Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance.

The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with castration-resistant prostate cancer (CRPC). However, not all patients respond, and resistance mechanisms are largely unknown. We hypothesized that genomic and transcriptional features from metastatic CRPC biopsies prior to treatment would be predictive of de novo treatment resistance. To this end, we conducted a phase II trial of enzalutamide treatment (160 mg/d) in 36 men with metastatic CRPC. Thirty-four patients were evaluable for the primary end point of a prostate-specific antigen (PSA)50 response (PSA decline ≥50% at 12 wk vs. baseline). Nine patients were classified as nonresponders (PSA decline <50%), and 25 patients were classified as responders (PSA decline ≥50%). Failure to achieve a PSA50 was associated with shorter progression-free survival, time on treatment, and overall survival, demonstrating PSA50's utility. Targeted DNA-sequencing was performed on 26 of 36 biopsies, and RNA-sequencing was performed on 25 of 36 biopsies that contained sufficient material. Using computational methods, we measured AR transcriptional function and performed gene set enrichment analysis (GSEA) to identify pathways whose activity state correlated with de novo resistance. TP53 gene alterations were more common in nonresponders, although this did not reach statistical significance (P = 0.055). AR gene alterations and AR expression were similar between groups. Importantly, however, transcriptional measurements demonstrated that specific gene sets-including those linked to low AR transcriptional activity and a stemness program-were activated in nonresponders. Our results suggest that patients whose tumors harbor this program should be considered for clinical trials testing rational agents to overcome de novo enzalutamide resistance.

Androgen receptor gene polymorphisms and maximal fat oxidation in healthy men. A longitudinal study / Polimorfismo del gen del receptor de andrógenos y oxidación máxima de grasa en hombres sanos. Estudio longitudinal

Introduction: Androgens play a major role in fat oxidation; however, the effects of androgens depend, among other factors, on the intrinsic characteristics of the androgen receptor (AR). Lower repetitions of CAG and GGN polymorphism appear to have a protective effect on fat accumulation in the transition from adolescent to mid-twenties. Whether a similar protective effect is present later in life remains unknown. The aims of this study were: a) to evaluate if extreme CAG and GGN repeat polymorphisms of the androgen receptors influence body fat mass, its regional distribution, resting metabolic rate (RMR), maximal fat oxidation capacity (MFO) and serum leptin, free testosterone and osteocalcin in healthy adult men; and b) to determine the longitudinal effects on fat tissue accumulation after 6.4 years of follow-up. Methods: CAG and GGN repeats length were measured in 319 healthy men (mean ± standard deviation [SD]: 28.3 ± 7.6 years). From these, we selected the subjects with extreme short (CAGS ≤ 19; n = 7) and long (CAGL ≥ 24; n = 10) CAG repeats, and the subjects with short (GGNS ≤ 22; n = 9) and long (GGNL ≥ 25; n = 10) GGN repeats. Body composition was assessed by DXA and serum levels of leptin, free testosterone and osteocalcin by ELISA. After 6.4 years of follow-up, DXA was repeated, and resting metabolic rate (RMR), MFO and VO2max determined by indirect calorimetry. Results: CAGS and CAGL subjects had similar RMR and accumulated comparable amounts of fat tissue over 6.4 ± 1.0 years of follow-up. However, CAGL had higher MFO and total lean mass than CAGS (p < 0.05). Men with GGNS accumulated greater amount of total fat mass than men with GGNL, particularly in the trunk region seven years later. This concurred with a greater MFO in the GGNL group (p < 0.05), who accumulated less fat mass. Free testosterone was associated with MFO in absolute values (r = 0.45; p < 0.05) and MFO per kg of lower extremity lean mass per height squared (r = 0.35; p < 0.05). Conclusions: CAG and GGN repeat polymorphisms may influence muscle fat oxidation capacity and may have a role in the accumulation of fat over the years (AU)

Introducción: los andrógenos juegan un papel importante en la oxidación de grasas; sin embargo, el efecto de los andrógenos depende, entre otros factores, de las características intrínsecas del receptor de andrógenos (RA). Un menor número de repeticiones CAG y GGN del RA parecen tener un efecto protector sobre la acumulación de grasa en la transición de la adolescencia hasta la veintena. Se desconoce si adelante en la vida persiste un efecto protector similar. Los objetivos de este estudio fueron: a) evaluar si repeticiones extremas de los polimorfismos CAG y GGN del RA influyen sobre la masa grasa corporal, su distribución regional, la tasa metabólica en reposo (RMR), la máxima oxidación de grasas (MFO) y la concentración sérica de leptina, testosterona libre y osteocalcina en hombres sanos; y b) determinar los efectos longitudinales sobre la acumulación de grasa después de 6.4 años de seguimiento. Métodos: la longitud de las repeticiones de CAG y GGN fueron medidas en 319 hombres sanos (media ± desviación estándar [SD]: 28,3 ± 7,6 años). De estos, seleccionamos los sujetos con repeticiones del CAG extremas cortas (CAGS ≤ 19; n = 7) y largas (CAGL ≥ 24; n = 10), y los sujetos con repeticiones del GGN extremas cortas (GGNS ≤ 22; n = 9) y largas (GGNL ≥ 25; n = 10). Se evaluaron la composición corporal mediante DXA y los niveles séricos de leptina, testosterona libre y osteocalcina por ELISA. Tras 6.4 años de seguimiento el DXA fue repetido, y la tasa metabólica en reposo (RMR), máxima oxidación de grasas (MFO) y VO2max fueron determinados mediante calorimetría indirecta. Resultados: los grupos CAGS y CAGL fueron comparables en RMR y cantidad de tejido graso tras 6,4 ± 1,0 años de seguimiento. Sin embargo, el grupo CAGL tuvo mayor MFO y masa libre de grasa que el grupo CAGS (p < 0,05). Los hombres con GGNS acumularon mayor cantidad de masa grasa total que los hombres con GGNL, particularmente en la región del tronco siete años después. Esto concordó con un mayor MFO en el grupo GGNL (p < 0,05), que acumuló menos masa grasa. La testosterona libre se asoció con el MFO en valores absolutos (r = 0,45; p < 0,05) y con MFO expresado por kg de masa libre de grasa de las piernas al cuadrado (r = 0,35; p < 0,05). Conclusiones: las repeticiones del polimorfismo del CAG y GGN pueden influenciar la capacidad muscular de oxidación de grasas y pueden tener un rol en la acumulación de grasa con los años (AU)

Effects of cypermethrin on cytokeratin 8/18 and androgen receptor expression in the adult mouse Sertoli cell / Efectos de cipermetrina sobre la expresión de citoqueratinas 8/18 y el receptor de andrógenos en la célula de sertoli del ratón adulto

Background. With the explosive population growth an increased use of land for cultivation purposes and the usage of biotechnologies in agriculture—such as pesticides—respond to the need for more efficient systems. However, improper application of pesticides has a negative effect on the environment, on exposed animals and on humans. Cypermethrin, a synthetic pyrethroid, is an insecticide with low risk to human and animal health and with broad insecticidal activity against a large number of pests. Studies in humans and animals show morphological and functional alterations in different organs exposed to cypermethrin. Pyrethroids are chemicals with structural similarity to pyrethrins and possess increased toxicity to insects over mammals. Objective. This research analyzes the variations of the state of differentiation of Sertoli cells and androgen receptor expression in testes of healthy adult mice exposed to cypermethrin. Material and method. Mice were divided into three groups: control 1 (untreated), control 2 (inoculated intraperitoneally with 0.1ml of vegetable oil), and the experimental group 3 (inoculated with 1/5 of the lethal dose 50 (LD50=485mg/kg) of cypermethrin). Results. Cypermethrin exerts acute and chronic effects on Sertoli cells in the testis of the adult mouse. These effects are manifested by the significant increase in epithelial height and the dedifferentiation of Sertoli cells evidenced through the presence of the Ck 8/18-type intermediate filament—a characteristic of differentiating cells—especially considering the functional cyclicity of the testicular compartment. Conclusions. Cypermethrin significantly affects the structure and function of Sertoli cells through the cytoskeleton and the state of maturation (AU)

Antecedentes. Con el crecimiento explosivo de la población, un mayor uso de la tierra con fines de cultivo y el uso de las biotecnologías en la agricultura—como pesticidas—responden a la necesidad de sistemas más eficientes. Sin embargo, la aplicación inadecuada de pesticidas tiene un efecto negativo sobre el medio ambiente, en los animales expuestos y en los seres humanos. La cipermetrina, un piretroide sintético, es un insecticida de bajo riesgo para la salud humana y animal, y con una amplia actividad insecticida frente a un gran número de plagas. Los estudios en seres humanos y animales muestran alteraciones morfológicas y funcionales en diferentes órganos expuestos a la cipermetrina. Los piretroides son sustancias químicas con estructura muy similar a las piretrinas, a menudo más tóxicas para insectos que para mamíferos. Objetivo. La presente investigación analiza las variaciones del estado de diferenciación de las células de Sertoli y de la expresión del receptor de andrógeno en testículos de ratones adultos sanos expuestos experimentalmente a cipermetrina. Material y método. Los animales fueron distribuidos en 3 grupos: control 1 (n= 3) sin tratamiento, control 2 (n = 15) inoculados con 0,1ml de aceite vegetal vía intraperitoneal, y el grupo 3 y experimental (n = 15) inoculados con 1/5 de la dosis letal 50 (LD50= 485mg/kg) de cipermetrina. Resultados. Se observó que la cipermetrina tiene efectos agudos y crónicos sobre las células de Sertoli en el testículo de ratón adulto. Estos efectos se demuestran por el aumento significativo de la altura epitelial, como también por una desdiferenciación de las células de Sertoli a través de la presencia de los filamentos intermedios tipo CK8/18, característico de células en diferenciación, más aun considerando la ciclicidad funcional del compartimiento testicular. Conclusiones. La cipermetrina afecta significativamente a la estructura y la funcionalidad de las células de Sertoli, a través del citoesqueleto y el estado de maduración (AU)

Chronic exposure to anabolic androgenic steroids alters neuronal function in the mammalian forebrain via androgen receptor- and estrogen receptor-mediated mechanisms.

Anabolic androgenic steroids (AAS) can promote detrimental effects on social behaviors for which GABA type A (GABA(A)) receptor-mediated circuits in the forebrain play a critical role. While all AAS bind to androgen receptors (AR), they may also be aromatized to estrogens and thus potentially impart effects via estrogen receptors (ER). Chronic exposure of wild-type male mice to a combination of chemically distinct AAS increased action potential (AP) frequency, selective GABA(A) receptor subunit mRNAs, and GABAergic synaptic current decay in the medial preoptic area (mPOA). Experiments performed with pharmacological agents and in AR-deficient Tfm mutant mice suggest that the AAS-dependent enhancement of GABAergic transmission in wild-type mice is AR-mediated. In AR-deficient mice, the AAS elicited dramatically different effects, decreasing AP frequency, spontaneous IPSC amplitude and frequency and the expression of selective GABA(A) receptor subunit mRNAs. Surprisingly, in the absence of AR signaling, the data indicate that the AAS do not act as ER agonists, but rather suggest a novel in vivo action in which the AAS inhibit aromatase and impair endogenous ER signaling. These results show that the AAS have the capacity to alter neuronal function in the forebrain via multiple steroid signaling mechanisms and suggest that effects of these steroids in the brain will depend not only on the balance of AR- versus ER-mediated regulation for different target genes, but also on the ability of these drugs to alter steroid metabolism and thus the endogenous steroid milieu.