Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives.

Over 120 small-molecule kinase inhibitors (SMKIs) have been approved worldwide for treating various diseases, with nearly 70 FDA approvals specifically for cancer treatment, focusing on targets like the epidermal growth factor receptor (EGFR) family. Kinase-targeted strategies encompass monoclonal antibodies and their derivatives, such as nanobodies and peptides, along with innovative approaches like the use of kinase degraders and protein kinase interaction inhibitors, which have recently demonstrated clinical progress and potential in overcoming resistance. Nevertheless, kinase-targeted strategies encounter significant hurdles, including drug resistance, which greatly impacts the clinical benefits for cancer patients, as well as concerning toxicity when combined with immunotherapy, which restricts the full utilization of current treatment modalities. Despite these challenges, the development of kinase inhibitors remains highly promising. The extensively studied tyrosine kinase family has 70% of its targets in various stages of development, while 30% of the kinase family remains inadequately explored. Computational technologies play a vital role in accelerating the development of novel kinase inhibitors and repurposing existing drugs. Recent FDA-approved SMKIs underscore the importance of blood-brain barrier permeability for long-term patient benefits. This review provides a comprehensive summary of recent FDA-approved SMKIs based on their mechanisms of action and targets. We summarize the latest developments in potential new targets and explore emerging kinase inhibition strategies from a clinical perspective. Lastly, we outline current obstacles and future prospects in kinase inhibition.

Progress and Innovative Combination Therapies in Trop-2-Targeted ADCs.

Precise targeting has become the main direction of anti-cancer drug development. Trophoblast cell surface antigen 2 (Trop-2) is highly expressed in different solid tumors but rarely in normal tissues, rendering it an attractive target. Trop-2-targeted antibody-drug conjugates (ADCs) have displayed promising efficacy in treating diverse solid tumors, especially breast cancer and urothelial carcinoma. However, their clinical application is still limited by insufficient efficacy, excessive toxicity, and the lack of biological markers related to effectiveness. This review summarizes the clinical trials and combination therapy strategies for Trop-2-targeted ADCs, discusses the current challenges, and provides new insights for future advancements.

A comprehensive investigation on the receptor BSG expression reveals the potential risk of healthy individuals and cancer patients to 2019-nCoV infection.

BACKGROUND: Coronavirus disease-2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a newly emerging coronavirus. BSG (basigin) is involved in the tumorigenesis of multiple tumors and recently emerged as a novel viral entry receptor for SARS-CoV-2. However, its expression profile in normal individuals and cancer patients are still unclear. METHODS: We performed a comprehensive analysis of the expression and distribution of BSG in normal tissues, tumor tissues, and cell lines via bioinformatics analysis and experimental verification. In addition, we investigated the expression of BSG and its isoforms in multiple malignancies and adjacent normal tissues, and explored the prognostic values across pan-cancers. Finally, we conducted function analysis for co-expressed genes with BSG. RESULTS: We found BSG was highly conserved in different species, and was ubiquitously expressed in almost all normal tissues and significantly increased in some types of cancer tissues. Moreover, BSG at mRNA expression level was higher than ACE2 in normal lung tissues, and lung cancer tissues. High expression of BSG indicated shorter overall survival (OS) in multiple tumors. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that BSG is mostly enriched in genes for mitochondria electron transport, oxidoreduction-driven active transmembrane transporter activity, mitochondrial inner membrane, oxidative phosphorylation, and genes involving COVID-19. CONCLUSIONS: Our present work emphasized the value of targeting BSG in the treatment of COVID-19 and cancer, and also provided several novel insights for understanding the SARS-CoV-2 pandemic.

SLC25A17 inhibits autophagy to promote triple-negative breast cancer tumorigenesis by ROS-mediated JAK2/STAT3 signaling pathway.

BACKGROUND: SLC25A17, a peroxisomal solute carrier, has been implicated in various physiological and pathological processes. However, its precise roles and underlying mechanisms in triple-negative breast cancer (TNBC) remain incompletely understood. METHODS: The expression and survival data of breast cancer were derived from TCGA and GEO databases. A variety of in vitro assays were conducted, including proliferation, apoptosis, cell cycle, migration, and invasion. Reactive oxygen species (ROS) were measured by immunofluorescence microscopy and flow cytometry. The levels of autophagy were assessed by mRFP-GFP-LC3 confocal microscopy scanning, western blotting, and electron microscopy. RESULTS: SLC25A17 was highly expressed in breast cancer tissues, which was found to be associated with unfavorable prognosis. Functional assays demonstrated that SLC25A17 knockdown suppressed proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion. Moreover, it prompted apoptosis and autophagy. On the other hand, SLC25A17 knockdown promoted autophagy through triggering ROS accumulation, which was counteracted by N-acetyl-l-cysteine (NAC). Furthermore, the pro-apoptotic effect of SLC25A17 knockdown was reversed when treated with autophagy inhibitor 3-MA in TNBC cells, suggesting that SLC25A17 knockdown-induced autophagic cell death. Mechanistically, SLC25A17 performed its function through regulation JAK2/STAT3 signaling in TNBC. In a nude mice xenograft study, SLC25A17 knockdown markedly decreased breast tumor growth and metastasis. CONCLUSION: SLC25A17 up-regulation may be a critical factor driving TNBC progression by modulating ROS production and autophagy. Consequently, targeting SLC25A17 could be an effective therapeutic strategy against TNBC.

Hetrombopag plus recombinant human thrombopoietin for chemotherapy-induced thrombocytopenia in patients with solid tumors.

Background: Chemotherapy-induced thrombocytopenia (CIT) is a common hematological complication in patients with cancer. Hetrombopag is a novel thrombopoietin receptor agonist that has shown an additive effect in stimulating platelet production when combined with recombinant human thrombopoietin (rhTPO). Objectives: This multicenter retrospective cohort study aimed to evaluate the efficacy and safety of hetrombopag plus rhTPO compared with rhTPO alone for CIT. Methods: A total of 294 patients with solid tumors and CIT (platelet count, <50 × 109/L) who received either rhTPO plus hetrombopag (146 patients) or rhTPO alone (148 patients) at 3 centers from January to December 2022 were included in the study. The primary outcome was a platelet count at least 50 × 109/L higher than the baseline value within 14 days. Chemotherapy dose reductions/delays, bleeding, and adverse events were reported. Results: One hundred twenty patients (82.2%) in the rhTPO-hetrombopag group vs 100 patients (67.6%) in the rhTPO group achieved the primary outcome (P = .005). This significant difference persisted in adjusted analysis (odds ratio, 2.01; 95% CI, 1.12-3.60). A total of 115 patients (78.8%) in the rhTPO-hetrombopag group and 101 patients (68.2%) in the rhTPO group avoided chemotherapy dose reductions/delays (P = .041). There was no significant difference in bleeding rates, and adverse events were mild and similar between the 2 groups. No deaths occurred. Conclusion: Compared to rhTPO alone, our findings suggest that the combination of hetrombopag and rhTPO is safe and more effective in patients with CIT.

Molecular markers that predict response to combined radiotherapy and immunotherapy in patients with lung adenocarcinoma: a bioinformatics analysis.

Background: Immunotherapy has had a high success rate in treating lung adenocarcinoma (LUAD) for several decades. However, many patients do not benefit from immunotherapy alone. Recent studies revealed that a combination of immunotherapy and radiotherapy (RT) stimulates a good systemic immune response to LUAD. However, clinical and experimental evidence suggest that RT may give rise to primary immunodeficiency, facilitating tumor immunity escape. Little is known about the molecular mechanisms whereby RT and stereotactic body radiotherapy (SBRT) influence tumor immunogenicity and the effectiveness of immunotherapy in patients with LUAD. Methods: We investigated molecular markers that predict response to combination of immunotherapy and SBRT in the treatment of LUAD using bioinformatics. Results: SBRT significantly upregulated the expression of PTPRC, LILRB2, TLR8, CCR5, and PLEK and significantly downregulated the expression of CXCL13, CD19, and LTA. Among these genes, the expression of PTPRC, TLR8, and CCR5 was associated with responsiveness to immunotherapy after SBRT. However, only TLR8 and CCR5 expression were associated with an improved prognosis. Further analysis revealed that TLR8 and CCR5 expression increased responsiveness to immunotherapy by promoting M0 macrophage and memory B cell infiltration of LUAD tissues. Conclusions: In patients with LUAD, TLR8 and CCR5 expression are potential markers of a favorable response to combined immunotherapy and RT.

Association between systemic immune-inflammation index and diabetes: a population-based study from the NHANES.

Background: Systemic Immune-Inflammation Index (SII) has been reported to be associated with diabetes. We aimed to assess possible links between SII and diabetes. Methods: Data were obtained from the 2017-2020 National Health and Nutrition Examination Survey (NHANES) database. After removing missing data for SII and diabetes, we examined patients older than 20 years. Simultaneously, the relationship between SII and diabetes was examined using weighted multivariate regression analysis, subgroup analysis, and smooth curve fitting. Results: There were 7877 subjects in this study, the average SII was 524.91 ± 358.90, and the prevalence of diabetes was 16.07%. Weighted multivariate regression analysis found that SII was positively associated with diabetes, and in model 3, this positive association remained stable (OR = 1.04; 95% CI: 1.02-1.06; p = 0.0006), indicating that each additional unit of SII, the possibility of having diabetes increased by 4%. Gender, age, BMI, regular exercise, high blood pressure, and smoking did not significantly affect this positive link, according to the interaction test (p for trend>0.05). Discussion: Additional prospective studies are required to examine the precise connection between higher SII levels and diabetes, which may be associated with higher SII levels.

Diagnostic and prognostic role of circRNAs in pancreatic cancer: a meta-analysis.

Background: Circular RNAs (circRNAs) are types of endogenous noncoding RNAs produced by selective splicing that are expressed highly specifically in various organisms and tissues and have numerous clinical implications in the regulation of cancer development and progression. Since circRNA is resistant to digestion by ribonucleases and has a long half-life, there is increasing evidence that circRNA can be used as an ideal candidate biomarker for the early diagnosis and prognosis of tumors. In this study, we aimed to reveal the diagnostic and prognostic value of circRNA in human pancreatic cancer (PC). Methods: A systematic search for publications from inception to 22 July 2022 was conducted on Embase, PubMed, Web of Science (WOS), and the Cochrane Library databases. Available studies that correlated circRNA expression in tissue or serum with the clinicopathological, diagnostic, and prognostic values of PC patients were enrolled. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were used to evaluate clinical pathological characteristics. Area under the curve (AUC), sensitivity, and specificity were adopted to assess diagnostic value. Hazard ratios (HRs) were utilized to assess disease-free survival (DFS) and overall survival (OS). Results: This meta-analysis enrolled 32 eligible studies, including six on diagnosis and 21 on prognosis, which accounted for 2,396 cases from 245 references. For clinical parameters, high expression of carcinogenic circRNA was significantly associated with degree of differentiation (OR = 1.85, 95% CI = 1.47-2.34), TNM stage (OR = 0.46, 95% CI = 0.35-0.62), lymph node metastasis (OR = 0.39, 95% CI = 0.32-0.48), and distant metastasis (OR = 0.26, 95% CI = 0.13-0.51). As for clinical diagnostic utility, circRNA could discriminate patients with pancreatic cancer from controls, with an AUC of 0.86 (95% CI: 0.82-0.88), a relatively high sensitivity of 84%, and a specificity of 80% in tissue. In terms of prognostic significance, carcinogenic circRNA was correlated with poor OS (HR = 2.00, 95% CI: 1.76-2.26) and DFS (HR = 1.96, 95% CI: 1.47-2.62). Conclusion: In summary, this study demonstrated that circRNA may act as a significant diagnostic and prognostic biomarker for pancreatic cancer.

Comprehensive analysis of prognostic value, immune implication and biological function of CPNE1 in clear cell renal cell carcinoma.

Background: Elevated expression of Copine-1 (CPNE1) has been proved in various cancers; however, the underlying mechanisms by which it affects clear cell renal cell carcinoma (ccRCC) are unclear. Methods: In this study, we applied multiple bioinformatic databases to analyze the expression and clinical significance of CPNE1 in ccRCC. Co-expression analysis and functional enrichment analysis were investigated by LinkedOmics, cBioPortal and Metascape. The relationships between CPNE1 and tumor immunology were explored using ESTIMATE and CIBERSORT method. In vitro experiments, CCK-8, wound healing, transwell assays and western blotting were conducted to investigate the effects of gain- or loss-of-function of CPNE1 in ccRCC cells. Results: The expression of CPNE1 was notably elevated in ccRCC tissues and cells, and significantly correlated with grade, invasion range, stage and distant metastasis. Kaplan-Meier and Cox regression analysis displayed that CPNE1 expression was an independent prognostic factor for ccRCC patients. Functional enrichment analysis revealed that CPNE1 and its co-expressed genes mainly regulated cancer-related and immune-related pathways. Immune correlation analysis showed that CPNE1 expression was significantly related to immune and estimate scores. CPNE1 expression was positively related to higher infiltrations of immune cells, such as CD8+ T cells, plasma cells and regulatory T cells, exhibited lower infiltrations of neutrophils. Meanwhile, elevated expression of CPNE1 was characterized by high immune infiltration levels, increased expression levels of CD8+ T cell exhaustion markers (CTLA4, PDCD1 and LAG3) and worse response to immunotherapy. In vitro functional studies demonstrated that CPNE1 promoted proliferation, migration and invasion of ccRCC cells through EGFR/STAT3 pathway. Conclusion: CPNE1 is a reliable clinical predictor for the prognosis of ccRCC and promotes proliferation and migration by activating EGFR/STAT3 signaling. Moreover, CPNE1 significantly correlates with immune infiltration in ccRCC.

Imaging analysis and predictive nomogram construction for degenerative lumbar spondylolisthesis with severe clinical symptom based on propensity score matching.

Intervertebral disc degeneration, local lumbar segmental morphology changes, and atrophy of multifidus muscle have been considered to be associated with degenerative lumbar spondylolisthesis. However, there remains a great deal of controversy. To further investigate their relationship with degenerative lumbar spondylolisthesis, we conducted a retrospective study that included 67 patients with degenerative spondylolisthesis and 182 control subjects. Propensity score matching was employed to match the case group and the control group. Disc height was evaluated by the anterior disc height index (DHIA) and posterior disc height index (DHIP). Local lumbar segmental morphology was assessed by segmental lordosis (SL). The fatty infiltration and atrophy of multifidus muscle was evaluated by multifidus muscle net content (MFNC). Our results indicate that DHIA, DHIP, SL, and MFNC in the case group were significantly lower than in the control group. Furthermore, the DHIA, DHIP, and MFNC of the slipped segment (L4/5) were lower than those of the non-slipped segment (L3/4). Correlation analysis showed a high relationship between DHIA and MFNC and the degree of degenerative lumbar spondylolisthesis. Logistic regression analysis revealed that DHIA and MFNC might act as protective factors against the development of degenerative lumbar spondylolisthesis. Additionally, a prognostic nomogram was developed and validated to assess the likelihood of patients with severe symptoms requiring surgical intervention.

Identification of MTHFD2 as a prognostic biomarker and ferroptosis regulator in triple-negative breast cancer.

Background: Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial bifunctional enzyme encoded in the nucleus. It plays a significant role in the regulation of glucose, nucleic acid, and folate metabolism, and maintains redox balance in the cells. The present study aimed at elucidating the potential function and mechanisms of MTHFD2 and explored the correlation between ferroptosis and MTHFD2 in triple-negative breast cancer. Methods: MTHFD2 expression, survival analysis, and clinical correlation were performed using data from various online databases including TCGA, GEO, HPA, GTEX, Kaplan-Meier Plotter, PrognoScan, and UALCAN databases. Genomic alterations and CNV analysis were performed using the cBioPortal and GSCA databases. Potential functions and mechanisms were explored by enrichment analysis. The tumor microenvironment was identified by the TIMER database. In vitro, RT-qPCR and western blot assays were utilized to identify the MTHFD2 expression and the knockdown effects in breast cancer. CCK8, cell wound healing, transwell, and flow cytometry assays were used to identify the potential function of MTHFD2 in TNBC cells. MDA, GSH detection, and flow cytometry assays were performed to identify ferroptosis. Western blot assays were performed to measure the protein expression of all target genes. Results: MTHFD2 expression levels were up-regulated in the majority of cancers and particularly in TNBC, in which higher expression levels indicated a poorer prognosis. Enrichment analyses showed that MTHFD2 is involved in various tumor-related biological processes. MTHFD2 expression was found to strongly correlate with multiple immune cell infiltration. In vitro, the knockdown of MTHFD2 suppresses the proliferation, apoptosis, migration, and invasion in TNBC cells. In addition, the MTHFD2 knockdown significantly enhanced intracellular ROS and lipid peroxidation and decreased intracellular GSH. The expressions of SLC7A11, GPX4, and NRF2 were down-regulated by the MTHFD2 knockdown. Conclusion: MTHFD2 could be a crucial molecular biomarker for predicting patient prognosis and a novel therapeutic target in TNBC. In addition, MTHFD2 is a potential ferroptosis regulatory gene in TNBC.

The landscape of chimeric antigen receptor T cell therapy in breast cancer: Perspectives and outlook.

Chimeric antigen receptor-T (CAR-T) cell therapy is a revolutionary adoptive cell therapy, which could modify and redirect T cells to specific tumor cells. Since CAR-T cell therapy was first approved for B cell-derived malignancies in 2017, it has yielded unprecedented progress in hematological tumors and has dramatically reshaped the landscape of cancer therapy in recent years. Currently, cumulative evidence has demonstrated that CAR-T cell therapy could be a viable therapeutic strategy for solid cancers. However, owing to the immunosuppressive tumor microenvironment (TME) and heterogenous tumor antigens, the application of CAR-T cell therapy against solid cancers requires circumventing more challenging obstacles. Breast cancer is characterized by a high degree of invasiveness, malignancy, and poor prognosis. The review highlights the underlying targets of CAR-T cell therapy in breast cancer, summarizes the challenges associated with CAR-T cell therapy, and proposes the strategies to overcome these challenges, which provides a novel approach to breast cancer treatment.

Construction of an Immune-Related lncRNA Signature That Predicts Prognosis and Immune Microenvironment in Osteosarcoma Patients.

Osteosarcoma is one of the most common bone tumors in teenagers. We hope to provide a reliable method to predict the prognosis of osteosarcoma and find potential targets for early diagnosis and precise treatment. To address this issue, we performed a detailed bioinformatics analysis based on the Cancer Genome Atlas (TCGA). A total of 85 osteosarcoma patients with gene expression data and clinicopathological features were included in this study, which was considered the entire set. They were randomly divided into a train set and a test set. We identified six lncRNAs (ELFN1-AS1, LINC00837, OLMALINC, AL669970.3, AC005332.4 and AC023157.3), and constructed a signature that exhibited good predictive ability of patient survival and metastasis. What's more, we found that risk score calculated by the signature was positively correlated to tumor purity, CD4+ naive T cells, and negatively correlated to CD8+ T cells. Furthermore, we investigated each lncRNA in the signature and found that these six lncRNAs were associated with tumorigenesis and immune cells in the tumor microenvironment. In conclusion, we constructed and validated a signature, which had good performance in the prediction of survival, metastasis and immune microenvironment. Our study indicated possible mechanisms of these lncRNAs in the development of osteosarcoma, which may provide new insights into the precise treatment of osteosarcoma.

Inhibition of PDK1 enhances radiosensitivity and reverses epithelial-mesenchymal transition in nasopharyngeal carcinoma.

BACKGROUND: Radioresistance challenges the clinical outcomes of nasopharyngeal carcinoma (NPC). The 3-phosphoinositide-dependent protein kinase 1 (PDK1) is a crucial kinase of PI3K/AKT signaling pathway which has been implicated in the process of radioresistance. However, the role of PDK1 in NPC remains largely unclear. METHODS: The expression of PDK1 was determined by immunohistochemistry and Western blot. The effects of RNA interference and pharmacologic inhibitor of PDK1 in combination with irradiation were investigated. RESULTS: Overexpression of PDK1 was correlated with poor prognosis in patients with NPC. PDK1 depletion enhanced radiosensitivity of NPC cells both in vitro and in vivo. Additionally, a specific PDK1 inhibitor also had the potential to enhance radiosensitivity in radioresistant NPC cells. Mechanistically, PDK1 depletion inhibited various targets of AKT including mTOR and GSK-3ß and reversed the epithelial-mesenchymal transition. CONCLUSIONS: These findings indicated that PDK1 might be a potential target for NPC.

FERMT1 contributes to the migration and invasion of nasopharyngeal carcinoma through epithelial-mesenchymal transition and cell cycle arrest.

BACKGROUND: Fermitin family member 1 (FERMT1) is significantly overexpressed in human cancers and associated with poor prognosis, but its contributions to tumorigenesis and nasopharyngeal carcinoma (NPC) progression remain unclear. METHODS: The public GEO database was examined to investigate the role of FERMT1. Immunohistochemistry (IHC) staining of FERMT1 was performed in NPC tissues to corroborate the results. Western blotting and qRT-PCR were performed to test the expression of related proteins and mRNAs. Cell counting kit-8 assay (CCK8 assay) and colony formation assays were carried out to investigate the association of FERMT1 expression with NPC cell proliferation. The wound healing assay and Transwell assay were used to detect the migration and invasion of NPC cells. Flow cytometric analysis was conducted to detect the cell cycle transition of NPC cells. Co-immunoprecipitation (Co-IP) was employed to identify the correlation of FEMRT1 and Nod-like receptor family protein 3 (NLRP3). Xenograft tumors were generated to investigate the effect of FERMT1 on the growth of NPC cells in vivo. RESULTS: Here, we found that FERMT1 was upregulated in NPC tissues and correlated with the clinicopathological characteristics of NPC patients. Moreover, knockdown of FERMT1 significantly decreased cell proliferation, migration and invasion by mediating epithelial-mesenchymal transition (EMT) and cell cycle arrest of NPC cells both in vitro and in vivo. Knockdown FERMT1 inhibited EMT through directly binding to the NLRP3 and inhibited NF-kB signaling pathway. CONCLUSION: These data indicated that FERMT1 could be a good potential therapeutic target for NPC treatment.

Infiltration of LPAR5+ macrophages in osteosarcoma tumor microenvironment predicts better outcomes.

Introduction: Tumor microenvironment (TME) has been shown to be extensively involved in tumor development. However, the dynamic change of TME components and their effects are still unclear. Here, we attempted to identify TME-related genes that could help predict survival and may be potential therapeutic targets. Methods: Data was collected from UCSC Xena and GEO database. ESTIMATE and CIBERSORT algorithms were applied to estimate the components and the proportions of TIICs in TME. We analyzed the gene expression differences of immune components and stromal components, respectively, and finally got the overlapped DEGs. Through protein-protein interaction (PPI) network and univariate Cox regression analysis based on shared DEGs, we screened out and validated the TME-related genes. Focusing on this gene, we analyzed the expression and prognostic value of this gene, and investigated its relationship with immune cells by correlation analysis, single cell analysis, immunohistochemistry and immunofluorescence analysis. Results: Through a series analysis, we found that the proportion of immune and stromal components was an important prognostic factor, and screened out a key gene, LPAR5, which was highly correlated with prognosis and metastasis. And the expression of LPAR5 was positively correlated with immune cells, especially macrophages, indicating LPAR5+ macrophages played an important role in tumor microenvironment of osteosarcoma. Meanwhile, the genes in LPAR5 high expression group were enriched in immune-related activities and pathways, and differentially expressed genes between LPAR5+ macrophages and LPAR5- macrophages were enriched in the biological processes associated with phagocytosis and antigen presentation. What' more, we found that LPAR5 was mainly expressed in TME, and high LPAR5 expression predicting a better prognosis. Conclusion: We identified a TME-related gene, LPAR5, which is a promising indicator for TME remodeling in osteosarcoma. Particularly, LPAR5+ macrophages might have great potential to be a prognostic factor and therapeutic target for osteosarcoma.

Construction of a circRNA-miRNA-mRNA Regulatory Network Reveals Potential Mechanism and Treatment Options for Osteosarcoma.

BACKGROUND: Osteosarcoma is a common malignant primary bone tumor in adolescents and children. Numerous studies have shown that circRNAs were involved in the proliferation and invasion of various tumors. However, the role of circRNAs in osteosarcoma remains unclear. Here, we aimed to explore the regulatory network among circRNA-miRNA-mRNA in osteosarcoma. METHODS: The circRNA (GSE140256), microRNA (GSE28423), and mRNA (GSE99671) expression profiles of osteosarcoma were collected from the Gene Expression Omnibus (GEO) database. Differentially expressed circRNAs, miRNAs and mRNAs were identified. CircRNA-miRNA interactions and miRNA-mRNA interactions were determined by Circular RNA Interactome (CircInteractome) database and microRNA Data Integration Portal (mirDIP) database, respectively. Then, we constructed a regulatory network. Function enrichment analysis of miRNA and mRNA was performed by DIANA-miRPath v3.0 and Metascape database, respectively. mRNAs with significant prognostic value were identified based on expression profiles from The Cancer Genome Atlas (TCGA) database, and we constructed a subnetwork for them. To make the most of the network, we used the CLUE database to predict potential drugs for the treatment of osteosarcoma based on mRNA expression in the network. And we used the STITCH database to analyze and validate the interactions among these drugs and mRNAs, and to further screen for potential drugs. RESULTS: A total of 9 circRNAs, 19 miRNAs, 67 mRNAs, 54 pairs of circRNA-miRNA interactions and 110 pairs of miRNA-mRNA interactions were identified. A circRNA-miRNA-mRNA network was constructed. Function enrichment analysis indicated that these miRNAs and mRNAs in the network were involved in the process of tumorigenesis and immune response. Among these mRNAs, STC2 and RASGRP2 with significantly prognostic value were identified, and we constructed a subnetwork for them. Based on mRNA expression in the network, three potential drugs, quinacridine, thalidomide and zonisamide, were screened for the treatment of osteosarcoma. Among them, quinacridine and thalidomide have been proved to have anti-tumor effects in previous studies, while zonisamide has not been reported. And a corresponding drug-protein interaction network was constructed. CONCLUSION: Overall, we constructed a circRNA-miRNA-mRNA regulatory network to investigate the possible mechanism in osteosarcoma, and predicted that quinacridine, thalidomide and zonisamide could be potential drugs for the treatment of osteosarcoma.

CT assessment of the increased density of cerebral vessels in plateau region.

In this study, the relationship between the brain parenchymal density, the cerebral vessel density, the mean corpuscular hemoglobin (MCH) content, the mean corpuscular hemoglobin concentration (MCHC), and the morbidity associated with lacunar infarction of residents living in either the plains or the plateau regions were analyzed and compared for their potential clinical implications. Clinical data from the brain CT scans of individuals living in either the plain or plateau regions (129 each) were collected. Specifically, the CT values for basal ganglia, the middle cerebral artery, and the superior sagittal sinus, along with the number of patients with lacunar infarction, were collected. In addition, the MCH and MCHC values were measured in blood samples collected within 48 h following the CT scans. For statistical analysis, an independent sample t-test, Pearson's correlation test (permutation test), and Chi-squared test were employed. The inhabitants of the plateau had a significantly higher CT value of basal ganglia, the middle cerebral artery, and superior sagittal sinus and also higher levels of MCH and MCHC in the blood (ps < 0.001) than the inhabitants of the plains region. Further, there was a significant positive correlation between the three aforementioned CT values and the MCH and MCHC findings. However, no significant differences were found in the morbidity of lacunar infarction between these two regions (p > 0.05). The inhabitants in the plateau have a significantly higher brain parenchymal density, higher CT value for cerebral vessels density, and higher blood MCH and MCHC levels in comparison with individuals occupying the plains. Concurrently, the parenchymal density and the CT values are shown to be positively correlated with the MCH and MCHC content in the blood.

Identification novel prognostic signatures for Head and Neck Squamous Cell Carcinoma based on ceRNA network construction and immune infiltration analysis.

Background: Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with high mortality and morbidity worldwide, but the underlying biological mechanisms of molecules and tumor infiltrating-immune cells (TIICs) are still unknown. Methods and Results: We obtained mRNAs, lncRNAs, and miRNAs expression profiles of 546 HNSCC from The Cancer Genome Atlas (TCGA) database to develop a ceRNA network. CIBERSORT was employed to estimate the fraction of 22 types of TIICs in HNSCC. Univariate and multivariate Cox regression and lasso regression analyses were used to develop prognostic signatures. Then, two novel risk signatures were constructed respectively based on six ceRNAs (ANLN, KIT, PRKAA2, NFIA, PTX3 and has-miR-148a-3p) and three immune cells (naïve B cells, regulatory T cells and Neutrophils). Kaplan-Meier (K-M) analysis and Cox regression analysis further proved that these two signatures were significant prognostic factors independent of multiple clinicopathological characteristics. Two nomograms were built based on ceRNAs-riskScore and TIICs-riskScore that could be used to predict the prognosis of HNSCC. Co-expression analysis showed significant correlations between miR-148a-3p and naive B cells, naive B cells and plasmas cells. Conclusion: Through construction of the ceRNA network and estimation of TIICs, we established two risk signatures and their nomograms with excellent utility, which indicated the potential molecular and cellular mechanisms, and predicted the prognosis of HNSCC.

Overexpression of P4HA1 Is Correlated with Poor Survival and Immune Infiltrates in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is a major pathological type of lung cancer. Understanding the mechanism of LUAD at the molecular level is important for a clinical decision. In this study, we use bioinformatic analysis to explore the prognostic value of P4HA1 in lung adenocarcinoma (LUAD) and the relationship with prognosis and tumor-infiltrating immune cells (TIICs). The results showed that the expression of P4HA1 was significantly higher in tumor tissues than in normal tissues for LUAD patients. Upregulated P4HA1 was related to stage and T classification. Kaplan-Meier analysis indicated that upregulation of P4HA1 was significantly related to worse overall survival (OS). Univariate and multivariate Cox analysis indicated P4HA1 remained to be an independent prognostic factor. GSEA showed that several cancer-related and immune-related signaling pathways exhibited prominently differential enrichment in P4HA1-high expression phenotype. In addition, the expression of P4HA1 was significantly correlated with proportion of several TIICs, particularly B cells and CD4+ T cells. In conclusion, our study confirmed that P4HA1 is a promising biomarker of poor prognosis and relates to immune infiltrates in LUAD.