Military Medical Research最新文献

{"title":"In situ genetic engineering of host T-cells based on acellular scaffold strategy: a big but also small step for solid tumor immunotherapy","authors":"Shu-Yan Han, Zi-Xuan Zhao, Jun Wu","doi":"10.1186/s40779-024-00517-8","DOIUrl":"https://doi.org/10.1186/s40779-024-00517-8","url":null,"abstract":"<p>The advent of targeted T-cell therapy, with chimeric antigen receptor (CAR) T-cell therapy as the most prominent example, has yielded significant clinical efficacy for both relapsed and refractory hematological malignancies. However, this form of T-cell immunotherapy is often accompanied by severe systemic toxicities, suboptimal response rates, and host immune rejection in clinical settings, which detracts from its therapeutic utility. Additional concerns, such as the time-intensive ex vivo manufacturing process and the substantial treatment costs, also require resolution. Beyond these limitations, the use of CAR T-cell therapy against solid tumors presents an ongoing and formidable challenge. The extensive heterogeneity and complex spatial organization of solid tumors, along with their associated microenvironments, have impeded the broader clinical adoption of T-cell-based tumor immunotherapies [1, 2].</p><p>In the work of Dandia et al. [3], a novel strategy was reported that utilizes an acellular three-dimensional scaffold-based localized approach to program host T cells in situ, thus addressing several major challenges faced by traditional T-cell therapies and offering new hope for the elimination of solid tumors. The polyethylene glycol (PEG) scaffolds, conjugated with poly-L-lysine (PLL) and loaded with ovalbumin (OVA)-specific T-cell receptors (TCRs) lentiviruses (LVs), were implanted in B16-OVA melanoma-bearing mice and demonstrated significant anti-solid tumor efficacy. These bioactive scaffolds effectively recruited host T cells to the tumor site, transduced them with OVA-specific TCRs, and enabled them to home to tumors and draining lymph nodes. This facilitated in vivo T-cell genetic engineering and solid tumor immunotherapy. On one hand, this approach circumvented the need for in vitro manipulation and large-scale expansion of allogeneic T cells by directly utilizing host cells, thereby reducing the common risks associated with traditional adoptive cell therapies. On the other hand, unlike systemic delivery, the scaffold-based in situ localized administration minimized the incidence of “on-target, off-tumor” effects and enhanced the efficiency of regional immunomodulation, making it particularly effective at overcoming immunosuppression within solid tumors.</p><p>As is widely recognized, the ultimate goal of preclinical research is to facilitate successful clinical translation into practical medicine. The unquestionable benefits of this novel in situ immunomodulation strategy include its streamlined one-step, one-day process, as well as its high-efficiency targeting and programming of solid tumors, which engender considerable optimism for the immunotherapy of solid tumors with its ease of operation, reduced cost, and exceptional efficacy. However, the promising results of the current proof-of-concept study represent merely the beginning, and numerous considerations must be addressed before this approach can be applied clinically.</","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"300 2 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2024-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139668057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alleviating mitochondrial dysfunction in diabetic cardiomyopathy through the Adipsin and Irak2 pathways","authors":"Mabel L. Cummins, Grace Delmonte, Skylar Wechsler, Joseph J. Schlesinger","doi":"10.1186/s40779-024-00513-y","DOIUrl":"https://doi.org/10.1186/s40779-024-00513-y","url":null,"abstract":"<p>Diabetic cardiomyopathy (DCM) is a major cause of heart failure in diabetic patients. It progresses asymptomatically prior to the onset of severe cardiac symptoms [1]; therefore, elucidating the underlying mechanisms of DCM is critical to providing early treatment options. This commentary elaborates on the findings of Jiang et al. [2], who investigated the role of adipokine hormone, Adipsin, as a cardioprotective factor in DCM. We provide an exposition and alternative treatment considerations, like Fisetin, and discuss the potential of investigating other cellular targets implicated in cardiac dysfunction, like the interleukin-1 receptor-associated kinase-like 2 (Irak2) protein [3] and protein kinase R [4].</p><p>Elevated circulation of fatty acids (FAs) in diabetes leads to their ectopic accumulation in other organs, like the heart. This accumulation causes lipotoxicity, exacerbates oxidative stress and leads to cell and organ dysfunction [1]. When the excess utilization and uptake of lipids exceeds the adaptation of the heart, myocardial contractile function decreases, leading to heart failure. A treatment to reverse myocardial lipotoxicity and treat damaged mitochondrial tissue is currently unknown [5]. However, Adipsin (an adipokine implicated in poor cardiovascular function resulting from diabetes mellitus) may regulate myocardial metabolism and function.</p><p>Jiang et al. [2] measured cardiac function, lipid accumulation, and FAs oxidation in myocardial cells treated with Adipsin overexpression or <i>Irak2</i> knockdown (a protein downstream of Adipsin). Adipsin is a metabolic hormone used to control metabolism and fat homeostasis [1]. Overall, they found significant improvement in myocardial function, FAs oxidation, and electron transport chain activity, and decreased lipid accumulation in these cells, suggesting that Adipsin and Irak2 may be used to treat damaged mitochondrial tissue and alleviate myocardial lipotoxicity in patients with DCM. This research illuminates a novel mechanism of Adipsin alteration in DCM, revealing a potential method to reduce mitochondrial dysfunction.</p><p>First, Jiang et al. [2] established how Adipsin induces myocardial protection through interactions with the Irak2 protein in cardiomyocytes. In the mouse model, they found that Adipsin overexpression inhibited Irak2 translocation to the mitochondria, which increased prohibitin (Phb) and optic atrophy protein 1 (Opa1) levels, improving mitochondrial structure and mitochondrial electron transport chain activity. Jiang et al. [2] also induced DCM through a high-fat diet, which mimics only the early stages of diabetes, as the animals do not develop β-cell failure [6]. The combination of streptozotocin and a high-fat diet induces the onset and development into later stages of diabetes, including the organ damage observed in DCM [7]. To account for the pathology of DCM more thoroughly, we suggest that further work confirm the role of Adipsin through this meth","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"23 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139657633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nickel's carcinogenicity: the need of more studies to progress.","authors":"Consolato M Sergi","doi":"10.1186/s40779-024-00509-8","DOIUrl":"10.1186/s40779-024-00509-8","url":null,"abstract":"","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"8"},"PeriodicalIF":16.7,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10809529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139546850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antimicrobial resistance crisis: could artificial intelligence be the solution?","authors":"Guang-Yu Liu, Dan Yu, Mei-Mei Fan, Xu Zhang, Ze-Yu Jin, Christoph Tang, Xiao-Fen Liu","doi":"10.1186/s40779-024-00510-1","DOIUrl":"10.1186/s40779-024-00510-1","url":null,"abstract":"<p><p>Antimicrobial resistance is a global public health threat, and the World Health Organization (WHO) has announced a priority list of the most threatening pathogens against which novel antibiotics need to be developed. The discovery and introduction of novel antibiotics are time-consuming and expensive. According to WHO's report of antibacterial agents in clinical development, only 18 novel antibiotics have been approved since 2014. Therefore, novel antibiotics are critically needed. Artificial intelligence (AI) has been rapidly applied to drug development since its recent technical breakthrough and has dramatically improved the efficiency of the discovery of novel antibiotics. Here, we first summarized recently marketed novel antibiotics, and antibiotic candidates in clinical development. In addition, we systematically reviewed the involvement of AI in antibacterial drug development and utilization, including small molecules, antimicrobial peptides, phage therapy, essential oils, as well as resistance mechanism prediction, and antibiotic stewardship.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"7"},"PeriodicalIF":21.1,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10804841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139519305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monitoring of urinary iodine concentration in naval pilots: should iodine be supplemented or limited at coastal stations?","authors":"Jia Zeng, Qi Li, Xiang Lu, Dan-Dan Liu, Rong-Guan Jiao, Yan-Qing Jiang, Yan-Bing Liu, Wan-Qing Xu, Jun Ma, Guo-Li Gu","doi":"10.1186/s40779-024-00511-0","DOIUrl":"10.1186/s40779-024-00511-0","url":null,"abstract":"","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"6"},"PeriodicalIF":16.7,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10802043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139512907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gulf War illness with or without post-traumatic stress disorder: differential symptoms and immune responses.","authors":"Faith Nguyen, Ashok K Shetty","doi":"10.1186/s40779-023-00508-1","DOIUrl":"10.1186/s40779-023-00508-1","url":null,"abstract":"","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"5"},"PeriodicalIF":21.1,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10785439/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139425083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPR65 as a potential novel therapeutic target for the treatment of hepatic fibrosis","authors":"Leila Gobejishvili","doi":"10.1186/s40779-023-00507-2","DOIUrl":"https://doi.org/10.1186/s40779-023-00507-2","url":null,"abstract":"&lt;p&gt;Hepatic fibrosis is a consequence of chronic liver disease, which can lead to cirrhosis and liver failure. There is no Food and Drugs Administration approved therapy for liver fibrosis to date; hence, identifying effective therapeutic targets is an urgent need. Hepatic macrophages play a critical role in both initiation and progression of fibrosis. While resident liver macrophages, Kupffer cells are considered more anti-inflammatory, recent view has demonstrated that monocyte-derived macrophages (MoMs) are more pro-inflammatory and pro-fibrogenic [1]. Moreover, MoMs exhibit more plasticity and undergo M1/M2 “polarization”. The research by Zhang et al. [2] identified GPR65 signaling as a novel mechanism responsible for hepatic macrophage M1 polarization during liver injury and fibrosis. Notably, the role of this receptor in modulating inflammatory responses by various cells in other tissues has been previously reported [3]. However, the role of GPR65 in liver inflammation and fibrosis has not been examined until now.&lt;/p&gt;&lt;p&gt;GPR65 is a member of the proton-activated G protein-coupled receptor (GPCR) family, which serves as pH sensor and is expressed in metabolically important organs, including liver [3]. GPR65 is mainly expressed in immune cells (eosinophils, CD4&lt;sup&gt;+&lt;/sup&gt; T cells, and macrophages). Tissue injury and inflammation is often accompanied by a local acidification and pH changes, which is sensed by various proton-activated GPCRs including GPR65. Zhang et al. [2] found that the hepatic expression of GPR65 was significantly upregulated in patients with fibrosis and in two distinct experimental mouse models of fibrosis. These observations indicate that GPR65 upregulation is not specific to a single etiology of fibrosis but rather common for fibrogenesis. The authors also showed that, within the liver cells, &lt;i&gt;Gpr65&lt;/i&gt; mRNA levels were the highest in isolated liver macrophages, which increased in fibrotic liver. However, it was not clear which cells co-expressed GPR65 in the liver tissue. Relevant to its role in macrophage polarization, authors used various approaches to demonstrate that GPR65 expression was associated with pro-inflammatory M1 macrophage phenotype in vitro. The authors also addressed the role of extracellular acidification in the macrophage polarization. Specifically, they showed that acidic pH promoted the inflammatory phenotype in hepatic macrophages, partly in a GPR65-dependent manner. However, it was interesting that acidic pH did not increase GPR65, which indicates that although acidic environment in inflamed liver drives GPR65-dependent macrophage polarization, it does not affect GPR65 expression.&lt;/p&gt;&lt;p&gt;To show the relevance and causal relationship of GPR65 in fibrogenesis, the authors first used &lt;i&gt;Gpr65&lt;/i&gt; knockout mice in their studies. Liver transcriptomic analyses demonstrated that while &lt;i&gt;Gpr65&lt;/i&gt; deletion did not have a significant effect on baseline liver homeostasis, it affected various inflammatory a","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"8 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139398173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acellular scaffold-based approach for in situ genetic engineering of host T-cells in solid tumor immunotherapy.","authors":"Hiren Y Dandia, Mamatha M Pillai, Deepak Sharma, Meghna Suvarna, Neha Dalal, Ayush Madhok, Arvind Ingle, Shubhada V Chiplunkar, Sanjeev Galande, Prakriti Tayalia","doi":"10.1186/s40779-023-00503-6","DOIUrl":"10.1186/s40779-023-00503-6","url":null,"abstract":"<p><strong>Background: </strong>Targeted T-cell therapy has emerged as a promising strategy for the treatment of hematological malignancies. However, its application to solid tumors presents significant challenges due to the limited accessibility and heterogeneity. Localized delivery of tumor-specific T-cells using biomaterials has shown promise, however, procedures required for genetic modification and generation of a sufficient number of tumor-specific T-cells ex vivo remain major obstacles due to cost and time constraints.</p><p><strong>Methods: </strong>Polyethylene glycol (PEG)-based three-dimensional (3D) scaffolds were developed and conjugated with positively charged poly-L-lysine (PLL) using carbamide chemistry for efficient loading of lentiviruses (LVs) carrying tumor antigen-specific T-cell receptors (TCRs). The physical and biological properties of the scaffold were extensively characterized. Further, the scaffold loaded with OVA-TCR LVs was implanted in B16F10 cells expressing ovalbumin (B16-OVA) tumor model to evaluate the anti-tumor response and the presence of transduced T-cells.</p><p><strong>Results: </strong>Our findings demonstrate that the scaffolds do not induce any systemic inflammation upon subcutaneous implantation and effectively recruit T-cells to the site. In B16-OVA melanoma tumor-bearing mice, the scaffolds efficiently transduce host T-cells with OVA-specific TCRs. These genetically modified T-cells exhibit homing capability towards the tumor and secondary lymphoid organs, resulting in a significant reduction of tumor size and systemic increase in anti-tumor cytokines. Immune cell profiling revealed a significantly high percentage of transduced T-cells and a notable reduction in suppressor immune cells within the tumors of mice implanted with these scaffolds.</p><p><strong>Conclusion: </strong>Our scaffold-based T-cell therapy presents an innovative in situ localized approach for programming T-cells to target solid tumors. This approach offers a viable alternative to in vitro manipulation of T-cells, circumventing the need for large-scale in vitro generation and culture of tumor-specific T-cells. It offers an off-the-shelf alternative that facilitates the use of host cells instead of allogeneic cells, thereby, overcoming a major hurdle.</p>","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"3"},"PeriodicalIF":16.7,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10765574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139087474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-1 receptor associated kinase 2 is a functional downstream regulator of complement factor D that controls mitochondrial fitness in diabetic cardiomyopathy","authors":"Stanislovas S. Jankauskas, Fahimeh Varzideh, Pasquale Mone, Urna Kansakar, Francesco Di Lorenzo, Angela Lombardi, Gaetano Santulli","doi":"10.1186/s40779-023-00506-3","DOIUrl":"https://doi.org/10.1186/s40779-023-00506-3","url":null,"abstract":"&lt;p&gt;Diabetic cardiomyopathy is a disorder of the cardiac muscle that affects patients with diabetes. The exact mechanisms underlying diabetic cardiomyopathy are mostly unknown, but several factors have been implicated in the pathogenesis of the disease and its progression towards heart failure, including endothelial dysfunction, autonomic neuropathy, metabolic alterations, oxidative stress, and alterations in ion homeostasis, especially calcium transients [1]. In &lt;i&gt;Military Medical Research&lt;/i&gt;, Jiang et al. [2] sought to determine the functional role of complement factor D (Adipsin) in the pathophysiology of diabetic cardiomyopathy.&lt;/p&gt;&lt;p&gt;Complement factor D is a protein secreted into the bloodstream mainly by adipocytes. It is also known as Adipsin, C3 pro-activator convertase, or properdin factor D esterase. The protein is a member of the trypsin family of serine proteases and has a high level of expression in fat, implying a functional role for adipose tissue in immune system biology. Complement factor D is involved in the alternative pathway of the complement system where it cleaves factor B1 [3].&lt;/p&gt;&lt;p&gt;HFD feeding is usually used to obtain animal models of type 2 diabetes mellitus (T2DM), because chronic HFD feeding is capable of inducing hyperglycemia, insulin resistance and glucose intolerance, and similar manifestations of T2DM. Animal models that can nicely recapitulate human T2DM are crucial to examine the pathogenesis and intervention strategies for diabetes and diabetic complications [4, 5].&lt;/p&gt;&lt;p&gt;In their experimental setting, Jiang et al. [2] observed that HFD feeding for 6 months induced a pronounced hyperglycemia as well as diastolic and systolic cardiac dysfunction. They detected reduced serum levels of complement factor D starting at the 2nd month of HFD feeding, which is consistent with previous observations showing that circulating levels of complement factor D decreased in obese patients [6]; such reduction may be due to high activity or resistance, albeit the exact causes are not fully known.&lt;/p&gt;&lt;p&gt;Mass spectrometry (MS) analysis was used to screen the potential proteins that directly interact with complement factor D in cardiomyocytes [2]. The top 5 proteins with high MS scores were interleukin-1 receptor-associated kinase like 2 (Irak2), hemoglobin subunit beta-1 (Hbb-b1), hemoglobin subunit alpha (Hb-α), myosin regulatory light chain 2 (Myl2), and myosin light chain 3 (Myl3). After reviewing the functions of these proteins, Jiang et al. [2] noticed that Irak2 is known to participate in the regulation of cardiomyocyte apoptosis in models of diabetic cardiomyopathy. Additionally, mitochondrial translocation of Irak2 regulates oxidative metabolism in adipocytes [7].&lt;/p&gt;&lt;br/&gt;&lt;p&gt;Irak2 is one of the two putative serine/threonine kinases that are associated with the IL-1 receptor upon stimulation. It is involved in the IL-1 receptor/Toll-like receptor (TLR) signaling cascade and is known to act as an adaptor in the TLR-MyD88-TN","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"225 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139083862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disentangling the effects of PTSD from Gulf War Illness in male veterans via a systems-wide analysis of immune cell, cytokine, and symptom measures","authors":"Esha Sultana, Nandan Shastry, Rishabh Kasarla, Jacob Hardy, Fanny Collado, Kristina Aenlle, Maria Abreu, Emily Sisson, Kimberly Sullivan, Nancy Klimas, Travis J. A. Craddock","doi":"10.1186/s40779-023-00505-4","DOIUrl":"https://doi.org/10.1186/s40779-023-00505-4","url":null,"abstract":"One-third of veterans returning from the 1990–1991 Gulf War reported a myriad of symptoms including cognitive dysfunction, skin rashes, musculoskeletal discomfort, and fatigue. This symptom cluster is now referred to as Gulf War Illness (GWI). As the underlying mechanisms of GWI have yet to be fully elucidated, diagnosis and treatment are based on symptomatic presentation. One confounding factor tied to the illness is the high presence of post-traumatic stress disorder (PTSD). Previous research efforts have demonstrated that both GWI and PTSD are associated with immunological dysfunction. As such, this research endeavor aimed to provide insight into the complex relationship between GWI symptoms, cytokine presence, and immune cell populations to pinpoint the impact of PTSD on these measures in GWI. Symptom measures were gathered through the Multidimensional fatigue inventory (MFI) and 36-item short form health survey (SF-36) scales and biological measures were obtained through cytokine & cytometry analysis. Subgrouping was conducted using Davidson Trauma Scale scores and the Structured Clinical Interview for Diagnostic and statistical manual of mental disorders (DSM)-5, into GWI with high probability of PTSD symptoms (GWIH) and GWI with low probability of PTSD symptoms (GWIL). Data was analyzed using Analysis of variance (ANOVA) statistical analysis along with correlation graph analysis. We mapped correlations between immune cells and cytokine signaling measures, hormones and GWI symptom measures to identify patterns in regulation between the GWIH, GWIL, and healthy control groups. GWI with comorbid PTSD symptoms resulted in poorer health outcomes compared with both Healthy control (HC) and the GWIL subgroup. Significant differences were found in basophil levels of GWI compared with HC at peak exercise regardless of PTSD symptom comorbidity (ANOVA F = 4.7, P = 0.01,) indicating its potential usage as a biomarker for general GWI from control. While the unique identification of GWI with PTSD symptoms was less clear, the GWIL subgroup was found to be delineated from both GWIH and HC on measures of IL-15 across an exercise challenge (ANOVA F > 3.75, P < 0.03). Additional differences in natural killer (NK) cell numbers and function highlight IL-15 as a potential biomarker of GWI in the absence of PTSD symptoms. We conclude that disentangling GWI and PTSD by defining trauma-based subgroups may aid in the identification of unique GWI biosignatures that can help to improve diagnosis and target treatment of GWI more effectively.","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"25 1","pages":""},"PeriodicalIF":21.1,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139077474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}