Multifactor dimensionality reduction method identifies novel SNP interactions in the WNT protein interaction networks that are associated with recurrence risk in colorectal cancer.

Background: Interactions among genetic variants are rarely studied but may explain a part of the variability in patient outcomes. Objectives: In this study, we aimed to identify 1 to 3 way interactions among SNPs from five Wnt protein interaction networks that predict the 5-year recurrence risk in a cohort of stage I-III colorectal cancer patients. Methods: 423 patients recruited to the Newfoundland Familial Colorectal Cancer Registry were included. Five Wnt family member proteins (Wnt1, Wnt2, Wnt5a, Wnt5b, and Wnt11) were selected. The BioGRID database was used to identify the proteins interacting with each of these proteins. Genotypes of the SNPs located in the interaction network genes were retrieved from a genome-wide SNP genotype data previously obtained in the patient cohort. The GMDR 0.9 program was utilized to examine 1-, 2-, and 3-SNP interactions using a 5-fold cross validation step. Top GMDR 0.9 models were assessed by permutation testing and, if significant, prognostic associations were verified by multivariable logistic regression models. Results: GMDR 0.9 has identified novel 1, 2, and 3-way SNP interactions associated with 5-year recurrence risk in colorectal cancer. Nine of these interactions were multi loci interactions (2-way or 3-way). Identified interaction models were able to distinguish patients based on their 5-year recurrence-free status in multivariable regression models. The significance of interactions was the highest in the 3-SNP models. Several of the identified SNPs were eQTLs, indicating potential biological roles of the genes they were associated with in colorectal cancer recurrence. Conclusions: We identified novel interacting genetic variants that associate with 5-year recurrence risk in colorectal cancer. A significant portion of the genes identified were previously linked to colorectal cancer pathogenesis or progression. These variants and genes are of interest for future functional and prognostic studies. Our results provide further evidence for the utility of GMDR models in identifying novel prognostic biomarkers and the biological importance of the Wnt pathways in colorectal cancer.

Examining SNP-SNP interactions and risk of clinical outcomes in colorectal cancer using multifactor dimensionality reduction based methods.

Background: SNP interactions may explain the variable outcome risk among colorectal cancer patients. Examining SNP interactions is challenging, especially with large datasets. Multifactor Dimensionality Reduction (MDR)-based programs may address this problem. Objectives: 1) To compare two MDR-based programs for their utility; and 2) to apply these programs to sets of MMP and VEGF-family gene SNPs in order to examine their interactions in relation to colorectal cancer survival outcomes. Methods: This study applied two data reduction methods, Cox-MDR and GMDR 0.9, to study one to three way SNP interactions. Both programs were run using a 5-fold cross validation step and the top models were verified by permutation testing. Prognostic associations of the SNP interactions were verified using multivariable regression methods. Eight datasets, including SNPs from MMP family genes (n = 201) and seven sets of VEGF-family interaction networks (n = 1,517 SNPs) were examined. Results: ∼90 million potential interactions were examined. Analyses in the MMP and VEGF gene family datasets found several novel 1- to 3-way SNP interactions. These interactions were able to distinguish between the patients with different outcome risks (regression p-values 0.03-2.2E-09). The strongest association was detected for a 3-way interaction including CHRM3.rs665159_EPN1.rs6509955_PTGER3.rs1327460 variants. Conclusion: Our work demonstrates the utility of data reduction methods while identifying potential prognostic markers in colorectal cancer.

The opioid peptide biphalin modulates human corneal epithelial wound healing in vitro.

PURPOSE: Analgesic drugs, including nonselective opioids and non-steroidal anti-inflammatory drugs, should be used with great precautions to relieve pain after trauma to the corneal epithelium because of their unfavorable effects on wound healing. Biphalin is a synthetic opioid peptide that has been demonstrated to possess a strong analgesic effect on rodents. The purpose of this study is to investigate the effects of biphalin on human corneal epithelial wound healing. METHODS: An immortalized human corneal epithelial cell (HCEC) culture was used to analyze the effects of biphalin on wound healing. The toxicity of biphalin at various concentrations was measured by the MTT assay. The effects of 1µM and 10µM biphalin on wound closure, cell migration and proliferation were tested in an in vitro scratch assay of HCECs. Naloxone, a non-selective competitive opioid receptor antagonist, was also used to inhibit the effects of biphalin in all experiments. RESULTS: Biphalin did not cause any toxic effect on HCECs at concentrations lower than 100µM at various incubation time points. Biphalin significantly increased wound healing at 1µM concentration in an in vitro scratch assay of HCECs (P<0.05). It also significantly increased migration of HCECs (P<0.01). There was no significant difference between the biphalin and control groups of HCECs in the Ki67 proliferation assay. CONCLUSION: Biphalin, which is a synthetic opioid peptide, promotes corneal epithelial wound healing by increasing cell migration. This role should be evaluated in further in vivo and clinical studies.

A comprehensive analysis of SNPs and CNVs identifies novel markers associated with disease outcomes in colorectal cancer.

We aimed to examine the associations of a genome-wide set of single nucleotide polymorphisms (SNPs) and 254 copy number variations (CNVs) and/or insertion/deletions (INDELs) with clinical outcomes in colorectal cancer patients (n = 505). We also aimed to investigate whether their associations changed (e.g., appeared, diminished) over time. Multivariable Cox proportional hazards and piece-wise Cox regression models were used to examine the associations. The Cancer Genome Atlas (TCGA) datasets were used for replication purposes and to examine the gene expression differences between tumor and nontumor tissue samples. A common SNP (WBP11-rs7314075) was associated with disease-specific survival with P-value of 3.2 × 10-8 . Association of this region with disease-specific survival was also detected in the TCGA patient cohort. Two expression quantitative trait loci (eQTLs) were identified in this locus that were implicated in the regulation of ERP27 expression. Interestingly, expression levels of ERP27 and WBP11 were significantly different between colorectal tumors and nontumor tissues. Three SNPs predicted the risk of recurrent disease only after 5 years postdiagnosis. Overall, our study identified novel variants, one of which also showed an association in the TCGA dataset, but no CNVs/INDELs, that associated with outcomes in colorectal cancer. Three SNPs were candidate predictors of long-term recurrence/metastasis risk.

The Prognostic Importance of Immunohistochemical Biomarkers in Diffuse Large B-Cell Lymphoma

ABSTRACT Objective: Molecular methods have practical difficulties in identifying sub-groups of diffuse large B-cell lymphoma (DLBCL) in routine clinical practice. The goal of this study was to sub-classify DLBCL patients into sub-groups by immunohistochemical method and to evaluate the effects of sub-groups on prognosis. Methods: For this purpose, the lymph node biopsy specimens of 40 patients with DLBCL have stained with monoclonal antibody immunostains of cluster of differentiation 10, B-cell lymphoma 6 and multiple myeloma oncogene 1 (MUM1). Results: As a result, 6 (15%) patients have germinal centre B-cell like (GCB) phenotype and 34 (85%) patients have non-GCB phenotype. The overall survival (OS) and event-free survival (EFS) was 31.00 ± 15.49 months and 27.66 ± 17.95 months in GCB phenotype, respectively. The OS and EFS were 23.79 ± 17.82 months and 20.97 ± 17.12 months in non-GCB phenotype, respectively. Conclusion: Multiple myeloma oncogene 1 has reached statistical significance among immunostains, and was found negatively correlated with OS and EFS. If these markers are standardized in the future, more accurate treatment schedules will be determined.

Powerful rare variant association testing in a copula-based joint analysis of multiple phenotypes.

In genetic association studies of rare variants, the low power of association tests is one of the main challenges. In this study, we propose a new single-marker association test called C-JAMP (Copula-based Joint Analysis of Multiple Phenotypes), which is based on a joint model of multiple phenotypes given genetic markers and other covariates. We evaluated its performance and compared its empirical type I error and power with existing univariate and multivariate single-marker and multi-marker rare-variant tests in extensive simulation studies. C-JAMP yielded unbiased genetic effect estimates and valid type I errors with an adjusted test statistic. When strongly dependent traits were jointly analyzed, C-JAMP had the highest power in all scenarios except when a high percentage of variants were causal with moderate/small effect sizes. When traits with weak or moderate dependence were analyzed, whether C-JAMP or competing approaches had higher power depended on the effect size. When C-JAMP was applied with a misspecified copula function, it still achieved high power in some of the scenarios considered. In a real-data application, we analyzed sequencing data using C-JAMP and performed the first genome-wide association studies of high-molecular-weight and medium-molecular-weight adiponectin plasma concentrations. C-JAMP identified 20 rare variants with p-values smaller than 10-5 , while all other tests resulted in the identification of fewer variants with higher p-values. In summary, the results indicate that C-JAMP is a powerful, flexible, and robust method for association studies, and we identified novel candidate markers for adiponectin. C-JAMP is implemented as an R package and freely available from https://cran.r-project.org/package=CJAMP.

The long-term survival characteristics of a cohort of colorectal cancer patients and baseline variables associated with survival outcomes with or without time-varying effects.

BACKGROUND: Colorectal cancer is the third most common cancer in the world. In this study, we assessed the long-term survival characteristics and prognostic associations and potential time-varying effects of clinico-demographic variables and two molecular markers (microsatellite instability (MSI) and BRAF Val600Glu mutation) in a population-based patient cohort followed up to ~ 19 years. METHODS: The patient cohort included 738 incident cases diagnosed between 1999 and 2003. Cox models were used to analyze the association between the variables and a set of survival outcome measures (overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS), metastasis-free survival (MFS), recurrence/metastasis-free survival (RMFS), and event-free survival (EFS)). Cox proportional hazard (PH) assumption was tested for all variables, and Cox models with time-varying effects were used if any departure from the PH assumption was detected. RESULTS: During the follow-up, ~ 61% patients died from any cause, ~ 26% died from colorectal cancer, and ~ 10% and ~ 20% experienced recurrences and distant metastases, respectively. Stage IV disease and post-diagnostic recurrence or metastasis were strongly linked to risk of death from colorectal cancer. If a patient had survived the first 6 years without any disease-related event (i.e., recurrence, metastasis, or death from colorectal cancer), their risks became very minimal after this time period. Distinct sets of markers were associated with different outcome measures. In some cases, the effects by variables were constant throughout the follow-up. For example, MSI-high tumor phenotype and older age at diagnosis predicted longer MFS times consistently over the follow-up. However, in some other cases, the effects of the variables varied with time. For example, adjuvant radiotherapy treatment was associated with increased risk of metastasis in patients who received this treatment after 5.5 years post-diagnosis, but not before that. CONCLUSIONS: This study describes the long-term survival characteristics of a prospective cohort of colorectal cancer patients, relationships between baseline variables and a detailed set of patient outcomes over a long time, and time-varying effects of a group of variables. The results presented advance our understanding of the long-term prognostic characteristics in colorectal cancer and are expected to inspire future studies and clinical care strategies.

Correction to: A genome-wide association study identifies single nucleotide polymorphisms associated with time-to-metastasis in colorectal cancer.

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The effect of blue thermal treatment on endodontic instruments and apical debris extrusion during retreatment procedures.

AIM: To determine the effect of blue thermal treatment on Reciproc (VDW, Munich, Germany) endodontic instruments and the amount of apically extruded debris during retreatment procedures. METHODOLOGY: Thirty extracted mandibular molar teeth having mesial roots with a degree of curvature less than 20° and having an initial apical size equivalent to a size 10 K-file were selected. The mesial roots of the teeth were removed from the cementoenamel junction to obtain a 15-mm root length. The mesiobuccal canals were prepared to size F2 using the ProTaper Universal system (Dentsply Sirona, Ballaigues, Switzerland), filled with gutta-percha and 2Seal (VDW) using the lateral compaction technique and then randomly divided into two groups (n = 15). The root fillings were removed with one of the following instruments using a crown-down preparation technique: M-Wire Reciproc or Reciproc Blue (both VDW). Apically extruded debris was collected in pre-weighed Eppendorf tubes. The Eppendorf tubes were then stored in an incubator at 70 °C for five days to evaporate the distilled water. The data were analysed using the Mann-Whitney U test (P = 0.05). RESULTS: Reciproc Blue (1.42 ± 0.4491 mg) extruded significantly less debris apically than M-Wire Reciproc (2.56 ± 1.0232 mg) (P < 0.05). CONCLUSIONS: Blue thermal treatment of Reciproc instruments was associated with less debris extrusion during retreatment procedures.

A genome-wide association study identifies single nucleotide polymorphisms associated with time-to-metastasis in colorectal cancer.

BACKGROUND: Differentiating between cancer patients who will experience metastasis within a short time and who will be long-term survivors without metastasis is a critical aim in healthcare. The microsatellite instability (MSI)-high tumor phenotype is such a differentiator in colorectal cancer, as patients with these tumors are unlikely to experience metastasis. Our aim in this study was to determine if germline genetic variations could further differentiate colorectal cancer patients based on the long-term risk and timing of metastasis. METHODS: The patient cohort consisted of 379 stage I-III Caucasian colorectal cancer patients with microsatellite stable or MSI-low tumors. We performed univariable analysis on 810,622 common single nucleotide polymorphisms (SNPs) under different genetic models. Depending on the long-term metastasis-free survival probability estimates, we applied a mixture cure model, Cox proportional hazards regression model, or log-rank test. For SNPs reaching Bonferroni-corrected significance (p < 6.2 × 10- 8) having valid genetic models, multivariable analysis adjusting for significant baseline characteristics was conducted. RESULTS: After adjusting for significant baseline characteristics, specific genotypes of ten polymorphisms were significantly associated with time-to-metastasis. These polymorphisms are three intergenic SNPs, rs5749032 (p = 1.28 × 10- 10), rs2327990 (p = 9.59 × 10- 10), rs1145724 (p = 3 × 10- 8), and seven SNPs within the non-coding sequences of three genes: FHIT (p = 2.59 × 10- 9), EPHB1 (p = 8.23 × 10- 9), and MIR7515 (p = 4.87 × 10- 8). CONCLUSIONS: Our results suggest novel associations of specific genotypes of SNPs with early metastasis in Caucasian colorectal cancer patients. These associations, once replicated in other patient cohorts, could assist in the development of personalized treatment strategies for colorectal cancer patients.

Associations of single nucleotide polymorphisms with mucinous colorectal cancer: genome-wide common variant and gene-based rare variant analyses.

BACKGROUND: Colorectal cancer has significant impact on individuals and healthcare systems. Many genes have been identified to influence its pathogenesis. However, the genetic basis of mucinous tumor histology, an aggressive subtype of colorectal cancer, is currently not well-known. This study aimed to identify common and rare genetic variations that are associated with the mucinous tumor phenotype. METHODS: Genome-wide single nucleotide polymorphism (SNP) data was investigated in a colorectal cancer patient cohort (n = 505). Association analyses were performed for 729,373 common SNPs and 275,645 rare SNPs. Common SNP association analysis was performed using univariable and multivariable logistic regression under different genetic models. Rare-variant association analysis was performed using a multi-marker test. RESULTS: No associations reached the traditional genome-wide significance. However, promising genetic associations were identified. The identified common SNPs significantly improved the discriminatory accuracy of the model for mucinous tumor phenotype. Specifically, the area under the receiver operating characteristic curve increased from 0.703 (95% CI: 0.634-0.773) to 0.916 (95% CI: 0.873-0.960) when considering the most significant SNPs. Additionally, the rare variant analysis identified a number of genetic regions that potentially contain causal rare variants associated with the mucinous tumor phenotype. CONCLUSIONS: This is the first study applying both common and rare variant analyses to identify genetic associations with mucinous tumor phenotype using a genome-wide genotype data. Our results suggested novel associations with mucinous tumors. Once confirmed, these results will not only help us understand the biological basis of mucinous histology, but may also help develop targeted treatment options for mucinous tumors.

Child neglect and abuse: a global glimpse within the framework of evidence perspective.

AIM: This systematic review was conducted in order to integrate evidence-based knowledge and experience related to child neglect and abuse into the nursing literature. BACKGROUND: The negative and intense effects of neglect and abuse on an individual can last into adulthood. Nurses who are in close contact with such cases have an important role to play in detecting child neglect and abuse and supporting the families involved. When nurses fulfil this role, it is important that evidence-based information and interventions are known to ensure that the process is a healthy one. DATA SOURCES: Medline/Pubmed and Cochrane Library databases, from 2012 to 2016. REVIEW METHODS: The PRISMA guide, a basic search algorithm, was used as a basis for the review. RESULTS: This systematic research involved 32 articles that met the criteria. When the characteristics of the studies were examined, it was found that one study dealt with physical abuse, seven studies dealt with sexual abuse, 21 studies with neglect and abuse and three studies with all abuse types. It was also found that 16% addressed intervention, 22% addressed the relationship between abuse and other factors, 31% addressed prevention and 31% addressed the defining dimension. CONCLUSIONS: It has been found that, in general, all types of negligence and abuse are studied together and that nurses lack the knowledge and skills needed to assess childhood neglect and abuse. IMPLICATIONS FOR NURSING AND HEALTH POLICIES: Nurses have a critical role to play in identifying the dark spots and associated factors in the story of individuals because they are health professionals who are in close contact with patients. It is recommended that guidelines be developed and used in the diagnosis and treatment of abuse and neglect. Thus, in these cases, the standardization of care will be achieved.

XRCC3 Thr241Met and TYMS variable number tandem repeat polymorphisms are associated with time-to-metastasis in colorectal cancer.

BACKGROUND: Metastasis is a major cause of mortality in cancer. Identifying prognostic factors that distinguish patients who will experience metastasis in the short-term and those that will be free of metastasis in the long-term is of particular interest in current medical research. The objective of this study was to examine if select genetic polymorphisms can differentiate colorectal cancer patients based on timing and long-term risk of metastasis. METHODS: The patient cohort consisted of 402 stage I-III colorectal cancer patients with microsatellite instability (MSI)-low (MSI-L) or microsatellite stable (MSS) tumors. We applied multivariable mixture cure model, which is the proper model when there is a substantial group of patients who remain free of metastasis in the long-term, to 26 polymorphisms. Time-dependent receiver operator characteristic (ROC) curve analysis was performed to determine the change in discriminatory accuracy of the models when the significant SNPs were included. RESULTS: After adjusting for significant baseline characteristics, two polymorphisms were significantly associated with time-to-metastasis: TT and TC genotypes of the XRCC3 Thr241Met (p = 0.042) and the 3R/3R genotype of TYMS 5'-UTR variable number tandem repeat (VNTR) (p = 0.009) were associated with decreased time-to-metastasis. ROC curves showed that the discriminatory accuracy of the model is increased slightly when these polymorphisms were added to the significant baseline characteristics. CONCLUSIONS: Our results indicate XRCC3 Thr241Met and TYMS 5'-UTR VNTR polymorphisms are associated with time-to-metastasis, and may have potential biological roles in expediting the metastatic process. Once replicated, these associations could contribute to the development of precision medicine for colorectal cancer patients.

Estimating and testing direct genetic effects in directed acyclic graphs using estimating equations.

In genetic association studies, it is important to distinguish direct and indirect genetic effects in order to build truly functional models. For this purpose, we consider a directed acyclic graph setting with genetic variants, primary and intermediate phenotypes, and confounding factors. In order to make valid statistical inference on direct genetic effects on the primary phenotype, it is necessary to consider all potential effects in the graph, and we propose to use the estimating equations method with robust Huber-White sandwich standard errors. We evaluate the proposed causal inference based on estimating equations (CIEE) method and compare it with traditional multiple regression methods, the structural equation modeling method, and sequential G-estimation methods through a simulation study for the analysis of (completely observed) quantitative traits and time-to-event traits subject to censoring as primary phenotypes. The results show that CIEE provides valid estimators and inference by successfully removing the effect of intermediate phenotypes from the primary phenotype and is robust against measured and unmeasured confounding of the indirect effect through observed factors. All other methods except the sequential G-estimation method for quantitative traits fail in some scenarios where their test statistics yield inflated type I errors. In the analysis of the Genetic Analysis Workshop 19 dataset, we estimate and test genetic effects on blood pressure accounting for intermediate gene expression phenotypes. The results show that CIEE can identify genetic variants that would be missed by traditional regression analyses. CIEE is computationally fast, widely applicable to different fields, and available as an R package.

The oral adverse effects of isotretinoin treatment in acne vulgaris patients: A prospective, case-control study.

BACKGROUND: Isotretinoin is the most effective therapy to treat severe acne vulgaris and its systemic adverse effects have been well documented, but little is known on dental side effects over the course of treatment. OBJECTIVES: This prospective case-control study aimed to evaluate the oral adverse effects of isotretinoin in Turkish patients with acne vulgaris; compare oral conditions between patients and normal controls; and investigate the association between salivary parameters and International Caries Detection and Assessment System (ICDAS) scores. MATERIALS AND METHODS: For 6 months, the patients (n = 45) received isotretinoin daily (0.5 mg/kg). The age-matched untreated controls (n = 45) were patients without acne. Both groups were examined before the study and at 6 months for salivary flow, buffer capacity, microbiologic tests, and caries status (based on the ICDAS). Salivary parameters and ICDAS scores were analyzed by Spearman's rank correlations. Data were statistically analyzed by the Mann-Whitney U test, Wilcoxon signed rank tests, and McNemar's Chi-square tests (P < 0.05). RESULTS: Twenty-two isotretinoin-treated patients and 18 controls completed the study. At baseline, the groups were not significantly different in the evaluated parameters (P > 0.05). At 6 months in the isotretinoin-treated group, salivary flow and buffer capacity significantly decreased, and the ICDAS scores significantly increased (P < 0.05). The changes in these criteria from baseline were insignificant in the controls (P > 0.05). Intraoral pathogen counts were not significantly different between the groups, compared to baseline (P > 0.05). Stimulated salivary parameters in both groups were not correlated significantly with the ICDAS scores. CONCLUSIONS: Isotretinoin significantly affected salivary flow, buffer capacity, caries lesion activity scores for 6 months. However, salivary parameters and caries lesion activity scores had no significant correlations.

Comparison of single-marker and multi-marker tests in rare variant association studies of quantitative traits.

In genetic association studies of rare variants, low statistical power and potential violations of established estimator properties are among the main challenges of association tests. Multi-marker tests (MMTs) have been proposed to target these challenges, but any comparison with single-marker tests (SMTs) has to consider that their aim is to identify causal genomic regions instead of variants. Valid power comparisons have been performed for the analysis of binary traits indicating that MMTs have higher power, but there is a lack of conclusive studies for quantitative traits. The aim of our study was therefore to fairly compare SMTs and MMTs in their empirical power to identify the same causal loci associated with a quantitative trait. The results of extensive simulation studies indicate that previous results for binary traits cannot be generalized. First, we show that for the analysis of quantitative traits, conventional estimation methods and test statistics of single-marker approaches have valid properties yielding association tests with valid type I error, even when investigating singletons or doubletons. Furthermore, SMTs lead to more powerful association tests for identifying causal genes than MMTs when the effect sizes of causal variants are large, and less powerful tests when causal variants have small effect sizes. For moderate effect sizes, whether SMTs or MMTs have higher power depends on the sample size and percentage of causal SNVs. For a more complete picture, we also compare the power in studies of quantitative and binary traits, and the power to identify causal genes with the power to identify causal rare variants. In a genetic association analysis of systolic blood pressure in the Genetic Analysis Workshop 19 data, SMTs yielded smaller p-values compared to MMTs for most of the investigated blood pressure genes, and were least influenced by the definition of gene regions.

Germline INDELs and CNVs in a cohort of colorectal cancer patients: their characteristics, associations with relapse-free survival time, and potential time-varying effects on the risk of relapse.

INDELs and CNVs are structural variations that may play roles in cancer susceptibility and patient outcomes. Our objectives were a) to computationally detect and examine the genome-wide INDEL/CNV profiles in a cohort of colorectal cancer patients, and b) to examine the associations of frequent INDELs/CNVs with relapse-free survival time. We also identified unique variants in 13 Familial Colorectal Cancer Type X (FCCX) cases. The study cohort consisted of 495 colorectal cancer patients. QuantiSNP and PennCNV algorithms were utilized to predict the INDELs/CNVs using genome-wide signal intensity data. Duplex PCR was used to validate predictions for 10 variants. Multivariable Cox regression models were used to test the associations of 106 common variants with relapse-free survival time. Score test and the multivariable Cox proportional hazards models with time-varying coefficients were applied to identify the variants with time-varying effects on the relapse-free survival time. A total of 3486 distinct INDELs/CNVs were identified in the patient cohort. The majority of these variants were rare (83%) and deletion variants (81%). The results of the computational predictions and duplex PCR results were highly concordant (93-100%). We identified four promising variants significantly associated with relapse-free survival time (P < 0.05) in the multivariable Cox proportional hazards regression models after adjustment for clinical factors. More importantly, two additional variants were identified to have time-varying effects on the risk of relapse. Finally, 58 rare variants were identified unique to the FCCX cases; none of them were detected in more than one patient. This is one of the first genome-wide analyses that identified the germline INDEL/CNV profiles in colorectal cancer patients. Our analyses identified novel variants and genes that can biologically affect the risk of relapse in colorectal cancer patients. Additionally, for the first time, we identified germline variants that can potentially be early-relapse markers in colorectal cancer.

Genetic association analysis based on a joint model of gene expression and blood pressure.

Recent work on genetic association studies suggests that much of the heritable variation in complex traits is unexplained, which indicates a need for using more biologically meaningful modeling approaches and appropriate statistical methods. In this study, we propose a biological framework and a corresponding statistical model incorporating multilevel biological measures, and illustrate it in the analysis of the real data provided by the Genetic Analysis Workshop (GAW) 19, which contains whole genome sequence (WGS), gene expression (GE), and blood pressure (BP) data. We investigate the direct effect of single-nucleotide variants (SNVs) on BP and GE, while considering the non-directional dependence between BP and GE, by using copula functions to jointly model BP and GE conditional on SNVs. We implement the method for analysis on a genome-wide scale, and illustrate it within an association analysis of 68,727 SNVs on chromosome 19 that lie in or around genes with available GE measures. Although there is no indication for inflated type I errors under the proposed method, our results show that the association tests have smaller p values than tests under univariate models for common and rare variants using single-variant tests and gene-based multimarker tests. Hence, considering multilevel biological measures and modeling the dependence structure between these measures by using a plausible graphical approach may lead to more informative findings than standard univariate tests of common variants and well-recognized gene-based rare variant tests.

Novel visual system homeobox 1 gene mutations in Turkish patients with keratoconus.

The aim of this study was to screen the visual system homeobox 1 (VSX1) gene in Turkish patients with keratoconus (KC). The patient group consisted of 44 patients who had undergone corneal transplant surgery before the age of 30, for advanced and rapidly progressive KC. The control group comprised 250 healthy individuals. We detected two missense mutations, D144N and D295Y, in exon 2 and exon 5 of the VSX1 gene, respectively, using next-generation sequencing analysis. The pathologic effects of the D144N and D295Y missense mutations on protein function were determined with bioinformatic analysis tools, SIFT, PolyPhen, and MutationTaster. Aspartic acid at the 144th position was more preserved among species than aspartic acid at the 295th position of the VSX1 protein. In the control group, five different genetic variations were detected, two of which (rs8123716 and rs12480307) were synonymous with variations in the patient group. Our results suggested that the D144N and D295Y mutations might have a role in the pathogenesis of KC disease.

Enhancement of two photon absorption properties and intersystem crossing by charge transfer in pentaaryl boron-dipyrromethene (BODIPY) derivatives.

Novel BODIPY derivatives containing N,N-diphenylamine, 4-methoxyphenyl, 2,4-dimethoxyphenyl, triphenylamine, and 1-pyrene moieties were designed and synthesized for the first time by employing the palladium-catalyzed Suzuki-Miyaura coupling on pentaaryl boron dipyrromethene compounds. The effect of various moieties and charge transfer on linear and nonlinear optical absorption was investigated. It was found that moieties with strong electron donor properties and long conjugation lengths increase charge transfer and enhance intersystem crossing in the investigated compounds. Besides, the investigated compounds showed strong two photon absorption properties at near infrared wavelengths (800 nm and 900 nm), which is required for two photon photodynamic therapy. Two photon absorption cross section values were found to be 83, 454, 331, 472 and 413 GM for , , , and compounds at 800 nm wavelength, respectively. The highest two-photon absorption cross-section value was obtained for the compound containing a triphenylamine moiety due to its more efficient charge transfer characteristics. Strong two-photon absorption properties in the near infrared region, efficient intersystem crossing and heavy atom free nature of the investigated compounds make them good candidates for two photon photodynamic therapy applications. We believe that this work will be one of the leading studies for two-photon photodynamic therapy applications of pentaaryl BODIPY derivatives.