Perspectives and Factors Related to Pre-exposure Prophylaxis Use Among Young Men Who Have Sex With Men in the United States: A Mixed-Methods Study on the Role of History of PrEP Use.

ABSTRACT: This study quantitatively examined factors related to young men who have sex with men (YMSM)'s decisions to use pre-exposure prophylaxis (PrEP) by their history of PrEP use and qualitatively elicited their perspectives on PrEP options. Higher proportions of YMSM who had never used (vs. ever used) PrEP considered the following factors as important in their decisions to use PrEP: (a) Returning to PrEP follow-up visits (p = .02), (b) having to talk about sex/PrEP with providers (p = .013), (c) people assuming they are infected with HIV (p = .021), (d) family finding out about their PrEP use (p = .001), and (e) friends finding out about their PrEP use (p = .008). Through inductive content analysis, qualitative data showed that a higher proportion of YMSM who had never used PrEP (vs. ever used) expressed concerns about HIV stigma from nonaffirming health care providers and the potential risk of inadvertently revealing their LGBTQ+ identity to others, which were described as potential barriers to PrEP use. Overall, our findings suggest that future interventions may consider tailoring PrEP messaging to YMSM's history of PrEP use, which may ultimately increase PrEP uptake and adherence.

Monocytic MDSCs exhibit superior immune suppression via adenosine and depletion of adenosine improves efficacy of immunotherapy.

Immune checkpoint inhibitor (ICI) therapy is effective against many cancers for a subset of patients; a large percentage of patients remain unresponsive to this therapy. One contributing factor to ICI resistance is accumulation of monocytic myeloid-derived suppressor cells (M-MDSCs), a subset of innate immune cells with potent immunosuppressive activity against T lymphocytes. Here, using lung, melanoma, and breast cancer mouse models, we show that CD73-expressing M-MDSCs in the tumor microenvironment (TME) exhibit superior T cell suppressor function. Tumor-derived PGE2, a prostaglandin, directly induces CD73 expression in M-MDSCs via both Stat3 and CREB. The resulting CD73 overexpression induces elevated levels of adenosine, a nucleoside with T cell-suppressive activity, culminating in suppression of antitumor CD8+ T cell activity. Depletion of adenosine in the TME by the repurposed drug PEGylated adenosine deaminase (PEG-ADA) increases CD8+ T cell activity and enhances response to ICI therapy. Use of PEG-ADA can therefore be a therapeutic option to overcome resistance to ICIs in cancer patients.

Prediction of Sex and the Potential Use of On-Demand PrEP Among Young Men Who Have Sex With Men in the United States.

BACKGROUND: On-demand dosing of preexposure prophylaxis (PrEP) requires accurate prediction of sex; however, prediction abilities among young men who have sex with men (YMSM) have not been characterized. SETTING: A nationally recruited prospective cohort of YMSM ages 16-24 years. METHODS: We followed 120 YMSM for 8 weeks using digital daily surveys (DDSs) to measure engagement in and prediction of anal sex over 24 hours, along with condom use and other encounter-level circumstances. Our main outcome, an "unpredicted spontaneous encounter," was defined as an anal sex encounter that occurred without sufficient prior knowledge to (hypothetically) enable protective on-demand PrEP use according to dosing guidelines. We operationalized this outcome as an anal sex encounter for which a participant indicated: (1) on the prior day's DDS that there was a low likelihood of sex occurring in the subsequent 24 hours (unpredicted) and (2) on the current day's DDS that he knew ≤2 hours in advance that the encounter would occur (spontaneous). RESULTS: Approximately one-third of all anal sex encounters during the study period were unpredicted and spontaneous and would not have been protected (hypothetically) by on-demand dosing. More than two-thirds of participants experienced such an encounter and almost three-quarters of all acts were condomless. CONCLUSIONS: On-demand PrEP to prevent HIV acquisition may be challenging for many YMSM. Clinical and public health approaches that account for patients' predictive abilities alongside their dosing preferences may help to optimize selection of and adherence to PrEP dosing strategies.

Exosome-based cancer vaccine for prevention of lung cancer.

Background: Our earlier work has shown that a unique stem cell-based vaccine that comprises of murine embryonic stem cells (ESCs) and murine fibroblasts expressing the immunostimulant granulocyte-macrophage colony stimulating factor (GM-CSF) successfully protects mice from the outgrowth of an implantable form of murine lung cancer. The use of live ESCs raises the potential risks of inducing teratomas and autoimmunity. We have attempted to improve the safety and utility of this prophylactic vaccine by employing exosomes derived from murine ESCs engineered to produce GM-CSF (ES-exo/GM-CSF vaccine). Methods: We have previously reported that ES-exo/GM-CSF immunization does protect mice from the outgrowth of an implantable form of murine lung cancer. Here, we have investigated the cancer prevention efficacy of ES-exo/GM-CSF vaccine in an experimental metastasis model of murine lung cancer, in which Lewis lung carcinoma (LLC) cells were administered into female C57BL/6 mice (8 weeks of age) through tail vein injection and subsequently LLC tumors were established in lungs. Results: Our objective is to test the anti-cancer efficacy of ES-exo/GM-CSF vaccine in a mouse model of metastatic lung cancer. Our studies indicate that vaccination of mice with ES-exo/GM-CSF vaccine inhibited the growth of metastatic lung tumors. ES-exo/GM-CSF vactionation reduced lung tumor burden from 1.86% in non-vaccinated, LLC-challenged mice to 0.036% in corresponding vacinnated mice. Importantly, control exosomes without GM-CSF failed to provide protection against metastasized pulmonary tumors. The efficacy of ES-exo/GM-CSF vaccination was associated with a decrease in the frequencies of tumor-infiltrating immunosuppressive immune cells, including T regulatory cells, myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages, as well as an increase in effector cytokine production from intra-tumoral CD8+ T cells. Conclusions: Overall, our research provides a novel strategy for developing a cell-free prophylactic vaccine against lung tumors.

Single-Cell Immune Mapping of Melanoma Sentinel Lymph Nodes Reveals an Actionable Immunotolerant Microenvironment.

PURPOSE: Improving our understanding of the immunologic response to cancer cells within the sentinel lymph nodes (SLN) of primary tumors is expected to identify new approaches to stimulate clinically meaningful cancer immunity. EXPERIMENTAL DESIGN: We used mass cytometry by time-of-flight (CyTOF), flow cytometry, and T-cell receptor immunosequencing to conduct simultaneous single-cell analyses of immune cells in the SLNs of patients with melanoma. RESULTS: We found increased effector-memory αß T cells, TCR clonality, and γδ T cells selectively in the melanoma-bearing SLNs relative to non-melanoma-bearing SLNs, consistent with possible activation of an antitumor immune response. However, we also observed a markedly immunotolerant environment in the melanoma-bearing SLNs indicated by reduced and impaired NK cells and increased levels of CD8+CD57+PD-1+ cells, which are known to display low melanoma killing capabilities. Other changes observed in melanoma-bearing SLNs when compared with non-melanoma-bearing SLNs include (i) reduced CD8+CD69+ T cell/T regulatory cell ratio, (ii) high PD-1 expression on CD4+ and CD8+ T cells, and (iii) high CTLA-4 expression on γδ T cells. CONCLUSIONS: Our data suggest that these immunologic changes compromise antimelanoma immunity and contribute to a high relapse rate. We propose the development of clinical trials to test the neo-adjuvant administration of anti-PD-1 antibodies prior to SLN resection in patients with stage III melanoma. See related commentary by Lund, p. 1996.

Assembly and Operation of an Acoustofluidic Device for Enhanced Delivery of Molecular Compounds to Cells.

Efficient intracellular delivery of biomolecules is required for a broad range of biomedical research and cell-based therapeutic applications. Ultrasound-mediated sonoporation is an emerging technique for rapid intracellular delivery of biomolecules. Sonoporation occurs when cavitation of gas-filled microbubbles forms transient pores in nearby cell membranes, which enables rapid uptake of biomolecules from the surrounding fluid. Current techniques for in vitro sonoporation of cells in suspension are limited by slow throughput, variability in the ultrasound exposure conditions for each cell, and high cost. To address these limitations, a low-cost acoustofluidic device has been developed which integrates an ultrasound transducer in a PDMS-based fluidic device to induce consistent sonoporation of cells as they flow through the channels in combination with ultrasound contrast agents. The device is fabricated using standard photolithography techniques to produce the PDMS-based fluidic chip. An ultrasound piezo disk transducer is attached to the device and driven by a microcontroller. The assembly can be integrated inside a 3D-printed case for added protection. Cells and microbubbles are pushed through the device using a syringe pump or a peristaltic pump connected to PVC tubing. Enhanced delivery of biomolecules to human T cells and lung cancer cells is demonstrated with this acoustofluidic system. Compared to bulk treatment approaches, this acoustofluidic system increases throughput and reduces variability, which can improve cell processing methods for biomedical research applications and manufacturing of cell-based therapeutics.

Predictive risk factors associated with cholangitis following ERCP.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) with stent placement is used for the management of many pancreaticobiliary disorders. It is generally safe with a few short-term complications. The risk factors for the development of post-ERCP cholangitis due to stent occlusion have not been previously described. This study identified such risk factors among patients undergoing ERCP and stent placement for pancreatic or biliary obstruction. METHODS: 3648 ERCPs performed at the University of Louisville from 2008 to 2016 were reviewed. Data including patient demographics, diagnostic, laboratory, and ERCP related data were included. Patients were classified as having post-ERCP cholangitis if they developed jaundice, fever, right upper quadrant abdominal pain, and confirmatory findings of stent occlusion and/or purulent drainage at the time of repeat ERCP. These patients were compared to those who did not develop post-ERCP cholangitis using univariate and multivariate analyses. RESULTS: A total of 431 patients met inclusion criteria. Of these, 57 (13.2%) developed post-ERCP cholangitis. The average age of patients was 57 years with 57% women and 43% men. On univariate analysis, patients developing post-ERCP cholangitis were more likely to be of increased age, have higher white blood cell count (WBC), total bilirubin (TBili), AST, ALT, and alkaline phosphatase (AlkPhos), and a decreased serum albumin level. Risk factors for post-ERCP cholangitis due to stent occlusion identified on multivariate analysis include: a diagnosis of cancer, the placement of multiple biliary stents at index ERCP, and low serum albumin level. CONCLUSIONS: The development of post-ERCP cholangitis due to stent occlusion is strongly associated with the presence of malignancy, the placement of multiple biliary stents, and low serum albumin. A decreased threshold to monitor for stent occlusion, including routine liver function tests and prophylactic stent removal or exchange, should be employed in patients with these characteristics.