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

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Pang, Wanyong; Earley, Bernadette; Sweeney, Torres; Gath, Vivian; Crowe, Mark A

2009-09-23

Castration of male cattle has been shown to elicit inflammatory reactions and acute inflammation is initiated and sustained by the participation of cytokines. Sixty continental x 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. 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-gamma, IL-6, IL-8 and TNF-alpha at 12 h and 24 h post treatment. Burd castrates had greater (P castrates had greater (P castrates at 12 h post-castration. Burd castrates had greater (P castration. In the epididymis, Burd castrates had greater (P castrates had greater (P = 0.049) IL-10 mRNA levels than Band castrates at 12 h post-castration. 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.

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

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

2016-01-01

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

Epidemiology of surgical castration of dogs and cats in the United States.

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Trevejo, Rosalie; Yang, Mingyin; Lund, Elizabeth M

2011-04-01

To estimate the prevalence of surgical castration among dogs and cats evaluated at private US veterinary hospitals and to determine the influence of sex, age, breed, geographic location, and prepaid wellness plan enrollment on the likelihood of castration. Retrospective period prevalence study. 320,172 cats and 1,339,860 dogs examined at 651 hospitals during 2007 Procedures-Univariate and multivariate analyses were used to compare prevalence among subpopulations for each species. The overall prevalence of castration was 82% in cats and 64% in dogs. Prevalence increased significantly with age in both species. Among cats, males were slightly more likely to be castrated than females (prevalence ratio [PR] = 1.03) and mixed breeds slightly less likely than purebreds (PR = 0.99). Among dogs, males were less likely to be castrated than females (PR = 0.93) and mixed breeds more likely than purebreds (PR = 1.19). Prevalence was lowest in dogs in the Southeastern United States (61%). Dogs and cats on a wellness plan were more likely to be castrated than those not on a plan (PR = 1.33 and 1.18, respectively). Among commonly reported dog breeds, pit bull-type dogs (27%) and Chihuahuas (46%) were least likely to be castrated. Many young adult (1- to Chihuahua), and dogs in the Southeastern United States. Additional research is needed to evaluate the potential impact of wellness programs on an owner's decision to have his or her pet castrated.

Gender Preference in the Sexual Attractions, Fantasies, and Relationships of Voluntarily Castrated Men.

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Handy, Ariel B; Jackowich, Robyn A; Wibowo, Erik; Johnson, Thomas Wayne; Wassersug, Richard J

2016-03-01

Some men seek castration outside a clear medical need. This study explored how their sexuality changed after castration. To explore changes in preferred gender(s) of sexual attraction, fantasy, and relationships in voluntarily castrated men with or without gonadal hormone therapy. A questionnaire was posted at http://www.eunuch.org that yielded data on men who had been voluntarily castrated physically (n = 198) or chemically (n = 96). Respondents were asked to report retrospectively on their sexuality, including their sexual activity and which gender(s) they were sexually attracted to, fantasized about, or had sexual relations with 6 months to 1 year before and after castration. A substantial proportion of men remained sexually active after castration; 37% had sex at least several times per week. Most respondents did not report a change in preferred gender(s) of attraction (65%, n = 181), fantasies (62%, n = 169), or sexual relationships (66%, n = 163), although approximately 20% to 30% of respondents did report such changes and 8% to 11% became non-sexual after castration. Respondents who were attracted to and fantasized about "only men" or who had sexual relationship with "only women" before castration were the least likely to report a change subsequent to castration. Respondents who were taking neither supplemental testosterone nor estrogen were more likely to report (i) becoming attracted to no one, (ii) fantasizing about no one, and (iii) becoming sexually inactive. Sexual changes in voluntarily castrated men vary and can be influenced by various factors including the use of supplemental testosterone or estrogen therapy. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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

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Fassah, Dilla Mareistia; Jeong, Jin Young; Baik, Myunggi

2018-04-01

This study was performed to understand transcriptional changes in the genes involved in gluconeogenesis and glycolysis pathways following castration of bulls. Twenty Korean bulls were weaned at average 3 months of age, and castrated at 6 months. Liver tissues were collected from bulls (n = 10) and steers (n = 10) of Korean cattle, and hepatic gene expression levels were measured using quantitative real-time polymerase chain reaction. We examined hepatic transcription levels of genes encoding enzymes for irreversible reactions in both gluconeogenesis and glycolysis as well as genes encoding enzymes for the utilization of several glucogenic substrates. Correlations between hepatic gene expression and carcass characteristics were performed to understand their associations. Castration increased the mRNA (3.6 fold; pcastration. Castration increased mRNA levels of both lactate dehydrogenase A (1.5 fold; pCastration increased mRNA levels of glycerol kinase (2.7 fold; pCastration also increased mRNA levels of propionyl-CoA carboxylase beta (mitochondrial) (3.5 fold; pCastration increases transcription levels of critical genes coding for enzymes involved in irreversible gluconeogenesis reactions from pyruvate to glucose and enzymes responsible for incorporation of glucogenic substrates including lactate, glycerol, and propionate. Hepatic gluconeogenic gene expression levels were associated with intramuscular fat deposition.

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

Science.gov (United States)

2016-07-01

Prostate Cancer Research Symposium- Prostate Cancer Epigenetic Reprogramming of the Androgen Receptor in Castration Resistant Prostate Cancer , May19... cancer cells rely critically on the androgen receptor (AR) for initiation, growth and progression to castration resistant prostate cancer (CRPC...Androgen receptor, castration resistant prostate cancer , Enzalutamide , kinases. 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER

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

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F.G. Telles

2016-12-01

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

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

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Brand, T; Slob, A K

1988-09-15

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

Effects of Topical Anaesthetic and Buccal Meloxicam Treatments on Concurrent Castration and Dehorning of Beef Calves.

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Van der Saag, Dominique; White, Peter; Ingram, Lachlan; Manning, Jaime; Windsor, Peter; Thomson, Peter; Lomax, Sabrina

2018-02-28

The use of pain relief during castration and dehorning of calves on commercial beef operations can be limited by constraints associated with the delivery of analgesic agents. As topical anaesthetic (TA) and buccal meloxicam (MEL) are now available in Australia, offering practical analgesic treatments for concurrent castration and dehorning of beef calves, a study was conducted to determine their efficacy in providing pain relief when applied separately or in combination. Weaner calves were randomly allocated to; (1) no castration and dehorning/positive control (CONP); (2) castration and dehorning/negative control (CONN); (3) castration and dehorning with buccal meloxicam (BM); (4) castration and dehorning with topical anaesthetic (TA); and (5) castration and dehorning with buccal meloxicam and topical anaesthetic (BMTA). Weight gain, paddock utilisation, lying activity and individual behaviours following treatment were measured. CONP and BMTA calves had significantly greater weight gain than CONN calves ( p castrated calves spent more time walking ( p = 0.024) and less time eating ( p castration and amputation dehorning.

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

African Journals Online (AJOL)

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

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

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Sang-Woo Kim

2016-05-01

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

Transcriptome changes favoring intramuscular fat deposition in the longissimus muscle following castration of bulls.

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Jeong, J; Bong, J; Kim, G D; Joo, S T; Lee, H-J; Baik, M

2013-10-01

Castration increases intramuscular fat (IMF) deposition, improving beef quality in cattle. The present study was performed to determine the global transcriptome changes following castration of bulls and to identify genes associated with IMF deposition in the longissimus dorsi (LM) of Korean cattle. A customized bovine CombiMatrix oligonucleotide microarray was constructed, and transcriptome changes following castration were determined by microarray hybridization. Transcriptome comparison between bulls and steers indicated that 428 of 8,407 genes were differentially expressed in the LM by greater than two fold (P castration. Castration upregulated transcription of adipogenic perilipin 2 (PLIN2) and visfatin, lipogenic fatty acid synthase, fatty acid esterification 1-acylglycerol-3-phosphate O-acyltransferase 5, and many fatty acid oxidation-related genes. Many TCA cycle and OP genes were also transcriptionally upregulated. Correlation analysis indicated that the IMF content in the LM was highly correlated with mRNA levels of PLIN2 (r = 0.70, P castration shifts transcription of lipid metabolism genes, favoring IMF deposition by increasing adipogenesis, lipogenesis, and triglyceride synthesis. This study also indicated that castration increases transcription of genes involved in fatty acid oxidation and subsequent energy production (TCA and OP genes). Our microarray analysis provided novel information that castration alters the transcriptome associated with lipid/energy metabolism, favoring IMF deposition in the LM.

Castration of piglets under CO2-gas anaesthesia.

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

2008-11-01

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

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

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Dilla Mareistia Fassah

2018-04-01

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

Depression of nocturnal pineal serotonin N-acetyltransferase activity in castrate male rats

International Nuclear Information System (INIS)

Rudeen, P.K.; Reiter, R.J.; Texas Univ., San Antonio

1980-01-01

Pineal serotonin N-acetyltransferase (NAT) activity was examined in intact rats, castrated rats, and in rats that had been castrated and had received testosterone proprionate. Castration resulted in significantly depressing nocturnal levels of pineal NAT (p<0.05) when compared to enzyme activity in intact rats. Testosterone proprionate administration restored plasma LH levels to normal values in castrate rats but did not induce nocturnal pineal enzyme activity to levels seen in the pineal glands of intact rats. The data substantiate the existence of a feedback control of pineal biosynthetic activity by the hypophyseal-gonadal system, but the identity of the hormone(s) responsible for regulation of pineal NAT activity is not known. (author)

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.

Assessment and management of pain associated with castration in cattle.

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Coetzee, Johann F

2013-03-01

Validated pain assessment tools are needed to support approval of analgesic compounds to alleviate pain associated with castration. Accelerometers, videography, heart rate variability, electroencephalography, thermography, and plasma neuropeptide measurement to assess behavioral, physiologic, and neuroendocrine changes associated with castration are discussed. Preemptive local and systemic analgesia are also reviewed. Previous studies found that preemptive administration of nonsteroidal antiinflammatory drug (NSAID) and local anesthesia significantly decreased peak serum cortisol concentration after castration. Local anesthesia alone tended to decrease peak cortisol concentrations more than NSAIDs, whereas NSAIDs alone tended to decrease the area under the cortisol-time curve more than local anesthesia alone. Copyright © 2013 Elsevier Inc. All rights reserved.

An interesting experience of radiation castration in a patient of advanced breast carcinoma

International Nuclear Information System (INIS)

Matsubara, Sho; Suzuki, Hitoshi; Mine, Hiroko; Maeda, Manabu; Shibuya, Hitoshi

1980-01-01

Castration by irradiation was attempted in a patient with advanced breast cancer. Although a dose of irradiation sufficient for castration was given through the field usually used radiation castration, neither cessation of menstruation nor decrease in serum estradiol value could be observed. The subsequent hysteosalpingography revealed that the markedly malpositioned bilateral ovaries were not included within the beam of radiation. The field of irradiation to the malpositioned ovaries was determined based upon the hysterosalpingographic finding and a dose of 1,200 rad to the ovaries resulted in reduction of serum estradiol value in such a degree as surgical castration. (author)

The evolution of intermediate castration virulence and ant coexistence in a spatially structured environment.

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Szilágyi, András; Scheuring, István; Edwards, David P; Orivel, Jerome; Yu, Douglas W

2009-12-01

Theory suggests that spatial structuring should select for intermediate levels of virulence in parasites, but empirical tests are rare and have never been conducted with castration (sterilizing) parasites. To test this theory in a natural landscape, we construct a spatially explicit model of the symbiosis between the ant-plant Cordia nodosa and its two, protecting ant symbionts, Allomerus and Azteca. Allomerus is also a castration parasite, preventing fruiting to increase colony fecundity. Limiting the dispersal of Allomerus and host plant selects for intermediate castration virulence. Increasing the frequency of the mutualist, Azteca, selects for higher castration virulence in Allomerus, because seeds from Azteca-inhabited plants are a public good that Allomerus exploits. These results are consistent with field observations and, to our knowledge, provide the first empirical evidence supporting the hypothesis that spatial structure can reduce castration virulence and the first such evidence in a natural landscape for either mortality or castration virulence.

Banding or Burdizzo castration and carprofen administration on peripheral leukocyte inflammatory cytokine transcripts.

Science.gov (United States)

Pang, W Y; Earley, B; Murray, M; Sweeney, T; Gath, V; Crowe, M A

2011-02-01

The objective was to investigate if Banding or Burdizzo castration of bulls would alter the gene expression profile of a range of peripheral leukocyte inflammatory cytokines (IL-1, IL-6, IL-8, IL-10, interferon-γ and tumor necrosis factor-α) and to determine if the administration of carprofen (C) before castration would affect the expression of these genes. Thirty Holstein-Friesian bulls (5.5 months; Mean 191±(SEM) 3.7 kg) were blocked by weight and randomly assigned to one of five treatments: (1) untreated control (CON); (2) Banding castration at 0 min (BAND); (3) BAND following an i.v. injection of 1.4 mg/kg BW of carprofen (C) at -20 min (BAND+C); (4) Burdizzo castration at 0 min (BURD); or (5) BURD following 1.4 mg/kg BW of carprofen at -20 min (BURD+C). Blood samples were collected at 1 h before castration and 6, 24 and 48 h post-castration for routine hematology and quantitative real-time PCR analysis of cytokine gene expression analysis. Generally, there were no differences (P>0.05) among treatment groups in hematological variables following castration. Cortisol concentrations were unchanged throughout the experimental period in CON bulls. BURD animals had greater cortisol concentrations than BAND and CON animals at 6 h post treatment. Transitory effects were observed only in the expression of IL-6 and TNF-α. The relative expression of IL-6 was greater in the BURD than in the BAND treatment (Pcarprofen administration can affect IL-6 gene expression levels in BURD castrated animals. Copyright © 2010 Elsevier Ltd. All rights reserved.

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

Science.gov (United States)

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

2004-05-01

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

Effect of tasting and information on consumer opinion about pig castration

NARCIS (Netherlands)

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

2013-01-01

Our research explored the relative importance of pig castration amongst other aspects of animal welfare, and the potential impact of information and sensory experiences on European Union (EU) consumers' preferences. The EU is considering a future ban on surgical pig castration by 2018 which may

Effect of castration method and analgesia on inflammation, behavior, growth performance, and carcass traits in feedlot cattle.

Science.gov (United States)

Roberts, S L; Powell, J G; Hughes, H D; Richeson, J T

2018-02-15

Our objective was to determine the effect of castration timing, method, and use of the analgesic meloxicam (MEL) on inflammation, behavior, performance, and carcass traits in feedlot cattle. This study was a randomized complete block design conducted over a 3-yr period. In total, 194 crossbred beef calves from a single ranch origin were randomized at birth to receive one of five treatments arranged as a 2 × 2 + 1 factorial: 1) bulls castrated within 48 h of birth (CON), 2) bulls surgically castrated on day 0 without MEL (SUR), 3) bulls surgically castrated on day 0 with MEL (SUR + MEL), 4) bulls band castrated on d 0 without MEL (BAN), and 5) bulls band castrated on day 0 with MEL (BAN + MEL). Upon feedlot arrival (day -11; average 287 ± 2.03 d of age), animals were blocked by initial BW (224 ± 4.5 kg) and assigned randomly to treatment pens in three consecutive years (n = 2 pens per treatment in each year). Oral MEL was administered at 1 mg/kg BW concurrent with applicable castration treatment on day 0. Data were analyzed using the MIXED and GLIMMIX procedures of SAS with pen (year) serving as experimental unit. From days 0 to 7, ADG was reduced (P = 0.01) for surgical (-0.42) compared to band (0.43 kg/d) castration. Conversely, ADG was increased for surgical (1.74) vs. band (1.46 kg/d) castration from days 14 to 32. There was also an overall (day 0 to final) improvement in ADG for MEL (P = 0.02), but no effect of castration method was observed (P = 0.81). The CON group had the greatest (P = 0.05) marbling score. Backfat thickness was increased (P = 0.01) for MEL. A treatment × day interaction (P = 0.04) existed for serum haptoglobin, with SUR having the greatest (P castrated treatment reduced (P = 0.01) serum haptoglobin concentration on day 1. Relative to baseline, standing duration for surgical castration was increased 113 min (P castration on day 0. Step count was greatest for BAN, intermediate for CON, and least for surgical (P castration, whereas

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

Directory of Open Access Journals (Sweden)

Songhua Wang

2014-04-01

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

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.

Effect of timing of subcutaneous meloxicam administration on indicators of pain after knife castration of weaned calves.

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Meléndez, D M; Marti, S; Pajor, E A; Moya, D; Gellatly, D; Janzen, E D; Schwartzkopf-Genswein, K S

2017-12-01

The newly revised Canadian Codes of Practice for the management of beef cattle requires that as of 2018, calves older than 6 mo of age be castrated using pain control. Castration is a husbandry procedure commonly done without pain control, and there is a lack of agreement on an effective pain mitigation strategy specific to castration. The aim of this study was to identify the optimal time of administration of meloxicam prior to castration. Thirty-four Angus and Angus crossbred bull calves (282 ± 28.0 kg BW) were randomly assigned to 1 of 3 treatments receiving a single s.c. injection of meloxicam (0.5 mg/kg BW): 6 h (6H; = 11), 3 h (3H; = 12), or immediately (0H; = 11) before knife castration. Measurements included visual analog scale (VAS), head movement (HM), accelerometer movement (AM) and strain gauge exertion force (EF) on the squeeze chute, stride length (SL), lying and standing behavior, salivary cortisol (SC), haptoglobin, serum amyloid A (SAA), substance P (SP), and scrotal temperature (ST). Samples were collected on d -7, -5, -2, -1, and immediately before castration (T0) and 30, 60, 120, and 240 min and 1, 2, 5, 7, 14, 21, and 28 d after castration, except for VAS, AM, EF, and HM, which were obtained at the time of castration. A time × treatment effect ( = 0.01) was observed for SP, where 0H had lower concentrations than 3H and 6H calves 1 d after castration, whereas 3H calves tended to have greater levels than 6H calves 5 d after castration. Mean ST was greater ( castration, whereas 6H and 3H calves had greater ST compared to 0H calves 240 min after castration. On d 1 after castration, 6H calves had greater ST than 0H and 3H calves, whereas 0H calves had greater ST compared to 3H and 6H calves on d 28 after castration. The SL tended ( = 0.09) to be shorter in 3H and 6H calves than 0H calves 30, 60, 120, and 240 min after castration. Number of peaks from the AM between 2 and 3 SD above or below the mean were greater ( = 0.03) in 3H and 6H calves than

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

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

2012-04-01

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

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

African Journals Online (AJOL)

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

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

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2015-10-01

castration-resistance of each subset in humans. We also measured castration-resistance of isolated subsets in vitro in the presence or absence of DHT in...microns). In vitro growth in the absence of DHT also demonstrates castration-resistant properties of the intermediate/luminal progenitor cells...subsets without DHT compared to DHT -containing media, demonstrating castration-resistance). 4 4) other achievements: We found that tumors

Sox2 Is an Androgen Receptor-Repressed Gene That Promotes Castration-Resistant Prostate Cancer

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Kregel, Steven; Kiriluk, Kyle J.; Rosen, Alex M.; Cai, Yi; Reyes, Edwin E.; Otto, Kristen B.; Tom, Westin; Paner, Gladell P.; Szmulewitz, Russell Z.; Vander Griend, Donald J.

2013-01-01

Despite advances in detection and therapy, castration-resistant prostate cancer continues to be a major clinical problem. The aberrant activity of stem cell pathways, and their regulation by the Androgen Receptor (AR), has the potential to provide insight into novel mechanisms and pathways to prevent and treat advanced, castrate-resistant prostate cancers. To this end, we investigated the role of the embryonic stem cell regulator Sox2 [SRY (sex determining region Y)-box 2] in normal and malignant prostate epithelial cells. In the normal prostate, Sox2 is expressed in a portion of basal epithelial cells. Prostate tumors were either Sox2-positive or Sox2-negative, with the percentage of Sox2-positive tumors increasing with Gleason Score and metastases. In the castration-resistant prostate cancer cell line CWR-R1, endogenous expression of Sox2 was repressed by AR signaling, and AR chromatin-IP shows that AR binds the enhancer element within the Sox2 promoter. Likewise, in normal prostate epithelial cells and human embryonic stem cells, increased AR signaling also decreases Sox2 expression. Resistance to the anti-androgen MDV3100 results in a marked increase in Sox2 expression within three prostate cancer cell lines, and in the castration-sensitive LAPC-4 prostate cancer cell line ectopic expression of Sox2 was sufficient to promote castration-resistant tumor formation. Loss of Sox2 expression in the castration-resistant CWR-R1 prostate cancer cell line inhibited cell growth. Up-regulation of Sox2 was not associated with increased CD133 expression but was associated with increased FGF5 (Fibroblast Growth Factor 5) expression. These data propose a model of elevated Sox2 expression due to loss of AR-mediated repression during castration, and consequent castration-resistance via mechanisms not involving induction of canonical embryonic stem cell pathways. PMID:23326489

Effect of anti-gonadotropin-releasing factor vaccine and band castration on indicators of welfare in beef cattle.

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Marti, S; Devant, M; Amatayakul-Chantler, S; Jackson, J A; Lopez, E; Janzen, E D; Schwartzkopf-Genswein, K S

2015-04-01

Angus crossbred bulls (n = 60; 257 ± 5.4 d of age; initial BW 358.8 ± 3.78 kg) were used to study the effect of a vaccine against gonadotropin-releasing factor (GnRF) and band castration on behavioral and physiological indicators of pain. Cattle were randomly assigned to 1 of 3 treatments: bulls, band-castrated calves without pain mitigation (castrated), and immune-vaccinated animals administered an anti-GnRF vaccine (vaccinated). All animals were fitted with a radio frequency ear tag so that individual animal feed intake and feeding behavior were recorded daily over the entire trial using an electronic feed bunk monitoring system. Two doses of anti-GnRF vaccine were administrated on d -35 and 0 and band castration was performed on d 0. Animal BW was recorded weekly starting on d -36 until d 56. Visual analog scores (VAS) were measured on d -36 -35, -1, and 0, and salivary cortisol concentration was measured at -30, 0, 30, 60, 120, and 270 min on d -35 and 0 after castration. Saliva and blood were obtained on d 1, 2, 5, and 7 and weekly until d 56 for determination of cortisol and complete blood cell count. Video data were collected for pain, sexual, and aggressive behavior daily the first week and once a week until d 56. Data were analyzed with a mixed-effect model with castration, time, and their interactions as main effects. Vaccinated calves had reduced ADG and intake (P castrated calves had reduced ADG and intake (P castration. However, on d 0, castrated cattle had greater cortisol concentrations and VAS (P 0.05) between treatments on d 0, 1, and 2. At d 56, vaccinated calves had greater (P castrated calves and both had less final BW than bulls. There was no indication that vaccination caused any physiological or behavioral changes indicative of pain. In contrast, band castration resulted in elevated cortisol scores and VAS indicative of a pain response and behavior related to pain (P castration in beef cattle under North American feedlot practices.

Effects of Castration on Expression of Lipid Metabolism Genes in the Liver of Korean Cattle

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Baik, Myunggi; Nguyen, Trang Hoa; Jeong, Jin Young; Piao, Min Yu; Kang, Hyeok Joong

2015-01-01

Castration induces the accumulation of body fat and deposition of intramuscular fat in Korean cattle, resulting in improved beef quality. However, little is known about the metabolic adaptations in the liver following castration. To understand changes in lipid metabolism following castration, hepatic expression levels of lipid metabolism genes were compared between Korean bulls and steers. Steers had higher (p

Castration resistant prostate cancer in the year 2013

International Nuclear Information System (INIS)

Marencak, J.

2013-01-01

Prostate cancer (PC) is the most frequent solid neoplasm in Europe and therefore is regarded as one of the major medical problems of the male population. PC is extremely complicated and interindividual different tumor. The method of treatment depends on several factors, but mainly on the stage of prostate cancer. The term Hormone resistant (refractory) prostate cancer (HRPC) was used in older terminology. HRPC is cancer that progresses despite castrate levels of testosterone achieved androgen deprivation therapy (ADT), which is resistant to any hormonal therapy. Currently is increasingly used (instead of name HRPC) name CRPC – so called PC resistant for castration (CRPC – castration resistant prostate cancer), which is still able to respond to certain hormonal manipulation, although it meets the the criteria for HRPC. Objectives of article: provide information to the general medical community (and especially urologists and oncologists) mainly about a treatment of complicated issues of CRPC. The basic data on the current and future. The article presented basic data on the current and future possibilities of such therapy and increasing basic knowledge about treating CRPC should improve the care of patients with advanced PC. (author)

Effects of Topical Anaesthetic and Buccal Meloxicam Treatments on Concurrent Castration and Dehorning of Beef Calves

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Dominique Van der Saag

2018-02-01

Full Text Available The use of pain relief during castration and dehorning of calves on commercial beef operations can be limited by constraints associated with the delivery of analgesic agents. As topical anaesthetic (TA and buccal meloxicam (MEL are now available in Australia, offering practical analgesic treatments for concurrent castration and dehorning of beef calves, a study was conducted to determine their efficacy in providing pain relief when applied separately or in combination. Weaner calves were randomly allocated to; (1 no castration and dehorning/positive control (CONP; (2 castration and dehorning/negative control (CONN; (3 castration and dehorning with buccal meloxicam (BM; (4 castration and dehorning with topical anaesthetic (TA; and (5 castration and dehorning with buccal meloxicam and topical anaesthetic (BMTA. Weight gain, paddock utilisation, lying activity and individual behaviours following treatment were measured. CONP and BMTA calves had significantly greater weight gain than CONN calves (p < 0.001. CONN calves spent less time lying compared to BMTA calves on all days (p < 0.001. All dehorned and castrated calves spent more time walking (p = 0.024 and less time eating (p < 0.001 compared to CONP calves. There was a trend for CONP calves to spend the most time standing and CONN calves to spend the least time standing (p = 0.059. There were also trends for the frequency of head turns to be lowest in CONP and BMTA calves (p = 0.098 and tail flicks to be highest in CONN and BM calves (p = 0.061. The findings of this study suggest that TA and MEL can potentially improve welfare and production of calves following surgical castration and amputation dehorning.

Comparative study of 2 surgical techniques for castration of guinea pigs (Cavia porcellus).

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Guilmette, Josée; Langlois, Isabelle; Hélie, Pierre; El Warrak, Alexander de Oliveira

2015-10-01

The objective of this study was to compare 2 surgical approaches (scrotal or abdominal) for castration of guinea pigs and to investigate post-operative infection rates with either technique. Forty-eight guinea pigs were castrated by scrotal or abdominal technique after being randomly assigned to 1 of 2 groups (n = 24). Individuals were either castrated by an experienced exotic animal surgeon (n = 12) or by an experienced small animal surgeon (n = 12). Surgical wounds were evaluated daily before euthanasia for histological evaluation 2 wks after surgery. Post-operative infection rate was significantly higher in the scrotal group than in the abdominal group, with a higher rate for the experienced small animal surgeon. Castration of guinea pigs with the abdominal technique is significantly faster and has a significantly lower post-operative infection rate than the scrotal technique.

Testosterone Depletion by Castration May Protect Mice from Heat-Induced Multiple Organ Damage and Lethality

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Ruei-Tang Cheng

2010-01-01

Full Text Available When the vehicle-treated, sham-operated mice underwent heat stress, the fraction survival and core temperature at +4 h of body heating were found to be 5 of 15 and 34.4∘C±0.3∘C, respectively. Castration 2 weeks before the start of heat stress decreased the plasma levels of testosterone almost to zero, protected the mice from heat-induced death (fraction survival, 13/15 and reduced the hypothermia (core temperature, 37.3∘C. The beneficial effects of castration in ameliorating lethality and hypothermia can be significantly reduced by testosterone replacement. Heat-induced apoptosis, as indicated by terminal deoxynucleotidyl- transferase- mediatedαUDP-biotin nick end-labeling staining, were significantly prevented by castration. In addition, heat-induced neuronal damage, as indicated by cell shrinkage and pyknosis of nucleus, to the hypothalamus was also castration-prevented. Again, the beneficial effects of castration in reducing neuronal damage to the hypothalamus as well as apoptosis in multiple organs during heatstroke, were significantly reversed by testosterone replacement. The data indicate that testosterone depletion by castration may protect mice from heatstroke-induced multiple organ damage and lethality.

[Painful procedures in small ruminants - castration of rams and bucks. - An overview].

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Bauer, Benjamin; Hannemann, Regina; Lendl, Christine; Strobel, Heinz; Ganter, Martin

2018-04-01

The castration of farm animals is practiced routinely throughout the world and the procedure is subject to different levels of regulation in different countries. In Germany, painful procedures in animals are regulated by the animal welfare act. However, the indications for acceptable methods of lamb and kid castration are still under discussion. There are distinct differences between the theoretical requirements of this legislation and experiences in practice. When male lambs are kept for many months with their dams, or with ewe lambs, castration is essential to avoid unwanted pregnancies and the slaughter of pregnant females. In the opinion of the authors, it is essential that castration of small ruminants must remain possible. However, the methods used for these painful procedures need to be reassessed and if necessary new regulations established. When castration is necessary, sufficient anaesthesia and analgesia must be used irrespective of species, age and method. To make this possible potent anaesthetics and analgesics urgently need to be licensed for use in these species. This would provide an evidence base for their use and extricate veterinary practitioners from the need to use the cascade system with its associated liabilities. Current literature has been reviewed here and possible new approaches discussed in order to establish solutions that are suitable for the animals, their keepers and veterinarians. Schattauer GmbH.

A survey of castration methods and associated livestock management practices performed by bovine veterinarians in the United States.

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Coetzee, Johann F; Nutsch, Abbey L; Barbur, Laura A; Bradburn, Ryan M

2010-03-03

Castration of male calves destined for beef production is a common management practice performed in the United States amounting to approximately 15 million procedures per year. Societal concern about the moral and ethical treatment of animals is increasing. Therefore, production agriculture is faced with the challenge of formulating animal welfare policies relating to routine management practices such as castration. To enable the livestock industry to effectively respond to these challenges there is a need for more data on management practices that are commonly used in cattle production systems. The objective of this survey was to describe castration methods, adverse events and husbandry procedures performed by U.S. veterinarians at the time of castration. Invitations to participate in the survey were sent to email addresses of 1,669 members of the American Association of Bovine Practitioners and 303 members of the Academy of Veterinary Consultants. After partially completed surveys and missing data were omitted, 189 responses were included in the analysis. Surgical castration with a scalpel followed by testicular removal by twisting (calves 90 kg) was the most common method of castration used. The potential risk of injury to the operator, size of the calf, handling facilities and experience with the technique were the most important considerations used to determine the method of castration used. Swelling, stiffness and increased lying time were the most prevalent adverse events observed following castration. One in five practitioners report using an analgesic or local anesthetic at the time of castration. Approximately 90% of respondents indicated that they vaccinate and dehorn calves at the time of castration. Over half the respondents use disinfectants, prophylactic antimicrobials and tetanus toxoid to reduce complications following castration. The results of this survey describe current methods of castration and associated management practices employed by

A survey of castration methods and associated livestock management practices performed by bovine veterinarians in the United States

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Bradburn Ryan M

2010-03-01

Full Text Available Abstract Background Castration of male calves destined for beef production is a common management practice performed in the United States amounting to approximately 15 million procedures per year. Societal concern about the moral and ethical treatment of animals is increasing. Therefore, production agriculture is faced with the challenge of formulating animal welfare policies relating to routine management practices such as castration. To enable the livestock industry to effectively respond to these challenges there is a need for more data on management practices that are commonly used in cattle production systems. The objective of this survey was to describe castration methods, adverse events and husbandry procedures performed by U.S. veterinarians at the time of castration. Invitations to participate in the survey were sent to email addresses of 1,669 members of the American Association of Bovine Practitioners and 303 members of the Academy of Veterinary Consultants. Results After partially completed surveys and missing data were omitted, 189 responses were included in the analysis. Surgical castration with a scalpel followed by testicular removal by twisting (calves 90 kg was the most common method of castration used. The potential risk of injury to the operator, size of the calf, handling facilities and experience with the technique were the most important considerations used to determine the method of castration used. Swelling, stiffness and increased lying time were the most prevalent adverse events observed following castration. One in five practitioners report using an analgesic or local anesthetic at the time of castration. Approximately 90% of respondents indicated that they vaccinate and dehorn calves at the time of castration. Over half the respondents use disinfectants, prophylactic antimicrobials and tetanus toxoid to reduce complications following castration. Conclusions The results of this survey describe current methods of

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

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

2016-06-13

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

Effect of intravenous sodium salicylate administration prior to castration on plasma cortisol and electroencephalography parameters in calves.

Science.gov (United States)

Bergamasco, L; Coetzee, J F; Gehring, R; Murray, L; Song, T; Mosher, R A

2011-12-01

Nociception is an unavoidable consequence of many routine management procedures such as castration in cattle. This study investigated electroencephalography (EEG) parameters and cortisol levels in calves receiving intravenous sodium salicylate in response to a castration model. Twelve Holstein calves were randomly assigned to the following groups: (i) castrated, untreated controls, (ii) 50 mg/kg sodium salicylate IV precastration, were blood sampled at 0, 5, 10, 20, 30, 45, 60, 90, 120, 150, 180, 240, 360, and 480 min postcastration. The EEG recording included baseline, castration, immediate recovery (0-5 min after castration), middle recovery (5-10 min after castration), and late recovery (10-20 min after castration). Samples were analyzed by competitive chemiluminescent immunoassay and fluorescence polarization immunoassay for cortisol and salicylate, respectively. EEG visual inspection and spectral analysis were performed. Statistical analyses included anova repeated measures and correlations between response variable. No treatment effect was noted between the two groups for cortisol and EEG measurements, namely an attenuation of acute cortisol response and EEG desynchronization in sodium salicylate group. Time effects were noted for EEG measurements, cortisol and salicylates levels. Significant correlations between cortisol and EEG parameters were noted. These findings have implications for designing effective analgesic regimens, and they suggest that EEG can be useful to monitor pain attributable to castration. © 2011 Blackwell Publishing Ltd.

Castration, dopamine and food choice: a cost/benefit test in male hamsters.

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Chu, Lucy; Wood, Ruth I

2002-10-17

Testosterone is essential for copulation, and contributes to sexual motivation. In addition, castrated males are fatter and less active, suggesting that androgens may play a role in non-sexual behaviors, including food-related responses. To test this hypothesis, male hamsters were trained with a cost/benefit test, which compares operant responding for more-preferred food versus ad libitum consumption of lab chow. Males were tested before and after castration. The effect of the dopamine antagonist, haloperidol, on instrumental responses in intact and castrated males was also determined. Food-deprived hamsters responded vigorously for 45 mg Bio-Serv pellets in daily 30-min tests (665 presses, 6.0+/-0.9 g). When lab chow was available, males continued to respond for pellets (3.6+/-0.6 g) over chow ad libitum (1.2+/-0.3 g). Dopamine is central to this response because haloperidol (1.0 mg/kg i.p.) reversed food intake (pellets: 0.5+/-0.1 g; chow 2.0+/-0.5 g). Castration had no effect on operant responding for pellets alone (6.6+/-0.7 g). When chow was present, castrates consumed an even greater proportion of their total food intake as pellets [6.0+/-0.4 g pellets (92%), 1.6+/-0.5 g chow (8%), vs. 75 and 25%, respectively, for intact males]. This is contrary to our original hypothesis. In addition, castration did not change the effects of haloperidol on food intake: (0.4+/-0.1 g pellets; 1.6+/-0.5 g chow). These results support previous findings in rats that dopamine affects response allocation in a cost/benefit test. However, they do not support the hypothesis that testosterone modifies the allocation of food-related responses.

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

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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

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

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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 (Pcastration (41±1.2 pg/mL), possibly because the sample was collected after the lidocaine ring block was administered, which was likely painful, and because of separation from the dam and restraint. Values began to drop by d 3 (34±1.2 pg/mL) and leveled out by d 21 (30±1.2 pg/mL; Pcastration 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.

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

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Fredson Vieira e Silva

2008-12-01

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

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.

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

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Sebastien Taurin

2014-01-01

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

Effects of castration on expression of lipid metabolism genes in the liver of korean cattle.

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Baik, Myunggi; Nguyen, Trang Hoa; Jeong, Jin Young; Piao, Min Yu; Kang, Hyeok Joong

2015-01-01

Castration induces the accumulation of body fat and deposition of intramuscular fat in Korean cattle, resulting in improved beef quality. However, little is known about the metabolic adaptations in the liver following castration. To understand changes in lipid metabolism following castration, hepatic expression levels of lipid metabolism genes were compared between Korean bulls and steers. Steers had higher (pcastration of bulls. However, we found no differences in the hepatic expression levels of genes related to triglyceride synthesis (mitochondrial glycerol-3-phosphate acyltransferase, diacylglycerol O-acyltransferase 1 and 2) and fatty acid (FA) oxidation (carnitine palmitoyltransferase 1A, C-4 to C-12 straight chain acyl-CoA dehydrogenase, very long chain acyl-CoA dehydrogenase) between bulls and steers. No differences in gene expression for very-low-density lipoprotein (VLDL) secretion, including apolipoprotein B mRNA and microsomal triglyceride transfer protein (MTTP) protein, were observed in the liver although MTTP mRNA levels were higher in steers compared to bulls. In conclusion, FA synthesis may contribute to increased hepatic lipid deposition in steers following castration. However, hepatic lipid metabolism, including triglyceride synthesis, FA oxidation, and VLDL secretion, was not significantly altered by castration. Our results suggest that hepatic lipid metabolism does not significantly contribute to increased body fat deposition in steers following castration.

Effects of Castration on Expression of Lipid Metabolism Genes in the Liver of Korean Cattle

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Myunggi Baik

2015-01-01

Full Text Available Castration induces the accumulation of body fat and deposition of intramuscular fat in Korean cattle, resulting in improved beef quality. However, little is known about the metabolic adaptations in the liver following castration. To understand changes in lipid metabolism following castration, hepatic expression levels of lipid metabolism genes were compared between Korean bulls and steers. Steers had higher (p<0.001 hepatic lipids contents and higher (p<0.01 mRNA levels of lipogenic acetyl-CoA carboxylase. This differential gene expression may, in part, contribute to increased hepatic lipid content following the castration of bulls. However, we found no differences in the hepatic expression levels of genes related to triglyceride synthesis (mitochondrial glycerol-3-phosphate acyltransferase, diacylglycerol O-acyltransferase 1 and 2 and fatty acid (FA oxidation (carnitine palmitoyltransferase 1A, C-4 to C-12 straight chain acyl-CoA dehydrogenase, very long chain acyl-CoA dehydrogenase between bulls and steers. No differences in gene expression for very-low-density lipoprotein (VLDL secretion, including apolipoprotein B mRNA and microsomal triglyceride transfer protein (MTTP protein, were observed in the liver although MTTP mRNA levels were higher in steers compared to bulls. In conclusion, FA synthesis may contribute to increased hepatic lipid deposition in steers following castration. However, hepatic lipid metabolism, including triglyceride synthesis, FA oxidation, and VLDL secretion, was not significantly altered by castration. Our results suggest that hepatic lipid metabolism does not significantly contribute to increased body fat deposition in steers following castration.

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

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

2015-08-01

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

Experience with the delegation of anaesthesia for disbudding and castration to trained and certified livestock owners.

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Alsaaod, Maher; Doherr, Marcus G; Greber, Deborah; Steiner, Adrian

2014-02-04

Anaesthesia is mandatory for disbudding and castrating calves and lambs of any age, in Switzerland. According to the "anaesthesia delegation model" (ADM), anaesthesia for disbudding calves delegation of anaesthesia for disbudding calves and procedures II and III were anaesthesia for castrating calves and lambs. Procedure I was performed with local anaesthesia in all farms of 51.8% of the veterinary practices, while this was only 39.3% and 7.6% for procedures II and III (p delegation of anaesthesia to certified farmers may be a promising model to reinforce the obligation to provide local anaesthesia for disbudding and castrating calves, but to a lesser extent for castrating lambs.

Effect of Surgical and Immunological Castration on Haematological ...

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olayemitoyin

Summary: Welfare concerns are growing regarding surgical castration (SC) in pets, necessitating the need for non-surgical alternatives. ..... Doctoral Thesis. Swedish ... Pharmacological advances in canine and feline reproduction. Topics in.

Metastatic castration-resistant prostate cancer: time for innovation.

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

2015-01-01

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

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

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

2012-07-01

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

Abiraterone in the treatment of metastatic castration-resistant prostate cancer

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Mostaghel EA

2014-01-01

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

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

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Mauro Silvani

2015-09-01

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

Castration-Resistant Lgr5+ Cells Are Long-Lived Stem Cells Required for Prostatic Regeneration

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Bu-er Wang

2015-05-01

Full Text Available The adult prostate possesses a significant regenerative capacity that is of great interest for understanding adult stem cell biology. We demonstrate that leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5 is expressed in a rare population of prostate epithelial progenitor cells, and a castration-resistant Lgr5+ population exists in regressed prostate tissue. Genetic lineage tracing revealed that Lgr5+ cells and their progeny are primarily luminal. Lgr5+ castration-resistant cells are long lived and upon regeneration, both luminal Lgr5+ cells and basal Lgr5+ cells expand. Moreover, single Lgr5+ cells can generate multilineage prostatic structures in renal transplantation assays. Additionally, Lgr5+ cell depletion revealed that the regenerative potential of the castrated adult prostate depends on Lgr5+ cells. Together, these data reveal insights into the cellular hierarchy of castration-resistant Lgr5+ cells, indicate a requirement for Lgr5+ cells during prostatic regeneration, and identify an Lgr5+ adult stem cell population in the prostate.

A meta-analysis of cortisol concentration, vocalization, and average daily gain associated with castration in beef cattle.

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Canozzi, Maria Eugênia Andrighetto; Mederos, America; Manteca, Xavier; Turner, Simon; McManus, Concepta; Zago, Daniele; Barcellos, Júlio Otávio Jardim

2017-10-01

A systematic review and meta-analysis (MA) were performed to summarize all scientific evidence for the effects of castration in male beef cattle on welfare indicators based on cortisol concentration, average daily gain (ADG), and vocalization. We searched five electronic databases, conference proceedings, and experts were contacted electronically. The main inclusion criteria involved completed studies using beef cattle up to one year of age undergoing surgical and non-surgical castration that presented cortisol concentration, ADG, or vocalization as an outcome. A random effect MA was conducted for each indicator separately with the mean of the control and treated groups. A total of 20 publications reporting 26 studies and 162 trials were included in the MA involving 1814 cattle. Between study heterogeneity was observed when analysing cortisol (I 2 =56.7%) and ADG (I 2 =79.6%). Surgical and non-surgical castration without drug administration compared to uncastrated animals showed no change (P≥0.05) in cortisol level. Multimodal therapy for pain did not decrease (P≥0.05) cortisol concentration after 30min when non-surgical castration was performed. Comparison between surgical castration, with and without anaesthesia, showed a tendency (P=0.077) to decrease cortisol levels after 120min of intervention. Non-surgical and surgical castration, performed with no pain mitigation, increased and tended to increase the ADG by 0.814g/d (P=0.001) and by 0.140g/d (P=0.091), respectively, when compared to a non-castrated group. Our MA study demonstrates an inconclusive result to draw recommendations on preferred castration practices to minimize pain in beef cattle. Copyright © 2017 Elsevier Ltd. All rights reserved.

Impact of oral meloxicam administration before and after band castration on feedlot performance and behavioral response in weanling beef bulls.

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Repenning, P E; Ahola, J K; Callan, R J; French, J T; Giles, R L; Bigler, B J; Coetzee, J F; Wulf, L W; Peel, R K; Whittier, J C; Fox, J T; Engle, T E

2013-10-01

Two experiments evaluated the effects of band castration and oral administration of an analgesic in association with castration on performance and behavioral and physiological responses in yearling beef bulls. In Exp. 1 Angus and Charolais-crossbred bull calves (n = 127; 309.8 ± 59.04 kg BW) and in Exp. 2 Hereford, Angus, and Hereford × Angus crossbred bulls (n = 30; 300.8 ± 4.96 kg BW) were stratified by BW and randomly assigned to 1 of 3 treatments: 1) band castration (BAND), 2) band castration with oral administration of meloxicam (BAND-MEL), and 3) sham castration (SHAM). The BAND and SHAM procedures were completed on d 0. The SHAM treatment consisted of all animal manipulations associated with band castration without band application. Meloxicam was administered on d -1, 0, and 1 (1.0, 0.5, and 0.5 mg/kg, respectively) via an oral bolus. Body weight and a subjective chute score (CS) were collected on d -1, 0, 1, 7, 14, and 21 (d 28 Exp. 1 only). In Exp. 2, jugular blood samples were collected immediately before castration and 24 h postcastration for substance P (SP) analysis. In Exp. 2, video documentation on d 0 was used to determine range of vertical head motion (DIST) on a subset of animals during treatment administration. In both experiments, ADG was similar (P ≥ 0.50) between BAND and BAND-MEL, but ADG in SHAM cattle was greater (P castrates in Exp. 1 and 2, respectively. In Exp. 1, CS did not differ (P ≥ 0.26) between BAND and BAND-MEL on any day, but castrates exhibited less desirable CS on d 1 and 28 than SHAM cattle. In Exp. 2, CS was not affected (P ≥ 0.41) by castration or the presence of meloxicam. In Exp. 2, DIST did not differ (P = 0.57) between BAND and BAND-MEL, but when pooled, castrates exhibited greater (P = 0.04) DIST than SHAM. In Exp. 2, plasma SP concentrations were similar between BAND and BAND-MEL (P = 0.81) and between castrates vs. sham cattle (P = 0.67). Results indicate no impact of meloxicam administration on performance

New possibilities and view for treatment of castration resistant prostate cancer

International Nuclear Information System (INIS)

Barilla, R.; Andrasina, I.

2012-01-01

Prostate cancer is currently known as the most common cancer and the second leading cause of death from cancer in men in Western population. Advanced prostate cancer is initially sensitive to androgen-deprivation therapy (ADT) but later on progresses to castration resistant state. Understanding the mechanisms that transform prostate cancer (PCA) into a castration-resistant state enables investigators to explore suppression of extraresticular andronegs and other critical pathways to suggest appropriate and rational therapeutic design. Docetaxel based chemotherapy is established as the standard first line chemotherapy in patients with metastatic castration-resistant advanced prostate cancer with improved survival. However, prognosis remains poor and median survival is usually not longer than 2 years. Several Phase III studies have been completed recently, e.g. with new antiandrogens, new taxanes, immunotherapy and therapeutic antibodies. Multidisciplinary management and optimization of their role and and the most appropriate timing is the most important task in the treatment of advanced prostate cancer. (author)

Weight gain of piglets subject to different protocols of castration

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Marcos Paulo Antunes de Lima

2014-06-01

Full Text Available ABSTRACT. Lima M.P.A., Gehrcke M.I., Laskoski F., Cristani J. & Oleskovicz N. [Weight gain of piglets subject to different protocols of castration.] Desempenho de ganho de peso de leitões após diferentes protocolos de castração. Revista Brasileira de Medicina Veterinária, 36(2:209-214, 2014. Departamento de Medicina Veterinária, Centro de Ciências Agroveterinárias, Universidade do Estado de Santa Catarina, Av. Luiz de Camões 2090, Conta Dinheiro, Lages, SC 88520-000, Brasil. E-mail: marcos_paulo@hotmail.com The aim this study was to evaluate the performance of weight gain of piglets castrated, and three methods of sedation and or local anesthesia compared with the traditional method recommended by the standards of Good Practices in Swine Production. We used 100 male pigs, seven days old, weighing 2.9 ± 0.50 kg, which were randomly divided into four groups: (BP Practice, in which the animals were castrated without anesthesia or analgesia, L (Lidocaine, which received 0.5 mL of lidocaine without epinephrine in each spermatic cord; SL (sedation/lidocaine which were sedated with tramadol 4mg.kg-1 and midazolam 1 mg.kg-1 intramuscular (IM, associated with the local block with 0.5 mL of lidocaine without epinephrine administered in each spermatic cord, and S (sedation, which received tramadol 4mg.kg-1 and midazolam 1mg.kg-1 IM. Recorded the weight of the animals at birth, the seventh day preceding the castration procedure, and 20 days old at the time of weaning. The data were evaluated by One Way ANOVA (ANOVA followed by Tukey test (P<0.05. The mean weights of animals at weaning were 6.15±0.86, 6.02±1.06, 5.96±0.19 and 5.51±1.14 and the average daily weight gain, the day of Castration at weaning was 0.23±0.05, 0.24±0.04, 0.23±0.06 and 0.19±0.05 respectively, for BP groups, L, SL and S. There were no significant differences between the values of the groups studied. The use of sedation protocols and or anesthetic to perform the

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

NARCIS (Netherlands)

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

2012-01-01

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

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

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2017-12-01

AWARD NUMBER: W81XWH-13-1-0163 TITLE: Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer ...Prostate Cancer 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Feng Yang, Ph.D. 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: fyang@bcm.edu...W81XWH-13-1-0163 " Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer " Introduction AR signaling

Evaluation of common vaginal tunic ligation during field castration in draught colts.

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Carmalt, J L; Shoemaker, R W; Wilson, D G

2008-09-01

The objective of this study was to determine if ligation of the common vaginal tunic could prevent or reduce the incidence of omental herniation and eventration in draught colts undergoing routine field castration. It was found that common vaginal tunic ligation, while not completely preventing omental herniation and evisceration, significantly reduced the incidence of these complications and should be considered in those males deemed at increased risk of significant post castration complications.

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

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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. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effects of pain mitigation and method of castration on behavior and feedlot performance in cull beef bulls.

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Repenning, P E; Ahola, J K; Callan, R J; Fox, J T; French, J T; Giles, R L; Peel, R K; Whittier, J C; Engle, T E

2013-10-01

The objectives of this study were to evaluate the effects of castration method (banding vs. surgical) and use of analgesia on behavior and feedlot performance in cull bulls. Angus, Hereford, and Angus-crossbred bulls (n = 20; initial BW = 384 ± 59.3 kg; 336 ± 20.1 d old) were housed in feedlot pens equipped with the ability to measure individual daily feed intake. A balanced randomized block design using a 2 × 2 factorial arrangement of treatments was used. A multimodal analgesia (MMA) protocol was used and consisted of sutcutaneous ketamine stun containing butorphanol (0.01 mg/kg BW), xylazine (0.02 mg/kg BW), ketamine (0.04 mg/kg BW), and a local 2% lidocaine hydrochloride anesthetic block of the spermatic cords (10 mL/cord) and scrotum (10 mL) on d 0. Flunixin meglumine (1.2 mg/kg) was administered intravenously on d 0, 1, 2, and 3 to MMA cattle. Cattle were stratified to treatments based on breed, BW, age, and a temperament score. Treatments included 1) band castration without analgesia (BND), 2) band castration with analgesia (BND-MMA), 3) surgical castration without analgesia (SURG), and 4) surgical castration with analgesia (SURG-MMA). All castrations were performed on d 0. Chute exit velocity (EV) and time in chute (TIC) were collected on d -9, 0, 1, 2, and 13. Willingness-to-enter-chute (WTE) score, rectal temperature (TEMP), heart rate (HR), and respiration (RESP) were collected on d 0, 1, 2, 3, and 13. Cattle were weighed on d -9 and 13 while feeding behaviors were collected continuously for 57 d precastration and 28 d postcastration. There was a tendency (P cattle receiving analgesia. Both SURG treatments exhibited elevated TEMP on d 1 (P castrates during the first week postcastration. Results suggest that pain mitigation reduces the impact of castration on ADG and DMI.

Quantitative estimation of the cost of parasitic castration in a Helisoma anceps population using a matrix population model.

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Negovetich, N J; Esch, G W

2008-10-01

Larval trematodes frequently castrate their snail intermediate hosts. When castrated, the snails do not contribute offspring to the population, yet they persist and compete with the uninfected individuals for the available food resources. Parasitic castration should reduce the population growth rate lambda, but the magnitude of this decrease is unknown. The present study attempted to quantify the cost of parasitic castration at the level of the population by mathematically modeling the population of the planorbid snail Helisoma anceps in Charlie's Pond, North Carolina. Analysis of the model identified the life-history trait that most affects lambda, and the degree to which parasitic castration can lower lambda. A period matrix product model was constructed with estimates of fecundity, survival, growth rates, and infection probabilities calculated in a previous study. Elasticity analysis was performed by increasing the values of the life-history traits by 10% and recording the percentage change in lambda. Parasitic castration resulted in a 40% decrease in lambda of H. anceps. Analysis of the model suggests that decreasing the size at maturity was more effective at reducing the cost of castration than increasing survival or growth rates of the snails. The current matrix model was the first to mathematically describe a snail population, and the predictions of the model are in agreement with published research.

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

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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 (Pcastration 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.

Sortilin regulates progranulin action in castration-resistant prostate cancer cells.

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Tanimoto, Ryuta; Morcavallo, Alaide; Terracciano, Mario; Xu, Shi-Qiong; Stefanello, Manuela; Buraschi, Simone; Lu, Kuojung G; Bagley, Demetrius H; Gomella, Leonard G; Scotlandi, Katia; Belfiore, Antonino; Iozzo, Renato V; Morrione, Andrea

2015-01-01

The growth factor progranulin is as an important regulator of transformation in several cellular systems. We have previously demonstrated that progranulin acts as an autocrine growth factor and stimulates motility, proliferation, and anchorage-independent growth of castration-resistant prostate cancer cells, supporting the hypothesis that progranulin may play a critical role in prostate cancer progression. However, the mechanisms regulating progranulin action in castration-resistant prostate cancer cells have not been characterized. Sortilin, a single-pass type I transmembrane protein of the vacuolar protein sorting 10 family, binds progranulin in neurons and negatively regulates progranulin signaling by mediating progranulin targeting for lysosomal degradation. However, whether sortilin is expressed in prostate cancer cells and plays any role in regulating progranulin action has not been established. Here, we show that sortilin is expressed at very low levels in castration-resistant PC3 and DU145 cells. Significantly, enhancing sortilin expression in PC3 and DU145 cells severely diminishes progranulin levels and inhibits motility, invasion, proliferation, and anchorage-independent growth. In addition, sortilin overexpression negatively modulates Akt (protein kinase B, PKB) stability. These results are recapitulated by depleting endogenous progranulin in PC3 and DU145 cells. On the contrary, targeting sortilin by short hairpin RNA approaches enhances progranulin levels and promotes motility, invasion, and anchorage-independent growth. We dissected the mechanisms of sortilin action and demonstrated that sortilin promotes progranulin endocytosis through a clathrin-dependent pathway, sorting into early endosomes and subsequent lysosomal degradation. Collectively, these results point out a critical role for sortilin in regulating progranulin action in castration-resistant prostate cancer cells, suggesting that sortilin loss may contribute to prostate cancer progression.

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

OpenAIRE

Sweeney Torres; Earley Bernadette; Pang Wanyong; Gath Vivian; Crowe Mark A

2009-01-01

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). S...

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

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

2015-01-01

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

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

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Hari Purnomo

2012-03-01

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

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

Prostate cancer remains a leading cause of cancer-related mortality worldwide owing to our inability to treat effectively castration-resistant tumors. To understand the signaling mechanisms sustaining castration-resistant growth, we implemented a mass spectrometry-based quantitative proteomic app...

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

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Musk, Gabrielle C.; Hyndman, Timothy H.; Lehmann, Heidi S.; Tuke, S. Jonathon; Collins, Teresa; Johnson, Craig B.

2017-01-01

Simple Summary Surgical castration of cattle is a common husbandry procedure, and although this procedure is known to cause pain in cattle and other species, in some countries it is often performed without anaesthesia or analgesia. Society is increasingly aware of this animal welfare issue and it is creating pressure to drive research into animal welfare science with the aim of identifying practical and economical approaches to pain management in livestock. To effectively manage pain, a pain assessment must be performed. Pain assessment methods are often subjective and therefore influenced by the observer. Ideally, objective assessments that generate consistent and repeatable results between observers should be identified. Bos indicus bull calves were divided into four groups: no castration (NC, n = 6); castration with pre-operative local anaesthetic (CL n = 12); castration with pre-operative anti-inflammatory medication (CM, n = 12); and, castration without pain relief (C, n = 12). A range of objective assessments was performed: bodyweight measurements, activity, and rest levels, and four different compounds in the blood. The results of this study suggest that animals rest for longer periods after the pre-operative administration of anti-inflammatory medication. The other objective assessments measured in this study were not able to consistently differentiate between treatment groups. These findings emphasise the need for alternative quantifiable and objective indicators of pain in Bos indicus bull calves. Abstract The aim of the study was to assess pain in Bos indicus bull calves following surgical castration. Forty-two animals were randomised to four groups: no castration (NC, n = 6); castration with pre-operative lidocaine (CL, n = 12); castration with pre-operative meloxicam (CM, n = 12); and, castration alone (C, n = 12). Bodyweight was measured regularly and pedometers provided data on activity and rest from day −7 (7 days prior to surgery) to 13. Blood

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

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Roberts, S L; Hughes, H D; Burdick Sanchez, N C; Carroll, J A; Powell, J G; Hubbell, D S; Richeson, J T

2015-08-01

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 immunomodulation and whether concurrent oral administration of meloxicam (1 mg/kg BW) would alter these responses. On d -1, crossbred bull calves ( = 30; initial BW = 227.4 ± 10.3 kg) were fitted with indwelling jugular catheters and rectal temperature (RT) recording devices, placed into individual stanchions, and randomly assigned to 1 of 3 treatments. Treatment application occurred at h 0 and consisted of 1) intact bull calves treated with sham castration (CON), 2) bulls surgically castrated without meloxicam administration (CAS), and 3) bulls surgically castrated with oral meloxicam (1 mg/kg BW) administration (MEL). Blood samples were collected at 0.5-h intervals from h -2 to 4, 1.0-h intervals from h 4 to 8, and 12-h intervals from h 12 to 72. Serum was analyzed for cortisol and haptoglobin (Hp) concentrations using ELISA. Whole blood was analyzed for complete blood counts at -2, 0, 2, 4, 6, 8, 12, 24, 36, 48, 60, and 72 h, and RT was recorded in 5-min intervals. Postcastration RT was greatest for MEL (39.04), intermediate for CAS (38.99), and least for CON (38.93°C; ≤ 0.01). Serum cortisol was increased ( castration reduced the acute inflammatory response in castrates, as evidenced by a reduction in Hp and certain leukocyte concentrations; it also caused a delayed increase in RT. Further research is needed to determine if this reduced acute inflammatory response would equate to improved health and/or performance after castration.

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

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Fassah, Dilla Mareistia; Jeong, Jin Young

2018-01-01

Objective This study was performed to understand transcriptional changes in the genes involved in gluconeogenesis and glycolysis pathways following castration of bulls. Methods Twenty Korean bulls were weaned at average 3 months of age, and castrated at 6 months. Liver tissues were collected from bulls (n = 10) and steers (n = 10) of Korean cattle, and hepatic gene expression levels were measured using quantitative real-time polymerase chain reaction. We examined hepatic transcription levels of genes encoding enzymes for irreversible reactions in both gluconeogenesis and glycolysis as well as genes encoding enzymes for the utilization of several glucogenic substrates. Correlations between hepatic gene expression and carcass characteristics were performed to understand their associations. Results Castration increased the mRNA (3.6 fold; pgluconeogenesis reactions from pyruvate to glucose and enzymes responsible for incorporation of glucogenic substrates including lactate, glycerol, and propionate. Hepatic gluconeogenic gene expression levels were associated with intramuscular fat deposition. PMID:29502393

Abiraterone in the treatment of metastatic castration-resistant prostate cancer

International Nuclear Information System (INIS)

Mostaghel, Elahe A

2014-01-01

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

Effect of castration age on slaughtering performance of Piemontese male cattle

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C. Lazzaroni

2010-01-01

Full Text Available Calves castration represents an old and traditional practice to obtain animal work force, but for technical, economic and social reasons in the last half of the 20th century it was left. The recent renewal of Piemontese steers rearing in the breed’s native diffusion area, for quality meat production (Biagini et al., 2001, has been spurred also for the interest in local typical dishes. Traditionally, in Piedmont calves were castrated before puberty (about 6 month of age, but now also later (12-14 month of age to benefit by the bull higher growing rate.

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

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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.

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

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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 castration. Also, BA calves had a greater (P castration and a lower feed intake and ADG at wk 2 and 3 and wk 6 and 7 after castration, respectively, compared to CT. Treatment KP had

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

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

2014-10-07

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.

Starvation reveals the cause of infection-induced castration and gigantism

Science.gov (United States)

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

2014-01-01

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. PMID:25143034

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

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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.

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

Science.gov (United States)

Slama-Scemama, A

1976-05-17

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

Correlation between LH secretion in castrated rats with cellular proliferation and synthesis of DNA in the anterior pituitary gland.

Science.gov (United States)

Romano, M I; Machiavelli, G A; Pérez, R L; Carricarte, V; Burdman, J A

1984-07-01

The relationship between the release of LH and the synthesis of DNA was studied in the anterior pituitary gland of castrated rats. Cell types were characterized immunocytochemically. Castration significantly (P less than 0.01) increased the concentration of LH in serum (1326%) and the incorporation of [3H]thymidine into pituitary DNA (72%). This was accompanied by an increment in the activity of the enzyme DNA polymerase-alpha (58%) and in the number of mitoses (from 2 +/- 0.1/mm2 in intact rats to 21 +/- 0.8/mm2 15 days after castration). Only 20% of the mitoses found in the pituitary gland of castrated rats were positively stained with the antiserum against the beta-subunit of LH. The other 80% did not stain either with LH antiserum or with antisera against the other pituitary hormones. There was a significant (P less than 0.01) increase in the number of LH cells in castrated rats (48%). All the changes produced in the anterior pituitary gland after castration were prevented by the administration of dihydrotestosterone. The results demonstrate that a stimulation of LH release is followed by an increase of DNA synthesis and cell proliferation of gonadotrophs in the anterior pituitary gland.

Effects of a topical anaesthetic formulation and systemic carprofen, given singly or in combination, on the cortisol and behavioural responses of Merino lambs to castration.

Science.gov (United States)

Paull, D R; Lee, C; Colditz, I G; Fisher, A D

2009-06-01

To determine the effectiveness of a topical anaesthetic formulation (Tri-Solfen) with or without the administration of a non-steroidal anti-inflammatory drug (carprofen) on the pain and distress response associated with ring or surgical castration of ram lambs. Merino ram lambs (n = 78) were allocated to 10 treatment groups: 4 groups of knife-castrated lambs and 4 groups of ring-castrated lambs received carprofen (4 mg/kg SC) and Tri-Solfen; 2 control groups (sham) received carprofen at 0 or 4 mg/kg SC. Measurements included plasma cortisol and haptoglobin concentrations, haematology, and behaviour, including posture. Knife-castrated lambs had higher peak cortisol and integrated cortisol responses for the first 6 h after treatment and greater concentration s of circulating acute phase proteins than ring-castrated lambs, both of which were significantly different from the sham controls. Tri-Solfen applied to the knife castration wound significantly reduced both the peak plasma cortisol concentration and the integrated cortisol response for the first 6 h and improved lying behaviour in the first 12 h. Carprofen reduced the cortisol response to knife castration at 30 min, but elevated the cortisol responses at 24 and 48 h. Carprofen nearly halved the number of acute pain behaviours associated with ring castration. There were no significant additive or synergistic effects from combining the analgesic treatments. Tri-Solfen applied to the tail wound provided no detectible benefits during ring castration + tail docking. The physiological and behavioural responses suggest that ring castration has less impact on the lamb than knife castration. The specific analgesic treatments can provide modest amelioration of the pain and discomfort associated with castration. Alternative doses or application methods may enhance their efficacy.

Chemical castration in cattle with intratesticular injection of sodium chloride: Effects on stress and inflammatory markers.

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Oliveira, Fernando C; Ferreira, Carlos E R; Haas, Cristina S; Oliveira, Leonardo G; Mondadori, Rafael G; Schneider, Augusto; Rovani, Monique T; Gonçalves, Paulo B D; Vieira, Arnaldo D; Gasperin, Bernardo G; Lucia, Thomaz

2017-03-01

Intratesticular injection (ITI) of sodium chloride (NaCl) is efficient for chemical castration of young calves, but its effects on calves welfare are unknown. Two experiments were conducted to evaluate the effects of ITI of 20% NaCl on stress and inflammatory markers in calves less than 20 days old and to assess the efficiency of ITI of 30% NaCl in 5 months old calves. In Experiment 1, control calves were only restrained and compared to calves submitted to castration through surgery (SC) and ITI with 20% NaCl (n = 9/group). No differences were observed for the eye corner temperature measured by thermography from 60 s before to 60 s after the procedures (P > 0.05). In the SC group, acute serum cortisol levels increased at 30 and 60 min after the procedure, but increased levels in the ITI group occurred only at 30 min (P  0.05). Scrotal temperature was higher at D1 in the SC group than for the other groups, but lowest at D4 compared to the control (both P castration through ITI of 20% NaCl in young calves was followed by slight stress and inflammatory responses compared to surgical castration. However, ITI of 30% NaCl was ineffective for chemical castration of 5 months old calves. Copyright © 2016 Elsevier Inc. All rights reserved.

Intratesticular hypertonic sodium chloride solution treatment as a method of chemical castration in cattle.

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Neto, Olmiro Andrade; Gasperin, Bernardo G; Rovani, Monique T; Ilha, Gustavo F; Nóbrega, Janduí E; Mondadori, Rafael G; Gonçalves, Paulo B D; Antoniazzi, Alfredo Q

2014-10-15

Castration of male calves is necessary for trading to facilitate handling and prevent reproduction. However, some methods of castration are traumatic and lead to economic losses because of infection and myiasis. The objective of the present study was to evaluate the efficiency of intratesticular injection (ITI) of hypertonic sodium chloride (NaCl; 20%) solution in male calf castration during the first weeks of life. Forty male calves were allocated to one of the following experimental groups: negative control-surgically castrated immediately after birth; positive control -intact males; G1-ITI from 1- to 5-day old; G2-ITI from 15- to 20-day old; and G3-ITI from 25- to 30-day old. Intratesticular injection induced coagulative necrosis of Leydig cells and seminiferous tubules leading to extensive fibrosis. Testosterone secretion and testicular development were severely impaired in 12-month-old animals from G1 and G2 groups (P<0.05), in which no testicular structure and sperm cells were observed during breeding soundness evaluation. Rectal and scrotal temperatures were not affected by different procedures. In conclusion, ITI of hypertonic NaCl solution induces sterility and completely suppresses testosterone secretion when performed during the first 20 days of life. Copyright © 2014 Elsevier Inc. All rights reserved.

Empirical support for optimal virulence in a castrating parasite.

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Knut Helge Jensen

2006-07-01

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

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

African Journals Online (AJOL)

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2017-09-15

Sep 15, 2017 ... Abstract. Growing consumer awareness about animal welfare has led to the assessment of the impact of .... the incidence and associated effects of aggressive and sexual behaviour (Aasen, 2000). ... Motivation for castration.

Annotating MYC Status in Treatment-Resistant Metastatic Castration-Resistant Prostate Cancer With Gallium-68 Citrate PET

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2017-09-01

which avidly binds to circulating transferrin) labeled transferrin (Tf) can detect MYC-positive prostate cancer tumors, since the transferrin receptor ...Castration-Resistant Prostate Cancer with Androgen Receptor - Axis Imaging. Journal of nuclear medicine : official publication, Society of Nuclear...AWARD NUMBER: W81XWH-16-1-0469 TITLE: Annotating MYC Status in Treatment-Resistant Metastatic Castration- Resistant Prostate Cancer With

Influence of Multiple Infection and Relatedness on Virulence: Disease Dynamics in an Experimental Plant Population and Its Castrating Parasite

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

2014-01-01

The level of parasite virulence, i.e., the decrease in host's fitness due to a pathogen, is expected to depend on several parameters, such as the type of the disease (e.g., castrating or host-killing) and the prevalence of multiple infections. Although these parameters have been extensively studied theoretically, few empirical data are available to validate theoretical predictions. Using the anther smut castrating disease on Silene latifolia caused by Microbotryum lychnidis-dioicae, we studied the dynamics of multiple infections and of different components of virulence (host death, non-recovery and percentage of castrated stems) during the entire lifespan of the host in an experimental population. We monitored the number of fungal genotypes within plants and their relatedness across five years, using microsatellite markers, as well as the rates of recovery and host death in the population. The mean relatedness among genotypes within plants remained at a high level throughout the entire host lifespan despite the dynamics of the disease, with recurrent new infections. Recovery was lower for plants with multiple infections compared to plants infected by a single genotype. As expected for castrating parasites, M. lychnidis-dioicae did not increase host mortality. Mortality varied across years but was generally lower for plants that had been diseased the preceding year. This is one of the few studies to have empirically verified theoretical expectations for castrating parasites, and to show particularly i) that castrated hosts live longer, suggesting that parasites can redirect resources normally used in reproduction to increase host lifespan, lengthening their transmission phase, and ii) that multiple infections increase virulence, here in terms of non-recovery and host castration. PMID:24892951

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

Science.gov (United States)

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

2017-01-01

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

Effect of cortisol infusion patterns and castration on metabolic and immunological indices of stress response in cattle.

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Ting, S T L; Earley, B; Crowe, M A

2004-05-01

This study tested the hypotheses that: (1) either acute stress induced by Burdizzo castration, or cortisol infusion would modulate plasma glucose, insulin and growth hormone (GH) concentrations; and (2) immune modulation induced by cortisol would be dependent on the pattern, intensity and duration of circulating cortisol concentrations. Fifty 9.2-month-old Holstein x Friesian bulls (232 +/- 2.0 kg) were blocked by weight and randomly assigned to one of five treatments (n = 10 per treatment): (1) sham handled control; (2) Burdizzo castration; (3) hydrocortisone infusion to mimic the castration-induced secretion pattern of cortisol; (4) hourly pulse infusion of hydrocortisone; and (5) sustained infusion of hydrocortisone for 8h. Blood samples were collected intensively on day 0, and weekly from days 1 to 35. Castration acutely increased plasma cortisol, GH and haptoglobin concentrations, suppressed lymphocyte in vitro interferon-gamma (IFN-gamma) production, but had no effect on plasma glucose and insulin concentrations. Cortisol infusion to simulate the castration-induced secretion pattern of cortisol, and pulse infusion of cortisol did not suppress the IFN-gamma production. A sustained infusion of cortisol resulted in the transient suppression of IFN-gamma production. Moreover, the sustained cortisol infusion resulted in increased plasma glucose, insulin and GH concentrations. The overall 14-day feed intakes and 35-day growth rates were not affected by treatments. In conclusion, cortisol infusion to induce immune suppression in vivo occurred only at pharmacological doses. Within physiological ranges, cortisol was not associated with the suppression of immune function, indicating that during castration cortisol per se is not responsible for the suppression of in vitro IFN-gamma production.

Noninvasive assessment of autonomic activity for evaluation of pain in calves, using surgical castration as a model.

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Stewart, M; Verkerk, G A; Stafford, K J; Schaefer, A L; Webster, J R

2010-08-01

The role of the autonomic nervous system (ANS) in mediating eye temperature responses during painful procedures was examined in thirty 4-mo-old bull calves randomly assigned to 4 treatments: 1) sham handling control (C; n=8), 2) surgical castration (SC; n=6), 3) local anesthesia with sham handling (LAC; n=8), and 4) local anesthesia with surgical castration (LASC; n=8). Maximum eye temperature ( degrees C), measured by infrared thermography, heart rate (HR), and heart rate variability (HRV) were recorded continuously from 25 min before to 20 min after castration. The HRV was analyzed by examining segments of 512 interbeat intervals before and after treatments and comparing the root mean square of successive differences (RMSSD), high and low frequency (HF and LF, respectively) power, and the ratio of LF and HF powers (LF:HF). Jugular blood samples were analyzed for norepinephrine and epinephrine in C and SC treatments and for cortisol during all treatments. There was an immediate increase in HR following castration in SC (+15.3+/-2.8 beats/min) and LASC (+6.3+/-2.4 beats/min) calves. Eye temperature increased during the 20-min observation period in SC and LASC calves (+0.47+/-0.05 degrees C and +0.28+/-0.05 degrees C, respectively), and there was a small increase in C calves (+0.10+/-0.05 degrees C). Following castration in SC calves, there was an increase in RMSSD (+25.8+/-6.4) and HF power (+11.0+/-6.5) and LF:HF decreased (-2.1+/-0.7). Following castration in LASC, there was an increase in RMSSD (+18.1+/-4.9) and a decrease in LF power (-10.2+/-5.0). Cortisol increased above baseline within 15 min following treatment in both castrated groups, but was greater for SC calves (+18.4+/-2.3 ng/mL) than for LASC calves (+11.1+/-1.9 ng/mL). After castration, norepinephrine increased 3-fold and epinephrine increased by half in SC calves but not in C calves. There were no changes in HR, HRV, or cortisol responses to C or LAC treatments. Local anesthetic reduced, but did

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

African Journals Online (AJOL)

marbling, and fat thickness on the eye muscle between the three castrated groups. ... to compare the growth and development, feedlot performance and carcass .... is dependent upon the secretion of testosterone in the case of the bull. Thus ...

Effect of castration age on weight and size of some bones in Piemontese male cattle

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C. Lazzaroni

2010-04-01

Full Text Available Effect of pre- and post-pubertal castration on bone weight and measurements has been studied in 3 groups of Piemontese male cattle (EC - early castrated, LC - late castrated, IM - intact reared in the same environmental conditions and slaughtered at about 18 month of age, at about 550 kg of l.w., and at the same commercial fattening degree. At side commercial dissection all separated bones were weighted, and on the main ones (scapula, humerus, radius, femur, and tibia linear measures were recorded and then some conformation ratios were calculated (weight/length, length/width, and length/circumference. Data were analysed by GLM ANCOVA procedure, correcting data on side weight to avoid bias due to differences in carcass weight. No differences were found in side bone weight (23.58 ± 2.61 kg, so as in single bone weight, measures and ratios.

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

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

2017-04-01

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

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

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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

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

Science.gov (United States)

2017-09-01

Resistant Prostate Cancer PRINCIPAL INVESTIGATOR: Dolores Di Vizio, MD, PhD CONTRACTING ORGANIZATION: Cedars-Sinai Medical Center Los Angeles...Castration-Resistant Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-16-1-0397 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Dolores Di...biopsy” changing the landscape of precision medicine. 15. SUBJECT TERMS Metastatic Castration Resistant Prostate Cancer , Extracellular Vesicles

Effects of topical anaesthetic and buccal meloxicam on average daily gain, behaviour and inflammation of unweaned beef calves following surgical castration.

Science.gov (United States)

Van der Saag, D; Lomax, S; Windsor, P A; Taylor, C; Thomson, P; Hall, E; White, P J

2018-02-26

Although the pain caused by castration of calves is a significant animal welfare issue for the beef industry, analgesia is not always used for this procedure, largely because of practical limitations associated with injectable forms of pain relief. Novel analgesic formulations have now been developed for livestock to allow topical and buccal administration, offering practical options to improve cattle welfare if shown to be effective. To assess the effects of topical anaesthetic (TA) and buccal meloxicam (BM) on average daily gain (ADG), behaviour and inflammation following surgical castration of beef calves, a total of 50 unweaned bull calves were randomly allocated to: (1) sham castration (SHAM, n=10); (2) surgical castration (C, n=10); (3) surgical castration with pre-operative buccal meloxicam (CBM, n=10); (4) surgical castration with post-operative topical anaesthetic (CTA, n=10); and (5) surgical castration with pre-operative buccal meloxicam and post-operative topical anaesthetic (CBMTA, n=10). Calves were recorded on video for 5 h following treatment and the frequency and duration of specific behaviours displayed by each animal was later observed for 5 min every hour (total of 25 min). Average daily gain was calculated 1, 2 and 6 days following treatment. Scrotal diameter measurements and photographs of wounds were collected from all castrated calves 1, 2 and 6 days following treatment to evaluate inflammation and wound healing. Infrared photographs were used to identify maximum scrotal temperature. Digital photographs were used to visually score wounds on a numerical rating scale of 1 to 5, with signs of inflammation increasing and signs of healing decreasing with progressive scores. Sham castration calves displayed significantly less, and C calves displayed significantly more foot stamps than all other calves (P=0.005). Observations on the duration of time that calves displayed a hypometric 'stiff gait' locomotion, indicated that SHAM calves tended to

Performance and nutritional evaluation of beef cattle raised on pasture, castrated at different ages, with and without supplementation

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Anilza Andréia da Rocha

2012-04-01

Full Text Available The objective of this study was to evaluate performance and nutritional traits of beef cattle raised on pastures, castrated at different ages, with and without supplementation. Forty-four crossbred young bulls with predominance of Zebu breed at initial average age of 120±30 days were used in the experiment. Animals were distributed in a completely randomized design in a factorial arrangement with four ages of castration and two supplementation systems. The animals were distributed into four groups and placed on Brachiaria decumbens Stapf pastures, where they were fed concentrate supplementation or mineral salt ad libtum (control. Animals were castrated at 120, 240 and 360 days of age with average body weight of 115, 175 and 276 kg, castrated or not, in each supplementation group. Concentrate supplement composition and the amount supplied to the animals varied according to the time of the year and development phase of the animals. Trials were carried out to evaluate nutritional variables in each of the following phases: suckling, growth in the dry season and growth in the dry/rainy transition season. Concentrate supplementation improved the use of pasture, although it may have caused substitutive effect in all seasons evaluated. Castration of the animals before the dry season impaired animal development until the following dry/rainy transition season, especially when carried out during weaning. Concentrate supply may reduce some effects of this stress.

Development of Castration Resistant Prostate Cancer can be Predicted by a DNA Hypermethylation Profile.

Science.gov (United States)

Angulo, Javier C; Andrés, Guillermo; Ashour, Nadia; Sánchez-Chapado, Manuel; López, Jose I; Ropero, Santiago

2016-03-01

Detection of DNA hypermethylation has emerged as a novel molecular biomarker for prostate cancer diagnosis and evaluation of prognosis. We sought to define whether a hypermethylation profile of patients with prostate cancer on androgen deprivation would predict castrate resistant prostate cancer. Genome-wide methylation analysis was performed using a methylation cancer panel in 10 normal prostates and 45 tumor samples from patients placed on androgen deprivation who were followed until castrate resistant disease developed. Castrate resistant disease was defined according to EAU (European Association of Urology) guideline criteria. Two pathologists reviewed the Gleason score, Ki-67 index and neuroendocrine differentiation. Hierarchical clustering analysis was performed and relationships with outcome were investigated by Cox regression and log rank analysis. We found 61 genes that were significantly hypermethylated in greater than 20% of tumors analyzed. Three clusters of patients were characterized by a DNA methylation profile, including 1 at risk for earlier castrate resistant disease (log rank p = 0.019) and specific mortality (log rank p = 0.002). Hypermethylation of ETV1 (HR 3.75) and ZNF215 (HR 2.89) predicted disease progression despite androgen deprivation. Hypermethylation of IRAK3 (HR 13.72), ZNF215 (HR 4.81) and SEPT9 (HR 7.64) were independent markers of prognosis. Prostate specific antigen greater than 25 ng/ml, Gleason pattern 5, Ki-67 index greater than 12% and metastasis at diagnosis also predicted a negative response to androgen deprivation. Study limitations included the retrospective design and limited number of cases. Epigenetic silencing of the mentioned genes could be novel molecular markers for the prognosis of advanced prostate cancer. It might predict castrate resistance during hormone deprivation and, thus, disease specific mortality. Gene hypermethylation is associated with disease progression in patients who receive hormone therapy. It

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

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Rosenberg JE

2012-01-01

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

Attenuation of acute plasma cortisol response in calves following intravenous sodium salicylate administration prior to castration.

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Coetzee, J F; Gehring, R; Bettenhausen, A C; Lubbers, B V; Toerber, S E; Thomson, D U; Kukanich, B; Apley, M D

2007-08-01

Pain associated with castration in cattle is an animal welfare concern in beef production. This study examined the effect of oral aspirin and intravenous (i.v.) sodium salicylate on acute plasma cortisol response following surgical castration. Twenty bulls, randomly assigned to the following groups, (i) uncastrated, untreated controls, (ii) castrated, untreated controls, (iii) 50 mg/kg sodium salicylate i.v. precastration and (iv) 50 mg/kg aspirin (acetylsalicylic acid) per os precastration, were blood sampled at 3, 10, 20, 30, 40, 50 min and 1, 1.5, 2, 4, 6, 8, 10 and 12 h postcastration. Samples were analyzed by competitive chemiluminescent immunoassay and fluorescence polarization immunoassay for cortisol and salicylate, respectively. Data were analyzed using noncompartmental analysis, a simple cosine model, anova and t-tests. Intravenous salicylate V(d(ss)) was 0.18 L/kg, Cl(B) was 3.36 mL/min/kg and t(1/2 lambda) was 0.63 h. Plasma salicylate concentrations above 25 microg/mL coincided with significant attenuation in peak cortisol concentrations (P = 0.029). Peak salicylate concentrations following oral aspirin administration was castrated groups was significantly higher than uncastrated controls (P = 0.018). These findings have implications for designing drug regimens to provide analgesia during routine animal husbandry procedures.

Stress responses in lambs castrated with three different methods

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Paola Sandra Nicolussi

2010-01-01

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

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

African Journals Online (AJOL)

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

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

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

2012-01-01

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

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

African Journals Online (AJOL)

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

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

Science.gov (United States)

2017-12-01

Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER... receptor (AR) targeted therapies, prostate cancer adapts. One way it adapts is by upregulating another hormone receptor , the glucocorticoid receptor (GR...trial. 15. SUBJECT TERMS Castration resistant prostate cancer (CRPC); Androgen Receptor (AR); Glucocorticoid receptor (GR); Enzalutamide;

Docetaxel, Carboplatin, and Rucaparib Camsylate in Treating Patients With Metastatic Castration Resistant Prostate Cancer With Homologous Recombination DNA Repair Deficiency

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2018-02-20

ATM Gene Mutation; BRCA1 Gene Mutation; BRCA2 Gene Mutation; Castration Levels of Testosterone; Castration-Resistant Prostate Carcinoma; Homologous Recombination Deficiency; Prostate Carcinoma Metastatic in the Bone; PSA Level Greater Than or Equal to Two; PSA Progression; Stage IV Prostate Adenocarcinoma AJCC v7

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

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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.

The effects of castration on the growth parameters, carcass yield and meat chemical composition of intensively reared Common Pheasant (Phasianus colchicus colchicus L.

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Renata Baric-Rafaj

2010-01-01

Full Text Available The effects of castration on growth performance, carcass characteristics and chemical composition of m. iliotibilais cranialis and m. pectoralis superficialis of pheasants were examined. Forty pheasants reared in commercial pheasantry were included in the experiment. Half of the pheasants were castrated at 8 weeks of age. Values for live weight tended to be higher in castrated pheasants in the 24th week (P<0.1 and values for weight gain were significantly higher between the 16th and 24th weeks (P<0.05. Feed-to-gainratio (8th – 32nd week was significantly better (P<0.05 in castrated pheasants. Eviscerated weight and dressing percentage at 32nd week were not significantly different between treatments. The chemical composition of m. iliotibilais cranialis and m. pectoralis superficialis showed significantly higher values of fat (P<0.01 and moisture (P<0.05 in castrated pheasants in comparison with intact ones. Protein content of both muscles was higher in intact pheasants (P<0.05. Body part weights were not influenced by the treatment with the exception of heart weight, which was significantly higher in the intact pheasants (P<0.05. We concluded that castration tended to improve growth performance only in the first 24 weeks of the fattening period and, therefore, continuation of fattening after that period is no longer feasible. The most important characteristic of the castrated pheasant’s meat was an increased amount of fat. More studies under different feeding and alternative breeding systems are necessary to improve production.

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

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Matthew A Ingersoll

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

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

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

2015-01-01

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

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

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Leclercq, Caroline; Prunier, Armelle; Merlot, Elodie

2014-01-01

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

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

Spontaneous electroencephalographic changes in a castration model as an indicator of nociception: a comparison between donkeys and ponies.

Science.gov (United States)

Grint, N J; Johnson, C B; Clutton, R E; Whay, H R; Murrell, J C

2015-01-01

Donkeys are believed to be less demonstrative of pain than ponies. Research into comparative sensory processing between these species is required to elucidate these behavioural differences. To compare changes in the electroencephalogram (EEG) recorded during castration between donkeys and ponies. Prospective clinical study. Six ponies and 6 donkeys were castrated under halothane anaesthesia after acepromazine premedication and thiopental anaesthetic induction. Markers were inserted into the EEG recording at the time of skin incision (skin) and emasculation (emasc) for both testicles (T1 and T2) during a closed castration. Raw EEG data were analysed and the EEG variables median frequency (F50 ), total power (Ptot ) and spectral edge frequency (F95 ) derived using standard techniques. Baseline values of F50 , Ptot and F95 for each animal were used to calculate the percentage change from baseline at T1skin, T2skin, T1emasc and T2emasc. Decreased F50 values relative to baseline were observed in 4 ponies and 2 donkeys across all castration time points. In the remaining animals, the F50 value increased compared with baseline. Both donkey and pony groups showed an overall decrease in Ptot values compared with baseline at T1skin, but the magnitude of the decrease was significantly less (P = 0.004) in ponies than in donkeys. Donkeys demonstrated an overall greater increase (P = 0.05) in F95 values at T1skin relative to baseline compared with ponies. Electroencephalographic responses to the noxious stimulus of castration were noted in both donkeys and ponies. Donkeys demonstrated a greater change in Ptot in response to castration than ponies; thus, donkeys appear to demonstrate a cerebral cortical response to a noxious stimulus that is similar to or greater than that in ponies, suggesting that their subtle behavioural expression of pain is not due to a difference in cortical processing of noxious sensory stimuli. © 2014 EVJ Ltd.

Castration-resistant prostate cancer: AUA Guideline.

Science.gov (United States)

Cookson, Michael S; Roth, Bruce J; Dahm, Philipp; Engstrom, Christine; Freedland, Stephen J; Hussain, Maha; Lin, Daniel W; Lowrance, William T; Murad, Mohammad Hassan; Oh, William K; Penson, David F; Kibel, Adam S

2013-08-01

This Guideline is intended to provide a rational basis for the management of patients with castration-resistant prostate cancer based on currently available published data. A systematic review and meta-analysis of the published literature was conducted using controlled vocabulary supplemented with keywords relating to the relevant concepts of prostate cancer and castration resistance. The search strategy was developed and executed by reference librarians and methodologists to create an evidence report limited to English-language, published peer-reviewed literature. This review yielded 303 articles published from 1996 through 2013 that were used to form a majority of the guideline statements. Clinical Principles and Expert Opinions were used for guideline statements lacking sufficient evidence-based data. Guideline statements were created to inform clinicians on the appropriate use of observation, androgen-deprivation and antiandrogen therapy, androgen synthesis inhibitors, immunotherapy, radionuclide therapy, systemic chemotherapy, palliative care and bone health. These were based on six index patients developed to represent the most common scenarios encountered in clinical practice. As a direct result of the significant increase in FDA-approved therapeutic agents for use in patients with metastatic CRPC, clinicians are challenged with a multitude of treatment options and potential sequencing of these agents that, consequently, make clinical decision-making more complex. Given the rapidly evolving nature of this field, this guideline should be used in conjunction with recent systematic literature reviews and an understanding of the individual patient's treatment goals. In all cases, patients' preferences and personal goals should be considered when choosing management strategies. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Decision Making for Cryptorchid Castration; a Retrospective Analysis of 280 Cases

NARCIS (Netherlands)

Huppes, Tsjester; Stout, Tom A.E.; Ensink, Jos M.

Abstract The location of an undescended testicle influences the choice of surgical technique for efficient cryptorchid castration. We review a standardized protocol for preoperative examination to dictate surgical approach to cryptorchidism. Cases are split into two periods: 2004–2006 and 2007–2014.

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

International Nuclear Information System (INIS)

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

1986-01-01

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

A survey of castration methods and associated livestock management practices performed by bovine veterinarians in the United States

OpenAIRE

Bradburn Ryan M; Barbur Laura A; Nutsch Abbey L; Coetzee Johann F

2010-01-01

Abstract Background Castration of male calves destined for beef production is a common management practice performed in the United States amounting to approximately 15 million procedures per year. Societal concern about the moral and ethical treatment of animals is increasing. Therefore, production agriculture is faced with the challenge of formulating animal welfare policies relating to routine management practices such as castration. To enable the livestock industry to effectively respond t...

Desempenho produtivo, características de carcaça e avaliação econômica de bovinos cruzados, castrados e não-castrados, terminados em pastagens de Brachiaria decumbens Productive performance, carcass characteristics and economic evaluation of castrated and non-castrated crossbred bovines finished in Brachiaria decumbens pastures

Directory of Open Access Journals (Sweden)

L.C.V. Ítavo

2008-10-01

Full Text Available Avaliou-se o efeito da castração sobre o desempenho produtivo e sobre as características de carcaça e realizou-se a avaliação econômica de bovinos terminados em pastagens de Brachiaria decumbens. Foram utilizados oito novilhos Canchim-Nelore com 14 meses de idade, sendo quatro animais castrados e quatro não-castrados, com média de peso corporal de 273,2kg. O delineamento foi inteiramente ao acaso com quatro repetições por tratamento. Os animais receberam, diariamente, 0,7% do PC de suplemento proteíco-energético e foram abatidos aos 26 meses de idade. O peso de abate e o ganho médio diário (GMD diferiram entre castrados e não-castrados, com médias de 441,0 e 482,2kg e 0,6 e 0,7kg/dia, respectivamente. Não houve efeito da castração sobre as características avaliadas, com exceção do peso de abate, do peso da carcaça quente, 252,3 versus 229,9kg, da cor da carne, 3,25 versus 4,50 pontos e da espessura da gordura subcutânea, 0,6 versus 1,4mm, respectivamente, para não-castrados e castrados. A lucratividade por animal e por hectare foi de 14,5 e 15,8% para não-castrados e 4,5 e 5,8% para castrados, respectivamente. Sugere-se a utilização de bovinos não-castrados suplementados em pastagens de Brachiaria decumbens.The effect of the castration on the productive performance and carcass characteristics was studied, as well as, the economic evaluation of finished bovines raised on Brachiaria decumbens pastures. Eight Canchim-Nellore steers aging 14-months-old were used, being four castrated and four non-castrated, averaging 273.2kg body weight. It was used a completely randomized design with four repetitions per treatment. The animals received 0.7% of their body weight of proteic-energetic supplement and were slaughtered at 26 months of age. The weight at slaughtering and the average daily weight gain differed between castrated and non-castrated, averaging 441.0 and 482.2kg, and 0.6 and 0.7kg/day, respectively. No effects of

Behavior and handling of physically and immunologically castrated market pigs on farm and going to market.

Science.gov (United States)

Guay, K; Salgado, G; Thompson, G; Backus, B; Sapkota, A; Chaya, W; McGlone, J J

2013-11-01

Physical castration is a common management practice on commercial swine farms in the United States to reduce the incidence of boar taint and aggressive behavior. One alternative to physical castration (PC) is to immunologically castrate (IC) male pigs by blocking the gonadotropin-releasing factor (GnRF), thereby reducing levels of LH, FSH, testosterone, and androstenone. The objectives of this study were to evaluate the effects of IC on pig behavior, human-pig interactions, and handling during and after transport. Pigs were given the first immunization at wk 7 of the grower-finisher period, and second immunizations were given at wk 11, 13, or 14 of the grower-finisher period. Behaviors of PC and IC barrows were sampled at 3 time points after entering finishing at 9 wk of age: 7 wk before first injection, 16 wk (after immunization was complete) into finishing, and 1 d before marketing (16 to 19 wk into finishing). Handling during loading and unloading of trailers going to market was also quantified. Before the first injection, intact males showed increased aggression (P=0.014) and mounting (P=0.048), whereas PC barrows spent more (P=0.003) time feeding than intact males. There were treatment×time interactions for lying (P=0.018), aggression (P<0.001), and standing (P=0.009) behaviors. Few differences were observed in pig-human interactions between PC and IC barrows, with IC and PC approaching people in the same amount of time, but IC barrows were more (P<0.001) aggressive in chewing and rubbing on the test person's pant leg and boots. When handling and loading for processing in the home barn, PC barrows were more (P<0.05) vocal than IC barrows. Fewer dead and down pigs were observed among IC (0%) compared with PC barrows (1.17%). Immunological castration may result in similar or improved animal welfare compared to the stress of physical castration without pain relief.

the effect of castration and plane of nutrition on growth and carcass ...

African Journals Online (AJOL)

controlling precisely the conditions of the experiments because of the ... large numbers at low cost. Further, they ... that castratic,n of male rats leads to a reduction in growth, ..... Effects of hormones on rat muscle protein synthesis in vitro. Fed.

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

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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.

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

NARCIS (Netherlands)

Klep, L.M.F.

2008-01-01

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

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

Directory of Open Access Journals (Sweden)

Jae-Kyung Myung

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

Optimum Drug Combinations for the Sedation of Growing Boars Prior to Castration

Science.gov (United States)

Lehmann, Heidi S.; Blache, Dominique; Drynan, Eleanor; Tshewang, Pema; Blignaut, David J. C.; Musk, Gabrielle C.

2017-01-01

Simple Summary Pigs are notoriously challenging patients. They are difficult to handle so the use of predictable and safe sedation techniques is required for husbandry and surgical procedures. Various combinations of sedative and analgesic drugs have been previously investigated in this species, though the combination of midazolam and detomidine with either butorphanol or morphine has not been reported for sedation in pigs. The use of these combinations was investigated in the context of adequate sedation to allow castration of boars with the aid of local anaesthetic infiltration. The combination of midazolam, detomidine with butorphanol provided a more reliable sedation combination than that including morphine. It is proposed that this combination of drugs would be useful for sedation during painful husbandry procedures in pigs. Abstract Juvenile male pigs were sedated for castration. Eight five-month old boars were sedated twice (two weeks apart) with a combination of detomidine (0.1 mg/kg), midazolam (0.2 mg/kg) and either butorphanol (0.2 mg/kg) (Group MDB, n = 8) or morphine (0.2 mg/kg) (Group MDM, n = 8) intramuscularly. The boars were positioned in lateral recumbency and lidocaine (200 mg total) was injected into the testicle and scrotal skin. Castration of a single testicle was performed on two occasions. Sedation and reaction (to positioning and surgery) scores, pulse rate, respiratory rate, haemoglobin oxygen saturation, body temperature, arterial blood gas parameters and the times to immobility and then recovery were recorded. Atipamezole was administered if spontaneous recovery was not evident within 60 min of sedative administration. Data were compared with either a paired-sample t-test or a Wilcoxon-Signed Rank Test. There was no difference in sedation score, body temperature, respiratory rate and haemoglobin oxygen saturation between MDB and MDM. Mild hypoxaemia was noted in both groups. There was less reaction to castration after MDB. The pulse rate

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

, development of sustained side-effects, or abiraterone acetate becoming available in the respective country. The primary outcome was the number of adverse events arising during study treatment and within 30 days of discontinuation. Efficacy measures (time to prostate-specific antigen [PSA] progression and time......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...

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

Castration in breast cancer. Surgery or radiation

International Nuclear Information System (INIS)

Hernandez Munoz, G.

1977-01-01

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

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

Directory of Open Access Journals (Sweden)

Liang Y

2016-05-01

Full Text Available Yayun Liang,1 Benford Mafuvadze,1 Johannes D Aebi,2 Salman M Hyder1 1Dalton Cardiovascular Research Center and Department of Biomedical Sciences, University of Missouri-Columbia, Columbia, MO, USA; 2Medicinal Chemistry, Roche Pharma Research and Early Development (pRED, Roche Innovation Center Basel, F Hoffmann-La Roche Ltd., Basel, Switzerland Abstract: Standard treatment for primary prostate cancer includes systemic exposure to chemotherapeutic drugs that target androgen receptor or antihormone therapy (chemical castration; however, drug-resistant cancer cells generally emerge during treatment, limiting the continued use of systemic chemotherapy. Patients are then treated with more toxic standard therapies. Therefore, there is an urgent need for novel and more effective treatments for prostate cancer. The cholesterol biosynthetic pathway is an attractive therapeutic target for treating endocrine-dependent cancers because cholesterol is an essential structural and functional component of cell membranes as well as the metabolic precursor of endogenous steroid hormones. In this study, we have examined the effects of RO 48-8071 (4'-[6-(allylmethylaminohexyloxy]-4-bromo-2'-fluorobenzophenone fumarate; Roche Pharmaceuticals internal reference: RO0488071 (RO, which is an inhibitor of 2, 3-oxidosqualene cyclase (a key enzyme in the cholesterol biosynthetic pathway, on prostate cancer cells. Exposure of both hormone-dependent and castration-resistant human prostate cancer cells to RO reduced prostate cancer cell viability and induced apoptosis in vitro. RO treatment reduced androgen receptor protein expression in hormone-dependent prostate cancer cells and increased estrogen receptor β (ERβ protein expression in both hormone-dependent and castration-resistant prostate cancer cell lines. Combining RO with an ERβ agonist increased its ability to reduce castration-resistant prostate cancer cell viability. In addition, RO effectively suppressed the

A systematic review of methods for quantifying serum testosterone in patients with prostate cancer who underwent castration.

Science.gov (United States)

Comas, I; Ferrer, R; Planas, J; Celma, A; Regis, L; Morote, J

2018-03-01

The clinical practice guidelines recommend measuring serum testosterone in patients with prostate cancer (PC) who undergo castration. The serum testosterone concentration should be IA) has become widespread, although their metrological characteristics do not seem appropriate for quantifying low testosterone concentrations. The objective of this review is to analyse the methods for quantifying testosterone and to establish whether there is scientific evidence that justifies measuring it in patients with PC who undergo castration, through liquid chromatography attached to a mass spectrometry in tandem (LC-MSMS). We performed a search in PubMed with the following MeSH terms: measurement, testosterone, androgen suppression and prostate cancer. We selected 12 studies that compared the metrological characteristics of various methods for quantifying serum testosterone compared with MS detection methods. IAs are standard tools for measuring testosterone levels; however, there is evidence that IAs lack accuracy and precision for quantifying low concentrations. Most chemiluminescent IAs overestimate their concentration, especially below 100ng/dL. The procedures that use LC-MSMS have an adequate lower quantification limit and proper accuracy and precision. We found no specific evidence in patients with PC who underwent castration. LC-MSMS is the appropriate method for quantifying low serum testosterone concentrations. We need to define the level of castration with this method and the optimal level related to better progression of the disease. Copyright © 2017 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

Erotic Imagery and Self-Castration in Transvestism/Transsexualism: A Case Report

Science.gov (United States)

van Kammen, Daniel P.; Money, John

1977-01-01

After nearly 30 years of marriage, a 51-year-old man castrated himself to fulfill a long-standing fantasy of being a girl. It led the patient to elect low-dose maintenance on androgen to permit some degree of continued marital sex. The rehabilitative program as a transvestite man has continued for three years. (Author)

Effect of subcutaneous Meloxicam on indicators of acute pain and distress after castration and branding in 2 mo old beef calves.

Science.gov (United States)

Meléndez, D M; Marti, S; Pajor, E A; Moya, D; Gellatly, D; Janzen, E D; Schwartzkopf-Genswein, K S

2018-06-15

The aim of this study was to assess knife castration and knife castration + branding in 2-mo old calves, and the effect of a single dose of s.c. meloxicam at mitigating pain indicators. Seventy-one Angus crossbred bull calves (128 ± 18.5 kg of BW) were used in a 3 × 2 factorial design where main factors included procedure: sham (control calves, CT; n = 23), knife (KN; n = 24) or knife + branding (BK; n = 24) and medication: single s.c. administration of lactated ringer solution (NM; n = 35) or a single dose of 0.5 mg/kg of s.c. meloxicam (M; n = 36). Physiological samples were collected at T0, 60, 90, 120 and 180 min and on d 1, 2, 3 and 7 after procedure, while behavioral observations were evaluated at 2 to 4 h and 1, 2, 3 and 7 days after procedure. A procedure × time effect (P 0.10) were observed for salivary cortisol, substance P and scrotal temperature min after the procedure or for cortisol, substance P, serum amyloid A, stride length or behavioral observations on d after the procedure. Overall, BK calves presented greater physiological and behavioral indicators of acute pain than KN calves, suggesting that the combination of knife castration + branding was more painful. Meloxicam administered s.c. was effective at reducing physiological and behavioral indicators of acute pain associated with knife castration and knife castration + branding.

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

NARCIS (Netherlands)

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

2012-01-01

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

Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer.

Science.gov (United States)

Fizazi, Karim; Tran, NamPhuong; Fein, Luis; Matsubara, Nobuaki; Rodriguez-Antolin, Alfredo; Alekseev, Boris Y; Özgüroğlu, Mustafa; Ye, Dingwei; Feyerabend, Susan; Protheroe, Andrew; De Porre, Peter; Kheoh, Thian; Park, Youn C; Todd, Mary B; Chi, Kim N

2017-07-27

Abiraterone acetate, a drug that blocks endogenous androgen synthesis, plus prednisone is indicated for metastatic castration-resistant prostate cancer. We evaluated the clinical benefit of abiraterone acetate plus prednisone with androgen-deprivation therapy in patients with newly diagnosed, metastatic, castration-sensitive prostate cancer. In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 1199 patients to receive either androgen-deprivation therapy plus abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus dual placebos (the placebo group). The two primary end points were overall survival and radiographic progression-free survival. After a median follow-up of 30.4 months at a planned interim analysis (after 406 patients had died), the median overall survival was significantly longer in the abiraterone group than in the placebo group (not reached vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to 0.76; P<0.001). The median length of radiographic progression-free survival was 33.0 months in the abiraterone group and 14.8 months in the placebo group (hazard ratio for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly better outcomes in all secondary end points were observed in the abiraterone group, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate-specific antigen progression (P<0.001 for all comparisons), along with next symptomatic skeletal events (P=0.009). These findings led to the unanimous recommendation by the independent data and safety monitoring committee that the trial be unblinded and crossover be allowed for patients in the placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia were higher in the abiraterone group. The addition of abiraterone

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

International Nuclear Information System (INIS)

Marencak, J.

2014-01-01

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

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...

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

Directory of Open Access Journals (Sweden)

D. Biagini

2010-04-01

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

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

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

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

2018-03-01

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

Daily and seasonal variations of serum testosterone levels in bulls after chemical or surgical castration

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Feher, T.; Bodrogi, L. (Semmelweis Orvostudomanyi Egyetem, Budapest (Hungary). 1. Belklinika); Makray, S. (Mezoegazdasagi Foeiskola, Kaposvar (Hungary))

1985-01-01

The dynamics of serum testosterone levels were studied by a radio-immunological assay (RIA) in 7-9 months old Holstein-Friesian bulls. Significant correlation was found between the hormone level and age (rather than body mass) of adult animals. The daily dynamics of hormone level varied to a large extent indicating that only several and repeated hormonal investigations allowed the evaluation of hormonal state and sexual function in bulls. The serum testosterone lewel was the highest in October and the lowest in April; the seasonal differences were not significant. The hormone level of blood was minimal already 24 hours after the surgical castration. Chemical castration (tannic acid-ZnSOsub(4) injection into both testes) resulted in a slower and more moderate decrease of the hormone concentration.

Daily and seasonal variations of serum testosterone levels in bulls after chemical or surgical castration

International Nuclear Information System (INIS)

Feher, Tibor; Bodrogi, Lajos

1985-01-01

The dynamics of serum testosterone levels were studied by a radio-immunological assay (RIA) in 7-9 months old Holstein-Friesian bulls. Significant correlation was found between the hormone level and age (rather than body mass) of adult animals. The daily dynamics of hormone level varied to a large extent indicating that only several and repeated hormonal investigations allowed the evaluation of hormonal state and sexual function in bulls. The serum testosterone lewel was the highest in October and the lowest in April; the seasonal differences were not significant. The hormon level of blood was minimal already 24 hours after the surgical castration. Chemical castration (tannic acid-ZnSOsub(4) injection into both testes) resulted in a slower and more moderate decrease of the hormone concentration. (author)

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

Science.gov (United States)

Sakata, J T; Crews, D

2004-08-01

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

Overview of treatment of castration-resistant prostate cancer

International Nuclear Information System (INIS)

Obertova, J.

2012-01-01

Prostatic cancer is a very heterogenic disease. Initial treatment of metastatic disease is androgen deprivation therapy, however upon the time eventually all cases develop castrate resistant disease (CRCP). In CRPC the combination of docetaxel with prednisone is considered to be the gold standard first line therapy with prolongation of overall survival. Until recently there was not standardly defined second line treatment. According to the international guidelines of today cabazitaxel and abirateron is recommended as second line therapy. The objective of this article is to present a review of the therapy of CRPC upon results from randomised phase III clinical trials. (author)

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

DEFF Research Database (Denmark)

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

2017-01-01

Castration resistant prostate cancer (CRPC) is a stage of relapse that arises after various forms of androgen ablation therapy (ADT) and causes significant morbidity and mortality. However, the mechanism underlying progression to CRPC remains poorly understood. Here, we report that YAP1, which...... is negatively regulated by AR, influences prostate cancer (PCa) cell self-renewal and CRPC development. Specifically, we found that AR directly regulates the methylation of YAP1 gene promoter via the formation of a complex with Polycomb group protein EZH2 and DNMT3a. In normal conditions, AR recruits EZH2......-differentiation of PCa cells to stem/progenitor-like cells (PCSC), which potentially contribute to disease recurrence. Finally, the knock down of YAP1 expression or the inhibition of YAP1 function by Verteporfin in TRAMP prostate cancer mice significantly suppresses tumor recurrence following castration. In conclusion...

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.

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

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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.

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

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John McGlone

2016-08-01

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

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

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O’Connor Erin K

2012-05-01

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

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

Science.gov (United States)

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

2017-10-11

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

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 ( 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 quality similar to PC barrows and gilts.

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

International Nuclear Information System (INIS)

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

1990-01-01

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

Casodex (bicalutamide) 150-mg monotherapy compared with castration in patients with previously untreated nonmetastatic prostate cancer

DEFF Research Database (Denmark)

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

1998-01-01

To compare the efficacy, tolerability, and quality of life benefits of bicalutamide (Casodex) 150-mg/day monotherapy and castration in previously untreated nonmetastatic (M0) advanced prostate cancer....

Carcaça de borregos Ile de France inteiros ou castrados e Hampshire down castrados abatidos aos doze meses de idade Carcass of intact or castrated Ile de France and castrated Hampshire down lambs slaughtered at twelve months of age

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Edson Luis de Azambuja Ribeiro

2001-06-01

Full Text Available Um total de 24 borregos, sendo oito Ile de France inteiros, oito Ile de France castrados e oito Hampshire Down castrados, foram utilizados com o objetivo de avaliar características qualitativas e quantitativas da carcaça. Os animais foram mantidos exclusivamente em pastagem de grama Coast-Cross, sendo abatidos aos 12 meses de idade. As carcaças provenientes de animais inteiros da raça Ile de France apresentaram significativamente maior percentagem de pescoço do que as de animais castrados da mesma raça, sendo essa a única diferença encontrada entre esses dois grupos. Porém, foram observadas diferenças na composição tecidual da paleta entre as raças, sendo que os animais da raça Ile de France (inteiros ou castrados apresentaram maior percentual de músculo e maior relação músculo/osso do que os animais da raça Hampshire Down. Os resultados indicam que, por não haver diferenças importantes entre carcaças e carnes de animais inteiros e castrados abatidos aos 12 meses de idade, o uso da castração pode ser dispensado em sistemas intensivos de produção de carne ovinaA total of 24 lambs, eight intact Ile de France, eight castrated Ile de France and eight castrated Hampshire Down, were used in this experiment with the main objective of evaluating quantitative and qualitative carcass traits. The animals were raised on a Coast-Cross pasture and slaughtered at 12 months of age. Carcasses from intact Ile de France lambs had significantly more neck than carcasses from castrated Ile de France lambs. No other differences were observed between carcasses from intact or castrated Ile de France. However, differences between breeds were observed for tissue composition of the shoulder. Shoulders from Ile de France carcasses (intact or castrated presented greater percentage of muscles and greater relation of muscles/bones than shoulders from Hampshire Down lambs. Results indicate that intact males can be recommended for sheep meat production

Effect of ketoprofen, lidocaine local anesthesia, and combined xylazine and lidocaine caudal epidural anesthesia during castration of beef cattle on stress responses, immunity, growth, and behavior.

Science.gov (United States)

Ting, S T L; Earley, B; Hughes, J M L; Crowe, M A

2003-05-01

To determine the effects of burdizzo castration alone or in combination with ketoprofen (K), local anesthesia (LA), or caudal epidural anesthesia (EPI) on plasma cortisol, acute-phase proteins, interferon-gamma production, growth, and behavior of beef cattle, 50 Holstein x Friesian bulls (13 mo old, 307 +/- 5.3 kg) were assigned to (n = 10/treatment): 1) control (handled; C); 2) burdizzo castration (B); 3) B following K (3 mg/ kg of BW i.v.; BK); 4) B following LA (8 mL into each testis and 3 mL s.c. along the line where the jaws of the burdizzo were applied with 2% lidocaine HCl; BLA); and 5) B following EPI (0.05 mg/kg of BW of xylazine HCl and 0.4 mg/kg of BW of lidocaine HCl as caudal epidural; BEPI). The area under the cortisol curve against time was lower (P castration groups than in C. On d 7, haptoglobin and fibrinogen concentrations remained higher (P castration increased plasma cortisol and acute-phase proteins, and suppressed immune function and growth rates. Local anesthesia prolonged the increase in acute-phase proteins. Ketoprofen was more effective than LA or EPI in decreasing cortisol and partially reversed the reduction in ADG following castration. The use of K or EPI was more effective than LA in decreasing pain-associated behavioral responses observed during the first 6 h after treatment. Systemic analgesia with ketoprofen, a non-steroidal antiinflammatory drug, was more effective in reducing inflammatory responses associated with castration than LA or EPI.

Src controls castration recurrence of CWR22 prostate cancer xenografts

International Nuclear Information System (INIS)

Su, Bing; Gillard, Bryan; Gao, Lingqiu; Eng, Kevin H; Gelman, Irwin H

2013-01-01

Recurrence of prostate cancer (CaP) after androgen-deprivation therapy continues to have the greatest impact on patient survival. Castration-recurrent (CR)-CaP is likely driven by the activation of androgen receptor (AR) through multiple mechanisms including induction of AR coregulators, AR mutants or splice variants, and AR posttranslational modification such as phosphorylation by Src-family and Ack1 tyrosine kinases. Here, we address whether Src is required for the CR growth of human CWR22 CaP xenografts. The shRNA-mediated Src knockdown or treatment with the Src inhibitors, dasatinib or KXO1, reduced CaP recurrence over controls and increased time-to-recurrence following castration. Moreover, CR-CaP [Src-shRNA] tumors that recurred had similar Src protein and activation levels as those of parental cells, strengthening the notion that Src activity is required for progression to CR-CaP. In contrast, the ability of dasatinib or KXO1 to inhibit Src kinase activity in vitro did not correlate with their ability to inhibit serum-driven in vitro proliferation of CR and androgen-dependent stable cell lines derived from CWR22 tumors (CWR22Rv1 and CWR22PC, respectively), suggesting that the in vitro proliferation of these CaP lines is Src independent. Taken together, these findings strongly suggest that Src is a potent and specific therapeutic target for CR-CaP progression

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......-CSF, especially at cycle 1 and in men aged > or =75 years, is important and improves tolerability in senior adults treated with cabazitaxel....

Estimation of body tissue gain of entire and castrated male pigs at ...

African Journals Online (AJOL)

Rates of tissue gain and body composition of 18 entire (E) and 18 castrated (C) male pigs, fed at one of two levels of feeding (high (H) or low (L)), were investigated in a 2x2 factorial experiment. Calorimetric, energy and nitrogen balances were carried out on each animal at 30, 60 and 90 kg live weight. The animals were ...

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

Science.gov (United States)

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

2001-07-01

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

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

Science.gov (United States)

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

2010-08-01

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

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

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Afif Rieth Nery-Aguiar

2016-02-01

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

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

A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer.

Science.gov (United States)

Chang, Kai-Hsiung; Li, Rui; Kuri, Barbara; Lotan, Yair; Roehrborn, Claus G; Liu, Jiayan; Vessella, Robert; Nelson, Peter S; Kapur, Payal; Guo, Xiaofeng; Mirzaei, Hamid; Auchus, Richard J; Sharifi, Nima

2013-08-29

Growth of prostate cancer cells is dependent upon androgen stimulation of the androgen receptor (AR). Dihydrotestosterone (DHT), the most potent androgen, is usually synthesized in the prostate from testosterone secreted by the testis. Following chemical or surgical castration, prostate cancers usually shrink owing to testosterone deprivation. However, tumors often recur, forming castration-resistant prostate cancer (CRPC). Here, we show that CRPC sometimes expresses a gain-of-stability mutation that leads to a gain-of-function in 3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which catalyzes the initial rate-limiting step in conversion of the adrenal-derived steroid dehydroepiandrosterone to DHT. The mutation (N367T) does not affect catalytic function, but it renders the enzyme resistant to ubiquitination and degradation, leading to profound accumulation. Whereas dehydroepiandrosterone conversion to DHT is usually very limited, expression of 367T accelerates this conversion and provides the DHT necessary to activate the AR. We suggest that 3βHSD1 is a valid target for the treatment of CRPC. Copyright © 2013 Elsevier Inc. All rights reserved.

Molecular biology of castration-resistant prostate cancer: basis for the novel therapeutic targets.

Science.gov (United States)

Mellado, Begoña; Marin Aguilera, Mercedes; Pereira, Maria Veronica

2013-06-01

Prostate cancer cells express the androgen receptor (AR) and need the presence of androgens to survive. Androgen suppression is the gold standard first-line therapy for metastatic disease. Almost all prostate cancer patients initially respond to hormonal therapy, but most of them gradually develop castration-resistant progression. Recent evidence has shown that progression at the castration resistant prostate cancer (CRPC) stage is often mediated by AR signalling. Importantly, subsequent AR androgen inhibition, by abiraterone acetate or enzalutamide, has shown to improve patients' survival. Several mechanisms that enhance AR signalling in an androgen-depleted environment have been elucidated:(1) AR mutations that allow activation by low androgen levels or by other endogenous steroids, (2) AR amplification and/or overexpression,(3)increased local intracrine synthesis of androgens, (4) changes in AR cofactors and (5) cross-talk with cytokines and growth factors. Today, there are under development a number of novel agents targeting the AR signaling pathway. This article reviews the postulated mechanisms of AR-driven resistance to androgen suppression that have contributed to the development of new hormonal therapeutic strategies in prostate cancer.

Metastatic castration-resistant prostate cancer: a current view on drug therapy and alternative tumor cell regulation

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R. A. Gafanov

2018-01-01

Full Text Available Prostate cancer (PC is one of the most common causes of death from malignant neoplasms in men in many countries around the world. Transmission of the signal in the androgenic axis of regulation is crucial for the development and progression of PC. Despite the constant dependence on androgen receptor signals in castration resistance, the use of new anti-androgenic drugs invariably leads to the stability  of the ongoing treatment. The interaction of androgen receptor and alternative (phosphoinositide-3-kinases, PI3K pathways in the regulation of cells can be one of the mechanisms of resistance to treatment. In this article, we describe current treatments for metastatic castration-resistant PC and the possible role of the PI3K pathway in the pathogenesis and progression of PC.

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

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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...... change were registered during treatment with CA and previous/subsequent novel androgen receptor targeting therapies. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. A median of 6 versus 5 treatment cycles was administered in patients treated...

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

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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...

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

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

2017-08-01

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

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

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Mokhamad Fakhrul Ulum

2017-09-01

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

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

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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.

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

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

2017-09-29

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

Neuropeptide Y in the forebrain of the adult male cichlid fish Oreochromis mossambicus: distribution, effects of castration and testosterone replacement.

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Sakharkar, Amul J; Singru, Praful S; Sarkar, Koustav; Subhedar, Nishikant K

2005-08-22

We studied the organization of the neuropeptide Y (NPY)-immunoreactive system in the forebrain of adult male cichlid fish Oreochromis mossambicus and its response to castration and testosterone replacement by using morphometric methods. Immunoreactivity for NPY was widely distributed in the forebrain, and the pattern generally resembled that in other teleosts. Whereas immunoreactivity was conspicuous in the ganglia of nervus terminalis (NT; or nucleus olfactoretinalis), a weak reaction was detected in some granule cells in the olfactory bulb and in the cells of area ventralis telencephali pars lateralis (Vl). Moderately to intensely immunoreactive cells were distinctly seen in the nucleus entopeduncularis (NE), nucleus preopticus (NPO), nucleus lateralis tuberis (NLT), paraventricular organ (PVO), and midbrain tegmentum (MT). NPY fibers were widely distributed in the forebrain. Castration for 10/15 days resulted in a drastic loss of immunoreactivity in the cells of NE (P<0.001) and a significant decrease (P<0.01) in their cell nuclear size. However, cell nuclei of the NT neurons showed a significant increase in size. A highly significant reduction in the NPY-immunoreactive fiber density (P<0.001) was observed in several areas of the forebrain. Although testosterone replacement reversed these changes, fibers in some areas showed supranormal responses. Immunoreactive cells in Vl, NPO, NLT, PVO, and MT and fiber density in some other areas did not respond to castration. We suggest that the NPY-immunoreactive elements that respond to castration and testosterone replacement may serve as the substrate for processing the positive feedback action of the steroid hormone. (c) 2005 Wiley-Liss, Inc.

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

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

2018-01-01

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

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

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Vishnu, Prakash; Tan, Winston W

2010-06-24

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. 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. 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.

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

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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...

Effect of castration and crossbreeding on meat quality traits of Maremmana beef cattle

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Manuel Juárez

2010-01-01

Full Text Available The aim of this trial was to evaluate the influence of castration and crossbreeding on some meat quality traits of Maremmana breed calves. Meat quality attributes were determined in carcasses from thirty male animals: 11 intact Maremmana males (MM, 10 intact crossbreeding males (CB, 9 Maremmana steers (ST. Meat composition, texture, colour and intramuscular lipid profile of Longissimus thoracis muscle were analysed after 8 days of ageing. Meat from intact Maremmana males showed a general tendency to be tougher and with a higher saturated fatty acids content than the other groups but this trend is only partially confirmed by analysis of WBSr (3.58 kg MM vs. 2.70 kg ST; P<0.05 and total collagen (5.35 mg MM vs. 3.05 g ST; P<0.05 data. Nevertheless insoluble collagen is higher in males than in steers and crossbreeds. As to saturated fatty acids content, the only significant difference is between MM and CB (48.30% vs. 44.1%; P<0.05. In addition to its practical utility in management, castration showed some positive effects on meat quality characteristics, as well as crossbreeding.

The influence of androgens, anti-androgens, and castration on cell proliferation in the jejunal and colonic crypt epithelia, and in dimethylhydrazine-induced adenocarcinoma of rat colon.

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Tutton, P J; Barkla, D H

1982-01-01

Androgenic hormones have previously been shown to promote cell proliferation in the small intestine of rat and androgen receptors have been demonstrated in carcinomata of the large intestine of rat. In this study the influence of testosterone and of castration on epithelial cell proliferation in the small intestine, the large intestine and in dimethylhydrazine-induced colonic tumours is compared. Cell proliferation in the small intestine and in colonic tumours was accelerated by testosterone treatment, and cell proliferation in colonic tumours, but not in the small intestine, was retarded following castration. Cell proliferation in colonic tumours was also inhibited by the anti-androgenic drug, Flutamide. Testosterone and castration each failed to influence cell proliferation in the colonic crypt epithelium of both normal and carcinogen-treated animals.

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...

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

OpenAIRE

Howe, Lisa

2015-01-01

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

Experimental study of apoptosis in the prostate tissue following castration

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Y Doustar

2008-02-01

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

Effect of castration at 10 months of age on growth physiology and behavior of male feral beef cattle.

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Álvarez-Rodríguez, Javier; Albertí, Pere; Ripoll, Guillermo; Blasco, Isabel; Sanz, Albina

2017-07-01

This study compared the growth performance, plasma testosterone and cortisol levels around castration at 10 months of age, and plasma insulin-like growth factor (IGF)-I concentration and flight speed, in intact bulls and steers from 10 to 21 months of age in a feral Spanish breed. Fourteen bulls (366.5 ± 48.5 kg live weight) were assigned at random to one of two treatments: surgically castrated (steers) or intact (bulls), and submitted to an identical fattening period. Steers reared until heavy live weights (21 months of age) grew slowly and had lower plasma IGF-I concentrations than intact bulls. These differences were mainly highlighted the month after surgery (11 months of age) and the last part of the fattening period (from 19 to 21 months of age). After surgical castration (11 and 12 months of age), steers showed a tendency to display greater flight speed values than intact bulls but baseline plasma cortisol concentration did not differ between groups at this time. At the end, steers and bulls reached nearly similar temperament, as flight speed did not differ between them. The results confirm the role of IGF-I as a key anabolic hormone in male beef cattle and thus it may reflect growth differences due to altered sex steroids production. © 2016 Japanese Society of Animal Science.

Weekly ascorbic acid infusion in castration-resistant prostate cancer patients

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

2017-01-01

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

Androgen receptor expression in Circulating Tumor Cells from castration-resistant prostate cancer patients with novel endocrine agents

NARCIS (Netherlands)

Crespo, M.; van Dalum, Guus; Ferraldeschi, R.; Zafeiriou, Z.; Sideris, S.; Lorente, D.; Bianchini, D.; Rodrigues, D.N.; Rijsnaes, R.; Miranda, S.; Figueiredo, I.; Flohr, P.; Nowakowska, K.; de Bono, J.S.; Terstappen, Leonardus Wendelinus Mathias Marie; Attard, G.

2015-01-01

Background: Abiraterone and enzalutamide are novel endocrine treatments that abrogate androgen receptor (AR) signalling in castration-resistant prostate cancer (CRPC). Here, we developed a circulating tumour cells (CTCs)-based assay to evaluate AR expression in real-time in CRPC and investigated

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

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Miladinović-Stefanović Dušica

2014-01-01

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

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

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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.

Evaluation of the prophylactic effect and curative efficacy of fipronil 1% pour on (Topline) on post-castration scrotal myiasis caused by Cochliomyia hominivorax in cattle.

Science.gov (United States)

Lima, W S; Malacco, M A F; Bordin, E L; Oliveira, E L

2004-11-10

A field trial was carried out during a summer-fall period on a commercial beef cattle farm in Minas Gerais State, located in the Southeast of Brazil. In order to evaluate the prophylactic effect and the curative efficacy of fipronil in a 1% solution, 200 Zebu crossbred bulls, with ages varying from 20 to 30 months and weights from 233 to 362 kg, were selected. The bulls were assigned by ranked pair to an untreated control group (A) or to a treated group (B), resulting in 100 animals per group. All experimental animals were surgically castrated on day 0, following routine procedures. After castration all animals in the group B were treated with 10 mg/kg bw of a 1% fipronil solution, topically on the dorsal mid-line. The wounds were individually inspected on days: 2, 4, 7, 10, 14, 17, 21, 28 and 35. After castration the animals were naturally exposed to Cochliomyia hominivorax and remained in the same pasture throughout the trial. Among the animals in the control group, 83 were observed to harbor C. hominivorax eggs, with a total of 97 ovipositions, and among those 73 animals had active myiasis. In group B (fipronil 1%), 66 animals showed C. hominivorax eggs, with 92 ovipositions and five animals with active myiasis. Most ovipositions and active myiasis were detected until seven days post-castration for both groups. Wound parasite infestation evidenced bleeding, serous purulent exudation and presence of active C. hominivorax larvae. Treatment with fipronil 1% had a prophylactic effect on scrotal wounds against the development of C. hominivorax larvae in more than 95% of the treated animals for up to 17 days after castration. The treatment showed partial protection of 66% and 50% on days 21 and 28 post-treatment (pt), respectively. Three animals from the control group and one from the treated group showed active screwworms on day 21 pt, and one animal from the treated group and two from the control group also presented C. hominivorax larvae on scrotal wounds on day 28

Relationship between release of LH and incorporation of tritiated thymidine in the anterior pituitary gland of the castrated female rat.

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Machiavelli, G A; Romano, M I; Burdman, J A

1985-06-01

Castration of female rats during diestrus increases the concentration of circulating LH from days 3 and the incorporation of 3H thymidine into pituitary DNA from day 5. Both effects are completely abolished by the administration of dihydrotestosterone. Although the i.v. injection of LHRH markedly enhances the concentration of LH in serum, it does not modify the incorporation of 3H thymidine into pituitary DNA. Castration might produce a maximal stimulation in 3H thymidine incorporation and a further stimulation of LH release with LHRH is unable to enhance the incorporation of the radioactive precursor. The results suggest a relationship between LH secretion and DNA synthesis in the pituitary gland of the rat.

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

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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.

Endocrine testicular function and spermatogenesis persist in calves after partial scrotal resection but not Burdizzo castration.

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Pieler, D; Wohlsein, P; Peinhopf, W; Aurich, J E; Erber, R; Ille, N; Baumgärtner, W; Aurich, C

2014-06-01

Bull calves for fattening are often castrated during the first weeks of life. Because androgens stimulate growth, there is an interest in males that are infertile but exposed to endogenous testicular steroids. Such a situation occurs in cryptorchids and has been imitated by shortening the scrotum to an extent that the testes are located in a near-inguinal position. In this study, effects of partial scrotal resection (SR) and Burdizzo castration (BZ) on endocrine testicular function, testes histology and on weight at slaughter were studied and compared to orchidectomized (OR) and gonad-intact calves (CO; n = 10 per group; age at castration, 54 ± 3 days; fattening period, 474 ± 11 days). Plasma testosterone concentrations were determined repeatedly, and testes were collected for histopathology at slaughter. We hypothesized that SR inhibits spermatogenesis without loss of testicular steroidogenesis. Group SR animals gained more weight than groups OR and BZ (P < 0.01). Plasma testosterone concentration increased in groups SR and CO (P < 0.01 vs. BZ and OR). Histologically, in all SR animals, testicular and epididymal tissue was identified with a seminiferous epithelium of up to three-cell layers in two animals. Germ cells including elongated spermatids were present in three animals. Shortening of the scrotum thus induced varying degrees of testicular degeneration but 3/10 animals had to be suspected as fertile. In one BZ animal, spermatids were identified whereas in the remaining BZ animals, testes and epididymides consisted of sclerotic fibrous tissue. Partial SR thus induced a cryptorchid-like status but fertility in individual animals must be assumed. Copyright © 2014 Elsevier Inc. All rights reserved.

Nanocarrier-mediated delivery of α-mangostin for non-surgical castration of male animals

OpenAIRE

Yostawonkul, Jakarwan; Surassmo, Suvimol; Namdee, Katawut; Khongkow, Mattaka; Boonthum, Chatwalee; Pagseesing, Sasithon; Saengkrit, Nattika; Ruktanonchai, Uracha Rungsardthong; Chatdarong, Kaywalee; Ponglowhapan, Suppawiwat; Yata, Teerapong

2017-01-01

The overpopulation of abandoned and stray companion animals has become a global crisis. The main purpose of this study was to develop a novel nanomedicine-based antifertility compound for non-surgical castration of male animals. Mangosteen (Garcinia mangostana L) pericarp extract has been shown to exhibit anti-fertility property. α-mangostin (AM)-loaded nanostructured lipid carrier (AM-NLC) was developed to improve male germ cell apoptosis. This study was conducted to investigate physicochemi...

Weekly ascorbic acid infusion in castration-resistant prostate cancer patients

DEFF Research Database (Denmark)

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

2017-01-01

of this treatment. Methods: This non-comparative, single-center, phase II trial included patients with chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC) from an outpatient clinic to evaluate the efficacy and safety of IV AA therapy. Patients received weekly infusions of AA (week 1, 5 g....../L was recorded at week 12. Among the secondary endpoints, no signs of disease remission were observed. In total, 53 adverse events (AEs) were recorded. Eleven were graded as "serious". Three AEs were directly related to AA, and all of which were related to fluid load. Conclusions: Infusion with 60 g of AA did...

The effects of nitric oxide-cGMP pathway stimulation on dopamine in the medial preoptic area and copulation in DHT-treated castrated male rats.

Science.gov (United States)

Sato, Satoru M; Wersinger, Scott R; Hull, Elaine M

2007-08-01

Dopamine (DA) in the medial preoptic area (MPOA) provides important facilitative influence on male rat copulation. We have shown that the nitric oxide-cGMP (NO-cGMP) pathway modulates MPOA DA levels and copulation. We have also shown that systemic estradiol (E(2)) maintains neuronal NO synthase (nNOS) immunoreactivity in the MPOA of castrates, as well as relatively normal DA levels. This effect of E(2) on nNOS probably accounts for at least some of the previously demonstrated behavioral facilitation by intra-MPOA E(2) administration in castrates. Therefore, we hypothesized that stimulation of the MPOA NO-cGMP pathway in dihydrotestosterone (DHT)-treated castrates should restore DA levels and copulatory behaviors. Reverse-dialysis of a NO donor, sodium nitroprusside (SNP), increased extracellular DA in the MPOA of DHT-treated castrates and restored the ability to copulate to ejaculation in half of the animals. A cGMP analog, 8-Br-cGMP, also increased extracellular DA, though not as robustly, but did not restore copulatory ability. The effectiveness of the NO donor in restoring copulation and MPOA DA levels is consistent with our hypothesis. However, the lack of behavioral effects of 8-Br-cGMP, despite its increase in MPOA DA, suggests that NO may have additional mediators in the MPOA in the regulation of copulation. Furthermore, the suboptimal copulation seen in the NO donor-treated animals suggests the importance of extra-MPOA systems in the regulation of copulation.

Feeding Response of Tree Fodder Bhimal (Grewia optiva on Growth Performance of Castrated Male Goats

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Luma Nidhi Pandey

2017-05-01

Full Text Available Bhimal (Grewia optiva is a fodder tree mostly found in mid hills of mid and far western region of Nepal. Bhimal could constitutes one of the main livestock green fodders, especially for goats when fresh green fodder become limited during the winter dry season. However, the feeding value of Bhimal leaves on growth performance of castrated goats probably has not been evaluated so far. Therefore, an experiment was conducted to evaluate the effect of Bhimal leaves feeding on growth performance of castrated male goats for 90 days. Altogether 16 growing castrated male goats of same breed, age and body weight were selected and equally divided into four treatments T1, T2, T3 and T4 with four replications by using Completely Randomized Design (CRD. Four types of experimental diets were prepared having various levels (0 to 100% of Bhimal leaves as fodder. Experimental animals of Treatment 1 were fed with seasonal fodder + 100 g concentrate mixture, Treatment 2 with 100% Bhimal fodder + 100 g concentrate mixture, Treatment 3with 75% Bhimal fodder + 25% seasonal fodder + 100 g concentrate mixture, while Treatment 4 with 50% Bhimal fodder + 50% season fodder + 100 g concentrate mixture. All diets were fed ad-lib and experimental animals had free access to drinking water. The diets offered and refusal was measured daily and weight change was observed fortnightly. The result showed that fodder intake (g/d/animal and total dry matter intake (TDMI g/kg live weight of goats differed significantly (P<0.01, but concentrate intake was not differed significantly (P<0.01 among treatments. The highest dry matter intake per animal /day was in Treatment 2 (52.75 g/kg live weight followed by Treatment 4, Treatment 3 and Treatment 1 (51.7, 48.56 and 32.69 g/kg live weight, respectively.The average daily gain in body weight was observed highest in Treatment 2 (66.66 g/d followed by Treatment 3 (31.66 g/d and Treatment 4 (30.83 g. The growth rate was significantly (P<0

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

Net requirements of energy, protein and macrominerals for weight gain of grazing beef cattle castrated at different ages, with and without supplementation

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Anilza Andréia da Rocha

2012-02-01

Full Text Available The objective of this experiment was to estimate the requirements of energy, protein and macrominerals of grazing crossbreds calves, in Brachiaria decumbens Stapf pasture, castrated at different ages, with and without supplementation. Forty-seven young calves at initial age of 120±30.1 days and 115.3±1.97 kg of live weight were used. To estimate net energy requirements for weight gain, a regression equation between energy retained in the gain and empty body weight gain and metabolic empty body weight was obtained. For estimation of net protein requirements for weight gain, a regression equation was adjusted between protein retained in gain and empty body weight gain and energy content of this gain. Net requirements of Ca, P, Mg and Na for weight gain were determined by the equation Y' = a.b. Xb-1, in which a and b represent the intercept and the coefficient of the alometric equation of macromineral body content prediction, respectively. Neither castration nor concentrate supplementation affects body weight gain net requirements, except the ones of Ca, which were higher for non-castrated animals.

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

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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.

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

DEFF Research Database (Denmark)

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

2010-01-01

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

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

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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...

The parasitic castration and gigantism of Lymnaea truncatula infected with the larval stages of Fasciola hepatica.

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Wilson, R A; Denison, J

1980-01-01

The shells of Lymnaea truncatula infected with the larval stages of Fasciola hepatica were significantly longer than those of comparable uninfected controls. The dry mass (tissue, shell + parasite) of the same infected snails, 56 days after infection, was approximately twice that of the controls (tissue + shell). The increased mass of infected snails was not due to a disproportionate increase in shell weight relative to tissues. Infected snails maintained at 20 degrees C had virtually ceased egg production by 21 days post-infection whereas control snails continued to lay eggs steadily for the duration of the experiment. The dry mass of snail tissue plus the cumulative dry weight of eggs produced was taken as an indication of the ability of control snails to generate biomass. Similarly the tissue mass plus cumulative egg weight and parasite weight was taken as an indication of the ability of the infected snails to generate biomass. The control and infected snails were not significantly different in this respect indicating that the gigantism of infected snails could be the result of a switch in nutrient supply from reproduction to somatic tissue growth and parasite growth. Castration was brought about 17-21 days after infection as a result of the direct consumption of the ovotestis by a proportion of the redial population. In a separate experiment it was demonstrated that a population of infected snails maintained at 20 degrees C survived as long as a similar group of control snails. The findings with this host-parasite system are discussed in relation to possible mechanisms causing castration and gigantism in other digene-snail interactions, and in relation to parasitic castration in other groups. It is concluded that the observed gigantism of infected snails is more likely to have a nutritional rather than endocrine origin.

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

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...

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

DEFF Research Database (Denmark)

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

2014-01-01

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

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

Science.gov (United States)

2016-12-01

MRI  analysis   (data  not   shown).  There   is  no  noticeable   normal   epithelium   in   the   castrated   Ptenpc...recruitment  of  MDSCs  to  the  TME  of   Ptenpc-­‐/-­‐Smad4pc-­‐/-­‐  tumors,  we  assessed  the  impact  of   pharmacologic ...B 9 Methodology:   We   used   pharmacological   approach   to   inhibit   CXCL5   and

Androgen Receptor Antagonism By Divalent Ethisterone Conjugates In Castrate-Resistant Prostate Cancer Cells

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Levine, Paul M.; Lee, Eugine; Greenfield, Alex; Bonneau, Richard; Logan, Susan K.; Garabedian, Michael J.; Kirshenbaum, Kent

2013-01-01

Sustained treatment of prostate cancer with Androgen Receptor (AR) antagonists can evoke drug resistance, leading to castrate-resistant disease. Elevated activity of the AR is often associated with this highly aggressive disease state. Therefore, new therapeutic regimens that target and modulate AR activity could prove beneficial. We previously introduced a versatile chemical platform to generate competitive and non-competitive multivalent peptoid oligomer conjugates that modulate AR activity. In particular, we identified a linear and a cyclic divalent ethisterone conjugate that exhibit potent anti-proliferative properties in LNCaP-abl cells, a model of castrate-resistant prostate cancer. Here, we characterize the mechanism of action of these compounds utilizing confocal microscopy, time-resolved fluorescence resonance energy transfer, chromatin immunoprecipitation, flow cytometry, and microarray analysis. The linear conjugate competitively blocks AR action by inhibiting DNA binding. In addition, the linear conjugate does not promote AR nuclear localization or co-activator binding. In contrast, the cyclic conjugate promotes AR nuclear localization and induces cell-cycle arrest, despite its inability to compete against endogenous ligand for binding to AR in vitro. Genome-wide expression analysis reveals that gene transcripts are differentially affected by treatment with the linear or cyclic conjugate. Although the divalent ethisterone conjugates share extensive chemical similarities, we illustrate that they can antagonize the AR via distinct mechanisms of action, establishing new therapeutic strategies for potential applications in AR pharmacology. PMID:22871957

Metalloproteinase 11, potential marker and molecular target in advanced and castration-resistant prostate cancer. Culture study of peritumoral fibroblasts.

Science.gov (United States)

Fernandez-Gomez, J M; Eiro, N; García-Rodríguez, J J; Quintás-Blanco, A; Gonzalez-Ruiz de León, C; Perez de Haro, M L; Vizoso-Piñero, F

To analyze the expression of metalloprotein 11 (MMP11) in cultured fibroblasts obtained from human prostate tumors with different clinical and pathological characteristics. For this study we analyzed samples of transrectal prostate biopsies from tumors with different characteristics, treated with or whithout androgen deprivation (AD). After optimization of the culture method, fibroblasts were isolated and cultured to perform the study (PCR) of MMP11 mRNA. Finally, 37 cases were studied: 5 samples of benign prostatic hyperplasia, 14 cases with localized neoplasms (7 high-risk according to the D'Amico classification), 5 with metastasic tumors (bone metastases), and 13 treated with AD therapy, of which 6 fulfilled the requirements to be defined as resistant to castration. In tumors without AD therapy, MMP11 expression was significantly higher (P=.001) in fibroblasts of higher grade tumors. A significant (P=.001) correlation was found between PSA and expression of MMP11 in fibroblast s and a significant increase of MMP11 expression in metastatic tumors. In tumors with AD therapy, a significantly greater expression of MMP11 was observed in resistant to castration patients than in those sensitive to castration (P=.003). In advanced prostate tumors or in stages of increased tumor aggressiveness, the production of MMP11 by fibroblasts is significantly greater than in non-metastatic tumors or in AD sensitive tumors. Copyright © 2016 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

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

Science.gov (United States)

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

2015-09-01

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

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

Science.gov (United States)

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

2008-11-01

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

Accuracy of serum luteinizing hormone and serum testosterone measurements to assess the efficacy of medical castration in prostate cancer patients.

Science.gov (United States)

Morote, Juan; Comas, Imma; Ferrer, Roser; Planas, Jacques; Celma, Anna; Regis, Lucas

2017-10-22

Luteinizing hormone-releasing hormone (LH-RH) agonists are the standard for androgen deprivation therapy (ADT) in prostate cancer (PCa) patients. Current guidelines recommend serum testosterone measurement to assess the efficacy of ADT and to define castration resistance. However, serum testosterone does not reflect the exclusive effect of castration due to its extratesticular production. The aim of this study is to analyze if serum LH reflects better than serum testosterone the activity of LH-RH agonists. Serum LH and serum testosterone were measured with chemiluminescent immunoassay (CLIA) in a cohort study of 1091 participants: 488 PCa patients "on LH-RH agonists", 303 "off LH-RH agonist" in whom LH-RH agonists were withdrawn, and 350 men with PCa suspicion "no LH-RH agonist" who never received LH-RH agonists. In a validation cohort of 147 PCa patients, 124 on "LH-RH agonists" and 19 "off LH-RH agonists", serum testosterone was also measured with liquid chromatography and tandem mass spectrometry (LC MSMS). The area under the curve (AUC) to distinguish patients "on versus off LH-RH agonists" was 0.997 for serum LH and 0.740 for serum testosterone, P < 0.001. The 97.5 percentile of serum LH in patients "on LH-RH agonists" was 0.97 U/L, been the most efficient threshold 1.1 U/L. The AUCs for serum LH, testosterone measured with CLIA and with LC MSMS, in the validation cohort, were respectively 1.000, 0.646 and 0.814, P < 0.001. The efficacy to distinguish patients "on versus off LH-RH agonists" was 98.6%, 78.3%, and 89.5% respectively, using 1.1 U/L as threshold for serum LH and 50 ng/dL for serum testosterone regardless the method. Serum LH is more accurate than serum testosterone regardless the method, to distinguish patients "on versus off LH-RH agonists". The castrate level of serum LH is 1.1 U/l. These findings suggest that assessment of LH-RH agonist efficacy and castration resistance definition should be reviewed.

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

Directory of Open Access Journals (Sweden)

Ying-Ying Zhang

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

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

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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.

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

NARCIS (Netherlands)

Beer, T.M.; Armstrong, A.J.; Rathkopf, D.; Loriot, Y.; Sternberg, C.N.; Higano, C.S.; Iversen, P.; Evans, C.P.; Kim, C.S.; Kimura, G.; Miller, K.; Saad, F.; Bjartell, A.S.; Borre, M.; Mulders, P.; Tammela, T.L.; Parli, T.; Sari, S.; Os, S. van; Theeuwes, A.; Tombal, B.

2017-01-01

Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naive metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated the

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

Science.gov (United States)

2016-10-01

receptor, castration-resistant prostate cancer, DNA binding domain, androgen response element, AR inhibitor, chromatin, x-ray crystallography , pre-clinical...14228 (months 1-30) 3.2. Synthesis of derivatives of our lead compounds (months 6-30). 3.3.Experimental evaluation of the developed synthetic

Prognostic factor analysis in patients with advanced prostate cancer treated by castration plus anandron or placebo: A final update

NARCIS (Netherlands)

de Reijke, Theo; Derobert, Eric

2002-01-01

Purpose: Different outcome results have been published in trials comparing maximal androgen blockade (MAB) with chemical or surgical castration alone. The conflicting results could be explained by the fact that patients were included with different prognostic factors. In this new analysis of the

Population-based study on use of chemotherapy in men with castration resistant prostate cancer

OpenAIRE

Lissbrant, Ingela Franck; Garmo, Hans; Widmark, Anders; Stattin, P?r

2013-01-01

Background. Chemotherapy prolongs life and relieves symptoms in men with castration resistant prostate cancer (CRPC). There is limited information on a population level on the use of chemotherapy for CRPC. Material and methods. To assess the use of chemotherapy in men with CRPC we conducted a register-based nationwide population-based study in Prostate Cancer data Base Sweden (PCBaSe) and a nationwide in-patient drug register (SALT database) between May 2009 and December 2010. We assumed that...

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

Science.gov (United States)

2017-09-01

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

Effects of castration age, dietary protein level and lysine/methionine ratio on animal performance, carcass and meat quality of Friesian steers intensively reared.

Science.gov (United States)

Prado, I N; Campo, M M; Muela, E; Valero, M V; Catalan, O; Olleta, J L; Sañudo, C

2014-09-01

The effects of castration age, dietary protein level and the dietary lysine/methionine (lys/met) ratio on animal performance, carcass characteristics and meat quality were studied in 64 intensively reared Friesian steers. Animals underwent castration procedures at 15 days old or at 5 months old. Dietary treatments started at 90 days old, with eight animals from each castration age randomly allocated to each treatment: 14.6% v. 16.8% CP (DM basis), and 3.0 v. 3.4 lys/met, on a 2×2×2 design. The recommended ratio of 3.0 was reached with supplementation of protected methionine. Steers were slaughtered at 443.5±26.2 kg live weight when they reached 12 months old approximately. Average daily gain, cold carcass weight or carcass classification were not affected by any studied effect. Muscle moisture (P=0.024), C18:2n-6 percentage (P=0.047), polyunsaturated fatty acid/saturated fatty acid (P=0.049) and n-6/n-3 (P=0.003) were higher in late castrated animals. Both high levels of dietary protein (P=0.008) and lys/met ratio (P=0.048) increased the percentage of muscle in the carcass. A level of 16.8% of CP in the diet also increased the percentage of monounsaturated fatty acids in the intramuscular fat (P=0.032), whereas a ratio lys/met of 3.4 decreased the percentage of saturated fatty acids (P=0.028). Thus, it is recommended using diets with a high protein level (16.8%) and a high lys/met ratio (3.4) in animals slaughtered at a young age, in order to obtain carcasses with high muscle content without negatively affecting productive traits or intramuscular fat composition.

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.

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

Science.gov (United States)

2017-09-01

Splicing of Androgen Receptor (AR) Gene in Castration-Resistant Prostate Cancer (CRPC) 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Jer...Epigenetic regulation of androgen receptor signaling in prostate cancer . Epigenetics. 5, 100-104. 2. Duan LL, Rai G , Roggero C, Zhang Q-J, Wei Q... Prostate Cancer (CRPC) PRINCIPAL INVESTIGATOR: Hsieh, Jer-Tsong CONTRACTING ORGANIZATION: University of Texas Southwestern Medical Center

Histone 2B-GFP Label-Retaining Prostate Luminal Cells Possess Progenitor Cell Properties and Are Intrinsically Resistant to Castration

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Dingxiao Zhang

2018-01-01

Full Text Available The existence of slow-cycling luminal cells in the prostate has been suggested, but their identity and functional properties remain unknown. Using a bigenic mouse model to earmark, isolate, and characterize the quiescent stem-like cells, we identify a label-retaining cell (LRC population in the luminal cell layer as luminal progenitors. Molecular and biological characterizations show that these luminal LRCs are significantly enriched in the mouse proximal prostate, exhibit relative dormancy, display bipotency in both in vitro and in vivo assays, and express a stem/progenitor gene signature with resemblance to aggressive prostate cancer. Importantly, these LRCs, compared with bulk luminal cells, maintain a lower level of androgen receptor (AR expression and are less androgen dependent and also castration resistant in vivo. Finally, analysis of phenotypic markers reveals heterogeneity within the luminal progenitor cell pool. Our study establishes luminal LRCs as progenitors that may serve as a cellular origin for castration-resistant prostate cancer.

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

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

2010-01-01

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

Cotargeting of Androgen Synthesis and Androgen Receptor Expression as a Novel Treatment for Castration Resistant Prostate Cancer

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2017-08-01

disease [2-4]. The major mechanism underlying the development of CRPC is the reactivation of the androgen receptor (AR), the driver of prostate cancer ...Epigenetic Activator of Androgen Receptor Expression in Castration- Resistant Prostate Cancer . Indiana Basic Urological Research (IBUR) Symposium...principal discipline(s) of the project? Androgen receptor (AR) is the driver of prostate cancer development and progression and is the validated

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

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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

Randomized, Placebo-Controlled, Phase III Trial of Sunitinib Plus Prednisone Versus Prednisone Alone in Progressive, Metastatic, Castration-Resistant Prostate Cancer

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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...

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

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Evans, Christopher P; Higano, Celestia S; Keane, Thomas; Andriole, Gerald; Saad, Fred; Iversen, Peter; Miller, Kurt; Kim, Choung-Soo; Kimura, Go; Armstrong, Andrew J; Sternberg, Cora N; Loriot, Yohann; de Bono, Johann; Noonberg, Sarah B; Mansbach, Hank; Bhattacharya, Suman; Perabo, Frank; Beer, Tomasz M; Tombal, Bertrand

2016-10-01

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. To assess the effects of enzalutamide versus placebo in patients from PREVAIL based on site and extent of baseline disease. One thousand seven hundred and seventeen asymptomatic or minimally symptomatic patients were randomized to enzalutamide (n=872) or placebo (n=845). Subgroup analyses included nonvisceral (only bone and/or nodal; n=1513), visceral (lung and/or liver; n=204), low-volume bone disease (1 in patients with visceral disease (HR, 0.82; 95% CI, 0.55-1.23). Enzalutamide was well tolerated in patients with or without visceral disease. Enzalutamide provided clinically significant benefits 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. Patients with metastatic castration-resistant prostate cancer-including those with or without visceral disease or widespread bone disease-benefitted from enzalutamide, an active well-tolerated therapy. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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

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

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Leclercq, C; Prunier, A; Merlot, E

2014-05-01

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

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...... at Rigshospitalet, Denmark, and compare the results with phase III trial outcomes. MATERIAL AND METHODS: Single-centre, retrospective study including consecutive patients managed on AA for more than 2-year period. Treatment consisted of 1,000mg AA and 5mg prednisone twice daily. Outcomes of interest were prostate...

Restoration of the cellular secretory milieu overrides androgen dependence of in vivo generated castration resistant prostate cancer cells overexpressing the androgen receptor.

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Patki, Mugdha; Huang, Yanfang; Ratnam, Manohar

2016-07-22

It is believed that growth of castration resistant prostate cancer (CRPC) cells is enabled by sensitization to minimal residual post-castrate androgen due to overexpression of the androgen receptor (AR). Evidence is derived from androgen-induced colony formation in the absence of cell-secreted factors or from studies involving forced AR overexpression in hormone-dependent cells. On the other hand, standard cell line models established from CRPC patient tumors (e.g., LNCaP and VCaP) are hormone-dependent and require selection pressure in castrated mice to re-emerge as CRPC cells and the resulting tumors then tend to be insensitive to the androgen antagonist enzalutamide. Therefore, we examined established CRPC model cells produced by castration of mice bearing hormone-dependent cell line xenografts including CRPC cells overexpressing full-length AR (C4-2) or co-expressing wtAR and splice-variant AR-V7 that is incapable of ligand binding (22Rv1). In standard colony formation assays, C4-2 cells were shown to be androgen-dependent and sensitive to enzalutamide whereas 22Rv1 cells were incapable of colony formation under identical conditions. However, both C4-2 and 22Rv1 cells formed colonies in conditioned media derived from the same cells or from HEK293 fibroblasts that were proven to lack androgenic activity. This effect was (i) not enhanced by androgen, (ii) insensitive to enzalutamide, (iii) dependent on AR (in C4-2) and on AR-V7 and wtAR (in 22Rv1) and (iv) sensitive to inhibitors of several signaling pathways, similar to androgen-stimulation. Therefore, during progression to CRPC in vivo, coordinate cellular changes accompanying overexpression of AR may enable cooperation between hormone-independent activity of AR and actions of cellular secretory factors to completely override androgen-dependence and sensitivity to drugs targeting hormonal factors. Copyright © 2016 Elsevier Inc. All rights reserved.

Castration and testosterone induced changes in the pinealocytes of roseringed parakeet, Psittacula krameri, during different phases of the annual testicular cycle.

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Maitra, S K; Dey, M

1994-08-01

The pinealocytes in male roseringed parakeets (Psittacula krameri) were studied following bilateral castration and/or therapeutic administration of testosterone during the preparatory (June-July), progressive (Nov.-Dec.), pre-breeding (Jan.-Feb.) and breeding (March-April) phases of the annual testicular cycle. The responses of the pineal to either treatment were found to be almost identical throughout the investigation. In each reproductive phase, the pineal appeared to be hypertrophied following castration and the effect was reversed by therapeutic administration of testosterone, while hormonal treatment to the intact parakeets induced regressive changes in the pinealocytes. Collectively, the results of the current study support the hypothesis that the testis through its hormone testosterone exerts inhibitory influences on the activity of pineal, and may thus be considered as being involved in the determination of an inverse relationship between the pineal and the testis during the annual cycle of free-living parakeets.

Imaging response during therapy with radium-223 for castration-resistant prostate cancer with bone metastases

DEFF Research Database (Denmark)

Keizman, D; Fosboel, M O; Reichegger, H

2017-01-01

BACKGROUND: The imaging response to radium-223 therapy is at present poorly described. We aimed to describe the imaging response to radium-223 treatment. METHODS: We retrospectively evaluated the computed tomography (CT) and bone scintigraphy response of metastatic castration-resistant prostate c....../or radiological) may be noted during the first 3 months, and should not be confused with progression. Imaging by CT scan should be considered after three and six doses of radium-223 to rule out extraskeletal disease progression....

Transmission and scanning electron microscopy study of the characteristics and morphology of pericytes and novel desmin-immunopositive perivascular cells before and after castration in rat anterior pituitary gland.

Science.gov (United States)

Jindatip, Depicha; Fujiwara, Ken; Kouki, Tom; Yashiro, Takashi

2012-09-01

Pericytes are perivascular cells associated with microcirculation. Typically, they are localized close to the capillary wall, underneath the basement membrane, and have sparse cytoplasm and poorly developed cell organelles. However, the specific properties of pericytes vary by organ and the conditions within organs. We recently demonstrated that pericytes in rat anterior pituitary gland produce type I and III collagens. The present study attempted to determine the morphological characteristics of these pituitary pericytes. Castrated rats were used as a model of hormonal and vascular changes in the gland. Pericytes, as determined by desmin immunohistochemistry, were more numerous and stained more intensely in castrated rats. Transmission electron microscopy revealed that pituitary pericytes displayed the typical characteristics of pericytes. In pituitary sections from castrated rats, the Golgi apparatus of pericytes was well developed and the rough endoplasmic reticulum was elongated. Additionally, scanning electron microscopy revealed four pericyte shapes: oval, elongate, triangular, and multiangular. As compared with normal rats, the proportion of oval pericytes was lower, and the proportions of the other three shapes were higher, in castrated rats. These results suggest that pericytes change their fine structure and cell shape in response to hormonal and vascular changes in the anterior pituitary gland. In addition, a novel type of perivascular cell was found by desmin immunoelectron microscopy. The morphological properties of these cells were dissimilar to those of pericytes. The cells were localized in the perivascular space, had no basement membrane, and contained dilated rough endoplasmic reticulum. This new cell type will require further study of its origin and characteristics.

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

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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

Alfaxalone for maintenance of anaesthesia in ponies undergoing field castration: continuous infusion compared with intravenous boluses.

Science.gov (United States)

Deutsch, Julia; Ekiri, Abel; de Vries, Annemarie

2017-07-01

To compare alfaxalone as continuous intravenous (IV) infusion with intermittent IV injections for maintenance of anaesthesia in ponies undergoing castration. Prospective, randomized, 'blinded' clinical study. A group of 33 entire male Welsh ponies undergoing field castration. After preanaesthetic medication with IV detomidine (10 μg kg -1 ) and butorphanol (0.05 mg kg -1 ), anaesthesia was induced with IV diazepam (0.05 mg kg -1 ) followed by alfaxalone (1 mg kg -1 ). After random allocation, anaesthesia was maintained with either IV alfaxalone 2 mg kg -1  hour -1 (group A; n = 16) or saline administered at equal volume (group S; n = 17). When necessary, additional alfaxalone (0.2 mg kg -1 ) was administered IV. Ponies were breathing room air. Using simple descriptive scales, surgical conditions and anaesthesia recovery were scored. Total amount of alfaxalone, ponies requiring additional alfaxalone and time to administration, time from induction to end of infusion and end of infusion to standing were noted. Indirect arterial blood pressure, pulse and respiratory rates, end-expiratory carbon dioxide partial pressure and arterial haemoglobin oxygen saturation were recorded every 5 minutes. Data were analysed using Student t, Mann-Whitney U and chi-square tests, where appropriate (p < 0.05). Total amount of alfaxalone administered after induction of anaesthesia (0.75 ± 0.27 versus 0.17 ± 0.23 mg kg -1 ; p < 0.0001) and time to standing (14.8 ± 4 versus 11.6 ± 4 minutes; p = 0.044) were higher in group A compared to group S. Ponies requiring additional alfaxalone boluses [four (group A) versus seven (group S)] and other measured variables were similar between groups; five ponies required oxygen supplementation [three (group A) versus two (group S)]. Continuous IV infusion and intermittent administration of alfaxalone provided similar anaesthesia quality and surgical conditions in ponies undergoing field castration. Less alfaxalone

Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer

DEFF Research Database (Denmark)

Bryce, A H; Alumkal, J J; Armstrong, A

2017-01-01

monitoring alone to determine disease status on therapy. This approach has not been adequately tested. METHODS: Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide......BACKGROUND: Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA...... treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant...

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

Science.gov (United States)

Scott, Lesley J

2017-09-01

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

The Stromal Contribution to the Development of Resistance to New Generation Drugs by Castrate Resistant Prostate Cancers

Science.gov (United States)

2016-05-01

and by further increasing their outputs of T and DHT . Finally, in Aim 3, I will attempt to demonstrate in cell co-culture models that Sonic Hh produced...of CRPC through their ability to synthesize T and DHT upon Hh stimulation from metastatic PCa cells, and whether this adaptation can increase...backdoor pathway, which bypasses testosterone (T) as an intermediate for dihydrotestosterone ( DHT ) (3, 9-11). 4 After ADT, recurrence as castration

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

Science.gov (United States)

2015-10-01

abiraterone treatment by further increasing their expressions of steroidogenic genes and by further increasing their outputs of T and DHT . Finally, we...support (stromal) cells within a bone metastasis have a supportive role in the development of CRPC through their ability to synthesize T and DHT upon Hh...dihydrotestosterone ( DHT ) (3, 9-11). 4 After ADT, recurrence as castration-resistant disease is common (8). For PCa, the most common site for metastasis is bone

Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment

NARCIS (Netherlands)

Badrising, S.; Noort, V van; Oort, I.M. van; Berg, H.P. van den; Los, M.; Hamberg, P.; Coenen, J.L.; Eertwegh, A.J. van den; Jong, I.J. de; Kerver, E.D.; Tinteren, H. van; Bergman, A.M.

2014-01-01

BACKGROUND: Enzalutamide (Enz) and abiraterone acetate (AA) are hormone treatments that have a proven survival advantage in patients with metastatic, castration-resistant prostate cancer who previously received docetaxel (Doc). Recently, limited activity of AA after Enz and of Enz after AA was

Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer

Directory of Open Access Journals (Sweden)

Paul S. Rennie

2013-06-01

Full Text Available Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the androgen/ligand binding site. Unfortunately, with the inevitable progression of the cancer to castration resistance, many of these drugs become ineffective. However, there are numerous other regulatory sites on this protein that have not been exploited therapeutically. The regulation of AR activity involves a cascade of complex interactions with numerous chaperones, co-factors and co-regulatory proteins, leading ultimately to direct binding of AR dimers to specific DNA androgen response elements within the promoter and enhancers of androgen-regulated genes. As part of the family of nuclear receptors, the AR is organized into modular structural and functional domains with specialized roles in facilitating their inter-molecular interactions. These regions of the AR present attractive, yet largely unexploited, drug target sites for reducing or eliminating androgen signaling in prostate cancers. The design of small molecule inhibitors targeting these specific AR domains is only now being realized and is the culmination of decades of work, including crystallographic and biochemistry approaches to map the shape and accessibility of the AR surfaces and cavities. Here, we review the structure of the AR protein and describe recent advancements in inhibiting its activity with small molecules specifically designed to target areas distinct from the receptor’s androgen binding site. It is anticipated that these new classes of anti-AR drugs will provide an additional

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

DEFF Research Database (Denmark)

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

2017-01-01

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

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

Directory of Open Access Journals (Sweden)

Archibald M

2016-01-01

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

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

NARCIS (Netherlands)

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

2016-01-01

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

Androgen receptor (AR) degradation enhancer ASC-J9® in an FDA-approved formulated solution suppresses castration resistant prostate cancer cell growth.

Science.gov (United States)

Cheng, Max A; Chou, Fu-Ju; Wang, Keliang; Yang, Rachel; Ding, Jie; Zhang, Qiaoxia; Li, Gonghui; Yeh, Shuyuan; Xu, Defeng; Chang, Chawnshang

2018-03-28

ASC-J9 ® is a recently-developed androgen receptor (AR)-degradation enhancer that effectively suppresses castration resistant prostate cancer (PCa) cell proliferation and invasion. The optimal half maximum inhibitory concentrations (IC 50 ) of ASC-J9 ® at various PCa cell confluences (20%, 50%, and 100%) were assessed via both short-term MTT growth assays and long-term clonogenic proliferation assays. Our results indicate that the IC 50 values for ASC-J9 ® increased with increasing cell confluency. The IC 50 values were significantly decreased in PCa AR-positive cells compared to PCa AR-negative cells or in normal prostate cells. This suggests that ASC-J9 ® may function mainly via targeting the AR-positive PCa cells with limited unwanted side-effects to suppress the surrounding normal prostate cells. Mechanism dissection indicated that ASC-J9 ® might function via altering the apoptosis signals to suppress the PCa AR-negative PC-3 cells. Preclinical studies using multiple in vitro PCa cell lines and an in vivo mouse model with xenografted castration-resistant PCa CWR22Rv1 cells demonstrated that ASC-J9 ® has similar AR degradation effects when dissolved in FDA-approved solvents, including DMSO, PEG-400:Tween-80 (95:5), DMA:Labrasol:Tween-80 (10:45:45), and DMA:Labrasol:Tween-20 (10:45:45). Together, results from preclinical studies suggest a potential new therapy with AR-degradation enhancer ASC-J9 ® may potentially be ready to be used in human clinical trials in order to better suppress PCa at later castration resistant stages. Copyright © 2017 Elsevier B.V. All rights reserved.

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

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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; pPREVAIL provides more complete assessment of the clinical benefit of enzalutamide. PREVAIL is registered on ClinicalTrials.gov as NCT01212991. According to data from longer follow-up, enzalutamide continued to provide benefit over placebo in patients with metastatic castration-resistant prostate cancer. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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

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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.

Study the Origin and Mechanisms of Castration Resistance Characterized by Outgrowth of Prostate Cancer Cells with Low/Negative Androgen Receptor

Science.gov (United States)

2017-12-01

Prostate Cancer Cells with Low/Negative Androgen Receptor 5b. GRANT NUMBER W81XWH-15-1-0540 5c. PROGRAM...role of androgen receptor (AR) signaling in disease progression, the current approach to treat prostate cancer is AR-targeted therapy. While this... Prostate cancer ; Androgen receptor ; Castration-resistant prostate cancer (CRPC); Enzalutamide resistance; GREB1; p300 6 Accomplishments Specific

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

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...

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

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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.

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

DEFF Research Database (Denmark)

Bahl, A; Oudard, S; Tombal, B

2013-01-01

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

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

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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…

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

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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.

Detection of AR-V7 mRNA in whole blood may not predict the effectiveness of novel endocrine drugs for castration-resistant prostate cancer.

Science.gov (United States)

Takeuchi, Takumi; Okuno, Yumiko; Hattori-Kato, Mami; Zaitsu, Masayoshi; Mikami, Koji

2016-01-01

A splice variant of androgen receptor (AR), AR-V7, lacks in androgen-binding portion and leads to aggressive cancer characteristics. Reverse transcription-polymerase chain reactions (PCRs) and subsequent nested PCRs for the amplification of AR-V7 and prostate-specific antigen (PSA) transcripts were done for whole blood of patients with prostate cancer and male controls. With primary reverse transcription PCRs, AR-V7 and PSA were detected in 4.5% and 4.7% of prostate cancer, respectively. With nested PCRs, AR-V7 messenger RNA (mRNA) was positive in 43.8% of castration-sensitive prostate cancer and 48.1% of castration-resistant prostate cancer (CRPC), while PSA mRNA was positive in 6.3% of castration-sensitive prostate cancer and 18.5% of CRPC. Whole-blood samples of controls showed AR-V7 mRNA expression by nested PCR. Based on multivariate analysis, expression of AR-V7 mRNA in whole blood was not significantly correlated with clinical parameters and PSA mRNA in blood, while univariate analysis showed a correlation between AR-V7 mRNA and metastasis at initial diagnosis. Detection of AR-V7 mRNA did not predict the reduction of serum PSA in patients with CRPC following abiraterone and enzalutamide administration. In conclusion, AR-V7 mRNA expression in normal hematopoietic cells may have annihilated the manifestation of aggressiveness of prostate cancer and the prediction of the effectiveness of abiraterone and enzalutamide by the assessment of AR-V7 mRNA in blood.

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

International Nuclear Information System (INIS)

Lemos, C.C.S.; Tovar, A.M.F.; Guimarães, M.A.M.; Bregman, R.

2013-01-01

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

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

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Wang, Ya-Ning; Wang, Hong-Cheng; Zhang, Song; Hong, Jie-Yun; Guo, Hong-Fang; Chen, Dai; Yang, Yang; Zan, Lin-Sen

2017-01-01

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

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

Science.gov (United States)

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

2011-12-01

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

Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer

International Nuclear Information System (INIS)

Montgomery, Bruce; Nelson, Peter S; Vessella, Robert; Kalhorn, Tom; Hess, David; Corey, Eva

2010-01-01

Estrogens suppress tumor growth in prostate cancer which progresses despite anorchid serum androgen levels, termed castration resistant prostate cancers (CRPC), although the mechanisms are unclear. We hypothesize that estrogen inhibits CRPC in anorchid animals by suppressing tumoral androgens, an effect independent of the estrogen receptor. The human CRPC xenograft LuCaP 35V was implanted into orchiectomized male SCID mice and established tumors were treated with placebo, 17β-estradiol or 17β-estradiol and estrogen receptor antagonist ICI 182,780. Effects of 17β-estradiol on tumor growth were evaluated and tissue testosterone (T) and dihydrotestosterone (DHT) evaluated by mass spectrometry. Treatment of LuCaP 35V with 17β-estradiol slowed tumor growth compared to controls (tumor volume at day 21: 785 ± 81 mm 3 vs. 1195 ± 84 mm 3 , p = 0.002). Survival was also significantly improved in animals treated with 17β-estradiol (p = 0.03). The addition of the estrogen receptor antagonist ICI 182,780 did not significantly change survival or growth. 17β-estradiol in the presence and absence of ICI 182,780 suppressed tumor testosterone (T) and dihydrotestosterone (DHT) as assayed by mass spectrometry. Tissue androgens in placebo treated LuCaP 35V xenografts were; T = 0.71 ± 0.28 pg/mg and DHT = 1.73 ± 0.36 pg/mg. In 17β-estradiol treated LuCaP35V xenografts the tissue androgens were, T = 0.20 ± 0.10 pg/mg and DHT = 0.15 ± 0.15 pg/mg, (p < 0.001 vs. controls). Levels of T and DHT in control liver tissue were < 0.2 pg/mg. CRPC in anorchid animals maintains tumoral androgen levels despite castration. 17β-estradiol significantly suppressed tumor T and DHT and inhibits growth of CRPC in an estrogen receptor independent manner. The ability to manipulate tumoral androgens will be critical in the development and testing of agents targeting CRPC through tissue steroidogenesis

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

Directory of Open Access Journals (Sweden)

Oliver Sartor

2015-06-01

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

Pharmacokinetics and physiologic effects of intramuscularly administered xylazine hydrochloride-ketamine hydrochloride-butorphanol tartrate alone or in combination with orally administered sodium salicylate on biomarkers of pain in Holstein calves following castration and dehorning.

Science.gov (United States)

Baldridge, Sarah L; Coetzee, Johann F; Dritz, Steve S; Reinbold, James B; Gehring, Ronette; Havel, James; Kukanich, Butch

2011-10-01

To determine the pharmacokinetic parameters of xylazine, ketamine, and butorphanol (XKB) administered IM and sodium salicylate (SAL) administered PO to calves and to compare drug effects on biomarkers of pain and distress following sham and actual castration and dehorning. 40 Holstein bull calves from 3 farms. Calves weighing 108 to 235 kg (n = 10 calves/group) received one of the following treatments prior to sham (period 1) and actual (period 2) castration and dehorning: saline (0.9% NaCl) solution IM (placebo); SAL administered PO through drinking water at concentrations from 2.5 to 5 mg/mL from 24 hours prior to period 1 to 48 hours after period 2; butorphanol (0.025 mg/kg), xylazine (0.05 mg/kg), and ketamine (0.1 mg/kg) coadministered IM immediately prior to both periods; and a combination of SAL and XKB (SAL+XKB). Plasma drug concentrations, average daily gain (ADG), chute exit velocity, serum cortisol concentrations, and electrodermal activity were evaluated. ADG (days 0 to 13) was significantly greater in the SAL and SAL+XKB groups than in the other 2 groups. Calves receiving XKB had reduced chute exit velocity in both periods. Serum cortisol concentrations increased in all groups from period 1 to period 2. However, XKB attenuated the cortisol response for the first hour after castration and dehorning and oral SAL administration reduced the response from 1 to 6 hours. Administration of XKB decreased electrodermal activity scores in both periods. SAL administered PO through drinking water decreased cortisol concentrations and reduced the decrease in ADG associated with castration and dehorning in calves.

Patient-derived Hormone-naive Prostate Cancer Xenograft Models Reveal Growth Factor Receptor Bound Protein 10 as an Androgen Receptor-repressed Gene Driving the Development of Castration-resistant Prostate Cancer.

Science.gov (United States)

Hao, Jun; Ci, Xinpei; Xue, Hui; Wu, Rebecca; Dong, Xin; Choi, Stephen Yiu Chuen; He, Haiqing; Wang, Yu; Zhang, Fang; Qu, Sifeng; Zhang, Fan; Haegert, Anne M; Gout, Peter W; Zoubeidi, Amina; Collins, Colin; Gleave, Martin E; Lin, Dong; Wang, Yuzhuo

2018-06-01

Although androgen deprivation therapy is initially effective in controlling growth of hormone-naive prostate cancers (HNPCs) in patients, currently incurable castration-resistant prostate cancer (CRPC) inevitably develops. To identify CRPC driver genes that may provide new targets to enhance CRPC therapy. Patient-derived xenografts (PDXs) of HNPCs that develop CRPC following host castration were examined for changes in expression of genes at various time points after castration using transcriptome profiling analysis; particular attention was given to pre-CRPC changes in expression indicative of genes acting as potential CRPC drivers. The functionality of a potential CRPC driver was validated via its knockdown in cultured prostate cancer cells; its clinical relevance was established using data from prostate cancer patient databases. Eighty genes were found to be significantly upregulated at the CRPC stage, while seven of them also showed elevated expression prior to CRPC development. Among the latter, growth factor receptor bound protein 10 (GRB10) was the most significantly and consistently upregulated gene. Moreover, elevated GRB10 expression in clinical prostate cancer samples correlated with more aggressive tumor types and poorer patient treatment outcome. GRB10 knockdown markedly reduced prostate cancer cell proliferation and activity of AKT, a well-established CRPC mediator. A positive correlation between AKT activity and GRB10 expression was also found in clinical cohorts. GRB10 acts as a driver of CRPC and sensitizes androgen receptor pathway inhibitors, and hence GRB10 targeting provides a novel therapeutic strategy for the disease. Development of castration-resistant prostate cancer (CRPC) is a major problem in the management of the disease. Using state-of-the-art patient-derived hormone-naive prostate cancer xenograft models, we found and validated the growth factor receptor bound protein 10 gene as a driver of CRPC, indicating that it may be used as a

Neutralizing VEGF bioactivity with a soluble chimeric VEGF receptor protein flt (1-3) IGG inhibits testosterone stimulated prostate growth in castrated mice

International Nuclear Information System (INIS)

Hammarsten, P.; Lissbrant, E.; Lissbrant, I.-F.; Haeggstroem-Rudolfsson, S.; Bergh, A.; Ferrara, N.

2003-01-01

Recent studies show that testosterone stimulated growth of the glandular tissue in the ventral prostate in adult castrated rats is preceded by increased epithelial VEGF synthesis, endothelial cell proliferation, vascular growth, and increased blood flow. These observations suggest that testosterone stimulated prostate growth could be angiogenesis dependent, and that VEGF could play a central role in this. To test this hypothesis adult male mice were castrated and after one week treated with testosterone and vehicle, or with testosterone and a soluble chimeric VEGF-receptor flt(1-3)IgG protein. Treatment with testosterone markedly increased endothelial cell proliferation, vascular volume and organ weight in the ventral prostate lobe in the vehicle groups, but these responses were inhibited but not fully prevented by anti-VEGF treatment. The testosterone stimulated increase in epithelial cell proliferation was unaffected by flt(1-3)IgG, but endothelial and epithelial cell apoptosis were increased in the anti-VEGF compared to the vehicle treated group. This study, together with our previous observations, suggest that testosterone stimulates vascular growth in the ventral prostate lobe indirectly by increasing epithelial VEGF synthesis and that this is a necessary component in testosterone stimulated prostate growth

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

Science.gov (United States)

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

2015-05-01

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

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

Directory of Open Access Journals (Sweden)

Lin Hui-Ping

2011-08-01

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

The Imbalance Attitude of the Journalists in Six Chemical Castration Texts: An SFLCritical Discourse Analysis

Directory of Open Access Journals (Sweden)

Mustofa Kamal

2017-10-01

Full Text Available This research investigates how journalists behave in texts. The analysis focuses on the exploitation of attitudinal lexis. This is qualitatively explored through attitude and graduation. The data sources were columns of news, taken from an online version of The Jakarta Post on June sixth 2016. Having been selected using criterion-based sampling technique, the sources of data resulted in six chemical castration texts. The procedure of investigation consists of domain, taxonomic, componential, and cultural value analysis. The result shows that journalists are relatively subjective in reporting news by unbalancing the pros and cons, relatively inconsistent in work from delivering news to criticizing government officials, and relatively provocative by up-scaling critical evaluations against the government policy on sex offenders.

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

Science.gov (United States)

2017-12-01

AWARD NUMBER: W81XWH-13-1-0162 TITLE: Using a Novel Transgenic Mouse Model to Study c -Myc Oncogenic Pathway in Castration Resistance and...DATES COVERED 15Sept2013 - 14Sept2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Using a Novel Transgenic Mouse Model to Study c -Myc Oncogenic...ABSTRACT We previously made a PB-Cre4/Ai-Myc model for Cre-induced and androgen-independent expression of c -Myc and Luc2 in prostate. This is designed

FOXA1 promotes tumor progression in prostate cancer and represents a novel hallmark of castration-resistant prostate cancer.

Science.gov (United States)

Gerhardt, Josefine; Montani, Matteo; Wild, Peter; Beer, Marc; Huber, Fabian; Hermanns, Thomas; Müntener, Michael; Kristiansen, Glen

2012-02-01

Forkhead box protein A1 (FOXA1) modulates the transactivation of steroid hormone receptors and thus may influence tumor growth and hormone responsiveness in prostate cancer. We therefore investigated the correlation of FOXA1 expression with clinical parameters, prostate-specific antigen (PSA) relapse-free survival, and hormone receptor expression in a large cohort of prostate cancer patients at different disease stages. FOXA1 expression did not differ significantly between benign glands from the peripheral zone and primary peripheral zone prostate carcinomas. However, FOXA1 was overexpressed in metastases and particularly in castration-resistant cases, but was expressed at lower levels in both normal and neoplastic transitional zone tissues. FOXA1 levels correlated with higher pT stages and Gleason scores, as well as with androgen (AR) and estrogen receptor expression. Moreover, FOXA1 overexpression was associated with faster biochemical disease progression, which was pronounced in patients with low AR levels. Finally, siRNA-based knockdown of FOXA1 induced decreased cell proliferation and migration. Moreover, in vitro tumorigenicity was inducible by ARs only in the presence of FOXA1, substantiating a functional cooperation between FOXA1 and AR. In conclusion, FOXA1 expression is associated with tumor progression, dedifferentiation of prostate cancer cells, and poorer prognosis, as well as with cellular proliferation and migration and with AR signaling. These findings suggest FOXA1 overexpression as a novel mechanism inducing castration resistance in prostate cancer. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Antioxidant supplementation decreases the cell death rate in the prostatic stromal tissue of long-term castrated rats

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Guilherme Fartes

2012-06-01

Full Text Available OBJECTIVE: The purpose of this study was to compare the effects of castration on cell death rate of the adult rat prostates and to evaluate the benefic action of alpha tocopherol supplementation to avoid apoptosis post-orchiectomy. MATERIAL AND METHODS: Thirty male Wistar rats weighing 250-300g were divided into three groups: group I - they were subjected to bilateral orchiectomy and sacrificed eight weeks after the procedure; group II - subjected to bilateral orchiectomy and alpha-tocopherol supplementation for four weeks preceding the procedure; and group III - subjected to bilateral orchiectomy and alpha-tocopherol supplementation for four weeks preceding the procedure and for eight weeks afterwards. At the end of the experiment, the prostatectomy was performed in all rats. The presence of oxidative stress was determined by assaying the blood level of 8-isoprostane and the occurrence of apoptosis was evaluated by identification of active caspase-3 through immunohistochemical analysis. RESULTS: The statistic analysis of active caspase-3 showed that in the long-term castrated group the detection was higher than in groups were the alpha-tocopherol was supplemented (p=0.007. Analysis of 8-isoprostane levels showed higher concentrations of reactive oxygen species in group I compared to other groups (p<0.05. Groups II and III presented active caspase-3 lower than in group I (p<0.05. CONCLUSION: Our exploratory analyses demonstrate a method to study the aging process and its influence on oxidative stress of prostatic tissue and cells death rate. Based on our results we can suggest that alpha tocopherol supplementation can decrease the apoptotic process as well as the oxidative stress levels induced by androgen deprivation of the prostate gland.

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

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

2014-01-01

BACKGROUND: Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel...... 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...... fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly...

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.

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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

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

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

2015-01-01

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

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

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Yang C

2017-02-01

Full Text Available Chunguang Yang,1,* Xueyou Ma,1,* Zhihua Wang,1 Xing Zeng,1 Zhiquan Hu,1 Zhangqun Ye,1 Guanxin Shen2 1Department of Urology, Tongji Hospital, 2Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China *These authors contributed equally to this work 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

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.

Noninvasive Detection of AR-FL/AR-V7 as a Predictive Biomarker for Therapeutic Resistance in Men with Metastatic Castration-Resistant Prostate Cancer

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2017-10-01

acknowledged federal support) 5. Antonarakis ES, Armstrong AJ, Dehm SM, Luo J. Androgen receptor variant-driven prostate cancer : clinical implications...Resistant Prostate Cancer abstract Purpose A splice variant of the androgen receptor , AR-V7, confers resistance to AR-targeted therapies (ATTs) but not...androgen receptor ; AR-V7, androgen receptor splice variant 7; mCRPC, metastatic castration-resistant prostate cancer ; n/N, number of patients in that

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

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Käpyaho, K; Kallio, A; Jänne, J

1984-01-01

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

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

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

2017-01-01

Background aims  We investigated whether the addition of an autologous dendritic cell–based cancer vaccine (DCvac) induces an immune response in patients with metastatic castration-resistant prostate cancer treated with docetaxel.  Methods  Forty-three patients were randomized 1:1 to receive up...... twice through treatment cycles 1–4 and once through treatment cycles 5–10. Immune cell composition and antigen-specific responses were analyzed using flow cytometry, ELISpot and delayed type hypersensitivity (DTH) tests. Toxicity was graded according to Common Terminology Criteria for Adverse Events...... to local reactions. Decline in myeloid-derived suppressor cells at the third treatment cycle was found to be an independent predictor of DSS.  Conclusions  The addition of DCvac was safe. Immune responses were detected in approximately half of the patients investigated....

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

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V. B. Matveev

2017-01-01

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

Pharmacodynamic study of the oral hedgehog pathway inhibitor, vismodegib, in patients with metastatic castration-resistant prostate cancer.

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Maughan, Benjamin L; Suzman, Daniel L; Luber, Brandon; Wang, Hao; Glavaris, Stephanie; Hughes, Robert; Sullivan, Rana; Harb, Rana; Boudadi, Karim; Paller, Channing; Eisenberger, Mario; Demarzo, Angelo; Ross, Ashely; Antonarakis, Emmanuel S

2016-12-01

Hedgehog (Hh) pathway signaling has been implicated in prostate cancer tumorigenesis and metastatic development and may be upregulated even further in the castration-resistant state. We hypothesized that antagonism of the Hh pathway with vismodegib in men with metastatic castration-resistant prostate cancer (mCRPC) would result in pathway engagement, inhibition and perhaps induce measurable clinical responses in patients. This is a single-arm study of oral daily vismodegib in men with mCRPC. All patients were required to have biopsies of the tumor and skin (a surrogate tissue) at baseline and after 4 weeks of therapy. Ten patients were planned for enrollment. The primary outcome was the pharmacodynamic assessment of Gli1 mRNA suppression with vismodegib in tumor tissue. Secondary outcomes included PSA response rates, progression-free survival (PFS), overall survival (OS) and safety. Nine patients were enrolled. Gli1 mRNA was significantly suppressed by vismodegib in both tumor tissue (4/7 evaluable biopsies, 57%) and benign skin biopsies (6/8 evaluable biopsies, 75%). The median number of treatment cycles completed was three, with a median PFS of 1.9 months (95% CI 1.3, NA), and a median OS of 7.04 months (95% CI 3.4, NA). No patient achieved a PSA reduction or a measurable tumor response. Safety data were consistent with the known toxicities of vismodegib. Hh signaling, as measured by Gli1 mRNA expression in mCRPC tissues, was suppressed with vismodegib in the majority of patients. Despite this pharmacodynamic response that indicated target inhibition in some patients, there was no apparent signal of clinical activity. Vismodegib will not be developed further as monotherapy in mCRPC.

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

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

2017-12-22

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

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......) castrated under field conditions. Methods: SAA concentrations were determined on days 0, 3, and 8. Six horses were subsequently excluded because of elevated SAA concentrations on day 0. Of the remaining 50 horses, 26 were administered nonsteroidal anti-inflammatory drug (NSAID) therapy and 24 were...... administered NSAID and 25,000 U/kg procaine penicillin on day 0, 1, and 2. Results: SAA concentrations increased significantly from preoperative levels in both groups, and on day 8 concentrations were significantly (P o .02) higher in horses administered only NSAID than in those administered procaine penicillin...

Effect of testosterone administration on lead induced zincprotoporphyrin in blood concentration in castrated male rabbits

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Wibowo, A.A.E.; Zielhuis, R.L.

1981-11-01

The influence of testosterone propionate on the concentration of zincprotoporphyrin in blood (ZPP) of castrated lead treated rabbits was investigated. The experimental design allowed comparison of the relative ZPP increase (RZI) in testosterone treated and non testosterone treated rabbits. Testosterone was administered by subcutaneous injection of 3 mg/kg body weight/day for 7 consecutive days directly prior to the lead exposure, which was performed by subcutaneous injection of 0.50 mg lead acetate/kg body weight, three times a week for 7 weeks. No effect was found on the hemoglobin concentration (Hb) and hematocrit (Ht) and on the increase of body weight during the experiment. But the increase of RZI in the non testosterone treated rabbits was significantly steeper and earlier than in the testosterone treated group. The possible consequences of the findings had been further commented on.

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

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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.

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

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

2017-06-01

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

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

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Stefanie V Schütz

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

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

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

2017-02-15

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

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

Science.gov (United States)

Aragon-Ching, Jeanny B

2014-01-01

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.

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

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Jennifer H. Gunter

2012-01-01

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

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

Science.gov (United States)

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

2012-01-01

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

AR copy number and AR signaling-directed therapies in castration-resistant prostate cancer.

Science.gov (United States)

Salvi, Samanta; Conteduca, Vincenza; Lolli, Cristian; Testoni, Sara; Casadio, Valentina; Zaccheroni, Andrea; Rossi, Lorena; Burgio, Salvatore Luca; Menna, Cecilia; Schepisi, Giuseppe; De Giorgi, Ugo

2017-11-22

Adaptive upregulation of androgen receptor (AR) is the most common event involved in the progression from hormone sensitive to castration-resistant prostate cancer (CRPC). AR signaling remains the main target of new AR signalling-directed therapies such as abiraterone and enzalutamide in CRPC patients. In this review, we discuss general mechanisms of resistance to AR-targeted therapies, with a focus on the role of AR copy number (CN). We reported methods and clinical applications of AR CN evaluation in tissue and liquid biopsy, thus to have a complete information regarding its role as predictive and prognostic biomarker. Outcomes of CRPC patients are reported to be highly variable as consequence of tumor heterogeneity. AR CN could contribute to patient selection and tumor monitoring in CRPC treated with new anti-cancer treatment as abiraterone and enzalutamide. Further studies to investigate AR CN effect to these agents and its potential combination with other prognostic or predictive clinical factors are necessary in the context of harmonized clinical trial design. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Qualidade da carne de cordeiros castrados e não-castrados confinados sob dois fotoperíodos Meat quality of feedlot castrated or intact male lambs exposed to two photoperiod lengths

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Manoel Henrique Klein Júnior

2006-08-01

Full Text Available Objetivou-se avaliar a qualidade da carne por meio da determinação da composição centesimal e das características físicas da paleta e do lombo de 20 cordeiros mestiços Ideal, não-castrados (NC e castrados (C, submetidos a fotoperíodos curto, de 12 horas (FC, e longo, de 18 horas (FL. Os animais foram divididos ao acaso em esquema fatorial 2 x 2 (condição sexual x fotoperíodo, em quatro tratamentos (NC em FC; C em FC; NC em FL; e C em FL, com cinco repetições, sendo terminados em confinamento individual até que atingissem 37 kg de PV. A qualidade da carne foi determinada em amostras da paleta e do músculo Longissimus lumborum (LL. Os mais baixos teores de umidade e os mais altos de EE, tanto na paleta como no lombo, foram determinados na carne dos animais castrados. O fotoperíodo longo influenciou significativamente os teores de EE e proteína total do músculo LL. A capacidade de retenção de água foi afetada pelo FL, no qual foram encontrados percentuais mais baixos. Não houve efeito do fotoperíodo nem da condição sexual sobre a capacidade de absorção de água e a perda de peso por cozimento do músculo LL. Os valores de força de cisalhamento (FoCi na carne de cordeiros NC e dos submetidos ao FL foram superiores aos da carne dos animais castrados ou expostos ao FC.The objective of this study was to evaluate muscle composition and physical-chemical characteristics of 20 intact and castrated crossbred Ideal male lambs exposed to either a short photoperiod (SP of 12 h or to a long photoperiod (LP of 18 h. Animals were randomly assigned to four treatments (T in a 2 x 2 factorial arrangement with five repetitions as follows: intact lambs exposed to a SP; castrated lambs exposed to a SP; intact lambs exposed to a LP or castrated lambs exposed to a LP. Animals were maintained in individual pens until they reached 37 kg of body weight. Meat quality was determined in meat samples from the blade and from the Longissimus lumborum

Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial.

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Tannock, Ian F; Fizazi, Karim; Ivanov, Sergey; Karlsson, Camilla Thellenberg; Fléchon, Aude; Skoneczna, Iwona; Orlandi, Francisco; Gravis, Gwenaelle; Matveev, Vsevolod; Bavbek, Sevil; Gil, Thierry; Viana, Luciano; Arén, Osvaldo; Karyakin, Oleg; Elliott, Tony; Birtle, Alison; Magherini, Emmanuelle; Hatteville, Laurence; Petrylak, Daniel; Tombal, Bertrand; Rosenthal, Mark

2013-07-01

Docetaxel plus prednisone is standard first-line chemotherapy for men with metastatic castrate-resistant prostate cancer. Aflibercept is a recombinant human fusion protein that binds A and B isoforms of VEGF and placental growth factor, thereby inhibiting angiogenesis. We assessed whether the addition of aflibercept to docetaxel and prednisone would improve overall survival in men with metastatic castrate-resistant prostate cancer compared with the addition of placebo to docetaxel and prednisone. VENICE was a phase 3, multicentre, randomised double-blind placebo-controlled parallel group study done in 31 countries (187 sites). Men with metastatic castrate-resistant prostate cancer, adequate organ function, and no prior chemotherapy were treated with docetaxel (75 mg/m(2) intravenously every 3 weeks) and oral prednisone (5 mg twice daily) and randomly allocated (1:1) to receive aflibercept (6 mg/kg) or placebo, intravenously, every 3 weeks. Treatment allocation was done centrally via an interactive voice response system, using a computer-generated sequence with a permuted-block size of four and stratified according Eastern Co-operative Group performance status (0-1 vs 2). Patients, investigators, and other individuals responsible for study conduct and data analysis were masked to treatment assignment. Aflibercept or placebo vials were supplied in identical boxes. The primary endpoint was overall survival using intention-to-treat analysis. This is the primary analysis of the completed trial. The study is registered with ClinicalTrials.gov, number NCT00519285 FINDINGS: Between Aug 17, 2007, and Feb 11, 2010, 1224 men were randomly allocated to treatment: 612 to each group. At final analysis, median follow-up was 35 months (IQR 29-41) and 873 men had died. Median overall survival was 22·1 months (95·6% CI 20·3-24·1) in the aflibercept group and 21·2 months (19·6-23·8) in the placebo group (stratified hazard ratio 0·94, 95·6% CI 0·82-1·08; p=0·38). We

Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer

DEFF Research Database (Denmark)

Graff, J N; Baciarello, G; Armstrong, A J

2016-01-01

BACKGROUND: Prostate cancer disproportionately affects older men. Because age affects treatment decisions, it is important to understand the efficacy and tolerability of therapies for advanced prostate cancer in elderly men. This analysis describes efficacy and safety outcomes in men aged ≥75 years......-resistant prostate cancer. Overall survival (OS) and radiographic progression-free survival (rPFS) were coprimary end points. Subgroup analysis of men aged ≥75 years (elderly) and men aged ... who received enzalutamide, an androgen receptor inhibitor, in the phase III PREVAIL trial. PATIENTS AND METHODS: PREVAIL was a randomised, double-blind, multinational study of oral enzalutamide 160 mg/day (N = 872) versus placebo (N = 845) in chemotherapy-naive men with metastatic castration...

Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy.

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Liu, Vincent Wing Sun; Yau, Wing Lung; Tam, Chun Wai; Yao, Kwok-Ming; Shiu, Stephen Yuen Wing

2017-05-31

A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7), nuclear factor-kappa B (NF-κB) was activated and could result in up-regulated interleukin ( IL ) -6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC) pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT₁ receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion.

Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7-Induced Nuclear Factor-Kappa B (NF-κB Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC Therapy

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Vincent Wing Sun Liu

2017-05-01

Full Text Available A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7, nuclear factor-kappa B (NF-κB was activated and could result in up-regulated interleukin (IL-6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT1 receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion.

Transcript Levels of Androgen Receptor Variant 7 and Ubiquitin-Conjugating Enzyme 2C in Hormone Sensitive Prostate Cancer and Castration-Resistant Prostate Cancer.

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Lee, Chan Ho; Ku, Ja Yoon; Ha, Jung Min; Bae, Sun Sik; Lee, Jeong Zoo; Kim, Choung-Soo; Ha, Hong Koo

2017-01-01

This study is designed to identify the androgen receptor variant 7 (AR-V7) status, clinical significance of AR-V7 in hormone sensitive prostate cancer (HSPC). Then, we evaluated AR-V7 and changes of its target gene, ubiquitin-conjugating enzyme E2C (UBE2C) which is an anaphase-promoting complex/cyclosome (APC/C)-specific ubiquitin-conjugating enzyme, in castration-resistant prostate cancer (CRPC) in serial tumor biopsies from patients receiving androgen deprivation therapy. We used RT-PCR and Q-PCR assay to evaluate AR-V7, androgen receptor full length (AR-FL), and UBE2C in tumor biopsies from patients with HSPC and CRPC. We examined associations between mRNA expression of AR-V7 and clinicopathologic factors. Furthermore, to identify other potential genes involved in the development of CRPC, RNA sequencing was conducted, using paired prostate cancer (PCa) tissues obtained immediately prior to treatment and at the time of therapeutic resistance. A total of 13 HSPC patients and three CRPC patients were enrolled. Neither a high Gleason score (score of 8 and 9) nor a high risk of PCa (a high risk of locally advanced PCa according to NCCN guidelines) was correlated with mRNA expression of AR-V7 in HSPC (P = 0.153 and P = 0.215). The mRNA expression of AR-FL, but not AR-V7, was significantly associated with the mRNA expression of UBE2C level in HSPC (P = 0.007). However, increased expression of AR-V7, not AR-FL, paralleled increased expression of UBE2C in the CRPC specimens (P = 0.03). AR-V7 expression status before ADT was likely related to shorter CRPC development in patients treating ADT. The result of the RNA-sequencing analysis using serial samples from the same patient before and after castration demonstrated an increased level of the PI3K regulatory subunit 1 (P = 0.018). Our study revealed the role of UBE2C as a marker of the androgen signaling pathway in PCa. Differential gene expression analysis using serial samples from the same patient

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

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Parente, Phillip; Parnis, Francis; Gurney, Howard

2014-09-01

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

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

International Nuclear Information System (INIS)

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

2017-01-01

Therapy with the alpha-emitter radium-223 chloride ("2"2"3Ra) is an innovative therapeutic option in patients with metastasized, castration-resistant prostate cancer. However, radiotherapy can lead to hematopoietic toxicity. The aim of this study was to determine if "2"2"3Ra therapy induces an impairment of cellular antimicrobial immune responses. In 11 patients receiving "2"2"3Ra treatment, lymphocyte proliferation and the production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10) were determined, using lymphocyte transformation testing and ELISpot, respectively. Lymphocyte function after stimulation with mitogens and microbial antigens was assessed prior to therapy and at day 1, 7 and 28 after therapy. Lymphocyte proliferation and the production of interferon-γ and interleukin-10 towards mitogens and antigens remained unchanged after therapy. Consistent with these in vitro data, we did not observe infectious complications after treatment. The results argue against an impairment of lymphocyte function after "2"2"3Ra therapy. Thus, immune responses against pathogens should remain unaffected. (orig.)

Resistance to BET Inhibitor Leads to Alternative Therapeutic Vulnerabilities in Castration-Resistant Prostate Cancer.

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Pawar, Aishwarya; Gollavilli, Paradesi Naidu; Wang, Shaomeng; Asangani, Irfan A

2018-02-27

BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration-resistant prostate cancer (CRPC). Several BET inhibitors (BETi) that displace BRD4 from chromatin are being evaluated in clinical trials for CRPC. Here, we describe mechanisms of acquired resistance to BETi that are amenable to targeted therapies in CRPC. BETi-resistant CRPC cells displayed cross-resistance to a variety of BETi in the absence of gatekeeper mutations, exhibited reduced chromatin-bound BRD4, and were less sensitive to BRD4 degraders/knockdown, suggesting a BRD4-independent transcription program. Transcriptomic analysis revealed reactivation of AR signaling due to CDK9-mediated phosphorylation of AR, resulting in sensitivity to CDK9 inhibitors and enzalutamide. Additionally, increased DNA damage associated with PRC2-mediated transcriptional silencing of DDR genes was observed, leading to PARP inhibitor sensitivity. Collectively, our results identify the therapeutic limitation of BETi as a monotherapy; however, our BETi resistance data suggest unique opportunities for combination therapies in treating CRPC. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

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

International Nuclear Information System (INIS)

Du, Yong; Carrio, Ignasi; De Vincentis, Giuseppe; Fanti, Stefano; Ilhan, Harun; Mommsen, Caroline; Nitzsche, Egbert; Sundram, Francis; Vogel, Wouter; Oyen, Wim; Lewington, Val

2017-01-01

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

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

Energy Technology Data Exchange (ETDEWEB)

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

2017-09-15

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

PSMA-Based Radioligand Therapy for Metastatic Castration-Resistant Prostate Cancer: The Bad Berka Experience Since 2013.

Science.gov (United States)

Kulkarni, Harshad R; Singh, Aviral; Schuchardt, Christiane; Niepsch, Karin; Sayeg, Manal; Leshch, Yevgeniy; Wester, Hans-Juergen; Baum, Richard P

2016-10-01

A potential milestone in personalized nuclear medicine is theranostics of metastatic castration-resistant prostate cancer (mCRPC) based on molecular imaging using PET/CT with 68 Ga-labeled prostate-specific membrane antigen (PSMA) ligands and molecular radiotherapy using PSMA-targeted radioligand therapy (PRLT) with 177 Lu-PSMA ligands. 68 Ga-PSMA PET/CT enables accurate detection of mCRPC lesions with high diagnostic sensitivity and specificity and provides quantitative and reproducible data that can be used to select patients for PRLT and therapeutic monitoring. Our comprehensive experience over the last 3 years using different radioligands indicates that PRLT is highly effective for the treatment of mCRPC, even in advanced cases, and potentially lends a significant benefit to overall and progression-free survival. Additionally, significant improvement in clinical symptoms and excellent palliation of pain can be achieved. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Antiproliferative activity of novel imidazopyridine derivatives on castration-resistant human prostate cancer cells.

Science.gov (United States)

Muniyan, Sakthivel; Chou, Yu-Wei; Ingersoll, Matthew A; Devine, Alexus; Morris, Marisha; Odero-Marah, Valerie A; Khan, Shafiq A; Chaney, William G; Bu, Xiu R; Lin, Ming-Fong

2014-10-10

Metastatic prostate cancer (mPCa) relapses after a short period of androgen deprivation therapy and becomes the castration-resistant prostate cancer (CR PCa); to which the treatment is limited. Hence, it is imperative to identify novel therapeutic agents towards this patient population. In the present study, antiproliferative activities of novel imidazopyridines were compared. Among three derivatives, PHE, AMD and AMN, examined, AMD showed the highest inhibitory activity on LNCaP C-81 cell proliferation, following dose- and time-dependent manner. Additionally, AMD exhibited significant antiproliferative effect against a panel of PCa cells, but not normal prostate epithelial cells. Further, when compared to AMD, its derivative DME showed higher inhibitory activities on PCa cell proliferation, clonogenic potential and in vitro tumorigenicity. The inhibitory activity was apparently in part due to the induction of apoptosis. Mechanistic studies indicate that AMD and DME treatments inhibited both AR and PI3K/Akt signaling. The results suggest that better understanding of inhibitory mechanisms of AMD and DME could help design novel therapeutic agents for improving the treatment of CR PCa. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

PTEN loss promotes intratumoral androgen synthesis and tumor microenvironment remodeling via aberrant activation of RUNX2 in castration-resistant prostate cancer

Science.gov (United States)

Yang, Yinhui; Bai, Yang; He, Yundong; Zhao, Yu; Chen, Jiaxiang; Ma, Linlin; Pan, Yunqian; Hinten, Michael; Zhang, Jun; Karnes, R. Jeffrey; Kohli, Manish; Westendorf, Jennifer J.; Li, Benyi; Zhu, Runzhi; Huang, Haojie; Xu, Wanhai

2018-01-01

Purpose Intratumoral androgen synthesis (IAS) is a key mechanism promoting androgen receptor (AR)reactivation and anti-androgen resistance in castration-resistant prostate cancer (CRPC). However, signaling pathways driving aberrant IAS remain poorly understood. Experimental Design The effect of components of the AKT-RUNX2-osteocalcin (OCN)-GPRC6A-CREB signaling axis on expression of steroidogenesis genes CYP11A1 and CYP17A1 and testosterone level were examined in PTEN-null human PCa cell lines. Pten knockout mice were employed to examine the effect of Runx2 heterozygous deletion or abiraterone acetate (ABA), a prodrug of the CYP17A1 inhibitor abiraterone on Cyp11a1 and Cyp17a1 expression, testosterone level and tumor microenvironment (TME) remodeling in vivo. Results We uncovered that activation of the AKT-RUNX2-OCN-GPRC6A-CREB signaling axis induced expression of CYP11A1 and CYP17A1 and testosterone production in PTEN-null PCa cell lines in culture. Deletion of Runx2 in Pten homozygous knockout prostate tumors decreased Cyp11a1 and Cyp17a1 expression, testosterone level and tumor growth in castrated mice. ABA treatment also inhibited testosterone synthesis and alleviated Pten loss-induced tumorigenesis in vivo. Pten deletion induced TME remodeling, but Runx2 heterozygous deletion or ABA treatment reversed the effect of Pten loss by decreasing expression of the collagenase Mmp9. Conclusions Abnormal RUNX2 activation plays a pivotal role in PTEN loss-induced IAS and TME remodeling, suggesting that the identified signaling cascade represents a viable target for effective treatment of PTEN-null PCa including CRPC. PMID:29167276

Effects of tramadol or morphine in dogs undergoing castration on intra-operative electroencephalogram responses and post-operative pain.

Science.gov (United States)

Kongara, K; Chambers, J P; Johnson, C B; Dukkipati, V S R

2013-11-01

To compare the effects of pre-operatively administered tramadol with those of morphine on electroencephalographic responses to surgery and post-operative pain in dogs undergoing castration. Dogs undergoing castration were treated with either pre-operative morphine (0.5 mg/kg S/C, n = 8) or tramadol (3 mg/kg S/C, n = 8). All dogs also received 0.05 mg/kg acepromazine and 0.04 mg/kg atropine S/C in addition to the test analgesic. Anaesthesia was induced with thiopentone administered I/V to effect and maintained with halothane in oxygen. Respiratory rate, heart rate, end-tidal halothane tension (EtHal) and end-tidal CO2 tension (EtCO2) were monitored throughout surgery. Electroencephalograms (EEG) were recorded continuously using a three electrode montage. Median frequency (F50), total power (Ptot) and 95% spectral edge frequency (F95) derived from EEG power spectra recorded before skin incision (baseline) were compared with those recorded during ligation of the spermatic cords of both testicles. Post-operatively, pain was assessed after 1, 3, 6 and 9 h using the short form of the Glasgow composite measure pain scale (CMPS-SF). Dogs premedicated with tramadol had higher mean F50 (12.2 (SD 0.2) Hz) and lower Ptot (130.39 (SD 12.1) µv(2)) compared with those premedicated with morphine (11.5 (SD 0.2) Hz and 161.8 (SD 15.1) µv(2), respectively; p0.05). The F95 of the EEG did not differ between the two groups during the ligation of either testicle (p > 0.05). Post-operatively, no significant differences in the CMPS-SF score were found between animals premedicated with tramadol and morphine at any time during the post-operative period. No dog required rescue analgesia. Tramadol and morphine administered pre-operatively provided a similar degree of post-operative analgesia in male dogs at the doses tested.

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

International Nuclear Information System (INIS)

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

2015-10-01

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

Características de carcaças de bovinos Nelore inteiros vs castrados em duas idades, terminados em confinamento Carcass characteristics of Nellore cattle kept intact or castrated at two ages, feedlot finished

Directory of Open Access Journals (Sweden)

Aline Kellermann de Freitas

2008-06-01

Full Text Available Objetivou-se avaliar os rendimentos em carcaça e cortes primários de bovinos da raça Nelore, submetidos aos tratamentos: C13 = castrados aos 13 meses de idade (n=26; C18 = novilhos castrados aos 18 meses de idade antes do confinamento (n=26 e INT = novilhos inteiros (n=25. Os animais foram confinados por 100 dias, recebendo dieta com 12% de proteína bruta, 2,9 Mcal de energia digestível/kg de matéria seca (MS e relação volumoso:concentrado de 60:40 (base na MS, e abatidos aos 22 meses de idade. O delineamento experimental utilizado foi o inteiramente casualizado. Os INT apresentaram maiores pesos ao abate (395,00 kg, de carcaça quente (214,89 kg e de carcaça fria - PCF (212,21 kg que os castrados, não ocorrendo diferenças entre os castrados. Os INT apresentaram maior rendimento de carcaça fria (53,71% e área de olho-de-lombo (AOL (61,23 cm² que os C13 (51,99% e 56,59 cm², respectivamente, não havendo diferenças entre C13 vs C18 e C18 vs INT. A condição sexual não influenciou o rendimento de carcaça quente, a perda por resfriamento da carcaça, AOL/100 kg PCF, comprimento de carcaça, comprimento e perímetro do braço e peso de ponta de agulha. Os INT apresentaram menores valores para espessura de gordura em relação aos castrados, que não diferiram entre si. Machos INT apresentaram maior percentual de dianteiro (40,13 e menores de ponta de agulha (10,22 e de traseiro (50,24 em relação aos C13 (38,33; 11,09 e 51,77, respectivamente e C18 (38,82; 10,73 e 51,46, respectivamente, que não diferiram entre si. Em valores absolutos, os INT apresentaram maior peso de dianteiro que os castrados, que não foram diferentes entre si, e maior peso de traseiro que os C13.Carcass dressing and primary cuts of Nellore cattle, submitted to the treatments: C13 = steers castrated at 13 months of age (n=26; C18 = steers castrated at 18 months of age before feedlot (n=26 and INT = intact males (n=25 was evaluated in this researach. The

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

Science.gov (United States)

Käpyaho, K; Kallio, A; Jänne, J

1984-05-01

2-Difluoromethylornithine totally prevented any increases in putrescine and spermidine concentrations in the ventral prostate of castrated rats during a 6-day testosterone treatment. Prostatic ornithine decarboxylase activity was inhibited by 80%, whereas S-adenosylmethionine decarboxylase was stimulated by more than 9-fold. In seminal vesicle, the inhibition of putrescine and spermidine accumulation, as well as of ornithine decarboxylase activity, was only minimal, and no stimulation of S-adenosylmethionine decarboxylase was observed. Administration of methylglyoxal bis(guanylhydrazone) to castrated androgen-treated rats resulted in a marked increase in concentrations of all prostatic polyamines. Prostatic ornithine decarboxylase activity was nearly 2 times and adenosylmethionine decarboxylase activity 9 times higher than that of the testosterone-treated animals. In contrast with ventral prostate, methylglyoxal bis(guanylhydrazone) treatment inhibited moderately the accumulation of spermidine and spermine in seminal vesicle, although both ornithine decarboxylase and S-adenosylmethionine decarboxylase activities were stimulated. Difluoromethylornithine inhibited significantly the weight gain of ventral prostate, but methylglyoxal bis(guanylhydrazone) produced a substantial increase in prostatic weight. These changes were largely due to the fact that the volume of prostatic secretion was greatly decreased by difluoromethylornithine, whereas methylglyoxal bis(guanylhydrazone) increased the amount of secretion. Treatment with difluoromethylornithine strikingly increased the methylglyoxal bis(guanylhydrazone) content of both ventral prostate and seminal vesicle, but even under these conditions the drug concentration remained low in comparison with other tissues. The results indicate that a combined use of these two polyamine anti-metabolites does not necessarily result in a synergistic growth inhibition of the androgen-induced growth of male accessory sexual glands.

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

Directory of Open Access Journals (Sweden)

Ali Zhang

2015-10-01

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

Methylated Glutathione S-transferase 1 (mGSTP1) is a potential plasma free DNA epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer

OpenAIRE

Mahon, K L; Qu, W; Devaney, J; Paul, C; Castillo, L; Wykes, R J; Chatfield, M D; Boyer, M J; Stockler, M R; Marx, G; Gurney, H; Mallesara, G; Molloy, P L; Horvath, L G; Clark, S J

2014-01-01

Background: Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS). Methods: Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort ...

Profile of apalutamide in the treatment of metastatic castration-resistant prostate cancer: evidence to date.

Science.gov (United States)

Chong, Julio T; Oh, William K; Liaw, Bobby C

2018-01-01

Advances in therapies have led to the approval of six therapeutic agents since 2004, each demonstrating overall survival benefit in randomized studies, and these have significantly improved the outlook for men facing metastatic castration-resistant prostate cancer (CRPC). More recently, efforts have been directed at trying to effect change at earlier phases of the disease. Apalutamide (ARN-509), a second-generation androgen receptor antagonist, recently received approval in the nonmetastatic (M0) CRPC space. Similar to enzalutamide, apalutamide inhibits the binding of androgen to androgen receptor (AR), nuclear translocation of the androgen-AR complex, and binding of AR transcription complex to DNA-binding sites and transcription elements. Phase I and II trial experience demonstrates the safety and tolerability of apalutamide, as well as its efficacy in effecting prostate-specific antigen response and radiographic-free survival in CRPC. US Food and Drug Administration approval in M0 CRPC was granted following positive results from the phase III SPARTAN study, where apalutamide demonstrated significant improvements in metastasis-free survival and time to symptomatic progression as compared to placebo.

Common structural and epigenetic changes in the genome of castration-resistant prostate cancer.

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Friedlander, Terence W; Roy, Ritu; Tomlins, Scott A; Ngo, Vy T; Kobayashi, Yasuko; Azameera, Aruna; Rubin, Mark A; Pienta, Kenneth J; Chinnaiyan, Arul; Ittmann, Michael M; Ryan, Charles J; Paris, Pamela L

2012-02-01

Progression of primary prostate cancer to castration-resistant prostate cancer (CRPC) is associated with numerous genetic and epigenetic alterations that are thought to promote survival at metastatic sites. In this study, we investigated gene copy number and CpG methylation status in CRPC to gain insight into specific pathophysiologic pathways that are active in this advanced form of prostate cancer. Our analysis defined and validated 495 genes exhibiting significant differences in CRPC in gene copy number, including gains in androgen receptor (AR) and losses of PTEN and retinoblastoma 1 (RB1). Significant copy number differences existed between tumors with or without AR gene amplification, including a common loss of AR repressors in AR-unamplified tumors. Simultaneous gene methylation and allelic deletion occurred frequently in RB1 and HSD17B2, the latter of which is involved in testosterone metabolism. Lastly, genomic DNA from most CRPC was hypermethylated compared with benign prostate tissue. Our findings establish a comprehensive methylation signature that couples epigenomic and structural analyses, thereby offering insights into the genomic alterations in CRPC that are associated with a circumvention of hormonal therapy. Genes identified in this integrated genomic study point to new drug targets in CRPC, an incurable disease state which remains the chief therapeutic challenge. ©2012 AACR.

Silencing CAPN2 Expression Inhibited Castration-Resistant Prostate Cancer Cells Proliferation and Invasion via AKT/mTOR Signal Pathway

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Pu Li

2017-01-01

Full Text Available The mRNA expression of CAPN2 was upregulated in CRPC cells (DU145 and PC3 than that in non-CRPC cells. Silencing CAPN2 expression could inhibit DU145 and PC3 cells proliferation by cell cycle arrest at G1 phase. Knockdown of CPAN2 level suppressed the migration and invasion capacity of CRPC cells by reducing matrix metalloproteinase-2 (MMP-2 and MMP-9 activation, as well as repressing the phosphorylation protein expression of AKT and mTOR. In addition, we found that the expression of CAPN2 was elevated in Pca tissues than that in normal control tissues. Therefore, we showed the important roles of CAPN2 in the development and progression in CRPC cells, suggesting a new therapeutic intervention for treating castration-resistant prostate cancer patients.

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

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Maughan, Benjamin L; Antonarakis, Emmanuel S

2015-12-01

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

Prediction of overall survival for patients with metastatic castration-resistant prostate cancer: development of a prognostic model through a crowdsourced challenge with open clinical trial data.

Science.gov (United States)

Guinney, Justin; Wang, Tao; Laajala, Teemu D; Winner, Kimberly Kanigel; Bare, J Christopher; Neto, Elias Chaibub; Khan, Suleiman A; Peddinti, Gopal; Airola, Antti; Pahikkala, Tapio; Mirtti, Tuomas; Yu, Thomas; Bot, Brian M; Shen, Liji; Abdallah, Kald; Norman, Thea; Friend, Stephen; Stolovitzky, Gustavo; Soule, Howard; Sweeney, Christopher J; Ryan, Charles J; Scher, Howard I; Sartor, Oliver; Xie, Yang; Aittokallio, Tero; Zhou, Fang Liz; Costello, James C

2017-01-01

Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease. Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interest-namely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a

Second-Line Hormonal Therapy for Men With Chemotherapy-Naïve, Castration-Resistant Prostate Cancer: American Society of Clinical Oncology Provisional Clinical Opinion.

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Virgo, Katherine S; Basch, Ethan; Loblaw, D Andrew; Oliver, Thomas K; Rumble, R Bryan; Carducci, Michael A; Nordquist, Luke; Taplin, Mary-Ellen; Winquist, Eric; Singer, Eric A

2017-06-10

Purpose ASCO provisional clinical opinions (PCOs) offer direction to the ASCO membership after publication or presentation of potential practice-changing data. This PCO addresses second-line hormonal therapy for chemotherapy-naïve men with castration-resistant prostate cancer (CRPC) who range from being asymptomatic with only biochemical evidence of CRPC to having documented metastases but minimal symptoms. Clinical Context The treatment goal for CRPC is palliation. Despite resistance to initial androgen deprivation therapy, most men respond to second-line hormonal therapies. However, guidelines have neither addressed second-line hormonal therapy for nonmetastatic CRPC nor provided specific guidance with regard to the chemotherapy-naïve population. Recent Data Six phase III randomized controlled trials and expert consensus opinion inform this PCO. Provisional Clinical Opinion For men with CRPC, a castrate state should be maintained indefinitely. Second-line hormonal therapy (eg, antiandrogens, CYP17 inhibitors) may be considered in patients with nonmetastatic CRPC at high risk for metastatic disease (rapid prostate-specific antigen doubling time or velocity) but otherwise is not suggested. In patients with radiographic evidence of metastases and minimal symptoms, enzalutamide or abiraterone plus prednisone should be offered after discussion with patients about potential harms, benefits, costs, and patient preferences. Radium-223 and sipuleucel-T also are options. No evidence provides guidance about the optimal order of hormonal therapies for CRPC beyond second-line treatment. Prostate-specific antigen testing every 4 to 6 months is reasonable for men without metastases. Routine radiographic restaging generally is not suggested but can be considered for patients at risk for metastases or who exhibit symptoms or other evidence of progression. Additional information is available at www.asco.org/genitourinary-cancer-guidelines and www.asco.org/guidelineswiki .

Bladder outlet obstruction (BOO) in men with castration-resistant prostate cancer.

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Rom, Maximilian; Waldert, Matthias; Schatzl, Georg; Swietek, Natalia; Shariat, Shahrokh F; Klatte, Tobias

2014-07-01

To evaluate the frequency of bladder outlet obstruction (BOO) and detrusor overactivity (DO) in patients with castration-resistant prostate cancer (CRPC) and lower urinary tract symptoms (LUTS). Our prospective urodynamics database was queried. Inclusion criteria were CRPC and an International Prostate Symptom Score (IPSS) ≥ 20. Exclusion criteria were previous local therapy to the prostate gland, known urethral stricture disease, and a neurological component of LUTS. Twenty-one patients were identified. Urodynamic findings were analysed and compared with those of a matched cohort of 42 patients with benign prostatic enlargement (BPE). The median age of patients in the CRPC group was 74 years, and the median prostate-specific antigen (PSA) level at the time of the urodynamic study was 90 ng/mL. According to the BOO index, three patients (14%) were obstructed, three were equivocally obstructed (14%) and 15 were unobstructed. DO was seen in 12 patients (57%). Compared with the BPE group, patients with CRPC had lower cystometric bladder capacities (P = 0.003), were less likely to have BOO (14 vs 43%, P = 0.009) and more likely to have DO (57 vs 29%, P = 0.028). This study generates the hypothesis that only a minority of CRPC patients with LUTS have BOO, and that more than half of patients have DO. LUTS in CRPC may therefore be seldom attributable to BOO, but are, at least in part, related to DO and reduced cystometric capacity. A urodynamic investigation may be necessary before palliative transurethral resection of the prostate to select appropriate candidates. Larger prospective studies are needed to confirm our findings. © 2013 The Authors. BJU International © 2013 BJU International.

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

DEFF Research Database (Denmark)

Bødker, A; Balslev, E; Iversen, H G

1997-01-01

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

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

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Letícia Cristina COSTA E SILVA

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

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

Science.gov (United States)

Henningsson, S; Persson, L; Rosengren, E

1979-02-01

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

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.

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

International Nuclear Information System (INIS)

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

2011-01-01

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

Non-Coding RNAs in Castration-Resistant Prostate Cancer: Regulation of Androgen Receptor Signaling and Cancer Metabolism.

Science.gov (United States)

Shih, Jing-Wen; Wang, Ling-Yu; Hung, Chiu-Lien; Kung, Hsing-Jien; Hsieh, Chia-Ling

2015-12-04

Hormone-refractory prostate cancer frequently relapses from therapy and inevitably progresses to a bone-metastatic status with no cure. Understanding of the molecular mechanisms conferring resistance to androgen deprivation therapy has the potential to lead to the discovery of novel therapeutic targets for type of prostate cancer with poor prognosis. Progression to castration-resistant prostate cancer (CRPC) is characterized by aberrant androgen receptor (AR) expression and persistent AR signaling activity. Alterations in metabolic activity regulated by oncogenic pathways, such as c-Myc, were found to promote prostate cancer growth during the development of CRPC. Non-coding RNAs represent a diverse family of regulatory transcripts that drive tumorigenesis of prostate cancer and various other cancers by their hyperactivity or diminished function. A number of studies have examined differentially expressed non-coding RNAs in each stage of prostate cancer. Herein, we highlight the emerging impacts of microRNAs and long non-coding RNAs linked to reactivation of the AR signaling axis and reprogramming of the cellular metabolism in prostate cancer. The translational implications of non-coding RNA research for developing new biomarkers and therapeutic strategies for CRPC are also discussed.

Amelioration of sexual behavior and motor activity deficits in a castrated rodent model with a selective androgen receptor modulator SARM-2f.

Directory of Open Access Journals (Sweden)

Megumi Morimoto

Full Text Available Sarcopenia and cachexia present characteristic features of a decrease in skeletal muscle mass and strength, anorexia, and lack of motivation. Treatments for these diseases have not yet been established, although selective androgen receptor modulators (SARMs are considered as therapeutic targets. We previously reported that a novel SARM compound, SARM-2f, exhibits anabolic effect on muscles, with less stimulatory effect on prostate weight compared with testosterone, in rat Hershberger assays and cancer cachexia models. In this study, we studied the mechanism of action for SARM-2f selectivity and also assessed whether the muscle increase by this compound might lead to improvement of muscle function and physical activity. First, we examined the tissue distribution of SARM-2f. Tissue concentration was 1.2-, 1.6-, and 1.9-fold as high as the plasma concentration in the levator ani muscle, brain, and prostate, respectively. This result showed that the tissue-selective pharmacological effect did not depend on SARM-2f concentration in the tissues. The ability of SARM-2f to influence androgen receptor (AR-mediated transcriptional activation was examined by reporter assays using human normal prostate epithelial cells (PrEC and skeletal muscle cells (SKMC. SARM-2f exerted higher activity against AR in SKMC than in PrEC. Mammalian two hybrid assays showed different co-factor recruitment patterns between SARM-2f and dihydrotestosterone. Next, we studied the effect of SARM-2f on motivation and physical functions such as sexual behavior and motor activities in castrated rat or mouse models. SARM-2f restored the sexual behavior that was lost by castration in male rats. SARM-2f also increased voluntary running distance and locomotor activities. These results suggest that tissue-specific AR regulation by SARM-2f, but not tissue distribution, might account for its tissue specific androgenic effect, and that the muscle mass increase by SARM-2f leads to improvement

Epigenetic markers in circulating cell-free DNA as prognostic markers for survival of castration-resistant prostate cancer patients.

Science.gov (United States)

Hendriks, Rianne J; Dijkstra, Siebren; Smit, Frank P; Vandersmissen, Johan; Van de Voorde, Hendrik; Mulders, Peter F A; van Oort, Inge M; Van Criekinge, Wim; Schalken, Jack A

2018-04-01

Noninvasive biomarkers to guide personalized treatment for castration-resistant prostate cancer (CRPC) are needed. In this study, we analyzed hypermethylation patterns of two genes (GSTP1 and APC) in plasma cell-free DNA (cfDNA) of CRPC patients. The aim of this study was to analyze the cfDNA concentrations and levels of the epigenetic markers and to assess the value of these biomarkers for prognosis. In this prospective study, patients were included before starting new treatment after developing CRPC. The blood samples were collected prior to start of the treatment and at three time points thereafter. cfDNA was extracted from 1.5 mL of plasma and before performing a methylation-specific PCR, bisulfate modification was carried out. The median levels of cfDNA, GSTP1, and APC copies in the baseline samples of CRPC patients (n = 47) were higher than in controls (n = 30). In the survival analysis, the group with baseline marker levels below median had significant less PCa-related deaths (P-values Prostate Published by Wiley Periodicals, Inc.

[14C]Fluciclovine (alias anti-[14C]FACBC) uptake and ASCT2 expression in castration-resistant prostate cancer cells

International Nuclear Information System (INIS)

Ono, Masahiro; Oka, Shuntaro; Okudaira, Hiroyuki; Nakanishi, Takeo; Mizokami, Atsushi; Kobayashi, Masato; Schuster, David M.; Goodman, Mark M.; Shirakami, Yoshifumi; Kawai, Keiichi

2015-01-01

Introduction: trans-1-Amino-3-[ 18 F]fluorocyclobutanecarboxylic acid ([ 18 F]fluciclovine, also known as anti-[ 18 F]FACBC), is a tracer for positron emission tomography (PET) imaging for detection of tumors such as prostate cancer (PCa). Our previous study showed that ASCT2 (Na + -dependent amino acid transporter (AAT)) mediates fluciclovine uptake in androgen-dependent PCa cells; its expression is influenced by androgen, a key hormone in the progression of primary PCa and castration-resistant prostate cancer (CRPC). In this study, we investigated the uptake mechanisms and feasibility of [ 18 F]fluciclovine for CRPC in the androgen-dependent PCa cell line LNCaP and LNCaP-derivatives LNCaP-SF and LN-REC4. Methods: LNCaP-SF was established after long-term cultivation of LNCaP in steroid-free conditions, and LN-Pre and LN-REC4 were established from LNCaP inoculated in intact and castrated severe combined immunodeficient mice, respectively. Uptake and competitive inhibition experiments were performed with trans-1-amino-3-fluoro[1- 14 C]cyclobutanecarboxylic acid ([ 14 C]fluciclovine) to characterize the involvement of AATs in androgen-dependent PCa (LNCaP and LN-Pre) and CRPC-like (LNCaP-SF and LN-REC4) cell lines. AAT expression was analyzed by Western blotting, and [ 14 C]fluciclovine uptake in androgen-dependent PCa and CRPC-like cell lines were investigated in the presence or absence of dihydrotestosterone (DHT). Results: The contribution of Na + -dependent AATs to [ 14 C]fluciclovine uptake in all cell lines was 88−98%, and [ 14 C]fluciclovine uptake was strongly inhibited by L-glutamine and L-serine, the substrates for Na + -dependent alanine-serine-cysteine (system ASC) AATs, in the presence of Na + . DHT enhanced ASCT2 expression in LNCaP, LN-Pre, and LN-REC4, but not in LNCaP-SF, and the responses of ASCT2 expression to DHT correlated with [ 14 C]fluciclovine uptake. Conclusions: System ASC, especially ASCT2, could play a major role in [ 14 C

AR-V7 in Peripheral Whole Blood of Patients with Castration-resistant Prostate Cancer: Association with Treatment-specific Outcome Under Abiraterone and Enzalutamide.

Science.gov (United States)

Seitz, Anna Katharina; Thoene, Silvia; Bietenbeck, Andreas; Nawroth, Roman; Tauber, Robert; Thalgott, Mark; Schmid, Sebastian; Secci, Ramona; Retz, Margitta; Gschwend, Jürgen E; Ruland, Jürgen; Winter, Christof; Heck, Matthias M

2017-11-01

It has been demonstrated that androgen receptor splice variant 7 (AR-V7) expression in circulating tumor cells (CTCs) predicts poor treatment response in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone or enzalutamide. To develop a practical and robust liquid profiling approach for direct quantification of AR-V7 in peripheral whole blood without the need for CTC capture and to determine its potential for predicting treatment response in mCRPC patients. Whole blood samples from a prospective biorepository of 85 mCRPC patients before treatment initiation with abiraterone (n=56) or enzalutamide (n=29) were analyzed via droplet digital polymerase chain reaction. The association of AR-V7 status with prostate-specific antigen (PSA) response defined by PSA decline ≥50% and with PSA-progression-free survival (PSA-PFS), clinical PFS, and overall survival (OS) was assessed. High AR-V7 expression levels in whole blood were detectable in 18% (15/85) of patients. No patient with high AR-V7 expression achieved a PSA response, and AR-V7 status was an independent predictor of PSA response in multivariable logistic regression analysis (p=0.03). High AR-V7 expression was associated with shorter PSA-PFS (median 2.4 vs 3.7 mo; pAR-V7 expression remained an independent predictor of shorter PSA-PFS (hazard ratio [HR] 7.0, 95% confidence interval [CI] 2.3-20.7; pAR-V7 mRNA levels in whole blood is a simple and promising approach to predict poor treatment outcome in mCRPC patients receiving abiraterone or enzalutamide. We established a method for determining AR-V7 status in whole blood. This test predicted treatment resistance in patients with metastatic castration-resistant prostate cancer undergoing treatment with abiraterone or enzalutamide. Prospective validation is needed before application to clinical practice. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Symptoms and Impacts in Non-Metastatic Castration-Resistant Prostate Cancer: Qualitative Study Findings.

Science.gov (United States)

Tomaszewski, Erin L; Moise, Pierre; Krupnick, Robert N; Downing, Jared; Meyer, Margaret; Naidoo, Shevani; Holmstrom, Stefan

2017-10-01

We developed a conceptual model to define key concepts associated with patients' experiences with the signs, symptoms, and impacts of non-metastatic castration-resistant prostate cancer (M0-CRPC). A targeted review of peer-reviewed literature, and other publicly available information, identified and categorized symptoms and impacts related to early-stage prostate cancer. Semi-structured interviews with five clinical experts helped determine the most relevant and important concepts for patients with M0-CRPC. Qualitative interviews with 17 patients with M0-CRPC identified the most frequently experienced symptoms and impacts, and their degree of interference with patients' lives. The findings from these three lines of evidence were summarized in a conceptual model. Literature searches identified mainly urinary, intestinal, and sexual symptoms. Experts noted the symptoms most frequently mentioned by patients include erectile dysfunction, loss of sexual desire or interest, incontinence/leaking, urgency, and hot flashes. Patient interviews confirmed the high frequency of erectile dysfunction, loss of libido, urinary urgency, and incontinence. The most frequently mentioned impacts expressed by patients were the need to monitor/plan for urinary frequency, interference with/restriction of daily activities, and frustration or anxiety over diagnosis, symptoms, or treatment. Symptoms and impacts most frequently experienced by patients were typically not those with the greatest effects on their lives; rather, those with the greatest consequences were related to treatment. The leading concerns associated with M0-CRPC were related to voiding and sexual dysfunction. The most relevant symptoms and impacts expressed by patients may be a consequence of therapy rather than of the disease.

Protective effects of seahorse extracts in a rat castration and testosterone-induced benign prostatic hyperplasia model and mouse oligospermatism model.

Science.gov (United States)

Xu, Dong-Hui; Wang, Li-Hong; Mei, Xue-Ting; Li, Bing-Ji; Lv, Jun-Li; Xu, Shi-Bo

2014-03-01

This study investigated the effects of seahorse (Hippocampus spp.) extracts in a rat model of benign prostatic hyperplasia (BPH) and mouse model of oligospermatism. Compared to the sham operated group, castration and testosterone induced BPH, indicated by increased penile erection latency; decreased penis nitric oxide synthase (NOS) activity; reduced serum acid phosphatase (ACP) activity; increased prostate index; and epithelial thickening, increased glandular perimeter, increased proliferating cell nuclear antigen (PCNA) index and upregulation of basic fibroblast growth factor (bFGF) in the prostate. Seahorse extracts significantly ameliorated the histopathological changes associated with BPH, reduced the latency of penile erection and increased penile NOS activity. Administration of seahorse extracts also reversed epididymal sperm viability and motility in mice treated with cyclophosphamide (CP). Seahorse extracts have potential as a candidate marine drug for treating BPH without inducing the side effects of erectile dysfunction (ED) or oligospermatism associated with the BPH drug finasteride. Copyright © 2014 Elsevier B.V. All rights reserved.

Safety of Abiraterone Acetate in Castration-resistant Prostate Cancer Patients With Concomitant Cardiovascular Risk Factors.

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Procopio, Giuseppe; Grassi, Paolo; Testa, Isabella; Verzoni, Elena; Torri, Valter; Salvioni, Roberto; Valdagni, Riccardo; de Braud, Filippo

2015-10-01

The aim of this study was to evaluate the safety profile of abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC) men with cardiovascular comorbidity, as little conclusive safety data are available in this patient subset. A retrospective analysis of mCRPC patients with controlled cardiovascular comorbidities, receiving AA 1000 mg administered orally once daily and prednisone 5 mg twice daily, between April 2011 and July 2012, was performed. All clinical and instrumental variables and toxicity data were analyzed by descriptive statistics: mean, standard deviation, minimum and maximum values for continuous variables, and absolute and relative frequencies for categorical variables. A total of 51 mCRPC patients were evaluated. Metastatic sites included the bone (74%), lungs, and liver (26%). All patients were previously treated with at least 2 lines of hormone and 1 docetaxel-based chemotherapy. Preexisting cardiac risk factors included hypertension (41%), cardiac ischemia (12%), arrhythmias (6%), dislipidemia (18%), and hyperglycemia (30%). No grade 3-4 adverse events were observed. Grade 1-2 adverse events included fluid retention (18%), asthenia (15%), and hypertension (16%). Median progression-free survival was 5.1 months (95% confidence interval, 0.5-12). Prostate specific antigen assessment revealed a good overall disease control rate (64%). AA appears to be safe and well tolerated even in patients with cardiovascular comorbidities or with increased risk factors for cardiovascular diseases.

Efeito da castração sobre parâmetros químicos, físico-químicos e sensoriais da carne caprina de animais mestiços Effect of castration on chemical, phisico-chemical and sensorial parameters of the "mestiço" goat meat

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Marta Suely MADRUGA

2000-04-01

Full Text Available Foi estudado o efeito da castração sobre a umidade, cinzas, gordura, proteína, cálcio, ferro, fósforo, valores de pH, atividade de água, aparência, aroma caprino, aroma de carne assada, sabor, suculência, maciez, textura e qualidade total da carne caprina de animais mestiços. Dentre os parâmetros analisados, rigorosamente a castração dos animais teve efeito significativo apenas em relação ao cálcio, cujo teor aumentou em 33%.The effect of castration on moisture, ashes, fat, protein, calcium, iron, phosphorus, pH value, water activity, appearance, "goaty" aroma, roasted meat aroma, flavour, juiciness, tenderness, texture and overall palatability of goat meat from "mestiços" animals were studied. Among the parameters analysed, the castration of animals had a significant effect only on calcium content, whose content increased in 33%.

Baseline prostate-specific antigen levels following treatment with abiraterone acetate as a prognostic factor in castration-resistant prostate cancer.

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Hiroshige, Tasuku; Eguchi, Yoshiro; Yoshizumi, Osamu; Chikui, Katsuaki; Kumagai, Hisaji; Kawaguchi, Yoshihiro; Onishi, Rei; Hayashi, Tokumasa; Watanabe, Kouta; Mitani, Tomotaro; Saito, Koujiro; Igawa, Tsukasa

2018-05-01

The aim of the present study was to investigate the prognostic factors associated with progression-free survival (PFS) and overall survival (OS) times in patients with castration-resistant prostate cancer (CRPC) who received treatment with abiraterone acetate (AA) in routine clinical settings. A total of 93 patients treated with AA between September 2014 and February 2017 were selected and their medical records were analyzed retrospectively. The median PFS time of docetaxel (DTX)-naïve patients was 171 days, and that of post-DTX patients was 56 days. The OS time of DTX-naïve patients did not reach the median. The median OS time of post-DTX patients was 761 days. Multivariate analyses identified baseline prostate-specific antigen (PSA) level prior to treatment with AA and the PSA response rate as independent prognostic factors for PFS time, and baseline PSA prior to treatment with AA as the only independent prognostic factor for OS time. The results of the present study indicate that the baseline PSA level prior to treatment with AA is a notable prognostic factor in patients with CRPC.

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

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

2010-01-01

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

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

International Nuclear Information System (INIS)

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

2015-01-01

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

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

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

2015-12-25

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

Clinical Outcomes from Androgen Signaling-directed Therapy after Treatment with Abiraterone Acetate and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302.

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Smith, Matthew R; Saad, Fred; Rathkopf, Dana E; Mulders, Peter F A; de Bono, Johann S; Small, Eric J; Shore, Neal D; Fizazi, Karim; Kheoh, Thian; Li, Jinhui; De Porre, Peter; Todd, Mary B; Yu, Margaret K; Ryan, Charles J

2017-07-01

In the COU-AA-302 trial, abiraterone acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling-directed therapies following abiraterone acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent abiraterone acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (≥50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6-not estimable) for subsequent abiraterone acetate plus prednisone and 2.8 mo (range 1.8-not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent abiraterone acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with abiraterone acetate plus prednisone or enzalutamide for patients who progressed on abiraterone acetate is associated with limited clinical benefit. This analysis showed limited clinical benefit for subsequent abiraterone acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with abiraterone acetate plus prednisone. This analysis does not support prioritization of subsequent abiraterone acetate plus prednisone or enzalutamide following initial therapy with abiraterone acetate plus prednisone. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Nuclear-specific AR-V7 Protein Localization is Necessary to Guide Treatment Selection in Metastatic Castration-resistant Prostate Cancer.

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Scher, Howard I; Graf, Ryon P; Schreiber, Nicole A; McLaughlin, Brigit; Lu, David; Louw, Jessica; Danila, Daniel C; Dugan, Lyndsey; Johnson, Ann; Heller, Glenn; Fleisher, Martin; Dittamore, Ryan

2017-06-01

Circulating tumor cells (CTCs) expressing AR-V7 protein localized to the nucleus (nuclear-specific) identify metastatic castration-resistant prostate cancer (mCRPC) patients with improved overall survival (OS) on taxane therapy relative to the androgen receptor signaling inhibitors (ARSi) abiraterone acetate, enzalutamide, and apalutamide. To evaluate if expanding the positivity criteria to include both nuclear and cytoplasmic AR-V7 localization ("nuclear-agnostic") identifies more patients who would benefit from a taxane over an ARSi. The study used a cross-sectional cohort. Between December 2012 and March 2015, 193 pretherapy blood samples, 191 of which were evaluable, were collected and processed from 161 unique mCRPC patients before starting a new line of systemic therapy for disease progression at the Memorial Sloan Kettering Cancer Center. The association between two AR-V7 scoring criteria, post-therapy prostate-specific antigen (PSA) change (PTPC) and OS following ARSi or taxane treatment, was explored. One criterion required nuclear-specific AR-V7 localization, and the other required an AR-V7 signal but was agnostic to protein localization in CTCs. Correlation of AR-V7 status to PTPC and OS was investigated. Relationships with survival were analyzed using multivariable Cox regression and log-rank analyses. A total of 34 (18%) samples were AR-V7-positive using nuclear-specific criteria, and 56 (29%) were AR-V7-positive using nuclear-agnostic criteria. Following ARSi treatment, none of the 16 nuclear-specific AR-V7-positive samples and six of the 32 (19%) nuclear-agnostic AR-V7-positive samples had ≥50% PTPC at 12 weeks. The strongest baseline factor influencing OS was the interaction between the presence of nuclear-specific AR-V7-positive CTCs and treatment with a taxane (hazard ratio 0.24, 95% confidence interval 0.078-0.79; p=0.019). This interaction was not significant when nuclear-agnostic criteria were used. To reliably inform treatment selection

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

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

2017-10-01

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

Pengaruh kastrasi terhadap performan produksi Sapi Persilangan Wagyu berdasarkan umur yang berbeda

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Kuswati Kuswati

2016-12-01

Full Text Available The purpose of this research was to know the effect of castration to Wagyu crossbreed cattle production performance based on age difference and know the appropriate age to do castration. The materials used in this research were 37 heads of 3-month old and 28 heads 4 months calf castration. The method was case studies with purposive sampling. Data were analyzed using unpaired t test. The results showed that the calf castration age of 3 months and 4 months showed significantly different (P <0.05 in daily body weight gain and feed conversion. The average daily weight gain of 3 months old calf castration was 0.78 kg / head / day and 4 months old calf castration was 0.85 kg / head / day and feed conversion of 3 months old calf castration was 5.14 and 4 months old calf castration was 4.48, while the feed intake of the research results were not significantly different. The average feed consumption of 3 months old calf castration was 3.82 kg / head / day and 4 months old calf castration was 3.66 kg / head / day. Calves were castrated on 4 months old showed higher daily weight gain than the calf castration on 3 months old. This could be concluded that 4 months old was more appropriate to do castration. Keywords: Average daily gain, calf stock, feed convertion, castration

Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial.

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Rathkopf, Dana E; Beer, Tomasz M; Loriot, Yohann; Higano, Celestia S; Armstrong, Andrew J; Sternberg, Cora N; de Bono, Johann S; Tombal, Bertrand; Parli, Teresa; Bhattacharya, Suman; Phung, De; Krivoshik, Andrew; Scher, Howard I; Morris, Michael J

2018-05-01

Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients. To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS. PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016. Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment. Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for soft-tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman ρ and Kendall τ via Clayton copula. In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0

Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial.

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Chi, Kim N; Higano, Celestia S; Blumenstein, Brent; Ferrero, Jean-Marc; Reeves, James; Feyerabend, Susan; Gravis, Gwenaelle; Merseburger, Axel S; Stenzl, Arnulf; Bergman, Andries M; Mukherjee, Som D; Zalewski, Pawel; Saad, Fred; Jacobs, Cindy; Gleave, Martin; de Bono, Johann S

2017-04-01

Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer. SYNERGY was a phase 3, multicentre, open-label, randomised trial set at 134 study centres in 12 countries. Patients were eligible for participation if they had: metastatic castration-resistant prostate cancer and had received no previous chemotherapy; prostate-specific antigen greater than 5 ng/mL; and a Karnofsky performance score of 70% or higher. Patients were randomly assigned 1:1 centrally to either the docetaxel, prednisone, and custirsen combination or docetaxel and prednisone alone. Patients were not masked to treatment allocation. Randomisation was stratified by opioid use for cancer-related pain and radiographic evidence of progression. All patients received docetaxel 75 mg/m 2 intravenously with 5 mg of prednisone orally twice daily. Patients assigned docetaxel, prednisone, and custirsen received weekly doses of custirsen 640 mg intravenously after three loading doses of 640 mg. The primary endpoint was overall survival analysed in the intention-to-treat population. Patients who received at least one study dose were included in the safety analysis set. This trial is registered with ClinicalTrials.gov, number NCT01188187. The trial is completed and final analyses are reported here. Between Dec 10, 2010, and Nov 7, 2012, 1022 patients were enrolled to the trial, of whom 510 were assigned docetaxel, prednisone, and custirsen and 512 were allocated docetaxel and prednisone. No difference in overall survival was recorded between the two groups (median survival 23·4 months [95% CI 20·9-24·8] with docetaxel, prednisone, and custirsen vs

CARACTERÍSTICAS DE CARCAÇA E DA CARNE DE BOVINOS MESTIÇOS NÃO-CASTRADOS OU SUBMETIDOS A DIFERENTES MÉTODOS DE CASTRAÇÃO

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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.

Características físico-químicas da carne de bubalinos e de bovinos castrados e inteiros Chemical physical meat characteristics of buffaloes and cattle entire and castrated

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Victor Cruz Rodrigues

2004-12-01

Full Text Available As características físico-químicas da carne de bovinos Nelore (NE, F1 Nelore x Sindi (NS e de búfalos Mediterrâneos (BM castrados e inteiros foram avaliadas. O delineamento experimental foi o inteiramente casualizado em esquema fatorial 3 x 2 (três grupos genéticos x duas condições sexuais com 24 parcelas. Os animais foram confinados, receberam a mesma dieta e foram abatidos com média de 437,5 kg. As amostras de carne foram obtidas do músculo Longissimus dorsi entre a 11ª e 12ª costelas. A carne de animais inteiros ofereceu maior teor de umidade (73,6 vs 71,0%, de proteína (87,5 vs 78,6% e de minerais (4,33 vs 3,85% e menor teor de gordura (8,9 vs 16,8% que castrados. A carne de bovinos NE teve maior teor de gordura (15,4% que NS (12,5% e BM (10,8%, não havendo diferença para a condição sexual dentro do grupo de BM. A luminosidade, intensidade do vermelho e intensidade do amarelo da carne e da gordura foram semelhantes entre NE, NS e BM, enquanto os castrados alcançaram maior luminosidade (39,0 vs 37,2 e intensidade do amarelo (1,82 vs 0,87 que inteiros, mas a intensidade do vermelho da carne e a luminosidade, intensidade do vermelho e intensidade do amarelo da gordura foram semelhantes entre grupos genéticos e condição sexual. A carne de BM apresentou menor força de cisalhamento (3,75 kgf que NS (4,85 kgf e NE (5,9 kgf, bem como dos castrados (4,5 kgf em relação aos inteiros (5,2 kgf, mas não houve diferença entre grupo genético e condição sexual para perda por cozimento e para pH final. A carne de búfalos e animais inteiros apresentou menor teor de gordura, sem perder o valor nutritivo, maciez e a baixa perda por cozimento.Meat physical and chemical characteristics of Nellore (NE and F1 Nellore x Sindi (NS cattle and Mediterranean buffaloes (BM castrated and entire were evaluated. The experimental design was completely randomized in a factorial arrangement 3 (genetic groups x 2 (sexual conditions with 24 plots

Evaluation of Tumor Viability for Primary and Bone Metastases in Metastatic Castration-Resistant Prostate Cancer Using Whole-Body Magnetic Resonance Imaging

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Hiromichi Iwamura

2018-01-01

Full Text Available In contrast to bone scan and computed tomography (CT, which depend on osteoblastic response to detect bone metastasis, whole-body magnetic resonance imaging (WB-MRI may be able to directly detect viable tumors. A 75-year-old male who had progressive metastatic prostate cancer during primary androgen deprivation therapy was referred to our hospital. Although bone scan and CT showed multiple bone metastases, WB-MRI suggested nonviable bone metastasis and viable tumor of the primary lesion. Prostate needle biopsy demonstrated viable prostate cancer cells from 10 of 12 cores. In contrast, CT-guided needle biopsy from bone metastasis of the lumbar vertebra revealed no malignant cells. Based on these findings, we reasoned that viable tumor cells inducing disease progression may primarily exist in the primary lesions and not in the metastatic lesions, and combined prostate radiotherapy and systemic hormonal therapy resulted in successful clinical response and disease control. The use of WB-MRI to detect viable disease lesions may enable us to design optimal treatment strategies for patients with metastatic castration-resistant prostate cancer.

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

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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.

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

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A. V. Rudakova

2014-11-01

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.

Can palliative radiotherapy influence prostate-specific antigen response in patients with castrate-resistant prostate cancer treated with systemic therapy (chemotherapy or abiraterone)?—a report of three cases

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Hingorani, Mohan; Dixit, Sanjay; Pugazhenthi, Pattu; Hawkyard, Simon; Robertson, Andrew; Khafagy, Richard

2015-01-01

Palliative radiotherapy (pRT) is primarily employed for palliation of bone pain in patients with castrate-resistant prostate cancer (CRPC). However, evidence that pRT influences prostate-specific antigen response in patients with CRPC on systemic therapy is lacking. We describe three cases of CRPC progressing after treatment with docetaxel (n=2) and abiraterone (n=1), who responded unusually after pRT for bone pain with the development of a significant biochemical response and restoration of response to systemic therapy. The possibility of pRT influencing metastatic disease in CRPC has not been previously reported, and raises the possibility of radiation-induced modulation of anti-tumor immune response mechanisms that may play a role in the restoration of response to systemic treatment

Antitumour Activity and Safety of Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Abiraterone Acetate Plus Prednisone for ≥24 weeks in Europe.

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de Bono, Johann S; Chowdhury, Simon; Feyerabend, Susan; Elliott, Tony; Grande, Enrique; Melhem-Bertrandt, Amal; Baron, Benoit; Hirmand, Mohammad; Werbrouck, Patrick; Fizazi, Karim

2018-07-01

Enzalutamide and abiraterone acetate plus prednisone, which target the androgen receptor axis, have expanded the treatment of advanced prostate cancer. Retrospective analyses suggest some cross-resistance between these two drugs when used sequentially, but robust, prospective studies have not yet been reported. To fulfil a regulatory postregistration commitment by evaluating the efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed following abiraterone acetate plus prednisone treatment. Multicentre, single-arm, open-label study, enrolled patients with progressing mCRPC after ≥24 wk of abiraterone acetate plus prednisone treatment. All patients maintained castration therapy during the trial. Prior chemotherapy was allowed but not required. Patients received enzalutamide 160mg/d orally. The primary endpoint was radiographic progression-free survival. Secondary endpoints were overall survival, prostate-specific antigen (PSA) response, and time-to-PSA progression. Safety data were also assessed. Kaplan-Meier methods were used to descriptively analyse time-to-event endpoints. Overall, 214 patients received enzalutamide treatment, 145 of whom were chemotherapy-naïve. Median radiographic progression-free survival was 8.1 mo (95% confidence interval: 6.1-8.3); median overall survival had not been reached. Unconfirmed PSA response rate was 27% (48 of 181). Median time-to-PSA progression was 5.7 mo (95% confidence interval: 5.6-5.8). The most common treatment-emergent adverse events were fatigue (32%), decreased appetite (25%), asthenia (18%), back pain (17%), and arthralgia (16%). No seizures were reported. Enzalutamide showed antitumour activity in some patients with mCRPC who had previously progressed following ≥24 wk of abiraterone acetate plus prednisone treatment. Patients with mCRPC who progressed on previous abiraterone acetate plus prednisone treatment, with or without prior chemotherapy

[Subcutaneous transplants of juvenile rat testicular tissues continue to develop and secret androgen in adult rats].

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Yu, Zhou; Wang, Tong; Cui, Jiangbo; Song, Yajuan; Ma, Xianjie; Su, Yingjun; Peng, Pai

2017-12-01

Objective To explore the effects of subcutaneous microenvironment of adult rats on survival, development and androgen secretion of Leydig cells of transplanted juvenile rat testis. Methods Healthy adult SD rats were randomly divided into control group, sham group, castrated group and non-castrated group. Rats in the control group were kept intact, no testis was transplanted subcutaneously after adult recipients were castrated in the sham group; 5-7-day juvenile rat testes were transplanted subcutaneously in the castrated group, with one testis per side; Testes resected from juvenile rats were directly transplanted subcutaneously on both sides of the recipients in the non-castrated group. The grafts were obtained and weighed 4 weeks later. Then the histological features of the grafts were examined by HE staining; the expression and distribution of hydroxysteroid 17-beta dehydrogenase 1 (HSD-17β1) were investigated by immunohistochemistry; and the serum androgen level was determined by ELISA. Results The average mass of grafts obtained from the castrated group was significantly higher than that of the non-castrated group. Immunohistochemistry indicated that Leydig cells were visible in the tissues from both the castrated and non-castrated groups, but the number of HSD-17β1-posotive cells in the castrated group was larger than that in the non-castrated group. ELISA results showed that the serum androgen level was higher in the control group and non-castrated group than in the sham group and castrated group, and compared with the sham group, the serum androgen level in the castrated group was significantly higher. Conclusion The juvenile rat testis subcutaneously transplanted could further develop under the adult recipient rat skin, and the Leydig cells of grafts harbored the ability to produce and secret androgen.

Relationship between release of LH and incorporation of tritiated thymidine in the anterior pituitary gland of the castrated male rat: effect of LHRH and its highly active analogue buserelin.

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Romano, M I; Machiavelli, G A; Alonso, G E; Burdman, J A

1986-01-01

Castration of the adult male rat significantly (P less than 0.01) increased the concentration of LH in serum and the incorporation of (3H) thymidine into the pituitary DNA. The administration of a single dose of LHRH or its analogue buserelin stimulated the release of LH but it did not modify (3H) thymidine incorporation. When multiple doses of LHRH or buserelin were injected, there was a significant (P less than 0.01) inhibition of LH release and also the incorporation of (3H) thymidine into the DNA of the anterior pituitary gland was significantly (P less than 0.01) diminished. These observations are compatible with the idea of the close relationship between hormonal release and DNA synthesis in the anterior pituitary gland of the rat.

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

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Neuza R. W. Lima

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

DBC1 promotes castration-resistant prostate cancer by positively regulating DNA binding and stability of AR-V7.

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Moon, Sue Jin; Jeong, Byong Chang; Kim, Hwa Jin; Lim, Joung Eun; Kwon, Ghee Young; Kim, Jeong Hoon

2018-03-01

Constitutively active AR-V7, one of the major androgen receptor (AR) splice variants lacking the ligand-binding domain, plays a key role in the development of castration-resistant prostate cancer (CRPC) and anti-androgen resistance. However, our understanding of the regulatory mechanisms of AR-V7-driven transcription is limited. Here we report DBC1 as a key regulator of AR-V7 transcriptional activity and stability in CRPC cells. DBC1 functions as a coactivator for AR-V7 and is required for the expression of AR-V7 target genes including CDH2, a mesenchymal marker linked to CRPC progression. DBC1 is required for recruitment of AR-V7 to its target enhancers and for long-range chromatin looping between the CDH2 enhancer and promoter. Mechanistically, DBC1 enhances DNA-binding activity of AR-V7 by direct interaction and inhibits CHIP E3 ligase-mediated ubiquitination and degradation of AR-V7 by competing with CHIP for AR-V7 binding, thereby stabilizing and activating AR-V7. Importantly, DBC1 depletion suppresses the tumorigenic and metastatic properties of CRPC cells. Our results firmly establish DBC1 as a critical AR-V7 coactivator that plays a key role in the regulation of DNA binding and stability of AR-V7 and has an important physiological role in CRPC progression.

Who benefits from reduced reproduction in parasitized hosts? An experimental test using the Pasteuria ramosa-Daphnia magna system.

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Mageroy, Jon H; Grepperud, Eldfrid J; Jensen, Knut Helge

2011-12-01

We investigated whether parasites or hosts benefit from reduced reproduction in infected hosts. When parasites castrate their hosts, the regain of host reproduction is necessary for castration to be a host adaptation. When infecting Daphnia magna with Pasteuria ramosa, in a lake water based medium, 49 2% of the castrated females regained reproduction. We investigated the relationship between castration level, and parasite and host fitness proxies to determine the adaptive value of host castration. Hosts which regained reproduction contained less spores and had a higher lifetime reproduction than permanently castrated hosts. We also found a negative correlation between parasite and host lifetime reproduction. For hosts which regained reproduction we found no optimal level of castration associated with lifetime reproduction. These results support the view that host castration only is adaptive to the parasite in this system. In addition, we suggest that permanent castration might not be the norm under natural conditions in this system. Finally, we argue that a reduction in host reproduction is more likely to evolve as a property favouring parasites rather than hosts. To our knowledge this is the only experimental study to investigate the adaptive value of reduced host reproduction when castrated hosts can regain reproduction.

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

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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

Comparative efficacy, tolerability, and survival outcomes of various radiopharmaceuticals in castration-resistant prostate cancer with bone metastasis: a meta-analysis of randomized controlled trials

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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

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

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

2017-06-01

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

Economical impact of orchiectomy for advanced prostate cancer

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Paula Adriano A. P. de

2003-01-01

Full Text Available PURPOSE: To demonstrate the economical impact of surgical castration in comparison to the medical castration for patients with advanced prostate cancer. MATERIAL AND METHODS: Between January 2001 and December 2001, 32 patients with advanced prostate cancer underwent bilateral sub-capsular orchiectomy at our Hospital. The costs of this procedure were compared to the costs of medical castration with LH-RH analogues. RESULTS: The costs of the surgical procedure were extremely reduced when compared to published data on the medical treatment. Surgical castration did not have any stronger negative impact on the evolution of these patients when compared to medical castration. CONCLUSION: Surgical castration is an efficient and low cost treatment for advanced prostate cancer.

Tumour cell lysate-loaded dendritic cell vaccine induces biochemical and memory immune response in castration-resistant prostate cancer patients.

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Reyes, D; Salazar, L; Espinoza, E; Pereda, C; Castellón, E; Valdevenito, R; Huidobro, C; Inés Becker, M; Lladser, A; López, M N; Salazar-Onfray, F

2013-09-17

Recently, we produced a tumour antigen-presenting cells (TAPCells) vaccine using a melanoma cell lysate, called TRIMEL, as an antigen source and an activation factor. Tumour antigen-presenting cells induced immunological responses and increased melanoma patient survival. Herein, we investigated the effect of TAPCells loaded with prostate cancer cell lysates (PCCL) as an antigen source, and TRIMEL as a dendritic cell (DC) activation factor; which were co-injected with the Concholepas concholepas haemocyanin (CCH) as an adjuvant on castration-resistant prostate cancer (CRPC) patients. The lysate mix capacity, for inducing T-cell activation, was analysed by flow cytometry and Elispot. Delayed-type hypersensitivity (DTH) reaction against PCCL, frequency of CD8(+) memory T cells (Tm) in blood and prostate-specific antigen (PSA) levels in serum were measured in treated patients. The lysate mix induced functional mature DCs that were capable of activating PCCL-specific T cells. No relevant adverse reactions were observed. Six out of 14 patients showed a significant decrease in levels of PSA. DTH(+) patients showed a prolonged PSA doubling-time after treatment. Expansion of functional central and effector CD8(+) Tm were detected. Treatment of CRPC patients with lysate-loaded TAPCells and CCH as an adjuvant is safe: generating biochemical and memory immune responses. However, the limited number of cases requires confirmation in a phase II clinical trial.

Delayed response after repeated {sup 177}Lu-PSMA-617 radioligand therapy in patients with metastatic castration resistant prostate cancer

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Rahbar, Kambiz; Schaefers, Michael [University Hospital Muenster, Department of Nuclear Medicine, Muenster (Germany); Boegeman, Martin [University Hospital Muenster, Department of Urology, Muenster (Germany); Yordanova, Anna; Essler, Markus; Ahmadzadehfar, Hojjat [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Eveslage, Maria [University Hospital Muenster, Institute for Biostatistics, Muenster (Germany)

2018-02-15

Radioligand therapy (RLT) using Lutetium-177 labeled PSMA-617 (Lu-PSMA) ligand is a new therapeutic option for salvage therapy in heavily pretreated patients with metastatic castration resistant prostate cancer. The aim of this retrospective study was to analyze response in patients receiving 3 cycles of Lu-PSMA. Seventy-one patients (median age: 72 years; range 44-87) received 3 cycles of RLT with Lu-PSMA (mean administered activity: 6.016 ± 0.543 GBq) every 8 weeks. Response was evaluated using serum PSA levels and a PSA decline ≥50% was considered as biochemical response. Additionally, any PSA decline after the first cycle was evaluated for further therapy effects after the second and third cycle. A total of 213 cycles were performed in 71 patients. Data for response and adverse events were available for all patients. A PSA decline ≥50% and some PSA decline occurred in 56% and 66% of the patients. Of 30 patients with a PSA response after the first cycle, 28 remained responders and 12/41 of non-responders responded to further therapy cycles. RLT with Lu-177-PSMA-617 shows respectable response rates. In this retrospective analysis, a relevant number of patients showed a delayed response, even if they did not respond to the first cycle of the therapy. (orig.)

Lycopene Enhances Docetaxel's Effect in Castration-Resistant Prostate Cancer Associated with Insulin-like Growth Factor I Receptor Levels1

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Tang, Yaxiong; Parmakhtiar, Basmina; Simoneau, Anne R; Xie, Jun; Fruehauf, John; Lilly, Michael; Zi, Xiaolin

2011-01-01

Docetaxel is currently the most effective drug for the treatment of castration-resistant prostate cancer (CRPC), but it only extends life by an average of 2 months. Lycopene, an antioxidant phytochemical, has antitumor activity against prostate cancer (PCa) in several models and is generally safe. We present data on the interaction between docetaxel and lycopene in CRPC models. The growth-inhibitory effect of lycopene on PCa cell lines was positively associated with insulin-like growth factor I receptor (IGF-IR) levels. In addition, lycopene treatment enhanced the growth-inhibitory effect of docetaxel more effectively on DU145 cells with IGF-IR high expression than on those PCa cell lines with IGF-IR low expression. In a DU145 xenograft tumor model, docetaxel plus lycopene caused tumor regression, with a 38% increase in antitumor efficacy (P = .047) when compared with docetaxel alone. Lycopene inhibited IGF-IR activation through inhibiting IGF-I stimulation and by increasing the expression and secretion of IGF-BP3. Downstream effects include inhibition of AKT kinase activity and survivin expression, followed by apoptosis. Together, the enhancement of docetaxel's antitumor efficacy by lycopene supplementation justifies further clinical investigation of lycopene and docetaxel combination for CRPC patients. CRPC patients with IGF-IR-overexpressing tumors may be most likely to benefit from this combination. PMID:21403837

Post hoc analysis of Japanese patients from the placebo-controlled PREVAIL trial of enzalutamide in patients with chemotherapy-naive, metastatic castration-resistant prostate cancer—updated results

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Ueda, Takeshi

2017-01-01

Abstract A post hoc analysis of interim results from PREVAIL, a Phase III, double-blind, placebo-controlled trial of men with metastatic castration-resistant prostate cancer, demonstrated that the treatment effects, safety and pharmacokinetics of enzalutamide in Japanese patients were generally consistent with those of the overall population. A recent longer term analysis of PREVAIL demonstrated continued benefit of enzalutamide treatment over placebo. Here, we report results from a post hoc analysis of Japanese patients enrolled in PREVAIL at the prespecified number of deaths for the final analysis. In Japanese patients, enzalutamide reduced the risk of death by 35% (hazard ratio, 0.65; 95% confidence interval, 0.28–1.51) and the risk of investigator-assessed radiographic progression or death by 60% (hazard ratio, 0.40; 95% confidence interval, 0.18–0.90). These results show that treatment effects and safety in Japanese patients in the final analysis of PREVAIL continued to be generally consistent with those of the overall population. PMID:28003320

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

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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

Evaluation of the use of midazolam as a co-induction agent with ketamine for anaesthesia in sedated ponies undergoing field castration.

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Allison, A; Robinson, R; Jolliffe, C; Taylor, P M

2018-05-01

There are limited investigations comparing ketamine to a ketamine-midazolam co-induction. To compare quality and safety of general anaesthesia induced using ketamine alone with anaesthesia co-induced using ketamine and midazolam. Randomised, double blinded, placebo controlled trial. After i.v. detomidine (20 μg/kg) thirty-eight ponies undergoing field castration received either 0.06 mg/kg (0.6 mL/50 kg) midazolam (group M) or 0.6 mL/50 kg placebo (group P) with 2.2 mg/kg ketamine i.v. for anaesthetic induction. Quality of anaesthetic induction, endotracheal intubation, surgical relaxation and recovery were scored using combinations of simple descriptive and visual analogue scales. Time of sedation, induction, start of endotracheal intubation, first movement, sternal recumbency and standing were recorded, as were time, number and total quantity of additional i.v. detomidine and ketamine injections. Cardiorespiratory variables were assessed every 5 min. Adverse effects were documented. Data were tested for normality and analysed with a mixed model ANOVA, Fisher's exact test, unpaired Students' t test and Wilcoxon Rank-sum as appropriate; Pketamine (P = 0.04). Time (minutes) from induction to first movement (PKetamine-midazolam co-induction compared to ketamine alone improved quality of induction, ease of intubation and muscle relaxation without impacting recovery quality. © 2017 EVJ Ltd.

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

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

2010-03-01

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

Vitamin K2, a menaquinone present in dairy products targets castration-resistant prostate cancer cell-line by activating apoptosis signaling.

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Dasari, Subramanyam; Samy, Angela Lincy Prem Antony; Kajdacsy-Balla, Andre; Bosland, Maarten C; Munirathinam, Gnanasekar

2018-05-01

The aim of this study was to evaluate the therapeutic effects of vitamin K2 (VK2) on castration-resistant prostate cancer (CRPC) and its anti-cancer mechanisms in a pre-clinical study using a VCaP cell line (ATCC ® CRL-2876™) which was established from a vertebral bone metastasis from a patient with hormone refractory prostate cancer. Our data showed that VK2 significantly inhibited CRPC VCaP cell proliferation in a dose-dependent manner at 48 h treatment in vitro. In addition, VK2 reduced the migration potential of VCaP cells and inhibited anchorage-independent growth of these cells. Our results also showed that VK2 induces apoptosis in VCaP cells. Furthermore, VK2 enforced growth arrest in VCaP cells by activating cellular senescence. Notably, VK2 treatment elevated the levels of reactive oxygen species in VCaP cells. Western blot analysis revealed that VK2 downregulated the expression of androgen receptor, BiP, survivin, while activating caspase-3 and -7, PARP-1 cleavage, p21 and DNA damage response marker, phospho-H2AX in VCaP cells. In conclusion, our study suggests that VK2 might be a potential anti-cancer agent for CRPC by specifically targeting key anti-apoptotic, cell cycle progression and metastasis-promoting signaling molecules. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

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

2017-06-01

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

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

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Wen-Juan Li

2013-11-01

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

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

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

2014-04-28

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

Prognostic factors and risk stratification in patients with castration-resistant prostate cancer receiving docetaxel-based chemotherapy.

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Yamashita, Shimpei; Kohjimoto, Yasuo; Iguchi, Takashi; Koike, Hiroyuki; Kusumoto, Hiroki; Iba, Akinori; Kikkawa, Kazuro; Kodama, Yoshiki; Matsumura, Nagahide; Hara, Isao

2016-03-22

While novel drugs have been developed, docetaxel remains one of the standard initial systemic therapies for castration-resistant prostate cancer (CRPC) patients. Despite the excellent anti-tumor effect of docetaxel, its severe adverse effects sometimes distress patients. Therefore, it would be very helpful to predict the efficacy of docetaxel before treatment. The aims of this study were to evaluate the potential value of patient characteristics in predicting overall survival (OS) and to develop a risk classification for CRPC patients treated with docetaxel-based chemotherapy. This study included 79 patients with CRPC treated with docetaxel. The variables, including patient characteristics at diagnosis and at the start of chemotherapy, were retrospectively collected. Prognostic factors predicting OS were analyzed using the Cox proportional hazard model. Risk stratification for overall survival was determined based on the results of multivariate analysis. PSA response ≥50 % was observed in 55 (69.6 %) of all patients, and the median OS was 22.5 months. The multivariate analysis showed that age, serum PSA level at the start of chemotherapy, and Hb were independent prognostic factors for OS. In addition, ECOG performance status (PS) and the CRP-to-albumin ratio were not significant but were considered possible predictors for OS. Risk stratification according to the number of these risk factors could effectively stratify CRPC patients treated with docetaxel in terms of OS. Age, serum PSA level at the start of chemotherapy, and Hb were identified as independent prognostic factors of OS. ECOG PS and the CRP-to-albumin ratio were not significant, but were considered possible predictors for OS in Japanese CRPC patients treated with docetaxel. Risk stratification based on these factors could be helpful for estimating overall survival.

Phase I dose-escalation and pharmacokinetic study (TED 11576) of cabazitaxel in Japanese patients with castration-resistant prostate cancer.

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Mukai, Hirofumi; Takahashi, Shunji; Nozawa, Masahiro; Onozawa, Yusuke; Miyazaki, Jun; Ohno, Keiji; Suzuki, Kazuhiro

2014-04-01

The purpose of the study is to analyze the pharmacokinetic (PK) profile of cabazitaxel and evaluate its safety and tolerability as a 1-h IV infusion every 3 weeks in Japanese patients with castration-resistant prostate cancer (CRPC). Seventeen patients were treated with cabazitaxel at doses of 20 and 25 mg/m(2) for PK analyses. Dose escalation was performed only in the absence of dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) was the highest dose at which less than 33 % of the patients developed DLT. Cabazitaxel exhibited a triphasic elimination profile with a long terminal half-life of 116 ± 29.0 or 113 ± 28.0 h after IV infusion of 20 or 25 mg/m(2) cabazitaxel, respectively. The major differences in the PK parameters of cabazitaxel and docetaxel were cabazitaxel's fairly high clearance rate, representing approximately half the hepatic flow, and its large volume of distribution at steady-state conditions. No DLT was observed during Cycle 1. Mild-to-moderate hematological adverse events (AEs), including neutropenia, and other AEs typically associated with taxanes were observed; all AEs were manageable. Cabazitaxel at 25 mg/m(2) every 3 weeks was selected as the MTD in Japanese patients. The PK parameters of cabazitaxel in Japanese CRPC patients were comparable with those previously determined in Caucasian subjects. The safety and tolerability of cabazitaxel were also comparable in both ethnic populations.

CX4945 suppresses the growth of castration-resistant prostate cancer cells by reducing AR-V7 expression.

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Deng, Chuangzhong; Chen, Jieping; Guo, Shengjie; Wang, Yanjun; Zhou, Qianghua; Li, Zaishang; Yang, Xingping; Yu, Xingsu; Zhang, Zhenfeng; Zhou, Fangjian; Han, Hui; Yao, Kai

2017-08-01

The aberrant expression of casein kinase 2 (CK2) has been reported to be involved in the tumorigenesis and progression of prostate cancer. The inhibition of CK2 activity represses androgen-dependent prostate cancer cells by attenuating the androgen receptor (AR) signaling pathway. In this study, we examined the effect of CK2 inhibition in castration-resistant prostate cancer (CRPC) cells, in which AR variants (ARVs) play a predominant role. A newly synthetic CK2 selective inhibitor CX4945 was utilized to study the effect of CK2 inhibition in CRPC cells by CCK8 assay and colony formation assay. Protein and mRNA levels of full-length AR (AR-FL) and AR-V7 were determined by qPCR and western blot, respectively. The nuclear translocation of p50 and p65 was assessed to reflect the activity of the NF-κB pathway. CX4945 reduced the proliferation of CRPC cells in a dose-dependent and time-dependent manner. AR-V7 rather than AR-FL was downregulated by CX4945 in both the mRNA and protein level. Furthermore, CX4945 could restore the sensitivity of CRPC cells to bicalutamide. The analysis of possible mechanisms demonstrated that the inhibition of CK2 diminished the phosphorylation of p65 at ser529 and thus attenuated the activity of the NF-κB pathway. The inhibition of CK2 by CX4945 can repress the viability of CRPC cells and restore their sensitivity to anti-androgen therapy by suppressing AR-V7. This finding presents a potential option for the treatment of prostate cancer, especially CRPC.

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

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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

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

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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

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

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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.

Phase III Study of Cabozantinib in Previously Treated Metastatic Castration-Resistant Prostate Cancer: COMET-1.

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Smith, Matthew; De Bono, Johann; Sternberg, Cora; Le Moulec, Sylvestre; Oudard, Stéphane; De Giorgi, Ugo; Krainer, Michael; Bergman, Andries; Hoelzer, Wolfgang; De Wit, Ronald; Bögemann, Martin; Saad, Fred; Cruciani, Giorgio; Thiery-Vuillemin, Antoine; Feyerabend, Susan; Miller, Kurt; Houédé, Nadine; Hussain, Syed; Lam, Elaine; Polikoff, Jonathan; Stenzl, Arnulf; Mainwaring, Paul; Ramies, David; Hessel, Colin; Weitzman, Aaron; Fizazi, Karim

2016-09-01

Cabozantinib is an inhibitor of kinases, including MET and vascular endothelial growth factor receptors, and has shown activity in men with previously treated metastatic castration-resistant prostate cancer (mCRPC). This blinded phase III trial compared cabozantinib with prednisone in patients with mCRPC. Men with progressive mCRPC after docetaxel and abiraterone and/or enzalutamide were randomly assigned at a two-to-one ratio to cabozantinib 60 mg once per day or prednisone 5 mg twice per day. The primary end point was overall survival (OS). Bone scan response (BSR) at week 12 as assessed by independent review committee was the secondary end point; radiographic progression-free survival (rPFS) and effects on circulating tumor cells (CTCs), bone biomarkers, serum prostate-specific antigen (PSA), and symptomatic skeletal events (SSEs) were exploratory assessments. A total of 1,028 patients were randomly assigned to cabozantinib (n = 682) or prednisone (n = 346). Median OS was 11.0 months with cabozantinib and 9.8 months with prednisone (hazard ratio, 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = .213). BSR at week 12 favored cabozantinib (42% v 3%; stratified Cochran-Mantel-Haenszel P < .001). rPFS was improved in the cabozantinib group (median, 5.6 v 2.8 months; hazard ratio, 0.48; 95% CI, 0.40 to 0.57; stratified log-rank P < .001). Cabozantinib was associated with improvements in CTC conversion, bone biomarkers, and post-random assignment incidence of SSEs but not PSA outcomes. Grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone (71% v 56% and 33% v 12%, respectively). Cabozantinib did not significantly improve OS compared with prednisone in heavily treated patients with mCRPC and progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving BSR, rPFS, SSEs, CTC conversions, and bone biomarkers but not PSA outcomes. © 2016 by

Analytical Validation and Clinical Qualification of a New Immunohistochemical Assay for Androgen Receptor Splice Variant-7 Protein Expression in Metastatic Castration-resistant Prostate Cancer.

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Welti, Jonathan; Rodrigues, Daniel Nava; Sharp, Adam; Sun, Shihua; Lorente, David; Riisnaes, Ruth; Figueiredo, Ines; Zafeiriou, Zafeiris; Rescigno, Pasquale; de Bono, Johann S; Plymate, Stephen R

2016-10-01

The androgen receptor splice variant-7 (AR-V7) has been implicated in the development of castration-resistant prostate cancer (CRPC) and resistance to abiraterone and enzalutamide. To develop a validated assay for detection of AR-V7 protein in tumour tissue and determine its expression and clinical significance as patients progress from hormone-sensitive prostate cancer (HSPC) to CRPC. Following monoclonal antibody generation and validation, we retrospectively identified patients who had HSPC and CRPC tissue available for AR-V7 immunohistochemical (IHC) analysis. Nuclear AR-V7 expression was determined using IHC H score (HS) data. The change in nuclear AR-V7 expression from HSPC to CRPC and the association between nuclear AR-V7 expression and overall survival (OS) was determined. Nuclear AR-V7 expression was significantly lower in HSPC (median HS 50, interquartile range [IQR] 17.5-90) compared to CRPC (HS 135, IQR 80-157.5; pprostate cancer. A higher level of AR-V7 identifies a group of patients who respond less well to certain prostate cancer treatments and live for a shorter period of time. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Post hoc analysis of Japanese patients from the placebo-controlled PREVAIL trial of enzalutamide in patients with chemotherapy-naive, metastatic castration-resistant prostate cancer-updated results.

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Kimura, Go; Ueda, Takeshi

2017-03-01

A post hoc analysis of interim results from PREVAIL, a Phase III, double-blind, placebo-controlled trial of men with metastatic castration-resistant prostate cancer, demonstrated that the treatment effects, safety and pharmacokinetics of enzalutamide in Japanese patients were generally consistent with those of the overall population. A recent longer term analysis of PREVAIL demonstrated continued benefit of enzalutamide treatment over placebo. Here, we report results from a post hoc analysis of Japanese patients enrolled in PREVAIL at the prespecified number of deaths for the final analysis. In Japanese patients, enzalutamide reduced the risk of death by 35% (hazard ratio, 0.65; 95% confidence interval, 0.28-1.51) and the risk of investigator-assessed radiographic progression or death by 60% (hazard ratio, 0.40; 95% confidence interval, 0.18-0.90). These results show that treatment effects and safety in Japanese patients in the final analysis of PREVAIL continued to be generally consistent with those of the overall population. © The Author 2016. Published by Oxford University Press.

Effects of extract of Buddleja officinalis eye drops on androgen receptors of lacrimal gland cells of castrated rats with dry eye.

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Peng, Qing-Hua; Yao, Xiao-Lei; Wu, Quan-Long; Tan, Han-Yu; Zhang, Jing-Rong

2010-01-01

To evaluate the effects of the extract of Buddleja officinalis eye drops in basic tears secretory volume, tear film stability, expression of androgen receptors (AR) in castrated rats with dry eye, and to investigate the therapeutic effects of the extract of Buddleja officinalis on dry eye caused by gonadal hormones level imbalance. Forty-five Wistar masculinity rats were divided at random into nine groups, including normal groups (A1, A2 and A3); model groups (B1, B2 and B3); therapy groups with extract of Buddleja officinalis eye drops (C1, C2 and C3). The "1" stood for being fed for 1 month, and "2" for 2 months, and "3" for 3 months. The dry eye model was established with orchiectomy on groups B and C. Group C was treated with Buddleja officinalis extract eye drops for one month. All rats were checked with Schirmer I test (SIT) and tear film break-up time (BUT). Expression of AR was analyzed by flow cytometer (FCM). The SIT value of group C was significantly higher than that of group B (PBuddleja officinalis is the flavonoids that can significantly inhibit happening of dry eye of rat after androgen level lowered. Its mechanism is like androgen's and it can display androgen-like activity to keep basic tears secretory volume and tear film stability.

Pharmacokinetics of ketamine and its metabolite norketamine administered at a sub-anesthetic dose together with xylazine to calves prior to castration.

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Gehring, R; Coetzee, J F; Tarus-Sang, J; Apley, M D

2009-04-01

The objective of this study was to evaluate the plasma pharmacokinetics of ketamine and its active metabolite norketamine administered intravenously at a dose of 0.1 mg/kg together with xylazine (0.05 mg/kg) to control the pain associated with castration in calves. A two-compartment model with an additional metabolite compartment linked to the central compartment was used to simultaneously describe the time-concentration profiles of both ketamine and its major metabolite norketamine. Parameter values estimated from the time-concentration profiles observed in this study were volume of the central compartment (V(c) = 132.82 +/- 68.23 mL/kg), distribution clearance (CL(D) = 15.49 +/- 2.56 mL/min/kg), volume of the peripheral compartment (V(T) = 257.05 +/- 41.65 mL/kg), ketamine clearance by the formation of the norketamine metabolite (CL(2M) = 8.56 +/- 7.37 mL/kg/min) and ketamine clearance by other routes (CL(o) = 16.41 +/- 3.42 mL/kg/min). Previously published data from rats suggest that the metabolite norketamine contributes to the analgesic effect of ketamine, with a potency that is one-third of the parent drug. An understanding of the time-concentration relationships and the disposition of the parent drug and its metabolite is therefore important for a better understanding of the analgesic potential of ketamine in cattle.

Pengaruh Kastrasi Terhadap Performan Produksi Sapi Persilangan Wagyu Berdasarkan Umur Yang Berbeda

OpenAIRE

Kuswati, Kuswati; Ravenska, Ravenska; Hapsari, Nareswara; Yekti, Aulia Puspita Anugra; Susilawati, Trinil

2016-01-01

The purpose of this research was to know the effect of castration to Wagyu crossbreed cattle production performance based on age difference and know the appropriate age to do castration. The materials used in this research were 37 heads of 3-month old and 28 heads 4 months calf castration. The method was case studies with purposive sampling. Data were analyzed using unpaired t test. The results showed that the calf castration age of 3 months and 4 months showed significantly different (P <...

Pengaruh kastrasi terhadap performan produksi Sapi Persilangan Wagyu berdasarkan umur yang berbeda

OpenAIRE

Kuswati Kuswati; Ravenska Ravenska; Nareswara Hapsari; Aulia Puspita Anugra Yekti; Trinil Susilawati

2016-01-01

The purpose of this research was to know the effect of castration to Wagyu crossbreed cattle production performance based on age difference and know the appropriate age to do castration. The materials used in this research were 37 heads of 3-month old and 28 heads 4 months calf castration. The method was case studies with purposive sampling. Data were analyzed using unpaired t test. The results showed that the calf castration age of 3 months and 4 months showed significantly different (P

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

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

2016-02-01

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

Shifting paradigms in the estimation of survival for castration-resistant prostate cancer: A tertiary academic center experience.

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Afshar, Mehran; Evison, Felicity; James, Nicholas D; Patel, Prashant

2015-08-01

Castration-resistant prostate cancer (CRPC) has retained a guarded prognosis, with historical survival estimates of 18 to 24 months. However, the landscape of available therapy has changed, and the emphasis has altered from supportive to active treatment. Few large series from real-world populations exist in the contemporary era with fully mature survival data to confirm the indication based on clinical trials that patients with CRPC are surviving far longer than the historical estimates. We aim to review a large patient cohort with CRPC and provide mature survival data. Using the electronic histopathology database at Queen Elizabeth Hospital, Birmingham, UK, all prostate-specific antigentest results between April 2006 and September 2007 were extracted, and patients satisfying the American Society for Radiation Oncology (ASTRO) definition of hormone failure were identified. Electronic records were reviewed and variables were collected, including survival, treatment, biochemistry, histopathology, and demographics. Probability of survival, and of developing metastasis or CRPC, was determined using the Kaplan-Meier method. Patients were stratified into 3 groups, namely, D0--no metastasis at diagnosis but later appearance, D1--no metastasis at diagnosis or at last follow-up, and D2--metastasis at diagnosis. From 8,062 patient-prostate-specific antigen episodes, we identified 447 patients meeting the criteria. A notes review revealed 147 patients with CRPC. Median overall survival (OS) from diagnosis was 84.7 months (95% CI: 73-89), and 129 deaths had occurred (88%). Median OS from diagnosis for D0, D1, and D2 patients was 100.4, 180.1, and 58.9 months, respectively (Pdata benefit clinicians and patients in understanding prognosis and treatment choices. Importantly, our patients were diagnosed before the current wave of novel therapeutics for CRPC, so survival for men diagnosed today may be more than our findings. Copyright © 2015 Elsevier Inc. All rights reserved.

Combination treatment with docetaxel and histone deacetylase inhibitors downregulates androgen receptor signaling in castration-resistant prostate cancer.

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Park, Sang Eun; Kim, Ha-Gyeong; Kim, Dong Eun; Jung, Yoo Jung; Kim, Yunlim; Jeong, Seong-Yun; Choi, Eun Kyung; Hwang, Jung Jin; Kim, Choung-Soo

2018-04-01

Backgrounds Since most patients with castration-resistant prostate cancer (CRPC) develop resistance to its standard therapy docetaxel, many studies have attempted to identify novel combination treatment to meet the large clinical unmet need. In this study, we examined whether histone deacetylase inhibitors (HDACIs) enhanced the effect of docetaxel on AR signaling in CRPC cells harboring AR and its splice variants. Methods HDACIs (vorinostat and CG200745) were tested for their ability to enhance the effects of docetaxel on cell viability and inhibition of AR signaling in CRPC 22Rv1 and VCaP cells by using CellTiter-Glo™ Luminescent cell viability assay, synergy index analysis and Western blotting. The nuclear localization of AR was examined via immunocytochemical staining in 22Rv1 cells and primary tumor cells from a patient with CRPC. Results Combination treatment with HDACIs (vorinostat or CG200745) and docetaxel synergistically inhibited the growth of 22Rv1 and VCaP cells. Consistently, the combination treatment decreased the levels of full-length AR (AR-FL), AR splice variants (AR-Vs), prostate-specific antigen (PSA), and anti-apoptotic Bcl-2 proteins more efficiently compared with docetaxel or vorinostat alone. Moreover, the combination treatment accelerated the acetylation and bundling of tubulin, which significantly inhibited the nuclear accumulation of AR in 22Rv1 cells. The cytoplasmic colocalization of AR-FL and AR-V7 with microtubule bundles increased after combination treatment in primary tumor cells from a patient with CRPC. Conclusions The results suggested that docetaxel, in combination with HDACIs, suppressed the expression and nuclear translocation of AR-FL and AR-Vs and showed synergistic anti-proliferative effect in CRPC cells. This combination therapy may be useful for the treatment of patients with CRPC.

Perfil hematológico de ratas castradas e intactas induzidas experimentalmente ao hipertireoidismo

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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.

Carcass physical composition and physic-chemical characteristics of meat from Nellore cattle

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Aline Kellermann de Freitas

2016-04-01

Full Text Available Assessment of carcass physical composition and physicochemical characteristics of meat from Nellore males distributed randomly into three treatments: males castrated at 13 months of age at puberty (n=26; castrated at 18 months of age, 15 days before confinement (n=26; and young bulls (n=25. For the evaluation of meat chemical characteristics, we used samples of 12 animals taken at random from each treatment. The experimental design was completely randomized. Animals were slaughtered at 22 months of age after 100 days of confinement. The carcasses of young bulls showed higher contents of muscle (66.46 % and bone (16.03 %, and lower fat content (17.66 %, in relation to that of steers castrated at 13 (62.83,15.28, and 22.11 %, respectively or 18 months (63.99, 15.29, and 21.53%, respectively, which did not differ amongst themselves. The meat of young bulls was darker (3.07 points than the meat from those castrated at 13 months of age (3.43 points, while the meat from those castrated at 18 months displayed an intermediate color (3.29 points, not differing from the others. Young bulls yielded meat with lower content of intramuscular fat (3.18 points and lipids (3.81% in relation to those castrated at 13 (4.58 points and 6.77%, respectively or 18 months (4.52 points and 5.66%, respectively. Protein content was higher (P 0.05 by the age of castration, with young bulls having lower values in relation to the castrated males. Castration of Nellore young bulls in early puberty increases the edible portion of the carcass due to the higher body fat deposit.

Effects of alcohol feeding on androgen receptors in the rat pituitary gland

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Chung, K.W.

1987-01-01

Specific binding of testosterone-1β,2β- 3 H by cytosol from anterior pituitary gland of ethanol-fed, isocaloric control, and castrated control and ethanol-fed rats with or without testosterone treatment has been investigated by charcoal assay. The number of androgen binding sites was significantly reduced in alcohol-fed rats when compared to the isocaloric control value, with no significant change in Kd. Castration significantly increased the number of receptor sites in control rats and when castrated control animals were treated with testosterone the binding sites were decreased to the intact control level. In contrast, castration or testosterone given to castrated alcohol-fed rats did not alter alcohol-induced reduction of the receptor sites. The binding affinity (Kd) is identical in all groups. The concentration of serum luteinizing hormone (LH) was significantly lower in alcohol-fed rats when compared to that of normal controls. An increased serum LH level with a decreased testosterone level was noted in castrated control rats. However, castration of alcohol-fed rats had little or no effects on the concentrations of LH and testosterone. Administration of testosterone suppressed castration-induced high LH in control rats but alcohol induced reduction of LH level was not altered by this treatment. These findings indicate that alcohol exerts a suppressive effect on the content of androgen receptors and secretory functions of gonadotropins in the pituitary gland. 23 references, 1 figure, 1 table

The Effect of Immunocastration on Some Meat Quality Characteristics

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Ioana Andronie

2015-05-01

Full Text Available Surgical castration of male pigs has become increasingly less accepted at present due to the fact that it is a direct animal welfare concern. UE welfare conditions demand that this method be dropped starting 2018 in order to eliminate the stress and associated pain it induces. Immunocastration is one of the alternatives to surgical castration that ensures male pig welfare and eliminates the boar smell of the meat. The objective of this research has been to identify the immunocastration effects on meat quality, compared with the meat from surgically castrated pigs. The animals assessed during research were fattening PIC pigs, grouped into two lots: surgically castrated pigs (SC and immunocastrated pigs (IC. Pig immunization was achieved by means of ImprovacTM. The results have shown that immunocastrated pigs recorded a 60.2% carcass meat compared to the 59.69% carcass meat achieved in surgically castrated pigs, thus displaying statistically insignificant differences (p≥0.05. Fat layer thickness was significantly lower in immunocastrated pigs compared to the marker lot (p≤0.05. Mycoplasma hyopneumoniae lung lesions recorded were lower in immunocastrated pigs compared to the surgically castrated animals (p≥0.05. Despite the fact that differences have been statistically insignificant, we are able to confirm that immunocastrated pigs display a lower incidence of respiratory disease compared to surgically castrated pigs.  In this study there were not significant differences in meat quality between surgically castrated pigs and immunocastrated pigs.

Skeletal-related events significantly impact health-related quality of life in metastatic castration-resistant prostate cancer: data from PREVAIL and AFFIRM trials.

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Saad, F; Ivanescu, C; Phung, D; Loriot, Y; Abhyankar, S; Beer, T M; Tombal, B; Holmstrom, S

2017-03-01

We investigated the impact of skeletal-related events (SREs) on health-related quality of life (HRQoL) in patients with metastatic castration-resistant prostate cancer (mCRPC) in phase III trials of enzalutamide versus placebo. Patients with mCRPC experiencing at least one SRE during AFFIRM and PREVAIL were assessed for trajectory-adjusted mean change in HRQoL by first SRE using Functional Assessment of Cancer Therapy-Prostate (FACT-P; AFFIRM, three domains, and PREVAIL, nine domains) and EQ-5D (PREVAIL) instruments. First SREs caused HRQoL deterioration in both trials. Spinal cord compression had the largest impact, with clinically meaningful reductions in seven of nine FACT-P domains in PREVAIL and all three in AFFIRM (mean (95% confidence interval (CI)) change in FACT-P total score -16.95 (-26.47, -7.44) and -9.69 (-16.10, -3.27), respectively). In PREVAIL, first SREs caused clinically meaningful declines in EQ-5D utility index, irrespective of category; spinal cord compression had the largest impact (mean (95% CI) change -0.24 (-0.39, -0.08)). In AFFIRM, FACT-P and FACT-General total scores showed clinically meaningful declines after radiation/surgery to bone. SREs were associated with clinically meaningful functional declines in the daily lives of patients with mCRPC. Spinal cord compression had the largest impact on HRQoL.

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

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

2017-08-01

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

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.

Early Prediction of Therapy Response to Abiraterone Acetate Using PSA Subforms in Patients with Castration Resistant Prostate Cancer

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Katrin Schlack

2016-09-01

Full Text Available The purpose of this study was to evaluate the prognostic ability of early changes of total prostate specific antigen (tPSA, free PSA (fPSA, [−2]proPSA and the Prostate Health Index (PHI following initiation of Abiraterone-therapy in men with castration resistant prostate cancer (mCRPC. In 25 patients, PSA-subforms were analyzed before and at 8–12 weeks under therapy as prognosticators of progression-free-survival (PFS and overall survival (OS. Comparing patients with a PFS < vs. ≥12 months by using Mann–Whitney–Wilcoxon Tests, the relative-median-change of tPSA (−0.1% vs. −86.8%; p = 0.02, fPSA (12.1% vs. −55.3%; p = 0.03 and [−2]proPSA (8.1% vs. −59.3%; p = 0.05 differed significantly. For men with ≤ vs. >15 months of OS there was a non-significant trend for a difference in the relative-median-change of fPSA (17.0% vs. −46.3%; p = 0.06. In Kaplan–Meier analyses, declining fPSA and [−2]proPSA were associated with a longer median PFS (13 months, 95% confidence interval (CI: 9.6–16.4 vs. 10 months, 95% CI: 3.5–16.5; p = 0.11, respectively. Correspondingly, decreasing fPSA and [−2]proPSA values indicated an OS of 32 months (95% CI: not reached (NR compared to 21 months in men with rising values (95% CI: 7.7–34.3; p = 0.14, respectively. We concluded that the addition of fPSA- and [−2]proPSA-changes to tPSA-information might be further studied as potential markers of early Abiraterone response in mCRPC patients.

PET/CT With 68Ga-DOTA-TATE for Diagnosis of Neuroendocrine: Differentiation in Patients With Castrate-Resistant Prostate Cancer.

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Gofrit, Ofer Nathan; Frank, Stephen; Meirovitz, Amichay; Nechushtan, Hovav; Orevi, Marina

2017-01-01

Castrate-resistant prostate cancer (CRPC) often shows histological evidence of neuroendocrine differentiation (NED). To evaluate the extent of NED in patients with CRPC, we used PET/CT with Ga-[DOTA-Tyr]-octreotate (Ga-DOTA-TATE), a somatostatin analog that binds somatostatin receptor 2 with high affinity. This radiotracer is used in imaging of neuroendocrine tumors. Twelve patients (mean age, 65 [SD, 12] years) with CRPC were studied. Their mean prostate-specific antigen level at scanning was 85.6 (SD, 144.6) ng/mL. PET/CT images were obtained after the injection of 120 to 200 MBq of Ga-DOTA-TATE. All participants had at least 1 blastic metastasis demonstrating uptake of Ga-DOTA-TATE (mean SUVmax of 5.3 [SD, 2.3]). In 6 patients, moderately high to high uptakes (SUVmax, >5) were seen. Patients with multiple bone metastases had a significantly higher SUVmax compared with patients with few metastases (mean of 5.8 vs 3.8, P = 0.05). In 4 patients, lytic bone lesions or lymph node metastases also showed uptake of the tracer (mean SUVmax of 7.2 [SD, 3.2]). Uptake of the radiotracer was also observed in bones showing normal architecture in CT, suggesting that NED cells appear early during metastases development. Uptake of Ga-DOTA-TATE is a common finding in metastases of CRPC patients, suggesting that NED is frequent in these patients. In half of the patients, widespread uptake of Ga-DOTA-TATE was observed. This suggests that the possibility of treating selected CRCP patients with anti-neuroendocrine tumor therapies should be explored and that Ga-DOTA-TATE scanning could have a role in predicting the efficacy of these treatments.

Comparable amounts of sex steroids are made outside the gonads in men and women: strong lesson for hormone therapy of prostate and breast cancer.

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Labrie, Fernand; Cusan, Leonello; Gomez, José Luis; Martel, Céline; Bérubé, René; Bélanger, Patrick; Bélanger, Alain; Vandenput, Liesbeth; Mellström, Dan; Ohlsson, Claes

2009-01-01

The objective of this study was comparison of circulating androgens and their metabolites as well as estrogens measured for the first time by a validated mass spectrometry technology in 60-80-year-old men and women of comparable age. Castration in men (n=34) reduces the total androgen pool by only about 60% as indicated by the decrease in the serum levels of the glucuronide metabolites of androgens compared to intact men (n=1302). Such data are in agreement with the 50 to 75% decrease in intraprostatic dihydrotestosterone (DHT) concentration after castration. Most interestingly, the same amounts of androgens and estrogens are found in postmenopausal women (n=369) and castrated men of comparable age. The most significant therapeutic implication of these findings is the absolute need to add a pure (nonsteroidal) antiandrogen to castration in men with prostate cancer in order to block the action of the 25 to 50% DHT left in the prostate after castration. Not adding an antiandrogen to castration in men treated for prostate cancer is equivalent to not prescribing a blocker of estrogens in women suffering from breast cancer because they are postmenopausal and have low circulating estradiol.

The influence of sex and gonadectomy on hepatic and brain fatty acid composition, lipogenesis and β-oxidation.

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Starčević, K; Filipović, N; Šperanda, M; Đidara, M; Mašek, T

2017-08-01

The aim of this study was to investigate the influence of sex and castration of rats on liver and brain fatty acid profile and liver mRNA expression of genes involved in lipogenesis and β-oxidation. Castration significantly increased body weight and liver index and decreased serum triglyceride content in the female rats. The fatty acid composition of the liver tissue was influenced by sex and castration. Male rats had higher content of C16:0, C18:1n7, C18:2n6 and C22:5n3, while female rats had higher content of C18:0, C20:4n6 and C22:6n3. Castration of male rats decreased differences caused by sex for C18:2n6, C20:4n6 and C22:6n3. Values for C16:1n7 were higher in the castrated male rats in comparison with all other groups. Liver phospholipids showed a distribution of fatty acids similar to the total lipids. Brain total lipids and phospholipids were not influenced by sex or castration. Castration increased ∆6D gene expression in both the sexes, while ∆5D and ∆9D increased in females and males respectively. Gonadectomy increased expression of the FASN gene in the females and decreased CPT1 and ACOX1 gene expression in the liver tissue of male rats. The observed results of lipid peroxidation, measured by TBARS, were the lowest in the intact females in comparison with all other groups. In conclusion, sex strongly influences both SFA and PUFA in liver tissue, and castration decreases these differences only for PUFA. Castration also influences the expression of the genes involved in lipid metabolism differently in male and female rats, with an increase in lipogenic genes in female rats and a decrease in key genes for mitochondrial and peroxisomal β-oxidation in male rats. Journal of Animal Physiology and Animal Nutrition © 2016 Blackwell Verlag GmbH.

External validation and newly development of a nomogram to predict overall survival of abiraterone-treated, castration-resistant patients with metastatic prostate cancer

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Yun-Jie Yang

2018-01-01

Full Text Available Abiraterone acetate is approved for the treatment of castration-resistant prostate cancer (CRPC; however, its effects vary. An accurate prediction model to identify patient groups that will benefit from abiraterone treatment is therefore urgently required. The Chi model exhibits a good profile for risk classification, although its utility for the chemotherapy-naive group is unclear. This study aimed to externally validate the Chi model and develop a new nomogram to predict overall survival (OS. We retrospectively analyzed a cohort of 110 patients. Patients were distributed among good-, intermediate-, and poor-risk groups, according to the Chi model. The good-, intermediate-, and poor-risk groups had a sample size of 59 (53.6%, 34 (30.9%, and 17 (15.5% in our dataset, and a median OS of 48.4, 29.1, and 10.5 months, respectively. The C-index of external validation of Chi model was 0.726. Univariate and multivariate analyses identified low hemoglobin concentrations (<110 g l−1, liver metastasis, and a short time interval from androgen deprivation therapy to abiraterone initiation (<36 months as predictors of OS. Accordingly, a new nomogram was developed with a C-index equal to 0.757 (95% CI, 0.678–0.836. In conclusion, the Chi model predicted the prognosis of abiraterone-treated, chemotherapy-naive patients with mCRPC, and we developed a new nomogram to predict the overall survival of this group of patients with less parameters.

Differential expression of genes associated with lipid metabolism in longissimus dorsi of Korean bulls and steers.

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Bong, Jin Jong; Jeong, Jin Young; Rajasekar, Panchamoorthy; Cho, Young Moo; Kwon, Eung Gi; Kim, Hyeong Cheol; Paek, Bong Hyun; Baik, Myunggi

2012-07-01

The objective of this study was to compare expression of genes associated with lipid deposition and removal between bulls and steers in the longissimus dorsi muscle (LM) tissue of Korean cattle. Castration increased the expression of lipid uptake lipoprotein lipase, fatty acid translocase, and fatty acid transport protein 1 in LM. Castration increased lipogenic gene expression of both acetyl-CoA carboxylase and fatty acid synthase. In contrast, castration downregulated lipolytic gene expression of both adipose triglyceride lipase (ATGL) and monoglyceride lipase. Steers showed higher expression levels of insulin signaling phospho-v-akt murine thymoma viral oncogene homolog 1 than bulls but lower protein levels of nuclear Forkhead box O 1 (FoxO1) than bulls, suggesting that increased insulin signaling following castration decreases nuclear FoxO1 levels, leading to downregulation of ATGL gene expression. These findings suggest that castration contributes to increases in lipid uptake and lipogenesis and a decrease in lipolysis, resulting in improved marbling. Copyright © 2012 Elsevier Ltd. All rights reserved.

Randomized, placebo-controlled, phase III trial of sunitinib plus prednisone versus prednisone alone in progressive, metastatic, castration-resistant prostate cancer.

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Michaelson, M Dror; Oudard, Stephane; Ou, Yen-Chuan; Sengeløv, Lisa; Saad, Fred; Houede, Nadine; Ostler, Peter; Stenzl, Arnulf; Daugaard, Gedske; Jones, Robert; Laestadius, Fredrik; Ullèn, Anders; Bahl, Amit; Castellano, Daniel; Gschwend, Juergen; Maurina, Tristan; Chow Maneval, Edna; Wang, Shaw-Ling; Lechuga, Maria Jose; Paolini, Jolanda; Chen, Isan

2014-01-10

We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of metastatic castration-resistant prostate cancer (mCRPC). Men with progressive mCRPC after docetaxel-based chemotherapy were randomly assigned 2:1 to receive sunitinib 37.5 mg/d continuously or placebo. Patients also received oral prednisone 5 mg twice daily. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS). Two interim analyses were planned. Overall, 873 patients were randomly assigned to receive sunitinib (n = 584) or placebo (n = 289). The independent data monitoring committee stopped the study for futility after the second interim analysis. After a median overall follow-up of 8.7 months, median OS was 13.1 months and 11.8 months for sunitinib and placebo, respectively (hazard ratio [HR], 0.914; 95% CI, 0.762 to 1.097; stratified log-rank test, P = .168). PFS was significantly improved in the sunitinib arm (median 5.6 v 4.1 months; HR, 0.725; 95% CI, 0.591 to 0.890; stratified log-rank test, P < .001). Toxicity and rates of discontinuations because of adverse events (AEs; 27% v 7%) were greater with sunitinib than placebo. The most common treatment-related grade 3/4 AEs were fatigue (9% v 1%), asthenia (8% v 2%), and hand-foot syndrome (7% v 0%). Frequent treatment-emergent grade 3/4 hematologic abnormalities were lymphopenia (20% v 11%), anemia (9% v 8%), and neutropenia (6% v < 1%). The addition of sunitinib to prednisone did not improve OS compared with placebo in docetaxel-refractory mCRPC. The role of antiangiogenic therapy in mCRPC remains investigational.

Attitudes of Serbian food technology students towards surgical and immunocastration of boars and their sensitivity to androstenone and skatole

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Tomasevic, I.; Đekić, I.; Font-i-Furnols, M.; Aluwé, M.; Čandek-Potokar, M.; Bonneau, M.; Weiler, U.

2017-09-01

Various European Union pork chain actors and stakeholders agreed in 2010 on a road map to voluntarily abandon piglet castration by 1 January 2018. Because currently in Serbia, male piglets are surgically castrated and consumers are not used to the boar taint odour and flavour, the introduction of boar meat may modify the acceptability of pork. The objective of the study was to investigate the attitudes, awareness and opinions of future Serbian food technologist towards surgical castration of boars and its alternatives, and to test their sensitivity to androstenone and skatole. We found that they were concerned about the animal welfare issues and that they were willing to pay a little more for meat from animals treated with dignity. This was more so if they were females and less so if they had had a rural upbringing. They strongly believed that surgical castration is painful for the animals, but at the same time agreed that meat from castrated pigs is of better quality. Their ambiguous attitudes regarding efficacy and quality of alternatives to surgical castration clearly indicated the knowledge gap that must be filled by appropriate modifications of the curriculum. Students demonstrated average sensitivity to both androstenone and skatole. Females exhibited higher intensities of difference in both cases.

Effect of time interval between the second Improvest® dose and slaughter and corn dried distillers grains with solubles feeding strategies on carcass composition, primal cutout, and pork quality of immunologically castrated pigs.

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Harris, E K; Mellencamp, M A; Johnston, L J; Cox, R B; Shurson, G C

2017-05-01

Effects of dried distillers grains with solubles (DDGS) feeding strategies on carcass composition, primal cutout, and lean quality of immunologically castrated (IC; n=863) pigs were evaluated, and consisted of: 1) corn-soybean meal (CS) diet (PCon); 2) CS+40% DDGS (NCon); 3) CS+40, 30, 20, or 10% DDGS fed in phases 1 to 4, respectively (SD); or 4) CS+40% DDGS fed in phase 1 to 3 and CS in phase 4 (WD). All pigs received the first dose of Improvest® at 11weeks. of age, and the second dose was administered at either 9, 7, or 5weeks. before slaughter at 24weeks. of age. The SD and WD improved carcass dressing percentage and resulted in intermediate primal cut yields and pork loin quality compared with pigs fed PCon and NCon. Increasing the time interval between second dose of Improvest® and slaughter increased adipose tissue accretion but did not affect lean quality of pork. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dose-dependent effects of dihydrotestosterone in the streptozotocin-induced diabetic rat kidney

OpenAIRE

Xu, Qin; Prabhu, Anjali; Xu, Shujing; Manigrasso, Michaele B.; Maric, Christine

2009-01-01

We recently reported that castration exacerbates albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis associated with diabetic renal disease. The aim of the present study was to examine whether these effects of castration can be attenuated with dihydrotestosterone (DHT) supplementation. The study was performed in castrated male Sprague-Dawley, streptozotocin-induced diabetic rats treated with 0 mg/day DHT (DHT0), 0.75 mg/day DHT (DHT0.75), or 2.0 mg/day DHT (DHT2.0) for 14 wk. Tre...

A randomized, double-blind, placebo-controlled phase 2 study of maintenance therapy with tasquinimod in patients with metastatic castration-resistant prostate cancer responsive to or stabilized during first-line docetaxel chemotherapy

DEFF Research Database (Denmark)

Fizazi, K; Ulys, A; Sengeløv, L

2017-01-01

) to receive tasquinimod (0.25-1.0 mg/day orally) or placebo. The primary end point was radiologic progression-free survival (rPFS); secondary efficacy end points included: overall survival (OS); PFS on next-line therapy (PFS 2) and symptomatic PFS, assessed using the Brief Pain Inventory (BPI) questionnaire...... duration of treatment was 18.7 weeks (range 0.6-102.7 weeks) for the tasquinimod arm and 19.2 weeks (range 0.4-80.0 weeks) for the placebo arm. Median (90% CI) rPFS was 31.7 (24.3-53.7) and 22.7 (16.1-25.9) weeks in the tasquinimod and placebo arms, respectively [HR (90% CI) 0.6 (0.4-0.9), P = 0...... in the tasquinimod and placebo arms (97.2% versus 94.3%, respectively), whereas severe TEAEs (NCI-CTC Grade 3-5) incidence was higher in the tasquinimod group (50.7% versus 27.1%). Conclusions: Randomized trials testing new drugs as maintenance can be successfully conducted after chemotherapy in castrate...

Dual role of preputial gland secretion and its major components in sex recognition of mice.

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Zhang, Jian-Xu; Liu, Ying-Juan; Zhang, Jin-Hua; Sun, Lixing

2008-10-20

This study was aimed at validating the sexual attractiveness of hexadecanol and hexadecyl acetate, two putative pheromone compounds, from preputial gland secretion of mice. These two compounds have been reported to be among the major components of preputial gland secretion in both sexes but higher in quantity in males than females. In this study, we show that castration suppressed the production of the two compounds, further suggesting their association with maleness. Adding preputial gland secretion and the synthetic analogs of the two compounds to castrated male urine at their physiological levels in intact males increased the attractiveness of castrated male urine to female mice, showing that the two compounds were indeed male pheromones. Furthermore, their sexual attractiveness disappeared upon removing the vomeronasal organs (VNOs) from female recipients. Replenishing castrated male urine with preputial gland secretion and the two compounds at their physiological levels in females increased the attractiveness of castrated male urine to males. Such a reversal of sexual attractiveness for hexadecanol and hexadecyl acetate suggests that they had opposing dual effects in sexual attractiveness in a dosage-dependent manner.

Effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan and theophylline in patients with metastatic castration-resistant prostate cancer.

Science.gov (United States)

Chi, K N; Tolcher, A; Lee, P; Rosen, P J; Kollmannsberger, C K; Papadopoulos, K P; Patnaik, A; Molina, A; Jiao, J; Pankras, C; Kaiser, B; Bernard, A; Tran, N; Acharya, M

2013-01-01

To assess the effect of abiraterone acetate plus prednisone on the pharmacokinetics of dextromethorphan HBr (CYP2D6 substrate) and theophylline (CYP1A2 substrate) in patients with metastatic castration-resistant prostate cancer (mCRPC). Men with progressive metastatic mCRPC who failed gonadotropin-releasing hormone therapy and ≥1 lines of chemotherapy were enrolled. Patients received two doses of dextromethorphan HBr-30 mg (n = 18; group A) or theophylline-100 mg (n = 16; group B) under fasting conditions; one dose on cycle 1, day -8, and the other dose on cycle 1, day 8. Only patients with extensive CYP2D6 metabolizing status were assigned to group A. All patients received continuous daily oral abiraterone acetate (1,000 mg) plus prednisone (10 mg) starting on cycle 1, day 1. Coadministration of abiraterone acetate plus prednisone increased the systemic exposure of dextromethorphan by approximately 100%. Ratios of geometric means for maximum plasma concentration (C(max)) (275.36%) and area under plasma concentration-time curves from time 0 to 24 h (AUC(24h)) (268.14%) of dextromethorphan were outside the bioequivalence limit. The pharmacokinetics of theophylline was unaltered following coadministration of abiraterone acetate plus prednisone. Ratios of geometric means [C(max); 102.36% and AUC(24h); 108.03%] of theophylline exposure parameters were within the bioequivalence limit. The safety profile of abiraterone acetate was consistent with reported toxicities. Abiraterone acetate plus prednisone increased the exposure of dextromethorphan, suggesting a need for caution when coadministrating with known CYP2D6 substrates. The pharmacokinetics of theophylline was unaffected when coadministered with abiraterone acetate plus prednisone.

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

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

2018-03-20

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

Enzalutamide in Patients With Castration-Resistant Prostate Cancer Progressing After Docetaxel: Retrospective Analysis of the Swiss Enzalutamide Named Patient Program.

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Papazoglou, Dimitrios; Wannesson, Luciano; Berthold, Dominik; Cathomas, Richard; Gillessen, Silke; Rothermundt, Christian; Hasler, Loretta; Winterhalder, Ralph; Barth, Andreas; Mingrone, Walter; Nussbaum, Catrina Uhlmann; von Rohr, Lukas; von Burg, Philippe; Schmid, Mathias; Richner, Jürg; Baumann, Sylvia; Kühne, Reto; Stenner, Frank; Rothschild, Sacha I

2017-06-01

Enzalutamide is a second-generation androgen receptor (AR) inhibitor that binds to and blocks the AR with higher affinity than previously available AR inhibitors. High activity has been proven in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and in chemotherapy-naive patients with mCRPC. However, its activity in patients previously treated with other novel agents (for example, abiraterone and/or cabazitaxel), remains controversial. The aim of this retrospective analysis of the Swiss Enzalutamide Named Patient Program was to evaluate clinical efficacy and safety of enzalutamide treatment in patients with mCRPC progressing after docetaxel and other lines of therapy considering different treatment sequences. We report on 44 patients treated with enzalutamide. The median survival time from diagnosis of CPRC was 41.1 months (95% confidence interval [CI], 32.3-49.8 months). Enzalutamide was used as a second, third, fourth, fifth, sixth, or seventh-line therapy in 13%, 20%, 31%, 20%, 11%, and 2% of patients. The median duration of enzalutamide treatment was 3.0 months (range, 1-21 months). Median progression-free survival was 3.0 months (95% CI, 2.4-3.7 months). The estimated median overall survival was 6.3 months (95% CI, 4.6-8.1 months). Sixteen patients (36.4%) had a prostate-specific antigen decrease of ≥ 30%, and 11 patients (25.0%) of ≥ 50%, respectively. In multivariate analysis, the absence of previous therapy with abiraterone and a prostate-specific antigen response of ≥ 50% on enzalutamide therapy were significantly associated with overall survival on enzalutamide treatment. Our results show that enzalutamide has modest activity in extensively pretreated patients. However, there is a subgroup of patients achieving benefit from enzalutamide therapy even after pretreatment with abiraterone. Copyright © 2016 Elsevier Inc. All rights reserved.

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

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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 < 0.001). A similar AMH profile in CO and SR indicates that SR did not induce a true cryptorchid state. In groups OR and BZ, AMH was undetectable. Plasma inhibin concentration was higher in groups CO and SR than BZ and OR (P < 0.001). Plasma LH and FSH concentrations decreased over time (P < 0.001) and were higher in groups BZ and OR than SR and CO (P < 0.001). In the testes, immunolabeling for AMH existed in Sertoli cells of CO and SR but not 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. Copyright © 2016 Elsevier Inc. All rights reserved.

Vascular morphologic and functional effect of endogenous androgens in an experimental atherosclerotic rabbits model

International Nuclear Information System (INIS)

Echeverry, Dario; Delgadillo, Alexandra; Montes, Felix

2007-01-01

Previous clinical and experimental studies suggest that androgens could have adverse, neutral or beneficial effect on atherosclerosis and its clinical manifestations. Methods: an experimental, randomized controlled study in 40 New Zeland white male rabbits was realized. 20 rabbits underwent orchidectomy and 20 were fed with an atherogenic diet for 20 weeks. These were distributed in four groups: 1. non-castrated under normal diet, 2. Castrated under normal diet, 3. non-castrated under atherogenic diet, and 4. Castrated under atherogenic diet. Total cholesterol and free testosterone were measured. After euthanasia, arterial relaxation independent of endothelium was quantified in aorta, as well as the one depending on endothelium, in vitro, and histomorphometric analysis of thoracic aorta were made in order to quantify the atherosclerotic plaque formation. Results: animals that had a normal diet (n=20) had total cholesterol of 51.1 ± 8.5 mg/dl and those with atherogenic diet of 429.2 ± 262.0 mg/dl (p< 0.001). Testosterone levels in the non- castrated group were 2.1 ± 0.3 ng/ml and in the castrated were 0.8 ± 0.4 ng/ml (p= 0.024). In non-castrated rabbits the effect of hypercholesterolemia (366 ± 226.1 mg/dl) inducing atherosclerotic plaque and functional vascular alteration was mild. On the other hand, atherogenic diet in castrated rabbits induced an increment in total cholesterol from 387.6 ± 292.7 mg/dl (p <0.001) and severe morphological changes such as plaque area 2.6 ± 2.3mm (p <0.001), vessel plaque/area 0.25 ± 0.1 (p <0.001) and area index of plaque/area of the media 0.4 ± 0.3 (p <0.001). Endothelium independent relaxation percentage was 85.5 ± 14.3% (p = NS) and endothelium dependent relaxation was 38.5 ± 201% (p = 0.03). Conclusion: This study realized in rabbits demonstrates that endogenous testosterone might have a preventive effect on atherosclerosis and favor endothelium dependent vascular relaxation in the presence of severe

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....... In order to overcome these various types of heterogeneity and to compare like with like, the treatment comparison should be stratified a posteriori by question (i.e., type of castration or type of anti-androgen studied) and by study. In this way, one may draw valid conclusions. Of course, those trials...

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

The PREVAIL Study

DEFF Research Database (Denmark)

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

2016-01-01

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...... 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...

{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

Vimentin and Ki67 expression in circulating tumour cells derived from castrate-resistant prostate cancer.

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Lindsay, C R; Le Moulec, S; Billiot, F; Loriot, Y; Ngo-Camus, M; Vielh, P; Fizazi, K; Massard, C; Farace, F

2016-02-29

High circulating tumor cell (CTC) counts are associated with poor prognosis in advanced prostate cancer, and recently CTC number was suggested to be a surrogate for survival in metastatic castrate-resistant prostate cancer (mCRPC). Ki67 and vimentin are well-characterised markers of tumour cell proliferation and the epithelial-mesenchymal transition (EMT), respectively. Here we asked if the expression of vimentin and Ki67 in CTCs offered prognostic or predictive information in mCRPC. In two separate patient cohorts, anti-vimentin or anti-Ki67 antibodies were added to the free channel in the CellSearch® system for analysis of peripheral blood samples. For each cohort, association of CTC number with clinical characteristics were assessed using Fisher's exact, Mann-Whitney and chi-squared tests. Kaplan-Meier method and log-rank tests were used to analyse overall survival (OS) of vimentin-expressing and Ki67-expressing CTC patient cohorts. In this retrospective analysis, CTC vimentin expression was analysed in 142 blood samples from 93 patients, and CTC Ki67 expression was analysed in 90 blood samples from 51 patients. In the vimentin cohort, 80/93 (86 %) of baseline samples from patients were CTC-positive overall (≥1 total CTC per 7.5 mls blood), and 30/93 (32.3 %) vimentin CTC-positive (≥1 vimentin-positive CTC per 7.5 mls blood). 41/51 (80.4 %) of baseline samples from patients in the Ki67 cohort were CTC-positive overall, and 23/51 (45.1 %) Ki67 CTC-positive (≥1 Ki67-positive CTC per 7.5 mls blood). There was no significant difference in baseline PSA in patients with vimentin-positive CTC at baseline versus those with no vimentin-positive CTC at baseline (p = 0.33). A significant reduction in OS was shown in patients with vimentin-positive CTC compared to those without vimentin-positive CTC (median 305 days vs 453 days, p = 0.0293). There was no significant difference in baseline PSA in patients with Ki67-positive CTC at baseline versus those without Ki67

Vimentin and Ki67 expression in circulating tumour cells derived from castrate-resistant prostate cancer

International Nuclear Information System (INIS)

Lindsay, C. R.; Le Moulec, S.; Billiot, F.; Loriot, Y.; Ngo-Camus, M.; Vielh, P.; Fizazi, K.; Massard, C.; Farace, F.

2016-01-01

High circulating tumor cell (CTC) counts are associated with poor prognosis in advanced prostate cancer, and recently CTC number was suggested to be a surrogate for survival in metastatic castrate-resistant prostate cancer (mCRPC). Ki67 and vimentin are well-characterised markers of tumour cell proliferation and the epithelial-mesenchymal transition (EMT), respectively. Here we asked if the expression of vimentin and Ki67 in CTCs offered prognostic or predictive information in mCRPC. In two separate patient cohorts, anti-vimentin or anti-Ki67 antibodies were added to the free channel in the CellSearch® system for analysis of peripheral blood samples. For each cohort, association of CTC number with clinical characteristics were assessed using Fisher’s exact, Mann-Whitney and chi-squared tests. Kaplan-Meier method and log-rank tests were used to analyse overall survival (OS) of vimentin-expressing and Ki67-expressing CTC patient cohorts. In this retrospective analysis, CTC vimentin expression was analysed in 142 blood samples from 93 patients, and CTC Ki67 expression was analysed in 90 blood samples from 51 patients. In the vimentin cohort, 80/93 (86 %) of baseline samples from patients were CTC-positive overall (≥1 total CTC per 7.5 mls blood), and 30/93 (32.3 %) vimentin CTC-positive (≥1 vimentin-positive CTC per 7.5 mls blood). 41/51 (80.4 %) of baseline samples from patients in the Ki67 cohort were CTC-positive overall, and 23/51 (45.1 %) Ki67 CTC-positive (≥1 Ki67-positive CTC per 7.5 mls blood). There was no significant difference in baseline PSA in patients with vimentin-positive CTC at baseline versus those with no vimentin-positive CTC at baseline (p = 0.33). A significant reduction in OS was shown in patients with vimentin-positive CTC compared to those without vimentin-positive CTC (median 305 days vs 453 days, p = 0.0293). There was no significant difference in baseline PSA in patients with Ki67-positive CTC at baseline versus those without Ki67

Changes in quality of goat meat after alterations in animal Handling - doi:10.5020/18061230.2007.p33

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Frederico José Beserra

2012-01-01

Full Text Available This study aimed at evaluating the effect of animal handling, consisting in castration and cashew nut diet supplementation, on the cholesterol content and percentage composition of the muscles that constitute the leg meat cut from crossbred goats, grown in Ceará State. A case experimental design was applied with twenty male-animals with 5-6 months age and mean weight of 12 Kg, randomly divided in two groups of castrated (10 and intact (10 animals. In individual bays, they received during 5 months, two food regimen based on dried elephant grass (Pennisetum purpureum and a standard isoproteic ration (corn and soy oil, one of them with the addition of 13% cashew nut bran (CNB, forming four sub-groups: A1 (intact with no CNB supplemented diet; A2 (intact with CNB supplemented diet; B1 (castrated with no CNB supplemented diet and B2 (castrated with CNB supplemented diet. The castration associated with the CNB supplementation increased the meat’s fat yield from 1.16% to 3.57% and the cholesterol content from 36.47 mg/100g to 62.30 mg/100g. The ash yield decreased from 1.14% to 1.04%. The castration isolated only reduced moisture yield from 75.98% on sub-group A2 to 74.19% on sub-group B2. In intact animals that fed diet supplemented with CNB the protein decreased from 20.58% to 18.85% (P < 0.05 (sub-groups A1 and A2. The increased cholesterol content was highly correlated with the increase of the fat (93% In conclusion, these results showed that the combined use of castration and cashew nut bran (13% diet negatively influenced the dietetic and nutritional quality of goat leg meat.

Early cannabinoid exposure influences neuroendocrine and reproductive functions in male mice: I. Prenatal exposure.

Science.gov (United States)

Dalterio, S; Steger, R; Mayfield, D; Bartke, A

1984-01-01

Maternal exposure to delta 9-tetrahydrocannabinol (THC), the major psychoactive constituent in marihuana, or to the non-psychoactive cannabinol (CBN) or cannabidiol (CBD) alters endocrine functions and concentrations of brain biogenic amines in their male offspring. Prenatal CBN exposure on day 18 of gestation resulted in decreased plasma FSH levels, testicular testosterone (T) concentrations, and seminal vesicles weights, but increased plasma levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) post-castration in adulthood. Prenatal exposure to THC significantly enhanced the responsiveness of the testes to intratesticular LH injection in vivo and tended to increase human chorionic gonadotropin (hCG)-stimulated T production by decapsulated testes in vitro. In the CBN-exposed mice, hCG-stimulated T production was enhanced, while CBD exposure had no effect. Prenatal THC exposure altered the negative feedback effects of exogenous gonadal steroids in castrated adults, with lower plasma T and FSH levels after 20 micrograms T than in castrated controls. In contrast, CBD-exposed mice had higher levels of LH in plasma post-castration. In CBN-exposed adults, two weeks post-castration the concentration of norepinephrine (NE) and dopamine (DA) in hypothalamus and remaining brain were reduced, while levels of serotonin (5-HT) and its metabolite, 5-HIAA, were elevated compared to that in castrated OIL-controls. Prenatal CBD-exposure also reduced NE and elevated 5-HT and 5-HIAA, but did not affect DA levels post-castration. Concentrations of brain biogenic amines were not influenced by prenatal THC exposure in the present study. A single prenatal exposure to psychoactive or non-psychoactive components of marihuana results in long term alterations in the function of the hypothalamo-pituitary-gonadal axis. Changes in the concentrations of brain biogenic amines may be related to these effects of prenatal cannabinoids on endocrine function in adult male mice.

A Phase II Trial of Docetaxel with Rapid Androgen Cycling as a Treatment for Patients with Prostate Cancer

Science.gov (United States)

Rathkopf, Dana; Carducci, Michael A.; Morris, Michael J.; Slovin, Susan F.; Eisenberger, Mario A.; Pili, Roberto; Denmeade, Samuel R.; Kelsen, Moshe; Curley, Tracy; Priet, Regina; Collins, Connie; Fleisher, Martin; Heller, Glenn; Baker, Sharyn D.; Scher, Howard I.

2011-01-01

Purpose We evaluated rapid androgen cycling in combination with docetaxel for men with progressive non-castrate prostate cancers. Methods Non-castrate patients with ≤ 6 months of hormones were eligible. Cohort 1 (63 patients ) received 6 28-day cycles of docetaxel (75 mg/m2), leuprolide and 7 days of topical testosterone. Cohort 2 (39 patients) received 9 21-day cycles of docetaxel (70 mg/m2), leuprolide and 3 days of testosterone. The primary endpoint was the proportion of patients at 18 months who achieved non -castrate testosterone levels (>150 ng/dl) and an undetectable PSA (≤ 0.05, ≤0.5, or ≤2.0 ng/ml with prior prostatectomy, radiotherapy, or no definitive therapy, respectively). Cytochrome P450 3A4 (CYP3A4) activity and docetaxel pharmacokinetics were evaluated. Results A higher proportion of patients achieved the undetectable PSA outcome at 18 months in cohort 2 relative to cohort 1 (13% vs. 0%). The 16% incidence of febrile neutropenia was higher than observed in patients was castration-resistant disease, which may have been related to a 50% reduction in overall docetaxel clearance in the non-castrate group. There was no alteration in CYP3A4 activity (P=0.87) or docetaxel clearance (P=0.88) between cycles. Conclusions The undetectable PSA endpoint allows for a rapid screening of interventions for further study. Increasing the number of docetaxel cycles following a shorter period of testosterone repletion, and a longer duration of testosterone depletion, increased the proportion of men who achieved an undetectable PSA. The higher-than-expected incidence of febrile neutropenia may have been related to the reduced overall docetaxel clearance in patients with non-castrate vs castrate testosterone levels. PMID:18565882

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

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Rhéure Alves-Lopes

2017-01-01

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

Effect of gonadotropin secretion rate on the radiosensitivity of the rat luteinizing hormone-releasing hormone neuron and gonadotroph

International Nuclear Information System (INIS)

Winterer, J.; Barnes, K.M.; Lichter, A.S.; Deluca, A.M.; Loriaux, D.L.; Cutler, G.B. Jr.

1988-01-01

To test the hypothesis that the functional state of hypothalamic LHRH neurons and pituitary gonadotrophs might alter their radiosensitivity, we determined the experimental conditions under which the gonadotropin response to castration could be impaired by a single dose of cranial irradiation. Single doses of cranial irradiation greater than 2000 rads were lethal to unshielded rats. Shielding of the oropharynx and esophagus allowed the animals to survive doses up to 5000 rads. Doses between 2000 and 5000 rads had no effect on basal gonadotropin levels for as long as 3 months after irradiation. Irradiation caused a dose- and time-dependent impairment, however, in the gonadotropin response to castration. Impairment of the gonadotropin levels of castrate animals occurred in animals that were irradiated either before or after castration. However, rats irradiated in the castrate state showed a decreased susceptibility to irradiation damage. Additionally, stimulation of the pituitary by LHRH agonist (LHRHa) 3 h before irradiation significantly reduced the impairment of gonadotropin secretion 12-20 weeks after irradiation (P less than 0.05). Thus, increased functional activity of the rat hypothalamus or pituitary at the time of irradiation, induced by either castration or acute LHRHa administration, was associated with some protection against the gonadotropin-lowering effect of irradiation. Based upon these data, we hypothesize that stimulation of gonadotropin secretion at the time of therapeutic cranial irradiation in humans might protect against subsequent impairment of gonadotropin secretion

Hormone therapy in metastatic prostate cancer

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Jebelameli P

1997-09-01

Full Text Available Only orchiectomy is still commonly used today either as a single therapy or in combination regimens. Hypophysectomy & adrenalectomy showed such devastating effects on the endocrine equilibrium as to be inconsistent with an acceptable quality of life or even with survival. Chemical adrenalectomy was also tried with drugs (eg. aminoglutethmide, spironolactone leading to consequences superimposable to those of surgical adrenalectomy. Along with orchiectomy, three groups of substances are commonly used today for the hormonal therapy of prostate cancer: estrogens, LHRH agonists & anti androgens. Bilateral orchiectomy removes 90-95% of circulating testosterone. Clinical studies document 60-80% of positive responders to castration, on continued evaluation, relapse occurs usually within 6-24 months in responders, with a death rate of 50% within 6 months. The androgenic activity still remaining after castration may explain the partial & progressively decreasing effectiveness of this & other testosterone reducing therapies. Antiandrogens define substances that act directly at the target site, where interacting with steroid hormone receptors, they impede the binding of androgens. A trend towards the combination of testosterone-reducing & androgen-blocking treatment is developing in modern therapy of prostate cancer. This is due to the complementary characteristics of the two different pharmacological mechanisms that are involved. In this study castration+antiandrogen is compared to castration alone. The results demonstrate a significantly greater percentage of positive objective & subjective responses with antiandrogen than with placebo. In addition survival time was increased in patients treated with castration+antiandrogen than castration+placebo.

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

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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.

Preliminary study of the specific endothelin a receptor antagonist zibotentan in combination with docetaxel in patients with metastatic castration-resistant prostate cancer.

Science.gov (United States)

Trump, Donald L; Payne, Heather; Miller, Kurt; de Bono, Johann S; Stephenson, Joe; Burris, Howard A; Nathan, Faith; Taboada, Maria; Morris, Thomas; Hubner, Andreas

2011-09-01

This two-part study assessed the safety and tolerability of combined treatment with zibotentan (ZD4054), a specific endothelin A receptor antagonist, plus docetaxel in patients with metastatic castration-resistant prostate cancer. Part A was an open-label, dose-finding phase to determine the safety and toxicity profile of zibotentan in combination with docetaxel. Patients received once-daily oral zibotentan 10 mg (initial cohort) or 15 mg in combination with docetaxel 75 mg/m(2) (administered on day 1 of each 21-day cycle) for up to 10 cycles. Part B was a double-blind phase which evaluated the safety and preliminary activity of zibotentan plus docetaxel. Patients were randomized 2:1 to receive zibotentan (at the highest tolerated dose identified in part A) plus docetaxel or placebo plus docetaxel. Six patients were enrolled in part A (n  = 3, zibotentan 10 mg; n = 3, zibotentan 15 mg). No dose-limiting toxicity was observed, thus zibotentan 15 mg in combination with docetaxel was evaluated in part B (n = 20, zibotentan plus docetaxel; n = 11, placebo plus docetaxel). CTCAE grade ≥3, most commonly neutropenia or leucopenia, were reported in 10 (50%) and nine (82%) patients in the zibotentan and placebo groups, respectively. One (17%) patient receiving placebo achieved complete response, two (22%) patients receiving zibotentan achieved partial response and stable disease occurred in six (67%) and three (50%) patients receiving zibotentan and placebo, respectively. The tolerability of zibotentan plus docetaxel was consistent with the known profiles of each drug. Sufficient preliminary activity was seen with this combination to merit continued development. Copyright © 2011 Wiley-Liss, Inc.

Influence of testosterone on the distribution of 65Zn-binding proteins in the prostate and seminal vesicles of rats

International Nuclear Information System (INIS)

Arlt, R.; Foerster, R.; Scherr, F.; Guenther, T.

1977-01-01

65 Zn (7.4 MBq; 200 μCi) was injected intravenously into normal, castrated and castrated, testosteronesubstituted rats. After 1,24 and 48 hours, the distribution of 65 Zn-binding proteins in the 100,000 g supernatant of the prostate and seminal vesicles was investigated by separation on Sephadex G 100. The prostate and seminal vesicles from any one rat showed the same distribution pattern of 65 Zn-proteins. In castrated rats, the incorporation of 65 Zn was, however, 5-6 times lower than in the normal or castrated, testosterone-substituted rats. One hour after the injection, the highest activity of 65 Zn was found in proteins in the molecular weight range above 100,000. After 48 hours the greatest proportion of 65 Zn was present in the protein peak corresponding to 28,000 Daltons. (orig.) 891 AJ [de

The effects of a slow release GnRH agonist implant on male rabbits

DEFF Research Database (Denmark)

Goericke-Pesch, Sandra Kathrin; Groeger, Gesa; Wehrend, Axel

2015-01-01

Surgical castration is done in male pet rabbits for reproduction control, to reduce inter-male aggression and to control hyper-sexuality, territory marking and aggression against humans. Alternatives to surgical castration are requested because of a relatively great anaesthetic risk in rabbits....... Long-term application of a GnRH agonist implant results in a fully reversible "hormonal" castration in male dogs, cats, boars and many other species. Therefore, the present study using New Zealand White hybrid and German Giant rabbits aimed to investigate the effects of a 4.7mg deslorelin implant...

Genotype modulates testosterone-dependent activity and reactivity in male mice.

Science.gov (United States)

Broida, J; Svare, B

1983-03-01

Adult castration significantly reduced the homecage locomotor activity of both inbred C57BL/6J and DBA/2J and outbred Rockland-Swiss (R-S) male mice. Castrated C57BL animals exhibited greater reductions in this behavior than did the other genotypes. Locomotor activity in a novel environment (reactivity) was also reduced by castration but only for inbred males. In both test situations, postcastration reductions in ambulation were prevented by implants of testosterone (T)-containing Silastic capsules. Thus, testicular hormones promote activity and reactivity in the male mouse in a genotype-dependent fashion.

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...

Lactate dehydrogenase predicts combined progression-free survival after sequential therapy with abiraterone and enzalutamide for patients with castration-resistant prostate cancer.

Science.gov (United States)

Mori, Keiichiro; Kimura, Takahiro; Onuma, Hajime; Kimura, Shoji; Yamamoto, Toshihiro; Sasaki, Hiroshi; Miki, Jun; Miki, Kenta; Egawa, Shin

2017-07-01

An array of clinical issues remains to be resolved for castration-resistant prostate cancer (CRPC), including the sequence of drug use and drug cross-resistance. At present, no clear guidelines are available for the optimal sequence of use of novel agents like androgen-receptor axis-targeted (ARAT) agents, particularly enzalutamide, and abiraterone. This study retrospectively analyzed a total of 69 patients with CRPC treated with sequential therapy using enzalutamide followed by abiraterone or vice versa. The primary outcome measure was the comparative combined progression-free survival (PFS) comprising symptomatic and/or radiographic PFS. Patients were also compared for total prostate-specific antigen (PSA)-PFS, overall survival (OS), and PSA response. The predictors of combined PFS and OS were analyzed with a backward-stepwise multivariate Cox model. Of the 69 patients, 46 received enzalutamide first, followed by abiraterone (E-A group), and 23 received abiraterone, followed by enzalutamide (A-E group). The two groups were not significantly different with regard to basic data, except for hemoglobin values. In a comparison with the E-A group, the A-E group was shown to be associated with better combined PFS in Kaplan-Meier analysis (P = 0.043). Similar results were obtained for total PSA-PFS (P = 0.049), while OS did not differ between groups (P = 0.62). Multivariate analysis demonstrated that pretreatment lactate dehydrogenase (LDH) values and age were significant predictors of longer combined PFS (P < 0.05). Likewise, multivariate analysis demonstrated that pretreatment hemoglobin values and performance status were significant predictors of longer OS (P < 0.05). The results of this study suggested the A-E sequence had longer combined PSA and total PSA-PFS compared to the E-A sequence in patients with CRPC. LDH values in sequential therapy may serve as a predictor of longer combined PFS. © 2017 Wiley Periodicals, Inc.

Effect of epidural tramadol and lignocaine on physiological and behavioural changes in goats subjected to castration with a high tension band.

Science.gov (United States)

Ajadi, R A; Owanikin, A O; Martins, M M; Gazal, O S

2012-11-01

To compare the effect of a single epidural injection of either lignocaine or tramadol on behavioural changes, anaesthetic indices, leucocyte parameters, erythrocyte sedimentation rates and concentration of cortisol in plasma in goats subjected to castration by high tension band. Ten male goats weighing 14.4 (SD 0.7) kg were randomly allocated to anaesthesia with epidural injections of tramadol (3 mg/kg), or lignocaine (4 mg/kg). Following anaesthesia, a rubber ring was applied and tensioned to the scrotal neck of each goat. Behavioural changes were noted as they occurred, and the onset of drug action (time between epidural injection and loss of pedal reflex) and duration of antinociception (time interval between disappearance and reappearance of pedal withdrawal reflex) were determined. Hearts rates, respiratory rates and rectal temperatures were determined every 15 minutes for a 90-minute period, while blood was obtained for determination of white cell counts, erythrocyte sedimentation rates and concentrations of cortisol. Anaesthetic indices were compared using Student's t-test, while physiological parameters were compared using an ANOVA for repeated measurements. Goats treated with epidural tramadol were not recumbent and continued rumination while goats treated with epidural lignocaine were recumbent and did not continue rumination. The onset of analgesia was longer (p=0.01) in goats treated with epidural tramadol (5.0 minutes; SD 1.2) than goats treated with epidural lignocaine (3.0 minutes; SD 1.1), while duration of analgesia was shorter (p=0.003) in goats treated with epidural tramadol (47.2 minutes; SD 13.1) than goats treated with epidural lignocaine (89.8 minutes; SD 23.1). There was no significant difference in heart rates, respiratory rates and erythrocyte sedimentation rates, while the concentration of cortisol in plasma differed (pcattle and where the ability of the animal to maintain standing is desired.

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

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

Inhibition of Androgen Receptor Function and Level in Castration-Resistant Prostate Cancer Cells by 2-[(isoxazol-4-ylmethyl)thio]-1-(4-phenylpiperazin-1-yl)ethanone.

Science.gov (United States)

Masoodi, Khalid Z; Eisermann, Kurtis; Yang, Zhenyu; Dar, Javid A; Pascal, Laura E; Nguyen, Minh; O'Malley, Katherine; Parrinello, Erica; Feturi, Firuz G; Kenefake, Alex N; Nelson, Joel B; Johnston, Paul A; Wipf, Peter; Wang, Zhou

2017-10-01

The androgen receptor (AR) plays a critical role in the development of castration-resistant prostate cancer (CRPC) as well as in the resistance to the second-generation AR antagonist enzalutamide and the selective inhibitor of cytochrome P450 17A1 (CYP17A1) abiraterone. Novel agents targeting AR may inhibit the growth of prostate cancer cells resistant to enzalutamide and/or abiraterone. Through a high-throughput/high-content screening of a 220,000-member small molecule library, we have previously identified 2-[(isoxazol-4-ylmethyl)thio]-1-(4-phenylpiperazin-1-yl)ethanone (IMTPPE) (SID 3712502) as a novel small molecule capable of inhibiting AR transcriptional activity and protein level in C4-2 prostate cancer cells. In this study, we show that IMTPPE inhibits AR-target gene expression using real-time polymerase chain reaction, Western blot, and luciferase assays. IMTPPE inhibited proliferation of AR-positive, but not AR-negative, prostate cancer cells in culture. IMTPPE inhibited the transcriptional activity of a mutant AR lacking the ligand-binding domain (LBD), indicating that IMTPPE inhibition of AR is independent of the LBD. Furthermore, animal studies showed that IMTPPE inhibited the growth of 22Rv1 xenograft tumor, a model for enzalutamide-resistant prostate cancer. These findings suggest that IMTPPE is a potential lead compound for developing clinical candidates for the treatment of CRPC, including those resistant to enzalutamide. Copyright © 2017 Endocrine Society.

Development and Implementation of a High-Throughput High-Content Screening Assay to Identify Inhibitors of Androgen Receptor Nuclear Localization in Castration-Resistant Prostate Cancer Cells

Science.gov (United States)

Nguyen, Minh M.; Dar, Javid A.; Ai, Junkui; Wang, Yujuan; Masoodi, Khalid Z.; Shun, Tongying; Shinde, Sunita; Camarco, Daniel P.; Hua, Yun; Huryn, Donna M.; Wilson, Gabriela Mustata; Lazo, John S.; Nelson, Joel B.; Wipf, Peter

2016-01-01

Abstract Patients with castration-resistant prostate cancer (CRPC) can be treated with abiraterone, a potent inhibitor of androgen synthesis, or enzalutamide, a second-generation androgen receptor (AR) antagonist, both targeting AR signaling. However, most patients relapse after several months of therapy and a majority of patients with relapsed CRPC tumors express the AR target gene prostate-specific antigen (PSA), suggesting that AR signaling is reactivated and can be targeted again to inhibit the relapsed tumors. Novel small molecules capable of inhibiting AR function may lead to urgently needed therapies for patients resistant to abiraterone, enzalutamide, and/or other previously approved antiandrogen therapies. Here, we describe a high-throughput high-content screening (HCS) campaign to identify small-molecule inhibitors of AR nuclear localization in the C4-2 CRPC cell line stably transfected with GFP-AR-GFP (2GFP-AR). The implementation of this HCS assay to screen a National Institutes of Health library of 219,055 compounds led to the discovery of 3 small molecules capable of inhibiting AR nuclear localization and function in C4-2 cells, demonstrating the feasibility of using this cell-based phenotypic assay to identify small molecules targeting the subcellular localization of AR. Furthermore, the three hit compounds provide opportunities to develop novel AR drugs with potential for therapeutic intervention in CRPC patients who have relapsed after treatment with antiandrogens, such as abiraterone and/or enzalutamide. PMID:27187604

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...

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

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

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

Experiment list: SRX286386 [Chip-atlas[Archive

Lifescience Database Archive (English)

Full Text Available 60.2,17474 GSM1146465: FoxA1 Cast [prostate, castrated+vehicle]; Mus musculus; ChIP-Seq source_name=FoxA1_Ca...st || strain=wild type ICR || tissue=prostate || age=8-12 weeks old || treatment=castrated+vehicle || chip a

EFEITOS DA CASTRAÇÃO SOBRE CARACTERÍSTICAS FÍSICO-QUÍMICAS E CELULARES DO LÍQUIDO PERITONEAL DE EQUINOS

Directory of Open Access Journals (Sweden)

Paula Alessandra Di Filippo

2016-07-01

Full Text Available As one of the most frequently performed surgical techniques and the constant association with complications, ten animals were submitted to castration and physical, chemical and cytological peritoneal fluid characteristics were evaluated. The peritoneal fluid samples were obtained before surgery and after castration. It was evaluated the color and turbidity, total concentration and count of differential leukocyte, lactate, protein and phosphorus, as well as the activity of CK, AST, LDH and FA. After castration, the peritoneal fluid has become reddish and cloudy, there was an increase in protein, lactate and phosphorus as well the activity of CK, AST, AP and LDH. The changes were not associated with the development of postoperative complications and were due to inflammatory response triggered by surgical trauma. The analysis of peritoneal fluid can assist in post castration monitoring to the aiming the early and efficiently resolution of possible complications.

Hypogonadism alters cecal and fecal microbiota in male mice.

Science.gov (United States)

Harada, Naoki; Hanaoka, Ryo; Hanada, Kazuki; Izawa, Takeshi; Inui, Hiroshi; Yamaji, Ryoichi

2016-11-01

Low testosterone levels increase the risk for cardiovascular disease in men and lead to shorter life spans. Our recent study showed that androgen deprivation via castration altered fecal microbiota and exacerbated risk factors for cardiovascular disease, including obesity, impaired fasting glucose, excess hepatic triglyceride accumulation, and thigh muscle weight loss only in high-fat diet (HFD)-fed male mice. However, when mice were administered antibiotics that disrupted the gut microbiota, castration did not increase cardiovascular risks or decrease the ratio of dried feces to food intake. Here, we show that changes in cecal microbiota (e.g., an increased Firmicutes/Bacteroidetes ratio and number of Lactobacillus species) were consistent with changes in feces and that there was a decreased cecal content secondary to castration in HFD mice. Castration increased rectal body temperature and plasma adiponectin, irrespective of diet. Changes in the gut microbiome may provide novel insight into hypogonadism-induced cardiovascular diseases.

Third-line treatment and 177Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review

International Nuclear Information System (INIS)

Edler von Eyben, Finn; Roviello, Giandomenico; Kiljunen, Timo; Kairemo, Kalevi; Joensuu, Timo; Uprimny, Christian; Virgolini, Irene

2018-01-01

There is a controversy as to the relative efficacy of 177 Lu prostate specific membrane antigen (PSMA) radioligand therapy (RLT) and third-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of our systematic review was to elucidate whether 177 Lu-PSMA RLT and third-line treatment have similar effects and adverse effects (PROSPERO ID CRD42017067743). The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Searches in Pubmed and Embase selected articles up to September 2017. A search in ClinicalTrials.gov indicated ongoing studies. The meta-analysis used the random-effects model. Twelve studies including 669 patients reported 177 Lu-PSMA RLT. Overall, 43% of the patients had a maximum decline of PSA of ≥50% following treatment with 177 Lu-PSMA RLT. The treatment with 177 Lu-PSMA-617 and 177 Lu-PSMA for imaging and therapy (I and T) had mainly transient adverse effects. Sixteen studies including 1338 patients reported third-line treatment. Overall, 21% of the patients had a best decline of PSA of ≥50% following third-line treatment. After third-line treatment with enzalutamide and cabazitaxel, adverse effects caused discontinuation of treatment for 10% to 23% of the patients. 177 Lu-PSMA RLT gave a best PSA decline ≥50% more often than third-line treatment (mean 44% versus 22%, p = 0.0002, t test). 177 Lu-PSMA RLT gave objective remission more often than third-line treatment (overall 31 of 109 patients versus 43 of 275 patients, p = 0.004, χ 2 test). Median survival was longer after 177 Lu-PSMA RLT than after third-line treatment, but the difference was not statistically significant (mean 14 months versus 12 months, p = 0.32, t test). Adverse effects caused discontinuation of treatment more often for third-line treatment than for 177 Lu-PSMA RLT (22 of 66 patients versus 0 of 469 patients, p < 0.001, χ 2 test). As for patients with mCRPC, treatment with 177 Lu

PSA time to nadir as a prognostic factor of first-line docetaxel treatment in castration-resistant prostate cancer: evidence from patients in Northwestern China.

Science.gov (United States)

Wu, Kai-Jie; Pei, Xin-Qi; Tian, Ge; Wu, Da-Peng; Fan, Jin-Hai; Jiang, Yu-Mei; He, Da-Lin

2018-01-01

Docetaxel-based chemotherapy remains the first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) in China; however, the prognostic factors associated with effects in these patients are still controversial. In this study, we retrospectively reviewed the data from 71 eligible Chinese patients who received docetaxel chemotherapy from 2009 to 2016 in our hospital and experienced a reduction of prostate-specific antigen (PSA) level ≥50% during the treatment and investigated the potential role of time to nadir (TTN) of PSA. TTN was defined as the time from start of chemotherapy to the nadir of PSA level during the treatment. Multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival (OS). In these patients, the median of TTN was 17 weeks. Patients with TTN ≥17 weeks had a longer response time to chemotherapy compared to TTN PSA progression in patients with TTN ≥17 weeks was 11.44 weeks compared to 5.63 weeks when TTN was PSA level at the diagnosis of cancer (HR: 4.337, 95% CI: 1.616-11.645, P = 0.004), duration of initial androgen deprivation therapy (HR: 2.982, 95% CI: 1.104-8.045, P = 0.031), neutrophil-to-lymphocyte ratio (HR: 3.963, 95% CI: 1.380-11.384, P = 0.011), and total PSA response (Class 1 [PSA remains an important prognostic marker in predicting therapeutic outcome in Chinese population who receive chemotherapy for mCRPC and have >50% PSA remission.

PSA response to cabazitaxel is associated with improved progression-free survival in metastatic castration-resistant prostate cancer: the non-interventional QoLiTime study.

Science.gov (United States)

Hammerer, Peter; Al-Batran, Salah-Eddin; Windemuth-Kieselbach, Christine; Keller, Martin; Hofheinz, Ralf-Dieter

2018-03-01

To evaluate the association between prostate-specific antigen (PSA) response and progression-free and overall survival in men with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel. Men with mCRPC receiving cabazitaxel (25 mg/m 2 , every 3 weeks) plus oral prednis(ol)one (10 mg/day) were enrolled in the non-interventional, prospective QoLiTime study. Main outcome measures were progression-free survival and overall survival, in all patients and in those who showed a ≥ 50 or a ≥ 30% decrease in PSA relative to baseline after four cycles of cabazitaxel, as well as quality-of-life parameters. Of the 527 men (median age 72 years), 266 received ≥ 4 cycles of cabazitaxel and had PSA response data. After four cycles, 34.6% of men achieved a PSA decrease ≥ 50% and 49.6% a decrease ≥ 30%. Median progression-free survival was 7.7 (95% CI 6.2, 9.5) months, and overall survival was 19.5 (95% CI 16.0, 30.9) months, corresponding to 1-year event rates of 39.4 and 78.8%, respectively. Median progression-free survival was longer in PSA responders versus non-responders (15.7 vs 5.5 months at 50% cut-off; 15.7 vs 5.3 months for 30% cut-off; both P PSA response after four cycles of cabazitaxel is associated with improved progression-free survival in men with mCRPC treated with cabazitaxel plus prednis(ol)one.

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)

Androgen receptors in the pelvic diaphragm muscles of dogs with and without perineal hernia.

Science.gov (United States)

Mann, F A; Nonneman, D J; Pope, E R; Boothe, H W; Welshons, W V; Ganjam, V K

1995-01-01

Levator ani and coccygeus muscle estrogen and androgen receptors were measured in 6, healthy, > or = 5-year-old, noncastrated, male Beagles (controls) and in 24 dogs with perineal hernia. Estrogen and androgen receptor analyses were performed on levator ani and coccygeus muscle specimens obtained from control dogs at the time of castration; contralateral levator ani and coccygeus muscle specimens were assayed 2 months after castration. During herniorrhaphy of dogs with perineal hernia, levator ani (non-castrated, n = 12; castrated, n = 7) and/or coccygeus (noncastrated, n = 5; castrated, n = 4) muscle biopsy specimens were obtained for estrogen and androgen receptor analyses. For estrogen and androgen receptor assays, each muscle biopsy specimen was homogenized in Tris-EDTA-glycerol buffer, and centrifuged at 30,000 x g; extracts were used for binding with ligands: [3H]methyltrienolone (3HR1881) for androgen receptors, and [3H]estradiol-17 beta for estrogen receptors. Extracts were incubated overnight at 0 to 4 C. Nonspecific binding was estimated, using 100-fold concentration of cold ligands. Bound and free hormones were separated, using hydroxylapatite batch assay. Receptor numbers for each tissue were calculated as femtomoles (fmol) per milligram of protein. Quantified data were compared between precastration and postcastration controls, using a paired t-test. One-way ANOVA and Bonferroni post-hoc test were used to compare values for precastration controls, postcastration controls, castrated dogs with perineal hernia, and noncastrated dogs with perineal hernia. Significance was set at P < 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of social isolation, gender and familiarity with the experimental procedure on tests of porcine nociceptive thresholds

DEFF Research Database (Denmark)

di Giminiani, Pierpaolo; Stausholm, Julie S.; Viitasaari, Eliina

2015-01-01

Objective To investigate the effects of habituation and isolation on mechanical nociceptive thresholds in pigs at the pelvic limbs and at the tail. Study design Prospective randomized multifactorial study. Animals Thirty-two healthy castrated male (experiment 1), and 12 castrated male and 12 female...

Evaluation of local anaesthetic efficacy of the crude extract of ...

African Journals Online (AJOL)

ADEYEYE

Assessment of pain induced by castration in piglets: behavioural and physiologic responses over the subsequent five days. Applied Animal Behaviour Science, 82: 201-. 218. Horn T, Marx G & Borell E (1999). Behaviours of piglets during castration with and without local anaesthesia. Deutsche Tierarztliche. Wochenschrift ...

Aversion substance(s) of the rat coagulating glands

Science.gov (United States)

Gawienowski, Anthony M.; Berry, Iver J.; Kennelly, James J.

1982-01-01

The aversive substance(s) present in adult male urine were not found in castrate rat urine. Removal of the coagulating glands also resulted in a loss of the aversion compounds. The aversion substances were restored to the urine after androgen treatment of the castrate rats.

Genomics and systems biology of boar taint and meat quality in pigs

DEFF Research Database (Denmark)

Drag, Markus; Kogelman, Lisette JA; Meinert, Lene

2015-01-01

, economic losses associated with castrated pigs and a ban on castration in the EU effective by 2018. The main objective of the PhD project is to unravel the underlying mechanisms of BT at the genomic, transcriptomic and phenotypic levels as well as its connection with sensory meat quality (SMQ) in order...... to enable optimized breeding strategies as alternative to castration. Male pigs with different genetic merit of BT were selected and tissue from liver and testes were subjected to transcriptomic profiling by stranded paired end RNA-Seq which produced ~30 mio. reads per sample. The reads were subjected...

Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time.

Science.gov (United States)

Smith, Matthew R; Saad, Fred; Oudard, Stephane; Shore, Neal; Fizazi, Karim; Sieber, Paul; Tombal, Bertrand; Damiao, Ronaldo; Marx, Gavin; Miller, Kurt; Van Veldhuizen, Peter; Morote, Juan; Ye, Zhishen; Dansey, Roger; Goessl, Carsten

2013-10-20

Denosumab, an anti-RANK ligand monoclonal antibody, significantly increases bone metastasis-free survival (BMFS; hazard ratio [HR], 0.85; P = .028) and delays time to first bone metastasis in men with nonmetastatic castration-resistant prostate cancer (CRPC) and baseline prostate-specific antigen (PSA) ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤ 10.0 months. To identify men at greatest risk for bone metastasis or death, we evaluated relationships between PSA and PSADT with BMFS in the placebo group and the efficacy and safety of denosumab in men with PSADT ≤ 10, ≤ 6, and ≤ 4 months. A total of 1,432 men with nonmetastatic CRPC were randomly assigned 1:1 to monthly subcutaneous denosumab 120 mg or placebo. Enrollment began February 2006; primary analysis cutoff was July 2010, when approximately 660 men were anticipated to have developed bone metastases or died. In the placebo group, shorter BMFS was observed as PSADT decreased below 8 months. In analyses by shorter baseline PSADT, denosumab consistently increased BMFS by a median of 6.0, 7.2, and 7.5 months among men with PSADT ≤ 10 (HR, 0.84; P = .042), ≤ 6 (HR, 0.77; P = .006), and ≤ 4 months (HR, 0.71; P = .004), respectively. Denosumab also consistently increased time to bone metastasis by PSADT subset. No difference in survival was observed between treatment groups for the overall study population or PSADT subsets. Patients with shorter PSADT are at greater risk for bone metastasis or death. Denosumab consistently improves BMFS in men with shorter PSADT and seems to have the greatest treatment effects in men at high risk for progression.

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

Energy Technology Data Exchange (ETDEWEB)

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

2017-09-15

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

Effect of Visceral Disease Site on Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer Treated With Enzalutamide in the PREVAIL Trial.

Science.gov (United States)

Alumkal, Joshi J; Chowdhury, Simon; Loriot, Yohann; Sternberg, Cora N; de Bono, Johann S; Tombal, Bertrand; Carles, Joan; Flaig, Thomas W; Dorff, Tanya B; Phung, De; Forer, David; Noonberg, Sarah B; Mansbach, Hank; Beer, Tomasz M; Higano, Celestia S

2017-10-01

The Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy (PREVAIL) trial was unique as it included patients with visceral disease. This analysis was designed to describe outcomes for the subgroup of men from PREVAIL with specific sites of visceral disease to help clinicians understand how these patients responded to enzalutamide prior to chemotherapy. Prespecified analyses examined the coprimary endpoints of radiographic progression-free survival (rPFS) and overall survival (OS) only. All other efficacy analyses were post hoc. The visceral subgroup was divided into liver or lung subsets. Patients with both liver and lung metastases were included in the liver subset. Of the 1717 patients in PREVAIL, 204 (12%) had visceral metastases at screening (liver only or liver/lung metastases, n = 74; lung only metastases, n = 130). In patients with liver metastases, enzalutamide was associated with an improvement in rPFS (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.22-0.90) but not OS (HR, 1.04; 95% CI, 0.57-1.87). In patients with lung metastases only, the HR for rPFS (0.14; 95% CI, 0.06-0.36) and the HR for OS (0.59; 95% CI, 0.33-1.06) favored enzalutamide over placebo. Patients with liver metastases had worse outcomes than those with lung metastases, regardless of treatment. Enzalutamide was well tolerated in patients with visceral disease. Enzalutamide is an active first-line treatment option for men with asymptomatic or mildly symptomatic chemotherapy-naive metastatic castration-resistant prostate cancer and visceral disease. Patients with lung-only disease fared better than patients with liver disease, regardless of treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Systemic therapy in men with metastatic castration-resistant prostate cancer:American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline.

Science.gov (United States)

Basch, Ethan; Loblaw, D Andrew; Oliver, Thomas K; Carducci, Michael; Chen, Ronald C; Frame, James N; Garrels, Kristina; Hotte, Sebastien; Kattan, Michael W; Raghavan, Derek; Saad, Fred; Taplin, Mary-Ellen; Walker-Dilks, Cindy; Williams, James; Winquist, Eric; Bennett, Charles L; Wootton, Ted; Rumble, R Bryan; Dusetzina, Stacie B; Virgo, Katherine S

2014-10-20

To provide treatment recommendations for men with metastatic castration-resistant prostate cancer (CRPC). The American Society of Clinical Oncology and Cancer Care Ontario convened an expert panel to develop evidence-based recommendations informed by a systematic review of the literature. When added to androgen deprivation, therapies demonstrating improved survival, improved quality of life (QOL), and favorable benefit-harm balance include abiraterone acetate/prednisone, enzalutamide, and radium-223 ((223)Ra; for men with predominantly bone metastases). Improved survival and QOL with moderate toxicity risk are associated with docetaxel/prednisone. For asymptomatic/minimally symptomatic men, improved survival with unclear QOL impact and low toxicity are associated with sipuleucel-T. For men who previously received docetaxel, improved survival, unclear QOL impact, and moderate to high toxicity risk are associated with cabazitaxel/prednisone. Modest QOL benefit (without survival benefit) and high toxicity risk are associated with mitoxantrone/prednisone after docetaxel. No benefit and excess toxicity are observed with bevacizumab, estramustine, and sunitinib. Continue androgen deprivation (pharmaceutical or surgical) indefinitely. Abiraterone acetate/prednisone, enzalutamide, or (223)Ra should be offered; docetaxel/prednisone should also be offered, accompanied by discussion of toxicity risk. Sipuleucel-T may be offered to asymptomatic/minimally symptomatic men. For men who have experienced progression with docetaxel, cabazitaxel may be offered, accompanied by discussion of toxicity risk. Mitoxantrone may be offered, accompanied by discussion of limited clinical benefit and toxicity risk. Ketoconazole or antiandrogens (eg, bicalutamide, flutamide, nilutamide) may be offered, accompanied by discussion of limited known clinical benefit. Bevacizumab, estramustine, and sunitinib should not be offered. There is insufficient evidence to evaluate optimal sequences or

Suppression of LIM and SH3 Domain Protein 1 (LASP1) Negatively Regulated by Androgen Receptor Delays Castration Resistant Prostate Cancer Progression.

Science.gov (United States)

Dejima, Takashi; Imada, Kenjiro; Takeuchi, Ario; Shiota, Masaki; Leong, Jeffrey; Tombe, Tabitha; Tam, Kevin; Fazli, Ladan; Naito, Seiji; Gleave, Martin E; Ong, Christopher J

2017-02-01

LIM and SH3 domain protein 1 (LASP1) has been implicated in several human malignancies and has been shown to predict PSA recurrence in prostate cancer. However, the anti-tumor effect of LASP1 knockdown and the association between LASP1 and the androgen receptor (AR) remains unclear. The aim of this study is to clarify the significance of LASP1 as a target for prostate cancer, and to test the effect of silencing LASP1 in vivo using antisense oligonucleotides (ASO). A tissue microarray (TMA) was performed to characterize the differences in LASP1 expression in prostate cancer treated after hormone deprivation therapy. Flow cytometry was used to analyze cell cycle. We designed LASP1 ASO for knockdown of LASP1 in vivo studies. The expression of LASP1 in TMA was increased after androgen ablation and persisted in castration resistant prostate cancer (CRPC). Also in TMA, compared with LNCaP cell, LASP1 expression is elevated in CRPC cell lines (C4-2 and VehA cells). Interestingly, suppression of AR elevated LASP1 expression conversely, AR activation decreased LASP1 expression. Silencing of LASP1 reduced cell growth through G1 arrest which was accompanied by a decrease of cyclin D1. Forced overexpression of LASP1 promoted cell cycle and induced cell growth which was accompanied by an increase of cyclin D1. Systemic administration of LASP1 ASO with athymic mice significantly inhibited tumor growth in CRPC xenografts. These results indicate that LASP1 is negatively regulated by AR at the transcriptional level and promotes tumor growth through induction of cell cycle, ultimately suggesting that LASP1 may be a potential target in prostate cancer treatment. Prostate 77:309-320, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Prostate-specific antigen kinetics and outcomes in patients with bone metastases from castration-resistant prostate cancer treated with or without zoledronic acid.

Science.gov (United States)

Saad, Fred; Segal, Scott; Eastham, James

2014-01-01

Zoledronic acid (ZOL) is a standard therapy for the prevention of skeletal-related events (SREs) in patients with castration-resistant prostate cancer (CRPC). Although prostate-specific antigen (PSA) is an established marker for monitoring prostate cancer patients, correlations between PSA and disease outcomes during ZOL therapy are unclear. To evaluate the relationships among PSA kinetics, bone-directed therapy with ZOL, and clinical outcomes in men with bone metastases from CRPC using a ZOL phase 3 trial database. Exploratory analyses from a phase 3 trial in men with bone metastases from CRPC (n=643) randomized to ZOL or placebo every 3 wk. PSA levels during the first 3 mo of the study were evaluated in linear and logarithmic (log) models stratified using prognostic factors established in a ZOL phase 3 trial and a CRPC nomogram. Relative risks of SREs, bone disease progression (BDP), and death were calculated per 1 log (nanograms per milliliter) PSA increase. Baseline PSA models used the study median (PSA: 77.3 ng/ml) as the high/low cut-off point. A total of 202 placebo- and 434 ZOL-treated patients were assessable. In both groups, PSA increases correlated with significantly increased risks of death, BDP, and first SRE. In the placebo and ZOL groups, associated increases in risk per 1 log (nanograms per milliliter) PSA increase were 29% (p<0.0001) and 10% (p<0.0074), respectively, for BDP, and 24% (p=0.0010) and 13% (p=0.0079), respectively, for first SRE. Limitations include the retrospective nature of these analyses and the potential confounding effects of concurrent antineoplastic therapies. PSA is an important prognostic tool for survival in patients with bone metastases from CRPC, and these analyses show that PSA is also prognostic for BDP and SREs regardless of bone-targeted therapy. Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Differences in treatment patterns among patients with castration-resistant prostate cancer treated by oncologists versus urologists in a US managed care population

International Nuclear Information System (INIS)

Engel-Nitz, Nicole M; Alemayehu, Berhanu; Parry, David; Nathan, Faith

2011-01-01

Differences in treatment patterns, health care resource utilization, and costs between patients with castration-resistant prostate cancer (CRPC) treated by oncologists and those treated by urologists were examined. Patients aged ≥40 with CRPC were identified using claims from a large US managed health care plan between July 2001 and December 2007. A 6-month baseline period was used to assess patient characteristics. Patients with visits to an urologist, without visits to an oncologist, were assigned to the urology cohort, and patients with visits to an oncologist, with or without visits to an urologist, were assigned to the oncology cohort. Treatment patterns, health care resource utilization, and costs during a variable follow-up period were compared between cohorts using descriptive statistics and Lin’s regression. The urology cohort had fewer comorbid illnesses (P < 0.001) and patients were less likely to have other cancers during baseline (P < 0.001) or to die during follow-up (P = 0.004) compared with the oncology cohort. The oncology cohort patients were significantly more likely to have a claim for hormones (74.5% vs 61.1%; P < 0.001), chemotherapy (46.9% vs 10.2%, P < 0.001), and radiation (22.3% vs 3.7%, P < 0.0001) over follow-up. Mean unadjusted health care costs were higher in the oncology vs the urology cohort (US$31,896 vs US$15,318, respectively; P < 0.001). At 6 years follow-up, cumulative adjusted CRPC-specific costs were significantly higher among patients treated by oncologists with chemotherapy than among patients treated by urologists. CRPC patients treated by oncologists had greater use of hormones, chemotherapy, and radiation; higher percentages of patients with inpatient stays, emergency room, and ambulatory visits; and higher health care costs, than patients treated by urologists

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

Directory of Open Access Journals (Sweden)

Martin Boegemann

2017-02-01

Full Text Available 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 and 17 with 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 < 0.01. In MVA, ECOG > 0–1 and baseline LDH > UNL remained independent prognosticators. After 8 weeks of Abiraterone NLR-change to <5 prognosticated worse PFS (five versus 12 months (HR: 4.1 (95%CI:1.1–15.8; p = 0.04. MVA showed a trend towards worse PFS for NLR-change to <5 (p = 0.11. NLR-change to <5 led to non-significant shorter median OS (seven versus 16 months (HR: 2.3 (95%CI:0.7–7.1; p = 0.15. MVA showed non-significant difference for OS. We concluded baseline NLR <5 is associated with improved survival. In contrast, in patients with baseline NLR >5, NLR-change to <5 after eight weeks of Abiraterone was associated with worse survival and should be interpreted carefully.

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

Expression quantitative trait loci reveals genes and pathways associated with boar taint in pigs

DEFF Research Database (Denmark)

Drag, Markus; Hansen, Mathias Brygger; Kadarmideen, Haja N

Boar taint (BT) is an offensive odour or taste of meat from a proportion of non-castrated male pigs due to skatole and androstenone accumulation in adipose tissue. Castration is an effective strategy to avoid BT but is currently under debate due to animal welfare concerns. This study aimed...

Terapeutiske vacciner er et nyt behandlings-princip ved kastrationsresistent prostatacancer

DEFF Research Database (Denmark)

Djurhuus, Sissal Sigmundsdòttir; Brasso, Klaus; Berg, Kasper Drimer

2015-01-01

Therapeutic vaccines is a novel approach in castration-resistant prostate cancer treatment Castration-resistant prostate cancer (CRPC) is defined as tumour progression despite castrate levels of serum testosterone. During the past decade a number of new therapies, including chemo­therapy and novel...... endocrine agents have been approved for CRPC treatment. The continued need for new effective drugs in CRPC has led to development of a novel therapeutic approach in CRPC treatment. Therapeutic vaccines activate the immune system to kill prostate cancer cells. This review describes recent pivotal phase 2...... and 3 trials of CRPC vaccines and discusses the impact on future CRPC management....

Androgenic dependence of exophytic tumor growth in a transgenic mouse model of bladder cancer: a role for thrombospondin-1

Directory of Open Access Journals (Sweden)

Yao Jorge L

2008-04-01

Full Text Available Abstract Background Steroid hormones influence mitogenic signaling pathways, apoptosis, and cell cycle checkpoints, and it has long been known that incidence of bladder cancer (BC in men is several times greater than in women, a difference that cannot be attributed to environmental or lifestyle factors alone. Castration reduces incidence of chemically-induced BC in rodents. It is unclear if this effect is due to hormonal influences on activation/deactivation of carcinogens or a direct effect on urothelial cell proliferation or other malignant processes. We examined the effect of castration on BC growth in UPII-SV40T transgenic mice, which express SV40 T antigen specifically in urothelium and reliably develop BC. Furthermore, because BC growth in UPII-SV40T mice is exophytic, we speculated BC growth was dependent on angiogenesis and angiogenesis was, in turn, androgen responsive. Methods Flat panel detector-based cone beam computed tomography (FPDCT was used to longitudinally measure exophytic BC growth in UPII-SV40T male mice sham-operated, castrated, or castrated and supplemented with dihydrotestosterone (DHT. Human normal bladder and BC biopsies and mouse bladder were examined quantitatively for thrombospondin-1 (TSP1 protein expression. Results Mice castrated at 24 weeks of age had decreased BC volumes at 32 weeks compared to intact mice (p = 0.0071 and castrated mice administered DHT (p = 0.0233; one-way ANOVA, JMP 6.0.3, SAS Institute, Inc.. Bladder cancer cell lines responded to DHT treatment with increased proliferation, regardless of androgen receptor expression levels. TSP1, an anti-angiogenic factor whose expression is inhibited by androgens, had decreased expression in bladders of UPII-SV40T mice compared to wild-type. Castration increased TSP1 levels in UPII-SV40T mice compared to intact mice. TSP1 protein expression was higher in 8 of 10 human bladder biopsies of normal versus malignant tissue from the same patients. Conclusion

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

International Nuclear Information System (INIS)

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

2017-01-01

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

Third-line treatment and {sup 177}Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review

Energy Technology Data Exchange (ETDEWEB)

Edler von Eyben, Finn [Center of Tobacco Control Research, Odense (Denmark); Roviello, Giandomenico [San Donato Hospital, Department of Oncology, Medical Oncology Unit, Arezzo (Italy); University of Trieste, Department Medical, Surgery, and Health Sciences, Trieste (Italy); Kiljunen, Timo; Kairemo, Kalevi; Joensuu, Timo [Docrates Cancer Center, Helsinki (Finland); Uprimny, Christian; Virgolini, Irene [University Hospital Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria)

2018-03-15

There is a controversy as to the relative efficacy of {sup 177}Lu prostate specific membrane antigen (PSMA) radioligand therapy (RLT) and third-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of our systematic review was to elucidate whether {sup 177}Lu-PSMA RLT and third-line treatment have similar effects and adverse effects (PROSPERO ID CRD42017067743). The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Searches in Pubmed and Embase selected articles up to September 2017. A search in ClinicalTrials.gov indicated ongoing studies. The meta-analysis used the random-effects model. Twelve studies including 669 patients reported {sup 177}Lu-PSMA RLT. Overall, 43% of the patients had a maximum decline of PSA of ≥50% following treatment with {sup 177}Lu-PSMA RLT. The treatment with {sup 177}Lu-PSMA-617 and {sup 177}Lu-PSMA for imaging and therapy (I and T) had mainly transient adverse effects. Sixteen studies including 1338 patients reported third-line treatment. Overall, 21% of the patients had a best decline of PSA of ≥50% following third-line treatment. After third-line treatment with enzalutamide and cabazitaxel, adverse effects caused discontinuation of treatment for 10% to 23% of the patients. {sup 177}Lu-PSMA RLT gave a best PSA decline ≥50% more often than third-line treatment (mean 44% versus 22%, p = 0.0002, t test). {sup 177}Lu-PSMA RLT gave objective remission more often than third-line treatment (overall 31 of 109 patients versus 43 of 275 patients, p = 0.004, χ{sup 2} test). Median survival was longer after {sup 177}Lu-PSMA RLT than after third-line treatment, but the difference was not statistically significant (mean 14 months versus 12 months, p = 0.32, t test). Adverse effects caused discontinuation of treatment more often for third-line treatment than for {sup 177}Lu-PSMA RLT (22 of 66 patients versus 0 of 469 patients, p < 0.001, χ{sup 2

Chemosterilization: Spermatogenesis, Steroidogenesis ...

African Journals Online (AJOL)

the oxidative stress inducing (i.e., reactive oxygen species generating) ... of fertility is in direct relation to the degree of motility of sperm.[10] ... female. Furthermore, chemical castration had a greater effect on the decrease of aggression than surgical castration.[16]. In 2001, a study was performed to determine the effects.

Sexing or Specularizing the Doppelgänger: A Recourse to Poe's ‘Ligeia'

DEFF Research Database (Denmark)

Sencindiver, Susan Yi

2010-01-01

the guise of castration - forms a conceptually coherent nucleus at the interface of both the uncanny and the doppelgänger motif. Doppelgänger narratives are racked with the persistent themes of unreliable vision that pertain to the transposition of symbolic castration. It is not only blindness that figures...

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

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

Methylated Glutathione S-transferase 1 (mGSTP1) is a potential plasma free DNA epigenetic marker of prognosis and response to chemotherapy in castrate-resistant prostate cancer.

Science.gov (United States)

Mahon, K L; Qu, W; Devaney, J; Paul, C; Castillo, L; Wykes, R J; Chatfield, M D; Boyer, M J; Stockler, M R; Marx, G; Gurney, H; Mallesara, G; Molloy, P L; Horvath, L G; Clark, S J

2014-10-28

Glutathione S-transferase 1 (GSTP1) inactivation is associated with CpG island promoter hypermethylation in the majority of prostate cancers (PCs). This study assessed whether the level of circulating methylated GSTP1 (mGSTP1) in plasma DNA is associated with chemotherapy response and overall survival (OS). Plasma samples were collected prospectively from a Phase I exploratory cohort of 75 men with castrate-resistant PC (CRPC) and a Phase II independent validation cohort (n=51). mGSTP1 levels in free DNA were measured using a sensitive methylation-specific PCR assay. The Phase I cohort identified that detectable baseline mGSTP1 DNA was associated with poorer OS (HR, 4.2 95% CI 2.1-8.2; P<0.0001). A decrease in mGSTP1 DNA levels after cycle 1 was associated with a PSA response (P=0.008). In the Phase II cohort, baseline mGSTP1 DNA was a stronger predictor of OS than PSA change after 3 months (P=0.02). Undetectable plasma mGSTP1 after one cycle of chemotherapy was associated with PSA response (P=0.007). We identified plasma mGSTP1 DNA as a potential prognostic marker in men with CRPC as well as a potential surrogate therapeutic efficacy marker for chemotherapy and corroborated these findings in an independent Phase II cohort. Prospective Phase III assessment of mGSTP1 levels in plasma DNA is now warranted.

The PREVAIL trial of enzalutamide in men with chemotherapy-naïve, metastatic castration-resistant prostate cancer: Post hoc analysis of Korean patients.

Science.gov (United States)

Kim, Choung-Soo; Theeuwes, Ad; Kwon, Dong Deuk; Choi, Young Deuk; Chung, Byung Ha; Lee, Hyun Moo; Lee, Kang Hyun; Lee, Sang Eun

2016-05-01

This post hoc analysis evaluated treatment effects, safety, and pharmacokinetics of enzalutamide in Korean patients in the phase 3, double-blind, placebo-controlled PREVAIL trial. Asymptomatic or mildly symptomatic chemotherapy-naive men with metastatic castration-resistant prostate cancer that progressed on androgen deprivation therapy received 160 mg/d oral enzalutamide or placebo (1:1) until death or discontinuation due to radiographic progression or skeletal-related event and initiation of subsequent therapy. Coprimary end points were centrally assessed radiographic progression-free survival (rPFS) and overall survival (OS). Secondary end points included investigator-assessed rPFS, time to initiation of chemotherapy, time to prostate-specific antigen (PSA) progression, PSA response (≥50% decline), and time to skeletal-related event. Of 1,717 total patients, 78 patients were enrolled in Korea (enzalutamide, n=40; placebo, n=38). Hazard ratios (95% confidence interval) for enzalutamide versus placebo were 0.23 (0.02-2.24) for centrally assessed rPFS, 0.77 (0.28-2.15) for OS, 0.21 (0.08-0.51) for time to chemotherapy, and 0.31 (0.17-0.56) for time to PSA progression. A PSA response was observed in 70.0% of enzalutamide-treated and 10.5% of placebo-treated Korean patients. Adverse events of grade ≥3 occurred in 33% of enzalutamide-treated and 11% of placebo-treated Korean patients, with median treatment durations of 13.0 and 5.1 months, respectively. At 13 weeks, the plasma concentration of enzalutamide plus N-desmethyl enzalutamide was similar in Korean and non-Korean patients (geometric mean ratio, 1.04; 90% confidence interval, 0.97-1.10). In Korean patients, treatment effects and safety of enzalutamide were consistent with those observed in the overall PREVAIL study population (ClinicalTrials.gov Identifier: NCT01212991).

Comparison of Timed Automata with Discrete Event Simulation for Modeling of Biomarker-Based Treatment Decisions: An Illustration for Metastatic Castration-Resistant Prostate Cancer.

Science.gov (United States)

Degeling, Koen; Schivo, Stefano; Mehra, Niven; Koffijberg, Hendrik; Langerak, Rom; de Bono, Johann S; IJzerman, Maarten J

2017-12-01

With the advent of personalized medicine, the field of health economic modeling is being challenged and the use of patient-level dynamic modeling techniques might be required. To illustrate the usability of two such techniques, timed automata (TA) and discrete event simulation (DES), for modeling personalized treatment decisions. An early health technology assessment on the use of circulating tumor cells, compared with prostate-specific antigen and bone scintigraphy, to inform treatment decisions in metastatic castration-resistant prostate cancer was performed. Both modeling techniques were assessed quantitatively, in terms of intermediate outcomes (e.g., overtreatment) and health economic outcomes (e.g., net monetary benefit). Qualitatively, among others, model structure, agent interactions, data management (i.e., importing and exporting data), and model transparency were assessed. Both models yielded realistic and similar intermediate and health economic outcomes. Overtreatment was reduced by 6.99 and 7.02 weeks by applying circulating tumor cell as a response marker at a net monetary benefit of -€1033 and -€1104 for the TA model and the DES model, respectively. Software-specific differences were observed regarding data management features and the support for statistical distributions, which were considered better for the DES software. Regarding method-specific differences, interactions were modeled more straightforward using TA, benefiting from its compositional model structure. Both techniques prove suitable for modeling personalized treatment decisions, although DES would be preferred given the current software-specific limitations of TA. When these limitations are resolved, TA would be an interesting modeling alternative if interactions are key or its compositional structure is useful to manage multi-agent complex problems. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights

Prognostic value of 18F-choline PET/CT metabolic parameters in patients with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide

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Caroli, Paola; Fantini, Lorenzo; Celli, Monica; Paganelli, Giovanni; Matteucci, Federica [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Nuclear Medicine Unit, Meldola (Italy); De Giorgi, Ugo; Conteduca, Vincenza; Rossi, Lorena [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Department of Medical Oncology, Meldola (Italy); Scarpi, Emanuela [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Unit of Biostatistics and Clinical Trials Unit, Meldola (Italy); Moretti, Andrea; Galassi, Riccardo [Morgagni Pierantoni Hospital, Nuclear Medicine Unit, Forli (Italy); Bianchi, Emanuela [Infermi Hospital, Department of Medical Oncology, Rimini (Italy)

2018-03-15

The role of 18F-choline positron emission tomography/computed tomography (FCH-PET/CT) in patients with metastatic castration-resistant prostate cancer (mCRPC) has been firmly established in recent years. We analyzed the prognostic value of functional parameters such as mean standardized uptake volume (SUVmean), maximum standardized uptake volume (SUVmax), metabolic total volume (MTV; the volume of interest consisting of all spatially connected voxels within a fixed threshold of 40% of the SUVmax), and total lesion activity (TLA: the product of MTV and mean standardized uptake value) estimated with FCH-PET/CT in mCRPC patients in progression after docetaxel and treated with new antiandrogen receptor therapies, abiraterone or enzalutamide. We retrospectively studied 94 mCRPC patients, mean age 74 years (range 42-90), previously treated with docetaxel who were treated with either abiraterone (n = 52) or enzalutamide (n = 42). An FCH-PET/CT was performed at baseline, and patients were evaluated on a monthly basis for serological PSA response and every 3 months for radiological response. We measured MTV, SUVmean, SUVmax and TLA for each lesion and analyzed the sum of MTV (SMTV), SUVmean (SSUVmean), SUVmax (SSUVmax) and TLA (STLA) values for a maximum of 20 lesions. Univariate analysis was used to correlate these data with PFS and OS. We observed a median SMTV of 130 cm{sup 3}, median SSUVmax of 106.5 and a median STLA of 495,070. All of these parameters were significant for PFS and OS in univariate analysis, while only STLA was significant for PFS and OS in multivariate analysis after adjusting for lesion and age (p < 0.0001 and p = 0.001, respectively). Baseline PSA values maintained a certain reliability for OS (p = 0.034). Semiquantitative parameters of FCH-PET/CT play a prognostic role in mCRCP patients treated with abiraterone or enzalutamide. (orig.)

Overall survival and response pattern of castration-resistant metastatic prostate cancer to multiple cycles of radioligand therapy using [177Lu]Lu-PSMA-617.

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Ahmadzadehfar, Hojjat; Wegen, Simone; Yordanova, Anna; Fimmers, Rolf; Kürpig, Stefan; Eppard, Elisabeth; Wei, Xiao; Schlenkhoff, Carl; Hauser, Stefan; Essler, Markus

2017-08-01

Up to 30% of patients with castration-resistant prostate cancer (CRPC) do not show any response to the first cycle of radioligand therapy (RLT) with [ 177 Lu]Lu-PSMA-617 (Lu-PSMA). We evaluated patient response to the second and third cycles of RLT in patients that underwent at least three cycles. The second aim of this study was to calculate the median overall survival (OS) of responders and non-responders after the first cycle and after all three cycles of RLT. CRPC patients were treated with Lu-PSMA, with a median interval of 8 weeks between each cycle. The tumour marker prostate-specific antigen (PSA) was used as the marker for response evaluation. Fifty-two patients underwent a total of 190 cycles of RLT (3-6 cycles per patient). Of these, 80.8% showed a decline in PSA 2 months after the first cycle, with 44.2% showing a PSA decline of ≥50%. When compared to baseline PSA, 73.1% showed a PSA decline after the third cycle. 50% of patients that did not show any response to the first cycle also did not respond to the second and third cycles. The median OS was 60 weeks in all patients. The median OS was significantly longer for patients that showed any PSA decline after the first cycle compared to patients without PSA decline (68 vs. 33 weeks). There was a significant difference in median OS between responders and non-responders for a change in PSA after the third cycle compared to baseline PSA. Patients with a positive response to RLT, regardless of the rate of decline, had a significantly longer median OS. Of the patients that did not show any response to the first cycle, 50% responded to the second or third cycles.

Denosumab and Bone Metastasis–Free Survival in Men With Nonmetastatic Castration-Resistant Prostate Cancer: Exploratory Analyses by Baseline Prostate-Specific Antigen Doubling Time

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Smith, Matthew R.; Saad, Fred; Oudard, Stephane; Shore, Neal; Fizazi, Karim; Sieber, Paul; Tombal, Bertrand; Damiao, Ronaldo; Marx, Gavin; Miller, Kurt; Van Veldhuizen, Peter; Morote, Juan; Ye, Zhishen; Dansey, Roger; Goessl, Carsten

2013-01-01

Purpose Denosumab, an anti–RANK ligand monoclonal antibody, significantly increases bone metastasis–free survival (BMFS; hazard ratio [HR], 0.85; P = .028) and delays time to first bone metastasis in men with nonmetastatic castration-resistant prostate cancer (CRPC) and baseline prostate-specific antigen (PSA) ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤ 10.0 months. To identify men at greatest risk for bone metastasis or death, we evaluated relationships between PSA and PSADT with BMFS in the placebo group and the efficacy and safety of denosumab in men with PSADT ≤ 10, ≤ 6, and ≤ 4 months. Patients and Methods A total of 1,432 men with nonmetastatic CRPC were randomly assigned 1:1 to monthly subcutaneous denosumab 120 mg or placebo. Enrollment began February 2006; primary analysis cutoff was July 2010, when approximately 660 men were anticipated to have developed bone metastases or died. Results In the placebo group, shorter BMFS was observed as PSADT decreased below 8 months. In analyses by shorter baseline PSADT, denosumab consistently increased BMFS by a median of 6.0, 7.2, and 7.5 months among men with PSADT ≤ 10 (HR, 0.84; P = .042), ≤ 6 (HR, 0.77; P = .006), and ≤ 4 months (HR, 0.71; P = .004), respectively. Denosumab also consistently increased time to bone metastasis by PSADT subset. No difference in survival was observed between treatment groups for the overall study population or PSADT subsets. Conclusion Patients with shorter PSADT are at greater risk for bone metastasis or death. Denosumab consistently improves BMFS in men with shorter PSADT and seems to have the greatest treatment effects in men at high risk for progression. PMID:24043751

Further Studies on the Utilization of Cocoa Husk in Ruminant Rations

African Journals Online (AJOL)

The effect on body weight changes of sheep and goats and digestibility of maintenance rations in which cocoa husk constituted, 0%, 20%, 40% and 50% of the basal ration respectively were studied. These rations were fed to wethers and castrated goats (castrates) in two separate but concurrent digestibility trials. There was ...

[Effects of extract of Buddleja officinalis eye drops on androgen receptors of lacrimal gland cells of castrated rats with dry eye].

Science.gov (United States)

Peng, Qing-Hua; Yao, Xiao-Lei; Wu, Quan-Long

2012-01-01

To observe the effects of the extract of Buddleja officinalis eye drops (EBOED) on basic tears secretory volume, tear film stability, and expressions of androgen receptors (AR) in castrated rats with dry eye, and to investigate the mechanism of EBOED on dry eye caused by decreased anti-androgen levels. Forty-five male Wistar rats were randomly divided into the blank group, the model group, and the treatment group (treated by EBOED), respectively. Rats in each group were further divided into three sub-groups (fed for one month, two months, and three months, respectively). There were totally nine groups, with five in each. The dry eye model was established with orchiectomy of rats in the model group and the treatment group. EBOED was given to rats in the treatment group for one successive month. Schirmer I test (SIT) and breakup time of tear film (BUT) were determined in all experimental rats. Expressions of AR was analyzed by flow cytometer. Ths SIT value, BUT, and AR positive rate in the model group at the 1st, 2nd, 3rd month were lower than those in the blank group of the same time points (P < 0.01). There was statistical difference in SIT value, BUT, and AR positive rate between the model group and the treatment group at the three time points (P < 0.01). Take the three-month subgroup as an example, the SIT value in the treatment group was (12.667 +/- 5.221) mm, obviously higher than that in the model group (2.676 +/- 1.987) mm. The BUT in the treatment group was (11.758 +/- 4.415) s, obviously longer than that of the model group (4.667 +/- 2.108) s. The AR positive rate in the treatment group was 49.33% +/- 3.44%, obviously higher than that of the model group (33.32% +/- 7.12%, all P < 0.01). The main components of EBOED was the flavonoids which could significantly inhibit the occurrence of dry eye in rats with decreased androgen levels. Its mechanism might possibly be similar to androgen.

PSMA targeted radioligandtherapy in metastatic castration resistant prostate cancer after chemotherapy, abiraterone and/or enzalutamide. A retrospective analysis of overall survival

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Rahbar, K.; Schaefers, M. [University Hospital Muenster, Department of Nuclear Medicine, Muenster (Germany); Boegemann, M. [University Hospital Muenster, Department of Urology, Muenster (Germany); Yordanova, A.; Essler, M.; Ahmadzadehfar, H. [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Eveslage, M. [University Hospital Muenster, Institute of Biostatistics and Clinical Research, Muenster (Germany)

2018-01-15

Our aim was to evaluate overall survival and parameters prognosticating longer survival in a large and homogeneous group of patients treated with {sup 177}Lu-PSMA-617 radioligand therapy with heavily pretreated advanced metastatic castration resistant prostate cancer. A total of 104 patients were treated with 351 cycles of {sup 177}Lu-PSMA-617. Prostate specific antigen (PSA) changes after the first cycle of therapy were documented prior to a second cycle. Patients were followed-up for overall survival (OS). Any PSA decline, PSA decline ≥50%, initial PSA, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), visceral metastases and cumulative injected activity were analyzed and evaluated according to OS. Multivariable analysis with parameters with a p-value ≤0.05 in univariate analysis was performed, additionally adjusting for age and presence of visceral metastases. A total of 51 patients (49%) died during the observation period. The majority of patients (97%) presented with bone metastases, 77% with lymph node metastases and 32% with visceral metastases. All patients were treated with at least one line of chemotherapy. Either abiraterone or enzalutamide had been given in 100% of the patients. Any PSA decline occurred in 70 (67%) and a PSA decline ≥50% in 34 (33%) of patients after the first cycle. The median OS was 56.0 weeks (95%CI: 50.5-61.5). Initial PSA decline ≥50%, initial LDH, visceral metastases, second line chemotherapy or prior radium-223 did not have an effect on survival, whereas any initial PSA decline, initial ALP <220 U/L and cumulative injected activity ≥18.8 GBq were associated with a longer survival. A step-by-step analysis revealed a PSA decline ≥20.87% as the most noticeable cut-off prognosticating longer survival, which remained an independent prognosticator of improved OS in the multivariate analysis. {sup 177}Lu-PSMA-617 RLT is a new effective therapeutic and seems to prolong survival in patients with advanced m

"1"7"7Lu-PSMA-617 radioligand therapy and outcome in patients with metastasized castration-resistant prostate cancer

International Nuclear Information System (INIS)

Braeuer, Axel; Grubert, Lena Sophie; Roll, Wolfgang; Schaefers, Michael; Rahbar, Kambiz; Schrader, Andres Jan; Boegemann, Martin

2017-01-01

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

Protection of estrogen in portal hypertension gastropathy: an experimental model

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Maria Isabel Morgan-Martins

2011-09-01

Full Text Available CONTEXT: Portal hypertension is a complication secondary to cirrhosis that is characterized by increased blood flow and/or vascular resistance in the portal system, causing the appearance of a hyperdynamic collateral circulation. Partial portal vein ligation is an experimental model used in rats to study the pathophysiological mechanisms involved in pre-hepatic portal hypertension. Estrogen E2 is an antioxidant molecule with various physiological actions. OBJECTIVES: To evaluate the antioxidant activity of endogenous estrogen in an experimental model of partial portal vein ligation by comparing intact with castrated rats. METHODS: Twenty Wistar rats, weighing on average 250 g were used and divided into four groups: sham-operated (SO; intact (I with partial portal vein ligation (I + PPVL, castrated (C and castrated with partial ligation of the vein (C + PPVL. Day 1: castration or sham-operation; day 7, PPVL surgery; on day 15 post-PPVL, portal pressure in the mesenteric vein of rats was measured on polygraph Letica. Lipid peroxidation in the stomach was assessed using the technique of thiobarbituric acid reactive substances and activity of antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase. Statistical analysis was done with ANOVA - Student-Newman-Keuls (mean ± SE, and P<0.05 was considered as significant. RESULTS: Portal pressure was significantly increased in C + PPVL as compared to the other groups. There was no significant difference in the group of intact rats. TBARS showed significant damage in C and C + PPVL in relation to others. Antioxidant enzymes were significantly increased in the castrated rats with subsequent PPVL as compared to the other groups. CONCLUSION: We suggest that estrogen E2 plays a protective role in intact compared with castrated rats because it presents hydrophenolic radicals in its molecule, thus acting as an antioxidant in this experimental model.

Protection of estrogen in portal hypertension gastropathy: an experimental model.

Science.gov (United States)

Morgan-Martins, Maria Isabel; Jacques, Simone Iahnig; Hartmann, Renata Minuzzo; Marques, Camila Moraes; Marroni, Cláudio Augusto; Marroni, Norma Possa

2011-01-01

Portal hypertension is a complication secondary to cirrhosis that is characterized by increased blood flow and/or vascular resistance in the portal system, causing the appearance of a hyperdynamic collateral circulation. Partial portal vein ligation is an experimental model used in rats to study the pathophysiological mechanisms involved in pre-hepatic portal hypertension. Estrogen E2 is an antioxidant molecule with various physiological actions. To evaluate the antioxidant activity of endogenous estrogen in an experimental model of partial portal vein ligation by comparing intact with castrated rats. Twenty Wistar rats, weighing on average 250 g were used and divided into four groups: sham-operated (SO); intact (I) with partial portal vein ligation (I + PPVL), castrated (C) and castrated with partial ligation of the vein (C + PPVL). Day 1: castration or sham-operation; day 7, PPVL surgery; on day 15 post-PPVL, portal pressure in the mesenteric vein of rats was measured on polygraph Letica. Lipid peroxidation in the stomach was assessed using the technique of thiobarbituric acid reactive substances and activity of antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase. Statistical analysis was done with ANOVA - Student-Newman-Keuls (mean ± SE), and P<0.05 was considered as significant. Portal pressure was significantly increased in C + PPVL as compared to the other groups. There was no significant difference in the group of intact rats. TBARS showed significant damage in C and C + PPVL in relation to others. Antioxidant enzymes were significantly increased in the castrated rats with subsequent PPVL as compared to the other groups. We suggest that estrogen E2 plays a protective role in intact compared with castrated rats because it presents hydrophenolic radicals in its molecule, thus acting as an antioxidant in this experimental model.

Androgen-dependent and independent process of bone formation in the distal segment of Os penis in the rat.

Science.gov (United States)

Murakami, R; Izumi, K; Yamaoka, I

1995-11-01

The distal segment of the os penis of the rat develops as a fibrocartilage which is replaced with non-lamellar bone by endochondral ossification after puberty. Development of the fibrocartilage and its calcification have been shown to be induced by androgens, but androgen-dependency of the endochondral ossification has not been studied in detail. In the present study, immature male rats of various ages were castrated and the ossification of the fibrocartilage of os penis was examined. In rats castrated at 6 weeks, when the fibrocartilage was scarcely calcified, ossification did not occur even at 24 weeks. When the castrated rats were treated with testosterone, ossification started before 12 weeks of age. In rats castrated at 8 weeks, when the fibrocartilage was heavily calcified, endochondral ossification was observed in some of the animals (5/7) at 24 weeks of age. The results of this study indicate that once the fibrocartilage is calcified, the endochondral ossification can take place without androgen, although the androgen can promote the process of ossification.

[Activity of the hypophyseal-thyroid gland system in relation to the funcitonal state of the sex glands. Report I].

Science.gov (United States)

Babichev, V N; Samsonova, V M

1975-01-01

Experiments were conducted on intact female rats; it was revealed that the content of protein-bound iodine (PBI) in the blood depended on the stage of the estral cycle. It was decreased at the metestrus and diestrus stages. Castration produced an even greater reduction in the blood PBI content. The blood PBI content proved to elevate in administration of estradiol dipropionate (EDP) to castrated rats. The TSH content in the hypophysis increased at the metestrus and diestrus stages and decreased at the proestrus and estrus stages. The relationship was reverse in the case with the blood TTH content. Castration was followed by a marked increase in the TSH content in the hypophysis accompanied by a reduction in the blood hormone level. The TSH concentration in the hypophysis decreased and in the blood increased under the effect of EDP in castrated animals. The data obtained indicated that the interrelationship between the thyroid gland and the sex glands was realized at the level of the hypophysis, and possibly, of the hypothalamus.