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PDF file - 52KB, This table includes the primer sequences used for the qPCR analysis done in this study.

Background Life-long 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 potentially have lower risk on decline in renal function than warfarin. The aim of this study was to examine the renal outcomes among rivaroxaban, edoxaban, dabigatran and warfarin. Method Using a clinical database from a single-center, this cohort study identified 2203 adults with AF who started anticoagulation therapy between July 1, 2013 and December 31, 2020. Inverse probability of treatment weighting was adopted to balance baseline characteristics among four groups. The primary outcome was a composite of cardiorenal outcomes, involving ≥ 30% decline in estimated glomerular filtration rate (eGFR), renal failure, cardiovascular death, and renal death. Other renal outcomes of interest including ≥ 30% decline in eGFR, doubling of serum creatinine, the incidence of acute kidney injury (AKI) and renal failure, were analyzed. Result We studied 595 patients on warfarin, who were compared to 244, 1070 and 289 patients on dabigatran, rivaroxaban and edoxaban, respectively. After propensity score weighting, dabigatran was associated with significantly lower risk of ≥ 30% decline in eGFR (hazard ratio [HR]: 0.69; 95% confidence interval [CI]: 0.497 to 0.951; p = 0.0237), doubling of serum creatinine (HR:0.49; 95% CI: 0.259 to 0.927; p = 0.0282), and the composite of cardiorenal outcomes (HR:0.67; 95% CI: 0.485 – 0.913; p = 0.0115) compared with warfarin. Rivaroxaban and edoxaban did not show statistically significant protective effects on any renal outcomes, compared to warfarin. Conclusion In this retrospective, single center study, patients treated with dabigatran had significantly reduced risk of decline in renal function and cardiorenal events, when compared to those treated with warfarin. In contrast, rivaroxaban and edoxaban were not associated with lower risk of AKI and renal failure when compared to warfarin.

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

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.

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 IL1β 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. Cancer Immunol Res; 4(1); 72–82. ©2015 AACR.

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 17β-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.

cope 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 ERβ, 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.

We report observations of molecular oxygen (O$_2$) rotational transitions at 487 GHz, 774 GHz, and 1121 GHz toward Orion Peak A. The O2 lines at 487 GHz and 774 GHz are detected at velocities of 10-12 km/s with line widths 3 km/s; however, the transition at 1121 GHz is not detected. The observed line characteristics, combined with the results of earlier observations, suggest that the region responsible for the O$_2$ emission is 9" (6e16 cm) in size, and is located close to the H2 Peak 1position (where vibrationally-excited H$_2$ emission peaks), and not at Peak A, 23" away. The peak O2 column density is 1.1e18/cm2. The line velocity is close to that of 621 GHz water maser emission found in this portion of the Orion Molecular Cloud, and having a shock with velocity vector lying nearly in the plane of the sky is consistent with producing maximum maser gain along the line-of-sight. The enhanced O$_2$ abundance compared to that generally found in dense interstellar clouds can be explained by passage of a low-velocity C-shock through a clump with preshock density 2e4/cm3, if a reasonable flux of UV radiation is present. The postshock O$_2$ can explain the emission from the source if its line of sight dimension is ~10 times larger than its size on the plane of the sky. The special geometry and conditions required may explain why O$_2$ emission has not been detected in the cores of other massive star-forming molecular clouds., 28 pages, 13 figures

Black raspberries (BRBs) and their component anthocyanins have been evaluated for chemopreventive potential against colorectal cancer. Because the anthocyanins are not well absorbed, more attention is being focused on protocatechuic acid (PCA), a metabolite of BRB anthocyanins produced by gut microflora. It has been known for some time that PCA exhibits preventative effects on the development of colorectal cancer in rodents. Metabolic reprograming which refers to altered nutrient uptake and use is thought to be essential for rapid cancer cell proliferation. Primary bile acids (BAs) are synthesized in the liver from the metabolism of cholesterol via cholesterol 7 alpha-hydroxylase (CYP7A1), a microsomal cytochrome p450 enzyme. The majority of primary bile acids are recycled through enterohepatic circulation, and a small fraction is further metabolized to cytotoxic secondary bile acids by intestinal anaerobic bacteria. Bile acids (BAs), especially secondary BAs, have been reported as the major dietary-related risk factor in colon carcinogenesis. The present study determined if BRBs influence the development of dysplastic lesions in the colon of ApcMin mice and whether this is associated with changes in the diversity of gut bacteria and bile acid metabolism. Diets containing 5% BRBs, 500 ppm PCA or 1000 ppm PCA significantly decreased numbers of dysplastic lesions in the small intestine and colon of Min mice. 5% BRBs significantly increased lactobacillus in feces; 500 ppm PCA but not 1000 ppm PCA, significantly increased numbers of fecal bifidobacteria and lactobacillus. Metabolomic analysis showed that BRBs significantly increase cholate in plasma of the Min mice, suggesting that BRBs increased cholesterol metabolism. Further, PCA and BRBs did not alter mRNA expression of BAs-activated receptors (FXR and VDR) and their target genes (Shp, FGF15 and IBABP). In addition, PCA and BRBs significantly decreased mRNA expression of Cyclin D1 in small intestine of the Min mice. Changes in bile acid metabolism could affect fat absorption and subsequently impact fatty acid metabolism. 5% BRB diet significantly increased levels of anti-inflammatory polyunsaturated fatty acids (PUFAs; eicosapentaenoate (EPA; 20:5n3) and docosahexaenoate (DHA; 22:6n3) in the plasma. Studies are ongoing to investigate if BRBs and PCA affect the activity of CYP7A1 in the liver. In conclusion, our results suggest for the first time that one of BRBs and PCA's chemopreventive and anti-inflammatory mechanisms is through its ability to alter gut bacteria and bile acid metabolism. Supported by R01 CA148818 to L-S Wang Citation Format: Chieh-Ti Kuo, Hsin-Tzu Wang, Jo-Hsin Chen, Jibran Siddiqui, Matthew R. Young, Shakir Saud, Gary Stoner, Li-Shu Wang. Black raspberries and protocatechuic acid protectively alter gut bacteria and bile acid metabolism in ApcMin/+ mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2134. doi:10.1158/1538-7445.AM2014-2134

Endometrial cancer is the most common type of gynecologic cancer and annually comprises 3% of all cancer deaths of women in the United States. Additionally, ∼80% of cases are type I endometrial cancer, mainly associated with Pten abnormalities. It was estimated that up to 90% of type I endometrial cancer patients are overweight/obese. Therefore, a regimen to prevent obesity associated tumorigenesis is the most important for type I endometrial cancer. In the current study, the Pten heterozygous (+/-) female mice were used as the model, to study the potentially chemopreventive effects by black raspberries (BRBs). At 3-4 weeks old, Pten (+/-) and wild type female mice were divided into four treatment groups, fed with either AIN-93G control diet (CD), CD with 5% BRBs, 58% fat to induce obesity (HF),or HF with 5% BRBs. All of mice were euthanized at 28 weeks old. In wild type mice, no malignant lesion was identified. In Pten (+/-) mice, HF diet increased 10% focal glandular hyperplasia with atypia lesions when compared with CD diet. Dietary administration of BRBs decreased 19% focal glandular hyperplasia with atypia lesions when compared with CD group. Specifically, BRBs in HF diet inhibited 32% obesity-induced endometrial malignant lesions and significantly lowed lesion multiplicity. Furthermore, cytokine profiles in plasma by Bio-Plex Assay revealed dietary BRBs decreased IL-1β and IL-17A, and lowed TNF-α and GM-CSF when compared with CD and HF group, respectively. In conclusion, this study for the first time suggested BRBs are chemopreventive for obesity-induced endometrial tumorigenesis. Citation Format: Jo-Hsin Chen, Irene Aguilera-Barrantes, Chieh-Ti Kuo, Leena Hilakivi-Clarke, Gary D. Stoner, Janet S. Rader, Yi-Wen Huang. Chemopreventive effects of black raspberries in endometrial cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2150. doi:10.1158/1538-7445.AM2014-2150