Leukocytospermia induces intraepithelial recruitment of dendritic cells and increases SIV replication in colorectal tissue explants.

Mucosal exposure to infected semen accounts for the majority of HIV-1 transmission events, with rectal intercourse being the route with the highest estimated risk of transmission. Yet, the impact of semen inflammation on colorectal HIV-1 transmission has never been addressed. Here we use cynomolgus macaques colorectal tissue explants to explore the effect of leukocytospermia, indicative of male genital tract inflammation, on SIVmac251 infection.

Construction and optimization of gene expression signatures for prediction of survival in two-arm clinical trials.

Background: Gene expression signatures for the prediction of differential survival of patients undergoing anti-cancer therapies are of great interest because they can be used to prospectively stratify patients entering new clinical trials, or to determine optimal treatment for patients in more routine clinical settings. Unlike prognostic signatures however, predictive signatures require training set data from clinical studies with at least two treatment arms. As two-arm studies with gene expression profiling have been rarer than similar one-arm studies, the methodology for constructing and optimizing predictive signatures has been less prominently explored than for prognostic signatures.

Assembly of the Entire Carbon Backbone of a Stereoisomer of the Antitumor Marine Natural Product Hemicalide.

A strategy for the assembly of the entire carbon backbone of a stereoisomer of the antitumor marine natural product hemicalide has been investigated. The devised convergent approach relies on Horner-Wadsworth-Emmons and Julia-Kocienski olefination reactions for the construction of the C6=C7 and C34=C35 double bonds, respectively, an aldol reaction to create the C27-C28 bond, and a Suzuki-Miyaura cross-coupling as the endgame to form the C15-C16 bond.

Acetaminophen and lipopolysaccharide act in synergy for the production of pro-inflammatory cytokines in murine RAW264.7 macrophages.

There is extensive evidence that pro-inflammatory cytokines produced by macrophages are involved in toxicity induced by drugs such as acetaminophen (APAP). We investigated the effect of subtoxic concentrations of acetaminophen in conjunction with bacterial lipopolysaccharide (LPS) on the expression of the pro-inflammatory cytokines TNFalpha and IL-1beta using the mouse macrophage cell line RAW264.7 as a model.

Diethylnitrosamine initiation does not alter clofibric acid-induced hepatocarcinogenesis in the rat.

Clofibric acid (CLO) is a nongenotoxic hepatocarcinogen in rodents that causes altered hepatocellular foci and/or neoplasms. Initiation by DNA-damaging agents such as diethylnitrosamine (DEN) accelerates focus and tumor appearance and could therefore significantly contribute to shortening of the regulatory 2-year rodent carcinogenicity bioassays. However, it is crucial to evaluate the histological and molecular impact of initiation with DEN on hepatocarcinogenesis promoted by CLO.

Positive in vivo heterologous gene regulation by electric pulses delivery with metallothionein I gene promoter.

Background: In vivo electrotransfer is a physical method of gene delivery in various tissues and organs. It is a promising strategy for the systemic secretion of therapeutic proteins and for DNA vaccination. Nevertheless, for the success of gene therapy in clinics, it is essential to develop gene regulation systems.

American Association for Cancer Research 1999: 10-14 April, Philadelphia, Pennsylvania.

No genuinely new targets or drugs were disclosed; instead, data about known therapeutic approaches and compounds were consolidated. The results of Phase I clinical trials were presented for the two farnesyl transferase inhibitors R 115777 and L 778,123. These results will certainly contribute to the debate concerning the best way to use signal transduction inhibitors in clinic.

American Association for Cancer Research 1998: promises and prospects for the next century.

The American Association for Cancer Research (AACR) meeting of this year highlighted the progress made with farnesyl transferase inhibitors; two compounds have now entered Phase I clinical trials: R 115777 (Janssen) and SCH 66336 (Schering Plough) and several others are nearing clinical testing. Several new protein kinase inhibitors from Warner Lambert and Novartis were also discussed. Angiogenesis (as well as apoptosis) also featured, with many pharmaceutical companies and academic institutions having programmes in this area of cancer research.

Multinational pharmaceutical companies gather in Berlin.

The 39th Annual General Meeting of the Pharma Documentation Ring (PDR) was held in Berlin, Germany, on September 26, 1997. Common themes reported on included the impact and widespread use of intranet technology; expansion in end-user searching; experience with electronic journals; and programs for the development of electronic archiving and document management systems. Other sessions discussed aspects of chemistry systems; copyright; drug information systems on development products; information management, in-house management of databases; Intranet/Internet activities; and patents.

Transcriptional activation of the metallothionein I gene by electric pulses in vivo: basis for the development of a new gene switch system.

Background: In vivo gene transfer to skeletal muscle is a promising strategy for the treatment of muscular disorders and for the systemic delivery of therapeutic proteins. Nevertheless, for a safe and effective protein production, the spatial and temporal control of gene expression is critical. The existing regulating systems rely on the use of an exogenously regulatory protein and/or an inducer drug whose pharmacological properties are of major concerns for therapeutic applications in humans.

Benzo[f]naphtyridones: a new family of topical antibacterial agents active on multi-resistant Gram-positive pathogens.

The synthesis and antibacterial activity of benzo[f][1,7]naphtyridone derivatives are reported. These compounds are potent antibacterial agents with a Gram-positive spectrum of activity. They are active against multi-resistant cocci, especially Staphylococcus aureus strains.

NLS bioconjugates for targeting therapeutic genes to the nucleus.

One of the major steps limiting non-viral gene transfer efficiency is the entry of plasmid DNA from the cytoplasm into the nucleus of transfected cells. Trafficking of nuclear proteins from the cytoplasm into the nucleus through nuclear pore complexes is mediated by the presence of nuclear localization sequences (NLS) on proteins. Viral DNA and RNA also require interaction with cellular machinery for efficient nuclear import.

Polypeptide composition of an adenovirus type 5 used in cancer gene therapy.

For cancer gene therapy, a recombinant adenovirus serotype 5 named RPR/INGN201 has been constructed by susbtitution of the E1 region with human tumor suppressor gene p53. The protein components of RPR/INGN201 virions were separated by reversed-phase HPLC and were individually identified by electrospray time-of-flight mass spectrometry and N-terminal sequencing, both on intact proteins and on their proteolytic fragments after trypsin digestion. Twenty-five peptide components of the proteome (including fiber) with greater than 0.

Synthesis of anticonvulsive AMPA antagonists: 4-oxo-10-substituted-imidaz.

The overstimulation of excitatory amino acid receptors such as the glutamate AMPA receptor has been implicated in the physiopathogenesis of epilepsy as well as in acute and chronic neurodegenerative disorders. An original series of readily water soluble 4-oxo-10-substituted-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid derivatives was synthesized. The most potent derivative 6a exhibited nanomolar binding affinity (IC50 = 35nM) and antagonist activity (IC50 = 6nM) at ionotropic AMPA receptor.

Critical assessment of the nuclear import of plasmid during cationic lipid-mediated gene transfer.

Background: Cationic lipid-mediated gene transfer is a promising approach for gene therapy. However, despite the significant amount of lipoplexes internalized by target cells, transgene expression remains too low. Obstacles to nuclear accumulation of plasmid DNA include: the passage of DNA across the cellular membrane, the dismantling of nucleolipidic particles in the cytoplasm and the nuclear import of plasmid DNA.

Synthesis and biological evaluation of benzo[b]naphthyridones, a series of new topical antibacterial agents.

We describe here the synthesis and biological evaluation of a series of benzo[b]naphthyridones, a new family of tricyclic antibacterial compounds that have a gram-positive spectrum of activity. RP60556A, one of the most potent of these compounds, is bactericidal against multiresistant cocci, especially multiresistant Staphylococcus aureus strains. Its physico-chemical and biological properties make it particularly suitable for topical antibacterial use.

Bioisosteres of 9-carboxymethyl-4-oxo-imidazo[1,2-a]indeno-[1,2-e]pyrazin-2-carboxylic acid derivatives. Progress towards selective, potent in vivo AMPA antagonists with longer durations of action.

A novel series of 2- and 9-disubstituted heterocyclic-fused 4-oxo-indeno[1,2-e]pyrazin derivatives was synthesized. One of them, the 9-(1H-tetrazol-5-ylmethyl)-4-oxo-5,10-dihydroimidazo[1,2-a]indeno[1,2-e]pyrazin-2-yl phosphonic acid 4i exhibited a strong and a selective binding affinity for the AMPA receptor (IC50 = 13 nM) and demonstrated potent antagonist activity (IC50 = 6nM) at the ionotropic AMPA receptor. This compound also displayed good anticonvulsant properties against electrically-induced convulsions after ip and iv administration with ED50 values between 0.

Synthesis and potent anticonvulsant activities of 4-oxo-imidazo[1,2-a]inden.

The over-stimulation of excitatory amino acid receptors such as the glutamate AMPA receptor has been suggested to be associated with neurodegenerative disorders. Here we describe an original series of readily water soluble 4-oxo-imidazo[1,2-a] indeno[1,2-e]pyrazin-8- and -9-carboxylic (acetic) acid derivatives. One of these compounds, 4f, exhibited nanomolar binding affinity, potent competitive antagonism at the ionotropic AMPA receptor and a long duration of anticonvulsant activity after administration by parenteral route in vivo.

The antioxidant ebselen prevents neurotoxicity and clinical symptoms in a primate model of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), via its major metabolite 1-methyl-4-phenylpyridinium (MPP(+)), produces in primates including humans clinical, biochemical, and neuropathological changes similar to those which occur in idiopathic Parkinson's disease. Ebselen is an antioxidant drug with glutathione peroxidase-like activity and a proven neuroprotective action in stroke patients. Here we show that Ebselen, when administered before, during, and after MPTP injections, prevents both neuronal loss and clinical symptoms in a primate MPTP model of Parkinson's disease.

8-Methylureido-10-amino-10-methyl-imidazo[1,2-a]indeno[1,2-e] pyrazine-4-ones: highly in vivo potent and selective AMPA receptor antagonists.

Water soluble 8-methylureido-10-amino-10-methyl-imidazo[1,2-a]indeno[1,2-e]pyraz ine-4-one 4 represents a novel class of highly potent and selective AMPA receptors antagonists with in vivo activity. The dextrorotatory isomer (+)-4 was found to display the highest affinity with an IC50 of 10 nM. It also exhibited very good anticonvulsant effects after i.

High-level protein secretion into blood circulation after electric pulse-mediated gene transfer into skeletal muscle.

Numerous diseases are linked to the absence or insufficient concentration of a specific plasma protein. Gene transfer is an appealing strategy for correction of such diseases. We report high and sustained plasma secretion of human secreted alkaline phosphatase and of human Factor IX by skeletal muscle of mice.

Effects of RPR 118723, a novel antagonist at the glycine site of the NMDA receptor, in vitro.

RPR 118723 ((8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno[1, 2-b]pyrazin-5-yl) acetic acid) was previously reported to exhibit potent affinity for the glycine site of the N-methyl-D-aspartate (NMDA) receptor-channel complex in the nanomolar range (K(i)=3.1+/-0. 8 nM).

The anti-oxidant ebselen antagonizes the release of the apoptogenic factor cytochrome c induced by Fe2+/citrate in rat liver mitochondria.

We studied the effects of ebselen (a seleno-organic anti-oxidant), on the release of the apoptogenic factor, cytochrome c, in two different experimental situations damaging mitochondria: (1) Fe(2+)/citrate, known to induce lipid peroxidation consecutively to an oxidative stress; and (2) atractyloside, a ligand of the adenine nucleotide translocator. The effects of ebselen were compared to those of butylated hydroxytoluene (BHT, an inhibitor of lipid peroxidation), and cyclosporine A (CsA, a classical pore antagonist). Ebselen, like BHT, inhibited Fe(2+)/citrate-induced release of cytochrome c, whereas CsA was inactive.

Indeno[1,2-b]pyrazin-2,3-diones: a new class of antagonists at the glycine site of the NMDA receptor with potent in vivo activity.

Indeno¿1,2-bpyrazin-2,3-diones have been identified as a novel series of potent ligands on the glycine site of the NMDA receptor. To improve their in vivo activities, an acetic acid-type side chain was introduced to the 5-position, giving water-soluble compounds when formulated as the sodium salt (>10 mg/mL). Introduction of a chlorine atom in the 8-position led to a dramatic improvement of anticonvulsant activity and this was surprising since this change did not improve binding affinity.