Therapeutic hyperthermia regulates complement C3 activation and suppresses tumor development through HSPA5/NFκB/CD55 pathway in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is endemic in Southern China and Southeast Asia. Hyperthermia is widely used in combination with chemotherapy and radiotherapy to enhance therapeutic efficacy in NPC treatment, but the underlying anti-tumor mechanisms of hyperthermia remain unclear. Complement C3 has been reported to participate in the activation of immune system in the tumor microenvironment, leading to tumor growth inhibition. In this study, we aimed to explore the effect and mechanisms of hyperthermia and investigate the functional role of complement C3 in NPC hyperthermia therapy (HT). The serum levels of complement C3 before and after hyperthermia therapy in patients with NPC were analyzed. NPC cell lines SUNE1 and HONE1 were used for in vitro experiment to evaluate the function of complement C3 and HT on cell proliferation and apoptosis. SUNE1 xenograft mouse model was established and tumor-bearing mice were treated in water bath at a constant temperature of 43°C. Tumor samples were collected at different time points to verify the expression of complement C3 by immunohistochemical staining and western blot. The differential expressed genes after hyperthermia were analyzed by using RNA sequencing. We found that complement could enhance hyperthermia effect on suppressing proliferation and promoting apoptosis of tumor cells in NPC. Hyperthermia decreased the mRNA expression of complement C3 in tumor cells, but promoted the aggregation and activation circulating C3 in NPC tumor tissue. By using in vitro hyperthermia-treated NPC cell lines and SUNE1 xenograft tumor-bearing mice, we found that the expression of heat shock protein 5 (HSPA5) was significantly upregulated. Knockdown of HSPA5 abrogated the anti-tumor effect of hyperthermia. Moreover, we demonstrated that hyperthermia downregulated CD55 expression via HSPA5/NFκB (P65) signaling and activated complement cascade. Our findings suggest that therapeutic hyperthermia regulates complement C3 activation and suppresses tumor development via HSPA5/NFκB/CD55 pathway in NPC.

A prognostic nomogram incorporating tumor size and lymph node size for patients with nasopharyngeal carcinoma.

PURPOSE: The goal of this study was to establish a nomogram that included pre-treatment tumor size and lymph node (LN) size to assess personalized overall survival (OS) of patients with nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results dataset was used to extract statistics for 1083 individuals with NPC (training cohort). In the validation cohort, 266 patients were included from the Affiliated Cancer Hospital & Institute of Guangzhou Medical University. Age, tumor-node-metastasis (TNM) stage, pre-treatment tumor size, and LN size were chosen in both the training and validation sets to build a nomogram to forecast the 3-year and 5-year OS probability using the multivariate Cox regression model. Using the C-index, calibration plot, and receiver operating characteristic (ROC) curve, the predictive model's predictive value and discriminative capacity were determined. RESULTS: Pre-treatment tumor size, LN size, age, and TNM stage were all independent prognostic factors in the multivariate analysis. After combining these characteristics, a nomogram with a C-index of 0.7367 in the training cohort and 0.795 in the validation cohort was created, suggesting strong predictive capacity. Analysis of the ROC curve revealed that the constructed nomogram was clinically applicable. CONCLUSIONS: In patients with NPC, the developed nomogram, which includes pre-treatment tumor size, LN size, age, and TNM stage, is a reliable predictive predictor of OS.

Dissecting gastric cancer heterogeneity and exploring therapeutic strategies using bulk and single-cell transcriptomic analysis and experimental validation of tumor microenvironment and metabolic interplay.

Gastric cancer, the fifth most prevalent cancer worldwide, is often diagnosed in advanced stages with limited treatment options. Examining the tumor microenvironment (TME) and its metabolic reprogramming can provide insights for better diagnosis and treatment. This study investigates the link between TME factors and metabolic activity in gastric cancer using bulk and single-cell RNA-sequencing data. We identified two molecular subtypes in gastric cancer by analyzing the distinct expression patterns of 81 prognostic genes related to the TME and metabolism, which exhibited significant protein-level interactions. The high-risk subtype had increased stromal content, fibroblast and M2 macrophage infiltration, elevated glycosaminoglycans/glycosphingolipids biosynthesis, and fat metabolism, along with advanced clinicopathological features. It also exhibited low mutation rates and microsatellite instability, associating it with the mesenchymal phenotype. In contrast, the low-risk group showed higher tumor content and upregulated protein and sugar metabolism. We identified a 15-gene prognostic signature representing these characteristics, including CPVL, KYNU, CD36, and GPX3, strongly correlated with M2 macrophages, validated through single-cell analysis and an internal cohort. Despite resistance to immunotherapy, the high-risk group showed sensitivity to molecular targeted agents directed at IGF-1R (BMS-754807) and the PI3K-mTOR pathways (AZD8186, AZD8055). We experimentally validated these promising drugs for their inhibitory effects on MKN45 and MKN28 gastric cells. This study unveils the intricate interplay between TME and metabolic pathways in gastric cancer, offering potential for enhanced diagnosis, patient stratification, and personalized treatment. Understanding molecular features in each subtype enriches our comprehension of gastric cancer heterogeneity and potential therapeutic targets.

Impact of Smoking on Response to the First-Line Treatment of Advanced ALK-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis.

Background: The impact of smoking on the efficacy of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) treatment is controversial and has not been systematically explored in the first-line setting. We performed a systematic review based on a pairwise meta-analysis and a Bayesian network meta-analysis (NMA) to address this issue. Methods: PubMed, Embase, Web of Science, Cochrane Library, Clinical-Trials.gov, and other resources were searched until 5 January 2022. Progression-free survival (PFS) was considered the main outcome of interest. Randomized controlled trials with smoking status analysis were included. Cochrane Risk of Bias Tool was performed to assess the risk of bias. Random effects models were adopted conservatively in meta-analysis. The NMA was performed in a Bayesian framework using the "gemtc" version 1.0-1 package of R-4.1.2 software. Results: A total of 2,484 patients from nine studies were eligible for this study, with 1,547 never-smokers (62.3%) and 937 smokers (37.7%). In a pairwise meta-analysis, in the overall population, no significant difference was found between never-smokers and smokers. However, in the subgroup analyses based on crizotinib-controlled studies, anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) derived better PFS in the smoking group over the never-smoking group in the Asian population (HR = 0.17, 95%CI = 0.09-0.31 in the smoking group, HR = 0.39, 95%CI = 0.24-0.65 in the never-smoking group, p = 0.04, low quality of evidence). In NMA, among never-smokers, lorlatinib ranked the highest for PFS (SUCRA = 96.2%), but no significant superiority was found among the new-generation ALK-TKIs except for ceritinib. In smokers, low-dose alectinib performed best (SUCRA = 95.5%) and also demonstrated a significant superiority over ensartinib (HR = 0.23, 95%CI = 0.08-0.68, very low quality of evidence), brigatinib (HR = 0.38, 95%CI = 0.14-0.99, low quality of evidence), ceritinib (HR = 0.24, 95%CI = 0.09-0.66, low quality of evidence), crizotinib (HR = 0.18, 95%CI = 0.08-0.41, moderate quality of evidence), and chemotherapy (HR = 0.11, 95%CI = 0.05-0.28, low quality of evidence). Conclusion: In general, smoking may not affect the treatment efficacy of advanced ALK-positive NSCLC in the first-line setting. However, alectinib may perform better in the smoking Asian population. Moreover, lorlatinib in never-smokers and low-dose alectinib in smokers could be considered optimal first-line therapy for advanced ALK-positive NSCLC. Acceptable limitations of evidence, such as study risk of bias, inconsistency, and imprecision, were present in this NMA.