Dynamic gut microbiome changes following regional intestinal lymphatic obstruction in primates.

The pathogenesis of inflammatory bowel disease (IBD) has been linked with lymphostasis, but whether and how lymphatic obstruction might disturb the intestinal microbiome in the setting of Crohn's Disease (CD) is currently unknown. We employed a new model of CD in African Green monkeys, termed 'ATLAS' (African green monkey truncation of lymphatics with obstruction and sclerosis), to evaluate how gut lymphatic obstruction alters the intestinal microbiome at 7, 21 and 61 days. Remarkable changes in several microbial sub- groupings within the gut microbiome were observed at 7 days post-ATLAS compared to controls including increased abundance of Prevotellaceae and Bacteroidetes-Prevotella-Porphyromonas (BPP), which may contribute to disease activity in this model of gut injury. To the best of our knowledge, these findings represent the first report linking lymphatic structural/gut functional changes with alterations in the gut microbiome as they may relate to the pathophysiology of CD.

Genome-wide profiling reveals transcriptional repression of MYC as a core component of NR4A tumor suppression in acute myeloid leukemia.

Acute myeloid leukemias (AMLs) are a heterogeneous group of diseases that are sustained by relatively rare leukemia-initiating cells (LICs) that exhibit diverse genetic and phenotypic properties. AML heterogeneity presents a major challenge to development of targeted therapies, and effective treatment will require targeting of common molecular drivers of AML maintenance. The orphan nuclear receptors NR4A1 and NR4A3 are potent tumor suppressors of AML. They are silenced in all human AML LICs, irrespective of patient cytogenetics, and their deletion in mice leads to postnatal AML development. In the current report, we address the tumor-suppressive mechanisms and therapeutic potential of NR4As for AML intervention. We show that rescue of either NR4A1 or NR4A3 inhibits the leukemogenicity of AML cells in vivo and reprograms a subset of gene signatures that distinguish primary human LICs from normal hematopoietic stem cells (HSCs), irrespective of subtype. Central to NR4A reprogramming is the acute suppression of an LIC submodule that includes the transcriptional repression of MYC. Additionally, we show that upregulation of MYC is an acute preleukemic consequence of NR4A deletion and that MYC suppression functionally contributes to NR4A antileukemic effects. Collectively, these results identify NR4As as novel targets for AML therapeutic intervention and reveal molecular targets of NR4A tumor suppression, including the suppression of MYC.

Zinc acetate treatment in Wilson's disease.

OBJECTIVE: To briefly review the pathophysiology and diagnosis of Wilson's disease, and to evaluate the pharmacology, pharmacokinetics, clinical utility, adverse effects, dosing regimens, and pharmacoeconomics of zinc acetate therapy in Wilson's disease. DATA SOURCES: A MEDLINE search (December 1966-December 1996) of the English-language literature using the terms zinc and Wilson's disease was conducted to identify pertinent clinical trials, review articles, and case reports. Additional articles were selected from bibliographies of the reviewed literature. STUDY SELECTION AND DATA EXTRACTION: Due to the rarity of the disease, all articles were considered for possible inclusion in this review. Single case reports are referenced, but were not selected for evaluation. DATA SYNTHESIS: Wilson's disease, an inherited disorder of copper metabolism, is fatal if untreated. The chelating drugs penicillamine and trientine have been the mainstay of therapy; however, adverse reactions of chelators often interfere with successful treatment. Recently, zinc acetate was approved in the US for maintenance therapy in patients initially treated with a chelating agent. Although studies evaluating large populations are lacking zinc therapy has demonstrated exceptional safety and efficacy over a period of 40 years. Zinc acetate can be used during pregnancy and for the treatment of presymptomatic patients, although data do not support its use as monotherapy in patients with acute neurologic or hepatic disease. CONCLUSIONS: Zinc acetate is an effective maintenance therapy for patients with Wilson's disease. Negligible toxicity, compared with that of previously approved treatments, is a major advantage.