Novel Aurora Kinase Inhibitor-Based Combination Therapies for PTCL

Peripheral T-cell lymphomas (PTCLs) are a rare, heterogeneous group of T-cell non-Hodgkin’s lymphomas (T-NHL) that display distinct clinical and biological features. Despite a detailed understanding of PTCL transformation, there is no current accepted standard of care for newly diagnosed or relapsed/refractory (r/r) patients. PTCL are highly proliferative neoplasms with an immunosuppressive microenvironment that elaborates drug resistance to current therapies with poor outcomes. Aurora kinases (AKs) are a family of mitotic oncogenic serine/threonine kinases (A, B/C) that are aberrantly expressed in PTCL, providing a growth advantage. Alisertib, an AK-A inhibitor, blocks the mitotic phase of the cell cycle resulting in apoptosis. Preclinical and clinical trials in PTCL demonstrated an ~30% response rate in r/r PTCL similar to other investigational agents. In order to improve response rates, alisertib-based combination therapies were tested with HDAC inhibitors, romidepsin and vorinostat, in phase Ib trials. To improve response rates to alisertib, we evaluated alisertib-induced polyploidy as a drug resistance mechanism by targeting microtubules with vincristine. In addition, we also targeted immunosuppression-induced proliferation with an anti-PD-L1 antibody and PI3K inhibition in PTCL. Targeting aberrant proliferation and immunosuppression is a novel strategy that warrants evaluation in clinical trials for PTCL, an unmet clinical need

Undercover Girl- The FBI\u27s Lesbian: A Note on Resources

Historical investigation is never easy, but deciphering gay and lesbian history often turns out to be more than usually convoluted. The players lead at least two lives—public and private — and secrets abound. Clues appear in unconventional sources, beyond the library and beyond theory. If you are lucky, the search develops its own momentum. This is how the story of undercover girl Angela Calomiris (1915-95), Angie to her friends, whose life was touched by extraordinary events, revealed itself to me

Built environment assessment: Multidisciplinary perspectives.

Context:As obesity has become increasingly widespread, scientists seek better ways to assess and modify built and social environments to positively impact health. The applicable methods and concepts draw on multiple disciplines and require collaboration and cross-learning. This paper describes the results of an expert team׳s analysis of how key disciplinary perspectives contribute to environmental context-based assessment related to obesity, identifies gaps, and suggests opportunities to encourage effective advances in this arena. Evidence acquisition:A team of experts representing diverse disciplines convened in 2013 to discuss the contributions of their respective disciplines to assessing built environments relevant to obesity prevention. The disciplines include urban planning, public health nutrition, exercise science, physical activity research, public health and epidemiology, behavioral and social sciences, and economics. Each expert identified key concepts and measures from their discipline, and applications to built environment assessment and action. A selective review of published literature and internet-based information was conducted in 2013 and 2014. Evidence synthesis:The key points that are highlighted in this article were identified in 2014-2015 through discussion, debate and consensus-building among the team of experts. Results focus on the various disciplines׳ perspectives and tools, recommendations, progress and gaps. Conclusions:There has been significant progress in collaboration across key disciplines that contribute to studies of built environments and obesity, but important gaps remain. Using lessons from interprofessional education and team science, along with appreciation of and attention to other disciplines׳ contributions, can promote more effective cross-disciplinary collaboration in obesity prevention

The Impact of Peer Mentoring on Marketing Content Mastery

This article describes and assesses a course design that uses peer mentors to facilitate a collaborative, hands-on learning experience in an introductory marketing course. Results demonstrate that peer mentoring increased content mastery and had a positive effect on students’ perceptions of the learning experience. Peer marketing mentors, along with the faculty team, achieved success in providing a demanding and engaging learning environment that meets the needs of learners and equips them with content knowledge required of career-ready professionals. A step-by-step guide is provided to enable others to develop a similar experience for students in their institutions

Effectiveness of a comprehensive mental skills curriculum in enhancing surgical performance: Results of a randomized controlled trial

INTRODUCTION: We hypothesized that the implementation of a novel mental skills curriculum (MSC) during laparoscopic simulator training would improve mental skills and performance, and decrease stress. METHODS: Sixty volunteer novices were randomized into intervention and control groups. All participants received FLS training while the intervention group also participated in the MSC. Skill transfer and retention were assessed on a live porcine model after training and 2 months later, respectively. Performance was assessed using the Test of Performance Strategies-2 (TOPS-2) for mental skills, FLS metrics for laparoscopic performance, and the State Trait Anxiety Inventory (STAI-6) and heart rate (HR) for stress. RESULTS: Fifty-five participants (92%) completed training and the transfer test, and 46 (77%) the retention test. There were no significant differences between groups at baseline. Compared to controls the intervention group significantly improved their mental skill use, demonstrated higher laparoscopic skill improvement during retention, and reported less stress during the transfer test. CONCLUSIONS: The MSC implemented in this study effectively enhanced participants' mental skill use, reduced cognitive stress in the operating room with a small impact on laparoscopic performance

Efficacy of Leukemia Inhibitory Factor as a Therapeutic for Permanent Large Vessel Stroke Differs among Aged Male and Female Rats

Preclinical studies using rodent models of stroke have had difficulty in translating their results to human patients. One possible factor behind this inability is the lack of studies utilizing aged rodents of both sexes. Previously, this lab showed that leukemia inhibitory factor (LIF) promoted recovery after stroke through antioxidant enzyme upregulation. This study examined whether LIF promotes neuroprotection in aged rats of both sexes. LIF did not reduce tissue damage in aged animals, but LIF-treated female rats showed partial motor skill recovery. The LIF receptor (LIFR) showed membrane localization in young male and aged rats of both sexes after stroke. Although LIF increased neuronal LIFR expression in vitro, it did not increase LIFR in the aged brain. Levels of LIFR protein in brain tissue were significantly downregulated between young males and aged males/females at 72 h after stroke. These results demonstrated that low LIFR expression reduces the neuroprotective efficacy of LIF in aged rodents of both sexes. Furthermore, the ability of LIF to promote motor improvement is dependent upon sex in aged rodents

Distinct immune signatures in directly treated and distant tumors result from TLR adjuvants and focal ablation.

Both adjuvants and focal ablation can alter the local innate immune system and trigger a highly effective systemic response. Our goal is to determine the impact of these treatments on directly treated and distant disease and the mechanisms for the enhanced response obtained by combinatorial treatments. Methods: We combined RNA-sequencing, flow cytometry and TCR-sequencing to dissect the impact of immunotherapy and of immunotherapy combined with ablation on local and systemic immune components. Results: With administration of a toll-like receptor agonist agonist (CpG) alone or CpG combined with same-site ablation, we found dramatic differences between the local and distant tumor environments, where the directly treated tumors were skewed to high expression of F4/80, Cd11b and Tnf and the distant tumors to enhanced Cd11c, Cd3 and Ifng. When ablation was added to immunotherapy, 100% (n=20/20) of directly treated tumors and 90% (n=18/20) of distant tumors were responsive. Comparing the combined ablation-immunotherapy treatment to immunotherapy alone, we find three major mechanistic differences. First, while ablation alone enhanced intratumoral antigen cross-presentation (up to ~8% of CD45+ cells), systemic cross-presentation of tumor antigen remained low. Combining same-site ablation with CpG amplified cross-presentation in the draining lymph node (~16% of CD45+ cells) compared to the ablation-only (~0.1% of CD45+ cells) and immunotherapy-only cohorts (~10% of CD45+ cells). Macrophages and DCs process and present this antigen to CD8+ T-cells, increasing the number of unique T-cell receptor rearrangements in distant tumors. Second, type I interferon (IFN) release from tumor cells increased with the ablation-immunotherapy treatment as compared with ablation or immunotherapy alone. Type I IFN release is synergistic with toll-like receptor activation in enhancing cytokine and chemokine expression. Expression of genes associated with T-cell activation and stimulation (Eomes, Prf1 and Icos) was 27, 56 and 89-fold higher with ablation-immunotherapy treatment as compared to the no-treatment controls (and 12, 32 and 60-fold higher for immunotherapy-only treatment as compared to the no-treatment controls). Third, we found that the ablation-immunotherapy treatment polarized macrophages and dendritic cells towards a CD169 subset systemically, where CD169+ macrophages are an IFN-enhanced subpopulation associated with dead-cell antigen presentation. Conclusion: While the local and distant responses are distinct, CpG combined with ablative focal therapy drives a highly effective systemic immune response

Modelling the impact of vector control on lymphatic filariasis programmes: current approaches and limitations

Vector control is widely considered an important tool for lymphatic filariasis (LF) elimination but is not usually included in programme budgets and has often been secondary to other policy questions in modelling studies. Evidence from the field demonstrates that vector control can have a large impact on programme outcomes and even halt transmission entirely, but implementation is expensive. Models of LF have the potential to inform where and when resources should be focused, but often simplify vector dynamics and focus on capturing human prevalence trends, making them comparatively ill-designed for direct analysis of vector control measures. We review the recent modelling literature and present additional results using a well-established model, highlighting areas of agreement between model predictions and field evidence, and discussing the possible determinants of existing disagreements. We conclude that there are likely to be long-term benefits of vector control, both on accelerating programmes and preventing resurgence. Key words: lymphatic filariasis; vector control; modelling; elimination; resurgence

Phylogenetic classification of Escherichia coli O157:H7 strains of human and bovine origin using a novel set of nucleotide polymorphisms

Novel SNPs from human and bovine O157:H7 E. coli isolates are mapped, revealing that the majority of human disease is caused by a bovine subset of this strain