Ventricular Netrin-1 deficiency leads to defective pyramidal decussation and mirror movement in mice.

The corticospinal tract (CST) is the principal neural pathway responsible for conducting voluntary movement in the vertebrate nervous system. Netrin-1 is a well-known guidance molecule for midline crossing of commissural axons during embryonic development. Families with inherited Netrin-1 mutations display congenital mirror movements (CMM), which are associated with malformations of pyramidal decussation in most cases. Here, we investigated the role of Netrin-1 in CST formation by generating conditional knockout (CKO) mice using a Gfap-driven Cre line. A large proportion of CST axons spread laterally in the ventral medulla oblongata, failed to decussate and descended in the ipsilateral spinal white matter of Ntn1Gfap CKO mice. Netrin-1 mRNA was expressed in the ventral ventricular zone (VZ) and midline, while Netrin-1 protein was transported by radial glial cells to the ventral medulla, through which CST axons pass. The level of transported Netrin-1 protein was significantly reduced in Ntn1Gfap CKO mice. In addition, Ntn1Gfap CKO mice displayed increased symmetric movements. Our findings indicate that VZ-derived Netrin-1 deletion leads to an abnormal trajectory of the CST in the spinal cord due to the failure of CST midline crossing and provides novel evidence supporting the idea that the Netrin-1 signalling pathway is involved in the pathogenesis of CMM.

Maternal and embryonic signals cause functional differentiation of luminal epithelial cells and receptivity establishment.

Embryo implantation requires temporospatial maternal-embryonic dialog. Using single-cell RNA sequencing for the uterus from 2.5 to 4.5 days post-coitum (DPC) and bulk sequencing for the corresponding embryos of 3.5 and 4.0 DPC pregnant mice, we found that estrogen-responsive luminal epithelial cells (EECs) functionally differentiated into adhesive epithelial cells (AECs) and supporting epithelial cells (SECs), promoted by progesterone. Along with maternal signals, embryonic Pdgfa and Efna3/4 signaling activated AECs and SECs, respectively, enhancing the attachment of embryos to the endometrium and furthering embryo development. This differentiation process was largely conserved between humans and mice. Notably, the developmental defects of SOX9-positive human endometrial epithelial cells (similar to mouse EEC) were related to thin endometrium, whereas functional defects of SEC-similar unciliated epithelial cells were related to recurrent implantation failure (RIF). Our findings provide insights into endometrial luminal epithelial cell development directed by maternal and embryonic signaling, which is crucial for endometrial receptivity.

The role of PTEN in primary sensory neurons in processing itch and thermal information in mice.

PTEN is known as a tumor suppressor and plays essential roles in brain development. Here, we report that PTEN in primary sensory neurons is involved in processing itch and thermal information in adult mice. Deletion of PTEN in the dorsal root ganglia (DRG) is achieved in adult Drg11-CreER: PTENflox/flox (PTEN CKO) mice with oral administration of tamoxifen, and CKO mice develop pathological itch and elevated itch responses on exposure to various pruritogens. PTEN deletion leads to ectopic expression of TRPV1 and MrgprA3 in IB4+ non-peptidergic DRG neurons, and the TRPV1 is responsive to capsaicin. Importantly, the elevated itch responses are no longer present in Drg11-CreER: PTENflox/flox: TRPV1flox/flox (PTEN: TRPV1 dCKO) mice. In addition, thermal stimulation is enhanced in PTEN CKO mice but blunted in dCKO mice. PTEN-involved regulation of itch-related gene expression in DRG neurons provides insights for understanding molecular mechanism of itch and thermal sensation at the spinal level.

Progress in the genetic studies of spermatogenesis abnormalities.

About 15% couples suffer from infertility, half of which are caused by male factors. Male infertility usually manifests as teratozoospermia, oligospermia and/or asthenospermia, of which the most severe form is azoospermia. In this review, we summarize the recent progress in the study of genetic factors involved in nonobstructive azoospermia and teratozoospermia, Recently, with the rapid development of high-throughput chips and sequencing technologies, many genetic factors of spermatogenesis have been discovered and analyzed. For the nonobstructive azoospermia, genome-wide association studies (GWAS) and high-throughput sequencing revealed many risk loci of nonobstructive azoospermia. For the teratozoospermia, the application of whole-exome sequencing (WES) revealed a series of disease-causing genes, greatly enriching our knowledge of teratozoospermia including multiple morphological abnormalities of the flagella (MMAF). The discovery of lots of disease genes helped the characterization of the pathological mechanisms of male infertility. Therefore, a comprehensive and in-depth understanding of genetic factors in spermatogenesis abnormalities will play important roles in the clinical diagnosis, treatment and genetic counseling of male infertility.

Cholesterol metabolic enzyme Ggpps regulates epicardium development and ventricular wall architecture integrity in mice.

During embryonic heart development, the progenitor cells in the epicardium would migrate and differentiate into noncardiomyocytes in myocardium and affect the integrity of ventricular wall, but the underlying mechanism has not been well studied. We have found that myocardium geranylgeranyl diphosphate synthase (Ggpps), a metabolic enzyme for cholesterol biosynthesis, is critical for cardiac cytoarchitecture remodelling during heart development. Here, we further reveal that epicardial Ggpps could also regulate ventricular wall architecture integrity. Epicardium-specific deletion of Ggpps before embryonic day 10.5 (E10.5) is embryonic lethal, whereas after E13.5 is survival but with defects in the epicardium and ventricular wall structure. Ggpps deficiency in the epicardium enhances the proliferation of epicardial cells and disrupts cell‒cell contact, which makes epicardial cells easier to invade into ventricular wall. Thus, the fibroblast proliferation and coronary formation in myocardium were found enhanced that might disturb the coronary vasculature remodelling and ventricular wall integrity. These processes might be associated with the activation of YAP signalling, whose nuclear distribution is blocked by Ggpps deletion. In conclusion, our findings reveal a potential link between the cholesterol metabolism and heart epicardium and myocardium development in mammals, which might provide a new view of the cause for congenital heart diseases and potential therapeutic target in pathological cardiac conditions.

Diagnostic and Predictive Values of Strain Ratios in the Regions of Interests in Reference Tissue for Breast Tumor.

PURPOSE: To investigate the diagnostic and predictive value of strain ratios in the regions of interests (ROIs) in reference tissue for breast tumor. PATIENTS AND METHODS: A total of 707 lesions in 665 consecutive patients were examined with B-mode Breast Imaging-Reporting and Data System (BI-RADS) and Ultrasonic elastography (UE). Elasticity score (ES) and strain ratio (SR) in each lesion were calculated. Receiver operating characteristic (ROC) curves were used to assess the diagnostic value of BI-RADS, ES, SR1, SR2, BI-RADS combined with ES (BI-RADS+ES), BI-RADS combined with SR1 (BI-RADS+SR1), and BI-RADS combined with SR2 (BI-RADS+SR2). The sensitivity, specificity, and areas under the ROC curves (Az) were obtained. Scatter plots were generated to demonstrate the correlation between SR1 and SR2. Kruskal-Walls H-test, Mann-Whitney U-test and one-way ANOVA were performed to evaluate SRs and tumor-related variables. Multiple linear regression analysis was carried out to determine variables independently associated with SRs. RESULTS: BI-RADS had high sensitivity and low specificity in the diagnosis of breast tumor. The specificity of BI-BADS combined with ES or SR was even higher. The Az value of BI-RADS+ES or BI-RADS+SRs was higher than that of BI-RADS (P < 0.001). The Az value of ES was higher than those of SR1 and SR2 (P < 0.001), and those of SR1 and SR2 were similar. SR1 and SR2 were highly positively correlated. There was no statistical difference between Az values of BI-RADS+ES, BI-RADS+SR1, and BI-RADS+SR2. Indistinct margin, high histologic grade, histological type, and negative human epidermal growth factor receptor (Her-2) were associated with SR1 and SR2. Progesterone receptor (PR) status and molecular subtype were associated with SR2. Histologic grade and tumor margin were significantly associated with SR1, and tumor margin was associated with SR2. CONCLUSION: SRs in different ROIs in the reference tissue at the same depth showed no different diagnostic value for breast tumor. Both SR1 and SR2 could be useful in assessing the biological characteristics of invasive breast carcinoma.

Novel insight from the first lung transplant of a COVID-19 patient.

BACKGROUND: To reveal detailed histopathological changes, virus distributions, immunologic properties and multi-omic features caused by SARS-CoV-2 in the explanted lungs from the world's first successful lung transplantation of a COVID-19 patient. MATERIALS AND METHODS: A total of 36 samples were collected from the lungs. Histopathological features and virus distribution were observed by optical microscope and transmission electron microscope (TEM). Immune cells were detected by flow cytometry and immunohistochemistry. Transcriptome and proteome approaches were used to investigate main biological processes involved in COVID-19-associated pulmonary fibrosis. RESULTS: The histopathological changes of the lung tissues were characterized by extensive pulmonary interstitial fibrosis and haemorrhage. Viral particles were observed in the cytoplasm of macrophages. CD3+ CD4- T cells, neutrophils, NK cells, γ/δ T cells and monocytes, but not B cells, were abundant in the lungs. Higher levels of proinflammatory cytokines iNOS, IL-1ß and IL-6 were in the area of mild fibrosis. Multi-omics analyses revealed a total of 126 out of 20,356 significant different transcription and 114 out of 8,493 protein expression in lung samples with mild and severe fibrosis, most of which were related to fibrosis and inflammation. CONCLUSIONS: Our results provide novel insight that the significant neutrophil/ CD3+ CD4- T cell/ macrophage activation leads to cytokine storm and severe fibrosis in the lungs of COVID-19 patient and may contribute to a better understanding of COVID-19 pathogenesis.

Dietary habits and risk of hepatocellular carcinoma among hepatitis B surface antigen carriers: A prospective cohort study in China.

OBJECTIVE: In this prospective cohort study, we aimed to evaluate the association between dietary habits and the risk of developing hepatocellular carcinoma (HCC) in hepatitis B surface antigen (HBsAg)-positive carriers in Qidong, an hepatitis B virus (HBV)-epidemic area in China. METHODS: A total of 3199 HBsAg carriers aged 30-70 years in a prospective cohort in Qidong, China from 2007 to 2011 were included in the study. At baseline, all participants self-reported their dietary habits in a questionnaire interview. A follow-up check-up was performed every 6 months to identify HCC cases until November 2017. Cox's regression analysis and an interaction analysis were performed to estimate the relative risks of HCC in terms of baseline diet. RESULTS: Among 3199 HBsAg-positive participants, 270 developed HCC (143.86/100 000 person-years [PYs]). Compared with participants who rarely consume garlic, the risk of HCC in those who consumed it ≥ once per week decreased along with the increase in frequency (HR = 1.00, 0.90 and 0.62 in those who consumed it rarely vs those who consumed it 1-6 times per week and ≥ 7 times per week, respectively). This study found a synergistic effect between garlic and tea consumption on the risk of HCC (P = 0.039 for a multiplicative interaction). CONCLUSIONS: HBsAg carriers should improve their diet. Regular consumption of garlic and tea drinking may reduce the HCC incidence in HBsAg carriers.

The prognostic role of HBV infection in chronic lymphocytic leukemia.

PURPOSE: We attempt to assess the impact of hepatis-B virus (HBV) status on the prognosis of chronic lymphocytic leukemia (CLL) using a Chinese case cohort. METHODS: Five hundred and one consecutive newly diagnosed subjects with CLL were enrolled in this case cohort. HBV infection was defined as hepatitis B surface antigen (HBsAg) positive or hepatitis-B core antibody (HBcAb) positive. Univariate and stepwise multivariate Cox regression analyses were used to screen the prognostic risk factors associated with the end point of time-to-treatment (TTT) or overall survival (OS). Bootstrap re-sampling method was used to evaluate the model's internal validity. The discriminative ability of the models was evaluated using time-dependent receiver-operator characteristic (ROC) curves and corresponding areas under the curve (AUC). RESULTS: One hundred and twenty-one subjects (24%) among 501 patients were HBV positive. HBV infection was an independent predictor for the prognosis of TTT (HR = 1.37; 95% CI 1.04-1.80) or OS (HR =2.85; 95% CI 1.80-4.52). The AUCs for HBV infection were 0.62 (95% CI 0.58-0.66) for TTT and 0.69 (95% CI 0.66-0.72) for OS, respectively. When we combined HBV infection with the traditional clinical and biological factors, significant improvements for model's discrimination were observed for TTT [AUC: 0.81 (95% CI: 0.77-0.85) vs. 0.78 (95% CI: 0.74-0.82), P < 0.001] and OS [AUC: 0.81 (95% CI 0.76-0.86) vs. 0.76 (95% CI 0.71-0.82), P < 0.001). Further bootstrap re-sampling method revealed good internal consistence for the final optimal models (Average AUC: 0.78 for TTT and 0.79 for OS based on 1000 bootstraps). CONCLUSIONS: Our results indicated that HBV infection should be served as an important risk predictor for prognosis of CLL (TTT and OS).

Rare association of two cardiovascular malformations successfully corrected in a single surgery: a case report.

BACKGROUND: Partial anomalous pulmonary venous connection (PAPVC) without an atrial septal defect (ASD) associated with coarctation of the aortic arch is a rare congenital cardiac anomaly. This rare combination is only described in a few studies; none report the correction of these two malformations in a single surgery. CASE PRESENTATION: A 5-year-old girl was admitted to our hospital because the echocardiography revealed coarctation of the aortic arch; this diagnosis was confirmed by computed tomography (CT), which also showed her left superior pulmonary vein draining into the vertical vein without ASD (Fig. 1). She exhibited no special clinical symptoms. Her upper-limb blood pressure was approximately 110/90 mmHg, whereas her lower-limb blood pressure was approximately 75/50 mmHg. CONCLUSIONS: We surgically repaired the case of PAPVC to the vertical vein with aortic coarctation, in which the two cardiovascular malformations were corrected in a single surgery without cardiopulmonary bypass.

Genetic variants in ERBB4 is associated with chronic hepatitis B virus infection.

BACKGROUND: The role of ERBB4 in liver disease has seldom been reported. This study aims to find genetic markers at ERBB4 for chronic hepatitis B virus (HBV) infection and determine the role of ERBB4 in liver injury. METHODS: We selected and genotyped three single nucleotide polymorphisms and one insertion/deletion (Ins/Del) at the 5' and 3' untranslated region (UTR) of ERBB4 in a case-control study including 1344 pairs of HBV carriers and HBV natural clearance subjects. The luciferase reporter system was applied to study the regulative role of Ins/Del on ERBB4. Further, ERBB4 knockout mice were used to study the role of ERBB4 in liver injury. Proteomic quantification was performed by HPLC-MS/MS analysis to identify liver protein profile change between liver-specific ERBB4 knockout and control mice. RESULTS: rs6147150 Ins/Del and rs1836724 T>C at the 3' UTR of ERBB4 were associated with reduced risk of chronic HBV infection (P = 0.002 and 0.004, respectively). Besides, the 12bp deletion at the 3' UTR increased ERBB4 expression due to lacking let-7c binding site. In addition, loss of ERBB4 led to more severe acute or chronic inflammation in mouse liver injury models. Further, quantitative proteomic analysis and data from the cancer genome atlas revealed that ACLY, an enzyme key for de novo lipogenesis, was negatively correlated with ERBB4. CONCLUSIONS: ERBB4 plays protective role from liver injury and its 3'UTR genetic variants could be genetic markers for chronic HBV infection.

Prognostic impact of Epstein-Barr virus (EBV)-DNA copy number at diagnosis in chronic lymphocytic leukemia.

Epstein-Barr virus (EBV)-DNA is detected in the blood of some persons with chronic lymphocytic leukemia (CLL) at diagnosis. Whether this is important in the development or progression of CLL is controversial. We interrogated associations between blood EBV-DNA copy number and biological and clinical variables in 243 new-diagnosed consecutive subjects with CLL. Quantification of EBV-DNA copies was done by real-time quantitative PCR (RQ-PCR). All subjects had serological evidence of prior EBV-infection. However, only 24 subjects (10%) had a EBV-DNA-positive test at diagnosis. EBV-DNA-positive subjects at diagnosis had lower hemoglobin concentrations and platelet levels, higher thymidine kinase-1 and serum ferritin levels, un-mutated IGHV genes and a greater risk of Richter transformation compared with EBV-DNA-negative subjects. Percent CD20-, CD148- and ZAP70-positive cells and mean fluorescence intensity (MFI) of each cluster designation were also increased in EBV-DNA-positive subjects at diagnosis. EBV-DNA test positivity was associated with a briefer time-to-treatment interval (HR 1.85; [95% confidence interval, 1.13, 3.03]; P=0.014) and worse survival (HR 2.77; [1.18, 6.49]; P=0.019). Reduction in EBV copies was significantly associated with therapy-response. A positive blood EBV-DNA test at diagnosis and sequential testing of EBV copies during therapy were significantly associated with biological and clinical variables, time-to-treatment, therapy-response and survival. If validated these data may be added to CLL prognostic scoring systems.

[Photocatalytic degradation of acetamiprid by TiO2 and Xe lamp: kinetics and degradation intermediates].

Photocatalytic degradation kinetics of acetamiprid was studied by both of single-variable-at-a-time (SVAT) and central composite design (CCD) experiments based on four factors, such as catalyst dosages, substrate concentration, temperature and pH values. The results indicated that degradation of acetamiprid followed pseudo first-order kinetics by Langmuir-Hinshelwood model, increased with the increasing of temperature and the decreasing of substrate concentration. The photocatalytic degradation kinetic rate of acetamiprid was low in acid solutions, while high in weak acidic and alkaline solutions. After studying the synergistic effects of these four classic parameters, the optimal experiment conditions for photocatalytic degradation of acetamiprid were obtained as follows: TiO2 at 2.30 g x L(-1), initial acetamiprid concentration of 90.0 µmol x L(-1), temperature of 37.5 degrees C and pH value at 5.0. Lastly, 7 degradation intermediates of acetamiprid were detected during photocatalytic process by HPLC, and 6 of them exhibited more polar than the parent molecule.

[Association of polymorphisms of potassium voltage-gated channel, KQT-like subfamily, member 1 and type 2 diabetes in Jiangsu province, China].

OBJECTIVE: To study the association of polymorphisms in the potassium voltage-gated channel, KQT-like subfamily,member 1(KCNQ1) gene with type 2 diabetes in Chinese population from Jiangsu province. METHODS: Subjects consisting of 2925 cases and 3281 controls were enrolled from a community based cohort study of type 2 diabetes in Wuxi in 2007 and a community based cross-sectional survey on chronic non-communicable disease in Nantong in 2009. Epidemiological questionnaire survey and physical examinations were conducted and 10 h overnight fasting blood samples of 5 ml were drawn for all subjects.Genotypes were determined by TaqMan OpenArray Genotyping System and i-PLEX Sequenom MassARRAY platform. The relationship between KCNQ1 gene polymorphism and risk of type 2 diabetes after adjustment for age,sex and body mass index (BMI) was analyzed. RESULTS: The C allele of rs2237897, rs2237892 and rs2237895 at KCNQ1 increased the risk of type 2 diabetes with adjusted OR (95%CI) value being 1.41(1.30-1.54), 1.35(1.24-1.47), 1.22(1.12-1.33) respectively (all P value < 0.05) under the additive genetic model after adjusted by age,sex and BMI. Stratification analyses in additive genetic model showed that the C allele of rs2237897 increased the risk of type 2 diabetes in subgroups stratified by age ( ≤ 56 years and > 56 years), sex (females and males), BMI (< 24 kg/m(2) and ≥ 24 kg/m(2)) with OR (95%CI) value being 1.39(1.22-1.59), 1.43(1.28-1.60), 1.40(1.26-1.55), 1.44(1.26-1.66), 1.48(1.33-1.66), 1.34(1.17-1.53) respectively (all P value< 0.05). CONCLUSION: Polymorphisms of rs2237897, rs2237892 and rs2237895 in the KCNQ1 gene were associated with occurrence of type 2 diabetes among Jiangsu province population.

[Forest resources in Qungyuan County of Liaoning, Northeast China: the structure and optimal spatial allocation].

By using RS/GIS techniques and the method of multiple objective grey situation decision, and in considering the forest economic benefits (biomass and stand productivity) and ecological benefits (water and soil conservation) , an optimal spatial allocation of the present forest types in Qingyuan County of Liaoning, Northeast China was approached in this study. After the optimization of spatial allocation, the structural proportions of different forest types in Qingyuan County changed obviously, with the area of coniferous forests reduced from 43% to 23% , the area of broadleaved forests reduced from 51% to 31% , the area of mixed coniferous-broadleaf forests increased from 3% to 43% , and the area of shrubs remained unchanged. As compared with the results before optimization, the biomass, stand productivity, and water conservation function of the forest ecosystem in Qingyuan County after optimization increased by 0.6%, 2.1% , and 31.7%, respectively, and the soil conservation function remained unchanged. It could be concluded that after the optimization of spatial allocation, the forest ecosystem of Qingyuan County could maintain its soil conservation function, and, at the time of keeping higher timber production, fully exert waler conservation function, realizing the maximization of the economic and ecological benefits of the forest ecosystem.

[Single nucleotide polymorphism in flanking region of miR-30c influences the maturing process of miR-30c in lung carcinoma].

OBJECTIVE: To investigate the effect of a common polymorphism rs928508(A/G) in flanking region of miR-30c on the expression of pri, pre and mature miR-30c, and discuss the effect of this polymorphism on the maturing process of miR-30c in lung carcinoma. METHODS: The pGL3-promoter-miR-30c-A and pGL3-promoter-miR-30c-G luciferase plasmids were created containing A or G allele of miR-30c flanking region. Taqman assay was used to genotype rs928508 polymorphism in 50 lung cancer tissues. RT-PCR was performed to determine the expression of pri-miR-30c, pre-miR-30c, mature miR-30c and miR-30c host gene NFYC in the 50 lung cancer tissues. RESULTS: The luciferase expression level of the pGL3-promoter-miR-30c-A construct group was not significantly different compared with that in the the pGL3-promoter-miR-30c-G construct group (A549 cells, P = 0.758; 293A cells, P = 0.554; CHO cells, P = 0.175). The results demonstrated that rs928508(A/G) variant had no effect on the transcriptional regulation of pri-miR-30c. In the genotype-phenotype collection analysis of the 50 lung cancer tissues, the expression of pre-miR-30c and mature miR-30c for rs928508 AG/GG genotypes showed significantly lower levels compared with those in the AA genotype (P = 0.009, P = 0.011). However, the expression of pri-miR-30c showed no significant difference between AG/GG genotypes and AA genotype. Similarly, the expression of host NFYC gene was correlated with pri-miR-30c, showed no significant difference between AG/GG genotypes and AA genotype. CONCLUSION: The rs928508(A/G) polymorphism in flanking region of miR-30c could influence the processing from pri-miR-30c to mature miR-30c, but does not influence the transcription of pri-miR-30c.

[Random forest analysis of high dimensional case and control study of lung cancer].

OBJECTIVE: To investigate the performance of random forest method as a SNP screening procedure in high dimensional case-control data of lung cancer. METHODS: This study included 500 lung cancer patients and 517 controls. A total of 5 ml venous blood sample was collected from each participant. The genotypes were classified by GoldenGate platform, and 399 SNPs were selected. The random forest method was first applied to reduce the dimension, and then the traditional logistic regression method was used to analyze the variables and the genetic susceptibility between lung cancer and multiple SNPs was analyzed by AUC (areas under receiver operation characteristics (ROC) curves). RESULTS: Fifty important variables, whose average importance scores were highest and whose error rates were lowest, were selected by random forest method. The importance scores of environmental variables (smoking, age and gender) were all listed at top 20, which were respectively 4.05, 3.12 and 1.16. After adjusting 3 environmental variables and false discovery rate (FDR), 6 SNPs were still significantly associated with lung cancer (FDR-P < 0.05). However, if traditional logistic regression analysis were directly applied, no significant SNPs were found. The likelihood testing result of AUC of the 2 ROC (one curve only included environmental variables and the other curve included environmental variables and SNPs) were 0.6491 ± 0.0172 and 0.6811 ± 0.0166 respectively; showed statistical significance of the association between the 6 SNPs and lung cancer (χ² = 43.82, P = 3.6×10⁻¹¹). CONCLUSION: Random forest analysis could first remove the turbulent SNPs and then make the analysis by logistic regression method. This could improve the testing efficacy, which is significantly better than single logistic regression analysis.

Genetic variants in the PI3K/PTEN/AKT/mTOR pathway predict platinum-based chemotherapy response of advanced non-small cell lung cancers in a Chinese population.

OBJECTIVE: The PI3K/PTEN/AKT/mTOR signaling pathway has been implicated in resistance to cisplatin. In the current study, we determined whether common genetic variations in this pathway are associated with platinum-based chemotherapy response and clinical outcome in advanced non-small cell lung cancer (NSCLC) patients. METHODS: Seven common single nucleotide polymorphisms (SNPs) in core genes of this pathway were genotyped in 199 patients and analyzed for associations with chemotherapy response, progression-free survival (PFS) and overall survival (OS). RESULTS: Logistic regression analysis revealed an association between AKT1 rs2494752 and response to treatment. Patients carrying heterozygous AG had an increased risk of disease progression after two cycles of platinum-based chemotherapy compared to those with AA genotype (Adjusted odds ratio (OR)=2.18, 95% confidence interval (CI): 1.00-4.77, which remained significant in the stratified analyses). However, log-rank test and cox regression detected no association between these polymorphisms in the PI3K pathway genes and survival in advanced NSCLC patients. CONCLUSIONS: Our findings suggest that genetic variants in the PI3K/PTEN/AKT/mTOR pathway may predict platinum-based chemotherapy response in advanced NSCLC patients in a Chinese population.

Genetic variants of NBS1 predict clinical outcome of platinum-based chemotherapy in advanced non-small cell lung cancer in Chinese.

OBJECTIVE: NBS1 plays a key role in the repair of DNA double-strand break (DSB). We conducted this study to investigate the effect of two critical polymorphisms (rs1805794 and rs13312840) in NBS1 on treatment response and prognosis of advanced non-small cell lung cancer (NSCLC) patients with platinum-based chemotherapy. METHODS: Using TaqMan methods, we genotyped the two polymorphisms in 147 NSCLC patients. Odds ratios (ORs) and their 95% confidential intervals (CIs) were calculated as a measure of difference in the response rate of platinum-based chemotherapy using logistic regression analysis. The Kaplan-Meier and log-rank tests were used to assess the differences in progression-free survival (PFS) and overall survival (OS). Cox proportional hazards model was applied to assess the hazard ratios (HRs) for PFS and OS. RESULTS: Neither of the two polymorphisms was significantly associated with treatment response of platinum-based chemotherapy. However, patients carrying the rs1805794 CC variant genotype had a significantly improved PFS compared to those with GG genotype (16.0 vs. 8.0 months, P = 0.040). Multivariable cox regression analysis further showed that rs1805974 was a significantly favorable prognostic factor for PFS [CC/CG vs. GG: Adjusted HR = 0.62, 95% CI: 0.39-0.99; CC vs. CG/GG: Adjusted HR = 0.56, 95% CI: 0.32-0.97). Similarly, rs13312840 with a small sample size also showed a significant association with PFS (CC vs. CT/TT: Adjusted HR = 25.62, 95% CI: 1.53-428.39). CONCLUSIONS: Our findings suggest that NBS1 polymorphisms may be genetic biomarkers for NSCLC prognosis especially PFS with platinum-based chemotherapy in the Chinese population.