Leptin Induces Epigenetic Regulation of Transient Receptor Potential Melastatin 7 in Rat Adrenal Pheochromocytoma Cells.

Obesity elevates the plasma level of leptin, which has been associated with hypertension. Our recent studies in mice demonstrated that leptin increases blood pressure by activating the carotid sinus nerve, which transmits the chemosensory input from carotid bodies (CBs) to the medullary centers, and that the effect of leptin is mediated via Trpm7 (TRP [transient receptor potential] melastatin 7) channels in CB glomus cells. We also found that Trpm7 overexpression and Trpm7 promoter demethylation in CBs correlate positively with the hyperleptinemia and leptin receptor overexpression in CBs. Hence, we postulated that leptin epigenetically regulates Trpm7 expression in CBs. We addressed our hypothesis by using rat adrenal pheochromocytoma (PC12) cells as a model of CB glomus cells. PC12 cells expressing LEPRb (long, active form of leptin receptor) showed dramatic induction of the promoter activity and expression of Trpm7 upon leptin treatment. The increased Trpm7 expression coincided with the reduction of CpG site-specific methylation and trimethylation of H3K27 (H3 [histone 3] K27 [lysine 27]) and the increase of acetylation of H3K27 and trimethylation of H3K4 (H3 lysine 4) at the Trpm7 promoter. The inhibitor of STAT3 (signal transducer and activator of transcription 3) signaling, SD1008, reversed the leptin-induced Trpm7 promoter activity via modulations of the binding of pSTAT3 (phosphorylated STAT3) and DNMT3B (DNA methyltransferase 3B) and modifications of H3K27 and H3K4 at the Trpm7 promoter. Our results suggest that leptin-activated pSTAT3 epigenetically regulates the transcription of Trpm7 through DNA methylation and histone modifications. Because epigenetic changes are reversible, targeting epigenetic modifications of Trpm7 may serve as a new therapeutic approach for the treatment of hypertension in obesity.

End-of-Life Characteristics Associated With Short Hospice Length of Stay for Patients With Solid Tumors Enrolled in Phase I Clinical Trials.

BACKGROUND: Patients participating in phase I trials represent a population with advanced cancer and symptoms, with quality-of-life implications arising from both disease and treatment. Transitions to end-of-life care for these patients have received little attention. Good empirical data are needed to better understand the role of advance care planning and palliative care during phase I trial transitions. We investigated how physician-patient communication at the time of disease progression, patient characteristics, and patterns of care were associated with end-of-life care. METHODS: We conducted a retrospective chart review of all patients with solid tumors enrolled in phase I trials at a comprehensive cancer center from January 2015 to December 2017. We captured physician-patient communication during disease progression. Among patients who died, we assessed palliative care referral, advance care planning, place of death, healthcare use in the final month of life, hospice enrollment, and hospice length of stay (LOS). Factors independently associated with a short hospice LOS (defined as ≤3 days) were estimated from a multivariable model building approach. RESULTS: Among 207 participants enrolled in phase I intervention studies at Johns Hopkins Hospital, the median age was 61 years (range, 31-91 years), 48% were women, 21% were members of racial minority groups, and 41.5% were referred from an outside institution. At the time of disease progression, 53% had goals of care documented, 47% were previously referred to palliative care, and 41% discussed hospice with their oncologist. A total of 82% of decedents died within 1 year of study enrollment, and 85% enrolled in hospice. Among the 147 participants who enrolled in hospice, 22 (15%) had a short LOS (≤3 days). Factors independently associated with an increased risk of short hospice LOS in the multivariable model included age >65 years (odds ratio [OR], 1.12; 95% CI, 1.01-1.24; P=.04), whereas remaining at the same institution (OR, 0.72; 95% CI, 0.65-0.80; P<.001) and referral to palliative care before progression (OR, 0.83; 95% CI, 0.75-0.92; P<.001) were associated with a decreased risk of short hospice LOS. CONCLUSIONS: Reported data support the benefit of palliative care for patients in phase I trials and the risks associated with healthcare transitions for all patients, particularly older adults, regardless of care received. Leaving a clinical trial is a time when clear communication is paramount. Phase I studies will continue to be vital in advancing cancer treatment. It is equally important to advance the support provided to patients who transition off these trials.

PSMA Theranostics: Review of the Current Status of PSMA-Targeted Imaging and Radioligand Therapy.

Prostate-specific membrane antigen (PSMA) has been the subject of extensive investigation in the past two decades as a promising molecular target for prostate cancer (PCa). Its appealing molecular features have enabled the development of a novel diagnostic and therapeutic-thus "theranostic"-approach to PCa. There is now substantial evidence of the high sensitivity of PSMA-targeted imaging for PCa lesions and growing evidence of the therapeutic efficacy of PSMA radioligand therapy for metastatic castration-resistant prostate cancer. This article presents a broad overview of the current status of PSMA theranostics, including current evidence, potential clinical impact, and active areas of research.

The impact of integrated disease management in high-risk COPD patients in primary care.

Patients with chronic obstructive pulmonary disease (COPD) have a reduced quality of life (QoL) and exacerbations that drive health service utilization (HSU). A majority of patients with COPD are managed in primary care. Our objective was to evaluate an integrated disease management, self-management, and structured follow-up intervention (IDM) for high-risk patients with COPD in primary care. This was a one-year multi-center randomized controlled trial. High-risk, exacerbation-prone COPD patients were randomized to IDM provided by a certified respiratory educator and physician, or usual physician care. IDM received case management, self-management education, and skills training. The primary outcome, COPD-related QoL, was measured using the COPD Assessment Test (CAT). Of 180 patients randomized from 8 sites, 81.1% completed the study. Patients were 53.6% women, mean age 68.2 years, post-bronchodilator FEV1 52.8% predicted, and 77.4% were Global Initiative for Obstructive Lung Disease Stage D. QoL-CAT scores improved in IDM patients, 22.6 to 14.8, and worsened in usual care, 19.3 to 22.0, adjusted difference 9.3 (p < 0.001). Secondary outcomes including the Clinical COPD Questionnaire, Bristol Knowledge Questionnaire, and FEV1 demonstrated differential improvements in favor of IDM of 1.29 (p < 0.001), 29.6% (p < 0.001), and 100 mL, respectively (p = 0.016). Compared to usual care, significantly fewer IDM patients had a severe exacerbation, -48.9% (p < 0.001), required an urgent primary care visit for COPD, -30.2% (p < 0.001), or had an emergency department visit, -23.6% (p = 0.001). We conclude that IDM self-management and structured follow-up substantially improved QoL, knowledge, FEV1, reduced severe exacerbations, and HSU, in a high-risk primary care COPD population. Clinicaltrials.gov NCT02343055.