p38 MAPK Inhibition Mitigates Hypoxia-Induced AR Signaling in Castration-Resistant Prostate Cancer.

BACKGROUND: Aberrant androgen receptor (AR) signaling is a major driver of castration-resistant prostate cancer (CRPC). Tumor hypoxia increases AR signaling and is associated with treatment resistance in prostate cancer. Heat shock protein 27 (Hsp27) is a molecular chaperone that is activated in response to heat shock and hypoxia. Hsp27 has previously been reported to facilitate AR nuclear translocation in a p38 mitogen-activated protein kinase (MAPK) dependent manner in castration-sensitive prostate cancer cell lines. Here, we evaluated the potential for inhibiting p38 MAPK/Hsp27 mediated AR signaling under normoxia and hypoxia in experimental models of CRPC. METHODS: We inhibited p38 MAPK with SB203580 in prostate cancer cell lines and measured Hsp27 phosphorylation, AR activity, cell proliferation, and clonogenicity under normoxia and hypoxia. AR activity was measured using an androgen response element driven reporter assay and qPCR to measure expression of AR target genes. Xenograft-bearing mice were treated with SB203580 to measure tumor growth and serum prostate specific antigen (PSA). RESULTS: Our results indicate that p38 MAPK and Hsp27 are activated under normoxia and hypoxia in response to androgens in CRPC cells. p38 MAPK inhibition diminished Hsp27 activation and the hypoxia-mediated increase in AR activity. Additionally, inhibition of p38 MAPK activity decreased proliferation and survival of CRPC cells in vitro and prolonged the survival of tumor-bearing mice. CONCLUSIONS: These results suggest that p38 MAPK inhibition may represent a therapeutic strategy to disrupt AR signaling in the heterogeneous CRPC tumor microenvironment.

Predictors of participant nonadherence in lung cancer screening programs: a systematic review and meta-analysis.

The low nonadherence rates reported by large low-dose computed tomography (LDCT) lung cancer screening trials were not necessarily replicated outside of trial conditions. This systematic review and meta-analysis identified predictors of participant nonadherence to returning for annual LDCT screening. The systematic review protocol was registered at PROSPERO (CRD42019118347). MEDLINE, EMBASE, CINAHL, AgeLine, grey literature sources, and reference lists of included studies were searched until March 1st, 2020. Primary research articles were eligible for inclusion if they screened current or former smokers using LDCT as their primary screening modality and reported on participant demographics or programmatic interventions that predicted nonadherence. Risk of bias assessment was performed at both study and outcome levels. The primary outcome was predictors of nonadherence. The secondary outcomes were relative risks (RR) of second round nonadherence based on identified predictors, which were calculated using random-effects meta-analyses. Across 13 included studies (total n = 15,790; range: 157-3642), the overall rate of nonadherence was 28% (95% CI: 20-37%). Studies identified greater nonadherence in participants younger than 60 or older than 74, with longer travel distances to screening centers, and having a low risk perception of lung cancer. Meta-analyses identified higher nonadherence in community-based compared to academic-based programs, but this did not reach significance (32% versus 27%; p = 0.32). Current smokers were more likely to be nonadherent compared to former smokers (RR 1.23, 95% CI: 1.09-1.40; p < 0.01) while white participants were less likely nonadherent compared to non-white participants (RR 0.69, 95% CI: 0.60-0.81; p < 0.0001). No differences existed between male and female participants (RR 0.99, 95% CI: 0.85-1.15; p = 0.85). Programmatic interventions, including dedicated program coordinators, reminder calls/letters, and mobile LDCT scanners reduced nonadherence in lung cancer screening programs. These interventions should be targeted/tailored toward the subpopulations with the highest nonadherence rates.

Suicide epigenetics, a review of recent progress.

BACKGROUND: Suicide results in over 800,000 deaths every year, making it a major public health concern worldwide. It is highly complex, with genetic and environmental influences. Epigenetic mechanisms, including DNA methylation, miRNA, and histone modifications, could explain the complex interplay of environmental risk factors with genetic risk factors in the emergence of suicidal behavior. METHODS: Here, we review the literature on suicide epigenetics over the past 10 years. RESULTS: There has been significant progress in the field of suicide epigenetics, with emerging findings in the brain-derived neurotrophic factor and hypothalamic-pituitary-adrenal axis genes. LIMITATIONS: Studying patient subgroups is needed in order to extract more comparable and reproducible epigenetic findings in suicide. CONCLUSIONS: It is crucial to consider suicidal patients or suicide victims' distal and proximal past history e.g., early-life adversity and psychiatric disorder in epigenetic studies of suicidality.