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Complex diseases seriously affect people's physical and mental health. The discovery of disease-causing genes has become a target of research. With the emergence of bioinformatics and the rapid development of biotechnology, to overcome the inherent difficulties of the long experimental period and high cost of traditional biomedical methods, researchers have proposed many gene prioritization algorithms that use a large amount of biological data to mine pathogenic genes. However, because the currently known gene-disease association matrix is still very sparse and lacks evidence that genes and diseases are unrelated, there are limits to the predictive performance of gene prioritization algorithms. Based on the hypothesis that functionally related gene mutations may lead to similar disease phenotypes, this paper proposes a PU induction matrix completion algorithm based on heterogeneous information fusion (PUIMCHIF) to predict candidate genes involved in the pathogenicity of human diseases. On the one hand, PUIMCHIF uses different compact feature learning methods to extract features of genes and diseases from multiple data sources, making up for the lack of sparse data. On the other hand, based on the prior knowledge that most of the unknown gene-disease associations are unrelated, we use the PU-Learning strategy to treat the unknown unlabeled data as negative examples for biased learning. The experimental results of the PUIMCHIF algorithm regarding the three indexes of precision, recall, and mean percentile ranking (MPR) were significantly better than those of other algorithms. In the top 100 global prediction analysis of multiple genes and multiple diseases, the probability of recovering true gene associations using PUIMCHIF reached 50% and the MPR value was 10.94%. The PUIMCHIF algorithm has higher priority than those from other methods, such as IMC and CATAPULT., (Copyright © 2020 Wang, Zhang, Wang, Han and Guo.)

The imbalance of helper T cell (Th) 1/Th2 differentiation is involved in the development of allergic rhinitis (AR). Recent studies reveal the regulatory function of exosomes on Th1/Th2 differentiation. However, the key mediator in exosomes that modulate such response remains unclear. In this study, the expression of long-noncoding RNA GAS5 (LncGAS5) was detected in exosomes which were isolated from AR patient nasal mucus (AR-EXO) and ovalbumin (OVA)-stimulated nasal epithelial cells (OVA-EXO). Th1/Th2 differentiation was induced in naïve CD4 + T cells, and the percentage of IFN-γ expressing cells (Th1 cells) and IL-4 expressing cells (Th2 cells) was detected using flow cytometry. The result showed that LncGAS5 was upregulated in AR epithelial samples, AR-EXO, and OVA-EXO. The coincubation of AR-EXO and CD4 + T cells suppressed Th1 differentiation and promoted Th2 differentiation, which is mediated by LncGAS5 in AR-EXO. The LncGAS5 in AR-EXO inhibited transcription and expression of EZH2, and it also inhibited T-bet expression at mRNA and protein levels. The gain-of-function and loss-of-function experiments suggested that LncGAS5 mediates Th1/Th2 differentiation partly through downregulating T-bet and EZH2. In summary, our findings demonstrated that LncGAS5 in AR epithelium-derived exosomes is the key mediator in Th1/Th2 differentiation, providing a possible therapeutic target of AR., (Copyright © 2019. Published by Elsevier Ltd.)

Objectives: Lung cancer (LC) is often accompanied by significant methylation abnormalities. This study aimed to develop a decision tree (DT) accompanied the stature homeobox 2 gene (SHOX2) / prostaglandin E receptor 4 (PTGER4) gene DNA methylation with traditional tumor marker in the differential diagnosis of benign and malignant lung nodule., Methods: We performed a study with 104 patients enrolled in the LC group and 36 patients in the benign lung diseases group. All the clinical data of these patients were collected through electronic medical record. Total Methylation (TM) status of both SHOX2 and PTGER4 was defined as methylation levels of SHOX2 plus methylation levels of PTGER4. One-way analysis was used to compare the concentrations of serum samples and t-test was used to compare pairwise mean values between groups. Receiver operating curve (ROC) was used to evaluate the diagnostic value. Furthermore, the strategy was validated in 19 LC patients and 11 patients with benign lung diseases., Results: There were significant differences between the concentration of neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), cytokeratin 19 fragments (CYFRA21 -1) and the methylation levels of SHOX2, PTGER4 and TM in lung benign diseases and cancer group. The AUCs of NSE, CEA, CYFRA21 -1, Methylation SHOX2, Methylation PTGER4 and TM were 0.721 (95% CI: 0.627-0.816), 0.753 (95% CI: 0.673-0.833) and 0.778(95% CI: 0.700-0.856), 0.851(0.786-0.916), 0.847(0.780-0.913) and 0.861(0.800-0.922) respectively. We developed a DT model with TM and CYFRA21 -1 used in this study, and the area under the curve (AUC) of DT was 0.921 and the sensitivity up to 0.856. In the validation cohort, the AUC of SHOX2, PTGER4 and TM was also much higher than traditional serum markers., Conclusions: Our results indicated that the DT model calculated from the TM and CYFRA21 -1 can accurately classify LC and benign diseases, which showed better diagnostic performance than traditional serum parameter.

Noninvasive tools for the prognosis of α-fetoprotein negative hepatocellular carcinoma (HCC) are urgently needed. The present study proposed a prognostic system based on preoperative plasma prothrombin time and fibrinogen (PT/Fbg system). With respect to α-fetoprotein (AFP)-negative HCC, we compared the prognostic value in PT/Fbg system, Glasgow Prognostic Score, and aminotransferase/aspartate aminotransferase ratio. The present study retrospectively analyzed patient characteristics, clinicopathological factors, and the level of pretreatment biomarkers in 628 patients with HCC. Patients with increased PT and Fbg levels were allocated a score of 2, patients with only one of these abnormalities were assigned score 1, and patients with neither of these abnormalities were allocated a score of 0. The following distributions of the PT/Fbg system scores were observed: 187 (29.78%) patients had a score of 0, 305 (30.65%) had a score of 1, and 134 (22.69%) patients had a preoperative score of 2. The prognostic significance of the PT/Fbg system was determined using univariate and multivariate Cox hazard analyses in AFP-negative HCC. Multivariate analysis revealed that patients with a higher PT/Fbg system exhibited worse overall survival (OS) than patients with a lower PT/Fbg system. Our study proposes preoperative evaluation of the plasma PT/Fbg system to predict the OS of patients with AFP-negative HCC.

In this work, the effects of α-linolenic acid (ALA) loaded in oil-in-water (O/W) and water-in-oil-in-water (W/O/W) microemulsions on cell viability, lactic dehydrogenase (LDH) viability, and reactive oxygen species (ROS) levels were examined using Cell Counting Kit-8 (CCK-8), an LDH assay kit, and a fluorescence microscope, respectively. The CCK-8 assay demonstrated that ALA inhibited MDA-MB-231 human breast cancer cell proliferation in a dose-dependent manner. Further, the results of LDH activity and ROS levels revealed that ALA-induced cancer cell damage was closely related to oxidative stress. Under the irradiation of ultraviolet light, the microemulsion without any added fluorescent dye would emit bright blue fluorescence, and the fluorescent images of the cells treated with ALA-loaded O/W and W/O/W microemulsions at different incubation times were taken, which exhibited long-term photostability and biocompatibility. In addition, the fluorescence mechanism of the microemulsion was explained by immobilizing surfactant molecules with aggregation-induced emission (AIE) properties at the water-oil interface through the microemulsion with a self-assembled structure. These findings showed the potential application of O/W and W/O/W microemulsions as the label-free delivery carriers in long-term imaging of living cells and real-time release monitoring of nutrients.

The differentiation of human mesenchymal stem cells (hMSCs) into hepatocyte-like cells in vitroprovides a promising candidate for cell therapy of liver diseases, and cell aggregates have been proposed to improve the efficiency of expansion and differentiation. Previously, we engineered multicellular aggregates incorporating human E-cadherin fusion protein (hE-cad-Fc)-coated poly(lactic-co-glycolic acid) (PLGA) microparticles (hE-cad-PLGAs), and a significant improvement was obtained in both cellular proliferation of and cytokine secretion by hMSCs. In this study, hepatic differentiation of hMSCs was induced by a biomimetic microenvironment consisting of these engineered aggregates and a cocktail of specific cytokines. The ratio of hE-cad-PLGAs to hMSCs in engineered hMSCs aggregates was optimized to 1:3 for hepatic differentiation. The expressions of hepatic-specific markers were significantly promoted, and cell polarity and activated drug metabolism enzymes were established in MSC/hE-cad-PLGA aggregates compared with MSC and MSC/PLGA aggregates. Moreover, the expressions of stemness and definitive endoderm markers confirmed effectively induced endoderm differentiation in MSC/hE-cad-PLGA aggregates, which was consistent with the pattern of embryonic development. After pre-differentiation for 1 week, the MSC/hE-cad-PLGA aggregates continuously progressed the hepatic phenotype expression in healthy rat peritoneum. Therefore, the biomimetic microenvironment constructed by hE-cad-PLGAs in engineered multicellular aggregates was able to promote the process of endoderm differentiation and the subsequent hepatic differentiation of hMSCs. It would be appropriate for applied research in hepatotoxic drug screening and cell-based treatment of liver diseases. By optimizing with other cytokine cocktail, the engineered multicellular aggregates can be applied to the construction of other endoderm-derived organs. STATEMENT OF SIGNIFICANCE: The differentiation of mesenchymal stem cells (MSCs) into hepatocyte-like cells in vitroprovides a promising for cell therapy for liver diseases, and cell aggregates have been proposed to improve the expansion and differentiation efficiency. Here, engineered multicellular aggregates were constructed by E-cadherin modified microparticles (hE-cad-PLGAs) construct a biomimetic microenvironment to promote the process of endoderm differentiation and the subsequent hepatic differentiation of hMSCs. Furthermore, after pre-differentiation for 1 week, the MSC/hE-cad-PLGA aggregates continuously progressed the hepatic phenotype expression in healthy rat peritoneum. Therefore, engineered multicellular aggregates with hE-cad-PLGAs would be appropriate for applied research in hepatotoxic drug screening and cell-based treatment of liver diseases, and provide a promising method in the construction of other endoderm-derived organs., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Risperidone has been used to treat the symptoms of schizophrenia and to reduce its relapse. However, the responses to treatment show great variability among patients. The potassium channel has been reported as an effective target for antipsychotics. KCNH7 , a member of the voltage-gated K + channel Kv11 family, is primarily expressed in the brain. Here, we assessed the genetic association of KCNH7 with risperidone responses in 393 schizophrenia patients. The patients were treated with risperidone for 6 weeks. The reduction rates of Positive and Negative Syndrome Scale (PANSS) scores were determined to quantify drug response. We also examined the associations between six single-nucleotide polymorphisms (SNPs) of KCNH7 and the risperidone responses for a total of 6 weeks. The SNP rs77699177 (C > T) in the KCNH7 gene intron was significantly associated with the treatment response reflected by the PANSS reduction rate (CC, 55.8 ± 23.0; TC, 70.9 ± 20.3, P = 0.000110), indicating that patients with the TC genotype have better efficacy for antipsychotic therapy. The rs2241240 SNP also showed a significant association with treatment responses after 6 weeks of treatment ( P = 0.00256). The findings indicate that the voltage-gated K + channel KCNH7 is a potential functional marker for the identification of the response to risperidone treatment in schizophrenia patients. Note: The study was registered under clinical trial number ChiCTR-RNC-09000522 (http://www.chictr.org/).

Purpose: We systematically reviewed studies to provide current evidence about the incidence and risk of alopecia in patients undergoing valproic acid (VPA) therapy., Methods: We retrieved relevant publications and gathered data on alopecia in patients taking VPA and other drugs from prospective studies., Results: Twenty-five articles met the inclusion criteria, and the overall incidence of alopecia in patients receiving VPA therapy was 11% (95% confidence interval (CI): 0.08-0.13). The pooled risk of alopecia showed a significant difference between patients treated with VPA and all other drugs (odds ratio (OR) 5.02, 95% CI: 3.58-7.03), other epileptic drugs (AEDs) (OR 4.82, 95% CI: 3.32-7.00) and other non-AEDs (OR 5.84, 95% CI: 2.67-12.81). Compared to other drugs, VPA increased the risk of alopecia both in patients with migraine headaches (OR 6.05, 95% CI: 2.89-12.63) and patients with epilepsy (OR 5.29, 95% CI: 3.53-7.92), and the increase risk was reported more frequently in patients with migraine. Both lower doses (OR 4.38, 95% CI: 2.32-8.25) and shorter treatments (OR 4.98, 95% CI: 2.41-10.25) with VPA posed a high risk of alopecia compared to other drugs, as did higher doses and longer treatment times., Conclusions: Based on our findings, VPA was significantly associated with a risk of alopecia compared to other drugs, and the risk did not depend on the dose and treatment time., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective : As a member of the Wnt family, WNT6 contributes to tumorigenesis and the development of various types of cancer. However, the expression status of WNT6 in colorectal liver metastasis (CRLM) and its prognostic value remain to be elucidated. In this study, we evaluated the association of WNT6 expression with survival outcomes in CRLM patients undergoing liver resection. Methods : The medical records of 106 consecutive CRLM patients undergoing curative tumor resection between October 1996 and December 2011 were retrospectively selected. WNT6 expression was detected using immunohistochemistry (IHC) analyses on paraffin-embedded specimens. The IHC score was determined according to the percentage and intensity of positively stained cells. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and the log-rank test, and independent prognostic factors were determined by Cox regression modeling. Results : We found that WNT6 was commonly expressed in 93.4% (99/106) of colorectal cancer tissues. The median IHC score of WNT6 expression was significantly lower in patients receiving preoperative chemotherapy than those without preoperative chemotherapy (1.33 vs. 2.33, P = 0.033). Survival analysis indicated that patients with high WNT6 expression had poorer 5-year OS than those with low WNT6 expression (31.0% vs. 62.2%, P = 0.012). The 5-year OS rate was significantly lower in the high WNT6 group than in the low WNT6 group (36.8% vs. 79.9%, P = 0.013) in low-risk patients but was comparable among the high-risk patients (22.7% vs. 34.7%, P = 0.433). Multivariate analysis indicated that high WNT6 expression was independently associated with poor OS (hazard ratio [HR]: 2.089; 95% confidence interval [CI]: 1.231-3.545; P = 0.006). Conclusions : High expression of WNT6 was associated with unfavorable oncologic prognosis in patients with CRLM undergoing liver resection. Detection of WNT6 expression may be valuable for guiding postoperative treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

The aim of this study is to establish and validate an effective prognostic nomogram in patients with AFP-negative hepatocellular carcinoma (HCC). The nomogram was based on a primary cohort that consisted of 419 patients with clinicopathologically diagnosed with HCC, all the data was gathered from 2008 to 2014 in Sun Yat-sen University Cancer Center. All the model factors were determined by univariate and multivariate Cox hazard analysis. The concordance index (C-index) and calibration curve were used to determine the predictive accuracy and discriminative ability of the nomogram, and compared with the TNM staging systems on HCC. Internal validation was assessed. An independent validation cohort contained 150 continuous patients from 2014 to 2015. Independent factors for overall survival (OS) were body mass index (BMI), tumor stage, distant metastases, HBs Ag, lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGT), and albumin (ALB), which were all contained into the nomogram. The calibration curve for probability of OS showed good agreement between prediction by nomogram and actual observation. The C-index of nomogram was 0.807 (95% CI: 0.770-0.844), which was superior to the C-index of AJCC TNM Stage (0.697). The AUC was 0.809(95%CI: 0.762-0.857). In the validation cohort, the nomogram still gave good discrimination (C-index: 0.866, 95% CI: 00.796-0.936; AUC: 0.832, 95%CI: 0.747-0.917) and good calibration. Decision curve analysis demonstrated that the nomogram was clinically useful. Moreover, patients were divided into three distinct risk groups for OS by the nomogram: low risk group, middle risk group and a high risk group, respectively. The proposed nomogram presents more accurate and useful prognostic prediction for patients with AFP-negative HCC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Purpose: The present study aimed to compare the chemotherapeutic regimens of gemcitabine plus cisplatin (GC) vs pemetrexed plus cisplatin (PC) in bladder cancer (BC) with vascular invasion and/or distant metastasis., Methods: From January 2010 to January 2017, 53 patients with advanced or metastatic BC were included and randomly divided into two groups. Patients in the GC group were administered 1,000 mg/m 2 gemcitabine on day 1 and 15 and 70 mg/m 2 cisplatin on day 1 as an IV infusion. Patients in the PC group were administered 500 mg/m 2 pemetrexed on day 1 and 15 and 70 mg/m2 cisplatin on day 1 as an IV infusion. The two regimens were repeated every 28 days. Patients were treated for about 4-6 cycles until the occurrence of severe toxicity or patient refusal., Results: The median overall survival (OS) and the median progression-free survival (PFS) in the GC group were significantly higher than that in the PC group (OS: p=0.033 and PFS: p=0.039, respectively). Besides, the response rates and disease control were obviously higher in the GC group (68% and 86%, respectively) compared to the PC group (44% and 56%, respectively), although without statistical significance. Regarding toxicity, higher rates of neutropenia and nausea in the PC group were noted, while thrombocytopenia was more frequent in the GC group., Conclusions: The gemcitabine plus cisplatin combination was more effective and well tolerated in patients with advanced or metastatic BC compared to the pemetrexed plus cisplatin regimen.

Objective: To investigate the function of repair gene LIG4 in radiosensitivity enhancement of rectal cancer cells by curcumin., Methods: Human rectal cancer cells HT-29 were cultured in normal. LIG4-overexpression HT-29 cells and blank control plasmid HT-29 cells were established by gene transfection. Both kind of HF-29 cells were further randomly divided into curcumin group, radiotherapy group, curcumin plus radiotherapy group (combined group) and control group. The growth inhibition and apoptosis of cells were detected by MTT and Annexin V/PI respectively. Change of tumor volume was observed in nude mouse xenograft model, and the apoptosis of tumor cells was analyzed by TUNEL., Results: Regarding blank control plasmid HT-29 cells, the growth inhibition rate and apoptosis rate in combined group were significantly higher than those in radiotherapy group(all P<0.05); tumor volume of nude mouse in combined group was significantly smaller than that in radiotherapy group, and the apoptotic index in combined group was significantly higher than that in radiotherapy group (all P<0.05). However, regarding LIG4-overexpression HT-29 cells, the growth inhibition rate and apoptosis rate were not significantly different between combined group and radiotherapy group(all P>0.05); the tumor volume of nude mouse and the apoptotic index were also not significantly different between combined group and radiotherapy group (all P>0.05)., Conclusion: Down-regulation of LIG4 is an important mechanism of radiosensitivity enhancement of rectal cancer cells by curcumin.

Objective: Aimed to analyse the clinical features of the patients with sphenoid sinus mucocele, achieve earlier diagnosis and more timely intervention and decrease the occurrence of misdiagnoses., Method: A retrospective study was first conducted in patients with sphenoid sinus mucoele treated in Xiangya hospital from Jan 2000 to Jan 2015. Then literature reports on this disease were collected and analyzed from China National Knowledge Infrastructure (CNKI) and Wan Fang database., Result: We collected 82 patients with sphenoid sinus mucocele treated in Xiangya hospital. There were 52 patients presented with headache, 31 patients presented with visual impairment, 10 patients presented with cranial nerve palsy, 2 patients presented with exophthalmos, 15 patients presented with nasal symptoms, and 5 patients with no obvious symptoms. There was no significant difference for symptoms distribution between male and female patients (P > 0.05). Among 45 patients with headache as first symptom and 10 patients with ethmoid sinus mucocele, there were 18 patients and 8 patients subsequently suffering from visual impairment, respectively. We also collected 161 patients in literature except for enrolling, the 82 patients treated in Xiangya hospital, and found that headache was the most common symptom, followed by visual impairment, in the two independent cohorts., Conclusion: To the best of our knowledge, this is the study of maximum sample for sphenoid sinus mucocele in China. Headache and visual impairment are the most common symptoms for sphenoid sinus mucocele. Surgical treatment should be early performed when the desease accompanied with headache or ethmoid sinus mucocele, to avoid other complications such as visual impairment and even blindness.

Background: Targeting the immune checkpoints in solid tumors becomes hot recently. Programmed cell death ligand 1 (PD-L1) is ligand for programmed death 1 (PD-1), which is known to negatively regulate T-cell activation. In the present study, we investigated the expression of PD-L1 in tumor specimens of gastric cancer and its relationships with clinicopathological variables and survival., Methods: The expression of PD-L1 in 132 surgically resected specimens of stage II and III gastric cancer was evaluated by immunohistochemistry in microarray tissue., Results: Expression of PD-L1 was observed in 50.8% (67/132) of gastric cancer tumor specimens. Patients whose tumor size over 5cm had a higher positive rate of PD-L1 expression. There was no relationship between the expression of PD-L1 and other clinicopathological variables including age, gender, clinical stage, location as well as histological differentiation. PD-L1 positive patients had significantly poorer survival than negative patients. The 5-year survival rates was 83.1% in those with PD-L1 negative patients and 50.7% for PD-L1 positive patients (P<0.001). The multivariate analysis indicated that both PD-L1 positive and Tumor-node-metastasis stage were independent prognostic factors in gastric cancer patients (P=0.001 and 0.025, respectively)., Conclusions: The expression of PD-L1 was found in half of stages II and III gastric cancer patients. Positive of PD-L1 expression indicated poor survival in Chinese stages II and III gastric adenocarcinoma patients. These results may provide the clue for immunotherapy in the adjuvant treatment setting of gastric cancer patients.

Recently, bipolar fuzzy sets have been studied and applied a bit enthusiastically and a bit increasingly. In this paper we prove that bipolar fuzzy sets and [0,1](2)-sets (which have been deeply studied) are actually cryptomorphic mathematical notions. Since researches or modelings on real world problems often involve multi-agent, multi-attribute, multi-object, multi-index, multi-polar information, uncertainty, or/and limit process, we put forward (or highlight) the notion of m-polar fuzzy set (actually, [0,1] (m)-set which can be seen as a generalization of bipolar fuzzy set, where m is an arbitrary ordinal number) and illustrate how many concepts have been defined based on bipolar fuzzy sets and many results which are related to these concepts can be generalized to the case of m-polar fuzzy sets. We also give examples to show how to apply m-polar fuzzy sets in real world problems.

Background: To study etiology of clinically diagnosed non A-E hepatitis., Methods: HBV, TTV, human parvovirus B19, SENV DNA were detected by nested polymerase chain reactions (nPCR), while HGV, HCV RNA were tested by reverse transcription nested polymerase chain reactions (RT-nPCR)., Results: Of 60 patients with clinically diagnosed non A-E hepatitis, 30 (50.0%) were HBV DNA positive alone, 10 (16.7%) HBV and TTV DNA positive, 6 (10.0%) HBV and B19 DNA positive; 1 (1.7%) HBV, SENV DNA and HCV RNA positive, 1 (1.7%) HCV RNA positive alone, 1 (1.7%) HCV RNA and B19 DNA positive, 2 (3.3%) B19 DNA positive alone, 1 (1.7%) TTV DNA positive alone, and the remaining 8 (13.3%) negative for all viruses. All the 60 patients were HGV RNA negative. There were no differences in serum biochemical markers of hepatitis B patients with or without TTV or B19 virus infection., Conclusions: HBV is a major etiologic agent for the clinically diagnosed non A-E hepatitis. HGV, TTV, B19 and SEBV may not be associated with nonA-E hepatitis.