Risultati per: L'automisurazione della pressione arteriosa: I target pressori

Background
PARP inhibitors (PARPi) have been licensed for the maintenance therapy of patients with metastatic pancreatic cancer carrying pathogenic germline BRCA1/2 mutations. However, mutations in BRCA1/2 are notably rare in pancreatic cancer.

Objective
There is a significant unmet clinical need to broaden the utility of PARPi.

Design
RNA sequencing was performed to screen potential targets for PARPi sensitivity. The synthetic lethal effects were verified in patient-derived xenograft (PDX), xenograft and patient-derived organoid models. Mechanisms were explored via LC-MS/MS, coimmunoprecipitation, laser microirradiation, immunofluorescence, the homologous recombination (HR) or non-homologous end joining (NHEJ) reporter system, in situ proximity ligation assay and live-cell time-lapse imaging analyses.

Results
Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is an exploitable vulnerability. TPX2 was downregulated in PDX models sensitive to PARPi, and TPX2 inhibition conferred synthetic lethality to PARPi both in vitro and in vivo. Mechanistically, TPX2 functions in a cell cycle-dependent manner. In the S/G2 phase, ATM-mediated TPX2 S634 phosphorylation promotes BRCA1 recruitment to double-strand breaks (DSBs) for HR repair, whereas non-phosphorylated TPX2 interacts with 53BP1 to recruit it for NHEJ. The balance between phosphorylated and non-phosphorylated TPX2 determines the DSB repair pathway choice. During mitosis, TPX2 phosphorylation enhances Aurora A activity, promoting mitotic progression and chromosomal stability. Targeting TPX2 S634 phosphorylation with a cell-penetrating peptide causes genomic instability and mitotic catastrophe and enhances PARPi sensitivity. Additionally, the inhibition of TPX2 or S634 phosphorylation combined with gemcitabine further sensitised pancreatic cancer to PARPi.

Conclusions
Our findings revealed the dual-functional significance of TPX2 in controlling DNA DSB repair pathway choice and mitotic progression, suggesting a potential therapeutic strategy involving PARPi for patients with pancreatic cancer.

Stroke, Volume 56, Issue Suppl_1, Page A96-A96, February 1, 2025. Background:White Matter Hyperintensities (WMH) are a radiographic manifestation of cerebral small vessel disease (CSVD), representing myelin and axonal loss. Currently, no drugs specifically target or reduce the burden of WMH. Integrating genomic and proteomic data may identify proteins as potential targets to slow WMH progression. Particularly promising are proteins that serve as pathway-level hubs through which polygenic effects converge.Methods:We analyzed data from 53,014 participants enrolled in the UK Biobank. The analytical pipeline involved (Figure 1): 1) linear regression analyses between a polygenic risk score of WMH (from 27 independent variants) and normalized levels of 2,923 proteins ascertained at baseline, adjusting for age, sex, and genetic principal components; 2) evaluation of proteins selected in step 1 for association with WMH volume, ascertained through dedicated research MRIs; 3) mediation analyses to confirm that proteins with significant and directionally concordant associations with both the polygenic score and WMH are indeed mediators of the polygenic score-WMH relationship; 4) Mendelian Randomization using cis-protein quantitative trait loci as instruments to evaluate the causality between selected proteins and WMH and other clinical manifestation of CSVD. Each step was adjusted for multiple testing using Bonferroni correction.Results:Our analyses identified two proteins (Cathepsin B and ECHDC3) that met all the criteria to mediate the polygenic effect of CSVD on WMH. However, only one of these, Cathepsin B, was confirmed by Mendelian Randomization (Beta: -0.092, SE: 0.003, P

Stroke, Volume 56, Issue Suppl_1, Page A15-A15, February 1, 2025. Background:Ischemic stroke (IS) is a multifactorial disease with a significant genetic component contributing about 40% of the risk. Current prevention strategies focus on risk factor control, but integrating genomic and proteomic data could uncover key molecular targets for more effective treatments based on genetic insights.Objective:To utilize a comprehensive multi-omic approach to identify novel drug targets that mediate the genetic risk of IS.Methods:We analyzed genomic and proteomic data from 53,014 UK Biobank participants. Using a polygenic risk score (PRS) for IS from 43 independent risk variants, we deployed four analytical steps (Fig. 1, all steps corrected for multiple testing): (1) linear regression between PRS and 2,923 standardized protein levels measured at baseline, adjusted for age, sex, and genetic principal components; (2) association between selected proteins and IS; (3) Mendelian Randomization to assess causality for the proteins from (1+2), and (4) mediation to quantify the intermediary role of causal proteins in the PRS-stroke relationship. To provide clinical context, we conducted a proof-of-concept analysis using Alzheimer’s disease (AD) given APOE’s established role in AD risk.Results:We found 15 proteins that causally mediate the association between polygenic risk and IS (Fig. 2). The identified proteins are involved in cell adhesion (e.g. CD34, CD48, PODXL), inflammatory pathways (e.g. CD28, CD300A, NCR1), angiogenesis (FGF5, MET), and protein glycosylation (GALNT10, GCNT1), influencing vascular integrity, immune response, and blood vessel formation. Mediated effects range from 1-5% per protein and two proteins served as targets for existing or developing drugs (Tab. 1). As proof-of-concept, we discovered five proteins with significant mediation in AD, the strongest effect seen in APOE (10% mediated effect) and MENT (5%), confirming their known roles in neurodegenerative processes.Conclusion:This multi-omic strategy successfully identified 15 proteins mediating polygenic risk of IS, highlighting crucial pathways such as cell adhesion, inflammation, angiogenesis, and glycosylation. These findings can advance targeted therapies for stroke risk in primary prevention. Our proof-of-concept study illustrates the clinical meaning of the proteins in comparison with the known impact of APOE on AD. Future work should focus on validating these targets in clinical settings and exploring drug repurposing opportunities.

Stroke, Volume 56, Issue Suppl_1, Page AWP21-AWP21, February 1, 2025. Background and Purpose：Increasing evidence has shown that lipid metabolism disorder and oxidative stress play crucial roles in pathogenesis of ischemic stroke, both of which are closely related to ferroptosis. Edaravone dexboneol (Eda.B) is clinically used in China for acute ischemic stroke management as a brain protectant. It consists of two ingredients, edaravone and (+)-dexborneol, exerting antioxidant, free radical scavenging, and anti-inflammation. This study aimed to identify their respective specific targets and to elucidate molecular mechanisms underlying their synergistically anti-ischemic stroke effects.Methods:Ischemic stroke was induced in Male C57BL/6 mice by transient middle cerebral artery occlusion (tMCAO). Mice was injected intravenously with Eda.B upon reperfusion and then each day for consecutive 14 days. Neuroprotective effect, glial scar formation and pro-inflammatory factors levels, lipid droplets (LDs), lysosomal and mitochondrial damage were assessed. The click chemistry was applied for lysosomal heat shock protein (Hsp70) and mitochondrial voltage-dependent anion channel 2 (VDAC2) palmitoylation. The surface plasmon resonance (SPR) and biotin probe labelling and computer molecular docking were used to detect the respective target for Edaravone and dexboneol.Results:Eda.B protects neuronal cell death, and inhibits glial scar and neuroinflammation. Mechanistically, edaravone and dexboneol synergistically suppress astrocytic ferroptosis pathway and lipid metabolism disorder. Among these two components: edaravone reverses OGD/Re-induced astrocytic lipid disorder via targeting activation of mitochondrial carnitine o-palmitoyltransferase 1A (CPT1A), thereby reducing LDs accumulation and LDs-mediated Hsp70 and VDAC2 palmitoylation, protecting lysosomal and mitochondrial damage; Dexborneol targets activation of antioxidant enzyme PRDX1, which can suppress the OGD/Re-induced NLRP3 inflammasome activation and inflammation. We unexpectedly found that CPT1A can bind to and activate PRDX1. Edaravone activating CPT1A promotes the interaction between CPT1A and PRDX1, further enhancing PRDX1 activation, producing synergistically effect with dexborneol in antioxidant and anti-inflammation.Conclusions:This study demonstrates for the first time that CPT1A and PRDX1 are the key targets for edaravone and dexboneol, respectively. These two drugs enhance the interaction between CPT1A and PRDX1, causing synergistically anti-ischemic stroke effects.

Stroke, Volume 56, Issue Suppl_1, Page AWP306-AWP306, February 1, 2025. Introduction:Previous studies have suggested that increased body fat is associated with elevated cardiovascular disease (CVD) risk. We have previously shown that apart from common vascular risk factor modification, adipose tissue-specific factors, such as adiponectin, may mediate the relationship between body fat and vascular risk. Here, we use large-scale omics data to explore whether pharmacologic targeting of the adiponectin pathway may contribute to lowering CVD risk.Methods:To proxy the effect of pharmacologically perturbing the adiponectin pathway we used a drug-target mendelian randomization (MR) approach. We selected genome-wide, independent (r2 0.05). Results were consistent in sensitivity analyses. After FDR correction per proteomic dataset (p-FDR < 0.05), higher genetically-proxied,ADIPOQ-mediated circulating adiponectin levels were associated with proteins involved in various pathways including the inflammatory (e.g.CXCL17,CRP), thrombogenic (e.g. factor X, plasminogen), cardiometabolic (e.g.IGFBPL1,NOTCH3), and oncologic (e.gIL9) pathways(Figures 1, 2).Conclusions:Pharmacologic targeting of circulating adiponectin levels may be associated with decreased risk of CAD and covert brain damage. The extent that this effect is driven by pleiotropic mediatory proteomic pathways warrants further research.

Stroke, Volume 56, Issue Suppl_1, Page AWP345-AWP345, February 1, 2025. Introduction:Ischemic stroke is an acute metabolic and cerebrovascular disease that leads to high mortality and disability rate in the world. Database analysis in patients and rodents suggest Syndecan-4 (Sdc4) may play a potential role in ischemic stroke, but the underlying mechanisms remain unclear. As a kind of transmembrane core protein, Sdc4 may initiate intracellular signaling via either its protein core ectodomain or cytoplasmic domain. Therefore, it is of great significance to investigate the specific function of Sdc4 and its potential as a novel therapeutic target in ischemic stroke.Methods:The serum level of shed Sdc4 extracellular domain in patients with ischemic stroke and mice with transient middle cerebral artery occlusion (MCAO) was determined. Sdc4 global knockout mice (GKO) and their wildtype (WT) littermates were generated and subjected to MCAO to investigate whether Sdc4 deficiency alters functional outcome following ischemic stroke and its underlying mechanisms. Infarct volume, neurological deficits, neuroinflammation, and blood-brain barrier (BBB) integrity were assessed.Results:Shed Sdc4 level in the serum of both patients with ischemic stroke and mice with MCAO was decreased acutely at 24 hours after disease onset, while cerebral Sdc4 expression was significantly increased in the ipsilateral brain hemisphere of mice. Infiltrated macrophages were identified as the major cerebral source of Sdc4. Sdc4 deficiency reduced the infarct volume in mice subjected to MCAO, compared to that of the WT controls. Neurological deficit and neuroinflammation were also attenuated in Sdc4 GKO mice following MCAO. Furthermore, Sdc4 GKO mice showed an improved BBB integrity.Conclusions:These results reveal that altered serum and cerebral Sdc4 level are implicated in the pathogenesis of ischemic stroke. Genetic deletion of Sdc4 significantly prevents brain injury in mice at 24 hours following MCAO. Further investigation is warranted to explore underlying mechanisms of Sdc4 mediated brain injury in ischemic stroke.

Stroke, Volume 56, Issue Suppl_1, Page AWP218-AWP218, February 1, 2025. Background:Identifying patients likely to have significant hematoma expansion (HE) has been a challenge in clinical trials of intracerebral hemorrhage (ICH). Non-contrast CT (NCCT) markers of HE have been described. Time from symptom onset to CT affects the predictive value of these markers, with limited data in the ultra-early time period (33% or >6ml from baseline. Regression analyses were adjusted for treatment group and baseline hematoma volume.Results:There were 246 patients included in this analysis (median age 67 years, 38.8% female, median time from onset to imaging 75 min [IQR 59-88 min], 50.4% tranexamic acid), of whom 105 (42.7%) had HE on 24-hour imaging. Inter-rater agreement was excellent for all NCCT markers (kappa score >0.8). Most patients (85.7%) had ≥1 marker of HE. The most frequent marker was the swirl sign (74.3%) and the least frequent was the blend sign (7.3%) (Table 1). HE occurred more often in patients with any marker at baseline (45.5% vs 25.6%, p=0.03). The blend sign (15.2% vs 1.4%, p

Circulation, Volume 151, Issue 3, Page e30-e30, January 21, 2025.

Circulation, Ahead of Print. BACKGROUND:Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PAs) and progressive increase in pulmonary vascular resistance leading to right ventricular failure. Although several drugs are approved for the treatment of PAH, mortality rates remain high. Accumulating evidence supports a pathological function of integrins in vessel remodeling, which are gaining renewed interest as drug targets. However, their role in PAH remains largely unexplored.METHODS:The expression of the RGD (arginylglycylaspartic acid)–binding integrin α5β1 was assessed in PAs, PA smooth muscle cells, and PA endothelial cells from patients with PAH and controls using NanoString, immunoblotting, and Mesoscale Discovery assays. RNA sequencing was conducted to identify gene networks regulated by α5β1 inhibition in PAH PA smooth muscle cells. The therapeutic efficacy of α5β1 inhibition was evaluated using a novel small molecule inhibitor and selective neutralizing antibodies in Sugen/hypoxia and monocrotaline rat models, with validation by an external contract research organization. Comparisons were made against standard-of-care therapies (ie, macitentan, tadalafil) and sotatercept and efficacy was assessed using echocardiographic, hemodynamic, and histological assessments. Ex vivo studies using human precision-cut lung slices were performed to further assess the effects of α5β1 inhibition on pulmonary vascular remodeling.RESULTS:We found that the arginine-glycine-aspartate RGD-binding integrin α5β1 is upregulated in PA endothelial cells and PA smooth muscle cells from patients with PAH and remodeled PAs from animal models. Blockade of the integrin α5β1 or depletion of the α5 subunit downregulated FOXM1 (forkhead box protein M1)–regulated gene networks, resulting in mitotic defects and inhibition of the pro-proliferative and apoptosis-resistant phenotype of PAH cells. We demonstrated that α5β1 integrin blockade safely attenuates pulmonary vascular remodeling and improves hemodynamics and right ventricular function and matched or exceeded the efficacy of standard of care and sotatercept in multiple preclinical models. Ex vivo studies further validated its potential in reversing advanced remodeling in human precision-cut lung slices.CONCLUSIONS:These findings establish α5β1 integrin as a pivotal driver of PAH pathology and we propose its inhibition as a novel, safe, and effective therapeutic strategy for PAH.

Background
Tumourigenesis in right-sided and left-sided colons demonstrated distinct features.

Objective
We aimed to characterise the differences between the left-sided and right-sided adenomas (ADs) representing the early stage of colonic tumourigenesis.

Design
Single-cell and spatial transcriptomic datasets were analysed to reveal alterations between right-sided and left-sided colon ADs. Cells, animal experiments and clinical specimens were used to verify the results.

Results
Single-cell analysis revealed that in right-sided ADs, there was a significant reduction of goblet cells, and these goblet cells were dysfunctional with attenuated mucin biosynthesis and defective antigen presentation. An impairment of the mucus barrier led to biofilm formation in crypts and subsequent bacteria invasion into right-sided ADs. The regions spatially surrounding the crypts with biofilm occupation underwent an inflammatory response by lipopolysaccharide (LPS) and an apoptosis process, as revealed by spatial transcriptomics. A distinct S100A11+ epithelial cell population in the right-sided ADs was identified, and its expression level was induced by bacterial LPS and peptidoglycan. S100A11 expression facilitated tumour growth in syngeneic immunocompetent mice with increased myeloid-derived suppressor cells (MDSC) but reduced cytotoxic CD8+ T cells. Targeting S100A11 with well-tolerated antagonists of its receptor for advanced glycation end product (RAGE) (Azeliragon) significantly impaired tumour growth and MDSC infiltration, thereby boosting the efficacy of anti-programmed cell death protein 1 therapy in colon cancer.

Conclusion
Our findings unravelled that dysfunctional goblet cells and consequential bacterial translocation activated the S100A11-RAGE axis in right-sided colon ADs, which recruits MDSCs to promote immune evasion. Targeting this axis by Azeliragon improves the efficacy of immunotherapy in colon cancer.

Introduction
Preclinical studies have shown that oxygen therapy can improve ischaemic brain tissue oxygen tension, reduce reperfusion injury after revascularisation, promote neuroregeneration and inhibit inflammatory responses potentially exerting a beneficial effect after endovascular treatment (EVT) in patients with acute ischaemic stroke (AIS). However, the optimal fraction of inspired oxygen (FiO2) during EVT under general anaesthesia is currently unknown. Therefore, we are conducting a randomised controlled trial (RCT) to evaluate the impact of high-concentration oxygen vs low-concentration normobaric oxygen on early neurological function after EVT.

Methods and analysis
The Oxy-TARGET trial is an ongoing prospective, open-label, parallel-design RCT being conducted at Beijing Tiantan Hospital, Capital Medical University. It aims to enrol 200 anterior circulation AIS patients undergoing EVT under general anaesthesia between February 2024 and December 2026. Eligible participants are randomly assigned at a 1:1 ratio to receive FiO2=80% or FiO2=30% through endotracheal intubation, with the gas flow rate set at 4 L/min. The inspiratory oxygen concentration at the tracheal intubation site (delivered FiO2) was recorded concurrently. The primary outcome is the incidence of early neurological improvement (a National Institutes of Health Stroke Scale (NIHSS) score

This cohort study evaluates the use of urate-lowering therapy to achieve target serum urate levels in patients with gout and stage 3 chronic kidney disease.

Objectives
The US Preventive Services Task Force recommends screening of adults aged 35–70 with a body mass index ≥25 kg/m2 for type 2 diabetes and referral of individuals who screen positive for pre-diabetes to evidence-based prevention strategies. The diabetes burden in the USA is predicted to triple by 2060 necessitating strategic diabetes prevention efforts, particularly in areas of highest need. This study aimed to identify pre-diabetes hotspots using geospatial mapping to inform targeted diabetes prevention strategies. A ‘hotspot’ is defined as a cluster of 3 or more neighbouring census tracts with elevated pre-diabetes prevalence.

Design
A cross-sectional study using ArcGIS software to geospatially map pre-diabetes prevalence hotspots. We used health system and census data to identify pre-diabetes hotspots using a systematic five-step geoprocessing approach that made use of incremental spatial autocorrelation and Getis-Ord Gi*.

Setting
This study was set in Kaiser Permanente Northern California (KPNC), an integrated health delivery system with over four million members.

Participants
KPNC adults ages 35–70 who underwent a haemoglobin A1c (HbA1c) or fasting plasma glucose (FPG) screening test in 2019 were mapped to census tracts in Northern California. People were considered to have pre-diabetes with an HbA1c of 5.7%–6.4% (39–46 mmol/mol) or FPG 100–125 mg/dL.

Primary and secondary outcome measures
Individual and census-level characteristics were compared between hotspots and non-hotspots using 2 and Wilcoxon rank sum tests, as well as risk differences (RDs) and Hodges-Lehmann (HL) estimates of location shift. Individual-level characteristics were derived from electronic health records and administrative data, while census-level characteristics were derived from the 2019 American Community Survey.

Results
A total of 760 044 adults met the study inclusion criteria and 40% had pre-diabetes. Individuals in pre-diabetes hotspots were less likely to be non-Hispanic white (33.6% vs 50.6%, RD: –17.04%, 95% CI –17.26% to –16.81%, p

Mood disorders and DGBI are highly prevalent, commonly co-morbid and lack fully effective therapies. Although SSRIs are first line pharmacological treatments for these disorders, they may impart adverse effects including anxiety, anhedonia, dysmotility and, in children exposed in utero, an increased risk of cognitive, mood and gastrointestinal disorders. SSRIs act systemically to block SERT and enhance serotonergic signaling in the brain, intestinal epithelium and enteric neurons. Yet, the compartments that mediate the therapeutic and adverse effects of SSRIs are unknown, as is whether gestational SSRI exposure directly contributes to human DGBI development.

Background
Cholangiocarcinoma (CCA) is a very difficult-to-treat cancer. Chemotherapies are little effective and response to immune checkpoint inhibitors is limited. Therefore, new therapeutic strategies need to be identified.

Objective
We characterised the enzyme protein arginine-methyltransferase 5 (PRMT5) as a novel therapeutic target in CCA.

Design
We evaluated the expression of PRMT5, its functional partner MEP50 and methylthioadenosine phosphorylase (MTAP)—an enzyme that modulates the sensitivity of PRMT5 to pharmacological inhibitors—in human CCA tissues. PRMT5-targeting drugs, currently tested in clinical trials for other malignancies, were assessed in human CCA cell lines and organoids, as well as in two immunocompetent CCA mouse models. Transcriptomic, proteomic and functional analyses were performed to explore the underlying antitumoural mechanisms.

Results
PRMT5 and MEP50 proteins were correlatively overexpressed in most CCA tissues. MTAP was absent in 25% of intrahepatic CCA. PRMT5-targeting drugs markedly inhibited CCA cell proliferation, synergising with cisplatin and gemcitabine and hindered the growth of cholangiocarcinoma organoids. PRMT5 inhibition blunted the expression of oncogenic genes involved in chromatin remodelling and DNA repair, consistently inducing the formation of RNA loops and promoting DNA damage. Treatment with PRMT5-targeting drugs significantly restrained the growth of experimental CCA without adverse effects and concomitantly induced the recruitment of CD4 and CD8 T cells to shrinking tumourous lesions.

Conclusion
PRMT5 and MEP50 are frequently upregulated in human CCA, and PRMT5-targeting drugs have significant antitumoural efficacy in clinically relevant CCA models. Our findings support the evaluation of PRMT5 inhibitors in clinical trials, including their combination with cytotoxic and immune therapies.

Several studies have highlighted the significance of targeting fat mass and obesity-associated protein (FTO) in gastrointestinal cancers including hepatocellular carcinoma (HCC) .1 The recent study from the group of Irene Oi-Lin Ng presented in Gut by Chen et al2 introduces new insights into the molecular dynamics of HCC, focusing on the pivotal role of FTO in the disease’s pathophysiology. Functioning as an eraser of N6-methyladenosine (m6A), FTO modulates RNA stability and translation. In the context of HCC, FTO’s activity leads to the stabilisation of oncogenic transcripts, thereby promoting cancer cell proliferation and survival.3 The study identifies glycoprotein non-metastatic melanoma protein B (GPNMB) as a downstream effector of FTO (figure 1). By diminishing the m6A modification on GPNMB, FTO enhances its stability, thereby protecting it from YTHDF2-mediated degradation. This stabilisation facilitates the incorporation of GPNMB into small extracellular vesicles (sEVs), which are…