The androgen receptor (AR) signaling axis plays a critical role in the development, function and homeostasis of the prostate. The classical action of AR is to regulate gene transcriptional processes via AR nuclear translocation, binding to androgen response elements on target genes and recruitment of, or crosstalk with, transcription factors. Prostate cancer initiation and progression is also uniquely dependent on AR. Androgen deprivation therapy remains the standard of care for treatment of advanced prostate cancer. Despite an initial favorable response, almost all patients invariably progress to a more aggressive, castrate-resistant phenotype. Considerable evidence now supports the concept that development of castrate-resistant prostate cancer (CRPC) is causally related to continued transactivation of AR. Understanding the critical events and complexities of AR signaling in the progression to CRPC is essential in developing successful future therapies. This review provides a synopsis of AR structure and signaling in prostate cancer progression, with a special focus on recent findings on the role of AR in CRPC. Clinical implications of these findings and potential directions for future research are also outlined.

Among the several changes that occur in the aged brain is an increase in the concentration of the proinflammatory cytokine interleukin-1␤ that is coupled with a deterioration in cell function. This study investigated the possibility that treatment with the polyunsaturated fatty acid eicosapentaenoic acid might prevent interleukin-1␤-induced deterioration in neuronal function. Assessment of four markers of apoptotic cell death, cytochrome c translocation, caspase-3 activation, poly-(ADP-ribose) polymerase cleavage, and terminal dUTP nick-end staining, revealed an age-related increase in each of these measures, and the evidence presented indicates that treatment of aged rats with eicosapentaenoate reversed these changes as well as the accompanying increases in interleukin-1␤ concentration and p38 activation. The data are consistent with the idea that activation of p38 plays a significant role in inducing the changes described since interleukin-1␤-induced activation of cytochrome c translocation and caspase-3 activation in cortical tissue in vitro were reversed by the p38 inhibitor SB203580. The age-related increases in interleukin-1␤ concentration and p38 activation in cortex were mirrored by similar changes in hippocampus. These changes were coupled with an age-related deficit in long term potentiation in perforant path-granule cell synapses, while eicosapentaenoate treatment was associated with reversal of age-related changes in interleukin-1␤ and p38 and with restoration of long term potentiation. Increased expression of the proinflammatory cytokine interleukin-1␤ (IL-1␤)1 has been linked with neurodegenerative disorders like Down's syndrome, Alzheimer's disease, and Parkinson's disease (1, 2). Consistent with the view that IL-1␤ plays a role in deterioration of cell function are the findings that IL-1␤ expression is increased, in parallel with cell damage, in experimental models of ischemia (3), excitotoxicity (4), and traumatic lesions (5). Indeed, IL-1␤ has been shown to trigger cell death in primary cultures of human fetal neurons (6) and inhibition of caspase-1, which leads to formation of active IL-1␤, and blocks lipopolysaccharide-induced changes in cell morphology, which are consistent with cell death (7).IL-1␤ has been shown to stimulate the mitogen-activated protein kinases p38 and c-Jun NH 2 -terminal kinase (8, 9), and activation of both c-Jun NH 2 -terminal kinase (10, 11) and p38 (10, 12-16) has been closely linked with apoptotic cell death. Significantly, an increase in p38 activity has been coupled with apoptotic changes in Alzheimer's disease (17, 18). Concomitant increases in IL-1␤ concentration and p38 activity have been reported in the aged rat brain (19 -21); in hippocampus these changes are correlated with compromised synaptic function and with an age-related impairment in long term potentiation (LTP) (19 -22), while consistent with the high expression of IL-1␤ and IL-1RI in hippocampus is the finding that the cytokine depresses LTP in dentate gyrus (8,19,20,23,24). Significantly, we have ...

Background The emergence of the coronavirus disease (COVID-19) pandemic in March 2020 created unprecedented challenges in the provision of scheduled ambulatory cancer care. As a result, there has been a renewed focus on video-based telehealth consultations as a means to continue ambulatory care. Objective The aim of this study is to analyze the change in video visit volume at the University of California, San Francisco (UCSF) Comprehensive Cancer Center in response to COVID-19 and compare patient demographics and appointment data from January 1, 2020, and in the 11 weeks after the transition to video visits. Methods Patient demographics and appointment data (dates, visit types, and departments) were extracted from the electronic health record reporting database. Video visits were performed using a HIPAA (Health Insurance Portability and Accountability Act)-compliant video conferencing platform with a pre-existing workflow. Results In 17 departments and divisions at the UCSF Cancer Center, 2284 video visits were performed in the 11 weeks before COVID-19 changes were implemented (mean 208, SD 75 per week) and 12,946 video visits were performed in the 11-week post–COVID-19 period (mean 1177, SD 120 per week). The proportion of video visits increased from 7%-18% to 54%-72%, between the pre– and post–COVID-19 periods without any disparity based on race/ethnicity, primary language, or payor. Conclusions In a remarkably brief period of time, we rapidly scaled the utilization of telehealth in response to COVID-19 and maintained access to complex oncologic care at a time of social distancing.

Exposure to irradiation leads to detrimental changes in several cell types. In this study we assessed the changes induced in hippocampus by exposure of rats to whole body irradiation; the findings reveal that irradiation leads to apoptotic cell death in hippocampus, and as a consequence, long term potentiation in perforant path-granule cell synapses is markedly impaired. The evidence is consistent with the view that irradiation induced an increase in reactive oxygen species and that this leads to stimulation of the stress-activated protein kinase, JNK, and activation of the transcription factor, c-Jun. Consequent upon activation of JNK, a cascade of cell signaling events was stimulated that ultimately resulted in apoptosis, as suggested by parallel increases in cytochrome c translocation, caspase-3 activation, poly-(ADP-ribose) polymerase cleavage, and terminal dUTP nick-end labeling staining. Treatment of rats with eicosapentaenoic acid inhibited the irradiation-induced increase in reactive oxygen species production and the subsequent cellular signaling events, suggesting that oxidative stress triggered apoptotic cell death in the hippocampus of rats exposed to irradiation. Significantly, when the compromise in cell viability induced by irradiation was prevented by eicosapentaenoic acid, long term potentiation was sustained in a manner similar to that in the sham-treated control group.

Purpose Spliced variant forms of androgen receptor (AR-Vs) have been identified recently in castration-resistant prostate cancer (CRPC) cell lines and clinical samples. We identified the cistrome and gene signature of AR-Vs in CRPC cell lines and determined the clinical significance of AR-Vs regulated genes. Materials and Methods The CRPC cell line 22Rv1, which expresses both full length androgen receptor (AR-FL) and AR-Vs endogenously, was used as the research model. We established 22Rv1-ARFL−/ARVs+ and 22Rv1- ARFL−/ARVs− through RNA interference. ChIP-seq and microarray techniques were used to identify cistrome and gene expression profiles of AR-Vs in the absence of androgen. Results AR-Vs binding sites were identified in 22Rv1-ARFL−/ARVs+. A set of genes was found to be regulated uniquely by AR-Vs, but not by full-length AR in the absence of androgen. Integrated analysis revealed that some genes are modulated by AR-Vs directly. Unsupervised clustering analysis showed that the AR-Vs gene signature can differentiate not only benign from malignant prostate tissue, but also localized prostate cancer from metastatic CRPC specimens. Some genes that were modulated uniquely by AR-Vs also correlated with histological grade and biochemical failure. Conclusions We conclude that AR-Vs can bind to DNA independently of full-length AR in the absence of androgen and modulate a unique set of genes that is not regulated by AR-FL. The AR-Vs gene signature correlates with disease progression, and distinguishes between primary cancer and CRPC specimens, as well as benign and malignant prostate specimens.

IMPORTANCE Active surveillance (AS) is now recognized as the preferred management option for most low-risk prostate cancers to minimize risks of overtreatment. Despite increasing use of AS in the US, wide regional variability has been observed, and these regional variations in contemporary practice have not been well described.OBJECTIVE To explore variations between county and Surveillance, Epidemiology, and End Results (SEER) regions in AS in the US. DESIGN, SETTING, AND PARTICIPANTSA cohort study using the SEER Prostate with Watchful Waiting (WW) database linked to the County Area Health Resource File for detailed county-level demographics and physician distribution data was conducted from January 2010 to December 2015. Analysis was performed in October 2020. A total of 79 825 men with clinically localized, low-risk prostate cancer eligible for AS or WW were included. EXPOSURES Multiple patient-, county-, and SEER region-level factors, including age, year of diagnosis, county-level densities of urologists, radiation oncologists, primary care physicians, and SEER registry region. MAIN OUTCOMES AND MEASURESUse of AS or WW as the initial reported treatment strategy were noted. Hierarchical mixed-effect logistic regression models were used to evaluate clustered random regional variation on use of AS or WW. Temporal trends by year in proportions of initial treatment type, as well as county-level local variation, were also estimated.

Eicosapentaenoic acid (EPA) protects hippocampus from age-related and irradiation-induced changes that lead to impairment in synaptic function; the evidence suggests that this is due to its anti-inflammatory effects, specifically preventing changes induced by the proinflammatory cytokine, interleukin-1b . In this study, we have investigated the possibility that EPA may prevent the effects of lipopolysaccharide (LPS) administration, which have been shown to lead to deterioration of synaptic function in rat hippocampus. The data indicate that treatment of hippocampal neurones with EPA abrogated the LPS-induced increases in phosphorylation of the mitogen-activated protein kinase, c-Jun N-terminal kinase (JNK), the transcription factor, c-Jun and the mitochondrial protein, Bcl-2. In parallel, we report that intraperitoneal administration of LPS to adult rats increases phosphorylation of JNK, c-Jun and Bcl-2 in hippocampal tissue and that these changes are coupled with increased IL-1b concentration. Treatment of rats with EPA abrogates these effects and also blocks the LPS-induced impairment in longterm potentiation in perforant path-granule cell synapses that accompanies these changes. We propose that the neuroprotective effect of EPA may be dependent on its ability to inhibit the downstream consequences of JNK activation.

Total glans resurfacing is a viable and acceptable option for glans preservation in patients with localized penile cancer. It demonstrates acceptable functional and oncologic outcomes. We believe that total glans resurfacing should be considered in all cases of localized penile cancer.