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Sample records for castration

  1. A passion for castration: characterizing men who are fascinated with castration, but have not been castrated.

    Science.gov (United States)

    Roberts, Lesley F; Brett, Michelle A; Johnson, Thomas W; Wassersug, Richard J

    2008-07-01

    A number of men have extreme castration ideations. Many only fantasize about castration; others actualize their fantasies. We wish to identify factors that distinguish those who merely fantasize about being castrated from those who are at the greatest risk of genital mutilation. Seven hundred thirty-one individuals, who were not castrated, responded to a survey posted on http://www.eunuch.org. We compared the responses of these "wannabes" to those of 92 men who were voluntarily castrated and responded to a companion survey. Main Outcome Measures. Respondents answered the questionnaire items relating to demographics, origin of interest in castration, and ambition toward eunuchdom. Two categories of wannabes emerged. A large proportion ( approximately 40%) of wannabes' interest in castration was singularly of a fetishistic nature, and these men appeared to be at a relatively low risk of irreversible genital mutilation. Approximately 20% of the men, however, appeared to be at great risk of genital mutilation. They showed a greater desire to reduce libido, change their genital appearance, transition out of male, and prevent sexually offensive behavior. Nineteen percent of all wannabes have attempted self-castration, yet only 10% have sought medical assistance. We identify several motivating factors for extreme castration ideations and provide a classification for reasons why some males desire orchiectomies. Castration ideations fall under several categories of the Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. (DSM-IV), most notably a Gender Identity Disorder other than male-to-female (MtF) transsexual (i.e., male-to-eunuch) and a Body Identity Integrity Disorder. Physicians need to be aware of males who have strong desires for emasculation without a traditional MtF transsexual identity.

  2. Castrating parasites and colonial hosts.

    Science.gov (United States)

    Hartikainen, H; Okamura, B

    2012-04-01

    Trajectories of life-history traits such as growth and reproduction generally level off with age and increasing size. However, colonial animals may exhibit indefinite, exponential growth via modular iteration thus providing a long-lived host source for parasite exploitation. In addition, modular iteration entails a lack of germ line sequestration. Castration of such hosts by parasites may therefore be impermanent or precluded, unlike the general case for unitary animal hosts. Despite these intriguing correlates of coloniality, patterns of colonial host exploitation have not been well studied. We examined these patterns by characterizing the responses of a myxozoan endoparasite, Tetracapsuloides bryosalmonae, and its colonial bryozoan host, Fredericella sultana, to 3 different resource levels. We show that (1) the development of infectious stages nearly always castrates colonies regardless of host condition, (2) castration reduces partial mortality and (3) development of transmission stages is resource-mediated. Unlike familiar castrator-host systems, this system appears to be characterized by periodic rather than permanent castration. Periodic castration may be permitted by 2 key life history traits: developmental cycling of the parasite between quiescent (covert infections) and virulent infectious stages (overt infections) and the absence of germ line sequestration which allows host reproduction in between bouts of castration.

  3. Surgical castration, coercion and ethics

    DEFF Research Database (Denmark)

    Ryberg, Jesper; Petersen, Thomas Søbirk

    2014-01-01

    John McMillan's detailed ethical analysis concerning the use of surgical castration of sex offenders in the Czech Republic and Germany is mainly devoted to considerations of coercion.1 This is not surprising. When castration is offered as an option to offenders and, at the same time, constitutes...... the only means by which these offenders are likely to be released from prison, it is reasonable—and close to the heart of modern medical ethics—to consider whether the offer involves some kind of coercion. However, despite McMillan's seemingly careful consideration of this question, it appears to us...

  4. Effect of surgical and immunological castration on haematological ...

    African Journals Online (AJOL)

    The PCV and HB of dogs surgically castrated increased progressively up to16th week after castration but only up to10 weeks in dogs immunologically castrated. Both PCV and HB decreased progressively after 10 weeks in dogs immunologically castrated. Similarly, the WBC of dogs surgically castrated steadily increased ...

  5. Acute Cold / Restraint Stress in Castrated Rats

    Directory of Open Access Journals (Sweden)

    Farideh Zafari Zangeneh

    2008-09-01

    Full Text Available Objective: The present study aimed to determine whether castration altered osmotically stimulated vasopressin (VP release and urinary volume and what is the role of endocrine-stress axis in this process.Materials and methods: Totally 108 mice were studied in two main groups of castrated (n=78 and control (n=30. Each group was extracted by acute cold stress (4◦C for 2h/day, restraint stress (by syringes 60cc 2h/day and cold/restraint stress. The castrated group was treated in sub groups of testosterone, control (sesame oil as vehicle of testosterone. Propranolol as blocker of sympathetic nervous system was given to both groups of castrated mice and main control.Results: Our results showed that, there is interactions between testosterone and sympathetic nervous system on vasopressin, because urine volume was decreased only in testoctomized mice with cold/restraint and cold stress (P<0.001; propranolol as the antagonist of sympathetic nervous system could block and increase urine volume in castrated mice. This increased volume of urine was due to acute cold stress, not restraint stress (p<0.001. The role of testosterone, noradrenalin (NA and Vasopressin (VP in the acute cold stress is confirmed, because testosterone could return the effect of decreased urine volume in control group (P<0.001. Conclusion: Considering the effect of cold/restraint stress on urinary volume in castrated mice shows that there is interaction between sex hormone (testosterone, vasopressin and adrenergic systems.

  6. Live and carcass measurements of steers castrated at three different ...

    African Journals Online (AJOL)

    marbling, and fat thickness on the eye muscle between the three castrated groups. However, it was obvious ... calves are castrated between the ages of 2 and 6 months whereas the occasional producer castrates his ... (average of three measurements across the eye muscle) was measured. Marbling of the eye muscle was ...

  7. Retardation of muscle growth in castrated male mice: further ...

    African Journals Online (AJOL)

    Retardation of muscle growth in castrated male mice was studied as an evidence for the influence of hormones on the development of muscle mass. Male albino mice were castrated at 28days of age by open castration method. The weights and the muscle mass indices (mg muscle weight per gram body weight) of the ...

  8. Analysis of possible reasons for dissolution of stallion after castration

    Directory of Open Access Journals (Sweden)

    Stevančević Milenko

    2008-01-01

    Full Text Available Within the practical training of students of the fifth year of studies of veterinary medicine, a demonstration was performed of stallion castration. The owner of the horse decided to take this step because of the unpredictable temperament of the stallion. The castration was carried out under general anaesthesia. The stallion was laid down and immobilized for castration in keeping with the so-called in-the-field conditions. The castration pro­ceeded without any complications, and the postoperative course was in order. Three days after castration, the horse died with symptoms of colic. The autopsy showed obturation of the ileum and ileocecal valve by Parascaris equorum parasites.

  9. Pig castration: will the EU manage to ban pig castration by 2018?

    Science.gov (United States)

    De Briyne, Nancy; Berg, Charlotte; Blaha, Thomas; Temple, Déborah

    2016-01-01

    In 2010, the 'European Declaration on alternatives to surgical castration of pigs' was agreed. The Declaration stipulates that from January 1, 2012, surgical castration of pigs shall only be performed with prolonged analgesia and/or anaesthesia and from 2018 surgical castration of pigs should be phased out altogether. The Federation of Veterinarians of Europe together with the European Commission carried out an online survey via SurveyMonkey© to investigate the progress made in different European countries. This study provides descriptive information on the practice of piglet castration across 24 European countries. It gives also an overview on published literature regarding the practicability and effectiveness of the alternatives to surgical castration without anaesthesia/analgesia. Forty usable survey responses from 24 countries were received. Besides Ireland, Portugal, Spain and United Kingdom, who have of history in producing entire males, 18 countries surgically castrate 80% or more of their male pig population. Overall, in 5% of the male pigs surgically castrated across the 24 European countries surveyed, castration is performed with anaesthesia and analgesia and 41% with analgesia (alone). Meloxicam, ketoprofen and flunixin were the most frequently used drugs for analgesia. Procaine was the most frequent local anaesthetic. The sedative azaperone was frequently mentioned even though it does not have analgesic properties. Half of the countries surveyed believed that the method of anaesthesia/analgesia applied is not practicable and effective. However, countries that have experience in using both anaesthesia and post-operative analgesics, such as Norway, Sweden, Switzerland and The Netherlands, found this method practical and effective. The estimated average percentage of immunocastrated pigs in the countries surveyed was 2.7% (median = 0.2%), where Belgium presented the highest estimated percentage of immunocastrated pigs (18%). The deadlines of January 1

  10. Meat quality of castrated and non-castrated Santa Ines lambs subjected to food restriction

    Directory of Open Access Journals (Sweden)

    Dayanne Lima de Sousa

    2016-06-01

    Full Text Available This study aimed to evaluate the quality of meat of castrated and non-castrated Santa Ines lambs submitted to food restriction. Were used 30 lambs, 15 castrated and 15 non-castrated, about two months of age and average initial body weight of 13.00 ± 1.49 kg. The lambs were distributed in a completely randomized design in a factorial arrangement 3 x 2 (restriction level x sex class, according to the amount of food provided. The duration of the experiment was determined by the time required for the animals in the one of the groups achieved 28 kg of body weight. There was interaction between food restriction levels and sex class to the variables intensity of yellow color and pH in the longissimus lumborum muscle and the shear force in the semimembranosus muscle. In non-castrated animals, the intensity of yellow color was higher in the longissimus lumborum muscle at the level of 30% of food restriction. There was no significant interaction between food restriction levels and sex class for the quality aspects related to color saturation, color tone, luminosity, red intensity, water holding capacity and cooking losses in longissimus lumborum and semimembranosus muscles. Although food restriction and sex class have influenced the variables related to the quality of meat of the animals evaluated, the mean values are considered acceptable by the literature. The feeding restriction levels and sex class influence some important features of quality of Santa Ines lamb meat.

  11. Evaluation of Pinhole castration as an alternative technique for goat ...

    African Journals Online (AJOL)

    Evaluation of Pinhole castration as an alternative technique for goat sterilization. J Okwee-Acai, J Acon, D Okello-Owiny, B Agwai, J Oloya. Abstract. La ligature in situ du cordon spermatique (Castration Pinhole) a été décrite comme une technique originale peu invasive de castration des veaux. La présente étude avait pour ...

  12. [Castration of dogs from the standpoint of behaviour therapy].

    Science.gov (United States)

    Kuhne, F

    2012-04-24

    The castration of dogs is an amputation covered by Section 6 (1) of the Animal Protection Law in Germany. Apart from the general indications given by veterinary medicine, castration of an animal is a potential method of animal behaviour therapy. However, the highly variable, individual effects of castration on behaviour require detailed diagnosis by the veterinarian. Castration appears to exert its strongest influence on sexually dimorphic behaviour patterns in male dogs, e.g. status- related aggression, urine marking, mounting, house-soiling problems, and roaming. An indication to castrate a bitch is maternal aggression. When evaluating the effects of castration, one should always consider individual circumstances, such as learning experience (for example in the case of "experienced copulators"), age, and pack behaviour (if there is more than one dog in the household). Additional benefits of castration include a reduction in the dog's general activity level, decreased preparatory arousal and a decline in the dog's ability to focus its attention fully on the target of attack. As a result, it is much easier for the owner to disrupt and manage or control the dog's agonistic intentions. However, castration is not the ultimate remedy in dog-handling. Any decision in this respect should be based on a precise behaviour- related indication. Otherwise, such surgery may well violate the Animal Protection Law.

  13. Practices and Concerns of Castration of Dogs in Nigeria | Ajadi ...

    African Journals Online (AJOL)

    This study evaluated the practices and concerns regarding castration, and level of awareness of Nigerian Veterinarians on alternatives to surgical castration in dogs. Questionnaires were distributed to one hundred veterinarians during the 2012 annual Veterinary Association Conference. The questionnaire comprised of the ...

  14. Castration of male livestock and the potential of immunocastration to ...

    African Journals Online (AJOL)

    Growing consumer awareness about animal welfare has led to the assessment of the impact of common farming practices, such as physical castration, on animal well-being under production conditions. Physical castration is used in livestock industries to prevent indiscriminate breeding, control aggression, and improve ...

  15. Evaluation Of Surgical Castration For Prostate Cancer At Nnewi ...

    African Journals Online (AJOL)

    Objective. To evaluate the average time of follow-up of patients with advanced prostate cancer after surgical castration and to assess the difficulties associated with follow-up of patients. Patients and Methods. 89 case notes of patients who had surgical castration for advanced prostate cancer were reviewed. Information on ...

  16. Delayed physeal closure associated with castration in cats

    International Nuclear Information System (INIS)

    May, C.; Bennett, D.; Downham, D.Y.

    1991-01-01

    Radiographs of 152 cats under four years of age were examined for evidence of physeal closure. Radiographic closure was compared between entire male, castrated male, and female (neutered and entire] cats. Physeal closure in castrated males was delayed when compared to that of entire males

  17. Castration in breast cancer. Surgery or radiation

    International Nuclear Information System (INIS)

    Hernandez Munoz, G.

    1977-01-01

    A summary is done on the indication of oophorectomy - by surgery or radiation - in the treatment of breast cancer. Prophylactic - and therapeutic oophorectomy are analysed. It is concluded that the treatment of advanced cancer is a fight against time, once the survival of patients ought to be prolonged with the minor number of therapeutic agents, avoiding the usage of them all at once not to exaust them. Castration performed with therapeutic purposes in pre-or post-menopause patients with hyperestrogenism is the first link in the chain of paliative treatment of advanced breast cancer. (M.A.) [pt

  18. Two cases of paraprostatic cysts in castrated male dogs.

    Science.gov (United States)

    Goodrich, Zachary J; Wilke, Vicki L; Root Kustritz, Margaret V

    2011-01-01

    Two castrated male dogs presented for evaluation of tenesmus. Presurgical evaluations included complete physical examinations, serum biochemistry, abdominal ultrasonography, and MRI (case 2 only). Paraprostatic cysts were diagnosed in both cases based on the results of abdominal ultrasonography, MRI, and histopathology of tissue samples obtained during exploratory laparotomy. To the authors' knowledge, the two cases presented herein are the first documented cases of paraprostatic cysts that developed after castration in male dogs. Paraprostatic cysts should be considered in the differential diagnoses for castrated male dogs with prostatic disease.

  19. Inhibition of the RANK/RANKL signaling with osteoprotegerin prevents castration-induced acceleration of bone metastasis in castration-insensitive prostate cancer.

    Science.gov (United States)

    Takayama, Koichiro; Inoue, Takamitsu; Narita, Shintaro; Maita, Shinya; Huang, Mingguo; Numakura, Kazuyuki; Tsuruta, Hiroshi; Saito, Mitsuru; Maeno, Atsushi; Satoh, Shigeru; Tsuchiya, Norihiko; Habuchi, Tomonori

    2017-07-01

    Androgen deprivation therapy (ADT) for patients with metastatic or locally advanced prostate cancer reduces bone mineral density by stimulating receptor activator of nuclear factor kappa-B (RANK) signaling in osteoclasts. The involvement of the RANK/RANKL signaling in ADT-induced acceleration of bone metastasis in castration-insensitive prostate cancer was examined in a murine model using osteoprotegerin (OPG). Male Balb/c nude mice were divided into three groups: the non-castration, castration, and castration + OPG groups. PC-3M-luc-C6 was injected into the left ventricle of the mice. Recombinant OPG was injected intravenously twice weekly in the castration + OPG group. In-vivo imaging system (IVIS ® ) determined that the prevalence and photon counts of bone metastasis in the castration group were significantly higher than that in the non-castration and castration + OPG groups. The mean number of RANKL-positive osteoblasts and the mean serum RANKL level in the castration group were significantly higher than those in the non-castration group. RANKL-enhanced activation of osteoclasts was attenuated in the castration + OPG group. These results suggest that the mechanisms of RANK/RANKL signaling are involved in the ADT-induced acceleration of bone metastasis in castration-insensitive prostate cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Effect of Surgical and Immunological Castration on Haematological ...

    African Journals Online (AJOL)

    olayemitoyin

    . Cloud, Minnesota, USA. Summary: Welfare concerns are growing regarding surgical castration (SC) in pets, necessitating the need for non-surgical alternatives. Administration of vaccines against gonadotropins releasing hormone (GnRH) ...

  1. Influenced by Castration and Diet Performance and feed Utilisation ...

    African Journals Online (AJOL)

    , 1971; Field; ... treatments and assessed.for.feed. ,qigestibillty, nitrogen utilization and water intake. There were little castration and diet 'effects on ...... The excess water is excreted as urine and with it the excess ash and nitrogenous products.

  2. [Pinealectomy and early castration in the female Wistar rat].

    Science.gov (United States)

    Slama-Scemama, A

    1976-05-17

    Pinealectomy does not significantly modify the level of pituitary and plasma gonadotropins in intact and in castrated female Rats from brith to 75 days of age. Only the weight of the thyroid gland is higher in pinealectomized rats.

  3. Molecular Indicators of Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2015-12-01

    with these drugs,7-9 both agents were ap- proved by the Food and Drug Administration for the treatment of metastatic castration-resistant prostate... testosterone (អ ng per deciliter [1.73 nmol per liter]) with continued androgen- deprivation therapy, and documented metastases, as confirmed on...clinical trials for patients with progressive prostate cancer and castrate levels of testosterone : recommendations of the Prostate Cancer Clinical

  4. Castration of a Black Rhinoceros Diceros Bicornis Minor

    Directory of Open Access Journals (Sweden)

    V de Vos

    1980-12-01

    Full Text Available A black rhinoceros (Diceros bicornis minor in the Addo Elephant National Park was castrated in order to prevent the possibility of an aotic inducing gene to be introduced into the Addo population. The classic castration technique was used. It was subsequently found that the rhino showed a drastic change in behaviour, and is at this stage predictably timid, which is not the case with his testis carrying compeers.

  5. Castration of a Black Rhinoceros Diceros Bicornis Minor

    Directory of Open Access Journals (Sweden)

    V de Vos

    1980-01-01

    Full Text Available A black rhinoceros (Diceros bicornis minor in the Addo Elephant National Park was castrated in order to prevent the possibility of an aotic inducing gene to be introduced into the Addo population. The classic castration technique was used. It was subsequently found that the rhino showed a drastic change in behaviour, and is at this stage predictably timid, which is not the case with his testis carrying compeers.

  6. Treatment outcomes of chemical castration on Korean sex offenders.

    Science.gov (United States)

    Koo, Kyo Chul; Shim, Geum Sook; Park, Hyoun Hee; Rha, Koon Ho; Choi, Young Deuk; Chung, Byung Ha; Hong, Sung Joon; Lee, Jae Woo

    2013-08-01

    After the recent enactment of the chemical castration legislation for sex offenders in Korea, we sought to report primary treatment outcomes for 38 patients at the National Forensic Hospital since 2011. After chemical castration, these patients experienced reductions in frequency and intensity of sexual drive, frequency of masturbation and sexual fantasies. The incidence of adverse effects was similar to that of previous reports. Serial hormonal evaluations showed an association between testosterone level and degree of paraphilic and non-paraphilic sexual thoughts. A notable finding was an unexpected upsurge of testosterone levels with intense sexual drive and fantasy observed during the first 2 months after cessation of treatment. This suggested the need for a temporary anti-androgen therapy or close surveillance during this period. When proper precautions are taken, chemical castration may be an effective treatment strategy for paraphilic and non-paraphilic sex offenders. Copyright © 2013 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.

  7. [Targeted radionuclide therapy for castration-resistant prostate cancer].

    Science.gov (United States)

    Nakamura, Katsumasa; Ohga, Saiji; Sasaki, Tomonari; Baba, Shingo; Honda, Hiroshi

    2014-12-01

    Although patients with castration-resistant prostate cancer frequently have metastases to the bone, they have a relatively favorable prognosis. Therefore, it is important to keep or improve the level of patient's quality of life. The use of strontium-89 for the management of the pain from bone metastasis was approved in 2007 in Japan. A new bone-targeting radiopharmaceuticals using radium-223 is also promising, because a randomized trial showed an overall survival advantage of radium-223 in prostate patients with bone metastases. In this review, we summarize the role of targeted radionuclide therapy for castration-resistant prostate cancer, focusing on strontium-89 and radium-223.

  8. Open standing castration in Thoroughbred racehorses in Hong Kong: Prevalence and severity of complications 30 days post-castration.

    Science.gov (United States)

    Rosanowski, S M; MacEoin, F; Graham, R J T Y; Riggs, C M

    2018-05-01

    Complications following open standing castration (OSC) in Thoroughbred racehorses are well recognised but variation in their prevalence and severity between populations is not well documented. To describe the prevalence and severity of complications in the 30 days following OSC. A retrospective cohort study of veterinary clinical records relating to horses that underwent OSC between July 2007 and July 2012. Complications were graded on a severity score from N, no complications, to C3, severe complications. Additional data were accessed for each horse including age, import date, racing history, trainer and veterinarian performing the castration. Bacterial culture and antimicrobial sensitivities were performed on a limited number of castration wounds that became infected. In total, 250 horses were castrated in Hong Kong using the OSC technique over the period of the study. Sixty percent (150/250) of horses experienced some type of post-castration complication, with eight horses experiencing a severe (C3) complication requiring intensive veterinary treatment. Scrotal swelling, funiculitis and seroma formation were present in 70.0%, 36.7% and 24.7% of cases respectively. Most horses experiencing complications required wound reopening (87.3%; 131/150), and/or an extended course of first-line antimicrobials and/or nonsteroidal anti-inflammatory drugs (75/150; 50.0%). Eight horses had cultures submitted for bacterial sensitivity, with 17 bacterial isolates grown. In vitro, the bacteria cultured were sensitive to enrofloxacin (76%; 13/17) and ceftiofur (100%; 17/17). Resistance was detected to penicillin, gentamicin, oxytetracycline, metronidazole and trimethoprim-sulfadiazine. Differences in post-castration management cannot be accounted for in this study. Complications following OSC in horses in Hong Kong were common. The majority were mild and were successfully treated using antimicrobials and simple wound management. Given the high rate of complications and

  9. Morphologic and biochemical changes in male rat lung after surgical and pharmacological castration

    Directory of Open Access Journals (Sweden)

    M.S. Ojeda

    2000-03-01

    Full Text Available The morphology of the rat lung was studied by light microscopy in different situations: after surgical and pharmacological castration and after administration of testosterone to the castrated rat to determine if the androgen is required to maintain the normal morphology of the lung. We also determined the effect of flutamide on the phospholipid composition of both the surfactant and microsomes of the lung. Rats were separated into five groups: I - control non-castrated rats, II - castrated rats sacrificed 21 days after castration, III - castrated rats that received testosterone daily from day 2 to day 21 after castration, IV - castrated rats that received testosterone from day 15 to day 21 after castration, and V - control rats injected with flutamide for 7 days. The amount of different phospholipids in the surfactant and microsomes of the lung was measured in group I and V rats. At the light microscopy level, the surgical and pharmacological castration provoked alterations in the morphology of the lung, similar to that observed in human lung emphysema. The compositions of surfactant and microsomes of the lung were similar to those previously reported by us for the surgically castrated rats. These results indicate that androgens are necessary for the normal morphology as well as for some metabolic aspects of the lung.

  10. Varieties of Castration Experience: Relevance to Contemporary Psychoanalysis and Psychodynamic Psychotherapy.

    Science.gov (United States)

    Taylor, Graeme J

    2016-03-01

    Although Freud considered castration to be one of the two major anxieties of human life, the castration complex has been relatively neglected in contemporary psychoanalytic writing and is insufficiently discussed in presentations of clinical cases. This article discusses the relevance of the concept to contemporary psychoanalysis and psychodynamic psychotherapy, in particular the important contributing role of castration conflicts in the pathogenesis of a wide range of clinical symptoms. The author begins by briefly reviewing some classical and contemporary psychoanalytic ideas about castration to show how the concept has broadened and is currently used not only to signify fear of damage to or loss of the genital, but also metaphorically to indicate a threat to or loss of any valued human characteristic or function. He outlines Brenner's distinction between castration anxiety and castration depression, and reviews the role of childhood trauma in intensifying castration conflicts. He then illustrates the clinical application of these ideas by describing aspects of his psychotherapeutic work with three male patients who presented with a variety of symptoms and distressing psychological experiences that were gradually resolved through the analysis of underlying castration anxiety and/or castration depression. Although castration anxiety is frequently intermingled with separation anxiety, the author concludes that with many traumatized patients castration conflicts are in the foreground and the therapist needs to focus on the patient's proneness to humiliation, powerlessness, and shame.

  11. RETARDATION OF MUSCLE GROWTH IN CASTRATED MALE MICE:

    African Journals Online (AJOL)

    the absolute weights and the muscle mass indices of the muscles of castrated males were ... Muscles, Mice. INTRODUCTION rat levator ani muscles. It was noted that the hypertrophy of the muscle was a result. Muscles of adult male mice are invariably of increase in myofibrilar material .... (1976): Skeletal muscle cellularity.

  12. Preliminary study on the effect of castration and testosterone ...

    African Journals Online (AJOL)

    To study the effect of castration and testosterone replacement on the testosterone level of the New Zealand rabbit, 16 apparently healthy adult male rabbits were used. The animals were divided into four groups with each group having four rabbits. The first group served as the control group. The rabbits in the second group ...

  13. An Evaluation of Pinhole Castration as an Alternative Technique for ...

    African Journals Online (AJOL)

    We evaluated pinhole castration as an alternative technique for dog population control in resource poor rural communities of Gulu, Northern Uganda. Through a campaign dubbed 'Big Fix Gulu', households in selected communities were mobilized using radio announcements, posters and school visits, to present dogs for ...

  14. Castration of piglets under CO2-gas anaesthesia.

    Science.gov (United States)

    Gerritzen, M A; Kluivers-Poodt, M; Reimert, H G M; Hindle, V; Lambooij, E

    2008-11-01

    It has become common practice in pig fattening production systems to castrate young boar piglets without the use of anaesthesia. In this study, we examined whether or not CO2 gas is capable of inducing an acceptable anaesthetic state during which castration can be performed. The first step was to identify the most promising CO2/O2 mixture. Based on the results from this first experiment, a mixture of 70% CO2 + 30% O2 was chosen for further investigation as a potential anaesthetic during the castration of young piglets. Thereby, it was established whether the duration and depth of anaesthesia were acceptable for castration where the animal has to be insensible and unconscious. Physiological effects were assessed based on electroencephalogram (EEG) and electrocardiogram (ECG) measurements, blood gas values and behavioural responses. During the induction phase, the only typical behaviour the piglets exhibited when exposed to the 70/30 gas mixture was heavy breathing. All piglets (n = 25) lost consciousness after approximately 30 s according to the EEG. Heart rate decreased slowly during the induction phase, a serious drop occurred when piglets lost their posture. Immediately after this drop, the heart rate neared zero or showed a very irregular pattern. Shortly after loss of posture, most animals showed a few convulsions. None of the animals showed any reaction to castration in behaviour and/or on the EEG and ECG. On average, the piglets recovered within 59 s, i.e. EEG returned to its pre-induction pattern and piglets were able to regain a standing position. After 120 s, heart rate returned to pre-induction levels. In order to explore the usage range of CO2 concentration, 24 piglets were exposed to 60% CO2 + 20% O2 + 20% N2 for up to 30 s after loss of consciousness (as registered on EEG), and castrated after removal from the chamber. Sixteen of the 24 animals showed a reaction to the castration on the EEG. To establish the maximum time piglets survive in 70% CO2 + 30

  15. Lower Testosterone Levels With Luteinizing Hormone-Releasing Hormone Agonist Therapy Than With Surgical Castration: New Insights Attained by Mass Spectrometry

    NARCIS (Netherlands)

    van der Sluis, T.M.; Bui, H.N.; Meuleman, E.J.H.; Heijboer, A.C.; Hartman, J.F.; van Adrichem, N.; Boeve, E.; de Ronde, W.; van Moorselaar, R.J.A.; Vis, A.N.

    2012-01-01

    Purpose: Androgen deprivation therapy by bilateral orchiectomy (surgical castration) or luteinizing hormone-releasing hormone agonist therapy (medical castration) is recommended for advanced or metastatic prostate cancer. Both methods aim at reducing serum testosterone concentrations to a castrate

  16. Lower testosterone levels with luteinizing hormone-releasing hormone agonist therapy than with surgical castration: new insights attained by mass spectrometry

    NARCIS (Netherlands)

    van der Sluis, Tim M.; Bui, Hong N.; Meuleman, Eric J. H.; Heijboer, Annemieke C.; Hartman, Jeroen F.; van Adrichem, Nick; Boevé, Egbert; de Ronde, Willem; van Moorselaar, R. Jeroen A.; Vis, André N.

    2012-01-01

    Androgen deprivation therapy by bilateral orchiectomy (surgical castration) or luteinizing hormone-releasing hormone agonist therapy (medical castration) is recommended for advanced or metastatic prostate cancer. Both methods aim at reducing serum testosterone concentrations to a castrate level

  17. Metastatic castration-resistant prostate cancer: time for innovation.

    Science.gov (United States)

    Tucci, Marcello; Scagliotti, Giorgio Vittorio; Vignani, Francesca

    2015-01-01

    Androgen deprivation is the mainstay of advanced prostate cancer treatment. Despite initial responses, almost all patients progress to castration-resistant prostate cancer (CRPC). The understanding of the biology of CRPC and the evidence that CRPC still remains driven by androgen receptor signaling led to the discovery of new therapeutic targets. In the last few years, large Phase III trials showed improvements in survival and outcomes and led to the approval of a CYP17 inhibitor (abiraterone), an androgen receptor antagonist (enzalutamide), the taxane cabazitaxel, an α-emitter (radium-223), the bone resorption-targeting drug denosumab and an immunotherapy (sipuleucel-T). This article describes the molecular mechanisms underlying castration resistance, discusses recent and ongoing trials and offers some insights into identifying the best sequence of new drugs.

  18. Choline Autoradiography of Human Prostate Cancer Xenograft: Effect of Castration

    Directory of Open Access Journals (Sweden)

    Hossein Jadvar

    2008-05-01

    Full Text Available The purpose of this study was to investigate the effects of castration and tracer uptake time interval on the level of radiolabeled choline accumulation in murine-implanted human prostate tumor xenografts using quantitative autoradiography. We implanted androgen-dependent (CWR22 and androgen-independent (PC3 human prostate cancer cells in castrated (n = 9 and noncastrated (n = 9 athymic male mice and allowed tumors to grow to 1 cm3. The mice were euthanized at 5, 10, and 20 minutes after injection of 5 µCi [14C]-choline. Mice were prepared for quantitative autoradiography with density light units of viable tumor sections converted to units of radioactivity (nCi/mm2 using calibration. Two-group comparisons were performed using a two-tailed Student t-test with unequal variance and with a significance probability level of less than .05. Two-group comparisons between the means of the tracer uptake level for each tumor type at each of three time points for each of two host types showed that (1 the level of tracer localization in the two tumor types was affected little in relation to the host type and (2 PC3 tumor uptake level tended to increase slowly with time only in the noncastrated host, whereas this was not observed in the castrated host or with CWR22 tumor in either host type. The uptake time interval and castration do not appear to significantly affect the level of radiolabeled choline uptake by the human prostate cancer xenograft.

  19. Targeting Mitochondrial Inhibitors for Metastatic Castrate Resistant Prostate Cancer

    Science.gov (United States)

    2017-09-01

    niclosamide and 7 hydroxy-β-Lapachone (7OH β-Lap) analog lipophilic mitochondria toxins (MT) to human serum albumin (HSA) via a PSA specific peptide... human serum albumin (HSA) via a PSA specific peptide linker sequence to systemically deliver these novel agents via the blood so that these cell...effect”. Keywords Metastatic castration resistant prostate cancer, mitochondria toxins, human serum albumin , PSA-activated prodrugs Accomplishments

  20. Overcoming Autophagy to Induce Apoptosis in Castration Resistant Prostate Cancer

    Science.gov (United States)

    2015-10-01

    AWARD NUMBER: W81XWH-12-1-0529 TITLE: Overcoming Autophagy to Induce Apoptosis in Castration Resistant Prostate Cancer PRINCIPAL...survival mechanism and led cells to undergo apoptosis . Survival mechanisms elicited by CRPC C4-2B cells when treated with Enza may be blocked by...Targeting cancer cell metabolism: the combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells. Cancer

  1. Castration-resistant prostate cancer: systemic therapy in 2012

    Directory of Open Access Journals (Sweden)

    Fernando C. Maluf

    2012-01-01

    Full Text Available Prostate cancer is the most common non-cutaneous neoplasm in the male population worldwide. It is typically diagnosed in its early stages, and the disease exhibits a relatively indolent course in most patients. Despite the curability of localized disease with prostatectomy and radiation therapy, some patients develop metastatic disease and die. Although androgen deprivation is present in the majority of patients with metastatic prostate cancer, a state of androgen resistance eventually develops. Castration-resistant prostate cancer, defined when there is progression of disease despite low levels of testosterone, requires specialized care, and improved communication between medical and urologic oncologists has been identified as a key component in delivering effective therapy. Despite being considered a chemoresistant tumor in the past, the use of a prostate-specific antigen has paved the way for a new generation of trials for castration-resistant prostate cancer. Docetaxel is a life-prolonging chemotherapy that has been established as the standard first-line agent in two phase III clinical trials. Cabazitaxel, a novel taxane with activity in cancer models resistant to paclitaxel and docetaxel, is the only agent that has been compared to a chemotherapy control in a phase III clinical trial as a second-line therapy; it was found to prolong the overall survival of patients with castration-resistant prostate cancer previously treated with docetaxel when compared to mitoxantrone. Other agents used in this setting include abiraterone and sipuleucel-T, and novel therapies are continually being investigated in an attempt to improve the outcome for patients with castration-resistant prostate cancer.

  2. Androgen deprivation therapy (castration therapy) and pedophilia: What's new.

    Science.gov (United States)

    Silvani, Mauro; Mondaini, Nicola; Zucchi, Alessandro

    2015-09-30

    Andrology is a constantly evolving discipline, embracing social problems like pedophilia and its pharmacological treatment. With regard to chemical castration, the andrologist may perform an important role as part of a team of specialists. At present, no knowledge is available regarding hormonal, chromosomal or genetic alterations involved in pedophilia. International legislation primarily aims to defend childhood, but does not provide for compulsory treatment. We reviewed international literature that, at present, only comprises a few reports on research concerning androgen deprivation. Most of these refer to the use of leuprolide acetate, rather than medroxyprogesterone and cyproterone acetate, which present a larger number of side effects. Current opinions on chemical castration for pedophilia are discordant. Some surveys confirm that therapy reduces sexual thoughts and fantasies, especially in recidivism. On the other hand, some authors report that chemical castration does not modify the pedophile's personality. In our opinion, once existing legislation has changed, andrologists could play a significant role in the selection of patients to receive androgen deprivation therapy, due in part to their knowledge about its action and side effects.

  3. Eunuchs in contemporary society: characterizing men who are voluntarily castrated (part I).

    Science.gov (United States)

    Johnson, Thomas W; Brett, Michelle A; Roberts, Lesley F; Wassersug, Richard J

    2007-07-01

    Some males desire to be emasculated for no medical reason. These individuals are often secretive about their desires and little is known about their background and motivation. We sought to characterize these modern eunuchs and to identify risk factors for genital self-mutilation or self-administered chemical castration. We posted a questionnaire on the Eunuch Archive ( http://www.eunuch.org) that was responded to by 135 voluntarily castrated males. Questionnaire data were supplemented by accompanying narrative responses and several personal interviews. Participants answered questionnaire items pertaining to their knowledge about androgen deprivation, the nature of their castration, and the length of time between initial presentation of castration paraphilia and castration. These questionnaire data allowed us to compare and contrast voluntary chemical and physical eunuchs. The physical castrations were largely premeditated, with an average of 18 years from the time that an individual developed interest in being a eunuch to the time of their actual castration. We identified four factors that may promote castration ideations: (i) abuse sustained during childhood, including parental threats of castration; (ii) homosexuality; (iii) exposure to animal castration during youth; and (iv) religious condemnation of sexuality. Chemical eunuchs were more likely to have sought castration for libido control or to advance transition from male to female (P Identity Disorder and Gender Identity Disorders occur among those who self-identify as eunuch. We present evidence that the majority of self-identified voluntary eunuchs are not male-to-female transsexuals. Whereas the majority identify as male, many view themselves as in an alternate nonmale, nonfemale, gender space. We therefore suggest that male-to-eunuch is a valid transgender identity.

  4. Peripubertal castration of male rats, adult open field ambulation and partner preference behavior.

    Science.gov (United States)

    Brand, T; Slob, A K

    1988-09-15

    The validity of the hypothesis put forward earlier, that testicular secretions during puberty have an organizing effect on open field ambulation was examined. Male rats were castrated or sham-operated at days 21, 43 or 70. At the age of 17 weeks the males were tested in an automated, octagonal open field (3 consecutive days, 3 min/day) for locomotor activity. Male rats castrated at day 21 or day 43 ambulated more than sham-castrated controls. Males castrated at day 70 did not differ from sham-castrated controls. It thus appears that pubertal testicular secretion(s) organize adult open field locomotor activity in male rats. From 18 weeks of age partner preference behavior was tested in the same open field apparatus with one adjacent cage containing an ovariectomized female and an opposite one containing an ovariectomized female brought into heat. The females in the adjacent cages were separated from the experimental males in the octagonal cage by wire mesh. Peripubertally castrated males did not show a clear-cut partner preference, whereas the intact males preferred the vicinity of the estrous female. There were no differences among the males castrated either before, during or after puberty. Testosterone treatment (crystalline T in silastic capsules) caused peripubertally castrated males to prefer the estrous female. Thus, adult partner preference behavior does not seem to be organized by peripubertal testicular androgens.

  5. live and carcass characteristics of bulls and steers castrated at three ...

    African Journals Online (AJOL)

    and following a finishing period on a moderate level of nutrrtion the animals were slaughtered at l2 to l3 months of age. There was a linear decrease in hight at wither's as the age at castration was delayed. The steers castrated at 3 months had the poorest performance throughout the trial. The buLls produced the heaviest ...

  6. Effects of castration, level of feeding and body weight on Energy ...

    African Journals Online (AJOL)

    Efects of castration, feeding level and body weight on energy partition and efficiency of energy utilisation in growing pigs were studies. Eighteen entire and 18 castrated males, fed on either high (3.34 x maintenance) or low (225 x maintenance) level of feeding in a 2x2 factorial design, with 9 pigs per treatment were used.

  7. Effects of age/weight and castration on fatty acids composition in ...

    African Journals Online (AJOL)

    This study investigates the effects of age/weight and castration on the fatty acid composition and the qualities of pork and pork fat. Thirty hybrid male pigs (50% Meishan x 50% Large White) were used. Fifteen were castrated within the first two days of age and the other fifteen remained entire. At 12 weeks of age, the pigs ...

  8. Effects of castration on growth rate, body and visceral organ weights ...

    African Journals Online (AJOL)

    Effects of castration on growth rate, body and visceral organ weights of pigs were investigated using data from intact males, intact females of Large White pigs full or half castrated at 2, 4, or 6 weeks of age. Body weights and feed intake were recorded to the nearest 0.1 kg at weekly intervals from birth, while weights of ...

  9. Stress responses in lambs castrated with three different methods

    Directory of Open Access Journals (Sweden)

    Paola Sandra Nicolussi

    2010-01-01

    Full Text Available The present work was conducted to evaluate the animal response to stress in lambs caused by three different castration techniques. Forty-six male lambs aged 4-5 months were randomly allocated to one of four groups including Burdizzo (B, scrotal ablation (SA, orchiectomy (OR and control handling (H. Local anaesthesia (lidocaine 2% was administered in both spermatic cords and the scrotal neck of lambs before each treatment. Blood samples were collected at -30, -10, +1, +20, +40, +60, +120, and +180 minutes. Serum cortisol concentrations were determined using a competitive immunoassay and the area under the curve (AUC was calculated for each lamb. The following biochemical parameters were assayed for each animal at each time point: alanine aminotransferase (ALT, aspartate aminotransferase (AST, lactate dehydrogenase (LDH, creatine kinase (CK and glucose (GLU. The time needed for total lesion resolution and weight gain of each animal was recorded. Orchiectomy elicits the greatest cortisol response, significantly greater than that seen in similarly handled controls (P≤0.01, Burdizzo and scrotal ablation groups (P≤0.05. The serum cortisol AUC was higher in the scrotal ablation group (P≤0.05 than controls, but lower than in the orchiectomy group (P≤0.05. The Burdizzo group didn’t differ from controls. Serum glucose levels of the castrated lambs differed significantly from the control group, following a trend similar to cortisol. No change was seen in ALT, AST, LDH or CK. No difference in weight gain was seen among the groups. Our results suggest that use of the Burdizzo is the preferable castration technique for adult lambs, while scrotal ablation is a valid surgical alternative to orchiectomy and permits more rapid wound healing that is ideal for extensive management where flocks are not under close observation.

  10. Castration resistant prostate cancer - something new in the year 2014?

    International Nuclear Information System (INIS)

    Marencak, J.

    2014-01-01

    Prostate cancer (PC) is the most frequent solid neoplasm in Europe and therefore is regarded as one of the major medical problem of the male population. PC is extremely complicated and interindividual different tumor. The method of treatment depends on several factors, but mainly on the stage of prostate cancer. The term Hormone resistant (refractory) prostate cancer (HRPC) was used in older terminology. HRPC is cancer that progresses despite castrate levels of testosterone achieved androgen deprivation therapy (ADT), which is resistant to any hormonal therapy. Currently is increasingly used (instead of name HRPC) name CRPC – so called PC resistant for castration (CRPC – castration resistant prostate cancer), which is still able to respond to certain hormonal manipulation, although it meets the the criteria for HRPC. This state probably arises from either clonal selection of androgen – independent cell lines or increased ligand – independent activation of androgen receptors. Men with CRPC are quite a heterogeneous group; they include men with increasing prostate specific antigen (PSA) only and no demonstrable metastases, and men who have many bone and/ or visceral metastases, pain and poor functional status. Survival can range from only a few months to 4 years or more. Historically, therapy had little effect beyond modest palliation. More recently, significantly more options have become available and there are now several treatments that not only improve quality of life and pain palliation, but also increase overall survival. Some of the trials with important results for the treatment of CRPC are summarized in this paper. Objectives of article: provide information to the general medical community (and especially urologists and oncologists) about the possible pathogenesis of CRPC, complicated issues of treatment and evaluation of its effectiveness in patients with CRPC. The article presented basic data on the current and future possibilities of such therapy

  11. Empirical support for optimal virulence in a castrating parasite.

    Directory of Open Access Journals (Sweden)

    Knut Helge Jensen

    2006-07-01

    Full Text Available The trade-off hypothesis for the evolution of virulence predicts that parasite transmission stage production and host exploitation are balanced such that lifetime transmission success (LTS is maximised. However, the experimental evidence for this prediction is weak, mainly because LTS, which indicates parasite fitness, has been difficult to measure. For castrating parasites, this simple model has been modified to take into account that parasites convert host reproductive resources into transmission stages. Parasites that kill the host too early will hardly benefit from these resources, while postponing the killing of the host results in diminished returns. As predicted from optimality models, a parasite inducing castration should therefore castrate early, but show intermediate levels of virulence, where virulence is measured as time to host killing. We studied virulence in an experimental system where a bacterial parasite castrates its host and produces spores that are not released until after host death. This permits estimating the LTS of the parasite, which can then be related to its virulence. We exposed replicate individual Daphnia magna (Crustacea of one host clone to the same amount of bacterial spores and followed individuals until their death. We found that the parasite shows strong variation in the time to kill its host and that transmission stage production peaks at an intermediate level of virulence. A further experiment tested for the genetic basis of variation in virulence by comparing survival curves of daphniids infected with parasite spores obtained from early killing versus late killing infections. Hosts infected with early killer spores had a significantly higher death rate as compared to those infected with late killers, indicating that variation in time to death was at least in part caused by genetic differences among parasites. We speculate that the clear peak in lifetime reproductive success at intermediate killing times

  12. Quality Characteristics and Composition of the Muscle from Entire and Castrate Elk in Korea

    Directory of Open Access Journals (Sweden)

    Sang-Woo Kim

    2016-05-01

    Full Text Available The objective of the research was to determine the chemical composition as well as the physicochemical properties of the longissimus muscle from Korean entire and castrate elk. Twelve elk stags were raised and fed on concentrate with ad libitum hay. All animals were equally divided into castrated and non-castrated (entire males, and slaughtered at 5 year of age. It was found that entire elk, in comparison with castrate elk, had higher content of moisture and lower content of fat (p<0.05. Compared with entire males, the castrates had lower pH and shear force values (p<0.05. However, castrates had higher L*, a*, and b* values compared with entires (p<0.05. An analysis of the fatty acid profile revealed that the muscles of entire and castrate elk had the most abundant concentrations of the following fatty acids: palmitic acid (C16:0 of the saturated fatty acid, and oleic acid (C18:1n-9 of the unsaturated fatty acid. The entire elk contains higher proportions of linoleic acid (C18:3n6, eicosenoic acid (C20:1n9, and arachidonic acid (C20:4n6 (p<0.05. Cholesterol content in elk was not affected by castration. The predominant free amino acid was glutamic acid related to umami taste. It is apparent that the castrate animals carried higher content of histidine, isoleucine, and leucine than those of the entire group (p<0.05. In this study, it was concluded that venison quality of elk is affected by castration and these results can provide fundamental information for venison production.

  13. Objective measures for the assessment of post-operative pain in bos indicus bull calves following castration

    DEFF Research Database (Denmark)

    Musk, Gabrielle C.; Jacobsen, Stine; Hyndman, Timothy H.

    2017-01-01

    The aim of the study was to assess pain in Bos indicus bull calves following surgical castration. Forty-two animals were randomised to four groups: no castration (NC, n = 6); castration with pre-operative lidocaine (CL, n = 12); castration with pre-operative meloxicam (CM, n = 12); and, castration...... in the concentrations of SAA, haptoglobin, and fibrinogen in all of the groups from day 0 to 3. Iron concentrations were not different at the time points it was measured. The results of this study suggest that animals rest for longer periods after the pre-operative administration of meloxicam. The other objective...

  14. Parasitic castration by Xenos vesparum depends on host gender.

    Science.gov (United States)

    Cappa, Federico; Manfredini, Fabio; Dallai, Romano; Gottardo, Marco; Beani, Laura

    2014-07-01

    Host castration represents a mechanism used by parasites to exploit energy resources from their hosts by interfering with their reproductive development or to extend host lifespan by removing risks associated with reproductive activity. One of the most intriguing groups of parasitic castrators is represented by the insects belonging to the order Strepsiptera. The macroparasite Xenos vesparum can produce dramatic phenotypic alterations in its host, the paper wasp Polistes dominula. Parasitized female wasps have undeveloped ovaries and desert the colony without performing any social task. However, very little attention has been given to the parasitic impact of X. vesparum on the male phenotype. Here, we investigated the effects of this parasite on the sexual behaviour and the morpho-physiology of P. dominula males. We found that, differently from female wasps, parasitized males are not heavily affected by Xenos: they maintain their sexual behaviour and ability to discriminate between female castes. Furthermore, the structure of their reproductive apparatus is not compromised by the parasite. We think that our results, demonstrating that the definition of X. vesparum as a parasitoid does not apply to infected males of P. dominula, provide a new perspective to discuss and maybe reconsider the traditional view of strepsipteran parasites.

  15. Update on castrate-resistant prostate cancer: 2010.

    Science.gov (United States)

    Lassi, Kiran; Dawson, Nancy A

    2010-05-01

    Prostate cancer remains a medical dilemma and a major cause of morbidity and mortality in many western countries. It represents the most common cancer in US men, with an estimated 192 280 new cases diagnosed in 2009. The median survival for men with metastatic castrate-resistant prostate cancer is 1-2 years, with improvements in survival seen primarily with docetaxel-based therapies. The purpose of this article is to discuss developments of novel agents in the field of metastatic castration-resistant prostate cancer (CRPC), including new cytotoxic agents, immune-based therapies, circulating tumor markers and targeting agents. During this past year, several promising approaches yielded disappointing results in the phase III setting (GVAX); nonetheless, expectations for other agents (Abiraterone, MDV3100, Zibotentan, immunotherapy agents) still remain high. Systemic therapy options are limited in CRPC and survival benefit remains to be seen with the new therapies. Circulating tumor cells continue to provide important prognostic information and will likely become an important aspect of future clinical decision-making.

  16. Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand break repair.

    Science.gov (United States)

    Tarish, Firas L; Schultz, Niklas; Tanoglidi, Anna; Hamberg, Hans; Letocha, Henry; Karaszi, Katalin; Hamdy, Freddie C; Granfors, Torvald; Helleday, Thomas

    2015-11-04

    Chemical castration improves responses to radiotherapy in prostate cancer, but the mechanism is unknown. We hypothesized that this radiosensitization is caused by castration-mediated down-regulation of nonhomologous end joining (NHEJ) repair of DNA double-strand breaks (DSBs). To test this, we enrolled 48 patients with localized prostate cancer in two arms of the study: either radiotherapy first or radiotherapy after neoadjuvant castration treatment. We biopsied patients at diagnosis and before and after castration and radiotherapy treatments to monitor androgen receptor, NHEJ, and DSB repair in verified cancer tissue. We show that patients receiving neoadjuvant castration treatment before radiotherapy had reduced amounts of the NHEJ protein Ku70, impaired radiotherapy-induced NHEJ activity, and higher amounts of unrepaired DSBs, measured by γ-H2AX foci in cancer tissues. This study demonstrates that chemical castration impairs NHEJ activity in prostate cancer tissue, explaining the improved response of patients with prostate cancer to radiotherapy after chemical castration. Copyright © 2015, American Association for the Advancement of Science.

  17. Castration modulates singing patterns and electrophysiological properties of RA projection neurons in adult male zebra finches

    Directory of Open Access Journals (Sweden)

    Songhua Wang

    2014-04-01

    Full Text Available Castration can change levels of plasma testosterone. Androgens such as testosterone play an important role in stabilizing birdsong. The robust nucleus of the arcopallium (RA is an important premotor nucleus critical for singing. In this study, we investigated the effect of castration on singing patterns and electrophysiological properties of projection neurons (PNs in the RA of adult male zebra finches. Adult male zebra finches were castrated and the changes in bird song assessed. We also recorded the electrophysiological changes from RA PNs using patch clamp recording. We found that the plasma levels of testosterone were significantly decreased, song syllable’s entropy was increased and the similarity of motif was decreased after castration. Spontaneous and evoked firing rates, membrane time constants, and membrane capacitance of RA PNs in the castration group were lower than those of the control and the sham groups. Afterhyperpolarization AHP time to peak of spontaneous action potential (AP was prolonged after castration.These findings suggest that castration decreases song stereotypy and excitability of RA PNs in male zebra finches.

  18. Long-term weight gain and economic impact in pigs castrated under local anaesthesia

    Directory of Open Access Journals (Sweden)

    F.G. Telles

    2016-12-01

    Full Text Available Castration is a controversial practice in swine production because in some countries is still performed without anaesthesia, and therefore causes intense suffering and stress to animals. This study investigated the effect of pre-surgical administration of local anaesthesia (LA on the growth performance of piglets until the end of the growth phase (102 days. Piglets aged 3 to 5 days were selected in pairs of similar weights and same age. They were originated from 22 litters. The groups were randomly assigned to one of two treatments. Castration was performed with (LA; n = 45 or without (NLA; n = 45 intra-testicular administration of 0.5 mL of 2% lidocaine plus adrenaline per testicle, administered by an automatic repeating vaccinator. Castration was performed 10 min later. Average daily weight gain and economic impact were evaluated between the intervals before castration until 21 (weaning phase, before castration until 60 (end of the initial nursery phase and before castration until 102 (growth phase days of age. Average daily weight gain data were analyzed by comparing the average daily weight gain between the weaning phase, 60 and 102 days of age versus the initial weight (pre-castration. At the end of the growing phase, animals treated with LA showed greater weight gain than animals castrated without anaesthesia. LA also showed improved cost:benefit ratio and theore might provide greater economic benefit under the conditions used in this study. Our findings have proved that castration with LA improves long-term weight gain of piglets.

  19. Testosterone improves erectile function through inhibition of reactive oxygen species generation in castrated rats

    Directory of Open Access Journals (Sweden)

    Rui Li

    2016-05-01

    Full Text Available Testosterone is overwhelmingly important in regulating erectile physiology. However, the associated molecular mechanisms are poorly understood. The purpose of this study was to explore the effects and mechanisms of testosterone in erectile dysfunction (ED in castrated rats. Forty male Sprague-Dawley rats were randomized to four groups (control, sham-operated, castration and castration-with-testosterone-replacement. Reactive oxygen species (ROS production was measured by dihydroethidium (DHE staining. Erectile function was assessed by the recording of intracavernous pressure (ICP and mean arterial blood pressure (MAP. Protein expression levels were examined by western blotting. We found that castration reduced erectile function and that testosterone restored it. Nitric oxide synthase (NOS activity was decrease in the castrated rats, and testosterone administration attenuated this decrease (each p < 0.05. The testosterone, dihydrotestosterone, cyclic guanosine monophosphate (cGMP and cyclic adenosine monophosphate (cAMP concentrations were lower in the castrated rats, and testosterone restored these levels (each p < 0.05. Furthermore, the cyclooxygenase-2 (COX-2 and prostacyclin synthase (PTGIS expression levels and phospho-endothelial nitric oxide synthase (p-eNOS, Ser1177/endothelial nitric oxide synthase (eNOS ratio were reduced in the castrated rats compared with the controls (each p < 0.05. In addition, the p40phox and p67phox expression levels were increased in the castrated rats, and testosterone reversed these changes (each p < 0.05. Overall, our results demonstrate that testosterone ameliorates ED after castration by reducing ROS production and increasing the activity of the eNOS/cGMP and COX-2/PTGIS/cAMP signaling pathways.

  20. Total antiradical activity in male castrated piglets blood: reference values

    Directory of Open Access Journals (Sweden)

    Carlo Corino

    2010-01-01

    Full Text Available Blood samples from 146 male castrated piglets in the range of 10-47kg body weight were collected from the same farm and analysed for total antiradical activity in order to determine reference intervals. Data were tested for normality and then submitted to reference limit evaluation. The reference values found in piglets, expressed as half-hemolysis time (59.34 – 93.60 and 43.94 – 66.90 minutes for blood and red blood cell, respectively, are lower than those found in humans; further studies are needed to extend reference values study to female and to animals of different weight classes and different genetic type.

  1. New Therapeutics to Treat Castrate-Resistant Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Ömer Acar

    2013-01-01

    Full Text Available The effective treatment of castrate-resistant prostate cancer (CRPC has proven to be very challenging. Until recently, docetaxel was the only therapeutic demonstrated to extend overall patient survival. Yet recently, a considerable number of new therapeutics have been approved to treat CRPC patients. These remarkable advances now give new tools for the therapeutic management of late-stage prostate cancer. In this review, we will examine mechanistic and clinical data of several newly approved therapeutics including the chemotherapeutic cabazitaxel, antiandrogen enzalutamide, endocrine disruptor abiraterone acetate, immunotherapy sipuleucel-T, and bone-targeting radiopharmaceutical alpharadin. In addition, we will examine other promising therapeutics that are currently in Phase III trials.

  2. Acute physiological responses to castration-related pain in piglets: the effect of two local anesthetics with or without meloxicam.

    Science.gov (United States)

    Bonastre, C; Mitjana, O; Tejedor, M T; Calavia, M; Yuste, A G; Úbeda, J L; Falceto, M V

    2016-09-01

    Methods to reduce castration-related pain in piglets are still issues of concern and interest for authorities and producers. Our objectives were to estimate the effectiveness of two protocols of local anesthesia (lidocaine and the combination of lidocaine+bupivacaine) as well as the use of meloxicam as a postoperative analgesic in alleviating castration-related pain, measured by acute physiological responses. Eight groups (15 piglets/group) were included in the study: (1) castration without anesthesia or analgesia, without meloxicam (TRAD WITHOUT), (2) castration without anesthesia or analgesia, but with meloxicam (TRAD WITH), (3) handling without meloxicam (SHAM WITHOUT), (4) handling with meloxicam (SHAM WITH), (5) castration after local anesthesia with lidocaine but without meloxicam (LIDO WITHOUT), (6) castration after local anesthesia with lidocaine and meloxicam (LIDO WITH), (7) castration after local anesthesia with lidocaine+bupivacaine without meloxicam (LIDO+BUPI WITHOUT), (8) castration after local anesthesia with lidocaine+bupivacaine and meloxicam (LIDO+BUPI WITH). Acute physiological responses measured included skin surface temperature and serum glucose and cortisol concentrations. On days 4 and 11 post-castration BW was recorded and average daily gain was calculated over this period. Furthermore, piglet mortality was recorded over the 11-day post-castration period. Administration of local anesthetic or meloxicam did not prevent the decrease in skin surface temperature associated with castration. Lidocaine reduced the increase in glucose concentration associated with castration. For castrated pigs, the joint use of lidocaine and meloxicam caused a significant decrease in cortisol concentration; the combination of intratesticular lidocaine and bupivacaine did not seem to be more effective than lidocaine alone. No effect of treatments on mortality and growth were detected.

  3. Experimental study of apoptosis in the prostate tissue following castration

    Directory of Open Access Journals (Sweden)

    Y Doustar

    2008-02-01

    Full Text Available The Prostate gland is one of the accessory reproductive glands with important physiological functions necessary for successful reproduction. This gland depends on the presence of sex hormones including androgens for its natural function and normal growth and development. So in the case of hyperplasia, hypertrophy or other prostatic disease the most successful and efficient method of treatment is androgenic control that in some cases is unavoidable. The purpose of this study was to investigate the effects of androgenic depletion states by means of castration on the induction of apoptosis in the epithelial glandular cells of the prostate tissue. Two groups of male dogs each containing 5 animals per group were used in this study. The dogs were under observation for 1 month to detect any possible diseases or disorders. After this period the dogs in the treatment group underwent open castration to decrease the levels of the androgenic hormones in the blood while the dogs in the control group were left intact. One week after surgery, the prostate glands of control and treatment animals were collected and used to prepare microscopic sections. The sections were evaluated following staining with TUNEL (TerminaldeoxyNucleotidyl (dUTP transferase-mediated End Labeling and H&E methods. The Mann – Whitney U test was used for statistical analysis. Histopathological studies in the treatment group revealed the presence of various forms of apoptotic cells in the glandular epithelium. Average number of apoptotic cells in ten microscopic fields were significantly higher in the treatment group compared with the control group (p

  4. Protein and Amino Acid Profile of Filial Etawah Crossbred and Castrated Filial Boer Crossbred Goat Meat

    Directory of Open Access Journals (Sweden)

    Hari Purnomo

    2012-03-01

    Full Text Available The aim of this study was to know the protein content and amino acid profile of filial Etawah and castrated Boer goat meat. The results were expected to be used as information about protein content and amino acid composition of filial Etawah and filial castrated Boer goat meat and  as a reference for further experiment about different livestock. The material of the research were loin meat, front  and back thigh of filial Etawah and filial castrated Boer goat meat. Data were analysed with t-test. The results showed that castrated filial Boer goat meat had significantly higher protein content  and 7 essensial amino acids namely lysine, leucine, arginine, phenylalanine, isoleucine, valine and histidine compared to the one from filial Etawah goat meat. Key words: protein, amino acid profiles, goat  meat

  5. In vivo quantitative phosphoproteomic profiling identifies novel regulators of castration-resistant prostate cancer growth

    DEFF Research Database (Denmark)

    Jiang, Nan; Hjorth-Jensen, Kim; Hekmat, Omid

    2015-01-01

    timing. Interestingly, these phenotypic changes occur in the absence of obvious alterations in the activity of AKT, MAPK or mTORC1 pathways, suggesting that PAK2 and YAP1 may represent novel targets for the treatment of castration-resistant prostate cancer. Pharmacologic inhibitors of PAK2 (PF-3758309......Prostate cancer remains a leading cause of cancer-related mortality worldwide owing to our inability to treat effectively castration-resistant tumors. To understand the signaling mechanisms sustaining castration-resistant growth, we implemented a mass spectrometry-based quantitative proteomic...... approach and use it to compare protein phosphorylation in orthotopic xenograft tumors grown in either intact or castrated mice. This investigation identified changes in phosphorylation of signaling proteins such as MEK, LYN, PRAS40, YAP1 and PAK2, indicating the concomitant activation of several oncogenic...

  6. Castration promotes welfare in group-housed male Swiss outbred mice maintained in educational institutions.

    Science.gov (United States)

    Vaughan, Lewis M; Dawson, Jane S; Porter, Paula R; Whittaker, Alexandra L

    2014-01-01

    Educational institutions maintain group-housed mice of both sexes for training veterinarians and technicians in husbandry, medication, and sampling procedures. Mice kept in all-male groups may experience poor welfare due to fighting. Castrated mice may be used to replace gonadally intact males for such training programs. In this prospective cohort study, 80 castrated and 80 control (intact) male mice were studied over 3 mo to monitor aggression frequency and injury levels. Behavioral observations were performed twice weekly by using an all-occurrences sampling method to quantify behavioral events and the number and severity of bite wounds. Under these housing conditions, group-housed male mice castrated postpubertally exhibited significantly less aggression than did intact male mice. Castration therefore improves welfare in group-housed male mice and thus provides a husbandry alternative to individually housing animals in nonstudy situations.

  7. Temporal patterns of inflammatory gene expression in local tissues after banding or burdizzo castration in cattle

    Directory of Open Access Journals (Sweden)

    Sweeney Torres

    2009-09-01

    Full Text Available Abstract Background Castration of male cattle has been shown to elicit inflammatory reactions and acute inflammation is initiated and sustained by the participation of cytokines. Methods Sixty continental × beef bulls (Mean age 12 ± (s.e. 0.2 months; Mean weight 341 ± (s.e. 3.0 kg were blocked by weight and randomly assigned to one of three treatments (n = 20 animals per treatment: 1 untreated control (Con; 2 banding castration at 0 min (Band; 3 Burdizzo castration at 0 min (Burd. Samples of the testis, epididymis and scrotal skin were collected surgically from 5 animals from each group at 12 h, 24 h, 7 d, and 14 d post-treatment, and analysed using real-time PCR. A repeated measurement analysis (Proc GLM was performed using SAS. If there was no treatment and time interaction, main effects of treatment by time were tested by ANOVA. Results Electrophoresis data showed that by 7 d post-castration RNA isolated from all the testicle samples of the Burd castrated animals, the epididymis and middle scrotum samples from Band castrates were degraded. Transitory effects were observed in the gene expression of IFN-γ, IL-6, IL-8 and TNF-α at 12 h and 24 h post treatment. Burd castrates had greater (P Conclusion Banding castration caused more inflammatory associated gene expression changes to the epididymis and scrotum than burdizzo. Burdizzo caused more severe acute inflammatory responses, in terms of pro-inflammatory cytokine gene expression, in the testis and epididymis than banding.

  8. Self-castration by a transsexual woman: financial and psychological costs: a case report.

    Science.gov (United States)

    St Peter, Matthew; Trinidad, Anton; Irwig, Michael S

    2012-04-01

    The out-of-pocket cost for an elective orchiectomy, which is often not covered by health insurance, is a significant barrier to male-to-female transsexuals ready to proceed with their physical transition. This and other barriers (lack of access to a surgeon willing to perform the operation, waiting times, and underlying psychological and psychiatric conditions) lead a subset of transsexual women to attempt self-castration. Little information has been published on the financial costs and implications of self-castration to both patients and health care systems. We compare the financial and psychological costs of elective surgical orchiectomy vs. self-castration in the case of a transsexual woman in her 40s. We interviewed the patient and her providers and obtained financial information from local reimbursement and billing specialists. After experiencing minor hemorrhage following the self-castration, our patient presented to the emergency department and underwent a bilateral inguinal exploration, ligation and removal of bilateral spermatic cords, and complicated scrotal exploration, debridement, and closure. She was admitted to the psychiatric service for a hospital stay of three days. The total bill was U.S. $14,923, which would compare with U.S. $4,000 for an elective outpatient orchiectomy in the patient's geographical area. From a financial standpoint, an elective orchiectomy could have cost the health care system significantly less than a hospital admission with its associated additional costs. From a patient safety standpoint, elective orchiectomy is preferable to self-castration which carries significant risks such as hemorrhage, disfigurement, infection, urinary fistulae, and nerve damage. Healthcare providers of transsexual women should carefully explore patient attitudes toward self-castration and work toward improving access to elective orchiectomy to reduce the number of self-castrations and costs to the overall health care system. Further research on the

  9. Sox2 is an androgen receptor-repressed gene that promotes castration-resistant prostate cancer.

    Directory of Open Access Journals (Sweden)

    Steven Kregel

    Full Text Available Despite advances in detection and therapy, castration-resistant prostate cancer continues to be a major clinical problem. The aberrant activity of stem cell pathways, and their regulation by the Androgen Receptor (AR, has the potential to provide insight into novel mechanisms and pathways to prevent and treat advanced, castrate-resistant prostate cancers. To this end, we investigated the role of the embryonic stem cell regulator Sox2 [SRY (sex determining region Y-box 2] in normal and malignant prostate epithelial cells. In the normal prostate, Sox2 is expressed in a portion of basal epithelial cells. Prostate tumors were either Sox2-positive or Sox2-negative, with the percentage of Sox2-positive tumors increasing with Gleason Score and metastases. In the castration-resistant prostate cancer cell line CWR-R1, endogenous expression of Sox2 was repressed by AR signaling, and AR chromatin-IP shows that AR binds the enhancer element within the Sox2 promoter. Likewise, in normal prostate epithelial cells and human embryonic stem cells, increased AR signaling also decreases Sox2 expression. Resistance to the anti-androgen MDV3100 results in a marked increase in Sox2 expression within three prostate cancer cell lines, and in the castration-sensitive LAPC-4 prostate cancer cell line ectopic expression of Sox2 was sufficient to promote castration-resistant tumor formation. Loss of Sox2 expression in the castration-resistant CWR-R1 prostate cancer cell line inhibited cell growth. Up-regulation of Sox2 was not associated with increased CD133 expression but was associated with increased FGF5 (Fibroblast Growth Factor 5 expression. These data propose a model of elevated Sox2 expression due to loss of AR-mediated repression during castration, and consequent castration-resistance via mechanisms not involving induction of canonical embryonic stem cell pathways.

  10. Hepatic transcriptional changes in critical genes for gluconeogenesis following castration of bulls

    Directory of Open Access Journals (Sweden)

    Dilla Mareistia Fassah

    2018-04-01

    Full Text Available Objective This study was performed to understand transcriptional changes in the genes involved in gluconeogenesis and glycolysis pathways following castration of bulls. Methods Twenty Korean bulls were weaned at average 3 months of age, and castrated at 6 months. Liver tissues were collected from bulls (n = 10 and steers (n = 10 of Korean cattle, and hepatic gene expression levels were measured using quantitative real-time polymerase chain reaction. We examined hepatic transcription levels of genes encoding enzymes for irreversible reactions in both gluconeogenesis and glycolysis as well as genes encoding enzymes for the utilization of several glucogenic substrates. Correlations between hepatic gene expression and carcass characteristics were performed to understand their associations. Results Castration increased the mRNA (3.6 fold; p<0.01 and protein levels (1.4 fold; p< 0.05 of pyruvate carboxylase and mitochondrial phosphoenolpyruvate carboxykinase genes (1.7 fold; p<0.05. Hepatic mRNA levels of genes encoding the glycolysis enzymes were not changed by castration. Castration increased mRNA levels of both lactate dehydrogenase A (1.5 fold; p<0.05 and lactate dehydrogenase B (2.2 fold; p<0.01 genes for lactate utilization. Castration increased mRNA levels of glycerol kinase (2.7 fold; p<0.05 and glycerol-3-phosphate dehydrogenase 1 (1.5 fold; p<0.05 genes for glycerol utilization. Castration also increased mRNA levels of propionyl-CoA carboxylase beta (mitochondrial (3.5 fold; p<0.01 and acyl-CoA synthetase short chain family member 3 (1.3 fold; p = 0.06 genes for propionate incorporation. Conclusion Castration increases transcription levels of critical genes coding for enzymes involved in irreversible gluconeogenesis reactions from pyruvate to glucose and enzymes responsible for incorporation of glucogenic substrates including lactate, glycerol, and propionate. Hepatic gluconeogenic gene expression levels were associated with intramuscular

  11. Routine castration in 568 draught colts: incidence of evisceration and omental herniation.

    Science.gov (United States)

    Shoemaker, R; Bailey, J; Janzen, E; Wilson, D G

    2004-05-01

    Castration is one of the most common routine surgical procedures performed in the horse, from which a number of potential complications can arise. We undertook a prospective evaluation of short-term complications associated with castration of draught colts over a 3-year period (1998-2000). To compare castration complications in a large number of draught foals with previously published literature. Five hundred and sixty-eight draught colts, age 4 or 5 months, were castrated in field conditions. Foals were observed for complications for 24 h post operatively. There was no significant difference in complication rates between open and closed surgical techniques. Inguinal/scrotal hernia rate was 4.6% (26/568) prior to surgery, and evisceration of the small intestine occurred in 4.8% (27/568). Foals observed to eviscerate underwent immediate surgical correction with an overall survival rate of 72.2% (13/18). Omental herniation was seen in 2.8% (16/568) of colts. This study showed no difference between the closed and open techniques of castration and the rate of omental herniation or evisceration. The evisceration rate in combination with the omental and presurgical herniation rates approached 12.2%, which is high enough to warrant further examination. Future investigation should help to assess predisposing factors for evisceration. Regardless of the technique employed, herniation appears to pose a significant risk to draught foals undergoing castration.

  12. Efficacy of oral meloxicam suspension for prevention of pain and inflammation following band and surgical castration in calves.

    Science.gov (United States)

    Olson, M E; Ralston, Brenda; Burwash, Les; Matheson-Bird, Heather; Allan, Nick D

    2016-06-13

    Castration is one of the most common procedures performed on beef and dairy cattle. The objective of the study was to determine the efficacy of meloxicam oral suspension in reducing pain and inflammation in calves following band or surgical castration. Two identical trials with the exception of the method of castration (Band Castration Study 1 and Surgical Castration Study 2) were conducted. Sixty (60) healthy Holstein calves 4 to 5 months of age (138-202 Kg) were used. Animals received either Meloxicam Oral Suspension at a dose of 1 mg/kg BW (n = 15 Study 1 and 15 Study 2) or Saline (n = 15 Study 1 and 15 Study 2) 2 h before castration. Physiological (Heart Rate, Plasma Cortisol and Plasma Substance P) and Behavioral (Visual Analog Scale (VAS), Accelerometers and tail Pedometers) evaluations were conducted before (day -1) and after Castration (Day 0, 1, 2, 3). Inflammation was evaluated daily by providing an individual animal score (Study1) or with a measurement of scrotal thickness (Study 2). Heart rates were significantly greater in control animals following band and surgical castration. Plasma cortisol and substance P were significantly reduced in animals receiving Meloxicam Oral Suspension. Control animals had significantly greater VAS scores. Accelerometers showed that meloxicam treated animals had a significantly greater motion index and number of steps as well as less % time lying and number of lying bouts. The scrotal inflammation (based on scrotal swelling) was significantly decreased in the meloxicam treated animals compared to the control animals on day 1, day 2 and 3. Meloxicam Oral Suspension was able to significantly reduce the display of painful behaviors and physiological responses to pain in band castrated and surgical castrated calves for up to 72 h following a single oral treatment of 1 mg/kg body weight. Meloxicam Oral Suspension was able to significantly reduce scrotal inflammation in band castrated and surgical castrated calves.

  13. Emerging therapies in castrate-resistant prostate cancer.

    Science.gov (United States)

    Lassi, Kiran; Dawson, Nancy A

    2009-05-01

    Prostate cancer continues to represent a major health problem. It represents the most common cancer in US men, with an estimated 186 320 new cases diagnosed in 2008. It is the second leading cause of cancer death in men in the United States. Despite several attempts, the median survival for men with metastatic castrate-resistant prostate cancer is 1-2 years, with improvements in survival seen primarily with docetaxel-based therapies. Treatment options are limited, and there is a clear need for therapies that improve outcome. The purpose of this article is to discuss recent developments in the field of metastatic hormone-refractory prostate cancer, including new cytotoxic agents, antiproliferative agents, immune-based therapies, circulating tumor markers and antiangiogenic agents. During this last year, several promising approaches yielded disappointing results in the phase III setting (GVAX, satraplatin, DN-101); nonetheless, expectations for other agents (abiraterone, zibotentan, Provenge) still remain high. These new agents will need to demonstrate survival benefit for approval. Circulating tumor cells have been shown to provide important prognostic information and are anticipated to be incorporated in future clinical decision-making.

  14. Emerging targeted therapies for castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Vincenzo eAdamo

    2012-05-01

    Full Text Available Until recently, few therapeutic options were available for patients with castration-resistant prostate cancer (CRPC. Since 2010, four new molecules with a demonstrated benefit (sipuleucel-T, cabazitaxel, abiraterone and denosumab have been approved in this setting, and to-date several other agents are under investigation in clinical trials. The purpose of this review is to present an update of targeted therapies for CRPC. Presented data are obtained from literature and congress reports updated until December 2011. Targeted therapies in advanced phases of clinical development include novel hormone-therapeutic, intracellular molecular pathways inhibiting, anti-angiogenic, bone microenvironment targeting and immunotherapeutic agents. Radium-223 and MDV3100 demonstrated a survival advantage in phase III trials and the road for their introduction in clinical practice is rapidly ongoing. Results are also awaited for phase III studies currently underway or planned with new drugs given as monotherapy (TAK-700, cabozantinib, tasquinimod, PROSTVAC-VF, ipilimumab or in combination with docetaxel (custirsen, aflibercept, dasatinib, zibotentan. Optimal timing, right combination and/or sequencing of emerging therapies as well as use of more sensitive biological markers to individualize therapies for CRPC remain challenging and studies to investigate these aspects are needed.

  15. Effects of surgical and chemical castration on spatial learning ability in relation to cell proliferation and apoptosis in hippocampus.

    Science.gov (United States)

    Shin, Mal-Soon; Chung, Kyung Jin; Ko, Il-Gyu; Kim, Sang-Hoon; Jin, Jun-Jang; Kim, Sung-Eun; Lee, Jae-Min; Ji, Eun-Sang; Kim, Tae-Woon; Cho, Han-Sam; Kim, Chang Hee; Cho, Young-Sam; Kim, Chang-Ju; Kim, Khae-Hawn

    2016-04-01

    Chemical castration using luteinizing hormone-releasing hormone agonists and/or anti-androgens is an alternative to surgical castration. Goserelin and bicalutamide are representative drugs used for chemical castration. The effects of chemical castration on sexual functions are well documented; however, the possibility that chemical castration might induce undesirable effects on brain functions has been raised. We investigated the effects of chemical castration and surgical castration on spatial learning ability in relation to cell proliferation and apoptosis in hippocampus. Bilateral orchiectomy was performed for surgical castration, and chemical castration was induced by treatment with goserelin or bicalutamide for 28 days. To find out the effects of goserelin and bicalutamide with those of orchiectomy on the spatial learning ability, radial eight-arm maze test was performed. To find out the effects of goserelin and bicalutamide with those of orchiectomy in relation to cell proliferation and apoptosis in the hippocampus, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining, and immunohistochemistry for 5-bromo-2'-deoxyuridine, doublecortin, and caspase-3 were performed. Western blot for brain-derived neurotrophic factor, tyrosine kinase receptor B, Bax, and Bcl-2 in the hippocampus was also performed. Orchiectomy caused deterioration of spatial learning ability with suppression of cell proliferation and enhancement of apoptosis in the hippocampus. However, treatment with goserelin and bicalutamide had no effect on spatial learning ability. Cell proliferation and apoptosis were not altered by treatment with goserelin and bicalutamide either. Surgical castration causes deterioration of spatial learning ability, while chemical castration does not impair spatial learning ability. We should find out further mechanisms affect to the relationship between androgen level and neurogenesis and neuronal apoptosis.

  16. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant

    Science.gov (United States)

    Sun, Shihua; Sprenger, Cynthia C.T.; Vessella, Robert L.; Haugk, Kathleen; Soriano, Kathryn; Mostaghel, Elahe A.; Page, Stephanie T.; Coleman, Ilsa M.; Nguyen, Holly M.; Sun, Huiying; Nelson, Peter S.; Plymate, Stephen R.

    2010-01-01

    Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are due to the generation of constitutively active AR splice variants, but the mechanisms by which these splice variants could mediate such effects are not fully understood. Here we have identified what we believe to be a novel human AR splice variant in which exons 5, 6, and 7 are deleted (ARv567es) and demonstrated that this variant can contribute to cancer progression in human prostate cancer xenograft models in mice following castration. We determined that, in human prostate cancer cell lines, ARv567es functioned as a constitutively active receptor, increased expression of full-length AR (ARfl), and enhanced the transcriptional activity of AR. In human xenografts, human prostate cancer cells transfected with ARv567es cDNA formed tumors that were resistant to castration. Furthermore, the ratio of ARv567es to ARfl expression within the xenografts positively correlated with resistance to castration. Importantly, we also detected ARv567es frequently in human prostate cancer metastases. In summary, these data indicate that constitutively active AR splice variants can contribute to the development of castration-resistant prostate cancers and may serve as biomarkers for patients who are likely to suffer from early recurrence and are candidates for therapies directly targeting the AR rather than ligand. PMID:20644256

  17. A Novel Role for Raloxifene Nanomicelles in Management of Castrate Resistant Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Sebastien Taurin

    2014-01-01

    Full Text Available Of patients with castrate resistant prostate cancer (CRPC, less than 25–33% survive more than five years. Recent studies have implicated estrogen, acting either alone or synergistically with androgens in the development of castrate resistant prostate cancer. Several in vitro and in vivo studies, as well as a limited number of clinical trials, have highlighted the potential of selective estrogen receptor modulators, such as raloxifene (Ral for the treatment of castrate resistant prostate cancer. However, the poor oral bioavailability and metabolism of selective estrogen receptor modulators limit their efficiency in clinical application. To overcome these limitations, we have used styrene co-maleic acid (SMA micelle to encapsulate raloxifene. Compared to free drug, SMA-Ral micelles had 132 and 140% higher cytotoxicity against PC3 and DU 145 prostate cell lines, respectively. SMA-Ral effectively inhibits cell cycle progression, increases apoptosis, and alters the integrity of tumor spheroid models. In addition, the micellar system induced changes in expression and localization of estrogen receptors, epidermal growth factor receptor (EGFR, and downstream effectors associated with cell proliferation and survival. Finally, SMA-Ral treatment decreased migration and invasion of castrate resistant prostate cancer cell lines. In conclusion, SMA-Ral micelles can potentially benefit new strategies for clinical management of castrate resistant prostate cancer.

  18. Large Oncosomes: A Novel Liquid Biopsy for Genetic Profiling in Patients with Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2017-09-01

    Resistant Prostate Cancer PRINCIPAL INVESTIGATOR: Dolores Di Vizio, MD, PhD CONTRACTING ORGANIZATION : Cedars-Sinai Medical Center Los Angeles...biopsy” changing the landscape of precision medicine. 15. SUBJECT TERMS Metastatic Castration Resistant Prostate Cancer, Extracellular Vesicles...the “liquid biopsy” and changing the landscape of precision medicine. Keywords Prostate Cancer, Metastatic Castration Resistant Prostate Cancer

  19. Ham and belly processing characteristics of immunological castrated barrows (Improvest) fed ractopamine hydrochloride (Paylean).

    Science.gov (United States)

    Lowe, B K; Overholt, M F; Gerlemann, G D; Carr, S N; Rincker, P J; Schroeder, A L; Petry, D B; McKeith, F K; Allee, G L; Dilger, A C

    2016-02-01

    Effects of sex class (physically castrated, PC or immunologically castrated, IC) and diet (0 or 5mg/kg ractopamine hydrochloride, RAC) on characteristics of ham and bellies were determined from pigs slaughtered in three groups with similar ending live weights. One carcass per pen per marketing group (n=8) was selected to evaluate further processing characteristics. Data were analyzed as a 2×2 factorial design with a split plot in time and fixed effects of sex, diet, marketing group, and their interactions. IC fresh bellies were thinner (P0.05) fresh ham or belly characteristics but decreased (P<0.01) fat in cured PC bellies. Marketing group affected (P<0.05) fresh quality, processing characteristics, and composition of hams and bellies. Immunological castration and RAC produced leaner finished products but did not alter processing yield of hams or bacon. Copyright © 2015 Elsevier Ltd. All rights reserved.

  20. Effect of age and castration on serum anti-Müllerian hormone concentration in male alpacas.

    Science.gov (United States)

    Ciccarelli, Michela; Tibary, Ahmed; Campbell, Alexis J; Conley, Alan J

    2018-01-01

    The synthesis of anti-Müllerian Hormone (AMH) by the Sertoli cells in males is crucial for sexual differentiation. There are no studies on AMH in Camelids. The objectives of this research were to 1) compare AMH serum concentrations in prepubertal and adult male alpacas and 2) determine the effect of castration on these concentrations in adult males to provide a validation of a commercial AMH test in alpacas. Serum samples were obtained from 15 prepubertal animals (5 for each age groups of 6, 7 and 8 months) and from 5 adult males (age 5-9 years), pre- and 24 h post-castration. AMH was determined with a quantitative ELISA according to the manufacture's instructions. There was not significant difference (P < 0.05) in AMH level (pg/ml) between pre-pubertal (549.9 ± 120.8, 789.4 ± 172.3, 597.5 ± 177.3 for ages 4, 7, and 8 months, respectively) and adult alpacas (938.7 ± 175.9). In adult males, AMH concentration decreased significantly following castration (P < 0.05) (938.7 ± 383.5 pg/ml) pre-castration, and 222.1 ± 116.5 pg/ml) after castration). There was a positive correlation between testosterone levels and AMH. In conclusion, the quantitative assay used is a reliable test to determine AMH in alpacas. The AMH level in prepubertal and adult alpacas appear to not differ, contrarily from other mammals, this requires further investigation. The decrease in serum AMH concentrations after castration suggests that measurement of this hormone can be used to diagnose bilateral cryptorchid or hemicastrated unilateral cryptorchid animals in this species. Published by Elsevier Inc.

  1. Current perspectives on the optimal age to spay/castrate dogs and cats

    Directory of Open Access Journals (Sweden)

    Howe LM

    2015-05-01

    Full Text Available Lisa M HoweDepartment of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USAAbstract: Spaying and castrating of dogs and cats has been considered for decades to be a routine standard of practice in veterinary medicine in the US for the prevention of numerous undesirable behaviors, medical conditions, and diseases. Additionally, the procedures have been promoted as a method of curbing the severe pet-overpopulation problem in the US. Recently, however, this routine practice has come under scrutiny and become a very controversial topic. The general wisdom and safety of the procedures have been questioned by those who are concerned that the procedures may have some unintended consequences that are only recently being recognized. The purpose of this paper is to critically examine the scientific literature regarding elective spay/castration procedures and present both risks and benefits of elective gonadectomy. After the literature is examined, it becomes clear that there may not be a single absolute optimal age to spay or castrate all dogs and cats, but that the optimal age may be dependent upon several factors, including species, breed, body size, and breed-specific diseases, among others. Determining the optimal age to perform elective gonadectomy is much clearer in cats, and the literature demonstrates that the procedures can typically be safely performed at any age after 6–8 weeks of age. The optimal age to spay or castrate dogs of certain breeds (rottweiler, golden retriever, Labrador retriever, and vizsla is becoming less clear as studies are being conducted as to the health benefits and risks in those breeds. This review will examine these controversies and make recommendations as to the optimal age to spay/castrate dogs based upon the scientific literature.Keywords: gonadectomy (neuter, ovariohysterectomy (spay, castration, neoplasia, longevity, orthopedic

  2. Effects of neonatal surgical castration or immunocastration on the adrenal axis of males pigs

    OpenAIRE

    Prunier, Armelle; Robic, Annie; Leclercq, Caroline; Feve, Katia; Merlot, Elodie

    2015-01-01

    To explore the effect of the suppression of testicular hormones on the adrenal axis, we compared entire pigs (E, n = 18), pigs castrated early in life (SC, surgical castration at 5-6 days of age, n = 14) and pigs submitted to immunocastration around puberty (IC, vaccination against Improvac® at 88 and 117 days of age, n = 16). ). Saliva samples were collected at 112 and 147 days of age at various times during the day (9:00, 11:00, 17:00, 23:00, 5:00 and 9:00). Blood samples were collected jus...

  3. Metabolism of purine nucleotide in the liver and kidney of castrated rats

    International Nuclear Information System (INIS)

    Pizzichini, M.; Di Stefano, A.; Marinello, E.; Matteucci, G.

    1986-01-01

    The authors compare the metabolism of free purine nucleotides and of RNA in the liver and kidney of adult male rats before and after castration. The authors incorporated C 14-formate into the acid-soluble bases and into RNA. The C 14-formate was injected intraperitoneally and the acid-soluble purines were purified by acid hydrolysis and separated by ion exchange chromatography. It is shown that the total base content does not significantly change after castration. The specific activity shows no variation in the kidney and no significant increase is observed in the liver. The weight falls in both categories

  4. Comparative proteomic analysis of longissimus dorsi muscle in immuno- and surgically castrated male pigs.

    Science.gov (United States)

    Shi, Xuebin; Li, Chunbao; Cao, Miaodan; Xu, Xinglian; Zhou, Guanghong; Xiong, Youling L

    2016-05-15

    We compared proteomic profiles of male pig muscles after active immunization against gonadotropin releasing hormone (GnRH) and surgical castration. Longissimus dorsi samples were collected from immunocastration (IC) and surgical castration (SC) groups (n=15 each). Muscle proteins were extracted and then identified by data-independent label-free nano LC-MS/MS. A total of 610 proteins were identified, 50 of which were differentially expressed (Pimmunity were abundant in IC group. Several heat shock proteins (HSPs) and laminins were abundant in SC group. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Changes of pituitary and penile structure in male adult rats following castration and high-fat diet.

    Science.gov (United States)

    Lu, Y L; Jiang, B R; Xia, F Z; Zhai, H L; Chen, Y; Yu, J; Zhao, L J; Wang, N J; Qiao, J; Yang, L Z

    2011-02-01

    To investigate the influence of low androgen levels and high-fat diet on the structure of pituitary and penis in male rats. Ten-week-old adult male Sprague-Dawley rats were randomly divided into 2 groups, one fed a high-fat diet the other fed a normal diet; each group consisted of 3 subgroups: controls, castrated rats (with low androgen), and castrated rats given undecanoate replenishment. After 11 weeks, the structure of pituitary and penis were observed under light microscopy. Immunohistochemistry was used to assess the expression of FSH in pituitary and cyclooxygenase-2 (COX-2) in corpora cavernosa penis. The structures of pituitary and penis in castrated rats were injured, and were more damaged in castration together with high-fat diet. Immunohistochemistry showed FSH expression in castrated rats pituitary while castrated rats on a high-fat diet had less positive staining than those on a normal diet. Vascular structure of corpora cavernosa penis, showed a strongly positive COX-2 expression in high-fat diet rats. Castration and high-fat diet could induce structural damages of pituitary and penis in male rats. Replacement with testosterone could partially restore the impaired structure. The positive expression of COX-2 implied inflammatory pathway existence on vascular structure of penis in high-fat diet and low-androgen male rats.

  6. Hsp90 inhibitor 17-AAG inhibits progression of LuCaP35 xenograft prostate tumors to castration resistance.

    Science.gov (United States)

    O'Malley, Katherine J; Langmann, Gabrielle; Ai, Junkui; Ramos-Garcia, Raquel; Vessella, Robert L; Wang, Zhou

    2012-07-01

    Advanced prostate cancer is currently treated with androgen deprivation therapy (ADT). ADT initially results in tumor regression; however, all patients eventually relapse with castration-resistant prostate cancer. New approaches to delay the progression of prostate cancer to castration resistance are in desperate need. This study addresses whether targeting Heat shock protein 90 (HSP90) regulation of androgen receptor (AR) can inhibit prostate cancer progression to castration resistance. The HSP90 inhibitor 17-AAG was injected intraperitoneally into nude mice bearing LuCaP35 xenograft tumors to determine the effect of HSP90 inhibition on prostate cancer progression to castration resistance and host survival. Administration of 17-AAG maintained androgen-sensitivity, delayed the progression of LuCaP35 xenograft tumors to castration resistance, and prolonged the survival of host. In addition, 17-AAG prevented nuclear localization of endogenous AR in LuCaP35 xenograft tumors in castrated nude mice. Targeting Hsp90 or the mechanism by which HSP90 regulates androgen-independent AR nuclear localization and activation may lead to new approaches to prevent and/or treat castration-resistant prostate cancer. Copyright © 2011 Wiley Periodicals, Inc.

  7. Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Huber, Marie L; Haynes, Laura; Parker, Chris

    2012-01-01

    survival benefit. Previously unpublished data from the sipuleucel-T trials show worse overall survival in older vs younger patients in the placebo groups, which have not been shown previously to be prognostic for survival in castration-resistant prostate cancer patients receiving chemotherapy. Because two...

  8. Prolactin is associated with the development of photorefractoriness in intact, castrated, and testosterone-implanted starlings

    International Nuclear Information System (INIS)

    Goldsmith, A.R.; Nicholls, T.J.

    1984-01-01

    Using radioimmunoassays, prolactin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured in the plasma of intact, castrated, and testosterone-implanted male starlings. Two groups of birds (intact and castrated males) were transferred when photosensitive from short (8-hr) to long (16-hr) day lengths; in both cases plasma prolactin levels increased steadily reaching a peak after 5 weeks of photostimulation, at the time of the onset of photorefractoriness. Three groups (intacts, castrates, and castrates implanted with Silastic capsules containing testosterone) were exposed to day lengths increasing by 30 min per week from 8 to 16 hr. Again, prolactin levels increased in a similar fashion in all three groups at the time of refractoriness, which occurred when the day length reached 15-16 hr. Thus the timing of photorefractoriness and the associated rise in prolactin secretion which occur in response to photostimulation do not depend upon the presence of the gonads and are not affected when testosterone is maintained at a constant high level. Nor is the increase in prolactin altered when the cycle of gonadotrophin secretion which normally precedes it is completely suppressed by the implantation of a testosterone capsule. It would seem that prolactin secretion in the starling is stimulated by transfer from short to long day lengths, but not as a consequence of high gonadotrophin or androgen secretion rates

  9. Metastatic castration-resistant prostate cancer: new therapies, novel combination strategies and implications for immunotherapy

    NARCIS (Netherlands)

    Drake, C.G.; Sharma, P.; Gerritsen, W.R.

    2014-01-01

    For the past decade, docetaxel has remained the global standard of care for frontline treatment of metastatic castration-resistant prostate cancer (mCRPC). Until recently, there were limited options for patients with mCRPC following docetaxel failure or resistance, but now the approved treatment

  10. Current and emerging treatment options for castration-resistant prostate cancer: a focus on immunotherapy

    NARCIS (Netherlands)

    Gerritsen, W.R.; Sharma, P.

    2012-01-01

    BACKGROUND: Castration-resistant prostate cancer is a disease with limited treatment options. However, the ongoing elucidation of the mechanisms underlying this disease continues to support the development of not only novel agents, but also innovative approaches. Among these therapies, immunotherapy

  11. New EU Policies Towards Animal Welfare: The Relative Importance of Pig Castration

    NARCIS (Netherlands)

    Kallas, Z.; Gil, J.M.; Panella-Riera, N.; Blanch, M.; Tacken, G.M.L.; Chevillon, P.; Roest, de K.; Oliver, M.A.

    2012-01-01

    Animal welfare is becoming one of the most contentious issues in animal husbandry and meat production industries. We assess the relative importance of animal welfare, with respect to pig castration and the avoidance of boar taint, alongside different attributes of pork meat, amongst consumers in six

  12. The first experience in using abiraterone acetate in patients with castration-refractory prostate cancer

    Directory of Open Access Journals (Sweden)

    L. M. Rapoport

    2015-01-01

    Full Text Available Even in the mid-twentieth century, Huggins and Hodges proved the susceptibility of prostate cancer cells to hormonal manipulations, by using surgical castration as an example. An average of 18–36 months after initiation of first-line hormonal therapy, patients develop the castration resistance in prostate cancer, one of the causes of which was hyperproduction of the tumor receptors of prostate cancer cells and their hypersusceptibility to the castration levels of testosterone. Long-term treatment in patients with castration-refractory prostate cancer was extremely symptomatic and quality of life and overall survival were low. In the 2000s, investigations aimed at designing drugs to treat this category of patients were underway, which have culminated in the advent of three drugs (two of which belong to chemotherapy that are now used in the Russian Federation. The second-line hormonal agent abiraterone acetate (Zytiga is one of these drugs, which was officially registered in 2011. Its mechanism of action is due to inhibition of the enzyme CYP17, leading to the blocked synthesis of testosterone at all levels, including at the intracrine level, and achieving testosterone levels below the postcastration ones. The paper reviews the literature regarding abiraterone acetate and the first experience in using second-line hormonal therapy in three patients.

  13. Phase I/II study on docetaxel, gemcitabine and prednisone in castrate refractory metastatic prostate cancer

    DEFF Research Database (Denmark)

    Buch-Hansen, Trine Zeeberg; Bentzen, Lise Nørgaard; Hansen, Steinbjoern

    2010-01-01

    DGP, maximum of eight courses, until progression or unacceptable toxicity. Docetaxel 75 mg/m(2) was administered intravenously day 1, gemcitabine was given day 1 and 8 in doses increasing from 600 to 1,000 mg/m(2) every third week. Patients had castrate refractory metastatic prostate cancer (CRMPC......), adequate function of liver, kidney and bone marrow; ECOG performance status...

  14. Safety of cabazitaxel in senior adults with metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Heidenreich, Axel; Bracarda, Sergio; Mason, Malcolm

    2014-01-01

    BACKGROUND: Cabazitaxel/prednisone has been shown to prolong survival versus mitoxantrone/prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or after docetaxel. Subsequently, compassionate-use programmes (CUPs) and expanded-access progra...

  15. Canine prostate carcinoma: epidemiological evidence of an increased risk in castrated dogs.

    NARCIS (Netherlands)

    Teske, E.; Naan, E.C.; Dijk, E.M. van; Garderen, E. van; Schalken, J.A.

    2002-01-01

    The present retrospective study investigated the frequency of prostate carcinoma (PCA) among prostate abnormalities in dogs and determined whether castration influences the incidence of PCA in dogs. During the years 1993-1998, 15363 male dogs were admitted to the Utrecht University Clinic of

  16. Abiraterone acetate for patients with metastatic castration-resistant prostate cancer progressing after chemotherapy

    DEFF Research Database (Denmark)

    Sternberg, Cora N; Castellano, Daniel; Daugaard, Gedske

    2014-01-01

    BACKGROUND: In the final analysis of the phase 3 COU-AA-301 study, abiraterone acetate plus prednisone significantly prolonged overall survival compared with prednisone alone in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. Here, we present the fina...

  17. The non-steroidal antiandrogen, bicalutamide ('Casodex'), may preserve bone mineral density as compared with castration

    DEFF Research Database (Denmark)

    Tyrrell, C J; Blake, G M; Iversen, P

    2003-01-01

    The impact of bicalutamide (Casodex) monotherapy on bone mineral density (BMD) was investigated in patients with locally advanced prostate cancer. BMD was assessed after treatment with bicalutamide 150 mg daily ( n=21) or by medical castration (goserelin acetate 3.6 mg every 28 days) ( n=8...

  18. Stilbenes inhibit androgen receptor expression in 22Rv1 castrate-resistant prostate cancer cells

    Science.gov (United States)

    Androgen receptor (AR) signaling plays an important role in the development and progression of prostate cancer (PCa). Importantly, AR continues to be expressed in advanced stages of castrate-resistant PCa (CRPC), where it can have ligand- independent activity. Identification of naturally occurring s...

  19. YAP1 regulates prostate cancer stem cell-like characteristics to promote castration resistant growth

    DEFF Research Database (Denmark)

    Jiang, Ning; Ke, Binghu; Hjort-Jensen, Kim

    2017-01-01

    Castration resistant prostate cancer (CRPC) is a stage of relapse that arises after various forms of androgen ablation therapy (ADT) and causes significant morbidity and mortality. However, the mechanism underlying progression to CRPC remains poorly understood. Here, we report that YAP1, which...

  20. [Expressions of HO-2 and CO in the corpus cavernosum of castrated rats].

    Science.gov (United States)

    Wang, Bai-xin; Chen, Mei; Wang, Jing-tao; Wang Shu-qiu; Xu, Hui; Liu, Lei; Qin, Wen-bo; Qiu, Hong-bin

    2015-05-01

    To explore the expressions of HO-2 and CO in the corpus cavernosum of castrated rats in order to further study the pathogenesis of erectile dysfunction (ED). We randomly divided 72 male SD rats into four groups: normal control, sham operation, castration, and castration + ZnPP. We detected intracavernous pressure (ICP) and penile erection in the basic condition and after apomorphine (APO) induction, determined the expression of the HO-2 protein in the corpus cavernosum by laser scanning confocal microscopy, and measured the level of CO by spectrophotometry during different periods of penile erection. The ICP in the basic condition and that after APO induction and the rate of penile erection were decreased significantly in the castration group ([11.68 ± 0.69] mmHg, [54.81 ± 3.86] mmHg, and 33.3%) and the castration + ZnPP group ([11.20 ± 0.71] mmHg, [41.17 ± 5.41] mmHg, and 22.2%) as compared with the normal control ([22.83 ± 2.66] mmHg, [66.92 ± 7.77] mm-Hg, and 100%) and the sham operation group ([23.35 ±2.22] mmHg, [70.43 ?7. 22] mmHg, and 100%) (all P ZnPP group was remarkably reduced in comparison with that in the castration group (P ZnPP group (390.1 ± 29.7 and 526.0 ± 52.5) compared with the normal control (512.7 ±57.4 and 1145.2 ± 89.8) and the sham operation group (583.7 ± 8.0 and 1016.3 ± 79.8), the expression of the HO-2 protein significantly decreased in the castration group (445.4 ± 23.7 and 847.4 ± 35.0) (P ZnPP than in the castration group during penile erection (P ZnPP group ([12.52 ± 1.05], [21.90 ± 1.02], and [16.56 ± 0.55] x 10(-7) nmol/L) as compared with the normal control ([26.76 ± 1.41], [48.25 ± 1.01], and [27.10 ± 1.58 ] x 10(-7) nmol/L) and the sham operation group ([25.41 ± 2.09], [ 47.90 ± 1.22], and [25.67 ± 1.20] x 10(-7) nmol/L) (P ZnPP than in the castration group during penile erection (P < 0.01). Decreased expressions of HO-2 and CO may correlate with erectile dysfunction in castrated rats.

  1. Gender Differences in the Anatomy of the Perineal Glands in Guinea Pigs and the Effect of Castration

    DEFF Research Database (Denmark)

    Iburg, T. M.; Arnbjerg, J.; Ruelokke, M. L.

    2013-01-01

    of the anatomical consequences of castration on the male perineal glands is sparse. To examine these uncertainties related to gender, perineal glands from 13 sexually mature pet guinea pigs were examined macro- and microscopically. Clear gender differences in the anatomy of perineal glands were found, and castrated...... excretory duct on each side of the slightly everted perineal sac. However, the reason for this gender difference is not clear. In castrated males, the orifices were atrophied and difficult to see. In addition, the sebaceous glands of the hair follicles in the skin folds of the perineal opening were smaller...

  2. Differential expression and co-expression gene networks reveal candidate biomarkers of boar taint in non-castrated pigs

    DEFF Research Database (Denmark)

    Drag, Markus; Skinkyté-Juskiené, Ruta; Do, Duy N.

    2017-01-01

    Boar taint (BT) is an offensive odour or taste observed in pork from a proportion of non-castrated male pigs. Surgical castration is effective in avoiding BT, but animal welfare issues have created an incentive for alternatives such as genomic selection. In order to find candidate biomarkers, gene...... expression profiles were analysed from tissues of non-castrated pigs grouped by their genetic merit of BT. Differential expression analysis revealed substantial changes with log-transformed fold changes of liver and testis from -3.39 to 2.96 and -7.51 to 3.53, respectively. Co-expression network analysis...

  3. Performance of intact and castrated beef cattle in an intensive croppasture rotation system

    Directory of Open Access Journals (Sweden)

    Tercilio Turini

    2015-07-01

    Full Text Available This research had as objective to evaluate the performance of intact or castrated beef cattle in a croppasture rotation system. The experiment was conducted during 2004 and 2005, and carried out at the Cooperativa Agropecuária Mourãoense (COAMO Experimental Farm, in Campo Mourão city, Paraná state. It was used a completely randomized design, with two treatments, intact or castrated. Forty ½Angus+½Nelore crossbred animals, with average age of nine months, were used. Half of the animals were castrated at weaning, and the other half was kept intact. Pasture was composed of two areas. The winter field, established after soybean crop, was composed by a mixture of black oat (Avena strigosa and Italian ryegrass (Lolium multiforum. The summer field was composed by stargrass (Cynodon nlemfuensis and Mombaça grass (Panicum maximum. During the winter time it was used a continues grazing system, with regulator animals (put and take, and during the summer an intensive rotational system, with regulator animals and fixed grazing period. Intact animals presented higher average daily weight gain (0.907 vs 0.698 kg, slaughter weight (490.9 vs 442.2 kg, and hot carcass weight (250.2 vs 232.6 kg. Slaughter age was influenced by sexual condition, being lesser in the intact animals. Carcass dressing percentage was similar for the groups. Castrated animals showed better finishing fat cover and backfat thickness (3.45 vs 2.70 mm compared to intact ones. Therefore, it can be concluded that intact animals presents better performance than castrated ones when finished in an intensive crop-pasture rotation system, however, they may not present the minimum required fat cover, when slaughter at young ages.

  4. Testosterone Deficiency Causes Endothelial Dysfunction via Elevation of Asymmetric Dimethylarginine and Oxidative Stress in Castrated Rats.

    Science.gov (United States)

    Kataoka, Tomoya; Hotta, Yuji; Maeda, Yasuhiro; Kimura, Kazunori

    2017-12-01

    Testosterone is believed to mediate the penile erectile response by producing adequate nitric oxide; therefore, testosterone deficiency results in erectile dysfunction through decreased nitric oxide bioavailability. However, the mechanisms underlying endothelial dysfunction in testosterone deficiency remain unclear. To investigate the mechanism of endothelial dysfunction in a rat model of testosterone deficiency. Rats were distributed into 3 groups: castrated (Cast), castrated and supplemented with testosterone (Cast + T), and sham (Sham). In the Cast + T group, castrated rats were treated daily with subcutaneous testosterone (3 mg/kg daily) for 4 weeks; Sham and Cast rats received only the vehicle. Erectile function using intracavernosal pressure and mean arterial pressure measurements after electrical stimulation of the cavernous nerve, endothelial function using isometric tension, asymmetric dimethylarginine (ADMA) levels using ultra-performance liquid chromatography and tandem mass spectrometry, and inflammatory biomarker expression were performed 4 weeks after the operation. In the Cast group, the ratio of intracavernosal pressure to mean arterial pressure significantly decreased, acetylcholine-induced relaxation was lower, and serum ADMA, oxidative stress, and inflammation biomarker levels were significantly increased (P Testosterone injection significantly improved each of these parameters (P testosterone deficiency on erectile function and the effect of testosterone replacement therapy. This study provides evidence of the influence of testosterone deficiency on endothelial function by investigating ADMA and oxidative stress. A major limitation of this study is the lack of a direct link of increased ADMA by oxidative stress to inflammation. Testosterone deficiency increased not only ADMA levels but also oxidative stress and inflammation in castrated rats, which can cause damage to the corpus cavernosum, resulting in erectile dysfunction. Kataoka T, Hotta Y

  5. The effect of carbohydrate restriction on prostate cancer tumor growth in a castrate mouse xenograft model.

    Science.gov (United States)

    Caso, Jorge; Masko, Elizabeth M; Ii, Jean A Thomas; Poulton, Susan H; Dewhirst, Mark; Pizzo, Salvatore V; Freedland, Stephen J

    2013-04-01

    No- and low-carbohydrate diets delay tumor growth compared to western diet (WD) in prostate cancer (PCa) xenograft studies. The effect of these diets in concert with androgen deprivation is unknown. A total of 160 male SCID mice were injected with 1× 10(5) LAPC-4 human PCa cells. Of these, 150 mice were castrated and randomized to an ad libitum WD or fed via a paired-feeding protocol with a no-carbohydrate ketogenic diet (NCKD), 10% carbohydrate diet, or 20% carbohydrate diet. The remaining 10 mice were not castrated and were fed an ad libitum WD. The mice were sacrificed once volumes reached 1,000 mm3 and survival tested using the log-rank test. Serum from the median surviving 8 mice/group was assayed for insulin, IGF-1, and IGFBP-3. Body weights were roughly equal among groups. The 10 non-castrated mice experienced accelerated tumor growth. Among castrated mice, WD had the most rapid tumor growth; 20% carbohydrate diet the slowest (P = 0.046). Survival was not significantly different among the various carbohydrate restricted groups (P = 0.51). When pooled, there was a non-significant trend (P = 0.11) in improved survival among the carbohydrate restricted diets versus WD. No significant difference in serum insulin, IGF-1, and IGFBP-3 levels was noted among all groups at pre-randomization or at sacrifice. A 20% carbohydrate diet slowed tumor growth versus a WD. Though the benefit of carbohydrate restriction was somewhat less than in prior studies in non-castrate mice, these data still suggest diets achievable in humans may play a role in PCa management. Copyright © 2012 Wiley Periodicals, Inc.

  6. Effect of local infusion of NSAID analgesics administered alone or in combination on the pain associated with band castration in calves.

    Science.gov (United States)

    Paull, D R; Small, A H; Lee, C; Labeur, L; Colditz, I G

    2015-08-01

    To evaluate the analgesic efficacy of flunixin alone or in combination with diclofenac administered locally to the scrotum at the time of band castration of calves. Angus bull calves (n = 40; ≈7-9 weeks old) were allocated to four treatment groups (n = 10 per group) to examine the effects of two non-steroidal anti-inflammatory analgesics (NSAIDs) administered locally at the time of band castration: sham control; castration + flunixin; castration + flunixin + diclofenac; castration + saline. The NSAIDs and saline were administered subcutaneously into the scrotum under the band. Blood was sampled at -0.5, 0.5, 1.5, 3, 12, 24, 48 and 72 h relative to castration. Haematology parameters and plasma cortisol levels were determined in samples at all time points and plasma haptoglobin levels determined in samples collected at -0.5, 24, 48 and 72 h. Pain avoidance and postural behaviours were measured for 2 and 12 h, respectively, after castration. Band-castrated calves exhibited significantly higher peak cortisol and higher integrated cortisol responses during the first 6 h post-castration relative to sham controls. Individual active pain avoidance behaviours observed for 1 h post-castration were not significantly different between treatment groups; however; the sum of the total behaviours was significantly increased by castration (P = 0.023). Postural changes included increased abnormal ventral lying for all castrated groups and decreased normal standing and increased combined abnormal postures for the flunixin- and saline-treated groups. Growth rates of calves were not affected by treatments during weeks 1 and 2 post-castration; however, growth rates of castrated calves were significantly lower than those of sham-treated calves in week 3 post-castration (1.41 vs 0.84, 0.75 and 0.56±0.19 kg/day for sham, flunixin-, flunixin + diclofenac- and saline-treated groups, respectively). The administration of flunixin or flunixin + diclofenac intrascrotally at several sites

  7. Longitudinal tracking of subpopulation dynamics and molecular changes during LNCaP cell castration and identification of inhibitors that could target the PSA−/lo castration-resistant cells

    Science.gov (United States)

    Rycaj, Kiera; Cho, Eun Jeong; Liu, Xin; Chao, Hsueh-Ping; Liu, Bigang; Li, Qiuhui; Devkota, Ashwini K.; Zhang, Dingxiao; Chen, Xin; Moore, John; Dalby, Kevin N.; Tang, Dean G.

    2016-01-01

    We have recently demonstrated that the undifferentiated PSA−/lo prostate cancer (PCa) cell population harbors self-renewing long-term tumor-propagating cells that are refractory to castration, thus representing a therapeutic target. Our goals here are, by using the same lineage-tracing reporter system, to track the dynamic changes of PSA−/lo and PSA+ cells upon castration in vitro, investigate the molecular changes accompanying persistent castration, and develop large numbers of PSA−/lo PCa cells for drug screening. To these ends, we treated LNCaP cells infected with the PSAP-GFP reporter with three regimens of castration, i.e., CDSS, CDSS plus bicalutamide, and MDV3100 continuously for up to ~21 months. We observed that in the first ~7 months, castration led to time-dependent increases in PSA−/lo cells, loss of AR and PSA expression, increased expression of cancer stem cell markers, and many other molecular changes. Meanwhile, castrated LNCaP cells became resistant to high concentrations of MDV3100, chemotherapeutic drugs, and other agents. However, targeted and medium-throughput library screening identified several kinase (e.g., IGF-1R, AKT, PI3K/mTOR, Syk, GSK3) inhibitors as well as the BCL2 inhibitor that could effectively sensitize the LNCaP-CRPC cells to killing. Of interest, LNCaP cells castrated for >7 months showed evidence of cyclic changes in AR and the mTOR/AKT signaling pathways potentially involving epigenetic mechanisms. These observations indicate that castration elicits numerous molecular changes and leads to enrichment of PSA−/lo PCa cells. The ability to generate large numbers of PSA−/lo PCa cells should allow future high-throughput screening to identify novel therapeutics that specifically target this population. PMID:26871947

  8. Effects of neonatal surgical castration and immunocastration in male pigs on blood T lymphocytes and health markers

    OpenAIRE

    Leclercq, Caroline; Prunier, Armelle; Merlot, Elodie

    2014-01-01

    Surgical castration in pig husbandry is criticized for welfare reasons. Thus, it is necessary to evaluate alternative ways of rearing male pigs, such as entire or immunocastrated animals. Immunocastration is a vaccination directed against gonadotropin-releasing hormone (GnRH) to suppress the production of sexual hormones. This study aimed at investigating the effects of these two methods of castration in comparison with intact male pigs on blood T-lymphocyte subsets and function, the immunogl...

  9. Two's a crowd? Crowding effect in a parasitic castrator drives differences in reproductive resource allocation in single vs double infections.

    Science.gov (United States)

    Fong, Caitlin R; Moron, Nancy A; Kuris, Armand M

    2017-04-01

    The 'crowding effect' is a result of competition by parasites within a host for finite resources. Typically, the severity of this effect increases with increasing numbers of parasites within a host and manifests in reduced body size and thus fitness. Evidence for the crowding effect is mixed - while some have found negative effects, others have found a positive effect of increased parasite load on parasite fitness. Parasites are consumers with diverse trophic strategies reflected in their life history traits. These distinctions are useful to predict the effects of crowding. We studied a parasitic castrator, a parasite that usurps host reproductive energy and renders the host sterile. Parasitic castrators typically occur as single infections within hosts. With multiple parasitic castrators, we expect strong competition and evidence of crowding. We directly assess the effect of crowding on reproductive success in a barnacle population infected by a unique parasitic castrator, Hemioniscus balani, an isopod parasite that infects and blocks reproduction of barnacles. We find (1) strong evidence of crowding in double infections, (2) increased frequency of double infections in larger barnacle hosts with more resources and (3) perfect compensation in egg production, supporting strong space limitation. Our results document that the effects of crowding are particularly severe for this parasitic castrator, and may be applicable to other castrators that are also resource or space limited.

  10. Novel therapeutic approaches for the treatment of castration-resistant prostate cancer.

    Science.gov (United States)

    Heidegger, Isabel; Massoner, Petra; Eder, Iris E; Pircher, Andreas; Pichler, Renate; Aigner, Friedrich; Bektic, Jasmin; Horninger, Wolfgang; Klocker, Helmut

    2013-11-01

    Prostate cancer is a leading cause of cancer death in men in developed countries. Once the tumor has achieved a castration-refractory metastatic stage, treatment options are limited with the average survival of patients ranging from two to three years only. Recently, new drugs for treatment of castration-resistant prostate cancer (CRPC) have been approved, and others are in an advanced stage of clinical testing. In this review we provide an overview of the new therapeutic agents that arrived in the clinical praxis or are tested in clinical studies and their mode of action including hormone synthesis inhibitors, new androgen receptor blockers, bone targeting and antiangiogenic agents, endothelin receptor antagonists, growth factor inhibitors, novel radiotherapeutics and taxanes, and immunotherapeutic approaches. Results and limitations from clinical studies as well as future needs for improvement of CRPC treatments are critically discussed. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  11. Contractile properties of rat fast-twitch skeletal muscle during reinnervation - Effects of testosterone and castration

    Science.gov (United States)

    Yeagle, S. P.; Mayer, R. F.; Max, S. R.

    1983-01-01

    The peroneal nerve of subject rats were crushed 1 cm from the muscle in order to examine the isometric contractile properties of skeletal muscle in the recovery sequency during reinnervation of normal, castrated, and testosterone-treated rats. The particular muscle studied was the extensor digitorum longus, with functional reinnervation first observed 8-9 days after nerve crush. No evidence was found that either castration or testosterone injections altered the process of reinnervation after the nerve crush, with the conclusion being valid at the 0.05 p level. The most reliable index of reinnervation was found to be the twitch:tetanus ratio, a factor of use in future studies of the reinnervation of skeletal muscle.

  12. [Perineal hernia in dogs--colopexy, vasopexy, cystopexy and castration as elective therapies in 32 dogs].

    Science.gov (United States)

    Maute, A M; Koch, D A; Montavon, P M

    2001-07-01

    In 32 male dogs colopexy, vasopexy, cystopexy and castration was performed for the treatment of perineal hernia. Recurrence rate in this study is 22%, what is comparable to other studies using different methods. The degree of severity and the number of complications is lower with this technique than with others. Enlargement of the prostate was evident in 59% and bladder retroflexion in 22% of the dogs. A celiotomy allows to recognize, assess, reduce and fix displaced organs which is not possible by using other methods. The aim is to regain the tubular structure of the ampulla recti and to fix prostate and bladder cranioventrally to the pelvic entrance. The castration performed at the same time causes the prostate gland to atrophy within 2-3 weeks, what makes the pelvic entrance even wider and the dogs return to normal defecation.

  13. A profile of enzalutamide for the treatment of advanced castration resistant prostate cancer

    International Nuclear Information System (INIS)

    Greasley, Rosa; Khabazhaitajer, Mohammad; Rosario, Derek J

    2015-01-01

    Recent advances in understanding the mechanisms underlying the development and progression of castration resistant prostate cancer from androgen-sensitive prostate cancer have provided new avenues exploring efficacious therapies in a disease which is the second leading cause of cancer deaths among men in the western world. In the evolution of second generation anti-androgens, enzalutamide, a novel androgen-receptor signaling inhibitor, has emerged targeting multiple steps within the androgenic stimulation pathway. This review discusses what is currently known of the mechanisms surrounding castration resistant prostate cancer development and the current human clinical trials to determine whether enzalutamide presents a new hope for men with advanced prostate cancer. The issues of therapy resistance, withdrawal effects and cross-resistance are briefly touched upon

  14. Current perspectives on the optimal age to spay/castrate dogs and cats

    OpenAIRE

    Howe, Lisa

    2015-01-01

    Lisa M HoweDepartment of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USAAbstract: Spaying and castrating of dogs and cats has been considered for decades to be a routine standard of practice in veterinary medicine in the US for the prevention of numerous undesirable behaviors, medical conditions, and diseases. Additionally, the procedures have been promoted as a method of curbing the severe pet-over...

  15. Effects of Castration, Level ofFeed~"and Body Weight on Enel'gY' i,

    African Journals Online (AJOL)

    Ejects·ofca\\·tration:jee(iing'level and body weight on energy partition and ejficiency of energy utilisaJion in grmying ... by O. 13. Energy reqUirement for rriaiflte,!ante (ME", ) was D. J 0 nigJier /n the entire'ihan Castrated males and tended .. , , ,. ,"". ' \\. ' . . , ...... study, how~v~i, Jlo attempt was inade to adjust I·types' of·pigs .

  16. Andrographolide Targets Androgen Receptor Pathway in Castration-Resistant Prostate Cancer

    OpenAIRE

    Liu, Chengfei; Nadiminty, Nagalakshmi; Tummala, Ramakumar; Chun, Jae Yeon; Lou, Wei; Zhu, Yezi; Sun, Meng; Evans, Christopher P.; Zhou, Qinghua; Gao, Allen C.

    2011-01-01

    Androgen receptor (AR) signaling not only plays a pivotal role in the development of androgen-dependent prostate cancer but is also important in the growth and survival of castration-resistant prostate cancer (CRPC). The first line of treatment of androgen-dependent prostate cancer is the use of androgen deprivation therapy. However, most patients will eventually relapse due to development of CRPC. Thus, development of a strategy to target AR for treatment of CRPC is urgently needed. The auth...

  17. Study of the mechanisms behind the additive effect of neoadjuvant castration on radiotherapy for prostate cancer

    OpenAIRE

    Tarish, Firas L.

    2015-01-01

    Castration improves responses to radiotherapy (RT) in prostate cancer with unknown mechanism. An understanding of what happens at the cellular and molecular level in prostate cancer cells, while reducing their access to androgens and then exposing them to ionizing radiation (IR), would give us an opportunity to optimize the treatment and may also inspire novel therapeutic approaches. Paper I: Growth of solid tumours such as prostate cancer is characterized by neovasculari...

  18. Chemical castration by a single bilateral intra-testicular injection of ...

    African Journals Online (AJOL)

    ADEYEYE

    Sokoto Journal of Veterinary Sciences. (P-ISSN 1595-093X/ E-ISSN 2315-6201). Mohammed & James/Sokoto Journal of Veterinary Sciences (2013) 11(1): 62-65. http://dx.doi.org/10.4314/sokjvs.v11i1.10. Chemical castration by a single bilateral intra-testicular injection of chlorhexidine gluconate and cetrimide in bucks.

  19. Abiraterone in the treatment of metastatic castration-resistant prostate cancer

    International Nuclear Information System (INIS)

    Mostaghel, Elahe A

    2014-01-01

    Androgen deprivation therapy remains the single most effective treatment for the initial therapy of advanced prostate cancer, but is uniformly marked by progression to castration-resistant prostate cancer (CRPC). Residual tumor androgens and androgen axis activation are now recognized to play a prominent role in mediating CRPC progression. Despite suppression of circulating testosterone to castrate levels, castration does not eliminate androgens from the prostate tumor microenvironment and residual androgen levels are well within the range capable of activating the androgen receptor (AR) and AR-mediated gene expression. Accordingly, therapeutic strategies that more effectively target production of intratumoral androgens are necessary. The introduction of abiraterone, a potent suppressor of cytochrome P450 17 α-hydroxysteroid dehydrogenase-mediated androgen production, has heralded a new era in the hormonal treatment of men with metastatic CRPC. Herein, the androgen and AR-mediated mechanisms that contribute to CRPC progression and establish cytochrome P450 17 α-hydroxysteroid dehydrogenase as a critical therapeutic target are briefly reviewed. The mechanism of action and pharmacokinetics of abiraterone are reviewed and its recently described activity against AR and 3-β-hydroxysteroid dehydrogenase is discussed. The Phase I and II data initially demonstrating the efficacy of abiraterone and Phase III data supporting its approval for patients with metastatic CRPC are reviewed. The safety and tolerability of abiraterone, including the incidence and management of side effects and potential drug interactions, are discussed. The current place of abiraterone in CRPC therapy is reviewed and early evidence regarding cross-resistance of abiraterone with taxane therapy, mechanisms of resistance to abiraterone, and observations of an abiraterone withdrawal response are presented. Future directions in the use of abiraterone, including optimal dosing strategies, the role of

  20. Effect of estrogen therapy on vascular perlecan and metalloproteinases 2 and 9 in castrated rats.

    Science.gov (United States)

    Pompei, L M; Steiner, M L; Theodoro, T R; Souza, P Z; Romanini, A C A; Coulson-Thomas, V; Pinhal, M A S; Fernandes, C E

    2013-02-01

    To study the effects of estrogen therapy on the expression of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) and perlecan in the vascular wall. Twenty 180-day-old Wistar rats were castrated and treated 1 week later for a period of 4 weeks with one of the following: (1) placebo; (2) 0.5 μg/day estradiol benzoate (E(2)B); (3) 5 μg/day E(2)B; (4) 50 μg/day E(2)B. A fifth group consisted of rats that had not been castrated. Following treatment, expression of MMP-2 and MMP-9 mRNA (MMP-2([RNA]) and MMP-9([RNA]), respectively) was analyzed by real-time PCR, and expression of MMP-2 (MMP-2([IH])), MMP-9 (MMP-9([IH])) and perlecan was quantified by immunohistochemistry, in carotid walls. There were no differences among castrated groups for MMP-2([RNA]) (p = 0.1969) and for MMP-9([RNA]) (p = 0.1828); however, a correlation was observed between E(2)B dose and MMP-9([RNA]) levels (r = 0.471, p = 0.018). Differences among groups were observed for MMP-2([IH]), MMP-9([IH]) and perlecan (p < 0.0001), wherein higher levels were observed in animals treated with estrogen therapy, correlating with E(2)B doses in the case of MMP-9 (r = 0.441, p = 0.026) and perlecan (r = 0.574, p = 0.005). Estrogen therapy correlates with higher levels of MMP-2, MMP-9 and perlecan in the extracellular matrix of carotid walls in castrated rats, in a dose-dependent manner. There was a dose-response effect of E(2)B on the expression of MMP-9 mRNA and, possibly, MMP-2 mRNA.

  1. Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells.

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    Matthew A Ingersoll

    Full Text Available Prostate cancer (PCa is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents.

  2. Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells.

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    Ingersoll, Matthew A; Lyons, Anastesia S; Muniyan, Sakthivel; D'Cunha, Napoleon; Robinson, Tashika; Hoelting, Kyle; Dwyer, Jennifer G; Bu, Xiu R; Batra, Surinder K; Lin, Ming-Fong

    2015-01-01

    Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents.

  3. Surgical castration with pain relief affects the health and productive performance of pigs in the suckling period.

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    Morales, Joaquin; Dereu, Andre; Manso, Alberto; de Frutos, Laura; Piñeiro, Carlos; Manzanilla, Edgar G; Wuyts, Niels

    2017-01-01

    Surgical castration is still practiced in many EU countries to avoid undesirable aggressive behavior and boar taint in male pigs. However, evidence shows that castration is painful and has a detrimental influence on pig health. This study investigated the clinical and productive effects of surgical castration in the suckling period. A total of 3696 male pigs, 3 to 6 days old, comprising of 721 litters from two different farms were included in the study. Within each litter, half of the males were kept as intact males (IM) and half were surgically castrated (CM). Surgical castration was conducted by a trained farmer. Average daily gain (ADG), body weight at weaning (BWW), percentage of pre-weaning mortality (PWM) and antibiotic usage were measured. Pig major acute phase protein (PigMAP) serum concentrations were analyzed prior to castration, and on days 1 and 10 after castration. Productive performance data were analyzed using a linear mixed model. Mortality and percentage of pigs treated with antibiotics were analyzed using the Fisher's exact test. No overall differences in BWW and ADG were observed between the two groups. However, differences were observed when the same effects were analyzed in the 25% lightest, 50% medium and 25% heaviest pigs at birth. PWM was higher in CM than in IM groups (6.3% vs 3.6%; p <  0.001), especially in the light (12.2% vs 6.2%; p =  0.02) and in the medium (5.5% vs 2.7%; p =  0.04) weight groups. In the heaviest pigs group PWM was not affected by castration, but IM tended to show higher ADG ( p =  0.06) and showed higher BWW (8.0 kg vs 7.8 kg; p =  0.05) than CM. There were no differences in percentage of pigs treated with antibiotics between the two groups (5.8% vs 5.8%; p  = 0.98) in this study. Furthermore, PigMAP was increased in CM the day after castration (0.944 mg/ml vs 0.847 mg/ml; p  = 0.025), but there was no difference between CM and IM groups at day 10. Surgical castration has a negative impact on

  4. The Effect of Garlic Extract Addition on The Cholesterol Content of Male Castrated Crossbred Boer Meat

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    Imam Thohari

    2012-02-01

    Full Text Available The objective of this research was to find out the effect of garlic extract addition on the content of male castrated Crossbred Boer meat cholesterol. Materials of this research were loin (Latissimus dorsi, leg (Bicep femoris, and shoulder (Triceps of four male castrated Crossbred Boer goats. The meat part was ground together and 25 gram was taken for sample preparation. The garlic extract levels were 0% (E0, 1% (E1, 2% (E2, and 3% (E3. The results showed that garlic extract did not give a significant effect on the total cholesterol, LDL, and HDL of Crossbred Boer meat. It seemed that garlic extract could decrease the cholesterol and phospholipids content of the blood but the use of extract up to 2% could not decrease the cholesterol in meat significantly. However, the use of 3% garlic extract showed an unpredictable result i.e.: the chromatograms did not show any cholesterol content in meat. It was recommended to conduct a further research by applying garlic extract between 2% up to 3%.   Keywords: cholesterol, garlic extract, male castrated Crossbred Boer meat

  5. Analysis of the Ki-67 index in the vaginal epithelium of castrated rats treated with tamoxifen

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    Afif Rieth Nery-Aguiar

    2016-02-01

    Full Text Available OBJECTIVES: Vaginal atrophy and breast cancer are common conditions in postmenopausal women and tamoxifen is the standard endocrine treatment for hormone-sensitive tumors. The present study aimed to assess the effect of tamoxifen on Ki-67 protein expression in the vaginal epithelium of castrated rats. MATERIAL AND METHODS: Forty Wistar-Hannover adult, virgin, castrated rats were randomly divided into two groups, group I (control, n=20 and group II (tamoxifen, n=20, receiving 0.5 ml of propylene glycol and 250 µg of tamoxifen diluted in 0.5 ml of propylene glycol, respectively, daily by gavage for 30 days. On the 31st day, the rats were euthanized and their vaginas were removed and fixed in 10% buffered formalin for the immunohistochemical study of Ki-67 protein expression. Data were analyzed by the Levene and Student’s t tests (p<0.05. RESULTS: The mean index of Ki-67 expression in the rat vagina of groups I and II was 4.04±0.96 and 26.86±2.19, respectively (p<0.001. CONCLUSIONS: According to the results of the present study, tamoxifen, at the dose and treatment length used, induced a significant increase in the cell proliferation of the vaginal mucosa in castrated rats, as evaluated by Ki-67 protein expression.

  6. Public opinion towards castration without anaesthesia and lack of access to pasture in beef cattle production.

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    Lemos Teixeira, Dayane; Larraín, Rafael; Melo, Oscar; Hötzel, María José

    2018-01-01

    Recent publications have shown that citizens in developing nations are gaining interest in farm animal welfare. The aims of this study were to assess the opinion of Chilean citizens about surgical castration without anaesthesia and lack of access to pasture in beef cattle production, to investigate how involvement in livestock production influences opinions, and to evaluate if different types of information would affect their opinion towards these management practices. The study was carried out in the Metropolitan Region of Santiago, Chile, and consisted of two surveys with 400 participants in each study. The first one used an online, self-administered questionnaire and the second one used a face to face questionnaire. The second questionnaire had four information treatments assigned randomly to survey participants (no information; negative information; negative and positive information; positive information). Most participants were aware that the two management practices are common in beef production systems and were opposed to them. Involvement in animal production was associated with greater acceptance of both management practices and participants that had visited a beef production farm before the study were more likely to support castration without anaesthesia in Survey 1. Belonging to any socioeconomic group and providing negative or positive information had no impact on participants' opinion. The results show a disconnection between the views of participants recruited for this study and beef production systems that do not provide pain control for male cattle surgical castration or provide little or no access to pasture.

  7. Comparison of Intramuscular or Subcutaneous Injections vs. Castration in Pigs—Impacts on Behavior and Welfare

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    John McGlone

    2016-08-01

    Full Text Available Physical castration (PC is painful and stressful for nursing piglets. One alternative to PC is immunological castration (IC, but the pain and stress of handling associated with injections have not been assessed. The objectives of this study were to measure the pain and distress of subcutaneous (SQ and intramuscular (IM injections compared to PC in piglets, and to compare SQ or IM injections in finishing pigs. After farrowing, 3 to 5 d old male piglets were randomly assigned to (control no handling treatment (NO, sham-handling (SHAM, IM, SQ, or PC. Finishing pigs were assigned to NO, SHAM, IM, or SQ. Behavior was monitored for 1 h prior and 1 h post treatment in each age group. Social, feeding behaviors, and signs of pain were recorded. Finishing pigs treated with SQ injections had higher feeding behaviors pre-treatment than they did post-treatment. Overall, physical castrations caused measurable pain-like behaviors and general behavioral dysregulation at a much higher level than the other treatment groups. SQ and IM injections did not cause either significant behavioral or physiological alterations in piglets. SQ injections caused a decrease in finishing pig feed behaviors post treatment ( p = 0.02 and SHAM treated finishing pigs spent significantly more time lying than the other treatment groups. In general IM and SQ injections did not cause any other significant changes in behavior or physiology.

  8. Effect of castration age on weight and size of some muscles in Piemontese male cattle

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    D. Biagini

    2010-04-01

    Full Text Available Effect of pre- and post-pubertal castration on muscle weight and measurements has been studied in 3 groups of Piemontese male cattle (EC - early castrated, LC - late castrated, IM - intact reared in the same environmental conditions and slaughtered at about 18 month of age, at about 550 kg of l.w., and at the same commercial fattening degree. At side commercial dissection all separated muscles or meat cuts were weighted, and on the most regular ones (regular roll, shoulder clod – “copertina”, blade filet, strip loin, tenderloin, and eye round linear measures were recorded and then some conformation ratios (weight/length, length/width, and length/circumference were calculated. Data were analysed by GLM ANCOVA procedure, correcting data on side weight to avoid bias due to differences in carcass weight. Differences were found in meat weight, heavier in IM than in LC and EC (P<0.05, and fat weight, heavier in LC and EC than IM (P<0.01. Only the blade filet weight/length and length/circumference ratios were higher in EC than LC and IM (P<0.05 and in IM than EC (P<0.05 respectively, showing the poor effect of sexual neutralisation on weight and size of the considered muscles.

  9. Inhibition of androgen receptor by decoy molecules delays progression to castration-recurrent prostate cancer.

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    Jae-Kyung Myung

    Full Text Available Androgen receptor (AR is a member of the steroid receptor family and a therapeutic target for all stages of prostate cancer. AR is activated by ligand binding within its C-terminus ligand-binding domain (LBD. Here we show that overexpression of the AR NTD to generate decoy molecules inhibited both the growth and progression of prostate cancer in castrated hosts. Specifically, it was shown that lentivirus delivery of decoys delayed hormonal progression in castrated hosts as indicated by increased doubling time of tumor volume, prolonged time to achieve pre-castrate levels of serum prostate-specific antigen (PSA and PSA nadir. These clinical parameters are indicative of delayed hormonal progression and improved therapeutic response and prognosis. Decoys reduced the expression of androgen-regulated genes that correlated with reduced in situ interaction of the AR with androgen response elements. Decoys did not reduce levels of AR protein or prevent nuclear localization of the AR. Nor did decoys interact directly with the AR. Thus decoys did not inhibit AR transactivation by a dominant negative mechanism. This work provides evidence that the AR NTD plays an important role in the hormonal progression of prostate cancer and supports the development of AR antagonists that target the AR NTD.

  10. Correlating phosphoproteomic signaling with castration resistant prostate cancer survival through regression analysis.

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    Lescarbeau, Reynald; Kaplan, David L

    2014-03-04

    Prostate cancer most commonly presents as initially castration dependent, however in a minority of patients the disease will progress to a state of castration resistance. Here, approaches for correlating alterations in the phosphoproteome with androgen independent cell survival in the LNCaP, PC3, and MDa-PCa-2b cell lines are discussed. The performance of the regression techniques multiple linear, ridge, principal component, and partial least squares regression is compared. The predictive performance of these algorithms over randomized data sets and using the Akaike Information Criterion is explored, and principal component and partial least squares regression are found to outperform other regression approaches. The effect of altering the number of features versus observations on the R(2) value and predictive performance is also examined using the partial least squares regression model. Utilizing these approaches "drivers" of castration resistant disease can be identified whose modulation alters phenotypic outcomes. These data provide an empirical comparison of the various considerations when statistically analyzing phosphorylation data with the aim of correlating with phenotypic outcomes.

  11. Androgen deprivation therapy (castration therapy and pedophilia: What’s new

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    Mauro Silvani

    2015-09-01

    Full Text Available Andrology is a constantly evolving discipline, embracing social problems like pedophilia and its pharmacological treatment. With regard to chemical castration, the andrologist may perform an important role as part of a team of specialists. At present, no knowledge is available regarding hormonal, chromosomal or genetic alterations involved in pedophilia. International legislation primarily aims to defend childhood, but does not provide for compulsory treatment. We reviewed international literature that, at present, only comprises a few reports on research concerning androgen deprivation. Most of these refer to the use of leuprolide acetate, rather than medroxyprogesterone and cyproterone acetate, which present a larger number of side effects. Current opinions on chemical castration for pedophilia are discordant. Some surveys confirm that therapy reduces sexual thoughts and fantasies, especially in recidivism. On the other hand, some authors report that chemical castration does not modify the pedophile’s personality. In our opinion, once existing legislation has changed, andrologists could play a significant role in the selection of patients to receive androgen deprivation therapy, due in part to their knowledge about its action and side effects.

  12. Influence of multiple infection and relatedness on virulence: disease dynamics in an experimental plant population and its castrating parasite.

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    Buono, Lorenza; López-Villavicencio, Manuela; Shykoff, Jacqui A; Snirc, Alodie; Giraud, Tatiana

    2014-01-01

    The level of parasite virulence, i.e., the decrease in host's fitness due to a pathogen, is expected to depend on several parameters, such as the type of the disease (e.g., castrating or host-killing) and the prevalence of multiple infections. Although these parameters have been extensively studied theoretically, few empirical data are available to validate theoretical predictions. Using the anther smut castrating disease on Silene latifolia caused by Microbotryum lychnidis-dioicae, we studied the dynamics of multiple infections and of different components of virulence (host death, non-recovery and percentage of castrated stems) during the entire lifespan of the host in an experimental population. We monitored the number of fungal genotypes within plants and their relatedness across five years, using microsatellite markers, as well as the rates of recovery and host death in the population. The mean relatedness among genotypes within plants remained at a high level throughout the entire host lifespan despite the dynamics of the disease, with recurrent new infections. Recovery was lower for plants with multiple infections compared to plants infected by a single genotype. As expected for castrating parasites, M. lychnidis-dioicae did not increase host mortality. Mortality varied across years but was generally lower for plants that had been diseased the preceding year. This is one of the few studies to have empirically verified theoretical expectations for castrating parasites, and to show particularly i) that castrated hosts live longer, suggesting that parasites can redirect resources normally used in reproduction to increase host lifespan, lengthening their transmission phase, and ii) that multiple infections increase virulence, here in terms of non-recovery and host castration.

  13. Evalution of the castrated male Sprague-Dawley rat as a model of the metabolic syndrome and type 2 diabetes.

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    Christoffersen, B; Raun, K; Svendsen, O; Fledelius, C; Golozoubova, V

    2006-08-01

    Low testosterone levels have been shown to be predictive for the development of the metabolic syndrome in men. The aim of this study was to describe effects of testosterone deficiency on metabolic syndrome-related parameters in male rats in order to evaluate the rat as a model for the human metabolic syndrome related to low testosterone levels. Male Sprague-Dawley rats were castrated or sham operated at 16 weeks of age and fed either a standard or a high energy diet. Measured parameters were: food intake, body weight, fat distribution, energy expenditure, physical activity and blood/plasma parameters related to glucose and lipid metabolism. Castration led to an increase in the amount of subcutaneous fat, but did not result in any changes in the visceral fat. Fasting blood glucose levels were increased and free fatty acids concentration decreased in the castrated rats from 2 weeks after castration and throughout the study, whereas no significant differences between the groups were found in any of the other parameters measured. A high-energy diet did not change the response to castration in male Sprague-Dawley rats. Compared to humans rats respond differently to testosterone deficiency. Only few of the features typical for the human metabolic syndrome were observed in castrated male Sprague-Dawley rats. Therefore, we conclude that with the present experimental setup the castrated rat is not an optimal model for studies on the influence of testosterone deficiency on body fat distribution and the development of other central components of the metabolic syndrome.

  14. HLDF-6 peptide affects behavioral reactions and organism functions dependent on androgen hormones in normal and castrated male mice.

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    Rzhevsky, D I; Zhokhov, S S; Babichenko, I I; Goleva, A V; Goncharenko, E N; Baizhumanov, A A; Murashev, A N; Lipkin, V M; Kostanyan, I A

    2005-04-15

    The hexapeptide Thr-Gly-Glu-Asn-His-Arg (HLDF-6), which was first identified as an active fragment of the human leukemia differentiation factor (HLDF) molecule, displays differentiation-inducing, neuroprotective and anti-drug abuse activities. Most of its in vivo effects were revealed only on male animals. We have studied HLDF-6 effects on a variety of organism functions and behavioral reactions, which are known to be dependent on androgen steroid hormones, both on castrated and normal (sham-operated) animals. Male NMRI mice were castrated or sham-operated at the age of 55 days (after puberty). After that, HLDF-6 peptide was injected daily during 3 weeks, followed by behavioral, morphological and biochemical testing. HLDF-6 increased testosterone level (1.5- to 2-fold) both in sham-operated and castrated animals. Sexual activity and pain sensitivity, which are strongly reduced in castrates, were completely or partially recovered by HLDF-6. At the same time, the peptide caused some effects similar to castration in sham-operated animals: aggression and locomotor activity were decreased; oral grooming was prolonged. Morphological studies of accessory sex glands showed that HLDF-6 partially normalizes the morphology and functional activity of seminal vesicles in castrates, but it does not prevent castration-induced apoptosis of prostate epithelial cells. Based on these observations, we can assume that HLDF-6 peptide displays at least two effects on androgen hormones metabolism in males: it stimulates testosterone biosynthesis by both testes and adrenals and simultaneously inhibits its conversion to dihydrotestosterone (DHT), most probably by diminution of 5alpha-reductase isoform 1 mRNA expression.

  15. Abiraterone in the treatment of metastatic castration-resistant prostate cancer

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    Mostaghel EA

    2014-01-01

    Full Text Available Elahe A Mostaghel Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Abstract: Androgen deprivation therapy remains the single most effective treatment for the initial therapy of advanced prostate cancer, but is uniformly marked by progression to castration-resistant prostate cancer (CRPC. Residual tumor androgens and androgen axis activation are now recognized to play a prominent role in mediating CRPC progression. Despite suppression of circulating testosterone to castrate levels, castration does not eliminate androgens from the prostate tumor microenvironment and residual androgen levels are well within the range capable of activating the androgen receptor (AR and AR-mediated gene expression. Accordingly, therapeutic strategies that more effectively target production of intratumoral androgens are necessary. The introduction of abiraterone, a potent suppressor of cytochrome P450 17 α-hydroxysteroid dehydrogenase-mediated androgen production, has heralded a new era in the hormonal treatment of men with metastatic CRPC. Herein, the androgen and AR-mediated mechanisms that contribute to CRPC progression and establish cytochrome P450 17 α-hydroxysteroid dehydrogenase as a critical therapeutic target are briefly reviewed. The mechanism of action and pharmacokinetics of abiraterone are reviewed and its recently described activity against AR and 3-β-hydroxysteroid dehydrogenase is discussed. The Phase I and II data initially demonstrating the efficacy of abiraterone and Phase III data supporting its approval for patients with metastatic CRPC are reviewed. The safety and tolerability of abiraterone, including the incidence and management of side effects and potential drug interactions, are discussed. The current place of abiraterone in CRPC therapy is reviewed and early evidence regarding cross-resistance of abiraterone with taxane therapy, mechanisms of resistance to abiraterone, and observations of an

  16. Does the timing of estrogen administration after castration affect its ability to preserve sexual interest in male rats?--exploring the critical period hypothesis.

    Science.gov (United States)

    Wibowo, Erik; Wassersug, Richard J

    2013-02-17

    Loss of libido is a major side effect that reduces the quality of life of prostate cancer patients on androgen-deprivation therapy. Estrogen restores sexual interest to some extent in castrated male mammals; however, the beneficial effects of estrogen vary greatly among different studies. We investigated whether the timing of estrogen treatment after castration affected its ability to restore sexual interest in male rats. For each rat, sexual behavior was tested with receptive female rats before castration, and after 2 weeks of either oil alone (as a control) or oil plus estradiol (E2) treatment administered via Silastic tubes implanted immediately, at 1 month (Short-Term), or at 3 months (Long-Term) after castration. Intromission frequency decreased and genital sniffing frequency increased significantly after castration compared to pre-castration levels, regardless of the testing time post-castration. E2 treatment at any time point did not reverse these changes. However, more E2-treated than control rats exhibited mounting behavior, with a significant difference between the Long-Term groups. Mounting frequency did not differ from pre-castration levels for either E2 or control rats under the Immediate condition, but declined significantly in rats treated with oil only under both the Short- and Long-Term conditions. In contrast, E2 treatment elevated mounting frequency above the castrate levels to a similar extent in both the Short and Long-term groups. In conclusion, E2 administration partially restores sexual interest in castrated male rats, and the length of post-castration delay in E2 administration does not affect the ability of E2 to restore mounting behavior. Copyright © 2012 Elsevier Inc. All rights reserved.

  17. Influence of castration-induced testosterone and estradiol deficiency on obesity and glucose metabolism in male Göttingen minipigs.

    Science.gov (United States)

    Christoffersen, Berit Oestergaard; Gade, Laust Peter; Golozoubova, Valeria; Svendsen, Ove; Raun, Kirsten

    2010-10-01

    Low testosterone and estradiol concentrations are predictive for the development of the metabolic syndrome in men and women, respectively. The aim of this study was to investigate the influence of sex hormone deficiency on food intake, body weight, body composition and glucose metabolism in male Göttingen minipigs. Five adult male Göttingen minipigs were studied before castration (pre-cast), 10-18 days (post-cast 1) and 10-11 weeks (post-cast 2) after castration. Parameters of interest were food intake, body weight, body fat percentage and sex hormone concentrations. Furthermore glucose tolerance, glucagon suppression, insulin resistance, beta cell function and disposition index were evaluated by oral and intravenous glucose tolerance tests. Castration led to almost complete disappearance of circulating testosterone and estradiol and secondarily to increased food intake, body weight and body fat percentage. Ten-eighteen days sex hormone deficiency (post-cast 1) did not significantly change any of the investigated metabolic parameters compared to pre-cast levels. Ten weeks after castration (post-cast 2) significant insulin resistance, glucose intolerance and hyperglucagonemia was found, and the beta cell function and the disposition index both were decreased. In conclusion, castration-induced sex hormone deficiency in male Göttingen minipigs results in hyperphagia, obesity and disturbed glucose metabolism, which are some of the features typical for the human metabolic syndrome.

  18. Objective Measures for the Assessment of Post-Operative Pain in Bos indicus Bull Calves Following Castration

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    Gabrielle C Musk

    2017-09-01

    Full Text Available The aim of the study was to assess pain in Bos indicus bull calves following surgical castration. Forty-two animals were randomised to four groups: no castration (NC, n = 6; castration with pre-operative lidocaine (CL, n = 12; castration with pre-operative meloxicam (CM, n = 12; and, castration alone (C, n = 12. Bodyweight was measured regularly and pedometers provided data on activity and rest from day −7 (7 days prior to surgery to 13. Blood was collected for the measurement of serum amyloid A (SAA, haptoglobin, fibrinogen, and iron on days 0, 3 and 6. Bodyweight and pedometry data were analysed with a mixed effect model. The blood results were analysed with repeated measure one-way analysis of variance (ANOVA. There was no treatment effect on bodyweight or activity. The duration of rest was greatest in the CM group and lowest in the C group. There was a significant increase in the concentrations of SAA, haptoglobin, and fibrinogen in all of the groups from day 0 to 3. Iron concentrations were not different at the time points it was measured. The results of this study suggest that animals rest for longer periods after the pre-operative administration of meloxicam. The other objective assessments measured in this study were not able to consistently differentiate between treatment groups.

  19. Growth performance of immunologically castrated (with Improvest) barrows (with or without ractopamine) compared to gilt, physically castrated barrow, and intact male pigs.

    Science.gov (United States)

    Puls, C L; Rojo, A; Ellis, M; Boler, D D; McKeith, F K; Killefer, J; Gaines, A M; Matzat, P D; Schroeder, A L

    2014-05-01

    The study used a randomized complete block design (blocking factor was date of start on test) with 5 treatments: 1) physically castrated barrows (PC), 2) intact males (IM), 3) gilts (G), 4) immunologically castrated barrows (IC), and 5) immunologically castrated barrows fed ractopamine at 5 mg/kg (IC+RAC). The study used 192 pigs and was performed from the 16 wk of age (67.2 ± 2.52 kg BW) to a pen mean BW of 132.5 ± 3.60 kg. For IC+RAC, ractopamine was fed for the final 23 d of the study. Pigs were housed in groups of 4 (10 groups for PC, IM, G, and IC and 8 groups for IC+RAC) in a finishing building at a floor space of 1.18 m(2)/pig. Diets were formulated to meet requirements of IM except that the diet for the IC+RAC fed during the ractopamine feeding period was formulated to meet requirements of pigs on that treatment. Pigs had ad libitum access to feed and water throughout the study period and were individually weighed at the start, wk 2 and 4, and subsequently every week until the end of study. For the overall study period, IC had greater (P ≤ 0.05) ADG than the other genders (1,150, 1,024, 1,064, and 954 g/d for IC, PC, IM, and G, respectively; SEM = 25.8) and required fewer days to reach slaughter weight than the other genders (58.1, 61.6, 61.6, and 66.5 d for IC, PC, IM, and G, respectively; SEM = 1.26). Overall ADFI was less (P ≤ 0.05) for IM and G than IC and PC, which were similar (P > 0.05) in this respect (3.11, 3.06, 2.68, and 2.75 kg/d for IC, PC, IM, and G, respectively; SEM = 0.061). Overall G:F was greater (P ≤ 0.05) for IM than the other genders; IC had greater overall G:F than PC and G, which were similar in this respect (0.371, 0.335, 0.397, and 0.347 kg/kg for IC, PC, IM, and G, respectively; SEM = 0.0068). Immunologically castrated barrows had greater (P ≤ 0.05) ADG (30.7%) and ADFI (22.5%) than PC from the second week following the second Improvest dose to the end of the study. During the ractopamine feeding period, IC+RAC had

  20. Removing the taint : bottlenecks and possible directions for a solution in the marketing of the meat of non-castrated male pigs

    NARCIS (Netherlands)

    Klep, L.M.F.

    2008-01-01

    Wageningen UR has published a summary note on the subject of the castration of boars. There is a need in practice for a summary in simple language of the present knowledge about castration and the possible directions for a solution. This note summarises the knowledge gained up to the present.

  1. Systemic treatment with epidermal growth factor but not insulin-like growth factor I decreases the involution of the prostate in castrated rats

    DEFF Research Database (Denmark)

    Tørring, N; Vinter-Jensen, L; Sørensen, Flemming Brandt

    2000-01-01

    Epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) are strong inducers of proliferation to prostate cells cultured in serum-free medium. Accordingly we wanted to study the growth of the prostate gland in castrated rats after treatment with EGF, IGF-I and testosterone. Castrated...

  2. Opinion of the scientific panel on animal health and welfare on a request from the commission related to welfare aspects of the castration of piglets

    DEFF Research Database (Denmark)

    Gunn, Michael; Allen, Paul; Bonneau, Michel

    2004-01-01

    Report - Annex to the Opinion of the Scientific Panel on Animal Health and Welfare on a request from the Commission related to welfare aspects of the castration of piglets......Report - Annex to the Opinion of the Scientific Panel on Animal Health and Welfare on a request from the Commission related to welfare aspects of the castration of piglets...

  3. Effects of testosterone dose on spatial memory among castrated adult male rats.

    Science.gov (United States)

    Wagner, Benjamin A; Braddick, Valerie C; Batson, Christopher G; Cullen, Brendan H; Miller, L Erin; Spritzer, Mark D

    2018-03-01

    Previous research on the activational effects of testosterone on spatial memory has produced mixed results, possibly because such effects are dose-dependent. We tested a wide range of testosterone doses using two spatial memory tasks: a working-reference memory version of the radial-arm maze (RAM) and an object location memory task (OLMT). Adult male Sprague-Dawley rats were castrated or sham-castrated and given daily injections of drug vehicle (Oil Sham and Oil GDX) or one of four doses of testosterone propionate (0.125, 0.250, 0.500, and 1.000 mg T) beginning seven days before the first day of behavioral tests and continuing throughout testing. For the RAM, four arms of the maze were consistently baited on each day of testing. Testosterone had a significant effect on working memory on the RAM, with the Oil Sham, 0.125 mg T, and 0.500 mg T groups performing better than the Oil GDX group. In contrast, there was no significant effect of testosterone on spatial reference memory on the RAM. For the OLMT, we tested long-term memory using a 2 h inter-trial interval between first exposure to two identical objects and re-exposure after one object had been moved. Only the 0.125 and 0.500 mg T groups showed a significant increase in exploration of the moved object during the testing trials, indicating better memory than all other groups. Testosterone replacement restored spatial memory among castrated male rats on both behavioral tasks, but there was a complex dose-response relationship; therefore, the therapeutic value of testosterone is likely sensitive to dose. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Guaiphenesin-ketamine-xylazine infusion to maintain anesthesia in mules undergoing field castration.

    Science.gov (United States)

    Vullo, Cecilia; Carluccio, Augusto; Robbe, Domenico; Meligrana, Marina; Petrucci, Linda; Catone, Giuseppe

    2017-10-11

    In order to determine whether a combination of guaiphenesin, ketamine and xylazine can induce safe and satisfactory anaesthesia in mules undergoing field castration, eight healthy adult intact male mules were employed. They were premedicated with intravenous (IV) xylazine (1.3 mg/kg); an additional dose of xylazine (0.3 mg/kg IV) was administered in case of inadequate depth of sedation. Anaesthesia was induced with IV thiopental (6 mg/kg). The quality of sedation and induction was recorded. Anaesthesia was maintained with an infusion of guaiphenesin (50 mg/mL), ketamine (2 mg/mL) and xylazine (1 mg/mL) (GKX). The spermatic cord of each testis was infiltrated with 5 mL of 2% lidocaine. During anaesthesia heart rate (HR), respiratory rate (RR), rectal temperature (RT) and haemoglobin oxygen saturation (SpO 2 ) were measured every 5 min. The data were analysed with simple one-way analysis of variance (ANOVA). A P value anesthesia, time of surgery and time of recovery were recorded. Only one mule required an additional dose of xylazine to achieve a satisfactory depth of sedation. Thiopental at the dose of 6 mg/kg IV resulted in smooth induction and lateral recumbency in all animals. GKX provided adequate anaesthesia to perform castration in all mules. Muscle relaxation was deemed adequate and physiological variables remained stable and within references values during the anaesthesia and did not change in response to surgical stimulation. Time (mean ± standard deviation) from the end of the infusion to sternal recumbency and time from sternal recumbency to standing were 27.7 ± 4.6 and 30.1 ± 7.7 min, respectively. The combination of xylazine, thiopental and GKX provides satisfactory short-term anaesthesia in mules undergoing field castration.

  5. Evaluation of learning curves for ovariohysterectomy of dogs and cats and castration of dogs.

    Science.gov (United States)

    Freeman, Lynetta J; Ferguson, Nancy; Fellenstein, Carol; Johnson, Ron; Constable, Peter D

    2017-08-01

    OBJECTIVE To define learning curves for fourth-year veterinary students performing ovariohysterectomy procedures in dogs and cats and castration in dogs. DESIGN Retrospective study. SAMPLE 3,196 ovariohysterectomies or castrations performed in dogs and cats by 88 veterinary students during a spay-neuter surgery and animal shelter rotation (n = 3,056) or by 1 experienced general practitioner (n = 140). PROCEDURES Data collected from medical records included patient signalment, type and duration of procedure, and sequence (by date and time) of the procedure within a list of procedures of the same type generated for each student. For each procedure type, geometric mean surgery time and 95% confidence intervals were determined for each number of surgeries completed by ≥ 10 students. Median surgery times for the same procedure types were determined for the experienced practitioner. The learning curve for each procedure was modeled with nonlinear (3-factor exponential equation with a nonzero asymptote) and linear regression. For each procedure, the asymptote (optimal surgery time) for students was compared with the experienced practitioner's median surgery time. RESULTS 2,945 surgeries (mean, 33/student) performed by ≥ 10 students were analyzed. Surgery time decreased in a nonlinear manner as student experience increased for castration of adult or pediatric dogs and ovariohysterectomy of pediatric dogs and adult or pediatric cats. Surgery time decreased in a linear manner as experience increased for ovariohysterectomy of adult dogs. CONCLUSIONS AND CLINICAL RELEVANCE To the authors' knowledge, this was the first study to map surgery times for common surgical procedures consecutively performed by veterinary students. Results clearly indicated the value of repetition to improve surgical skills (as measured by surgery time) during a 3-week period.

  6. CURRENT POSSIBILITIES OF TREATMENT FOR VISCERAL METASTASES IN PATIENTS WITH METASTATIC CASTRATION-REFRACTORY PROSTATE CANCER

    Directory of Open Access Journals (Sweden)

    A. V. Govorov

    2014-07-01

    Full Text Available Medications increasing the survival of patients with metastatic castration-refractory prostate cancer (CRPC are lacking today. In the past 3 years, in the pharmaceutical market there have been a few novel drugs to treat progressive prostate cancer. Abiraterone acetate is an androgen synthesis inhibitor, which is also used to increase the survival of patients with metastatic CRPC that progresses after chemotherapy. The results of treatment for metastatic CRPC depend on a number of factors. Visceral metastases are poor predictors of the course of the disease. The results of abiraterone acetate treatment were analyzed in CRPC patients with visceral metastases.

  7. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer

    DEFF Research Database (Denmark)

    Beer, Tomasz M; Armstrong, Andrew J; Rathkopf, Dana

    2017-01-01

    Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naïve metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated......, back pain, constipation, and arthralgia. This final analysis of PREVAIL provides more complete assessment of the clinical benefit of enzalutamide. PREVAIL is registered on ClinicalTrials.gov as NCT01212991. PATIENT SUMMARY: According to data from longer follow-up, enzalutamide continued to provide...

  8. Weekly ascorbic acid infusion in castration-resistant prostate cancer patients

    DEFF Research Database (Denmark)

    Nielsen, Torben K.; Højgaard, Martin; Andersen, Jon T.

    2017-01-01

    of this treatment.  Methods: This non-comparative, single-center, phase II trial included patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC) from an outpatient clinic to evaluate the efficacy and safety of IV AA therapy. Patients received weekly infusions of AA (week 1, 5 g...... μg/L was recorded at week 12. Among the secondary endpoints, no signs of disease remission were observed. In total, 53 adverse events (AEs) were recorded. Eleven were graded as "serious". Three AEs were directly related to AA, and all of which were related to fluid load.  Conclusions: Infusion...

  9. Drug development for metastatic castration-resistant prostate cancer: current status and future perspectives.

    Science.gov (United States)

    Lassi, Kiran; Dawson, Nancy A

    2011-04-01

    Prostate cancer represents a third of all newly diagnosed cancers in men in the USA with an estimated incidence of 192,280 cases and 27,360 deaths in 2009. It continues to be a major cause of cancer-related morbidity and mortality, and there is an urgent need for new treatments. Historically, systemic therapy options were limited after progression on docetaxel-based chemotherapy. This article reviews current data on the novel therapeutics demonstrating activity in metastatic castration-resistant prostate cancer and their future role in the treatment of this disease with a poor prognosis.

  10. Effects of late castration, zeranol and breed group on growth, feed efficiency and carcass characteristics of late maturing bovine males.

    Science.gov (United States)

    Gregory, K E; Ford, J J

    1983-04-01

    A total of 280 young bulls representing five breed groups with an average age of about 1 yr were assigned to five experimental treatments as follows: (1) emasculator castration at d 0, (2) surgical castration at d 0, (3) intact, (4) intact and implanted at d 0 and 70 with 36 mg of zeranol and (5) intact and implanted at d 0 with 72 mg zeranol. All animals were slaughtered and carcass data were collected after a feeding period of 141 d. Method of castration did not affect rate of gain. Intact males not implanted with zeranol gained 38.6% more (P less than .01) during the 141 d period than castrate males. Intact males from the two zeranol implant treatment groups did not differ from each other in gain, but averaged 11.1% more (P less than .01) during the 141 d period than males from the intact treatment group not implanted. Castrate males required 40.4% more (P less than .01) metabolizable energy (ME) and dry matter (DM)/kg gain than intact males not implanted, but intact males implanted with zeranol did not require less (P greater than .05) ME or DM/kg gain than intact males not implanted. Males castrated at about 1 yr showed a progressive decrease in secondary sex characteristics during the 141 d feeding period, while males from the three intact treatments showed a progressive increase. Zeranol did not have an effect on testicular weight or on aggressive male behavioral characteristics. Castrate males had greater (P less than .01) fat thickness at 12th rib, higher (P less than .01) marbling score and lower (P less than .01) cutability and retail product percentage than the males from the three intact treatments, which did not differ (P greater than .05) from each other in traits associated with carcass composition. The effect of treatment on lean color score, though significant, was not of major importance; all treatments produced meat of acceptable color. The longissimus muscle of castrate males had a finer texture (P less than .01) than longissimus muscle from

  11. Enzalutamide for the treatment of metastatic castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Rodriguez-Vida A

    2015-06-01

    Full Text Available Alejo Rodriguez-Vida,1 Myria Galazi,1 Sarah Rudman,1 Simon Chowdhury,1 Cora N Sternberg2 1Medical Oncology Department, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 2Medical Oncology Department, San Camillo and Forlanini Hospitals, Rome, Italy Abstract: In recent years, several nonhormonal and hormonal agents, including enzalutamide, have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC on the basis of improved overall survival in prospective clinical trials. The incorporation of these agents has revolutionized the treatment of CRPC but has also raised the question of what is the ideal sequence of administering them. Enzalutamide is a nonsteroidal second-generation antiandrogen that has been approved for the treatment of metastatic CRPC both in the post-docetaxel and chemotherapy-naïve settings. This article reviews the pharmacological characteristics of enzalutamide, the efficacy studies which led to its approval, its safety profile, and quality of life-related parameters as well as its place in the sequential treatment and management of metastatic prostate cancer. Keywords: enzalutamide, antiandrogen, ADT, androgen receptor, castration resistant prostate cancer, overall survival

  12. Bilateral testicular self-castration due to cannabis abuse: a case report

    Directory of Open Access Journals (Sweden)

    Stuurman-Wieringa Roos E

    2011-08-01

    Full Text Available Abstract Introduction The self-mutilating patient is an unusual psychiatric presentation in the emergency room. Nonetheless, serious underlying psychiatric pathology and drug abuse are important background risk factors. A careful stepwise approach in the emergency room is essential, although the prognosis, follow-up, and eventual rehabilitation can be problematic. We present a unique and original case of bilateral self-castration caused by cannabis abuse. Case Presentation We report a case of a 40-year-old Berber man, who was presented to our emergency room with externalization of both testes using his long fingernails, associated with hemodynamic shock. After stabilization of his state, our patient was admitted to the operating room where hemostasis was achieved. Conclusion The clinical characteristics of self-mutilation are manifold and there is a lack of agreement about its etiology. The complex behavior associated with drug abuse may be one cause of self-mutilation. Dysfunction of the inhibitory brain circuitry caused by substance abuse could explain why this cannabis-addicted patient lost control and self-mutilated. To the best of our knowledge, this is the first case report which presents an association between self-castration and cannabis abuse.

  13. The potential for castration of domestic animals by active immunization against GnRH

    International Nuclear Information System (INIS)

    Gonzalez, A.; Allen, A.F.; Murphy, B.D.; Mapletoft, R.J.; Cohen, R.

    1990-01-01

    Trials have been carried out in sheep and beef cattle in attempts to induce immunity against gonadotropin releasing hormone (GnRH), with the objective of using immunocastration as a replacement for surgical castration. Of the protein carriers used, ovalbumin and horse albumin yielded highest responses, with keyhole limpet haemocyanin (KLH) being a potent substitute for both. Different adjuvants were also used. In these trials, highest titre responses were obtained using Freund's complete (FCA) or Freund's incomplete (FIA) adjuvant in cattle and sheep. Although no adjuvant was found to yield as high a response as FCA and Alhydrogel, an aluminium hydroxide adjuvant generally yielded a high response in cattle and sheep. The results from the trials in beef calves indicate that active immunization against GnRH does not affect average daily gains, total body weight gain or carcass dressing percentage. The results suggest the potential of immunocastration as a substitute for surgical castration in cattle and sheep. (author). 30 refs, 8 figs, 2 tabs

  14. Parasitic castration promotes coevolutionary cycling but also imposes a cost on sex.

    Science.gov (United States)

    Ashby, Ben; Gupta, Sunetra

    2014-08-01

    Antagonistic coevolution between hosts and parasites is thought to drive a range of biological phenomena including the maintenance of sexual reproduction. Of particular interest are conditions that produce persistent fluctuations in the frequencies of genes governing host-parasite specificity (coevolutionary cycling), as sex may be more beneficial than asexual reproduction in a constantly changing environment. Although many studies have shown that coevolutionary cycling can lead to the maintenance of sex, the effects of ecological feedbacks on the persistence of these fluctuations in gene frequencies are not well understood. Here, we use a simple deterministic model that incorporates ecological feedbacks to explore how parasitic reductions in host fecundity affect the maintenance of coevolutionary cycling. We demonstrate that parasitic castration is inherently destabilizing and may be necessary for coevolutionary cycling to persist indefinitely, but also reduces the likelihood that sexually reproducing individuals will find a fertile partner, which may select against sex. These findings suggest that castrators can play an important role in shaping host evolution and are likely to be good targets for observing fluctuations in gene frequencies that govern specificity in host-parasite interactions. © 2014 The Author(s). Evolution © 2014 The Society for the Study of Evolution.

  15. Andrographolide targets androgen receptor pathway in castration-resistant prostate cancer.

    Science.gov (United States)

    Liu, Chengfei; Nadiminty, Nagalakshmi; Tummala, Ramakumar; Chun, Jae Yeon; Lou, Wei; Zhu, Yezi; Sun, Meng; Evans, Christopher P; Zhou, Qinghua; Gao, Allen C

    2011-02-01

    Androgen receptor (AR) signaling not only plays a pivotal role in the development of androgen-dependent prostate cancer but is also important in the growth and survival of castration-resistant prostate cancer (CRPC). The first line of treatment of androgen-dependent prostate cancer is the use of androgen deprivation therapy. However, most patients will eventually relapse due to development of CRPC. Thus, development of a strategy to target AR for treatment of CRPC is urgently needed. The authors have previously identified andrographolide as an inhibitor of interleukin-6, which can suppress tumor growth of prostate cancer cells by screening compounds from the Prestwick Natural compound library. In this study, they identified that andrographolide can inhibit AR expression and prostate cancer cell growth and induce apoptosis. Andrographolide is able to down-regulate AR expression at both mRNA and protein levels, prevents its nuclear translocation, and inhibits transactivation of its target genes. Andrographolide prevents the binding of Hsp90 to AR, resulting in proteasome-mediated AR degradation. Furthermore, andrographolide inhibits castration-resistant C4-2 cell growth by reducing AR expression and activity. Thus, andrographolide can be developed as a potential therapeutic agent for prostate cancer by inhibition of androgen receptor signaling.

  16. The effects of castration followed testosterone supplementation in prostatic complex of Artibeus planirostris (Chiroptera: Phyllostomidae).

    Science.gov (United States)

    Puga, Cíntia C I; Beguelini, Mateus R; Morielle-Versute, Eliana; Vilamaior, Patricia S L; Taboga, Sebastião R

    2016-06-01

    The prostatic complex (ventral and dorsal regions) of Artibeus planirostris exhibits seasonal variations throughout the year. Circulating testosterone was correlated with prostate weight, showing an increase from autumn to summer, with the highest peak in summer corresponding to the largest breeding season. This indicates that the level of serum testosterone influences variations in both testicular and prostatic weights. Serum testosterone levels seem to be closely related to the different responses of these glands throughout the year. The castration (consequent suppression of testosterone) and subsequent hormone supplementation may elucidate the relationship of these two glandular types with testosterone. Thus, the aim of this study was to evaluate the effect of castration and the testosterone supplementation in the male prostatic complex of A. planirostris. The results indicated that both prostatic regions were affected by the ablation of testosterone, presenting a decrease in cell proliferation and an increase in apoptosis. Similarly, the prostate was responsive to hormonal supplementation, having a recovery of the active morphophysiological pattern with testosterone supplementation. However, data have shown that the ventral region was more sensitive to changes in testosterone than the dorsal, presenting greater cell renewal. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. [Effects of extract of Buddleja officinalis on prevention of dry eye in castrated rabbits].

    Science.gov (United States)

    Peng, Qing-Hua; Yao, Xiao-lei; Wu, Quan-long; Chen, Mei

    2008-11-01

    To assess the preventive effects of extract of Buddleja officinalis on dry eye in castrated rabbits and to discuss the mechanism of these effects. It was a experimental study. Thirty male rabbits were divided equally into normal group (A), disease group (B) and treatment group (C, D, and E). The dry eye model was established with orchiectomy (ORX) in Group B, C, D and E. Group C, D and E were gastrically perfused with single-dose or double-does of Buddleja officinalis extract or genistein for 30 days. All rabbits were examined with Schirmer I test (SIT). TGF-beta1, IL-1beta, TNF-alpha, Fas, FasL, Bax and bcl-2 were detected by immunohistochemistry. Morphological and ultrastructure changes were observed by electron microscopy. The SIT value of group C, D, E was significantly greater than that of group B (P Buddleja officinalis has a significant effect on the prevention of experimental dry eye in castrated male rabbits. The main components of extract of Buddleja officinalis are the flavonoids. The flavonoids display androgen-like activity. Therefore, it can adjust gonadal hormone level in vivo. As a result, it can inhibit local inflammation in lacrimal gland and reduce apoptosis of lacrimal gland cells.

  18. The Little Mermaid: an icon of woman's condition in patriarchy, and the human condition of castration.

    Science.gov (United States)

    Tseëlon, E

    1995-10-01

    Hans Christian Andersen's story 'The Little Mermaid' is read as a creation myth and a metaphor for woman's condition in patriarchy, broadly conceptualised within a Lacanian framework. In the first part, the psychoanalytic concept of castration (broadly conceptualised as containing any existential severance which forms the basis for sexual difference and subjectivity) is utilised to argue that the myth is about a construction of (mostly female) subjectivity through a series of separations or splits: (1) birth, (2) growing up, (3) desire and (4) death. Birth and death are read as representing real separations. Growing up is read as structured around a symbolic castration of tongue and voice, while desire is read as structured around lack. In the second part the ideological implications of Disney's adaptation of the original for its symbolic status are explored. It is argued that by simplifying and externalising internal complex conflicts in the Andersen story, Disney's version reduces the myth to a fairy tale, and reproduces the ideology of romantic love.

  19. Chemical castration: It is an acceptable solution for preventing the commission of sex crimes against minors?

    Directory of Open Access Journals (Sweden)

    Miladinović-Stefanović Dušica

    2014-01-01

    Full Text Available In addition to envisaging criminal offences which incriminate the different forms of sexual violence against minor and introducing stricter forms of punishment for sex offenders, the formal social reaction to sex crimes against minors often involves a series of measures aimed at monitoring the convicted offenders after they have served their sentences. These measures are basically aimed at reducing the risk of recidivism. One of these measures is a special pharmacological treatment, generally known as chemical castration, which is applied for the purpose of suppressing the offender's sexual urges and reducing sexual misconduct. In spite of being an appealing solution, chemical castration is acceptable only under specific conditions. Hence, this matter has to be regulated with exquisite caution in order to avoid the objections that this treatment constitutes a violation of the prohibition of torture, inhuman and degrading treatment and punishment, as well as a violation of the right to respect for private life and the right to establish a family.

  20. A comparison of slice characteristics and sensory characteristics of bacon from immunologically castrated barrows with bacon from physically castrated barrows, boars, and gilts.

    Science.gov (United States)

    Little, K L; Kyle, J M; Bohrer, B M; Schroeder, A L; Fedler, C A; Prusa, K J; Boler, D D

    2014-12-01

    The objectives were to compare slice characteristics and sensory attributes of bacon from immunologically castrated (IC) barrows with bacon from other sexes using a trained sensory panel. Bacon was obtained for sensory evaluation from 3 experiments. In Exp. 1, trimmed and squared bellies (n=180) of IC barrows, IC barrows fed ractopamine hydrochloride (IC+RAC), physically castrated (PC) barrows, intact males (IM), and gilts were used. Data were analyzed as a general linear mixed model and pen (n=48) served as the experimental unit. Treatment (sex or diet) was a fixed effect in all 3 experiments. In Exp. 2, untrimmed, natural fall bellies (n=96) from IC and PC barrows fed 0 or 30% or a withdrawal distillers dried grains with solubles (DDGS) program when slaughtered at 5 wk after the second dose (25 wk of age) were used. In Exp. 3, untrimmed, natural fall bellies (n=96) from IC and PC barrows fed the same experimental diets as in experiment 2 but slaughtered at 7 wk after the second dose (27 wk of age) were used. Data from Exp. 2 and 3 were analyzed as a 2×3 factorial arrangement in a randomized complete block design and pen was the experimental unit. Bellies from all 3 experiments were processed using the same protocols. In Exp. 1, IM had the greatest (Pbacon aroma and flavor among all treatments. No differences were detected among the other treatment groups for bacon aroma or flavor. There were no differences in bacon aroma or off-flavor between IC and PC barrows slaughtered at 5 wk after the second dose regardless of DDGS feeding program. Bacon from PC barrows was saltier (Pbacon from IC barrows when slaughtered at 5 wk after the second dose. There were no differences in bacon aroma, off-aroma, bacon flavor, or saltiness between IC and PC barrows slaughtered at 7 wk after the second dose regardless of DDGS feeding program. Total slice area of bacon slices from IC barrows slaughtered at 5 wk after the second dose were less (Pbacon even when feeding differing DDGS

  1. Cabazitaxel Versus Docetaxel As First-Line Therapy for Patients With Metastatic Castration-Resistant Prostate Cancer

    DEFF Research Database (Denmark)

    Oudard, Stéphane; Fizazi, Karim; Sengeløv, Lisa

    2017-01-01

    Purpose In patients with metastatic castration-resistant prostate cancer (mCRPC), overall survival (OS) is significantly improved with cabazitaxel versus mitoxantrone after prior docetaxel treatment. FIRSTANA ( ClinicalTrials.gov identifier: NCT01308567) assessed whether cabazitaxel 20 mg/m(2) (C...

  2. Histochemical studies on genetical control of hormonal enzyme inducibility in the mouse. VI. Effects of short term castration

    DEFF Research Database (Denmark)

    Kjaer, K; Kirkeby, S; Blecher, S R

    1983-01-01

    The regional histology and esterase activity of the mouse epididymis after 24, 48, and 72 hr castration is reported. Differential sensitivity to androgen deprivation among the various epithelial cell types is described, allowing of positive identification of the cell types previously observed...

  3. A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2016-12-01

    AWARD NUMBER: W81XWH-14-1-0021 TITLE: A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer 5b. GRANT NUMBER...receptor (AR) targeted therapies, prostate cancer adapts. One way it adapts is by upregulating another hormone receptor, the glucocorticoid receptor

  4. Sipuleucel-T: Autologous Cellular Immunotherapy for Men with Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Robert B. Sims

    2011-01-01

    Full Text Available Sipuleucel T is an autologous cellular immunotherapy designed to stimulate an immune response in men diagnosed with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory prostate cancer. Sipuleucel T improves overall survival and provides an additional treatment option for this patient population.

  5. Intratesticular and subcutaneous lidocaine alters the intraoperative haemodynamic responses and heart rate variability in male cats undergoing castration

    NARCIS (Netherlands)

    Moldal, E.R.; Eriksen, T.; Kirpensteijn, J.; Nødtvedt, A.; Kristensen, A.T.; Sparta, F.M.; Haga, H.A.

    2013-01-01

    Abstract OBJECTIVE: To evaluate the usefulness of intratesticular and subcutaneous lidocaine in alleviating the intraoperative nociceptive response to castration, measured by pulse rate (PR) and mean arterial pressure (MAP), and to test the applicability of heart rate variability (HRV) analysis in

  6. Cabazitaxel in patients with metastatic castration-resistant prostate cancer: results of a compassionate use program in the Netherlands

    NARCIS (Netherlands)

    Wissing, M.D.; Oort, I.M. van; Gerritsen, W.R.; Eertwegh, A.J. van den; Coenen, J.L.; Bergman, A.M.; Gelderblom, H.

    2013-01-01

    BACKGROUND: Cabazitaxel has been reimbursed as a second-line therapy for patients with metastatic castrate-resistant prostate cancer (mCRPC) in the Netherlands since 2011. Before reimbursement was available, cabazitaxel was provided through a Compassionate Use Program (CUP). We report the results of

  7. Effects of castration and weaning conducted concurrently or consecutively on behaviour, blood traits and performance in beef calves.

    Science.gov (United States)

    Lambertz, C; Farke-Röver, A; Moors, E; Gauly, M

    2015-01-01

    The objectives of this study were to evaluate the effects of Burdizzo castration and abrupt weaning on the behaviour, blood traits and performance of beef calves when weaning was conducted concurrently or consecutively to castration. In total, 64 male beef calves aged between 6 and 7 months were assigned to a 2×2 factorial design with the following treatment groups (n=16 animals per treatment): (1) castrated and concurrently weaned in week 0 (CAS-WEA); (2) castrated in week 0 and weaned in week 4 (CAS-CON); (3) bulls weaned in week 0 (BUL-WEA); and (4) bulls weaned in week 4 (BUL-CON). The behaviour of the calves was observed for 3 days following weaning. Blood was collected weekly from weeks 0 to 5 and analysed for the acute-phase protein haptoglobin, and neutrophil and lymphocyte percentages. BW was recorded weekly from weeks 0 to 7. Animals were slaughtered at 17 months and weight, dressing percentage and carcass classifications were recorded. On day 1 after weaning, the number of vocalizations (calls/10 min) was higher in BUL-WEA (7.2) and CAS-WEA (5.4) than in calves of CAS-CON (2.8) and BUL-CON (2.9) groups (Panimals spent 20% lying on day 1 after weaning compared with 40% in CAS-WEA and BUL-WEA calves (P0.05). WEA groups showed an increased average daily gain (ADG) during weeks 0 to 3 and a reduced ADG during 4 to 7 weeks in comparison with CON animals. At slaughter, bulls were about 80 kg heavier than castrates and had a superior dressing percentage and carcass classification (P>0.05). In conclusion, weaning had a greater effect on the number of vocalizations, standing/walking and lying behaviour and ADG compared with Burdizzo castration. In comparison with undertaking the procedures separately, concurrent castration and weaning neither affected behaviour and haematological parameters nor impaired performance. There was no evidence that the concurrent application of both treatments markedly increased the stress response compared with their application at

  8. Systemic treatment with Epidermal Growth Factor (EGF)but not Insulin like Growth Factor (IGF-I) decrease the involution of the Prostate in Castrated Rats

    DEFF Research Database (Denmark)

    Tørring, Niels; Lars, Vinter-Jensen; Sørensen, Flemming Brandt

    2000-01-01

    Epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) are strong inducers of proliferation to prostate cells cultured in serum-free medium. Accordingly we wanted to study the growth of the prostate gland in castrated rats after treatment with EGF, IGF-I and testosterone. Castrated...... Wistar rats were treated with growth factors (EGF 35 microg/rat per day; IGF-I 350 microg/rat per day) or testosterone (2 mg/rat per day) for 3 days either immediately after or 10 days after castration. Prostate tissue was examined by stereological and immunohistochemical techniques and by enzyme...

  9. Systemic treatment with epidermal growth factor but not insulin-like growth factor I decreases the involution of the prostate in castrated rats

    DEFF Research Database (Denmark)

    Tørring, N; Vinter-Jensen, L; Sørensen, Flemming Brandt

    2000-01-01

    Epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) are strong inducers of proliferation to prostate cells cultured in serum-free medium. Accordingly we wanted to study the growth of the prostate gland in castrated rats after treatment with EGF, IGF-I and testosterone. Castrated...... Wistar rats were treated with growth factors (EGF 35 microg/rat per day; IGF-I 350 microg/rat per day) or testosterone (2 mg/rat per day) for 3 days either immediately after or 10 days after castration. Prostate tissue was examined by stereological and immunohistochemical techniques and by enzyme...

  10. Photoperiodic regulation of body mass, food intake, hibernation, and reproduction in intact and castrated male European hamsters, Cricetus cricetus.

    Science.gov (United States)

    Canguilhem, B; Vaultier, J P; Pévet, P; Coumaros, G; Masson-Pévet, M; Bentz, I

    1988-08-01

    A group of sexually active male European hamsters were raised either in short-photoperiod conditions (SP; LD 8:16) or in long-photoperiod conditions (LP; LD 16:8) from their capture at the end of the hibernation period. Another group of hamsters was castrated in April and gonadectomized animals were maintained in SP and cold (7 degrees C) or in a succession of SP and LP plus cold. Another group, castrated in May or in September and raised in LP conditions, was transferred in September to SP conditions and cold. 1. Normal hamsters raised in continuous SP or LP apparently did not show signs of rhythmic behavior, except possibly in gonadal activity. 2. Body weight increased continuously, plasma testosterone levels oscillated between 1.5 and 2.5 ng/ml, and animals raised in SP and in cold did not enter hibernation. 3. Similar results were also found in castrated animals kept in SP conditions and cold. 4. The sequence LP-SP induced a decrease in food intake and body weight and a decrease in plasma testosterone levels and triggered entry into hibernation in both intact and castrated animals. 5. After 6 months continuously in SP and with exposure to cold spontaneous recrudescence in food intake and body weight occurred and hibernation ended in both intact and castrated animals. 6. In normal animals a spontaneous increase in plasma testosterone levels was observed. 7. In both normal and gonadectomized animals the phase of refractoriness could be broken by exposure to LP conditions. 8. The critical photoperiod lies between 15 and 15.5 h. These results demonstrate that the European hamster is a photoperiodic species.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Synergistic antitumor activities of docetaxel and octreotide associated with apoptotic-upregulation in castration-resistant prostate cancer.

    Directory of Open Access Journals (Sweden)

    Sha Zhu

    Full Text Available Androgen deprivation therapy has become the fist-line treatment of metastatic prostate cancer; however, progression to castrate resistance disease occurs in the majority of patients. Thus, there is an urgent need for improvements in therapy for castration-resistant prostate cancer. The aims of the present study were to determine the efficacy somatostatin analogue octreotide (OCT combined with a low dose of docetaxel (DTX using castration resistant prostate cancer cells and to investigate the involved molecular mechanisms in vitro. The anti-proliferative and synergism potential effects were determined by MTT assay. Induction of apoptosis was analyzed employing annexing V and propidium iodide staining and flow cytometry. VEGFA, CASP9, CASP3 and ABCB1 gene expression was evaluated by RT-PCR and Q-RT-PCR analysis. OCT in combination with DTX treatments on DU145 cell migration was also evaluated. Investigation revealed that combined administration of DTX and OCT had significant, synergistically greater cytotoxicity than DTX or OCT treatment alone. The combination of the two drugs caused a more marked increase in apoptosis and resulted in greater suppression of invasive potential than either individual agent. There was obvious increase in caspase 3 expression in the OCT alone and two-drug combined treatment groups, however, VEGFA expression was markedly suppressed in them. These results support the conclusion that somatostatin analogues combined with docetaxel may enhance the chemotherapy efficacies through multiple mechanisms in castration-resistant PCa cell line. This work provides a preclinical rationale for the therapeutic strategies to improve the treatment in castrate resistance disease.

  12. Cholesterol biosynthesis inhibitor RO 48-8071 suppresses growth of hormone-dependent and castration-resistant prostate cancer cells.

    Science.gov (United States)

    Liang, Yayun; Mafuvadze, Benford; Aebi, Johannes D; Hyder, Salman M

    2016-01-01

    Standard treatment for primary prostate cancer includes systemic exposure to chemotherapeutic drugs that target androgen receptor or antihormone therapy (chemical castration); however, drug-resistant cancer cells generally emerge during treatment, limiting the continued use of systemic chemotherapy. Patients are then treated with more toxic standard therapies. Therefore, there is an urgent need for novel and more effective treatments for prostate cancer. The cholesterol biosynthetic pathway is an attractive therapeutic target for treating endocrine-dependent cancers because cholesterol is an essential structural and functional component of cell membranes as well as the metabolic precursor of endogenous steroid hormones. In this study, we have examined the effects of RO 48-8071 (4'-[6-(allylmethylamino)hexyloxy]-4-bromo-2'-fluorobenzophenone fumarate; Roche Pharmaceuticals internal reference: RO0488071) (RO), which is an inhibitor of 2, 3-oxidosqualene cyclase (a key enzyme in the cholesterol biosynthetic pathway), on prostate cancer cells. Exposure of both hormone-dependent and castration-resistant human prostate cancer cells to RO reduced prostate cancer cell viability and induced apoptosis in vitro. RO treatment reduced androgen receptor protein expression in hormone-dependent prostate cancer cells and increased estrogen receptor β (ERβ) protein expression in both hormone-dependent and castration-resistant prostate cancer cell lines. Combining RO with an ERβ agonist increased its ability to reduce castration-resistant prostate cancer cell viability. In addition, RO effectively suppressed the growth of aggressive castration-resistant human prostate cancer cell xenografts in vivo without any signs of toxicity to experimental animals. Importantly, RO did not reduce the viability of normal prostate cells in vitro. Our study is the first to demonstrate that the cholesterol biosynthesis inhibitor RO effectively suppresses growth of human prostate cancer cells. Our

  13. Chemical Castration Using Iron (III Chloride Hexahydrate (KEBIRI KIMIAWI MENGGUNAKAN FERIKLORIDA HEKSAHIDRAT

    Directory of Open Access Journals (Sweden)

    Mokhamad Fakhrul Ulum

    2017-09-01

    Full Text Available Chemical castration is a method that can be applied easily without any surgical intervention in animals. This study utilized iron (III chloride hexahydrate (FeCl3.6H2O as a new material for chemical castration in mice. Twenty seven adult male mice were divided into five groups: FeCl3 20% (n = 6, FeCl3 10% (n = 6, FeCl3 5.0% (n = 6, FeCl3 2.5% (n = 6, and control NaCl 0.9% (n = 3. A 0.2 mL of NaCl 0.9% or FeCl3 in various concentrations was injected intra-testicularly on each testis of the mice. Post-castration survival rate with LD50 values was obtained at the concentrations between 2.5-5.0% of FeCl3 groups, and 100% mice survived in the control group. The size of testis and concentration of spermatozoa decreased, in contrast with the increased concentration of FeCl3 solution used seven days post-injection compared to the control group. ABSTRAK Kebiri/kastrasi kimiawi secara injeksi intra-testis merupakan metode pengebiriam yang dapat dilakukan dengan mudah tanpa prosedur bedah pada hewan. Penelitian ini memanfaatkan larutan besi (ferri/III klorida (FeCl3 sebagai bahan baru untuk tindakan kebiri kimiawi pada mencit. Mencit jantan dewasa umur lima bulan sebanyak 27 ekor dibagi dalam lima kelompok yaitu FeCl3 20% (n=6, FeCl3 10% (n=6, FeCl3 5,0% (n=6, FeCl3 2,5% (n=6 dan kontrol NaCl 0,9% (n=3. Larutan FeCl3 sebanyak 0,2 mL diinjeksikan secara intra-testikel pada setiap organ testis. Daya hidup pascakebiri injeksi nilai LD 50 diperoleh pada kelompok FeCl3 konsentrasi di antara 2,5-5,0 % dan kelompok kontrol 100 % hidup. Organ testis dalam skrotum mengalami pengecilan ukuran dan konsentrasi spermatozoa mengalami penurunan seiring dengan peningkatan konsentrasi larutan FeCl3 yang digunakan setelah tujuh hari pasca injeksi dibandingkan dengan kontrol.

  14. New Biomarkers for Selecting the Best Therapy Regimens in Metastatic Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Heidegger, Isabel; Heidenreich, Axel; Pfister, David

    2017-02-01

    Prostate cancer is the most common cancer in men. In recent years, several new targeted therapeutic agents for the treatment of metastatic castration resistant prostate cancer (mCRPC) have been developed. These include androgen receptor targeting agents, new taxanes, radium-223, and immunotherapies. In this short review, we provide a summary of clinical and preclinical biomarkers for each of these new treatment strategies, also including new markers currently presented in conference papers only. Moreover, we address the role of these biomarkers in clinical routine with the aim to select best-personalized treatment strategies for patients. Finally, we provide a decision tree for selecting the proper therapy for patients with mCRPC according to the discussed biomarkers.

  15. Dendritic cell vaccination in combination with docetaxel for patients with metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Kongsted, Per; Borch, Troels Holz; Ellebaek, Eva

    2017-01-01

    Background aims  We investigated whether the addition of an autologous dendritic cell–based cancer vaccine (DCvac) induces an immune response in patients with metastatic castration-resistant prostate cancer treated with docetaxel.  Methods  Forty-three patients were randomized 1:1 to receive up......: 5.5 versus 5.7 months (P = 0.62, log rank) and 21.9 versus 25.1 months (P = 0.60, log rank). Nine (50%) and 14 (78%) patients treated with docetaxel and DCvac had a TAA-specific or vaccine-specific immune response in the ELISpot and DTH analysis, respectively. Vaccine induced toxicity was limited...

  16. Impact of treatment delay in Radium-223 therapy of metastatic castration-resistant prostate cancer patients

    DEFF Research Database (Denmark)

    Fosbøl, Marie Øbro; Petersen, Peter Meidahl; Daugaard, Gedske

    2018-01-01

    BACKGROUND: Radium-223-dichloride (Ra-223) is an alpha-emitting, bone seeking radionuclide therapy approved for patients with metastatic castration-resistant prostate cancer (mCRPC). In the fall of 2014, a global temporary shortage of Ra-223 occurred for 2 months due to production irregularities....... The aim of this study was to assess whether prolonged interval between Ra-223 cycles to non-disease related causes had a negative impact on clinical outcome of therapy. MATERIALS AND METHODS: Retrospective single-center study of mCRPC patients who initiated Ra-223 therapy in the period from March 2014......, respectively. Follow-up period was 18 months after first Ra-223 cycle. RESULTS: A total of 50 consecutive patients initiated Ra-223 therapy in the time period. Seventeen of 50 patients (34%) had prolonged interval between cycles due to delivery problems. Median delay was 4 weeks (range 3-9 weeks). Patients...

  17. Androgen receptor variant-7: an important predictive biomarker in castrate resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Oliver Sartor

    2015-06-01

    Full Text Available The recent manuscript in New England Journal of Medicine by Antonarakis et al. [1] has important clinical implications. This study evaluates mRNA expression of a particular androgen receptor splice variant-7 (AR-V7, in circulating tumor cells (CTCs from metastatic castrate-resistant prostate cancer (mCRPC patients receiving enzalutamide or abiraterone. The findings were striking, none of the 18 patients with detectable AR-V7 in CTCs had prostate-specific antigen (PSA responses. Further, the median time to PSA progression after enzalutamide or abiraterone treatment was only 1.3-1.4 months in AR-V7-positive patients as compared to 5.3-6.1 months in AR-V7 negative patients. AR-V7 in CTCs was also associated with shorter survival.

  18. Targeting Met and VEGFR Axis in Metastatic Castration-Resistant Prostate Cancer: 'Game Over'?

    Science.gov (United States)

    Modena, Alessandra; Massari, Francesco; Ciccarese, Chiara; Brunelli, Matteo; Santoni, Matteo; Montironi, Rodolfo; Martignoni, Guido; Tortora, Giampaolo

    2016-08-01

    Despite recent advances that have been made in the therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC), effective management of bone metastases remains a key goal not yet reached. The receptor tyrosine kinase MET and the vascular endothelial growth factor receptor (VEGFR) seem to play an important role in prostate cancer progression and pathological bone turnover, representing potential targets for improving clinical outcomes in mCRPC. Studies evaluating agents that target one or both these pathways have demonstrated modest activity but no improvement in overall survival. Nevertheless, this therapeutic strategy seems to still be a promising and engaging area of prostate cancer research and the interest in better understanding the MET/VEGFR axis and the mechanism of action of these inhibitors is growing. This review describes the rationale for targeting MET and VEGFR pathway in mCRPC and provides the clinical data available to date and an update on ongoing trials.

  19. Investigating BRCA Mutations: A Breakthrough in Precision Medicine of Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Modena, Alessandra; Iacovelli, Roberto; Scarpa, Aldo; Brunelli, Matteo; Ciccarese, Chiara; Fantinel, Emanuela; Bimbatti, Davide; Massari, Francesco; Martignoni, Guido; Tortora, Giampaolo

    2016-10-01

    Despite the development of novel effective therapeutic strategies, metastatic castration-resistant prostate cancer (mCRPC) remains a disease with a lethal course and a high biological and molecular heterogeneity. To date, germline mutations in the BRCA gene represent one of the main risk factors for developing prostate cancer, with a strong association with aggressive phenotype and poor clinical outcomes. A better understanding of the genomic landscape of prostate cancer has strengthened the idea that "synthetic lethality" of this disease might be useful in cancer-drug discovery, focusing on agents such as platinum compounds and poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi). In this review, we summarize the main data available on BRCA mutations and discuss the clinical implications of these genomic aberrations in the management of prostate cancer, stressing the need to identify prognostic and predictive biomarkers and to deeply understand the mechanisms of treatment resistance, in order to maximize personalized medicine protocols and therefore clinical benefit.

  20. Abiraterone Acetate: A Review in Metastatic Castration-Resistant Prostrate Cancer.

    Science.gov (United States)

    Scott, Lesley J

    2017-09-01

    Oral abiraterone acetate (Zytiga ® ) is a selective inhibitor of CYP17 and thereby inhibits androgen biosynthesis, with androgen signalling crucial in the progression from primary to metastatic prostate cancer (PC) and subsequently, in the development of metastatic castration-resistant PC (mCRPC). In large phase 3 trials and in the clinical practice setting, oral abiraterone acetate in combination with prednisone was an effective treatment and had an acceptable, manageable tolerability and safety profile in chemotherapy-naive and docetaxel-experienced men with mCRPC. In the pivotal global phase 3 trials, relative to placebo (+prednisone), abiraterone acetate (+prednisone) prolonged overall survival (OS) at data maturity (final analysis) and radiographic progression-free survival (rPFS) at all assessed timepoints. Given its efficacy in prolonging OS and its convenient once-daily oral regimen, in combination with prednisone, abiraterone acetate is an important first-line option for the treatment of mCRPC.

  1. A combination of sorafenib and nilotinib reduces the growth of castrate-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Archibald M

    2016-01-01

    Full Text Available Monica Archibald,1 Tara Pritchard,1 Hayley Nehoff,1 Rhonda J Rosengren,1 Khaled Greish,1,2 Sebastien Taurin1 1Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; 2Aljawhara Centre for Molecular Medicine, Arabian Gulf University, Manama, Kingdom of Bahrain Abstract: Castrate-resistant prostate cancer (CRPC remains incurable due to the lack of effective therapies. Several tyrosine kinases have been implicated in the development and growth of CRPC, as such targeting these kinases may offer an alternative therapeutic strategy. We established the combination of two tyrosine kinase inhibitors (TKIs, sorafenib and nilotinib, as the most cytotoxic. In addtion, to improve their bioavailability and reduce their metabolism, we encapsulated sorafenib and nilotinib into styrene-co-maleic acid micelles. The micelles’ charge, size, and release rate were characterized. We assessed the effect of the combination on the cytotoxicity, cell cycle, apoptosis, protein expression, tumor spheroid integrity, migration, and invasion. The micelles exhibited a mean diameter of 100 nm, a neutral charge, and appeared highly stable. The micellar TKIs promoted greater cytotoxicity, decreased cell proliferation, and increased apoptosis relative to the free TKIs. In addition, the combination reduced the expression and activity of several tyrosine kinases and reduced tumor spheroid integrity and metastatic potential of CRPC cell lines more efficiently than the single treatments. The combination increased the therapeutic potential and demonstrated the relevance of a targeted combination therapy for the treatment of CRPC. In addition, the efficacy of the encapsulated drugs provides the basis for an in vivo preclinical testing. Keywords: sorafenib, nilotinib, castrate-resistant prostate cancer, tyrosine kinase inhibitors, nanomedicine

  2. Estradiol enhances the acquisition of lithium chloride-induced conditioned taste aversion in castrated male rats

    Science.gov (United States)

    Lin, Shih-Fan; Tsai, Yuan-Feen; Tai, Mei-Yun; Yeh, Kuei-Ying

    2015-10-01

    The present study examined the effects of short-term treatment with ovarian hormones on the acquisition of conditioned taste aversion (CTA). Adult male rats were castrated and randomly divided into LiCl- and saline-treated groups. Nineteen days after castration, all of the animals were subjected to 23.5-h daily water deprivation for seven successive days (day 1 to day 7). On the conditioning day (day 8), the rats received either a 4 ml/kg of 0.15 M LiCl or the same dose of saline injection immediately after administration of a 2 % sucrose solution during the 30-min water session. Starting from day 6, rats in both groups received one of the following treatments: daily subcutaneous injection of (1) estradiol alone (30 μg/kg; estradiol benzoate (E) group), (2) estradiol plus progesterone (500 μg; E + progesterone (P) group), or (3) olive oil. From day 9 to day 11, all of the rats were given daily two-bottle preference tests during the 30-min fluid session. The estradiol and estradiol plus progesterone treatments in the LiCl groups resulted in significantly lower preference scores for the sucrose solution compared with the olive oil treatment groups, but no difference in preference score was seen between these two groups. These results indicate that both the estradiol and estradiol plus progesterone treatments in the LiCl groups enhanced the acquisition of CTA learning and suggest that estradiol affects the acquisition of CTA mediated by an activational effect in male rats, whereas progesterone treatment does not influence the effects of estradiol on the acquisition of CTA.

  3. Impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the TROPIC trial

    DEFF Research Database (Denmark)

    Bahl, A; Oudard, S; Tombal, B

    2013-01-01

    Cabazitaxel significantly improves overall survival (OS) versus mitoxantrone in patients with metastatic castration-resistant prostate cancer after docetaxel failure. We examined patient survival at 2 years and tumour-related pain with cabazitaxel versus mitoxantrone....

  4. Effects on performance and meat quality of Holstein bulls fed high concentrate diets without implants following immunological castration.

    Science.gov (United States)

    Marti, S; Jackson, J A; Slootmans, N; Lopez, E; Hodge, A; Pérez-Juan, M; Devant, M; Amatayakul-Chantler, S

    2017-04-01

    The objective of this study was to evaluate the effect of the GnRH vaccine on the performance and meat quality of Holstein bulls fed high concentrate diets. A total of 493 approximately 7month old bulls (initial BW 298±1.2kg) were allocated into 3 treatment groups, intact bulls (n=164), animals surgically castrated at 15 to 17d of the study (n=164), and animals vaccinated on 0 and 28d of the study with the GnRH vaccine (n=165). Animals were slaughtered between 131 and 133d and carcass quality was evaluated. Hot carcass weight, dressing percentage, fat classification and meat quality parameters did not differ significantly between surgically castrated and vaccinated animals but differed (P<0.05) from intact bulls. Carcass classification, pH at 26h, and fat color were not affected by treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Development of a New Class of Drugs To Inhibit All Forms of Androgen Receptor in Castration Resistant Prostate Cancers

    Science.gov (United States)

    2016-10-01

    concentration of VPC-14449 suppressed the mitosis gene UBE2C, a known target of ARV7 (Hu et al., 2012, Cancer Res.). Fig. 6. PCa cell were cultured...Prostate Cancers PRINCIPAL INVESTIGATOR: Paul Rennie CONTRACTING ORGANIZATION: University of British Columbia Vancouver V6T 1Z3 REPORT DATE...All Forms of Androgen Receptor in Castration-Resistant Prostate Cancers 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT

  6. The Stromal Contribution to the Development of Resistance to New-Generation Drugs by Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2015-10-01

    Castration-Resistant Prostate Cancer PRINCIPAL INVESTIGATOR: Amy Lubik RECIPIENT: University of British Columbia Vancouver, BC Canada V6H 3Z6 REPORT...PERFORMING ORGANIZATION REPORT NUMBER University of British Columbia Vancouver, BC Canada V6H 3Z6 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES...be beneficial for tumors that involved steroidogenesis evoked by paracrine Hh signaling, as compliment to traditional targeting of the AR and

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

    Directory of Open Access Journals (Sweden)

    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.

  8. The assessment of facial expressions in piglets undergoing tail docking and castration: towards the development of the Piglet Grimace Scale

    Directory of Open Access Journals (Sweden)

    Pierpaolo Di Giminiani

    2016-11-01

    Full Text Available Many piglets are exposed to potentially painful husbandry procedures within the first week of life, including tail docking and castration, without the provision of either anaesthesia or analgesia. The assessment methods used to evaluate pain experienced by piglets are often affected by low specificity and practical limitations, prompting the investigation of alternative methodologies. The assessment of changes in facial expression following a painful event has been successfully applied to several species. The objective of this pilot study was to evaluate the utility of a Grimace Scale applied to neonatal pigs to evaluate pain evoked by tail docking and castration.Eight female piglets, sus scrofa domesticus (Landrace/Large White X synthetic sire line underwent tail docking and 15 male piglets (75% Large White and 25% Belgian Landrace were exposed to the castration procedure. Clear images of the faces of the piglets were collected immediately pre- and post-procedure. The images were used by experienced observers to identify Facial Action Units (FAU which changed in individuals over this period and a scoring scale was depicted in a training manual. A set of randomly selected images were then combined in a scorebook, which was evaluated after training by 30 scorers, blind to the treatment. The scale for most FAU was used with a high level of consistency across all observers. Tail docking induced a significant change (P<0.05 only in the ‘orbital tightening’ Action Unit, whereas no change in any unit was observed in castrated piglets. In this initial stage of development, orbital tightening at least seems to have the potential to be applied to investigate painful conditions in neonatal pigs. Nonetheless, more studies are needed to assess its full effectiveness and to evaluate the influence of possible confounds (e.g. handling stress on the observed changes in facial expressions.

  9. 5alphaDH-DOC (5alpha-dihydro-deoxycorticosterone) activates androgen receptor in castration-resistant prostate cancer.

    Science.gov (United States)

    Uemura, Motohide; Honma, Seijiro; Chung, Suyoun; Takata, Ryo; Furihata, Mutsuo; Nishimura, Kazuo; Nonomura, Norio; Nasu, Yasutomo; Miki, Tsuneharu; Shuin, Taro; Fujioka, Tomoaki; Okuyama, Akihiko; Nakamura, Yusuke; Nakagawa, Hidewaki

    2010-08-01

    Prostate cancer often relapses during androgen-depletion therapy, even under the castration condition in which circulating androgens are drastically reduced. High expressions of androgen receptor (AR) and genes involved in androgen metabolism indicate a continued role for AR in castration-resistant prostate cancers (CRPCs). There is increasing evidence that some amounts of 5alpha-dihydrotestosterone (DHT) and other androgens are present sufficiently to activate AR within CRPC tissues, and enzymes involved in the androgen and steroid metabolism, such as 5alpha-steroid reductases, are activated in CRPCs. In this report, we screened eight natural 5alphaDH-steroids to search for novel products of 5alpha-steroid reductases, and identified 11-deoxycorticosterone (DOC) as a novel substrate for 5alpha-steroid reductases in CRPCs. 11-Deoxycorticosterone (DOC) and 5alpha-dihydro-deoxycorticosterone (5alphaDH-DOC) could promote prostate cancer cell proliferation through AR activation, and type 1 5alpha-steroid reductase (SRD5A1) could convert from DOC to 5alphaDH-DOC. Sensitive liquid chromatography-tandem mass spectrometric analysis detected 5alphaDH-DOC in some clinical CRPC tissues. These findings implicated that under an extremely low level of DHT, 5alphaDH-DOC and other products of 5alpha-steroid reductases within CRPC tissues might activate the AR pathway for prostate cancer cell proliferation and survival under castration.

  10. Prostate radiation in non-metastatic castrate refractory prostate cancer provides an interesting insight into biology of prostate cancer

    Directory of Open Access Journals (Sweden)

    Pascoe Abigail C

    2012-03-01

    Full Text Available Abstract Background The natural history of non-metastatic castrate refractory prostate cancer is unknown and treatment options are limited. We present a retrospective review of 13 patients with locally advanced or high risk prostate cancer, initially treated with hormone monotherapy and then treated with prostate radiation after becoming castration refractory. Findings Median PSA response following prostate radiation was 67.4%. Median time to biochemical progression following radiotherapy was 15 months and to detection of metastatic disease was 18.5 months. Median survival from castration resistance (to date of death or November 2011 was 60 months, with median survival from RT 42 months. Conclusion Prostate radiation appears to be beneficial even in patients with potential micrometastatic disease, which supports the hypothesis that the primary tumour is important in the progression of prostate cancer. These results are an interesting addition to the literature on the biology of prostate cancer especially as this data is unlikely to be available in the future due to combined prostate radiation and androgen deprivation therapy now being the standard of care.

  11. The Role of Docetaxel in Non-Castrate Resistant Metastatic Prostate Cancer: An Evidence-based Case Report

    Directory of Open Access Journals (Sweden)

    Fakhri Rahman

    2017-04-01

    Full Text Available Aim: to learn the role of docetaxel in non-castrate resistant prostate cancer patient. Methods: literature search was conducted to find relevant study comparing the combination of docetaxel and androgen deprivation therapy (ADT to ADT alone in non-castrate resistant prostate cancer using PubMed, Cohrane Library, Proquest, EBSCO, and Scopus database. Quality assessment of studies was done using Bond University Rapid Critical Appraisal of a Systematic Review. Results: we found 494 studies from literature search, but only two studies were included in final selection. Based on validity assessment, we chose one study to be discussed further. This study showed that combination of docetaxel and ADT is better than ADT alone in regards of overall survival (HR 0.64; 95% CI 0.55, 0.75; p<0.0001; NNT=3, biochemical progression free survival (HR 0.63; 95% CI 0.57, 0.69; p<0.0001; NNT=2 and clinical progression free survival (HR 0.73; 95% CI 0.64, 0.84; p<0.0001; NNT=2. Benefit of docetaxel and ADT combination was especially seen in high volume disease (HR 0.67; 95% CI 0.54, 0.83; p=0.0003; NNT=3. Conclusion: addition of docetaxel into ADT has beneficial effects in terms of overall survival and progression free survival in patients with non-castrate resistant metastatic prostate cancer.

  12. Androgen-mediated development of irradiation-induced thyroid tumors in rats: dependence on animal age during interval of androgen replacement in castrated males

    International Nuclear Information System (INIS)

    Hofmann, C.; Oslapas, R.; Nayyar, R.; Paloyan, E.

    1986-01-01

    When male Long-Evans rats at age 8 weeks were radiation treated (40 microCi Na131I), thyroid follicular adenomas and carcinomas were observed at age 24 months with a high incidence of 94%. Castration of males prior to irradiation significantly reduced this tumor incidence to 60%. When testosterone (T) was replaced in castrated, irradiated male rats, differentially increased incidences of thyroid tumors occurred. Immediate (age 2-6 mo) or early (age 6-12 mo) T replacement at approximate physiologic levels led to thyroid follicular tumor incidences of 100 and 82%, respectively, whereas intermediate (12-18 mo) or late (18-24 mo) T treatment led to only 70 and 73% incidences, respectively. Continuous T replacement (2-24 mo) in castrated irradiated male rats raised thyroid tumor incidence to 100%. Since elevated thyroid-stimulating hormone (TSH) is a reported requisite for development of radiation-associated thyroid tumors, the effects of T on serum TSH levels were examined. Mean serum TSH values in all irradiated animal groups were significantly elevated above age-matched nonirradiated animals at 6, 12, 18, and 24 months. Serum TSH levels were higher in continuous T-replaced irradiated castrates than in intact, irradiated males, whereas such intact male TSH levels were greater than those for irradiated castrates without T treatment. Interval T replacement in castrated male rats was associated with increased serum TSH levels during the treatment interval and with lowered TSH levels after discontinuation of T treatment, particularly in irradiated rats. However, when irradiated, castrated males received late T replacement (age 18-24 mo), there was no elevation of TSH at the end of the treatment interval. An indirect effect of T via early stimulation of TSH may be partly responsible for the high incidence of irradiation-induced thyroid tumors in rats

  13. Effect of immunological castration management strategy on lipid oxidation and sensory characteristics of bacon stored under simulated food service conditions.

    Science.gov (United States)

    Herrick, R T; Tavárez, M A; Harsh, B N; Mellencamp, M A; Boler, D D; Dilger, A C

    2016-07-01

    The objectives of this study were to determine the effect of 1) immunological castration (Improvest, a gonadotropin releasing factor analog-diphtheria toxoid conjugate) management strategy (age at slaughter and time of slaughter after second dose) and 2) sex on lipid oxidation and sensory characteristics of bacon stored under simulated food service conditions. For Objective 1, immunological castration management strategies included 24-wk-old immunologically castrated (IC) barrows 4, 6, 8, or 10 wk after the second Improvest dose (ASD); 26-wk-old IC barrows 6 wk ASD; and 28-wk-old IC barrows 8 wk ASD ( = 63). Objective 2 ( = 97) included IC barrows, physically castrated (PC) barrows, and gilts slaughtered at 24, 26, and 28 wks of age. Bellies from 2 slaughter dates were manufactured into bacon under commercial conditions. Bacon slices were laid out on parchment paper, packaged in oxygen-permeable poly-vinyl-lined boxes, and frozen (-33°C) for 1, 4, 8, or 12 wk to simulate food service conditions. At the end of each storage period, bacon was evaluated for lipid oxidation, moisture and lipid content, and sensory characteristics. Data from both objectives were analyzed using the MIXED procedure in SAS with belly as the experimental unit. For both objectives, as storage time increased, lipid oxidation of bacon increased ( bacon from IC barrows increased as time of slaughter ASD increased ( bacon across management strategies. For the evaluation of sex effects in Objective 2, lipid oxidation was greater ( 0.05). After 12 wk of frozen storage, lipid oxidation values for IC barrows, PC barrows, and gilts were still below 0.5 mg malondialdehyde/kg of meat, the threshold at which trained panelists may deem a food to be rancid. In conclusion, bacon shelf life characteristics were not altered by the immunological castration management strategy and bacon from IC barrows was similar to bacon from gilts. Therefore, bacon from IC barrows would result in shelf life and sensory

  14. Lymphocyte function following radium-223 therapy in patients with metastasized, castration-resistant prostate cancer

    International Nuclear Information System (INIS)

    Barsegian, Vahe; Moeckel, Daniel; Mueller, Stefan P.; Bockisch, Andreas; Horn, Peter A.; Lindemann, Monika

    2017-01-01

    Therapy with the alpha-emitter radium-223 chloride ( 223 Ra) is an innovative therapeutic option in patients with metastasized, castration-resistant prostate cancer. However, radiotherapy can lead to hematopoietic toxicity. The aim of this study was to determine if 223 Ra therapy induces an impairment of cellular antimicrobial immune responses. In 11 patients receiving 223 Ra treatment, lymphocyte proliferation and the production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10) were determined, using lymphocyte transformation testing and ELISpot, respectively. Lymphocyte function after stimulation with mitogens and microbial antigens was assessed prior to therapy and at day 1, 7 and 28 after therapy. Lymphocyte proliferation and the production of interferon-γ and interleukin-10 towards mitogens and antigens remained unchanged after therapy. Consistent with these in vitro data, we did not observe infectious complications after treatment. The results argue against an impairment of lymphocyte function after 223 Ra therapy. Thus, immune responses against pathogens should remain unaffected. (orig.)

  15. Impact of castration with or without alpha-tocopherol supplementation on the urethral sphincter of rats

    Directory of Open Access Journals (Sweden)

    Mirian Kracochansky

    2012-04-01

    Full Text Available OBJECTIVE: To analyze the impact of low levels of testosterone induced by orchiectomy and the effect of alpha-tocopherol supplementation on oxidative stress in the urethral sphincter. MATERIALS AND METHODS: Forty male Wistar rats weighing 250-300g were divided into four groups with 10 each: Sham group; Orchiectomy group: bilateral orchiectomy; Orchiectomy-pre-Tocopherol group: bilateral orchiectomy preceded by alpha-tocopherol supplementation for four weeks; Orchiectomy-full-Tocopherol group: bilateral orchiectomy with alpha-tocopherol supplementation for four weeks preceding the procedure and for eight weeks afterwards. At the protocol end, animals were euthanized and had the sphincter analyzed stereologically focusing on collagen and muscle fibers percentage. Oxidative stress levels were determined using 8-epi-PGF2. RESULTS: The 8-epi-PGF2 levels were statistically higher (p < 0.0003 in the Orchiectomy group compared to others groups while Sham and Orchiectomy-full-Tocopherol groups presented statistically similar values (p = 0.52. Collagen volumetric densities were significantly lower in Sham and Orchiectomy-full-Tocopherol groups (p < 0.022. Sham group presented statistically greater muscle fiber percent. CONCLUSION: Castration caused oxidative stress in the urethral sphincter complex, with increased collagen deposition. Alpha-tocopherol had a protective effect and its supplementation for twelve weeks provided the greatest protection.

  16. Practical recommendations for radium-223 treatment of metastatic castration-resistant prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Du, Yong [The Royal Marsden NHS Foundation Trust, Department of Nuclear Medicine and PET/CT, London (United Kingdom); Carrio, Ignasi [Hospital Sant Pau, Barcelona (Spain); De Vincentis, Giuseppe [Policlinico Umberto I University Hospital Rome, Rome (Italy); Fanti, Stefano [University Hospital Bologna, Bologna (Italy); Ilhan, Harun [Ludwig-Maximilians-University Hospital, Munich (Germany); Mommsen, Caroline [Praxis fuer diagnostische und therapeutische Nuklearmedizin Berlin, Berlin (Germany); Nitzsche, Egbert [Canton Hospital Aarau, Aarau (Switzerland); Sundram, Francis [University Hospital Southampton NHS Foundation Trust, Southampton (United Kingdom); Vogel, Wouter [The Netherlands Cancer Institute, Amsterdam (Netherlands); Oyen, Wim [The Royal Marsden NHS Foundation Trust, Department of Nuclear Medicine and PET/CT, London (United Kingdom); The Institute of Cancer Research, London (United Kingdom); Lewington, Val [Guy' s and St Thomas' NHS Foundation Trust, London (United Kingdom)

    2017-09-15

    Radium Ra 223 dichloride (radium-223, Xofigo registered) is the first targeted alpha therapy for patients with castration-resistant prostate cancer and symptomatic bone metastases. Radium-223 provides a new treatment option for this setting, but also necessitates a new treatment management approach. We provide straightforward and practical recommendations for European nuclear medicine centres to optimize radium-223 service provision. An independent research consultancy agency observed radium-223 procedures and conducted interviews with all key staff members involved in radium-223 treatment delivery in 11 nuclear medicine centres across six countries (Germany, Italy, the Netherlands, Spain, Switzerland and the UK) experienced in administering radium-223. The findings were collated and discussed at a meeting of experts from these centres, during which key consensus recommendations were defined. The recommendations cover centre organization and preparation; patient referral; radium-223 ordering, preparation and disposal; radium-223 treatment delivery/administration; and patient experience. Guidance includes structured coordination and communication within centres and multidisciplinary teams, focusing on sharing best practice to provide high-quality, patient-centred care throughout the treatment pathway. These expert recommendations are intended to complement existing management guidelines. Sharing best practice and experience will help nuclear medicine centres to optimize radium-223 service provision and improve patient care. (orig.)

  17. Inhibiting autophagy overcomes docetaxel resistance in castration-resistant prostate cancer cells.

    Science.gov (United States)

    Wang, Quan; He, Wei-Yang; Zeng, Yi-Zhou; Hossain, Arman; Gou, Xin

    2018-02-19

    This study investigates the docetaxel-resistant mechanism and explores the effect of tea polyphenols (TP) on autophagy and its related mechanism in human castration-resistant prostate cancer (CRPC) cell lines PC3 and DU145. Immunofluorescence assay and annexin V-FITC/PI double staining flow cytometry were used to analyze the apoptosis and autophagy of PC3 and DU145 cells. The expression of autophagy-related proteins was detected by western bolt. Docetaxel could induce autophagy and apoptosis, together with the expression increase in p-JNK, p-Bcl-2 and Beclin1. The level of autophagy was remarkably decreased, but apoptosis was increased after combining with TP. In addition, the expression of p-mTOR was increased after combining with TP. Docetaxel induces protective autophagy in CRPC cells by JNK pathway activation and then Bcl-2 phosphorylation and Beclin1 dissociation. TP activates mTOR pathway, which ultimately inhibits docetaxel-induced autophagy and improves therapeutic efficacy of docetaxel in CRPC cells.

  18. Radium-223 in treatment of castration-resistant prostate cancer with skeletal metastases

    Directory of Open Access Journals (Sweden)

    V. B. Matveev

    2017-01-01

    Full Text Available More than 90 % of patients with metastatic castration-resistant prostate cancer (CRPC have radiologically confirmed skeletal metastases. Traditional treatment methods such as administration of painkillers, external beam therapy, bisphosphonates or denosumab, as well as injections of strontium-89 or samarium-153 radionuclides, have only palliative effect and in some cases can postpone development of skeletal complications. Alpha-emitter radium-223 dichloride (Ra-223; alpharadin previously is currently one of the known drugs with proven effectiveness in relation to increasing overall survival of patients with CRPC. Ra-223 was developed specifically for patients with CRPC and symptomatic skeletal metastases. The drug targets the areas of skeletal tissue remodeling. Ra-223 is the therapy of choice in patients with CRPC and skeletal metastases and without confirmed visceral metastases before and after docetaxel chemotherapy. Chemotherapy after treatment with Ra-223 is a possible and satisfactory tolerable treatment option. Combination of Ra-223 with abiraterone, enzalutamide, or denosumab is, apparently, effective and safe, but further studies are necessary.

  19. Resistance to abiraterone in castration-resistant prostate cancer: a review of the literature.

    Science.gov (United States)

    Giacinti, Silvana; Bassanelli, Maria; Aschelter, Anna Maria; Milano, Annalisa; Roberto, Michela; Marchetti, Paolo

    2014-11-01

    Persistent androgen signaling is functionally significant in castration-resistant prostate cancer (CRPC) and it is actually considered a validated therapeutic target. Residual intra-tumoral androgens compensate for the effects of androgen ablation, activating the androgen receptor (AR), AR-mediated gene expression and driving CRPC. The intra-tumoral biosynthesis of androgens takes place in different ways and cytochrome P450 17A1 (CYP17A1) has a crucial role in this context. Abiraterone, a CYP17A1 inhibitor, has shown impressive results in pre- and post-chemotherapy settings, prolonging the survival of patients with CRPC. However, not all patients respond to the treatment and most responders develop resistance, with a widely variable duration of response. Although many hypotheses are emerging, the mechanisms of resistance to abiraterone treatment have not yet been elucidated. The aim of the present review is to describe the main data currently available on resistance to abiraterone. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  20. Clinical Relevance of Androgen Receptor Splice Variants in Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Maughan, Benjamin L; Antonarakis, Emmanuel S

    2015-12-01

    Metastatic castration-resistant prostate cancer (mCRPC) currently benefits from a wealth of treatment options, yet still remains lethal in the vast majority of patients. It is becoming increasingly understood that this disease entity continues to evolve over time, acquiring additional and diverse resistance mechanisms with each subsequent therapy used. This dynamic relationship between treatment pressure and disease resistance can be challenging for the managing clinician. The recent discovery of alternate splice variants of the androgen receptor (AR) is one potential mechanism of escape in mCRPC, and recognizing this resistance mechanism might be important for optimal treatment selection for our patients. AR-V7 appears to be the most relevant AR splice variant, and early clinical data suggest that it is a negative prognostic marker in mCRPC. Emerging evidence also suggests that detection of AR-V7 may be associated with resistance to novel hormonal therapy (abiraterone and enzalutamide) but may be compatible with sensitivity to taxane chemotherapy (docetaxel and cabazitaxel). Adding to this complexity is the observation that AR-V7 is a dynamic marker whose status may change across time and depending on selective pressures induced by different therapies. Finally, it is possible that AR-V7 may represent a therapeutic target in mCRPC if drugs can be designed that degrade or inhibit AR splice variants or block their transcriptional activity. Several such agents (including galeterone, EPI-506, and bromodomain/BET inhibitors) are now in clinical development.

  1. Reactive oxygen species induction by cabazitaxel through inhibiting Sestrin-3 in castration resistant prostate cancer

    Science.gov (United States)

    Kosaka, Takeo; Hongo, Hiroshi; Miyazaki, Yasumasa; Nishimoto, Koshiro; Miyajima, Akira; Oya, Mototsugu

    2017-01-01

    Reactive oxygen species (ROS) production induced by taxanes in cancer cells may influence the taxane-induced cell death or the drug resistance. We investigated the correlation between the cytotoxic effect of taxanes and ROS production in human castration-resistant prostate cancer (CRPC) cell lines. Three human prostate cancer cell lines were treated with increasing concentrations of docetaxel or cabazitaxel in vitro. Cabazitaxel showed significantly higher cytotoxic efficacy than docetaxel in human CRPC cells, accompanied by elevated ROS production detected by FACS analysis. To investigate whether cabazitaxel-mediated cell death was caused by the ROS generation induced by cabazitaxel, we treated CRPC cells in the presence of antioxidant NAC. NAC reduced the cytotoxic effect induced by cabazitaxel. We found that ROS elimination by Sestrin-3 (SESN3) was significantly inhibited by cabazitaxel, but not by docetaxel. These results indicate higher sensitivity of human CRPC to cabazitaxel compared to docetaxel involves ROS production through inhibiting the expression of antioxidant enzyme SESN3. PMID:29152111

  2. Castration resistant prostate cancer (CRPC): state of the art, perspectives and new challenges.

    Science.gov (United States)

    Massari, Francesco; Maines, Francesca; Modena, Alessandra; Brunelli, Matteo; Bria, Emilio; Artibani, Walter; Martignoni, Guido; Tortora, Giampaolo

    2013-07-01

    The rapid approval of several novel agents has given prostate cancer patients and their treating physicians many new and effective therapeutic options. Four new medical therapies were recently approved on the basis of prolonged overall survival in castration-resistant prostate cancer (CRPC) patients: sipuleucel-T, cabazitaxel, abiraterone acetate and MDV3100. Additionally, there are several other promising prostate cancer agents in late-stage development, including PROSTVAC-VF, orteronel and radium-223 chloride, each with a novel mechanism of action. The treatment paradigm for these patients is rapidly evolving, with future study needed to define the optimal sequencing and potential combinations of these new agents. In this review, we discuss the recent progress in understanding the biology of this disease and examining the development of a variety of new agents with promising activity and a favorable toxicity profile, that have been investigated in the setting of hormonal, cytotoxic, immune and targeted therapy. In this new therapeutic setting of CRPC, clinicians will have an opportunity to balance benefits and harms of these new agents in an individual context.

  3. Cabazitaxel: more than a new taxane for metastatic castrate-resistant prostate cancer?

    Science.gov (United States)

    Mita, Alain C; Figlin, Robert; Mita, Monica M

    2012-12-15

    The taxanes are recognized as a major class of chemotherapeutic agents; however, mechanisms of innate and acquired resistance can limit their usefulness. Cabazitaxel, a novel taxane with microtubule-stabilizing potency similar to docetaxel, exhibits activity against tumor cell lines resistant to paclitaxel and docetaxel. Cabazitaxel showed linear pharmacokinetics and a terminal elimination half-life comparable with that of docetaxel, findings which support dosing as a single infusion in three-week treatment cycles. Dose-ranging studies recommended doses of 20 or 25 mg/m(2) every three weeks. Antitumor activity was shown in patients with advanced cancer and chemotherapy failure (including taxane failure). Other early studies investigated the efficacy of cabazitaxel in pretreated metastatic breast cancer, either as a single agent or in combination with capecitabine. Objective antitumor response rates of up to 24% and sustained tumor stabilizations were also observed. The TROPIC phase III study, conducted in patients with metastatic castrate-resistant prostate cancer previously treated with docetaxel, established cabazitaxel as the first chemotherapeutic agent to offer a survival advantage in this patient population. Across these studies, the dose-limiting hematologic toxicity was neutropenia (including febrile neutropenia), usually controllable with colony-stimulating factor/granulocyte-colony stimulating factor support. ©2012 AACR.

  4. Lymphocyte function following radium-223 therapy in patients with metastasized, castration-resistant prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Barsegian, Vahe; Moeckel, Daniel [Helios Kliniken, Institute of Nuclear Medicine, Schwerin (Germany); Mueller, Stefan P.; Bockisch, Andreas [University Hospital Essen, Department of Nuclear Medicine, Essen (Germany); Horn, Peter A.; Lindemann, Monika [University Hospital Essen, Institute for Transfusion Medicine, Essen (Germany)

    2017-02-15

    Therapy with the alpha-emitter radium-223 chloride ({sup 223}Ra) is an innovative therapeutic option in patients with metastasized, castration-resistant prostate cancer. However, radiotherapy can lead to hematopoietic toxicity. The aim of this study was to determine if {sup 223}Ra therapy induces an impairment of cellular antimicrobial immune responses. In 11 patients receiving {sup 223}Ra treatment, lymphocyte proliferation and the production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10) were determined, using lymphocyte transformation testing and ELISpot, respectively. Lymphocyte function after stimulation with mitogens and microbial antigens was assessed prior to therapy and at day 1, 7 and 28 after therapy. Lymphocyte proliferation and the production of interferon-γ and interleukin-10 towards mitogens and antigens remained unchanged after therapy. Consistent with these in vitro data, we did not observe infectious complications after treatment. The results argue against an impairment of lymphocyte function after {sup 223}Ra therapy. Thus, immune responses against pathogens should remain unaffected. (orig.)

  5. Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer.

    Science.gov (United States)

    Chang, Kai-Hsiung; Li, Rui; Papari-Zareei, Mahboubeh; Watumull, Lori; Zhao, Yan Daniel; Auchus, Richard J; Sharifi, Nima

    2011-08-16

    In the majority of cases, advanced prostate cancer responds initially to androgen deprivation therapy by depletion of gonadal testosterone. The response is usually transient, and metastatic tumors almost invariably eventually progress as castration-resistant prostate cancer (CRPC). The development of CRPC is dependent upon the intratumoral generation of the potent androgen, dihydrotestosterone (DHT), from adrenal precursor steroids. Progression to CRPC is accompanied by increased expression of steroid-5α-reductase isoenzyme-1 (SRD5A1) over SRD5A2, which is otherwise the dominant isoenzyme expressed in the prostate. DHT synthesis in CRPC is widely assumed to require 5α-reduction of testosterone as the obligate precursor, and the increased expression of SRD5A1 is thought to reflect its role in converting testosterone to DHT. Here, we show that the dominant route of DHT synthesis in CRPC bypasses testosterone, and instead requires 5α-reduction of androstenedione by SRD5A1 to 5α-androstanedione, which is then converted to DHT. This alternative pathway is operational and dominant in both human CRPC cell lines and fresh tissue obtained from human tumor metastases. Moreover, CRPC growth in mouse xenograft models is dependent upon this pathway, as well as expression of SRD5A1. These findings reframe the fundamental metabolic pathway that drives CRPC progression, and shed light on the development of new therapeutic strategies.

  6. Challenges in the sequencing of therapies for the management of metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Parente, Phillip; Parnis, Francis; Gurney, Howard

    2014-09-01

    Prior to 2010, docetaxel was the standard option for chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC). Today, the picture is vastly different: several additional therapies have each demonstrated a survival benefit such that we now have chemotherapy (cabazitaxel), androgen suppressive agents (abiraterone acetate and enzalutamide), a cellular vaccine (sipuleucel-T) and radium-233 (for symptomatic bone metastases). With several other agents in the pipeline for late-stage disease, the future looks promising for mCRPC. As the available data are not able to inform as to the optimum sequencing of therapy, this remains a challenge. This paper draws on insights from published and ongoing clinical studies to provide a practical patient-focused approach to maximize the benefits of the current therapeutic armamentarium. Preliminary sequencing suggestions are made based on clinical trial criteria. But until more data become available, clinical gestalt, experience, cost and individual patient preferences will continue to drive choices. © 2014 Wiley Publishing Asia Pty Ltd.

  7. ECF chemotherapy for liver metastases due to castration-resistant prostate cancer.

    Science.gov (United States)

    Gupta, Shruti; Potvin, Kylea; Ernst, D Scott; Whiston, Frances; Winquist, Eric

    2014-09-01

    Most men with metastatic castration-resistant prostate cancer (CRPC) have biochemical response to docetaxel, but the objective response rate is low. Liver metastases are uncommon with CRPC and associated with shorter survival. More active treatment might benefit these patients. Epirubicin, cisplatin and flurouracil (ECF) is a standard regimen for gastric cancer and response in CRPC liver metastases has been reported. We reviewed our experience with ECF in CRPC with the primary objective of determining its anti-tumour activity in patients with liver metastatic CRPC. Men with CRPC treated with ECF were identified from electronic databases and data were extracted from medical records. Men with tumours showing neuroendocrine features were excluded. In total, we identified 14 CRPC patients treated with ECF were identified, of which 8 had liver metastases. The median age was 56 (range: 42-76) and all had multiple poor prognostic features. A median of 6 cycles of ECF were administered (range: 1-10) and toxicities were similar to previous reports. Of the 8 patients with liver metastases, 5 had partial remission. ECF was highly active in this small selected group of younger men with liver metastases from CRPC and multiple poor prognostic features. Despite important limitations, this is the third report of high objective response rates with ECF in CRPC. Objective response rates are low with current monotherapies. A higher probability of ORR is preferred for critical organ disease, therefore the anti-tumour activity should encourage testing of ECF in comparison to the most active current therapies.

  8. Targeting heat shock proteins in metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Azad, Arun A; Zoubeidi, Amina; Gleave, Martin E; Chi, Kim N

    2015-01-01

    The survival of malignant cells is constantly threatened by a myriad of cellular insults. In the context of such proteotoxic stress, cancer cells activate cytoprotective adaptive pathways. Heat shock proteins (HSPs) are highly conserved molecular chaperones that are expressed at low levels under normal conditions, but upregulated by cellular stress. As molecular chaperones, HSPs control the stability and function of client proteins, preventing aggregation of misfolded proteins, facilitating intracellular protein trafficking, maintaining protein conformation to enable ligand binding, phosphorylating proteins in signalling complexes and degrading severely damaged proteins via the ubiquitin-proteasome pathway. A key client protein of several HSPs is the androgen receptor (AR). HSPs facilitate binding of dihydrotestosterone to the AR, and enhance AR-mediated transcriptional activity. The integral role of HSPs in AR function speaks to their potential utility as therapeutic targets in castration-resistant prostate cancer (CRPC), a disease state characterized by persistent activation of the androgen-AR axis. Inhibition of HSPs has the additional benefit of potentially modulating signalling and transcriptional networks that are associated with HSP client proteins in CRPC cells. As a consequence, HSPs represent highly attractive targets in the development of treatments for CRPC.

  9. Ganho de peso e características de carcaça de bovinos Nelore castrados ou não-castrados terminados em confinamento Weight gain and characteristics of carcass of castrated or non-castrated Nellore cattle finished in confinement

    Directory of Open Access Journals (Sweden)

    Fredson Vieira e Silva

    2008-12-01

    ético.The objective of this work was to evaluate weight gain and carcass characteristics Nellore cattle, castrated or non-castrated, finished in confinement. It was used Thirty six animals with 24 months old and initial 445.30 kg BW (non-castrated or 449.57 kg BW (castrated at 400 kg BW. The animals were slaughtered at 50 days of confinement, when reached 516.30 kg BW (non-castrated and 506.86 kg BW (castrated. Non-castrated animals did not have an increase in final BW, but showed higher weight gain (1.42 and 1.15 kg. Hot carcass weight (272.77 and 261.89 kg and cold carcass weight (266.13 and 258.24 kg did not differ between non-castrated and castrated animals. Non-castrated animals showed higher hot carcass yield (52.88 vs. 51.65% however, cold carcass yield was similar between groups (51.55 and 52.39%, due to smaller chilling loss in castrated animals (2.43 vs. 1.40%. Special hindquarter absolute weights (133.07 and 131.55 kg, forequarter (105.65 and 100.09 kg and spare ribs (27.41 and 26.60 kg did not differ between non-castrated and castrated animals. Forequarter relative values castrated animals were higher than the non-castrated (50.93 versus 50.00%. The striploin of non-castrated animals was heavier than that of castrated (8.41 vs. 7.90 kg. Fat thickness (2.05 vs. 2.21 mm and loin eye area (66.98 versus 67.48 cm² did not differ between non-castrated and castrated animals. Cold carcass pH in predetermined time until setting of rigor mortis is also similar between and non-castrated and castrated animals. Non-castrated and castrated animals have satisfactory carcass weight, but have not fat thickness less than 3 mm, when confined for 50 days with diet based on sugar cane and concentrate. To match the fat thickness, the diet of the animals must be balanced with higher energy level.

  10. Effects of ractopamine administration and castration method on muscle fiber characteristics and sensory quality of the longissimus muscle in two Piétrain pig genotypes.

    Science.gov (United States)

    Li, Hui; Gariépy, Claude; Jin, Ye; Font I Furnols, Maria; Fortin, Jacinthe; Rocha, Luiene M; Faucitano, Luigi

    2015-04-01

    Single and combined effects of ractopamine supplementation (RAC, 7.5 vs. 0 ppm), castration method (surgical castration: SC vs. immuno-castration: IM) and genotype (genotype A: GA vs. GB containing 25% or 50% Piétrain) were determined on longissimus muscle (LM) fiber traits and quality of pork (n=512). RAC increased fiber IIX cross-sectional area (P=0.009) and decreased glycolytic potential (P=0.02) and pork tenderness (Pcombination affected some fiber traits and some quality parameters but differences reported were small indicating these treatments or their combination could be used without major prejudice to meat quality. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

  11. Cytochrome oxidase activity in the preoptic area correlates with differences in sexual behavior of intact and castrated male leopard geckos (Eublepharis macularius).

    Science.gov (United States)

    Sakata, J T; Crews, D

    2004-08-01

    Although the utility of analyzing behavioral experience effects on neural cytochrome oxidase (CO) activity is well recognized, the behavioral correlates of endogenous differences in CO activity have rarely been explored. In male leopard geckos (Eublepharis macularius), the incubation temperature experienced during embryogenesis (IncT) and age affect CO activity in the preoptic area (POA), an area that modulates copulatory behavior. In this study, the authors assessed whether differences in POA CO activity correlate with differences in sexual behavior in intact and castrated geckos. Males with IncT- and age-dependent increases in POA CO activity mounted females with shorter latencies while intact and after castration and ejaculated more frequently after castration. The authors discuss the predictive value of CO activity and propose similar parallels in other species.

  12. Effects of neonatal surgical castration and immunocastration in male pigs on blood T lymphocytes and health markers.

    Science.gov (United States)

    Leclercq, C; Prunier, A; Merlot, E

    2014-05-01

    Surgical castration in pig husbandry is criticized for welfare reasons. Thus, it is necessary to evaluate alternative ways of rearing male pigs, such as entire or immunocastrated animals. Immunocastration is a vaccination directed against gonadotropin-releasing hormone (GnRH) to suppress the production of sexual hormones. This study aimed at investigating the effects of these two methods of castration in comparison with intact male pigs on blood T-lymphocyte subsets and function, the immunoglobulin (Ig) response to an influenza vaccine and health markers during sexual development. A total of 70 animals were allocated to three experimental groups: entire (E), surgically castrated at 5 to 6 days of age (SC), and immunized against GnRH at 3 and 4 months of age (IC). Blood samples were collected at 3, 4 and 5 months. At slaughter, global health status and body and spleen weights were measured. Results showed that SC male pigs had fewer blood lymphocytes than E pigs at 4 and 5 months (Ppigs did not differ significantly from E pigs. The percentages of CD3+, CD3+CD4+ and CD3+CD8+ lymphocytes were not altered by treatment (P>0.1). Compared with E pigs, the SC pigs had a higher percentage of CD3+CD4+CD8+ cells at 4 months, whereas the IC pigs had a higher percentage at 5 months (Ppigs had a lower percentage than E pigs at 4 and 5 months (Ppigs did not differ significantly from E pigs at any age. However, there were no consequences on T-lymphocyte proliferation and total IgG or anti-influenza Ig. At slaughter, relative spleen weight was decreased in IC pigs, whereas pneumonia score was decreased in SC pigs relatively to E pigs. Overall, no clear functional consequences of either method on commercial pig immune abilities were demonstrated, but more investigations are required to ascertain this conclusion.

  13. Comparison of caudal and pre-scrotal castration for management of perineal hernia in dogs between 2004 and 2014.

    Science.gov (United States)

    Snell, W L; Orsher, R J; Larenza-Menzies, M P; Popovitch, C A

    2015-09-01

    To compare peri- and post-operative complications associated with caudal scrotal castration (CSC) and perineal hernia repair with pre-scrotal castration (PSC) in conjunction with another surgical procedure. Medical records were reviewed for 51 intact male dogs that were admitted to the Veterinary Emergency and Surgical Center, Levittown, PA, and underwent a CSC and perineal hernia repair using an internal obturator muscle flap (IOMF) between 2004 and 2014. Perioperative, and major and minor post-operative complications noted within the 2 week follow up period were reported and compared to 91 intact male dogs that underwent a PSC in conjunction with a second surgical procedure. There were no recorded perioperative or major post-operative complications in either group. There were 3/51 (6%) minor post-operative complications in the CSC group compared to 6/91 (7%) in the PSC group. There were 2/51 (4%) and 4/91 (4%) cases that developed heat, erythema and swelling associated with the incision site and 1/51 (2%) and 2/91 (2%) cases that developed scrotal swelling in the CSC and PSC groups, respectively. Overall, there was no difference in the prevalence of minor complications between the two groups (p=0.86). Caudal scrotal castration was not associated with more perioperative or postoperative complications relative to PSC. Utilising the CSC approach eliminates the need to aseptically prepare and drape a second site when carrying out perineal hernia repair, as well as the need for patient repositioning. Thus, we recommend that CSC be the preferred surgical technique when performing orchiectomy in dogs concurrent with perineal hernia repair.

  14. The sexuality and social performance of androgen-deprived (castrated) men throughout history: implications for modern day cancer patients.

    Science.gov (United States)

    Aucoin, Michael William; Wassersug, Richard Joel

    2006-12-01

    Androgen-deprivation therapy (ADT) via either surgical or chemical castration is the standard treatment for advanced prostate cancer (PCa). In North America, it is estimated that more than 40,000 men start ADT each year. The side effects of this treatment are extensive and include gynecomastia, erectile dysfunction, and reduced libido. These changes strongly challenge patients' self-identity and sexuality. The historical term for a man who has been castrated is 'eunuch', now a pejorative term implying overall social and sexual impotence. In this paper, we review key historical features of eunuch social performance and sexuality from a variety of cultures in order to assess the validity of contemporary stereotypes of the androgen-deprived male. Data were taken from secondary sources on the history of Byzantium, Roman Antiquity, Early Islamic societies, the Ottoman Empire, Chinese Dynasties, and the Italian Castrati period. This cross-cultural survey shows that castrated men consistently held powerful social positions that yielded great political influence. Many eunuchs were recognized for their loyalty, managerial style, wisdom, and pedagogical skills. Furthermore, rather than being consistently asexual and celibate, they were often sexually active. In certain cultures, they were objects of sexual desire for males, or females, or both. Collectively, the historical accounts suggest that, given the right cultural setting and individual motivation, androgen deprivation may actually enhance rather than hinder both social and sexual performance. We conclude that eunuch history contradicts the presumption that androgen deprivation necessarily leads to social and sexual impotence. The capabilities and accomplishments of eunuchs in the past gives patients on ADT grounds for viewing themselves in a positive light, where they are neither socially impotent nor sexually chaste.

  15. SOD mimetics: A Novel Class of Androgen Receptor Inhibitors that Suppresses Castration-Resistant Growth of Prostate Cancer

    Science.gov (United States)

    Thomas, Rusha; Sharifi, Nima

    2011-01-01

    Advanced prostate cancer (PCa) is the second-leading cause of cancer-related deaths among American men. The androgen receptor (AR) is vital for PCa progression, even in the face of castrate levels of serum testosterone following androgen ablation therapy, a mainstay therapy for advanced PCa. Downregulation of superoxide dismutase 2 (SOD2), a major intracellular antioxidant enzyme, occurs progressively during PCa progression to advanced states, and is known to promote AR activity in PCa. Therefore, this study investigated the effects of SOD mimetics on AR expression and function in AR-dependent LNCaP, CWR22Rv1, and LAPC-4AD PCa cells. Treatment with Tempol, a SOD mimetic, not only lowered cellular superoxide levels, but also concomitantly attenuated AR transcriptional activity and AR target gene expression in a dose- and time-dependent manner, in the presence and absence of dihydrotestosterone, the major endogenous AR agonist. Tempol's inhibition of AR was mediated, in large part, by its ability to decrease AR protein via increased degradation, in the absence of any inhibitory effects on other nuclear receptors. Tempol's inhibitory effects on AR were also reproducible with other SOD mimetics, MnTBAP and MnTMPyP. Importantly, Tempol's effects on AR function were accompanied by significant in vitro and in vivo reduction in castration-resistant PCa survival and growth. Collectively, this study has demonstrated for the first time that SOD mimetics, by virtue of their ability to suppress AR function, may be beneficial in treating the currently incurable castration-resistant PCa in which SOD2 expression is highly suppressed. PMID:22172488

  16. Sedation with Xylazine-Diazepam and Epidural Administration of Lidocaine and Xylazine for Castration and Ovariohysterectomy in Cats

    Directory of Open Access Journals (Sweden)

    Bizhan Ziaei

    2010-06-01

    Full Text Available The aim of this study was to determine whether anesthesia consisting of sedation induced by intramuscular administration of xylazine-diazepam and lumbosacral analgesia induced by epidural administration of lidocaine and xylazine is satisfactory for castration and ovariohysterectomy in cats. Six adult (3 male and 3 female, 2.5 ± 0.5 years of age cats (mean body weight ± SD, 2.2 ± 0.44 kg were used in this study. Cats were sedated with xylazine (1-2 mg kg-1 IM and diazepam (0.2 mg kg-1, IM and 5 minutes later a 2% solution of lidocaine (0.5ml/4.5kg and xylazine (1 mg kg-1 were administered into the lumbosacral epidural space. Open castration technique or ventral midline routine ovariohysterectomy were performed. Time to onset, duration and cranial spread of analgesia were recorded. Heart rate, respiratory rate and rectal temperature were recorded at time 0 (prior to epidural drugs administration as a base line values and at 10, 20, 30, 45 and 60 minutes after the epidural administration. Onset time of analgesia was 4.0 ± 0.63 min (Mean ± SEM and duration of analgesia was 89.5 ± 3.0 min (Mean ± SEM. However, surgical procedures were completed within 25-37 min. There were significant decrease in heart rate and rectal temperature values and significant increase in respiratory rate (P < 0.001. Intramuscular administration of xylazine-diazepam for sedation and epidural administration of lidocaine and xylazine for analgesia provided satisfactory analgesia for castration and ovariohysterectomy in cats. Utilizing epidural anesthetic technique with this combination is most useful for spaying surgery, especially when the surgical procedure can be completed in < 40 minutes.

  17. Phase II Study of Pomalidomide in Patients with Castration-Resistant Prostate Cancer

    International Nuclear Information System (INIS)

    Amato, Robert J.; Glode, L. Michael; Podolnick, Jeremy; Knight, Robert; Crawford, David

    2011-01-01

    Pomalidomide is a distinct immunomodulatory agent that also displays anti-proliferative and proapoptotic activity. The purpose of this study was to assess the efficacy and safety of pomalidomide for the treatment of chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (CRPC). Methods: Pomalidomide was administered orally in doses of 1 or 2 mg/day without interruption. Follow ups were conducted every 4 weeks with evaluation of study outcomes at 12 weeks. The principal study outcomes were PSA response, time to progression (TTP) using RECIST, overall survival (OS), and safety. A total of 32 patients were enrolled: 15 in the 1 mg/day cohort (median baseline PSA level of 12.30 ng/mL [0.8–236.0]), and 17 in the 2 mg/day cohort (median baseline PSA level of 12.50 ng/mL [0.6–191.8]). Results: In the 1 mg cohort disease was stabilized for ≥28 days in eight patients, and median TTP was 2.90 months. In the 2 mg cohort, PSA decreased ≥50% in three patients, disease was stabilized for ≥28 days in seven patients, and median TTP was 5.87 months. Toxicity in both cohorts was predominantly grade 1 or 2; 2 grade 3 toxicity (fatigue) occurred in the 1 mg cohort, and 5 grade 3 toxicities (chest pain, diarrhea, epigastric pain, impaction, pain) occurred in the 2 mg cohort. One grade 4 toxicity of cardiac ischemia occurred. Conclusions: Pomalidomide shows promising activity in patients with CRPC and has an acceptable safety profile

  18. [Experience with cabazitaxel therapy for patients with metastatic castrate resistant prostate cancer in Hungary].

    Science.gov (United States)

    Maráz, Anikó; Boér, Katalin; Dankovics, Zsófia; Dank, Magdolna; Lahm, Erika; Petrányi, Ágota; Révész, János; Ruzsa, Ágnes; Szûcs, Miklós; Valikovics, Anikó; Vas, Mária; Küronya, Zsófia

    2017-12-18

    Our aim was to assess the efficacy and adverse effects of cabazitaxel (CBZ), a chemotherapeutic agent that can be administered to patients with metastatic castrate resistant prostate cancer (mCRPC) after docetaxel (DOC) therapy. We retrospectively analyzed data of CBZ received by mCRPC patients in 12 Hungarian oncological centers between 01/2016 and 06/2017. CBZ (25 or 20 mg/m2 q3w) was administered after DOC. Physical and laboratory examinations were performed in every cycle, tumor response was evaluated in every third cycle based on PCWG2 criteria. Adverse effects were evaluated based on CTCAE 4.0. Data of 60 patients were analyzed. CBZ was administered in 2nd and 3rd lines in 31.6% and 46.6%, while in 4th and 5th lines in 15% and 6.6% patients, respectively. Its starting dose was 25 mg/m2 and 20 mg/m2 in 65% and 35% of cases, respectively. The median number of cycles was 5. Progression-free survival and overall survival were 5.52 and 15.77 months, respectively. Survival results were similar in case of DOC-CBZ-ART/alfaradin and DOC-ART/alfaradin-CBZ sequences. Adverse effects were detected in 63,3% of patients. The most common adverse effects were neutropenia, anemia, and diarrhea. Our observations suggest that CBZ, with the appropriate support and chemotherapeutic experience, is well-tolerated and effective therapy of mCRPC after DOC.

  19. 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.

  20. Platinum-based chemotherapy for variant castrate-resistant prostate cancer.

    Science.gov (United States)

    Aparicio, Ana M; Harzstark, Andrea L; Corn, Paul G; Wen, Sijin; Araujo, John C; Tu, Shi-Ming; Pagliaro, Lance C; Kim, Jeri; Millikan, Randall E; Ryan, Charles; Tannir, Nizar M; Zurita, Amado J; Mathew, Paul; Arap, Wadih; Troncoso, Patricia; Thall, Peter F; Logothetis, Christopher J

    2013-07-01

    Clinical features characteristic of small-cell prostate carcinoma (SCPC), "anaplastic," often emerge during the progression of prostate cancer. We sought to determine the efficacy of platinum-based chemotherapy in patients meeting at least one of seven prospectively defined "anaplastic" clinical criteria, including exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low prostate-specific antigen levels relative to tumor burden, or short response to androgen deprivation therapy. A 120-patient phase II trial of first-line carboplatin and docetaxel (CD) and second-line etoposide and cisplatin (EP) was designed to provide reliable clinical response estimates under a Bayesian probability model with early stopping rules in place for futility and toxicity. Seventy-four of 113 (65.4%) and 24 of 71 (33.8%) were progression free after four cycles of CD and EP, respectively. Median overall survival (OS) was 16 months [95% confidence interval (CI), 13.6-19.0 months]. Of the seven "anaplastic" criteria, bulky tumor mass was significantly associated with poor outcome. Lactic acid dehydrogenase strongly predicted for OS and rapid progression. Serum carcinoembryonic antigen (CEA) concentration strongly predicted OS but not rapid progression. Neuroendocrine markers did not predict outcome or response to therapy. Our findings support the hypothesis that patients with "anaplastic" prostate cancer are a recognizable subset characterized by a high response rate of short duration to platinum-containing chemotherapies, similar to SCPC. Our results suggest that CEA is useful for selecting therapy in men with castration-resistant prostate cancer and consolidative therapies to bulky high-grade tumor masses should be considered in this patient population. ©2013 AACR.

  1. Optimizing the treatment of metastatic castration-resistant prostate cancer: a Latin America perspective.

    Science.gov (United States)

    Sade, Juan Pablo; Báez, Carlos Alberto Vargas; Greco, Martin; Martínez, Carlos Humberto; Avitia, Miguel Ángel Álvarez; Palazzo, Carlos; Toriz, Narciso Hernández; Trujillo, Patricia Isabel Bernal; Bastos, Diogo Assed; Schutz, Fabio Augusto; Bella, Santiago; Nogueira, Lucas; Shore, Neal D

    2018-03-19

    Prostate cancer is a significant burden and cause of mortality in Latin America. This article reviews the treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) and provides consensus recommendations to assist Latin American prostate cancer specialists with clinical decision making. A multidisciplinary expert panel from Latin America reviewed the available data and their individual experience to develop clinical consensus opinions for the use of life-prolonging agents in mCRPC, with consideration given to factors influencing patient selection and treatment monitoring. There is a lack of level 1 evidence for the best treatment sequence or combinations in mCRPC. In this context, consensus recommendations were provided for the use of taxane-based chemotherapies, androgen receptor axis-targeted agents and targeted alpha therapy, for patients in Latin America. Prostate-specific antigen (PSA) changes alone, during treatment, should be treated with caution; PSA may not be a suitable biomarker for radium-223. Bone scans and computed tomography are the standard imaging modalities in Latin America. Imaging should be prompted during treatment where symptomatic decline and/or significant worsening of laboratory evaluations are reported, or where a course of therapy has been completed and another antineoplastic agent is under consideration. Recommendations and guidance for treatment options in Latin America are provided in the context of country-level variable access to approved agents and technologies for treatment monitoring. Patients should be treated with the purpose of prolonging overall survival and preserving quality of life through increasing the opportunity to administer all available life-prolonging therapies when appropriate.

  2. Perioperative mortality in cats and dogs undergoing spay or castration at a high-volume clinic.

    Science.gov (United States)

    Levy, J K; Bard, K M; Tucker, S J; Diskant, P D; Dingman, P A

    2017-06-01

    High volume spay-neuter (spay-castration) clinics have been established to improve population control of cats and dogs to reduce the number of animals admitted to and euthanazed in animal shelters. The rise in the number of spay-neuter clinics in the USA has been accompanied by concern about the quality of animal care provided in high volume facilities, which focus on minimally invasive, time saving techniques, high throughput and simultaneous management of multiple animals under various stages of anesthesia. The aim of this study was to determine perioperative mortality for cats and dogs in a high volume spay-neuter clinic in the USA. Electronic medical records and a written mortality log were used to collect data for 71,557 cats and 42,349 dogs undergoing spay-neuter surgery from 2010 to 2016 at a single high volume clinic in Florida. Perioperative mortality was defined as deaths occurring in the 24h period starting with the administration of the first sedation or anesthetic drugs. Perioperative mortality was reported for 34 cats and four dogs for an overall mortality of 3.3 animals/10,000 surgeries (0.03%). The risk of mortality was more than twice as high for females (0.05%) as for males (0.02%) (P=0.008) and five times as high for cats (0.05%) as for dogs (0.009%) (P=0.0007). High volume spay-neuter surgery was associated with a lower mortality rate than that previously reported in low volume clinics, approaching that achieved in human surgery. This is likely to be due to the young, healthy population of dogs and cats, and the continuous refinement of techniques based on experience and the skills and proficiency of teams that specialize in a limited spectrum of procedures. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Effects of buddleja officinalis total flavonoids on serum testosterone level of castrated male rats with xeroma

    Directory of Open Access Journals (Sweden)

    Wen-Juan Li

    2013-11-01

    Full Text Available AIM:To observe buddleja officinalis total flavonoids' effect on the basal tear secretion amount, tear film stability, lacrimal gland histomorphology and serum testosterone level of castrated male rat model with xeroma, to study the mechanism of rat xeroma caused by buddleja officinalis total flavones' anti-sex hormones disorders.MEATHODS: A total of 150 Wistar male rats of 1 month old, weighted about 200g, were randomly divided into 5 groups with 30 rats in each group with A representing normal group; B representing sham operation group; C representing surgery control group; D representing group treated with androgen; E representing group treated with buddleja officinalis total flavonoids. For the groups C, D, E, the bilateral testicle and epididymis were excised; For group B, scrota were incised without removal of the testicles, as the sham operation group; For group A, nothing was done. One week after modeling when the wound was to be healed, drug was given to each group. Respectively at the 1st month, 3rd, and 5th months after treatment, 10 rats were randomly selected in each group, to receive Schirmer I test, tear breakup time measurement. Blood serum testosterone levels were tested in the fifth month. RESUITS: For groups D and E, the Schirmer I test measurements were significantly higher than that of group C(PPPCONCLUSION: Decreased androgen levels can lead to xeroma, and removal of bilateral testes and epididymis can successfully establish the animal models of xeroma in rats caused by decreased androgen levels. Buddleja officinalis total flavonoids have androgenic effect, which produces the similar treatment effect of xeroma with testosterone propionate. Buddleja officinalis total flavonoids may become a new treatment for xeroma.

  4. Phase II Study of Pomalidomide in Patients with Castration-Resistant Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Amato, Robert J., E-mail: robert.amato@uth.tmc.edu [Memorial Hermann Cancer Center, University of Texas, 6410 Fannin Street, Suite 830, Houston, TX 77030 (United States); Glode, L. Michael [Health Science Center, University of Colorado, Denver, CO 80217 (United States); University of Colorado Cancer Center, Aurora, CO 80045 (United States); Podolnick, Jeremy [Memorial Hermann Cancer Center, University of Texas, 6410 Fannin Street, Suite 830, Houston, TX 77030 (United States); Knight, Robert [Celgene Corporation, Summit, NJ 07901-3915 (United States); Crawford, David [Health Science Center, University of Colorado, Denver, CO 80217 (United States); University of Colorado Cancer Center, Aurora, CO 80045 (United States)

    2011-09-02

    Pomalidomide is a distinct immunomodulatory agent that also displays anti-proliferative and proapoptotic activity. The purpose of this study was to assess the efficacy and safety of pomalidomide for the treatment of chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (CRPC). Methods: Pomalidomide was administered orally in doses of 1 or 2 mg/day without interruption. Follow ups were conducted every 4 weeks with evaluation of study outcomes at 12 weeks. The principal study outcomes were PSA response, time to progression (TTP) using RECIST, overall survival (OS), and safety. A total of 32 patients were enrolled: 15 in the 1 mg/day cohort (median baseline PSA level of 12.30 ng/mL [0.8–236.0]), and 17 in the 2 mg/day cohort (median baseline PSA level of 12.50 ng/mL [0.6–191.8]). Results: In the 1 mg cohort disease was stabilized for ≥28 days in eight patients, and median TTP was 2.90 months. In the 2 mg cohort, PSA decreased ≥50% in three patients, disease was stabilized for ≥28 days in seven patients, and median TTP was 5.87 months. Toxicity in both cohorts was predominantly grade 1 or 2; 2 grade 3 toxicity (fatigue) occurred in the 1 mg cohort, and 5 grade 3 toxicities (chest pain, diarrhea, epigastric pain, impaction, pain) occurred in the 2 mg cohort. One grade 4 toxicity of cardiac ischemia occurred. Conclusions: Pomalidomide shows promising activity in patients with CRPC and has an acceptable safety profile.

  5. ASC-J9 Suppresses Castration-Resistant Prostate Cancer Growth through Degradation of Full-length and Splice Variant Androgen Receptors

    Directory of Open Access Journals (Sweden)

    Shinichi Yamashita

    2012-01-01

    Full Text Available Early studies suggested androgen receptor (AR splice variants might contribute to the progression of prostate cancer (PCa into castration resistance. However, the therapeutic strategy to target these AR splice variants still remains unresolved. Through tissue survey of tumors from the same patients before and after castration resistance, we found that the expression of AR3, a major AR splice variant that lacks the AR ligand-binding domain, was substantially increased after castration resistance development. The currently used antiandrogen, Casodex, showed little growth suppression in CWR22Rv1 cells. Importantly, we found that AR degradation enhancer ASC-J9 could degrade both full-length (fAR and AR3 in CWR22Rv1 cells as well as in C4-2 and C81 cells with addition of AR3. The consequences of such degradation of both fAR and AR3 might then result in the inhibition of AR transcriptional activity and cell growth in vitro. More importantly, suppression of AR3 specifically by short-hairpin AR3 or degradation of AR3 by ASC-J9 resulted in suppression of AR transcriptional activity and cell growth in CWR22Rv1-fARKD (fAR knockdown cells in which DHT failed to induce, suggesting the importance of targeting AR3. Finally, we demonstrated the in vivo therapeutic effects of ASC-J9 by showing the inhibition of PCa growth using the xenografted model of CWR22Rv1 cells orthotopically implanted into castrated nude mice with undetectable serum testosterone. These results suggested that targeting both fAR- and AR3-mediated PCa growth by ASC-J9 may represent the novel therapeutic approach to suppress castration-resistant PCa. Successful clinical trials targeting both fAR and AR3 may help us to battle castration-resistant PCa in the future.

  6. Effect of ACTH and CRH on Plasma Levels of Cortisol and Prostaglandin F2α Metabolite in Cycling Gilts and Castrated Boars

    Directory of Open Access Journals (Sweden)

    Kindahl H

    2005-12-01

    Full Text Available The present study was designed to evaluate the effects of synthetic ACTH (1–24, tetracosactid and porcine CRH on the plasma levels of cortisol and PGF2α metabolite in cycling gilts (n = 3 and castrated boars (n = 3. The experiments were designed as crossover studies for each gender separately. Each animal received, during three consecutive days; 1 ACTH (Synacthen® Depot at a dose of 10 μg/kg body weight in 5 ml physiological saline, 2 porcine CRH at a dose 0.6 μg/kg body weight in 5 ml physiological saline or 3 physiological saline (5 ml. The test substances were administered via an indwelling jugular cannula in randomized order according to a Latin square. The administration of ACTH to cycling gilts resulted in concomitant elevations of cortisol and PGF2α metabolite with peak levels reached at 70.0 ± 10.0 and 33.3 ± 6.7 min, respectively. Similarly, the administration of ACTH to castrated boars resulted in concomitant elevation of cortisol and PGF2α metabolite with peak levels reached at 60.0 ± 0.0 and 20.0 ± 0.0 min, respectively. Cortisol peaked at 20 min after administration of CRH in both cycling gilts and castrated boars with maximum levels of 149.3 ± 16.5 nmol/1 and 138.3 ± 10.1 nmol/1, respectively. It can be concluded that administration of synthetic ACTH (tetracosactid to pigs caused a concomitant elevation of cortisol and PGF2α metabolite levels in both cycling gilts as well as castrated boars. The administration of CRH to pigs resulted in an elevation of cortisol levels in both cycling gilts and castrated boars. Conversely, PGF2α metabolite levels were not influenced by the administration of CRH either in cycling gilts or in castrated boars.

  7. Effect of ACTH and CRH on Plasma Levels of Cortisol and Prostaglandin F2α Metabolite in Cycling Gilts and Castrated Boars

    Directory of Open Access Journals (Sweden)

    Madej A

    2006-12-01

    Full Text Available The present study was designed to evaluate the effects of synthetic ACTH (1–24, tetracosactid and porcine CRH on the plasma levels of cortisol and PGF2α metabolite in cycling gilts (n = 3 and castrated boars (n = 3. The experiments were designed as crossover studies for each gender separately. Each animal received, during three consecutive days; 1 ACTH (Synacthen® Depot at a dose of 10 μg/kg body weight in 5 ml physiological saline, 2 porcine CRH at a dose 0.6 μg/kg body weight in 5 ml physiological saline or 3 physiological saline (5 ml. The test substances were administered via an indwelling jugular cannula in randomized order according to a Latin square. The administration of ACTH to cycling gilts resulted in concomitant elevations of cortisol and PGF2α metabolite with peak levels reached at 70.0 ± 10.0 and 33.3 ± 6.7 min, respectively. Similarly, the administration of ACTH to castrated boars resulted in concomitant elevation of cortisol and PGF2α metabolite with peak levels reached at 60.0 ± 0.0 and 20.0 ± 0.0 min, respectively. Cortisol peaked at 20 min after administration of CRH in both cycling gilts and castrated boars with maximum levels of 149.3 ± 16.5 nmol/1 and 138.3 ± 10.1 nmol/1, respectively. It can be concluded that administration of synthetic ACTH (tetracosactid to pigs caused a concomitant elevation of cortisol and PGF2α metabolite levels in both cycling gilts as well as castrated boars. The administration of CRH to pigs resulted in an elevation of cortisol levels in both cycling gilts and castrated boars. Conversely, PGF2α metabolite levels were not influenced by the administration of CRH either in cycling gilts or in castrated boars.

  8. A case report of enzalutamide administration in a dialysis-dependent patient with castration-resistant prostate cancer.

    Science.gov (United States)

    Tsang, Erica S; de Haan, Marie; Eigl, Bernhard J

    2018-03-01

    Enzalutamide, an androgen receptor signaling inhibitor, is a standard of care treatment for metastatic castration-resistant prostate cancer. We present the first reported case of enzalutamide in a patient with end-stage renal disease, on dialysis. While there were no significant toxicities, a sustained increase in systolic blood pressure was maintained after starting enzalutamide, suggestive of a degree of drug accumulation. Further evaluation of novel hormonal agents in end-stage renal disease patients should be encouraged as this population is typically excluded from clinical trials.

  9. Impact of Transmammary-Delivered Meloxicam on Biomarkers of Pain and Distress in Piglets after Castration and Tail Docking

    Science.gov (United States)

    Bates, Jessica L.; Karriker, Locke A.; Stock, Matthew L.; Pertzborn, Kelly M.; Baldwin, Luke G.; Wulf, Larry W.; Lee, C. J.; Wang, Chong; Coetzee, Johann F.

    2014-01-01

    To investigate a novel route for providing analgesia to processed piglets via transmammary drug delivery, meloxicam was administered orally to sows after farrowing. The objectives of the study were to demonstrate meloxicam transfer from sows to piglets via milk and to describe the analgesic effects in piglets after processing through assessment of pain biomarkers and infrared thermography (IRT). Ten sows received either meloxicam (30 mg/kg) (n = 5) or whey protein (placebo) (n = 5) in their daily feedings, starting four days after farrowing and continuing for three consecutive days. During this period, blood and milk samples were collected at 12-hour intervals. On Day 5 after farrowing, three boars and three gilts from each litter were castrated or sham castrated, tail docked, and administered an iron injection. Piglet blood samples were collected immediately before processing and at predetermined times over an 84-hour period. IRT images were captured at each piglet blood collection point. Plasma was tested to confirm meloxicam concentrations using a validated high-performance liquid chromatography-mass spectrometry method. Meloxicam was detected in all piglets nursing on medicated sows at each time point, and the mean (± standard error of the mean) meloxicam concentration at castration was 568.9±105.8 ng/mL. Furthermore, ex-vivo prostaglandin E2 (PGE2) synthesis inhibition was greater in piglets from treated sows compared to controls (p = 0.0059). There was a time-by-treatment interaction for plasma cortisol (p = 0.0009), with meloxicam-treated piglets demonstrating lower cortisol concentrations than control piglets for 10 hours after castration. No differences in mean plasma substance P concentrations between treatment groups were observed (p = 0.67). Lower cranial skin temperatures on IRT were observed in placebo compared to meloxicam-treated piglets (p = 0.015). This study demonstrates the successful transfer of meloxicam from sows to

  10. Low-dose testosterone alleviates vascular damage caused by castration in male rats in puberty via modulation of the PI3K/AKT signaling pathway.

    Science.gov (United States)

    Zhao, Jing; Liu, Ge-Li; Wei, Ying; Jiang, Li-Hong; Bao, Peng-Li; Yang, Qing-Yan

    2016-09-01

    The aim of the present study was to investigate the effect of testosterone on glucolipid metabolism and vascular injury in male rats, and examine the underlying molecular mechanisms. A total of 40 male Sprague-Dawley rats were divided into a control group (n=10), high-fat-diet + castration group (n=10), high‑fat‑diet + castration + low dose testosterone group (n=10), and high-fat-diet + castration + high dose testosterone group (n=10). Hematoxylin and eosin staining was performed to evaluate the morphology of the thoracic aortic tissues. Immunohistochemical staining was used to detect biomarkers of the phosphoinositide 3‑kinase (PI3K) signaling pathway. The mRNA and protein expression levels of PI3K, AKT, insulin receptor substrate‑1 (IRS‑1), glucose transporter type 4 (GLUT‑4), nuclear factor (NF)‑κB and tumor necrosis factor (TNF)‑α in the aortas were determined using quantitative polymerase chain reaction and Western blot analyses, respectively. Apoptosis in the aortic tissues was detected using a TUNEL assay. Castration induced apoptosis in the animals fed a high‑fat‑diet, whereas low dose testosterone replacement ameliorated the apoptosis in the aorta. However, the levels of apoptosis was more severe following high‑dose testosterone treatment. Low‑dose testosterone induced upregulation in the levels of IRS‑1, AKT, GLUT‑4 protein, NF‑κB, TNF‑α and PI3K, compared with those in the animals fed a high‑fat diet following castration. A high dose of testosterone resulted in a significant decrease in the levels of IRS‑1, AKT, GLUT‑4, NF‑κB, TNF‑α and PI3K. Compared with the rats in the high‑fat diet + castration group, a low dose of testosterone induced upregulation in the mRNA levels of IRS‑1, AKT and GLUT‑4, and downregulation of the mRNA levels of NF‑κB, TNF‑α and PI3K. A high dose of testosterone resulted in a significant decrease in the levels of IRS‑1, AKT and GLUT‑4, and marked

  11. Effects of Supplemental Glutamine on Growth Performance, Plasma Parameters and LPS-induced Immune Response of Weaned Barrows after Castration

    Directory of Open Access Journals (Sweden)

    C. B. Hsu

    2012-05-01

    Full Text Available Two experiments were conducted to investigate the effects of supplemental glutamine on growth performance, plasma parameters and LPS-induced immune response of weaned barrows after castration. In experiment 1, forty-eight weaned male piglets were used and fed maize and soybean meal diets supplemented with 0 (Control or 2% L-Gln (Gln+ for 25 days. The results indicated that the Gln+ group tended to increase average daily gain compared to control in stages of days 7 to 14 and 0 to 25. The Gln+ had significantly better feed efficiency than the control group did during days 14 to 25 and 0 to 25. The plasma blood urea nitrogen and alkaline phosphatase contents of Gln+ group were higher than those of the control group on day 14 post-weaning. In experiment 2, sixteen weaned male piglets were injected with E. coli K88+ lipopolysaccharide (LPS on day 14 post-weaning. The results showed that the Gln+ group had lower concentrations of plasma adrenocorticotrophic hormone and cortisol than the control group on day 14 pre-LPS challenge. In addition, Gln+ group had higher plasma IgG concentration than the control group for pre- or post-LPS challenged on day 14 post-weaning. In summary, dietary supplementation of Gln was able to alleviate the stressful condition and inflammation associated with castration in weaned barrows, and to improve their immunity and growth performance in the early starter stage.

  12. Effect of castration on renal glycosaminoglycans and their urinary excretion in male and female rats with chronic renal failure

    Energy Technology Data Exchange (ETDEWEB)

    Lemos, C.C.S. [Disciplina de Nefrologia, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ (Brazil); Tovar, A.M.F. [Laboratório de Tecido Conjuntivo, Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ (Brazil); Guimarães, M.A.M. [Departamento de Patologia e Laboratórios, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ (Brazil); Bregman, R. [Disciplina de Nefrologia, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ (Brazil)

    2013-08-10

    Glycosaminoglycans (GAGs) participate in a variety of processes in the kidney, and evidence suggests that gender-related hormones participate in renal function. The aim of this study was to analyze the relationship of GAGs, gender, and proteinuria in male and female rats with chronic renal failure (CRF). GAGs were analyzed in total kidney tissue and 24-h urine of castrated (c), male (M), and female (F) Wistar control (C) rats (CM, CMc, CF, CFc) and after 30 days of CRF induced by 5/6 nephrectomy (CRFM, CRFMc, CRFF, CRFFc). Total GAG quantification and composition were determined using agarose and polyacrylamide gel electrophoresis, respectively. Renal GAGs were higher in CF compared to CM. CRFM presented an increase in renal GAGs, heparan sulfate (HS), and proteinuria, while castration reduced these parameters. However, CRFF and CRFFc groups showed a decrease in renal GAGs concomitant with an increase in proteinuria. Our results suggest that, in CRFM, sex hormones quantitatively alter GAGs, mainly HS, and possibly the glomerular filtration barrier, leading to proteinuria. The lack of this response in CRFMc, where HS did not increase, corroborates this theory. This pattern was not observed in females. Further studies of CRF are needed to clarify gender-dependent differences in HS synthesis.

  13. Effects of immunological castration (Improvest) on further processed belly characteristics and commercial bacon slicing yields of finishing pigs.

    Science.gov (United States)

    Kyle, J M; Bohrer, B M; Schroeder, A L; Matulis, R J; Boler, D D

    2014-09-01

    Objectives were to compare fresh belly characteristics, further processed belly characteristics, and commercial bacon slicing yields of immunologically castrated (IC) barrows, IC barrows fed ractopamine hydrochloride (IC+RAC), physically castrated (PC) barrows, intact males, and gilts. One hundred eighty-eight bellies from pigs housed in single sex pens (n = 48) slaughtered at 130 kg ending live weight were evaluated for flop distance, length, width, thickness, and fatty acid composition. Bellies were injected, thermally processed, and sliced according to standard protocols at a USDA federally inspected facility. Complete slices were sorted by trained plant personnel. Then, sliced bellies were individually packaged to maintain anatomical orientation. The effects of treatments were analyzed as a generalized linear mixed model with pen of pigs serving as the experimental unit for all comparisons. Belly thickness was not different (P ≥ 0.11) in bellies from IC barrows (3.74 cm) compared with bellies from IC+RAC (3.60 cm), PC barrows (3.94 cm), or gilts (3.64 cm); however, bellies were 0.42 cm thicker (P bacon manufactured from IC barrows were less than both PC barrows and gilts.

  14. Effects of Eurycoma longifolia jack on laevator ani muscle in both uncastrated and testosterone-stimulated castrated intact male rats.

    Science.gov (United States)

    Ang, H H; Cheang, H S

    2001-10-01

    It has been reported that Eurycoma longifolia Jack commonly known as Tongkat Ali has gained notoreity as a symbol of man's ego and strength by the Malaysian men because it increases male virility and sexual prowess during sexual activities. As such, the effects of 200, 400 and 800 mg/kg of butanol, methanol, water and chloroform fractions of E. longifolia Jack were studied on the laevator ani muscle in both uncastrated and testosterone-stimulated castrated intact male rats after dosing them for 12 consecutive weeks. Results showed that 800 mg/kg of butanol, methanol, water and chloroform fractions of E. longifolia Jack significantly increased (p<0.05) the leavator ani muscle to 58.56+/-1.22, 58.23+/-0.31, 60.21 +/-0.86 and 62.35 +/-0.98 mg/100 g body weight, respectively, when compared with the control (untreated) in the uncastrated intact male rats and 49.23+/-0.82, 52.23+/-0.36, 50.21+/-0.66 and 52.35+/-0.58 mg/100 g body weight, respectively, when compared to control (untreated) in the testosterone-stimulated castrated intact male rats. Hence, the pro-androgenic effect as shown by this study further supported the traditional use of this plant as an aphrodisiac.

  15. Solution Formulation Development and Efficacy of MJC13 in a Preclinical Model of Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    Liang, Su; Bian, Xiaomei; Liang, Dong; Sivils, Jeffrey C.; Neckers, Leonard M.; Cox, Marc B.; Xie, Huan

    2015-01-01

    MJC13, a novel FKBP52 targeting agent, has potential use for the treatment of castrate-resistant prostate cancer. The purpose of this work was to develop a solution formulation of MJC13, and obtain its efficacy profile in a human prostate cancer xenograft mouse model. Preformulation studies were conducted to evaluate the physicochemical properties. Co-solvent systems were evaluated for aqueous solubility and tolerance. A human prostate cancer xenograft mouse model was established by growing 22Rv1 prostate cancer cells in C.B-17 SCID mice. The optimal formulation was used to study the efficacy of MJC13 in this preclinical model of castrate-resistant prostate cancer. We found that MJC13 was stable (at least for 1 month), very lipophilic (logP = 6.49), poorly soluble in water (0.28 μg/mL), and highly plasma protein bound (> 98%). The optimal formulation consisting of PEG 400 and Tween 80 (1:1, v/v) allowed us to achieve a MJC13 concentration of 7.5 mg/mL, and tolerated an aqueous environment. After twice weekly intratumoral injection with 10 mg/kg MJC13 in this formulation for 4 consecutive weeks, tumor volumes were significantly reduced compared to vehicle-treated controls. PMID:25380396

  16. Solution formulation development and efficacy of MJC13 in a preclinical model of castration-resistant prostate cancer.

    Science.gov (United States)

    Liang, Su; Bian, Xiaomei; Liang, Dong; Sivils, Jeffrey C; Neckers, Leonard M; Cox, Marc B; Xie, Huan

    2016-01-01

    MJC13, a novel FKBP52 targeting agent, has potential use for the treatment of castration-resistant prostate cancer. The purpose of this work was to develop a solution formulation of MJC13, and obtain its efficacy profile in a human prostate cancer xenograft mouse model. Preformulation studies were conducted to evaluate the physicochemical properties. Co-solvent systems were evaluated for aqueous solubility and tolerance. A human prostate cancer xenograft mouse model was established by growing 22Rv1 prostate cancer cells in C.B-17 SCID mice. The optimal formulation was used to study the efficacy of MJC13 in this preclinical model of castrate-resistant prostate cancer. We found that MJC13 was stable (at least for 1 month), highly lipophilic (logP = 6.49), poorly soluble in water (0.28 µg/mL), and highly plasma protein bound (>98%). The optimal formulation consisting of PEG 400 and Tween 80 (1:1, v/v) allowed us to achieve a MJC13 concentration of 7.5 mg/mL, and tolerated an aqueous environment. After twice weekly intratumoral injection with 10 mg/kg MJC13 in this formulation for four consecutive weeks, tumor volumes were significantly reduced compared to vehicle-treated controls.

  17. Enzalutamide treatment in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy and abiraterone acetate

    DEFF Research Database (Denmark)

    Thomsen, Frederik Birkebaek; Røder, Martin Andreas; Rathenborg, Per

    2014-01-01

    OBJECTIVE: The aim of this study was to record prostate-specific antigen (PSA) response and overall survival (OS) for a group of metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide following progression after abiraterone treatment in the post-chemotherapy se......OBJECTIVE: The aim of this study was to record prostate-specific antigen (PSA) response and overall survival (OS) for a group of metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide following progression after abiraterone treatment in the post......-chemotherapy setting. MATERIAL AND METHODS: Twenty-four mCRPC patients with progression after abiraterone treatment following primary docetaxel therapy received enzalutamide 160 mg/day. The percentage PSA response was recorded following first line docetaxel, abiraterone and enzalutamide treatment. Fischer's exact test......, Mann-Whitney U test and linear regression model were used to test for differences in PSA response. RESULTS: All patients had a follow-up of at least 3 months. The median PSA response following 1 month of enzalutamide was -12% (range -56% to 76%), while the median best PSA response was -22% (-76% to 76...

  18. Co-introduction of a steroid with docetaxel chemotherapy for metastatic castration-resistant prostate cancer affects PSA flare.

    Science.gov (United States)

    Shiota, Masaki; Yokomizo, Akira; Takeuchi, Ario; Kiyoshima, Keijiro; Inokuchi, Junichi; Tatsugami, Katsunori; Shiga, Ken-Ichiro; Koga, Hirofumi; Yamaguchi, Akito; Naito, Seiji; Eto, Masatoshi

    2016-12-01

    To investigate the potential relationship of steroid usage with prostate-specific antigen (PSA) flare as well as the prognostic impact of PSA flare, which is known to occur in 10-20% of patients with metastatic castration-resistant prostate cancer during docetaxel chemotherapy. This study included 71 patients with metastatic castration-resistant prostate cancer treated by docetaxel chemotherapy with co-introduction of a steroid. PSA flare was defined as a transient PSA increase followed by a PSA decrease. PSA flare was recognized in 7.0-23.9% of patients according to the definition used. Intriguingly, men with steroid intake before the initiation of docetaxel chemotherapy experienced significantly fewer PSA flares. The progression-free survival rate in men with PSA flare was equivalent to that of PSA responders, but significantly better than men with PSA failure. Our results suggest that de novo steroid co-introduction with docetaxel chemotherapy induces the PSA flare phenomenon. This novel finding may account for the mechanism of PSA flare as well as being valuable for distinguishing PSA elevation attributable to PSA flare from that attributable to PSA failure. © 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.

  19. Influence of sex and castration on growth performance and carcass quality of crossbred pigs from 2 Large White sire lines.

    Science.gov (United States)

    Morales, J I; Cámara, L; Berrocoso, J D; López, J P; Mateos, G G; Serrano, M P

    2011-11-01

    In total, 360 pigs slaughtered at 125 kg of BW and destined for the dry-cured industry were used to study the influence of sex and castration [immunocastrated males (IMC), surgically castrated males (CM), and intact females (IF)] in 2 terminal Large White sire lines [Top York (TY) and Tempo (TE)] on growth performance and carcass and meat quality. The female line was Large White × Landrace. The IMC pigs were immunized against gonadotropin-releasing factor (GnRF) with Improvac at 78 (experimental d 16) and 126 (experimental d 64, 48 d before slaughter) d of age. Each of the 6 treatments was replicated 6 times (10 pigs/pen). Through the day of the first Improvac injection (62 to 78 d of age), IMC and IF grew at a slower rate (P ham yields than CM, with IMC being intermediate. Crossbreds from TE sires grew at a faster rate (P ham yield, but less (P ham yield compared with crossbreds from TY sires. Immunocastrated pigs can replace CM for the production of heavy pigs destined for the dry-cured industry. Because of increased carcass weight, crossbreds from TE sires may have an advantage over crossbreds from TY sires.

  20. Budget Impact of Enzalutamide for Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Bui, Cat N; O'Day, Ken; Flanders, Scott; Oestreicher, Nina; Francis, Peter; Posta, Linda; Popelar, Breanna; Tang, Hong; Balk, Mark

    2016-02-01

    Prostate cancer is expected to account for approximately one quarter of all new diagnoses of cancer in American men in 2015. The cost of prostate cancer care is expected to reach $15.1 billion by the year 2020, up from $11.9 billion in 2010. Given the high burden of prostate cancer, health care payers are interested in quantifying the potential budget impact of new therapies. To estimate the budget impact of enzalutamide for the treatment of chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) from a U.S. payer perspective. A model was developed to assess the budget impact of enzalutamide for treatment of chemotherapy-naïve mCRPC patients in a hypothetical 1-million-member U.S. health plan over a 1-year time horizon. Comparators included abiraterone acetate, sipuleucel-T, radium Ra 223 dichloride, and docetaxel. Epidemiologic data, including National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) incidence rates, were used to estimate the number of chemotherapy-naïve mCRPC patients. Dosing, administration, duration of therapy, and adverse event rates were based on package inserts and pivotal studies. Drug costs were obtained from RED BOOK and Centers for Medicare & Medicaid Services (CMS) average sales price pricing files, costs of administration and monitoring from the CMS physician fee schedule, and adverse events from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project and published literature. Market shares were estimated for each comparator before and after adoption of enzalutamide. The incremental aggregate budget impact, per patient per year (PPPY), per patient per month (PPPM), and per member per month (PMPM), was calculated. One-way sensitivity analyses were performed. In a population of 115 chemotherapy-naïve mCRPC patients, adopting enzalutamide had an annual incremental budget impact of $510,641 ($4,426 PPPY, $369 PPPM, and $0.04 PMPM). Results were most sensitive to

  1. Pain in castration-resistant prostate cancer with bone metastases: a qualitative study

    Directory of Open Access Journals (Sweden)

    Gater Adam

    2011-10-01

    Full Text Available Abstract Background Bone metastases are a common painful and debilitating consequence of castration-resistant prostate cancer (CPRC. Bone pain may predict patients' prognosis and there is a need to further explore CRPC patients' experiences of bone pain in the overall context of disease pathology. Due to the subjective nature of pain, assessments of pain severity, onset and progression are reliant on patient assessment. Patient reported outcome (PRO measures, therefore, are commonly used as key endpoints for evaluating the efficacy of CRPC treatments. Evidence of the content validity of leading PRO measures of pain severity used in CRPC clinical trials is, however, limited. Methods To document patients' experience of CRPC symptoms including pain, and their impact on health-related quality of life (HRQL, semi-structured in-depth qualitative interviews were conducted with 17 patients with CRPC and bone metastases. The content validity of the Present Pain Intensity (PPI scale from the McGill Pain Questionnaire (MPQ, and the 'Average Pain' and 'Worst Pain' items of the Brief Pain Inventory Short-Form (BPI-SF was also assessed. Results Patients with CRPC and bone metastases present with a constellation of symptoms that can have a profound effect on HRQL. For patients in this study, bone pain was the most prominent and debilitating symptom associated with their condition. Bone pain was chronic and, despite being generally well-managed by analgesic medication, instances of breakthrough cancer pain (BTcP were common. Cognitive debriefing of the selected PRO measures of pain severity highlighted difficulties among patients in understanding the verbal response scale (VRS of the MPQ PPI scale. There were also some inconsistencies in the way in which the BPI-SF 'Average Pain' item was interpreted by patients. In contrast, the BPI-SF 'Worst Pain' item was well understood and interpreted consistently among patients. Conclusions Study findings support the

  2. Comparison of intramuscular alfaxalone and ketamine combined with dexmedetomidine and butorphanol for castration in cats.

    Science.gov (United States)

    Khenissi, Latifa; Nikolayenkova-Topie, Olga; Broussaud, Ségolène; Touzot-Jourde, Gwenola

    2017-08-01

    Objectives Cardiorespiratory parameters and anaesthesia quality in cats anaesthetised with either intramuscular (IM) alfaxalone or ketamine both combined with dexmedetomidine and butorphanol for castration were evaluated. Methods Thirty-two client-owned cats were randomly assigned to receive either alfaxalone (A; 3 mg/kg IM) or ketamine (K; 5 mg/kg IM), combined with dexmedetomidine (10 μg/kg) and butorphanol (0.2 mg/kg). Heart rate (HR), respiratory rate (RR) and rectal temperature (T°) were recorded prior to drug administration. Pulse rate (PR) and RR were recorded 10 (T 10 ) and 15 (T 15 ) mins after injection (T 0 ). Cardiorespiratory values (PR, RR, SPO 2 , blood pressure, P E 'CO 2 ) were recorded every 5 mins for the duration of the procedure. Pain at injection, intubation and recovery were evaluated with simple descriptive scores. Feasibility of anaesthesia was evaluated by the number of top-ups of anaesthetic needed. Cat attitude, ability to walk and presence of ataxia were assessed several times after extubation (T exmin ) and the time between injection and extubation recorded. Pain was assessed at T ex120 and T ex240 with the 4Avet-pain score. Results The RR was significantly lower in group K at T 10 (RR K = 28 ±13.35 breaths per minute [brpm], RR A = 43.24 ±7.04 brpm) and T 15 (RR K = 28 ±11.53 brpm vs RR A = 43 ±12.18 brpm). Time to extubation was significantly longer in group A (T A = 62 ±14.6 mins, T K = 45.13 ± 7.38 mins). Cats in group K needed more top-ups, were more ataxic at T ex120 , had a worse recovery score at T ex60 and were less willing to walk at T ex30 . Conclusions and relevance Cats receiving alfaxalone had a longer but better quality recovery. Cardiorespiratory parameters were stable and within clinically acceptable values following IM injection of either alfaxalone or ketamine in healthy cats. Intramuscular alfaxalone is a suitable alternative to ketamine for short procedures requiring anaesthesia when used in combination

  3. Physicians' behavior influences the health and economic impact of applying circulating tumor cells as response marker in metastatic castration-resistant prostate cancer

    NARCIS (Netherlands)

    Degeling, K; Mehra, N.; Koffijberg, H; de Bono, J.S.; Ijzerman, M J

    2016-01-01

    Objectives: Treatment decisions in metastatic castration-resistant prostate cancer (mCRPC) vary between physicians, even though expert opinion guidelines exist to guide the interpretation of information from multiple time-dependent imaging modalities and markers. We aimed to investigate whether

  4. Effects of immunological castration and distiller's dried grains with solubles on carcass cutability and commercial bacon slicing yields of barrows slaughtered at two time points.

    Science.gov (United States)

    Tavárez, M A; Bohrer, B M; Asmus, M D; Schroeder, A L; Matulis, R J; Boler, D D; Dilger, A C

    2014-07-01

    Male pigs were randomly assigned to a castration method at birth and allotted to 48 pens (28 pigs/pen). Physically castrated (PC) barrows were castrated at 2 d of age; immunologically castrated (IC) barrows were administered Improvest (GnRF analog diphtheria toxoid conjugate; Zoetis, Kalamazoo, MI) at 16 and 20 wk of age. Distiller's dried grains with solubles (DDGS) feeding strategies included either 0% DDGS (control), 30% DDGS (30% DDGS) fed from 6 wk of age to slaughter, or 30% DDGS fed from 6 wk of age to second dose of Improvest and then fed 0% DDGS until slaughter (withdrawal). Four barrows closest to the median pen weight at 4.5 wk after second dose were selected for evaluation; two were randomly selected and slaughtered at 5 wk and the other two at 7 wk after second dose. Data from each slaughter time were analyzed independently as a 2 × 3 factorial design with pen as the experimental unit. At 5 wk after second dose, bone-in lean cutting yields were 2.63% units greater (P Bacon slicing yields (percentage of green weight) were 6.10% units less (P Bacon slicing yields (percentage of green weight) were 4.27% units less (P = 0.05) in IC compared with PC. These data suggested that while bacon slicing yield was reduced in IC barrows fed control and 30% DDGS compared with PC barrow counterparts, withdrawal of DDGS improved bacon slicing yields of IC barrows.

  5. Effect of abiraterone acetate treatment on the quality of life of patients with metastatic castration-resistant prostate cancer after failure of docetaxel chemotherapy

    NARCIS (Netherlands)

    Harland, S.; Staffurth, J.; Molina, A.; Hao, Y.; Gagnon, D.D.; Sternberg, C.N.; Cella, D.; Fizazi, K.; Logothetis, C.J.; Kheoh, T.; Haqq, C.M.; Bono, J.S. de; Scher, H.I.; Mulders, P.F.; et al.,

    2013-01-01

    BACKGROUND: In a recent randomised, double-blind, phase III clinical trial among 1195 patients with metastatic castration-resistant prostate cancer (mCRPC) who had failed docetaxel chemotherapy, abiraterone acetate was shown to significantly prolong overall survival compared with prednisone alone.

  6. Phase I/II trial of cabazitaxel plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone

    NARCIS (Netherlands)

    Massard, C.; Mateo, J.; Loriot, Y.; Pezaro, C.; Albiges, L.; Mehra, N.; Varga, A.; Bianchini, D.; Ryan, C.J.; Petrylak, D.P.; Attard, G.; Shen, L.; Fizazi, K.; Bono, J. De

    2017-01-01

    Background: Abiraterone and cabazitaxel improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted an open-label phase I/II trial of cabazitaxel plus abiraterone to assess the antitumor activity and tolerability in patients with progressive mCRPC after

  7. Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer

    DEFF Research Database (Denmark)

    Beer, Tomasz M; Kwon, Eugene D; Drake, Charles G

    2017-01-01

    Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases. Pat...

  8. Prostate-specific Antigen Decline After 4 Weeks of Treatment with Abiraterone Acetate and Overall Survival in Patients with Metastatic Castration-resistant Prostate Cancer

    NARCIS (Netherlands)

    Rescigno, P.; Lorente, D.; Bianchini, D.; Ferraldeschi, R.; Kolinsky, M.P.; Sideris, S.; Zafeiriou, Z.; Sumanasuriya, S.; Smith, A.D.; Mehra, N.; Jayaram, A.; Perez-Lopez, R.; Mateo, J.; Parker, C.; Dearnaley, D.P.; Tunariu, N.; Reid, A.; Attard, G.; Bono, J.S. de

    2016-01-01

    BACKGROUND: The availability of multiple new treatments for metastatic castration-resistant prostate cancer (mCRPC) mandates earlier treatment switches in the absence of a response. A decline in prostate-specific antigen (PSA) is widely used to monitor treatment response, but is not validated as an

  9. The PSA−/lo prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration

    Science.gov (United States)

    Qin, Jichao; Liu, Xin; Laffin, Brian; Chen, Xin; Choy, Grace; Jeter, Collene; Calhoun-Davis, Tammy; Li, Hangwen; Palapattu, Ganesh S.; Pang, Shen; Lin, Kevin; Huang, Jiaoti; Ivanov, Ivan; Li, Wei; Suraneni, Mahipal V.; Tang, Dean G.

    2012-01-01

    SUMMARY Prostate cancer (PCa) is heterogeneous and contains both differentiated and undifferentiated tumor cells, but the relative functional contribution of these two cell populations remains unclear. Here we report distinct molecular, cellular, and tumor-propagating properties of PCa cells that express high (PSA+) and low (PSA−/lo) levels of the differentiation marker PSA. PSA−/lo PCa cells are quiescent and refractory to stresses including androgen deprivation, exhibit high clonogenic potential, and possess long-term tumor-propagating capacity. They preferentially express stem cell genes and can undergo asymmetric cell division generating PSA+ cells. Importantly, PSA−/lo PCa cells can initiate robust tumor development and resist androgen ablation in castrated hosts, and harbor highly tumorigenic castration-resistant PCa cells that can be prospectively enriched using ALDH+CD44+α2β1+ phenotype. In contrast, PSA+ PCa cells possess more limited tumor-propagating capacity, undergo symmetric division and are sensitive to castration. Together, our study suggests PSA−/lo cells may represent a critical source of castration-resistant PCa cells. PMID:22560078

  10. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial

    DEFF Research Database (Denmark)

    de Bono, Johann Sebastian; Oudard, Stephane; Ozguroglu, Mustafa

    2010-01-01

    Cabazitaxel is a novel tubulin-binding taxane drug with antitumour activity in docetaxel-resistant cancers. We aimed to compare the efficacy and safety of cabazitaxel plus prednisone with those of mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer with progre...

  11. Using Castration Surgery in Male Rats to Demonstrate the Physiological Effects of Testosterone on Seminal Vesicle Anatomy in an Undergraduate Laboratory Setting

    Science.gov (United States)

    Belanger, Rachelle M.; Conant, Stephanie B.; Grabowski, Gregory M.

    2013-01-01

    Rats can be used as a model organism to teach physiological concepts in a laboratory setting. This article describes a two-part laboratory that introduces students to hypothesis testing, experimental design, the appropriate use of controls and surgical techniques. Students perform both a castration and sham-control surgery on male rats and test…

  12. Histone Deacetylase Inhibitors Restore Cell Surface Expression of the Coxsackie Adenovirus Receptor and Enhance CMV Promoter Activity in Castration-Resistant Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Laura Kasman

    2012-01-01

    Full Text Available Adenoviral gene therapy using the death receptor ligand TRAIL as the therapeutic transgene can be safely administered via intraprostatic injection but has not been evaluated for efficacy in patients. Here we investigated the efficacy of adenoviral TRAIL gene therapy in a model of castration resistant prostate cancer and found that intratumoral injections can significantly delay tumor growth but cannot eliminate established lesions. We hypothesized that an underlying cause is inefficient adenoviral delivery. Using the LNCaP progression model of prostate cancer we show that surface CAR expression decreases with increasing tumorigenicity and that castration resistant C4-2b cells were more difficult to transduce with adenovirus than castration sensitive LNCaP cells. Many genes, including CAR, are epigenetically silenced during transformation but a new class of chemotherapeutic agents, known as histone deacetylase inhibitors (HDACi, can reverse this process. We demonstrate that HDACi restore CAR expression and infectivity in C4-2b cells and enhance caspase activation in response to infection with a TRAIL adenovirus. We also show that in cells with high surface CAR expression, HDACi further enhance transgene expression from the CMV promoter. Thus HDACi have multiple beneficial effects, which may enhance not only viral but also non-viral gene therapy of castration resistant prostate cancer.

  13. Effect of feed restriction on the performance and behaviour of pigs immunologically castrated with Improvac®.

    Science.gov (United States)

    Quiniou, N; Monziols, M; Colin, F; Goues, T; Courboulay, V

    2012-09-01

    For centuries, entire male pigs have been castrated to reduce the risk of boar taint. However, physical castration of pig is increasingly being questioned with regard to animal welfare considerations. Immunization against gonadotrophin releasing hormone (GnRH) provides an alternative to physical castration. Using the currently available commercial product (Improvac®; Pfizer Animal Health), a two-dose regimen of a GnRH vaccine is administered. After the second vaccination, a substantial increase in feed consumption has been reported, which may be associated with increased body fatness and decreased feed efficiency when compared with unvaccinated entire male pigs. The aim of the present study was to investigate the effect of a feed restriction on these traits and on the behaviour of 120 group-housed entire males (five pigs/pen) vaccinated against GnRH. The first vaccination was performed at 62 days of age and the second (V2) at 130 days of age. Pigs were slaughtered in two batches 4 to 5 weeks after V2. They were either offered feed ad libitum over the 22 to 114 kg BW range (AL treatment) or ad libitum up to a maximum of 2.50 (R2.50 treatment) or 2.75 kg/day per pig (R2.75 treatment). Behavioural observations and skin lesion scoring were conducted 1 week before V2, and 1 and 3 weeks after V2. At slaughter, the volumetric lean meat content was measured using an X-ray computed tomography scanner. Between V2 and slaughter, the average feed intakes for the R2.75 and R2.50 treatments were 15% and 22% lower than the average AL feed intake (3.20 kg/day), respectively. Feed restriction was associated with a reduced average daily gain after V2 (846, 932 and 1061 g/day in the R2.50, R2.75 and AL groups, P < 0.01) but had no effect on the feed conversion ratio (3.00 kg feed/kg BW gain on average, P = 0.62). No difference was observed in the lean meat content (71.8%, 70.7% and 70.4% in the R2.50, R2.75 and AL groups, P = 0.14), despite a reduced backfat thickness measured in

  14. [Risk factors for predicting severe leukopenia induced by docetaxel plus prednisolone in patients with Castration-Resistant Prostate cancer].

    Science.gov (United States)

    Takada, Shinya; Tamaki, Shinya; Nagamori, Satoshi; Endou, Masayuki

    2015-05-01

    The purpose of this study was to extract the risk factors for GradeB3 leukopenia induced by docetaxel plus prednisolone (DP)therapy administered to patients with castration-resistant prostate cancer. Rates of 59% for GradeB3 leukopenia and 11% for FN were observed. On multivariate analysis, the pretreatment white blood cell count(OR=0.502, 95%CI: 0.292- 0.862, p=0.01)was significantly associated with severe leukopenia induced by DP therapy. In addition, on univariate analysis, the pretreatment platelet count, disease extent, and bilirubin level were significant factors. We consider it necessary to immediately treat patients with these risks with G-CSF.

  15. Buprenorphine provides better anaesthetic conditions than butorphanol for field castration in ponies: results of a randomised clinical trial.

    Science.gov (United States)

    Rigotti, C; De Vries, A; Taylor, P M

    A prospective, randomised, blinded, clinical trial in 47 ponies compared butorphanol and buprenorphine administered intravenously with detomidine prior to castration under anaesthesia. Detomidine 12 μg/kg intravenously was followed by butorphanol 25 μg/kg (BUT) or buprenorphine 5 μg/kg (BUP) before induction of anaesthesia with intravenous ketamine and diazepam. Quality of sedation, induction and recovery from anaesthesia, response to tactile stimulation, and surgical conditions were scored. If anaesthesia was inadequate 'rescue' was given with intravenous ketamine (maximum three doses) followed by intravenous thiopental and detomidine. Time from induction to first rescue, total ketamine dose and number of rescues were recorded. Postoperative locomotor activity was scored and abnormal behaviour noted. Simple descriptive scales were used for all scoring. Data were analysed using two-way analysis of variance, t tests, Mann-Whitney or Fisher's exact tests as appropriate; Pbuprenorphine appeared to provide better intraoperative analgesia. British Veterinary Association.

  16. The expression of receptors for estrogen and epithelial growth factor in the male rabbit prostate and prostatic urethra following castration

    DEFF Research Database (Denmark)

    Bødker, A; Balslev, E; Iversen, H G

    1997-01-01

    In the lower urinary tract of the male rabbit, estrogen receptors (ERs) are restricted to the urethra and the prostatic stroma. At present, the function of ERs in these tissues is not known. Epithelial growth factor (EGF) stimulates proliferation of epidermal and epithelial tissues, and several...... were included as controls. In the control group, ERs were found in the urothelial lining and lamina propria of the prostatic urethra, and in the prostatic stroma. EGF receptors were demonstrated in the epithelial lining of the prostatic urethra and the glandular epithelium of the prostate. Following...... castration, the expression of ERs, assessed as the increase in the number of positively stained specimens, increased significantly in the lamina propria of the prostatic urethra and the prostatic stroma. EGF receptor expression increased significantly in the epithelial lining of the prostatic urethra...

  17. Cabazitaxel as second-line or third-line therapy in patients with metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Kongsted, Per; Svane, Inge M; Lindberg, Henriette

    2016-01-01

    evaluated. Common Terminology Criteria for Adverse Events were used to register grade 3-4 nonhematological toxicity during treatment with CA. Baseline metastatic castration-resistant prostate cancer-related prognostic factors, duration of therapy, and maximum prostate-specific antigen (PSA) percentage...... with second-line and third-line CA (P=0.483). Events with grade 3-4 nonhematological toxicity were equally distributed in the two groups (32 vs. 35%, P=0.80). PSA responses were observed in 46 and 17% of patients treated with second-line and third-line CA (P=0.002). PFS (5.5 vs. 3.3 months, P=0.087, log rank......-line or third-line therapy. Although PFS and the frequency of PSA responders favored patients treated with second-line CA, one treatment sequence could not be considered superior to the other in this study....

  18. Do skeletal-related events predict overall survival in men with metastatic castration-resistant prostate cancer?

    Science.gov (United States)

    Howard, L E; De Hoedt, A M; Aronson, W J; Kane, C J; Amling, C L; Cooperberg, M R; Terris, M K; Divers, C H; Valderrama, A; Freedland, S J

    2016-12-01

    Skeletal-related events (SREs) including pathologic fracture, spinal cord compression, radiation to bone and surgery to bone, are common in men with bone metastatic castration-resistant prostate cancer (mCRPC). Men with mCRPC are at high risk of death. Whether SREs predict mortality is unclear. We tested the association between SREs and overall survival (OS) in a multiethnic cohort with bone mCRPC, controlling for key covariates unavailable in claims data such as bone pain, number of bone metastases and PSA doubling time (PSADT). We collected data on 233 men diagnosed with nonmetastatic castration-resistant prostate cancer (CRPC) in 2000-2013 at two Veterans Affairs hospitals who later progressed to bone metastases. First occurrence of SRE and OS were collected from the medical records. Cox models were used to test the association between SRE and OS, treating SRE as a time-dependent variable. We adjusted for age, year, race, treatment center, biopsy Gleason, primary treatment to the prostate, PSA, PSADT, months from androgen deprivation therapy to CRPC, months from CRPC to metastasis and number of bone metastases at initial bone metastasis diagnosis. In a secondary analysis, we also adjusted for bone pain. During follow-up, 88 (38%) patients had an SRE and 198 (85%) died. After adjusting for risk factors, SRE was associated with increased mortality (hazard ratio (HR)=1.67; 95% confidence interval (CI) 1.22-2.30; P=0.001). When bone pain was added to the model, the association of SREs and OS was attenuated, but remained significant (HR=1.42; 95% CI 1.01-1.99; P=0.042). SREs are associated with increased mortality in men with bone mCRPC. Further studies on the impact of preventing SREs to increase survival are warranted.

  19. Effects of selected neuropeptides, mating status and castration on male reproductive tract movements and immunolocalization of neuropeptides in earwigs.

    Science.gov (United States)

    Rankin, Susan M; TeBrugge, Victoria A; Murray, Jill A; Schuler, Ashley M; Tobe, Stephen S

    2009-01-01

    In earwigs, the male reproductive system is complex, comprising accessory glands and long dual intromittent organs for transfer of materials to the female and for removal of rival sperm. We investigated potential factors altering contractions of the male reproductive tracts in vitro. Tracts from 0-day (newly emerged) males displayed relatively little motility in vitro; however, those from 5-day (intermediate stage of sexual maturity) and 8-day (fully mature) males pulsed vigorously. Both 1 and 100 nM proctolin (RYLPT-OH) stimulated the rate of contraction of reproductive tracts from both 5-day and 8-day males. In contrast, 1 nM and 100 nM FGLa AST (cockroach allatostatin) did not affect pulsations. However, 10 microM FGLa AST decreased activity of reproductive tracts. Mating decreased motility of tracts from 5-day old males, but did not alter motility of tracts from 8-day old males. Castration of larvae significantly suppressed reproductive tract motility in subsequent 8-day old adults compared with those of intact or sham-operated adults. Castration also suppressed seminal vesicle size. Lastly, we assessed the presence and distribution of proctolin-like and allatostatin-like immunoreactivity in tissues. Immunoreactivity to FGLa AST and proctolin was widespread, occurring in the brain and ventral ganglia. Surprisingly, we did not detect immunoreactivity to either FGLa AST or proctolin within the reproductive system; however, proctolin immunoreactivity was evident in nerves extending from the terminal ganglion of 8-day, but not 0-day, males. Collectively, these experiments demonstrate that the male earwig reproductive system is an appropriate model for use in addressing sexual maturation and activities in male insects.

  20. Evaluation of total intravenous anesthesia with propofol-guaifenesin-medetomidine and alfaxalone-guaifenesin-medetomidine in Thoroughbred horses undergoing castration.

    Science.gov (United States)

    Aoki, Motoki; Wakuno, Ai; Kushiro, Asuka; Mae, Naomi; Kakizaki, Masashi; Nagata, Shun-Ichi; Ohta, Minoru

    2017-12-22

    Anesthetic and cardiorespiratory effects of total intravenous anesthesia (TIVA) technique using propofol-guaifenesin-medetomidine (PGM) and alfaxalone-guaifenesin-medetomidine (AGM) were preliminarily evaluated in Thoroughbred horses undergoing castration. Twelve male Thoroughbred horses were assigned randomly into two groups. After premedication with intravenous (IV) administrations of medetomidine (5.0 µg/kg) and butorphanol (0.02 mg/kg), anesthesia was induced with guaifenesin (10 mg/kg IV), followed by either propofol (2.0 mg/kg IV) (group PGM: n=6) or alfaxalone (1.0 mg/kg IV) (group AGM: n=6). Surgical anesthesia was maintained for 60 min at a constant infusion of either propofol (3.0 mg/kg/hr) (group PGM) or alfaxalone (1.5 mg/kg/hr) (group AGM), in combination with guaifenesin (80 mg/kg/hr) and medetomidine (3.0 µg/kg/hr). Responses to surgical stimuli, cardiorespiratory values, and induction and recovery characteristics were recorded throughout anesthesia. During anesthesia induction, one horse paddled in group PGM. All horses from group AGM were maintained at adequate anesthetic depth for castration. In group PGM, 3 horses showed increased cremaster muscle tension and one showed slight movement requiring additional IV propofol to maintain surgical anesthesia. No horse exhibited apnea, although arterial oxygen tension decreased in group AGM to less than 60 mmHg. Recovery quality was good to excellent in both groups. In conclusion, TIVA using PGM and AGM infusion was available for 60 min anesthesia in Thoroughbred horses. TIVA techniques using PGM and AGM infusion provided clinically acceptable general anesthesia with mild cardiorespiratory depression. However, inspired air should be supplemented with oxygen to prevent hypoxemia during anesthesia.

  1. Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease

    Directory of Open Access Journals (Sweden)

    Harrison MR

    2013-01-01

    Full Text Available Michael R Harrison, Terence Z Wong, Andrew J Armstrong, Daniel J GeorgeDuke Cancer Institute, Durham, NC, USABackground: Radium-223 chloride (223Ra; Alpharadin is an alpha-emitting radioisotope that targets areas of osteoblastic metastasis and is excreted by the small intestine. When compared with beta-emitters (eg, strontium-89, samarium-153, 223Ra delivers a high quantity of energy per track length with short tissue penetration.Objective: This review describes the mechanism, radiobiology, and preclinical development of 223Ra and discusses the clinical data currently available regarding its safety and efficacy profile.Methods: Data from clinical trials including abstracts were collected and reviewed using the PubMed Database, as well as the American Society of Clinical Oncology abstract database.Conclusion: Current bone-targeted therapies fall into two main categories: antiresorptive agents (eg, zoledronic acid, denosumab, which have been shown to delay skeletal-related events, and radiopharmaceuticals (eg, samarium-153, which may have a role in pain palliation. Historically, neither antiresorptive agents nor radiopharmaceuticals have shown definitive evidence of improved overall survival or other antitumor effects in metastatic castrate-resistant prostate cancer (mCRPC. Radiopharmaceuticals are limited by myelosuppresion, thrombocytopenia, and renal excretion. In a recently reported randomized Phase III trial in men with symptomatic bone-metastatic CRPC who had received or were ineligible for docetaxel chemotherapy, 223Ra treatment resulted in improved overall survival and delayed skeletal-related events. Toxicity consisted of minor gastrointestinal side effects and mild neutropenia and thrombocytopenia that were rarely severe. Pending regulatory approval, 223Ra may represent a unique and distinct option for an important subgroup of patients with mCRPC; future trials should address its use in combination or in sequence with existing and novel

  2. Recherche d'un âge optimal de castration chez la race bovine Alur en système d'élevage extensif au Zaïre

    Directory of Open Access Journals (Sweden)

    Dibanzilua, M.

    1993-01-01

    Full Text Available Determination of the optimum age for castration by the Alur cattle breed under extensive production in Zaire. Considering a few difficultes which seem to hinder the popularization of the castration technique in the real environment of Ituri (North Eastern Zaire, the authors suggest the trend towards the reducing of the age margin regularly observed during the running of that operation. It appeared that the age between 3 and 5 months seems favourable for the popularizer as well as for the animal and the breeder regarding the operation, the stress and the meat quality. Considering the yields in butchery the carcass weights of castrated animals are nearly the same as those of non castrated ones.

  3. Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: the SPARC trial.

    NARCIS (Netherlands)

    Sternberg, C.N.; Petrylak, D.P.; Sartor, O.; Witjes, J.A.; Demkow, T.; Ferrero, J.M.; Eymard, J.C.; Falcon, S.; Calabro, F.; James, N.; Bodrogi, I.; Harper, P.; Wirth, M.; Berry, W.; Petrone, M.E.; McKearn, T.J.; Noursalehi, M.; George, M.; Rozencweig, M.

    2009-01-01

    PURPOSE: This multinational, double-blind, randomized, placebo-controlled, phase III trial assessed the efficacy and tolerability of the oral platinum analog satraplatin in patients with metastatic castrate-refractory prostate cancer (CRPC) experiencing progression after one prior chemotherapy

  4. Effects of feeding ractopamine hydrochloride (Paylean) to physical and immunological castrates (Improvest) in a commercial setting on growth performance and carcass characteristics.

    Science.gov (United States)

    Lowe, B K; Gerlemann, G D; Carr, S N; Rincker, P J; Schroeder, A L; Petry, D B; McKeith, F K; Allee, G L; Dilger, A C

    2014-08-01

    Growth performance and carcass characteristics of physically castrated (PC) and immunologically castrated (IC) pigs fed ractopamine hydrochloride (RAC; 5 mg/kg) were evaluated in 64 pens of 22 pigs each. Male pigs were randomly assigned to castration method at birth. Pigs in the PC group were physically castrated at 5 d of age while IC pigs were administered Improvest at 11 and 18 wk of age. Pigs entered the grow-finish barn at approximately 9 wk of age (d 0). Dietary treatments (control or RAC) were initiated on d 87. Final treatment arrangement was a 2 × 2 factorial of castration method and diet. Data were analyzed using a mixed model with fixed effects of castration method, diet, market group, and all 2- and 3-way interactions. Pen was the experimental unit. From d 0 to 65, IC pigs had 11.2% greater (P < 0.01) G:F and 11.6% less (P < 0.01) ADFI than PC pigs, but ADG was increased 1.0% in PC pigs compared with IC pigs (P < 0.01). From d 65 to 87, IC pigs had 7.9% greater (P < 0.01) ADG and 12.1% greater (P < 0.01) G:F than PC pigs while having similar (P = 0.16) ADFI. At the initiation of diet (RAC) treatments, BW of all treatments were similar (P ≥ 0.32). From d 87 to 120 (RAC feeding period), IC pigs had 10.0% greater (P < 0.01) ADG and 10.5% greater (P < 0.01) ADFI than PC pigs while having similar (P = 0.64) G:F. Feeding RAC increased (P < 0.01) ADG by 16.9% and G:F by 17.9% while having no effect (P = 0.42) on ADFI from d 87 to 120. There were no significant interactions between castration method and diet on growth performance from d 87 to 120. For the entire study (d 0-120), IC pigs had 2.6% greater (P < 0.01) ADG, 4.6% less (P < 0.01) ADFI, and 7.3% greater (P < 0.01) G:F than PC pigs. Averaged over market groups, IC pigs were 2.5 kg heavier (P < 0.01) and had similar (P = 0.10) carcass weights and 1.8 percentage units less (P < 0.01) dressing yields than PC pigs. Additionally, IC pigs had 1.3 mm less (P < 0.01) fat and 1.7 mm less (P < 0.01) loin depth

  5. Effects of time after a second dose of immunization against GnRF (Improvest) independent of age at slaughter on commercial bacon slicing characteristics of immunologically castrated barrows.

    Science.gov (United States)

    Tavárez, M A; Bohrer, B M; Herrick, R T; Mellencamp, M A; Matulis, R J; Ellis, M; Boler, D D; Dilger, A C

    2016-01-01

    The objective was to determine the effects of time after a second dose of anti-GnRF immunization on fresh belly characteristics and slicing yields of immunologically castrated (IC) barrows, physically castrated (PC) barrows and gilts slaughtered at 24 weeks of age. The second dose was staggered so that IC barrows were slaughtered at 4, 6, 8, or 10 weeks after the second dose. Fresh belly characteristics (N=141) were collected at slaughter and bacon was manufactured commercially. The main effects in the model were treatment and the random effects of block and block within replication. Thickness, flop distance, and lipid content increased (L; Pbacon slicing characteristics in IC barrows. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Role of the 5-HT1A autoreceptor in the enhancement of fluvoxamine-induced increases in prefrontal dopamine release by adrenalectomy/castration in mice

    Directory of Open Access Journals (Sweden)

    Shigeru Hasebe

    2015-02-01

    Full Text Available We have found that fluvoxamine-induced increases in prefrontal dopamine release are enhanced by adrenalectomy/castration and 5-HT1A receptors are involved in the enhancement. This study examined which 5-HT1A autoreceptors or postsynaptic receptor play a key role in the enhancement in mice. Adrenalectomy/castration-induced enhancement of fluvoxamine-induced increase in the dopamine release was not blocked by local perfusion with the 5-HT1A receptor antagonist WAY100635 (10 μM, while it was blocked by systemic administration of WAY100635 at low dose (0.1 mg/kg which blocked preferentially autoreceptor-mediated responses. These finding suggests that 5-HT1A autoreceptors play a key role in the enhancement of prefrontal dopamine release.

  7. Clinical evaluation of total intravenous anesthesia using a combination of propofol and medetomidine following anesthesia induction with medetomidine, guaifenesin and propofol for castration in Thoroughbred horses.

    Science.gov (United States)

    Oku, Kazuomi; Kakizaki, Masashi; Ono, Keiichi; Ohta, Minoru

    2011-12-01

    Seven Thoroughbred horses were castrated under total intravenous anesthesia (TIVA) using propofol and medetomidine. After premedication with medetomidine (5.0 µg/kg, intravenously), anesthesia was induced with guaifenesin (100 mg/kg, intravenously) and propofol (3.0 mg/kg, intravenously) and maintained with constant rate infusions of medetomidine (0.05 µg/kg/min) and propofol (0.1 mg/kg/min). Quality of induction was judged excellent to good. Three horses showed insufficient anesthesia and received additional anesthetic. Arterial blood pressure changed within an acceptable range in all horses. Decreases in respiratory rate and hypercapnia were observed in all horses. Three horses showed apnea within a short period of time. Recovery from anesthesia was calm and smooth in all horses. The TIVA-regimen used in this study provides clinically effective anesthesia for castration in horses. However, assisted ventilation should be considered to minimize respiratory depression.

  8. Targeting Hsp27/eIF4E interaction with phenazine compound: a promising alternative for castration-resistant prostate cancer treatment.

    Science.gov (United States)

    Hajer, Ziouziou; Claudia, Andrieu; Erik, Laurini; Sara, Karaki; Maurizio, Fermeglia; Ridha, Oueslati; David, Taieb; Michel, Camplo; Olivier, Siri; Sabrina, Pricl; Maria, Katsogiannou; Palma, Rocchi

    2017-09-29

    The actual strategy to improve current therapies in advanced prostate cancer involves targeting genes activated by androgen withdrawal, either to delay or prevent the emergence of the castration-refractory phenotype. However, these genes are often implicated in several physiological processes, and long-term inhibition of survival proteins might be accompanied with cytotoxic effects. To avoid this problem, an alternative therapeutic strategy relies on the identification and use of compounds that disrupt specific protein-protein interactions involved in androgen withdrawal. Specifically, the interaction of the chaperone protein Hsp27 with the initiation factor eIF4E leads to the protection of protein synthesis initiation process and enhances cell survival during cell stress induced by castration or chemotherapy. Thus, in this work we aimed at i) identifying the interaction site of the Hsp27/eIF4E complex and ii) interfere with the relevant protein/protein association mechanism involved in castration-resistant progression of prostate cancer. By a combination of experimental and modeling techniques, we proved that eIF4E interacts with the C-terminal part of Hsp27, preferentially when Hsp27 is phosphorylated. We also observed that the loss of this interaction increased cell chemo-and hormone-sensitivity. In order to find a potential inhibitor of Hsp27/eIF4E interaction, BRET assays in combination with molecular simulations identified the phenazine derivative 14 as the compound able to efficiently interfere with this protein/protein interaction, thereby inhibiting cell viability and increasing cell death in chemo- and castration-resistant prostate cancer models in vitro and in vivo .

  9. Reversible lysine-specific demethylase 1 antagonist HCI-2509 inhibits growth and decreases c-MYC in castration- and docetaxel-resistant prostate cancer cells.

    Science.gov (United States)

    Gupta, S; Weston, A; Bearrs, J; Thode, T; Neiss, A; Soldi, R; Sharma, S

    2016-12-01

    Lysine-specific demethylase 1 (LSD1 or KDM1A) overexpression correlates with poor survival and castration resistance in prostate cancer. LSD1 is a coregulator of ligand-independent androgen receptor signaling promoting c-MYC expression. We examined the antitumor efficacy of LSD1 inhibition with HCI-2509 in advanced stages of prostate cancer. Cell survival, colony formation, histone methylation, c-MYC level, c-MYC expression, cell cycle changes and in vivo efficacy were studied in castration-resistant prostate cancer cells upon treatment with HCI-2509. In vitro combination studies, using HCI-2509 and docetaxel, were performed to assess the synergy. Cell survival, colony formation, histone methylation and c-myc levels were studied in docetaxel-resistant prostate cancer cells treated with HCI-2509. HCI-2509 is cytotoxic and inhibits colony formation in castration-resistant prostate cancer cells. HCI-2509 treatment causes a dose-dependent increase in H3K9me2 (histone H3lysine 9) levels, a decrease in c-MYC protein, inhibition of c-MYC expression and accumulation in the G0/G1 phase of the cell cycle in these cells. PC3 xenografts in mice have a significant reduction in tumor burden upon treatment with HCI-2509 with no associated myelotoxicity or weight loss. More synergy is noted at sub-IC 50 (half-maximal inhibitory concentration) doses of docetaxel and HCI-2509 in PC3 cells than in DU145 cells. HCI-2509 has growth-inhibitory efficacy and decreases the c-myc level in docetaxel-resistant prostate cancer cells. LSD1 inhibition with HCI-2509 decreases the c-MYC level in poorly differentiated prostate cancer cell lines and has a therapeutic potential in castration- and docetaxel-resistant prostate cancer.

  10. Use of serum amyloid A and other acute phase reactants to monitor the inflammatory response after castration in horses: a field study.

    Science.gov (United States)

    Jacobsen, S; Jensen, J C; Frei, S; Jensen, A L; Thoefner, M B

    2005-11-01

    Early recognition of excessive inflammation and infectious complications after surgery, leading to early institution of therapy, reduces post operative discomfort and facilitates recovery. Because serum amyloid A (SAA) is a highly sensitive marker of inflammation, measurements of SAA and other acute phase reactants in the equine surgical patient may be valuable in assisting clinical assessment of post operative inflammation. To investigate changes in inflammatory markers after castration and to correlate levels of acute phase reactants with clinical severity of inflammation after castration. Leucocyte numbers and blood levels of iron, SAA and fibrinogen were determined before castration and on Days 3 and 8 post operatively in 2 groups of horses; Group 1 (n = 11) had mild post operative inflammation and an uncomplicated recovery and Group 2 (n = 7) had local clinical signs of moderate to severe inflammation. Both groups had elevated serum SAA levels at Day 3 post operatively. In Group 1 concentrations had returned to preoperative levels by Day 8, whereas in Group 2 concentrations remained elevated. Plasma fibrinogen concentrations in serum increased to equal levels in both groups and stayed elevated throughout the study period. Serum iron concentrations of Group 1 did not change in response to castration, whereas concentrations in Group 2 decreased below preoperative levels on Day 8. Leucocyte numbers remained unchanged during the post operative period in both groups. Serum SAA and iron profiles reflected the course of inflammation and their levels correlated with the clinical severity of inflammation. In contrast, fever and changes in leucocyte numbers, which are usually considered to be hallmarks of inflammation and infection, were not useful for monitoring post operative recovery. Measurements of SAA and iron may improve post operative monitoring. As sustained inflammation may indicate that the surgical wound has become infected, SAA and iron measurements may

  11. Differential effects of 2-difluoromethylornithine and methylglyoxal bis(guanylhydrazone) on the testosterone-induced growth of ventral prostate and seminal vesicles of castrated rats.

    OpenAIRE

    Käpyaho, K; Kallio, A; Jänne, J

    1984-01-01

    2-Difluoromethylornithine totally prevented any increases in putrescine and spermidine concentrations in the ventral prostate of castrated rats during a 6-day testosterone treatment. Prostatic ornithine decarboxylase activity was inhibited by 80%, whereas S-adenosylmethionine decarboxylase was stimulated by more than 9-fold. In seminal vesicle, the inhibition of putrescine and spermidine accumulation, as well as of ornithine decarboxylase activity, was only minimal, and no stimulation of S-ad...

  12. Immunolocalization of estrogen and androgen receptors in the caput epididymidis of the fat sand rat (Psammomys obesus): Effects of seasonal variations, castration and efferent duct ligation.

    Science.gov (United States)

    Menad, Rafik; Smaï, Souaâd; Moudilou, Elara; Khammar, Farida; Exbrayat, Jean-Marie; Gernigon-Spychalowicz, Thérèse

    2014-05-01

    The fat sand rat (Psammomys obesus) is a model to study seasonal reproductive cycle changes and several metabolic disorders. In order to show a possible involvement of estrogens in the male reproductive functions, the expression of estrogen receptors (ESR1 and ESR2) and androgen receptor (AR) were investigated in the caput epididymidis of fat sand rats during the breeding season, resting season, after castration, after castration followed by testosterone treatment, and after ligation of efferent ducts. In the breeding season, principal cells presented a strong immunostaining of AR in both nuclei and cytoplasm, a strong staining of ESR1, mainly in the apical zone, and a strong immunoexpression of ESR2, mainly in nuclei. In the resting season, a moderate immunostaining of AR in both cytoplasm and nuclei was observed. ESR1 staining showed a strong immunoreactivity in the nuclei. In contrast, the nuclei were negative for ESR2. After castration, a low and selective signal distribution was observed: the nuclei were moderately positive for AR and ESR2, and negative for ESR1. After castration and testosterone treatment, an androgen-dependence for AR and the restoration of ESR1 but not ESR2 immunoexpression were observed. After ligation of the efferent ducts, a considerable reduction of AR immunoreactivity was observed in contrast to ESR1 and ESR2, which gave a strong immunostaining signal. These results illustrate the complexity of the regulation of the androgen and estrogen receptor expression in the epididymis and argue for the coexistence of both androgenic and estrogenic pathways. Copyright © 2013 Elsevier GmbH. All rights reserved.

  13. Consumer response to the possible use of a vaccine method to control boar taint v. physical piglet castration with anaesthesia: a quantitative study in four European countries.

    Science.gov (United States)

    Vanhonacker, F; Verbeke, W

    2011-05-01

    In most European countries, male piglets being reared for meat are physically castrated without anaesthesia in order to avoid boar taint and to safeguard sensory meat quality. This method is increasingly criticised for its violation of piglet welfare. Alternative methods are being researched and castration with anaesthesia or analgesia and vaccination (immunisation) against gonadotropin-releasing hormone (using Improvac®, Pfizer GmbH) have been proposed as possible solutions. In addition to efficacy, the successful introduction and adoption of the vaccine method by stakeholders in pig supply chains are expected to depend on a favourable reception by consumers. This large-scale quantitative cross-country study (n = 4031) involving representative samples of consumers in France, Germany, the Netherlands and Belgium does not support the reserved attitude of stakeholders who fear potential low market acceptance. The vaccine method was actually preferred by the majority of consumers surveyed (69.6% of the participants) and it was perceived as equally effective in terms of avoiding boar taint; 43.8% of the consumers reported an intention to seek out pork from pigs where the vaccine had been used to control boar taint, whereas 33.7% reported an intention to avoid pork from pigs physically castrated with anaesthesia. Consumers' favourable dispositions to the vaccine method were independent of dominant ethical, health or price orientations when purchasing pork.

  14. Delineation of human prostate cancer evolution identifies chromothripsis as a polyclonal event and FKBP4 as a potential driver of castration resistance.

    Science.gov (United States)

    Federer-Gsponer, Joël R; Quintavalle, Cristina; Müller, David C; Dietsche, Tanja; Perrina, Valeria; Lorber, Thomas; Juskevicius, Darius; Lenkiewicz, Elisabeth; Zellweger, Tobias; Gasser, Thomas; Barrett, Michael T; Rentsch, Cyrill A; Bubendorf, Lukas; Ruiz, Christian

    2018-02-27

    Understanding the evolutionary mechanisms and genomic events leading to castration resistant (CR) prostate cancer (PC) is key to improve the outcome of this otherwise deadly disease. Here, we delineated the tumour history of seven patients progressing to castration resistance by analysing matched prostate cancer tissues before and after castration. We performed genomic profiling of DNA-content based flow-sorted populations in order to define the different evolutionary patterns. In one patient, we discovered that a catastrophic genomic event, known as chromothripsis, resulted in multiple CRPC tumour populations with distinct, potentially advantageous copy number aberrations, including an amplification of FK506 Binding Protein 4 (FKBP4, also known as FKBP52), a protein enhancing the transcriptional activity of androgen receptor signalling. Analysis of FKBP4 protein expression in more than 500 prostate cancer samples revealed increased expression in CRPC in comparison to hormone-naïve (HN) PC. Moreover, elevated FKBP4 expression was associated with poor survival of patients with HNPC. We propose FKBP4 amplification and overexpression as a selective advantage in the process of tumour evolution and as a potential mechanism associated with the development of CRPC. Furthermore, FKBP4 interaction with androgen receptor may provide a potential therapeutic target in PC. This article is protected by copyright. All rights reserved.

  15. Mitosis phase enrichment with identification of mitotic centromere-associated kinesin as a therapeutic target in castration-resistant prostate cancer.

    Science.gov (United States)

    Sircar, Kanishka; Huang, Heng; Hu, Limei; Liu, Yuexin; Dhillon, Jasreman; Cogdell, David; Aprikian, Armen; Efstathiou, Eleni; Navone, Nora; Troncoso, Patricia; Zhang, Wei

    2012-01-01

    The recently described transcriptomic switch to a mitosis program in castration-resistant prostate cancer (CRPC) suggests that mitotic proteins may be rationally targeted at this lethal stage of the disease. In this study, we showed upregulation of the mitosis-phase at the protein level in our cohort of 51 clinical CRPC cases and found centrosomal aberrations to also occur preferentially in CRPC compared with untreated, high Gleason-grade hormone-sensitive prostate cancer (Pcancer cases (n = 108). Our results showed enrichment of mitosis-phase genes and pathways, with progression to both castration-resistant and chemotherapy-resistant disease. The mitotic centromere-associated kinesin (MCAK) was identified as a novel mitosis-phase target in prostate cancer that was overexpressed in multiple CRPC gene-expression datasets. We found concordant gene expression of MCAK between our parent and murine CRPC xenograft pairs and increased MCAK protein expression with clinical progression of prostate cancer to a castration-resistant disease stage. Knockdown of MCAK arrested the growth of prostate cancer cells suggesting its utility as a potential therapeutic target.

  16. Stage-dependent behavioural changes but early castration induced by the acanthocephalan parasite Polymorphus minutus in its Gammarus pulex intermediate host.

    Science.gov (United States)

    Bailly, Yann; Cézilly, Frank; Rigaud, Thierry

    2018-03-01

    Multidimensionality in parasite-induced phenotypic alterations (PIPA) has been observed in a large number of host-parasite associations, particularly in parasites with complex life cycles. However, it is still unclear whether such a syndrome is due to the successive activation of independent PIPAs, or results from the synchronous disruption of a single mechanism. The aim of the present study was to investigate the onset and progression of two PIPAs (a behavioural alteration: reversion of geotaxis, and castration) occurring in the crustacean amphipod Gammarus pulex infected with the acanthocephalan Polymorphus minutus, at different parasite developmental stages. Modifications of geotaxis in hosts differed according to the parasite developmental stage. Whereas the cystacanth stage induced a negative geotaxis (exposing the gammarid to predation by birds, the definitive hosts), the acanthella stage, not yet infective for the definitive host, induced a stronger positive geotaxis (presumably protecting gammarids from bird predation). In contrast, castration was almost total at the acanthella stage, with no significant variation in the intensity according to parasite maturation. Finally, no significant correlation was found between the intensity of behavioural changes and the intensity of castration. We discuss our results in relation with current views on the evolution of multidimensionality in PIPA.

  17. Docetaxel chemotherapy in metastatic castration-resistant prostate cancer: cost of care in Medicare and commercial populations.

    Science.gov (United States)

    Armstrong, A; Bui, C; Fitch, K; Sawhney, T Goss; Brown, B; Flanders, S; Balk, M; Deangelis, J; Chambers, J

    2017-06-01

    To estimate the healthcare costs and characteristics of docetaxel chemotherapy episodes of care for men with metastatic castration-resistant prostate cancer (mCRPC). This study used the Medicare 5% sample and MarketScan Commercial (2010-2013) claims data sets to identify men with mCRPC and initial episodes of docetaxel treatment. Docetaxel episodes included docetaxel claim costs from the first claim until 30 days after the last claim, with earlier termination for death, insurance disenrollment, or the end of a 24-month look-forward period from initial docetaxel index date. Docetaxel drug claim costs were adjusted for 2011 generic docetaxel introduction, while other costs were adjusted to 2015 values using the national average annual unit cost increase. This study identified 281 Medicare-insured and 155 commercially insured men, with 325 and 172 docetaxel episodes, respectively. The average number of cycles (unique docetaxel infusion days) per episode was 6.9 for Medicare and 6.3 for commercial cohorts. The average cost per episode was $28,792 for Medicare and $67,958 for commercial cohorts, with docetaxel drug costs contributing $2,588 and $13,169 per episode, respectively. The average cost per episode on docetaxel infusion days was $8,577 (30%) for Medicare and $28,412 (42%) for commercial. Non-docetaxel infusion day costs included $7,074 (25%) for infused or injected drugs for Medicare, $10,838 (16%) for commercial cohorts, and $6,875 (24%) and $9,324 (14%) for inpatient admissions, respectively. The applicability is only to the metastatic castration-resistance clinical setting, rather than the metastatic hormone-sensitive setting, and the lack of data on the cost effectiveness of different sequencing strategies of a range of systemic therapies including enzalutamide, abiraterone, radium-223, and taxane chemotherapy. The majority of docetaxel episode costs in Medicare and commercial mCRPC populations were non-docetaxel drug costs. Future research should evaluate

  18. Clinical study investigating the role of lymphadenectomy, surgical castration and adjuvant hormonal treatment in endometrial stromal sarcoma.

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    Amant, F; De Knijf, A; Van Calster, B; Leunen, K; Neven, P; Berteloot, P; Vergote, I; Van Huffel, S; Moerman, P

    2007-11-05

    The objective of this study is to assess the therapeutic importance of surgical castration, adjuvant hormonal treatment and lymphadenectomy in endometrial stromal sarcoma (ESS). A retrospective and multicentric search was performed. Clinicopathologic data were retrieved from cases that were confirmed to be ESS after central pathology review. The protocol was approved by the Ethical Committee. ESS was confirmed histopathologically in 34 women, but follow-up data were available in only 31 women. Surgical treatment (n=31) included hysterectomy with or without bilateral salpingo-oophorectomy (BSO) in 23 out of 31 (74%) and 8 out of 31 (26%) cases, respectively. Debulking surgery was performed in 6 out of 31 cases (19%). Stage distribution was as follows: 22 stage I, 4 stage III and 5 stage IV. Women with stage I disease recurred in 4 out of 22 (18%) cases. Among stage I women undergoing hormonal treatment with or without BSO, 3 out of 15 (20%) and 1 out of 7 (14%) relapsed, respectively. Among stages III-IV women receiving adjuvant hormonal treatment or not, 1 out of 5 (20%) and 3 out of 4 (75%) relapsed, respectively (differences=55.0%, 95% CI=-6.8-81.2%). Kaplan-Meier curves show comparable recurrence rates for stage I disease without adjuvant hormonal treatment when compared to stages III-IV disease treated with surgery and adjuvant hormonal treatment. Furthermore, women taking hormones at diagnosis have a better outcome when compared to women not taking hormonal treatment. Three out of 31 (9%) patients had a systematic lymphadenectomy whereas 3 out of 31 (9%) had a lymph node sampling. In one case, obvious nodal disease was encountered at presentation. Isolated retroperitoneal recurrence occurred in 1 out of 31 (3%) of all cases and in 1 out of 8 (13%) recurrences. This single woman later also developed lung and abdominal metastases. Leaving lymph nodes in situ does not appear to alter the clinical outcome of ESS. Although numbers are low, the retrospective data

  19. Overexpression of hepatocyte growth factor in SBMA model mice has an additive effect on combination therapy with castration

    Energy Technology Data Exchange (ETDEWEB)

    Ding, Ying [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Adachi, Hiroaki, E-mail: hadachi-ns@umin.org [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Department of Neurology, University of Occupational and Environmental Health School of Medicine, 1-1 Iseigaoka, Yahata-nishi-ku, Kitakyushu 807-8555 (Japan); Katsuno, Masahisa [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Huang, Zhe [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Department of Neurology, University of Occupational and Environmental Health School of Medicine, 1-1 Iseigaoka, Yahata-nishi-ku, Kitakyushu 807-8555 (Japan); Jiang, Yue-Mei; Kondo, Naohide; Iida, Madoka; Tohnai, Genki; Nakatsuji, Hideaki [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Funakoshi, Hiroshi [Center for Advanced Research and Education, Asahikawa Medical University, 1-1-1- Higashinijo Midorigaoka, Asahikawa 078-8510 (Japan); Nakamura, Toshikazu [Neurogen Inc., 1-1-52-201 Nakahozumi, Ibaraki 567-0034 (Japan); Sobue, Gen, E-mail: sobueg@med.nagoya-u.ac.jp [Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Research Division of Dementia and Neurodegenerative Disease, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan)

    2015-12-25

    Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ)-encoding tract within the androgen receptor (AR) gene. The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem and diffuse nuclear accumulation and nuclear inclusions of mutant AR in residual motor neurons and certain visceral organs. Hepatocyte growth factor (HGF) is a polypeptide growth factor which has neuroprotective properties. To investigate whether HGF overexpression can affect disease progression in a mouse model of SBMA, we crossed SBMA transgenic model mice expressing an AR gene with an expanded CAG repeat with mice overexpressing HGF. Here, we report that high expression of HGF induces Akt phosphorylation and modestly ameliorated motor symptoms in an SBMA transgenic mouse model treated with or without castration. These findings suggest that HGF overexpression can provide a potential therapeutic avenue as a combination therapy with disease-modifying therapies in SBMA. - Highlights: • HGF overexpression ameliorates the motor phenotypes of the SBMA mouse model. • HGF overexpression induces Akt phosphorylation in the SBMA mouse model. • This is the first report of combination therapy in a mouse model of polyQ diseases.

  20. ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer.

    Science.gov (United States)

    Wang, Junjian; Zou, June X; Xue, Xiaoqian; Cai, Demin; Zhang, Yan; Duan, Zhijian; Xiang, Qiuping; Yang, Joy C; Louie, Maggie C; Borowsky, Alexander D; Gao, Allen C; Evans, Christopher P; Lam, Kit S; Xu, Jianzhen; Kung, Hsing-Jien; Evans, Ronald M; Xu, Yong; Chen, Hong-Wu

    2016-05-01

    The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice. Taken together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa.

  1. Global analysis of transcription in castration-resistant prostate cancer cells uncovers active enhancers and direct androgen receptor targets.

    Science.gov (United States)

    Toropainen, Sari; Niskanen, Einari A; Malinen, Marjo; Sutinen, Päivi; Kaikkonen, Minna U; Palvimo, Jorma J

    2016-09-19

    Androgen receptor (AR) is a male sex steroid-activated transcription factor (TF) that plays a critical role in prostate cancers, including castration-resistant prostate cancers (CRPC) that typically express amplified levels of the AR. CRPC-derived VCaP cells display an excessive number of chromatin AR-binding sites (ARBs) most of which localize to distal inter- or intragenic regions. Here, we analyzed direct transcription programs of the AR in VCaP cells using global nuclear run-on sequencing (GRO-seq) and integrated the GRO-seq data with the ARB and VCaP cell-specific TF-binding data. Androgen immediately activated transcription of hundreds of protein-coding genes, including IGF-1 receptor and EGF receptor. Androgen also simultaneously repressed transcription of a large number of genes, including MYC. As functional enhancers have been postulated to produce enhancer-templated non-coding RNAs (eRNAs), we also analyzed the eRNAs, which revealed that only a fraction of the ARBs reside at functional enhancers. Activation of these enhancers was most pronounced at the sites that also bound PIAS1, ERG and HDAC3, whereas binding of HDAC3 and PIAS1 decreased at androgen-repressed enhancers. In summary, our genome-wide data of androgen-regulated enhancers and primary target genes provide new insights how the AR can directly regulate cellular growth and control signaling pathways in CPRC cells.

  2. Effects of Eurycoma longifolia Jack (Tongkat Ali) on the initiation of sexual performance of inexperienced castrated male rats.

    Science.gov (United States)

    Ang, H H; Cheang, H S; Yusof, A P

    2000-01-01

    We studied the effects of Eurycoma longifolia Jack, commonly known as Tongkat Ali in Malaysia, on the initiation of sexual performance and the weights of sexual accessories in inexperienced castrated male rats. The doses of 200, 400 and 800 mg/kg body weight, which were extracted from E. longifolia Jack, were orally administered to the rats twice daily for 10 days prior to the tests and continued throughout the test period. Testosterone was used as a positive control after injecting 15 mg/kg daily subcutaneously for 32 days. Results showed that E. longifolia Jack produced a dose-dependent increase in sexual performance of the treated animals, but the E. longifolia Jack groups showed lower sexual performance in mounting, intromission and ejaculation than the testosterone group. Further results also showed that E. longifolia Jack promoted the growth of both ventral prostate and seminal vesicles as compared with the control, but the growth of sexual accessories at 800 mg/kg of butanol, methanol, water and chloroform fractions of E. longifolia Jack was less than that of testosterone treated group. The present study therefore gives further evidence of the folkuse of E. longifolia as an aphrodisiac.

  3. Pharmacoeconomic analysis of enzalutamide and abiraterone for treatment of chemotherapy naive patients with metastatic castration resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    N. A. Avxentyev

    2017-01-01

    Full Text Available Introduction. Enzalutamide and abiraterone are used for treatment of metastatic castration resistant prostate cancer (mCRPC. Both drugs were proved to be effective in randomized control trials.Objective. This pharmacoeconomic evaluation compared enzalutamide and abiraterone used prior to chemotherapy in patients with mCRPC from the Russian healthcare system perspective.Materials and methods. Based on clinical trials results we proposed an mCRPC Markov chain stochastic process model and calculated medical costs per 1 mCRPC patient. We also conducted cost – effectiveness, cost – utility and budget impact analysis.Results. Monthly medication costs for enzalutamide was 29 478 rubles (11.7 % less than for abiraterone + prednisolone. The 4 year total medical costs for enzalutamide was 318 thousand rubles (5.0 % less than for abiraterone + prednisolone. Enzalutamide was also found to be cost – effective compared to abiraterone.Conclusions. Enzalutamide is a rational option for mCRPC treatment.

  4. Polyamine metabolism in the kidneys of castrated and testosterone-treated mice after administration of methylglyoxal bis(guanylhydrazone).

    Science.gov (United States)

    Henningsson, S; Persson, L; Rosengren, E

    1979-02-01

    The effects of methylglyoxal bis(guanylhydrazone) on S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50) activity were studied in the mouse kidney stimulated to growth by testosterone administration. The drug was found a potent inhibitor of the enzyme in vitrol Administration of methylglyoxal bis(guanylhydrazone) in vivo resulted in a transient inhibition followed by a strong enhancement of the enzyme activity. Dialysis of the kidney extract, to remove remaining methylglyoxal bis(guanylhydrazone), revealed a great and rapid increase in the activity of S-adenosyl-L-methionine decarboxylase. Injections of testosterone to castrated mice resulted in a marked increase in kidney weight and an accumulation of renal putrescine, spermidine and spermine. These effects of testosterone could not be blocked by simultaneous injections of methylglyoxal bis(guanylhydrazone). It appears that due to secondary effects by which the inhibition of methylglyoxal bis(guanylhydrazone) on S-adenosyl-L-methionine decarboxylase activity is circumvented the inhibitor seems to be of uncertain value in attempts to decrease selectively the in vivo levels of polyamines.

  5. Ractopamine hydrochloride and immunological castration in pigs. Part 1: fresh belly characteristics for bacon processing and quality

    Directory of Open Access Journals (Sweden)

    Letícia Cristina COSTA E SILVA

    Full Text Available Abstract The effects of ractopamine and immunological castration on belly characteristics, processing yield, physicochemical and sensory quality of bacon were investigated from two crossbred pigs under different conditions of animal production, diet, management and slaughter arranged in factorial design using 2 ractopamine levels (0 and 7.5 ppm and 3 genders (barrows, immunocastrated and gilts. Before processing, belly firmness, weight, length, width and thickness were measured, and then, bacon processing yield evaluated. After processing, bacon slices were digitally imaged and analyzed for lean meat and fat areas, pH, instrumental color of meat and fat, cooking loss and sensory quality. The ractopamine did not alter belly characteristics, but significantly increased the process yield and decreased cooking loss. Barrows and immunocastrated pigs showed firmer bellies, which could be advantageous for bacon processing and slicing. Barrows presented the highest total area of bacon slices. The results of this study indicate that both techniques ractopamine in the finishing diets and immunocastration of pigs can be combined with no further consequences for belly processing and to bacon quality and with some advantages.

  6. Saikosaponin-d: A potential chemotherapeutics in castration resistant prostate cancer by suppressing cancer metastases and cancer stem cell phenotypes.

    Science.gov (United States)

    Zhong, Di; Zhang, Hui-Jian; Jiang, Yao-Dong; Wu, Peng; Qi, Huan; Cai, Chao; Zheng, Shao-Bin; Dang, Qiang

    2016-06-10

    Androgen deprivation therapy is the gold standard regimen for advanced Prostate cancer (PCa) patients, nevertheless, patients eventually develop into castration-resistant prostate cancer (CRPC). Currently only a few chemotherapeutics are available for CRPC. Therefore, it is critical for identifying a new drug. In this study, we will explore a new agent, Saikosaponin-d (SSd), for CRPC therapy based on its mechanism of action. DU145 and CWR22Rv1 cells representing CRPC were employed in this study. A series of cell, biochemical, and molecular biologic assays such as Immunofluorescence, Zymography, Sphere formation, Colony formation, and MTT were used. Finally, we find SSd can significantly inhibit the growth of PCa cells in both dose- and time-dependent and suppress the colony formation during a long-term drug administration, it also can inhibit their migration and invasion abilities, which was accompanied by reverse the epithelial-mesenchymal transition (EMT) and suppress MMP2/9 expression as well as activities. Furthermore, SSd can suppress cancer stem cell (CSC) phenotypes such as self-renewal ability. Mechanistically, SSd blocks Wnt/β-catenin signaling pathway by decreasing GSK3β phosphorylation to affect EMT and CSC. These findings demonstrate the mechanism of anti-cancer activity of SSd in targeting EMT and CSC, suggesting SSd can be a potent agent for CRPC therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Parasitic castration, growth, and sex steroids in the freshwater bonefish Cyphocharax gilbert (Curimatidae infested by Riggia paranensis (Cymothoidea

    Directory of Open Access Journals (Sweden)

    Neuza R. W. Lima

    Full Text Available Cyphocharax gilbert shows parasitic castration when infested by the crustacean Riggia paranensis, being unable to reproduce. Fish were sampled in the middle rio Itabapoana, Brazil, to study the prevalence of parasitism, growth, and sex steroid concentrations, considering the body size, sex, and reproductive condition of specimens. Most of the fish analyzed were infested (56.0%. The presence of two lines on the scales was more frequent among infested fish (22.0% than among fish without parasites (12.0% for females and 10.0% for males. The occurrence of three lines on the scales was rare (3.5% among infested and 2.0% among females without parasites. These results suggest that growth of the host is faster than that of non infested fish. The serum concentrations of sex steroids from fish without parasites varied at different gonadal development stages (17 beta-estradiol: 60.0 to 976.7 pg/ml; total testosterone: 220.0 to 3,887.7 pg/ml. All infested fish had lower levels of the two sex steroids and undeveloped gonads. Sex steroids levels in infested females were close to those in females at post-spawning stages. Total testosterone concentrations of infested males were below those of males at early gonadal maturation stage. These results suggest that R. paranensis reduces the reproductive capacity of C. gilbert by affecting the host endocrine system.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Complete response to ethnylestradiol prolonged for almost two years in patients with castration-resistant prostate cancer.

    Science.gov (United States)

    Hongo, Hiroshi; Kosaka, Takeo; Oya, Mototsugu

    2014-11-01

    An 80-year-old man with an elevated prostate-specific antigen (PSA) level of 120 ng/mL) presented to the hospital in February 2011. A prostate needle biopsy was performed, and pathological examination revealed prostatic adenocarcinoma. The Gleason score was 4+5=9. Computed tomography revealed metastases of the pelvic lymph nodes. Combined androgen blockade was started. The PSA concentration decreased to 1.68 ng/mL, but started increasing again in August 2012 to 6.08 ng/mL. Although bicalutamide was discontinued due to antiandrogen withdrawal syndrome, the PSA concentration increased even more. The PSA concentration reached 21.62 ng/mL in September 2012, at which time ethnylestradiol was started. The PSA concentration decreased again and has remained below the limit of sensitivity for almost 2 years. To our knowledge, this is first case report describing a complete response to ethnylestradiol that lasted for almost 2 years in a patient with castration-resistant prostate cancer.

  10. Should We Try Antiandrogen Withdrawal in Castration-Resistant Prostate Cancer Patients? Insights From a Retrospective Study.

    Science.gov (United States)

    Hongo, Hiroshi; Kosaka, Takeo; Mizuno, Ryuichi; Ezaki, Taisuke; Matsumoto, Kazuhiro; Morita, Shinya; Shinoda, Kazunobu; Shinojima, Toshiaki; Kikuchi, Eiji; Miyajima, Akira; Oya, Mototsugu

    2016-12-01

    It remains uncertain whether those with response to antiandrogen withdrawal (AAW) have a better prognosis. We investigated the predictors of a better response to AAW and overall survival after acquiring resistance to first-line androgen deprivation therapy inpatients with castration-resistant prostate cancer (CRPC). We retrospectively reviewed the medical records of 87 CRPC patients treated at Keio University Hospital. Sixty-seven of 87 CRPC patients underwent AAW. We analyzed clinicopathologic parameters to identify predictors of survival in CRPC patients and investigated predictors of good response to AAW. Younger age, longer duration of androgen deprivation therapy before CRPC development, and better response to AAW were independent favorable prognostic factors for overall survival. Although better response to AAW was a favorable prognostic factor in this study, trying AAW was not significantly related to overall survival. Duration of hormone therapy was significantly longer in those whose disease responded to AAW (69.9 ± 11.0 months) than those with no response (45.3 ± 5.2 months). The prognostic benefit of AAW was not clearly determined in this study. However, AAW might be beneficial in patients who have favorable prognostic factors for a response to AAW-that is, those who have received hormone therapy for a long period. However, AAW should not be done in patients who do not have favorable factors and who had a high prostate-specific antigen level at the time of their prostate cancer diagnosis. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. The Influence of Prednisone on the Efficacy of Cabazitaxel in Men with Metastatic Castration-Resistant Prostate Cancer

    Science.gov (United States)

    Buonerba, Carlo; Sonpavde, Guru; Vitrone, Francesca; Bosso, Davide; Puglia, Livio; Izzo, Michela; Iaccarino, Simona; Scafuri, Luca; Muratore, Margherita; Foschini, Francesca; Mucci, Brigitta; Tortora, Vincenzo; Pagliuca, Martina; Ribera, Dario; Riccio, Vittorio; Morra, Rocco; Mosca, Mirta; Cesarano, Nicola; Di Costanzo, Ileana; De Placido, Sabino; Di Lorenzo, Giuseppe

    2017-01-01

    Background: Cabazitaxel is a second-generation taxane that is approved for use with concomitant low dose daily prednisone in metastatic castration resistant prostate cancer (mCRPC) after docetaxel failure. Since the role of daily corticosteroids in improving cabazitaxel efficacy or ameliorating its safety profile has not been adequately investigated so far, we compared outcomes of patients receiving cabazitaxel with or without daily corticosteroids in a retrospective single-Institution cohort of mCRPC patients. Patients and methods: Medical records of deceased patients with documented mCRPC treated with cabazitaxel following prior docetaxel between January, 2011 and January, 2017 were reviewed at the single participating center. Patients who were receiving daily doses of systemic corticosteroids other than low dose daily prednisone or prednisolone (30% PSA decline at 12 weeks. Prednisone use was not significantly prognostic for overall survival or PSA decline ≥30% rates on regression analyses. Importantly, a >30% PSA decline at 12, but not at 3, 6, 9 weeks, was prognostic for improved survival at multivariate analysis Conclusions: The data presented here support the hypothesis that omitting daily corticosteroids in cabazitaxel-treated patients has no negative impact on either survival or safety profile. In the large prospective trial CABACARE, cabazitaxel-treated patients will be randomized to receive or not receive daily prednisone. The CABACARE (EudraCT n. 2016-003646-81) study is currently ongoing at University Federico II of Naples and at other multiple participating centers in Italy. PMID:28928853

  12. Inhibition of Androgen Receptor Nuclear Localization and Castration-Resistant Prostate Tumor Growth by Pyrroloimidazole-based Small Molecules.

    Science.gov (United States)

    Masoodi, Khalid Z; Xu, Yadong; Dar, Javid A; Eisermann, Kurtis; Pascal, Laura E; Parrinello, Erica; Ai, Junkui; Johnston, Paul A; Nelson, Joel B; Wipf, Peter; Wang, Zhou

    2017-10-01

    The androgen receptor (AR) is a ligand-dependent transcription factor that controls the expression of androgen-responsive genes. A key step in androgen action, which is amplified in castration-resistant prostate cancer (CRPC), is AR nuclear translocation. Small molecules capable of inhibiting AR nuclear localization could be developed as novel therapeutics for CRPC. We developed a high-throughput screen and identified two structurally-related pyrroloimidazoles that could block AR nuclear localization in CRPC cells. We show that these two small molecules, 3-(4-ethoxyphenyl)-6,7-dihydro-5 H -pyrrolo[1,2- a ]imidazole (EPPI) and 3-(4-chlorophenyl)-6,7-dihydro-5 H -pyrrolo[1,2- a ]imidazole (CPPI) can inhibit the nuclear localization and transcriptional activity of AR and reduce the proliferation of AR-positive but not AR-negative prostate cancer cell lines. EPPI and CPPI did not inhibit nuclear localization of the glucocorticoid receptor or the estrogen receptor, suggesting they selectively target AR. In LNCaP tumor xenografts, CPPI inhibited the proliferation of relapsed LNCaP tumors. These findings suggest that EPPI and CPPI could serve as lead structures for the development of therapeutic agents for CRPC. Mol Cancer Ther; 16(10); 2120-9. ©2017 AACR . ©2017 American Association for Cancer Research.

  13. Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Zhao, Yu; Wang, Liguo; Ren, Shancheng; Wang, Lan; Blackburn, Patrick R; McNulty, Melissa S; Gao, Xu; Qiao, Meng; Vessella, Robert L; Kohli, Manish; Zhang, Jun; Karnes, R Jeffrey; Tindall, Donald J; Kim, Youngsoo; MacLeod, Robert; Ekker, Stephen C; Kang, Tiebang; Sun, Yinghao; Huang, Haojie

    2016-04-19

    The androgen receptor (AR) is required for castration-resistant prostate cancer (CRPC) progression, but the function and disease relevance of AR-bound enhancers remain unclear. Here, we identify a group of AR-regulated enhancer RNAs (e.g., PSA eRNA) that are upregulated in CRPC cells, patient-derived xenografts (PDXs), and patient tissues. PSA eRNA binds to CYCLIN T1, activates P-TEFb, and promotes cis and trans target gene transcription by increasing serine-2 phosphorylation of RNA polymerase II (Pol II-Ser2p). We define an HIV-1 TAR RNA-like (TAR-L) motif in PSA eRNA that is required for CYCLIN T1 binding. Using TALEN-mediated gene editing we further demonstrate that this motif is essential for increased Pol II-Ser2p occupancy levels and CRPC cell growth. We have uncovered a P-TEFb activation mechanism and reveal altered eRNA expression that is related to abnormal AR function and may potentially be a therapeutic target in CRPC. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  14. Activation of P-TEFb by Androgen Receptor-Regulated Enhancer RNAs in Castration-Resistant Prostate Cancer

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    Yu Zhao

    2016-04-01

    Full Text Available The androgen receptor (AR is required for castration-resistant prostate cancer (CRPC progression, but the function and disease relevance of AR-bound enhancers remain unclear. Here, we identify a group of AR-regulated enhancer RNAs (e.g., PSA eRNA that are upregulated in CRPC cells, patient-derived xenografts (PDXs, and patient tissues. PSA eRNA binds to CYCLIN T1, activates P-TEFb, and promotes cis and trans target gene transcription by increasing serine-2 phosphorylation of RNA polymerase II (Pol II-Ser2p. We define an HIV-1 TAR RNA-like (TAR-L motif in PSA eRNA that is required for CYCLIN T1 binding. Using TALEN-mediated gene editing we further demonstrate that this motif is essential for increased Pol II-Ser2p occupancy levels and CRPC cell growth. We have uncovered a P-TEFb activation mechanism and reveal altered eRNA expression that is related to abnormal AR function and may potentially be a therapeutic target in CRPC.

  15. Effects of extract of Buddleja officinalis on partial inflammation of lacrimal gland in castrated rabbits with dry eye.

    Science.gov (United States)

    Yao, Xiao-Lei; Peng, Qing-Hua; Peng, Jun; Tan, Han-Yu; Wu, Quan-Long; Wu, Da-Li; Chen, Mei; Li, Chuan-Ke; Li, Dian; Zhu, Hui-An

    2010-01-01

    To assess the effects of extract of Buddleja officinalis on tear secretion volume, tear film stability, expressions of TGF-β1, IL-1β, TNF-α in lacrimal gland of castrated rabbits with dry eye. A total of 30 victory rabbits were divided averagely into normal group(A), model group(B), therapy group with low dose extract of Buddleja officinalis (C), therapy group with high dose extract of Buddleja officinalis (D) and therapy group with genistein (E). The dry eye model was established with orchiectomy on Group B, C, D, E. Group C, D, E were administered intragastrically with corresponding dose extract of Buddleja officinalis or genistein for 30 days. All rabbits were detected with SIT. TGF-β1, IL-1β, TNF-α were detected with immunohistochemistry and the ultrastructure of lacrimal gland was observed under transmission electron microscope. The SIT value of group C, D, E were respectively 13.167±4.957, 14.667±5.279, 8.667±0.516, obviously higher than that of group B 5.667±2.338 (PBuddleja officinalis can adjust lacrimal gland partial inflammation of dry eye.

  16. Effects of eye drops of Buddleja officinalis Maxim. extract on lacrimal gland cell apoptosis in castrated rats with dry eye.

    Science.gov (United States)

    Peng, Qing-hua; Yao, Xiao-lei; Wu, Quan-long; Tan, Han-yu; Zhang, Jing-rong

    2010-03-01

    To explore the possible mechanism of eye drops of Buddleja officinalis extract in treating dry eye of castrated rats by analyzing the expressions of Bax and Bcl-2 proteins. Forty-five Wistar male rats were randomly divided into sham-operated group, untreated group and eye drops of Buddleja officinalis Maxim. extract (treatment) group. The dry eye model was established with orchiectomy in the untreated group and treatment group. Rats in the treatment group were treated with eye drops of Buddleja officinalis Maxim. extract, one drop once, three times daily. Eyes of rats in the sham-operated group and untreated group were instilled with normal saline. After one-, two-, or three-month treatment, five rats in each group were scarified respectively. Then samples were taken to detect related indices. Expressions of Bax and Bcl-2 of lacrimal gland were checked by immunohistochemical method and quantity of apoptotic cells was counted. After one-, two- or three-month treatment, the quantities of expressions of Bax in acinar epithelial cells and glandular tube cells were significantly lower, and those of Bcl-2 were significantly higher in the treatment group than in the untreated group, and the quantities of apoptotic cells of the treatment group were significantly lower than those of the untreated group (PBuddleja officinalis Maxim. are flavonoids, which can significantly inhibit cell apoptosis in lacrimal gland.

  17. Effects of ractopamine on growth performance and carcass characteristics of immunologically and physically castrated barrows and gilts.

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    Puls, C L; Ellis, M; McKeith, F K; Gaines, A M; Schroeder, A L

    2014-10-01

    The study was performed to evaluate the effect of feeding ractopamine (RAC) to physically castrated barrows (PC), immunologically castrated barrows (IC), and gilts (gilts) using a randomized complete block design with a 3 × 3 factorial arrangement of treatments: 1) sex (PC, IC, and gilts) and 2) RAC inclusion level (0, 5, and 7.5 mg/kg). The IC received 2 doses of gonadotropin releasing factor analog-diphtheria toxoid conjugate (Improvest; Zoetis, Kalamazoo, MI) at the start of the study (wk 16 of age; 69.6 ± 2.96 kg BW) and 4 wk later. The study used 180 pigs housed in groups of 4 (5 groups/sex × RAC subclass) and was performed over a fixed time of 61 d with RAC being fed for the final 26 d of study. Diets were formulated to meet requirements of intact males for the first 35 d and of intact males fed 7.5 mg/kg RAC for the remainder of the study. Pigs had ad libitum access to feed and water throughout the study period. At the end of the study, pigs were harvested at a commercial facility and HCW and last rib backfat thickness were measured. There were no treatment interactions (P > 0.05) for any variables. For the overall study period, IC had greater (P ≤ 0.05) overall ADG compared to PC, which grew faster (P ≤ 0.05) than gilts (1,246, 1,083, and 1,025 g/d for IC, PC, and gilts, respectively; SEM = 20.3); ADFI was lower (P ≤ 0.05) for gilts than IC and PC, which had similar ADFI (3.36, 3.37, and 2.87 kg/d, respectively; SEM = 0.051); and G:F was greater (P ≤ 0.05) for IC than gilts and greater for gilts than PC (0.371, 0.322, and 0.358 kg/kg, respectively; SEM = 0.0039). For the period from the second dose to the end of study, IC had greater (P ≤ 0.05) ADG (28.6%), ADFI (12.3%), and G:F (14.3%) than PC. Carcass yield was lower (P ≤ 0.05) for IC compared to PC and gilts (72.8, 75.0, and 74.6%, respectively; SEM = 0.25). Feeding RAC increased (P ≤ 0.05) ADG (15.7 and 14.5% for 5 and 7.5 mg/kg, respectively), G:F (17.1 and 16.4%, respectively

  18. Multiple phenotypes of prostatic glandular cells in castrated dogs after individual or combined treatment with androgen and estrogen. Morphometric, ultrastructural, and cytochemical distinctions.

    Science.gov (United States)

    Merk, F B; Warhol, M J; Kwan, P W; Leav, I; Alroy, J; Ofner, P; Pinkus, G S

    1986-04-01

    To demonstrate a potential for multidirectional differentiation in mature prostatic epithelium, 17 beta-estradiol 17-cyclopentylpropionate (ECP) and 5 alpha-androstane-3 alpha, 17 beta-diol dipropionate (3 alpha-diol DP) were administered individually and in combination to castrated dogs. Quantitative ultrastructural and cytochemical methods were used to distinguish phenotypes of glandular cells in the various hormonal environments. Castration-induced glandular cell regression was accompanied by an increased nuclear to cytoplasmic ratio; by enhanced keratin positivity, expressed as dispersed immunolabeled tonofilaments; and by an absence of peanut agglutinin (PNA) binding sites on luminal membranes. Administration of ECP resulted in squamous metaplasia as well as hypertrophy of the glandular epithelium. The hypertrophied estrogen-modified glandular (EMG) cells were characterized by a new population of small (0.29 micron in diameter) secretory granules, bundles of tonofilaments, and PNA-positive luminal membranes. Treatment of castrated dogs with 3 alpha-diol DP produced a greater epithelial hypertrophy than ECP. These cells were characterized by larger (0.49 micron in diameter) secretory granules, dispersed tonofilaments, and no detectable PNA receptors. Joint administration of ECP and 3 alpha-diol DP caused a florid response including squamous metaplasia and hypertrophy of the glandular epithelium which was associated with the emergence of a novel phenotype in androgen-estrogen modified glandular (A-EMG) cells. In A-EMG cells, secretory granules were similar in size to those found in 3 alpha-diol DP-dominated epithelium whereas tonofilaments often appeared in bundles and luminal membranes were PNA positive, i.e., features found in EMG cells. Our results indicate that atrophic canine prostatic glandular cells possess pluripotentiality of response to sex hormones.

  19. TMPRSS2- driven ERG expression in vivo increases self-renewal and maintains expression in a castration resistant subpopulation.

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    Orla M Casey

    Full Text Available Genomic rearrangements commonly occur in many types of cancers and often initiate or alter the progression of disease. Here we describe an in vivo mouse model that recapitulates the most frequent rearrangement in prostate cancer, the fusion of the promoter region of TMPRSS2 with the coding region of the transcription factor, ERG. A recombinant bacterial artificial chromosome including an extended TMPRSS2 promoter driving genomic ERG was constructed and used for transgenesis in mice. TMPRSS2-ERG expression was evaluated in tissue sections and FACS-fractionated prostate cell populations. In addition to the anticipated expression in luminal cells, TMPRSS2-ERG was similarly expressed in the Sca-1(hi/EpCAM(+ basal/progenitor fraction, where expanded numbers of clonogenic self-renewing progenitors were found, as assayed by in vitro sphere formation. These clonogenic cells increased intrinsic self renewal in subsequent generations. In addition, ERG dependent self-renewal and invasion in vitro was demonstrated in prostate cell lines derived from the model. Clinical studies have suggested that the TMPRSS2-ERG translocation occurs early in prostate cancer development. In the model described here, the presence of the TMPRSS2-ERG fusion alone was not transforming but synergized with heterozygous Pten deletion to promote PIN. Taken together, these data suggest that one function of TMPRSS2-ERG is the expansion of self-renewing cells, which may serve as targets for subsequent mutations. Primary prostate epithelial cells demonstrated increased post transcriptional turnover of ERG compared to the TMPRSS2-ERG positive VCaP cell line, originally isolated from a prostate cancer metastasis. Finally, we determined that TMPRSS2-ERG expression occurred in both castration-sensitive and resistant prostate epithelial subpopulations, suggesting the existence of androgen-independent mechanisms of TMPRSS2 expression in prostate epithelium.

  20. Chemical composition and tenderness of longissimus dorsi muscle from non- castrated Murrah buffaloes slaughtered at different weights

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    A. de Amorim Ramos

    2010-02-01

    Full Text Available Buffalo meat production has been arising interest breeder and emerges as alternative to consumer, more and more demanding of the quality products. Thus, this research was conducted to study the chemical composition and tenderness of Longissimus dorsi muscle from 10 non-castrated Murrah buffaloes slaughtered at different weights. The research was carried in feedlot of School of Veterinary Medicine and Animal Science of the Sao Paulo State University, Botucatu, São Paulo, Brazil. Animals were divided in two groups, received diet ad libitum and slaughtered when reached 450 and 500 kg of live weight. The experiment design was completely randomized, with five repetitions to each treatment. Meat sample from Longissimus dorsi muscle, taken between 12th and 13th ribs, were carried analysis of moisture, crude protein, fat, ash, Longissimus muscle area (LMA, fat thickness (FT, marbling, calorie and tenderness. It did not have significant difference between the groups. Average values at of 76.0; 20.7; 2.1 and 1.2 of moisture, crude protein, fat and ash respectively, were obtained. Calorie, tenderness, LMA, FT and marbling were obtained at average values of 132 kcal/100g; 3.94 kgf; 34.2 cm²; 5.9 mm and 2 points, respectively. Values obtained for tenderness are similar in the literature and has been proving that buffalo meat is tender (< 5kgf. Positive correlation was observed between the protein percentage and the shear force of the meat. The buffalo meat is excellent alternative source of red protein of high biological value to feeding of Brazilian consumers.

  1. Risk of cardiovascular thrombotic events after surgical castration versus gonadotropin-releasing hormone agonists in Chinese men with prostate cancer

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    Jeremy YC Teoh

    2015-06-01

    Full Text Available We investigated the cardiovascular thrombotic risk after surgical castration (SC versus gonadotropin-releasing hormone agonists (GnRHa in Chinese men with prostate cancer. All Chinese prostate cancer patients who were treated with SC or GnRHa from year 2000 to 2009 were reviewed and compared. The primary outcome was any new-onset of cardiovascular thrombotic events after SC or GnRHa, which was defined as any event of acute myocardial infarction or ischemic stroke. The risk of new-onset cardiovascular thrombotic event was compared between the SC group and the GnRHa group using Kaplan-Meier method. Multivariate Cox regression analysis was performed to adjust for other potential confounding factors. A total of 684 Chinese patients was included in our study, including 387 patients in the SC group and 297 patients in the GnRHa group. The mean age in the SC group (75.3 ± 7.5 years was significantly higher than the GnRHa group (71.8 ± 8.3 years (P < 0.001. There was increased risk of new cardiovascular thrombotic events in the SC group when compared to the GnRHa group upon Kaplan-Meier analysis (P = 0.014. Upon multivariate Cox regression analysis, age (hazard ratio [HR] 1.072, 95% confidence interval [CI] 1.04-1.11, P< 0.001, hyperlipidemia (HR 2.455, 95% CI 1.53-3.93, P< 0.001, and SC (HR 1.648, 95% CI 1.05-2.59, P= 0.031 were significant risk factors of cardiovascular thrombotic events. In conclusion, SC was associated with increased risk of cardiovascular thrombotic events when compared to GnRHa. This is an important aspect to consider while deciding on the method of androgen deprivation therapy, especially in elderly men with known history of hyperlipidemia.

  2. Consequences of an Early PSA Response to Enzalutamide Treatment for Japanese Patients with Metastatic Castration-resistant Prostate Cancer.

    Science.gov (United States)

    Kato, Haruo; Furuya, Yosuke; Miyazawa, Yoshiyuki; Miyao, Takeshi; Syuto, Takahiro; Nomura, Masashi; Sekine, Yoshitaka; Koike, Hidekazu; Matsui, Hiroshi; Shibata, Yasuhiro; Ito, Kazuto; Suzuki, Kazuhiro

    2016-11-01

    Recent studies have shown that an early prostate-specific antigen (PSA) response to androgen receptor (AR)-targeting agents in metastatic castration-resistant prostate cancer (mCRPC) is associated with a better prognosis. We analyzed early PSA response to enzalutamide and oncological outcomes to study their prognostic significance in the Japanese population. Fifty-one patients with mCRPC (26 of pre-docetaxel and 25 of post-docetaxel status) were treated with enzalutamide. The PSA progression-free survival (PFS), radiographic PFS (rPFS) and overall survival (OS) were assessed. The association of rPFS and OS in patients with an early PSA response at 4 weeks after commencement of enzalutamide was studied. Early PSA responses were significantly associated with a longer rPFS (median of 47.9 vs. 20.1 weeks, pPSA response; median of 40.9 vs. 20.1 weeks, p=0.016, in patients exhibiting a 30% PSA response). OS was also significantly associated with an early PSA response (p=0.002 for patients exhibiting a 50% PSA response, p=0.003 for patients exhibiting a 30% PSA response). Multivariate analysis showed that the predictors of a 50% PSA response were an interval to mCRPC and a docetaxel treatment history, while the predictor of a 30% PSA response was a docetaxel treatment history. Furthermore, a 50% PSA response was independently prognostic of rPFS. An early PSA response to enzalutamide was significantly associated with a longer rPFS and OS. This information will aid in the management of patients treated with enzalutamide. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  3. Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer: post hoc analysis of PREVAIL.

    Science.gov (United States)

    Bryce, A H; Alumkal, J J; Armstrong, A; Higano, C S; Iversen, P; Sternberg, C N; Rathkopf, D; Loriot, Y; de Bono, J; Tombal, B; Abhyankar, S; Lin, P; Krivoshik, A; Phung, D; Beer, T M

    2017-06-01

    Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA monitoring alone to determine disease status on therapy. This approach has not been adequately tested. Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide in the PREVAIL study were analyzed post hoc for rising versus nonrising PSA (empirically defined as >1.05 vs ⩽1.05 times the PSA level from 3 months earlier) at the time of radiographic progression. Clinical characteristics and disease outcomes were compared between the rising and nonrising PSA groups. Of 265 PREVAIL patients with radiographic progression and evaluable PSA levels on the enzalutamide arm, nearly one-quarter had a nonrising PSA. Median progression-free survival in this cohort was 8.3 months versus 11.1 months in the rising PSA cohort (hazard ratio 1.68; 95% confidence interval 1.26-2.23); overall survival was similar between the two groups, although less than half of patients in either group were still at risk at 24 months. Baseline clinical characteristics of the two groups were similar. Non-rising PSA at radiographic progression is a common phenomenon in mCRPC patients treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant on serial serum PSA measurement may more accurately identify disease progression.

  4. Effects of ractopamine administration and castration method on the response to preslaughter stress and carcass and meat quality in pigs of two Piétrain genotypes.

    Science.gov (United States)

    Rocha, L M; Bridi, A M; Foury, A; Mormède, P; Weschenfelder, A V; Devillers, N; Bertoloni, W; Faucitano, L

    2013-08-01

    The objective of this study was to evaluate the effects of ractopamine supplementation, castration method, and their interaction on the behavioral and physiological response to preslaughter stress and carcass and meat quality of 2 Piétrain genotypes. A total of 1,488 male pigs (115 ± 5 kg BW) were distributed according to a 2 × 2 × 2 factorial arrangement of treatments. The first factor was ractopamine supplementation with 2 groups of pigs (376 and 380 pigs each) receiving 7.5 mg/kg of ractopamine (RAC) or not (NRAC) in their diet during the last 28 d of the finishing period. The second factor was castration method, with 744 surgical castrates (SC) and 744 immunized males (IM), and the third factor was the genotype with 2 crossbreeds containing 50% (genotype A, GA; n = 744) or 25% (genotype B, GB; n = 744) Piétrain genetics. Surgical castration took place at 2 d of age, whereas immunization against gonadotropin-releasing factor (GnRF) was performed through 2 subcutaneous injections of GnRF analog (Improvest, 2 mL) at 10 and 4 wk before slaughter. At loading more vocal stimulation was needed by the handler to drive GB pigs forward through the farm alley (P = 0.01) and RAC-fed GB pigs through the ramp (P = 0.02). Feeding RAC to IM increased the number of fights in lairage compared with SC (P = 0.03). Feeding RAC shortened fighting bouts compared with NRAC pigs (P = 0.05). The SC-GA pigs showed a greater gastrointestinal tract temperature during unloading (P = 0.05) and lairage time (P = 0.03). Blood creatine kinase (CK) concentrations were greater (P = 0.04) in SC compared with IM, and no difference was found in the concentrations of stress hormones in urine collected postmortem. Dressing yield was greater (P = 0.01) in RAC and SC-GB pigs. Carcasses from RAC pigs and IM were leaner than those from NRAC and SC pigs (P ractopamine, as it seems to promote production of lean carcasses without compromising animal welfare and pork quality.

  5. Effects of feeding ractopamine hydrochloride (Paylean) to physical and immunological castrates (Improvest) in a commercial setting on carcass cutting yields and loin quality.

    Science.gov (United States)

    Lowe, B K; Gerlemann, G D; Carr, S N; Rincker, P J; Schroeder, A L; Petry, D B; McKeith, F K; Allee, G L; Dilger, A C

    2014-08-01

    Effects of feeding ractopamine (RAC; 5 mg/kg) to physically castrated (PC) and immunologically castrated (IC) pigs on carcass characteristics, cutting yields, and loin quality were evaluated using 285 carcasses. Male pigs were randomly assigned to sex treatments (PC and IC) at birth and fed the same nursery diets before allotment into 32 pens with 22 pigs per pen in a grow-finish barn. Pigs in the PC group were physically castrated at approximately 5 d of age, and pigs in the IC group were administered Improvest at 11 and 18 wk of age. Diet treatments (control or RAC) were initiated on study d 87. Pigs were marketed at 12 d (4.5 wk post-second Improvest dose), 19 d (5.5 wk post-second Improvest dose), and 33 d (7.5 wk post-second Improvest dose) following the start of final diet treatments. Three carcasses per pen were selected for evaluation of cutting yields and loin quality. Data were analyzed using PROC MIXED in SAS with fixed effects of sex, diet, market group, and their interaction; carcass (N = 285) was the experimental unit. Carcasses from RAC-fed pigs were heavier (P 0.05) between RAC-fed and control-fed carcasses when evaluating LM color, marbling, firmness, pH, drip loss, and tenderness. Carcasses from IC pigs had greater (P < 0.05) boneless lean yields, bone-in lean yields, and total carcass cutting yields than PC carcasses. There were minimal differences (P < 0.05) in LM marbling, firmness, composition, and tenderness between PC and IC pigs. There was an interaction (P = 0.03) between sex and diet for LM composition. Control-fed PC loins had more (P < 0.01) lipid than all other treatment combinations. Market group had effects (P < 0.05) on carcass cutting yields, LM color, marbling and firmness scores, pH, purge loss, composition, and tenderness. The results from this study indicated RAC and immunological castration were additive in terms of improving carcass cutting yields while having minimal effects on pork quality.

  6. Transcriptome analysis of mRNA and microRNAs in intramuscular fat tissues of castrated and intact male Chinese Qinchuan cattle.

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    Ying-Ying Zhang

    Full Text Available Intramuscular fat (IMF is known to enhance beef palatability and can be markedly increased by castration. However, there is little understanding of the molecular mechanism underlying the IMF deposition after castration of beef cattle. We hypothesize that genetic regulators function differently in IMF from bulls and steers. Therefore, after detecting serum testosterone and lipid parameter, as well as the contents of IMF at 6, 12, 18 and 24 months, we have investigated differentially expressed (DE microRNAs (miRNAs and mRNAs in IMF of bulls and steers at 24 months of age in Qinchuan cattle using next-generation sequencing, and then explored the possible biopathways regulating IMF deposition. Serum testosterone levels were significantly decreased in steers, whereas IMF content, serum total cholesterol (TC, low-density lipoprotein cholesterol (LDL-C and triglycerides (TGs were markedly increased in steers. Comparing the results of steers and bulls, 580 upregulated genes and 1,120 downregulated genes in IMF tissues were identified as DE genes correlated with IMF deposition. The upregulated genes were mainly associated with lipid metabolism, lipogenesis and fatty acid transportation signalling pathways, and the downregulated genes were correlated with immune response and intracellular signal transduction. Concurrently, the DE miRNAs-important players in adipose tissue accumulation induced by castration-were also examined in IMF tissues; 52 DE miRNAs were identified. The expression profiles of selected genes and miRNAs were also confirmed by quantitative real-time PCR (qRT-PCR assays. Using integrated analysis, we constructed the microRNA-target regulatory network which was supported by target validation using the dual luciferase reporter system. Moreover, Ingenuity Pathway Analysis (IPA software was used to construct a molecular interaction network that could be involved in regulating IMF after castration. The detected molecular network is closely

  7. Subcutaneous testosterone transport characteristics in castrated Wister rats with controlled drug delivery composites containing poly(ethylene glycol)(Msub(n)=1900-2100)

    International Nuclear Information System (INIS)

    Yoshida, Masaru; Asano, Masaharu; Kaetsu, Isao; Yamanaka, Hidetoshi; Nakai, Katsuyuki; Yasuda, Hisako; Shida, Keizo.

    1984-01-01

    The radiation polymerized testosterone-vinyl ester copolymer delivery composites containing poly(ethylene glycol)(Msub(n)=1900-2100) as a transportable promoter were implanted subcutaneously in castrated Wistar rats over a period of at most 90 days. The in vivo cumulative amounts of testosterone released from the above composite on the 7th, 30th, and 90th day from implantation were 498, 2120, and 6913μg, respectively. These values were about 3.2 times larger than those released in vivo from the composites containing no poly(ethylene glycol). The comparison of in vitro and in vivo cumulative amounts of testosterone released from polyethylene glycol-containing composites showed that the in vivo cumulative amount of released drug was about 2 times larger than that in vitro. It was concluded from these results that poly(ethylene glycol) effectively acted as a drug-transportable promoter when the composite was implanted subcutaneously in rats. This is also suggested from the results of serum testosterone concentration and physiological response (as a measure of changes in weight of the ventral prostates) in castrated rats with drug delivery composites. (author)

  8. The effect of estrogen on the sexual interest of castrated males: Implications to prostate cancer patients on androgen-deprivation therapy.

    Science.gov (United States)

    Wibowo, Erik; Wassersug, Richard J

    2013-09-01

    Androgen deprivation therapy (ADT) for prostate cancer (PCa) treatment causes sexual dysfunction. We review here the effects of estrogen on the sexual performance of androgen-deprived males. The major findings are: 1. Estrogen receptors are present in brain centers that are important for sexual behavior; as well as in male reproductive organs, in a pattern suggesting that estrogen may have some role in orgasmic function and genital skin sensitivity. 2. Estrogen restores sexual interest above castrate levels in many vertebrates including reptiles, birds and mammals; but multiple factors contribute to the magnitude of this effect. 3. Data from castrated men, aromatase-deficient men, male-to-female transsexuals, and men on antiandrogens all suggest that estrogen can maintain some libido in androgen-deprived men. We discuss the general benefits of estrogen therapy to quality of life of men on ADT, the potential risks of this treatment, and possible treatment regimes for estrogen therapy in males. Unless contraindicated, we propose that PCa patients on ADT would benefit from supplemental parenteral estrogen. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  9. The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Maryam Ghotbaddini

    2015-07-01

    Full Text Available The reported biological effects of TCDD include induction of drug metabolizing enzymes, wasting syndrome and tumor promotion. TCDD elicits most of its effects through binding the aryl hydrocarbon receptor (AhR. TCDD induced degradation of AhR has been widely reported and requires ubiquitination of the protein. The rapid depletion of AhR following TCDD activation serves as a mechanism to modulate AhR mediated gene induction. In addition to inducing AhR degradation, TCDD has been reported to induce degradation of hormone receptors. The studies reported here, evaluate the effect of TCDD exposure on androgen receptor (AR expression and activity in androgen-sensitive LNCaP and castration-resistant C4-2 prostate cancer cells. Our results show that TCDD exposure does not induce AhR or AR degradation in C4-2 cells. However, both AhR and AR are degraded in LNCaP cells following TCDD exposure. In addition, TCDD enhances AR phosphorylation and induces expression of AR responsive genes in LNCaP cells. Our data reveals that TCDD effect on AR expression and activity differs in androgen-sensitive and castration-resistant prostate cancer cell models.

  10. Effect of testosterone supplementation on nitroso-redox imbalance, cardiac metabolism markers, and S100 proteins expression in the heart of castrated male rats.

    Science.gov (United States)

    Regouat, N; Cheboub, A; Benahmed, M; Belarbi, A; Hadj-Bekkouche, F

    2018-01-01

    The aim of this study was to investigate the effects of castration and testosterone supplementation on nitroso-redox status, cardiac metabolism markers, and S100 proteins expression in the heart of male rats. 50 male Wistar rats were randomized into five groups with ten animals each: group 1: control intact (CON); group 2: sham operated (Sh-O); group 3: sesame oil-treated rats (S-oil); group 4: gonadoectomized (GDX); and group 5: gonadoectomized rats treated with testosterone (GDX-T) for 8 weeks. Our results showed myofibrillar weaving, apoptosis, inflammation, and fibrosis (as reflected by increased activity of MMP 9 and MMP 2) in the heart of gonadoectomized rats. Testosterone supplementation restored the normal structure of the heart. In addition, a state of nitroso-redox imbalance was observed in the heart of castrated rats with increased NO (425.1 ± 322.8 vs. 208 ± 67.06, p ˂ 0.05) and MDA (33.18 ± 9.45 vs. 22.04 ± 7.13, p ˂ 0.05) and decreased GSH levels (0.71 ± 0.13 vs. 1.09 ± 0.19, p = 0.001). Testosterone treatment leads to a re-establish of only NO levels (425.1 ± 322.8 vs. 210.4 ± 114.3, p > 0.05). Markers of cardiac metabolism showed an enhancement of LDH activity (12725 ± 4604 vs. 5381 ± 3122, p ˂ 0.05) in the heart of castrated rats. This was inversed by testosterone replacement (12725 ± 4604 vs. 5781 ± 5187, p ˂ 0.05). Furthermore, castration induced heart's accumulation of triglycerides (37.24 ± 6.17 vs. 27.88 ± 6.47, p ˂ 0.05) and total cholesterol (61.44 ± 3.59 vs. 54.11 ± 7.55, p ˂ 0.05), which were significantly reduced by testosterone supplementation (29.03 ± 2.47 vs. 37.24 ± 6.17, p ˂ 0.05) and (47.9 ± 4.15 vs. 61.44 ± 3.59, p ˂ 0.001). Cardiomyocytes of castrated rats showed a decreased immunoexpression of S100 proteins compared to control animals. A restoration of S100 proteins immunostaining in cardiomyocyte cytoplasm was observed after testosterone

  11. Circulating tumor cells in patients with metastatic castration resistant prostate cancer: exploratory findings at a tertiary referral hospital

    Directory of Open Access Journals (Sweden)

    Fosså SD

    2014-09-01

    Full Text Available Sophie D Fosså,1 Siri L Hess,1 Elisabeth Paus,2 Elin Borgen3 1National Resource Center for Late Effects after Cancer Treatment, 2Department of Medical Biochemistry, 3Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Radiumhospital, Oslo, Norway Objectives: In patients with metastatic castration-resistant prostate cancer (mCRPC, the finding of less than five circulating tumor cells (CTCs/7.5 mL blood before start of cytotoxic treatment or shortly thereafter indicates prolonged survival. In this descriptive pilot study, we investigated whether this association depends on the sequence of the therapeutic attempts. Patients and methods: CTCs were determined in 41 mCRPC patients before and 2–3 months after starting first-line treatment with docetaxel (group 1 or second-line treatment with either radium-223 (group 2 or placebo/best supportive care (group 3. A "favorable" CTC count was defined as <5 CTC/7.5 mL blood. The results were related to overall survival. Results: Pretreatment, six of ten men in group 1, three of 19 in group 2, and three of 12 patients in group 3 had a favorable CTC count, leading to a significant difference between first- and second-line therapy (P=0.04. Decrease of pretreatment elevated CTCs to a favorable CTC count was significantly more often observed in patients on first-line therapy (three of four patients than on second-line treatment (two of 26 men (P=0.03. A favorable CTC count before or shortly after treatment start was observed in nine of ten patients on first-line and in eight of 31 men on second-line therapy (P=0.01. A favorable CTC count pretreatment or 2–3 months after therapy start was associated with beneficial overall survival in the three groups combined and in each group analyzed separately. Conclusion: In mCRPC, a favorable CTC count before or 2–3 months after start of therapy is associated with length of overall survival, though such favorable CTC counts are observed

  12. Src promotes castration-recurrent prostate cancer through androgen receptor-dependent canonical and non-canonical transcriptional signatures.

    Science.gov (United States)

    Chattopadhyay, Indranil; Wang, Jianmin; Qin, Maochun; Gao, Lingqiu; Holtz, Renae; Vessella, Robert L; Leach, Robert W; Gelman, Irwin H

    2017-02-07

    Progression of prostate cancer (PC) to castration-recurrent growth (CRPC) remains dependent on sustained expression and transcriptional activity of the androgen receptor (AR). A major mechanism contributing to CRPC progression is through the direct phosphorylation and activation of AR by Src-family (SFK) and ACK1 tyrosine kinases. However, the AR-dependent transcriptional networks activated by Src during CRPC progression have not been elucidated. Here, we show that activated Src (Src527F) induces androgen-independent growth in human LNCaP cells, concomitant with its ability to induce proliferation/survival genes normally induced by dihydrotestosterone (DHT) in androgen-dependent LNCaP and VCaP cells. Src induces additional gene signatures unique to CRPC cell lines, LNCaP-C4-2 and CWR22Rv1, and to CRPC LuCaP35.1 xenografts. By comparing the Src-induced AR-cistrome and/or transcriptome in LNCaP to those in CRPC and LuCaP35.1 tumors, we identified an 11-gene Src-regulated CRPC signature consisting of AR-dependent, AR binding site (ARBS)-associated genes whose expression is altered by DHT in LNCaP[Src527F] but not in LNCaP cells. The differential expression of a subset (DPP4, BCAT1, CNTNAP4, CDH3) correlates with earlier PC metastasis onset and poorer survival, with the expression of BCAT1 required for Src-induced androgen-independent proliferation. Lastly, Src enhances AR binding to non-canonical ARBS enriched for FOXO1, TOP2B and ZNF217 binding motifs; cooperative AR/TOP2B binding to a non-canonical ARBS was both Src- and DHT-sensitive and correlated with increased levels of Src-induced phosphotyrosyl-TOP2B. These data suggest that CRPC progression is facilitated via Src-induced sensitization of AR to intracrine androgen levels, resulting in the engagement of canonical and non-canonical ARBS-dependent gene signatures.

  13. 177Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer: safety, efficacy, and quality of life assessment

    International Nuclear Information System (INIS)

    Yadav, Madhav Prasad; Ballal, Sanjana; Tripathi, Madhavi; Damle, Nishikant Avinash; Bal, Chandrasekhar; Sahoo, Ranjit Kumar; Seth, Amlesh

    2017-01-01

    The purpose of this study was to evaluate the efficacy and safety of a novel theranostic agent, 177 Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer (mCRPC). Thirty-one mCRPC patients with progressive disease despite second-line hormonal therapy and/or docetaxel chemotherapy were recruited for the study. All patients underwent diagnostic 68 Ga-PSMA-HBED-CCPET/CT, prior to inclusion for therapy. Included patients then underwent quarterly 177 Lu-DKFZ-PSMA-617 therapy. Hematological, kidney function, liver function tests, and serum PSA levels were recorded before and after therapy at 2 weeks, 4 weeks, and 3 month intervals. Biochemical response was assessed with trend in serum PSA levels. Metabolic response was assessed by PERCIST 1 criteria. Clinical response was assessed by visual analogue score (VASmax) analgesic score (AS), Karanofsky performance status (KPS), and toxicity and response criteria of the Eastern Cooperative Oncology Group (ECOG) criteria. The mean age of patients was 65.93 ± 9.77 years (range: 38-81 years). The mean activity administered in the 31 patients was 5069 ± 1845 MBq ranging from one to four cycles. There was a decline in the mean serum PSA levels from the baseline (baseline: 275 ng/mL, post 1st cycle therapy: 141.75 ng/mL). Based on biochemical response criteria 2/31, 20/31, 3/31, and 6/31 had complete response (CR), partial response(PR), stable disease (SD), and progressive disease (PD), respectively. Metabolic response revealed 2/6 patients with CR, and the remaining 3/6 patients with PR and 1/6 patients with SD. The mean VASmax score decreased from 7.5 to 3. The mean analgesic score decreased from 2.5 to 1.8 after therapy. The mean KPS score improved from 50.32 to 65.42 after therapies. The mean ECOG performance status improved from 2.54 to 1.78 after therapy. Two patients experienced grade I and grade II hemoglobin toxicity each. None of the patients experienced nephrotoxicity or hepatotoxicity. 177 Lu

  14. {sup 177}Lu-PSMA-617 radioligand therapy and outcome in patients with metastasized castration-resistant prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Braeuer, Axel; Grubert, Lena Sophie; Roll, Wolfgang; Schaefers, Michael; Rahbar, Kambiz [University Hospital Muenster, Department of Nuclear Medicine, Muenster (Germany); Schrader, Andres Jan; Boegemann, Martin [University Hospital Muenster, Department of Urology, Muenster (Germany)

    2017-09-15

    Radioligand therapies targeting prostate-specific membrane antigen (PSMA) have been established for the treatment of metastasized castration-resistant prostate cancer (mCRPC) in the last decade and show promising response rates and a favourable toxicity profile. The aim of this study was to evaluate the overall survival (OS) and to identify parameters predicting outcome in mCRPC patients treated with {sup 177}Lu-PSMA-617. Between December 2014 and January 2017, 59 consecutive patients (median age 72 years); interquartile range, (IQR, 66-76 years) with mCRPC, who had been treated with at least one next-generation antihormonal drug as well as chemotherapy, were included in this study. Biochemical response was evaluated using Prostate Cancer Working Group 3 (PCWG3) criteria. Survival was evaluated using Kaplan-Meier estimates and Cox regression proportional hazards model. Toxicity was assessed using Common Toxicity Criteria for Adverse Events (CTCAE). The study was approved by the local ethics committee. The 59 patients were treated with a total of 159 cycles (median 3 cycles, range 1-7) of {sup 177}Lu-PSMA-617 (median dose 6.11 GBq, IQR 5.9-6.3 GBq). The median follow-up was 24 weeks (IQR 15-36 weeks). Follow-up data for at least 12 weeks (PCWG3) were available in 76% (45) of the patients. For outcome results data from all patients treated with at least one cycle were analysed. A decline in prostate-specific antigen (PSA) of ≥50% occurred in 53%, and a decline in PSA of any amount in 91% of patients. The estimated median OS was 32 weeks. An initial alkaline phosphatase (ALP) level <220 U/L and a PSA decline after the first cycle were associated with a longer OS (56 vs. 28 weeks, p < 0.01, and 56 vs. 29 weeks, p = 0.04, respectively). The median estimated PSA progression-free survival (PPFS) was 18 weeks. Only ALP level <220 U/L was significantly associated with a longer PPFS (41 vs. 18 weeks, p < 0.01). A PSA decline after the first cycle of {sup 177}Lu-PSMA-617

  15. Long-term clinical impact of PSA surge in castration-resistant prostate cancer patients treated with abiraterone.

    Science.gov (United States)

    Conteduca, Vincenza; Caffo, Orazio; Lolli, Cristian; Aieta, Michele; Scarpi, Emanuela; Bianchi, Emanuela; Maines, Francesca; Schepisi, Giuseppe; Salvi, Samanta; Massari, Francesco; Carrozza, Francesco; Veccia, Antonello; Chiuri, Vincenzo E; Campadelli, Enrico; Facchini, Gaetano; De Giorgi, Ugo

    2017-06-01

    Early changes in PSA have been evaluated in association to treatment outcome. The aim of this study was to assess PSA surge phenomenon in castration-resistant prostate cancer (CRPC) patients treated with abiraterone and to correlate those variations with long-term treatment outcome. We retrospectively evaluated 330 CRPC patients in 11 Italian hospitals, monitoring PSA levels at baseline and every 4 weeks. Other clinical, biochemical and molecular parameters were determined at baseline. We considered PSA surge as PSA increase within the first 8 weeks from starting abiraterone more than 1% from baseline followed by a PSA decline. The log-rank test was applied to compare survival between groups of patients according to PSA surge. The impact of PSA surge on survival was evaluated by Cox regression analyses. A total of 330 patients with CRPC, median age 74 years (range, 45-90), received abiraterone (281 chemotherapy-treated and 49 chemotherapy-naïve). PSA surge was observed in 20 (7%) post-chemotherapy and 2 (4%) chemotherapy-naïve patients. For overall patients presenting PSA surge, timing of PSA peak from baseline was 5 ± 1.8 weeks and PSA rise from baseline was 21 ± 18.4%. The overall median follow-up was 23 months (range 1-62). No significant differences in progression-free survival and overall survival were observed between patients with and without PSA surge (P = 0.16 and =0.86, respectively). In addition, uni- and multivariate analyses showed no baseline factors related to PSA surge. PSA surge occurs in both chemotherapy-treated and chemotherapy-naïve patients treated with abiraterone resulting, however, in no long-term impact on outcome. Physicians and patients should be aware of PSA surge challenge to prevent a premature discontinuation of potentially effective therapy with abiraterone. Further larger and prospective studies are warranted to investigate this not infrequent phenomenon. © 2017 Wiley Periodicals, Inc.

  16. Influence of abiraterone acetate on neuroendocrine differentiation in chemotherapy-naive metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Dong, Baijun; Fan, Liancheng; Wang, Yanqing; Chi, Chenfei; Ma, Xiaowei; Wang, Rui; Cai, Wen; Shao, Xiaoguang; Pan, Jiahua; Zhu, Yinjie; Shangguan, Xun; Xin, Zhixiang; Hu, Jianian; Xie, Shaowei; Kang, Xiaonan; Zhou, Lixin; Xue, Wei

    2017-05-01

    To determine the influence of abiraterone Acetate (AA) on neuroendocrine differentiation (NED) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). We conducted an analysis in 115 chemotherapy-naïve mCRPC patients who would be treated with chemotherapy. The serum levels of chromogranin A (CgA), neurone-specific enolase (NSE) were measured in 67 mCRPC patients without AA treatment and 48 patients after the failure of AA treatment, in which these markers were also measured in 34 patients before and after 6 months of AA treatment. Comparative t-test was used to evaluate the serial changes of serum NED markers during AA treatment and univariate and multivariate analyses were performed to test the influence of AA treatment on NED. Serum CgA were NSE were evaluated to be above the upper limit of normal (ULN) in 56 (48.7%) and 29 (25.2%) patients before chemotherapy. In 34 patients with serial evaluation, serum CgA level of 14 patients and NSE of 14 patients increased after the failure of AA treatment. There was no significant difference of NED markers (CgA or NSE variation (P = 0.243) between at baseline and after the failure of AA treatment. Compared with the CgA elevation group in the first 6 months of AA treatment and baseline supranormal CgA group, the CgA decline group, and baseline normal CgA group has a much longer median PSA PFS (14.34 vs 10.00 months, P < 0.001, and 14.23 vs 10.30 months, P = 0.02) and rPFS, respectively (18.33 vs 11.37 months, P < 0.001, and 17.10 vs 12.07 months, P = 0.03). In logistic univariate analysis, AA treatment and its duration were not independent factors influencing NED. We hypothesized that AA might not significantly lead to progression of NED of mCRPC in general. Furthermore, we found there was heterogeneity in changes of NED markers in different mCRPC patients during AA treatment. Serial CgA and NSE evaluation might help clinicians guide clinical treatment of m

  17. Componentes não-integrantes da carcaça de novilhos não-castrados ou castrados terminados em confinamento e abatidos aos 16 ou 26 meses de idade Non-carcass components of castrate and non-castrated cattle finished in feedlot and slaughtered at 16 or 26 months of age

    Directory of Open Access Journals (Sweden)

    Fernando Kuss

    2008-10-01

    Full Text Available Foram avaliados os componentes não-integrantes da carcaça de novilhos terminados em confinamento e abatidos aos 16 (superjovem ou 26 (jovem meses de idade. A dieta foi formulada com 50% de volumoso e 50% de concentrado e continha 11,8% de proteína bruta e 2,83 Mcal de energia digestível por kg de matéria seca. Animais superjovens apresentaram maior rendimento de corpo vazio (92,39 versus 89,76% para os jovens, como resultado de seu menor conteúdo gastrintestinal (35,23 versus 53,46 kg para os jovens. Animais não-castrados apresentaram maior peso de cabeça (13,84 versus 12,35 kg, patas (11,12 versus 8,96 kg e couro (46,44 versus 37,71 kg em comparação aos castrados, o que está relacionado ao seu maior peso corporal (541,26 versus 445,47 kg. Observou-se influência da interação categoria x condição sexual sobre o peso absoluto dos órgãos vitais (coração, fígado e pulmões e dos componentes do trato gastrintestinal. O peso total de órgãos vitais e do trato gastrintestinal foi maior nos animais não-castrados, mas deixou de ser significativo quando ajustado para peso de corpo vazio (PCV e de abate (PA. Animais superjovens apresentaram maior peso absoluto das gorduras interna (25,91 versus 20,13 kg e de toalete (13,96 versus 10,98 kg. A castração dos animais resultou em maior participação de gordura interna calculada em relação ao peso de corpo vazio e ao peso de abate.The non-carcass components of castrated and non-castrated cattle (sex condition finished in feedlot and slaughtered at 16 (super young or 26 (young months of age (animal category were evaluated. The diet was formulated to contain 11.8% of CP and 2.83 Mcal/kg DM of DE with 50:50 forage to concentrate ratio (%MS. Super young animals showed higher of empty body dressing percentage (92.39 versus 89.76%, as a result of their lower gastrointestinal content (35.23 versus 53.46 kg as compared to the young animals. Non-castrate animals showed higher head weight (13

  18. The Role of PCA 3 as a Prognostic Factor in Patients with Castration-resistant Prostate Cancer (CRPC) Treated with Docetaxel.

    Science.gov (United States)

    Bourdoumis, Andreas; Chrisofos, Michael; Stasinou, Theodora; Christopoulos, Panagiotis; Mourmouris, Panagiotis; Kostakopoulos, Athanasios; Deliveliotis, Charalambos

    2015-05-01

    To investigate potential fluctuations in prostate cancer antigen 3 (PCA 3) scores in castration-resistant prostate cancer (CRPC) patients treated with docetaxel and investigate the assay as a potential prognostic factor. This was a prospective observational cohort study. Inclusion criteria included patients on hormonal treatment who were recently diagnosed with CRPC. Exclusion criteria included patients previously having radical treatment (surgery or radiotherapy) and patients who have completed the first cycle of chemotherapy. All urine samples were collected and analyzed using the Progensa® assay. Samples were collected before starting chemotherapy and at 12 months. A prospective database was created including routine blood tests, prostate staging and prostate-specific antigen (PSA) levels throughout the study period. The effects of chemotherapy were also recorded. Between January 2010 and February 2013, 12 patients were included in the study out of an initial cohort of 23 patients with CRPC. Mean follow-up was 14.8 months. Mean age at CRPC diagnosis was 73.8 years (±3.6 SD). Mean Gleason score was 8, with PSA 84.23 ng/ml (±158 SD). Mean duration of androgen deprivation treatment (ADT) was 45.16 months (±34.9 SD). Mean time to castrate-resistant state was 46.58 months (±35.3 SD). All twelve (n=12, 100%) patients had non-assessable PCA 3 scores at baseline and at 12 months follow-up. As a direct consequence, statistical analysis was not performed as the anticipated change in PCA 3 scores was not identified and correlation between measurable differences was not possible. All patients tolerated chemotherapy and completed the scheduled cycles with no serious adverse effects. To our knowledge, this is the first prospective study to demonstrate lack of expression of PCA3 in CRPC, with the result apparently not influenced by chemotherapy. There appears to be a strong association between hormonal treatment and lack of PCA 3 expression. It is still unknown whether

  19. Beyond Castration and Culling

    DEFF Research Database (Denmark)

    Palmer, Clare; Pedersen, Hanne Gervi; Sandøe, Peter

    2018-01-01

    suppressing sexual behavior in both sexes. The paper is anchored by considering ethical issues raised by four diverse cases: the use of pharmaceutical fertility control in (a) male slaughter pigs, (b) domesticated stallions and mares, (c) male companion dogs and (d) female white-tailed deer. Ethical concerns...

  20. Zinc injection as a novel castration method in beef bulls: effects on performance, behavior, and testosterone and haptoglobin concentration.

    Science.gov (United States)

    Ball, Jase J; Kegley, Elizabeth B; Lawrence, Ty E; Roberts, Shelby L; Powell, Jeremy G; Richeson, John T

    2018-04-03

    28 d monitoring period. No difference in standing time (P ≥ 0.85) or lying bouts (P = 0.35) occurred. Zinc injection resulted in sterilization but did not cause complete cessation of testicular function evidenced by testosterone concentrations more similar to BUL than BAN. This resulted in overall increased BW and G:F for INJ vs. BAN, yet the acute phase response was markedly greater directly after Zn injection. Collectively, Zn injection resulted in outcomes more similar to BUL than BAN, implying minimal efficacy of INJ as a castration method in older bulls arriving to the feedlot.

  1. Reflections on the therapeutic use of 223RaCl2 for bone metastases resulting from prostate cancer resistant to castration

    International Nuclear Information System (INIS)

    Astudillo V, A. J.; Paredes G, L.

    2015-10-01

    In January 2014 the Comision Federal para la Proteccion contra Riesgos Sanitarios of the Ministry of Health in Mexico, authorize the use of 223 RaCl 2 as the first radiopharmaceutical emitter α for therapeutic purposes in cases of bone metastases resulting from prostate cancer resistant to castration. The paper analyzes the main variables that affect the metrological traceability using activity meters to evaluate the gamma activity of 223 RaCl 2 in hospitals, because it has a chain of complex decay with alpha, beta and gamma emitters, so was important to verify if a gamma activity measurement for a multiple emitter is reliable to determine the total alpha absorbed dose to bone in a patient. (Author)

  2. Obesity is associated with castration-resistant disease and metastasis in men treated with androgen deprivation therapy after radical prostatectomy: results from the SEARCH database.

    Science.gov (United States)

    Keto, Christopher J; Aronson, William J; Terris, Martha K; Presti, Joseph C; Kane, Christopher J; Amling, Christopher L; Freedland, Stephen J

    2012-08-01

    Study Type - Prognosis (cohort series). Level of Evidence 2a. What's known on the subject? and What does the study add? The incidence and prevalence of obesity in the USA and Europe is increasing. Higher body mass index is associated with a lower risk of overall prostate cancer diagnosis but also with an increased risk of high grade prostate cancer. Obese men undergoing primary therapy with radical prostatectomy or external beam radiation are more likely to experience a biochemical recurrence after treatment compared with normal weight men. Finally, obesity is associated with increased prostate-cancer-specific mortality. We hypothesized that obese men on androgen deprivation therapy may be at increased risk for prostate cancer progression. Previous studies have shown that obese men have lower levels of testosterone compared with normal weight men. Additionally, one previous study found that obese men have higher levels of testosterone on androgen deprivation therapy. Men with higher levels of testosterone on androgen deprivation therapy are at increased risk of prostate cancer progression. We found that men with higher body mass index were at increased risk of progression to castration-resistant prostate cancer, development of metastases and prostate-cancer-specific mortality. When we adjusted for various clinicopathological characteristics, obese men were at increased risk of progression to castration-resistant prostate cancer and development of metastases. The results of our study help generate hypotheses for further study regarding the mechanisms between obesity and aggressive prostate cancer. • To investigate whether obesity predicts poor outcomes in men starting androgen deprivation therapy (ADT) before metastasis, since previous studies found worse outcomes after surgery and radiation for obese men. • A retrospective review was carried out of 287 men in the SEARCH database treated with radical prostatectomy between 1988 and 2009. • Body mass index (BMI

  3. Predictors of Chemotherapy-Induced Toxicity and Treatment Outcomes in Elderly Versus Younger Patients With Metastatic Castration-Resistant Prostate Cancer

    DEFF Research Database (Denmark)

    Kongsted, Per; Svane, Inge Marie; Lindberg, Henriette

    2016-01-01

    used to evaluate treatment-related toxicity and efficacy. Logistic and Cox regression models were used to predict toxicity and survival. RESULTS: Age ≥ 75 years (odds ratio [OR], 2.33), baseline levels of hemoglobin (OR, 0.89), and previous metastatic epidural spinal cord compression (MESCC; OR, 1......BACKGROUND: In the present study, we examined possible predictors of chemotherapy-induced toxicity, treatment outcomes, and the consequences of dose reductions in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving standard docetaxel. PATIENTS AND METHODS: Medical.......70) were predictive of grade 3 and 4 nonhematologic toxicity. Previous MESCC was associated with a greater risk of febrile neutropenia (OR, 2.74). The median progression-free survival (PFS) and overall survival (OS) were 6.4 and 15.4 months, respectively. Survival was similar in the older (age ≥ 75 years...

  4. Silencing CAPN2 Expression Inhibited Castration-Resistant Prostate Cancer Cells Proliferation and Invasion via AKT/mTOR Signal Pathway

    Directory of Open Access Journals (Sweden)

    Pu Li

    2017-01-01

    Full Text Available The mRNA expression of CAPN2 was upregulated in CRPC cells (DU145 and PC3 than that in non-CRPC cells. Silencing CAPN2 expression could inhibit DU145 and PC3 cells proliferation by cell cycle arrest at G1 phase. Knockdown of CPAN2 level suppressed the migration and invasion capacity of CRPC cells by reducing matrix metalloproteinase-2 (MMP-2 and MMP-9 activation, as well as repressing the phosphorylation protein expression of AKT and mTOR. In addition, we found that the expression of CAPN2 was elevated in Pca tissues than that in normal control tissues. Therefore, we showed the important roles of CAPN2 in the development and progression in CRPC cells, suggesting a new therapeutic intervention for treating castration-resistant prostate cancer patients.

  5. Protective effects of seahorse extracts in a rat castration and testosterone-induced benign prostatic hyperplasia model and mouse oligospermatism model.

    Science.gov (United States)

    Xu, Dong-Hui; Wang, Li-Hong; Mei, Xue-Ting; Li, Bing-Ji; Lv, Jun-Li; Xu, Shi-Bo

    2014-03-01

    This study investigated the effects of seahorse (Hippocampus spp.) extracts in a rat model of benign prostatic hyperplasia (BPH) and mouse model of oligospermatism. Compared to the sham operated group, castration and testosterone induced BPH, indicated by increased penile erection latency; decreased penis nitric oxide synthase (NOS) activity; reduced serum acid phosphatase (ACP) activity; increased prostate index; and epithelial thickening, increased glandular perimeter, increased proliferating cell nuclear antigen (PCNA) index and upregulation of basic fibroblast growth factor (bFGF) in the prostate. Seahorse extracts significantly ameliorated the histopathological changes associated with BPH, reduced the latency of penile erection and increased penile NOS activity. Administration of seahorse extracts also reversed epididymal sperm viability and motility in mice treated with cyclophosphamide (CP). Seahorse extracts have potential as a candidate marine drug for treating BPH without inducing the side effects of erectile dysfunction (ED) or oligospermatism associated with the BPH drug finasteride. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. PSA time to nadir as a prognostic factor of first-line docetaxel treatment in castration-resistant prostate cancer: evidence from patients in Northwestern China

    Directory of Open Access Journals (Sweden)

    Kai-Jie Wu

    2018-01-01

    Full Text Available Docetaxel-based chemotherapy remains the first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC in China; however, the prognostic factors associated with effects in these patients are still controversial. In this study, we retrospectively reviewed the data from 71 eligible Chinese patients who received docetaxel chemotherapy from 2009 to 2016 in our hospital and experienced a reduction of prostate-specific antigen (PSA level ≥50% during the treatment and investigated the potential role of time to nadir (TTN of PSA. TTN was defined as the time from start of chemotherapy to the nadir of PSA level during the treatment. Multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival (OS. In these patients, the median of TTN was 17 weeks. Patients with TTN ≥17 weeks had a longer response time to chemotherapy compared to TTN 50% PSA remission.

  7. Effect of castration on the susceptibility of male rats to the sleep deprivation-induced impairment of behavioral and synaptic plasticity.

    Science.gov (United States)

    Hajali, Vahid; Sheibani, Vahid; Ghazvini, Hamed; Ghadiri, Tahereh; Valizadeh, Toktam; Saadati, Hakimeh; Shabani, Mohammad

    2015-09-01

    In both human and animal studies, the effect of sleep deficiency on cognitive performances has mostly been studied during adulthood in males, but very little data exist concerning the effects of poor sleep in gonadal hormones-depleted status, such as aging or gonadectomized (GDX) male animal models. The present study investigated the potential modulatory effects of the endogenous male sex hormones on the 48h REM sleep deprivation (SD)-induced cognitive and synaptic impairments by comparing the gonadally intact with castrated male rats, a rodent model of androgen-deprived male animals. The multiple platform method was used for inducing REM-SD and spatial performances were evaluated using Morris water maze (MWM) task. Early long-term potentiation (E-LTP) was measured in area CA1 of the hippocampus and PCR and western blotting assays were employed to assess brain derived neurotrophic factor (BDNF) gene and protein expression in the hippocampus. To reveal any influence of sleep loss on stress level, we also evaluated the plasma corticosterone levels of animals. Regardless of reproductive status, REM-SD significantly disrupted short-term memory and LTP, as well as hippocampal BDNF expression. The corticosterone levels were not significantly changed following REM-SD neither in intact nor in GDX male rats. These findings suggest that depletion of male sex steroid hormones by castration does not lead to any heightened sensitivity of male animals to the deleterious effects of 48h REM-SD on cognitive and synaptic performances. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. The treatment patterns of castration-resistant prostate cancer in Japan, including symptomatic skeletal events and associated treatment and healthcare resource use.

    Science.gov (United States)

    Uemura, Hiroji; DiBonaventura, Marco; Wang, Ed; Ledesma, Dianne Athene; Concialdi, Kristen; Aitoku, Yasuko

    2017-10-01

    Real-world treatment patterns of bone metastatic castration-resistant prostate cancer (mCRPC) in Japan were examined, focusing on treatment patterns and resource use differences attributed to symptomatic skeletal events (SSEs). Urologists (N = 176) provided retrospective chart data for patients with mCRPC (N = 445) via online surveys. Descriptive analyses and chi-square tests evaluated treatment patterns and their differences by SSE presence; generalized linear mixed models examined healthcare resource utilization differences as a function of SSEs. Patients were on average 73.6 years old (SD = 8.3), diagnosed with prostate cancer 5.1 years (SD = 6.2), castration-resistant 2.3 years (SD=2.0), and had 7.9 bone metastases sites (SD=12.4). Novel anti-hormones showed increased adoption as mCRPC treatment. Simultaneously, luteinizing hormone-releasing hormone (LHRH) agonist/antagonist use was common (43.6% of patients in 1 st line), even as CRPC treatment had started. SSEs were uncommon (2-3% per treatment line; 5% at any time), but were associated with increased opioids, strontium-89, bisphosphonates, and NSAIDs use, plus increased healthcare visits (all p < .05). LHRH agonist/antagonist treatment combinations remain the mCRPC treatment mainstay in Japan. However, novel anti-hormone therapies are becoming well-accepted in practice. SSEs were associated with increased healthcare resource and analgesic use, highlighting the need for efficient symptom management.

  9. Differential effects of 2-difluoromethylornithine and methylglyoxal bis(guanylhydrazone) on the testosterone-induced growth of ventral prostate and seminal vesicles of castrated rats.

    Science.gov (United States)

    Käpyaho, K; Kallio, A; Jänne, J

    1984-05-01

    2-Difluoromethylornithine totally prevented any increases in putrescine and spermidine concentrations in the ventral prostate of castrated rats during a 6-day testosterone treatment. Prostatic ornithine decarboxylase activity was inhibited by 80%, whereas S-adenosylmethionine decarboxylase was stimulated by more than 9-fold. In seminal vesicle, the inhibition of putrescine and spermidine accumulation, as well as of ornithine decarboxylase activity, was only minimal, and no stimulation of S-adenosylmethionine decarboxylase was observed. Administration of methylglyoxal bis(guanylhydrazone) to castrated androgen-treated rats resulted in a marked increase in concentrations of all prostatic polyamines. Prostatic ornithine decarboxylase activity was nearly 2 times and adenosylmethionine decarboxylase activity 9 times higher than that of the testosterone-treated animals. In contrast with ventral prostate, methylglyoxal bis(guanylhydrazone) treatment inhibited moderately the accumulation of spermidine and spermine in seminal vesicle, although both ornithine decarboxylase and S-adenosylmethionine decarboxylase activities were stimulated. Difluoromethylornithine inhibited significantly the weight gain of ventral prostate, but methylglyoxal bis(guanylhydrazone) produced a substantial increase in prostatic weight. These changes were largely due to the fact that the volume of prostatic secretion was greatly decreased by difluoromethylornithine, whereas methylglyoxal bis(guanylhydrazone) increased the amount of secretion. Treatment with difluoromethylornithine strikingly increased the methylglyoxal bis(guanylhydrazone) content of both ventral prostate and seminal vesicle, but even under these conditions the drug concentration remained low in comparison with other tissues. The results indicate that a combined use of these two polyamine anti-metabolites does not necessarily result in a synergistic growth inhibition of the androgen-induced growth of male accessory sexual glands.

  10. Second-Line Hormonal Therapy for Men With Chemotherapy-Naïve, Castration-Resistant Prostate Cancer: American Society of Clinical Oncology Provisional Clinical Opinion.

    Science.gov (United States)

    Virgo, Katherine S; Basch, Ethan; Loblaw, D Andrew; Oliver, Thomas K; Rumble, R Bryan; Carducci, Michael A; Nordquist, Luke; Taplin, Mary-Ellen; Winquist, Eric; Singer, Eric A

    2017-06-10

    Purpose ASCO provisional clinical opinions (PCOs) offer direction to the ASCO membership after publication or presentation of potential practice-changing data. This PCO addresses second-line hormonal therapy for chemotherapy-naïve men with castration-resistant prostate cancer (CRPC) who range from being asymptomatic with only biochemical evidence of CRPC to having documented metastases but minimal symptoms. Clinical Context The treatment goal for CRPC is palliation. Despite resistance to initial androgen deprivation therapy, most men respond to second-line hormonal therapies. However, guidelines have neither addressed second-line hormonal therapy for nonmetastatic CRPC nor provided specific guidance with regard to the chemotherapy-naïve population. Recent Data Six phase III randomized controlled trials and expert consensus opinion inform this PCO. Provisional Clinical Opinion For men with CRPC, a castrate state should be maintained indefinitely. Second-line hormonal therapy (eg, antiandrogens, CYP17 inhibitors) may be considered in patients with nonmetastatic CRPC at high risk for metastatic disease (rapid prostate-specific antigen doubling time or velocity) but otherwise is not suggested. In patients with radiographic evidence of metastases and minimal symptoms, enzalutamide or abiraterone plus prednisone should be offered after discussion with patients about potential harms, benefits, costs, and patient preferences. Radium-223 and sipuleucel-T also are options. No evidence provides guidance about the optimal order of hormonal therapies for CRPC beyond second-line treatment. Prostate-specific antigen testing every 4 to 6 months is reasonable for men without metastases. Routine radiographic restaging generally is not suggested but can be considered for patients at risk for metastases or who exhibit symptoms or other evidence of progression. Additional information is available at www.asco.org/genitourinary-cancer-guidelines and www.asco.org/guidelineswiki .

  11. Phase I Clinical Trial of the CYP17 Inhibitor Abiraterone Acetate Demonstrating Clinical Activity in Patients With Castration-Resistant Prostate Cancer Who Received Prior Ketoconazole Therapy

    Science.gov (United States)

    Ryan, Charles J.; Smith, Matthew R.; Fong, Lawrence; Rosenberg, Jonathan E.; Kantoff, Philip; Raynaud, Florence; Martins, Vanessa; Lee, Gloria; Kheoh, Thian; Kim, Jennifer; Molina, Arturo; Small, Eric J.

    2010-01-01

    Purpose Abiraterone acetate is a prodrug of abiraterone, a selective inhibitor of CYP17, the enzyme catalyst for two essential steps in androgen biosynthesis. In castration-resistant prostate cancers (CRPCs), extragonadal androgen sources may sustain tumor growth despite a castrate environment. This phase I dose-escalation study of abiraterone acetate evaluated safety, pharmacokinetics, and effects on steroidogenesis and prostate-specific antigen (PSA) levels in men with CPRC with or without prior ketoconazole therapy. Patients and Methods Thirty-three men with chemotherapy-naïve progressive CRPC were enrolled. Nineteen patients (58%) had previously received ketoconazole for CRPC. Bone metastases were present in 70% of patients, and visceral involvement was present in 18%. Three patients (9%) had locally advanced disease without distant metastases. Fasted or fed cohorts received abiraterone acetate doses of 250, 500, 750, or 1,000 mg daily. Single-dose pharmacokinetic analyses were performed before continuous daily dosing. Results Adverse events were predominantly grade 1 or 2. No dose-limiting toxicities were observed. Hypertension (grade 3, 12%) and hypokalemia (grade 3, 6%; grade 4, 3%) were the most frequent serious toxicities and responded to medical management. Confirmed ≥ 50% PSA declines at week 12 were seen in 18 (55%) of 33 patients, including nine (47%) of 19 patients with prior ketoconazole therapy and nine (64%) of 14 patients without prior ketoconazole therapy. Substantial declines in circulating androgens and increases in mineralocorticoids were seen with all doses. Conclusion Abiraterone acetate was well tolerated and demonstrated activity in CRPC, including in patients previously treated with ketoconazole. Continued clinical study is warranted. PMID:20159824

  12. Efficacy and Safety of Enzalutamide vs Bicalutamide in Younger and Older Patients with Metastatic Castration Resistant Prostate Cancer in the TERRAIN Trial.

    Science.gov (United States)

    Siemens, D Robert; Klotz, Laurence; Heidenreich, Axel; Chowdhury, Simon; Villers, Arnauld; Baron, Benoit; van Os, Steve; Hasabou, Nahla; Wang, Fong; Lin, Ping; Shore, Neal D

    2018-01-01

    Enzalutamide significantly prolonged median progression-free survival vs bicalutamide in chemotherapy naïve men with metastatic castration resistant prostate cancer in the TERRAIN (Enzalutamide versus Bicalutamide in Castrate Men with Metastatic Prostate Cancer) trial. In this post hoc analysis we investigated the influence of age on the efficacy and safety of enzalutamide vs bicalutamide in this population. Patients were randomized 1:1 to enzalutamide 160 mg per day or bicalutamide 50 mg per day. Progression-free survival, time to prostate specific antigen progression and safety were analyzed post hoc in younger (age less than 75 years) and older (age 75 years or greater) subgroups. Enzalutamide significantly reduced the risk of disease progression or death vs bicalutamide in patients younger than 75 years (HR 0.38, 95% CI 0.27-0.52, p <0.0001) and 75 years old or older (HR 0.59, 95% CI 0.37-0.92, p = 0.018). Time to prostate specific antigen progression was also significantly prolonged with enzalutamide vs bicalutamide in each subgroup. The adverse event distribution between treatments was similar in each subgroup except for more (5% or greater difference between subgroups) atrial fibrillation, urinary tract infections, falls and decreased appetite as well as less extremity pain and hot flushing in enzalutamide treated patients 75 years old or older, and less back pain and hot flushing in bicalutamide treated patients 75 years old or older. Grade 3 or greater cardiac events were more frequent in enzalutamide treated and bicalutamide treated patients who were 75 years old or older vs younger than 75 years. Fatigue was more frequent in enzalutamide treated patients with a similar distribution in each age subgroup. Enzalutamide improved clinical outcomes vs bicalutamide irrespective of age. Increased falls and cardiac events suggest caution when prescribing to older patients (age 75 years or greater) with significant comorbidity. Copyright © 2018 American

  13. 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

    DEFF Research Database (Denmark)

    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...... on ERG-status. Risk reclassification and time-dependent area under the ROC curves were used to assess the discriminative ability of ERG-status. Time to PSA-nadir, proportion achieving PSA-nadir ≤0.2 ng/ml, and risk of PCa-specific death were secondary endpoints. RESULTS: Median follow-up was 6.8 years...

  14. 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

  15. Pharmacokinetics and physiologic effects of intramuscularly administered xylazine hydrochloride-ketamine hydrochloride-butorphanol tartrate alone or in combination with orally administered sodium salicylate on biomarkers of pain in Holstein calves following castration and dehorning.

    Science.gov (United States)

    Baldridge, Sarah L; Coetzee, Johann F; Dritz, Steve S; Reinbold, James B; Gehring, Ronette; Havel, James; Kukanich, Butch

    2011-10-01

    To determine the pharmacokinetic parameters of xylazine, ketamine, and butorphanol (XKB) administered IM and sodium salicylate (SAL) administered PO to calves and to compare drug effects on biomarkers of pain and distress following sham and actual castration and dehorning. 40 Holstein bull calves from 3 farms. Calves weighing 108 to 235 kg (n = 10 calves/group) received one of the following treatments prior to sham (period 1) and actual (period 2) castration and dehorning: saline (0.9% NaCl) solution IM (placebo); SAL administered PO through drinking water at concentrations from 2.5 to 5 mg/mL from 24 hours prior to period 1 to 48 hours after period 2; butorphanol (0.025 mg/kg), xylazine (0.05 mg/kg), and ketamine (0.1 mg/kg) coadministered IM immediately prior to both periods; and a combination of SAL and XKB (SAL+XKB). Plasma drug concentrations, average daily gain (ADG), chute exit velocity, serum cortisol concentrations, and electrodermal activity were evaluated. ADG (days 0 to 13) was significantly greater in the SAL and SAL+XKB groups than in the other 2 groups. Calves receiving XKB had reduced chute exit velocity in both periods. Serum cortisol concentrations increased in all groups from period 1 to period 2. However, XKB attenuated the cortisol response for the first hour after castration and dehorning and oral SAL administration reduced the response from 1 to 6 hours. Administration of XKB decreased electrodermal activity scores in both periods. SAL administered PO through drinking water decreased cortisol concentrations and reduced the decrease in ADG associated with castration and dehorning in calves.

  16. Amelioration of sexual behavior and motor activity deficits in a castrated rodent model with a selective androgen receptor modulator SARM-2f.

    Directory of Open Access Journals (Sweden)

    Megumi Morimoto

    Full Text Available Sarcopenia and cachexia present characteristic features of a decrease in skeletal muscle mass and strength, anorexia, and lack of motivation. Treatments for these diseases have not yet been established, although selective androgen receptor modulators (SARMs are considered as therapeutic targets. We previously reported that a novel SARM compound, SARM-2f, exhibits anabolic effect on muscles, with less stimulatory effect on prostate weight compared with testosterone, in rat Hershberger assays and cancer cachexia models. In this study, we studied the mechanism of action for SARM-2f selectivity and also assessed whether the muscle increase by this compound might lead to improvement of muscle function and physical activity. First, we examined the tissue distribution of SARM-2f. Tissue concentration was 1.2-, 1.6-, and 1.9-fold as high as the plasma concentration in the levator ani muscle, brain, and prostate, respectively. This result showed that the tissue-selective pharmacological effect did not depend on SARM-2f concentration in the tissues. The ability of SARM-2f to influence androgen receptor (AR-mediated transcriptional activation was examined by reporter assays using human normal prostate epithelial cells (PrEC and skeletal muscle cells (SKMC. SARM-2f exerted higher activity against AR in SKMC than in PrEC. Mammalian two hybrid assays showed different co-factor recruitment patterns between SARM-2f and dihydrotestosterone. Next, we studied the effect of SARM-2f on motivation and physical functions such as sexual behavior and motor activities in castrated rat or mouse models. SARM-2f restored the sexual behavior that was lost by castration in male rats. SARM-2f also increased voluntary running distance and locomotor activities. These results suggest that tissue-specific AR regulation by SARM-2f, but not tissue distribution, might account for its tissue specific androgenic effect, and that the muscle mass increase by SARM-2f leads to improvement

  17. Cdc20/p55 mediates the resistance to docetaxel in castration-resistant prostate cancer in a Bim-dependent manner.

    Science.gov (United States)

    Wu, Fei; Lin, Yun; Cui, Peng; Li, Hongyun; Zhang, Lechao; Sun, Zeqiang; Huang, Shengliang; Li, Shun; Huang, Shiming; Zhao, Qingli; Liu, Qingyong

    2018-03-31

    At least to date, no effective treatment for advanced castration-resistant prostate cancer (CRPC) has been established. Recent studies indicated that cell division cycle 20 homolog (Cdc20) overexpression is associated with poor prognosis in patients with castration-resistant prostate cancer. However, the mechanism of Cdc20 in the development of docetaxel resistance in CRPC remains elusive. In this study, the transcription of Cdc20 was confirmed in three independent CRPC cell lines derived from different tissues, including LNCaP, PC3, and DU145. Docetaxel resistant (DR) cell lines were generated within the background of DU145 and PC3. The protein levels of Cdc20 and the biological phenotype were detected in both wild-type and DR cell lines. To further explore the mechanism of Cdc20 overexpression, stable cell lines with Cdc20 or Bcl-2 interacting mediator of cell death (Bim) deprivation were generated and examined for biological parameters. In addition, a specific Cdc20 inhibitor was used in DR cell lines to explore the potential solution for docetaxel resistant CRPC. Here, we identified Cdc20 is overexpressed in docetaxel resistant CRPC cell lines, including LNCaP, PC3, and DU145. We also reported that DR cell lines, which mimic the recurrent prostate cancer cells after docetaxel treatment, have higher levels of Cdc20 protein compared with the CRPC cell lines. Interestingly, the protein levels of Bim, an E3 ligase substrate of Cdc20, were decreased in DR cell lines compared with the wild-type, while the mRNA levels were similar. More importantly, in DR cell lines, the biological phenotype induced by Cdc20 deletion could be significantly reversed by the additional knockdown of Bim. As a result, docetaxel resistant prostate cancer cells treated with the pharmacological Cdc20 inhibitor became sensitive to docetaxel treatment. In conclusion, our data collectively demonstrated that Cdc20 overexpression facilitates the docetaxel resistant of the CRPC cell lines in a Bim

  18. Amelioration of sexual behavior and motor activity deficits in a castrated rodent model with a selective androgen receptor modulator SARM-2f.

    Science.gov (United States)

    Morimoto, Megumi; Amano, Yuichiro; Oka, Masahiro; Harada, Ayako; Fujita, Hisashi; Hikichi, Yukiko; Tozawa, Ryuichi; Yamaoka, Masuo; Hara, Takahito

    2017-01-01

    Sarcopenia and cachexia present characteristic features of a decrease in skeletal muscle mass and strength, anorexia, and lack of motivation. Treatments for these diseases have not yet been established, although selective androgen receptor modulators (SARMs) are considered as therapeutic targets. We previously reported that a novel SARM compound, SARM-2f, exhibits anabolic effect on muscles, with less stimulatory effect on prostate weight compared with testosterone, in rat Hershberger assays and cancer cachexia models. In this study, we studied the mechanism of action for SARM-2f selectivity and also assessed whether the muscle increase by this compound might lead to improvement of muscle function and physical activity. First, we examined the tissue distribution of SARM-2f. Tissue concentration was 1.2-, 1.6-, and 1.9-fold as high as the plasma concentration in the levator ani muscle, brain, and prostate, respectively. This result showed that the tissue-selective pharmacological effect did not depend on SARM-2f concentration in the tissues. The ability of SARM-2f to influence androgen receptor (AR)-mediated transcriptional activation was examined by reporter assays using human normal prostate epithelial cells (PrEC) and skeletal muscle cells (SKMC). SARM-2f exerted higher activity against AR in SKMC than in PrEC. Mammalian two hybrid assays showed different co-factor recruitment patterns between SARM-2f and dihydrotestosterone. Next, we studied the effect of SARM-2f on motivation and physical functions such as sexual behavior and motor activities in castrated rat or mouse models. SARM-2f restored the sexual behavior that was lost by castration in male rats. SARM-2f also increased voluntary running distance and locomotor activities. These results suggest that tissue-specific AR regulation by SARM-2f, but not tissue distribution, might account for its tissue specific androgenic effect, and that the muscle mass increase by SARM-2f leads to improvement of physical

  19. Effects of two doses of buprenorphine four or six hours apart on nociceptive thresholds, pain and sedation in dogs after castration.

    Science.gov (United States)

    Slingsby, L S; Taylor, P M; Waterman-Pearson, A E

    2006-11-18

    Twenty-eight dogs were randomly allocated into two groups. They were premedicated with either 10 or 20 microg/kg buprenorphine and 0.05 mg/kg acepromazine administered intramuscularly, and then anaesthetised with intravenous thiopentone to effect and maintained with isoflurane in 100 per cent oxygen. The dogs underwent routine castration, and a second dose of 10 microg/kg buprenorphine was administered four hours after the first or 20 microg/kg six hours after the first dose. Levels of pain and sedation were scored on a visual analogue scale and in terms of the dogs' requirement for rescue analgesia, and mechanical nociceptive thresholds were measured at the hock and wound at premedication and one, two, three, four, five, six, seven, 10 and 21 to 22 hours later. Pain scores were low in both groups, with a trend for lower scores in the high dose group; administration of the second dose of buprenorphine further decreased the pain scores. Buprenorphine produced good preoperative sedation and the level of sedation decreased over time after surgery. Administration of the second high dose of buprenorphine did not increase the level of sedation. Both doses of buprenorphine prevented hyperalgesia at the wound and hock postoperatively. Three dogs given the low dose and one dog given the high dose required rescue analgesia with carprofen.

  20. Complete biochemical (prostate-specific antigen) response to sipuleucel-T with enzalutamide in castration-resistant prostate cancer: a case report with implications for future research.

    Science.gov (United States)

    Graff, Julie N; Drake, Charles G; Beer, Tomasz M

    2013-02-01

    To describe the case of a patient with castration-resistant, metastatic prostate cancer who achieved a complete and durable biochemical response after treatment with sipuleucel-T while continuing with enzalutamide and to explore the immunologic basis for such a response. We obtained serial prostate-specific antigen (PSA) measurements and bone scans to assess the patient's response to enzalutamide followed by the addition of sipuleucel-T. Using preclinical and clinical data, we describe his response through known immunobiologic mechanisms. This patient's PSA level became undetectable during treatment with enzalutamide and began to increase again after 14 months. He opted for treatment with sipuleucel-T, while continuing with the enzalutamide. This resulted in another complete PSA response 6 months after exposure to sipuleucel-T. Sipuleucel-T typically does not produce significant PSA reductions, and, to the best of our knowledge, only 1 previous report of a durable complete PSA response in a patient with metastatic disease has been published. The timing of this response supports an immune mechanism. The biologic rationale for the combination, coupled with the clinical result observed in our patient, provides a basis for studies of the combination of sipuleucel-T and enzalutamide. Published by Elsevier Inc.

  1. Infestation pattern and parasitic castration of the crustacean Riggia paranensis (Crustacea: Cymothoidea on the fresh water fish Cyphocharax gilbert (Teleostei: Curimatidae

    Directory of Open Access Journals (Sweden)

    Juliana de Souza Azevedo

    Full Text Available Cyphocharax gilbert infested by Riggia paranensis shows parasitic castration. The prevalence of parasitism in C. gilbert varied among different environments, being higher in the middle rio Itabapoana. Fish were collected monthly using two cast nets (thrown 30 times during the day and gillnets kept in the river during 12 hour, from sunset to sunrise, between September 1997 and August 2000. Infestation pattern was investigated on 1358 specimens. Most of them were infested (57.9%, with one or two parasites; the majority (62.9% was collected during the rainy season (spring-summer. The parasite did not show preference for sex or size of hosts. A total of 91.5% of the 511 examined parasites had a body size that represented 10.1% to 20% of host standard length. The reproductive condition of 311 specimens of R. paranensis was analyzed checking the presence of oocytes in the ovarian and eggs or embryos in the marsupium. Nearly 73% of them were at reproductive phase, and had a body size that represented 5.1% to 20% of host standard length. The size of the immature parasites varied from 0.1% to 5% of the host size. The results suggest that R. paranensis may adopt a fast growth rate strategy and increase the investment in reproduction when they occupy most of the host's pericardial space.

  2. Tumour cell lysate-loaded dendritic cell vaccine induces biochemical and memory immune response in castration-resistant prostate cancer patients.

    Science.gov (United States)

    Reyes, D; Salazar, L; Espinoza, E; Pereda, C; Castellón, E; Valdevenito, R; Huidobro, C; Inés Becker, M; Lladser, A; López, M N; Salazar-Onfray, F

    2013-09-17

    Recently, we produced a tumour antigen-presenting cells (TAPCells) vaccine using a melanoma cell lysate, called TRIMEL, as an antigen source and an activation factor. Tumour antigen-presenting cells induced immunological responses and increased melanoma patient survival. Herein, we investigated the effect of TAPCells loaded with prostate cancer cell lysates (PCCL) as an antigen source, and TRIMEL as a dendritic cell (DC) activation factor; which were co-injected with the Concholepas concholepas haemocyanin (CCH) as an adjuvant on castration-resistant prostate cancer (CRPC) patients. The lysate mix capacity, for inducing T-cell activation, was analysed by flow cytometry and Elispot. Delayed-type hypersensitivity (DTH) reaction against PCCL, frequency of CD8(+) memory T cells (Tm) in blood and prostate-specific antigen (PSA) levels in serum were measured in treated patients. The lysate mix induced functional mature DCs that were capable of activating PCCL-specific T cells. No relevant adverse reactions were observed. Six out of 14 patients showed a significant decrease in levels of PSA. DTH(+) patients showed a prolonged PSA doubling-time after treatment. Expansion of functional central and effector CD8(+) Tm were detected. Treatment of CRPC patients with lysate-loaded TAPCells and CCH as an adjuvant is safe: generating biochemical and memory immune responses. However, the limited number of cases requires confirmation in a phase II clinical trial.

  3. Multicentre phase I/II study of PI-88, a heparanase inhibitor in combination with docetaxel in patients with metastatic castrate-resistant prostate cancer.

    Science.gov (United States)

    Khasraw, M; Pavlakis, N; McCowatt, S; Underhill, C; Begbie, S; de Souza, P; Boyce, A; Parnis, F; Lim, V; Harvie, R; Marx, G

    2010-06-01

    Docetaxel (Taxotere) improve survival and prostate-specific antigen (PSA) response rates in patients with metastatic castrate-resistant prostate cancer (CRPC). We studied the combination of PI-88, an inhibitor of angiogenesis and heparanase activity, and docetaxel in chemotherapy-naive CRPC. We conducted a multicentre open-label phase I/II trial of PI-88 in combination with docetaxel. The primary end point was PSA response. Secondary end points included toxicity, radiologic response and overall survival. Doses of PI-88 were escalated to the maximum tolerated dose; whereas docetaxel was given at a fixed 75 mg/m(2) dose every three weeks Twenty-one patients were enrolled in the dose-escalation component. A further 35 patients were randomly allocated to the study to evaluate the two schedules in phase II trial. The trial was stopped early by the Safety Data Review Board due to a higher-than-expected febrile neutropenia of 27%. In the pooled population, the PSA response (50% reduction) was 70%, median survival was 61 weeks (6-99 weeks) and 1-year survival was 71%. The regimen of docetaxel and PI-88 is active in CRPC but associated with significant haematologic toxicity. Further evaluation of different scheduling and dosing of PI-88 and docetaxel may be warranted to optimise efficacy with a more manageable safety profile.

  4. Effects of extract of Buddleja officinalis eye drops on androgen receptors of lacrimal gland cells of castrated rats with dry eye.

    Science.gov (United States)

    Peng, Qing-Hua; Yao, Xiao-Lei; Wu, Quan-Long; Tan, Han-Yu; Zhang, Jing-Rong

    2010-01-01

    To evaluate the effects of the extract of Buddleja officinalis eye drops in basic tears secretory volume, tear film stability, expression of androgen receptors (AR) in castrated rats with dry eye, and to investigate the therapeutic effects of the extract of Buddleja officinalis on dry eye caused by gonadal hormones level imbalance. Forty-five Wistar masculinity rats were divided at random into nine groups, including normal groups (A1, A2 and A3); model groups (B1, B2 and B3); therapy groups with extract of Buddleja officinalis eye drops (C1, C2 and C3). The "1" stood for being fed for 1 month, and "2" for 2 months, and "3" for 3 months. The dry eye model was established with orchiectomy on groups B and C. Group C was treated with Buddleja officinalis extract eye drops for one month. All rats were checked with Schirmer I test (SIT) and tear film break-up time (BUT). Expression of AR was analyzed by flow cytometer (FCM). The SIT value of group C was significantly higher than that of group B (PBuddleja officinalis is the flavonoids that can significantly inhibit happening of dry eye of rat after androgen level lowered. Its mechanism is like androgen's and it can display androgen-like activity to keep basic tears secretory volume and tear film stability.

  5. Time to prostate specific antigen (PSA) nadir may predict rapid relapse in men with metastatic castration-resistant prostate cancer (CRPC) receiving docetaxel chemotherapy.

    Science.gov (United States)

    Thomas, Betsan M; Smith, Christian; Evans, Jessica; Button, Michael R; Kumar, Satish; Palaniappan, Nachi; Staffurth, John; Tanguay, Jacob S; Lester, Jason F

    2013-12-01

    Docetaxel has been shown to improve survival in patients with metastatic castrate-resistant prostate cancer (mCRPC). There is no clear consensus regarding the optimum duration of chemotherapy. If patients at greater risk of rapid disease relapse could be identified when on chemotherapy, appropriate follow-up strategies could be put into place. The aim of our study was to find prostate specific antigen (PSA) characteristics that predict a shorter disease response to docetaxel chemotherapy. Data from 41 consecutive mCRPC patients treated with three-weekly docetaxel chemotherapy at a single centre between February 2010 and February 2012 were retrospectively analysed. All patients had ≥50% reduction in their PSA with chemotherapy. The relationship between time to PSA nadir (TTN) and PSA halving time with time to PSA progression and overall chemotherapy response duration was analysed. TTN was a strong predictor of the duration of chemotherapy response and time to PSA progression. When TTN was ≥16 weeks, the mean duration of response to chemotherapy was 37.5 weeks compared to 19.9 weeks when TTN PSA progression was 12.8 weeks if TTN was ≥16 weeks and 8.2 weeks TTN was <16 weeks (95% CI 0.63-8.60; p = 0.024). We observed that a TTN from the initiation of chemotherapy of <16 weeks for patients with mCRPC is an independent predictor of shorter duration of response and shorter progression-free survival.

  6. Addressing the expected survival benefit for clinical trial design in metastatic castration-resistant prostate cancer: Sensitivity analysis of randomized trials.

    Science.gov (United States)

    Massari, Francesco; Modena, Alessandra; Ciccarese, Chiara; Pilotto, Sara; Maines, Francesca; Bracarda, Sergio; Sperduti, Isabella; Giannarelli, Diana; Carlini, Paolo; Santini, Daniele; Tortora, Giampaolo; Porta, Camillo; Bria, Emilio

    2016-02-01

    We performed a sensitivity analysis, cumulating all randomized clinical trials (RCTs) in which patients with metastatic castration-resistant prostate cancer (mCRPC) received systemic therapy, to evaluate if the comparison of RCTs may drive to biased survival estimations. An overall survival (OS) significant difference according to therapeutic strategy was more likely be determined in RCTs evaluating hormonal drugs versus those studies testing immunotherapy, chemotherapy or other strategies. With regard to control arm, an OS significant effect was found for placebo-controlled trials versus studies comparing experimental treatment with active therapies. Finally, regarding to docetaxel (DOC) timing, the OS benefit was more likely to be proved in Post-DOC setting in comparison with DOC and Pre-DOC. These data suggest that clinical trial design should take into account new benchmarks such as the type of treatment strategy, the choice of the comparator and the phase of the disease in relation to the administration of standard chemotherapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Efficacy of Abiraterone and Enzalutamide in Pre- and Postdocetaxel Castration-Resistant Prostate Cancer: A Trial-Level Meta-Analysis

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    Mike Fang

    2017-01-01

    Full Text Available We examined the comparative efficacies of first-line abiraterone and enzalutamide in pre- and postdocetaxel settings in castration-resistant prostate cancer (CRPC through a trial level meta-analysis. A mixed method approach was applied to 19 unique studies containing 17 median overall survival (OS estimates and 13 median radiographic progression-free survival (PFS estimates. We employed a random-effects meta-analysis to compare efficacies of abiraterone and enzalutamide with respect to OS and PFS. In the predocetaxel setting, enzalutamide use was associated with an increase in median OS of 5.9 months (p<0.001, hazard ratio (HR = 0.81, and an increase in median PFS of 8.3 months (p<0.001, HR = 0.47 compared to abiraterone. The advantage of enzalutamide improved after adjusting for baseline Gleason score to 19.5 months (p<0.001 and 14.6 months (p<0.001 in median OS and PFS, respectively. In the postdocetaxel setting, the advantage of enzalutamide use was nominally significant for median PFS (1.2 months p=0.02 without adjustment and 2.2 months and p=0.0007 after adjustment; there was no significant difference in median OS between the two agents. The results from this comprehensive meta-analysis suggest a survival advantage with the use of first-line enzalutamide over abiraterone in CRPC and highlight the need for prospective clinical trials.

  8. Comparative efficacy, tolerability, and survival outcomes of various radiopharmaceuticals in castration-resistant prostate cancer with bone metastasis: a meta-analysis of randomized controlled trials

    Directory of Open Access Journals (Sweden)

    Tunio M

    2015-09-01

    Full Text Available Mutahir Tunio,1 Mushabbab Al Asiri,1 Abdulrehman Al Hadab,1 Yasser Bayoumi2 1Radiation Oncology, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia; 2Radiation Oncology, National Cancer Institute, Cairo University, Cairo, Egypt Background: A meta-analysis was conducted to assess the impact of radiopharmaceuticals (RPs in castration-resistant prostate cancer (CRPC on pain control, symptomatic skeletal events (SSEs, toxicity profile, quality of life (QoL, and overall survival (OS.Materials and methods: The PubMed/MEDLINE, CANCERLIT, EMBASE, Cochrane Library database, and other search engines were searched to identify randomized controlled trials (RCTs comparing RPs with control (placebo or radiation therapy in metastatic CRPC. Data were extracted and assessed for the risk of bias (Cochrane’s risk of bias tool. Pooled data were expressed as odds ratio (OR, with 95% confidence intervals (CIs; Mantel–Haenszel fixed-effects model.Results: Eight RCTs with a total patient population of 1,877 patients were identified. The use of RP was associated with significant reduction in pain intensity and SSE (OR: 0.63, 95% CI: 0.51–0.78, I2=27%, P<0.0001, improved QoL (OR: 0.71, 95% CI: 0.55–0.91, I2=65%, three trials, 1,178 patients, P=0.006, and a minimal improved OS (OR: 0.84, 95% CI: 0.64–1.04, I2=47%, seven trials, 1,845 patients, P=0.11. A subgroup analysis suggested an improved OS with radium-223 (OR: 0.68, 95% CI: 0.51–0.90, one trial, 921 patients and strontium-89 (OR: 0.21, 95% CI: 0.05–0.91, one trial, 49 patients. Strontium-89 (five trials was associated with increased rates of grade 3 and 4 thrombocytopenia (OR: 4.26, 95% CI: 2.22–8.18, P=0.01, leucopenia (OR: 7.98, 95% CI: 1.82–34.95, P=0.02, pain flare (OR: 6.82, 95% CI: 3.42–13.55, P=0.04, and emesis (OR: 3.61, 95% CI: 1.76–7.40, P=0.02.Conclusion: The use of RPs was associated with significant reduction in SSEs and improved QoL, while the radium-223

  9. Efeito da trimegestona sobre o tecido mamário de ratas castradas Effect of trimegestone on mammary gland of castrated rats

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    Luciana de Oliveira Marques

    2011-07-01

    Full Text Available OBJETIVO: Avaliar o efeito da trimegestona sobre a proliferação celular do tecido mamário de ratas castradas. MÉTODOS: Foram utilizadas 45 ratas adultas e virgens, da linhagem Wistar, submetidas à castração. Após o 60º dia da castração, confirmado o hipoestrogenismo, os animais foram divididos aleatoriamente em três grupos, conforme o tratamento proposto: controle (n=15 recebeu soro fisiológico 0,9%; estrogênio (n=15 recebeu 17 beta-estradiol; e combinado (n=15 recebeu 17 beta-estradiol associado à trimegestona, todos por 60 dias consecutivos. Após o término do tratamento, procedeu-se a exérese das mamas inguinais, destinadas a análise morfométrica pela coloração de hematoxilina e eosina (HE e imuno-histoquímica pela quantificação do anticorpo anti-PCNA no tecido mamário, seguido de eutanásia. Os parâmetros morfométricos avaliados foram: proliferação celular epitelial, atividade secretora e alteração do estroma mamário. Ocorreram nove óbitos durante o experimento. As variáveis foram submetidas à análise estatística adotando-se como significante pPURPOSE: To evaluate the efect of trimegestone on the histological changes of the mammary tissue of castrated rats. METHODS: Forty-five virgin female Wistar rats were used after oophorectomy. Sixty days after surgery, with hypoestrogenisms confirmed, the experimental rats were randomly assigned to three groups of 15 animals each, when then the specific treatment for each group was started. The control group (C and experimental groups 1 and 2 respectively received 0.9% saline solution, 17-beta-estradiol and 17-beta-estradiol in combination with trimegestone for 60 consecutive days. After the end of treatment , the inguinal mammary glands were removed, stained with hematoxylin and eosin (HE for morphometry and examined by immunohistochemistry for the quantification of anti-PCNA antibody in the mammary tissue, followed by euthanasia. The morphometric parameters

  10. Detection and quantification of223Ra uptake in bone metastases of patients with castration resistant prostate carcinoma, with the aim of determining the absorbed dose in the metastases.

    Science.gov (United States)

    Mínguez, P; Gómez de Iturriaga, A; Fernández, I L; Rodeño, E

    To obtain the necessary acquisition and calibration parameters in order to evaluate the possibility of detecting and quantifying 223 Ra uptake in bone metastases of patients treated for castration resistant prostate carcinoma. Furthermore, in the cases in which the activity can be quantified, to determine the absorbed dose. Acquisitions from a Petri dish filled with 223 Ra were performed in the gamma camera. Monte Carlo simulations were also performed to study the partial volume effect. Formulae to obtain the detection and quantification limits of 223 Ra uptake were applied to planar images of two patients 7 days post-administration of 55kBq/kg of 223 Ra. In order to locate the lesions in advance, whole-body scans and SPECT/CT images were acquired after injecting 99m Tc-HDP. The optimal energy window was found to be at 82keV with a medium-energy collimator MEGP. Of the lesions found in the patients, only those that had been detected in both the AP and PA projections could be quantified. These lesions were those which had shown a higher 99m Tc-HDP uptake. The estimated values of absorbed doses ranged between 0.7Gy and 7.8Gy. Of the lesions that can be detected, it is not possible to quantify the activity uptake in some of them, which means that the absorbed dose cannot be determined either. This does not mean that the absorbed dose in these lesions can be regarded as negligible. Copyright © 2017 Elsevier España, S.L.U. y SEMNIM. All rights reserved.

  11. Cytotoxic effects of escin on human castration-resistant prostate cancer cells through the induction of apoptosis and G2/M cell cycle arrest.

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    Piao, Songzhe; Kang, Minyong; Lee, Young Ju; Choi, Woo Suk; Chun, Yang-Sook; Kwak, Cheol; Kim, Hyeon Hoe

    2014-10-01

    To evaluate the in vitro and in vivo effects of escin on human castration-resistant prostate cancer (CRPC) cells, PC-3 and DU-145. The inhibition of cell proliferation and its mechanism were assessed through a cytotoxicity assay, flow cytometry, and Western blot. The in vivo efficacy of escin in CRPC cells was assessed using a xenograft tumor model subcutaneously established in BALB/c nude mice. The treatment with escin significantly reduced cell viability of CRPC cells in a dose- and time-dependent manner. Escin induced apoptosis in a time-dependent manner, which was accompanied by increases in pro-apoptotic (BCL-2 associated X protein, cleaved-caspase3, and cleaved-poly [adenosine diphosphate-ribose] polymerase) proteins and decreases in antiapoptotic (X-linked inhibitor of apoptosis protein, cellular inhibitor of apoptosis protein-1, cellular inhibitor of apoptosis protein-2B-cell leukemia/lymphoma-2, and B-cell lymphoma-extra large) proteins. Escin induced G2/M-phase cell cycle arrest and thus led to a significant decrease in the expression of cyclinB1 and its activating partner cyclin-dependent kinase 1, with the concomitant induction of p21. In addition, escin significantly inhibited the growth of CRPC cells in xenograft models. The results show that escin induced cytotoxic effects on CRPC cells through the induction of apoptosis and G2/M cell cycle arrest, indicating it may be a novel therapeutic agent for CRPC. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Multicenter phase II trial of the heat shock protein 90 inhibitor, retaspimycin hydrochloride (IPI-504), in patients with castration-resistant prostate cancer.

    Science.gov (United States)

    Oh, William K; Galsky, Matthew D; Stadler, Walter M; Srinivas, Sandy; Chu, Franklin; Bubley, Glenn; Goddard, J; Dunbar, Joi; Ross, Robert W

    2011-09-01

    To evaluate clinical activity and safety of retaspimycin hydrochloride (IPI-504) in patients with castration-resistant prostate cancer (CRPC). A single-arm trial was conducted in 2 cohorts: group 1, chemotherapy naive; group 2, docetaxel-treated. IPI-504 was administered intravenously at 400 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle. Trial expansion was planned if ≥1 prostate-specific antigen (PSA) or radiographic response was noted per cohort. Pharmacokinetic samples were collected after the first dose; safety was assessed throughout. A total of 19 patients were enrolled (4 in group 1; 15 in group 2), with a median age of 66 years (range 49-78). Group 2 had received a median of 2 previous chemotherapy regimens. All group 2 patients had bone metastases; 66% had measurable soft tissue or visceral metastases. One group 1 patient remained on-trial for 9 cycles; his PSA level declined 48% from baseline. No PSA response was observed in the other patients. Adverse events reported in >25% of the study population included nausea (47%), diarrhea (42%), fatigue (32%), anorexia (26%), and arthralgia (26%). Two patients in group 2 died on-trial, involving study drug-related events of hepatic failure and ketoacidosis, respectively. Heat shock protein 90 inhibition with IPI-504 administered as a single agent had a minimal effect on the PSA level or tumor burden and was associated with unacceptable toxicity in several patients. Therefore, additional evaluation in CRPC patients is not warranted. IPI-504 is being investigated at less-intensive doses and schedules in other tumor types. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Overall survival and response pattern of castration-resistant metastatic prostate cancer to multiple cycles of radioligand therapy using [{sup 177}Lu]Lu-PSMA-617

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    Ahmadzadehfar, Hojjat; Wegen, Simone; Yordanova, Anna; Kuerpig, Stefan; Eppard, Elisabeth; Wei, Xiao; Schlenkhoff, Carl; Essler, Markus [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Fimmers, Rolf [University of Bonn, Institute for Medical Biometry, Informatics and Epidemiology, Bonn (Germany); Hauser, Stefan [University Hospital Bonn, Department of Urology, Bonn (Germany)

    2017-08-15

    Up to 30% of patients with castration-resistant prostate cancer (CRPC) do not show any response to the first cycle of radioligand therapy (RLT) with [{sup 177}Lu]Lu-PSMA-617 (Lu-PSMA). We evaluated patient response to the second and third cycles of RLT in patients that underwent at least three cycles. The second aim of this study was to calculate the median overall survival (OS) of responders and non-responders after the first cycle and after all three cycles of RLT. CRPC patients were treated with Lu-PSMA, with a median interval of 8 weeks between each cycle. The tumour marker prostate-specific antigen (PSA) was used as the marker for response evaluation. Fifty-two patients underwent a total of 190 cycles of RLT (3-6 cycles per patient). Of these, 80.8% showed a decline in PSA 2 months after the first cycle, with 44.2% showing a PSA decline of ≥50%. When compared to baseline PSA, 73.1% showed a PSA decline after the third cycle. 50% of patients that did not show any response to the first cycle also did not respond to the second and third cycles. The median OS was 60 weeks in all patients. The median OS was significantly longer for patients that showed any PSA decline after the first cycle compared to patients without PSA decline (68 vs. 33 weeks). There was a significant difference in median OS between responders and non-responders for a change in PSA after the third cycle compared to baseline PSA. Patients with a positive response to RLT, regardless of the rate of decline, had a significantly longer median OS. Of the patients that did not show any response to the first cycle, 50% responded to the second or third cycles. (orig.)

  14. Epidermal Growth Factor Receptor Status in Circulating Tumor Cells as a Predictive Biomarker of Sensitivity in Castration-Resistant Prostate Cancer Patients Treated with Docetaxel Chemotherapy

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    Takatsugu Okegawa

    2016-11-01

    Full Text Available Objective: We examined whether epidermal growth factor receptor (EGFR expression in circulating tumor cells (CTCs can be used to predict survival in a population of bone-metastatic castration-resistant prostate cancer (mCRPC patients treated with docetaxel chemotherapy. Methods: All patients with mCRPC who had experienced treatment failure with androgen-deprivation therapy and had received docetaxel chemotherapy were eligible. CTCs and EGFR expression in CTCs were enumerated with the CellSearch System in whole blood. This system is a semi-automated system that detects and enriches epithelial cells from whole blood using an EpCAM antibody-based immunomagnetic capture. In addition, the EGFR-positive CTCs were assessed using CellSearch® Tumor Phenotyping Reagent EGFR. Results: The median CTC count at baseline before starting trial treatment was eight CTCs per 7.5 mL of blood (range 0–184. There were 37 patients (61.7% who had ≥5 CTCs, with median overall survival of 11.5 months compared with 20.0 months for 23 patients (38.3% with <5 CTCs (p < 0.001. A total of 15 patients (40.5%, 15/37 with five or more CTCs were subjected to automated immunofluorescence staining and cell sorting for EGFR protein. Patients with EGFR-positive CTCs had a shorter overall survival (OS (5.5 months than patients with EGFR-negative CTCs (20.0 months. CTCs, EGFR-positive CTCs, and alkaline phosphatase (ALP were independent predictors of overall survival time (p = 0.002, p < 0.001, and p = 0.017, respectively. Conclusion: CTCs may be an independent predictor of OS in CRPC treated with docetaxel chemotherapy. The EGFR expression detected in CTCs was important for assessing the response to chemotherapy and predicting disease outcome.

  15. Predicting time to castration resistance in hormone sensitive prostate cancer by a personalization algorithm based on a mechanistic model integrating patient data.

    Science.gov (United States)

    Elishmereni, Moran; Kheifetz, Yuri; Shukrun, Ilan; Bevan, Graham H; Nandy, Debashis; McKenzie, Kyle M; Kohli, Manish; Agur, Zvia

    2016-01-01

    Prostate cancer (PCa) is a leading cause of cancer death of men worldwide. In hormone-sensitive prostate cancer (HSPC), androgen deprivation therapy (ADT) is widely used, but an eventual failure on ADT heralds the passage to the castration-resistant prostate cancer (CRPC) stage. Because predicting time to failure on ADT would allow improved planning of personal treatment strategy, we aimed to develop a predictive personalization algorithm for ADT efficacy in HSPC patients. A mathematical mechanistic model for HSPC progression and treatment was developed based on the underlying disease dynamics (represented by prostate-specific antigen; PSA) as affected by ADT. Following fine-tuning by a dataset of ADT-treated HSPC patients, the model was embedded in an algorithm, which predicts the patient's time to biochemical failure (BF) based on clinical metrics obtained before or early in-treatment. The mechanistic model, including a tumor growth law with a dynamic power and an elaborate ADT-resistance mechanism, successfully retrieved individual time-courses of PSA (R(2) = 0.783). Using the personal Gleason score (GS) and PSA at diagnosis, as well as PSA dynamics from 6 months after ADT onset, and given the full ADT regimen, the personalization algorithm accurately predicted the individual time to BF of ADT in 90% of patients in the retrospective cohort (R(2) = 0.98). The algorithm we have developed, predicting biochemical failure based on routine clinical tests, could be especially useful for patients destined for short-lived ADT responses and quick progression to CRPC. Prospective studies must validate the utility of the algorithm for clinical decision-making. © 2015 Wiley Periodicals, Inc.

  16. Clinical Impact of the Number of Treatment Cycles in First-Line Docetaxel for Patients With Metastatic Castration-Resistant Prostate Cancer.

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    Kongsted, Per; Svane, Inge Marie; Lindberg, Henriette; Sengeløv, Lisa

    2017-04-01

    We investigated the impact of the number of docetaxel cycles administered in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with first-line chemotherapy. Charts from 421 consecutive patients who initiated standard treatment with docetaxel-based chemotherapy (75 mg/m 2 every 3 weeks) between 2007 and 2013 were reviewed. Patients who received patients were divided into 2 groups on the basis of whether or not ≥ 9 cycles of docetaxel were administered (n = 108 and 184, respectively). Reasons for treatment discontinuation and postdocetaxel treatments were registered. Prostate-specific antigen (PSA) responses were defined as a confirmed ≥ 50% decrease in baseline PSA levels. Overall survival (OS) was calculated from start of therapy using the Kaplan-Meier method. Cox proportional hazards were calculated to estimate the effect of clinical variables on OS. OS was longer in patients treated with ≥ 9 cycles of docetaxel (21.9 months vs. 17.2 months; P patients treated with ≥ 9 cycles of docetaxel when only patients ending docetaxel because of toxicity or treatment conclusion (22.3 vs. 19.4 months; P = .048, log rank) or patients who achieved a PSA response (22.3 vs. 18.7 months; P = .012, log rank) were evaluated. mCRPC-related prognostic factors and patients who received ≥ 1 subsequent line of therapy post-docetaxel were well balanced. On the basis of our retrospective findings, a superior OS was found in patients treated with ≥ 9 cycles of docetaxel when adjusting for known prognostic factors. Dose reductions might increase the number of docetaxel cycles administered. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. [18F]-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography of LAPC4-CR Castration-Resistant Prostate Cancer Xenograft Model in Soft Tissue Compartments1

    Science.gov (United States)

    McCall, Keisha C.; Cheng, Su-Chun; Huang, Ying; Kohl, Nancy E.; Tupper, Tanya; Van den Abbeele, Annick D.; Zukotynski, Katherine A.; Sweeney, Christopher J.

    2015-01-01

    Preclinical xenograft models have contributed to advancing our understanding of the molecular basis of prostate cancer and to the development of targeted therapy. However, traditional preclinical in vivo techniques using caliper measurements and survival analysis evaluate the macroscopic tumor behavior, whereas tissue sampling disrupts the microenvironment and cannot be used for longitudinal studies in the same animal. Herein, we present an in vivo study of [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) designed to evaluate the metabolism within the microenvironment of LAPC4-CR, a unique murine model of castration-resistant prostate cancer. Mice bearing LAPC4-CR subcutaneous tumors were administered [18F]-FDG via intravenous injection. After a 60-minute distribution phase, the mice were imaged on a PET/CT scanner with submillimeter resolution; and the fused PET/CT images were analyzed to evaluate tumor size, location, and metabolism across the cohort of mice. The xenograft tumors showed [18F]-FDG uptake that was independent of tumor size and was significantly greater than uptake in skeletal muscle and liver in mice (Wilcoxon signed-rank P values of .0002 and .0002, respectively). [18F]-FDG metabolism of the LAPC4-CR tumors was 2.1 ± 0.8 ID/cm3*wt, with tumor to muscle ratio of 7.4 ± 4.7 and tumor to liver background ratio of 6.7 ± 2.3. Noninvasive molecular imaging techniques such as PET/CT can be used to probe the microenvironment of tumors in vivo. This study showed that [18F]-FDG-PET/CT could be used to image and assess glucose metabolism of LAPC4-CR xenografts in vivo. Further work can investigate the use of PET/CT to quantify the metabolic response of LAPC4-CR to novel agents and combination therapies using soft tissue and possibly bone compartment xenograft models. PMID:26055171

  18. Differences in treatment patterns among patients with castration-resistant prostate cancer treated by oncologists versus urologists in a US managed care population

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    Engel-Nitz, Nicole M; Alemayehu, Berhanu; Parry, David; Nathan, Faith

    2011-01-01

    Differences in treatment patterns, health care resource utilization, and costs between patients with castration-resistant prostate cancer (CRPC) treated by oncologists and those treated by urologists were examined. Patients aged ≥40 with CRPC were identified using claims from a large US managed health care plan between July 2001 and December 2007. A 6-month baseline period was used to assess patient characteristics. Patients with visits to an urologist, without visits to an oncologist, were assigned to the urology cohort, and patients with visits to an oncologist, with or without visits to an urologist, were assigned to the oncology cohort. Treatment patterns, health care resource utilization, and costs during a variable follow-up period were compared between cohorts using descriptive statistics and Lin’s regression. The urology cohort had fewer comorbid illnesses (P < 0.001) and patients were less likely to have other cancers during baseline (P < 0.001) or to die during follow-up (P = 0.004) compared with the oncology cohort. The oncology cohort patients were significantly more likely to have a claim for hormones (74.5% vs 61.1%; P < 0.001), chemotherapy (46.9% vs 10.2%, P < 0.001), and radiation (22.3% vs 3.7%, P < 0.0001) over follow-up. Mean unadjusted health care costs were higher in the oncology vs the urology cohort (US$31,896 vs US$15,318, respectively; P < 0.001). At 6 years follow-up, cumulative adjusted CRPC-specific costs were significantly higher among patients treated by oncologists with chemotherapy than among patients treated by urologists. CRPC patients treated by oncologists had greater use of hormones, chemotherapy, and radiation; higher percentages of patients with inpatient stays, emergency room, and ambulatory visits; and higher health care costs, than patients treated by urologists

  19. Androgen Receptor Modulation Optimized for Response (ARMOR) Phase I and II Studies: Galeterone for the Treatment of Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Montgomery, Bruce; Eisenberger, Mario A; Rettig, Matthew B; Chu, Franklin; Pili, Roberto; Stephenson, Joseph J; Vogelzang, Nicholas J; Koletsky, Alan J; Nordquist, Luke T; Edenfield, William J; Mamlouk, Khalid; Ferrante, Karen J; Taplin, Mary-Ellen

    2016-03-15

    Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies [Androgen Receptor Modulation Optimized for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study. In ARMOR1, 49 patients received increasing doses (650-2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700-3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed. In ARMOR1, across all doses, 49.0% (24/49) achieved a ≥30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a ≥50% PSA decline (PSA50). In ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was well tolerated; the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. Most were mild or moderate in severity and required no action and there were no apparent mineralocorticoid excess (AME) events. The efficacy and safety from ARMOR1 and ARMOR2 part 1 and the pharmacokinetic results support the galeterone tablet dose of 2,550 mg/d for further study. Galeterone was well tolerated and demonstrated pharmacodynamic changes consistent with its selective, multifunctional AR signaling inhibition. ©2015 American Association for Cancer Research.

  20. Systemic therapy in men with metastatic castration-resistant prostate cancer:American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline.

    Science.gov (United States)

    Basch, Ethan; Loblaw, D Andrew; Oliver, Thomas K; Carducci, Michael; Chen, Ronald C; Frame, James N; Garrels, Kristina; Hotte, Sebastien; Kattan, Michael W; Raghavan, Derek; Saad, Fred; Taplin, Mary-Ellen; Walker-Dilks, Cindy; Williams, James; Winquist, Eric; Bennett, Charles L; Wootton, Ted; Rumble, R Bryan; Dusetzina, Stacie B; Virgo, Katherine S

    2014-10-20

    To provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC). The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature. When added to androgen deprivation, therapies demonstrating improved survival, improved quality of life (QOL), and favorable benefit-harm balance include abiraterone acetate/prednisone, enzalutamide, and radium-223 ((223)Ra; for men with predominantly bone metastases). Improved survival and QOL with moderate toxicity risk are associated with docetaxel/prednisone. For asymptomatic/minimally symptomatic men, improved survival with unclear QOL impact and low toxicity are associated with sipuleucel-T. For men who previously received docetaxel, improved survival, unclear QOL impact, and moderate to high toxicity risk are associated with cabazitaxel/prednisone. Modest QOL benefit (without survival benefit) and high toxicity risk are associated with mitoxantrone/prednisone after docetaxel. No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib. Continue androgen deprivation (pharmaceutical or surgical) indefinitely. Abiraterone acetate/prednisone, enzalutamide, or (223)Ra should be offered; docetaxel/prednisone should also be offered, accompanied by discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomatic men. For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk. Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered, accompanied by discussion of limited known clinical benefit. Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to evaluate optimal sequences or

  1. Comparison of Timed Automata with Discrete Event Simulation for Modeling of Biomarker-Based Treatment Decisions: An Illustration for Metastatic Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Degeling, Koen; Schivo, Stefano; Mehra, Niven; Koffijberg, Hendrik; Langerak, Rom; de Bono, Johann S; IJzerman, Maarten J

    2017-12-01

    With the advent of personalized medicine, the field of health economic modeling is being challenged and the use of patient-level dynamic modeling techniques might be required. To illustrate the usability of two such techniques, timed automata (TA) and discrete event simulation (DES), for modeling personalized treatment decisions. An early health technology assessment on the use of circulating tumor cells, compared with prostate-specific antigen and bone scintigraphy, to inform treatment decisions in metastatic castration-resistant prostate cancer was performed. Both modeling techniques were assessed quantitatively, in terms of intermediate outcomes (e.g., overtreatment) and health economic outcomes (e.g., net monetary benefit). Qualitatively, among others, model structure, agent interactions, data management (i.e., importing and exporting data), and model transparency were assessed. Both models yielded realistic and similar intermediate and health economic outcomes. Overtreatment was reduced by 6.99 and 7.02 weeks by applying circulating tumor cell as a response marker at a net monetary benefit of -€1033 and -€1104 for the TA model and the DES model, respectively. Software-specific differences were observed regarding data management features and the support for statistical distributions, which were considered better for the DES software. Regarding method-specific differences, interactions were modeled more straightforward using TA, benefiting from its compositional model structure. Both techniques prove suitable for modeling personalized treatment decisions, although DES would be preferred given the current software-specific limitations of TA. When these limitations are resolved, TA would be an interesting modeling alternative if interactions are key or its compositional structure is useful to manage multi-agent complex problems. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights

  2. Effectiveness and safety of cabazitaxel chemotherapy for metastatic castration-resistant prostatic carcinoma on Turkish patients (The Anatolian Society of Medical Oncology).

    Science.gov (United States)

    Süner, A; Aydın, D; Hacıoğlu, M B; Doğu, G G; İmamoğlu, G I; Menekşe, S; Pilancı, K N; Yazıcı, Ö K; Koca, D; Karaağaç, M; Akyol, M; Akman, T; Ergen, S; Avcı, N; Kaçan, T; Bozkurt, O; Kefeli, U; Urakçı, Z; Araz, M; Arpacı, E; Harputlu, H; Sevinç, A

    2016-04-01

    Prostate cancer is among the most common cancers in males. Prostate cancer is androgen dependent in the beginning, but as time progresses, it becomes refractory to androgen deprivation treatment. At this stage, docetaxel has been used as standard treatment for years. Cabazitaxel has become the first chemotherapeutic agent which has been shown to increase survival for patients with metastatic Castrate Resistant Prostate Cancer (mCRPC) that progresses after docetaxel. Phase 3 TROPIC study demonstrated that cabazitaxel prolongs survival. In this study, we evaluated a total of 103 patients who took cabazitaxel chemotherapy for mCRPC diagnosis in 21 centers of Turkey, retrospectively. This study included patients who progressed despite docetaxel treatments, had ECOG performance score between 0-2, and used cabazitaxel treatment. Patients received cabazitaxel 25 mg/m2 at every 3 weeks, and prednisolone 5 mg twice a day. Median number of cabazitaxel cures was 5.03 (range: 1-17). Cabazitaxel response evaluation detected that 34% of the patients had a partial response, 22.3% had stable disease and 32% had a progressive disease. Grade 3-4 hematological toxicities were neutropenia (28.2%), neutropenic fever (14.5%), anemia (6.7%), and thrombocytopenia (3.8%). In our study, median progression-free survival (PFS) was 7.7 months and overall survival (OS) was 10.6 months. This study reflects toxicity profile of Turkish patients as a Caucasian race. We suggest that cabazitaxel is a safe and effective treatment option for mCRPC patients who progress after docetaxel. Moreover, ethnicity may play important roles both in treatment response and in toxicity profile.

  3. Effect of supplementing crossbred Xhosa lop-eared goat castrates with Moringa oleifera leaves on growth performance, carcass and non-carcass characteristics.

    Science.gov (United States)

    Moyo, Busani; Masika, Patrick J; Muchenje, Voster

    2012-04-01

    The objective of the study was to determine the effect of supplementing Moringa oleifera leaves (MOL) on growth performance, carcass and non-carcass characteristics of crossbred Xhosa lop-eared goats. A total of 24 castrated goats aged 8 months, with a mean initial weight of 15.1 ± 2.3 kg, were randomly divided into three diet groups with eight goats in each. The duration of the trial was 60 days. All goats received a basal diet of grass hay (GH) ad libitum and wheat bran (200 g/day each). The MOL and sunflower cake (SC) groups were fed additional 200 g of dried M. oleifera leaves and 170 g of SC, respectively. The third group (GH) did not receive any additional ration. The crude protein of MOL (23.75%) and SC (23.27%) were higher (P < 0.05) than that of the GH diet (14.08%). The attained average daily weight gain for goats fed MOL, SC and GH were 103.3, 101.3 and 43.3 g, respectively (P < 0.05). Higher (P < 0.05) feed intakes observed were in SC (491.5 g) and MOL (490.75 g) compared with GH (404.5 g). The hot carcass weight was higher (P < 0.05) for SC (10.48 kg) and MOL (10.34 kg) than for the GH group (8.59 kg). The dressing percentage in SC (55.8%) and MOL (55.1%) were higher (P < 0.05) than that of the GH (52.9%). The growth performance and carcass characteristics of SC and MOL goats were not different. Feeding MOL or SC improved the growth performance and carcass characteristics of goats in an almost similar way, which indicates that M. oleifera could be used as an alternative protein supplement in goats.

  4. Preliminary study of the specific endothelin a receptor antagonist zibotentan in combination with docetaxel in patients with metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Trump, Donald L; Payne, Heather; Miller, Kurt; de Bono, Johann S; Stephenson, Joe; Burris, Howard A; Nathan, Faith; Taboada, Maria; Morris, Thomas; Hubner, Andreas

    2011-09-01

    This two-part study assessed the safety and tolerability of combined treatment with zibotentan (ZD4054), a specific endothelin A receptor antagonist, plus docetaxel in patients with metastatic castration-resistant prostate cancer. Part A was an open-label, dose-finding phase to determine the safety and toxicity profile of zibotentan in combination with docetaxel. Patients received once-daily oral zibotentan 10 mg (initial cohort) or 15 mg in combination with docetaxel 75 mg/m(2) (administered on day 1 of each 21-day cycle) for up to 10 cycles. Part B was a double-blind phase which evaluated the safety and preliminary activity of zibotentan plus docetaxel. Patients were randomized 2:1 to receive zibotentan (at the highest tolerated dose identified in part A) plus docetaxel or placebo plus docetaxel. Six patients were enrolled in part A (n  = 3, zibotentan 10 mg; n = 3, zibotentan 15 mg). No dose-limiting toxicity was observed, thus zibotentan 15 mg in combination with docetaxel was evaluated in part B (n = 20, zibotentan plus docetaxel; n = 11, placebo plus docetaxel). CTCAE grade ≥3, most commonly neutropenia or leucopenia, were reported in 10 (50%) and nine (82%) patients in the zibotentan and placebo groups, respectively. One (17%) patient receiving placebo achieved complete response, two (22%) patients receiving zibotentan achieved partial response and stable disease occurred in six (67%) and three (50%) patients receiving zibotentan and placebo, respectively. The tolerability of zibotentan plus docetaxel was consistent with the known profiles of each drug. Sufficient preliminary activity was seen with this combination to merit continued development. Copyright © 2011 Wiley-Liss, Inc.

  5. Alterations of androgen receptor-regulated enhancer RNAs (eRNAs) contribute to enzalutamide resistance in castration-resistant prostate cancer.

    Science.gov (United States)

    Zhao, Jingwen; Zhao, Yu; Wang, Liguo; Zhang, Jun; Karnes, R Jeffrey; Kohli, Manish; Wang, Guixia; Huang, Haojie

    2016-06-21

    Enzalutamide is a second-generation anti-androgen for treatment of castration-resistant prostate cancer (CPRC). It prolongs survival of CRPC patients, but its overall survival benefit is relatively modest (4.8 months) and by 24 months most patients progress on enzalutamide. To date, however, the molecular mechanisms underlying enzalutamide resistance remain elusive. Herein, we report enzalutamide treatment-induced alterations of androgen receptor (AR)-regulated enhancer RNAs (AR-eRNAs) and their roles in enzalutamide-resistant growth and survival of CRPC cells. AR chromatin immunoprecipitation and high throughput sequencing (ChIP-seq) and RNA-seq analyses revealed that 188 and 227 AR-eRNAs were differentially expressed in enzalutamide-resistant LNCaP and C4-2 cells, respectively. The AR-eRNAs upregulated in C4-2 cells and downregulated in LNCaP cells were selected through meta-analysis. Expression of AR-eRNAs and related mRNAs in the loci of FTO, LUZP2, MARC1 and NCAM2 were further verified by real-time RT-PCR. Silencing of LUZP2 inhibited, but silencing of MARC1 increased the growth of enzalutamide-resistant C4-2 cells. Intriguingly, meta-analysis showed that expression of LUZP2 mRNA increased in primary tumors compared to normal prostate tissues, but decreased again in metastatic CRPC. Our findings suggest that eRNA alteration profiling is a viable new approach to identify functional gene loci that may not only contribute to enzalutamide-resistant growth of CRPC, but also serve as new targets for CRPC therapy.

  6. Efficacy of a buccal meloxicam formulation for pain relief in Merino lambs undergoing knife castration and tail docking in a randomised field trial.

    Science.gov (United States)

    Small, A H; Belson, S; Holm, M; Colditz, I G

    2014-10-01

    To assess the efficacy of oral transmucosal meloxicam for pain relief in lambs at marking. A blinded, placebo-controlled, randomised, block design field study of 60 Merino lambs aged 7-10 weeks allocated to placebo and meloxicam treatments and studied in two cohorts of 30. Placebo-treated lambs received 1 mL/10 kg of drug vehicle and meloxicam-treated lambs received 1 mg/kg meloxicam at 10 mg/mL. Treatments were administered into the buccal cavity immediately before knife castration and hot-iron tail docking. Lambs were then released into a grassed paddock (0.34 ha). Time to mother-up was recorded and behaviours were observed every 15 min for 8 h and again for 45 min at 24 h. The sequence in which lambs exited the paddock with their mothers was then recorded. Weight change and wound scores were recorded 4 and 7 days after marking. Meloxicam did not affect mothering-up. In the 8 h following marking, meloxicam led to a 7-fold reduction (P meloxicam group spent significantly less time in standing postures and tended to spend more time grazing, suckling and in normal lying postures. At 24 h, the meloxicam group spent more time lying and less time standing. There was no effect of treatments on the sequence in which lambs moved into a fresh paddock or on weight change. The buccal meloxicam formulation provided substantial analgesia to lambs on the day of marking. Slight benefits were evident the following morning. © 2014 Australian Veterinary Association.

  7. Exponential rise in prostate-specific antigen (PSA) during anti-androgen withdrawal predicts PSA flare after docetaxel chemotherapy in patients with castration-resistant prostate cancer.

    Science.gov (United States)

    Han, Kyung Seok; Hong, Sung Joon

    2015-03-01

    To investigate the relationship between rising patterns of prostate-specific antigen (PSA) before chemotherapy and PSA flare during the early phase of chemotherapy in patients with castration-resistant prostate cancer (CRPC). This study included 55 patients with CRPC who received chemotherapy and in whom pre-treatment or post-treatment PSA levels could be serially obtained. The baseline parameters included age, performance, Gleason score, PSA level, and disease extent. PSA doubling time was calculated using the different intervals: the conventional interval from the second hormone manipulation following the nadir until anti-androgen withdrawal (PSADT1), the interval from the initial rise after anti-androgen withdrawal to the start of chemotherapy (PSADT2), and the interval from the nadir until the start of chemotherapy (PSADT3). The PSA growth patterns were analyzed using the ratio of PSADT2 to PSADT1. There were two growth patterns of PSA doubling time: 22 patients (40.0%) had a steady pattern with a more prolonged PSADT2 than PSADT1, while 33 (60.0%) had an accelerating pattern with a shorter PSADT2 than PSADT1. During three cycles of chemotherapy, PSA flare occurred in 11 patients (20.0%); of these patients, 3 were among 33 (9.1%) patients with an accelerating PSA growth pattern and 8 were among 22 patients (36.4%) with a steady PSA growth pattern (p=0.019). Multivariate analysis showed that only PSA growth pattern was an independent predictor of PSA flare (p=0.034). An exponential rise in PSA during anti-androgen withdrawal is a significant predictor for PSA flare during chemotherapy in CRPC patients.

  8. PSA response to cabazitaxel is associated with improved progression-free survival in metastatic castration-resistant prostate cancer: the non-interventional QoLiTime study.

    Science.gov (United States)

    Hammerer, Peter; Al-Batran, Salah-Eddin; Windemuth-Kieselbach, Christine; Keller, Martin; Hofheinz, Ralf-Dieter

    2018-03-01

    To evaluate the association between prostate-specific antigen (PSA) response and progression-free and overall survival in men with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel. Men with mCRPC receiving cabazitaxel (25 mg/m 2 , every 3 weeks) plus oral prednis(ol)one (10 mg/day) were enrolled in the non-interventional, prospective QoLiTime study. Main outcome measures were progression-free survival and overall survival, in all patients and in those who showed a ≥ 50 or a ≥ 30% decrease in PSA relative to baseline after four cycles of cabazitaxel, as well as quality-of-life parameters. Of the 527 men (median age 72 years), 266 received ≥ 4 cycles of cabazitaxel and had PSA response data. After four cycles, 34.6% of men achieved a PSA decrease ≥ 50% and 49.6% a decrease ≥ 30%. Median progression-free survival was 7.7 (95% CI 6.2, 9.5) months, and overall survival was 19.5 (95% CI 16.0, 30.9) months, corresponding to 1-year event rates of 39.4 and 78.8%, respectively. Median progression-free survival was longer in PSA responders versus non-responders (15.7 vs 5.5 months at 50% cut-off; 15.7 vs 5.3 months for 30% cut-off; both P PSA response after four cycles of cabazitaxel is associated with improved progression-free survival in men with mCRPC treated with cabazitaxel plus prednis(ol)one.

  9. PSA time to nadir as a prognostic factor of first-line docetaxel treatment in castration-resistant prostate cancer: evidence from patients in Northwestern China.

    Science.gov (United States)

    Wu, Kai-Jie; Pei, Xin-Qi; Tian, Ge; Wu, Da-Peng; Fan, Jin-Hai; Jiang, Yu-Mei; He, Da-Lin

    2018-01-01

    Docetaxel-based chemotherapy remains the first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) in China; however, the prognostic factors associated with effects in these patients are still controversial. In this study, we retrospectively reviewed the data from 71 eligible Chinese patients who received docetaxel chemotherapy from 2009 to 2016 in our hospital and experienced a reduction of prostate-specific antigen (PSA) level ≥50% during the treatment and investigated the potential role of time to nadir (TTN) of PSA. TTN was defined as the time from start of chemotherapy to the nadir of PSA level during the treatment. Multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival (OS). In these patients, the median of TTN was 17 weeks. Patients with TTN ≥17 weeks had a longer response time to chemotherapy compared to TTN PSA progression in patients with TTN ≥17 weeks was 11.44 weeks compared to 5.63 weeks when TTN was PSA level at the diagnosis of cancer (HR: 4.337, 95% CI: 1.616-11.645, P = 0.004), duration of initial androgen deprivation therapy (HR: 2.982, 95% CI: 1.104-8.045, P = 0.031), neutrophil-to-lymphocyte ratio (HR: 3.963, 95% CI: 1.380-11.384, P = 0.011), and total PSA response (Class 1 [PSA remains an important prognostic marker in predicting therapeutic outcome in Chinese population who receive chemotherapy for mCRPC and have >50% PSA remission.

  10. Development and Validation of A Bioanalytical Method to Quantitate Enzalutamide and its Active Metabolite N-Desmethylenzalutamide in Human Plasma: Application to Clinical Management of Metastatic Castration-Resistant Prostate Cancer Patients.

    Science.gov (United States)

    Benoist, Guillemette E; van der Meulen, Eric; van Oort, Inge M; Beumer, Jan Hendrik; Somford, Diederik M; Schalken, Jack A; Burger, David M; van Erp, Nielka P

    2018-02-05

    Enzalutamide is a potent androgen-signaling receptor inhibitor and is licensed for the treatment of metastatic castration-resistant prostate cancer. N-desmethylenzalutamide is the active metabolite of enzalutamide. A method to quantitate enzalutamide and its active metabolite was developed and validated according to the European Medicine Agency (EMA) guidelines. Enzalutamide and N-desmethylenzalutamide were extracted by protein precipitation, separated on a C18 column with gradient elution and analyzed with tandem quadruple mass spectrometry in positive ion mode. A stable deuterated isotope (D6-enzalutamide) was used as an internal standard. The method was tested and stability was studied in real life patients with metastatic castration-resistant prostate cancer patients treated with enzalutamide. The calibration curve covered the range of 500-50000 ng/mL. Within- and between-day precisions were <8% and accuracies were within 108% for both enzalutamide and N-desmethylenzalutamide. Precisions for lower-limit-of-quantification level were <10% and accuracies within 116% for enzalutamide and N-desmethylenzalutamide. Enzalutamide and N-desmethylenzalutamide stability was proven for 24 hours for whole blood at ambient temperature, and 23 days for plasma at both ambient temperature and 2-8 °C. Long-term patient plasma stability was shown for 14 months at -40 °C. This bioanalytical method was successfully validated and applied to determine plasma concentrations of enzalutamide and N-desmethylenzalutamide in clinical studies and in routine patient care.

  11. Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial.

    Science.gov (United States)

    Fizazi, Karim; Massard, Christophe; Bono, Petri; Jones, Robert; Kataja, Vesa; James, Nicholas; Garcia, Jorge A; Protheroe, Andrew; Tammela, Teuvo L; Elliott, Tony; Mattila, Leena; Aspegren, John; Vuorela, Annamari; Langmuir, Peter; Mustonen, Mika

    2014-08-01

    ODM-201 is a novel androgen receptor (AR) inhibitor designed to block the growth of prostate cancer cells through high-affinity binding to the AR and inhibition of AR nuclear translocation. This trial assessed ODM-201's safety, pharmacokinetics, and activity in men with metastatic castration-resistant prostate cancer. The ARADES trial is an open-label phase 1-2 trial undertaken in 23 hospitals across Europe and USA with ongoing long-term follow-up. Men with progressive metastatic castration-resistant prostate cancer, who had castrate concentrations of testosterone and an Eastern Cooperative Oncology Group score of 0-1 were enrolled. In the phase 1 part of the trial, patients were given oral ODM-201 at a starting daily dose of 200 mg, which was increased to 400 mg, 600 mg, 1000 mg, 1400 mg, and 1800 mg. In phase 2, patients were randomly assigned centrally and stratified by previous chemotherapy and treatment with CPY17 inhibitors, to receive one of three daily doses of ODM-201 (200 mg, 400 mg, and 1400 mg). The primary endpoint in phase 1 was safety and tolerability, whereas in phase 2 it was the proportion of patients with a PSA response (50% or greater decrease in serum PSA) at week 12. All analyses included patients who had received at least one dose of ODM-201. This trial is registered with ClinicalTrials.gov, number NCT01317641, and NCT01429064 for the follow-up after 12 weeks. We enrolled patients between April 5, 2011, and March 12, 2013. In phase 1, 24 patients were enrolled to six sequential cohorts of three to six patients and received a daily dose of ODM-201, 200-1800 mg. No dose-limiting toxic effects were reported and the maximum tolerated dose was not reached. In phase 1, three patients reported eight adverse events of grade 3 (fracture, muscle injury, laceration, paralytic ileus, pain, presyncope, urinary retention, and vomiting) and one patient had a grade 4 adverse event (lymphoedema). None of the grade 3-4 adverse events were deemed to be related

  12. Lu-177-PSMA-617 Prostate-Specific Membrane Antigen Inhibitor Therapy in Patients with Castration-Resistant Prostate Cancer: Stability, Bio-distribution and Dosimetry

    Directory of Open Access Journals (Sweden)

    Levent Kabasakal

    2017-06-01

    Full Text Available Objective: The aim of the study was to estimate the radiation-absorbed doses and to study the in vivo and in vitro stability as well as pharmacokinetic characteristics of lutetium-177 (Lu-177 prostate-specific membrane antigen (PSMA-617. Methods: For this purpose, 7 patients who underwent Lu-177-PSMA therapy were included into the study. The injected Lu-177-PSMA-617 activity ranged from 3.6 to 7.4 GBq with a mean of 5.2±1.8 GBq. The stability of radiotracer in saline was calculated up to 48 h. The stability was also calculated in blood and urine samples. Post-therapeutic dosimetry was performed based on whole body and single photon emission computed tomography/computed tomography (SPECT/CT scans on dual-headed SPECT/CT system. Results: The radiochemical yield of Lu-177-PSMA-617 was >99%. It remained stable in saline up to 48 h. Analyses of the blood and urine samples showed a single radioactivity peak even at 24 hours after injection. Half-life of the distribution and elimination phases were calculated to be 0.16±0.09 and 10.8±2.5 hours, respectively. The mean excretion rate was 56.5±8.8% ranging from 41.5% to 65.4% at 24 h. Highest radiation estimated doses were calculated for parotid glands and kidneys (1.90±1.19 and 0.82±0.25 Gy/GBq respectively. Radiation dose given to the bone marrow was significantly lower than those of kidney and parotid glands (p<0.05 (0.030±0.008 Gy/GBq. Conclusion: Lu-177-PSMA-617 is a highly stable compound both in vitro and in vivo. Lu-177-PSMA-617 therapy seems to be a safe method for the treatment of castration-resistant prostate cancer patients. The fractionation regime that enables the longest duration of tumor control and/or survival will have to be developed in further studies.

  13. Assessment of a prognostic model, PSA metrics and toxicities in metastatic castrate resistant prostate cancer using data from Project Data Sphere (PDS)

    Science.gov (United States)

    Hamilton, Robert J.; Abdallah, Kald; Pintilie, Melania; Joshua, Anthony M.

    2017-01-01

    Background Prognostic models in metastatic castrate resistant prostate cancer (mCRPC) may have clinical utility. Using data from PDS, we aimed to 1) validate a contemporary prognostic model (Templeton et al., 2014) 2) evaluate prognostic impact of concomitant medications and PSA decrease 3) evaluate factors associated with docetaxel toxicity. Methods We accessed data on 2,449 mCRPC patients in PDS. The existing model was validated with a continuous risk score, time-dependent receiver operating characteristic (ROC) curves, and corresponding time-dependent Area under the Curve (tAUC). The prognostic effects of concomitant medications and PSA response were assessed by Cox proportional hazards models. One year tAUC was calculated for multivariable prognostic model optimized to our data. Conditional logistic regression models were used to assess associations with grade 3/4 adverse events (G3/4 AE) at baseline and after cycle 1 of treatment. Results Despite limitations of the PDS data set, the existing model was validated; one year AUC, was 0.68 (95% CI 95% CI, .66 to .71) to 0.78 (95%CI, .74 to .81) depending on the subset of datasets used. A new model was constructed with an AUC of .74 (.72 to .77). Concomitant medications low molecular weight heparin and warfarin were associated with poorer survival, Metformin and Cox2 inhibitors were associated with better outcome. PSA response was associated with survival, the effect of which was greatest early in follow-up. Age was associated with baseline risk of G3/4 AE. The odds of experiencing G3/4 AE later on in treatment were significantly greater for subjects who experienced a G3/4 AE in their first cycle (OR 3.53, 95% CI 2.53–4.91, p < .0001). Conclusion Despite heterogeneous data collection protocols, PDS provides access to large datasets for novel outcomes analysis. In this paper, we demonstrate its utility for validating existing models and novel model generation including the utility of concomitant medications in

  14. {sup 177}Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer: safety, efficacy, and quality of life assessment

    Energy Technology Data Exchange (ETDEWEB)

    Yadav, Madhav Prasad; Ballal, Sanjana; Tripathi, Madhavi; Damle, Nishikant Avinash; Bal, Chandrasekhar [All India Institute of Medical Sciences, Department of Nuclear Medicine, Ansari Nagar, New Delhi (India); Sahoo, Ranjit Kumar [All India Institute of Medical Sciences, Department of Medical Oncology, BR Ambedkar Rotary Cancer Hospital, New Delhi (India); Seth, Amlesh [All India Institute of Medical Sciences, Department of Urology, New Delhi (India)

    2017-01-15

    The purpose of this study was to evaluate the efficacy and safety of a novel theranostic agent, {sup 177}Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer (mCRPC). Thirty-one mCRPC patients with progressive disease despite second-line hormonal therapy and/or docetaxel chemotherapy were recruited for the study. All patients underwent diagnostic{sup 68}Ga-PSMA-HBED-CCPET/CT, prior to inclusion for therapy. Included patients then underwent quarterly {sup 177}Lu-DKFZ-PSMA-617 therapy. Hematological, kidney function, liver function tests, and serum PSA levels were recorded before and after therapy at 2 weeks, 4 weeks, and 3 month intervals. Biochemical response was assessed with trend in serum PSA levels. Metabolic response was assessed by PERCIST 1 criteria. Clinical response was assessed by visual analogue score (VASmax) analgesic score (AS), Karanofsky performance status (KPS), and toxicity and response criteria of the Eastern Cooperative Oncology Group (ECOG) criteria. The mean age of patients was 65.93 ± 9.77 years (range: 38-81 years). The mean activity administered in the 31 patients was 5069 ± 1845 MBq ranging from one to four cycles. There was a decline in the mean serum PSA levels from the baseline (baseline: 275 ng/mL, post 1st cycle therapy: 141.75 ng/mL). Based on biochemical response criteria 2/31, 20/31, 3/31, and 6/31 had complete response (CR), partial response(PR), stable disease (SD), and progressive disease (PD), respectively. Metabolic response revealed 2/6 patients with CR, and the remaining 3/6 patients with PR and 1/6 patients with SD. The mean VASmax score decreased from 7.5 to 3. The mean analgesic score decreased from 2.5 to 1.8 after therapy. The mean KPS score improved from 50.32 to 65.42 after therapies. The mean ECOG performance status improved from 2.54 to 1.78 after therapy. Two patients experienced grade I and grade II hemoglobin toxicity each. None of the patients experienced nephrotoxicity or hepatotoxicity

  15. [(18)F]-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography of LAPC4-CR Castration-Resistant Prostate Cancer Xenograft Model in Soft Tissue Compartments.

    Science.gov (United States)

    McCall, Keisha C; Cheng, Su-Chun; Huang, Ying; Kohl, Nancy E; Tupper, Tanya; Van den Abbeele, Annick D; Zukotynski, Katherine A; Sweeney, Christopher J

    2015-06-01

    Preclinical xenograft models have contributed to advancing our understanding of the molecular basis of prostate cancer and to the development of targeted therapy. However, traditional preclinical in vivo techniques using caliper measurements and survival analysis evaluate the macroscopic tumor behavior, whereas tissue sampling disrupts the microenvironment and cannot be used for longitudinal studies in the same animal. Herein, we present an in vivo study of [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) designed to evaluate the metabolism within the microenvironment of LAPC4-CR, a unique murine model of castration-resistant prostate cancer. Mice bearing LAPC4-CR subcutaneous tumors were administered [(18)F]-FDG via intravenous injection. After a 60-minute distribution phase, the mice were imaged on a PET/CT scanner with submillimeter resolution; and the fused PET/CT images were analyzed to evaluate tumor size, location, and metabolism across the cohort of mice. The xenograft tumors showed [(18)F]-FDG uptake that was independent of tumor size and was significantly greater than uptake in skeletal muscle and liver in mice (Wilcoxon signed-rank P values of .0002 and .0002, respectively). [(18)F]-FDG metabolism of the LAPC4-CR tumors was 2.1 ± 0.8 ID/cm(3)*wt, with tumor to muscle ratio of 7.4 ± 4.7 and tumor to liver background ratio of 6.7 ± 2.3. Noninvasive molecular imaging techniques such as PET/CT can be used to probe the microenvironment of tumors in vivo. This study showed that [(18)F]-FDG-PET/CT could be used to image and assess glucose metabolism of LAPC4-CR xenografts in vivo. Further work can investigate the use of PET/CT to quantify the metabolic response of LAPC4-CR to novel agents and combination therapies using soft tissue and possibly bone compartment xenograft models. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Subsequent Chemotherapy and Treatment Patterns After Abiraterone Acetate in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302.

    Science.gov (United States)

    de Bono, Johann S; Smith, Matthew R; Saad, Fred; Rathkopf, Dana E; Mulders, Peter F A; Small, Eric J; Shore, Neal D; Fizazi, Karim; De Porre, Peter; Kheoh, Thian; Li, Jinhui; Todd, Mary B; Ryan, Charles J; Flaig, Thomas W

    2017-04-01

    Treatment patterns for metastatic castration-resistant prostate cancer (mCRPC) have changed substantially in the last few years. In trial COU-AA-302 (chemotherapy-naïve men with mCRPC), abiraterone acetate plus prednisone (AA) significantly improved radiographic progression-free survival and overall survival (OS) when compared to placebo plus prednisone (P). This post hoc analysis investigated clinical responses to docetaxel as first subsequent therapy (FST) among patients who progressed following protocol-specified treatment with AA, and characterized subsequent treatment patterns among older (≥75 yr) and younger (AA arm received subsequent treatment with one or more agents approved for mCRPC. Efficacy analysis was performed for patients for whom baseline and at least one post-baseline prostate-specific antigen (PSA) values were available. Baseline and at least one post-baseline PSA values were available for 100 AA patients who received docetaxel as FST. While acknowledging the limitations of post hoc analyses, 40% (40/100) of these patients had an unconfirmed ≥50% PSA decline with first subsequent docetaxel therapy, and 27% (27/100) had a confirmed ≥50% PSA decline. The median docetaxel treatment duration among these 100 patients was 4.2 mo. Docetaxel was the most common FST among older and younger patients from each treatment arm. However, 43% (79/185) of older patients who progressed on AA received no subsequent therapy for mCRPC, compared with 17% (60/361) of younger patients. Patients with mCRPC who progress with AA treatment may still derive benefit from subsequent docetaxel therapy. These data support further assessment of treatment patterns following AA treatment for mCRPC, particularly among older patients. ClinicalTrials.gov NCT00887198. Treatment patterns for advanced prostate cancer have changed substantially in the last few years. This additional analysis provides evidence of clinical benefit for subsequent chemotherapy in men with advanced

  17. Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302).

    Science.gov (United States)

    Rathkopf, Dana E; Smith, Matthew R; de Bono, Johann S; Logothetis, Christopher J; Shore, Neal D; de Souza, Paul; Fizazi, Karim; Mulders, Peter F A; Mainwaring, Paul; Hainsworth, John D; Beer, Tomasz M; North, Scott; Fradet, Yves; Van Poppel, Hendrik; Carles, Joan; Flaig, Thomas W; Efstathiou, Eleni; Yu, Evan Y; Higano, Celestia S; Taplin, Mary-Ellen; Griffin, Thomas W; Todd, Mary B; Yu, Margaret K; Park, Youn C; Kheoh, Thian; Small, Eric J; Scher, Howard I; Molina, Arturo; Ryan, Charles J; Saad, Fred

    2014-11-01

    Abiraterone acetate (an androgen biosynthesis inhibitor) plus prednisone is approved for treating patients with metastatic castration-resistant prostate cancer (mCRPC). Study COU-AA-302 evaluated abiraterone acetate plus prednisone versus prednisone alone in mildly symptomatic or asymptomatic patients with progressive mCRPC without prior chemotherapy. Report the prespecified third interim analysis (IA) of efficacy and safety outcomes in study COU-AA-302. Study COU-AA-302, a double-blind placebo-controlled study, enrolled patients with mCRPC from April 2009 to June 2010. A total of 1088 patients were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1). Patients were randomised 1:1 to abiraterone 1000mg plus prednisone 5mg twice daily by mouth versus prednisone. Co-primary end points were radiographic progression-free survival (rPFS) and overall survival (OS). Median times to event outcomes were estimated using the Kaplan-Meier method. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the Cox model, and treatment comparison used the log-rank test. The O'Brien-Fleming Lan-DeMets α-spending function was used for OS. Adverse events were summarised descriptively. With a median follow-up duration of 27.1 mo, improvement in rPFS was statistically significant with abiraterone treatment versus prednisone (median: 16.5 vs 8.2 mo; HR: 0.52 [95% CI, 0.45-0.61]; ppatient-reported outcomes improved. While the post hoc nature of the long-term safety analysis is a limitation, the safety profile with longer treatment exposure was consistent with prior reports. The updated IA of study COU-AA-302 in patients with mCRPC without prior chemotherapy confirms that abiraterone delays disease progression, pain, and functional deterioration and has clinical benefit with a favourable safety profile, including in patients treated for ≥24 mo. Study COU-AA-302, ClinicalTrials.gov number, NCT00887198. The updated results of this ongoing study

  18. ErbB-2 signaling plays a critical role in regulating androgen-sensitive and castration-resistant androgen receptor-positive prostate cancer cells.

    Science.gov (United States)

    Muniyan, Sakthivel; Chen, Siu-Ju; Lin, Fen-Fen; Wang, Zhengzhong; Mehta, Parmender P; Batra, Surinder K; Lin, Ming-Fong

    2015-11-01

    While androgen deprivation therapy (ADT) reduces tumor burden, autocrine growth factor loops such as human epidermal growth factor receptor 2 (HER2/ErbB-2/neu) have been proposed to contribute to prostate cancer (PCa) survival and relapse. However, the role of ErbB-2 in regulating androgen-sensitive (AS) and castration-resistant (CR) cell proliferation remains unclear. Here, we determined the role of ErbB-2 in PCa progression and survival under steroid-reduced conditions using two independent PCa cell progression models. In AR-positive androgen-independent (AI) PCa cells that exhibit the CR phenotype, ErbB-2 was constitutively activated, compared to corresponding AS PCa cells. In AS LNCaP C-33 cells, androgen-induced ErbB-2 activation through ERK1/2 mediates PCa cell proliferation. Further, the ErbB-2-specific but not EGFR-specific inhibitor suppresses basal and androgen-stimulated cell proliferation and also blocks ERK1/2 activation. ErbB-2 ectopic expression and cPAcP siRNA transfection of LNCaP C-33 cells each increases ErbB-2 tyrosine phosphorylation, correlating with increased AI PSA secretion and cell proliferation. Conversely, trapping ErbB-2 by transfected endoplasmic reticulum-targeting ScFv5R expression vector abolished DHT-induced LNCaP C-33 cell growth. Moreover, inhibition of ErbB-2 but not EGFR in AI LNCaP C-81 and MDA PCa2b-AI PCa cells significantly abolished AI cell growth. In contrast to androgens via ErbB-2/ERK1/2 signaling in AS PCa cells, the inhibition of ErbB-2 abrogated AI cell proliferation by inhibiting the cell survival protein Akt in those AI cells. These results suggest that ErbB-2 is a prominent player in mediating the ligand-dependent and -independent activation of AR in AS and AI/CR PCa cells respectively for PCa progression and survival. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. AR-V7 in circulating tumor cells cluster as a predictive biomarker of abiraterone acetate and enzalutamide treatment in castration-resistant prostate cancer patients.

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    Okegawa, Takatsugu; Ninomiya, Naoki; Masuda, Kazuki; Nakamura, Yu; Tambo, Mitsuhiro; Nutahara, Kikuo

    2018-03-05

    We examined whether androgen receptor splice variant 7 (AR-V7) in circulating tumor cell(CTC)clusters can be used to predict survival in patients with bone metastatic castration resistant-prostate cancer (mCRPC) treated with abiraterone or enzalutamide. We retrospectively enrolled 98 patients with CRPC on abiraterone or enzalutamide, and investigated the prognostic value of CTC cluster detection (+ v -) and AR-V7 detection (+ v -) using a CTC cluster detection - based AR-V7 mRNA assay. We examined ≤50% prostate-specific antigen (PSA) responses, PSA progression-free survival (PSA-PFS), clinical and radiological progression-free survival (radiologic PSF), and overall survival (OS). We then assessed whether AR-V7 expression in CTC clusters identified after On-chip multi-imaging flow cytometry was related to disease progression and survival after first-line systemic therapy. All abiraterone-treated or enzalutamide-treated patients received prior docetaxel. The median follow-up was 20.7 (range: 3.0-37.0) months in the abiraterone and enzalutamide cohorts, respectively. Forty-nine of the 98 men (50.0%) were CTC cluster (-), 23 of the 98 men (23.5%) were CTC cluster(+)/AR-V7(-), and 26 of the 98 men (26.5%) were CTC cluster(+)/AR-V7(+). CTC cluster(+)/AR-V7(+) patients were more likely to have EOD ≥3 at diagnosis (P = 0.003), pain (P = 0.023), higher alkaline phosphatase levels (P cluster(+), CTC cluster(+)/AR-V7(-), and ALP >UNL were independently associated with a poor PSA-PFS, radiographic PFS, and OS in abiraterone-treated patients and enzalutamide-treated patients. The CTC clusters and AR-V7-positive CTC clusters detected were important for assessing the response to abiraterone or enzalutamide therapy and for predicting disease outcome. © 2018 Wiley Periodicals, Inc.

  20. PSMA targeted radioligandtherapy in metastatic castration resistant prostate cancer after chemotherapy, abiraterone and/or enzalutamide. A retrospective analysis of overall survival

    Energy Technology Data Exchange (ETDEWEB)

    Rahbar, K.; Schaefers, M. [University Hospital Muenster, Department of Nuclear Medicine, Muenster (Germany); Boegemann, M. [University Hospital Muenster, Department of Urology, Muenster (Germany); Yordanova, A.; Essler, M.; Ahmadzadehfar, H. [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Eveslage, M. [University Hospital Muenster, Institute of Biostatistics and Clinical Research, Muenster (Germany)

    2018-01-15

    Our aim was to evaluate overall survival and parameters prognosticating longer survival in a large and homogeneous group of patients treated with {sup 177}Lu-PSMA-617 radioligand therapy with heavily pretreated advanced metastatic castration resistant prostate cancer. A total of 104 patients were treated with 351 cycles of {sup 177}Lu-PSMA-617. Prostate specific antigen (PSA) changes after the first cycle of therapy were documented prior to a second cycle. Patients were followed-up for overall survival (OS). Any PSA decline, PSA decline ≥50%, initial PSA, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), visceral metastases and cumulative injected activity were analyzed and evaluated according to OS. Multivariable analysis with parameters with a p-value ≤0.05 in univariate analysis was performed, additionally adjusting for age and presence of visceral metastases. A total of 51 patients (49%) died during the observation period. The majority of patients (97%) presented with bone metastases, 77% with lymph node metastases and 32% with visceral metastases. All patients were treated with at least one line of chemotherapy. Either abiraterone or enzalutamide had been given in 100% of the patients. Any PSA decline occurred in 70 (67%) and a PSA decline ≥50% in 34 (33%) of patients after the first cycle. The median OS was 56.0 weeks (95%CI: 50.5-61.5). Initial PSA decline ≥50%, initial LDH, visceral metastases, second line chemotherapy or prior radium-223 did not have an effect on survival, whereas any initial PSA decline, initial ALP <220 U/L and cumulative injected activity ≥18.8 GBq were associated with a longer survival. A step-by-step analysis revealed a PSA decline ≥20.87% as the most noticeable cut-off prognosticating longer survival, which remained an independent prognosticator of improved OS in the multivariate analysis. {sup 177}Lu-PSMA-617 RLT is a new effective therapeutic and seems to prolong survival in patients with advanced m

  1. [Effects of extract of Buddleja officinalis eye drops on androgen receptors of lacrimal gland cells of castrated rats with dry eye].

    Science.gov (United States)

    Peng, Qing-Hua; Yao, Xiao-Lei; Wu, Quan-Long

    2012-01-01

    To observe the effects of the extract of Buddleja officinalis eye drops (EBOED) on basic tears secretory volume, tear film stability, and expressions of androgen receptors (AR) in castrated rats with dry eye, and to investigate the mechanism of EBOED on dry eye caused by decreased anti-androgen levels. Forty-five male Wistar rats were randomly divided into the blank group, the model group, and the treatment group (treated by EBOED), respectively. Rats in each group were further divided into three sub-groups (fed for one month, two months, and three months, respectively). There were totally nine groups, with five in each. The dry eye model was established with orchiectomy of rats in the model group and the treatment group. EBOED was given to rats in the treatment group for one successive month. Schirmer I test (SIT) and breakup time of tear film (BUT) were determined in all experimental rats. Expressions of AR was analyzed by flow cytometer. Ths SIT value, BUT, and AR positive rate in the model group at the 1st, 2nd, 3rd month were lower than those in the blank group of the same time points (P < 0.01). There was statistical difference in SIT value, BUT, and AR positive rate between the model group and the treatment group at the three time points (P < 0.01). Take the three-month subgroup as an example, the SIT value in the treatment group was (12.667 +/- 5.221) mm, obviously higher than that in the model group (2.676 +/- 1.987) mm. The BUT in the treatment group was (11.758 +/- 4.415) s, obviously longer than that of the model group (4.667 +/- 2.108) s. The AR positive rate in the treatment group was 49.33% +/- 3.44%, obviously higher than that of the model group (33.32% +/- 7.12%, all P < 0.01). The main components of EBOED was the flavonoids which could significantly inhibit the occurrence of dry eye in rats with decreased androgen levels. Its mechanism might possibly be similar to androgen.

  2. {sup 18}F-Fluorocholine PET/CT for early response assessment in patients with metastatic castration-resistant prostate cancer treated with enzalutamide

    Energy Technology Data Exchange (ETDEWEB)

    De Giorgi, Ugo; Conteduca, Vincenza; Burgio, Salvatore Luca; Menna, Cecilia; Rossi, Lorena; Amadori, Dino [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Department of Medical Oncology, Meldola (Italy); Caroli, Paola; Paganelli, Giovanni; Matteucci, Federica [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Diagnostic Nuclear Medicine Unit, Meldola (Italy); Scarpi, Emanuela [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Unit of Biostatistics and Clinical Trials, Meldola (Italy); Moretti, Andrea; Galassi, Riccardo [Morgagni-Pierantoni Hospital, Nuclear Medicine Unit, Forli (Italy)

    2015-07-15

    We investigated the role of {sup 18}F-methylcholine (FCH) PET/CT in the early evaluation of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide. The study group comprised 36 patients with a median age of 72 years (range 48-90 years) who were treated with enzalutamide 160 mg once daily after at least one chemotherapeutic regimen with docetaxel. Patients were evaluated monthly for serological prostate-specific antigen (PSA) response. FCH PET/CT was performed at baseline and repeated after 3-6 weeks. Univariate and multivariate Cox regression models addressed potential predictors of progression-free survival (PFS) and overall survival (OS). At a median follow-up of 24.2 months (range 1.8-27.3 months), 34 patients were evaluable for early FCH PET/CT evaluation of response, and of these 17 showed progressive disease (PD) and 17 had stable disease or a partial response. A decrease in PSA level of more than 50 % was observed in 21 patients. Early FCH PET/CT PD predicted radiological PD 3 months in advance of CT in 12 of 18 patients (66 %) and was discordant with the decrease in PSA level in 13 patients. In 6 of these, biochemical PD was confirmed in 2 months. In multivariate analysis, only decrease in PSA level and FCH PET/CT were significant predictors of PFS (p = 0.0005 and p = 0.029, respectively), whereas decrease in PSA level alone was predictive of OS (p = 0.007). This is one of the first studies to evaluate the role of FCH PET/CT as an early predictor of outcome in mCRPC patients treated with enzalutamide. Our preliminary results suggest that the combination of FCH PET/CT and decrease in PSA level could be a valid tool to predict PFS in mCRPC patients. PSA remains the single most important prognostic factor, while FCH PET/CT does not add more information on OS beyond that obtained from PSA. Further studies in larger populations are needed to confirm these data and to clarify the role of FCH PET/CT in predicting response

  3. Novel prognostic markers in the serum of patients with castration-resistant prostate cancer derived from quantitative analysis of the pten conditional knockout mouse proteome.

    Science.gov (United States)

    Kälin, Martin; Cima, Igor; Schiess, Ralph; Fankhauser, Niklaus; Powles, Tom; Wild, Peter; Templeton, Arnoud; Cerny, Thomas; Aebersold, Ruedi; Krek, Wilhelm; Gillessen, Silke

    2011-12-01

    Metastatic castration-resistant prostate cancer (mCRPC) is associated with a poor outcome. Prognostic information is useful and aids treatment decisions. However, current nomograms based on clinical parameters alone have weak prognostic accuracy. Therefore, the identification of new prognostic serum biomarkers could be useful. To assess if quantitative analysis of the phosphatase and tensin homolog (Pten) conditional knockout mouse proteome reveals significant prognostic biomarkers in mCRPC and to compare the accuracy of these biomarkers with known prognostic factors. Fifty-seven patients with mCRPC were evaluated retrospectively. Prognostic factors used in clinical nomograms were assessed from the records. New candidate biomarkers in patients' sera were derived using a cancer genetics-guided model we recently described, screening the murine Pten-dependent glycoproteome. Quantification in patients' sera was performed by either mass spectrometry-based targeted proteomics or enzyme-linked immunosorbent assays. Prognostic biomarkers for survival were identified based on Kaplan-Meier models. In a second step, random forest analysis was performed to identify a prognostic signature combined from the pooled data of known predictors and newly identified biomarkers. With univariate analysis, 13 new significant prognostic factors for survival in the sera of mCRPC patients were found with a Bonferroni-corrected level of significance <5%. Random forest analysis revealed a five-factor predictor (thrombospondin 1; C-reactive protein; poliovirus receptor-related 1; ephrin-A5; and membrane metallo-endopeptidase) with an accuracy of 96% and 94% for 12- and 24-mo survival, respectively. This means that, in our dataset, the error was reduced by 15% compared to using the Halabi et al. nomogram. The retrospective nature of the work and absence of a validating dataset is the major limitation of this work. Analysis of the serum proteome in mCRPC patients based on our Pten conditional

  4. Reproducibility and repeatability of semi-quantitative 18F-fluorodihydrotestosterone (FDHT) uptake metrics in castration-resistant prostate cancer metastases: a prospective multi-center study.

    Science.gov (United States)

    Vargas, Hebert Alberto; Kramer, Gem M; Scott, Andrew M; Weickhardt, Andrew; Meier, Andreas A; Parada, Nicole; Beattie, Bradley J; Humm, John L; Staton, Kevin D; Zanzonico, Pat B; Lyashchenko, Serge K; Lewis, Jason S; Yaqub, Maqsood; Sosa, Ramon E; van den Eertwegh, Alfons J; Davis, Ian D; Ackermann, Uwe; Pathmaraj, Kunthi; Schuit, Robert C; Windhorst, Albert D; Chua, Sue; Weber, Wolfgang A; Larson, Steven M; Scher, Howard I; Lammertsma, Adriaan A; Hoekstra, Otto; Morris, Michael J

    2018-04-06

    18 F-fluorodihydrotestosterone ( 18 F-FDHT) is a radiolabeled analogue of the androgen receptor's primary ligand that is currently being credentialed as a biomarker for prognosis, response, and pharmacodynamic effects of new therapeutics. As part of the biomarker qualification process, we prospectively assessed its reproducibility and repeatability in men with metastatic castration-resistant prostate cancer (mCRPC). Methods: We conducted a prospective multi-institutional study of mCRPC patients undergoing two (test/re-test) 18 F-FDHT PET/CT scans on two consecutive days. Two independent readers evaluated all examinations and recorded standardized uptake values (SUVs), androgen receptor-positive tumor volumes (ARTV), and total lesion uptake (TLU) for the most avid lesion detected in each of 32 pre-defined anatomical regions. The relative absolute difference and reproducibility coefficient (RC) of each metric were calculated between the test and re-test scans. Linear regression analyses, intra-class correlation coefficients (ICC), and Bland-Altman plots were used to evaluate repeatability of 18 F-FDHT metrics. The coefficient of variation (COV) and ICC were used to assess inter-observer reproducibility. Results: Twenty-seven patients with 140 18 F-FDHT-avid regions were included. The best repeatability among 18 F-FDHT uptake metrics was found for SUV metrics (SUV max , SUVmean, and SUVpeak), with no significant differences in repeatability found among them. Correlations between the test and re-test scans were strong for all SUV metrics (R2 ≥ 0.92; ICC ≥ 0.97). The RCs of the SUV metrics ranged from 21.3% for SUVpeak to 24.6% for SUV max The test and re-test ARTV and TLU, respectively, were highly correlated (R2 and ICC ≥ 0.97), although variability was significantly higher than that for SUV (RCs > 46.4%). The PSA levels, Gleason score, weight, and age did not affect repeatability, nor did total injected activity, uptake measurement time, or differences in

  5. Lactate dehydrogenase predicts combined progression-free survival after sequential therapy with abiraterone and enzalutamide for patients with castration-resistant prostate cancer.

    Science.gov (United States)

    Mori, Keiichiro; Kimura, Takahiro; Onuma, Hajime; Kimura, Shoji; Yamamoto, Toshihiro; Sasaki, Hiroshi; Miki, Jun; Miki, Kenta; Egawa, Shin

    2017-07-01

    An array of clinical issues remains to be resolved for castration-resistant prostate cancer (CRPC), including the sequence of drug use and drug cross-resistance. At present, no clear guidelines are available for the optimal sequence of use of novel agents like androgen-receptor axis-targeted (ARAT) agents, particularly enzalutamide, and abiraterone. This study retrospectively analyzed a total of 69 patients with CRPC treated with sequential therapy using enzalutamide followed by abiraterone or vice versa. The primary outcome measure was the comparative combined progression-free survival (PFS) comprising symptomatic and/or radiographic PFS. Patients were also compared for total prostate-specific antigen (PSA)-PFS, overall survival (OS), and PSA response. The predictors of combined PFS and OS were analyzed with a backward-stepwise multivariate Cox model. Of the 69 patients, 46 received enzalutamide first, followed by abiraterone (E-A group), and 23 received abiraterone, followed by enzalutamide (A-E group). The two groups were not significantly different with regard to basic data, except for hemoglobin values. In a comparison with the E-A group, the A-E group was shown to be associated with better combined PFS in Kaplan-Meier analysis (P = 0.043). Similar results were obtained for total PSA-PFS (P = 0.049), while OS did not differ between groups (P = 0.62). Multivariate analysis demonstrated that pretreatment lactate dehydrogenase (LDH) values and age were significant predictors of longer combined PFS (P < 0.05). Likewise, multivariate analysis demonstrated that pretreatment hemoglobin values and performance status were significant predictors of longer OS (P < 0.05). The results of this study suggested the A-E sequence had longer combined PSA and total PSA-PFS compared to the E-A sequence in patients with CRPC. LDH values in sequential therapy may serve as a predictor of longer combined PFS. © 2017 Wiley Periodicals, Inc.

  6. Downregulation of androgen receptors by NaAsO2via inhibition of AKT-NF-κB and HSP90 in castration resistant prostate cancer.

    Science.gov (United States)

    Kim, Yunlim; Park, Sang Eun; Moon, Jeong-Weon; Kim, Bong-Min; Kim, Ha-Gyeong; Jeong, In Gab; Yoo, Sangjun; Ahn, Jae Beom; You, Dalsan; Pak, Jhang Ho; Kim, Sujong; Hwang, Jung Jin; Kim, Choung-Soo

    2017-07-01

    Androgen and androgen receptor (AR) play essential roles in the development and maintenance of prostate cancer. The recently identified AR splice variants (AR-Vs) have been considered as a plausible mechanism for the primary resistance against androgen deprivation therapy (ADT) in castration-resistant prostate cancer (CRPC). Sodium meta-arsenite (NaAsO 2 ; KML001; Kominox), a trivalent arsenical, is an orally bioavailable and water soluble, which is currently in phase I/II clinical trials for the treatment of prostate cancer. It has a potent anti-cancer effect on prostate cancer cells and xenografts. The aim of this study was to examine the effect of NaAsO 2 on AR signaling in LNCaP and 22Rv1 CRPC cells. We used hormone-sensitive LNCaP cells, hormone-insensitive 22Rv1 cells, and CRPC patient-derived primary cells. We analyzed anti-cancer effect of NaAsO 2 using real-time quantitative reverse transcription-PCR, Western blotting, immunofluorescence staining and CellTiter Glo® luminescent assay. Statistical evaluation of the results was performed by one-way ANOVA. NaAsO 2 significantly reduced the translocation of AR and AR-Vs to the nucleus as well as their level in LNCaP and 22Rv1 cells. Besides, the level of the prostate-specific antigen (PSA), downstream target gene of AR, was also decreased. This compound was also an effective modulator of AKT-dependent NF-κB activation which regulates AR. NaAsO 2 significantly inhibited phosphorylation of AKT and expression and nuclear translocation of NF-κB. We then investigated the effect of NaAsO 2 on AR stabilization. NaAsO 2 promoted HSP90 acetylation by down-regulating HDAC6, which reduces the stability of AR in prostate cancer cells. Here, we show that NaAsO 2 disrupts AR signaling at multiple levels by affecting AR expression, stability, and degradation in primary tumor cell cultures from prostate cancer patients as well as CRPC cell lines. These results suggest that NaAsO 2 could be a novel therapeutics for prostate

  7. Efeitos da Corticosteroidoterapia na Uretra e na Bexiga de Ratas Castradas antes e durante Reposição Estrogênica Effects of Corticosteroids in the Urethra and Bladder of Castrated Female Rats before and during Estrogen Replacement Teraphy

    Directory of Open Access Journals (Sweden)

    João Batista dos Santos Junior

    2000-12-01

    five groups. Group I - ten castrated female rats; Group II - eleven castrated female rats which receivedintraperitoneally 15 mg/kg weight prednisolone, for 26 days; Group III - twelve castrated female rats which received the same amount of corticosteroid, during the same time, and subcutaneously 10 mg/kg 17 beta-estradiol, in the last five days before they were sacrificed; Group IV - eleven castrated rats which received placebo for 26 days; and Group V - no castrated female rats which received the same dose of corticosteroid during the same time as in Group II. Results: we observed an average of 1.8 vessels in the bladder of the castrated group which received corticosteroid, a similar number to that of those which received corticosteroid and estrogen, compared with 0.8 vessel in the placebo group. Regarding the urethra, 0.7 vessel was observed in the group which received corticosteroid, as compared with 0.9 vessel in the group treated with corticosteroid associated with estrogen and 0.4 in the placebo group. Regarding the mucous membrane, the vesical epithelium thickness of 14.1 mm in the placebo group increased to 20.6 mm in that with corticosteroid and to 22.6 mm in that with corticosteroid plus estrogen. The urethral epithelium thickness of 12.4 mm in the placebo group increased to 15.1 mm in the group with corticosteroid and to 16.7 mm in that with corticosteroid plus estrogen. Conclusion: corticosteroids significantly increased the vascularization and the thickness of the vesical and urethral epithelia of castrated female rats.

  8. Phase I clinical trial of sipuleucel-T combined with escalating doses of ipilimumab in progressive metastatic castrate-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Scholz M

    2017-03-01

    Full Text Available Mark Scholz,1 Sabrina Yep,1 Micah Chancey,1 Colleen Kelly,1 Ken Chau,1 Jeffrey Turner,1 Richard Lam,1 Charles G Drake,2,3 1Prostate Oncology Specialists, Inc., Marina del Rey, CA, 2The Sidney Kimmel Cancer Center, 3The James Buchanan Brady Urological Institute, John Hopkins Medical Institutions, Baltimore, MD, USA Background: Sipuleucel-T (SIP-T, which functions by stimulating cancer-specific dendritic cells, prolongs survival in men with prostate cancer. Ipilimumab (IPI achieved a borderline survival advantage in a large randomized trial. SIP-T and IPI are potentially synergistic. Patients and Methods: Nine men with progressive metastatic castrate-resistant prostate cancer (mCRPC were treated prospectively with SIP-T followed immediately by IPI with one of the following doses of IPI: 1 mg/kg at 1 week after SIP-T; 1 mg/kg at 1 and 4 weeks after SIP-T; or 1 mg/kg at 1, 4, and 7 weeks after SIP-T. Three patients were evaluated at each level. Cancer-specific immunoglobulins directed at granulocyte-macrophage-colony-stimulating factor/prostatic acid phosphatase (PAP fusion protein (PA2024 and PAP were measured prior to SIP-T, after SIP-T, 1 week after IPI, every other month for 5 months, then every 3 months for an additional 12 months. Results: Adverse events of SIP-T were consistent with previous reports. IPI only caused a transient grade 1 rash in one patient. Median age, Gleason score, and number of previous hormonal interventions were 77 years, 8, and 3, respectively. Eight men had bone metastases and one had lymph node metastasis. Statistically significant increases in serum immunoglobulin G (IgG and IgG-IgM specific for PA2024 and PAP occurred after SIP-T. An additional statistically significant increase in the aforementioned immunoglobulins – above the levels achieved by SIP-T – occurred after IPI. Median clinical follow-up was 36 months (range: 26–40. Three patients died from progressive disease after 9, 18, and 20 months. Out of the

  9. Abiraterone Acetate for the Treatment of Chemotherapy-Naïve Metastatic Castration-Resistant Prostate Cancer: An Evidence Review Group Perspective of an NICE Single Technology Appraisal.

    Science.gov (United States)

    Ramaekers, Bram L T; Riemsma, Rob; Tomini, Florian; van Asselt, Thea; Deshpande, Sohan; Duffy, Steven; Armstrong, Nigel; Severens, Johan L; Kleijnen, Jos; Joore, Manuela A

    2017-02-01

    The National Institute for Health and Care Excellence (NICE) invited Janssen, the company manufacturing abiraterone acetate (AA; tradename Zytiga ® ), to submit evidence for the clinical and cost effectiveness of AA in combination with prednisone/prednisolone (AAP) compared with watchful waiting (i.e. best supportive care [BSC]) for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the Evidence Review Group (ERG). This paper presents a summary of the company submission (CS), the ERG report, subsequent addenda, and the development of the NICE guidance for the use of this drug in England and Wales by the Appraisal Committee (AC). The ERG produced a critical review of the clinical and cost effectiveness of AAP based on the CS. An important question in this appraisal was, according to the ERG, whether AAP followed by docetaxel is more effective than BSC followed by docetaxel. In the COU-AA-302 trial, 239 of 546 (43.8 %) AAP patients and 304 of 542 (56.1 %) BSC patients received docetaxel as subsequent therapy, following AA or placebo. The results for this specific group of patients were not presented in the CS; therefore, the ERG asked the company to provide these data in the clarification letter; however, these data were presented as commercial-in-confidence and cannot therefore be reported here. The ERG's critical assessment of the company's economic evaluation highlighted a number of concerns, including (a) not using the intention-to-treat (ITT) population; (b) inconsistencies in estimating prediction equations; (c) not fully incorporating the impact of adverse events; (d) incorrectly incorporating the new patient access scheme (PAS); and (e) the assumption that AA non-compliance leads to recoverable drug costs. Although some of these issues were adjusted in the ERG base case, the ERG could not estimate

  10. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial.

    Science.gov (United States)

    Tannock, Ian F; Fizazi, Karim; Ivanov, Sergey; Karlsson, Camilla Thellenberg; Fléchon, Aude; Skoneczna, Iwona; Orlandi, Francisco; Gravis, Gwenaelle; Matveev, Vsevolod; Bavbek, Sevil; Gil, Thierry; Viana, Luciano; Arén, Osvaldo; Karyakin, Oleg; Elliott, Tony; Birtle, Alison; Magherini, Emmanuelle; Hatteville, Laurence; Petrylak, Daniel; Tombal, Bertrand; Rosenthal, Mark

    2013-07-01

    Docetaxel plus prednisone is standard first-line chemotherapy for men with metastatic castrate-resistant prostate cancer. Aflibercept is a recombinant human fusion protein that binds A and B isoforms of VEGF and placental growth factor, thereby inhibiting angiogenesis. We assessed whether the addition of aflibercept to docetaxel and prednisone would improve overall survival in men with metastatic castrate-resistant prostate cancer compared with the addition of placebo to docetaxel and prednisone. VENICE was a phase 3, multicentre, randomised double-blind placebo-controlled parallel group study done in 31 countries (187 sites). Men with metastatic castrate-resistant prostate cancer, adequate organ function, and no prior chemotherapy were treated with docetaxel (75 mg/m(2) intravenously every 3 weeks) and oral prednisone (5 mg twice daily) and randomly allocated (1:1) to receive aflibercept (6 mg/kg) or placebo, intravenously, every 3 weeks. Treatment allocation was done centrally via an interactive voice response system, using a computer-generated sequence with a permuted-block size of four and stratified according Eastern Co-operative Group performance status (0-1 vs 2). Patients, investigators, and other individuals responsible for study conduct and data analysis were masked to treatment assignment. Aflibercept or placebo vials were supplied in identical boxes. The primary endpoint was overall survival using intention-to-treat analysis. This is the primary analysis of the completed trial. The study is registered with ClinicalTrials.gov, number NCT00519285 FINDINGS: Between Aug 17, 2007, and Feb 11, 2010, 1224 men were randomly allocated to treatment: 612 to each group. At final analysis, median follow-up was 35 months (IQR 29-41) and 873 men had died. Median overall survival was 22·1 months (95·6% CI 20·3-24·1) in the aflibercept group and 21·2 months (19·6-23·8) in the placebo group (stratified hazard ratio 0·94, 95·6% CI 0·82-1·08; p=0·38). We

  11. A phase 2 study of OSI-906 (linsitinib, an insulin-like growth factor receptor-1 inhibitor) in patients with asymptomatic or mildly symptomatic (non-opioid requiring) metastatic castrate resistant prostate cancer (CRPC).

    Science.gov (United States)

    Barata, Pedro; Cooney, Matthew; Tyler, Allison; Wright, John; Dreicer, Robert; Garcia, Jorge A

    2018-02-23

    Background The inhibition of insulin-like growth factor receptor-1 (IGF-1R) induces cell cycle arrest and enhancing the effect of castration by delay of progression of human prostate cancer models. Linsitinib is a small molecule and potent dual inhibitor of IGF-1R and insulin receptor tyrosine kinase activity. We report results of a single-arm, phase II study evaluating the safety and efficacy of linsitinib in men with chemotherapy-naïve asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC). Methods Patients received at 150 mg orally twice daily on a 28-day cycle. The primary endpoint was prostate specific (PSA) response at 12 weeks and correlative studies included circulating tumor cells (CTCs) and circulating endothelial cells (CECs). Results Seventeen patients, median age 68 (55-78) and pre-treatment PSA of 55.23 (2.46-277.60) were enrolled and completed 12 weeks of therapy. All but two patients discontinued therapy secondary to PSA progression, which met the predefined futility criteria and led to early termination of this study. Overall best response (RECIST v1.1) included a partial response in 1 patient and stable disease in 8 patients. Higher baseline CTCs were associated with higher pre-treatment PSA levels (Spearman r = 0.49, p = 0.04) but no correlation between PSA progression and CTCs/CECs were observed. Most common adverse events included fatigue, nausea/vomiting, AST/ALT changes and prolonged QT interval. Conclusions Single-agent linsitinib was safe and well tolerated but failed to show activity in men with mCRPC. These results highlight the complexity of using IGF-1R as a therapeutic target in this patient population. ClinicalTrials.gov NCT01533246.

  12. Histomorfometria do tecido ósseo em ratas castradas tratadas com tibolona Bone tissue histomorphometry in castrated rats treated with tibolone

    Directory of Open Access Journals (Sweden)

    Ana Carolina Bergmann de Carvalho

    2010-06-01

    Full Text Available INTRODUÇÃO E OBJETIVO: O efeito da tibolona utilizada em alta dose e por tempo prolongado foi analisado mediante estudo histomorfométrico de tíbias e fêmures de ratas castradas. MÉTODOS: O experimento utilizou 20 ratas Wistar, com peso médio de 250 g. Os animais foram distribuídos aleatoriamente em três grupos: ooforectomizado recebendo tibolona (OVX + T (n = 9, ooforectomizado (OVX (n = 6 e grupo controle não ooforectomizado (C (n = 5. Deu-se início ao protocolo experimental 30 dias após a ooforectomia, perdurando por 20 semanas, com administração de tibolona (1 mg/dia a OVX + T e carboximetilcelulose a OVX. O grupo C não foi submetido a qualquer tratamento. Tíbias e fêmures direitos foram fixados em formol a 10% tamponado, descalcificados e processados para inclusão em parafina. Os cortes histológicos foram corados mediante hematoxilina-eosina para análise histomorfométrica. Mediram-se a espessura cortical e a cavidade medular em cortes transversais de tíbia e fêmur e percentual de porosidade e densidade trabecular em cortes longitudinais de fêmur. RESULTADO E DISCUSSÃO: Não houve diferença estatística entre OVX e OVX + T nas diversas análises. Os resultados demonstram que a tibolona não melhorou de forma significativa a qualidade óssea, porém preservou a massa óssea cortical, nas diáfises femoral e tibial, e o osso trabecular, nos côndilos femorais. O uso prolongado de tibolona em concomitância com alta dose pode ter influenciado tais efeitos, já que estudos recentes têm preconizado a utilização de doses mais baixas na prevenção da osteoporose. CONCLUSÃO: A ooforectomia ocasionou perda óssea nas regiões analisadas; a tibolona, apesar de não ter aumentado a massa óssea, manteve-a em níveis satisfatórios.INTRODUCTION AND OBJECTIVE: The effect of tibolone administered in high dose over a prolonged period was analyzed through histomorphometry of tibia and femur samples from castrated rats. METHODS

  13. Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy.

    Science.gov (United States)

    Liu, Vincent Wing Sun; Yau, Wing Lung; Tam, Chun Wai; Yao, Kwok-Ming; Shiu, Stephen Yuen Wing

    2017-05-31

    A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7), nuclear factor-kappa B (NF-κB) was activated and could result in up-regulated interleukin ( IL ) -6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC) pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT₁ receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion.

  14. Efficacy Against Human Prostate Cancer by Prostate-specific Membrane Antigen-specific, Transforming Growth Factor-β Insensitive Genetically Targeted CD8+T-cells Derived from Patients with Metastatic Castrate-resistant Disease.

    Science.gov (United States)

    Zhang, Qiang; Helfand, Brian T; Carneiro, Benedito A; Qin, Weijun; Yang, Ximing J; Lee, Chung; Zhang, Weipeng; Giles, Francis J; Cristofanilli, Massimo; Kuzel, Timothy M

    2017-12-21

    Current immunotherapy has limited efficacy on metastatic castrate-resistant prostate cancer (mCRPC). We therefore sought to improve the antitumor ability of mCRPC patient-derived CD8 + T-cells by the endowment of specificity to prostate-specific membrane antigen (PSMA) and insensitivity to immunosuppressant molecule transforming growth factor-β (TGF-ß) under the control of herpes simplex virus-1 thymidine kinase. CD8 + T-cells were collected by leukapheresis and cultured in a Food and Drug Administration-approved Cell Processing Work Station. We developed a chimeric antigen receptor retroviral construct using an anti-PSMA chimeric immunoglobulin-T-cell receptor(ζ) gene (PZ1) and dominant negative TGF-ß type II receptor (TßRIIDN), that could induce CD8 + T-cells to be PSMA reactive and insensitive to TGF-ß. Cr 51 release assay was performed on PC-3 and PC-3-PSMA. The further antitumor functions of PSMA-specific, TGF-ß insensitive CD8 + T-cells was evaluated using an immunodeficient RAG-1 -/- mouse model. We found PSMA-specific, TGF-ß insensitive CD8 + T-cells from mCRPC were expanded with strong expression of PZ1 and thymidine kinase genes, and their growth was not suppressed by TGF-ß. The survival of these cells decreased sharply after treatment with ganciclovir. Treatment of PSMA-specific TGF-ß, insensitive CD8 + T-cells was associated with 61.58% specific lysis on PC-3-PSMA, and significantly suppressed PC3-PSMA tumor compared with the PC3 tumor. A large amount of tumor apoptosis and CD8 + T-cell infiltration were found only in the PC3-PSMA tumor. This study verified that PSMA-specific, TGF-ß insensitive CD8 + T-cells derived from mCRPC patients could be successfully expanded and used to overcome the immunosuppressive effects of the tumor microenvironment to control PSMA-expressing PC in vitro and in vivo. This may provide a promising approach for men with mCRPC who fail androgen deprivation therapy. We investigated the role of a novel chimeric antigen

  15. Effect of time interval between the second Improvest® dose and slaughter and corn dried distillers grains with solubles feeding strategies on carcass composition, primal cutout, and pork quality of immunologically castrated pigs.

    Science.gov (United States)

    Harris, E K; Mellencamp, M A; Johnston, L J; Cox, R B; Shurson, G C

    2017-05-01

    Effects of dried distillers grains with solubles (DDGS) feeding strategies on carcass composition, primal cutout, and lean quality of immunologically castrated (IC; n=863) pigs were evaluated, and consisted of: 1) corn-soybean meal (CS) diet (PCon); 2) CS+40% DDGS (NCon); 3) CS+40, 30, 20, or 10% DDGS fed in phases 1 to 4, respectively (SD); or 4) CS+40% DDGS fed in phase 1 to 3 and CS in phase 4 (WD). All pigs received the first dose of Improvest® at 11weeks. of age, and the second dose was administered at either 9, 7, or 5weeks. before slaughter at 24weeks. of age. The SD and WD improved carcass dressing percentage and resulted in intermediate primal cut yields and pork loin quality compared with pigs fed PCon and NCon. Increasing the time interval between second dose of Improvest® and slaughter increased adipose tissue accretion but did not affect lean quality of pork. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Effectiveness of different corn dried distillers grains with solubles feeding strategies and increasing the time intervals between the second Improvest dose and slaughter of immunologically castrated pigs on belly and pork fat quality.

    Science.gov (United States)

    Harris, E K; Mellencamp, M A; Johnston, L J; Cox, R B; Shurson, G C

    2018-01-01

    Effects of dried distillers grains with solubles (DDGS) feeding strategies (a corn-soybean meal (CS) fed continously; CS+40% DDGS fed continously; CS+40, 30, 20, or 10% DDGS in 4 phases, respectively; or CS+40% DDGS in phases 1 to 3 and CS in phase 4 before slaughter) on belly and pork fat quality of immunologically castrated (n=192) pigs were evaluated. All pigs received the first Improvest dose at 11week of age, and the second dose at 9, 7, or 5week before slaughter at 24week of age. Increasing the time interval of the second Improvest dose before slaughter reduced IV in all fat depots and increased belly thickness. Gradually decreasing dietary DDGS and DDGS withdrawal feeding strategies reduced IV in all fat depots. Calculated IV were greater using the Meadus et al. (2010) equation compared with using the AOCS (1998) equation because it includes more long-chain unsaturated fatty acids. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Características físico-químicas da carne de bubalinos e de bovinos castrados e inteiros Chemical physical meat characteristics of buffaloes and cattle entire and castrated

    Directory of Open Access Journals (Sweden)

    Victor Cruz Rodrigues

    2004-12-01

    Full Text Available As características físico-químicas da carne de bovinos Nelore (NE, F1 Nelore x Sindi (NS e de búfalos Mediterrâneos (BM castrados e inteiros foram avaliadas. O delineamento experimental foi o inteiramente casualizado em esquema fatorial 3 x 2 (três grupos genéticos x duas condições sexuais com 24 parcelas. Os animais foram confinados, receberam a mesma dieta e foram abatidos com média de 437,5 kg. As amostras de carne foram obtidas do músculo Longissimus dorsi entre a 11ª e 12ª costelas. A carne de animais inteiros ofereceu maior teor de umidade (73,6 vs 71,0%, de proteína (87,5 vs 78,6% e de minerais (4,33 vs 3,85% e menor teor de gordura (8,9 vs 16,8% que castrados. A carne de bovinos NE teve maior teor de gordura (15,4% que NS (12,5% e BM (10,8%, não havendo diferença para a condição sexual dentro do grupo de BM. A luminosidade, intensidade do vermelho e intensidade do amarelo da carne e da gordura foram semelhantes entre NE, NS e BM, enquanto os castrados alcançaram maior luminosidade (39,0 vs 37,2 e intensidade do amarelo (1,82 vs 0,87 que inteiros, mas a intensidade do vermelho da carne e a luminosidade, intensidade do vermelho e intensidade do amarelo da gordura foram semelhantes entre grupos genéticos e condição sexual. A carne de BM apresentou menor força de cisalhamento (3,75 kgf que NS (4,85 kgf e NE (5,9 kgf, bem como dos castrados (4,5 kgf em relação aos inteiros (5,2 kgf, mas não houve diferença entre grupo genético e condição sexual para perda por cozimento e para pH final. A carne de búfalos e animais inteiros apresentou menor teor de gordura, sem perder o valor nutritivo, maciez e a baixa perda por cozimento.Meat physical and chemical characteristics of Nellore (NE and F1 Nellore x Sindi (NS cattle and Mediterranean buffaloes (BM castrated and entire were evaluated. The experimental design was completely randomized in a factorial arrangement 3 (genetic groups x 2 (sexual conditions with 24 plots

  18. Inhibition of Androgen Receptor Function and Level in Castration-Resistant Prostate Cancer Cells by 2-[(isoxazol-4-ylmethyl)thio]-1-(4-phenylpiperazin-1-yl)ethanone.

    Science.gov (United States)

    Masoodi, Khalid Z; Eisermann, Kurtis; Yang, Zhenyu; Dar, Javid A; Pascal, Laura E; Nguyen, Minh; O'Malley, Katherine; Parrinello, Erica; Feturi, Firuz G; Kenefake, Alex N; Nelson, Joel B; Johnston, Paul A; Wipf, Peter; Wang, Zhou

    2017-10-01

    The androgen receptor (AR) plays a critical role in the development of castration-resistant prostate cancer (CRPC) as well as in the resistance to the second-generation AR antagonist enzalutamide and the selective inhibitor of cytochrome P450 17A1 (CYP17A1) abiraterone. Novel agents targeting AR may inhibit the growth of prostate cancer cells resistant to enzalutamide and/or abiraterone. Through a high-throughput/high-content screening of a 220,000-member small molecule library, we have previously identified 2-[(isoxazol-4-ylmethyl)thio]-1-(4-phenylpiperazin-1-yl)ethanone (IMTPPE) (SID 3712502) as a novel small molecule capable of inhibiting AR transcriptional activity and protein level in C4-2 prostate cancer cells. In this study, we show that IMTPPE inhibits AR-target gene expression using real-time polymerase chain reaction, Western blot, and luciferase assays. IMTPPE inhibited proliferation of AR-positive, but not AR-negative, prostate cancer cells in culture. IMTPPE inhibited the transcriptional activity of a mutant AR lacking the ligand-binding domain (LBD), indicating that IMTPPE inhibition of AR is independent of the LBD. Furthermore, animal studies showed that IMTPPE inhibited the growth of 22Rv1 xenograft tumor, a model for enzalutamide-resistant prostate cancer. These findings suggest that IMTPPE is a potential lead compound for developing clinical candidates for the treatment of CRPC, including those resistant to enzalutamide. Copyright © 2017 Endocrine Society.

  19. Health Economics and Radium-223 (Xofigo®) in the Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Case History and a Systematic Review of the Literature.

    Science.gov (United States)

    Norum, Jan; Traasdahl, Erik R; Totth, Arpad; Nieder, Carsten; Olsen, Jan Abel

    2015-07-30

    Prostate cancer (PC) is the most common cancer in Western countries. Recent advances in the treatment of metastatic castration resistant prostate cancer (mCRPC) have caused significant pressure on health care budgets. We aimed to exemplify this dilemma presenting an example, radium-223 (Xofigo®), and review the literature. A 74-year-old man diagnosed with mCRPC was referred to our department in October 2014 for radium-223 therapy. We faced the following dilemma: is radium-223 standard therapy? Is it cost-effective? Medline was searched employing the following search criteria: "radium-223", "alpharadin", "Xofigo" and "prostate". Exclusion and inclusion criteria were applied. Guidelines and cost-effectiveness analyses were focused. We also searched the websites of ASCO, ESMO and ISPOR. The web was searched, using Yahoo and Google search engines, for Health Technology Assessments (HTAs). 181 publications were identified in the Medline database. Only four studies included the word "cost", three "economics" and none "budget" in heading or abstract. None of the publications were thorough of cost analysis (cost-effectiveness, cost-utility, cost-minimizing or cost-of-illness analysis). Six HTAs and eight national guidelines were identified. The cost per quality adjusted life years was indicated €80.000-94,000. HTAs concluded reimbursement being not recommendable or no ultimate statement could be made. One pointed towards a limited use with caution. Guidelines were based on data from randomized clinical trials (RCTs). Health economics was not considered when guidelines were made. Most HTAs concluded this therapy not cost-effective or there was insufficient data for final conclusions. Licensing and reimbursement processes should be run simultaneously.

  20. A phase I study of combined docetaxel and repeated high activity {sup 186}Re-HEDP in castration-resistant prostate cancer (CRPC) metastatic to bone (the TAXIUM trial)

    Energy Technology Data Exchange (ETDEWEB)

    Dodewaard-de Jong, Joyce M. van; Bloemendal, Haiko J. [Meander Medical Centre, Department of Internal Medicine, Amersfoort (Netherlands); Klerk, John M.H. de; Haas, Marie J. de [Meander Medical Centre, Department of Nuclear Medicine, Amersfoort (Netherlands); Bezooijen, Bart P.J. van [Meander Medical Centre, Department of Urology, Amersfoort (Netherlands); Wilson, Richard H.; O' Sullivan, Joe M. [Queen' s University Belfast, Centre for Cancer Research and Cell Biology, Belfast, N. Ireland (United Kingdom)

    2011-11-15

    Bone-seeking radiopharmaceuticals have palliative benefit in castration-resistant prostate cancer (CRPC) metastatic to bone. Recent studies have shown improvement of survival and quality of life when radiopharmaceuticals were given repeatedly or in combination with chemotherapy. We designed a phase I study combining docetaxel and {sup 186}Re-labelled hydroxyethylidene diphosphonate (HEDP) in men with CRPC and bone metastases to evaluate toxicity. A dose escalation schedule was designed consisting of four dose levels with a standard dosage of docetaxel (75 mg/m{sup 2} 3-weekly). {sup 186}Re-HEDP was given in increasing activities (1,250 MBq up to 2,500 MBq) after the third and sixth cycle of docetaxel. Dose limiting toxicity (DLT) was defined as any grade 4 toxicity lasting more than 7 days or any grade 3 toxicity that did not recover within 10 days. Three patients were planned for each dose level expanding to six if a DLT occurred. Fourteen patients were recruited with a median age of 64.6 years. One DLT, grade 3 thrombocytopenia lasting >10 days, occurred at dose level 3 leading to expansion of this group to six. One of these patients had an episode of acute renal failure which resolved. Because of production problems of {sup 186}Re-HEDP dose level 4 was not started. Combined therapy with docetaxel and {sup 186}Re-HEDP is generally well tolerated in patients with CRPC metastatic to bone. We will conduct a randomized phase II study using three cycles of docetaxel 75 mg/m{sup 2} 3-weekly followed by {sup 188}Re-HEDP 40 MBq/kg body weight, followed by another three cycles of docetaxel 75 mg/m{sup 2}, followed by {sup 188}Re-HEDP 20 MBq/kg body weight. (orig.)

  1. Dose-response characteristics of neonatal exposure to genistein on pituitary responsiveness to gonadotropin releasing hormone and volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) in postpubertal castrated female rats.

    Science.gov (United States)

    Faber, K A; Hughes, C L

    1993-01-01

    Estrogen exposure during critical periods of development promotes androgenization of the brain, which is reflected in altered morphology, behavior, and cyclic hormone secretion in females. Previous work in our laboratory demonstrated that neonatal female rats injected with pharmaceutical or naturally occurring estrogens had decreased GnRH-induced LH secretion and increased volume of the SDN-POA as 42 day castrates. The current experiment defines the dose-response characteristics of neonatal exposure to the isoflavonoid phytoestrogen genistein (G) on pituitary sensitivity to GnRH and SDN-POA volume. Litters of rat pups received subcutaneous injections of either corn oil, 1, 10, 100, 200, 400, 500, or 1000 micrograms of G on days 1 to 10 of life. The litters were ovariectomized and weaned on day 21. On day 42 blood was drawn from right atrial catheters immediately prior to, 5, 10, 15, and 30 min following a single injection of 50 ng/kg of GnRH. Only the 10 micrograms dose of G was associated with increased pituitary response to GnRH, while progressive increases in exposure levels of G were associated with decreasing LH secretion. The SDN-POA volume was increased in only the 500 micrograms and 1000 micrograms exposure groups compared to controls. The results confirm that low doses of G have nonandrogenizing, pituitary-sensitizing effects, while higher doses of G mimic the more typical effects of estrogens. The use of both morphologic and physiologic end points more completely defines the reproductive consequences of environmental estrogen exposure during critical periods of CNS development.

  2. A phase I study of personalized peptide vaccination using 14 kinds of vaccine in combination with low-dose estramustine in HLA-A24-positive patients with castration-resistant prostate cancer.

    Science.gov (United States)

    Noguchi, Masanori; Uemura, Hirotsugu; Naito, Seiji; Akaza, Hideyuki; Yamada, Akira; Itoh, Kyogo

    2011-04-01

    To evaluate the safety, tolerability, immune response, and antitumor activity of a combination of personalized peptide vaccination (PPV) and estramustine phosphate (EMP) in patients with castration-resistant prostate cancer (CRPC). In a phase I dose-escalation study, four peptides showing the highest levels of peptide-specific immunoglobulin G (IgG) to 14 vaccine candidates (ITK-1) were subcutaneously injected every week in three different dose settings (1, 3, and 5 mg per peptide) for 6 weeks with a low dose of EMP, and the patients were followed by maximum 2 years extension study either weekly or bi-weekly six times PPV as one course with a low dose of EMP. Fifteen patients were enrolled in the phase I study. No serious treatment-related adverse events were observed. The most common adverse events were grade 2 skin reactions at the injection sites. The maximum acceptable dose of ITK-1 was 8.643 mg. There were no treatment-related systemic adverse events of grade 3 or more, and maximum tolerated dose could not be determined. Cytotoxic T lymphocyte responses measured by interferon-γ release assay were boosted in 10 of 15 (67%) patients, and IgG responses were boosted in 7 of 15 (47%) patients. Twelve patients proceeded to the extension study, and the median survival time was 23.8 months during a median follow-up of 23.8 months. PPV treatment for HLA-A24 positive patients with CRPC could be recommended for further stages of clinical trials because of its safety and the higher frequency of boosting immune responses. Copyright © 2010 Wiley-Liss, Inc.

  3. Independent association between time to prostate-specific antigen (PSA) nadir and PSA progression-free survival in patients with docetaxel-naïve, metastatic castration-resistant prostate cancer receiving abiraterone acetate, but not enzalutamide.

    Science.gov (United States)

    Miyake, Hideaki; Hara, Takuto; Tamura, Keita; Sugiyama, Takayuki; Furuse, Hiroshi; Ozono, Seiichiro; Fujisawa, Masato

    2017-06-01

    The objective of this study was to compare the prognostic effect of time to prostate-specific antigen (PSA) nadir (TTPN) after treatment with abiraterone acetate (AA) and enzalutamide (Enz) in patients with docetaxel-naïve, metastatic castration-resistant prostate cancer (mCRPC). This study included a total of 297 consecutive patients with mCRPC, of whom 125 and 172 received AA and Enz, respectively, without previous treatment with docetaxel and subsequently achieved any degree of PSA reduction after the administration of either agent. The mean values of TTPN in the AA and Enz groups were 19 and 14 weeks, respectively. Despite the lack of significant differences in several parameters according to the mean TTPN in the Enz group, patients with TTPN>19 weeks were characterized by longer duration of androgen deprivation therapy, better performance status, lower incidence of bone metastasis, lower value of nadir PSA, and higher incidence of PSA response than those with TTPN ≤19 weeks in the AA group. The PSA progression-free survival (PFS) in patients with TTPN >19 weeks was significantly superior when compared with TTPN ≤19 weeks in the AA group; however, there was no significant effect of the mean TTPN on the PSA-PFS in the Enz group. Furthermore, TTPN was identified as one of the independent predictors of PSA-PFS in the AA group but not in Enz group. A longer time to reach a PSA nadir after treatment with AA, but not Enz, appeared to be associated with favorable disease control in patients with docetaxel-naïve mCRPC. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Características de carcaça e da carne de suínos machos castrados e imunocastrados alimentados com diferentes níveis nutricionais Carcass characteristics and meat of surgically castrated and immunocastrated pigs fed different nutritional levels

    Directory of Open Access Journals (Sweden)

    Eloiza Lanferdini

    2012-11-01

    Full Text Available O trabalho foi realizado para avaliar as características de carcaça e carne de suínos machos castrados e imunocastrados alimentados com dietas contendo diferentes níveis nutricionais. O delineamento experimental foi inteiramente casualizado com quatro tratamentos principais (T1-suínos machos castrados alimentados com dieta basal; T2-machos imunocastrados alimentados com dieta basal; T3-machos imunocastrados alimentados com dieta basal+3% aminoácidos e energia; T4-machos imunocastrados alimentados com dieta basal+5% aminoácidos e energia e dois tratamentos secundários com ou sem ractopamina dentro de cada tratamento principal. Os suínos machos castrados apresentaram peso de abate 3,3% inferior (PThe study was carried out to evaluate the carcass characteristics and meat of surgically castrated and immunocastrated pigs fed with different nutritional levels. The animals were distribuited in a completely randomized experimental design with four main treatments (T1-surgically castrated pigs fed with basal diet; T2-immunocastrated pigs fed with basal diet; T3-immunocastrated pigs fed with basal diet+3% amino acids and energy; T4-immunocastrated pigs fed with basal diet+5% amino acids and energy and two secondary treatments with or without ractopamine within each main treatment. The surgically castrated pigs had slaughter weight 3.3% lower (P<0.05, cold carcass weight 1.4% higher (P<0.05 and loin chop weight 13% higher (P<0.05 compared to immunocastred pigs. The immunocastrated pigs supplemented with 5% more amino acids and energy had rib 19% more heavier (P<0.05 and higher values (P<0.05 in the color b* (yellow-blue in the meat to 45min and 24h post-slaughter compared with surgically castrated pigs fed with basal diet. Supplementation with 5% amino acids and energy increases weight and yield of rib and changes the value of color b* (yellow-blue in the meat to 45min and 24h post-slaughter male pigs immunocastrated.

  5. Características de carcaça e qualidade de carne de bovinos inteiros ou castrados da raça Nelore, suplementados ou não durante o primeiro inverno Carcass characteristics and meat quality of intact or castrated bovines, supplemented or not during the first winter

    Directory of Open Access Journals (Sweden)

    Saulo Malaguido Climaco

    2006-12-01

    Full Text Available Este trabalho teve como objetivo avaliar características quantitativas e qualitativas da carcaça e da carne de bovinos inteiros e castrados, suplementados ou não durante o primeiro inverno. Foram utilizados 40 bovinos Nelore, machos, inteiros e castrados, com peso inicial e idade média de 300kg e 14 meses, submetidos a dois tratamentos: SUP - os animais foram mantidos em pasto e receberam suplementação (0,5% do peso vivo constituída por 25% de farelo de soja e 75% de milho em grão triturado, durante o primeiro inverno (01/06/2003 a 21/09/2003; NSU- animais mantidos em pasto, sem suplementação. Após o abate, à idade média de 28 meses, foram avaliadas as características de carcaça. Os animais do tratamento NSU apresentaram maior (P0,05 quanto à espessura de gordura subcutânea entre animais inteiros e castrados (2,20 vs 4,17mm, respectivamente, porém os castrados apresentaram maior (PThis research was aimed at evaluating quantitative and qualitative characteristics of the carcass and meat from intact or castrated beef cattle, supplemented or not supplemented during the first winter. Forty Nellore males, intact or castrated, with initial weight and age of 300kg and 14 months, were submitted to the treatments: 1 SUP - Animals on pasture and supplemented (0.5% of the live body weight with concentrated (25% of soybean meal and 75% of ground corn during the first winter (06/01/2003 to 09/21/2003, and 2 NSU - Animals on pasture, without supplementation. At slaughter, on an average age of 28 months, the carcass characteristics were evaluated. Animals of the NSU treatment presented the largest (P0.05 for fat thickness between castrated and intact animals (4.17 vs 2.20 mm, respectively, however, castrated animals presented greater (P<0.05 fat percentage in the carcass (16.68 vs 11.34% and more tender meat (6.57 vs 7.50kgf than the intact animals. Intact and non-supplemented animals presented backfat thickness lower than required by the

  6. Comparative therapeutic use of Risedronate and Calcarea phosphorica - allopathy versus homeopathy - in bone repair in castrated rats Comparação do uso terapêutico de Risedronato e Calcarea phosphorica - alopatia versus homeopatia - no reparo ósseo em ratos castrados

    OpenAIRE

    Cristina Werkman; Giselle Segnini Senra; Rosilene Fernandes da Rocha; Adriana Aigotti Haberbeck Brandão

    2006-01-01

    Osteoporosis, a disease characterized by progressive bone loss, has been the target of several studies in the past few years. It results in a much higher risk for fractures and might cause slower bone lesion healing. The aim of this work was to study the effects of Risedronate (allopathic medicine) and Calcarea phosphorica 6CH (homeopathic medicine) on the repair of bone lesions in male rats with osteoporosis induced by castration. Eighty-four three-month-old rats were used divided into four ...

  7. Comparative therapeutic use of Risedronate and Calcarea phosphorica - allopathy versus homeopathy - in bone repair in castrated rats Comparação do uso terapêutico de Risedronato e Calcarea phosphorica - alopatia versus homeopatia - no reparo ósseo em ratos castrados

    Directory of Open Access Journals (Sweden)

    Cristina Werkman

    2006-09-01

    Full Text Available Osteoporosis, a disease characterized by progressive bone loss, has been the target of several studies in the past few years. It results in a much higher risk for fractures and might cause slower bone lesion healing. The aim of this work was to study the effects of Risedronate (allopathic medicine and Calcarea phosphorica 6CH (homeopathic medicine on the repair of bone lesions in male rats with osteoporosis induced by castration. Eighty-four three-month-old rats were used divided into four groups of twenty-one animals each. Three groups where castrated and one group was submitted to Sham surgery. One month later, cortical lesions were made in all animals' tibiae and, after one day, the different experimental treatments began according to the following groups: CR - castrated/Risedronate (1 mg/kg/day; CCp - castrated/Calcarea phosphorica 6CH (3 drops/day; CP - castrated/placebo and SP - Sham/placebo. The animals were sacrificed at seven, fourteen and twenty-eight days after the beginning of the treatments and had their tibiae removed. Digital radiographs of the tibiae were taken and analyzed in order to evaluate the optical density of the defect area. Then, they were decalcified and processed for histological and histomorphometrical analysis. The data were submitted to ANOVA, and to the Tukey and Dunnett tests (5%. The allopathic and homeopathic treatments led to different bone formation as regards remodeling and maturation aspects. Further research is necessary to access the resistance and quality of the newly formed bone.A osteoporose, doença caracterizada pela perda de massa óssea, tem sido alvo de estudos nos últimos anos. Fraturas decorrentes da osteoporose são muito comuns e podem apresentar consolidação mais lenta. O objetivo deste trabalho foi avaliar o efeito do risedronato (medicamento alopático e da Calcarea phosphorica 6CH (medicamento homeopático no reparo de lesões ósseas em ratos com osteoporose induzida por castra

  8. The {sup 68}Ga/{sup 177}Lu theragnostic concept in PSMA targeting of castration-resistant prostate cancer: correlation of SUV{sub max} values and absorbed dose estimates

    Energy Technology Data Exchange (ETDEWEB)

    Scarpa, Lorenza; Buxbaum, Sabine; Kendler, Dorota; Decristoforo, Clemens; Uprimny, Christian; Virgolini, Irene [Medical University Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria); Fink, Katharina [Medical University Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria); Medical University of Innsbruck, Department of Radiotherapy / Radiation Oncology, Innsbruck (Austria); Bektic, Jasmin; Horninger, Wolfgang [Medical University of Innsbruck, Department of Urology, Innsbruck (Austria); Gruber, Leonhard [Medical University of Innsbruck, Department of Radiology, Innsbruck (Austria); Lukas, Peter [Medical University of Innsbruck, Department of Radiotherapy / Radiation Oncology, Innsbruck (Austria)

    2017-05-15

    A targeted theragnostic approach based on increased expression of prostate-specific membrane antigen (PSMA) on PC cells is an attractive treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Ten consecutive mCRPC patients were selected for {sup 177}Lu-PSMA617 therapy on the basis of PSMA-targeted {sup 68}Ga-PSMA-HBED-CC PET/CT diagnosis showing extensive and progressive tumour load. Following dosimetry along with the first therapy cycle restaging ({sup 68}Ga-PSMA-HBED-CC and {sup 18}F-NaF PET/CT) was performed after 2 and 3 therapy cycles (each 6.1 ± 0.3 GBq, range 5.4-6.5 GBq) given intravenously over 30 minutes, 9 ± 1 weeks apart. PET/CT scans were compared to {sup 177}Lu-PSMA617 24-hour whole-body scans and contrast-enhanced dual-phase CT. Detailed comparison of SUVmax values and absorbed tumour doses was performed. {sup 177}Lu-PSMA617 dosimetry indicated high tumour doses for skeletal (3.4 ± 1.9 Gy/GBq; range 1.1-7.2 Gy/GBq), lymph node (2.6 ± 0.4 Gy/GBq; range 2.3-2.9 Gy/GBq) as well as liver (2.4 ± 0.8 Gy/GBq; range 1.7-3.3 Gy/GBq) metastases whereas the dose for tissues/organs was acceptable in all patients for an intention-to-treat activity of 18 ± 0.3 GBq. Three patients showed partial remission, three mixed response, one stable and three progressive disease. Decreased {sup 177}Lu-PSMA617 and {sup 68}Ga-PSMA-HBED-CC uptake (mean SUVmax values 20.2 before and 15.0 after 2 cycles and 11.5 after 3 cycles, p < 0.05) was found in 41/54 skeletal lesions, 12/13 lymph node metastases, 3/5 visceral metastases and 4/4 primary PC lesions. Due to substantial individual variance, dosimetry is mandatory for a patient-specific approach following {sup 177}Lu-PSMA617 therapy. Higher activities and/or shorter treatment intervals should be applied in a larger prospective study. (orig.)

  9. Prospective evaluation of [{sup 11}C]Choline PET/CT in therapy response assessment of standardized docetaxel first-line chemotherapy in patients with advanced castration refractory prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Schwarzenboeck, Sarah M.; Krause, Bernd J. [Technical University of Munich, Department of Nuclear Medicine, Klinikum rechts der Isar, Munich (Germany); Rostock University Medical Centre, Department of Nuclear Medicine, Rostock (Germany); Eiber, Matthias; Schwaiger, Markus [Technical University of Munich, Department of Nuclear Medicine, Klinikum rechts der Isar, Munich (Germany); Kundt, Guenther [Rostock University Medical Centre, Department of Biostatistics and Informatics, Rostock (Germany); Retz, Margitta; Treiber, Uwe; Nawroth, Roman; Gschwend, Juergen E.; Thalgott, Mark [Technical University of Munich, Department of Urology, Klinikum rechts der Isar, Munich (Germany); Sakretz, Monique; Kurth, Jens [Rostock University Medical Centre, Department of Nuclear Medicine, Rostock (Germany); Rummeny, Ernst J. [Technical University of Munich, Institute of Radiology, Klinikum rechts der Isar, Munich (Germany)

    2016-11-15

    The aim of this study was to prospectively evaluate the value of [{sup 11}C] Choline PET/CT in monitoring early and late response to a standardized first-line docetaxel chemotherapy in castration refractory prostate cancer (mCRPC) patients. Thirty-two patients were referred for [{sup 11}C] Choline PET/CT before the start of docetaxel chemotherapy, after one and ten chemotherapy cycles (or - in case of discontinuation - after the last administered cycle) for therapy response assessment. [{sup 11}C] Choline uptake (SUV{sub max}, SUV{sub mean}), CT derived Houndsfield units (HU{sub max}, HU{sub mean}), and volume of bone, lung, and nodal metastases and local recurrence were measured semi-automatically at these timepoints. Change in SUV{sub max}, SUV{sub mean}, HU{sub max}, HU{sub mean,} and volume was assessed between PET 2 and 1 (early response assessment, ERA) and PET 3 and 1 (late response assessment, LRA) on a patient and lesion basis. Results of PET/CT were compared to clinically used RECIST 1.1 and clinical criteria based therapy response assessment including PSA for defining progressive disease (PD) and non-progressive disease (nPD), respectively. Relationships between changes of SUV{sub max} and SUV{sub mean} (early and late) and changes of PSA{sub early} and PSA{sub late} were evaluated. Prognostic value of initial SUV{sub max} and SUV{sub mean} was assessed. Statistical analyses were performed using SPSS. In the patient-based ERA and LRA there were no statistically significant differences in change of choline uptake, HU, and volume between PD and nPD applying RECIST or clinical response criteria. In the lesion-based ERA, decrease in choline uptake of bone metastases was even higher in PD (applying RECIST criteria), whereas in LRA the decrease was higher in nPD (applying clinical criteria). There were only significant correlations between change in choline uptake and PSA in ERA in PD, in LRA no significant correlations were discovered. Initial SUV{sub max

  10. Impact of bone-targeted therapies in chemotherapy-naïve metastatic castration-resistant prostate cancer patients treated with abiraterone acetate: post hoc analysis of study COU-AA-302.

    Science.gov (United States)

    Saad, Fred; Shore, Neal; Van Poppel, Hendrik; Rathkopf, Dana E; Smith, Matthew R; de Bono, Johann S; Logothetis, Christopher J; de Souza, Paul; Fizazi, Karim; Mulders, Peter F A; Mainwaring, Paul; Hainsworth, John D; Beer, Tomasz M; North, Scott; Fradet, Yves; Griffin, Thomas A; De Porre, Peter; Londhe, Anil; Kheoh, Thian; Small, Eric J; Scher, Howard I; Molina, Arturo; Ryan, Charles J

    2015-10-01

    Metastatic castration-resistant prostate cancer (mCRPC) often involves bone, and bone-targeted therapy (BTT) has become part of the overall treatment strategy. Investigation of outcomes for concomitant BTT in a post hoc analysis of the COU-AA-302 trial, which demonstrated an overall clinical benefit of abiraterone acetate (AA) plus prednisone over placebo plus prednisone in asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients. This report describes the third interim analysis (prespecified at 55% overall survival [OS] events) for the COU-AA-302 trial. Patients were grouped by concomitant BTT use or no BTT use. Radiographic progression-free survival and OS were coprimary end points. This report describes the third interim analysis (prespecified at 55% OS events) and involves patients treated with or without concomitant BTT during the COU-AA-302 study. Median follow-up for OS was 27.1 mo. Median time-to-event variables with 95% confidence intervals (CIs) were estimated using the Kaplan-Meier method. Adjusted hazard ratios (HRs), 95% CIs, and p values for concomitant BTT versus no BTT were obtained via Cox models. While the post hoc nature of the analysis is a limitation, superiority of AA and prednisone versus prednisone alone was demonstrated for clinical outcomes with or without BTT use. Compared with no BTT use, concomitant BTT significantly improved OS (HR 0.75; p=0.01) and increased the time to ECOG deterioration (HR 0.75; pAA was similar to that reported for AA in the overall intent-to-treat population. Osteonecrosis of the jaw (all grade 1/2) with concomitant BTT use was reported in AA with concomitant BTT was safe and well tolerated in men with chemotherapy-naïve mCRPC. The benefits of AA on clinical outcomes were increased with concomitant BTT. Treatment of advanced prostate cancer often includes bone-targeted therapy. This post hoc analysis showed that in patients with advanced prostate cancer who were treated with abiraterone acetate and

  11. Relationship between patient-reported outcomes and clinical outcomes in metastatic castration-resistant prostate cancer: post hoc analysis of COU-AA-301 and COU-AA-302.

    Science.gov (United States)

    Cella, D; Traina, S; Li, T; Johnson, K; Ho, K F; Molina, A; Shore, N D

    2018-02-01

    Patient-reported outcomes (PROs) are used to assess benefit-risk in drug development. The relationship between PROs and clinical outcomes is not well understood. We aim to elucidate the relationships between changes in PRO measures and clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC). We investigated relationships between changes in self-reported fatigue, pain, functional well-being (FWB), physical well-being (PWB) and prostate cancer-specific symptoms with overall survival (OS) and radiographic progression-free survival (rPFS) after 6 and 12 months of treatment in COU-AA-301 (N = 1195) or COU-AA-302 (N = 1088). Eligible COU-AA-301 patients had progressed after docetaxel and had Eastern Cooperative Oncology Group performance status (ECOG PS) ≤ 2. Eligible COU-AA-302 patients had no prior chemotherapy and ECOG PS 0 or 1. Patients were treated with abiraterone acetate (1000 mg/day) plus prednisone (10 mg/day) or prednisone alone daily. Association between self-reported fatigue, pain and functional status, and OS and/or rPFS, using pooled data regardless of treatment, was assessed. Cox proportional hazard regression modeled time to death or radiographic progression. In COU-AA-301 patients, PRO improvements were associated with longer OS and longer time to radiographic progression versus worsening or stable PROs (P AA-302 patients, worsening PROs were associated with higher likelihood of radiographic progression (P ≤ 0.025) compared with improved or stable PROs. In multivariate models, worsening PWB remained associated with worse rPFS. The 12-month analysis confirmed the 6-month results. PROs are significantly associated with clinically relevant time-to-event efficacy outcomes in clinical trials and may complement and help predict traditional clinical practice methods for monitoring patients for disease progression. © The Author 2017. Published by Oxford University Press on behalf of the European Society for

  12. Uptake of Radium-223 Dichloride and Early [18F]NaF PET Response Are Driven by Baseline [18F]NaF Parameters: a Pilot Study in Castration-Resistant Prostate Cancer Patients.

    Science.gov (United States)

    Letellier, Arthur; Johnson, Alison C; Kit, Nicolas How; Savigny, Jean-François; Batalla, Alain; Parienti, Jean-Jacques; Aide, Nicolas

    2017-10-12

    The purpose of this study is to identify predictive factors on baseline [ 18 F]NaF positron emission tomography (PET)/computed tomography (CT) of early response to radium-223 dichloride after 3 cycles of treatment in metastatic castration-resistant prostate cancer patients. Analysis of 152 metastases was performed in six consecutive patients who underwent [ 18 F]NaF PET/CT at baseline and for early monitoring after 3 cycles of radium-223 dichloride. All metastases depicted on whole-body [ 18 F]NaF PET/CT were contoured and CT (density in Hounsfield units, sclerotic, mixed, or lytic appearance) as well as [ 18 F]NaF [maximum standardized uptake value (SUV max ), SUV mean , and lesion volume (V 18F-NaF )] patterns were recorded. Tumor response was defined as percentage change in SUV max and SUV mean between baseline and post-treatment PET. Bone lesions were defined as stable, responsive, or progressive, according to thresholds derived from a recent multicentre test-retest study in [ 18 F]NaF PET/CT. Total [ 18 F]NaF uptake in metastases, defined as MATV × SUV mean , was correlated to uptake of radium-223 on biodistribution scintigraphy performed 7 days after the first cycle of treatment. Among metastases, 116 involved the axial skeleton and 36 the appendicular skeleton. Lesions were sclerotic in 126 cases and mixed in 26 cases. No lytic lesion was depicted. ROC analysis showed that SUV max and SUV mean were better predictors of lesion response than V 18F-NaF and density on CT (P < 0.0001 and P = 0.001, respectively). SUV max and SUV mean were predictors of individual tumor response in separate multivariate models (P = 0.01 and P = 0.02, respectively). CT pattern (mixed versus sclerotic) and lesion density were independent predictors only when assessing response with delta SUV max (P = 0.002 and 0.007, respectively). A good correlation between total [ 18 F]NaF uptake within metastases and their relative radium-223 uptake assessed by two observers 7

  13. Phase I/II trials of {sup 186}Re-HEDP in metastatic castration-resistant prostate cancer: post-hoc analysis of the impact of administered activity and dosimetry on survival

    Energy Technology Data Exchange (ETDEWEB)

    Denis-Bacelar, Ana M.; Chittenden, Sarah J.; Divoli, Antigoni; Flux, Glenn D. [The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, Joint Department of Physics, London (United Kingdom); Dearnaley, David P.; Johnson, Bernadette [The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, Division of Radiotherapy and Imaging, London (United Kingdom); O' Sullivan, Joe M. [Queen' s University Belfast, Centre for Cancer Research and Cell Biology, Belfast (United Kingdom); McCready, V.R. [Brighton and Sussex University Hospitals NHS Trust, Department of Nuclear Medicine, Brighton (United Kingdom); Du, Yong [The Royal Marsden Hospital NHS Foundation Trust, Department of Nuclear Medicine and PET/CT, London (United Kingdom)

    2017-04-15

    To investigate the role of patient-specific dosimetry as a predictive marker of survival and as a potential tool for individualised molecular radiotherapy treatment planning of bone metastases from castration-resistant prostate cancer, and to assess whether higher administered levels of activity are associated with a survival benefit. Clinical data from 57 patients who received 2.5-5.1 GBq of {sup 186}Re-HEDP as part of NIH-funded phase I/II clinical trials were analysed. Whole-body and SPECT-based absorbed doses to the whole body and bone lesions were calculated for 22 patients receiving 5 GBq. The patient mean absorbed dose was defined as the mean of all bone lesion-absorbed doses in any given patient. Kaplan-Meier curves, log-rank tests, Cox's proportional hazards model and Pearson's correlation coefficients were used for overall survival (OS) and correlation analyses. A statistically significantly longer OS was associated with administered activities above 3.5 GBq in the 57 patients (20.1 vs 7.1 months, hazard ratio: 0.39, 95 % CI: 0.10-0.58, P = 0.002). A total of 379 bone lesions were identified in 22 patients. The mean of the patient mean absorbed dose was 19 (±6) Gy and the mean of the whole-body absorbed dose was 0.33 (±0.11) Gy for the 22 patients. The patient mean absorbed dose (r = 0.65, P = 0.001) and the whole-body absorbed dose (r = 0.63, P = 0.002) showed a positive correlation with disease volume. Significant differences in OS were observed for the univariate group analyses according to disease volume as measured from SPECT imaging of {sup 186}Re-HEDP (P = 0.03) and patient mean absorbed dose (P = 0.01), whilst only the disease volume remained significant in a multivariable analysis (P = 0.004). This study demonstrated that higher administered activities led to prolonged survival and that for a fixed administered activity, the whole-body and patient mean absorbed doses correlated with the extent of disease, which, in turn, correlated

  14. Characterising Castrate Tolerant Prostate Cancer Cells

    OpenAIRE

    ASHLEE KATE CLARK

    2017-01-01

    Prostate cancer is a prevalent disease in aging males. This thesis explores prostate cancer cells that escape current therapy and give rise to end-stage disease. Using sophisticated experimental approaches, this important cancer cell population was identified and characterised in human prostate cancer tissues.  Our discoveries will eventually lead to improved cancer treatments for men with prostate cancer.

  15. Desempenho de cordeiros inteiros ou submetidos a diferentes métodos de castração abatidos aos 30 kg de peso vivo Performance of intact or submitted to different methods of castration lambs slaughtered at 30 kg of live weight

    Directory of Open Access Journals (Sweden)

    Edson Luis de Azambuja Ribeiro

    2003-06-01

    Full Text Available Foram utilizados neste experimento 31 cordeiros cruzados Hampshire Down, Ile de France e Suffolk, distribuídos em quatro tratamentos: inteiros ou castrados com burdizzo, borracha ou faca. A castração ocorreu aos 58 dias de idade. Após o desmame, aos 84 dias, os animais foram confinados até atingirem o peso vivo de 30 a 32 kg, quando abatidos. Não houve diferença significativa entre os tratamentos e entre os grupos genéticos para os pesos ao nascimento, desmame e abate, para o ganho de peso médio diário do nascimento ao abate e para a idade ao abate. As médias para os ganhos de peso foram 0,179; 0,177; 0,170 e 0,147 kg e para a idade ao abate de 152,0; 156,0; 161,5 e 188,9 dias para os cordeiros inteiros, castrados com burdizzo, com borracha e com faca, respectivamente. Os cordeiros Hampshire Down, Ile de France e Suffolk ganharam, respectivamente, 0,176; 0,163 e 0,166 kg diariamente. Os animais inteiros apresentaram menores rendimentos verdadeiros de carcaça quente ou fria; não havendo outras diferenças importantes entre os tratamentos para as demais características de carcaça estudadas. Os cordeiros Hampshire Down apresentaram maiores rendimentos de carcaça fria, enquanto os Suffolk tiveram menores rendimentos verdadeiros de carcaça e menor percentagem de pescoço, e os Ile de France apresentaram as carcaças mais curtas. O peso ao nascimento teve efeito significativo sobre o ganho de peso e a idade ao abate dos cordeiros. Os resultados mostraram não haver diferenças no desempenho de cordeiros inteiros ou castrados por diferentes métodos abatidos entre 30 e 32 kg de peso vivo, e que pode ocorrer diferenças entre animais de diferentes grupos genéticos quando abatidos com peso semelhante.Thirty-one Hampshire Down, Ile de France and Suffolk crossbred lambs divided into four treatments: intact, castrated with burdizzo, with rubber bands and with knife, were used in this experiment. Castration occurred at 58 days of age. After

  16. Reflections on the therapeutic use of {sup 223}RaCl{sub 2} for bone metastases resulting from prostate cancer resistant to castration; Reflexiones sobre el uso terapeutico de {sup 223}RaCl{sub 2} para metastasis osea derivada de cancer de prostata resistente a la castracion

    Energy Technology Data Exchange (ETDEWEB)

    Astudillo V, A. J.; Paredes G, L., E-mail: armando.astudillo@inin.gob.mx [ININ, Carretera Mexico-Toluca s/n, 52750 Ocoyoacac, Estado de Mexico (Mexico)

    2015-10-15

    In January 2014 the Comision Federal para la Proteccion contra Riesgos Sanitarios of the Ministry of Health in Mexico, authorize the use of {sup 223}RaCl{sub 2} as the first radiopharmaceutical emitter α for therapeutic purposes in cases of bone metastases resulting from prostate cancer resistant to castration. The paper analyzes the main variables that affect the metrological traceability using activity meters to evaluate the gamma activity of {sup 223}RaCl{sub 2} in hospitals, because it has a chain of complex decay with alpha, beta and gamma emitters, so was important to verify if a gamma activity measurement for a multiple emitter is reliable to determine the total alpha absorbed dose to bone in a patient. (Author)

  17. The phenomenon of castration during antiquity ظاهرة الخصاء خـــلال العصور القديمة

    Directory of Open Access Journals (Sweden)

    Dr. Amer Agag Hamid al-Janabi د.عامر عجاج حميد الجنابي

    2015-01-01

    Full Text Available The subject of castration in ancient times is one of the very important issues, and the importance of this topic because it including matters within the door of history was silent about it , and perhaps it was why this subject Including this section due to his topic of allergies and stay away from indulging in it because the vocabulary used may have Researcher to refrain from mentioned for entry to it because he will be in the immoral side, according to the reader, on the one hand, on the other hand, the sensitivity of wading in it comes from the hand compromising some sacred symbols, it is imperative for the researcher, who is running in this area that is exposed to some of the caliphs and historical figures who had a presence in this subject, and their presence here was negative in many of the aforementioned incompatible with Islamic law and social custom accidents, even founded a common phenomenon campus of Islam, which is not to promote one form or another to the process of castration, as well as use a number of those symbols eunuchs for sexual purposes and this certainly contradicts to Divine Holy of Islam , so the researcher in this topic need to have the courage and boldness to fight it, hence the importance of this subject, let alone say that the move away from such a topics would probably stay this task of history joints without enlightenment and search, and will remain in limbo, not It must be said that the Orientalists wrote just likes of these topics in the impressive and unique research, so as to deprive some of them in writing and without being influenced by the tendency of the hand of the authorities and they wrote with neutrality and that was one of the reasons for the success of their writings and been Famous.

  18. Balanço eletrolítico para suínos machos castrados em crescimento mantidos em ambiente de alta temperatura Electrolyte balance of growing males castrated swines in a high temperature environment

    Directory of Open Access Journals (Sweden)

    Anilce de Araujo Brêtas

    2011-02-01

    Full Text Available Avaliou-se o efeito do balanço eletrolítico (BE em rações com diferentes níveis de eletrólitos para suínos na fase de crescimento criados em alta temperatura. Foram utilizados 200 suínos machos castrados, com peso inicial de 25,3±1,3 kg e final de 68,8±3,4 kg, distribuídos em delineamento experimental inteiramente casualizado com cinco tratamentos e quatro repetições com dez animais por unidade experimental, para a fase de crescimento T1(testemunha ração sem suplementação de eletrólitos 191 mEq/kg; T2 (NaHCO3 ração suplementada bicarbonato de sódio (NaHCO3 250 mEq/kg; T3 (NaHCO3+KCl ração suplementada NaHCO3 e cloreto de potássio (KCl 250 mEq/kg; T4 (NaHCO3 ração suplementada NaHCO3 300 mEq/kg; e T5 (NaHCO3+KCl ração suplementada com NaHCO3 e KCl 300 mEq/kg. As variáveis avaliadas foram consumo de ração, ganho de peso, consumo de nitrogênio, consumo de lisina, eficiência de utilização de nitrogênio para ganho, eficiência de utilização de lisina para ganho, conversão alimentar e os parâmetros fisiológicos, frequência respiratória e temperatura retal. Foi coletado sangue para mensurar as concentrações sorológicas de Na, Cl e K. A temperatura média foi 29,65±3,80º C com UR do ar 69,6±10,4%, Temperatura do Globo Negro de 31,95±1,98º C e Índice de Temperatura do Globo Úmido em 80,51±2,44. Os níveis de BE reduziram (P0,05. A correção do BE não influenciou o desempenho dos suínos.The effect of electrolyte balance (EB in diets with different levels of electrolytes for growing swine under high environmental temperature was evaluated. Two hundred castrated pigs with initial weight of 25.3±1.3 kg and final weight of 68.8±3.4 kg were allotted in a completely randomized experimental design with five treatments and four replicates with 10 pigs per experimental unit, for the growing phase T1 (control diet without electrolyte 191 mEq/kg; T2 (NaHCO3 diet supplemented with sodium bicarbonate (NaHCO3

  19. Desenvolvimento ponderal de bovinos de corte de diferentes grupos genéticos de Charolês x Nelore inteiros ou castrados aos oito meses Growth of beef cattle from different genetic groups of Charolais x Nellore intact or castrated at eight months

    Directory of Open Access Journals (Sweden)

    Lígia Pigatto Pereira

    2000-12-01

    Full Text Available O objetivo deste trabalho foi avaliar animais inteiros ou castrados aos oito meses, de diferentes sistemas de acasalamento (SA: de raça definida (D, cruzados da primeira (G1 e da segunda (G2 geração, e de diferentes grupos genéticos (GG em cada SA, D: Charolês (C vs Nelore (N, G1: ½CN vs ½NC e G2: ¾CN vs ¾NC, quanto ao desenvolvimento ponderal desde o nascimento até o abate. Foram utilizados 78 animais desmamados aos três meses, confinados dos 7 aos 12 meses (primeiro inverno/primavera, mantidos em pastagem natural (PN dos 12 aos 20 meses (segundo verão/outono e confinados dos 20 aos 24 meses (segundo inverno/primavera, quando foram abatidos. Foi observada heterose de 20,44% para G1 e 14,44% para G2 no peso aos 24 meses. Entre os definidos, o C foi mais pesado que o N em todas as idades avaliadas. Na G2, ocorreram diferenças em peso (PThe objective of this work was to evaluate the growth of beef cattle intact or castrated at eight months, from different mating systems (MS: straightbreds (S, crossbreds of first (G1 and second (G2 generation, and of different genetic groups (GG in each MS, S: Charolais (C vs Nellore (N, G1: ½CN vs ½NC and G2: ¾CN vs ¾NC. Seventy-eight animals, weaned at three months, were submitted to feedlot from 7 to 12 months (first winter/spring, maintained in native pasture (NP from 12 to 20 months (second summer/autumn, and finished in feedlot from 20 to 2 4 months (second winter/spring, when they were slaughtered. Heterosis of 20.44% for G1 and 14.44% for G2 was observed for weight at 24 months. The C was heavier than the N in all ages. In the G2, the ¾CN was heavier (P<.05 at three, eight and twelve months. Intact animals presented higher (P<.05 ADG than the castrated ones during the first feedlot period, but in NP no difference occurred between sexual condition. Heterosis for weight per day of age was 22.25% for G1 and 14.54% for G2. The G2 animals had lower ADG than the S and G1 during the first feedlot

  20. Redução da proteína bruta da ração para suínos machos castrados dos 15 aos 30 kg mantidos em termoneutralidade Reduction of crude protein level of ration to castrated swine from 15 to 30 kg maintained in a termoneutral environment (22ºC

    Directory of Open Access Journals (Sweden)

    Rony Antonio Ferreira

    2003-12-01

    Full Text Available Um experimento foi conduzido para avaliar a influência da redução da proteína bruta (PB e suplementação de aminoácidos sintéticos sobre o desempenho de suínos machos castrados mantidos em ambiente termoneutro (22ºC. Foram utilizados 60 leitões mestiços (Landrace x Large White com peso médio inicial de 15,0 kg e idade média de 53,1 dias, em delineamento inteiramente ao acaso, com cinco tratamentos (18, 17, 16, 15 e 14% PB, seis repetições e dois animais por unidade experimental. As rações experimentais foram fornecidas à vontade até o final do experimento, quando os animais atingiram o peso médio de 30,2 kg. A temperatura média no interior da sala foi mantida em 22ºC, com umidade relativa de 82,3%. O Índice de Temperatura de Globo e Umidade calculado no período foi de 69,6. Não se observou efeito da redução do nível de proteína bruta da ração sobre as variáveis de desempenho (consumo de ração, ganho de peso e conversão alimentar. As taxas de deposição de proteína e gordura também não foram influenciadas pela redução da PB na ração. Os tratamentos influenciaram os pesos absoluto e relativo do estômago e o peso absoluto do intestino, sendo os maiores valores observados em animais que receberam a ração com maior nível de proteína bruta. Concluiu-se que o nível de PB da ração pode ser reduzido de 18 para 14%, sem prejudicar o desempenho de suínos machos dos 15 aos 30 kg mantidos em ambiente termoneutro, desde que devidamente suplementadas com aminoácidos essenciais limitantes.One experiment was conducted to evaluate the influence of reduction of the crude protein (CP level of ration with amino acid supplementation on performance of castrated males swines maintained in a termoneutral environment (22ºC. A total of sixty crossbred swines (Landrace x Large White, with average initial weight of 15.0 kg and 53.1 days old, was allotted to a completely randomized design with five treatments (18, 17, 16

  1. Physical (Surgical) Castration as Treatment of Male Sex Offenders?

    Czech Academy of Sciences Publication Activity Database

    Škvain, Petr

    2014-01-01

    Roč. 97, č. 1 (2014), s. 40-47 ISSN 0026-9301 Institutional support: RVO:68378122 Keywords : sex offenders * treatment of sex offenders * Czech Republic Subject RIV: AG - Legal Sciences Impact factor: 0.136, year: 2014

  2. Live and carcass measurements of steers castrated at three different ...

    African Journals Online (AJOL)

    Moontlike redes vir die swak prestasie van die osse wat op 3 maande gekastreer is, word bespreek. 'n Ekonomiese analise het getoon dat R4,3-miljoen meer verdien kan word indien aile produsente landswyd hul bulkalwers of kort na geboorte, of op. 6-maande-ouderdom kastreer. S.-Afr. Tydskr. Veek. 1986, 16: 151 -154.

  3. Castration causes progressive reduction of length of the rabbit penis ...

    African Journals Online (AJOL)

    Anatomy Journal of Africa. Journal Home · ABOUT THIS JOURNAL · Advanced Search · Current Issue · Archives · Journal Home > Vol 3, No 3 (2014) >. Log in or Register to get access to full text downloads.

  4. Castration causes progressive reduction of length of the rabbit penis ...

    African Journals Online (AJOL)

    Androgenic hormones are important in normal embryonic development and maintenance of the structural integrity of the penis. This structural integrity is vital in the physiology of penile erection. Its alteration may therefore lead to functional impairment resulting in erectile dysfunction as seen in hypogonadic conditions.

  5. TRAF4 and Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2017-10-01

    activation of AR. Ubiquitination is an important post-translational modification regulating protein degradation, trafficking, activity, and protein ... protein interaction. Deregulation of the ubiquitin pathways has been implicated in a number of diseases including cancers. Targeting the...specific PTEN deletion mouse line to examine the role of TRAF4 in prostate cancer development. 4. Impact (1) The impact on the development of the

  6. Castration of dromedary camel through prescrotal midline incision ...

    African Journals Online (AJOL)

    In 14/165 animals (8.5%) postoperative infection (sepsis) developed, which healed in two to three weeks after open wound management. The remaining 151 animals had an uneventful recovery, but a slight edematous swelling of the scrotum was observed in 8 of the 151 animals (5.3%), which was self-limiting and of no ...

  7. Castration Induced Neuroendocrine Mediated Progression of Prostate Cancer

    Science.gov (United States)

    2008-09-01

    Short-Term Therapy with Bacillus Calmette-Guerin (BCG) in Patients with Non-Muscle-Invasive Bladder Cancer. Eur Urol. epub. 10. 2007 Cambio A.J...Leonhardt M, Janssen M, Konrad L, Bjartell A, Abrahamsson PA. Neurogenic origin of human prostate endocrine cells. Urology 1999; 53: 1041–1048. 13 Luttrell...membrane (Corning, Inc.). A549 cells were then infected with a mix of DMEM, virus-containing supernatant (1:1), and polybrene (4 Ag/mL). After

  8. Castration Induced Neuroendocrine Mediated Progression of Prostate Cancer

    National Research Council Canada - National Science Library

    Evans, Christopher P

    2006-01-01

    ... enhancer region, which is primarily stimulated by androgens. We have shown that gastrin-releasing peptide prostate cancer cells have their growth in soft agar inhibited by the specific Src inhibitor AZD0530...

  9. Redução do nível de proteína bruta e suplementação de aminoácidos em rações para suínos machos castrados mantidos em ambiente termoneutro dos 30 aos 60 kg Reduction of crude protein levels of ration with amino acid supplementation to castrated swines maintained in a termoneutral environment from 30 to 60 kg

    Directory of Open Access Journals (Sweden)

    Rony Antonio Ferreira

    2005-04-01

    Full Text Available Este estudo foi conduzido para avaliar a influência da redução do nível de proteína bruta (PB da ração com suplementação de aminoácidos sobre o desempenho de suínos machos castrados (Landrace x Large White mantidos em ambiente termoneutro. Cinqüenta leitões mestiços (peso médio inicial de 30,2 kg foram distribuídos em delineamento experimental inteiramente ao acaso, com cinco tratamentos (17, 16, 15, 14 e 13% PB, cinco repetições e dois animais por unidade experimental. As rações experimentais e a água foram fornecidas à vontade até o final do experimento, quando os animais atingiram o peso médio de 60,2 kg. A temperatura média no interior da sala foi mantida em 22,0ºC e a umidade relativa média em 82,8%, correspondendo a um índice de temperatura de globo e umidade (ITGU de 69,2. A redução do nível de PB da ração influenciou o ganho de peso (GP dos animais; aqueles que consumiram a ração com 17% de PB apresentaram redução significativa no GP em relação aos que receberam as rações com 15 e 14% de PB. O consumo de ração e a conversão alimentar não foram influenciados pelos tratamentos. A redução do nível de PB aumentou as deposições de gordura e de proteína na carcaça e levou à diminuição da excreção de nitrogênio total. O nível de PB da ração para suínos machos dos 30 aos 60 kg mantidos em ambiente termoneutro pode ser reduzido de 17 para 13%, sem influenciar negativamente o desempenho, desde que as rações sejam devidamente suplementadas com aminoácidos essenciais limitantes.An study was conducted to evaluate the influence of reduction of crude protein (CP levels and amino acid supplementation in diets on the performance of castrated swines (Landracex Large White maintained in a termoneutral environment. Fifty crossbreed piglets (average initial body weight of 30.2 kg were allotted to a completely randomized experimental design with five treatments (17, 16, 15, 14 and 13% CP and

  10. Qualidade e composição química da carne de bovinos de corte inteiros ou castrados de diferentes grupos genéticos Charolês x Nelore Quality and composition of meat from entire or castrated beef cattle from different Charolais x Nellore genetic groups

    Directory of Open Access Journals (Sweden)

    Fabiano Nunes Vaz

    2001-04-01

    Full Text Available Utilizaram-se 70 bovinos machos de três sistemas de acasalamento, puros Charolês (Ch e Nelore (Ne, mestiços G1: 1/2 Ch + 1/2 Ne (1/2 Ch e 1/2 Ne + 1/2 Ch (1/2 Ne e mestiços G2: 3/4 Ch + 1/4 Ne (3/4 Ch e 3/4 Ne + 1/4 Ch (3/4 Ne. O número de animais por grupo genético foi, respectivamente, 15, 12, 8, 12, 14 e 9. Trinta e cinco animais foram castrados (C aos sete meses e 35 foram mantidos inteiros (I. Os animais foram confinados dos 20 aos 24 meses, quando foram abatidos. Para avaliação da carne, foi utilizado o músculo longissimus dorsi. Não houve interação significativa entre grupo genético e estado sexual para nenhuma das variáveis estudadas. Os machos I apresentaram carne mais escura (3,05 contra 3,78 pontos com menor marmoreio (4,26 contra 5,75 pontos e menos extrato etéreo (1,73 contra 2,88%. Entretanto, a área de longissimus dorsi foi maior (66,03 contra 60,50 cm² e a carne com melhor palatabilidade, suculência e mais macia. Na comparação entre grupos genéticos, os Ch apresentaram maior longissimus dorsi. Na primeira geração de cruzamento (G1, animais 1/2 Ch apresentaram maior marmoreio e teor de extrato etéreo e menor quebra à cocção que os 1/2 Ne. Entre os animais G2, os animais 3/4 Ne mostraram maior quebra ao descongelamento e teor de extrato etéreo na carne. Na G1, o nível de heterose chegou a 18,54% para área de longissimus dorsi, 28,10% para teor de extrato etéreo e 64,01% para marmoreio da carne. Na G2, a heterose foi de -17,37% para a textura da carne e 10,40% para área de longissimus dorsi.Seventy beef males of three breeding systems (BS, straightbreds Charolais (Ch and Nellore (Ne, G1 crossbreds: 1/2 Ch + 1/2 Ne (1/2 Ch and 1/2 Ne + 1/2 Ch (1/2 Ne and G2 crossbreds: 3/4 Ch + 1/4 Ne (3/4 Ch and 3/4 Ne + 1/4 Ch (3/4 Ne were used. The number of animals by genetic group was, respectively, 15, 12, 8, 12, 14 and 9. Thirty-five males were castrated (C at seven months and 35 were kept intact (I. The animals

  11. Redução da proteína bruta da ração e suplementação de aminoácidos para suínos machos castrados dos 15 aos 30 kg mantidos em ambiente de alta temperatura Effect of feeding reduced crude protein, amino acid-supplemented diets on performance of castrated swine from 15 to 30 kg on high environmental temperature

    Directory of Open Access Journals (Sweden)

    Rony Antonio Ferreira

    2006-06-01

    Full Text Available Um experimento foi conduzido para avaliar a influência da redução da proteína bruta (PB e da suplementação de aminoácidos sintéticos em rações sobre o desempenho de suínos machos castrados mantidos em ambiente de alta temperatura (32ºC. Foram utilizados 60 leitões mestiços (Landrace x Large White com peso médio inicial de 15,2 kg, distribuídos em um delineamento inteiramente ao acaso, com cinco tratamentos (18, 17, 16, 15 e 14% de PB, seis repetições e dois animais por unidade experimental. As rações experimentais foram fornecidas à vontade até o final do experimento, quando os animais atingiram o peso médio de 29,9 kg. A temperatura média no interior da sala foi mantida em 32,3ºC, com umidade relativa de 75,9% e índice de temperatura de globo e umidade de 82,6. Não houve efeito da redução do nível de proteína da ração sobre o desempenho (consumo de ração, ganho de peso e conversão alimentar dos suínos. Os consumos de lisina e energia digestíveis também não foram influenciados pelos tratamentos. Verificou-se redução gradativa no consumo diário de nitrogênio. Quanto às deposições de proteína (DP e de gordura (DG na carcaça, os tratamentos influenciaram somente a DG. Os pesos de fígado e de estômago (tanto absoluto como relativo e o peso relativo de rins foram maiores nos animais que receberam a ração com maior nível de PB. A redução de 18 para 14% no nível de PB da ração não influencia negativamente o desempenho de suínos machos dos 15 aos 30 kg mantidos em ambiente de alta temperatura, desde que a ração seja devidamente suplementada com aminoácidos essenciais limitantes.A trial was conducted to evaluate the effect of reduced CP, amino acid-supplemented diets on performance of castrated males swines on high environmental temperature (32ºC. A total of sixty crossbred piglets (Landrace x Large White averaging initial weight of 15.2 kg was allotted to completely randomized experimental

  12. Evolving Role of Bone Biomarkers in Castration-Resistant Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Janet E. Brown

    2010-09-01

    Full Text Available The preferential metastasis of prostate cancer cells to bone disrupts the process of bone remodeling and results in lesions that cause significant pain and patient morbidity. Although prostate-specific antigen (PSA is an established biomarker in prostate cancer, it provides only limited information relating to bone metastases and the treatment of metastatic bone disease with bisphosphonates or novel noncytotoxic targeted or biological agents that may provide clinical benefits without affecting PSA levels. As bone metastases develop, factors derived from bone metabolism are released into blood and urine, including N- and C-terminal peptide fragments of type 1 collagen and bone-specific alkaline phosphatase, which represent potentially useful biomarkers for monitoring metastatic bone disease. A number of clinical trials have investigated these bone biomarkers with respect to their diagnostic, prognostic, and predictive values. Results suggest that higher levels of bone biomarkers are associated with an increased risk of skeletal-related events and/or death. As a result of these findings, bone biomarkers are now being increasingly used as study end points, particularly in studies investigating novel agents with putative bone effects. Data from prospective clinical trials are needed to validate the use of bone biomarkers and to confirm that marker levels provide additional information beyond traditional methods of response evaluation for patients with metastatic prostate cancer.

  13. &timation of Body ~ Gain of Entire and Castrated Male ~ at Two ...

    African Journals Online (AJOL)

    mats in the lying area. During nutrient balance. periods, pigs were moved to the calorimeter building and housed in mobile metabolism crates designed for separate collection of urine and faeces. Diet and feeding. A single, pelleted diet was used throughout the experiment. The composition of the diet. (g/kg as fed) was as ...

  14. Epithelial Plasticity in Castration-Resistant Prostate Cancer: Biology of the Lethal Phenotype

    Science.gov (United States)

    2014-07-01

    and suggestions for ther- apeutic interventions to address EP in PC. Cancer Metastasis Rev 2 Preclinical evidence of EP in PC EP in epithelial-origin...Szabadkai, I., Daub, H., Keri, G., & Ullrich, A. (2008). AXL is a potential target for therapeutic intervention in breast cancer progression. Cancer ... Testicular Cancer Lecture and 2011 Prostate Cancer Lecture 11.2010 Talk entitled: “CRPC: What Else is Out There?” for the UK Cancer Convention, Royal

  15. Radium-223 therapy of advanced metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Fosbøl, Marie Øbro; Petersen, Peter Meidahl; Kjaer, Andreas

    2018-01-01

    ) can serve as a prognostic biomarker of overall survival (OS) and hematological toxicity, as well as a tool for response assessment in patients with mCRPC treated with223RaCl2Methods:Retrospective study of the Danish cohort of mCRPC patients who received223RaCl2therapy between March 2014 and October...... ratio 2.65 [95% CI: 1.5-4.71];P= 0.001). Likewise, baseline BSI was prognostic for occurrence of hematological toxicity and patients with BSI > 5 had an odds ratio of 3.02 (95% CI: 1.2-7.8;P= 0.02) for toxicity. BSI declined during therapy in 44% of patients who completed three cycles of223RaCl2(n= 52......) and in 84% of patients after EOT (n= 32). There was no significant association between change in BSI during therapy and OS.Conclusion:BSI is a promising biomarker for late-stage mCRPC patients receiving223RaCl2for prognostication of OS and hematological toxicity. Further prospective studies are needed...

  16. Administration of perioperative penicillin reduces postoperative serum amyloid A response in horses being castrated standing

    DEFF Research Database (Denmark)

    Busk, Peter; Jacobsen, Stine; Martinussen, Torben

    2010-01-01

    Objectives: To compare postoperative inflammatory responses in horses administered perioperative procaine penicillin and those not administered penicillin using acute phase protein serum amyloid A (SAA) as a marker of inflammation. Study Design: Randomized clinical trial. Animals: Stallions (n = 50...... administered NSAID and 25,000 U/kg procaine penicillin on day 0, 1, and 2. Results: SAA concentrations increased significantly from preoperative levels in both groups, and on day 8 concentrations were significantly (P o .02) higher in horses administered only NSAID than in those administered procaine penicillin...

  17. Epithelial Plasticity in Castration-Resistant Prostate Cancer: Biology of the Lethal Phenotype

    Science.gov (United States)

    2011-07-01

    mesenchymal tran- 585 sitions. J Clin Invest 2009;119:1429–37. 3.586 Acloque H, Adams MS, Fishwick K, Bronner- Fraser M, Nieto MA. 587 Epithelial-mesenchymal...resistance and metastatic progression, hallmarks of malig- nancy .2,3 Indeed, induction of EMT in breast cancer model systems generates properties of self...expression signature [0080] AT3-T cells sometimes formed tight clusters resembling protospheres. While sphere formation is not an exclusive

  18. Epithelial Plasticity in Castration-Resistant Prostate Cancer: Biology of the Lethal Phenotype

    Science.gov (United States)

    2012-07-01

    Translational Medicine, 2012, 4(126). 4. Kirschmann, D.A., et al. Molecular Pathways: Vasculogenic Mimicry in Tumor Cells: Diagnostic and Therapeutic...cells with features of vasculogenic mimicry .4 • Fluorescence in situ hybridization for cell ploidy, TMPRSS2-ERG status, PTEN loss, and AR...molecular signatures. In adult animals , epithelial and mesenchymal cells usually remain in one phenotypic state; that is, epithelial cells do not change

  19. Developing Novel Therapeutics Targeting Undifferentiated and Castration-Resistant Prostate Cancer Stem Cells

    Science.gov (United States)

    2015-10-01

    in vivo cytotoxicities of the conjugated JRM2 peptide and finishing up screening and validating the kinase inhibitor library screening. 15. SUBJECT...cells were purified out and then lysed to infect bacteria K91, from which 960 and 704 tet/kan- resistant bacterial colonies were generated from GFP+ and...Figure 2A; data not shown). To determine whether JRM2 can preferentially bind to the PSA-/lo LNCaP cells, we made several versions of JRM2 conjugates

  20. Phosphoproteomic Assessment of Therapeutic Kinases for Personalized Therapy in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2016-10-01

    Faltermeier CM, Carlin DE, Flemming DT, Wong CK, Newton Y, Sudha S, Vashisht AA, Huang J, Wohlschlegel JA, Graeber TG, Witte ON#, Stuart JM# (2016...Graham, ..., Thomas G. Graeber, Owen N. Witte, Joshua M. Stuart Correspondence justin.drake@cinj.rutgers.edu (J.M.D.), owenwitte@mednet.ucla.edu (O.N.W...relative phosphorylation of peptides (Figures S4C–S4H). We asked if the high differential kinase activities in CRPC compared to pri- mary prostate cancer

  1. Castration Has Antihypertensive and Organoprotective Effects in Male but Not in Female Heterozygous Ren-2 Rats

    Czech Academy of Sciences Publication Activity Database

    Vaněčková, Ivana; Husková, Z.; Vaňourková, Z.; Červenka, L.

    2011-01-01

    Roč. 34, č. 1 (2011), s. 46-52 ISSN 1420-4096 R&D Projects: GA MŠk(CZ) 1M0510 Institutional research plan: CEZ:AV0Z50110509 Keywords : Ren-2 rats * hypertension * sexual dimorphism * age * sex hormones * renin-angiotensin system Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery Impact factor: 1.464, year: 2011

  2. Androgen Deprivation Enhances PLZF-Repressed Cistrome that Promotes the Castration-Resistant Phenotype

    Science.gov (United States)

    2014-10-01

    regulated network is activated when AR binds enhancer elements and modulates specific enhancer–promoter looping. Kallikrein-related peptidase 3 (KLK3... peptidase 3 (KLK3) enhancer, one of the strongest AR-bound enhancers in prostate cancer cells, produces KLK3 eRNA (KLK3e), which impacts androgen

  3. Dual-Targeting of AR and Akt Pathways by Berberine in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2016-10-01

    knockout mice. A. The weight of the GU- bloc is normalized by body weight and presented as mean±standard deviation, n=6. B. Representative photos ...presented as mean ± standard deviation, n=6. B, Representative photos of the GU bloc in each group. 0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 High...Brigham D, Moon M, Maneval EC, Chen I, Darimont B, Hager JH. A Clinically Relevant Androgen Receptor Mutation Confers Resistance to Second-Generation

  4. New therapies for relapsed castration-resistant prostate cancer based on peptide analogs of hypothalamic hormones

    Directory of Open Access Journals (Sweden)

    Andrew V Schally

    2015-01-01

    Full Text Available It is a pleasure to contribute our presentation at the International Prostate Forum of the Annual Meeting of the American Urological Association (AUA to this special issue of the Asian Journal of Andrology.

  5. Dual-Targeting of AR and Akt Pathways by Berberine in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2014-08-01

    underlying the downregulation of full-length and splice variants of AR by the phytochemical berberine (BBR). We concluded that BBR inhibits the...and AKT expression in prostatic tissues. A-D, tissues from Pten wild-type mice. E-H, tissues from Pten knockout mice. Image analysis was...as immunohistochemistry (IHC) staining analysis showed BEZ235 effectively reduced AKT phosphorylation in prostatic tissues from the Pten-null mice

  6. the tnfluence of breed, castration and age on muscle fibre type and ...

    African Journals Online (AJOL)

    Analysis of vaiance results of musc'le fibre types of the M semimembranosus, M. semitendinosu s (dark) and. M. semitendinosus (li9ht)ol'Afrikaner and Friesland bulls of ages between birth and 24 months. Parameter. Percentage red muscle fibres. Percentage intermediary muscle fibres. Percentage white muscle fibres. A.

  7. The effect of castration and plane of nutrition on growth and carcass ...

    African Journals Online (AJOL)

    South African Journal of Animal Science. Journal Home · ABOUT THIS JOURNAL · Advanced Search · Current Issue · Archives · Journal Home > Vol 3, No 1 (1973) >. Log in or Register to get access to full text downloads.

  8. Investigating Genomic Mechanisms of Treatment Resistance in Castration Resistant Prostate Cancer

    Science.gov (United States)

    2015-05-01

    Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202- 4302. Respondents should...PATENTS, AND LICENCES None REPORTABLE OUTCOMES Two clinical protocols and a laboratory protocol for the work have been developed for this...2011 University of California, San Francisco Fellowship Urologic Oncology LICENSES, CERTIFICATION 2004 Medical Licensure, California ( Licence

  9. Uncarboxylated Osteocalcin and Gprc6a Axis Produce Intratumoral Androgens in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2016-05-01

    including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and...growth. 6. PUBLICATIONS, ABSRACTS, AND PRESENTATIONS: None. 7. INVENTIONS, PATENTS AND LICENCES : None. 8. REPORTABLE OUTCOMES

  10. the effect of castration and plane of nutrition on growth and carcass ...

    African Journals Online (AJOL)

    . Although the results of studies using rats cannot be applied directly to problems of ..... may not necessarily be a good index of testicular steroid production, this postulate is tenuous. Further study is required to examine the influence of plane of ...

  11. Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2017-12-01

    Abstracts, and Presentations……….….……………. 16 7. Inventions, Patents and Licenses …………………………………… 17 8. Reportable Outcomes..……………………………………………… 17...continuous passaging LNCaP cells with stable knockdown of MAPK4 led to decreased knockdown efficiency, potentially due to the growth disadvantage of...LNCaP cells with stable knockdown of MAPK4 led to decreased knockdown efficiency, potentially due to the growth disadvantage of those cells with

  12. Understanding the Role of MDSCs in Castration-Resistant Prostate Cancer and Metastasis

    Science.gov (United States)

    2016-12-01

    organs  such  as  the  liver,  skin,   intestine ,  and  pancreas   [22],  the  role  for  the  Hippo–YAP  pathway  in...important role in development and cancer in organs such as the liver, skin, intestine , and pan- creas (25–27), the role for the Hippo–YAP pathway in...Pharmacologic depletion of MDSCs using Gr1 antibody, Pep-H6 peptibody, or CXCR2 inhibitor arrested prostate progression at the high-grade PIN stage whereas

  13. Chemical castration by a single bilateral intra-testicular injection of ...

    African Journals Online (AJOL)

    Six apparently healthy Borno white bucks weighing 15± 1.6 kg and aged 1.3± 0.3 years were used for this study. Two and half (2.5) ml Purit® (chlorhexidine gluconate 0.3% B.P W/V and cetrimide 3.0% B.P W/V CAPL Lagos) were injected bilaterally into the caudae of each epididymis following sedation with xylazine ...

  14. Novel Therapeutic Targets to Inhibit Tumor Microenvironment-Induced Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2014-10-01

    NUMBER (include area code ) Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 3 Annual Progress Report W81XWH-13-1-0163 Novel Therapeutic...Kim IY, Ahn HJ, Zelner DJ, Shaw JW, Lang S, Kato M, Oefelein MG, Miyazono K, Nemeth JA, Kozlowski JM, Lee C. Loss of expression of transforming

  15. CpG-STAT3siRNA for Castration-Resistant Prostate Cancer Therapy

    Science.gov (United States)

    2015-12-01

    and thumb to draw back skin of above and below the eye then carefully insert the 30G needle at ~45° angle at the corner of the eye , lateral to the...retroorbital injections, mice should not receive more than single injection per day. Additional injections are possible only when using alternate eyes with 1...lately reported in MDSCs associated with several types of human cancers, such as melanoma , head and neck, renal, breast, and pancreatic cancers (15, 21

  16. Understanding and Targeting Tumor Microenvironment in Prostate Cancer to Inhibit Tumor Progression and Castration Resistance

    Science.gov (United States)

    2016-10-01

    DISTRIBUTION STATEMENT: Approved for Public Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the...overall survival. (G) Kaplan-Meier survival curve showing the significant delay of mortality caused by Pep-H6 peptibody treatment of Ptenpc-/-Smad4pc...purchased from US Biomax Tissue Microarray) for YAP1. Interestingly, YAP1 is expressed in basal cells, but not in the luminal cells of the normal

  17. Sexual trauma and castration anguish: freudian courses in light of Lacan's contributions

    OpenAIRE

    Couto, Luiza Vieira; Chaves, Wilson Camilo

    2009-01-01

    Este trabalho tem como objetivo articular os conceitos de trauma sexual e angústia de castração a partir dos textos freudianos e à luz das contribuições de Lacan. Em Freud, estes conceitos acompanham a construção da psicanálise enquanto campo de investigação do inconsciente. O inconsciente nos indica o vazio fundamental que movimenta o desejo, a ausência do objeto. A fantasia, através do que se orienta o desejo, representa a permanência do objeto faltoso, a alienação do eu no Ideal de um gozo...

  18. Glyphosate Vedotin for Treatment of Bone Metastatic Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2015-07-01

    physical therapy , or surgical intervention. However, surgery is generally recommended for all symptomatic patients younger than 60 with a full...Park MK, Moon Y, Kim WU, et al. IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kappaB- and PI3-kinase...Hwang SY, Kim JY, Kim KW, Park MK, Moon Y, Kim WU, Kim HY. IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via

  19. Developing Novel Therapeutics Targeting Undifferentiated and Castration-Resistant Prostate Cancer Stem Cells

    Science.gov (United States)

    2016-10-01

    display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE 2. REPORT TYPE Annual 3. DATES...cell numbers compared to the time-matched control LNCaP-GFP cells (Figure 1F). We further characterized LNCaP-GFP and LNCaP-MDV cells at crisis point...cadherin, SLUG , and vimentin), and CSCs (i.e., CD44, integrin α2β1, and ABCG2) [2-4, 20, 25-33] (Figure 3B; Supplementary Figure S3). Flow

  20. Super-Penetrant Androgen Receptor: Overcoming Enzalutamide Sensitivity in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2016-07-01

    Enzalutamide- biotin conjugate bound streptavidin sepharose beads (beads linked to another inhibitor DZ1-067-PEG linker, as negative control) were...a PEG linker with a terminal amine attached to biotin so that the bound proteins can be captured on the streptavidin coated sepharose beads. 3...and (b) the identification of a novel AR acetylation site (K609) in the DNA binding domain of the AR in Enzalutamide resistant metastatic CRPC cells

  1. Overcoming Autophagy to Induce Apoptosis in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2016-12-01

    We started our study with saracatinib but had to switch to enzalutamide due to the halted effort by the pharmaceutical companies for the Src kinase...cells utilizes for aberrant AR activation, intracrine androgen synthesis and kinase pathway mediated AR activation in the absence of androgen, were...Interleukin-6 regulates androgen synthesis in prostate cancer cells. Clin Cancer Res, 2009. 15(15): p. 4815-22. 17. Nagabhushan, M., et al., CWR22: the

  2. Novel Therapeutic Targets to Inhibit Tumor Microenvironment-Induced Castration Resistant Prostate Cancer

    Science.gov (United States)

    2016-10-01

    extracted from laser -captured PCa cells from human CRPC tumors revealed that MAPK4 expression is strongly correlated with AR activation (expression...Approved for Public Release; Distribution Unlimited The views, opinions and/or findings contained in this report are those of the author(s) and...signaling induced the expression of several AR targets as well as MAPK4 in PCa LNCaP cells, and that MAPK4 induced ligand-independent AR activation in

  3. Methadone in combination with medetomidine as premedication prior to ovariohysterectomy and castration in the cat.

    Science.gov (United States)

    Slingsby, Louisa S; Bortolami, Elisa; Murrell, Joanna C

    2015-10-01

    The aim of the study was to evaluate the tolerability, sedative and analgesic effects of methadone in combination with medetomidine for premedication prior to neutering in healthy cats. This was an assessor-blinded, randomised, clinical research study. Forty-five cats were recruited and divided into three treatment groups of 15. Following premedication with medetomidine (20 µg/kg) and one of the three test drugs - methadone 0.5 mg/kg, buprenorphine 20 µg/kg or butorphanol 0.4 mg/kg intramuscularly - anaesthesia was induced with propofol and maintained with isoflurane, and neutering was carried out. Sedation and physiological parameters were assessed before premedication, after premedication before induction of anaesthesia, and at 90 mins and 2, 3, 4, 6, 7, 8 and 24 h after premedication. Pain and mechanical nociceptive threshold were assessed at similar time points. There were no differences between groups with respect to age, sex, duration of anaesthesia or surgery. Most cats had low pain scores in the postoperative period, with small differences in pain scores between groups at individual time points only. Five, two and no cats required additional rescue analgesia in the postoperative period in the butorphanol, methadone and buprenorphine groups, respectively, representing no significant difference between groups. Medetomidine combined with methadone for premedication prior to neutering in healthy cats provided adequate analgesia for the first 6 h after administration with no adverse effects; effects overall were comparable with medetomidine combined with buprenorphine or butorphanol. Administration of further analgesia with methadone at 6 h and a non-steroidal anti-inflammatory drug at 8 h provided adequate analgesia for the first 24 h after surgery. © ISFM and AAFP 2014.

  4. Enzalutamide Antitumour Activity Against Metastatic Castration-resistant Prostate Cancer Previously Treated with Docetaxel and Abiraterone

    DEFF Research Database (Denmark)

    Brasso, Klaus; Thomsen, Frederik B; Schrader, Andres J

    2015-01-01

    prostate-specific antigen (PSA) kinetics, patient characteristics, and progression-free survival, respectively. Kaplan-Meier survival analysis and Cox proportional hazard analysis were performed. RESULTS AND LIMITATIONS: We identified 137 patients who prior to enzalutamide had progressed following a median...... on enzalutamide following disease progression on taxane-based chemotherapy and abiraterone was modest, but patients who experience a PSA decline >30% or 50%, respectively, with enzalutamide in this setting had longer survival. PATIENT SUMMARY: Enzalutamide produces modest prostate-specific antigen (PSA) responses...... of eight cycles of docetaxel and seven courses of abiraterone. The median time on enzalutamide was 3.2 mo; median OS from the time patients started enzalutamide was 8.3 mo (95% confidence interval, 6.8-9.8). Only 45 (38%) and 22 (18%) patients had PSA declines (unconfirmed) >30% and 50%, respectively...

  5. Docetaxel in very elderly men with metastatic castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Hui-Li Wong

    2015-06-01

    Conclusions: Very elderly patients (80 + years with mCRPC are infrequently included in clinical trials, yet the use of chemotherapy in this population is likely to increase. Our series demonstrates significant response rates to docetaxel chemotherapy, but that a substantial number of patients had treatment-related complications. This highlights the need for careful patient selection and optimization of chemotherapy dosing.

  6. A single-center experience with abiraterone as treatment for metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Thortzen, Anita; Thim, Stine; Røder, Martin Andreas

    2016-01-01

    -specific antigen (PSA) response, clinical and radiological progression, and overall survival. RESULTS: A total of 73 consecutive patients with mCRPC undergoing treatment with AA between November 2012 and October 2014 were included. Median follow-up was 9.9 (0.9-23.4) months. PSA decline>50% was found in 39...... trial. Except for PSA response (>50% decline) in patients managed with AA, postchemotherapy results were inferior to phase III studies. This is most likely because of patient selection, which is a typical weakness when transferring results from phase III trials into clinical practice....

  7. Docetaxel rechallenge after an initial good response in patients with metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Oudard, Stéphane; Kramer, Gero; Caffo, Orazio

    2015-01-01

    CRPC with a good response to first-line docetaxel [serum prostate specific antigen (PSA) decrease ≥50%; no clinical/radiological progression]. We analysed the impact of management at relapse (docetaxel rechallenge or non-taxane-based therapy) on PSA response, symptomatic response (performance status....... At relapse, 223 patients were rechallenged with docetaxel (82.5%) and 47 received non-taxane-based therapy. There was no significant difference in median OS {18.2 [95% confidence interval (CI) 16.1-22.00] and 16.8 [95%CI 13.4-21.5] months, respectively, P = 0.35}. However, good PSA response and symptom...... relief/stable disease were more frequent on docetaxel rechallenge (40.4% vs 10.6%, P PSA). A PFI of >6 months and added estramustine predicted a good PSA response and symptomatic response on docetaxel rechallenge but only a PFI of >6 months predicted longer OS. Haemoglobin (

  8. Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Bryce, A H; Alumkal, J J; Armstrong, A

    2017-01-01

    BACKGROUND: Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA...... in the PREVAIL study were analyzed post hoc for rising versus nonrising PSA (empirically defined as >1.05 vs ⩽1.05 times the PSA level from 3 months earlier) at the time of radiographic progression. Clinical characteristics and disease outcomes were compared between the rising and nonrising PSA groups. RESULTS......: Of 265 PREVAIL patients with radiographic progression and evaluable PSA levels on the enzalutamide arm, nearly one-quarter had a nonrising PSA. Median progression-free survival in this cohort was 8.3 months versus 11.1 months in the rising PSA cohort (hazard ratio 1.68; 95% confidence interval 1...

  9. [Effect of constant illumination on the response to castration in rats].

    Science.gov (United States)

    Guisado, E; López, F; González, M D; Pinilla, L; Collado, M D; Aguilar, E

    1983-09-01

    The effects of constant light from birth on compensatory ovarian or testicular hypertrophy and gonadotropins levels after gonadectomy have been studied. Ovarian hypertrophy was not affected by constant light either in young or adult rats. The degree of testicular hypertrophy increased in young males submitted to constant light without changes in FSH levels after hemicastration. FSH and LH levels after gonadectomy were similar in young and adult females, while those levels were higher for adult males than for young ones. Constant light increases LH and FSH postcastration levels in young males without effects in the other groups.

  10. Effect of castration and protein level of diet on the growth ...

    African Journals Online (AJOL)

    Les principaux résultats de cette étude ont montré une augmentation linéaire de la consommation alimentaire avec l'augmentation du niveau de protéines de la ... Considérant les conditions de gestion dans la ferme MALO, la ration avec 20,4 % de PB avec un rapport Energie/protéine de 216,34 semble être l'aliment de ...

  11. Effects of castration on penile extracellular matrix morphology in domestic cats.

    Science.gov (United States)

    Borges, Nathalia Cs; Pereira-Sampaio, Marco A; Pereira, Vivian Alves; Abidu-Figueiredo, Marcelo; Chagas, Maurício Alves

    2017-12-01

    Objectives This study was undertaken to verify the possible modifications caused by hormonal deprivation in the extracellular matrix in the penises of neutered cats. Methods Twenty-seven penises from domestic shorthair cats were collected: 14 samples from intact cats and 13 from neutered cats. Sections were stained with Weigert's resorcin-fuchsin, hematoxylin and eosin, and picrosirius red. Histomorphometric analysis was performed using light microscopy and image analysis software. The following parameters were analyzed: density of the elastic fibers and collagen fibers in the corpus spongiosum; density of the elastic fibers in the tunica albuginea of the corpus cavernosum and the tunica albuginea of the corpus spongiosum; luminal area of the urethra; area of the corpus spongiosum; area of the corpus cavernosum; and thickness of the urethral epithelium. The data were analyzed using the Shapiro-Wilk test to verify the normal distribution, and groups were compared using Student's t-test; P cats and neutered cats in the density of elastic fibers in the tunica albuginea of the corpus cavernosum (8.13% ± 1.38% vs 3.11% ± 0.66%), tunica albuginea of the corpus spongiosum (4.37% ± 1.08% vs 3.30% ± 1.01%) and corpus spongiosum (6.28% ± 3.03% vs 4.10% ± 2.19%), and density of collagen fibers in the corpus spongiosum (34.11% ± 10.86% vs 44.21% ± 12.72%). Conclusions and relevance The results show a significant decrease in the density of the elastic fibers and a significant increase of the density of the collagen fibers in the corpus spongiosum in neutered animals. This suggests that the compliance of the periurethral region is reduced, and these changes could be a predisposing factor for urethral obstructive disease.

  12. Effects of ractopamine hydrochloride and immunological castration in pigs. Part 2: belly quality characteristics and fatty acid composition

    Directory of Open Access Journals (Sweden)

    Letícia Cristina COSTA E SILVA

    Full Text Available Abstract The effects of immunocastration and ractopamine in the diet on the belly quality were investigated from two crossbred pigs under different conditions of production, diet, management, and slaughter arranged in factorial design using two levels of addition of ractopamine in the diet, 0 and 7.5 ppm, and three genders (gilts, immunocastrated and barrows. The quality of bellies were analyzed for chemical composition, pH, meat and fat color, backfat thickness and fatty acid profile of the fat. The addition of ractopamine showed no significant influence on pH, color and chemical composition in two crossbred pigs. The immunocastrated had thicker belly backfat compared to the bellies of the gilts. The contents of fatty acids polyunsaturated, linoleic, linoleic, arachidonic, total omega 3 and omega 6 were higher for immunocastrated pigs, as well as presenting values greater than 0.4 for the PUFA:SFA ratio, thus, providing bellies with better nutritional quality. The bellies of the gilts and immunocastrated pigs had higher concentrations of iodine value, indicative of higher unsaturated fat content. The results indicated that the addition of ractopamine and immunocastration had little influence on the quality of bellies as well as in their fatty acid profiles, suggesting the continuity of implementation of these techniques.

  13. Identification and Targeting of Candidate Preexisting Lurker Cells That Give Rise to Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2016-10-01

    prostate tumors. CD74 staining in a tissue microarray containing both local prostate tumors and lymph node metastases is shown. Examples of CD74...De Marzo et al., 1999, 2003). PIA cells are thought to exhibit an intermediate state of differentia- tion between basal and luminal cells and are...both basal and luminal cells are sufficient to initiate prostate cancer following Pten deletion, with differences in tumor outcome de- pending on the

  14. Carcass characteristics and meat quality of intact or castrated bovines, supplemented or not during the first winter

    OpenAIRE

    Climaco, Saulo Malaguido; Ribeiro, Edson Luis de Azambuja; Rocha, Marco Antônio da; Mizubuti, Ivone Yurika; Silva, Leandro das Dores Ferreira da; Noro, Lina Yumi; Turini, Tercílio

    2006-01-01

    Este trabalho teve como objetivo avaliar características quantitativas e qualitativas da carcaça e da carne de bovinos inteiros e castrados, suplementados ou não durante o primeiro inverno. Foram utilizados 40 bovinos Nelore, machos, inteiros e castrados, com peso inicial e idade média de 300kg e 14 meses, submetidos a dois tratamentos: SUP - os animais foram mantidos em pasto e receberam suplementação (0,5% do peso vivo) constituída por 25% de farelo de soja e 75% de milho em grão triturado,...

  15. Development of Small Molecule Activators of Protein Phosphotase 2A (SMAPs) for the Treatment of Castration Resistant Prostate Cancer

    Science.gov (United States)

    2016-10-01

    recently developed a series of small molecules that activate PP2A and thereby exert anticancer effects in cell culture and xenograft models. This...molecules that activate PP2A and thereby exert anticancer effects in cell culture and xenograft models. This proposal focuses on a third generation...months. 9 Changes that had a significant impact on expenditures Significant changes in use or care of human subjects, vertebrate animals

  16. Annotating MYC Status in Treatment-Resistant Metastatic Castration-Resistant Prostate Cancer With Gallium-68 Citrate PET

    Science.gov (United States)

    2017-09-01

    washed and incubated with 10 µCi 125I-Tf for 30 min at 37o C. After washing twice with PBS, the cell associated 6 Author Manuscript Published...cells (4 x 105) were incubated with vehicle, (+)-JQ-1 (1 µM) and IBET- 151 (1 µM) at 37 degrees Celsius for 48 hours. Cells were lysed, and the mRNA...American Association for Cancer Research. Manufacturer-provided ordered subsets expectation maximization (OS-EM) algorithm was used for

  17. A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate Resistant Prostate Cancer

    Science.gov (United States)

    2015-12-01

    AWARD NUMBER: W81XWH-14-1-0021 TITLE: A Pharmacokinetic /Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER A Pharmacokinetic /Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...dose limiting toxicities. Based on safety and pharmacokinetics it is anticipated this will be the recommended phase II dose, and that the phase II

  18. The effect of circulating estradiol concentrations on gonadotropin secretion in young and old castrated male-to-female transsexuals

    NARCIS (Netherlands)

    ten Kulve, J.S.; de Jong, F.H.; de Ronde, W.

    2011-01-01

    Context. In aging men, circulating testosterone (T) declines which is associated with an increase in the levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) , albeit insufficient to maintain T at its original level. It has been speculated that a higher sensitivity of the

  19. Small Molecule Antagonists of the Nuclear Androgen Receptor for the Treatment of Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Johnson, James K; Skoda, Erin M; Zhou, Jianhua; Parrinello, Erica; Wang, Dan; O'Malley, Katherine; Eyer, Benjamin R; Kazancioglu, Mustafa; Eisermann, Kurtis; Johnston, Paul A; Nelson, Joel B; Wang, Zhou; Wipf, Peter

    2016-08-11

    After a high-throughput screening campaign identified thioether 1 as an antagonist of the nuclear androgen receptor, a zone model was developed for structure-activity relationship (SAR) purposes and analogues were synthesized and evaluated in a cell-based luciferase assay. A novel thioether isostere, cyclopropane (1S,2R)-27, showed the desired increased potency and structural properties (stereospecific SAR response, absence of a readily oxidized sulfur atom, low molecular weight, reduced number of flexible bonds and polar surface area, and drug-likeness score) in the prostate-specific antigen luciferase assay in C4-2-PSA-rl cells to qualify as a new lead structure for prostate cancer drug development.

  20. The Stromal Contribution to the Development of Resistance to New Generation Drugs by Castrate Resistant Prostate Cancers

    Science.gov (United States)

    2016-05-01

    SUMMARY: 3a. Brief Overview of the Clinical Problem Addressed by the Project: In adult males , the normal functioning of the prostate is dependent on...significant role in acquired resistance of a prostate tumor to hormone therapies. Based upon our preliminary data showing that primary prostate stromal cells...pathway. 15. SUBJECT TERMS Prostate Cancer, Hedgehog signaling, Hormone Therapy, Intratumoral, Steroidogenesis, Androgens, Smoothened Agonists

  1. Immunological castration temporarily reduces testis size and function without long-term effects on libido and sperm quality in boars.

    Science.gov (United States)

    Lugar, D W; Rhoads, M L; Clark-Deener, S G; Callahan, S R; Revercomb, A K; Prusa, K J; Estienne, M J

    2017-04-01

    The objective was to determine the effects of immunization against gonadotropin-releasing hormone on reproductive characteristics in boars. A total of 72 boars were used in a randomized design with three treatments: single immunization (SI) (10 weeks of age) or double immunization (DI) (10 and 15 weeks of age) with Improvest® and intact controls (no Improvest®; CNT) (n=24/group). At 10, 15, 20, 25 and 40 weeks of age, blood was collected and serum harvested to evaluate testosterone concentrations. Testosterone concentrations were less for DI boars compared with CNT boars and SI boars at 20 and 25 weeks (PLibido was assessed at 32, 36, 47, 60 and 63 weeks of age and semen collected at 60 weeks of age was analyzed for indicators of quality. There were no effects of treatment (P=0.41) or treatment by week (P=0.71) on libido. Semen volume, gel weight and total number of sperm cells, determined in a subset of boars (n=3/treatment), were not different among treatments. Sperm concentration was greater for DI than SI (P=0.01), and tended to be greater for DI compared with CNT (P=0.10). Sperm motility tended to be greater for DI boars compared with CNT boars (P=0.066). In conclusion, our results show that there are no long-term effects of immunocastration on reproductive characteristics in boars.

  2. Identification and Targeting of Candidate Pre-Existing Lurker Cells that Give Rise to Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2014-10-01

    PE, CD45-APCeFluor 780, HLA-A/B/C- biotin , Streptavidin - APC, and Streptavidin -APC-eFluor 780 (eBiosciences); CD49f- Alexa Fluor 647 and CD26-FITC...resulting in the integration of viral DNA into the genome of the target cell and all of its progeny. If both adenocarcinoma and squamous phenotypes within...microdissection was performed on neighboring adenocarcinoma and squamous phenotypes within an individual lesion (region X) and DNA was isolated

  3. Development of a New Class of Drugs to Inhibit All Forms of Androgen Receptor in Castration Resistant Prostate Cancers

    Science.gov (United States)

    2016-10-01

    models with impaired function of PSA enhancer RNA (eRNA). Hauptman Woodward Institute Site (Gewirth, PI ): Nothing to Report Vancouver Prostate Centre...Activities for University of Minnesota Site (Dehm, PI ) In the first reporting period, the major activities consisted of a) Testing the effects of...derivative VPC14449 on AR chromatin binding using chromatin fractionation techniques. Major Activities for Hauptman Woodward Institute Site (Gewirth, PI ) In

  4. Differential expression and co-expression gene networks reveal candidate biomarkers of boar taint in non-castrated pigs

    DEFF Research Database (Denmark)

    Drag, Markus; Skinkyté-Juskiené, Ruta; Do, Duy N.

    2017-01-01

    metabolism (GSTO1, GSR, FMO3) of skatole and androstenone in liver to steroidgenesis (HSD17B7, HSD17B8, CYP27A1), regulation of steroidgenesis (STARD10, CYB5R3) and GnRH signalling (MAPK3, MAP2K2, MAP3K2) in testis. Overrepresented pathways included "Ribosome", "Protein export" and "Oxidative phosphorylation...

  5. Treatment of Bone Metastases with Radium-223 in Patients with Castration Resistant Prostate Cancer (CRPC): Alternative or Complementary to Innovative Molecular Therapies?

    International Nuclear Information System (INIS)

    Bombardieri, Emilio

    2013-01-01

    The skeletal metastatic disease is a real clinical problem. Approximately 70% of patients with prostate or breast cancer and 35% of those with advanced lung, thyroid, and kidney cancers will develop skeletal metastases, which cause considerable morbidity. Several options are available for treatment, to be used either alone or in various combinations: hormones in case of hormone-sensitive tumours, chemotherapy, biphosphonates, external beam radiation therapy, surgery (in pathologic or impending fracture), bone-seeking radiopharmceuticals, and also molecular therapies. Focusing our attention to patients with prostate cancer, 50% of patients with bone metastases develop skeletal related events (SREs) such as: severe pain, pathologic fractures, spinal compression syndrome, malignant hypercalcemia, bone marrow suppression. All these SREs require adequate therapy since generally determine several functional impairments and worsen the prognosis. It is well known that skeletal complications reduce the quality of life affecting different aspects, physical, functional end emotional. SREs are associated also with lower survival

  6. Evaluation of Alpha-Therapy with Radium-223-Dichloride in Castration Resistant Metastatic Prostate Cancer—the Role of Gamma Scintigraphy in Dosimetry and Pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Kalevi Kairemo

    2015-07-01

    Full Text Available Radium-223-dichloride (223RaCl2 is a new bone-seeking calcium analogue alpha-emitter, which has obtained marketing authorization for the treatment skeletal metastases of hormone-refractory prostate cancer. The current treatment regimen is based on six consecutive doses of 223RaCl2 at 4 week intervals and the administered activity dose, 50 kBq/kg per cycle is based on patient weight. We analyzed two patients using quantitative serial gamma imaging to estimate dosimetry in tumors and see possible pharmacokinetic differences in the treatment cycles. The lesions were rather well visualized in gamma scintigraphy in spite of low gamma activity (<1.1% gamma radiation at 0, 7 and 28 days using 30–60 min acquisition times. Both our patients analyzed in serial gamma imagings, had two lesions in the gamma imaging field, the mean counts of the relative intensity varied from 27.8 to 36.5 (patient 1, and from 37.4 to 82.2 (patient 2. The half-lives varied from 1.8 days to 4.5 days during the six cycles (patient 1, and from 1.5 days to 3.6 days (patient 2, respectively. In the lesion half-lives calculated from the imaging the maximum difference between the treatment cycles in the same lesion was 2.0-fold (1.8 vs. 3.6. Of these patients, patient 1 demonstrated a serum PSA response, whereas there was no PSA response in patient 2. From our data, there were maximally up to 4.0-fold differences (62.1 vs. 246.6 between the relative absorbed radiation doses between patients as calculated from the quantitative standardized imaging to be delivered in only two lesions, and in the same lesion the maximum difference in the cycles was up to 2.3-fold (107.4 vs. 246.6. Our recommendation based on statistical simulation analysis, is serial measurement at days 0–8 at least 3 times, this improve the accuracy significantly to study the lesion activities, half-lives or calculated relative absorbed radiation doses as calculated from the imaging. Both our patients had originally two metastatic sites in the imaging field; the former patient demonstrated a serum PSA response and the latter demonstrated no PSA response. In these two patients there was no significant difference in the lesion activities, half-lives or calculated relative absorbed radiation doses as calculated from the quantitative imaging. Our results, although preliminary, suggest that dose monitoring can be included as a part of this treatment modality. On the other hand, from the absorbed radiation doses, the response cannot be predicted because with very similar doses, only the former patient responded.

  7. Evaluation of Alpha-Therapy with Radium-223-Dichloride in Castration Resistant Metastatic Prostate Cancer-the Role of Gamma Scintigraphy in Dosimetry and Pharmacokinetics.

    Science.gov (United States)

    Kairemo, Kalevi; Joensuu, Timo; Rasulova, Nigora; Kiljunen, Timo; Kangasmäki, Aki

    2015-07-30

    Radium-223-dichloride ((223)RaCl₂) is a new bone-seeking calcium analogue alpha-emitter, which has obtained marketing authorization for the treatment skeletal metastases of hormone-refractory prostate cancer. The current treatment regimen is based on six consecutive doses of (223)RaCl₂ at 4 week intervals and the administered activity dose, 50 kBq/kg per cycle is based on patient weight. We analyzed two patients using quantitative serial gamma imaging to estimate dosimetry in tumors and see possible pharmacokinetic differences in the treatment cycles. The lesions were rather well visualized in gamma scintigraphy in spite of low gamma activity (2.0-fold (1.8 vs. 3.6). Of these patients, patient 1 demonstrated a serum PSA response, whereas there was no PSA response in patient 2. From our data, there were maximally up to 4.0-fold differences (62.1 vs. 246.6 ) between the relative absorbed radiation doses between patients as calculated from the quantitative standardized imaging to be delivered in only two lesions, and in the same lesion the maximum difference in the cycles was up to 2.3-fold (107.4 vs. 246.6). Our recommendation based on statistical simulation analysis, is serial measurement at days 0-8 at least 3 times, this improve the accuracy significantly to study the lesion activities, half-lives or calculated relative absorbed radiation doses as calculated from the imaging. Both our patients had originally two metastatic sites in the imaging field; the former patient demonstrated a serum PSA response and the latter demonstrated no PSA response. In these two patients there was no significant difference in the lesion activities, half-lives or calculated relative absorbed radiation doses as calculated from the quantitative imaging. Our results, although preliminary, suggest that dose monitoring can be included as a part of this treatment modality. On the other hand, from the absorbed radiation doses, the response cannot be predicted because with very similar doses, only the former patient responded.

  8. Sex and parasites: genomic and transcriptomic analysis of Microbotryum lychnidis-dioicae, the biotrophic and plant-castrating anther smut fungus.

    Science.gov (United States)

    Perlin, Michael H; Amselem, Joelle; Fontanillas, Eric; Toh, Su San; Chen, Zehua; Goldberg, Jonathan; Duplessis, Sebastien; Henrissat, Bernard; Young, Sarah; Zeng, Qiandong; Aguileta, Gabriela; Petit, Elsa; Badouin, Helene; Andrews, Jared; Razeeq, Dominique; Gabaldón, Toni; Quesneville, Hadi; Giraud, Tatiana; Hood, Michael E; Schultz, David J; Cuomo, Christina A

    2015-06-16

    The genus Microbotryum includes plant pathogenic fungi afflicting a wide variety of hosts with anther smut disease. Microbotryum lychnidis-dioicae infects Silene latifolia and replaces host pollen with fungal spores, exhibiting biotrophy and necrosis associated with altering plant development. We determined the haploid genome sequence for M. lychnidis-dioicae and analyzed whole transcriptome data from plant infections and other stages of the fungal lifecycle, revealing the inventory and expression level of genes that facilitate pathogenic growth. Compared to related fungi, an expanded number of major facilitator superfamily transporters and secretory lipases were detected; lipase gene expression was found to be altered by exposure to lipid compounds, which signaled a switch to dikaryotic, pathogenic growth. In addition, while enzymes to digest cellulose, xylan, xyloglucan, and highly substituted forms of pectin were absent, along with depletion of peroxidases and superoxide dismutases that protect the fungus from oxidative stress, the repertoire of glycosyltransferases and of enzymes that could manipulate host development has expanded. A total of 14% of the genome was categorized as repetitive sequences. Transposable elements have accumulated in mating-type chromosomal regions and were also associated across the genome with gene clusters of small secreted proteins, which may mediate host interactions. The unique absence of enzyme classes for plant cell wall degradation and maintenance of enzymes that break down components of pollen tubes and flowers provides a striking example of biotrophic host adaptation.

  9. Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Graff, J N; Baciarello, G; Armstrong, A J

    2016-01-01

    BACKGROUND: Prostate cancer disproportionately affects older men. Because age affects treatment decisions, it is important to understand the efficacy and tolerability of therapies for advanced prostate cancer in elderly men. This analysis describes efficacy and safety outcomes in men aged ≥75 years...... for an overall higher incidence of falls among elderly patients than younger patients [84/609 (13.8%) versus 62/1106 (5.6%)] and among elderly patients receiving enzalutamide than those receiving placebo [61/317 (19.2%) versus 23/292 (7.9%)]. CONCLUSIONS: Elderly men benefited from treatment with enzalutamide...... in terms of OS and rPFS. Enzalutamide was well tolerated in the elderly subgroup and those aged falls. CLINICAL TRIAL IDENTIFIER: NCT01212991, ClinicalTrials.gov....

  10. A Randomized Phase 2 Trial of 177Lu Radiolabeled Anti-PSMA Monoclonal Antibody J591in Patients with High-Risk Castrate, Biochemically Relapsed Prostate Cancer

    Science.gov (United States)

    2012-09-01

    administration (NOTE: J591 is cpartially leared via liver resulting in non-specific uptake) A B C D Over a decade of clinical experience [Akhtar et...3.3 – 2184.6). 3 with ECOG PS 0, 27 PS 1, 2 PS 2; 97% had bone mets, 25% extra-osseous visceral mets (2 liver , 5 lung, 1 adrenal). The majority (18 pts...recurrent PC is the presence of undetected metastatic disease. Conventional imaging techniques such as transrectal ultrasonography , magnetic resonance

  11. Randomized, Placebo-Controlled, Phase III Trial of Sunitinib Plus Prednisone Versus Prednisone Alone in Progressive, Metastatic, Castration-Resistant Prostate Cancer

    DEFF Research Database (Denmark)

    Michaelson, M Dror; Oudard, Stephane; Ou, Yen-Chuan

    2014-01-01

    /d continuously or placebo. Patients also received oral prednisone 5 mg twice daily. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS). Two interim analyses were planned. RESULTS: Overall, 873 patients were randomly assigned to receive sunitinib (n.......762 to 1.097; stratified log-rank test, P = .168). PFS was significantly improved in the sunitinib arm (median 5.6 v 4.1 months; HR, 0.725; 95% CI, 0.591 to 0.890; stratified log-rank test, P

  12. Phase I/II clinical trial of dendritic-cell based immunotherapy (DCVAC/PCa) combined with chemotherapy in patients with metastatic, castration-resistant prostate cancer.

    Science.gov (United States)

    Podrazil, Michal; Horvath, Rudolf; Becht, Etienne; Rozkova, Daniela; Bilkova, Pavla; Sochorova, Klara; Hromadkova, Hana; Kayserova, Jana; Vavrova, Katerina; Lastovicka, Jan; Vrabcova, Petra; Kubackova, Katerina; Gasova, Zdenka; Jarolim, Ladislav; Babjuk, Marek; Spisek, Radek; Bartunkova, Jirina; Fucikova, Jitka

    2015-07-20

    We conducted an open-label, single-arm Phase I/II clinical trial in metastatic CRPC (mCRPC) patients eligible for docetaxel combined with treatment with autologous mature dendritic cells (DCs) pulsed with killed LNCaP prostate cancer cells (DCVAC/PCa). The primary and secondary endpoints were safety and immune responses, respectively. Overall survival (OS), followed as a part of the safety evaluation, was compared to the predicted OS according to the Halabi and MSKCC nomograms. Twenty-five patients with progressive mCRPC were enrolled. Treatment comprised of initial 7 days administration of metronomic cyclophosphamide 50 mg p.o. DCVAC/PCa treatment consisted of a median twelve doses of 1 × 107 dendritic cells per dose injected s.c. (Aldara creme was applied at the site of injection) during a one-year period. The initial 2 doses of DCVAC/PCa were administered at a 2-week interval, followed by the administration of docetaxel (75 mg/m2) and prednisone (5 mg twice daily) given every 3 weeks until toxicity or intolerance was observed. The DCVAC/PCa was then injected every 6 weeks up to the maximum number of doses manufactured from one leukapheresis. No serious DCVAC/PCa-related adverse events have been reported. The median OS was 19 months, whereas the predicted median OS was 11.8 months with the Halabi nomogram and 13 months with the MSKCC nomogram. Kaplan-Meier analyses showed that patients had a lower risk of death compared with both MSKCC (Hazard Ratio 0.26, 95% CI: 0.13-0.51) and Halabi (Hazard Ratio 0.33, 95% CI: 0.17-0.63) predictions. We observed a significant decrease in Tregs in the peripheral blood. The long-term administration of DCVAC/PCa led to the induction and maintenance of PSA specific T cells. We did not identify any immunological parameter that significantly correlated with better OS. In patients with mCRPC, the combined chemoimmunotherapy with DCVAC/PCa and docetaxel was safe and resulted in longer than expected survival. Concomitant chemotherapy did not preclude the induction of specific anti-tumor cytotoxic T cells.

  13. Correlation between frequencies of blood monocytic myeloid-derived suppressor cells, regulatory T cells and negative prognostic markers in patients with castration-resistant metastatic prostate cancer

    DEFF Research Database (Denmark)

    Idorn, Manja; Køllgaard, Tania; Kongsted, Per

    2014-01-01

    in establishing an immune suppressive environment in patients with PC. Moreover, correlation of M-MDSC frequency with known prognostic markers and the observed impact on OS could reflect a possible role in tumor progression. Further insight into the generation and function of MDSC and their interplay with Tregs......Myeloid-derived suppressor cells (MDSC) are believed to play a role in immune suppression and subsequent failure of T cells to mount an efficient anti-tumor response, by employing both direct T-cell inhibition as well as induction of regulatory T cells (Tregs). Investigating the frequency...... with known negative prognostic markers in patients with PC including elevated levels of lactate dehydrogenase and prostate-specific antigen. Accordingly, high levels of M-MDSC were associated with a shorter median overall survival. Our data strongly suggest that M-MDSC, possibly along with Tregs, play a role...

  14. Does the Androgen Receptor (AR)-Regulated Map Kinase Phosphatase 1 (MKP-1) Enhance Castration-Resistant Prostate Cancer Survival under Therapeutic Stress?

    Science.gov (United States)

    2016-03-01

    in breast cancer models, and is inversely associated with apoptosis in preclinical prostate cancer models. Androgen and glucocorticoid signaling can... effects of both hormonal and chemotherapies. To date, significant progress has been made including optimization of MKP-1 protein detection...with apoptosis in preclinical prostate cancer models. Androgen and glucocorticoid signaling can induce MKP-1 expression; as mCRPC remains driven by

  15. 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 tr