Pancreatic β-cell identity loss is increasingly recognized as a critical pathogenic contributor to β-cell failure in type 2 diabetes (T2D), but the specific mechanism remains to be characterized. In this study, we demonstrate that zinc accumulation contributes to β-cell identity loss during diabetes progression in both human and mouse islets. Using a model of human embryonic stem cell-derived islets (SC-islets), we reveal that accumulated zinc triggers the integrated stress response (ISR), with elevated ATF4 expression in SC-β cells. This, in turn, initiates expression of the α cell-specific transcription factor ARX, resulting in the conversion of β cells to α cells, thus forming a zinc-ATF4-ARX regulatory axis. Like primary β cells, SC-β cells also undergo identity loss after transplantation into diabetic animals, which can be prevented by an ISR inhibitor, resulting in improved glycemic control. Furthermore, both genetic depletion and chemical inhibition of zinc accumulation effectively safeguard SC-β cells from identity loss and enhance their efficacy in diabetic animals. Our study thus reveals a pathogenic mechanism in which zinc accumulation induces β-cell identity loss through lineage-tracing approaches and proposes a protective strategy to counteract this process.

Neoadjuvant chemotherapy (NACT) has become a standard treatment for patients with locally advanced gastric cancer (GC), yet the effects of NACT on natural killer (NK) cells remain insufficiently characterized. In this study, we investigated the immune remodeling induced by NACT in paired tumor samples from GC patients and in a murine model, aiming to uncover mechanisms that could guide combination strategies with immunotherapy. We observed enhanced infiltration of antitumor immune cells, particularly CD8⁺ T cells and NK cells, after NACT in both human and mouse tumors, with elevated levels of these cells correlating with improved clinical responses. In vivo depletion experiments confirmed that NK cells contributed to the antitumor efficacy of NACT. In vitro, NACT-treated tumor cells displayed enhanced chemotactic effects on NK92 cells. Mechanistically, NACT activated the mitogen-activated protein kinase (MAPK) pathway in GC cells, inducing CCL8 secretion and facilitating NK cell recruitment. Notably, in an advanced GC patient, the combination of NACT and adoptive NK cell transfer resulted in increased peripheral NK cell counts and a favorable clinical response. Together, these findings reveal that NACT stimulates NK cell recruitment through tumor-derived CCL8 via MAPK activation and support a promising therapeutic rationale for combining NACT with NK cell-based immunotherapy in GC.

OBJECTIVE:This review aims to examine the challenges of opportunistic viral infections in transplant recipients on long-term immunosuppression and to explore the potential of emerging immunotherapies to improve infection management. METHODS:We summarize the mechanisms and effects of current clinical immunosuppressants, outline the incidence of viral infections following various organ transplants, and discuss the limitations of existing antiviral pharmacotherapies. Furthermore, we systematically review recent advances in novel immunotherapies that harness the patient's immune system. RESULTS:While immunosuppressive regimens significantly improve graft survival, they increase susceptibility to viral infections. Emerging immunotherapies demonstrate promising potential in managing these infections, yet their application in transplant recipients remains underexplored. CONCLUSION:Innovative immunotherapies represent a promising avenue for overcoming the limitations of conventional treatments. Their integration into transplantation practice may enhance long-term outcomes, although further clinical validation is needed.

Malignant tumors pose a significant threat to human health, and conventional cancer therapies are limited by inadequate targeting, leading to severe side effects. Exosomes, as extracellular vesicles mediating intercellular communication, exhibit advantages such as low immunogenicity, high biocompatibility, and low toxicity. After modification, engineered exosomes can be employed as targeted delivery vehicles in tumor therapy. This review summarizes the cellular origin, production methods, engineering strategies, and drug-loading routes of engineered exosomes, discusses their applications in cancer treatment, and delves into the challenges and issues in translating engineered exosomes to clinical practice, aiming to provide insights for exosome engineering research.

Pancreatic β cell loss by cellular stress contributes to diabetes pathogenesis. Nevertheless, the fundamental mechanism of cellular stress regulation remains elusive. Here, it is found that elevated zinc transportation causes excessive cellular stress in pancreatic β cells in diabetes. With gene-edited human embryonic stem cell-derived β cells (SC-β cells) and human primary islets, the results reveal that elevated zinc transportation initiates the integrated stress response (ISR), and ultimately leads to β cell death. By contrary, genetic abolishment of zinc transportation shields β cells from exacerbated endoplasmic reticulum stress (ER stress) and concurrent ISR. To target excessive zinc transportation with a chemical inhibitor, an isogenic SC-β cells based drug-screening platform is established. Surprisingly, independent of its traditional role as protein synthesis inhibitor at a high-dose (10 µm), low-dose (25 nm) anisomycin significantly inhibits zinc transportation and effectively prevents β cell loss. Remarkably, in vivo administration of anisomycin in mice demonstrates protective effects on β cells and prevents type 2 diabetes induced by high-fat diet. Overall, elevated zinc transportation is identified as a crucial driver of β cell loss and low-dose anisomycin as a potential therapeutic molecule for diabetes.

Malignant melanoma is a highly fatal disease closely associated with sex hormones. This study aimed to evaluate the global burden and trends of malignant melanoma based on menopausal status. Data on the prevalence, disability-adjusted life years (DALYs), and mortality of malignant melanoma were obtained from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021. Age 55 was used as a threshold for menopausal status to assess global, regional, and national trends in disease burden among women. In 2021, the age-standardized prevalence rate (ASPR) of malignant melanoma was higher in women than men under 55 years but lower in women over 55 years. From 1990 to 2021, the ASPR for premenopausal women increased from 14.23 [95% uncertainty interval (UI) (13.79-14.60)] to 16.53 [95% UI (15.09-17.78)], while the age-standardized DALYs rate (ASDR) decreased from 14.04 [95% UI (12.20-15.61)] to 11.83 [95% UI (9.20-14.35)], and the age-standardized mortality rate (ASMR) decreased from 0.27 [95% UI (0.24-0.30)] to 0.23 [95% UI (0.18-0.28)]. For postmenopausal women, the ASPR increased from 55.01 [95% UI (51.71-57.23)] to 81.43 [95% UI (74.33-87.03)], while the ASDR decreased from 63.88 [95% UI (58.39-69.64)] to 56.11 [95% UI (48.79-63.66)], and the ASMR decreased from 2.96 [95% UI (2.69-3.19)] to 2.73 [95% UI (2.36-3.07)]. The disease burden was highest in high socio-demographic index (SDI) regions but has recently decreased, whereas a gradual increase was observed in high-middle SDI regions. At the national level, New Zealand had the highest ASPR for both premenopausal and postmenopausal women, with values of 245.63 [95% UI (209.56, 279.91)] and 909.37 [95% UI (754.63, 1037.39)], respectively. Regional variations in population-level determinants of disease burden were identified. The risk and prognosis of malignant melanoma in women may differ by menopausal status due to the interplay of sex hormones and the immune system. Further research is needed to develop tailored screening and treatment strategies for women across diverse SDI regions and menopausal statuses.

Identifying inflammation-induced leukocyte subsets and their derived circulating factors has been instrumental in understanding the progression of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Nevertheless, how primary inflammation-induced nonleukocyte populations in distal organs contribute to ALI/ARDS remains poorly defined. Here, we report one population of erythroblast-like cells (Ter-cells) deriving from megakaryocyte-erythroid progenitor cells with a unique Ter-119+CD45-CD71+ phenotype in ALI/ARDS. Ter-cells induced by the spleen are chemoattracted into the lung to inhibit the progression of ALI by secreting the neurotrophic factor artemin into the blood and BAL fluid. In vivo blockade of Ter-cell-derived artemin aggravates lung injury, and artemin deficiency abolishes Ter-cells' antiinflammatory ability. We confirm the presence of circulating artemin in patients with ARDS and show that significantly elevated artemin correlates with good prognosis. We propose that Ter-cells and the secreted artemin play important roles in ALI/ARDS, with prognostic and therapeutic implications.

Adoptive transfer of chimeric antigen receptor (CAR)-modified natural killer (NK) cells represents a transformative approach that has significantly advanced clinical outcomes in patients with malignant hematological conditions. However, the efficacy of CAR-NK cells in treating solid tumors is limited by their exhaustion, impaired infiltration and poor persistence in the immunosuppressive tumor microenvironment (TME). As NK cell functional states are associated with IL-2 cascade, we engineered mesothelin-specific CAR-NK cells that secrete neoleukin-2/15 (Neo-2/15), an IL-2Rβγ agonist, to resist immunosuppressive polarization within TME. The adoptively transferred Neo-2/15-armored CAR-NK cells exhibited enhanced cytotoxicity, less exhaustion and longer persistence within TME, thereby having superior antitumor activity against pancreatic cancer and ovarian cancer. Mechanistically, Neo-2/15 provided sustained and enhanced downstream IL-2 receptor signaling, which promotes the expression of c-Myc and nuclear respiratory factor 1 (NRF1) in CAR-NK cells. This upregulation was crucial for maintaining mitochondrial adaptability and metabolic resilience, ultimately leading to increased cytotoxicity and pronounced persistence of CAR-NK cells within the TME. The resistance against TME immunosuppressive polarization necessitated the upregulation of NRF1, which is essential to the augmentative effects elicited by Neo-2/15. Overexpression of NRF1 significantly bolsters the antitumor efficacy of CAR-NK cells both in vitro and in vivo, with increased ATP production. Collectively, Neo-2/15-expressing CAR-NK cells exerts superior antitumor effects by exhaustion-resistance and longer survival in solid tumors.

Malignant tumors pose a significant threat to human health, and conventional cancer therapies are limited by inadequate targeting, leading to severe side effects. Exosomes, as extracellular vesicles mediating intercellular communication, exhibit advantages such as low immunogenicity, high biocompatibility, and low toxicity. After modification, engineered exosomes can be employed as targeted delivery vehicles in tumor therapy. This review summarizes the cellular origin, production methods, engineering strategies, and drug-loading routes of engineered exosomes, discusses their applications in cancer treatment, and delves into the challenges and issues in translating engineered exosomes to clinical practice, aiming to provide insights for exosome engineering research.

Follicular lymphoma (FL), derived from germinal centre (GC) B cells, is a kind of systemic neoplasm. Even though FL is indolent, it remains an incurable haematology Neoplasm. Accumulating evidence has suggested that the circulating cytokine is associated with the development of FL, yet the causal relationship between FL and circulating cytokines remains undetermined. Therefore, we conducted a two-sample Mendelian randomization (MR) to confirm the causal link between FL and levels of circulating cytokines with the use of summary data on circulating cytokines and FL. All these data from genome-wide association study were derived from the Genome-wide pQTL mapping which contains 14,824 individuals. FL data were acquired exclusively from FinnGen, where 218,792 individuals (522 cases vs. 218,270 controls) were involved. Various statistical methods, including the inverse variance weighted method (IVW), weighted median (WME), simple model, weighted model (WM) and MR-Egger, were used to evaluate the potential causal connection between circulating cytokines and FL. Sensitivity analysis, which involves the examination of the heterogeneity, pleiotropy, and leave-one-out method, was also performed to ensure more trustworthy results. A bidirectional MR test was performed to evaluate the direction of causal association between circulating cytokines and FL. Combining all the steps of MR analysis, we revealed four causal cytokines: C-X-C motif chemokine ligand 5 (CXCL5), interleukin-15 receptor A (IL15RA), interleukin-20 (IL20), and neurotrophin-3 (NT-3). The risk of FL may be inversely linked to CXCL5 (OR=0.73, CI: 0.545-0.979, P=0.036), IL-15RA (OR=0.669, CI: 0.451-0.993, P=0.046), and IL-20 (OR=0.565, CI: 0.325-0.981, P=0.043) but positively linked to NT-3 (OR=1.872, CI: 1.063-3.297, P=0.03). In addition, in our study, no causal effect of FL on cytokines was demonstrated and no significant heterogeneity and pleiotropy were found. Our research revealed the causal relationship between cytokines and FL, along with both the anti-protective effect of CXCL5, IL-15RA, and IL-20 and the protective effect of neurotrophin-3 on FL. These findings aim to provide new clues regarding the pathogenesis of FL and to extend the potential of circulating cytokines to therapeutic interventions.

Non-alcoholic fatty liver disease (NAFLD) is a complex disease characterized by a massive accumulation of lipids in the liver, with a continuous progression of simple steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. Non-alcoholic fatty liver disease is associated with obesity, insulin resistance, and metabolic syndrome; it is a severe public health risk and is currently the most common liver disease of the world. In addition to the fatty infiltration of the liver in non-alcoholic fatty liver disease patients, the field of liver transplantation faces similar obstacles. NAFLD and NASH primarily involve lipotoxicity, inflammation, oxidative stress, and insulin resistance. However, the precise mechanisms and treatments remain unclear. Therapeutic approaches encompass exercise, weight control, as well as treatments targeting antioxidants and anti-inflammatory pathways. The role of animal models in research has become crucial as a key tool to explore the molecular mechanisms and potential treatments for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Here, we summarized the current understanding of the pathogenesis of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis and discussed animal models commonly used in recent years.

AbstractExosomes, a specific subset of extracellular vesicles, have diverse functions in various biological processes. In the field of cancer research, there has been a growing interest in the potential of exosomes to act as versatile vehicles for targeted tumor imaging and therapy. In this study, we constructed a targeted delivery platform using hypoimmunogenic exosomes by genetically modifying β2‐microglobulin knocking‐out HEK‐293F cells to express a fusion protein, referred to as αMUC1‐Exo, which comprises the exosomal membrane‐enriched platelet‐derived growth factor receptor, intracellular nanoluciferase, and extracellular anti‐MUC1 single‐chain variable fragment. The findings of this study indicate that αMUC1‐Exos exhibited notable drug delivery properties toward MUC1‐positive pancreatic cancer cells, resulting in a substantial inhibition of tumor growth. Moreover, these exosomes demonstrated a high level of biosafety and the absence of any adverse effects. The application of engineered exosomes as a vehicle for drug delivery holds promise for enhancing the immunogenicity of neoplastic cells following treatment, thereby inducing antitumor immune memory in mice with intact immune systems, and also improving the response to anti‐PD1 therapy. This approach utilizing engineered exosomes for Gemcitabine administration holds promise as a potential strategy for overcoming drug resistance in pancreatic carcinoma thereby improving the overall treatment efficacy.

Over the past decade, chimeric antigen receptor (CAR)-T cell therapy has emerged as a revolutionary immunotherapeutic approach to combat cancer. This therapy constructs a CAR on the surface of T cells through genetic engineering techniques. The CAR is formed from a combination of antibody-derived or ligand-derived domains and T-cell receptor (TCR) domains. This enables T cells to specifically bind to and activate against tumor cells. However, the efficacy of CAR-T cells in solid tumors remains inconclusive due to several challenges such as poor tumor trafficking, infiltration, and the immunosuppressive tumor microenvironment (TME). In response, CAR natural killer (CAR-NK) and CAR macrophages (CAR-M) have been developed as complementary strategies for solid tumors. CAR-NK cells do not require HLA compatibility, demonstrate reduced toxicity, and are thus seen as potential substitutes for CAR-T cells. Furthermore, CAR-M immunotherapy is also being researched and has shown phagocytic capabilities and tumor-antigen presentation. This study discusses the features, advantages, and limitations of CAR-T, CAR-NK, and CAR-M cells in the treatment of solid tumors and suggests prospective solutions for enhancing the efficacy of CAR host-cell-based immunotherapy.

BackgroundPancreatic ductal adenocarcinoma (PDAC), a leading cause of cancer mortality, has a complex pathogenesis involving various immune cells, including B cells and their subpopulations. Despite emerging research on the role of these cells within the tumor microenvironment (TME), the detailed molecular interactions with tumor-infiltrating immune cells (TIICs) are not fully understood.MethodsWe applied CIBERSORT to quantify TIICs and naive B cells, which are prognostic for PDAC. Marker genes from scRNA-seq and modular genes from weighted gene co-expression network analysis (WGCNA) were integrated to identify naive B cell-related genes. A prognostic signature was constructed utilizing ten machine-learning algorithms, with validation in external cohorts. We further assessed the immune cell diversity, ESTIMATE scores, and immune checkpoint genes (ICGs) between patient groups stratified by risk to clarify the immune landscape in PDAC.ResultsOur analysis identified 994 naive B cell-related genes across single-cell and bulk transcriptomes, with 247 linked to overall survival. We developed a 12-gene prognostic signature using Lasso and plsRcox algorithms, which was confirmed by 10-fold cross-validation and showed robust predictive power in training and real-world cohorts. Notably, we observed substantial differences in immune infiltration between patients with high and low risk.ConclusionOur study presents a robust prognostic signature that effectively maps the complex immune interactions in PDAC, emphasizing the critical function of naive B cells and suggesting new avenues for immunotherapeutic interventions. This signature has potential clinical applications in personalizing PDAC treatment, enhancing the understanding of immune dynamics, and guiding immunotherapy strategies.

Background: Recent researches found that mitochondrial functions were substantially involved in tumor progression, whereas the particular mechanism is unrecognized. Coiled-Coil Domain-Containing Protein 58 (CCDC58), one of the mitochondrial matrix import factors, acts as a novel regulator or stabilizer involved in mitochondrial protein import machinery. Whether and how an up-regulation of CCDC58 causes poor prognosis of patients in Hepatocellular Carcinoma (HCC) still required further researches. Methods: Tumor immune estimation resource (TIMER), Hepatocellular Carcinoma Database (HCCDB) and UALCAN databases were utilized to explore the expression level in diverse types of tumors compared with normal tissues. The prognostic potential of CCDC58 mRNA was evaluated via the Kaplan-Meier plotter, Gene Expression Profiling Interactive Analysis (GEPIA) and the Human Protein Atlas (HPA) databases. Corresponding clinicopathological factors were analyzed in Kaplan-Meier plotter. According to the median of mRNA expression levels of CCDC58, we divided The Cancer Genome Atlas (TCGA) data of HCC patients into two groups, highly expressed one and lowly expressed one, so as to perform the enrichment analyses of Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Protein-Protein Interaction (PPI) Network was constructed by STRING site and the co-expressed genes were functionally enriched. Immunohistochemistry was adopted to detect protein expression of CCDC58 in HCC patients. Results: This study indicated that CCDC58 protein expression level was obviously higher in HCC than that in paired paracancerous tissues. The up-regulated CCDC58 mRNA is prone to poor prognosis of patients in HCC through various indexes, such as overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), relapse-free survival (RFS) and progression-free survival (PFS). Additionally, univariate and multivariate Cox regression analyses suggested that CCDC58 could be viewed as an independent risk factor for HCC patients. The expression of CCDC58 is associated with 28 GO terms related to mitochondria and 5 KEGG pathways including oxidative phosphorylation. The PPI network revealed 10 interactive proteins about constituent components of mitochondria. Conclusions: These findings demonstrated CCDC58 to be a potential diagnostic and prognostic biomarker in HCC and correlated with mitochondria acting on tumor biosynthesis and energy production. It is reliable for CCDC58 to be targeted to design novel treatments for HCC patients.

Organ transplantation is currently the most effective treatment for end-stage organ failure. Post transplantation diabetes mellitus (PTDM) is a severe complication after organ transplantation that seriously affects the short-term and long-term survival of recipients. However, PTDM is often overlooked or poorly managed in its early stage. This article provides an overview of the incidence, and pathogenesis of and risk factors for PTDM, aiming to gain a deeper understanding of PTDM and improve the quality of life of recipients.

For decades, tumor-bearing murine models established using tumor cell lines have been the most commonly used models to study human cancers. Even though there are several studies reported that implant sites caused disparities in tumor behaviors, few of them illuminated the positional effect on immunotherapy. Herein, we describe surgical techniques for a novel orthotopic implantation of syngeneic pancreatic ductal adenocarcinoma (PDAC) tissue slices. This method has a high success modeling rate and stable growth kinetics, which makes it useful for testing novel therapeutics. Pathological examination indicated that the orthotopic tumor displayed poor vascularization, desmoplastic stromal reaction, and a highly immunosuppressive tumor microenvironment. This unique microenvironment resulted in limited response to PD1/CTLA4 blockade therapy and anti-MUC1 (αMUC1) CAR-T transfer treatment. To reverse the suppressive tumor microenvironment, we developed gene modified T-cells bearing a chimeric receptor in which activating receptor NKG2D fused to intracellular domains of 4-1BB and CD3ζ (NKG2D CAR). The NKG2D CAR-T cells target myeloid-derived suppressor cells (MDSCs), which overexpress Rae1 (NKG2D ligands) within the TME. Results indicated that NKG2D CAR-T cells eliminated MDSCs and improved antitumor activity of subsequently infused CAR-T cells. Moreover, we generated a bicistronic CAR-T, including αMUC1 CAR and NKG2D CAR separated by a P2A element. Treatment with the dual targeted bicistronic CAR-T cells also resulted in prolonged survival of orthotopic model mice. In summary, this study describes construction of a novel orthotopic PDAC model through implantation of tissue slices and discusses resistance to immunotherapy from the perspective of a PDAC microenvironment. Based on the obtained results, it is evident that elimination MDSCs by NKG2D CAR could rescue the impaired CAR-T cell activity.

Islet transplantation is an ideal option for the treatment of brittle diabetes. In this protocol, isolated and purified islets were transplanted via the hepatic portal vein into a blood group compatible recipient (Rickels and Robertson, Endocr Rev 40:631–668, 2019). In contrast to pancreas transplantation, this technique is less invasive and has fewer posttransplantation complications. Although the clinical outcomes of islet transplantation have improved dramatically after the Edmonton protocol was proposed, there is still much room for improvement. Islet transplantation in mice is one of the most commonly used models in islet transplantation studies. By implanting islets under the renal capsule, the rejection, survival, blood sugar fluctuations and C-peptide secretion of islets can be observed in real time. Our model is of great scientific and clinical significance for studying immune rejection in islet transplantation, improving the transplantation effect, and further prolonging the survival of transplanted islets (Shapiro et al., Nat Rev Endocrinol 13:268–277, 2017).