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Background: Precision medicine has the potential to improve cardiovascular disease (CVD) risk prediction in individuals with type 2 diabetes (T2D). Methods: We conducted a systematic review and meta-analysis of longitudinal studies to identify potentially novel prognostic factors that may improve CVD risk prediction in T2D. Out of 9380 studies identified, 416 studies met inclusion criteria. Outcomes were reported for 321 biomarker studies, 48 genetic marker studies, and 47 risk score/model studies. Results: Out of all evaluated biomarkers, only 13 showed improvement in prediction performance. Results of pooled meta-analyses, non-pooled analyses, and assessments of improvement in prediction performance and risk of bias, yielded the highest predictive utility for N-terminal pro b-type natriuretic peptide (NT-proBNP) (high-evidence), troponin-T (TnT) (moderate-evidence), triglyceride-glucose (TyG) index (moderate-evidence), Genetic Risk Score for Coronary Heart Disease (GRS-CHD) (moderate-evidence); moderate predictive utility for coronary computed tomography angiography (low-evidence), single-photon emission computed tomography (low-evidence), pulse wave velocity (moderate-evidence); and low predictive utility for C-reactive protein (moderate-evidence), coronary artery calcium score (low-evidence), galectin-3 (low-evidence), troponin-I (low-evidence), carotid plaque (low-evidence), and growth differentiation factor-15 (low-evidence). Risk scores showed modest discrimination on internal validation, with lower performance on external validation. Conclusions: Despite high interest in this topic, very few studies conducted rigorous analyses to demonstrate incremental predictive utility beyond established CVD risk factors for T2D. The most promising markers identified were NT-proBNP, TnT, TyG and GRS-CHD, with the highest strength of evidence for NT-proBNP. Further research is needed to determine their clinical utility in risk stratification and management of CVD in T2D.

High MEF2D expression correlates with cancer cells mesenchymal and invasive features.

MEF2D expression in colorectal carcinoma, paired adjacent tissue and normal (S1); Associations of MEF2D expression with clinicopathological features in CRC (S2); Primers used in this study (S3); Antibodies used in this study (S4).

Epithelial–mesenchymal transition (EMT) is an essential mechanism of metastasis, including in colorectal cancer. Although EMT processes are often triggered in cancer cells by their surrounding microenvironment, how EMT-relevant genes control these processes is not well understood. In multiple types of cancers, the transcription factor MEF2D has been implicated in cell proliferation, but its contributions to metastasis have not been addressed. Here, we show MEF2D is overexpressed in clinical colorectal cancer tissues where its high expression correlates with metastatic process. Functional investigations showed that MEF2D promoted cancer cell invasion and EMT and that it was essential for certain microenvironment signals to induce EMT and metastasis in vivo. Mechanistically, MEF2D directly regulated transcription of the EMT driver gene ZEB1 and facilitated histone acetylation at the ZEB1 promoter. More importantly, MEF2D responded to various tumor microenvironment signals and acted as a central integrator transducing multiple signals to activate ZEB1 transcription. Overall, our results define a critical function for MEF2D in upregulating EMT and the metastatic capacity of colorectal cancer cells. Further, they offer new insights into how microenvironment signals activate EMT-relevant genes and deepen the pathophysiologic significance of MEF2D, with potential implications for the prevention and treatment of metastatic colorectal cancer. Cancer Res; 76(17); 5054–67. ©2016 AACR.

Legends for Supplementary Figures S1-S4.

Description of additional methods and procedures used in the study. Also includes Supplementary References.

OBJECTIVE Several studies support associations between relative leukocyte telomere length (rLTL), a biomarker of biological aging and type 2 diabetes. This study investigates the relationship between rLTL and the risk of glycemic progression in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS In this cohort study, consecutive Chinese patients with type 2 diabetes (N = 5,506) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied. rLTL was measured using quantitative PCR. Glycemic progression was defined as the new need for exogenous insulin. RESULTS The mean (SD) age of the 5,349 subjects was 57.0 (13.3) years, and mean (SD) follow-up was 8.8 (5.4) years. Baseline rLTL was significantly shorter in the 1,803 subjects who progressed to insulin requirement compared with the remaining subjects (4.43 ± 1.16 vs. 4.69 ± 1.20). Shorter rLTL was associated with a higher risk of glycemic progression (hazard ratio [95% CI] for each unit decrease [to ∼0.2 kilobases]: 1.10 [1.06–1.14]), which remained significant after adjusting for confounders. Baseline rLTL was independently associated with glycemic exposure during follow-up (β = −0.05 [−0.06 to −0.04]). Each 1-kilobase decrease in absolute LTL was on average associated with a 1.69-fold higher risk of diabetes progression (95% CI 1.35–2.11). Two-sample Mendelian randomization analysis showed per 1-unit genetically decreased rLTL was associated with a 1.38-fold higher risk of diabetes progression (95% CI 1.12–1.70). CONCLUSIONS Shorter rLTL was significantly associated with an increased risk of glycemic progression in individuals with type 2 diabetes, independent of established risk factors. Telomere length may be a useful biomarker for glycemic progression in people with type 2 diabetes.

Therapeutic resistance is a major challenge in multiple myeloma treatment. Understanding the underlying mechanisms is required to develop effective strategies against drug resistance and improve the prognosis of myeloma patients. Here, we identify osteocytes, the major cellular component of bone tissue, as key regulators of myeloma therapeutic resistance. Osteocyte-derived exosomes can be efficiently taken up by myeloma cells and exert a protective effect against chemotherapy-induced apoptosis. Mechanistic studies further reveal that osteocyte-derived exosomal miR-483-3p and miR-513a-5p promote cancer stem cell-like features in myeloma cells by regulating HIF-1α stabilization, thus conferring myeloma cells resistance to chemotherapy. Strikingly, combination treatment of miR-483-3p and miR-513a-5p inhibitors significantly reduces tumor burden and potentiates the therapeutic efficacy of bortezomib in the myeloma mouse model. Our findings, therefore, demonstrate the functional impact of osteocytes on myeloma therapeutic resistance, and suggest that osteocyte-derived exosomal miRNAs may serve as potential therapeutic targets for overcoming drug resistance in multiple myeloma.

Because of the instability and Fenton reactivity of non-precious metal nitrogen-carbon based catalyst when processing the oxygen reduction reaction (ORR), seeking for electrocatalysts with highly efficient performance becomes very highly desired to speed up the commercialization of fuel cell. Herein, chromium (Cr)-N

Aims/hypothesis Few large-scale prospective studies have investigated associations between relative leucocyte telomere length (rLTL) and kidney dysfunction in individuals with type 2 diabetes. We examined relationships between rLTL and incident end-stage kidney disease (ESKD) and the slope of eGFR decline in Chinese individuals with type 2 diabetes. Methods We studied 4085 Chinese individuals with type 2 diabetes observed between 1995 and 2007 in the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data. rLTL was measured using quantitative PCR. ESKD was diagnosed based on the ICD-9 code and eGFR. Results In this cohort (mean ± SD age 54.3 ± 12.6 years) followed up for 14.1 ± 5.3 years, 564 individuals developed incident ESKD and had shorter rLTL at baseline (4.2 ± 1.2 vs 4.7 ± 1.2, p n = 3521). On Cox regression analysis, each ∆∆Ct decrease in rLTL was associated with an increased risk of incident ESKD (HR 1.21 [95% CI 1.13, 1.30], p 1c, lipids, renal function and other risk factors (HR 1.11 [95% CI 1.03, 1.19], p = 0.007). Shorter rLTL at baseline was associated with rapid decline in eGFR (>4% per year) during follow-up (unadjusted OR 1.22 [95% CI 1.15, 1.30], p p = 0.024). Conclusions/interpretation rLTL is independently associated with incident ESKD and rapid eGFR loss in individuals with type 2 diabetes. Telomere length may be a useful biomarker for the progression of kidney function and ESKD in type 2 diabetes. Graphical abstract

Women with polycystic ovary syndrome (PCOS) have an increased risk of developing type 2 diabetes. FGF19, FGF21 and lipocalin-2 have emerged as important markers of metabolic risk. This study aims to compare the levels of FGF19, FGF21 and lipocalin-2 between subjects with or without PCOS, and to investigate the relationship between proteins and diabetes progression. In this nested case–control cohort study, 128 Chinese PCOS women and 128 controls were recruited and followed-up. All subjects underwent the oral glucose tolerance test for the evaluation of glycaemic status. Baseline serum protein levels were measured using ELISA. Compared with controls, PCOS subjects had higher levels of FGF19 (P < 0.001) and FGF21 (P = 0.022), but had lower lipocalin-2 (P < 0.001). In total, 20.8% of PCOS and 9.2% of controls developed diabetes over a mean duration of 10.4 ± 1.2 and 11.3 ± 0.5 years, respectively. Logistic regression analyses suggested FGF19 was positively associated with diabetes progression in controls, after adjusting for age, follow-up duration, waist and fasting glucose (P = 0.026, odds ratio (OR) (95% CI): 7.4 (1.3–43.6)), and the positive relationship between FGF21 and diabetes progression in controls was attenuated by adjusting for age and follow-up duration (P = 0.183). Lipocalin-2 was positively correlated with diabetes progression in PCOS group (P = 0.026, OR (95% CI)): 2.5 (1.1–5.6)); however, this became attenuated after adjusting for waist and fasting glucose (P = 0.081). In conclusion, there is differential expression of FGF19, FGF21, and lipocalin-2 in PCOS. The serum level of FGF19, and FGF21 is associated with diabetes progression in women without PCOS, while lipocalin-2 was related to diabetes progression in PCOS women.

SummaryHuman islets are widely used in research for understanding pathophysiological mechanisms leading to diabetes. Sex, age, and body mass index (BMI) are key donor traits influencing insulin secretion. Islet function is also regulated by an intricate network of microRNAs. Here, we profiled 754 microRNAs and 58,190 transcripts in up to 131 different human islet donor preparations (without diabetes) and assessed their association with donor traits. MicroRNA analyses identified miR-199a-5p and miR-214-3p associated with sex, age and BMI; miR-147b with sex and age; miR-378a-5p with sex and BMI; miR-542-3p, miR-34a-3p, miR-34a-5p, miR-497-5p and miR-99a-5p with age and BMI. There were 959 mRNA transcripts associated with sex (excluding those from sex-chromosomes), 940 with age and 418 with BMI. MicroRNA-199a-5p and miR-214-3p levels inversely associate with transcripts critical in islet function, metabolic regulation, and senescence. Our analyses identify human islet cell microRNAs influenced by donor traits.Graphical abstract

Synchronous fluorescence spectroscopy and differential scanning calorimetry were applied to evaluate the stabilities of the peanut, corn, sunflower, and rapeseed oil. The results showed that when t...

In this paper we consider the Degasperis-Procesi equation, which is an approximation to the incompressible Euler equation in shallow water regime. First we provide the existence of solitary wave solutions for the original DP equation and the general theory of geometric singular perturbation. Then we prove the existence of solitary wave solutions for the equation with a special local delay convolution kernel and a special nonlocal delay convolution kernel by using the geometric singular perturbation theory and invariant manifold theory. According to the relationship between solitary wave and homoclinic orbit, the Degasperis-Procesi equation is transformed into the slow-fast system by using the traveling wave transformation. It is proved that the perturbed equation also has a homoclinic orbit, which corresponds to a solitary wave solution of the delayed Degasperis-Procesi equation.

Feifei Cheng,1 Jiang Liu,1 Yundong Zhang,1 Qiuxiang You,1 Bo Chen,2 Jing Cheng,1 Chunyan Deng1 1Department of Neurology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, People’s Republic of China; 2Department of Pharmacology, College of Pharmacy, Chongqing Medical University, Chongqing 401120, People’s Republic of ChinaCorrespondence: Chunyan Deng Email dcycq_2008@163.comBackground: The dysregulation of long non-coding RNAs is a frequent finding in glioblastoma (GBM) and is considered as a crucial mechanism contributing to GBM oncogenesis and progression. The biological roles and underlying mechanisms of action of UBA6 antisense RNA 1 (UBA6-AS1) in GBM have been rarely investigated. Therefore, the aim of the present study was to investigate in detail the role of UBA6-AS1 in the modulation of the malignant properties of GBM and explore the possible underlying mechanism(s).Methods: The expression of UBA6-AS1 in GBM was determined via reverse transcription-quantitative PCR. Cell Counting Kit-8 assay, flow cytometric analysis, Transwell migration and invasion assays, and in vivo tumorigenicity assay were applied to elucidate the biological effects of UBA6-AS1 on GBM cells. The possible biological events associated with UBA6-AS1 were investigated by luciferase reporter, RNA immunoprecipitation (RIP) and rescue assays.Results: UBA6-AS1 was overexpressed in GBM, which was consistent with the data from The Cancer Genome Atlas database. In the case of UBA6-AS1 depletion, GBM cell proliferation, migration and invasion were notably decreased and cell apoptosis was enhanced in vitro. Additionally, knockdown of UBA6-AS1 suppressed the proliferation of GBM cells in vivo. Mechanistically, UBA6-AS1 functioned as a competing endogenous RNA by adsorbing miR-760 and, consequently, upregulating homeobox A2 (HOXA2) expression. Rescue experiments demonstrated that the UBA6-AS1 silencing-mediated regulatory effects on GBM cells were reversed by the decrease of miR-760 or restoration of HOXA2 expression.Conclusion: Therefore, the results of the present study revealed that UBA6-AS1 promoted the malignant progression of GBM via targeting the miR-760/HOXA2 axis, thereby representing a promising effective target for the treatment of GBM.Keywords: UBA6 antisense RNA 1, long non-coding RNA, homeobox A2, glioblastoma

Context Leukocyte telomere length (LTL) is a biomarker of biological aging and is associated with metabolic diseases such as type 2 diabetes. Insufficient maternal vitamin D was associated with increased risk for many diseases and adverse later life outcomes. Objective This study investigates the relationship between vitamin D levels and offspring LTL at early life. Methods This observational, longitudinal, hospital-based cohort study included eligible mother-child pairs from the HAPO Hong Kong Field Centre, with 853 offspring at age 6.96 ± 0.44 (mean ± SD) years. LTL was measured using real-time polymerase chain reaction while serum vitamin D metabolites 25(OH)D2, 25(OH)D3, and 3-epi-25(OH)D3 were measured in maternal blood (at gestation 24-32 weeks) and cord blood by liquid chromatography–mass spectrometry. Results LTL at follow-up was significantly shorter in boys compared with girls (P Conclusion Our findings suggest 25(OH)D3 and 3-epi-25(OH)D3 in utero may impact on childhood LTLs, highlighting a potential link between maternal vitamin D and biological aging.

Objective. The objective of the study is to investigate the relationships between fetuin-B, thyroid autoimmunity (TAI), and pregnancy outcomes in women undergoing in vitro fertilization and embryo transfer (IVF-ET). Design, Patients, and Measurements. In this prospective study, 180 women who were preparing for pregnancy with IVF-ET were included. There were 120 women with TAI positive and 60 negative controls matched with age and BMI. Results. The 180 women had mean ± SD age of 31.4 ± 4.0 years, with a mean ± SD BMI of 21.0 ± 1.6 kg/m2. There was a significant difference in the level of fetuin-B in women with TAI positive compared with TAI negative group (65.2 ± 18.5 vs. 76.4 ± 25.1, P = 0.001 ). Fetuin-B had a negative relationship with thyroid antibodies even after adjusting for other variables (OR (95%CI) = 0.98 (0.96–0.99), P = 0.002 ). Compared with women with TAI negative, those with TAI positive had a significantly higher risk of low fertilization (20.0% vs. 6.7%; P = 0.035 ). And we found no difference in terms of pregnancy, abortion, implantation, and live birth rate between the two groups. Logistic regression analysis showed that both fetuin-B and TAI were the independent factors to lead the low fertilization of IVF-ET (OR (95%CI) = 0.96 (0.94–0.99) and 4.084 (1.39–15.30), P = 0.004 and 0.019, respectively). Conclusion. Fetuin-B was significantly associated with TAI and low fertilization rate in women undergoing IVF-ET. Decreased fetuin-B in women with TAI may be the underlying reason for the lower IVF-ET success rate.

Aims To investigate association between skin autofluorescence (SAF) and cardiovascular events (CVE) and assess its predictive value in Chinese adults with type 2 diabetes (T2D). Materials and methods SAF was measured non-invasively in 3806 Chinese adults with T2D between 2016 and 2019 with CVE as primary endpoint and individual components as secondary endpoints. Cox proportional hazard models were used to examine associations between SAF and endpoints with adjustment for conventional risk factors. C-statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were performed to evaluate SAF's predictive value. Results During a median 1.8 (interquartile range, 1.2–3.1) years of follow-up, 172 individuals experienced CVE. Multivariate Cox model showed that SAF was independently associated with CVE (HR 1.18 per SD, 95% CI [1.02, 1.37]), coronary heart disease (HR 1.29 per SD, 95% CI [1.02, 1.63]), and congestive heart failure (HR 1.53 per SD, 95% CI [1.14, 2.05]). SAF yielded additional value on CVE risk stratification with enhanced IDI (95% CI) (0.023 [0.001, 0.057]) and continuous NRI (0.377 [0.002, 0.558]) over traditional risk factors. Conclusions Higher SAF was independently associated with CVE in Chinese adults with T2D and yielded incremental predictive information for CVE. SAF has potential as a prognostic maker for CVE.

Leukocyte telomere length (LTL) is a biomarker of biological aging, and has been associated with metabolic diseases such as type 2 diabetes (T2DM). Insufficient maternal vitamin D (25(OH)D) has also been associated with increased disease risk for many diseases and adverse later life outcomes. The association between maternal and cord blood total 25(OH)D and LTL was examined in mother-child pairs from the HAPO Hong Kong Field Centre, including 815 offspring at age (mean±SD) 6.96 ± 0.44 years. LTL was measured using real-time polymerase chain reaction and serum 25(OH)D2, 25(OH)D3 and 3-epi-25(OH)D3 were measured in maternal blood (at gestation 24-32 weeks) and cord blood by liquid chromatography-mass spectrometry. Children LTL at follow-up was significantly shorter in boys compared to girls (p Disclosure K. Wong: None. B. E. Metzger: None. W. Lowe: None. W. H. Tam: None. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. F. Cheng: None. D. Mao: None. C. K. P. Lim: Stock/Shareholder; Self; GemVCare Ltd. R. Wang: None. C. H. Tam: None. M. A. Joglekar: None. A. A. Hardikar: None. A. Jenkins: Advisory Panel; Self; Abbott Diabetes, Sanofi-Aventis, Other Relationship; Self; Amgen Inc., Research Support; Self; Abbott, International Diabetes Federation, JDRF, Medtronic, Mylan N. V.

Few studies have investigated the relationship between rLTL and mortality in patients with type 2 diabetes in a large prospective study, particularly in the Asian population. This study investigates the relationship between rLTL and the risk of death in Chinese patients with type 2 diabetes.Consecutive Chinese patients with type 2 diabetes (N = 5349) from the Hong Kong Diabetes Register with stored baseline DNA and available follow-up data were studied. rLTL was measured using a quantitative polymerase chain reaction. Mortality and clinical outcomes were obtained based on ICD-9 codes.The mean (SD) age of the subjects was 57.5 (13.3) years and mean (SD) follow-up duration was 13.4 (5.5) years. Baseline rLTL was significantly shorter in the 1925 subjects who subsequently died compared with the remaining subjects (4.3 ± 1.2 vs. 4.7 ± 1.2, P 0.001). Shorter rLTL was associated with a higher risk of mortality (HR: 1.19 (1.14-1.23), P 0.001), which remained significant after adjusting for traditional risk factors.Shorter rLTL was significantly associated with an increased risk of all-cause and CVD mortality in patients with type 2 diabetes, independent of established risk factors. Telomere length may be a useful biomarker for mortality risk in patients with type 2 diabetes.

OBJECTIVE Several studies support potential links between relative leukocyte telomere length (rLTL), a biomarker of biological aging, and type 2 diabetes. This study investigates relationships between rLTL and incident cardiovascular disease (CVD) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Consecutive Chinese patients with type 2 diabetes (N = 5,349) from the Hong Kong Diabetes Register for whom DNA obtained at baseline was stored and follow-up data were available were studied. rLTL was measured by using quantitative PCR. CVD was diagnosed on the basis of ICD-9 code. RESULTS Mean follow-up was 13.4 years (SD 5.5 years). rLTL was correlated inversely with age, diabetes duration, blood pressure, HbA1c, and urine albumin-to-creatinine ratio (ACR), and positively with estimated glomerular filtration rate (eGFR) (all P < 0.001). Subjects with CVD at baseline had a shorter rLTL (4.3 ± 1.2 ΔΔCt) than did subjects without CVD (4.6 ± 1.2 ΔΔCt) (P < 0.001). Of the 4,541 CVD-free subjects at baseline, the 1,140 who developed CVD during follow-up had a shorter rLTL (4.3 ± 1.2 ΔΔCt) than those who remained CVD-free after adjusting for age, sex, smoking, and albuminuria status (4.7 ± 1.2 ΔΔCt) (P < 0.001). In Cox regression models, shorter rLTL was associated with higher risk of incident CVD (for each unit decrease, hazard ratio 1.252 [95% CI 1.195–1.311], P < 0.001), which remained significant after adjusting for age, sex, BMI, systolic blood pressure, LDL cholesterol, HbA1c, eGFR, and ACR (hazard ratio 1.141 [95% CI 1.084–1.200], P < 0.001). CONCLUSIONS rLTL is significantly shorter in patients with type 2 diabetes and CVD, is associated with cardiometabolic risk factors, and is independently associated with incident CVD. Telomere length may be a useful biomarker for CVD risk in patients with type 2 diabetes.

Telomeres are regions of repetitive nucleotide sequences at the ends of chromosomes. Telomere length is a marker of DNA damage, which is often considered a biomarker for biological ageing, and has also been linked with cardiovascular disease, diabetes, and cancer. Emerging studies have highlighted the role of genetic and environmental factors, and explored the effect of modulating telomere length. We provide an overview of studies to date on diabetes and telomere length, and compare different methods and assays for evaluating telomere length and telomerase activity. We highlight the limitations of current studies and areas that warrant further research to unravel the link between diabetes and telomere length. The value of adding telomere length to clinical risk factors to improve risk prediction of diabetes and related complications also merits further investigation.

The kinetic resolution of (R,S)-1-(4-chlorophenyl)ethylamine was accomplished using a commercial lipase from Candida antarctica (Novozym 435). The performance of this lipase was investigated for the enantioselective amidation of (R,S)-1-(4-chlorophenyl)ethylamine, leaving the target product (S)-1-(4-chlorophenyl)ethylamine in its unreacted form. The effects of various types of solvents and an acyl donor, the molar ratio of the substrate to the acyl donor, and the reaction temperature were studied. The optimum reaction conditions were found to result in amidation with methyl 2-tetrahydrofuroate at 40°C in methyl tert-butyl ether, with a substrate/acyl donor molar ratio of 1:2.4. The conversion rate of (R,S)-1-(4-chlorophenyl)ethylamine was 52%, with an enantiomeric excess of 99% towards the unreacted substrate in a reaction time of 22 hours. Finally, using optically pure (S)-1-(4-chlorophenyl)ethylamine as the raw material, the chemical synthesis of (S)-N-(1-(4-chlorphenyl)ethyl)-2-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylthio)acetamide, a novel triazolopyrimidine herbicide, was achieved, and the total yield and purity were 83.5% and 95.3%, respectively.

Only a few esterases have been used for the synthesis of optically pure fungicide. For example, (R)-metalaxyl synthesized using esterase-involved bioreaction displays fungicide activity, whereas (S)-enantiomer is redundant. However, the biosynthesis of (R)-metalaxyl is currently hampered by the lower activity, selectivity and thermostability of esterase. Therefore, to obtain a better biocatalyst, several esterase genes were cloned from Pseudochrobactrum asaccharolyticum WZZ003. The esterase PAE07, among eight enzymes, was selected because it exhibited the highest hydrolysis activity toward (R,S)-DMPM. The DNA and amino acid sequence analysis suggested that PAE07 is a new member of lipolytic enzyme family V. The enzymatic properties of PAE07 toward (R,S)-DMPM and model substrate (p-nitrophenyl acetate) were investigated. PAE07 was found to be a highly active esterase with excellent enantioselectivity. The reaction conditions including temperatureand pH were optimized, and the effects of metal ions, organic solvents and detergents were also investigated. Results indicated that PAE07 is a competitive candidate for (R)-metalaxyl manufacturing.

Disposed cigarette butt is one of the biggest solid, non-biodegradable wastes across the world. Cigarette butts (CBs) made of cellulose acetate are good candidates for the initial raw materials of carbon materials synthesis, providing a possible way for waste CBs recycling. Herein a carbonaceous adsorbent derived from waste CBs was prepared for the heavy metals removal from aqueous solution. The product activated at 500 °C has a maximum adsorption capacity for lead ions, which has a favorable balance of high specific surface area and abundant O-containing functional groups, facilitating the adsorption of heavy metals ions. The adsorption experiments showed that the pH of the solution played a pivotal role in the adsorption of heavy metals by CBs-derived activated carbons and the optimal pH for the adsorption was around 5. Effective adsorption of chromium (Cr3+), cobalt (Co2+), nickel (Ni2+), lead (Pb2+) and cadmium (Cd2+) demonstrated that the prepared materials can be used for multiple heavy metal ions removal. The prepared materials were able to adsorb Pb2+ within ten minutes, and the adsorption process can be well described by the pseudo-second order model, indicating that the chemical adsorption is the rate determining step for the adsorption process. The equilibrium data followed the Langmuir isotherm model and the corresponding maximum adsorption capacity for Pb2+ was 249.3 mg g−1. Considering the merits of low cost, easy synthesis pathway and excellent removal ability of heavy metals, CBs-derived carbonaceous adsorbent exhibits potential application in the fields of heavy metal contaminated water treatment.

High performance electronic package requires good control of electrical contact resistance at the package pad and second level interconnect (SLI) socket contact interface for power delivery and thermal management. In this paper, a modeling framework incorporating electrical contact theories is developed to investigate contact resistance of the given multi-layer plating system. The effects of some potential electrical contact resistance variation contributing factors are studied and quantified. The parameters studied include contact normal force, microhardness and thickness of constituent plating layers, phosphorus content percentage in electroless plated Ni layer, metallic nanofilm size effect, and existence of NiO contaminant film.

In this study, a newly isolated strain screened from the indoxacarb-rich agricultural soils, Bacillus cereus WZZ006, has a high stereoselectivity to racemic substrate 5-chloro-1-oxo-2,3-dihydro-2-hydroxy-1H-indene-2-carboxylic acid methyl ester. (S)-5-chloro-1-oxo-2,3-dihydro-2-hydroxy-1H-indene-2-carboxylic acid methyl ester was obtained by bio-enzymatic resolution. After the 36-hour hydrolysis in 50-mM racemic substrate under the optimized reaction conditions, the e.e.s was up to 93.0% and the conversion was nearly 53.0% with the E being 35.0. Therefore, B cereus WZZ006 performed high-level ability to produce (S)-5-chloro-1-oxo-2,3-dihydro-2-hydroxy-1H-indene-2-carboxylic acid methyl ester. This study demonstrates a new biocatalytic process route for preparing the indoxacarb chiral intermediates and provides a theoretical basis for the application of new insecticides in agricultural production.

Epithelial–mesenchymal transition (EMT) is an essential mechanism of metastasis, including in colorectal cancer. Although EMT processes are often triggered in cancer cells by their surrounding microenvironment, how EMT-relevant genes control these processes is not well understood. In multiple types of cancers, the transcription factor MEF2D has been implicated in cell proliferation, but its contributions to metastasis have not been addressed. Here, we show MEF2D is overexpressed in clinical colorectal cancer tissues where its high expression correlates with metastatic process. Functional investigations showed that MEF2D promoted cancer cell invasion and EMT and that it was essential for certain microenvironment signals to induce EMT and metastasis in vivo. Mechanistically, MEF2D directly regulated transcription of the EMT driver gene ZEB1 and facilitated histone acetylation at the ZEB1 promoter. More importantly, MEF2D responded to various tumor microenvironment signals and acted as a central integrator transducing multiple signals to activate ZEB1 transcription. Overall, our results define a critical function for MEF2D in upregulating EMT and the metastatic capacity of colorectal cancer cells. Further, they offer new insights into how microenvironment signals activate EMT-relevant genes and deepen the pathophysiologic significance of MEF2D, with potential implications for the prevention and treatment of metastatic colorectal cancer. Cancer Res; 76(17); 5054–67. ©2016 AACR.

// Lupin Jiang 1 , Juanjuan Shan 2, 3 , Junjie Shen 2 , Yanzhou Wang 1 , Ping Yan 1 , Limei Liu 2 , Wenxu Zhao 2 , Yanmin Xu 2 , Wei Zhu 2 , Li Su 2 , Jun Chen 2 , Feifei Cheng 2 , Hong Yao 1 , Huicheng Xu 1 , Cheng Qian 2 , Zhiqing Liang 1 1 Department of Obstetrics & Gynecology, Southwest Hospital, Third Military Medical University, Chongqing, China 2 Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China 3 Key Laboratory of Biorheological Science and Technology, Ministry of Education, Bioengineering College, Chongqing University, Chongqing, China Correspondence to: Zhiqing Liang, email: zhi.lzliang@gmail.com Cheng Qian, email: cqian8634@gmail.com Keywords: hepatocellular carcinoma, androgen/androgen receptor axis, Nanog, cancer stem cells, CRISPR/Cas9 Received: February 03, 2016 Accepted: April 16, 2016 Published: May 5, 2016 ABSTRACT Hepatocellular carcinoma (HCC) is one of the most common and malignant cancers. The HCC incidence gets a strong sexual dimorphism as men are the major sufferers in this disaster. Although several studies have uncovered the presentative correlation between the axis of androgen/androgen receptor (AR) and HCC incidence, the mechanism is still largely unknown. Cancer stem cells (CSCs) are a small subgroup of cancer cells contributing to multiple tumors malignant behaviors, which play an important role in oncogenesis of various cancers including HCC. However, whether androgen/AR axis involves in regulation of HCC cells stemness remains unclear. Our previous study had identified that the pluripotency factor Nanog is not only a stemness biomarker, but also a potent regulator of CSCs in HCC. In this study, we revealed androgen/AR axis can promote HCC cells stemness by transcriptional activation of Nanog expression through directly binding to its promoter. In HCC tissues, we found that AR expression was abnormal high and got correlation with Nanog. Then, by labeling cellular endogenous Nanog with green fluorescent protein (GFP) through CRISPR/Cas9 system, it verified the co-localization of AR and Nanog in HCC cells. With in vitro experiments, we demonstrated the axis can promote HCC cells stemness, which effect is in a Nanog-dependent manner and through activating its transcription. And the xenografted tumor experiments confirmed the axis effect on tumorigenesis facilitation in vivo . Above all, we revealed a new sight of androgen/AR axis roles in HCC and provided a potential way for suppressing the axis in HCC therapy.

// Feifei Cheng 1,2 , Li Su 1 and Cheng Qian 1 1 Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China 2 School of Life Science, Zhejiang Sci-Tech University, Hangzhou, China Correspondence to: Cheng Qian, email: // Keywords : liquid biopsy, circulating tumor DNA, biology, biomarker, targeted therapies Received : November 06, 2015 Accepted : April 24, 2016 Published : May 19, 2016 Abstract Tissue biopsy is the standard diagnostic procedure for cancers and also provides a material for genotyping, which can assist in the targeted therapies of cancers. However, tissue biopsy-based cancer diagnostic procedures have limitations in their assessment of cancer development, prognosis and genotyping, due to tumor heterogeneity and evolution. Circulating tumor DNA (ctDNA) is single- or double-stranded DNA released by the tumor cells into the blood and it thus harbors the mutations of the original tumor. In recent years, liquid biopsy based on ctDNA analysis has shed a new light on the molecular diagnosis and monitoring of cancer. Studies found that the screening of genetic mutations using ctDNA is highly sensitive and specific, suggesting that ctDNA analysis may significantly improve current systems of tumor diagnosis, even facilitating early-stage detection. Moreover, ctDNA analysis is capable of accurately determining the tumor progression, prognosis and assisting in targeted therapy. Therefore, using ctDNA as a liquid biopsy may herald a revolution for tumor management. Herein, we review the biology of ctDNA, its detection methods and potential applications in tumor diagnosis, treatment and prognosis.