One step ahead: Innovation in core facilities.

Core facilities—originally founded to give scientists access to a specific technology or service—have expanded to become incubators for new technologies and services. While it has many benefits, it also creates unique problems and challenges.[Image: see text]

Synthesis of a 6-Aza-Isoindolinone-Based Inhibitor of Phosphoinositide 3-Kinase γ via Ruthenium-Catalyzed [2 + 2 + 2] Cyclotrimerization.

Phosphoinositide 3-kinase (PI3Kγ) is a drug target that has been implicated in the treatment of a range of diseases. We have developed a synthesis of a novel PI3Kγ inhibitor containing a 1,2-dihydro-3H-pyrrolo[3,4-]pyridin-3-one scaffold. The key step in the synthesis involved a ruthenium-catalyzed [2 + 2 + 2] cyclotrimerization reaction between a diyne and an alkoxycarbonyl isocyanate, a previously unreported coupling partner in such a reaction.

Design and synthesis of bridged piperidine and piperazine isosteres.

We have developed versatile methods toward the synthesis of a variety of piperidine/piperazine bridged isosteres of pridopidine. The compounds were assessed against the D2 receptor in agonist and antagonist modes and against the D4 receptor in agonist mode. hERG Binding and the ADME profiles were studied.

Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS).

The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.

Institutional core facilities: prerequisite for breakthroughs in the life sciences: Core facilities play an increasingly important role in biomedical research by providing scientists access to sophisticated technology and expertise.

Core facilities have become an important resource in biomedical research, providing scientists with access to sophisticated instrumentation and expertise. To enable scientists to perform ever more complex and difficult experiments, core facilities not only need to constantly upgrade technology and expertise, but also cooperate and pool their assets. [Image: see text]

Discovery and Characterization of a Water-Soluble Prodrug of a Dual Inhibitor of Bacterial DNA Gyrase and Topoisomerase IV.

Benzimidazole 1 is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With the goal of improving key drug-like properties, namely, the solubility and the formulability of 1, an effort to identify prodrugs was undertaken. This has led to the discovery of a phosphate ester prodrug 2.

Discovery of Highly Isoform Selective Thiazolopiperidine Inhibitors of Phosphoinositide 3-Kinase γ.

A series of high affinity second-generation thiazolopiperidine inhibitors of PI3Kγ were designed based on some general observations around lipid kinase structure. Optimization of the alkylimidazole group led to inhibitors with higher levels of PI3Kγ selectivity. Additional insights into PI3K isoform selectivity related to sequence differences in a known distal hydrophobic pocket are also described.

Second-generation antibacterial benzimidazole ureas: discovery of a preclinical candidate with reduced metabolic liability.

Compound 3 is a potent aminobenzimidazole urea with broad-spectrum Gram-positive antibacterial activity resulting from dual inhibition of bacterial gyrase (GyrB) and topoisomerase IV (ParE), and it demonstrates efficacy in rodent models of bacterial infection. Preclinical in vitro and in vivo studies showed that compound 3 covalently labels liver proteins, presumably via formation of a reactive metabolite, and hence presented a potential safety liability. The urea moiety in compound 3 was identified as being potentially responsible for reactive metabolite formation, but its replacement resulted in loss of antibacterial activity and/or oral exposure due to poor physicochemical parameters.

The Research Biobank of the Year Competition of the European, Middle Eastern and African Society for Biopreservation and Biobanking (ESBB): aims and achievements.

With the increasing number of research biobanks and the importance of their role in supporting medical and biological research, the development and sharing of biobanking best practices and benchmarking standards has become paramount. To promote outstanding biobank services for research, the Research Biobank of the Year Competition (RBYC) has been inaugurated by the European, Middle-Eastern, and African Society for Biopreservation and Biobanking (ESBB) in October 2013. The procedures for the call and evaluation procedure, including the newly developed scoring system, are presented here.

Conditional modulation of membrane protein expression in cultured cells mediated by prion protein recognition of short phosphorothioate oligodeoxynucleotides.

We demonstrate that the levels of native as well as transfected prion protein (PrP) are lowered in various cell lines exposed to phosphorothioate oligodeoxynucleotides (PS-DNA) and can be rapidly reverted to their normal amounts by removal of PS-DNA. This transient modulation was independent of the glycosylation state of PrP, and in addition, all three PrP glycoforms were susceptible to PS-DNA treatment. Deletion of the N-terminal domain (amino acids 23-99), but not of the other domains of PrP, abrogated its PS-DNA-mediated down-regulation.

Azithromycin does not prevent six-month myointimal proliferation but attenuates the transient systemic inflammation occurring after coronary stenting.

Objectives: Stent implantation produces a systemic increase of inflammatory markers that correlates with Chlamydophila pneumoniae infection in atherosclerotic plaque. We performed a clinical intervention study to investigate the effect of antibiotic treatment on 6-month follow-up angiographic minimal luminal diameter after stenting.

Methods: Ninety patients were randomly assigned to oral azithromycin or placebo in a double-blinded and randomized fashion.

Hip and nonvertebral fracture prediction in nursing home patients: role of bone ultrasound and bone marker measurements.

Context: Absolute fracture risk in nursing home patients is the highest among the communities studied. Screening for high-risk patients in such an environment is usually difficult.

Objective: The objective was to investigate whether quantitative bone ultrasound measurements and/or markers of bone turnover/metabolism help in predicting which patients will incur hip or nonvertebral fractures.

Type 2 diabetes mellitus in nursing home patients: effects on bone turnover, bone mass, and fracture risk.

Context: Fractures are a major health burden in elderly institutionalized persons. Type 2 diabetes mellitus (DM) has a high prevalence in nursing home patients and has been associated with positive effects on bone mass in younger, community-dwelling elderly.

Objective: The objective of this study was to investigate whether type 2 DM affects bone mass, bone turnover, or prospective fracture rates in frail, elderly women living in nursing homes.

Low-density lipoprotein triglycerides associated with low-grade systemic inflammation, adhesion molecules, and angiographic coronary artery disease: the Ludwigshafen Risk and Cardiovascular Health study.

Background: Markers of systemic inflammation and LDL cholesterol (LDL-C) have been considered independent risk factors of coronary artery disease (CAD). We examined whether alterations of LDL metabolism not reflected by LDL-C were associated with low-grade inflammation, vascular injury, and CAD.

Methods And Results: We studied 739 subjects with stable angiographic CAD and 570 matched control subjects in which CAD had been ruled out by angiography.

Association of antibodies to chlamydial lipopolysaccharide with the endovascular presence of Chlamydophila pneumoniae in carotid artery disease.

Atherosclerotic lesions often harbor Chlamydophila pneumoniae (C. pneumoniae). The objective of the present study was to examine whether serological tests are able to predict individual endovascular infection.

Prolonged monitoring of troponin T for the detection of anthracycline cardiotoxicity in adults with hematological malignancies.

The study was performed to describe the time course of serum cardiac troponin T (cTnT) elevations for the early detection of anthracycline cardiotoxicity. cTnT was analyzed serially in 78 patients with hematological malignancies receiving 142 treatment cycles including various anthracyclines. cTnT positivity was defined as an increase in cTnT >or=0.

Monitoring of cardiac function by serum cardiac troponin T levels, ventricular repolarisation indices, and echocardiography after conditioning with fractionated total body irradiation and high-dose cyclophosphamide.

Objectives: Highly differing rates of cardiac complications associated with high-dose cyclophosphamide (CY) have been reported, and only one clinical study has been performed on the cardiotoxic effects of CY monotherapy following total body irradiation (TBI).

Patients And Methods: We prospectively evaluated the potential cardiotoxic effects of conditioning with fractionated total body irradiation and high-dose cyclophosphamide (TBI/CY) by serial measurement of serum cardiac troponin T (cTnT), assessment of systolic and diastolic echocardiographic parameters and analysis of ventricular repolarisation indices (QT-dispersion and corrected QT-dispersion) in 30 adult patients with haematological malignancies undergoing haematopoietic stem cell transplantation.

Results: There was no evidence of pretreatment cardiac dysfunction in any patient.

Aspirin inhibits Chlamydia pneumoniae-induced nuclear factor-kappa B activation, cytokine expression, and bacterial development in human endothelial cells.

Objective: Chlamydia pneumoniae has been associated with atherosclerosis. Infection of vascular endothelial cells with C pneumoniae increases the expression of proatherogenic cytokines mediated by nuclear factor (NF)-kappaB, a transcription factor. The present study was designed to test the effect of aspirin on C pneumoniae-induced NF-kappaB activation, interleukin expression, and bacterial development in cultured human endothelial cells.

Hyperhomocyst(e)inemia and Chlamydia pneumoniae IgG seropositivity in patients with coronary artery disease.

Elevated levels of homocyst(e)ine and infection by Chlamydia pneumoniae have been hypothesized individually to play a role in coronary artery disease (CAD), but the mechanisms are unclear. Data on a possible association are not available. We investigated the correlation between IgG antibody titers against C.

[Helicobacter pylori and cytomegalovirus infection and atherosclerosis: an assessment of the current status].

An association between Helicobacter pylori infection or cytomegalovirus infection and atherosclerosis has been described. During the last four years, new evidence evolved from a number of studies, which allows to reevaluate the clinical impact of this association. Current knowledge suggests that the association between atherosclerosis and Helicobacter pylori may be accounted for by chance or by confounding from a secondary phenomenon.

Vitamin E attenuates oxidative stress induced by intravenous iron in patients on hemodialysis.

Intravenous iron application to anemic patients on hemodialysis leads to an "oversaturation" of transferrin. As a result, non-transferrin-bound, redox-active iron might induce lipid peroxidation. To test the hypothesis that vitamin E attenuates lipid peroxidation in patients receiving 100 mg of iron(III) hydroxide sucrose complex intravenously during a hemodialysis session, 22 patients were investigated in a randomized cross-over design, either with or without a single oral dose of 1200 IU of all-rac-alpha-tocopheryl acetate taken 6 h before the hemodialysis session.

A double-blind randomized-phase II trial comparing immunization with antiidiotype goat antibody vaccine SCV 106 versus unspecific goat antibodies in patients with metastatic colorectal cancer.

This article reports on the first double-blind randomized clinical study with an antiidiotype antibody vaccine in patients with metastatic colorectal carcinoma. The study was performed to determine immunological parameters, efficacy, and tolerability of the vaccine. Forty-two patients with metastatic colorectal cancer were randomly assigned to multiple immunizations with goat IgG antiidiotype vaccine SCV 106 (n = 21) or unspecific goat IgG as controls (n = 21).

Prior cytomegalovirus infection does not predict clinical outcome after percutaneous transluminal coronary angioplasty.

Background: A direct association between human cytomegalovirus (HCMV) infection and the development of restenosis after coronary angioplasty has been suggested. The aim of this prospective study was to evaluate the value of HCMV serology in predicting the clinical outcome after percutaneous transluminal coronary angioplasty (PTCA).

Methods And Results: 112 patients undergoing elective PTCA were included in the study.

Coronary angioplasty induces rise in Chlamydia pneumoniae-specific antibodies.

Chlamydia pneumoniae is frequently found in atherosclerotic lesions, and high titers of specific antibodies are associated with increased risk for acute myocardial infarction. However, a causative relation has not been established yet. We performed a prospective study of 93 patients undergoing percutaneous transluminal coronary angioplasty (PTCA) to investigate whether angioplasty influences Chlamydia-specific antibody titers and whether there is an association with restenosis.

Humoral immune response to human cytomegalovirus in patients undergoing percutaneous transluminal coronary angioplasty.

Possible causal relations between prior human cytomegalovirus (HCMV) infection and atherosclerosis and between HCMV reactivation and restenosis after coronary angioplasty have been suggested. We investigated patterns of antibodies directed to HCMV in 112 patients undergoing percutaneous transluminal coronary angioplasty (PTCA) and in a group of sex- and age-matched controls (blood donors without evidence of atherosclerosis). Levels of antibodies to HCMV were measured by enzyme-linked immunosorbent assay (ELISA) of serum samples drawn before and 5 weeks after PTCA.