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Recombinant IL-2 has been approved for the treatment of melanoma and renal cancer. However, IL-2 therapy is limited by its short half-life in circulation and the associated toxicities that emerge as a result of high systemic exposure. To overcome these limitations, we developed a localized cytokine LOCOcyteTM platform composed of allogeneic and engineered cells which produce potent immune effector molecules for local delivery with temporal regulation of activity. Administration of AVB-001 in mice and non-human primates demonstrated that IL2 local concentration (IP space) was 100x higher than the systemic concentration. Additional studies in mice demonstrated dose-dependent levels of IL2 in the intraperitoneal cavity in mice. Treatment of peritoneal tumors in mice using a single administration of AVB-001 provided sustained eradication of peritoneal tumors in an ovarian cancer mouse model. Our data in mice confirmed local increases in activation (CD25+CD8+) (8.6 fold) and proliferation (Ki67+CD8+)(3.4 fold) of cytotoxic T cells within the IP space in comparison to sham mice. Finally, a single administration of AVB-001 led to therapeutic levels of IL2 in the IP space in NHP and produced local and systemic T cell biomarker profiles that predict efficacy, AVB-001 was well tolerated by all animals with no abnormal clinical observations during the study. Our findings demonstrate that the LOCOcyteTM platform has a dose-dependent PK/PD effect, is safe and efficacious in animal models and enables itself to deliver a diverse set of cytokines alone or in combination which is presently explored. Combined, our pre-clinical results provide a rationale for testing AVB-001 in ovarian cancer patients.

Pancreatic β-cell failure is key to type 2 diabetes (T2D) onset and progression. We assessed whether human β-cell dysfunction induced by metabolic stress is reversible, evaluated the molecular pathways underlying persistent or transient damage, and explored the relationships with T2D islet traits. Twenty-six human islet preparations were exposed to several lipo- and/or glucotoxicity conditions, some of which impaired insulin release depending on stressor type, concentration and combination. Interestingly, reversal of dysfunction occurred after wash out for some, but not for all, of the lipoglucotoxic insults. Islet transcriptomes assessed by RNA-sequencing and eQTL analysis identified specific pathways underlying β-cell failure and recovery. Notably, comparison of a large number of human T2D islet transcriptomes with those of persistent or reversible β-cell lipoglucotoxicity showed shared gene expression signatures. The identification of mechanisms associated with human β-cell dysfunction and recovery, and their overlap with T2D islet traits provide novel insights into T2D pathogenesis and should foster the development of improved β-cell targeted therapeutic strategies.

The cervical spine functions to position the head while maintaining stability and protecting the spinal cord. The anatomy of the cervical spine dictates the amount of physiologic motion at each level. Knowledge of the normal biomechanical anatomy of the cervical spine is imperative to the understanding of the biomechanics of injury to the cervical spine. There are a variety of reproducible injury patterns based on the direction and magnitude of force applied to the cervical spine. Knowledge of these forces can allow an understanding of the mechanical and neurologic stability of the cervical spine and can also help guide treatment options. It is also important to understand the mechanism of injury and injured cervical structures based on radiographic findings, as often patients will present with neurologic examinations that also reflect noncervical spine-related injuries. The goal of this chapter is to present a review of the normal biomechanics of the cervical spine, in addition to presenting different injury patterns of the cervical spine from the minor to life-threatening, with the goal of maximizing postinjury function by ensuring proper treatment protocols are followed.

Stock returns are correlated with contemporaneous earnings growth, dividend growth, future real activity, and other cash-flow proxies. The correlation between cash-flow proxies and stock returns may arise from association of cash-flow proxies with one-period expected returns, cash-flow news, and/or expected-return news. We use Campbell's (1991) return decomposition to measure the relative importance of these three effects in regressions of returns on cash-flow proxies. In some of the popular specifications, variables that are motivated as proxies for cash-flow news also track a nontrivial proportion of one-period expected returns and expected-return news. As a result, the R2 from a regression of returns on cash-flow proxies may overstate or understate the importance of cash-flow news as a source of return variance.

Using the Lehman Fixed Income Database, this paper provides the first comprehensive study of expected firm (not equity) returns. After accounting for the debt component of the firm return, I find that many of the cross sectional determinants of expected equity and debt returns are nonexistent at the level of the firm. Cross sectional variation in expected firm returns is small relative to expected equity returns. In general, my results suggest that capital structure, not firm level, effects play a major role in understanding many security-specific asset pricing regularities. The emphasis on capital structure effects challenges various firm level rational and irrational theories motivating the book-to-market, short-term momentum, and long-term reversal effects in equity returns.