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A prognostic matrix gene expression signature defines functional glioblastoma phenotypes and niches.Research Square Jun 2024. Interactions among tumor, immune, and vascular niches play major roles in driving glioblastoma (GBM) malignancy and treatment responses. The composition,...
. Interactions among tumor, immune, and vascular niches play major roles in driving glioblastoma (GBM) malignancy and treatment responses. The composition, heterogeneity, and localization of extracellular core matrix proteins (CMPs) that mediate such interactions, however, are not well understood. . Here, through computational genomics and proteomics approaches, we analyzed the functional and clinical relevance of CMP expression in GBM at bulk, single cell, and spatial anatomical resolution. . We identified genes encoding CMPs whose expression levels categorize GBM tumors into CMP expression-high (M-H) and CMP expression-low (M-L) groups. CMP enrichment is associated with worse patient survival, specific driver oncogenic alterations, mesenchymal state, infiltration of pro-tumor immune cells, and immune checkpoint gene expression. Anatomical and single-cell transcriptome analyses indicate that matrisome gene expression is enriched in vascular and leading edge/infiltrative niches that are known to harbor glioma stem cells driving GBM progression. Finally, we identified a 17-gene CMP expression signature, termed Matrisome 17 (M17) signature that further refines the prognostic value of CMP genes. The M17 signature is a significantly stronger prognostic factor compared to MGMT promoter methylation status as well as canonical subtypes, and importantly, potentially predicts responses to PD1 blockade. . The matrisome gene expression signature provides a robust stratification of GBM patients by survival and potential biomarkers of functionally relevant GBM niches that can mediate mesenchymal-immune cross talk. Patient stratification based on matrisome profiles can contribute to selection and optimization of treatment strategies.
PubMed: 38947019
DOI: 10.21203/rs.3.rs-4541464/v1 -
Research Square Jun 2024Background DNA methylation plays a critical role in asthma development, but differences in DNA methylation among adults with varying asthma severity or asthma endotypes...
Background DNA methylation plays a critical role in asthma development, but differences in DNA methylation among adults with varying asthma severity or asthma endotypes are less well-defined. Objective To examine how DNA methylomic patterns differ among adults with asthma based on asthma severity and airway inflammation. Methods Peripheral blood T cells from 35 adults with asthma in Beijing, China were serially collected over time (130 samples total) and analyzed for global DNA methylation using the Illumina MethylationEPIC Array. Differential methylation was compared among subjects with varying airway inflammation and severity, as measured by fraction of exhaled nitric oxide, forced expiratory volume in one second (FEV1), and Asthma Control Test (ACT) scores. Results Significant differences in DNA methylation were noted among subjects with different degrees of airway inflammation and asthma severity. These differences in DNA methylation were annotated to genes that were enriched in pathways related to asthma or T cell function and included gene ontology categories related to MHC class II assembly, T cell activation, interleukin (IL)-1, and IL-12. Genes related to P450 drug metabolism, glutathione metabolism, and developmental pathways were also differentially methylated in comparisons between subjects with high vs low FEV1 and ACT. Notable genes that were differentially methylated based on asthma severity included , several members of the family, , , , and several genes downstream of the and signaling pathway. Conclusion These findings demonstrate how adults with asthma of varying severity possess differences in peripheral blood T cell DNA methylation that contribute to the phenotype and severity of their overall disease.
PubMed: 38946998
DOI: 10.21203/rs.3.rs-4476948/v1 -
Research Square Jun 2024Ribosome heterogeneity has emerged as an important regulatory control feature for determining which proteins are synthesized, however, the influence of age on ribosome...
Ribosome heterogeneity has emerged as an important regulatory control feature for determining which proteins are synthesized, however, the influence of age on ribosome heterogeneity is not fully understood. Whether mRNA transcripts are selectively translated in young versus old cells and whether dysregulation of this process drives organismal aging is unknown. Here we examined the role of ribosomal RNA (rRNA) methylation in maintaining appropriate translation as organisms age. In a directed RNAi screen, we identified the 18S rRNA N6'-dimethyl adenosine (m6,2A) methyltransferase, dimt-1, as a regulator of C. elegans lifespan and stress resistance. Lifespan extension induced by dimt-1 deficiency required a functional germline and was dependent on the known regulator of protein translation, the Rag GTPase, raga-1, which links amino acid sensing to the mechanistic target of rapamycin complex (mTORC)1. Using an auxin-inducible degron tagged version of dimt-1, we demonstrate that DIMT-1 functions in the germline after mid-life to regulate lifespan. We further found that knock-down of dimt-1 leads to selective translation of transcripts important for stress resistance and lifespan regulation in the C. elegans germline in mid-life including the cytochrome P450 daf-9, which synthesizes a steroid that signals from the germline to the soma to regulate lifespan. We found that dimt-1 induced lifespan extension was dependent on the daf-9 signaling pathway. This finding reveals a new layer of proteome dysfunction, beyond protein synthesis and degradation, as an important regulator of aging. Our findings highlight a new role for ribosome heterogeneity, and specific rRNA modifications, in maintaining appropriate translation later in life to promote healthy aging.
PubMed: 38946979
DOI: 10.21203/rs.3.rs-4421268/v1 -
Research Square Jun 2024Background The demethylating agent decitabine (DAC) effectively inhibits tumor growth and metastasis by targeting ESR1 methylation to restore estrogen receptor alpha...
Background The demethylating agent decitabine (DAC) effectively inhibits tumor growth and metastasis by targeting ESR1 methylation to restore estrogen receptor alpha (ERα) signaling and promoting cellular differentiation in models of human osteosarcoma (OSA). Whether this pathway can be targeted in canine OSA patients is unknown. Methods Canine OSA tumor samples were tested for ERα expression and ESR1 promoter methylation. Human (MG63.3) and canine (MC-KOS) OSA cell lines and murine xenografts were treated with DAC and , respectively. Samples were assessed using mRNA sequencing and tissue immunohistochemistry. Results ESR1 is methylated in a subset of canine OSA patient samples and the MC-KOS cell line. DAC treatment led to enhanced differentiation as demonstrated by increased ALPL expression, and suppressed tumor growth and . Metastatic progression was inhibited, particularly in the MG63.3 model, which expresses higher levels of DNA methyltransferases DNMT1 and 3B. DAC treatment induced significant alterations in immune response and cell cycle pathways. Conclusion DAC treatment activates ERα signaling, promotes bone differentiation, and inhibits tumor growth and metastasis in human and canine OSA. Additional DAC-altered pathways and species- or individual-specific differences in DNMT expression may also play a role in DAC treatment of OSA.
PubMed: 38946977
DOI: 10.21203/rs.3.rs-4451060/v1 -
MedRxiv : the Preprint Server For... Jun 2024Epigenome-wide association studies (EWAS) aim to identify differentially methylated loci associated with complex traits and disorders. EWAS of cigarette smoking shows...
Epigenome-wide association studies (EWAS) aim to identify differentially methylated loci associated with complex traits and disorders. EWAS of cigarette smoking shows some of the most widespread DNA methylation (DNAm) associations in blood. However, traditional EWAS cannot differentiate between causation and confounding, leading to ambiguity in etiological interpretations. Here, we apply an integrated approach combining Mendelian Randomization and twin-based Direction-of-Causation analyses (MR-DoC) to examine causality underlying smoking-associated blood DNAm changes in the Netherlands Twin Register (N=2577). Evidence across models suggests that current smoking's causal effects on DNAm likely drive many of the previous EWAS findings, implicating functional pathways relevant to several adverse health outcomes of smoking, including hemopoiesis, cell- and neuro-development, and immune regulation. Additionally, we find evidence of potential reverse causal influences at some DNAm sites, with 17 of these sites enriched for gene regulatory functional elements in the brain. The top three sites with evidence of DNAm's effects on smoking annotate to genes involved in G protein-coupled receptor signaling ( , ) and innate immune response ( ), elucidating potential biological risk factors for smoking. This study highlights the utility of integrating genotypic and DNAm measures in twin cohorts to clarify the causal relationships between health behaviors and blood DNAm.
PubMed: 38946972
DOI: 10.1101/2024.06.19.24309184 -
Research Square Jun 2024Spastic cerebral palsy, the most common pediatric-onset disabling condition with an estimated prevalence of 0.2% in children, is a complex condition characterized by...
Spastic cerebral palsy, the most common pediatric-onset disabling condition with an estimated prevalence of 0.2% in children, is a complex condition characterized by stiff movement, muscle contractures, and abnormal gait that can diminish quality of life. Spastic CP accounts for approximately 83% of all CP cases and frequently co-occurs with other complex conditions, like epilepsy. An estimated 42% of spastic CP cases have co-occurring epilepsy. Unfortunately, CP is often difficult to diagnose. Although most children with CP are born with it or acquire it immediately after birth, many are not identified until after 19 months of age with CP diagnosis often not confirmed until 5 years of age. New bioinformatic approaches to identify CP earlier are needed. Recent studies indicate that altered DNA methylation patterns associated with CP may have diagnostic value. The potential confounding effects of co-occurrent epilepsy on these patterns are not known. We evaluated machine learning classification of CP patients with or without co-occurring epilepsy. Whole blood samples were collected from 30 study participants diagnosed with epilepsy (n=4), spastic CP (n=10), both (n=8), or neither (n=8). A novel Support-Vector-Machine learning algorithm was developed to identify methylation loci that have ability to classify CP from controls in the presence or absence of epilepsy. This algorithm was also employed to measure classification ability of identified methylation loci. After preprocessing of data, isolation of important methylation loci was performed in a binary comparison between CP and controls, as well as in a 4-way scheme, encapsulating epilepsy diagnoses. The classification ability was similarly assessed. CP Classification performance wasevaluated with and without inclusion of epilepsy as a feature. Median F1 scoreswere 0.67 in 4-class comparison, and 1.0 in the binary classification, outperforming Linear-Discriminant-Analysis (0.57 and 0.86, respectively). This novel algorithm was able to classify study participants with spastic CPand/or epilepsy from controls with significant performance. The algorithm shows promise for rapid identification in methylation data of diagnostic methylation loci. In this model, Support Vector Machines outperformed Linear Discriminant Analysis in classification. In the evaluation of epigenetics-based diagnostics for CP, epilepsy may not be a significant confounding factor.
PubMed: 38946953
DOI: 10.21203/rs.3.rs-4560364/v1 -
Advancing Surveillance Strategies for Hepatocellular Carcinoma: A New Era of Efficacy and Precision.Journal of Clinical and Experimental... 2024Hepatocellular carcinoma (HCC) is one of the few cancers with a 5-year survival that has remained below 20%; however, prognosis differs by tumor stage at diagnosis.... (Review)
Review
Hepatocellular carcinoma (HCC) is one of the few cancers with a 5-year survival that has remained below 20%; however, prognosis differs by tumor stage at diagnosis. Curative treatment options among patients with early-stage HCC afford a median survival of 5-10 years. Accordingly, international society guidelines recommend semi-annual HCC surveillance in at-risk patients, including those with cirrhosis or high-risk chronic hepatitis B infection. Surveillance is associated with increased early-stage HCC detection and curative treatments, leading to reduced HCC-related mortality. Abdominal ultrasound has been the cornerstone for HCC surveillance for the past two decades, but recent data have highlighted its suboptimal sensitivity for early-stage HCC detection, particularly in patients with obesity and those with non-viral etiologies of liver disease. The combination of ultrasound plus alpha fetoprotein (AFP) has higher sensitivity for early-stage HCC detection than ultrasound alone, although the combination still misses over one-third of HCC at an early stage. Emerging imaging and blood-based biomarker strategies have promising data in biomarker phase 2 (case-control) and phase 3 (cohort) studies. Beyond ultrasound, Magnetic resonance imaging (MRI) is the best-studied imaging strategy, with superior sensitivity and specificity compared to ultrasound in a cohort study. Abbreviated MRI protocols have been proposed to address concerns about MRI radiological capacity, costs, and patient acceptance. Of biomarker strategies, GALAD (a panel including gender, age, AFP, AFP-L3, and DCP) is the best validated, with promising sensitivity for early-stage HCC detection in a national multi-center cohort study. Liquid biopsy biomarkers, including methylated DNA markers, have also shown promising accuracy in case-control studies. Abbreviated MRI and GALAD are now entering prospective trials that examine clinical outcomes such as early-stage HCC detection and screening-related harms, which are essential data to understand for adoption in clinical practice. As additional surveillance strategies become available, it will allow an era of precision surveillance in which optimal surveillance modalities are tailored to individual patient risk and expected test performance.
PubMed: 38946864
DOI: 10.1016/j.jceh.2024.101448 -
RSC Advances Jun 2024Complexes tris((1-ferrocenyl-1-1,2,3-triazol-4-yl)methyl)amine (3), bis((1-ferrocenyl-1-1,2,3-triazol-4-yl)methyl)amine (6),...
Complexes tris((1-ferrocenyl-1-1,2,3-triazol-4-yl)methyl)amine (3), bis((1-ferrocenyl-1-1,2,3-triazol-4-yl)methyl)amine (6), bis((1-ferrocenyl-1-1,2,3-triazol-4-yl)methyl)ether (7), and 1-ferrocenyl-1-1,2,3-triazol-4-yl)methanamine (9) were synthesized using the copper-catalyzed click reaction. Complexes 3, 6, 7, and 9 were characterized using NMR (H and {H}) and IR spectroscopy, elemental analysis, and mass spectrometry. Structures of 3, 7, and 9 in the solid state were determined using single-crystal X-ray diffraction. It was found that the triazole rings were planar and slightly twisted with respect to the cyclopentadienyl groups attached to them. Chains and 3D network structures were observed due to the presence of π⋯π and C-H⋯N interactions between the cyclopentadienyl and triazole ligands. A reversible redox behavior of the Fc groups between 239 and 257 mV with multicycle stability was characteristic for all the compounds, revealing that the electrochemically generated species Fc remained soluble in dichloromethane. Electrochemical sensor tests demonstrated the applicability of all the complexes to enhance the quantification sensing behavior of the screen-printed carbon electrode (SPCE) toward Cd, Pb, and Cu ions.
PubMed: 38946768
DOI: 10.1039/d4ra04023f -
Chemical Communications (Cambridge,... Jul 2024Here we report stepwise methylation of end-on bridging dinitrogen to a hydrazido ligand to a pentamethylhydrazinium salt, which is mediated by a titanium system with a...
Here we report stepwise methylation of end-on bridging dinitrogen to a hydrazido ligand to a pentamethylhydrazinium salt, which is mediated by a titanium system with a tripodal aryloxide supporting ligand. The results constitute a synthetic cycle for pentamethylhydrazinium formation from dinitrogen and methyl iodide. We also describe silylation of the dinitrogen complex and carboxylation of the hydrazido complex.
PubMed: 38946396
DOI: 10.1039/d4cc02080d -
Natural Product Research Jul 2024The chemical investigation of the methanol trunk bark extract of led to the isolation of a new flavanone, 5,7,4'-trihydroxy-3',5'-bis(3-methylbutadienyl)flavanone...
The chemical investigation of the methanol trunk bark extract of led to the isolation of a new flavanone, 5,7,4'-trihydroxy-3',5'-bis(3-methylbutadienyl)flavanone (trivially named senegalensisnone) (), together with seven known compounds, abyssinone-V-4'--methyl ether (), abyssinone V (), Calopocarpin (), genistein ) mixture of stigmasterol () and -sitosterol () and -sitosterol-3---D-glucopyranoside (). The structures of the isolates were elucidated by extensive spectroscopic and spectrometric analyses (1D and 2D NMR, ESI-MS) and by comparison with previously reported data. The absolute configuration of was deduced based on comparison of its experimental CD with that of similar compound. All the compounds were tested for their antibacterial, antifungal and antioxidant activities. Compound displayed weak antibacterial activity against with MIC value of 62.5 g/mL. All the isolates were found to be inactive as antioxidant agents in the DPPH, ABTS and FRAP assays.
PubMed: 38946337
DOI: 10.1080/14786419.2024.2364258