Transcutaneous Vaccination with Conjugate Typhoid Vaccine Vi-DT Induces Systemic, Mucosal, and Memory Anti-Polysaccharide Responses.

Transcutaneous vaccination can induce both mucosal and systemic immune responses. However, there are few data on anti-polysaccharide responses following transcutaneous vaccination of polysaccharides, despite the role that anti-polysaccharide responses play in protecting against intestinal mucosal and respiratory pathogens. Whether transcutaneous vaccination with a conjugate polysaccharide vaccine would be able to induce memory responses is also unknown.

Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition.

Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFR(T790M) gatekeeper mutation can occur either by selection of pre-existing EGFR(T790M)-positive clones or via genetic evolution of initially EGFR(T790M)-negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target EGFR(T790M); treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity.

Heterogeneity Underlies the Emergence of EGFRT790 Wild-Type Clones Following Treatment of T790M-Positive Cancers with a Third-Generation EGFR Inhibitor.

Unlabelled: Rociletinib is a third-generation EGFR inhibitor active in lung cancers with T790M, the gatekeeper mutation underlying most first-generation EGFR drug resistance. We biopsied patients at rociletinib progression to explore resistance mechanisms. Among 12 patients with T790M-positive cancers at rociletinib initiation, six had T790-wild-type rociletinib-resistant biopsies.

Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations.

Unlabelled: BRAF mutations occur in approximately 10% of colorectal cancers. Although RAF inhibitor monotherapy is highly effective in BRAF-mutant melanoma, response rates in BRAF-mutant colorectal cancer are poor. Recent clinical trials of combined RAF/EGFR or RAF/MEK inhibition have produced improved efficacy, but patients ultimately develop resistance.

Evaluation in mice of a conjugate vaccine for cholera made from Vibrio cholerae O1 (Ogawa) O-specific polysaccharide.

Background: Protective immunity against cholera is serogroup specific. Serogroup specificity in Vibrio cholerae is determined by the O-specific polysaccharide (OSP) of lipopolysaccharide (LPS). Generally, polysaccharides are poorly immunogenic, especially in young children.

Identification of in vivo-induced bacterial proteins during human infection with Salmonella enterica serotype Paratyphi A.

Salmonella enterica serotype Paratyphi A is a human-restricted pathogen and the cause of paratyphoid A fever. Using a high-throughput immunoscreening technique, in vivo-induced antigen technology (IVIAT), we identified 20 immunogenic bacterial proteins expressed in humans who were bacteremic with S. Paratyphi A but not those expressed in S.

In vivo expression of Salmonella enterica serotype Typhi genes in the blood of patients with typhoid fever in Bangladesh.

Background: Salmonella enterica serotype Typhi is the cause of typhoid fever. It is a human-restricted pathogen, and few data exist on S. Typhi gene expression in humans.

Simple, direct conjugation of bacterial O-SP-core antigens to proteins: development of cholera conjugate vaccines.

Bacterial O-SP-core antigens can be conjugated to proteins in the same, simple way as synthetic, linker-equipped carbohydrates by applying squaric acid chemistry. Introduction of spacers (linkers) to either O-SP-core antigens or protein carriers, which is involved in commonly applied protocols, is not required. The newly developed method described here consists of preparation of a squaric acid monoester derivative of O-SP-core antigen, utilizing the amino group inherent in the core, and reaction of the monoester with the carrier protein.

Interferon-γ and proliferation responses to Salmonella enterica Serotype Typhi proteins in patients with S. Typhi Bacteremia in Dhaka, Bangladesh.

Background: Salmonella enterica serotype Typhi is a human-restricted intracellular pathogen and the cause of typhoid fever. Cellular immune responses are required to control and clear Salmonella infection. Despite this, there are limited data on cellular immune responses in humans infected with wild type S.

Analysis of Salmonella enterica serotype paratyphi A gene expression in the blood of bacteremic patients in Bangladesh.

Background: Salmonella enterica serotype Paratyphi A is a human-restricted cause of paratyphoid fever, accounting for up to a fifth of all cases of enteric fever in Asia.

Methodology/principal Findings: In this work, we applied an RNA analysis method, Selective Capture of Transcribed Sequences (SCOTS), and cDNA hybridization-microarray technology to identify S. Paratyphi A transcripts expressed by bacteria in the blood of three patients in Bangladesh.

Characterization of anti-Salmonella enterica serotype Typhi antibody responses in bacteremic Bangladeshi patients by an immunoaffinity proteomics-based technology.

Salmonella enterica serotype Typhi is the cause of typhoid fever and a human-restricted pathogen. Currently available typhoid vaccines provide 50 to 90% protection for 2 to 5 years, and available practical diagnostic assays to identify individuals with typhoid fever lack sensitivity and/or specificity. Identifying immunogenic S.

Transcutaneous immunization with a synthetic hexasaccharide-protein conjugate induces anti-Vibrio cholerae lipopolysaccharide responses in mice.

Antibodies specific for Vibrio cholerae lipopolysaccaride (LPS) are common in humans recovering from cholera, and constitute a primary component of the vibriocidal response, a serum complement-mediated bacteriocidal response correlated with protection against cholera. In order to determine whether transcutaneous immunization (TCI) with a V. cholerae neoglycoconjugate (CHO-BSA) comprised of a synthetic terminal hexasaccharide of the O-specific polysaccharide of V.

Transcutaneous immunization with Clostridium difficile toxoid A induces systemic and mucosal immune responses and toxin A-neutralizing antibodies in mice.

Clostridium difficile is the leading cause of nosocomial infectious diarrhea. C. difficile produces two toxins (A and B), and systemic and mucosal anti-toxin A antibodies prevent or limit C.

Transcutaneous immunization with toxin-coregulated pilin A induces protective immunity against Vibrio cholerae O1 El Tor challenge in mice.

Toxin-coregulated pilin A (TcpA) is the main structural subunit of a type IV bundle-forming pilus of Vibrio cholerae, the cause of cholera. Toxin-coregulated pilus is involved in formation of microcolonies of V. cholerae at the intestinal surface, and strains of V.

Defective B cell responses in the absence of SH2D1A.

More than half of patients with X-linked lympho-proliferative disease, which is caused by a defect in the intracellular adapter protein SH2D1A, suffer from an extreme susceptibility to Epstein-Barr virus. One-third of these patients, however, develop dysgammaglobulenemia without an episode of severe mononucleosis. Here we show that in SH2D1A(-/-) mice, both primary and secondary responses of all Ig subclasses are severely impaired in response to specific antigens.