DNA repair: the culprit for tumor-initiating cell survival?

The existence of “tumor-initiating cells” (TICs) has been a topic of heated debate for the last few years within the field of cancer biology. Their continuous characterization in a variety of solid tumors has led to an abundance of evidence supporting their existence. TICs are believed to be responsible for resistance against conventional treatment regimes of chemotherapy and radiation, ultimately leading to metastasis and patient demise. This review summarizes DNA repair mechanism(s) and their role in the maintenance and regulation of stem cells. There is evidence supporting the hypothesis that TICs, similar to embryonic stem (ES) cells and hematopoietic stem cells (HSCs), display an increase in their ability to survive genotoxic stress and injury. Mechanistically, the ability of ES cells, HSCs and TICs to survive under stressful conditions can be attributed to an increase in the efficiency at which these cells undergo DNA repair. Furthermore, the data presented in this review summarize the results found by our lab and others demonstrating that TICs have an increase in their genomic stability, which can allow for TIC survival under conditions such as anticancer treatments, while the bulk population of tumor cells dies. We believe that these data will greatly impact the development and design of future therapies being engineered to target and eradicate this highly aggressive cancer cell population

The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10−8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution

Attributable risk and potential impact of interventions to reduce household air pollution associated with under-five mortality in South Asia

Abstract Background Solid fuel use is the major source of household air pollution (HAP) and accounts for a substantial burden of morbidity and mortality in low and middle income countries. To evaluate and compare childhood mortality attributable to HAP in four South Asian countries. Methods A series of Demographic and Health Survey (DHS) datasets for Bangladesh, India, Nepal and Pakistan were used for analysis. Estimates of relative risk and exposure prevalence relating to use of cooking fuel and under-five mortality were used to calculate population attributable fractions (PAFs) for each country. Potential impact fractions (PIFs) were also calculated assessing theoretical scenarios based on published interventions aiming to reduce exposure prevalence. Results There are an increased risk of under-five mortality in those exposed to cooking fuel compared to those not exposed in the four South Asian countries (OR = 1.30, 95% CI = 1.07–1.57, P = 0.007). Combined PAF estimates for South Asia found that 66% (95% CI: 43.1–81.5%) of the 13,290 estimated cases of under-five mortality was attributable to HAP. Joint PIF estimates (assuming achievable reductions in HAP reported in intervention studies conducted in South Asia) indicates 47% of neonatal and 43% of under-five mortality cases associated with HAP could be avoidable in the four South Asian countries studied. Conclusions Elimination of exposure to use of cooking fuel in the household targeting valuable intervention strategies (such as cooking in separate kitchen, improved cook stoves) could reduce substantially under-five mortality in South Asian countries

LIG4 mediates Wnt signalling-induced radioresistance

Despite the implication of Wnt signalling in radioresistance, the underlying mechanisms are unknown. Here we find that high Wnt signalling is associated with radioresistance in colorectal cancer (CRC) cells and intestinal stem cells (ISCs). We find that LIG4, a DNA ligase in DNA double-strand break repair, is a direct target of β-catenin. Wnt signalling enhances non-homologous end-joining repair in CRC, which is mediated by LIG4 transactivated by β-catenin. During radiation-induced intestinal regeneration, LIG4 mainly expressed in the crypts is conditionally upregulated in ISCs, accompanied by Wnt/β-catenin signalling activation. Importantly, among the DNA repair genes, LIG4 is highly upregulated in human CRC cells, in correlation with β-catenin hyperactivation. Furthermore, blocking LIG4 sensitizes CRC cells to radiation. Our results reveal the molecular mechanism of Wnt signalling-induced radioresistance in CRC and ISCs, and further unveils the unexpected convergence between Wnt signalling and DNA repair pathways in tumorigenesis and tissue regeneration