Clinical significance of nonerythrocytic spectrin Beta 1 (SPTBN1) in human kidney renal clear cell carcinoma and uveal melanoma: a study based on Pan-Cancer Analysis.

BACKGROUND: Nonerythrocytic spectrin beta 1 (SPTBN1) is an important cytoskeletal protein that involves in normal cell growth and development via regulating TGFß/Smad signaling pathway, and is aberrantly expressed in various cancer types. But, the exact role of SPTBN1 in pan-cancer is still unclear. This report aimed to display expression patterns and prognostic landscapes of SPTBN1 in human cancers, and further assess its prognostic/therapeutic value and immunological role in kidney renal carcinoma (KIRC) and uveal melanoma (UVM). METHODS: We firstly analyzed expression patterns and prognostic landscapes of SPTBN1 in human cancers using various databases and web-based tools. The relationships between SPTBN1 expression and survival/tumor immunity in KIRC and UVM were further investigated via R packages and TIMER 2.0 platform. The therapeutic roles of SPTBN1 in KIRC and UVM were also explored via R software. Following this, the prognostic value and cancer immunological role of SPTBN1 in KIRC and UVM were validated in our cancer patients and GEO database. RESULTS: Overall, cancer tissue had a lower expression level of SPTBN1 frequently in pan-cancer, compared with those in adjacent nontumor one. SPTBN1 expression often showed a different effect on survival in pan-cancer; upregulation of SPTBN1 was protective to the survival of KIRC individuals, which was contrary from what was found in UVM patients. In KIRC, there were significant negative associations between SPTBN1 expression and pro-tumor immune cell infiltration, including Treg cell, Th2 cell, monocyte and M2-macrophage, and expression of immune modulator genes, such as tumor necrosis factor superfamily member 9 (TNFSF9); while, in UVM, these correlations exhibited opposite patterns. The following survival and expression correlation analysis in our cancer cohorts and GEO database confirmed these previous findings. Moreover, we also found that SPTBN1 was potentially involved in the resistance of immunotherapy in KIRC, and the enhance of anti-cancer targeted treatment in UVM. CONCLUSIONS: The current study presented compelling evidence that SPTBN1 might be a novel prognostic and therapy-related biomarker in KIRC and UVM, shedding new light on anti-cancer strategy.

Development and validation of a nomogram based on common biochemical indicators for survival prediction of children with high-risk neuroblastoma: A valuable tool for resource-limited hospitals.

BACKGROUND: Despite multiple attempts have been made to develop risk stratification within high-risk neuroblastoma (NB) patients (age of diagnosis ≥ 18 month-old with metastatic NB), the definition of "ultra high-risk NB" is still lack of consensus, and indicators for identifying this subgroup are still unclear. This study aimed to develop a nomogram based on easy-to-obtain blood-derived biofactors for identifying ultra high-risk NB patients with highest risk of death within 3 or 5 years. METHODS: One hundred sixty-seven NB patients who treated at Sun Yat-sen University Cancer Center between 2015 and 2023 were recruited and clustered randomly into training and validation cohorts (116 and 51 cases, respectively). Univariate and multivariate Cox analysis were performed in training set to screen independent prognostic indicators for constructing nomogram model of predicting 1-, 3- and 5-year overall survival (OS). The discrimination power of the nomogram in training and validation sets were assessed by concordance index (C-index) and calibration plot. Based on the risk score obtained from nomogram model, the prognostic accuracy of 1-, 3- and 5-year OS rates in training and validation cohorts were further evaluated using the area under receiver operating characteristic (ROC) curves (AUC). RESULTS: Through univariate and multivariate Cox analysis, independent prognostic indicators, including serum lactate dehydrogenase (LDH) and albumin (ALB), were identified in training set, and used to establish a nomogram model. The model showed good discrimination power with C-index in training cohort being 0.706 (95%CI: 0.633-0.788). According to the cut-point calculated based on the established nomogram, patients with a nomogram score > 34 points could be stratified to ultra high-risk NB subgroup, and this subgroup had poorer OS than those in non-ultra one (p < 0.001). AUC values of ROC curves for 3- and 5-year OS rates in the training set were 0.758 and 0.756, respectively. Moreover, based on the cut-point score (34 points) developed in training set, The model also showed good discrimination power with C-index of 0.773 (95%CI: 0.664-0.897) and powerful prognostic accuracy of AUC for 3- and 5-year OS rates being 0.825 and 0.826, respectively, in validation cohort. CONCLUSIONS: We developed a simple-to-use nomogram based on common laboratory indicators to identify the subgroup of ultra high-risk NB before treatment, providing these children even from developing countries or regions access to intensified multimodal treatments earlier and thus improving their long-term outcome.

Phosphoserine phosphatase as a prognostic biomarker in patients with gastric cancer and its potential association with immune cells.

BACKGROUND: Because of dismal prognosis in gastric cancer, identifying relevant prognostic factors is necessary. Phosphoserine phosphatase (PSPH) exhibits different expression patterns in many cancers and has been reported to affect the prognosis of patients with cancer. In this study, we examined the prognostic role of metabolic gene PSPH in gastric cancer based on the TCGA dataset and our hospital-based cohort cases. METHODS: We collected and analysed RNA-seq data of Pan-cancer and gastric cancer in the TCGA dataset and PSPH expression data obtained from immunohistochemical analysis of 243 patients with gastric cancer from Sun Yat-sen University cancer center. Further, Kaplan-Meier survival analysis and Cox analysis were used to assess the effect of PSPH on prognosis. The ESTIMATE and Cibersort algorithms were used to elucidate the relationship between PSPH and the abundance of immune cells using the TCGA dataset. RESULTS: We observed that PSPH expression displayed considerably high in gastric cancer and it was significantly associated with inferior prognosis (P = 0.043). Surprisingly, there was a significant relationship between lower immune scores and high expression of PSPH (P < 0.05). Furthermore, patients with a low amount of immune cells exhibited poor prognosis (P = 0.046). The expression of PSPH significantly increased in activated memory CD4 T cells, resting NK cells and M0 macrophages (P = 0.037, < 0.001, and 0.005, respectively). CONCLUSIONS: This study highlighted that PSPH influences the prognosis of patients with gastric cancer, and this is associated with the infiltration of tumour immune cells, indicating that PSPH may be a new immune-related target for treating gastric cancer.

Polymorphisms in matricellular SPP1 and SPARC contribute to susceptibility to papillary thyroid cancer.

There is a compelling need to identify novel genetic variants for papillary thyroid cancer (PTC) susceptibility. The Cancer Genome Atlas (TCGA) data showed associations between SPP1 and SPARC mRNA overexpression and aggressive behaviors of PTC, which prompted us to assess potential associations between genetic variants in these genes and PTC risk. Three highly linked SPARC loci (rs1054204, rs3210714, and rs3549) contributed to reduced PTC risk under a codominant model (odds ratio [OR], 0.79-0.80). Variant CAG alleles at these loci significantly enhanced SPARC transcription activation upon cotransfection with miR-29b and miR-495 when compared to the common alleles GGC (all P < 0.05). The three SPARC polymorphisms interacted with SPP1 rs4754, with elevated joint ORs of 2.43, 2.52, and 2.52, respectively. Additionally, interaction between SPP1 rs2358744 and SPARC rs2304052 was observed. Our study revealed associations between SPP1 and SPARC polymorphisms that, individually or in combination, are involved in PTC susceptibility.

Histopathological growth patterns correlate with the immunoscore in colorectal cancer liver metastasis patients after hepatectomy.

Various scoring systems have been proposed to predict the postoperative prognosis of colorectal liver metastasis (CRLM), including the clinical risk score (CRS), the immunoscore and so on. Recently, histopathological growth patterns (HGPs) have been recognized. However, the correlation between HGPs and the immunoscore, and their prognostic values in patients with CRLM after liver resection remain undetermined. In this study, HGPs were retrospectively evaluated in H&E-stained slides from 166 CRLM patients. The immunoscore was calculated according to the densities of immunostained CD3 + and CD8 + cells. A risk score combining HGPs, the immunoscore and the CRS was defined and divided patients into the low-, medium- and high-risk group. Our results showed that the densities of CD3 + and CD8 + cells were higher in the desmoplastic HGP (dHGP) group than in the non-dHGP group, and the proportion of high immunoscores was also higher in the dHGP group (51.9% vs. 33.0%, respectively, P = 0.020). Patients with the dHGP had significantly longer relapse-free survival (RFS) and overall survival (OS) than those with the non-HGP. The low-risk group showed significantly higher 2-year RFS and 5-year OS rates than the other two groups (RFS: 76.2%, 43.7% and 33.1%, respectively; P < 0.001; OS: 89.7%, 54.4% and 33.3%, respectively; P < 0.001). In conclusion, the dHGP correlates with relatively high immunoscores, predicting a favorable prognosis independent of the immunoscore and CRS. A novel risk score combining HGPs, the immunoscore and the CRS may be used for the stratification of CRLM patients' survival.

The Immunoscore system predicts prognosis after liver metastasectomy in colorectal cancer liver metastases.

BACKGROUND: The Immunoscore was initially established to evaluate the prognosis of stage I/II/III colorectal cancer patients. However, the feasibility of the Immunoscore for the prognosis of colorectal cancer liver metastases (CRCLM) has not been reported. METHODS: Liver metastases in 249 CRCLM patients were retrospectively analyzed. The Immunoscore was assessed according to the counts and densities of CD3+ and CD8+ T cells in the central- and peritumoral areas by immunohistochemistry. The prognostic role of the Immunoscore for relapse-free survival (RFS) and overall survival (OS) was analyzed with Kaplan-Meier curves and Cox multivariate models, and confirmed via an internal validation. Receiver operating characteristic (ROC) curves were plotted to compare the prognostic values of the Immunoscore and the clinical risk score (CRS) system. RESULTS: CRCLM patients with high Immunoscores (> 2) had significantly longer RFS [median RFS (95% confidence interval; 95% CI) 21.4 (7.8-35.1) vs. 8.7 (6.8-10.5) months, P < 0.001] and OS [median OS (95% CI): not reached vs. 28.7 (23.2-34.2) months, P < 0.001] than those with low Immunoscores (≤ 2). After stratification by CRS, the Immunoscore retained a statistically significant prognostic value for OS. The areas under the ROC curves (AUROCs) of the Immunoscore and the CRS system for RFS were 0.711 [95% CI 0.642-0.781] and 0.675[95% CI 0.601-0.749] (P = 0.492), whereas the AUROC of the Immunoscore system for OS was larger than that of the CRS system [0.759 (95% CI 0.699-0.818) vs. 0.660 (95% CI 0.592-0.727); P = 0.029]. CONCLUSIONS: The Immunoscore of liver metastases can be applied to predict the prognosis of CRCLM patients following liver resection.

Serum microRNA profiles as diagnostic biomarkers for HBV-positive hepatocellular carcinoma.

BACKGROUND & AIMS: The discovery of effective and reliable biomarkers to detect hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC) at an early stage may improve the survival of HCC. The aim of this study was to establish serum microRNA (miRNA) profiles as diagnostic biomarkers for HBV-positive HCC. METHODS: We used deep sequencing to screen serum miRNAs in a discovery cohort (n=100). Quantitative polymerase chain reaction (qPCR) assays were then applied to evaluate the expression of selected miRNAs. A diagnostic 2-miRNA panel was established by a logistic regression model using a training cohort (n=182). The predicted probability of being detected as HCC was used to construct the receiver operating characteristic (ROC) curve. Area under the ROC curve (AUC) was used to assess the diagnostic performance of the selected miRNA panel. RESULTS: The predicted probability of being detected as HCC by the 2-miRNA panel was calculated by: logit P=-2.988 + 1.299 × miR-27b-3p + 1.245 × miR-192-5p. These results were further confirmed in a validation cohort (n=246).The miRNA panel provided a high diagnostic accuracy of HCC (AUC=0.842, P<.0001 for training set; AUC=0.836, P<.0001 for validation set respectively). In addition, the miRNA panel showed better prediction of HCC diagnosis than did alpha-foetoprotein (AFP). The miRNA panel also differentiated HCC from healthy (AUC=0.823, P<.0001), and cirrhosis patients (AUC=0.859, P<.0001) respectively. CONCLUSIONS: Differentially expressed serum miRNAs may have considerable clinical value in HCC diagnosis, and be particularly helpful for AFP-negative HCC.

Association between serum uric acid levels and cerebral white matter lesions in Chinese individuals.

PURPOSE/AIM OF THE STUDY: We aimed to evaluate the association between serum uric acid (SUA) levels and cerebral white matter lesions (WMLs) in Chinese individuals. MATERIAL AND METHODS: We prospectively identified patients aged 50 years and older in neurology department from July 2014 to March 2015. Both periventricular WMLs (P-WMLs) and deep WMLs (D-WMLs) were identified on magnetic resonance imanging (MRI) scans and the severity was graded using the Fazekas method. Multivariate logistic regression analyses were performed to examine the association between SUA and WMLs. RESULTS: A total of 480 eligible participants were enrolled in this study. SUA level in severe group was much higher than that in mild group (for P-WMLs: 320.21 ± 79.97 vs. 286.29 ± 70.18, p = 0.000; for D-WMLs: 314.71 ± 74.74 vs. 290.07 ± 74.04, p = 0.031). Subgroup analyses showed that higher SUA level was associated with higher severity of P-WMLs in women, but not in male patients. Multivariate logistic regression analyses showed that SUA was still associated with increased risk of higher severity of P-WMLs (OR = 1.003, 95% = 1.000-1.006), but not D-WMLs. CONCLUSION: Elevated SUA level was independently associated with greater odds of higher severity of P-WMLs, particularly in women.

Effects of manganese deficiency on chondrocyte development in tibia growth plate of Arbor Acres chicks.

The aim of this study was to investigate the effects of manganese (Mn) deficiency on chondrocyte development in tibia growth plate. Ninety 1-day-old Arbor Acres chicks were randomly divided into three groups and fed on control diet (60 mg Mn/kg diet) and manganese deficient diets (40 mg Mn/kg diet, manganese deficiency group I; 8.7 mg Mn/kg diet, manganese deficiency group II), respectively. The width of the proliferative zone of growth plate was measured by the microscope graticule. Chondrocyte apoptosis was estimated by TUNEL staining. Gene expression of p21 and Bcl-2, and expression of related proteins were analyzed by quantitative real time reverse transcription polymerase chain reaction and immunohistochemistry, respectively. Compared with the control group, manganese deficiency significantly decreased the proliferative zone width and Bcl-2 mRNA expression level, while significantly increased the apoptotic rates and the expression level of p21 gene in chondrocytes. The results indicate that manganese deficiency had a negative effect on chondrocyte development, which was mediated by the inhibition of chondrocyte proliferation and promotion of chondrocyte apoptosis.

Telmisartan-induced PPARγ activity attenuates lipid accumulation in VSMCs via induction of autophagy.

Foam cell formation is the hallmark of atherosclerosis. Both telmisartan and autophagy protect against the development of atherosclerosis. However, it has yet to be elucidated whether telmisartan prevents vascular smooth muscle cell (VSMC)-derived foam cell formation. Vascular smooth muscle cells isolated from the thoracic aorta of male C57BL/6J mice were used for this study. To induce foam cell formation, primary VSMCs were incubated in 80 µg/ml oxLDL for 24 h. LC3, beclin-1, PPARγ, AMPK, p-AMPK, mTOR and p-mTOR expression were determined via Western blot. Lipid accumulation was evaluated via oil red O staining and intracellular total cholesterol level measurement. Our study demonstrated that telmisartan dose-dependently increased the expression of beclin-1, the LC3II/LC3I ratio and the quantity of GFP-labeled autophagosomes, displaying a peak effect at 10 µM. In control siRNA-transfected VSMCs, telmisartan (10 µM) decreased lipid droplet accumulation and the total cholesterol level significantly. In contrast, in Atg7 siRNA-transfected VSMCs, telmisartan failed to attenuate lipid accumulation. In addition, telmisartan dose-dependently increased the expression of PPARγ and p-AMPK and decreased the expression of p-mTOR. GW9662 attenuated the telmisartan-induced increase in PPARγ expression, the LC3-II/LC3-I ratio and p-AMPK expression and the telmisartan-induced decrease in p-mTOR expression. Compound C restored mTOR activity and abolished the increase in the LC3-II/LC3-I ratio. Rapamycin significantly reduced p-mTOR expression and increased the LC3-II/LC3-I ratio. In conclusion, this study provides evidence that the chronic pharmacological activation of the PPARγ-mediated autophagy pathway using telmisartan may represent a promising therapeutic strategy for atherosclerosis.

The association between leukoaraiosis and carotid atherosclerosis: a systematic review and meta-analysis.

The association between large-artery atherosclerosis and leukoaraiosis (LA) has been increasingly reported with inconsistent conclusion. This systematic review examines the relationship between LA and carotid atherosclerosis, manifested as atherosclerotic stenosis, plaques and increased intima-media thickness (IMT). PubMed, Embase, and Web of Science were searched for articles published up to February 2014. Thirty-two studies that examined the relationship between LA and carotid atherosclerosis were included. All statistical analysis was conducted with Review Manager 5.2.4. Finally, 32 studies including 17,721 patients were identified. There were 7 (30%) out of 23 studies reporting significant association between LA and carotid stenosis; 11 (79%) out of 14 studies reporting significant association between LA and carotid plaque; all 9 studies reporting significant association between LA and carotid IMT; one study showing an association between LA and CAWT (similar to the role of the IMT). The quantitative meta-analysis of 10 studies showed that carotid atherosclerosis was not associated with LA (OR: 1.10; 95% CI: 0.61-1.98). A significant association was found between LA and carotid plaque (OR = 3.53; 95% CI = 1.83-6.79), and the result of IMT group showed that IMT increased risk of LA (MD = 0.11; 95% CI = 0.01-0.22). This systematic review suggested that LA has a tendency of association with carotid plaques but no association with simple carotid stenosis.

Association between intercellular adhesion molecule-1 gene K469E polymorphism and the risk of stroke in a Chinese population: a meta-analysis.

Several epidemiologic studies have evaluated the association between intercellular adhesion molecule-1 (ICAM-1) gene K469E polymorphism and stroke, but the results were inconsistent. The present meta-analysis was performed to investigate the relationship between K469E polymorphism and stroke in the Chinese population. A comprehensive search for related studies from the electronic databases of PubMed, Embase, Web of Science, CBMdisc and CNKI as well as a manual search of the references of identified articles was performed. Data were extracted to calculate for allelic, additive, dominant and recessive models using pooled odds ratios (ORs) along with 95% confidence intervals (CIs) by Review Manager 5.0 and Stata 11.0. Different effect models, subgroup analysis, sensitivity analysis, publication bias and power calculations were used to improve the comprehensive analysis. Finally, a total of 12 studies containing 1593 cases and 1555 controls were included in the final meta-analysis. No evidence of significant association between ICAM-1 gene K469E polymorphism and stroke was found in all four models (allelic model: OR = 1.07, 95%CI = 0.78-1.47; additive model: OR = 1.21, 95% CI = 0.67-2.16 (EE vs. KK); OR = 1.04, 95%CI = 0.75-1.45 (EK vs. KK); dominant model: OR = 1.07, 95% CI = 0.73-1.56; and recessive model: OR = 1.18, 95% CI = 0.77-1.83, respectively) based on the overall population, as well as subgroup analysis and sensitivity analysis. In conclusion, the present meta-analysis showed no evidence of significant association between ICAM-1 gene K469E polymorphism and stroke in the Chinese population. Nonetheless, this conclusion should be interpreted cautiously due to the low statistical power and considerable heterogeneity. Therefore, larger sample-size studies with homogeneous cases and well-matched controls are needed to further address this correlation.

MET amplification is not rare and predicts unfavorable clinical outcomes in patients with recurrent/metastatic gastric cancer after chemotherapy.

BACKGROUND: Several large studies have reported an extremely low incidence of MET gene amplification (GA) in patients with radically resected gastric cancer. This study was conducted to evaluate the prevalence and prognostic role of MET in patients with recurrent=metastatic gastric cancer who received chemotherapy. METHODS: MET GA and protein expression of recurrent=metastatic gastric cancer samples were evaluated by fluorescence in situ hybridization and immunohistochemistry (IHC), respectively. RESULTS: This retrospective study included 232 patients with recurrent=metastatic gastric cancer. MET GA and strong protein expression(IHC31) were observed in 8.3% (19 of 230 samples) and 9.6% (22 of 229 samples) of samples, respectively. A significant correlation was observed between MET GA and protein expression (r = 0.378; P<.001). MET GA was correlated with poor performance status(P<.001) and poorly differentiated tumors (P=.0015). Both MET GA and IHC 31 expression were associated with a substantially shorter median overall survival (OS) and progression-free survival (PFS). The median OS and PFS for patients with MET GA versus those without MET GA were 5.7 months versus 15.5 months (P<.001) and 3.6 months versus 6.9 months (P<.001), respectively. The median OS and PFS for patients with MET IHC 31 expression versus IHC 0 to 21 expression were 6.3 months versus 15.1 months(P<.001) and 3.6 months versus 7.0 months (P<.001), respectively. CONCLUSIONS: In patients with recurrent=metastatic gastric cancer,MET amplification and strong protein expression are not rare and appear to be significantly associated with unfavorable clinical outcomes.

Overcoming multidrug resistance in microbials using nanostructures self-assembled from cationic bent-core oligomers.

Novel cationic molecules based on rigid terephthalamide-bisurea cores flanked by imidazolium moieties are described. In aqueous media, these compounds self-assemble into supramolecular nanostructures with distinct morphologies. The compound with optimal hydrophilic/hydrophobic balance displays potent antimicrobial activity and high selectivity towards clinically-isolated MRSA without inducing drug-resistance. These self-assembled cationic antimicrobial nanostructures show promise for the prevention and treatment of multidrug-resistant infections.

Profiling plasma microRNA in nasopharyngeal carcinoma with deep sequencing.

BACKGROUND: The goal of this study was to establish a plasma microRNA profile by use of next-generation sequencing that could aid in assessment of patient prognosis in nasopharyngeal carcinoma (NPC). METHODS: Two panels of NPC patients and healthy controls (HCs) were recruited for this study. We used deep sequencing to screen plasma microRNAs. Differentially expressed microRNAs were verified by quantitative real-time PCR (qPCR). Kaplan-Meier survival analysis with the log-rank test was used to compare overall survival (OS) and progression-free survival (PFS) between groups. RESULTS: Twenty-three plasma miRNAs with differential expression levels were selected for qPCR analysis on an independent set including 100 NPC patients and 55 HCs. NPC patients with low concentrations of miR-483-5p and miR-103 had better prognosis for 5-year OS than those with high concentrations (87.5% vs 55.8%, P < 0.001; 80.9% vs 62.3%, P = 0.031). Those with low concentrations of miR-29a and let-7c had poorer prognosis (54.8% vs 82.8%, P = 0.002; 56.3% vs 84.6%, P = 0.001). A 3-signature miRNA integrated with clinical stage was further identified in an independent set. We calculated a prognostic index score and classified patients into low-, medium-, and high-risk groups. Five-year OS among the 3 groups was significantly different (90.9%, 66.7%, and 23.8%; P < 0.001). By multivariate analysis, a high-risk score was the most significantly unfavorable prognostic factor independent of other clinical variables (P < 0.001, hazard ratio = 15.1, 95% CI = 5.2-43.9). CONCLUSIONS: Differentially expressed plasma miRNAs as identified by next-generation sequencing can be helpful for predicting survival in NPC patients.

A meta-analysis of the relationship between MTHFR gene A1298C polymorphism and the risk of adult stroke.

BACKGROUND: The association between methylenetetrahydrofolate reductase (MTHFR) gene A1298C polymorphism and adult stroke remains controversial. The present article was designed to clarify this relationship through pooled analysis of the numerous epidemiological studies focusing on this association. METHODS: We comprehensively searched all published papers in electronic database including PubMed, Embase, Web of Science, Chinese Biomedical Literature on disc (CBMdisc) and China National Knowledge Infrastructure (CNKI) up to 2013. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) for allelic (C allele vs. A allele), additive (CC vs. AA), dominant (CC+AC vs. AA), and recessive (CC vs. AA+AC) models were calculated. Subgroup and sensitivity analyses were performed to detect the heterogeneity and examine the reliability of results, respectively. Begg's funnel plots and Egger's regression test were used to assess the potential publication bias. RESULTS: A total of fifteen studies containing 2,361 cases and 2,653 controls were included in the final meta-analysis. The combined results of overall analysis showed that there was significant association between MTHFR gene A1298C polymorphism and adult stroke (allelic model: OR=1.36, 95% CI=1.11-1.67; additive model: OR=1.88, 95% CI=1.12-3.18; dominant model: OR=1.33, 95% CI=1.08-1.65 and recessive model: OR=1.77, 95% CI=1.07-2.94, respectively). On subgroup analysis by ethnicity of study population, significant association was shown in meta-analysis based on Asian population (allelic model: OR=1.40, 95% CI=1.19-1.65; additive model: OR=2.58, 95% CI=1.34-4.96; dominant model: OR=1.44, 95% CI=1.20-1.73 and recessive model: OR=2.12, 95% CI=1.20-3.76, respectively), but not in Caucasian population (allelic model: OR=1.30, 95% CI=0.93-1.82; additive model: OR=1.65, 95% CI=0.81-3.33; dominant model: OR=1.17, 95% CI=0.86-1.61 and recessive model: OR=1.70, 95% CI=0.83-3.50, respectively). In addition, the heterogeneity was effectively removed or decreased by limiting the included studies with population of Asian ethnicity. Furthermore, the corresponding pooled ORs were not materially changed in all genetic models of meta-analysis after limiting the included studies with population-based controls. However, except the recessive model, publication bias presented in the allelic, additive, dominant models identified by the Begg's funnel plots and Egger's regression test. CONCLUSIONS: In conclusion, the overall analysis suggests that MTHFR gene A1298C polymorphism plays an important role in the development of adult stroke. Genotype CC of MTHFR-1298A/C could increase the risk of stroke and may act as a predictor for clinical evaluation, especially in the Asian population. More studies with large-scale and different ethnicities are required to further confirm our findings.

Toll-like receptor 4 gene Asp299Gly polymorphism in ischemic cerebrovascular disease: a meta-analysis.

Epidemiological studies have evaluated the association between Toll-like receptor 4 (TLR4) gene Asp299Gly (rs4986790) polymorphism and the risk of ischemic cerebrovascular disease, but the results are inconsistent. In an effort to clarify earlier inconclusive results, a meta-analysis was performed. We searched the PubMed, Web of Science, Embase, Cochrane database, Clinicaltrials.gov, Current Controlled Trials, CNKI, CBMdisc, Chinese Clinical Trial Registry and Google Scholar until up to 20 July 2013. Additionally, hand searching of the references of identified articles was performed. Original observational studies investigating the association between TLR4 gene Asp299Gly polymorphism and ischemic cerebrovascular disease risk were included. All statistical analyses were performed using Stata 11.0. The search strategy identified 1038 potentially relevant articles, seven of which were included in the final meta-analysis, covering a total of 1767 cases and 2785 controls. Overall, no significant association was found between TLR4 gene Asp299Gly polymorphism and ischemic cerebrovascular disease risk (for G allele versus A allele: OR = 0.95, 95% CI = 0.75-1.21, p = 0.69; for G/G+A/G versus A/A: OR = 0.96, 95% CI = 0.75-1.22, p = 0.73). In addition, the similar results were obtained in the sensitivity analysis based on studies with the high quality. In summary, the present meta-analysis indicates that TLR4 gene Asp299Gly polymorphism is not associated with increased ischemic cerebrovascular disease risk.

Formononetin attenuates psoriasiform inflammation by regulating interferon signaling pathway.

BACKGROUND: Psoriasis is a long-lasting, inflammatory, continuous illness caused through T cells and characterized mainly by abnormal growth and division of keratinocytes. Currently, corticosteroids are the preferred option. However, prolonged use of traditional topical medication can lead to adverse reactions and relapse, presenting a significant therapeutic obstacle. Improved alternative treatment options are urgently required. Formononetin (FMN) is a representative component of isoflavones in Huangqi (HQ) [Astragalus membranaceus (Fisch.) Bge.]. It possesses properties that reduce inflammation, combat oxidation, inhibit tumor growth, and mimic estrogen. Although FMN has been shown to ameliorate skin barrier devastation via regulating keratinocyte apoptosis and proliferation, there are no reports of its effectiveness in treating psoriasis. OBJECTIVE: Through transcriptomics clues and experimental investigation, we aimed to elucidate the fundamental mechanisms underlying FMN's action on psoriasis. MATERIALS AND METHODS: Cell viability was examined using CCK8 assay in this study. The results of analysis of differentially expressed genes (DEGs) between FMN-treated HaCaT cells and normal HaCaT cells using RNA-sequencing (RNA-seq) were presented on volcano plots and heatmap. Enrichment analysis was conducted on DEGs using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO), and results were validated through RT-qPCR verification. After 12 days of FMN treatment in psoriasis mouse model, we gauged the PASI score and epidermis thickness. A variety of techniques were used to assess FMN's effectiveness on inhibiting inflammation and proliferation related to psoriasis, including RT-qPCR, HE staining, western blot, and immunohistochemistry (IHC). RESULTS: The findings indicated that FMN could suppress the growth of HaCaT cells using CCK8 assay (with IC50 = 40.64 uM) and 20 uM FMN could reduce the level of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) to the greatest extent. FMN-treated HaCaT cells exhibited 985 up-regulated and 855 down-regulated DEGs compared to normal HaCaT cells. GO analysis revealed that DEGs were linked to interferon (IFN) signaling pathway. Furthermore, FMN improved pathological features, which encompassed decreased erythema, scale, and thickness scores of skin lesions in psoriasis mouse model. In vivo experiments confirmed that FMN down-regulated expression of IFN-α, IFN-ß, IFN-γ, decreased secretion of TNF-α and IL-17 inflammatory factors, inhibited expression of IFN-related chemokines included Cxcl9, Cxcl10, Cxcl11 and Cxcr3 and reduced expression of transcription factors p-STAT1, p-STAT3 and IFN regulatory factor 1 (IRF1) in the imiquimod (IMQ) group. CONCLUSIONS: In summary, these results suggested that FMN played an anti-inflammatory and anti-proliferative role in alleviating psoriasis by inhibiting IFN signaling pathway, and FMN could be used as a potential therapeutic agent.

High EGFR copy number predicts benefits from tyrosine kinase inhibitor treatment for non-small cell lung cancer patients with wild-type EGFR.

BACKGROUND: This study was designed to determine whether advanced non-small-cell lung cancer (NSCLC) patients with high copy number of epidermal growth factor receptor (EGFR) can benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). METHODS: EGFR gene copy number was assessed by fluorescence in situ hybridization (FISH) and EGFR mutations was tested using Luminex xTAG technology in 502 TKI-treated NSCLC patients. The association between both biomarkers and clinical benefit from EGFR-TKI were analyzed. RESULTS: EGFR FISH+and EGFR mutations were significantly associated with higher response rates (37.2% and 43.7%, respectively), superior progression-free survival (PFS) (FISH+, 11.2 months; hazard ratio [HR], 0.51; 95% CI, 0.42 to 0.62; p<0.001; mutation+, 11.7 months; HR, 0.37; 95% CI, 0.31 to 0.45; p<0.001) and overall survival (OS) (FISH+, 30.2 months; HR, 0.51; 95% CI, 0.40 to 0.65; p<0.001; mutation+, 30.2 months; HR, 0.45; 95% CI, 0.36 to 0.58; p<0.001). In patients with wild-type EGFR, EGFR FISH+correlated with longer PFS than EGFR FISH- status (4.4 months vs. 2.0 months; HR, 0.56; 95% CI, 0.41 to 0.75; p<0.001), so did amplification (5.0 months vs. 2.0 months; HR, 0.43; 95% CI, 0.24 to 0.76; p=0.003). However, FISH+had no association with improved PFS in EGFR-mutated patients (HR, 0.77; 95% CI, 0.57 to 1.03; p=0.076). CONCLUSIONS: A combined analysis of EGFR FISH and mutation is an effective predictor of EGFR-TKI therapy. Specifically, a high EGFR copy number may predict benefit from TKIs treatment for NSCLC patients with wild-type EGFR.