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Marcelo dos Santos Ana Maria da Cunha Mercante Iúri Drumond Louro Ant?nio José Gon?alves Marcos Brasilino de Carvalho Eloiza Helena Tajara da Silva Adriana Madeira álvares da Silva 《PloS one》2012,7(9)
Background
Oral squamous cell carcinoma is an important cause of death and morbidity wordwide and effective prognostic markers are still to be discovered. HIF1α protein is associated with hypoxia response and neovascularization, essential conditions for solid tumors survival. The relationship between HIF1α expression, tumor progression and treatment response in head and neck cancer is still poorly understood.Patients and Methods
In this study, we investigated HIF1α expression by immunohistochemistry in tissue microarrays and its relationship with clinical findings, histopathological results and survival of 66 patients with squamous cell carcinoma of the lower mouth.Results
Our results demonstrated that high HIF1α expression is associated with local disease-free survival, independently from the choice of treatment. Furthermore, high expression of HIF1α in patients treated with postoperative radiotherapy was associated with survival, therefore being a novel prognostic marker in squamous cell carcinoma of the mouth. Additionally, our results showed that MVD was associated with HIF1α expression and local disease relapse.Conclusion
These findings suggest that HIF1α expression can be used as a prognostic marker and predictor of postoperative radiotherapy response, helping the oncologist choose the best treatment for each patient. 相似文献2.
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Background
The close subcellular proximity of different actin filament crosslinking proteins suggests that these proteins may cooperate to organize F-actin structures to drive complex cellular functions during cell adhesion, motility and division. Here we hypothesize that α-actinin and filamin, two major F-actin crosslinking proteins that are both present in the lamella of adherent cells, display synergistic mechanical functions.Methodology/Principal Findings
Using quantitative rheology, we find that combining α-actinin and filamin is much more effective at producing elastic, solid-like actin filament networks than α-actinin and filamin separately. Moreover, F-actin networks assembled in the presence of α-actinin and filamin strain-harden more readily than networks in the presence of either α-actinin or filamin.Significance
These results suggest that cells combine auxiliary proteins with similar ability to crosslink filaments to generate stiff cytoskeletal structures, which are required for the production of internal propulsive forces for cell migration, and that these proteins do not have redundant mechanical functions. 相似文献7.
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Background
Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal mucosa, involving a complex interaction between genetic and environmental factors. Evidence suggests that polymorphisms in the gene coding for mitochondrial ribosomal protein L4 (MRPL4), located in close proximity to intercellular adhesion molecule-1 (ICAM-1) gene on chromosome location 19p13.2, may influence the risk factor for the development of AR.Objective
The aim of our study was to investigate any association between AR susceptibility and polymorphisms in ICAM-1 gene, as well as associations between AR risk and polymorphisms in MRPL4, nuclear factor-kappaB (NF-κB) and tumor necrosis factor alpha(TNF-α) genes, associated with ICAM-1 expression.Methods
A cohort of 414 patients with AR and 293 healthy controls was enrolled from the Han Chinese population in Beijing, China. Blood was drawn for DNA extraction and total serum immunoglobulin E (IgE). A total of 14 single nucleotide polymorphisms (SNPs) in ICAM-1, NF-κB, TNF-α, and MRPL4 genes were selected using the CHB genotyping data from the International Haplotype Mapping (HapMap) and assessed for differences in frequencies of the alleles and genotypes between the AR patients and control subjects.Results
TNF-α SNP rs1799964 and MRPL4 SNP rs11668618 were found to occur in significantly greater frequencies in the AR group compared to control group. There were no significant associations between SNPs in NF-κB, ICAM-1 and AR. The SNP-SNP interaction information analysis further indicated that there were no synergistic effects among the selected sets of polymorphisms.Conclusions
Our results suggest a strong association between AR risk and polymorphisms of MRPL4 and TNF-α genes in Han Chinese population. 相似文献10.
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Rajesh Panigrahi Sidhartha Hazari Sruti Chandra Partha K. Chandra Sibnarayan Datta Ramazan Kurt Craig E. Cameron Zhuhui Huang Haitao Zhang Robert F. Garry Luis A. Balart Srikanta Dash 《PloS one》2013,8(8)
Purpose
Although chronic hepatitis C virus (HCV) infection has been treated with the combination of interferon alpha (IFN-α) and ribavirin (RBV) for over a decade, the mechanism of antiviral synergy is not well understood. We aimed to determine the synergistic antiviral mechanisms of IFN-α and RBV combination treatment using HCV cell culture.Methods
The antiviral efficacy of IFN-α, RBV alone and in combination was quantitatively measured using HCV infected and replicon cell culture. Direct antiviral activity of these two drugs at the level of HCV internal ribosome entry site (IRES) mediated translation in Huh-7 cell culture was investigated. The synergistic antiviral effect of IFN-α and RBV combination treatment was verified using both the CalcuSyn Software and MacSynergy Software.Results
RBV combination with IFN-α efficiently inhibits HCV replication cell culture. Our results demonstrate that IFN-α, interferon lambda (IFN-λ) and RBV each inhibit the expression of HCV IRES-GFP and that they have a minimal effect on the expression of GFP in which the translation is not IRES dependent. The combination treatments of RBV along with IFN-α or IFN-λ were highly synergistic with combination indexes <1. We show that IFN-α treatment induce levels of PKR and eIF2α phosphorylation that prevented ribosome loading of the HCV IRES-GFP mRNA. Silencing of PKR expression in Huh-7 cells prevented the inhibitory effect of IFN-α on HCV IRES-GFP expression. RBV also blocked polyribosome loading of HCV-IRES mRNA through the inhibition of cellular IMPDH activity, and induced PKR and eIF2α phosphorylation. Knockdown of PKR or IMPDH prevented RBV induced HCV IRES-GFP translation.Conclusions
We demonstrated both IFN-α and RBV inhibit HCV IRES through prevention of polyribosome formation. The combination of IFN-α and RBV treatment synergistically inhibits HCV IRES translation via using two different mechanisms involving PKR activation and depletion of intracellular guanosine pool through inhibition of IMPDH. 相似文献14.
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Background
von Hippel-Lindau disease is characterized by a spectrum of hypervascular tumors, including renal cell carcinoma, hemangioblastoma, and pheochromocytoma, which occur with VHL genotype-specific differences in penetrance. VHL loss causes a failure to regulate the hypoxia inducible factors (HIF-1α and HIF-2α), resulting in accumulation of both factors to high levels. Although HIF dysregulation is critical to VHL disease-associated renal tumorigenesis, increasing evidence points toward gradations of HIF dysregulation contributing to the degree of predisposition to renal cell carcinoma and other manifestations of the disease.Methodology/Principal Findings
This investigation examined the ability of disease-specific VHL missense mutations to support the assembly of the VBC complex and to promote the ubiquitylation of HIF. Our interaction analysis supported previous observations that VHL Type 2B mutations disrupt the interaction between pVHL and Elongin C but maintain partial regulation of HIF. We additionally demonstrated that Type 2B mutant pVHL forms a remnant VBC complex containing the active members ROC1 and Cullin-2 which retains the ability to ubiquitylate HIF-1α.Conclusions
Our results suggest that subtypes of VHL mutations support an intermediate level of HIF regulation via a remnant VBC complex. These findings provide a mechanism for the graded HIF dysregulation and genetic predisposition for cancer development in VHL disease. 相似文献19.