Pub Date : 2024-02-12DOI: 10.1186/s40779-024-00514-x
Marcin M Kamiński
{"title":"ADP-dependent glucokinase: the ancient, archaeal key to prostate cancer.","authors":"Marcin M Kamiński","doi":"10.1186/s40779-024-00514-x","DOIUrl":"10.1186/s40779-024-00514-x","url":null,"abstract":"","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"10"},"PeriodicalIF":21.1,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10860298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139717730","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}
Pub Date : 2024-02-08DOI: 10.1186/s40779-024-00515-w
Qiang Cai, Quazi T H Shubhra
{"title":"Deciphering the molecular interplay and tumorigenesis in hepatocellular carcinoma through insights into FBXL6 and KRAS<sup>G12D</sup>.","authors":"Qiang Cai, Quazi T H Shubhra","doi":"10.1186/s40779-024-00515-w","DOIUrl":"10.1186/s40779-024-00515-w","url":null,"abstract":"","PeriodicalId":18581,"journal":{"name":"Military Medical Research","volume":"11 1","pages":"9"},"PeriodicalIF":21.1,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10851466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139702897","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}
Pub Date : 2024-02-03DOI: 10.1186/s40779-024-00517-8
Shu-Yan Han, Zi-Xuan Zhao, Jun Wu
<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.</
由于这些功能化生物材料具有化学加工性强、成本效益高、供应充足和可扩展性强等优点，它们有望成为新治疗模式的竞争者。最后，肿瘤抗原逸出和异质性带来的挑战，尤其是在实体瘤中，使得阐明基因和表观遗传学的多样性及其潜在的运行机制，对于个体肿瘤的定制治疗和治疗剂的标准化生产至关重要。毫无疑问，目前迫切需要加强跨学科合作和整合新技术[5, 6]。例如，利用高分辨率、时空控制的单细胞成像技术可以阐明分子信号通路和支配免疫细胞活动的潜在机制；在高通量测序、机器学习和计算预测的推动下，新抗原的发现和筛选可以使个性化免疫疗法受益。此外，多种空间 omics、人工智能和临床肿瘤学的整合有助于构建肿瘤微环境中的互动网络，加强对患者的临床管理。总之，本研究[3]提出的新型一体化 PEG-PLL 平台提供了一种原位转导宿主 T 细胞的创新策略，对实体瘤产生了显著的抗肿瘤效果。虽然这一突破为免疫细胞疗法的新范例铺平了道路，但我们认识到，在未来几年中，必须投入更多的努力来彻底改变实体瘤的治疗方法。CAR:嵌合抗原受体LVs:慢病毒OVA:卵清蛋白PEG:聚乙二醇PLL:聚 L-赖氨酸TCRs:T 细胞受体Zhu C, Wu Q, Sheng T, Shi J, Shen X, Yu J, et al.Bioact Mater.2024;33:377-95.CAS PubMed Google Scholar Liu H, Shen W, Liu W, Yang Z, Yin D, Xiao C. From oncolytic peptides to oncolytic polymers: a new paradigm for oncotherapy.Bioact Mater.2024;31:206-30.CAS PubMed Google Scholar Dandia HY, Pillai MM, Sharma D, Suvarna M, Dalal N, Madhok A, et al. Acellular scaffold-based approach for in situ genetic engineering of host T-cells in solid tumor immunotherapy.Mil Med Res. 2024;11(1):3.CAS PubMed PubMed Central Google Scholar Dagher OK, Posey AD Jr.CAR T 和 CAR NK 细胞癌症疗法的岔路口。Nat Immunol.2023;24(12):1994-2007.Article CAS PubMed Google Scholar Walsh LA, Quail DF.利用空间技术解码肿瘤微环境。Nat Immunol.2023;24(12):1982-93.Article CAS PubMed Google Scholar Liu L, Yoon CW, Yuan Z, Guo T, Qu Y, He P, et al. Cellular and molecular imaging of CAR-T cell-based immunotherapy.Adv Drug Deliv Rev. 2023; 203: 115135.Article CAS PubMed Google Scholar Download referencesNot applicable.本研究得到了国家自然科学基金项目（52173150）、广州市科技计划市校联合资助项目（2023A03J0001）和中国公共卫生基金博士后基金项目（GZC20233297）的资助。作者及工作单位香港科技大学（广州）生物科学与生物医学工程研究中心，中国广东省广州市南沙区，邮编：511400韩淑艳，赵子璇 &；Jun WuDepartment of Nephrology, Center of Kidney and Urology, the Seven Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, ChinaShu-Yan HanDivision of Life Science, the Hong Kong University of Science and Technology, Hong Kong, 999077、ChinaJun Wu作者：韩淑艳查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者赵子轩查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者吴俊查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者ContributionsSYH和JW构思了评论。SYH和ZXZ进行了文献检索并撰写了初稿。JW 指导并修改了主要稿件。伦理批准和参与同意书不适用.发表同意书不适用.利益冲突作者声明他们没有利益冲突.开放存取本文采用知识共享署名 4.0 许可协议进行许可。
{"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}
Pub Date : 2024-02-01DOI: 10.1186/s40779-024-00513-y
Mabel L. Cummins, Grace Delmonte, Skylar Wechsler, Joseph J. Schlesinger
<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
[4]发现，菲赛汀化合物通过增加心脏葡萄糖代谢和抑制蛋白激酶 R（减少心脏炎症和细胞凋亡）来保护心脏功能。这些研究确定了 FAs 氧化的上游机制，可在发生之前防止异位脂质积累，因此必须通过实验比较这些治疗方法与 Adipsin 的影响，以确保 DCM 得到有效治疗。由于预防和治疗方法很少，而且很少有早期症状可用于诊断，DCM 已成为一个公共卫生问题，促使研究人员了解其发病机制。由于糖尿病是一种复杂的疾病，有多个潜在的代谢过程，因此必须在糖尿病的不同阶段和不同的潜在病因中验证 Adipsin 的作用。有关 Irak2 在改善糖尿病导致的心脏功能退化方面的潜力的研究还很少；我们建议将这种蛋白及其上游效应因子作为治疗 DCM 的另一种可能更彻底的方法进行研究。这些研究途径与 Jiang 等人[2]的有希望的发现相结合，具有针对脂质积累的潜在治疗应用，以缓解心肌功能障碍并恢复线粒体结构。这些见解也可能为其他器官异位脂质积累的治疗提供参考。DCM:糖尿病心肌病FAs:脂肪酸Irak2:白介素-1受体相关激酶样2Phb:抑制素Opa1:视神经萎缩蛋白1Chavali V, Tyagi SC, Mishra PK.糖尿病心肌病的预测和预防。Diabetes Metab Syndr Obes.2013;6:151-60.PubMed PubMed Central Google Scholar Jiang MY, Man WR, Zhang XB, Zhang XH, Duan Y, Lin J, et al. Adipsin inhibits Irak2 mitochondrial translocation and improves fatty acid β-oxidation to alleviate diabetic cardiomyopathy.Mil Med Res. 2023;10(1):63.CAS PubMed PubMed Central Google Scholar Zheng J, Ma Y, Guo X, Wu J. Immunological characterization of stroke-heart syndrome and identification of inflammatory therapeutic targets.Front Immunol.2023;14:1227104.Article CAS PubMed PubMed Central Google Scholar AlTamimi JZ, BinMowyna MN, AlFaris NA, Alagal RI, El-Kott AF, Al-Farga AM.Fisetin protects against streptozotocin-induced diabetic cardiomyopathy in rats by suppressing fatty acid oxidation and inhibiting protein kinase R. Saudi Pharm J. 2021;29(1):27-42.Article CAS PubMed Google Scholar Nakamura K, Miyoshi T, Yoshida M, Akagi S, Saito Y, Ejiri K, et al. Pathophysiology and treatment of diabetic cardiomyopathy and heart failure in patients with diabetes mellitus.2022;23(7):3587.Article CAS PubMed PubMed Central Google Scholar Reed MJ, Meszaros K, Entes LJ, Claypool MD, Pinkett JG, Gadbois TM, et al.代谢。2000;49(11):1390-4.Article CAS PubMed Google Scholar Barrière DA, Noll C, Roussy G, Lizotte F, Kessai A, Kirby K, et al. Combination of high-fat/high-fructose diet and low-dose streptozotocin to model long-term type-2 diabetes complications.Sci Rep. 2018;8(1):424.Article PubMed PubMed Central Google Scholar Zhou H, Wang H, Yu M, Schugar RC, Qian W, Tang F, et al. IL-1 induces mitochondrial translocation of Irak2 to suppress oxidative metabolism in adipocytes.Nat Immunol.2020;21(10):1219-31.Article CAS PubMed PubMed Central Google Scholar Roberts NW, González-Vega M, Berhanu TK, Mull A, García J, Heydemann A. Successful metabolic adaptation leading to the prevention of high fat diet-induced murine cardiac remodeling.Cardiovasc Diabetol.2015;14:127.Article PubMed PubMed Central Google Scholar Download referencesNot applicable.This work was supported by the Office of Naval Research Grant (N00014-22-1-2184).Authors and AffiliationsDepartment of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, 37212, USAMabel L. Cummins, Grace Delmona et al.Cummins, Grace Delmonte & Skylar WechslerDivision of Critical Care Medicine, Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, 37212, USAJoseph J. SchlesingerAuthorsMabel L．Schlesinger作者Mabel L. Cummins查看作者发表的论
{"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}
Pub Date : 2024-01-25DOI: 10.1186/s40779-024-00509-8
Consolato M Sergi
{"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}
Pub Date : 2024-01-23DOI: 10.1186/s40779-024-00510-1
Guang-Yu Liu, Dan Yu, Mei-Mei Fan, Xu Zhang, Ze-Yu Jin, Christoph Tang, Xiao-Fen Liu
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.
{"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}
Pub Date : 2024-01-12DOI: 10.1186/s40779-023-00508-1
Faith Nguyen, Ashok K Shetty
{"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}
Pub Date : 2024-01-08DOI: 10.1186/s40779-023-00507-2
Leila Gobejishvili
<p>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.</p><p>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<sup>+</sup> 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, <i>Gpr65</i> 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.</p><p>To show the relevance and causal relationship of GPR65 in fibrogenesis, the authors first used <i>Gpr65</i> knockout mice in their studies. Liver transcriptomic analyses demonstrated that while <i>Gpr65</i> deletion did not have a significant effect on baseline liver homeostasis, it affected various inflammatory a
作者提供的大量数据表明，巨噬细胞以依赖 GPR65 的方式释放的肿瘤坏死因子-α、IL-6 和 TGF-β1 是造血干细胞活化和肝细胞损伤的关键驱动因素。这一观察结果表明，GPR65 在细胞-细胞通讯中发挥着重要作用，而细胞-细胞通讯可使肝细胞损伤和造血干细胞活化在纤维化过程中得以延续。从临床角度来看，这项研究表明，抑制 GPR65 在减轻纤维化过程中的关键致病事件方面具有治疗潜力。需要指出的是，在这些研究中，GPR65 抑制/缺失不仅能预防纤维化的发生，还能减轻纤维化的发展，这表明 GPR65 可作为肝纤维化的治疗靶点。代谢功能障碍相关性脂肪性肝炎（MASH）中的纤维化翻译发现。Sci Transl Med.2023;15(716):eadi0759.Article CAS PubMed PubMed Central Google Scholar Zhang K, Zhang MX, Meng XX, Zhu J, Wang JJ, He YF, et al. Targeting GPR65 alleviates hepatic inflammation and fibrosis by suppressing the JNK and NF-κB pathways.Mil Med Res. 2023;10(1):56.PubMed Central Google Scholar Imenez Silva PH, Camara NO, Wagner CA.质子激活的 G 蛋白偶联受体在病理生理学中的作用。Am J Physiol Cell Physiol.二氧化碳诱导的细胞外 pH 值降低通过 CREB 激活上调人真皮成纤维细胞中 TGF-β1 的表达，从而增强细胞外基质成分的产生。Exp Dermatol.2023;32(10):1651-62.Article CAS PubMed Google Scholar Download referencesNot applicable.Not applicable.Authors and AffiliationsDepartment of Physiology, University of Louisville School of Medicine, Louisville, KY, 40202, USALeila GobejishviliAhorsLeila GobejishviliView author publications您也可以在PubMed Google Scholar中搜索该作者ContributionsLG撰写了手稿。通讯作者Leila Gobejishvili.伦理批准和参与同意书不适用.发表同意书不适用.利益冲突作者声明不存在利益冲突。本注释指的是可在 https://doi.org/10.1186/s40779-023-00494-4 在线查阅的文章。开放存取本文采用知识共享署名 4.0 国际许可协议，该协议允许以任何媒介或格式使用、共享、改编、分发和复制本文，但须注明原作者和出处，提供知识共享许可协议链接，并说明是否进行了修改。本文中的图片或其他第三方材料均包含在文章的知识共享许可协议中，除非在材料的署名栏中另有说明。如果材料未包含在文章的知识共享许可协议中，且您打算使用的材料不符合法律规定或超出许可使用范围，您需要直接从版权所有者处获得许可。要查看该许可的副本，请访问 http://creativecommons.org/licenses/by/4.0/。除非在数据的信用行中另有说明，否则知识共享公共领域专用免责声明 (http://creativecommons.org/publicdomain/zero/1.0/) 适用于本文提供的数据。转载与许可引用本文Gobejishvili, L. GPR65作为治疗肝纤维化的潜在新型治疗靶点。Military Med Res 11, 4 (2024). https://doi.org/10.1186/s40779-023-00507-2Download citationReceived：11 December 2023Accepted: 27 December 2023Published: 08 January 2024DOI: https://doi.org/10.1186/s40779-023-00507-2Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KeywordsInflammationFibrosisG protein coupled receptor 65Macrophages
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Pub Date : 2024-01-04DOI: 10.1186/s40779-023-00503-6
Hiren Y Dandia, Mamatha M Pillai, Deepak Sharma, Meghna Suvarna, Neha Dalal, Ayush Madhok, Arvind Ingle, Shubhada V Chiplunkar, Sanjeev Galande, Prakriti Tayalia
Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
背景：靶向 T 细胞疗法已成为治疗血液恶性肿瘤的一种前景广阔的策略。然而，由于有限的可及性和异质性，将其应用于实体瘤面临巨大挑战。使用生物材料局部递送肿瘤特异性 T 细胞已显示出前景，但由于成本和时间限制，基因修饰和体内外产生足够数量肿瘤特异性 T 细胞所需的程序仍是主要障碍：方法：开发了基于聚乙二醇（PEG）的三维（3D）支架，并利用卡巴酰胺化学方法将其与带正电荷的聚-L-赖氨酸（PLL）共轭，以有效装载携带肿瘤抗原特异性T细胞受体（TCR）的慢病毒（LVs）。对该支架的物理和生物特性进行了广泛表征。此外，还将负载有 OVA-TCR LVs 的支架植入表达卵清蛋白的 B16F10 细胞（B16-OVA）肿瘤模型中，以评估抗肿瘤反应和转导 T 细胞的存在：结果：我们的研究结果表明，支架皮下植入后不会诱发任何全身性炎症，并能有效地将 T 细胞募集到该部位。在 B16-OVA 黑色素瘤小鼠体内，支架能有效地将 OVA 特异性 TCR 转导宿主 T 细胞。这些经过基因修饰的 T 细胞具有向肿瘤和次级淋巴器官归巢的能力，从而显著缩小了肿瘤大小，并增加了全身抗肿瘤细胞因子。免疫细胞图谱显示，在植入这些支架的小鼠肿瘤中，转导 T 细胞的比例很高，抑制性免疫细胞明显减少：我们基于支架的T细胞疗法提供了一种创新的原位局部T细胞靶向治疗方法。这种方法为体外操作 T 细胞提供了一种可行的替代方案，避免了大规模体外生成和培养肿瘤特异性 T 细胞的需要。它提供了一种现成的替代方法，便于使用宿主细胞而非异体细胞，从而克服了一个主要障碍。
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