Diet, Sports, and Psychological Stress as Modulators of Breast Cancer Risk: Focus on OPRM1 Methylation

Background: DNA methylation is influenced by environmental factors and contributes to adverse modification of cancer risk and clinicopathological features.Methods: A case-control study (402 newly diagnosed cases, 470 controls) was conducted to evaluate the effect of environmental factors and OPRM1 methylation in peripheral blood leukocyte (PBL) DNA on the risk of breast cancer. A case-only study (373 cases) was designed to evaluate the effects of environmental factors on OPRM1 methylation in tumor tissue and the relationship of methylation with clinicopathological features.Results: We found a significant association between hypermethylation of OPRM1 and the risk of breast cancer (OR = 1.914, 95%CI = 1.357–2.777). OPRM1 hypermethylation in PBL DNA combined with low intake of vegetable, garlic, soybean, poultry, and milk; high pork intake; less regular sports and a high psychological stress index significantly increased the risk of breast cancer. Soybean intake (OR = 0.425, 95%CI: 0.231–0.781) and regular sports (OR = 0.624, 95%CI: 0.399–0.976) were associated with OPRM1 hypermethylation in tumor DNA. OPRM1 hypermethylation in tumor tissue was correlated with estrogen receptor (ER) (OR = 1.945, 95%CI: 1.262–2.996) and progesterone receptor (PR) (OR = 1.611, 95%CI: 1.069–2.427) negative status; in addition, OPRM1 hypermethylation in PBL DNA was associated with human epidermal growth factor receptor 2 (HER-2) negative status (OR = 3.673, 95%CI: 1.411–9.564).Conclusion: A healthy diet, psychosocial adaptability, and regular sports are very beneficial for breast cancer prevention and progress, especially for OPRM1 hypermethylation carriers. Personalized treatment considering the correlation between OPRM1 hypermethylation and ER and PR status may provide a novel benefit for breast cancer patients.

Telomere Shortening linked to Disability and Mitochondrial DNA Copy Number in Patients with Relapsing-Remitting Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease that affects the nervous system. Peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-CN) are potential biomarkers of disability and neurological damage. The present work evaluated LTL and mtDNA-CN in 75 relapsing-remittent MS (RRMS) patients 50 of whom had an Expanded Disability Status Scale (EDSS) 0 to 3 (mild-moderate disability), and 25 had an EDSS of 3.5 to 7 (severe disability). Absolute LTL and absolute mtDNA-CN were measured via real-time polymerase chain reaction (qPCR). The LTL and mtDNA-CN were significantly lower in RRMS severe disability than in RRMS mild-moderate disability (3.924 ± 0.124 vs 2.854 ± 0.092, p<00001; 75.14 ± 1.77 vs 68.06 ± 1.608, p<0.00001, respectively). The LTL and mtDNA-CN showed a linear correlation in RRMS with mild-moderate disability (r=0.2986, p=0.0351). In addition, in a binary logistic regression model the LTL can predict severe disability (AUC=0.697, p=0.0031, cutoff ≤ 3.0875 Kb, sensitivity= 73.1%, specificity=62.5%), the prediction is improved by including age to the model (AUC=0.765, <0.0001, sensitivity=78.26%, specificity=81.25%). Aging is closely linked to the development of disability in RRMS and can be evaluated through LTL and mtDNA-CN absolute quantification.

Telomere Shortening linked to Disability and Mitochondrial DNA Copy Number in Patients with Relapsing-Remitting Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease that affects the nervous system. Peripheral blood leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNA-CN) are potential biomarkers of disability and neurological damage. The present work evaluated LTL and mtDNA-CN in 75 relapsing-remittent MS (RRMS) patients 50 of whom had an Expanded Disability Status Scale (EDSS) 0 to 3 (mild-moderate disability), and 25 had an EDSS of 3.5 to 7 (severe disability). Absolute LTL and absolute mtDNA-CN were measured via real-time polymerase chain reaction (qPCR). The LTL and mtDNA-CN were significantly lower in RRMS severe disability than in RRMS mild-moderate disability (3.924 ± 0.124 vs 2.854 ± 0.092, p<00001; 75.14 ± 1.77 vs 68.06 ± 1.608, p<0.00001, respectively). The LTL and mtDNA-CN showed a linear correlation in RRMS with mild-moderate disability (r=0.2986, p=0.0351). In addition, in a binary logistic regression model the LTL can predict severe disability (AUC=0.697, p=0.0031, cutoff ≤ 3.0875 Kb, sensitivity= 73.1%, specificity=62.5%), the prediction is improved by including age to the model (AUC=0.765, <0.0001, sensitivity=78.26%, specificity=81.25%). Aging is closely linked to the development of disability in RRMS and can be evaluated through LTL and mtDNA-CN absolute quantification.

FOXO3, Telomere Dynamics, and Healthy Brain Aging: A COBRE Study

Human longevity is linked to genetic, cellular, and other complex biological and psychosocial traits. Aging is typically accompanied by gradual brain atrophy and cognitive decline, but the mechanisms are unclear. Cellular aging, characterized by telomere shortening and altered telomerase activity, is related to mortality and brain aging. Decelerated brain aging is associated with greater peripheral blood leukocyte telomere length (LTL) and, we hypothesize, may be linked to FOXO3 genotype. We will use MRI to assess brain structure and function cross-sectionally in 100 Kuakini Honolulu Heart Program Offspring. Atrophy and disrupted functional connectivity, markers of brain aging, will be examined in relation to FOXO3 and LTL. Associations between brain structural and functional differences, FOXO3 genotype and LTL will be investigated over a wide range of ages, controlling for other biological and psychosocial factors. Results may provide insight into mechanisms influencing the rate of brain aging, and may eventually extend human healthspan.

Leukocyte neutrophil ratio (NLR) as biomarker for neuroinflammation in patients with intracerebral haemorrhage and traumatic brain injury

Circulating inflammatory markers may predict the broad clinical spectrum of traumatic brain injury (TBI). The present study aimed to illustrate the role of leukocytes, precisely neutrophil and lymphocytes, in neuroinflammation as a new vista in neuro-critical care. Search terms were: elevations in peripheral blood leukocytes counts, neutrophil, lymphocyte with precisely neutrophil to lymphocyte ratios, associated with adverse outcomes of traumatic brain injury, pre and post-operative conditions of intracerebral haemorrhage, seizures, delirium, non-convulsive status epilepticus, confusion, aphasia, agitation, coma, disability and death. As a result, we identified 16 publications describing leukocyte biomarkers associated with neuroinflammation following TBI from PubMed, Cochrane Registry of Controlled Trials, Medline and Embase (Ovid) on randomised controlled trials (RCTs), non-RCTs and cohort studies published in the last decade. This study concluded that elevations in peripheral blood leukocyte and neutrophil to lymphocyte ratios could predict adverse outcomes of a cerebral haemorrhage.

The Effect of Phytochemical Extracts on Cytokine Gene Expression

Background: In the last century, nutritional supplements have shown a wide spectrum of biochemical effects, most notably about immunomodulation and countering inflammation. Objective: This study investigates the impact of phytochemical compounds that are present in different quantities of pomegranate, grape seeds and garlic extracts on the expression of inflammatory (IL1β and IL6) and anti-inflammatory (IL10) genes, the effects of polymorphisms in these genes on this response. Methods: Human peripheral blood leukocyte cultures were treated with pomegranate (1.2% or 2.4%), garlic (0.5% or 1.2%), or grape seed (1.2% or 2.4%) extracts. Gene expression was assessed with real-time polymerase chain reaction (PCR). Polymorphisms of the cytokine genes were analyzed using allele-specific PCR. Results: Pomegranate extract (2.4%) reduced the transcription of IL1β by 16-fold in comparison to control. The expression of IL6 relative to the control after the addition of grape seed extract (1.2%) was reduced by 100-fold. The grape seeds extract (1.2%) showed the effect of increasing transcription for IL10 compared to the control. The level of IL1β transcription in culture with garlic extract depends on the genotype of the cell for -31T>C polymorphism (r = 0.67 p = 0.03). There is correlation between polymorphism -174G>C and level gene expression IL6 (r=-0.66, p = 0.04) after adding grape seeds extract. Conclusion: The phytochemical compounds in pomegranate extracts and grape seed extracts play the role of anti-inflammatory by decreasing the gene expression of IL1β, IL6 and increasing the transcription of IL10.

Shorter Leukocyte Telomere Length Is Associated with Worse Survival of Patients with Bladder Cancer and Renal Cell Carcinoma

Background: Telomeres are protein–DNA complexes at the tips of linear chromosomes. They protect the DNA from end-to-end fusion and exonucleolytic degradation. Shortening of telomeric DNA during aging can generate dysfunctional telomeres, promoting tumorigenesis. More recent data indicate that both short and long telomeres of peripheral blood leukocyte (PBL) cells can serve as prognostic biomarkers for cancer risk and may be associated with survival of patients with solid cancers. Telomere length in PBL cells could also be a potential prognostic biomarker for survival in bladder cancer (BC) or renal cell carcinoma (RCC). Methods: The relative telomere length (RTL) of PBL cells was assessed in patients with BC (n = 144) and RCC (n = 144) by using qPCR. A control population of patients without malignant disease (NC, n = 73) was included for comparison. The correlation and association of RTL with histopathological parameters and overall survival (OS) were evaluated. Results: Patients with BC and RCC had significantly shorter telomeres compared to patients without malignant disease. Within the cancer cohorts, multivariate analysis revealed that short RTL is an independent predictor of worse survival in BC (p = 0.039) and RCC (p = 0.041). Conclusion: Patients with BC and RCC had significantly shorter telomeres compared to the normal population. Shorter RTL in BC and RCC was an independent predictor of reduced survival.

Are dietary factors involved in the association of CDH4 methylation and breast cancer risk?

DNA methylation is one of the most important epigenetic modifications in breast cancer (BC) development, and long-term dietary habits have been shown to alter DNA methylation. Cadherin-4 (CDH4, a member of the cadherin family) encodes Ca2+-dependent cell-cell adhesion glycoproteins. We conducted a case-control study (380 newly-diagnosed breast cancers and 439 cancer-free controls) to explore the relationship of CDH4 methylation in peripheral blood leukocyte DNA (PBL), as well as its combined and interactive effects with dietary factors and lifestyle on BC risk. A case-only study (335 newly-diagnosed breast cancers) was conducted to analyze the association between CDH4 methylation in breast tissue DNA and dietary factors. CDH4 methylation were detected using quantitative methylation specific PCR (qMSP). Unconditional logistic regressions were used to analyze the association of CDH4 methylation in PBL DNA and BC risk. Cross-over analysis and unconditional logistic regression were used to calculate the combined and interactive effects between CDH4 methylation in PBL DNA and dietary factors in BC. CDH4 hypermethylation was significantly associated with increased BC risk in PBL DNA (ORadjusted (ORadj)= 2.70, 95% confidence interval (CI)= 1.90-3.83, P<0.001). CDH4 hypermethylation also showed significant combined effects with the consumption of <500 g/week vegetables (ORadj=4.33, 95% CI=2.63-7.10), ≤3 times/week allium vegetables (ORadj=7.00, 95% CI=4.17-11.77), <3 times/week fish (ORadj=7.92, 95% CI=3.79-16.53), <3 times/week milk (ORadj=6.30, 95% CI=3.41-11.66), >3 times/week overnight food (ORadj=4.63, 95% CI=2.69-7.99), ≥250 g/week pork (ORadj=5.59, 95% CI=2.94-10.62), and <1 time/month physical activity (ORadj=4.72, 95% CI=2.87-7.76). Moreover, consuming milk ≥ 1 times/month was significantly related with decreased risk of CDH4 methylation (OR=0.61, 95% CI=0.38-0.99) in breast tissue. Our findings may provide direct guidance on the dietary intake for specific methylated carriers to decrease their risk for developing BC.