Band 26, Heft 2

Gliomas are particularly challenging due to their high invasiveness, frequent recurrence, and elevated mortality rates. Despite the availability of treatments like surgery, radiation, and chemotherapy, each of these methods faces significant limitations. This has led to a pressing demand for new strategies against gliomas. In this landscape, mesenchymal stem cells (MSCs) have shown significant potential in recent years. However, the application of MSCs in glioma therapy encounters various challenges. A significant advancement in this field is the utilization of exosomes (Exo), key secretions of MSCs. These exosomes not only carry the benefits inherent in MSCs but also exhibit unique physicochemical properties that make them effective drug carriers. Consequently, MSCs Exo is gaining recognition as a sophisticated drug delivery system, specifically designed for glioma treatment. The scope of MSCs Exo goes beyond being just an innovative drug delivery mechanism; it also shows potential as a standalone therapeutic option. This article aims to provide a detailed summary of the essential role of MSCs Exo in glioma progression and its growing importance as a drug delivery carrier in the fight against this formidable disease.

Objectives Integrin subunit beta-like 1 (ITGBL1), a member of the epidermal growth factor (EGF)-like protein family, encodes a beta integrin-related protein that is mainly associated with the development of specific tumours and immune-related signalling pathways. This work aimed to explore the possibility that ITGBL1 functions as a novel target gene for immunotherapy and could be a cancer prognostic molecule. Methods The mRNA data for ITGBL1 were obtained from the public databases The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) and Gene Expression Omnibus (GEO). Using GEPIA, the differential expression of ITGBL1 in different tumour stages was identified. Cancer prognostic correlations were explored using Kaplan–Meier survival analysis and forest plots. A combination of Gene Set Enrichment Analysis (GSEA), TIMER2.0 and the R package was applied to analyse the ITGBL1-enriched related pathways. The NCI-60 drug database was examined using CellMiner TM . Cytological experiments were conducted to confirm ITGBL1’s impact on cancer cells. Results Our research has shown that ITGBL1 is differentially expressed in 26 cancers, and high ITGBL1 expression predicts a poorer survival prognosis in some specific cancers. Additionally, we found that ITGBL1 is enriched in immune-related pathways, which are closely linked to immunomodulatory molecules, immune-infiltrating cells, and immunomodulatory factors. The results of tumor mutational burden (TMB) and microsatellite instability (MSI) also indicate that the expression of ITGBL1 is beneficial for improving tumor immunotherapy efficacy. Furthermore, a number of antitumor agents associated with ITGBL1 expression have been identified. Finally, knockdown of ITGBL1 restricts the ability of gastric and colorectal cancer cells to proliferate and migrate. Conclusions Our study demonstrates that ITGBL1 can be utilized to accurately prognosticate cancer and has opened up new avenues for the investigation of tumor immune mechanisms and the development of more efficacious immunotherapies.

Objectives MicroRNA-302a (miR-302a) has been implicated in the oncogenic processes, but its role in hepatocellular carcinoma (HCC) chemoresistance and related mechanisms are still unclear. Therefore, the aim of this study was to investigate the role of miR-302a in HCC chemoresistance and elucidate its underlying mechanism. Methods In this study, we detected the level of miR-302a in HCC tissues (including chemoresistant and chemosensitive tissues), non-tumor tissues, liver cancer cell lines, and 5-fluorouracil (5-FU)-resistant cells (HepG2/R). Additionally, we conducted cell viability, apoptosis, and autophagy analyses as well as assessed the levels of cleaved caspase-3, cleaved caspase-9, microtubule-associated protein 1 light chain 3 beta II (LC3B-II), Akt, and UNC-51 like kinase 1 (ULK1) in HepG2 cells transfected with miR-302a mimic or inhibitor prior to 5-FU treatment. Lastly, we predicted the target of miR-302a and verified the relationship between miR-302a and Akt by luciferase reporter and functional repair assays. Results Our results revealed that miR-302a was down-regulated in HCC tissues (p<0.01), especially in chemoresistant tissues (p<0.01). Consistently, the miR-302a level exhibited a lower expression in HepG2/R cells compared to their parental cells (p<0.01). Furthermore, the 5-FU-induced apoptosis and autophagy of HepG2 cells were promoted by miR-302a over-expression and diminished by miR-302a inhibition (p<0.01). Target analysis revealed that miR-302a could directly target Akt. Moreover, miR-302a inhibited Akt expression and subsequently elevated ULK1 expression (p<0.01). Inhibition of ULK1 could abrogate the sensitization of overexpressed miR-302a to 5-FU in HepG2 cells (p<0.01). Conclusions Altogether, our results demonstrate that the down-regulation of miR-302a promotes 5-FU resistance in HCC by attenuating the Akt/ULK1 axis-dependent autophagy and apoptosis.

Objectives To investigaed the role of endoplasmic reticulum stress (ERS)-related long non-coding RNAs (lncRNAs) in stomach adenocarcinoma (STAD) using TCGA data. Methods This study integrated clinical, transcriptomic, and tumor data from the Cancer Genome Atlas (TCGA). The expression of ERS genes was evaluated, alongside their association with identified lncRNAs. Gene set enrichment analysis and immune cell infiltration analysis were performed to elucidate the biological pathways influenced by these lncRNAs. Results The study identified five lncRNAs – AC012055.1, LINC01235, LINC00571, LINC02073, and CFAP61-AS1 – strongly correlated with ERS pathways and cancer prognosis. A prognostic model based on these lncRNAs was developed and validated across low- and high-risk groups. Potential biological pathways associated with these lncRNAs were uncovered through immune cell infiltration and GSEA. Additionally, screening identified drugs potentially effective against STAD, highlighting co-expressed genes as probable therapeutic targets. Conclusions This research offers detailed insights into the molecular mechanisms of STAD, enhancing understanding of potential therapeutic targets and showing promise for clinical applications.

Objectives Protein Arginine Methyltransferase 5 ( PRMT5 ) is an enzyme that regulates gene expression and protein function through arginine methylation. Its association with isocitrate dehydrogenase (IDH) mutation in Grade-4 astrocytoma was rarely investigated. Our aim was to aim to explore the association between IDH mutation and PRMT5 and its effect on tumor recurrence. Methods A retrospective cohort of 34 patients with Grade 4 astrocytoma has been tested for PRMT5 expression using protein and gene expression arrays. The impact of IDH-mutation and PRMT5 expression on tumor recurrence was explored. Results IDH-wildtype was detected in 13 tumors. PRMT5 protein was highly expressed in 30 tumors and the expression was low in four tumors. PRMT5 gene expression was upregulated in 33 tumors and downregulated in a single tumor case. Tumors with different PRMT5 gene expressions and IDH mutation were found to have a significant statistical difference in recurrence-free interval (RFI) (p-value<0.001). IDH-wildtype glioblastoma with upregulated PRMT5 gene or protein expression showed earlier tumor recurrence compared to IDH-mutant Grade 4 astrocytoma with upregulated PRMT5 expression. Conclusions The association between IDH mutation and PRMT5 in IDH-mutant Grade 4 astrocytoma or IDH-wildtype glioblastoma is indirectly bidirectional. PRMT5 upregulation in glioblastoma can lead to increased cell proliferation and tumor regrowth.

Objectives Prostate cancer features have been linked to mutations in the  BRCA1  and  BRCA2  genes. Assessing the status of  BRCA1  and  BRCA2  gene carriers in patients contributes to accurate diagnosis, disease prognosis as well as appropriate targeted treatment methods. This study evaluated the prevalence of these mutations in Vietnamese prostate cancer patients and assessed their correlation with clinical features. Methods A cross-sectional study was performed at Bach Mai Hospital between 2021 and 2022. We enrolled 60 prostate cancer patients. Next-generation gene sequencing was used to identify BRCA1 and BRCA2 mutations in formalin-fixed paraffin-embedded samples. Patients with somatic gene mutations underwent further germline mutation analysis. We also reported a case series following the British Medical Journal guidelines, detailing the clinical course of such patients. Results Patients with BRCA2 pathogenic variants revealed no BRCA1 mutations, although different mutations were identified. Two patients showed germline mutations. Patients with BRCA mutations were younger (average age: 66.2 years) than those with non-mutations (72.1 years) at diagnosis. High Gleason scores, lymph node metastases, and distant metastases were more prevalent in the mutation group. One patient with germline BRCA mutation had aggressive prostate cancer and early resistance to non-PARPi (Poly ADP-ribose polymerase inhibitors) treatments. Conclusions We provide preliminary data on BRCA mutations in Vietnamese patients with prostate cancer, suggesting that BRCA2 mutations correlate with aggressive disease characteristics. Our findings further elucidate the clinical implications of these mutations.

Objectives Brain metastasis is the most lethal metastatic site for patients with breast cancer, and the incidence of brain metastasis is increasing every year. Microglia act a pivotal part in promoting the proliferation and metastasis of breast cancer cells in the brain. Therefore, understanding the biological process of brain metastasis in breast cancer is important to improve therapeutic outcomes and prolong the survival of patients. Materials and Methods The role of microglia on the prognosis of patients with breast cancer with brain metastasis was verified by immunohistochemistry and the Kaplan–Meier curve. Cell experiments in vitro were used to analyze the effect of microglia on cell proliferation, migration and invasion. Knockdown of cell migration-inducing hyaluronan-binding protein (CEMIP) expression and co-culture experiments were carried out to study the mechanism of microglia on the progression of brain metastasis of breast cancer. Results We found that microglia may shorten the survival time of patients with breast cancer by regulating the expression of CEMIP in brain metastatic tumors. Co-culture experiments in vitro indicated that microglia enhance the proliferation, migration, and invasion abilities of brain metastatic breast cancer cells; however, the knockdown of CEMIP expression suppresses this effect. In addition, we also found that CEMIP expression, increased by microglia, activates the JAK2/STAT3 pathway in brain metastatic breast cancer cells, which induces the secretion of CCL2, IL-6, TGF-β, and VEGF. CCL2 recruits microglia to gather around brain metastases, whereas IL-6, TGF-β, and VEGF induce high CEMIP expression, triggering a positive feedback loop between microglia and brain metastatic breast cancer cells. Conclusions Our study proposes a possible mechanism of microglia promoting brain metastasis of breast cancer, indicating that both microglia and CEMIP may be valuable therapeutic targets for patients with breast cancer with brain metastasis.

Objectives Dysregulation of RNA modifications has emerged as a contributor to cancer, but the clinical implication of RNA modification-related genes remains largely unclear. The study focused on well-studied RNA modification modalities (m 6 A, m 1 A, m 5 C and m 7 G) in bladder cancer, and proposed a machine learning-based integrative approach for establishing a consensus RNA modification-based signature. Methods Multiple publicly available bladder cancer cohorts were enrolled. A novel RNA modification-based classification was proposed via consensus clustering analysis. RNA modification-related genes were subsequently selected through WGCNA. A machine learning-based integrative framework was implemented for constructing a consensus RNA modification-based signature. Results Most RNA modifiers were dysregulated in bladder tumours at the multi-omics levels. Two RNA modification clusters were identified, with diverse prognostic outcomes. A consensus RNA modification-based signature was established, which displayed stable and powerful efficacy in prognosis estimation. Notably, the signature was superior to conventional clinical indicators. High-risk tumours presented the activation of tumourigenic pathways, with the activation of metabolism pathways in low-risk tumours. The low-risk group was more sensitive to immune-checkpoint blockade, with the higher sensitivity of the high-risk group to cisplatin and paclitaxel. Genes in the signature: AKR1B1 , ANXA1 , CCNL2 , OAS1 , PTPN6 , SPINK1 and TNFRSF14 were specially expressed in distinct T lymphocytes of bladder tumours at the single-cell level, potentially participating in T cell-mediated antitumour immunity. They were transcriptionally and post-transcriptionally modulated, and might become potentially actionable therapeutic targets. Conclusions Altogether, the consensus RNA modification-based signature may act as a reliable and hopeful tool for improving clinical decision-making for individual bladder cancer patients.

Objectives Tertiary lymphoid structures (TLSs) are increasingly recognized as pivotal formations in antitumor immunity, with many mature TLSs relating to favorable prognosis in a variety of cancers. Analysis of the transcriptome data provided an opportunity to investigate the relationship between TLSs and the clinical outcomes of patients. Methods We performed transcriptome analysis to examine the expression patterns of 79 TLS-related genes within 32 cancers from The Cancer Genome Atlas, correlating these patterns to the clinical outcomes of patients. To improve the analysis, we developed a novel prognostic signature (TLSig) and validated its robust performance via multiple independent cancer cohorts. Results Our results demonstrated that the expression of TLS-related genes exhibited significant heterogeneity across cancers; and that TLSig was significantly associated with patient prognosis within most cancer types. Specifically, TLSig expressed potential prediction of whether patients would benefit from immunotherapy and presented significant interactions with epithelial to mesenchymal transition (EMT) and the cell cycle. Moreover, a difference in the distribution of TLSs between tumor and nontumor tissues was observed, which was validated in hepatocellular carcinoma (HCC) samples. We further investigated the potential mechanism for the difference in the distribution of TLSs between tumor and nontumor tissues of HCC, and observed the connection between TLSs and human leucocyte antigen (HLA). Conclusions In summary, our results demonstrated the prognostic value of TLSs in predicting patient prognosis and provided new insights into the molecular mechanism of TLSs in cancer.

Objectives Osteosarcoma stands as a highly aggressive primary bone malignancy with a notable penchant for metastasis and a grim prognosis. The exploration of metabolic gene signatures, particularly those involved in glycolysis and cholesterol synthesis, has recently garnered attention for their potential to predict cancer progression and therapeutic outcomes. This study probes the prognostic value of a glycolysis and cholesterol synthesis-related gene signature (GCSRG) in osteosarcoma, along with its influence on the tumor immune microenvironment. Methods A comprehensive bioinformatics approach was applied to osteosarcoma samples from the TCGA database, incorporating unsupervised clustering to delineate patient subsets, differential gene expression analysis to identify key metabolic pathways, and survival analysis to ascertain prognostic validity. Results The investigation yielded a distinct GCSRG with significant prognostic capabilities. Notably, a high GCSRG score correlated with worse patient outcomes but revealed a marked enrichment in immune cell infiltration within the tumor milieu, suggesting a complex relationship between metabolism and immune surveillance in osteosarcoma. Conclusion The GCSRG emerges as a promising biomarker for osteosarcoma prognosis, offering new vistas for assessing patient suitability for immunotherapeutic interventions. The potential of the GCSRG to act as a guide for personalized treatment strategies is highlighted, underscoring the need for strategic therapeutic modulation based on metabolic and immune interactions to improve patient prognosis in osteosarcoma.

Objectives The prevalence of thyroid cancer has shown a progressive rise over time. This study aimed to explore the expression and underlying mechanisms of decorin (DCN) in follicular thyroid carcinoma (FTC), employing bioinformatics analysis and immunohistochemistry techniques. Methods The GSE27155 dataset was obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and core DEGs were identified through data mining and analysis using the R language and online databases. The expression of core DEGs was validated using The Cancer Genome Atlas database. Additionally, the correlation between DCN and clinicopathological stage, tumor-infiltrating lymphocytes, and hotspot molecules in thyroid cancer was assessed using the Gene Expression Profiling Interactive Analysis and TIMER databases. Immunohistochemical (IHC) analysis was then conducted to verify the differential expression of core DCN in FTC and adjacent tissues. Results We confirmed the downregulation of three DEGs (DCN, GPC3, and PDGFRA). Furthermore, the analysis revealed a significant association between DCN expression and the clinical stage of patients with thyroid cancer (p<0.0001). DCN expression and the infiltration of several immune cells were positively correlated (p<0.01). A significant positive correlation was also noted between DCN and the NRAS and KRAS genes (partial cor>0, p<0.05). Immunohistochemical analyses revealed a significantly lower staining score (3.071 ± 2.493) for DCN protein in cancer tissues than that in adjacent tissues (8.643 ± 2.094) (p<0.0001). Conclusions DCN is underexpressed and contributes to tumor progression in FTC. Thus, DCN serves as a tumor suppressor gene in FTC and a promising therapeutic target.

Background Molecular International Prognostic Scoring System (IPSS-M) is a newly developed prognostic model for myelodysplastic neoplasms (MDS), but has not yet been used widely. In this study, we aimed to compare the IPSS-M with the traditional Revised International Prognostic Scoring System (IPSS-R) in predicting the prognosis of decitabine treated-MDS patients. Patients and methods This retrospective cohort study was conducted on 19 newly diagnosed MDS patients who were examined for 51 gene mutations and received decitabine treatment. The survival analysis, including overall survival (OS), progression-free survival (PFS), and leukemia-free survival (LFS), was performed using the Kaplan–Meier method. Comparisons between the risk groups were carried out according to the IPSS-R and IPSS-M models. Results Among the 19 MDS patients, 12 (63.2 %) showed myeloid gene mutations, with the highest frequency of mutations in ASXL1 , RUNX1 , SRSF2 , TET2 , and TP53 (15.8 %). Survival analysis found that the OS was significantly different between the risk groups of both IPSS-R and IPSS-M models, but the PFS and LFS showed significant differences between the risk groups in only the IPSS-M model. The PFS of the moderate, high, and very high-risk groups were 34.66, 25.00, and 15.33 months (p=0.031); respectively. The LFS of the moderate, high, and very high-risk groups were 39.20, 25.00, and 18.37 months, (p=0.039); respectively. Conclusions Our results found that IPSS-M was better than IPSS-R in predicting the PFS and LFS of decitabine-treated MDS patients, IPSS-M may be superior to IPSS-R in predicting the prognosis of MDS patients.

Objectives Paraganglioma (PGL) is a rare extra-adrenal neuroendocrine tumor, and intrapericardial PGL is extremely rare. We report a rare case of intrapericardial nonfunctional PGL, which may be used as a reference for further analysis. Case presentation This article presents the case of a 65-year-old woman with a 2-year history of lower extremity pain. Ultrasound revealed a hypoechoic mass adjacent to the right atrium, compressing and narrowing the right atrium. Computed tomography (CT) showed a low-density mass with marked enhancement suggestive of a solitary fibrous tumor or a vasogenic tumor of pericardial origin. Cardiac magnetic resonance imaging (MRI) confirmed the location and provided a primary diagnosis of solitary fibrous tumor, hemangioma, or hemangiosarcoma. The patient eventually underwent pericardial tumor resection, and the diagnosis of PGL was confirmed by postoperative histopathology. Conclusions Pathology is considered the gold standard for the diagnosis of PGL. Imaging examinations can provide valuable information for the diagnosis and management of intrapericardial PGL, and surgery remains the treatment of choice.

Objectives Patients suffering from refractory acute promyelocytic leukemia with central nervous system relapse often have a poor prognosis. Among these patients, those with PLZF::RARA rearrangement exhibit poor responses to all-trans retinoic acid and conventional chemotherapy. Venetoclax, a selective inhibitor of B-cell lymphoma-2, can cross the blood–brain barrier and has been widely applied to acute myeloid leukemia therapy recently. Case presentation A case of central nervous system relapse in a patient with acute promyelocytic leukemia harboring PLZF::RARA rearrangement was successfully treated with anthracycline cytotoxic chemotherapy and cytarabine in combination with venetoclax, resulting in complete remission. Liquid chromatography-tandem mass spectrometry revealed that the concentration of venetoclax in the cerebrospinal fluid (CSF) was approximately 1/1,000 of that in plasma. Following the first treatment course, the patient’s bone marrow sample tested negative for PLZF::RARA . After the third treatment course, abnormal promyelocytic leukemia cells in the CSF were not detected using flow cytometry, and the PLZF::RARA test in the CSF remained negative. Conclusions This case report highlights a new approach for the treatment of central nervous system relapse in patients with PLZF::RARA -positive acute promyelocytic leukemia.