[Articles] Comparative cardiovascular effectiveness of newer glucose-lowering drugs in elderly with type 2 diabetes: a target trial emulation cohort study

In the elderly, use of GLP1-RAs and SGLT-2is was associated with reduced rates of 3P-MACE and HHF compared to DPP-4is, independent of age. SGLT-2is were also associated with reduced rates of HHF compared to GLP1-RAs, largely independent of age, in this population of individuals aged 70 years and above. This provides real-world evidence on the comparative cardiovascular effectiveness of the three most recent glucose-lowering medications and may help strengthen implementation of guidelines into clinical practice.

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Marzo 2025

Comparative effectiveness of methadone take-home dose initiation in British Columbia, Canada: protocol for a population-based retrospective cohort study using target trial guidelines

Introduction
Due to inferior safety profile and higher risk of diversion than buprenorphine/naloxone, guidelines typically recommend stringent eligibility criteria such as daily witnessed ingestion of methadone for at least 12 weeks before considering take-home doses. Recent research has focused on whether or not to initiate take-home methadone doses, often using pandemic-era data when temporary prescribing changes provided a natural experiment on the impact of access to take-home doses. However, none of these studies adequately examined the optimal timing and criteria for safely starting take-home doses to enhance treatment outcomes. To determine the optimal timing for initiating methadone take-home doses, we will compare the effects of different initiation times on time to treatment discontinuation, all-cause mortality and acute-care visits among individuals who completed methadone induction in British Columbia, Canada, from 2010 to 2022.

Methods and analysis
We propose emulating a target trial using linked population-level health administrative data for all individuals aged 18 or older living in British Columbia, Canada, completing methadone induction between 1 January 2010 and 31 December 2022. The exposure strategies will include no take-home dosing and take-home dose initiation in ≤4, 5–12, 13–24 and 25–52 weeks since completed induction. The outcomes will include the time to treatment discontinuation, all-cause mortality and acute-care visits. We propose a per-protocol analysis with a clone-censor-weighting approach to address the immortal time bias implicit in the comparison of alternative take-home dose initiation times. Subgroup and sensitivity analyses, including cohort restrictions, study timeline variations, eligibility criteria modifications and outcome reclassifications, are proposed to assess the robustness of our results.

Ethics and dissemination
The protocol, cohort creation and analysis plan have been classified and approved as a quality improvement initiative by Providence Health Care Research Ethics Board and the Simon Fraser University Office of Research Ethics. Results will be disseminated to local advocacy groups and decision-makers, national and international clinical guideline developers, presented at international conferences and published in peer-reviewed journals.

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Marzo 2025

Lipoprotein(a) as a Pharmacological Target: Premises, Promises, and Prospects

Circulation, Volume 151, Issue 6, Page 400-415, February 11, 2025. Atherosclerotic cardiovascular disease is a major health concern worldwide and requires effective preventive measures. Lp(a) (lipoprotein [a]) has recently garnered attention as an independent risk factor for astherosclerotic cardiovascular disease, with proinflammatory and prothrombotic mechanisms contributing to its atherogenicity. On an equimolar basis, Lp(a) is ~5 to 6 times more atherogenic than particles that have been widely associated with adverse cardiovascular outcomes, such as LDL (low-density lipoprotein). Lp(a) can enter the vessel wall, leading to the accumulation of oxidized phospholipids in the arterial intima, which are crucial for initiating plaque inflammation and triggering vascular disease progression. In addition, Lp(a) may cause atherothrombosis through interactions between apoA (apolipoprotein A) and the platelet PAR-1 (protease-activated receptor 1) receptor, as well as competitive inhibition of plasminogen. Because Lp(a) is mostly determined on genetic bases, a 1-time assessment in a lifetime can suffice to identify patients with elevated levels. Mendelian randomization studies and post hoc analyses of randomized trials of LDL cholesterol–lowering drugs showed a causal link between Lp(a) concentrations and cardiovascular outcomes, with therapeutic reduction of Lp(a) expected to contribute to estimated cardiovascular risk mitigation. Many Lp(a)-lowering drugs, including monoclonal antibodies, small interfering ribonucleic acids, antisense oligonucleotides, small molecules, and gene editing compounds, are at different stages of clinical investigation and show promise for clinical use. In particular, increased Lp(a) testing and treatment are expected to have a substantial impact at the population level, enabling the identification of high-risk individuals and the subsequent prevention of a large number of cardiovascular events. Ongoing phase 3 trials will further elucidate the cardiovascular benefits of Lp(a) reduction over the long term, offering potential avenues for targeted interventions and improved cardiovascular outcomes.

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Febbraio 2025

Energy management education for persons living with long COVID-related fatigue (EMERGE): protocol of a two-parallel arms target trial emulation study in a multicentre outpatient intervention setting with an online control group register

Introduction
Energy management education (EME) is a manualised, evidence-based self-management education programme developed and delivered by occupational therapists for persons living with chronic disease-related fatigue. Studies have shown that EME can positively affect self-efficacy, fatigue impact and quality of life in persons with chronic conditions, while data on persons with long COVID are lacking.
The primary aim is to evaluate if adding EME to the standard care improves outcomes in persons with long COVID-related fatigue. The secondary aim is to explore the energy management behavioural strategies applied in daily routines and investigate the influencing factors of implementing behavioural changes. The third aim is to perform a cost-effectiveness analysis of EME.

Methods and analysis
Using observational data, we will emulate a prospective two-parallel arms target trial to assess whether adding EME to the standard care is associated with improved outcomes in patients with long COVID-related fatigue. The estimated sample size to detect a post-intervention difference of 1.5 points in self-efficacy to implement energy conservation strategies with 90% power (0.05 alpha) is 122 people (1:1 ratio).
Persons with long COVID-related fatigue who follow EME as part of their standard care will be recruited and included in the experimental group (EG), while potential participants for the control group (CG) will be recruited from a register and prospectively matched to a participant in the EG by applying the propensity score technique. The ‘standard of care’ of the CG will include any intervention, except occupational therapy-based EME in peer groups. The causal contrast of interest will be the per-protocol effect. Four self-reported questionnaires (fatigue impact, self-efficacy in performing energy management strategies, competency in performing daily activities, health-related quality of life) will be administered at baseline (T0; week 0), after lesson 7 (T1; week 6), post-intervention (T2; week 14) and follow-up (T3, week 24). Our main assessment will be at T2. Disease-related and productivity cost data will be collected, and a cost-effectiveness profile of the EME intervention will be compared with standard care.

Ethics and dissemination
Ethical approval has been obtained from the competent Swiss ethics commission.
Findings will be reported (1) to the study participants; (2) to patient organisations and hospitals supporting EMERGE; (3) to funding bodies; (4) to the national and international occupational therapy community and healthcare policy; (5) will be presented at local, national, and international conferences and (6) will be disseminated by peer-review publications.

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Febbraio 2025

TPX2 serves as a novel target for expanding the utility of PARPi in pancreatic cancer through conferring synthetic lethality

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.

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Febbraio 2025

Abstract 96: Integrated Genomic and Proteomic Profiling Support Cathepsin-B as a Drug Repurposing Target in Cerebral Small Vessel Disease

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

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Gennaio 2025

Abstract 15: Integrated Genomic and Proteomic Drug Target Discovery for Ischemic Stroke

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.

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Gennaio 2025

Abstract WP21: The novel target and mechanism of clinically used Edaravone dexborneol for ischemic stroke in China

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.

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Gennaio 2025

Abstract WP306: Exploring the Cardiovascular Effect and Downstream Proteomic Signature of Pharmacologic Targeting of Circulating Adiponectin Levels in a Drug-Target Mendelian Randomization Framework

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.

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Gennaio 2025

Abstract WP345: Syndecan-4 Is a Novel Target for Protecting Brain Against Ischemic Stroke

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.

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Gennaio 2025

Abstract WP218: Non-contrast computed tomography markers of hematoma expansion in the ultra-early timeframe: a potential trial target?

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

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Gennaio 2025

Exploring Integrin α5β1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights From Comprehensive Multicenter Preclinical Studies

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.

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Gennaio 2025