Integrative mRNA profiling comparing cultured primary cells with clinical samples reveals PLK1 and C20orf20 as therapeutic targets in cutaneous squamous cell carcinoma

This work was funded by DebRA, the dystrophic epidermolysis bullosa research association (http:// www.debra.org.uk

Maternal BMI is positively associated with human milk fat: a systematic review and meta-regression analysis

Background Lack of robust estimates of human-milk nutrient composition and influential maternal factors, such as body composition, are barriers to informing nutrition policies and programs. Objective The objective was to understand the relation between maternal BMI and human-milk energy, fat, and/or total protein. Methods Four electronic databases (MEDLINE, Embase, CINAHL, and Web of Science) were searched. Outcomes assessed were human-milk energy (kcal/L), fat (g/L), and total protein (g/L) from mothers 1 to 6 mo postpartum. Studies with data on maternal BMI or weight and height that quantified human-milk energy, fat, or protein between 1 and 6 mo postpartum were eligible. Random-effects meta-regression weighted by the inverse of the study-level SE was completed for each of the 3 outcomes. The certainty of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Results A total of 11,373 titles and abstracts were identified, and after full-text screening, 69 articles of 66 studies were included. Meta-regression results showed a positive association between maternal BMI and human-milk fat (β: 0.56 g/L; 95% CI: 0.034, 1.1; P = 0.04; I2 = 93.7%, n = 63 datapoints). There was no significant association between maternal BMI and human-milk energy (β: 3.9 kcal/L; 95% CI: −1.6, 9.5; P = 0.16, I2 = 93.3%, n = 40 datapoints) or total protein (β: 0.13 g/L; 95% CI: −0.16, 0.41; P = 0.37, I2 = 99.1%, n = 40 datapoints). The certainty of evidence for human-milk energy was low and the certainty of evidence for fat and total protein was very low. Conclusions Meta-regression analysis of available literature suggested an association between maternal BMI and human-milk fat between 1 and 6 mo postpartum. Future studies are needed to confirm the relation between maternal BMI; variation in human-milk energy, fat, and protein content; and the implications for child growth and development. This review is registered with International Prospective Register of Systematic Reviews (PROSPERO 2018 CRD42018098808) at https://www.crd.york.ac.uk/prospero/

Diverse p63 and p73 isoforms regulate Delta 133p53 expression through modulation of the internal TP53 promoter activity

In response to stress, p53 binds and transactivates the internal TP53 promoter, thus regulating the expression of its own isoform, Δ133p53α. Here, we report that, in addition to p53, at least four p63/p73 isoforms regulate Δ133p53 expression at transcriptional level: p63β, ΔNp63α, ΔNp63β and ΔNp73γ. This regulation occurs through direct DNA-binding to the internal TP53 promoter as demonstrated by chromatin immunoprecipitation and the use of DNA-binding mutant p63. The promoter regions involved in the p63/p73-mediated transactivation were identified using deleted, mutant and polymorphic luciferase reporter constructs. In addition, we observed that transient expression of p53 family members modulates endogenous Δ133p53α expression at both mRNA and protein levels. We also report concomitant variation of p63 and Δ133p53 expression during keratinocyte differentiation of HaCat cells and induced pluripotent stem cells derived from mutated p63 ectodermal dysplasia patients. Finally, proliferation assays indicated that Δ133p53α isoform regulates the anti-proliferative activities of p63β, ΔNp63α, ΔNp63β and ΔNp73γ. Overall, this study shows a strong interplay between p53, p63 and p73 isoforms to orchestrate cell fate outcome

Trading N and O. Part 4: Asymmetric synthesis of syn-β-substituted-α-amino acids

A total of nine enantiopure syn-β-substituted-α-amino acids have been synthesised, comprising both syn-β-hydroxy-α-amino acids and syn-β-fluoro-α-amino acids. The key step in the synthetic strategy towards these syn-β-substituted-α-amino acids involves a stereospecific rearrangement, which proceeds via the intermediacy of the corresponding aziridinium ions. The requisite enantiopure syn-α-hydroxy-β-amino esters were prepared via asymmetric aminohydroxylation of the corresponding α,β-unsaturated esters followed by epimerisation of the resultant anti-α-hydroxy-β-amino esters at the C(2)-position. Subsequent activation of the α-hydroxy moiety as a leaving group followed by displacement by the β-amino substituent gave the corresponding aziridinium species. Regioselective in situ ring-opening of the aziridinium intermediates with either water or fluoride gave the corresponding syn-β-hydroxy-α-amino ester or syn-β-fluoro-α-amino ester, respectively, and N-deprotection and ester hydrolysis afforded the target syn-β-substituted-α-amino acids as single diastereoisomers in good overall yield

Positive feedback between p53 and TRF2 during telomere-damage signalling and cellular senescence

The telomere-capping complex (shelterin) protects functional telomeres from initiating unwanted DNA damage response. Uncapped telomeres at the end of cellular replicative lifespan lose this protective mechanism and trigger DNA damage signaling to activate p53 and thereby induce replicative senescence. Here we identify a signaling pathway involving p53, Siah-1, a p53-inducible E3 ubiquitin ligase, and TRF2, a component of the shelterin complex. Endogenous Siah-1 and TRF2 were up- and down-regulated, respectively, at replicative senescence with activated p53. A series of experimental manipulations of p53 showed that p53 induced Siah-1 and repressed TRF2 protein levels. The p53-dependent ubiquitination and proteasomal degradation of TRF2 were attributed to the E3 ligase activity of Siah-1. Siah-1 knockdown stabilized TRF2 and delayed the onset of cellular replicative senescence, suggesting the role of Siah-1 and TRF2 in p53-regulated senescence. This study reveals that p53, a downstream effector of the telomere-initiated damage signaling, also functions upstream of the shelterin complex

p53 isoform profiling in glioblastoma and injured brain

The tumor suppressor p53 has been found to be the most commonly mutated gene in human cancers; however, the frequency of p53 mutations varies from 10–70% across different cancer types. This variability can partly be explained by inactivating mechanisms aside from direct genomic polymorphisms. The p53 gene encodes 12 isoforms, which have been shown to modulate full-length p53 activity in cancer. In this study, we characterized p53 isoform expression patterns in glioblastoma, gliosis, non-tumor brain, and neural progenitor cells by SDS-PAGE, immunoblot, mass spectrometry, and RT-PCR. At the protein level, we found that the most consistently expressed isoform in glioblastoma, Δ40p53, was uniquely expressed in regenerative processes, such as those involving neural progenitor cells and gliosis compared to tumor samples. Isoform profiling of glioblastoma tissues revealed the presence of both Δ40p53 and full-length p53, neither of which were detected in non-tumor cerebral cortex. Upon xenograft propagation of tumors, p53 levels increased. The variability of overall p53 expression and relative levels of isoforms suggest fluctuations in subpopulations of cells with greater or lesser capacity for proliferation, which can change as the tumor evolves under different growth conditions