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Abstract Gliomas are the most common tumors of the central nervous system, with glioblastoma (GBM) being particularly aggressive and fatal. Current treatments for GBM, including surgery and chemotherapy, are limited by tumor aggressiveness and the blood-brain barrier. Therefore, understanding the molecular mechanisms driving GBM growth is essential. Mitochondria, key players in cellular energy production, have been implicated in cancer development. In this study, we investigated the expression of mitochondrial transcription elongation factor (TEFM) in gliomas and its potential role in tumor progression. Analysis of data from The Cancer Genome Atlas (TCGA) revealed that TEFM transcript levels were significantly higher in glioma tissues compared to adjacent normal tissues. High TEFM expression was associated with poor survival outcomes in glioma patients. Furthermore, TEFM was notably upregulated in glioma tissue and in primary glioma cells derived from local patients, while its expression was relatively low in normal tissues and astrocytes. Silencing or knockout of TEFM significantly inhibited glioma cell growth, proliferation, clonogenicity, migration, and invasion, while inducing apoptosis and activating caspases. In contrast, ectopic overexpression of TEFM promoted tumorigenic activity, enhancing the malignant behavior of glioma cells. Co-expression analysis identified a strong correlation between TEFM and the epithelial-mesenchymal transition (EMT) pathway in gliomas. Notably, the expression of EMT markers, such as N-cadherin and Vimentin, decreased upon TEFM knockdown or knockout. Additionally, TEFM depletion impaired mitochondrial function, disrupting the mitochondrial respiratory chain in glioma cells. In vivo experiments demonstrated that TEFM knockout effectively suppressed the growth of subcutaneous glioma xenografts in nude mice. Collectively, these findings highlight the critical role of TEFM in GBM growth and invasion, suggesting that it could serve as a promising therapeutic target for glioma treatment. Graphical Abstract

Abstract FOXA1 (Forkhead Box A1) and FOXA2 (Forkhead Box A2) serve as pioneering transcription factors that build gene expression capacity and play a central role in biological processes, including organogenesis and differentiation, glycolipid metabolism, proliferation, migration and invasion, and drug resistance. Notably, FOXA1 and FOXA2 may exert antagonistic, synergistic, or complementary effects in the aforementioned biological processes. This article focuses on the molecular mechanisms and clinical relevance of FOXA1 and FOXA2 in steroid hormone-induced malignancies and highlights potential strategies for targeting FOXA1 and FOXA2 for cancer therapy. Furthermore, the article describes the prospect of targeting upstream regulators of FOXA1/FOXA2 to regulate its expression for cancer therapy because of the drug untargetability of FOXA1/FOXA2.

IntroductionRadiation therapy (RT) is one of the primary treatment options for early-stage non-small cell lung cancer (ES-NSCLC). Therefore, accurately predicting the overall survival (OS) rate following radiotherapy is crucial for implementing personalized treatment strategies. This work aims to develop a dual-radiomics (DR) model to (1) predict 3-year OS in ES-NSCLC patients receiving RT using pre-treatment CT images, and (2) provide explanations between feature importanceand model prediction performance.MethodsThe publicly available TCIA Lung1 dataset with 132 ES-NSCLC patients received RT were studied: 89/43 patients in the under/over 3-year OS group. For each patient, two types of radiomic features were examined: 56 handcrafted radiomic features (HRFs) extracted within gross tumor volume, and 512 image deep features (IDFs) extracted using a pre-trained U-Net encoder. They were combined as inputs to an explainable boosting machine (EBM) model for OS prediction. The EBM’s mean absolute scores for HRFs and IDFs were used as feature importance explanations. To evaluate identified feature importance, the DR model was compared with EBM using either (1) key or (2) non-key feature type only. Comparison studies with other models, including supporting vector machine (SVM) and random forest (RF), were also included. The performance was evaluated by the area under the receiver operating characteristic curve (AUCROC), accuracy, sensitivity, and specificity with a 100-fold Monte Carlo cross-validation.ResultsThe DR model showed highestperformance in predicting 3-year OS (AUCROC=0.81 ± 0.04), and EBM scores suggested that IDFs showed significantly greater importance (normalized mean score=0.0019) than HRFs (score=0.0008). The comparison studies showed that EBM with key feature type (IDFs-only demonstrated comparable AUCROC results (0.81 ± 0.04), while EBM with non-key feature type (HRFs-only) showed limited AUCROC (0.64 ± 0.10). The results suggested that feature importance score identified by EBM is highly correlated with OS prediction performance. Both SVM and RF models were unable to explain key feature type while showing limited overall AUCROC=0.66 ± 0.07 and 0.77 ± 0.06, respectively. Accuracy, sensitivity, and specificity showed a similar trend.DiscussionIn conclusion, a DR model was successfully developed to predict ES-NSCLC OS based on pre-treatment CT images. The results suggested that the feature importance from DR model is highly correlated to the model prediction power.

Abstract Background Mecapegfilgrastim, a long‐acting granulocyte‐colony stimulating factor has been approved for reducing the incidence of infection, particularly febrile neutropenia (FN), in China. Objective We conducted a multicenter prospective observational study to examine the safety and effectiveness of mecapegfilgrastim in preventing neutropenia in gastrointestinal patients receiving the chemotherapy, including S‐1/capecitabine‐based regimens or the fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/fluorouracil, leucovorin, and oxaliplatin (FOLFOX)/fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX) regimens. Method Five hundred and sixty‐one gastrointestinal patients from 40 sites across China, between May 2019 and November 2021, were included. The administration of mecapegfilgrastim was prescribed at the discretion of local physicians. Results The most common adverse drug reactions (ADRs) of any grade for all patients was increased white blood cells (2.9%). Grade 3/4 ADRs were observed for anemia (0.2%), decreased white blood cells (0.2%), and decreased neutrophil count (0.2%). Among the 116 patients who received S‐1/capecitabine‐based chemotherapy throughout all cycles, ADRs of any grade included anemia (1.7%), myalgia (0.9%), and increased alanine aminotransferase (0.9%). No grade 3/4 ADRs were observed. In 414 cycles of patients who underwent S‐1/capecitabine‐based regimens, only one (0.2%) cycle experienced grade 4 neutropenia. In the FOLFIRINOX, FOLFOXIRI, and FOLFOX chemotherapy regimens, grade 4 neutropenia occurred in one (2.7%) of 37 cycles, four (4.7%) of 85 cycles, and two (1.2%) of 167 cycles, respectively. Conclusion In a real‐world setting, mecapegfilgrastim has proven effective in preventing severe neutropenia in gastrointestinal patients following chemotherapy. This includes commonly used moderate or high‐risk FN regimens or regimens containing S1/capecitabine, all of which have demonstrated favorable efficacy and safety profiles.

Abstract Hepatocellular carcinoma (HCC) is a global health problem. Its incidence and mortality are increasing. Exploring novel therapeutic targets against HCC is important and urgent. We here explored the expression and potential function of Gαi2 (G protein subunit alpha i2) in HCC. The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) database shows that the number of Gαi2 transcripts in HCC tissues is significantly higher than that in the normal liver tissues. Moreover, Gαi2 overexpression in HCC correlates with poor prognosis of the patients. Gαi2 mRNA and protein expression are also elevated in local HCC tissues and different human HCC cells. In patient-derived primary HCC cells and immortalized HepG2 cells, Gαi2 silencing (by targeted shRNA) or knockout (KO, by the dCas9-sgRNA method) largely suppressed cell proliferation and motility, while inducing cell cycle arrest and caspase-apoptosis activation. Moreover, Gαi2 silencing or KO-induced reactive oxygen species (ROS) production and oxidative injury in primary and HepG2 HCC cells. Whereas different antioxidants ameliorated Gαi2-shRNA-induced anti-HCC cell activity. Using a lentiviral construct, Gαi2 overexpression further augmented proliferation and motility of primary and immortalized HCC cells. Further studies revealed that the binding between the transcription factor early growth response zinc finger transcription factor 1 (EGR1) and Gαi2 DNA promoter was significantly increased in HCC tissues and cells. In vivo, intratumoral injection of Gαi2 shRNA adeno-associated virus significantly hindered HCC xenograft growth in nude mice. Moreover, the growth of Gαi2-KO HCC xenografts in the nude mice was remarkably slow. Gαi2 depletion, oxidative injury, and apoptosis induction were detected in Gαi2-silenced or Gαi2-KO HCC xenografts. Together, overexpressed Gαi2 is required for HCC cell growth in vitro and in vivo, representing as a novel and promising diagnosis marker and therapeutic target of HCC.

Abstract The expression, biological functions and underlying molecular mechanisms of endothelial cell-specific molecule 1 (ESM1) in human cervical cancer remain unclear. Bioinformatics analysis revealed that ESM1 expression was significantly elevated in human cervical cancer tissues, correlating with patients’ poor prognosis. Moreover, ESM1 mRNA and protein upregulation was detected in local cervical cancer tissues and various cervical cancer cells. In established and primary cervical cancer cells, ESM1 shRNA or CRISPR/Cas9-induced ESM1 KO hindered cell proliferation, cell cycle progression, in vitro cell migration and invasion, and induced significant apoptosis. Whereas ESM1 overexpression by a lentiviral construct accelerated proliferation and migration of cervical cancer cells. Further bioinformatics studies and RNA sequencing data discovered that ESM1-assocaited differentially expressed genes (DEGs) were enriched in PI3K-Akt and epithelial-mesenchymal transition (EMT) cascades. Indeed, PI3K-Akt cascade and expression of EMT-promoting proteins were decreased after ESM1 silencing in cervical cancer cells, but increased following ESM1 overexpression. Further studies demonstrated that SYT13 (synaptotagmin 13) could be a primary target gene of ESM1. SYT13 silencing potently inhibited ESM1-overexpression-induced PI3K-Akt cascade activation and cervical cancer cell migration/invasion. In vivo, ESM1 knockout hindered SiHa cervical cancer xenograft growth in mice. In ESM1-knockout xenografts tissues, PI3K-Akt inhibition, EMT-promoting proteins downregulation and apoptosis activation were detected. In conclusion, overexpressed ESM1 is important for cervical cancer growth in vitro and in vivo, possibly by promoting PI3K-Akt activation and EMT progression. ESM1 represents as a promising diagnostic marker and potential therapeutic target of cervical cancer.

Serous ovarian cancer is the most common and primary death type in ovarian cancer. In recent studies, tumor microenvironment and tumor immune infiltration significantly affect the prognosis of ovarian cancer. This study analyzed the four gene expression types of ovarian cancer in TCGA database to extract differentially expressed genes and verify the prognostic significance. Meanwhile, functional enrichment and protein interaction network analysis exposed that these genes were related to immune response and immune infiltration. Subsequently, we proved these prognostic genes in an independent data set from the GEO database. Finally, multivariate cox regression analysis revealed the prognostic significance of TAP1 and CXCL13. The genetic alteration and interaction network of these two genes were shown. Then, we established a nomogram model related to the two genes and clinical risk factors. This model performed well in Calibration plot and Decision Curve Analysis. In conclusion, we have obtained a list of genes related to the immune microenvironment with a better prognosis for serous ovarian cancer, and based on this, we have tried to establish a clinical prognosis model.

Abstract Background PRKAA1 encodes α-subunit of 5-AMP-activated protein kinase (AMPK), which has been implicated in the pathogenesis of carcinoma of the stomach. Previous works have suggested that polymorphisms in the PRKAA1 may be associated with the risk of non-cardiac gastric cancer (NCGC), but whether PRKAA1 polymorphisms are related to clinical pathologic characteristics of gastric cancer and its clinical outcome is largely unknown. Methods We carried out a case-control study including a total of 481 gastric cancer patients and 490 healthy controls. The genotypes of enrolled polymorphisms were identified with Sequenom MassARRAY platform. Results This study showed that rs10074991 GG genotype (adjusted OR = 1.44, 95%CI:0.99–2.09, p = 0.056) has a borderline significantly increased risk for gastric cancer, which was consistent with the result of additive model (adjusted OR = 1.21, 95%CI:1.01–1.46, p = 0.042). In similar, an increased risk of gastric cancer was also observed for rs13361707 TC genotype (adjusted OR = 1.47, 95%CI: 1.01–2.14, p = 0.043; additive model: adjusted OR = 1.22, 95%CI: 1.02–1.47, p = 0.033). Furthermore, the rs154268 and rs461404 were also found associated with increased gastric cancer risk, which may be influenced by age, tumor type and differentiation, and tumor stage. Haplotype analysis indicated A-G-C-T-C-G haplotype (rs6882903, rs10074991, rs13361707, rs3805490, rs154268 and rs461404) is associated with increased risk of gastric cancer (OR = 1.29, 95%CI: 1.02–1.62, p = 0.035). The univariate analysis for overall survival (OS) revealed that both of rs10074991 and rs13361707 variants are associated with poor OS in patients with NCGC. Conclusion This case-control study provided the evidence thatrs13361707CC, rs10074991GG, rs461404GG, and rs154268CC are associated with increased gastric cancer risk, especially for NCGC, and that patients with rs10074991 G or rs13361707 C allele have a poor OS.

Background and objective Raf kinase inhibitory protein (RKIP) belongs to the phosphatidylethanolamine binding protein (PEBP) family. RKIP is an endogenous inhibitor of the Raf-1-MEK1/2-ERK1/2 signaling pathway, NFkappaB signaling pathway and G protein coupled receptors signaling pathway. The aim of this study is to explore the expression of RKIP in lung squamous cell carcinoma, and the relationship between RKIP expression and clinical pathology of lung squamous cell carcinoma. Methods The expression of RKIP mRNA was detected in 56 lung squamous cell carcinoma tissues and adjacent cancer tissues by RT-PCR. The expression level of RKIP protein was detected by Western blot. The positive rates of RKIP expression in cancer tissues and adjacent cancer tissues were analyzed. Results RKIP mRNA positive expression rate in cancer tissues was significantly lower than that in adjacent cancer tissues (P < 0.05). The positive rate of RKIP mRNA expression in the cancer tissues with lymph node metastasis was significantly lower than that without lymph node metastasis (P < 0.05). RKIP mRNA expression has no remarkable correlation with age, sex, tumor differentiation and size (P > 0.05). RKIP protein expression in the cancer tissues was significantly lower than that in adjacent cancer tissues (P < 0.05). Conclusion The deficiency of RKIP expression is positively correlated with carcinogenesis and invasion metastasis of lung squamous cell carcinoma.