MICA and MICB are expressed by many human cancers as a result of cellular stress, and can tag cells for elimination by cytotoxic lymphocytes through natural killer group 2D (NKG2D) receptor activation. However, tumors evade this immune recognition pathway through proteolytic shedding of MICA and MICB proteins. We rationally designed antibodies targeting the MICA α3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA and MICB by human cancer cells. These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and reduced human melanoma metastases in a humanized mouse model. Antitumor immunity was mediated mainly by natural killer (NK) cells through activation of NKG2D and CD16 Fc receptors. This approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity.

Existing strategies to enhance peptide immunogenicity for cancer vaccination generally require direct peptide alteration, which beyond practical issues may impact peptide presentation and result in vaccine variability. Here, we report a simple adsorption approach using polyethyleneimine (PEI) in a mesoporous silica micro-rod (MSR) vaccine to enhance antigen immunogenicity. The MSR-PEI vaccine significantly enhanced host dendritic cell activation and T cell response over the existing MSR vaccine and bolus vaccine formulations. Impressively, a single injection of the MSR-PEI vaccine using an E7 peptide completely eradicated large established TC-1 tumors in ~80% of mice and generated immunological memory. When immunized with a pool of B16F10 or CT26 neoantigens, the MSR-PEI vaccine eradicated established lung metastases, controlled tumor growth and synergized with anti-CTLA4 therapy. Our findings using three independent tumor models suggest that the MSR-PEI vaccine approach may serve as a facile and powerful multi-antigen platform to enable robust personalized cancer vaccination.

Mucopolysaccharide diseases (MPS) are caused by deficiency of glycosaminoglycan (GAG) degrading enzymes, leading to GAG accumulation. Neurodegenerative MPS diseases exhibit cognitive decline, behavioural problems and shortened lifespan. We have characterised neuropathological changes in mouse models of MPSI, IIIA and IIIB to provide a better understanding of these events.Wild-type (WT), MPSI, IIIA and IIIB mouse brains were analysed at 4 and 9 months of age. Quantitative immunohistochemistry showed significantly increased lysosomal compartment, GM2 ganglioside storage, neuroinflammation, decreased and mislocalised synaptic vesicle associated membrane protein, (VAMP2), and decreased post-synaptic protein, Homer-1, in layers II/III-VI of the primary motor, somatosensory and parietal cortex. Total heparan sulphate (HS), was significantly elevated, and abnormally N-, 6-O and 2-O sulphated compared to WT, potentially altering HS-dependent cellular functions. Neuroinflammation was confirmed by significantly increased MCP-1, MIP-1α, IL-1α, using cytometric bead arrays. An overall genotype effect was seen in all parameters tested except for synaptophysin staining, neuronal cell number and cortical thickness which were not significantly different from WT. MPSIIIA and IIIB showed significantly more pronounced pathology than MPSI in lysosomal storage, astrocytosis, microgliosis and the percentage of 2-O sulphation of HS. We also observed significant time progression of all genotypes from 4–9 months in lysosomal storage, astrocytosis, microgliosis and synaptic disorganisation but not GM2 gangliosidosis. Individual genotype*time differences were disparate, with significant progression from 4 to 9 months only seen for MPSIIIB with lysosomal storage, MPSI with astrocytocis and MPSIIIA with microgliosis as well as neuronal loss. Transmission electron microscopy of MPS brains revealed dystrophic axons, axonal storage, and extensive lipid and lysosomal storage. These data lend novel insight to MPS neuropathology, suggesting that MPSIIIA and IIIB have more pronounced neuropathology than MPSI, yet all are still progressive, at least in some aspects of neuropathology, from 4–9 months.

Purpose: Nosocomial infections caused by Acinetobacter species is of increasing concern in critically ill patients, and the risk factors for this infection are not well established. The present investigation was done to determine incidence of nosocomial Acinetobacter infections. Our study retrospectively attempts to find risk and prognostic factors for the nosocomial acquisition of Acinetobacter infection. Methods: The medical records of 43 patients with Acinetobacter infection during two-year period (Oct1998-Oct2000) were reviewed to find the factors involved in the nosocomial acquisition of Acinetobacter. Acinetobacter isolates that were obtained from these patients were phenotypically typed using carbon assimilation tests. Antimicrobial susceptibility testing results were noted from the microbiology records. Results: Acinetobacter baumannii accounted for 41.8% (n=18) of all the infections. By multivariate logistic regression analysis, only resistant antibiotype {(Ceftazidime-OR, 7.13 [95% CI, 1 to 46]; P= 0.044); (Cefotaxime-OR, 6.09 [CI, 0.87 to 30]; P = 0.045)} and mechanical ventilation (OR, 5.84 [CI, 0.83 to 31]; P = 0.05) were found to be potential independent risk factors for mortality. Overall mortality rate was 33%. Conclusions: Most of A. baumannii isolates were multidrug resistant in our set up and infections due to them were associated with high mortality. Prevention of Multiple drug resistant (MDR) A. baumannii infections was achieved after discontinuation of cefotaxime in ICU. Infection with resistant clones and mechanical ventilation were found to be potential independent risk factors for mortality.