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Epigenetic regulation plays a crucial role in the development and progression of cancer, including the regulation of antitumor immunity. The reversible nature of epigenetic modifications offers potential therapeutic avenues for cancer treatment. In particular, histone deacetylase (HDAC) inhibitors (HDACis) have been shown to promote antitumor T cell immunity by regulating myeloid cell types, enhancing tumor Ag presentation, and increasing expression of chemokines. HDACis are currently being evaluated to determine whether they can increase the response rate of immune checkpoint inhibitors in cancer patients. Although the potential direct effect of HDACis on T cells likely impacts antitumor immunity, little is known about how HDAC inhibition alters the transcriptomic profile of T cells. In this article, we show that two clinical-stage HDACis profoundly impact gene expression and signaling networks in CD8+ and CD4+ T cells. Specifically, HDACis promoted T cell effector function by enhancing expression of TNF-α and IFN-γ and increasing CD8+ T cell cytotoxicity. Consistently, in a murine tumor model, HDACis led to enrichment of CD8+ T cell subsets with high expression of effector molecules (Prf1, Ifng, Gzmk, and Grmb) but also molecules associated with T cell exhaustion (Tox, Pdcd1, Lag3, and Havcr2). HDACis further generated a tumor microenvironment dominated by myeloid cells with immune suppressive signatures. These results indicate that HDACis directly and favorably augment T cell effector function but also increase their exhaustion signal in the tumor microenvironment, which may add a layer of complexity for achieving clinical benefit in combination with immune checkpoint inhibitors., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Purpose: The adenosine 2A receptor (A2AR) mediates the immunosuppressive effects of adenosine in the tumor microenvironment and is highly expressed in non-small cell lung cancer (NSCLC). Taminadenant (PBF509/NIR178) is an A2AR antagonist able to reactivate the antitumor immune response., Patients and Methods: In this phase I/Ib, dose-escalation/expansion study, patients with advanced/metastatic NSCLC and ≥1 prior therapy received taminadenant (80-640 mg, orally, twice a day) with or without spartalizumab (anti-programmed cell death-1, 400 mg, i.v., every 4 weeks). Primary endpoints were safety, tolerability, and feasibility of the combination., Results: During dose escalation, 25 patients each received taminadenant alone or with spartalizumab; 19 (76.0%) and 9 (36.0%) had received prior immunotherapy, respectively. Dose-limiting toxicities (all Grade 3) with taminadenant alone were alanine/aspartate aminotransferase increase and nausea [n = 1 (4.0%) each; 640 mg], and in the combination group were pneumonitis [n = 2 (8.0%); 160 and 240 mg] and fatigue and alanine/aspartate aminotransferase increase [n = 1 (4.0%) each; 320 mg]; pneumonitis cases responded to steroids rapidly and successfully. Complete and partial responses were observed in one patient each in the single-agent and combination groups; both were immunotherapy naïve. In the single-agent and combination groups, 7 and 14 patients experienced stable disease; 7 and 6 patients were immunotherapy pretreated, respectively., Conclusions: Taminadenant, with and without spartalizumab, was well tolerated in patients with advanced NSCLC. The maximum tolerated dose of taminadenant alone was 480 mg twice a day, and 240 mg twice a day plus spartalizumab. Efficacy was neither a primary or secondary endpoint; however, some clinical benefit was noted regardless of prior immunotherapy or programmed cell death ligand-1 status., (©2022 American Association for Cancer Research.)

Evidence suggests that migrants may underutilize USA health care because of misconceptions about immigration-related consequences of health care use. This study aimed to explore whether common misconceptions about the immigration consequences of seeking health care, receiving an HIV test, and being diagnosed with HIV were associated with participant self-report of never having received an HIV test. The study sample comprised 297 adult, sexually active, documented and undocumented Spanish-speaking Latino migrants. Participants completed a cross-sectional survey via ACASI. In multiple logistic regression analyses controlling for sociodemographic variables and HIV stigma, misconceptions about laws emerged as a strong predictor of never having received an HIV test (p < .001). Associations between participants' endorsement of misconceptions and their HIV testing history suggest that incorrect perceptions of laws do deter some subgroups of USA Latino migrants from HIV testing. Identifying misconceptions about negative immigration consequences of engaging in important health behaviors should be a community health research priority.

Guided by a community-based participatory research and systems-based approach, this 3-year mixed-methods case study describes the experiences and capacity development of a Community-Academic Advisory Board (CAB) formed to adapt, implement, and evaluate an evidence-based childhood obesity treatment program in a medically underserved region. The CAB included community, public health, and clinical (n = 9) and academic partners (n = 9). CAB members completed capacity evaluations at 4 points. Partners identified best practices that attributed to the successful execution and continued advancement of project goals. The methodological framework and findings can inform capacity development and sustainability of emergent community-academic collaborations.

To develop, pilot test, and conduct psychometric analyses of an innovative scale measuring the influence of perceived immigration laws on Latino migrants' HIV-testing behavior. The Immigration Law Concerns Scale (ILCS) was developed in three phases: Phase 1 involved a review of law and literature, generation of scale items, consultation with project advisors, and subsequent revision of the scale. Phase 2 involved systematic translation- back translation and consensus-based editorial processes conducted by members of a bilingual and multi-national study team. In Phase 3, 339 sexually active, HIV-negative Spanish-speaking, non-citizen Latino migrant adults (both documented and undocumented) completed the scale via audio computer-assisted self-interview. The psychometric properties of the scale were tested with exploratory factor analysis and estimates of reliability coefficients were generated. Bivariate correlations were conducted to test the discriminant and predictive validity of identified factors. Exploratory factor analysis revealed a three-factor, 17-item scale. subscale reliability ranged from 0.72 to 0.79. There were significant associations between the ILCS and the HIV-testing behaviors of participants. Results of the pilot test and psychometric analysis of the ILCS are promising. The scale is reliable and significantly associated with the HIV-testing behaviors of participants. Subscales related to unwanted government attention and concerns about meeting moral character requirements should be refined.

Objective: Using a community-based participatory research and systems-based approach, the purpose of this community case study is to describe the planning process and first-year experiences of community-academic advisory board (CAB) partners involved with the development of an evidence-based childhood obesity treatment program in a medically underserved region., Method: Regional community partners ( n = 9; Pittsylvania/Danville Health District, Children's Healthcare Center, Danville Parks & Recreation, and Danville Boys & Girls Club) and academic partners ( n = 9) met monthly to select and adapt an evidence-based childhood obesity program, develop evaluation and recruitment protocols, and plan for program implementation. In the first 3 months, members developed a mixed-methods capacity evaluation, administered at 3 and 11 months following the first CAB meeting., Results: Most capacity dimensions were rated highly and demonstrated no significant change over time. However, perceptions of trust approached a significant increase ( p = .055), the ability to resolve conflicts significantly increased ( p = .018), and participation and influ-ence perceptions significantly decreased ( p = .001). Qualitative analysis elucidated members' experiences and key facilitator and barrier themes emerged., Conclusions: Similarities and differences between community and academic members' experiences allowed synthesis of best practices and lessons learned. The methodological framework and best practices can inform the capacity development for new community-academic collaborations.

Exposure to radiation, particularly a large or total-body dose, weakens the immune system through loss of bone marrow precursor cells, as well as diminished populations of circulating and tissue-resident immune cells. One such population is the skin-resident immune cells. Changes in the skin environment can be of particular importance as the skin is also host to a number of commensal organisms, including Candida albicans , a species of fungus that causes opportunistic infections in immunocompromised patients. In a previous study, we found that a 6 Gy sublethal dose of radiation in mice caused a reduction of cutaneous dendritic cells, indicating that the skin may have a poorer response to infection after irradiation. In this study, the same 6 Gy sublethal radiation dose led to a weakened response to a C. ablicans cutaneous infection, which resulted in systemic dissemination from the ear skin to the kidneys. However, this impaired response was mitigated through the use of interleukin-12 (IL-12) administered to the skin after irradiation. Concomitantly with this loss of local control of infection, we also observed a reduction of CD4 + and CD8 + T cells in the skin, as well as the reduced expression of IFN-γ, CXCL9 and IL-9, which influence T-cell infiltration and function in infected skin. These changes suggest a mechanism by which an impaired immune environment in the skin after a sublethal dose of radiation increases susceptibility to an opportunistic fungal infection. Thus, in the event of radiation exposure, it is important to include antifungal agents, or possibly IL-12, in the treatment regimen, particularly if wounds are involved that result in loss of the skin's physical barrier function.

Persons living with HIV (PLWH) report disproportionately high levels of exposure to traumatic events in childhood and adulthood. Traumatic experiences are associated with negative health and behavioral outcomes. Current research in this area seeks to further explicate the myriad health effects of trauma on PLWH and the pathways through which trauma operates. In this paper, we review articles published in English between January 2014 and June 2015 that examine traumatic experiences among PLWH, including intimate partner violence (IPV), domestic abuse, child abuse, and other forms of violence. A selection of studies examining trauma among PLWH and its associations with mental health, antiretroviral medication adherence, clinical outcomes, HIV disclosure, and sexual risk behaviors were included. Studies describing trauma coping strategies and interventions were also included. We conclude with recommendations for care of trauma-exposed PLWH and directions for future research.

The United States continues to be a prime target for attack by terrorist organizations in which nuclear detonation and dispersal of radiological material are legitimate threats. Such attacks could have devastating consequences to large populations, in the form of radiation injury to various human organ systems. One of these at risk organs is the cutaneous system, which forms both a physical and immunological barrier to the surrounding environment and is particularly sensitive to ionizing radiation. Therefore, increased efforts to develop medical countermeasures for treatment of the deleterious effects of cutaneous radiation exposure are essential. Interleukin-12 (IL-12) was shown to elicit protective effects against radiation injury on radiosensitive systems such as the bone marrow and gastrointestinal tract. In this article, we examined if IL-12 could protect the cutaneous system from a combined radiation injury in the form of sublethal total body irradiation and beta-radiation burn (β-burn) directly to the skin. Combined radiation injury resulted in a breakdown in skin integrity as measured by transepidermal water loss, size of β-burn lesion and an exacerbated loss of surveillant cutaneous dendritic cells. Interestingly, intradermal administration of IL-12 48 h postirradiation reduced transepidermal water loss and burn size, as well as retention of cutaneous dendritic cells. Our data identify IL-12 as a potential mitigator of radiation-induced skin injury and argue for the further development of this cytokine as a radiation countermeasure.

Radiation therapy (RT) continues to be a cornerstone in the treatment for many cancers. Unfortunately, not all individuals respond effectively to RT resulting clinically in two groups consisting of nonresponders (progressive disease) and responders (tumor control/cure). The mechanisms that govern the outcome of radiotherapy are poorly understood. Interestingly, a new paradigm has emerged demonstrating that the immune system mediates many of the antitumor effects of RT. Therefore, we hypothesized that the immune response following RT may dictate the efficacy of treatment. To examine this, we developed a tumor model that mirrors this clinically relevant phenomenon in which mice bearing Colon38, a colon adenocarcinoma, were treated locally with 15Gy RT resulting in both nonresponders and responders. More importantly, we were able to distinguish responders from nonresponders as early as 4 days post-RT allowing for the unique opportunity to identify critical events that ultimately determined the effectiveness of therapy. Intratumoral immune cells and interferon-gamma were increased in responsive tumors and licensed CD8 T cells to exhibit lytic activity against tumor cells, a response that was diminished in tumors refractory to RT. Combinatorial treatment with RT and the immunomodulatory cytokine IL-12 resulted in complete remission of cancer in 100% of cases compared to a cure rate of only 12% with RT alone. Similar data were obtained when IL-12 was delivered by microspheres. Therefore, the efficacy of RT may depend on the strength of the immune response induced after radiotherapy. Additionally, immunotherapy that further stimulates the immune cells may enhance the effectiveness of RT., (© 2013 UICC.)

Despite ongoing recommendations to engage health-disparate populations in the initiation and execution of community-based research, few studies report on the process of community engagement. The action-oriented Comprehensive Participatory Planning and Evaluation (CPPE) process is designed to guide community health planning and evaluation. This article describes how the CPPE process was utilized within a community-based participatory research initiative aimed at addressing obesity in the health-disparate Dan River Region. Encouraging community engagement in formulating research agendas and promoting ownership of health solutions will be key to improving obesity risk factors among Dan River Region residents and similar vulnerable communities.