OncoTargets and therapy最新文献

Inflammatory bowel disease (IBD) is a family of chronic inflammatory diseases such as Crohn's disease (CD) and ulcerative colitis (UC). Among the serious malignancies that can arise from IBD, colorectal cancer is particularly prevalent. Individuals suffering from both IBD and CRC often endure similar symptoms, which include diarrhea, rectal bleeding, abdominal discomfort, weight decline, and profound exhaustion. Sanyeqing is a traditional herbaceous medicinal plant with anti-tumor, anti-inflammatory, analgesic, heat-clearing, detoxifying, and liver-protecting effects. Here, we summarize the possible molecular mechanisms of IBD and CRC, and summarize the potential role of Sanyeqing in clinical therapy for IBD and CRC. Investigating the etiology of enteritis and intestinal cancer, as well as exploring Sanyeqing's potential as a preventive and therapeutic agent, is of paramount importance in the battle against these diseases.

Background: Precocious brain metastasis in lung cancer, diagnosed through surgical resection before primary lung cancer detection, represents a unique clinical scenario with limited research. This study aims to investigate the clinical characteristics, prognosis, and the impact of different treatments on survival outcomes in this distinct population.

Materials and methods: We retrospectively analyzed clinical outcomes of lung cancer patients newly diagnosed following brain metastasis decompression surgery in our institute, over a period from July 2012 to May 2023. Patient demographics including gender, age, surgical approach, pathological findings, receipt of radiotherapy, systemic treatment modalities, and presence of druggable mutations were documented. Druggable mutations were defined as actionable genetic alterations (AGAs) detected in patients for which corresponding targeted therapeutic agents were available.

Results: Among 64 patients analyzed, 53 (82.8%) were diagnosed with adenocarcinoma; 38 (59.4%) harbored druggable mutations. There was only one patient with small cell carcinoma in this series. Types of druggable mutations were discussed in the study. The clinical stage was IVB among 38 (59.4%) patients. Forty-nine (76.6%) patients had metastatic brain lesions with number ≦3. Thirty-five (54.7%) patients received post-operative radiotherapy. The cohort's median overall survival (OS) was 19.6 months. Patients with druggable mutations had an OS longer than patients without druggable mutation (46.0 vs 14.5 months, Log rank test p =0.004). Among patients with druggable mutations, we found no difference in characteristics between patients with and without post-operative cranial radiotherapy. Patients receiving post-operative cranial radiotherapy did not show significantly better clinical efficacy than patients without radiotherapy (adjusted hazard ratio: 0.68, 95% confidence interval 0.16 to 2.91).

Conclusion: In patients with precocious brain metastases from lung cancer, the presence of druggable mutations and subsequent targeted therapy significantly extended survival, whereas post-operative brain radiotherapy may not confer additional survival benefits. These findings highlight the importance of molecular profiling and targeted therapy in this unique patient population.

Background: Disulfidptosis, a novel pattern of regulatory cell death, provides a valuable opportunity to gain deeper comprehension of tumor pathogenesis and treatment strategies. However, its biological mechanism in esophageal squamous cell carcinoma (ESCC) has yet to be completely elucidated.

Materials and methods: From the Gene Expression Omnibus (GEO) GSE53625 dataset, we obtained RNA-seq data and clinical information. An analysis of Pearson correlation was utilized to screen disulfidptosis-related lncRNAs (DRLs), followed by LASSO and multivariate Cox regression analysis to construct a prognostic signature. The reliability and accuracy of this signature were verified on internal validation sets, including training (n= 90), testing (n= 89), and GSE53625 entire (n= 179) sets, as well as external sets, including TCGA-ESCC (n= 81) and GSE53624 (n= 119) sets. Additionally, mutation data comes from TCGA database was utilized for validating tumor mutation burden (TMB) analysis. In cell lines, an analysis of lncRNA differential expression was conducted using qRT-PCR.

Results: Ultimately, six DRLs were utilized to construct a prognostic signature. Across all sets, Kaplan-Meier analysis indicated that high-risk ESCC patients have a poorer prognosis (p < 0.05), and ROC analysis showed that the AUC values at 1, 3, and 5 years all exceeded 0.6. Moreover, disparities were observed in immune phenotype scores, tumor infiltration of immune cells, functional enrichment, TIDE score, immune function, and TMB among the two risk groups. Additionally, individuals at high risk showed higher sensitivity to erlotinib, acetalax, gefitinib, lapatinib, sapitinib, and afatinib.

Conclusion: Through bioinformatics analysis, a novel and robust DRLs signature for ESCC was established, providing new insights into the prognosis prediction and potential treatment strategies. Nevertheless, this study is retrospective and relies on public databases, with a limited sample size within the datasets. In the future, it is essential to conduct more extensive validation of the prognostic value and efficacy in real ESCC cohorts.

Background: Colorectal cancer (CRC) is a significant contributor to cancer-related mortality globally. Despite the availability of treatments such as surgery, chemotherapy, and radiotherapy, these interventions are often accompanied by severe side effects and suboptimal patient outcomes. Recent studies have suggested that lidocaine, a widely used local anesthetic, may possess anti-tumor properties in various cancer types. This study aims to explore the impact of lidocaine on CRC cell lines, HCT 116 and SW480, to evaluate its potential as a therapeutic agent.

Methods: In vitro assays were conducted to assess the effect of lidocaine on the proliferation, migration, and invasion of CRC cells. The suppression of cell proliferation and induction of apoptosis were confirmed using colony formation, EdU, and TUNEL assays. RNA sequencing was performed on lidocaine-treated HCT 116 cells to identify differentially expressed genes and enriched biological pathways. A prognostic signature based on 16 genes was developed and validated using clinical data.

Results: Lidocaine significantly inhibited the proliferation, migration, and invasion of CRC cells in a dose-dependent manner. The assays confirmed that lidocaine suppressed cell proliferation and induced apoptosis. RNA sequencing revealed 8002 differentially expressed genes in lidocaine-treated HCT 116 cells, with significant enrichment of key pathways such as the estrogen signaling pathway and MAPK pathway. A prognostic signature based on 16 genes was developed and validated, providing a predictive model for patient survival. These findings suggest that lidocaine has potential as a therapeutic agent for CRC treatment, although further in vivo studies are required to clarify its mechanisms and optimize its clinical application.

[This retracts the article DOI: 10.2147/OTT.S248797.].

[This retracts the article DOI: 10.2147/OTT.S35322.].

Purpose: Combination therapies of chemotherapeutic agents and immunotherapy have shown promising results in the treatment of cold tumors. Various chemotherapies trigger immunogenic cell death (ICD) and release of hallmarks immunogenic damage associated molecular patterns (DAMPs) that have been related with immunostimulatory activities, leading to better patient prognosis. We aim to optimize in vitro assays to detect DAMPs release in response to chemotherapeutic agents using a colorectal cancer (CRC) organoids model.

Methods: CRC patient-derived organoids (PDOs) were treated either with oxaliplatin (OXA) or with 5-fluorouracil (5FU) and viability was measured with CellTiter-Glo3D Cell viability assay. Calreticulin (CALR) and high mobility group box 1 protein (HMGB1) intracellular translocation was assessed in immunofluorescence microscopy and quantified via co-localization with wheat germ agglutinin (WGA) and DAPI. Extracellular release of adenosine triphosphate (ATP) was quantified via specific luminescence assays.

Results: The results showed that CRC PDOs release DAMPs in a patient-specific manner in response to OXA and 5FU treatments.

Conclusion: This study successfully used immunofluorescence and luminescence methods to detect ICD-associated DAMPs release in CRC PDOs in response to chemotherapeutic treatments. This approach allows the recognition of patient-specific ICD activation and could help predict patient response to therapies.

Background: As a novel oral Exportin 1 (XPO1) inhibitor, selinexor at 80 or 100 mg has demonstrated efficacy in treating relapsed/refractory multiple myeloma (RRMM), nonetheless, this dosage has shown poor tolerability.

Objective: To explore the optimal dosage of selinexor, we evaluated the efficacy and safety of 60 vs 40 mg selinexor, combine with regimen comprising pomalidomide and dexamethasone in RRMM.

Design: 21 patients with RRMM were enrolled to receive selinexor (60 or 40 mg once weekly), together with pomalidomide (4 mg/day on days 1-21) and dexamethasone (40 mg once weekly); the SPD-60 group (6 patients) vs SPD-40 group (15 patients).

Methods: The clinical response and efficacy of the two groups were continuously followed up, and statistical analysis was carried out to screen out the dose group with fewer side effects and better efficacy. The primary endpoint was (objective response rates) ORR. The secondary endpoints included treatment safety and tolerability, progression-free survival (PFS) and overall survival (OS).

Results: The ORR of the SPD-60 and SPD-40 groups were 33.3% and 46.7% respectively (P=0.773). With a median follow-up of 20.9 months, the median PFS was 6.2 months and the median OS was not achieved across all treated patients. The median PFS for SPD-60 group was 4.3 months, while for SPD-40 was 8.0 months (P=0.618). The 1-year OS rate were 66.7% for SPD-60 group and 85.1% for the SPD-40 group (P=0.308). The most common hematological adverse events were neutropenia (SPD-60 group 50% vs SPD-40 group 53.3%) and thrombocytopenia (50% vs 46.7%). Fatigue (83.3% vs 40%), infection (50% vs 53.3%), and nausea (83.3% vs 40%) were the most common non-hematologic adverse effects.

Conclusion: The SPD-40 regimen may be more clinically applicable than SPD-60, as it elicited fewer adverse effects while demonstrating equivalent efficacy.

Trial registration: ClinicalTrials.gov: NCT04941937.

Introduction: Metabolism-related genes (MRGs) critically influence cancer prognosis, yet their role in gastric carcinoma (GC) remains poorly understood.

Methods: We analyzed 24,991 genes from 407 GC patients in TCGA to identify a metabolic gene-based prognostic signature. In vitro and in vivo functional experiments validated key findings, while transcriptional regulation mechanisms were explored through promoter interaction assays.

Results: A robust 10-metabolic gene signature was identified as strongly predictive of recurrence-free survival (RFS) in GC. Elevated insulin-like growth factor binding protein 1 (IGFBP1) expression correlated with reduced overall survival and disease-free survival. Functional studies demonstrated IGFBP1's oncogenic role in promoting GC proliferation and metastasis. Mechanistically, zinc finger protein X-linked (ZFX) activated IGFBP1 transcription by directly binding to its promoter.

Discussion: We established a prognostic nomogram integrating the 10-metabolic gene signature for GC RFS prediction. IGFBP1 emerges as a potential therapeutic target and biomarker, with ZFX-driven transcriptional activation as a novel regulatory axis in GC progression.

Background: Gastric cancer (GC) is the fifth most prevalent cancer worldwide and the fourth leading cause of cancer-related mortality. MAM Domain Containing 2 (MAMDC2) has been involved in many cancers. However, the impact of MAMDC2 on gastric cancer was unclear. This study aimed to investigate the role and mechanism of MAMDC2 in gastric cancer.

Methods: Differential genes in gastric cancer are analyzed by GEO, TCGA, MSigDB database, R-packet limma, and Wilcoxon test. Survival analysis is performed through the R package survival. Construct a PPI network through the STRING database. Enrichment analysis is performed by Metascape. The infiltration level of gastric cancer immune cells is calculated by CIBERSORT. In addition, the expression of MAMDC2 was analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction (RT-qPCR). siMAMDC2 was used to knock down the specific gene. Cell counting kit-8 (CCK-8) assay, colony formation assay, and cell migration were applied to evaluate the function of MAMDC2 in gastric cancer cells.

Results: In the present study, we revealed a significant upregulation of MAMDC2 in gastric cancer tissues and cells. Knocking down MAMDC2 inhibited the proliferation and migration of gastric cancer cells, while overexpression of MAMDC2 produced the opposite results. Furthermore, MAMDC2 may be an independent factor in poor prognosis in gastric cancer patients.

Conclusion: These results illustrated that MAMDC2 promoted the proliferation and migration of gastric cancer cells. The newly identified MAMDC2 provides novel insight into the pathogenesis of gastric cancer.