The combination of exon sequencing and metabolomics to establish a molecular typing system for gastric cancer.

Background: Gastric cancer (GC) is one of the most common malignant tumors in the world. It has become increasingly difficult to meet the needs of precision therapy using the existing molecular typing system. Therefore, developing a more effective molecular typing system for GC is urgent. Methods: In this study, 100 Chinese GC patients were included. Whole-exome sequencing (WES) and metabolomics analysis were performed to reveal the characteristics of genomic and metabolic changes. Results: In WES, nonsynonymous mutations accounted for the majority. Based on metabolomics, GC has been divided into three subtypes with distinct metabolic features. Importantly, we ultimately divided GC into four subtypes with different metabolic characteristics, genomic alterations, and clinical prognoses by incorporating biomics analysis. Conclusions: Integrating biological features, we constructed a novel molecular system for GC that was closely related to genetics and metabolism, providing new insights for further understanding the heterogeneity and formulating precise treatment strategies.

Copper Nanodrugs with Controlled Morphologies through Aqueous Atom Transfer Radical Polymerization.

Copper (Cu) nanodrugs can be facilely prepared through atom transfer radical polymerization (ATRP) in an aqueous medium. However, it is difficult to control the morphology of Cu nanodrugs and thereby optimize their anticancer activity. In this work, aqueous ATRP was combined with polymerization-induced self-assembly (PISA) to prepare Cu nanodrugs with various morphologies. We mapped the relationship between polymerization condition and product morphology in which each morphology shows a wide preparation window. Decreasing the reaction temperature and feeding more Cu catalysts can improve the mobility of chains, facilitating the morphology evolution from sphere to other high-order morphologies. The resultant Cu nanodrugs with high monomer conversion and high Cu loading efficiency could be easily taken by cancer cells, showing excellent anticancer efficacy in vitro. This work proposed a potential strategy to prepare Cu nanodrugs with a specific morphology in batches, providing the method to optimize the anticancer efficacy through morphology control.

ALK-Rearranged Renal Cell Carcinoma: A Multi-Institutional Study of 9 Cases With Expanding the Morphologic and Molecular Genetic Spectrum.

ALK-rearranged renal cell carcinoma (ALK-RCC) is rare, molecularly defined RCC subtype in the recently published fifth edition of World Health Organization classification of tumors. In this study, we described 9 ALK-RCCs from a clinicopathologic, immunohistochemical, and molecular genetic aspect, supporting and extending upon the observations by previous studies regarding this rare subgroup of RCC. There were 6 male and 3 female patients with ages ranging from 14 to 59 years (mean, 34.4 years). None of the patients had sickle cell trait. The diagnosis was based on radical or partial nephrectomy specimen for 8 patients and on biopsy specimen for 1. Tumor size ranged from 2.5 to 7.2 cm (mean, 2.8 cm). Follow-up was available for 6 of 9 patients (6-36 months); 5 had no tumor recurrence or metastasis and 1 developed lung metastasis at 24 months. The patient was subsequently treated with resection of the metastatic tumor followed by crizotinib-targeted therapy, and he was alive without tumor 12 months later. Histologically, the tumors showed a mixed growth of multiple patterns, including papillary, solid, tubular, tubulocystic, cribriform, and corded, often set in a mucinous background. The neoplastic cells had predominantly eosinophilic cytoplasm. Focally, clear cytoplasm with polarized nuclei and subnuclear vacuoles (n = 1), and pale foamy cytoplasm (n = 1) were observed on the tumor cells. The biopsied tumor showed solid growth of elongated tubules merging with bland spindle cells. Other common and uncommon features included psammomatous microcalcifications (n = 5), rhabdoid cells (n = 4), prominent intracytoplasmic vacuoles (n = 4), prominent chronic inflammatory infiltrate (n = 3), signet ring cell morphology (n = 2), and pleomorphic cells (n = 2). By immunohistochemistry, all 9 tumors were diffusely positive for ALK(5A4) and 4 of 8 tested cases showed reactivity for TFE3 protein. By fluorescence in situ hybridization analysis, ALK rearrangement was identified in all the 9 tumors; none of the tested tumors harbored TFE3 rearrangement (0/4) or gains of chromosomes 7 and 17 (0/3). ALK fusion partners were identified by RNA-sequencing in all 8 cases analyzed, including EML4 (n = 2), STRN (n = 1), TPM3 (n = 1), KIF5B (n = 1), HOOK1 (n = 1), SLIT1 (n = 1), and TPM1(3'UTR) (n = 1). Our study further expands the morphologic and molecular genetic spectrum of ALK-RCC.

The role of FERMT2 in the tumor microenvironment and immunotherapy in pan-cancer using comprehensive single-cell and bulk sequencing.

FERMT2 has been identified as a participant in integrin-linked kinase signaling pathways, influencing epithelial-mesenchymal transition and thereby affecting tumor initiation, progression, and invasion. While the character of FERMT2 in the tumor microenvironment (TME) as well as its implications for immunotherapy remain unclear. Thus, we conducted a comprehensive analysis to assess the prognostic significance of FERMT2 using Kaplan-Meier analysis. In addition, we employed enrichment analysis to uncover potential underlying molecular mechanisms. Using "Immunedeconv" package, we evaluated the immune characteristics of FERMT2 within TME. Furthermore, we determined the expression levels of FERMT2 in various cell types within TME, based on single-cell sequencing data. To confirm the co-expression of FERMT2 and markers of cancer-associated fibroblasts (CAFs), we performed multiplex immunofluorescence staining on tissue paraffin sections across various cancer types. Our analysis disclosed a significant correlation between elevated FERMT2 expression and unfavorable prognosis in specific cancer types. Furthermore, we identified a strong correlation between FERMT2 expression and diverse immune-related factors, including immune checkpoint molecules, immune cell infiltration, microsatellite instability (MSI), and tumor mutational burden (TMB). Additionally, there was a significant correlation between FERMT2 expression and immune-related pathways, particularly those associated with activating, migrating, and promoting the growth of fibroblasts in diverse cancer types. Interestingly, we observed consistent co-expression of FERMT2 in both malignant tumor cells and stromal cells, particularly within CAFs. Notably, our findings also indicated that FERMT2, in particular, exhibited elevated expression levels within tumor tissues and co-expressed with α-SMA in CAFs based on the multiplex immunofluorescence staining results.

MEF2D facilitates liver metastasis of gastric cancer cells through directly inducing H1X under IL-13 stimulation.

Liver metastasis is the most common metastatic occurrence in gastric cancer patients, although the precise mechanism behind it remains unclear. Through a combination of proteomics and quantitative RT-PCR, our study has revealed a significant correlation between the upregulation of myocyte enhancer factor-2D (MEF2D) and both distant metastasis and poor prognosis in gastric cancer patients. In mouse models, we observed that overexpressing or knocking down MEF2D in gastric cancer cells respectively promoted or inhibited liver metastasis. Furthermore, our research has demonstrated that MEF2D regulates the transcriptional activation of H1X by binding to the H1X promoter. This regulation leads to the upregulation of H1X, which, in turn, promotes the in vivo metastasis of gastric cancer cells along with the upregulation of the downstream gene ß-CATENIN. Additionally, we found that the expression of MEF2D and H1X at both mRNA and protein levels can be induced by the inflammatory factor IL-13, and this induction exhibits a time gradient dependence. In human gastric cancer tissues, the expression of IL13RA1, the receptor for IL-13, positively correlates with the expression of MEF2D and H1X. IL13RA1 has been identified as an intermediate receptor through which IL-13 regulates MEF2D. In conclusion, our findings suggest that MEF2D plays a crucial role in promoting liver metastasis of gastric cancer by upregulating H1X and downstream target ß-CATENIN in response to IL-13 stimulation. Targeting MEF2D could therefore be a promising therapeutic strategy for the clinical management of gastric cancer. STATEMENT OF SIGNIFICANCE: MEF2D promotes its transcriptional activation in gastric cancer cells by binding to the H1X promoter and is upregulated by IL-13-IL13RA1, thereby promoting distant metastasis of gastric cancer.

Three years follow-up of neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer.

Neoadjuvant chemoimmunotherapy plays a crucial role in resectable non-small cell lung cancer (NSCLC). Neoadjuvant chemotherapy before sleeve lobectomy was safe and feasible, but the impact of neoadjuvant chemoimmunotherapy before sleeve lobectomy was unclear. In our retrospective study, patients diagnosed as stage IIB to IIIB resectable NSCLC between December 1, 2018 and December 1, 2020 in the Department of Thoracic Surgery, Zhejiang Cancer Hospital were collected. We analyzed the efficacy and safety of neoadjuvant chemoimmunotherapy for resectable NSCLC patients and analyzed the impact of different types of surgery on postoperative complications, surgical difficulty, and long-term survival. In total, 56 patients were included in this retrospective study. With a median follow-up of 35 months, 1-year EFS, 2-year EFS, and 3-year EFS were 87.5%, 80.4%, and 76.7%, respectively. 1-year OS, 2-year OS, and 3-year OS were 96.4%, 91.1%, and 85.6%. respectively. Both median EFS and OS were not reached. The percentage of patients with pCR was 51.8%. 48 (85.7%) patients had nodal downstaging and primary tumor downstaging. In 40 (61.4%) patients occurred neoadjuvant chemoimmunotherapy-related adverse events (AEs), most of them of Grade 1 and 2. Postoperative complications occurred in 19 (33.9%) patients. Subgroup analysis showed that sleeve lobectomy was related to better survival and had no impact on operation duration, hospital stay, intraoperative blood loss, and postoperative complications. Neoadjuvant chemoimmunotherapy led to a high pCR rate, favorable 3-year survival rate, and acceptable AEs. Sleeve lobectomy was safe and related to better survival.

Copper Nanodrugs by Atom Transfer Radical Polymerization.

In this study, some copper catalysts used for atom transfer radical polymerization (ATRP) were explored as efficient anti-tumor agents. The aqueous solution of copper-containing nanoparticles with uniform spheric morphology was in situ prepared through a copper-catalyzed activator generated by electron transfer (AGET) ATRP in water. Nanoparticles were then directly injected into tumor-bearing mice for antitumor chemotherapy. The copper nanodrugs had prolonged blood circulation time and enhanced accumulation at tumor sites, thus showing potent antitumor activity. This work provides a novel strategy for precise and large-scale preparation of copper nanodrugs with high antitumor activity.

Stem cell landscape aids in tumor microenvironment identification and selection of therapeutic agents in gastric cancer.

Gastric cancer stem cells (GCSCs) are strongly associated with the refractory characteristics of gastric cancer, including drug resistance, recurrence, and metastasis. The prognosis for advanced gastric cancer patients treated with multimodal therapy after surgery remains discouraging. GCSCs hold promise as therapeutic targets for GC patients. We obtained 26 sets of stem cell-related genes from the StemChecker database. The Consensus clustering algorithm was employed to discern three distinct stemness subtypes. Prognostic outcomes, components of the tumor microenvironment (TME), and responses to therapies were compared among these subtypes. Following this, a stemness-risk model was formulated using weighted gene correlation network analysis (WGCNA), alongside Cox regression and random survival forest analyses. The C2 subtype predominantly showed enrichment in negative prognostic CSC gene sets and demonstrated an immunosuppressive TME. This specific subtype exhibited minimal responsiveness to immunotherapies and demonstrated reduced sensitivity to drugs. Four pivotal genes were integrated into the construction of the stemness model. Gastric cancer patients with higher stemness-risk scores demonstrated poorer prognoses, a greater presence of immunosuppressive components in TME, and lower rates of treatment response. Subset analysis indicated that only the low-stemness risk subtype derives benefit from 5-fluorouracil-based adjuvant chemotherapy. The model's effectiveness in immunotherapeutic prediction was further validated in the PRJEB25780 cohort. Our study categorized gastric cancer patients into three stemness subtypes, each demonstrating distinct prognoses, components of TME infiltration, and varying sensitivity or resistance to standard chemotherapy or targeted therapy. We propose that the stemness risk model may help the development of well-grounded treatment recommendations and prognostic assessments.