Esophageal cancer, including esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), has a poor prognosis and limited therapeutic options. Chimeric antigen receptor (CAR)-T cells represent a potential ESCC treatment. In this study, we examined CD276 expression in healthy and esophageal tumor tissues and explored the tumoricidal potential of CD276-targeting CAR-T cells in ESCC. CD276 was strongly and homogenously expressed in ESCC and EAC tumor lesions but mildly in healthy tissues, representing a good target for CAR-T cell therapy. We generated CD276-directed CAR-T cells with a humanized antigen-recognizing domain and CD28 or 4-1BB co-stimulation. CD276-specific CAR-T cells efficiently killed ESCC tumor cells in an antigen-dependent manner both in vitro and in vivo. In patient-derived xenograft models, CAR-T cells induced tumor regression and extended mouse survival. In addition, CAR-T cells generated from patient T cells demonstrated potent cytotoxicity against autologous tumor cells. Our study indicates that CD276 is an attractive target for ESCC therapy, and CD276-targeting CAR-T cells are worth testing in ESCC clinical trials.

Many studies have demonstrated the crucial roles of 5-methylcytosine (m5C) RNA methylation in cancer pathogenesis. Two datasets, including TCGA-KIRP and ICGC, and related clinical information were downloaded, where the expression of 13 m5C regulators was examined. We applied LASSO regression to construct a multi-m5C-regulator-based signature in the TCGA cohort, which was further validated using the ICGC cohort. Univariate and multivariate Cox regressions were applied to evaluate the independent prognostic value of our model. The differences in biological functions and immune characterizations between high and low-risk groups divided based on the risk scores were also investigated via multiple approaches, such as enrichment analyses, mutation mining, and immune scoring. Finally, the sensitivities of commonly used targeted drugs were tested, and the connectivity MAP (cMAP) was utilized to screen potentially effective molecules for patients in the high-risk group. Experimental validation was done following qPCR tests in Caki-2 and HK-2 cell lines. 3 m5C regulators, including ALYREF, DNMT3B and YBX1, were involved in our model. Survival analysis revealed a worse prognosis for patients in the high-risk group. Cox regression results indicated our model's superior predictive performance compared to single-factor prognostic evaluation. Functional enrichment analyses indicated a higher mutation frequency and poorer tumor microenvironment of patients in the high-risk group. qPCR-based results revealed that ALYREF, DNMT3B, and YBX1 were significantly up-regulated in Caki-2 cell lines compared with HK-2 cell lines. Molecules like BRD-K72451865, Levosimendan, and BRD-K03515135 were advised by cMAP for patients in the high-risk group. Our study presented a novel predictive model for KIRP prognosis. Furthermore, the results of our analysis provide new insights for investigating m5C events in KIRP pathogenesis.

Background and Objectives: Spinal cord injury (SCI) leads to debilitating neurological deficits primarily due to the inflammatory response triggered by secondary injury mechanisms. Microglial activation and polarization significantly influence this response, with pro‐inflammatory (M1) polarization exacerbating damage and anti‐inflammatory (M2) polarization promoting repair. MS4A7, a membrane‐bound protein involved in immune regulation, has been implicated in inflammation, but its role in SCI remains unexplored. This study investigates the function of MS4A7 in modulating microglial polarization and its downstream effects on the inflammatory response in SCI, focusing on the cGAS‐STING‐NLRP3 axis.Methods: A combination of in vivo and in vitro approaches, including mouse SCI models and BV2 microglial cells, was employed. Differential gene expression analysis was conducted using the GSE93561 dataset. MS4A7 expression was modulated using shRNA and overexpression plasmids. Microglial polarization was assessed via immunofluorescence, RT‐qPCR, and ELISA for M1 (iNOS, IL‐1β, TNF‐α) and M2 (Arg1, IL‐10, CD206) markers. Pyroptosis and inflammasome activation were examined using PI staining, LDH release, and NLRP3/GSDMD assays. The role of the cGAS‐STING pathway was evaluated using activators (diABZI) and inhibitors (C‐176), and NLRP3 inflammasome activity was pharmacologically inhibited with MCC950.Results: MS4A7 was significantly upregulated in SCI tissues (p < 0.01). Knockdown of MS4A7 reduced M1 markers (iNOS, IL‐1β, and TNF‐α) and increased M2 markers (Arg1, IL‐10, and CD206), promoting anti‐inflammatory polarization (p < 0.05). Conversely, MS4A7 overexpression enhanced M1 polarization and pyroptosis through the NLRP3 inflammasome. In vivo, MS4A7 knockdown improved locomotor recovery (BMS score, p < 0.05) and alleviated pain‐related behaviors (PWL and PWT, p < 0.01). The cGAS‐STING pathway mediated NLRP3 activation, with pharmacological inhibition mitigating pro‐inflammatory effects and favoring tissue repair.Conclusions: In this study, we found that MS4A7 exacerbates inflammation and promotes M1 polarization via the cGAS‐STING‐NLRP3 axis in SCI. Targeting MS4A7 and its associated pathways offers potential therapeutic strategies to mitigate neuroinflammation and enhance recovery. These findings provide new insights into the molecular mechanisms underlying SCI pathophysiology and highlight MS4A7 as a promising therapeutic target.

Background. Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. Successful treatment of CRC relies on accurate early diagnosis, which is currently a challenge due to its complexity and personalized pathologies. Thus, novel molecular biomarkers are needed for early CRC detection. Methods. Gene and microRNA microarray profiling of CRC tissues and miRNA‐seq data were analyzed. Candidate microRNA biomarkers were predicted using both CRC‐specific network and miRNA‐BD tool. Validation analyses were carried out to interrogate the identified candidate CRC biomarkers. Results. We identified miR‐451a as a potential early CRC biomarker circulating in patient’s serum. The dysregulation of miR‐451a was revealed both in primary tumors and in patients’ sera. Downstream analysis validated the tumor suppressor role of miR‐451a and high sensitivity of miR‐451a in CRC patients, further confirming its potential role as CRC circulation biomarker. Conclusion. The miR‐451a is a potential circulating biomarker for early CRC diagnosis.

The association of XPA rs1800975 polymorphism with breast cancers has been reported in several studies, but the results were conflicting. In order to analyze the association between XPA rs1800975 polymorphism and the risk of breast cancer, a meta-analysis was performed in the present study. The literature search for relevant studies was conducted in PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang Med Online databases. The odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were calculated using fixed-effect/random-effects models by the STATA 12.0 software. The sources of heterogeneity were analyzed by subgroup analysis. Six case-control studies involving 5069 subjects (2338 patients and 2731 healthy controls) were included in the present meta-analysis. In the pooled analysis, no obvious association was found between XPA rs1800975 polymorphism and the risk of breast cancer in all genetic models. However, in subgroup analysis based on ethnicity, XPA rs1800975 polymorphism was found to be related to decreased breast cancer risk in non-Asians in the recessive model (OR = 0.80, 95% CI = 0.64–1.00, P = .045). Moreover, source of control subgroup analysis demonstrated that XPA rs1800975 polymorphism might decrease the risk of breast cancer in population-based group in the recessive model (OR = 0.80, 95% CI = 0.64–1.00, P = .045). XPA rs1800975 polymorphism may decrease the risk of breast cancer in both non-Asians and population-based patients. Large sample size and well-designed study is needed for further assessing the role of XPA polymorphism in breast cancer risk.

Objectives: Endoplasmic reticulum (ER) stress‐induced protein homeostasis perturbation is a core pathological element in the pathogenesis of neurodegenerative diseases. This study aims to clarify the unique role played by C/EBP homologous protein (CHOP) as a biomarker of the unfolded protein response (UPR) in the etiology of chronic pain and related cognitive impairments following chronic constrictive nerve injury (CCI).Methods: The memory capability following CCI was assessed utilizing the Morris water maze (MWM) and fear conditioning test (FCT). Activation of the UPR was quantified by assessing levels of CHOP and key ER stress sensors. The terminal deoxynucleotidyl transferase (TdT) dUTP nick‐end labeling (TUNEL) assay and the levels of cleaved caspase‐3 were utilized to assess apoptosis level. Synaptic plasticity was assessed via a modified Golgi‐Cox staining method, and long‐term potentiation (LTP) measurements were taken. Neuronal activity was determined by immunofluorescence and fiber photometry. Knockdown of CHOP and alleviation of ER stress were selectively induced by LV‐Ddit3‐shRNAs and the chemical chaperone 4‐phenylbutyric acid (4‐PBA), respectively.Results: Mice subjected to CCI displayed enduring pain and cognitive impairments evident on Days 21–28 post‐surgery. Following CCI, changes in the dorsal CA1 (dCA1) manifested as ER dilation, upregulation of CHOP and upstream signaling molecules, reduced dendritic spine density, and PSD95 levels, and impaired LTP. Additionally, the co‐localization of CaMKIIα/c‐Fos and CaMKIIα^dCA1‐mediated calcium signaling was significantly reduced, while the activation of CaMKIIα was found to mitigate cognitive impairments in CCI mice. Selective knockdown of CHOP enhanced synaptic plasticity and CaMKIIα neuron activity, while 4‐PBA treatment alleviated ER stress, synergistically improving cognitive deficits associated with chronic pain.Conclusion: CCI‐induced CHOP upregulation impairs dCA1 synaptic plasticity and neuronal activity, leading to chronic pain‐related cognitive deficits.