Triple-negative breast cancer (TNBC) is characterized by high invasion, prone metastasis, frequent recurrence and poor prognosis. Unfortunately, the curative effects of current clinical therapies, including surgery, radiotherapy, chemotherapy and immunotherapy, are still limited in patients with TNBC. In this study, we showed that the heterogeneous expression at the protein level and subcellular location of mesothelin (MSLN), a potential target for chimeric antigen receptor-T (CAR-T) cell therapy in TNBC, which is caused by acidification of the tumor microenvironment, may be the main obstacle to therapeutic efficacy. Alkalization culture or sodium bicarbonate administration significantly promoted the membrane expression of MSLN and enhanced the killing efficiency of MSLN-CAR-T cells bothin vitroandin vivo, and the same results were also obtained in other cancers with high MSLN expression, such as pancreatic and ovarian cancers. Moreover, mechanistic exploration revealed that the attenuation of autophagy-lysosome function caused by microenvironmental alkalization inhibited the degradation of MSLN. Hence, alkalization of the microenvironment improves the consistency and high expression of the target antigen MSLN and constitutes a routine method for treating diverse solid cancersviaMSLN-CAR-T cells.

Abstract Objective: To investigate the phenotypic and genetic associations between asthma and melanoma. Methods: Initially, we conducted a cross-sectional study utilizing data sourced from the National Health and Nutrition Examination Survey (NHANES) spanning the years 2009 to 2016. In the survey, individuals answering "Yes" to "Ever been told you have asthma?" were categorized as asthma patients, while those answering "yes" to "Ever told you had cancer or malignancy?" and specifying "melanoma" were defined as melanoma patients. We employed a multivariate logistic regression model to evaluate the observed association between asthma and melanoma risk. Subsequently, the Mendelian randomization (MR) approach, a novel method minimizing bias and establishing causal relationships, was utilized asthma dataincluding childhood-onset (347,481 controls and 46,802 cases), adult-onset (347,481 controls and 9,676 cases), and overall onset (347,481 controls and 22,296 cases) were retrieved from GWAS databases, alongside melanoma data (32697 samples) obtained from the FinnGen. Two-sample MR analysis was conducted to evaluate the causal relationship between asthma and melanoma, with the Inverse Variance Weighting (IVW) method as the primary data analysis approach. Results: The observational study encompassed a total of 23,218 participants, including 129 melanoma patients. In the unadjusted multivariate logistic regression model, asthma was associated with a reduced risk of melanoma (odds ratio [OR] = 0.404, 95% confidence interval [CI] = 0.188-0.869, P=0.023). Similar results were observed after adjusting for gender, age, race, and education level (OR = 0.439, 95% CI = 0.209-0.922, P=0.034). However, further adjustments for variables such as BMI, poverty to income ratio, diabetes, alcohol use, smoking, hypertension, hyperlipidemia, and skin reaction to sun after non-exposure, outdoor time did not yield statistically significant results (OR = 0.675, 95% CI = 0.205-2.223, P=0.522). Mendelian analysis also failed to demonstrate a causal relationship between asthma and melanoma risk. Conclusion: While there may be an association between asthma and a reduced risk of melanoma, no causal relationship exists between the two. Further prospective studies with larger sample sizes are warranted to corroborate our findings.

The incidence of brain metastasis (BM) is gradually increasing, and the prognosis and therapeutic effect are poor. The emergence of immunotherapy has brought hope for the development of BM treatments. This study revealed that compared with primary cancers, BMs have a colder and more acidic tumor microenvironment (TME), resulting in reduced protein levels of mesothelin (MSLN), a promising target for chimeric antigen receptor-T (CAR-T) cell therapy for triple-negative breast cancer (TNBC) with BMs. These factors could significantly decrease the efficiency of MSLN-CAR-T cells in TNBC BMs. Pantoprazole (PPZ) administration at the most commonly used dose in the clinic notably increased the pH of the TME, inhibited lysosomal activity, increased the membrane levels of the MSLN protein and improved the killing ability of MSLN-CAR-T cells both in vitro and in vivo. Similar results were obtained in non-small cell lung cancer BMs. Hence, when administered in combination with CAR-T cells, PPZ, which increases the protein levels of target antigens, may constitute a new immunotherapeutic strategy for treating solid tumors with BMs.

Background Protein lactylation is a new way for the “metabolic waste” lactic acid to perform novel functions. Nevertheless, our understanding of the contribution of protein lactylation to both tumor progression and therapeutic interventions remains imited. The construction of a scoring system for lactylation to predict the prognosis of pan-cancer patients and to evaluate the tumor immune microenvironment (TIME) would improve our understanding of the clinical significance of lactylation. Methods Consensus clustering analysis of lactylation-related genes was used to cluster 177 pancreatic adenocarcinoma (PAAD) patients. Subsequently, a scoring system was developed using the least absolute shrinkage and selection operator (LASSO) regression. Internal validation and external validation were both conducted to assess and confirm the predictive accuracy of the scoring system. Finally, leucine rich repeat containing 1 (LRRC1), a newly discovered lactylation-related gene, was analyzed in PAAD in vitro. Results Utilizing the profiles of 332 lactylation-related genes, a total of 177 patients with PAAD were segregated into two distinct groups. LacClusterhigh patients had a poorer prognosis than LacClusterlow patients. Through the differential analysis between the LacClusterhigh and LacClusterlow groups, we identified additional genes associated with lactylation. These genes were then integrated to construct the LacCluster-enhanced system, which enabled more accurate prognosis prediction for patients with PAAD. Then, a lactylation index containing three genes (LacI-3) was constructed using LASSO regression. This was done to enhance the usability of the LacCluster-enhanced system in the clinic. Compared to those in the LacI-3high subgroup, patients in the LacI-3low subgroup exhibited increased expression of immune checkpoint-related genes, more immune cell infiltration, lower tumor mutation burdens, and better prognoses, indicating a “hot tumor” phenotype. Moreover, knocking down the expression of LRRC1, the hub gene in the LacI-3 scoring system, inhibited PAAD cell invasion, migration, and proliferation in vitro. Ultimately, the significance of LacI-3 across cancers was confirmed. Conclusion Our findings strongly imply that protein lactylation may represent a new approach to diagnosing and treating malignant tumors.

The development of radiotherapy technology improved outcomes in rectal cancer. Nevertheless, radiotherapy resistance has become a significant problem. This resistance is associated with tumor microenvironment (TME) hypoxia, cell cycle block, and related genetic alterations. We designed a novel miRNA-delivered and improved hypoxic microenvironment sensitization therapy for rectal cancer. With the protection of Zeolitic Imidazolate Framework-8 (ZIF-8) and the delivery of nano-manganese dioxide particles, the nanocomplex exhibited outstanding catalytic mimetic activity in decomposing hydrogen peroxide into oxygen, thus significantly reversing the TME hypoxia. The radiosensitizer miRNA-181a induces DNA damage directly after radiotherapy. We loaded miR181a into the MnO2@ZIF-8-polyethylene glycol nanocomplex to prevent its degradation in the circulatory system and successfully carry miR181a into the tumor. MiR181a-MnO2@ZIF-8 overcame radioresistance and enhanced therapeutic efficacy in a subcutaneous tumor model. This multiple sensitization strategy of the combined delivery of miR181a with MnO2@ZIF-8 nanoenzymes provides a promising therapeutic approach for rectal cancer.

Radiation-induced skin injury (RISI) is a common complication of radiotherapy. Interferon-alpha inducible protein 6 (IFI6) significantly reduces the radiation sensitivity of HaCaT cells. Sodium alginate (SA) has substantial moisturizing properties. Graphene oxide (GO) is a suitable substrate with physical antibacterial properties. Therefore, we designed materials to modify IFI6 using the biogule of polydopamine (PDA) connected to GO/SA. The structure, size, morphology, and elemental compositions of IFI6-PDA@GO/SA were analyzed. Cytological studies suggested that IFI6-PDA@GO/SA is non-toxic to HaCaT cells, with antibacterial properties. It promotes migration and vascularization and inhibits apoptosis. These cells express IFI6 after irradiation. The mouse model suggested that IFI6-PDA@GO/SA promotes wound healing and reduces reactive oxygen species expression. IFI6-PDA@GO/SA accelerates RISI healing, possibly by initiating the SSBP1/HSF1 signaling pathway. In addition, IFI6-PDA@GO/SA improves the immune microenvironment. This study constitutes the first use of IFI6 as a RISI wound-healing material.

Radiation-induced skin injury (RISI) is the primary adverse effect and dose-limiting factor for radiotherapy, and there is no effective treatment. Interferon-alpha inducible protein 6 (IFI6) is upregulated after exposure to ionizing radiation in HaCaT cells. It significantly promotes the proliferation of these cells and reduces radiation sensitivity. miR181a also reduces radiosensitivity. Therefore, we designed materials to modify IFI6 and miR181a through the erythrocyte membrane (EM) and hemoglobin (HB) to enhance local circulation and biocompatibility and play a long-term and stable role. Structure, size, morphology, and elemental compositions of miR181a@EM-HB-IFI6 were analyzed using transmission electron microscopy, X-ray diffraction patterns, Fourier transform infrared spectroscopy, UV-Vis-NIR, zeta potential, and protein electrophoresis. Cytological studies suggested that miR181a@EM-HB-IFI6 is non-toxic to HaCaT cells, promotes their migration, vascularization, inhibits apoptosis, and expresses IFI6 after irradiation. A mouse model suggested that miR181a@EM-HB-IFI6 promotes wound healing and reduces reactive oxygen species expression. miR181a@EM-HB-IFI6 accelerates RISI healing, possibly by initiating the SSBP1/HSF1 signaling pathway. In addition, miR181a@EM-HB-IFI6 can also improve the immune microenvironment. In conclusion, IFI6 and miR181a were used as RISI wound-healing materials for the first time.

Herein, a series of environmentally friendly dressings were specially fabricated from graphene oxide (GO) membrane (a high quality substrate with antibacterial function) and Daptomycin (antibacterial function)/Epidermal growth factor (EGF, wound healing function) for the purpose of antibacterial applications. A performance comparison was designed by employing four dressing samples, including the neat GO membrane (Group A), GO membrane-Daptomycin (Group B), GO membrane-EGF (Group C), and GO membrane-Daptomycin/EGF (Group D). The results analyzed using Fourier transform infrared spectroscopy suggested that Daptomycin and EGF might be adhered to the GO membrane. The contact angle test showed that the hydrophilicity of material gradually increased from Group A to Group D. Groups B and D displayed similar in vitro antibacterial activities, better than those of Groups A and C (their antibacterial performances were similar to each other); all the four experimental groups outperformed the control group (P > 0.05). On the other hand, Groups C and D could promote the proliferation effectively within 1–7 days (P < 0.05), and they also showed similar activities in the cell migration, which were higher than those of Groups A and B (close to each other); all the experimental groups outdid the control group (P < 0.05). Moreover, by monitoring the expression levels of PCNA and CD31 , samples from Group D could promote both angiogenesis and cell reproduction when covering the skin defects (P < 0.05). At the seventh days after the injury, the control and experimental groups of A, B, C, and D displayed healing rates of 40.6%, 53.0%, 66.8%, 60.1%, and 68.3%, respectively. Based on a successful fabrication of GO membrane-Daptomycin/EGF dressings, antibacterial effects as well as growth-promoting performance were well realized by samples in Group D. This is benifitial for the wound healing to a great extent.