T Cell Receptor-Engaging Monoclonal Antibodies Mobilize the Anti-Tumor Functions of Invariant Natural Killer T Cells.

Invariant natural killer T cells (iNKTs) are innate-type T lymphocytes that directly kill tumor cells or tumor-growth promoting immunosuppressive cells such astumor-associated macrophages. Additionally, iNKTs robustly transactivate the antitumor functions of T, B, natural killer, and dendritic cells as well as reinvigorate exhausted immune cells in the tumor microenvironment. As such, iNKTs make excellent candidates for inclusion in anti-cancer cellular therapies. However, to capitalize on the potential benefits of iNKT cell-based approaches, it is imperative that we develop new and clinically viable strategies to enhance their antitumor function. To that end, two novel monoclonal antibodies (mAbs) that selectively bind to the human (NKTT320) or murine (NKT14m) invariant T cell receptor have been recently developed and characterized. Studies using purified human iNKTs (in vitro) and a model of non-human primate (in vivo) reveal that NKTT320 promotes swift, vigorous and sustained iNKT cell activation that is accompanied by robust production of inflammatory mediators and bystander immune cell activation. Furthermore, NKTT320 augments expression of cytotoxic markers and human iNKT cell degranulation. Similarly, NKT14m prompts dramatic murine iNKT cell activation and functional response both in vitro and in vivo. However, antitumor efficacy of a single dose of NKT14m injection in tumor-bearing mice is limited and tumor-model dependent. In contrast, combination treatment of NKT14m with either low dose interleukin (IL)-12 or the chemotherapeutic agent, cyclophosphamide results in a superior antitumor response in vivo. This is evident by activation of both iNKTs and other immune cells, prolonged survival of the tumor-challenged mice, and long-lasting immunity. Collectively, these recent studies justify further development of anti-iTCR mAbs that can be used alone or in conjunction with immunomodulatory agents to enhance iNKT cell antitumor immunity against various cancers.

Process optimization and evaluation of the effects of different time-temperature sous vide cooking on physicochemical, textural, and sensory characteristics of whiteleg shrimp (Litopenaeusvannamei).

The objective of the current study was to optimize the cook-chill conditions of high-value whiteleg shrimp (Litopenaeus vannamei) processed using the sous vide (SV) technique and to assess the effects of various time-temperature combinations on the physicochemical, textural, and sensory qualities. For optimization, a Response Surface Methodology (RSM) approach utilizing a Central Composite Design (CCD) was adopted. Optimum SV cooking conditions to acquire minimum texture (hardness) of 7235 g was 13.48 min and 81.87 °C, expressible moisture of 18.48% was 14.5 min and 84.5 °C, and cook loss of 5.58% was 5 min and 75 °C. Texture (hardness) and expressible moisture decreased while cooking loss increased with increasing time-temperature treatment. Redness and yellowness values increased (p < 0.05) with increasing SV cooking time-temperature, but lightness values were nearly consistent in all treatments. With increasing time and temperature, TBARs and total carotenoid content increased (p < 0.05). However, the TBARs values were within accepted limits and ranged from 0.05 to 0.08 mg malonaldehyde/kg. Sensory evaluation indicated that all SV cooked samples were well accepted, with overall scores ≥7. These results suggest that the SV cooking temperature and time had a substantial impact on the textural, physicochemical, and sensory characteristics of shrimp. In addition, increasing time-temperature increased cooking and moisture loss, but decreased hardness and higher sensory scores made the product more acceptable to consumers.

A Cross-Sectional Descriptive Analysis of Diversity, Equity, and Inclusion Presence Among United States Occupational and Environmental Medicine Residency Program Websites.

OBJECTIVE: To evaluate the presence of diversity, equity, and inclusion (DEI) among US occupational and environmental medicine (OEM) residency program websites. METHODS: In January to February 2022, two independent reviewers evaluated the websites of all 24 US accredited OEM residency programs and documented the presence of 10 predetermined DEI metrics and resident/faculty photographs and biographies. RESULTS: Program websites included a median of 1 (0-3) DEI element with 46% of websites containing none of the DEI metrics. Faculty photographs and biographies were included in 83% and 75% of websites, respectively. Resident photographs and biographies were included in 50% and 25% of websites, respectively. CONCLUSIONS: Many OEM residency program websites lack DEI presence. Programs should consider presenting information relevant to DEI on their websites to help attract more diverse applicant pools.

Ruxolitinib Ameliorates Airway Hyperresponsiveness and Lung Inflammation in a Corticosteroid-Resistant Murine Model of Severe Asthma.

Asthma prevalence has increased considerably over the decades and it is now considered as one of the most common chronic disorders in the world. While the current anti-asthmatic therapies are effective for most asthma patients, there are 5-10% subjects whose disease is not controlled by such agents and they account for about 50% of the asthma-associated healthcare costs. Such patients develop severe asthma (SA), a condition characterized by a dominant Th1/Th17 cytokine response that is accompanied by Type 2 (T2)-low endotype. As JAK (Janus Kinase) signaling is very important for the activation of several cytokine pathways, we examined whether inhibition of JAKs might lessen the clinical and laboratory manifestations of SA. To that end, we employed a recently described murine model that recapitulates the complex immune response identified in the airways of human SA patients. To induce SA, mice were sensitized with house dust mite extract (HDME) and cyclic (c)-di-GMP and then subsequently challenged with HDME and a lower dose of c-di-GMP. In this model, treatment with the JAK inhibitor, Ruxolitinib, significantly ameliorated all the features of SA, including airway hyperresponsiveness and lung inflammation as well as total IgE antibody titers. Thus, these studies highlight JAKs as critical targets for mitigating the hyper-inflammation that occurs in SA and provide the framework for their incorporation into future clinical trials for patients that have severe or difficult-to manage asthma.

Proposed Mitigation and Adaptation Strategies Related to Climate Change: Guidance for OEM Professionals.

Climate change is an urgent challenge amplified by socioeconomic factors that demands thoughtful public health responses from OEM professionals. This guidance statement from the American College of Occupational and Environmental Medicine focuses on the different strategies that these health professionals can implement to protect workers from health impacts associated with climate change hazards, foster workplace resilience in the face of rapidly changing environments, and take the necessary steps to mitigate the effects of global climate change.

Na+/H+ Exchanger Regulatory Factor 1 Mediates the Pathogenesis of Airway Inflammation in a Murine Model of House Dust Mite-Induced Asthma.

Na+/H+ exchanger regulatory factor 1 (NHERF1), a class I PDZ-binding protein, regulates G protein-coupled receptor signaling in some cell types. NHERF1 also functions as a scaffolding protein and activates non-G protein-coupled receptor signaling pathways, thereby contributing to the pathogenesis of various diseases. Although we have previously shown that NHERF1 regulates mast cell functions, there is little information regarding the role of NHERF1 in other immune cells. How NHERF1 regulates the pathogenesis of allergic disease such as asthma also remains unknown. In the current study, we show that NHERF1 promotes allergic airway inflammation in a house dust mite extract (HDME)-induced mouse model of asthma. Specifically, HDME-specific serum IgE levels, airway leukocyte numbers, and goblet cell hyperplasia were reduced in NHERF1+/- mice as compared with NHERF1+/+ mice. Interestingly, the gene expression of inflammatory (IL-17a, IL-25, and IL-33) as well as T helper 2 (Th2) cytokines (IL-4, IL-5, and IL-13) and several chemokines that recruit eosinophils, neutrophils, and lymphocytes were also decreased in the lungs of NHERF1+/- mice exposed to HDME. Consistent with these observations, microRNAs regulating mucus production, inflammation, Th2 effector functions, and IL-13 expression were increased in the lungs of HDME-treated NHERF1+/- mice. Overall, our studies reveal a unique role for NHERF1 in regulating asthma pathogenesis, and further elucidation of the mechanisms through which NHERF1 modulates allergic inflammation will lead to the development of new therapeutic strategies for asthma.

G Protein-Coupled Receptor Kinase 2 (GRK2) Regulates T Cell Response in a Murine Model of House Dust Mite-Induced Asthma.

G protein-coupled receptor kinase 2 (GRK2) is an adapter protein that modulates G protein-coupled receptor (GPCR) signaling. It also regulates the functions and activity of other intracellular proteins in many cell types. Accordingly, GRK2 is thought to contribute to disease progression by a variety of mechanisms related to its multifunctional roles. Indeed, GRK2 levels are enhanced in patient samples as well as in preclinical models of several diseases. We have previously shown that GRK2 regulates mast cell functions, and thereby contributes to exacerbated inflammation during allergic reactions. In the current study, we observed that GRK2 levels are enhanced in the lungs of human asthma patients and in mice sensitized to house dust mite extract (HDME) allergen. Consistent with these findings, interleukin (IL)-4 and IL-13 levels were reduced in the lungs of GRK2+/- mice in a HMDE mouse model of asthma. Because Th2 cells are the major source of these cytokines during asthma, we determined the role of GRK2 in regulating T cell-specific responses in our HMDE mouse model. We observed a significant reduction of airway hyperresponsiveness (AHR), lung eosinophil and lymphocyte counts, serum IgE, Th2 cytokines (IL-4 and IL-13), goblet cell hyperplasia and mucus production in mice that had reduced GRK2 expression specifically in T cells. Collectively, our studies reveal an important role for GRK2 in regulating T cell response during asthma pathogenesis and further elucidation of the mechanisms through which GRK2 modulates airway inflammation will lead to the development of new therapeutic strategies for asthma.

Workers' Compensation Elements in Different Jurisdictions in the United States.

: Over the decades, the workers' compensation system has provided many injured workers with a significant guarantee of both medical and financial support when they have been injured on the job. To be effective, workers' compensation systems at a minimum should include principles that require the addressing of medical causation, determination of an individual's functional ability both pre- and post-injury to include activity restrictions, return-to-work capability and disability, meeting jurisdiction-specific reporting requirements of the workers' compensation reporting requirements, and having knowledge of other perspectives of the various authorities and jurisdictions present in the United States. ACOEM lays out a description of various aspects of workers' compensations systems in the United States, with recommendations for minimal standards and best practices. This paper limits itself to the discussion of jurisdictions within the United States and ACOEM strongly recommends that providers consult directly with the states in which they are working as there are state variations in workers' compensation.

Safely Returning America to Work: Part I: General Guidance for Employers.

: Businesses are struggling to re-open as the world continues to deal with the coronavirus 2019 (COVID-19) pandemic. The reopening of businesses will require employers to implement safe return-to-work strategies through evaluation, testing, work modifications, and development of appropriate workplace policies. There will be unique challenges along the way as no one approach will be ideal for all workplaces and industries. This document is intended to provide return-to-work guidance for both employers and the occupational and environmental medicine physicians who will be supporting businesses in implementing safe return-to-work strategies.