng/mL, insufficiency as <30 ng/mL and deficiency as ≤20 ng/mL. Osteopenia was defined as T scores between −1 to −2.5 and osteoporosis when T scores ≤−2.5. Results: Of the initial cohort of 130 black men, 111 (85.4%) patients underwent ADT. At baseline, average BMI was 28.1 ± 5.9 with 43.3% of men being overweight and 30.8% obese. More than one-third of the patients had pre-existing dyslipidemia while 28.8% were diabetics. 50% were vitamin-D deficient while 41% had low bone mass. Conclusions: Black men with PCa presenting for consideration of ADT have a high prevalence of existing metabolic risk factors. Close monitoring of this patient population is needed during ADT to prevent and treat metabolic complications

Cardiometabolic and Skeletal Risk Factors in Black Men with Prostate Cancer Starting Androgen Deprivation Therapy

Directory of Open Access Journals (Sweden)

Orvar Gunnarsson

2015-04-01

Full Text Available Background: Androgen deprivation therapy (ADT for prostate cancer (PCa is associated with multiple metabolic complications, previously predominantly evaluated in the white population. Methods: A chart-based retrospective review was conducted on black patients with PCa, considered for ADT, from September 2007 to July 2010. Baseline data were collected on body mass index (BMI, vitamin-D status, bone mineral density (BMD, dyslipidemia and diabetes. Overweight and obesity were classified as BMI ≥ 25 and BMI ≥ 30, respectively. Vitamin-D sufficiency was defined as levels ≥30 ng/mL, insufficiency as <30 ng/mL and deficiency as ≤20 ng/mL. Osteopenia was defined as T scores between −1 to −2.5 and osteoporosis when T scores ≤−2.5. Results: Of the initial cohort of 130 black men, 111 (85.4% patients underwent ADT. At baseline, average BMI was 28.1 ± 5.9 with 43.3% of men being overweight and 30.8% obese. More than one-third of the patients had pre-existing dyslipidemia while 28.8% were diabetics. 50% were vitamin-D deficient while 41% had low bone mass. Conclusions: Black men with PCa presenting for consideration of ADT have a high prevalence of existing metabolic risk factors. Close monitoring of this patient population is needed during ADT to prevent and treat metabolic complications.

Androgen-deprivation therapy-induced aggressive prostate cancer with neuroendocrine differentiation

Directory of Open Access Journals (Sweden)

Julia Lipianskaya

2014-08-01

Full Text Available Most prostate cancers (PCas are classified as acinar type (conventional adenocarcinoma which are composed of tumor cells with luminal differentiation including the expression of androgen receptor (AR and prostate-specific antigen (PSA. There are also scattered neuroendocrine (NE cells in every case of adenocarcinoma. The NE cells are quiesecent, do not express AR or PSA, and their function remains unclear. We have demonstrated that IL8-CXCR2-P53 pathway provides a growth-inhibitory signal and keeps the NE cells in benign prostate and adenocarcinoma quiescent. Interestingly, some patients with a history of adenocarcinoma recur with small cell neuroendocrine carcinoma (SCNC after hormonal therapy, and such tumors are composed of pure NE cells that are highly proliferative and aggressive, due to P53 mutation and inactivation of the IL8-CXCR2-P53 pathway. The incidence of SCNC will likely increase due to the widespread use of novel drugs that further inhibit AR function or intratumoral androgen synthesis. A phase II trial has demonstrated that platinum-based chemotherapy may be useful for such therapy-induced tumors.

External Beam Radiation Therapy and Abiraterone in Men With Localized Prostate Cancer: Safety and Effect on Tissue Androgens

International Nuclear Information System (INIS)

Cho, Eunpi; Mostaghel, Elahe A.; Russell, Kenneth J.; Liao, Jay J.; Konodi, Mark A.; Kurland, Brenda F.; Marck, Brett T.; Matsumoto, Alvin M.; Dalkin, Bruce L.; Montgomery, R. Bruce

2015-01-01

Purpose: Optimizing androgen suppression may provide better control of localized prostate cancer (PCa). Numerous trials have supported the benefit of combining androgen deprivation therapy with definitive radiation therapy in men with locally advanced or high-grade disease. Addition of abiraterone to luteinizing hormone-releasing hormone agonist (LHRHa) with radiation has not been reported. We examined the safety of this combination as well as its impact on androgen suppression. Methods and Materials: A prospective, phase 2 study was conducted in men with localized PCa treated with 6 months of neoadjuvant and concurrent abiraterone with LHRHa and radiation. Duration of adjuvant LHRHa was at the discretion of the treating clinician. Prostate biopsy assays were obtained prior to the start of therapy and prior to radiation. Sera and tissue androgen levels were measured by liquid chromatography-tandem mass spectrometry. Results: A total of 22 men with intermediate- (n=3) and high-risk PCa (n=19) received study therapy. Sixteen men completed the intended course of abiraterone, and 19 men completed planned radiation to 77.4 to 81 Gy. Radiation to pelvic nodes was administered in 20 men. The following grade 3 toxicities were reported: lymphopenia (14 patients), fatigue (1 patient), transaminitis (2 patients), hypertension (2 patients), and hypokalemia (1 patient). There were no grade 4 toxicities. All 21 men who complied with at least 3 months of abiraterone therapy had a preradiation prostate-specific antigen (PSA) concentration nadir of <0.3 ng/mL. Median levels of tissue androgen downstream of CYP17A were significantly suppressed after treatment with abiraterone, and upstream steroids were increased. At median follow-up of 21 months (range: 3-37 months), only 1 patient (who had discontinued abiraterone at 3 months) had biochemical relapse. Conclusions: Addition of abiraterone to LHRHa with radiation is safe and achieves effective prostatic androgen suppression

External Beam Radiation Therapy and Abiraterone in Men With Localized Prostate Cancer: Safety and Effect on Tissue Androgens

Energy Technology Data Exchange (ETDEWEB)

Cho, Eunpi [University of Washington School of Medicine, Seattle, Washington (United States); Fred Hutchinson Cancer Research Center, Seattle, Washington (United States); Mostaghel, Elahe A. [Fred Hutchinson Cancer Research Center, Seattle, Washington (United States); Russell, Kenneth J.; Liao, Jay J.; Konodi, Mark A. [University of Washington School of Medicine, Seattle, Washington (United States); Kurland, Brenda F. [University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Marck, Brett T. [Veterans Affairs Puget Sound Health Care System, Seattle, Washington (United States); Matsumoto, Alvin M. [University of Washington School of Medicine, Seattle, Washington (United States); Veterans Affairs Puget Sound Health Care System, Seattle, Washington (United States); Dalkin, Bruce L. [University of Washington School of Medicine, Seattle, Washington (United States); Montgomery, R. Bruce, E-mail: rbmontgo@uw.edu [University of Washington School of Medicine, Seattle, Washington (United States)

2015-06-01

Purpose: Optimizing androgen suppression may provide better control of localized prostate cancer (PCa). Numerous trials have supported the benefit of combining androgen deprivation therapy with definitive radiation therapy in men with locally advanced or high-grade disease. Addition of abiraterone to luteinizing hormone-releasing hormone agonist (LHRHa) with radiation has not been reported. We examined the safety of this combination as well as its impact on androgen suppression. Methods and Materials: A prospective, phase 2 study was conducted in men with localized PCa treated with 6 months of neoadjuvant and concurrent abiraterone with LHRHa and radiation. Duration of adjuvant LHRHa was at the discretion of the treating clinician. Prostate biopsy assays were obtained prior to the start of therapy and prior to radiation. Sera and tissue androgen levels were measured by liquid chromatography-tandem mass spectrometry. Results: A total of 22 men with intermediate- (n=3) and high-risk PCa (n=19) received study therapy. Sixteen men completed the intended course of abiraterone, and 19 men completed planned radiation to 77.4 to 81 Gy. Radiation to pelvic nodes was administered in 20 men. The following grade 3 toxicities were reported: lymphopenia (14 patients), fatigue (1 patient), transaminitis (2 patients), hypertension (2 patients), and hypokalemia (1 patient). There were no grade 4 toxicities. All 21 men who complied with at least 3 months of abiraterone therapy had a preradiation prostate-specific antigen (PSA) concentration nadir of <0.3 ng/mL. Median levels of tissue androgen downstream of CYP17A were significantly suppressed after treatment with abiraterone, and upstream steroids were increased. At median follow-up of 21 months (range: 3-37 months), only 1 patient (who had discontinued abiraterone at 3 months) had biochemical relapse. Conclusions: Addition of abiraterone to LHRHa with radiation is safe and achieves effective prostatic androgen suppression

Selective androgen receptor modulators: in pursuit of tissue-selective androgens.

Science.gov (United States)

Omwancha, Josephat; Brown, Terry R

2006-10-01

The androgen receptor mediates the androgenic and anabolic activity of the endogenous steroids testosterone and 5alpha-dihydrotestosterone. Current knowledge of the androgen receptor protein structure, and the molecular mechanisms surrounding the binding properties and activities of agonists and antagonists has led to the design and development of novel nonsteroidal ligands with selected tissue-specific androgen receptor agonist and antagonist activities. The activity of these compounds, termed selective androgen receptor modulators (SARMs), is directed toward the maintenance or enhancement of anabolic effects on bone and muscle with minimal androgenic effects on prostate growth. SARMs are of potential therapeutic value in the treatment of male hypogonadism, osteoporosis, frailty and muscle wasting, burn injury and would healing, anemia, mood and depression, benign prostatic hyperplasia and prostate cancer.

Targeting the androgen receptor pathway in castration-resistant prostate cancer: progresses and prospects

Science.gov (United States)

Ferraldeschi, R; Welti, J; Luo, J; Attard, G; de Bono, JS

2015-01-01

Androgen receptor (AR) signaling is a critical pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. However, over time, most tumors become resistant to ADT. The view of castration-resistant prostate cancer (CRPC) has changed dramatically in the last several years. Progress in understanding the disease biology and mechanisms of castration resistance led to significant advancements and to paradigm shift in the treatment. Accumulating evidence showed that prostate cancers develop adaptive mechanisms for maintaining AR signaling to allow for survival and further evolution. The aim of this review is to summarize molecular mechanisms of castration resistance and provide an update in the development of novel agents and strategies to more effectively target the AR signaling pathway. PMID:24837363

Genetic Predictors of Fatigue in Prostate Cancer Patients Treated with Androgen Deprivation Therapy: Preliminary Findings

Science.gov (United States)

Jim, Heather S.L.; Park, Jong Y.; Permuth-Wey, Jennifer; Rincon, Maria A.; Phillips, Kristin M.; Small, Brent J.; Jacobsen, Paul B.

2012-01-01

Background Fatigue is a common and distressing side effect of androgen deprivation therapy (ADT) for prostate cancer. The goal of the current study was to examine the relationship between changes in fatigue following initiation of ADT and single nucleotide polymorphisms (SNPs) in three pro-inflammatory cytokine genes: interleukin-1 beta (IL1B), interleukin-6 (IL6), and tumor necrosis factor alpha (TNFA). Methods As part of a larger study, men with prostate cancer (n=53) were recruited prior to initiation of ADT. Fatigue was assessed at recruitment and six months after initiation of ADT. DNA was extracted from blood drawn at baseline. Results Patients with the IL6-174 (rs1800795) G/C or C/C genotype displayed greater increases in fatigue intrusiveness, frequency, and duration than the G/G genotype (p values≤0.05), although inclusion of age, race, and baseline depressive symptomatology in the model attenuated these relationships (p values≤0.09). Patients with the TNFA-308 (rs1800629) G/A genotype showed greater increases in fatigue severity than the G/G genotype (p=0.02). IL1B-511 (rs16944) genotype did not significantly predict changes in fatigue (p values>0.46). Patients with higher numbers of variants displayed greater increases in fatigue duration and interference (p values≤0.02) than patients with lower numbers of variants. Conclusions Prostate cancer patients treated with ADT who carry variant alleles of the IL6 and TNFA genes are susceptible to heightened fatigue. These preliminary data lend support for the role of genetic variation in the development of cancer-related fatigue secondary to ADT. Findings are relevant to attempts to develop personalized approaches to cancer treatment. PMID:22475653

A quality assurance audit: phase III trial of maximal androgen deprivation in prostate cancer (TROG 96.01).

Science.gov (United States)

Steigler, A; Mameghan, H; Lamb, D; Joseph, D; Matthews, J; Franklin, I; Turner, S; Spry, N; Poulsen, M; North, J; Kovacev, O; Denham, J

2000-02-01

In 1997 the Trans-Tasman Radiation Oncology Group (TROG) performed a quality assurance (QA) audit of its phase III randomized clinical trial investigating the effectiveness of different durations of maximal androgen deprivation prior to and during definitive radiation therapy for locally advanced carcinoma of the prostate (TROG 96.01). The audit reviewed a total of 60 cases from 15 centres across Australia and New Zealand. In addition to verification of technical adherence to the protocol, the audit also incorporated a survey of centre planning techniques and a QA time/cost analysis. The present report builds on TROG's first technical audit conducted in 1996 for the phase III accelerated head and neck trial (TROG 91.01) and highlights the significant progress TROG has made in the interim period. The audit provides a strong validation of the results of the 96.01 trial, as well as valuable budgeting and treatment planning information for future trials. Overall improvements were detected in data quality and quantity, and in protocol compliance, with a reduction in the rate of unacceptable protocol violations from 10 to 4%. Audit design, staff education and increased data management resources were identified as the main contributing factors to these improvements. In addition, a budget estimate of $100 per patient has been proposed for conducting similar technical audits. The next major QA project to be undertaken by TROG during the period 1998-1999 is an intercentre dosimetry study. Trial funding and staff education have been targeted as the key major issues essential to the continued success and expansion of TROG's QA programme.

The role of androgen deprivation therapy on biochemical failure and distant metastasis in intermediate-risk prostate cancer: effects of radiation dose escalation

International Nuclear Information System (INIS)

Ludwig, Michelle S; Kuban, Deborah A; Du, Xianglin L; Lopez, David S; Yamal, Jose-Miguel; Strom, Sara S

2015-01-01

To determine whether the effect of androgen deprivation therapy (ADT) on the risk of biochemical failure varies at different doses of radiation in patients treated with definitive external beam radiation for intermediate risk prostate cancer (IRPC). This study included 1218 IRPC patients treated with definitive external beam radiation therapy to the prostate and seminal vesicles from June 1987 to January 2009 at our institution. Patient, treatment, and tumor information was collected, including age, race, Gleason score, radiation dose, PSA, T-stage, and months on ADT. The median follow-up was 6 years. A total of 421(34.6%) patients received ADT, 211 (17.3%) patients experienced a biochemical failure, and 38 (3.1%) developed distant metastasis. On univariable analyses, higher PSA, earlier year of diagnosis, higher T-stage, lower doses of radiation, and the lack of ADT were associated with an increased risk of biochemical failure. No difference in biochemical failure was seen among different racial groups or with the use of greater than 6 months of ADT compared with less than 6 months. On multivariate analysis, the use of ADT was associated with a lower risk of biochemical failure than no ADT (HR, 0.599; 95% CI, 0.367-0.978; P < 0.04) and lower risk of distant metastasis (HR, 0.114; 95% CI, 0.014-0.905; P = 0.04). ADT reduced the risk of biochemical failure and distant metastasis in both low- and high dose radiation groups among men with intermediate-risk PCa. Increasing the duration of ADT beyond 6 months did not reduce the risk of biochemical failures. Better understanding the benefit of ADT in the era of dose escalation will require a randomized clinical trial

Effects of sleep deprivation on cognition.

Science.gov (United States)

Killgore, William D S

2010-01-01

Sleep deprivation is commonplace in modern society, but its far-reaching effects on cognitive performance are only beginning to be understood from a scientific perspective. While there is broad consensus that insufficient sleep leads to a general slowing of response speed and increased variability in performance, particularly for simple measures of alertness, attention and vigilance, there is much less agreement about the effects of sleep deprivation on many higher level cognitive capacities, including perception, memory and executive functions. Central to this debate has been the question of whether sleep deprivation affects nearly all cognitive capacities in a global manner through degraded alertness and attention, or whether sleep loss specifically impairs some aspects of cognition more than others. Neuroimaging evidence has implicated the prefrontal cortex as a brain region that may be particularly susceptible to the effects of sleep loss, but perplexingly, executive function tasks that putatively measure prefrontal functioning have yielded inconsistent findings within the context of sleep deprivation. Whereas many convergent and rule-based reasoning, decision making and planning tasks are relatively unaffected by sleep loss, more creative, divergent and innovative aspects of cognition do appear to be degraded by lack of sleep. Emerging evidence suggests that some aspects of higher level cognitive capacities remain degraded by sleep deprivation despite restoration of alertness and vigilance with stimulant countermeasures, suggesting that sleep loss may affect specific cognitive systems above and beyond the effects produced by global cognitive declines or impaired attentional processes. Finally, the role of emotion as a critical facet of cognition has received increasing attention in recent years and mounting evidence suggests that sleep deprivation may particularly affect cognitive systems that rely on emotional data. Thus, the extent to which sleep deprivation

Hormonal response recovery after long-term androgen deprivation therapy in patients with prostate cancer.

Science.gov (United States)

Planas, Jacques; Celma, Ana; Placer, José; Cuadras, Mercè; Regis, Lucas; Gasanz, Carlos; Trilla, Enrique; Salvador, Carlos; Lorente, David; Morote, Juan

2016-12-01

The aim of this study was to evaluate hormonal recovery after cessation of androgen deprivation therapy (ADT) in a group of elderly prostate cancer patients. Forty patients with locally advanced or metastatic prostate cancer, with a mean age of 71.5 years [95% confidence interval (CI) 69.1-73.9], were treated with ADT for a mean duration of 74.6 months (95% CI 59.7-89.5 months). Mean follow-up time after ADT cessation was 36.5 months (95% CI 30.6-42.3 months). Serum testosterone and luteinizing hormone (LH) were determined at 6 month intervals after ADT cessation. After 18 months of follow-up, all patients had recovered normal LH levels, while 38% of patients still presented castration levels of testosterone (50 ng/dl). Neither age at start of ADT nor clinical stage reached statistical significance. Only time under ADT was correlated with testosterone recovery (p = .031). Kaplan-Meier curves were obtained. Mean time for testosterone recovery was 14.5 months (95% CI 6.5-22.6 months) in patients treated with ADT for less than 60 months compared to 29.3 months (95% CI 19.6-39.1 months) in patients treated with ADT for more than 60 months (log-rank p = .029). Age did not correlate with testosterone recovery in a group of elderly prostate cancer patients in whom ADT was stopped. Testosterone recovery after ADT cessation was significantly correlated with time under ADT treatment. Significant implications related to economic aspects of the dosage schedule may be considered.

Clinical outcomes and nadir prostate-specific antigen (PSA) according to initial PSA levels in primary androgen deprivation therapy for metastatic prostate cancer.

Science.gov (United States)

Kitagawa, Yasuhide; Ueno, Satoru; Izumi, Kouji; Kadono, Yoshifumi; Mizokami, Atsushi; Hinotsu, Shiro; Akaza, Hideyuki; Namiki, Mikio

2016-03-01

To investigate the clinical outcomes of metastatic prostate cancer patients and the relationship between nadir prostate-specific antigen (PSA) levels and different types of primary androgen deprivation therapy (PADT). This study utilized data from the Japan Study Group of Prostate Cancer registry, which is a large, multicenter, population-based database. A total of 2982 patients treated with PADT were enrolled. Kaplan-Meier analysis was used to compare progression-free survival (PFS) and overall survival (OS) in patients treated using combined androgen blockade (CAB) and non-CAB therapies. The relationships between nadir PSA levels and PADT type according to initial serum PSA levels were also investigated. Among the 2982 enrolled patients, 2101 (70.5 %) were treated with CAB. Although CAB-treated patients had worse clinical characteristics, their probability of PFS and OS was higher compared with those treated with a non-CAB therapy. These results were due to a survival benefit with CAB in patients with an initial PSA level of 500-1000 ng/mL. Nadir PSA levels were significantly lower in CAB patients than in non-CAB patients with comparable initial serum PSA levels. A small survival benefit for CAB in metastatic prostate cancer was demonstrated in a Japanese large-scale prospective cohort study. The clinical significance of nadir PSA levels following PADT was evident, but the predictive impact of PSA nadir on OS was different between CAB and non-CAB therapy.

Bone stroma-derived cells change coregulators recruitment to androgen receptor and decrease cell proliferation in androgen-sensitive and castration-resistant prostate cancer cells

International Nuclear Information System (INIS)

Villagran, Marcelo A.; Gutierrez-Castro, Francisco A.; Pantoja, Diego F.; Alarcon, Jose C.; Fariña, Macarena A.; Amigo, Romina F.; Muñoz-Godoy, Natalia A.; Pinilla, Mabel G.; Peña, Eduardo A.; Gonzalez-Chavarria, Ivan; Toledo, Jorge R.; Rivas, Coralia I.; Vera, Juan C.; McNerney, Eileen M.; Onate, Sergio A.

2015-01-01

Prostate cancer (CaP) bone metastasis is an early event that remains inactive until later-stage progression. Reduced levels of circulating androgens, due to andropause or androgen deprivation therapies, alter androgen receptor (AR) coactivator expression. Coactivators shift the balance towards enhanced AR-mediated gene transcription that promotes progression to androgen-resistance. Disruptions in coregulators may represent a molecular switch that reactivates latent bone metastasis. Changes in AR-mediated transcription in androgen-sensitive LNCaP and androgen-resistant C4-2 cells were analyzed for AR coregulator recruitment in co-culture with Saos-2 and THP-1. The Saos-2 cell line derived from human osteosarcoma and THP-1 cell line representing human monocytes were used to display osteoblast and osteoclast activity. Increased AR activity in androgen-resistant C4-2 was due to increased AR expression and SRC1/TIF2 recruitment and decreased SMRT/NCoR expression. AR activity in both cell types was decreased over 90% when co-cultured with Saos-2 or THP-1 due to dissociation of AR from the SRC1/TIF2 and SMRT/NCoR coregulators complex, in a ligand-dependent and cell-type specific manner. In the absence of androgens, Saos-2 decreased while THP-1 increased proliferation of LNCaP cells. In contrast, both Saos-2 and THP-1 decreased proliferation of C4-2 in absence and presence of androgens. Global changes in gene expression from both CaP cell lines identified potential cell cycle and androgen regulated genes as mechanisms for changes in cell proliferation and AR-mediated transactivation in the context of bone marrow stroma cells. - Highlights: • Decreased corepressor expression change AR in androgen-resistance prostate cancer. • Bone stroma-derived cells change AR coregulator recruitment in prostate cancer. • Bone stroma cells change cell proliferation in androgen-resistant cancer cells. • Global gene expression in CaP cells is modified by bone stroma cells in co

Bone stroma-derived cells change coregulators recruitment to androgen receptor and decrease cell proliferation in androgen-sensitive and castration-resistant prostate cancer cells

Energy Technology Data Exchange (ETDEWEB)

Villagran, Marcelo A.; Gutierrez-Castro, Francisco A.; Pantoja, Diego F.; Alarcon, Jose C.; Fariña, Macarena A.; Amigo, Romina F.; Muñoz-Godoy, Natalia A. [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Pinilla, Mabel G. [Department of Medical Specialties, School of Medicine, University of Concepcion, Concepcion (Chile); Peña, Eduardo A.; Gonzalez-Chavarria, Ivan; Toledo, Jorge R.; Rivas, Coralia I.; Vera, Juan C. [Department of Physiopathology, School of Biological Sciences, University of Concepcion, Concepcion (Chile); McNerney, Eileen M. [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Onate, Sergio A., E-mail: sergio.onate@udec.cl [Molecular Endocrinology and Oncology Laboratory, University of Concepcion, Concepcion (Chile); Department of Medical Specialties, School of Medicine, University of Concepcion, Concepcion (Chile); Department of Urology, State University of New York at Buffalo, NY (United States)

2015-11-27

Prostate cancer (CaP) bone metastasis is an early event that remains inactive until later-stage progression. Reduced levels of circulating androgens, due to andropause or androgen deprivation therapies, alter androgen receptor (AR) coactivator expression. Coactivators shift the balance towards enhanced AR-mediated gene transcription that promotes progression to androgen-resistance. Disruptions in coregulators may represent a molecular switch that reactivates latent bone metastasis. Changes in AR-mediated transcription in androgen-sensitive LNCaP and androgen-resistant C4-2 cells were analyzed for AR coregulator recruitment in co-culture with Saos-2 and THP-1. The Saos-2 cell line derived from human osteosarcoma and THP-1 cell line representing human monocytes were used to display osteoblast and osteoclast activity. Increased AR activity in androgen-resistant C4-2 was due to increased AR expression and SRC1/TIF2 recruitment and decreased SMRT/NCoR expression. AR activity in both cell types was decreased over 90% when co-cultured with Saos-2 or THP-1 due to dissociation of AR from the SRC1/TIF2 and SMRT/NCoR coregulators complex, in a ligand-dependent and cell-type specific manner. In the absence of androgens, Saos-2 decreased while THP-1 increased proliferation of LNCaP cells. In contrast, both Saos-2 and THP-1 decreased proliferation of C4-2 in absence and presence of androgens. Global changes in gene expression from both CaP cell lines identified potential cell cycle and androgen regulated genes as mechanisms for changes in cell proliferation and AR-mediated transactivation in the context of bone marrow stroma cells. - Highlights: • Decreased corepressor expression change AR in androgen-resistance prostate cancer. • Bone stroma-derived cells change AR coregulator recruitment in prostate cancer. • Bone stroma cells change cell proliferation in androgen-resistant cancer cells. • Global gene expression in CaP cells is modified by bone stroma cells in co

Long-lasting masculinizing effects of postnatal androgens on myelin governed by the brain androgen receptor

Science.gov (United States)

Abi Ghanem, Charly; Degerny, Cindy; Hussain, Rashad; Liere, Philippe; Pianos, Antoine; Tourpin, Sophie; Habert, René; Schumacher, Michael

2017-01-01

The oligodendrocyte density is greater and myelin sheaths are thicker in the adult male mouse brain when compared with females. Here, we show that these sex differences emerge during the first 10 postnatal days, precisely at a stage when a late wave of oligodendrocyte progenitor cells arises and starts differentiating. Androgen levels, analyzed by gas chromatography/tandem-mass spectrometry, were higher in males than in females during this period. Treating male pups with flutamide, an androgen receptor (AR) antagonist, or female pups with 5α-dihydrotestosterone (5α-DHT), revealed the importance of postnatal androgens in masculinizing myelin and their persistent effect into adulthood. A key role of the brain AR in establishing the sexual phenotype of myelin was demonstrated by its conditional deletion. Our results uncover a new persistent effect of postnatal AR signaling, with implications for neurodevelopmental disorders and sex differences in multiple sclerosis. PMID:29107990

Predictors of Fracture Risk and Bone Mineral Density in Men with Prostate Cancer on Androgen Deprivation Therapy

Directory of Open Access Journals (Sweden)

Katherine Neubecker

2011-01-01

Full Text Available Decrease of bone mineral density (BMD and fracture risk is increased in men with prostate cancer receiving androgen deprivation therapy (ADT. We looked at possible predictors of decreased BMD and increased fracture risk in men with prostate cancer; most of whom were on ADT. In a retrospective study, we analyzed serum, BMD, and clinical risk factors used in the Fracture Risk Assessment (FRAX tool and others in 78 men with prostate cancer with reported height loss. The subjects were divided in two groups: 22 men with and 56 without vertebral fractures. 17 of the 22 men with vertebral fractures on spine X-rays did not know they had a vertebral fracture. Of those 17 men, 9 had not previously qualified for treatment based on preradiograph FRAX score calculated with BMD, and 6 based on FRAX calculated without BMD. Performing spine films increased the predictive ability of FRAX for vertebral fracture. Vertebral fracture was better predicted by FRAX for other osteoporotic fractures than FRAX for hip fractures. The inclusion of BMD in FRAX calculations did not affect the predictive ability of FRAX. The PSA level showed a positive correlation with lumbar spine BMD and accounted for about 9% of spine BMD.

A pilot study of exercise in men with prostate cancer receiving androgen deprivation therapy

International Nuclear Information System (INIS)

Lee, C Ellen; Leslie, William D; Lau, YK James

2012-01-01

Androgen deprivation therapy (ADT) is the mainstay therapy for men with prostate cancer. However, there are musculoskeletal side effects from ADT that increase the risk for osteoporosis and fracture, and can compromise the quality of life of these individuals. The objectives of this study are to determine the efficacy of a home-based walking exercise program in promoting bone health, physical function and quality of life in men with prostate cancer receiving ADT. A 12-month prospective, single-blinded, randomized controlled trial will be conducted to compare the Exercise Group with the Control Group. Sixty men with prostate cancer who will be starting ADT will be recruited and randomly assigned to one of the two groups: the Exercise Group will receive instructions in setting up an individualized 12-month home-based walking exercise program, while the Control Group will receive standard medical advice from the attending physician. A number of outcome measures will be used to assess bone health, physical function, and health-related quality of life. At baseline and 12 months, bone health will be assessed using dual-energy X-ray absorptiometry. At baseline and every 3 months up to 12 months, physical function will be evaluated using the Functional Assessment of Chronic Illness Therapy - Fatigue Scale, Activities-specific Balance Confidence Scale, Short Physical Performance Battery, and Six-Minute Walk Test; and health-related quality of life will be assessed using the Functional Assessment of Cancer Therapy Prostate Module and the Medical Outcomes Study 12-item Short Form Health Survey Version 2. A mixed multiple analysis of variance will be used to analyze the data. Musculoskeletal health management remains a challenge in men with prostate cancer receiving ADT. This study addresses this issue by designing a simple and accessible home-based walking exercise program that will potentially have significant impact on reducing the risk of fracture, promoting physical

Beyond T and DHT - novel steroid derivatives capable of wild type androgen receptor activation.

Science.gov (United States)

Mostaghel, Elahe A

2014-01-01

While androgen deprivation therapy (ADT) remains the primary treatment for metastatic prostate cancer (PCa), castration does not eliminate androgens from the prostate tumor microenvironment, and residual intratumoral androgens are implicated in nearly every mechanism by which androgen receptor (AR)-mediated signaling promotes castration-resistant disease. The uptake and intratumoral (intracrine) conversion of circulating adrenal androgens such as dehydroepiandrosterone sulfate (DHEA-S) to steroids capable of activating the wild type AR is a recognized driver of castration resistant prostate cancer (CRPC). However, less well-characterized adrenal steroids, including 11-deoxcorticosterone (DOC) and 11beta-hydroxyandrostenedione (11OH-AED) may also play a previously unrecognized role in promoting AR activation. In particular, recent data demonstrate that the 5α-reduced metabolites of DOC and 11OH-AED are activators of the wild type AR. Given the well-recognized presence of SRD5A activity in CRPC tissue, these observations suggest that in the low androgen environment of CRPC, alternative sources of 5α-reduced ligands may supplement AR activation normally mediated by the canonical 5α-reduced agonist, 5α-DHT. Herein we review the emerging data that suggests a role for these alternative steroids of adrenal origin in activating the AR, and discuss the enzymatic pathways and novel downstream metabolites mediating these effects. We conclude by discussing the potential implications of these findings for CRPC progression, particularly in context of new agents such as abiraterone and enzalutamide which target the AR-axis for prostate cancer therapy.

Falls and Frailty in Prostate Cancer Survivors: Current, Past, and Never Users of Androgen Deprivation Therapy.

Science.gov (United States)

Winters-Stone, Kerri M; Moe, Esther; Graff, Julie N; Dieckmann, Nathan F; Stoyles, Sydnee; Borsch, Carolyn; Alumkal, Joshi J; Amling, Christopher L; Beer, Tomasz M

2017-07-01

To compare the prevalence of and association between falls and frailty of prostate cancer survivors (PCSs) who were current, past or never users of androgen deprivation therapy (ADT). Cross-sectional. Mail and electronic survey. PCSs (N = 280; mean age 72 ± 8). Cancer history, falls, and frailty status (robust, prefrail, frail) using traditionally defined and obese phenotypes. Current (37%) or past (34%) ADT users were more than twice as likely to have fallen in the previous year as never users (15%) (P = .002). ADT users had twice as many recurrent falls (P users were more likely to be classified as prefrail or frail than never users (15%) (P users than never users (25%) (P < .001). Traditional and obese frailty significantly increased the likelihood of reporting falls in the previous year (odds ratio (OR) = 2.15, 95% CI = 1.18-3.94 and OR = 2.97, 95% CI = 1.62-5.58, respectively) and was also associated with greater risk of recurrent falls (OR = 3.10, 95% CI = 1.48-6.5 and OR = 3.99, 95% CI = 1.79-8.89, respectively). Current and past exposure to ADT is linked to higher risk of falls and frailty than no treatment. PCSs should be appropriately counseled on fall prevention strategies, and approaches to reduce frailty should be considered. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

The Effects of Sleep Deprivation on Pain

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Kundermann, Bernd; Krieg, Jürgen-Christian; Schreiber, Wolfgang; Lautenbacher, Stefan

2004-01-01

Chronic pain syndromes are associated with alterations in sleep continuity and sleep architecture. One perspective of this relationship, which has not received much attention to date, is that disturbances of sleep affect pain. To fathom this direction of cause, experimental human and animal studies on the effects of sleep deprivation on pain processing were reviewed. According to the majority of the studies, sleep deprivation produces hyperalgesic changes. Furthermore, sleep deprivation can c...

Avoidance of androgen deprivation therapy in radiorecurrent prostate cancer as a clinically meaningful endpoint for salvage cryoablation.

Science.gov (United States)

Ginsburg, Kevin B; Elshafei, Ahmed; Yu, Changhong; Jones, J Stephen; Cher, Michael L

2017-10-01

To investigate the ability of salvage cryoablation of the prostate (SCAP) to delay the need for androgen deprivation therapy (ADT) in local recurrence after radiation therapy to the prostate using the Cryo-On-Line Database (COLD) registry. The COLD registry is comprised of a combination of retrospectively and prospectively collected data on patients undergoing primary and SCAP. Patients with local recurrence after radiation therapy were identified. Kaplan-Meier analysis was used to calculate ADT-free survival. We identified 898 patients that have undergone SCAP in the COLD registry. Overall, the calculated 5-year ADT-free survival probability was 0.713. When stratified by D'Amico risk group, 264 high-risk patients (71.9%), 234 intermediate-risk (86.7%),and 228 low-risk (87.7%) were free of ADT post-SCAP. This correlates with a 5-year ADT-free survival of 60.7, 73.9, and 82.4%, respectively. Patients with post-SCAP PSA nadir of <0.2 ng/mL had a 5 year ADT-free survival of 87.1% compared to 48.7% with a PSA nadir ≥0.2 ng/mL. Pre-operative ADT use or full versus partial gland SCAP did not have an effect on ADT use post-operatively. In 118 (55.4%) of patients with post-operative biochemical recurrence, ADT was not used. For patients with local recurrence after radiation, SCAP is an option that provides a high chance of avoiding or delaying ADT. The potential to delay ADT and its associated side effects should be a part of counseling sessions with the patient when discussing treatment options for locally recurrent prostate cancer after radiation. Avoidance of ADT is more clinically relevant than PSA elevation. © 2017 Wiley Periodicals, Inc.

External beam radiation therapy and a low-dose-rate brachytherapy boost without or with androgen deprivation therapy for prostate cancer

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Strom, Tobin J.; Hutchinson, Sean Z.; Shrinath, Kushagra; Cruz, Alex A.; Figura, Nicholas B.; Nethers, Kevin; Biagioli, Matthew C.; Fernandez, Daniel C.; Heysek, Randy V.; Wilder, Richard B., E-mail: richard.wilder@moffitt.org [Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States)

2014-07-15

Purpose: To assess outcomes with external beam radiation therapy (EBRT) and a low-dose-rate (LDR) brachytherapy boost without or with androgen deprivation therapy (ADT) for prostate cancer. Materials and Methods: From January 2001 through August 2011, 120 intermediate-risk or high-risk prostate cancer patients were treated with EBRT to a total dose of 4,500 cGy in 25 daily fractions and a palladium-103 LDR brachytherapy boost of 10,000 cGy (n = 90) or an iodine-125 LDR brachytherapy boost of 11,000 cGy (n = 30). ADT, consisting of a gonadotropin-releasing hormone agonist ± an anti-androgen, was administered to 29/92 (32%) intermediate-risk patients for a median duration of 4 months and 26/28 (93%) high-risk patients for a median duration of 28 months. Results: Median follow-up was 5.2 years (range, 1.1-12.8 years). There was no statistically-significant difference in biochemical disease-free survival (bDFS), distant metastasis-free survival (DMFS), or overall survival (OS) without or with ADT. Also, there was no statistically-significant difference in bDFS, DMFS, or OS with a palladium-103 vs. an iodine-125 LDR brachytherapy boost. Conclusions: There was no statistically-significant difference in outcomes with the addition of ADT, though the power of the current study was limited. The Radiation Therapy Oncology Group 0815 and 0924 phase III trials, which have accrual targets of more than 1,500 men, will help to clarify the role ADT in locally-advanced prostate cancer patients treated with EBRT and a brachytherapy boost. Palladium-103 and iodine-125 provide similar bDFS, DMFS, and OS. (author)

Sphingosine kinase-1 mediates androgen-induced osteoblast cell growth

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Martin, Claire [CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse F-31000 (France); Universite de Toulouse, UPS, IPBS, Toulouse F-31000 (France); Lafosse, Jean-Michel [CHU Toulouse, Hopital Rangueil, Service d' orthopedie et Traumatologie, Toulouse F-31000 (France); Malavaud, Bernard [CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse F-31000 (France); Universite de Toulouse, UPS, IPBS, Toulouse F-31000 (France); CHU Toulouse, Hopital Rangueil, Service d' Urologie et de Transplantation Renale, Toulouse F-31000 (France); Cuvillier, Olivier, E-mail: olivier.cuvillier@ipbs.fr [CNRS, Institut de Pharmacologie et de Biologie Structurale, Toulouse F-31000 (France); Universite de Toulouse, UPS, IPBS, Toulouse F-31000 (France)

2010-01-01

Herein we report that the lipid kinase sphingosine kinase-1 (SphK1) is instrumental in mediating androgen-induced cell proliferation in osteoblasts. Dihydrotestosterone (DHT) triggered cell growth in steroid-deprived MC3T3 cells, which was associated with a rapid stimulation of SphK1 and activation of both Akt and ERK signaling pathways. This mechanism relied on functional androgen receptor/PI3K/Akt nongenotropic signaling as pharmacological antagonists could block SphK1 stimulation by DHT and its consequences. Finally, SphK1 inhibition not only abrogated DHT-induced ERK activation but also blocked cell proliferation, while ERK inhibition had no impact, suggesting that SphK1 was critical for DHT signaling yet independently of the ERK.

Prevention of Gynecomastia and Breast Pain Caused by Androgen Deprivation Therapy in Prostate Cancer: Tamoxifen or Radiotherapy?

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Arruda Viani, Gustavo, E-mail: gusviani@gmail.com [Department of Radiation Oncology, Marilia Medical School, Marilia, Sao Paulo (Brazil); Bernardes da Silva, Lucas Godoi; Stefano, Eduardo Jose [Department of Radiation Oncology, Marilia Medical School, Marilia, Sao Paulo (Brazil)

2012-07-15

Purpose: To determine, in a meta-analysis, whether gynecomastia and breast pain rates in men with prostate cancer treated with androgen deprivation therapy (ADT) are reduced if treated with prophylactic radiotherapy (RT) or tamoxifen (TMX). Methods and Materials: The MEDLINE, EMBASE, CANCERLIT, and Cochrane Library databases, as well as proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing RT or TMX with observation for men with prostate cancer using ADT. Results: Six RCTs (three RT trials and three TMX trials, N = 777 patients total) were identified that met the study criteria. Pooled results from these RCTs comparing RT vs. observation showed a significant reduction in the incidence of gynecomastia and breast pain rates in patients treated with RT (odds ratio [OR] = 0.21, 95% confidence interval [CI] = 0.12-0.37, p < 0.0001, and OR = 0.34, 95% CI 0.20-0.57, p < 0.0001, respectively). Use of RT resulted in an absolute risk reduction (ARR) of 29.4% and 19.9%, with a number needed to treat (NNT) of 3.4 and 5 to avoid one case of gynecomastia and breast pain, respectively. Pooled results from trials comparing TMX vs. observation showed a statistical benefit for breast pain and gynecomastia in favor of TMX arms (OR = 0.04, 95% CI = 0.02-0.08, p < 0.0001 and OR = 0.07, 95% CI = 0.0-0.14, p < 0.00001). TMX resulted in an ARR = 64.1% and 47.6%, with an NNT of 1.56 and 2.1 to avoid one case of gynecomastia and breast pain, respectively. Considering adverse effects, TMX was 6 times more adverse effects than RT. Conclusions: Our data have shown that both TMX and RT prevented gynecomastia and breast pain in patients with prostate cancer receiving ADT for prostate cancer. Although TMX was two times more effective in preventing gynecomastia, RT should represent an effective and safe treatment option, to take into account mainly in patients with cardiovascular risk factors or thrombotic diathesis.

Prevention of Gynecomastia and Breast Pain Caused by Androgen Deprivation Therapy in Prostate Cancer: Tamoxifen or Radiotherapy?

International Nuclear Information System (INIS)

Arruda Viani, Gustavo; Bernardes da Silva, Lucas Godói; Stefano, Eduardo Jose

2012-01-01

Purpose: To determine, in a meta-analysis, whether gynecomastia and breast pain rates in men with prostate cancer treated with androgen deprivation therapy (ADT) are reduced if treated with prophylactic radiotherapy (RT) or tamoxifen (TMX). Methods and Materials: The MEDLINE, EMBASE, CANCERLIT, and Cochrane Library databases, as well as proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing RT or TMX with observation for men with prostate cancer using ADT. Results: Six RCTs (three RT trials and three TMX trials, N = 777 patients total) were identified that met the study criteria. Pooled results from these RCTs comparing RT vs. observation showed a significant reduction in the incidence of gynecomastia and breast pain rates in patients treated with RT (odds ratio [OR] = 0.21, 95% confidence interval [CI] = 0.12–0.37, p < 0.0001, and OR = 0.34, 95% CI 0.20–0.57, p < 0.0001, respectively). Use of RT resulted in an absolute risk reduction (ARR) of 29.4% and 19.9%, with a number needed to treat (NNT) of 3.4 and 5 to avoid one case of gynecomastia and breast pain, respectively. Pooled results from trials comparing TMX vs. observation showed a statistical benefit for breast pain and gynecomastia in favor of TMX arms (OR = 0.04, 95% CI = 0.02–0.08, p < 0.0001 and OR = 0.07, 95% CI = 0.0–0.14, p < 0.00001). TMX resulted in an ARR = 64.1% and 47.6%, with an NNT of 1.56 and 2.1 to avoid one case of gynecomastia and breast pain, respectively. Considering adverse effects, TMX was 6 times more adverse effects than RT. Conclusions: Our data have shown that both TMX and RT prevented gynecomastia and breast pain in patients with prostate cancer receiving ADT for prostate cancer. Although TMX was two times more effective in preventing gynecomastia, RT should represent an effective and safe treatment option, to take into account mainly in patients with cardiovascular risk factors or thrombotic diathesis.

A quality assurance audit: phase iii trial of maximal androgen deprivation in prostate cancer (TROG 96.01)

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Steigler, A.; Kovacev, O.; Denham, J.; Lamb, D.; North, J.

2000-01-01

In 1997 the Trans-Tasman Radiation Oncology Group (TROG) performed a quality assurance (QA) audit of its phase III randomized clinical trial investigating the effectiveness of different durations of maximal androgen deprivation prior to and during definitive radiation therapy for locally advanced carcinoma of the prostate (TROG 96.01). The audit reviewed a total of 60 cases from 15 centres across Australia and New Zealand. In addition to verification of technical adherence to the protocol, the audit also incorporated a survey of centre planning techniques and a QA time/cost analysis. The present report builds on TROG's first technical audit conducted in 1996 for the phase III accelerated head and neck trial (TROG 91.01) and highlights the significant progress TROG has made in the interim period. The audit provides a strong validation of the results of the 96.01 trial, as well as valuable budgeting and treatment planning information for future trials. Overall improvements were detected in data quality and quantity, and in protocol compliance, with a reduction in the rate of unacceptable protocol violations from 10 to 4%. Audit design, staff education and increased data management resources were identified as the main contributing factors to these improvements. In addition, a budget estimate of $100 per patient has been proposed for conducting similar technical audits. The next major QA project to be undertaken by TROG during the period 1998-1999 is an intercentre dosimetry study. Trial funding and staff education have been targeted as the key major issues essential to the continued success and expansion of TROG's QA programme. Copyright (1999) Blackwell Science Pty Ltd

Meta-Analysis of the Antidepressant Effects of Acute Sleep Deprivation.

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Boland, Elaine M; Rao, Hengyi; Dinges, David F; Smith, Rachel V; Goel, Namni; Detre, John A; Basner, Mathias; Sheline, Yvette I; Thase, Michael E; Gehrman, Philip R

To provide a quantitative meta-analysis of the antidepressant effects of sleep deprivation to complement qualitative reviews addressing response rates. English-language studies from 1974 to 2016 using the keywords sleep deprivation and depression searched through PubMed and PsycINFO databases. A total of 66 independent studies met criteria for inclusion: conducted experimental sleep deprivation, reported the percentage of the sample that responded to sleep deprivation, provided a priori definition of antidepressant response, and did not seamlessly combine sleep deprivation with other therapies (eg, chronotherapeutics, repetitive transcranial magnetic stimulation). Data extracted included percentage of responders, type of sample (eg, bipolar, unipolar), type of sleep deprivation (eg, total, partial), demographics, medication use, type of outcome measure used, and definition of response (eg, 30% reduction in depression ratings). Data were analyzed with meta-analysis of proportions and a Poisson mixed-effects regression model. The overall response rate to sleep deprivation was 45% among studies that utilized a randomized control group and 50% among studies that did not. The response to sleep deprivation was not affected significantly by the type of sleep deprivation performed, the nature of the clinical sample, medication status, the definition of response used, or age and gender of the sample. These findings support a significant effect of sleep deprivation and suggest the need for future studies on the phenotypic nature of the antidepressant response to sleep deprivation, on the neurobiological mechanisms of action, and on moderators of the sleep deprivation treatment response in depression. © Copyright 2017 Physicians Postgraduate Press, Inc.

Perceived barriers and facilitators to physical activity in men with prostate cancer: possible influence of androgen deprivation therapy.

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Keogh, J W L; Patel, A; MacLeod, R D; Masters, J

2014-03-01

While physical activity is beneficial for men with prostate cancer, too few perform sufficient activity for such benefit. This study examined perceptions of men with prostate cancer of their barriers and facilitators to physical activity, and how androgen deprivation therapy (ADT) may influence these perceptions. Two focus groups were conducted, involving six ADT and eight non-ADT patients respectively. Data were transcribed verbatim and themes developed using a general inductive thematic approach. Facilitators to physical activity common to both groups of cancer survivors included clinician and spousal involvement, with pre-existing co-morbidities and increased age cited as barriers by both groups. The ADT subgroup cited personal involvement as a facilitator to physical activity, with fatigue, reduced motivation and a relative lack of specific advice from their clinician as additional barriers. The non-ADT subgroup had no additional facilitators to physical activity but cited time constraints as a barrier. These results highlight the important role that cancer clinicians and spouses play in promoting physical activity for men with prostate cancer and how ADT may influence their other facilitators and barriers. As physical activity is beneficial for prostate cancer survivors, especially those on ADT, cancer clinicians should regularly discuss physical activity with their patients. © 2013 John Wiley & Sons Ltd.

Pretreatment Serum Testosterone and Androgen Deprivation: Effect on Disease Recurrence and Overall Survival in Prostate Cancer Patients Treated With Brachytherapy

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Taira, Al V.; Merrick, Gregory S.; Galbreath, Robert W.; Butler, Wayne M.; Wallner, Kent E.; Allen, Zachariah A.; Lief, Jonathan H.; Adamovich, Edward

2009-01-01

Purpose: Low testosterone has been implicated as a possible adverse prognostic factor in patients with newly diagnosed prostate cancer. We evaluated the impact of pretreatment serum testosterone on survival after prostate brachytherapy. Methods and Materials: From October 2001 to November 2004, 619 patients underwent brachytherapy and 546 had a pretreatment serum testosterone level measured. Pretreatment serum testosterone levels were assigned by the following criteria: below-normal (n = 105), low normal (n = 246), mid normal (n = 132), high normal (n = 50), and above normal (n = 13). Median follow-up was 5.2 years. Cause of death was determined for each deceased patient. Results: Six-year biochemical progression-free survival (bPFS), cause-specific survival (CSS), and overall survival (OS) were 97.7%, 99.8%, and 89.2%. When comparing patients with low or low normal testosterone with those with average or higher testosterone, there was no significant difference in bPFS (97.6% vs. 98.4%; p = 0.72), CSS (99.8% vs. 100%; p = 0.72), or OS (88.9% vs. 90.8%; p = 0.73). Among patients with average and higher pretreatment testosterone, there was no significant difference in outcomes when comparing patients who did and did not receive androgen deprivation therapy (ADT). For patients with low or low normal testosterone levels, there was no significant difference in bPFS or CSS when comparing patients who did and did not receive ADT. However, there was a trend toward lower OS in patients with baseline lower testosterone levels who also received ADT (83.9% vs. 91.3%, p = 0.075). Conclusions: Low pretreatment testosterone levels alone did not affect disease recurrence or OS. Patients with baseline low testosterone who also were treated with ADT had a trend toward decreased OS.

Androgen Receptor Splice Variants and Resistance to Taxane Chemotherapy

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2015-10-01

or absence of 10 nM DHT . Dual-luciferase assay was performed at 24 h post treatment using the Dual-luciferase Reporter Assay System (Promega). The...were cultured under androgen-deprived condition unless specified. DHT , 1 nmol/L for 24 hours. Xu et al. Cancer Res; 75(17) September 1, 2015 Cancer...the dihydrotestosterone ( DHT ) groups, 1 nmol/L DHT was added at 24 hours after transfection. At 48 hours after transfection, cells were fixed with 70

Free Testosterone During Androgen Deprivation Therapy Predicts Castration-Resistant Progression Better Than Total Testosterone.

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Regis, Lucas; Planas, Jacques; Carles, Joan; Maldonado, Xavier; Comas, Inma; Ferrer, Roser; Morote, Juan

2017-01-01

The optimal degree of testosterone suppression in patients with prostate cancer undergoing androgen deprivation therapy remains in question. Furthermore, serum free testosterone, which is the active form of testosterone, seems to correlate with intraprostatic testosterone. Here we compared free and total serum testosterone as predictors of survival free of castration resistance. Total testosterone (chemiluminescent assay, lower sensitivity 10 ng/dl) and free testosterone (analogue-ligand radioimmunoassay, lower sensitivity 0.05 pg/ml) were determined at 6 months of LHRH agonist treatment in a prospective cohort of 126 patients with prostate cancer. During a mean follow-up of 67 months (9-120), 75 (59.5%) events of castration-resistant progression were identified. Multivariate analysis and survival analysis according to total testosterone cutoffs of 50, 32, and 20 ng/dl, and free testosterone cutoffs of 1.7, 1.1, and 0.7 pg/ml were performed. Metastatic spread was the most powerful predictor of castration resistance, HR: 2.09 (95%CI: 1.18-3.72), P = 0.012. Gleason score, baseline PSA and PSA at 6 months were also independents predictors, but not free and total testosterone. Stratified analysis was conducted on the basis of the status of metastatic diseases and free testosterone was found to be an independent predictor of survival free of castration resistance in the subgroup of patients without metastasis, HR: 2.12 (95%CI: 1.16-3.85), P = 0.014. The lowest threshold of free testosterone which showed significant differences was 1.7 pg/ml, P = 0.003. Free testosterone at 6 months of LHRH agonist treatment seems to be a better surrogate than total testosterone to predict castration resistance in no metastatic prostate cancer patients. Prostate 77:114-120, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Positive and negative mood in men with advanced prostate cancer undergoing androgen deprivation therapy: considering the role of social support and stress.

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Benedict, Catherine; Dahn, Jason R; Antoni, Michael H; Traeger, Lara; Kava, Bruce; Bustillo, Natalie; Zhou, Eric S; Penedo, Frank J

2015-08-01

Advanced prostate cancer patients often undergo androgen deprivation therapy (ADT). Advanced disease and adverse ADT side effects are often debilitating and negatively impact mood. Social support has been shown to mitigate detrimental effects of stress on mood. This study sought to characterize positive and negative mood in this select patient population and determine whether social support moderated relations between stress and mood. Participants (N = 80) completed the Interpersonal Support Evaluation List, Perceived Stress Scale, and Derogatis Affect Balance Scale at a single time point. Hierarchical regression models evaluated relations among social support, stress, and mood controlling for relevant covariates. Standard moderation analyses were performed. Participants reported higher levels of negative and positive mood compared with published means of localized prostate cancer patients. Overall, mood was more positive than negative. Stress levels were comparable to cancer populations with recurrent disease. Moderated regression analyses showed that social support partially buffered the effects of stress on positive mood; men with high stress and low support reported the lowest levels of positive mood. The model with negative mood as the dependent measure did not support moderation; that is, the relationship between stress and negative mood did not differ by level of social support. Among individuals living with advanced prostate cancer, social support may be an important factor that sustains positive mood in the presence of stress. Future work should examine the extent to which social support prospectively impacts health-related quality of life by promoting positive mood. Limitations include cross-sectional design, which precludes causal inferences. Copyright © 2014 John Wiley & Sons, Ltd.

Androgen receptor polyglutamine repeat length (AR-CAGn) modulates the effect of testosterone on androgen-associated somatic traits in Filipino young adult men.

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Ryan, Calen P; Georgiev, Alexander V; McDade, Thomas W; Gettler, Lee T; Eisenberg, Dan T A; Rzhetskaya, Margarita; Agustin, Sonny S; Hayes, M Geoffrey; Kuzawa, Christopher W

2017-06-01

The androgen receptor (AR) mediates expression of androgen-associated somatic traits such as muscle mass and strength. Within the human AR is a highly variable glutamine short-tandem repeat (AR-CAGn), and CAG repeat number has been inversely correlated to AR transcriptional activity in vitro. However, evidence for an attenuating effect of long AR-CAGn on androgen-associated somatic traits has been inconsistent in human populations. One possible explanation for this lack of consistency is that the effect of AR-CAGn on AR bioactivity in target tissues likely varies in relation to circulating androgen levels. We tested whether relationships between AR-CAGn and several androgen-associated somatic traits (waist circumference, lean mass, arm muscle area, and grip strength) were modified by salivary (waking and pre-bed) and circulating (total) testosterone (T) levels in young adult males living in metropolitan Cebu, Philippines (n = 675). When men's waking T was low, they had a reduction in three out of four androgen-associated somatic traits with lengthening AR-CAGn (p AR-CAGn was associated with an increase in these same somatic traits. Our finding that longer AR-CAGn predicts greater androgen-associated trait expression among high-T men runs counter to in vitro work, but is generally consistent with the few prior studies to evaluate similar interactions in human populations. Collectively, these results raise questions about the applicability of findings derived from in vitro AR-CAGn studies to the receptor's role in maintaining androgen-associated somatic traits in human populations. © 2017 Wiley Periodicals, Inc.

Anti-androgen effects of cypermethrin on the amino- and carboxyl-terminal interaction of the androgen receptor

International Nuclear Information System (INIS)

Hu, Jin-xia; Li, Yan-fang; Pan, Chen; Zhang, Jin-peng; Wang, Hong-mei; Li, Jing; Xu, Li-chun

2012-01-01

Graphical abstract: Both the known AR antagonist nilutamide and the pyrethroid insecticide cypermethrin inhibited DHT-induced AR N/C interaction in the mammalian two-hybrid assay. However, cypermethrin was a weaker androgen antagonist than nilutamide. Highlights: ► We have developed the mammalian two-hybrid assay. ► The assay displayed appropriate response to DHT and nilutamide. ► The N/C interaction was induced by DHT in a dose-dependent manner. ► Nilutamide inhibited DHT-induced AR N/C interaction. ► Cypermethrin exhibits inhibitory effects on DHT-induced AR N/C interaction. -- Abstract: The pyrethroid insecticide, cypermethrin has been demonstrated to be an environmental anti-androgen in the androgen receptor (AR) reporter gene assay. The amino- and carboxyl-terminal (N/C) interaction is required for transcription potential of the AR. In order to characterize the anti-androgen effects of cypermethrin involved in the N/C interaction of AR, the mammalian two-hybrid assay has been developed in the study. The fusion vectors pVP16-ARNTD, pM-ARLBD and the pG5CAT Reporter Vector were cotransfected into the CV-1 cells. The assay displayed appropriate response to the potent, classical AR agonist 5α-dihydrotestosterone (DHT) and known AR antagonist nilutamide. The N/C interaction was induced by DHT from 10 −11 M to 10 −5 M in a dose-dependent manner. Nilutamide did not activate N/C interaction, while inhibited DHT-induced AR N/C interaction at the concentrations from 10 −7 M to 10 −5 M. Treatment of CV-1 cells with cypermethrin alone did not activate the reporter CAT. Cypermethrin significantly decreased the DHT-induced reporter CAT expression at the higher concentration of 10 −5 M. The mammalian two-hybrid assay provides a promising tool both for defining mechanism involved in AR N/C interaction of EDCs and for screening of chemicals with androgen agonistic and antagonistic activities. Cypermethrin exhibits inhibitory effects on the DHT-induced AR N

The Central Effects of Androgenic-anabolic Steroid Use.

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Mędraś, Marek; Brona, Anna; Jóźków, Paweł

: Millions of men use androgenic-anabolic steroids (AAS) to stimulate muscle growth and improve physical appearance. Although 1 out of 3 people who uses androgenic-anabolic steroids develops a steroid use disorder, the effects of the drugs on the central nervous system and the psyche are still not well understood. Although most addictive substances improve mood immediately after administration, AAS exert less pronounced euphoric effects. Instead, they are primarily taken for the delayed gratification of increased muscle mass. Withdrawal from AAS may lead to a range of somatic and psychiatric symptoms, and, in many cases, comprehensive treatment supervised by an endocrinologist and a psychiatrist is required.

Structural characteristics of anabolic androgenic steroids contributing to binding to the androgen receptor and to their anabolic and androgenic activities. Applied modifications in the steroidal structure.

Science.gov (United States)

Fragkaki, A G; Angelis, Y S; Koupparis, M; Tsantili-Kakoulidou, A; Kokotos, G; Georgakopoulos, C

2009-02-01

Anabolic androgenic steroids (AAS) are synthetic derivatives of testosterone introduced for therapeutic purposes providing enhanced anabolic potency with reduced androgenic effects. Androgens mediate their action through their binding to the androgen receptor (AR) which is mainly expressed in androgen target tissues, such as the prostate, skeletal muscle, liver and central nervous system. This paper reviews some of the wide spectrum of testosterone and synthetic AAS structure modifications related to the intended enhancement in anabolic activity. The structural features of steroids necessary for effective binding to the AR and those which contribute to the stipulation of the androgenic and anabolic activities are also presented.

What do PSA changes after radiotherapy with or without prior androgen deprivation mean?

International Nuclear Information System (INIS)

Denham, J.W.; Woodhead, D.; Lamb, D.S.; Duchesne, G.

2003-01-01

The TROG 96.01 randomised patients with Stage B2 and C prostate cancer to radiotherapy alone to 66 Gy (RT), 3 months maximal androgen deprivation (MAD) with goserelin and flutamide prior to and during RT, and 6 months MAD prior to and during RT. Minimum follow up time is now 3 years. Prior to preliminary analysis of one of the trial's main endpoints biochemical relapse free survival (bRFS), the prostate-specific antigen (PSA) time course for every patient was evaluated to assess the performance of the ASTRO definition of biochemical failure (BF). Following MAD and RT PSA levels immediately rise in the majority of cases (PSA 'rebound'). In over 50% of cases, PSA levels then plateau at <1 ng/ml for 2 - 3 years prior to clear evidence of failure. Premature diagnosis of BF is possible in some of these cases. Fluctuations in PSA level ('bouncing') are more frequent after MAD and RT. As a result there can be difficulty in interpreting the ASTRO definition of BF in cases where overall PSA trend is upwards shortly after completion of therapy. In patients experiencing BF, the rate of PSA rise often corresponds to the site of failure. PSA doubling times (DT) under 7 months are usually associated with development of bony metastases, while DTs greater than that are usually associated with local failure. Decline in PSA levels following RT alone is frequently not mono-exponential and patients with those patterns experience lower PSA nadir levels and are subject to lower risks of all forms of relapse. These patients also survive longer. In cases where PSA descent patterns are discernable after MAD and RT, opposite trends are seen. Caution is necessary in diagnosing BF after MAD plus RT. Variations in the natural history of prostate cancer are reflected by variations in the rate of PSA changes following therapy. The importance of monitoring this marker and evaluating its time course is emphasised. Prospective studies are needed

Efficacy of walking exercise in promoting cognitive-psychosocial functions in men with prostate cancer receiving androgen deprivation therapy

Directory of Open Access Journals (Sweden)

Lee C

2012-07-01

Full Text Available Abstract Background Prostate cancer is the most commonly diagnosed non-melanoma cancer among men. Androgen deprivation therapy (ADT has been the core therapy for men with advanced prostate cancer. It is only in recent years that clinicians began to recognize the cognitive-psychosocial side effects from ADT, which significantly compromise the quality of life of prostate cancer survivors. The objectives of the study are to determine the efficacy of a simple and accessible home-based, walking exercise program in promoting cognitive and psychosocial functions of men with prostate cancer receiving ADT. Methods A 6-month prospective, single-blinded, randomized controlled trial will be conducted to compare the Exercise Group with the Control Group. Twenty men with prostate cancer starting ADT will be recruited and randomly assigned to one of the two groups: the Exercise Group will receive instructions in setting up an individualized 6-month home-based, walking exercise program, while the Control Group will receive standard medical advice from the attending physician. The primary outcomes will be psychosocial and cognitive functions. Cognitive functions including memory, attention, working memory, and executive function will be assessed using a battery of neurocognitive tests at baseline and 6 months. Psychosocial functions including depression, anxiety and self-esteem will be assessed at baseline, 3 and 6 months using the Center for Epidemiological Studies Depression Scale, Spielberger State-Trait Anxiety Inventory, and Rosenberg Self-Esteem Scale. Discussion The significance of the cognitive-psychosocial side effects of ADT in men with prostate cancer has only been recently recognized, and the management remains unclear. This study addresses this issue by designing a simple and accessible home-based, exercise program that may potentially have significant impact on reducing the cognitive and psychosocial side effects of ADT, and ultimately

Androgen effects on skeletal muscle: implications for the development and management of frailty

Directory of Open Access Journals (Sweden)

Matthew DL O'Connell

2014-04-01

Full Text Available Androgens have potent anabolic effects on skeletal muscle and decline with age in parallel to losses in muscle mass and strength. This loss of muscle mass and function, known as sarcopenia, is the central event in development of frailty, the vulnerable health status that presages adverse outcomes and rapid functional decline in older adults. The potential role of falling androgen levels in the development of frailty and their utility as function promoting therapies in older men has therefore attracted considerable attention. This review summarizes current concepts and definitions in muscle ageing, sarcopenia and frailty, and evaluates recent developments in the study of androgens and frailty. Current evidence from observational and interventional studies strongly supports an effect of androgens on muscle mass in ageing men, but effects on muscle strength and particularly physical function have been less clear. Androgen treatment has been generally well-tolerated in studies of older men, but concerns remain over higher dose treatments and use in populations with high cardiovascular risk. The first trials of selective androgen receptor modulators (SARMs suggest similar effects on muscle mass and function to traditional androgen therapies in older adults. Important future directions include the use of these agents in combination with exercise training to promote functional ability across different populations of older adults, as well as more focus on the relationships between concurrent changes in hormone levels, body composition and physical function in observational studies.

Large institutional variations in use of androgen deprivation therapy with definitive radiotherapy in a population-based cohort of men with intermediate- and high-risk prostate cancer.

Science.gov (United States)

Ong, Wee Loon; Foroudi, Farshad; Evans, Sue; Millar, Jeremy

2017-11-01

To evaluate the pattern of use of androgen deprivation therapy (ADT) with definitive radiotherapy (RT) in men with prostate cancer (PCa) in a population-based study in Australia. This is a prospective cohort of men with intermediate- and high-risk PCa, captured in the population-based Prostate Cancer Outcome Registry Victoria, who were treated with definitive prostate RT between January 2010 and December 2015. The primary outcome of interest was ADT utilization. Chi-squared test for trend was used to evaluate the temporal trend in the use of ADT over the study period. Multivariate logistic regressions were used to evaluate the effects of patient-, tumour- and treatment-related factors, and treatment institutions (public/ private and metropolitan/ regional) on the likelihood of ADT utilization. A total of 1806 men were included in the study, 199 of whom (11%) had favourable National Comprehensive Cancer Network (NCCN) intermediate-risk disease (i.e. only one intermediate-risk feature, primary Gleason grade 3, and variation in the use of ADT between public vs private and metropolitan vs regional institutions. © 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.

Steroid Androgen Exposure during Development Has No Effect on Reproductive Physiology of Biomphalaria glabrata.

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Satwant Kaur

Full Text Available Gastropod mollusks have been proposed as alternative models for male reproductive toxicity testing, due to similarities in their reproductive anatomy compared to mammals, together with evidence that endocrine disrupting chemicals can cause effects in some mollusks analogous to those seen in mammals. To test this hypothesis, we used the freshwater pulmonate snail, Biomphalaria glabrata, for which various genetic tools and a draft genome have recently become available, to investigate the effects of two steroid androgens on the development of mollusk secondary sexual organs. Here we present the results of exposures to two potent androgens, the vertebrate steroid; 5α-dihydrotestosterone (DHT and the pharmaceutical anabolic steroid; 17α-methyltestosterone (MT, under continuous flow-through conditions throughout embryonic development and up to sexual maturity. Secondary sexual gland morphology, histopathology and differential gene expression analysis were used to determine whether steroid androgens stimulated or inhibited organ development. No significant differences between tissues from control and exposed snails were identified, suggesting that these androgens elicited no biologically detectable response normally associated with exposure to androgens in vertebrate model systems. Identifying no effect of androgens in this mollusk is significant, not only in the context of the suitability of mollusks as alternative model organisms for testing vertebrate androgen receptor agonists but also, if applicable to other similar mollusks, in terms of the likely impacts of androgens and anti-androgenic pollutants present in the aquatic environment.

Baicalein suppresses the androgen receptor (AR)-mediated prostate cancer progression via inhibiting the AR N-C dimerization and AR-coactivators interaction.

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Xu, Defeng; Chen, Qiulu; Liu, Yalin; Wen, Xingqiao

2017-12-01

Androgen receptor (AR) plays a critical role in prostate cancer (PCa) development and progression. Androgen deprivation therapy with antiandrogens to reduce androgen biosynthesis or prevent androgens from binding to AR are widely used to suppress AR-mediated PCa growth. However, most of ADT may eventually fail with development of the castration resistance after 12-24 months. Here we found that a natural product baicalein can effectively suppress the PCa progression via targeting the androgen-induced AR transactivation with little effect to AR protein expression. PCa cells including LNCaP, CWR22Rv1, C4-2, PC-3, and DU145, were treated with baicalein and luciferase assay was used to evaluate their effect on the AR transactivation. Cell growth and IC 50 were determined by MTT assay after 48 hrs treatment. RT-PCR was used to evaluate the mRNA levels of AR target genes including PSA, TMPRSS2, and TMEPA1. Western blot was used to determine AR and PSA protein expression. The natural product of baicalein can selectively inhibit AR transactivation with little effect on the other nuclear receptors, including ERα, and GR. At a low concentration, 2.5 μM of baicalein effectively suppresses the growth of AR-positive PCa cells, and has little effect on AR-negative PCa cells. Mechanism dissection suggest that baicalein can suppress AR target genes (PSA, TMPRSS2, and TMEPA1) expression in both androgen responsive LNCaP cells and castration resistant CWR22Rv1 cells, that may involve the inhibiting the AR N/C dimerization and AR-coactivators interaction. Baicalein may be developed as an effective anti-AR therapy via its ability to inhibit AR transactivation and AR-mediated PCa cell growth.

Intensity-Modulated Radiotherapy Reduces Gastrointestinal Toxicity in Patients Treated With Androgen Deprivation Therapy for Prostate Cancer

International Nuclear Information System (INIS)

Sharma, Navesh K.; Li Tianyu; Chen, David Y.; Pollack, Alan; Horwitz, Eric M.; Buyyounouski, Mark K.

2011-01-01

Purpose: Androgen deprivation therapy (AD) has been shown to increase late Grade 2 or greater rectal toxicity when used concurrently with three-dimensional conformal radiotherapy (3D-CRT). Intensity-modulated radiotherapy (IMRT) has the potential to reduce toxicity by limiting the radiation dose received by the bowel and bladder. The present study compared the genitourinary and gastrointestinal (GI) toxicity in men treated with 3D-CRT+AD vs. IMRT+AD. Methods and Materials: Between July 1992 and July 2004, 293 men underwent 3D-CRT (n = 170) or IMRT (n = 123) with concurrent AD (<6 months, n = 123; ≥6 months, n = 170). The median radiation dose was 76 Gy for 3D-CRT (International Commission on Radiation Units and Measurements) and 76 Gy for IMRT (95% to the planning target volume). Toxicity was assessed by a patient symptom questionnaire that was completed at each visit and recorded using a Fox Chase Modified Late Effects Normal Tissue Task radiation morbidity scale. Results: The mean follow-up was 86 months (standard deviation, 29.3) for the 3D-CRT group and 40 months (standard deviation, 9.7) for the IMRT group. Acute GI toxicity (odds ratio, 4; 95% confidence interval, 1.6-11.7; p = .005) was significantly greater with 3D-CRT than with IMRT and was independent of the AD duration (i.e., <6 vs. ≥6 months). The interval to the development of late GI toxicity was significantly longer in the IMRT group. The 5-year Kaplan-Meier estimate for Grade 2 or greater GI toxicity was 20% for 3D-CRT and 8% for IMRT (p = .01). On multivariate analysis, Grade 2 or greater late GI toxicity (hazard ratio, 2.1; 95% confidence interval, 1.1-4.3; p = .04) was more prevalent in the 3D-CRT patients. Conclusion: Compared with 3D-CRT, IMRT significantly decreased the acute and late GI toxicity in patients treated with AD.

The PPARγ ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

International Nuclear Information System (INIS)

Moss, Patrice E.; Lyles, Besstina E.; Stewart, LaMonica V.

2010-01-01

The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPARγ ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPARγ ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPARγ ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPARγ. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPARγ and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

Female adipocyte androgen synthesis and the effects of insulin

Directory of Open Access Journals (Sweden)

David Cadagan

2014-01-01

Full Text Available The metabolic syndrome is a cluster of metabolic disorders characterized by insulin resistance and hyperinsulinaemia, and its presence can increase the risk of cardiovascular disease significantly. The metabolic syndrome is associated with increased circulating androgen levels in women, which may originate from the ovaries and adrenal glands. Adipocytes are also able to synthesise steroid hormones, and this output has been hypothesised to increase with elevated insulin plasma concentrations. However, the contribution of the adipocytes to the circulating androgen levels in women with metabolic syndrome is limited and the effects of insulin are not fully understood. The aim of this study was to investigate the presence of steroid precursors and synthetic enzymes in human adipocyte biopsies as markers of possible adipocyte androgen synthesis. We examined pre and mature adipocytes taken from tissue biopsies of abdominal subcutaneous adipose tissue of participating women from the Department of Obstetrics and Gynaecology, of the Royal Derby Hospital. The results showed the potential for localised adipocyte androgen synthesis through the presence of the androgen precursor progesterone, as well as the steroid-converting enzyme 17α-hydroxylase. Furthermore, we found the controlled secretion of androstenedione in vitro and that insulin treatment caused levels to increase. Continued examination of a localised source of androgen production is therefore of clinical relevance due to its influence on adipocyte metabolism, its negative impact on female steroidogenic homeostasis, and the possible aggravation this may have when associated to obesity and obesity related metabolic abnormalities such as hyperinsulinaemia.

Effects of acute sleep deprivation and caffeine supplementation on anaerobic performance.

Science.gov (United States)

Moore, Joss; McDonald, Ciaran; McIntyre, Alan; Carmody, Kevin; Donne, Bernard

2018-01-01

Athletes involved in team sports may be subject to varying degrees of sleep deprivation either before or after training and competition. Despite the belief among athletes and coaches of the importance of adequate sleep for ensuing performance, the effect of sleep loss on team-sport anaerobic performance remains unclear. There is conflicting evidence in the scientific literature as to the impact of acute sleep deprivation and caffeine supplementation on anaerobic performance indices. The purpose of this study is to investigate the effect of 24 hours of acute sleep deprivation on anaerobic performance and the effect of caffeine supplementation on anaerobic performance in the sleep deprived state. 11 club level games players (n=11, 25±4 yr, 178±7.5 cm, 80.2±10.4 kg, 15.1±5.6% body fat) participated in a repeated measures double-blinded placebo control trial. Following familiarisation, each participant returned for testing on three separate occasions. One of the testing sessions took place following a night of normal sleep and the other two sessions took place following 24 hours of sleep deprivation with supplementation of either placebo or 6 mg.kg- 1 of caffeine. During each testing session participants performed the vertical jump height, 20-m straight sprint, Illinois speed agility test and 5-m shuttle run. No significant differences were detected comparing non sleep deprived and sleep deprived interventions in any of the assessed outcome measures. There were also no significant differences observed in any of the outcome measures when comparing caffeine and placebo data in the sleep deprived state. In this cohort of athletes, a 24-h period of acute sleep deprivation did not have any significant impact on anaerobic performance. Caffeine also did not have any effect of on anaerobic performance in the sleep-deprived state.

Effects of acute sleep deprivation and caffeine supplementation on anaerobic performance

Directory of Open Access Journals (Sweden)

Joss Moore

Full Text Available Purpose: Athletes involved in team sports may be subject to varying degrees of sleep deprivation either before or after training and competition. Despite the belief among athletes and coaches of the importance of adequate sleep for ensuing performance, the effect of sleep loss on team-sport anaerobic performance remains unclear. There is conflicting evidence in the scientific literature as to the impact of acute sleep deprivation and caffeine supplementation on anaerobic performance indices. The purpose of this study is to investigate the effect of 24 hours of acute sleep deprivation on anaerobic performance and the effect of caffeine supplementation on anaerobic performance in the sleep deprived state. Methods: 11 club level games players (n=11, 25±4 yr, 178±7.5 cm, 80.2±10.4 kg, 15.1±5.6% body fat participated in a repeated measures double-blinded placebo control trial. Following familiarisation, each participant returned for testing on three separate occasions. One of the testing sessions took place following a night of normal sleep and the other two sessions took place following 24 hours of sleep deprivation with supplementation of either placebo or 6 mg.kg- 1 of caffeine. During each testing session participants performed the vertical jump height, 20-m straight sprint, Illinois speed agility test and 5-m shuttle run. Results: No significant differences were detected comparing non sleep deprived and sleep deprived interventions in any of the assessed outcome measures. There were also no significant differences observed in any of the outcome measures when comparing caffeine and placebo data in the sleep deprived state. Conclusion: In this cohort of athletes, a 24-h period of acute sleep deprivation did not have any significant impact on anaerobic performance. Caffeine also did not have any effect of on anaerobic performance in the sleep-deprived state.

Effect of Cuscuta reflexa Roxb on androgen-induced alopecia.

Science.gov (United States)

Pandit, Shweta; Chauhan, Nagendra Singh; Dixit, V K

2008-09-01

Alopecia is a psychologically distressing condition. Androgenetic alopecia, which affects millions of men and women, is an androgen-driven disorder. Here, Cuscuta reflexa Roxb is evaluated for hair growth activity in androgen-induced alopecia. Petroleum ether extract of C. reflexa was studied for its hair growth-promoting activity. Alopecia was induced in albino mice by testosterone administration for 20 days. Its inhibition by simultaneous administration of extract was evaluated using follicular density, anagen/telogen ratio, and microscopic observation of skin sections. To investigate the mechanism of observed activity, in vitro experiments were performed to study the effect of extract and its major component on activity of 5alpha-reductase enzyme. Petroleum ether extract of C. reflexa exhibited promising hair growth-promoting activity as reflected from follicular density, anagen/telogen ratio, and skin sections. Inhibition of 5alpha-reductase activity by extract and isolate suggest that the extract reversed androgen-induced alopecia by inhibiting conversion of testosterone to dihydrotestosterone. The petroleum ether extract of C. reflexa and its isolate is useful in treatment of androgen-induced alopecia by inhibiting the enzyme 5alpha-reductase.

A nonlinear competitive model of the prostate tumor growth under intermittent androgen suppression.

Science.gov (United States)

Yang, Jing; Zhao, Tong-Jun; Yuan, Chang-Qing; Xie, Jing-Hui; Hao, Fang-Fang

2016-09-07

Hormone suppression has been the primary modality of treatment for prostate cancer. However long-term androgen deprivation may induce androgen-independent (AI) recurrence. Intermittent androgen suppression (IAS) is a potential way to delay or avoid the AI relapse. Mathematical models of tumor growth and treatment are simple while they are capable of capturing the essence of complicated interactions. Game theory models have analyzed that tumor cells can enhance their fitness by adopting genetically determined survival strategies. In this paper, we consider the survival strategies as the competitive advantage of tumor cells and propose a new model to mimic the prostate tumor growth in IAS therapy. Then we investigate the competition effect in tumor development by numerical simulations. The results indicate that successfully IAS-controlled states can be achieved even though the net growth rate of AI cells is positive for any androgen level. There is crucial difference between the previous models and the new one in the phase diagram of successful and unsuccessful tumor control by IAS administration, which means that the suggestions from the models for medication can be different. Furthermore we introduce quadratic logistic terms to the competition model to simulate the tumor growth in the environment with a finite carrying capacity considering the nutrients or inhibitors. The simulations show that the tumor growth can reach an equilibrium state or an oscillatory state with the net growth rate of AI cells being androgen independent. Our results suggest that the competition and the restraint of a limited environment can enhance the possibility of relapse prevention. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of sleep deprivation on neural functioning: an integrative review

NARCIS (Netherlands)

Boonstra, T.W.; Stins, J.F.; Daffertshofer, A.; Beek, P.J.

2007-01-01

Sleep deprivation has a broad variety of effects on human performance and neural functioning that manifest themselves at different levels of description. On a macroscopic level, sleep deprivation mainly affects executive functions, especially in novel tasks. Macroscopic and mesoscopic effects of

Inhibition of glycogen synthase kinase-3β counteracts ligand-independent activity of the androgen receptor in castration resistant prostate cancer.

Directory of Open Access Journals (Sweden)

Stefanie V Schütz

Full Text Available In order to generate genomic signals, the androgen receptor (AR has to be transported into the nucleus upon androgenic stimuli. However, there is evidence from in vitro experiments that in castration-resistant prostate cancer (CRPC cells the AR is able to translocate into the nucleus in a ligand-independent manner. The recent finding that inhibition of the glycogen-synthase-kinase 3β (GSK-3β induces a rapid nuclear export of the AR in androgen-stimulated prostate cancer cells prompted us to analyze the effects of a GSK-3β inhibition in the castration-resistant LNCaP sublines C4-2 and LNCaP-SSR. Both cell lines exhibit high levels of nuclear AR in the absence of androgenic stimuli. Exposure of these cells to the maleimide SB216763, a potent GSK-3β inhibitor, resulted in a rapid nuclear export of the AR even under androgen-deprived conditions. Moreover, the ability of C4-2 and LNCaP-SSR cells to grow in the absence of androgens was diminished after pharmacological inhibition of GSK-3β in vitro. The ability of SB216763 to modulate AR signalling and function in CRPC in vivo was additionally demonstrated in a modified chick chorioallantoic membrane xenograft assay after systemic delivery of SB216763. Our data suggest that inhibition of GSK-3β helps target the AR for export from the nucleus thereby diminishing the effects of mislocated AR in CRPC cells. Therefore, inhibition of GSK-3β could be an interesting new strategy for the treatment of CRPC.

New Insights into the Androgen-Targeted Therapies and Epigenetic Therapies in Prostate Cancer

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Abhijit M. Godbole

2011-01-01

Full Text Available Prostate cancer is the most common cancer in men in the United States, and it is the second leading cause of cancer-related death in American men. The androgen receptor (AR, a receptor of nuclear family and a transcription factor, is the most important target in this disease. While most efforts in the clinic are currently directed at lowering levels of androgens that activate AR, resistance to androgen deprivation eventually develops. Most prostate cancer deaths are attributable to this castration-resistant form of prostate cancer (CRPC. Recent work has shed light on the importance of epigenetic events including facilitation of AR signaling by histone-modifying enzymes, posttranslational modifications of AR such as sumoylation. Herein, we provide an overview of the structure of human AR and its key structural domains that can be used as targets to develop novel antiandrogens. We also summarize recent findings about the antiandrogens and the epigenetic factors that modulate the action of AR.

The Prevalence of Cardiac Risk Factors in Men with Localized Prostate Cancer Undergoing Androgen Deprivation Therapy in British Columbia, Canada

Directory of Open Access Journals (Sweden)

Margot K. Davis

2015-01-01

Full Text Available Background. While androgen deprivation therapy (ADT reduces the risk of prostate cancer-specific mortality in high-risk localized prostate cancer, it adversely affects cardiovascular (CV risk factor profiles in treated men. Methods. We retrospectively reviewed the charts of 100 consecutive men with intermediate- or high-risk localized prostate cancer referred to the British Columbia Cancer Agency for ADT. Data on CV risk factors and disease were collected and Framingham risk scores were calculated. Results. The median age of the study cohort was 73 years. Established cardiovascular disease was present in 25% of patients. Among patients without established CV disease, calculated Framingham risk was high in 65%, intermediate in 33%, and low in 1%. Baseline hypertension was present in 58% of patients, dyslipidemia in 51%, and diabetes or impaired glucose tolerance in 24%. Hypertension was more prevalent in the study cohort than in an age- and sex-matched population sample (OR 1.74, P=0.006; diabetes had a similar prevalence (OR 0.93, P=0.8. Conclusions. Patients receiving ADT have a high prevalence of cardiovascular disease and risk factors and are more likely to be hypertensive than population controls. Low rates of CV risk screening suggest opportunities for improved primary and secondary prevention of CV disease in this population.

Health Effects of Sleep Deprivation,

Science.gov (United States)

1990-06-01

of an inordinate sleep loss (as hunger and thirst prevent us from going too long without food and water). Because of this, it takes great personal...drug-refractory depression. Neuropsychology 13:111-116, 1985. 82. Dowd PJ: Sleep deprivation effects on the vestibular habituation process. J Apply

Cardiotoxic effects of cocaine and anabolic-androgenic steroids in the athlete.

Science.gov (United States)

Welder, A A; Melchert, R B

1993-04-01

Cocaine and anabolic-androgenic steroid abuse have become major drug problems in the United States. Cocaine has been designated as "the drug of greatest national health concern" while as many as 1 million Americans have used or are currently using anabolic-androgenic steroids to promote athletic performance and/or improve physical appearance. Unfavorable cardiovascular events have been linked to both cocaine and anabolic-androgenic steroid abuse in healthy, physically active individuals. Deaths of several United States athletes in 1986 focused attention on the life-threatening cardiovascular consequences of cocaine abuse. Reports of myocardial injury with anabolic-androgenic steroid abuse are anecdotal. Nevertheless, case reports have illustrated the alarming cardiotoxic potential of these steroids in athletes. Anabolic-androgenic steroids were correlated to myocardial infarction in weight lifters and cardiomyopathy in a former professional football player. From the total emergency room episodes where cocaine was mentioned in 1990, approximately 66% of these episodes occurred in young individuals 18-29 years of age. Over 500,000 of the individuals currently taking anabolic-androgenic steroids for nonmedical purposes are high-school children. Because cocaine and anabolic-androgenic steroids are used improperly, more focus needs to be paid to the toxic mechanisms of their adverse effects. Therefore, the purpose of this review is to discuss mechanisms whereby exercise and/or exercise training may alter the cardiovascular responses to these drugs. Furthermore, we would like to illustrate that contrary to the popular belief, acute and chronic abuse of cocaine and anabolic-androgenic steroids have a negative impact on exercise performance.

Establishment of prostate cancer spheres from a prostate cancer cell line after phenethyl isothiocyanate treatment and discovery of androgen-dependent reversible differentiation between sphere and neuroendocrine cells.

Science.gov (United States)

Chen, Yamei; Cang, Shundong; Han, Liying; Liu, Christina; Yang, Patrick; Solangi, Zeeshan; Lu, Quanyi; Liu, Delong; Chiao, J W

2016-05-03

Prostate cancer can transform from androgen-responsive to an androgen-independent phenotype. The mechanism responsible for the transformation remains unclear. We studied the effects of an epigenetic modulator, phenethyl isothiocyanate (PEITC), on the androgen-responsive LNCaP cells. After treatment with PEITC, floating spheres were formed with characteristics of prostate cancer stem cells (PCSC). These spheres were capable of self-renewal in media with and without androgen. They have been maintained in both types of media as long term cultures. Upon androgen deprivation, the adherent spheres differentiated to neuroendocrine cells (NEC) with decreased proliferation, expression of androgen receptor, and PSA. NEC reverse differentiated to spheres when androgen was replenished. The sphere cells expressed surface marker CD44 and had enhanced histone H3K4 acetylation, DNMT1 down-regulation and GSTP1 activation. We hypothesize that PEITC-mediated alteration in epigenomics of LNCaP cells may give rise to sphere cells, whereas reversible androgenomic alterations govern the shuttling between sphere PCSC and progeny NEC. Our findings identify unrecognized properties of prostate cancer sphere cells with multi-potential plasticity. This system will facilitate development of novel therapeutic agents and allow further exploration into epigenomics and androgenomics governing the transformation to hormone refractory prostate cancer.

Effects of Acute Sleep Deprivation Resulting from Night Shift Work on Young Doctors.

Science.gov (United States)

Sanches, Inês; Teixeira, Fátima; dos Santos, José Moutinho; Ferreira, António Jorge

2015-01-01

To evaluate sleep deprivation and its effects on young physicians in relation to concentration capacity and psychomotor performance. Eighteen physicians aged 26 - 33 years were divided into 2 groups: non-sleep deprived group (with no night work) and sleep deprived group (minimum 12 hour of night work/week). We applied Pittsburgh Sleep Quality Index to screen the presence of sleep pathology and Epworth Sleepiness Scale to evaluate subjective daytime sleepiness; we used actigraphy and sleep diary to assess sleep hygiene and standard sleep-wake cycles. To demonstrate the effects of sleep deprivation, we applied Toulouse-Piéron's test (concentration test) and a battery of three reaction time tasks after the night duty. Sleep deprived group had higher daytime sleepiness on Epworth Sleepiness Scale (p sleep deprivation was higher (p sleep during the period of night duty was 184.2 minutes to sleep deprived group and 397.7 minutes to non-sleep deprived group (p sleep deprived group had more omissions (p Sleep deprived group; in reaction to instruction test the sleep deprived group showed worse perfection index (p sleep deprivation resulting from nocturnal work in medical professions is associated with a reduction in attention and concentration and delayed response to stimuli. This may compromise patient care as well as the physician's health and quality of life. It is essential to study the effects of acute sleep deprivation on the cognitive abilities and performance of health professionals.

The effect of REM sleep deprivation on motivation for food reward.

Science.gov (United States)

Hanlon, Erin C; Andrzejewski, Matthew E; Harder, Bridgette K; Kelley, Ann E; Benca, Ruth M

2005-08-30

Prolonged sleep deprivation in rats produces a characteristic syndrome consisting of an increase in food intake yet a decrease in weight. Moreover, the increase in food intake generally precedes the weight loss, suggesting that sleep deprivation may affect appetitive behaviors. Using the multiple platform method to produce rapid eye movement (REM) sleep deprivation, we investigated the effect of REM sleep deprivation (REMSD) on motivation for food reward utilizing food-reinforced operant tasks. In acquisition or maintenance of an operant task, REM sleep-deprived rats, with or without simultaneous food restriction, decreased responding for sucrose pellet reward in comparison to controls, despite the fact that all REM sleep-deprived rats lost weight. Furthermore, the overall response deficit of the REM sleep-deprived rats was due to a within-session decline in responding. REM sleep-deprived rats showed evidence of understanding the contingency of the task comparable to controls throughout deprivation period, suggesting that the decrements in responding were not primarily related to deficits in learning or memory. Rather, REM sleep deprivation appears to alter systems involved in motivational processes, reward, and/or attention.

Effects of combined exposure to anti-androgens on development and sexual dimorphic behaviour in rats

DEFF Research Database (Denmark)

Christiansen, Sofie

Summary Background: Androgens are key regulators of male sexual differentiation during the in utero and early postnatal development. Exposure to endocrine disrupting chemicals (EDCs) that counteract androgen action at some stage in these periods can permanently demasculinise male foetuses and lead......?  Is sexually dimorphic behaviour in rats affected at lower dose levels of anti-androgens and thereby a more sensitive endpoint than morphological effects on the male external reproductive organs? The thesis is based on the results of in vivo studies where mated female Wistar rats were exposed to anti......-androgens either alone or in mixtures during pregnancy and lactation. The endpoints examined for anti-androgenic effects in the offspring were: Anogenital distance (AGD), nipple retention (NR), and external (morphological) malformations in pups and sexually mature male rats. Furthermore, the effects of the anti...

Defining biochemical failure after radiotherapy with and without androgen deprivation for prostate cancer

International Nuclear Information System (INIS)

Buyyounouski, Mark K.; Hanlon, Alexandra L.; Eisenberg, Debra F.; Horwitz, Eric M.; Feigenberg, Steven J.; Uzzo, Robert G.; Pollack, Alan

2005-01-01

Purpose: To compare several characteristics of alternative definitions of biochemical failure (BF) in men with extended follow-up after radiotherapy (RT) with or with androgen deprivation therapy (ADT) for prostate cancer. Methods and Materials: From December 1, 1991, to April 30, 1998, 688 men with Stage T1c-T3NX-N0M0 prostate cancer received RT alone (n = 586) or RT plus ADT (n = 102) with a minimal follow-up of 4 years and five or more 'ADT-free' posttreatment prostate-specific antigen levels. BF was defined by three methods: (1) the ASTRO definition (three consecutive rises in prostate-specific antigen level); (2) a modified American Society for Therapeutic Radiology Oncology (ASTRO) definition requiring two additional consecutive rises when a decline immediately subsequent to three consecutive rises occurred; and (3) the 'Houston' or nadir plus 2-ng/mL definition (a rise of at least 2 ng/mL greater than the nadir). The sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were determined for each using clinical progression as the endpoint. Furthermore, the misclassification rates for a steadily rising prostate-specific antigen level, ability to satisfy the proportional hazards (RT with or without ADT), effects of short follow-up, and intervals to the diagnosis of BF were compared. Results: The misclassification rate for BF using the nadir plus 2-ng/mL definition was 2% for RT alone and 0% for RT plus ADT compared with 0% and 0% for the modified ASTRO definition, and 5% and 23% for the ASTRO definition, respectively. The hazard rates for RT alone and RT plus ADT were proportional only for the nadir plus 2 ng/mL definition and seemingly unaffected by the length of follow-up. For RT with or without ADT, the nadir plus 2 ng/mL definition was the most specific (RT, 80% vs. RT plus ADT, 75%) with the greatest positive predictive value (RT, 36% vs. RT plus ADT, 25%) and overall accuracy (RT, 81% vs. RT plus ADT, 77%). A

Cues of fatigue: effects of sleep deprivation on facial appearance.

Science.gov (United States)

Sundelin, Tina; Lekander, Mats; Kecklund, Göran; Van Someren, Eus J W; Olsson, Andreas; Axelsson, John

2013-09-01

To investigate the facial cues by which one recognizes that someone is sleep deprived versus not sleep deprived. Experimental laboratory study. Karolinska Institutet, Stockholm, Sweden. Forty observers (20 women, mean age 25 ± 5 y) rated 20 facial photographs with respect to fatigue, 10 facial cues, and sadness. The stimulus material consisted of 10 individuals (five women) photographed at 14:30 after normal sleep and after 31 h of sleep deprivation following a night with 5 h of sleep. Ratings of fatigue, fatigue-related cues, and sadness in facial photographs. The faces of sleep deprived individuals were perceived as having more hanging eyelids, redder eyes, more swollen eyes, darker circles under the eyes, paler skin, more wrinkles/fine lines, and more droopy corners of the mouth (effects ranging from b = +3 ± 1 to b = +15 ± 1 mm on 100-mm visual analog scales, P sleep deprivation (P sleep deprivation, nor associated with judgements of fatigue. In addition, sleep-deprived individuals looked sadder than after normal sleep, and sadness was related to looking fatigued (P sleep deprivation affects features relating to the eyes, mouth, and skin, and that these features function as cues of sleep loss to other people. Because these facial regions are important in the communication between humans, facial cues of sleep deprivation and fatigue may carry social consequences for the sleep deprived individual in everyday life.

Sleep deprivation effects on object discrimination task in zebrafish (Danio rerio).

Science.gov (United States)

Pinheiro-da-Silva, Jaquelinne; Silva, Priscila Fernandes; Nogueira, Marcelo Borges; Luchiari, Ana Carolina

2017-03-01

The zebrafish is an ideal vertebrate model for neurobehavioral studies with translational relevance to humans. Many aspects of sleep have been studied, but we still do not understand how and why sleep deprivation alters behavioral and physiological processes. A number of hypotheses suggest its role in memory consolidation. In this respect, the aim of this study was to analyze the effects of sleep deprivation on memory in zebrafish (Danio rerio), using an object discrimination paradigm. Four treatments were tested: control, partial sleep deprivation, total sleep deprivation by light pulses, and total sleep deprivation by extended light. The control group explored the new object more than the known object, indicating clear discrimination. The partially sleep-deprived group explored the new object more than the other object in the discrimination phase, suggesting a certain degree of discriminative performance. By contrast, both total sleep deprivation groups equally explored all objects, regardless of their novelty. It seems that only one night of sleep deprivation is enough to affect discriminative response in zebrafish, indicating its negative impact on cognitive processes. We suggest that this study could be a useful screening tool for cognitive dysfunction and a better understanding of the effect of sleep-wake cycles on cognition.

Effects of a Group-Mediated Exercise and Dietary Intervention in the Treatment of Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: Results From the IDEA-P Trial.

Science.gov (United States)

Focht, Brian C; Lucas, Alexander R; Grainger, Elizabeth; Simpson, Christina; Fairman, Ciaran M; Thomas-Ahner, Jennifer M; Buell, Jackie; Monk, J Paul; Mortazavi, Amir; Clinton, Steven K

2018-04-19

Although androgen-deprivation therapy (ADT) is the foundation of treatment for prostate cancer, the physiological impacts of ADT result in functional decline and enhanced risk of chronic disease and metabolic syndrome. The Individualized Diet and Exercise Adherence Pilot Trial (IDEA-P) is a single-blind, randomized, pilot trial comparing the effects of a group-mediated, cognitive-behavioral (GMCB) exercise and dietary intervention (EX+D) with those of a standard-of-care (SC) control during the treatment of prostate cancer patients undergoing ADT. A total of 32 prostate cancer patients (M age = 66.28, SD = 7.79) undergoing ADT were randomly assigned to the 12-week EX+D intervention (n = 16) or control (n = 16). The primary outcome in IDEA-P was change in mobility performance with secondary outcomes including body composition and muscular strength. Blinded assessment of outcomes were obtained at baseline and at 2- and 3-month follow-ups. Favorable adherence and retention rates were observed, and no serious intervention-related adverse events were documented. Intent-to-treat ANCOVA controlling for baseline value and ADT duration demonstrated that EX+D resulted in significantly greater improvements in mobility performance (p < .02), muscular strength (p < .01), body fat percentage (p < .05), and fat mass (p < .03) at 3-month follow-up, relative to control. Findings from the IDEA-P trial suggest that a GMCB-based EX+D intervention resulted in significant, clinically meaningful improvements in mobility performance, muscular strength, and body composition, relative to controls. Collectively, these results suggest that the EX+D was a safe and well-tolerated intervention for prostate cancer patients on ADT. The utility of implementing this approach in the treatment of prostate cancer patients on ADT should be evaluated in future large-scale efficacy trials. NCT02050906.

Duration of Androgen Deprivation in Locally Advanced Prostate Cancer: Long-Term Update of NRG Oncology RTOG 9202

International Nuclear Information System (INIS)

Lawton, Colleen A.F.; Lin, Xiaolei; Hanks, Gerald E.; Lepor, Herbert; Grignon, David J.; Brereton, Harmar D.; Bedi, Meena; Rosenthal, Seth A.; Zeitzer, Kenneth L.; Venkatesan, Varagur M.; Horwitz, Eric M.; Pisansky, Thomas M.; Kim, Harold; Parliament, Matthew B.; Rabinovitch, Rachel; Roach, Mack; Kwok, Young; Dignam, James J.; Sandler, Howard M.

2017-01-01

Purpose: Trial RTOG 9202 was a phase 3 randomized trial designed to determine the optimal duration of androgen deprivation therapy (ADT) when combined with definitive radiation therapy (RT) in the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate. Long-term follow-up results of this study now available are relevant to the management of this disease. Methods and Materials: Men (N=1554) with adenocarcinoma of the prostate (cT2c-T4, N0-Nx) with a prostate-specific antigen (PSA) <150 ng/mL and no evidence of distant metastasis were randomized (June 1992 to April 1995) to short-term ADT (STAD: 4 months of flutamide 250 mg 3 times per day and goserelin 3.6 mg per month) and definitive RT versus long-term ADT (LTAD: STAD with definitive RT plus an additional 24 months of monthly goserelin). Results: Among 1520 protocol-eligible and evaluable patients, the median follow-up time for this analysis was 19.6 years. In analysis adjusted for prognostic covariates, LTAD improved disease-free survival (29% relative reduction in failure rate, P<.0001), local progression (46% relative reduction, P=.02), distant metastases (36% relative reduction, P<.0001), disease-specific survival (30% relative reduction, P=.003), and overall survival (12% relative reduction, P=.03). Other-cause mortality (non–prostate cancer) did not differ (5% relative reduction, P=.48). Conclusions: LTAD and RT is superior to STAD and RT for the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate and should be considered the standard of care.

Recognizing False Biochemical Failure Calls After Radiation With or Without Neo-Adjuvant Androgen Deprivation for Prostate Cancer

International Nuclear Information System (INIS)

Denham, James W.; Kumar, Mahesh; Gleeson, Paul S.; Lamb, David S.; Joseph, David FRANZCR.; Atkinson, Chris FRANZCR.; Matthews, John FRANZCR.; Tai, K.-H.; Spry, Nigel A.; Christie, David; Turner, Sandra FRANZCR.; Greer, Peter B.; D'Este, Catherine; Steigler, Allison

2009-01-01

Purpose: We studied prostate-specific antigen (PSA) changes after radiation with or without neoadjuvant androgen deprivation to determine posttreatment PSA scenarios in which false-positive biochemical failures (FPBF) are most likely to occur. Methods and Materials: In the Trans-Tasman Radiation Oncology 96.01 Group trial, patients with T2b, 2c, 3, 4 N0 prostate cancer were randomized to 3 or 6 months goserelin and flutamide (STAD) before and during 66 Gy to the prostate and seminal vesicles (XRT) or to XRT alone. Piecewise longitudinal changes in PSA before relapse were characterized and quantified to determine which might cause FPBF calls. Results: Between 1996 and 2000, 802 eligible patients were randomized. Of these, 492 met the criteria for American Society for Therapeutic Radiology and Oncology (ASTRO) failure and 467 for Phoenix failure. Seventy-seven ASTRO fails and 39 Phoenix fails were deemed false positives (FPs). The majority of FPBFs were associated with the 'plateauing' in PSA values that follow posttreatment nadir. FPBFs were particularly common in men treated with STAD, in whom small, consecutive PSA rises before or during this phenomenon triggered 56 FP ASTRO fail calls. In these men, the Phoenix fail criteria triggered only 15 FPBF calls. However, the Phoenix criteria were more vulnerable than ASTRO to short-term isolated PSA rises during plateau, which resulted in 15 Phoenix fail calls but only 3 FP ASTRO fails. Conclusions: The Phoenix definition avoided 50% of FPBF calls that occurred with the ASTRO definition. Failures should be confirmed by further PSA rises before investigation and treatment is considered.

Duration of Androgen Deprivation in Locally Advanced Prostate Cancer: Long-Term Update of NRG Oncology RTOG 9202

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Lawton, Colleen A.F., E-mail: clawton@mcw.edu [Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Lin, Xiaolei [University of Chicago, Chicago, Illinois (United States); Hanks, Gerald E. [Fox Chase Cancer Center, Philadelphia, Pennsylvania (United States); Lepor, Herbert [New York University, New York, New York (United States); Grignon, David J. [Indiana University, Indianapolis, Indiana (United States); Brereton, Harmar D. [Northeast Radiation Oncology Center, Dunmore, Pennsylvania (United States); Bedi, Meena [Medical College of Wisconsin, Milwaukee, Wisconsin (United States); Rosenthal, Seth A. [Sutter General Hospital, Sacramento, California (United States); Zeitzer, Kenneth L. [Albert Einstein Medical Center, Philadelphia, Pennsylvania (United States); Venkatesan, Varagur M. [London Regional Cancer Program, London, Ontario (Canada); Horwitz, Eric M. [Fox Chase Cancer Center, Philadelphia, Pennsylvania (United States); Pisansky, Thomas M. [Mayo Clinic, Rochester, Minnesota (United States); Kim, Harold [Wayne State University-Karmanos Cancer Institute, Detroit, Michigan (United States); Parliament, Matthew B. [Cross Cancer Institute, Edmonton, Alberta (Canada); Rabinovitch, Rachel [University of Colorado Denver, Denver, Colorado (United States); Roach, Mack [University of California, San Francisco, California (United States); Kwok, Young [University of Maryland Medical System, Baltimore, Maryland (United States); Dignam, James J. [University of Chicago, Chicago, Illinois (United States); NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania (United States); Sandler, Howard M. [Cedars-Sinai Medical Center, Los Angeles, California (United States)

2017-06-01

Purpose: Trial RTOG 9202 was a phase 3 randomized trial designed to determine the optimal duration of androgen deprivation therapy (ADT) when combined with definitive radiation therapy (RT) in the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate. Long-term follow-up results of this study now available are relevant to the management of this disease. Methods and Materials: Men (N=1554) with adenocarcinoma of the prostate (cT2c-T4, N0-Nx) with a prostate-specific antigen (PSA) <150 ng/mL and no evidence of distant metastasis were randomized (June 1992 to April 1995) to short-term ADT (STAD: 4 months of flutamide 250 mg 3 times per day and goserelin 3.6 mg per month) and definitive RT versus long-term ADT (LTAD: STAD with definitive RT plus an additional 24 months of monthly goserelin). Results: Among 1520 protocol-eligible and evaluable patients, the median follow-up time for this analysis was 19.6 years. In analysis adjusted for prognostic covariates, LTAD improved disease-free survival (29% relative reduction in failure rate, P<.0001), local progression (46% relative reduction, P=.02), distant metastases (36% relative reduction, P<.0001), disease-specific survival (30% relative reduction, P=.003), and overall survival (12% relative reduction, P=.03). Other-cause mortality (non–prostate cancer) did not differ (5% relative reduction, P=.48). Conclusions: LTAD and RT is superior to STAD and RT for the treatment of locally advanced nonmetastatic adenocarcinoma of the prostate and should be considered the standard of care.

The Effects of Sleep Deprivation on Soccer Skills.

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Pallesen, Ståle; Gundersen, Hilde Stokvold; Kristoffersen, Morten; Bjorvatn, Bjørn; Thun, Eirunn; Harris, Anette

2017-08-01

Many athletes sleep poorly due to stress, travel, and competition anxiety. In the present study, we investigated the effects of sleep deprivation on soccer skills (juggling, dribbling, ball control, continuous kicking, 20 and 40 m sprint, and 30 m sprint with changes of direction). In all, 19 male junior soccer players (14-19 years old) were recruited and participated in a cross-balanced experimental study comprising two conditions; habitual sleep and 24 hours sleep deprivation. In both conditions, testing took place between 8 a.m. and 10 a.m. Order of tests was counterbalanced. Each test was conducted once or twice in a sequence repeated three times. The results revealed a negative effect of sleep deprivation on the continuous kicking test. On one test, 30 meter sprint with directional changes, a significant condition × test repetition interaction was found, indicating a steeper learning curve in the sleep deprived condition from Test 1 to Test 2 and a steeper learning curve in the rested condition from Test 2 to Test 3. The results are discussed in terms of limitations and strengths, and recommendations for future studies are outlined.

Sleep disturbance in men receiving androgen deprivation therapy for prostate cancer: The role of hot flashes and nocturia.

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Gonzalez, Brian D; Small, Brent J; Cases, Mallory G; Williams, Noelle L; Fishman, Mayer N; Jacobsen, Paul B; Jim, Heather S L

2018-02-01

Patients with prostate cancer receiving androgen deprivation therapy (ADT) are at risk of sleep disturbance; however, to the authors' knowledge, the mechanisms by which ADT may affect sleep are not well understood. The current study compared objective and subjective sleep disturbance in ADT recipients and controls and examined whether sleep disturbance in ADT recipients is attributable to the influence of ADT on hot flashes and nocturia. Patients with prostate cancer were assessed before or within 1 month after the initiation of ADT as well as 6 months and 12 months later (78 patients). Patients with prostate cancer were treated with prostatectomy only (99 patients) and men with no history of cancer (108 men) were assessed at similar intervals. Participants self-reported their sleep disturbance (Insomnia Severity Index) and interference from hot flashes (Hot Flash Related Daily Interference Scale). One hundred participants also wore actigraphs for 3 days at the 6-month assessment to measure objective sleep disturbance and reported their nocturia frequency. ADT recipients reported worse sleep disturbance, higher rates of clinically significant sleep disturbance, and greater hot flash interference than controls (Ps≤.03). In cross-sectional analyses among those with actigraphy data, ADT recipients had greater objective sleep disturbance and more episodes of nocturia (Pshot flashes (Pshot flash interference. Future studies should examine behavioral and pharmacologic interventions to address these symptoms among ADT recipients. Cancer 2018;124:499-506. © 2017 American Cancer Society. © 2017 American Cancer Society.

Effects of androgen on immunohistochemical localization of androgen receptor and Connexin 43 in mouse ovary.

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Yang, Mei; Li, Jianhua; An, Yulin; Zhang, Shuiwen

2015-10-01

Androgens have essential roles in the regulation of follicular development and female fertility. Androgen excess is the leading defect in polycystic ovary syndrome (PCOS) patients and involved in the ovarian dysfunction. The aim of this study was to elucidate the regarding regulatory role of androgen in the follicular development of female mouse. Immunohistochemical staining and Western blot analyses were performed to detect androgen receptor (AR) and Connexin 43 (Cx43) expression in ovaries from both control and testosterone-treated group mice. In this study, localizations of AR and Cx43 were dramatically altered in testosterone-treated mouse ovaries. In addition, AR expression was significantly increased, whereas Cx43 expression was markedly decreased after testosterone treatment. Alterations of AR and Cx43 expression by testosterone with concomitant reduction of MII oocytes. Overall, these results suggest the involvement of androgen in the regulation of AR and Cx43 localizations in mouse ovary. Alterations of AR and Cx43 expression by testosterone may affect normal folliculogenesis. Together these findings will enable us to begin understanding the important roles of AR and Cx43 actions in the regulation of follicular development, as well as providing insights into the role of AR and Cx43 actions in the androgen-associated reproductive diseases such as PCOS. Copyright © 2015 Elsevier Ltd. All rights reserved.

The PPAR{gamma} ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

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Moss, Patrice E.; Lyles, Besstina E.; Stewart, LaMonica V., E-mail: lstewart@mmc.edu

2010-12-10

The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPAR{gamma} ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPAR{gamma} ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPAR{gamma} ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPAR{gamma}. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPAR{gamma} and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

Effect of Monocular Deprivation on Rabbit Neural Retinal Cell Densities.

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Mwachaka, Philip Maseghe; Saidi, Hassan; Odula, Paul Ochieng; Mandela, Pamela Idenya

2015-01-01

To describe the effect of monocular deprivation on densities of neural retinal cells in rabbits. Thirty rabbits, comprised of 18 subject and 12 control animals, were included and monocular deprivation was achieved through unilateral lid suturing in all subject animals. The rabbits were observed for three weeks. At the end of each week, 6 experimental and 3 control animals were euthanized, their retinas was harvested and processed for light microscopy. Photomicrographs of the retina were taken and imported into FIJI software for analysis. Neural retinal cell densities of deprived eyes were reduced along with increasing period of deprivation. The percentage of reductions were 60.9% (P < 0.001), 41.6% (P = 0.003), and 18.9% (P = 0.326) for ganglion, inner nuclear, and outer nuclear cells, respectively. In non-deprived eyes, cell densities in contrast were increased by 116% (P < 0.001), 52% (P < 0.001) and 59.6% (P < 0.001) in ganglion, inner nuclear, and outer nuclear cells, respectively. In this rabbit model, monocular deprivation resulted in activity-dependent changes in cell densities of the neural retina in favour of the non-deprived eye along with reduced cell densities in the deprived eye.

Why do winners keep winning? Androgen mediation of winner but not loser effects in cichlid fish

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Oliveira, Rui F.; Silva, Ana; Canário, Adelino V.M.

2009-01-01

Animal conflicts are influenced by social experience such that a previous winning experience increases the probability of winning the next agonistic interaction, whereas a previous losing experience has the opposite effect. Since androgens respond to social interactions, increasing in winners and decreasing in losers, we hypothesized that socially induced transient changes in androgen levels could be a causal mediator of winner/loser effects. To test this hypothesis, we staged fights between dyads of size-matched males of the Mozambique tilapia (Oreochromis mossambicus). After the first contest, winners were treated with the anti-androgen cyproterone acetate and losers were supplemented with 11-ketotestosterone. Two hours after the end of the first fight, two contests were staged simultaneously between the winner of the first fight and a naive male and between the loser of first fight and another naive male. The majority (88%) of control winners also won the second interaction, whereas the majority of control losers (87%) lost their second fight, thus confirming the presence of winner/loser effects in this species. As predicted, the success of anti-androgen-treated winners in the second fight decreased significantly to chance levels (44%), but the success of androgenized losers (19%) did not show a significant increase. In summary, the treatment with anti-androgen blocks the winner effect, whereas androgen administration fails to reverse the loser effect, suggesting an involvement of androgens on the winner but not on the loser effect. PMID:19324741

Effects of sleep deprivation on central auditory processing

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Liberalesso Paulo Breno

2012-07-01

Full Text Available Abstract Background Sleep deprivation is extremely common in contemporary society, and is considered to be a frequent cause of behavioral disorders, mood, alertness, and cognitive performance. Although the impacts of sleep deprivation have been studied extensively in various experimental paradigms, very few studies have addressed the impact of sleep deprivation on central auditory processing (CAP. Therefore, we examined the impact of sleep deprivation on CAP, for which there is sparse information. In the present study, thirty healthy adult volunteers (17 females and 13 males, aged 30.75 ± 7.14 years were subjected to a pure tone audiometry test, a speech recognition threshold test, a speech recognition task, the Staggered Spondaic Word Test (SSWT, and the Random Gap Detection Test (RGDT. Baseline (BSL performance was compared to performance after 24 hours of being sleep deprived (24hSD using the Student’s t test. Results Mean RGDT score was elevated in the 24hSD condition (8.0 ± 2.9 ms relative to the BSL condition for the whole cohort (6.4 ± 2.8 ms; p = 0.0005, for males (p = 0.0066, and for females (p = 0.0208. Sleep deprivation reduced SSWT scores for the whole cohort in both ears [(right: BSL, 98.4 % ± 1.8 % vs. SD, 94.2 % ± 6.3 %. p = 0.0005(left: BSL, 96.7 % ± 3.1 % vs. SD, 92.1 % ± 6.1 %, p  Conclusion Sleep deprivation impairs RGDT and SSWT performance. These findings confirm that sleep deprivation has central effects that may impair performance in other areas of life.

Long-term outcomes from dose-escalated image-guided intensity-modulated radiotherapy with androgen deprivation: encouraging results for intermediate- and high-risk prostate cancer

Directory of Open Access Journals (Sweden)

Wilcox SW

2014-08-01

Full Text Available Shea W Wilcox,1,4 Noel J Aherne,2,4 Linus C Benjamin,1 Bosco Wu,1 Thomaz de Campos Silva,3 Craig S McLachlan,4 Michael J McKay,3,5 Andrew J Last,1 Thomas P Shakespeare1–4 1North Coast Cancer Institute, Port Macquarie, NSW, Australia; 2North Coast Cancer Institute, Coffs Harbour, NSW, Australia; 3North Coast Cancer Institute, Lismore, NSW, Australia; 4The University of New South Wales, Rural Clinical School, Sydney, NSW, Australia; 5The University of Sydney, Sydney, NSW, Australia Purpose: Dose-escalated (DE radiotherapy in the setting of localized prostate cancer has been shown to improve biochemical disease-free survival (bDFS in several studies. In the same group of patients, androgen deprivation therapy (ADT has been shown to confer a survival benefit when combined with radiotherapy doses of up to 70 Gy; however, there is currently little long-term data on patients who have received high-dose intensity-modulated radiotherapy (IMRT with ADT. We report the long-term outcomes in a large cohort of patients treated with the combination of DE image-guided IMRT (IG-IMRT and ADT. Methods and materials: Patients with localized prostate cancer were identified from a centralized database across an integrated cancer center. All patients received DE IG-IMRT, combined with ADT, and had a minimum follow up of 12 months post-radiotherapy. All relapse and toxicity data were collected prospectively. Actuarial bDFS, metastasis-free survival, prostate cancer-specific survival, and multivariate analyses were calculated using the SPSS v20.0 statistical package. Results: Seven hundred and eighty-two eligible patients were identified with a median follow up of 46 months. Overall, 4.3% of patients relapsed, 2.0% developed distant metastases, and 0.6% died from metastatic prostate cancer. At 5-years, bDFS was 88%, metastasis-free survival was 95%, and prostate cancer-specific survival was 98%. Five-year grade 2 genitourinary and gastrointestinal toxicity was 2

Expression profiles and functional associations of endogenous androgen receptor and caveolin-1 in prostate cancer cell lines.

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Bennett, Nigel C; Hooper, John D; Johnson, David W; Gobe, Glenda C

2014-05-01

In prostate cancer (PCa) patients, the protein target for androgen deprivation and blockade therapies is androgen receptor (AR). AR interacts with many proteins that function to either co-activate or co-repress its activity. Caveolin-1 (Cav-1) is not found in normal prostatic epithelium, but is found in PCa, and may be an AR co-regulator protein. We investigated cell line-specific signatures and associations of endogenous AR and Cav-1 in six PCa cell lines of known androgen sensitivity: LNCaP (androgen sensitive); 22Rv1 (androgen responsive); PC3, DU145, and ALVA41 (androgen non-reliant); and RWPE1 (non-malignant). Protein and mRNA expression profiles were compared and electron microscopy used to identify cells with caveolar structures. For cell lines expressing both AR and Cav-1, knockdown techniques using small interfering RNA against AR or Cav-1 were used to test whether diminished expression of one affected the other. Co-sedimentation of AR and Cav-1 was used to test their association. A reporter assay for AR genomic activity was utilized following Cav-1 knockdown. AR-expressing LNCaP and 22Rv1 cells had low endogenous Cav-1 mRNA and protein. Cell lines that expressed little or no AR (DU145, PC3, ALVA41, and RWPE1) expressed high endogenous levels of Cav-1. AR knockdown in LNCaP cells had little effect on Cav-1, but Cav-1 knockdown inhibited AR expression and genomic activity. These data show endogenous AR and Cav-1 mRNA and protein expression is inversely related in PCa cells, with Cav-1 acting on the androgen/AR signaling axis possibly as an AR co-activator, demonstrated by diminished AR genomic activity following Cav-1 knockdown. © 2013 Wiley Periodicals, Inc.

Androgenic effect of honeybee drone milk in castrated rats: roles of methyl palmitate and methyl oleate.

Science.gov (United States)

Seres, A B; Ducza, E; Báthori, M; Hunyadi, A; Béni, Z; Dékány, M; Hajagos-Tóth, J; Verli, J; Gáspár, Róbert

2014-04-28

Numerous honeybee (Apis mellifera) products have been used in traditional medicine to treat infertility and to increase vitality in both men and women. Drone milk (DM) is a relatively little-known honeybee product with a putative sexual hormone effect. The oestrogenic effect of a fraction of DM has recently been reported in rats. However, no information is available on the androgenic effects of DM. The purpose of the present study was to determine the androgen-like effect of DM in male rats and to identify effective compounds. A modified Hershberger assay was used to investigate the androgenic effect of crude DM, and the plasma level of testosterone was measured. The prostatic mRNA and protein expression of Spot14-like androgen-inducible protein (SLAP) were also examined with real-time PCR and Western blot techniques. GC-MS and NMR spectroscopic investigations were performed to identify the active components gained by bioactivity-guided fractionation. The crude DM increased the relative weights of the androgen-dependent organs and the plasma testosterone level in castrated rats and these actions were flutamide-sensitive. DM increased the tissue mRNA and protein level of SLAP, providing further evidence of its androgen-like character. After bioactivity-guided fractionation, two fatty acid esters, methyl palmitate (MP) and methyl oleate (MO), were identified as active compounds. MP alone showed an androgenic effect, whereas MO increased the weight of androgen-sensitive tissues and the plasma testosterone level only in combination. The experimental data of DM and its active compounds (MO and MP) show androgenic activity confirming the traditional usage of DM. DM or MP or/and MO treatments may project a natural mode for the therapy of male infertility. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Androgens and alopecia.

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Kaufman, Keith D

2002-12-30

Androgens have profound effects on scalp and body hair in humans. Scalp hair grows constitutively in the absence of androgens, while body hair growth is dependent on the action of androgens. Androgenetic alopecia, referred to as male pattern hair loss (MPHL) in men and female pattern hair loss (FPHL) in women, is due to the progressive miniaturization of scalp hair. Observations in both eunuchs, who have low levels of testicular androgens, and males with genetic 5alpha-reductase (5alphaR) deficiency, who have low levels of dihydrotestosterone (DHT), implicate DHT as a key androgen in the pathogenesis of MPHL in men. The development of finasteride, a type 2-selective 5alphaR inhibitor, further advanced our understanding of the role of DHT in the pathophysiology of scalp alopecia. Controlled clinical trials with finasteride demonstrated improvements in scalp hair growth in treated men associated with reductions in scalp DHT content, and a trend towards reversal of scalp hair miniaturization was evident by histopathologic evaluation of scalp biopsies. In contrast to its beneficial effects in men, finasteride did not improve hair growth in postmenopausal women with FPHL. Histopathological evaluation of scalp biopsies confirmed that finasteride treatment produced no benefit on scalp hair in these women. These findings suggest that MPHL and FPHL are distinct clinical entities, with disparate pathophysiologies. Studies that elucidate the molecular mechanisms by which androgens regulate hair growth would provide greater understanding of these differences. Copyright 2002 Elsevier Science Ireland Ltd.

Sleep deprived and sweating it out: the effects of total sleep deprivation on skin conductance reactivity to psychosocial stress.

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Liu, Jean C J; Verhulst, Silvan; Massar, Stijn A A; Chee, Michael W L

2015-01-01

We examined how sleep deprivation alters physiological responses to psychosocial stress by evaluating changes in skin conductance. Between-subjects design with one group allocated to 24 h of total sleep deprivation and the other to rested wakefulness. The study took place in a research laboratory. Participants were 40 healthy young adults recruited from a university. Sleep deprivation and feedback. Electrodermal activity was monitored while participants completed a difficult perceptual task with false feedback. All participants showed increased skin conductance levels following stress. However, compared to well-rested participants, sleep deprived participants showed higher skin conductance reactivity with increasing stress levels. Our results suggest that sleep deprivation augments allostatic responses to increasing psychosocial stress. Consequentially, we propose sleep loss as a risk factor that can influence the pathogenic effects of stress. © 2014 Associated Professional Sleep Societies, LLC.

Prostate-specific antigen (Pasa) bounce and other fluctuations: Which biochemical relapse definition is least prone to PSA false calls? An analysis of 2030 men treated for prostate cancer with external beam or brachytherapy with or without adjuvant androgen deprivation therapy

International Nuclear Information System (INIS)

Pickles, Tom

2006-01-01

Purpose: To determine the false call (FC) rate for prostate-specific antigen (PSA) relapse according to nine different PSA relapse definitions after a PSA fluctuation (bounce) has occurred after external beam radiation therapy (EBRT) or brachytherapy, with or without adjuvant androgen deprivation therapy. Methods and Materials: An analysis of a prospective database of 2030 patients was conducted. Prostate-specific antigen relapse was scored according to the American Society for Therapeutic Radiology and Oncology (ASTRO), Vancouver, threshold + n, and nadir + n definitions for the complete data set and then compared against a truncated data set, with data subsequent to the height of the bounce deleted. The FC rate was calculated for each definition. Results: The bounce rate, with this very liberal definition of bounce, was 58% with EBRT and 84% with brachytherapy. The FC rate was lowest with nadir + 2 and + 3 definitions (2.2% and 1.6%, respectively) and greatest with low-threshold and ASTRO definitions (32% and 18%, respectively). The ASTRO definition was particularly susceptible to FC when androgen deprivation therapy was used with radiation (24%). Discussion: New definitions of biochemical non-evidence of disease that are more robust than the ASTRO definition have been identified. Those with the least FC rates are the nadir + 2 and nadir + 3 definitions, both of which are being considered to replace the ASTRO definition by the 2005 meeting of the Radiation Therapy Oncology Group-ASTRO consensus panel

Psychological Effect of an Analogue Traumatic Event Reduced by Sleep Deprivation.

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Porcheret, Kate; Holmes, Emily A; Goodwin, Guy M; Foster, Russell G; Wulff, Katharina

2015-07-01

To examine the effect of sleep deprivation compared to sleep, immediately after experimental trauma stimuli on the development of intrusive memories to that trauma stimuli. Participants were exposed to a film with traumatic content (trauma film). The immediate response to the trauma film was assessed, followed by either total sleep deprivation (sleep deprived group, N = 20) or sleep as usual (sleep group, N = 22). Twelve hours after the film viewing the initial psychological effect of the trauma film was measured and for the subsequent 6 days intrusive emotional memories related to the trauma film were recorded in daily life. Academic sleep laboratory and participants' home environment. Healthy paid volunteers. On the first day after the trauma film, the psychological effect as assessed by the Impact of Event Scale - Revised was lower in the sleep deprived group compared to the sleep group. In addition, the sleep deprived group reported fewer intrusive emotional memories (mean 2.28, standard deviation [SD] 2.91) compared to the sleep group (mean 3.76, SD 3.35). Because habitual sleep/circadian patterns, psychological health, and immediate effect of the trauma film were similar at baseline for participants of both groups, the results cannot be accounted for by pre-existing inequalities between groups. Our findings suggest that sleep deprivation on one night, rather than sleeping, reduces emotional effect and intrusive memories following exposure to experimental trauma. © 2015 Associated Professional Sleep Societies, LLC.

Additional androgen deprivation makes the difference. Biochemical recurrence-free survival in prostate cancer patients after HDR brachytherapy and external beam radiotherapy

International Nuclear Information System (INIS)

Schiffmann, Jonas; Tennstedt, Pierre; Beyer, Burkhard; Boehm, Katharina; Tilki, Derya; Salomon, Georg; Graefen, Markus; Lesmana, Hans; Platz, Volker; Petersen, Cordula; Kruell, Andreas; Schwarz, Rudolf

2015-01-01

The role of additional androgen deprivation therapy (ADT) in prostate cancer (PCa) patients treated with combined HDR brachytherapy (HDR-BT) and external beam radiotherapy (EBRT) is still unknown. Consecutive PCa patients classified as D'Amico intermediate and high-risk who underwent HDR-BT and EBRT treatment ± ADT at our institution between January 1999 and February 2009 were assessed. Multivariable Cox regression models predicting biochemical recurrence (BCR) were performed. BCR-free survival was assessed with Kaplan-Meier analyses. Overall, 392 patients were assessable. Of these, 221 (56.4 %) underwent trimodality (HDR-BT and EBRT and ADT) and 171 (43.6 %) bimodality (HDR-BT and EBRT) treatment. Additional ADT administration reduced the risk of BCR (HR: 0.4, 95 % CI: 0.3-0.7, p < 0.001). D'Amico high-risk patients had superior BCR-free survival when additional ADT was administered (log-rank p < 0.001). No significant difference for BCR-free survival was recorded when additional ADT was administered to D'Amico intermediate-risk patients (log-rank p = 0.2). Additional ADT administration improves biochemical control in D'Amico high-risk patients when HDR-BT and EBRT are combined. Physicians should consider the oncological benefit of ADT administration for these patients during the decision-making process. (orig.) [de

Androgen insensitivity syndrome: gonadal androgen receptor activity

International Nuclear Information System (INIS)

Coulam, C.B.; Graham, M.L.; Spelsberg, T.C.

1984-01-01

To determine whether abnormalities of the androgen receptor previously observed in skin fibroblasts from patients with androgen insensitivity syndrome also occur in the gonads of affected individuals, androgen receptor activity in the gonads of a patient with testicular feminization syndrome was investigated. Using conditions for optimal recovery of androgen receptor from human testes established by previous studies, we detected the presence of a high-affinity (dissociation constant . 3.2 X 10(-10) mol/L), low-capacity (4.2 X 10(-12) mol/mg DNA), androgen-binding protein when tritium-labeled R1881 was incubated at 4 degrees C with nuclear extracts from the gonads of control patients or from a patient with testicular feminization syndrome but not when incubated at 37 degrees C. Thus this patient has an androgen receptor with a temperature lability similar to that of receptors from normal persons

Heat shock protein 90 chaperone complex inhibitor enhanced radiosensitivity through modification of response to hormone and degradation of androgen receptor in hormone sensitive prostate cancer cell line

International Nuclear Information System (INIS)

Mitsuhashi, N.; Harashima, K.; Akimoto, T.

2003-01-01

It is easily speculated that androgen or androgen deprivation affects proliferative activity or radiosensitivity, but there has been enough information how androgen or androgen deprivation influences the response to radiation. In this setting, the effect of dihydrotestosterone (DHT) on cellular growth and radiosensitivity was examined in hormone-responsive human prostate cancer cell line (LnCap). The binding of androgen receptor (AR) with heat shock protein 90 (Hsp90) plays an important role in stability of the function of receptor. It was, therefore, examined how Hsp90 chaperone complex inhibitor modified the effect of DHT on radiosensitivity in addition to the effect of DHT, especially focusing on AR and its downstream signal transduction pathways. Hydroxy-flutamide (OH-flutamide) was also used to confirm the effect of activation of AR on radiosensitivity because AR of LnCap has a point mutation, leading to activation of AR caused by the binding of OH-flutamide. Radicicol was used as a Hsp90 chaperone complex inhibitor, and incubated with cells at a concentration of 500 nM. Radicicol was incubated with cells for 9 h, and cells were irradiated 1 h after the start of incubation. DHT and OH-flutamide were incubated with cells until staining. DHT or OH-flutamide resulted in stimulation of cellular growth in contrast to inhibition of cellular growth caused by higher concentrations, so that we adopted 1 nM as a concentration of DHT and 1μM as a concentration of OH-flutamide. DHT or OH-flutamide in combination with radiation resulted in slight decrease in radiosensitivity compared with radiation alone. Radicicol at a concentration of 500 nM in combination with DHT or OH-flutamide abolished decrease in radiosensitivity caused by DHT or OH-flutamide. In terms of the expression of AR, radicicol in combination with radiation and/or DHT, OH-flutamide induced degradation of AR. In consistent with degradation of AR, the expression of prostate specific antigen (PSA) decreased

Bipolar Androgen Therapy for Men With Androgen Ablation Naïve Prostate Cancer: Results From the Phase II BATMAN Study.

Science.gov (United States)

Schweizer, Michael T; Wang, Hao; Luber, Brandon; Nadal, Rosa; Spitz, Avery; Rosen, D Marc; Cao, Haiyi; Antonarakis, Emmanuel S; Eisenberger, Mario A; Carducci, Michael A; Paller, Channing; Denmeade, Samuel R

2016-09-01

We have previously documented a paradoxical anti-tumor effect when castration-resistant prostate cancer patients were treated with intermittent, high-dose testosterone (i.e., Bipolar Androgen Therapy; BAT). Because, an adaptive increase in androgen receptor expression following chronic androgen deprivation therapy (ADT) may underlie this effect, we tested whether men with hormone-sensitive (HS) prostate cancer (PC) would also respond to BAT if given following a 6-month ADT lead-in. Asymptomatic HS PC patients with low metastatic burden or non-metastatic biochemically recurrent disease were enrolled. Following 6-month of ADT, those with a PSA <4 ng/ml went on to receive alternating 3-month cycles of BAT and ADT. BAT was administered as intramuscular testosterone (T) cypionate or enanthate 400 mg on Days (D) 1, 29, and 57. ADT was continued throughout the study to allow rapid cycling from near castrate to supraphysiologic range T following T injections. The primary endpoint was the percent of patients with a PSA <4 ng/ml after 18 months. Secondary endpoints included radiographic response and quality of life (QoL). Twenty-nine of 33 patients received BAT following the ADT lead-in. The primary endpoint was met, with 17/29 men (59%, 90% confidence interval: 42-74%) having a PSA <4 ng/ml at 18 months. Ten patients receiving BAT had RECIST evaluable disease, and eight (80%) objective responses were observed (four complete; four partial). Three patients progressed per RECIST criteria and three had unconfirmed progression on bone scan. Men treated with 6-month of ADT had improved QoL following the first cycle of BAT as measured by the SF-36, FACT-P, and IIEF surveys. BAT demonstrated preliminary efficacy in men with HS PC following 6-month of ADT. BAT may improve QoL in men treated with ADT. Prostate 76:1218-1226, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The effects of sleep deprivation on emotional empathy.

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Guadagni, Veronica; Burles, Ford; Ferrara, Michele; Iaria, Giuseppe

2014-12-01

Previous studies have shown that sleep loss has a detrimental effect on the ability of the individuals to process emotional information. In this study, we tested the hypothesis that this negative effect extends to the ability of experiencing emotions while observing other individuals, i.e. emotional empathy. To test this hypothesis, we assessed emotional empathy in 37 healthy volunteers who were assigned randomly to one of three experimental groups: one group was tested before and after a night of total sleep deprivation (sleep deprivation group), a second group was tested before and after a usual night of sleep spent at home (sleep group) and the third group was tested twice during the same day (day group). Emotional empathy was assessed by using two parallel versions of a computerized test measuring direct (i.e. explicit evaluation of empathic concern) and indirect (i.e. the observer's reported physiological arousal) emotional empathy. The results revealed that the post measurements of both direct and indirect emotional empathy of participants in the sleep deprivation group were significantly lower than those of the sleep and day groups; post measurement scores of participants in the day and sleep groups did not differ significantly for either direct or indirect emotional empathy. These data are consistent with previous studies showing the negative effect of sleep deprivation on the processing of emotional information, and extend these effects to emotional empathy. The findings reported in our study are relevant to healthy individuals with poor sleep habits, as well as clinical populations suffering from sleep disturbances. © 2014 European Sleep Research Society.

Risk factors for bone loss with prostate cancer in Korean men not receiving androgen deprivation therapy

Directory of Open Access Journals (Sweden)

Sun-Ouck Kim

2009-04-01

Full Text Available PURPOSE: Preexisting bone loss in men with prostate cancer is an important issue due to the accelerated bone loss during androgen deprivation therapy (ADT. In addition, a high prostate-specific antigen (PSA level has been reported to be related to bone metabolism. This study assessed the factors associated with osteoporosis in Korean men with non-metastatic prostate cancer before undergoing ADT. MATERIAL AND METHODS: The study enrolled patients admitted for a prostate biopsy because of a high PSA or palpable nodule on a digital rectal examination. We divided the patients (n = 172 according to the results of the biopsy: group I, non-metastatic prostate cancer (n = 42 and group II, benign prostatic hypertrophy (BPH; n = 130. The lumbar bone mineral density (BMD was evaluated using quantitative computed tomography. The demographic, health status, lifestyle, body mass index (BMI, serum testosterone concentration, and disease variables in prostate cancer (Gleason score, clinical stage, and PSA were analyzed prospectively to determine their effect on the BMD. RESULTS: The estimated mean T-score was higher in group I than in group II (-1.96 ± 3.35 vs. -2.66 ± 3.20, but without statistic significance (p = 0.235. The significant factors correlated with BMD in group I were a high serum PSA (ß = -0.346, p = 0.010 and low BMI (ß = 0.345, p = 0.014 in the multiple linear regression model. Also old age (r = -0.481, p = 0.001, a high serum PSA (r = -0.571, p < 0.001, low BMI (r = 0.598, p < 0.001, and a high Gleason’s score (r = -0.319, p = 0.040 were the factors related to BMD in the correlation. The significant factors correlated with BMD in group II were old age (ß = -0.324, p = 0.001 and BMI (ß = 0.143, p = 0.014 in the multiple linear regression model. CONCLUSIONS: The risk factors for osteoporosis in men with prostate cancer include a low BMI, and elevated serum PSA. Monitoring BMD from the outset of ADT is a logical first step in the clinical

A polymorphism in a transporter of testosterone is a determinant of androgen independence in prostate cancer.

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Sharifi, Nima; Hamada, Akinobu; Sissung, Tristan; Danesi, Romano; Venzon, David; Baum, Caitlin; Gulley, James L; Price, Douglas K; Dahut, William L; Figg, William D

2008-08-05

To determine if patients with advanced prostate cancer carrying a polymorphism that codes for a more active testosterone transporter have less durable responses to androgen-deprivation therapy (ADT) than patients not carrying this polymorphism. We previously determined that a polymorphism in SLCO1B3 affects testosterone transport and that those men who have at least one wild-type T allele at the 334 T > G polymorphism in this gene have a shorter survival. We hypothesized that the T allele which increases testosterone transport would be associated with a shorter interval from ADT to androgen independence. We examined the association between this SLCO1B3 polymorphism and time from ADT to androgen independence, ADT to prostate-specific antigen (PSA) nadir and PSA nadir to androgen independence in 68 Caucasian patients with advanced prostate cancer who were treated with ADT with metastatic disease (D2) or biochemical failure with no metastatic disease (D0). When examined separately, patients in the individual stages tended to have a shorter time to androgen independence with the T allele in the D0 (P = 0.11) and D2 (P = 0.18) groups. Combining these groups and stratifying by stage yielded a statistically significant shorter time to androgen independence with the T allele (P = 0.048). A polymorphism in a transporter that increases testosterone import is associated with a shorter time to androgen independence in patients with prostate cancer who are treated with ADT.

The 'Timing of Androgen-Deprivation therapy in incurable prostate cancer' protocol (TOAD)--where are we now? Synopsis of the Victorian Cooperative Oncology Group PR 01-03 and Trans-Tasman Radiation Oncology Group 03.06 clinical trial.

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Duchesne, Gillian M; Woo, Henry H

2014-11-01

To outline the development of the 'Timing of Androgen Deprivation' (TOAD) protocol, a collaborative randomised clinical trial under the auspices of the Cancer Council Victoria, the Trans-Tasman Radiation Oncology Group, and the Urological Society of Australia and New Zealand (USANZ), which opened to recruitment in 2004. The principal hypothesis for the trial was that the early introduction of androgen-deprivation therapy (ADT; experimental arm) at the time when curative therapies are no longer considered an option, would improve overall survival for these patients, whilst maintaining an acceptable quality of life; compared with waiting for disease progression or the development of symptoms (control arm). An increase in overall survival at 5 years of 10% was judged to be clinically worthwhile. Recruitment was slow, with fewer than half of the protocol requirement of 750 patients eventually accrued, but nonetheless it is considered that the trial will still contribute a major source of evidence in this area. The study closed to follow-up at the end of 2013, with data analysis commencing mid-2014, and with the primary publication anticipated to be submitted by the end of 2014. The question of timing of ADT remains relevant in the current era of newer and more varied treatment methods. Even with the advent of novel chemotherapy and the biological agents that are undergoing investigation for progressively earlier disease stages, the dilemma of when to commence palliative treatment in an asymptomatic patient will remain, unless or until these agents are shown to increase overall survival. The TOAD trial will contribute to answering at least in part, some of these questions. © 2014 The Authors. BJU International © 2014 BJU International.

The effects of sleep deprivation on dissociable prototype learning systems.

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Maddox, W Todd; Glass, Brian D; Zeithamova, Dagmar; Savarie, Zachary R; Bowen, Christopher; Matthews, Michael D; Schnyer, David M

2011-03-01

The cognitive neural underpinnings of prototype learning are becoming clear. Evidence points to 2 different neural systems, depending on the learning parameters. A/not-A (AN) prototype learning is mediated by posterior brain regions that are involved in early perceptual learning, whereas A/B (AB) is mediated by frontal and medial temporal lobe regions. To investigate the effects of sleep deprivation on AN and AB prototype learning and to use established prototype models to provide insights into the cognitive-processing locus of sleep-deprivation deficits. Participants performed an AN and an AB prototype learning task twice, separated by a 24-hour period, with or without sleep between testing sessions. Eighteen West Point cadets participated in the sleep-deprivation group, and 17 West Point cadets participated in a control group. Sleep deprivation led to an AN, but not an AB, performance deficit. Prototype model analyses indicated that the AN deficit was due to changes in attentional focus and a decrease in confidence that is reflected in an increased bias to respond non-A. The findings suggest that AN, but not AB, prototype learning is affected by sleep deprivation. Prototype model analyses support the notion that the effect of sleep deprivation on AN is consistent with lapses in attentional focus that are more detrimental to AN than to AB. This finding adds to a growing body of work that suggests that different performance changes associated with sleep deprivation can be attributed to a common mechanism of changes in simple attention and vigilance.

Genomic and non-genomic effects of androgens in the cardiovascular system: clinical implications.

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Lucas-Herald, Angela K; Alves-Lopes, Rheure; Montezano, Augusto C; Ahmed, S Faisal; Touyz, Rhian M

2017-07-01

The principle steroidal androgens are testosterone and its metabolite 5α-dihydrotestosterone (DHT), which is converted from testosterone by the enzyme 5α-reductase. Through the classic pathway with androgens crossing the plasma membrane and binding to the androgen receptor (AR) or via mechanisms independent of the ligand-dependent transactivation function of nuclear receptors, testosterone induces genomic and non-genomic effects respectively. AR is widely distributed in several tissues, including vascular endothelial and smooth muscle cells. Androgens are essential for many developmental and physiological processes, especially in male reproductive tissues. It is now clear that androgens have multiple actions besides sex differentiation and sexual maturation and that many physiological systems are influenced by androgens, including regulation of cardiovascular function [nitric oxide (NO) release, Ca 2+ mobilization, vascular apoptosis, hypertrophy, calcification, senescence and reactive oxygen species (ROS) generation]. This review focuses on evidence indicating that interplay between genomic and non-genomic actions of testosterone may influence cardiovascular function. © 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Three linked nomograms for predicting biochemical failure in prostate cancer treated with radiotherapy plus androgen deprivation therapy

International Nuclear Information System (INIS)

Lopez-Torrecilla, Jose; Boladeras, Anna; Angeles Cabeza, Maria; Zapatero, Almudena; Jove, Josep; Esteban, Luis M.; Henriquez, Ivan; Casana, Manuel; Mengual, Jose Luis; Gonzalez-San Segundo, Carmen; Gomez-Caamano, Antonio; Hervas, Asuncion; Munoz, Julia Luisa; Sanz, Gerardo

2015-01-01

Nomograms were established to predict biochemical recurrence (BCR) after radiotherapy (RT) with a low weight of the characteristic variables of RT and androgen deprivation therapy (ADT). Our aim is to provide a new stratified tool for predicting BCR at 4 and 7 years in patients treated using RT with radical intent. A retrospective, nonrandomized analysis was performed on 5044 prostate cancer (PCa) patients with median age 70 years, who received RT - with or without ADT - between November 1992 and May 2007. Median follow-up was 5.5 years. BCR was defined as a rise in serum prostate-specific antigen (PSA) of 2 ng/ml over the post-treatment PSA nadir. Univariate association between predictor variables and BCR was assessed by the log-rank test, and three linked nomograms were created for multivariate prognosis of BCR-free survival. Each nomogram corresponds to a category of the Gleason score - either 6,7, or 8-10 - and all of them were created from a single proportional hazards regression model stratified also by months of ADT (0, 1-6, 7-12, 13-24, 25-36, 36-60). The performance of this model was analyzed by calibration, discrimination, and clinical utility. Initial PSA, clinical stage, and RT dose were significant variables (p < 0.01). The model showed a good calibration. The concordance probability was 0.779, improving those obtained with other nomograms (0.587, 0.571, 0.554) in the database. Survival curves showed best clinical utility in a comparison with National Comprehensive Cancer Network (NCCN) risk groups. For each Gleason score category, the nomogram provides information on the benefit of adding ADT to a specific RT dose. (orig.) [de

Epigenomic Regulation of Androgen Receptor Signaling: Potential Role in Prostate Cancer Therapy

Directory of Open Access Journals (Sweden)

Vito Cucchiara

2017-01-01

Full Text Available Androgen receptor (AR signaling remains the major oncogenic pathway in prostate cancer (PCa. Androgen-deprivation therapy (ADT is the principle treatment for locally advanced and metastatic disease. However, a significant number of patients acquire treatment resistance leading to castration resistant prostate cancer (CRPC. Epigenetics, the study of heritable and reversible changes in gene expression without alterations in DNA sequences, is a crucial regulatory step in AR signaling. We and others, recently described the technological advance Chem-seq, a method to identify the interaction between a drug and the genome. This has permitted better understanding of the underlying regulatory mechanisms of AR during carcinogenesis and revealed the importance of epigenetic modifiers. In screening for new epigenomic modifiying drugs, we identified SD-70, and found that this demethylase inhibitor is effective in CRPC cells in combination with current therapies. The aim of this review is to explore the role of epigenetic modifications as biomarkers for detection, prognosis, and risk evaluation of PCa. Furthermore, we also provide an update of the recent findings on the epigenetic key processes (DNA methylation, chromatin modifications and alterations in noncoding RNA profiles involved in AR expression and their possible role as therapeutic targets.

Additional androgen deprivation makes the difference. Biochemical recurrence-free survival in prostate cancer patients after HDR brachytherapy and external beam radiotherapy

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Schiffmann, Jonas; Tennstedt, Pierre; Beyer, Burkhard; Boehm, Katharina; Tilki, Derya; Salomon, Georg; Graefen, Markus [University Medical Center Hamburg-Eppendorf, Martini-Clinic Prostate Cancer Center, Hamburg (Germany); Lesmana, Hans; Platz, Volker; Petersen, Cordula; Kruell, Andreas; Schwarz, Rudolf [University Medical Center Hamburg-Eppendorf, Department of Radiation oncology, Hamburg (Germany)

2015-04-01

The role of additional androgen deprivation therapy (ADT) in prostate cancer (PCa) patients treated with combined HDR brachytherapy (HDR-BT) and external beam radiotherapy (EBRT) is still unknown. Consecutive PCa patients classified as D'Amico intermediate and high-risk who underwent HDR-BT and EBRT treatment ± ADT at our institution between January 1999 and February 2009 were assessed. Multivariable Cox regression models predicting biochemical recurrence (BCR) were performed. BCR-free survival was assessed with Kaplan-Meier analyses. Overall, 392 patients were assessable. Of these, 221 (56.4 %) underwent trimodality (HDR-BT and EBRT and ADT) and 171 (43.6 %) bimodality (HDR-BT and EBRT) treatment. Additional ADT administration reduced the risk of BCR (HR: 0.4, 95 % CI: 0.3-0.7, p < 0.001). D'Amico high-risk patients had superior BCR-free survival when additional ADT was administered (log-rank p < 0.001). No significant difference for BCR-free survival was recorded when additional ADT was administered to D'Amico intermediate-risk patients (log-rank p = 0.2). Additional ADT administration improves biochemical control in D'Amico high-risk patients when HDR-BT and EBRT are combined. Physicians should consider the oncological benefit of ADT administration for these patients during the decision-making process. (orig.) [German] Der Nutzen einer zusaetzlichen Hormonentzugstherapie (ADT, ''androgen deprivation therapy'') fuer Patienten mit Prostatakarzinom (PCa), welche mit einer Kombination aus HDR-Brachytherapie (HDR-BT) und perkutaner Bestrahlung (EBRT) behandelt werden, ist weiterhin ungeklaert. Fuer diese Studie wurden konsekutive, nach der D'Amico-Risikoklassifizierung in ''intermediate'' und ''high-risk'' eingeteilte Patienten ausgewaehlt, die zwischen Januar 1999 und Februar 2009 in unserem Institut eine kombinierte Therapie aus HDR-BT, EBRT ± ADT erhalten haben. Eine

Effects of triazole fungicides on androgenic disruption and CYP3A4 enzyme activity.

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Lv, Xuan; Pan, Liumeng; Wang, Jiaying; Lu, Liping; Yan, Weilin; Zhu, Yanye; Xu, Yiwen; Guo, Ming; Zhuang, Shulin

2017-03-01

Triazole fungicides are widely used as broad-spectrum fungicides, non-steroidal antiestrogens and for various industrial applications. Their residues have been frequently detected in multiple environmental and human matrices. The increasingly reported toxicity incidents have led triazole fungicides as emerging contaminants of environmental and public health concern. However, whether triazole fungicides behave as endocrine disruptors by directly mimicking environmental androgens/antiandrogens or exerting potential androgenic disruption indirectly through the inhibition of cytochrome P450 (CYP450) enzyme activity is yet an unresolved question. We herein evaluated five commonly used triazole fungicides including bitertanol, hexaconazole, penconazole, tebuconazole and uniconazole for the androgenic and anti-androgenic activity using two-hybrid recombinant human androgen receptor (AR) yeast bioassay and comparatively evaluated their effects on enzymatic activity of CYP3A4 by P450-Glo™ CYP3A4 bioassay. All five fungicides showed moderate anti-androgenic activity toward human AR with the IC 50 ranging from 9.34 μM to 79.85 μM. The anti-androgenic activity remained no significant change after the metabolism mediated by human liver microsomes. These fungicides significantly inhibited the activity of CYP3A4 at the environmental relevant concentrations and the potency ranks as tebuconazole > uniconazole > hexaconazole > penconazole > bitertanol with the corresponding IC 50 of 0.81 μM, 0.93 μM, 1.27 μM, 2.22 μM, and 2.74 μM, respectively. We found that their anti-androgenic activity and the inhibition potency toward CYP3A4 inhibition was significantly correlated (R 2 between 0.83 and 0.97, p pesticides and structurally similar chemicals should fully consider potential androgenic disrupting effects and the influences on the activity of CYP450s. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of Presurgical Treatment for Prostate Cancer

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In this study, men diagnosed with androgen-sensitive prostate cancer with intermediate- or high-risk features will be examined with mpMRI, undergo targeted biopsies, and be treated with neoadjuvant androgen deprivation therapy.

Psychological and Behavioral Effects of Anabolic-Androgenic Steroids.

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Bahrke, Michael S.

This review of the literature on the psychological and behavioral effects of anabolic-androgenic steroids (AS) first looks at aspects of the history and prevalence of AS use in competitive sports. Research suggests that one-quarter to one-half million adolescents in the United States have used, or are currently using AS. Some effects of androgens…

Increasing women's sexual desire: The comparative effectiveness of estrogens and androgens.

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Cappelletti, Maurand; Wallen, Kim

2016-02-01

Both estradiol and testosterone have been implicated as the steroid critical for modulating women's sexual desire. By contrast, in all other female mammals only estradiol has been shown to be critical for female sexual motivation and behavior. Pharmaceutical companies have invested heavily in the development of androgen therapies for female sexual desire disorders, but today there are still no FDA approved androgen therapies for women. Nonetheless, testosterone is currently, and frequently, prescribed off-label for the treatment of low sexual desire in women, and the idea of testosterone as a possible cure-all for female sexual dysfunction remains popular. This paper places the ongoing debate concerning the hormonal modulation of women's sexual desire within a historical context, and reviews controlled trials of estrogen and/or androgen therapies for low sexual desire in postmenopausal women. These studies demonstrate that estrogen-only therapies that produce periovulatory levels of circulating estradiol increase sexual desire in postmenopausal women. Testosterone at supraphysiological, but not at physiological, levels enhances the effectiveness of low-dose estrogen therapies at increasing women's sexual desire; however, the mechanism by which supraphysiological testosterone increases women's sexual desire in combination with an estrogen remains unknown. Because effective therapies require supraphysiological amounts of testosterone, it remains unclear whether endogenous testosterone contributes to the modulation of women's sexual desire. The likelihood that an androgen-only clinical treatment will meaningfully increase women's sexual desire is minimal, and the focus of pharmaceutical companies on the development of androgen therapies for the treatment of female sexual desire disorders is likely misplaced. Copyright © 2015 Elsevier Inc. All rights reserved.

Sex-dependent effects of sleep deprivation on myocardial sensitivity to ischemic injury.

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Zoladz, Phillip R; Krivenko, Anna; Eisenmann, Eric D; Bui, Albert D; Seeley, Sarah L; Fry, Megan E; Johnson, Brandon L; Rorabaugh, Boyd R

2016-01-01

Sleep deprivation is associated with increased risk of myocardial infarction. However, it is unknown whether the effects of sleep deprivation are limited to increasing the likelihood of experiencing a myocardial infarction or if sleep deprivation also increases the extent of myocardial injury. In this study, rats were deprived of paradoxical sleep for 96 h using the platform-over-water method. Control rats were subjected to the same condition except the control platform was large enough for the rats to sleep. Hearts from sleep deprived and control rats were subjected to 20 min ischemia on a Langendorff isolated heart system. Infarct size and post ischemic recovery of contractile function were unaffected by sleep deprivation in male hearts. In contrast, hearts from sleep-deprived females exhibited significantly larger infarcts than hearts from control females. Post ischemic recovery of rate pressure product and + dP/dT were significantly attenuated by sleep deprivation in female hearts, and post ischemic recovery of end diastolic pressure was significantly elevated in hearts from sleep deprived females compared to control females, indicating that post ischemic recovery of both systolic and diastolic function were worsened by sleep deprivation. These data provide evidence that sleep deprivation increases the extent of ischemia-induced injury in a sex-dependent manner.

Effect of Sleep Deprivation on the Male Reproductive System in Rats.

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Choi, Ji Ho; Lee, Seung Hoon; Bae, Jae Hyun; Shim, Ji Sung; Park, Hong Seok; Kim, Young Sik; Shin, Chol

2016-10-01

There has been no study reporting on the influence of sleep deprivation on the male reproductive system including sperm quality. In this study, we hypothesized that sleep deprivation could lead to adverse effect on the male reproductive system. The rats were divided into three groups: 1) control (home-cage, n = 10); 2) SD4 (sleep deprivation for 4 days, n = 10); and 3) SD7 (sleep deprivation for 7 days, n = 10). Sleep deprivation was performed by a modified multiple platform method. Sperm quality (sperm motion parameters and counts), hormone levels (corticosterone and testosterone), and the histopathology of testis were evaluated and compared between the three groups. A statistically significant reduction (P = 0.018) was observed in sperm motility in the SD7 group compared to those of the control group. However, there were no significant differences in other sperm motion parameters, or in sperm counts of the testis and cauda epididymis between three groups. Compared with the control group, the SD4 (P = 0.033) and SD7 (P = 0.002) groups exhibited significant increases of corticosterone levels, but significant decreases of testosterone levels were found in the SD4 (P = 0.001) and SD7 (P Sleep deprivation may have an adverse effect on the male reproductive system in rats.

Androgen Bioassay for the Detection of Nonlabeled Androgenic Compounds in Nutritional Supplements.

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Cooper, Elliot R; McGrath, Kristine C Y; Li, XiaoHong; Heather, Alison K

2018-01-01

Both athletes and the general population use nutritional supplements. Athletes often turn to supplements hoping that consuming the supplement will help them be more competitive and healthy, while the general population hopes to improve body image or vitality. While many supplements contain ingredients that may have useful properties, there are supplements that are contaminated with compounds that are banned for use in sport or have been deliberately adulterated to fortify a supplement with an ingredient that will produce the advertised effect. In the present study, we have used yeast cell and mammalian cell androgen bioassays to characterize the androgenic bioactivity of 112 sports supplements available from the Australian market, either over the counter or via the Internet. All 112 products did not declare an androgen on the label as an included ingredient. Our findings show that six out of 112 supplements had strong androgenic bioactivity in the yeast cell bioassay, indicating products spiked or contaminated with androgens. The mammalian cell bioassay confirmed the strong androgenic bioactivity of five out of six positive supplements. Supplement 6 was metabolized to weaker androgenic bioactivity in the mammalian cells. Further to this, Supplement 6 was positive in a yeast cell progestin bioassay. Together, these findings highlight that nutritional supplements, taken without medical supervision, could expose or predispose users to the adverse consequences of androgen abuse. The findings reinforce the need to increase awareness of the dangers of nutritional supplements and highlight the challenges that clinicians face in the fast-growing market of nutritional supplements.

Implementation of High-Dose-Rate Brachytherapy and Androgen Deprivation in Patients With Prostate Cancer

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Lilleby, Wolfgang, E-mail: wolfgang.lilleby@ous-hf.no [Cancer Clinic, Oslo University Hospital, Norwegian Radiumhospital, Department of Radiotherapy and Oncology, Oslo (Norway); Tafjord, Gunnar; Raabe, Nils K. [Cancer Clinic, Oslo University Hospital, Norwegian Radiumhospital, Department of Radiotherapy and Oncology, Oslo (Norway)

2012-07-01

Purpose: To evaluate outcome (overall survival [OS], the actuarial 5-year cancer-specific survival [CSS], disease-free survival [DFS], biochemical failure-free survival [BFS]), complications and morbidity in patients treated with high-dose-rate brachytherapy (HDR-BT) boost and hormonal treatment with curative aims. Methods: Between 2004 and 2009, 275 prospectively followed pN0/N0M0 patients were included: 19 patients (7%) with T2, Gleason score 7 and prostate-specific antigen (PSA) <10 and 256 patients (93%) with T3 or Gleason score 8-10 or PSA >20 received multimodal treatment with conformal four-field radiotherapy (prostate/vesiculae 2 Gy Multiplication-Sign 25) combined with HDR-BT (iridium 192; prostate 10 Gy Multiplication-Sign 2) with long-term androgen deprivation therapy (ADT). Results: After a median observation time of 44.2 months (range, 10.4-90.5 months) 12 patients had relapsed clinically and/or biochemically and 10 patients were dead, of which 2 patients died from prostate cancer. Five-year estimates of BFS, CSS, DFS, and OS rates were 98.5%, 99.3%, 95.6%, and 96.3%, respectively. None of the patients with either Gleason score <8 or with intermediate risk profile had relapsed. The number of HDR-BT treatments was not related to outcome. Despite of age (median, 65.7 years; range, 45.7-77 years) and considerable pretreatment comorbidity in 39 of 275 patients, Genitourinary treatment-related morbidity was moderate with long-lasting Radiation Therapy Oncology Group Grade 2 voiding problems in 26 patients (9.5%) and occasionally mucous discharge in 20 patients (7%), none with Grade >2 for gastrointestinal at follow-up. Complications during implantations were related to pubic arch interference (4 patients) and lithotomy time, causing 2 patients to develop compartment syndrome. Conclusion: Despite still preliminary observations, our 5-year outcome estimates favor the implementation of high-dose-rate brachytherapy in high-risk patients combined with conformal

National Trends and Predictors of Androgen Deprivation Therapy Use in Low-Risk Prostate Cancer

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Yang, David D. [Harvard Medical School, Boston, Massachusetts (United States); Muralidhar, Vinayak [Department of Medicine, Harvard Medical School, Boston, Massachusetts (United States); Brigham and Women' s Hospital, Boston, Massachusetts (United States); Mahal, Brandon A. [Harvard Radiation Oncology Program, Boston, Massachusetts (United States); Labe, Shelby A.; Nezolosky, Michelle D.; Vastola, Marie E.; King, Martin T.; Martin, Neil E.; Orio, Peter F. [Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts (United States); Dana-Farber Cancer Institute, Boston, Massachusetts (United States); Brigham and Women' s Hospital, Boston, Massachusetts (United States); Choueiri, Toni K. [Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts (United States); Dana-Farber Cancer Institute, Boston, Massachusetts (United States); Brigham and Women' s Hospital, Boston, Massachusetts (United States); Trinh, Quoc-Dien [Division of Urological Surgery, Harvard Medical School, Boston, Massachusetts (United States); Brigham and Women' s Hospital, Boston, Massachusetts (United States); Spratt, Daniel E. [Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts (United States); University of Michigan, Ann Arbor, Michigan (United States); Hoffman, Karen E. [Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts (United States); The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Feng, Felix Y. [Department of Radiation Oncology, Harvard Medical School, Boston, Massachusetts (United States); Departments of Urology & Medicine and Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California (United States); and others

2017-06-01

Purpose: Androgen deprivation therapy (ADT) is not recommended for low-risk prostate cancer because of its lack of benefit and potential for harm. We evaluated the incidence and predictors of ADT use in low-risk disease. Methods and Materials: Using the National Cancer Database, we identified 197,957 patients with low-risk prostate cancer (Gleason score of 3 + 3 = 6, prostate-specific antigen level <10 ng/mL, and cT1-T2a) diagnosed from 2004 to 2012 with complete demographic and treatment information. We used multiple logistic regression to evaluate predictors of ADT use and Cox regression to examine its association with all-cause mortality. Results: Overall ADT use decreased from 17.6% in 2004 to 3.5% in 2012. In 2012, 11.5% of low-risk brachytherapy patients and 7.6% of external beam radiation therapy patients received ADT. Among 82,352 irradiation-managed patients, predictors of ADT use included treatment in a community versus academic cancer program (adjusted odds ratio [AOR], 1.60; 95% confidence interval [CI], 1.50-1.71; P<.001; incidence, 14.0% vs 6.0% in 2012); treatment in the South (AOR, 1.51), Midwest (AOR, 1.81), or Northeast (AOR, 1.90) versus West (P<.001); and brachytherapy use versus external beam radiation therapy (AOR, 1.32; 95% CI, 1.27-1.37; P<.001). Among 25,196 patients who did not receive local therapy, predictors of primary ADT use included a Charlson-Deyo comorbidity score of ≥2 versus 0 (AOR, 1.42; 95% CI, 1.06-1.91; P=.018); treatment in a community versus academic cancer program (AOR, 1.61; 95% CI, 1.37-1.90; P<.001); and treatment in the South (AOR, 1.26), Midwest (AOR, 1.52), or Northeast (AOR, 1.28) versus West (P≤.008). Primary ADT use was associated with increased all-cause mortality in patients who did not receive local therapy (adjusted hazard ratio, 1.28; 95% CI, 1.14-1.43; P<.001) after adjustment for age and comorbidity. Conclusions: ADT use in low-risk prostate cancer has declined nationally but may remain an issue

Time on androgen deprivation therapy and adaptations to exercise: secondary analysis from a 12-month randomized controlled trial in men with prostate cancer.

Science.gov (United States)

Taaffe, Dennis R; Buffart, Laurien M; Newton, Robert U; Spry, Nigel; Denham, James; Joseph, David; Lamb, David; Chambers, Suzanne K; Galvão, Daniel A

2018-02-01

To explore if duration of previous exposure to androgen deprivation therapy (ADT) in men with prostate cancer (PCa) undertaking a year-long exercise programme moderates the exercise response with regard to body composition and muscle performance, and also to explore the moderator effects of baseline testosterone, time since ADT, and baseline value of the outcome. In a multicentre randomized controlled trial, 100 men who had previously undergone either 6 months (short-term) or 18 months (long-term) of ADT in combination with radiotherapy, as part of the TROG 03.04 RADAR trial, were randomized to 6 months supervised exercise, followed by a 6-month home-based maintenance programme, or to printed physical activity educational material for 12 months across 13 university-affiliated exercise clinics in Australia and New Zealand. The participants were long-term survivors of PCa with a mean age of 71.7 ± 6.4 years, and were assessed for lower extremity performance (repeated chair rise), with a subset of men (n = 57) undergoing additional measures for upper and lower body muscle strength and body composition (lean mass, fat mass, appendicular skeletal muscle [ASM]) by dual X-ray absorptiometry. Data were analysed using generalized estimating equations. Time on ADT significantly moderated the exercise effects on chair rise (β interaction = -1.3 s, 95% confidence interval [CI] -2.6 to 0.0), whole-body lean mass (β interaction = 1194 g, 95% CI 234 to 2153) and ASM mass (β interaction = 562 g, 95% CI 49 to 1075), and approached significance for fat mass (β interaction = -1107 g, 95% CI -2346 to 132), with greater benefits for men previously on long-term ADT. At 6 months, the intervention effects on chair rise time -1.5 s (95% CI -2.5 to -0.5), whole-body lean mass 824 g (95% CI 8 to 1640), ASM mass 709 g (95% CI 260 to 1158), and fat mass -1377 g (95% CI -2156 to -598) were significant for men previously on long-term ADT, but not for men on short-term ADT. At 12 months, the

The effects of oviposition-site deprivation on Anopheles gambiae reproduction

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Dieter Kathryne L

2012-10-01

Full Text Available Abstract Background The African malaria mosquito, Anopheles gambiae, depends on availability of suitable surface water for oviposition. Short and long dry spells occur throughout the year in many parts of its range that limit its access to oviposition sites. Although not well understood, oviposition-site deprivation has been found to rapidly reduce egg batch size and hatch rate of several mosquito species. We conducted laboratory experiments to assess these effects of oviposition-site deprivation on An. gambiae and to evaluate the role of nutrition and sperm viability as mediators of these effects. Methods Anopheles gambiae adults (1–2 d old from the G3 laboratory colony were assigned to the following treatment groups: oviposition-deprived (fed once and then deprived of oviposition site for 7 or 14 d, multiple-fed control (fed regularly once a week and allowed to lay eggs without delay, and age matched blood-deprived control (fed once, three days before water for oviposition was provided. Egg batch size and hatch rate were measured. In the second experiment two additional treatment groups were included: oviposition-deprived females that received either a second (supplemental blood meal or virgin males (supplemental mating 4 days prior to receiving water for oviposition. Results An. gambiae was highly sensitive to oviposition-site deprivation. Egg batch size dropped sharply to 0–3.5 egg/female within 14 days, due to reduced oviposition rate rather than a reduced number of eggs/batch. Egg hatch rate also fell dramatically to 0-2% within 7 days. The frequency of brown eggs that fail to tan was elevated. A supplemental blood meal, but not ‘supplemental insemination,’ recovered the oviposition rate of females subjected to oviposition-site deprivation. Similarly, a supplemental blood meal, but not ‘supplemental insemination,’ partly recovered hatch rate, but this increase was marginally significant (P  Conclusions Even a short dry spell

Effects of fenoterol on the skeletal system depend on the androgen level.

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Śliwiński, Leszek; Cegieła, Urszula; Pytlik, Maria; Folwarczna, Joanna; Janas, Aleksandra; Zbrojkiewicz, Małgorzata

2017-04-01

The role of sympathetic nervous system in the osseous tissue remodeling is not clear enough. The effects of fenoterol, a selective β 2 -adrenomimetic drug, on the skeletal system of normal and androgen deficient (orchidectomized) rats were studied in vivo. Osteoclastogenesis and mRNA expression in osteoblasts were investigated in vitro in mouse cell cultures. Fenoterol administered to animals with physiological androgen level unfavorably affected the skeletal system, damaging the bone microarchitecture. Androgen deficiency induced osteoporotic changes, and fenoterol protected the osseous tissue from consequences of androgen deficiency. The results of in vitro studies correlated with the in vivo observations. A significantly increased number of osteoclasts in bone marrow cell cultures to which testosterone and fenoterol were added simultaneously was demonstrated. In cultures without the addition of testosterone, fenoterol significantly inhibited osteoclastogenesis in comparison with control cultures. The results indicate the favorable action of fenoterol in conditions of testosterone deficiency, and its destructive influence upon the skeleton in the presence of androgens. The results confirm the key role of sympathetic nervous system in the regulation of bone remodeling. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

Androgen Induces Adaptation to Oxidative Stress in Prostate Cancer: Implications for Treatment with Radiation Therapy

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Jehonathan H. Pinthus

2007-01-01

Full Text Available Radiation therapy is a standard treatment for prostate cancer (PC. The postulated mechanism of action for radiation therapy is the generation of reactive oxygen species (ROS. Adjuvant androgen deprivation (AD therapy has been shown to confer a survival advantage over radiation alone in high-risk localized PC. However, the mechanism of this interaction is unclear. We hypothesize that androgens modify the radioresponsiveness of PC through the regulation of cellular oxidative homeostasis. Using androgen receptor (AR+ 22rv1 and AR− PC3 human PC cell lines, we demonstrated that testosterone increased basal reactive oxygen species (bROS levels, resulting in dose-dependent activation of phospho-p38 and pAKT, increased expression of clusterin, catalase, manganese superoxide dismutase. Similar data were obtained in three human PC xenografts; WISH-PC14, WISH-PC23, CWR22, growing in testosterone-supplemented or castrated SCID mice. These effects were reversible through AD or through incubation with a reducing agent. Moreover, testosterone increased the activity of catalase, superoxide dismutases, glutathione reductase. Consequently, AD significantly facilitated the response of AR+ cells to oxidative stress challenge. Thus, testosterone induces a preset cellular adaptation to radiation through the generation of elevated bROS, which is modified by AD. These findings provide a rational for combined hormonal and radiation therapy for localized PC.

The predictive value of ERG protein expression for development of castration-resistant prostate cancer in hormone-naïve advanced prostate cancer treated with primary androgen deprivation therapy

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Berg, Kasper Drimer; Røder, Martin A; Thomsen, Frederik B

2015-01-01

BACKGROUND: Biomarkers predicting response to primary androgen deprivation therapy (ADT) and risk of castration-resistant prostate cancer (CRPC) is lacking. We aimed to analyse the predictive value of ERG expression for development of CRPC. METHODS: In total, 194 patients with advanced and....../or metastatic prostate cancer (PCa) treated with first-line castration-based ADT were included. ERG protein expression was analysed in diagnostic specimens using immunohistochemistry (anti-ERG, EPR3864). Time to CRPC was compared between ERG subgroups using multiple cause-specific Cox regression stratified......-negative group, respectively. Compared to a model omitting ERG-status, the ERG-stratified model showed comparable AUC values 1 year (77.6% vs. 78.0%, P = 0.82), 2 years (71.7% vs. 71.8%, P = 0.85), 5 years (68.5% vs. 69.9%, P = 0.32), and 8 years (67.9% vs. 71.4%, P = 0.21) from ADT initiation. No differences...

Delayed rectal and urinary symptomatology in patients treated for prostate cancer by radiotherapy with or without short term neo-adjuvant androgen deprivation

International Nuclear Information System (INIS)

Christie, David; Denham, James; Steigler, Allison; Lamb, David; Turner, Sandra; Mameghan, Hedy; Joseph, David; Matthews, John; Franklin, Ian; Atkinson, Chris; North, John; Poulsen, Michael; Spry, Nigel A.; Tai, Keen-Hun; Wynne, Chris; Duchesne, Gillian; Kovacev, Olga; Francis, Lynne; Kramar, Andrew; D'Este, Cate; Bill, Dana

2005-01-01

Background and purpose: To identify contributing factors to delayed rectal and urinary symptoms in a randomised trial comparing different durations of maximal androgen deprivation (MAD), given prior to radiotherapy, for locally advanced prostate cancer. Patients and methods: Between 1996 and 2000, 818 patients with stages T2b,c, 3 and 4 prostate cancer were entered into a trial comparing 0, 3 and 6 months of MAD prior to and during radiotherapy. Their delayed normal tissue effects were recorded by their treating doctors using standardised scales and by the patients using a self-assessment questionnaire regularly. Time to occurrence and prevalence data were analysed. Results: Rectal and urinary symptom levels were observed to vary markedly over time in at least 80% of patients, with some indicating lasting resolution of symptoms. Prevalence rates were found to be substantially lower than actuarial probability rates. Baseline symptom levels and greatest acute symptom levels were both very powerful predictors. Obstructive lower urinary tract symptoms were noted to improve during the first 4 years after radiotherapy in approximately 60% of cases in each treatment arm. However, the treatment arm itself was not shown to influence these improvements in other univariate or multivariate analyses. MAD was shown to reduce both time to occurrence and prevalence of delayed proctopathic symptoms, but this effect was confirmed statistically in the 3 month treatment arm only. Multivariate models indicated that higher levels of haemoglobin prior to any treatment may in some way protect against delayed proctopathic symptoms. Conclusions: Prevalence data provide more clinically meaningful estimates of risk of delayed effects in normal tissues where assessment relies substantially on reported symptom levels. In these tissues consideration of the impact of baseline symptom levels and pathologies, and greatest acute symptom levels in analyses of delayed effects appears mandatory

Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

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Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered.

In Vitro Androgen Bioassays as a Detection Method for Designer Androgens

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Alison K. Heather

2013-02-01

Full Text Available Androgens are the class of sex steroids responsible for male sexual characteristics, including increased muscle mass and decreased fat mass. Illicit use of androgen doping can be an attractive option for those looking to enhance sporting performance and/or physical appearance. The use of in vitro bioassays to detect androgens, especially designer or proandrogens, is becoming increasingly important in combating androgen doping associated with nutritional supplements. The nutritional sports supplement market has grown rapidly throughout the past decade. Many of these supplements contain androgens, designer androgens or proandrogens. Many designer or proandrogens cannot be detected by the standard highly-sensitive screening methods such as gas chromatography-mass spectrometry because their chemical structure is unknown. However, in vitro androgen bioassays can detect designer and proandrogens as these assays are not reliant on knowing the chemical structure but instead are based on androgen receptor activation. For these reasons, it may be advantageous to use routine androgen bioassay screening of nutraceutical samples to help curb the increasing problem of androgen doping.

PTTG1, A novel androgen responsive gene is required for androgen-induced prostate cancer cell growth and invasion

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Zhang, Zheng; Jin, Bo; Jin, Yaqiong; Huang, Shengquan; Niu, Xiaohua; Mao, Zebin; Xin, Dianqi

2017-01-01

Androgens (AR) play an important role in initiation and progression of prostate cancer. It has been shown that AR exert their effects mainly through the androgen-activated AR which binds to androgen response elements (AREs) in the regulatory regions of target genes to regulate the transcription of androgen-responsive genes, thus, identification of AR downstream target gene is critical to understand androgen function in prostate cancer. In this study, our results showed that androgen treatment of LNCaP cells induced PTTG1 expression, which was blocked by the androgen receptor antagonist, Casodex. Bioinformatics analysis and experiments using PTTG1 promoter deletion mutants showed that the PTTG1 promoter contains a putative androgen response element (ARE), which localizes in the −851 to −836 region of the promoter. Androgen activated androgen receptor (AR) binding to this ARE was confirmed by Chromatin immunoprecipitation (ChIP) assay. Furthermore, Knockdown of PTTG1 expression using short hairpin RNA significantly reduced androgen-induced LNCaP cell growth and invasion. In addition, we showed PTTG1 is highly expressed in metastasis prostate cancer tissue. These results suggest that PTTG1 is a novel downstream target gene of androgen receptor and take part in prostate cancer proliferation and metastasis. - Highlights: • Androgen treatment of LNCaP cells induced PTTG1 expression. • Knockdown of PTTG1 expression significantly reduced androgen-induced LNCaP cell growth and invasion. • PTTG1 is highly expressed in metastasis prostate cancer tissue. • PTTG1 is a novel downstream target gene of androgen receptor.

The effects of extended work under sleep deprivation conditions on team-based performance.

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Pilcher, June J; Vander Wood, Melissa A; O'Connell, Kristina L

2011-07-01

Teamwork is becoming increasingly common in today's workplaces; however, little research has examined how well teams perform under sleep deprivation conditions. The purpose of the current study was to examine the effect of extended work under sleep deprivation conditions on team performance. A total of 24 participants were sleep deprived for 30 h and completed 16 h of sustained operations during the last portion of the sleep deprivation period. The participants completed the Wombat, a complex task including vigilance and cognitive components, with a partner in four 24-min testing sessions during the sustained operations period. The results indicated that team performance increased during the work period while, within each testing session, team performance on vigilance tasks remained stable and overall performance decreased. The current results suggest that performance on two-person teams results in improved performance but does not fully counteract the decreases in performance within each work period. Performance in two-person teams increased across an extended work shift under sleep deprivation conditions. However, vigilance performance remained stable while overall performance decreased when examining performance in 8-min segments. These results suggest that averaging team-based performance over a longer testing period may mask the negative effects of sleep deprivation. STATEMENT OF RELEVANCE: Performance in two-person teams increased across an extended work shift under sleep deprivation conditions. However, vigilance performance remained stable while overall performance decreased when examining performance in 8-min segments. These results suggest that averaging team-based performance over a longer testing period may mask the negative effects of sleep deprivation.

Sleep-deprivation effect on human performance: a meta-analysis approach

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Candice D. Griffith; Candice D. Griffith; Sankaran Mahadevan

2006-05-01

Human fatigue is hard to define since there is no direct measure of fatigue, much like stress. Instead fatigue must be inferred from measures that are affected by fatigue. One such measurable output affected by fatigue is reaction time. In this study the relationship of reaction time to sleep deprivation is studied. These variables were selected because reaction time and hours of sleep deprivation are straightforward characteristics of fatigue to begin the investigation of fatigue effects on performance. Meta-analysis, a widely used procedure in medical and psychological studies, is applied to the variety of fatigue literature collected from various fields in this study. Meta-analysis establishes a procedure for coding and analyzing information from various studies to compute an effect size. In this research the effect size reported is the difference between standardized means, and is found to be -0.6341, implying a strong relationship between sleep deprivation and performance degradation.

Differential effects of androgens on coronary blood flow regulation and arteriolar diameter in intact and castrated swine

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O’Connor Erin K

2012-05-01

Full Text Available Abstract Background Low endogenous testosterone levels have been shown to be a risk factor for the development of cardiovascular disease and cardiovascular benefits associated with testosterone replacement therapy are being advocated; however, the effects of endogenous testosterone levels on acute coronary vasomotor responses to androgen administration are not clear. The objective of this study was to compare the effects of acute androgen administration on in vivo coronary conductance and in vitro coronary microvascular diameter in intact and castrated male swine. Methods Pigs received intracoronary infusions of physiologic levels (1–100 nM of testosterone, the metabolite 5α-dihydrotestosterone, and the epimer epitestosterone while left anterior descending coronary blood flow and mean arterial pressure were continuously monitored. Following sacrifice, coronary arterioles were isolated, cannulated, and exposed to physiologic concentrations (1–100 nM of testosterone, 5α-dihydrotestosterone, and epitestosterone. To evaluate effects of the androgen receptor on acute androgen dilation responses, real-time PCR and immunohistochemistry for androgen receptor were performed on conduit and resistance coronary vessels. Results In vivo, testosterone and 5α-dihydrotestosterone produced greater increases in coronary conductance in the intact compared to the castrated males. In vitro, percent maximal dilation of microvessels was similar between intact and castrated males for testosterone and 5α-dihydrotestosterone. In both studies epitestosterone produced significant increases in conductance and microvessel diameter from baseline in the intact males. Androgen receptor mRNA expression and immunohistochemical staining were similar in intact and castrated males. Conclusions Acute coronary vascular responses to exogenous androgen administration are increased by endogenous testosterone, an effect unrelated to changes in androgen receptor expression.

The Effects of Sleep Deprivation on Item and Associative Recognition Memory

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Ratcliff, Roger; Van Dongen, Hans P. A.

2018-01-01

Sleep deprivation adversely affects the ability to perform cognitive tasks, but theories range from predicting an overall decline in cognitive functioning because of reduced stability in attentional networks to specific deficits in various cognitive domains or processes. We measured the effects of sleep deprivation on two memory tasks, item…

Aging Worsens the Effects of Sleep Deprivation on Postural Control

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Robillard, Rébecca; Prince, François; Filipini, Daniel; Carrier, Julie

2011-01-01

Falls increase with age and cause significant injuries in the elderly. This study aimed to determine whether age modulates the interactions between sleep deprivation and postural control and to evaluate how attention influences these interactions in the elderly. Fifteen young (24±2.7 y.o.) and 15 older adults (64±3.2 y.o.) stood still on a force plate after a night of sleep and after total sleep deprivation. Center of pressure range and velocity were measured with eyes open and with eyes closed while participants performed an interference task, a control task, and no cognitive task. Sleep deprivation increased the antero-posterior range of center of pressure in both age groups and center of pressure speed in older participants only. In elderly participants, the destabilizing effects of sleep deprivation were more pronounced with eyes closed. The interference task did not alter postural control beyond the destabilization induced by sleep loss in older subjects. It was concluded that sleep loss has greater destabilizing effects on postural control in older than in younger participants, and may therefore increase the risk of falls in the elderly. PMID:22163330

Aging worsens the effects of sleep deprivation on postural control.

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Robillard, Rébecca; Prince, François; Filipini, Daniel; Carrier, Julie

2011-01-01

Falls increase with age and cause significant injuries in the elderly. This study aimed to determine whether age modulates the interactions between sleep deprivation and postural control and to evaluate how attention influences these interactions in the elderly. Fifteen young (24±2.7 y.o.) and 15 older adults (64±3.2 y.o.) stood still on a force plate after a night of sleep and after total sleep deprivation. Center of pressure range and velocity were measured with eyes open and with eyes closed while participants performed an interference task, a control task, and no cognitive task. Sleep deprivation increased the antero-posterior range of center of pressure in both age groups and center of pressure speed in older participants only. In elderly participants, the destabilizing effects of sleep deprivation were more pronounced with eyes closed. The interference task did not alter postural control beyond the destabilization induced by sleep loss in older subjects. It was concluded that sleep loss has greater destabilizing effects on postural control in older than in younger participants, and may therefore increase the risk of falls in the elderly.

Causes of Mortality After Dose-Escalated Radiation Therapy and Androgen Deprivation for High-Risk Prostate Cancer

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Tendulkar, Rahul D.; Hunter, Grant K.; Reddy, Chandana A.; Stephans, Kevin L.; Ciezki, Jay P.; Abdel-Wahab, May; Stephenson, Andrew J.; Klein, Eric A.; Mahadevan, Arul; Kupelian, Patrick A.

2013-01-01

Purpose: Men with high-risk prostate cancer have other competing causes of mortality; however, current risk stratification schema do not account for comorbidities. We aim to identify the causes of death and factors predictive for mortality in this population. Methods and Materials: A total of 660 patients with high-risk prostate cancer were treated with definitive high-dose external beam radiation therapy (≥74 Gy) and androgen deprivation (AD) between 1996 and 2009 at a single institution. Cox proportional hazards regression analysis was conducted to determine factors predictive of survival. Results: The median radiation dose was 78 Gy, median duration of AD was 6 months, and median follow-up was 74 months. The 10-year overall survival (OS) was 60.6%. Prostate cancer was the leading single cause of death, with 10-year mortality of 14.1% (95% CI 10.7-17.6), compared with other cancers (8.4%, 95% CI 5.7-11.1), cardiovascular disease (7.3%, 95% CI 4.7-9.9), and all other causes (10.4%, 95% CI 7.2-13.6). On multivariate analysis, older age (HR 1.55, P=.002) and Charlson comorbidity index score (CS) ≥1 (HR 2.20, P<.0001) were significant factors predictive of OS, whereas Gleason score, T stage, prostate-specific antigen, duration of AD, radiation dose, smoking history, and body mass index were not. Men younger than 70 years of age with CS = 0 were more likely to die of prostate cancer than any other cause, whereas older men or those with CS ≥1 more commonly suffered non-prostate cancer death. The cumulative incidences of prostate cancer-specific mortality were similar regardless of age or comorbidities (P=.60). Conclusions: Men with high-risk prostate cancer are more likely to die of causes other than prostate cancer, except for the subgroup of men younger than 70 years of age without comorbidities. Only older age and presence of comorbidities significantly predicted for OS, whereas prostate cancer- and treatment-related factors did not

Minnelide Inhibits Androgen Dependent, Castration Resistant Prostate Cancer Growth by Decreasing Expression of Androgen Receptor Full Length and Splice Variants.

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Isharwal, Sumit; Modi, Shrey; Arora, Nivedita; Uhlrich, Charles; Giri, Bhuwan; Barlass, Usman; Soubra, Ayman; Chugh, Rohit; Dehm, Scott M; Dudeja, Vikas; Saluja, Ashok; Banerjee, Sulagna; Konety, Badrinath

2017-05-01

With almost 30,000 deaths per year, prostate cancer is the second-leading cause of cancer-related death in men. Androgen Deprivation Therapy (ADT) has been the corner stone of prostate cancer treatment for decades. However, despite an initial response of prostate cancer to ADT, this eventually fails and the tumors recur, resulting in Castration Resistant Prostate Cancer (CRPC). Triptolide, a diterpene triepoxide, has been tested for its anti-tumor properties in a number of cancers for over a decade. Owing to its poor solubility in aqueous medium, its clinical application had been limited. To circumvent this problem, we have synthesized a water-soluble pro-drug of triptolide, Minnelide, that is currently being evaluated in a Phase 1 clinical trial against gastrointestinal tumors. In the current study, we assessed the therapeutic potential of Minnelide and its active compound triptolide against androgen dependent prostate cancer both in vitro as well as in vivo. Cell viability was measured by a MTT based assay after treating prostate cancer cells with multiple doses of triptolide. Apoptotic cell death was measured using a caspase 3/7 activity. Androgen Receptor (AR) promoter-binding activity was evaluated by using luciferase reporter assay. For evaluating the effect in vivo, 22Rv1 cells were implanted subcutaneously in animals, following which, treatment was started with 0.21 mg/kg Minnelide. Our study showed that treatment with triptolide induced apoptotic cell death in CRPC cells. Triptolide treatment inhibited AR transcriptional activity and decreased the expression of AR and its splice variants both at the mRNA and the protein level. Our studies show that triptolide inhibits nuclear translocation of Sp1, resulting in its decreased transcriptional activity leading to downregulation of AR and its splice variants in prostate cancer cells. In vivo, Minnelide (0.21 mg/kg) regressed subcutaneous tumors derived from CRPC 22RV1 at our study endpoint. Our animal

A Comparison Between Low-Dose-Rate Brachytherapy With or Without Androgen Deprivation, External Beam Radiation Therapy With or Without Androgen Deprivation, and Radical Prostatectomy With or Without Adjuvant or Salvage Radiation Therapy for High-Risk Prostate Cancer.

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Ciezki, Jay P; Weller, Michael; Reddy, Chandana A; Kittel, Jeffrey; Singh, Harguneet; Tendulkar, Rahul; Stephans, Kevin L; Ulchaker, James; Angermeier, Kenneth; Stephenson, Andrew; Campbell, Steven; Haber, Georges-Pascal; Klein, Eric A

2017-04-01

We compare the efficacy and toxicity among the 3 major modalities available used to treat high-risk prostate cancer (HRCaP). From 1996 to 2012, 2557 HRCaP patients were treated: 734 received external beam radiation therapy (EBRT) with or without androgen deprivation therapy (ADT), 515 received low-dose-rate prostate brachytherapy (LDR) with or without ADT, and 1308 received radical prostatectomy (RP) with or without EBRT. Biochemical relapse-free survival (bRFS), clinical relapse-free survival (cRFS), and prostate cancer-specific mortality (PCSM) were assessed. Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.03. The log-rank test compared bRFS and cRFS among the modalities, and Cox regression identified factors associated with bRFS and cRFS. Gray's test compared differences in late toxicity and PSCM among the modalities. Competing risk regression identified factors associated with PCSM. The median follow-up time and age were 63.5 months and 65 years, respectively. The bRFS at 5 and 10 years, respectively, was 74% and 53% for EBRT, 74% and 52% for LDR, and 65% and 47% for RP (P=.0001). The cRFS at 5 and 10 years, respectively, was 85% and 73% for EBRT, 90% and 76% for LDR, and 89% and 75% for RP (P=.121). The PCSM at 5 and 10 years, respectively, was 5.3% and 11.2% for EBRT, 3.2% and 3.6% for LDR, and 2.8% and 6.8% for RP (P=.0004). The 10-year cumulative incidence of ≥grade 3 genitourinary toxicity was 8.1% for EBRT, 7.2% for LDR, and 16.4% for RP (PLDR, and 1.0% for RP (PLDR, or RP yields efficacy showing better bRFS for LDR and EBRT relative to RP, equivalence for cRFS, and a PCSM advantage of LDR and RP over EBRT. The toxicity is lowest for LDR. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of Afternoon Nap Deprivation on Adult Habitual Nappers’ Inhibition Functions

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Qingwei Chen

2018-01-01

Full Text Available Multiple studies have established the effects of afternoon naps on cognition. However, relatively few studies have investigated the domain of executive functions. Moreover, the effects of napping on inhibition are far from conclusive. The present study employed adult habitual nappers to investigate the effects of afternoon nap deprivation on response-based inhibition assessed by a Go/No-go task and stimulus-based inhibition assessed by a Flanker task and on alertness assessed by a psychomotor vigilance test (PVT and the Karolinska Sleepiness Scale (KSS. The results showed that afternoon nap deprivation significantly decreased participants’ accuracy and reaction speed for the Go/No-go task but not for the Flanker task. In addition, participants’ alertness was significantly impaired after nap deprivation in terms of increased subjective sleepiness and worse PVT performance. Task-specific effects of napping on inhibition were demonstrated. The implications of the results are discussed.

Growth Inhibition by Testosterone in an Androgen Receptor Splice Variant-Driven Prostate Cancer Model.

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Nakata, Daisuke; Nakayama, Kazuhide; Masaki, Tsuneo; Tanaka, Akira; Kusaka, Masami; Watanabe, Tatsuya

2016-12-01

Castration resistance creates a significant problem in the treatment of prostate cancer. Constitutively active splice variants of androgen receptor (AR) have emerged as drivers for resistance to androgen deprivation therapy, including the next-generation androgen-AR axis inhibitors abiraterone and enzalutamide. In this study, we describe the characteristics of a novel castration-resistant prostate cancer (CRPC) model, designated JDCaP-hr (hormone refractory). JDCaP-hr was established from an androgen-dependent JDCaP xenograft model after surgical castration. The expression of AR and its splice variants in JDCaP-hr was evaluated by immunoblotting and quantitative reverse transcription-polymerase chain reaction. The effects of AR antagonists and testosterone on JDCaP-hr were evaluated in vivo and in vitro. The roles of full-length AR (AR-FL) and AR-V7 in JDCaP-hr cell growth were evaluated using RNA interference. JDCaP-hr acquired a C-terminally truncated AR protein during progression from the parental JDCaP. The expression of AR-FL and AR-V7 mRNA was upregulated by 10-fold in JDCaP-hr compared with that in JDCaP, indicating that the JDCaP and JDCaP-hr models simulate castration resistance with some clinical features, such as overexpression of AR and its splice variants. The AR antagonist bicalutamide did not affect JDCaP-hr xenograft growth, and importantly, testosterone induced tumor regression. In vitro analysis demonstrated that androgen-independent prostate-specific antigen secretion and cell proliferation of JDCaP-hr were predominantly mediated by AR-V7. JDCaP-hr cell growth displayed a bell-shaped dependence on testosterone, and it was suppressed by physiological concentrations of testosterone. Testosterone induced rapid downregulation of both AR-FL and AR-V7 expression at physiological concentrations and suppressed expression of the AR target gene KLK3. Our findings support the clinical value of testosterone therapy, including bipolar androgen therapy, in the

Anabolic-androgenic steroids for alcoholic liver disease

DEFF Research Database (Denmark)

Rambaldi, Andrea; Iaquinto, Gaetano; Gluud, Christian

2002-01-01

The objectives were to assess the beneficial and harmful effects of anabolic-androgenic steroids for alcoholic liver disease.......The objectives were to assess the beneficial and harmful effects of anabolic-androgenic steroids for alcoholic liver disease....

Androgenic alopecia; the risk–benefit ratio of Finasteride

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David L. Rowland

2018-04-01

Full Text Available Finasteride is currently approved and largely used as a therapeutic option for androgenetic alopecia. Apparently a safe drug and effective at the onset, several concerns appeared over time regarding the frequency and magnitude of finasteride adverse effects, which in some cases seem to be even irreversible. This paper presents administration of finasteride in androgenic alopecia from two distinct perspectives. On one hand, androgenic alopecia is a condition that affects especially the self-image and esteem, aspects that are subjective, namely changeable and thus relative. On the other hand, this condition presents a multifactorial etiology, androgens being only in part involved. In addition, androgens have their own physiological roles within the body, so that any androgenic suppression should be carefully advised. Yet, adverse effects induced by Finasteride are only in part documented and treatable. Finally, alternative therapeutic approaches (like topical finasteride become available, so that the oral administration of Finasteride for androgenic alopecia should be in our opinion reevaluated. As a conclusion, a very detailed and informed discussion should take place with such patients accepting to start a therapy with finasteride for androgenic alopecia.

A phase II trial of androgen deprivation therapy (ADT) plus chemotherapy as initial treatment for local failures or advanced prostate cancer.

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Amato, Robert; Stepankiw, Mika; Gonzales, Patricia

2013-06-01

Long-term hormonal ablation in prostate cancer is associated with decreased overall health and quality of life. Few reports emphasized the role of chemotherapy in the management of early stage prostate cancer. This study analyzed the safety and efficacy of androgen deprivation therapy (ADT) plus chemotherapy as initial treatment for patients identified as local failures or not eligible for prostatectomy or radiation therapy due to advanced disease presentation. Enrolled patients received ADT in the form of leuprolide every 12 weeks for 24 months with bicalutamide initiating after the completion of chemotherapy. Chemotherapy consisted of ketoconazole and doxorubicin for weeks 1, 3, and 5 and estramustine and docetaxel and for weeks 2, 4 and 6. During weeks 7 and 8, no treatment was received. Forty-six patients were enrolled, and forty-five patients were evaluable. Median progression-free survival (PFS) was 23.4 months. Median overall survival (OS) was 53.7 months. Out of 45 patients with measurable disease, 22 patients had an objective response: 9 patients achieved a complete response; 2 patients achieved a partial response; 10 patients achieved stable disease. Frequent grade 3 adverse events included elevated ALT (17 %), hypokalemia (13 %), and hypophosphatemia (13 %). Grade 4 adverse events were rare and included low bicarbonate (2 %), hypokalemia (2 %), leukocytopenia (2 %), and neutropenia (2 %). The treatment demonstrated clinical benefit in all patient subsets with minimal reversible treatment-related adverse events. Subgroup analysis suggests that having prior local therapy resulted in greater PFS and OS.

Androgen and taxol cause cell type-specific alterations of centrosome and DNA organization in androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cells

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Schatten, H.; Ripple, M.; Balczon, R.; Weindruch, R.; Chakrabarti, A.; Taylor, M.; Hueser, C. N.

2000-01-01

We investigated the effects of androgen and taxol on the androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cell lines. Cells were treated for 48 and 72 h with 0.05-1 nM of the synthetic androgen R1881 and with 100 nM taxol. Treatment of LNCaP cells with 0.05 nM R1881 led to increased cell proliferation, whereas treatment with 1 nM R1881 resulted in inhibited cell division, DNA cycle arrest, and altered centrosome organization. After treatment with 1 nM R1881, chromatin became clustered, nuclear envelopes convoluted, and mitochondria accumulated around the nucleus. Immunofluorescence microscopy with antibodies to centrosomes showed altered centrosome structure. Although centrosomes were closely associated with the nucleus in untreated cells, they dispersed into the cytoplasm after treatment with 1 nM R1881. Microtubules were only faintly detected in 1 nM R1881-treated LNCaP cells. The effects of taxol included microtubule bundling and altered mitochondria morphology, but not DNA organization. As expected, the androgen-independent prostate cancer cell line DU145 was not affected by R1881. Treatment with taxol resulted in bundling of microtubules in both cell lines. Additional taxol effects were seen in DU145 cells with micronucleation of DNA, an indication of apoptosis. Simultaneous treatment with R1881 and taxol had no additional effects on LNCaP or DU145 cells. These results suggest that LNCaP and DU145 prostate cancer cells show differences not only in androgen responsiveness but in sensitivity to taxol as well. Copyright 2000 Wiley-Liss, Inc.

Androgens as double-edged swords: Induction and suppression of follicular development.

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Pan, Jie-Xue; Zhang, Jun-Yu; Ke, Zhang-Hong; Wang, Fang-Fang; Barry, John A; Hardiman, Paul J; Qu, Fan

2015-01-01

Androgens, which are mediated via the androgen receptor (AR), play important roles in normal follicular development and female fertility. However, just like a double-edged sword, besides the positive effects of androgen on follicular development, abnormal androgen levels, especially as in hyperandrogenism, seriously suppress normal follicular development. A crucial balance exists between the importance of androgens in follicular development and their negative effects when in excess. As the first meiotic division and epigenetic reprogramming are two critical events in oogenesis, abnormal androgen levels or deficiency in androgen/AR signaling in the ovary may affect these vital events. Oocytes have a tendency to develop genomic instability, thus resulting in an increasing incidence of unpredictable adult diseases. Although many studies have explored the effects of androgens and AR on follicular development, the conclusions are controversial and there has been no thorough review of this topic. This review focuses on the roles of androgens in the physiological process of follicular development, summarizes new insights into the roles of androgens in the arrested development of follicles, and discusses the potential risk of adult diseases originating from abnormal follicular androgen levels or androgen receptor signals, which may determine areas for future studies.

Phenotypic Plasticity, Bet-Hedging, and Androgen Independence in Prostate Cancer: Role of Non-Genetic Heterogeneity

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Mohit Kumar Jolly

2018-03-01

Full Text Available It is well known that genetic mutations can drive drug resistance and lead to tumor relapse. Here, we focus on alternate mechanisms—those without mutations, such as phenotypic plasticity and stochastic cell-to-cell variability that can also evade drug attacks by giving rise to drug-tolerant persisters. The phenomenon of persistence has been well-studied in bacteria and has also recently garnered attention in cancer. We draw a parallel between bacterial persistence and resistance against androgen deprivation therapy in prostate cancer (PCa, the primary standard care for metastatic disease. We illustrate how phenotypic plasticity and consequent mutation-independent or non-genetic heterogeneity possibly driven by protein conformational dynamics can stochastically give rise to androgen independence in PCa, and suggest that dynamic phenotypic plasticity should be considered in devising therapeutic dosing strategies designed to treat and manage PCa.

The effects of low-intensity cycling on cognitive performance following sleep deprivation.

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Slutsky, Alexis B; Diekfuss, Jed A; Janssen, James A; Berry, Nate T; Shih, Chia-Hao; Raisbeck, Louisa D; Wideman, Laurie; Etnier, Jennifer L

2017-10-15

This study examined the effect of 24h of sleep deprivation on cognitive performance and assessed the effect of acute exercise on cognitive performance following sleep deprivation. Young, active, healthy adults (n=24, 14 males) were randomized to control (age=24.7±3.7years, BMI=27.2±7.0) or exercise (age=25.3±3.3years, BMI=25.6±5.1) groups. Cognitive testing included a 5-min psychomotor vigilance task (PVT), three memory tasks with increasing cognitive load, and performance of the PVT a second time. On morning one, cognitive testing followed a typical night's sleep. Following 24-h of sustained wakefulness, cognitive testing was conducted again prior to and after the acute intervention. Participants in the exercise condition performed low-intensity cycling (∼40%HRR) for 15-min and those in the control condition sat quietly on the bike for 15-min. t-Tests revealed sleep deprivation negatively affected performance on the PVT, but did not affect memory performance. Following the acute intervention, there were no cognitive performance differences between the exercise and rested conditions. We provide support for previous literature suggesting that during simple tasks, sleep deprivation has negative effects on cognitive performance. Importantly, in contrast to previous literature which has shown multiple bouts of exercise adding to cognitive detriment when combined with sleep deprivation, our results did not reveal any further detriments to cognitive performance from a single-bout of exercise following sleep deprivation. Copyright © 2017 Elsevier Inc. All rights reserved.

Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

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Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

2016-01-01

Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3-6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered.

Effect of Monocular Deprivation on Rabbit Neural Retinal Cell Densities

OpenAIRE

Mwachaka, Philip Maseghe; Saidi, Hassan; Odula, Paul Ochieng; Mandela, Pamela Idenya

2015-01-01

Purpose: To describe the effect of monocular deprivation on densities of neural retinal cells in rabbits. Methods: Thirty rabbits, comprised of 18 subject and 12 control animals, were included and monocular deprivation was achieved through unilateral lid suturing in all subject animals. The rabbits were observed for three weeks. At the end of each week, 6 experimental and 3 control animals were euthanized, their retinas was harvested and processed for light microscopy. Photomicrographs of ...

Advantages and Limitations of Androgen Receptor-Based Methods for Detecting Anabolic Androgenic Steroid Abuse as Performance Enhancing Drugs

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Bailey, Kathy; Yazdi, Tahmineh; Masharani, Umesh; Tyrrell, Blake; Butch, Anthony; Schaufele, Fred

2016-01-01

Testosterone (T) and related androgens are performance enhancing drugs (PEDs) abused by some athletes to gain competitive advantage. To monitor unauthorized androgen abuse, doping control programs use mass spectrometry (MS) to detect androgens, synthetic anabolic-androgenic steroids (AASs) and their metabolites in an athlete’s urine. AASs of unknown composition will not be detected by these procedures. Since AASs achieve their anabolic effects by activating the Androgen Receptor (AR), cell-based bioassays that measure the effect of a urine sample on AR activity are under investigation as complementary, pan-androgen detection methods. We evaluated an AR BioAssay as a monitor for androgen activity in urine pre-treated with glucuronidase, which releases T from the inactive T-glucuronide that predominates in urine. AR BioAssay activity levels were expressed as ‘T-equivalent’ concentrations by comparison to a T dose response curve. The T-equivalent concentrations of androgens in the urine of hypogonadal participants supplemented with T (in whom all androgenic activity should arise from T) were quantitatively identical to the T measurements conducted by MS at the UCLA Olympic Analytical Laboratory (0.96 ± 0.22). All 17 AASs studied were active in the AR BioAssay; other steroids were inactive. 12 metabolites of 10 commonly abused AASs, which are used for MS monitoring of AAS doping because of their prolonged presence in urine, had reduced or no AR BioAssay activity. Thus, the AR BioAssay can accurately and inexpensively monitor T, but its ability to monitor urinary AASs will be limited to a period immediately following doping in which the active AASs remain intact. PMID:26998755

Advantages and Limitations of Androgen Receptor-Based Methods for Detecting Anabolic Androgenic Steroid Abuse as Performance Enhancing Drugs.

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Bailey, Kathy; Yazdi, Tahmineh; Masharani, Umesh; Tyrrell, Blake; Butch, Anthony; Schaufele, Fred

2016-01-01

Testosterone (T) and related androgens are performance enhancing drugs (PEDs) abused by some athletes to gain competitive advantage. To monitor unauthorized androgen abuse, doping control programs use mass spectrometry (MS) to detect androgens, synthetic anabolic-androgenic steroids (AASs) and their metabolites in an athlete's urine. AASs of unknown composition will not be detected by these procedures. Since AASs achieve their anabolic effects by activating the Androgen Receptor (AR), cell-based bioassays that measure the effect of a urine sample on AR activity are under investigation as complementary, pan-androgen detection methods. We evaluated an AR BioAssay as a monitor for androgen activity in urine pre-treated with glucuronidase, which releases T from the inactive T-glucuronide that predominates in urine. AR BioAssay activity levels were expressed as 'T-equivalent' concentrations by comparison to a T dose response curve. The T-equivalent concentrations of androgens in the urine of hypogonadal participants supplemented with T (in whom all androgenic activity should arise from T) were quantitatively identical to the T measurements conducted by MS at the UCLA Olympic Analytical Laboratory (0.96 ± 0.22). All 17 AASs studied were active in the AR BioAssay; other steroids were inactive. 12 metabolites of 10 commonly abused AASs, which are used for MS monitoring of AAS doping because of their prolonged presence in urine, had reduced or no AR BioAssay activity. Thus, the AR BioAssay can accurately and inexpensively monitor T, but its ability to monitor urinary AASs will be limited to a period immediately following doping in which the active AASs remain intact.

Inhibition of progression of androgen-dependent prostate LNCaP tumors to androgen independence in SCID mice by oral caffeine and voluntary exercise.

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Zheng, Xi; Cui, Xiao-Xing; Huang, Mou-Tuan; Liu, Yue; Wagner, George C; Lin, Yong; Shih, Weichung Joe; Lee, Mao-Jung; Yang, Chung S; Conney, Allan H

2012-01-01

The effect of oral caffeine or voluntary running wheel exercise (RW) alone or in combination on the progression of human androgen-dependent LNCaP prostate tumors to androgen independence in male severe combined immunodeficiency mice was determined. The mice were injected subcutaneously with LNCaP cells, and when the tumors reached a moderate size, the mice were surgically castrated and treated with caffeine (0.40 mg/ml drinking water) or RW alone or in combination for 42 days. We found that caffeine administration or RW inhibited the progression and growth of androgen-dependent LNCaP tumors to androgen independence, and a combination of the 2 regimens was more effective than the individual regimens alone. The ratios of the percent mitotic cells/caspase-3 positive cells in tumors from the caffeine-treated, RW-treated, or combination-treated mice were decreased by 34%, 38%, and 52%, respectively. Caffeine treatment increased the percentage of mitotic tumor cells undergoing apoptosis (lethal mitosis) whereas RW inhibited the increase in interleukin-6 that occurred during the progression of LNCaP tumors from androgen dependence to androgen independence. Our results indicate that oral administration of caffeine in combination with voluntary exercise may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence.

The Effects of Two Types of Sleep Deprivation on Visual Working Memory Capacity and Filtering Efficiency

OpenAIRE

Drummond, Sean P. A.; Anderson, Dane E.; Straus, Laura D.; Vogel, Edward K.; Perez, Veronica B.

2012-01-01

Sleep deprivation has adverse consequences for a variety of cognitive functions. The exact effects of sleep deprivation, though, are dependent upon the cognitive process examined. Within working memory, for example, some component processes are more vulnerable to sleep deprivation than others. Additionally, the differential impacts on cognition of different types of sleep deprivation have not been well studied. The aim of this study was to examine the effects of one night of total sleep depri...

Was cultural deprivation in fact sensory deprivation? Deprivation, retardation and intervention in the USA.

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Raz, Mical

2011-01-01

In the 1950s, the term "deprivation" entered American psychiatric discourse. This article examines how the concept of deprivation permeated the field of mental retardation, and became an accepted theory of etiology. It focuses on sensory deprivation and cultural deprivation, and analyzes the interventions developed, based on these theories. It argues that the controversial theory of cultural deprivation derived its scientific legitimization from the theory of sensory deprivation, and was a highly politicized concept that took part in the nature-nurture debate.

Favorable outcomes in locally advanced and node positive prostate cancer patients treated with combined pelvic IMRT and androgen deprivation therapy

International Nuclear Information System (INIS)

Lilleby, Wolfgang; Narrang, Amol; Tafjord, Gunnar; Vlatkovic, Ljiljana; Russnes, Kjell Magne; Stensvold, Andreas; Hole, Knut Håkon; Tran, Phuoc; Eilertsen, Karsten

2015-01-01

The most appropriate treatment for men with prostate cancer and positive pelvic nodes, N+, is an area of active controversy. We report our 5-years outcomes in men with locally advanced prostate cancer (T1-T4N0-N1M0) treated with definitive radiotherapy encompassing the prostate and pelvic lymph nodes (intensity modulated radiotherapy, IMRT) and long-term androgen deprivation therapy (ADT). Of the 138 consecutive eligible men all living patients have been followed up to almost 5 years. Survival endpoints for 5-year biochemical failure-free survival (BFFS), relapse-free survival (RFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were assessed by Kaplan-Meier analysis. Univariate and multivariate Cox regression proportional hazards models were constructed for all survival endpoints. The RTOG morbidity grading system for physician rated toxicity was applied. Patients with locally advanced T3-T4 tumors (35 %) and N1 (51 %) have favorable outcome when long-term ADT is combined with definitive radiotherapy encompassing pelvic lymph nodes. The 5-year BFFS, RFS, PCSS and OS were 71.4, 76.2, 94.5 and 89.0 %, respectively. High Gleason sum (9–10) had a strong independent prognostic impact on BFFS, RFS and OS (p = 0.001, <0.001, and 0.005 respectively). The duration of ADT (= > 28 months) showed a significant independent association with improved PCSS (p = 0.02) and OS (p = 0.001). Lymph node involvement was not associated with survival endpoints in the multivariate analysis. The radiotherapy induced toxicity seen in our study population was moderate with rare Grade 3 GI side effects and up to 11 % for Grade 3 GU consisting mainly of urgency and frequency. Pelvic IMRT in combination with long-term ADT can achieve long-lasting disease control in men with N+ disease and unfavorable prognostic factors. The online version of this article (doi:10.1186/s13014-015-0540-3) contains supplementary material, which is available to authorized users

The effects of two types of sleep deprivation on visual working memory capacity and filtering efficiency.

Science.gov (United States)

Drummond, Sean P A; Anderson, Dane E; Straus, Laura D; Vogel, Edward K; Perez, Veronica B

2012-01-01

Sleep deprivation has adverse consequences for a variety of cognitive functions. The exact effects of sleep deprivation, though, are dependent upon the cognitive process examined. Within working memory, for example, some component processes are more vulnerable to sleep deprivation than others. Additionally, the differential impacts on cognition of different types of sleep deprivation have not been well studied. The aim of this study was to examine the effects of one night of total sleep deprivation and 4 nights of partial sleep deprivation (4 hours in bed/night) on two components of visual working memory: capacity and filtering efficiency. Forty-four healthy young adults were randomly assigned to one of the two sleep deprivation conditions. All participants were studied: 1) in a well-rested condition (following 6 nights of 9 hours in bed/night); and 2) following sleep deprivation, in a counter-balanced order. Visual working memory testing consisted of two related tasks. The first measured visual working memory capacity and the second measured the ability to ignore distractor stimuli in a visual scene (filtering efficiency). Results showed neither type of sleep deprivation reduced visual working memory capacity. Partial sleep deprivation also generally did not change filtering efficiency. Total sleep deprivation, on the other hand, did impair performance in the filtering task. These results suggest components of visual working memory are differentially vulnerable to the effects of sleep deprivation, and different types of sleep deprivation impact visual working memory to different degrees. Such findings have implications for operational settings where individuals may need to perform with inadequate sleep and whose jobs involve receiving an array of visual information and discriminating the relevant from the irrelevant prior to making decisions or taking actions (e.g., baggage screeners, air traffic controllers, military personnel, health care providers).

The effects of two types of sleep deprivation on visual working memory capacity and filtering efficiency.

Directory of Open Access Journals (Sweden)

Sean P A Drummond

Full Text Available Sleep deprivation has adverse consequences for a variety of cognitive functions. The exact effects of sleep deprivation, though, are dependent upon the cognitive process examined. Within working memory, for example, some component processes are more vulnerable to sleep deprivation than others. Additionally, the differential impacts on cognition of different types of sleep deprivation have not been well studied. The aim of this study was to examine the effects of one night of total sleep deprivation and 4 nights of partial sleep deprivation (4 hours in bed/night on two components of visual working memory: capacity and filtering efficiency. Forty-four healthy young adults were randomly assigned to one of the two sleep deprivation conditions. All participants were studied: 1 in a well-rested condition (following 6 nights of 9 hours in bed/night; and 2 following sleep deprivation, in a counter-balanced order. Visual working memory testing consisted of two related tasks. The first measured visual working memory capacity and the second measured the ability to ignore distractor stimuli in a visual scene (filtering efficiency. Results showed neither type of sleep deprivation reduced visual working memory capacity. Partial sleep deprivation also generally did not change filtering efficiency. Total sleep deprivation, on the other hand, did impair performance in the filtering task. These results suggest components of visual working memory are differentially vulnerable to the effects of sleep deprivation, and different types of sleep deprivation impact visual working memory to different degrees. Such findings have implications for operational settings where individuals may need to perform with inadequate sleep and whose jobs involve receiving an array of visual information and discriminating the relevant from the irrelevant prior to making decisions or taking actions (e.g., baggage screeners, air traffic controllers, military personnel, health care

Recent progress in the development of protein-protein interaction inhibitors targeting androgen receptor-coactivator binding in prostate cancer.

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Biron, Eric; Bédard, François

2016-07-01

The androgen receptor (AR) is a key regulator for the growth, differentiation and survival of prostate cancer cells. Identified as a primary target for the treatment of prostate cancer, many therapeutic strategies have been developed to attenuate AR signaling in prostate cancer cells. While frontline androgen-deprivation therapies targeting either the production or action of androgens usually yield favorable responses in prostate cancer patients, a significant number acquire treatment resistance. Known as the castration-resistant prostate cancer (CRPC), the treatment options are limited for this advanced stage. It has been shown that AR signaling is restored in CRPC due to many aberrant mechanisms such as AR mutations, amplification or expression of constitutively active splice-variants. Coregulator recruitment is a crucial regulatory step in AR signaling and the direct blockade of coactivator binding to AR offers the opportunity to develop therapeutic agents that would remain effective in prostate cancer cells resistant to conventional endocrine therapies. Structural analyses of the AR have identified key surfaces involved in protein-protein interaction with coregulators that have been recently used to design and develop promising AR-coactivator binding inhibitors. In this review we will discuss the design and development of small-molecule inhibitors targeting the AR-coactivator interactions for the treatment of prostate cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effects of sleep deprivation on serum cortisol level and mental health in servicemen.

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Song, Hong-Tao; Sun, Xin-Yang; Yang, Ting-Shu; Zhang, Li-Yi; Yang, Jia-Lin; Bai, Jing

2015-06-01

This study aimed to investigate the effects of sleep deprivation on serum cortisol level and mental health and explore the correlations between them in servicemen. A total of 149 out of the 207 Chinese servicemen were randomly selected to go through 24hour sleep deprivation, leaving the rest (58) as the control group, before and after which their blood samples were drawn for cortisol measurement. Following the procedure, all the participants were administered the Military Personnel Mental Disorder Prediction Scale, taking the military norm as baseline. The results revealed that the post-deprivation serum cortisol level was positively correlated with the factor score of mania in the sleep deprivation group (rSp=0.415, pSleep deprivation could significantly increase serum cortisol level and may affect mental health in servicemen. The increase of serum cortisol level is significantly related to mania disorder during sleep deprivation. Copyright © 2015 Elsevier B.V. All rights reserved.

Androgens regulate gene expression in avian skeletal muscles.

Directory of Open Access Journals (Sweden)

Matthew J Fuxjager

Full Text Available Circulating androgens in adult reproductively active male vertebrates influence a diversity of organ systems and thus are considered costly. Recently, we obtained evidence that androgen receptors (AR are expressed in several skeletal muscles of three passeriform birds, the golden-collared manakin (Manacus vitellinus, zebra finch (Taenopygia guttata, and ochre-bellied flycatcher (Mionectes oleagieus. Because skeletal muscles that control wing movement make up the bulk of a bird's body mass, evidence for widespread effects of androgen action on these muscles would greatly expand the functional impact of androgens beyond their well-characterized effects on relatively discrete targets throughout the avian body. To investigate this issue, we use quantitative PCR (qPCR to determine if androgens alter gene mRNA expression patterns in wing musculature of wild golden-collared manakins and captive zebra finches. In manakins, the androgen testosterone (T up-regulated expression of parvalbumin (PV and insulin-like growth factor I (IGF-I, two genes whose products enhance cellular Ca(2+ cycling and hypertrophy of skeletal muscle fibers. In T-treated zebra finches, the anti-androgen flutamide blunted PV and IGF-I expression. These results suggest that certain transcriptional effects of androgen action via AR are conserved in passerine skeletal muscle tissue. When we examined wing muscles of manakins, zebra finches and ochre-bellied flycatchers, we found that expression of PV and IGF-I varied across species and in a manner consistent with a function for AR-dependent gene regulation. Together, these findings imply that androgens have the potential to act on avian muscle in a way that may enhance the physicality required for successful reproduction.

Performance comparison of two androgen receptor splice variant 7 (AR-V7) detection methods.

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Bernemann, Christof; Steinestel, Julie; Humberg, Verena; Bögemann, Martin; Schrader, Andres Jan; Lennerz, Jochen K

2018-01-23

To compare the performance of two established androgen receptor splice variant 7 (AR-V7) mRNA detection systems, as paradoxical responses to next-generation androgen-deprivation therapy in AR-V7 mRNA-positive circulating tumour cells (CTC) of patients with castration-resistant prostate cancer (CRPC) could be related to false-positive classification using detection systems with different sensitivities. We compared the performance of two established mRNA-based AR-V7 detection technologies using either SYBR Green or TaqMan chemistries. We assessed in vitro performance using eight genitourinary cancer cell lines and serial dilutions in three AR-V7-positive prostate cancer cell lines, as well as in 32 blood samples from patients with CRPC. Both assays performed identically in the cell lines and serial dilutions showed identical diagnostic thresholds. Performance comparison in 32 clinical patient samples showed perfect concordance between the assays. In particular, both assays determined AR-V7 mRNA-positive CTCs in three patients with unexpected responses to next-generation anti-androgen therapy. Thus, technical differences between the assays can be excluded as the underlying reason for the unexpected responses to next-generation anti-androgen therapy in a subset of AR-V7 patients. Irrespective of the method used, patients with AR-V7 mRNA-positive CRPC should not be systematically precluded from an otherwise safe treatment option. © 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.

Effects of acute sleep deprivation on state anxiety levels: a systematic review and meta-analysis.

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Pires, Gabriel Natan; Bezerra, Andreia Gomes; Tufik, Sergio; Andersen, Monica Levy

2016-08-01

Increased anxiety levels have been widely recognized as one of the most important consequences of sleep deprivation. However, despite this general consensus, there are still aspects of this relationship, such as the extent of the anxiogenic potential and the specific effects of different types of sleep deprivation, which remain unclear. As no broad review has been undertaken to evaluate this relationship, we performed a systematic review and meta-analysis regarding the effects of sleep deprivation on state anxiety. Our search strategy encompassed two databases - Pubmed/Medline and Scopus - through which we were able to identify 756 articles. After the selection process, 18 articles, encompassing 34 experiments, composed our final sample. Our analyses indicate that sleep deprivation, whether total or not, leads to a significant increase in state anxiety levels, but sleep restriction does not. Regarding the effect of the length of the period of sleep deprivation, no significant results were observed, but there was a notable tendency for an increase in anxiety in longer sleep deprivations. With regard to tools, the State-Trait Anxiety Inventory (STAI) seems to be the best one to measure sleep-induced anxiogenesis, while the Profile of Mood States (POMS) presented inconclusive results. In conclusion, it can be affirmed that sleep deprivation induces a state of increased anxiety, with similar results also in the case of total sleep deprivation; however, results in more specific experimental conditions are not definitive. Copyright © 2016 Elsevier B.V. All rights reserved.

The effect of one night's sleep deprivation on adolescent neurobehavioral performance.

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Louca, Mia; Short, Michelle A

2014-11-01

To investigate the effects of one night's sleep deprivation on neurobehavioral functioning in adolescents. Participants completed a neurobehavioral test battery measuring sustained attention, reaction speed, cognitive processing speed, sleepiness, and fatigue every 2 h during wakefulness. Baseline performance (defined as those test bouts between 09:00 and 19:00 on days 2 and 3, following two 10-h sleep opportunities) were compared to performance at the same clock time the day following total sleep deprivation. The sleep laboratory at the Centre for Sleep Research. Twelve healthy adolescents (6 male), aged 14-18 years (mean = 16.17, standard deviation = 0.83). Sustained attention, reaction speed, cognitive processing speed, and subjective sleepiness were all significantly worse following one night without sleep than following 10-h sleep opportunities (all main effects of day, P Sleep deprivation led to increased variability on objective performance measures. There were between-subjects differences in response to sleep loss that were task-specific, suggesting that adolescents may not only vary in terms of the degree to which they are affected by sleep loss but also the domains in which they are affected. These findings suggest that one night of total sleep deprivation has significant deleterious effects upon neurobehavioral performance and subjective sleepiness. These factors impair daytime functioning in adolescents, leaving them at greater risk of poor academic and social functioning and accidents and injuries.

Effect of 24 Hours of Sleep Deprivation on Auditory and Linguistic Perception: A Comparison among Young Controls, Sleep-Deprived Participants, Dyslexic Readers, and Aging Adults

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Fostick, Leah; Babkoff, Harvey; Zukerman, Gil

2014-01-01

Purpose: To test the effects of 24 hr of sleep deprivation on auditory and linguistic perception and to assess the magnitude of this effect by comparing such performance with that of aging adults on speech perception and with that of dyslexic readers on phonological awareness. Method: Fifty-five sleep-deprived young adults were compared with 29…

A Novel Dietary Flavonoid Fisetin Inhibits Androgen Receptor Signaling and Tumor Growth in Athymic Nude Mice

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Khan, Naghma; Asim, Mohammad; Afaq, Farrukh; Zaid, Mohammad Abu; Mukhtar, Hasan

2010-01-01

Androgen receptor (AR)–mediated signaling plays an important role in the development and progression of prostate cancer (PCa). Hormonal therapies, mainly with combinations of antiandrogens and androgen deprivation, are the mainstay treatment for advanced disease. However, emergence of androgen resistance largely due to inefficient antihormone action limits their therapeutic usefulness. Here, we report that fisetin, a novel dietary flavonoid, acts as a novel AR ligand by competing with the high-affinity androgen to interact with the ligand binding domain of AR. We show that this physical interaction results in substantial decrease in AR stability and decrease in amino-terminal/carboxyl-terminal (N-C) interaction of AR. This results in blunting of AR-mediated transactivation of target genes including prostate-specific antigen (PSA). In addition, treatment of LNCaP cells with fisetin decreased AR protein levels, in part, by decreasing its promoter activity and by accelerating its degradation. Fisetin also synergized with Casodex in inducing apoptosis in LNCaP cells. Treatment with fisetin in athymic nude mice implanted with AR-positive CWR22Rυ1 human PCa cells resulted in inhibition of tumor growth and reduction in serum PSA levels. These data identify fisetin as an inhibitor of AR signaling axis and suggest that it could be a useful chemopreventive and chemotherapeutic agent to delay progression of PCa. PMID:18922931

Neuroendocrine prostate cancer (NEPCa) increased the neighboring PCa chemo-resistance via altering the PTHrP/p38/Hsp27/androgen receptor (AR)/p21 signals

Science.gov (United States)

Cui, Yun; Sun, Yin; Hu, Shuai; Luo, Jie; Li, Lei; Li, Xin; Yeh, Shuyuan; Jin, Jie; Chang, Chawnshang

2016-01-01

Prostatic neuroendocrine cells (NE) are an integral part of prostate cancer (PCa) that are associated with PCa progression. As the current androgen-deprivation therapy (ADT) with anti-androgens may promote the neuroendocrine PCa (NEPCa) development, and few therapies can effectively suppress NEPCa, understanding the impact of NEPCa on PCa progression may help us to develop better therapies to battle PCa. Here we found NEPCa cells could increase the docetaxel-resistance of their neighboring PCa cells. Mechanism dissection revealed that through secretion of PTHrP, NEPCa cells could alter the p38/MAPK/Hsp27 signals in their neighboring PCa cells that resulted in increased androgen receptor (AR) activity via promoting AR nuclear translocation. The consequences of increased AR function might then increase docetaxel-resistance via increasing p21 expression. In vivo xenograft mice experiments also confirmed NEPCa could increase the docetaxel-resistance of neighboring PCa, and targeting this newly identified PTHrP/p38/Hsp27/AR/p21 signaling pathway with either p38 inhibitor (SB203580) or sh-PTHrP may result in improving/restoring the docetaxel sensitivity to better suppress PCa. PMID:27375022

Can Economic Deprivation Protect Health? Paradoxical Multilevel Effects of Poverty on Hispanic Children’s Wheezing

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Collins, Timothy W.; Kim, Young-an; Grineski, Sara E.; Clark-Reyna, Stephanie

2014-01-01

Prior research suggests that economic deprivation has a generally negative influence on residents’ health. We employ hierarchical logistic regression modeling to test if economic deprivation presents respiratory health risks or benefits to Hispanic children living in the City of El Paso (Texas, USA) at neighborhood- and individual-levels, and whether individual-level health effects of economic deprivation vary based on neighborhood-level economic deprivation. Data come from the US Census Bureau and a population-based survey of El Paso schoolchildren. The dependent variable is children’s current wheezing, an established respiratory morbidity measure, which is appropriate for use with economically-deprived children with an increased likelihood of not receiving a doctor’s asthma diagnosis. Results reveal that economic deprivation (measured based on poverty status) at both neighborhood- and individual-levels is associated with reduced odds of wheezing for Hispanic children. A sensitivity analysis revealed similar significant effects of individual- and neighborhood-level poverty on the odds of doctor-diagnosed asthma. Neighborhood-level poverty did not significantly modify the observed association between individual-level poverty and Hispanic children’s wheezing; however, greater neighborhood poverty tends to be more protective for poor (as opposed to non-poor) Hispanic children. These findings support a novel, multilevel understanding of seemingly paradoxical effects of economic deprivation on Hispanic health. PMID:25101769

Can Economic Deprivation Protect Health? Paradoxical Multilevel Effects of Poverty on Hispanic Children’s Wheezing

Directory of Open Access Journals (Sweden)

Timothy W. Collins

2014-08-01

Full Text Available Prior research suggests that economic deprivation has a generally negative influence on residents’ health. We employ hierarchical logistic regression modeling to test if economic deprivation presents respiratory health risks or benefits to Hispanic children living in the City of El Paso (Texas, USA at neighborhood- and individual-levels, and whether individual-level health effects of economic deprivation vary based on neighborhood-level economic deprivation. Data come from the US Census Bureau and a population-based survey of El Paso schoolchildren. The dependent variable is children’s current wheezing, an established respiratory morbidity measure, which is appropriate for use with economically-deprived children with an increased likelihood of not receiving a doctor’s asthma diagnosis. Results reveal that economic deprivation (measured based on poverty status at both neighborhood- and individual-levels is associated with reduced odds of wheezing for Hispanic children. A sensitivity analysis revealed similar significant effects of individual- and neighborhood-level poverty on the odds of doctor-diagnosed asthma. Neighborhood-level poverty did not significantly modify the observed association between individual-level poverty and Hispanic children’s wheezing; however, greater neighborhood poverty tends to be more protective for poor (as opposed to non-poor Hispanic children. These findings support a novel, multilevel understanding of seemingly paradoxical effects of economic deprivation on Hispanic health.

Effects of Foveal Ablation on Emmetropization and Form-Deprivation Myopia

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Smith, Earl L.; Ramamirtham, Ramkumar; Qiao-Grider, Ying; Hung, Li-Fang; Huang, Juan; Kee, Chea-su; Coats, David; Paysse, Evelyn

2009-01-01

Purpose Because of the prominence of central vision in primates, it has generally been assumed that signals from the fovea dominate refractive development. To test this assumption, the authors determined whether an intact fovea was essential for either normal emmetropization or the vision-induced myopic errors produced by form deprivation. Methods In 13 rhesus monkeys at 3 weeks of age, the fovea and most of the perifovea in one eye were ablated by laser photocoagulation. Five of these animals were subsequently allowed unrestricted vision. For the other eight monkeys with foveal ablations, a diffuser lens was secured in front of the treated eyes to produce form deprivation. Refractive development was assessed along the pupillary axis by retinoscopy, keratometry, and A-scan ultrasonography. Control data were obtained from 21 normal monkeys and three infants reared with plano lenses in front of both eyes. Results Foveal ablations had no apparent effect on emmetropization. Refractive errors for both eyes of the treated infants allowed unrestricted vision were within the control range throughout the observation period, and there were no systematic interocular differences in refractive error or axial length. In addition, foveal ablation did not prevent form deprivation myopia; six of the eight infants that experienced monocular form deprivation developed myopic axial anisometropias outside the control range. Conclusions Visual signals from the fovea are not essential for normal refractive development or the vision-induced alterations in ocular growth produced by form deprivation. Conversely, the peripheral retina, in isolation, can regulate emmetropizing responses and produce anomalous refractive errors in response to abnormal visual experience. These results indicate that peripheral vision should be considered when assessing the effects of visual experience on refractive development. PMID:17724167

Development of a Nomogram Model Predicting Current Bone Scan Positivity in Patients Treated with Androgen-Deprivation Therapy for Prostate Cancer

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Gotto, Geoffrey T.; Yu, Changhong; Bernstein, Melanie; Eastham, James A.; Kattan, Michael W.

2014-01-01

Purpose: To develop a nomogram predictive of current bone scan positivity in patients receiving androgen-deprivation therapy (ADT) for advanced prostate cancer; to augment clinical judgment and highlight patients in need of additional imaging investigations. Materials and methods: A retrospective chart review of bone scan records (conventional 99mTc-scintigraphy) of 1,293 patients who received ADT at the Memorial Sloan-Kettering Cancer Center from 2000 to 2011. Multivariable logistic regression analysis was used to identify variables suitable for inclusion in the nomogram. The probability of current bone scan positivity was determined using these variables and the predictive accuracy of the nomogram was quantified by concordance index. Results: In total, 2,681 bone scan records were analyzed and 636 patients had a positive result. Overall, the median pre-scan prostate-specific antigen (PSA) level was 2.4 ng/ml; median PSA doubling time (PSADT) was 5.8 months. At the time of a positive scan, median PSA level was 8.2 ng/ml; 53% of patients had PSA <10 ng/ml; median PSADT was 4.0 months. Five variables were included in the nomogram: number of previous negative bone scans after initiating ADT, PSA level, Gleason grade sum, and history of radical prostatectomy and radiotherapy. A concordance index value of 0.721 was calculated for the nomogram. This was a retrospective study based on limited data in patients treated in a large cancer center who underwent conventional 99mTc bone scans, which themselves have inherent limitations. Conclusion: This is the first nomogram to predict current bone scan positivity in ADT-treated prostate cancer patients, providing high predictive accuracy. PMID:25386410

Development of a nomogram model predicting current bone scan positivity in patients treated with androgen-deprivation therapy for prostate cancer

Directory of Open Access Journals (Sweden)

Michael eKattan

2014-10-01

Full Text Available Purpose: To develop a nomogram predictive of current bone scan positivity in patients receiving androgen-deprivation therapy (ADT for advanced prostate cancer; to augment clinical judgment and highlight patients in need of additional imaging investigations.Materials and Methods: A retrospective chart review of bone scan records (conventional 99mTc-scintigraphy of 1,293 patients who received ADT at the Memorial Sloan-Kettering Cancer Center from 2000 to 2011. Multivariable logistic regression analysis was used to identify variables suitable for inclusion in the nomogram. The probability of current bone scan positivity was determined using these variables and the predictive accuracy of the nomogram was quantified by concordance index.Results: In total, 2,681 bone scan records were analyzed and 636 patients had a positive result. Overall, the median pre-scan prostate-specific antigen (PSA level was 2.4 ng/ml; median PSA doubling time (PSADT was 5.8 months. At the time of a positive scan, median PSA level was 8.2 ng/ml; 53% of patients had PSA <10 ng/ml; median PSADT was 4.0 months. Five variables were included in the nomogram: number of previous negative bone scans after initiating ADT, PSA level, Gleason grade sum, and history of radical prostatectomy and radiotherapy. A concordance index value of 0.721 was calculated for the nomogram. This was a retrospective study based on limited data in patients treated in a large cancer centre who underwent conventional 99mTc bone scans, which themselves have inherent limitations. Conclusions: This is the first nomogram to predict current bone scan positivity in ADT-treated prostate cancer patients, providing high predictive accuracy.

Androgen circle of polycystic ovary syndrome.

Science.gov (United States)

Homburg, Roy

2009-07-01

Although the aetiology of polycystic ovary syndrome (PCOS) is still not known and the search for causative genes is proving elusive, it is generally agreed that hyperandrogenism is at the heart of the syndrome. Here, it is proposed that excess androgens are the root cause of PCOS starting from their influence on the female fetus in programming gene expression, producing the characteristic signs and symptoms which are then exacerbated by a propagation of excess ovarian androgen production from multiple small follicles, anovulation and insulin resistance in the reproductive life-span, thus setting up a vicious perpetual circle of androgen excess. This opinion paper, rather than being a full-scale review, is intentionally biased in support of this hypothesis that androgen excess is the 'root of all evil' in PCOS; in the hope that its acceptance could lead to more direct treatment of the syndrome in all its facets rather than the symptomatic treatment of side effects of androgen excess that we are addressing today.

A Comparison Between Low-Dose-Rate Brachytherapy With or Without Androgen Deprivation, External Beam Radiation Therapy With or Without Androgen Deprivation, and Radical Prostatectomy With or Without Adjuvant or Salvage Radiation Therapy for High-Risk Prostate Cancer

International Nuclear Information System (INIS)

Ciezki, Jay P.; Weller, Michael; Reddy, Chandana A.; Kittel, Jeffrey; Singh, Harguneet; Tendulkar, Rahul; Stephans, Kevin L.; Ulchaker, James; Angermeier, Kenneth; Stephenson, Andrew; Campbell, Steven; Haber, Georges-Pascal; Klein, Eric A.

2017-01-01

Purpose: We compare the efficacy and toxicity among the 3 major modalities available used to treat high-risk prostate cancer (HRCaP). Methods and Materials: From 1996 to 2012, 2557 HRCaP patients were treated: 734 received external beam radiation therapy (EBRT) with or without androgen deprivation therapy (ADT), 515 received low-dose-rate prostate brachytherapy (LDR) with or without ADT, and 1308 received radical prostatectomy (RP) with or without EBRT. Biochemical relapse-free survival (bRFS), clinical relapse-free survival (cRFS), and prostate cancer–specific mortality (PCSM) were assessed. Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.03. The log-rank test compared bRFS and cRFS among the modalities, and Cox regression identified factors associated with bRFS and cRFS. Gray's test compared differences in late toxicity and PSCM among the modalities. Competing risk regression identified factors associated with PCSM. Results: The median follow-up time and age were 63.5 months and 65 years, respectively. The bRFS at 5 and 10 years, respectively, was 74% and 53% for EBRT, 74% and 52% for LDR, and 65% and 47% for RP (P=.0001). The cRFS at 5 and 10 years, respectively, was 85% and 73% for EBRT, 90% and 76% for LDR, and 89% and 75% for RP (P=.121). The PCSM at 5 and 10 years, respectively, was 5.3% and 11.2% for EBRT, 3.2% and 3.6% for LDR, and 2.8% and 6.8% for RP (P=.0004). The 10-year cumulative incidence of ≥grade 3 genitourinary toxicity was 8.1% for EBRT, 7.2% for LDR, and 16.4% for RP (P<.0001). The 10-year cumulative incidence of ≥grade 3 gastrointestinal toxicity was 4.6% for EBRT, 1.1% for LDR, and 1.0% for RP (P<.0001). Conclusion: HRCaP treated with EBRT, LDR, or RP yields efficacy showing better bRFS for LDR and EBRT relative to RP, equivalence for cRFS, and a PCSM advantage of LDR and RP over EBRT. The toxicity is lowest for LDR.

A Comparison Between Low-Dose-Rate Brachytherapy With or Without Androgen Deprivation, External Beam Radiation Therapy With or Without Androgen Deprivation, and Radical Prostatectomy With or Without Adjuvant or Salvage Radiation Therapy for High-Risk Prostate Cancer

Energy Technology Data Exchange (ETDEWEB)

Ciezki, Jay P., E-mail: ciezkij@ccf.org [Taussig Cancer Institute, Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio (United States); Weller, Michael; Reddy, Chandana A.; Kittel, Jeffrey; Singh, Harguneet; Tendulkar, Rahul; Stephans, Kevin L. [Taussig Cancer Institute, Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio (United States); Ulchaker, James; Angermeier, Kenneth; Stephenson, Andrew; Campbell, Steven; Haber, Georges-Pascal; Klein, Eric A. [Glickman Urological and Kidney Institute, Department of Urology, Cleveland Clinic, Cleveland, Ohio (United States)

2017-04-01

Purpose: We compare the efficacy and toxicity among the 3 major modalities available used to treat high-risk prostate cancer (HRCaP). Methods and Materials: From 1996 to 2012, 2557 HRCaP patients were treated: 734 received external beam radiation therapy (EBRT) with or without androgen deprivation therapy (ADT), 515 received low-dose-rate prostate brachytherapy (LDR) with or without ADT, and 1308 received radical prostatectomy (RP) with or without EBRT. Biochemical relapse-free survival (bRFS), clinical relapse-free survival (cRFS), and prostate cancer–specific mortality (PCSM) were assessed. Toxicity was assessed using the Common Terminology Criteria for Adverse Events, version 4.03. The log-rank test compared bRFS and cRFS among the modalities, and Cox regression identified factors associated with bRFS and cRFS. Gray's test compared differences in late toxicity and PSCM among the modalities. Competing risk regression identified factors associated with PCSM. Results: The median follow-up time and age were 63.5 months and 65 years, respectively. The bRFS at 5 and 10 years, respectively, was 74% and 53% for EBRT, 74% and 52% for LDR, and 65% and 47% for RP (P=.0001). The cRFS at 5 and 10 years, respectively, was 85% and 73% for EBRT, 90% and 76% for LDR, and 89% and 75% for RP (P=.121). The PCSM at 5 and 10 years, respectively, was 5.3% and 11.2% for EBRT, 3.2% and 3.6% for LDR, and 2.8% and 6.8% for RP (P=.0004). The 10-year cumulative incidence of ≥grade 3 genitourinary toxicity was 8.1% for EBRT, 7.2% for LDR, and 16.4% for RP (P<.0001). The 10-year cumulative incidence of ≥grade 3 gastrointestinal toxicity was 4.6% for EBRT, 1.1% for LDR, and 1.0% for RP (P<.0001). Conclusion: HRCaP treated with EBRT, LDR, or RP yields efficacy showing better bRFS for LDR and EBRT relative to RP, equivalence for cRFS, and a PCSM advantage of LDR and RP over EBRT. The toxicity is lowest for LDR.

Effects of different sleep deprivation protocols on sleep perception in healthy volunteers.

Science.gov (United States)

Goulart, Leonardo I; Pinto, Luciano R; Perlis, Michael L; Martins, Raquel; Caboclo, Luis Otavio; Tufik, Sergio; Andersen, Monica L

2014-10-01

To investigate whether different protocols of sleep deprivation modify sleep perception. The effects of total sleep deprivation (TD) and selective rapid eye movement (REM) sleep deprivation (RD) on sleep perception were analyzed in normal volunteers. Thirty-one healthy males with normal sleep were randomized to one of three conditions: (i) normal uninterrupted sleep; (ii) four nights of RD; or (iii) two nights of TD. Morning perception of total sleep time was evaluated for each condition. Sleep perception was estimated using total sleep time (in hours) as perceived by the volunteer divided by the total sleep time (in hours) measured by polysomnography (PSG). The final value of this calculation was defined as the perception index (PI). There were no significant differences among the three groups of volunteers in the total sleep time measured by PSG or in the perception of total sleep time at baseline condition. Volunteers submitted to RD exhibited lower sleep PI scores as compared with controls during the sleep deprivation period (P sleep deprivation reduced the ability of healthy young volunteers to perceive their total sleep time when compared with time measured by PSG. The data reinforce the influence of sleep deprivation on sleep perception. Copyright © 2014 Elsevier B.V. All rights reserved.

Differential Effects of Leptin on the Invasive Potential of Androgen-Dependent and -Independent Prostate Carcinoma Cells

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Dayanand D. Deo

2008-01-01

Full Text Available Obesity has been linked with an increased risk of prostate cancer. The formation of toxic free oxygen radicals has been implicated in obesity mediated disease processes. Leptin is one of the major cytokines produced by adipocytes and controls body weight homeostasis through food intake and energy expenditure. The rationale of the study was to determine the impact of leptin on the metastatic potential of androgen-sensitive (LNCaP cells as well as androgen-insensitive (PC-3 and DU-145 cells. At a concentration of 200_nm, LNCaP cells showed a significant increase (20% above control; P<.0001 in cellular proliferation without any effect on androgen-insensitive cells. Furthermore, exposure to leptin caused a significant (P<.01 to P<.0001 dose-dependent decrease in migration and invasion of PC3 and Du-145 prostate carcinoma cell lines. At the molecular level, exposure of androgen-independent prostate cancer cells to leptin stimulates the phosphorylation of MAPK at early time point as well as the transcription factor STAT3, suggesting the activation of the intracellular signaling cascade upon leptin binding to its cognate receptor. Taken together, these results suggest that leptin mediates the invasive potential of prostate carcinoma cells, and that this effect is dependent on their androgen sensitivity.

The Buzz About Anabolic Androgenic Steroids: Electrophysiological Effects in Excitable Tissues

Science.gov (United States)

Oberlander, Joseph G.; Penatti, Carlos A. A.; Porter, Donna M.; Henderson, Leslie P.

2012-01-01

Anabolic androgenic steroids (AAS) comprise a large and growing class of synthetic androgens used clinically to promote tissue-building in individuals suffering from genetic disorders, injuries and diseases. Despite these beneficial therapeutic applications, the predominant use of AAS is illicit: these steroids are self-administered to promote athletic performance and body image. Hand in hand with the desired anabolic actions of the AAS are untoward effects on the brain and behavior. While the signaling routes by which the AAS impose both beneficial and harmful actions may be quite diverse, key endpoints are likely to include ligand-gated and voltage-dependent ion channels that govern the activity of electrically excitable tissues. Here we review the known effects of AAS on molecular targets that play critical roles in controlling electrical activity, with a specific focus on the effects of AAS on neurotransmission mediated by GABAA receptors in the central nervous system (CNS). PMID:22576754

MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease.

Science.gov (United States)

Schiffer, Lina; Kempegowda, Punith; Arlt, Wiebke; O'Reilly, Michael W

2017-09-01

Female androgen excess and male androgen deficiency manifest with an overlapping adverse metabolic phenotype, including abdominal obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and an increased risk of cardiovascular disease. Here, we review the impact of androgens on metabolic target tissues in an attempt to unravel the complex mechanistic links with metabolic dysfunction; we also evaluate clinical studies examining the associations between metabolic disease and disorders of androgen metabolism in men and women. We conceptualise that an equilibrium between androgen effects on adipose tissue and skeletal muscle underpins the metabolic phenotype observed in female androgen excess and male androgen deficiency. Androgens induce adipose tissue dysfunction, with effects on lipid metabolism, insulin resistance and fat mass expansion, while anabolic effects on skeletal muscle may confer metabolic benefits. We hypothesise that serum androgen concentrations observed in female androgen excess and male hypogonadism are metabolically disadvantageous, promoting adipose and liver lipid accumulation, central fat mass expansion and insulin resistance. © 2017 The authors.

Illicit use of androgens and other hormones: recent advances.

Science.gov (United States)

Kanayama, Gen; Pope, Harrison G

2012-06-01

To summarize recent advances in studies of illicit use of androgens and other hormones. Androgens and other appearance-enhancing and performance-enhancing substances are widely abused worldwide. Three notable clusters of findings have emerged in this field in recent years. First, studies almost unanimously find that androgen users engage in polypharmacy, often ingesting other hormones (e.g., human growth hormone, thyroid hormones, and insulin), ergo/thermogenic drugs (e.g., caffeine, ephedrine, and clenbuterol), and classical drugs of abuse (e.g., cannabis, opiates, and cocaine). Second, reports of long-term psychiatric and medical adverse effects of androgens continue to accumulate. In cardiovascular research particularly, controlled studies have begun to supersede anecdotal evidence, strengthening the case that androgens (possibly acting synergistically with other abused drugs) may cause significant morbidity and even mortality. Third, it is increasingly recognized that androgen use may lead to a dependence syndrome with both psychological and physiological origins. Androgen dependence likely affects some millions of individuals worldwide, and arguably represents the least studied major class of illicit drug dependence. Given mounting evidence of the adverse effects of androgens and associated polypharmacy, this topic will likely represent an expanding area of research and an issue of growing public health concern.

Effects of sleep deprivation on retrieval and reconsolidation of morphine reward memory in rats.

Science.gov (United States)

Shi, Hai-Shui; Luo, Yi-Xiao; Xue, Yan-Xue; Wu, Ping; Zhu, Wei-Li; Ding, Zeng-Bo; Lu, Lin

2011-04-01

Relapse induced by exposure to cues associated with drugs of abuse is a major challenge to the treatment of drug addiction. Drug seeking can be inhibited by manipulation of the reconsolidation of drug-related memory. Sleep has been proposed to be involved in various memory processes. However, the role of sleep in drug reward memory is not clear. The present study used conditioned place preference to examine the effects of total sleep deprivation on retrieval and reconsolidation of morphine reward memory in rats. Six-hour total sleep deprivation had no effect on the retrieval of morphine reward memory. However, sleep deprivation from 0-6 h, but not 6-12 h, after re-exposure disrupted the reconsolidation of morphine reward memory. This impairment was not attributable to the formation of an aversive associative memory between the drug-paired context and sleep deprivation. Our findings suggest that sleep plays a critical role in morphine reward memory reconsolidation, and sleep deprivation may be a potential non-pharmacotherapy for the management of relapse associated with drug-related memory. Copyright © 2011 Elsevier Inc. All rights reserved.

Nutritional Effect on Androgen-Response Gene Expression and Prostate Tumor Growth

National Research Council Canada - National Science Library

Wang, Zhou

2001-01-01

.... The dietary influence on ventral prostate weight does not seem to involve androgen action axis because dietary components did not influence the expression of several androgen-response genes, serum testosterone...

Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor

Science.gov (United States)

Coleman, Daniel J.; Van Hook, Kathryn; King, Carly J.; Schwartzman, Jacob; Lisac, Robert; Urrutia, Joshua; Sehrawat, Archana; Woodward, Josha; Wang, Nicholas J.; Gulati, Roman; Thomas, George V.; Beer, Tomasz M.; Gleave, Martin; Korkola, James E.; Gao, Lina; Heiser, Laura M.; Alumkal, Joshi J.

2016-01-01

Prostate cancer is the most commonly diagnosed and second-most lethal cancer among men in the United States. The vast majority of prostate cancer deaths are due to castration-resistant prostate cancer (CRPC) – the lethal form of the disease that has progressed despite therapies that interfere with activation of androgen receptor (AR) signaling. One emergent resistance mechanism to medical castration is synthesis of intratumoral androgens that activate the AR. This insight led to the development of the AR antagonist enzalutamide. However, resistance to enzalutamide invariably develops, and disease progression is nearly universal. One mechanism of resistance to enzalutamide is an F877L mutation in the AR ligand-binding domain that can convert enzalutamide to an agonist of AR activity. However, mechanisms that contribute to the agonist switch had not been fully clarified, and there were no therapies to block AR F877L. Using cell line models of castration-resistant prostate cancer (CRPC), we determined that cellular androgen content influences enzalutamide agonism of mutant F877L AR. Further, enzalutamide treatment of AR F877L-expressing cell lines recapitulated the effects of androgen activation of F877L AR or wild-type AR. Because the BET bromodomain inhibitor JQ-1 was previously shown to block androgen activation of wild-type AR, we tested JQ-1 in AR F877L-expressing CRPC models. We determined that JQ-1 suppressed androgen or enzalutamide activation of mutant F877L AR and suppressed growth of mutant F877L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. PMID:27276681

Evaluation of urinary prostate cancer antigen-3 (PCA3) and TMPRSS2-ERG score changes when starting androgen-deprivation therapy with triptorelin 6-month formulation in patients with locally advanced and metastatic prostate cancer

DEFF Research Database (Denmark)

Martínez-Piñeiro, Luis; Schalken, Jack A; Cabri, Patrick

2014-01-01

change at 6 months, according to baseline variables. Other outcome measures included urinary PCA3 and TMPRSS2-ERG scores and statuses, and serum testosterone and prostate-specific antigen (PSA) levels at baseline and at 1, 3 and 6 months after initiation of ADT. Safety was assessed by recording adverse......OBJECTIVE: To assess prostate cancer antigen-3 (PCA3) and TMPRSS2-ERG scores in patients with advanced and metastatic prostate cancer at baseline and after 6 months of treatment with triptorelin 22.5 mg, and analyse these scores in patient-groups defined by different disease characteristics....... PATIENTS AND METHODS: The Triptocare study was a prospective, open-label, multicentre, single-arm, Phase III study of triptorelin 22.5 mg in men with locally advanced or metastatic prostate cancer, who were naïve to androgen-deprivation therapy (ADT). The primary objective was to model the urinary PCA3...

Vinclozolin--no transgenerational inheritance of anti-androgenic effects after maternal exposure during organogenesis via the intraperitoneal route.

Science.gov (United States)

Schneider, Steffen; Marxfeld, Heike; Gröters, Sibylle; Buesen, Roland; van Ravenzwaay, Bennard

2013-06-01

The goal of this study was to examine the potential transgenerational inheritance of anti-androgenic effects induced by Vinclozolin administered intraperitoneally to pregnant Wistar rats (Crl:WI[Han]). Dams were dosed with Vinclozolin at 0, 4 or 100mg/kg bw/d on gestation days 6-15. Male offspring of F1-F3 generations were bred with untreated females to yield F2-F4 offspring. No evident anti-androgenic effects were observed at 4mg/kg bw/d, but a case of hypospadias as well as delayed sexual maturation in F1 male offspring was observed as a sign of anti-androgenicity at 100mg/kg bw/d. However, F1-F3 males developed normally to sexual maturity and were able to mate and to generate healthy progeny. Sperm count, morphology and motility were not affected in F1-F4 generation male offspring. In conclusion, transgenerational inheritance of Vinclozolin's anti-androgenic effects was not evident in outbred Wistar rats. Copyright © 2013 Elsevier Inc. All rights reserved.

Effect of monocular deprivation on rabbit neural retinal cell densities

Directory of Open Access Journals (Sweden)

Philip Maseghe Mwachaka

2015-01-01

Conclusion: In this rabbit model, monocular deprivation resulted in activity-dependent changes in cell densities of the neural retina in favour of the non-deprived eye along with reduced cell densities in the deprived eye.

Sleep deprivation in bright and dim light : antidepressant effects on major depressive disorder

NARCIS (Netherlands)

Burg, W. van den; Bouhuys, A.L.; Hoofdakker, R.H. van den; Beersma, D.G.M.

Twenty-three patients with a major depressive disorder were deprived of a night’s sleep twice weekly, one week staying up in the dimly lit living room of the ward (< 60 lux), and one week in a brightly lit room (> 2000 lux). Immediate, but transient beneficial effects of sleep deprivation were

[Effect of acupuncture on pattern-visual evoked potential in rats with monocular visual deprivation].

Science.gov (United States)

Yan, Xing-Ke; Dong, Li-Li; Liu, An-Guo; Wang, Jun-Yan; Ma, Chong-Bing; Zhu, Tian-Tian

2013-08-01

To explore electrophysiology mechanism of acupuncture for treatment and prevention of visual deprivation effect. Eighteen healthy 15-day Evans rats were randomly divided into a normal group, a model group and an acupuncture group, 6 rats in each one. Deprivation amblyopia model was established by monocular eyelid suture in the model group and acupuncture group. Acupuncture was applied at "Jingming" (BL 1), "Chengqi" (ST 1), "Qiuhou" (EX-HN 7) and "Cuanzhu" (BL 2) in the acupuncture group. The bilateral acupoints were selected alternately, one side for a day, and totally 14 days were required. The effect of acupuncture on visual evoked potential in different spatial frequencies was observed. Under three different kinds of spatial frequencies of 2 X 2, 4 X 4 and 8 X 8, compared with normal group, there was obvious visual deprivation effect in the model group where P1 peak latency was delayed (P0.05). Under spatial frequency of 4 X 4, N1-P1 amplitude value was maximum in the normal group and acupuncture group. With this spatial frequency the rat's eye had best resolving ability, indicating it could be the best spatial frequency for rat visual system. The visual system has obvious electrophysiology plasticity in sensitive period. Acupuncture treatment could adjust visual deprivation-induced suppression and slow of visual response in order to antagonism deprivation effect.

Platelet-rich plasma in androgenic alopecia: Myth or an effective tool

Directory of Open Access Journals (Sweden)

Swapna S Khatu

2014-01-01

Full Text Available Platelet-rich plasma (PRP has become a newer method for the treatment of various types of alopecia. In this prospective study, safety, efficacy and feasibility of PRP injections in treating androgenic alopecia were assessed. Eleven patients suffering from hair loss due to androgenic alopecia and not responding to 6 months treatment with minoxidil and finasteride were included in this study. The hair pull test was performed before every treatment session. A total volume of 2-3 cc PRP was injected in the scalp by using an insulin syringe. The treatment was repeated every two weeks, for a total of four times. The outcome was assessed after 3 months by clinical examination, macroscopic photos, hair pull test and patient′s overall satisfaction. Results: A significant reduction in hair loss was observed between first and fourth injection. Hair count increased from average number of 71 hair follicular units to 93 hair follicular units. Therefore, average mean gain is 22.09 follicular units per cm 2. After the fourth session, the pull test was negative in 9 patients. Conclusion: PRP injection is a simple, cost effective and feasible treatment option for androgenic alopecia, with high overall patient satisfaction.

Effects of sleep deprivation on cognitive and physical performance in university students.

Science.gov (United States)

Patrick, Yusuf; Lee, Alice; Raha, Oishik; Pillai, Kavya; Gupta, Shubham; Sethi, Sonika; Mukeshimana, Felicite; Gerard, Lothaire; Moghal, Mohammad U; Saleh, Sohag N; Smith, Susan F; Morrell, Mary J; Moss, James

2017-01-01

Sleep deprivation is common among university students, and has been associated with poor academic performance and physical dysfunction. However, current literature has a narrow focus in regard to domains tested, this study aimed to investigate the effects of a night of sleep deprivation on cognitive and physical performance in students. A randomized controlled crossover study was carried out with 64 participants [58% male ( n  = 37); 22 ± 4 years old (mean ± SD)]. Participants were randomized into two conditions: normal sleep or one night sleep deprivation. Sleep deprivation was monitored using an online time-stamped questionnaire at 45 min intervals, completed in the participants' homes. The outcomes were cognitive: working memory (Simon game© derivative), executive function (Stroop test); and physical: reaction time (ruler drop testing), lung function (spirometry), rate of perceived exertion, heart rate, and blood pressure during submaximal cardiopulmonary exercise testing. Data were analysed using paired two-tailed T tests and MANOVA. Reaction time and systolic blood pressure post-exercise were significantly increased following sleep deprivation (mean ± SD change: reaction time: 0.15 ± 0.04 s, p  = 0.003; systolic BP: 6 ± 17 mmHg, p  = 0.012). No significant differences were found in other variables. Reaction time and vascular response to exercise were significantly affected by sleep deprivation in university students, whilst other cognitive and cardiopulmonary measures showed no significant changes. These findings indicate that acute sleep deprivation can have an impact on physical but not cognitive ability in young healthy university students. Further research is needed to identify mechanisms of change and the impact of longer term sleep deprivation in this population.

Discovery and therapeutic promise of selective androgen receptor modulators.

Science.gov (United States)

Chen, Jiyun; Kim, Juhyun; Dalton, James T

2005-06-01

Androgens are essential for male development and the maintenance of male secondary characteristics, such as bone mass, muscle mass, body composition, and spermatogenesis. The main disadvantages of steroidal androgens are their undesirable physicochemical and pharmacokinetic properties. The recent discovery of nonsteroidal selective androgen receptor modulators (SARMs) provides a promising alternative for testosterone replacement therapies with advantages including oral bioavailability, flexibility of structural modification, androgen receptor specificity, tissue selectivity, and the lack of steroid-related side effects.

Anabolic-androgenic steroids for alcoholic liver disease

DEFF Research Database (Denmark)

Rambaldi, A; Gluud, C

2006-01-01

Alcohol is one of the most common causes of liver disease in the Western World. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease.......Alcohol is one of the most common causes of liver disease in the Western World. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease....

Anabolic-androgenic steroids for alcoholic liver disease

DEFF Research Database (Denmark)

Rambaldi, A; Iaquinto, G; Gluud, C

2003-01-01

Alcohol is one of the most common causes of liver disease in the Western World today. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease.......Alcohol is one of the most common causes of liver disease in the Western World today. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease....

Effects of anabolic-androgens on brain reward function

Directory of Open Access Journals (Sweden)

Emanuela eMhillaj

2015-08-01

Full Text Available Androgens are mainly prescribed to treat several diseases caused by testosterone deficiency. However, athletes try to promote muscle growth by manipulating testosterone levels or assuming the so called androgen anabolic steroids (AAS. These substances were originally synthesized to obtain anabolic effects greater than testosterone. Although AAS are rarely prescribed compared to testosterone, the off-label utilization is very wide. Furthermore, combination of different steroids, and doses largely higher than those used in therapy are common. Symptoms of the chronic use of supra-therapeutic doses of AAS include anxiety, depression, aggression, paranoia, distractibility, confusion, amnesia. Interestingly, some studies have shown that AAS elicited electroencephalographic changes similar to those observed with amphetamine abuse. Among the AAS abusers, the frequency of side effects is higher, with psychiatric complications such as labile mood, lack of impulse control and high violence. On the other hand, AAS addiction studies are complex because the collection of data is very difficult due to reticent subjects and can be biased by many variables, including physical exercise, that alter the reward system. Moreover, it has been reported that AAS may imbalance neurotransmitter systems involved in reward process, leading to an increased sensitivity toward opioid narcotics and central stimulants. The aim of this review is to discuss what is present in literature in regard to steroid abuse and alteration of reward system in preclinical and clinical studies.

The promotion on cell growth of androgen-dependent prostate cancer by antimony via mimicking androgen activity.

Science.gov (United States)

Zhang, Changwen; Li, Penghao; Wen, Yingwu; Feng, Guowei; Liu, Yu; Zhang, Yangyi; Xu, Yong; Zhang, Zhihong

2018-05-15

Antimony is a widely used heavier pnictogens in industry, and its toxicity has been a matter of concern. Although previous studies have suggested that antimony may have the function as either a tumor suppressor or an oncogene in several cancers, the molecular basis underlying antimony-mediated transformation is still unclear. In the current study, we attempt to elucidate the potential role of antimony in the development of prostate cancer. Our results showed that the concentration of antimony was much higher in serum of prostate cancer patients, and was closely associated with poor outcome of patients who underwent radical prostatectomy. Additionally, low dose of antimony could promote proliferation and invasion of androgen-dependent prostate cancer cell line LNCaP cells in vitro and in vivo. The mechanistic studies demonstrated that exposure to antimony triggered the phosphorylation of androgen receptor (AR), which transcriptionally regulates the expression of androgen-related targets, including PSA and NKX3.1. Overall, our results unearthed that antimony could promote tumor growth by mimicking androgen activity in androgen-dependent prostate cancer cells. Therefore, these findings expanded our understanding on the molecular mechanism of antimony in tumorigenesis and tumor progression of prostate cancer, and it appears to be an inspiring strategy to restrain prostate cancer by inhibiting antimony-induced androgen-like effects. Copyright © 2018 Elsevier B.V. All rights reserved.

Molecular basis of androgen insensitivity

NARCIS (Netherlands)

Brinkmann, A.; Jenster, G.; Ris-Stalpers, C.; van der Korput, H.; Brüggenwirth, H.; Boehmer, A.; Trapman, J.

1996-01-01

Male sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. In the X-linked androgen insensitivity syndrome, defects in the

Sleep deprivation as an experimental model system for psychosis: Effects on smooth pursuit, prosaccades, and antisaccades.

Science.gov (United States)

Meyhöfer, Inga; Kumari, Veena; Hill, Antje; Petrovsky, Nadine; Ettinger, Ulrich

2017-04-01

Current antipsychotic medications fail to satisfactorily reduce negative and cognitive symptoms and produce many unwanted side effects, necessitating the development of new compounds. Cross-species, experimental behavioural model systems can be valuable to inform the development of such drugs. The aim of the current study was to further test the hypothesis that controlled sleep deprivation is a safe and effective model system for psychosis when combined with oculomotor biomarkers of schizophrenia. Using a randomized counterbalanced within-subjects design, we investigated the effects of 1 night of total sleep deprivation in 32 healthy participants on smooth pursuit eye movements (SPEM), prosaccades (PS), antisaccades (AS), and self-ratings of psychosis-like states. Compared with a normal sleep control night, sleep deprivation was associated with reduced SPEM velocity gain, higher saccadic frequency at 0.2 Hz, elevated PS spatial error, and an increase in AS direction errors. Sleep deprivation also increased intra-individual variability of SPEM, PS, and AS measures. In addition, sleep deprivation induced psychosis-like experiences mimicking hallucinations, cognitive disorganization, and negative symptoms, which in turn had moderate associations with AS direction errors. Taken together, sleep deprivation resulted in psychosis-like impairments in SPEM and AS performance. However, diverging somewhat from the schizophrenia literature, sleep deprivation additionally disrupted PS control. Sleep deprivation thus represents a promising but possibly unspecific experimental model that may be helpful to further improve our understanding of the underlying mechanisms in the pathophysiology of psychosis and aid the development of antipsychotic and pro-cognitive drugs.

Effects of 2,4-D and DCP on the DHT-induced androgenic action in human prostate cancer cells.

Science.gov (United States)

Kim, Hyun-Jung; Park, Young In; Dong, Mi-Sook

2005-11-01

2,4-Dichlorophenoxyacetic acid (2,4-D) and its metabolite 2,4-dichlorophenol (DCP) are used extensively in agriculture as herbicides, and are suspected of potential endocrine disruptor activity. In a previous study, we showed that these compounds exhibited synergistic androgenic effects by co-treatment with testosterone in the Hershberger assay. To elucidate the mechanisms of the synergistic effects of these compounds on the androgenicity of testosterone, the androgenic action of 2,4-D and DCP was characterized using a mammalian detection system in prostate cancer cell lines. In in vitro assay systems, while 2,4-D or DCP alone did not show androgenic activity, 2,4-D or DCP with 5alpha-dihydroxytestosterone (DHT) exhibited synergistic androgenic activities. Co-treatment of 10 nM 2,4-D or DCP with 10 nM DHT was shown to stimulate the cell proliferation by 1.6-fold, compared to 10 nM DHT alone. In addition, in transient transfection assays, androgen-induced transactivation was also increased to a maximum of 32-fold or 1.28-fold by co-treatment of 2,4-D or DCP with DHT, respectively. However, 2,4-D and DCP exerted no effects on either mRNA or protein levels of AR. In a competitive AR binding assay, 2,4-D and DCP inhibited androgen binding to AR, up to 50% at concentrations of approximately 0.5 microM for both compounds. The nuclear translocation of green fluorescent protein-AR fusion protein in the presence of DHT was promoted as the result of the addition of 2,4-D and DCP. Collectively, these results that 2,4-D and DCP enhanced DHT-induced AR transcriptional activity might be attributable, at least in part, to the promotion of AR nuclear translocation.

The effects of total sleep deprivation on Bayesian updating

Directory of Open Access Journals (Sweden)

David L. Dickinson

2008-02-01

Full Text Available Subjects performed a decision task (Grether, 1980 in both a well-rested and experimentally sleep-deprived state. We found two main results: 1 final choice accuracy was unaffected by sleep deprivation, and yet 2 the estimated decision model differed significantly following sleep-deprivation. Following sleep deprivation, subjects placed significantly less weight on new information in forming their beliefs. Because the altered decision process still maintains decision accuracy, it may suggest that increased accident and error rates attributed to reduced sleep in modern society stem from reduced auxiliary function performance (e.g., slowed reaction time, reduced motor skills or other components of decision making, rather than the inability to integrate multiple pieces of information.

Spinal multiparametric MRI and DEXA changes over time in men with prostate cancer treated with androgen deprivation therapy: a potential imaging biomarker of treatment toxicity

International Nuclear Information System (INIS)

Martin, Jarad; Arm, Jameen; Smart, Joanne; Palazzi, Kerrin; Capp, Anne; Ainsworth, Paul; Cowin, Gary

2017-01-01

To explore changes in bone mineral density (BMD) measured by DEXA and MRS fat fraction (FF), Dixon FF, and ADC in lower spinal vertebral bodies in men with prostate cancer treated with androgen deprivation therapy (ADT). Twenty-eight men were enrolled onto a clinical trial. All received ADT. DEXA imaging was performed at baseline and 12 months. L-spine MRI was done at baseline and 6 months. The number of patients who underwent DEXA, Dixon, ADC, and MRS at baseline/follow-up were 28/27, 28/26, 28/26, and 22/20. An increase in FF was observed from T11 to S2 (average 1 %/vertebra). There was a positive correlation between baseline MRS FF and Dixon FF (r = 0.85, p < 0.0001) and a negative correlation between MRS FF and ADC (r = -0.56, p = 0.036). Over 6 months, MRS FF increased by a median of 25 % in relative values (p = 0.0003), Dixon FF increased (p < 0.0001) and ADC values decreased (p = 0.0014). Men with >5 % BMD loss after 1 year had triple the percentage increase in MRS FF at 6 months (61.1 % vs. 20.9 %, p = 0.19). Changes are observed on L-spine MRI after 6 months of ADT. Further investigation is warranted of MRS change as a potential predictive biomarker for later BMD loss. (orig.)

Spinal multiparametric MRI and DEXA changes over time in men with prostate cancer treated with androgen deprivation therapy: a potential imaging biomarker of treatment toxicity

Energy Technology Data Exchange (ETDEWEB)

Martin, Jarad [Calvary Mater Newcastle, Department of Radiation Oncology, Newcastle, New South Wales (Australia); University of Newcastle, School of Medicine and Public Health, Newcastle, New South Wales (Australia); University of Queensland, Centre for Advanced Imaging, Brisbane, Queensland (Australia); Arm, Jameen [Hunter New England Imaging, Newcastle, New South Wales (Australia); Smart, Joanne [Calvary Mater Newcastle, Department of Radiation Oncology, Newcastle, New South Wales (Australia); Palazzi, Kerrin [CREDITSS, Hunter Medical Research Institute, Newcastle, New South Wales (Australia); Capp, Anne [Calvary Mater Newcastle, Department of Radiation Oncology, Newcastle, New South Wales (Australia); University of Newcastle, School of Medicine and Public Health, Newcastle, New South Wales (Australia); Ainsworth, Paul [Hunter New England Health, Department of Urology, Newcastle, New South Wales (Australia); Cowin, Gary [University of Queensland, Centre for Advanced Imaging, Brisbane, Queensland (Australia)

2017-03-15

To explore changes in bone mineral density (BMD) measured by DEXA and MRS fat fraction (FF), Dixon FF, and ADC in lower spinal vertebral bodies in men with prostate cancer treated with androgen deprivation therapy (ADT). Twenty-eight men were enrolled onto a clinical trial. All received ADT. DEXA imaging was performed at baseline and 12 months. L-spine MRI was done at baseline and 6 months. The number of patients who underwent DEXA, Dixon, ADC, and MRS at baseline/follow-up were 28/27, 28/26, 28/26, and 22/20. An increase in FF was observed from T11 to S2 (average 1 %/vertebra). There was a positive correlation between baseline MRS FF and Dixon FF (r = 0.85, p < 0.0001) and a negative correlation between MRS FF and ADC (r = -0.56, p = 0.036). Over 6 months, MRS FF increased by a median of 25 % in relative values (p = 0.0003), Dixon FF increased (p < 0.0001) and ADC values decreased (p = 0.0014). Men with >5 % BMD loss after 1 year had triple the percentage increase in MRS FF at 6 months (61.1 % vs. 20.9 %, p = 0.19). Changes are observed on L-spine MRI after 6 months of ADT. Further investigation is warranted of MRS change as a potential predictive biomarker for later BMD loss. (orig.)

Pharmacodynamics of selective androgen receptor modulators.

Science.gov (United States)

Yin, Donghua; Gao, Wenqing; Kearbey, Jeffrey D; Xu, Huiping; Chung, Kiwon; He, Yali; Marhefka, Craig A; Veverka, Karen A; Miller, Duane D; Dalton, James T

2003-03-01

The present study aimed to identify selective androgen receptor modulators (SARMs) with in vivo pharmacological activity. We examined the in vitro and in vivo pharmacological activity of four chiral, nonsteroidal SARMs synthesized in our laboratories. In the in vitro assays, these compounds demonstrated moderate to high androgen receptor (AR) binding affinity, with K(i) values ranging from 4 to 37 nM, and three of the compounds efficaciously stimulated AR-mediated reporter gene expression. The compounds were then administered subcutaneously to castrated rats to appraise their in vivo pharmacological activity. Androgenic activity was evaluated by the ability of these compounds to maintain the weights of prostate and seminal vesicle, whereas levator ani muscle weight was used as a measure of anabolic activity. The maximal response (E(max)) and dose for half-maximal effect (ED(50)) were determined for each compound and compared with that observed for testosterone propionate (TP). Compounds S-1 and S-4 demonstrated in vivo androgenic and anabolic activity, whereas compounds S-2 and S-3 did not. The activities of S-1 and S-4 were tissue-selective in that both compounds stimulated the anabolic organs more than the androgenic organs. These two compounds were less potent and efficacious than TP in androgenic activity, but their anabolic activity was similar to or greater than that of TP. Neither S-1 nor S-4 caused significant luteinizing hormone or follicle stimulating hormone suppression at doses near the ED(50) value. Thus, compounds S-1 and S-4 were identified as SARMs with potent and tissue-selective in vivo pharmacological activity, and represent the first members of a new class of SARMs with selective anabolic effects.

Targets to treat androgen excess in polycystic ovary syndrome.

Science.gov (United States)

Luque-Ramírez, Manuel; Escobar-Morreale, Héctor Francisco

2015-01-01

The polycystic ovary syndrome (PCOS) is a common androgen disorder in reproductive-aged women. Excessive biosynthesis and secretion of androgens by steroidogenic tissues is its central pathogenetic mechanism. The authors review the potential targets and new drugs to treat androgen excess in PCOS. Besides our lab's experience, a systematic search (MEDLINE, Cochrane library, ClinicalTriasl.gov, EU Clinical Trials Register and hand-searching) regarding observational studies, randomized clinical trials, systematic reviews, meta-analyses and patents about this topic was performed. PCOS has a heterogeneous clinical presentation. It is unlikely that a single drug would cover all its possible manifestations. Available treatments for androgen excess are not free of side effects that are of particular concern in these women who suffer from cardiometabolic risk even without treatment. A precise characterization of the source of androgen excess must tailor antiandrogenic management in each woman, avoiding undesirable side effects.

Sensitivity and validity of psychometric tests for assessing driving impairment: effects of sleep deprivation.

Science.gov (United States)

Jongen, Stefan; Perrier, Joy; Vuurman, Eric F; Ramaekers, Johannes G; Vermeeren, Annemiek

2015-01-01

To assess drug induced driving impairment, initial screening is needed. However, no consensus has been reached about which initial screening tools have to be used. The present study aims to determine the ability of a battery of psychometric tests to detect performance impairing effects of clinically relevant levels of drowsiness as induced by one night of sleep deprivation. Twenty four healthy volunteers participated in a 2-period crossover study in which the highway driving test was conducted twice: once after normal sleep and once after one night of sleep deprivation. The psychometric tests were conducted on 4 occasions: once after normal sleep (at 11 am) and three times during a single night of sleep deprivation (at 1 am, 5 am, and 11 am). On-the-road driving performance was significantly impaired after sleep deprivation, as measured by an increase in Standard Deviation of Lateral Position (SDLP) of 3.1 cm compared to performance after a normal night of sleep. At 5 am, performance in most psychometric tests showed significant impairment. As expected, largest effect sizes were found on performance in the Psychomotor Vigilance Test (PVT). Large effects sizes were also found in the Divided Attention Test (DAT), the Attention Network Test (ANT), and the test for Useful Field of View (UFOV) at 5 and 11 am during sleep deprivation. Effects of sleep deprivation on SDLP correlated significantly with performance changes in the PVT and the DAT, but not with performance changes in the UFOV. From the psychometric tests used in this study, the PVT and DAT seem most promising for initial evaluation of drug impairment based on sensitivity and correlations with driving impairment. Further studies are needed to assess the sensitivity and validity of these psychometric tests after benchmark sedative drug use.

Sensitivity and validity of psychometric tests for assessing driving impairment: effects of sleep deprivation.

Directory of Open Access Journals (Sweden)

Stefan Jongen

Full Text Available To assess drug induced driving impairment, initial screening is needed. However, no consensus has been reached about which initial screening tools have to be used. The present study aims to determine the ability of a battery of psychometric tests to detect performance impairing effects of clinically relevant levels of drowsiness as induced by one night of sleep deprivation.Twenty four healthy volunteers participated in a 2-period crossover study in which the highway driving test was conducted twice: once after normal sleep and once after one night of sleep deprivation. The psychometric tests were conducted on 4 occasions: once after normal sleep (at 11 am and three times during a single night of sleep deprivation (at 1 am, 5 am, and 11 am.On-the-road driving performance was significantly impaired after sleep deprivation, as measured by an increase in Standard Deviation of Lateral Position (SDLP of 3.1 cm compared to performance after a normal night of sleep. At 5 am, performance in most psychometric tests showed significant impairment. As expected, largest effect sizes were found on performance in the Psychomotor Vigilance Test (PVT. Large effects sizes were also found in the Divided Attention Test (DAT, the Attention Network Test (ANT, and the test for Useful Field of View (UFOV at 5 and 11 am during sleep deprivation. Effects of sleep deprivation on SDLP correlated significantly with performance changes in the PVT and the DAT, but not with performance changes in the UFOV.From the psychometric tests used in this study, the PVT and DAT seem most promising for initial evaluation of drug impairment based on sensitivity and correlations with driving impairment. Further studies are needed to assess the sensitivity and validity of these psychometric tests after benchmark sedative drug use.

Androgenic anabolic steroids also impair right ventricular function.

Science.gov (United States)

Kasikcioglu, Erdem; Oflaz, Huseyin; Umman, Berrin; Bugra, Zehra

2009-05-01

Chronic anabolic steroid use suppresses left ventricular functions. However, there is no information regarding the chronic effects of anabolic steroids on right ventricular function which also plays a key role in global cardiac function. The main objective of the present study was to investigate the effects of androgenic anabolic steroids usage among athletes on remodeling the right part of the heart. Androgenic-anabolic steroids-using bodybuilders had smaller diastolic velocities of both ventricles than drug-free bodybuilders and sedentary counterparts. This study shows that androgenic anabolic steroids-using bodybuilders exhibited depressed diastolic functions of both ventricles.

Behavioral and genetic effects promoted by sleep deprivation in rats submitted to pilocarpine-induced status epilepticus.

Science.gov (United States)

Matos, Gabriela; Ribeiro, Daniel A; Alvarenga, Tathiana A; Hirotsu, Camila; Scorza, Fulvio A; Le Sueur-Maluf, Luciana; Noguti, Juliana; Cavalheiro, Esper A; Tufik, Sergio; Andersen, Monica L

2012-05-02

The interaction between sleep deprivation and epilepsy has been well described in electrophysiological studies, but the mechanisms underlying this association remain unclear. The present study evaluated the effects of sleep deprivation on locomotor activity and genetic damage in the brains of rats treated with saline or pilocarpine-induced status epilepticus (SE). After 50 days of pilocarpine or saline treatment, both groups were assigned randomly to total sleep deprivation (TSD) for 6 h, paradoxical sleep deprivation (PSD) for 24 h, or be kept in their home cages. Locomotor activity was assessed with the open field test followed by resection of brain for quantification of genetic damage by the single cell gel electrophoresis (comet) assay. Status epilepticus induced significant hyperactivity in the open field test and caused genetic damage in the brain. Sleep deprivation procedures (TSD and PSD) did not affect locomotor activity in epileptic or healthy rats, but resulted in significant DNA damage in brain cells. Although PSD had this effect in both vehicle and epileptic groups, TSD caused DNA damage only in epileptic rats. In conclusion, our results revealed that, despite a lack of behavioral effects of sleep deprivation, TSD and PSD induced genetic damage in rats submitted to pilocarpine-induced SE. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Prenatal and adult androgen activities in alcohol dependence.

Science.gov (United States)

Lenz, B; Mühle, C; Braun, B; Weinland, C; Bouna-Pyrrou, P; Behrens, J; Kubis, S; Mikolaiczik, K; Muschler, M-R; Saigali, S; Sibach, M; Tanovska, P; Huber, S E; Hoppe, U; Eichler, A; Heinrich, H; Moll, G H; Engel, A; Goecke, T W; Beckmann, M W; Fasching, P A; Müller, C P; Kornhuber, J

2017-07-01

Alcohol dependence is more prevalent in men than in women. The evidence for how prenatal and adult androgens influence alcohol dependence is limited. We investigated the effects of prenatal and adult androgen activity on alcohol dependence. Moreover, we studied how the behaviours of pregnant women affect their children's prenatal androgen load. We quantified prenatal androgen markers (e.g., second-to-fourth finger length ratio [2D : 4D]) and blood androgens in 200 early-abstinent alcohol-dependent in-patients and 240 controls (2013-2015, including a 12-month follow-up). We also surveyed 134 women during pregnancy (2005-2007) and measured the 2D : 4D of their children (2013-2016). The prenatal androgen loads were higher in the male alcohol-dependent patients compared to the controls (lower 2D : 4D, P = 0.004) and correlated positively with the patients' liver transaminase activities (P alcohol withdrawal severity (P = 0.019). Higher prenatal androgen loads and increasing androgen levels during withdrawal predicted earlier and more frequent 12-month hospital readmission in alcohol-dependent patients (P alcohol (P = 0.010) and tobacco consumption (P = 0.017), and lifetime stressors (P = 0.019) of women during pregnancy related positively to their children's prenatal androgen loads (lower 2D : 4D). Androgen activities in alcohol-dependent patients and behaviours of pregnant women represent novel preventive and therapeutic targets of alcohol dependence. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Further Evaluation of Androgen Therapy In Aplastic Anemia: With Special Reference to Correlation Between Response to Androgen and EEI

International Nuclear Information System (INIS)

Whang, Kee Suk

1967-01-01

Patients with aplastic anemia were treated with a combination of depo-testosterone cyclopentylpropionate (Upjohn) and dexamethasone. In 7 of 15 patients treated, there was response in which either a significant increase in hemoglobin concentration, a prolonged interval or a cessation of blood transfusion requirement developed during androgen therapy. Younger patients with cellular marrow appeared to be better responding to androgen. EEI (Effective Erythropoietic Index) formulated by Gardner and Nathan (1966) which was a helpful measurement as to whether patients with myelofibrosis would response to androgen, was evaluated in patients with aplastic anemia. It was concluded that EEI as well as ferrokinetics indices (Plasma- 59 Fe-disappearance rate, RBC 59 Fe net incorporation) did not significantly correlate with the degree of response to androgen in aplastic anemia.

Effects of sleep deprivation on cognitive and physical performance in university students

OpenAIRE

Patrick, Yusuf; Lee, Alice; Raha, Oishik; Pillai, Kavya; Gupta, Shubham; Sethi, Sonika; Mukeshimana, Felicite; Gerard, Lothaire; Moghal, Mohammad U.; Saleh, Sohag N.; Smith, Susan F.; Morrell, Mary J.; Moss, James

2017-01-01

Sleep deprivation is common among university students, and has been associated with poor academic performance and physical dysfunction. However, current literature has a narrow focus in regard to domains tested, this study aimed to investigate the effects of a night of sleep deprivation on cognitive and physical performance in students. A randomized controlled crossover study was carried out with 64 participants [58% male (n?=?37); 22???4 years old (mean???SD)]. Participants were randomized i...

Tuberculosis notifications in England: the relative effects of deprivation and immigration.

Science.gov (United States)

Tocque, K; Doherty, M J; Bellis, M A; Spence, D P; Williams, C S; Davies, P D

1998-03-01

Metropolitan areas of England, including London boroughs, in 1991. To investigate the relative importance of deprivation, immigration and the elderly in explaining variations in tuberculosis rate. A retrospective study using multiple Poisson regression models to assess the interrelationship between various population parameters. Significant differences ere observed between London and other metropolitan districts in the measures of tuberculosis, immigration and the elderly. In addition, all population parameters were significantly intercorrelated in London: areas with a high proportion of immigrants had high levels of deprivation and low proportions of elderly. In other metropolitan districts, only immigration and the Jarman index were significantly associated, and removing the immigration component from the index removed this statistical significance. Multiple Poisson regression models revealed that the immigrant index had the strongest explanatory power in explaining tuberculosis rates, but there were significant interactions between this and measures of urban deprivation indices. That is, there was a greater effect of increasing deprivation at lower levels of immigration than at higher levels. This phenomenon was more pronounced in London boroughs than other metropolitan districts. The elderly index had no significant influence on tuberculosis rates. Although the association between tuberculosis and deprivation previously reported for the city of Liverpool is confirmed across all urban areas of England, the immigrant proportion of the population has a greater statistical power in explaining variations in rates of urban tuberculosis. However, tuberculosis notifications can be most accurately predicted by combining both measures than by either one alone.

Influence of testosterone on synaptic transmission in the rat medial vestibular nuclei: estrogenic and androgenic effects.

Science.gov (United States)

Grassi, S; Frondaroli, A; Di Mauro, M; Pettorossi, V E

2010-12-15

In brainstem slices of young male rat, we investigated the influence of the neuroactive steroid testosterone (T) on the synaptic responses by analyzing the field potential evoked in the medial vestibular nucleus (MVN) by vestibular afferent stimulation. T induced three distinct and independent long-term synaptic changes: fast long-lasting potentiation (fLP), slow long-lasting potentiation (sLP) and long-lasting depression (LD). The fLP was mediated by 17β-estradiol (E(2)) since it was abolished by blocking the estrogen receptors (ERs) or the enzyme converting T to E(2). Conversely, sLP and LD were mediated by 5α-dihydrotestosterone (DHT) since they were prevented by blocking the androgen receptors (ARs) or the enzyme converting T to DHT. Therefore, the synaptic effects of T were mediated by its androgenic or estrogenic metabolites. The pathways leading to estrogenic and androgenic conversion of T might be co-localized since, the occurrence of fLP under block of androgenic pathway, and that of sLP and LD under estrogenic block, were higher than those observed without blocks. In case of co-localization, the effect on synaptic transmission should depend on the prevailing enzymatic activity. We conclude that circulating and neuronal T can remarkably influence synaptic responses of the vestibular neurons in different and opposite ways, depending on its conversion to estrogenic or androgenic metabolites. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

The effect of oral contraception on cardiometabolic risk factors in women with elevated androgen levels.

Science.gov (United States)

Krysiak, Robert; Gilowska, Małgorzata; Okopień, Bogusław

2017-02-01

In unselected reproductive-aged women, use of combined estrogen-progestin oral contraceptive pills has been linked with an increased risk of vascular disease. The aim of this study was to investigate the effect of oral contraception on cardiometabolic risk factors in a population of women with hyperandrogenism. The study included 16 untreated women with elevated testosterone levels and 15 matched healthy women who were then treated with oral contraceptive pills containing ethinyl estradiol (30μg) and drospirenone (3mg). Plasma lipids, glucose homeostasis markers, circulating levels of androgens, uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen and homocysteine, as well as urinary albumin-to-creatinine ratio (UACR) were assessed at baseline and after 12 weeks of treatment. Compared to healthy women, women with elevated androgen levels showed increased plasma levels of hsCRP, fibrinogen and homocysteine, as well as a higher value of UACR. Oral contraception reduced androgen levels only in hyperandrogenic women. In healthy women, ethinyl estradiol plus drospirenone increased plasma levels of insulin, hsCRP, fibrinogen and homocysteine, while in women with elevated androgen levels their effect was limited only to a small increase in hsCRP. Our results suggest that a deteriorating effect of oral contraceptive pills containing ethinyl estradiol and drospirenone in hyperandrogenic women is weaker than in healthy young women and that ethinyl estradiol/drospirenone combination therapy may be safely used in the former group of patients. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

ANABOLIC ANDROGENIC STEROIDS AND ADVERSE EVENTS OF THEIR APPLICATION

Directory of Open Access Journals (Sweden)

Nina Đukanović

2011-08-01

Full Text Available Anabolic androgenic steroids are synthetic compounds originating from testosterone. Their main effects are the control of development and expression of male secondary sexual characteristics, which are known as androgenic effects, and encourage muscle growth or anabolic effects. Anabolic androgenic steroids are most commonly used illegal substances. Besides these physiological effects, which are achieved using therapeutic doses of these preparations, higher doses than recommended, especially over the longer term, may be associated with the emergence of numerous adverse events. Adverse events may be registered in almost all organs and organ systems, but usually include changes in the reproductive system, skin, liver and cardiovascular system.

Short-term visual deprivation reduces interference effects of task-irrelevant facial expressions on affective prosody judgments

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Ineke eFengler

2015-04-01

Full Text Available Several studies have suggested that neuroplasticity can be triggered by short-term visual deprivation in healthy adults. Specifically, these studies have provided evidence that visual deprivation reversibly affects basic perceptual abilities. The present study investigated the long-lasting effects of short-term visual deprivation on emotion perception. To this aim, we visually deprived a group of young healthy adults, age-matched with a group of non-deprived controls, for 3 hours and tested them before and after visual deprivation (i.e., after 8 h on average and at 4 week follow-up on an audio-visual (i.e., faces and voices emotion discrimination task. To observe changes at the level of basic perceptual skills, we additionally employed a simple audio-visual (i.e., tone bursts and light flashes discrimination task and two unimodal (one auditory and one visual perceptual threshold measures. During the 3 h period, both groups performed a series of auditory tasks. To exclude the possibility that changes in emotion discrimination may emerge as a consequence of the exposure to auditory stimulation during the 3 h stay in the dark, we visually deprived an additional group of age-matched participants who concurrently performed unrelated (i.e., tactile tasks to the later tested abilities. The two visually deprived groups showed enhanced affective prosodic discrimination abilities in the context of incongruent facial expressions following the period of visual deprivation; this effect was partially maintained until follow-up. By contrast, no changes were observed in affective facial expression discrimination and in the basic perception tasks in any group. These findings suggest that short-term visual deprivation per se triggers a reweighting of visual and auditory emotional cues, which seem to possibly prevail for longer durations.

Sleep deprivation and adverse health effects in United States Coast Guard responders to Hurricanes Katrina and Rita.

Science.gov (United States)

Bergan, Timothy; Thomas, Dana; Schwartz, Erica; McKibben, Jodi; Rusiecki, Jennifer

2015-12-01

Disaster responders are increasingly called upon to assist in various natural and manmade disasters. A critical safety concern for this population is sleep deprivation; however, there are limited published data regarding sleep deprivation and disaster responder safety. We expanded upon a cross-sectional study of 2695 United States Coast Guard personnel who responded to Hurricanes Katrina and Rita. Data were collected via survey on self-reported timing and location of deployment, missions performed, health effects, medical treatment sought, average nightly sleep, and other lifestyle variables. We created a 4-level sleep deprivation metric based on both average nightly reported sleep (d5hours; >5hours) and length of deployment (d2weeks; >2weeks) to examine the association between sustained sleep deprivation and illnesses, injuries, and symptoms using logistic regression to calculate odds ratios (ORs) and 95% confidence intervals. The strongest, statistically significant positive ORs for the highest sleep deprivation category compared with the least sleep-deprived category were for mental health and neurologic effects, specifically depression (OR=6.76), difficulty concentrating (OR=8.33), and confusion (OR=11.34), and for dehydration (OR=9.0). Injuries most strongly associated with sleep deprivation were twists, sprains, and strains (OR=6.20). Most health outcomes evaluated had monotonically increasing ORs with increasing sleep deprivation, and P tests for trend were statistically significant. Agencies deploying disaster responders should understand the risks incurred to their personnel by sustained sleep deprivation. Improved planning of response efforts to disasters can reduce the potential for sleep deprivation and lead to decreased morbidity in disaster responders. Published by Elsevier Inc.

Androgen receptor expression in human ovarian and uterine tissue of long term androgen-treated transsexual women

NARCIS (Netherlands)

D. Chadha; T.D. Pache; F.J. Huikeshoven (Frans); A.O. Brinkmann (Albert); Th.H. van der Kwast (Theo)

1994-01-01

textabstractAndrogen receptor (AR) modulation in human uteri and ovaries of long term androgen-treated transsexual female patients was investigated. Androgen receptor expression was evaluated immunohistochemically in the ovaries of 11 and the endometria and myometria of six androgen-treated

Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells.

Science.gov (United States)

Hsieh, Chen-Lin; Cai, Changmeng; Giwa, Ahmed; Bivins, Aaronica; Chen, Shao-Yong; Sabry, Dina; Govardhan, Kumara; Shemshedini, Lirim

2008-07-01

Cellular changes that affect the androgen receptor (AR) can cause prostate cancer to transition from androgen dependent to androgen independent, which is usually lethal. One common change in prostate tumors is overexpression of the AR, which has been shown to lead to androgen-independent growth of prostate cancer cells. This led us to hypothesize that expression of a hyperactive AR would be sufficient for androgen-independent growth of prostate cancer cells. To test this hypothesis, stable lune cancer prostate (LNCaP) cell lines were generated, which express a virion phosphoprotein (VP)16-AR hybrid protein that contains full-length AR fused to the strong viral transcriptional activation domain VP16. This fusion protein elicited as much as a 20-fold stronger transcriptional activity than the natural AR. Stable expression of VP16-AR in LNCaP cells yielded androgen-independent cell proliferation, while under the same growth conditions the parental LNCaP cells exhibited only androgen-dependent growth. These results show that expression of a hyperactive AR is sufficient for androgen-independent growth of prostate cancer cells. To study the molecular basis of this enhanced growth, we measured the expression of soluble guanylyl cyclase-alpha1 (sGCalpha1), a subunit of the sGC, an androgen-regulated gene that has been shown to be involved in prostate cancer cell growth. Interestingly, the expression of sGCalpha1 is androgen independent in VP16-AR-expressing cells, in contrast to its androgen-induced expression in control LNCaP cells. RNA(I)-dependent inhibition of sGCalpha1 expression resulted in significantly reduced proliferation of VP16-AR cells, implicating an important role for sGCalpha1 in the androgen-independent growth of these cells.

THE EFFECTS OF 30 HOURS SLEEP DEPRIVATION ON BASIC FOOTBALL SKILLS OF SOCCER PLAYERS

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Mehrdad Hefzollesan

2012-08-01

Full Text Available The aim of this study is to determine the effect of sleep deprivation on the passing and shooting skills of football players. To this end, 18 students of Sahand University, with age range 20 to 24 years performed basic soccer skills (shoot and pass in the pre-test and post test stages. In this study to assess these skills, the test "Mor - Christian" has been used. In the first step, subjects conducted the shoot and pass test as pre-test after 8 hours sleep a night. 10 days later, to ensure the validity of tests and test results on the learning effect, subjects did the same test again after 8 hours sleep a night. In the third stage, 30 hours of sleep deprivation as an independent variable imposed on the subjects and then the test was repeated and experimental test results were compared as recorded using paired t-test. The findings showed that 30 hour sleep deprivation decreases passing and shooting skills implementation skills (p <0.001. Therefore, the findings showed that sleep deprivation can be a devastating effect on basic football skills.

Effects of mental resilience on neuroendocrine hormones level changes induced by sleep deprivation in servicemen.

Science.gov (United States)

Sun, Xinyang; Dai, Xuyan; Yang, Tingshu; Song, Hongtao; Yang, Jialin; Bai, Jing; Zhang, Liyi

2014-12-01

The aim of this study was to investigate the effects of mental resilience on the changes of serum rennin, angiotensin, and cortisol level induced by sleep deprivation in servicemen. By random cluster sampling, a total of 160 servicemen, aged from 18 to 30, were selected to undergo 24-hour total sleep deprivation and administered the military personnel mental resilience scale after the deprivation procedure. The sleep deprivation procedure started at 8 a.m. on Day 8 and ended at 8 a.m. on Day 9 after 7 days of normal sleep for baseline preparation. Blood samples were drawn from the 160 participants at 8 a.m. respectively on Day 8 and Day 9 for hormonal measurements. All blood samples were analyzed using radioimmunoassay. As hypothesized, serum rennin, angiotensin II, and cortisol level of the participants after sleep deprivation were significantly higher than those before (P problem-solving skill and willpower were the leading influence factors for the increases of serum rennin and cortisol respectively induced by sleep deprivation. We conclude that mental resilience plays a significant role in alleviating the changes of neurohormones level induced by sleep deprivation in servicemen.

Gendered Peer Involvement in Girls with Congenital Adrenal Hyperplasia: Effects of Prenatal Androgens, Gendered Activities, and Gender Cognitions.

Science.gov (United States)

Berenbaum, Sheri A; Beltz, Adriene M; Bryk, Kristina; McHale, Susan

2018-05-01

A key question in understanding gender development concerns the origins of sex segregation. Children's tendencies to interact with same-sex others have been hypothesized to result from gender identity and cognitions, behavioral compatibility, and personal characteristics. We examined whether prenatal androgen exposure was related to time spent with boys and girls, and how that gendered peer involvement was related to sex-typed activities and gender identity and cognitions. We studied 54 girls with congenital adrenal hyperplasia (CAH) aged 10-13 years varying in degree of prenatal androgen exposure: 40 girls with classical CAH (C-CAH) exposed to high prenatal androgens and 14 girls with non-classical CAH (NC-CAH) exposed to low, female-typical, prenatal androgens. Home interviews and questionnaires provided assessments of gendered activity interests and participation, gender identity, and gender cognitions. Daily phone calls over 7 days assessed time spent in gendered activities and with peers. Girls with both C-CAH and NC-CAH interacted more with girls than with boys, with no significant group differences. The groups did not differ significantly in gender identity or gender cognitions, but girls with C-CAH spent more time in male-typed activities and less time in female-typed activities than did girls with NC-CAH. Time spent with girls reflected direct effects of gender identity/cognitions and gender-typed activities, and an indirect effect of prenatal androgens (CAH type) through gender-typed activities. Our results extend findings that prenatal androgens differentially affect gendered characteristics and that gendered peer interactions reflect combined effects of behavioral compatibility and feelings and cognitions about gender. The study also shows the value of natural experiments for testing hypotheses about gender development.

Further Evaluation of Androgen Therapy In Aplastic Anemia: With Special Reference to Correlation Between Response to Androgen and EEI

Energy Technology Data Exchange (ETDEWEB)

Whang, Kee Suk [Kyungpook National University School of Medicine, Deagu (Korea, Republic of)

1967-03-15

Patients with aplastic anemia were treated with a combination of depo-testosterone cyclopentylpropionate (Upjohn) and dexamethasone. In 7 of 15 patients treated, there was response in which either a significant increase in hemoglobin concentration, a prolonged interval or a cessation of blood transfusion requirement developed during androgen therapy. Younger patients with cellular marrow appeared to be better responding to androgen. EEI (Effective Erythropoietic Index) formulated by Gardner and Nathan (1966) which was a helpful measurement as to whether patients with myelofibrosis would response to androgen, was evaluated in patients with aplastic anemia. It was concluded that EEI as well as ferrokinetics indices (Plasma-{sup 59}Fe-disappearance rate, RBC {sup 59}Fe net incorporation) did not significantly correlate with the degree of response to androgen in aplastic anemia.

Effect of organochlorine pesticides on human androgen receptor activation in vitro

International Nuclear Information System (INIS)

Lemaire, Geraldine; Terouanne, Beatrice; Mauvais, Pascale; Michel, Serge; Rahmani, Roger

2004-01-01

Many persistent organochlorine pesticides (OCs) have been implicated in adverse effects, that is, reproductive and developmental effects, in man and in wildlife alike. It has been hypothesized that these so-called xeno-hormones could be responsible for the increased incidence in various male sexual differentiation disorders such as hypospadias, cryptorchidism, low sperm counts and quality. In this report, OCs, called endocrine disrupters, were tested for their interaction with the androgen receptor. The stable prostatic cell line PALM, which contains a human androgen receptor (hAR) expression vector and the reporter MMTV-luciferase, was used to characterize the response of hAR to OC and was compared with synthetic androgen compound R1881. We found that all the OC pesticides tested were able to shift the agonist [ 3 H]-R1881 from its binding site to the AR in competitive binding assays. In addition, these compounds antagonize - in a dose-dependent manner - the AR-mediated transcription by synthetic AR ligand R1881. None of the pesticides reacted as agonists. These results demonstrate that OC endocrine activities in vivo probably result from direct and specific binding to the AR ligand-binding domain. Although the antagonistic potential of OC pesticides is lower than that of hydroxyflutamide, they are capable of disrupting the male hormone signaling pathway. Because these chemicals are extremely persistent and tend to bioaccumulate, these results support the hypothesis that the recent increase in the incidence of male sexual disorders could be due to long exposure to ubiquitous OC pesticides found in the environment

Estrogens and Androgens in Skeletal Physiology and Pathophysiology.

Science.gov (United States)

Almeida, Maria; Laurent, Michaël R; Dubois, Vanessa; Claessens, Frank; O'Brien, Charles A; Bouillon, Roger; Vanderschueren, Dirk; Manolagas, Stavros C

2017-01-01

Estrogens and androgens influence the growth and maintenance of the mammalian skeleton and are responsible for its sexual dimorphism. Estrogen deficiency at menopause or loss of both estrogens and androgens in elderly men contribute to the development of osteoporosis, one of the most common and impactful metabolic diseases of old age. In the last 20 years, basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies have changed considerably the landscape of our understanding of bone biology as well as the relationship between sex steroids and the physiology and pathophysiology of bone metabolism. Together with the appreciation of the side effects of estrogen-related therapies on breast cancer and cardiovascular diseases, these advances have also drastically altered the treatment of osteoporosis. In this article, we provide a comprehensive review of the molecular and cellular mechanisms of action of estrogens and androgens on bone, their influences on skeletal homeostasis during growth and adulthood, the pathogenetic mechanisms of the adverse effects of their deficiency on the female and male skeleton, as well as the role of natural and synthetic estrogenic or androgenic compounds in the pharmacotherapy of osteoporosis. We highlight latest advances on the crosstalk between hormonal and mechanical signals, the relevance of the antioxidant properties of estrogens and androgens, the difference of their cellular targets in different bone envelopes, the role of estrogen deficiency in male osteoporosis, and the contribution of estrogen or androgen deficiency to the monomorphic effects of aging on skeletal involution. Copyright © 2017 the American Physiological Society.

HEALTH EFFECTS OF SLEEP DEPRIVATION ON NURSES WORKING SHIFTS.

Science.gov (United States)

Stanojevic, Cedomirka; Simic, Svetlana; Milutinovic, Dragana

2016-10-01

Atypical work schedules cause reduced sleep, leading to drowsiness, fatigue, decline of cognitive performance and health problems among the members of the nursing staff. The study was aimed at reviewing current knowledge and attitudes concerning the impact of sleep disorders on health and cognitive functions among the members of the nursing staff. Sleep and Interpersonal Relations in Modern Society. The modern 24-hour society involves more and more employees (health services, police departments, public transport) in non-standard forms of work. In European Union countries, over 50% of the nursing staff work night shifts, while in the United States of America 55% of nursing staff work more than 40 hours a week, and 30-70% of nurses sleep less than six hours before their shift. Cognitive Effects of Sleep Deprivation. Sleep deprivation impairs the performance of tasks that require intensive and prolonged attention which increases the number of errors in patients care, and nurses are subject to incre- ased risk of traffic accidents. Sleep Deprivation and Health Disorders. Sleep deprived members of the nursing staff are at risk of obesity, diabetes, gastrointestinal disorders and cardiovascular disease. The risk factors for breast cancer are increased by 1.79 times. and there is a significantly higher risk for colorectal carcinoma. Too long or repeated shifts reduce the opportunity for sleep, shorten recovery time in nurses, thus endangering their safety and health as well as the quality of care and patients' safety. Bearing in mind the significance of the problerm it is necessary to conduct the surveys of sleep quality and health of nurses in the Republic of Serbia as well in order to tackle this issue which is insufficiently recognized.

Effects of Extreme Sleep Deprivation on Human Performance

Energy Technology Data Exchange (ETDEWEB)

Tuan Tran; Kimberly R. Raddatz; Elizabeth T. Cady; Bradford Amstutz; Pete D. Elgin; Christopher Vowels; Gerald Deehan

2007-04-01

Sleep is a fundamental recuperative process for the nervous system. Disruption of this homeostatic drive can lead to severe impairments of the operator’s ability to perceive, recognize, and respond to emergencies and/or unanticipated events, putting the operator at risk. Therefore, establishing a comprehensive understanding of how sleep deprivation influences human performance is essential in order to counter fatigue or to develop mitigation strategies. The goal of the present study was to examine the psychological effects of prolonged sleep deprivation (approx. 75 hrs) over a four-day span on a general aviation pilot flying a fixed-based flight simulator. During the study, a series of tasks were employed every four hours in order to examine the pilot’s perceptual and higher level cognitive abilities. Overall, results suggest that the majority of cognitive and perceptual degradation occurs between 30-40 hours into the flight. Limitations and future research directions are also discussed.

Prostate specific antigen (PSA) kinetic as a prognostic factor in metastatic prostate cancer receiving androgen deprivation therapy: systematic review and meta-analysis.

Science.gov (United States)

Afriansyah, Andika; Hamid, Agus Rizal Ardy Hariandy; Mochtar, Chaidir Arif; Umbas, Rainy

2018-01-01

Aim: Metastatic prostate cancer (mPCa) has a poor outcome with median survival of two to five years. The use of androgen deprivation therapy (ADT) is a gold standard in management of this stage.  Aim of this study is to analyze the prognostic value of PSA kinetics of patient treated with hormonal therapy related to survival from several published studies Method: Systematic review and meta-analysis was performed using literature searching in the electronic databases of MEDLINE, Science Direct, and Cochrane Library. Inclusion criteria were mPCa receiving ADT, a study analyzing Progression Free Survival (PFS), Overall Survival (OS), or Cancer Specific Survival (CSS) and prognostic factor of survival related to PSA kinetics (initial PSA, PSA nadir, and time to achieve nadir (TTN)). The exclusion criteria were metastatic castration resistant of prostate cancer (mCRPC) and non-metastatic disease. Generic inverse variance method was used to combine hazard ratio (HR) within the studies. Meta-analysis was performed using Review Manager 5.2 and a p-value PSA and PFS. In addition, there was no association between initial PSA and CSS/ OS. We found association of reduced PFS (HR 2.22; 95% CI 1.82 to 2.70) and OS/ CSS (HR 3.31; 95% CI 2.01-5.43) of patient with high PSA nadir. Shorter TTN was correlated with poor result of survival either PFS (HR 2.41; 95% CI 1.19 - 4.86) or CSS/ OS (HR 1.80; 95%CI  1.42 - 2.30) Conclusion: Initial PSA before starting ADT do not associated with survival in mPCa.  There is association of PSA nadir and TTN with survival.

Dual conception of risk in the Iowa Gambling Task: Effects of sleep deprivation and test-retest gap

Directory of Open Access Journals (Sweden)

Varsha eSingh

2013-09-01

Full Text Available Risk in the Iowa Gambling Task (IGT is often understood in terms of intertemporal choices, i.e., preference for immediate outcomes in favor of delayed outcomes is considered risky. According to behavioral economics, decision makers refrain from choosing the short-sighted immediate gain because, over time (10 trials, the immediate gains result in a net loss. Instead decision makers are expected to maximize their gains by choosing options that, over time (10 trials, result in net gain. However, task choices are sometimes made on the basis of the frequency of reward and punishment such that infrequent punishments are favored over frequent punishments. The presence of these two attributes (intertemporality and frequency may correspond to the emotion-cognition dichotomy and reflect a dual conception of risk. Decision making on the basis of the two attributes was tested under two conditions: test-retest gap and sleep deprivation. An interaction between these two was expected to attenuate the difference between the two attributes (n=40 male. Analysis of the effects of IGT attribute type (intertemporal vs. frequency, sleep deprivation (sleep deprivation vs. no sleep deprivation, and test-retest gap (short vs. long showed a significant effect of IGT attribute type thus confirming the difference between the two attributes. Sleep deprivation had no effect on the attributes, but test-retest gap and the three-way interaction between attribute type, test-retest gap, and sleep deprivation were significant. Post-hoc tests showed sleep deprivation and short test-retest gap to attenuate the difference between the two attributes. As expected intertemporal decision making benefited from repeated task exposure. The findings add to understanding of the emotion-cognition dichotomy and show a time-dependent effect of a universally experienced constraint (sleep deprivation.

Effects of Partial and Acute Total Sleep Deprivation on Performance across Cognitive Domains, Individuals and Circadian Phase

Science.gov (United States)

Lo, June C.; Groeger, John A.; Santhi, Nayantara; Arbon, Emma L.; Lazar, Alpar S.; Hasan, Sibah; von Schantz, Malcolm; Archer, Simon N.; Dijk, Derk-Jan

2012-01-01

Background Cognitive performance deteriorates during extended wakefulness and circadian phase misalignment, and some individuals are more affected than others. Whether performance is affected similarly across cognitive domains, or whether cognitive processes involving Executive Functions are more sensitive to sleep and circadian misalignment than Alertness and Sustained Attention, is a matter of debate. Methodology/Principal Findings We conducted a 2 × 12-day laboratory protocol to characterize the interaction of repeated partial and acute total sleep deprivation and circadian phase on performance across seven cognitive domains in 36 individuals (18 males; mean ± SD of age = 27.6±4.0 years). The sample was stratified for the rs57875989 polymorphism in PER3, which confers cognitive susceptibility to total sleep deprivation. We observed a deterioration of performance during both repeated partial and acute total sleep deprivation. Furthermore, prior partial sleep deprivation led to poorer cognitive performance in a subsequent total sleep deprivation period, but its effect was modulated by circadian phase such that it was virtually absent in the evening wake maintenance zone, and most prominent during early morning hours. A significant effect of PER3 genotype was observed for Subjective Alertness during partial sleep deprivation and on n-back tasks with a high executive load when assessed in the morning hours during total sleep deprivation after partial sleep loss. Overall, however, Subjective Alertness and Sustained Attention were more affected by both partial and total sleep deprivation than other cognitive domains and tasks including n-back tasks of Working Memory, even when implemented with a high executive load. Conclusions/Significance Sleep loss has a primary effect on Sleepiness and Sustained Attention with much smaller effects on challenging Working Memory tasks. These findings have implications for understanding how sleep debt and circadian rhythmicity

External Beam Radiation Therapy or Brachytherapy With or Without Short-course Neoadjuvant Androgen Deprivation Therapy: Results of a Multicenter, Prospective Study of Quality of Life

Energy Technology Data Exchange (ETDEWEB)

Gay, Hiram A., E-mail: hiramgay@wustl.edu [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Sanda, Martin G. [Department of Urology, Emory University School of Medicine, Atlanta, Georgia (United States); Liu, Jingxia; Wu, Ningying [Division of Public Health Sciences, Washington University School of Medicine, St. Louis, Missouri (United States); Hamstra, Daniel A. [Texas Center for Proton Therapy, Irving, Texas (United States); Wei, John T.; Dunn, Rodney L. [Department of Urology, University of Michigan, Ann Arbor, Michigan (United States); Klein, Eric A. [Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio (United States); Sandler, Howard M. [Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, California (United States); Saigal, Christopher S. [Department of Urology, University of California at Los Angeles, Los Angeles, California (United States); Litwin, Mark S. [Department of Urology, University of California at Los Angeles, Los Angeles, California (United States); Health Policy and Management, University of California at Los Angeles, Los Angeles, California (United States); Kuban, Deborah A. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Hembroff, Larry [Institute for Public Policy and Social Research, Michigan State University, East Lansing, Michigan (United States); Regan, Meredith M. [Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (United States); Chang, Peter [Department of Surgery, Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (United States); Michalski, Jeff M. [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Regan, Meredith; Hembroff, Larry; Wei, John T.; Hamstra, Dan; and others

2017-06-01

Purpose: The long-term effects of neoadjuvant androgen deprivation therapy (NADT) with radiation therapy on participant-reported health-related quality of life (HRQOL) have not been characterized in prospective multicenter studies. We evaluated HRQOL for 2 years among participants undergoing radiation therapy (RT) with or without NADT for newly diagnosed, early-stage prostate cancer. Methods and Materials: We analyzed longitudinal cohort data from the Prostate Cancer Outcomes and Satisfaction with Treatment Quality Assessment Consortium to ascertain the HRQOL trajectory of men receiving NADT with external beam RT (EBRT) or brachytherapy. HRQOL was measured using the expanded prostate cancer index composite 26-item questionnaire at 2, 6, 12, and 24 months after the initiation of NADT. We used the χ{sup 2} or Fisher exact test to compare the shift in percentages between groups that did or did not receive NADT. Analyses were conducted at the 2-sided 5% significance level. Results: For subjects receiving EBRT, questions regarding the ability to have an erection, ability to reach an orgasm, quality of erections, frequency of erections, ability to function sexually, and lack of energy were in a significantly worse dichotomized category for the patients receiving NADT. Comparing the baseline versus 24-month outcomes, 24%, 23%, and 30% of participants receiving EBRT plus NADT shifted to the worse dichotomized category for the ability to reach an orgasm, quality of erections, and ability to function sexually compared with 14%, 13%, and 16% in the EBRT group, respectively. Conclusions: Compared with baseline, at 2 years, participants receiving NADT plus EBRT compared with EBRT alone had worse HRQOL, as measured by the ability to reach orgasm, quality of erections, and ability to function sexually. However, no difference was found in the ability to have an erection, frequency of erections, overall sexual function, hot flashes, breast tenderness/enlargement, depression

External Beam Radiation Therapy or Brachytherapy With or Without Short-course Neoadjuvant Androgen Deprivation Therapy: Results of a Multicenter, Prospective Study of Quality of Life

International Nuclear Information System (INIS)

Gay, Hiram A.; Sanda, Martin G.; Liu, Jingxia; Wu, Ningying; Hamstra, Daniel A.; Wei, John T.; Dunn, Rodney L.; Klein, Eric A.; Sandler, Howard M.; Saigal, Christopher S.; Litwin, Mark S.; Kuban, Deborah A.; Hembroff, Larry; Regan, Meredith M.; Chang, Peter; Michalski, Jeff M.; Regan, Meredith; Hembroff, Larry; Wei, John T.; Hamstra, Dan

2017-01-01

Purpose: The long-term effects of neoadjuvant androgen deprivation therapy (NADT) with radiation therapy on participant-reported health-related quality of life (HRQOL) have not been characterized in prospective multicenter studies. We evaluated HRQOL for 2 years among participants undergoing radiation therapy (RT) with or without NADT for newly diagnosed, early-stage prostate cancer. Methods and Materials: We analyzed longitudinal cohort data from the Prostate Cancer Outcomes and Satisfaction with Treatment Quality Assessment Consortium to ascertain the HRQOL trajectory of men receiving NADT with external beam RT (EBRT) or brachytherapy. HRQOL was measured using the expanded prostate cancer index composite 26-item questionnaire at 2, 6, 12, and 24 months after the initiation of NADT. We used the χ"2 or Fisher exact test to compare the shift in percentages between groups that did or did not receive NADT. Analyses were conducted at the 2-sided 5% significance level. Results: For subjects receiving EBRT, questions regarding the ability to have an erection, ability to reach an orgasm, quality of erections, frequency of erections, ability to function sexually, and lack of energy were in a significantly worse dichotomized category for the patients receiving NADT. Comparing the baseline versus 24-month outcomes, 24%, 23%, and 30% of participants receiving EBRT plus NADT shifted to the worse dichotomized category for the ability to reach an orgasm, quality of erections, and ability to function sexually compared with 14%, 13%, and 16% in the EBRT group, respectively. Conclusions: Compared with baseline, at 2 years, participants receiving NADT plus EBRT compared with EBRT alone had worse HRQOL, as measured by the ability to reach orgasm, quality of erections, and ability to function sexually. However, no difference was found in the ability to have an erection, frequency of erections, overall sexual function, hot flashes, breast tenderness/enlargement, depression, lack of

Health-risk behaviour in deprived neighbourhoods compared with non-deprived neighbourhoods

DEFF Research Database (Denmark)

Algren, Maria Holst; Bak, Carsten Kronborg; Berg-Beckhoff, Gabriele

2015-01-01

in deprived neighbourhoods compared with those who live in non-deprived neighbourhoods and to summarise what kind of operationalisations of neighbourhood deprivation that were used in the studies. METHODS: PRISMA guidelines for systematic reviews were followed. Systematic searches were performed in Pub......Med, Embase, Web of Science and Sociological Abstracts using relevant search terms, Boolean operators, and truncation, and reference lists were scanned. Quantitative observational studies that examined health-risk behaviour in deprived neighbourhoods compared with non-deprived neighbourhoods were eligible...... for inclusion. RESULTS: The inclusion criteria were met by 22 studies. The available literature showed a positive association between smoking and physical inactivity and living in deprived neighbourhoods compared with non-deprived neighbourhoods. In regard to low fruit and vegetable consumption and alcohol...

Effects of acute caffeine withdrawal on Short Category Test performance in sleep-deprived individuals.

Science.gov (United States)

Killgore, William D S; Kahn-Greene, Ellen T; Killgore, Desiree B; Kamimori, Gary H; Balkin, Thomas J

2007-12-01

Caffeine is a popular stimulant often used to counter the effects of sleep loss and fatigue. Withdrawal from caffeine may produce mild declines in simple cognitive capacities such as attention and concentration, but it is unclear whether more complex cognitive functions, such as abstract reasoning or concept formation, may be similarly affected. To assess the effect of acute caffeine withdrawal on executive functioning during sleep deprivation, 26 healthy volunteers were administered in double-blind form either repeated doses of caffeine or placebo over two nights of continuous wakefulness. The 108-item Short Category Test was administered after 56 hr. of total sleep deprivation (9 hr. post-caffeine administration). The caffeine group scored significantly more poorly, making approximately 57% more errors on the test than the placebo group. These findings suggest that acute caffeine withdrawal during prolonged sleep deprivation has an adverse effect on abstract reasoning and concept formation.

The effect of sleep deprivation on BOLD activity elicited by a divided attention task.

Science.gov (United States)

Jackson, Melinda L; Hughes, Matthew E; Croft, Rodney J; Howard, Mark E; Crewther, David; Kennedy, Gerard A; Owens, Katherine; Pierce, Rob J; O'Donoghue, Fergal J; Johnston, Patrick

2011-06-01

Sleep loss, widespread in today's society and associated with a number of clinical conditions, has a detrimental effect on a variety of cognitive domains including attention. This study examined the sequelae of sleep deprivation upon BOLD fMRI activation during divided attention. Twelve healthy males completed two randomized sessions; one after 27 h of sleep deprivation and one after a normal night of sleep. During each session, BOLD fMRI was measured while subjects completed a cross-modal divided attention task (visual and auditory). After normal sleep, increased BOLD activation was observed bilaterally in the superior frontal gyrus and the inferior parietal lobe during divided attention performance. Subjects reported feeling significantly more sleepy in the sleep deprivation session, and there was a trend towards poorer divided attention task performance. Sleep deprivation led to a down regulation of activation in the left superior frontal gyrus, possibly reflecting an attenuation of top-down control mechanisms on the attentional system. These findings have implications for understanding the neural correlates of divided attention and the neurofunctional changes that occur in individuals who are sleep deprived.

Long-term effects of neighbourhood deprivation on diabetes risk: quasi-experimental evidence from a refugee dispersal policy in Sweden.

Science.gov (United States)

White, Justin S; Hamad, Rita; Li, Xinjun; Basu, Sanjay; Ohlsson, Henrik; Sundquist, Jan; Sundquist, Kristina

2016-06-01

Although studies have shown associations between neighbourhood quality and chronic disease outcomes, such associations are potentially confounded by the selection of different types of people into different neighbourhood environments. We sought to identify the causal effects of neighbourhood deprivation on type 2 diabetes risk, by comparing refugees in Sweden who were actively dispersed by government policy to low-deprivation, moderate-deprivation, or high-deprivation neighbourhoods. In this quasi-experimental study, we analysed national register data for refugees who arrived in Sweden aged 25-50 years, at a time when the government policy involved quasi-random dispersal of refugees to neighbourhoods with different levels of poverty and unemployment, schooling, and social welfare participation. Individuals in our sample were assigned to a neighbourhood categorised as high deprivation (≥1 SD above the mean), moderate deprivation (within 1 SD of the mean), or low deprivation (≥1 SD below the mean). The primary outcome was new diagnosis of type 2 diabetes between Jan 1, 2002, and Dec 31, 2010. We used multivariate logistic and linear regressions to assess the effects of neighbourhood deprivation on diabetes risk, controlling for potential confounders affecting neighbourhood assignment and assessing effects of cumulative exposure to different neighbourhood conditions. We included data for 61 386 refugees who arrived in Sweden during 1987-91 and who were assigned to one of 4833 neighbourhoods. Being assigned to an area deemed high deprivation versus low deprivation was associated with an increased risk of diabetes (odds ratio [OR] 1·22, 95% CI 1·07-1·38; p=0·001). In analyses that included fixed effects for assigned municipality, the increased diabetes risk was estimated to be 0·85 percentage points (95% CI -0·030 to 1·728; p=0·058). Neighbourhood effects grew over time such that 5 years of additional exposure to high-deprivation versus low-deprivation

Anabolic androgenic steroids reverse the beneficial effect of exercise on tendon biomechanics: an experimental study.

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Tsitsilonis, Serafim; Chatzistergos, Panayiotis E; Panayiotis, Chatzistergos E; Mitousoudis, Athanasios S; Athanasios, Mitousoudis S; Kourkoulis, Stavros K; Stavros, Kourkoulis K; Vlachos, Ioannis S; Ioannis, Vlachos S; Agrogiannis, George; George, Agrogiannis; Fasseas, Konstantinos; Konstantinos, Fasseas; Perrea, Despina N; Despina, Perrea N; Zoubos, Aristides B; Aristides, Zoubos B

2014-06-01

The effect of anabolic androgenic steroids on tendons has not yet been fully elucidated. Aim of the present study was the evaluation of the impact of anabolic androgenic steroids on the biomechanical and histological characteristics of Achilles tendons. Twenty-four male Wistar rats were randomized into four groups with exercise and anabolic steroids (nandrolone decanoate) serving as variables. Protocol duration was 12 weeks. Following euthanasia, tendons' biomechanical properties were tested with the use of a modified clamping configuration. Histological examination with light and electron microscopy were also performed. In the group of anabolic steroids and exercise the lowest fracture stress values were observed, while in the exercise group the highest ones. Histological examination by light and electron microscopy revealed areas of collagen dysplasia and an increased epitendon in the groups receiving anabolic steroids and exercise. These findings suggest that anabolic androgenic steroids reverse the beneficial effect of exercise, thus resulting in inferior maximal stress values. Copyright © 2013 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.

Effects of experimental sleep deprivation on anxiety-like behavior in animal research: Systematic review and meta-analysis.

Science.gov (United States)

Pires, Gabriel Natan; Bezerra, Andréia Gomes; Tufik, Sergio; Andersen, Monica Levy

2016-09-01

Increased acute anxiety is a commonly reported behavioral consequence of sleep deprivation in humans. However, rodent studies conducted so far produced inconsistent results, failing to reproduce the same sleep deprivation induced-anxiety observed in clinical experiments. While some presented anxiogenesis as result of sleep deprivation, others reported anxiolysis. In face of such inconsistencies, this article explores the effects of experimental sleep deprivation on anxiety-like behavior in animal research through a systematic review and a series of meta-analyses. A total of 50 of articles met our inclusion criteria, 30 on mice, 19 on rats and one on Zebrafish. Our review shows that sleep deprivation induces a decrease in anxiety-like behavior in preclinical models, which is opposite to results observed in human settings. These results were corroborated in stratified analyses according to species, sleep deprivation method and anxiety measurement technique. In conclusion, the use of animal models for the evaluation of the relationship between sleep deprivation lacks translational applicability and new experimental tools are needed to properly evaluate sleep deprivation-induced anxiogenesis in rodents. Copyright © 2016 Elsevier Ltd. All rights reserved.

Is Androgen Deprivation Therapy Necessary in All Intermediate-Risk Prostate Cancer Patients Treated in the Dose Escalation Era?

International Nuclear Information System (INIS)

Castle, Katherine O.; Hoffman, Karen E.; Levy, Lawrence B.; Lee, Andrew K.; Choi, Seungtaek; Nguyen, Quynh N.; Frank, Steven J.; Pugh, Thomas J.; McGuire, Sean E.; Kuban, Deborah A.

2013-01-01

Purpose: The benefit of adding androgen deprivation therapy (ADT) to dose-escalated radiation therapy (RT) for men with intermediate-risk prostate cancer is unclear; therefore, we assessed the impact of adding ADT to dose-escalated RT on freedom from failure (FFF). Methods: Three groups of men treated with intensity modulated RT or 3-dimensional conformal RT (75.6-78 Gy) from 1993-2008 for prostate cancer were categorized as (1) 326 intermediate-risk patients treated with RT alone, (2) 218 intermediate-risk patients treated with RT and ≤6 months of ADT, and (3) 274 low-risk patients treated with definitive RT. Median follow-up was 58 months. Recursive partitioning analysis based on FFF using Gleason score (GS), T stage, and pretreatment PSA concentration was applied to the intermediate-risk patients treated with RT alone. The Kaplan-Meier method was used to estimate 5-year FFF. Results: Based on recursive partitioning analysis, intermediate-risk patients treated with RT alone were divided into 3 prognostic groups: (1) 188 favorable patients: GS 6, ≤T2b or GS 3+4, ≤T1c; (2) 71 marginal patients: GS 3+4, T2a-b; and (3) 68 unfavorable patients: GS 4+3 or T2c disease. Hazard ratios (HR) for recurrence in each group were 1.0, 2.1, and 4.6, respectively. When intermediate-risk patients treated with RT alone were compared to intermediate-risk patients treated with RT and ADT, the greatest benefit from ADT was seen for the unfavorable intermediate-risk patients (FFF, 74% vs 94%, respectively; P=.005). Favorable intermediate-risk patients had no significant benefit from the addition of ADT to RT (FFF, 94% vs 95%, respectively; P=.85), and FFF for favorable intermediate-risk patients treated with RT alone approached that of low-risk patients treated with RT alone (98%). Conclusions: Patients with favorable intermediate-risk prostate cancer did not benefit from the addition of ADT to dose-escalated RT, and their FFF was nearly as good as patients with low-risk disease

Coping with the effects of deprivation : Development and upbringing of Romanian adoptees in the Netherlands

NARCIS (Netherlands)

Rijk, C.H.A.M.

2008-01-01

This thesis describes the effects of early life deprivation on Romanian adopted children in the Netherlands. These children have been exposed to (severe) deprivation in the period they have spend in Romanian children’s homes or hospitals. For a group of 72 families, who had adopted 80 Romanian

The effects of age, sleep deprivation, and altitude on complex performance.

Science.gov (United States)

1985-05-01

Little research has been concerned with the combined effects on performance of age, sleep deprivation, and altitude. This study examined their potential interaction with laboratory tasks measuring aviation-related psychological functions. : Healthy m...

Treatment of gynecomastia in patients with prostate cancer and androgen deprivation.

Science.gov (United States)

Bautista-Vidal, C; Barnoiu, O; García-Galisteo, E; Gómez-Lechuga, P; Baena-González, V

2014-01-01

Gynecomastia, defined as benign proliferation of glandular breast tissue has a prevalence of 32% to 72% in the male. In the urology setting, it is associated to patients with prostate cancer and hormone treatment with a prevalence of 15% in the case of complete hormone blockage and 75% in monotherapy. The different options of treatment in prostate cancer have changed in recent decades. Thus, we have focused on this subject to evaluate the different therapy options of hormone manipulation induced gynecomastia in prostate cancer patients. To synthesize the available evidence on the different therapeutic options in prostate cancer patients who develop gynecomastia due to the use of nonsteroidal antiandrogens and to generate a diagnostic algorithm and treatment. Using the PICO type structured search strategy (Patient or problem, Intervention, Comparison, Outcome or result) in the data bases of PubMed-Medline and Cochrane, identification was made of the relevant studies related to the treatment of gynecomastia in Prostate Cancer patients treated with nonsteroidal antiandrogens. We have found 3 possible therapeutic options for the treatment of gynecomastia and mastodynia in patients with hormone deprivation therapy for prostate cancer. The 10Gy radiotherapy would be an option for the treatment of gynecomastia, although not all the patients need prophylactic treatment since only 50% report moderate-severe discomfort. Another option is the use of drugs such as tamoxifen 20mg/day that lead to a significant decrease in the mammary effects. Gynecomastia and mastodynia, given their high incidence, make the physical examination a fundamental tool for all patients before initiating treatment with antiandrogens. The use of tamoxifen 20mg/day is the best treatment and prevention option against gynecomastia and mastodynia, while in the case of long-course established gynecomastia, surgery is the gold standard. Copyright © 2012 AEU. Published by Elsevier Espana. All rights reserved.

Differential effects of genistein on prostate cancer cells depend on mutational status of the androgen receptor.

Directory of Open Access Journals (Sweden)

Abeer M Mahmoud

Full Text Available Blocking the androgen receptor (AR activity is the main goal of therapies for advanced prostate cancer (PCa. However, relapse with a more aggressive, hormone refractory PCa arises, which harbors restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 µmol/L stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy.

Sleep deprivation impairs cAMP signalling in the hippocampus

NARCIS (Netherlands)

Vecsey, Christopher G; Baillie, George S; Jaganath, Devan; Havekes, Robbert; Daniels, Andrew; Wimmer, Mathieu; Huang, Ted; Brown, Kim M; Li, Xiang-Yao; Descalzi, Giannina; Kim, Susan S; Chen, Tao; Shang, Yu-Ze; Zhuo, Min; Houslay, Miles D; Abel, Ted

2009-01-01

Millions of people regularly obtain insufficient sleep. Given the effect of sleep deprivation on our lives, understanding the cellular and molecular pathways affected by sleep deprivation is clearly of social and clinical importance. One of the major effects of sleep deprivation on the brain is to

Sleep deprivation affects reactivity to positive but not negative stimuli.

Science.gov (United States)

Pilcher, June J; Callan, Christina; Posey, J Laura

2015-12-01

The current study examined the effects of partial and total sleep deprivation on emotional reactivity. Twenty-eight partially sleep-deprived participants and 31 totally sleep-deprived participants rated their valence and arousal responses to positive and negative pictures across four testing sessions during the day following partial sleep deprivation or during the night under total sleep deprivation. The results suggest that valence and arousal ratings decreased under both sleep deprivation conditions. In addition, partial and total sleep deprivation had a greater negative effect on positive events than negative events. These results suggest that sleep-deprived persons are more likely to respond less to positive events than negative events. One explanation for the current findings is that negative events could elicit more attentive behavior and thus stable responding under sleep deprivation conditions. As such, sleep deprivation could impact reactivity to emotional stimuli through automated attentional and self-regulatory processes. Copyright © 2015 Elsevier Inc. All rights reserved.

Sleep deprivation suppresses aggression in Drosophila

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Kayser, Matthew S; Mainwaring, Benjamin; Yue, Zhifeng; Sehgal, Amita

2015-01-01

Sleep disturbances negatively impact numerous functions and have been linked to aggression and violence. However, a clear effect of sleep deprivation on aggressive behaviors remains unclear. We find that acute sleep deprivation profoundly suppresses aggressive behaviors in the fruit fly, while other social behaviors are unaffected. This suppression is recovered following post-deprivation sleep rebound, and occurs regardless of the approach to achieve sleep loss. Genetic and pharmacologic approaches suggest octopamine signaling transmits changes in aggression upon sleep deprivation, and reduced aggression places sleep-deprived flies at a competitive disadvantage for obtaining a reproductive partner. These findings demonstrate an interaction between two phylogenetically conserved behaviors, and suggest that previous sleep experiences strongly modulate aggression with consequences for reproductive fitness. DOI: http://dx.doi.org/10.7554/eLife.07643.001 PMID:26216041

Effects of selective REM sleep deprivation on prefrontal gamma activity and executive functions.

Science.gov (United States)

Corsi-Cabrera, M; Rosales-Lagarde, A; del Río-Portilla, Y; Sifuentes-Ortega, R; Alcántara-Quintero, B

2015-05-01

Given that the dorsolateral prefrontal cortex is involved in executive functions and is deactivated and decoupled from posterior associative regions during REM sleep, that Gamma temporal coupling involved in information processing is enhanced during REM sleep, and that adult humans spend about 90 min of every 24h in REM sleep, it might be expected that REM sleep deprivation would modify Gamma temporal coupling and have a deteriorating effect on executive functions. We analyzed EEG Gamma activity and temporal coupling during implementation of a rule-guided task before and after REM sleep deprivation and its effect on verbal fluency, flexible thinking and selective attention. After two nights in the laboratory for adaptation, on the third night subjects (n=18) were randomly assigned to either selective REM sleep deprivation effectuated by awakening them at each REM sleep onset or, the same number of NREM sleep awakenings as a control for unspecific effects of sleep interruptions. Implementation of abstract rules to guide behavior required greater activation and synchronization of Gamma activity in the frontopolar regions after REM sleep reduction from 20.6% at baseline to just 3.93% of total sleep time. However, contrary to our hypothesis, both groups showed an overall improvement in executive task performance and no effect on their capacity to sustain selective attention. These results suggest that after one night of selective REM sleep deprivation executive functions can be compensated by increasing frontal activation and they still require the participation of supervisory control by frontopolar regions. Copyright © 2015 Elsevier B.V. All rights reserved.

Effect of essential amino acids on enteroids: Methionine deprivation suppresses proliferation and affects differentiation in enteroid stem cells

International Nuclear Information System (INIS)

Saito, Yuki; Iwatsuki, Ken; Hanyu, Hikaru; Maruyama, Natsuki; Aihara, Eitaro; Tadaishi, Miki; Shimizu, Makoto; Kobayashi-Hattori, Kazuo

2017-01-01

We investigated the effects of essential amino acids on intestinal stem cell proliferation and differentiation using murine small intestinal organoids (enteroids) from the jejunum. By selectively removing individual essential amino acids from culture medium, we found that 24 h of methionine (Met) deprivation markedly suppressed cell proliferation in enteroids. This effect was rescued when enteroids cultured in Met deprivation media for 12 h were transferred to complete medium, suggesting that Met plays an important role in enteroid cell proliferation. In addition, mRNA levels of the stem cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) decreased in enteroids grown in Met deprivation conditions. Consistent with this observation, Met deprivation also attenuated Lgr5-EGFP fluorescence intensity in enteroids. In contrast, Met deprivation enhanced mRNA levels of the enteroendocrine cell marker chromogranin A (ChgA) and markers of K cells, enterochromaffin cells, goblet cells, and Paneth cells. Immunofluorescence experiments demonstrated that Met deprivation led to an increase in the number of ChgA-positive cells. These results suggest that Met deprivation suppresses stem cell proliferation, thereby promoting differentiation. In conclusion, Met is an important nutrient in the maintenance of intestinal stem cells and Met deprivation potentially affects cell differentiation. - Highlights: • Met influences the proliferation of enteroids. • Met plays a crucial role in the maintenance of stem cells. • Met deprivation potentially promotes differentiation into secretory cells.

State dependent valuation: the effect of deprivation on risk preferences.

Directory of Open Access Journals (Sweden)

Dino J Levy

Full Text Available The internal state of an organism affects its choices. Previous studies in various non-human animals have demonstrated a complex, and in some cases non-monotonic, interaction between internal state and risk preferences. Our aim was to examine the systematic effects of deprivation on human decision-making across various reward types. Using both a non-parametric approach and a classical economic analysis, we asked whether the risk attitudes of human subjects towards money, food and water rewards would change as a function of their internal metabolic state. Our findings replicate some previous work suggesting that, on average, humans become more risk tolerant in their monetary decisions, as they get hungry. However, our specific approach allowed us to make two novel observations about the complex interaction between internal state and risk preferences. First, we found that the change in risk attitude induced by food deprivation is a general phenomenon, affecting attitudes towards both monetary and consumable rewards. But much more importantly, our data indicate that rather than each subject becoming more risk tolerant as previously hypothesized based on averaging across subjects, we found that as a population of human subjects becomes food deprived the heterogeneity of their risk attitudes collapses towards a fixed point. Thus subjects who show high-risk aversion while satiated shift towards moderate risk aversion when deprived but subjects who are risk tolerant become more risk averse. These findings demonstrate a more complicated interaction between internal state and risk preferences and raise some interesting implications for both day-to-day decisions and financial market structures.

State dependent valuation: the effect of deprivation on risk preferences.

Science.gov (United States)

Levy, Dino J; Thavikulwat, Amalie C; Glimcher, Paul W

2013-01-01

The internal state of an organism affects its choices. Previous studies in various non-human animals have demonstrated a complex, and in some cases non-monotonic, interaction between internal state and risk preferences. Our aim was to examine the systematic effects of deprivation on human decision-making across various reward types. Using both a non-parametric approach and a classical economic analysis, we asked whether the risk attitudes of human subjects towards money, food and water rewards would change as a function of their internal metabolic state. Our findings replicate some previous work suggesting that, on average, humans become more risk tolerant in their monetary decisions, as they get hungry. However, our specific approach allowed us to make two novel observations about the complex interaction between internal state and risk preferences. First, we found that the change in risk attitude induced by food deprivation is a general phenomenon, affecting attitudes towards both monetary and consumable rewards. But much more importantly, our data indicate that rather than each subject becoming more risk tolerant as previously hypothesized based on averaging across subjects, we found that as a population of human subjects becomes food deprived the heterogeneity of their risk attitudes collapses towards a fixed point. Thus subjects who show high-risk aversion while satiated shift towards moderate risk aversion when deprived but subjects who are risk tolerant become more risk averse. These findings demonstrate a more complicated interaction between internal state and risk preferences and raise some interesting implications for both day-to-day decisions and financial market structures.

Evolution of the androgen-induced male phenotype.

Science.gov (United States)

Fuxjager, Matthew J; Miles, Meredith C; Schlinger, Barney A

2018-01-01

The masculine reproductive phenotype varies significantly across vertebrates. As a result, biologists have long recognized that many of the mechanisms that support these phenotypes-particularly the androgenic system-is evolutionarily labile, and thus susceptible to the effects of selection for different traits. However, exactly how androgenic signaling systems vary in a way which results in dramatically different functional outputs, remain largely unclear. We explore this topic here by outlining four key-but non-mutually exclusive-hypotheses that propose how the mechanisms of androgenic signaling might change over time to potentiate the emergence of phenotypical variation in masculine behavior and physiology. We anchor this framework in a review of our own studies of a tropical bird called the golden-collared manakin (Manacus vitellinus), which has evolved an exaggerated acrobatic courtship display that is heavily androgen-dependent. The result is an example of how the cellular basis of androgenic action can be modified to support a unique reproductive repertoire. We end this review by highlighting a broad pathway forward to further pursue the intricate ways by which the mechanisms of hormone action evolve to support processes of adaptation and animal design.

Augmented Reality as a Countermeasure for Sleep Deprivation.

Science.gov (United States)

Baumeister, James; Dorrlan, Jillian; Banks, Siobhan; Chatburn, Alex; Smith, Ross T; Carskadon, Mary A; Lushington, Kurt; Thomas, Bruce H

2016-04-01

Sleep deprivation is known to have serious deleterious effects on executive functioning and job performance. Augmented reality has an ability to place pertinent information at the fore, guiding visual focus and reducing instructional complexity. This paper presents a study to explore how spatial augmented reality instructions impact procedural task performance on sleep deprived users. The user study was conducted to examine performance on a procedural task at six time points over the course of a night of total sleep deprivation. Tasks were provided either by spatial augmented reality-based projections or on an adjacent monitor. The results indicate that participant errors significantly increased with the monitor condition when sleep deprived. The augmented reality condition exhibited a positive influence with participant errors and completion time having no significant increase when sleep deprived. The results of our study show that spatial augmented reality is an effective sleep deprivation countermeasure under laboratory conditions.

Lack of benefit for the addition of androgen deprivation therapy to dose-escalated radiotherapy in the treatment of intermediate- and high-risk prostate cancer.

LENUS (Irish Health Repository)

Krauss, Daniel

2012-02-01

PURPOSE: Assessment of androgen deprivation therapy (ADT) benefits for prostate cancer treated with dose-escalated radiotherapy (RT). METHODS AND MATERIALS: From 1991 to 2004, 1,044 patients with intermediate- (n = 782) or high-risk (n = 262) prostate cancer were treated with dose-escalated RT at William Beaumont Hospital. Patients received external-beam RT (EBRT) alone, brachytherapy (high or low dose rate), or high dose rate brachytherapy plus pelvic EBRT. Intermediate-risk patients had Gleason score 7, prostate-specific antigen (PSA) 10.0-19.9 ng\\/mL, or Stage T2b-T2c. High-risk patients had Gleason score 8-10, PSA >\\/=20, or Stage T3. Patients were additionally divided specifically by Gleason score, presence of palpable disease, and PSA level to further define subgroups benefitting from ADT. RESULTS: Median follow-up was 5 years; 420 patients received ADT + dose-escalated RT, and 624 received dose-escalated RT alone. For all patients, no advantages in any clinical endpoints at 8 years were associated with ADT administration. No differences in any endpoints were associated with ADT administration based on intermediate- vs. high-risk group or RT modality when analyzed separately. Patients with palpable disease plus Gleason >\\/=8 demonstrated improved clinical failure rates and a trend toward improved survival with ADT. Intermediate-risk patients treated with brachytherapy alone had improved biochemical control when ADT was given. CONCLUSION: Benefits of ADT in the setting of dose-escalated RT remain poorly defined. This question must continue to be addressed in prospective study.

Androgens and polycystic ovary syndrome.

Science.gov (United States)

Nisenblat, Vicki; Norman, Robert J

2009-06-01

Polycystic ovary syndrome (PCOS) is a common complex endocrine genetic disorder, which involves overproduction of androgens, leading to heterogeneous range of symptoms and associated with increased metabolic and cardiovascular morbidity. This review focuses on androgen biosynthesis, use, metabolism in PCOS and clinical consequences of hyperandrogenism. Controversial definition of the disorder and different phenotypic subgroups present a challenge for clinical and basic research. Further investigation of different phenotypes highlights the fact that PCOS probably represents a group of disorders with different etiologies. Prenatal androgen exposure and adolescent studies suggest early in life androgen excess as initiating factor of PCOS, but insufficient evidence available to confirm this hypothesis. Various intracellular signaling pathways implicated in PCOS steroidogenesis and in androgen action have been studied, however, PCOS pathogenesis remains obscure. Growing evidence links androgens with pathophysiology of PCOS and metabolic derangements. Despite intensive investigation, etiology and underlying mechanisms of PCOS remain unclear, warranting further investigation. Better understanding of molecular and genetic basis might lead to invention of novel therapeutic approaches. Long-term interventional studies that lower androgen levels in women with hyperandrogenism might protect against metabolic and cardiovascular comorbidities are needed.

Androgen Ablation Augments Prostate Cancer Vaccine Immunogenicity Only When Applied After Immunization

Science.gov (United States)

Koh, Yi T.; Gray, Andrew; Higgins, Sean A.; Hubby, Bolyn; Kast, W. Martin

2009-01-01

Background Androgen ablation (AA) causes apoptosis of normal and neoplastic prostate cells. It is a standard treatment for advanced prostate cancer. Androgen ablation-mediated immunological effects include bone marrow hyperplasia, thymic regeneration, T and B cell lymphopoeisis and restoration of age-related peripheral T cell dysfunction. Androgens also regulate the transcription of several cytokines. Dendritic cells (DC) are the most potent antigen presenting cells that can activate antigen-specific naïve T cells. Despite myriad clinical trials involving DC-based prostate cancer immunotherapies, the effects of AA on DC function remain largely uncharacterized. Therefore, we investigated the effects of AA on DC and whether it could improve the efficacy of prostate cancer immunotherapy. Methods Cytokine expression changes due to AA were quantified by multiplex ELISA. Flow cytometry was used to assess AA-mediated effects on DC maturation and expression of costimulatory markers. Mixed leukocyte reactions and cell-mediated lysis assays elucidated the role of androgens in DC function. The effect of AA on the efficacy of vaccination against a prostate tumor-associated antigen was tested using Elispot assays. Results Androgen ablation increased dendritic cell maturation and costimulatory marker expression, but had no effect on DC costimulatory function. However, DC isolated from castrated mice increased the expression of key cytokines by antigen-experienced T cells while decreasing their expression in naïve cells. Finally, androgen ablation improved immune responses to vaccination only when applied after immunization. Conclusion Androgen ablation causes differential effects of DC on primary and secondary T cell responses, thus augmenting vaccine immunogenicity only when applied after immunization. PMID:19143030

Combined Effect of food deprivation and serotonin injection on plasma prolactin and glucose levels in irradiated rats

International Nuclear Information System (INIS)

Girgis, R.B.; Abdel-Fattah, K.I.; Khamis, F.I.; Abu Zaid, N.M.

2004-01-01

The present study aims to investigate the role of serotonin (5-HT) on the homeostasis of plasma prolactin and glucose in rats induced by gamma irradiation and food deprivation. Animals were divided into seven groups; control, irradiated at a dose level of 6 Gy, injected with 500 mg/kg b.wt. 5-HT intra-peritoneally, injected with 5-HT before irradiation food deprived for 48 hrs then irradiated, food deprived then injected with 5-HT, and food deprived then injected with 5-HT before whole body irradiation. Samples were collected at 1,3, 7 and 14 days post irradiation. The results showed that gamma irradiation firstly elevated prolactin (PRL) levels in plasma (1 and 3 days) then the levels decreased after 7 and 14 days as compared to control values. Rats received serotonin before irradiation exhibited an increased level of PRL after 14 days post irradiation compared to control value, while the level decreased after 1, 3, 7 days post irradiation. Food deprivation for 48 hrs altered the effect of serotonin and /or irradiation on PRL levels in plasma. Rats injected with serotonin showed a decreased level of plasma prolactin in food deprived rats, 3 days post injection. The obtained results showed that serotonin causes variable effects on plasma prolactin compared to control values. Glucose plasma levels were increased in both irradiated and serotonin injected rats before irradiation, and also in serotonin injected rats as compared to control values. Irradiation of rats after 48 hrs food deprivation induced an increase in plasma glucose levels measured throughout the different experimental periods. Injection of serotonin to rats after 48 hrs food deprivation before irradiation increased plasma glucose levels after 1, 3, 7 and 14 days compared to control value. Also, injection of serotonin to 48 hrs food deprived rats increased glucose levels during all examined days of experiment.It could be concluded that serotonin may have a variable mechanism controlling prolactin

Biochemical failure and the temporal kinetics of prostate-specific antigen after radiation therapy with androgen deprivation

International Nuclear Information System (INIS)

Buyyounouski, Mark K.; Hanlon, Alexandra L.; Horwitz, Eric M.; Uzzo, Robert G.; Pollack, Alan

2005-01-01

Purpose: The accuracy of the American Society of Therapeutic Radiation Oncology consensus definition of biochemical failure (BF) after radiation therapy (RT) and androgen deprivation (AD) has been questioned, because posttreatment prostate-specific antigen (PSA) levels typically rise after release from AD, and misclassification of BF may be made. The temporal kinetics of posttreatment PSA levels was examined to define the error in the classification of BF. Methods and Materials: Between December 1, 1991 and April 30, 1998, 688 men with T1c-T3 NX/0 M0 prostate cancer received three-dimensional conformal RT alone (n = 586) or in combination with either short-term (STAD: 3 to 12 months, n = 82) or long-term (LTAD: 12 to 36 months, n = 20) AD. Follow-up, calculated from the end of all treatment, was ≥48 months. The mean posttreatment PSA was calculated in 3-month intervals. Results: The median posttreatment clinical follow-up period was 76 months (range, 48-152 months). The posttreatment PSA values from the end of all treatment for the RT+STAD-BF group showed an initial period of rise followed by a period of decline at 30 months and then a continued rise again. The decline in the mean posttreatment PSA is explained in part by stabilization in PSA level after 3 consecutive rises. Nonbiochemical failures (NBF) after RT+STAD had a relatively constant mean PSA over time of approximately 0.5 ng/mL. Unlike the RT+STAD-NBF profile, the RT+LTAD-NBF profile rose continuously and steadily to a level approaching 1 ng/mL. The RT+LTAD-BF profile rose continuously but at a slower rate over time. Nine RT+STAD-NBF patients (22%) and 2 RT+LTAD-BF (29%) patients experienced 3 consecutive rises followed by a subsequent decline and stabilization of PSA compared to 10 RT-BF patients (5%). Redistributing these misclassified patients to their respective NBF groups changed the mean posttreatment PSA profiles as follows: The RT+LTAD-BF profile rose constantly and steadily with a doubling

Differential effects of total and partial sleep deprivation on salivary factors in Wistar rats.

Science.gov (United States)

Lasisi, Dr T J; Shittu, S T; Meludu, C C; Salami, A A

2017-01-01

Aim of this study was to investigate the effects of sleep deprivation on salivary factors in rats. Animals were randomly assigned into three groups of 6 animals each as control, total sleep deprivation (TSD) and partial sleep deprivation (PSD) groups. The multiple platform method was used to induce partial and total sleep deprivation for 7days. On the 8th day, stimulated saliva samples were collected for the analysis of salivary lag time, flow rate, salivary amylase activity, immunoglobulin A secretion rate and corticosterone levels using ELISA and standard kinetic enzyme assay. Data were analyzed using ANOVA with Dunnett T3 post hoc tests. Salivary flow rate reduced significantly in the TSD group compared with the PSD group as well as the control group (p=0.01). The secretion rate of salivary IgA was significantly reduced in the TSD group compared with the control group (p=0.04). Salivary amylase activity was significantly elevated in the TSD group compared with the PSD group as well as control group (psalivary lag time and levels of corticosterone among the groups. These findings suggest that total sleep deprivation is associated with reduced salivary flow rate and secretion rate of IgA as well as elevated levels of salivary amylase activity in rats. However, sleep recovery of four hours in the PSD group produced ameliorative effects on the impaired functions of salivary glands. Copyright © 2016 Elsevier Ltd. All rights reserved.

Upfront Androgen Deprivation Therapy With Salvage Radiation May Improve Biochemical Outcomes in Prostate Cancer Patients With Post-Prostatectomy Rising PSA

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Jang, Joanne W. [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Hwang, Wei-Ting [Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Guzzo, Thomas J.; Wein, Alan J. [Department of Urology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Haas, Naomi B. [Department of Medical Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Both, Stefan [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States); Vapiwala, Neha, E-mail: vapiwala@uphs.upenn.edu [Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA (United States)

2012-08-01

Purpose: The addition of androgen deprivation therapy (ADT) to definitive external beam radiation therapy (RT) improves outcomes in higher-risk prostate cancer patients. However, the benefit of ADT with salvage RT in post-prostatectomy patients is not clearly established. Our study compares biochemical outcomes in post-prostatectomy patients who received salvage RT with or without concurrent ADT. Methods and Materials: Of nearly 2,000 post-prostatectomy patients, we reviewed the medical records of 191 patients who received salvage RT at University of Pennsylvania between 1987 and 2007. Follow-up data were obtained by chart review and electronic polling of the institutional laboratory database and Social Security Death Index. Biochemical failure after salvage RT was defined as a prostate-specific antigen of 2.0 ng/mL above the post-RT nadir or the initiation of ADT after completion of salvage RT. Results: One hundred twenty-nine patients received salvage RT alone, and 62 patients received combined ADT and salvage RT. Median follow-up was 5.4 years. Patients who received combined ADT and salvage RT were younger, had higher pathologic Gleason scores, and higher rates of seminal vesicle invasion, lymph node involvement, and pelvic nodal irradiation compared with patients who received salvage RT alone. Patients who received combined therapy had improved biochemical progression-free survival (bPFS) compared with patients who received RT alone (p = 0.048). For patients with pathologic Gleason scores {<=}7, combined RT and ADT resulted in significantly improved bPFS compared to RT alone (p = 0.013). Conclusions: These results suggest that initiating ADT during salvage RT in the post-prostatectomy setting may improve bPFS compared with salvage RT alone. However, prospective randomized data are necessary to definitively determine whether hormonal manipulation should be used with salvage RT. Furthermore, the optimal nature and duration of ADT and the patient subgroups in

Regulation of expression of Na+,K+-ATPase in androgen-dependent and androgen-independent prostate cancer

NARCIS (Netherlands)

L.J. Blok (Leen); G.T.G. Chang; M. Steenbeek-Slotboom (M.); W.M. van Weerden (Wytske); H.G. Swarts; J.J.H.H.M. de Pont (J. J H H M); G.J. van Steenbrugge (Gert Jan); A.O. Brinkmann (Albert)

1999-01-01

textabstractThe β1-subunit of Na+,K+-ATPase was isolated and identified as an androgen down-regulated gene. Expression was observed at high levels in androgen-independent as compared to androgen-dependent (responsive) human prostate cancer cell lines and xenografts when grown in the presence of

Cervical Length and Androgens in Pregnant Women With Polycystic Ovary Syndrome: Has Metformin Any Effect?

Science.gov (United States)

Shetelig Løvvik, Tone; Stridsklev, Solhild; Carlsen, Sven M; Salvesen, Øyvind; Vanky, Eszter

2016-06-01

Women with polycystic ovary syndrome (PCOS) have increased risk of preterm delivery. Shortening of the cervix is a sign of preterm delivery. This study aimed to investigate potential effect of metformin on cervical length and whether androgen levels correlate with cervical length in PCOS pregnancies. This was a sub-study of a randomized, placebo-controlled, multicenter study (The PregMet study) performed at 11 secondary or tertiary centers from 2005 to 2009. Two-hundred sixty-one pregnancies of 245 women with PCOS, age 18-42 years participated. Participants were randomly assigned to metformin or placebo from first trimester to delivery. We compared cervical length and androgen levels in metformin and placebo groups at gestational weeks 19 and 32. We also explored whether cervical length correlated with androgen levels. We found no difference in cervical length between the metformin and the placebo groups at gestational week 19 and 32. Dehydroepiandrosterone (DHEAS) tended to be higher in the metformin group. There were no correlations between androgens and cervical length at week 19. At gestational week 32, androstenedione (P = .02) and DHEAS (P = .03) showed a trend toward negative correlation to cervical length. High androstenedione level correlated with shortening of cervical length from week 19 to 32 when adjusted for confounders (P = .003). T (P = .03), DHEAS (P = .02), and free testosterone index (P = .03) showed a similar trend. Metformin in pregnancy did not affect cervical length in women with PCOS. High maternal androgen levels correlated with cervical shortening from the second to the third trimester of pregnancy, as a sign of cervical ripening.

Androgen receptor expression in human ovarian and uterine tissue of long term androgen-treated transsexual women

OpenAIRE

Chadha, D.; Pache, T.D.; Huikeshoven, Frans; Brinkmann, Albert; Kwast, Theo

1994-01-01

textabstractAndrogen receptor (AR) modulation in human uteri and ovaries of long term androgen-treated transsexual female patients was investigated. Androgen receptor expression was evaluated immunohistochemically in the ovaries of 11 and the endometria and myometria of six androgen-treated transsexual female patients. This was compared with AR expression in the ovaries and uteri of premenopausal and postmenopausal women not receiving treatment and in 10 ovaries of female patients with polycy...

Opposite effects of sleep deprivation on the continuous reaction times in patients with liver cirrhosis and normal persons.

Science.gov (United States)

Lauridsen, Mette Munk; Frøjk, Jesper; de Muckadell, Ove B Schaffalitzky; Vilstrup, Hendrik

2014-09-01

The continuous reaction times (CRT) method describes arousal functions. Reaction time instability in a patient with liver disease indicates covert hepatic encephalopathy (cHE). The effects of sleep deprivation are unknown although cirrhosis patients frequently suffer from sleep disorders. The aim of this study was to determine if sleep deprivation influences the CRT test. Eighteen cirrhosis patients and 27 healthy persons were tested when rested and after one night's sleep deprivation. The patients filled out validated sleep quality questionnaires. Seven patients (38%) had unstable reaction times (a CRTindex sleep that was not related to their CRT tests before or after the sleep deprivation. In the healthy participants, the sleep deprivation slowed their reaction times by 11% (p sleep deprivation normalized or improved the reaction time stability of the patients with a CRTindex below 1.9 and had no effect in the patients with a CRTindex above 1.9. There was no relation between reported sleep quality and reaction time results. Thus, in cirrhosis patients, sleep disturbances do not lead to 'falsely' slowed and unstable reaction times. In contrast, the acute sleep deprivation slowed and destabilized the reaction times of the healthy participants. This may have negative consequences for decision-making.

Predicting Psychotic-Like Experiences during Sensory Deprivation

Science.gov (United States)

Daniel, Christina; Mason, Oliver J.

2015-01-01

Aims. This study aimed to establish the contribution of hallucination proneness, anxiety, suggestibility, and fantasy proneness to psychotic-like experiences (PLEs) reported during brief sensory deprivation. Method. Twenty-four high and 22 low hallucination-prone participants reported on PLEs occurring during brief sensory deprivation and at baseline. State/trait anxiety, suggestibility, and fantasy proneness were also measured. Results. Both groups experienced a significant increase in PLEs in sensory deprivation. The high hallucination prone group reported more PLEs both at baseline and in sensory deprivation. They also scored significantly higher on measures of state/trait anxiety, suggestibility, and fantasy proneness, though these did not explain the effects of group or condition. Regression analysis found hallucination proneness to be the best predictor of the increase in PLEs, with state anxiety also being a significant predictor. Fantasy proneness and suggestibility were not significant predictors. Conclusion. This study suggests the increase in PLEs reported during sensory deprivation reflects a genuine aberration in perceptual experience, as opposed to increased tendency to make false reports due to suggestibility of fantasy proneness. The study provides further support for the use of sensory deprivation as a safe and effective nonpharmacological model of psychosis. PMID:25811027

Predicting Psychotic-Like Experiences during Sensory Deprivation

Directory of Open Access Journals (Sweden)

Christina Daniel

2015-01-01

Full Text Available Aims. This study aimed to establish the contribution of hallucination proneness, anxiety, suggestibility, and fantasy proneness to psychotic-like experiences (PLEs reported during brief sensory deprivation. Method. Twenty-four high and 22 low hallucination-prone participants reported on PLEs occurring during brief sensory deprivation and at baseline. State/trait anxiety, suggestibility, and fantasy proneness were also measured. Results. Both groups experienced a significant increase in PLEs in sensory deprivation. The high hallucination prone group reported more PLEs both at baseline and in sensory deprivation. They also scored significantly higher on measures of state/trait anxiety, suggestibility, and fantasy proneness, though these did not explain the effects of group or condition. Regression analysis found hallucination proneness to be the best predictor of the increase in PLEs, with state anxiety also being a significant predictor. Fantasy proneness and suggestibility were not significant predictors. Conclusion. This study suggests the increase in PLEs reported during sensory deprivation reflects a genuine aberration in perceptual experience, as opposed to increased tendency to make false reports due to suggestibility of fantasy proneness. The study provides further support for the use of sensory deprivation as a safe and effective nonpharmacological model of psychosis.

Anabolic Androgenic Steroid Use in Teens: Prevalence, Demographics, and Perception of Effects

Science.gov (United States)

Lorang, Melissa; Callahan, Bryan; Cummins, Kevin M.; Achar, Suraj; Brown, Sandra A.

2011-01-01

Multiple risks are associated with early use of anabolic androgenic steroids, yet public understanding is limited and teen use not uncommon. The present study surveyed 4,231 high school students to understand prevalence of use, association with athletics and other substance use and expectations of drug effects. While overall rates of steroid use…

Androgens and Hypertension in Men and Women: a Unifying View.

Science.gov (United States)

Moretti, Costanzo; Lanzolla, Giulia; Moretti, Marta; Gnessi, Lucio; Carmina, Enrico

2017-05-01

This review was designed to revaluate the androgen role on the mechanisms of hypertension and cardiovascular risks in both men and women. Sex steroids are involved in the regulation of blood pressure, but pathophysiological mechanism is not well understood. Androgens have an important effect on metabolism, adipose and endothelial cell function, and cardiovascular risk in both men and women. A focal point in this contest is represented by the possible gender-specific regulation of different tissues and in particular of the adipose cell. Available data confirm that androgen deficiency is linked to increased prevalence of hypertension and cardiovascular diseases. Adipocyte dysfunction seems to be the main involved mechanism. Androgen replacement reduces inflammation state in man, protecting by metabolic syndrome progression. In women, androgen excess has been considered as promoting factor of cardiovascular risk. However, recent data suggest that excessive androgen production has little effect per se in inducing hypertension in young women of reproductive age. Also in postmenopausal women, data on relative androgen excess and hypertension are missing, while adrenal androgen deficiency has been associated to increased mortality. Molecular mechanisms linking androgen dysregulation to hypertension are almost Unknown, but they seem to be related to increased visceral fat, promoting a chronic inflammatory state through different mechanisms. One of these may involve the recruitment and over-activation of NF-kB, a ubiquitous transcription factor also expressed in adipose cells, where it may cause the production of cytokines and other immune factors. The NF-kB signalling pathway may also influence brown adipogenesis leading to the preferential enlargement of visceral adipocytes. Chronic inflammation and adipocyte dysfunction may alter endothelial function leading to hypertension. Both in men and in women, particularly in the post-menopausal period, hypoandrogenism seems to be

Effects of androgenic-anabolic steroids in athletes.

Science.gov (United States)

Hartgens, Fred; Kuipers, Harm

2004-01-01

Androgenic-anabolic steroids (AAS) are synthetic derivatives of the male hormone testosterone. They can exert strong effects on the human body that may be beneficial for athletic performance. A review of the literature revealed that most laboratory studies did not investigate the actual doses of AAS currently abused in the field. Therefore, those studies may not reflect the actual (adverse) effects of steroids. The available scientific literature describes that short-term administration of these drugs by athletes can increase strength and bodyweight. Strength gains of about 5-20% of the initial strength and increments of 2-5 kg bodyweight, that may be attributed to an increase of the lean body mass, have been observed. A reduction of fat mass does not seem to occur. Although AAS administration may affect erythropoiesis and blood haemoglobin concentrations, no effect on endurance performance was observed. Little data about the effects of AAS on metabolic responses during exercise training and recovery are available and, therefore, do not allow firm conclusions. The main untoward effects of short- and long-term AAS abuse that male athletes most often self-report are an increase in sexual drive, the occurrence of acne vulgaris, increased body hair and increment of aggressive behaviour. AAS administration will disturb the regular endogenous production of testosterone and gonadotrophins that may persist for months after drug withdrawal. Cardiovascular risk factors may undergo deleterious alterations, including elevation of blood pressure and depression of serum high-density lipoprotein (HDL)-, HDL2- and HDL3-cholesterol levels. In echocardiographic studies in male athletes, AAS did not seem to affect cardiac structure and function, although in animal studies these drugs have been observed to exert hazardous effects on heart structure and function. In studies of athletes, AAS were not found to damage the liver. Psyche and behaviour seem to be strongly affected by AAS

The Impact of Sleep Deprivation on the Brain

Science.gov (United States)

Trošt Bobić, Tatjana; Šečić, Ana; Zavoreo, Iris; Matijević, Valentina; Filipović, Branimir; Kolak, Željka; Bašić Kes, Vanja; Ciliga, Dubravka; Sajković, Dubravka

2016-09-01

Each sleep phase is characterized by specific chemical, cellular and anatomic events of vital importance for normal neural functioning. Different forms of sleep deprivation may lead to a decline of cognitive functions in individuals. Studies in this field make a distinction between total sleep deprivation, chronic sleep restriction, and the situation of sleep disruption. Investigations covering the acute effects of sleep deprivation on the brain show that the discovered behavioral deficits in most cases regenerate after two nights of complete sleep. However, some studies done on mice emphasize the possible chronic effects of long-term sleep deprivation or chronic restriction on the occurrence of neurodegenerative diseases such as Alzheimer’s disease and dementia. In order to better understand the acute and chronic effects of sleep loss, the mechanisms of neural adaptation in the situations of insufficient sleep need to be further investigated. Future integrative research on the impact of sleep deprivation on neural functioning measured through the macro level of cognitive functions and the micro molecular and cell level could contribute to more accurate conclusions about the basic cellular mechanisms responsible for the detected behavioral deficits occurring due to sleep deprivation.

Effects of Xenoestrogen and Androgen Mixtures on Ovarian Transcriptome of the Fathead Minnow

Science.gov (United States)

Endocrine disrupting chemicals (EDCs), such as the estrogens ethinylestradiol (EE2) and bisphenol A (BPA), and androgens like 17â-trenbolone (TRB) can occur as mixtures in aquatic environments. To date, however, most studies with EDCs in fish have focused on their effects as indi...

Lifestyle intervention program in deprived obese adult patients and their non-deprived counterparts.

Directory of Open Access Journals (Sweden)

Celine Loddo

Full Text Available Although it is known that the prevalence of obesity is high in deprived patients, the link between deprivation and obesity, and the impact of deprivation on compliance and efficacy of a lifestyle intervention program are not known.Deprivation was assessed in 40 patients (23 Females, mean±SD age: 49±17 years from the diabetology department and 140 patients (101 Females, age: 50±15 years from the nutrition department of Bordeaux University hospital. Eighty-seven patients suffering from obesity were evaluated before and after a tailored, multidisciplinary lifestyle intervention. Deprivation was assessed using EPICES scores. Deprivation was defined with an EPICES score > 30.Deprived patients suffering from obesity had significantly higher current (43.8 ±8.4 versus 40.9 ± 5.5 kg/m2, p = 0,02 and maximal BMI (46.1± 8.6 versus 42.3± 5.2 kg/m2, p = 0.002 compared to non-deprived obese. Percentage of body weight loss was not different according to deprivation (4.74 ± 0.75 versus 4.65 ± 1.04%, p = 0.9. EPICES scores were not different according to adherence to lifestyle intervention program (20.5 ± 8.5 versus 29.9 ± 3.9 versus 29.0 ±2.5, no follow up versus partial follow up versus total follow up, p = 0,58.Deprived patients suffering from obesity have a more serious disease than non-deprived patients. However, neither compliance to the lifestyle intervention program nor body weight loss differed between deprived patients with obesity and non-deprived ones. Deprivation should not be a limitation when enrolling patients with obesity in lifestyle intervention programs.

Lifestyle intervention program in deprived obese adult patients and their non-deprived counterparts.

Science.gov (United States)

Loddo, Celine; Pupier, Emilie; Amour, Rémy; Monsaingeon-Henry, Maud; Mohammedi, Kamel; Gatta-Cherifi, Blandine

2017-01-01

Although it is known that the prevalence of obesity is high in deprived patients, the link between deprivation and obesity, and the impact of deprivation on compliance and efficacy of a lifestyle intervention program are not known. Deprivation was assessed in 40 patients (23 Females, mean±SD age: 49±17 years) from the diabetology department and 140 patients (101 Females, age: 50±15 years) from the nutrition department of Bordeaux University hospital. Eighty-seven patients suffering from obesity were evaluated before and after a tailored, multidisciplinary lifestyle intervention. Deprivation was assessed using EPICES scores. Deprivation was defined with an EPICES score > 30. Deprived patients suffering from obesity had significantly higher current (43.8 ±8.4 versus 40.9 ± 5.5 kg/m2, p = 0,02) and maximal BMI (46.1± 8.6 versus 42.3± 5.2 kg/m2, p = 0.002) compared to non-deprived obese. Percentage of body weight loss was not different according to deprivation (4.74 ± 0.75 versus 4.65 ± 1.04%, p = 0.9). EPICES scores were not different according to adherence to lifestyle intervention program (20.5 ± 8.5 versus 29.9 ± 3.9 versus 29.0 ±2.5, no follow up versus partial follow up versus total follow up, p = 0,58). Deprived patients suffering from obesity have a more serious disease than non-deprived patients. However, neither compliance to the lifestyle intervention program nor body weight loss differed between deprived patients with obesity and non-deprived ones. Deprivation should not be a limitation when enrolling patients with obesity in lifestyle intervention programs.

The prognostic value of expression of HIF1α, EGFR and VEGF-A, in localized prostate cancer for intermediate- and high-risk patients treated with radiation therapy with or without androgen deprivation therapy

Directory of Open Access Journals (Sweden)

Weber Damien C

2012-04-01

Full Text Available Abstract Purpose Androgens stimulate the production of hypoxia-inducible factor (HIF1α and ultimately vascular endothelial growth factor (VEGF-A. Additionally, epithelial growth factor (EGF mediates HIF1α production. Carbonic anhydrase IX (CAIX expression is associated with tumor cell hypoxia in a variety of malignancies. This study assesses the prognostic relation between HIF1α, VEGF-A, EGF Receptor and CAIX expression by immunochemistry in diagnostic samples of patients with intermediate- and high-risk localized prostate cancer treated with radiation therapy, with or without androgen deprivation therapy (ADT. Materials and methods Between 1994 and 2004, 103 prostate cancer patients (mean age, 68.7 ± 6.2, with prostate cancer (mean PSA, 13.3 ± 3.7, were treated with radiation therapy (RT, median dose, 74 Gy. Fifty seven (55.3% patients received ADT (median duration, 6 months; range, 0 – 24. Median follow-up was 97.6 months (range, 5.9 – 206.8. Results Higher EGFR expression was significantly (p = 0.04 correlated with higher Gleason scores. On univariate analysis, HIF1α nuclear expression was a significant (p = 0.02 prognostic factor for biological progression-free survival (bPFS. A trend towards significance (p = 0.05 was observed with EGFR expression and bPFS. On multivariate analysis, low HIF1α nuclear (p = 0.01 and high EGFR (p = 0.04 expression remained significant adverse prognostic factors. Conclusions Our study suggests that high nuclear expression of HIF1α and low EGFR expression in diagnostic biopsies of prostate cancer patients treated with RT ± ADT is associated with a good prognosis.

Gender differences in sleep deprivation effects on risk and inequality aversion: evidence from an economic experiment.

Science.gov (United States)

Ferrara, Michele; Bottasso, Anna; Tempesta, Daniela; Carrieri, Marika; De Gennaro, Luigi; Ponti, Giovanni

2015-01-01

Excessive working hours--even at night--are becoming increasingly common in our modern 24/7 society. The prefrontal cortex (PFC) is particularly vulnerable to the effects of sleep loss and, consequently, the specific behaviors subserved by the functional integrity of the PFC, such as risk-taking and pro-social behavior, may be affected significantly. This paper seeks to assess the effects of one night of sleep deprivation on subjects' risk and social preferences, which are probably the most explored behavioral domains in the tradition of Experimental Economics. This novel cross-over study employs thirty-two university students (gender-balanced) participating to 2 counterbalanced laboratory sessions in which they perform standard risk and social preference elicitation protocols. One session was after one night of undisturbed sleep at home, and the other was after one night of sleep deprivation in the laboratory. Sleep deprivation causes increased sleepiness and decreased alertness in all subjects. After sleep loss males make riskier decisions compared to the rested condition, while females do the opposite. Females likewise show decreased inequity aversion after sleep deprivation. As for the relationship between cognitive ability and economic decisions, sleep deprived individuals with higher cognitive reflection show lower risk aversion and more altruistic behavior. These results show that one night of sleep deprivation alters economic behavior in a gender-sensitive way. Females' reaction to sleep deprivation, characterized by reduced risky choices and increased egoism compared to males, may be related to intrinsic psychological gender differences, such as in the way men and women weigh up probabilities in their decision-making, and/or to the different neurofunctional substrate of their decision-making.

Gender Differences in Sleep Deprivation Effects on Risk and Inequality Aversion: Evidence from an Economic Experiment

Science.gov (United States)

Ferrara, Michele; Bottasso, Anna; Tempesta, Daniela; Carrieri, Marika; De Gennaro, Luigi; Ponti, Giovanni

2015-01-01

Excessive working hours—even at night—are becoming increasingly common in our modern 24/7 society. The prefrontal cortex (PFC) is particularly vulnerable to the effects of sleep loss and, consequently, the specific behaviors subserved by the functional integrity of the PFC, such as risk-taking and pro-social behavior, may be affected significantly. This paper seeks to assess the effects of one night of sleep deprivation on subjects’ risk and social preferences, which are probably the most explored behavioral domains in the tradition of Experimental Economics. This novel cross-over study employs thirty-two university students (gender-balanced) participating to 2 counterbalanced laboratory sessions in which they perform standard risk and social preference elicitation protocols. One session was after one night of undisturbed sleep at home, and the other was after one night of sleep deprivation in the laboratory. Sleep deprivation causes increased sleepiness and decreased alertness in all subjects. After sleep loss males make riskier decisions compared to the rested condition, while females do the opposite. Females likewise show decreased inequity aversion after sleep deprivation. As for the relationship between cognitive ability and economic decisions, sleep deprived individuals with higher cognitive reflection show lower risk aversion and more altruistic behavior. These results show that one night of sleep deprivation alters economic behavior in a gender-sensitive way. Females’ reaction to sleep deprivation, characterized by reduced risky choices and increased egoism compared to males, may be related to intrinsic psychological gender differences, such as in the way men and women weigh up probabilities in their decision-making, and/or to the different neurofunctional substrate of their decision-making. PMID:25793869

Gender differences in sleep deprivation effects on risk and inequality aversion: evidence from an economic experiment.

Directory of Open Access Journals (Sweden)

Michele Ferrara

Full Text Available Excessive working hours--even at night--are becoming increasingly common in our modern 24/7 society. The prefrontal cortex (PFC is particularly vulnerable to the effects of sleep loss and, consequently, the specific behaviors subserved by the functional integrity of the PFC, such as risk-taking and pro-social behavior, may be affected significantly. This paper seeks to assess the effects of one night of sleep deprivation on subjects' risk and social preferences, which are probably the most explored behavioral domains in the tradition of Experimental Economics. This novel cross-over study employs thirty-two university students (gender-balanced participating to 2 counterbalanced laboratory sessions in which they perform standard risk and social preference elicitation protocols. One session was after one night of undisturbed sleep at home, and the other was after one night of sleep deprivation in the laboratory. Sleep deprivation causes increased sleepiness and decreased alertness in all subjects. After sleep loss males make riskier decisions compared to the rested condition, while females do the opposite. Females likewise show decreased inequity aversion after sleep deprivation. As for the relationship between cognitive ability and economic decisions, sleep deprived individuals with higher cognitive reflection show lower risk aversion and more altruistic behavior. These results show that one night of sleep deprivation alters economic behavior in a gender-sensitive way. Females' reaction to sleep deprivation, characterized by reduced risky choices and increased egoism compared to males, may be related to intrinsic psychological gender differences, such as in the way men and women weigh up probabilities in their decision-making, and/or to the different neurofunctional substrate of their decision-making.

Effects of Sleep Deprivation on Hypoglycemia-Induced Cognitive Impairment and Recovery in Adults With Type 1 Diabetes.

Science.gov (United States)

Inkster, Berit E; Zammitt, Nicola N; Ritchie, Stuart J; Deary, Ian J; Morrison, Ian; Frier, Brian M

2016-05-01

To ascertain whether hypoglycemia in association with sleep deprivation causes greater cognitive dysfunction than hypoglycemia alone and protracts cognitive recovery after normoglycemia is restored. Fourteen adults with type 1 diabetes underwent a hyperinsulinemic, hypoglycemic clamp on two separate occasions. Before one glucose clamp, the participants stayed awake overnight to induce sleep deprivation. Participants were randomized and counterbalanced to the experimental condition. Cognitive function tests were performed before and during hypoglycemia and for 90 min after restoration of normoglycemia. Cognitive impairment during hypoglycemia did not differ significantly between the sleep-deprived and non-sleep-deprived conditions. However, in the sleep-deprived state, digit symbol substitution scores and choice reaction times were significantly poorer during recovery (P sleep deprivation, such as tiredness, were removed. Hypoglycemia per se produced a significant decrement in cognitive function; coexisting sleep deprivation did not have an additive effect. However, after restoration of normoglycemia, preceding sleep deprivation was associated with persistence of hypoglycemic symptoms and greater and more prolonged cognitive dysfunction during the recovery period. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Androgen Receptor Signaling in Bladder Cancer

OpenAIRE

Li, Peng; Chen, Jinbo; Miyamoto, Hiroshi

2017-01-01

Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific differences in bladder cancer. This review summarizes and discusses the available data, suggesting the involvement of androgens and/or the androgen receptor pathways in u...

Dual conception of risk in the Iowa Gambling Task: effects of sleep deprivation and test-retest gap.

Science.gov (United States)

Singh, Varsha

2013-01-01

Risk in the Iowa Gambling Task (IGT) is often understood in terms of intertemporal choices, i.e., preference for immediate outcomes in favor of delayed outcomes is considered risky decision making. According to behavioral economics, healthy decision makers are expected to refrain from choosing the short-sighted immediate gain because, over time (10 trials of the IGT), the immediate gains result in a long term loss (net loss). Instead decision makers are expected to maximize their gains by choosing options that, over time (10 trials), result in delayed or long term gains (net gain). However, task choices are sometimes made on the basis of the frequency of reward and punishment such that frequent rewards/infrequent punishments are favored over infrequent rewards/frequent punishments. The presence of these two attributes (intertemporality and frequency of reward) in IGT decision making may correspond to the emotion-cognition dichotomy and reflect a dual conception of risk. Decision making on the basis of the two attributes was tested under two conditions: delay in retest and sleep deprivation. An interaction between sleep deprivation and time delay was expected to attenuate the difference between the two attributes. Participants were 40 male university students. Analysis of the effects of IGT attribute type (intertemporal vs. frequency of reinforcement), sleep deprivation (sleep deprivation vs. no sleep deprivation), and test-retest gap (short vs. long delay) showed a significant within-subjects effect of IGT attribute type thus confirming the difference between the two attributes. Sleep deprivation had no effect on the attributes, but test-retest gap and the three-way interaction between attribute type, test-retest gap, and sleep deprivation were significantly different. Post-hoc tests revealed that sleep deprivation and short test-retest gap attenuated the difference between the two attributes. Furthermore, the results showed an expected trend of increase in

Unique Approaches to Androgen Effects on Prostate Cancer

National Research Council Canada - National Science Library

Rosner, W; Kahn, S. M

2007-01-01

Sex hormone-binding globulin (SHBG) is a plasma protein that binds andrngens and it acts as a transducer of androgen signaling at the plasma membrane of prostate cancer cells The human prostate cancer cell line LNCaP in addition...

Effects of sucrose concentration and water deprivation on Pavlovian conditioning and responding for conditioned reinforcement.

Science.gov (United States)

Tabbara, Rayane I; Maddux, Jean-Marie N; Beharry, Priscilla F; Iannuzzi, Jessica; Chaudhri, Nadia

2016-04-01

An appetitive Pavlovian conditioned stimulus (CS) can predict an unconditioned stimulus (US) and acquire incentive salience. We tested the hypothesis that US intensity and motivational state of the subject would influence Pavlovian learning and impact the attribution of incentive salience to an appetitive Pavlovian CS. To this end, we examined the effects of sucrose concentration and water deprivation on the acquisition of Pavlovian conditioning and responding for a conditioned reinforcer. Male Long-Evans rats (Harlan; 220-240 g) receiving 3% (3S) or 20% (20S) sucrose were either non-water deprived or given water for 1 hr per day. During Pavlovian conditioning sessions, half the rats in each concentration and deprivation condition received a 10-s CS paired with 0.2 ml of sucrose (16 trials/session; 3.2 ml/session). The remainder received unpaired CS and US presentations. Entries into a port where sucrose was delivered were recorded. Next, responding for conditioned reinforcement was tested, wherein pressing an active lever produced the CS and pressing an inactive lever had no consequences. CS-elicited port entries increased, and latency to the first CS-elicited port entry decreased across sessions in paired groups. Water deprivation augmented these effects, whereas sucrose concentration had no significant impact on behavior. Responding for conditioned reinforcement was observed in the 20S water-deprived, paired group. Thus, water deprivation can facilitate the acquisition of Pavlovian conditioning, potentially by enhancing motivational state, and a high-intensity US and a high motivational state can interact to heighten the attribution of incentive salience to an appetitive Pavlovian CS. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Cues of fatigue: effects of sleep deprivation on facial appearance

NARCIS (Netherlands)

Sundelin, T.; Lekander, M.; Kecklund, G.; van Someren, E.J.W.; Olsson, A.; Axelsson, J.

2013-01-01

Study Objective: To investigate the facial cues by which one recognizes that someone is sleep deprived versus not sleep deprived. Design: Experimental laboratory study. Setting: Karolinska Institutet, Stockholm, Sweden. Participants: Forty observers (20 women, mean age 25 ± 5 y) rated 20 facial

Androgens and the ageing male

DEFF Research Database (Denmark)

Juul, Anders; Skakkebaek, Niels E

2002-01-01

Hypogonadal men share a variety of signs and symptoms such as decreased muscle mass, osteopoenia, increased fat mass, fatigue, decreased libido and cognitive dysfunctions. Controlled trials have demonstrated favourable effects of androgen substitution therapy on these signs and symptoms in men...... 'andropause' has been suggested. However, testosterone levels show no or only modest variation with age in men; with large prospective studies suggesting a maximal decline of total testosterone of 1.6% per year. Thus, in contrast to the sudden arrest of gonadal activity in females around menopause, men do...... not have an andropause. As large placebo-controlled studies of androgen treatment in elderly males are lacking, proper risk assessment of adverse effects such as prostate cancer following testosterone treatment in elderly males is completely lacking. In the future, testosterone therapy may prove beneficial...

Dioxin-like exposures and effects on estrogenic and androgenic exposures and micronuclei frequency in mother-newborn pairs

DEFF Research Database (Denmark)

Pedersen, Marie; Halldorsson, Thorhallur I; Mathiesen, Line

2010-01-01

In utero exposure to environmental dioxin-like, estrogen and androgen compounds can cause adverse health effects. Little is known about potential interactions in vivo between dioxin-like compounds, estrogens and androgens during fetal development in humans. Therefore we explored the potential...... interactions in vivo between dioxin-like compounds, estrogens, androgens using chemical-activated luciferase expression (CALUX)(R) bioassays in maternal and umbilical cord blood plasma concurrently collected at the time of planned Caesarean section from 98 healthy pregnancies. The dioxin-like activity was also...... determined after placental transfer of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the ex vivo human placenta perfusion system. Similar dioxin-like activity in maternal and cord blood (37 versus 33pg CALUX(R)-TEQ/g plasma lipids, P>0.05) was detected and it demonstrates transplacental transfer. Increased...

Androgen receptor-dependent and -independent mechanisms driving prostate cancer progression: Opportunities for therapeutic targeting from multiple angles

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Hoang, David T; Iczkowski, Kenneth A; Kilari, Deepak; See, William; Nevalainen, Marja T

2017-01-01

Despite aggressive treatment for localized cancer, prostate cancer (PC) remains a leading cause of cancer-related death for American men due to a subset of patients progressing to lethal and incurable metastatic castrate-resistant prostate cancer (CRPC). Organ-confined PC is treated by surgery or radiation with or without androgen deprivation therapy (ADT), while options for locally advanced and disseminated PC include radiation combined with ADT, or systemic treatments including chemotherapy. Progression to CRPC results from failure of ADT, which targets the androgen receptor (AR) signaling axis and inhibits AR-driven proliferation and survival pathways. The exact mechanisms underlying the transition from androgen-dependent PC to CRPC remain incompletely understood. Reactivation of AR has been shown to occur in CRPC despite depletion of circulating androgens by ADT. At the same time, the presence of AR-negative cell populations in CRPC has also been identified. While AR signaling has been proposed as the primary driver of CRPC, AR-independent signaling pathways may represent additional mechanisms underlying CRPC progression. Identification of new therapeutic strategies to target both AR-positive and AR-negative PC cell populations and, thereby, AR-driven as well as non-AR-driven PC cell growth and survival mechanisms would provide a two-pronged approach to eliminate CRPC cells with potential for synthetic lethality. In this review, we provide an overview of AR-dependent and AR-independent molecular mechanisms which drive CRPC, with special emphasis on the role of the Jak2-Stat5a/b signaling pathway in promoting castrate-resistant growth of PC through both AR-dependent and AR-independent mechanisms. PMID:27741508

Skill execution and sleep deprivation: effects of acute caffeine or creatine supplementation - a randomized placebo-controlled trial

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Kilduff Liam P

2011-02-01

Full Text Available Abstract Background We investigated the effects of sleep deprivation with or without acute supplementation of caffeine or creatine on the execution of a repeated rugby passing skill. Method Ten elite rugby players completed 10 trials on a simple rugby passing skill test (20 repeats per trial, following a period of familiarisation. The players had between 7-9 h sleep on 5 of these trials and between 3-5 h sleep (deprivation on the other 5. At a time of 1.5 h before each trial, they undertook administration of either: placebo tablets, 50 or 100 mg/kg creatine, 1 or 5 mg/kg caffeine. Saliva was collected before each trial and assayed for salivary free cortisol and testosterone. Results Sleep deprivation with placebo application resulted in a significant fall in skill performance accuracy on both the dominant and non-dominant passing sides (p Conclusion Acute sleep deprivation affects performance of a simple repeat skill in elite athletes and this was ameliorated by a single dose of either caffeine or creatine. Acute creatine use may help to alleviate decrements in skill performance in situations of sleep deprivation, such as transmeridian travel, and caffeine at low doses appears as efficacious as higher doses, at alleviating sleep deprivation deficits in athletes with a history of low caffeine use. Both options are without the side effects of higher dose caffeine use.

Effect of socioeconomic deprivation on waiting time for cardiac surgery: retrospective cohort study

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Pell, Jill P; Pell, Alastair C H; Norrie, John; Ford, Ian; Cobbe, Stuart M

2000-01-01

Objective To determine whether the priority given to patients referred for cardiac surgery is associated with socioeconomic status. Design Retrospective study with multivariate logistic regression analysis of the association between deprivation and classification of urgency with allowance for age, sex, and type of operation. Multivariate linear regression analysis was used to determine association between deprivation and waiting time within each category of urgency, with allowance for age, sex, and type of operation. Setting NHS waiting lists in Scotland. Participants 26 642 patients waiting for cardiac surgery, 1 January 1986 to 31 December 1997. Main outcome measures Deprivation as measured by Carstairs deprivation category. Time spent on NHS waiting list. Results Patients who were most deprived tended to be younger and were more likely to be female. Patients in deprivation categories 6 and 7 (most deprived) waited about three weeks longer for surgery than those in category 1 (mean difference 24 days, 95% confidence interval 15 to 32). Deprived patients had an odds ratio of 0.5 (0.46 to 0.61) for having their operations classified as urgent compared with the least deprived, after allowance for age, sex, and type of operation. When urgent and routine cases were considered separately, there was no significant difference in waiting times between the most and least deprived categories. Conclusions Socioeconomically deprived patients are thought to be more likely to develop coronary heart disease but are less likely to be investigated and offered surgery once it has developed. Such patients may be further disadvantaged by having to wait longer for surgery because of being given lower priority. PMID:10617517

Developmental programming by androgen affects the circadian timing system in female mice.

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Mereness, Amanda L; Murphy, Zachary C; Sellix, Michael T

2015-04-01

Circadian clocks play essential roles in the timing of events in the mammalian hypothalamo-pituitary-ovarian (HPO) axis. The molecular oscillator driving these rhythms has been localized to tissues of the HPO axis. It has been suggested that synchrony among these oscillators is a feature of normal reproductive function. The impact of fertility disorders on clock function and the role of the clock in the etiology of endocrine pathology remain unknown. Polycystic ovarian syndrome (PCOS) is a particularly devastating fertility disorder, affecting 5%-10% of women at childbearing age with features including a polycystic ovary, anovulation, and elevated serum androgen. Approximately 40% of these women have metabolic syndrome, marked by hyperinsulinemia, dyslipidemia, and insulin resistance. It has been suggested that developmental exposure to excess androgen contributes to the etiology of fertility disorders, including PCOS. To better define the role of the timing system in these disorders, we determined the effects of androgen-dependent developmental programming on clock gene expression in tissues of the metabolic and HPO axes. Female PERIOD2::luciferase (PER2::LUC) mice were exposed to androgen (dihydrotestosterone [DHT]) in utero (Days 16-18 of gestation) or for 9-10 wk (DHT pellet) beginning at weaning (pubertal androgen excess [PAE]). As expected, both groups of androgen-treated mice had disrupted estrous cycles. Analysis of PER2::LUC expression in tissue explants revealed that excess androgen produced circadian misalignment via tissue-dependent effects on phase distribution. In vitro treatment with DHT differentially affected the period of PER2::LUC expression in tissue explants and granulosa cells, indicating that androgen has direct and tissue-specific effects on clock gene expression that may account for the effects of developmental programming on the timing system. © 2015 by the Society for the Study of Reproduction, Inc.

Double Trouble? The Effects of Sleep Deprivation and Chronotype on Adolescent Affect

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Dagys, Natasha; McGlinchey, Eleanor L.; Talbot, Lisa S.; Kaplan, Katherine A.; Dahl, Ronald E.; Harvey, Allison G.

2012-01-01

Background: Two understudied risk factors that have been linked to emotional difficulties in adolescence are chronotype and sleep deprivation. This study extended past research by using an experimental design to investigate the role of sleep deprivation and chronotype on emotion in adolescents. It was hypothesized that sleep deprivation and an…

Acute versus chronic partial sleep deprivation in middle-aged people: differential effect on performance and sleepiness.

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Philip, Pierre; Sagaspe, Patricia; Prague, Mélanie; Tassi, Patricia; Capelli, Aurore; Bioulac, Bernard; Commenges, Daniel; Taillard, Jacques

2012-07-01

To evaluate the effects of acute sleep deprivation and chronic sleep restriction on vigilance, performance, and self-perception of sleepiness. Habitual night followed by 1 night of total sleep loss (acute sleep deprivation) or 5 consecutive nights of 4 hr of sleep (chronic sleep restriction) and recovery night. Eighteen healthy middle-aged male participants (age [(± standard deviation] = 49.7 ± 2.6 yr, range 46-55 yr). Multiple sleep latency test trials, Karolinska Sleepiness Scale scores, simple reaction time test (lapses and 10% fastest reaction times), and nocturnal polysomnography data were recorded. Objective and subjective sleepiness increased immediately in response to sleep restriction. Sleep latencies after the second and third nights of sleep restriction reached levels equivalent to those observed after acute sleep deprivation, whereas Karolinska Sleepiness Scale scores did not reach these levels. Lapse occurrence increased after the second day of sleep restriction and reached levels equivalent to those observed after acute sleep deprivation. A statistical model revealed that sleepiness and lapses did not progressively worsen across days of sleep restriction. Ten percent fastest reaction times (i.e., optimal alertness) were not affected by acute or chronic sleep deprivation. Recovery to baseline levels of alertness and performance occurred after 8-hr recovery night. In middle-aged study participants, sleep restriction induced a high increase in sleep propensity but adaptation to chronic sleep restriction occurred beyond day 3 of restriction. This sleepiness attenuation was underestimated by the participants. One recovery night restores daytime sleepiness and cognitive performance deficits induced by acute or chronic sleep deprivation. Philip P; Sagaspe P; Prague M; Tassi P; Capelli A; Bioulac B; Commenges D; Taillard J. Acute versus chronic partial sleep deprivation in middle-aged people: differential effect on performance and sleepiness. SLEEP 2012;35(7):997-1002.

Effects of Statin on Arrhythmia and Heart Rate Variability in Healthy Persons With 48-Hour Sleep Deprivation.

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Chen, Wei Ren; Liu, Hong Bin; Sha, Yuan; Shi, Yang; Wang, Hao; Yin, Da Wei; Chen, Yun Dai; Shi, Xiang Min

2016-10-31

It has been reported that sleep deprivation is associated with cardiac autonomic disorder, inflammation, and oxidative stress. Statins have significant cardiovascular protective effects in patients with cardiovascular disease. This study aimed to investigate the protective effect of statins on arrhythmia and heart rate variability in young healthy persons after 48-hour sleep deprivation. This study enrolled 72 young healthy participants aged 26.5±3.5 years. All participants received 48-hour continuous ambulatory electrocardiogram monitoring. Arrhythmia, time, and frequency domain parameters were analyzed for all participants. The primary end point, low/high frequency ratio, was significantly lower in the statin group than in the control group (2.48±1.12 versus 3.02±1.23, Psleep deprivation, low frequency-the frequency of premature atrial complexes and premature ventricular complexes-was significantly decreased in the statin group compared with the control group (Psleep deprivation in the statin group compared with the control group (Psleep deprivation. This finding should be confirmed by larger scale trials. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02496962. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.