Long-lasting cigarette smoking alterations in immune function occur in cannabis smokers, possibly rendering them vulnerable to smoking-related tumors in later life.

Background: Active cigarette smoking leads to increased CXCL5 production. CXCL5 mediates the immune response by attracting immune cells to areas of inflammation. Elevated CXCL5 levels are associated with various inflammatory diseases and tumorigenesis. In addition, smoking is linked to an increase in the level of the cytokine CEACAM6 in the bloodstream of smokers. CEACAM6 is increased in pancreatic adenocarcinoma, breast cancer, non small cell lung cancer, gastric cancer, colon cancer and other cancers and promotes tumor progression, invasion, and metastasis. Although cytokine secretion in the innate immune response returns to nonsmoker levels after quitting smoking, the effects on the adaptive response appear to persist for years or decades due to epigenetic memory. As a result, epigenetic changes induced by smoking may contribute to long-lasting alterations in immune function, including elevated CXCL5 and CEACAM6. The effects of cannabis smoking might be similar. Methods: In the current study we used UK Biobank (UKB) data to assess the relationship of CXCL5, CEACAM6, and pulmonary function to cigarette and cannabis smoking. Our UK Biobank application was approved as UKB project 57245 (S.L., P.H.R.). Our analysis included all subjects with smoking and/or marijuana use data in the UK Biobank database. Circulating levels of CXCL5 and CEACAM6 were from UKB Olink data. Individual CXCL5 and CEACAM6 levels are NPX, Normalized Protein expression, Olink arbitrary unit in Log2 scale (Olink Proteomics AB, Uppsala, Sweden; http://www.olink.com). Results: Current smokers and past smokers had elevated circulating levels of CXCL5 and CECAM6. In multivariate analysis, current, past, or no smoking history was significantly related to CXCL5 level and CECAM6 levels, independent of the effects of age, sex. Frequency of cannabis use had a similar effect. In multivariate analysis, frequency of cannabis use was significantly related to CXCL5 level and CECAM6 levels, independent of the effects of age, sex, and years between last cannabis use and enrollment in study. Conclusion: we can confirm a previous report of epigenetic changes induced by cigarette smoking that may contribute to long-lasting alterations in immune function related to CXCL5 and CEACAM6. In addition, we have found that these same long-lasting smoking alterations in immune function related to CXCL5 and CEACAM6 occur in cannabis smokers, possibly rendering them vulnerable to smoking-related tumors in later life.

Association of Kallikrein Related Peptidase 3 (KLK3) gene with dermatophytosis in the UK biobank cohort.

BACKGROUND: In a previous genome wide association study (GWAS) of UK Biobank (UKB) data, we identified one susceptibility locus, tubulointerstitial nephritis antigen (TINAG), with genome wide significance for dermatophytosis. We used genotype calls from file UKB22418. These data are derived directly from Affymetrix DNA microarrays but are missing many genotype calls. Using computationally efficient approaches, UKB has entered imputed genotypes into a second dataset, UKB22828, increasing the number of testable variants by over 100-fold to 96 million variants. METHODS: In the current study, we used UKB imputed genotypes in UKB22828 to identify dermatophytosis susceptibility loci. To identify cases of dermatophytosis, we used ICD10 code B35, which covers tinea barbae, tinea capitis, tinea unguium, tinea manuum, tinea pedis, tinea corporis, tinea imbricata, tinea cruris, other dermatophytoses and dermatophytosis, unspecified. We used PLINK, a whole-genome association analysis toolset, to analyse the UKB22828 chromosome files. RESULTS: GWAS summary (Manhattan) plot of the meta-analysis association statistics highlighted two susceptibility loci, TINAG and Kallikrein Related Peptidase 3 (KLK3), with genome wide significance for dermatophytosis. KLK3, also known as prostate specific antigen (PSA), belongs to a subclass of serine proteases with a variety of physiological functions. CONCLUSION: KLK3 may be a dermatophytosis susceptibility gene. KLK3 could affect risk of dermatophytosis, since kallikreins are necessary for normal homeostasis of the skin.

Increased KCNN4 Expression Is Correlated With Poor Survival in Lower Grade Glioma.

BACKGROUND/AIM: Networks of glioma cells are linked to small groups of pacemaker cells in which levels of calcium ions pulse periodically, driving a signal through the network that causes tumor growth. Using inhibitors, one study blocked the activity of the Ca2+ activated potassium-channel protein KCa3.1 in in vitro models and mice, preventing the proliferation of glioma cells and tumor expansion. Marked reduction of tumor cell viability occurred within the entire network, as well as reduced tumor growth in mice and extended animal survival. MATERIALS AND METHODS: KCa3.1 is encoded by the gene potassium calcium-activated channel subfamily N member 4 (KCNN4) on the chromosomal location 19q13.31. We used the Cancer Genome Atlas (TCGA) to evaluate the effect of KCNN4 on human glioma survival in the TCGA Lower Grade Glioma (LGG) dataset. RESULTS: In humans, KCNN4 is prognostic in glioma; high expression is unfavorable. In addition, KCNN4 copy number variations are prognostic. Increased masked copy number segments are unfavorable in lower grade glioma. KCNN4 is lost in gliomas with the 1p 19q co-deletion, which may explain in part the comparatively favorable prognosis of 1p 19q co-deletion tumors. CONCLUSION: Our finding of increased KCNN4 expression related to poor survival in human lower grade glioma suggests that developing novel therapies, such as KCa3.1-inhibiting drugs, might be worthwhile.

Predicted Configuration and Stability of the ATAD2/SOX10 Complex Using Molecular Dynamics Simulations.

BACKGROUND/AIM: ATAD2, a melanoma competence factor, forms a protein complex with SOX10 that facilitates expression of SOX10 developmental target genes. The complex enables a strong transcriptional response to oncogenes such as BRAFV600E and is sufficient to endow oncogenic competence to melanocytes. The elucidation of the ADAT2/SOX10 complex structure may facilitate the development of drugs that can block formation of the complex. MATERIALS AND METHODS: We used the ClusPro web server for protein-protein docking to visualize and analyze the complex and GROMACS to perform molecular dynamics simulations. RESULTS: ClusPro protein docking analysis demonstrated the central position of ADAT2 in the ADAT2/SOX10 complex. Molecular dynamics simulations of ATAD2 docked to SOX10 suggest that ATAD2/SOX10 is not a stable structure. CONCLUSION: The central position of ADAT2 in the complex suggested that ADAT2 complexed to SOX10 may have the capability to modify multiple functions of the latter, one of which allows BRAFV600E to impart increased oncogenic function to melanocytes. The results of the molecular dynamics simulations imply that the ADAT2/SOX10 complex is not stable and might be disrupted by a therapeutic molecule, reducing the risk of melanoma. Knowledge of the ADAT2/SOX10 complex structure may facilitate the development of drugs that can block complex formation.

Androgen Deprivation Therapy Unrelated to Alzheimer's Disease in the UK Biobank Cohort.

BACKGROUND/AIM: In a meta-analysis of 14 studies, men who received androgen deprivation therapy (ADT) for prostate cancer had a higher risk of dementia and/or Alzheimer disease (AD) than men who did not receive ADT. The effect was more pronounced when ADT was given for more than 12 months. However, in all these analyses, two of the strongest AD risk factors after age, family history of AD and the apolipoprotein e4 allele, were not included. In the current study, we have used data from the UK Biobank (UKB) that incorporates these two factors. PATIENTS AND METHODS: Our analysis included all subjects with prostate cancer and AD. Prostate cancer diagnosis was ascertained using the 10th Revision of the International Classification of Diseases (ICD10), C61. AD diagnosis was ascertained using the 10th Revision of the International Classification of Diseases (ICD10) G30. Single nucleotide polymorphism (SNP) data for rs429358 and rs7412 were used to determine ApoE genotypes. ADT was in UKB field 20003, Treatment/medication code, Medications. Family history of AD was in UKB data fields 20107, Illnesses of father; 20110, Illnesses of mother; 20111, Illnesses of siblings. RESULTS: We studied 13,203 men with prostate cancer. The age of 132 subjects that received ADT was 64±5.6 (mean±standard deviation), and the age of 13,071 subjects that did not receive ADT was 62±5.6 (p<0.001). ADT was not associated with AD, but Apoe3e3 was significantly associated with diminished risk of AD when compared to e4e4. Moreover, every year of age was associated with increased risk of AD. ADT was unrelated to AD (p=0.997). CONCLUSION: Our UK Biobank data analysis does not confirm that ADT causes AD in men with prostate cancer. Large studies that include family history of AD and ApoeE genotype are needed. Mendelian randomization would also be desirable for a more definitive result.

Chromosome 1p deletion in colorectal cancer and lower grade glioma: possible relationship with the enteric nervous system.

Background: Enteric neurons and enteric glial cells are a part of the enteric nervous system, which is sometimes referred to as the "second brain" of the body. This complex network of neurons controls various functions of the gastrointestinal tract, including motility, secretion, and blood flow. Research has shown that there is a connection between enteric neurons and the development of colorectal cancer, although the exact mechanisms are still being studied. Methods: Because of the potential influence of chromosome mutations that may be common to both gliomas and colorectal cancer, we used the Cancer Genome Atlas (TCGA) to examine these mutations. Results: 166 of 506 lower grade gliomas had the 1p 19q co-deletion. 150 of 616 colorectal cancers had a 1p deletion but no 19q deletion. Conclusion: Colorectal cancer cells adhere to and migrate along the neurons of the enteric nervous system. Therefore, cancer cells might be expected to pick up mutations from neurons and enteric glial cells during recombination events. We hypothesize that the chromosome 1p deletion in colorectal cancer above is not a chance event and instead was acquired from adjacent enteric glial cells. Chromosome 1p co-deletion may confer better survival in patients with lower grade glioma in part because of loss of the MycBP oncogene, which is important in glioma development. Enteric glia might have the chromosome 1p deletion but lack the chromosome 19q deletion of CNS gliomas, making them much less vulnerable to malignant transformation than CNS gliomas. Indeed, evidence exists for a tumor suppressor gene on chromosome 19q associated with human astrocytomas, oligodendrogliomas, and mixed gliomas.

EARS2 significantly coexpresses with PALB2 in breast and pancreatic cancer.

BACKGROUND: PALB2 (BRCA2 partner and localizer) is a BRCA2-interacting protein that is required for BRCA2 genome caretaker tasks and interacts with BRCA1. Women with PALB2 mutation have a 40% to 60% higher risk of breast cancer, almost equivalent to women who have BRCA mutations. PALB2 mutation may also increase the risk of pancreatic cancer. New guidelines for PALB2 mutation in breast cancer advise pancreatic cancer screening, which includes M.R.I.s of the pancreas as well as endoscopic ultrasonography, for women who have a family history of pancreatic cancer. Using the Cancer Genome Atlas (TCGA) and The Human Protein Atlas we examined genes that co-express with PALB2 in breast and pancreatic cancer. METHODS: We used cBioPortal for Cancer Genomics to analyze data in TCGA. cBioPortal provides visualization, analysis and download of large-scale cancer genomics data sets. We used the UCSC Xena Browser to additionally analyze gene expression in TCGA. RESULTS: Six genes, EARS2, ARL6IP1, DNAJA3, KNOP1, RPUSD1, and TMEM186, significantly coexpressed with PALB2 in both breast and pancreatic cancer. Glutamyl-tRNA synthetase 2 (EARS2) was the only gene coexpressing with PALB2 in the breast and pancreatic cancer subjects that was significantly related to pancreatic cancer survival. Elevated PALB2 and EARS2 gene expression are both significantly associated with the PAM50 Luminal B subtype and high risk of recurrence, suggesting why these women may need active intervention, such as prophylactic mastectomy. CONCLUSIONS: EARS2 expression might be a risk factor for pancreatic cancer in breast cancer patients with PALB2 mutations. By assessing EARS2 expression in breast tumors, the clinician might obtain a second piece of information that, with family history of pancreatic cancer, could inform the decision to perform pancreatic cancer screening.

The Association Between Selenium, Selenoprotein P (SEPP1), Fluid Intelligence, and Exercise in the UK Biobank Cohort.

BACKGROUND: In the mouse hippocampus, exercise boosts neurogenesis. Increased levels of the selenium transport protein selenoprotein P (SEPP1) in the serum of exercised animals may contribute to the impact of exercise. SEPP1 is a protein that aids in the delivery of selenium to the brain. The effect of exercise on mouse brain precursor cell proliferation was diminished when SEPP1 or its receptor were genetically depleted. Selenium supplementation in the diet had the same effect as exercise in reducing some of the cognitive impairments associated with aging. METHODS: In the current analysis, we sought to determine the association of selenium, the SEPP1 gene, fluid intelligence, and exercise in the UK Biobank Cohort. We analyzed SEPP1 single nucleotide polymorphism (SNP) rs7579, a single nucleotide variation (SNV), position chr5:42800706, C > T, minor allele frequency T = 0.281. Its consequence is a 3'- UTR variant. The 3'-UTR contains regulatory regions that post-transcriptionally influence gene expression and is responsible for selenoprotein synthesis. SNP rs7579 has been implicated in multiple forms of cancer. The univariate general linear model of SPSS (IBM Corp., Armonk, NY) was used to rule out the effects of age, years of education, and vigorous activity on fluid intelligence score, with fluid intelligence score as the dependent variable, rs7579 genotype, and selenium supplements as fixed factors, and age, years of education, and vigorous activity as covariates. RESULTS: The effect of rs7579 genotype on fluid intelligence score was insignificant (p = 0.702). The effect of selenium supplements on fluid intelligence score was insignificant (p = 0.107). The interaction of rs7579 genotype and selenium supplements was insignificant (p = 0.911) and unrelated to the significant effects of age (p < 0.001), years of education (p < 0.001), and vigorous activity (p < 0.001) on fluid intelligence score.  Conclusion: Our multivariate analysis of SEPP1 genotype, selenium supplement use, and fluid intelligence scores is consistent with the negligible effect selenium supplements seem to have on cognition. Selenium is found in nuts, dairy products, and grains. These foods can provide sufficient selenium for health. Selenium supplements are not recommended.

Cannabis, Intraocular Pressure, and the Growth Arrest-Specific 7 (GAS7) Gene: A Retrospective Analysis.

Background Intraocular pressure (IOP) is a highly heritable risk factor for primary open-angle glaucoma (POAG), with at least 27 related genes; however, we are still not aware as to which receptors or genes that the main components of cannabis use to lower IOP. Methods In the current study, we used data from the UK Biobank (UKBB) to assess the relationship of growth arrest-specific 7 (GAS7) with IOP and cannabis in 37,046 subjects. GAS7, at chromosome 17p31.1, is quite close to a cannabis receptor at chromosome 17p31.3. For comparison, we chose a second IOP/glaucoma gene, CDKN2B-AS1 on chromosome 9p21.3, with no known relationship to cannabis. In addition, we examined the effect of CB1, GPR18, and cannabis on IOP; these two genes are associated with cannabis IOP reduction in mice. Results Total cannabis use versus IOP and genotypes of GAS7 SNP rs9913911 in the 37,046 subjects showed significant variation [p<0.001, univariate analysis of variance (ANOVA)]. Carriers of the GAS7 rs9913911 minor allele G had lower IOP with increased cannabis use. Total cannabis use versus IOP of genotypes of CDKN2B-AS1 SNP rs944801 in 37,046 subjects had IOP variability with cannabis use that was insignificant (p=0.138). We analyzed the relationship of CB1 SNP rs806365 and GPR18 SNP rs3742130 with cannabis use and IOP, which was insignificant. CB1 and GPR18 are probably not involved in cannabis-associated human IOP reduction, unlike what has been reported in mice. Conclusion Cannabis-based treatments, which apparently act on the GAS7 gene, can be utilized to reduce IOP. However, their disadvantages outweigh their advantages, which was not the case when the initial reports of marijuana's effects on IOP were published in the 1970s. Hence, cannabis-based glaucoma treatments are now of questionable value.

Constipation and Cigarette Smoking Are Independent Influences for Parkinson's Disease.

Background Tobacco smokers have reduced Parkinson's disease (PD) risk. Some patients with PD experience constipation long before they develop mobility problems, and constipation is a frequent complaint of people who try to stop smoking. Recently, the gut microbiome has been implicated in PD. Methods In the present study, we analyzed the relationship between smoking and constipation in subjects with PD and controls. We wished to determine whether the effects of smoking and constipation were independent or whether they might be interrelated. To evaluate the relationship, we used a cohort of subjects from the UK Biobank (UKB). Results In 501,174 subjects, the decreased risk of Parkinson's disease with increased smoking was significant (p < 0.001, two-tailed Fisher's exact test). The increased risk of constipation in subjects with PD was significant (p = 0.001, two-tailed Fisher's exact test). Logistic regression was performed; sex, age, constipation, and smoking were the independent variables, and PD present or absent was the dependent variable. The PD odds ratio (OR) for males was 1.790 (95% confidence interval (CI): 1.629-1.966) times that for females, indicating that PD is more common in men. The risk of PD increased by 1.140 (95% CI: 1.131-1.149) with every year of age. Constipation increased the risk of PD by 4.043 (95% CI: 1.901-8.599). Smoking diminished PD risk by 0.772 (95% CI: 0.690-0.863). Drinking coffee was associated with a reduced risk of PD (OR: 0.815 (95% CI: 0.730-0.909). Drinking tea reduced PD risk by 0.979 (95% CI: 0.962-0.997) for each cup per day. The effects of sex, age, constipation, smoking, drinking coffee, and drinking tea were independent and significant. Conclusion Our analysis suggests that the favorable effect of smoking on PD is independent of the detrimental effect of constipation. Smoking reduces PD risk because it not only stimulates the bowel to empty and prevents constipation but also alters the gut microbiome. Another factor, perhaps the tobacco component diterpenoids, may be responsible for the PD risk-reducing effect.

Marijuana and Myocardial Infarction in the UK Biobank Cohort.

BACKGROUND: Atrial fibrillation, ventricular tachycardia, acute coronary syndromes, and cardiac arrest have been attributed to marijuana. But the National Academy of Science's 2017 Report, The Health Effects of Cannabis and Cannabinoids, found limited evidence that acute marijuana smoking is positively associated with an increased risk of acute myocardial infarction, and uncovered no evidence to support or refute associations between any chronic effects of marijuana use and increased risk of myocardial infarct (MI). AIMS: We sought to determine the association of marijuana smoking with MI in the UK Biobank cohort. Because red wine is a mood-altering substance, we compared the effect of marijuana with red wine on MI incidence. METHODS: Our analysis included all subjects with MI. The diagnosis was ascertained using the 10th Revision of the International Classification of Diseases (ICD10 I21). Marijuana was recorded in UKB Category 143, medical conditions, marijuana use. Cigarette smoking information was from UKB Category 100058, smoking. To compare marijuana smoking with the effect of wine drinking we used data from UKB Category 10051, alcohol. RESULTS: With marijuana use, MI incidence decreased (p < 0.001, two tail Fisher exact test). Red wine was associated with lower MI incidence, although the incidence begins to rise at 11 or more glasses per week (p < 0.001, two tail Fisher exact test). Multivariate analysis was done with logistic regression, MI dependent variable, cigarette pack-years, diabetes type 2, sex, BMI, hypertension, marijuana use, age, red wine consumption, independent variables. Odds ratio (O.R.) 0.844 associated with marijuana use indicates that MI was less likely in marijuana users and was comparable to the effect of red wine (O.R. 0.847). CONCLUSION: Marijuana, which has not been shown to have the favorable physiologic effects of red wine on the heart, does reduce MI risk to an extent comparable to red wine. Perhaps both affect the heart by reducing stress.

A Component or Multiple Components of Bleeding Gums May Ameliorate Both Glaucoma and Alzheimer's Disease.

BACKGROUND: Although clinical studies have shown an increased prevalence of primary open-angle glaucoma (POAG) in patients with Alzheimer's disease (AD), a population-based epidemiologic study from Denmark found no increased risk of Alzheimer's disease in patients with glaucoma, and other studies have failed to demonstrate a link. However, a possible relationship between POAG and AD might manifest in their association with oral pathology. Dental caries, periodontal disease, stomatitis, and the related inflammatory burden increase AD risk, while oral pathology and the oral microbiome correlate with POAG vulnerability. To further examine the relationship, we analyzed POAG, AD, and oral disease in the UK Biobank (UKBB) cohort. METHODS: Our analysis included all subjects with POAG and AD. POAG diagnosis was ascertained using the 10th Revision of the International Classification of Diseases (ICD-10), H40.11. AD diagnosis was ascertained using the 10th Revision of the International Classification of Diseases (ICD-10), G30. Oral cavity, ulceration, stomatitis, periodontitis, teeth, and dental problems were in UKBB data field 6149. RESULTS: A "yes" answer to a question about bleeding gums is associated with a greater proportional POAG reduction (24.2%) than a "yes" answer to having none of the six listed problems (6.3%). Similarly, bleeding gums were associated with a greater proportional AD reduction (46.2% versus 16.9%). Logistic regression controlling for age and sex showed that bleeding gums (no/yes) were negatively associated with AD (odds ratio (OR) = 0.713, 95% confidence interval (CI) = 0.521-0.976, p = 0.035). Age-weighted least-squares linear regression showed that the lower corneal-compensated intraocular pressure (IOP) in the left eye was associated with bleeding gums (unstandardized regression coefficient = -0.174, p < 0.001), controlling for type 2 diabetes and past smoking. CONCLUSION: It is difficult to predict what component or components of periodontal inflammation might be ameliorating POAG and AD. Prostaglandin is a possibility. Identification of the component or components could lead to new treatments for POAG and AD. Further studies are warranted.

Druggable genetic targets in endometrial cancer✰,✰✰.

BACKGROUND: FBXW7 is frequently somatically mutated in grade 3 endometrioid endometrial cancers (G3EECs) and serous endometrial cancers (SECs), high-risk cancers associated with poor prognosis. CRISPR-edited cell lines identified the proteomic and phosphoproteomic effects of FBXW7 mutation in 3 high-risk endometrial cancers (ECs), including altered protein levels of L1CAM and TGM2. This result is important because L1CAM and TGM2 are druggable proteins that could represent new therapeutic targets. METHODS: We used cBioPortal for Cancer Genomics to analyze data in The Cancer Genome Atlas (TCGA). We used the UCSC Xena Browser to analyze gene expression. For differential gene expression analysis, the gene ontology molecular function 2018 version was used. The analysis was focused on determined genes. RESULTS: FBXW7 mutations affect gene expression of L1CAM but are unrelated to TGM2 gene expression. L1CAM gene expression is significantly related to survival. Patients with lower L1CAM gene expression have better survival. FBXW7 mutations are unrelated to survival. TGM2 gene expression is unrelated to FBXW7 mutations. TGM2 gene expression is unrelated to survival, all tumor grades or grade 3 alone. CONCLUSION: We agree with Urick et al. that L1CAM may be a promising druggable target in endometrial carcinoma. The lack of relationship of TGM2 expression with FBXW7 mutations and endometrial cancer survival suggests that TGM2 might not be of as much value as a druggable target, compared to L1CAM. However, the fact that a certain alteration is not prognostic for cancer survival does not necessarily mean that the alteration will not be targetable. More data, such as inhibition of each gene by calculating drug targetability, may be required to support this conclusion.