Atypical squamous cells in urine cytology are associated with a significant risk of high-grade malignancy.

BACKGROUND: Atypical squamous cells (ASC) in urine cytology are rarely found, and their clinical significance is not well studied. Previous studies were limited by a small number of cases and a lack of objective grading of ASC and/or their correlation with accompanying urothelial cell abnormality (UCA). METHODS: The institutional database was searched over 10 years for urine cytology reports containing ASC or from patients who had a concurrent diagnoses of high-grade (HG) urothelial carcinoma with squamous differentiation or squamous carcinoma. ASC were defined as keratinized squamous cells and were subcategorized as reactive, koilocytosis, low-grade (LG) atypia, and HG atypia. Correlations with age, sex, specimen type, accompanying UCA, number of ASC, and the risk of HG malignancy (ROHM) were assessed. RESULTS: ASC were present in 0.15% of all urine specimens (123 of 81,018). Slides and clinical follow-up were available on 91 patients (median age, 71 years). LG and HG squamous atypia had ROHMs of 70% and 92%, respectively. ASC accompanied and not accompanied by UCA had ROHMs of 37% and 94%, respectively. Most malignancies (34 of 67; 51%) showed rare ASC in urine. Reactive changes and koilocytosis had 0% ROHM. CONCLUSIONS: ASC in urine cytology is a significant finding and is associated with a high ROHM. In the absence of accompanying UCA, LG squamous atypia had a lower ROHM than HG atypia. In the presence of UCA, LG and HG squamous atypia had ROHMs of over 90%. These findings suggest that ASC and their grade of atypia should be noted in the cytology report, and clinicians should be made aware of their clinical significance.

Rare Cause of Gastrointestinal Bleeding: A Case Report of Pancreatic Arteriovenous Malformation.

BACKGROUND Arteriovenous malformation is an unusual cause of gastrointestinal bleeding, particularly in the pancreas. A definitive treatment strategy is not yet established. CASE REPORT We present the case of a 37-year-old man with underlying hypertension and no significant family history who presented with a 3-month history of intermittent epigastric pains and unintentional weight loss of 5 kg in 2 months. The upper endoscopy showed a large duodenal ulcer, which was uncontrolled with a standard dose of proton pump inhibitors. An abdominal computed tomography scan with contrast was indicated and revealed an enhanced mass of 2.5×3.5×4 cm in size, located on the second and third parts of the duodenum and head of the pancreas, indicating an arteriovenous malformation. On day 10 of hospitalization, the patient suddenly had melena and a drop of hemoglobin level to 5.6 g/dL; angiography intervention was successful to control the bleeding. However, gastrointestinal bleeding recurred after 2 weeks, and the patient successfully underwent a Whipple procedure. CONCLUSIONS The diagnosis and therapeutic management of arteriovenous malformations are uniquely challenging; therefore, pancreatic arteriovenous malformations should be listed on the differential diagnosis, particularly in those cases with non-healing and large duodenal ulcers. Otherwise, early imaging modalities should be performed to confirm the diagnosis. In particular, angiography can temporarily control bleeding before proceeding with more definitive therapy.

Purification of Coffee Polyphenols Extracted from Coffee Pulps (Coffee arabica L.) Using Aqueous Two-Phase System.

Coffee pulp is an abundant residue from the coffee industry, but it still contains large amounts of valuable compounds such as polyphenols. The extraction of polyphenols from coffee pulp by the conventional method is accompanied by contaminated compounds. This study, therefore, applied an aqueous two-phase system consisting of different ratios of ethanol/ammonium sulfate to eliminate impurities from coffee-pulp crude extract. The purification efficiency was evaluated via total polyphenol content, antioxidant activity and two major polyphenols in coffee pulps including chlorogenic acid and caffeic acid. Results showed that phenolic compounds mostly predominated in the alcohol-rich phase in which the antioxidant activity was greatly increased after the purification process. Compared to un-purified crude-coffee extract, the antioxidant activity of the purified samples increased approximately 34%, which was assumed to occur due to the slight increase of chlorogenic acid and caffeic acid. Fourier-transform infrared spectroscopy supported the effectiveness of the purification process by eliminating some impurities.

Ectopic adrenal cortical tissue presenting as gastrohepatic ligament "lymph node" diagnosed by fine-needle aspiration: A case report.

Ectopic adrenal cortical tissue has been reported in several locations, most often involving the retroperitoneal fat close to the adrenal gland. The reported cases presenting adjacent or proximal to the stomach are rare and mostly diagnosed on histology. To our knowledge, the cytologic features of ectopic adrenal cortical tissue diagnosed on fine needle aspiration are not well documented in the cytology literature. We describe the cytologic features of ectopic adrenal cortex which initially presented on imaging study as an enlarged gastrohepatic ligament "lymph node" on a patient with gastric signet ring cell carcinoma. The aspirates showed small clusters and cords of uniform cells with abundant vacuolated to densely compact cytoplasm, occasionally stripped nuclei, and delicate frayed cytoplasmic membranes dispersed in a bubbly, vacuolated background. Immunohistochemical stains performed on the corresponding cell block showed these cells were positive for SF-1 and negative for PAX 8. The corresponding biopsy showed similar findings in addition to immunoreactivity to inhibin. Because the cytologic features of ectopic adrenal cortical tissue especially on unusual sites could easily mimic malignant neoplasms, familiarity with the cytologic features in conjunction with immunohistochemical stains are key in arriving at the correct diagnosis and avoiding misdiagnosis.

Arachidin-1, a Prenylated Stilbenoid from Peanut, Enhances the Anticancer Effects of Paclitaxel in Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer (TNBC) is one of the deadliest forms of breast cancer. Investigating alternative therapies to increase survival rates for this disease is essential. To this end, the cytotoxic effects of the prenylated stilbenoids arachidin-1 (A-1) and arachidin-3 (A-3), and non-prenylated resveratrol (RES) were evaluated in human TNBC cell lines as potential adjuvants for paclitaxel (Pac). A-1, alone or in combination with Pac, showed the highest cytotoxicity in TNBC cells. Apoptosis was further evaluated by measuring key apoptosis marker proteins, cell cycle arrest, and intracellular reactive oxygen species (ROS) generation. Furthermore, the cytotoxic effect of A-1 combined with Pac was also evaluated in a 3D spheroid TNBC model. The results showed that A-1 decreased the Pac IC50 approximately 2-fold in TNBC cells. The synergistic combination of A-1 and Pac arrested cells in G2/M phase and activated p53 expression. In addition, the combined treatment increased intracellular ROS generation and induced apoptosis. Importantly, the combination of A-1 with Pac inhibited TNBC spheroid growth. Our results demonstrated that A-1 in combination with Pac inhibited cell proliferation, induced apoptosis through mitochondrial oxidative stress, and reduced TNBC spheroid growth. These findings underscore the impactful effects of the prenylated stilbenoid A-1 as a novel adjuvant for Pac chemotherapy in TNBC treatment.

Multicellular Cell Seeding on a Chip: New Design and Optimization towards Commercialization.

This paper shows both experimental and in-depth theoretical studies (including simulations and analytical solutions) on a microfluidic platform to optimize its design and use for 3D multicellular co-culture applications, e.g., creating a tissue-on-chip model for investigating diseases such as pulmonary arterial hypertension (PAH). A tissue microfluidic chip usually has more than two channels to seed cells and supply media. These channels are often separated by barriers made of micro-posts. The optimization for the structures of these micro-posts and their spacing distances is not considered previously, especially for the aspects of rapid and cost-efficient fabrication toward scaling up and commercialization. Our experimental and theoretical (COMSOL simulations and analytical solutions) results showed the followings: (i) The cell seeding was performed successfully for this platform when the pressure drops across the two posts were significantly larger than those across the channel width. The circular posts can be used in the position of hexagonal or other shapes. (ii) In this work, circular posts are fabricated and used for the first time. They offer an excellent barrier effect, i.e., prevent the liquid and gel from migrating from one channel to another. (iii) As for rapid and cost-efficient production, our computer-aided manufacturing (CAM) simulation confirms that circular-post fabrication is much easier and more rapid than hexagonal posts when utilizing micro-machining techniques, e.g., micro-milling for creating the master mold, i.e., the shim for polymer injection molding. The findings open up a possibility for rapid, cost-efficient, large-scale fabrication of the tissue chips using micro-milling instead of expensive clean-room (soft) lithography techniques, hence enhancing the production of biochips via thermoplastic polymer injection molding and realizing commercialization.

Sirt3 Pharmacologically Promotes Insulin Sensitivity through PI3/AKT/mTOR and Their Downstream Pathway in Adipocytes.

Sirtuin-3 (Sirt3) is a major mitochondrial deacetylase enzyme that regulates multiple metabolic pathways, and its expression is decreased in diabetes type 1 and type 2 diabetes. This study aimed to elucidate Sirt3's molecular mechanism in regulating insulin sensitivity in adipocytes that can contribute to the effort of targeting Sirt3 for the treatment of obesity and type 2 diabetes. We found that the Sirt3 activator honokiol (HNK) induced adipogenesis compared to the control, in contrast to Sirt3 inhibitor, 3-TYP. Accordingly, HNK increased expression of adipocyte gene markers, gene-involved lipolysis and glucose transport (GLUT4), while 3-TYP reduced expression of those genes. Interestingly, 3-TYP caused an increase in gene expression of adipocyte-specific cytokines including IL6, resistin, and TNF-α. However, changes in adipocyte-specific cytokines in HNK treated cells were not significant. In addition, HNK stimulated insulin pathway by promoting insulin receptor beta (IRß) and PI3K/AKT/mTOR pathways, resulting in an increase in phosphorylation of the forkhead family FoxO1/FoxO3a/FoxO4 and glycogen synthase kinase-3 (GSK-3ß), opposing 3-TYP. In line with these findings, HNK increased free fatty acid and glucose uptake, contrary to 3-TYP. In conclusion, Sirt3 activator-HNK induced adipogenesis and lipolysis reduced adipocytes specific cytokines. Intriguingly, HNK activated insulin signaling pathway and increased free fatty acid as well as glucose uptake and transport, in sharp contrast to 3-TYP. These results indicate that, via insulin signaling regulation, Sirt3 activation by HNK improves insulin resistance, while Sirt3 inhibition by 3-TYP might precipitate insulin resistance.

Arachidin-1, a Prenylated Stilbenoid from Peanut, Induces Apoptosis in Triple-Negative Breast Cancer Cells.

Triple-negative breast cancer (TNBC) is unresponsive to typical hormonal treatments, causing it to be one of the deadliest forms of breast cancer. Investigating alternative therapies to increase survival rates for this disease is essential. The goal of this study was to assess cytotoxicity and apoptosis mechanisms of prenylated stilbenoids in TNBC cells. The prenylated stilbenoids arachidin-1 (A-1) and arachidin-3 (A-3) are analogs of resveratrol (RES) produced in peanut upon biotic stress. The anticancer activity of A-1 and A-3 isolated from peanut hairy root cultures was determined in TNBC cell lines MDA-MB-231 and MDA-MB-436. After 24 h of treatment, A-1 exhibited higher cytotoxicity than A-3 and RES with approximately 11-fold and six-fold lower IC50, respectively, in MDA-MB-231 cells, and nine-fold and eight-fold lower IC50, respectively, in MDA-MB-436 cells. A-1 did not show significant cytotoxicity in the non-cancerous cell line MCF-10A. While A-1 blocked cell division in G2-M phases in the TNBC cells, it did not affect cell division in MCF-10A cells. Furthermore, A-1 induced caspase-dependent apoptosis through the intrinsic pathway by activating caspase-9 and PARP cleavage, and inhibiting survivin. In conclusion, A-1 merits further research as a potential lead molecule for the treatment of TNBC.

Epigenetic Mechanisms as Emerging Therapeutic Targets and Microfluidic Chips Application in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a disease that progress over time and is defined as an increase in pulmonary arterial pressure and pulmonary vascular resistance that frequently leads to right-ventricular (RV) failure and death. Epigenetic modifications comprising DNA methylation, histone remodeling, and noncoding RNAs (ncRNAs) have been established to govern chromatin structure and transcriptional responses in various cell types during disease development. However, dysregulation of these epigenetic mechanisms has not yet been explored in detail in the pathology of pulmonary arterial hypertension and its progression with vascular remodeling and right-heart failure (RHF). Targeting epigenetic regulators including histone methylation, acetylation, or miRNAs offers many possible candidates for drug discovery and will no doubt be a tempting area to explore for PAH therapies. This review focuses on studies in epigenetic mechanisms including the writers, the readers, and the erasers of epigenetic marks and targeting epigenetic regulators or modifiers for treatment of PAH and its complications described as RHF. Data analyses from experimental cell models and animal induced PAH models have demonstrated that significant changes in the expression levels of multiple epigenetics modifiers such as HDMs, HDACs, sirtuins (Sirt1 and Sirt3), and BRD4 correlate strongly with proliferation, apoptosis, inflammation, and fibrosis linked to the pathological vascular remodeling during PAH development. The reversible characteristics of protein methylation and acetylation can be applied for exploring small-molecule modulators such as valproic acid (HDAC inhibitor) or resveratrol (Sirt1 activator) in different preclinical models for treatment of diseases including PAH and RHF. This review also presents to the readers the application of microfluidic devices to study sex differences in PAH pathophysiology, as well as for epigenetic analysis.

Sirt3 regulates adipogenesis and adipokine secretion via its enzymatic activity.

The purpose of this research was to identify if Sirt3 plays a role in marrow adipogenesis and adipokines secretion, especially adiponectin using bone marrow-derived stroma (ST2) cell model. Sirt3 overexpression leads to a significant increase in adipogenesis compared to controls. The induction of adipogenesis by Sirt3 is associated with increased gene expression of adipocyte markers as well as adiponectin/adipokines. In sharp contrast, the inhibition of Sirt3 exhibited significantly decreased adipogenesis, adipocyte markers, and adiponectin/adipokines compared to the controls. Interestingly, perilipin 1 (Plin 1) expression was decreased in Sirt3 induction but increased in Sirt3 inhibition. One hundred and fifteen mitochondrial acetylated peptides from 67 mitochondrial proteins had lower levels of acetylation in adipocytes induced by Sirt3 overexpression (Sirt3OE) compared to the control. Of the 67 proteins less enriched in acetylation, 22 acetylated proteins were decreased by more than twofold. These proteins are considered potential Sirt3 substrates in adipogenesis. In conclusion, Sirt3 has a novel, important role in modulating adipogenesis and adiponectin/adipokine expression. The connection axis among Sirt3-adipogenesis-adipokines was linked to its substrates by mass spectrometry analysis. These findings contribute to the efforts of revealing Sirt3 functions and Sirt3 usage as a potential target for treatment of metabolic homeostasis and diseases including type 2 diabetes.

Renal malakoplakia mimicking a malignancy and diagnosed by fine-needle aspiration: A case report.

Malakoplakia is a rare, granulomatous disease that affects a wide variety of organs and can have a clinical and radiographic presentation resembling that of malignancy. The genitourinary tract is the most commonly involved site. There are scant reported cases presenting as a locally advanced renal mass and even rarer, diagnosed by fine-needle aspiration (FNA) cytology. We report clinical, imaging, cytologic, and histological findings of an interesting case of malakoplakia initially diagnosed by FNA cytology. We also briefly review the literature and emphasize the importance of recognizing this entity when encountered in an aspirate material, which can help mitigate the diagnostic confusion of malakoplakia for clinicians.

Catalytic Asymmetric Carbene Transfer Reactions of Diazo Oxime Ethers with Olefins and Their Synthetic Applications.

The first catalytic asymmetric cyclopropanation of diazo oxime ethers with olefins was developed. In the presence of a Ru(II)-Pheox catalyst, various optically active cyclopropyl oxime derivatives were obtained in high yields (up to 99%) with high enantioselectivities (up to 98% ee). Furthermore, optically active cyclopropyl oxime ethers could be successfully converted into the corresponding cyclopropyl methylamine derivatives via metal hydride and Grignard reagent mediated Beckmann rearrangement, which are potential candidates for the assessment of biological and pharmaceutical activities.

Association between in-hospital guideline adherence and postdischarge major adverse outcomes of patients with acute coronary syndrome in Vietnam: a prospective cohort study.

OBJECTIVE: We aimed to determine the association between physician adherence to prescribing guideline-recommended medications during hospitalisation and 6-month major adverse outcomes of patients with acute coronary syndrome in Vietnam. DESIGN: Prospective cohort study. SETTING: The study was carried out in two public hospitals in Vietnam between January and October 2015. Patients were followed for 6 months after discharge. PARTICIPANTS: Patients who survived during hospitalisation with a discharge diagnosis of acute coronary syndrome and who were eligible for receiving at least one of the four guideline-recommended medications. EXPOSURES: Guideline adherence was defined as prescribing all guideline-recommended medications at both hospital admission and discharge for eligible patients. Medications were antiplatelet agents, beta-blockers, ACE inhibitors or angiotensin II receptor blockers and statins. MAIN OUTCOME MEASURE: Six-month major adverse outcomes were defined as all-cause mortality or hospital readmission due to cardiovascular causes occurring during 6 months after discharge. Cox regression models were used to estimate the association between guideline adherence and 6-month major adverse outcomes. RESULTS: Overall, 512 patients were included. Of those, there were 242 patients (47.3%) in the guideline adherence group and 270 patients (52.3%) in the non-adherence group. The rate of 6-month major adverse outcomes was 30.5%. A 29% reduction in major adverse outcomes at 6 months after discharge was found for patients of the guideline adherence group compared with the non-adherence group (adjusted HR, 0.71; 95% CI, 0.51 to 0.98; p=0.039). Covariates significantly associated with the major adverse outcomes were percutaneous coronary intervention, prior heart failure and renal insufficiency. CONCLUSIONS: In-hospital guideline adherence was associated with a significant decrease in major adverse outcomes up to 6 months after discharge. It supports the need for improving adherence to guidelines in hospital practice in low-income and middle-income countries like Vietnam.

Sirtuin-3 Promotes Adipogenesis, Osteoclastogenesis, and Bone Loss in Aging Male Mice.

Sirtuin-3 (Sirt3) is an essential metabolic regulatory enzyme that plays an important role in mitochondrial metabolism, but its role in bone marrow and skeletal homeostasis remains largely unknown. In this study, we hypothesize that increased expression of Sirt3 plays a role in skeletal aging. Using mice that overexpress Sirt3 [i.e., Sirt3 transgenic (Sirt3Tg)], we show that Sirt3 is a positive regulator of adipogenesis and osteoclastogenesis and a negative regulator of skeletal homeostasis. Sirt3Tg mice exhibited more adipocytes in the tibia compared with control mice. Bone marrow stromal cells (BMSCs) from Sirt3Tg mice displayed an enhanced ability to differentiate into adipocytes compared with control BMSCs. We found a 2.5-fold increase in the number of osteoclasts on the bone surface in Sirt3Tg mice compared with control mice (P < 0.03), and increased osteoclastogenesis in vitro. Importantly, Sirt3 activates the mechanistic target of rapamycin (mTOR) pathway to regulate osteoclastogenesis. Sirt3Tg male mice exhibited a significant reduction in cortical thickness at the tibiofibular junction (P < 0.05). In summary, Sirt3 activity in bone marrow cells is associated with increased adipogenesis, increased osteoclastogenesis through activation of mTOR signaling, and reduced bone mass. Interestingly, Sirt3 expression in bone marrow cells increases during aging, suggesting that Sirt3 promotes age-related adipogenesis and osteoclastogenesis associated with bone loss. These findings identify Sirt3 as an important regulator of adipogenesis and skeletal homeostasis in vivo and identify Sirt3 as a potential target for the treatment of osteoporosis.

Osteoblast-derived FGF9 regulates skeletal homeostasis.

FGF9 has complex and important roles in skeletal development and repair. We have previously observed that Fgf9 expression in osteoblasts (OBs) is regulated by G protein signaling and therefore the present study was done to determine whether OB-derived FGF9 was important in skeletal homeostasis. To directly test this idea, we deleted functional expression of Fgf9 gene in OBs using a 2.3kb collagen type I promoter-driven Cre transgenic mouse line (Fgf9OB-/-). Both Fgf9 knockout (Fgf9OB-/-) and the Fgf9 floxed littermates (Fgf9fl/fl) mice were fully backcrossed and maintained in an FBV/N background. Three month old Fgf9OB-/- mice displayed a significant decrease in cancellous bone and bone formation in the distal femur and a significant decrease in cortical thickness at the TFJ. Strikingly, female Fgf9OB-/- mice did not display altered bone mass. Continuous treatment of mouse BMSCs with exogenous FGF9 inhibited mouse BMSC mineralization while acute treatment increased the proliferation of progenitors, an effect requiring the activation of Akt1. Our results suggest that mature OBs are an important source of FGF9, positively regulating skeletal homeostasis in male mice. Osteoblast-derived FGF9 may serve a paracrine role to maintain the osteogenic progenitor cell population through activation of Akt signaling.

Anti-Citrullinated Protein Antibodies Are Associated With Neutrophil Extracellular Traps in the Sputum in Relatives of Rheumatoid Arthritis Patients.

OBJECTIVE: Studies suggest that rheumatoid arthritis (RA)-related autoimmunity is initiated at a mucosal site. However, the factors associated with the mucosal generation of this autoimmunity are unknown, especially in individuals who are at risk of future RA. Therefore, we tested anti-cyclic citrullinated peptide (anti-CCP) antibodies in the sputum of RA-free first-degree relatives (FDRs) of RA patients and patients with classifiable RA. METHODS: We evaluated induced sputum and serum samples from 67 FDRs and 20 RA patients for IgA anti-CCP and IgG anti-CCP, with cutoff levels for positivity determined in a control population. Sputum was also evaluated for cell counts, neutrophil extracellular traps (NETs) using sandwich enzyme-linked immunosorbent assays for protein/nucleic acid complexes, and total citrulline. RESULTS: Sputum was positive for IgA and/or IgG anti-CCP in 14 of 20 RA patients (70%) and 17 of 67 FDRs (25%), including a portion of FDRs who were serum anti-CCP negative. In the FDRs, elevations of sputum IgA and IgG anti-CCP were associated with elevated sputum cell counts and NET levels. IgA anti-CCP was associated with ever smoking and with elevated sputum citrulline levels. CONCLUSION: Anti-CCP is elevated in the sputum of FDRs, including seronegative FDRs, suggesting that the lung may be a site of anti-CCP generation in this population. The association of anti-CCP with elevated cell counts and NET levels in FDRs supports a hypothesis that local airway inflammation and NET formation may drive anti-CCP production in the lung and may promote the early stages of RA development. Longitudinal studies are needed to follow the evolution of these processes relative to the development of systemic autoimmunity and articular RA.

Molecular Level Characterization of the Structure and Interactions in Peptide-Functionalized Metal-Organic Frameworks.

We use density functional theory, newly parameterized molecular dynamics simulations, and last generation 15 N dynamic nuclear polarization surface enhanced solid-state NMR spectroscopy (DNP SENS) to understand graft-host interactions and effects imposed by the metal-organic framework (MOF) host on peptide conformations in a peptide-functionalized MOF. Focusing on two grafts typified by MIL-68-proline (-Pro) and MIL-68-glycine-proline (-Gly-Pro), we identified the most likely peptide conformations adopted in the functionalized hybrid frameworks. We found that hydrogen bond interactions between the graft and the surface hydroxyl groups of the MOF are essential in determining the peptides conformation(s). DNP SENS methodology shows unprecedented signal enhancements when applied to these peptide-functionalized MOFs. The calculated chemical shifts of selected MIL-68-NH-Pro and MIL-68-NH-Gly-Pro conformations are in a good agreement with the experimentally obtained 15 N NMR signals. The study shows that the conformations of peptides when grafted in a MOF host are unlikely to be freely distributed, and conformational selection is directed by strong host-guest interactions.

Dynamic interplay between locus-specific DNA methylation and hydroxymethylation regulates distinct biological pathways in prostate carcinogenesis.

BACKGROUND: Despite the significant global loss of DNA hydroxymethylation marks in prostate cancer tissues, the locus-specific role of hydroxymethylation in prostate tumorigenesis is unknown. We characterized hydroxymethylation and methylation marks by performing whole-genome next-generation sequencing in representative normal and prostate cancer-derived cell lines in order to determine functional pathways and key genes regulated by these epigenomic modifications in cancer. RESULTS: Our cell line model shows disruption of hydroxymethylation distribution in cancer, with global loss and highly specific gain in promoter and CpG island regions. Significantly, we observed locus-specific retention of hydroxymethylation marks in specific intronic and intergenic regions which may play a novel role in the regulation of gene expression in critical functional pathways, such as BARD1 signaling and steroid hormone receptor signaling in cancer. We confirm a modest correlation of hydroxymethylation with expression in intragenic regions in prostate cancer, while identifying an original role for intergenic hydroxymethylation in differentially expressed regulatory pathways in cancer. We also demonstrate a successful strategy for the identification and validation of key candidate genes from differentially regulated biological pathways in prostate cancer. CONCLUSIONS: Our results indicate a distinct function for aberrant hydroxymethylation within each genomic feature in cancer, suggesting a specific and complex role for the deregulation of hydroxymethylation in tumorigenesis, similar to methylation. Subsequently, our characterization of key cellular pathways exhibiting dynamic enrichment patterns for methylation and hydroxymethylation marks may allow us to identify differentially epigenetically modified target genes implicated in prostate cancer tumorigenesis.

The Performance of a Modified Glasgow Blatchford Score in Predicting Clinical Interventions in Patients with Acute Nonvariceal Upper Gastrointestinal Bleeding: A Vietnamese Prospective Multicenter Cohort Study.

BACKGROUND/AIMS: To compare the performance of a modified Glasgow Blatchford score (mGBS) to the Glasgow Blatchford score (GBS) and the pre-endoscopic Rockall score (RS) in predicting clinical interventions in Vietnamese patients with acute nonvariceal upper gastrointestinal bleeding (ANVUGIB). METHODS: A prospective multicenter cohort study was conducted in five tertiary hospitals from May 2013 to February 2014. The mGBS, GBS, and pre-endoscopic RS scores were prospectively calculated for all patients. The accuracy of mGBS was compared with that of GBS and preendoscopic RS using area under the receiver operating characteristic curve (AUC). Clinical interventions were defined as blood transfusions, endoscopic or radiological intervention, or surgery. RESULTS: There were 395 patients including 128 (32.4%) needing endoscopic treatment, 117 (29.6%) requiring blood transfusion and two (0.5%) needing surgery. In predicting the need for clinical intervention, the mGBS (AUC, 0.707) performed as well as the GBS (AUC, 0.708; p=0.87) and outperformed the pre-endoscopic RS (AUC, 0.594; p<0.001). However, none of these scores effectively excluded the need for endoscopic intervention at a threshold of 0. CONCLUSIONS: mGBS performed as well as GBS and better than pre-endoscopic RS for predicting clinical interventions in Vietnamese patients with ANVUGIB. (Gut Liver 2016;10375- 381).