HDAC7 Is a Repressor of Myeloid Genes Whose Downregulation Is Required for Transdifferentiation of Pre-B Cells into Macrophages

B lymphopoiesis is the result of several cell-commitment, lineage-choice, and differentiation processes. Every differentiation step is characterized by the activation of a new, lineage-specific, genetic program and the extinction of the previous one. To date, the central role of specific transcription factors in positively regulating these distinct differentiation processes to acquire a B cell-specific genetic program is well established. However, the existence of specific transcriptional repressors responsible for the silencing of lineage inappropriate genes remains elusive. Here we addressed the molecular mechanism behind repression of non-lymphoid genes in B cells. We report that the histone deacetylase HDAC7 was highly expressed in pre-B cells but dramatically down-regulated during cellular lineage conversion to macrophages. Microarray analysis demonstrated that HDAC7 re-expression interfered with the acquisition of the gene transcriptional program characteristic of macrophages during cell transdifferentiation; the presence of HDAC7 blocked the induction of key genes for macrophage function, such as immune, inflammatory, and defense response, cellular response to infections, positive regulation of cytokines production, and phagocytosis. Moreover, re-introduction of HDAC7 suppressed crucial functions of macrophages, such as the ability to phagocytose bacteria and to respond to endotoxin by expressing major pro-inflammatory cytokines. To gain insight into the molecular mechanisms mediating HDAC7 repression in pre-B cells, we undertook co-immunoprecipitation and chromatin immunoprecipitation experimental approaches. We found that HDAC7 specifically interacted with the transcription factor MEF2C in pre-B cells and was recruited to MEF2 binding sites located at the promoters of genes critical for macrophage function. Thus, in B cells HDAC7 is a transcriptional repressor of undesirable genes. Our findings uncover a novel role for HDAC7 in maintaining the identity of a particular cell type by silencing lineage-inappropriate genes

Influenza vaccination for immunocompromised patients: systematic review and meta-analysis from a public health policy perspective.

Immunocompromised patients are vulnerable to severe or complicated influenza infection. Vaccination is widely recommended for this group. This systematic review and meta-analysis assesses influenza vaccination for immunocompromised patients in terms of preventing influenza-like illness and laboratory confirmed influenza, serological response and adverse events

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

The transcriptional repressor HDAC7 promotes apoptosis and c-Myc downregulation in particular types of leukemia and lymphoma

The generation of B cells is a complex process requiring several cellular transitions, including cell commitment and differentiation. Proper transcriptional control to establish the genetic programs characteristic of each cellular stage is essential for the correct development of B lymphocytes. Deregulation of these particular transcriptional programs may result in a block in B-cell maturation, contributing to the development of hematological malignancies such as leukemia and lymphoma. However, very little is currently known about the role of transcriptional repressors in normal and aberrant B lymphopoiesis. Here we report that histone deacetylase 7 (HDAC7) is underexpressed in pro-B acute lymphoblastic leukemia (pro-B-ALL) and Burkitt lymphoma. Ectopic expression of HDAC7 induces apoptosis, leads to the downregulation of c-Myc and inhibits the oncogenic potential of cells in vivo, in a xenograft model. Most significantly, we have observed low levels of HDAC7 expression in B-ALL patient samples, which is correlated with the increased levels of c-Myc. From a mechanistic angle, we show that ectopically expressed HDAC7 localizes to the nucleus and interacts with the transcription factor myocyte enhancer factor C (MEF2C) and the corepressors HDAC3 and SMRT. Accordingly, both the HDAC7-MEF2C interaction domain as well as its catalytic domain are involved in the reduced cell viability induced by HDAC7. We conclude that HDAC7 has a potent anti-oncogenic effect on specific B-cell malignancies, indicating that its deregulation may contribute to the pathogenesis of the disease.This work was supported by a grant from the Spanish Ministry of Economy and Competitiveness (MINECO; SAF2011-28290; to MP). MP was supported by a Ramón y Cajal contract from the Spanish Ministry of Science and Innovation (MICIIN). LR-G was supported by an IDIBELL PhD fellowship. NL-B acknowledges the funding from MICIIN (SAF2012-36199)

Integrating biodiversity, remote sensing, and auxiliary information for the study of ecosystem functioning and conservation at large spatial scales

Assessing patterns and processes of plant functional, taxonomic, genetic, and structural biodiversity at large scales is essential across many disciplines, including ecosystem management, agriculture, ecosystem risk and service assessment, conservation science, and forestry. In situ data housed in databases necessary to perform such assessments over large parts of the world are growing steadily. Integrating these in situ data with remote sensing (RS) products helps not only to improve data completeness and quality but also to account for limitations and uncertainties associated with each data product. Here, we outline how auxiliary environmental and socioeconomic data might be integrated with biodiversity and RS data to expand our knowledge about ecosystem functioning and inform the conservation of biodiversity. We discuss concepts, data, and methods necessary to assess plant species and ecosystem properties across scales of space and time and provide a critical discussion of outstanding issues

The Aberdeen Children of the 1950s cohort study: background, methods and follow-up information on a new resource for the study of life course and intergenerational influences on health.

In this paper we introduce and describe in detail an addition to the UK's population-based resources for the investigation of biological and social influences on health across the life course and between generations: the Aberdeen Children of the 1950s study. We also provide an account of postwar Aberdeen when study members were growing up, report on findings of analyses of data from the original survey on which this study is based and its follow-up, assess the strengths and limitations of the study, and outline current and future research directions. This cohort comprises individuals born in Aberdeen, Scotland (UK) between 1950 and 1956, and is derived from 15 thousand subjects who took part in the Aberdeen Child Development Survey, a cross-sectional study of 'mental subnormality' (learning disability) in a population of all children who were attending Aberdeen primary schools in December 1962. Data collection included information on birthweight, gestational age, childhood height and weight, tests of cognition and behavioural disorder, and a range of multilevel socio-economic indicators. In 1998 we began the process of revitalising this cohort (now termed the Aberdeen Children of the 1950s study). We have been successful in ascertaining the current vital status and whereabouts of 98.5% of a target population of 12 150 subjects (6276 males, 5874 females) with full baseline data. The large majority (81%) of study participants still reside in Scotland and many (73%) have remained in the Grampian region which incorporates Aberdeen. At the present time, a total of almost 500 subjects are known to have died. Linkages to hospital admissions and other health endpoints captured through the Scottish Morbidity Records system have been completed. This includes an intergenerational linkage to approximately eight thousand deliveries in Scotland occurring to female members of the study population. A postal questionnaire to all traced surviving cohort members has also been distributed