An Overview of Epigenetic Changes in the Parkinson's Disease Brain.

Parkinson's disease is a progressive neurodegenerative disorder, predominantly of the motor system. Although some genetic components and cellular mechanisms of Parkinson's have been identified, much is still unknown. In recent years, emerging evidence has indicated that non-DNA-sequence variation (in particular epigenetic mechanisms) is likely to play a crucial role in the development and progression of the disease. Here, we present an up-to-date overview of epigenetic processes including DNA methylation, DNA hydroxymethylation, histone modifications and non-coding RNAs implicated in the brain of those with Parkinson's disease. We will also discuss the limitations of current epigenetic research in Parkinson's disease, the advantages of simultaneously studying genetics and epigenetics, and putative novel epigenetic therapies.

Socioeconomic factors associated with uptake and satisfaction with a post-hospitalization meals benefit in Medicare Advantage.

BACKGROUND: Kaiser Permanente Southern California began offering a 4-week supplemental benefit of home-delivered meals to Medicare Advantage members after discharge from a hospitalization for heart failure and other medical conditions in 2021. The purpose of this study is to explore the associations between socioeconomic disadvantage and food insecurity with patient uptake of and satisfaction with the meals. METHODS: Data for this cross-sectional study were drawn from survey and electronic medical record data for members referred for the meals benefit (n = 6169) and linked to a hospitalization encounter (n = 2254) between January and December 2021. Uptake was assessed using vendor records; measures of socioeconomic status included the neighborhood deprivation index (NDI) and prior receipt of medical financial assistance (MFA) from the health system. Patients were invited to complete an email or phone survey about their satisfaction with the meals and food insecurity. Multivariable log-binomial regression models were used to examine the association between socioeconomic disadvantage and food insecurity with meals uptake and satisfaction. RESULTS: Sixty-two percent of patients referred for the benefit accepted the meals (mean age: 79 ± 9, 59% people of color). While there was no significant relationship between NDI and meals uptake (RR: 0.99, 95% CI: 0.92-1.07, p = 0.77), patients who received prior MFA were more likely to accept the meals (RR: 1.09, 95% CI: 1.02-1.16, p < 0.01). Sixty-nine percent of patients who completed the survey (23% response rate) reported that meals were very or extremely helpful. Patients with food insecurity (29% of survey respondents) were more likely to report that the meals were helpful for their recovery compared to food secure patients (RR: 1.21, 95% CI: 1.09-1.35, p < 0.01). CONCLUSIONS: The home-delivered meals appeared to be particularly utilized by and helpful to patients with greater financial strain and/or food insecurity, suggesting that supplemental benefits could be more targeted toward addressing unmet needs of vulnerable adults.

Development and Characterisation of a New Patient-Derived Xenograft Model of AR-Negative Metastatic Castration-Resistant Prostate Cancer.

As the treatment landscape for prostate cancer gradually evolves, the frequency of treatment-induced neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer (DNPC) that is deficient for androgen receptor (AR) and neuroendocrine (NE) markers has increased. These prostate cancer subtypes are typically refractory to AR-directed therapies and exhibit poor clinical outcomes. Only a small range of NEPC/DNPC models exist, limiting our molecular understanding of this disease and hindering our ability to perform preclinical trials exploring novel therapies to treat NEPC/DNPC that are urgently needed in the clinic. Here, we report the development of the CU-PC01 PDX model that represents AR-negative mCRPC with PTEN/RB/PSMA loss and CTNN1B/TP53/BRCA2 genetic variants. The CU-PC01 model lacks classic NE markers, with only focal and/or weak expression of chromogranin A, INSM1 and CD56. Collectively, these findings are most consistent with a DNPC phenotype. Ex vivo and in vivo preclinical studies revealed that CU-PC01 PDX tumours are resistant to mCRPC standard-of-care treatments enzalutamide and docetaxel, mirroring the donor patient's treatment response. Furthermore, short-term CU-PC01 tumour explant cultures indicate this model is initially sensitive to PARP inhibition with olaparib. Thus, the CU-PC01 PDX model provides a valuable opportunity to study AR-negative mCRPC biology and to discover new treatment avenues for this hard-to-treat disease.