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Cellular and Molecular Life Sciences :... Jun 2024Cetuximab resistance has been a major challenge for head and neck squamous cell carcinoma (HNSCC) patients receiving targeted therapy. However, the mechanism that causes...
Cetuximab resistance has been a major challenge for head and neck squamous cell carcinoma (HNSCC) patients receiving targeted therapy. However, the mechanism that causes cetuximab resistance, especially microRNA (miRNA) regulation, remains unclear. Growing evidence suggests that miRNAs may act as "nuclear activating miRNAs" for targeting promoter regions or enhancers related to target genes. This study elucidates a novel mechanism underlying cetuximab resistance in HNSCC involving the nuclear activation of KDM7A transcription via miR-451a. Herein, small RNA sequencing, quantitative real-time polymerase chain reaction (qRT‒PCR) and fluorescence in situ hybridization (FISH) results provided compelling evidence of miR-451a nuclear enrichment in response to cetuximab treatment. Chromatin isolation via RNA purification, microarray analysis, and bioinformatic analysis revealed that miR-451a interacts with an enhancer region in KDM7A, activating its expression and further facilitating cetuximab resistance. It has also been demonstrated that the activation of KDM7A by nuclear miR-451a is induced by cetuximab treatment and is AGO2 dependent. Logistic regression analyses of 87 HNSCC samples indicated the significance of miR-451a and KDM7A in the development of cetuximab resistance. These discoveries support the potential of miR-451a and KDM7A as valuable biomarkers for cetuximab resistance and emphasize the function of nuclear-activating miRNAs.
Topics: Humans; MicroRNAs; Cetuximab; Drug Resistance, Neoplasm; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Jumonji Domain-Containing Histone Demethylases; Argonaute Proteins; Animals; Mice; Cell Nucleus; Female; Mice, Nude
PubMed: 38943031
DOI: 10.1007/s00018-024-05324-x -
Scientific Reports Jun 2024Breast cancer is a prevalent and significant cause of mortality in women, and manifests as six molecular subtypes. Its further histologic classification into...
Breast cancer is a prevalent and significant cause of mortality in women, and manifests as six molecular subtypes. Its further histologic classification into non-invasive ductal or lobular carcinoma (DCIS) and invasive carcinoma (ILC or IDC) underscores its heterogeneity. The ubiquitin-proteasome system plays a crucial role in breast cancer, with inhibitors targeting the 26S proteasome showing promise in clinical treatment. The Cullin-RING ubiquitin ligases, including CUL3, have direct links to breast cancer. This study focuses on CUL3 as a potential biomarker, leveraging high-throughput sequencing, gene expression profiling, experimental and data analysis tools. Through comprehensive analysis using databases like GEPIA2 and UALCAN, as well as TCGA datasets, CUL3's expression and its association with prognostic values were assessed. Additionally, the impact of CUL3 overexpression was explored in MCF-7 and MDA-MB-231 breast cancer cell lines, revealing distinct differences in molecular and phenotypic characteristics. We further profiled its expression and localization in breast cancer tissues identifying prominent differences between luminal A and TNBC tumors. Conclusively, CUL3 was found to be associated with cell cycle progression, and DNA damage response, exhibiting diverse roles depending on the tumor's molecular type. It exhibits a tendency to act as an oncogene in triple-negative tumors and as a tumor suppressor in luminal A types, suggesting a potential significance in breast cancer progression and therapeutic directions.
Topics: Humans; Cullin Proteins; Female; Prognosis; Breast Neoplasms; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; Gene Expression Profiling; MCF-7 Cells; Triple Negative Breast Neoplasms
PubMed: 38942922
DOI: 10.1038/s41598-024-65692-z -
Communications Biology Jun 2024Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of renal cancer, accounting for over 75% of cases. The asymptomatic nature of the disease contributes...
Clear cell renal cell carcinoma (ccRCC) is the most prevalent form of renal cancer, accounting for over 75% of cases. The asymptomatic nature of the disease contributes to late-stage diagnoses and poor survival. Highly vascularized and immune infiltrated microenvironment are prominent features of ccRCC, yet the interplay between vasculature and immune cells, disease progression and response to therapy remains poorly understood. Using droplet-based single-cell RNA sequencing we profile 50,236 transcriptomes from paired tumor and healthy adjacent kidney tissues. Our analysis reveals significant heterogeneity and inter-patient variability of the tumor microenvironment. Notably, we discover a previously uncharacterized vasculature subpopulation associated with epithelial-mesenchymal transition. The cell-cell communication analysis reveals multiple modes of immunosuppressive interactions within the tumor microenvironment, including clinically relevant interactions between tumor vasculature and stromal cells with immune cells. The upregulation of the genes involved in these interactions is associated with worse survival in the TCGA KIRC cohort. Our findings demonstrate the role of tumor vasculature and stromal cell populations in shaping the ccRCC microenvironment and uncover a subpopulation of cells within the tumor vasculature that is associated with an angiogenic phenotype.
Topics: Humans; Carcinoma, Renal Cell; Kidney Neoplasms; Single-Cell Analysis; Tumor Microenvironment; Gene Expression Profiling; Phenotype; Gene Expression Regulation, Neoplastic; Endothelial Cells; Transcriptome; Epithelial-Mesenchymal Transition; Male; Female
PubMed: 38942917
DOI: 10.1038/s42003-024-06478-x -
Scientific Reports Jun 2024Salinity has become a major environmental concern for agricultural lands, leading to decreased crop yields. Hence, plant biology experts aim to genetically improve...
Salinity has become a major environmental concern for agricultural lands, leading to decreased crop yields. Hence, plant biology experts aim to genetically improve barley's adaptation to salinity stress by deeply studying the effects of salt stress and the responses of barley to this stress. In this context, our study aims to explore the variation in physiological and biochemical responses of five Tunisian spring barley genotypes to salt stress during the heading phase. Two salinity treatments were induced by using 100 mM NaCl (T1) and 250 mM NaCl (T2) in the irrigation water. Significant phenotypic variations were detected among the genotypes in response to salt stress. Plants exposed to 250 mM of NaCl showed an important decline in all studied physiological parameters namely, gas exchange, ions concentration and relative water content RWC. The observed decreases in concentrations ranged from, approximately, 6.64% to 40.76% for K, 5.91% to 43.67% for Na, 14.12% to 52.38% for Ca, and 15.22% to 38.48% for Mg across the different genotypes and salt stress levels. However, under salinity conditions, proline and soluble sugars increased for all genotypes with an average increase of 1.6 times in proline concentrations and 1.4 times in soluble sugars concentration. Furthermore, MDA levels rose also for all genotypes, with the biggest rise in Lemsi genotype (114.27% of increase compared to control). Ardhaoui and Rihane showed higher photosynthetic activity compared to the other genotypes across all treatments. The stepwise regression approach identified potassium content, K/Na ratio, relative water content, stomatal conductance and SPAD measurement as predominant traits for thousand kernel weight (R2 = 84.06), suggesting their significant role in alleviating salt stress in barley. Overall, at heading stage, salt accumulation in irrigated soils with saline water significantly influences the growth of barley by influencing gas exchange parameters, mineral composition and water content, in a genotype-dependent manner. These results will serve on elucidating the genetic mechanisms underlying these variations to facilitate targeted improvements in barley's tolerance to salt stress.
Topics: Hordeum; Salt Stress; Water; Minerals; Genotype; Salinity; Sodium Chloride
PubMed: 38942909
DOI: 10.1038/s41598-024-65967-5 -
Scientific Reports Jun 2024Preterm born (PTB) infants are at risk for injuries related to oxidative stress. We investigated the association between antioxidant and neurodevelopmental gene...
Preterm born (PTB) infants are at risk for injuries related to oxidative stress. We investigated the association between antioxidant and neurodevelopmental gene polymorphisms and oxidative stress parameters in PTB male young adults and their term-born counterparts at rest and during exercise. Healthy young PTB (N = 22) and full-term (N = 15) males underwent graded exercise tests in normobaric normoxic (FO = 0.21) and hypoxic (FO = 0.13) conditions. CAT rs1001179 was associated with decrease in nitrites in the whole group and in PTB individuals (P = 0.017 and P = 0.043, respectively). GPX1 rs1050450 was associated with decrease in ferric reducing antioxidant power in the whole group and in full-term individuals (P = 0.017 and P = 0.021, respectively). HIF1A rs11549465 was associated with decrease in nitrotyrosine and increase in malondialdehyde (P = 0.022 and P = 0.018, respectively). NOTCH4 rs367398 was associated with increase in advanced oxidation protein products and nitrites (P = 0.002 and P = 0.004, respectively) in hypoxia. In normoxia, NOTCH4 rs367398 was associated with increase in malondialdehyde in the whole group (P = 0.043). BDNF rs6265 was associated with decreased nitrites/nitrates in the whole group and in PTB individuals (P = 0.009 and P = 0.043, respectively). Polymorphisms in investigated genes and PTB might influence oxidative stress response after exercise in normoxic or hypoxic conditions far beyond the neonatal period in young male adults.
Topics: Humans; Oxidative Stress; Male; Hypoxia; Antioxidants; Polymorphism, Single Nucleotide; Young Adult; Infant, Newborn; Glutathione Peroxidase GPX1; Hypoxia-Inducible Factor 1, alpha Subunit; Catalase; Adult; Glutathione Peroxidase; Infant, Premature; Nitrites; Malondialdehyde; Tyrosine; Premature Birth
PubMed: 38942829
DOI: 10.1038/s41598-024-65647-4 -
Nature Communications Jun 2024Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic...
Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that PIKFYVE is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy. Genetic and pharmacological studies demonstrate that PIKfyve ablation enhances the function of CD11c cells (predominantly dendritic cells) via selectively altering the non-canonical NF-κB pathway. Both loss of Pikfyve in CD11c cells and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively regulates the function of CD11c cells, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.
Topics: Animals; Humans; Dendritic Cells; Mice; Phosphatidylinositol 3-Kinases; CD11c Antigen; Morpholines; Cell Line, Tumor; Immunotherapy; Neoplasms; Mice, Inbred C57BL; Female; Immune Checkpoint Inhibitors; NF-kappa B; T-Lymphocytes; Protein Kinase Inhibitors; Hydrazones; Pyrimidines
PubMed: 38942798
DOI: 10.1038/s41467-024-48931-9 -
Cell Death & Disease Jun 2024Aging and obesity pose significant threats to public health and are major contributors to muscle atrophy. The trends in muscle fiber types under these conditions and the...
Aging and obesity pose significant threats to public health and are major contributors to muscle atrophy. The trends in muscle fiber types under these conditions and the transcriptional differences between different muscle fiber types remain unclear. Here, we demonstrate distinct responses of fast/glycolytic fibers and slow/oxidative fibers to aging and obesity. We found that in muscles dominated by oxidative fibers, the proportion of oxidative fibers remains unchanged during aging and obesity. However, in muscles dominated by glycolytic fibers, despite the low content of oxidative fibers, a significant decrease in proportion of oxidative fibers was observed. Consistently, our study uncovered that during aging and obesity, fast/glycolytic fibers specifically increased the expression of genes associated with muscle atrophy and inflammation, including Dkk3, Ccl8, Cxcl10, Cxcl13, Fbxo32, Depp1, and Chac1, while slow/oxidative fibers exhibit elevated expression of antioxidant protein Nqo-1 and downregulation of Tfrc. Additionally, we noted substantial differences in the expression of calcium-related signaling pathways between fast/glycolytic fibers and slow/oxidative fibers in response to aging and obesity. Treatment with a calcium channel inhibitor thapsigargin significantly increased the abundance of oxidative fibers. Our study provides additional evidence to support the transcriptomic differences in muscle fiber types under pathophysiological conditions, thereby establishing a theoretical basis for modulating muscle fiber types in disease treatment.
Topics: Aging; Obesity; Animals; Gene Expression Profiling; Glycolysis; Male; Mice; Mice, Inbred C57BL; Muscle Fibers, Skeletal; Transcriptome; Muscle Fibers, Slow-Twitch; Humans
PubMed: 38942747
DOI: 10.1038/s41419-024-06851-y -
Aging Jun 2024Blood transfusion is a common therapeutic procedure in hospitalized patients. Red blood cell (RBC) units undergo various biochemical and morphological changes during...
BACKGROUND AND OBJECTIVES
Blood transfusion is a common therapeutic procedure in hospitalized patients. Red blood cell (RBC) units undergo various biochemical and morphological changes during storage (storage lesion). miRNAs have been studied intensively regarding cellular metabolic processes, but the effect of miRNAs on blood storage is not well defined.
MATERIALS AND METHODS
We performed bioinformatics analysis on the public data set of miRNA expression of RBC based on R language, and performed the Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis on the target genes of differentially expressed miRNA. The expression of miRNA differential genes in blood samples stored at different times was verified by qRT-PCR. Next, we used ELISA and qRT-PCR to verify the expression of IL-1β, IL-6, IL-12 and TNF-α in blood at day 1 and day 42. In addition, , we transfected macrophages with overexpressed miRNA, and the effects of overexpressed miRNA on macrophage polarization and the release of inflammatory factors were verified by flow cytometry and qRT-PCR and ELISA.
RESULTS
This study combined bioinformatics analysis and experiments to discover the differentially expressed miRNAs in long-term stored blood. The results showed that compared to fresh blood samples, the inflammatory factors were significantly doubled by ELISA, as well as the higher mRNA expression at 42 day. Experimentally verified that miR-33a-5p promoted the M1 type macrophage polarization and increased the release of related inflammatory factors through PPARα/ACC2/AMPK/CPT-1a axis regulation.
CONCLUSIONS
This study elucidates a potential mechanism of inflammatory factor accumulation in long-term stored blood, providing a theoretical basis and a potential target to prevent transfusion-related adverse reactions.
PubMed: 38942609
DOI: 10.18632/aging.205925 -
Aging Jun 2024Down Syndrome (DS) is a common genetic disorder characterized by an extra copy of chromosome 21, leading to dysregulation of various metabolic pathways. Oxidative stress...
Down Syndrome (DS) is a common genetic disorder characterized by an extra copy of chromosome 21, leading to dysregulation of various metabolic pathways. Oxidative stress in DS is associated with neurodevelopmental defects, neuronal dysfunction, and a dementia onset resembling Alzheimer's disease. Additionally, chronic oxidative stress contributes to cardiovascular diseases and certain cancers prevalent in DS individuals. This study investigates the impact of ageing on oxidative stress and liver fibrosis using a DS murine model (Ts2Cje mice). Our results show that DS mice show increased liver oxidative stress and impaired antioxidant defenses, as evidenced by reduced glutathione levels and increased lipid peroxidation. Therefore, DS liver exhibits an altered inflammatory response and mitochondrial fitness as we showed by assaying the expression of HMOX1, CLPP, and the heat shock proteins Hsp90 and Hsp60. DS liver also displays dysregulated lipid metabolism, indicated by altered expression of PPARα, PPARγ, FATP5, and CTP2. Consistently, these changes might contribute to non-alcoholic fatty liver disease development, a condition characterized by liver fat accumulation. Consistently, histological analysis of DS liver reveals increased fibrosis and steatosis, as showed by Col1a1 increased expression, indicative of potential progression to liver cirrhosis. Therefore, our findings suggest an increased risk of liver pathologies in DS individuals, particularly when combined with the higher prevalence of obesity and metabolic dysfunctions in DS patients. These results shed a light on the liver's role in DS-associated pathologies and suggest potential therapeutic strategies targeting oxidative stress and lipid metabolism to prevent or mitigate liver-related complications in DS individuals.
PubMed: 38942607
DOI: 10.18632/aging.205970 -
RMD Open Jun 2024To investigate the efficacy, safety, pharmacokinetics and pharmacodynamics of nipocalimab in participants with moderate to severe active rheumatoid arthritis (RA) and... (Randomized Controlled Trial)
Randomized Controlled Trial
Nipocalimab, an anti-FcRn monoclonal antibody, in participants with moderate to severe active rheumatoid arthritis and inadequate response or intolerance to anti-TNF therapy: results from the phase 2a IRIS-RA study.
OBJECTIVES
To investigate the efficacy, safety, pharmacokinetics and pharmacodynamics of nipocalimab in participants with moderate to severe active rheumatoid arthritis (RA) and inadequate response or intolerance to ≥1 antitumour necrosis factor agent.
METHODS
In this phase 2a study, participants with RA seropositive for anticitrullinated protein antibodies (ACPA) or rheumatoid factors were randomised 3:2 to nipocalimab (15 mg/kg intravenously every 2 weeks) or placebo from Weeks 0 to 10. Efficacy endpoints (primary endpoint: change from baseline in Disease Activity Score 28 using C reactive protein (DAS28-CRP) at Week 12) and patient-reported outcomes (PROs) were assessed through Week 12. Safety, pharmacokinetics and pharmacodynamics were assessed through Week 18.
RESULTS
53 participants were enrolled (nipocalimab/placebo, n=33/20). Although the primary endpoint did not reach statistical significance for nipocalimab versus placebo, a numerically higher change from baseline in DAS28-CRP at Week 12 was observed (least squares mean (95% CI): -1.03 (-1.66 to -0.40) vs -0.58 (-1.24 to 0.07)), with numerically higher improvements in all secondary efficacy outcomes and PROs. Serious adverse events were reported in three participants (burn infection, infusion-related reaction and deep vein thrombosis). Nipocalimab significantly and reversibly reduced serum immunoglobulin G, ACPA and circulating immune complex levels but not serum inflammatory markers, including CRP. ACPA reduction was associated with DAS28-CRP remission and 50% response rate in American College of Rheumatology (ACR) criteria; participants with a higher baseline ACPA had greater clinical improvement.
CONCLUSIONS
Despite not achieving statistical significance in the primary endpoint, nipocalimab showed consistent, numerical efficacy benefits in participants with moderate to severe active RA, with greater benefit observed for participants with a higher baseline ACPA.
TRIAL REGISTRATION NUMBER
NCT04991753.
Topics: Humans; Arthritis, Rheumatoid; Male; Female; Middle Aged; Treatment Outcome; Antirheumatic Agents; Severity of Illness Index; Antibodies, Monoclonal, Humanized; Aged; Adult; Tumor Necrosis Factor-alpha; Double-Blind Method; Patient Reported Outcome Measures; Anti-Citrullinated Protein Antibodies
PubMed: 38942592
DOI: 10.1136/rmdopen-2024-004278