ABSTRACT
Lower urinary tract symptoms (LUTS) are highly prevalent, and their treatment is mainly focused on the control of symptoms. Histamine intolerance (HIT) has been related to a variety of systemic symptoms. DAO deficiency has been identified as a significant factor contributing to histamine intolerance (HIT). Preclinical evidence indicates the involvement of histamine in the lower urinary tract. This study aimed to assess the prevalence of diamine oxidase deficiency (DAO) in a prospective cohort of 100 patients with at least moderate LUTS. A genetic study of four single nucleotide polymorphisms (SNPs) (c.-691G>T, c.47C>T, c.995C>T, and c.1990C>G) was performed. HIT was found in 85.9% of patients. The prevalence of at least one minor allele in the SNPs analyzed was 88%, without gender differences. Storage symptoms were more intense in the presence of HIT as well as asthenia and neurological and musculoskeletal symptoms. The presence of minor alleles of the AOC1 gene was associated with a higher intensity of symptoms. Minor alleles from c.-691G>T and c.47C>T SNPs were also associated with a greater severity of obstructive symptoms. Thirty-one percent of patients presented the four SNPS with at least one associated minor allele. The relationship between HIT and LUTS in a mixed population of men and women found in this study supports further investigations to define the pathophysiology of histamine in LUTS.
ABSTRACT
The androgen-signaling axis plays a pivotal role in the pathogenesis of prostate cancer. Since the landmark discovery by Huggins and Hodges, gonadal depletion of androgens has remained a mainstay of therapy for advanced disease. However, invariably progression to castration-resistant prostate cancer (CRPC) occurs within 2-3 years of initiation of ADT. Multiple mechanisms of resistance help contribute to the progression to castration resistant disease, and the androgen receptor (AR) remains an important driver in this progression. Molecular mechanisms behind AR reactivation in CRPC include AR gene amplification and overexpression, AR mutations, expression of constitutively active AR variants, intratumoral and adrenal androgen synthesis and promiscuous AR activation by other factors. Other AR-independent resistance mechanisms, including activation of glucocorticoid receptor, impairment of DNA repair pathways, immune-mediated resistance, neuroendocrine differentiation and microRNA expression, are also discussed. Castration-resistant prostate cancer is a complicated disease, characterized by multiple resistance mechanisms to androgen deprivation treatment, and it remains an incurable disease. An understanding of the mechanisms underlying this resistance is necessary to identify future therapeutic targets as well as the identification and validation of novel predictive biomarkers of resistance; they may lead to improved therapeutics for mCRPC patients.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Humans , Male , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/etiology , Receptors, Androgen/genetics , Receptors, Androgen/physiologyABSTRACT
El eje de señalización de andrógenos desempeña un papel fundamental en la patogénesis del cáncer de próstata. Desde el descubrimiento histórico de Huggins y Hodges, la depleción androgénica permanece como la piedra angular en el tratamiento de la enfermedad avanzada. Sin embargo, de forma invariable, la progresión a cáncer de próstata resistente a la castración se produce dentro de los 2-3 años posteriores al inicio de la terapia de deprivación androgénica (TDA). Múltiples mecanismos de resistencia ayudan a la progresión a la enfermedad resistente a la castración, y el receptor de andrógenos (RA) sigue siendo un impulsor importante en esta progresión. Los mecanismos moleculares que subyacen a la reactivación del RA en el cáncer de próstata resistente a la castración (CPRC) incluyen la amplificación y sobreexpresión del RA, mutaciones del RA, expresión de variantes constitutivamente activas del RA, síntesis de andrógenos intratumorales y suprarrenales y activación promiscua del RA por otros factores. También se discuten otros mecanismos de resistencia independientes del RA, que incluyen la activación del receptor de glucocorticoides, la alteración de las vías de reparación del ADN, la resistencia mediada por mecanismos inmunes, la diferenciación neuroendocrina y la expresión de microARN. El cáncer de próstata resistente a la castración es una enfermedad compleja, se caracteriza por múltiples mecanismos de resistencia al tratamiento de deprivación de andrógenos, y sigue siendo una enfermedad incurable. La comprensión de los mecanismos que subyacen a esta resistencia es necesaria para identificar objetivos terapéuticos futuros, así como la identificación y validación de nuevos biomarcadores predictivos de resistencia, lo que puede conducir a una mejora terapéutica para pacientes con CPRC
The androgen-signaling axis plays a pivotal role in the pathogenesis of prostate cancer. Since the landmark discovery by Huggins and Hodges, gonadal depletion of androgens has remained a mainstay of therapy for advanced disease. However, invariably progression to castration-resistant prostate cancer (CRPC) occurs within 2-3 years of initiation of ADT. Multiple mechanisms of resistance help contribute the progression to castration resistant disease, and the androgen receptor (AR) remains an important driver in this progression. Molecular mechanisms behind AR reactivation in CRPC include AR gene amplification and overexpression, AR mutations, expression of constitutively active AR variants, intratumoral and adrenal androgen synthesis and promiscuous AR activation by other factors. Other AR-independent resistance mechanisms, including activation of glucocorticoid receptor, impairment of DNA repair pathways, immune-mediated resistance, neuroendocrine differentiation and microRNA expression, are also discussed. Castration-resistant prostate cancer is a complicated disease, characterized by multiple resistance mechanisms to androgen deprivation treatment, and it remains an incurable disease. An understanding of the mechanisms underlying this resistance is necessary to identify future therapeutic targets as well as the identification and validation of novel predictive biomarkers of resistance; they may lead to improved therapeutics for mCRPC patients
