A role for Langerhans cells (LC) in the induction of immune responses in the skin has yet to be conclusively demonstrated. We used skin immunization with OVA protein to induce immune responses against OVA-expressing melanoma cells. Mice injected with OVA-specific CD8+ T cells and immunized with OVA onto barrier-disrupted skin had increased numbers of CD8+ T cells in the blood that produced IFN-γ and killed target cells. These mice generated accelerated cytotoxic responses after secondary immunization with OVA. Prophylactic or therapeutic immunization with OVA onto barrier-disrupted skin inhibited the growth of B16.OVA tumors. LC played a critical role in the immunization process because depletion of LC at the time of skin immunization dramatically reduced the tumor-protective effect. The topically applied Ag was presented by skin-derived LC in draining lymph nodes to CD8+ T cells. Thus, targeting of tumor Ags to LC in vivo is an effective strategy for tumor immunotherapy.

In summary, our data suggest that DCs in tumors have limited antigen-presenting function. Inefficient antigen presentation extends to the tumor-draining lymph node, and may affect the generation of antitumor immune responses.

Objective To develop a probability model of matching into a US ophthalmology residency program using San Francisco Matching Program (SF Match) data. Design Retrospective data analysis of de-identified application and matching data. Participants Registrants for the 2013, 2014, and 2015 ophthalmology residency matches conducted by the SF Match. Methods Descriptive statistics of candidates, comparison of continuous and categorical variables between matched and nonmatched candidates, and linear regression modeling were performed. A recursive partitioning method was used to create a probability of matching algorithm. Main Outcome Measures Probability of successfully matching based on quantifiable candidate characteristics. Results Over the 3-year period, 1,959 individuals submitted an average of 64 applications and received a mean of nine interview invitations. The overall match rate was 71%, with 78% matching at one of their top five choices. Successful matches were more likely to occur in US medical school graduates (78% vs 20%, p < 0.001) and applicants on their first attempt (76% vs 29%, p < 0.001). The association between matching and number of programs applied became negative with > 48 applications. Probability of matching was “high” (> 80%) among US graduates with a step 1 United States Medical Licensing Examination (USMLE)score>243(regardless of number of programs applied to), a step 1 USMLE score of 231 to 243 who applied to at least 30 programs, and first-time applicants with a step 1 score >232. No international medical graduates or repeat applicants had a “high” probability of matching. Conclusions Although advice must be individualized for each candidate, applicants for ophthalmology residency who fall into a “high” probability of matching group are likely to be successful with applications to 45 or fewer programs. Applying to 80 or more programs should be considered for international medical graduates and/or applicants who are previously unmatched. Modification of the match application data form may allow more detailed analysis of variables such as Alpha Omega Alpha or Gold Humanism Honor Society membership, research activity, and composite evaluation on a standardized letter of recommendation.

BackgroundAtypical antipsychotic agents (AAP) alleviate the symptoms of severe mental health disorders, such as schizophrenia, by antagonizing dopamine and serotonin receptors. Recently, AAP have also been shown to exhibit immunomodulatory properties in the central nervous system (CNS).ObjectiveBuilding on research which demonstrated the ability of the AAP risperidone and clozapine to modify the disease course of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), we aimed to more fully investigate the potential of clozapine as a possible treatment for MS.ResultsWe report that orally administered clozapine significantly reduced the disease severity of EAE in a dose-dependent manner and was effective when administered prophylactically and therapeutically. In comparison to risperidone, quetiapine, and olanzapine, clozapine was the best at reducing disease severity. While clozapine-treated mice had only modest changes to peripheral leukocytes and cytokine responses, these animals had significantly fewer CNS-infiltrating CD4 T cells and myeloid cells. Furthermore, the CNS myeloid cells displayed a less activated phenotype in mice treated with clozapine. Finally, we found that co-administration of clozapine with glatiramer acetate enhanced disease protection compared to either treatment alone.ConclusionThese studies indicate that clozapine is an effective immunomodulatory agent with the potential to treat immune-mediated diseases such as MS.

Water-soluble quinone oxidoreductases capable of reducing quinone substrates via a concerted two-electron mechanism have been implicated in bacterial antioxidant defence. Twoelectron transfer avoids formation of dangerously reactive semi-quinone intermediates, moreover previous work in Pseudomonas putida indicated a direct protective effect for the quinols generated by an over-expressed oxidoreductase. Here, the Pseudomonas aeruginosa orthologs of five quinone oxidoreductases--MdaB, ChrR, WrbA, NfsB, and NQO1--were tested for their possible role in defending P. aeruginosa against H2O2 challenge. In in vitro assays, each enzyme was shown to reduce quinone substrates with only minimal semiquinone formation. However, when each was individually over-expressed in P. aeruginosa no overt H2O2-protective phenotype was observed. It was shown that this was due to a masking effect of the P. aeruginosa catalase, KatA; in a katA mutant, H2O2 challenged strains over-expressing the WrbA and MdaB orthologs grew significantly better than the empty plasmid control. A growth advantage was also observed for H2O2 challenged P. putida strains over-expressing P. aeruginosa wrbA, mdaB or katA. Despite not conferring a growth advantage to wild type P. aeruginosa, it is possible that these quinone oxidoreductases defend against H2O2 toxicity at lower concentrations.