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BACKGROUND: Keratoconus (KC) is a corneal ectasia disease in which the vision of some patients cannot achieve satisfaction by spectacle corrections. However, not everyone can embrace contact lenses to achieve better vision. Perceptual learning (PL) is a potential treatment for vision improvement in such patients. PURPOSE: To investigate the effectiveness and maintenance of PL on vision improvement in KC patients corrected with spectacles. DESIGN: Randomized, double-blind clinical trial. PARTICIPANTS: Thirty-five non-progressive KC patients aged 9 years or older with unsatisfied spectacle-corrected vision were enrolled. METHODS: Non-progressive KC patients with best spectacle-corrected distance visual acuity (CDVA) of 0 to 1.0 logMAR (Snellen equivalent range 20/20 to 20/200) and contact lenses intolerant were enrolled. Eligible subjects were randomized into PL and control groups to receive PL and placebo training for 3 months, respectively. Spectacle-corrected visual acuity, contrast sensitivity function (CSF), stereoacuity, and visual functioning and quality of life questionnaires were measured at baseline, 3 months, and 6 months of follow-up. Statistics were analyzed following the intention-to-treat (ITT) principle. RESULTS: After 3 months of training, the CDVA of patients in the PL group improved as compared to the placebo group (0.17 ± 0.15 logMAR vs. 0.02 ± 0.06 logMAR; P = 0.0006). Eight out of seventeen (47.06 %) patients in the PL group reached CDVA improvement ≥ 2 lines (P=0.0010). This improvement persisted for at least 6 months (from baseline) as compared to the placebo group (0.17 ± 0.17 logMAR vs. 0.01 ± 0.07 logMAR; P = 0.0011). The increase of CSF in the PL group mainly was found for moderate spatial frequency (0.11 ± 0.17 log units at 3 cpd; 0.12 ± 0.19 log units at 6 cpd). Linear regression indicated that patients with worse initial CDVA achieved better gains in CDVA after PL (P = 0.009). No side effects were observed and no subjects quit because of training difficulties. CONCLUSION: Three-month perceptual learning improved vision in KC patients and the improvement maintained after 3 months of treatment cessation. The results indicate that perceptual learning may be a promising therapy for KC patients with unsatisfied spectacle-corrected visual acuity.

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Reactions of [Et4N][Tp*WS3(CuCl)3] (1) (Tp* = hydridotris(3,5-dimethylpyrazol-1-yl)borate) with 2 equiv. of AgOTf (OTf- = trifluoromethanesulfonate) and 1 equiv. of several bidentate pyridine ligands including 2,5-bis(pyridine-4-yl)thiazolo[5,4-d]thiazole (L1), 2,7-di(pyridin-4-yl)-9H-fluorene (L2), 2,7-di(pyridin-4-yl)-9H-carbazole (L3), and 2,7-di(pyridin-4-yl)-9H-fluoren-9-one (L4) afforded four W/Cu/S cluster-based supramolecular compounds [(Tp*WS3Cu2Cl)2(L1)] (2), {[(Tp*WS3Cu3)2(µ-Cl)2(µ4-Cl)]2(L2)2}(OTf)2 (3), {[(Tp*WS3Cu3)2(µ-Cl)2(µ4-Cl)]2(L3)2}(OTf)2 (4) and {[(Tp*WS3Cu3)2(µ-Cl)2(µ4-Cl)]2(L4)2}(OTf)2 (5). Compounds 2-5 were characterized by elemental analysis, IR, UV-vis, 1H NMR, and single-crystal X-ray diffraction analysis. The neutral cluster 2 behaves as a supramolecular wire constructed by L1 bridging two butterfly-shaped [Tp*WS3Cu2Cl] cores. The cluster cations of 3-5 contain two [(Tp*WS3Cu3)2(µ-Cl)2(µ4-Cl)]+ cores linked by two L2, L3, or L4 ligands, which finally formed a cationic supramolecular rectangle. The third-order nonlinear-optical (NLO) properties of 3-5 in DMF were also investigated by Z-scan techniques and their NLO responses were enhanced compared to those of their precursor 1.

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Manganese(III) porphyrins (MnIIIPs) as MRI contrast agents (CAs) have drawn particular attention due to their high longitudinal relaxivity (r1) and unique biodistribution. In this work, two MnIIIP-based oligomers, MnPD and MnPT, were designed to further improve the relaxivity with ease of synthesis. The two compounds were fully characterized and their nuclear magnetic relaxation dispersion (NMRD) profiles were acquired with a fast field cycling NMR relaxometer. Both of the compounds exhibited extended high molar r1 at high fields, higher than that of Gd-DTPA, the first clinical gadolinium(III)-based MRI CA. The r1 value of per manganese atom increased with the increasing number of MnIIIP building blocks, suggesting rotational correlation time (τR) played dominant role in the r1 dispersion. The toxicity of the two MnIIIPs and the imaging effectiveness were estimated in vitro and in vivo. With good biocompatibility, significant contrast enhancement, and complete excretion in 24 h, MnPD and MnPT are both promising for high field clinical applications. The applied strategy also potentially provided a facile approach for creation of more MnIIIP oligomer as efficient T1 MRI CAs.

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Objective To summarize the characteristics of lymph node metastasis in patients with papillary thyroid carcinoma accompanied with Graves disease,and to provide evidence for clinical treatment. Methods Totally 98 patients with papillary thyroid carcinoma and Graves disease who had been treated in Peking Union Medical College Hospital from January 2004 to December 2013 were divided into the lymph node metastasis positive group (n=34) and lymph node metastasis negative group (n=64). The general information,blood biochemical results,pathological results,and prognoses were compared between these two groups. Results These two groups showed no significant differences in gender (χ2=0.2113,P=0.6458),age (t=1.7000,P=0.0922),tumor diameter (t=1.2559,P=0.2122),and multifocal tumors (χ2=1.9170,P=0.1661). The median level of thyrotropin receptor antibody (TR-Ab) value in the lymph node metastasis positive group was 4.84 U/L,which was significantly higher than that in the negative group which was 2.99 U/L (t=2.0169,P=0.0465). There were no significant differences in serum thyroid stimulating hormone (t=0.0257,P=0.9800),free triiodothyronine (t=1.3610,P=0.1770),free thyroxine (t=0.0082,P=0.9930),thyroid peroxidase antibody (t=0.0177,P=0.9860),and thyroglobulin antibody levels (t=1.1450,P=0.2550) between two groups. The postoperative pathological results showed that tumor capsular invasion rate (26.5% vs. 9.38%;χ2=5.006,P=0.0253) and lymph node recurrence rate (14.7% vs. 1.56%;χ2=4.583,P=0.0323) were significantly higher in the positive group than in the negative group. The distal metastasis rate in the positive group and negative group were 5.88% and 0,respectively. Conclusions There is no definite association between lymph node metastasis and tumor size in patients with thyroid papillary carcinoma associated with Graves disease. The risk factors for lymph node metastasis include TR-Ab and tumor capsular invasion,with a higher incidence of lymph nodes recurrence.

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Objective To examine the expression of cell division cycle associated 2 (CDCA 2) in pancreatic ductal adenocarcinoma (PDAC) and investigate its role in prognosis of PDAC patients. Methods This retrospective study included 155 PDAC patients who underwent surgical treatment and complete post-operative follow-up. Clinicopathologic data were collected through clinical database. Tissue microarray was constructed and immunohistochemistry was performed to detect CDCA2 expression in the PDAC tumor tissues and adjacent non-tumor tissues. Clinicopathological characteristics between high and low CDCA2 expression were compared. Correlation of CDCA2 expressions with patients' survival was analyzed using Kaplan-Meier method and Cox regression analysis. Results Expression of CDCA2 in PDAC cells was significantly higher than that in adjacent non-tumor tissues (U=4056.5, P<0.001). Univariate analysis showed that CDCA2 expression [hazard ratio (HR)=1.574, 95% confidence interval (CI)=1.014-2.443, P=0.043] and node metastasis (HR=1.704, 95%CI=1.183-2.454, P=0.004) were significantly associated with prognosis. Cox regression analysis showed CDCA2 expression was not an independent prognostic risk factor (HR=1.418, 95%CI=0.897-2.242, P=0.135) for PDCA patients. Stratification survival analysis demonstrated CDCA2 expression as an independent prognostic risk factor in male patients (HR=2.554, 95%CI=1.446-4.511, P=0.003) or in non-perineural invasion patients (HR=2.290, 95%CI=1.146-4.577, P=0.012). Conclusions CDCA2 is highly expressed in PDAC tumor tissue. Although CDCA2 is not an independent prognostic risk factor for PDAC patients, it might be used to help predict prognosis of male or non-perineural invasion patients of PDAC.

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G-protein-coupled receptor kinase 2 (GRK2) was found to regulate biological behaviors in some cancers, including pancreatic cancer (PC). However, its clinicopathologic and prognostic implications in cancer remain unclear. This study was designed to address the issues in PC. Expression of GRK2 was measured by Western blotting and tissue microarray-based immunohistochemical staining in 3 and 171 patients with PC, respectively. The H-score was used to evaluate the staining results. In addition, GRK2 expression was correlated with clinicopathologic variables and overall survival. Finally, the prognostic value of GRK2 was validated in a publically available PC dataset, GSE21501. It was suggested that GRK2 expression was highly up-regulated in 2 out of 3 tumor samples, in contrast to corresponding non-tumor ones. Furthermore, H-score of GRK2 staining was significantly higher in tumor than in non-tumor tissues. Tumoral expression of GRK2 was significantly associated with T stage. Univariate analysis showed that high GRK2 expression in tumor tissues was predictive for poor overall survival of PC. However, GRK2 expression was not identified as an independent prognostic marker in multivariate Cox regression test, although close to the statistical significance. In dataset GSE21501, GRK2 was also revealed to be prognostic. Our data establish that GRK2 is overexpressed in PC, and might serve as a potential indicator of unfavorable prognosis.

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Human leucocyte antigen G (HLA-G) was shown to be associated with immune suppression and unfavorable prognosis in multiple types of cancers. However, its expression in pancreatic cancer (PC) was less investigated. Particularly, its roles in PC remain unknown. The present study aimed to address the issues. Expression of HLA-G was detected by Western blot and tissue microarray-based immunohistochemical staining in 10 and 158 patients with PC, respectively. In addition, tumor infiltrating lymphocytes (TIL) labeled by CD3 staining, as a marker of host immune response, were counted. Finally, immunohistochemical HLA-G expression was linked to clinicopathologic variables, TIL number and overall survival. It was found that HLA-G was overexpressed in 4 out of 10 patients. For staining, HLA-G expression was much higher in tumor than in non-tumor tissues. Tumoral expression of HLA-G was closely associated with T stage. Intratumoral CD3-positive TIL in tumors with diffuse HLA-G expression was less than that in those with negative or local HLA-G expression, but no significant differences for stromal TIL were observed. Univariate analysis found that diffuse HLA-G expression in tumor tissues and low intratumoral CD3-positive TIL number were of predictive significance for poor overall survival of PC. Furthermore, HLA-G expression and intratumoral CD3-positive TIL number were identified, by multivariate Cox regression test, as independent prognostic factors. Our data suggest that HLA-G impairs host immune response and predicts poor prognosis in PC.

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OBJECTIVE: To investigate the changes in the expression of glucose-regulated protein 78 (GRP78) in the occurrence and progression of pancreatic cancer in mouse models. METHODS: The mouse models of chronic pancreatitis,pancreatic intraepithelial neoplasia (PanIN), and pancreatic cancer were successfully established by dimethyl benzene and anthracene (DMBA) embedding in situ. GRP78 expression was detected in various stages by immunohistochemistry. RESULTS: Of these 60 mouse models, 18 mice (30%) died during the observation period. Two months after the embedding,the survived mice were sacrificed,and HE staining and IHC staining were performed. Among these mice, 9 (15%) developed chronic pancreatitis; 18 (30%) had PanIN [PanIN1,5 (8.3%);P anIN2,9 (15%); and PanIN 3,4 (6.7%)];15 (25%) developed pancreatic cancer. Immunohistochemistry showed that the expression of GRP78 in pancreatic cancer tissue was significantly higher than that in adjacent noncancerous duct cells (χ(2)=13.39,P =0.000). Also, GRP78 expression in pancreatic cancer tissue and high grade PanIN was significantly higher than that in low grade PanIN and chronic pancreatitis (χ(2)=17.84,P=0.000). CONCLUSION: The expression of GRP78 remarkably differs in different stages of pancreatic cancer and therefore is associated with the occurrence and progression of this disease.

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AIM: Previous research has suggested that Ephrin receptor A3 (EphA3) plays signaling roles in the processes of inflammation by regulating lymphocyte migration and proliferation. In this study, we investigated whether the EphA3 gene polymorphism was associated with disease progression of chronic hepatitis B virus (HBV) infection. METHODS: The EphA3 variant rs9310117 was genotyped in 1245 unrelated Han Chinese HBV carriers including 800 cases and 445 controls. χ(2) test was used to examine the difference in allele frequencies and genotype distributions between groups. The association between the polymorphism and disease progression of HBV infection was conducted by unconditional logistic regression analysis. RESULTS: Statistical analysis revealed that the genetic variant was significantly associated with the occurrence of chronic severe hepatitis B (CSHB). We observed that subjects bearing at least one T allele (C/T or T/T genotype) had a decreased susceptibility to chronic severe hepatitis B compared with those bearing C/C genotype (P = 0.003, odds ratio = 0.560; 95% confidence interval, 0.381-0.824, recessive model). Genotype C/T had also been confirmed to protect subjects from suffering chronic severe hepatitis B (P = 0.001, odds ratio = 0.498; 95% confidence interval, 0.330-0.752, additive model). CONCLUSION: Our results suggest that the genetic alteration at EphA3 locus plays a role in the occurrence of chronic severe hepatitis B.

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The host genetic compound plays a vital role in determining clinical outcomes of hepatitis B virus (HBV) infection. The tumor necrosis factor receptor-associated factor family member-associated nuclear factor-κB (NF-κB) activator (TANK) takes part in the tumor necrosis factor-α (TNF-α)-mediated NF-κB signaling pathway and the interferon (IFN)-induction pathways that have relevance to HBV-related liver disease. In this report, we explored whether the intronic polymorphism rs3820998 of the TANK gene was associated with outcomes of HBV infection by binary logistic regression analysis. A total of 1305 unrelated Han Chinese patients recruited from Wuhan, including 180 acute-on-chronic hepatitis B liver failure (ACLF-HBV) patients, 331 HBV-related liver cirrhosis (LC) patients, 308 HBV-related hepatocellular carcinoma (HCC) patients, and 486 asymptomatic HBV carriers (AsC) were genotyped using the TaqMan probe method. Logistic analysis revealed that the single-nucleotide polymorphism (SNP) rs3820998 was significantly associated with susceptibility to ACLF-HBV (dominant model, OR 0.643, 95% CI 0.428,0.964, p=0.033; additive model, OR 0.640, 95% CI 0.414,0.990, p=0.045), and LC (recessive model, OR 0.398, 95% CI 0.164,0.966, p=0.042; additive model, OR 0.379, 95% CI 0.155,0.928, p=0.034). These results indicate that the G > T variant is a protective factor in the development of ACLF-HBV and LC, and that the SNP rs3820998 in the TANK gene may play a role in mediating susceptibility to ACLF-HBV and LC in a Chinese Han population.

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To investigate the effect of hepatitis B virus X protein(HBx) on CtBP-interacting protein(CtIP) which is an important repair factor of DNA double strand break damage in HepG2 cells induced by bleomycin. A HBx stably expressing HepG2 cell line and a control HepG2 cell line with empty vector transfected were established. After the double strand break (DSB) damage occurred, the mRNA and protein levels of CtIP were detected by Real-time PCR and Western blot assay respectively, cell cycle profiles and apoptotic cell death were determined by a flow cytometry, and the position of CtIP in cells was observed by confocal laser scanning microscopy. It showed that HepG2 cells transfected with hepatitis B virus X gene could stably express HBx protein. After being induced by bleomycin, the percentage of apoptotic cell was 16.90%+/-0.89% in HBx stably expressing HepG2 cell line and 15.30%+/-0.86% in control cell line, respectively (q = 2.074, P is more than to 0.05). While the percentage of death cell was 8.71%+/-0.74% in HBx stably expressing HepG2 cell line and 4.90%+/-0.46% in control cell line, respectively (q = 7.126, P is less than to 0.01). The two cell lines manifested the increase of G2/M arrest and significant difference existed between the two cell lines. HBx down regulated the expression levels of CtIP and its mRNA. The CtIP level was 0.66+/-0.04 in HepG2-HBx cell and 0.73+/-0.05 in HepG2-vec cell, respectively (t = 2.314, P is less than to 0.05). The relative mRNA level was 1.00+/-0.06 in HepG2-HBx cell and 1.23+/-0.08 in HepG2-vec cell, respectively (t = 2. 732, P is less than to 0.05). We also found that CtIP was concentrated in the cell nucleus. The research suggests that HBx may affect DNA-repair pathways by disrupting the expression of CtIP.

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