UNASSIGNED: Pancreatic adenocarcinoma (PAAD) is a formidable challenge in oncology research, with a complex pathogenesis that requires to be explored. Major Vault Protein (MVP) is the principal structural component of the vault complex, and its expression level is remarkably upregulated in various cancers. Extensive investigations have been conducted to explore the role of MVP in specific cancer contexts, yet the potential molecular mechanisms and biological functions of MVP in PAAD still remain considerably elusive. This study aims to explore the role of MVP as a novel immune-related biomarker in the pathogenesis and clinical treatment of PAAD.
UNASSIGNED: Gene expression data and clinical information were collected from TCGA, GTEx and GEO databases. Survival, prognostic and functional enrichment analysis were employed with R software. Immunological correlation analysis was performed using TIMER2.0, TIDE scores, TISIDB and TISCH. Epigenetic analysis was implemented by MethSurv, CPTAC, UALCAN, and cBioPortal. Drug analysis was conducted using Enrichr and CellMiner. Moreover, cellular experiments, like RNA interference, qRT-PCR, Western blot, cell cycle analysis, cell apoptosis analysis, colony formation assay, transwell assay, and wound healing assay, were performed for verifying the functional properties of MVP in the PAAD progression.
UNASSIGNED: We demonstrated an abnormally upregulated expression of MVP in PAAD tissues, which notably correlated with an adverse prognosis in PAAD patients. Functional analysis suggested the conceivable involvement of MVP in immune modulation, and immunotherapy. Additionally, we identified genetic alterations, reduced promoter methylation, and heightened phosphorylation in MVP. We also clarified Suloctidil and Tetradioxin as the most notable potential drugs targeting MVP in PAAD. Moreover, our experimental observations consistently highlighted the significant impact of MVP deficiency on impeding PAAD cell proliferation, inhibiting cell migration, and accelerating cell apoptosis. Interestingly, a potential link between MVP and ERK or AKT pathways was displayed, which opens new avenues for further exploration of the molecular mechanisms of MVP-targeted therapies in PAAD.
UNASSIGNED: This study systematically describes MVP as an immune-related biomarker with remarkable potential for predicting the prognosis, tumor progression and immunotherapeutic efficacy in PAAD.

During the progression of renal cell carcinoma (RCC), tumor growth, metastasis and treatment response heterogeneity are regulated by both the tumor itself and the tumor microenvironment (TME). The aim of the present study was to investigate the role of the TME in RCC and construct a crosstalk network for clear cell RCC (ccRCC). An additional aim was to evaluate whether TNF receptor superfamily member 1A (TNFRSF1A) is a potential therapeutic target for ccRCC. Single-cell data analysis of RCC was performed using the GSE152938 dataset, focusing on key cellular components and their involvement in the ccRCC TME. Additionally, cell-cell communication was analyzed to elucidate the complex network of the ccRCC microenvironment. Analyses of data from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium databases were performed to further mine the key TNF receptor genes, with a particular focus on the prediction and assessment of the cancer-associated features of TNFRSF1A. In addition, following the silencing of TNFRSF1A using small interfering RNA in the 786-O ccRCC cell line, a number of in vitro experiments were conducted to further investigate the cancer-promoting characteristics of TNFRSF1A. These included 5-ethynyl-2\'-deoxyuridine incorporation, Cell Counting Kit-8, colony formation, Transwell, cell cycle and apoptosis assays. The TNF signaling pathway was found to have a critical role in the development of ccRCC. Based on the specific crosstalk identified between TNF and TNFRSF1A, the communication of this signaling pathway within the TME was elucidated. The results of the cellular phenotype experiments indicated that TNFRSF1A promotes the proliferation, migration and invasion of ccRCC cells. Consequently, it is proposed that targeting TNFRSF1A may disrupt tumor progression and serve as a therapeutic strategy. In conclusion, by understanding the TME and identifying significant crosstalk within the TNF signaling pathway, the potential of TNFRSF1A as a therapeutic target is highlighted. This may facilitate an advance in precision medicine and improve the prognosis for patients with RCC.

Protein arginine methyltransferase 5 (PRMT5) is over-expressed in a wide variety of cancers and is implicated as having a key oncogenic role, achieved in part through its control of the master transcription regulator E2F1. We investigated the relevance of PRMT5 and E2F1 in neuroblastoma (NB) and found that elevated expression of PRMT5 and E2F1 occurs in poor prognosis high-risk disease and correlates with an amplified Myelocytomatosis viral-related oncogene, neuroblastoma-derived (MYCN) gene. Our results show that MYCN drives the expression of splicing factor genes that, together with PRMT5 and E2F1, lead to a deregulated alternative RNA splicing programme that impedes apoptosis. Pharmacological inhibition of PRMT5 or inactivation of E2F1 restores normal splicing and renders NB cells sensitive to apoptosis. Our findings suggest that a sustained cancer-relevant alternative RNA splicing programme desensitises NB cells to apoptosis, and identify PRMT5 as a potential therapeutic target for high-risk disease.

Fatty acid synthase (FASN) is a critical enzyme essential for the production of fats in the body. The abnormal expression of FASN is associated with different types of malignancies, including ovarian cancer. FASN plays a crucial role in cell growth and survival as a metabolic oncogene, although the specific processes that cause its dysregulation are still unknown. FASN interacts with signaling pathways linked to the progression of cancer. Pharmacologically inhibiting or inactivating the FASN gene has shown potential in causing the death of cancer cells, offering a possible treatment approach. This review examines the function of FASN in ovarian cancer, namely its level of expression, influence on the advancement of the disease, and its potential as a target for therapeutic interventions.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a progressive and devastating muscle disease, resulting from the absence of dystrophin. This leads to cell membrane instability, susceptibility to contraction-induced muscle damage, subsequent muscle degeneration, and eventually disability and early death of patients. Currently, there is no cure for DMD. Our recent studies identified that lipin1 plays a critical role in maintaining myofiber stability and integrity. However, lipin1 gene expression levels are dramatically reduced in the skeletal muscles of DMD patients and mdx mice.
METHODS: To identify whether increased lipin1 expression could prevent dystrophic pathology, we employed unique muscle-specific mdx:lipin1 transgenic (mdx:lipin1Tg/0) mice in which lipin1 was restored in the dystrophic muscle of mdx mice, intramuscular gene delivery, as well as cell culture system.
RESULTS: We found that increased lipin1 expression suppressed muscle degeneration and inflammation, reduced fibrosis, strengthened membrane integrity, and resulted in improved muscle contractile and lengthening force, and muscle performance in mdx:lipin1Tg/0 compared to mdx mice. To confirm the role of lipin1 in dystrophic muscle, we then administered AAV1-lipin1 via intramuscular injection in mdx mice. Consistently, lipin1 restoration inhibited myofiber necroptosis and lessened muscle degeneration. Using a cell culture system, we further found that differentiated primary mdx myoblasts had elevated expression levels of necroptotic markers and medium creatine kinase (CK), which could be a result of sarcolemmal damage. Most importantly, increased lipin1 expression levels in differentiated myoblasts from mdx:lipin1Tg/0 mice substantially inhibited the elevation of necroptotic markers and medium CK levels.
CONCLUSIONS: Overall, our data suggest that lipin1 is a promising therapeutic target for the treatment of dystrophic muscles.

Osteosarcoma (OS) is a heterogeneous malignant spindle cell tumor that is aggressive and has a poor prognosis. Although combining surgery and chemotherapy has significantly improved patient outcomes, the prognosis for OS patients with metastatic or recurrent OS has remained unsatisfactory. Therefore, it is imperative to gain a fresh perspective on OS development mechanisms and treatment strategies. After studying single-cell RNA sequencing (scRNA-seq) data in public databases, we identified seven OS subclonal types based on intra-tumor heterogeneity. Subsequently, we constructed a prognostic model based on pro-protein synthesis osteosarcoma (PPS-OS)-associated genes. Correlation analysis showed that the prognostic model performs extremely well in predicting OS patient prognosis. We also demonstrated that the independent risk factors for the prognosis of OS patients were tumor primary site, metastatic status, and risk score. Based on these factors, nomograms were constructed for predicting the 3- and 5-year survival rates. Afterward, the investigation of the tumor immune microenvironment (TIME) revealed the vital roles of γδ T-cell and B-cell activation. Drug sensitivity analysis and immune checkpoint analysis identified drugs that have potential application value in OS. Finally, the jumping translocation breakpoint (JTB) gene was selected for experimental validation. JTB silencing suppressed the proliferation, migration, and invasion of OS cells. Therefore, our research suggests that PPS-OS-related genes facilitate the malignant progression of OS and may be employed as prognostic indicators and therapeutic targets in OS.

BACKGROUND: Cancers, particularly lung adenocarcinoma (LUAD), represent a major global health concern. However, the role of FAM72D in various cancers, including LUAD, remains poorly understood.
METHODS: We utilized databases such as The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx) and online tools to investigate the correlation between FAM72D expression and its prognostic, diagnostic, and mutational significance, as well as its impact on immune cell infiltration across multiple cancers. Additionally, we developed LUAD cell lines overexpressing FAM72D to confirm its oncogenic role.
RESULTS: FAM72D expression was elevated in cancerous tissues compared to noncancerous tissues, with diagnostic and prognostic implications in many cancers, including LUAD. Moreover, associations were identified between FAM72D expression and diverse immune subtypes, alongside factors such as microsatellite instability, neoantigens, and tumour mutational burden across pan-cancers. Additionally, FAM72D was associated with immune infiltration and various immune checkpoint-related genes in LUAD. In vitro experiments demonstrated that FAM72D promoted cell proliferation, colony formation, and migration, while inhibiting apoptosis in LUAD cells.
CONCLUSIONS: Our study establishes associations between FAM72D expression and diagnosis, prognosis, and tumour immunity across multiple cancers, as well as its oncogenic effects in LUAD. FAM72D shows promise as a biomarker and therapeutic target in LUAD.

Glioblastoma (GBM) remains the most lethal primary brain tumor, characterized by dismal survival rates. Novel molecular targets are urgently required to enhance therapeutic outcomes. A combination of bioinformatics analysis and experimental validation was employed to investigate the role of EGFLAM in GBM. The Chinese Glioma Genome Atlas provided a platform for gene expression profiling, while siRNA-mediated knockdown and overexpression assays in GBM cell lines, alongside in vivo tumorigenesis models, facilitated functional validation. EGFLAM was found to be significantly overexpressed in GBM tissues, correlating with adverse prognostic factors and higher tumor grades, particularly in patients over the age of 41. Functional assays indicated that EGFLAM is vital for maintaining GBM cell proliferation, viability, and invasiveness. Knockdown of EGFLAM expression led to a marked decrease in tumorigenic capabilities. Proteomic interactions involving EGFLAM, such as with NUP205, were implicated in cell cycle regulation, providing insight into its oncogenic mechanism. In vivo studies further demonstrated that silencing EGFLAM expression could inhibit tumor growth, underscoring its therapeutic potential. The study identifies EGFLAM as a pivotal oncogenic factor in GBM, serving as both a prognostic biomarker and a viable therapeutic target. These findings lay the groundwork for future research into EGFLAM-targeted therapies, aiming to improve clinical outcomes for GBM patients.

Background: Parkinson\'s disease (PD) is marked by the loss of dopaminergic neurons in the substantia nigra pars compacta, leading to motor and cognitive dysfunctions. The molecular mechanisms underlying synaptic alterations in PD remain elusive, with a focus on the role of Itga5 in synaptic integrity and motor coordination and TAT-Itga5 was designed to suppress PTEN activity in this investigation. Methods: This study utilized MPTP-induced PD animal models to investigate the expression and role of Itga5 in the striatum. Techniques included quantitative PCR, Western blotting, immunostaining, CRISPR-CasRx-mediated knockdown, electrophysiological assays, behavioral tests, and mass spectrometry. Results: Itga5 expression was significantly reduced in MPTP-induced PD models. In these models, a marked decrease in dendritic spine density and a shift towards thinner spines in striatal GABA neurons were observed, suggesting impaired synaptic integration. Knockdown of Itga5 resulted in reduced dendritic branching, decreased mushroom spines, and increased thin spines, altering synaptic architecture. Electrophysiological analyses revealed changes in action potential and spontaneous excitatory postsynaptic currents, indicating altered synaptic transmission. Motor behavior assessments showed that Itga5 deficiency led to impairments in fine motor control and coordination. Furthermore, Itga5 was found to interact with PTEN, affecting AKT signaling crucial for synaptic development and motor coordination. Conclusion: The study demonstrates that Itga5 plays a critical role in maintaining synaptic integrity and motor coordination in PD. The Itga5-PTEN-AKT pathway represents a potential therapeutic target for addressing synaptic and motor dysfunctions in PD.

Hematological and neurological expressed 1 (HN1), also known as Jupiter microtubule associated homolog 1 (JPT1), is a highly conserved protein with widespread expression in various tissues. Ectopic elevation of HN1 has been observed in multiple cancers, highlighting its role in tumorigenesis and progression. Both proteomics and transcriptomics reveal that HN1 is closely associated with severe disease progression, poor prognostic and shorter overall survival. HN1\'s involvement in cancer cell proliferation and metastasis has been extensively investigated. Overexpression of HN1 is associated with increased tumor growth and disease progression, while its depletion leads to cell cycle arrest and apoptosis. The pivotal role of HN1 in cancer progression, particularly in proliferation, migration, and invasion, underscores its significance in cancer metastasis. Validation of the efficacy and safety of HN1 inhibition, along with the development of diagnostic methods to determine HN1 expression levels in patients, is essential for the translation of HN1-targeted therapies into clinical practice. Overall, HN1 emerges as a valuable prognostic marker and therapeutic target in cancer, and further investigations hold the potential to improve patient outcomes by impeding metastasis and enhancing treatment strategies.