A Mouse Model of Post-Arthroplasty Staphylococcus aureus Joint Infection to Evaluate In Vivo the Efficacy of Antimicrobial Implant Coatings

Post-arthroplasty infections represent a devastating complication of total joint replacement surgery, resulting in multiple reoperations, prolonged antibiotic use, extended disability and worse clinical outcomes. As the number of arthroplasties in the U.S. will exceed 3.8 million surgeries per year by 2030, the number of post-arthroplasty infections is projected to increase to over 266,000 infections annually. The treatment of these infections will exhaust healthcare resources and dramatically increase medical costs.To evaluate novel preventative therapeutic strategies against post-arthroplasty infections, a mouse model was developed in which a bioluminescent Staphylococcus aureus strain was inoculated into a knee joint containing an orthopaedic implant and advanced in vivo imaging was used to measure the bacterial burden in real-time. Mice inoculated with 5x10(3) and 5x10(4) CFUs developed increased bacterial counts with marked swelling of the affected leg, consistent with an acute joint infection. In contrast, mice inoculated with 5x10(2) CFUs developed a low-grade infection, resembling a more chronic infection. Ex vivo bacterial counts highly correlated with in vivo bioluminescence signals and EGFP-neutrophil fluorescence of LysEGFP mice was used to measure the infection-induced inflammation. Furthermore, biofilm formation on the implants was visualized at 7 and 14 postoperative days by variable-pressure scanning electron microscopy (VP-SEM). Using this model, a minocycline/rifampin-impregnated bioresorbable polymer implant coating was effective in reducing the infection, decreasing inflammation and preventing biofilm formation.Taken together, this mouse model may represent an alternative pre-clinical screening tool to evaluate novel in vivo therapeutic strategies before studies in larger animals and in human subjects. Furthermore, the antibiotic-polymer implant coating evaluated in this study was clinically effective, suggesting the potential for this strategy as a therapeutic intervention to combat post-arthroplasty infections

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

People Construal: Social Categorization and Trait Evaluations of Visually Perceived Groups

Our social world is populated by groups—students in classrooms, co-workers in teams, soldiers in platoons, and more. Social psychological research on person construal has established the processes and consequences of perceiving an individual, yet, we know less about our perception of groups. Here, I integrate person construal theory with vision science findings on ensemble perception to outline a framework of people construal, or how we make inferences and judgments about visually perceived groups. Overall, I propose that people construal relies on both social categories (e.g., a group’s gender ratio) and visual cues to within-category variability (e.g., facial masculinity or femininity). Study Set 1 examined whether perceivers were sensitive to a group’s gender ratio and whether this gender ratio impacted evaluative judgments. Studies 1 and 2 showed that within a half second, perceivers were relatively accurate in estimating the number of men within a twelve-person group, and that as a group’s gender ratio shifted from men to women participants associated the group with more threat, measured both explicitly and implicitly. Study 3 revealed that group threat evaluations were derived from participants perceived number of men and not inferences about men's perceived cohesiveness within the group. Study 4 underscored the influence of visual cues to men's gender typicality on group evaluations. Results showed that groups of masculine men, compared to feminine men, were rated as having more men and as more threatening. Study Set 2 shifted to questions of social category activation and social categorization. Study 5 revealed that group gender ratio and men’s gender typicality interacted to influence subsequent social category activation. Specifically, groups of majority masculine men facilitated activation of the category “man” to a greater degree than groups of majority feminine men. Study 6 revealed that participants categorized majority masculine men groups as “majority men” with higher accuracy and in a faster, more direct manner, compared to majority feminine men groups. Together, these results build a framework of people construal, advancing research beyond our perception of the individual to reveal insights into the role social categories and visual cues play in our perception of groups

Pervasive and Pernicious Underestimation of Asian Americans’ Support for Affirmative Action

Polling data show that 69% of Asian American voters favor affirmative action. However, Asian Americans were featured prominently by the organization Students for Fair Admissions, which played a central role in the Supreme Court’s decision to overturn affirmative action. This may distort people’s estimates of Asian Americans’ support for affirmative action. Two studies (N = 695) found that people, even Asian Americans, underestimated Asian Americans’ support for affirmative action. Three follow-up studies (N = 1,625), where we manipulated perceived Asian Americans’ support for affirmative action or the Supreme Court’s decision, found no evidence that such information affected White people’s support for affirmative action. In Study 6 (N = 365), however, we found that Asian Americans were more likely to agree with the Supreme Court’s decision to overturn affirmative action when they saw that a majority of Asian Americans supported the court ruling (relative to a control condition in which no information was presented). This suggests that the widespread misperception of Asian Americans’ support for affirmative action and their central role in the Supreme Court cases may ultimately create a self-fulfilling prophecy that could shift individual Asian Americans’ own attitude about affirmative action