Paradoxical sleep deprivation and restriction promote castration-like effects and local inflammatory responses in male gerbil prostate.

Paradoxical sleep deprivation (PSD) presents different effects on metabolism and neurological functions. In addition, over long duration, sleep restriction (SR) can promote permanent changes. The prostate is an endocrine-dependent organ with homeostatic regulation directly related to hormone levels. Our study proposed to demonstrate the experimental prostatic effects of PSD (96 h), PSD with recovery (PSR - 96/96 h), and sleep restriction (SR - 30 PSD cycles/recovery). PSD and SR promoted decrease in serum testosterone and significant increase in serum and intraprostatic corticosterone. In agreement, androgen receptors (AR) were less expressed and glucocorticoid receptors (GR) were enhanced in PSR and SR. Thus, the prostate, especially under SR, demonstrates a castration-like effect due to loss of responsiveness and sensitization by androgens. SR triggered an important inflammatory response through enhancement of serum and intraprostatic pro- (IL-1α, IL-6, TNF-α) and anti-inflammatory (IL-10) cytokines. Furthermore, the respective receptors of anti-inflammatory cytokines (IL-1RI and TNF-R) were highly expressed in the prostatic epithelium and stroma. PSR can partially restore prostate homeostasis, as it restores testosterone and the prostate proliferation index, in addition to promoting balance in the inflammatory response that is considered protective. PSD and SR are key factors in the endocrine axis that coordinate prostatic homeostasis, and significant changes in these factors have consequences on prostate functionality.

Cull guinea pigs: carcass and non-carcass traits in males and females compared to their fattening counterparts.

Culling of guinea pigs can provide a large number of animals per year for meat production, but little information is available in the scientific literature on the carcass characteristics and non-carcass components of these animals. The objective of this study was to evaluate the carcass and non-carcass characteristics of cull guinea pigs in comparison to their fattening counterparts. Forty-eight fattening (3 months-age, 24 females and 24 males) and forty-eight cull (14 months-age, 24 females and 24 males) guinea pigs were slaughtered and carcass yield, linear measurements, tissular composition, and non-carcass components were evaluated. In general, cull guinea pigs had higher carcass, tissue, and non-carcass component weights. Cull male and both female guinea pig groups had similar carcass yields. Cull animals had higher carcass and hind leg lengths, lumbar and thoracic circumferences, and carcass compactness than their young counterparts. However, a sex effect was found for leg compactness depending on whether they were fattened or cull. Tissue percentages values were similar between fattening and culling animals of the same sex. However, females had a higher percentage of fat tissue than males. Fattening females had the best muscle to bone ratio, followed by cull males. The non-carcass elements were more represented in fattening animals than in culls, probably due to an allometric growth of the viscera in relation to the rest of the body. In commercial and cooking terms, this information is valuable for producers and researchers who need to understand the factors that influence carcass characteristics of guinea pigs.

Later-age neutering causes lower risk of early-onset urinary incontinence than early neutering-a VetCompass target trial emulation study.

There is growing evidence supporting clinically important associations between age at neutering in bitches and subsequent urinary incontinence (UI), although much of this evidence to date is considered weak. Target trial emulation is an innovative approach in causal inference that has gained substantial attention in recent years, aiming to simulate a hypothetical randomised controlled trial by leveraging observational data. Using anonymised veterinary clinical data from the VetCompass Programme, this study applied the target trial emulation framework to determine whether later-age neutering (≥ 7 to ≤ 18 months) causes decreased odds of early-onset UI (diagnosed < 8.5 years) compared to early-age neutering (3 to < 7 months). The study included bitches in the VetCompass database born from January 1, 2010, to December 31, 2012, and neutered between 3 and 18 months old. Bitches were retrospectively confirmed from the electronic health records as neutered early or later. The primary outcome was a diagnosis of early-onset UI. Informed from a directed acyclic graph, data on the following covariates were extracted: breed, insurance status, co-morbidities and veterinary group. Inverse probability of treatment weighting was used to adjust for confounding, with inverse probability of censoring weighting accounting for censored bitches. The emulated trial included 612 early-age neutered bitches and 888 later-age neutered bitches. A pooled logistic regression outcome model identified bitches neutered later at 0.80 times the odds (95% CI 0.54 to 0.97) of early-onset UI compared with bitches neutered early. The findings show that later-age neutering causes reduced odds of early-onset UI diagnosis compared with early-age neutering. Decision-making on the age of neutering should be carefully considered, with preference given to delaying neutering until after 7 months of age unless other major reasons justify earlier surgery. The study is one of the first to demonstrate successful application of the target trial framework to veterinary observational data.

[Experience of Pembrolizumab Administration in A Patient with Castration-Resistant Microsatellite Instability-High Prostate Cancer].

Castration-resistant prostate cancer and multiple lymph node and ventral bladder metastases in an 87 year-old man progressed despite various systemic therapies, including chemotherapy. Because his prostate surgical specimen displayed a microsatellite instability (MSI) -high status, pembrolizumab 200 mg/body treatment was started. After six courses of treatment, his prostate-specific antigen (PSA) level decreased by 83% versus that at treatment initiation (from 408.78 ng/ml to 69.54 ng/ml), and the para-aortic lymph node metastasis was reduced in size on imaging. After 13 courses, his PSA level (462.59 ng/ml) exceeded that at the start of treatment, and progressive disease was detected on imaging. Although case reports of pembrolizumab for MSI-high prostate cancer remain few because of its rarity, it is an important therapeutic option and further clinical research is required.

[Chinese expert consensus on the follow-up management of patients with prostate cancer receiving medical castration therapy（2024 edition）].

With the advancement of prostate cancer (PCa) diagnosis and treatment technology, the 5-year survival rate has remarkably increased, and PCa has entered the era of chronic disease management. Medical castration therapy remains the cornerstone treatment option for PCa patients, and run throughout the various stages of patient treatment. The disease progression, treatment-related adverse reactions and related complications of PCa patients after medical castration have become a major problem in the long-term management of PCa patients, affecting the survival and quality of life of patients. In addition to focus on the disease management of prostate patients during diagnosis and treatment, patients should be closely followed up after medical castration, especially for those at the critical stage of disease treatment. Testosterone or other indicators should be monitored at important nodes of the disease (the point of initiation disease phase and the point of treatment switch) to avoid missing the optimal treatment window. Follow-up management of PCa should take into account the characteristics of the treatment stage of the disease (disease stage, previous symptoms, prognostic factors and treatment strategy) and patients' own demands, and personalized follow-up strategies should be recommended to better increase patients' treatment compliance and improve patients' prognosis. Currently, there is a lack of guidelines or consensus on the management on the follow-up and quality of life of PCa patients after medical castration in China. Therefore, the Chinese Prostate Cancer Consortium has organized domestic experts to formulate this consensus, with the aim of providing a reference for the management on the follow-up and quality of life of PCa patients receiving medical castration therapy, and to further improve the prognosis and quality of life of PCa patients in China.

Microbiome Dysbiosis Is Associated with Castration Resistance and Cancer Stemness in Metastatic Prostate Cancer.

Prostate cancer is the second leading cause of death in males in America, with advanced prostate cancers exhibiting a 5-year survival rate of only 32%. Castration resistance often develops during the course of treatment, but its pathogenesis is poorly understood. This study explores the human microbiome for its implications in castration resistance and metastasis in prostate cancer. RNA sequencing data were downloaded for the bone and soft tissue biopsies of patients with metastatic castration-resistant prostate cancer. These included both metastatic and adjacent normal biopsies. These sequences were mapped to bacterial sequences, yielding species-level counts. A vast majority of species were found to be significantly underabundant in the CRPC samples. Of these, numerous were found to correlate with the expression of known markers of castration resistance, including AR, PI3K, and AKT. Castration resistance-associated signaling pathways were also enriched with these species, including PI3K-AKT signaling and endocrine resistance. For their implications in cancer aggression and metastasis, cancer stem cell markers were further explored for a relation to these species. EGFR and SLC3A2 were widely downregulated, with a greater abundance of most species. Our results suggest that the microbiome is heavily associated with castration resistance and stemness in prostate cancer. By considering the microbiome's importance in these factors, we may better understand the highly aggressive and highly invasive nature of castration-resistant prostate cancer, allowing for the needed improvements in the treatment of this disease.

Bone-Modifying Agents in Patients With High-Risk Metastatic Castration-Sensitive Prostate Cancer Treated With Abiraterone Acetate.

Importance: The association between the use of bone-modifying agents (BMAs) and the outcomes among patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with abiraterone acetate plus prednisone (AAP) remains unclear. Objective: To investigate the association between BMA use and the outcomes of patients with mCSPC receiving AAP. Design, Setting, and Participants: In this cohort study, a post hoc analysis of individual participant data from the LATITUDE trial was performed. The LATITUDE trial, a phase 3 randomized clinical trial, aimed to assess the efficacy of AAP and androgen deprivation therapy (ADT) vs dual-placebo and ADT in patients with high-risk mCSPC (data cutoff, August 15, 2018). Eligible patients had newly diagnosed prostate cancer with metastases and at least 2 of 3 high-risk factors (Gleason score ≥8, presence of ≥3 lesions on bone scan, or presence of measurable visceral metastasis). The trial was conducted at 235 sites in 34 countries. Data for the present study were evaluated from July 18 to September 23, 2023. Exposures: Use of BMAs was defined as the administration of bisphosphonates and denosumab within 90 days before and after randomization. Main Outcomes and Measures: The primary outcomes were time to skeletal-related events (SREs) and overall survival (OS). An SRE was defined as a clinical or pathological fracture, spinal cord compression, palliative radiation to bone, or surgery involving bone. Differences in these outcomes were examined using the restricted mean survival time from inverse probability of treatment weighting-adjusted Kaplan-Meier curves, estimated until the last event was observed (longest time observed, 63.9 months). Treatment × covariate interactions were analyzed using weighted Cox proportional hazards regression models for the total cohort. Results: In the total cohort of 1199 patients (956 [79.7%] younger than 75 years), 597 (49.8%) received AAP and ADT, including 474 (79.4%) younger than 75 years and 384 (64.3%) with more than 10 bone metastases (AAP cohort); 602 (50.2%) were treated with dual placebo and ADT, including 482 (80.1%) younger than 75 years and 377 (62.6%) with more than 10 bone metastases (ADT cohort). In the AAP cohort, 132 patients (22.1%) received BMAs, while in the ADT cohort, 131 (21.8%) did. Zoledronic acid was the most frequently administered BMA in both the AAP (93 [70.5%]) and the ADT (88 [67.2%]) cohorts. During the median follow-up of 51.8 (IQR, 47.2-57.0) months in the AAP cohort, BMA use was associated with a longer time to SRE (difference, 7.8 [95% CI, 4.2-11.3] months) but not with OS (difference, 1.6 [95% CI, -2.5 to 5.8] months). In the ADT cohort, BMA use was associated with both time to SRE (difference, 9.3 [95% CI, 5.2-13.3] months) and OS (difference, 5.5 [95% CI, 3.2-9.8] months). No evidence was found that the outcomes of BMA varied by AAP or ADT (hazard ratio for time to SRE, 0.99 [95% CI, 0.48-2.08]; P = .99 for interaction; hazard ratio for OS, 1.31 [95% CI, 0.88-1.96]; P = .18 for interaction). Conclusions and Relevance: The findings of this cohort study suggest that use of BMAs was associated with a longer time to SRE in patients with high-risk mCSPC treated with ADT, with or without AAP, suggesting that BMA use might provide benefits to this population.

Evidence of castrations in fleas of small mammals (Chiroptera and Rodentia) from Argentina.

Morphological abnormalities in fleas seem to be common in nature and are under reported in Argentina. In this note, we describe anomalies in two males and one female of Alectopsylla unisetosa Mahnert (Ischnopsyllidae) and one of Polygenis sp. (Rhopalopsyllidae) male collected from small mammals in the provinces of Neuquen and Salta, Argentina. In all specimens, the anomalies were observed at the level of the genitalia recognized as partial castration. The structures mainly affected were the modified abdominal segments, the aedeagus (in male), and the spermatheca (in female). The present communication is the first one devoted exclusively to teratogenous fleas in Argentina.

Cohabitation with receptive females under D2-type agonism in adulthood restores partner preference and brain dimorphism in the SDN-POA following neonatal gonadectomy in male rats.

Perinatal testosterone, or its metabolite estradiol, organize the brain toward a male phenotype. Male rodents with insufficient testosterone during this period fail to display sexual behavior and partner preference for receptive females in adulthood. However, cohabitation with non-reproductive conspecifics under the influence of a D2 agonist facilitates the expression of conditioned partner preference via Pavlovian learning in gonadally intact male rats. In the present experiment, three groups of neonatal PD1 males (N = 12/group) were either gonadectomized (GDX), sham-GDX, or left intact and evaluated for social preferences and sexual behaviors as adults. We then examined whether the effects of GDX could be reversed by conditioning the males via cohabitation with receptive females under the effects of the D2 agonist quinpirole (QNP) or saline, along with the size of some brain regions, such as the sexually dimorphic nucleus of the preoptic area (SDN-POA), suprachiasmatic nucleus (SCN), posterior dorsal medial amygdala (MeApd) and ventromedial hypothalamus (VMH). Results indicated that neonatal GDX resulted in the elimination of male-typical sexual behavior, an increase in same-sex social preference, and a reduction of the area of the SDN-POA. However, GDX-QNP males that underwent exposure to receptive females in adulthood increased their social preference for females and recovered the size in the SDN-POA. Although neonatal GDX impairs sexual behavior and disrupts partner preference and brain dimorphism in adult male rats, Pavlovian conditioning under enhanced D2 agonism ameliorates the effects on social preference and restores brain dimorphism in the SDN-POA without testosterone.

Identifying the target population and preventive strategies to combat feline obesity.

Feline obesity continues to be a priority health and welfare issue. Most research surrounding obesity currently focuses on obesity treatment. However, treatment for feline obesity is slow, often unsuccessful and not without consequences. Identifying high-risk populations for obesity onset is crucial for developing and implementing preventive strategies. This review identifies post-gonadectomy kittens aged 5-12 months as the primary target population for obesity prevention in domestic cats and highlights dietary and feeding management strategies to be implemented for obesity prevention.

ERBB3 Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature.

PURPOSE: Despite successful clinical management of castration-sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer is only 32%. Combination treatment strategies to prevent disease recurrence are increasing, albeit in biomarker-unselected patients. Identifying a biomarker in CSPC to stratify patients who will progress on standard-of-care therapy could guide therapeutic strategies. EXPERIMENTAL DESIGN: Targeted deep sequencing was performed for the University of Illinois (UI) cohort (n = 30), and immunostaining was performed on a patient tissue microarray (n = 149). Bioinformatic analyses identified pathways associated with biomarker overexpression (OE) in the UI cohort, consolidated RNA sequencing samples accessed from Database of Genotypes and Phenotypes (n = 664), and GSE209954 (n = 68). Neutralizing antibody patritumab and ectopic HER3 OE were utilized for functional mechanistic experiments. RESULTS: We identified ERBB3 OE in diverse patient populations with CSPC, where it was associated with advanced disease at diagnosis. Bioinformatic analyses showed a positive correlation between ERBB3 expression and the androgen response pathway despite low dihydrotestosterone and stable expression of androgen receptor (AR) transcript in Black/African American men. At the protein level, HER3 expression was negatively correlated with intraprostatic androgen in Black/African American men. Mechanistically, HER3 promoted enzalutamide resistance in prostate cancer cell line models and HER3-targeted therapy resensitized therapy-resistant prostate cancer cell lines to enzalutamide. CONCLUSIONS: In diverse patient populations with CSPC, ERBB3 OE was associated with high AR signaling despite low intraprostatic androgen. Mechanistic studies demonstrated a direct link between HER3 and enzalutamide resistance. ERBB3 OE as a biomarker could thus stratify patients for intensification of therapy in castration-sensitive disease, including targeting HER3 directly to improve sensitivity to AR-targeted therapies.

Characterizing the real-world economic burden of metastatic castration-sensitive prostate cancer in the United States.

AIMS: To describe healthcare resource utilization (HRU) and costs of patients with metastatic castration-sensitive prostate cancer (mCSPC). METHODS: Linked data from Flatiron Metastatic PC Core Registry and Komodo's Healthcare Map were evaluated (01/2016-12/2021). Patients with chart-confirmed diagnoses for metastatic PC without confirmed castration resistance in Flatiron who initiated androgen deprivation therapy (ADT) monotherapy or advanced therapy for mCSPC in 2017 or later (index date) with a corresponding pharmacy or medical claim in Komodo Health were included. Advanced therapies considered were androgen-receptor signaling inhibitors, chemotherapies, estrogens, immunotherapies, poly ADP-ribose polymerase inhibitors, and radiopharmaceuticals. Patients with <12 months of continuous insurance eligibility before index were excluded. Per-patient-per-month (PPPM) all-cause and PC-related HRU and costs (medical and pharmacy; from a payer's perspective in 2022 $USD) were described in the 12-month baseline period and follow-up period (from the index date to castration resistance, end of continuous insurance eligibility, end of data availability, or death). RESULTS: Of 871 patients included (mean age: 70.6 years), 52% initiated ADT monotherapy as their index treatment without documented advanced therapy use. During baseline, 31% of patients had a PC-related inpatient admission and 94% had a PC-related outpatient visit; mean all-cause costs were $2551 PPPM and PC-related costs were $839 PPPM with $787 PPPM attributable to medical costs. Patients had a mean follow-up of 15 months, during which 38% had a PC-related inpatient admission and 98% had a PC-related outpatient visit; mean all-cause costs were $5950 PPPM with PC-related total costs of $4363 PPPM, including medical costs of $2012 PPPM. LIMITATIONS: All analyses were descriptive; statistical testing was not performed. Treatment effectiveness and clinical outcomes were not assessed. CONCLUSION: This real-world study demonstrated a significant economic burden in mCSPC patients, and a propensity to use ADT monotherapy in clinical practice despite the availability and guideline recommendations of advanced life-prolonging therapies.

Half-life of serum anti-Müllerian hormone and changes after gonadectomy in adult female and male dogs with normal and abnormal gonads.

Anti-Müllerian hormone (AMH) is a biomarker for the presence of gonadal tissue. Changes in serum AMH after gonadectomy are not well established, and its serum half-life is unknown in dogs. We measured serum AMH with a validated electro-chemiluminescent immunoassay in adult female (n = 12) and male (n = 7) dogs with normal gonads, as well as in dogs with gonadal pathology (ovarian remnant syndrome, ORS n = 3, testicular tumor [Leydig cell, Sertoli cell, seminoma] n = 3, unilateral abdominal cryptorchid n = 4) on the day of gonadectomy (D0), and on D3, D7, D14 (females and males), and D21, D28 (males only). Males had higher AMH concentrations than females independent of gonadal status (P < 0.001). Dogs with ORS had lower initial AMH (0.45 ± 0.43 ng/ml) than bitches with normal gonads (1.16 ± 0.44 ng/ml; P = 0.027). Cryptorchid dogs had higher initial concentrations (80.57 ± 52.81 ng/ml) than males with normal gonads (7.92 ± 2.45 ng/ml; P = 0.004), and those with testicular tumors (18.63 ± 5.04 ng/ml) were intermediate (P ≥ 0.250). AMH decreased over time (P ≤ 0.012) and was 0.01-0.04 ng/ml by D14 in females and 0.02-0.12 ng/ml by D28 in males. Serum half-life in the whole study population was 2.85 ± 0.51 days and did not differ between groups. In conclusion, serum AMH can differentiate between intact and gonadectomized status of adult dogs by 14 days after ovario(hyster)ectomy in females and by 28 days after surgical castration in males.

Amphibian newts as experimental models for studying weight gain after castration.

Vertebrate animals often exhibit sexual dimorphism in body shape. In mammals, decreases in sex hormones caused by testicular castration can affect body shape and occasionally lead to pathologies such as obesity. Post-castration obesity can also be problematic for the health of companion animals, including non-mammals. In order to understand the mechanism of post-castration obesity in vertebrates other than mammals, experimental models are required. We examined whether the Iberian ribbed newt, which has recently become a popular experimental model for amphibian research, could serve as a model for analyzing changes in body shape after castration. In newts, new testes can be regenerated after removal of differentiated testes. We analyzed changes in body shape by removing the testes under conditions in which they could regenerate or conditions in which they could not regenerate. Removal of the testes reduced blood testosterone levels. The body weight and abdominal girth of the newts were increased compared with normal male newts. Transcriptome analysis of the liver showed that a set of genes related to lipid metabolism was continuously up-regulated in castrated newts. Our study suggests that changes in body shape after castration are common in vertebrates. Iberian ribbed newts are thus a suitable model for comparative studies of the long-term physiologic- and endocrine-level effects of castration.

PRESTO: A Phase III, Open-Label Study of Intensification of Androgen Blockade in Patients With High-Risk Biochemically Relapsed Castration-Sensitive Prostate Cancer (AFT-19).

PURPOSE: Patients with biochemically recurrent prostate cancer (BRPC) after radical prostatectomy and a short PSA doubling time are at risk for distant metastases. Apalutamide, an androgen receptor antagonist, and abiraterone acetate plus prednisone (AAP) prolong survival in the metastatic setting. We evaluated whether intensification of androgen-deprivation therapy (ADT) improves outcomes in BRPC. PATIENTS AND METHODS: PRESTO is a randomized phase III, open-label trial in patients with BRPC and PSA doubling time ≤9 months (ClinicalTrials.gov identifier: NCT03009981). Patients were randomly assigned 1:1:1 to receive a finite 52-week treatment course with ADT control, ADT + apalutamide, or ADT + apalutamide + AAP. The primary end point was PSA progression-free survival (PSA-PFS), defined as serum PSA >0.2 ng/mL after treatment completion. RESULTS: Five hundred three patients were enrolled. The median PSA was 1.8 ng/mL (IQR, 1.0-3.6). At the first planned interim analysis, both experimental arms significantly prolonged PSA-PFS compared with the control arm (median, 24.9 months for ADT + apalutamide v 20.3 months for ADT; hazard ratio [HR], 0.52 [95% CI, 0.35 to 0.77]; P = .00047; median, 26.0 months for ADT + apalutamide + AAP v 20.0 months for ADT; HR, 0.48 [95% CI, 0.32 to 0.71]; P = .00008). Median time to testosterone recovery did not differ across treatment arms. The most common grade ≥3 adverse event was hypertension (7.5%, 7.4%, and 18% in ADT, ADT + apalutamide, and ADT + apalutamide + AAP arms, respectively). CONCLUSION: Intensified AR blockade for a finite duration prolongs PSA-PFS with a manageable safety profile, without adversely affecting time to testosterone recovery. The addition of apalutamide to ADT should be considered in patients with high-risk BRPC.