X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

• MeSH
• androgeny * genetika   MeSH
• celogenomová asociační studie * MeSH
• genetická predispozice k nemoci MeSH
• jednonukleotidový polymorfismus MeSH
• ledviny MeSH
• lidé MeSH
• lidské chromozomy X genetika   MeSH
• responzivní elementy MeSH
• tetraspaniny genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• Názvy látek
• androgeny * MeSH
• tetraspaniny MeSH
• TSPAN6 protein, human MeSH Prohlížeč

BACKGROUND: In the CARD study, cabazitaxel significantly improved radiographic progression-free survival and overall survival versus abiraterone or enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel and the alternative androgen signalling-targeted inhibitor. Here, we report the quality-of-life outcomes from the CARD study. METHODS: CARD was a randomised, multicentre, open-label, phase 4 study involving 62 clinical sites across 13 European countries. Patients (aged ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status ≤2) with confirmed metastatic castration-resistant prostate cancer were randomly assigned (1:1) by means of an interactive voice-web response system to receive cabazitaxel (25 mg/m2 intravenously every 3 weeks, 10 mg daily prednisone, and granulocyte colony-stimulating factor) versus abiraterone (1000 mg orally once daily plus 5 mg prednisone twice daily) or enzalutamide (160 mg orally daily). Stratification factors were ECOG performance status, time to disease progression on the previous androgen signalling-targeted inhibitor, and timing of the previous androgen signalling-targeted inhibitor. The primary endpoint was radiographic progression-free survival; here, we present more detailed analyses of pain (assessed using item 3 on the Brief Pain Inventory-Short Form [BPI-SF]) and symptomatic skeletal events, alongside preplanned patient-reported outcomes, assessed using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and the EuroQoL-5 dimensions, 5 level scale (EQ-5D-5L). Efficacy analyses were done in the intention-to-treat population. Pain response was analysed in the intention-to-treat population with baseline and at least one post-baseline assessment of BPI-SF item 3, and patient-reported outcomes (PROs) were analysed in the intention-to-treat population with baseline and at least one post-baseline assessment of either FACT-P or EQ-5D-5L (PRO population). Analyses of skeletal-related events were also done in the intention-to-treat population. The CARD study is registered with ClinicalTrials.gov, NCT02485691, and is no longer enrolling. FINDINGS: Between Nov 17, 2015, and Nov 28, 2018, of 303 patients screened, 255 were randomly assigned to cabazitaxel (n=129) or abiraterone or enzalutamide (n=126). Median follow-up was 9·2 months (IQR 5·6-13·1). Pain response was observed in 51 (46%) of 111 patients with cabazitaxel and 21 (19%) of 109 patients with abiraterone or enzalutamide (p<0·0001). Median time to pain progression was not estimable (NE; 95% CI NE-NE) with cabazitaxel and 8·5 months (4·9-NE) with abiraterone or enzalutamide (hazard ratio [HR] 0·55, 95% CI 0·32-0·97; log-rank p=0·035). Median time to symptomatic skeletal events was NE (95% CI 20·0-NE) with cabazitaxel and 16·7 months (10·8-NE) with abiraterone or enzalutamide (HR 0·59, 95% CI 0·35-1·01; log-rank p=0·050). Median time to FACT-P total score deterioration was 14·8 months (95% CI 6·3-NE) with cabazitaxel and 8·9 months (6·3-NE) with abiraterone or enzalutamide (HR 0·72, 95% CI 0·44-1·20; log-rank p=0·21). There was a significant treatment effect seen in changes from baseline in EQ-5D-5L utility index score in favour of cabazitaxel over abiraterone or enzalutamide (p=0·030) but no difference between treatment groups for change from baseline in EQ-5D-5L visual analogue scale (p=0·060). INTERPRETATION: Since cabazitaxel improved pain response, time to pain progression, time to symptomatic skeletal events, and EQ-5D-5L utility index, clinicians and patients with metastatic castration-resistant prostate cancer can be reassured that cabazitaxel will not reduce quality of life when compared with treatment with a second androgen signalling-targeted inhibitor. FUNDING: Sanofi.

• MeSH
• androgeny genetika   MeSH
• androsteny aplikace a dávkování   škodlivé účinky   MeSH
• antagonisté androgenů aplikace a dávkování   škodlivé účinky   MeSH
• benzamidy MeSH
• fenylthiohydantoin aplikace a dávkování   škodlivé účinky   analogy a deriváty   MeSH
• kvalita života MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• nádory prostaty rezistentní na kastraci farmakoterapie   epidemiologie   patologie   MeSH
• nitrily MeSH
• přežití bez známek nemoci MeSH
• senioři MeSH
• taxoidy aplikace a dávkování   škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze IV MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• abiraterone MeSH Prohlížeč
• androgeny MeSH
• androsteny MeSH
• antagonisté androgenů MeSH
• benzamidy MeSH
• cabazitaxel MeSH Prohlížeč
• enzalutamide MeSH Prohlížeč
• fenylthiohydantoin MeSH
• nitrily MeSH
• taxoidy MeSH

Proximate control of the development of sexual dimorphism is still hotly debated in reptiles. In some squamates, many male-typical exaggerated traits including body size were assumed to be controlled by masculinization by male gonadal androgens. We performed a manipulative experiment to test the importance of this mechanism in the development of pronounced sexual differences in body size and size of head casque in the chameleon Chamaeleo calyptratus. Castrated males attained male-typical body size highly deviating from the body size of control females. Ontogenetic allometries of casque size on head length revealed that sexes depart considerably in casque growth later in the ontogeny; however, castrated males still follow male-typical casque growth. Paradoxically, exogenous testosterone led in females to slight increase of casque size, which might reflect interference with the feminizing effects of female gonadal hormones. The results in males strongly suggest that masculinization by male gonadal androgens during growth is not required for the development of sexual dimorphism in body size and casque size in the chameleon. The ontogeny of sexually dimorphic body size and exaggerated traits in at least some squamates is likely controlled by other proximate mechanism, possibly by feminization by ovarian hormones.

• MeSH
• androgeny genetika   metabolismus   MeSH
• gonády metabolismus   MeSH
• ještěři anatomie a histologie   genetika   růst a vývoj   metabolismus   MeSH
• kastrace MeSH
• lebka anatomie a histologie   metabolismus   MeSH
• pohlavní dimorfismus * MeSH
• testosteron genetika   metabolismus   MeSH
• velikost těla genetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• androgeny MeSH
• testosteron MeSH

Responsive genes for fish embryos have been identified so far for some endocrine pathways but not for androgens. Using transcriptome analysis and multiple concentration-response modeling, we identified putative androgen-responsive genes in zebrafish embryos exposed to 0.05-5000 nM 11-ketotestosterone for 24 h. Four selected genes with sigmoidal concentration-dependent expression profiles (EC50 = 6.5-30.0 nM) were characterized in detail. The expression of cyp2k22 and slco1f4 was demonstrated in the pronephros; lipca was detected in the liver, and sult2st3 was found in the olfactory organs and choroid plexus. Their expression domains, the function of human orthologs, and a pathway analysis suggested a role of these genes in the metabolism of hormones. Hence, it was hypothesized that they were induced to compensate for elevated hormone levels. The induction of sult2st3 and cyp2k22 by 11-ketotestosterone was repressed by co-exposure to the androgen receptor antagonist nilutamide supporting a potential androgen receptor mediated regulation. Sensitivity (expressed as EC50 values) of sult2st3 and cyp2k22 gene expression induction after exposure to other steroidal hormones (11-ketotestosterone ∼ testosterone > progesterone > cortisol > ethinylestradiol) correlated with their known binding affinities to zebrafish androgen receptor. Hence, these genes might represent potential markers for screening of androgenic compounds in the zebrafish embryo.

• MeSH
• androgenní receptory genetika   MeSH
• androgeny genetika   metabolismus   MeSH
• antagonisté androgenů farmakologie   MeSH
• dánio pruhované embryologie   genetika   MeSH
• embryo nesavčí účinky léků   MeSH
• ethinylestradiol farmakologie   MeSH
• exprese genu účinky léků   MeSH
• imidazolidiny farmakologie   MeSH
• lidé MeSH
• stanovení celkové genové exprese MeSH
• testosteron analogy a deriváty   farmakologie   MeSH
• vývojová regulace genové exprese účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-ketotestosterone MeSH Prohlížeč
• androgenní receptory MeSH
• androgeny MeSH
• antagonisté androgenů MeSH
• ethinylestradiol MeSH
• imidazolidiny MeSH
• nilutamide MeSH Prohlížeč
• testosteron MeSH

Androgen receptor (AR) expression in prostate cancer (CaP) cells varies due to the multiple changes including epigenetic modifications such as DNA methylation and histone deacetylation. DNA methyltransferase and histone deacetylase inhibitors are promising for the treatment of CaP. The aim of our study was to analyze the 5-aza-2'-deoxycytidine (Aza‑dC) and sodium butyrate (NaB) effects on CaP cells with modified AR gene expression. The androgen-independent human prostate cancer cell lines PC3 (lacking a functional AR) and DU145 (strongly limited expression due to methylations in the AR gene) were used. PCR of bisulfite-modified DNA and RT-PCR with bisulfite-sequencing were used for AR gene analysis of DU145 and PC3 cells following their treatment with Aza-dC and/or NaB. Re-acetylated histones around the AR gene were detected by conventional PCR of immunoprecipitated DNA obtained from treated cells. In both cell lines without the AR expression, the combined treatment was followed with significant decrease of cell viability. The co-treatment of DU145 cells caused site-specific demethylation in the AR promoter region followed by gene re-expression and increased acetylation in histones H3 and H4. The co-treatment with Aza-dC and NaB was the most effective in demethylation and re-expression of the AR gene. In the AR gene promoter, the location and density of deme-thylated CpGs indicated the existence of distinct promoter hot spot that could be a target of AR gene inactivation therapy of CaP patients during androgen deprivation.

• MeSH
• 5' nepřekládaná oblast MeSH
• acetylace účinky léků   MeSH
• androgenní receptory biosyntéza   genetika   metabolismus   MeSH
• androgeny genetika   metabolismus   MeSH
• azacytidin analogy a deriváty   farmakologie   MeSH
• decitabin MeSH
• DNA genetika   MeSH
• histondeacetylasy genetika   metabolismus   MeSH
• histony genetika   metabolismus   MeSH
• inhibitory histondeacetylas farmakologie   MeSH
• kyselina máselná farmakologie   MeSH
• lidé MeSH
• methyltransferasy antagonisté a inhibitory   genetika   metabolismus   MeSH
• metylace DNA účinky léků   MeSH
• nádorové buněčné linie MeSH
• nádory prostaty rezistentní na kastraci farmakoterapie   enzymologie   genetika   metabolismus   MeSH
• promotorové oblasti (genetika) účinky léků   genetika   MeSH
• viabilita buněk účinky léků   genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 5' nepřekládaná oblast MeSH
• androgenní receptory MeSH
• androgeny MeSH
• AR protein, human MeSH Prohlížeč
• azacytidin MeSH
• decitabin MeSH
• DNA MeSH
• histondeacetylasy MeSH
• histony MeSH
• inhibitory histondeacetylas MeSH
• kyselina máselná MeSH
• methyltransferasy MeSH