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Background: Latent genetic instability has been associated with an increased risk for several cancers. We used the comet assay (single-cell gel electrophoresis) to assess whether genetic instability, as reflected by susceptibility to DNA damage, was associated with the risk of bladder cancer in a case-control study. Methods: We used the comet assay to measure baseline and benzo[a]pyrene diol epoxide (BPDE)- and [gamma]-radiation-induced DNA damage in individual peripheral blood lymphocytes from 114 incident case patients with bladder cancer and 145 matched healthy control subjects. All subjects provided personal information, including smoking history. DNA damage was visualized with the comet assay and quantified by the Olive tail moment parameter, a relative measure. Multivariable analysis was used to assess relative risks for bladder cancer associated with DNA damage. All statistical tests were two-sided. Results: Baseline levels of DNA damage were statistically significantly higher in case patients (tail moment = 1.40) than in control subjects (tail moment = 1.21) (difference = 0.19, 95% confidence interval [CI] = 0.04 to 0.32; P = .015), as were [gamma]-radiation-induced (tail moment = 4.76 versus 4.22; difference = 0.54, 95% CI = 0.11 to 0.96; P = .013) and BPDE-induced (tail moment = 4.06 versus 3.45; difference = 0.61, 95% CI = 0.23 to 0.99; P = .002) DNA damage. When data were dichotomized at the median value for DNA damage in control subjects and adjusted for age, sex, ethnicity, and smoking status, an increased estimated relative risk of bladder cancer was statistically significantly associated with DNA damage at baseline (odds ratio [OR] = 1.84, 95% CI = 1.07 to 3.15) and after [gamma]-radiation (OR = 1.81, 95% CI = 1.04 to 3.14) but not after BPDE treatment (OR = 1.69, 95% CI = 0.98 to 2.93). Conclusion: Latent genetic instability as measured by the comet assay is associated with an increased estimated relative risk of bladder cancer.

This study aims to identify and characterize neurobiological markers for major depressive disorder (MDD) from resting-state brain functional MRI. We examined the abnormality in the regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) in first-episode, drug-naive major depressive disorder (fMDD), and remitted major depressive disorder (rMDD) and correlated these fluctuations with clinical markers of MDD. We conducted a retrospective study and reviewed the medical records of 43 patients with fMDD. Overall, 13 of the 43 patients who had at least 3 years of follow-up care and the 17-item Hamilton Depression rating scale less than 7 took no antidepressants for more than half a year at the end of the 3-year follow-up. We further chose a group of 14 healthy controls matched for age, sex and education level with patients with rMDD. Multiple comparison analysis was performed for ALFF and ReHo. The statistical significance level was set at Pvalue of less than 0.05. We examined whether there were differences among the three groups in the whole-brain ALFF and ReHo during resting state. Compared with healthy controls, patients with fMDD showed significant decrease of ReHo in the right anterior lobe of cerebellum and significant increase of ReHo in the right inferior temporal gyrus, and significant decrease of ALFF in the left inferior parietal lobule and right caudate nucleus. Compared with patients with rMDD, those with fMDD showed significant increase of ReHo in the right fusiform gyrus and the left middle temporal gyrus, and significant increase of ALFF in the right superior temporal gyrus. Compared with healthy controls, patients with rMDD showed significant increase of ReHo in the right supramarginal and significant decrease of ReHo in the right precuneus, and significant decrease of ALFF in the right lingual gyrus and in the left superior frontal lobe. Only patients with fMDD showed the relatively robust increase in intrinsic activity of temporal gyrus. The temporal gyrus may play a critical role in depressive symptomatology. Abnormal right fusiform gyrus, left middle temporal gyrus, and right superior temporal gyrus alterations were present only in patients with rMDD but not in patients with fMDD, indicating that these alterations may be a therapeutic target for MDD. Abnormal right supramarginal, right precuneus, right lingual gyrus and left superior frontal lobe alterations were present only in patients with rMDD and not in healthy control, and thus may be used as a state marker of MDD.

Supplemental Digital Content is available in the text.Increasing evidence suggests that microRNA (miRNA)-30e is implicated in the cognitive symptoms of many neuropsychiatric diseases. Our previous studies showed that miRNA-30e is associated with cognitive impairment in schizophrenia and depression. Neuroimaging studies have suggested that cognitive impairment is best characterized as abnormal local activity or a disconnection syndrome. Therefore, we constructed a cognitively impaired overexpressing miRNA-30e rat model for study using functional MRI (fMRI). The model was developed by transfected lentiviral particles carrying the miRNA-30e into the hippocampal dentate gyrus. The Morris water maze and open-field test were used to evaluate cognitive ability. We used the regional homogeneity approach to analyze resting-state fMRI data to explore the changes in regional synchronization. We then used Granger causality analysis to explore connectivity between the hippocampus, striatum, and thalamus. The model group showed higher regional homogeneity in the right hippocampus and striatum. One-way Granger causality connections were observed from the thalamus to the hippocampus in the model group, whereas connections from the thalamus to the striatum were observed in normal rats. After fluoxetine treatment, we found indirect connections between the thalamus and the striatum; we also found connections from the hippocampus to the striatum after Shuganjieyu capsule treatment. Our results support the hypothesis that cognitive impairment is related to disrupted local functionality or aberrant brain connectivity, with antidepressant drugs partially reversing cognitive impairment. The characteristics of resting-state fMRI in miRNA-30e overexpressing rats can provide further evidence for investigating the neural mechanisms of cognitive impairment in mental disorders. Video abstract; Supplemental digital content 1, http://links.lww.com/WNR/A385.

While there has been no objective biomarker available for both diagnosis and prognosis of schizophrenia, compelling evidence suggests that the glutamatergic system may influence susceptibility to schizophrenia. To test genetic association of the glutamatergic system with schizophrenia and abnormal brain activities in resting‐state patients with schizophrenia, a two‐stage association study was performed in 454 patients and 480 controls, followed by regional homogeneity (ReHo) analysis of resting‐state functional magnetic resonance imaging in 48 first‐episode medication‐free patients and 43 well‐matched controls. The differences in ReHo between genotypes of interest were initially tested by the Student's t‐test and the 2 × 2 (genotypes × disease status) ANOVA was then performed to identify the main effects of genotypes, disease status and their interactions in schizophrenia. The stage‐1 study showed association of the DAOAand PSEN2genes with schizophrenia in a small sample; the stage‐2 study with an expanded sample confirmed the disease association for 2‐SNP and 3‐SNP haplotypes, and the cis‐phase interactions between rs2391191 and some other SNPs in the DAOAgene. Four clusters with altered ReHo in the bilateral culmen, left putamen and left cuneus were associated with rs2391191. Main effects of rs2391191 genotypes were found in the left putamen. The left cuneus showed a genotype × disease status interaction. In conclusion, the DAOAgene may confer genetic risk of schizophrenia and associate with the altered ReHo in schizophrenia; genotype effect and its interaction with disease status may contribute to the altered ReHo, leading to specific ReHo in schizophrenic brain due to glutamatergic modulation. © 2013 Wiley Periodicals, Inc.

Compelling evidence suggests that there is a considerable overlap in structural and functional alternation in the brain between different neuropsychiatric disorders. However, whether these overlaps are specific for schizophrenia has yet to be investigated. A total of 36 patients with paranoid schizophrenia, 43 patients with major depressive disorder (MDD), and 44 healthy controls were recruited to undergo resting‐state functional magnetic resonance imaging (rs‐fMRI) for analysis of regional homogeneity (ReHo). Twelve regions of interest (ROIs) in the frontal and temporal lobes were generated and one‐way ANOVA was performed to test the ReHo differences within these ROIs between the above three groups. The ReHo values within ROIs were extracted to investigate whether a left‐right asymmetry existed in a mental disorder. One‐way ANOVA showed significant differences in ReHo in the right superior frontal gyrus and left superior temporal gyrus; post hoc analysis revealed that schizophrenic patients had lower ReHo in the left superior temporal gyrus than either control subjects or patients with MDD. Increased ReHo was observed in the right superior frontal gyrus in schizophrenic patients compared with control subjects, and a left‐less‐than‐right asymmetry was also found in this region in schizophrenic patients. The above alterations in ReHo were not affected by age and genders. Our study suggests that the altered ReHo in the superior frontal and temporal gyrus may be specific for schizophrenia rather than MDD. A left‐less‐than‐right asymmetry activation pattern may exist in the resting‐state superior frontal gyrus in schizophrenia. This finding would be helpful for better understanding the pathological mechanisms of schizophrenia. © 2012 Wiley Periodicals, Inc.

Resting state functional brain networks have been widely studied in brain disease research. However, it is currently unclear whether abnormal resting state functional brain network metrics can be used with machine learning for the classification of brain diseases. Resting state functional brain networks were constructed for 28 healthy controls and 38 major depressive disorder patients by thresholding partial correlation matrices of 90 regions. Three nodal metrics were calculated using graph theory-based approaches. Nonparametric permutation tests were then used for group comparisons of topological metrics, which were used as classified features in six different algorithms. We used statistical significance as the threshold for selecting features and measured the accuracies of six classifiers with different number of features. A sensitivity analysis method was used to evaluate the importance of different features. The result indicated that some of the regions exhibited significantly abnormal nodal centralities, including the limbic system, basal ganglia, medial temporal, and prefrontal regions. Support vector machine with radial basis kernel function algorithm and neural network algorithm exhibited the highest average accuracy (79.27 and 78.22, respectively) with 28 features (P<0.05). Correlation analysis between feature importance and the statistical significance of metrics was investigated, and the results revealed a strong positive correlation between them. Overall, the current study demonstrated that major depressive disorder is associated with abnormal functional brain network topological metrics and statistically significant nodal metrics can be successfully used for feature selection in classification algorithms.

The precise mechanism of major depressive disorder (MDD) is poorly understood. On the basis of the neurotrophin hypothesis, initial findings from our previous studies, and the functions of epidermal growth factor (EGF) in the central nervous system, we proposed that EGF might contribute to the development of MDD, which was investigated in this study.

Major depressive disorder (MDD) is a common chronic mental disease with diverse clinical presentation. Although the genome‐wide association study (GWAS) has remarkably facilitated the understanding of genetic mechanisms of MDD at a deep molecular level, the combined effect of these disease‐underlying genes still needs further investigation. A total of 1,062 unrelated patients with MDD and 992 unrelated healthy subjects were recruited from a Chinese Han population to test 16 MDD‐associated genes identified by GWAS. A tag SNP‐based linkage‐disequilibrium map was then constructed over the loci that showed MDD association in the study sample. Of the 16 genes tested, EHD3 and FREM3 were associated with MDD in the Chinese population. The conditional test showed disease association for the rs619002(EHD3)‐rs1112714(FREM3) combination (P= 0.0059) and for the rs644926(EHD3)‐rs13130123(FREM3) combination (P= 0.007), of which a reduced risk was found for the rs619002(G)‐rs1112714(T) combination (OR = 0, P= 4.02 × 10−6) and for the rs644926(A)‐rs11938298(G) combination (OR = 0.12, 95% CI = 0.035–0.39, P= 3.85 × 10−6). Quantitative trait analysis revealed that rs13130123 in the FREM3 locus was strongly associated with the insomnia early symptom in patients carrying the rs619002(G) allele (P= 0.001) and those carrying the rs644926(A) allele (P= 0.00077). The combined effect of the EHD3 and FREM3 genes may play an important role in developing MDD. © 2012 Wiley Periodicals, Inc.

The XRCC3 protein participates in DNA double-strand breaks and recombinational repair. A single C-to-T nucleotide change at codon 241 (Thr241Met) has been identified in the XRCC3 gene. Using a hospital-based case–control approach, the authors studied the XRCC3 polymorphism as a possible genetic risk factor for lung carcinoma in African Americans and Mexican Americans. A total of 112 patients with lung carcinoma were frequency matched with 190 control participants on the basis of age, gender, and ethnicity. Polymerase chain reaction-restriction fragment length polymorphism molecular analysis was used successfully to identify the XRCC3 polymorphism in peripheral blood lymphocytes. No significant association between the XRCC3 variant allele polymorphism (odds ratio [OR], 1.25; 95% confidence interval [95% CI], 0.72–2.15) and lung carcinoma risk was noted. However, a significantly increased risk for lung carcinoma (OR, 5.20; 95% CI, 1.59–17.03) was evident in heavy smokers with the variant T-allele genotypes. Furthermore, a joint effect of the T-allele and heavy smoking was observed (OR, 37.31; 95% CI, 11.43–121.72). The XRCC3 polymorphism appeared to be associated with increased risk of lung carcinoma in certain subgroups. It is plausible that the association is very heavily dependent on the degree of smoking. Further studies with larger sample sizes will be necessary to confirm these findings. Cancer 2003. © 2003 American Cancer Society. DOI 10.1002/cncr.11692

XPA, a DNA binding protein in the nucleotide excision repair (NER) pathway, modulates damage recognition. Recently, a common single-nucleotide polymorphism (A → G) of unknown function was identified in the 5′ non-coding region of the XPA gene. Because a deficiency in NER is associated with an increased risk of lung cancer, we evaluated the role of this polymorphism in 695 lung cancer case patients and 695 age-, sex-, ethnicity- and smoking-matched control subjects. We also studied the effect of this polymorphism on NER capacity in a subset sample for whom the host cell reactivation data were available. The presence of one or two copies of the G allele was associated with a reduced lung cancer risk for Caucasians {adjusted odds ratio (ORadj) = 0.69 [95% confidence interval (CI) = 0.53–0.90]}, Mexican-Americans [ORadj = 0.32 (95% CI = 0.12–0.83)] and African-Americans [ORadj = 0.45 (95% CI = 0.16–1.22)]. In Caucasians, ever smokers with one or more copies of the G allele were observed to have a significantly reduced risk of lung cancer. Control subjects with one or two copies of the G allele demonstrated more efficient DRC than did those with the homozygous A allele. Our data suggest that the XPA 5′ non-coding region polymorphism modulates NER capacity and is associated with decreased lung cancer risk, especially in the presence of exposure to tobacco carcinogens.

Because insulin-like growth factors (IGFs) and their binding proteins have been implicated in the development of prostate, breast, colon and lung cancer, we examined the role of IGF-1 and IGF binding protein-3 levels in bladder cancer risk.

Supplemental Digital Content is available in the text

Major Depression (MD) is a highly inherited psychiatric disorder. The norepinephrine transporter (NET) gene plays important role in pathophysiology of MD. This study attempted to examine the relationship between polymorphisms of NETgene and MD.