Cardiac and renal outcomes of direct oral anticoagulants in patients with atrial fibrillation.

BACKGROUND: Oral anticoagulation therapy with warfarin or direct oral anticoagulants (DOACs) is the mainstay for stroke prevention in patients with non-valvular atrial fibrillation (AF). The DOACs might have a lower risk of declining renal function than warfarin. This study aimed to compare renal outcomes among rivaroxaban, edoxaban, dabigatran, and warfarin. METHOD: This cohort study identified 2203 adults with AF who started anticoagulation therapy between 1 July 2013 and 31 December 2020, in a clinical database at a single centre. Inverse probability of treatment weighting was adopted to balance baseline characteristics among four anticoagulants treatment groups. The primary outcome was a composite of cardiac and renal outcomes, involving a ≥30% decline in estimated glomerular filtration rate (eGFR), renal failure and cardiovascular death. RESULTS: After propensity score weighting, dabigatran was associated with significantly lower risks of a ≥30% decline in eGFR (hazard ratio [HR]: .69, 95% confidence interval [CI]: .497-.951, p = .0237), doubling of the serum creatinine level (HR: .49, 95% CI: .259-.927, p = .0282) and the cardiac and renal outcome composite (HR: .67, 95% CI: .485-.913, p = .0115) than warfarin. Rivaroxaban and edoxaban did not show significant protective effects on renal outcomes compared to warfarin. CONCLUSION: In this study, patients treated with dabigatran had significantly reduced risks of declining renal function and composite cardiac and renal events than those treated with warfarin. However, rivaroxaban and edoxaban were not associated with lower risks of any renal outcomes than warfarin. More studies are warranted to investigate and compare the impact of renal function between different DOACs in patients with AF.

A qualitative study on the development of pharmacist-managed clinics in Taiwan.

WHAT IS KNOWN AND OBJECTIVE: Pharmacist-managed clinics (PMCs) are established to solve drug-related problems and enhance the quality of care of ambulatory patients. Although the benefits of such services have been demonstrated, little is known about PMC operations, especially outside the United States. The aim of this study was to explore how PMCs were established and to discuss implementation issues of PMCs in Taiwan. METHODS: A purposive sample of pharmacists, pharmacy administrators and physicians involved with PMCs was recruited from hospitals of varying scales across Taiwan. Semi-structured, individual interviews were conducted to understand the perceptions of the clinical service of PMCs. Interviews were transcribed verbatim and analysed by thematic analysis to find underlying themes. RESULTS: A total of 12 pharmacists, 5 pharmacy administrators and 3 physicians from 8 institutions were interviewed. Pharmacists spent 4 to 20 h per week at PMCs, and the practice experiences of PMC ranged from 1 to 6 years. PMCs have been provided in these institutions for 4 to 11 years with an average volume of 28 h and 25 patient visits weekly. Study participants described influential factors in establishing PMCs, including clinical expertise, attitude towards patient care and trust building with collaborating physicians. Operational concerns in implementing PMCs included role clarifications, manpower shortage, inadequate advanced training or certification, regulatory issues and a lack of service promotion. WHAT IS NEW AND CONCLUSION: This research broadens the understanding of operating PMC services and reveals key requirements and concerns regarding the care model, which can be useful for other countries. Resolving perceived barriers and collecting other stakeholders' perspectives may reinforce the integration of PMCs into patient care in the future.

miR-137 is a tumor suppressor in endometrial cancer and is repressed by DNA hypermethylation.

Endometrial cancer is the most common gynecological cancer in the United States. We wanted to identify epigenetic aberrations involving microRNAs (miRNAs), whose genes become hypermethylated in endometrial primary tumors. By integrating known miRNA sequences from the miRNA database (miRBase) with DNA methylation data from methyl-CpG-capture sequencing, we identified 111 differentially methylated regions (DMRs) associated with CpG islands (CGIs) and miRNAs. Among them, 22 DMRs related to 29 miRNAs and within 8 kb of CGIs were hypermethylated in endometrial tumors but not in normal endometrium. miR-137 was further validated in additional endometrial primary tumors. Hypermethylation of miR-137 was found in both endometrioid and serous endometrial cancer (P < 0.01), and it led to the loss of miR-137 expression. Treating hypermethylated endometrial cancer cells with epigenetic inhibitors reactivated miR-137. Moreover, genetic overexpression of miR-137 suppressed cancer cell proliferation and colony formation in vitro. When transfected cancer cells were implanted into nude mice, the cells that overexpressed miR-137 grew more slowly and formed smaller tumors (P < 0.05) than vector transfectants. Histologically, xenograft tumors from cancer cells expressing miR-137 were less proliferative (P < 0.05), partly due to inhibition of EZH2 and LSD1 expression (P < 0.01) in both the transfected cancer cells and tumors. Reporter assays indicated that miR-137 targets EZH2 and LSD1. These results suggest that miR-137 is a tumor suppressor that is repressed in endometrial cancer because the promoter of its gene becomes hypermethylated.

Hypermethylation of miR-203 in endometrial carcinomas.

OBJECTIVES: Aberrant expression of SOX4 in endometrial cancer has been identified and partially was contributed to hypermethylation of miR-129-2. Other miRNAs are suspected to influence SOX 4 as well. The current study seeks to identify other hypermethylated miRNAs that regulate SOX4 in endometrial carcinomas. METHODS: Methylation levels of miRNA promoter regions were measured by combined bisulfite restriction analysis (COBRA) and pyrosequencing assays. Gene expression was determined by RT-qPCR. Methylation level of a miRNA locus was corrected with clinicopathologic factors for 252 gynecological specimens. RESULTS: In silico analysis identified 13 miRNA loci bound on the 3'-UTR of SOX4. Using COBRA assays, increased methylation of miR-203, miR-219-2, miR-596, and miR-618 was detected in endometrial cancer cells relative to those seen in a normal cell line and in normal endometrium. Transfection of a miR-203 mimic decreased SOX4 gene expression. Hypermethylation of miR-203 was detected in 52% of type I endometrioid endometrial carcinomas (n=131) but was not seen in any of 10 uninvolved normal endometria (P<0.001). Methylation status of miR-203 was significantly associated with microsatellite instability and MLH1 methylation in endometrial tumors (P<0.001). Furthermore, hypermethylation of miR-203 was found in endometrioid and clear endometrial subtype tumors, but not in cervical squamous cell and ovarian carcinomas. CONCLUSIONS: Hypermethylation of miR-203 is a frequent event in endometrial carcinomas and is strongly associated with microsatellite instability and MLH1 methylation status. Thus, miR-203 methylation level might represent a marker for patients with endometrioid and clear endometrial sub-cancers.

Living with Parkinson's disease: disease and medication experiences of patients and caregivers.

PURPOSE: Symptoms and medication use in patients with Parkinson's disease (PD) affect the quality of life of patients and caregivers, yet prior research seldom focused on their experiences with medications. This study explored comprehensive living and medication experience from patients with PD and their caregivers. METHODS: Patients diagnosed with PD for ≥2 years, with or without their caregivers, were recruited from an outpatient clinic in Taiwan. Semi-structured in-depth interviews were conducted based on the Common Sense Model. A qualitative content analysis was used to identify salient themes from verbatim transcripts. RESULTS: In total, 15 patients and eight caregivers were interviewed. Five themes were derived: (1) symptoms and help-seeking behaviours before a diagnosis, (2) emotional impacts and life adaptations after a PD diagnosis, (3) life affected by medications, (4) experiences of caregivers in taking care of PD patients, and (5) communication between doctors and patients. CONCLUSIONS: Patients frequently adjusted their daily schedules to live with PD and the medication side effects. Caregivers struggle to overcome caring burdens and to stay positive to support patients. More attention on providing medication information, mental support, and communication between stakeholders is needed to improve the quality of life of patients and caregivers.

Preventive Effects by Black Raspberries of Endometrial Carcinoma Initiation and Promotion Induced by a High-Fat Diet.

SCOPE: The chemopreventive effects of black raspberries (BRBs) have not been studied in endometrial tumorigenesis. Here, they are examined in a mouse model of endometrial cancer. METHODS AND RESULTS: Wild-type and Pten heterozygous (+/-) female mice are weaned at 3 weeks and fed with four AIN-93G diets: 93G; 93G+5% BRBs powder; high-fat (HF); and HF+5% BRBs. Body weight and diet consumption are recorded weekly until the mice are euthanized at 28 weeks of age. Mice fed with HF diets are found to significantly gain body weight over time. BRBs are not found to affect the development of obesity. Mice in the HF+BRBs group consume less food than the HF-only mice. HF+BRBs diets suppress uterine tumor initiation and promotion more than the HF-only diet by inhibiting cell proliferation. It also reduces HF-induced levels of plasma leptin and 17ß-estradiol (E2). Urolithin A, a metabolite of BRBs, suppresses cell proliferation induced by leptin and E2. CONCLUSION: BRBs are preventive in HF-mediated uterine tumorigenesis because they suppress cell growth and plasma leptin and E2 levels.

Urolithin A suppresses the proliferation of endometrial cancer cells by mediating estrogen receptor-α-dependent gene expression.

SCOPE: Obese and overweight women are at high risk of developing endometrial cancer; indeed, many of endometrial cancer patients are obese. The increased number and size of adipocytes due to obesity elevate levels of circulating estrogens that stimulate cell proliferation in the endometrium. However, black raspberries are a promising approach to preventing endometrial cancer. METHODS AND RESULTS: We examined 17 black raspberry constituents and metabolites (10 µM or 10 µg/mL, 48 h) for their ability to prevent endometrial cancer cells from proliferating. Urolithin A (UA) was most able to suppress proliferation in a time- and dose-dependent manner (p < 0.05). It arrested the G2/M phase of the cell cycle by upregulating cyclin-B1, cyclin-E2, p21, phospho-cdc2, and CDC25B. UA also acted as an estrogen agonist by modulating estrogen receptor-α (ERα) dependent gene expression in ER-positive endometrial cancer cells. UA enhanced the expression of ERß, PGR, pS2, GREB1 while inhibiting the expression of ERα and GRIP1. Coincubating UA-treated cells with the estrogen antagonist ICI182,780 abolished UA's estrogenic effects. Knocking down ERα suppressed PGR, pS2, and GREB gene expression but increased GRIP1 expression. Thus, UA's actions appear to be mediated through ERα. CONCLUSION: This study suggests that UA modulates ERα-dependent gene expression, thereby inhibiting endometrial cancer proliferation.

Dietary Consumption of Black Raspberries or Their Anthocyanin Constituents Alters Innate Immune Cell Trafficking in Esophageal Cancer.

Freeze-dried black raspberries (BRB), their component anthocyanins (AC), and a metabolite of BRB ACs, protocatechuic acid (PCA), inhibit the development of esophageal cancer in rats induced by the carcinogen, N-nitrosomethylbenzylamine (NMBA). All three components reduce inflammation in the esophagus and in plasma. The present study determined the relation of changes in inflammatory markers to infiltration of innate immune cells into NMBA-treated esophagus. Rats were injected with NMBA (0.35 mg/kg) for 5 weeks while on control diet. Following NMBA treatment, rats were fed diets containing 6.1% BRB powder, an AC-rich fraction of BRBs (3.8 µmol/g), or 500 ppm PCA. At weeks 15, 25, and 35, inflammatory biomarker expression in the plasma and esophagus was quantified, and infiltration of immune cells in the esophagus was examined. At all three time points, BRB, AC, and PCA similarly affected cytokine production in the esophagus and plasma of NMBA-treated rats, relative to the NMBA-only control. These included decreased expression of the proinflammatory cytokine IL1ß and increased expression of the anti-inflammatory cytokine IL10. Moreover, all three diets also increased the expression of IL12, a cytokine that activates both cytolytic natural killer and CD8(+) T cells. In addition, the three diets also decreased infiltration of both macrophages and neutrophils into the esophagus. Overall, our results suggest that another mechanism by which BRBs, ACs, and PCA inhibit NMBA-induced esophageal tumorigenesis is by altering cytokine expression and innate immune cell trafficking into tumor tissues.

Chemoprevention of esophageal cancer with black raspberries, their component anthocyanins, and a major anthocyanin metabolite, protocatechuic acid.

Diets containing either freeze-dried black raspberries (BRBs) or their polyphenolic anthocyanins (ACs) have been shown to inhibit the development of N-nitrosomethylbenzylamine (NMBA)-induced esophageal cancer in rats. The present study was conducted to determine whether PCA, a major microbial metabolite of black raspberry (BRB) ACs, also prevents NMBA-induced esophageal cancer in rats. F344 rats were injected with NMBA three times a week for 5 weeks and then fed control or experimental diets containing 6.1% BRBs, an anthocyanin (AC)-enriched fraction derived from BRBs, or protocatechuic acid (PCA). Animals were exsanguinated at weeks 15, 25, and 35 to quantify the development of preneoplastic lesions and tumors in the esophagus, and to relate this to the expression of inflammatory biomarkers. At weeks 15 and 25, all experimental diets were equally effective in reducing NMBA-induced esophageal tumorigenesis, as well as in reducing the expression of pentraxin-3 (PTX3), a cytokine produced by peripheral blood mononuclear cells in response to interleukin (IL)-1ß and TNF-α. All experimental diets were also active at reducing tumorigenesis at week 35; however, the BRB diet was significantly more effective than the AC and PCA diets. Furthermore, all experimental diets inhibited inflammation in the esophagus via reducing biomarker (COX-2, iNOS, p-NF-κB, and sEH) and cytokine (PTX3) expression. Overall, our data suggest that BRBs, their component ACs, and PCA inhibit NMBA-induced esophageal tumorigenesis, at least in part, by their inhibitory effects on genes associated with inflammation.