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Objective: Non-melanoma skin cancer (NMSC) is the most common malignancy with annually rising incidence. The aim of this study was to estimate the association between three coding polymorphisms (Arg399Gln, Arg194Trp, and Arg280His) of the DNA repair gene X-ray repair cross-complementing group 1 (XRCC1) and NMSC susceptibility. Methods: Online databases were searched to retrieve case-control studies published between January 2000 and November 2016. Pooled odds ratio (OR) and 95% confidence interval (CI) were employed to assess the strength of association. Overall, 10 relevant studies were finally included for analysis, including 3,143 NMSC patients and 3,540 controls. For each polymorphism of XRCC1 gene, there were 3,050 cases and 3,463 controls for Arg399Gln, 914 cases and 1,182 controls for Arg194Trp, and 279 cases and 413 controls for Arg280His. Results: Our results showed that these three polymorphisms in the XRCC1 coding region were not associated with increased risk of NMSC in the total studied population. However, subgroup analysis by ethnicities demonstrated that Gln/Arg genotype of Arg399Gln polymorphism was associated with increased risk of NMSC under the heterogeneous model in Asian populations (Gln/Arg vs Arg/Arg: OR =1.39, 95% CI =1.04-1.87, P=0.03); subgroup analysis by tumor types showed that Trp/Trp genotype of Arg194Trp was positively associated with decreased cancer risk in squamous-cell skin cancer (SCC) type under the homogeneous model (Trp/Trp vs Arg/Arg: OR =0.38, 95% CI =0.16-0.92, P=0.03). Conclusion: Our results suggested that Arg399Gln variant of XRCC1 gene might be a risk factor for NMSC in Asian populations, and Arg194Trp variant of XRCC1 gene might be a protective factor for patients with SCC. In addition, future case-control studies are still needed to further evaluate the effect of XRCC1 polymorphisms in NMSC risk. [ABSTRACT FROM AUTHOR]

Purpose: Cytoskeleton is critical for carcinoma cell proliferation, migration, and invasion. Sad-1 and UNC-84 domain containing 1 (SUN1) is one of the core linkers of nucleoskeleton and cytoskeleton. However, the functions of SUN1 in lung adenocarcinoma are largely unknown. Methods: In this study, we first transduced the lentivirus delivering the short hairpin RNA (shRNA) against SUN1 to lung adenocarcinoma cells (A549 and 95D cells) with high efficiency. After lentivirus infection, quantitative real-time polymerase chain reaction and Western blotting were used to detect the expressions of SUN1 mRNA and protein. The cell proliferation and colony formation were detected by MTT assay and colony formation assay, respectively. The cell distribution in the cell cycle was analyzed by flow cytometry. Results: Both mRNA and protein levels of SUN1 were significantly decreased in A549 and 95D cells after lentivirus infection, as indicated by quantitative real-time polymerase chain reaction and Western blot. Next, we found that cell proliferation and colony formation were markedly reduced in SUN1 silenced cells. Moreover, suppression of SUN1 led to cell cycle arrest at G0/G1 phase. Furthermore, Cyclin D1, CDK6, and CDK2 expressions were obviously reduced in A549 cells after SUN1 silencing. Conclusion: These results suggest that SUN1 plays an essential role in proliferation of lung adenocarcinoma cells in vitro and may be used as a potential therapeutic target for the treatment of lung adenocarcinoma in the future. [ABSTRACT FROM AUTHOR]

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein expressed primarily in the liver, formerly known to maintain plasma lipid homeostasis by regulating lowdensity lipoprotein receptor levels, and its exact role in the radioresistance of prostate cancer (PCa) remains unclear. We aim to investigate the function of PCSK9 in the radioresistance of PCa cells. Methods: PCSK9 small interfering RNA (siRNA) was introduced into the PCa cells by transient transfection. Then, cells were exposed to ionizing radiation (IR) at indicated dose rates. Cell damage was detected using cell counting kit-8 (CCK-8) and Hoechest 33342/propidium iodide (PI) staining. Rhodamine-123 (Rho-123) dye was used to assay mitochondrial membrane potential alteration. Western blot was used to detect the apoptosis-related protein expression. Results: PCSK9 siRNA treatment significantly protected PCa cells from IR-induced cell damage, including enhancing cell viability, reducing apoptosis, and inhibiting MMPs. Moreover, PCSK9 siRNA repressed the increase of cytochrome C (cyto C), caspase-3, and B-cell leukemia/lymphoma 2 (Bcl-2)-associated X (Bax) expressions induced by IR and promoted Bcl-2 expression, which might partially interpret the radioprotective role of PCSK9 siRNA in PCa cells. Conclusion: PCSK9 might impact on radiosensitivity through mitochondrial pathways and serve as a novel therapeutic target for PCa patients. [ABSTRACT FROM AUTHOR]

Purpose: Various genetic variants have been reported to be linked to an increased risk of meningioma. However, no confirmed conclusion has been obtained. The purpose of the study was to investigate potential meningioma-associated gene polymorphisms, based on published evidence. Materials and methods: An updated meta-analysis was performed in September 2016. After electronic database searching and study screening, we selected eligible case-control studies and extracted data for meta-analysis, using Mantel-Haenszel statistics. P-values, pooled odds ratios (ORs), and 95% confidence intervals were calculated. Results: We finally selected eight genes with ten polymorphisms: MLLT10 rs12770228, CASP8 rs1045485, XRCC1 rs1799782, rs25487, MTHFR rs1801133, rs1801131, MTRR rs1801394, MTR rs1805087, GSTM1 null/present, and GSTT1 null/present. Results of meta-analyses showed that there was increased meningioma risk in case groups under all models of MLLT10 rs12770228 (all OR >1, P<0.001), compared with control groups. Similar results were observed under the allele, homozygote, dominant, and recessive models of MTRR rs1801394 (all OR >1, P<0.05), and the heterozygote and dominant models of MTHFR rs1801131 in the Caucasian population (all OR >1, P<0.05). However, no significantly increased meningioma risks were observed for CASP8 rs1045485, XRCC1 rs25487, rs1799782, MTHFR rs1801133, MTR rs1805087, or GSTM1/GSTT1 null mutations. Conclusion: Our updated meta-analysis provided statistical evidence for the role of MLLT10 rs12770228, MTRR rs1801394, and MTHFR rs1801131 in increased susceptibility to meningioma. [ABSTRACT FROM AUTHOR]

Background: Latest studies show that low-energy extracorporeal shock wave therapy (ESWT) can upregulate levels of vascular endothelial growth factor (VEGF). VEGF can ease nervous tissue harm after spinal cord injury (SCI). This study aims to explore whether low-energy ESWT can promote expression of VEGF, protect nervous tissue after SCI, and improve motor function. Methods: Ninety adult female rats were divided into the following groups: Group A (simple laminectomy), Group B (laminectomy and low-energy ESWT), Group C (spinal cord injury), and Group D (spinal cord injury and low-energy ESWT). Impinger was used to cause thoracic spinal cord injury. Low-energy ESWT was applied as treatment after injury three times a week, for 3 weeks. After SCI, the Basso, Beattie, and Bresnahan (BBB) scale was used to evaluate motor function over a period of 42 days at different time points. Hematoxylin and eosin (HE) staining was used to evaluate nerve tissue injury. Neuronal nuclear antigen (NeuN) staining was also used to evaluate loss of neurons. Polymerase chain reaction was used to detect mes- senger RNA (mRNA) expression of VEGF and its receptor fms-like tyrosine kinase 1 (Flt-1). Immunostaining was used to evaluate VEGF protein expression level in myeloid tissue. Results: BBB scores of Groups A and B showed no significant result related to dyskinesia. HE and NeuN staining indicated that only using low-energy ESWT could not cause damage of nervous tissue in Group B. Recovery of motor function at 7, 35, and 42 days after SCI in Group D was better than that in Group C (P<0.05). Compared with Group C, number of NeuN- positive cells at 42 days after SCI increased significantly (P<0.05). The mRNA levels of VEGF and Flt-1 and VEGF expression at 7 days after SCI in Group D were significantly higher than those in Group C (P<0.05). Conclusion: Low-energy ESWT promotes expression of VEGF, decreases secondary damage of nerve tissue, and improves recovery of motor function. It can be regarded as one mode of clinical routine adjunctive therapy for spinal injury. [ABSTRACT FROM AUTHOR]

Objective: B-cell-lymphoma-2 (Bcl-2) is a proto-oncogene that plays an important role in the regulation of apoptosis and cell survival. However, there are much conflicting data in the literature concerning the association between Bcl-2 and prognosis in non-small-cell lung cancer (NSCLC). There is little in the way of meta-analysis focused on Bcl-2 and its effect on NSCLC prognosis. This study was performed to provide an assessment of whether expression levels of Bcl-2 are associated with prognosis in patients with NSCLC. Materials and methods: We searched PubMed, the Cochrane Library, and China National Knowledge Infrastructure for all eligible studies. The combined hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) in terms of overall survival were evaluated. Results: Fifty published studies including 6,863 patients with lung cancer were included in this meta-analysis. Overall, Bcl-2 was expressed in 33% of the NSCLC tumors studied. Our analysis indicates that NSCLC patients with Bcl-2-positive expression have a better prognosis than those with Bcl-2-negative expression in both Asian and non-Asian study populations (HR 0.79, 95% CI 0.72-0.87, P<0.00001). However, Bcl-2-positive expression seems to have no significant impact on survival of stage I NSCLC patients. Conclusion: Our results indicated that Bcl-2 might be a useful prognostic marker for NSCLC generally. Larger clinical trials are needed to confirm the prognostic value of Bcl-2 in stage I NSCLC. [ABSTRACT FROM AUTHOR]

Proto-oncogene Raf1 serves as a part of the mitogen-activated protein kinases/extracellular signal-regulated kinase signal transduction pathway and regulates cell migration, apoptosis, and differentiation. Although a large number of studies have shown that Raf1 is overexpressed in various kinds of cancer, little is known about the association between Raf1 and miRNAs in thyroid carcinoma. This study proves that Raf1 is overexpressed in thyroid cancer, which has been confirmed by many other studies. Besides, we identify that Raf1 is a direct target of mi-15a/b, mi-16, and mi-195 by dual luciferase reporter assay. We also find that the expression of mi-195 is downregulated in 50 pairs of thyroid tumor tissues compared to the adjacent nontumor tissues, while there is no difference in the expression of mi-15a/b and mi-16 between the groups. Furthermore, exogenous overexpression of mi-195 significantly inhibits the protein expression of Raf1 and blocks the thyroid cancer cell proliferation. Our findings delineate a novel mechanism for the regulation of Raf1 in thyroid cancer, which may help to provide a new direction for the treatment of thyroid cancer. [ABSTRACT FROM AUTHOR]

Lung adenocarcinomas have diverse genetic and morphological backgrounds and are usually classified according to their distinct oncogenic mutations (or so-called driver mutations) and histological subtypes (the dec novo classification proposed by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society [IASLC/ ATS/ERS]). Although both these classifications are essential for personalized treatment, their integrated clinical effect remains unclear. Therefore, we analyzed 981 lung adenocarcinomas to detect the potential correlation and combined effect of oncogenic mutations and histological subtype on prognosis. Analysis for oncogenic mutations included the direct sequencing of EGFR, KRAS, HER2, BRAF, PIK3CA, ALK, and RET for oncogenic mutations/rearrangements, and a rereview of the IASLC/ATS/ERS classification was undertaken. Eligible tumors included 13 atypical adenomatous hyperplasia/adenocarcinoma in situ, 20 minimally invasive adenocarcinomas, 901 invasive adenocarcinomas, 44 invasive mucinous adenocarcinomas, and three other variants. The invasive mucinous adenocarcinomas had a lower prevalence of EGFR mutations but a higher prevalence of KRAS, ALK, and HER2 mutations than invasive adenocarcinomas. Smoking, a solid predominant pattern, and a mucinous component were independently associated with fewer EGFR mutations. The ALK rearrangements were more frequently observed in tumors with a minor mucinous component, while the KRAS mutations were more prevalent in smokers. In addition, 503 patients with stage I-IIIA tumors were analyzed for overall survival (OS) and relapse-free survival. The stage and histological pattern were independent predictors of relapse-free survival, and the pathological stage was the only independent predictor for the OS. Although patients with the EGFR mutations had better OS than those without the mutations, no oncogenic mutation was an independent predictor of survival. Oncogenic mutations were associated with the novel IASLC/ATS/ERS classification, which facilitates a morphology-based mutational analysis strategy. The combination of these two classifications might not increase the prognostic ability, but it provides essential information for personalized treatment. [ABSTRACT FROM AUTHOR]

Background: The clinicopathologic characteristics of tumors expressing programmed death (PD-1) ligands (PD-Ls) PD-L1 or PD-L2 and their associations with common driver mutations in lung adenocarcinoma are not clearly defined, despite the progression of anti-PD-1/PD-L1 immunotherapy. Methods: PD-L1 and PD-L2 expression was measured by immunohistochemistry in 143 surgically resected lung adenocarcinomas and was correlated with clinical variables, histologic subtypes, and the mutational status of EGFR, KRAS, HER2, and ALK. Results: Positive PD-L1 expression was significantly associated with more advanced T status, N status, and pathologic stage. Histologically, lung adenocarcinomas with positive PD-L1 staining were less likely to be adenocarcinoma in situ or minimally invasive adenocarcinoma and more likely to have solid predominant subtype. Both PD-L1 expression (odds ratio =1.984, 95% confidence interval =1.010-3.894; P=0.047) and PD-L2 expression (odds ratio =2.328, 95% confidence interval =1.201-4.512; P=0.012) were independent predictors of poor overall survival. When the combined PD-L expression and pathologic stage were used together to predict overall survival, the concordance index increased to 0.763, and the Akaike information criteria value decreased to 356.08. Conclusion: We defined the clinicopathologic features of lung adenocarcinomas with high expression of PD-L1 and PD-L2. We further demonstrated the role of PD-L expression as a useful prognostic marker for lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Purpose: We performed this analysis to improve the understanding of the clinicopathological characteristics and clinical outcome of non-small cell lung cancer (NSCLC) patients harboring the primary epidermal growth factor receptor (EGFR) T790M mutation along with activating EGFR mutation. Methods: Resected tumors from 1903 NSCLC patients were analyzed for mutation in EGFR, as well as KRAS (Kirsten rat sarcoma viral oncogene homolog), BRAF (v-raf murine sarcoma viral oncogene homolog B), HER2 (human epidermal growth factor 2), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha), and EML4 (echinoderm microtubule associated protein like 4)-ALK (anaplastic lymphoma receptor tyrosine kinase) fusion. Fluorescence in situ hybridization was performed to define EGFR and c-MET (met proto-oncogene gene amplification. Expression of PIK3CA and p-Akt (phosphorylated protein kinase B) were tested using immunohistochemistry. Clinical and pathological data, including sex, age at diagnosis, stage, tumor differentiation, smoking history, histological subtype, relapse-free and overall survival, were further analyzed. Results: In all, 16 NSCLC patients were found to harbor primary EGFR T790M mutation, including 14 adenocarcinomas and two adenosquamous carcinomas, accounting for 2.04% of all the EGFR mutant cases and 0.84% of the total. No c-MET amplification was found to coexist with primary EGFR T790M. Fewer EGFR copy-number variations were found in samples harboring EGFR T790M mutations compared with those in patients with exon 19 deletions and L858R. Overall survival was significantly shorter for patients harboring EGFR T790M mutation than it was for patients with exon 19 deletions (logrank P=0.008). When taking patients harboring EGFR L858R or exon 19 deletions as one group, the overall survival was also significantly longer than that in patients with T790M mutation (logrank P=0.012). There was no significant difference in relapse-free survival among three subgroups of patients. Conclusion: Our study described the clinicopathological and molecular characteristics of NSCLC patients harboring primary EGFR T790M mutations. Its value of being a predictor for worse prognosis was established. Primary EGFR T790M mutation is a rare event in NSCLC cases, but the therapeutic strategies for this subtype of patients should be precisely considered. [ABSTRACT FROM AUTHOR]