Cytoprotective role of human dental pulp stem cell-conditioned medium in chemotherapy-induced alopecia.

BACKGROUND: Chemotherapy-induced alopecia (CIA) is a distressing adverse effect of chemotherapy, with an estimated incidence of 65% and limited treatment options. Cyclophosphamide (CYP) is a common alopecia-inducing chemotherapy agent. Human dental pulp stem cells (DPSCs) secrete several paracrine factors that up-regulate hair growth. Conditioned medium (CM) collected from DPSCs (DPSC-CM) promotes hair growth; culturing mesenchymal stem cells under hypoxic conditions can enhance this effect. METHODS: The effect of DPSC-CM cultured under normoxic (N-) and hypoxic (H-) conditions against CYP-mediated cytotoxicity in keratinocytes was examined using cell viability assay, lactate dehydrogenase (LDH) cytotoxicity assay, and apoptosis detection. The damage-response pathway was determined in a well-established CIA mouse model by analyzing macroscopic effects, histology, and apoptosis. Reverse transcription-quantitative PCR and Caspase-3/7 activity assay were used to investigate the impact of DPSC-CM on the molecular damage-response pathways in CYP-treated mice. The effect of post-CIA DPSC-CM application on post-CIA hair regrowth was analyzed by macroscopic effects and microstructure observation of the hair surface. Furthermore, to investigate the safety of DPSC-CM as a viable treatment option, the effect of DPSC-CM on carcinoma cell lines was examined by cell viability assay and a subcutaneous tumor model. RESULTS: In the cell viability assay, DPSC-CM was observed to increase the number of keratinocytes over varying CYP concentrations. Furthermore, it reduced the LDH activity level and suppressed apoptosis in CYP-treated keratinocytes. DPSC-CM exhibited the cytoprotective role in vivo via the dystrophic anagen damage-response pathway. While both N-CM and H-CM downregulated the Caspase-3/7 activity level, H-CM downregulated Caspase-3 mRNA expression. The proportion of post-CIA H-CM-treated mice with > 90% normal hair was nearly twice that of vehicle- or N-CM-treated mice between days 50 and 59 post-depilation, suggesting that post-CIA H-CM application may accelerate hair regrowth and improve hair quality. Furthermore, DPSC-CM suppressed proliferation in vitro in certain carcinoma cell lines and did not promote the squamous cell carcinoma (SCC-VII) tumor growth rate in mice. CONCLUSIONS: The potentiality of DPSC-CM and H-CM as a promising cytoprotective agent and hair regrowth stimulant, respectively, for CIA needs in-depth exploration.

Clinical retrospective analysis of peri-implant oral malignancies.

PURPOSE: Complications of implant prostheses have direct correlation with the increased use of implants for dental rehabilitation. In this study, we present cases of peri-implant oral malignancies (PIOM) around dental implants and a retrospective analysis of patients treated for PIOM. METHODS: The retrospective analysis was performed with patients treated for PIOM at the Department of Oral and Maxillofacial Surgery of the Seoul National University Dental Hospital between 2006 and 2014. The patient records were thoroughly screened for previous medical issues, human papilloma virus infections, and other clinical data with a focus on relevant information such as localization, time from implant insertion to the development of the carcinoma, implant type and prosthetic rehabilitation. RESULTS: Twenty-one patients were diagnosed with PIOM. The male-to-female ratio was 1.625. The mean age of the patients was 60.42 ± 9.35 years old. Three patients reported ongoing alcohol/tobacco consumption. Five patients had a history of previous oral cancer surgery or exhibited mucosal lesions. The time from implant placement until carcinoma diagnosis was 49.13 ± 33.63 months on average. Most PIOM patients (95.2%) were diagnosed with SCC. All patients had previously been treated for peri-implantitis. In 85.7% of the patients, prostheses were observed on the opposing teeth where PIOM occurred. CONCLUSION: Based on the review of these cases, it can be deduced that there is a possibility that implant treatment and galvanic currents between prosthesis may constitute an irritant and/or inflammatory cofactor which contributes to the formation and/or development of malignant tumors. Patients at potential risk may benefit from individualized recall intervals and careful evaluations.

Clinical and Biological Activity of Chemoimmunotherapy in Advanced Endometrial Adenocarcinoma: A Phase II Trial of the Big Ten Cancer Research Consortium.

Purpose: The objective of this study was to assess the efficacy and safety of pembrolizumab in combination with standard carboplatin/paclitaxel in patients with advanced endometrial cancer (EC). Patients and Methods: This single-arm, open-label, multi-center phase II study enrolled patients with RECIST measurable advanced EC. Patients could have received < 1 prior platinum-based regimen and < one non-platinum chemotherapy. The primary endpoint was objective response rate (ORR). Planned sample size of 46 subjects provided 80% power to detect 15% ORR improvement compared to historical control rate of 50%. Results: 46 patients were enrolled, and 43 were evaluable for ORR. Median age was 66 (range: 43-86). Thirty-four (73.9%) patients had recurrent and 12 (26.1%) primary metastatic EC. Patients received carboplatin AUC 6, paclitaxel 175mg/m2 and pembrolizumab 200mg IV every 3 weeks for up to 6 cycles. ORR was 74.4% (32/43), higher than historic controls (p = 0.001). Median PFS was 10.6 months (95% CI 8.3-13.9 months). The most common grade 1-2 treatment related adverse event (TRAEs) included anemia (56.5%), alopecia (47.8%), fatigue (47.8%) and neuropathy (13%), while the most common grade 3-4 TRAEs were lymphopenia, leukopenia, and anemia (19.6% each). High-dimensional spectral flow cytometry (CyTEK) identified enrichment in peripheral CD8+ and CD4+ T cell populations at baseline in responders. The CD8+ T cell compartment in responders exhibited greater expression levels of PD-1 and PD-L1 and higher abundance of effector memory CD8+ cells compared to non-responders. Conclusions: Addition of pembrolizumab to carboplatin and paclitaxel for advanced EC was tolerated and improved ORR compared to historical outcomes.

Classification of rat mammary carcinoma with large scale in vivo microwave measurements.

Mammary carcinoma, breast cancer, is the most commonly diagnosed cancer type among women. Therefore, potential new technologies for the diagnosis and treatment of the disease are being investigated. One promising technique is microwave applications designed to exploit the inherent dielectric property discrepancy between the malignant and normal tissues. In theory, the anomalies can be characterized by simply measuring the dielectric properties. However, the current measurement technique is error-prone and a single measurement is not accurate enough to detect anomalies with high confidence. This work proposes to classify the rat mammary carcinoma, based on collected large-scale in vivo S[Formula: see text] measurements and corresponding tissue dielectric properties with a circular diffraction antenna. The tissues were classified with high accuracy in a reproducible way by leveraging a learning-based linear classifier. Moreover, the most discriminative S[Formula: see text] measurement was identified, and to our surprise, using the discriminative measurement along with a linear classifier an 86.92% accuracy was achieved. These findings suggest that a narrow band microwave circuitry can support the antenna enabling a low-cost automated microwave diagnostic system.

Anticancer and antimutagenic activity of Silybum marianum L. and Eucalyptus camaldulensis Dehnh. against skin cancer induced by DMBA: In vitro and in vivo models.

The current study investigated the prospective effect of Silybum marianum L. and Eucalyptus camaldulensis Dehnh extracts against skin cancer. Skin cancer was induced by 7,12-dimethylbenz(a) anthracene (DMBA) in young Balb/c mice. Plant extracts were administered to animals orally, once/day (100mg/kg, 5 days/week) for the 20 weeks. Anticancer activity was examined via tumor progression, where antimutagenic activity was measured using 8-OHdG and sister chromatid exchange (SCE) levels. Eucalyptus camaldulensis Dehnh. leaves extract and Silybum marianum L. leaves extract significantly reduced 8-OHdG in cultured human lymphocytes in a dose-response manner (P<0.05). Similarly, the leave extracts of both plants significantly reduced chromosomal damage as measured by SCE levels (P<0.05). In the skin painting assay, the leave extracts of both plants significantly delayed the onset of tumors compared to DMBA treated group (P<0.05). The Silybum marianum leaves extract significantly reduced tumor incidence (P<0.01) and papilloma frequency (P<0.01) induced by DMBA. The Eucalyptus camaldulensis leaves extract significantly reduced the number of tumors per animal (P<0.05) and incidence of tumors (P<0.001). The in vitro and in vivo findings showed that leaves of Silybum marianum L. and Eucalyptus camaldulensis Dehnh. extracts might be a promising source for anticancer and antimutagenic agents against human cancer.

Effect of Voacamine upon inhibition of hypoxia induced fatty acid synthesis in a rat model of methyln-nitrosourea induced mammary gland carcinoma.

BACKGROUND: In the present study, fatty acid synthesis is targeted to combat mammary gland carcinoma by activating prolyl hydroxylase-2 with Voacamine alone and in combination with Tamoxifen. It was hypothesized that the activation of prolyl hydroxylase-2 would inhibit the hypoxia-induced fatty acid synthesis and mammary gland carcinoma. Mammary gland carcinoma was induced with a single dose administration of N-methyl-N-nitrosourea (50 mg/kg,i.p.) and treatment with Voacamine and Tamoxifen 15 days after carcinogen administration. RESULTS: At the end of the study, hemodynamic profiling of animals was recorded to assess the cardiotoxic potential of the drug. Blood serum was separated and subjected to nuclear magnetic resonance spectroscopy. Carmine staining and histopathology of mammary gland tissue were performed to evaluate the anti-angiogenic potential of the drug. The antioxidant potential of the drug was measured with antioxidant markers. Western blotting was performed to study the effect of the drug at the molecular level. CONCLUSION: Results of the study have shown that Voacamine treatment stopped further decrease in body weight of experimental animals. The hemodynamic study evidenced that Voacamine at a low dose is safe in cardiac patients. Microscopic evaluation of mammary gland tissue documented the anti-angiogenic potential of Voacamine and Tamoxifen therapy. Perturbed serum metabolites were also restored to normal along with antioxidant markers. Immunoblotting of mammary gland tissue also depicted restoration of proteins of the hypoxic and fatty acid pathway. Conclusively, Voacamine and its combination with Tamoxifen activated prolyl hydroxylase-2 to combat mammary gland carcinoma.

A role for keratin 17 during DNA damage response and tumor initiation.

High levels of the intermediate filament protein keratin 17 (K17) are associated with poor prognoses for several human carcinomas. Studies in mouse models have shown that K17 expression is positively associated with growth, survival, and inflammation in skin and that lack of K17 delays onset of tumorigenesis. K17 occurs in the nucleus of human and mouse tumor keratinocytes where it impacts chromatin architecture, gene expression, and cell proliferation. We report here that K17 is induced following DNA damage and promotes keratinocyte survival. The presence of nuclear K17 is required at an early stage of the double-stranded break (DSB) arm of the DNA damage and repair (DDR) cascade, consistent with its ability to associate with key DDR effectors, including γ-H2A.X, 53BP1, and DNA-PKcs. Mice lacking K17 or with attenuated K17 nuclear import showed curtailed initiation in a two-step skin carcinogenesis paradigm. The impact of nuclear-localized K17 on DDR and cell survival provides a basis for the link between K17 induction and poor clinical outcomes for several human carcinomas.

Oral administration of tartrazine (E102) accelerates the incidence and the development of 7,12-dimethylbenz(a) anthracene (DMBA)-induced breast cancer in rats.

BACKGROUND: Despite the considerable advances made in the treatment of cancer, it remains a global threat. Tartrazine (E102) is a synthetic dye widely used in food industries; it has recently been shown to induce oxidative stress (a well known risk factor of cancer) in rat tissues. The present work therefore aimed to assess the impact of a regular consumption of tartrazine on the incidence of breast cancer in rats. METHODS: Forty (40) Wistar rats aged 55 to 60 days were randomly assigned into 5 groups (n = 8) including two groups serving as normal controls and receiving distilled water (NOR) or tartrazine (NOR + TARZ). The three remaining groups were exposed to the carcinogen DMBA (50 mg/kg) and treated for 20 weeks with either distilled water (DMBA), tartrazine 50 mg/kg (DMBA + TARZ) or a natural dye (DMBA + COL). The parameters evaluated were the incidence, morphology and some biomarkers (CA 15-3, estradiol and α-fetoprotein) of breast cancer. The oxidative status and histomorphology of the tumors were also assessed. RESULTS: A regular intake of tartrazine led to an early incidence of tumors (100% in rats that received TARZ only vs 80% in rats that received DMBA only), with significantly larger tumors (p < 0.001) (mass = 3500 mg/kg and volume = 4 cm3). The invasive breast carcinoma observed on the histological sections of the animals of the DMBA + TARZ group was more developed than those of the DMBA group. The increase in serum α-fetoprotein (p < 0.05) and CA 15-3 (p < 0.01) levels corroborate the changes observed in tumors. The presence of oxidative activity in animals of the DMBA + TARZ group was confirmed by a significant decrease (p < 0.001) in the activity of antioxidant enzymes (SOD and catalase) as well as the level of GSH and increase in the level of MDA compared to the rats of the DMBA and NOR groups. CONCLUSION: Tartrazine therefore appears to be a promoter of DMBA-induced breast tumorigenesis in rats through its oxidative potential. This work encourages further studies on the mechanisms of action of tartrazine (E102) and its limits of use.

Genes Associated with Calcium Signaling are Involved in Alcohol-Induced Breast Cancer Growth.

BACKGROUND: Alcohol consumption is a risk factor for breast cancer, contributing to up to nearly 23,000 new cases each year. Mechanistic studies show that alcohol increases tumor aggressiveness and metastatic potential, promotes angiogenesis, induces chronic inflammation, and dysregulates RNA polymerase III-related genes. Alcohol has also been shown to affect estrogen signaling in breast cancer, including in our study of the transcriptomic effects of alcohol in breast cancer cells. METHODS: To elucidate mechanisms of action of alcohol in breast cancer, we carried out secondary analyses of our alcohol-responsive transcriptome data using gene ontology and pathway databases and analysis tools and cistromic data analysis of candidate transcription factors which may mediate the transcriptomic alterations. Predicted alcohol-responsive pathways and mechanisms were perturbed and examined experimentally in breast cancer cells. The clinical relevance of identified genes was determined by expression profiles in patient samples and correlation with disease outcomes and alcohol consumption in previously published study cohorts. RESULTS: Gene ontology analysis showed that alcohol alters the expression of many metabolism-related genes, and cistromic data of differentially expressed genes revealed the potential involvement of nuclear factor of activated T cells 3 (NFATC3) in mediating the transcriptomic effects of alcohol. Pathway analysis also predicted regulation of calcium signaling by alcohol in breast cancer cells. Chemical perturbation of this pathway reversed the effect of alcohol on breast cancer cell growth and reduced the elevated cytosolic Ca2+ levels induced by alcohol. Expression levels of alcohol-responsive genes in tumor samples from breast cancer patients are associated with poor disease outcomes. Moreover, expression of some of these genes was altered in breast cancer patients who consumed alcohol previously as compared to those who did not drink. CONCLUSION: Alcohol alters expression of genes that regulate intracellular calcium levels and downstream signaling pathways which drive breast cancer cell proliferation and disease progression.

The prevalence of esophageal cancer after caustic and pesticide ingestion: A nationwide cohort study.

Habits such as smoking and alcohol drinking and existing esophageal malfunction are considered the main risk factors for esophageal carcinogenesis. Caustic ingestion of acidic or alkaline agents or strong irritants can induce severe esophageal corrosive injury and increase esophageal cancer risk. We studied the relationship between esophageal carcinoma and acute detergent or pesticide poisoning by using nationwide health insurance data. Methodology/Principle findings: We compared a pesticide/detergent intoxication cohort (N = 21,840) and an age- and gender-matched control cohort (N = 21,840) identified from the National Health Insurance Research Database between 2000 and 2011. We used the multivariable Cox proportional model to determine esophageal carcinoma risk. The overall incidence density of esophageal cancer was 1.66 per 10,000 person-years in the comparison cohort and 4.36 per 10,000 person-years in the pesticide/detergent intoxication cohort. The corresponding adjusted hazard ratio (HR) for esophageal cancer was 2.33 (95% confidence interval [CI] = 1.41-3.86) in the pesticide/detergent intoxication cohort compared with the control cohort. Patients with corrosive and detergent intoxication did not have a higher risk of esophageal cancer (adjusted HR = 0.98, 95% CI = 0.29-3.33) than those without pesticide/detergent intoxication. However, patients with pesticide intoxication had a significantly higher risk of esophageal cancer (adjusted HR = 2.52, 95% CI = 1.52-4.18) than those without pesticide/detergent intoxication. Conclusion: In the present study, after adjusting for conventional risk factors, we observed that pesticide intoxication could exert substantial effects through increased esophageal cancer risk. However, patients with detergent intoxication may not have an increased risk of esophageal cancer.

Aristolochic acid mutational signature defines the low-risk subtype in upper tract urothelial carcinoma.

Rationale: Dietary exposure to aristolochic acids and similar compounds (collectively, AA) is a significant risk factor for nephropathy and subsequent upper tract urothelial carcinoma (UTUC). East Asian populations, who have a high prevalence of UTUC, have an unusual genome-wide AA-induced mutational pattern (COSMIC signature 22). Integrating mutational signature analysis with clinicopathological information may demonstrate great potential for risk ranking this UTUC subtype. Methods: We performed whole-genome sequencing (WGS) on 90 UTUC Chinese patients to extract mutational signatures. Genome sequencing data for urinary cell-free DNA from 26 UTUC patients were utilized to noninvasively identify the mutational signatures. Genome sequencing for primary tumors on 8 out of 26 patients was also performed. Metastasis-free survival (MFS) and cancer-specific survival (CSS) were measured using Kaplan-Meier methods. Results: Data analysis showed that a substantial proportion of patients harbored the AA mutational signature and were associated with AA-containing herbal drug intake, female gender, poor renal function, and multifocality. Field cancerization was found to partially contribute to multifocality. Nevertheless, AA Sig subtype UTUC patients exhibited favorable outcomes of CSS and MFS compared to the No-AA Sig subtype. Additionally, AA Sig subtype patients showed a higher tumor mutation burden, higher numbers of predicted neoantigens, and infiltrating lymphocytes, suggesting the potential for immunotherapy. We also confirmed the AA signature in AA-treated human renal tubular HK-2 cells. Notably, the AA subtype could be ascertained using a clinically applicable sequencing strategy (low coverage) in both primary tumors and urinary cell-free DNA as a basis for therapy selection. Conclusion: The AA mutational signature as a screening tool defines low-risk UTUC with therapeutic relevance. The AA mutational signature, as a molecular prognostic marker using either ureteroscopy and/or urinary cell-free DNA, is especially useful for diagnostic uncertainty when kidney-sparing treatment and/or immune checkpoint inhibitor therapy were considered.

Divergent molecular profile of PIK3CA gene in arsenic-associated bladder carcinoma.

The activation of PIK3CA in bladder carcinoma (BlCa) with its recurrent mutations in exon 9 and 20 were well reported. But the association of arsenic on the activation of the pathway is not well elucidated. Therefore, we aimed to analyse the effect of arsenic on the genetic (copy number variation/mutation) and expression profiles of PIK3CA in primary BlCa samples. Infrequent amplification (16%) of the PIK3CA locus was observed, with higher frequency among the arsenic-high (AsH) than arsenic-low (AsL) samples. Frequent (54%) tumour-specific mutations in exon 9 and 20 of PIK3CA were observed in the BlCa samples with prevalent (47%) C>T transition mutations. Exon 9 and 20 harboured 48% and 73% of the total mutations, respectively, with 37% in E542K/E545K and 25% of the mutation in H1047Y/R. Though mutation frequency in AsH and AsL was found to be comparable, we observed some arsenic-specific mutation at c.1633G>A, c.1634A>C (E545K) and c.2985C>T and c.3130G>T mutations, as well as prevalent transverse mutations of A>C and G>T in AsH group. Furthermore, 73% of the BlCa samples showed overexpression (mRNA/protein) of PIK3CA with genetic alterations (amplification/mutation), significantly (P = 0.01) higher in AsH group. However, 36% of the samples showed overexpressed PIK3CA, independent of mutation or amplification, signifying a transcriptional upregulation of PIK3CA gene. Therefore, the expression status of NFκB, a transcription factor of PIK3CA, was assessed and found to be significantly correlated with the overexpression of PIK3CA (mRNA/protein) in AsH group. Similarly, the expression pattern of pAKT1 (Thr 308) was also found to be significantly correlated with PIK3CA overexpression. Finally, AsH patients with the overexpression of PIK3CA or NFκB had the worst overall survival, signifying a strong impact of arsenic on this pathway and outcome of the patients. Thus, our study showed that the arsenic-associated differential molecular profile of PIK3CA/AKT1/NFkB in BlCa has an important role in the molecular pathogenesis of the disease.

Genotoxicity and carcinogenicity of ivermectin and amoxicillin in vivo systems.

Antiparasitic substances are chemicals used to control or kill endoparasites and ectoparasites. Based on the premise that Ivermectin (IVM) and Amoxicillin (AMX) are commonly considered in parasitic control in mammals, the present study aimed to evaluate the carcinogenic and genotoxic potential of different concentrations of IVM and AMX through the detection of epithelial tumor test in Drosophila melanogaster. Third-instar larvae descending from the cross between wts/TM3, Sb1 females and mwh/mwh males were treated with different concentrations of IVM (2.9, 5.8, 11.6 and 23.2 x 10-17 mM) or AMX (1.37, 2.74, 5.48 and 10.9 x 10-16mM). The results revealed that IVM increased the frequency of epithelial tumor in D. melanogaster considering all evaluated concentrations, while AMX showed no carcinogenic effect. Furthermore, the Micronucleus (MN) test in Tradescantia pallida was used to evaluate the genotoxic effect of IVM and AMX. T. pallida individuals were exposed for 8 hours at different concentrations of IVM (5.71, 11.42, 22.84 and 45.68 x 10-5mM) or AMX (5.13, 10.26, 20.52 and 41.05 x 10-3mM). Findings showed an increase in the frequency of micronuclei in T. pallida treated with 11.42, 22.84 and 45.68 x 10-5mM of IVM. We conclude that chronic exposure to IVM is directly associated with events resulting from genetic instability (genotoxicity and carcinogenicity). On the other hand, AMX was neither carcinogenic nor genotoxic for D. melanogaster and T. pallida.

Deletion of cadherin-17 enhances intestinal permeability and susceptibility to intestinal tumour formation.

Cadherin-17 is an adhesion molecule expressed specifically in intestinal epithelial cells. It is frequently underexpressed in human colorectal cancer. The physiological function of cadherin-17 and its role in tumourigenesis have not yet been determined. We used the transcription activator-like effector nuclease technique to generate a Cdh17 knockout (KO) mouse model. Intestinal tissues were analysed with histological, immunohistochemical and ultrastructural methods. Colitis was induced by oral administration of dextran sulphate sodium (DSS), and, to study effects on intestinal tumourigenesis, mice were given azoxymethane (AOM) and DSS to induce colitis-associated cancer. Cdh17 KO mice were viable and fertile. The histology of their small and large intestines was similar to that of wild-type mice. The junctional architecture of the intestinal epithelium was preserved. The loss of cadherin-17 resulted in increased permeability and susceptibility to DSS-induced colitis. The AOM/DSS model demonstrated that Cdh17 KO enhanced tumour formation and progression in the intestine. Increased nuclear translocation of Yap1, but not of ß-catenin, was identified in the tumours of Cdh17 KO mice. In conclusion, cadherin-17 plays a crucial role in intestinal homeostasis by limiting the permeability of the intestinal epithelium. Cadherin-17 is also a tumour suppressor for intestinal epithelia. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Comparison of arsenic methylation capacity and polymorphisms of arsenic methylation genes between bladder cancer and upper tract urothelial carcinoma.

Arsenic exposure is an environmental risk factor for urothelial carcinoma (UC). The natural history of upper tract urothelial carcinoma (UTUC) differs from that of bladder cancer (BC). However, the risk factors of BC and UTUC are not exactly the same and should be discussed separately. The aims of this study were to evaluate 1) the association between arsenic methylation capacity and UTUC and/or BC, separately, and 2) the association between polymorphisms of the arsenic metabolism-related genes AS3MT, GSTOs, and PNP against BC and/or UTUC, separately. We conducted a hospital-based study and collected 216 BC and 212 UTUC cases, and 813 healthy controls, from September 2007 to October 2011. Urinary arsenic profiles were measured using high-performance liquid chromatography-hydride generator-atomic absorption spectrometry. The polymorphisms of AS3MT, GSTO, and PNP were identified using the Sequenom MassARRAY platform with iPLEX Gold chemistry. We found that inefficient arsenic methylation capacity was associated with BC in a significant dose-response relationship, but only found that high urinary total arsenic concentration was related to the risk of UTUC, also in a significant dose-response manner. Those with a total urinary arsenic level of > 30.28 µg/L compared to ≤ 9.78 µg/L, had a odds ratio (OR), and 95% confidence interval (CI) of UTUC, of 4.80 (2.22-10.39). The polymorphisms of AS3MT rs11191438, AS3MT rs10748835, and AS3MT rs1046778 were related to the risk of BC and UTUC, while the polymorphisms of AS3MT rs3740393, AS3MT rs11191453, and AS3MT rs11191454 were associated with arsenic methylation capacity. The AS3MT gene polymorphisms and arsenic methylation capacity appear to independently affect the risk of BC and UTUC.

Geminin ablation in vivo enhances tumorigenesis through increased genomic instability.

Geminin, a DNA replication licensing inhibitor, ensures faithful DNA replication in vertebrates. Several studies have shown that geminin depletion in vitro results in rereplication and DNA damage, whereas increased expression of geminin has been observed in human cancers. However, conditional inactivation of geminin during embryogenesis has not revealed any detectable DNA replication defects. In order to examine its role in vivo, we conditionally inactivated geminin in the murine colon and lung, and assessed chemically induced carcinogenesis. We show here that mice lacking geminin develop a significantly higher number of tumors and bear a larger tumor burden than sham-treated controls in urethane-induced lung and azoxymethane/dextran sodium sulfate-induced colon carcinogenesis. Survival is also significantly reduced in mice lacking geminin during lung carcinogenesis. A significant increase in the total number and grade of lesions (hyperplasias, adenomas, and carcinomas) was also confirmed by hematoxylin and eosin staining. Moreover, increased genomic aberrations, identified by increased ATR and γH2AX expression, was detected with immunohistochemistry analysis. In addition, we analyzed geminin expression in human colon cancer, and found increased expression, as well as a positive correlation with ATM/ATR levels and a non-monotonic association with γH2AX. Taken together, our data demonstrate that geminin acts as a tumor suppressor by safeguarding genome stability, whereas its overexpression is also associated with genomic instability. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Genetic aberrations of the K-ras proto-oncogene in bladder cancer in relation to pesticide exposure.

In Egypt, bladder cancer is one of the most popular cancers, accounting for 31% of all cancer cases. It ranks first in males about 16.2% of male cancer. The incidence in rural areas among males is near 32 per 100,000. The exact etiology of bladder cancer is still unknown; K-ras gene is known as a critical DNA target for chemical carcinogens such as pesticide. Some occupational hazard exposure is thought to be directly genotoxic, while others might enhance the mutagenicity and carcinogenicity of directly acting genotoxic agents. Analysis of the relationship between pesticide exposure and mutation in the K-ras gene in human bladder cancer. One hundred patients were diagnosed with bladder cancer and two hundred controls attended the outpatient clinic; after taking consent and filling a questionnaire for age, sex, occupation and pesticide exposure, surgically resected specimens were collected and the samples were used to determine the k-ras mutation. Blood samples were taken to analyze the level of acetylcholinesterase enzyme and level of P53. The present study indicated that pesticide exposure may play a great role in malignant transformation of the bladder cells through mutation in the K-ras gene; there was a significant correlation between the acetylcholinesterase enzyme level and k-ras mutation (p < 0.001). The results revealed that the level of P53 was significantly high in comparison with the control group (p < 0.001). These findings give an alarm to decrease the amount of pesticides used in our area; also, p53 may be used as an indicator to bladder cancer.