Translational cancer research最新文献

Background: Bladder urothelial carcinoma (BLCA), like other cancers, is strongly associated with genetic and epigenetic changes. TWIST1 is an epithelial-mesenchymal transition (EMT) promoter that has been linked to the development of many malignancies. It is still unclear, however, what role TWIST1 plays in BLCA, and the relationship between TWIST1 transcript levels and its promoter methylation and immune infiltration has been reported even less. This study aimed to reveal the potential role of TWIST1 promoter methylation-related changes in BLCA.

Methods: Transcriptional expression data of TWIST1 in BLCA were acquired from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and University of Alabama at Birmingham (UALCAN) databases. TWIST1 methylation levels and prognosis were sourced from Gene Expression Profiling Interactive Analysis 2 (GEPIA2), LinkedOmics, cBio Cancer Genomics Portal (c-BioPortal), MethSurv, and DNA Methylation Information Visualization Database (DNMIVD) databases. The methylation status of the BLCA-associated TWIST1 in preoperative and postoperative urinary exfoliated cells was subsequently analyzed using methylation-specific real-time fluorescence polymerase chain reaction, with validation of accuracy through pyrophosphate sequencing. Finally, from the Gene Set Cancer Analysis (GSCA) and Tumor-Immune System Interaction Database (TISIDB) databases, we obtained the association between TWIST1 transcript expression and DNA methylation and cancer immune infiltration and immunolabelling.

Results: Our study demonstrated that TWIST1 expression was down-regulated in BLCA, which was negatively correlated with DNA methylation. The association between TWIST1 promoter hypermethylation and the progression, staging, grading, and recurrence of BLCA is highly significant. Furthermore, we revealed that hypermethylation of both the preoperative and postoperative TWIST1 promoters is useful as a biomarker for monitoring BLCA recurrence, particularly when considering the methylation status of specific CpG sites. Additionally, we observed that TWIST1 expression, promoter methylation, and immune infiltration immunoreactive markers correlated significantly in BLCA.

Conclusions: We propose that TWIST1 holds great promise as a diagnostic and therapeutic target for BLCA, with the potential to influence tumor progression and patient prognosis through the regulation of immune cell infiltration. We hope these findings contribute valuable insights to the field of BLCA research.

Non-small cell lung cancer (NSCLC) represents over 80% of lung cancer cases and has a high mortality worldwide, however, targeting common epidermal growth-factor receptor (EGFR) alterations (i.e., del19, L858R) has provided a paradigm shift in the treatment of NSCLC. Uncommon EGFR mutations, however, show variable efficacy to EGFR-targeted drugs depending on the molecular alterations within exons 18-21 which underlying biological mechanism are far from being clear. The substitution mutations of G719X in exon 18, L861Q in exon 21, S768I in exon 20, and exon 20 insertions are the most frequent mutations among the uncommon mutations. The development of fourth-generation EGFR-tyrosine kinase inhibitor (TKIs) has gained increased interest as these drugs are able to inhibit resistance mutations (e.g., C797S) often detected in NSCLC patients' resistance to third-generation EGFR TKIs. BDTX-1535 is an orally bioavailable, brain-penetrating, mutation-selective, irreversible EGFR inhibitor with significant antitumour activity in NSCLCs and glioblastomas (phase I/II trials ongoing). It is a fourth-generation EGFR inhibitor that was found to overcome resistance to osimertinib in preclinical models and has shown promising activity in NSCLC patients harbouring C797S mutations. In experimental models BDTX-1535 was found to inhibit all common EGFR mutations and more than 50 of uncommon mutations including T790M, C797S, L718X, E709X, S784F, V834L and A289V, however, exon 20 insertions are inhibited to a much lesser extent. In addition, mutations in the extracellular domain of the EGF receptor (e.g., EGFRvII, III, IV) can be blocked as well. It should be noted that in up to 50% of all NSCLC patients who progress following osimertinib or other EGFR TKI therapy no underlying resistance mechanism can be identified suggesting that non-mutational signal transduction pathways may also be operative, and intratumoural heterogeneity has been found to be a major contributor to resistance and it consists of three main mechanisms: (I) drug-tolerant persister (DTP) cells, (II) chromosomal instability, and (III) extrachromosomal extracellular DNA (ecDNA) (seen in over 50% of NSCLCs) suggesting that novel EGFR TKIs will include many challenges in sufficiently targeting on-target resistance mechanisms. The development of novel drugs that can overcome TKI resistance in NSCLC patients harbouring the C797S mutation and beyond is, therefore, eagerly warranted.

Background: Myeloid neoplasms encompass disorders characterized by abnormal myeloid cell proliferation and differentiation, including myelodysplastic syndromes (MDS), myeloproliferative neoplasms, acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Formin-like protein 1 (FMNL1) is involved in the regulation of the actin cytoskeleton and is predominantly expressed in hematopoietic cells. Given its role in leukemia cell proliferation, survival, migration, and invasion, this study investigates FMNL1 expression in normal hematopoiesis and myeloid neoplasms and explores associations with clinical-laboratory characteristics, mutational status, and survival outcomes in AML.

Methods: Transcript levels of FMNL1 from several blood-forming cell populations and myeloid neoplasms were extracted from publicly available databases. Myeloid neoplasm cell lines were used for gene/protein expression and cell differentiation studies. Functional genomics analysis was performed using RNA-seq data from The Cancer Genome Atlas (TCGA) AML study, and drug sensitivity predictions were investigated using Beat AML and Genomics of Drug Sensitivity in Cancer (GDSC) datasets. Statistical analyses assessed the impact of FMNL1 expression on clinical outcomes.

Results: FMNL1 was highly expressed in metamyelocytes, neutrophils, and monocytes compared to hematopoietic stem cells, and its expression increased with granulocytic differentiation. FMNL1 expression was elevated in AML and CML patients compared to healthy donors. FMNL1 expression was not significantly associated with clinical-laboratory characteristics or survival outcomes but showed a higher frequency of WT1 transcription factor (WT1) mutations with low FMNL1 expression in AML patients. High FMNL1 expression in AML correlated with immune response and inflammatory activity pathways. FMNL1 mRNA levels influenced drug sensitivity in AML models, with correlations observed for specific antineoplastic agents.

Conclusions: FMNL1 plays a potential role in granulocyte differentiation and function, and its differential expression is linked to critical signaling pathways in leukemogenesis and inflammation. These findings highlight FMNL1's potential therapeutic implications in myeloid neoplasia, warranting further investigation.

Background: Phyllodes tumors (PTs) are breast neoplasms with varying degrees of malignancy, posing challenges in diagnosis and management. This case report focuses on a rare case of malignant phyllodes tumor of the breast (MPTB) in a 35-year-old woman.

Case description: This case report presents a complex scenario of a patient with extensive breast abnormalities, including a malignant PT in the left breast, ductal carcinoma in situ in both breasts, with axillary lymph node involvement. Radiological examinations revealed multiple masses with varying characteristics, leading to a challenging diagnosis. Considering a huge malignant breast tumor, surgery was suggested immediately without biopsy. Surgical intervention, including modified radical mastectomy, was performed, and pathological findings diagnosed of malignant PT with intraductal carcinoma. The patient experienced disease progression shortly after surgery, with metastases detected in the left axillary lymph node and both lungs at the third month after discharge. Despite further treatment is suggested, the patient refused the treatment options. The patient's condition rapidly deteriorated, leading to her unfortunate demise four months after surgery.

Conclusions: This case accentuates the complex nature of MPTB, highlighting the urgent need for seeking medical attention promptly, sufficient preoperative assessment, improved diagnostic techniques, interdisciplinary collaboration, and advanced treatment.

In the United States, there is expected to be about 82,000 cases of renal cell carcinoma (RCC) in 2024. At diagnosis, approximately 65% of patients with RCC will have disease localized to the kidney. For decades, the standard of care for patients with localized RCC has been surgery, which is often curative, followed by radiographic surveillance. However, after nephrectomy, patients may have up to 50% risk of recurrence. Thus, there has been a longstanding effort to reduce the recurrence of kidney cancer in the adjuvant setting after nephrectomy and/or metastasectomy. Over the past 30 years, a number of different therapeutic agents have been tested in the adjuvant setting including cytokines, autologous tumor cell vaccines, vascular endothelial growth factor (VEGF) pathway inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and most recently immune checkpoint inhibitors (ICIs). The vast majority of these adjuvant trials in RCC have shown no significant clinical benefit for patients. In 2021, the KEYNOTE-564 trial demonstrated that adjuvant pembrolizumab improved progression-free survival and more recently showed an overall survival benefit for patients with high risk of recurrence of clear cell RCC (ccRCC). These findings have ushered in a new standard of care for patients with ccRCC at high risk of recurrence after nephrectomy. Here, we provide an overview of the major adjuvant trials in RCC, with a focus on ccRCC, and provide a framework for the management of patients with high risk localized ccRCC.

Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is expressed in 20-25% of non-small cell lung cancer (NSCLC) and there is interest in CEACAM5 as a biomarker given its potential for blood-based detection and investigational study as a drug target. Increased expression of CEACAM5 has been observed in semi-solid lung adenocarcinoma lesions, which have an increased prevalence in women and never smokers. Given this association, sex-based differences in CEACAM5 were evaluated. The Cancer Genome Atlas (TCGA) data on CEACAM5 expression in NSCLC tumors (n=994) in women (n=398) and men (n=596) were analyzed for differences in expression of CEACAM5 based on sex and histologic subtypes of adenocarcinoma and for correlations with overall survival (OS). Among all stages of NSCLC, mean expression of CEACAM5 was 143.3 fragments per kilobase of transcript per million (FPKM) with differences observed between female and male patients (194.5 vs. 109.2 FPKM, P<0.0001) and between adenocarcinoma and squamous cell carcinoma (239.3 vs. 46.2 FPKM, P<0.0001). Differences persisted among combined sex and histology subgroups. High CEACAM5 was not predictive of survival in NSCLC or adenocarcinoma overall, but was associated with worse survival among stage I female patients with adenocarcinoma (5-year OS CEACAM5 high =33% vs. low =64%, log-rank P=0.008). Higher levels of CEACAM5 expression are observed in NSCLC tumors in female patients and adenocarcinoma histology. High CEACAM5 expression in lung adenocarcinoma is associated with worse survival among female patients. The biologic impact of sex on CEACAM5 as a biomarker warrants further study.

Background: Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy. The key problem lies in the complexity of the genome, so that drug resistance and relapse have become the main problems. Recent studies have found an association between synaptotagmin-like 4 (SYTL4) and drug resistance in triple-negative breast cancer and its high expression is correlated with poor prognosis; however, it is unclear whether this gene is associated with the prognosis of AML. This study aimed to investigate the role and action mechanism of SYTL4 in AML.

Methods: We downloaded gene expression profiles and corresponding clinical data from The Cancer Genome Atlas (TCGA) public database and conducted differential and survival analyses using the Limma and survival packages in R. The receiver operating characteristic (ROC) curve, univariate COX, and multivariate COX were used for gene prediction analysis. Co-expression analysis of SYTL4 was performed using Limma, and enrichment analysis of differentially expressed genes in the SYTL4 high- and low-expression groups was conducted. We performed immune cell infiltration using the CIBERSORTx algorithm.

Results: The expression level of SYTL4 was highest in the poor prognosis group, and lowest in the good prognosis group. Survival was better in the SYTL4 low expression group than that in the high expression group. The areas under the ROC curve for TCGA-Acute Myeloid Leukemia (TCGA-LAML) at 1, 3, and 5 years were 0.725, 0.683, and 0.787, respectively. Sushi repeat protein X-linked 2 (SRPX2), caveolae associated protein 2 (CAVIN2), and other genes were identified as positive regulators of SYTL4 expression, whereas lactoperoxidase (LPO), diacylglycerol lipase beta (DAGLB), and other genes were identified as negative regulators. Differentially expressed genes in the SYTL4 high- and low-expression groups were enriched in pathways such as the embryonic skeletal system and platelet alpha granules. Differences were observed in follicular helper T cells, Tregs, monocytes, and M2 macrophages between SYTL4 high- and low-expression groups.

Conclusions: SYTL4 expression negatively correlates with AML prognosis and may be associated with exosome secretion in AML.

Background: Growing evidence demonstrated that long non-coding RNAs (lncRNAs) are closely related with chemoresistance in colorectal cancer (CRC). Mitophagy serves as an essential factor to maintain the quality of tumor cells. However, it is unclear whether lncRNAs are involved in mitophagy regulation in CRC. The aim of this study is to evaluate whether lncRNAs are involved in regulating mitophagy and chemoresistance in CRC.

Methods: In this study, gain/loss of function was used to analyze the biological function influenced by apoptotic BCL2L1-antisense long non-coding RNA (ABALON). Western blot and JC-1 probe were carried out for detecting mitophagy. Chemosensitivity of CRC cells to 5-fluorouracil (5-FU) was determined using cell counting kit-8 (CCK-8), flow cytometry, colony formation and trans well assays.

Results: We found that ABALON expression was increased in CRC, especially in consensus molecular subtype 1 (CMS1) and highly expressed ABALON was related with tumor differentiation, tumor node metastasis (TNM) staging, and lymph node metastasis (P<0.05). ABALON knockdown led to impaired proliferation and enhanced apoptosis in CRC. Mitophagy variations primed by ABALON enhanced mitochondrial homeostasis. The half maximal inhibitory concentration (IC50) of 5-FU in ABALON interference groups declined, while ABALON overexpression elevated IC50. Furthermore, defective mitophagy not only rescued the proliferation, metastasis, and apoptosis induced by ABALON overexpression, but also, enhanced the anti-tumor effect of 5-FU in vivo.

Conclusions: Collectively, our study proposed that ABALON potentiates CRC progression via PINK1/Parkin mediated mitophagy, and ABALON is a promising therapeutic target in reversing 5-FU resistance.

Background: Hepatogastric fistula (HGF) is an uncommon occurrence that can be associated with various medical conditions. The primary causes typically involve peptic ulcer disease, infections (such as pyogenic, amoebic or tuberculosis), or iatrogenic factors (like post transarterial chemoembolization or radiotherapy). Massive gastrointestinal hemorrhage following HGF is extremely rare, with iodine-125 (¹²⁵I) seed migration to the stomach through HGF not previously documented. This report explores this unique case and reviews other recent instances of rare gastrointestinal hemorrhage due to HGF.

Case description: A 32-year-old man with chronic B viral hepatitis underwent emergency surgery to control bleeding due to hepatocellular carcinoma (HCC) rupture. One month postoperatively, an active residual tumor (44 mm × 33 mm) was found in the caudate lobe of the liver. The patient was admitted for percutaneous microwave coagulation therapy (PMCT) and ¹²⁵I seed implantation sequentially. No postoperative discomfort was observed. Subsequent intrahepatic HCC distant recurrences were successfully managed using PMCT and systemic treatments (molecular targeted drug and checkpoint inhibitor). Twenty months after the initial seed implantation in the caudate lobe, the patient was referred again owing to intrahepatic tumor recurrence in the right lobe and underwent repeat PMCT and ¹²⁵I seed implantation. Two days after the second ¹²⁵I seed implantation, the patient presented with severe upper gastrointestinal bleeding and epigastric pain. The caudate lobe was in communication with the lesser curvature of the stomach, resulting in the formation of the HGF. Subsequently, intermittent massive gastrointestinal hemorrhage occurred, and seed implantation in the caudate lobe migrated to the stomach through the HGF. Endoscopy and imaging confirmed HGF and seed migration to the stomach, and surgery was successfully performed.

Conclusions: A thorough clinical medical history and heightened vigilance are essential for diagnosing and managing this rare complication.