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Sample records for castration

  1. Surgical castration, coercion and ethics

    DEFF Research Database (Denmark)

    Ryberg, Jesper; Petersen, Thomas Søbirk

    2014-01-01

    that the matter is more complicated than his approach to it suggests. The first thing that adds to the complexity of the discussion concerns the alternative for sex offenders who do not accept the offer of castration. As mentioned, it is likely that these offenders will be kept in prison. McMillan even underlines......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...

  2. Acute Cold / Restraint Stress in Castrated Rats

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    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.

  3. Parasitic castration: the evolution and ecology of body snatchers

    Science.gov (United States)

    Lafferty, Kevin D.; Kuris, Armand M.

    2009-01-01

    Castration is a response to the tradeoff between consumption and longevity faced by parasites. Common parasitic castrators include larval trematodes in snails, and isopod and barnacle parasites of crustaceans. The infected host (with its many unique properties) is the extended phenotype of the parasitic castrator. Because an individual parasitic castrator can usurp all the reproductive energy from a host, and that energy is limited, intra- and interspecific competition among castrators is generally intense. These parasites can be abundant and can substantially depress host density. Host populations subject to high rates of parasitic castration appear to respond by maturing more rapidly.

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

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    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.

  5. [Experimental sialadenitis in castrated rats administered estrogens].

    Science.gov (United States)

    Fonseca, M M; Rins de David, M L; Gendelman, H

    1989-01-01

    Salivary glands are dependent on sexual hormones. The aim of the present work is to study the behavior of inflammatory response induced in animals that were castrated and injected with estrogens. Male adult wistar castrated rats (60-90 days) were used. A phlogogen pellet (zinc-oxide-turpentine essence) was placed between their sublingual and submaxillary glands and they were daily injected with 5 units of estrogen. The rats were killed after 8 and 12 days of treatment; submandibular pack was weighed, dissected and fixed in phormol Ph7 for its morphohistochemical study. Phlogogen pellet breaks out an acute inflammatory response that appears attenuated in castrated animals. Such character is enhanced when estrogens are used, disappearing ductal ectasis, becoming evident a granulation tissue of strange body in phagocytic activity and in contact with the pellet. As a consequence its follows that estrogen administration in castrated animals attenuates acute inflammatory response broken out by phlogogen pellet, determining characters with tendency to chronicity and giant cells differentiation of strange body.

  6. Resource efficiency and economic implications of alternatives to surgical castration without anaesthesia

    NARCIS (Netherlands)

    Roest, de K.; Montanari, C.; Fowler, T.; Baltussen, W.H.M.

    2009-01-01

    This paper presents an analysis of the economic implications of alternative methods to surgical castration without anaesthesia. Detailed research results on the economic implications of four different alternatives are reported. castration with local anaesthesia, castration with general anaesthesia,

  7. Castration of the Vietnamese pot-bellied boar: 8 cases

    OpenAIRE

    Østevik, Liv; Elmas, Colette; Rubio-Martinez, Luis M.

    2012-01-01

    Surgical techniques for castration of the Vietnamese pot-bellied boar and outcome are described. Vietnamese pot-bellied pig (VPBP) boars (n = 8) were admitted for castration. Data retrieved from medical records (2002–2011) for these pigs included signalment, history, reason for castration, perioperative management, surgical technique, and complications. Follow-up information was obtained from owners. A scrotal approach with closed technique was used for 6 boars with normally descended testes....

  8. Meloxicam mediates short-term behavioral changes of castrated calves

    Science.gov (United States)

    Castration may detrimentally affect the health and performance of weaned calves and painful procedures are increasingly a public concern. Therefore, practical pain mitigation is critical. The objective was to determine the effects of castration (by banding) with or without administration of meloxica...

  9. [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.

  10. Pain behaviour after castration of piglets; effect of pain relief with lidocaine and/or meloxicam

    NARCIS (Netherlands)

    Kluivers-Poodt, M.; Zonderland, J.J.; Verbraak, J.; Lambooij, E.; Hellebrekers, L.J.

    2013-01-01

    Behavioural responses and the effect of lidocaine and meloxicam on behaviour of piglets after castration were studied. A total of 144 piglets of 2 to 5 days of age were allocated to one of six treatments: castration (CAST), castration with lidocaine (LIDO), castration with meloxicam (MELO), castrati

  11. HUMAN RIGHTS AND PROSPECTS FOR APPLYING CHEMICAL CASTRATION IN RUSSIA

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    Suzanna Karoevna ABRAMYAN

    2014-01-01

    Full Text Available I The paper examined challenges related to applying chemical castration the Russian community has faced, and assessed the prospect for further implementation as well. The issue has triggered an ample debate in various circles as a new probable way to prevent sexual crime events. The authors inferred that chemical castration should be an option of a complex of measures for pre-venting relapse into pedophilia.

  12. Castration of a Black Rhinoceros Diceros Bicornis Minor

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    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.

  13. The kindest cut? Surgical castration, sex offenders and coercive offers.

    Science.gov (United States)

    McMillan, John

    2014-09-01

    The European Committee for the Prevention of Torture and Inhuman or Degrading Treatment or Punishment (CPT) have conducted visits and written reports criticising the surgical castration of sex offenders in the Czech Republic and Germany. They claim that surgical castration is degrading treatment and have called for an immediate end to this practice. The Czech and German governments have published rebuttals of these criticisms. The rebuttals cite evidence about clinical effectiveness and point out this is an intervention that must be requested by the sex offender and cannot occur without informed consent. This article considers a number of relevant arguments that are not discussed in these reports but which are central to how we might assess this practice. First, the article discusses the possible ways in which sex offenders could be coerced into castration and whether this is a decisive moral problem. Then, it considers a number of issues relevant to determining whether sex offenders are harmed by physical castration. The article concludes by arguing that sex offenders should not be coerced into castration, be that via threats or offers, but that there is no reason to think that this is occurring in the Czech Republic or Germany. In some cases, castration might be useful for reconfiguring a life that has gone badly awry and where there is no coercion, the European Committee for the Prevention of Torture and Inhuman or Degrading Treatment or Punishment are mistaken about this being degrading treatment.

  14. Reduction in pain suffered by lambs at castration.

    Science.gov (United States)

    Molony, V; Kent, J E; Hosie, B D; Graham, M J

    1997-03-01

    The acute pain produced by bloodless castrators was studied by comparing the behavioural and plasma cortisol changes in groups (n=8) of 3-week-old Dorset cross lambs after castration with a 22 cm (9") Burdizzo, a new power assisted castrator and by a combined method using a Burdizzo and elastrator ring. The time spent in abnormal postures (52-58 min) and the peak cortisol response (110-120 mmol l(-1)) were similar for the three methods, although the powered castrator produced a more sustained response. The Burdizzo method halved the incidence of active behaviours compared with the powered castrator and combined methods (16 versus 30, 32 counts). Intratesticular local anaesthetic administered 2 min before the Burdizzo castrator and combined method, or intramuscular injection of the non-steroidal anti-inflammatory drug diclofenac, 20 min before the application of a Burdizzo, significantly reduced the peak plasma cortisol response to 80 nmol l(-1). Diclofenac also significantly reduced the time spent trembling or in abnormal postures.

  15. Early and delayed castrations confer a similar survival advantage in TRAMP mice

    Institute of Scientific and Technical Information of China (English)

    Zai-Xian Zhang; Qing-Quan Xu; Xiao-Bo Huang; Ji-Chuan Zhu; Xiao-Feng Wang

    2009-01-01

    The most appropriate time to introduce androgen deprivation therapy for prostate cancer remains controversial. Our aim was to evaluate the effects of early versus delayed surgical castration on prostate cancer progression and survival in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. TRAMP mice were randomly divided into three groups: the early castration group (on which castration was performed at the age of 4 weeks), the delayed castration group (on which castration was performed when abdominal turnouts could be palpated), and the sham-castrated group. Mice were monitored daily throughout their lives until cancer-related death or the develop-ment of an obviously moribund appearance, at which time the individual mouse was killed. Androgen receptor expression in prostate turnouts was also evaluated. The results shows that the average lifespan in early castration, delayed castration and sham-castrated groups were 54.1 weeks, 59.9 weeks and 39.1 weeks, respectively. Both early castration and delayed castration conferred a statistically significant survival advantage when compared with the sham-castrated group (P<0.001). However, the difference in lifespan between the early castration group and the delayed castration group was not statistically significant (P=0.85). The increase in lifespan in the TRAMP mice that received either early or delayed castration correlated with lower G/B value (genitourinary tract weight/body weight) at death than the sham-castrated mice. In conclusion, early and delayed castrations in TRAMP mice pro-longed survival to a similar extent. This finding may provide a guide for clinical practice in prostate cancer therapy.

  16. Murine Prostate Micro-dissection and Surgical Castration.

    Science.gov (United States)

    Valkenburg, Kenneth C; Amend, Sarah R; Pienta, Kenneth J

    2016-05-11

    Mouse models are used extensively to study prostate cancer and other diseases. The mouse is an excellent model with which to study the prostate and has been used as a surrogate for discoveries in human prostate development and disease. Prostate micro-dissection allows consistent study of lobe-specific prostate anatomy, histology, and cellular characteristics in the absence of contamination of other tissues. Testosterone affects prostate development and disease. Androgen deprivation therapy is a common treatment for prostate cancer patients, but many prostate tumors become castration-resistant. Surgical castration of mouse models allows for the study of castration resistance and other facets of hormonal biology on the prostate. This procedure can be coupled with testosterone reintroduction, or hormonal regeneration of the prostate, a powerful method to study stem cell lineages in the prostate. Together, prostate micro-dissection and surgical castration opens up a multitude of opportunities for robust and consistent research of prostate development and disease. This manuscript describes the protocols for prostate micro-dissection and surgical castration in the laboratory mouse.

  17. Castration alters protein balance after high-frequency muscle contraction.

    Science.gov (United States)

    Steiner, Jennifer L; Fukuda, David H; Rossetti, Michael L; Hoffman, Jay R; Gordon, Bradley S

    2017-02-01

    Resistance exercise increases muscle mass by shifting protein balance in favor of protein accretion. Androgens independently alter protein balance, but it is unknown whether androgens alter this measure after resistance exercise. To answer this, male mice were subjected to sham or castration surgery 7-8 wk before undergoing a bout of unilateral, high-frequency, electrically induced muscle contractions in the fasted or refed state. Puromycin was injected 30 min before euthanasia to measure protein synthesis. The tibialis anterior was analyzed 4 h postcontraction. In fasted mice, neither basal nor stimulated rates of protein synthesis were affected by castration despite lower phosphorylation of mechanistic target of rapamycin in complex 1 (mTORC1) substrates [p70S6K1 (Thr389) and 4E-BP1 (Ser65)]. Markers of autophagy (LC3 II/I ratio and p62 protein content) were elevated by castration, and these measures remained elevated above sham values after contractions. Furthermore, in fasted mice, the protein content of Regulated in Development and DNA Damage 1 (REDD1) was correlated with LC3 II/I in noncontracted muscle, whereas phosphorylation of uncoordinated like kinase 1 (ULK1) (Ser757) was correlated with LC3 II/I in the contracted muscle. When mice were refed before contractions, protein synthesis and mTORC1 signaling were not affected by castration in either the noncontracted or contracted muscle. Conversely, markers of autophagy remained elevated in the muscles of refed, castrated mice even after contractions. These data suggest the castration-mediated elevation in baseline autophagy reduces the absolute positive shift in protein balance after muscle contractions in the refed or fasted states.

  18. New developments in the treatment of castration resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Roxanne Wadia

    2014-08-01

    Full Text Available In the past 5 years, the treatment and understanding of metastatic castrate resistant prostate cancer (CRPC have improved dramatically. Our understanding of the mechanisms of castration resistance has allowed for the development of new drugs to target prostate cancer, and our understanding of genetic mutations may give us new tools with which to more accurately diagnose and be able to predict the course of this heterogeneous disease. This article summarizes the recent advances in the understanding of the development of CRPC, as well as the new drugs and targets, which have evolved from this basic research.

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

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    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.

  20. Molecular Indicators of Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2015-12-01

    two components /kits. Briefly, the ProstateCancerSelect (Product No. T-1-520) kit was used to enrich CTC from 5ml blood using magnetic particles coated...in PatientsWithMetastatic Castration-Resistant Prostate Cancer Emmanuel S. Antonarakis, MD; Changxue Lu, PhD; Brandon Luber, ScM ; HaoWang, PhD; Yan

  1. Prostate progenitor cells proliferate in response to castration

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    Xudong Shi

    2014-07-01

    Full Text Available Androgen-deprivation is a mainstay of therapy for advanced prostate cancer but tumor regression is usually incomplete and temporary because of androgen-independent cells in the tumor. It has been speculated that these tumor cells resemble the stem/progenitor cells of the normal prostate. The purpose of this study was to examine the response of slow-cycling progenitor cells in the adult mouse prostate to castration. Proliferating cells in the E16 urogenital sinus were pulse labeled by BrdU administration or by doxycycline-controlled labeling of the histone-H2B GFP mouse. A small population of labeled epithelial cells in the adult prostate localized at the junction of the prostatic ducts and urethra. Fluorescence-activated cell sorting (FACS showed that GFP label-retaining cells were enriched for cells co-expressing stem cell markers Sca-1, CD133, CD44 and CD117 (4- marker cells; 60-fold enrichment. FACS showed, additionally, that 4-marker cells were androgen receptor positive. Castration induced proliferation and dispersal of E16 labeled cells into more distal ductal segments. When naïve adult mice were administered BrdU daily for 2 weeks after castration, 16% of 4-marker cells exhibited BrdU label in contrast to only 6% of all epithelial cells (P < 0.01. In sham-castrated controls less than 4% of 4-marker cells were BrdU labeled (P < 0.01. The unexpected and admittedly counter-intuitive finding that castration induced progenitor cell proliferation suggests that androgen deprivation therapy in men with advanced prostate cancer could not only exert pleiotrophic effects on tumor sub-populations but may induce inadvertent expansion of tumor stem cells.

  2. Effect of castration on performance and profitability of finishing cattle in rent feedlot

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    Marcos Aurélio Lopes

    2011-01-01

    Full Text Available Effects of castration on performance and profitability of finishing beef cattle in feedlot was evaluated and compared to no-castrated animals. Data came from a rent feedlot of beef cattle, conducted from August to November of 2005. Half of 50 animals, randomly chosen, were castrated by knife 18 days before the beginning of feedlot. Averages of initial body weight for castrated and no-castrated animals were 341kg and 347kg, while for final body weight were 437kg and 463kg, respectively. Were considered as expenses arroba value of thin cattle (R$50.00, and R$2.85 daily expenses per animal paid by cattle owner to “boitel”; and were considered as earnings sale of fat cattle at R$56.14 and R$54.14/arroba, respectively for castrated and no-castrated animals. For profitability analysis, CU$TO BOVINO CORTE software was utilized. Was tested the mean differences between castrated and intact groups by Student t test of average daily weight gains (GMPD and total weight gain (GMPT. Was acceptable the minimum level of confidence of 95%. Statistical analysis was performed in SPSS 17.0 program. Effect of castration negatively influenced animals´ performance, evaluated by weight gain, and, consequently profitability of the system, evaluated by net margin. Earnings from sale of additional arrobas of no-castrated animals were enough to compensate penalization practiced by packinghouses for these animals.

  3. Effect of local anaesthesia and/or analgesia on pain responses induced by piglet castration

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    Nyman Görel

    2011-05-01

    Full Text Available Abstract Background Surgical castration in male piglets is painful and methods that reduce this pain are requested. This study evaluated the effect of local anaesthesia and analgesia on vocal, physiological and behavioural responses during and after castration. A second purpose was to evaluate if herdsmen can effectively administer anaesthesia. Methods Four male piglets in each of 141 litters in five herds were randomly assigned to one of four treatments: castration without local anaesthesia or analgesia (C, controls, analgesia (M, meloxicam, local anaesthesia (L, lidocaine, or both local anaesthesia and analgesia (LM. Lidocaine (L, LM was injected at least three minutes before castration and meloxicam (M, LM was injected after castration. During castration, vocalisation was measured and resistance movements judged. Behaviour observations were carried out on the castration day and the following day. The day after castration, castration wounds were ranked, ear and skin temperature was measured, and blood samples were collected for analysis of acute phase protein Serum Amyloid A concentration (SAA. Piglets were weighed on the castration day and at three weeks of age. Sickness treatments and mortality were recorded until three weeks of age. Results Piglets castrated with lidocaine produced calls with lower intensity (p p p = 0.06, n.s. and the following day (p = 0.02. Controls had less swollen wounds compared to piglets assigned to treatments M, L and LM (p p = 0.005; p = 0.05 for C + L compared to M + LM. Ear temperature was higher (p Conclusions The study concludes that lidocaine reduced pain during castration and that meloxicam reduced pain after castration. The study also concludes that the herdsmen were able to administer local anaesthesia effectively.

  4. Castration of piglets under general anaesthesia: a possible approach

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    Iwan Nussbaumer

    2012-05-01

    Full Text Available Since January 2010 the castration of piglets without pain relief has been forbidden in Switzerland. Swiss pig farmers now have two choices, either vet-performed anaesthesia and analgesia by intramuscular injection or farmer-administered isofluran anaesthesia by an inhalation device. Many smaller pig producers, with less than 60 sows, have chosen injected anaesthesia for economic, user safety and environmental reasons.

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

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    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.

  6. Targeting Androgen Receptor Aberrations in Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Sharp, Adam; Welti, Jonathan; Blagg, Julian; de Bono, Johann S

    2016-09-01

    Androgen receptor (AR) splice variants (SV) have been implicated in the development of metastatic castration-resistant prostate cancer and resistance to AR targeting therapies, including abiraterone and enzalutamide. Agents targeting AR-SV are urgently needed to test this hypothesis and further improve the outcome of patients suffering from this lethal disease. Clin Cancer Res; 22(17); 4280-2. ©2016 AACRSee related article by Yang et al., p. 4466.

  7. New Therapeutics to Treat Castrate-Resistant Prostate Cancer

    OpenAIRE

    Ömer Acar; Tarık Esen; Lack, Nathan A.

    2013-01-01

    Hindawi Publishing Corporation The ScientificWorld Journal Volume 2013, Article ID 379641, 8 pages http://dx.doi.org/10.1155/2013/379641 Review Article New Therapeutics to Treat Castrate-Resistant Prostate Cancer Ömer Acar,1 TarJk Esen,1,2 and Nathan A. Lack1 1 VKF American Hospital, Guzelbahce sokak, Nisantasi, Istanbul 34365, Turkey 2 School of Medicine, Koc¸ University, Rumelifeneri Yolu, Sariyer, Istanbul 34450, Turkey Correspondence should be addressed to Natha...

  8. HIGH-INTENSITY FOCUSED ULTRASOUND CASTRATION FOR BREAST CANCER PATIENTS

    Institute of Scientific and Technical Information of China (English)

    王书文; 和新盈; 石景森; 赵东利; 李明众; 王诚; 薛文华

    2003-01-01

    Objective: To evaluate the safety and efficacy of external high-intensity focused ultrasound(HIFU) castration for breast cancerous patients after mastectomy if they are at a high risk of recurrence. Methods: We recruited 52 consecutive patients with primary operable breast cancer who were treated with mastectomy with excision of regional lymph nodes. Patients were positive for ER and PR immuno- cytochemical staining, node-positive, un-menopause, over 40 years old and were divided into two groups randomly. For castration, 26 patients received one or two times of HIFU treatment within five days, and the other patients received radiotherapy with DT 18Gy/9 f/11days. During and after the treatment, local changes and systemic response of the patients were observed. Results: After 1 month treatment, levels of serum E1 and E2 were significantly decreased compared to before treatment in HIFU groups (P<0.01 and P<0.001). The same changes were occurred in radiotherapy(RT) groups (P<0.05 and P<0.01). The levels of serum E1 or E2 in RT groups were higher than in HIFU groups (P<0.05). The symptom distribution of 'climacteric syndrome' of HIFU groups were significantly different from RT groups (P<0.01). The follow-up time was 4 months. The incidence of amenorrhea was 100% in all patients. No serious complications were seen. The temperature, pulse, blood pressure, and respiratory rate of the patients were almost normal. Conclusion: We have shown that the use of HIFU in the castrating of patients with breast cancer is feasible, safe and effective. This technology may provide a rapid noninvasive alterative to conventional bilateral oophorectomy or RT castration.

  9. Effect of meloxicam on gain and inflammatory response of calves castrated by banding post-weaning

    Science.gov (United States)

    Castration may detrimentally affect the health and performance of weaned calves, and painful procedures are increasingly becoming a public concern. The objective of this study was to determine the effects of castration (by banding) with or without administration of meloxicam, a non-steroid anti-infl...

  10. Targeting LSD1 Epigenetic Signature in Castration-Recurrent Prostate Cancer

    Science.gov (United States)

    2014-10-01

    AWARD NUMBER: W81XWH-13-1-0276 TITLE: Targeting LSD1 Epigenetic Signature in Castration...report 3. DATES COVERED 30 Sep 2013 - 29 Sep 2014 4. TITLE AND SUBTITLE Targeting LSD1 Epigenetic Signature in Castration-Recurrent Prostate

  11. Effect of castration timing and oral meloxicam administration on growth performance, inflammation, behavior and carcass quality of beef calves

    Science.gov (United States)

    Beef bull calves (n = 62) were assigned randomly, within sire breed, to 1 of 4 treatments at birth. Treatments were: 1) surgical castration near birth, 2) surgical castration near birth with oral administration of meloxicam (1 milligram/kilogram of body weight), 3) surgical castration at weaning (WN...

  12. Palliative care in castrate-resistant prostate cancer.

    Science.gov (United States)

    Rabow, Michael W; Lee, Michael Xiang

    2012-11-01

    Significant symptoms and suffering related to castrate-resistant prostate cancer (CRPC) are associated with the disease and its treatment. Increasingly, with advances in treatment efficacy, men can live with symptoms for long periods. Interdisciplinary palliative care teams (including physicians, nurses, social workers, chaplains, pharmacists, psychologists, physical therapists, and nutritionists) focused on symptom management and patients' goals of care can collaborate with prostate cancer surgeons, oncologists, and radiation oncologists to provide the best care for men at all stages of treatment, including end of life. This article reviews the benefits of palliative care in helping patients with CRPC manage symptoms and distress.

  13. Ultrastructure and morphometry of the urethral glands in normal, castrated, and testosterone-treated castrated male mice.

    Science.gov (United States)

    Parr, M B; Ren, H P; Kepple, L; Parr, E L; Russell, L D

    1993-07-01

    Recent studies of the urethral glands in the male mouse and rat have suggested that they are testosterone-dependent glands that may be potential sites for secretory immunity in the male genital tract. In the present study we describe the ultrastructural features of these glands in normal mice and provide quantitative data on the sizes of the acinar cells and their organelles in sham-, oil-, and testosterone-treated castrated mice. Acinar cells in urethral glands from normal mice contain numerous secretory granules, prominent Golgi complexes, elongated mitochondria, and an abundance of rough endoplasmic reticulum (RER) with large and dilated cisternae, all of which are features characteristic of secretory cells. In some acinar cells the cisternae of the RER were filled with closely packed, unbranched, straight, tubular structures that were oriented parallel to one another, that radiated from aggregates of dense material, or that were randomly arranged. In other acinar cells the cisternae of the RER showed a network of branching and anastomosing vesicular-like structures whose limiting membranes were occasionally seen in continuity with the membranes of the RER. Secretory acini showed large, unbranched tubules in the acinar lumen. When cut at right angles the large tubules exhibited a distinct fuzzy outer coat with fine projections radiating outwards. The ultrastructure of the acinar cells and the presence of tubules in the lumen suggests that they are engaged in secretion of a tubular protein. Morphometric analysis of acinar cells in the urethral glands showed that the mean volumes of nuclei, cytoplasm, secretory granules, vacuoles, and mitochondria were significantly reduced in castrated mice in comparison to either normal or testosterone-treated castrated mice. This confirms earlier observations that the urethral glands are targets of testosterone.

  14. Emerging Molecularly Targeted Therapies in Castration Refractory Prostate Cancer

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    Jesal C. Patel

    2013-01-01

    Full Text Available Androgen deprivation therapy (ADT with medical or surgical castration is the mainstay of therapy in men with metastatic prostate cancer. However, despite initial responses, almost all men eventually develop castration refractory metastatic prostate cancer (CRPC and die of their disease. Over the last decade, it has been recognized that despite the failure of ADT, most prostate cancers maintain some dependence on androgen and/or androgen receptor (AR signaling for proliferation. Furthermore, androgen independent molecular pathways have been identified as drivers of continued progression of CRPC. Subsequently, drugs have been developed targeting these pathways, many of which have received regulatory approval. Agents such as abiraterone, enzalutamide, orteronel (TAK-700, and ARN-509 target androgen signaling. Sipuleucel-T, ipilimumab, and tasquinimod augment immune-mediated tumor killing. Agents targeting classic tumorogenesis pathways including vascular endothelial growth factor, hepatocyte growth factor, insulin like growth factor-1, tumor suppressor, and those which regulate apoptosis and cell cycles are currently being developed. This paper aims to focus on emerging molecular pathways underlying progression of CRPC, and the drugs targeting these pathways, which have recently been approved or have reached advanced stages of development in either phase II or phase III clinical trials.

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

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    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.

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

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    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.

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

    Science.gov (United States)

    Li, Rui; Meng, Xianghu; Zhang, Yan; Wang, Tao; Yang, Jun; Niu, Yonghua; Cui, Kai; Wang, Shaogang

    2016-01-01

    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. PMID:27168996

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

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    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.

  19. Castration of dromedary camel through prescrotal midline incision

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    S.A. Taleb

    2012-10-01

    Full Text Available A total of 165 camels of different ages were castrated through a small, prescrotal midline incision between January, 2010 and December, 2011. The incision was closed with one interrupted, horizontal mattress suture using USP-2 chromic catgut. 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 significance. No primary or secondary postoperative bleeding was noticed in any of the animals. It was concluded that this technique was less time consuming with negligible postoperative care and complications when performed under standard surgical principles.

  20. New Therapeutics to Treat Castrate-Resistant Prostate Cancer

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    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.

  1. Castration-Resistant Prostate Cancer: Mechanisms, Targets, and Treatment

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    Teresa Maria Santos Amaral

    2012-01-01

    Full Text Available Patients with castration-resistant prostate cancer (CRPC, who progress after docetaxel therapy, had until very recently, only a few therapeutic options. Recent advances in this field brought about new perspectives in the treatment of this disease. Molecular, basic, and translational research has given us a better understanding on the mechanisms of CRPC. This great investment has turned into a more rational approach to the development of new drugs. Some of the new treatments are already available to our patients outside clinical trials and may include inhibitors of androgen biosynthesis; new chemotherapy agents; bone-targeted therapy; and immunotherapy. This paper aims to review the mechanisms of prostate cancer resistance, possible therapeutic targets, as well as new options to treat CRPC.

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

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    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.

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

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    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 (P<0.05) between immuno- and surgical castration. Twenty-two of 50 differentially expressed proteins were higher in abundance for IC group and 27 proteins with abundance change folds greater than 1.5 differed with castration methods. Proteins involved in cytoskeleton and immunity were abundant in IC group. Several heat shock proteins (HSPs) and laminins were abundant in SC group.

  5. Aphrodisiac properties of Tribulus Terrestris extract (Protodioscin) in normal and castrated rats.

    Science.gov (United States)

    Gauthaman, K; Adaikan, P G; Prasad, R N V

    2002-08-09

    Tribulus terrestris (TT) has long been used in the traditional Chinese and Indian systems of medicine for the treatment of various ailments and is popularly claimed to improve sexual functions in man. Sexual behaviour and intracavernous pressure (ICP) were studied in both normal and castrated rats to further understand the role of TT containing protodioscin (PTN) as an aphrodisiac. Adult Sprague-Dawley rats were divided into five groups of 8 each that included distilled water treated (normal and castrated), testosterone treated (normal and castrated, 10 mg/kg body weight, subcutaneously, bi-weekly) and TT treated (castrated, 5 mg/kg body weight, orally once daily). Decreases in body weight, prostate weight and ICP were observed among the castrated groups of rats compared to the intact group. There was an overall reduction in the sexual behaviour parameters in the castrated groups of rats as reflected by decrease in mount and intromission frequencies (MF and IF) and increase in mount, intromission, ejaculation latencies (ML, IL, EL) as well as post-ejaculatory interval (PEI). Compared to the castrated control, treatment of castrated rats (with either testosterone or TT extract) showed increase in prostate weight and ICP that were statistically significant. There was also a mild to moderate improvement of the sexual behaviour parameters as evidenced by increase in MF and IF; decrease in ML, IL and PEI. These results were statistically significant. It is concluded that TT extract appears to possess aphrodisiac activity probably due to androgen increasing property of TT (observed in our earlier study on primates).

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

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    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.

  7. Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer

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    2015-10-01

    N.L. Androgen receptors in hormone- dependent and castration-resistant prostate cancer. Pharmacol Ther 140, 223-38 (2013). 2. Claessens, F. et al...Derynck, R. Roles of autocrine TGF-beta receptor and Smad signaling in adipocyte differentiation . J Cell Biol 149, 667-82 (2000). Appendices: None. ...will relapse after ADT and become lethal castration- resistant PCa (CRPC). Interestingly, most CRPCs are still AR- dependent 1, 2. Hence, AR remains as

  8. Castration Therapy of Prostate Cancer Results in Downregulation of HIF-1{alpha} Levels

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    Al-Ubaidi, Firas L.T. [Department of Genetics, Microbiology and Toxicology, Stockholm University, Stockholm (Sweden); Department of Urology, Central Hospital, Vaesteras (Sweden); Schultz, Niklas [Department of Genetics, Microbiology and Toxicology, Stockholm University, Stockholm (Sweden); Egevad, Lars [Department of Oncology-Pathology, Karolinska Institutet, Stockholm (Sweden); Granfors, Torvald [Department of Urology, Central Hospital, Vaesteras (Sweden); Helleday, Thomas, E-mail: helleday@gmt.su.se [Department of Genetics, Microbiology and Toxicology, Stockholm University, Stockholm (Sweden); Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford (United Kingdom); Science for Life Laboratory, Stockholm University, Solna (Sweden)

    2012-03-01

    Background and Purpose: Neoadjuvant androgen deprivation in combination with radiotherapy of prostate cancer is used to improve radioresponsiveness and local tumor control. Currently, the underlying mechanism is not well understood. Because hypoxia causes resistance to radiotherapy, we wanted to test whether castration affects the degree of hypoxia in prostate cancer. Methods and Materials: In 14 patients with locally advanced prostate cancer, six to 12 prostatic needle core biopsy specimens were taken prior to castration therapy. Bilateral orchidectomy was performed in 7 patients, and 7 were treated with a GnRH-agonist (leuprorelin). After castrationm two to four prostatic core biopsy specimens were taken, and the level of hypoxia-inducible factor-1{alpha} (HIF-1{alpha}) in cancer was determined by immunofluorescence. Results: Among biopsy specimens taken before castration, strong HIF-1{alpha} expression (mean intensity above 30) was shown in 5 patients, weak expression (mean intensity 10-30) in 3 patients, and background levels of HIF-1{alpha} (mean intensity 0-10) in 6 patients. Downregulation of HIF-1{alpha} expression after castration was observed in all 5 patients with strong HIF-1{alpha} precastration expression. HIF-1{alpha} expression was also reduced in 2 of 3 patients with weak HIF-1{alpha} precastration expression. Conclusions: Our data suggest that neoadjuvant castration decreases tumor cell hypoxia in prostate cancer, which may explain increased radiosensitivity after castration.

  9. Maximal androgen blockade versus castration alone in patients with metastatic prostate cancer

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    Abeer A.Mahmoud; Eman A.El-Sharawy; Mohamed M.El-Bassiouny; Ramy R.Ghali

    2014-01-01

    Objective: Maximum androgen blockade (MAB), consisting of an antiandrogen plus either a luteinizing hormone-releasing hormone agonist (LHRHA) or orchiectomy, is a standard care for patients with prostate cancer. Although, clinical trial results have been equivocal, none has shown a significant advantage in favor of MAB over castration alone in metastatic prostate cancer and MAB has been the subject of considerable controversy. The aim of this study was to compare MAB (orchiectomy or LHRHA “Goserelin”) and anti-androgen “Bicalutamide” with castration alone (orchiectomy or LHRHA) in previ-ously untreated metastatic prostate cancer patients.Methods: Hundred eligible patients with adequate performance status and adequate hematologic, hepatic and renal functions were included. MAB arm, fifty patients underwent castration either surgicaly by orchiectomy or medicaly by receiving Goserelin (3.6 mg) depot, which was injected subcutaneously every 28 days plus bicalutamide 50 mg once daily. Castration alone arm, fifty patients underwent castration alone either surgicaly by orchiectomy or medicaly by receiving Goserelin (3.6 mg) depot.Results: During the period from January 2011 to January 2013, with a median folow up of 18 months (range 6 to 24 months), there were eight deaths (16%), in MAB arm and ten deaths (20%) in castration alone arm. At three months, there were 35 patients (70%) with prostate specific antigen (PSA) normalization (≤ 4 mg/dL) in MAB arm versus 17 patients (34%) with PSA normalization in castration alone arm (P = 0.001). The median progression free survival (PFS) times were 22.18 months (95% CI, 19.7 to 24.2 months) for MAB arm versus 22 months in castration alone arm (95% CI, 18 to 25.9 months;P = 0.045). The survival rates for MAB arm were 82% at 18 months and 70.6% at 24 months versus 78.7% at 18 months and 75.1% at 24 months in castration alone arm (P > 0.05). The median overal survival (OS) was not reached in either arm. Both hematological

  10. A comparison of androgen deprivation therapy versus surgical castration for patients with advanced prostatic carcinoma

    Institute of Scientific and Technical Information of China (English)

    Yu-hsiang LIN; Chien-lun CHEN; Chen-pang HOU; Phei-lang CHANG; Ke-hung TSUI

    2011-01-01

    Airn:To examine the outcomes of patients with advanced prostate carcinoma who underwent medical or surgical castration.Methods:A hundred twenty one consecutive cases of patients with advanced prostate carcinoma who underwent medicaI or surgical castration between 2001 and 2006 were retrospectively reviewed.Associations between clinicaI outcomes and prognostic scoring factors were determined based on the Reijke study.In the surgical and medical castration groups.the impact on the prostate-specific antigen(PSA)normalization rate,the rebound rate and the disease-free survivaI rate were evaluated.The mean foIlow-up was 36.1months.Results:In the initial 12 months.there were no statisticaI differences in the PSA normalization rate and the PSA rebound rate between the two groups.However,the PSA rebound rate after the 12th month(20.90%vs 40.74%.P=-0.0175)and the 18th month PSA normalization rate(59.70%vs 37.04%.P=0.0217)differed significantly between the two groups,and these differences were maintained to the end of the study.When comparing patients grouped according to Reijke prognosis scores.there was no difference between medical and surgical castration for the good prognosis group.However, among the patients given a poor prognosis,surgical castration was superior in terms of the PSA normalization rate,the PSA rebound rate.the tumor progression-free survival rate(P<0.001)and the overalI survivaI rate (P<0.001).Conclusion:Advanced prostate carcinoma patients with poor pretreatment prognosis scores should undergo surgical castration rather than medical castration for better PSA rebound rates and overaII survival.

  11. Healing of surgical castration wounds: a description and an evaluation of flunixin.

    Science.gov (United States)

    Mintline, E M; Varga, A; Banuelos, J; Walker, K A; Hoar, B; Drake, Daniel; Weary, D M; Coetzee, J F; Stock, M L; Tucker, C B

    2014-12-01

    Previous studies have shown that surgical castration wounds take between 10 and 61 d to heal. The objectives of this work were to describe healing, inflammation, lying behavior, and serum concentration of substance P after surgical castration in beef calves and to evaluate the effect of a possible intervention, a single injection of flunixin meglumine (1.1 mg/kg IV, a NSAID), on the healing process. Calves (mean±SE: 25±2.0 d of age; 54±1.4 kg BW) were surgically castrated with or without an injection of flunixin immediately before the procedure (n=24/treatment). Healing was measured with a 5-point scale (1=fresh wound, 5=no visible incision or inflammation) as well as weight gain, scrotal size, and scrotal surface temperature, on d 1, 2, 3, 7, 14, 21, 28, 35, 49, and 63 after castration. Serum concentration of substance P was recorded on all d, including d 0, but not d 63. Lying behavior was recorded with loggers from 2 d before to 29 d after castration. Inflammation, as measured by scrotal size, peaked on d 2 and 3 after the procedure (e.g., 51±1.0 mm on d 2 versus 28±1.3 mm before castration) and then declined with time (Pflunixin had more lying bouts than those that received saline (flunixin by time interaction; P=0.052), but this pattern emerged on and after d 8, well after the 3 to 8 h half-life of this NSAID. In conclusion, castration caused inflammation in the days that followed, and the wounds required a minimum of 4 wk to heal. Provision of an NSAID had no effect on these outcomes.

  12. Treatment sequencing in metastatic castrate-resistant prostate cancer

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    Oliver Sartor

    2014-06-01

    Full Text Available Six different treatments have demonstrated improved survival in phase III trials targeted to patients with metastatic castration-resistant prostate cancer (mCRPC. Front-line therapeutic options for mCRPC include docetaxel, sipuleucel-T, abiraterone and radium-223. Post-docetaxel options include cabazitaxel, abiraterone, enzalutamide and radium-223. Despite much progress in recent years, much is yet unknown and debates occur over optimal treatment choices and sequences. None of the new agents have been compared to one another, thus physicians in practice today must make choices based on non-randomized comparisons, toxicity considerations and various assumptions. Abiraterone is now moving into the front line mCRPC space given recent regulatory approvals and enzalutamide will follow soon. Both of the hormonal agents have less toxicity when compared to chemotherapeutic options and both of these hormonal agents are expected to be used in a considerable number of mCRPC patients in the years ahead. Little data are available for the post-abiraterone or post-enzalutamide setting. In this review the currently available sequencing data are summarized and interpreted. It is now clear that cross resistance is a potential issue between various treatments, especially those agents that target the androgen axis. This review highlights the need for additional studies to optimize the current treatments for these patients.

  13. Emerging targeted therapies for castration-resistant prostate cancer

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    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.

  14. Radium-223 in metastatic castration resistant prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Winston Vuong; Oliver Sartor; Sumanta K Pal

    2014-01-01

    In 2004, docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). For the next several years, there was a lull in drug approvals. However, from 2010 onwards, 5 additional therapies have been approved on the basis of showing a survival beneift in phase III studies. These agents include sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and (most recently) radium-223. Amongst radiopharmaceuticals currently used for advanced prostate cancer (e.g. samarium-153 and strontium-89), radium-223 possesses several unique properties. As an alpha-emitting compound, the agent produces a high-energy output over a short range, facilitating selective destruction of tissue within the bone in the region of osteoblastic lesions while sparing surrounding normal tissue. The current review will outline biological rationale for radium-223 and also provide an overview of preclinical and clinical development of the agent. Rational sequencing of radium-223 and combinations, in the increasingly complex landscape of mCRPC will be discussed, along with factors inlfuencing clinical implementation.

  15. Novel agents in the management of castration resistant prostate cancer

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    Shruti Chaturvedi

    2014-01-01

    Full Text Available Prostate cancer (PCa is a leading cause of cancer mortality in men and despite high cure rates with surgery and/or radiation, 30-40% of patients will eventually develop advanced disease. Androgen deprivation is the first line therapy for standard of care for men with advanced disease. Eventually however all men will progress to castration-resistant prostate cancer (CRPC. Insight into the molecular mechanisms of androgen resistance has led to the development of alternative novel hormonal agents. Newer hormonal agents such as abiraterone, enzalutamide and TOK-001; and the first cancer vaccine, Sipuleucel T have been approved for use in men with CRPC. The recognition of the importance of bone health and morbidity associated with skeletal related events has led to the introduction of the receptor activator of nuclear factor kappa-B-ligand inhibitor denosumab. Other molecularly targeted therapies have shown promise in pre-clinical studies, but this has not consistently translated into clinical efficacy. It is increasingly evident that CRPC is a heterogeneous disease and an individualized approach directed at identifying primary involvement of specific pathways could maximize the benefit from targeted therapies. This review focuses on targeted therapy for PCa with special emphasis on therapies that have been Food and Drug Administration approved for use in men with CRPC.

  16. Treatment sequencing in metastatic castrate-resistant prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Oliver Sartor; Silke Gillessen

    2014-01-01

    Six different treatments have demonstrated improved survival in phase III trials targeted to patients with metastatic castration-resistant prostate cancer (mCRPC). Front-line therapeutic options for mCRPC include docetaxel, sipuleucel-T, abiraterone and radium-223. Post-docetaxel options include cabazitaxel, abiraterone, enzalutamide and radium-223. Despite much progress in recent years, much is yet unknown and debates occur over optimal treatment choices and sequences. None of the new agents have been compared to one another, thus physicians in practice today must make choices based on non-randomized comparisons, toxicity considerations and various assumptions. Abiraterone is now moving into the front line mCRPC space given recent regulatory approvals and enzalutamide will follow soon. Both of the hormonal agents have less toxicity when compared to chemotherapeutic options and both of these hormonal agents are expected to be used in a considerable number of mCRPC patients in the years ahead. Little data are available for the post-abiraterone or post-enzalutamide setting. In this review the currently available sequencing data are summarized and interpreted. It is now clear that cross resistance is a potential issue between various treatments, especially those agents that target the androgen axis. This review highlights the need for additional studies to optimize the current treatments for these patients.

  17. Radium-223 in metastatic castration resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Winston Vuong

    2014-06-01

    Full Text Available In 2004, docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC. For the next several years, there was a lull in drug approvals. However, from 2010 onwards, 5 additional therapies have been approved on the basis of showing a survival benefit in phase III studies. These agents include sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and (most recently radium-223. Amongst radiopharmaceuticals currently used for advanced prostate cancer (e.g. samarium-153 and strontium-89, radium-223 possesses several unique properties. As an alpha-emitting compound, the agent produces a high-energy output over a short range, facilitating selective destruction of tissue within the bone in the region of osteoblastic lesions while sparing surrounding normal tissue. The current review will outline biological rationale for radium-223 and also provide an overview of preclinical and clinical development of the agent. Rational sequencing of radium-223 and combinations, in the increasingly complex landscape of mCRPC will be discussed, along with factors influencing clinical implementation.

  18. A changing landscape in castration resistant prostate cancer treatment

    Directory of Open Access Journals (Sweden)

    Alessandra eFelici

    2012-07-01

    Full Text Available Prostate cancer (PC is the leading cause of cancer and the second leading cause of cancer-death among men in the Western world. About 10%-20% of men with PC present with metastatic disease at diagnosis, while 20%-30% of patients diagnosed with localized disease will eventually develop metastases. Although most respond to initial androgen deprivation therapy (ADT, progression to castration resistant PC (CRPC is universal. In 2004 the docetaxel/prednisone regimen was approved for the management of patients with metastatic CRPC, becoming the standard first-line therapy. Recent advances have now led to an unprecedented number of new drug approvals within the past years, providing many new treatment options for patients with metastatic CRPC. Four new drugs have received U.S. Food and Drug Administration (FDA-approval in 2010 and 2011: sipuleucel-T, an immunotherapeutic agent; cabazitaxel, a novel microtubule inhibitor; abiraterone acetate, a new androgen biosynthesis inhibitor; and denosumab, a bone-targeting agent. The data supporting the approval of each of these agents are described in this review, as are current approaches in the treatment of metastatic CRPC and ongoing clinical trials of novel treatments and strategies.

  19. Complete androgen blockade safely allows for delay of cytotoxic chemotherapy in castration refractory prostate cancer

    Directory of Open Access Journals (Sweden)

    Rafael A. Kaliks

    2010-06-01

    Full Text Available PURPOSE: Complete androgen blockade (CAB does not prolong overall survival (OS in patients with castration refractory prostate cancer (CRPC. Although there is variable clinical benefit with second-line hormone manipulation, we do not know which patients might benefit the most. OBJECTIVES: To identify clinical predictors of benefit of complete androgen blockade. MATERIALS AND METHODS: We reviewed the records for 54 patients who received treatment with CAB in the setting of disease progression despite castration. We evaluated progression-free survival (PFS and OS according to PSA at diagnosis, Gleason scores, age, testosterone level, and duration of prior disease control during castration in first line treatment. RESULTS: Among 54 patients who received CAB, the median PFS was 9 months (CI 4.3-13.7 and OS was 36 months (CI 24-48. We did not find an effect of PSA at diagnosis (p = 0.32, Gleason score (p = 0.91, age (p = 0.69 or disease control during castration (p = 0.87 on PFS or OS. Thirty-four patients subsequently received chemotherapy, with a mean OS of 21 months (CI 16.4-25.5, median not reached. CONCLUSION: Age, Gleason score, PSA at diagnosis and length of disease control with castration did not affect PFS or OS. In the absence of predictors of benefit, CAB should still be considered in CRPC.

  20. 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

    pathways in castration-resistant tumors, a notion that was confirmed by tumor transcriptome analysis. Further analysis demonstrated that the activation of mTORC1, PAK2 and the increased levels of YAP1 in castration-resistant tumors can be explained by the loss of androgen inhibitory actions. The analysis...

  1. Effect of surgical castration with or without oral meloxicam on the acute inflammatory response in yearling beef bulls

    Science.gov (United States)

    Pain management and welfare are increasingly prevalent concerns within animal agriculture. Analgesics may alleviate pain and inflammation associated with castration of beef cattle. This study was conducted to elucidate the effects of surgical castration on the acute inflammatory response and immunom...

  2. Effects of a local anaesthetic and NSAID in castration of piglets, on the acute pain responses, growth and mortality

    NARCIS (Netherlands)

    Kluivers-Poodt, M.; Houx, B.B.; Robben, S.R.; Koop, G.; Lambooij, E.; Hellebrekers, L.J.

    2012-01-01

    The present study addresses the questions whether on-farm use of local anaesthesia with lidocaine leads to a reduction in pain responses during castration, and whether the non-steroidal anti-inflammatory drug meloxicam improves technical performance after castration of piglets. Five treatments were

  3. Effect of surgical castration with or without meloxicam on the acute inflammatory response in yearling beef bulls

    Science.gov (United States)

    Pain management and welfare are increasingly prevalent concerns within animal agriculture and oral analgesics may alleviate the pain associated with castration. This study was conducted to elucidate the effects of surgical castration on the acute inflammatory response and immunomodulation and whethe...

  4. 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 final...... analysis of an early-access protocol trial that was initiated after completion of COU-AA-301 to enable worldwide preapproval access to abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. METHODS: We did a multicentre, open-label, early......-access protocol trial in 23 countries. We enrolled patients who had metastatic castration-resistant prostate cancer progressing after taxane chemotherapy. Participants received oral doses of abiraterone acetate (1000 mg daily) and prednisone (5 mg twice a day) in 28-day cycles until disease progression...

  5. Castration-induced expression of caspase-1 in epithelia of accessory sex organs in male rats

    Institute of Scientific and Technical Information of China (English)

    Masao Izawa; Mitunori Kimura; Tomiko Yamada; Makoto Saji

    2001-01-01

    Aim: As an attempt to clarify the molecular basis of castration-induced apoptosis, this study was undertaken to demonstrate the expression of caspase-1 in male accessory sex organs of rats. Methods and results: cDNA of rat caspase-1 was cloned by reverse transcription-polymerase chain reaction from the ventral prostates. The open reading frame predicts 402 amino acids, which shows more than 91% and 63 % identity to those of mouse and human, respec tively. Northern analyses demonstrated the presence of castration-induced up-regulation of the 1.6 kb transcript in the ventral prostate and the seminal vesicles. Finally, the authors demonstrated the caspase-1 transcripts in the epithelia of these tissues by in situ hybridization analyses. Conclusion: Castration induces the expression of caspase-1 tran scripts in the epithelia of ventral prostate and seminal vesicle. These observations suggest a possible role of caspase-1 in apoptosis in male accessory sex organs.

  6. Modified-closed castration: a novel technique for sea otter (Enhydra lutris nereis) orchiectomies.

    Science.gov (United States)

    McDermott, Alexa J; Clauss, Tonya; Sakals, Sherisse; Mejia, Johanna; Radlinsky, MaryAnn G

    2013-09-01

    A novel surgical technique was used in the routine castrations of two intact male southern sea otters, Enhydra lutris nereis, housed at the Georgia Aquarium (Atlanta, Georgia, USA). This technique involved incising the parietal vaginal tunic to allow placement of double ligation of the ductus deferens, testicular artery, and pampiniform plexus en masse. After ligating and transecting these structures, they were introduced back into the tunic, which was closed with a circumferential ligature. The incision site was closed in a routine manner. Both otters recovered well from the procedure. One otter had mild cutaneous dehiscence postoperatively, and the other had no obvious complications. Benefits of this procedure include reduced risk of ligature slippage or loosening and resultant hemorrhage, as provided by the traditional open portion of the castration, and decreased postoperative swelling, as provided by the closed part of the castration. To the authors' knowledge, this is the first time this technique has been described for use in sea otters.

  7. Sipuleucel-T: in metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Plosker, Greg L

    2011-01-01

    Sipuleucel-T is an autologous active cellular immunotherapy used in the treatment of men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (CRPC). It is the first therapeutic cancer vaccine to receive US FDA approval. Approximately 3 days prior to each infusion of sipuleucel-T, patients undergo a leukapheresis procedure for collection of autologous peripheral blood mononuclear cells. Preparation of sipuleucel-T involves enrichment for antigen-presenting cells from the leukapheresis product and activation ex vivo with a recombinant fusion protein (PA2024). In the randomized, double-blind, placebo-controlled IMPACT study in patients with metastatic CRPC, sipuleucel-T was associated with a 22% relative reduction in the risk of death (hazard ratio 0.78; p = 0.03), which was the primary endpoint of the trial. After a median follow-up period of 34.1 months, median survival was 4.1 months longer with sipuleucel-T than placebo (25.8 vs 21.7 months). There was no significant between-group difference for the median time to objective disease progression (a secondary endpoint). Almost all patients treated with sipuleucel-T in clinical trials reported an adverse event, although these were mild or moderate in severity (grade 1 or 2) in most patients. The most common adverse events (e.g. infusion-related events, such as chills and fever) generally occurred within the first day after administration of sipuleucel-T and resolved within 2 days.

  8. Time-dependent effects of castration on the bladder function and histological changes in the bladder and blood vessels.

    Science.gov (United States)

    Magari, Tomohiro; Shibata, Yasuhiro; Arai, Seiji; Kashiwagi, Bunzo; Suzuki, Keiji; Suzuki, Kazuhiro

    2014-01-01

    We examined the effect of androgens on bladder blood flow (BBF), bladder function and histological changes in castrated male rats. Male Wistar rats were classified into unoperated group (control group), groups castrated at the age of 8 weeks (group 8wPC) and groups castrated at the age of 4 weeks (group 4wPC). Each rat was used at the age of 20 weeks. BBF was measured using fluorescent microspheres. Bladder cystometry was performed without anesthesia or restraint; the bladder was first irrigated with saline and then with 0.25% acetic acid (AA) solution. Maximum voiding pressure and voiding interval were measured. The bladder and iliac artery were histologically examined for differences in smooth muscle and quantity of collagen fiber to analyze the effect of castration on the smooth muscle content. No differences were noted in BBF following castration. The voiding intervals for all groups were shortened (P control group (Pcontrol group (Pblood vessels.

  9. Animal welfare versus food quality: factors influencing organic consumers' preferences for alternatives to piglet castration without anaesthesia.

    Science.gov (United States)

    Heid, Astrid; Hamm, Ulrich

    2013-10-01

    Surgical piglet castration without pain relief has been banned in organic farming in the EU since the beginning of 2012. Alternative methods therefore need to be implemented that improve animal welfare and solve the underlying problem of boar taint. This paper explores German organic consumers' preferences for piglet castration without pain relief and three alternative methods. In an innovative approach using a multi-criteria decision making procedure, qualitative data from focus group discussions were compared with quantitative results from Vickrey auctions. Overall, participants preferred all alternatives to castration without pain relief. Different aspects influenced willingness-to-pay for the methods. Animal welfare was important for the evaluation of castration without pain relief and castration with anaesthesia. Food safety played a major role for willingness-to-pay for immunocastration, while taste and, to some extent, animal welfare were dominant factors for fattening of boars. These differences should be considered when communicating the alternatives.

  10. 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

  11. Effects of meloxicam and flunixin on pain, stress and discomfort in male piglets during and after surgical castration.

    Science.gov (United States)

    Reiner, Gerald; Schollasch, Frauke; Hillen, Sonja; Willems, Hermann; Piechotta, Marion; Failing, Klaus

    2012-01-01

    Surgical castration of young male piglets is now a generally accepted cause of serious distress and impairment of animal welfare. Awareness of this problem has created the moral commitment to seek for practical and more humane alternatives. As one possible alternative, the application of analgesics has been installed in Germany as an interim solution by the QS system, thus mandatory for the majority of German pig producers.Two analgesics have been authorised for this purpose. Both have been shown a significant positive impact on cortisol levels if administered pre-operatively. However, their effects on pain, stress and discomfort during castration, and on the post-castration period are conflicting. Thus, the aim of the present study was to compare the effects of Meloxicam and Flunixin on cortisol levels, behavioural indices, vocalisation, and wound healing of surgical castrated piglets in the field. There was no difference in vocalisation during castration in analgesic treated and untreated piglets. Piglets castrated under analgesia still had significantly elevated serum cortisol levels 30 min post castration, when compared to the sham castrated group. Both analgesics led to a significant impairment of behavioural indices and wound healing. It is concluded that analgesics can improve the welfare of piglets during the first part of the post-castration period. However, the benefits may be considered small and may not meet the requirements of the EU. Hence it is of high importance to prevent the interim practice of surgical castration of male piglets under analgesics from becoming implemented as a permanent condition in pig production.

  12. Abiraterone plus prednisone improves survival in metastatic castration-resistant prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Scott T Tagawa; Himisha Beltran

    2011-01-01

    In essentially just 1 year's time,we have seen science translated into exciting new therapeutic agents for men with metastatic castration-resistant prostate cancer (CRPC),1 most recently with the United States Food and Drug Administration (FDA) approval of abiraterone acetate in combination with prednisone.2 While prostate cancer has been known to be highly responsive to surgical or medical castration for well over half a century,3 what was once termed 'hormone refractory' prostate cancer inevitably developed,leading to cancerrelated death.Many consider the introduction of chemotherapy for CRPC initially for symptomatic benefit,then with improvements in survival,a substantial step forward.

  13. Dual-Targeting of AR and Akt Pathways by Berberine in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2015-08-01

    maintained by serial passaging in castrated SCID mice. The tumors were cut into 25 mm3 pieces and implanted subcutaneously into castrated SCID mice...transactivate target genes. Cancer Research 2015 Jun 9, Epub ahead of print . Abstracts: Xichun Liu, Elisa Ledet, Yanfeng Qi, Yan Don, Oliver Sartor...expressed at a much lower level than AR-FL (Fig. S5). Moreover, AR-V7 and ARv567es can 230 heterodimerize (Fig. 3D ). Mutating D-box, but not the FxxLF

  14. Blood lipids and fatty acid composition of abdominal fat in castrated and intact male common pheasant (Colchicus colchicus

    Directory of Open Access Journals (Sweden)

    Petar Džaja

    2010-11-01

    Full Text Available The study was undertaken to examine the effects of castration on plasma lipids and on the fatty acid profile of abdominal fat in male pheasants. Thirty pheasants reared in a commercial pheasantry were included in the experiment. Half the pheasants were castrated at 8 weeks of age and the other half underwent sham surgery at the same age. Plasma levels of triglycerides and high density lipoproteins (HDL were significantly higher in the castrated pheasants. Values for cholesterol tended to be higher in castrated pheasants although without statistical significance. The fatty acid content of the abdominal fat from castrated and intact pheasants were primarily composed of oleic acid (42.58%-40.33%, followed by palmitic acid (25.25%-27.33%, linoleic (14.05%-12.65% and stearic acid (8.95%-9.40%. Castration also significantly influenced the fatty acid composition of abdominal fat. Compared to the intact pheasants, the fatty acid content of abdominal fat from castrated pheasants contained higher values for saturated fatty acids (SFA and lower values for unsaturated fatty acids (UFA, unsaturated to saturated fatty acids ratio (UFA/SFA and polyunsaturated to saturated fatty acids ratio (PUFA/SFA.

  15. Melatonin is as effective as testosterone in the prevention of soleus muscle atrophy induced by castration in rats.

    Science.gov (United States)

    Oner, Jale; Oner, Hakan; Sahin, Zeliha; Demir, Ramazan; Ustünel, Ismail

    2008-04-01

    The purpose of this experiment was to compare the weight, insulin-like growth factor-I (IGF-I) expression, and ultrastructure of the soleus muscle in growing castrated rats treated with testosterone or melatonin. In this study, adult male Wistar albino rats were used. The groups were arranged as sham, castrated, and testosterone- or melatonin-injected groups after castration. The soleus muscle samples were fixed in Bouin's solution for immunohistochemistry, and in 2.5% gluteraldehyde in 0.1 M phosphate buffer (pH 7.4). Whereas castration reduced the soleus weight and fiber diameter, testosterone and melatonin administration increased them. IGF-I immunostaining observed in the satellite cells and periphery of the myofibers was least intense in the castrated group. Strong staining of IGF-I was observed in the testosterone- and melatonin-administered groups. The ultrastructure of the soleus muscle in castrated animals showed the important ultrastructural modifications related to degeneration. In these groups, degenerative mitochondria, glycogen clusters under the sarcolemma, irregular Z lines, and loss of lamina externa were observed. The ultrastructure of myofibrils in the testosterone- and melatonin-injected groups was similar to that in sham groups in view of structure. In conclusion, we suggest that melatonin is as effective as testosterone in the prevention of atrophy induced by castration through the IGF-I axis.

  16. 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...

  17. 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...

  18. 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

    OBJECTIVE: To evaluate the benefit of docetaxel rechallenge in patients with metastatic castration-resistant prostate cancer (mCRPC) relapsing after an initial good response to first-line docetaxel. PATIENTS AND METHODS: We retrospectively reviewed the records of consecutive patients with mCRPC w...

  19. Testosterone Replacement Therapy Prevents Alterations of Coronary Vascular Reactivity Caused by Hormone Deficiency Induced by Castration.

    Science.gov (United States)

    Rouver, Wender Nascimento; Delgado, Nathalie Tristão Banhos; Menezes, Jussara Bezerra; Santos, Roger Lyrio; Moyses, Margareth Ribeiro

    2015-01-01

    The present study aimed to determine the effects of chronic treatment with different doses of testosterone on endothelium-dependent coronary vascular reactivity in male rats. Adult male rats were divided into four experimental groups: control (SHAM), castrated (CAST), castrated and immediately treated subcutaneously with a physiological dose (0.5 mg/kg/day, PHYSIO group) or supraphysiological dose (2.5 mg/kg/day, SUPRA group) of testosterone for 15 days. Systolic blood pressure (SBP) was assessed at the end of treatment through tail plethysmography. After euthanasia, the heart was removed and coronary vascular reactivity was assessed using the Langendorff retrograde perfusion technique. A dose-response curve for bradykinin (BK) was constructed, followed by inhibition with 100 μM L-NAME, 2.8 μM indomethacin (INDO), L-NAME + INDO, or L-NAME + INDO + 0.75 μM clotrimazole (CLOT). We observed significant endothelium-dependent, BK-induced coronary vasodilation, which was abolished in the castrated group and restored in the PHYSIO and SUPRA groups. Furthermore, castration modulated the lipid and hormonal profiles and decreased body weight, and testosterone therapy restored all of these parameters. Our results revealed an increase in SBP in the SUPRA group. In addition, our data led us to conclude that physiological concentrations of testosterone may play a beneficial role in the cardiovascular system by maintaining an environment that is favourable for the activity of an endothelium-dependent vasodilator without increasing SBP.

  20. 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) for a...

  1. 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 Compani

  2. 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

  3. Anxiety: the importunate companion. Psychoanalytic theory of castration and separation anxieties and implications for clinical technique.

    Science.gov (United States)

    Davies, Rosemary

    2012-10-01

    In this article I consider the implications of our differing psychoanalytic theories of anxiety on clinical technique. Drawing on differentiations between the focus on separation or castration anxiety and the relative neglect of the latter in contemporary writing, I look in detail at two clinical examples of psychoanalysis in borderline young adults to exemplify the issue.(1).

  4. 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

    ) for a median of 287 weeks. In 38% of castration compared with 17% of bicalutamide patients, femoral neck Z-scores were risk of fracture) and T-scores were ... females). Total hip Z-scores were lumbar spine BMD was affected by degenerative disease. These preliminary data suggest that there may be an advantage in terms of BMD in using bicalutamide monotherapy compared...

  5. Sipuleucel-T in patients with metastatic castration-resistant prostate cancer: an insight for oncologists

    OpenAIRE

    Garcia, Jorge A.

    2011-01-01

    Sipuleucel-T represents a novel immunotherapeutic compound designed to stimulate an immune response against castration-resistant prostate cancer (CRPC). Sipuleucel-T is an autologous active cellular immunotherapy product, which includes autologous dendritic cells pulsed ex vivo with PAP2024, a recombinant fusion protein made of prostatic acid phosphatase and granulocyte-macrophag...

  6. Targeted treatment of metastatic castration-resistant prostate cancer with sipuleucel-T immunotherapy

    NARCIS (Netherlands)

    Mulders, P.F.; Santis, M. de; Powles, T.; Fizazi, K.

    2015-01-01

    CONTEXT: Prostate cancer remains highly prevalent and has a poor clinical outcome once metastatic. Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T treatment extends survival but is independent of

  7. Castration-resistant prostate cancer: from new pathophysiology to new treatment

    NARCIS (Netherlands)

    Sridhar, S.S.; Freedland, S.J.; Gleave, M.E.; Higano, C.; Mulders, P.; Parker, C.; Sartor, O.; Saad, F.

    2014-01-01

    CONTEXT: Until recently, the only approved agent for metastatic castration-resistant prostate cancer (mCRPC) was docetaxel chemotherapy. But over the last 5 years, significant advances in the field have led to the approval of five new agents, each with different mechanisms of action and demonstratin

  8. Testosterone Replacement Therapy Prevents Alterations of Coronary Vascular Reactivity Caused by Hormone Deficiency Induced by Castration.

    Directory of Open Access Journals (Sweden)

    Wender Nascimento Rouver

    Full Text Available The present study aimed to determine the effects of chronic treatment with different doses of testosterone on endothelium-dependent coronary vascular reactivity in male rats. Adult male rats were divided into four experimental groups: control (SHAM, castrated (CAST, castrated and immediately treated subcutaneously with a physiological dose (0.5 mg/kg/day, PHYSIO group or supraphysiological dose (2.5 mg/kg/day, SUPRA group of testosterone for 15 days. Systolic blood pressure (SBP was assessed at the end of treatment through tail plethysmography. After euthanasia, the heart was removed and coronary vascular reactivity was assessed using the Langendorff retrograde perfusion technique. A dose-response curve for bradykinin (BK was constructed, followed by inhibition with 100 μM L-NAME, 2.8 μM indomethacin (INDO, L-NAME + INDO, or L-NAME + INDO + 0.75 μM clotrimazole (CLOT. We observed significant endothelium-dependent, BK-induced coronary vasodilation, which was abolished in the castrated group and restored in the PHYSIO and SUPRA groups. Furthermore, castration modulated the lipid and hormonal profiles and decreased body weight, and testosterone therapy restored all of these parameters. Our results revealed an increase in SBP in the SUPRA group. In addition, our data led us to conclude that physiological concentrations of testosterone may play a beneficial role in the cardiovascular system by maintaining an environment that is favourable for the activity of an endothelium-dependent vasodilator without increasing SBP.

  9. 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...

  10. Evaluation of the anaesthetic depth during piglet castration under an automated isoflurane-anaesthesia at farm level.

    Science.gov (United States)

    Schwennen, Cornelia; Kolbaum, Nina; Waldmann, Karl-Heinz; Höltig, Doris

    2016-01-01

    Piglet castration under isoflurane-anaesthesia could represent an alternative to the practice of castration without anaesthesia. The objective of this study was to evaluate practicality and effectiveness of an automated isoflurane-anaesthesia for castration. A field study on three different farms in Germany (farm A, B: 200 sows; C: 540 sows) was performed. In total, 1429 (1166 anaesthetised and 263 conventionally castrated) male piglets (age: 1-8 days; bodyweight: 0.7-3.7 kg) were monitored. All piglets were treated with nonsteroidal anti-inflammatory drugs directly before castration. Castration and anaesthesia were performed by the farm-manager in presence of a veterinarian. All farmers used the PIGNAP Pro® (Agrosystems GmbH, CH) anaesthetic device (5 vol.% isoflurane, 30% oxygen; flow rate: 2 l/min). Vocalisation and defensive movements of 1166 anaesthetised piglets was rated using a scoring system. Presence or absence of the palpebral- and flexor-reflex was noted. Approximately every second piglet was weighed and oxygen-saturation and pulse- frequency of 231 animals were measured during treatment. Rectal temperatures before and after castration of 264 anaesthetised and 263 conventionally castrated piglets were compared. Only 77% of the anaesthetised piglets showed a sufficient anaesthetic depth based on the assessment of reflexes as well as vocalisations and defensive movements. It was found that the probability for a sufficient depth of anaesthesia decreases with increasing age and weight. The measurements of the pulse-frequency and oxygen-saturation showed an average oxygen-saturation of 98% and an average heart rate of 270/min during anaesthesia. The conventionally castrated piglets had significantly higher rectal temperatures in comparison to the anaesthetised (p piglets is not adequate for commercial application of this technology.

  11. Labour time required for piglet castration with isoflurane-anaesthesia using shared and stationary inhaler devices.

    Science.gov (United States)

    Weber, Sabrina; Das, Gürbüz; Waldmann, Karl-Heinz; Gauly, Matthias

    2014-01-01

    Isoflurane-anaesthesia combined with an analgesic represents a welfare-friendly method of pain mitigation for castration of piglets. However, it requires an inhaler device, which is uneconomic for small farms. Sharing a device among farms may be an economical option if the shared use does not increase labour time and the resulting costs. This study aimed to investigate the amount and components of labour time required for piglet castration with isoflurane anaesthesia performed with stationary and shared devices. Piglets (N = 1579) were anaesthetised with isoflurane (using either stationary or shared devices) and castrated.The stationary devices were used in a group (n = 5) of larger farms (84 sows/farm on an average), whereas smaller farms (n = 7; 32 sows/farm on an average) shared one device. Each farm was visited four times and labour time for each process-step was recorded. The complete process included machine set-up, anaesthesia and castration by a practitioner, and preparation, collection and transport of piglets by a farmer. Labour time of the complete process was increased (P = 0.012) on farms sharing a device (266 s/piglet) compared to farms using stationary devices (177 s/ piglet), due to increased time for preparation (P = 0.055), castration (P = 0.026) and packing (P = 0.010) when sharing a device. However, components of the time budget of farms using stationary or shared devices did not differ significantly (P > 0.05). Cost arising from time spent by farmers did not differ considerably between the use of stationary (0.28 Euro per piglet) and shared (0.26 Euro) devices. It is concluded that costs arising from the increased labour time due to sharing a device can be considered marginal, since the high expenses originating from purchasing an inhaler device are shared among several farms.

  12. 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.

  13. Effects of castration and testosterone replacement on veno-occlusion during penile erection in the rat

    Institute of Scientific and Technical Information of China (English)

    Yu-TianDAI; VivienneStopper; RonaldLewis; ThomasMills

    1999-01-01

    Aim: To determine if androgens directly regulate veno-occlusion or if androgens act indirectly to maintain the penile strutures which control outflow. Methods: Using CASTRATE and TESTO rots, measurement was made of mean arterial pressure (MAP), intracavemosal pressure (CCP), and intracavemosal flow (CCF) during erection resulting from stimulation of the autonomic innervation of the penis. CCP and CCF were also measured during saline infusion into the cavemosal sinuses before and after treatment with sodium nitropmsside (SNP, a nitric oxide donor drug) to fully relax cavemosal smooth muscle. Penile tissue was also collected to measure the content of a actin and proliue and hydroxyproline to determine if brief withdrawal of androgenic support led to changes in the number of smooth muscle cells or the collagen content of the tissue. Resttlts: Infusion of saline into the cavemosal sinuses demonstrated that veno-occlusion was defective in CASTRATE rats while veno-occlusion was fully functional in TESTO animals.Funtmmore, veno-occlusion could be induced in CASTRATE rats if they were first neared with SNP. This observation suggests that failure of veno-occlusion in the CASTRATE rats is due to a deficiency in the production of NO resulting in a reduction in the degree of relaxation of the penile smooth muscle. The measurements of smooth muscle a a ctin and proline and hydroxyproline content of collagen showed that both were unaffected by castration and that the basic structure of the penis did not degenerate after one week without androgenic support. Conclusion: Thesere sults can be inteipreted to mean that androgens control the veno-occlusive mechanism indirectly via a NO dependent mechanism and not by maintaining the structures of the penis which are essential to veno-ocelusion. ( Asian J Androl 1999 Jun; 1: 53-59)

  14. 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...... to survive long-term castration. The possibility of an androgen binding protein, as described in the rat and rabbit, is suggested on morphological grounds. The epididymal body appears to contain a class of highly androgen sensitive cells that degenerate rapidly following castration and a second class...

  15. 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

    2016-03-22

    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.

  16. Novel molecular events associated with altered steroidogenesis induced by exposure to atrazine in the intact and castrate male rat

    Science.gov (United States)

    Toxicology is increasingly focused on molecular events comprising adverse outcome pathways. Atrazine activates the hypothalamic-pituitary adrenal axis, but relationships to gonadal alterations are unknown. We characterized hormone profiles and adrenal (intact and castrate) and te...

  17. Resource efficiency and economic implications of alternatives to surgical castration without anaesthesia.

    Science.gov (United States)

    de Roest, K; Montanari, C; Fowler, T; Baltussen, W

    2009-11-01

    This paper presents an analysis of the economic implications of alternative methods to surgical castration without anaesthesia. Detailed research results on the economic implications of four different alternatives are reported: castration with local anaesthesia, castration with general anaesthesia, immunocastration and raising entire males. The first three alternatives have been assessed for their impact on pig production costs in the most important pig-producing Member States of the EU. The findings on castration with anaesthesia show that cost differences among farms increase if the anaesthesia cannot be administered by farmers and when the veterinarian has to be called to perform it. The cost of veterinarian service largely affects the total average costs, making this solution economically less feasible in small-scale pig farms. In all other farms, the impact on production costs of local anaesthesia is however limited and does not exceed 1 €ct per kg. General anaesthesia administered by inhalation or injection of Ketamin in combination with a sedative (Azaperone, Midazolan) is more expensive. These costs depend heavily on farm size, as the inhalation equipment has to be depreciated on the largest number of pigs possible. The overall costs of immunocastration - including the cost of the work load for the farmer - has to be evaluated against the potential benefits derived from higher daily weight gain and feed efficiency in comparison with surgical castrates. The economic feasibility of this practice will finally depend on the price of the vaccine and on consumer acceptance of immunocastration. The improvement in feed efficiency may compensate almost entirely for the cost of vaccination. The main advantages linked to raising entire males are due to the higher efficiency of feed conversion, to the better growth rate and to the higher leanness of carcass. A higher risk of boar taint on the slaughter line has to be accounted for. Raising entire males should not

  18. Differential miRNA expression profiles in the longissimus dorsi muscle between intact and castrated male pigs.

    Science.gov (United States)

    Cai, Zhaowei; Zhang, Lifan; Jiang, Xiaoling; Sheng, Yifei; Xu, Ningying

    2015-04-01

    MicroRNAs (miRNAs) are important modulators of skeletal muscle development in multiple mammalian species, but their role in skeletal muscle growth in castrated male pigs has not been well studied. The aim of the present study was to determine the role of miRNAs in longissimus dorsi muscle under castration. Our results showed that castration caused a significant decrease in serum testosterone levels as well as carcass lean mass, but led to an increase in carcass fat mass. Moreover, miRNA expression profiles in skeletal muscle were significantly altered by castration, and seven differentially expressed miRNAs were discovered. More importantly, functional analysis suggested that these differentially expressed miRNAs and their targets are involved in the regulation of skeletal muscle contractile function and fat metabolism. Taken together, these results demonstrate altered miRNA expression in skeletal muscle of castrated male pigs, and suggest a potential mechanism underlying the effects of castration on porcine skeletal muscle growth.

  19. 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.

  20. Protein profiles in various epididymal segments of normal and castrated rats

    Institute of Scientific and Technical Information of China (English)

    PremenduP.Mathur; AileenMarshall; C.Y.Cheng

    2000-01-01

    Aim: Epididymal proteins are known to play an important role in the maturation of spermatozoa. We ought to determine if there are regional differences in androgen-dependent epididymal proteins. Methods: A group of adult rats was castrated and epididymides were removed three days following castration. The epididymides were dissected into caput,corpus and cauda segments, homogenized, and proteins were fractionated by anion exchange HPLC. Proteins in selected fractions were resolved by SDS-PAGE and visualized by silver staining. Results: It was observed that the levels of multiple proteins drastically reduced in the various regions of epididymis of the orchiectomized rats. Conclusion: The epididymal proteins appear to be useful markers to study androgenic action in the epididymis. ( Asian J Androl 2000 ;2: 57-64)

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

    Directory of Open Access Journals (Sweden)

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

    Science.gov (United States)

    2014-10-01

    AWARD NUMBER: W81XWH-12-1-0529 TITLE: Overcoming Autophagy to Induce Apoptosis in...code) Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 October 2014 Overcoming Autophagy to Induce Apoptosis in Castration...survival mechanism and led cells to undergo apoptosis . Survival mechanisms elicited by CRPC C4-2B cells when treated with Enza may be blocked by

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

    OpenAIRE

    Howe LM

    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...

  4. Osteoblasts promote castration-resistant prostate cancer by altering intratumoral steroidogenesis.

    Science.gov (United States)

    Hagberg Thulin, Malin; Nilsson, Maria E; Thulin, Pontus; Céraline, Jocelyn; Ohlsson, Claes; Damber, Jan-Erik; Welén, Karin

    2016-02-15

    The skeleton is the preferred site for prostate cancer (PC) metastasis leading to incurable castration-resistant disease. The increased expression of genes encoding steroidogenic enzymes found in bone metastatic tissue from patients suggests that up-regulated steroidogenesis might contribute to tumor growth at the metastatic site. Because of the overall sclerotic phenotype, we hypothesize that osteoblasts regulate the intratumoral steroidogenesis of castration resistant prostate cancer (CRPC) in bone. We here show that osteoblasts alter the steroidogenic transcription program in CRPC cells, closely mimicking the gene expression pattern described in CRPC. Osteoblast-stimulated LNCaP-19 cells displayed an increased expression of genes encoding for steroidogenic enzymes (CYP11A1, HSD3B1, and AKR1C3), estrogen signaling-related genes (CYP19A1, and ESR2), and genes for DHT-inactivating enzymes (UGT2B7, UGT2B15, and UGT2B17). The observed osteoblast-induced effect was exclusive to osteogenic CRPC cells (LNCaP-19) in contrast to osteolytic PC-3 and androgen-dependent LNCaP cells. The altered steroid enzymatic pattern was specific for the intratibial tumors and verified by immunohistochemistry in tissue specimens from LNCaP-19 xenograft tumors. Additionally, the overall steroidogenic effect was reflected by corresponding levels of progesterone and testosterone in serum from castrated mice with intratibial xenografts. A bi-directional interplay was demonstrated since both proliferation and Esr2 expression of osteoblasts were induced by CRPC cells in steroid-depleted conditions. Together, our results demonstrate that osteoblasts are important mediators of the intratumoral steroidogenesis of CRPC and for castration-resistant growth in bone. Targeting osteoblasts may therefore be important in the development of new therapeutic approaches.

  5. State-Of-The-Art Treatment in Castration-Resistant Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Elena Castro

    2014-11-01

    Full Text Available Prostate cancer (PrCa is the most common cancer type in men in developed countries. In the last few years, a dramatic change has occurred in the understanding of castration-resistant PrCa which has led to the development of new drugs that have an impact on patient survival. This review summarises the recent advances in the management of the disease.

  6. MiR-146-SIAH2-AR Signaling in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2015-09-01

    clinical response and PCa patients invariably relapse with more aggressive Castration-Resistant Prostate Cancer (CRPC). The mechanism of CRPC development...blocks AR-signaling often fails after significant initial clinical response and PCa patients invariably relapse with more aggressive form of PCa...proliferation of both parental LNCaP and MDAPCa2b cells but DHT did not increase proliferation of miR-146a inhibitor expressing cell lines (Fig. 6

  7. Targeted treatment of metastatic castration-resistant prostate cancer with sipuleucel-T immunotherapy

    OpenAIRE

    Mulders, Peter F.; Santis, Maria; Powles, Thomas; Fizazi, Karim

    2015-01-01

    Context Prostate cancer remains highly prevalent and has a poor clinical outcome once metastatic. Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T treatment extends survival but is independent of traditional short-term markers of treatment response observed with chemotherapy and contemporary hormonal treatments. Therefore, it is essential that clinicians understand the mechanism of action o...

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

    Directory of Open Access Journals (Sweden)

    Rosenberg JE

    2012-01-01

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

  9. Critical questions in metastatic castration-resistant prostate cancer: Integrating emerging clinical evidence and guideline recommendations

    OpenAIRE

    2016-01-01

    Metastatic castration-resistant prostate cancer (CRPC) typically confers a poor prognosis, however, novel advances in treatment options, as well as biomarkers for monitoring disease response and progression, have recently helped improve survival rates. Additionally, new guidelines provide some direction on incorporating these new treatments but some confusion still exists among clinicians about best methods for initiating treatment and the optimal sequencing of agents to prolong survival. In ...

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

    Science.gov (United States)

    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. PMID:26121643

  11. Using a Novel Transgenic Mouse Model to Study c-Myc Oncogenic Pathway in Castration Resistance and Chemoresistance of Prostate Cancer

    Science.gov (United States)

    2015-10-01

    Oncogenic Pathway in Castration Resistance and Chemoresistance of Prostate Cancer 3 Annual Progress Report W81XWH-13-1-0162 Using a Novel...Transgenic Mouse Model to Study c-Myc Oncogenic Pathway in Castration Resistance and Chemoresistance of Prostate Cancer Feng Yang, Ph.D. Department of...AWARD NUMBER: W81XWH-13-1-0162 TITLE: Using a Novel Transgenic Mouse Model to Study c-Myc Oncogenic Pathway in Castration Resistance and

  12. Statin derivatives as therapeutic agents for castration-resistant prostate cancer.

    Science.gov (United States)

    Ingersoll, Matthew A; Miller, Dannah R; Martinez, October; Wakefield, C Brent; Hsieh, Kuan-Chan; Simha, M Vijaya; Kao, Chai-Lin; Chen, Hui-Ting; Batra, Surinder K; Lin, Ming-Fong

    2016-12-01

    Despite recent advances in modern medicine, castration-resistant prostate cancer remains an incurable disease. Subpopulations of prostate cancer cells develop castration-resistance by obtaining the complete steroidogenic ability to synthesize androgens from cholesterol. Statin derivatives, such as simvastatin, inhibit cholesterol biosynthesis and may reduce prostate cancer incidence as well as progression to advanced, metastatic phenotype. In this study, we demonstrate novel simvastatin-related molecules SVA, AM1, and AM2 suppress the tumorigenicity of prostate cancer cell lines including androgen receptor-positive LNCaP C-81 and VCaP as well as androgen receptor-negative PC-3 and DU145. This is achieved through inhibition of cell proliferation, colony formation, and migration as well as induction of S-phase cell-cycle arrest and apoptosis. While the compounds effectively block androgen receptor signaling, their mechanism of inhibition also includes suppression of the AKT pathway, in part, through disruption of the plasma membrane. SVA also possess an added effect on cell growth inhibition when combined with docetaxel. In summary, of the compounds studied, SVA is the most potent inhibitor of prostate cancer cell tumorigenicity, demonstrating its potential as a promising therapeutic agent for castration-resistant prostate cancer.

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

    Directory of Open Access Journals (Sweden)

    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.

  14. Integrative Molecular Profiling Reveals Asparagine Synthetase Is a Target in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    Sircar, Kanishka; Huang, Heng; Hu, Limei; Cogdell, David; Dhillon, Jasreman; Tzelepi, Vassiliki; Efstathiou, Eleni; Koumakpayi, Ismaël H.; Saad, Fred; Luo, Dijun; Bismar, Tarek A.; Aparicio, Ana; Troncoso, Patricia; Navone, Nora; Zhang, Wei

    2013-01-01

    The identification of new and effective therapeutic targets for the lethal, castration-resistant stage of prostate cancer (CRPC) has been challenging because of both the paucity of adequate frozen tissues and a lack of integrated molecular analysis. Therefore, in this study, we performed a genome-wide analysis of DNA copy number alterations from 34 unique surgical CRPC specimens and 5 xenografts, with matched transcriptomic profiling of 25 specimens. An integrated analysis of these data revealed that the asparagine synthetase (ASNS) gene showed a gain in copy number and was overexpressed at the transcript level. The overexpression of ASNS was validated by analyzing other public CRPC data sets. ASNS protein expression, as detected by reverse-phase protein lysate array, was tightly correlated with gene copy number. In addition, ASNS protein expression, as determined by IHC analysis, was associated with progression to a therapy-resistant disease state in TMAs that included 77 castration-resistant and 40 untreated prostate cancer patient samples. Knockdown of ASNS by small-interfering RNAs in asparagine-deprived media led to growth inhibition in both androgen-responsive (ie, LNCaP) and castration-resistant (ie, C4-2B) prostate cancer cell lines and in cells isolated from a CRPC xenograft (ie, MDA PCa 180-30). Together, our results suggest that ASNS is up-regulated in cases of CRPC and that depletion of asparagine using ASNS inhibitors will be a novel strategy for targeting CRPC cells. PMID:22245216

  15. Starvation reveals the cause of infection-induced castration and gigantism.

    Science.gov (United States)

    Cressler, Clayton E; Nelson, William A; Day, Troy; McCauley, Edward

    2014-10-01

    Parasites often induce life-history changes in their hosts. In many cases, these infection-induced life-history changes are driven by changes in the pattern of energy allocation and utilization within the host. Because these processes will affect both host and parasite fitness, it can be challenging to determine who benefits from them. Determining the causes and consequences of infection-induced life-history changes requires the ability to experimentally manipulate life history and a framework for connecting life history to host and parasite fitness. Here, we combine a novel starvation manipulation with energy budget models to provide new insights into castration and gigantism in the Daphnia magna-Pasteuria ramosa host-parasite system. Our results show that starvation primarily affects investment in reproduction, and increasing starvation stress reduces gigantism and parasite fitness without affecting castration. These results are consistent with an energetic structure where the parasite uses growth energy as a resource. This finding gives us new understanding of the role of castration and gigantism in this system, and how life-history variation will affect infection outcome and epidemiological dynamics. The approach of combining targeted life-history manipulations with energy budget models can be adapted to understand life-history changes in other disease systems.

  16. Tissue fatty acid composition and estimated ∆ desaturase activity after castration in chicken broilers fed with linseed or sunflower oil.

    Science.gov (United States)

    Mašek, T; Starčević, K; Filipović, N; Stojević, Z; Brozić, D; Gottstein, Z; Severin, K

    2014-04-01

    The aims of this study were to investigate the influence of the short-term addition of sunflower and linseed oil and castration on fatty acid composition and desaturation indexes in chicken broilers. Forty-eight male Ross 308 chicken broilers were supplemented with 5% of sunflower or linseed oil. The four experimental groups were linseed oil supplementation and castration (LC), linseed oil without castration (LN), sunflower oil and castration (SC) and sunflower oil without castration (SN). There was no significant influence of castration or oil supplement on live weights, weight gain, feed intake or feed conversion. Castration resulted in an increase in polyunsaturated fatty acids (PUFA), total n3, n6, measured desaturation indexes and a decrease in the saturated fatty acid (SFA) and monounsaturated fatty acid (MUFA) content of abdominal fat. In breast muscle, castration increased PUFA and 18:3n3 values, while in the liver tissue, castration did not influence the parameters measured. Linseed oil supplementation significantly increased 18:3n3, n3 long chain polyunsaturated fatty acids (LC PUFA), total n3 and decreased total n6, n6/n3 ratio, and 20:4n6 content. Values for 20:4n6 were the highest in SC and the lowest in the LC group. Linseed oil also significantly decreased ∆5 and ∆4 desaturation indexes in the thighs and ∆5 and ∆5, 6 in abdominal fat and the liver. These results suggest that short-term supplementation of basal diet with 5% of linseed oil could significantly increase n3 LC PUFA and decrease n6/n3 ratio content in the edible tissues of chicken broilers, without adverse effects on growth performance. Meanwhile, castration only improved fatty acid profile in abdominal fat, which is not nutritionally important. The interactions observed between basal diet, supplemented oil, sex hormones and other non-nutritional factors must be elucidated in future trials in order to correctly predict the nutritional value of linseed-fed poultry.

  17. Changes in gene expression following androgen receptor blockade is not equivalent to androgen ablation by castration in the rat ventral prostate

    Indian Academy of Sciences (India)

    Anil M Limaye; Irfan Asangani; Thyagarajan Kalyani; Paturu Kondaiah

    2008-06-01

    Involution of the rat ventral prostate and concomitant modulation of gene expression post-castration is a well-documented phenomenon. While the rat castration model has been extensively used to study androgen regulation of gene expression in the ventral prostate, it is not clear whether all the gene expression changes post-castration are due to androgen depletion alone. To obtain insights into this, we performed differential display reverse transcriptase polymerase chain reaction (DD-RT-PCR) which resulted in the identification of castration and/or flutamide-regulated genes in the rat ventral prostate. These include clusterin, methionine adenosyl transferase II, and prostate-specific transcripts such as PBPC1BS, S100RVP and A7. While clusterin, PBPC1BS and methionine adenosyl transferase II are regulated by both castration and flutamide, S100 RVP and A7 are regulated by castration alone. Interestingly, we show that flutamide, unlike castration, does not induce apoptosis in the rat ventral prostate epithelium, which could be an underlying cause for the differential effects of castration and flutamide treatment. We propose that castration leads to enrichment and depletion of stromal and epithelial cell types, respectively, resulting in erroneous conclusions on some of the cell type-specific transcripts as being androgen regulated.

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

    Directory of Open Access Journals (Sweden)

    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

  19. Castration modifies aortic vasoreactivity and serum fatty acids in a sucrose-fed rat model of metabolic syndrome.

    Science.gov (United States)

    Perez, Israel; El Hafidi, Mohammed; Carvajal, Karla; Baños, Guadalupe

    2009-03-01

    Levels of testosterone and estradiol influence the incidence of cardiovascular diseases: generally, estrogens in females are protective before menopause; coronaropathies, hypertension, and dyslipidemias in normal men are more frequent at comparable ages. We investigated the modulation by castration of in vitro vasoreactivity, serum lipid content, and systolic blood pressure (SBP) in rats with sucrose-induced metabolic syndrome. The main characteristics of the rat model are: hypertriglyceridemia, moderately high blood pressure, intra-abdominal accumulation of adipose tissue, hyperinsulinemia, nephropathy, increased oxidative stress, and altered vasoreactivity. Male weanling rats received 30% sucrose solution for 16 weeks (metabolic syndrome; MS), controls (C) had plain water; both had commercial rodent chow. They were subdivided into five groups with two subgroups each: Group 1, intact C and MS rats, Groups 2-5, C and MS rats castrated for periods of 16, 12, 8, and 4 weeks. At the end of the study period, systolic blood pressure was measured, and blood and aortas were obtained for fatty acid determination and vasoreactivity assays, respectively. After 16 weeks' sucrose treatment MS aortas showed hypercontractility and decreased vasodilation. Palmitic and palmitoleic acids were increased in MS versus C. Arachidonic acid levels in MS were lower than in intact or castrated C. Long-term castration of 16 weeks normalized the levels of palmitic and oleic acids. With the shorter periods of castration, contractility increased and relaxation decreased in C and MS, but it was more significant in C. Regarding fatty acid composition, long-term castration increased polyunsaturated (arachidonic and eicosapentaenoic) fatty acids. The shorter periods did not modify the fatty acid profile in either C or MS. Metabolic syndrome altered SBP, aortic reactivity, and levels of fatty acids; castration of long duration normalized them in some cases.

  20. Effect of a topical anaesthetic formulation on the cortisol response to surgical castration of unweaned beef calves.

    Science.gov (United States)

    McCarthy, D; Lomax, S; Windsor, P A; White, P J

    2016-01-01

    Impracticality and cost of existing pain management strategies during surgical castration of beef cattle have limited their widespread implementation on-farm. A farmer-applied topical anaesthetic formulation, originally developed and used commercially to mitigate the pain of mulesing in lambs, was investigated for its potential use for managing pain in surgically castrated calves. This formulation contained lidocaine, bupivacaine, adrenalin and cetrimide. In this study, 24 Angus bull calves were randomly allocated to (1) surgical castration (C, n=8), (2) surgical castration with the post-operative application of topical anaesthetic (CTA, n=8) and (3) sham castration/control (CON, n=8). The experiment was conducted over 2 days, with treatment groups evenly represented across each day. Calves were habituated to handling before the experiment and blood samples were collected for plasma cortisol measurement at defined time periods before, at and post treatment, (at -0.5, 0 h, then +0.5, 1, 1.5, 2, 4 and 6 h). There was a significant effect of time on cortisol concentrations across all treatment groups (Pcortisol response at 0 h. The effect of treatment was not significant (P=0.077), however, there was a trend for CON calves to display lower cortisol concentrations than C and CTA calves and CTA calves to display lower cortisol concentrations than C calves. The mean area under the curve (AUC) of CON calves was significantly lower than those of C and CTA calves (P=0.04), however, there was no significant difference between the AUCs of CTA and C calves. Immediate application of topical anaesthetic after surgical castration did not significantly reduce plasma cortisol concentrations. However, the trend for CTA calves to display lower cortisol concentrations than C calves warrants further investigation into the use of TA for pain relief of surgically castrated beef calves.

  1. Effects of local anesthesia and flunixin meglumine on the acute cortisol response, behavior, and performance of young dairy calves undergoing surgical castration.

    Science.gov (United States)

    Webster, H B; Morin, D; Jarrell, V; Shipley, C; Brown, L; Green, A; Wallace, R; Constable, P D

    2013-10-01

    This study assessed the effects of flunixin meglumine (FM) and a local anesthetic block (LA) on postcastration performance, plasma cortisol concentration, and behavior in dairy calves. Thirty 2- to 3-mo-old Holstein-Friesian bull calves were allocated to 5 treatments: castration with LA (2% lidocaine injected into the testes and subcutaneously), castration with FM (1.1mg/kg, i.v.), castration with LA+FM, castration without drugs (CC), and sham castration (SC). Castration was performed using a Newberry knife and Henderson castrating tool. Feed intake and body weight gain were recorded for 10d postcastration. Plasma cortisol concentration and behavior frequency and duration were monitored for 8h postcastration. Variables with repeated measures were analyzed using PROC MIXED (SAS Institute Inc., Cary, NC); one-way ANOVA was used for nonrepeated measures. No differences in feed intake or body weight gain were detected among groups. Calves in the CC, LA, and FM groups had transient (<60, <60, and <45 min, respectively) increases in plasma cortisol concentration after castration, with a second increase at 120 min in the LA group, whereas cortisol concentration remained at baseline in the LA+FM and SC groups. Mean cortisol concentrations were lower for calves in the LA+FM and SC groups than in the CC group. The area under the plasma cortisol concentration curve during the first 3h postcastration was greater in CC- and LA-treated calves than in SC controls. Castration without drugs was associated with higher frequencies of crouching and statue standing and less oral activity compared with SC controls. Administering LA alone before castration was associated with higher frequencies of head turning, statue standing, and postural changes, and less feeding behavior compared with SC controls. More leg lifting to groom was seen in LA+FM-treated calves than in SC controls. Calves administered FM alone before castration exhibited less crouching than CC calves, fewer postural shifts

  2. Use of a gonadotropin releasing hormone agonist implant as an alternative for surgical castration in male ferrets (Mustela putorius furo).

    Science.gov (United States)

    Schoemaker, N J; van Deijk, R; Muijlaert, B; Kik, M J L; Kuijten, A M; de Jong, F H; Trigg, T E; Kruitwagen, C L J J; Mol, J A

    2008-07-15

    Surgical castration in ferrets has been implicated as an etiological factor in the development of hyperadrenocorticism in this species due to a castration-related increase in plasma gonadotropins. In search for a suitable alternative, the effect of treatment with the depot GnRH-agonist implant, deslorelin, on plasma testosterone concentrations and concurrent testes size, spermatogenesis, and the typical musky odor of intact male ferrets was investigated. Twenty-one male ferrets, equally divided into three groups, were either surgically castrated, received a slow release deslorelin implant or received a placebo implant. Plasma FSH and testosterone concentrations, testis size and spermatogenesis were all suppressed after the use of the deslorelin implant. The musky odor in the ferrets which had received a deslorelin implant was less compared to the ferrets which were either surgically castrated or had received a placebo implant. These results indicate that the deslorelin implant effectively prevents reproduction and the musky odor of intact male ferrets and is therefore considered a suitable alternative for surgical castration in these animals.

  3. 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...

  4. Update on options for treatment of metastatic castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Prakash Vishnu

    2010-03-01

    Full Text Available Prakash Vishnu, Winston W TanDivision of Hematology Oncology, Mayo Clinic, Jacksonville, FL, USABackground: Prostate cancer is one of the most common cancers in men in US and European countries. Despite having a favorable prognosis, the incidence of incurable metastatic disease and mortality in the US is about 28,000 per year. Although hormone-based androgen deprivation therapies typically result in rapid responses, nearly all patients eventually develop progressive castration-resistant disease state. With readily available prostate-specific antigen (PSA testing, most of these patients are asymptomatic and manifest progression simply as a rising PSA. In patients with castration-resistant prostate cancer (CRPC, the median survival is about 1–2 years, with improvements in survival seen mostly with docetaxel-based regimens. The purpose of this article is to review the recent developments in the treatment of advanced CRPC.Recent findings: Since the two landmark trials (TAX-327 and Southwest Oncology Group 99–16 in CRPC, several newer cytotoxic drugs (epothilones, satraplatin, targeted agents (abiraterone, MDV3100 and vaccines have been tested in phase II and III setting with promising results.Conclusions: The role of newer agents in the treatment of CRPC still needs to be validated by phase III trials, which are currently ongoing. Whilst the novel biomarkers, ‘circulating tumor cells’, have been shown to provide important prognostic information and are anticipated to be incorporated in future clinical decision-making, their exact utility and relevance calls for a larger prospective validation.Keywords: castration-resistant prostate cancer, novel therapies, mechanisms of resistance, circulating tumor cells

  5. Effects of icariin on erectile function and expression of nitric oxide synthase isoforms in castrated rats

    Institute of Scientific and Technical Information of China (English)

    Wu-Jiang Liu; Zhong-Cheng Xin; Hua Xin; Yi-Ming Yuan; Long Tian; Ying-Lu Guo

    2005-01-01

    Aim: To investigate the effect of icariin on erectile function and the expression of nitric oxide synthase (NOS)isoforms in castrated rats. Methods: Thirty-two adult male Wistar rats were randomly divided into one sham-operated group (A) and three castrated groups (B, C and D). One week after surgery, rats were treated with normal week after treatment, the erectile function of the rats was assessed by measuring intracavernosal pressure (ICP)during electrostimulation of the cavernosal nerve. The serum testosterone (ST) levels, the percent of smooth muscle (PSM) in trabecular tissue, and the expression of mRNA and proteins of neuronal nitric oxide synthase (nNOS),inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS) and phosphodiesterase V (PDE5) in corpus cavernosum (CC) were also evaluated. Results: ICP, PSM, ST and the expression of nNOS, iNOS, eNOS and PDE5 were significantly decreased in group B compared with those in group A (P < 0.01). However, ICP, PSM and the expression of nNOS and iNOS were increased in groups C and D compared with those in group B (P < 0.05).Changes in ST and the expression of eNOS and PDE5 were not significant (P > 0.05) in groups C and D compared with those in group B. Conclusion: Oral treatment with icariin (> 98.6 % purity) for 4 weeks potentially improves erectile function. This effect is correlated with an increase in PSM and the expression of certain NOS in the CC of castrated rats. These results suggest that icariin may have a therapeutic effect on erectile dysfunction.

  6. Role of Chemotherapy and Mechanisms of Resistance to Chemotherapy in Metastatic Castration-Resistant Prostate Cancer

    Science.gov (United States)

    Lohiya, Vipin; Aragon-Ching, Jeanny B.; Sonpavde, Guru

    2016-01-01

    Chemotherapy using the taxanes, docetaxel and cabazitaxel, remains an important therapeutic option in metastatic castration-resistant prostate cancer (CRPC). However, despite the survival benefits afforded by these agents, the survival increments are modest and resistance occurs universally. Efforts to overcome resistance to docetaxel by combining with biologic agents have heretofore been unsuccessful. Indeed, resistance to these taxanes is also associated with cross-resistance to the antiandrogen drugs, abiraterone and enzalutamide. Here, we discuss the various mechanisms of resistance to chemotherapy in metastatic CRPC and the potential role of emerging regimens and agents in varying clinical phases of development.

  7. 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.

  8. New drugs in the treatment of elderly patients with metastatic castration-resistance prostate cancer.

    Science.gov (United States)

    Genestreti, Giovenzio; Di Battista, Monica; Cavallo, Giovanna; Brandes, Alba A

    2016-08-03

    Treatment of prostate cancer is continually evolving and new therapies have become available. However, the management of elderly patients is challenging due to their age and comorbidities. Androgen deprivation therapy remains the mainstay treatment of hormonal-sensitive disease. Nevertheless, when disease becomes resistant to castration, docetaxel-based chemotherapy represents the standard rescue therapy irrespective of patient age. Recently, chemotherapeutic agents such as cabazitaxel and hormonal therapies such as abiraterone acetate and enzalutamide have been shown to improve survival in patients with progression of disease before or following docetaxel. This review focuses on the safety and efficacy results of these new drugs in elderly patients.

  9. Critical questions in metastatic castration-resistant prostate cancer: Integrating emerging clinical evidence and guideline recommendations

    Directory of Open Access Journals (Sweden)

    Mohamed Ali

    2016-01-01

    Full Text Available Metastatic castration-resistant prostate cancer (CRPC typically confers a poor prognosis, however, novel advances in treatment options, as well as biomarkers for monitoring disease response and progression, have recently helped improve survival rates. Additionally, new guidelines provide some direction on incorporating these new treatments but some confusion still exists among clinicians about best methods for initiating treatment and the optimal sequencing of agents to prolong survival. In this article, we review the literature and answer some frequently asked questions about treating men with metastatic CRPC, including choosing a first-line treatment, monitoring treatment response, and proceeding to additional lines of therapy.

  10. Time-dependent effects of castration on the bladder function and histological changes in the bladder and blood vessels

    Institute of Scientific and Technical Information of China (English)

    Tomohiro Magari; Yasuhiro Shibata; Seiji Arai; Bunzo Kashiwagi; Keiji Suzuki; Kazuhiro Suzuki

    2014-01-01

    We examined the effect of androgens on bladder blood lfow (BBF), bladder function and histological changes in castrated male rats. Male Wistar rats were classiifed into unoperated group (control group), groups castrated at the age of 8 weeks (group 8wPC) and groups castrated at the age of 4 weeks (group 4wPC). Each rat was used at the age of 20 weeks. BBF was measured using lfuorescent microspheres. Bladder cystometry was performed without anesthesia or restraint;the bladder was ifrst irrigated with saline and then with 0.25%acetic acid (AA) solution. Maximum voiding pressure and voiding interval were measured. The bladder and iliac artery were histologically examined for differences in smooth muscle and quantity of collagen ifber to analyze the effect of castration on the smooth muscle content. No differences were noted in BBF following castration. The voiding intervals for all groups were shortened (P<0.001) following AA irrigation. No signiifcant difference was noted in the maximum voiding pressure. Histological changes were observed in bladder and iliac artery. Smooth muscle/collagen ratio at the bladder was lower in groups 8wPC and 4wPC compared to the control group (P<0.01), while that at the iliac artery was decreased in group 4wPC compared to the control group (P<0.001). In conclusion, our ifndings indicate that castration does not alter BBF, but leads to histological changes in the bladder as well as its associated blood vessels.

  11. Dominant-negative androgen receptor inhibition of intracrine androgen-dependent growth of castration-recurrent prostate cancer.

    Directory of Open Access Journals (Sweden)

    Mark A Titus

    Full Text Available BACKGROUND: Prostate cancer (CaP is the second leading cause of cancer death in American men. Androgen deprivation therapy is initially effective in CaP treatment, but CaP recurs despite castrate levels of circulating androgen. Continued expression of the androgen receptor (AR and its ligands has been linked to castration-recurrent CaP growth. PRINCIPAL FINDING: In this report, the ligand-dependent dominant-negative ARΔ142-337 (ARΔTR was expressed in castration-recurrent CWR-R1 cell and tumor models to elucidate the role of AR signaling. Expression of ARΔTR decreased CWR-R1 tumor growth in the presence and absence of exogenous testosterone (T and improved survival in the presence of exogenous T. There was evidence for negative selection of ARΔTR transgene in T-treated mice. Mass spectrometry revealed castration-recurrent CaP dihydrotestosterone (DHT levels sufficient to activate AR and ARΔTR. In the absence of exogenous testosterone, CWR-R1-ARΔTR and control cells exhibited altered androgen profiles that implicated epithelial CaP cells as a source of intratumoral AR ligands. CONCLUSION: The study provides in vivo evidence that activation of AR signaling by intratumoral AR ligands is required for castration-recurrent CaP growth and that epithelial CaP cells produce sufficient active androgens for CaP recurrence during androgen deprivation therapy. Targeting intracrine T and DHT synthesis should provide a mechanism to inhibit AR and growth of castration-recurrent CaP.

  12. Effects of castration method and frequency of intramuscular injections of ketoprofen on behavioral and physiological indicators of pain in beef cattle.

    Science.gov (United States)

    Moya, D; González, L A; Janzen, E; Caulkett, N A; Fireheller, E; Schwartzkopf-Genswein, K S

    2014-04-01

    Two experiments were conducted to determine the effect of a single or multiple intramuscular (i.m.) injection of ketoprofen and castration technique on physiological and behavioral indicators of pain in beef calves. A total of 150 bull calves (284.8 ± 22.7 kg BW) were used in both experiments, each 1 conducted as a 3 × 2 factorial design, where main factors included castration technique--no castration (CT), surgical (SU), or band (BA)--and drug administration--physiological solution (PS) or i.m. injection of ketoprofen (KP; 3 mg Anafen/kg BW) in the neck of calves. Animals were weighed weekly during the experiment to calculate ADG. Behavioral responses indicative of pain and discomfort during the castration procedure were documented using a visual analog score (VAS) by an experienced observer who was blind to the treatments. Movements of the animals in the chute during castration were quantified using a strain gauge system mounted on the head gate to evaluate the escape response of the cattle. Pens were equipped with an automated feed bunk monitoring system enabling feed intake and feeding behavior to be continuously monitored for each individual. Thermographic images of the scrotal area were evaluated 24 and 0.5 h before castration, 0.5, 1, 24, 48, and 270 h postcastration, and weekly thereafter until the end of the trial. Blood samples were obtained postcastration to evaluate changes in total white blood cell (WBC) count and neutrophil-to-lymphocyte (N:L) ratio. Saliva samples were taken 24 and 0.5 h before castration, immediately after castration, and 0.5, 1, 2, 5, 24, and 48 h and then 5, 7, and 14 d after castration to determine cortisol concentration. Scrotal temperature, VAS, total WBC, N:L ratio, salivary cortisol, mobility, and pressure exerted in the chute were greater (P ketoprofen to improve the consistency of its effects as a pain mitigation strategy after castration.

  13. 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

    To compare treatment outcomes in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel (CA) as second-line or third-line therapy in the everyday clinical setting. Charts from 94 patients treated with CA as second-line (n=28) or third-line therapy (n=66) were...... 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...

  14. 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.

  15. Prostate Cancer Stem-like Cells Contribute to the Development of Castration-Resistant Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Diane Ojo

    2015-11-01

    Full Text Available Androgen deprivation therapy (ADT has been the standard care for patients with advanced prostate cancer (PC since the 1940s. Although ADT shows clear benefits for many patients, castration-resistant prostate cancer (CRPC inevitably occurs. In fact, with the two recent FDA-approved second-generation anti-androgens abiraterone and enzalutamide, resistance develops rapidly in patients with CRPC, despite their initial effectiveness. The lack of effective therapeutic solutions towards CRPC largely reflects our limited understanding of the underlying mechanisms responsible for CRPC development. While persistent androgen receptor (AR signaling under castration levels of serum testosterone (<50 ng/mL contributes to resistance to ADT, it is also clear that CRPC evolves via complex mechanisms. Nevertheless, the physiological impact of individual mechanisms and whether these mechanisms function in a cohesive manner in promoting CRPC are elusive. In spite of these uncertainties, emerging evidence supports a critical role of prostate cancer stem-like cells (PCSLCs in stimulating CRPC evolution and resistance to abiraterone and enzalutamide. In this review, we will discuss the recent evidence supporting the involvement of PCSLC in CRPC acquisition as well as the pathways and factors contributing to PCSLC expansion in response to ADT.

  16. Optimal Sequencing of New Drugs in Metastatic Castration-Resistant Prostate Cancer: Dream or Reality?

    Science.gov (United States)

    Caffo, Orazio; Lunardi, Andrea; Trentin, Chiara; Maines, Francesca; Veccia, Antonello; Galligioni, Enzo

    2016-01-01

    The availability of new drugs capable of improving the overall survival of patients with metastatic castration-resistant prostate cancer has led to the possibility of using them sequentially in the hope of obtaining a cumulative survival benefit. The new agents have already been administered as third-line treatments in patients who have previously received them as second line in everyday clinical practice, but the efficacy of this practice is not yet supported by clinical trial data, and evidence of possible cross-resistance has reinforced the debate concerning the best sequence to use in order to maximise the benefit. Furthermore, the situation is further complicated by the possibility of administering new hormonal agents to chemotherapy-naïve patients, and novel chemotherapeutic agents to hormone-sensitive patients. This article critically reviews the available data concerning the sequential use of new drugs, and discusses the real evidence concerning their optimal positioning in the therapeutic strategy of metastatic castration-resistant prostate cancer.

  17. Immunotherapy in castration-resistant prostate cancer: integrating sipuleucel-T into our current treatment paradigm.

    Science.gov (United States)

    Garcia, Jorge A; Dreicer, Robert

    2011-03-01

    The availability of several novel antibodies, coupled with viral, DNA, and dendritic-cell vaccines, has renewed interest in immunotherapeutic approaches to the treatment of advanced prostate cancer. Although promising, none of these approaches have led to major clinical activity, and in the case of cell-based immunotherapy with GVAX, new concerns about safety arose when this therapy was used in the castration-resistant setting. A more attractive yet toxic approach has also utilized a check-point blockade with CTLA-4 antibodies. Although initial clinical efficacy has been observed, toxicity appears to be the major limitation of its use in prostate cancer. Sipuleucel-T (Provenge) is an autologous active cellular immunotherapy product that includes autologous dendritic cells pulsed ex vivo with PAP2024, a recombinant fusion protein made of prostatic acid phosphataase (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Despite the lack of objective anti-tumor activity seen with sipuleucel-T, a recently reported phase III trial demonstrated a significant improvement in the overall survival of men with asymptomatic, minimally symptomatic metastatic castration-resistant prostate cancer (CRPC). This agent is the first FDA-approved novel immunotherapeutic compound for the treatment of a solid malignancy. A better understanding of how clinicians should incorporate this novel agent into the current management of CRPC is needed.

  18. Eugenic and sexual folklores and the castration of sex offenders in the Netherlands (1938-1968).

    Science.gov (United States)

    van der Meer, Theo

    2008-06-01

    This contribution questions the positive/negative eugenics dichotomy that typifies the historiography on the eugenic movement in the Netherlands and the claim that this movement was mostly marginal because only positive eugenics was pursued. From 1938 to 1968 in the Netherlands, after a decade of debates, 400 sex offenders who had been committed to asylums for the criminally insane were 'voluntarily' and 'therapeutically' castrated. For political reasons debates on castration, meant to create consensus, eliminated any reference to or connotation with eugenics, yet these policies were unthinkable without them. This article shows that thinking about social and sexual problems and their solutions in the 1930s were permeated by eugenic folklore which in turn was informed by sexual folklore. Both eugenic and sexual lore, as common sense, or as ways of knowing, were about individual and collective loss of self control which was referred to with a catch-all phrase: 'hypersexuality'. Although sexual classifications used in diagnosing sex offenders suggested the existence of discrete sexual categories, homosexuality for instance was not seen as a sexual alternative or as an identity but as the extent to which an offender suffered from a form of hypersexuality that threatened the fabric of society.

  19. 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

  20. Comparison among gilts, physical castrates, entire males, and immunological castrates in terms of growth performance, nitrogen and phosphorus retention, and carcass fat iodine value.

    Science.gov (United States)

    Elsbernd, A J; Stalder, K J; Karriker, L A; Patience, J F

    2015-12-01

    The main objective was to determine the nitrogen and P retention and energy digestibility of immunological castrates (IC), entire males (EM), physical castrates (PC), and gilts (G) during 3 growth phases. A second objective was to compare growth performance among the sexes. The final objective was to determine the carcass iodine value (IV) among the sexes. Twelve individually housed pigs (PIC 337 × C22/29) of each sex with an initial mean BW of 35.7 ± 0.6 kg and a final BW of 145.0 ± 1.3 kg were evaluated. Anti-gonadotropin-releasing factor injections were administered at d 23 and 15 for groups 1 and 2, respectively. The second injection was given on d 56 of the 98-d experiment. Nitrogen, P, and energy digestibility were measured the last 3 d of the 10-d metabolism period starting at mean BW of 39.5 ± 0.6, 73.7 ± 0.8, and 105.5 ± 0.9 kg for periods 1, 2, and 3, respectively. The third collection started 14 d after the second injection. Entire males and IC had superior overall ADG compared to PC and G ( 0.05). In the third collection period, nitrogen retention of IC was similar to that of both EM and PC ( sexes in the first collection; during the second collection, EM retained the greatest amount of P, G and PC retained the lowest, with IC being similar to all sexes. For the third collection, IC had P retention similar to that of EM, EM had retention similar to that of PC, and PC had retention similar to that of G ( > 0.05). However, G retained less P than EM or IC ( sexes in any of the collection periods ( > 0.05). The jowl IV was the lowest in IC and PC and highest in EM, with G being similar to all sexes ( sexes being similar. In conclusion, 2 wk after the second injection, IC transition to become more similar to PC in terms of nitrogen utilization but are still similar to EM in P utilization. These data suggest a feeding program for IC that is intermediate between EM and PC is required to meet their nutritional requirements.

  1. The behavioral assessment and alleviation of pain associated with castration in beef calves treated with flunixin meglumine and caudal lidocaine epidural anesthesia with epinephrine.

    Science.gov (United States)

    Currah, Jan M; Hendrick, Steven H; Stookey, Joseph M

    2009-04-01

    The objectives of this study were 1) to determine the effects of flunixin megulmine in combination with caudal epidural anesthesia as a postoperative analgesic in beef calves following surgical castration, and 2) to consider stride length and pedometry as potential behavioral assessment tools for detecting postcastration pain. Surgical castration was performed in 101 beef calves randomly assigned to 3 treatment subgroups: 1) castration without anesthesia (SURG); 2) castration following lidocaine with epinephrine caudal epidural anesthesia (SURG + EPI); 3) castration following lidocaine with epinephrine caudal epidural anesthesia and flunixin meglumine (SURG + EPI + F). Several outcomes, including pedometer counts, changes in stride length, subjective visual assessment of pain, instantaneous scan sampling of the calves' postoperative activities, and the amount of movement and vocalization during the castration procedure, were measured to identify and quantify pain. The results indicated that stride length and the number of steps taken by calves after castration appear to be good measures of pain. Significant differences found between treatment groups for stride length and visual assessments suggest that flunixin meglumine can be considered to provide visible pain relief up to 8 hours postcastration.

  2. HDAC6 regulates androgen receptor hypersensitivity and nuclear localization via modulating Hsp90 acetylation in castration-resistant prostate cancer.

    Science.gov (United States)

    Ai, Junkui; Wang, Yujuan; Dar, Javid A; Liu, June; Liu, Lingqi; Nelson, Joel B; Wang, Zhou

    2009-12-01

    The development of castration-resistant prostate cancer (PCa) requires that under castration conditions, the androgen receptor (AR) remains active and thus nuclear. Heat shock protein 90 (Hsp90) plays a key role in androgen-induced and -independent nuclear localization and activation of AR. Histone deacetylase 6 (HDAC6) is implicated, but has not been proven, in regulating AR activity via modulating Hsp90 acetylation. Here, we report that knockdown of HDAC6 in C4-2 cells using short hairpin RNA impaired ligand-independent nuclear localization of endogenous AR and inhibited PSA expression and cell growth in the absence or presence of dihydrotestosterone (DHT). The dose-response curve of DHT-stimulated C4-2 colony formation was shifted by shHDAC6 such that approximately 10-fold higher concentration of DHT is required, indicating a requirement for HDAC6 in AR hypersensitivity. HDAC6 knockdown also inhibited C4-2 xenograft tumor establishment in castrated, but not in testes-intact, nude mice. Studies using HDAC6-deficient mouse embryonic fibroblasts cells showed that inhibition of AR nuclear localization by HDAC6 knockdown can be largely alleviated by expressing a deacetylation mimic Hsp90 mutant. Taken together, our studies suggest that HDAC6 regulates AR hypersensitivity and nuclear localization, mainly via modulating HSP90 acetylation. Targeting HDAC6 alone or in combination with other therapeutic approaches is a promising new strategy for prevention and/or treatment of castration-resistant PCa.

  3. Identification and Targeting of Candidate Pre-Existing Lurker Cells that Give Rise to Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2015-10-01

    progenitor cells as the pre-existing “lurker” cells in primary prostate tumors, to evaluate potential therapeutic targets in intermediate luminal... progenitor cells, and to define candidate biomarkers in intermediate luminal progenitor cells that can predict prognosis and response to hormonal therapy...15. SUBJECT TERMS Prostate, epithelial, Androgen-deprivation therapy, Castration-resistant prostate cancer, luminal progenitor , intermediate cell

  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. Sipuleucel-T: autologous cellular immunotherapy for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer.

    Science.gov (United States)

    Sims, Robert B

    2011-01-01

    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.

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

    OpenAIRE

    Sims, Robert B.

    2011-01-01

    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.

  7. 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

    Perineal glands in guinea pigs are part of the sebaceous glandular complex. Their secretions are used for scent marking. This is important for social status and can be seen in both sexes and castrated males. Discrepancy exits about the existence of these glands in female guinea pigs and knowledge...

  8. Effects of castration on the immunoreactivity to NGF, BDNF and their receptors in the pelvic ganglia of the male rat

    Directory of Open Access Journals (Sweden)

    C Squillacioti

    2009-08-01

    Full Text Available Nerve growth factor (NGF and brain derived neurotrophic factor (BDNF and are members of the neurotrophin family, a family of neurotrophic factors that also includes neurotrophin (NT 3 and NT4/5. Neurotrophins have essential roles in the survival, development and differentiation of neurons in the central and peripheral nervous systems. Neurotrophins exert their effects by binding to corresponding receptors which are formed by the tyrosine protein kinases TrkA, TrkB and TrkC, and the low affinity neurotrophic receptor (p75NTR. In the present study, using immunohistochemistry and quantitative analysis, we have investigated immunoreactivity to BDNF, NGF, TrkB, p75NTR and TrkA in the pelvic ganglia of normal and castrated rats. Neurons of the pelvic ganglia expressed both these neurotrophins and their receptors. After castration the immunoreactivity persisted. However, the number of BDNF- and p75NTR–IR cells statistically significant decreased after castration. These results suggest that castration modulates the expression of neurotrophins and their receptors in pelvic autonomic neurons.

  9. Identification and Targeting of Candidate Pre-Existing Lurker Cells that Give Rise to Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2014-10-01

    propagation. Lgr5+ intestinal stem cells can initiate and maintain murine intestinal adenomas (6, 7). In mouse models of skin cancer, hair follicle bulge...AWARD NUMBER: W81XWH-13-1-0470 TITLE: Identification and Targeting of Candidate Pre... Targeting of Candidate Pre-Existing Lurker Cells that Give Rise to 5a. CONTRACT NUMBER Castration-Resistant Prostate Cancer 5b

  10. 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

  11. Disease Progression/Clinical Outcome Model for Castration-Resistant Prostate Cancer in Patients Treated with Eribulin

    NARCIS (Netherlands)

    Van Hasselt, J. G C; Gupta, A.; Hussein, Z.; Beijnen, J. H.; Schellens, J. H M; Huitema, A. D R

    2015-01-01

    Frameworks that associate cancer dynamic disease progression models with parametric survival models for clinical outcome have recently been proposed to support decision making in early clinical development. Here we developed such a disease progression clinical outcome model for castration-resistant

  12. 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 a

  13. 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

  14. Steroid Hormones and Antihormones can Reverse the Castration Induced Stimulation of the Pineal and Adrenal Karyomorphology and Cell Proliferation in Mice (Mus musculus

    Directory of Open Access Journals (Sweden)

    S. Chakraborty

    2011-01-01

    Full Text Available In the present investigation, influence of castration and castrated animals supplemented with steroid hormones and antihormones on pineal-adrenal karyomorphology and dynamics were studied in post pubertal male mice. A group of thirty five mice were orchidectomized and (N = 7 sham operated, were kept in laboratory condition for 30 days. Such castrated were separately supplemented with estradiol at a dose of 5 g, testosterone at a dose of 100 g and antihormones, tamoxifen at a dose of 500 g and flutamide at 2 g daily (all at doses per 100 g.b.w. for ten consecutive days following thirty days of post castration. Present data reveal that both pineal and adrenal gland nuclear size and cell proliferation were significantly increased in thirty days post orchidectomized mice compared to control animals. The values are control pinealocyte nuclear diameter (dim: 4.750.06; castrated pinealocyte nuclear diameter (m: 5.340.04 (p<0.001. Control pineal M% 1.250.07; castrated pineal M% 2.020.11 (p<0.001. In control adrenal, representative of zones was Z. fasciculata nuclear diameter (m (5.110.04; castrated Z. fasciculata nuclear diameter (m 5.410.03 (p<0.001. Control adrenal M% (1.030.06 castrated adrenal M% (1.630.09 p<0.001. It was further observed that such pineal and adrenal stimulation in orchidectomized mice were significantly decreased when orchidectomized mice were administered with steroid hormones (estradiol and testosterone and antihormones (tamoxifen and flutamide compared to orchidectomized mice. Our study indicates that there exists a mutual stimulatory relationship between pineal and adrenal under conditions of steroid deprivation. However, exogenous administration of steroid hormones and antihormones to those castrated mice caused inhibition of these two peripheral endocrine glands.

  15. AB154. Testosterone improves erectile function through regulation of nicotinamide adenine dinucleotide phosphate-oxidase and cyclooxygenase-2 expression in castrated rats

    Science.gov (United States)

    Li, Rui; Wang, Tao; Yang, Jun; Zhang, Yan; Niu, Yonghua; Wang, Shaogang; Ye, Zhangqun; Rao, Ke; Liu, Jihong

    2015-01-01

    Objective Testosterone significantly improves hypogonadal-related erectile dysfunction (ED). However, the molecular mechanisms are poorly understood. The purpose of this study was to explore the effect and mechanism of testosterone in castrated rats. Methods Forty male Sprague-Dawley rats were randomized to 4 groups (control, sham-operated, castration and castration-with-testosterone-replacement). After 2 months, reactive oxygen species (ROS) production was measured by dihydroethidium (DHE) staining. Erectile function was tested by recording intracavernosal pressure (ICP) and mean arterial blood pressure (MAP). Protein expression levels were examined by Western blot. Results Castration reduced erectile function, and testosterone restored it. The concentrations of testosterone, cyclic guanosine mono-phosphate (cGMP) and cyclic adenosine monophosphate (cAMP) were lower in castrated rats than in controls, and testosterone restored these decreases (each P<0.05). The expression levels of cyclooxygenase-2 (COX-2), prostacyclin synthase (PTGIS or PGIS), endothelial nitric oxide synthase (eNOS) and phospho-eNOS were reduced in castrated rats compared with controls. The expression levels were significantly elevated in rats treated with testosterone (each P<0.05). The expression levels of p40phox and p67phox were increased in castrated rats, and testosterone significantly reduced these increases (each P<0.05). ROS production was markedly enhanced in castrated rats, and testosterone administration reversed this effect (P<0.05). Conclusions Testosterone can ameliorate ED after castration by reducing ROS production and increasing activity of the eNOS/cGMP and COX-2/PTGIS/cAMP signaling pathways.

  16. 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.

  17. Oxidative stress markers in Thoroughbred horses after castration surgery under inhalation anesthesia.

    Science.gov (United States)

    Tsuzuki, Nao; Sasaki, Naoki; Kusano, Kanichi; Endo, Yoshiro; Torisu, Shidow

    2016-01-01

    Oxidative stress has been reported to occur during surgery. It is important to reduce intraoperative oxidative stress to improve the postoperative prognosis. However, there are no reports regarding oxidative stress related to surgery in horses. In the present study, we measured pre and postsurgical diacron-reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP); the oxidative stress index (OSI) was then calculated (OSI=d-ROMs/BAP × 100). d-ROMs were not significantly different between the pre and postsurgical periods. However, BAP significantly decreased after surgery (P=0.02), and OSI significantly increased after surgery (P=0.02). Based on these results, it suggested that castration surgery under inhalation anesthesia decreases the antioxidant potential and causes oxidative stress in horses.

  18. [Treatment sequence using newly developed agents for men with castration resistant prostate cancer].

    Science.gov (United States)

    Fujimoto, Naohiro

    2014-12-01

    Abiraterone acetate(AA), enzalutamide (EZL) and cabazitaxel (CBZ) are becoming available in Japan. Clinical trials demonstrated the benefit of these agents in men with castration resistant prostate cancer (CRPC). However, data on sequence therapy using these agents are very limited. Based on the mechanisms of agents and clinical data, AA and EZL may be indicated in early stage and CBZ may be indicated in late stage of CRPC. Prostate cancer is significantly heterogeneous between individuals and useful biomarkers for deciding the best treatment are unavailable yet. Therefore, it is hard to establish a standard sequence of the treatments. Until clinical trials demonstrate the best treatment sequence, individualized therapy is required for each patient based on patient and disease characteristics.

  19. Physiological and Behavioural Responses in Piglets Submitted to Castration: Preliminary Study

    Directory of Open Access Journals (Sweden)

    Chiara Lonardi

    2011-12-01

    Movement latency was measured for all treatments. Rectal temperature was measured before treatments H and CTD, and 1, 3, 5, 24 hours later. Blood samples for cortisol and lactate determination were collected 1 hour before treatments H and CTD, right after and 3, 5, 24 hours later. The significant increase of movement latency for CTD compared to H showed that pain can be assessed by this type of measure. Rectal temperature was significantly affected by time (P < 0.01 but not by treatment likely due to several factors that might have confounded the studied effect. Cortisol was significantly affected by interaction time*treatment (P < 0.01 particularly due to the high peak for CTD right after the surgical procedure. Lactate was modified only by time (P < 0.01. This preliminary study suggests that a non invasive and easy measure such as movement latency is a promising method to assess pain in piglets after surgical castration and tail docking.

  20. Evolving landscape and novel treatments in metastatic castrate-resistant prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Paul J Toren; Martin E Gleave

    2013-01-01

    Treatment options for castrate-resistant prostate cancer (CRPC) have advanced in recent years and significantly improved the outlook for patients with this aggressive and lethal disease.Further understanding of the biologyof CRPC has led to several new targeted therapies and continues to emphasize the importance of androgen receptor (AR) directed therapy.The treatment landscape is rapidly changing and further biologically rationale,biomarker-based ongoing clinical trials are needed.We review the recent results of major clinical trials in CRPC.New and investigational agents now in clinical evaluation are reviewed including inhibitors of angiogenesis,microtubules,chaperones,AR and intracellular kinases,as well as immunotherapy,radiopharmaceuticals and bone-targeted agents.The recent improvement in prognosis for CRPC brings continued optimism for further improvements.Thoughtful planning of clinical trials and further understanding of the mechanisms of resistance to therapies will allow for continued progress in patient care.

  1. 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

    BACKGROUND: Continuous stimulation of the androgen receptor (AR) axis is a prerequisite for growth in castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) is a potent inhibitor of extracellular and intracellular androgen synthesis by inhibition of the CYP-17 enzyme system, which...... has been shown to be up-regulated in CRPC. AA was recently introduced in the management of patients with metastatic CRPC (mCRPC) both before and after taxane-based chemotherapy. The purpose of this study is to report the initial clinical experience obtained from mCRPC patients managed on AA......% of the patients. Time to biochemical and radiological progression was 3.5 and 4.9 months, respectively. Overall survival was 13.2 months (95% CI: 9.0-17.4). CONCLUSION: Our initial experience with AA in the routine management of patients with mCRPC demonstrates an efficacy-effectiveness gap compared with clinical...

  2. 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.

  3. 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.

  4. 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

    Sipuleucel-T was approved by the US Food and Drug Administration on April 29, 2010, as an immunotherapy for late-stage prostate cancer. To manufacture sipuleucel-T, mononuclear cells harvested from the patient are incubated with a recombinant prostatic acid phosphatase (PAP) antigen and reinfused....... The manufacturer proposes that antigen-presenting cells exogenously activated by PAP induce endogenous T-cells to attack PAP-bearing prostate cancer cells. However, the lack of demonstrable tumor responses has prompted calls for scrutiny of the design of the trials in which sipuleucel-T demonstrated a 4-month...... 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...

  5. Clinical use of abiraterone in the treatment of metastatic castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Zobniw CM

    2014-08-01

    Full Text Available Chrystia M Zobniw,1 Alanna Causebrook,2 Mei Ka Fong1 1Department of Pharmacy, Roswell Park Cancer Institute, Buffalo, NY, USA; 2School of Pharmacy, Lake Erie College of Osteopathic Medicine, Erie, PA, USA Abstract: Prostate cancer remains the most common type of cancer among men in the United States. Treatment for metastatic prostate cancer has improved significantly over the years with more and more agents improving overall survival. This review will address the pathophysiology of prostate cancer followed by the mechanism of action and the pharmacokinetic properties of abiraterone. The review will also discuss the role of abiraterone in the treatment of metastatic castrate-resistant prostate cancer. Keywords: glucocorticoid receptor, CYP17, pipeline, enzalutamide, sipuleucel-T, drug resistance, radium-223 dichloride

  6. Challenges to improved therapeutics for metastatic castrate resistant prostate cancer: from recent successes and failures

    Directory of Open Access Journals (Sweden)

    Huang Xuan

    2012-07-01

    Full Text Available Abstract Men with metastatic castration-resistant prostate cancer (mCRPC carry poor prognosis despite the use of docetaxel-based regimens which has modest survival benefit shown by randomized clinical trials. Significant progress in the discovery of novel therapeutic agents has been made in the past few years. While sipuleucel-T, cabazitaxel, and abiraterone gained regulatory approval in 2010 and 2011, several highly promising candidates/regimens have failed in large scale clinical trials. Challenges remain to optimize the design and interpretation of clinical trial results and develop more effective strategies for mCRPC. In this review, we examined the positive and negative clinical trials in mCRPC in the past and discussed the various aspects of clinical trial design including selection of targets and appropriate outcome measures, biomarker development and implementation, and strategies for combination therapy.

  7. Sipuleucel-T in patients with metastatic castration-resistant prostate cancer: an insight for oncologists.

    Science.gov (United States)

    Garcia, Jorge A

    2011-03-01

    Sipuleucel-T represents a novel immunotherapeutic compound designed to stimulate an immune response against castration-resistant prostate cancer (CRPC). Sipuleucel-T is an autologous active cellular immunotherapy product, which includes autologous dendritic cells pulsed ex vivo with PAP2024, a recombinant fusion protein made of prostatic acid phosphatase and granulocyte-macrophage colony-stimulating factor. Despite the lack of prostate-specific antigen and objective response, a recent phase III randomized trial demonstrated a significant improvement in overall survival in asymptomatic and minimally symptomatic CRPC patients. This review summarizes the clinical development of Sipuleucel-T in CRPC that led to the regulatory approval of this compound in the USA.

  8. 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

    , AND PARTICIPANTS: Metastatic castration-resistant prostate cancer patients entering one of four European compassionate use programmes of enzalutamide. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was overall survival (OS). Secondary end points were association between OS and posttreatment...... 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....... Patients who had more than 30% or 50% falls in PSA had improved survival compared with patients who had no such PSA fall (11.4 mo vs 7.1 mo; p=0.001 and 12.6 vs 7.4 mo; p=0.007, respectively). Poor performance status and low haemoglobin was negatively associated with OS. CONCLUSIONS: Median OS...

  9. Intraperitoneal administration of gonadotropin-releasing hormone-PE40 induces castration in male rats

    Institute of Scientific and Technical Information of China (English)

    Li Yu; Zhong-Fang Zhang; Chun-Xia Jing; Feng-Lin Wu

    2008-01-01

    AIM: To evaluate the long-term effects of gonadotropin-releasing hormone (GnRH)-based vaccine on levels of GnRH antibody and testosterone, and vaccine-induced immunocastration on sexual behavior of male rats.METHODS: The rats were treated with GnRH-PE40 intraperitoneally every other day for 12 wk. GnRH antibody and testosterone level in rat blood were determined by ELISA and radioimmunoassay, respectively. Morphological changes in testes and sexual behavior of rats were evaluated.RESULTS: GnRH-PE40 induced a high production in GnRH antibody, decreased the serum testosterone level, testis atrophy and sexual function in rats.CONCLUSION: Intraperitoneal administration of GnRH-PE40 produces structural and functional castration of male rat reproductive system by inducing anti-GnRH antibody.

  10. 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.

  11. [Castration anxiety and oral envy in sexual relations. Analytic studies with ethnological observations].

    Science.gov (United States)

    Gerlach, A

    1995-01-01

    Ethno-psychoanalysis is the study of the unconscious in foreign cultures. It can however also be of use in understanding unconscious elements operative in our own culture. To illustrate the point, the author describes the "Koro" epidemic which occurs periodically on the island of Hainan off the south of coast of China. This epidemic largely affects young unmarried men and the author pinpoints the unconscious conflicts underlying this collective phenomenon. It transpires that the epidemic is in effect a species of rite of passage in which a group of young males make the communal attempt to overcome castration anxieties which are themselves the product of covert gender envy. In the second section, Gerlach reports on his psychoanalytic encounter with a young man in Germany displaying similar symptoms. The profounder dimensions of this condition were only comprehensible to the author on account of his knowledge of "Koro".

  12. New strategies for medical management of castration-resistant prostate cancer.

    Science.gov (United States)

    Asmane, Irène; Céraline, Jocelyn; Duclos, Brigitte; Rob, Lynn; Litique, Valère; Barthélémy, Philippe; Bergerat, Jean-Pierre; Dufour, Patrick; Kurtz, Jean-Emmanuel

    2011-01-01

    Although advanced prostate cancer patients respond very well to front-line androgen deprivation, failure to hormonal therapy most often occurs after a median time of 18-24 months. The care of castration-resistant prostate cancer (CRPC) has significantly evolved over the past decade, with the onset of first-line therapy with docetaxel. Although numerous therapy schedules have been investigated alongside docetaxel, in either first-line or salvage therapy, results were dismal. However, CRPC chemotherapy is currently evolving, with, on the one hand, new agents targeting androgen metabolism and, on the other hand, significant progress in chemotherapy drugs, particularly for second-line therapy. The aim of the present review is to describe the current treatments for CRPC chemotherapy alongside their challengers that might shortly become new standards. In this article, we discuss the most recent data from clinical trials to provide the reader with a comprehensive, state-of-the-art overview of CRPC chemotherapy and hormonal therapy.

  13. 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.

  14. Mechanism of action and clinical activity of tasquinimod in castrate-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Gupta N

    2014-02-01

    Full Text Available Neha Gupta, Omar Al Ustwani, Li Shen, Roberto Pili Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA Abstract: Castrate-resistant prostate cancer (CRPC is a disease where survival is poor and treatment is challenging. Over the past 3 years, significant advances in the field have been made with US Food and Drug Administration approval of new drugs for patients with CRPC. However, despite the presence of new approved drugs such as enzalutamide, abiraterone, sipuleucel-T, cabazitaxel, and alpharadin, there is still an unmet need for novel agents with different mechanisms of action to target CRPC. Based on earlier studies demonstrating therapeutic potential of a quinoline-3-carboxamide agent roquinimex as an anticancer drug, efforts were directed to identify other useful members in this class. Tasquinimod is a second-generation quinoline-3-carboxamide agent that is currently in final stages of clinical development as a treatment for CRPC. The preclinical studies of tasquinimod have formed the basis for its success as an antiangiogenic and immunomodulatory agent in this disease. Tasquinimod is an orally available agent that has shown efficacy and favorable safety profile as deduced by the results of Phase I and II clinical trials of this drug in prostate cancer. The place of tasquinimod in the treatment of CRPC patients is currently under examination in an ongoing Phase III clinical trial. In this review, we will discuss tasquinimod, starting from its discovery and current knowledge on potential mechanisms of action to its clinical potential in CRPC. Keywords: ABR-215050, quinoline-3-carboxamide, prostate adenocarcinoma, castration resistant

  15. 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......-linked immunosorbent assay (ELISA). Treatment with EGF inhibited the involution of the prostate (P prostate involution as compared to castrated controls. EGF treatment significantly increased the endogenous rat EGF in the ventral prostate, but cellular...

  16. 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......-linked immunosorbent assay (ELISA). Treatment with EGF inhibited the involution of the prostate (P prostate involution as compared to castrated controls. EGF treatment significantly increased the endogenous rat EGF in the ventral prostate, but cellular...

  17. A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice.

    Science.gov (United States)

    Fokidis, H Bobby; Yieng Chin, Mei; Ho, Victor W; Adomat, Hans H; Soma, Kiran K; Fazli, Ladan; Nip, Ka Mun; Cox, Michael; Krystal, Gerald; Zoubeidi, Amina; Tomlinson Guns, Emma S

    2015-06-01

    Dietary factors continue to preside as dominant influences in prostate cancer prevalence and progression-free survival following primary treatment. We investigated the influence of a low carbohydrate diet, compared to a typical Western diet, on prostate cancer (PCa) tumor growth in vivo. LNCaP xenograft tumor growth was studied in both intact and castrated mice, representing a more advanced castration resistant PCa (CRPC). No differences in LNCaP tumor progression (total tumor volume) with diet was observed for intact mice (P = 0.471) however, castrated mice on the Low Carb diet saw a statistically significant reduction in tumor growth rate compared with Western diet fed mice (P = 0.017). No correlation with serum PSA was observed. Steroid profiles, alongside serum cholesterol and cholesteryl ester levels, were significantly altered by both diet and castration. Specifically, DHT concentration with the Low Carb diet was 58% that of the CRPC-bearing mice on the Western diet. Enzymes in the steroidogenesis pathway were directly impacted and tumors isolated from intact mice on the Low Carb diet had higher AKR1C3 protein levels and lower HSD17B2 protein levels than intact mice on the Western diet (ARK1C3: P = 0.074; HSD17B2: P = 0.091, with α = 0.1). In contrast, CRPC tumors from mice on Low Carb diets had higher concentrations of both HSD17B2 (P = 0.016) and SRD5A1 (P = 0.058 with α = 0.1) enzymes. There was no correlation between tumor growth in castrated mice for Low Carb diet versus Western diet and (a) serum insulin (b) GH serum levels (c) insulin receptor (IR) or (d) IGF-1R in tumor tissue. Intact mice fed Western diet had higher serum insulin which was associated with significantly higher blood glucose and tumor tissue IR. We conclude that both diet and castration have a significant impact on the endocrinology of mice bearing LNCaP xenograft tumors. The observed effects of diet on cholesterol and steroid regulation impact tumor tissue DHT specifically and are

  18. EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor.

    Science.gov (United States)

    De Mol, Eva; Fenwick, R Bryn; Phang, Christopher T W; Buzón, Victor; Szulc, Elzbieta; de la Fuente, Alex; Escobedo, Albert; García, Jesús; Bertoncini, Carlos W; Estébanez-Perpiñá, Eva; McEwan, Iain J; Riera, Antoni; Salvatella, Xavier

    2016-09-16

    Castration-resistant prostate cancer is the lethal condition suffered by prostate cancer patients that become refractory to androgen deprivation therapy. EPI-001 is a recently identified compound active against this condition that modulates the activity of the androgen receptor, a nuclear receptor that is essential for disease progression. The mechanism by which this compound exerts its inhibitory activity is however not yet fully understood. Here we show, by using high resolution solution nuclear magnetic resonance spectroscopy, that EPI-001 selectively interacts with a partially folded region of the transactivation domain of the androgen receptor, known as transactivation unit 5, that is key for the ability of prostate cells to proliferate in the absence of androgens, a distinctive feature of castration-resistant prostate cancer. Our results can contribute to the development of more potent and less toxic novel androgen receptor antagonists for treating this disease.

  19. Sexual differentiation of oxytocin stress responsiveness: effect of neonatal androgenization, castration and a luteinizing hormone-releasing hormone antagonist.

    Science.gov (United States)

    Carter, D A; Saridaki, E; Lightman, S L

    1988-04-01

    The plasma OT increment following stress in rats is sexually dimorphic, females exhibiting greater responses than males. We have investigated the role of neonatal androgen secretion in determining the sex-typical level of response. Castration of male pups either surgically or functionally (GnRH antagonist treatment) within either 2 h or 5 days of birth did not elevate the OT responses of adult males. In contrast, androgenization of female pups (testosterone, 1.25 mg/pup) within 5 days of birth markedly reduced the OT stress responses of adults to a level insignificantly different to males. The results show that neonatal androgens can exert organizational effects on OT regulatory mechanisms. Since neonatal castration was ineffective it would appear that a prenatal defeminization or masculinization event determines OT stress responsiveness in males.

  20. N-Cadherin in Prostate Cancer: Downstream Pathways and their Translational Application for Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2012-09-01

    Prostate Center, University of British Columbia, Vancouver, British Columbia, Canada. 5Department of Pathology , Geffen School of Medicine, University...Medicine: doi:10.1038/nm.2236 a 0 .000 -0.100 BPH 0 .011 Untreated ( all grades) NHT treated ( all the time points) Recurrent ( documented...antibody (Clone32, BD Transduction Laboratories). (a) BPH : benign prostate hyperplasia; NHT: neoadjuvant hormone therapy; CRPC: castrate resistant

  1. Piecing the Puzzle Together: Docetaxel Cycles and Current Considerations in the Treatment of Metastatic Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Feinman, Hannah E; Price, Douglas K; Figg, William D

    2017-02-25

    Docetaxel is the current first line therapy for metastatic castration-resistant prostate cancer (mCRPC), but there is no standard number of docetaxel cycles given to patients. In their post hoc analysis of the Mainsail study, de Morrée et al. show that the number of docetaxel cycles administered to a patient is a significant factor contributing to overall survival. These findings warrant further investigation into the standardization of the number of docetaxel cycles administered.

  2. 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.

  3. Development of the Horse Grimace Scale (HGS as a pain assessment tool in horses undergoing routine castration.

    Directory of Open Access Journals (Sweden)

    Emanuela Dalla Costa

    Full Text Available BACKGROUND: The assessment of pain is critical for the welfare of horses, in particular when pain is induced by common management procedures such as castration. Existing pain assessment methods have several limitations, which reduce the applicability in everyday life. Assessment of facial expression changes, as a novel means of pain scoring, may offer numerous advantages and overcome some of these limitations. The objective of this study was to develop and validate a standardised pain scale based on facial expressions in horses (Horse Grimace Scale [HGS]. METHODOLOGY/PRINCIPAL FINDINGS: Forty stallions were assigned to one of two treatments and all animals underwent routine surgical castration under general anaesthesia. Group A (n = 19 received a single injection of Flunixin immediately before anaesthesia. Group B (n = 21 received Flunixin immediately before anaesthesia and then again, as an oral administration, six hours after the surgery. In addition, six horses were used as anaesthesia controls (C. These animals underwent non-invasive, indolent procedures, received the same treatment as group A, but did not undergo surgical procedures that could be accompanied with surgical pain. Changes in behaviour, composite pain scale (CPS scores and horse grimace scale (HGS scores were assessed before and 8-hours post-procedure. Only horses undergoing castration (Groups A and B showed significantly greater HGS and CPS scores at 8-hours post compared to pre operatively. Further, maintenance behaviours such as explorative behaviour and alertness were also reduced. No difference was observed between the two analgesic treatment groups. CONCLUSIONS: The Horse Grimace Scale potentially offers an effective and reliable method of assessing pain following routine castration in horses. However, auxiliary studies are required to evaluate different painful conditions and analgesic schedules.

  4. Partial response of liver metastases treated with abiraterone in castration-resistant prostate cancer: A case report

    OpenAIRE

    Marech,Ilaria; Vacca, Angelo; SIVESTRIS, NICOLA; Gnoni,Antonio; Lorusso, Vito

    2013-01-01

    Docetaxel is the current first-line treatment for castration-resistant prostate cancer (CRPC), following failure to respond to maximal androgen blockade (MAB). Patients who fail to respond to docetaxel may receive cabazitaxel or abiraterone; however, there are no recommendations on which of these two agents should be used first. Here, we present a case of a male patient suffering from CRPC with liver and lymph node metastases, in which abiraterone achieved a partial response, according to REC...

  5. 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.

  6. Cabozantinib inhibits growth of androgen-sensitive and castration-resistant prostate cancer and affects bone remodeling.

    Directory of Open Access Journals (Sweden)

    Holly M Nguyen

    Full Text Available Cabozantinib is an inhibitor of multiple receptor tyrosine kinases, including MET and VEGFR2. In a phase II clinical trial in advanced prostate cancer (PCa, cabozantinib treatment improved bone scans in 68% of evaluable patients. Our studies aimed to determine the expression of cabozantinib targets during PCa progression and to evaluate its efficacy in hormone-sensitive and castration-resistant PCa in preclinical models while delineating its effects on tumor and bone. Using immunohistochemistry and tissue microarrays containing normal prostate, primary PCa, and soft tissue and bone metastases, our data show that levels of MET, P-MET, and VEGFR2 are increasing during PCa progression. Our data also show that the expression of cabozantinib targets are particularly pronounced in bone metastases. To evaluate cabozantinib efficacy on PCa growth in the bone environment and in soft tissues we used androgen-sensitive LuCaP 23.1 and castration-resistant C4-2B PCa tumors. In vivo, cabozantinib inhibited the growth of PCa in bone as well as growth of subcutaneous tumors. Furthermore, cabozantinib treatment attenuated the bone response to the tumor and resulted in increased normal bone volume. In summary, the expression pattern of cabozantinib targets in primary and castration-resistant metastatic PCa, and its efficacy in two different models of PCa suggest that this agent has a strong potential for the effective treatment of PCa at different stages of the disease.

  7. Comparative Aroma Extract Dilution Analysis (cAEDA) of Fat from Tainted Boars, Castrated Male Pigs, and Female Pigs.

    Science.gov (United States)

    Gerlach, Christoph; Leppert, Jan; Santiuste, Alicia Chamarro; Pfeiffer, Anne; Boeker, Peter; Wüst, Matthias

    2017-01-12

    The aroma profile of porcine fat from tainted boars, female pigs, and castrated male pigs was investigated by application of comparative aroma extract dilution analysis (cAEDA) on a SAFE distillate of volatiles prepared from porcine back fat samples. The AEDA resulted in a total of 16 aroma active compounds for boar fat with flavor dilution (FD) factors ranging from 2 to 2048, whereas 12 aroma active compounds were found in fat of female pigs and 14 in fat of castrated male pigs, both with FD factors ranging from 2 to 32. Odor activity values (OAVs) of key components for each fat were identified: In boar fat androstenone, skatole, indole, and 2-aminoacetophenone showed highest OAVs, whereas 2,5-dimethylpyrazine, 2,4-decadienal, and δ-decalactone showed highest OAVs in fat of female pigs. Fat of castrated male pigs showed highest OAVs for skatole, indole, 1-octen-3-ol and methional. Finally, the off-flavor attributes of boar fat were successfully simulated by a recombinant of all odorants at their natural concentration level in deodorized sunflower oil.

  8. 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.

  9. 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

  10. Castration induces up-regulation of intratumoral androgen biosynthesis and androgen receptor expression in an orthotopic VCaP human prostate cancer xenograft model.

    Science.gov (United States)

    Knuuttila, Matias; Yatkin, Emrah; Kallio, Jenny; Savolainen, Saija; Laajala, Teemu D; Aittokallio, Tero; Oksala, Riikka; Häkkinen, Merja; Keski-Rahkonen, Pekka; Auriola, Seppo; Poutanen, Matti; Mäkelä, Sari

    2014-08-01

    Androgens are key factors involved in the development and progression of prostate cancer (PCa), and PCa growth can be suppressed by androgen deprivation therapy. In a considerable proportion of men receiving androgen deprivation therapy, however, PCa progresses to castration-resistant PCa (CRPC), making the development of efficient therapies challenging. We used an orthotopic VCaP human PCa xenograft model to study cellular and molecular changes in tumors after androgen deprivation therapy (castration). Tumor growth was monitored through weekly serum prostate-specific antigen measurements, and mice with recurrent tumors after castration were randomized to treatment groups. Serum prostate-specific antigen concentrations showed significant correlation with tumor volume. Castration-resistant tumors retained concentrations of intratumoral androgen (androstenedione, testosterone, and 5α-dihydrotestosterone) at levels similar to tumors growing in intact hosts. Accordingly, castration induced up-regulation of enzymes involved in androgen synthesis (CYP17A1, AKR1C3, and HSD17B6), as well as expression of full-length androgen receptor (AR) and AR splice variants (AR-V1 and AR-V7). Furthermore, AR target gene expression was maintained in castration-resistant xenografts. The AR antagonists enzalutamide (MDV3100) and ARN-509 suppressed PSA production of castration-resistant tumors, confirming the androgen dependency of these tumors. Taken together, the findings demonstrate that our VCaP xenograft model exhibits the key characteristics of clinical CRPC and thus provides a valuable tool for identifying druggable targets and for testing therapeutic strategies targeting AR signaling in CRPC.

  11. Intratumoral steroidogenesis in castration-resistant prostate cancer: a target for therapy.

    Science.gov (United States)

    Armandari, Inna; Hamid, Agus Rizal; Verhaegh, Gerald; Schalken, Jack

    2014-09-01

    Development of castration-resistant prostate cancer (CRPC) in a low androgen environment, arising from androgen deprivation therapy (ADT), is a major problem in patients with advanced prostate cancer (PCa). Several mechanisms have been hypothesized to explain the progression of PCa to CRPC during ADT, one of them is so called persistent intratumoral steroidogenesis. The existence of intratumoral steroidogenesis was hinted based on the residual levels of intraprostatic testosterone (T) and dihydrotestosterone (DHT) after ADT. Accumulating evidence has shown that the intraprostatic androgen levels after ADT are sufficient to induce cancer progression. Several studies now have demonstrated that PCa cells are able to produce T and DHT from different androgen precursors, such as cholesterol and the adrenal androgen, dehydroepiandrosterone (DHEA). Furthermore, up-regulation of genes encoding key steroidogenic enzymes in PCa cells seems to be an indicator for active intratumoral steroidogenesis in CRPC cells. Currently, several drugs are being developed targeting those steroidogenic enzymes, some of which are now in clinical trials or are being used as standard care for CRPC patients. In the future, novel agents that target steroidogenesis may add to the arsenal of drugs for CRPC therapy.

  12. 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.

  13. Aurora A regulates expression of AR-V7 in models of castrate resistant prostate cancer

    Science.gov (United States)

    Jones, Dominic; Noble, Martin; Wedge, Steve R.; Robson, Craig N.; Gaughan, Luke

    2017-01-01

    Androgen receptor variants (AR-Vs) provide a mechanism of therapy evasion in castrate-resistant prostate cancer (CRPC), yet mechanisms of regulation remain largely unknown. Here we investigate the role of Aurora A kinase on AR-Vs in models of CRPC and show depletion of Aurora A reduces AR-V target gene expression. Importantly, knockdown of Aurora A reconfigures splicing of AR pre-mRNA to discriminately down-regulate synthesis of AR-V transcripts, including AR-V7, without effecting full-length AR mRNA; and as a consequence, AR-V-driven proliferation and survival of CRPC cells is markedly reduced. Critically, these effects are reproduced by Aurora A inhibition. We show that Aurora A levels increase in advanced disease and AURKA is an AR-V target gene demonstrating a positive feedback mechanism of androgenic signalling in CRPC. In all, our data suggests that Aurora A plays a pivotal role in regulation of AR-V7 expression and represents a new therapeutic target in CRPC. PMID:28205582

  14. Recent Progress in Pharmaceutical Therapies for Castration-Resistant Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Qingzhong Hu

    2013-07-01

    Full Text Available Since 2010, six drugs have been approved for the treatment of castration-resistant prostate cancer, i.e., CYP17 inhibitor Abiraterone, androgen receptor antagonist Enzalutamide, cytotoxic agent Cabazitaxel, vaccine Sipuleucel-T, antibody Denosumab against receptor activator of nuclear factor kappa B ligand and radiopharmaceutical Alpharadin. All these drugs demonstrate improvement on overall survival, expect for Denosumab, which increases the bone mineral density of patients under androgen deprivation therapy and prolongs bone-metastasis-free survival. Besides further CYP17 inhibitors (Orteronel, Galeterone, VT-464 and CFG920, androgen receptor antagonists (ARN-509, ODM-201, AZD-3514 and EZN-4176 and vaccine Prostvac, more drug candidates with various mechanisms or new indications of launched drugs are currently under evaluation in different stages of clinical trials, including various kinase inhibitors and platinum complexes. Some novel strategies have also been proposed aimed at further potentiation of antitumor effects or reduction of side effects and complications related to treatments. Under these flourishing circumstances, more investigations should be performed on the optimal combination or the sequence of treatments needed to delay or reverse possible resistance and thus maximize the clinical benefits for the patients.

  15. Economic evaluation of sipuleucel-T immunotherapy in castration-resistant prostate cancer.

    Science.gov (United States)

    Holko, Przemysław; Kawalec, Paweł

    2014-01-01

    The objective is to examine the cost-utility of sipuleucel-T immunotherapy in asymptomatic or minimally symptomatic castration-resistant prostate cancer patients. The addition of sipuleucel-T immunotherapy to standard treatment led to a gain of 0.37 quality-adjusted life-year (QALY) at an additional cost of US$104,536. The incremental cost-utility ratio was US$283,000 per QALY saved. Threshold sensitivity analyses indicated that a price reduction of at least 53%, or application in a group of patients resulting in the relative reduction in the mortality rate of at least 39%, ought to augment the economic value of this regimen. Sipuleucel-T immunotherapy treatment at the current price with 96.5% certainty is not cost-effective. The specific group of patients who will benefit more from the treatment should be revealed and treated, or the cost of the vaccine should be lowered significantly to increase its economic value. Accounting for crossover treatment in control patients improves sipuleucel-T's value (US$132,000 per QALY saved) although further investigation is necessary.

  16. Current paradigms and evolving concepts in metastatic castration-resistant prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Snmanta Krnmar Pal; Oliver Sartor

    2011-01-01

    @@ Until recently,docetaxel-based therapy represented the only therapy shown to prolong survival in patients with metastatic castration-resistant prostate cancer (mCRPC).The past year and a half has been marked by unprecedented progress in treatments for this disease.Three positive phase III clinical trials have emerged,each evaluating agents (sipuleucel-T,cabazitaxel and abiraterone)with distinct mechanisms of action.Herein,the three pivotal trials are described alongside both past and current large phase III studies conducted in this mCRPC.The overall survival for patients with mCRPC treated in current clinical trials is considerably longer than noted in the past.We note that more recent trials with older agents have also shown improved survival and discuss potential non-therapeutic biases that influence this critical measure of outcome.The necessity for utilizing randomized trials when evaluating new therapeutics is emphasized given the changing prognosis in this mCRPC.

  17. Contemporary agents in the management of metastatic castration-resistant prostate cancer

    Science.gov (United States)

    Kapoor, Anil; Wu, Christopher; Shayegan, Bobby; Rybak, Adrian P.

    2016-01-01

    Docetaxel-based chemotherapy has been the standard of care for metastatic castration-resistant prostate cancer (mCRPC) since 2004. Over the past few years, there has been a significant paradigm shift in the treatment landscape of this disease. A deeper understanding of prostate cancer biology, along with the development of novel agents has created hope towards treating chemotherapy-naïve and resistant disease. Following the implementation of docetaxel as the first-line therapy for mCRPC, five novel therapies have demonstrated survival benefit in mCRPC. Cabazitaxel, abiraterone acetate, and enzalutamide are three agents recently approved for the treatment of mCRPC, having shown overall survival benefit in patients previously treated with docetaxel, while both abiraterone acetate and enzalutamide have also shown promise in the pre-docetaxel setting. Sipuleucel-T has shown overall survival benefit in asymptomatic mCRPC, while radium-223 provides survival benefit to patients with mCRPC who are symptomatic from their skeletal metastases in both docetaxel-naïve patients and post-docetaxel patients. Denosumab, an anti-RANKL antibody, has been approved for the prevention of skeletal-related events in patients with prostate cancer bone metastases. This review examines the phase 3 trials supporting the use of theses novel agents in the treatment of mCRPC. While these agents provide incremental increases in patient survival, further study to determine the best choice, combination, and/or sequencing of administration is still necessary. PMID:28096932

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

    Science.gov (United States)

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

    2012-02-22

    Sipuleucel-T was approved by the US Food and Drug Administration on April 29, 2010, as an immunotherapy for late-stage prostate cancer. To manufacture sipuleucel-T, mononuclear cells harvested from the patient are incubated with a recombinant prostatic acid phosphatase (PAP) antigen and reinfused. The manufacturer proposes that antigen-presenting cells exogenously activated by PAP induce endogenous T-cells to attack PAP-bearing prostate cancer cells. However, the lack of demonstrable tumor responses has prompted calls for scrutiny of the design of the trials in which sipuleucel-T demonstrated a 4-month 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-thirds of the cells harvested from placebo patients, but not from the sipuleucel-T arm, were frozen and not reinfused, a detrimental effect of this large repeated cell loss provides a potential alternative explanation for the survival "benefit." Patient safety depends on adequately addressing this alternative explanation for the trial results.

  19. Experience with octreotide depot in the treatment of castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    G. P. Kolesnikov

    2015-01-01

    Full Text Available Castration-resistant prostate cancer (CRPC is one of the most complex and unsolved problems in urologic oncology. The somatostatin analogue octreotide depot made in Russia may be used for its treatment. The paper gives the results of a trial of the efficiency and safety of treatment with octreotide depot 30 mg and dexamethasone in 20 patients aged 58 to 89 years with CRPC during continued androgen deprivation therapy. The duration of the trial was 3 months. A response was assessed from the serum levels of prostate-specific antigen (PCA, the time course of changes in general and biochemical blood test values, the degree of pain syndrome, and improvement in quality of life in a patient. A total response in reducing PSA was obtained in 70 % of the patents; overall, the best results were achieved in the group receiving octreotide before chemotherapy with docetaxel. The tolerability of octreotide deport with dexamethasone was good in all cases; no obvious adverse hematological and clinical reactions were noted.

  20. 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.

  1. Docetaxel Rechallenge in a Heavily Pretreated Patient With Castration-Resistant Prostate Cancer

    Science.gov (United States)

    Di Lorenzo, Giuseppe; Pagliuca, Martina; Perillo, Teresa; Benincasa, Alfonso; Bosso, Davide; De Placido, Sabino; Buonerba, Carlo

    2016-01-01

    Abstract Chemotherapy agents for patients with metastatic castration-resistant prostate cancer (mCRPC) include docetaxel and cabazitaxel. Although docetaxel is approved in the first-line treatment setting, a few studies have shown that selected patients can benefit from docetaxel rechallenge. We, here, report the case of a heavily pretreated mCRPC patient who reported clinical benefit from receiving docetaxel after previous exposure to docetaxel, cabazitaxel, abiraterone, and enzalutamide. After 4 cycles of treatment, patient's performance status had improved to 1, the hemoglobin level was 12.9 g/dL and his serum prostate specific antigen levels were reduced by >70%, with no treatment-related adverse events. Although docetaxel rechallenge is a therapeutic option for selected patients, the risk of cumulative toxicity described in literature must be carefully considered. As the risk of cabazitaxel-related cumulative toxicity is probably lower, retreatment with cabazitaxel rather than docetaxel may also be an option in the setting of heavily pretreated mCRPC patients. PMID:27057826

  2. Cabazitaxel for Metastatic Castration-Resistant Prostate Cancer: Retrospective Data Analysis from an Indian Centre

    Directory of Open Access Journals (Sweden)

    Vanita Noronha

    2016-08-01

    Full Text Available Objective: To determine the efficacy and safety of cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC patients from the named patient programme (NPP at our centre. Methods: mCRPC patients who progressed on docetaxel were given cabazitaxel intravenously every 3 weeks until disease progression or unacceptable toxicity occurred. Overall survival, progression-free survival, prostate-specific antigen response, quality of life (QOL changes, and safety were reported. Results: Nine men received cabazitaxel (median: 7 cycles; range: 1–27 under the NPP and were followed until death. Median survival was 14.07 months (1.07–23.80 and progression-free survival was 2.67 months (1.07–20.27. QOL was stable for most patients. Common adverse events (grade ≥3 were neutropenia (n = 8, anaemia (n = 4, and leucopenia (n = 4. Conclusion: These data from 9 patients are consistent with the results reported in the TROPIC study with a manageable safety profile.

  3. Comparison of methods for the reduction of acute pain produced by rubber ring castration or tail docking of week-old lambs.

    Science.gov (United States)

    Kent, J E; Molony, V; Graham, M J

    1998-01-01

    Behavioural and plasma cortisol changes were recorded for groups of eight Suffolk x Greyface lambs subjected to castration or tail docking using rubber rings with and without local anaesthetic treatment. Immediately after application of the rubber ring, local anaesthetic (2 x 0.2 ml 2% lignocaine) was administered either by needle and syringe or by high-pressure needleless injection into each side of the neck of the scrotum or tail at the site of the ring, or by high pressure needleless injection into the testes before ring application. In other groups, the innervation to the scrotum or tail was disabled by crushing with a powered bloodless castrator just proximal to the ring. Measurements were recorded in groups of control (handled) lambs, with and without local anaesthetic treatment. Application of local anaesthetic by high pressure needleless injection had little effect on either plasma cortisol values or behaviour of control lambs. For castration, application of the bloodless castrator and/or local anaesthetic at the ring site reduced the peak plasma cortisol concentration by 50% (P 0.05)]. Injection of local anaesthetic into the testes was less effective than injection into the neck of the scrotum at the site of the ring [reduction in abnormal lying postures (P < or = 0.05), 45 vs 71%, respectively]. The rapid action, effectiveness, and ease of application of these experimental methods may provide the basis for commercially viable methods for reducing the acute pain produced by rubber ring castration and tail docking of lambs.

  4. Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial

    NARCIS (Netherlands)

    Saad, F.; Fizazi, K.; Jinga, V.; Efstathiou, E.; Fong, P.C.; Hart, L.L.; Jones, R.; McDermott, R.; Wirth, M.; Suzuki, K.; MacLean, D.B.; Wang, L.; Akaza, H.; Nelson, J.; Scher, H.I.; Dreicer, R.; Webb, I.J.; Wit, R. de; Oort, I.M. van

    2015-01-01

    BACKGROUND: Orteronel is an investigational, partially selective inhibitor of CYP 17,20-lyase in the androgen signalling pathway, a validated therapeutic target for metastatic castration-resistant prostate cancer. We assessed orteronel in chemotherapy-naive patients with metastatic castration-resist

  5. Lean meat prediction with HGP, CGM and CSB-Image-Meater, with prediction accuracy evaluated for different proportions of gilts, boars and castrated boars in the pig population.

    Science.gov (United States)

    Engel, B; Lambooij, E; Buist, W G; Vereijken, P

    2012-02-01

    Prediction equations for the percentage lean meat in pig carcasses in The Netherlands were derived for the Hennessy Grading Probe 7, Capteur Gras/Maigre--Sydel and CSB-Image-Meater. Because castrated males are expected to vanish from the Dutch pig population in the near future, accuracy of prediction was evaluated for different scenarios representing a wide range of different proportions for entire males, castrated males and females in the Dutch pig population. The prediction equations for the instruments are in compliance with the EC regulations for prediction accuracy for the different scenarios. So, these equations will remain valid when castrated males are (gradually) removed from the Dutch slaughter population. Results of this study are of interest for researchers from countries or areas contemplating the use of one of the aforementioned instruments. The statistical approach for evaluation of prediction accuracy is of particular interest when changes in proportions of important subpopulations in the target population are foreseen.

  6. Response of male mice to odours of female mice in different stages of oestrous cycle: self-grooming behaviour and the effect of castration.

    Science.gov (United States)

    Achiraman, Shanmugam; SankarGanesh, Devaraj; Kannan, Soundarapandian; Kamalakkannan, Soundararajan; Nirmala, Natarajan; Archunan, Govindaraju

    2014-01-01

    The behavioural assays were carried out in a Y-maze wherein intact, castrated and testosterone-treated male mice were exposed to oestrus and non-oestrus urine samples. The intact male mice investigated more frequently and spent more time in the Y-maze arm with oestrus urine than in that with non-oestrus urine. In contrast, the castrated mice were not attracted to oestrus urine, whereas testosterone-treated mice showed preference for oestrus urine. The rate of self-grooming was higher in intact males in case of exposure to oestrus urine while the rate was lower with respect to non-oestrus urine. However, castrated mice exhibited less self-grooming behaviour which was partially restored by testosterone treatment. The results suggest that self-grooming behaviour is an indicator of detection and discrimination of oestrus by males, and supports the androgen role in male chemosensory ability to discriminate between oestrus and non-oestrus female odours.

  7. 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.

  8. Curcumin induces apoptosis and protective autophagy in castration-resistant prostate cancer cells through iron chelation

    Science.gov (United States)

    Yang, Chunguang; Ma, Xueyou; Wang, Zhihua; Zeng, Xing; Hu, Zhiquan; Ye, Zhangqun; Shen, Guanxin

    2017-01-01

    Background Curcumin induces apoptosis and autophagy in different cancer cells. Moreover, chemical and biological experiments have evidenced that curcumin is a biologically active iron chelator and induces cytotoxicity through iron chelation. We thus hypothesized that curcumin may induce apoptosis and autophagy in castration-resistant prostate cancer (CRPC) cells through its iron-chelating properties. Materials and methods CRPC cells were loaded with curcumin alone or in combination with ferric ammonium citrate (FAC). Cytotoxicity was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was assessed by flow cytometry, terminal deoxynucleotidyl transferase nick end labeling (TUNEL) assay and caspase activity. Autophagy status was analyzed by the detection of autophagosomes and light chain 3-II (LC3-II) using transmission electron microscopy and Western blot. Iron-binding activity of curcumin was assessed by spectrophotometry and MTT assay. The expression levels of transferrin receptor 1 (TfR1) and iron regulatory protein 1 (IRP1) were examined by Western blot. Results Curcumin induced apoptosis and autophagy in CRPC cells. Combining curcumin with autophagy inhibitors (3-methyladenine [3-MA]) synergized the apoptotic effect of curcumin. Moreover, curcumin bound to FAC at a ratio of ~1:1, as assessed by spectrophotometry and MTT assay. Apoptosis and autophagy induced by curcumin were counteracted by equal amounts of FAC. At apoptosis- and autophagy-inducing concentrations, curcumin enhanced the expression levels of TfR1 and IRP1, indicative of iron deprivation induced by curcumin. Conclusion Together, our results indicate that curcumin induces apoptosis and protective autophagy in CRPC cells, which are at least partially dependent on its iron-chelating properties. PMID:28243065

  9. Enzalutamide: targeting the androgen signalling pathway in metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Schalken, Jack; Fitzpatrick, John M

    2016-02-01

    Significant progress has been made in the understanding of the underlying cancer biology of castration-resistant prostate cancer (CRPC) with the androgen receptor (AR) signalling pathway remaining implicated throughout the prostate cancer disease continuum. Reactivation of the AR signalling pathway is considered to be a key driver of CRPC progression and, as such, the AR is a logical target for therapy in CRPC. The objective of this review was to understand the importance of AR signalling in the treatment of patients with metastatic CRPC (mCRPC) and to discuss the clinical benefits associated with inhibition of the AR signalling pathway. A search was conducted to identify articles relating to the role of AR signalling in CRPC and therapies that inhibit the AR signalling pathway. Current understanding of prostate cancer has identified the AR signalling pathway as a logical target for the treatment of CRPC. Available therapies that inhibit the AR signalling pathway include AR blockers, androgen biosynthesis inhibitors, and AR signalling inhibitors. Enzalutamide, the first approved AR signalling inhibitor, has a novel mode of action targeting AR signalling at three key stages. The direct mode of action of enzalutamide has been shown to translate into clinical responses in patients with mCRPC. In conclusion, the targeting of the AR signalling pathway in patients with mCRPC results in numerous clinical benefits. As the number of treatment options increase, more trials evaluating the sequencing and combination of treatments are required. This review highlights the continued importance of targeting a key driver in the progression of CRPC, AR signalling, and the clinical benefits associated with inhibition of the AR signalling pathway in the treatment of patients with CRPC.

  10. Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Mark N Stein; Neal Patel; Alexander Bershadskiy; Alisa Sokoloff; Eric A Singer

    2014-01-01

    Suppression of gonadal testosterone synthesis represents the standard ifrst line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer (CRPC), it is possible to detect persistent activation of the androgen receptor (AR) through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17α-hydroxylase and 17,20-lyase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a signiifcant improvement in overall survival (OS) with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17α-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone (ACTH), providing a rationale for development of CYP17 inhibitors with increased speciifcity for 17,20-lyase (orteronel, galeterone and VT-464) that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors;recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents;and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone beneift or restore abiraterone activity.

  11. Use of prednisone with abiraterone acetate in metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Auchus, Richard J; Yu, Margaret K; Nguyen, Suzanne; Mundle, Suneel D

    2014-12-01

    Abiraterone acetate, a prodrug of the CYP17A1 inhibitor abiraterone that blocks androgen biosynthesis, is approved for treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) in combination with prednisone or prednisolone 5 mg twice daily. This review evaluates the basis for the effects of prednisone on mineralocorticoid-related adverse events that arise because of CYP17A1 inhibition with abiraterone. Coadministration with the recommended dose of glucocorticoid compensates for abiraterone-induced reductions in serum cortisol and blocks the compensatory increase in adrenocorticotropic hormone seen with abiraterone. Consequently, 5 mg prednisone twice daily serves as a glucocorticoid replacement therapy when coadministered with abiraterone acetate, analogous to use of glucocorticoid replacement therapy for certain endocrine disorders. We searched PubMed to identify safety concerns regarding glucocorticoid use, placing a focus on longitudinal studies in autoimmune and inflammatory diseases and cancer. In general, glucocorticoid-related adverse events, including bone loss, immunosuppression, hyperglycemia, mood and cognitive alterations, and myopathy, appear dose related and tend to occur at doses and/or treatment durations greater than the low dose of glucocorticoid approved in combination with abiraterone acetate for the treatment of mCRPC. Although glucocorticoids are often used to manage tumor-related symptoms or to prevent treatment-related toxicity, available evidence suggests that prednisone and dexamethasone might also offer modest therapeutic benefit in mCRPC. Given recent improvements in survival achieved for mCRPC with novel agents in combination with prednisone, the risks of these recommended glucocorticoid doses must be balanced with the benefits shown for these regimens.

  12. Gradual reduction of testosterone using a gonadotropin-releasing hormone vaccination delays castration resistance in a prostate cancer model

    Science.gov (United States)

    Barranco, Jesús A. Junco; Millar, Robert P.; Fuentes, Franklin; Bover, Eddy; Pimentel, Eulogio; Basulto, Roberto; Calzada, Lesvia; Morán, Rolando; Rodríguez, Ayni; Garay, Hilda; Reyes, Osvaldo; Castro, Maria D.; Bringas, Ricardo; Arteaga, Niurka; Toudurí, Henio; Rabassa, Mauricio; Fernández, Yairis; Serradelo, Andrés; Hernández, Eduardo; Guillén, Gerardo E.

    2016-01-01

    In a previous study aimed to design a novel prostate cancer vaccine, the authors of the present study demonstrated the advantage of combining the adjuvants Montanide ISA 51 with very small size proteoliposomes (VSSP) to promote a significant humoral immune response to gonadotropin-releasing hormone (GnRH) in healthy animals. The present study compared the efficacy of this vaccine formulation versus the standard treatment currently available in terms of preventing the development of tumors in DD/S mice injected with Shionogi carcinoma (SC) 115 cells. The results demonstrated that 5 non-vaccinated control mice exhibited a fast tumor growth, and succumbed to the disease within 19–31 days. Mice immunized with the GnRH/Montanide ISA 51/VSSP vaccine exhibited a moderate decline in testosterone levels that was associated with a decrease in anti-GnRH antibody titers, which lead to a sustained tumor growth inhibition. In total, 2 mice in the immunized group exhibited complete remission of the tumor for the duration of the present study. In addition, castrated mice, which were used as a control for standard hormonal therapy, exhibited an accelerated decrease in tumor size. However, tumor relapse was observed between days 50 and 54, and between days 65 and 85, following the injection of SC 155 cells. Therefore, these mice were sacrificed at day 90. The present study concludes that the slow and moderate reduction of testosterone levels observed using the GnRH-based vaccine may delay the appearance of castration resistance in a Shionogi prostate cancer model. These findings suggest that this vaccine may be used to delay castration resistance in patients with prostate cancer. PMID:27446378

  13. 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

  14. Impact of transmammary-delivered meloxicam on biomarkers of pain and distress in piglets after castration and tail docking.

    Directory of Open Access Journals (Sweden)

    Jessica L Bates

    Full Text Available 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

  15. Castration-resistant prostate cancer (CRPC):the rise and fall of systemic chemotherapy. Shadows of recent phase 3 studies

    Institute of Scientific and Technical Information of China (English)

    Omar Abdel-Rahman

    2014-01-01

    Castration-resistant prostate cancer (CRPC) is defined as prostate cancer that recurs while a patient is receiving androgen deprivation therapy (ADT). Many treatment options have been suggested for this chal enging disease;starting from 2-year hormonal manipulations, mitoxantrne-and docetaxel-based regimens reaching to the overwhelming new systemic op-tions for CRPC (newer hormonal treatments, cytotoxic chemotherapies, bone-targeted agents and immunotherapeutics);and the question is:do the traditional cytotoxic regimens stil have a role amidst al these new options?

  16. Ear tagging in piglets: the cortisol response with and without analgesia in comparison with castration and tail docking.

    Science.gov (United States)

    Numberger, J; Ritzmann, M; Übel, N; Eddicks, M; Reese, S; Zöls, S

    2016-11-01

    The objectives of the present study were to compare the cortisol response caused by ear tagging piglets with the distress caused by other known painful husbandry procedures (e.g. castration and tail docking) and to evaluate the effectiveness of analgesia with meloxicam to reduce the cortisol response caused by these procedures. In total, 210 male piglets were randomised to equal numbers (n=30) into one of seven groups: a control group which was only handled (H), an ear tagged group that received no analgesia (ET), an ear tagged group with analgesia (ETM), a castration group with no analgesia (C), a castration group with analgesia (CM), a tail-docked group with no analgesia (TD) and a tail-docked group with analgesia (TDM). The procedures were carried out on day 3 or 4 after farrowing. Five blood samples were taken from each piglet: 30 min before the respective procedure (baseline value), and 30, 60 min, 4 and 7 h after processing, to assess cortisol concentrations. Means as well as the area under the curve (AUC) value were analysed and the effective sizes of the procedures were established. At 7 h after the experimental treatment, cortisol concentrations had returned to base values in all groups. ET evoked a greater cortisol response than H piglets at 30 min (Pcortisol response to ET was lower than C at 30 min (P=0.001) but did not differ significantly at the other sample times. The mean cortisol response was similar between ET and TD piglets over all sample times. Taking both intensity and duration of the cortisol response into account (AUC), ET evoked a greater response than TD. Analgesia (ETM) resulted in significantly lower cortisol levels than ET at 30 and 60 min post-procedure. Castration (C) provoked the highest cortisol response of all procedures; a significant analgesic effect (CM) was shown only at 4 h post-procedure. TD resulted in significantly higher cortisol levels than H piglets only at 30 min; analgesia (TDM) significantly reduced the cortisol

  17. Sipuleucel-T for the Treatment of Patients With Metastatic Castrate-resistant Prostate Cancer: Considerations for Clinical Practice.

    Science.gov (United States)

    Pieczonka, Christopher M; Telonis, Dimitrios; Mouraviev, Vladimir; Albala, David

    2015-01-01

    Sipuleucel-T treatment is associated with a significant and consistent survival benefit in patients with metastatic castrate-resistant prostate cancer. Most adverse events are infusion related, manageable, and of short duration. Early screening and diagnosis of metastatic disease is important, as the greatest survival benefit may occur in patients with a lower disease burden. The short duration of sipuleucel-T treatment facilitates the use of subsequent therapies. Sipuleucel-T is now being used in the clinic for patients with a lower disease burden. We present our own experience with the use of sipuleucel-T in the setting of a large urology practice.

  18. Low-dose prednisolone in first-line docetaxel for patients with metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

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

    2015-01-01

    BACKGROUND: Randomized studies have shown improved survival with the combination of docetaxel (D) and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC). We retrospectively investigated whether coadministration of low-dose glucocorticoids has clinical benefits.......001). P did not influence progression-free survival (P = 0.692, log-rank test) or overall survival when adjusting for baseline levels of hemoglobin, alkaline phosphatase, lactate dehydrogenase, prostate-specific antigen, and Eastern Cooperative Oncology Group performance status (hazard ratioP = 0.98, 95...

  19. Risk Factors for Metastatic Castration-Resistant Prostate Cancer (CRPC) Predict Long-Term Treatment with Docetaxel

    OpenAIRE

    Kawahara, Takashi; Miyoshi, Yasuhide; Sekiguchi, Zenkichi; Sano, Futoshi; Hayashi, Narihiko; Teranishi, Jun-ichi; Misaki, Hiroshi; Noguchi, Kazumi; Kubota, Yoshinobu; Uemura, Hiroji

    2012-01-01

    Purpose For patients with metastatic castration-resistant prostatic cancer (mCRPC), docetaxel plus prednisone leads to superior survival and a higher response rate compared with mitoxantrone plus prednisone. We analyzed the efficacy of long-term treatment with ≥10 cycles of docetaxel, and validated the risk group classification in predicting overall survival (OS) in Japanese patients with mCRPC. Patients and Methods Fifty-two patients with mCRPC were administered 55 mg/m2 docetaxel and 8 mg d...

  20. Two dimensional SDS PAGE analysis of epididymal tissue proteins of normal and castrated bulls (Bos taurus) and identification of an androgen dependant protein

    Institute of Scientific and Technical Information of China (English)

    Gurunathgouda patil; V Girish Kumar; SG Ramachandra; AJ Rao; S Nandi

    2012-01-01

    A study was undertaken with an objective of two dimensionalSDS-PAGE analysis of protein profile in tissues of all caput, corpus and cauda of epididymis in both castrated and normal bulls and identification of androgen dependent protein/s in the epididymal tissues of bull(Bos taurus). Two dimensionalSDS-PAGE analysis for protein spots of different molecular weight(MW) with pI3.5 to7.35 and pI >7.35 to9.3 between the three regions in the normal and castrated bull as well as between normal and castrated bull of a particular region revealed significant differences. Similarly, comparison between the three regions of the normal and castrated bull epididymis for the number of protein spots irrespective of theMW in pI range of3.5 to7.35 and pI range >7.35 to 9.3 revealed significant differences.The number of protein spots found to be significantly higher in caput, corpus and cauda epididymis of the normal bull when compared to similar region of the castrated bull epididymis.Most of the proteins, which are secreted, are havingMW between 20 and85 kDa.Six proteins, which are known to be highly dependent on androgens, are also of acidic in nature except for one protein havingbasic pH.A protein spot(pI:6.55-6.85, andMW: <20 kDa) which appeared at the same site in all the three regions of the epididymis in the normal bull but was absent at the same site in all the three regions of the castrated bull was subjected for identification of the protein byMALDI-MS.The results revealed that this protein is an interferon-stimulated protein and it could beISG15/UCRP.

  1. 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.

  2. 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.

  3. Overexpression of the potential kinase serine/ threonine/tyrosine kinase 1 (STYK 1) in castration-resistant prostate cancer.

    Science.gov (United States)

    Chung, Suyoun; Tamura, Kenji; Furihata, Mutsuo; Uemura, Motohide; Daigo, Yataro; Nasu, Yasutomo; Miki, Tsuneharu; Shuin, Taro; Fujioka, Tomoaki; Nakamura, Yusuke; Nakagawa, Hidewaki

    2009-11-01

    Despite high response rates and clinical benefits, androgen ablation often fails to cure advanced or relapsed prostate cancer because castration-resistant prostate cancer (CRPC) cells inevitably emerge. CRPC cells not only grow under castration, but also behave more aggressively, indicating that a number of malignant signaling pathways are activated in CRPC cells as well as androgen receptor signaling. Based on information from the gene expression profiles of clinical CRPC cells, we here identified one overexpressed gene, serine/threonine/tyrosine kinase 1 (STYK1), encoding a potential kinase, as a molecular target for CRPC. RNA and immunohistochemical analyses validated the overexpression of STYK1 in prostate cancer cells, and its expression was distinct in CRPC cells. Knockdown of STYK1 by siRNA resulted in drastic suppression of prostate cancer cell growth and, concordantly, enforced expression of STYK1 promoted cell proliferation, whereas ectopic expression of a kinase-dead mutant STYK1 did not. An in vitro kinase assay using recombinant STYK1 demonstrated that STYK1 could have some potential as a kinase, although its specific substrates are unknown. These findings suggest that STYK1 could be a possible molecular target for CRPC, and small molecules specifically inhibiting STYK1 kinase could be a possible approach for the development of novel CRPC therapies.

  4. 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.

  5. Racemic ketamine in comparison to S-ketamine in combination with azaperone and butorphanol for castration of pigs.

    Science.gov (United States)

    Bettschart-Wolfensberger, R; Stauffer, S; Hässig, M; Flaherty, D; Ringer, S K

    2013-12-01

    In this prospective blinded randomised study, 28 male 9 week old pigs of bodyweight 25 kg, were anaesthetised for castration using 5 mg/kg azaperone, 0.2 mg/kg butorphanol and 0.4 mg/kg meloxicam, in conjunction with either 15 mg/kg racemic ketamine (Keta-Race) or 9 mg/kg S-ketamine (S-Keta), all drugs being injected intramuscularly. Anaesthesia induction, maintenance and recovery were timed and scored. Insufficient anaesthesia was supplemented with ¼ the initial dose of ketamine or S-ketamine, respectively, administered intravenously. A t-test was utilised for analysis of timings, and, for repeated recovery time data, ANOVA was used. In relation to quantification and timing of supplemental drug doses, a chi square test was used and the scoring was analysed by two sample Wilcoxon rank-sum test. Ketamine re-dosing was required in 23 animals on a total of 46 occasions distributed evenly throughout both groups. The only group differences occurred during recovery, with the S-Keta group showing earlier movements, sternal recumbency and ability to stand. Three pigs in each group showed muscle fasciculations during the recovery period, while an additional two animals of the Keta-Race group exhibited marked and unacceptable paddling in recovery. In conclusion, S-ketamine at a dose rate of 60 % of that of racemic ketamine induced comparable anaesthesia for castration in pigs, but with superior recovery characteristics.

  6. An update on TroVax® for the treatment of progressive castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Abern M

    2011-05-01

    Full Text Available Michael Abern1, Howard L Kaufman2, Kalyan Latchamsetty11Department of Urology, Rush University Medical Center, Chicago, IL, USA; 2Department of General Surgery and Immunology and Microbiology, Rush University Medical Center, Chicago, IL, USAAbstract: Prostate cancer is a common human malignancy with few effective therapeutic options for treating advanced castration-resistant disease. The potential therapeutic effectiveness of immunotherapy and vaccines, in particular, has gained popularity based on the identification of prostate-associated antigens, potent expression vectors for vaccination, and data from recent clinical trials. A modified vaccinia Ankara (MVA virus expressing 5T4, a tumor-associated glycoprotein, has shown promise in preclinical studies and clinical trials in patients with colorectal and renal cell carcinoma. This review will discuss the rationale for immunotherapy in prostate cancer and describe preclinical and limited clinical data in prostate cancer for the MVA-5T4 (TroVax® vaccine.Keywords: castration resistance, prostate cancer, TroVax, vaccine

  7. 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.

  8. 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

  9. 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…

  10. Lean meat prediction with HGP, CGM and CSB-Image-Meater, with prediction accuracy evaluated for different proportions of gilts, boars and castrated boars in the pig population

    NARCIS (Netherlands)

    Engel, B.; Lambooij, E.; Buist, W.G.; Vereijken, P.F.G.

    2012-01-01

    Prediction equations for the percentage lean meat in pig carcasses in The Netherlands were derived for the Hennessy Grading Probe 7, Capteur Gras/Maigre - Sydel and CSB-Image-Meater. Because castrated males are expected to vanish from the Dutch pig population in the near future, accuracy of predicti

  11. Safety of cabazitaxel in senior adults with metastatic castration-resistant prostate cancer: results of the European compassionate-use programme

    NARCIS (Netherlands)

    Heidenreich, A.; Bracarda, S.; Mason, M.; Ozen, H.; Sengelov, L.; Oort, I.M. van; Papandreou, C.; Fossa, S.; Hitier, S.; Climent, M.A.

    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 programme

  12. 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

    PURPOSE: We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Men with progressive mCRPC after docetaxel-based chemotherapy were randomly assigned 2:1 to receive sunitinib 37.5 mg...

  13. 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.

  14. Efficacy and Safety of Abiraterone Acetate in Elderly (75 Years or Older) Chemotherapy Naive Patients with Metastatic Castration Resistant Prostate Cancer

    NARCIS (Netherlands)

    Smith, M.R.; Rathkopf, D.E.; Mulders, P.F.A.; Carles, J.; Poppel, H. Van; Li, J.; Kheoh, T.; Griffin, T.W.; Molina, A.; Ryan, C.J.

    2015-01-01

    PURPOSE: Metastatic castration resistant prostate cancer primarily affects elderly men. In this post hoc analysis we investigated the safety and efficacy of abiraterone acetate in elderly (age 75 years or greater) and younger (less than 75 years) patient subgroups at the prespecified interim analysi

  15. 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...

  16. Androgen receptor splice variant 7 (AR-V7) and drug efficacy in castration-resistant prostate cancer: Biomarker for treatment selection exclusion or inclusion?

    Science.gov (United States)

    Leibrand, Crystal R; Price, Douglas K; Figg, William D

    2016-05-01

    Currently there are no molecular biomarkers used to help guide treatment selection for those patients with castration-resistant prostate cancer. A recent study published in JAMA Oncology (Antonarakis et al.) presents evidence supporting the potential use of androgen receptor splice variant 7 as a biomarker for optimal treatment selection in this population.

  17. Effect of surgical castration of bull calves at different stages of maturity with or without analgesia on the acute phase response (APR) and complete blood count (CBC)

    Science.gov (United States)

    The study objective was to determine if surgical castration at birth or weaning impacts the acute phase response (APR) or complete blood counts (CBC) and whether concurrent administration of an oral analgesic (meloxicam) ameliorates inflammation. Bull calves (n=29) from the University of Arkansas re...

  18. Changes in testosterone and dihydrotestosterone levels in male rat accessory sex organs, serum, and seminal fluid after castration: establishment of a new highly sensitive simultaneous androgen measurement method.

    Science.gov (United States)

    Kashiwagi, Bunzo; Shibata, Yasuhiro; Ono, Yoshihiro; Suzuki, Ryota; Honma, Seijiro; Suzuki, Kazuhiro

    2005-01-01

    It is known that abnormal androgen dynamics in the tissues is a cause of androgen-dependent disorders. Investigation of tissue androgen levels could provide a clue to the elucidation of disorders. However, it is difficult to measure a trace amount of androgen in the tissues. We established a highly sensitive simultaneous quantification method of testosterone and dihydrotestosterone (DHT), which play the most important roles in the body among androgenic steroids in trace amounts, and investigated time course changes in testosterone and DHT levels in male accessory sex organs, serum, and seminal fluid after castration in rat models. In addition, changes in the testosterone/DHT ratio of male accessory sex organs and seminal fluid were observed. The simultaneous testosterone and DHT measurement method established by us was validated. Intra-assay variation and interassay precision and accuracy were all within +/-20%, and the quantification limits of testosterone and DHT were both 15.6 pg/g. With the use of this method, the testosterone and DHT levels in the prostate, seminal vesicles, and serum immediately after castration were similar to those previously reported. The testosterone and DHT levels were 350 pg/g and 605 pg/g, respectively; which showed dominance of DHT in seminal fluid, although it was not as marked as that in the male accessory sex organs. Androgens decreased with time after castration in the accessory sex organs, serum, and seminal fluid. In the prostate and seminal vesicles, testosterone and DHT decreased to about 50% and about 2% of the normal levels, respectively, 72 hours after castration. The serum levels were under the quantification limits 6 hours after castration and thereafter. In seminal fluid, the testosterone and DHT levels decreased to 49% and 35% of normal levels, respectively, 72 hours after castration. The testosterone/DHT ratio in the male accessory sex organs was lower in the prostate (0.06) than in the seminal vesicles (0

  19. In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure: effects on the prostate and its response to castration in senescent C57BL/6J mice.

    Science.gov (United States)

    Fritz, Wayne A; Lin, Tien-Min; Moore, Robert W; Cooke, Paul S; Peterson, Richard E

    2005-08-01

    In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure inhibits ventral, dorsolateral, and anterior prostate development in C57BL/6 mice. To determine if prostatic abnormalities persist into senescence, mice born to dams given TCDD (5 mug/kg, po) or vehicle on gestation day 13 were examined at 100 and 510 days of age. Half the mice were castrated ten days prior to necropsy in order to assess androgen dependence, while the remaining mice were sham castrated. Effects of TCDD on the dorsolateral and anterior prostate of senescent sham-castrated mice were relatively subtle, whereas the ventral prostate was rudimentary or absent. Castration of vehicle-exposed mice caused far greater reductions in prostate lobe weights, epithelial cell height, and androgen-dependent gene expression (MP25 and probasin) in young mice than in senescent ones, while cell proliferation was decreased by castration in young mice and increased in senescence. Responses to castration were similar at 100 days of age in vehicle- and TCDD-exposed mice. At 510 days, however, TCDD-exposed mice were substantially more responsive to castration by most indices than vehicle-exposed mice. These results demonstrate that prostatic androgen dependence in mice declines substantially with age in several key ways, and that in utero and lactational TCDD exposure protects against this decline. Surprisingly, TCDD increased the incidence of cribriform structures in dorsolateral prostate ducts, from 2-3% in vehicle-exposed senescent mice to 16% in sham-castrated and to 7% in castrated senescent mice. Collectively, these results demonstrate that effects of in utero and lactational TCDD exposure on the prostate persist into senescence, and suggest that in utero and lactational TCDD exposure retards the aging process in the prostate. However, because cribriform structures are often considered to be associated with prostate carcinogenesis, these results also suggest that TCDD exposure early in

  20. 去势对雄性大鼠心肌结构的影响%Influence of castration on myocardial structure of male rats

    Institute of Scientific and Technical Information of China (English)

    施超; 李艳香; 翟华玲; 姜博仁; 郭明皓; 陆颖理

    2011-01-01

    Objective To investigate the influence of low androgen on myocardial structure of male rats. Methods Male SD rats were randomly divided into control group (n =8), castration group (n =7) and androgen replacement group (n =8). Rats in control group underwent sham castration, those in castration group were castrated, and those in replacement group were given testosterone undecanoate after castration. Ten weeks later, serum concentration of testosterone was measured by radioimmunoassay. Pathological changes of myocardial tissues were observed by light microscopy and electron microscopy. Results Serum concentration of testosterone in castration group was significantly lower than those in control group and androgen replacement group (P < 0. 01). Light microscopy revealed that in castration group, there were myocardial swelling, hypertrophy, degeneration and nucleus enlargement, the nuclei significantly enlarged, the myocardial fibers fractured, dissolved, contracted and became wavy, and arranged in disorder. Electron microscopy revealed that in castration group, myocardial fibers arranged irregularly, fractured and dissolved, the glycogen and flat drop between muscle fibers accumulated, mitochondria swelled, most of the ridges in mitochondria were not clear, and the intercalated disk widened. Compared with castration group, the above-mentioned pathological changes in androgen replacement group were significantly lessened. Conclusion Obvious myocardial histopathological injury may occur in male rats after castration, and exogenous testosterone replacement therapy may work in some degree. Low androgen may do harm to myocardium of males.%目的 研究低雄激素对心肌组织结构的影响.方法 雄性SD大鼠随机分为对照组(n=8)、去势组(n=7)和雄激素替代组(n=8).对照组进行假去势手术;去势组进行去势手术;雄激素替代组进行去势手术后肌肉注射十一酸睾酮替代治疗.10周后取各组大鼠血清,放射免疫法测定

  1. Endocrine control of sexual behavior in sneaker males of the peacock blenny Salaria pavo: effects of castration, aromatase inhibition, testosterone and estradiol.

    Science.gov (United States)

    Gonçalves, David; Alpedrinha, João; Teles, Magda; Oliveira, Rui F

    2007-04-01

    The effects of castration and sex steroid manipulations on the expression of sexual behavior were investigated in a small fish, the peacock blenny, Salaria pavo. In this species, large males defend nests and attract females while small "sneaker" males reproduce by imitating the female morphology and courtship behavior in order to approach nests during spawning events and parasitically fertilize eggs. Sneakers switch into nest holders in their second breeding season, thus displaying both male and female-like sexual behavior during their lifetime. We tested the effects of castration and of an aromatase inhibitor (Fadrozole, F), testosterone (T) or 17beta-estradiol (E(2)) implants on the expression of male and female-like behavior in sneakers. Sneakers were either sham-operated, castrated or castrated and implanted with vehicle, F, T+F or E(2)+F. Seven days after the treatment, sneakers were placed in a tank with a nesting male, two ripe females and an available nest. Castrated fish had lower levels of circulating T and increased the time spent displaying female typical nuptial coloration. T implants had the opposite effect, inhibiting the expression of female-like behavior and coloration. E(2) implants had no significant effect on the display of sexual behavior but the frequency of aggressive displays decreased. The results agree with previous findings in sneakers of S. pavo that demonstrated an inhibition of female-like behavior by 11-ketotestosterone (11-KT). The reported increase in T and 11-KT production when sneakers change into nest holders may thus contribute to behaviorally defeminize sneakers. Contrarily, both T and E(2) failed to promote male-like behavior, suggesting that behavioral masculization during tactic switching depends on other neuroendocrine mechanisms or that the time length of the experiment was insufficient to induce male-like behavioral changes in sneakers.

  2. CH5137291, an androgen receptor nuclear translocation-inhibiting compound, inhibits the growth of castration-resistant prostate cancer cells.

    Science.gov (United States)

    Ishikura, Nobuyuki; Kawata, Hiromitsu; Nishimoto, Ayako; Nakamura, Ryo; Tsunenari, Toshiaki; Watanabe, Miho; Tachibana, Kazutaka; Shiraishi, Takuya; Yoshino, Hitoshi; Honma, Akie; Emura, Takashi; Ohta, Masateru; Nakagawa, Toshito; Houjo, Takao; Corey, Eva; Vessella, Robert L; Aoki, Yuko; Sato, Haruhiko

    2015-04-01

    Resistance of prostate cancer to castration is currently an unavoidable problem. The major mechanisms underlying such resistance are androgen receptor (AR) overexpression, androgen-independent activation of AR, and AR mutation. To address this problem, we developed an AR pure antagonist, CH5137291, with AR nuclear translocation-inhibiting activity, and compared its activity and characteristics with that of bicalutamide. Cell lines corresponding to the mechanisms of castration resistance were used: LNCaP-BC2 having AR overexpression and LNCaP-CS10 having androgen-independent AR activation. VCaP and LNCaP were used as hormone-sensitive prostate cancer cells. In vitro functional assay clearly showed that CH5137291 inhibited the nuclear translocation of wild-type ARs as well as W741C- and T877A-mutant ARs. In addition, it acted as a pure antagonist on the transcriptional activity of these types of ARs. In contrast, bicalutamide did not inhibit the nuclear translocation of these ARs, and showed a partial/full agonistic effect on the transcriptional activity. CH5137291 inhibited cell growth more strongly than bicalutamide in VCaP and LNCaP cells as well as in LNCaP-BC2 and LNCaP-CS10 cells in vitro. In xenograft models, CH5137291 strongly inhibited the tumor growth of LNCaP, LNCaP-BC2, and LNCaP-CS10, whereas bicalutamide showed a weaker effect in LNCaP and almost no effect in LNCaP-BC2 and LNCaP-CS10 xenografts. Levels of prostate-specific antigen (PSA) in plasma correlated well with the antitumor effect of both agents. CH5137291 inhibited the growth of LNCaP tumors that had become resistant to bicalutamide treatment. A docking model suggested that CH5137291 intensively collided with the M895 residue of helix 12, and therefore strongly inhibited the folding of helix 12, a cause of AR agonist activity, in wild-type and W741C-mutant ARs. In cynomolgus monkeys, the serum concentration of CH5137291 increased dose-dependently and PSA level decreased 80% at 100 mg/kg. CH

  3. Progression of metastatic castrate-resistant prostate cancer: impact of therapeutic intervention in the post-docetaxel space.

    Science.gov (United States)

    Sartor, A Oliver

    2011-04-23

    Despite the proven success of hormonal therapy for prostate cancer using chemical or surgical castration, most patients eventually will progress to a phase of the disease that is metastatic and shows resistance to further hormonal manipulation. This has been termed metastatic castrate-resistant prostate cancer (mCRPC). Despite this designation, however, there is evidence that androgen receptor (AR)-mediated signaling and gene expression can persist in mCRPC, even in the face of castrate levels of androgen. This may be due in part to the upregulation of enzymes involved in androgen synthesis, the overexpression of AR, or the emergence of mutant ARs with promiscuous recognition of various steroidal ligands. The therapeutic options were limited and palliative in nature until trials in 2004 demonstrated that docetaxel chemotherapy could significantly improve survival. These results established first-line docetaxel as the standard of care for mCRPC. After resistance to further docetaxel therapy develops, treatment options were once again limited. Recently reported results from phase 3 trials have shown that additional therapy with the novel taxane cabazitaxel (with prednisone), or treatment with the antiandrogen abiraterone (with prednisone) could improve survival for patients with mCRPC following docetaxel therapy. Compared with mitoxantrone/prednisone, cabazitaxel/prednisone significantly improved overall survival, with a 30% reduction in rate of death, in patients with progression of mCRPC after docetaxel therapy in the TROPIC trial. Similarly, abiraterone acetate (an inhibitor of androgen biosynthesis) plus prednisone significantly decreased the rate of death by 35% compared with placebo plus prednisone in mCRPC patients progressing after prior docetaxel therapy in the COU-AA-301 trial. Results of these trials have thus established two additional treatment options for mCRPC patients in the "post-docetaxel space." In view of the continued AR-mediated signaling on m

  4. Progression of metastatic castrate-resistant prostate cancer: impact of therapeutic intervention in the post-docetaxel space

    Directory of Open Access Journals (Sweden)

    Sartor A Oliver

    2011-04-01

    Full Text Available Abstract Despite the proven success of hormonal therapy for prostate cancer using chemical or surgical castration, most patients eventually will progress to a phase of the disease that is metastatic and shows resistance to further hormonal manipulation. This has been termed metastatic castrate-resistant prostate cancer (mCRPC. Despite this designation, however, there is evidence that androgen receptor (AR-mediated signaling and gene expression can persist in mCRPC, even in the face of castrate levels of androgen. This may be due in part to the upregulation of enzymes involved in androgen synthesis, the overexpression of AR, or the emergence of mutant ARs with promiscuous recognition of various steroidal ligands. The therapeutic options were limited and palliative in nature until trials in 2004 demonstrated that docetaxel chemotherapy could significantly improve survival. These results established first-line docetaxel as the standard of care for mCRPC. After resistance to further docetaxel therapy develops, treatment options were once again limited. Recently reported results from phase 3 trials have shown that additional therapy with the novel taxane cabazitaxel (with prednisone, or treatment with the antiandrogen abiraterone (with prednisone could improve survival for patients with mCRPC following docetaxel therapy. Compared with mitoxantrone/prednisone, cabazitaxel/prednisone significantly improved overall survival, with a 30% reduction in rate of death, in patients with progression of mCRPC after docetaxel therapy in the TROPIC trial. Similarly, abiraterone acetate (an inhibitor of androgen biosynthesis plus prednisone significantly decreased the rate of death by 35% compared with placebo plus prednisone in mCRPC patients progressing after prior docetaxel therapy in the COU-AA-301 trial. Results of these trials have thus established two additional treatment options for mCRPC patients in the "post-docetaxel space." In view of the continued AR

  5. Influence of hands-on experience on pig farmers' attitude towards alternatives for surgical castration of male piglets.

    Science.gov (United States)

    Aluwé, M; Vanhonacker, F; Millet, S; Tuyttens, A M

    2015-12-01

    This study evaluates the influence of practical experience with alternatives for surgical castration (SC) on farmer attitudes. Nineteen farmers in Flanders were surveyed before (ex-ante) and after (ex-post) performing each of five treatments on farm: 1) SC with analgesia (SCAN); 2) SC with CO2 anaesthesia (SCCO2); 3) immunocastration (IM); 4) production of entire males (EM); and 5) SC without pain relief (SCN). For SCCO2 and SCAN, farmers mainly experienced disadvantages in terms of increased labour, costs and complexity. Hands-on experience promoted EMas a valid alternative for SCN due to the actual and perceived improvement in performance and profitability as well as the reduced labour demands. Experience with IM did not fully fulfil the favourable ex-ante expectations resulting in a level of dissatisfaction and a less favourable general attitude ex-post.

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

    Science.gov (United States)

    Ding, Ying; Adachi, Hiroaki; Katsuno, Masahisa; Huang, Zhe; Jiang, Yue-Mei; Kondo, Naohide; Iida, Madoka; Tohnai, Genki; Nakatsuji, Hideaki; Funakoshi, Hiroshi; Nakamura, Toshikazu; Sobue, Gen

    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.

  7. Sipuleucel-T: a therapeutic cancer vaccine for the treatment of castration- or hormone-refractory prostate cancer.

    Science.gov (United States)

    Bulloch, Marilyn N; Elayan, Mohammed M; Renfroe, Holly R

    2011-11-01

    Sipuleucel-T is a therapeutic cancer vaccine approved for the treatment of castration- or hormone-refractory prostate cancer. Through a novel process, it activates the body's own antigen-presenting cells to induce an immune response to prostatic acid phosphatase, a protein found on prostate cancer cells. A treatment course consists of three total infusions spread 2 weeks apart. Throughout all phases of clinical trials, sipuleucel-T has been shown to be safe and well tolerated. Sipuleucel-T has demonstrated an ability to increase overall survival by approximately 4 months when compared with placebo. However, sipuleucel-T has not shown any improvement in affecting patients' time to disease progression.

  8. The Rationale for Optimal Combination Therapy With Sipuleucel-T for Patients With Castration-resistant Prostate Cancer.

    Science.gov (United States)

    Mouraviev, Vladimir; Mariados, Neil; Albala, David; Concepcion, Raoul S; Shore, Neal D; Sims, Robert B; Emberton, Mark; Pieczonka, Christopher M

    2014-01-01

    Immunotherapy encourages the recipient's own immune response to destroy cancer cells, and current evidence suggests that immunotherapies may be most beneficial in early metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T is the first therapeutic cancer vaccine to be approved by both the US Food and Drug Administration and European Medicines Agency for the treatment of asymptomatic or minimally symptomatic mCRPC. Combining immunotherapy with other treatments may have potent anticancer effects; cytoreductive therapies can release tumor antigens and promote a proinflammatory environment that could augment immunotherapies. However, some cytoreductive agents or coadministered drugs may be immunosuppressive. Understanding these interactions between different mCRPC treatment modalities may offer further potential to improve patient outcomes.

  9. Further analysis of PREVAIL: Enzalutamide use in chemotherapy-naïve men with metastatic castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Jeanny B Aragon-Ching

    2014-12-01

    Full Text Available PREVAIL was a phase III multinational, double-blind, placebo-controlled trial that enrolled chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC, which showed remarkable improvement in co-primary endpoints with an overall 81% reduction in the risk of radiographic progression, as well as 29% reduction in the risk of death in favor of the enzalutamide arm over placebo. All secondary endpoints including time to subsequent chemotherapy initiation and prostate specific antigen (PSA progression were in favor of the enzalutamide arm. The results of PREVAIL shows the utility of enzalutamide that would likely soon expand the indication to asymptomatic or minimally symptomatic men with mCRPC not previously treated with chemotherapy.

  10. Intensity of stromal changes is associated with tumor relapse in clinically advanced prostate cancer after castration therapy

    Institute of Scientific and Technical Information of China (English)

    JianPing Wu; WenBin Huang; Hui Zhou; LuWei Xu; JianHua Zhao; JiaGen Zhu; JiangHao Su; HongBin Sun

    2014-01-01

    Reactive stromal changes in prostate cancer(PCa) are likely involved in the emergence of castration‑resistant PCa(CRPC). This study was designed to investigate stromal changes in patients with clinically advanced PCa and analyze their prognostic signiifcance. Prostate needle biopsies obtained from 148patients before castration therapy were analyzed by Masson trichrome staining and immunohistochemical analysis of vimentin and desmin. Reactive stroma grading was inversely correlated with Gleason score. Stroma grade (Masson stain 82.8%vs 45.6%,P<0.001) and vimentin expression(P=0.005) were signiifcantly higher, and desmin expression (P=0.004) signiifcantly lower, in reactive stroma of tumors with a Gleason score of 6–7 than in adjacent peritumoral tissue. Kaplan‑Meier analysis showed a signiifcant association between reactive stroma grade in tumors and the occurrence of CRPC in patients with a Gleason score of 6–7(P=0.009). Furthermore, patients with higher vimentin or lower desmin expression had a shorter disease‑free period. In multivariate analysis, only vimentin expression was a signiifcant predictor of tumor relapse (hazard ratio 1.78, 95% conifdence interval 1.12–10.26,P=0.012). These ifndings indicate that the intensity of reactive stroma is associated with castration responsiveness, especially in patients with a lower Gleason score where the abundant stroma component is most frequently found. High expression of vimentin in tumor stroma was independently associated with poor outcomes in patients with Gleason scores of 6–7, and may serve as a new prognostic marker in daily practice.

  11. 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

  12. Radium-223 dichloride: illustrating the benefits of a multidisciplinary approach for patients with metastatic castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Renzulli II JF

    2015-06-01

    Full Text Available Joseph F Renzulli II, Jennifer Collins, Anthony Mega Genitourinary Multidisciplinary Clinic, The Miriam Hospital, Providence, RI, USAAbstract: Improving options for patients with metastatic castration-resistant prostate cancer (mCRPC provide latitude in designing treatment plans that meet patients' medical needs and personal goals. The field's rapid evolution opens avenues for contributions by multiple medical specialties and requires considering more options to ensure that each patient receives the most appropriate care. A multidisciplinary clinic (MDC focusing on patients with cancers of the genitourinary tract demonstrates an efficient and cost-effective means of integrating the diverse professional knowledge and skills needed to develop an optimal patient treatment plan. As a guide to establishing an MDC for patients with mCRPC, this article describes the operation of the Genitourinary MDC at The Miriam Hospital in Providence, RI – specifically, the successful incorporation of radium-223 dichloride (radium-223 into the treatment algorithm for men with mCRPC and symptomatic bone metastases. Radium-223 is a new treatment that, unlike earlier radionuclide therapies, has shown a survival advantage in a large randomized phase 3 trial (ALSYMPCA. The overall survival benefit was comparable to that of newer immuno- and hormonal therapies in similar populations. Radium-223 treatment also delayed onset of symptomatic skeletal events. Both benefits were independent of prior docetaxel therapy or concurrent bisphosphonate use. In our clinic, radium-223 is used primarily to extend patient survival. Patient selection, patient management, and treatment sequencing are discussed here in the context of a multidisciplinary environment. Keywords: radium-223 dichloride, prostate cancer, castration-resistant prostate cancer, multidisciplinary clinic, best practices

  13. Targeting autophagy overcomes Enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model

    Science.gov (United States)

    Nguyen, H G; Yang, J C; Kung, H-J; Shi, X-B; Tilki, D; Lara, P N; DeVere White, R W; Gao, A C; Evans, C P

    2014-01-01

    Macro-autophagy is associated with drug resistance in various cancers and can function as an adaptive response to maintain cell survival under metabolic stresses, including androgen deprivation. Androgen deprivation or treatment with androgen receptor (AR) signaling inhibitor (ARSI), Enzalutamide (MDV-3100, ENZA) or bicalutamide induced autophagy in androgen-dependent and in castration-resistant CaP (castration-resistant prostate cancer (CRPC)) cell lines. The autophagic cascade triggered by AR blockage, correlated with the increased light chain 3-II/I ratio and ATG-5 expression. Autophagy was observed in a subpopulation of C4-2B cells that developed insensitivity to ENZA after sustained exposure in culture. Using flow cytometry and clonogenic assays, we showed that inhibiting autophagy with clomipramine (CMI), chloroquine or metformin increased apoptosis and significantly impaired cell viability. This autophagic process was mediated by AMP-dependent protein kinase (AMPK) activation and the suppression of mammalian target of rapamycin (mTOR) through Raptor phosphorylation (Serine 792). Furthermore, small interfering RNA targeting AMPK significantly inhibited autophagy and promoted cell death in CaP cells acutely or chronically exposed to ENZA or androgen deprivation, suggesting that autophagy is an important survival mechanism in CRPC. Lastly, in vivo studies with mice orthotopically implanted with ENZA-resistant cells demonstrated that the combination of ENZA and autophagy modulators, CMI or metformin significantly reduced tumor growth when compared with control groups (P<0.005). In conclusion, autophagy is as an important mechanism of resistance to ARSI in CRPC. Antiandrogen-induced autophagy is mediated through the activation of AMPK pathway and the suppression of mTOR pathway. Blocking autophagy pharmacologically or genetically significantly impairs prostate cancer cell survival in vitro and in vivo, implying the therapeutics potential of autophagy inhibitors

  14. Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer.

    Science.gov (United States)

    McGrath, Meagan J; Binge, Lauren C; Sriratana, Absorn; Wang, Hong; Robinson, Paul A; Pook, David; Fedele, Clare G; Brown, Susan; Dyson, Jennifer M; Cottle, Denny L; Cowling, Belinda S; Niranjan, Birunthi; Risbridger, Gail P; Mitchell, Christina A

    2013-08-15

    It is now clear that progression from localized prostate cancer to incurable castrate-resistant prostate cancer (CRPC) is driven by continued androgen receptor (AR), signaling independently of androgen. Thus, there remains a strong rationale to suppress AR activity as the single most important therapeutic goal in CRPC treatment. Although the expression of ligand-independent AR splice variants confers resistance to AR-targeted therapy and progression to lethal castrate-resistant cancer, the molecular regulators of AR activity in CRPC remain unclear, in particular those pathways that potentiate the function of mutant AR in CRPC. Here, we identify FHL2 as a novel coactivator of ligand-independent AR variants that are important in CRPC. We show that the nuclear localization of FHL2 and coactivation of the AR is driven by calpain cleavage of the cytoskeletal protein filamin, a pathway that shows differential activation in prostate epithelial versus prostate cancer cell lines. We further identify a novel FHL2-AR-filamin transcription complex, revealing how deregulation of this axis promotes the constitutive, ligand-independent activation of AR variants, which are present in CRPC. Critically, the calpain-cleaved filamin fragment and FHL2 are present in the nucleus only in CRPC and not benign prostate tissue or localized prostate cancer. Thus, our work provides mechanistic insight into the enhanced AR activation, most notably of the recently identified AR variants, including AR-V7 that drives CRPC progression. Furthermore, our results identify the first disease-specific mechanism for deregulation of FHL2 nuclear localization during cancer progression. These results offer general import beyond prostate cancer, given that nuclear FHL2 is characteristic of other human cancers where oncogenic transcription factors that drive disease are activated like the AR in prostate cancer.

  15. Dimorphic expression of uncoupling protein-3 in golden hamster harderian gland: effects of castration and testosterone administration.

    Science.gov (United States)

    Santillo, Alessandra; Monteforte, Rossella; De Lange, Pieter; Lanni, Antonia; Farina, Paola; Baccari, Gabriella Chieffi

    2008-05-01

    Hamster (Mesocricetus auratus) harderian gland (HG) is a dimorphic orbital gland producing a copious lipid secretion. Two cell-types are present in hamster HG, type I in both sexes, type II only in males. In hamster HGs, we found a marked sexual dichotomy in the expression of uncoupling protein-3 (UCP3), a mitochondrial protein carrier, that probably exports fatty acid anions and fatty acid peroxides from the mitochondrial matrix. Following castration and/or testosterone treatment: (1) UCP3 levels correlated with the type II-cell percentage, not with testosterone levels, (2) in male HGs, UCP3 was comparable to female levels at 30 days post-castration (when the type II-cell percentage had fallen from 50 to 5%), although testosterone was already near zero at 15 days (when neither the type II-cell percentage nor the UCP3 level had fallen), and testosterone-replacement therapy prevented these changes. Testosterone-treated females possessed type II cells and a UCP3 level about twofold higher than in control females. Males displayed more intense UCP3 immunohistochemical positivity in type I HG cells than females. Hence, testosterone may indirectly control UCP3 expression by regulating the gland's morphological and lipid dimorphism. Straight-chain fatty acids [found in alkyl diacylglycerols (ADGs) in males] are oxidized predominantly in mitochondria, branched-chain fatty acids (abundant in ADGs in females) predominantly in peroxisomes, so we speculate that the higher UCP3 expression in males reflects greater fatty acid flux in HG mitochondria. This is supported by our finding that in female (not male) HGs, the peroxisome-rich fraction contained alpha-methylacyl-CoA racemase (AMACR), an enzyme important in the beta-oxidation of branched-chain fatty acids.

  16. Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomised phase 3 trial

    NARCIS (Netherlands)

    Basch, E.; Autio, K.; Ryan, C.J.; Mulders, P.; Shore, N.; Kheoh, T.; Fizazi, K.; Logothetis, C.J.; Rathkopf, D.; Smith, M.R.; Mainwaring, P.N.; Hao, Y.; Griffin, T.; Li, S.; Meyers, M.L.; Molina, A.; Cleeland, C.

    2013-01-01

    BACKGROUND: Abiraterone acetate plus prednisone significantly improves radiographic progression-free survival in asymptomatic or mildly symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer compared with prednisone alone. We describe analyses of data for patie

  17. 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.

  18. Space allowance influences individually housed Holstein bull calf innate immune measures and standing behaviors after castration at 3 weeks of age.

    Science.gov (United States)

    Calvo-Lorenzo, M S; Hulbert, L E; Ballou, M A; Fowler, A L; Luo, Y; Klasing, K C; Mitloehner, F M

    2017-03-01

    Dairy calves in the Southwest regions of the United States are typically raised individually in wooden hutches with 1.23 m(2) of space. The objective of the study was to determine if increased space allowance in wooden hutches influences measures of innate immunity and behaviors of Holstein bull calves pre- and postcastration. Calves were randomly assigned at 4 d of age to conventional (CONV; 1.23 m(2) of space; n = 18), moderate (MOD; 1.85 m(2) space; n = 17), or maximized space allowance (MAX; 3.71 m(2) space; n = 19) in hutches. Calves were surgically castrated at 24 d of age. Peripheral whole blood samples were collected at -1, +1, +5, and +12 d of castration. Accelerometer loggers (n = 16 calves per treatment) were used from -3 to +5 d of castration to assess standing behaviors. All calves decreased total standing duration the day of castration versus precastration. Overall, MAX spent the most time in the stand position postcastration versus CONV and MOD. Within treatments, MOD and MAX had increased plasma cortisol 1 d postcastration versus precastration. A treatment × time tendency was observed for cortisol at 12 d postcastration; MAX had the least circulating cortisol. A treatment × time tendency for circulating haptoglobin (Hp) was observed and Hp was greatest among CONV 1 d pre- and 12 d postcastration. Compared with precastration, CONV had increased Hp at 1, 5, and 12 d, whereas MOD had increased Hp at 5 d, and Hp remained similar within MAX. A treatment × time tendency for tumor necrosis factor-α (TNF-α) from lipopolysaccharide-stimulated whole blood was observed; at 1 d postcastration, MOD had the most TNF-α, whereas MAX had the least. Within MAX, calves had increased TNF-α from precastration to 5 d postcastration. A treatment × time interaction was observed for whole blood bactericidal activity against Escherichia coli (WB anti-E). The CONV tended to have the greatest WB anti-E at d -1, but at d 1 and 5 postcastration, CONV had the least WB

  19. Predictors of long-term response to abiraterone in patients with metastastic castration-resistant prostate cancer: a retrospective cohort study

    OpenAIRE

    Verzoni, Elena; De Giorgi, Ugo; Derosa, Lisa; Caffo, Orazio; Boccardo, Francesco; Facchini, Gaetano; Porcu, Luca; Vincenzo, Fabio De; Zaniboni, Alberto; Chiuri, Vincenzo Emanuele; Fratino, Lucia; Santini, Daniele; Adamo, Vincenzo; De Vivo, Rocco; Dinota, Angelo

    2016-01-01

    We aimed to identify clinical predictors of long-term response to abiraterone (defined as >12 months drug exposure) in a retrospective cohort of metastatic castration-resistant prostate cancer patients treated in post-docetaxel setting at 24 Italian centers. The Cox proportional hazards model was used to analyze the association between clinical features and the duration of drug exposure. Results were expressed as hazard ratios (HR) with associated 95% confidence intervals (CI). A total of 143...

  20. 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 cutting yields, RAC-fed carcasses had greater (P ≤ 0.03) bone-in lean and total carcass cutting yields than control-fed carcasses while there were no differences (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 cutting yields than PC carcasses. There were minimal differences (P 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.

  1. Sipuleucel-T for therapy of asymptomatic or minimally symptomatic, castrate-refractory prostate cancer: an update and perspective among other treatments

    OpenAIRE

    Gupta SG; Carballido ES; Fishman M

    2011-01-01

    Shilpa Gupta, Estrella Carballido, Mayer FishmanMoffitt Cancer Center and Research Institute, Tampa, FL, USAAbstract: Sipuleucel-T is an autologous cell immunotherapy for castrate-refractory prostate cancer, with US Food and Drug Administration (FDA) approval in asymptomatic or minimally symptomatic prostate cancer. In this review we address the background of prostate cancer incidence and other available therapy onto which sipuleucel-T treatment has been added, with discussion of hormone-ther...

  2. Male pre- and post-pubertal castration effect on live weight, components of empty body weight, estimated nitrogen excretion and efficiency in Piemontese hypertrofic cattle

    Directory of Open Access Journals (Sweden)

    Davide Biagini

    2011-04-01

    Full Text Available To evaluate the effect of sexual neutering and age of castration on empty body weight (EBW components and estimated nitrogen excretion and efficiency, a trial was carried out on 3 groups of double-muscled Piemontese calves: early castrated (EC, 5th month of age, late castrated (LC, 12th month of age and intact males (IM, control group. Animals were fed at the same energy and protein level and slaughtered at 18th month of age. Live and slaughtering performances and EBW components were recorded, whereas N excretion was calculated by difference between diet and weight gain N content. In live and slaughtering performances, IM showed higher final, carcass and total meat weight than EC and LC (P<0.01. In EBW components, IM showed higher blood and head weight than EC and LC (P<0.01 and 0.05 respectively, and differences were found between EC and LC for head weights (P<0.01. IM showed higher body crude protein (BCP than EC and LC (P<0.01 and 0.05 respectively, but BCP/EBW ratio was higher only in IM than EC (P<0.05. Estimated N daily gain was higher in IM than EC and LC (P<0.01. Only LC showed higher excretion than IM (P<0.05, and N efficiency was higher in IM than EC and LC (P<0.05 and 0.01 respectively. In conclusion, for the Piemontese hypertrophied cattle castration significantly increases N excretion (+7% and reduces N efficiency (-15%, leading to a lower level of sustainability.

  3. 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 (P<0.0001). Expression profiling of chemotherapy-resistant CRPC samples (n = 25) was performed, and the results were compared with data from primary chemotherapy-naïve CRPC (n = 10) and hormone-sensitive prostate cancer 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. PMID:22363599

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

    Directory of Open Access Journals (Sweden)

    Kanishka Sircar

    Full Text Available 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 (P<0.0001. Expression profiling of chemotherapy-resistant CRPC samples (n = 25 was performed, and the results were compared with data from primary chemotherapy-naïve CRPC (n = 10 and hormone-sensitive prostate cancer 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.

  5. Serum Levels of Insulin-Like Growth Factor-I, Thyroid Hormones and Skeletal Muscle Fiber Size in Castrated Lambs with and Without Androgen Treatment

    Directory of Open Access Journals (Sweden)

    Bani Z. Ismail

    2009-01-01

    Full Text Available Twelve, intact male lambs, 1-2- weeks old, were divided into 3 groups, Group W (4 lambs were castrated at age less than 1 month, group WT (4 lambs were castrated at the same age and treated with testosterone and group R (4 lambs were left intact and served as control. Testosterone Propionate replacement was administered intramuscularly at a dose of 12.5 mg started at the day of castration and continued every 2 days for 21 days, then at a dose of 25 mg every 2 weeks until slaughter. Serum insulin-like growth factor-1, T3 and T4 concentrations were measured using ELISA. Lambs were slaughtered at 8 months of age and semitendinosus and splenius muscles fiber areas were measured using digital image technique. In WT and R groups, IGF-I concentrations were significantly higher (p2 was significantly higher (p<0.05 than that of groups W and WT while the muscle fiber area of the semitendinosus muscle was not significantly different among all groups.

  6. HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network.

    Science.gov (United States)

    Ramos-Montoya, Antonio; Lamb, Alastair D; Russell, Roslin; Carroll, Thomas; Jurmeister, Sarah; Galeano-Dalmau, Nuria; Massie, Charlie E; Boren, Joan; Bon, Helene; Theodorou, Vasiliki; Vias, Maria; Shaw, Greg L; Sharma, Naomi L; Ross-Adams, Helen; Scott, Helen E; Vowler, Sarah L; Howat, William J; Warren, Anne Y; Wooster, Richard F; Mills, Ian G; Neal, David E

    2014-05-01

    Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c-Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co-factor associated with stem cell characteristics in neural tissue. Here we show that HES6 is up-regulated in aggressive human prostate cancer and drives castration-resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR, which is preferentially directed to a regulatory network enriched for transcription factors such as E2F1. In the clinical setting, we have uncovered a HES6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted by inhibition of PLK1 with restoration of sensitivity to castration. We have therefore shown for the first time the critical role of HES6 in the development of CRPC and identified its potential in patient-specific therapeutic strategies.

  7. HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network

    Science.gov (United States)

    Ramos-Montoya, Antonio; Lamb, Alastair D; Russell, Roslin; Carroll, Thomas; Jurmeister, Sarah; Galeano-Dalmau, Nuria; Massie, Charlie E; Boren, Joan; Bon, Helene; Theodorou, Vasiliki; Vias, Maria; Shaw, Greg L; Sharma, Naomi L; Ross-Adams, Helen; Scott, Helen E; Vowler, Sarah L; Howat, William J; Warren, Anne Y; Wooster, Richard F; Mills, Ian G; Neal, David E

    2014-01-01

    Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c-Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co-factor associated with stem cell characteristics in neural tissue. Here we show that HES6 is up-regulated in aggressive human prostate cancer and drives castration-resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR, which is preferentially directed to a regulatory network enriched for transcription factors such as E2F1. In the clinical setting, we have uncovered a HES6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted by inhibition of PLK1 with restoration of sensitivity to castration. We have therefore shown for the first time the critical role of HES6 in the development of CRPC and identified its potential in patient-specific therapeutic strategies. PMID:24737870

  8. Phytoestrogens selective for the estrogen receptor beta exert anti-androgenic effects in castration resistant prostate cancer.

    Science.gov (United States)

    Thelen, Paul; Wuttke, Wolfgang; Seidlová-Wuttke, Dana

    2014-01-01

    Prostate cancer is the leading cause of cancer death in men of the Western world. A castration-resistant prostate cancer (CRPC) eventually will arise when a local restricted prostate carcinoma was not cured duly by radical prostatectomy or radiation therapy. Although androgen ablation therapies are considered the gold standard for treatments of advanced prostate cancer there is no curative therapy available at present. In previous pre-clinical and clinical trials several phytoestrogens were investigated for their anticancer potential in various models for prostate cancer. Phytoestrogens feature tumour preventive characteristics and most probably are involved in the low incidence rate of hormone related cancers in Asian countries. Phytoestrogens such as isoflavones can have a marked impact on the most essential therapy target of CRPC i.e. the androgen receptor. Furthermore, functional analyses solidified the notion of such drugs as androgen antagonistic. Phytoestrogens commonly feature low toxicity combined with a potential of targeted therapy. Thus, these drugs qualify for conceivable implementation in prostate cancer patients under active surveillance. In addition, relapse prevention with these drugs after radical prostatectomy or radiation therapy might be considered. This article is part of a Special Issue entitled 'Phytoestrogens'.

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Cost-effectiveness of abiraterone treatment in patients with castration-resistant prostate cancer who previously received docetaxel therapy

    Directory of Open Access Journals (Sweden)

    A. V. Rudakova

    2014-01-01

    Full Text Available Background. Therapy for metastatic castration-resistant prostate cancer (CRPC is a serious problem that requires significant public health care expenditures.Objective: to evaluate the cost-effectiveness of abiraterone treatment in patients with metastatic CRPC who previously received docetaxel under the conditions of the budgetary public health system of the Russian Federation.Material and methods. Markovian simulation based on the COU-AA-301 randomized placebo-controlled Phase III study was used. Survival analysis was made in 70-year-old patients. The cost of abiraterone therapy corresponded to that of the 2013 auctions.Results. Abiraterone therapy in patients who have previously received docetaxel therapy causes an increase in average life expectancy by an average of 4.6 months and progression-free survival by 2.0 months. Moreover, the cost calculated with reference to one year of additional life will account for about 3.6 million rubles and that to one additional quality-adjusted life year will be about 5.45 million rubles.Conclusion. The cost-effectiveness of abiraterone therapy for metastatic CRPC in patients who have previously received docetaxel therapy is similar to that of other medicaments used in oncological practice under the conditions of the budgetary public health system of the Russian Federation. In this connection, abiraterone may be considered as an economically acceptable medical intervention in this clinical situation.

  11. Growth performance and carcass quality of immunocastrated and surgically castrated pigs from crossbreds from Duroc and Pietrain sires.

    Science.gov (United States)

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

    2013-08-01

    In total, 240 pigs were used to compare growth performance and carcass quality traits of immunocastrated males (ICM), surgically castrated males (SCM), and intact females (IF) of crossbreds from Large White × Landrace females and Duroc (DU) or Pietrain (PI) sires destined to the dry-cured industry. Between the 2 Improvac injections (87 and 137 d of age), ICM and IF had less ADG than SCM (P SCM (2.33, 2.55, and 2.77 kg/d; respectively; P SCM and IF (P SCM (0.346, 0.323, and 0.300 g/g; respectively; P SCM had greater ADG than IF (P SCM or IF. Carcasses from IF were leaner than carcasses from SCM with carcasses from ICM being intermediate (P SCM. Intramuscular fat content was lower for IF than for SCM with that of ICM being intermediate (3.5 vs. 3.9 and 3.7%; P SCM and IF. Intramuscular fat content in LM was less for IF than for SCM with ICM intermediate. Crossbreds from Duroc sires grew faster and had more intramuscular fat but less ham yield than crossbreds from Pietrain sires. Therefore, ICM should be preferred to SCM and Duroc crossbreds should be preferred to Pietrain crossbreds to produce carcasses destined to the production of primal cuts for the dry-cured industry.

  12. Combining p53 stabilizers with metformin induces synergistic apoptosis through regulation of energy metabolism in castration-resistant prostate cancer.

    Science.gov (United States)

    Chen, Long; Ahmad, Nihal; Liu, Xiaoqi

    2016-01-01

    Since altered energy metabolism is a hallmark of cancer, many drugs targeting metabolic pathways are in active clinical trials. The tumor suppressor p53 is often inactivated in cancer, either through downregulation of protein or loss-of-function mutations. As such, stabilization of p53 is considered as one promising approach to treat those cancers carrying wild type (WT) p53. Herein, SIRT1 inhibitor Tenovin-1 and polo-like kinase 1 (Plk1) inhibitor BI2536 were used to stabilize p53. We found that both Tennovin-1 and BI2536 increased the anti-neoplastic activity of metformin, an inhibitor of oxidative phosphorylation, in a p53 dependent manner. Since p53 has also been shown to regulate metabolic pathways, we further analyzed glycolysis and oxidative phosphorylation upon drug treatments. We showed that both Tennovin-1 and BI2536 rescued metformin-induced glycolysis and that both Tennovin-1 and BI2536 potentiated metformin-associated inhibition of oxidative phosphorylation. Of significance, castration-resistant prostate cancer (CRPC) C4-2 cells show a much more robust response to the combination treatment than the parental androgen-dependent prostate cancer LNCaP cells, indicating that targeting energy metabolism with metformin plus p53 stabilizers might be a valid approach to treat CRPC carrying WT p53.

  13. Metformin inhibits castration-induced EMT in prostate cancer by repressing COX2/PGE2/STAT3 axis.

    Science.gov (United States)

    Tong, Dali; Liu, Qiuli; Liu, Gaolei; Xu, Jing; Lan, Weihua; Jiang, Yao; Xiao, Hualiang; Zhang, Dianzheng; Jiang, Jun

    2017-03-28

    Castration is the standard therapeutic treatment for advanced prostate cancer but with limited benefit due to the profound relapse and metastasis. Activation of inflammatory signaling pathway and initiation of epithelial-mesenchymal transition (EMT) are closely related to drug resistance, tumor relapseas well as metastasis. In this study, we demonstrated that metformin is capable of inhibiting prostate cancer cell migration and invasion by repressing EMT evidenced by downregulating the mesenchymal markers N-cadherin, Vimentin, and Twist and upregulating the epithelium E-cadherin. These effects have also been observed in our animal model as well as prostate cancer patients. In addition, we showed the effects of metformin on the expression of genes involved in EMT through repressing the levels of COX2, PGE2 and phosphorylated STAT3. Furthermore, inactivating COX2 abolishes metformin's regulatory effects and exogenously administered PGE2 is capable of enhancing STAT3 phosphorylation and expression of EMT biomarker. We propose that metformin represses prostate cancer EMT and metastasis through targeting the COX2/PGE2/STAT3 axis. These findings suggest that metformin by itself or in combination with other anticancer drugs could be used as an anti-metastasis therapy.

  14. Evolving treatment approaches for the management of metastatic castration-resistant prostate cancer – role of radium-223

    Directory of Open Access Journals (Sweden)

    Mukherji D

    2014-05-01

    Full Text Available Deborah Mukherji,1 Imane El Dika,1 Sally Temraz,1 Mohammed Haidar,2 Ali Shamseddine11Department of Hematology/Oncology, 2Department of Nuclear Medicine, American University of Beirut Medical Center, Beirut, LebanonAbstract: Radium-223 is a first-in-class alpha particle-emitting radiopharmaceutical approved for the treatment of bone metastatic castration-resistant prostate cancer. Radium-223 is administered intravenously with no requirement for complex shielding and specifically targets areas of bone metastasis. In a randomized placebo-controlled Phase III study, treatment with radium-223 was shown to improve overall survival, time to skeletal-related events, and health-related quality of life. Apart from radium-223, the cytotoxic chemotherapy agents docetaxel and cabazitaxel, androgen biosynthesis inhibitor abiraterone acetate, novel anti-androgen enzalutamide, and immunotherapy sipuleucel-T have also been shown to improve survival of men with advanced prostate cancer in Phase III trials. This review will outline current treatment approaches for advanced prostate cancer with a focus on the role of radium-223 in changing treatment paradigms.Keywords: Alpharadin, alpha-emitting radionuclide, bone metastasis

  15. Development of sipuleucel-T: autologous cellular immunotherapy for the treatment of metastatic castrate resistant prostate cancer.

    Science.gov (United States)

    Sims, Robert B

    2012-06-19

    Sipuleucel-T, the first autologous cellular immunotherapy approved by the United States Food and Drug Administration, is designed to stimulate an immune response to prostate cancer. Sipuleucel-T is manufactured by culturing a patient's peripheral blood mononuclear cells, including autologous antigen presenting cells (APCs), with a recombinant protein comprising a tumor-associated antigen (prostatic acid phosphatase [PAP]) and granulocyte colony-macrophage stimulating factor (GM-CSF). A full course of treatment comprises 3 infusions of sipuleucel-T, given at approximately 2-week intervals. The pattern of APC activation is consistent with priming by the first infusion, and boosting by the second and third infusions. Preclinical and clinical studies have demonstrated evidence of a robust antigen-specific immune response that includes a progressive and persistent increase in antigen-specific cellular and humoral immune responses. Treatment with sipuleucel-T has demonstrated a survival benefit in Phase 3 studies of subjects with metastatic castrate resistant (hormone refractory) prostate cancer (mCRPC). Adverse events with sipuleucel-T were generally mild to moderate and resolved within 2 days. Serious adverse events, autoimmune events, and cerebrovascular events occurred at a similar rate to control subjects. As the first autologous cellular immunotherapy to demonstrate an improvement in overall survival in asymptomatic or minimally symptomatic mCRPC patients, sipuleucel-T represents a new treatment paradigm in oncology.

  16. Sipuleucel-T and Androgen Receptor-Directed Therapy for Castration-Resistant Prostate Cancer: A Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Renliang Yi

    2016-01-01

    Full Text Available New treatments, such as sipuleucel-T and androgen receptor- (AR- directed therapies (enzalutamide (Enz and abiraterone acetate (AA, have emerged and been approved for the management of castration-resistant prostate cancer (CRPC. There are still debates over their efficacy and clinical benefits. This meta-analysis aimed to investigate the efficacy and safety of sipuleucel-T and AR-directed therapies in patients with CRPC. RevMan 5.1 was used for pooled analysis and analysis of publication bias. Seven studies were included in the meta-analysis, with three studies in sipuleucel-T (totally 737 patients, 488 patients in treatment group, and 249 patients in placebo group and four in AR-directed therapies (totally 5,199 patients, 3,015 patients in treatment group, and 2,184 patients in placebo group. Treatment with sipuleucel-T significantly improved overall survival in patients with CRPC and was not associated with increased risk of adverse event of grade ≥3 (p>0.05. However, treatment with sipuleucel-T did not improve time-to-progression and reduction of prostate-specific antigen (PSA level ≥50% was not significantly different from that with placebo. AR-directed therapies significantly improved overall survival in patients with CRPC and improved time-to-progression and reduction of PSA level ≥50%. AR-directed therapies did not increase risk of adverse event of grade ≥3 (p>0.05.

  17. Sipuleucel-T and Androgen Receptor-Directed Therapy for Castration-Resistant Prostate Cancer: A Meta-Analysis.

    Science.gov (United States)

    Yi, Renliang; Chen, Baoxin; Duan, Peng; Zheng, Chanjiao; Shen, Huanyu; Liu, Qun; Yuan, Chen; Ou, Weilin; Zhou, Zhiheng

    2016-01-01

    New treatments, such as sipuleucel-T and androgen receptor- (AR-) directed therapies (enzalutamide (Enz) and abiraterone acetate (AA)), have emerged and been approved for the management of castration-resistant prostate cancer (CRPC). There are still debates over their efficacy and clinical benefits. This meta-analysis aimed to investigate the efficacy and safety of sipuleucel-T and AR-directed therapies in patients with CRPC. RevMan 5.1 was used for pooled analysis and analysis of publication bias. Seven studies were included in the meta-analysis, with three studies in sipuleucel-T (totally 737 patients, 488 patients in treatment group, and 249 patients in placebo group) and four in AR-directed therapies (totally 5,199 patients, 3,015 patients in treatment group, and 2,184 patients in placebo group). Treatment with sipuleucel-T significantly improved overall survival in patients with CRPC and was not associated with increased risk of adverse event of grade ≥3 (p > 0.05). However, treatment with sipuleucel-T did not improve time-to-progression and reduction of prostate-specific antigen (PSA) level ≥50% was not significantly different from that with placebo. AR-directed therapies significantly improved overall survival in patients with CRPC and improved time-to-progression and reduction of PSA level ≥50%. AR-directed therapies did not increase risk of adverse event of grade ≥3 (p > 0.05).

  18. Partial response of liver metastases treated with abiraterone in castration-resistant prostate cancer: A case report.

    Science.gov (United States)

    Marech, Ilaria; Vacca, Angelo; Sivestris, Nicola; Gnoni, Antonio; Lorusso, Vito

    2013-06-01

    Docetaxel is the current first-line treatment for castration-resistant prostate cancer (CRPC), following failure to respond to maximal androgen blockade (MAB). Patients who fail to respond to docetaxel may receive cabazitaxel or abiraterone; however, there are no recommendations on which of these two agents should be used first. Here, we present a case of a male patient suffering from CRPC with liver and lymph node metastases, in which abiraterone achieved a partial response, according to RECIST criteria. In the literature, visceral involvement in patients with advanced prostate cancer is an infrequent occurrence; it affects 18-22% of patients. In the pivotal study concerning docetaxel-resistant patients, abiraterone was compared with a placebo and the forest plot for survival demonstrated that patients with visceral involvement have significantly benefited from abiraterone. In the TROPIC trial comparing cabazitaxel with mitoxantrone, the proportion of patients with visceral disease was ∼25% in both arms and there was no difference in overall survival in this subgroup of patients. In our case, we observed a significant activity of abiraterone in lymph node and liver metastases. If confirmed in large studies, this observation may raise concerns over whether to treat patients suffering from CRPC and visceral metasis with chemotherapy or hormone therapy.

  19. 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.

  20. Sustained complete response to CTLA-4 blockade in a patient with metastatic, castration-resistant prostate cancer.

    Science.gov (United States)

    Graff, Julie N; Puri, Sachin; Bifulco, Carlo B; Fox, Bernard A; Beer, Tomasz M

    2014-05-01

    We present the case of a man with metastatic, castration-resistant prostate cancer, who had a complete prostate-specific antigen (PSA) response after 2½ doses of ipilimumab. His treatment course was complicated by diarrhea and autoimmune hepatitis, both of which resolved within 4 months. Sera and biopsy specimens were accessed, and sera from pretreatment and day 113 were analyzed. Augmented antibody responses were detected against 11 potential tumor antigens, with responses ranging from 5- to 20-fold in day 113 sera compared with baseline. Genes that were targets of a strong antibody response (arbitrarily set at 10-fold or greater increase) were analyzed by real-time PCR for expression in the tumor biopsy cDNA. Of the top 5 genes, only 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) could be identified in the amplified tumor biopsy cDNA. Using an antibody to HIBCH, immunohistochemical analysis documented strong expression of the protein. Together, these data suggest that an augmented antibody response to HIBCH, an antigen that was expressed by the patient's prostate cancer, could have contributed to the clinical response. After 16 months of PSA stability, he discontinued his androgen-suppression therapy. With the return of his testosterone, his PSA increased slightly, likely originating from his intact prostate. He has been disease free for the past 6 years without any additional therapy.

  1. MicroRNAs and Androgen Receptor 3′ Untranslated Region: A Missing Link in Castration-resistant Prostate Cancer?

    Science.gov (United States)

    Sikand, Kavleen; Barik, Sailen; Shukla, Girish C.

    2012-01-01

    The ligand-activated transcription factor, androgen receptor (AR) plays a central role in the development and progression of prostate cancer. Prostate cancer initiates as an androgen-dependent disease and further accumulation of multiple sequential genetic and epigenetic alterations transform it into an aggressive, castration-resistant prostate cancer (CRPC). The molecular basis of the transition from androgen-dependent prostate cancer to CRPC remains unclear. However, it is apparent that AR plays a pivotal role in this alteration. The recent discovery that microRNAs (miRNAs) can target the function of AR suggests a functional role of these non-coding RNAs in the pathogenesis of prostate cancer. miRNAs usually function by targeting the 3′ untranslated region (UTR) of a mRNA by base-pairing interactions and modulate translation either by destabilizing the message or by repression of protein synthesis in actively translating ribosomes. Here, we discuss the potential molecular pathways through which AR targeting miRNAs may promote CRPC. Modulation of AR expression by miRNAs presents a novel therapeutic option for prostate cancer, albeit it will likely be used in combination with the existing therapies. PMID:22468168

  2. 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.

  3. Docetaxel Rechallenge in a Heavily Pretreated Patient With Castration-Resistant Prostate Cancer: A Case Report and Review of Literature.

    Science.gov (United States)

    Di Lorenzo, Giuseppe; Pagliuca, Martina; Perillo, Teresa; Benincasa, Alfonso; Bosso, Davide; De Placido, Sabino; Buonerba, Carlo

    2016-04-01

    Chemotherapy agents for patients with metastatic castration-resistant prostate cancer (mCRPC) include docetaxel and cabazitaxel. Although docetaxel is approved in the first-line treatment setting, a few studies have shown that selected patients can benefit from docetaxel rechallenge.We, here, report the case of a heavily pretreated mCRPC patient who reported clinical benefit from receiving docetaxel after previous exposure to docetaxel, cabazitaxel, abiraterone, and enzalutamide.After 4 cycles of treatment, patient's performance status had improved to 1, the hemoglobin level was 12.9 g/dL and his serum prostate specific antigen levels were reduced by >70%, with no treatment-related adverse events.Although docetaxel rechallenge is a therapeutic option for selected patients, the risk of cumulative toxicity described in literature must be carefully considered.As the risk of cabazitaxel-related cumulative toxicity is probably lower, retreatment with cabazitaxel rather than docetaxel may also be an option in the setting of heavily pretreated mCRPC patients.

  4. Efeito da tibolona sobre o endométrio de ratas castradas Effect of tibolone on endometrium of castrated rats

    Directory of Open Access Journals (Sweden)

    José Augusto Soares Pantaleão

    2009-03-01

    Full Text Available OBJETIVO: avaliar o efeito do uso prolongado de alta dose de tibolona na morfologia do endométrio em ratas castradas. MÉTODOS: foram utilizadas 15 ratas Wistar, fêmeas, com idade de oito semanas e peso médio de 250 g. Todas as ratas foram submetidas à ooforectomia bilateral e 30 dias depois foi coletada citologia vaginal, verificando-se o status de menopausa. As ratas foram divididas aleatoriamente em dois grupos: o tratado (n=9 recebeu via oral 1 mg tibolona/dia; o controle (n=6 recebeu apenas solução do veículo carboximetilcelulose. Após 20 semanas de tratamento, todos os animais foram sedados e sacrificados por deslocamento cervical. Os úteros foram retirados e fixados em formol 10% tamponado. Ambos os cornos uterinos foram clivados em três regiões (proximal, medial, distal e processados para inclusão em parafina. Cortes histológicos corados com hematoxilina-eosina foram submetidos à análise morfológica e morfométrica. Foram avaliados os seguintes parâmetros: espessura do epitélio superficial endometrial, espessura do estroma endometrial, área endometrial, número absoluto de glândulas endometriais e número de glândulas/área endometrial. Os dados obtidos foram comparados mediante o teste t de Student. RESULTADOS: no Grupo Tibolona os úteros se apresentaram bem desenvolvidos e houve aumento significativo (pPURPOSE: to evaluate the effect of long-term use of a high dose of tibolone on the morphology of the endometrium of castrated female rats. METHODS: fifteen female Wistar rats, aged eight weeks and weighting about 250 g were used. All the female rats were submitted to bilateral oophorectomy and 30 days afterwards, vaginal cytology was collected, to verify the menopause status. The female rats were randomly divided in two groups. The Treatment Group (n=9 received 1 mg of tibolone/day orally; the Control Group (n=6 received a solution of carboxymethylcellulose vehicle. After 20 weeks of treatment, all the animals were

  5. The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer

    DEFF Research Database (Denmark)

    Evans, Christopher P; Higano, Celestia S; Keane, Thomas;

    2016-01-01

    in men with chemotherapy-naïve metastatic castration-resistant prostate cancer, with or without visceral disease, low- or high-volume bone disease, or lymph node only disease. PATIENT SUMMARY: Patients with metastatic castration-resistant prostate cancer-including those with or without visceral disease......BACKGROUND: Enzalutamide, an oral androgen receptor inhibitor, significantly improved overall survival (OS) and radiographic progression-free survival (rPFS) versus placebo in the PREVAIL trial of men with chemotherapy-naïve metastatic castration-resistant prostate cancer. OBJECTIVE: To assess...... the effects of enzalutamide versus placebo in patients from PREVAIL based on site and extent of baseline disease. DESIGN, SETTING, AND PARTICIPANTS: One thousand seven hundred and seventeen asymptomatic or minimally symptomatic patients were randomized to enzalutamide (n=872) or placebo (n=845). Subgroup...

  6. Food effects on abiraterone pharmacokinetics in healthy subjects and patients with metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Chi, Kim N; Spratlin, Jennifer; Kollmannsberger, Christian; North, Scott; Pankras, Catherine; Gonzalez, Martha; Bernard, Apexa; Stieltjes, Hans; Peng, Lixian; Jiao, James; Acharya, Milin; Kheoh, Thian; Griffin, Thomas W; Yu, Margaret K; Chien, Caly; Tran, Nam Phuong

    2015-12-01

    Food effect on abiraterone pharmacokinetics and safety on abiraterone acetate coadministration with low-fat or high-fat meals was examined in healthy subjects and metastatic castration-resistant prostate cancer (mCRPC) patients. Healthy subjects (n = 36) were randomized to abiraterone acetate (single dose, 1000 mg) + low-fat meal, + high-fat meal, and fasted state. mCRPC patients received repeated doses (abiraterone acetate 1000 mg + 5 mg prednisone twice daily; days 1-7) in a modified fasting state followed by abiraterone acetate plus prednisone within 0.5 hours post-low-fat (n = 6) or high-fat meal (n = 18; days 8-14). In healthy subjects, geometric mean (GM) abiraterone area under plasma concentration-time curve (AUC) increased ∼5- and ∼10-fold, respectively, with low-fat and high-fat meals versus fasted state (GM [coefficient of variation], 1942 [48] and 4077 [37] ng · h/mL vs 421 [67] ng · h/mL, respectively). In mCRPC patients, abiraterone AUC was ∼2-fold higher with a high-fat meal and similar with a low-fat meal versus modified fasting state (GM [coefficient of variation]: 1992 [34] vs 973 [58] ng · h/mL and 1264 [65] vs 1185 [90] ng · h/mL, respectively). Adverse events (all grade ≤ 3) were similar, with high-fat/low-fat meals or fasted/modified fasting state. Short-term dosing with food did not alter abiraterone acetate safety.

  7. Risk factors for metastatic castration-resistant prostate cancer (CRPC predict long-term treatment with docetaxel.

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    Takashi Kawahara

    Full Text Available PURPOSE: For patients with metastatic castration-resistant prostatic cancer (mCRPC, docetaxel plus prednisone leads to superior survival and a higher response rate compared with mitoxantrone plus prednisone. We analyzed the efficacy of long-term treatment with ≥10 cycles of docetaxel, and validated the risk group classification in predicting overall survival (OS in Japanese patients with mCRPC. PATIENTS AND METHODS: Fifty-two patients with mCRPC were administered 55 mg/m(2 docetaxel and 8 mg dexamethasone, every 3 or 4 weeks, simultaneously with hormonal therapy and daily oral dexamethasone. They were divided into two groups, short-term (9 or fewer cycles and long-term (10 or more cycles. Four risk factors including the presence of anemia, bone metastases, significant pain and visceral metastases were utilized for the risk group classification. RESULTS: Fourteen patients (27% had an elevation of PSA in spite of docetaxel treatment, while 23 patients (44% had a decline in PSA level, including 9 patients (17% whose PSA level declined by ≥50%. The median duration of OS after the initiation of this therapy was 11.2 months in the short-term group and 28.5 months in the long-term group. The good risk group showed a significant difference in OS compared with the intermediate and poor risk groups (P<0.001. The median number of cycles of treatment was 14, 4 and 3 for each risk group, respectively (p<0.01. CONCLUSIONS: The present study indicated that ≥10 cycles of this docetaxel therapy can significantly prolong survival in Japanese men with CRPC. This risk group classification for men with mCRPC at the initiation of this chemotherapy is useful.

  8. SU-D-303-01: Spatial Distribution of Bone Metastases In Metastatic Castrate-Resistant Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Perk, T; Bradshaw, T; Harmon, S; Perlman, S; Liu, G; Jeraj, R [University of Wisconsin, Madison, WI (United States)

    2015-06-15

    Purpose: Identification of metastatic bone lesions is critical in prostate cancer, where treatments may be more effective in patients with fewer lesions. This study aims characterize the distribution and spread of bone lesions and create a probability map of metastatic spread in bone. Methods: Fifty-five metastatic castrate-resistant prostate cancer patients received up to 3 whole-body [F-18]NaF PET/CT scans. Lesions were identified by physician on PET/CT and contoured using a threshold of SUV>15. An atlas-based segmentation method was used to create CT regions, which determined skeletal location of lesions. Patients were divided into 3 groups with low (N<40), medium (40100) numbers of lesions. A combination of articulated and deformable registrations was used to register the skeletal segments and lesions of each patient to a single skeleton. All the lesion data was then combined to make a probability map. Results: A total of 4038 metastatic lesions (mean 74, range 2–304) were identified. Skeletal regions with highest occurrence of lesions included ribs, thoracic spine, and pelvis with 21%, 19%, and 15% of the total number lesions and 8%, 18%, and 31 % of the total lesion volume, respectively. Interestingly, patients with fewer lesions were found to have a lower proportion of lesions in the ribs (9% in low vs. 27% in high number of lesions). Additionally, the probability map showed specific areas in the spine and pelvis where over 75% of patients had metastases, and other areas in the skeleton with a less than 2% of metastases. Conclusion: We identified skeletal regions with higher incidence of metastases and specific sub-regions in the skeleton that had high or low probability of occurrence of metastases. Additionally, we found that metastatic lesions in the ribs and skull occur more commonly in advanced disease. These results may have future applications in computer-aided diagnosis. Funding from the Prostate Cancer Foundation.

  9. MLN2238 synergizes BH3 mimetic ABT-263 in castration-resistant prostate cancer cells by induction of NOXA.

    Science.gov (United States)

    Wei, Xinghua; Zhou, Ping; Lin, Xuanting; Lin, Yurong; Wu, Sifeng; Diao, Pengfei; Xie, Haiqing; Xie, Keji; Tang, Ping

    2014-10-01

    Patients undergoing androgen blockade therapy develop castration-resistant prostate cancer (CRPC), which is associated with Bcl-2 upregulation and results in disease progression and death. In recent years, promising therapeutic agents, such as the BH3-only mimetic ABT-263 and proteasome inhibitors, have been developed and widely evaluated against a broad spectrum of cancer types, including prostate cancer, alone or in combination with other chemotherapeutic agents. In this study, the antitumor efficacy of ABT-263 and MLN2238 were evaluated as single agents and in combination in four CRPC cell lines: PC3, C4-2B, C4-2, and DU145. The viability of the treated cells and markers of apoptosis were assayed. Protein-protein interactions were analyzed by co-immunoprecipitation in drug-treated cells. Lentivirus-mediated short hairpin RNA was used to knockdown Bax, Mcl-1, and NOXA expressions. We found that ABT-263 and MLN2238 alone exhibited a mild cytotoxicity, and in combination, they elicited a synergistic cytotoxic effect in CRPC cells. The cell apoptosis induced by the combination drug treatment was evidenced by enhanced caspase-3 and Poly (ADP-ribose) polymerase (PARP) cleavage, and annexin-V-positive staining was significantly depleted by Bax knockdown. MLN2238 treatment upregulated NOXA and Mcl-1 expression, leading NOXA/Mcl-1 complexes to disassociate Bak from its complexes with Mcl-1 and enhancing ABT263-triggered Bax activation. NOXA knockdown by short hairpin RNA significantly attenuated the cytotoxicity of ABT-263 and MLN2238 co-administration. In conclusion, MLN2238 and ABT-263 synergistically triggered apoptosis in CRPC cells by upregulating NOXA and activating Bax, indicating a promising therapeutic strategy for the treatment of CRPC.

  10. Therapeutic options in docetaxel-refractory metastatic castration-resistant prostate cancer: a cost-effectiveness analysis.

    Directory of Open Access Journals (Sweden)

    Lixian Zhong

    Full Text Available BACKGROUND: Docetaxel is an established first-line therapy to treat metastatic castration-resistant prostate cancer (mCRPC. Recently, abiraterone and cabazitaxel were approved for use after docetaxel failure, with improved survival. National Institute for Health and Clinical Excellence (NICE preliminary recommendations were negative for both abiraterone (now positive in final recommendation and cabazitaxel (negative in final recommendation. OBJECTIVE: To evaluate the cost-effectiveness of abiraterone, cabazitaxel, mitoxantrone and prednisone for mCRPC treatment in US. METHODS: A decision-tree model was constructed to compare the two mCRPC treatments versus two placebos over 18 months from a societal perspective. Chance nodes include baseline pain as a severity indicator, grade III/IV side-effects, and survival at 18 months. Probabilities, survival and health utilities were from published studies. Model cost inputs included drug treatment, side-effect management and prevention, radiation for pain, and death associated costs in 2010 US dollars. RESULTS: Abiraterone is a cost-effective choice at $94K/QALY (quality adjusted life years compared to placebo in our base-case analysis. Cabazitaxel and abiraterone are the most effective, yet also most expensive agents. The incremental cost-effectiveness ratios (ICER at base-case are $101K/QALY (extended dominated for mitoxantrone vs. placebo, $91K/QALY for abiraterone vs. mitoxantrone, $956K/QALY for cabazitaxel vs. abiraterone. Abiraterone becomes less cost-effective as its AWP increases, or if the cost of mitoxantrone side-effect management decreases. Increases in the percentage of patients with baseline pain leads to an increased ICER for both mitoxantrone and abiraterone, but mitoxantrone does relatively better. Cabazitaxel remains not cost-effective. CONCLUSION: Our base case model suggests that abiraterone is a cost-effective option in docetaxel-refractory mCRPC patients. Newer treatments will also

  11. Cost-effectiveness analysis of abiraterone and sipuleucel-T in asymptomatic metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Gong, Cynthia L; Hay, Joel W

    2014-10-01

    Of patients diagnosed with prostate cancer, 0% to 20% experience disease progression to metastatic castration-resistant prostate cancer (mCRPC). Recently, 4 novel therapies have been introduced for the treatment of mCRPC; of these, abiraterone and sipuleucel-T have been studied in the asymptomatic, pre-docetaxel population. Both have shown clinical benefits compared with placebo. This study evaluated the cost-effectiveness of abiraterone acetate and sipuleucel-T compared with prednisone in asymptomatic, pre-docetaxel mCRPC from a US societal perspective. A Markov model was constructed to simulate stable disease, progressed disease, and death. Survival and event rates were derived from published clinical trial data. Costs were derived from the literature and government reimbursement schedules. Outcomes were measured as average cost-effectiveness ratios (ACERs), incremental cost-effectiveness ratios (ICERs), and net monetary benefits (NMBs). One-way and probabilistic sensitivity analyses were conducted to test the robustness of the model. The base-case ACER was $114K/quality-adjusted life-years (QALY) for abiraterone, $85K/QALY for sipuleucel-T, and $31K/QALY for prednisone. The base-case ICER was $389K/QALY for abiraterone and $547K/QALY for sipuleucel-T. Prednisone dominates both abiraterone and sipuleucel-T in terms of NMB at willingness-to-pay (WTP) thresholds of $400K or less. One-way sensitivity analyses revealed that the model was most sensitive to overall survival and utility inputs. Probabilistic sensitivity analyses showed abiraterone to be cost-effective 50% or more of the time at a WTP of greater than $400K, whereas sipuleucel-T was cost-effective 50% or more of the time at a WTP of greater than $270K. Neither abiraterone nor sipuleucel-T was found to be cost-effective compared with prednisone in the treatment of asymptomatic, pre-docetaxel mCRPC.

  12. 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.

  13. 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.

  14. 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 pigs and from IM compared with SC (P = 0.01 and P pigs (P = 0.006). In conclusion, immunization against GnRF more than the use of Pi

  15. 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...

  16. Ganho de peso e componentes do peso vivo em borregos Ile de France inteiros ou castrados e Hampshire Down castrados abatidos aos doze meses de idade Weight gain and live weight components of intact or castrated Ile de France and castrated Hampshire Down lambs slaughtered at twelve months of age

    Directory of Open Access Journals (Sweden)

    Edson Luis De Azambuja Ribeiro

    2000-04-01

    Full Text Available O principal objetivo deste trabalho foi o de avaliar o ganho de peso e os componentes do peso vivo em ovinos inteiros ou castrados abatidos aos 12 meses de idade. Foram usados 16 borregos Ile de France, sendo metade inteiros e metade castrados, e oito Hampshire Down castrados. Os borregos foram mantidos em pastagem de grama Coast-Cross e foram pesados dos três aos 12 meses de idade, quando abatidos. Não houve diferenças entre as raças para peso, ganhos de peso e para os componentes do peso vivo. Porém, os machos inteiros da raça Ile de France ganharam mais peso dos três aos 12 meses do que os castrados, com médias, respectivamente, de 0,078 e 0,063kg por dia; o ganho de peso médio diário para os borregos Hampshire Down foi de 0,064kg. As médias para os pesos vivos no abate e para os rendimentos de carcaça quente (entre parenteses foram: 38,54 (47,51%; 36,08 (47,82% e 36,44 (46,38%kg, respectivamente, para os borregos Ile de France inteiros, Ile de France castrados e Hampshire Down castrados. Os resultados indicam que, quando o abate for realizado aos 12 meses de idade, o uso de machos inteiros é recomendado devido ao seu maior ganho de peso.The main objective of this work was to evaluate the weight gain and live weight components of intact or castrated lambs slaughtered at 12 months of age. Sixteen Ile de France lambs, half intact and half castrated, and eight castrated Hampshire Down lambs were used in this experiment. The animals were kept on a Coast-Cross pasture from three to 12 months of age, and then slaughtered. There were no differences between breeds for weight, weight gain and live weight components. However, intact Ile de France lambs had a greater daily weight gain than castrated Ile de France lambs, with averages of 0.078 and 0.063kg, respectively; the average daily weight gain for the castrated Hampshire Down was 0.064kg. The averages for live weight before slaughtering and hot dressing percentage were: 38.54, 36

  17. Increased chromogranin A and neuron-specific enolase in rats with chronic nonbacterial prostatitis induced by 17-beta estradiol combined with castration

    Science.gov (United States)

    Fan, Song; Hao, Zong-Yao; Zhang, Li; Chen, Xian-Guo; Zhou, Jun; Zang, Yi-Fei; Tai, Sheng; Liang, Chao-Zhao

    2014-01-01

    Although chronic nonbacterial prostatitis (CNBP) is a common diagnosis in middle-aged men, the etiology of this disease remains poorly understood. Neuroendocrine cells play an important role in the neuroendocrine regulation of the prostate, and chromogranin A (CgA) and neuron-specific enolase (NSE) are regarded as classic markers of neuroendocrine cells. This study aimed to determine CgA and NSE levels in a CNBP rat model to evaluate the role of neuroendocrine cells in the pathogenesis of CNBP. For developing a CNBP rat model, we examined the ability of 17-beta estradiol and surgical castration alone or in combination to induce CNBP. Histologic inflammation of the prostate was assessed in CNBP-induced rats by hematoxylin-eosin staining, whereas CgA and NSE protein levels were assessed by immunohistochemistry, Western blot analysis, and enzyme-linked immunosorbent assays. Our results showed that 17-beta estradiol combined with castration successfully induced CNBP and that CgA and NSE levels were increased in the prostate of CNBP rats as compared to those without CNBP. These findings indicate that the neuroendocrine regulation mediated by neuroendocrine cells may be involved in the pathogenesis of CNBP. PMID:25120776

  18. Lipid oxidation, sensory characteristics, and color of fresh pork sausage from immunologically castrated pigs stored frozen for up to 12 weeks.

    Science.gov (United States)

    Jones-Hamlow, Katelyn A; Tavárez, Marcos A; Schroeder, Aubrey L; Dilger, Anna C

    2016-05-01

    Two studies were conducted to evaluate the quality characteristics of fresh sausage manufactured from immunologically castrated (IC) pigs, an emerging technology in the pork industry. Study 1: Fresh sausage patties from ground Boston butts fabricated from PC (physically castrated) pigs fed 0.55% SID (standard illeal digestible) lysine, IC pigs fed 0.55% SID lysine, and IC pigs fed 0.65% SID lysine were made and not standardized to a similar content of fat content. Study 2: fat and lean trim obtained from IC and PC pigs was made into fresh sausage patties, targeting 25% lipid. Patties (1.25 cm) were placed on trays and assigned to 0, 4, or 12 weeks frozen storage and then, after frozen storage, placed in simulated retail display conditions for 5 days. Patties were evaluated for color stability, sensory and textural properties, and lipid oxidation. Data were analyzed as a one way ANOVA with repeated measures where appropriate. In both studies, sausage discolored with both increased time in frozen storage and with increased time in retail display (P sausage in either study. Lipid oxidation did not differ by treatment in study 1. In study 2, lipid oxidation was reduced (P sausage.

  19. Automated Bone Scan Index as a quantitative imaging biomarker in metastatic castration-resistant prostate cancer patients being treated with enzalutamide

    DEFF Research Database (Denmark)

    Anand, Aseem; Morris, Michael J; Larson, Steven M;

    2016-01-01

    BACKGROUND: Having performed analytical validation studies, we are now assessing the clinical utility of the upgraded automated Bone Scan Index (BSI) in metastatic castration-resistant prostate cancer (mCRPC). In the present study, we retrospectively evaluated the discriminatory strength of the a......BACKGROUND: Having performed analytical validation studies, we are now assessing the clinical utility of the upgraded automated Bone Scan Index (BSI) in metastatic castration-resistant prostate cancer (mCRPC). In the present study, we retrospectively evaluated the discriminatory strength......-specific antigen (PSA), hemoglobin (HgB), and alkaline phosphatase (ALP) were obtained at baseline. Change in automated BSI and PSA were obtained from patients who have had bone scan at week 12 of treatment follow-up. Automated BSI was obtained using the analytically validated EXINI Bone(BSI) version 2. Kendall...... alone (C-index 0.73), p = 0.041. CONCLUSIONS: The upgraded and analytically validated automated BSI was found to be a strong predictor of OS in mCRPC patients. Additionally, the change in automated BSI demonstrated an additive clinical value to the change in PSA in mCRPC patients being treated...

  20. 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.

  1. Plumbagin Inhibits Prostate Carcinogenesis in Intact and Castrated PTEN Knockout Mice via Targeting PKCε, Stat3, and Epithelial-to-Mesenchymal Transition Markers.

    Science.gov (United States)

    Hafeez, Bilal Bin; Fischer, Joseph W; Singh, Ashok; Zhong, Weixiong; Mustafa, Ala; Meske, Louise; Sheikhani, Mohammad Ozair; Verma, Ajit Kumar

    2015-05-01

    Prostate cancer continues to remain the most common cancer and the second leading cause of cancer-related deaths in American males. The Pten deletions and/or mutations are frequently observed in both primary prostate cancers and metastatic prostate tissue samples. Pten deletion in prostate epithelium in mice results in prostatic intraepithelial neoplasia (PIN), followed by progression to invasive adenocarcinoma. The Pten conditional knockout mice [(Pten-loxp/loxp:PB-Cre4(+)) (Pten-KO)] provide a unique preclinical model to evaluate agents for efficacy for both the prevention and treatment of prostate cancer. We present here for the first time that dietary plumbagin, a medicinal plant-derived naphthoquinone (200 or 500 ppm) inhibits tumor development in intact as well as castrated Pten-KO mice. Plumbagin has shown no signs of toxicity at either of these doses. Plumbagin treatment resulted in a decrease expression of PKCε, AKT, Stat3, and COX2 compared with the control mice. Plumbagin treatment also inhibited the expression of vimentin and slug, the markers of epithelial-to-mesenchymal transition (EMT) in prostate tumors. In summary, the results indicate that dietary plumbagin inhibits growth of both primary and castration-resistant prostate cancer (CRPC) in Pten-KO mice, possibly via inhibition of PKCε, Stat3, AKT, and EMT markers (vimentin and slug), which are linked to the induction and progression of prostate cancer.

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

    Science.gov (United States)

    Ghotbaddini, Maryam; Powell, Joann B

    2015-07-06

    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.

  3. 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.

  4. Radium-223-Dichloride in Castration Resistant Metastatic Prostate Cancer—Preliminary Results of the Response Evaluation Using F-18-Fluoride PET/CT

    Directory of Open Access Journals (Sweden)

    Kalevi Kairemo

    2015-10-01

    Full Text Available The purpose of this study was to evaluate the outcome after Radium-223-dichloride (223RaCl2 treatment of patients with skeletal metastases of castration resistant prostate cancer using whole-body 18F-Fluoride PET/CT. Sodium 18F-fluoride [18F]-NaF PET/CT was performed prior the treatment of 223RaCl2, after the first cycle and after the sixth cycle. The skeletal metastases were analyzed quantitatively using modified PET response evaluation PERCIST criteria. The patients were also analyzed for S-PSA. All ten patients responded in [18F]-NaF scans after 6 cycles, but interim analysis after the 1st cycle did not give additional information about the outcome. The S-PSA decrease correlated with [18F]-NaF response, only 1 patient demonstrated progressive disease, i.e., >25% increase in S-PSA values during 223RaCl2. Our results (although preliminary suggest that 18F-Fluoride PET/CT is useful in the follow-up of castration resistant prostate cancer with skeletal metastases.

  5. {sup 11}C-Choline PET/CT in castration-resistant prostate cancer patients treated with docetaxel

    Energy Technology Data Exchange (ETDEWEB)

    Ceci, Francesco [University of Bologna, Service of Nuclear Medicine, S. Orsola-Malpighi Hospital, Bologna (Italy); Azienda Ospedaliero-Universitaria di Bologna, Policlinico S. Orsola-Malpighi, UO Medicina Nucleare PAD. 30, Bologna (Italy); Castellucci, Paolo; Graziani, Tiziano; Renzi, Riccardo; Fanti, Stefano [University of Bologna, Service of Nuclear Medicine, S. Orsola-Malpighi Hospital, Bologna (Italy); Schiavina, Riccardo; Borghesi, Marco; Brunocilla, Eugenio [University of Bologna, Department of Urology, S. Orsola-Malpighi Hospital, Bologna (Italy); Di Tullio, Piergiorgio; Ardizzoni, Andrea [University of Bologna, Department of Oncology, S. Orsola-Malpighi Hospital, Bologna (Italy)

    2016-01-15

    To investigate the role of {sup 11}C-choline PET/CT for evaluating the response to treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel in comparison with PSA response. Inclusion criteria were (a) proven mCRPC, (b) docetaxel as first line of chemotherapy (docetaxel 75 mg/m{sup 2} + prednisone 5 mg), and (c) {sup 11}C-choline PET/CT and PSA values assessed before and after docetaxel administration. A total of 61 patients were retrospectively enrolled (mean age 68.9 years, range 57 - 84 years). {sup 11}C-Choline PET/CT was performed at baseline before docetaxel treatment (PET1) and after the end of treatment (PET2). PSA values were measured before treatment (PSA1) and after treatment (PSA2). PET2 was reported as complete response (CR), partial response (PR) or stable disease (SD). Progressive disease (PD) was considered if a new lesion was seen. PSA trend was calculated from the change in absolute values between PSA1 and PSA2. A decrease of ≥50 % between PSA1 and PSA2 was considered a PSA response. Clinical, radiological and laboratory follow-up ranged from 6 to 53 months (mean 13.5 months). Of the 61 patients, 40 (65.5 %) showed PD on PET2, 13 (21.3 %) showed SD, 2 (3.4 %) showed PR, and 6 (9.8 %) showed CR. An increasing PSA trend was seen in 29 patients (47.5 %) and a decreasing PSA trend in 32 patients (52.5 %). A PSA response of ≥50 % was seen in 25 patients (41 %). Radiological PD was seen in 23 of the 29 patients (79.3 %) with an increasing PSA trend, in 16 of the 32 patients (50 %) with a decreasing PSA trend, and in 11 of the 25 patients (44 %) with a PSA response of ≥50 %. In the multivariate statistical analysis, the presence of more than ten bone lesions detected on PET1 was significantly associated with an increased probability of PD on PET2. No association was observed between PSA level and PD on PET2. Our results suggest that an increasing PSA trend measured after docetaxel treatment could be

  6. Improvement of a predictive model of castration-resistant prostate cancer: functional genetic variants in TGFβ1 signaling pathway modulation.

    Directory of Open Access Journals (Sweden)

    Ana L Teixeira

    Full Text Available Prostate cancer (PC is the most frequently diagnosed cancer in men. The acquisition of castration-resistant (CR phenotype is associated with the activation of signaling pathways mediated by growth factors. The TGFβ1 and its receptors have an important role in tumor progression, being the pro-apoptotic function modulated by the expression of TGFBR2. A single nucleotide polymorphism -875 G > A in TGFBR2 gene has been described, which may influence the expression levels of the receptor. Our purpose was to investigate the potential role of TGFBR2-875G>A in PC risk and in the response to androgen deprivation therapy (ADT. TGFBR2-875G>A polymorphism was studied by allelic discrimination using real-time polymerase chain reaction (PCR in 891 patients with PC and 874 controls. A follow-up study was undertaken to evaluate response to ADT. The TGFBR2 and SMAD7 mRNA expression were analyzed by a quantitative real-time PCR. We found that TGFBR2-875GG homozygous patients present lower expression levels of TGFBR2 mRNA (AA/AG: 2(-ΔΔCT =1.5, P=0.016. GG genotype was also associated with higher Gleason grade (OR=1.51, P=0.019 and increased risk of an early relapse after ADT (HR=1.47, P=0.024. The concordance (c index analysis showed that the definition of profiles that contains information regarding tumor characteristics associated with genetic information present an increased capacity to predict the risk for CR development (c-index model 1: 0.683 vs model 2: 0.736 vs model 3: 0.746 vs model 4: 0.759. The TGFBR2-875G>A contribution to an early relapse in ADT patients, due to changes in mRNA expression, supports the involvement of TGFβ1 pathway in CRPC. Furthermore, according to our results, we hypothesize the potential benefits of the association of genetic information in predictive models of CR development.

  7. The prognostic factors of effective ketoconazole treatment for metastatic castration-resistant prostate cancer: who can benefit from ketoconazole therapy?

    Institute of Scientific and Technical Information of China (English)

    Guo-Wen Lin; Xu-Dong Yao; Ding-Wei Ye; Yao Zhu; Shi-Lin Zhang; Bo Dai; Hai-Liang Zhang; Yi-Jun Shen; Chun-Guang Ma

    2012-01-01

    We investigated the prognostic value of some variables of effective ketoconazole treatment for metastatic castration-resistant prostate cancer (mCRPC).In total,163 patients with mCRPC were eligible,receiving ketoconazole 200-400 mg three times daily with replacement doses of prednisone.Progression-free survival (PFS) was calculated from the beginning of the ketoconazole therapy to the onset of disease progression.The prognostic value of different variables for PFS was assessed by Cox regression analysis.The median PFS was 2.6 months (0.5-8.6 months) for these patients.The serum testosterone level changed during therapy,which decreased when the prostate-specific antigen (PSA) declined; the serum testosterone level increased as the levels of PSA relapsed.The median PFS values for patients associated with different factors were the following:1.4 and 3.5 months for a nadir PSA of ≥ 0.2 and <0.2 ng ml-1,respectively (hazard rate (HR)=4.767,P<0.001); 3.1 and 1.6 months for a baseline testosterone of ≥-0.1 and <0.1 ng ml-1,respectively (HR=2.865,P=0.012); 2.8 and 1.9 months for a baseline haemoglobin of ≥ 120 and < 120 gl-1,respectively (HR=1.605,P<0.001); and 3.0 and 1.9 months for a PSA doubling time (PSADT) of ≥ 2.0 and <2.0 months,respectively (HR=1.454,P=0.017).A risk model was constructed according to the four factors that divided patients into three subgroups of low risk (0-1 factors),moderate risk (2 factors) and high risk (3-4 factors) with PFS values of 3.6,3.0 and 1∶4 months,respectively (HR=1.619,P<0.001).A nadir PSA of ≥ 0.2 ng ml-1,a baseline testosterone of <0.1 ng ml-1,a baseline haemoglobin of < 120 gl-1 and a PSADT of <2 months were associated with a poor PFS.This risk model could provide evidence to predict the survival benefit of ketoconazole therapy.

  8. Melatonin is able to prevent the liver of old castrated female rats from oxidative and pro-inflammatory damage.

    Science.gov (United States)

    Kireev, R A; Tresguerres, A C F; Garcia, C; Ariznavarreta, C; Vara, E; Tresguerres, Jesus A F

    2008-11-01

    The aim of this study was to investigate the effect of aging and ovariectomy on various physiological parameters related to inflammation and oxidative stress in livers obtained from old female rats, and the influence of chronic administration of melatonin on these animals. Twenty-four female Wistar rats of 22 months of age were used. Animals were divided into four experimental groups: two intact groups that were untreated or given melatonin (1 mg/kg/day), and two ovariectomized groups that also untreated and treated with melatonin (1 mg/kg/day). After 10 wk of treatment, rats were sacrificed by decapitation, and livers were collected and homogenized. A group of 2-month-old female rats was used as young controls. Protein expression of inducible nitric oxide synthase (iNOS), heme oxygenase-1 (HO-1), IL-6, TNF-alpha and IL-1beta were determined by Western blot analysis. The levels of nitric oxide metabolites (NO(x)), lipid hydroperoxide (LPO), TNF-alpha, IL-1beta, IL-6 and IL-10 were determined. Levels of LPO in the liver homogenates as well as iNOS protein expression and NO(x) levels were increased in old rats as compared with young animals; this effect was more evident in ovariectomized animals. Pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6 were significantly increased and anti-inflammatory IL-10 decreased during aging and after ovariectomy. Aging also significantly increased the expression of HO-1 protein, and ovariectomized rats showed an additional increase. Administration of melatonin, both to intact and to the ovariectomized animals significantly reduced NO(x), LPO levels and pro-inflammatory cytokines in the liver as compared with untreated rats. Significant rice in IL-10 and reductions in the iNOS, HO-1, IL-6, TNF-alpha and IL-1beta protein expression were also found in rats treated with melatonin. Oxidative stress and inflammation induced during aging in the liver are more marked in castrated than in intact females. Administration of melatonin

  9. State-of-the-Art Management for the Patient with Castration-Resistant Prostate Cancer in 2012.

    Science.gov (United States)

    Sartor, Oliver

    2012-01-01

    Much progress has been made in metastatic castration-resistant prostate cancer (CRPC), and multiple new U.S. Food and Drug Administration (FDA)-approved survival-prolonging drugs are now available. In 2004, docetaxel/prednisone was the first therapy shown to prolong survival. In 2010 and 2011, sipuleucel-T, cabazitaxel/prednisone, and abiraterone/prednisone were FDA approved. Two new agents, radium-223 and MDV-3100, have recently reported large phase III trials prolonging overall survival and will be submitted for regulatory approval in 2012. One can now begin to ask, is there an optimal sequence for therapies in metastatic CRPC? Despite the recent progress, there is much we do not know and virtually no information on this important question. We know that abiraterone/prednisone and cabazitaxel/prednisone are appropriate choices for a patient after receiving docetaxel, but we do not know what, if anything, represents the optimal sequence for abiraterone and cabazitaxel. In fact we do not understand how one therapy may affect the response to a subsequent therapy. We are also aware that the pre- and postdocetaxel spaces represent regulatory rather than biologic divisions. In addition, despite the proven role of docetaxel/prednisone, many patients with CRPC are not considered to be suitable for chemotherapy, and worldwide many never receive any form of chemotherapy. What is the optimal management for these patients? Taken together it is reasonable to assess patient preferences, prior therapies and response/tolerance to prior therapies, burden of disease, comorbidities, current symptoms, drug toxicities, out-of-pocket costs, etc., in clinical decision making. Given the many factors we do not know, it is hard to be dogmatic in approaching the therapeutic options for the patient with CRPC. We will likely soon move beyond the current sequencing paradigm and begin to assess new combinations in a systematic and rational fashion. Perhaps one day, in the not too distant future

  10. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial

    DEFF Research Database (Denmark)

    Kwon, Eugene D; Drake, Charles G; Scher, Howard I;

    2014-01-01

    chemotherapy. METHODS: We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one...

  11. Quercetin-loaded nanomicelles to circumvent human castration-resistant prostate cancer in vitro and in vivo

    Science.gov (United States)

    Zhao, Jing; Liu, Juan; Wei, Tuo; Ma, Xiaowei; Cheng, Qiang; Huo, Shuaidong; Zhang, Chunqiu; Zhang, Yanan; Duan, Xianglin; Liang, Xing-Jie

    2016-02-01

    Prostate cancer is highly prevalent and has become the second leading cause of cancer-related death in men. Its treatment remains a challenge in the clinic, particularly in patients who have advanced to ``castration-resistant prostate cancer'' (CRPC). Thus, more effective therapeutic strategies are required. Quercetin (QCT) is a natural flavonoid compound that has attracted increasing interest due to its anticancer activity. However, the clinical application of quercetin is largely hampered by its poor water solubility and low bioavailability. The objective of this study was to evaluate the therapeutic potential of novel QCT-loaded nanomicelles (M-QCTs) assembled from DSPE-PEG2000 for prostate cancer treatment. Our results indicated that QCT was efficiently encapsulated into micelles up to 1 mg mL-1, which corresponds to a 450-fold increase of its water solubility. In vitro studies showed that the half-maximal inhibitory concentration (IC50) value (20.2 μM) of M-QCTs was much lower than free QCT (>200 μM). Thus, M-QCTs were considerably more effective than free QCT in proliferation inhibition and apoptosis induction of human androgen-independent PC-3 cells. Furthermore, M-QCTs showed superior antitumor efficacy and the tumor proliferation rate reduced by 52.03% compared to the control group in the PC-3 xenograft mouse model, possibly due to increased accumulation of M-QCTs at the tumor site by the enhanced permeability and retention (EPR) effect. Collectively, our studies demonstrated that M-QCTs significantly increase drug accumulation at the tumor site and exhibit superior anticancer activity in prostate cancer. Thus, our nanomicelle-based drug delivery system constitutes a promising and effective therapeutic strategy for clinical treatment.Prostate cancer is highly prevalent and has become the second leading cause of cancer-related death in men. Its treatment remains a challenge in the clinic, particularly in patients who have advanced to ``castration

  12. 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

  13. 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.

  14. Sipuleucel-T for therapy of asymptomatic or minimally symptomatic, castrate-refractory prostate cancer: an update and perspective among other treatments.

    Science.gov (United States)

    Gupta, Shilpa; Carballido, Estrella; Fishman, Mayer

    2011-01-01

    Sipuleucel-T is an autologous cell immunotherapy for castrate-refractory prostate cancer, with US Food and Drug Administration (FDA) approval in asymptomatic or minimally symptomatic prostate cancer. In this review we address the background of prostate cancer incidence and other available therapy onto which sipuleucel-T treatment has been added, with discussion of hormone-therapy, chemotherapy, and other investigational immunotherapies. The sipuleucel-T manufacturing process, toxicity and clinical benefit are reviewed, along with an examination of the issue of clinical benefit to survival, independent of apparent changes of prostate-specific antigen (PSA) levels. Sipuleucel-T therapy is appraised from clinician, patient and immunotherapeutic perspectives, with reference to the clinical data from the pivotal trial, the mechanism of action, and the treatment process.

  15. Sipuleucel-T for therapy of asymptomatic or minimally symptomatic, castrate-refractory prostate cancer: an update and perspective among other treatments

    Directory of Open Access Journals (Sweden)

    Gupta SG

    2011-06-01

    Full Text Available Shilpa Gupta, Estrella Carballido, Mayer FishmanMoffitt Cancer Center and Research Institute, Tampa, FL, USAAbstract: Sipuleucel-T is an autologous cell immunotherapy for castrate-refractory prostate cancer, with US Food and Drug Administration (FDA approval in asymptomatic or minimally symptomatic prostate cancer. In this review we address the background of prostate cancer incidence and other available therapy onto which sipuleucel-T treatment has been added, with discussion of hormone-therapy, chemotherapy, and other investigational immunotherapies. The sipuleucel-T manufacturing process, toxicity and clinical benefit are reviewed, along with an examination of the issue of clinical benefit to survival, independent of apparent changes of prostate-specific antigen (PSA levels. Sipuleucel-T therapy is appraised from clinician, patient and immunotherapeutic perspectives, with reference to the clinical data from the pivotal trial, the mechanism of action, and the treatment process.Keywords: sipuleucel-T, immunotherapy, vaccine, immunotherapy, dendritic cells

  16. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors.

    Science.gov (United States)

    Cai, Changmeng; Chen, Sen; Ng, Patrick; Bubley, Glenn J; Nelson, Peter S; Mostaghel, Elahe A; Marck, Brett; Matsumoto, Alvin M; Simon, Nicholas I; Wang, Hongyun; Chen, Shaoyong; Balk, Steven P

    2011-10-15

    Relapse of castration-resistant prostate cancer (CRPC) that occurs after androgen deprivation therapy of primary prostate cancer can be mediated by reactivation of the androgen receptor (AR). One important mechanism mediating this AR reactivation is intratumoral conversion of the weak adrenal androgens DHEA and androstenedione into the AR ligands testosterone and dihydrotestosterone. DHEA and androstenedione are synthesized by the adrenals through the sequential actions of the cytochrome P450 enzymes CYP11A1 and CYP17A1, so that CYP17A1 inhibitors such as abiraterone are effective therapies for CRPC. However, the significance of intratumoral CYP17A1 and de novo androgen synthesis from cholesterol in CRPC, and the mechanisms contributing to CYP17A1 inhibitor resistance/relapse, remain to be determined. We report that AR activity in castration-resistant VCaP tumor xenografts can be restored through CYP17A1-dependent de novo androgen synthesis, and that abiraterone treatment of these xenografts imposes selective pressure for increased intratumoral expression of CYP17A1, thereby generating a mechanism for development of resistance to CYP17A1 inhibitors. Supporting the clinical relevance of this mechanism, we found that intratumoral expression of CYP17A1 was markedly increased in tumor biopsies from CRPC patients after CYP17A1 inhibitor therapy. We further show that CRPC cells expressing a progesterone responsive T877A mutant AR are not CYP17A1 dependent, but that AR activity in these cells is still steroid dependent and mediated by upstream CYP11A1-dependent intraturmoral pregnenolone/progesterone synthesis. Together, our results indicate that CRPCs resistant to CYP17A1 inhibition may remain steroid dependent and therefore responsive to therapies that can further suppress de novo intratumoral steroid synthesis.

  17. 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

  18. {sup 18}F-fluoromethylcholine (FCH) PET imaging in patients with castration-resistant prostate cancer: prospective comparison with standard imaging

    Energy Technology Data Exchange (ETDEWEB)

    McCarthy, Michael; Siew, Teck [Royal Perth Hospital, Department of Nuclear Medicine, Perth, WA (Australia); WA PET Service, Sir Charles Gairdner Hospital, Perth, WA (Australia); Campbell, Andrew [Royal Perth Hospital, Department of Nuclear Medicine, Perth, WA (Australia); Royal Perth Hospital, Department of Medical Engineering and Physics, Perth, WA (Australia); Lenzo, Nat [WA PET Service, Sir Charles Gairdner Hospital, Perth, WA (Australia); Spry, Nigel [Sir Charles Gairdner Hospital, Department of Radiation Oncology, Perth, WA (Australia); University of Western Australia, Faculty of Medicine and Pharmacology, School of Medicine, Perth (Australia); Vivian, Justin [Royal Perth Hospital, School of Surgery, UWA, Perth (Australia); Morandeau, Laurence [Sir Charles Gairdner Hospital, Department of Medical Technology and Physics, Perth, WA (Australia)

    2011-01-15

    The aim of the study was to assess the utility of {sup 18}F-fluorocholine (FCH), compared to standard imaging of bone scan (BS) and contrast-enhanced abdominopelvic computed tomography (CT), in patients with castration-resistant prostate carcinoma. FCH has shown promise as a metabolic imaging agent for prostate carcinoma. Twenty-six patients with castration-resistant prostate carcinoma had FCH, BS and CT imaging within a 2-month period. Individual FCH-positive lesions in bone were compared to the BS and soft tissue lesions were compared to CT. The lesions were then classified as concordant or discordant for the presence or absence of prostate cancer metastases. Discordant bone or soft tissue lesions were followed up with BS or CT, respectively, at 6-month intervals for up to 2 years or until a definitive diagnosis of the discordant lesion could be made. In 13 (50%) of the patients, all lesions identified were concordant; this included 5 patients in whom no lesions could be identified with any imaging modality. In 21 patients, 183 lesions were observed with 149 being concordant and 34 (19%) being discordant (13 patients). Based on follow-up, FCH correctly identified the presence or absence of disease in 27 of 34 lesions, and in 14 cases FCH-positive lesions, not identified on initial imaging, were confirmed as disease on follow-up. The sensitivity, specificity, accuracy, positive predictive and negative predictive values for lesion detection by FCH are 96% (92-98%), 96% (81-99%), 96% (93-97%), 99% (96-100%) and 81% (64-88%), respectively, with 95% confidence intervals shown in parentheses. In this patient cohort, FCH shows good initial concordance (81%) with BS and CT in the detection of metastatic prostate carcinoma. Follow-up of the cases where FCH was initially discordant with subsequent BS or CT shows that FCH was accurate in determining the presence or absence of prostate metastasis in 79% of lesions. While FCH imaging as compared to BS and CT in this patient

  19. ASC-J9(®) suppresses castration resistant prostate cancer progression via degrading the enzalutamide-induced androgen receptor mutant AR-F876L.

    Science.gov (United States)

    Wang, Ronghao; Lin, Wanying; Lin, Changyi; Li, Lei; Sun, Yin; Chang, Chawnshang

    2016-08-28

    Androgen deprivation therapy (ADT) with the newly developed powerful anti-androgen enzalutamide (Enz, also known as MDV3100) has promising therapeutic effects to suppress castration resistant prostate cancer (CRPC) and extending patients' lives an extra 4.8 months. However, most Enz therapy eventually fails with the development of Enz resistance. The detailed mechanisms how CRPC develops Enz resistance remain unclear and may involve multiple mechanisms. Among them, the induction of the androgen receptor (AR) mutant AR-F876L in some CRPC patients may represent one driving force that confers Enz resistance. Here, we demonstrate that the AR degradation enhancer, ASC-J9(®), not only degrades wild-type AR, but also has the ability to target AR-F876L. The consequence of suppressing AR-F876L may then abrogate AR-F876L mediated CRPC cell proliferation and metastasis. Thus, developing ASC-J9(®) as a new therapeutic approach may represent a novel therapy to better suppress CRPC that has already developed Enz resistance.

  20. Anti-Muellerian hormone, inhibin A, gonadotropins, and gonadotropin receptors in bull calves after partial scrotal resection, orchidectomy, and Burdizzo castration.

    Science.gov (United States)

    Scarlet, Dragos; Aurich, Christine; Ille, Natascha; Walter, Ingrid; Weber, Corinna; Pieler, Dagmar; Peinhopf, Walter; Wohlsein, Peter; Aurich, Jörg

    2017-01-01

    Eight-week-old calves were either castrated by partial scrotal resection (SR) without removing the testes (n = 10), Burdizzo (BZ) clamp (n = 10), orchidectomy (OR; n = 10), or were left gonad intact as controls (CO; n = 10). Concentrations of anti-Muellerian hormone (AMH), inhibin A, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in plasma were determined from 16 to 48 weeks of age. At 18 months, testes of SR, BZ, and CO bulls were obtained and the immunolocalization of LH and FSH receptors and AMH analyzed. Concentration of AMH in plasma of CO and SR bulls decreased with increasing age (P BZ, AMH was undetectable. Plasma inhibin concentration was higher in groups CO and SR than BZ and OR (P BZ and OR than SR and CO (P BZ bulls. FSH receptors were localized in Sertoli cells, Leydig cells, spermatocytes, and the epididymis of CO and SR animals, whereas LH receptors were restricted to Leydig cells. In BZ animals, FSH and LH receptors and AMH were absent, indicating complete testicular degeneration. In conclusion, AMH is a more reliable marker for the presence of testicular tissue in bulls than inhibin. Scrotal resection did not induce a true inguinal cryptorchid state but affected testicular responsiveness to gonadotropic stimulation.

  1. Infestation pattern and parasitic castration of the crustacean Riggia paranensis (Crustacea: Cymothoidea on the fresh water fish Cyphocharax gilbert (Teleostei: Curimatidae

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    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. Immunotherapy with Sipuleucel-T (APC8015 in patients with metastatic castration-refractory prostate cancer (mCRPC: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Tobias Engel Ayer Botrel

    2012-12-01

    Full Text Available Objective To perform a systematic review and meta-analysis of all randomized controlled trials comparing the efficacy of Sipuleucel-T versus placebo for asymptomatic or minimally symptomatic metastatic castration-refractory prostate cancer (mCRPC. Materials ans Methods Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The endpoints were overall survival (OS, time to progression (TTP and side effects. We performed a meta-analysis (MA of the published data. The results are expressed as Hazard Ratio (HR or Risk Ratio (RR, with their corresponding 95% confidence intervals (CI 95%. Results The final analysis included 3 trials comprising 737 patients. The TTP was similar in patients who received Sipuleucel-T or placebo (fixed effect: HR = 0.89; CI 95% = 0.75 to 1.05; p = 0.16, with no heterogeneity detected on this analysis (Chi2 = 2.14, df = 2 (P = 0.34; I2 = 6%. The results showed a higher overall survival in patients treated with Sipuleucel-T (fixed effect: HR = 0.74; CI 95% = 0.61 to 0.89; p = 0.001; NNT = 3. We found no heterogeneity on this analysis either (Chi2 = 1.46, df = 2 (P = 0.48; I2 = 0%. The incidence of adverse events (grade > 3 was the same in both groups. Conclusion Sipuleucel-T prolongs overall survival in patients with asymptomatic or minimally symptomatic mCRPC.

  3. The Role of the Neutrophil to Lymphocyte Ratio for Survival Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone

    Science.gov (United States)

    Boegemann, Martin; Schlack, Katrin; Thomes, Stefan; Steinestel, Julie; Rahbar, Kambiz; Semjonow, Axel; Schrader, Andres Jan; Aringer, Martin; Krabbe, Laura-Maria

    2017-01-01

    The purpose of this study was to examine the prognostic capability of baseline neutrophil-to-lymphocyte-ratio (NLR) and NLR-change under Abiraterone in metastatic castration-resistant prostate cancer patients. The impact of baseline NLR and change after eight weeks of treatment on progression-free survival (PFS) and overall survival (OS) was analyzed using Kaplan-Meier-estimates and Cox-regression. 79 men with baseline NLR 5 were analyzed. In baseline analysis of PFS NLR >5 was associated with non-significantly shorter median PFS (five versus 10 months) (HR: 1.6 (95%CI:0.9–2.8); p = 0.11). After multivariate adjustment (MVA), ECOG > 0–1, baseline LDH>upper limit of normal (UNL) and presence of visceral metastases were independent prognosticators. For OS, NLR >5 was associated with shorter survival (seven versus 19 months) (HR: 2.3 (95%CI:1.3–4.0); p 0–1 and baseline LDH > UNL remained independent prognosticators. After 8 weeks of Abiraterone NLR-change to 5, NLR-change to <5 after eight weeks of Abiraterone was associated with worse survival and should be interpreted carefully. PMID:28208664

  4. 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

  5. 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

  6. Novel flutamide regulated genes in the rat ventral prostate: differential modulation of their expression by castration and flutamide treatments%大鼠腹侧前列腺中受氟他胺调控的新基因:去势和氟他胺处理对其表达的调控

    Institute of Scientific and Technical Information of China (English)

    A. M. Limaye; I. Asangani; N. Bora; P. Kondaiah

    2007-01-01

    Aim: To identify flutamide regulated genes in the rat ventral prostate. Methods: Total RNA from ventral prostates of control and flutamide treated rats were isolated. Differentially expressed transcripts were identified using differential display reverse transcriptase polymerase chain reaction. The effect of castration on the expression of flutamideregulated transcripts was studied. Results: We have identified β2-microglobulin, cytoplasmic FMR1 interacting protein 2 and pumilio 1 as flutamide induced and spermine binding protein and ribophorin Ⅱ as flutamide repressed targets in the rat ventral prostate. Although flutamide treatment caused an induction of pumilio 1 mRNA, castration had no effect. Conclusion: Castration and flutamide treatments exert differential effects on gene expression. Flutamide might also have direct AR independent effects, which might have implications in the emergence of androgen independent prostate cancer and the failure of flutamide therapy.

  7. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study.

    Science.gov (United States)

    Beer, Tomasz M; Armstrong, Andrew J; Rathkopf, Dana; Loriot, Yohann; Sternberg, Cora N; Higano, Celestia S; Iversen, Peter; Evans, Christopher P; Kim, Choung-Soo; Kimura, Go; Miller, Kurt; Saad, Fred; Bjartell, Anders S; Borre, Michael; Mulders, Peter; Tammela, Teuvo L; Parli, Teresa; Sari, Suha; van Os, Steve; Theeuwes, Ad; Tombal, Bertrand

    2017-02-01

    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 the longer-term efficacy and safety of enzalutamide up to the prespecified number of deaths in the final analysis, which included an additional 20 mo of follow-up for investigator-assessed rPFS, 9 mo of follow-up for OS, and 4 mo of follow-up for safety. Enzalutamide reduced the risk of radiographic progression or death by 68% (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.28-0.37; p<0.0001) and the risk of death by 23% (HR 0.77, 95% CI 0.67-0.88; p=0.0002). Median investigator-assessed rPFS was 20.0 mo (95% CI 18.9-22.1) in the enzalutamide arm and 5.4 mo (95% CI 4.1-5.6) in the placebo arm. Median OS was 35.3 mo (95% CI 32.2-not yet reached) in the enzalutamide arm and 31.3 mo (95% CI 28.8-34.2) in the placebo arm. At the time of the OS analysis, 167 patients in the placebo arm had crossed over to receive enzalutamide. The most common adverse events in the enzalutamide arm were fatigue, 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.

  8. Effects of androgen deprivation therapy and bisphosphonate treatment on bone in patients with metastatic castration-resistant prostate cancer: results from the University of Washington Rapid Autopsy Series.

    Science.gov (United States)

    Morrissey, Colm; Roudier, Martine P; Dowell, Alex; True, Lawrence D; Ketchanji, Melanie; Welty, Christopher; Corey, Eva; Lange, Paul H; Higano, Celestia S; Vessella, Robert L

    2013-02-01

    Qualitative and quantitative bone features were determined in nondecalcified and decalcified bone from 20 predetermined bone sites in each of 44 patients who died with castration-resistant prostate cancer (CRPC), some of which received bisphosphonate treatment (BP) in addition to androgen-deprivation therapy (ADT). Thirty-nine of the 44 patients (89%) had evidence of bone metastases. By histomorphometric analysis, these bone metastases were associated with a range of bone responses from osteoblastic to osteolytic with a wide spectrum of bone responses often seen within an individual patient. Overall, the average bone volume/tissue volume (BV/TV) was 25.7%, confirming the characteristic association of an osteoblastic response to prostate cancer bone metastasis when compared with the normal age-matched weighted mean BV/TV of 14.7%. The observed new bone formation was essentially woven bone, and this was a localized event. In comparing BV/TV at metastatic sites between patients who had received BP treatment and those who had not, there was a significant difference (28.6% versus 19.3%, respectively). At bone sites that were not invaded by tumor, the average BV/TV was 10.1%, indicating significant bone loss owing to ADT that was not improved (11%) in those patients who had received BPs. Surprisingly, there was no significant difference in the number of osteoclasts present at the metastatic sites between patients treated or not treated with BPs, but in bone sites where the patient had been treated with BPs, giant osteoclasts were observed. Overall, 873 paraffin-embedded specimens and 661 methylmethacrylate-embedded specimens were analyzed. Our results indicate that in CRPC patients, ADT induces serious bone loss even in patients treated with BP. Furthermore, in this cohort of patients, BP treatment increased BV and did not decrease the number of osteoclasts in prostate cancer bone metastases compared with bone metastases from patients who did not receive BP.

  9. Repurposing Itraconazole as a Treatment for Advanced Prostate Cancer: A Noncomparative Randomized Phase II Trial in Men With Metastatic Castration-Resistant Prostate Cancer

    Science.gov (United States)

    Heath, Elisabeth I.; Smith, David C.; Rathkopf, Dana; Blackford, Amanda L.; Danila, Daniel C.; King, Serina; Frost, Anja; Ajiboye, A. Seun; Zhao, Ming; Mendonca, Janet; Kachhap, Sushant K.; Rudek, Michelle A.; Carducci, Michael A.

    2013-01-01

    Background. The antifungal drug itraconazole inhibits angiogenesis and Hedgehog signaling and delays tumor growth in murine prostate cancer xenograft models. We conducted a noncomparative, randomized, phase II study evaluating the antitumor efficacy of two doses of oral itraconazole in men with metastatic prostate cancer. Patients and Methods. We randomly assigned 46 men with chemotherapy-naïve metastatic castration-resistant prostate cancer (CRPC) to receive low-dose (200 mg/day) or high-dose (600 mg/day) itraconazole until disease progression or unacceptable toxicity. The primary endpoint was the prostate-specific antigen (PSA) progression-free survival (PPFS) rate at 24 weeks; a 45% success rate in either arm was prespecified as constituting clinical significance. Secondary endpoints included the progression-free survival (PFS) rate and PSA response rate (Prostate Cancer Working Group criteria). Exploratory outcomes included circulating tumor cell (CTC) enumeration, serum androgen measurements, as well as pharmacokinetic and pharmacodynamic analyses. Results. The high-dose arm enrolled to completion (n = 29), but the low-dose arm closed early (n = 17) because of a prespecified futility rule. The PPFS rates at 24 weeks were 11.8% in the low-dose arm and 48.0% in the high-dose arm. The median PFS times were 11.9 weeks and 35.9 weeks, respectively. PSA response rates were 0% and 14.3%, respectively. In addition, itraconazole had favorable effects on CTC counts, and it suppressed Hedgehog signaling in skin biopsy samples. Itraconazole did not reduce serum testosterone or dehydroepiandrostenedione sulfate levels. Common toxicities included fatigue, nausea, anorexia, rash, and a syndrome of hypokalemia, hypertension, and edema. Conclusion. High-dose itraconazole (600 mg/day) has modest antitumor activity in men with metastatic CRPC that is not mediated by testosterone suppression. PMID:23340005

  10. Predictors of long-term response to abiraterone in patients with metastastic castration-resistant prostate cancer: a retrospective cohort study

    Science.gov (United States)

    Verzoni, Elena; Giorgi, Ugo De; Derosa, Lisa; Caffo, Orazio; Boccardo, Francesco; Facchini, Gaetano; Porcu, Luca; Vincenzo, Fabio De; Zaniboni, Alberto; Chiuri, Vincenzo Emanuele; Fratino, Lucia; Santini, Daniele; Adamo, Vincenzo; Vivo, Rocco De; Dinota, Angelo; Messina, Caterina; Ricotta, Riccardo; Caserta, Claudia; Scavelli, Claudio; Susi, Marina; Tartarone, Alfredo; Surace, Giuseppe; Mosca, Alessandra; Bruno, Michele; Barni, Sandro; Grassi, Paolo; Procopio, Giuseppe

    2016-01-01

    We aimed to identify clinical predictors of long-term response to abiraterone (defined as >12 months drug exposure) in a retrospective cohort of metastatic castration-resistant prostate cancer patients treated in post-docetaxel setting at 24 Italian centers. The Cox proportional hazards model was used to analyze the association between clinical features and the duration of drug exposure. Results were expressed as hazard ratios (HR) with associated 95% confidence intervals (CI). A total of 143 patients met the inclusion criteria. Their median age was 73 years, median Gleason score 8 and median abiraterone exposure 20 months. At the univariate analysis, a significant correlation with the duration of abiraterone exposure was found for Gleason score (HR 0.82, 95% CI 0.71-0.96; p=0.012), PSA (HR 1.10, 95% CI 1.03-1.18; p=0.08) and lactic dehydrogenase levels (HR 1.22, 95% CI 1.02-1.46; p=0.027), while the association between lower alkaline phosphatase levels and treatment duration was marginally significant (HR 1.07, 95% CI 0.99-1.16; p=0.074). Only PSA and Gleason score were predictive of long-term treatment duration in the multivariate analysis. No other clinical factors resulted to be predictive of sustained response to abiraterone, including metastatic disease at diagnosis and visceral disease, suggesting that all subgroups of patients may derive a substantial clinical benefit from abiraterone treatment. These findings need to be validated in prospective, larger studies. PMID:27223078

  11. First Line Androgen Deprivation Therapy Duration Is Associated with the Efficacy of Abiraterone Acetate Treated Metastatic Castration-Resistant Prostate Cancer after Docetaxel

    Science.gov (United States)

    Li, Jian-Ri; Wang, Shian-Shiang; Yang, Cheng-Kuang; Chen, Chuan-Su; Ho, Hao-Chung; Chiu, Kun-Yuan; Hung, Chi-Feng; Cheng, Chen-Li; Yang, Chi-Rei; Chen, Cheng-Che; Wang, Shu-Chi; Lin, Chia-Yen; Ou, Yen-Chuan

    2017-01-01

    Introduction: We performed a chart review study in our castration-resistant prostate cancer (CRPC) patients who received Abiraterone acetate (AA) treatment after docetaxel and identified clinical markers which can predict treatment outcome. Materials and Methods: From 2012 to 2016, 64 patients who received docetaxel after CRPC followed by AA treatment were included. Clinical parameters were recorded and analysis was performed to identify associations between pre-treatment variables and treatment outcome. Results: Thirty three patients (51.6%) achieved a decrease in PSA of 50%. The median PSA progression-free survival and overall survival in the total cohort of 64 patients were 6.6 and 24 months, respectively. Adverse events (AEs) in all grades developed in 35.9% (23/64) patients and mostly were grade 1 or 2. The most common AEs were gastric upset, hypokalemia and elevated liver function tests. Of the eight variables analyzed, first line androgen deprivation therapy (ADT) duration showed positive association to progression free survival (HR 0.98, 95% CI [0.96–0.99], p = 0.012) and overall survival (HR 0.97, 95% CI [0.94–0.99], p = 0.019). Pre-AA PSA and PSA progression ratio showed negative association only to progression free survival (HR 1.0, 95% CI [1.000–1.002], p = 0.025, HR 1.01, 95% CI [1.00–1.01], p < 0.001, respectively). Conclusion: First line ADT duration was positively associated with AA treatment efficacy in progression free survival and overall survival. It can be used as a pre-treatment predictor. PMID:28243202

  12. A transient increase in eosinophils is associated with prolonged survival in men with metastatic castration-resistant prostate cancer who receive sipuleucel-T.

    Science.gov (United States)

    McNeel, Douglas G; Gardner, Thomas A; Higano, Celestia S; Kantoff, Philip W; Small, Eric J; Wener, Mark H; Sims, Robert B; DeVries, Todd; Sheikh, Nadeem A; Dreicer, Robert

    2014-10-01

    Sipuleucel-T is an autologous cellular immunotherapy used to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Traditional short-term indicators of clinical response commonly used with chemotherapy have not correlated with survival in patients treated with sipuleucel-T. This retrospective study aimed to evaluate laboratory parameters as possible early biomarkers associated with clinical benefit following sipuleucel-T treatment. Patients treated with sipuleucel-T from three randomized, controlled, phase III clinical trials in mCRPC were considered: IMPACT (NCT00065442; n = 512), D9901 (NCT00005947; n = 127), and D9902A (NCT01133704; n = 98). Patients from these trials were included in this study if their samples were analyzed by the central laboratory and if data were available from baseline and ≥ 1 posttreatment time point (n = 377). We found that sipuleucel-T treatment was associated with a transient increase in serum eosinophil count at week 6 that resolved by week 14 in 28% of patients (105 of 377). This eosinophil increase correlated with induced immune response, longer prostate cancer-specific survival [HR, 0.713; 95% confidence interval (CI), 0.525-0.970; P = 0.031], and a trend in overall survival (HR, 0.753; 95% CI, 0.563-1.008; P = 0.057). Median serum globulin protein levels also increased transiently, which was associated with antigen-specific antibody responses; however, this finding did not correlate with longer survival. We conclude that transient increases in eosinophils at week 6 may be a useful, objective, short-term indicator of global immune activation and survival benefit with sipuleucel-T in patients with mCRPC. This observation warrants prospective evaluation in future clinical trials.

  13. Cytochrome 450 1B1 (CYP1B1 polymorphisms associated with response to docetaxel in Castration-Resistant Prostate Cancer (CRPC patients

    Directory of Open Access Journals (Sweden)

    Price Douglas K

    2010-09-01

    Full Text Available Abstract Background The selection of patients according to key genetic characteristics may help to tailor chemotherapy and optimize the treatment in Castration-Resistant Prostate Cancer (CRPC patients. Functional polymorphisms within the cytochrome P450 1B1 (CYP1B1 gene have been associated with alterations in enzymatic expression and activity and may change sensitivity to the widely used docetaxel regimen. Methods CYP1B1 genotyping was performed on blood samples of 60 CRPC patients treated with docetaxel, using TaqMan probes-based assays. Association between CYP1B1-142C>G (leading to the 48ArgGly transition, 4326C>G (432LeuVal, and 4390A>G (453AsnSer polymorphisms and treatment response, progression-free-survival (PFS and overall-survival (OS was estimated using Pearson χ2 test, Kaplan-Meier curves and Log-rank test. Results Patients carrying the CYP1B1-432ValVal genotype experienced a significantly lower response-rate (P = 0.014, shorter progression-free-survival (P = 0.032 and overall-survival (P Conclusions CYP1B1-4326C>G (432LeuVal polymorphism emerged as possible predictive marker of response and clinical outcome to docetaxel in CRPC patients and may represent a potential new tool for treatment optimization. Larger prospective trials are warranted to validate these findings, which might be applied to the future practice of CRPC treatment.

  14. 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.

  15. A randomized phase II trial of personalized peptide vaccine plus low dose estramustine phosphate (EMP) versus standard dose EMP in patients with castration resistant prostate cancer.

    Science.gov (United States)

    Noguchi, Masanori; Kakuma, Tatsuyuki; Uemura, Hirotsugu; Nasu, Yasutomo; Kumon, Hiromi; Hirao, Yasuhiko; Moriya, Fukuko; Suekane, Shigetaka; Matsuoka, Kei; Komatsu, Nobukazu; Shichijo, Shigeki; Yamada, Akira; Itoh, Kyogo

    2010-07-01

    Personalized peptide vaccination (PPV) combined with chemotherapy could be a novel approach for many cancer patients. In this randomized study, we evaluated the anti-tumor effect and safety of PPV plus low-dose estramustine phosphate (EMP) as compared to standard-dose EMP for HLA-A2- or -A24-positive patients with castration resistant prostate cancer. Patients were randomized into groups receiving either PPV plus low-dose EMP (280 mg/day) or standard-dose EMP (560 mg/day). After disease progression, patients were switched to the opposite regime. The primary end point was progression-free survival (PFS). We randomly assigned 28 patients to receive PPV plus low-dose EMP and 29 patients to receive standard-dose EMP. Nineteen events in the PPV group and 20 events in the EMP group occurred during the first treatment. Median PFS for the first treatment was 8.5 months in the PPV group and 2.8 months in the EMP group with a hazard ratio (HR) of 0.28 (95% CI, 0.14-0.61; log-rank P = 0.0012), while there was no difference for median PFS for the second treatment. The HR for overall survival was 0.3 (95% CI, 0.1-0.91) in favor of the PPV plus low-dose EMP group (log-rank, P = 0.0328). The PPV plus low-dose EMP was well tolerated without major adverse effects and with increased levels of IgG and cytotoxic-T cell responses to the vaccinated peptides. PPV plus low-dose EMP was associated with an improvement in PSA-based PFS as compared to the standard-dose EMP alone.

  16. Efficacy of estramustine phosphate sodium hydrate (EMP) monotherapy in castration-resistant prostate cancer patients: report of 102 cases and review of literature.

    Science.gov (United States)

    Matsumoto, Kazuhiro; Tanaka, Nobuyuki; Hayakawa, Nozomi; Ezaki, Taisuke; Suzuki, Kenjiro; Maeda, Takahiro; Ninomiya, Akiharu; Nakamura, So

    2013-12-01

    This retrospective chart review study was conducted to evaluate the efficacy of estramustine phosphate sodium hydrate (EMP) monotherapy in patients with castration-resistant prostate cancer (CRPC) and to determine who would benefit from EMP therapy. EMP was administered at a daily dose of 560 mg to 102 patients as a third-line therapy, who had already received combined androgen blockade (CAB) and subsequent alternative antiandrogen therapy. The responses to EMP after its induction and its toxicity were evaluated. We also analyzed the association between the clinicopathological factors of the patients and their responses to EMP therapy. A reduction in the serum prostate-specific antigen (PSA) 4 weeks after induction was observed in 70 patients (68.6%), while 30 cases (29.4%) achieved more than 50% reduction of PSA. Long-term reduction of PSA from baseline for more than 6 months was observed in 31 patients (30.4%). EMP treatment was discontinued in 11 patients (10.8%) because of side effects (nausea in six patients, gynecomastia in three patients, eruption in one patient, and liver dysfunction in one patient). Multivariate analysis demonstrated that long duration of prior hormonal therapy was an independent favorable factor for reduced PSA levels, long responses, and overall survival. The data suggest that oral EMP administration as a third-line monotherapy is well tolerated and effective to some degree in patients with CRPC who have already received CAB and subsequent alternative antiandrogen therapy. Thus, EMP can be regarded as one treatment option, especially for patients whose prior duration of hormonal therapy was long.

  17. 雄激素非依赖性晚期转移性前列腺癌生存预后分析%The survival analysis of the advanced metastatic castration-resistant prostate cancer

    Institute of Scientific and Technical Information of China (English)

    马春光; 施国海; 秦晓健; 林国文; 杨立峰; 杨柏帅; 肖文军; 叶定伟; 姚旭东; 张世林; 戴波; 张海梁; 朱耀; 沈益君; 朱一平

    2009-01-01

    目的 分析雄激素非依赖性晚期转移性前列腺癌的预后相关因素.方法 1996年12月至2008年3月250例晚期转移性前列腺癌患者在内分泌治疗期间进展为雄激素非依赖性前列腺癌,对其进行随访,末次随访时间为2008年3月31日,中位随访时间为24个月(3~135个月).末次随访时131例生存,105例死亡,14例失访.利用统计学软件进行生存预后分析.结果 中位生存时间为30个月.1年牛存率79%,2年生存率59%,3年生存率41%.单因素分析及多因素分析显示:内分泌治疗过程中PSA最低值、达到PSA最低值时间、进展为雄激素非依赖性前列腺癌时PSA速率、内分泌治疗有效时间为独立预后冈素.结论 内分泌治疗过程中PSA最低值、达到PSA最低值时间、进展为雄激素非依赖性前列腺癌时的PSA速率和内分泌治疗有效时间为雄激素非依赖性晚期转移性前列腺癌生存时间的独立预后因素.%Objective To analyze predictive factors of advanced metastatic castration-resistant prostate cancer.Methods From December 1996 to March 2008,250 cases of advanced metastatic prostate cancer progressed into the stage of hormonal independent prostate cancer.The last follow-up date was 31 March 2008 and the median follow-up time was 24 months.During the follow-up,131 cases were alive,105cases were dead and 14 cases were lost to follow-up.Clinical and pathological information of the cases was analyzed to find the predictive factors that related to the prognosis.Results The median survival time of advanced metastatic castration-resistant prostate cancer was 30 months,and the one-year,two-year,three-year survival rate was 79%,59%,and 41%.The univariate analysis indicated that prostate specific antigen (PSA) at diagnosis,clinical stage,the PSA nadir during hormonal therapy,the time form the start of hormonal therapy to the PSA nadir,the time of response duration during hormonal therapy,PSA velocity (PSAV) and PSA doubling

  18. 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

    OpenAIRE

    Norum, Jan; Traasdahl, Erik R.; Totth, Arpad; Nieder, Carsten; Olsen, Jan Abel

    2015-01-01

    DOI: 10.5539/gjhs.v8n4p1 Creative Commons Attribution License 3.0 OBJECTIVES: 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. METHODS: A 74-year-old man diagnosed with mCRPC was referred to our department in O...

  19. Composição tecidual e qualidade da gordura na carne de cordeiros castrados e não castrados confinados sob dois fotoperíodos Tissue composition and fat quality of meat of intact or castrated male lambs confined under two photoperiods

    Directory of Open Access Journals (Sweden)

    M.H. Klein Júnior

    2008-04-01

    Full Text Available Avaliaram-se os efeitos do fotoperíodo e da castração sobre a composição dos tecidos da paleta e características de qualidade da gordura do lombo e da paleta, de 20 cordeiros mestiços Ideal, distribuídos em esquema fatorial 2 x 2 (dois fotoperíodos - curto (FC, com 12 horas de luz, e longo (FL, com 18 horas de luz, e duas condições sexuais - não castrados (NC e castrados (C, com cinco repetições. Os animais foram abatidos aos 37kg de peso corporal. Maior quantidade de gordura total ocorreu nos cordeiros C e mais tecido conjuntivo nos animais NC. A castração influenciou o resíduo mineral fixo (RMF, o extrato etéreo (EE e a proteína da gordura subcutânea. O efeito da interação entre fotoperíodo longo e castração resultou em aumento do teor de umidade na gordura intermuscular da paleta. A castração elevou o teor de EE e diminuiu o percentual de RMF. Não foi evidenciado efeito do fotoperíodo no EE dos músculos da paleta, e os animais castrados apresentaram gordura intramuscular mais elevada. Os níveis de colesterol da paleta foram mais elevados que os do lombo. Na carne de animais C, verificou-se maior quantidade de ácidos graxos saturados.The effects of photoperiod and castration on tissue muscle composition, fat physical-chemical composition, and cholesterol was determined for two muscles of 20 Ideal crossbred lambs. The animals were divided into four treatments: five intact males and five castrate during a short photoperiod of 12 light hours, and five intact males and five castrated during a long photoperiod of 18 light hours. The animals were allocated in individual pens, in two identical rooms, with light intensity of 300 lux, (intact and castrated animals x short and long photoperiod. The animals were slaughtered as they reached 37kg of body weight. Castrated lambs showed a significantly higher amount of total fat tissues while intact animals showed higher connective tissue for the shoulder tissue composition

  20. A longitudinal study of LH, gonadal and adrenal steroids in four intact Asian bull elephants (Elephas maximus) and one castrate African bull (Loxodonta africana) during musth and non-musth periods.

    Science.gov (United States)

    Yon, Lisa; Kanchanapangka, Sumolya; Chaiyabutr, Narongsak; Meepan, Sompast; Stanczyk, Frank Z; Dahl, Nancy; Lasley, Bill

    2007-05-01

    During their annual musth cycle, adult African and Asian bull elephants have increased gonadal androgens (testosterone [T], dihydrotestosterone [DHT], androstenedione [A4]). Because musth is a physiologically and psychologically stressful time, this study was conducted to investigate whether the adrenal glands (stimulated by stress) increase production of both glucocorticoids and androgens during musth. Weekly serum samples were taken for 11-15 months from four intact adult Asian bull elephants, and from a castrate African bull elephant who exhibits musth. Testosterone, androstenediol (A5), A4, luteinizing hormone (LH), cortisol, and dehydroepiandrosterone (DHEA) were measured in each sample. In three of the four intact bulls, all hormones measured increased during musth. Adrenal androgens were strongly correlated with LH and testicular androgens, though not to cortisol. None of the hormones measured in the castrate bull increased during his musth cycles. While the significance of adrenal activity in the elephant during musth has yet to be determined, this study provides evidence that the adrenal gland actively produces both glucocorticoids and androgens during musth in the Asian elephant.

  1. Androgen suppresses the proliferation of androgen receptor-positive castration-resistant prostate cancer cells via inhibition of Cdk2, CyclinA, and Skp2.

    Directory of Open Access Journals (Sweden)

    John M Kokontis

    Full Text Available The majority of prostate cancer (PCa patient receiving androgen ablation therapy eventually develop castration-resistant prostate cancer (CRPC. We previously reported that androgen treatment suppresses Skp2 and c-Myc through androgen receptor (AR and induced G1 cell cycle arrest in androgen-independent LNCaP 104-R2 cells, a late stage CRPC cell line model. However, the mechanism of androgenic regulation of Skp2 in CRPC cells was not fully understood. In this study, we investigated the androgenic regulation of Skp2 in two AR-positive CRPC cell line models, the LNCaP 104-R1 and PC-3AR Cells. The former one is an early stage androgen-independent LNCaP cells, while the later one is PC-3 cells re-expressing either wild type AR or mutant LNCaP AR. Proliferation of LNCaP 104-R1 and PC-3AR cells is not dependent on but is suppressed by androgen. We observed in this study that androgen treatment reduced protein expression of Cdk2, Cdk7, Cyclin A, cyclin H, Skp2, c-Myc, and E2F-1; lessened phosphorylation of Thr14, Tyr15, and Thr160 on Cdk2; decreased activity of Cdk2; induced protein level of p27(Kip1; and caused G1 cell cycle arrest in LNCaP 104-R1 cells and PC-3AR cells. Overexpression of Skp2 protein in LNCaP 104-R1 or PC-3AR cells partially blocked accumulation of p27(Kip1 and increased Cdk2 activity under androgen treatment, which partially blocked the androgenic suppressive effects on proliferation and cell cycle. Analyzing on-line gene array data of 214 normal and PCa samples indicated that gene expression of Skp2, Cdk2, and cyclin A positively correlates to each other, while Cdk7 negatively correlates to these genes. These observations suggested that androgen suppresses the proliferation of CRPC cells partially through inhibition of Cyclin A, Cdk2, and Skp2.

  2. Androgen suppresses the proliferation of androgen receptor-positive castration-resistant prostate cancer cells via inhibition of Cdk2, CyclinA, and Skp2.

    Science.gov (United States)

    Kokontis, John M; Lin, Hui-Ping; Jiang, Shih Sheng; Lin, Ching-Yu; Fukuchi, Junichi; Hiipakka, Richard A; Chung, Chi-Jung; Chan, Tzu-Min; Liao, Shutsung; Chang, Chung-Ho; Chuu, Chih-Pin

    2014-01-01

    The majority of prostate cancer (PCa) patient receiving androgen ablation therapy eventually develop castration-resistant prostate cancer (CRPC). We previously reported that androgen treatment suppresses Skp2 and c-Myc through androgen receptor (AR) and induced G1 cell cycle arrest in androgen-independent LNCaP 104-R2 cells, a late stage CRPC cell line model. However, the mechanism of androgenic regulation of Skp2 in CRPC cells was not fully understood. In this study, we investigated the androgenic regulation of Skp2 in two AR-positive CRPC cell line models, the LNCaP 104-R1 and PC-3AR Cells. The former one is an early stage androgen-independent LNCaP cells, while the later one is PC-3 cells re-expressing either wild type AR or mutant LNCaP AR. Proliferation of LNCaP 104-R1 and PC-3AR cells is not dependent on but is suppressed by androgen. We observed in this study that androgen treatment reduced protein expression of Cdk2, Cdk7, Cyclin A, cyclin H, Skp2, c-Myc, and E2F-1; lessened phosphorylation of Thr14, Tyr15, and Thr160 on Cdk2; decreased activity of Cdk2; induced protein level of p27(Kip1); and caused G1 cell cycle arrest in LNCaP 104-R1 cells and PC-3AR cells. Overexpression of Skp2 protein in LNCaP 104-R1 or PC-3AR cells partially blocked accumulation of p27(Kip1) and increased Cdk2 activity under androgen treatment, which partially blocked the androgenic suppressive effects on proliferation and cell cycle. Analyzing on-line gene array data of 214 normal and PCa samples indicated that gene expression of Skp2, Cdk2, and cyclin A positively correlates to each other, while Cdk7 negatively correlates to these genes. These observations suggested that androgen suppresses the proliferation of CRPC cells partially through inhibition of Cyclin A, Cdk2, and Skp2.

  3. {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

  4. {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

  5. Sipuleucel-T (Provenge) autologous vaccine approved for treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer.

    Science.gov (United States)

    Gardner, Thomas A; Elzey, Bennett D; Hahn, Noah M

    2012-04-01

    Sipuleucel-T (Provenge) (Sip-T) is first -in class as a therapeutic autologous vaccine approved for the treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer. This product is the culmination of decades of basic immunological and prostate cancer investigations and 13 y of clinical trial investigations. Sip-T represents a paradigm shift in cancer therapeutics and represents the first approved autologous therapeutic cancer vaccine, which has demonstrated a survival benefit. The potential benefit of this product is the excellent risk to benefit ratio, which will allow for the combination of this approach with other more toxic therapies. The favorable risk to benefit will also afford the opportunity for trials investigating this product earlier in the disease state and in combination with local therapies. The ability to target more localized or lower volume disease will maximize the therapeutic benefit over a longer period of time. The novelty of the platform of this approach could be used to treat any cancer with a tumor-specific cell surface target. The main product of Sip-T is the re-infusion of a patient's antigen presenting cells from leukapheresis after ex-vivo exposure to a chimeric protein of human GM-CSF and PAP. In metastatic CRPC patients three infusions of these activated cells over a month lead to statistically significant 4.1 mo increase in median survival and a 22.5% reduction in risk of death. The main side effect from this re-infusion of activated immune cells is a "flu-like" syndrome that includes chills, fatigue, fevers, back pain, nausea, joints aches and headaches in decreasing order of frequency. Immune monitoring during the clinical trials also demonstrated a specific cellular and antibody immune response, suggesting the proposed mechanism of adoptive immunotherapy to PAP was behind this survival benefit. This product also serves as a proof of principle for targeted immunotherapy for others

  6. Whole blood defensin mRNA expression is a predictive biomarker of docetaxel response in castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Kohli M

    2015-07-01

    Full Text Available Manish Kohli,1 Charles YF Young,2 Donald J Tindall,2 Debashis Nandy,1 Kyle M McKenzie,3 Graham H Bevan,4 Krishna Vanaja Donkena5 1Department of Oncology, 2Department of Urology, 3Department of Geriatric Medicine, Mayo Clinic, Rochester, MN, 4University of Rochester Medical Center, Rochester, NY, 5Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA Abstract: This study tested the potential of circulating RNA-based signals as predictive biomarkers for docetaxel response in patients with metastatic castration-resistant prostate cancer (CRPC. RNA was analyzed in blood from six CRPC patients by whole-transcriptome sequencing (total RNA-sequencing before and after docetaxel treatment using the Illumina’s HiSeq platform. Targeted RNA capture and sequencing was performed in an independent cohort of ten patients with CRPC matching the discovery cohort to confirm differential expression of the genes. Response to docetaxel was defined on the basis of prostate-specific antigen levels and imaging criteria. Two-way analysis of variance was used to compare differential gene expression in patients classified as responders versus nonresponders before and after docetaxel treatment. Thirty-four genes with two-fold differentially expressed transcripts in responders versus nonresponders were selected from total RNA-sequencing for further validation. Targeted RNA capture and sequencing showed that 13/34 genes were differentially expressed in responders. Alpha defensin genes DEFA1, DEFA1B, and DEFA3 exhibited significantly higher expression in responder patients compared with nonresponder patients before administration of chemotherapy (fold change >2.5. In addition, post-docetaxel treatment significantly increased transcript levels of these defensin genes in responders (fold change >2.8. Our results reveal that patients with higher defensin RNA transcripts in blood respond well to docetaxel therapy. We suggest that monitoring DEFA1, DEFA1B, and DEFA3

  7. Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5

    NARCIS (Netherlands)

    K. Fizazi (Karim); R. Jones (Robert); S. Oudard (Stéphane); E. Efstathiou (Eleni); F. Saad (Fred); R. de Wit (Ronald); J.S. de Bono (Johann); F.M. Cruz (Felipe Melo); G. Fountzilas (George); A. Ulys (Albertas); F. Carcano (Flavio); N. Agarwal (Neeraj); D. Agus (David); J. Bellmunt (Joaquim); D.P. Petrylak (Daniel P); S.-Y. Lee (Shih-Yuan); I.J. Webb (Iain J.); B. Tejura (Bindu); N. Borgstein (Niels); R. Dreicer (Robert)

    2015-01-01

    textabstractPurpose: Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. Patients and Methods: In our study, 1,099

  8. Efeito da castração pré-púbere sobre o desenvolvimento corporal de equinos - DOI: 10.4025/actascianimsci.v26i2.1883 Pre-puberty castration effect on equine body development - DOI: 10.4025/actascianimsci.v26i2.1883

    Directory of Open Access Journals (Sweden)

    Nilva Aparecida Nicolao Fonseca

    2004-04-01

    Full Text Available Foi realizado um experimento com o objetivo de avaliar o efeito da castração pré-púbere sobre o desenvolvimento corporal de cavalos de trabalho. Foram utilizados 18 potros meio-irmãos paternos, meio sangue mangalarga, dos quais 8 foram castrados aos 2 meses de idade. As características avaliadas foram as alturas da cernelha, do dorso, da anca, do costado e do esterno, os comprimentos do corpo e da garupa, as larguras do costado, da bacia, da anca e do peito e os perímetros da canela e torácico, as quais foram medidas aos 2, 12 e 24 meses de idade. Foram avaliados, também aos 24 meses, os índices de carga, de compacidade, corporal, anamorfósico, de altura peitoral e dactilo-torácico. Observou-se que, aos 24 meses, não ocorreram diferenças significativas entre os animais castrados e os não-castrados, exceto para peso vivo, perímetro torácico e índice de compacidade, que foram superiores para os animais não-castrados. Conclui-se que é viável a castração de animais jovens.Aiming to evaluate the effect of pre-puberty castration on traction horses' body development, the experiment was carried out with 18 cross breeding Mangalarga foals. The animals belonged to the same stallion offspring and were castrated at 2 months old. The following characteristics were measured at ages 2, 12 and 24 months: the hights of withers, back chine, hook, ribs and chest floor, the lengths of body and rump, the widths of thurl, hook and chest and the perimeters of limbs and thorax. Besides, loading, capacity, body, morphological, chest and dactyl-thorax indexes were also measured. The results showed that there were not significant differences between castrated and non-castrated animals for almost all measured characteristics. However, castrated horses had greater liveweight, thorax perimeter and index capacity than non-castrated animals. Thus, it was concluded that pre-puberty castration is feasible.

  9. 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

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    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.

  10. 转移性去势抵抗性前列腺癌化疗后预后的影响因素%Factors Influencing Prognosis of Metastatic Castration-resistant Prostate Cancer after Chemotherapy

    Institute of Scientific and Technical Information of China (English)

    庞华

    2014-01-01

    Objective To investigate prognostic factors of metastatic castration-resistant prostate cancer ( mCRPC ) trea-ted with docetaxel chemotherapy .Methods Age,Gleason score ,prostate-specific antigen ,blood baseline condition and hormone-sensitive time of 46 patients with mCRPC were recorded .Results Overall survival time of all patients was 3-45 months,the aver-age survival time was (21.34 ±2.13) months,median survival time was 19.36 months;cox regression analysis showed that Glea-son score,hemoglobin,hormone-sensitive time were related with the patient's survival time,RR values were 1.782,2.363 and 2.012,and P<0.05.Conclusion Gleason score,hemoglobin concentration ,and hormone-sensitive time before chemotherapy are prognostic factors of metastatic castration resistant prostate cancer .%目的:探讨采用多西紫杉醇化疗的转移性去势抵抗性前列腺癌( metastatic castration-resistant prostate canc-er,MCRPC)患者预后影响因素。方法以转移性去势抵抗性前列腺癌患者46例作为观察对象,记录患者化疗前年龄、Gleason评分、前列腺特异抗原(prostate-specific antigen,PSA)值、血常规等基线情况及激素敏感时间。结果患者总生存时间为3~45个月,平均生存期为(21.34±2.13)个月,中位生存时间为19.36个月;Cox回归结果提示,Gleason评分、血红蛋白水平、激素敏感时间与患者生存时间相关,RR值分别为1.782、2.363和2.012,且P<0.05。结论多西他赛化疗前Gleason评分、血红蛋白浓度及激素敏感时间,是转移性去势抵抗性前列腺癌患者的预后因素。

  11. Phase I clinical trial of sipuleucel-T combined with escalating doses of ipilimumab in progressive metastatic castrate-resistant prostate cancer

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    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

  12. Efficacy and safety of second-line agents for treatment of metastatic castration-resistant prostate cancer progressing after docetaxel. A systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Gianpaolo Perletti

    2015-07-01

    Full Text Available Objective: We performed a systematic review of the literature to assess the efficacy and the safety of second-line agents targeting metastatic castration-resistant prostate cancer (mCRPC that has progressed after docetaxel. Pooled-analysis was also performed, to assess the effectiveness of agents targeting the androgen axis via identical mechanisms of action (abiraterone acetate, orteronel. Materials and Methods: We included phase III randomized controlled trials that enrolled patients with mCRPC progressing during or after first-line docetaxel treatment. Trials were identified by electronic database searching. The primary outcome of the review was overall survival. Secondary outcomes were radiographic progression-free survival (rPFS and severe adverse effects (grade 3 or higher. Results: Ten articles met the inclusion criteria for the review. These articles reported the results of five clinical trials, enrolling in total 5047 patients. The experimental interventions tested in these studies were enzalutamide, ipilimumab, abiraterone acetate, orteronel and cabazitaxel. Compared to control cohorts (active drug-treated or placebotreated, the significant overall survival advantages achieved were 4.8 months for enzalutamide (hazard ratio for death vs. placebo: 0.63; 95% CI 0.53 to 0.75, P < 0.0001, 4.6 months for abiraterone (hazard ratio for death vs. placebo: 0.66, 95% CI 0.58 to 0.75, P < 0.0001 and 2.4 months for cabazitaxel (hazard ratio for death vs. mitoxantrone-prednisone: 0.70, 95% CI 0.59 to 0.83, p < 0.0001. Pooled analysis of androgen synthesis inhibitors orteronel and abiraterone resulted in significantly increased overall and progression-free survival for anti-androgen agents, compared to placebo (hazard ratio for death: 0.76, 95% CI 0.67 to 0.87, P < 0.0001; hazard ratio for radiographic progression: 0.7, 95% CI 0.63 to 0.77, P < 0.00001. Androgen synthesis inhibitors induced significant increases in risk ratios for adverse effects

  13. Alveolar Bone Reduction Curves of Castrated Rats after Incisors Extraction%去势大鼠下切牙拔除后牙槽骨吸收曲线的绘制

    Institute of Scientific and Technical Information of China (English)

    兰泽栋; 郑雅心; 吴琳琳

    2013-01-01

    目的:研究去势大鼠下切牙拔除后牙槽骨吸收曲线.方法:6组雄性Wistar大鼠在全麻下去势并拔除右下切牙,分别于0、1、2、4、8、12周处死.用软X线拍摄大鼠下颌骨,测量并计算出颊侧、舌侧牙槽骨高度和宽度的吸收值绘制曲线.结果:0~12周颊、舌侧牙槽骨高度吸收值表现为先快速增加后快速下降的曲线;而宽度吸收值未见明显变化.结论:该曲线可作为预防牙槽骨吸收的基础性研究.%Objective:To investigate the alveolar bones reduction curves of of castrated rats after incisors extraction.Methods:Six groups of Wistar rats were castrated after general anesthesia and the right lower incisors were extracted respectively.All rats were sacrificed at 0,1,2,4,8,12 weeks after tooth-extractions.After photographing the rats' mandibules with molybdenum target soft X-ray,we measured and calculated the vertical and horizontal dimension changes of buccal and lingual sides to draw curves.Results:The vertical resorption of buccal and lingual sides of alveolar bones appear to be rapid loss at first few weeks and declined dramatically thereafter during the 12 weeks.However,there were no significant changes of horizontal dimension.Conclusion:These curves can be a theoretical basis for preventing residual alveolar ridge resorption.

  14. Effects of Castration on Blood Testosterone Content,Growth Performance and APPearance Characteristics of Wannan Cattle Aged from 12 to 18 Months%去势对12~18月龄皖南牛血液睾酮含量、生长性能和外貌特征的影响

    Institute of Scientific and Technical Information of China (English)

    张兴隆; 汪先友; 何阳; 薛志杰; 杨莹; 曹兵海

    2014-01-01

    The purpose of this experiment was to study the effects of castration on blood testosterone content, growth performance and appearance characteristics of Wannan cattle aged from 12 to 18 months. Twelve Wan-nan cattle aged 12 months with similar body weight and body size were selected and assigned to 2 groups with 6 heads in each group. Cattle in one group were castrated,while those in the other group were not castrated. The results showed as follows:castration significantly reduced the average content of blood testosterone of Wannan cattle aged from 12 to 18 months( P 0.05),and the difference occurred in the first three months after castration;castration significantly reduced the average value of body length increased per month at 12 to 18 months of age( P0.05). It is concluded that castration can down-reg-ulate blood testosterone content,inhibited the growth of the body sizes shortly after castration,and changed the appearance characteristics of Wannan cattle,especially the development of muscle of neck and front 1 / 4 of trunk.%本试验目的是研究去势对12~18月龄皖南牛血液睾酮含量、生长性能和外貌特征的影响。选择12头12月龄体重与体尺相近的皖南牛随机分为2组,每组6头,一组进行去势处理,另一组未进行去势处理。结果表明:去势极显著减低了12~18月龄皖南牛血液睾酮含量的平均值(P<0.01)。去势组18月龄体重显著低于未去势组(P<0.05),这主要是由于去势后2个月平均日增重的大幅降低。去势组18月龄的体高要低于去未势牛组,但差异不显著( P>0.05),2组间的差异主要是在去势后3个月引起的;去势显著降低了12~18月龄月增加体斜长的平均值(P<0.05),影响主要发生在去势后5个月内;去势后2个月内去势组月增加胸围均低于未去势组,但差异不显著(P>0.05)。结果提示,去势能降低皖南牛血液睾酮含量,短期内抑

  15. 去势雄性大鼠肾上腺皮质束状带和网状带的变化及低雄激素对COX-2信号通路的影响%Changes in zona fasciculata and reticularis of adrenal cortex in castrated male rats and effect of low androgen on signal iathway of COX-2

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    施超; 陆颖理; 李艳香; 翟华玲; 姜博仁; 李影; 夏芳珍; 徐慧; 乔洁; 林东平

    2011-01-01

    Objective To investigate the changes in structure and function of zona fasciculata and reticularis of adrenal cortex in castrated male rats, and explore the effect of low androgen on the signal pathway of cyclooxgenase-2 (COX-2). Methods Thirty male SD rats aged 10 weeks were randomly divided into control group (n =8), castration group (n = 11) and replacement group ( n = 11). Rats in control group received sham castration, those in castration group underwent castration, and those in replacement group were managed with testosterone undecanoate (SO rag/kg per month) after castration. Ten weeks later, serum samples were collected for determination of serum concentrations of testosterone (T), corticosterone ( F) , adrenocorticotrophic hormone ( ACTH) , luteinizing hormone ( LH) and follicle-stimulating hormone (FSH) by radioimmunoassay, adrenal cortex tissues were obtained for observation of morphological changes in zona fasciculata and reticularis of adrenal cortex with HE staining by light microscopy and ultrastructural changes by transmission electron microscopy, and the expression of COX-2 mRNA in tissues of adrenal cortex and thoracoabdominal aorta was detected by RT-PCR. Results Serum T concentration in castration group was significantly lower than those in control group and replacement group (F<0.01), and serum concentrations of F, ACTH, LH and FSH in castration group were significantly higher than those in control group and replacement group (P<0.05). Cells in zona fasciculate and reticularis of adrenal cortex in castration group were larger, with bigger nuclei, more mitochondrion, better-developed smoothendoplasmic reticula and less lipid droplets. However, the morphology and infrastructure of cells in zona fasciculata and reticularis of adrenal cortex in replacement group were similar to those in control group. The expression of COX-2 mRNA in adrenal cortex tissues in castration group was significantly lower than that in control group and replacement group

  16. The Effect of Castration on the Synaptic Plasticity of HVC-RA in Adult Male Zebra Finch (Taeniopygia Guttata)%去势对成年雄性斑胸草雀HVC-RA突触可塑性的影响

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    陈小鑫; 王松华; 李东风

    2016-01-01

    应用在体电生理方法研究了去势前后成年雄性斑胸草雀发声运动通路中HVC-RA 突触的可塑性变化,进一步探讨雄激素在调节鸣唱行为中的作用和机制。结果表明:低频刺激可引起 HVC-RA突触群体峰电位幅度的短时程抑制( Short-term depression, STD),高频刺激可引起群体峰电位幅度的长时程抑制( Long-term depression, LTD)。而去势后30 d,鸣曲稳定时再给予同样的条件刺激,发现无论低频或高频刺激,HVC-RA 突触的短时程抑制和长时程抑制现象同时消失。研究结果显示:鸣曲稳定性可能依赖于HVC-RA通路的突触可塑性,雄激素在维持鸣曲稳定过程中发挥重要作用。%Songbirds are animal with the ability of vocal learning like human, and the neural basis of vocal learning is similar to the language learning of human. This study investigated the changes in synaptic plasticity of HVC-RA synapses in adult male zebra finches after castration with in vivo electrophysiology technique, analysed the potential functions and mechanisms of androgen in the process of modulating courtship song and song maintaining. The re-sults showed that low frequency stimulation induced short-term depression, high frequency stimulation induced long-term depression in HVC-RA synapses of adult male zebra finches. When the singing was stable after castration, we found that low or high frequency stimulation could not induce long-term or short-term synaptic depression. These re-sults suggested that the stability of singing may depend on HVC-RA synaptic plasticity, and androgens may play an important role in the song stability.

  17. Influência da castração e da idade de abate sobre as características subjetivas e instrumentais da carne de cordeiros Corriedale Effects of castration and slaughtering age on the subjective and instrumental characteristics of meat from Corriedale lambs

    Directory of Open Access Journals (Sweden)

    Eunice de Leon Rota

    2006-12-01

    Full Text Available Este trabalho foi realizado com o objetivo de avaliar o efeito da castração e da idade de abate sobre as características subjetivas e instrumentais da carne de cordeiros Corriedale criados em condições extensivas de pastagem natural. Foram utilizados 60 cordeiros machos (30 não-castrados e 30 castrados abatidos no ano de 2003, aos 120, 210 e 360 dias de idade, nos meses de fevereiro, maio e outubro, respectivamente. As avaliações da carne foram realizadas no músculo Longissimus dorsi. Pela análise da variância, verificou-se que não houve efeito da interação castração × idade de abate nas características estudadas. Foi encontrada significância para a idade de abate nas características subjetivas espessura de gordura de cobertura e marmoreio (os índices foram mais baixos nos animais mais velhos e em todas as características instrumentais avaliadas, principalmente maciez, que diminuiu com o aumento da idade de abate. O efeito da castração foi significativo somente no componente de cor L*. A qualidade da carne foi similar entre cordeiros Corriedale castrados e não-castrados criados extensivamente em pastagem natural, entretanto, a idade de abate influenciou a qualidade da carne, que foi melhor nos animais abatidos aos 120 dias.The objective of this trial was to evaluate the effects of castration and slaughtering age on subjective and instrumental characteristics of meat from Corriedale lambs raised on native pasture. Sixty male lambs (30 castrated and 30 intact slaughtered at 120, 210 and 360 days of age were used in this experiment. The Longissimus dorsi muscle was used for all meat evaluations and analysis. No significant castration × slaughtering age interaction was observed for the studied variables. A significant slaughtering age effect was found for meat fat thickness and marbling, which had lower scores in animals slaughtered at more advanced age as well as for all instrumental characteristics of the meat, mainly

  18. Incidence and relative risk of adverse events of special interest in patients with castration resistant prostate cancer treated with CYP-17 inhibitors: A meta-analysis of published trials.

    Science.gov (United States)

    Roviello, Giandomenico; Sigala, Sandra; Danesi, Romano; Re, Marzia Del; Bonetta, Alberto; Cappelletti, Maria Rosa; Zanotti, Laura; Bottini, Alberto; Generali, Daniele

    2016-05-01

    Abiraterone acetate and orteronel are two CYP-17 inhibitors that have been studied in prostate cancer. They have shown relevant toxicities, including fluid retention/oedema, hypokalaemia, hypertension, liver function test abnormalities and cardiac events. The goal of this study was to determine the risk of special adverse events related to CYP- 17 inhibitor in patients with metastatic castration-resistant prostate cancer (CRCP). Summary data from four randomized phase III trials comparing CYP-17 inhibitors and prednisone versus placebo and prednisone in metastatic CRCP patients were meta-analysed. Pooled risk ratios (RRs) for the risk of all-grade and grade 3-4 adverse events of special interest were calculated. Data from 4916 patients (2849 in the AA experimental arm; 2067 in the control arm) were analysed. The incidence of grade 3-4 adverse events was never more than 10% of the patients. However, compared with placebo, the CYP-17 inhibitor significantly increased the all-grade events of hypertension (RR=1.53; 95% CI=1.3-1.8; pevents, hypokalaemia (RR=4.23; 95% CI=1.28-13.99; p=0.02) and cardiac disorders (RR=1.55; 95% CI=1.18-2.05; p=0.002). A lot of adverse events such as hypertension, hypokalaemia, cardiac disorders and liver function test abnormalities are increased during CYP-17 inhibitor based therapy. Strict monitoring of these side effects should be considered during CYP- 17 inhibitor therapy in prostate cancer patients.

  19. 手术去势间断联合多西他赛治疗晚期前列腺癌的疗效观察%Clinic Study of Surgical Castration Intermittent Combined with Docetaxel for Advanced Prostate Cancer

    Institute of Scientific and Technical Information of China (English)

    李宏志; 刘民; 朱庆环; 郭丽晔; 李英杰; 孙志广

    2016-01-01

    目的:探讨手术去势间断联合多西他赛治疗晚期前列腺癌的临床疗效。方法收集75例转移性前列腺癌患者的病历资料。按照临床治疗方法不同将患者分为实验组和对照组,实验组28例,对照组47例。实验组患者采取睾丸切除去势+多西他赛治疗,对照组患者采取睾丸切除去势治疗。观察患者的临床疗效、PSA水平、疼痛评分及不良反应发生情况,观察患者生活质量评分变化情况。结果实验组患者治疗后PSA水平、疼痛评分低于治疗前和对照组,差异有统计学意义(P<0.05);治疗后,对照组患者PSA水平、疼痛评分低于治疗前,差异有统计学意义(P<0.05)。实验组患者红细胞、白细胞减少,恶心呕吐,骨髓抑制,手足综合征,脱发发生率显著低于对照组,差异有统计学意义(P<0.05)。实验组患者生活质量评分高于治疗前和对照组,差异有统计学意义(P<0.05);治疗后,对照组患者生活质量评分高于治疗前,差异有统计学意义( P<0.05)。实验组患者中位生存时间、无进展生存时间、2年生存率均高于对照组,差异有统计学意义(P<0.05)。结论手术去势间断联合多西他赛治疗晚期前列腺癌效果较好,能改善患者PSA水平、疼痛情况,减少不良反应发生情况,提高患者的生活质量,临床应用价值较高。%Objective To explore the clinical efficacy of surgical castration intermittent combined with docetaxel treat -ment for advanced prostate cancer .Methods 75 cases of patients with metastatic prostate cancer were divided into the experi-ment group and the control group .The control group were treated by testicular resection castration +docetaxel,the control group were treated by testicular resection castration .The clinical effects ,the levels of PSA ,the scores of pain ,complication ,the scores of quality of life were

  20. Effects of erzhibaihe extraction on the anxiety behavior of the female castrated rats%二至百合浓缩膏对去势雌性大鼠焦虑行为学的影响

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    靳冉; 翟建英; 岳枫; 张瀚涛; 陈霞; 刘丹; 李晋生

    2013-01-01

    目的探讨二至百合浓缩膏对去势雌性大鼠(双侧卵巢切除术)焦虑行为学的影响。方法3~4月龄Wistar雌性大鼠随机分成5组,假手术对照组,模型组,二至百合高、中、低剂量组。除假手术组,其余用手术摘除双侧卵巢建立去势更年期大鼠模型,给药组分别给予二至百合浓缩膏水溶液(1.92、0.96、0.48g/kg),假手术空白对照组和模型对照组给予相应容量的蒸馏水,连续45d。采用高架十字迷宫和明暗箱实验,观察实验大鼠行为学的变化。结果二至百合高剂量组可显著减低模型大鼠高架十字迷宫实验中OT%,与模型组比较差异有统计学意义(P<0.05)。二至百合高、中剂量组亦可显著升高大鼠明箱停留时间和穿箱次数,与模型组比较差异有统计学意义(均P<0.05)。结论二至百合浓缩膏具有较好的改善去势雌性模型大鼠焦虑症状的作用。%Objective To study the effects of Erzhibaihe extraction on the anxiety behavior of the female castrated rats. Methods 3-4 month-old female wistar rats were randomized into five groups with pseudo-operated group,model group,erzhibaihe high dose group, Medium dose group and low dose group. All rats were established the models of climacteric syndrome with ovariectomized surgical except pseudo-operated group. Treatment group were given Erzhibaihe extraction(1.92,0.96,0.48 g/kg)for 45 days, pseudo-operated group and model group rats were given corresponding volumes of distilled water.Then the elevated plus-maze test and light-dark transitions test were performed to observe behavior changes of rats. Results Compared with pseudo-operated group,the OE%(open arm entry percent)and OT%(open arm time percent)of model group rats were significantly reducedin the elevated plus-maze test.The OT% of Erzhibaihe high dose group were significantly reduced,and there were significantly differenceswith model group.In the light

  1. 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.)

  2. Research progress on the molecular signaling pathway of castration-resistant prostate cancer%去势抵抗性前列腺癌分子信号通路的研究进展

    Institute of Scientific and Technical Information of China (English)

    张秀娜; 赵伟; 高晓芳; 杨勇; 季晖

    2015-01-01

    在美国前列腺癌( PCa)是男性最常见的非皮肤性癌症以及癌症相关死亡的第二号杀手。雄激素与雄激素受体是前列腺癌的关键效应器,因此,雄激素剥夺治疗( ADT)是前列腺癌患者的一线治疗方法,并且效果良好,但是前列腺肿瘤最终复发并进展为去势抵抗性前列腺癌( CRPC)这一致命性形式。研究雄激素受体与去势抵抗性前列腺癌发生发展的关系及其可能的分子机制,可以为其临床诊断、治疗以及进一步的研究提供科学依据。%In United States,prostate cancer is the most commonly diagnosed non-cutaneous cancer in males and the second leading cause of cancer-related death for men. Androgen and the androgen receptor( AR)are critical effectors of prostate cancer. Consequently,androgen deprivation therapy( ADT)is typically employed as a first-line treatment for pros-tate cancer patients. While initial responses are generally positive,prostate tumors frequently recur and progress to a lethal form known as castration-resistant prostate cancer( CRPC). To study the relationship between androgen receptor and the initiation and development of CRPC,along with the possible molecular mechanisms,helps to diagnosis and treatment of cas-tration-resistant prostate cancer( CRPC),and provide the basis for further research.

  3. Co-targeting hexokinase 2-mediated Warburg effect and ULK1-dependent autophagy suppresses tumor growth of PTEN- and TP53-deficiency-driven castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Lei Wang

    2016-05-01

    Full Text Available Currently, no therapeutic options exist for castration-resistant prostate cancer (CRPC patients who have developed resistance to the second generation anti-androgen receptor (AR axis therapy. Here we report that co-deletion of Pten and p53 in murine prostate epithelium, often observed in human CRPC, leads to AR-independent CRPC and thus confers de novo resistance to second generation androgen deprivation therapy (ADT in multiple independent yet complementary preclinical mouse models. In contrast, mechanism-driven co-targeting hexokinase 2 (HK2-mediated Warburg effect with 2-deoxyglucose (2-DG and ULK1-dependent autophagy with chloroquine (CQ selectively kills cancer cells through intrinsic apoptosis to cause tumor regression in xenograft, leads to a near-complete tumor suppression and remarkably extends survival in Pten−/p53-deficiency-driven CRPC mouse model. Mechanistically, 2-DG causes AMPK phosphorylation, which in turn inhibits mTORC1-S6K1 translation signaling to preferentially block anti-apoptotic protein MCL-l synthesis to prime mitochondria-dependent apoptosis while simultaneously activates ULK1-driven autophagy for cell survival to counteract the apoptotic action of anti-Warburg effect. Accordingly, inhibition of autophagy with CQ sensitizes cancer cells to apoptosis upon 2-DG challenge. Given that 2-DG is recommended for phase II clinical trials for prostate cancer and CQ has been clinically used as an anti-malaria drug for many decades, the preclinical results from our proof-of-principle studies in vivo are imminently translatable to clinical trials to evaluate the therapeutic efficacy by the combination modality for a subset of currently incurable CRPC harboring PTEN and TP53 mutations.

  4. The Effect of Prior Androgen Synthesis Inhibition on Outcomes of Subsequent Therapy with Docetaxel in Patients with Metastatic Castrate Resistant Prostate Cancer: Results from a Retrospective Analysis of a Randomized Phase 3 Clinical Trial (CALGB 90401) (Alliance)

    Science.gov (United States)

    Aggarwal, Rahul; Halabi, Susan; Kelly, William Kevin; George, Daniel; Mahoney, John F.; Millard, Frederick; Stadler, Walter M.; Morris, Michael J.; Kantoff, Philip; Monk, J. Paul; Carducci, Michael; Small, Eric J.

    2013-01-01

    Background Preliminary data suggests a potential decreased benefit of docetaxel in metastatic castration-resistant prostate cancer (mCRPC) patients previously treated with abiraterone acetate, a novel androgen synthesis inhibitor (ASI). CALGB 90401 (Alliance), a phase 3 trial of mCRPC patients treated with docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes following docetaxel. Methods CALGB 90401 randomized 1050 men with chemotherapy-naïve, mCRPC to treatment with docetaxel and prednisone with either bevacizumab or placebo. 1005 men (96%) had data available regarding prior ketoconazole therapy. The effect of prior ketoconazole on overall survival (OS), progression-free survival (PFS), PSA decline, and objective response rate (ORR) observed was assessed using proportional hazards and Poisson regression method adjusted for validated prognostic factors and treatment arm. Results Baseline characteristics between patients with (N=277) and without (N=728) prior ketoconazole therapy were similar. There were no statistically significant differences between patients with and without prior ketoconazole therapy with respect to OS (median OS 21.1 vs. 22.3 months, stratified log-rank p-value=0.635); PFS (median PFS 8.1 vs. 8.6 months, stratified log-rank p-value=0.342); ≥50% PSA decline (61% vs. 66%, relative risk=1.09, adjusted p-value=0.129); or ORR (39% vs. 43%, relative risk=1.11, adjusted p-value=0.366). Conclusions As measured by OS, PFS, PSA and ORR, there is no evidence that prior treatment with ketoconazole impacts clinical outcomes in mCRPC patients treated with subsequent docetaxel-based therapy. Prospective studies are needed to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC. PMID:23913744

  5. Clinical Observation of High Intensity Focused Ultrasound Combined with Radiotherapy、Testicular Castration for Prostate Cancer%高强度聚焦超声联合放疗、睾丸去势治疗前列腺癌的疗效观察

    Institute of Scientific and Technical Information of China (English)

    唐勇军; 余建军; 冯慧萍

    2014-01-01

    目的:探讨高强度聚焦超声( HIFU)联合放疗、睾丸去势治疗前列腺癌的疗效。方法对38例已行放疗、睾丸去势治疗的前列腺癌进行HIFU治疗。结果15例(39%)前列腺特异性抗原(PSA)水平降至正常,20例(52%) PSA下降,2例(10%)仅症状缓解,有效率达92%。前列腺体积也明显缩小。结论 HIFU联合放疗、睾丸去势治疗前列腺癌,能有效控制肿瘤进展,为前列腺癌提供了1种新的有效治疗手段。%Objective To study the efficacy of high intensity focused ultrasound ( HIFU) combined with radiotherapy , testicular castration for prostate cancer .Methods 38 patients with prostate cancer who underwent radiotherapy and testicular castration were treated with HIFU.Results 15 cases (39%),prostate specific antigen (PSA) have fallen to normal,20 cases (52%) of the PSA declined,2 cases (10%) of symptoms relieved,effective rate was 92%.Prostate volume also narrowed con-siderably.Conclusion HIFU combined with radiotherapy and testicular castration can effectively control the progression of the tumor,it is a new effective treatment for prostate cancer .

  6. 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

  7. Contenido de glicosaminoglicanos del líquido sinovial de la articulación metacarpofalángica de caballos castrados y yeguas de diferentes edades Synovial fluid glycosaminoglycan concentration in metacarpophalangeal joint of castrated horses and mares of different ages

    Directory of Open Access Journals (Sweden)

    H. ADARMES

    2003-01-01

    Full Text Available Se midió la concentración de glicosaminoglicanos (GAGs del líquido sinovial en su valor total (GAGsT y de una fracción de éstos, que corresponde a los GAGs diferentes del ácido hialurónico o GAGs sulfatados (GAGsS, entre los que se describen condroitin sulfato y queratán sulfato. Las muestras de líquido sinovial se obtuvieron por artrocéntesis aséptica desde articulaciones metacarpofalángicas normales de equinos mestizos en matadero, después del beneficio de los animales. El exámen post mortem de las articulaciones permitió descartar articulaciones con evidencias de osteoartritis u otras patologías articulares. La normalidad del líquido sinovial se evaluó por de su aspecto y por las pruebas del coágulo de mucina y de concentración de proteínas (Total concentration of synovial fluid glycosaminoglycan (GAGs and a fraction of it (GAGsT which correspond to different GAGs from hyaluronic acid or sulfated GAGs (GAGsS that mainly consist of chondroitin sulfate and keratan sulfate, were measured. Samples of synovial fluid were taken from normal metacarpophalangeal joints of crossbred equines immediatelly after slaughter by aseptic needle aspiration. Post mortem joints examination showed that there was no gross evidence of osteoarthritis or other joint disease, based on the appearance of synovial membrane and articular cartilage. Synovial fluid samples were evaluated by its external appearance, protein concentration and mucin clot test. Samples were alloted in four age groups by teeth examination and divided in mares (m and castrated horses (c.h. as follows: 1.5 - 2 years (n = 23: 12 m. and 11 c.h.; 4 - 5 years (n = 15: 9 m. and 6 c.h.; 6 - 8 years (n = 23: 13 m. and 10 c.h. and over 10 years old (n = 17: 12 m. and 5 c.h.. A colorimetric method with Alcian Blue using different electrolyte concentrations was used to quantify these GAGs. There were no significant differences of GAGsT concentration between mares and castrated horses

  8. The activity of SN33638, an inhibitor of AKR1C3, on testosterone and 17β-estradiol production and function in castration-resistant prostate cancer and ER-positive breast cancer

    Directory of Open Access Journals (Sweden)

    Yarong Diana eYin

    2014-06-01

    Full Text Available AKR1C3 is a novel therapeutic target in castration-resistant prostate cancer (CRPC and ER-positive breast cancer because of its ability to produce testosterone and 17β-estradiol intratumorally, thus promoting nuclear receptor signaling and tumor progression. A panel of CRPC, ER-positive breast cancer and high/low AKR1C3-expressing cell lines were treated with SN33638, a selective inhibitor of AKR1C3, in the presence of hormone or prostaglandin precursors, prior to evaluation of cell proliferation and levels of 11β-prostaglandin F2α (11β-PGF2α, testosterone, 17β-estradiol and prostate-specific antigen (PSA. A meta-analysis of AKR1C3 mRNA expression in patient samples was also conducted, which revealed that AKR1C3 mRNA was upregulated in CRPC, but downregulated in ER-positive breast cancer. 11β-PGF2α and testosterone levels in the cell line panel correlated with AKR1C3 protein expression. SN33638 prevented 11β-PGF2α formation in cell lines that expressed AKR1C3, but partially inhibited testosterone formation and subsequently cell proliferation and/or PSA expression only in high (LAPC4 AKR1C3-overexpressing cells or moderate (22RV1 AKR1C3-expressing cell lines. SN33638 had little effect on 17β-estradiol production or estrone-stimulated cell proliferation in ER-positive breast cancer cell lines. Although SN33638 could prevent 11β-PGF2α formation, its ability to prevent testosterone and 17β-estradiol production and their roles in CRPC and ER-positive breast cancer progression was limited due to AKR1C3-independent steroid hormone production, except in LAPC4 AKR1C3 cells where the majority of testosterone was AKR1C3-dependent. These results suggest that inhibition of AKR1C3 is unlikely to produce therapeutic benefit in CRPC and ER-positive breast cancer patients, except possibly in the small subpopulation of CRPC patients with tumors that have upregulated AKR1C3 expression and are dependent on AKR1C3 to produce the testosterone required

  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. 甲状旁腺激素与雌激素对去势雌性大鼠牙槽骨代谢的影响%Influence of parathyroid hormone and estrogen on alveolar bone metabolism of castrated female rats

    Institute of Scientific and Technical Information of China (English)

    孙哲; 林志勇; 白广亮; 狄婧; 姜丽霞

    2014-01-01

    Objective To investigate the influence of parathyroid hormone and estrogen on alveolar bone metabolism of castrated female rats. Methods Sixty-six female Wistar rats which were healthy and 4 months old were divided into two groups, with group SHAM (n=18) and group ovariectomy (OVX) (n=48). After 8 weeks of ovariectomy, the osteoporosis model was confirmed by examing 8 ovariectomized and sham-operated rats. The rest 10 rats in group SHAM were the control group (group A). The rest 40 rats in group OVX were divided into ovariectomized group (group B), ovariectomized and treated with estrogen (group C), ovariectomized and treated with parathyroid hormone (group D), ovariectomized and treated with estrogen and parathyroid hormone (group E) at random with 10 in each group. Group A and B injected physiological saline (1 mL·kg-1), group C injected estradiol benzoate (10 μg·kg-1), group D injected parathyroid hormone (20 μg·kg-1), group E injected parathyroid hormone (20 μg·kg-1) and estradiol benzoate (10 μg·kg-1). The intraperitoneal injection were maken every other day to rats in each group, which continued for 8 weeks. The bone mineral density (BMD), bone histomorphology and serum Ca, P, alkaline phosphatase (ALP) were measured after therapy. Results After 8 weeks of ovariectomy, the lumbar BMD of ovariectomized rats were significantly declined compared with those of the sham-operated rats (P0.05). ALP values in group B was significantly higher than that in group A (P0.05),B组ALP值较A组明显升高(P<0.05)。结论间歇性、小剂量注射甲状旁腺激素能增加去势大鼠牙槽骨的骨密度和改善骨结构,与雌激素联合使用对骨质疏松的治疗有协同作用。

  11. 转移性去势抵抗性前列腺癌化疗与激素治疗策略%Strategies to chemotherapy andh ormone therapy in the treatment of metastatic castrate-resistantprostate canec r

    Institute of Scientific and Technical Information of China (English)

    孙卫兵

    2014-01-01

    以多西他赛为核心的化疗方案已经成为转移性去势抵抗性前列腺癌( metastatic castrate-resistant prostate cancer,mCRPC)治疗的一线方案。但在过去的几年中,一些新药的出现改善了患者的总体生存,同时也使优化个体化治疗方案成为可能。已有证据表明阿比特龙、卡巴他赛、镭-223、sipuleucel-T、恩杂鲁胺等与多西他赛一同使去势抵抗性前列腺癌患者生存获益。另外,mCRPC患者对多西他赛一线治疗初始反应良好,出现疾病进展后复治应作为一线治疗的延伸。这些新的治疗手段使mCRPC治疗方案更加复杂化,并且使以往的序贯治疗方案向基于一定规则的新的治疗方式转变。%Chemotherapy with docetaxel has become the first line treatment for metastatic castrate-resistantprostate canc-er ( mCRPC) , in the last few years, new agents have been developed to improve survival obviously in this setting and reach a possible optimal personalized treatment strategy.There is evidence to suggest that abiratone acetate, cabazitaxel, radium-223, sipuleucel-T and enzalutamide, together with docetaxel, have demonstrated a survival benefit in these pa-tients.The use of rechallenge with docetaxel in mCRPC patients with disease progression after a first response in the first line treatment should been considered as the extension.These new agents make the scenario more complicated and the chal-lenge to move from the old sequential to a new algorithm-based approach.

  12. 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.

    2016-01-01

    Background Metastatic castration-resistant prostate cancer (mCRPC) often involves bone, and bone-targeted therapy (BTT) has become part of the overall treatment strategy. Objective 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. Design, setting, and participants This report describes the third interim analysis (prespecified at 55% overall survival [OS] events) for the COU-AA-302 trial. Intervention Patients were grouped by concomitant BTT use or no BTT use. Outcome measurements and statistical analysis 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. Results and limitations 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; p < 0.001) and time to opiate use for cancer-related pain (HR 0.80; p = 0.036). The safety profile of concomitant BTT with AA 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 <3% of patients. Conclusions AA with concomitant BTT was safe and well tolerated in men with chemotherapy

  13. Avaliação histológica da próstata de cães adultos sexualmente intactos Prostatic histological evaluation in adult not castrated dogs

    Directory of Open Access Journals (Sweden)

    C.E. Fonseca Alves

    2010-06-01

    Full Text Available Avaliou-se histologicamente a próstata de 30 cães adultos e idosos sexualmente intactos que apresentavam ou não sintomatologia clínica de doença prostática, e verificou-se a incidência de possíveis alterações da glândula. Dentre as alterações encontradas, a hiperplasia prostática benigna constituiu o diagnóstico mais comum, 85,6% (n=24, seguida por prostatite crônica, 64,3% (n=18, displasia do epitélio glandular, 42,8% (n=12, atrofia do epitélio glandular, 39,3% (n=11, infiltrado inflamatório focal, 25% (n=7, dilatação glandular focal, 21,4% (n=6, prostatite aguda, 7,1% (n=2, metaplasia escamosa, 3,6%, (n=1, metástase de neoplasia sistêmica, 3,6% (n=1 e abscesso prostático, 3,6% (n=1. Como em muitos casos os cães são assintomáticos, ressalta-se a importância da realização rotineira de exames clínicos específicos, como o toque retal e a ultrassonografia, para o diagnóstico precoce e o tratamento das afecções prostáticas.The prostates of 30 not castrated old dogs with or without clinical symptoms of prostatic disease were histologically evaluated. It was observed the incidence of possible changes in the gland. Among the changes, benign prostatic hyperplasia (BPH was the most common diagnosis, accounting for 85.6% (n=24, followed by chronic prostatitis, 64.3% (n=18, dysplasia of the glandular epithelium, 42.8% (n=12, atrophy of the glandular epithelium, 39.3% (n=11, focal inflammatory infiltrate, 25% (n=7, focal glandular dilation, 21.4% (n=6, acute prostatitis, 7.1% (n=2, squamous metaplasia, 3.6% (n=1, metastasis of systemic neoplasia, 3.6% (n=1, and prostatic abscess, 3.6% (n=1. Because the lack of symptoms in most of dogs with prostatic changes, the specific clinic exams in routine, as rectal palpation and ultrasonography, are very important to early diagnosis and treatment of dogs with prostatic disease.

  14. Voluntary chemical castration of a mental patient.

    Science.gov (United States)

    Brahams, D

    1988-06-01

    Britain's High Court recently overruled two decisions of the Mental Health Act Commission that denied certification of a voluntary experimental drug treatment to a mental patient, holding that the standard for informed consent is determined not by the subjective judgment of the commissioners but by whether the patient knows the nature and likely effects of treatment and that its use in his case is a novel one. The background facts of the case involving a 27-year-old pedophile receiving goserelin implantations to reduce testosterone levels are presented and the issues of jurisdiction under the Mental Health Act 1983 and the commissioners' duty to act fairly and to consider the likely benefits of treatment are discussed.

  15. 杜仲叶对去势骨质疏松大鼠骨代谢的影响%Effect of eucommia ulmoides oliv leaves on bone metabolism in castrated osteoporotic rats

    Institute of Scientific and Technical Information of China (English)

    戴鹏; 邓鸣涛; 张立超; 朱美兰; 林思俭; 刘荣华; 罗军

    2012-01-01

    showed relative increases in BMD and smooth joint surface. Histopathology showed normal bone trabecular number. Biochemical tests showed that the levels of bone alkaline phosphatase, serum calcium, serum phosphorus, urinary calcium, and urinary phosphorus had no significant difference with those in normal control group. Conclusion Eucommia ulmoides oliv leaves can maintain bone metabolic balance, and prevent and treat osteoporosis in castrated rats. The effect is mainly on the increase of BMD, the increase of bone trabecular number, and the improvement of bone metabolic balance.

  16. Changes in aortic endothelium ultrastructure in male rats following castration, replacement with testosterone and administration of 5α-reductase inhibitor%去势或用5α-还原酶抑制剂后雄性大鼠血管内皮超微结构改变的研究

    Institute of Scientific and Technical Information of China (English)

    Y. L. Lu; L. Kuang; H. Zhu; H. Wu; X. F. Wang; Y. P. Pang; N. J. Wang; D. L. Yu

    2007-01-01

    Aim: To investigate the relationship between low androgen level and ultrastructure of vascular endothelium. Methods:Forty-eight male Sprague-Dawley rats were randomly divided into four groups: group A, normal rats with sham castration; group B, castrated rats; group C, castrated rats given testosterone (T) undecanoate; and group D, intact rats treated with 5α-reductase inhibitor. After 10 weeks of treatment or castration, rats in different groups were killed and serum T, free T (FT) and dihydrotestosterone (DHT) were measured. The aortic endothelia were scanned under electron microcopy and the Vascular Endothelium Structure Score (VESS) was computed. Results: Serum T and FT concentrations of rats in group B were significantly lower than those of the other three groups (P < 0.01);DHT concentrations of group D rats were significantly decreased (P < 0.01) when compared with those of groups A and C. Rats in groups B and D rats (with low androgen levels) had obvious damage to their endothelial surfaces,which appeared crimpled, rough, adhesive and ruptured, and had high destruction of VESS. Conclusion: These results suggest that low concentrations of T and DHT are associated with ultrastructural damage of the aortic endothelia in male rats.%目的:研究低雄性激素水平对雄性大鼠血管内皮超微结构改变的影响.方法:将48只雄性SD大鼠随机分成四组:A组为正常大鼠作为对照组,B组为雄性大鼠去势组,C组为去势后用十一酸睾酮(T)替代治疗大鼠组,D组为正常大鼠用5α-还原酶抑制剂治疗组,每组均为12只大鼠.10周后用放射免疫法测定血清睾酮,游离睾酮(Free Testosterone,FT)和双氢睾酮(Dihydrotestosterone,DHT)水平,用扫描电镜观察大鼠腹主动脉内皮的超微结构并给予血管内皮结构评分(VESS).结果:B组的血清睾酮和游离睾酮的水平与A、C、D组相比较有显著地降低(P<0.01);D组的双氢睾酮水平与A组和C组比较显著地降低(P<0.01);

  17. 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

  18. 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)

  19. Advances in understanding the mechanisms of anti-androgen ther-apeutic action and failure in castration-resistant prostate cancer%抗雄激素药物治疗去势抵抗型前列腺癌的机制研究进展

    Institute of Scientific and Technical Information of China (English)

    王前奔; 吴大勇

    2015-01-01

    Castration-resistant prostate cancer (CRPC) is the lethal form of prostate cancer with developed resistance to androgen deprivation therapy. However, anti-androgen therapy remains an important treatment option because androgen receptor activation is a major driver of the advanced phase of CRPC. Drug resistance is frequently manifested despite the development of various novel anti-an-drogens with significant clinical efficacy. This review introduces several drugs prevalently used to treat CRPC. The mechanisms of ac-tion and pathways to resistance of these drugs are also discussed.%去势抵抗型前列腺癌(castration-resistant prostate cancer,CRPC)是指经内分泌治疗产生耐药并继续发展的致命性前列腺癌,雄激素受体(androgen receptor,AR)激活途径仍是这一阶段前列腺癌发展的驱动机制,因此抗雄激素治疗仍然是重要的治疗手段之一。虽然许多新型抗雄激素治疗药物在临床治疗中显示了显著的疗效,但同时耐药也频繁出现。本文就近年来几种主要抗雄激素治疗药物的作用及相应的耐药机制进行综述。

  20. The European Medicines Agency Review of Abiraterone for the Treatment of Metastatic Castration-Resistant Prostate Cancer in Adult Men After Docetaxel Chemotherapy and in Chemotherapy-Naïve Disease: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

    Science.gov (United States)

    Lopez, Arantxa Sancho; Hemmings, Robert James; Jiménez, Jorge Camarero; Garcia-Carbonero, Rocio; Gallego, Isabel García; Giménez, Elena Valencia; O'Connor, Daniel; Giuliani, Rosa; Salmonson, Tomas; Pignatti, Francesco

    2013-01-01

    On September 5, 2011, abiraterone was approved in the European Union in combination with prednisone or prednisolone for the treatment of metastatic castration-resistant prostate cancer (CRPC) in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen. On December 18, 2012, the therapeutic indication was extended to include the use of abiraterone in combination with prednisone or prednisolone for the treatment of metastatic CRPC in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. Abiraterone is a selective, irreversible inhibitor of cytochrome P450 17α, an enzyme that is key in the production of androgens. Inhibition of androgen biosynthesis deprives prostate cancer cells from important signals for growth, even in cases of resistance to castration. At the time of European Union approval and in a phase III trial in CRPC patients who had failed at least one docetaxel-based chemotherapy regimen, median overall survival for patients treated with abiraterone was 14.8 months versus 10.9 months for those receiving placebo (hazard ratio, 0.65; 95% confidence interval 0.54–0.77; p < .0001). In a subsequent phase III trial in a similar but chemotherapy-naïve patient population, median radiographic progression-free survival was 16.5 months for patients in the abiraterone treatment arm versus 8.3 months for patients in the placebo arm (hazard ratio, 0.53; 95% confidence interval, 0.45–0.62; p < .0001). Abiraterone was most commonly associated with adverse reactions resulting from increased or excessive mineralocorticoid activity. These were generally manageable with basic medical interventions. The most common side effects (affecting more than 10% of patients) were urinary tract infection, hypokalemia, hypertension, and peripheral edema. PMID:23966222

  1. Predictive effect of androgen receptor splice variant 7 expression on time to castration resistance in patients with metastatic prostate cancer%前列腺癌组织中雄激素受体剪接变异体7表达对转移性前列腺癌患者激素敏感时间的预测作用

    Institute of Scientific and Technical Information of China (English)

    瞿元元; 叶定伟; 戴波; 孔蕴毅; 蔡旭; 常坤; 孙自捷; 张海梁; 朱耀

    2014-01-01

    receptor splice variant 7 (AR-V7) expression on time to castration resistance in patients with metastatic prostate cancer.Methods The data of 113 cases of advanced metastatic prostate cancer diagnosed by prostate biopsy in our institute from Jan.2002 to Jun.2010 were collected retrospectively.The median age at diagnosis was 70 years,ranged from 43 to 84 years.The median tPSA was 120.0 μg/L,ranged from 3.0 to 6 006.2 μg/L.There were 5 patients in M1a(4.4%),94 patients in M1b(83.2%) and 14 patients in M1c(12.4%).All patients received hormonal therapy.1mmunohistochemical staining and AR-V7 specific antibody were used to detect the expression of AR-V7 in prostate cancer tissues.Cox regression models were used to analyze the predictive role of patient characteristics including patient's age at diagnosis,tPSA level at diagnosis,Gleason score,clinical stage,PSA nadir during hormonal therapy,the time to PSA nadir and PSA half-life.The effect of AR-V7 expression on time to castration resistance was analyzed using Kaplan-Meier curves,and the differences were assessed using the log-rank test.Results The PSA nadir ranged from 0.0 to 143.0 μg/L and the median value was 0.7 μg/L.The time to PSA nadir ranged from 0.9 to 71.0 months and the median value was 8.1 months.The median PSA half life was 1.0 month,which ranged from 0.1 to 41.0 months.Followed up for a median time of 27 months,100 patients progressed to castration-resistant prostate cancer (CRPC) and the median time to castration resistance was 24 months.The expression of AR-V7 was positive in 23 out of 113 patients.Multivariate analysis showed that the expression of AR-V7 in prostate cancer (P=0.004,HR =2.223) and PSA nadir during hormonal therapy (P =0.035,HR =1.011) were independent predictive factors of time to castration resistance.The median time to castration resistance for patients with and without AR-V7 expression were (16.04±3.4) months and (30.04-6.0) months,respectively (P=0.001).Conclusions The expression

  2. Rendimentos de carcaça, dos cortes comerciais e da porção comestível de bubalinos Murrah castrados abatidos com diferentes períodos de confinamento Yields of carcass, retail cuts and retail beef cuts of castrated Murrah buffaloes slaughtered at different periods of feedlot

    Directory of Open Access Journals (Sweden)

    Paulo Francisco Nogueira Bomfim Ferreira Menegucci

    2006-12-01

    Full Text Available Avaliaram-se as características de carcaça de búfalos Murrah castrados terminados em confinamento. Foram utilizados 20 bubalinos Murrah (15 meses de idade e peso inicial de 207 kg, castrados e descornados, divididos em quatro grupos homogêneos e abatidos aos 75, 100, 125, 150 dias de confinamento, após período de adaptação. Ao abate, as carcaças foram identificadas, resfriadas por 24 horas para pesagem e cálculo dos rendimentos das meias-carcaças, dos cortes dianteiro, ponta-de-agulha, traseiro total e serrote. Não houve diferença estatística para o rendimento de carcaça. Os pesos de traseiro total, serrote e dianteiro apresentaram aumento linear, porém, observou-se efeito cúbico do período de confinamento sobre os rendimentos de traseiro total e dianteiro. Verificou-se ainda aumento linear dos pesos de filé-mignon, contrafilé, fraldinha, coxão mole, coxão duro, lagarto, sebo, porção comestível e ossos. O período de confinamento promoveu efeito linear decrescente sobre os rendimentos de patinho, músculo traseiro e maminha + alcatra e linear crescente para fraldinha e sebo.The objective of this trial was to evaluate the carcass traits of feedlot castrated Murrah buffaloes. Twenty castrated hornless Murrah buffaloes averaging 15 months of age and initial body weight of 207 kg were used. Animals were divided in four groups and slaughtered at 75, 100, 125 or 150 days of feedlot after an adaptation period. At slaughter, carcasses were identified, cooled for 24 hours, and weighed for calculation of yields of half carcass, hindquarter, spare ribs, forequarter, and sawcut. There was no significant difference for carcass yield comparing the different periods of feedlot. Weights of sawcut, forequarter, hindquarter, tenderloin, strip loin, thin skirt, topside, outside flat, eye round, tallow, retail beef cuts, and bones all increased linearly while significant cubic effects were observed for yields of forequarter and hindquarter

  3. Ameliorative effect of androgen therapy tear on film stability in castrate female rats%雄激素疗法对去势雌性大鼠泪膜稳定性的改善作用

    Institute of Scientific and Technical Information of China (English)

    高阳; 周瑾; 孙晓芳

    2015-01-01

    concentration was (3.38±0.24) ng/ml,S Ⅰ t was (6.37 ±0.45) mm/5 minutes and BUT was (7.54±0.55) seconds in the testosterone-injected group,which was significantly higher than that in the OVX model group (all at P =0.000).The positive staining of MUC5AC in rat conjunctival tissue weakened in the OVX model group compared with the normal control group,and the fluorescence intensity in the testosterone-injected group was stronger than that in the OVX model group.Regularly arranged microvilli and cell metabolism hiatus on the surface of corneal cells were seen in the normal control group and the sham group;while the microvilli were shorter and irregularly arranged,and the cell metabolism hiatus were disappeared in the OVX model group.However,microvilli and cell metabolism hiatus were close to normal ones in the testosterone-injected group.Conclusions Deterioration of tear secretion and instability of tear film are are probably associated with the lower serum androgen levels in castrated female rats.Systemic supplement of androgen can promote tear secretion,improve tear film stability and alleviate ocular surface damage.%背景 绝经期女性干眼的发病率明显高于男性,提示性激素在干眼的发病过程中可能发挥一定的作用,绝经期女性应用雌激素时于眼症状加重也提示雄激素可能参与干眼病程.雄激素的应用是否可以减轻干眼症状正在受到关注. 目的 探讨雄激素对去卵巢雌鼠泪液及泪膜稳定性的影响,探讨雄激素维持泪膜稳定性的可能作用机制. 方法 清洁级3月龄雌性性成熟Wistar大鼠48只按照随机数字表法分为正常对照组、假手术组、去势模型组和丙酸睾丸酮组,去势模型组和丙酸睾丸酮组大鼠行双侧卵巢摘除术以制备去势模型,造模后5同始丙酸睾丸酮组大鼠按3.75 mg/kg剂量肌内注射丙酸睾丸酮,每3天1次,持续6周,而假手术组大鼠仅切除腹内脂肪组织而不摘除卵巢.于丙

  4. Effects of Alendronate Sodium on Bone Mineral Density and Bone Marker in Prostate Cancer Elderly Pa-tients after Medical Castration Therapy%阿仑膦酸钠对前列腺癌老年患者药物去势治疗后骨密度和骨标志物的影响

    Institute of Scientific and Technical Information of China (English)

    段晓宇; 朱虹; 黄娟

    2016-01-01

    OBJECTIVE:To explore the effects of alendronate sodium on bone mineral density (BMD) and bone marker in prostate cancer elderly patients after medical castration therapy. METHODS:In perspective study,84 elderly patients undergoing medical castration therapy were selected and divided into treatment group(45 cases)and control group(39 cases)according to ran-dom number table. Control group received medical castration therapy+Calcium carbonate D3 tablets,1 tablet,po,qn;treatment group was additionally given Alendronate sodium tablets 70 mg,po,once a week,1 week after routine treatment,on the basis of control group. Treatment course of 2 groups lasted for 12 months. The levels of 25-OH-D,testosterone,BMD and bone marker were observed in 2 groups,and the occurrence of ADR was recorded. RESULTS:3 cases of treatment group and 1 case of control group dropped out of the study. Before treatment,there was no statistical significance in above indexes between 2 groups (P>0.05). After treatment,25-OH-D levels of 2 groups were increased slightly,but there was no statistical significance(P>0.05);tes-tosterone level of 2 groups were decreased significantly compared to before treatment,with statistical significance (P0.05). CONCLUSIONS:Alendronate sodium can prevent bone loss and reduce the rate of bone turnover in elderly patients with prostate cancer receiving medical castration therapy.%目的:探讨阿仑膦酸钠对前列腺癌老年患者药物去势治疗后骨密度(BMD)和骨标志物的影响。方法:本研究为前瞻性研究。选取84例拟行药物去势治疗的前列腺癌老年患者,按照随机数字表法分为治疗组(45例)和对照组(39例)。对照组患者给予药物去势治疗+碳酸钙D3片1片,po,qn;治疗组患者在此基础方案开始后1周给予阿仑膦酸钠片70 mg,po,每周1次。两组患者治疗时间均为12个月。观察两组患者25-羟基维生素D(25-OH-D)、睾酮、BMD、骨标志物水平,并

  5. 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

  6. 经尿道前列腺切除联合去势治疗伴膀胱出口梗阻的晚期前列腺癌的临床进展%Transurethral Resection of the Prostate Combined Castration in the Treatment of Bladder Outlet Obstruction in Patients with Advanced Prostate Cancer Clinical Progress

    Institute of Scientific and Technical Information of China (English)

    赵富

    2012-01-01

      目的对临床上所采用的经尿道前列腺切除联合去势的方法针对膀胱出口梗阻的晚期前列腺癌的治疗效果进行分析与探讨,并且对此方法治疗晚期前列腺癌的可行性做出分析。方法对本院的晚期前列腺癌的患者临床资料进行回顾性总结与分析,和手术后的随访。这些患者均接受过本院实施的经尿道前列腺切除联合去势手术,并且这些患者的晚期前列腺癌均伴随有膀胱出口梗阻。结果进行手术的所有患者均取得了较好的治疗效果,在术后的随访过程中并没有发现患者的意外死亡。患者在接受手术之后排尿良好、并且没有出现尿失禁。结论伴膀胱出口梗阻的晚期前列腺癌的患者在经过经尿道前列腺切除联合去势治疗均取得了较好的康复效果。因此,这是一种具有良好效果,可以进行临床推广应用的手术方法。%  Objective Of clinical the transurethral resection of the prostate joint castrated method in the bladder outlet obstruction of advanced prostate cancer treatment effect of analysis and discussion, and the method is the treatment of advanced prostate cancer to the feasibility analysis. Methods Our hospital since 2004 through February to March 2006 were between the advanced prostate cancer patients with the clinical data were retrospectively summary and analysis, and postoperative fol ow-up.These patients are trained in this hospital implementation of the urethra prostate gland excision with castration surgery, and these patients with advanced prostate cancer are accompanied by a bladder outlet obstruction,and these patients with advanced prostate cancer are accompanied by a bladder outlet obstruction. Results Surgery al of the patients have achieved good results,in the process of the fol ow-up and found no patients accidental death.Patients undergoing surgery urination and did not appear after good urinary incontinence. Conclution

  7. Development in the study of radium-223 chloride for treating castration-resistant prostate carcinoma with bone metastases%镭-223氯化物治疗去势抵抗性前列腺癌骨转移的研究进展

    Institute of Scientific and Technical Information of China (English)

    桂继琮; 刘兴党

    2015-01-01

    近年来,全世界前列腺癌的发病率和病死率不断增长,各种治疗方法的研究也进展迅速。镭-223发射的重α粒子(具有<100μm的超短波)靶向作用于骨转移部位和周围新骨生长区域。镭-223氯化物在药物临床试验中以稳定的安全性显著降低了患者的病死率,成为近来被寄予厚望的转移性去势抵抗性前列腺癌(CRPC)治疗领域的“主角”。2013年美国食品药品管理局已批准镭-223氯化物用于治疗有症状的骨转移、未发现内脏转移的CRPC患者。未来其联合治疗方案将会是研究的重点。%Prostate carcinoma rates and mortalities are increasing worldwide. The therapeutic landscape of castration-resistant prostate carcinoma (CRPC) has changed rapidly. Radium-223 chloride, which is a radiopharmaceutical agent, targets bone metastasis by emitting high-energy alpha-particles with extremely short range (<100 μm ) . This chemical is effective in reducing mortality without increasing toxicity. Thus, this agent has the potential to become a new alternative for treating patients with CRPC. The Food and Drug Administration approved radium-223 dichloride for treating patients with CRPC, symptomatic bone metastases, and unknown visceral metastatic disease in 2013. Therefore, combination and sequencing strategies will be future research directions.

  8. 外源性雌二醇对去势雌性Wistar大鼠晶状体上皮细胞雌激素受体表达的影响%Effects of estradiol on the expression of estrogen receptor in lens epithelial cell of castrated female Wistar rat

    Institute of Scientific and Technical Information of China (English)

    王萌萌; 宋秀君; 苏琪; 殷英霞

    2012-01-01

    ERβ:25.38±5.59 vs.27.75±7.13);去势组、去势+高剂量雌二醇点眼组、去势+低剂量雌二醇注射组LECs中ERα、ERβ阳性细胞平均吸光度(A)值均明显低于伪手术组,而去势+低剂量雌二醇点眼组则较去势组和去势+低剂量雌二醇注射组明显升高,差异均有统计学意义(P<0.05),但去势+高剂量雌二醇注射组LECs中ERα、ERβ平均A值均接近伪手术组(ERα:0.1859±0.0067 vs.0.1833±0.0087;ERβ:0.1686±0.0095 vs.0.1689±0.0059). 结论 LECs 中ERα和ERβ的表达水平与体内雌激素的水平有关.雌激素的不同给药途径对晶状体ER表达的影响不同;低剂量雌激素点眼可能优于其他高剂量雌激素给药方式.%Background Recently researches indicated that estrogen plays important role in maintaining the normal metabolism of lens. Objective This study was to investigate the changes of estrogen receptor( ER ) α and β expressions in lens upon estrogen level in castrated female rat. Methods Sixty clean adult female Wistar rats were randomized into castrated group,sham operation group,ovariectomy group,ovariectomy with low-dose estradiol eyedropping group,ovariectomy with high-dose estradiol eyedropping group,ovariectomy with low-dose estradiol injecting group and ovariectomy with high-dose estradiol injecting group,and 10 rats for each.The castrated animal models were established by ovariectomy for 5 months.Then 50%,100% oestradiol benzoate eyedrops were used 4 times per day respectively and 0.2 or 0.4 mg/kg oestradiol benzoate were intramuscularly injected at two-day interval for 6 weeks in corresponding experimental group.Serum estradiol concentration was detected in the rats of various groups at 5 months after ovariectomy and 6 weeks after administration of estradiol benzoate.The animals were sacrificed using the excessive anesthesia method and the lenses were obtained for the assay of ERα and ERβ expressions.The use of the animals complied with the Statement of

  9. 阉割对金华猪肝脏miR-122和miR-378表达量和膻味性状的影响%Effect of Castration on the Boar Taint and the Expression Variation of miR-122 and miR-378 in Liver of Jinhua Pig (Sus scrofa)

    Institute of Scientific and Technical Information of China (English)

    马义涛; 李艳华; 周辉云; 王颖; 徐宁迎

    2013-01-01

    microRNA是一种小分子RNA,是细胞内复杂而精确的调控网络的组成部分.为了研究阉割对miR-122和miR-378表达量的影响以及miR-122和miR-378对雄烯酮和粪臭素代谢的调控作用,本研究利用荧光定量PCR检测了miR-122和miR-378在不同生长阶段金华猪(Sus scrofa)公猪肝脏中的表达量变化及其在阉割和非阉割公猪体内表达量的差异,利用高效液相色谱法(high performance liquid chromatography,HPLC)检测了金华猪皮下脂肪的粪臭素含量,并预测了调控pre-miR-122和pre-miR-378转录的相关转录因子及miR-122和miR-378与雄烯酮、粪臭素代谢相关基因的靶关系.结果发现,miR-122在胚胎期高表达,随着日龄的增加表达量逐渐下降;miR-378在胚胎期高表达,生长期呈现先增后减的态势.阉割后两者的表达量均较同期非阉割组表达下调.并且阉割后皮下脂肪中粪臭素的含量显著下降(P<0.01).根据研究结果推测,阉割后激素水平的变化通过相关转录因子影响microRNA的表达,直接或间接影响雄烯酮和粪臭素代谢而实现对公猪膻味性状的调控.而在这个调控网络中,microRNA可能发挥了重要作用,为深入研究公猪膻味性状提供了一个新的思路.%MicroRNA(miRNA) is a class of small RNA,it is involved in the intracellular complicated and precise regulatory networks.In order to study the effect of castration on the expression of miR-122 and miR-378 and the regulation effect of miR-122 and miR-378 on androstenone and skatole metabolism,we detected the skatole content in subcutaneous fat of boars and barrows with the help of high performance liquid chromatography (HPLC) and the expression of miR-122 and miR-378 in various growth stages in liver of Jinhua Pig (Sus scrofa) by quantitative Real-time PCR (qRT-PCR) and analysed the expression variation between boars and barrows.The results showed that the skatole content in adipose tissue was higher (P<0.01) in boars

  10. Pre-chemotherapy lactate dehydrogenase as a prognostic predictor after docetaxel chemotherapy of castration resistant prostate cancer%化疗前血清乳酸脱氢酶对去势难治性前列腺癌预后预测价值

    Institute of Scientific and Technical Information of China (English)

    张姣; 王海涛; 杨庆; 杜君; 贾炜莹; 张鹏宇

    2015-01-01

    目的 探讨化疗前血清乳酸脱氢酶(lactate dehydrogenase,LDH)对去势难治性前列腺癌(castration-resistant prostate cancer,CRPC)预后的预测价值.方法 回顾性分析2008-01-01-2012-01-01天津医科大学肿瘤医院收治的58例单独使用多西他赛方案化疗CRPC患者的临床资料,根据化疗前LDH水平将所有患者分为高LDH组(LDH>248 U/L)和低LDH组(LDH≤248 U/L),比较两组患者的临床病理特点,分析LDH对患者预后的影响.结果 58例CRPC患者中,高LDH者28例(48.3%),低LDH者30例(51.7%).两组中位生存期分别为12和27个月,差异有统计学意义,P<0.001.诊断时TNM分期(x2=10.035,P=0.002)、Gleason评分(x2=10.008,P=0.002)、ECOG评分(x2 =5.584,P=0.018)、内脏转移(x2=13.114,P<0.001)、基线PSA(x2 =5.493,P=0.019)、化疗周期数(x2=9.501,P=0.002)、PSA反应(x2=17.215,P<0.001)和基线LDH(x2 =28.394,P<0.001)与CRPC患者预后相关.多因素分析显示,诊断时TNM分期、Gleason评分,化疗前是否内脏转移、化疗周期数、PSA反应和基线LDH是影响患者的独立预后因素,P值均<0.05.结论 化疗前高LDH者预后差,化疗前高LDH是CRPC患者的独立预后因素.

  11. Surgical sterilization in small mammals. Spay and castration.

    Science.gov (United States)

    Jenkins, J R

    2000-09-01

    The intrinsic physiologic and anatomic differences between small exotic mammals and the species that are more familiar to veterinary practitioners (i.e., dogs and cats) are substantial. This discussion is limited to rabbits, mice and rats (murid rodents), hamsters and gerbils (cricetid rodents), and guinea pigs and chinchillas (hystricomorph rodents). In addition to their anatomic and physiologic differences, differences in behaviors, such as their reaction to stress and pain, exist. Preoperative and postoperative care, basic surgical techniques unique to these species, and useful materials are discussed.

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

    Science.gov (United States)

    2015-10-01

    degradation via Skp-2 mediated ubiquitination Per the report by Shen et al. [11], activation of AMP- activation protein kinase (AMPK) by metformin...activation through neuropeptide (GRP) mediated signaling through the tyrosine kinases Src-Etk-Fak complex [15], the combination of saracatinib and... mediated AR activation of the GRP- Pro line. Enzalutamide is never the ideal treatment drug. Although metformin may cause AR degradation, especially

  13. Castration Induced Neuroendocrine Mediated Progression of Prostate Cancer

    Science.gov (United States)

    2008-09-01

    dependent Src and Smad1 signaling pathway is crucial for the development of diabetic nephropathy . Lab Invest 2006;86:927–39. 44. Kersten C, Dosen G...this and the in vivo study. c. Testing of inhibitory treatments on chimeric tumors in soft agar and in vivo. We have demonstrated...Christopher P. Evans, M.D. d. In vivo testing of inhibitory treatments at different time points. Since we have identified Src kinase as the key

  14. Avaliação do glicogênio hepático correlacionado com glicose sérica em ratas castradas sob tratamento com tibolona Evaluation of hepatic glycogen correlated with serum glucose in castrated rats under tibolone treatment

    Directory of Open Access Journals (Sweden)

    Porphirio José Soares Filho

    2011-10-01

    Full Text Available INTRODUÇÃO: O glicogênio representa a forma de armazenamento de açúcares na célula animal, sendo estocada naturalmente no hepatócito. Em sua dinâmica metabólica ocorre participação de receptores, hormônios e enzimas que mantêm e equilibram os níveis séricos desse componente. OBJETIVO: O presente estudo investigou a influência da tibolona no metabolismo glicídico hepático por meio de avaliação da presença do glicogênio hepático e níveis séricos de glicose. MATERIAL E MÉTODOS: Utilizamos ao todo 14 ratas Wistar, em menopausa cirúrgica comprovada citologicamente, tratadas diariamente com tibolona (n = 9 ou com placebo (n = 5 durante 20 semanas. Efetuou-se avaliação dos pesos do animal e do fígado e dos níveis de glicose sérica. O estudo morfológico foi realizado em cortes histológicos de tecido hepático, corados com hematoxilina e eosina (HE e com ácido periódico de Schiff (PAS, com e sem amilase salivar. Para avaliação do glicogênio no fígado, utilizou-se grade de estudo morfológico (GEM, que delineia as regiões metabólicas e circulatórias do lóbulo hepático. RESULTADOS: O peso dos animais foi menor no Grupo Tibolona, com glicose sérica em níveis mais baixos; já o peso relativo do fígado foi significativamente maior (p INTRODUCTION: Glycogen serves as glucose storage in animals and it is naturally found in hepatocytes. Receptors, hormones and enzymes, which maintain and balance serum levels of this component, participate in its metabolic dynamics. OBJECTIVE: This study investigated the influence of tibolone on the hepatic glycemic metabolism by assessing the presence of liver glycogen and serum glucose. MATERIAL AND METHODS: Fourteen castrated Wistar rats, cytologically validated as surgical menopause models, were treated with tibolone (n = 9 or placebo (n = 5 for 20 weeks. Their body and liver weight and serum glucose levels were assessed. The morphologic study was performed in histological

  15. Changes of the nitric oxide synthase-positive and nestin-positive neurons in the basal forebrain of castrated adult male rats following androgen replacement therapy%雄激素替代治疗后去势成年雄性大鼠基底前脑一氧化氮合酶及巢蛋白阳性神经元的变化

    Institute of Scientific and Technical Information of China (English)

    郭灵; 汪华侨; 袁群芳; 姚志彬

    2006-01-01

    BACKGROUND: The neurons in the medial septum (MS), vertical and horizontal limbs of diagonal band of Broca (vDB and hDB) in the basal forebrain contain rich androgen receptors (ARs) and estrogen receptors (ERs) by which androgen and estrogen can act dramatically on the neurons in the basal forebrain, subsequently affecting learning and memory processes.OBJECTIVE: To qualitatively and quantitatively investigate the effects of androgen replacement therapy on the nitric oxide synthase (NOS)-positive and nestin-positive neurons in the MS, vDB and hDB of castrated adult male rats.DESIGN: A randomly controlled study on experimental animals.SETTING: Department of Anatomy and Brain Research Laboratory of Zhngshan Medical College of Sun Yat-sen University.MATERIALS: The experiment was performed at Department of Anatomy and Brain Research Laboratory of Zhongshan Medical College of Sun Yatsen University from June 2001 to June 2002. Totally twenty-eight adult male Sprague-Dawley rats were randomly divided into four groups with seven rats in each group: androgen replacement therapy for 4 weeks following 24 hours of castration (ART1), androgen replacement therapy for 2 weeks following 2 weeks of castration (ART2), vehicle replacement therapy for 4weeks following 24 hours of castration (VRT), sham-operated group (Sham).INTERVENTIONS: ① ART1 group: The castrated rats received subcutaneous injection of testosterone proprionate (25 mg/kg) dissolved in 100 μL of sterile sesame oil every other day from 10:30 am to 11:00 am for 14 times (4 weeks). ② ART2 group: The castrated rats received subcutaneous injection of testosterone proprionate with the same dosage and method as ART1 group for 7 times (2 weeks). ③ The rats in VRT group received subcutaneous injection of 100μL of sterile sesame oil for 14 times (4 weeks) by the same regime as described above. ④ Rats in Sham group only received sham-operated treatments, and testes were intact and lived for 4 weeks.MAIN OUTCOME

  16. 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

  17. 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

  18. Neutrophil-to-lymphocyte ratio as a prognostic factor in patients with castration-resistant prostate cancer treated with docetaxel-based chemotherapy%化疗前中性粒细胞与淋巴细胞比值对接受多西他赛化疗的去势难治性前列腺癌患者预后的影响

    Institute of Scientific and Technical Information of China (English)

    张姣; 王海涛; 杨庆; 杜君; 贾炜莹; 张鹏宇

    2015-01-01

    目的:探讨化疗前中性粒细胞/淋巴细胞比值(neutrophil-to-lymphocyte ratio,NLR)对接受多西他赛化疗的去势难治性前列腺癌(castration resistant prostate cancer,CRPC)患者预后的影响.方法:回顾性分析2008年1月-2012年1月天津医科大学肿瘤医院收治的接受多西他赛方案化疗的48例CRPC患者的临床资料,分析NLR与临床资料和预后的关系.结果:本组48例患者中,高NLR(>3)患者24例,低NLR(≤3)患者24例,2组患者的TNM分期和内脏转移率差异有统计学意义(P值均< 0.05).高NLR组与低NLR组的中位生存时间分别为11和25个月(P<0.05).单因素分析结果显示,化疗前NLR、诊断时的TNM分期、Gleason评分、基线前列腺特异性抗原水平、美国东部肿瘤协作组体能状况评分、内脏转移、化疗周期数以及前列腺特异性抗原疗效是影响本组CRPC患者总生存的预后因素(P值均<0.05).COX多因素分析结果显示,化疗前NLR、内脏转移、化疗周期数以及前列腺特异性抗原疗效是影响多西他赛化疗的CRPC患者总生存的独立预后因素(P值均<0.05).结论:NLR是影响接受多西他赛化疗的CRPC患者总生存的独立危险因素,可作为对接受多西他赛化疗的CRPC患者的预后进行评估的有效指标.

  19. Risk factors analysis for castrate-resistant prostate cancer after prostate cancer treated with androgen deprivation therapy within 1 year%前列腺癌患者内分泌治疗后1年内进展为去势抵抗性前列腺癌的相关因素分析

    Institute of Scientific and Technical Information of China (English)

    熊太林; 贺大林; 樊桂玲; 李磊; 南勋义; 范晋海

    2014-01-01

    Objective To investigate the risk factors for castrate-resistant prostate cancer (CRPC) after prostate cancer treated with androgen deprivation therapy (ADT) within 1 year.Methods One hundred and thirty-one prostate cancer patients treated with ADT in our institute between Jan.2008 and Jan.2011 were selected for this study.Patients were followed up by telephone or in clinic,including serum testosterone,serum PSA,clinical symptoms,imaging studies,digital rectal examination (DRE),survival data,PSA nadir,time to PSA nadir and et al.We mainly studied the CRPC after prostate cancer treated with ADT within 1 year.In the 131 patients,the median age was 70 (ranged from 44-89) years.There were 13 patients (9.9%) less than 60 years,43 patients (32.8%) between 60 and 69 years,62 patients (47.3%) between 70 and 79 years,13 patients (9.9%) more than 80 years.The average body mass index (BMI) was 23.0 (ranged from 14.4-34.4) kg/m2.There were 10 patients less than 18.5 kg/m2,77 patients between 18.5 and 24.0 kg/m2,34 patients between 24.1 and 28.0 kg/m2,and 10 patients more than 28.0 kg/m2.The initial PSA was between 0.3 and 4 707.0 μg/L,there were 19 patients (14.5%) less than 20 μg/L,45 patients (34.4%) between 20 and 99 μg/L,67 patients (51.1%) more than 100 μg/L.One patient (0.7%) was in T1,39 patients (29.8%) in T2,59 patients (45.0%) in T3,32 patients (24.4%) in T4.5 patients (3.8%) were with Gleason score 4,13 patients (9.9%) were with Gleason score 5,24 patients (18.3%) were with Gleason score 6,51 patients (38.9%) were with Gleason score 7,26 patients (19.8%) were with Gleason score 8,9 patients (6.9%) were with Gleason score 9,3 patients (2.3%) were with Gleason score 10.Results There were 32 of 131 patients (24.4%) progressed to CRPC after treated with ADT within 1 year.In the CRPC group,there were 3 patients less than 60 years,15 patients between 60 and 69 years,12 patients between 70 and 79 years,2 patients more than 79 years

  20. Root of Slave after Ravaging and " Castrating or Spay " by Rural Power --The Second Part of the Series of Research Papers on Theme of "National Character in Novels of Lu Xun and Writers after the 1990s%被乡村权力蹂躏和“阉割”后的奴隶根性——鲁迅与1990年代后中国小说中“国民性”主题系列研究论文(二)

    Institute of Scientific and Technical Information of China (English)

    古大勇

    2012-01-01

    鲁迅小说开创的"国民性"主题在1990年代后中国小说中得到鲜明的承续,例如两者都典型地表现了被乡村权力蹂躏和"阉割"后顽固存留于乡民身上的奴隶根性。此种主题在1990年代后中国小说中频繁再现,表明了"改造国民性"的艰难,20世纪初鲁迅所孜孜以求的"改造国民性"的民族重任并没有完成。%The theme of "national character" created by Lu Xun distinctly continued in novels after the 1990s, for example, both typically displayed the theme of the root of obstinate slave that retained on the villager after ravaging and " castrating or spay " by rural power. This theme appeared frequently in the novels after the 1990s that demonstrated the difficult of transformation of national character.. The task of transformation of national character that proposed by Lu Xun has not completed now yet.

  1. Glyphosate Vedotin for Treatment of Bone Metastatic Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2015-07-01

    and AR gene mutations [2], may cause hypersensitivity of AR to low levels of both endocrine and intracrine androgens [3]. AR splicing variants may...Medium containing 10% fetal bovine serum (HyClone, Logan, UT, USA) and 100 IU/mL penicillin /streptomycin, in a 5% CO 2 humidified incubator at 37°C...USA) with 10% fetal bovine serum (FBS; Mediatech, Inc.) and 1% penicillin /streptomycin was used as the growth medium. Mouse prostate tissues were

  2. Super-Penetrant Androgen Receptor: Overcoming Enzalutamide Sensitivity in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2016-07-01

    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...694.8545 and 0.72 ppm) (Figure 3). This acetylation site mapped to the DNA binding domain of AR. Aim 2. Determine whether Enzalutamide-bound AR...Enzalutamide for 24 hours and fractionated the cells into nuclear and cytosolic fractions. The protein extracts were immunoblotted with AR and Actin

  3. Investigating Genomic Mechanisms of Treatment Resistance in Castration Resistant Prostate Cancer

    Science.gov (United States)

    2015-05-01

    management and strategies for survivorship in a Spanish - language community outreach and support program. As Chief Fellow I organized and planned... acquisition 6 protocol, and tumor is microdissected from surrounding tissue using laser capture microdissection. DNA and RNA are then isolated for analysis... acquisition of Aragon by Janssen the plan for this clinical trial was modified to become a Phase I, open-label, single-arm multicenter study of the

  4. BAY 1024767 blocks androgen receptor mutants found in castration-resistant prostate cancer patients.

    Science.gov (United States)

    Sugawara, Tatsuo; Lejeune, Pascale; Köhr, Silke; Neuhaus, Roland; Faus, Hortensia; Gelato, Kathy A; Busemann, Matthias; Cleve, Arwed; Lücking, Ulrich; von Nussbaum, Franz; Brands, Michael; Mumberg, Dominik; Jung, Klaus; Stephan, Carsten; Haendler, Bernard

    2016-02-01

    Androgen receptor (AR) mutations arise in patients developing resistance to hormone deprivation therapies. Here we describe BAY 1024767, a thiohydantoin derivative with strong antagonistic activity against nine AR variants with mutations located in the AR ligand-binding domain (LBD), and against wild-type AR. Antagonism was maintained, though reduced, at increased androgen levels. Anti-tumor efficacy was evidenced in vivo in the KuCaP-1 prostate cancer model which bears the W741C bicalutamide resistance mutation and in the syngeneic prostate cancer rat model Dunning R3327-G. The prevalence of six selected AR mutations was determined in plasma DNA originating from 100 resistant patients and found to be at least 12%. Altogether the results show BAY 1024767 to be a strong antagonist for several AR mutants linked to therapy resistance, which opens the door for next-generation compounds that can benefit patients based on their mutation profile.

  5. 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.

  6. Biomarkers for Taxane Sensitivity and Hormonal Resistance in Patients with Castration Resistant Prostate Cancer

    Science.gov (United States)

    2016-04-01

    RNA to perform qRT- PCR for splice variants and variant transcriptome. Results: As described in the annual report, the Rarecyte assay originally...modified by Antonarakis et al (1). This assay reliably isolated splice variant transcript as detected by QT- PCR from as low as 5 spiked LNCaP 95 cells...transfectant cells compared to controls (data not shown). 1b. Determine if CTC from abiraterone resistant prostate cancers contain splice variant

  7. CpG-STAT3siRNA for Castration-Resistant Prostate Cancer Therapy

    Science.gov (United States)

    2015-12-01

    STAT3 and NF-κB/RELA reduce tumor-initiating potential and viability of TLR9+ cancer cells in xenotransplanted prostate tumor models • STAT3 and NF... cells , such as leukemia and lymphoma, internalize the conjugate within 1–4 h at concentrations from 100 to 500 nM. Higher concentrations of the CpG...innate immune gene family is differentially influenced by DNA stress and p53 status in cancer cells . Cancer Res. 2012; 72:3948–3957. 7. Ilvesaro JM

  8. 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...

  9. Clinical and Preclinical Treatment Aspects of Castration Resistant Prostate Cancer (CRPC)

    NARCIS (Netherlands)

    H.J. Meulenbeld (Hielke)

    2012-01-01

    textabstractIn the Western countries prostate cancer is the most frequently diagnosed cancer, except for skin cancer, and the second leading cause of male cancer deaths. Prostate cancer tends to develop in men over the age of fifty and although it is one of the most prevalent types of cancer in men,

  10. Biomarkers for Taxane Sensitivity and Hormonal Resistance in Patients with Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2015-02-01

    metastasis 3. OVERALL PROJECT SUMMARY: Progress; Aim 1 Determine whether AR variants and the associated mitotic transcriptome can be isolated from blood spiked... mitotic transcriptome. 4 Aim 2. Determine whether AR variants and the associated mitotic transcriptome can be isolated from DTC acquired from men

  11. Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer

    DEFF Research Database (Denmark)

    Iversen, P; Tyrrell, C J; Kaisary, A V

    2000-01-01

    Nonsteroidal antiandrogen monotherapy may be a treatment option for some patients with advanced prostate cancer. We report a survival and safety update from an analysis of 2 studies in which patients with nonmetastatic (M0) locally advanced disease were treated with either 150 mg. bicalutamide...

  12. Radium-223 treatment of bone metastases from castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Mortensen, Jann; Højgaard, Liselotte

    2014-01-01

    The alpha emitter Radium-223 ((22)3Ra-Cl2) is a bone-seeking radionuclide studied as a new treatment for patients with bone metastases from hormone refractory prostate cancer. More than 1,000 patients have been included in clinical phase I-III tests showing significant reduction in alkaline...

  13. Developing Novel Therapeutics Targeting Undifferentiated and Castration-Resistant Prostate Cancer Stem Cells

    Science.gov (United States)

    2015-10-01

    to identify PCSC-specific homing peptides; and 2) To perform unbiased drug library screening to identify novel PCSC-targeting chemicals. In the past...Specific Aim 2, we have finished a targeted library screening to identify several compounds that could sensitize the AR-PSA- LNCaP cells. We have also...peptide and finishing up screening and validating the kinase inhibitor library screening .

  14. Understanding and Targeting Tumor Microenvironment in Prostate Cancer to Inhibit Tumor Progression and Castration Resistance

    Science.gov (United States)

    2015-10-01

    as being possible MDSCs. The definition of MDSC requires these cells being immunosuppressive in a standard T cell proliferation assay. Therefore...circulation as the cancer progresses. The MDSCs display potent immunosuppressive activity to limit T cell proliferation. Importantly, depletion of...dependent increase of infiltrating and circulating granulocytic MDSCs in the mouse model. These MDSCs display potent immunosuppressive activity

  15. Uncarboxylated Osteocalcin and Gprc6a Axis Produce Intratumoral Androgens in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2016-05-01

    state in the progression of prostate cancer . Recently, tumor cells have been shown to activate androgen receptor signaling via multiple pathways ...Gprc6a axis is functional in VCaP prostate cancer cells. This pathway can induce intra turmoral androgen synthesis through overexpression of...androgen biosynthetic enzyme expression. Together this pathway promotes prostate cancer bone metastasis and drive androgen receptor mediated bone tumor

  16. Epithelial Plasticity in Castration-Resistant Prostate Cancer: Biology of the Lethal Phenotype

    Science.gov (United States)

    2014-07-01

    others with a glandular well-differentiated epithelial appearance. Even R. L. Bitting :A. J. Armstrong (*) Division of Medical Oncology, Duke Cancer...mouse models of prostate and other cancers [31]. Furthermore, PC cell lines Normal prostate epithelium Genetic and epigenetic changes Epigenetic...model systems, including human ovarian carcinoma Cancer Metastasis Rev cells [145], renal tubular epithelium [146], and mammary epithelial cells [147

  17. Cost-effectiveness analysis of treatments for metastatic castration resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Matthew E. Pollard

    2017-01-01

    Conclusion: Based on the available survival data and current costs of treatment, all treatment strategies greatly exceed a commonly assumed societal willingness-to-pay threshold of US$100,000 per LYS. Improvements in this regard can only come with a reduction in pricing, better tailoring of treatment or significant enhancements in survival with clinical use of treatment combinations or sequences.

  18. Toward Maximizing Immunotherapy in Metastatic Castration Resistant Prostate Cancer – Rationale for Combinatorial Approaches Using Chemotherapy

    Directory of Open Access Journals (Sweden)

    Susan F Slovin

    2012-05-01

    Full Text Available Prostate cancer is particularly suited for active immunotherapy because of the expression of a distinctive number of antigens which are overexpressed on prostate cancer cells and cell lines. There is evidence in this disease that tumors promote immune tolerance starting early in the disease course. As such, chemotherapy, by suppressing tumors and activating immune system homeostatic mechanisms, may help overcome this tumor-induced immune tolerance. Sipuleucel-T which has recently been approved in the US, is an autologous cellule product immunotherapy that induces immune activity likely through activation of dendritic cells. This was associated with a survival benefit in the absence of significant toxicity. However, a post hoc analysis of phase III trial participants found a substantial survival benefit to receiving docetaxel some months after sipuleucel-T. However, another phase III immunotherapy trial combining a prostate cancer therapeutic vaccine G-VAX plus docetaxel versus standard docetaxel therapy in advanced prostate cancer, observed a lower overall survival with the vaccine regimen. These trials highlight major unresolved questions concerning the optimum choice, dosing, and timing of chemotherapy relative to active immunotherapy and the overall merits of considering this approach. The ideal treatment approach remains unclear; advances in biomarker validation and trial design may likely improve our ability to assess biologic benefit irrespective of the development of true anti-tumor immunity.

  19. Immunotherapy for castration-resistant prostate cancer: Progress and new paradigms

    NARCIS (Netherlands)

    Quinn, D.I.; Shore, N.D.; Egawa, S.; Gerritsen, W.R.; Fizazi, K.

    2015-01-01

    BACKGROUND: The approval of sipuleucel-T in conjunction with data from other immunotherapeutic trials for prostate cancer and other solid tumors demonstrates the potential of harnessing the patients immune system for long-term survival. Thus, a range of therapeutic approaches are under evaluation. T

  20. "I Hope Someone Castrates You, You Perverted Bastard": Martin Cole's Sex Education Film, "Growing Up"

    Science.gov (United States)

    Limond, David

    2009-01-01

    This paper concerns the response to the sex education film "Growing Up", made in 1971 by Dr Martin Cole, which used a combination of animation and live action to offer a frank and uncompromising account of sexual reproduction. As part of this, both male and female masturbation and an unsimulated act of male-female coitus featured in the…

  1. 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

    PURPOSE: We assessed the efficacy and toxicity of a fixed dose of docetaxel and prednisone, combined with escalating doses of gemcitabine (DGP). The primary endpoint was PSA response. METHODS: Fifteen patients were enrolled in the phase I and 50 patients entered the phase II. Patients were given...

  2. Novel Therapeutic Targets to Inhibit Tumor Microenvironment-Induced Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2014-10-01

    signaling in HPS19I cells, we transfected HPS19I cells with a (CAGA)12MLP (Smad binding sequence) reporter construct [41] and a pRL -null vector...transfected with (CAGA)12MLP and pRL -null vectors, and treated with 50 pM of TGF-β1 and different dosages of SD-208 compound for 24 hours. Cell lysates were...CAGA)12MLP [41] and 0.1 μg of pRL -null (Promega, Madison, WI, USA) in 12 well plate using FuGENE 6 transfection reagent (Roche Applied Sciences

  3. Role of IKKalpha and STAT3 in the Emergence of Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2013-06-01

    androgen-deprived tumor stroma we orally administered a DNA vaccine encoding FAP that is specifically delivered to secondary lymphoid tissues by a...molecular pathology 87, 189-194. Gabbiani, G. (2003). The myofibroblast in wound healing and fibrocontractive diseases. The Journal of pathology 200, 500...affecting wound healing. Journal of dental research 89, 219-229. Higgins, D. F., Biju, M. P., Akai, Y., Wutz, A., Johnson, R. S., and Haase, V. H

  4. Understanding the Role of MDSCs in Castration-Resistant Prostate Cancer and Metastasis

    Science.gov (United States)

    2015-10-01

    intern students , one medical intern student . These experiences have provided me the great opportunity to practice my mentoring and management skills. In...network of the tumor microenvironment (TMEN). MDSCs play a pivotal role in suppression of both innate and adaptive immunity and its presence is documented...and comprise two main subsets-- monocytic (Ly6Chi) and granulocytic (Ly6Ghi). It is well established that MDSCs suppress both innate and adaptive

  5. Metabolism of adrenal androgen and its impacts on prostate cancer after castration

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    @@ With the extensive utilization of PSA,digital rectum examination and transrectal ultrasound for screening in the aging population,the diagnosis of prostate cancer in China has markedly increased during the past years,particularly in developed regions.

  6. Epithelial Plasticity in Castration-Resistant Prostate Cancer: Biology of the Lethal Phenotype

    Science.gov (United States)

    2011-07-01

    the WGA protocol with sonication of DNA to remove unwanted DNA fragments that contribute to the increased noisiness in the assay, and then application...hormonal therapies (range) 2.5 (0–5) Prior chemotherapy 68% Prior bisphosphonates 73% Sites of metastatic disease Visceral (lung þ liver) 54% Lymph node...extend to stem cell markers and to treatment-induced 461 effects . For example, we observed an increased predomi- 462 nance of N-cadherin expression

  7. Increased expression of class III β-tubulin in castration-resistant human prostate cancer

    OpenAIRE

    Terry, S; Ploussard, G.; Allory, Y; Nicolaiew, N; Boissière-Michot, F; Maillé, P; Kheuang, L; Coppolani, E; Ali, A.; Bibeau, F; Culine, S; Buttyan, R; de la Taille, A; Vacherot, F

    2009-01-01

    Background: Class III β-tubulin (βIII-tubulin) is expressed in tissues of neuronal lineage and also in several human malignancies, including non-small-cell lung carcinoma, breast and ovarian cancer. Overexpression of βIII-tubulin in these tumours is associated with an unfavourable outcome and resistance to taxane-based therapies. At present, βIII-tubulin expression remains largely uncharacterised in prostate cancer. Methods: In this report, we evaluated the expression of βIII-tubulin in 138 d...

  8. Parasitic castration in Fissurella crassa (Archaeogastropoda due to an adult Digenea, Proctoeces lintoni (Fellodistomidae

    Directory of Open Access Journals (Sweden)

    Marcelo E. Oliva

    1992-03-01

    Full Text Available Specimens of Fissurella crassa (Archaeogastropoda from Ilo, southern Perú, are infected with the adult stage of the digenetic trematode Proctoeces lintoni (Fellodistomidae. The histopatological analysis of the male and female gonads show a strong effect of the parasite on the structure and function of these organs. P. lintoni live unencysted in the gonads, and the main mechanical damage is originated by the action of a well developed acetabulum. Chemical actions of parasitic secretions may also be involved. The infected gonads show altered structure and the gametogenic processes is aborted. There is no evidence of hemocytic response, but leucocite infiltration is evident at least in male infected gonads. An increased content of polysaccarides is evident in infected gonads.

  9. 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...46-54. [34] Narizhneva NV, Tararova ND, Ryabokon P, Shy- shynova I, Prokvolit A, Komarov PG, Purmal AA, Gudkov AV, Gurova KV. Small molecule screen

  10. Androgen Deprivation Enhances PLZF-Repressed Cistrome that Promotes the Castration-Resistant Phenotype

    Science.gov (United States)

    2014-10-01

    negative effect on pros- tate cancer cell proliferation. Accordingly, we report that an andro - gen-induced eRNA scaffolds the AR-associated protein...quantitative PCR (RT-qPCR) analyses in andro - gen-dependent LNCaP and VCaP, and androgen-independent LNCaP-abl cells (21) (Fig. 1B and Fig. S1 A and B...remains active in andro - gen-independent LNCaP-abl, androgens (DHT) did not stimulate their mRNA expression to a comparable magnitude as those in

  11. "I Hope Someone Castrates You, You Perverted Bastard": Martin Cole's Sex Education Film, "Growing Up"

    Science.gov (United States)

    Limond, David

    2009-01-01

    This paper concerns the response to the sex education film "Growing Up", made in 1971 by Dr Martin Cole, which used a combination of animation and live action to offer a frank and uncompromising account of sexual reproduction. As part of this, both male and female masturbation and an unsimulated act of male-female coitus featured in the film. Cole…

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

    Science.gov (United States)

    2015-10-01

    responsible for TALEN -based gene editing to develop AR- and AR-V-driven prostate cancer models with impaired function of PSA enhancer RNA (eRNA...cancer. I will be responsible for TALEN -based gene editing to develop AR- and AR-V-driven prostate cancer models with impaired function of PSA

  13. Development of a New Class of Drugs to Inhibit All Forms of Androgen Receptor in Castration-Resistant Prostate Cancers

    Science.gov (United States)

    2015-10-01

    AR variants in prostate cancer. I will be responsible for TALEN -based gene editing to develop AR- and AR-V-driven prostate cancer models with...full-length AR and truncated AR variants in prostate cancer. I will be responsible for TALEN -based gene editing to develop AR- and AR-V-driven

  14. Exploring AR-NFkappaB/p52-Targeted Inhibitors as Novel Therapy Against Castration-Resistant Prostate Cancer Progression

    Science.gov (United States)

    2014-05-01

    Bicalutamide Drug Concentration (uM) 0.01 0.1 1 10 100 % C on tro l F luo re sc en ce P ola riz at ion (m P) 0 20 40 60 80 100 ARP52 Drug...Concentration (uM) 0.1 1 10 100 % C on tro l F luo re sc en ce P ola riz at ion (m P) 0 20 40 60 80 100 120 140 drug arp52-01001 drug arp52-02001 drug arp52

  15. 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

    drugs for use in combination for daily dosing. The second objective is to use pharmacodynamic biomarkers to support the hypothesis that GR... biomarkers to support the hypothesis that GR antagonism in combination with AR antagonism will delay CRPC progression. This portion of the study will...Pain 1, 7.1 1, 7.1 Confusion 1, 7.1 1, 7.1 Depression 1, 7.1 Fatigue 6, 42.9 5, 35.7 1, 7.1 Gynecomastia 1, 7.1 Hot Flashes 2, 14.3 2, 14.3

  16. Successful sperm extraction and live birth after radiation, androgen deprivation and surgical castration for treatment of metastatic prostate cancer.

    Science.gov (United States)

    Wood, G J A; Hayden, R P; Tanrikut, C

    2017-02-01

    Fertility preservation has become an important aspect of cancer treatment given the gonadotoxic effects of oncologic therapies. It is now considered standard of care to offer sperm banking to men undergoing treatment for primaries that affect young individuals. Less is known regarding fertility preservation of patients afflicted with prostate cancer. This cohort has progressively expanded and grown younger in the post-PSA era. Prostatectomy, radiation, chemotherapy and androgen blockade all pose unique challenges to the infertility specialist. Optimum management becomes even more uncertain for those men with metastatic prostate cancer. Most of these individuals will have received multiple forms of therapy, each carrying a distinct insult to the patient's reproductive potential. We describe a case of successful ex vivo sperm extraction and live birth in a patient previously treated with radiation and chronic androgen deprivation for metastatic prostate cancer. The presented case demonstrates that conception after radiation therapy and chronic androgen deprivation is feasible. We propose that fertility counselling and sperm cryopreservation should be considered for all prostate cancer patients. Additionally, for those individuals undergoing external beam radiotherapy, testicular shielding should be routinely offered in the event further family building is desired.

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

    Science.gov (United States)

    2015-10-01

    J. Hamilton et al., Statin medication use and the risk of biochemical recurrence after radical prostatectomy. Cancer 116, 3389 (2010). 22. D. J. Mener...Prostate specific antigen reduction following statin therapy: Mechanism of action and review of the literature. IUBMB Life 62, 584 (2010). 23. I...Ortega et al., Simvastatin Reduces Steroidogenesis by Inhibiting Cyp17a1 Gene Expression in Rat Ovarian Theca-Interstitial Cells 1. Biol. Reprod. 86

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

    Science.gov (United States)

    2014-12-01

    study. From a PD standpoint, serum cortisol levels were measured before and after mifepristone at 300mg. Cortisol routinely doubled as expected...leaders in the field. The PI was able to share trial progress and garner support in the group for the trial, which was an excellent learning opportunity

  19. 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

    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...

  20. 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

    2013-01-01

    -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...

  1. LHRH agonists in prostate cancer : frequency of treatment, serum testosterone measurement and castrate level: consensus opinion from a roundtable discussion

    NARCIS (Netherlands)

    de Jong, Igle Jan; Eaton, Alan; Bladou, Franck

    2007-01-01

    Background: Options for lowering testosterone in patients with prostate cancer include bilateral orchiectomy, oestrogens and luteinising hormone-releasing hormone (LHRH) agonists. LHRH agonists have become widely used in the treatment of prostate cancer. Roundtable assembly: In May 2006, a team of e

  2. N-Cadherin in Prostate Cancer: Downstream Pathways and Their Translational Application for Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2012-09-01

    inhibition of downstream signaling pathways especially NF-κB and the PI3K/AKT pathways may serve as complementary therapies to N-cadherin targeting...N-cadherin–positive cells from LAPC9-CR tumors are also more tum- origenic than N-cadherin–negative cells (E.K. and R.E.R., unpublished data). A

  3. Matrine inhibits the proliferation, invasion and migration of castration-resistant prostate cancer cells through regulation of the NF-κB signaling pathway.

    Science.gov (United States)

    Li, Qi; Lai, Yiming; Wang, Chengbin; Xu, Guibin; He, Zheng; Shang, Xiaohong; Sun, Yi; Zhang, Fan; Liu, Leyuan; Huang, Hai

    2016-01-01

    Matrine is a naturally occurring alkaloid extracted from the Chinese herb Sophora flavescens. It has been demonstrated to exhibit antiproliferative properties, promote apoptosis and inhibit cell invasion in a number of cancer cell lines. It has also been shown to improve the efficacy of chemotherapy when it is combined with other chemotherapy drugs. However, the therapeutic efficacy of matrine for prostate cancer remains poorly understood. In the present study, we showed that matrine inhibited the proliferation, migration and invasion of both DU145 and PC-3 cells in a dose- and time-dependent manner. It also reduced the cell population at S phase and increased the cell population at sub-G1 phase. The increases in both the apoptotic cell population and cell population at S and sub-G1 phases consistently indicated a pro-apoptotic effect of matrine. Decreases in levels of P65, p-P65, IKKα/β, p-IKKα/β, IKBα and p-IKBα as detected by immunoblot analysis in the matrine-treated DU145 and PC-3 cells suggested an involvement of the NF-κB signaling pathway. Therefore, it is a novel promising addition to the current arsenal of chemotherapy drugs for the treatment of androgen-independent prostate cancer.

  4. Small molecule screening reveals a transcription-independent pro-survival function of androgen receptor in castration-resistant prostate cancer.

    Science.gov (United States)

    Narizhneva, Natalia V; Tararova, Natalia D; Ryabokon, Petro; Shyshynova, Inna; Prokvolit, Anatoly; Komarov, Pavel G; Purmal, Andrei A; Gudkov, Andrei V; Gurova, Katerina V

    2009-12-15

    In prostate cancer (PCa) patients, initial responsiveness to androgen deprivation therapy is frequently followed by relapse due to development of treatment-resistant androgen-independent PCa. This is typically associated with acquisition of mutations in AR that allow activity as a transcription factor in the absence of ligand, indicating that androgen-independent PCa remains dependent on AR function. Our strategy to effectively target AR in androgen-independent PCa involved using a cell-based readout to isolate small molecules that inhibit AR transactivation function through mechanisms other than modulation of ligand binding. A number of the identified inhibitors were toxic to AR-expressing PCa cells regardless of their androgen dependence. Among these, some only suppressed PCa cell growth (ARTIS), while others induced cell death (ARTIK). ARTIK, but not ARTIS, compounds caused disappearance of AR protein from treated cells. siRNA against AR behaved like ARTIK compounds, while a dominant negative AR mutant that prevents AR-mediated transactivation but does not eliminate the protein showed only a growth suppressive effect. These observations reveal a transcription-independent function of AR that is essential for PCa cell viability and, therefore, is an ideal target for anti-PCa treatment. Indeed, several of the identified AR inhibitors demonstrated in vivo efficacy in mouse models of PCa and are candidates for pharmacologic optimization.

  5. 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

    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...blinded 177Lu-J951 versus 111In-J591 (control) with a backbone of hormonal therapy (ketoconazole and hydro- cortisone ) and will undergo planar gamma camera

  6. A randomised comparison of 'Casodex' (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer

    DEFF Research Database (Denmark)

    Tyrrell, C J; Kaisary, A V; Iversen, P;

    1998-01-01

    To evaluate the efficacy and tolerability of 'Casodex' monotherapy (150 mg daily) for metastatic and locally advanced prostate cancer.......To evaluate the efficacy and tolerability of 'Casodex' monotherapy (150 mg daily) for metastatic and locally advanced prostate cancer....

  7. A Randomized Phase 2 Trial of 177Lu Radiolabeled Anti-PSMA Monoclonal Antibody J591 in Patients with High-Risk Castrate, Biochemically Relapsed Prostate Cancer

    Science.gov (United States)

    2014-09-01

    Christos, Marina Mikhail, John Chapin, David M. Nanus, Scott T. Tagawa Division of Hematology & Medical Oncology Weill Cornell Medical College Disclosures...Genetics, $26,196,300 Therapy and Mechanisms of Resistance, $87,912,713 Tumor Biology and Immunology, $51,016,047 In This Issue page 1

  8. A Randomized Phase 2 Trial of 177Lu Radiolabeled Anti-PSMA Biochemically Monoclonal Antibody J591 in Patients with High-Risk Castrate, Biochemically Relapsed Prostate Cancer

    Science.gov (United States)

    2010-09-01

    review on hold pending additional funding - University of Medicine and Dentistry , New Jersey – scientific review - Nevada Cancer Institute – scientific...BIOCHEMICALLY RELAPSED PROSTATE CANCER AFTER LOCAL THERAPY Scott T. Tagawa, Joseph Osborne, Paul J. Christos, Shankar Vallabhajosula, Kristen Petrillo

  9. Compensatory upregulation of tyrosine kinase Etk/BMX in response to androgen deprivation promotes castration-resistant growth of prostate cancer cells.

    Science.gov (United States)

    Dai, Bojie; Chen, Hege; Guo, Shengjie; Yang, Xi; Linn, Douglas E; Sun, Feng; Li, Wei; Guo, Zhiyong; Xu, Kexin; Kim, Oekyung; Kong, Xiangtian; Melamed, Jonathan; Qiu, Shaopeng; Chen, Hegang; Qiu, Yun

    2010-07-01

    We previously showed that targeted expression of non-receptor tyrosine kinase Etk/BMX in mouse prostate induces prostate intraepithelial neoplasia, implying a possible causal role of Etk in prostate cancer development and progression. Here, we report that Etk is upregulated in both human and mouse prostates in response to androgen ablation. Etk expression seems to be differentially regulated by androgen and interleukin 6 (IL-6), which is possibly mediated by the androgen receptor (AR) in prostate cancer cells. Our immunohistochemical analysis of tissue microarrays containing 112 human prostate tumor samples revealed that Etk expression is elevated in hormone-resistant prostate cancer and positively correlated with tyrosine phosphorylation of AR (Pearson correlation coefficient rho = 0.71, P < 0.0001). AR tyrosine phosphorylation is increased in Etk-overexpressing cells, suggesting that Etk may be another tyrosine kinase, in addition to Src and Ack-1, which can phosphorylate AR. We also showed that Etk can directly interact with AR through its Src homology 2 domain, and such interaction may prevent the association of AR with Mdm2, leading to stabilization of AR under androgen-depleted conditions. Overexpression of Etk in androgen-sensitive LNCaP cells promotes tumor growth while knocking down Etk expression in hormone-insensitive prostate cancer cells by a specific shRNA that inhibits tumor growth under androgen-depleted conditions. Taken together, our data suggest that Etk may be a component of the adaptive compensatory mechanism activated by androgen ablation in prostate and may play a role in hormone resistance, at least in part, through direct modulation of the AR signaling pathway.

  10. 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

    Onderzoeksresultaten laten zien dat het onwaarschijnlijk is dat er een eenvoudige oplossing bestaat voor het stoppen met castratie van beertjes in de varkenshouderij. Er dient gezocht te worden naar een combinatie van verschillende methoden. De berengeurproblematiek is primair een probleem van markt

  11. 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.

  12. A Randomized Phase 2 Trial of 177Lu Radiolabeled Anti-PSMA Monoclonal Antibody J591 in Patients With High-Risk Castrate Biochemically Relapsed Prostate Cancer

    Science.gov (United States)

    2015-09-01

    Sincerely , Rosemary Kraemer, Ph.D. Director, Human Research Protections Program Please note the following important information about this approval...sciences journal literature , and be made publicly available within twelve months of publication. The Library and RASP have prepared general information

  13. The HIF1A functional genetic polymorphism at locus +1772 associates with progression to metastatic prostate cancer and refractoriness to hormonal castration.

    Science.gov (United States)

    Fraga, Avelino; Ribeiro, Ricardo; Príncipe, Paulo; Lobato, Carlos; Pina, Francisco; Maurício, Joaquina; Monteiro, Cátia; Sousa, Hugo; Calais da Silva, F; Lopes, Carlos; Medeiros, Rui

    2014-01-01

    The hypoxia inducible factor 1 alpha (HIF1a) is a key regulator of tumour cell response to hypoxia, orchestrating mechanisms known to be involved in cancer aggressiveness and metastatic behaviour. In this study we sought to evaluate the association of a functional genetic polymorphism in HIF1A with overall and metastatic prostate cancer (PCa) risk and with response to androgen deprivation therapy (ADT). The HIF1A +1772 C>T (rs11549465) polymorphism was genotyped, using DNA isolated from peripheral blood, in 1490 male subjects (754 with prostate cancer and 736 controls cancer-free) through Real-Time PCR. A nested group of cancer patients who were eligible for androgen deprivation therapy was followed up. Univariate and multivariate models were used to analyse the response to hormonal treatment and the risk for developing distant metastasis. Age-adjusted odds ratios were calculated to evaluate prostate cancer risk. Our results showed that patients under ADT carrying the HIF1A +1772 T-allele have increased risk for developing distant metastasis (OR, 2.0; 95%CI, 1.1-3.9) and an independent 6-fold increased risk for resistance to ADT after multivariate analysis (OR, 6.0; 95%CI, 2.2-16.8). This polymorphism was not associated with increased risk for being diagnosed with prostate cancer (OR, 0.9; 95%CI, 0.7-1.2). The HIF1A +1772 genetic polymorphism predicts a more aggressive prostate cancer behaviour, supporting the involvement of HIF1a in prostate cancer biological progression and ADT resistance. Molecular profiles using hypoxia markers may help predict clinically relevant prostate cancer and response to ADT.

  14. 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

    records from 421 consecutive patients treated with first-line docetaxel (75 mg/m(2) every 3 weeks) and low-dose prednisolone from 2007 to 2013 at Herlev University Hospital were reviewed. Common Terminology Criteria for Adverse Events, version 4.0, and the Prostate Cancer Working Group 2 guidelines were...

  15. Inhibition of the Androgen Receptor Amino-Terminal Domain by a Small Molecule as Treatment for Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2013-10-01

    such as BADGE. 2H2O are inactive (21). The chlorohydrin group of EPI compounds may be required for activity to block AR transcription- al activity...063 were nega- tive controls, by analogy with the inactive analog BADGE. 2H2O (21). SDS-PAGE disrupts noncovalent interactions and is used to determine...TCEP), 100 μM biotin-azide reagent, and 1 mM CuSO4 . Samples were dialyzed overnight in 50 mM HEPES (pH 8.0), 150 mM NaCl, 0.1% SDS, and 1% Triton

  16. 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

    modulators. Identification of a mediator of resistance across therapy classes is a critically unmet need and would be a significant innovation in...prostate cancer (mCRPC) is clinically treated with both taxane chemotherapy and androgen pathway modulators. Identification of a mediator of resistance

  17. 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

    and function of immune suppressive cell subsets in the peripheral blood of 41 patients with prostate cancer (PC) and 36 healthy donors (HD) showed a significant increase in circulating CD14(+) HLA-DR(low/neg) monocytic MDSC (M-MDSC) and Tregs in patients with PC compared to HD. Furthermore, M-MDSC frequencies...... and other cell types may suggest ways to tackle their induction and/or function to improve immunological tumor control....

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

    OpenAIRE

    2015-01-01

    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 i...

  19. The HGF/c-MET Axis as a Critical Driver of Resistance to Androgen Suppression in Metastatic Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2015-10-01

    aspirates from 5 patients. We have obtained 6 blood samples for CTC analyses from 4 patients on abiraterone and 3 blood samples from 2 patients on...bone marrow aspirates has been slower than anticipated. We have addressed this in a number of ways, including pre- screening clinics for eligible...a graphene oxide based microfluidic device (GO Chip) to prostate cancer circulating tumor cell capture and analysis, AACR, 2015. *Patnaik, A

  20. Effects of muscle type, castration, age, and compensatory growth rate on androgen receptor mRNA expression in bovine skeletal muscle.

    Science.gov (United States)

    Brandstetter, A M; Pfaffl, M W; Hocquette, J F; Gerrard, D E; Picard, B; Geay, Y; Sauerwein, H

    2000-03-01

    The effect of testosterone on sexual dimorphism is evident by differential growth of forelimb and neck muscles in bulls and steers. Divergent hormone sensitivites may account for the differential growth rates of individual muscles. Therefore, the objective of this study was to compare androgen receptor (AR) expression in three different muscles of bulls and steers at various ages and growth rates. Thirty Montbéliard bulls and 30 steers were assigned to four slaughter age groups. Four or five animals of each sex were slaughtered at 4 and 8 mo of age. Animals in the remaining two slaughter groups (12 and 16 mo) were divided into groups of either restricted (R) or ad libitum (AL) access to feed. Five animals of each sex and diet were slaughtered at the end of the restricted intake period at 12 mo of age. To simulate compensatory growth, the remaining animals (R and AL) were allowed ad libitum access to feed until slaughter at 16 mo of age. Total RNA was extracted from samples of semitendinosus (ST), triceps brachii (TB), and splenius (SP) muscles. Androgen receptor mRNA was quantified in 200-ng total RNA preparations using an internally standardized reverse transcription (RT) PCR assay. Data were analyzed using 18S ribosomal RNA concentrations as a covariable. Steers had higher AR mRNA levels per RNA unit than bulls (P muscles (P muscle with increasing age. Between 4 and 12 mo of age, AR mRNA levels increased (P muscle AR expression, but steers exhibiting compensatory growth had higher AR mRNA levels than AL steers (P muscle-specific and may be modulated by circulating testicular hormones. These data suggest that the regulation of AR expression may be linked to allometric muscle growth patterns in cattle and compensatory gain in steers.

  1. Targeting Histone Demethylase GASC1/JMJD2C/KDM4C as a Novel Therapeutic Strategy in Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2013-09-01

    Vandenbos F, Otto J, et al. Molecular cytogenetic characterization of a metastatic lung sarcomatoid carcinoma: 9p23 neocentromere and 9p23-p24...amplification including JAK2 and JMJD2C. Cancer Genet Cytogenet . 2006;167:122-30. 6. Northcott PA, Nakahara Y, Wu X, Feuk L, Ellison DW, Croul S, et al...Primary Organ Site: Not Applicable *Special Consideration: Not Applicable *Choose Chemical Structure Disclosure: NOT APPLICABLE . No compounds

  2. 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

    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.......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...

  3. Lipidic characterization of Santa Inês lamb shoulder

    Directory of Open Access Journals (Sweden)

    Christian Albert Carvalho da Cruz

    2011-06-01

    Full Text Available The edible portion of the shoulder of 12 castrated and 12 non-castrated Santa Inês lambs slaughtered at different ages (84, 168, 210, 252 days were used. The shoulders were chemically analyzed to determine the quantity of total lipids, cholesterol, and fatty acids composition. Castrated and non-castrated lambs gained body weight (p = 0.0393, p = 0.0017 and half carcass weight (p = 0.0240, p = 0.0017, respectively. The shoulder weight was increased in the carcasses of non-castrated lambs (p = 0.0110. The edible portion of the shoulder of castrated lambs presented higher total lipids (16.09 g.100 g-1. The cholesterol content was influenced by castration (p = 0.0001 reducing with age. Castrated animals presented higher content of C18:1 T11, CLA, and C18:0. The shoulder weight is only increased with increasing age in the carcasses of non-castrated lambs. Castration influences the cholesterol content of the shoulder; however, both castrated and non-castrated lambs had their cholesterol contents reduced with increasing age. Castration and age interfered in the estearic acid concentration of the edible portion of lamb shoulder.

  4. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial

    NARCIS (Netherlands)

    Eertwegh, A.J. van den; Versluis, J.; Berg, H.P. van den; Santegoets, S.J.; Moorselaar, R.J. van; Sluis, T.M. van der; Gall, H.E.; Harding, T.C.; Jooss, K.; Lowy, I.; Pinedo, H.M.; Scheper, R.J.; Stam, A.G.; Blomberg, B.M. von; Gruijl, T.D. de; Hege, K.; Sacks, N.; Gerritsen, W.R.

    2012-01-01

    BACKGROUND: The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte ant

  5. Effect of Lijiang Maca on the sexual function of male hemi castrated rats%丽江产玛咖对雄性半去势大鼠性功能影响的实验研究

    Institute of Scientific and Technical Information of China (English)

    王曦晨; 姜京徽; 肖敏; 刘美; 陈海涛; 陈重华

    2016-01-01

    目的 研究丽江产玛咖对半去势大鼠交配能力与阴茎勃起功能的影响,评价其作用效果.方法 将♂大鼠随机分为6组,除正常对照组外,其余5组摘除右侧睾丸.正常对照、模型组(ig 10 mL·kg-1生理盐水)、阳性对照组(sc 2 mg· kg-1丙酸睾酮)及玛咖组(ig 0.64、0.32、0.16 g·kg-1玛咖)给药32 d,进行交配和勃起实验,记录骑跨潜伏期、骑跨次数、勃起潜伏期并检测血清睾酮(T)、促间质细胞激素(LH)、促精子生成素(FSH)水平、前列腺和精囊腺脏器系数等指标.结果 玛咖和丙酸睾酮能明显缩短半去势大鼠的骑跨潜伏期、勃起潜伏期,提高半去势大鼠的骑跨次数;显著降低血清中的LH水平,提高精囊腺脏器系数.结论 玛咖具有提高半去势大鼠的交配能力和阴茎勃起功能的作用,其机制可能与调整失衡的血清性激素水平有关.

  6. Pre-therapeutic dosimetry of normal organs and tissues of {sup 177}Lu-PSMA-617 prostate-specific membrane antigen (PSMA) inhibitor in patients with castration-resistant prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kabasakal, Levent; AbuQbeitah, Mohammad; Ayguen, Aslan; Yeyin, Nami [Istanbul University, Department of Nuclear Medicine, Cerrahpasa Medical Faculty, Istanbul (Turkey); Ocak, Meltem [Istanbul University, Department of Pharmaceutical Technology, Pharmacy Faculty, Istanbul (Turkey); Demirci, Emre [Sisli Etfal Training and Research Hospital, Department of Nuclear Medicine, Istanbul (Turkey); Toklu, Turkay [Yeditepe University Medical Faculty, Department of Nuclear Medicine, Istanbul (Turkey)

    2015-12-15

    {sup 177}Lu-617-prostate-specific membrane antigen (PSMA) ligand seems to be a promising tracer for radionuclide therapy of progressive prostate cancer. However, there are no published data regarding the radiation dose given to the normal tissues. The aim of the present study was to estimate the pretreatment radiation doses in patients who will undergo radiometabolic therapy using a tracer amount of {sup 177}Lu-labeled PSMA ligand. The study included seven patients with progressive prostate cancer with a mean age of 63.9 ± 3.9 years. All patients had prior PSMA positron emission tomography (PET) imaging and had intense tracer uptake at the lesions. The injected {sup 177}Lu-PSMA-617 activity ranged from 185 to 210 MBq with a mean of 192.6 ± 11.0 MBq. To evaluate bone marrow absorbed dose 2-cc blood samples were withdrawn in short variable times (3, 15, 30, 60, and 180 min and 24, 48, and 120 h) after injection. Whole-body images were obtained at 4, 24, 48, and 120 h post-injection (p.i.). The geometric mean of anterior and posterior counts was determined through region of interest (ROI) analysis. Attenuation correction was applied using PSMA PET/CT images. The OLINDA/EXM dosimetry program was used for curve fitting, residence time calculation, and absorbed dose calculations. The calculated radiation-absorbed doses for each organ showed substantial variation. The highest radiation estimated doses were calculated for parotid glands and kidneys. Calculated radiation-absorbed doses per megabecquerel were 1.17 ± 0.31 mGy for parotid glands and 0.88 ± 0.40 mGy for kidneys. The radiation dose given to the bone marrow was significantly lower than those of kidney and parotid glands (p < 0.05). The calculated radiation dose to bone marrow was 0.03 ± 0.01 mGy/MBq. Our first results suggested that {sup 177}Lu-PSMA-617 therapy seems to be a safe method. The dose-limiting organ seems to be the parotid glands rather than kidneys and bone marrow. The lesion radiation doses are within acceptable ranges; however, there is a substantial individual variance so patient dosimetry seems to be mandatory. (orig.)

  7. 卵巢移植对去势大鼠海马神经元形态及BDNF表达的影响%Ovarian transplantation on playing morphological changes and BDNF expression in hippocampal neurons of castrated rat

    Institute of Scientific and Technical Information of China (English)

    孔斌; 刘芳; 张文华; 黑常春; 张焱; 王燕蓉; 赵承军

    2012-01-01

    Objective: To observe the impact of ovarian transplantation on playing morphological changes and BDNF expression in rat hippocampal neurons, evaluation of ovarian transplantation on the protective effect in hippocampal neurons. Methods; The model groups were established by female SD rats were used for ovariectomy ( OVX) . One intervention group was transplanted the ovaries of SD rat within 3 days under the kidney capsule. Another group was injected diethyl-stilbestro( 1 ing/kg) intraperiteneally every other day. To observe hippocampal neuronal morphology by the electron microscopy and expression of BDNF by lmmunohistochemical method after the ovarian transplantation of the 4, 7, 14 and 28 days. Results: With the migration time, the serum estrogen and progesterone levels have gradually increased in ovarian transplantation group, while only estrogen have increased in diethylstilbestrol group. Morphology of hippocampal neurons in each group gradually improved, the ovarian transplantation group was significantly increased compared with diethylstilbestrol group, especially in 14 d and 28 d. Expression of BDNF in each group have all increased at every regions in the hippocampus, and the changes of transplantation group is remarkable in CA3 area in 14 d and 28 d ( P < 0.05). Conclusion: Ovarian transplantation can restore ovarian endocrine (unction, improve the morphology of hippocampal neurons andpromote the expression of BDNF. The neuroprotective role in the transplantation group was better than diethylstilbestrol group.%目的:观察卵巢移植后大鼠海马神经元形态变化及BDNF的表达,评价卵巢移植对海马神经元的保护效果.方法:制作去势SD大鼠模型,卵巢移植干预组在其肾被膜下移植出生3d内的SD乳鼠卵巢,外源性激素干预组隔天给予腹腔注射乙烯雌酚1mg/kg.分别于干预后的4、7、14和28d,电镜观察海马神经元形态及免疫组化观察BDNF的表达情况.结果:卵巢移植后随着移植时间的延长血清雌激素和孕酮水平都逐步升高,乙烯雌酚组仅雌激素水平升高;各组海马神经元形态逐渐好转,移植14d和28d组海马神经元的形态改善优于同期给药组.卵巢移植组和乙烯雌酚组BDNF的表达在各区均有所升高,卵巢移植14d和28d组CA3区尤为明显(P<0.05).结论:卵巢移植可以恢复卵巢内分泌功能,对海马神经元形态有改善作用及促进BDNF的表达,其神经元保护作用优于单纯乙烯雌酚干预组.

  8. 重读红色:浩然小说主人公眼里的阉割与乱伦%Red Reread: Castration and Incest for the People in Hao Ran's Stories

    Institute of Scientific and Technical Information of China (English)

    田晓菲

    2010-01-01

    @@ 文学作品总要放到上下文里来读.语境对于意义生产至关重要,也能让作品中未曾被发现的内容浮出水面.对社会主义中国"红色经典"的故事新编向我们揭示出原作情节与人物塑造本身潜在的意义或可能性.本篇论文以浩然(1932-2008)的两个短篇小说为例,说明将红色经典置于一个不同语境下进行重读也能产生同样效果.浩然也许是文化大革命时期最受欢迎的作家.他的长篇小说堪称"中国特色社会主义"真正的史诗,销量已经过百万;他的短篇小说在批评界受到的关注虽然不及长篇,却充分表现了阅读模式的变化如何影响文本的意义.然而,变化的阅读模式并不总是"事后"发生.

  9. 血管生成抑制剂在去势抵抗性前列腺癌治疗中的新发现%Antiangiogenic drugs for castration-resistant prostate cancer: Recent findings

    Institute of Scientific and Technical Information of China (English)

    黄道光

    2014-01-01

    近年来,去势抵抗性前列腺癌的治疗方法已由传统的抗雄激素及化疗提升到新的雄激素受体信号抑制剂、新一代紫杉醇及免疫疗法阶段.卡巴他赛、恩杂鲁胺、阿比特龙,放射性同位素镭223和sipuleucel-T随机临床试验显示能延长去势抵抗性前列腺癌患者生存期.然而,最终出现肿瘤抵抗也是难免的,去势抵抗性前列腺癌仍是一种主要临床负担,迫切需求新的治疗方法进一步改善CRPC患者生存期及生活质量.新生血管在前列腺癌的形成和进程中发挥至关重要的作用.部分临床试验显示,对失去手术和内分泌治疗时机的去势抵抗性前列腺癌,抗新生血管形成的靶向治疗是一种有效的补充疗法.本文将综述血管生成抑制剂在去势抵抗性前列腺癌治疗中的新发现.

  10. 去势抵抗性前列腺癌的发生发展机制及药物治疗新进展%Castration-resistant prostate cancer: current understanding of mechanisms and emerging novel agents

    Institute of Scientific and Technical Information of China (English)

    韩博; 戚美; 谭薇薇; 杨木易

    2015-01-01

    去势抵抗性前列腺癌(CRPC)患者预后极差.CRPC的发生和进展机制极为复杂,迄今尚未被完全阐明,因此治疗策略的选择仍是临床上极具挑战性的问题.近年来,治疗CRPC的新药不断涌现,包括雄激素合成抑制药物(阿比特龙)、雄激素受体(AR)抑制药物(恩杂鲁胺)、免疫治疗剂(sipuleucel-T)、放射剂(镭-223)和化疗药物(卡巴他赛)等.因而,针对CRPC的治疗有了更多选择,系统治疗亦发生了很大变化.简要综述近年来人们对CRPC发生发展机制的最新理解和最有前途的药物在CRPC治疗中获得的新进展.

  11. Clinical study of anti-androgen withdrawal syndrome in patients with castration resistant prostate cancer%去势抵抗前列腺癌患者抗雄激素撤除综合征的临床研究

    Institute of Scientific and Technical Information of China (English)

    刘光涛; 李菲菲; 曹建佳; 黄贵闽; 王开翔

    2016-01-01

    目的:研究抗雄激素撤退治疗对去势抵抗性前列腺癌患者的疗效和临床应用价值.方法:选择经手术去势+抗雄激素治疗并进展为去势抵抗性前列腺癌的患者28例,予停用比卡鲁胺,密切随访,每两周复查PSA,观察患者有效PSA下降开始时间和持续时间.结果:28例患者中有9例患者对抗雄激素撤退治疗有效,有效率为32.14%.有效开始时间多为4-6周,最长8周.有效持续时间范围12-46周,中位有效时间18周,平均有效时间21.77周.结论:对于新发现的去势抵抗性前列腺癌患者,在行进一步化疗等综合治疗前,抗雄激素撤除是一种可行的尝试.也是最为简单、经济的一种治疗选择.可作为二线内分泌治疗的一种重要治疗方式.

  12. Criminología Mediática, castración química a violadores y política criminal: ¿Eficientismo antigarantista?/Mediatic criminology, chemical castration to rappers and criminal policy

    Directory of Open Access Journals (Sweden)

    Italy Ciani Sotomayor

    2013-01-01

    Full Text Available La inseguridad que vivimos hoy en día y el hecho de que la mayoría de los delitos cometidos queden impunes ante la ineficacia de la gran mayoría de instituciones dedicadas a la procuración e impartición de justicia, han maximizado el fenómeno criminal. Los políticos, como una manera de reaccionar ante ello, es frecuente que pugnen por la creación de más delitos y penas más severas, creyendo que con esto mandan un mensaje positivo a la sociedad: tanto a víctimas como a criminales. Analizaremos el caso específico de la castración química como solución para frenar el delito de violación. Lo cierto es que estas propuestas casi siempre resultan contraproducentes, no nos hacen sentir más seguros y mucho menos inhiben la comisión de delitos, pues no es la forma de prevenirlos. El problema de fondo, como veremos, se encuentra en la ineficiencia del sistema de justicia penal mexicano, en la equivocada política criminal que hemos adoptado y en la ausencia de una política criminológica.

  13. Study on the Form and Constitution of Follicle Stimulating Hormone Cell of Adenohypophysis in Castrated Rat%去势大鼠腺垂体促卵泡素细胞形态结构研究

    Institute of Scientific and Technical Information of China (English)

    于祖茹; 章明放; 李玉玮; 李宝森; 赵风云; 王有志; 张富霞; 王素华

    2004-01-01

    目的:通过对去势大鼠腺垂体促卵泡素(FSH)细胞形态结构研究,探讨其变化的可能机制.方法:选发情周期规律WistarⅡ级雌性大鼠,随机分为实验组和对照组.对照组常规喂养,实验组切除双侧卵巢(OVX)常规喂养.4周和8周后处死动物取垂体进行垂体促卵泡素细胞形态结构观察.结果:实验组切除卵巢后4周,大鼠腺垂体促卵泡素(FSH)细胞平均密度及平均直径较对照组增加(P<0.01),胞浆内液泡增多,去势后8周这种变化更加明显或呈液泡状改变.结论:FSH细胞内液泡及其内含物与去势有关,可能为FSH细胞功能衰竭状态的特征性改变.

  14. 马鬃蛇对去势大鼠垂体雄激素受体水平的影响%Effects of Calotes versicolor on adenohypophysis androgen receptor level in mature castrated male rats

    Institute of Scientific and Technical Information of China (English)

    谢金鲜; 刘雪梅; 李萍; 李上球

    2007-01-01

    目的:研究马鬃蛇石油醚提取物(CVPE)对去势大鼠垂体雄激素受体水平的影响.方法:大鼠麻醉,无菌下摘除双侧睾丸及附睾.术后第14天随机分为4组.1组为模型组,灌胃(ig)生理盐水,2组为CVPE低剂量组2 g·kg-1,3组为高剂量组4 g·kg-1,4组为阳性药、组皮下注射(ih)丙酸睾丸素20 mg·kg-1.连续每天1次灌胃CVPE,21 d后采用免疫组化法测定垂体雄激素受体(AR)水平,用放射免疫法测定血清睾酮水平.结果:给药组(高、低剂量组)和阳性药组的雄激素受体阳性细胞数均明显多于模型组,并显著升高血清睾酮水平,与模型组比较有显著性差异(P低<0.05,P高<0.01).结论:CVPE可提高成年去势大鼠的垂体雄激素受体及血清睾酮水平,提示其可能通过垂体发挥作用.

  15. CARACTERÍSTICAS DE CARCAÇA E DA CARNE DE BOVINOS MESTIÇOS NÃO-CASTRADOS OU SUBMETIDOS A DIFERENTES MÉTODOS DE CASTRAÇÃO

    Directory of Open Access Journals (Sweden)

    Fabiano Nunes Vaz

    2014-12-01

    Full Text Available The objective of this study was to assess the effects of different castration methods applied to dairy crossbred males on carcass and meat traits, compared with noncastrated animals. Eighty-four males, with average age of ten months, were randomized into four groups of 21 animals: castrated using burdizzo tool, castrated by lateral incision in scrotum, castrated by cap removing (scrotum apex or kept intact (non-castrated. The slaughter of animals occurred in commercial slaughterhouse, at 30 months of age. Non-castrated animals showed higher cold carcass weight (208.0±6.2 kg than the males castrated by different methods (mean 192.0±6.4 kg. There was no difference in subcutaneous fat thickness among the groups, but when the measure was adjusted for carcass weight, there was a higher fat cover in animals castrated with burdizzo (.79± .08 mm/100 kg or lateral incision (.86± .09 mm/100 kg than non-castrated (.61± .05 mm/100 kg. Longissimus dorsi area was higher in noncastrated males (60.47±1.94 cm2 than males castrated with burdizzo tool (50.41±3.18 cm2 . There was not statistical difference for muscle/bone and muscle+fat/bone ratios among the groups, but the muscle/fat ratio was higher in non-castrated animals compared to castrated by cap removing and these were greater than castrated by lateral incision. There was no difference of meat sensorial characteristics, but the marbling score was higher in castrated with burdizzo tool (2.33± .20 points or castrated by cap removing (2.39± .20 points than the non castrated (1.77 ± 0.12 points. Castration method in crossbred dairy cattle males slaughtered with low weight does not promote changes in carcass and meat quality, but noncastrated animals have higher slaughter and cold carcass weights, and higher muscle percentage and muscle / fat ratio than castrated males.

  16. Perfil hematológico de ratas castradas e intactas induzidas experimentalmente ao hipertireoidismo

    Directory of Open Access Journals (Sweden)

    Carneiro R.A.

    2000-01-01

    Full Text Available The changes of red and white blood cells counts in intact and castrated rats with hyperthyroidism were analysed. A total of 108 five-month-old female Wistar rats, divided into four groups, were used as following: euthyroid castrated, euthyroid intact, hyperthyroid castrated and hyperthyroid intact. Nine animals of each group were killed at 30, 60 and 90 days to evaluate the red and white blood cells counts. The conclusion was that castration or hyperthyroidism did not affect both the red and white blood cells.

  17. Comparison of prostate gene expression and tissue weight changes as monitors of antiandrogen activity in GNRH-inhibited rats

    DEFF Research Database (Denmark)

    Nellemann, Christine Lydia; Lefevre, P. A.; Ashby, J.

    2003-01-01

    BACKGROUND: The Hershberger assay for antiandrogens and modifiers of steroid biosynthesis uses surgically-castrated rats. We described an adaptation of the assay using the GnRH inhibitor Antarelix in place of surgical castration [Ashby J, Lefevre PA, Deghenghi R, Wallis N. Regulatory Toxicology...

  18. Comparability of prostate trials

    DEFF Research Database (Denmark)

    Suciu, S; Sylvester, R; Iversen, P

    1993-01-01

    The present overview of advanced prostate cancer required the identification of randomized clinical trials studying the question of maximal androgen blockade versus the classic castration therapy. The heterogeneity of the trials concerned the type of castration (surgical or chemical) and the type...

  19. Histochemical studies on genetical control of hormonal enzyme inducibility in the mouse. IV: Cellular localization of androgen sensitive nonspecific esterase in the epididymis

    DEFF Research Database (Denmark)

    Kirkeby, S; Blecher, S R

    1981-01-01

    cell type, is shown to be androgen dependent. When mice of different strains were castrated or treated with antiandrogens, the characteristic histochemical reaction product disappeared or was greatly reduced. Androgen treatment of castrated animals caused the reaction in the cells concerned to return...

  20. Voluntary Genital Ablations: Contrasting the Cutters and Their Clients

    Directory of Open Access Journals (Sweden)

    Robyn A. Jackowich, BA

    2014-08-01

    Conclusions: This study may help identify individuals who are at risk of performing illegal castrations. That information may help healthcare providers protect individuals with extreme castration ideations from injuring themselves or others. Jackowich RA, Vale R, Vale K, Wassersug RJ, and Johnson TW. Voluntary genital ablations: Contrasting the cutters and their clients. Sex Med 2014;2:121–132.

  1. Experiment list: SRX286381 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available 7,533 GSM1146460: AR Cast1b [prostate, castrated+vehicle]; Mus musculus; ChIP-Seq source_name=AR_Cast1b || s...train=wild type ICR || tissue=prostate || age=8-12 weeks old || treatment=castrated+vehicle || chip antibody

  2. Experiment list: SRX286407 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available 19696667,94.8,45.4,7089 GSM1146486: AP2a Cast1a [caput epididymis, castrated+vehicle]; Mus musculus; ChIP-Se...q source_name=AP2a_Cast1a || strain=wild type ICR || tissue=caput epididymis || age=8-12 weeks old || treatment=castrated+vehicle

  3. Experiment list: SRX286391 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available 7,47.9,41.3,666 GSM1146470: rIgG1a [prostate, castrated+vehicle]; Mus musculus; ChIP-Seq source_name=rIgG1a ...|| strain=wild type ICR || tissue=prostate || age=8-12 weeks old || treatment=castrated+vehicle || chip anti

  4. Experiment list: SRX286408 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available 15944359,94.3,40.0,7036 GSM1146487: AP2a Cast1b [caput epididymis, castrated+vehicle]; Mus musculus; ChIP-Se...q source_name=AP2a_Cast1b || strain=wild type ICR || tissue=caput epididymis || age=8-12 weeks old || treatment=castrated+vehicle

  5. Experiment list: SRX286397 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available 6476: Hnf4a Cast1a [kidney, castrated+vehicle]; Mus musculus; ChIP-Seq source_name=Hnf4a_Cast1a || strain=wi...ld type ICR || tissue=kidney || age=8-12 weeks old || treatment=castrated+vehicle

  6. Experiment list: SRX286380 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available 2,497 GSM1146459: AR Cast1a [prostate, castrated+vehicle]; Mus musculus; ChIP-Seq source_name=AR_Cast1a || s...train=wild type ICR || tissue=prostate || age=8-12 weeks old || treatment=castrated+vehicle || chip antibody

  7. Experiment list: SRX286404 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available 2374,91.5,46.7,866 GSM1146483: AR Cast1 [caput epididymis, castrated+vehicle]; Mus musculus; ChIP-Seq source..._name=AR_Cast1 || strain=wild type ICR || tissue=caput epididymis || age=8-12 weeks old || treatment=castrated+vehicle

  8. Experiment list: SRX286394 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available 3: AR Cast1 [kidney, castrated+vehicle]; Mus musculus; ChIP-Seq source_name=AR_Cast1 || strain=wild type ICR... || tissue=kidney || age=8-12 weeks old || treatment=castrated+vehicle || chip an

  9. Experiment list: SRX286398 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available 6477: Hnf4a Cast1b [kidney, castrated+vehicle]; Mus musculus; ChIP-Seq source_name=Hnf4a_Cast1b || strain=wi...ld type ICR || tissue=kidney || age=8-12 weeks old || treatment=castrated+vehicle

  10. Effect of androgen deprivation on the expression of aquaporins in rat prostate and seminal vesicles.

    Science.gov (United States)

    Tian, J C; Xia, J Y; Jiang, J; Jiang, R; He, Y Z; Lin, H

    2016-04-01

    The aim of this study was to investigate the level of secretions of prostate and seminal vesicles and its association with the expression of AQP0, 1, 4, 5, 6 and 8 in castrated rats. Eight-week-old male Sprague-Dawley (SD) rats (n = 18) were randomly divided into control group, castrated rats group and castrated followed testosterone replacement group. Four weeks after surgery, the secretions and expression of AQP0, 1, 4, 5, 6 and 8 of prostate and seminal vesicles were determined. Serum testosterone was significantly lower in castrated groups than in control and testosterone replacement groups (P seminal vesicle secretions and the expressions of AQP0, 1, 4, 5, 6 and 8 in prostate and seminal vesicles were significantly lower in castrated group than in control and castrated followed testosterone replacement groups (P seminal vesicle secretions in castrated rats may be related to the decrease in AQP0, 1, 4, 5, 6 and 8 in prostatic tissue and seminal vesicles.

  11. Urethral glands of the male mouse contain secretory component and immunoglobulin A plasma cells and are targets of testosterone.

    Science.gov (United States)

    Parr, M B; Ren, H P; Russell, L D; Prins, G S; Parr, E L

    1992-12-01

    The occurrence and possible functions of mucosal immunity in the male urogenital tract have not been extensively investigated. In this study we used immunolabeling to localize secretory component (SC) and immunoglobulin (Ig) A in the urogenital tract of the male mouse. SC was located in the ventral prostate, while SC and IgA plasma cells were both detected in the urethral glands in the pelvic and bulbous portions of the urethra. SC and IgA were not observed elsewhere in the urogenital tract. We also examined the ventral prostate and urethral glands of sham-castrated, oil-treated castrated, and testosterone-treated castrated mice. There was a striking reduction in the size of the ventral prostate and urethral glands in oil-treated castrates compared to the other two groups, based on gross and histological morphology. Morphometric analysis showed that the cell and nuclear sizes of the urethral gland acinar cells were reduced after castration and restored to normal size by testosterone treatment. Androgen receptors (AR) were localized in the nuclei of urethral gland cells by immunocytochemistry using anti-AR antibodies. Labeling of SC and IgA plasma cells was similar in the urethral glands and ventral prostates of sham- and testosterone-treated castrates, but was reduced or absent at these sites in oil-treated castrates. These studies show that the ventral prostate and urethral glands may be sites for secretory immunity in the male murine urogenital tract, and that the urethral glands are targets for testosterone.

  12. Comparability of prostate trials

    DEFF Research Database (Denmark)

    Suciu, S; Sylvester, R; Iversen, P;

    1993-01-01

    The present overview of advanced prostate cancer required the identification of randomized clinical trials studying the question of maximal androgen blockade versus the classic castration therapy. The heterogeneity of the trials concerned the type of castration (surgical or chemical) and the type...... of antiandrogen (flutamide, Anandron, or cyproterone acetate) added to castration. This paper reviews the different types of heterogeneity that might exist among trials that are involved in the overview: study design, randomization procedure, treatment evaluation, statistical evaluation, and data maturity...... with a larger number of patients and a longer follow-up will contribute more to the overview's results....

  13. Is there a role for antiandrogen monotherapy in patients with metastatic prostate cancer?

    DEFF Research Database (Denmark)

    Kaisary, A V; Iversen, P; Tyrrell, C J;

    2001-01-01

    with a prostate specific antigen (PSA) level 400 ng/ml) may decide that quality of life and symptomatic benefits outweigh the slight survival disadvantage seen in clinical trials and opt for bicalutamide monotherapy as an alternative to castration.Prostate Cancer and Prostatic Diseases (2001) 4, 196-203.......Castration is the most widely used form of androgen ablation employed in the treatment of metastatic (M1) prostate cancer. Non-steroidal antiandrogen monotherapy is a potential alternative treatment option for men for whom castration is unacceptable or not indicated. Of the three non...

  14. Antiandrogen monotherapy: indications and results

    DEFF Research Database (Denmark)

    Iversen, Peter

    2002-01-01

    Many patients with prostate cancer for whom hormonal therapy is indicated are still physically and sexually active; quality of life is therefore a vital issue when considering treatment options. Traditional castration-based therapies, although effective, have implications with respect to quality...... with castration, in terms of sexual interest and physical capacity, in patients with either M0 and M1 stage disease. Data from a small subgroup of patients with stage M0 disease suggest that bicalutamide may also reduce the risk of osteoporosis compared with castration. Long-term therapy with bicalutamide 150-mg...

  15. 晚期前列腺癌药物去势中Gleason评分、血清PSA与疗效相关性研究%A relative analysis on the efficacy of medical castration in the treatment of metastatic prostate cancer patients to Gleason score and serum PSA level

    Institute of Scientific and Technical Information of China (English)

    黄苏溪; 王玉杰; 宋光鲁; 罗勇

    2007-01-01

    目的:探讨晚期前列腺癌(Pca)患者药物去势治疗过程中疗效与Gleason评分及血清前列腺特异性抗原(PSA)的相关性.方法:选择33例晚期Pca患者,给予黄体激素释放激素类似物(LHRH-A)+抗雄激素药物进行药物去势治疗,根据Gleason评分分为2~5分组、6~7分组、8~10分组,对3组血清PSA变化进行分析.结果: Gleason评分6~7分组的病人在治疗后3个月内血清PSA值下降最快,治疗后6个月时Gleason评分2~5分组病人血清PSA值恢复正常,而Gleason评分6~7分组与8~10分组病人血清PSA值则接近正常值范围 .不同Gleason评分组间血清PSA水平差异有统计学意义(F=5.396, P<0.05).结论:(1)Gleason评分、血清PSA水平与晚期Pca患者行药物去势疗法疗效有密切关系.(2)血清PSA变化是监测Pca复发与评价疗效的可靠瘤标.

  16. A prospective randomized trial: a comparison of the analgesic effect and toxicity of 153Sm radioisotope treatment in monotherapy and combined therapy including local external beam radiotherapy (EBRT) among metastatic castrate resistance prostate cancer (mCRPC) patients with painful bone metastases.

    Science.gov (United States)

    Baczyk, M; Milecki, P; Pisarek, M; Gut, P; Antczak, A; Hrab, M

    2013-01-01

    Bone metastases in prostate cancer constitute the most frequent cause of systemic failure in treatment, which results in numerous complications and finally leads to patient's death. Pain is one of the first and most important clinical symptoms of bone metastases and can be found among more than 80% of patients. Therefore, the most analgetic effective and simultaneously the least toxic treatment is an important point of therapeutic management in this group of patients. The aim of this prospective clinical trial was a comparison of analgetic effectiveness and toxicity of monotherapy with 153Sm isotope to combined therapy (153Sm + EBRT) among patients diagnosed with multiple painful bone metastases due to CRPC (mCRPC). 177 patients with mCRPC were included into the prospective randomised clinical trial in which 89 patients were assigned to the 153Sm isotope monotherapy, while 88 patients were assigned to the combined therapy including 153Sm isotope therapy and EBRT. All patients were diagnosed (bone scan and X-ray or/and CT or/and MRI) with painful bone metastases (bone pain intensity >= 6 according to VAS classification). The following additional inclusion criteria were established: histologically confirmed adenocarcinoma of prostate, multifocal bone metastases, no prior chemotherapy or palliative radiotherapy to bone. All patients signed informed consent.The combination of the isotope therapy with EBRT was more effective analgetic treatment than isotope therapy alone. The highest pain decline was noticed in the first weeks after treatment termination. In the whole group, a total or partial analgesic effect was observed among 154 (87%) patients while among 23 (13%) patients there was a lack of analgesic effect or even pain intensification. The results of this clinical trial demonstrated that for patients with multiple mCRPC it is recommended to combine the 153Sm isotope therapy with local EBRT because of a greater analgetic effect. It is important to note that combined therapy did not intensify the toxicity of treatment.

  17. Efeito da tibolona na morfologia do músculo esquelético, nas enzimas hepáticas e no nível sérico de glicose em ratas castradas Effect of tibolone on the morphology of skeletal muscle, liver enzymes and blood glucose level in castrated female rats

    Directory of Open Access Journals (Sweden)

    Porphirio José Soares Filho

    2012-06-01

    Full Text Available INTRODUÇÃO: O fígado é uma estrutura de elevada complexidade e é fundamental entender como determinadas substâncias podem afetar sua estrutura e suas funções. OBJETIVO: Analisar a influência da tibolona no metabolismo hepático por meio da avaliação de enzimas e metabólitos comumente utilizados em provas de função hepática. MÉTODOS: Foram utilizadas dez ratas Wistar, divididas em dois grupos: controle (n = 4 e tibolona (n = 6, em status de menopausa cirúrgica. A tibolona (1 mg foi administrada diariamente por gavagem durante 20 semanas, com avaliação periódica do peso corporal. Após sedação, efetuou-se coleta de sangue para avaliação bioquímica de albumina (Alb sérica, fosfatase alcalina (FA, transaminases (aspartato aminotransferase e alanina aminotransferase [AST/ALT], gama-glutamiltranspeptidase (GGT e glicose, mediante espectrofotometria. O músculo esquelético da coxa foi avaliado por histomorfometria em cortes histológicos corados com hematoxilina e eosina (HE. RESULTADOS: Os animais do grupo tibolona mostraram menor peso corporal, alterações musculares esqueléticas e discretas alterações bioquímicas. Além disso, AST e FA estavam diminuídas e GGT estava mais elevada, porém sem significância estatística. A histomorfometria do músculo revelou uma tendência de menor volume celular nesse grupo. CONCLUSÃO: A tibolona, administrada em alta dose e por tempo prolongado, não interfere de forma significativa nas funções metabólicas e de síntese hepáticas, bem como na permeabilidade da membrana celular, entretanto parece modular a expressão genômica da GGT. A tibolona apresenta influência sistêmica associada a menor peso e diminuição da massa muscular e aumento significativo no peso relativo do fígado, além de alteração da glicogenólise hepática e muscular, da gliconeogênese hepática e dos níveis de glicose circulante.INTRODUCTION: The liver is a highly complex structure and it is essential to understand how certain substances may affect its structure and functions. OBJECTIVE: Analyze the influence of tibolone on hepatic metabolism by assessing metabolites and enzymes commonly used in liver function tests. METHODS: Ten Wistar rats in surgical menopausal status were divided into two groups: control (n = 4 and tibolone (n = 6. Tibolone (1 mg was administered by gavage daily for 20 weeks and body weight was periodically assessed. After sedation, blood sampling was performed for biochemical evaluation of serum albumin (Alb, alkaline phosphatase (ALP, transaminases (aspartat aminotranferase and alanine aminotranferase [AST/ALT], gamma glutamyltranspeptidase (GGT and glucose by spectrophotometry. Hematoxylin and eosin-stained histological sections of the skeletal thigh muscle were assessed by histomorphometry. RESULTS: The animals in the tibolone group showed lower body weight, skeletal muscle alterations and slight biochemical changes. In the tibolone group, AST and ALP were decreased GGT was higher, but without a statistically significant difference. The muscle histomorphometry showed that the tibolone group tended to present a lower cell volume. CONCLUSION: Tibolone administered in high doses and for a prolonged period does not interfere significantly neither with liver metabolic functions nor liver synthesis, nor with cell membrane permeability. However, it seems to modulate the genomic expression of GGT. Tibolone has systemic influence on lower body weight, reduced muscle mass, and significant increase in relative liver weight. Additionally, liver and muscular glycogenolysis, liver gluconeogenesis and circulating glucose levels are altered.

  18. Expressions of S1P1-3 in the corpus cavernosum of castrated male rats%1-磷酸鞘氨醇受体1-3(S1P1-3)在去势雄性大鼠阴茎海绵体组织中的表达

    Institute of Scientific and Technical Information of China (English)

    陈学勤; 夏纪毅; 程波; 姜睿

    2016-01-01

    目的:探讨1-磷酸鞘氨醇受体1-3 (S1P1-3)在去势雄性大鼠阴茎海绵体内的表达,及其与NOS/NO/cGMP、RhoA/Rho激酶等信号通路的关系. 方法:18只8周龄健康雄性SD大鼠,随机分为去势组、对照组及去势后睾酮替代组(替代组)各6只,去势组和替代组大鼠切除双侧睾丸、附睾,替代组大鼠去势术后给予生理剂量丙酸睾酮3 mg/(kg·d)皮下注射4周,对照组为假手术组,去势组及对照组大鼠术后给予等量植物油皮下注射4周,12周龄时,测定各组大鼠阴茎海绵体内压/平均动脉压(ICPmax/MAP)、采用免疫组化和Western印迹分析S1P1-3、eNOS、P-eNOS、ROCK1、ROCK2在阴茎海绵体内的表达变化. 结果:去势组大鼠血清睾酮水平[(0.41±0.04)nmol/L]显著低于对照组[(16.01±1.02) nmol/L]及替代组[(15.84±1.32) nmol/L](P<0.01),而替代组与对照组睾酮水平无显著差异.去势组ICPmax/MAP比值在0V、3V和5V电刺激盆神经节时(0.088±0.014、0.323±0.014、0.432 ±0.012)均显著低于对照组(0.155±0.011、0.711±0.010、0.819±0.024)及替代组(0.153±0.012、0.696±0.017、0.763±0.027) (P <0.01),而对照组与替代组无显著差异.去势组S1P1、eNOS、P-eNOS的蛋白表达量[以目的蛋白占内参GAPDH的百分率表示:S1P1 (49.99±3.39)%,eNOS (46.82±3.81)%,P-eNOS (45.42±4.35)%]显著低于对照组[S1P1 (72.57±3.06)%,eNOS(89.76±3.98)%,P-eNOS(82.53±8.92)%]和替代组[S1P1 (71.77±4.43)%,eNOS (87.19±4.23)%,P-eNOS (79.82±7.38)%] (P <0.01),去势组S1P2、S1P3、ROCK1、ROCK2蛋白表达量[以目的蛋白占内参GAPDH的百分率表示:S1P2 (82.35±4.13)%,S1P3 (61.03±5.14)%,ROCK1 (74.50±4.02)%,ROCK2 (69.83±5.75)%]显著高于对照组[S1P2 (41.67±1.68)%,S1P3(31.66±2.67)%,ROCK1 (35.69±5.56)%),ROCK2 (39.85±7.17)%]和替代组[S1P2 (42.80 ±3.87)%,S1P3(32.25±4.22)%,ROCK1 (38.06±5.21)%,ROCK2 (42.36±4.44)%](P<0.01). 结论:雄激素缺乏导致大鼠ICPmax/MAP显著降低,可能与阴茎海绵体内S1P1表达下调、抑制eNOS/NO/cGMP信号通路,S1P2、S1P3表达升高、激活RhoA/Rho激酶信号通路有关.

  19. 雄激素调控RhoA/Rho激酶改善去势大鼠勃起功能障碍的机制研究%Androgen Improves Erectile Dysfunction by Regulating RhoA/Rho-kinase in Castrated Rats

    Institute of Scientific and Technical Information of China (English)

    2016-01-01

    目的 探究雄激素调控RhoA/Rho激酶改善去势大鼠勃起功能障碍的机制.方法 40只健康8周龄SD雄性大鼠随机分成4组:A组为对照组;B组为实验组,给予手术切除双侧睾丸;C、D组为干预组,大鼠手术去势后每天给予不同浓度的十一酸睾酮(安特尔)灌胃(C组:20mg/kg,D组:10mg/kg),其余组给予等量的生理盐水.治疗8周后,检测大鼠血清睾酮浓度,海绵体测压评价大鼠勃起功能,Western blot检测大鼠阴茎海绵体S1 P2/RhoA/Rho激酶的含量.结果 相较于A组[(17.08±1.53) nmol/L]、C组[(15.47±1.62) nmol/L]和D组[(8.73±2.12) nmol/L]大鼠的血清睾酮浓度,B组[(1.34±0.62)nmol/L]明显降低(均P<0.05);海绵体测压结果显示B组MaxICP/MAP明显小于A组、C组和D组(均P<0.05);Western blot检测S1P2、RhoA、ROCK1和ROCK2的蛋白在B组表达明显高于A组、C组和D组(均P<0.05).结论 应用安特尔进行雄激素替代治疗可以通过抑制S1P2/RhoA/Rho激酶的激活,从而抑制阴茎海绵体平滑肌收缩,改善去势大鼠勃起功能.

  20. Rationale for stereotactic body radiation therapy in treating patients with oligometastatic hormone-naïve prostate cancer

    Directory of Open Access Journals (Sweden)

    Onita eBhattasali

    2013-12-01

    Full Text Available Despite advances in treatment for metastatic prostate cancer, patients eventually progress to castrate-resistant disease and ultimately succumb to their cancer. Androgen deprivation therapy (ADT is the standard treatment for metastatic prostate cancer and has been shown to improve median time to progression and median survival time. Research suggests that castrate-resistant clones may be present early in the disease process prior to the initiation of ADT. These clones are not susceptible to ADT and may even flourish when androgen-responsive clones are depleted. Stereotactic body radiation therapy (SBRT is a safe and efficacious method of treating clinically localized prostate cancer and metastases. In patients with a limited number of metastatic sites, SBRT may have a role in eliminating castrate-resistant clones and possibly delaying progression to castrate-resistant disease.