Exosomal lncRNA XIST promotes perineural invasion of pancreatic cancer cells via miR-211-5p/GDNF.

Perineural invasion (PNI) is an essential form of tumor metastasis in multiple malignant cancers, such as pancreatic cancer, prostate cancer, and head and neck cancer. Growing evidence has revealed that pancreatic cancer recurrence and neuropathic pain positively correlate with PNI. Therefore, targeting PNI is a proper strategy for pancreatic cancer treatment. Exosomal lncRNA derived from pancreatic cancer cells is an essential component of the tumor microenvironment. However, whether exosomal lncXIST derived from pancreatic cancer cells can promote PNI and its exact mechanism remains to be elucidated. We show that lncXIST mediates nerve-tumor crosstalk via exosomal delivery. Our data reveal that exosomal lncXIST derived from pancreatic cancer cells is delivered to neural cells and promotes their release of glial-cell-line-derived neurotrophic factor (GDNF), essential in facilitating the PNI of pancreatic cancer. Mechanistically, microRNA-211-5p negatively regulates GDNF, and lncXIST serves as a miR-211-5p sponge. The function of exosomes in the dynamic interplay between nerves and cancer is confirmed in both in vivo and in vitro PNI models. Therefore, targeting pancreatic cancer cell-derived exosomal lncXIST may provide clues for a promising approach for developing a new strategy to combat PNI of pancreatic cancer.

Establishment and Clinical Application of the Nomogram Related to Risk or Prognosis of Hepatocellular Carcinoma: A Review.

Hepatocellular carcinoma (HCC) is the most prevalent primary liver malignancy, accounting for approximately 90% of all primary liver cancers, with high mortality and a poor prognosis. A large number of predictive models have been applied that integrate multiple clinical factors and biomarkers to predict the prognosis of HCC. Nomograms, as easy-to-use prognostic predictive models, are widely used to predict the probability of clinical outcomes. We searched PubMed with the keywords "hepatocellular carcinoma" and "nomogram", and 974 relative literatures were retrieved. According to the construction methodology and the real validity of the nomograms, in this study, 97 nomograms for HCC were selected in 77 publications. These 97 nomograms were established based on more than 100,000 patients, covering seven main prognostic outcomes. The research data of 56 articles are from hospital-based HCC patients, and 13 articles provided external validation results of the nomogram. In addition to AFP, tumor size, tumor number, stage, vascular invasion, age, and other common prognostic risk factors are included in the HCC-related nomogram, more and more biomarkers, including gene mRNA expression, gene polymorphisms, and gene signature, etc. were also included in the nomograms. The establishment, assessment and validation of these nomograms are also discussed in depth. This study would help clinicians construct and select appropriate nomograms to guide precise judgment and appropriate treatments.

Bispecific antibodies targeting BCMA, GPRC5D, and FcRH5 for multiple myeloma therapy: latest updates from ASCO 2023 Annual Meeting.

Several bispecific antibodies (bsAbs) targeting BCMA, GPRC5D, and FcRH5 are in clinical trials for heavily pretreated multiple myeloma (MM) patients. Teclistamab was approved for relapsed/refractory MM therapy in 2022, while elranatamab, linvoseltamab, F182112, talquetamab, and cevostamab are currently undergoing clinical trials. This study summarizes several latest reports on bsAbs for the treatment of MM from the ASCO 2023 Annual Meeting.

CD20 × CD3 bispecific antibodies for lymphoma therapy: latest updates from ASCO 2023 annual meeting.

Multiple bispecific antibodies (bsAbs) have been approved for cancer immunotherapy. Several CD20 × CD3 bsAbs have demonstrated significant anti-B-cell non-Hodgkin lymphoma (NHL) activity by engaging T cells to target CD20+ NHL cells in clinical trials. Mosunetuzumab, epcoritamab and glofitamab have been approved recently for B-cell NHL therapy. In this study, we summarized several latest reports on CD20 × CD3 bsAbs for the therapy of B-cell NHL from the ASCO 2023 annual meeting (ASCO2023).

New role of gramicidin A in RIG-I-like receptors-mediated IFN signalling.

The pattern recognition receptors (PRRs) sense exogenous molecular patterns most commonly derived from invading pathogens, to active the interferon (IFN) signalling. In the cytoplasm, the viral double-stranded RNAs (dsRNAs) are sensed by retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated protein 5 (MDA5), depending on the length and chemical properties. Through the binding and oligomerizing onto the RNAs, they form filament to initiate the signalling cascade. Regulation of these receptors' activities are essential for manipulating the strength of IFN signalling. Here, through the virtual screening of chemical reagents using the published MDA5-dsRNA complex structure (PDB: 4GL2), we identified an antibiotic, gramicidin A as a stimulator that enhanced MDA5-mediated IFN signalling. Cytotoxic assay and IFN signalling assay suggested that disruption of lipid membrane, which is a well-defined mechanism of gramicidin A to perform its action, was dispensable in this process. Sucrose gradient ultracentrifugation assay showed that the gramicidin A treatment enhanced MDA5 oligomerization status in the presence of dsRNA. Our work implicated a new role of gramicidin A in innate immunity and presented a new tool to manipulate MDA5 activity.

OSppc: A web server for online survival analysis using proteome of pan-cancers.

Prognostic biomarker, as a feasible and objective indicator, is valuable in the assessment of cancer risk. With the development of high-throughput sequencing technology, the screening of prognostic biomarkers has become easy, but it is difficult to screen prognostic markers based on proteomic data. In this study we developed a tool named Online consensus Survival analysis web server based on Proteome of Pan-cancers, abbreviated as OSppc, to evaluate the prognostic values of protein biomarkers. >8000 cancer cases with proteomic data, transcriptomic data and clinical follow-up information were collected from TCGA and CPTAC. 14,038 proteins (including proteins and their phosphorylated forms) analyzed by reverse-phase protein arrays and mass spectrometry in 33 types of cancers were collected. In OSppc, three analysis modules are provided, including Survival Analysis, Differential Analysis and Correlation Analysis. Survival analysis module exhibits HR with 95% CI and KM curves with log-rank p value of protein and mRNA levels of input genes. Differential analysis module shows the box plots of protein expression levels in different tissues. Correlation analysis module provides scatter plot with pearson's and spearman's correlation coefficient of the protein and its corresponding mRNA. OSppc can be accessed at http://bioinfo.henu.edu.cn/Protein/OSppc.html. SIGNIFICANCE: OSppc can analyze the association between protein, mRNA and prognosis, the correlation between proteome data and gene expression profiles, the differential expression of proteome data between subgroups such as normal and cancer as well. OSppc is registration-free and very valuable to evaluate the prognostic potency of protein of interests. OSppc is very valuable for researchers and clinicians to screen, develop and validate potential protein prognostic biomarkers in pan-cancers, and offers the opportunities to investigate the clinical important functional genes and therapeutic targets of cancers.

Longitudinal study of 2 patients with cyclic thrombocytopenia, STAT3 and MPL mutations.

Cyclic thrombocytopenia (CTP) is a rare disease of periodic platelet count oscillations. The pathogenesis of CTP remains elusive. To study the underlying pathophysiology and genetic and cellular associations with CTP, we applied systems biology approaches to 2 patients with stable platelet cycling and reciprocal thrombopoietin (TPO) cycling at multiple time points through 2 cycles. Blood transcriptome analysis revealed cycling of platelet-specific genes, which are in parallel with and precede platelet count oscillation, indicating that cyclical platelet production leads platelet count cycling in both patients. Additionally, neutrophil and erythrocyte-specific genes also showed fluctuations correlating with platelet count changes, consistent with TPO effects on hematopoietic progenitors. Moreover, we found novel genetic associations with CTP. One patient had a novel germline heterozygous loss-of-function (LOF) thrombopoietin receptor (MPL) c.1210G>A mutation, and both had pathogenic somatic gain-of-function (GOF) variants in signal transducer and activator of transcription 3 (STAT3). In addition, both patients had clonal T-cell populations that remained stable throughout platelet count cycles. These mutations and clonal T cells may potentially involve in the pathogenic baseline in these patients, rendering exaggerated persistent thrombopoiesis oscillations of their intrinsic rhythm upon homeostatic perturbations. This work provides new insights into the pathophysiology of CTP and possible therapies.

Analyzing the interactions of mRNAs, miRNAs and lncRNAs to predict ceRNA networks in bovine cystic follicular granulosa cells.

Cross-talk between competitive endogenous RNAs (ceRNAs) may play a critical role in revealing potential mechanism of bovine follicular cysts. Ovarian cyst has always been an intractable scientific problem and has led to considerable economic losses to bovine breeding industry. However, its pathogenesis and molecular mechanisms are still not well understood. Here, this study aimed to investigate the role of non-coding RNAs (ncRNAs) and the ceRNA networks in bovine follicular cyst. Whole transcriptome sequencing of bovine follicular granulosa cells (GCs) was conducted to obtain the expression profiles of mRNAs, lncRNAs and miRNAs. The results for the identified expressions of 8,003 mRNAs, 579 lncRNAs and 205 miRNAs were often altered between cystic and normal follicular GCs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed on these differentially expressed mRNAs. Furthermore, the ceRNA network combining mRNAs, miRNAs, and lncRNAs using several bioinformatics methods based on co-expression analysis between the differentially expressed RNAs was conducted. Finally, the lncRNA NONBTAT027373.1-miR-664b-HSD17B7 pathway was verified by dual-luciferase reporting assay and RNA binding protein immunoprecipitation (RIP) assay. LncRNA NONBTAT027373.1 sponged miR-664b in GCs and prevented miR-664b from binding to the HSD17B7 3'-UTR. These results indicated that genes and lncRNAs related to steroid hormone synthesis and energy metabolism could play important roles in the formation of bovine cystic follicles through the ceRNA mechanism and represent candidate targets for further research. This can be used as a practical guideline for promoting healthy and highly efficient development in the bovine industry.

High APLN Expression Predicts Poor Prognosis for Glioma Patients.

Apelin (APLN) is an endogenous ligand of the G protein-coupled receptor APJ (APLNR). APLN/APLNR system was involved in a variety of pathological and physiological functions, such as tumorigenesis and development. However, its prognostic roles in patients with central nervous system (CNS) cancers remain unknown. The present study was designed to explore the expression profile, prognostic significance, and interaction network of APLN/APLNR by integrating data from Oncomine, GEPIA, LOGpc, STRING, GeneMANIA, and immunohistochemical staining. The results demonstrated that APLN and APLNR mRNA expression were significantly increased in CNS cancers, including both low-grade glioma (LGG) and glioblastoma (GBM), when compared with normal CNS tissues. The high APLN, but not APLNR, expression was significantly correlated with overall survival (OS), recurrence free survival (RFS), and progression free survival (PFS) of LGG patients. However, neither APLN nor APLNR expression was significantly related to prognostic value in terms of OS, disease free interval (DFI), disease specific survival (DSS), or progression free interval (PFI) for GBM patients. Additionally, immunohistochemistry staining confirmed the increased APLN expression in tissues of LGG patients with grade II than grade I. These results showed that an elevated APLN level could predict poor OS, RFS, and PFS for LGG patients, and it could be a promising prognostic biomarker for LGG.

Define the Two Molecular Subtypes of Epithelioid Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a fatal disease of respiratory system. Despite the availability of invasive biomarkers with promising results, there are still significant diagnostic and therapeutic challenges in the treatment of MPM. One of three main mesothelioma cell types, epithelioid mesothelioma makes up approximately 70% of all mesothelioma cases. Different observational findings are under process, but the molecular heterogeneity and pathogenesis of epithelioid malignant pleural mesothelioma (eMPM) are still not well understood. Through molecular analysis, expression profiling data were used to determine the possibility and optimal number of eMPM molecular subtypes. Next, clinicopathological characteristics and different molecular pathways of each subtype were analyzed to prospect the clinical applications and advanced mechanisms of eMPM. In this study, we identified two distinct epithelioid malignant pleural mesothelioma subtypes with distinct gene expression patterns. Subtype I eMPMs were involved in steroid hormone biosynthesis, porphyrin and chlorophyll metabolism, and drug metabolism, while subtype II eMPMs were involved in rational metabolism, tyrosine metabolism, and chemical carcinogenesis pathways. Additionally, we identified potential subtype-specific therapeutic targets, including CCNE1, EPHA3, RNF43, ROS1, and RSPO2 for subtype I and CDKN2A and RET for subtype II. Considering the need for potent diagnostic and therapeutic biomarkers for eMPM, we are anticipating that our findings will help both in exploring underlying mechanisms in the development of eMPM and in designing targeted therapy for eMPM.

A Comprehensive Prognostic Analysis of Tumor-Related Blood Group Antigens in Pan-Cancers Suggests That SEMA7A as a Novel Biomarker in Kidney Renal Clear Cell Carcinoma.

Blood group antigen is a class of heritable antigenic substances present on the erythrocyte membrane. However, the role of blood group antigens in cancer prognosis is still largely unclear. In this study, we investigated the expression of 33 blood group antigen genes and their association with the prognosis of 30 types of cancers in 31,870 tumor tissue samples. Our results revealed that blood group antigens are abnormally expressed in a variety of cancers. The high expression of these antigen genes was mainly related to the activation of the epithelial-mesenchymal transition (EMT) pathway. High expression of seven antigen genes, i.e., FUT7, AQP1, P1, C4A, AQP3, KEL and DARC, were significantly associated with good OS (Overall Survival) in six types of cancers, while ten genes, i.e., AQP1, P1, C4A, AQP3, BSG, CD44, CD151, LU, FUT2, and SEMA7A, were associated with poor OS in three types of cancers. Kidney renal clear cell carcinoma (KIRC) is associated with the largest number (14 genes) of prognostic antigen genes, i.e., CD44, CD151, SEMA7A, FUT7, CR1, AQP1, GYPA, FUT3, FUT6, FUT1, SLC14A1, ERMAP, C4A, and B3GALT3. High expression of SEMA7A gene was significantly correlated with a poor prognosis of KIRC in this analysis but has not been reported previously. SEMA7A might be a putative biomarker for poor prognosis in KIRC. In conclusion, our analysis indicates that blood group antigens may play functional important roles in tumorigenesis, progression, and especially prognosis. These results provide data to support prognostic marker development and future clinical management.

Nomograms for prognostic risk assessment in glioblastoma multiforme: Applications and limitations.

Glioblastoma multiforme (GBM) is the most common and aggressive form of brain cancer. Prognosis evaluation is of great significance in guiding individualized treatment and monitoring of GBM. By integrating different prognostic variables, nomograms simplify the statistical risk prediction model into numerical estimates for death or recurrence, and are hence widely applied in prognosis prediction. In the past two decades, the application of high-throughput profiling technology and the establishment of TCGA database and other public data deposits have provided opportunities to identify cancer-related molecules and prognostic biomarkers. As a result, both molecular features and clinical characteristics of cancer have been reported to be the key factors in nomogram model construction. This article comprehensively reviewed 35 studies of GBM nomograms, analyzed the present situation of GBM nomograms, and discussed the role and significance of nomograms in personalized risk assessment and clinical treatment decision-making. To facilitate the application of nomograms in the prognostic prediction of GBM patients, a website has been established for the online access of nomograms based on the studies of this review, which is called Consensus Nomogram Spectrum for Glioblastoma (CNSgbm) and is accessible through https://bioinfo.henu.edu.cn/nom/NomList.jsp.

The Emerging Role of Long Non-Coding RNAs in Esophageal Cancer: Functions in Tumorigenesis and Clinical Implications.

Esophageal cancer (EC) is one of the most common malignancies of digestive tracts with poor five-year survival rate. Hence, it is very significant to further investigate the occurrence and development mechanism of esophageal cancer, find more effective biomarkers and promote early diagnosis and effective treatment. Long non-coding RNAs (lncRNAs) are generally defined as non-protein-coding RNAs with more than 200 nucleotides in length. Existing researches have shown that lncRNAs could act as sponges, guides, scaffolds, and signal molecules to influence the oncogene or tumor suppressor expressions at transcriptional, post-transcriptional, and protein levels in crucial cellular processes. Currently, the dysregulated lncRNAs are reported to involve in the pathogenesis and progression of EC. Importantly, targeting EC-related lncRNAs through genome editing, RNA interference and molecule drugs may be one of the most potential therapeutic methods for the future EC treatment. In this review, we summarized the biological functions and molecular mechanisms of lncRNAs, including oncogenic lncRNAs and tumor suppressor lncRNAs in EC. In addition, we generalized the excellent potential lncRNA candidates for diagnosis, prognosis and therapy in EC. Finally, we discussed the current challenges and opportunities of lncRNAs for EC.

miR-542-3p reduces antioxidant capacity in goat caput epididymal epithelial cells by targeting glutathione peroxidase 5 (GPx5).

The mammalian epididymis provides an optimal and antioxidative fluid microenvironment for post-testicular sperm maturation by secretion of antioxidant scavengers and removal of excessive ROS. MicroRNAs (miRNAs) are expressed in the epididymis and involved in the regulation of epididymis physiology and functions. However, whether miRNAs are involved in regulating the antioxidant capacity and oxidative damage in the epididymis is not well understood. This study was designed to investigate the role of miR-542-3p in the regulation of antioxidant capacity and oxidative damage in the epididymis of goats. Firstly, we determined the expression of miR-542-3p and glutathione peroxidase 5 (GPx5) in the epididymis of young and adult goats using RT-qPCR assay, and found that miR-542-3p and GPx5 exhibited inverse expression levels. Our results showed that the expression level of miR-542-3p in epididymis was upregulated (P < 0.05) in young goats compared to adult goats, whereas the expression level of GPx5 in epididymis was downregulated (P < 0.01) in young goats compared to adult goats. Next, we further investigated the roles and potential mechanisms of miR-542-3p in epididymis using goat caput epididymal epithelial cells (GCEECs) isolated from Tai-hang goats (9-month-old). Our results showed that the overexpression of miR-542-3p in GCEECs transfected with miR-542-3p mimics resulted in decreased (P < 0.05) antioxidant enzyme activities of superoxide dismutase (SOD) and catalase (CAT). Similarly, the overexpression of miR-542-3p in GCEECs resulted in decreased (P < 0.05) glutathione (GSH) content and total antioxidant capacity (TAOC). In addition, the overexpression of miR-542-3p in GCEECs resulted in increased (P < 0.05) malonaldehyde (MDA) content. The inverse results of SOD, CAT, GSH, TAOC and MDA were observed in the down-expression of miR-542-3p in GCEECs transfected with miR-542-3p inhibitors (P < 0.05). Furthermore, GPx5 was confirmed to be a validated target of miR-542-3p in GCEECs using a dual-luciferase reporter assay, and transfection of miR-542-3p mimics decreased (P < 0.05) the mRNA expression and protein level of GPx5. In conclusion, our results indicated that miR-542-3p reduced antioxidant capacity and increased oxidative damage in GCEECs by targeting GPx5. The present study further understands the regulation of antioxidant capacity and epididymal-specific GPx5 secretion in caput epididymidis.

OSgc: A Web Portal to Assess the Performance of Prognostic Biomarkers in Gastric Cancer.

Evaluating the prognostic value of genes of interest in different populations of gastric cancer (GC) is difficult and time-consuming for basic and translational researchers even though many datasets are available in public dataset depositories. In the current study, we developed a robust web-based portal called OSgc (Online consensus Survival analysis of gastric cancer) that enables easy and swift verification of known and novel biomarker candidates in GC. OSgc is composed of gene expression profiling data and clinical follow-up information of 1,824 clinical GC cases, which are collected from 7 public independent datasets derived from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). By OSgc, users input the official gene symbol and will promptly retrieve the Kaplan-Meier survival plot with hazard ratio (HR) and log rank p value on the output webpage, by which users could assess the prognostic value of interesting genes for GC patients. Five survival end points containing overall survival, progression-free survival, progression-free interval, relapse-free survival, and disease-free survival could be measured in OSgc. OSgc can greatly help cancer biologists and clinicians to explore the effect of gene expression on patient survival. OSgc is freely available without restrictions at http://bioinfo.henu.edu.cn/GC/GCList.jsp.

OShnscc: a novel user-friendly online survival analysis tool for head and neck squamous cell carcinoma based on RNA expression profiles and long-term survival information.

Head and neck squamous cell carcinoma (HNSCC), as the most common type (>90%) of head and neck cancer, includes various epithelial malignancies that arise in the nasal cavity, oral cavity, pharynx, and larynx. In 2020, approximately 878 | 000 new cases and 444 000 deaths linked to HNSCC occurred worldwide (Sung et al., 2021). Due to the associated frequent recurrence and metastasis, HNSCC patients have poor prognosis with a five-year survival rate of 40%-50% (Jou and Hess, 2017). Therefore, novel prognostic biomarkers need to be developed to identify high-risk HNSCC patients and improve their disease outcomes.