Discordant Effects of Licensed Meningococcal Serogroup B Vaccination on Invasive Disease and Nasal Colonization in a Humanized Mouse Model.

Background: The multicomponent meningococcal serogroup B vaccine (4CMenB) is an outer membrane vesicle and recombinant protein-based vaccine licensed to protect against serogroup B meningococcal disease. It remains unknown whether this vaccine will prevent carriage or transmission, key aspects in long-term vaccine success and disease eradication.

Methods: Using a "humanized" transgenic mouse model of nasal colonization, we took a systematic approach to estimate the potential for carriage prevention against antigenically diverse Neisseria meningitidis strains and to compare this protection to an invasive meningococcal disease challenge model.

Slam is an outer membrane protein that is required for the surface display of lipidated virulence factors in Neisseria.

Lipoproteins decorate the surface of many Gram-negative bacterial pathogens, playing essential roles in immune evasion and nutrient acquisition. In Neisseria spp., the causative agents of gonorrhoea and meningococcal meningitis, surface lipoproteins (SLPs) are required for virulence and have been extensively studied as prime candidates for vaccine development.

The molecular mechanism of Zinc acquisition by the neisserial outer-membrane transporter ZnuD.

Invading bacteria from the Neisseriaceae, Acinetobacteriaceae, Bordetellaceae and Moraxellaceae families express the conserved outer-membrane zinc transporter zinc-uptake component D (ZnuD) to overcome nutritional restriction imposed by the host organism during infection. Here we demonstrate that ZnuD is required for efficient systemic infections by the causative agent of bacterial meningitis, Neisseria meningitidis, in a mouse model. We also combine X-ray crystallography and molecular dynamics simulations to gain insight into the mechanism of zinc recognition and transport across the bacterial outer-membrane by ZnuD.

INNATE IMMUNITY. Cytosolic detection of the bacterial metabolite HBP activates TIFA-dependent innate immunity.

Host recognition of pathogen-associated molecular patterns (PAMPs) initiates an innate immune response that is critical for pathogen elimination and engagement of adaptive immunity. Here we show that mammalian cells can detect and respond to the bacterial-derived monosaccharide heptose-1,7-bisphosphate (HBP). A metabolic intermediate in lipopolysaccharide biosynthesis, HBP is highly conserved in Gram-negative bacteria, yet absent from eukaryotic cells.

A native outer membrane vesicle vaccine confers protection against meningococcal colonization in human CEACAM1 transgenic mice.

Background: The effect of protein-based meningococcal vaccines on prevention of nasopharyngeal colonization has been difficult to investigate experimentally because a reliable animal colonization model did not exist.

Methods: Human CEACAM1 transgenic mice, which can be colonized by meningococci, were immunized IP with one of two meningococcal native outer membrane vesicle (NOMV) vaccines prepared from mutants with attenuated endotoxin (lpxL1 knockout) and over-expressed sub-family B Factor H-binding proteins (FHbp). Animals were challenged intranasally two weeks after the third dose with wild-type strain H44/76, or were treated IP with anti-NOMV serum before and during the bacterial challenge.

Pretreatment of epithelial cells with live Streptococcus pneumoniae has no detectable effect on influenza A virus replication in vitro.

Influenza A virus (IAV) and Streptococcus pneumoniae (pneumococcus) are two major upper respiratory tract pathogens responsible for exacerbated disease in coinfected individuals. Despite several studies showing increased susceptibility to secondary bacterial infections following IAV infection, information on the direct effect of S. pneumoniae on IAV in vitro is unknown.

The ABC transporter encoded at the pneumococcal fructooligosaccharide utilization locus determines the ability to utilize long- and short-chain fructooligosaccharides.

Streptococcus pneumoniae is an important human pathogen that requires carbohydrates for growth. The significance of carbohydrate acquisition is highlighted by the genome encoding more than 27 predicted carbohydrate transporters. It has long been known that about 60% of pneumococci could utilize the fructooligosaccharide inulin as a carbohydrate source, but the mechanism of utilization was unknown.

Pneumococcal carbohydrate transport: food for thought.

Streptococcus pneumoniae relies exclusively on carbohydrates as a carbon source and devotes 30% of all transport mechanisms to carbohydrate import. Pneumococci utilize at least 32 carbohydrates in vitro. However, some proposed substrates are not human-derived, so it is unclear where they are encountered in the host niche, and other substrates remain unidentified.

6-Aminonicotinamide sensitizes human tumor cell lines to cisplatin.

The nicotinamide analogue 6-aminonicotinamide (6AN) is presently undergoing evaluation as a potential modulator of the action of various antineoplastic treatments. Most previous studies of this agent have focused on a three-drug regimen of chemical modulators that includes 6AN. In the present study, the effect of single-agent 6AN on the efficacy of selected antineoplastic drugs was assessed in vitro.

Sequence-dependent cytotoxicity of etoposide and paclitaxel in human breast and lung cancer cell lines.

Purpose: To evaluate the effect of schedule on the interaction of etoposide with paclitaxel in vitro against the A549 human lung cancer cell line and the MDA-231 and MCF-7 human breast cancer cell lines.

Methods: Exposure schedules that were 24-h concurrent, 24-h sequential, and sequential 24-h with a 24-h intervening drug-free period were quantitatively evaluated by the use of the median-effect principle and the combination index. The clonogenic assay was used to assess cytotoxicity, and calculations were done with computer software.

Cytotoxic synergy between pyrazoloacridine (NSC 366140) and cisplatin in vitro: inhibition of platinum-DNA adduct removal.

Pyrazoloacridine (PA), an acridine congener that has shown selective toxicity in solid tumor cells, full activity against noncycling and hypoxic cells, and promising activity in a recent Phase I trial, is currently undergoing Phase II testing as a solid tumor-selective agent. In the present study, clonogenic assays were used to examine the cytotoxic effects when PA was combined with other antineoplastic agents in A549 human non-small cell lung cancer cells in vitro. Data were analyzed by the median effect method.

Combinations of paclitaxel and etoposide in the treatment of lung cancer.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and etoposide are two chemotherapy agents with broad cytotoxic activity but different mechanisms of action and resistance. Previous in vitro studies of their combined cytotoxicity have yielded conflicting results. We evaluated the effects of drug scheduling in cell growth inhibition in lung and breast human cancer cell lines.

Cytotoxic effects of topotecan combined with various anticancer agents in human cancer cell lines.

Background: Topotecan (TPT) is a topoisomerase I poison that exhibits antineoplastic activity. Analysis of the cytotoxic effects of combinations of TPT and other anticancer agents has been limited.

Purpose: We assessed the cytotoxic effects produced by combinations of TPT and other antineoplastic agents in experiments involving multiple human cancer cell lines of diverse histologic origins.

Anaphylaxis after treatment with recombinant factor VIII.

Background: Treatment of hemophilia patients with recombinant factor VIII concentrates has not previously been associated with anaphylaxis.

Study Design And Methods: A 5-week-old boy with severe hemophilia A developed dyspnea, cyanosis, hypotension, and a diffuse urticarial rash following treatment with a recombinant factor VIII (Recombinate). To identify the cause of anaphylaxis in this patient, the vial lot was examined for the presence of endotoxin, and a checkerboard immunoblotting technique was used to test serum and/or plasma samples from the patient and mother for the presence of antibodies (IgA, IgG, IgE, and IgM) to Recombinate-related antigens (recombinant factor VIII, von Willebrand factor, human serum albumin, Chinese hamster ovary proteins, bovine serum albumin, mouse monoclonal anti-human factor VIII, polyethylene glycol 3350), and to ethylene oxide, the agent used to sterilize the infusion equipment.

RNA synthesis inhibitors alter the subnuclear distribution of DNA topoisomerase I.

The acute effect of RNA and DNA synthesis inhibitors on DNA topoisomerase (topo) I localization within cells was examined. Indirect immunofluorescence revealed that topo I was distributed throughout the nuclei but was concentrated in nucleoli of untreated K562 leukemia cells and A549 non-small cell lung cancer cells. Treatment with the DNA polymerase inhibitor aphidicolin did not alter this distribution.

Ion flow through a membrane: concentration and current responses to a step potential change.

Solutions of the simplified time-dependent Nernst-Planck electrodiffusion equations for various membrane models under the influence of a step voltage change are presented. Comparison of the results for a membrane with continuous sites to those for membranes with two, three or five intermediate sites shows little difference either qualitatively or quantitatively in the concentration of the diffusible ion inside the membrane, although some quantitative differences are evident in the calculated currents.