Correlation between Selenium and Zinc Levels and Survival among Prostate Cancer Patients.

The most prevalent type of cancer among males is prostate cancer. Survival is considered quite good, but it can be further improved when risk factors are optimized. One of these factors is micronutrients, including Se and Zn. To our knowledge, the interaction between Se and Zn and prostate cancer remains undescribed. This study aimed to investigate the optimal levels of selenium (Se) and zinc (Zn) and their impact on the survival of individuals diagnosed with prostate cancer. A total of 338 prostate cancer patients were enrolled in this study, which was conducted in Poland between 2009 and 2015. Mass spectrometry, which uses inductively coupled plasma mass, was used to assess serum element levels before treatment. The study participants were categorized into quartiles (QI-QIV) based on the distributions of Se and Zn levels observed among surviving participants. Cox regression was used to assess the association between serum Se and Zn levels and the survival of prostate cancer patients. Our results reveal the effect of combined Se and Zn levels on survival in prostate cancer patients (SeQI-ZnQI vs. SeQIV-ZnQIV; HR = 20.9). These results need further research to establish Se/Zn norms for different populations.

Genetic testing for homologous recombination repair (HRR) in metastatic castration-resistant prostate cancer (mCRPC): challenges and solutions.

Patients with metastatic castration-resistant prostate cancer (mCRPC) have an average survival of only 13 months. Identification of novel predictive and actionable biomarkers in the homologous recombination repair (HRR) pathway in up to a quarter of patients with mCRPC has led to the approval of targeted therapies like poly-ADP ribose polymerase inhibitors (PARPi), with the potential to improve survival outcomes. The approval of PARPi has led to guideline bodies such as the National Comprehensive Cancer Network (NCCN) to actively recommend germline and or somatic HRR gene panel testing to identify patients who will benefit from PARPi. However, there are several challenges as genetic testing is still at an early stage especially in low- and middle-income countries, with cost and availability being major impediments. In addition, there are issues such as choice of optimal tissue for genetic testing, archival, storage, retrieval of tissue blocks, interpretation and classification of variants in the HRR pathway, and the need for pretest and post-test genetic counseling. This review provides insights into the HRR gene mutations prevalent in mCRPC and the challenges for a more widespread gene testing to identify actionable germline pathogenic variants and somatic mutations in the HRR pathway, and proposes a clinical algorithm to enhance the efficiency of the gene testing process.

Endocannabinoid System as a Promising Therapeutic Target in Inflammatory Bowel Disease - A Systematic Review.

Inflammatory bowel disease (IBD) is a general term used to describe a group of chronic inflammatory conditions of the gastrointestinal tract of unknown etiology, including two primary forms: Crohn's disease (CD) and ulcerative colitis (UC). The endocannabinoid system (ECS) plays an important role in modulating many physiological processes including intestinal homeostasis, modulation of gastrointestinal motility, visceral sensation, or immunomodulation of inflammation in IBD. It consists of cannabinoid receptors (CB1 and CB2), transporters for cellular uptake of endocannabinoid ligands, endogenous bioactive lipids (Anandamide and 2-arachidonoylglycerol), and the enzymes responsible for their synthesis and degradation (fatty acid amide hydrolase and monoacylglycerol lipase), the manipulation of which through agonists and antagonists of the system, shows a potential therapeutic role for ECS in inflammatory bowel disease. This review summarizes the role of ECS components on intestinal inflammation, suggesting the advantages of cannabinoid-based therapies in inflammatory bowel disease.

Influence of the selenium level on overall survival in lung cancer.

BACKGROUND: Although the results of studies in populations with low selenium status indicate an inverse correlation between body selenium levels and the risk of the lung cancer, the effect of this microelement on survival has not been studied. MATERIALS AND METHODS: We performed a prospective study of 302 patients diagnosed with lung cancer in Szczecin, Poland. Selenium concentration in serum was measured at the time of diagnosis and before treatment. All patients were followed for a maximum of 80 months or until death. Vital status was obtained from the Polish National Death Registry. RESULTS: Using Cox proportional hazard analysis, performed for all individuals with lung cancer, the hazard ratio (HR) for death from all causes was 1.25 (95% CI: 0.86-1.83, P = 0.99) for patients in the lowest tertile compared to those in the highest tertile of serum selenium levels. Among the patients with stage I disease this relationship was significant (HR-2.73; P = 0.01) for selenium level in tertile 1 (<57 µg/L) compared to tertile 3 (>69 µg/L, reference). The 80 months crude survival after diagnosis was 79.5% (95% CI: 68.5-92.4%) for individuals in the highest tertile and 58.1% (95% CI: 45.1-74.9%) for individuals in the lowest tertile with stage I lung cancer. CONCLUSION: These results suggest that in patients undergoing treatment for stage I lung cancer, serum selenium levels at the time of diagnosis (>69 µg/L) may be associated with improved overall survival.

A Common Variant at the 14q32 Endometrial Cancer Risk Locus Activates AKT1 through YY1 Binding.

A recent meta-analysis of multiple genome-wide association and follow-up endometrial cancer case-control datasets identified a novel genetic risk locus for this disease at chromosome 14q32.33. To prioritize the functional SNP(s) and target gene(s) at this locus, we employed an in silico fine-mapping approach using genotyped and imputed SNP data for 6,608 endometrial cancer cases and 37,925 controls of European ancestry. Association and functional analyses provide evidence that the best candidate causal SNP is rs2494737. Multiple experimental analyses show that SNP rs2494737 maps to a silencer element located within AKT1, a member of the PI3K/AKT/MTOR intracellular signaling pathway activated in endometrial tumors. The rs2494737 risk A allele creates a YY1 transcription factor-binding site and abrogates the silencer activity in luciferase assays, an effect mimicked by transfection of YY1 siRNA. Our findings suggest YY1 is a positive regulator of AKT1, mediating the stimulatory effects of rs2494737 increasing endometrial cancer risk. Identification of an endometrial cancer risk allele within a member of the PI3K/AKT signaling pathway, more commonly activated in tumors by somatic alterations, raises the possibility that well tolerated inhibitors targeting this pathway could be candidates for evaluation as chemopreventive agents in individuals at high risk of developing endometrial cancer.

Serum Concentrations of Selenium and Copper in Patients Diagnosed with Pancreatic Cancer.

PURPOSE: Understanding of the etiology and pathogenesis of pancreatic cancer (PaCa) is still insufficient. This study evaluated the associations between concentrations of selenium (Se) and copper (Cu) in the serum of PaCa patients. MATERIALS AND METHODS: The study included 100 PaCa patients and 100 control subjects from the same geographical region in Poland. To determine the average concentration of Se, Cu, and ratio Cu:Se in the Polish population, assay for Se and Cu was performed in 480 healthy individuals. Serum levels of Se and Cu were measured using inductively coupled plasma mass spectrometry. RESULTS: In the control group, the average Se level was 76 µg/L and Cu 1,098 µg/L. The average Se level among PaCa patients was 60 µg/L and the mean Cu level was 1,432 µg/L. The threshold point at which any decrease in Se concentration was associated with PaCa was 67.45 µg/L. The threshold point of Cu level above which there was an increase in the prevalence of PaCa was 1,214.58 µg/L. In addition, a positive relationship was observed between increasing survival time and Se plasma level. CONCLUSION: This retrospective study suggests that low levels of Se and high levels of Cu might influence development of PaCa and that higher levels of Se are associated with longer survival in patients with PaCa. The results suggest that determining the level of Se and Cu could be incorporated into a risk stratification scheme for the selection and surveillance control examination to complement existing screening and diagnostic procedures.

Folate pathway gene polymorphisms and risk of childhood brain tumors: results from an Australian case-control study.

BACKGROUND: Recent research suggests that maternal folic acid supplementation is associated with a reduced risk of childhood brain tumors (CBT); polymorphisms in folate pathway genes could modify this association or directly influence CBT risk. METHODS: Associations between risk of CBT and folate pathway polymorphisms were investigated in a population-based case-control study in Australia (2005-2010). Cases were recruited through all Australian pediatric oncology centers and controls by national random digit dialing. Data were available from 321 cases and 552 controls. Six polymorphisms were genotyped in children and parents (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756A>G, MTR 5049C>A, and CBS 2199 T>C). Maternal folic acid use was ascertained via questionnaire. ORs were estimated using unconditional logistic regression. Case-parent trio analyses were also undertaken. RESULTS: There was weak evidence of a reduced risk of CBT for the MTRR 66GG genotype in the child or father: ORs 0.71 [95% confidence interval (CI), 0.48-1.07]; 0.54 (95% CI, 0.34-0.87), respectively. Maternal prepregnancy folic acid supplementation showed a stronger negative association with CBT risk where the child, mother, or father had the MTRR 66GG genotype (Pinteraction = 0.07, 0.10, and 0.18, respectively). CONCLUSIONS: Evidence for an association between folate pathway genotypes and CBT is limited in this study. There was possible protection by the MTRR 66GG genotype, particularly when combined with maternal prepregnancy folic acid supplementation; these results are novel and require replication. IMPACT: The possible interaction between folic acid supplementation and MTRR 66A>G, if confirmed, would strengthen evidence for prepregnancy folate protection against CBT.

Folate pathway gene polymorphisms, maternal folic acid use, and risk of childhood acute lymphoblastic leukemia.

BACKGROUND: Several studies suggest that maternal folic acid supplementation before or during pregnancy protects against childhood acute lymphoblastic leukemia (ALL). We investigated associations between ALL risk and folate pathway gene polymorphisms, and their modification by maternal folic acid supplements, in a population-based case-control study (2003-2007). METHODS: All Australian pediatric oncology centers provided cases; controls were recruited by national random digit dialing. Data from 392 cases and 535 controls were included. Seven folate pathway gene polymorphisms (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756 A>G, MTR 5049 C>A, CBS 844 Ins68, and CBS 2199 T>C) were genotyped in children and their parents. Information on prepregnancy maternal folic acid supplement use was collected. ORs were estimated with unconditional logistic regression adjusted for frequency-matched variables and potential confounders. Case-parent trios were also analyzed. RESULTS: There was some evidence of a reduced risk of ALL among children who had, or whose father had, the MTRR 66GG genotype: ORs 0.60 [95% confidence interval (CI) 0.39-0.91] and 0.64 (95% CI, 0.40-1.03), respectively. The ORs for paternal MTHFR 677CT and TT genotypes were 1.41 (95% CI, 1.02-1.93) and 1.81 (95% CI, 1.06-3.07). ORs varied little by maternal folic acid supplementation. CONCLUSIONS: Some folate pathway gene polymorphisms in the child or a parent may influence ALL risk. While biologically plausible, underlying mechanisms for these associations need further elucidation. IMPACT: Folate pathway polymorphisms may be related to risk of childhood ALL, but larger studies are needed for conclusive results.

Confirmation of childhood acute lymphoblastic leukemia variants, ARID5B and IKZF1, and interaction with parental environmental exposures.

Genome wide association studies (GWAS) have established association of ARID5B and IKZF1 variants with childhood acute lymphoblastic leukemia (ALL). Epidemiological studies suggest that environmental factors alone appear to make a relatively minor contribution to disease risk. The polygenic nature of childhood ALL predisposition together with the timing of environmental triggers may hold vital clues for disease etiology. This study presents results from an Australian GWAS of childhood ALL cases (n = 358) and population controls (n = 1192). Furthermore, we utilised family trio (n = 204) genotypes to extend our investigation to gene-environment interaction of significant loci with parental exposures before conception, and child's sex and age. Thirteen SNPs achieved genome wide significance in the population based case/control analysis; ten annotated to ARID5B and three to IKZF1. The most significant SNPs in these regions were ARID5B rs4245595 (OR 1.63, CI 1.38-1.93, P = 2.13×10(-9)), and IKZF1 rs1110701 (OR 1.69, CI 1.42-2.02, p = 7.26×10(-9)). There was evidence of gene-environment interaction for risk genotype at IKZF1, whereby an apparently stronger genetic effect was observed if the mother took folic acid or if the father did not smoke prior to pregnancy (respective interaction P-values: 0.04, 0.05). There were no interactions of risk genotypes with age or sex (P-values >0.2). Our results evidence that interaction of genetic variants and environmental exposures may further alter risk of childhood ALL however, investigation in a larger population is required. If interaction of folic acid supplementation and IKZF1 variants holds, it may be useful to quantify folate levels prior to initiating use of folic acid supplements.

Maternal dietary intake of folate and vitamins B6 and B12 during pregnancy and risk of childhood brain tumors.

Childhood brain tumors (CBT) are the second most common childhood cancers, yet their etiology is largely unknown. We investigated whether maternal gestational intake of folate and vitamins B6 and B12 was associated with CBT risk in a nationwide case-control study conducted 2005-2010. Case children 0-14 years were recruited from all 10 Australian pediatric oncology centers. Control children were recruited by national random digit dialing, frequency matched to cases on age, sex, and state of residence. Dietary intake was ascertained using food frequency questionnaires and adjusted for total energy intake. Data from 293 case and 726 control mothers were analyzed using unconditional logistic regression. The odds ratio (OR) for the highest versus lowest tertile of folate intake was 0.70 [95% confidence interval (CI): 0.48, 1.02]. The ORs appeared lower in mothers who drank alcohol during pregnancy (OR = 0.45, 95% CI: 0.22, 0.93), mothers who took folic acid (OR = 0.67, 95% CI: 0.42, 1.06) or B6/B12 supplements (OR = 0.51, 95% CI: 0.25, 1.06) and in children younger than 5 years (OR = 0.50, 95% CI: 0.27, 0.93). These findings are consistent with folate's crucial role in maintenance of genomic integrity and DNA methylation. Dietary intake of B6 and B12 was not associated with risk of CBT.

Can selenium levels act as a marker of colorectal cancer risk?

BACKGROUND: Selenium has attracted attention because of its antioxidant properties. Antioxidants protects cells from damage. Certain breakdown products of selenium are believed to prevent tumor growth by enhancing the immune cell activity and suppressing the development of tumor blood vessels. In this observational study, selenium level was measured in a series of patients from Poland and Estonia to determine a correlation between levels of this microelement and colorectal cancer risk. METHODS: A total of 169 colorectal cancer patients and 169 healthy controls were enrolled in the study after obtaining their informed consent. Selenium level in the blood serum was measured using Graphite Furnace Atomic Absorption Spectrometry (GFAAS). The statistical analysis was performed by Fisher's exact test. RESULTS: The threshold point of selenium level was 55 µg/l and 65 µg/l for Poland and Estonia respectively, for an increase in cancer risk. The lower levels of selenium were associated with greater risk of colorectal cancer. CONCLUSIONS: The result reveals a significant strong association between low selenium level and the colorectal cancer risk in both Estonian and Polish populations.

Maternal use of folic acid and other supplements and risk of childhood brain tumors.

BACKGROUND: Interest in a possible protective effect of maternal vitamin use before or during pregnancy against childhood brain tumors (CBT) and other childhood cancers has grown over the past decade. Our Australian study of CBTs, conducted between 2005 and 2011, investigated whether maternal use folic acid and other supplements was protective. METHODS: Case children were identified through the 10 Australian pediatric oncology centers and controls were recruited by national random digit dialing. Mothers of 327 cases and 867 control children provided information on supplement use before and during the index pregnancy, including brand name, dose, and timing. Data were analyzed using multivariable unconditional logistic regression. RESULTS: The OR for any maternal use of folic acid, use of folic acid without iron or vitamins B6, B12, C, or A, and any vitamin use before pregnancy, were: 0.68 [95% confidence interval (CI), 0.46-1.00; 0.55 (95% CI, 0.32-0.93) and 0.68 (95% CI, 0.46-1.01), respectively. The ORs for use of these supplements during pregnancy were also below unity, but generally closer to the null than those for the prepregnancy period. There was some evidence of an inverse dose-response during each time period. CONCLUSIONS: These results suggest that folic acid supplements before and possibly during pregnancy may protect against CBT. Such associations are biologically plausible through established mechanisms. IMPACT: This study provides evidence of a specific protective effect of prenatal folic acid supplementation against the risk of CBT that is not attributable to the actions of the other micronutrients investigated.

Brain transcriptome perturbations in the Hfe(-/-) mouse model of genetic iron loading.

Severe disruption of brain iron homeostasis can cause fatal neurodegenerative disease, however debate surrounds the neurologic effects of milder, more common iron loading disorders such as hereditary hemochromatosis, which is usually caused by loss-of-function polymorphisms in the HFE gene. There is evidence from both human and animal studies that HFE gene variants may affect brain function and modify risks of brain disease. To investigate how disruption of HFE influences brain transcript levels, we used microarray and real-time reverse transcription polymerase chain reaction to assess the brain transcriptome in Hfe(-/-) mice relative to wildtype AKR controls (age 10 weeks, n≥4/group). The Hfe(-/-) mouse brain showed numerous significant changes in transcript levels (p<0.05) although few of these related to proteins directly involved in iron homeostasis. There were robust changes of at least 2-fold in levels of transcripts for prominent genes relating to transcriptional regulation (FBJ osteosarcoma oncogene Fos, early growth response genes), neurotransmission (glutamate NMDA receptor Grin1, GABA receptor Gabbr1) and synaptic plasticity and memory (calcium/calmodulin-dependent protein kinase IIα Camk2a). As previously reported for dietary iron-supplemented mice, there were altered levels of transcripts for genes linked to neuronal ceroid lipofuscinosis, a disease characterized by excessive lipofuscin deposition. Labile iron is known to enhance lipofuscin generation which may accelerate brain aging. The findings provide evidence that iron loading disorders can considerably perturb levels of transcripts for genes essential for normal brain function and may help explain some of the neurologic signs and symptoms reported in hemochromatosis patients.

Maternal consumption of coffee and tea during pregnancy and risk of childhood ALL: results from an Australian case-control study.

OBJECTIVES: To investigate whether maternal coffee and/or tea consumption during the last 6 months of pregnancy was associated with risk of childhood ALL. METHODS: Data on coffee and tea drinking during pregnancy from 337 case mothers and 697 control mothers were analyzed using unconditional multivariable logistic regression. A meta-analysis of our findings with those of previous studies was also conducted. RESULTS: There was little evidence of an overall association between maternal coffee consumption and risk of ALL: OR 0.89 (95% CI 0.61, 1.30), although there was some suggestion that higher levels of intake might increase the risk in children of non-smoking mothers: OR for 2+ cups/day = 1.44 (95% CI 0.85, 2.42); this was supported by our meta-analysis. Risk was also elevated among cases with chromosomal translocations. The overall OR for maternal tea consumption was 0.82 (95% CI 0.56, 1.18), although the OR for T-cell ALL was 0.21 (95% CI 0.08, 0.51). Among ALL cases with translocations, the ORs for tea consumption tended to be elevated: OR = 1.70 (95% CI 0.79-3.68) for 2+ cups/day. CONCLUSIONS: The observed increased risk associated with coffee and tea consumption may be confined to ALL with translocations. These associations should be explored further in large international consortia.

Maternal folate and other vitamin supplementation during pregnancy and risk of acute lymphoblastic leukemia in the offspring.

The Australian Study of Causes of Acute Lymphoblastic Leukemia in Children (Aus-ALL) was designed to test the hypothesis, raised by a previous Western Australian study, that maternal folic acid supplementation during pregnancy might reduce the risk of childhood acute lymphoblastic leukemia (ALL). Aus-ALL was a national, population-based, multicenter case-control study that prospectively recruited 416 cases and 1,361 controls between 2003 and 2007. Detailed information was collected about maternal use of folic acid and other vitamin supplements before and during the index pregnancy. Data were analyzed using logistic regression, adjusting for matching factors and potential confounders. A meta-analysis with the results of previous studies of folic acid supplementation was also conducted. We found weak evidence of a protective effect of maternal folate supplementation before pregnancy against risk of childhood ALL, but no evidence for a protective effect of its use during pregnancy. A meta-analysis including this and 2 other studies, but not the study that raised the hypothesis, also found little evidence that folate supplementation during pregnancy protects against ALL: the summary odds ratios (ORs) for folate supplementation were 1.06 [95% confidence interval (CI): 0.77-1.48] with reference to no folate supplementation and 1.02 (95% CI: 0.86-1.20) with reference to no vitamin supplementation. For vitamin supplementation in general, the summary OR from a meta-analysis of 5 studies-including Aus-ALL-was 0.83 (95% CI: 0.73-0.94). Vitamin supplementation in pregnancy may protect against childhood ALL, but this effect is unlikely to be large or, if real, specifically due to folate.