Sorafenib modulates the radio sensitivity of hepatocellular carcinoma cells in vitro in a schedule-dependent manner

BACKGROUND: Hepatocellular carcinoma (HCC) has a high incidence and mortality. Radiotherapy and sorafenib have proven effective for HCC. Here, we investigated whether sorafenib modulated the response of HCC cells to irradiation in vitro, effect of timing of sorafenib, and the underlying mechanisms. METHODS: Cell viability of the HCC cell lines, SMMC-7721 and Bel-7402, was examined by the 3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2(4-sulfophenyl)-2 H-terazolium (MTT) assays. Clonogenic growth assays of SMMC-7721 and Bel-7402 were determined by colony formation assays. DNA damage was assessed by monitoring γ-HAX foci in irradiated cells with immunofluorescence microscopy, and cell cycle distribution changes were examined by flow cytometry. Effects of sorafenib (15 μM) added 30 min prior to radiation (pre-irradiation sorafenib) of SMMC-7721 and BEL-7402 or 24 h post-irradiation (post-irradiation sorafenib) on irradiated SMMC-7721 and BEL-7402 cells were compared to those of radiation alone or no treatment. RESULTS: The effect of sorafenib was dependent on its time of addition in relationship to irradiation of cells. Pre-irradiation sorafenib did not significantly affect the viability of SMMC-7221 and BEL-7402 cells compared with irradiation treatment alone. In contrast, post-irradiation sorafenib increased the sensitivity of irradiated SMMC-7221 and BEL-7402 cells significantly in a time-dependent manner. Pre-irradiation sorafenib significantly increased the surviving fraction of SMMC-7221 and BEL-7402 cells in clonogenic assays whereas post-irradiation sorafenib significantly reduced the surviving fractions of SMMC-7221 and BEL-7402 cells. SMMC-7721 cells treated with sorafenib 30 min before irradiation had significantly fewer cells with γ-H2AX foci (23.8 ± 2.9%) than SMMC-7721 cells receiving radiation alone (59.9 ± 2.4; P < 0.001). Similarly, BEL-7402 cells receiving sorafenib prior to irradiation had significantly fewer cells with γ-H2AX foci (46.4 ± 3.8%) than those receiving radiation alone (25.0 ± 3.0%; P < 0.001). In addition, irradiation (6 Gy) caused a significant increase in the percentage of both SMMC-7721 and BEL-7402 cells in G2/M at 12 to 16 h post irradiation, which was markedly delayed by pre-irradiation sorafenib. CONCLUSIONS: Sorafenib combined with irradiation exerted a schedule-dependent effect in HCC cells in vitro, which has significant implications for the combined use of sorafenib and radiotherapy for HCC patients

The role of EGFR mutation as a prognostic factor in survival after diagnosis of brain metastasis in non-small cell lung cancer: A systematic review and meta-analysis

Abstract Background The brain is a common site for metastasis in non-small-cell lung cancer (NSCLC). This study was designed to evaluate the relationship between the mutational of the epidermal growth factor receptor (EGFR) and overall survival (OS) in NSCLC patients with brain metastases. Methods Searches were performed in PubMed, EmBase, and the Cochrane Library to identify studies evaluating the association of EGFR mutation with OS in NSCLC patients through September 2017. Results 4373 NSCLC patients with brain metastases in 18 studies were involved. Mutated EGFR associated with significantly improved OS compared with wild type. Subgroup analyses suggested that this relationship persisted in studies conducted in Eastern, with retrospective design, with sample size ≥500, mean age of patients ≥65.0 years, percentage male < 50.0%, percentage of patients receiving tyrosine kinase inhibitor ≥30.0%. Finally, although significant publication bias was observed using the Egger test, the results were not changed after adjustment using the trim and fill method. Conclusions This meta-analysis suggests that EGFR mutation is an important predictive factor linked to improved OS for NSCLC patients with brain metastases. It can serve as a useful index in the prognostic assessment of NSCLC patients with brain metastases

NeurimmiRs and Postoperative Delirium in Elderly Patients Undergoing Total Hip/Knee Replacement: A Pilot Study

Objective: Postoperative delirium (POD) is a frequent complication after surgery and its occurrence is associated with poor outcomes. The pathophysiology of this complication is not clear, but identification of risk factors is important for positive postoperative outcomes. The purpose of this study was to investigate the associations between the preoperative expression levels of microRNA (miR)-146a, miR-125b, and miR-181c in cerebrospinal fluid (CSF) and serum and the development and severity of POD.Methods: Forty elderly patients aged 65 years old and older admitted for elective total hip/knee replacement under spinal anesthesia. Preoperatively, baseline cognitive function was assessed using the Mini-Mental State Examination. Each patient was interviewed daily on the first and second postoperative days. Delirium was diagnosed using the Confusion Assessment Method, and delirium severity was measured using the Memorial Delirium Assessment Scale (MDAS). Preoperative serum and CSF miR levels were determined by quantitative real-time PCR (qRT-PCR).Results: POD was detected in 27.5% (11/40) of patients. Up-regulation of miR-146a and miR-181c in CSF and down-regulation of miR-146a in serum were observed preoperatively in patients who developed POD, while patients with and without POD did not differ in serum or CSF levels of miR-125b. Delirious patients had higher CSF/serum ratios of miR-146a and miR-181c levels than non-delirious patients. The lower CSF miR-146a and CSF/serum miR-146a ratios were significantly associated with milder POD severity, represented by a lower MDAS score.Conclusion: The dysregulation of preoperative miR-146a and miR-181c in CSF and serum was associated with the development and severity of POD. These NeurimmiRs might participate in the neuropathogenesis of POD, pending further investigations.Clinical trial registration: this study was registered at ClinicalTrials.gov (NCT02817386)

Polymorphisms and a Haplotype in Heparanase Gene Associations with the Progression and Prognosis of Gastric Cancer in a Northern Chinese Population

Background: Human heparanase plays an important role in cancer development and single nucleotide polymorphisms (SNPs) in the heparanase gene (HPSE) have been shown to be correlated with gastric cancer. The present study examined the associations between individual SNPs or haplotypes in HPSE and susceptibility, clinicopathological parameters and prognosis of gastric cancer in a large sample of the Han population in northern China. Methodology/Principal Findings: Genomic DNA was extracted from formalin-fixed, paraffin-embedded normal gastric tissue samples from 404 patients and from blood from 404 healthy controls. Six SNPs were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. A chi-square (x2) test and unconditional logistic regression were used to analyze the risk of gastric cancer; a Log-rank test and Cox proportional hazards model were used to produce survival analysis and a Kaplan-Meier method was used to map survival curves. The mean genotyping success rates were more than 99 % in both groups. Haplotype CA in the block composed of rs11099592 and rs4693608 had a greater distribution in the group of Borrmann types 3 and 4 (P = 0.037), the group of a greater number of lymph node metastases (N3 vs N0 group, P = 0.046), and moreover was correlated to poor survival (CG vs CA: HR = 0.645, 95%CI: 0.421–0.989, P = 0.044). In addition, genotypes rs4693608 AA and rs4364254 TT were associated with poor survival (P = 0.030, HR = 1.527, 95%CI: 1.042–2.238 for rs4693608 AA; P = 0.013, HR = 1.546, 95%CI: 1.096–2.181 for rs4364254 TT). There were n

The Association between Individual SNPs or Haplotypes of Matrix Metalloproteinase 1 and Gastric Cancer Susceptibility, Progression and Prognosis

BACKGROUND: The single nucleotide polymorphisms (SNPs) in matrix metalloproteinase 1(MMP-1) play important roles in some cancers. This study examined the associations between individual SNPs or haplotypes in MMP-1 and susceptibility, clinicopathological parameters and prognosis of gastric cancer in a large sample of the Han population in northern China. METHODS: In this case-controlled study, there were 404 patients with gastric cancer and 404 healthy controls. Seven SNPs were genotyped using the MALDI-TOF MS system. Then, SPSS software, Haploview 4.2 software, Haplo.states software and THEsias software were used to estimate the association between individual SNPs or haplotypes of MMP-1 and gastric cancer susceptibility, progression and prognosis. RESULTS: Among seven SNPs, there were no individual SNPs correlated to gastric cancer risk. Moreover, only the rs470206 genotype had a correlation with histologic grades, and the patients with GA/AA had well cell differentiation compared to the patients with genotype GG (OR=0.573; 95%CI: 0.353-0.929; P=0.023). Then, we constructed a four-marker haplotype block that contained 4 common haplotypes: TCCG, GCCG, TTCG and TTTA. However, all four common haplotypes had no correlation with gastric cancer risk and we did not find any relationship between these haplotypes and clinicopathological parameters in gastric cancer. Furthermore, neither individual SNPs nor haplotypes had an association with the survival of patients with gastric cancer. CONCLUSIONS: This study evaluated polymorphisms of the MMP-1 gene in gastric cancer with a MALDI-TOF MS method in a large northern Chinese case-controlled cohort. Our results indicated that these seven SNPs of MMP-1 might not be useful as significant markers to predict gastric cancer susceptibility, progression or prognosis, at least in the Han population in northern China

MicroRNA-148b is frequently down-regulated in gastric cancer and acts as a tumor suppressor by inhibiting cell proliferation

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) are involved in cancer development and progression, acting as tumor suppressors or oncogenes. Our previous studies have revealed that miR-148a and miR-152 are significantly down-regulated in gastrointestinal cancers. Interestingly, miR-148b has the same "seed sequences" as miR-148a and miR-152. Although aberrant expression of miR-148b has been observed in several types of cancer, its pathophysiologic role and relevance to tumorigenesis are still largely unknown. The purpose of this study was to elucidate the molecular mechanisms by which miR-148b acts as a tumor suppressor in gastric cancer.</p> <p>Results</p> <p>We showed significant down-regulation of miR-148b in 106 gastric cancer tissues and four gastric cancer cell lines, compared with their non-tumor counterparts by real-time RT-PCR. <it>In situ </it>hybridization of ten cases confirmed an overt decrease in the level of miR-148b in gastric cancer tissues. Moreover, the expression of miR-148b was demonstrated to be associated with tumor size (P = 0.027) by a Mann-Whitney U test. We also found that miR-148b could inhibit cell proliferation <it>in vitro </it>by MTT assay, growth curves and an anchorage-independent growth assay in MGC-803, SGC-7901, BGC-823 and AGS cells. An experiment in nude mice revealed that miR-148b could suppress tumorigenicity <it>in vivo</it>. Using a luciferase activity assay and western blot, CCKBR was identified as a target of miR-148b in cells. Moreover, an obvious inverse correlation was observed between the expression of CCKBR protein and miR-148b in 49 pairs of tissues (P = 0.002, Spearman's correlation).</p> <p>Conclusions</p> <p>These findings provide important evidence that miR-148b targets CCKBR and is significant in suppressing gastric cancer cell growth. Maybe miR-148b would become a potential biomarker and therapeutic target against gastric cancer.</p

R-parity violation effect on the top-quark pair production at linear colliders

We investigate in detail the effects of the R-parity lepton number violation in the minimal supersymmetric standard model (MSSM) on the top-quark pair production via both $e^--e^+$ and $\gamma-\gamma$ collision modes at the linear colliders. We find that with the present experimental constrained $\rlap/{R}$ parameters, the effect from $\rlap/{R}$ interactions on the processes $e^+e^-\to t\bar{t}$ and $e^+e^- \to \gamma\gamma \to t\bar{t}$ could be significant and may reach -30% and several percent, respectively. Our results show that the $\rlap/{R}$ effects are sensitive to the c.m.s. energy and the relevant $\rlap/{R}$ parameters. However, they are not sensitive to squark and slepton masses when $m_{\tilde{q}} \geq 400 GeV$ (or $m_{\tilde{l}} \geq 300 GeV$) and are almost independent on the $\tan\beta$Comment: Accepted by Phys.Rev.