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The identification of somatic driver mutations in cancer has enabled therapeutic advances by identifying drug targets critical to disease causation. However, such genomic discoveries in oncology have not translated into advances for non-cancerous disease since point mutations in a single cell would be unlikely to cause non-malignant disease. An exception to this would occur if the mutation happened early enough in development to be present in a large percentage of a tissue's cellular population. We sought to identify the existence of somatic mutations occurring early in human development by ascertaining base-pair mutations present in one of a pair of monozygotic twins, but absent from the other and assessing evidence for mosaicism. To do so, we genome-wide genotyped 66 apparently healthy monozygotic adult twins at 506 786 high-quality single nucleotide polymorphisms (SNPs) in white blood cells. Discrepant SNPs were verified by Sanger sequencing and a selected subset was tested for mosaicism by targeted high-depth next-generation sequencing (20 000-fold coverage) as a surrogate marker of timing of the mutation. Two de novo somatic mutations were unequivocally confirmed to be present in white blood cells, resulting in a frequency of 1.2×10(-7) mutations per nucleotide. There was little evidence of mosaicism on high-depth next-generation sequencing, suggesting that these mutations occurred early in embryonic development. These findings provide direct evidence that early somatic point mutations do occur and can lead to differences in genomes between otherwise identical twins, suggesting a considerable burden of somatic mutations among the trillions of mitoses that occur over the human lifespan.

The high prevalence and heavy socioeconomic burden for caries of first permanent molars (FPMs) make the prevention of this disease a major public health goal. Current guidelines recommend a preference of fissure sealant (FS) over fluoride varnish (FV) based on two recent systematic reviews. However, evidences of these two studies are weak because of scarce data and some limitations. Besides, an upto-date large scale randomized controlled trial (RCT) reported commensurate effectiveness of these two techniques. Thus, in order to more accurately compare the clinical efficacy between FS and FV on caries prevention for FPMs, we carried out this systematic review and meta-analysis. A total of 8 RCTs involving 3289 participants and 6878 FPMs fulfilled the inclusion criteria. Our meta-analysis for the first time showed that there was no statistical difference on caries incidence or occlusal DMFS increment between sealant group and fluoride varnish group at 2~3 years' follow-up. In that sense, biannual applications of FV or FS may be equally effective on caries prevention for FPMs. These results do not support routine recommendation of FS over FV, thus shedding light on current conceptions. Our findings endow clinicians with a window to reconsider the choice between these two techniques. Caries is one of the most prevalent chronic diseases worldwide 1-5. Approximately 2.4 billion people, accounting for 35% of the world population, are affected by untreated caries 1,2. Though enormous public resources have been poured into caries prevention, the global prevalence of untreated caries remained stagnant during the last decades 1. Untreated caries can be much burdensome socioeconomically 3-5. The economic loss thereof amounts to hundreds of billions of dollars every year 3. As a matter of fact, the high prevalence associated with heavy disease burden make caries prevention a major public health goal. First permanent molars (FPMs) are of great significance to caries prevention 6,7. Decay of FPMs constitutes the biggest component of decayed missing filled tooth index (DMFT) among children and adolescents 8,9. As well as being highly prevalent, caries of FPMs also imposes an overwhelming disease burden. FPMs are the keys to establish permanent occlusion 10. Severe FPMs caries often cause pain and infection, diminished dietary intake and malocclusion 1,8-10. At present, two techniques, namely fluoride varnish (FV) and fissure sealant (FS), are introduced to prevent caries of FPMs, both proved effective 11,12. However, it still cannot be concluded clearly which of these two skills is clinically superior. Current practice guidelines recommend a preference for FS over FV 6,7. This recommendation was supported by two very recent systematic reviews. Meta-analysis of them favored FS rather than FV with statistical significance 6,7. But the evidences of these two studies were assessed as weak (Details of their limitations will be identified and discussed below). Besides, a large-scale, high-qualified RCT updated recently showed that ther...

The pulpotomy with pulp capping is aimed at retaining vital pulp with reparative dentin formation. Vascular endothelial growth factor (VEGF) plays a crucial role in dentin regeneration; however, its constant administrations in the human body is still problematic. Chitosan was widely studied as an effective carrier to deliver bioactive molecules in regenerative medicine. In this study, we conducted a chitosan/β-glycerophosphate (CS/β-GP) hydrogel as a VEGF-sustained release system and explored its effects on dental pulp stem cells (DPSCs). CS/β-GP hydrogel was manufactured using a sol-gel method. SEM assay showed the spongy and porous microstructure of the lyophilized hydrogels. DPSCs cultured in the CS/β-GP hydrogel kept adhesion and vitality. CCK-8 assay tested the promoted proliferation activity of DPSCs on the hydrogel. Besides, the added VEGF protein could continually release from VEGF/CS/β-GP hydrogel. The VEGF/CS/β-GP hydrogel could promote the odontogenic differentiation of DPSCs better than VEGF treatment without hydrogel. Our results suggested that CS/β-GP hydrogel could continually release VEGF and contribute to odontogenic differentiation of DPSCs, thus may become a potential carrier of bioactive molecules in pulp capping therapy.

Background The current randomized, controlled, multicenter clinical trial was conducted to investigate the efficacy of concurrent neoadjuvant chemotherapy (NCT) and estrogen deprivation in patients with estrogen receptor (ER)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. Methods Eligible patients with AJCC stage IIB to stage IIIC, ER‐positive, HER2‐negative breast cancer were enrolled and randomly assigned to receive NCT with or without estrogen deprivation. The primary endpoint was the objective response rate (ORR). Results A total of 249 patients were assigned to either neoadjuvant chemoendocrine therapy (NCET) (125 patients) or the NCT group (124 patients). In the intention‐to‐treat analysis, the ORR was found to be significantly higher in the NCET group compared with the NCT group (84.8% vs 72.6%; odds ratio, 2.11 [95% CI, 1.13‐3.95; P = .02). The efficacy of NCET was more prominent in tumors with a higher Ki‐67 index (>20%), with an ORR of 91.2% reported in the NCET group versus 68.7% in the NCT group (P = .001). The pathologic complete response and pathological response rates did not differ significantly between the 2 groups. Although there was no significant difference with regard to progression‐free survival (PFS) between the 2 groups (P = .188), patients with a higher baseline Ki‐67 index appeared to derive a greater PFS benefit from NCET (2‐year PFS rate of 91.5% in the NCET group vs 76.5% in the NCT group; P = .058). Adding endocrine agents to NCT did not result in significant differences in adverse events (grade 3 or 4; graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) between the 2 groups. Conclusions The addition of estrogen deprivation to NCT appears to improve the clinical response in patients with ER‐positive, HER2‐negative breast cancer, especially for those individuals with a higher Ki‐67 index. Patients with a higher Ki‐67 index might derive more PFS benefit from concurrent neoadjuvant treatment.

Beyond energy production, nutrient metabolism plays a crucial role in stem cell lineage determination. Changes in metabolism based on nutrient availability and dietary habits impact stem cell identity. Evidence suggests a strong link between metabolism and epigenetic mechanisms occurring during embryonic development and later life of offspring. Metabolism regulates epigenetic mechanisms such as modifications of DNA, histones, and microRNAs. In turn, these epigenetic mechanisms regulate metabolic pathways to modify the metabolome. One-carbon metabolism (OCM) is a crucial metabolic process involving transfer of the methyl groups leading to regulation of multiple cellular activities. OCM cycles and its related micronutrients are ubiquitously present in stem cells and feed into the epigenetic mechanisms. In this review, we briefly introduce the OCM process and involved micronutrients and discuss OCM-associated epigenetic modifications, including DNA methylation, histone modification, and microRNAs. We further consider the underlying OCM-mediated link between nutrition and epigenetic modifications in embryonic development.

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