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Pathology, Research and Practice Jun 2024Odontogenic tumors (OGTs), which originate from cells of odontogenic apparatus and their remnants, are rare entities. Primary intraosseous carcinoma NOS (PIOC), is one...
Odontogenic tumors (OGTs), which originate from cells of odontogenic apparatus and their remnants, are rare entities. Primary intraosseous carcinoma NOS (PIOC), is one of the OGTs, but it is even rarer and has a worse prognosis. The precise characteristics of PIOC, especially in immunohistochemical features and its pathogenesis, remain unclear. We characterized a case of PIOC arising from the left mandible, in which histopathological findings showed a transition from the odontogenic keratocyst to the carcinoma. Remarkably, the tumor lesion of this PIOC prominently exhibits malignant attributes, including invasive growth of carcinoma cell infiltration into the bone tissue, an elevated Ki-67 index, and lower signal for CK13 and higher signal for CK17 compared with the non-tumor region, histopathologically and immunohistopathologically. Further immunohistochemical analyses demonstrated increased expression of ADP-ribosylation factor (ARF)-like 4c (ARL4C) (accompanying expression of β-catenin in the nucleus) and yes-associated protein (YAP) in the tumor lesion. On the other hand, YAP was expressed and the expression of ARL4C was hardly detected in the non-tumor region. In addition, quantitative RT-PCR analysis using RNAs and dot blot analysis using genomic DNA showed the activation of Wnt/β-catenin signaling and epigenetic alterations, such as an increase of 5mC levels and a decrease of 5hmC levels, in the tumor lesion. A DNA microarray and a gene set enrichment analysis demonstrated that various types of intracellular signaling would be activated and several kinds of cellular functions would be altered in the pathogenesis of PIOC. Experiments with the GSK-3 inhibitor revealed that β-catenin pathway increased not only mRNA levels of ankyrin repeat domain1 (ANKRD1) but also protein levels of YAP and transcriptional co-activator with PDZ-binding motif (TAZ) in oral squamous cell carcinoma cell lines. These results suggested that further activation of YAP signaling by Wnt/β-catenin signaling may be associated with the pathogenesis of PIOC deriving from odontogenic keratocyst in which YAP signaling is activated.
PubMed: 38908335
DOI: 10.1016/j.prp.2024.155420 -
Drug Resistance Updates : Reviews and... Jun 2024Gemcitabine (GEM) based induction chemotherapy is a standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, approximately 15 % of...
Gemcitabine (GEM) based induction chemotherapy is a standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, approximately 15 % of patients are still resistant to GEM-containing chemotherapy, which leads to treatment failure. Nevertheless, the underlying mechanisms of GEM resistance remain poorly understood. Herein, based on a microarray analysis, we identified 221 dysregulated lncRNAs, of which, DYNLRB2-AS1 was one of the most upregulated lncRNAs in GEM-resistance NPC cell lines. DYNLRB2-AS1 was shown to function as contain an oncogenic lncRNA that promoted NPC GEM resistance, cell proliferation, but inhibited cell apoptosis. Mechanistically, DYNLRB2-AS1 could directly bind to the DHX9 protein and prevent its interaction with the E3 ubiquitin ligase PRPF19, and thus blocking PRPF19-mediated DHX9 degradation, which ultimately facilitated the repair of DNA damage in the presence of GEM. Clinically, higher DYNLRB2-AS1 expression indicated an unfavourable overall survival of NPC patients who received induction chemotherapy. Overall, this study identified the oncogenic lncRNA DYNLRB2-AS1 as an independent prognostic biomarker for patients with locally advanced NPC and as a potential therapeutic target for overcoming GEM chemoresistance in NPC.
PubMed: 38908233
DOI: 10.1016/j.drup.2024.101111 -
Molecular Cancer Therapeutics Jun 2024M2-like macrophages exhibit immunosuppressive activity and promote pancreatic cancer progression. Reactive oxygen species (ROS) affect macrophage polarization; however,...
M2-like macrophages exhibit immunosuppressive activity and promote pancreatic cancer progression. Reactive oxygen species (ROS) affect macrophage polarization; however, the mechanism remains unclear. This study aimed to elucidate the underlying molecular basis and design a gene therapy to inhibit M2-like polarization. Microarray analysis and IF staining were performed in M1-like and M2-like macrophages to ascertain the expression of CYBB, a major intracellular ROS source. Co-culture assay and syngeneic orthotopic pancreatic cancer mouse models were used to study the mechanism of M2-like skewing. Decoy oligodeoxynucleotides (ODNs) were designed to manipulate CYBB transcription to inhibit M2-like polarization and control tumor growth. Lipopolysaccharide (LPS) treatment polarized U937 cells to M1-like macrophages in which CYBB expression was increased. In contrast, co-culture with PANC-1 cells induced M2-like polarization in U937 cells with CYBB downregulation. High CD204 M2-like expression in combination with low CYBB expression was associated with the worst prognosis in pancreatic cancer patients. STAT6 and HDAC2 in U937 cells were activated by cancer cell-derived IL-4 after coculture and then bound to the CYBB promoter to repress CYBB expression, resulting in M2-like polarization. DPI that inhibits ROS production could block this action. Knockdown of STAT6 and HDAC2 also inhibited M2-like polarization and maintained the M1-like phenotype of U937 cells after coculture. Decoy ODNs interrupting the binding of STAT6 to the CYBB promoter counteracted M2-like polarization and tumor growth and triggered antitumor immunity in vivo. Gene therapy using STAT6-CYBB decoy ODNs can inhibit M2-like polarization, representing a potential therapeutic tool for pancreatic cancer.
PubMed: 38907533
DOI: 10.1158/1535-7163.MCT-23-0767 -
Molecular Neurobiology Jun 2024Spinal cord injury (SCI) is a serious central nervous system disease with no effective treatment strategy presently due to its complex pathogenic mechanism....
Spinal cord injury (SCI) is a serious central nervous system disease with no effective treatment strategy presently due to its complex pathogenic mechanism. N6-methyladenosine (m6A) methylation modification plays an important role in diverse physiological and pathological processes. However, our understanding of the potential mechanisms of messenger RNA (mRNA) and long non-coding RNAs (lncRNA) m6A methylation in SCI is currently limited. Here, comprehensive m6A profiles and gene expression patterns of mRNAs and lncRNAs in spinal cord tissues after SCI were identified using microarray analysis of immunoprecipitated methylated RNAs. A total of 3745 mRNAs (2343 hypermethylated and 1402 hypomethylated) and 738 lncRNAs (488 hypermethylated and 250 hypomethylated) were differentially methylated with m6A modifications in the SCI and sham rats. Functional analysis revealed that differentially m6A-modified mRNAs were mainly involved in immune inflammatory response, nervous system development, and focal adhesion pathway. In contrast, differentially m6A-modified lncRNAs were mainly related to antigen processing and presentation, the apoptotic process, and the mitogen-activated protein kinases (MAPKs) signaling pathway. In addition, combined analysis of m6A methylation and RNA expression results revealed that 1636 hypermethylated mRNAs and 262 hypermethylated lncRNAs were up-regulated, and 1571 hypomethylated mRNAs and 204 lncRNAs were down-regulated. Furthermore, we validated the altered levels of m6A methylation and RNA expression of five mRNAs (CD68, Gpnmb, Lilrb4, Lamp5, and Snap25) and five lncRNAs (XR_360518, uc.393 + , NR_131064, uc.280 - , and XR_597251) using MeRIP-qPCR and qRT-PCR. This study expands our understanding of the molecular mechanisms underlying m6A modification in SCI and provides novel insights to promote functional recovery after SCI.
PubMed: 38907070
DOI: 10.1007/s12035-024-04297-z -
Molecular Medicine Reports Aug 2024Septic acute kidney injury (AKI) is considered as a severe and frequent complication that occurs during sepsis. Mounting evidence has confirmed the pivotal pathogenetic...
Septic acute kidney injury (AKI) is considered as a severe and frequent complication that occurs during sepsis. Mounting evidence has confirmed the pivotal pathogenetic roles of microRNA (miRNA or miR) in sepsis‑induced AKI; however, the role of miRNAs and their underlying mechanisms in sepsis‑induced AKI have not been entirely understood. The present study aimed to elucidate the functions of special miRNAs during sepsis‑induced AKI and its underlying mechanism. First, a number of differently expressed miRNAs was identified based on the microarray dataset GSE172044. Subsequently, lipopolysaccharide (LPS) was used to induce AKI in mice, and the role of miR‑17‑5p on AKI was clarified. Finally, the related molecular mechanisms were further examined by western blotting and immunohistochemical analysis. MiR‑17‑5p was found to be continuously decreased and reached the bottom at h 24 after AKI in mice. Functionally, injection of agomiR‑17‑5p could observably improve renal injury and survival rate, as well as inhibit inflammatory cytokine production and renal cell apoptosis in mice after AKI. On the contrary, injection of antagomiR‑17‑5p aggravated LPS‑induced renal injury, inflammation and apoptosis in mice after AKI. Moreover, transforming growth factor β receptor 2 (TGFβR2) was identified as a direct target of miR‑17‑5p, and its downstream phosphorylated Smad3 was also suppressed by miR‑17‑5p upregulation. Taken together, these results demonstrated that miR‑17‑5p overexpression may exhibit a beneficial effect by attenuating LPS‑induced inflammation and apoptosis via regulating the TGFβR2/TGF‑β/Smad3 signaling pathway, indicating that miR‑17‑5p could act as a potential target for sepsis treatment.
Topics: Animals; MicroRNAs; Acute Kidney Injury; Sepsis; Apoptosis; Mice; Inflammation; Male; Receptor, Transforming Growth Factor-beta Type II; Lipopolysaccharides; Disease Models, Animal; Signal Transduction; Smad3 Protein; Mice, Inbred C57BL; Cytokines
PubMed: 38904199
DOI: 10.3892/mmr.2024.13263 -
International Journal of Medical... 2024Exploring potential biomarkers for predicting clinical outcomes and developing targeted therapies for acute myeloid leukemia (AML) is of utmost importance. This study...
Exploring potential biomarkers for predicting clinical outcomes and developing targeted therapies for acute myeloid leukemia (AML) is of utmost importance. This study aimed to investigate the expression pattern of the thioredoxin-interacting protein (TXNIP)/nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) pathway and its role in the prognosis of AML patients. In this study, we examined the prognostic value of TXNIP/NLRP3 pathway in AML patients using microarray data from Gene Expression Omnibus (GEO) and transcriptome data from the Cancer Genome Atlas (TCGA) to develop a prognostic model and validated the results by quantitative real-time PCR (qRT-PCR) in a validation cohort of 26 AML patients and 18 healthy individuals from Jinan University (JNU) database. Analysis of the GSE13159 database revealed that , () within the TXNIP/NLRP3 pathway were significantly upregulated and () was downregulated in AML patients (, = 0.031; , = 0.042; , = 0.038). Compared to high expression, AML patients with low expression had a longer overall survival (OS) in the GSE12417 dataset ( = 0.004). Moreover, both the training and validation results indicated that lower , , and expression were associated with favorable prognosis (GSE12417, = 0.009; TCGA, = 0.050; JNU, = 0.026). According to the receiver operating characteristic curve analysis, this model demonstrated a sensitivity of 84% for predicting three-year survival. These data might provide novel predictors for AML outcome and direction for further investigation of the possibility of using // genes in novel targeted therapies for AML.
Topics: Humans; NLR Family, Pyrin Domain-Containing 3 Protein; Leukemia, Myeloid, Acute; Carrier Proteins; Female; Male; Prognosis; Biomarkers, Tumor; Middle Aged; Interleukin-1beta; Inflammasomes; Signal Transduction; Adult; Aged; Gene Expression Regulation, Leukemic; Thioredoxins
PubMed: 38903927
DOI: 10.7150/ijms.96627 -
Frontiers in Immunology 2024Protein kinases are indispensable reversible molecular switches that adapt and control protein functions during cellular processes requiring rapid responses to internal...
INTRODUCTION
Protein kinases are indispensable reversible molecular switches that adapt and control protein functions during cellular processes requiring rapid responses to internal and external events. Bacterial infections can affect kinase-mediated phosphorylation events, with consequences for both innate and adaptive immunity, through regulation of antigen presentation, pathogen recognition, cell invasiveness and phagocytosis. (), a human respiratory tract pathogen and a major cause of community-acquired pneumoniae, affects phosphorylation-based signalling of several kinases, but the pneumococcal mediator(s) involved in this process remain elusive. In this study, we investigated the influence of pneumococcal HO on the protein kinase activity of the human lung epithelial H441 cell line, a generally accepted model of alveolar epithelial cells.
METHODS
We performed kinome analysis using PamGene microarray chips and protein analysis in Western blotting in H441 lung cells infected with wild type () or with -a deletion mutant strongly attenuated in HO production- to assess the impact of pneumococcal hydrogen peroxide (HO) on global protein kinase activity profiles.
RESULTS
Our kinome analysis provides direct evidence that kinase activity profiles in infected H441 cells significantly vary according to the levels of pneumococcal HO. A large number of kinases in H441 cells infected with are significantly downregulated, whereas this no longer occurs in cells infected with the mutant strain, which lacks HO In particular, we describe for the first time HO-mediated downregulation of Protein kinase B (Akt1) and activation of lymphocyte-specific tyrosine protein kinase (Lck) via HO-mediated phosphorylation.
Topics: Streptococcus pneumoniae; Hydrogen Peroxide; Humans; Phosphorylation; Host-Pathogen Interactions; Cell Line; Protein Kinases; Pneumococcal Infections; Signal Transduction
PubMed: 38903521
DOI: 10.3389/fimmu.2024.1414195 -
Genome Biology Jun 2024Copy number variation (CNV) is a key genetic characteristic for cancer diagnostics and can be used as a biomarker for the selection of therapeutic treatments. Using data...
BACKGROUND
Copy number variation (CNV) is a key genetic characteristic for cancer diagnostics and can be used as a biomarker for the selection of therapeutic treatments. Using data sets established in our previous study, we benchmark the performance of cancer CNV calling by six most recent and commonly used software tools on their detection accuracy, sensitivity, and reproducibility. In comparison to other orthogonal methods, such as microarray and Bionano, we also explore the consistency of CNV calling across different technologies on a challenging genome.
RESULTS
While consistent results are observed for copy gain, loss, and loss of heterozygosity (LOH) calls across sequencing centers, CNV callers, and different technologies, variation of CNV calls are mostly affected by the determination of genome ploidy. Using consensus results from six CNV callers and confirmation from three orthogonal methods, we establish a high confident CNV call set for the reference cancer cell line (HCC1395).
CONCLUSIONS
NGS technologies and current bioinformatics tools can offer reliable results for detection of copy gain, loss, and LOH. However, when working with a hyper-diploid genome, some software tools can call excessive copy gain or loss due to inaccurate assessment of genome ploidy. With performance matrices on various experimental conditions, this study raises awareness within the cancer research community for the selection of sequencing platforms, sample preparation, sequencing coverage, and the choice of CNV detection tools.
Topics: Humans; DNA Copy Number Variations; High-Throughput Nucleotide Sequencing; Software; Neoplasms; Computational Biology; Loss of Heterozygosity; Diploidy; Genome, Human; Cell Line, Tumor; Reproducibility of Results; Sequence Analysis, DNA
PubMed: 38902799
DOI: 10.1186/s13059-024-03294-8 -
BMC Bioinformatics Jun 2024Extracellular vesicle-derived (EV)-miRNAs have potential to serve as biomarkers for the diagnosis of various diseases. miRNA microarrays are widely used to quantify... (Comparative Study)
Comparative Study
BACKGROUND
Extracellular vesicle-derived (EV)-miRNAs have potential to serve as biomarkers for the diagnosis of various diseases. miRNA microarrays are widely used to quantify circulating EV-miRNA levels, and the preprocessing of miRNA microarray data is critical for analytical accuracy and reliability. Thus, although microarray data have been used in various studies, the effects of preprocessing have not been studied for Toray's 3D-Gene chip, a widely used measurement method. We aimed to evaluate batch effect, missing value imputation accuracy, and the influence of preprocessing on measured values in 18 different preprocessing pipelines for EV-miRNA microarray data from two cohorts with amyotrophic lateral sclerosis using 3D-Gene technology.
RESULTS
Eighteen different pipelines with different types and orders of missing value completion and normalization were used to preprocess the 3D-Gene microarray EV-miRNA data. Notable results were suppressed in the batch effects in all pipelines using the batch effect correction method ComBat. Furthermore, pipelines utilizing missForest for missing value imputation showed high agreement with measured values. In contrast, imputation using constant values for missing data exhibited low agreement.
CONCLUSIONS
This study highlights the importance of selecting the appropriate preprocessing strategy for EV-miRNA microarray data when using 3D-Gene technology. These findings emphasize the importance of validating preprocessing approaches, particularly in the context of batch effect correction and missing value imputation, for reliably analyzing data in biomarker discovery and disease research.
Topics: Extracellular Vesicles; MicroRNAs; Humans; Oligonucleotide Array Sequence Analysis; Amyotrophic Lateral Sclerosis; Gene Expression Profiling
PubMed: 38902629
DOI: 10.1186/s12859-024-05840-4 -
Clinical Nutrition ESPEN Aug 2024Home parenteral nutrition (HPN) is often cycled nocturnally and is expected to result in glucose intolerance and sleep disruption partly due to circadian misalignment....
Plasma metabolomics changes comparing daytime to overnight infusions of home parenteral nutrition in adult patients with short bowel syndrome: Secondary analysis of a clinical trial.
BACKGROUND
Home parenteral nutrition (HPN) is often cycled nocturnally and is expected to result in glucose intolerance and sleep disruption partly due to circadian misalignment. This study aimed to define the metabolic response when HPN is cycled during the daytime compared to overnight.
METHODS
This secondary analysis leveraged samples from a clinical trial in adults with short bowel syndrome consuming HPN (ClinicalTrials.gov: NCT04743960). Enrolled patients received 1 week of HPN overnight followed by 1 week of HPN during the daytime. Fasting blood samples were collected following each study period and global metabolic profiles were examined from plasma samples. Differential metabolite abundance was determined from normalized and scaled data using adjusted Linear Models for MicroArray Data models followed by pathway enrichment analysis.
RESULTS
Nine patients (mean age, 52.6 years; 78% female; mean BMI 20.7 kg/m) provided samples. Among 622 identified metabolites, changes were observed in 36 metabolites at P < 0.05 with higher abundance of fatty acids, long-chain and polyunsaturated fatty acids (Dihomo-gamma-linolenic acid, arachidonate (20:4n6), docosahexaenoate (DHA; 22:6n3)) and glycerolipids with daytime infusions. Enrichment analysis identified changes in pathways related to the biosynthesis of unsaturated fatty acids, d-arginine, and d-ornithine metabolism, and linoleic acid metabolism (P<0.05).
CONCLUSION
Daytime infusions of HPN may result in changes in circulating lipids and amino acid composing metabolic pathways previously implicated in circadian rhythms. As this is the first untargeted metabolomics study of HPN, larger studies are needed.
Topics: Humans; Female; Male; Middle Aged; Short Bowel Syndrome; Parenteral Nutrition, Home; Metabolomics; Adult; Circadian Rhythm
PubMed: 38901946
DOI: 10.1016/j.clnesp.2024.04.025