Aflatoxin Exposure during Early Life Is Associated with Differential DNA Methylation in Two-Year-Old Gambian Children

Background: DNA methylation is an epigenetic control mechanism that may be altered by environmental exposures. We have previously reported that in utero exposure to the mycotoxin and liver carcinogen aflatoxin B1 from the maternal diet, as measured using biomarkers in the mothers’ blood, was associated with differential DNA methylation in white blood cells of 6-month-old infants from The Gambia. Methods: Here we examined aflatoxin B1-associated differential DNA methylation in white blood cells of 24-month-old children from the same population (n = 244), in relation to the child’s dietary exposure assessed using aflatoxin albumin biomarkers in blood samples collected at 6, 12 and 18 months of age. HM450 BeadChip arrays were used to assess DNA methylation, with data compared to aflatoxin albumin adduct levels using two approaches; a continuous model comparing aflatoxin adducts measured in samples collected at 18 months to DNA methylation at 24 months, and a categorical time-dose model that took into account aflatoxin adduct levels at 6, 12 and 18 months, for comparison to DNA methylation at 24 months. Results: Geometric mean (95% confidence intervals) for aflatoxin albumin levels were 3.78 (3.29, 4.34) at 6 months, 25.1 (21.67, 29.13) at 12 months and 49.48 (43.34, 56.49) at 18 months of age. A number of differentially methylated CpG positions and regions were associated with aflatoxin exposure, some of which affected gene expression. Pathway analysis highlighted effects on genes involved with with inflammatory, signalling and growth pathways. Conclusions: This study provides further evidence that exposure to aflatoxin in early childhood may impact on DNA methylation

DNA methylome analysis identifies accelerated epigenetic aging associated with postmenopausal breast cancer susceptibility

Aim of the study A vast majority of human malignancies are associated with ageing, and age is a strong predictor of cancer risk. Recently, DNA methylation-based marker of ageing, known as ‘epigenetic clock’, has been linked with cancer risk factors. This study aimed to evaluate whether the epigenetic clock is associated with breast cancer risk susceptibility and to identify potential epigenetics-based biomarkers for risk stratification. Methods Here, we profiled DNA methylation changes in a nested case–control study embedded in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (n = 960) using the Illumina HumanMethylation 450K BeadChip arrays and used the Horvath age estimation method to calculate epigenetic age for these samples. Intrinsic epigenetic age acceleration (IEAA) was estimated as the residuals by regressing epigenetic age on chronological age. Results We observed an association between IEAA and breast cancer risk (OR, 1.04; 95% CI, 1.007–1.076, P = 0.016). One unit increase in IEAA was associated with a 4% increased odds of developing breast cancer (OR, 1.04; 95% CI, 1.007–1.076). Stratified analysis based on menopausal status revealed that IEAA was associated with development of postmenopausal breast cancers (OR, 1.07; 95% CI, 1.020–1.11, P = 0.003). In addition, methylome-wide analyses revealed that a higher mean DNA methylation at cytosine-phosphate-guanine (CpG) islands was associated with increased risk of breast cancer development (OR per 1 SD = 1.20; 95 %CI: 1.03–1.40, P = 0.02) whereas mean methylation levels at non-island CpGs were indistinguishable between cancer cases and controls. Conclusion Epigenetic age acceleration and CpG island methylation have a weak, but statistically significant, association with breast cancer susceptibility

Effect of wearing a helmet on the occurrence of head injuries in motorcycle riders in Benin: a case-control study

BACKGROUND: In Benin, motorcycles are the main means of transport for road users and are involved in more than half of crashes. This study aims to determine the effect of wearing a helmet on reducing head injuries in road crashes in Benin. METHODS: This case-control study took place in 2020 and focused on road trauma victims. The sample, consisting of 242 cases (trauma victims with head injuries) for 484 controls (without head injuries), was drawn from a database of traffic crash victims recruited from five hospitals across the country from July 2019 to January 2020. Four groups of independent variables were studied: socio-demographic and economic variables, history, behavioural variables including helmet use and road-related and environmental variables. To assess the shape of the association between the independent variables and the dependent variable, a descending step-by-step binary logistic regression model was performed using an explanatory approach. RESULTS: Fewer of the subjects with a head injury were wearing a helmet at the time of the crash 69.8% (95% CI = 63.6-75.6) compared to those without a head injury 90.3% (95% CI = 87.3-92.8). Adjusting for the other variables, subjects not wearing helmets were at greater risk of head injuries (OR = 3.8, 95% CI (2.5-5.7)); the head injury rating was 1.9 (95% CI = 1.2-3.3) times higher in subjects who were fatigued during the crash than among those who were not and 2.0 (95% CI = 1.2-3.3) times higher in subjects with no medical history. CONCLUSION: Failure to wear a helmet exposes motorcyclists to the risk of head injuries during crashes. It is important to increase awareness and better target such initiatives at the subjects most at risk

Doctor can I buy a new kidney? I've heard it isn't forbidden: what is the role of the nephrologist when dealing with a patient who wants to buy a kidney?

Organ trafficking is officially banned in several countries and by the main Nephrology Societies. However, this practice is widespread and is allowed or tolerated in many countries, hence, in the absence of a universal law, the caregiver may be asked for advice, placing him/her in a difficult balance between legal aspects, moral principles and ethical judgments. In spite of the Istanbul declaration, which is a widely shared position statement against organ trafficking, the controversy on mercenary organ donation is still open and some experts argue against taking a negative stance. In the absence of clear evidence showing the clinical disadvantages of mercenary transplantation compared to chronic dialysis, self-determination of the patient (and, with several caveats, of the donor) may conflict with other ethical principles, first of all non-maleficence. The present paper was drawn up with the participation of the students, as part of the ethics course at our medical school. It discusses the situation in which the physician acts as a counselor for the patient in the way of a sort of “reverse” informed consent, in which the patient asks advice regarding a complex personal decision, and includes a peculiar application of the four principles (beneficence, non-maleficence, justice and autonomy) to the donor and recipient parties

Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer1,2. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease3,4, rapid transformation to acute myeloid leukemia (AML)5, resistance to conventional therapies6–8 and dismal outcomes9. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations10. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R)11. Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response

Excess risk of death increases with time from first dialysis for patients on the waiting list: implications for renal allograft allocation policy

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Subgroups of patients registered on a kidney transplant waiting list have higher than usual mortality levels. This study used data from the French Renal Epidemiology and Information Network (REIN) Registry to quantify the impact over time of various comorbidities on the excess risk of death among patients on the waiting list. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Lexis diagrams were used to analyze time since onset of end-stage renal disease and time since registration on the waiting list. The number of excess deaths was calculated by comparison with the number of expected deaths in the general population of the same age and sex. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; During 45,013 person-years of follow-up, 7,224 patients died, 5,956 (82%) more than expected relative to the general population. There were 101 deaths among wait-listed dialysis patients, 76 more than expected. The excess risk of death increased by 45% per additional year on the waiting list (18-79%, p = 0.0005). Time from end-stage renal disease onset until list registration (p = 0.004), time since registration (p &lt; 0.001), age &gt;65 years (p = 0.008), the presence of a primary renal disease (p = 0.028), and the number of comorbidities (p = 0.035) were independent predictors of death while on the waiting list. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; The excess risk of death while on the waiting list increased faster in patients with comorbidities. These results require consideration of ways to accelerate access to transplantation in high-risk patients.</jats:p

Large-scale genome-wide screening of circulating microRNAs in clear cell renal cell carcinoma reveals specific signatures in late-stage disease

Circulating miRNAs have shown great promises as noninvasive diagnostic and predictive biomarkers in several solid tumors. While the miRNA profiles of renal tumors have been extensively explored, knowledge of their circulating counterparts is limited. Our study aimed to provide a large-scale genome-wide profiling of plasma circulating miRNA in clear-cell renal cell carcinoma (ccRCC). Plasma samples from 94 ccRCC cases and 100 controls were screened for 754 circulating micro-RNAs (miRNA) by TaqMan arrays. Analyses including known risk factors for renal cancer—namely, age, sex, hypertension, obesity, diabetes, tobacco smoking and alcohol consumption—highlighted that circulating miRNA profiles were tightly correlated with the stage of the disease. Advanced tumors, characterized as stage III and IV, were associated with specific miRNA signatures that significantly differ from both controls and earlier stage ccRCC cases. Molecular pathway enrichment analyses of their gene targets showed high similarities with alterations observed in renal tumors. Plasma circulating levels of miR-150 were significantly associated with RCC-specific survival and could marginally improve the predictive accuracy of clinical parameters in our series, including age at diagnosis, sex and conventional staging. In summary, our results suggest that circulating miRNAs may provide insights into renal cell carcinoma progression

Epigenetic remodelling of enhancers in response to estrogen deprivation and re-stimulation.

Estrogen hormones are implicated in a majority of breast cancers and estrogen receptor alpha (ER), the main nuclear factor mediating estrogen signaling, orchestrates a complex molecular circuitry that is not yet fully elucidated. Here, we investigated genome-wide DNA methylation, histone acetylation and transcription after estradiol (E2) deprivation and re-stimulation to better characterize the ability of ER to coordinate gene regulation. We found that E2 deprivation mostly resulted in DNA hypermethylation and histone deacetylation in enhancers. Transcriptome analysis revealed that E2 deprivation leads to a global down-regulation in gene expression, and more specifically of TET2 demethylase that may be involved in the DNA hypermethylation following short-term E2 deprivation. Further enrichment analysis of transcription factor (TF) binding and motif occurrence highlights the importance of ER connection mainly with two partner TF families, AP-1 and FOX. These interactions take place in the proximity of E2 deprivation-mediated differentially methylated and histone acetylated enhancers. Finally, while most deprivation-dependent epigenetic changes were reversed following E2 re-stimulation, DNA hypermethylation and H3K27 deacetylation at certain enhancers were partially retained. Overall, these results show that inactivation of ER mediates rapid and mostly reversible epigenetic changes at enhancers, and bring new insight into early events, which may ultimately lead to endocrine resistance