Background: Pancreatic cancer is one of the most lethal types of cancer with extremely poor diagnosis and prognosis, and chemo-resistance remains a major challenge. The dynamic and reversible N 6-methyladenosine (m 6 A) RNA modification has emerged as a new layer of epigenetic gene regulation. Methods: qRT-PCR and IHC were applied to examine ALKBH5 levels in normal and pancreatic cancer tissues. Cancer cell proliferation and chemo-resistance were evaluated by clonogenic formation, chemosensitivity detection, and Western blotting assays. m 6 A-seq was performed to identify target genes. We evaluated the inhibitory effect of ALKBH5 in both in vivo and in vitro models. Results: Here, we show that m 6 A demethylase ALKBH5 is downregulated in gemcitabine-treated patient-derived xenograft (PDX) model and its overexpression sensitized pancreatic ductal adenocarcinoma (PDAC) cells to chemotherapy. Decreased ALKBH5 levels predicts poor clinical outcome in PDAC and multiple other cancers. Furthermore, silencing ALKBH5 remarkably increases PDAC cell proliferation, migration, and invasion both in vitro and in vivo, whereas its overexpression causes the opposite effects. Global m 6 A profile revealed altered expression of certain ALKBH5 target genes, including Wnt inhibitory factor 1 (WIF-1), which is correlated with WIF-1 transactivation and mediation of the Wnt pathway. Conclusions: Our work uncovers the tumor suppressive and chemo-sensitizing function for ALKBH5, which provides insight into critical roles of m 6 A methylation in PDAC.

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The Protocadherin 10 (PCDH10) is inactivated often by promoter hypermethylation in various human tumors, but its possible functional role as a tumor suppressor gene is not established. In this study, we identify PCDH10 as a novel Wnt pathway regulatory element in endometrioid endometrial carcinoma (EEC). PCDH10 was downregulated in EEC tumor cells by aberrant methylation of its promoter. Restoring PCDH10 levels suppressed cell growth and triggered apoptosis in EEC cells and tumor xenografts. Gene expression profiling revealed as part of the transcriptomic changes induced by PCDH10 a reduction in levels of MALAT1, a long noncoding RNA, that mediated tumor suppression functions of PCDH10 in EEC cells. We found that MALAT1 transcription was regulated by Wnt/b-catenin signaling via TCF promoter binding and PCDH10 decreased MALAT1 by modulating this pathway. Clinically, MALAT1 expression was associated with multiple parameters in patients with EEC. Taken together, our findings establish a novel PCDH10-Wnt/b-catenin-MALAT1 regulatory axis that contributes to EEC development. Cancer Res; 74(18); 5103-17. Ó2014 AACR.

Aberrant expression and altered function of transcription factors (TFs) have vital roles in many aspects of tumor development and progression. In this study, we investigated the functional significance of a TF, Yin Yang1 (YY1) in tumorigenesis of endometrioid endometrial carcinoma (EEC). We demonstrated that YY1 is upregulated in EEC cell lines and primary tumors; and its expression is associated with tumor stages. Depletion of YY1 inhibits EEC cell proliferation and migration both in vitro and in vivo, whereas overexpression of YY1 promotes EEC cell growth. These results suggest that YY1 functions as an oncogenic factor in EEC. Transcriptome analysis revealed a significant effect of YY1 on critical aspects of EEC tumorigenesis through inhibition of APC expression. Further mechanistic investigation uncovered a new epigenetic silencing mode of APC by YY1 through recruitment of EZH2 and trimethylation of histone 3 lysine 27 on its promoter region. Moreover, YY1 overexpression was found to be a consequence of miR-193a-5p downregulation through direct miR-193a-5p-YY1 interplay. Our results therefore establish a novel miR-193a-5p-YY1-APC axis, which contributes to EEC development, and may serve as future intervention target.

We initiated the present work to explore whether neutrophil gelatinase-associated lipocalin (NGAL) could be used to predict the progression of diabetic nephropathy in type-2 diabetic patients. Seventy-four type-2 diabetic patients were divided into normo-, micro- and macro-albuminuria groups according to their 24 h-urinary albumin excreting rate. Serum and urine NGAL, and other clinical parameters were detected. Patients were followed and measurements were repeated 1 year later. An increased tendency of urine NGAL and a decreased tendency of serum NGAL were detected, from normo-albuminuria group to macro-albuminuria group. Serum NGAL was found to rise after follow-up. Moreover, urine NGAL was found to be correlated positively with cystatin C, urea nitrogen, and serum creatinine (SCr), and inversely with glomerular filtration rate (GFR), while serum NGAL correlated negatively with cystatin C and urea nitrogen, at both baseline and follow-up levels. The results indicate that NGAL correlates closely with renal function. Both serum and urine NGAL are sensitive for predicting the progression of type-2 diabetic nephropathy but they may change differently. Serum NGAL may be more useful in early detection and urine NGAL may be more meaningful in renal function assessment.

Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-pro t purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. The direct amidation of amino acid derivatives catalyzed by arylboronic acids has been examined. The reaction was generally slow compared to simple amine-carboxylic acid combinations though proceeded at 65~68 °C generally avoiding racemization. 3,4,5-Trifluorophenylboronic and o-nitrophenylboronic acids were found to be the best catalysts, though for the slower dipeptide formations, high catalyst loadings were required and an interesting synergistic catalytic effect using two arylboronic acids was discovered. ____________[a]

Reverse logistics (RL) has been regarded as a key driving force for remanufacturing. However, there are great uncertainties in terms of quality and quantity of used components for RL. There are also complexities in suppliers and operations. These make decision-making of RL very complex. In order to identify the best collection mode for used components, a demand-matching oriented Multiple Criteria Decision Making (MCDM) method is established. In this method, the damage level and remaining service life are firstly incorporated into the evaluation criteria of reuse modes, then a hybrid method (AHP-EW) that integrates Analytic Hierarchy Process (AHP) and Entropy Weight (EW) method is applied to derive criteria weights and the grey Multi-Attributive Border Approximation Area Comparison (MABAC) is adopted to rank the collection modes. Finally, sensitivity analysis is implemented to test the stability of the proposed method, and a demands-matching method is proposed to validate and evaluate the feasibility of the optimal alternative. The collection of used pressurizers is taken as case study to validate the applicability of the proposed model. The results showed the effectiveness of the proposed method in MCDM of RL.

There is a positive correlation between levels of HOXA-10 and E-cadherin expression in the endometrium, both of which are significantly reduced in women with RIF and RM compared with fertile control women. The findings suggest a potential role of HOXA-10 and E-cadherin in the implantation processes and altered expression in women with reproductive failure.