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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

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.

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)-1β 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. Cancer Prev Res; 7(6); 574–84. ©2014 AACR.

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

A sensitive broadband molecular line survey of the Sagittarius B2(N) star-forming region has been obtained with the HIFI instrument on the Herschel Space Observatory, offering the first high-spectral resolution look at this well-studied source in a wavelength region largely inaccessible from the ground (625-157 um). From the roughly 8,000 spectral features in the survey, a total of 72 isotopologues arising from 44 different molecules have been identified, ranging from light hydrides to complex organics, and arising from a variety of environments from cold and diffuse to hot and dense gas. We present an LTE model to the spectral signatures of each molecule, constraining the source sizes for hot core species with complementary SMA interferometric observations, and assuming that molecules with related functional group composition are cospatial. For each molecule, a single model is given to fit all of the emission and absorption features of that species across the entire 480-1910 GHz spectral range, accounting for multiple temperature and velocity components when needed to describe the spectrum. As with other HIFI surveys toward massive star forming regions, methanol is found to contribute more integrated line intensity to the spectrum than any other species. We discuss the molecular abundances derived for the hot core, where the local thermodynamic equilibrium approximation is generally found to describe the spectrum well, in comparison to abundances derived for the same molecules in the Orion KL region from a similar HIFI survey., Accepted to ApJ. 64 pages, 14 figures. Truncated abstract

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.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.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 (P0.001). Methylation status of miR-203 was significantly associated with microsatellite instability and MLH1 methylation in endometrial tumors (P0.001). Furthermore, hypermethylation of miR-203 was found in endometrioid and clear endometrial subtype tumors, but not in cervical squamous cell and ovarian carcinomas.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.

According to traditional gas-phase chemical models, O2 should be abundant in molecular clouds, but until recently, attempts to detect interstellar O2 line emission with ground- and space-based observatories have failed. Following the multi-line detections of O2 with low abundances in the Orion and rho Oph A molecular clouds with Herschel, it is important to investigate other environments, and we here quantify the O2 abundance near a solar-mass protostar. Observations of O2, at 487 GHz toward a deeply embedded low-mass Class 0 protostar, NGC 1333-IRAS 4A, are presented, using the HIFI instrument on the Herschel Space Observatory. Complementary data of the chemically related NO and CO molecules are obtained as well. The high spectral resolution data are analysed using radiative transfer models to infer column densities and abundances, and are tested directly against full gas-grain chemical models. The deep HIFI spectrum fails to show O2 at the velocity of the dense protostellar envelope, implying one of the lowest abundance upper limits of O2/H2 at, 15 pages, 13 figures, accepted by Astronomy & Astrophysics

The Astrophysical Journal 772.1 (2013): 117, reproduced by permission of the AAS, We present Herschel-HIFI, SPIRE, and PACS 50-670 μm imaging and spectroscopy of six FU Orionis-type objects and candidates (FU Orionis, V1735 Cyg, V1515 Cyg, V1057 Cyg, V1331 Cyg, and HBC 722), ranging in outburst date from 1936 to 2010, from the "FOOSH" (FU Orionis Objects Surveyed with Herschel) program, as well as ancillary results from Spitzer Infrared Spectrograph and the Caltech Submillimeter Observatory. In their system properties (L bol, T bol, and line emission), we find that FUors are in a variety of evolutionary states. Additionally, some FUors have features of both Class I and II sources: warm continuum consistent with Class II sources, but rotational line emission typical of Class I, far higher than Class II sources of similar mass/luminosity. Combining several classification techniques, we find an evolutionary sequence consistent with previous mid-IR indicators. We detect [O I] in every source at luminosities consistent with Class 0/I protostars, much greater than in Class II disks. We detect transitions of 13CO (J up of 5-8) around two sources (V1735 Cyg and HBC 722) but attribute them to nearby protostars. Of the remaining sources, three (FU Ori, V1515 Cyg, and V1331 Cyg) exhibit only low-lying CO, but one (V1057 Cyg) shows CO up to J = 23 → 22 and evidence for H2O and OH emission, at strengths typical of protostars rather than T Tauri stars. Rotational temperatures for "cool" CO components range from 20 to 81 K, for ∼ 1050 total CO molecules. We detect [C I] and [N II] primarily as diffuse emission, The research of J.-E. L. is supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology (No. 2012-044689).

Context. Models of pure gas-phase chemistry in well-shielded regions of molecular clouds predict relatively high levels of molecular oxygen, O-2, and water, H2O. These high abundances imply high cooling rates, leading to relatively short timescales for the evolution of gravitationally unstable dense cores, forming stars and planets. Contrary to expectations, the dedicated space missions SWAS and Odin typically found only very small amounts of water vapour and essentially no O-2 in the dense star-forming interstellar medium.Aims. Only toward rho OphA did Odin detect a very weak line of O-2 at 119 GHz in a beam of size 10 arcmin. The line emission of related molecules changes on angular scales of the order of some tens of arcseconds, requiring a larger telescope aperture such as that of the Herschel Space Observatory to resolve the O-2 emission and pinpoint its origin.Methods. We use the Heterodyne Instrument for the Far Infrared (HIFI) aboard Herschel to obtain high resolution O-2 spectra toward selected positions in the rho Oph A core. These data are analysed using standard techniques for O2 excitation and compared to recent PDR-like chemical cloud models.Results. The N-J = 3(3)-1(2) line at 487.2 GHz is clearly detected toward all three observed positions in the rho Oph A core. In addition, an oversampled map of the 5(4)-3(4) transition at 773.8 GHz reveals the detection of the line in only half of the observed area. On the basis of their ratios, the temperature of the O-2 emitting gas appears to vary quite substantially, with warm gas (greater than or similar to 50 K) being adjacent to a much colder region, of temperatures lower than 30 K.Conclusions. The exploited models predict that the O-2 column densities are sensitive to the prevailing dust temperatures, but rather insensitive to the temperatures of the gas. In agreement with these models, the observationally determined O-2 column densities do not seem to depend strongly on the derived gas temperatures, but fall into the range N(O-2) = 3 to greater than or similar to 6 x 10(15) cm(-2). Beam-averaged O-2 abundances are about 5 x 10(-8) relative to H-2. Combining the HIFI data with earlier Odin observations yields a source size at 119 GHz in the range of 4 to 5 arcmin, encompassing the entire rho Oph A core. We speculate that one of the reasons for the generally very low detection rate of O-2 is the short period of time during which O-2 molecules are reasonably abundant in molecular clouds.

International audience; We report observations of three rotational transitions of molecular oxygen (O2) in emission from the H2 Peak 1 position of vibrationally excited molecular hydrogen in Orion. We observed the 487 GHz, 774 GHz, and 1121 GHz lines using the Heterodyne Instrument for the Far Infrared on the Herschel Space Observatory, having velocities of 11 km s-1 to 12 km s-1 and widths of 3 km s-1. The beam-averaged column density is N(O2) = 6.5 × 1016 cm-2, and assuming that the source has an equal beam-filling factor for all transitions (beam widths 44, 28, and 19''), the relative line intensities imply a kinetic temperature between 65 K and 120 K. The fractional abundance of O2 relative to H2 is (0.3-7.3) × 10-6. The unusual velocity suggests an association with a ~5'' diameter source, denoted Peak A, the Western Clump, or MF4. The mass of this source is ~10 M sun and the dust temperature is >=150 K. Our preferred explanation of the enhanced O2 abundance is that dust grains in this region are sufficiently warm (T >= 100 K) to desorb water ice and thus keep a significant fraction of elemental oxygen in the gas phase, with a significant fraction as O2. For this small source, the line ratios require a temperature >=180 K. The inferred O2 column density sime5 × 1018 cm-2 can be produced in Peak A, having N(H2) ~= 4 × 1024 cm-2. An alternative mechanism is a low-velocity (10-15 km s-1) C-shock, which can produce N(O2) up to 1017 cm-2. Herschel is an ESA space observatory with science instruments provided by European-led Principal Investigator consortia and with important participation from NASA.

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

Berries have been reported to elicit chemopreventive effects in cell culture, in animal model systems and in humans. Bio-fractionation studies indicate that the chemopreventive effects of berries can be ascribed to their component anthocyanins, ellagitannins and compounds in the non-alcohol soluble (fiber) fraction. In the present study, 17 berry-related compounds were evaluated at concentrations ranging from 1- 50 μM for their anti-proliferative effects on cultured human endometrial cancer cell lines (ECC-1, Ishikawa and HEC1A). These compounds include the anthocyanins; cyandin-3-glucoside and cyanidin-3-rutinoside and their metabolite, protocatechuic acid; ellagic acid and its metabolites, urolithins A and B; and three oligosaccharides, four short-chain carboxylic acids and four lignans present in the fiber fraction. Cell proliferation assays indicated that urolithin A was the most effective inhibitor of the growth of all three endometrial cancer cell lines. Cell cycle analysis by flow cytometry revealed that urolithin A induced cell cycle arrest at the G2/M phase. This was associated with up-regulation of the protein expression of cyclins B1 and E2, p21, phospho-cdc2 and myt1 as determined by western blot analysis. Endometrial cells depend on progesterone to limit cellular growth because it is antagonistic to estrogen-mediated cell proliferation. It is of importance therefore, that urolithin A was found to reduce estrogen receptor alpha and induce progesterone receptor expression in all three cell lines. In summary, our findings suggest that urolithin A may be chemopreventive for endometrial cancer through modulating genes that control the G2/M phase of the cell cycle and that regulate steroid receptor expression. This research was supported, in part, by MCW Startup Funds to Y-W Huang. Citation Format: Yi-Wen Huang, Chieh-Ti Kuo, Jibran Siddiqui, Jo-Hsin Chen, Chung-Wai Shiau, Gary D. Stoner. Chemoprevention of endometrial cancer with urolithin A, a metabolite of berry ellagitannins. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3674. doi:10.1158/1538-7445.AM2013-3674