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Biomedicine & Pharmacotherapy =... May 2021Androgenic alopecia (AGA), also known as male pattern baldness, is one of the most common hair loss diseases worldwide. The main treatments of AGA include hair...
Androgenic alopecia (AGA), also known as male pattern baldness, is one of the most common hair loss diseases worldwide. The main treatments of AGA include hair transplant surgery, oral medicines, and LDL laser irradiation, although no treatment to date can fully cure this disease. Animal models play important roles in the exploration of potential mechanisms of disease development and in assessing novel treatments. The present study describes androgen receptor (AR) in C57BL/6 mouse hair follicles that can be activated by dihydrotestosterone (DHT) and translocate to the nucleus. This led to the design of a mouse model of androgen-induced AGA in vivo and in vitro. DHT was found to induce early hair regression, hair miniaturization, hair density loss, and changes in hair morphology in male C57BL/6 mice. These effects of DHT could be partly reversed by the AR antagonist bicalutamide. DHT had similar effects in an ex vivo model of hair loss. Evaluation of histology, organ culture, and protein expression could explain the mechanism by which DHT delayed hair regrowth.
Topics: Alopecia; Androgen Antagonists; Anilides; Animals; Dihydrotestosterone; Disease Models, Animal; Hair Follicle; Male; Mice; Mice, Inbred C57BL; Nitriles; Organ Culture Techniques; Receptors, Androgen; Signal Transduction; Tosyl Compounds
PubMed: 33517191
DOI: 10.1016/j.biopha.2021.111247 -
Journal of Clinical Research in... Aug 2023A significant rise in the number of trans adolescents seeking medical interventions has been reported in recent years. The aim of this study was to report the clinical...
OBJECTIVE
A significant rise in the number of trans adolescents seeking medical interventions has been reported in recent years. The aim of this study was to report the clinical features, treatment, and follow-up of adolescents with gender dysphoria (GD) with our increased experience.
METHODS
Twenty-six male-to-female (MTF) and twenty-seven female-to-male (FTM) adolescents who were referred to the GD-outpatient clinic between 2016 and 2022 were reviewed. The clinical and laboratory findings of thirty transgender adolescents (15 FTM /15 MTF) who received medical intervention were evaluated retrospectively.
RESULTS
Most individuals (60.4%) were admitted between 2020 and 2022, and the remaining (39.6%) were admitted between 2016 and 2019. At the time of referral, median age was 16.3 years [interquartile range (IQR) 1.53; range 13.2-19.4] in 26 MTF, and 16.4 years (IQR 1.74; range 11.7-21.6) in 27 FTM adolescents. The median age at pubertal blockage with gonadotropin-releasing hormone analog and androgen receptor blocker was 16.4 years (IQR 1.4; range 11.7-17.8) in 22 adolescents (9 MTF, 13 FTM), and 17.4 years (IQR 1.4; range 15.5-19.4) in 6 MTF individuals, respectively. Cross-sex hormone therapy was commenced in 21 adolescents (12 MTF, 9 FTM) at the median age of 17.7 years (IQR 0.61; range 16-19.5). Fifteen individuals (8 MTF, 7 FTM) have been transferred to the adult endocrinology department in transition clinics.
CONCLUSION
All treatments were generally well tolerated and effective, including bicalutamide, and no significant side effects were observed. Transition clinics played an important role in the better management of gender reassignment processes.
Topics: Adult; Humans; Male; Child; Female; Adolescent; Infant; Retrospective Studies; Gender Dysphoria; Turkey; Transsexualism; Transgender Persons
PubMed: 36987788
DOI: 10.4274/jcrpe.galenos.2023.2023-1-13 -
Frontiers in Immunology 2022Copper ions are essential for cellular physiology. Cuproptosis is a novel method of copper-dependent cell death, and the cuproptosis-based signature for glioma remains...
BACKGROUND
Copper ions are essential for cellular physiology. Cuproptosis is a novel method of copper-dependent cell death, and the cuproptosis-based signature for glioma remains less studied.
METHODS
Several glioma datasets with clinicopathological information were collected from TCGA, GEO and CGGA. Robust Multichip Average (RMA) algorithm was used for background correction and normalization, cuproptosis-related genes (CRGs) were then collected. The TCGA-glioma cohort was clustered using ConsensusClusterPlus. Univariate Cox regression analysis and the Random Survival Forest model were performed on the differentially expressed genes to identify prognostic genes. The cuproptosis-signature was constructed by calculating CuproptosisScore using Multivariate Cox regression analysis. Differences in terms of genomic mutation, tumor microenvironment, and enrichment pathways were evaluated between high- or low-CuproptosisScore. Furthermore, drug response prediction was carried out utilizing pRRophetic.
RESULTS
Two subclusters based on CRGs were identified. Patients in cluster2 had better clinical outcomes. The cuproptosis-signature was constructed based on CuproptosisScore. Patients with higher CuproptosisScore had higher WHO grades and worse prognosis, while patients with lower grades were more likely to develop IDH mutations or MGMT methylation. Univariate and Multivariate Cox regression analysis demonstrated CuproptosisScore was an independent prognostic factor. The accuracy of the signature in prognostic prediction was further confirmed in 11 external validation datasets. In groups with high-CuproptosisScore, PIK3CA, MUC16, NF1, TTN, TP53, PTEN, and EGFR showed high mutation frequency. IDH1, TP53, ATRX, CIC, and FUBP1 demonstrated high mutation frequency in low-CuproptosisScore group. The level of immune infiltration increased as CuproptosisScore increased. SubMap analysis revealed patients with high-CuproptosisScore may respond to anti-PD-1 therapy. The IC50 values of Bexarotene, Bicalutamide, Bortezomib, and Cytarabine were lower in the high-CuproptosisScore group than those in the low-CuproptosisScore group. Finally, the importance of IGFBP2 in TCGA-glioma cohort was confirmed.
CONCLUSION
The current study revealed the novel cuproptosis-based signature might help predict the prognosis, biological features, and appropriate treatment for patients with glioma.
Topics: Humans; Bexarotene; Bortezomib; Brain Neoplasms; Class I Phosphatidylinositol 3-Kinases; Copper; Cytarabine; DNA-Binding Proteins; ErbB Receptors; Gene Expression Regulation, Neoplastic; Glioma; Prognosis; RNA-Binding Proteins; Tumor Microenvironment; Apoptosis
PubMed: 36110851
DOI: 10.3389/fimmu.2022.998236 -
The New England Journal of Medicine Feb 2017Salvage radiation therapy is often necessary in men who have undergone radical prostatectomy and have evidence of prostate-cancer recurrence signaled by a persistently... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Salvage radiation therapy is often necessary in men who have undergone radical prostatectomy and have evidence of prostate-cancer recurrence signaled by a persistently or recurrently elevated prostate-specific antigen (PSA) level. Whether antiandrogen therapy with radiation therapy will further improve cancer control and prolong overall survival is unknown.
METHODS
In a double-blind, placebo-controlled trial conducted from 1998 through 2003, we assigned 760 eligible patients who had undergone prostatectomy with a lymphadenectomy and had disease, as assessed on pathological testing, with a tumor stage of T2 (confined to the prostate but with a positive surgical margin) or T3 (with histologic extension beyond the prostatic capsule), no nodal involvement, and a detectable PSA level of 0.2 to 4.0 ng per milliliter to undergo radiation therapy and receive either antiandrogen therapy (24 months of bicalutamide at a dose of 150 mg daily) or daily placebo tablets during and after radiation therapy. The primary end point was the rate of overall survival.
RESULTS
The median follow-up among the surviving patients was 13 years. The actuarial rate of overall survival at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (hazard ratio for death, 0.77; 95% confidence interval, 0.59 to 0.99; P=0.04). The 12-year incidence of death from prostate cancer, as assessed by means of central review, was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (P<0.001). The cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, as compared with 23.0% in the placebo group (P=0.005). The incidence of late adverse events associated with radiation therapy was similar in the two groups. Gynecomastia was recorded in 69.7% of the patients in the bicalutamide group, as compared with 10.9% of those in the placebo group (P<0.001).
CONCLUSIONS
The addition of 24 months of antiandrogen therapy with daily bicalutamide to salvage radiation therapy resulted in significantly higher rates of long-term overall survival and lower incidences of metastatic prostate cancer and death from prostate cancer than radiation therapy plus placebo. (Funded by the National Cancer Institute and AstraZeneca; RTOG 9601 ClinicalTrials.gov number, NCT00002874 .).
Topics: Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Combined Modality Therapy; Double-Blind Method; Follow-Up Studies; Gynecomastia; Humans; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Nitriles; Prostatectomy; Prostatic Neoplasms; Radiotherapy; Survival Rate; Tosyl Compounds
PubMed: 28146658
DOI: 10.1056/NEJMoa1607529 -
JAMA Oncology Apr 2021Decipher (Decipher Biosciences Inc) is a genomic classifier (GC) developed to estimate the risk of distant metastasis (DM) after radical prostatectomy (RP) in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Decipher (Decipher Biosciences Inc) is a genomic classifier (GC) developed to estimate the risk of distant metastasis (DM) after radical prostatectomy (RP) in patients with prostate cancer.
OBJECTIVE
To validate the GC in the context of a randomized phase 3 trial.
DESIGN, SETTING, AND PARTICIPANTS
This ancillary study used RP specimens from the phase 3 placebo-controlled NRG/RTOG 9601 randomized clinical trial conducted from March 1998 to March 2003. The specimens were centrally reviewed, and RNA was extracted from the highest-grade tumor available in 2019 with a median follow-up of 13 years. Clinical-grade whole transcriptomes from samples passing quality control were assigned GC scores (scale, 0-1). A National Clinical Trials Network-approved prespecified statistical plan included the primary objective of validating the independent prognostic ability of GC for DM, with secondary end points of prostate cancer-specific mortality (PCSM) and overall survival (OS). Data were analyzed from September 2019 to December 2019.
INTERVENTION
Salvage radiotherapy (sRT) with or without 2 years of bicalutamide.
MAIN OUTCOMES AND MEASURES
The preplanned primary end point of this study was the independent association of the GC with the development of DM.
RESULTS
In this ancillary study of specimens from a phase 3 randomized clinical trial, GC scores were generated from 486 of 760 randomized patients with a median follow-up of 13 years; samples from a total of 352 men (median [interquartile range] age, 64.5 (60-70) years; 314 White [89.2%] participants) passed microarray quality control and comprised the final cohort for analysis. On multivariable analysis, the GC (continuous variable, per 0.1 unit) was independently associated with DM (hazard ratio [HR], 1.17; 95% CI, 1.05-1.32; P = .006), PCSM (HR, 1.39; 95% CI, 1.20-1.63; P < .001), and OS (HR, 1.17; 95% CI, 1.06-1.29; P = .002) after adjusting for age, race/ethnicity, Gleason score, T stage, margin status, entry prostate-specific antigen, and treatment arm. Although the original planned analysis was not powered to detect a treatment effect interaction by GC score, the estimated absolute effect of bicalutamide on 12-year OS was less when comparing patients with lower vs higher GC scores (2.4% vs 8.9%), which was further demonstrated in men receiving early sRT at a prostate-specific antigen level lower than 0.7 ng/mL (-7.8% vs 4.6%).
CONCLUSIONS AND RELEVANCE
This ancillary validation study of the Decipher GC in a randomized trial cohort demonstrated association of the GC with DM, PCSM, and OS independent of standard clinicopathologic variables. These results suggest that not all men with biochemically recurrent prostate cancer after surgery benefit equally from the addition of hormone therapy to sRT.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT00002874.
Topics: Aged; Anilides; Follow-Up Studies; Genomics; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Recurrence, Local; Nitriles; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Tosyl Compounds
PubMed: 33570548
DOI: 10.1001/jamaoncol.2020.7671 -
The Journal of Steroid Biochemistry and... Feb 2020The formation of steroid hormones in peripheral target tissues is referred to as their intracrine formation. This process occurs in hormone dependent malignancies such... (Review)
Review
The formation of steroid hormones in peripheral target tissues is referred to as their intracrine formation. This process occurs in hormone dependent malignancies such as prostate and breast cancer in which the disease can be either castrate resistant or occur post-menopausally, respectively. In these instances, the major precursor steroid of androgens and estrogens is dehydroepiandrosterone (DHEA) and DHEA-SO. This article reviews the major pathways by which adrenal steroids are converted to the potent male sex hormones, testosterone (T) and 5α-dihydrotestosterone (5α-DHT) and the discrete enzyme isoforms involved in castration resistant prostate cancer. Previous studies have mainly utilized radiotracers to investigate these pathways but have not used prevailing concentrations of precursors found in castrate male human serum. In addition, the full power of stable-isotope dilution liquid chromatography tandem mass spectrometry has not been applied routinely. Furthermore, it is clear that adaptive responses occur in the transporters and enzyme isoforms involved in response to androgen deprivation therapy that need to be considered.
Topics: Humans; Intracellular Space; Male; Paracrine Communication; Prostate; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Steroids; Tumor Microenvironment
PubMed: 31614208
DOI: 10.1016/j.jsbmb.2019.105499 -
Neurotherapeutics : the Journal of the... Mar 2023Spinal and bulbar muscular atrophy (SBMA) is characterized by motor neuron (MN) degeneration that leads to slowly progressive muscle weakness. It is considered a...
Spinal and bulbar muscular atrophy (SBMA) is characterized by motor neuron (MN) degeneration that leads to slowly progressive muscle weakness. It is considered a neuromuscular disease since muscle has a primary role in disease onset and progression. SBMA is caused by a CAG triplet repeat expansion in the androgen receptor (AR) gene. The translated poly-glutamine (polyQ) tract confers a toxic gain of function to the mutant AR altering its folding, causing its aggregation into intracellular inclusions, and impairing the autophagic flux. In an in vitro SBMA neuronal model, we previously showed that the antiandrogen bicalutamide and trehalose, a natural disaccharide stimulating autophagy, block ARpolyQ activation, reduce its nuclear translocation and toxicity and facilitate the autophagic degradation of cytoplasmic AR aggregates. Here, in a knock-in SBMA mouse model (KI AR113Q), we show that bicalutamide and trehalose ameliorated SBMA pathology. Bicalutamide reversed the formation of the AR insoluble forms in KI AR113Q muscle, preventing autophagic flux blockage. We demonstrated that apoptosis is activated in KI AR113Q muscle, and that both compounds prevented its activation. We detected a decrease of mtDNA and an increase of OXPHOS enzymes, already at early symptomatic stages; these alterations were reverted by trehalose. Overall, bicalutamide and/or trehalose led to a partial recovery of muscle morphology and function, and improved SBMA mouse motor behavior, inducing an extension of their survival. Thus, bicalutamide and trehalose, by counteracting ARpolyQ toxicity in skeletal muscle, are valuable candidates for future clinical trials in SBMA patients.
Topics: Mice; Animals; Bulbo-Spinal Atrophy, X-Linked; Trehalose; Receptors, Androgen; Muscular Atrophy, Spinal; Anilides; Mice, Transgenic
PubMed: 36717478
DOI: 10.1007/s13311-023-01343-x -
British Journal of Cancer Nov 2021The combination of radiotherapy with bicalutamide is the standard treatment of prostate cancer patients with high-risk or locally advanced disease. Whether... (Comparative Study)
Comparative Study
INTRODUCTION
The combination of radiotherapy with bicalutamide is the standard treatment of prostate cancer patients with high-risk or locally advanced disease. Whether new-generation anti-androgens, like apalutamide, can improve the radio-curability of these patients is an emerging challenge.
MATERIALS AND METHODS
We comparatively examined the radio-sensitising activity of apalutamide and bicalutamide in hormone-sensitive (22Rv1) and hormone-resistant (PC3, DU145) prostate cancer cell lines. Experiments with xenografts were performed for the 22Rv1 cell line.
RESULTS
Radiation dose-response viability and clonogenic assays showed that apalutamide had a stronger radio-sensitising activity for all three cell lines. Confocal imaging for γΗ2Αx showed similar DNA double-strand break repair kinetics for apalutamide and bicalutamide. No difference was noted in the apoptotic pathway. A striking cell death pattern involving nuclear karyorrhexis and cell pyknosis in the G1/S phase was exclusively noted when radiation was combined with apalutamide. In vivo experiments in SCID and R2G2 mice showed significantly higher efficacy of radiotherapy (2 and 4 Gy) when combined with apalutamide, resulting in extensive xenograft necrosis.
CONCLUSIONS
In vitro and in vivo experiments support the superiority of apalutamide over bicalutamide in combination with radiotherapy in prostate cancer. Clinical studies are encouraged to show whether replacement of bicalutamide with apalutamide may improve the curability rates.
Topics: Anilides; Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chemoradiotherapy; Dose-Response Relationship, Radiation; Humans; Male; Mice; Nitriles; PC-3 Cells; Prostatic Neoplasms; Radiation-Sensitizing Agents; Thiohydantoins; Tosyl Compounds; Xenograft Model Antitumor Assays
PubMed: 34471256
DOI: 10.1038/s41416-021-01528-1