Search Results for: Il “grasso cattivo” impedisce alle cellule T killer di attaccare il cancro

Emilia più attrattiva. Cittadinanzattiva, nodo malattie croniche

Cnr, nuovo approccio potrebbe migliore sopravvivenza pazienti

Il focolaio di Kebsiella provocato da un nutriente parenterale

Da biopsia liquida a studio cellule epatiche, per malattie rare

Università Cattolica, usando bioinchiostri di idrogel e cellule

Focus su tumori ereditari e immunità nei contesti oncologici

Da Torino l’annuncio di un passo avanti nella lotta al cancro

La Presidenza del Consiglio aderisce a ‘Illumina novembre’

Objective
Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal cancers, marked by its lethality and limited treatment options, including the utilisation of checkpoint blockade (ICB) immunotherapy. Epigenetic dysregulation is a defining feature of tumourigenesis that is implicated in immune surveillance, but remains elusive in PDAC.

Design
To identify the factors that modulate immune surveillance, we employed in vivo epigenetic-focused CRISPR-Cas9 screen in mouse PDAC tumour models engrafted in either immunocompetent or immunodeficient mice.

Results
Here, we identified MED12 as a top hit, emerging as a potent negative modulator of immune tumour microenviroment (TME) in PDAC. Loss of Med12 significantly promoted infiltration and cytotoxicity of immune cells including CD8+ T cells, natural killer (NK) and NK1.1+ T cells in tumours, thereby heightening the sensitivity of ICB treatment in a mouse model of PDAC. Mechanistically, MED12 stabilised heterochromatin protein HP1A to repress H3K9me3-marked endogenous retroelements. The derepression of retrotransposons induced by MED12 loss triggered cytosolic nucleic acid sensing and subsequent activation of type I interferon pathways, ultimately leading to robust inflamed TME . Moreover, we uncovered a negative correlation between MED12 expression and immune resposne pathways, retrotransposon levels as well as the prognosis of patients with PDAC undergoing ICB therapy.

Conclusion
In summary, our findings underscore the pivotal role of MED12 in remodelling immnue TME through the epigenetic silencing of retrotransposons, offering a potential therapeutic target for enhancing tumour immunogenicity and overcoming immunotherapy resistance in PDAC.

Circulation, Volume 150, Issue Suppl_1, Page A4140672-A4140672, November 12, 2024. Background:osteoporosis (OP) and aortic stenosis (AS) are common in the elderly population, conferring a heavy world burden. Several epidemiological studies show a correlation between AS and OP independent of aging. However, the molecular and cellular mechanisms underlying stenotic calcification and OP remain poorly understood. Herein, this study aimed to identify crosstalk genes between OP and AS and potential mechanism.Method:AS and OP datasets were downloaded from the GEO database and were performed Weighted Gene Co-Expression Network Analysis (WGCNA) to get common key genes, and differential expression analysis to get common differentially expressed genes (DEGs). We also analyzed the protein–protein interactions (PPIs) of the common key genes and DEGs using the NetworkAnalyst online tool to find the intersection of correlated genes in OP and AS, the top 20 genes in each algorithm were selected as the candidate genes and the genes were calculated by more than six algorithms at the same time were chosen as candidate genes. We downloaded genes related to AS in the Comparative Toxicogenomics Database (CTD) to get the intersection with candidate genes as hub genes. The hub genes were certified in another OP dataset and AS dataset downloaded from GEO respectively.Result:665 common Genes from WGCNA, which were enriched in the myeloid leukocyte activation, secretory granule membrane, cell adhesion molecules.13 of them were screened as candidate genes by 12 prediction algorithms in the Cytoscape. 161 common DEGs were differentiated in another AS database and OP database, which were enriched in natural killer cell mediated immunity, collagen-containing extracellular.19 genes were recognized as candidate genes by Cytoscape in the same way. 15 hub genes were selected by intersecting with candidate genes and genes downloaded from CTD as hub genes, including CD226, CD247, CD38, CD4, CD96, FCGR2B, GNG2, GRB2, GAMB, HSD17B6, ITGB2, KSD17B6, ITGB2, KLRB1, NGF, PECAM1, SDC1. The transcription factors hub genes interaction network was constructed using TRRUST. Hub genes were certified in another AS and OP dataset. CD4, GZMB, SDC1 are upregulated remarkably in AS dataset, whereas SDC1 and ITGB2 are downregulated and GZMB is upregulated in OP dataset.Conclusion:GZMB, SDC1may be potential hub genes in AS and OP, through bioinformatic analysis, we identified potential biomarkers and therapeutic targets for AS and OP, providing a theoretical basis for future studies.

Circulation, Volume 150, Issue Suppl_1, Page AOr107-AOr107, November 12, 2024. Background:Innate T cells have both deleterious and protective roles in a range of diseases. Natural killer T (NKT) cells are a major type of innate T cell, but their role and clinical relevance after cardiac arrest (CA) are undefined.Hypothesis:In patients after CA, an early increase in diverse NKT (dNKT) cells correlates with good neurological outcomes. dNKT cells improve outcomes after CA by reducing inflammatory responses in the brain.Aims:To investigate the clinical relevance of dNKT cells after out-of-hospital CA (OHCA) and their roles in a murine CA model.Methods:A clinical retrospective cohort study of complete blood cell counts with differentials after OHCA. Single-cell RNA-seq and flow cytometry of circulating T cells in OHCA patients. Good neurological outcomes were defined as a Cerebral Performance Category of 1 or 2 at 30 days post-CA. Single-nucleus RNA-sequencing(-seq) of hippocampal cells (50,332 nuclei), RT-PCR, and flow cytometry of the brain 24 hours post-CA in mice.Results:In a large OHCA patient cohort (N=1,955), the percentage of lymphocytes early (less than 12 hours) after CA was independently associated with good neurological outcomes (adjusted odds ratio [95%CI], 1.08 [1.03-1.14], P=0.005). Transcriptional profiling of T cells in OHCA patients at single-cell resolution showed an increase in an innate T cell-like NCAM1+subset in patients with good neurological outcomes. This subset expressed cytotoxic, cytokine, and chemokine genes. Flow cytometry identified an early increase in circulating dNKT cells in patients with good neurological outcomes post-CA. In a murine model of CA, type II dNKT cells migrated to the brain after CA. NKT cell-deficient mice (Cd1d-/-) had increased neuronal injury and mortality after CA. Cd1d-/-mice had increased molecular and cellular inflammation compared to wild-type mice 24 hours post-CA. Global transcriptomic analysis of murine brain at single-nucleus resolution indicated NKT cells suppressed inflammatory axes post-CA in multiple cell types, including astrocytes, microglia, and inhibitory neurons. Treatment with sulfatide (a lipid antigen for dNKT cells) improved neurological function after CA.Conclusions:Early abundance of dNKT cells was associated with good neurological outcomes after OHCA. dNKT cells are neuroprotective after CA by suppressing inflammatory axes in the brain. Immunomodulation of dNKT cells via endogenous lipids is a potential treatment approach after CA.

Circulation, Volume 150, Issue Suppl_1, Page A4138570-A4138570, November 12, 2024. Introduction:Sepsis and systolic heart failure (sHF) often prompt hospitalization and require near diametrically opposite treatment strategies. We, therefore, studied whether sHF would impact outcomes in patients with sepsis spectra.Methods:We examined the National Inpatient Sample 2021 for adults admitted with sepsis spectra (sepsis, severe sepsis, and septic shock). We compared patients with sHF vs those without. STATA 18thedition was used for analyses. Age, gender, race, hypertension, diabetes, obesity, dyslipidemia, and Elixhauser comorbidity index were identified as confounders by univariate analyses and tested further with multivariate logistic regression models. The primary outcome was mortality. Secondary outcomes were the need for intubation, cardiac arrest, length of stay (LOS), and total hospital charges.Results:In 2021, nationwide, 3,030,351 adults were admitted for sepsis spectra, and 209,134 (6.9%) had concomitant sHF. Patients with sHF and sepsis spectra (as compared to those without sHF) were less likely female (35.5% vs. 48%), had a substantially higher likelihood of a prior MI, and nearly 50% were diabetic and hyperlipidemic with a higher comorbidity index. Baseline characteristics are in the Table.Sepsis and sHF resulted in substantially higher mortality (22.7%) as compared to patients with sepsis alone (14.9%) adjusted odds ratio (aOR) of 1.11 (CI 1.08-1.14; p-value < 0.001). Patients with sepsis and sHF were more likely to require intubation 22.2% vs. 14.0% aOR 1.21 (CI 1.18-1.25; p-value < 0.001), had more cardiac arrest 7.7% vs. 4.0% aOR 1.38 (CI 1.32-1.44; p-value < 0.001), and a longer LOS (11.9 vs 9.4 days adjusted incidence rate ratio (aIRR) 1.06; CI 1.05 – 1.08; p-value < 0.001). Consequently, total hospital charges were also higher, $189,415 vs $133,720, aIRR 1.15 (CI 1.13-1.18; p-value < 0.001).Conclusion:In 2021, nationwide, sepsis spectra remain a major cause of in-patient mortality. We demonstrate that the coexistence of systolic heart failure and sepsis dramatically worsens complications, mortality, and total hospital costs. This study is a call to action for the in-depth analyses of this very high-risk group of patients.

Circulation, Volume 150, Issue Suppl_1, Page A4142260-A4142260, November 12, 2024. Background:Congenital heart diseases (CHD) are the most common birth defects. Previous studies have revealed the susceptibility of CHD patients to immunodeficiency; however, the heterogeneity of immune cells landscape underlying CHD patients remains poorly understood.Research question:Are peripheral blood mononuclear cells dysregulated in pediatric CHD patients?Aims:We aimed to investigate the landscape of peripheral blood mononuclear cells in CHD patients with conotruncal defects by comparison against healthy controls.Methods:Peripheral blood samples were collected in 5 patients with conotruncal defects and 3 healthy children. We conducted single-cell transcriptome analysis on peripheral blood mononuclear cells from these samples.Results:The scheme of whole study was shown in Figure 1A. A total of 44,530 cells were identified after quality-control, clustered into 8 groups, and annotated with canonical PBMC markers (Figure 1B). Compared with healthy controls, patients were characterized with a prominent decrease in natural killer T (NKT) cells and an increased proportion of monocytes were observed (Figure 1C). Zooming into NK-like cells confirmed a significant contribution of NKT cells in difference between groups, whilst other types were similar in both groups (Figure 2A). The differentially expressed gene in NKT were enriched in pathway involving T helper cells differentiation, signal transduction and regulation (Figure 2B). Furthermore, NKT in patients showed a significantly lower proliferation score in contrast with a higher apoptosis score (Figure 2C&D). Although monocytes in patients were more in quantity, the composition of CD14+and CD16+subtypes were comparable between groups (Figure 3A). Concordantly, apoptosis score of monocytes were similar. However, the T cell proliferation score was lower in case group (Figure 3B&C). In addition, CD14+and CD16+monocytes both showed distinct transcriptome between groups and the differentially expressed genes were prevalently enriched in inflammation-related pathways (Figure 3D&E).Conclusion:Single-cell analysis revealed a dysregulated PBMC landscape in pediatric patients with conotruncal defects, exhibiting a prominent decrease in NKT population and an increased proportion of monocytes. Transcriptome analysis further indicated a less mature immune phenotype in NKT and monocytes differentiation. Future study is warranted to further investigate the roles of these cells on immunoregulation in these patients.