BACKGROUND: TP53 mutation (TP53 mut ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53 mut confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53 mut AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193). METHODS: Patients with newly diagnosed AML received decitabine 20 mg/m 2 for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53 mut was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines. RESULTS: Among 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53 mut AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53 mut AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53 mut versus wildtype TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53 mut AML were comparable to historical results with 10-day decitabine alone. CONCLUSIONS: Patients with TP53 mut AML have lower response rates and shorter survival with DEC10-VEN.

The Zic transcription factors play critical roles during embryonic development. Mutations in the ZIC2 gene are associated with human holoprosencephaly, but the etiology is still unclear. Here, we report a novel function for ZIC2 as a regulator of ␤-catenin⅐TCF4-mediated transcription. We show that ZIC2 can bind directly to the DNA-binding high mobility group box of TCF4 via its zinc finger domain and inhibit the transcriptional activity of the ␤-catenin⅐TCF4 complex. However, the binding of TCF4 to DNA was not affected by ZIC2. Zic2 RNA injection completely inhibited ␤-catenin-induced axis duplication in Xenopus embryos and strongly blocked the ability of ␤-catenin to induce expression of known Wnt targets in animal caps. Moreover, Zic2 knockdown in transgenic Xenopus Wnt reporter embryos led to ectopic Wnt signaling activity mainly at the midbrain-hindbrain boundary. Together, our results demonstrate a previously unknown role for ZIC2 as a transcriptional regulator of the ␤-catenin⅐TCF4 complex.

Background: Elevated plasma total homocysteine is an independent risk factor for cardiovascular disease and a sensitive marker of the inadequate vitamin B12 and folate insufficiency. Folate and vitamin B12 have a protective effect on cardiovascular disease. This population based study was conducted to evaluate the plasma total homocysteine, folate, and vitamin B12 in healthy Iranian individuals.

is the most frequently mutated gene in human cancer. Many mutant p53 proteins exert oncogenic gain-of-function (GOF) properties that contribute to metastasis, but the mechanisms mediating these functions remain poorly defined in vivo. To elucidate how mutant p53 GOF drives metastasis, we developed a traceable somatic osteosarcoma mouse model that is initiated with either a single mutation (p53R172H) or loss in osteoblasts. Our study confirmed that mutant mice developed osteosarcomas with increased metastasis as compared with-null mice. Comprehensive transcriptome RNA sequencing (RNA-seq) analysis of 16 tumors identified a cluster of small nucleolar RNAs (snoRNAs) that are highly up-regulated in p53 mutant tumors. Regulatory element analysis of these deregulated snoRNA genes identified strong enrichment of a common Ets2 transcription factor-binding site. Homozygous deletion of in p53 mutant mice resulted in strong down-regulation of snoRNAs and reversed the prometastatic phenotype of mutant p53 but had no effect on osteosarcoma development, which remained 100% penetrant. In summary, our studies identify Ets2 inhibition as a potential therapeutic vulnerability in p53 mutant osteosarcomas.

SummaryWiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency disease caused by mutations in the gene encoding the WAS protein (WASp). Here, induced pluripotent stem cells (iPSCs) were derived from a WAS patient (WAS-iPSC) and the endogenous chromosomal WAS locus was targeted with a wtWAS-2A-eGFP transgene using zinc finger nucleases (ZFNs) to generate corrected WAS-iPSC (cWAS-iPSC). WASp and GFP were first expressed in the earliest CD34+CD43+CD45− hematopoietic precursor cells and later in all hematopoietic lineages examined. Whereas differentiation to non-lymphoid lineages was readily obtained from WAS-iPSCs, in vitro T lymphopoiesis from WAS-iPSC was deficient with few CD4+CD8+ double-positive and mature CD3+ T cells obtained. T cell differentiation was restored for cWAS-iPSCs. Similarly, defects in natural killer cell differentiation and function were restored on targeted correction of the WAS locus. These results demonstrate that the defects exhibited by WAS-iPSC-derived lymphoid cells were fully corrected and suggests the potential therapeutic use of gene-corrected WAS-iPSCs.

RESULTS demonstrate high metabolic syndrome rate among target population especially in women. In view of correlation between metabolic syndrome and cardiovascular disease, it must be the priority for interventional preventive measures.

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RNA and protein analysis revealed the consistent upregulation of the neural transcription factors ZIC1 and ZIC4 in desmoid tumors and other fibroproliferative disorders. The 5 0 flanking region of the ZIC1 promoter was unmethylated in desmoid tumor fibroblasts, while a hypermethylated ZIC1 promoter was found in human and mouse cell lines not expressing the gene. In addition, expressing cells showed a H3K4me2 at the ZIC1 promoter, whereas non-expressing cells showed higher levels of H3K9me2 in the same region. To our knowledge, this is the first report describing ZIC1 expression in mesenchymal proliferations and a role for DNA methylation in the control of ZIC1 expression.