Cell Cycle Pathways Research Articles

High Glycolytic Activity Signature Reveals CCNB2 as a Key Therapeutic Target in Triple-Negative Breast Cancer.

Aerobic glycolysis and the cell cycle are well-established tumor hallmarks. Understanding their relationship could help to unravel the pathogenic mechanisms of breast cancer (BC) and suggest potential new strategies for treatment. Glycolysis-related genes (GRGs) were downloaded from the Reactome database and screened using univariate Cox analysis. The consensus clustering method was employed to identify a glycolytic activity signature (GAS) using the Gene Expression Omnibus (GEO) dataset. A nomogram risk prediction model was constructed using coefficients from univariate Cox analysis. Immune cell infiltration was evaluated using single-sample gene set enrichment analysis (ssGSEA) and the ESTIMATE algorithm. Gene co-expression modules were created using weighted correlation network analysis (WGCNA) to identify hub genes. Gene expression in three BC cell lines was quantified using Quantitative Reverse Transcriptase Polymera (qRT-PCR). Single-cell RNA sequencing (scRNA-seq) data was used to examine the relationship between GAS and hub genes. The sensitivity of different groups to cell cycle-related clinical drugs was also examined. BC with high GAS (HGAS) showed high tumor grade and recurrence rate. HGAS was a prognostic indicator of worse overall survival (OS) in BC patients. HGAS BC showed more abundant immune cells and significantly higher expression of immunomodulators compared to BC with low GAS (LGAS). HGAS BC also showed enhanced cell cycle pathway, with high mRNA and protein expression levels of Cyclin B2 (CCNB2), a key component of the cell cycle pathway. Importantly, scRNA-seq analysis revealed that elevated CCNB2 expression was positively correlated with HGAS in triple-negative BC (TNBC). This was validated in clinical samples from TNBC patients. High expression of CCNB2 was found in three BC cell lines, and was also an indicator of poor prognosis. HGAS BC showed high sensitivity to several cell cycle-related clinical drugs, with 9 of these also showing activity in BC with high CCNB2 expression. HGAS was associated with enhanced cell cycle pathway and immune activity in BC. These results suggest that CCNB2 is a potential key therapeutic target in BC patients.

Germline variant profiling of CHEK2 sequencing variants in breast cancer patients

The cell cycle checkpoint kinase 2 (CHEK2) is a tumor suppressor gene coding for a protein kinase with a role in the cell cycle and DNA repair pathways. Variants within CHEK2 are associated with an increased risk of developing breast, colorectal, prostate and several other types of cancer. Comprehensive genetic risk assessment leads to early detection of hereditary cancer and provides an opportunity for better survival. Multigene panel screening can identify the presence of pathogenic variants in hereditary cancer predisposition genes (HCPG), including CHEK2. Multigene panels, however, also result in large quantities of genetic data some of which cannot be interpreted and are classified as variants of uncertain significance (VUS). A VUS provides no information for use in medical management and leads to ambiguity in genetic counseling. In the absence of variant segregation data, in vitro functional analyses can be used to clarify variant annotations, aiding in accurate clinical management of patient risk and treatment plans. In this study, we performed whole exome sequencing (WES) to investigate the prevalence of germline variants in 210 breast cancer (BC) patients and conspicuously among the many variants in HCPGs that we found, we identified 16 individuals with non-synonymous or frameshift CHEK2 variants, sometimes along with additional variants within other BC susceptibility genes. Using this data, we investigated the prevalence of these CHEK2 variants in African American (AA) and Caucasian (CA) populations identifying the presence of two novel frameshift variants, c.1350delA (p.Val451Serfs*18) and c.1528delC (p.Gln510Argfs*3) and a novel missense variant, c262C>T (p.Pro88Ser). Along with the current clinical classifications, we assembled available experimental data and computational predictions of function for these CHEK2 variants, as well as explored the role these variants may play in polygenic risk assessment.

Comprehensive transcriptomic profiling of T-2 toxin-induced nephrotoxicity in mice

T-2 toxin, a trichothecene mycotoxin, is an important environmental pollutant that poses a threat globally to the health of humans and animals. It has been found to induce nephrotoxicity; however, the precise molecular mechanism involved remains unclear. In this study, mice were administered at a single dose of 2 mg/kg body weight T-2 toxin intraperitoneally, and kidney function and ultrastructural observations were assessed after 1 d, 3 d, and 7 d. Histopathological findings revealed that exposure to T-2 toxin caused noticeable tubular degeneration, necrosis and epithelial cell shedding in mouse kidneys. Transmission electron microscopy indicated that exposure to T-2 toxin caused mitochondrial swelling and vacuolization. Transcriptomic data revealed significant differences in the expression of 1122, 58, and 391 genes in kidney tissues 1 d, 3 d, or 7 d after T-2 toxin exposure, respectively. Moreover, after 1 d, the downregulated differentially expressed genes (DEGs) were found to be involved in the cell cycle, p53 signaling, and cellular senescence pathways, while the upregulated DEGs were found to be associated with the ribosomal pathway. Temporal changes in gene expression patterns (i.e., after 3 d and 7 d) and disturbances in cellular metabolism during the recovery period (7 d) were detected in mouse kidneys after exposure to T-2 toxin. In conclusion, this study is the first to provide a comprehensive comparative transcriptomic analysis of T-2 toxin exposure-induced nephrotoxicity-related gene regulation at different time points and to investigate the mechanism underlying the nephrotoxicity of T-2 toxin at the mRNA expression level.

Exploration of small molecule compounds targeting abdominal aortic aneurysm based on CMap database and molecular dynamics simulation.

The mitigation of abdominal aortic aneurysm (AAA) growth through pharmaceutical intervention offers the potential to avert the perils associated with AAA rupture and the subsequent need for surgical intervention. Nevertheless, the existing effective drugs for AAA treatment are limited, necessitating a pressing exploration for novel therapeutic medications. AAA-related transcriptome data were downloaded from GEO, and differentially expressed genes (DEGs) in AAA tissue were screened for GO and KEGG enrichment analyses. Small molecule compounds and their target proteins with negative connectivity to the AAA expression profile were predicted in the Connectivity Map (CMap) database. Molecular docking and molecular dynamics simulation were performed to predict the binding of the target protein to the small molecule compound, and the MM/GBSA method was used to calculate the binding free energy. Cluster analysis was performed using the cluster tool in the GROMACS package. An AAA cell-free model was built, and CETSA experiments were used to demonstrate the binding ability of small molecules to the target protein in cells. A total of 2244 DEGs in AAA were obtained through differential analysis, and the DEGs were mainly enriched in the tubulin binding biological function and cell cycle pathway. The CMap results showed that Apicidin had a potential therapeutic effect on AAA with a connectivity score of -97.74, and HDAC4 was the target protein of Apicidin. Based on literature, HDAC4-Apicidin was selected as the subsequent research object. The lowest affinity of Apicidin-HDAC4 molecular docking was -8.218kcal/mol. Molecular dynamics simulation results indicated that Apicidin-HDAC4 could form a stable complex. MM/GBSA analysis showed a total binding free energy of -55.40 ± 0.79kcal/mol, and cluster analysis showed that there were two main conformational clusters during the binding process, accounting for 22.4% and 57.8%, respectively. Apicidin could form hydrogen bonds with surrounding residues for stable binding. CETSA experiment proved the stable binding ability of Apicidin and HDAC4. Apicidin inhibited HDAC4 in AAA and exhibited favorable protein-ligand interactions and stability, making it a potential candidate drug for treating AAA.

Anoikis-related genes linked with patient outcome in pancreatic cancer

Anoikis is programmed cell death occurring upon cell detachment from the extracellular matrix. Cancer cells need to evade anoikis to be able to metastasize to distant sites. However, the molecular features and prognostic value of anoikis-related genes (ARGs) in pancreatic cancer remain unclear. In this study, we utilized transcriptome data from the TCGA and GSE102238 databases to identify 64 ARGs significantly associated with prognosis. We used the “ConsensusClusterPlus” R package to stratify patients into high and low-risk prognostic subgroups. The KEGG and GSEA analyses revealed that the clusters with poor prognosis were enriched for the ECM receptor interaction pathway, the TP53 signaling pathway, and the galactose metabolism pathway, and that the cell cycle pathway was upregulated. A prognostic model consisting of seven ARGs (SERPINE1, EGF, E2F1, MSLN, RAB27B, ETV7, MST1) was constructed using LASSO regression and when combined with clinicopathological parameters using Cox regression, a prognostic Nomogram was created, which demonstrated high prognostic utility. Among the biomarker candidates, we report ETV7 as a novel, independent prognostic marker in pancreatic cancer. ETV7 was highly expressed in KRAS and TP53 co-occurrent mutant TCGA patients, indicating that it may be regulated by the two major driver genes of pancreatic cancer.Therefore, targeting ETV7 could be a potential focus for future therapeutic studies.

Comprehensive genetic profiling and molecularly guided treatment for patients with primary CNS tumors

Despite major advances in molecular profiling and classification of primary brain tumors, personalized treatment remains limited for most patients. Here, we explored the feasibility of individual molecular profiling and the efficacy of biomarker-guided therapy for adult patients with primary brain cancers in the real-world setting within the molecular tumor board Freiburg, Germany. We analyzed genetic profiles, personalized treatment recommendations, and clinical outcomes of 102 patients with 21 brain tumor types. Alterations in the cell cycle, BRAF, and mTOR pathways most frequently led to personalized treatment recommendations. Molecularly informed therapies were recommended in 71% and implemented in 32% of patients with completed molecular diagnostics. The disease control rate following targeted treatment was 50% and the overall response rate was 30%, with a progression-free survival 2/1 ratio of at least 1.3 in 31% of patients. This study highlights the efficacy of molecularly guided treatment and the need for biomarker-stratified trials in brain cancers.

Pituitary tumor‑transforming gene 1 regulates the senescence and apoptosis of oral squamous cell carcinoma in a p21‑dependent DNA damage response manner.

Pituitary tumor‑transforming gene 1 (PTTG1), also known as securin, is a proto‑oncogene involved in the development of various cancers by promoting cell proliferation and mobility. However, its underlying biological mechanisms in oral squamous cell carcinoma (OSCC) progression remain unclear. in the present study, it was sought to elucidate the role of PTTG1 as an oncogene in OSCC progression and was attempted to unravel the underlying mechanism and impact of PTTG1 expression on cell cycle, cell death, and cellular senescence. The effect of double strand break on PTTG1 expression was investigated in OSCC growth. To identify the role of PTTG1 in OSCC growth, the cell viability and senescence was analyzed by EdU and senescence‑associated beta‑galactosidase (SA‑β‑gal) assay, respectively. To verify the DNA damage‑induced senescence of PTTG1, the chromosomal damage in OSCC was analyzed in vitro. Finally, the effect of PTTG1 on tumor growth and gene expression related to cell viability and DNA damaged‑induced senescence was investigated in vivo. PTTG1 expression was compared between OSCC and healthy patient samples (n=32) using reverse transcription‑quantitative PCR and immunohistochemistry; and it was found that PTTG1 expression was upregulated in OSCC. Small interfering RNA‑mediated knockdown of PTTG1 in two OSCC cell lines revealed that PTTG1 downregulation significantly inhibited cell proliferation and arrested the cell cycle pathway as evidenced by changes in checkpoint genes (such as cyclin D1, E and B1). PTTG1 knockdown also increased apoptosis, as evidenced by the upregulation of apoptotic genes [such as cleaved (c‑) Caspase‑7 and c‑poly (ADP‑ribose) polymerase]. Moreover, PTTG1 downregulation promoted cellular senescence, as shown by western blotting and SA‑β‑gal staining. Finally, senescence‑induced DNA damage was observed in OSCC cells, which accelerates genomic instability, through chromosomal damage analysis. Taken together, the present findings suggested that PTTG1 acts as a proto‑oncogene; regulates cell proliferation, cell cycle, cellular senescence and DNA damage in OSCC; and may serve as a novel diagnostic biomarker and potential therapeutic target for OSCC.

Cardiomyocyte proliferation and regeneration in congenital heart disease.

Despite advances in prenatal screening and a notable decrease in mortality rates, congenital heart disease (CHD) remains the most prevalent congenital disorder in newborns globally. Current therapeutic surgical approaches face challenges due to the significant rise in complications and disabilities. Emerging cardiac regenerative therapies offer promising adjuncts for CHD treatment. One novel avenue involves investigating methods to stimulate cardiomyocyte proliferation. However, the mechanism of altered cardiomyocyte proliferation in CHD is not fully understood, and there are few feasible approaches to stimulate cardiomyocyte cell cycling for optimal healing in CHD patients. In this review, we explore recent progress in understanding genetic and epigenetic mechanisms underlying defective cardiomyocyte proliferation in CHD from development through birth. Targeting cell cycle pathways shows promise for enhancing cardiomyocyte cytokinesis, division, and regeneration to repair heart defects. Advancements in human disease modeling techniques, CRISPR-based genome and epigenome editing, and next-generation sequencing technologies will expedite the exploration of abnormal machinery governing cardiomyocyte differentiation, proliferation, and maturation across diverse genetic backgrounds of CHD. Ongoing studies on screening drugs that regulate cell cycling are poised to translate this nascent technology of enhancing cardiomyocyte proliferation into a new therapeutic paradigm for CHD surgical interventions.

Identification of POU4F1 as a novel prognostic biomarker and therapeutic target in esophageal squamous cell carcinoma

BackgroundEsophageal cancer is a significant global health concern, ranking seventh in incidence and sixth in mortality. It encompasses two pathological types: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma, with ESCC being more prevalent globally and associated with higher mortality rates. The POU (Pit-Oct-Unc) domain family transcription factors, comprising 15 members, play important roles in embryonic development and organ formation. Aberrant expression of POUs has been observed in several human cancers, influencing cell proliferation, tumor invasion, and drug resistance. However, their specific role in ESCC remains unknown.MethodsWe analyzed TCGA and GEO databases to assess POUs expression in ESCC tissues. Kaplan-Meier and ROC analyses were used to evaluate the prognostic value of POUs. Gene Set Enrichment Analysis and Protein-Protein interaction network were used to explore the potential pathway. Functional assays (Cell Counting Kit-8, EdU Staining assay, and cloning formation assay) and mechanism analyses (RNA-seq, flow cytometry, and Western blot) were conducted to determine the effects of POU4F1 knockdown on ESCC cell phenotypes and signaling pathways.ResultsPOU4F1 and POU6F2 were upregulated in various cancer tissues, including ESCC, compared to normal tissues. POU4F1 expression was significantly correlated with patient survival and superior to previous models (AUC = 0.776). Knockdown of POU4F1 inhibited ESCC cell proliferation and affected cell cycle, autophagy, and DNA damage pathways in ESCC cells.ConclusionPOU4F1 is a novel and promising prognostic and therapeutic target for ESCC patients, providing insights into potential treatment strategies.

Synthesis and Antitumour Evaluation of Tricyclic Indole-2-Carboxamides against Paediatric Brain Cancer Cells.

Antitumour properties of some cannabinoids (CB) have been reported in the literature as early as 1970s, however there is no clear consensus to date on the exact mechanisms leading to cancer cell death. The indole-based WIN 55,212-2 and SDB-001 are both known as potent agonists at both CB1 and CB2 receptors, yet we demonstrate herein that only the former can exert in vitro antitumour effects when tested against a paediatric brain cancer cell line KNS42. In this report, we describe the synthesis of novel 3,4-fused tricyclic indoles and evaluate their functional potencies at both cannabinoid receptors, as well as their abilities to inhibit the growth or proliferation of KNS42 cells. Compared to our previously reported indole-2-carboxamides, these 3,4-fused tricyclic indoles had either completely lost activities, or, showed moderate-to-weak antagonism at both CB1 and CB2 receptors. Compound 23 displayed the most potent antitumour properties among the series. Our results further support the involvement of non-CB pathways for the observed antitumour activities of amidoalkylindole-based cannabinoids, in line with our previous findings. Transcriptomic analysis comparing cells treated or non-treated with compound 23 suggested the observed antitumour effects of 23 are likely to result mainly from disruption of the FOXM1-regulated cell cycle pathways.

Transcriptional dynamic changes in energy metabolism, protein synthesis and cell cycle regulation reveal the biological adaptation mechanisms of juvenile Acrossocheilus wenchowensis under acute temperature changes

In recent years, frequent acute temperature changes have posed a serious threat to the physiology and survival of fish. This study utilized RNA-Seq technology to analyze the transcriptional dynamics in the muscle tissues of Acrossocheilus wenchowensis under various acute temperature conditions (16◦C, 20◦C, 24◦C, 28◦C and 32◦C). Through comprehensive analysis, we identified 11509 differentially expressed genes (DEGs), a gene set (profiles 19) that was significantly up-regulated with increasing temperature, and two weighted gene co-expression network analysis (WGCNA) modules that were significantly correlated with acute temperature changes. Furthermore, we identified 28 transcription factors that are pivotal in oxidative stress and energy metabolism under acute temperature changes. Our results showed that, compared to the control group (24°C), KEGG functional enrichment analysis revealed significant enrichment of DEGs in the cell cycle, DNA replication, and p53 signaling pathway, with an overall trend of suppressed expression. This indicates that maintaining cell stability and reducing cell damage is an effective adaptive mechanism for A. wenchowensis to cope with acute temperature changes. Through STEM analysis and the black WGCNA module associated with high-temperature stress, we identified significant up-regulation of pathways and hub genes related to energy metabolism including oxidative phosphorylation, TCA cycle, purine metabolism, and glutathione metabolism, as well as the central roles of signal transduction pathways such as MAPK signaling pathway and AMPK signaling pathway, which synergistically regulate energy production. Under acute low-temperature stress, the turquoise WGCNA module highlighted significant up-regulation of hub genes associated with Ribosomal and Spliceosomal pathways related to protein synthesis and processing, as well as activation of calcium signaling pathways, which plays an important role in maintaining cellular function during low-temperature adaptation. These findings provide a critical theoretical and molecular basis for the adaptation of eurythermal fish to rapid temperature changes.

Identifying and validating the roles of the cuproptosis-related gene DKC1 in cancer with a focus on esophageal carcinoma

BackgroundEsophageal cancer is a common malignancy of the digestive tract. Despite remarkable advancements in its treatment, the overall prognosis for patients remains poor. Cuproptosis is a form of programmed cell death that affects the malignant progression of tumors. This study aimed to examine the impact of the cuproptosis-associated gene DKC1 on the malignant progression of esophageal cancer.MethodsClinical and RNA sequencing data of patients with esophageal cancer were extracted from The Cancer Genome Atlas (TCGA). Univariate Cox regression analysis was used to identify the differentially expressed genes related to cuproptosis that are associated with prognosis. We then validated the difference in the expression of DKC1 between tumor and normal tissues via three-dimensional multiomics difference analysis. Subsequently, we investigated the association between DKC1 expression and the tumor microenvironment by employing the TIMER2.0 algorithm, which was further validated in 96 single-cell datasets obtained from the TISCH database. Additionally, the functional role of DKC1 in pancarcinoma was assessed through GSEA. Furthermore, a comprehensive pancancer survival map was constructed, and the expression of DKC1 was verified in various molecular subtypes. By utilizing the CellMiner, GDSC, and CTRP databases, we successfully established a connection between DKC1 and drug sensitivity. Finally, the involvement of DKC1 in the progression of esophageal cancer was investigated through in vivo and in vitro experiments.ResultsIn this study, we identified a copper death-related gene, DKC1, in esophageal cancer. Furthermore, we observed varying levels of DKC1 expression across different tumor types. Additionally, we conducted an analysis to determine the correlation between DKC1 expression and clinical features, revealing its association with common cell cycle pathways and multiple metabolic pathways. Notably, high DKC1 expression was found to indicate poor prognosis in patients with various tumors and to influence drug sensitivity. Moreover, our investigation revealed significant associations between DKC1 expression and the expression of molecules involved in immune regulation and infiltration of lymphocyte subtypes. Ultimately, the increased expression of DKC1 in esophageal cancer tissues was verified using clinical tissue samples. Furthermore, DKC1-mediated promotion of esophageal cancer cell proliferation and migration was confirmed through both in vitro and in vivo experiments. Additionally, it is plausible that DKC1 may play a role in the regulation of cuproptosis.ConclusionIn this study, we conducted a systematic analysis of DKC1 and its regulatory factors and experimentally validated its excellent diagnostic and prognostic abilities in various cancers. Further research indicated that DKC1 may reshape the tumor microenvironment (TME), highlighting the potential of DKC1-based cancer treatment and its usefulness in predicting the response to chemotherapy.

DDX21 functions as a potential novel oncopromoter in pancreatic ductal adenocarcinoma: a comprehensive analysis of the DExD box family

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a highly lethal tumor with an ill-defined pathogenesis. DExD box (DDX) family genes are widely distributed and involved in various RNA metabolism and cellular biogenesis; their dysregulation is associated with aberrant cellular processes and malignancies. However, the prognostic significance and expression patterns of the DDX family in PDAC are not fully understood. The present study aimed to explore the clinical value of DDX genes in PDAC.MethodsDifferentially expressed DDX genes were identified. DDX genes related to prognostic signatures were further investigated using LASSO Cox regression analysis. DDX21 protein expression was analyzed using the UALCAN and human protein atlas (HPA) online tools and confirmed in 40 paired PDAC and normal tissues through Tissue Microarrays (TMA). The independent prognostic significance of DDX21 in PDAC was determined through the construction of nomogram models and calibration curves. The functional roles of DDX21 were investigated using gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). Cell proliferation, invasion, and migration were assessed using Cell Counting Kit-8, colony formation, Transwell, and wound healing assays.ResultsUpregulation of genes related to prognostic signatures (DDX10, DDX21, DDX60, and DDX60L) was significantly associated with poor prognosis of patients with PDAC based on survival and recurrence time. Considering the expression profile and prognostic values of the signature-related genes, DDX21 was finally selected for further exploration. DDX21 was overexpressed significantly at both the mRNA and protein levels in PDAC compared to normal pancreatic tissues. DDX21 expression, pathological stage, and residual tumor were significant independent prognostic indicators in PDAC. Moreover, functional enrichment analysis revealed that Genes co-expressed with DDX21 are predominantly involved in RNA metabolism, helicase activity, ribosome biogenesis, cell cycle, and various cancer-related pathways, such as PI3K/Akt signaling pathway and TGF-β signaling pathway. Furthermore, in vitro experiments confirmed that the knockdown of DDX21 significantly reduced MIA PaCa-2 cell viability, proliferation, migration, and invasion.ConclusionsFour signature-related genes could relatively precisely predict the prognosis of patients with PDAC. Specifically, DDX21 upregulation may signal an unfavorable prognosis by negatively affecting the biological properties of PDAC cells. DDX21 may be considered as a candidate therapeutic target in PDAC.

Single-cell RNA sequencing reveals placental response under environmental stress

The placenta is crucial for fetal development, yet the impact of environmental stressors such as arsenic exposure remains poorly understood. We apply single-cell RNA sequencing to analyze the response of the mouse placenta to arsenic, revealing cell-type-specific gene expression, function, and pathological changes. Notably, the Prap1 gene, which encodes proline-rich acidic protein 1 (PRAP1), is significantly upregulated in 26 placental cell types including various trophoblast cells. Our study shows a female-biased increase in PRAP1 in response to arsenic and localizes it in the placenta. In vitro and ex vivo experiments confirm PRAP1 upregulation following arsenic treatment and demonstrate that recombinant PRAP1 protein reduces arsenic-induced cytotoxicity and downregulates cell cycle pathways in human trophoblast cells. Moreover, PRAP1 knockdown differentially affects cell cycle processes, proliferation, and cell death depending on the presence of arsenic. Our findings provide insights into the placental response to environmental stress, offering potential preventative and therapeutic approaches for environment-related adverse outcomes in mothers and children.

Role of 14-3-3 protein family in the pathobiology of EBV in immortalized B cells and Alzheimer's disease.

Several studies have revealed that Epstein-Barr virus (EBV) infection raised the likelihood of developing Alzheimer's disease (AD) via infecting B lymphocytes. The purpose of the current investigation was to assess the possible association between EBV infection and AD. The microarray datasets GSE49628, GSE126379, GSE122063, and GSE132903 were utilized to extract DEGs by using the GEO2R tool of the GEO platform. The STRING tool was used to determine the interaction between the DEGs, and Cytoscape was used to visualize the results. The DEGs that were found underwent function analysis, including pathway and GO, using the DAVID 2021 and ClueGo/CluePedia. By using MNC, MCC, Degree, and Radiality of cytoHubba, we identified seven common key genes. Gene co-expression analysis was performed through the GeneMANIA web tool. Furthermore, expression analysis of key genes was performed through GTEx software, which have been identified in various human brain regions. The miRNA-gene interaction was performed through the miRNet v 2.0 tool. DsigDB on the Enrichr platform was utilized to extract therapeutic drugs connected to key genes. In GEO2R analysis of datasets with |log2FC|≥ 0.5 and p-value <0.05, 8386, 10,434, 7408, and 759 genes were identified. A total of 141 common DEGs were identified by combining the extracted genes of different datasets. A total of 141 nodes and 207 edges were found during the PPI analysis. The DEG GO analysis with substantial alterations disclosed that they are associated to molecular functions and biological processes, such as positive regulation of neuron death, autophagy regulation of mitochondrion, response of cell to insulin stimulus, calcium signaling regulation, organelle transport along microtubules, protein kinase activity, and phosphoserine binding. Kyoto Encyclopedia of Genes and Genomes analysis discovered the correlation between the DEGs in pathways of neurodegeneration: multiple disease, cell cycle, and cGMP-PKG signaling pathway. Finally, YWHAH, YWHAG, YWHAB, YWHAZ, MAP2K1, PPP2CA, and TUBB genes were identified that are strongly linked to EBV and AD. Three miRNAs, i.e., hsa-mir-15a-5p, hsa-let-7a-5p, and hsa-mir-7-5p, were identified to regulate most of hub genes that are associated with EBV and AD. Further top 10 significant therapeutic drugs were predicted. We have discovered new biomarkers and therapeutic targets for AD, as well as the possible biological mechanisms whereby infection with EBV may be involved in AD susceptibility for the first time.

Prognostic Significance of VAV3 Gene Variants and Expression in Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is characterized by high mortality and morbidity rates. Vav guanine nucleotide exchange factors (VAVs), crucial for signal transduction between cell membrane receptors and intracellular mediators, have been implicated in carcinogenesis. However, their potential prognostic value in RCC remains unclear. The impact of 150 common VAV polymorphisms on RCC risk and survival was investigated in a cohort of 630 individuals. Publicly available gene expression datasets were utilized to analyze VAV gene expression in relation to patient outcomes. The VAV3 rs17019888 polymorphism was significantly associated with RCC risk and overall survival after adjusting for false discovery rates. Expression quantitative trait loci analysis revealed that the risk allele of rs17019888 is linked to reduced VAV3 expression. Analysis of 19 kidney cancer gene expression datasets revealed lower VAV3 expression in RCC tissues compared to normal tissues, with higher expression correlating with better prognosis. Gene set enrichment analysis demonstrated that VAV3 negatively regulates the ubiquitin-proteasome system, extracellular matrix and membrane receptors, inflammatory responses, matrix metalloproteinases, and cell cycle pathways. Furthermore, elevated VAV3 expression was associated with increased infiltration of B cells, macrophages, and neutrophils into the RCC tumor microenvironment. Our findings suggest that VAV3 gene variants influence RCC risk and survival, contributing to a favorable prognosis in RCC.

A review of trilaciclib, a first-in-class cyclin-dependent kinase 4/6 inhibitor, for the management of metastatic small-cell lung cancer

AbstractCyclin-dependent kinases (CDKs) play a major role in regulating transitions within the cell cycle. Given the roles of CDK4/6 in promoting oncogenesis, selective inhibition of CDK4/6 has emerged as a novel approach for the treatment of breast cancer and various other tumors. While first and second generation CDK4/6 inhibitors were instrumental in targeting cell cycle pathways, they had numerous drawbacks such as limited selectivity and off-target effects. For that reason, a third generation of inhibitors was introduced and provided improved selectivity towards CDK4/6 leading to fewer side effects. To date, four compounds have been approved by the FDA as selective inhibitors of CDK4/6: palbociclib, ribociclib, abemaciclib, and trilaciclib. In this mini review, we summarize the biological, clinical, and chemical aspects of trilaciclib, a first-in-class CDK4/6 inhibitor notable for its dual role in cell cycle regulation and myelopreservation. Trilaciclib was granted FDA approval on February 2021, to improve the outcome of patients with metastatic-stage small cell lung cancer (SCLC) by protecting bone marrow suppression during chemotherapy.

Modulation of Apoptotic, Cell Cycle, DNA Repair, and Senescence Pathways by Marine Algae Peptides in Cancer Therapy.

Marine algae, encompassing both macroalgae and microalgae, have emerged as a promising and prolific source of bioactive compounds with potent anticancer properties. Despite their significant therapeutic potential, the clinical application of these peptides is hindered by challenges such as poor bioavailability and susceptibility to enzymatic degradation. To overcome these limitations, innovative delivery systems, particularly nanocarriers, have been explored. Nanocarriers, including liposomes, nanoparticles, and micelles, have demonstrated remarkable efficacy in enhancing the stability, solubility, and bioavailability of marine algal peptides, ensuring controlled release and prolonged therapeutic effects. Marine algal peptides encapsulated in nanocarriers significantly enhance bioavailability, ensuring more efficient absorption and utilization in the body. Preclinical studies have shown promising results, indicating that nanocarrier-based delivery systems can significantly improve the pharmacokinetic profiles and therapeutic outcomes of marine algal peptides. This review delves into the diverse anticancer mechanisms of marine algal peptides, which include inducing apoptosis, disrupting cell cycle progression, and inhibiting angiogenesis. Further research focused on optimizing nanocarrier formulations, conducting comprehensive clinical trials, and continued exploration of marine algal peptides holds great promise for developing innovative, effective, and sustainable cancer therapies.

Upregulation of the tumor suppressor gene LIN9 enhances tumorigenesis and predicts poor prognosis of lung adenocarcinoma

BackgroundLIN9, a gene associated with various cancers, is considered a tumor suppressor. However, the role of LIN9 in lung adenocarcinoma (LUAD) remains unknown. In this study, we aimed to assess the role of LIN9 in the occurrence and prognosis of LUAD. MethodsUsing three-tier HTSeq count RNA sequencing data from The Cancer Genome Atlas, we assessed LIN9 expression for the LUAD dataset using the DESeq2 R package and RT-qPCR experiments. Biological functions were assessed using gene set enrichment analysis (clusterProfiler and GOplot). The expression of LIN9 and the infiltration of immune cells were assessed by Single-sample gene set enrichment analysis. We conducted correlation study using clinical characteristics and receiver operating characteristic curve analysis. The predictive value of LIN9 was determined using univariate and multivariate Cox regression as well as Kaplan-Meier analysis. Additionally, functional studies were conducted to validate its role in the progression of LUAD. ResultsExpression of LIN9 was significantly elevated in LUAD, primarily influencing cell cycle, division, and signaling pathways. High LIN9 expression correlated positively with the infiltration of Th2 cells and inversely with that of plasmacytoid dendritic cells. Furthermore, LIN9 was associated with older age and advanced clinical stages, posing risks to overall, progression-free, and disease-specific survival. LIN9 served as a good diagnostic marker, particularly in females, patients aged over 65, and those with clinical N1–3 and M1 stages. Elevated LIN9 expression enhanced proliferation, migration, and invasion of LUAD cells. ConclusionHigh LIN9 expression potentially contributes to LUAD occurrence through cell cycle regulation and chromosomal modification. It promotes the malignant characteristics of LUAD cells and holds prognostic value for affected patients.

Supplementation of sodium acetate improves the growth performance and intestinal health of rabbits through Wnt/β-catenin signaling pathway.

Acetic acid, which is one of the most abundant short-chain fatty acids (SCFA) in rabbits' cecum, has been reported to play an important function during various physiological metabolic processes. The present study was conducted to elucidate the effects of sodium acetate on growth performance and intestinal health by evaluating feed intake and efficiency, diarrhea score, serum and cecum metabolites, cecal pH and SCFA, histological staining, nutritional composition of meat and gene expression profile of cecum in rabbits. As a result of sodium acetate supplement, the feed conversion ratio, diarrhea score, and diameter of muscle fiber were significantly decreased (P < 0.05). Additionally, dietary sodium acetate significantly increased in total area of muscle fibers and content of crude ash (P < 0.05). Dietary sodium acetate significantly increased serum glucose, total bile acid, and total cholesterol levels and decreased amylase, lipase, and tCO2 content (P < 0.05). Further examination suggested that sodium acetate supplementation enhanced the micro-environment of cecum, evidenced by significantly increased levels of total antioxidant capacity, total superoxide dismutase, and glutathione peroxidase, and decreased pH and amylase levels (P < 0.05). According to transcriptome sequencing of cecal tissues, differentially expressed genes were predominantly enriched in cell cycle, ABC transporters, and chemokine signaling pathways. Sodium acetate was further suggested to stimulate the proliferation and migration of rabbits' cecum epithelial cells by activating Wnt/β-catenin pathway both in vivo and in vitro. In conclusion, dietary sodium acetate supplementation improved growth performance and intestinal health in rabbits.