Cancer of the oral cavity is a serious disease, affecting about 30,000 individuals in US annually. There are several animal models of oral cancer, but each has certain disadvantages. As a new model, we investigated whether topical application of the tobacco smoke carcinogen, dibenzo[a,l]pyrene (DB[a,l]P) is mutagenic and carcinogenic in the oral cavity of the B6C3F1 lacI and B6C3F1 mouse, respectively. B6C3F1 lacI mice received DB[a,l]P (0, 3, 6, 12 nmol) 3× per week. B6C3F1 mice received the same doses and also 24 nmol. At 38 weeks mutagenesis was measured in oral tissues in lacI mice. For the high dose group, the mutant fraction (MF) in upper mucosa and tongue increased about twofold relative to that in vehicle-alone. The increases were statistically significant. The mutational profile in the DB[a,l]P-induced mutants was compared with that induced by benzo[a]pyrene (BaP) in oral tissue. BaP is mutagenic in many tissues when administered by gavage. The mutational profile for DB[a,l]P was more similar to that reported for p53 mutations in head and neck cancers than was that of BaP. At 47 weeks, oral squamous cell carcinomas (OSCC) were found in 31% of the high-dose B6C3F1 group. Elevations of p53 and COX-2 protein were observed in tumor and dysplastic tissue. As DB[a,l]P induces mutations and tumors in the oral cavity, and has a mutational profile in oral tissue similar to that found in p53 in human OSCC, the treatment protocol described here may represent a new and relevant model for cancer of the oral cavity.
Copy number variants (CNVs) are risk factors in neurodevelopmental disorders, including autism, epilepsy, intellectual disability (ID) and schizophrenia. Childhood onset schizophrenia (COS), defined as onset before the age of 13 years, is a rare and severe form of the disorder, with more striking array of prepsychotic developmental disorders and abnormalities in brain development. Because of the well-known phenotypic variability associated with pathogenic CNVs, we conducted whole genome genotyping to detect CNVs and then focused on a group of 46 rare CNVs that had well-documented risk for adult onset schizophrenia (AOS), autism, epilepsy and/or ID. We evaluated 126 COS probands, 69 of which also had a healthy full sibling. When COS probands were compared with their matched related controls, significantly more affected individuals carried disease-related CNVs (P = 0.017). Moreover, COS probands showed a higher rate than that found in AOS probands (P<0.0001). A total of 15 (11.9%) subjects exhibited at least one such CNV and four of these subjects (26.7%) had two. Five of 15 (4.0% of the sample) had a 2.5–3 Mb deletion mapping to 22q11.2, a rate higher than that reported for adult onset (0.3–1%) (P<0.001) or autism spectrum disorder and, indeed, the highest rate reported for any clinical population to date. For one COS subject, a duplication found at 22q13.3 had previously only been associated with autism, and for four patients CNVs at 8q11.2, 10q22.3, 16p11.2 and 17q21.3 had only previously been associated with ID. Taken together, these findings support the well-known pleiotropic effects of these CNVs suggesting shared abnormalities early in brain development. Clinically, broad CNV-based population screening is needed to assess their overall clinical burden.
Although genome-wide association studies (GWAS) are widely used to identify the genetic and environmental etiology of a trait, several key issues related to their statistical power and biological relevance have remained unexplored. Here, we describe a novel statistical approach, called functional GWAS or fGWAS, to analyze the genetic control of traits by integrating biological principles of trait formation into the GWAS framework through mathematical and statistical bridges. fGWAS can address many fundamental questions, such as the patterns of genetic control over development, the duration of genetic effects, as well as what causes developmental trajectories to change or stop changing. In statistics, fGWAS displays increased power for gene detection by capitalizing on cumulative phenotypic variation in a longitudinal trait over time and increased robustness for manipulating sparse longitudinal data.
We previously reported that dibenzo[a,l]pyrene (DB[a,l]P), the most potent known environmental carcinogen among polycyclic aromatic hydrocarbons (PAH) congeners, is carcinogenic in the oral tissues of mice. We have now developed a new mouse model which employs the oral application of the fjord region diol epoxide, (±)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DB[a,l]PDE), a metabolite of the tobacco smoke constituent DB[a,l]P, and we show its specific induction of oral squamous cell carcinoma (OSCC) in both tongue and other oral tissues. Groups of B6C3F1 mice (20/group) received 6 or 3 nmol of (±)-anti-DB[a,l]PDE administered into the oral cavity; 3 times per week for 38 weeks. Additional groups received the vehicle alone or were left untreated. Mice were sacrificed 42 weeks after the first carcinogen administration. The high dose induced 74 % and 100 % OSCC in the tongue and other oral tissues, respectively; the corresponding values at the lower dose were 45 % and 89 %. Using immunohistochemistry, we showed that DB[a,l]PDE resulted in overexpression of p53 and COX-2 proteins in malignant tissues when compared to normal oral tissues and tongues. Consistent with the carcinogenicity, we demonstrated powerful mutagenicity in cII gene in B6C3F1 (Big Blue) mouse tongue. The mutational profile in lacI reporter gene is similar to those detected in human head and neck cancer, and p53 mutations were observed in mouse oral tumor tissues. Taken together, we conclude that the formation of diol epoxides plays a major role among the mechanisms by which DB[a,l]P exerts its oral mutagenicity and tumorigenicity.
In genome-wide association (GWA) studies, test statistics that are efficient and robust across various genetic models are preferable, particularly for studying multiple diseases in the Wellcome Trust Case-Control Consortium (WTCCC, 2007, Nature 447, 661-678). A new test statistic, the minimum of the p-values of the trend test and Pearson's test, was considered by the WTCCC. It is referred to here as MIN2. Because the minimum of two p-values is no longer a valid p-value itself, the WTCCC only used it to rank single nucleotide polymorphisms (SNPs) but did not report the p-values of the associated SNPs when MIN2 was used for ranking. Given its importance in practice, we derive the asymptotic null distribution of MIN2, study some of its analytical properties related to GWA studies, and compare it with existing methods (the trend test, Pearson's test, MAX3, and the constrained likelihood ratio test [CLRT]) by simulations across a wide range of possible genetic models: the recessive (REC), additive (ADD), multiplicative (MUL), dominant (DOM), and overdominant models. The results show that MAX3 and CLRT have greater efficiency robustness than other tests when the REC, ADD/MUL, and DOM models are possible, whereas Pearson's test and MIN2 have greater efficiency robustness if the possible genetic models also include the overdominant model. We conclude that robust tests (MAX3, MIN2, CLRT, and Pearson's test) are preferable to a single trend test for initial GWA studies. The four robust tests are applied to more than 100 SNPs associated with 11 common diseases identified by the two WTCCC GWA studies.
Childhood-onset schizophrenia (COS), defined by the onset of illness before age 13 years, is a rare severe neurodevelopmental disorder of unknown etiology. Recently, sequencing studies have identified rare, potentially causative de novo variants in sporadic cases of adult-onset schizophrenia and autism. In this study, we performed exome sequencing of 17 COS trios in order to test whether de novo variants could contribute to this disease. We identified 20 de novo variants in 17 COS probands, which is consistent with the de novo mutation rate reported in the adult form of the disease. Interestingly, the missense de novo variants in COS have a high likelihood for pathogenicity and were enriched for genes that are less tolerant to variants. Among the genes found disrupted in our study, SEZ6, RYR2, GPR153, GTF2IRD1 , TTBK1 and ITGA6 have been previously linked to neuronal function or to psychiatric disorders, and thus may be considered as COS candidate genes.
(TAS2Rs) were found in the lung and act to relax airway smooth muscle (ASM) via intracellular Ca 2ϩ concentration signaling generated from restricted phospholipase C activation. As potential therapy, TAS2R agonists could be add-on treatment when patients fail to achieve adequate bronchodilation with chronic -agonists. The 2-adrenergic receptor (2AR) of ASM undergoes extensive functional desensitization. It remains unknown whether this desensitization affects TAS2R function, by cross talk at the receptors or distal common components in the relaxation machinery. We studied intracellular signaling and cell mechanics using isolated human ASM, mouse tracheal responses, and human bronchial responses to characterize TAS2R relaxation in the context of  2AR desensitization. In isolated human ASM, magnetic twisting cytometry revealed Ͼ90% loss of isoproterenol-promoted decrease in cell stiffness after 18-h exposure to albuterol. Under these same conditions of  2AR desensitization, the TAS2R agonist chloroquine relaxation response was unaffected. TAS2R-mediated stimulation of intracellular Ca 2ϩ concentration in human ASM was unaltered by albuterol pretreatment, in contrast to cAMP signaling, which was desensitized by Ͼ90%. In mouse trachea,  2AR desensitization by -agonist amounted to 92 Ϯ 6.0% (P Ͻ 0.001), while, under these same conditions, TAS2R desensitization was not significant (11 Ϯ 3.5%). In human lung slices, chronic -agonist exposure culminated in 64 Ϯ 5.7% (P Ͻ 0.001) desensitization of  2AR-mediated dilation of carbachol-constricted airways that was reversed by chloroquine. We conclude that there is no evidence for physiologically relevant cross-desensitization of TAS2R-mediated ASM relaxation from chronic -agonist treatment. These findings portend a favorable therapeutic profile for TAS2R agonists for the treatment of bronchospasm in asthma or chronic obstructive lung disease.
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