(Funded by the Beijing Municipal Health Bureau.)

N

Engl J Med 2010;363:2416-23.”
“Simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infection results in an early and enduring depletion of intestinal CD4(+) T cells. SIV and HIV bind integrin alpha 4 beta 7, thereby facilitating infection of lymphocytes that home to the gut-associated lymphoid tissue (GALT). Using an ex vivo flow cytometry assay, we found that SIVmac239-infected cells expressed significantly lower levels of integrin alpha 4 beta 7 than did uninfected cells. This finding suggested a potential viral effect on integrin alpha 4 beta 7 expression. Using an in vitro model, we confirmed that integrin alpha 4 beta 7 was downregulated on the surfaces of SIVmac239-infected cells. Further, modulation of integrin alpha 4 beta 7 was dependent on de novo synthesis of viral proteins, but neither cell death, the release of a soluble factor, nor a change in activation state was involved. GSK1210151A cost Downregulation of integrin alpha 4 beta 7 may have an unappreciated role in the CD4 depletion of the mucosal-associated lymphoid compartments, susceptibility to superinfection, and/or immune evasion.”
“Background: The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia (AML) are unknown.

Methods: Using massively parallel DNA sequencing, we identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in

the genome of cells from a patient with AML with a normal karyotype. We sequenced the exons of DNMT3A in 280 additional patients learn more with de novo AML to define recurring mutations.

Results: A total of 62 of 281 patients (22.1%) had mutations in DNMT3A

that were predicted to affect translation. We identified 18 different missense mutations, the most common of which was predicted to affect amino acid R882 (in 37 patients). We also identified six frameshift, six nonsense, and three splice-site mutations and a 1.5-Mbp deletion encompassing DNMT3A. These mutations were highly enriched Ribonucleotide reductase in the group of patients with an intermediate-risk cytogenetic profile (56 of 166 patients, or 33.7%) but were absent in all 79 patients with a favorable-risk cytogenetic profile (P<0.001 for both comparisons). The median overall survival among patients with DNMT3A mutations was significantly shorter than that among patients without such mutations (12.3 months vs. 41.1 months, P<0.001). DNMT3A mutations were associated with adverse outcomes among patients with an intermediate-risk cytogenetic profile or FLT3 mutations, regardless of age, and were independently associated with a poor outcome in Cox proportional-hazards analysis.

Conclusions: DNMT3A mutations are highly recurrent in patients with de novo AML with an intermediate-risk cytogenetic profile and are independently associated with a poor outcome. (Funded by the National Institutes of Health and others.)

N Engl J Med 2010;363:2424-33.