Moreover, treatment of acute myeloid leukemia (AML) cells with the BRD4 inhibitor JQ1 showed growth inhibition in a Trib1/Erg-dependent manner both in vitro and in vivo. Upregulation of ERG by TRIB1 was also observed in human AML cell lines, suggesting that Trib1 is a potential therapeutic target of Hoxa9-associated AML. Taken together, our study demonstrates a novel mechanism by which Trib1 modulates chromatin and Hoxa9-driven transcription in myeloid leukemogenesis.Somatic gene mutations are key determinants of outcome in patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). In particular, patients with TP53 mutations represent a distinct molecular cohort with uniformly poor prognosis. The precise pathogenetic mechanisms underlying these inferior outcomes have not been delineated. In this study, we characterized the immunological features of the malignant clone and alterations in the immune microenvironment in patients with TP53-mutant and wild-type MDS or sAML. Notably, PDL1 expression is significantly increased in hematopoietic stem cells of patients with TP53 mutations, which is associated with MYC upregulation and marked downregulation of MYC's negative regulator miR-34a, a p53 transcription target. Notably, patients with TP53 mutations display significantly reduced numbers of bone marrow-infiltrating OX40+ cytotoxic T cells and helper T cells, as well as decreased ICOS+ and 4-1BB+ natural killer cells.  https://www.selleckchem.com/products/ly333531.html  Further, highly immunosuppressive regulatory T cells (Tregs) (ie, ICOShigh/PD-1-) and myeloid-derived suppressor cells (PD-1low) are expanded in cases with TP53 mutations. Finally, a higher proportion of bone marrow-infiltrating ICOShigh/PD-1- Treg cells is a highly significant independent predictor of overall survival. We conclude that the microenvironment of TP53 mutant MDS and sAML has an immune-privileged, evasive phenotype that may be a primary driver of poor outcomes and submit that immunomodulatory therapeutic strategies may offer a benefit for this molecularly defined subpopulation.Vitamin C serves as a cofactor for Fe(II) and 2-oxoglutarate-dependent dioxygenases including TET family enzymes, which catalyze the oxidation of 5-methylcytosine into 5-hydroxymethylcytosine and further oxidize methylcytosines. Loss-of-function mutations in epigenetic regulators such as TET genes are prevalent in hematopoietic malignancies. Vitamin C deficiency is frequently observed in cancer patients. In this review, we discuss the role of vitamin C and TET proteins in cancer, with a focus on hematopoietic malignancies, T regulatory cells, and other immune system cells.
  Is there an association between advanced paternal age and congenital heart defects (CHD)?
 
  Advanced paternal age is associated with a 16% increase in the overall odds of CHD.
 
  CHD are the most common congenital malformations. Several risk factors for CHD have been identified in the literature, but the association between advanced paternal age and CHD remains unclear.
 
  We conducted a systematic literature search on MEDLINE and EMBASE (1960-2019) to identify studies assessing the association between advanced paternal age (≥35 years) and the risk of CHD, unrestrictive of language or sample size. We used a combination of Medical Subject Headings (MeSH) terms and free text words such as 'paternal age', 'paternal factors', 'father's age', 'parental age', 'heart', 'cardiac', 'cardiovascular', 'abnormalities, congenital', 'birth defects', 'congenital malformations' and 'congenital abnormalities'.
 
  We included observational studies aiming at assessing the association between paternal age and CHD. The included poable in population-based studies and in those with low risk of bias.
 
  The available evidence did not allow to assess (i) the risk of isolated CHD in population-based studies, (ii) the association between paternal age and the risk for specific CHD and (iii) the association between paternal age and CHD after adjustment for other risk factors, such as maternal age.
 
  Our findings suggest that advanced paternal age may be a risk factor for CHD. However, because the association is modest in magnitude, its usefulness as a criterion for targeted screening for CHD seems limited.
 
  None.
 
  CRD42019135061.
 CRD42019135061.
  Heavy metals are an indispensable part of industrial and agricultural development. As the cradle of China's industry and an important province for agricultural production, Jilin Province has been an area of concern about heavy metal pollution in the local environment and grains. In this study, we focused on four heavy metals that are harmful to humans arsenic (As), cadmium (Cd), methylmercury (MeHg), and inorganic arsenic (iAs). We determined the contents of these metals in 341 grain samples by using graphite furnace atomic absorption spectrometry and liquid chromatography-atomic fluorescence spectrometry and compared our results with the limit value of national standards. To evaluate the potential risk to human health, we determined the target hazard quotient and hazard index. Heavy metals were detected at these rates, from high to low Cd (48%) > iAs (20.8%) > MeHg (4.6%) > Pb (3%). Most of these values are far below the limit of national standards. The target hazard quotient and hazard index were both smaller than 1; thus, we conclude that heavy metal pollution in grains in Jilin Province is not serious and that people are not at high risk from heavy metals in grains.
 
  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 14 million cases and more than half million deaths. Given the absence of implemented therapies, new analysis, diagnosis, and therapeutics are of great importance.
 
  Analysis of SARS-CoV-2 genomes from the current outbreak reveals the presence of short persistent DNA/RNA sequences that are absent from the human genome and transcriptome (PmRAWs). For the PmRAWs with length 12, only four exist at the same location in all SARS-CoV-2. At the gene level, we found one PmRAW of size 13 at the Spike glycoprotein coding sequence. This protein is fundamental for binding in human ACE2 and further use as an entry receptor to invade target cells. Applying protein structural prediction, we localized this PmRAW at the surface of the Spike protein, providing a potential targeted vector for diagnostics and therapeutics. Additionally, we show a new pattern of relative absent words (RAWs), characterized by the progressive increase of GC content (Guanine and Cytosine) according to the decrease of RAWs length, contrarily to the virus and host genome distributions.