Association of Circulating Adipsin, Visfatin, and Adiponectin with Nonalcoholic Fatty Liver Disease in Adults: A Case-Control Study.

BACKGROUND/AIMS: Some adipokines, such as adiponectin and leptin, have been reported to be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), while the association of adipsin and visfatin with NAFLD still remains unclear. This study aimed to examine the association of circulating adipsin, visfatin, and adiponectin with NAFLD in Chinese adults. METHODS: We recruited a total of 211 eligible subjects, including 100 NAFLD cases and 111 age and sex frequency-matched controls. Circulating adipsin, visfatin, and adiponection concentrations were measured by enzymatic immunoassay. Unconditional logistic regression was conducted to assess the associations between quartiles of adipokines and NAFLD. RESULTS: Compared with the controls, NAFLD cases had higher levels of adipsin and lower levels of visfatin and adiponectin. By multivariate logistic analysis, adjusting for potential confounders, circulating adipsin levels were found to be positively associated with NAFLD risk, and circulating levels of visfatin and adiponectin were inversely associated with the risk of NAFLD (all p-trend < 0.05). The ORs were 3.76 (95% CI 1.27-11.08) for adipsin, 0.30 (95% CI 0.10-0.91) for visfatin, and 0.30 (95% CI 0.10-0.88) for adiponectin comparing subjects in the highest quartile with those in the lowest. After stratified by obesity status, the association of higher adipsin with increased risk of NAFLD was only observed in nonobese group. Additionally, the inverse association between adiponectin and NAFLD was found in both groups. CONCLUSIONS: These results indicated that increased circulating levels of adipsin and decreased circulating levels of visfatin and adiponectin were independently associated with the increased risk of NAFLD.

FGFR2 regulates Mre11 expression and double-strand break repair via the MEK-ERK-POU1F1 pathway in breast tumorigenesis.

The association between breast cancer risk and genetic variants of fibroblast growth factor receptor 2 (FGFR2) has been identified and repeatedly confirmed; however, the mechanism underlying FGFR2 in breast tumorigenesis remains obscure. Given that breast tumorigenesis is particularly related to DNA double-strand-break-repair (DSBR), we examined the hypothesis that FGFR2 is involved in DSBR. Our results show that expression of Mre11, a vital exonuclease in DSBR, is downregulated by FGFR2, which is further linked to decreased DSBR. Analysis of the Mre11 promoter revealed that POU1F1 mediates FGFR2-induced Mre11 downregulation. Furthermore, ERK, downstream of FGFR2, directly interacts with and phosphorylates POU1F1, increasing POU1F1 binding capacity to the Mre11 promoter and repressing Mre11 expression, which consequently affects DSBR and sensitizes breast cancer cells to chemotherapeutic treatments. The importance of the FGFR2-Mre11-DSBR link in cancer progression is suggested by the finding that genotypes of FGFR2 and Mre11 are associated with survival of breast cancer patients and that FGFR2 expression correlates with cancer prognosis specifically in patients receiving chemotherapy. This study yields important insight into the role of FGFR2 in breast tumorigenesis and may facilitate development of a useful therapeutic approach for breast cancer.

Functional variants at the 21q22.3 locus involved in breast cancer progression identified by screening of genome-wide estrogen response elements.

INTRODUCTION: Estrogen forms a complex with the estrogen receptor (ER) that binds to estrogen response elements (EREs) in the regulatory region of estrogen-responsive genes and regulates their transcription. Sequence variants in the regulatory regions have the potential to affect the transcription factor-regulatory sequence interaction, resulting in altered expression of target genes. This study explored the association between single-nucleotide polymorphisms (SNPs) within the ERE-associated sequences and breast cancer progression. METHODS: The ERE-associated sequences throughout the whole genome that have been demonstrated to bind ERα in vivo were blasted against online information from SNP data sets and 54 SNPs located adjacent to estrogen-responsive genes were selected for genotyping in two independent cohorts of breast cancer patients: 779 patients in the initial screening stage and another 888 in the validation stage. Deaths due to breast cancer or recurrence of breast cancer were defined as the respective events of interest, and the hazard ratios of individual SNPs were estimated based on the Cox proportional hazards model. Furthermore, functional assays were performed, and information from publicly available genomic data and bioinformatics platforms were used to provide additional evidence for the associations identified in the association analyses. RESULTS: The SNPs at 21q22.3 ERE were significantly associated with overall survival and disease-free survival of patients. Furthermore, these 21q22.3 SNPs (rs2839494 and rs1078272) could affect the binding of this ERE-associated sequence to ERα or Rad21 (an ERα coactivator), respectively, which resulted in a difference in ERα-activated expression of the reporter gene. CONCLUSION: These findings support the idea that functional variants in the ERα-regulating sequence at 21q22.3 are important in determining breast cancer progression.

The development of a nomogram model for predicting left recurrent laryngeal nerve lymph node metastasis in esophageal cancer based on radiomics and clinical factors.

Background: The lymph node dissection for esophageal cancer is controversial. Some prediction models of lymph node metastasis (LNM) use the short diameter of lymph nodes measured by computed tomography (CT) examination as a predictor, but the size of that for judging metastasis is still controversial. However, radiomics can extract some features in tumors that cannot be obtained by naked eyes, which may have a higher value in predicting LNM. In this study, a nomogram was developed based on radiomics and clinical factors to predict left recurrent laryngeal nerve lymph node (RLNN) metastasis in patients with esophageal squamous cell carcinoma (ESCC). Methods: There were 350 patients included in this retrospective study. And the postoperative pathological results determined whether there was left RLNN metastasis. A univariate analysis was conducted of the clinical data. The least absolute shrinkage and selection operator regression analysis was conducted to filter the radiomics features extracted from CT images. The multivariate logistic regression equation was used to construct a nomogram. The area under the curve (AUC) was used to evaluate the predictive ability. Due to the small sample size, we chose to perform internal validation after the model was established by 10-fold cross-validation, Harrell's concordance index (C-index), bootstrap validation and calibration. Results: Ultimately, 3 indicators were screened out; that is, tumor location, surface volume ratio, and run-length non-uniformity. We then constructed the nomogram using these 3 indicators. The model had good accuracy and calibration performance. It has an AUC of 0.903 (95% confidence interval: 0.861-0.945), a sensitivity of 0.873, and a specificity of 0.756. Ten-fold cross-validation showed that the sensitivity and specificity of the training set were 88.08% and 75.81%, and the validation set had a sensitivity of 85.08% and a specificity of 75.49%. The Brier score was 0.074, and C-index was 0.904, which indicated good consistency between the actual and predicted results. Conclusions: A nomogram constructed based on radiomics features and clinical factors can be used to predict the metastasis of left RLNN in patients with ESCC in a non-invasive way, which provided a reference for clinicians to formulate individualized lymph node dissection plans.

[Silencing Calreticulin Expression Inhibits Invasion Ability of SNK6 Cells in Vitro via Down-Regulating Expression of VEGF and MMP2/9].

OBJECTIVE: To investigate the effect of steadily down-regulating the expression of calreticulin (CALR) on the invasion of natural killer/T-cell lymphoma SNK6 cells, and explore its possible mechanism. METHODS: The sequences of specific short hairpin RNA (shRNA) targeting on human CALR were designed, and were inserted into pLKO.1-puro lentivirus vector, and the reconbinant lentivirus vector was obtained; the lentivirus particles were backed by three-plasmid system and transfected into SNK6 cells, the SNK6 cells stably down-regulating the CALR expression were sercened by puromytain, the CALR-silencing effect was verified by real-time PCR and Western blot. CCK-8 assay was used to evaluate the cell viability, The transwell invasion assays was used to analyse invasion of SNK6 cells. The mRNA expression of Calreticulin, MMP2, MMP9 and VEGF was determined by real time PCR, the protein expression of Calreticulin and GAPDH was analyzed by Western blot. RESULTS: The recombinant lentiviral vector pLKO.1-puro-shCALR was successfully constructed, packed into the lentivirus, then the SNK6 cells stably down-regulating Calreticulin expression was obtained. When Calreticulin was down-rengulated in SNK6 cells, the proliferation rate was reduced and the invasion ability was decreased; the mRNA levels of VEGF and MMP-2/9 also were reduced. CONCLUSION: The stable down-regnlation of CALR expression in SNK6 cells can attenuate the imvasiveness of SNK6 cells, which maybe related with transcriptional decrease of MMP2, MMP9 and VEGF.

The Effect of MicroRNA-124 Overexpression on Anti-Tumor Drug Sensitivity.

MicroRNAs play critical roles in regulating various physiological processes, including growth and development. Previous studies have shown that microRNA-124 (miR-124) participates not only in regulation of early neurogenesis but also in suppression of tumorigenesis. In the present study, we found that overexpression of miR-124 was associated with reduced DNA repair capacity in cultured cancer cells and increased sensitivity of cells to DNA-damaging anti-tumor drugs, specifically those that cause the formation of DNA strand-breaks (SBs). We then examined which DNA repair-related genes, particularly the genes of SB repair, were regulated by miR-124. Two SB repair-related genes, encoding ATM interactor (ATMIN) and poly (ADP-ribose) polymerase 1 (PARP1), were strongly affected by miR-124 overexpression, by binding of miR-124 to the 3¢-untranslated region of their mRNAs. As a result, the capacity of cells to repair DNA SBs, such as those resulting from homologous recombination, was significantly reduced upon miR-124 overexpression. A particularly important therapeutic implication of this finding is that overexpression of miR-124 enhanced cell sensitivity to multiple DNA-damaging agents via ATMIN- and PARP1-mediated mechanisms. The translational relevance of this role of miR-124 in anti-tumor drug sensitivity is suggested by the finding that increased miR-124 expression correlates with better breast cancer prognosis, specifically in patients receiving chemotherapy. These findings suggest that miR-124 could potentially be used as a therapeutic agent to improve the efficacy of chemotherapy with DNA-damaging agents.

Clinical effectiveness of aripiprazole in short-term treatment of tic disorder in children and adolescents: a naturalistic study.

BACKGROUND/PURPOSE: The purpose of this study was to evaluate the effectiveness and tolerability of aripiprazole in short-term treatment of children and adolescents with tic disorder (TD). METHODS: This was a 14-week, prospective, open-label flexible dose trial of aripiprazole. We enrolled patients with TD aged between 4 years and 18 years. They received aripiprazole (dose: 2.5 mg/day) initially, which was then adjusted according to clinical response. The severity was assessed by the Yale Global Tic Severity Score (YGTSS) at 0, 2, 6, 10, and 14 weeks. The linear mixed models were used for evaluation of the YGTSSs at each follow-up, which were compared with baseline scores. RESULTS: Eighty-one patients were enrolled in this study. Nine patients withdrew from the study with complaints of adverse side effects. Of the remaining 72 patients, 15 patients discontinued medications prematurely due to being free of symptoms for over 2 weeks. Two patients discontinued medications due to no significant improvement. The mean scores had significantly decreased since the 2nd week (p < 0.01). The mean reduction was 51.0% in the motor tic scores, 67.1% in the vocal tic scores, and 70.0% in the total YGTSSs. The common adverse effects were sedation (32.1%) and increased appetite (22.2%). A slight increase in average body weight was noted, from 32.7 to 33.7 kg (+1.0 kg, p < 0.05). CONCLUSION: Aripiprazole is effective for short-term treatment of TD, especially vocal tics, in children and adolescents with mild adverse effects. However, further double-blind trials against placebo or other medications are needed to verify the efficacy of aripiprazole in the pharmacotherapy of TD.

Prognostic factors of developmental outcome in neonatal seizures in term infants.

BACKGROUND: The purpose of this study was to identify prognostic indicators of neurodevelopmental outcome in term infants who experienced clinical neonatal seizure. METHODS: This is a retrospective, observational hospital-based study. Term infants who experienced clinical neonatal seizure between January 1999 and December 2009 were enrolled. Adverse outcomes were defined as death, cerebral palsy, global developmental delay, and/or epilepsy. The associations between adverse outcomes and 17 variables, including sex, mode of delivery, being small of gestational age, maternal illness, perinatal insults, meconium stained liquor, Apgar score at 1 and 5 minutes, seizure onset age, seizure type, etiology, electroencephalography (EEG) findings, antiepileptic drug efficacy, presence of metabolic acidosis, and cranial ultrasonographic findings, and presence of congenital heart disease were analyzed. RESULTS: Among the 232 enrolled infants, 125 had a normal outcome and 14 had mild functional disability (59.9%), and 55 (23.7%) survived with one or more neurodevelopmental impairments (7 with cerebral palsy, 48 with global developmental delay), and 38 (16.4%) died. Forty-seven (23.0%) of the 204 patients who survived after the first discharge had epilepsy. Ten variables were associated with adverse outcome on univariate analysis, but only four variables, i.e., including abnormal cranial ultrasonography findings, abnormal anterior cerebral artery resistance index, abnormal EEG findings, and presence of congenital heart disease were independent predictors on multivariate logistic regression analysis. CONCLUSION: In term infants with neonatal seizures, several risk factors related to adverse outcome were recognized. Physicians should pay more attention to these factors when handling patients with neonatal seizures.

99mTc-ethyl cysteinate dimer cranial single-photon emission computed tomography and serial cranial magnetic resonance imaging in a girl with isolated sulfite oxidase deficiency.

Isolated sulfite oxidase deficiency, a rare autosomal recessive inherited disorder, is easily misdiagnosed as the more common hypoxic-ischemic encephalopathy. A female term infant was diagnosed with isolated sulfite oxidase deficiency. Magnetic resonance imaging at ages 13 days, 2 months, and 10 months indicated diffuse edema with posterior predominance, followed by progressive multicystic encephalomalacia and brain atrophy with relatively sparing of the thalami. Single-photon emission computed tomography using (99m)Tc-ethyl cysteinate dimer at 2 months revealed decreased uptake in the frontal lobes. The characteristic neuroimaging findings in isolated sulfite oxidase deficiency help differentiate it from hypoxic insult. The correct diagnosis is helpful in genetic counseling for parents.

Microbial contaminations of laboratory mice and rats in Taiwan from 2004 to 2007.

Limited data are available on the pathogen status of contemporary rodent colonies in Taiwan. Here we summarized the rodent pathogen diagnostic records of the Taiwan National Laboratory Animal Center during a 4-y period that representing approximately 10% of the rodent colonies in Taiwan. Demand for pathogen diagnostic service increased continuously from 2004 to 2007, with a 20% increase each year. In 2007, more than 20% of the mouse colonies were positive for mouse parvovirus, mouse hepatitis virus, Theiler murine encephalomyelitis virus, and Mycoplasma pulmonis, with fewer colonies diagnosed as having infections of pneumonia virus of mice, mouse adenovirus, lymphocytic choriomeningitis virus, and reovirus. Almost 40% of tested rat colonies were positive for Mycoplasma pulmonis and rat parvovirus, with fewer colonies containing Kilham rat virus, sialodacryoadenitis virus, pneumonia virus of mice, Sendai virus, and Syphacia spp. These data provide a sound overall picture of the health status of mouse and rat colonies in Taiwan.