Meng Guo

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.

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.

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.

In recent years, the incidence of diabetes mellitus has grown exponentially worldwide. It is well-established that blood glucose monitoring is crucial to evaluate pancreatic islet function and determine the optimal medication regimen. However, most current blood glucose meters use invasive techniques, which can cause pain and infection. Non-invasive blood glucose monitoring techniques have gained significant attention as a potential solution to overcome the limitations of current monitoring methods. This review compares the progress and challenges of electrochemical, optical, and electromagnetic/microwave non-invasive blood glucose monitoring techniques to discuss future research trends. Due to the rapid development of wearable devices and transdermal biosensors, which provide efficient, stable, and cost-effective monitoring without the need for invasive blood samples, the market for non-invasive blood glucose monitoring is predicted to become more competitive.

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.

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.

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.