Discovery of bicyclic pyrazoles as class III histone deacetylase SIRT1 and SIRT2 inhibitors.

A series of bicyclic pyrazole carboxamides was synthesized and tested for inhibitory activity against the class III deacetylase sirtuin enzymes. Moderate to low micromolar inhibitory activities were obtained against SIRT1 and SIRT2. These bicyclic pyrazole compounds represent a new class of sirtuin inhibitors with a preference for SIRT1 over SIRT2.

Impact of an emergency medicine decision support and risk education system on computed tomography and magnetic resonance imaging use.

BACKGROUND: Increasing computed tomography (CT) and magnetic resonance imaging (MRI) use in the emergency department (ED) over the last decade is well documented. OBJECTIVE: Our aim was to assess the impact of an electronic decision support and risk education system (DS-RES) on CT/MRI use. METHODS: We conducted an age-, sex-, and risk-adjusted analysis of CT/MRI use and ED and inpatient rebound rates before and after implementation in 2009 at a Kaiser Permanente Northwest medical center. RESULTS: In the pre period, a total of 12,531 encounters occurred for unique patients within each of 10 chief complaint categories. In the post period, 16,864 total encounters occurred for unique patients within each chief complaint category, 11.4% of patients were at low risk and 24.8% and 63.8% were at medium and high risk, respectively. Adjusted CT/MRI use increased 1.1% (95% confidence interval [CI] 0%-2.3%) between pre and post periods. Among low-risk and medium-risk patients, CT/MRI use decreased by 5.0% (95% CI 2.5%-7.5%) and 10.4% (95% CI 7.9%-12.8%). Among patients at high risk, CT/MRI use increased by 3.9% (95% CI 2.5%-5.3%). The proportion of patients with a 3- or 7-day rebound to the ED or an inpatient facility decreased between pre and post periods by 1.4% (95% CI 0.7%-2.2%) and 0.7% (95% CI 0.2%-1.5%). CONCLUSIONS: DS-RES implementation did not decrease overall CT/MRI rates, but it was associated with a shift in use toward high-risk patients and less patient rebound to the ED and hospital. Further research is required to identify mechanisms underlying imaging utilization shifts.

Nell-1, a key functional mediator of Runx2, partially rescues calvarial defects in Runx2(+/-) mice.

Mesenchymal stem cell commitment to an osteoprogenitor lineage requires the activity of Runx2, a molecule implicated in the etiopathology of multiple congenital craniofacial anomalies. Through promoter analyses, we have recently identified a new direct transcriptional target of Runx2, Nell-1, a craniosynostosis (CS)-associated molecule with potent osteogenic properties. This study investigated the mechanistic and functional relationship between Nell-1 and Runx2 in regulating osteoblast differentiation. The results showed that spatiotemporal distribution and expression levels of Nell-1 correlated closely with those of endogenous Runx2 during craniofacial development. Phenotypically, cross-mating Nell-1 overexpression transgenic (CMV-Nell-1) mice with Runx2 haploinsufficient (Runx2(+/-)) mice partially rescued the calvarial defects in the cleidocranial dysplasia (CCD)-like phenotype of Runx2(+/-) mice, whereas Nell-1 protein induced mineralization and bone formation in Runx2(+/-) but not Runx2(-/-) calvarial explants. Runx2-mediated osteoblastic gene expression and/or mineralization was severely reduced by Nell-1 siRNA oligos transfection into Runx2(+/+) newborn mouse calvarial cells (NMCCs) or in N-ethyl-N-nitrosourea (ENU)-induced Nell-1(-/-) NMCCs. Meanwhile, Nell-1 overexpression partially rescued osteoblastic gene expression but not mineralization in Runx2 null (Runx2(-/-)) NMCCs. Mechanistically, irrespective of Runx2 genotype, Nell-1 signaling activates ERK1/2 and JNK1 mitogen-activated protein kinase (MAPK) pathways in NMCCs and enhances Runx2 phosphorylation and activity when Runx2 is present. Collectively, these data demonstrate that Nell-1 is a critical downstream Runx2 functional mediator insofar as Runx2-regulated Nell-1 promotes osteoblastic differentiation through, in part, activation of MAPK and enhanced phosphorylation of Runx2, and Runx2 activity is significantly reduced when Nell-1 is blocked or absent.

MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo.

Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clinical investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clinical investigation is warranted.

Acute stroke management.

Extract: Stroke is the third leading cause of death in the United States, coming in just behind cancer and coronary artery disease. It is, however, the leading cause of long-term disability. Stroke includes two major categories -- ischemic and hemorrhagic stroke (reduced blood supply and blood leakage, respectively), which both lead to a lack of adequate blood and oxygen supply to brain tissue, resulting in cell death. About 85% of strokes are ischemic. Ischemic strokes can also be divided into different categories based on their etiology and location. Acute ischemic stroke is an emergency, but a treatable condition especially since the TPA (tissue plasminogen activator, which is also a natural substance that helps dissolve blood clots in blood circulation) was approved by the U.S. FDA in 1995. Even though acute strokes are very common, there are still a lot of controversies about their acute management. Some of the major issues with regard to acute management of strokes are discussed here.

Synthetic AIDS vaccine by targeting HIV receptor.

A class of synthetic peptide immunogens for the cell surface HIV receptor complex has been developed to elicit antibodies that block viral entry by inhibiting gp120-CD4 interaction. These peptides extend our HIV receptor-directed approach from passive immunotherapy with mAb B4 (Proc. Natl. Acad. Sci. U.S.A. 96 (1999) 10367) to active immunization by a synthetic peptide-based vaccine. A peptide site from CD4 was identified as a B cell epitope capable of mimicking a susceptible site on the HIV receptor complex, and then rendered immunogenic. An effective target antigenic site (B cell epitope) for the cell surface HIV receptor complex was selected by epitope mapping from among diverse CD4 and chemokine receptor peptides. It is a cyclized sequence modified from the CDR2-like domain of CD4 (AA 39-66), that was predicted to produce steric hindrance of the discontinuous recognition site of mAb B4. The immunogenicity of the targeted epitope was augmented by tandem combination with promiscuous T helper cell epitopes (Th). The antibody response to this class of immunogens attained sufficient concentrations and affinities of the correct specificity to block the interactions of HIV env glycoprotein with the cellular receptor, and prevent infection. The polyclonal antibodies generated against these fusion constructs in multiple animal species neutralized a broad array of HIV-1 primary isolates from clades A to E. Despite eliciting antibodies to the key CD4 immunomodulatory molecule, the site-specific and chemically defined immunogens displayed no overt immunotoxicity in baboons and have potential for the immunotherapy and immunoprophylaxis of HIV infection.