Androgen receptor signaling regulates the transcriptome of prostate cancer cells by modulating global alternative splicing

Androgen receptor (AR), is a transcription factor and a member of a hormone receptor superfamily. AR plays a vital role in the progression of prostate cancer and is a crucial target for therapeutic interventions. While the majority of advanced-stage prostate cancer patients will initially respond to the androgen deprivation, the disease often progresses to castrate-resistant prostate cancer (CRPC). Interestingly, CRPC tumors continue to depend on hyperactive AR signaling and will respond to potent second-line antiandrogen therapies, including bicalutamide (CASODEX®) and enzalutamide (XTANDI®). However, the progression-free survival rate for the CRPC patients on antiandrogen therapies is only 8–19 months. Hence, there is a need to understand the mechanisms underlying CRPC progression and eventual treatment resistance. Here, we have leveraged next-generation sequencing and newly developed analytical methodologies to evaluate the role of AR signaling in regulating the transcriptome of prostate cancer cells. The genomic and pharmacologic stimulation and inhibition of AR activity demonstrates that AR regulates alternative splicing within cancer-relevant genes. Furthermore, by integrating transcriptomic data from in vitro experiments and in prostate cancer patients, we found that a significant number of AR-regulated splicing events are associated with tumor progression. For example, we found evidence for an inadvertent AR-antagonist-mediated switch in IDH1 and PL2G2A isoform expression, which is associated with a decrease in overall survival of patients. Mechanistically, we discovered that the epithelial-specific splicing regulators (ESRP1 and ESRP2), flank many AR-regulated alternatively spliced exons. And, using 2D invasion assays, we show that the inhibition of ESRPs can suppress AR-antagonist-driven tumor invasion. Our work provides evidence for a new mechanism by which AR alters the transcriptome of prostate cancer cells by modulating alternative splicing. As such, our work has important implications for CRPC progression and development of resistance to treatment with bicalutamide and enzalutamide

A Controversy That Has Been Tough to Swallow: Is the Treatment of Achalasia Now Digested?

Esophageal achalasia is a rare neurodegenerative disease of the esophagus and the lower esophageal sphincter that presents within a spectrum of disease severity related to progressive pathological changes, most commonly resulting in dysphagia. The pathophysiology of achalasia is still incompletely understood, but recent evidence suggests that degeneration of the postganglionic inhibitory nerves of the myenteric plexus could be due to an infectious or autoimmune mechanism, and nitric oxide is the neurotransmitter affected. Current treatment of achalasia is directed at palliation of symptoms. Therapies include pharmacological therapy, endoscopic injection of botulinum toxin, endoscopic dilation, and surgery. Until the late 1980s, endoscopic dilation was the first line of therapy. The advent of safe and effective minimally invasive surgical techniques in the early 1990s paved the way for the introduction of laparoscopic myotomy. This review will discuss the most up-to-date information regarding the pathophysiology, diagnosis, and treatment of achalasia, including a historical perspective. The laparoscopic Heller myotomy with partial fundoplication performed at an experienced center is currently the first line of therapy because it offers a low complication rate, the most durable symptom relief, and the lowest incidence of postoperative gastroesophageal reflux

A critical review and development of a conceptual model of exclusion from social relations for older people

Social exclusion is complex and dynamic, and it leads to the non-realization of social, economic, political or cultural rights or participation within a society. This critical review takes stock of the literature on exclusion of social relations. Social relations are defined as comprising social resources, social connections and social networks. An evidence review group undertook a critical review which integrates, interprets and synthesizes information across studies to develop a conceptual model of exclusion from social relations. The resulting model is a subjective interpretation of the literature and is intended to be the starting point for further evaluations. The conceptual model identifies individual risks for exclusion from social relations (personal attributes, biological and neurological risk, retirement, socio-economic status, exclusion from material resources and migration). It incorporates the evaluation of social relations, and the influence of psychosocial resources and socioemotional processes, sociocultural, social-structural, environmental and policy contextual influences on exclusion from social relations. It includes distal outcomes of exclusion from social relations, that is, individual well-being, health and functioning, social opportunities and social cohesion. The dynamic relationships between elements of the model are also reported. We conclude that the model provides a subjective interpretation of the data and an excellent starting point for further phases of conceptual development and systematic evaluation(s). Future research needs to consider the use of sophisticated analytical tools and an interdisciplinary approach in order to understand the underlying biological and ecopsychosocial associations that contribute to individual and dynamic differences in the experience of exclusion from social relation