Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated “hot” tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts “cold” tumors to hot, generates systemic CD8+ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.

Background: Acute cardiogenic shock is associated with high mortality rates. The Impella device is a microaxial left ventricular assist device that can be inserted through the axillary artery. The purpose of our study is to determine the role of the Axillary Impella devices on patients with acute cardiogenic shock. Methods: A retrospective chart review was conducted to identify patients who underwent Axillary Impella device placement for acute cardiogenic shock from January 1st, 2014 to September 30th, 2018 at a single institution. Inpatient records were examined to determine duration of device, length of stay (LOS), postoperative complications, and 30-day in-hospital mortality. Results: A total of 40 patients, who were primarily men (N = 29) with a mean age of 61.2 ± 10.7 years old, underwent Axillary Impella placement for cardiogenic shock. The primary reasons for implant were (1) required upgraded support from an Impella CP or intra-aortic balloon pump (iabp) to Impella 5.0, (2) to treat left ventricular (LV) distention for patients on extracorporeal mechanical oxygenation (ECMO), and (3) to provide longer term support and allow for mobilization of the patients in whom a device was already indwelling. Twenty-three of the patients had previous devices already in place including a Femoral Impella CP device or an iabp and 9 patients were on ECMO support. The duration of the device was 21.05 ± 17 days with the LOS of 40.8 ± 28 days for those patients. Seventeen of the patients went on to additional surgery including (1) Heartmate 3 device placement (N = 6), (2) other cardiac procedures such as surgical revascularization (N = 9), and orthotopic heart transplantation (N = 2). A total of 21 patients of the 40 (52%) died during their hospitalization with 7 patients (17%) having complications related to the Impella device. These complications included right arm ischemia or neuropathy (N = 3) and Impella malfunction requiring device replacement (N = 4). The majority of these devices were placed in the right axillary artery (N = 38) versus the left axillary artery (N = 2). Conclusions: A total of 58% (N = 23) of the study patients had previous mechanical support and 23% (N = 9) were on ECMO demonstrating the severity of disease and accounting for the high mortality. The Axillary Impella device allows for a minimally invasively placed device that is durable with a mean duration of 3 weeks. The Axillary artery Impella 5.0 provides upgraded full cardiac support while allowing for mobilization of the patient. In addition, it treats LV distention in patients on ECMO while avoiding sternotomy. Finally, the Axillary Impella provides time for decision making for explant, additional therapy with either long-term devices or orthotopic heart transplant.

BMP receptor inhibitors induce death of cancer cells through the downregulation of antiapoptotic proteins XIAP, pTAK1, and Id1-Id3. However, the current most potent BMP receptor inhibitor, DMH2, does not downregulate BMP signaling in vivo because of metabolic instability and poor pharmacokinetics. Here we identified the site of metabolic instability of DMH2 and designed a novel BMP receptor inhibitor, JL5. We show that JL5 has a greater volume of distribution and suppresses the expression of Id1 and pTak1 in tumor xenografts. Moreover, we demonstrate JL5-induced tumor cell death and tumor regression in xenograft mouse models without immune cells and humanized with adoptively transferred human immune cells. In humanized mice, JL5 additionally induces the infiltration of immune cells within the tumor microenvironment. Our studies show that the BMP signaling pathway is targetable in vivo and BMP receptor inhibitors can be developed as a therapeutic to treat cancer patients.

NKG2D is a C-type lectin-like receptor in the CD94/NKG2 family and is expressed by a variety of leukocyte populations including natural killer (NK) cells, γδ T cells, CD8+ T cells and certain innate lymphoid cell (ILC) subsets. NKG2D can bind proteins in two protein families – MIC and RAET1/ULBP. Expression of NKG2D ligands is low/absent under homeostatic conditions, but these proteins are upregulated in several contexts, including infection, cancer, physiologic stress, and senescence. NKG2D-driven activation of NK and CD8+ T cells has previously been shown to result in augmented control of infections and tumor growth. However, the role of NKG2D in the context of tissue injury and repair has not been established. Here we tested the effects of augmented NKG2D ligation in the context of a skin injury model. Biopsy punches were used to generate six 3- mm wounds on the dorsal surface of C57BL/6 mice. On days 0 and 1, NKG2D stimulating antibodies or isotype controls were injected into the peritoneal cavity and wound healing was assessed daily. Mice treated with NKG2D activating antibodies had more rapid wound repair than controls – wounds were healed by day 5 in NKG2D-treated mice as compared to day 7 in controls. Analogous results were observed in an ex vivo human skin model. Using a biolistic particle delivery system to induce upregulation of RAE (an NKG2D ligand), we observed more rapid wound repair compared to controls. Genetic ablation of NKG2D resulted in a 40% delay in wound healing. Moreover, depletion of NK1.1+ or CD8+ leukocytes blunted the benefit of NKG2D ligation, suggesting that T cells, NK cells, and/or ILCs may play a role in driving tissue repair. Thus, we demonstrate a potential therapeutic function of NKG2D engagement in tissue regeneration.

INTRODUCTION: Cumulative Sum (CuSum) is a real-time proficiency-monitoring tool adapted for simulation-based training. This study's purpose was to investigate long-term effects of a randomized prospective trial conducted on medical students assessing CuSum-guided curriculum against volume-based standards. METHODS: Prior study participants completed a survey assessing confidence, exposure, and feedback at 12 to 18 months post trial completion. They underwent triplicate testing of suturing, intubation, and central line placement (CVC), which was video-recorded and assessed by an expert evaluator. Baseline characteristics among repeat subjects were compared using chi-square tests. Retention and initial trial outcomes were compared using parametric statistical methods and linear regression to control for confounders.