To identify new genetic risk factors for cervical cancer, we conducted a genome-wide association study in the Han Chinese population. The initial discovery set included 1,364 individuals with cervical cancer (cases) and 3,028 female controls, and we selected a 'stringently matched samples' subset (829 cases and 990 controls) from the discovery set on the basis of principal component analysis; the follow-up stages included two independent sample sets (1,824 cases and 3,808 controls for follow-up 1 and 2,343 cases and 3,388 controls for follow-up 2). We identified strong evidence of associations between cervical cancer and two new loci: 4q12 (rs13117307, Pcombined, stringently matched=9.69×10(-9), per-allele odds ratio (OR)stringently matched=1.26) and 17q12 (rs8067378, Pcombined, stringently matched=2.00×10(-8), per-allele ORstringently matched=1.18). We additionally replicated an association between HLA-DPB1 and HLA-DPB2 (HLA-DPB1/2) at 6p21.32 and cervical cancer (rs4282438, Pcombined, stringently matched=4.52×10(-27), per-allele ORstringently matched=0.75). Our findings provide new insights into the genetic etiology of cervical cancer.

Inefficient homing of systemically infused mesenchymal stem cells (MSCs) limits the efficacy of existing MSC-based clinical graft-versus-host disease (GvHD) therapies. Secondary lymphoid organs (SLOs) are the major niches for generating immune responses or tolerance. MSCs home to a wide range of organs, but rarely to SLOs after intravenous infusion. Thus, we hypothesized that targeted migration of MSCs into SLOs may significantly improve their immunomodulatory effect. Here, chemokine receptor 7 (CCR7) gene, encoding a receptor that specifically guides migration of immune cells into SLOs, was engineered into a murine MSC line C3H10T1/2 by retrovirus transfection system (MSCs/CCR7). We found that infusion of MSCs/CCR7 potently prolonged the survival of GvHD mouse model. The infused MSCs/CCR7 migrate to SLOs, relocate in proximity with T lymphocytes, therefore, potently inhibited their proliferation, activation, and cytotoxicity. Natural killer (NK) cells contribute to the early control of leukemia relapse. Although MSCs/CCR7 inhibited NK cell activity in vitro coculture, they did not impact on the proportion and cytotoxic capacities of NK cells in the peripheral blood of GvHD mice. In an EL4 leukemia cell loaded GvHD model, MSCs/CCR7 infusion preserved the graft-versus-leukemia (GvL) effect. In conclusion, this study demonstrates that CCR7 guides migration of MSCs to SLOs and thus highly intensify their in vivo immunomodulatory effect while preserving the GvL activity. This exciting therapeutic strategy may improve the clinical efficacy of MSC based therapy for immune diseases.

It has been demonstrated in the literature that the transmission/disequilibrium test (TDT) has higher power than the affected-sib-pair (ASP) mean test when linkage disequilibrium (LD) is strong but that the mean test has higher power when LD is weak. Thus, for ASP data, it seems clear that the TDT should be used when LD is strong but that the mean test or other linkage tests should be used when LD is weak or absent. However, in practice, it may be difficult to follow such a guideline, because the extent of LD is often unknown. Even with a highly dense genetic-marker map, in which some markers should be located near the disease-predisposing mutation, strong LD is not inevitable. Besides the genetic distance, LD is also affected by many factors, such as the allelic heterogeneity at the disease locus, the initial LD, the allelic frequencies at both disease locus and marker locus, and the age of the mutation. Therefore, it is of interest to develop methods that are adaptive to the extent of LD. In this report, we propose a disequilibrium maximum-binomial-likelihood (DMLB) test that incorporates LD in the maximum-binomial-likelihood (MLB) test. Examination of the corresponding score statistics shows that this method adaptively combines two sources of information: (a) the identity-by-descent (IBD) sharing score, which is informative for linkage regardless of the existence of LD, and (b) the contrast between allele-specific IBD sharing score, which is informative for linkage only in the presence of LD. For ASP data, the proposed test has higher power than either the TDT or the mean test when the extent of LD ranges from moderate to strong. Only when LD is very weak or absent is the DMLB slightly less powerful than the mean test; in such cases, the TDT has essentially no power to detect linkage. Therefore, the DMLB test is an interesting approach to linkage detection when the extent of LD is unknown.

ObjectiveThis study aimed to explore whether concurrent chemoradiotherapy (CCRT) with or without Adjuvant Chemotherapy (AC) could improved the survival in stage II nasopharyngeal carcinoma (NPC).MethodsPatients with stage II NPC treated with CCRT (n=80) or CCRT+AC (n=40) or IMRT alone (n=42) between January 2007 and September 2014 were retrospectively analyzed. The three patient groups were matched based on prognostic factors. All patients were treated with IMRT. The endpoints were overall survival (OS), distant metastasis-free survival (DMFS), locoregional relapse-free survival (LRRFS), and failure-free survival (FFS). The treatment-related acute toxicity reactions between the three groups were compared also.ResultsThe three groups indicated similar outcomes: survival of the CCRT group, CCRT+AC group and RT alone group were (93.9%, 95.0%, 95.2%, P=0.937) for OS, (96.8%, 94.9%, 93.0%, P=0.756) for LRRFS, (91.1%, 97.5%, 100%, P=0.185) for DMFS and (84.9%, 92.5%, 93.0%, P=0.597) for FFS. Both the univariate and multivariate analysis indicated that older age predicted lower LRRFS and FFS. The CCRT and CCRT+AC groups showed more acute toxicity reactions, especially in bone marrow suppression, Liver dysfunction, gastrointestinal reactions (nausea/vomiting) and weight loss.ConclusionCCRT with/without AC could not improve the survival conditions of patients with stage II NPC, but remarkably increased treatment-associated acute toxic reactions when compared with IMRT alone.

BackgroundInflammatory response markers plays an important role in tumor progression. The aim of this analysis was to evaluate whether the neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) could predict the prognosis of nasopharyngeal carcinoma(NPC).Materials and Methods247 patients who underwent Intensity Modulated Radiation Therapy( IMRT )were enrolled from January 2012 and December 2012. NLR, and PLR were calculated from peripheral blood cell counts taken at pre-treatment. Optimal cutoff values of NLR and PLR were determined on the basis of receiver operating characteristic curve analysis. Overall survival (OS), progression-free survival(PFS), distant metastasis-free survival (DMFS) and loco-regional recurrence-free survival ( LRFS) rates were compared according to NLR and PLR level respectively. Multivariate analysis was performed to assess the prognostic value of NLR and PLR.ResultsThe 5-year estimated OS, PFS, LRFS and DFS were 87.2, 77.8, 96.9, and 86.2%, respectively. Our results shows that the NLR was significantly associated with T-stage (P < 0.05), N-stage (P < 0.05) and tumor stage(P < 0.05). PLR was significantly associated with T-stage (P < 0.05) and tumor stage(P < 0.05). NLR was an independent prognostic indicator for OS (HR: 3.259, P = 0.004), PFS (HR:7.093, P < 0.001), DMFS (HR: 6.576, P = 0.003), except for PLR. In subgroup analysis, adjuvant chemotherapy had no significantly improved survival for patients with high NLR.ConclusionsNLR is a strong prognostic factor for NPC patients. NLR might not be a useful indicator for selection of treatment strategies for loco-regionally advanced NPC.