Insights Into Colorectal Cancer Screening: A Multidatabase Cohort Study of Over 1.5 Million Taiwanese.

INTRODUCTION: Colorectal cancer (CRC) remains a significant public health concern. This study aims to provide a comprehensive understanding of the effectiveness of fecal immunochemical test (FIT) screening on CRC incidence and mortality, leveraging the scale of over 1.5 million randomly selected Taiwanese and more than 11.7 million person-years of follow-up. METHODS: This prospective cohort study merges data from 3 robust Taiwanese health databases: the CRC screening program, cancer registration, and death registration databases. Incidence and mortality rates of CRC were calculated based on age, sex, urbanization, and past screening status. Cox proportional hazard models were used to assess the association between screening statuses and CRC incidence or mortality, adjusting for age, sex, and urbanization levels. Statistical analysis of the data was conducted in 2021-2022. RESULTS: FIT screening was associated with a 33% reduction in CRC incidence and a 47% reduction in mortality. The study identified a dose-response relationship between the fecal hemoglobin concentration (f-HbC) levels and CRC risk. Participants with consistent FIT-negative results had significantly reduced CRC incidence and mortality risks, while those with one or more positive FIT results faced increased risks. Notably, compliance with follow-up examinations after a positive FIT significantly lowered mortality risk. CONCLUSIONS: This large-scale study validates the efficacy of FIT screening in reducing CRC incidence and mortality. It offers a nuanced understanding of how various screening statuses impact CRC risks, thus providing valuable insights for public health strategies aimed at CRC prevention.

Foxp2 Is Required for Nucleus Accumbens-mediated Multifaceted Limbic Function.

The forkhead box protein P2 (Foxp2), initially identified for its role in speech and language development, plays an important role in neural development. Previous studies investigated the function of the Foxp2 gene by deleting or mutating Foxp2 from developmental stages. Little is known about its physiological function in adult brains. Although Foxp2 has been well studied in the dorsal striatum, its function in the nucleus accumbens (NAc) of the ventral striatum remains elusive. Here, we examine the physiological function of Foxp2 in NAc of mouse brains. We conditionally knocked out Foxp2 by microinjections of AAV-EGFP-Cre viruses into the medial shell of NAc of Foxp2 floxed (cKO) mice. Immunostaining showed increased c-Fos positive cells in cKO NAc at basal levels, suggesting an abnormality in Foxp2-deficient NAc cells. Unbiased behavioral profiling of Foxp2 cKO mice showed abnormalities in limbic-associated function. Foxp2 cKO mice exhibited abnormal social novelty without preference for interaction with strangers and familiar mice. In appetitive reward learning, Foxp2 cKO mice failed to learn the time expectancy of food delivery. In fear learning, Foxp2 cKO mice exhibited abnormal increases in freezing levels in response to tone paired with foot shock during fear conditioning. The extinction of the fear response was also altered in Foxp2 cKO mice. In contrast, conditional knockout of Foxp2 in NAc did not affect locomotion, motor coordination, thermal pain sensation, anxiety- and depression-like behaviors. Collectively, our study suggests that Foxp2 has a multifaceted physiological role in NAc in the regulation of limbic function in the adult brain.

The Risk of Cancer-Associated and Radiotherapy-Associated Cardiovascular Diseases among Patients with Breast Cancer.

BACKGROUND: The cardio-related issues should be emphasized as the survival rates of breast cancer increased. We investigated the risk of coronary artery disease (CAD) and stroke due to breast cancer or radiotherapy. METHODS: In this retrospective cohort study, breast cancer patients diagnosed between 2007 and 2016 were recruited from Taiwan Cancer Registry Database and were followed until the end of 2018 by linking with the Taiwan National Health Insurance Database. The general population was randomly selected from the whole population in 2007. Standardized incidence ratios (SIR) were calculated to compare the risk of CAD and stroke between patients and the general population. Within the cohort, we included the patients diagnosed between 2011 and 2016. Cox proportional hazards model and subdistribution hazard function were used to investigate the associations of radiotherapy with the risk of CAD and stroke. RESULTS: Overall SIR of CAD was 0.82 (95% confidence interval [CI]: 0.78-0.86), while were 1.43 and 1.08 (95% CI: 1.30-1.55 and 1.00-1.16) 1 and 2 years after diagnosis, respectively. Overall SIR of stroke was 0.63 (95% CI: 0.60-0.67), the results were similar after considering the time since diagnosis. The adjusted hazard ratios (HR) for the associations of radiotherapy with CAD and stroke risk were 0.91 (95% [CI] = 0.76-1.09) and 0.84 (95% CI = 0.68-1.04), respectively. The results were similar by using subdistribution hazard function. CONCLUSIONS: The risk of CAD was higher within the first 2 years of breast cancer diagnosis. We found no association between radiotherapy and the risk of CAD and stroke.

Screening History and 7-Year Survival in 32,099 Colorectal Cancer Patients: A Population-Based Cohort Study.

Background: It is unclear whether colorectal cancer screening history, regardless of stage, is an independent predictor of survival, and if the screening advantage persists after diagnosis. 32 099 patients with colorectal cancer were enrolled in this population-based cohort study. Methods: We used data from the Taiwan Cancer Registry on patients with a first-time diagnosis of colorectal cancer between 2013 and 2015. In addition, we utilized data from a nationwide database of colorectal cancer screening programs to evaluate patients' screening histories, and sourced outcome data from the National Death Registry, tracking patients up to the last day of 2019. Results: Compared with fecal immunochemical testing (FIT)-positive patients with a follow-up examination, the adjusted hazard ratios (95% confidence intervals) for death from colorectal cancer were 1.40 (1.26-1.56) for FIT-positive patients without a follow-up examination, 1.63 (1.48-1.78) for FIT-negative patients, and 1.76 (1.65-1.89) for never screened patients. The adjusted hazard ratios for the FIT-positive patients with a follow-up examination increased when diagnosis was delayed by more than 12 months and were 1.2 after a 2-year delay. The adjusted hazard ratios for FIT-negative patients were approximately 2.0, decreased rapidly to 1.6, and stabilized after the 9th time-to-diagnosis month. Conclusion: In colorectal cancer patients, screening history prior to diagnosis is an independent prognostic factor, regardless of cancer stage or other variables. This study recommends that physicians take screening history into account during diagnosis to optimize follow-up and management for patients at higher risk.

Association between thyroid cancer and cardiovascular disease risk: a nationwide observation study.

Treatment with levothyroxine and radioiodine contribute alternative cardiovascular function in adults with thyroid cancer. The risks of long-term cardiovascular conditions among thyroid cancer patients is unknown. This study aimed to compare the incidence of coronary heart disease (CHD), ischemic stroke (IS), and atrial fibrillation (AF) among adults with thyroid cancer with that of the general population, especially when stratified by age (< 65 and ≥ 65 years old). This observational cohort study enrolled patients between January 1, 2011 and December 31, 2016 with a follow-up until December 31, 2018. This study analyzed the data of Taiwanese thyroid cancer patients registered on the National Taiwan Cancer Registry Database, with CHD and IS. SIR models were used to evaluate the association between thyroid cancer and CHD, IS, AF, and cardiovascular disease outcome, stratified by age and sex. SIR analyses were also conducted for both sexes, age groups (< 65, ≥ 65 years), and different follow-up years. After excluding 128 individuals (< 20 years or ≥ 85 years old) and with missing index data, 4274 eligible thyroid cancer patients without CHD history, 4343 patients without IS history, and 4247 patients without AF history were included for analysis. During the median follow-up of 3.5 (1.2) years among thyroid cancer patients, the observed number of new CHD events was 70; IS, 30; and AF, 20, respectively. The SIR was significantly higher for CHD (SIR, 1.57; 95% confidence interval [CI] 1.2-1.93) among thyroid cancer patients compared with the age- and sex-specific standardized population. However, the association between thyroid cancer and the risks of IS (SIR, 0.74; 95% CI 0.47-1), cardiovascular disease (SIR, 0.88; 95% CI 0.7-1.05), and atrial fibrillation (SIR, 0.74; 95% CI 0.42-1.06) were insignificant. Moreover, stratification by age < 65 or age ≥ 65 years old and by sex for CHD suggested that the diagnosis of thyroid cancer in the young may attenuate the CHD risk (SIR, 2.08; 95% CI 1.5-2.66), and the CVD risk was constant among both men (SIR, 1.63; 95% CI 1.03-2.24) and women (SIR, 1.53; 95% CI 1.06-1.99). The patients had persistent higher CHD risk for 5 years after cancer diagnosis. Thyroid cancer survivors have a substantial CHD risk, even at long-term follow-up, especially in those patients < 65 years old. Further research on the association between thyroid cancer and CHD risk is warranted.

Patterning and doping of transition metals in tungsten dichalcogenides.

Substitutional transition metal doping in two-dimensional (2D) layered dichalcogenides is of fundamental importance in manipulating their electrical, excitonic, magnetic, and catalytic properties through the variation of the d-electron population. Yet, most doping strategies are spatially global, with dopants embedded concurrently during the synthesis. Here, we report an area-selective doping scheme for W-based dichalcogenide single layers, in which pre-patterned graphene is used as a reaction mask in the high-temperature substitution of the W sublattice. The chemical inertness of the thin graphene layer can effectively differentiate the spatial doping reaction, allowing for local manipulation of the host 2D materials. Using graphene as a mask is also beneficial in the sense that it also acts as an insertion layer between the contact metal and the doped channel, capable of depinning the Fermi level for low contact resistivity. Tracing doping by means of chalcogen labelling, deliberate Cr embedment is found to become energetically favorable in the presence of chalcogen deficiency, assisting the substitution of the W sublattice in the devised chemical vapor doping scheme. Atomic characterization using scanning transmission electron microscopy (STEM) shows that the dopant concentration is controllable and varies linearly with the reaction time in the current doping approach. Using the same method, other transition metal atoms such as Mo, V, and Fe can also be doped in the patterned area.

Unusually high incidence of polyomavirus JC infection in the higher grade of colorectal cancer tissues in Taiwan.

INTRODUCTION: The human JC polyomavirus (JCPyV) has been detected in colorectal cancer (CRC) tissues and is suggested to contribute to CRC tumorigenesis. The rearrangement of the JCPyV regulatory region is supposedly associated with CRC development. The progression of CRC involves the stepwise accumulation of mutations. The large tumor antigen (LT) of JCPyV can trigger uncontrolled cell cycle progression by targeting oncogenes, and tumor suppressor genes, and causing chromosome instability. Few studies have focused on the presence of JCPyV DNA in the higher grade of CRC tissues. METHODS: We collected 95 tissue blocks from samples of stages I, II, III, and IV CRC. Nested PCR targeting the regulatory region of the viral genome was performed to determine the presence of JCPyV DNA in the various stages of colorectal cancer tissues. RESULTS: The nested PCR results showed that the positive rate of JCPyV DNA increased with the progression of CRC stages. The archetypal-like, non-rearrangement genotype of JCPyV with subtle mutations was the major genotype found in CRC samples. CONCLUSIONS: This finding in our study suggests that there may be an association between JCPyV and CRC progression.

The Risk of Ischemic Stroke in Head and Neck Cancer Patients and Those Who Were Treated with Radiotherapy: A Population-Based Cohort Study.

BACKGROUND: To investigate the standardized incidence ratios (SIR) of stroke in patients with head and neck cancer and their relationship to radiotherapy. METHODS: Patients with head and neck cancer ages 20-85 years were enrolled from 2007 to 2016 using the Taiwan Cancer Registry. The study endpoint was fatal and non-fatal ischemic stroke, ascertained by the National Health Insurance Research Database. Age- and sex-adjusted SIRs, categorized by 10-year age standardization, were used to compare the patients with head and neck cancer with a randomly selected 2,000,000 general population. We compared the risk of stroke in patients with head and neck cancer who received radiotherapy or surgery alone. Multivariable adjusted hazard ratios (HR) and 95% confidence intervals (CI) were obtained from Cox regression analysis with competing risk. RESULTS: Among 41,266 patients (mean age, 54.1 years; men, 90.6%) in the median follow-up period of 3.9 years, 1,407 strokes occurred. Compared with the general population, the overall SIR of stroke was 1.37 (95% CI, 1.30-1.44) in patients with head and neck cancer. In patients with head and neck cancer, the fully adjusted HR of stroke in those who received radiotherapy was 0.96 (95% CI, 0.83-1.10), compared with those who received surgery alone. CONCLUSIONS: Patients with head and neck cancer had a higher risk of fatal or non-fatal ischemic stroke. The risk of stroke was not higher in patients initially treated with radiotherapy. IMPACT: Oncologists should emphasize stroke prevention in all patients with head and neck cancer, not only in those who received radiotherapy.

Increased standardised incidence ratio of cardiovascular diseases among colorectal cancer patients.

PURPOSE: Evidence regarding the relationship between colorectal cancer and the risk of cardiovascular disease (CVD) is limited. Thus, in this study, we aimed to determine the standardised incidence ratio (SIR) of CVDs in colorectal cancer patients in Taiwan. METHODS: A population-based cohort study enrolling the incident colorectal cancer population based on the Cancer Registry Database from 2007 to 2016 was conducted (n = 94,233, mean age: 62.4 years, 43.0% women). New cases of CVD, including coronary heart disease and ischemic stroke, through 31 December 2018 were obtained from the National Health Insurance Research Database and National Death Registry. Compared with the general population (n = 1,977,659, mean age: 44.3 years, 49.6% women), age- and sex-specific SIRs for CVDs were calculated by the time since diagnosis. RESULTS: A total of 6852 cardiovascular events occurred in colorectal cancer patients during a median follow-up of 4.4 years. The SIR of CVD was highest in the first year after diagnosis (SIR: 1.45, 95% confidence interval: 1.39-1.50); however, this decreased to the same value as that of the general population in later years. Similar patterns were observed for the SIR of coronary heart disease. However, the SIR of ischemic stroke among colorectal cancer patients was low from the second year following cancer diagnosis. CONCLUSIONS: Colorectal cancer patients are at an increased risk of developing CVD, especially coronary heart disease, during the first 3 years following colorectal cancer diagnosis.

Room-temperature two-dimensional plasmonic crystal semiconductor lasers.

Room-temperature plasmonic-crystal lasers have been demonstrated with a square-lattice gold nano-pillar arrays on top of InGaAs/GaAs quamtum wells on a GaAs substrate. The lasing wavelength is tunable in the range of 865-1001 nm by varying the lattice period. The lasers exhibit an extremely narrow linewidth and small divergence angle so could have great potential for various applications. An unexpected mirror cavity effect has been observed and investigated. The mirror-cavity lasers have a very low threshold and could be developed to realize electrically-driven plasmonic lasers.

Ensemble forecasting of a continuously decreasing trend in bladder cancer incidence in Taiwan.

Bladder cancer is one of the most common malignancies involving the urinary system of about 1.65 million cases worldwide. To attain the 25 by 25 goal set by the World Health Organization (25% reduction in non-communicable diseases between 2015 and 2025), developing strategies to reduce cancer burdens is essential. The data of the study comprised the age-specific bladder cancer cases and total population numbers from age 25 to 85 and above from 1997 to 2016 in Taiwan. An ensemble age-period-cohort model was used to estimate bladder cancer incidence trends and forecast the trends to 2025. For men, the projected age-standardized incidence rates per 100,000 people in 2020 and 2025 are 13.0 and 10.4, respectively, with a 16.1% and 32.9% decrease projected from 2016 to 2020 and 2025, respectively. For women, the projected age-standardized incidence rates per 100,000 people in 2020 and 2025 are 4.7 and 3.7, respectively, with a 16.1% and 33.9% decrease projected from 2016 to 2020 and 2025, respectively. The age-specific bladder cancer incidence rates demonstrated a consistently downward trend after 2003 for all ages and both sexes. This study projects that the incidence rates of bladder cancer in Taiwan will continue to decrease, and more than a 25% reduction can be achieved from 2016 to 2025.

Human Costars Family Protein ABRACL Modulates Actin Dynamics and Cell Migration and Associates with Tumorigenic Growth.

Regulation of cellular actin dynamics is pivotal in driving cell motility. During cancer development, cells migrate to invade and spread; therefore, dysregulation of actin regulators is often associated with cancer progression. Here we report the role of ABRACL, a human homolog of the Dictyostelium actin regulator Costars, in migration and tumorigenic growth of cancer cells. We found a correlation between ABRACL expression and the migratory ability of cancer cells. Cell staining revealed the colocalization of ABRACL and F-actin signals at the leading edge of migrating cells. Analysis of the relative F-/G-actin contents in cells lacking or overexpressing ABRACL suggested that ABRACL promotes cellular actin distribution to the polymerized fraction. Physical interaction between ABRACL and cofilin was supported by immunofluorescence staining and proximity ligation. Additionally, ABRACL hindered cofilin-simulated pyrene F-actin fluorescence decay in vitro, indicating a functional interplay. Lastly, analysis on a colorectal cancer cohort demonstrated that high ABRACL expression was associated with distant metastasis, and further exploration showed that depletion of ABRACL expression in colon cancer cells resulted in reduced cell proliferation and tumorigenic growth. Together, results suggest that ABRACL modulates actin dynamics through its interaction with cofilin and thereby regulates cancer cell migration and participates in cancer pathogenesis.

Photon-Detection-Probability Simulation Method for CMOS Single-Photon Avalanche Diodes.

Single-photon avalanche diodes (SPADs) in complementary metal-oxide-semiconductor (CMOS) technology have excellent timing resolution and are capable to detect single photons. The most important indicator for its sensitivity, photon-detection probability (PDP), defines the probability of a successful detection for a single incident photon. To optimize PDP is a cost- and time-consuming task due to the complicated and expensive CMOS process. In this work, we have developed a simulation procedure to predict the PDP without any fitting parameter. With the given process parameters, our method combines the process, the electrical, and the optical simulations in commercially available software and the calculation of breakdown trigger probability. The simulation results have been compared with the experimental data conducted in an 800-nm CMOS technology and obtained a good consistence at the wavelength longer than 600 nm. The possible reasons for the disagreement at the short wavelength have been discussed. Our work provides an effective way to optimize the PDP of a SPAD prior to its fabrication.

A decision tree-based classifier for E-visit service provision.

This study proposes a decision tree-based e-visit classification approach (DTEVCA) to determine clinic visits qualified as e-visits using clinics' medical records and patients' demographic data. This study assumes that health care insurance will subsidise e-visit service costs, in which case, identifying patients who benefit most from e-visit service is essential. Using a large data set from Taiwan's National Health Insurance, this study verifies the efficiency and validity of the DTEVCA. Results indicate that this approach can accurately classify in-office clinic visits that could switch to e-visit services. The straightforward rules of this decision tree also give insurance agencies a clear guideline to understand the circumstances of using e-visits and predict the effects of implementing e-visits in Taiwan. Result of this study can help countries improve the policy formulation process for physicians' use, or for academic research. The DTEVCA can update classification rules using new data to correct biases and ensure the stability of the e-visit system. In addition, the concept of this approach is feasible not only for e-visit service but also for other 'new services' such as new products or new policies.

Decision tree-based classifier in providing telehealth service.

BACKGROUND: Although previous research showed that telehealth services can reduce the misuse of resources and urban-rural disparities, most healthcare insurers do not include telehealth services in their health insurance schemes. Therefore, no target variable exists for the classification approaches to learn from or train with. The problem of identifying the potential recipients of telehealth services when introducing telehealth services into health welfare or health insurance schemes becomes an unsupervised classification problem without a target variable. METHODS: We propose a HDTTCA approach, which is a systematic approach (the main process of HDTTCA involves (1) data set preprocessing, (2) decision tree model building, and (3) predicting and explaining of the most important attributes in the data set for patients who qualify for telehealth service) to identify those who are eligible for telehealth services. RESULTS: This work uses data from the NHIRD provided by the NHIA in Taiwan in 2012 as our research scope, which consist of 55,389 distinct hospitals and 653,209 distinct patients with 15,882,153 outpatient and 135,775 inpatient records. After HDTTCA produces the final version of the decision tree, the rules can be used to assign the values of the target variables in the entire NHIRD. Our data indicate that 3.56% (23,262 out of 653,209) of the patients are eligible for telehealth services in 2012. This study verifies the efficiency and validity of HDTTCA by using a large data set from the NHI of Taiwan. CONCLUSION: This study conducts a series of experiments 30 times to compare the HDTTCA results with the logistic regression findings by measuring their average performance and determining which model addresses the telehealth patient classification problem better. Four important metrics are used to compare the results. In terms of sensitivity, the decision trees generated by HDTTCA and the logistic regression model are on equal grounds. In terms of accuracy, specificity, and precision, the decision tree generated by HDTTCA provides a better performance than that of the logistic regression model. When HDTTCA is applied, the decision tree model generates a competitive performance and provides clear, easily understandable rules. Therefore, HDTTCA is a suitable choice in solving telehealth service classification problems.

Assessing performance of Taiwan hospitals using data envelopment analysis: In view of ownership.

With rapid economic development in Taiwan, people have greater awareness of health care and are paying more attention to it. From the perspective of hospital management, the scale of hospitals and efficiency improvement are of concern to hospital managers. However, the extent of efficiency will differ between public and private hospitals due to their different ownership and goals. The study aims to evaluate the efficiency of public and private hospitals and to investigate the influence of ownership on efficiency of hospitals. The differences between hospitals can be understood by analyzing the features of the organization of hospitals and their geographic environment. In this way, hospitals with relatively low efficiency will be able to make improvements based on concrete evidence. By means of the two-stage method, the efficiency scores of 182 hospitals in Taiwan are compared. In the first stage, the data envelopment analysis is applied to obtain the efficiency scores of hospitals. The results show that private hospitals are more efficient than public hospitals. In the second stage, Tobit regression is used to investigate the factors influencing efficiency obtained by the data envelopment analysis. The results indicate that there are differences between ownership in market competition and the average length of stay.

GSK3ß­mediated Ser156 phosphorylation modulates a BH3­like domain in BCL2L12 during TMZ­induced apoptosis and autophagy in glioma cells.

BH3 domains, classified initially as BCL2 homology domains, participate in both apoptosis and autophagy. Beclin­1 contains a BH3 domain, which is required for binding to antiapoptotic BCL2 homologs and BCL2­mediated inhibition of autophagy. BCL2­like 12 (BCL2L12) also harbors a BH3­like domain, which is 12 residues long and contains a LXXXAE/D motif. In a yeast two­hybrid system performed in the present study, BCL2L12 shared similar binding partnerships to antiapoptotic BCL2 homologs, such as Beclin­1. In addition, this BH3­like domain was involved in anti­apoptosis and drug­induced autophagy in glioma cell lines. Mutations in S156 and hydrophobic L213 to alanine counteracted the antiapoptotic properties of BCL2L12 and downregulated the activation of microtubule associated protein 1 light chain 3B (LC3B), autophagy­related (ATG)12­ATG5 conjugates and Beclin­1, compared with a BCL2L12 wild­type group. Molecular dynamics simulations revealed that phosphorylation at Ser156 of BCL2L12 (within α­6 and α­7 helices) influenced the BH3­like domain conformation (α­9 helix), indicating that glycogen synthase kinase (GSK) 3ß­mediated Ser156 phosphorylation modulated a BH3­like domain in BCL2L12. Altogether, the present findings indicated that BCL2L12 may participate in anti­apoptosis and autophagy via a BH3­like domain and GSK3ß­mediated phosphorylation at Ser156. Furthermore, blockade of temozolomide (TMZ)­induced autophagy by 3­methyladenine (3­MA) resulted in enhanced activation of apoptotic markers, as well as tumor suppresor protein p53 (p53) expression in U87MG cells. The present results suggested that p53 and O6­methylguanine DNA methyltransferase activation, and BCL2, BCL­extra large, Beclin­1 and BCL2L12 expression may be used as a detection panel to determine which patients can benefit from TMZ and ABT­737 combination treatment.

The origin of GSKIP, a multifaceted regulatory factor in the mammalian Wnt pathway.

GSK3ß interacting protein (GSKIP) is a naturally occurring negative regulator of GSK3ß and retains both the Protein Kinase A Regulatory subunit binding (PKA-RII) domain and GSK3ß interacting domain. Of these two domains, we found that PKA-RII is required for forming a working complex comprising PKA/GSKIP/GSK3ß/Drp1 to influence phosphorylation of Drp1 Ser637. In this study, bioinformatics and experimental explorations re-analyzing GSKIP's biofunctions suggest that the evolutionarily conserved Domain of Unknown Function (DUF727) is an ancestral prototype of GSKIP in prokaryotes, and acquired the C-terminal GSK3ß binding site (tail) in invertebrates except for Saccharomyces spp., after which the N-terminal PKA-RII binding region (head) evolved in vertebrates. These two regions mutually influence each other and modulate GSKIP binding to GSK3ß in yeast two-hybrid assays and co-immunoprecipitation. Molecular modeling showed that mammalian GSKIP could form a dimer through the L130 residue (GSK3ß binding site) rather than V41/L45 residues. In contrast, V41/L45P mutant facilitated a gain-of-function effect on GSKIP dimerization, further influencing binding behavior to GSK3ß compared to GSKIP wild-type (wt). The V41/L45 residues are not only responsible for PKA RII binding that controls GSK3ß activity, but also affect dimerization of GSKIP monomer, with net results of gain-of-function in GSKIP-GSK3ß interaction. In addition to its reported role in modulating Drp1, Ser637 phosphorylation caused mitochondrial elongation; we postulated that GSKIP might be involved in the Wnt signaling pathway as a scavenger to recruit GSK3ß away from the ß-catenin destruction complex and as a competitor to compete for GSK3ß binding, resulting in accumulation of S675 phosphorylated ß-catenin.

Association of Environmental Arsenic Exposure, Genetic Polymorphisms of Susceptible Genes, and Skin Cancers in Taiwan.

Deficiency in the capability of xenobiotic detoxification and arsenic methylation may be correlated with individual susceptibility to arsenic-related skin cancers. We hypothesized that glutathione S-transferase (GST M1, T1, and P1), reactive oxygen species (ROS) related metabolic genes (NQO1, EPHX1, and HO-1), and DNA repair genes (XRCC1, XPD, hOGG1, and ATM) together may play a role in arsenic-induced skin carcinogenesis. We conducted a case-control study consisting of 70 pathologically confirmed skin cancer patients and 210 age and gender matched participants with genotyping of 12 selected polymorphisms. The skin cancer risks were estimated by odds ratio (OR) and 95% confidence interval (CI) using logistic regression. EPHX1 Tyr113His, XPD C156A, and GSTT1 null genotypes were associated with skin cancer risk (OR = 2.99, 95% CI = 1.01-8.83; OR = 2.04, 95% CI = 0.99-4.27; OR = 1.74, 95% CI = 1.00-3.02, resp.). However, none of these polymorphisms showed significant association after considering arsenic exposure status. Individuals carrying three risk polymorphisms of EPHX1 Tyr113His, XPD C156A, and GSTs presented a 400% increased skin cancer risk when compared to those with less than or equal to one polymorphism. In conclusion, GSTs, EPHX1, and XPD are potential genetic factors for arsenic-induced skin cancers. The roles of these genes for arsenic-induced skin carcinogenesis need to be further evaluated.