搜索结果：Cardiovascular & hematological disorders drug targets

Blood diseases, such as leukemia, and particularly acute myeloid leukemia (AML), bring a severe burden on patients, while conventional therapies are often limited by poor target specificity, toxicity and drug resistance. This underscores the urgent need for innovative strategies in drug discovery. Computer-aided drug design (CADD) integrates computational biology, quantum chemistry, and systems pharmacology, has potential to meet this need. CADD employs advanced computational techniques such as molecular docking, molecular dynamics and virtual screening to accelerate drug design and screening through the more accurate prediction of ligands-targets binding affinities and high-throughput screening. The integrate of artificial intelligence (AI) with CADD has further improve the efficiency, speed and accuracy of drug design and screening through improved drugs-targets binding prediction, better structures optimization, and faster screening in AML drug development. This review delineates the mechanistic principles underlying major CADD methods and highlights their latest applications for AML-targeted therapeutics such as developing the next generation highly selective FMS-like tyrosine kinase 3 (FLT3) inhibitors, de novo design of inhibitors for novel targets like methyltransferase-like 3 (METTL3), and overcoming acquired drug resistance. Finally, we propose a future direction of personalized precision treatment assisted by CADD and AI driven models for drug response prediction and drugs combination recommendation. This review aims to serve as a key reference and inspiration for scientists working at the intersection of AI, CADD and AML drug discovery.

Leukemia is a malignancy of the hematopoietic system, and as its pathogenesis has become better understood, three generations of tyrosine kinase inhibitors (TKIs) have been developed. Ponatinib is the third-generation breakpoint cluster region (BCR) and Abelson (ABL) TKI, which has been influential in the leukemia therapy for a decade. Moreover, ponatinib is a potent multi-target kinase inhibitor that acts on various kinases, such as KIT, RET, and Src, making it a promising treatment option for triple-negative breast cancer (TNBC), lung cancer, myeloproliferative syndrome, and other diseases. The drug's significant cardiovascular toxicity poses a significant challenge to its clinical use, requiring the development of strategies to minimize its toxicity and side effects. In this article, the pharmacokinetics, targets, therapeutic potential, toxicity and production mechanism of ponatinib will be reviewed. Furthermore, we will discuss methods to reduce the drug's toxicity, providing new avenues for research to improve its safety in clinical use.

The six global nutrition targets (GNTs) related to low birthweight, exclusive breastfeeding, child growth (ie, wasting, stunting, and overweight), and anaemia among females of reproductive age were chosen by the World Health Assembly in 2012 as key indicators of maternal and child health, but there has yet to be a comprehensive report on progress for the period 2012 to 2021. We aimed to evaluate levels, trends, and observed-to-expected progress in prevalence and attributable burden from 2012 to 2021, with prevalence projections to 2050, in 204 countries and territories. The prevalence and attributable burden of each target indicator were estimated by age group, sex, and year in 204 countries and territories from 2012 to 2021 in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021, the most comprehensive assessment of causes of death, disability, and risk factors to date. Country-specific relative performance to date was evaluated with a Bayesian meta-regression model that compares prevalence to expected values based on Socio-demographic Index (SDI), a composite indicator of societal development status. Target progress was forecasted from 2021 up to 2050 by modelling past trends with meta-regression using a combination of key quantities and then extrapolating future projections of those quantities. In 2021, a few countries had already met some of the GNTs: five for exclusive breastfeeding, four for stunting, 96 for child wasting, and three for child overweight, and none met the target for low birthweight or anaemia in females of reproductive age. Since 2012, the annualised rates of change (ARC) in the prevalence of child overweight increased in 201 countries and territories and ARC in the prevalence of anaemia in females of reproductive age decreased considerably in 26 countries. Between 2012 and 2021, SDI was strongly associated with indicator prevalence, apart from exclusive breastfeeding (|r-|=0·46-0·86). Many countries in sub-Saharan Africa had a decrease in the prevalence of multiple indicators that was more rapid than expected on the basis of SDI (the differences between observed and expected ARCs for child stunting and wasting were -0·5% and -1·3%, respectively). The ARC in the attributable burden of low birthweight, child stunting, and child wasting decreased faster than the ARC of the prevalence for each in most low-income and middle-income countries. In 2030, we project that 94 countries will meet one of the six targets, 21 countries will meet two targets, and 89 countries will not meet any targets. We project that seven countries will meet the target for exclusive breastfeeding, 28 for child stunting, and 101 for child wasting, and no countries will meet the targets for low birthweight, child overweight, and anaemia. In 2050, we project that seven additional countries will meet the target for exclusive breastfeeding, five for low birthweight, 96 for child stunting, nine for child wasting, and one for child overweight, and no countries are projected to meet the anaemia target. Based on current levels and past trends, few GNTs will be met by 2030. Major reductions in attributable burden for exclusive breastfeeding and anthropometric indicators should be recognised as huge scientific and policy successes, but the comparative lack of progress in reducing the prevalence of each, along with stagnant anaemia in women of reproductive age and widespread increases in child overweight, suggests a tenuous status quo. Continued investment in preventive and treatment efforts for acute childhood illness is crucial to prevent backsliding. Parallel development of effective treatments, along with commitment to multisectoral, long-term policies to address the determinants and causes of suboptimal nutrition, are sorely needed to gain ground. Bill & Melinda Gates Foundation.

Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of patients with chronic myeloid leukemia (CML). However, few patients maintain remission after discontinuing TKIs, and most require long-term treatment. Prolonged use of TKIs is associated with an increased risk of cardiovascular events (CVEs), particularly in patients with pre-existing cardiovascular comorbidities. We present the case of a 37-year-old man with a decade-long history of severe dilated cardiomyopathy that responded inadequately to standard pharmacologic management, who was under consideration for heart transplantation. Following a diagnosis of CML, the patient experienced various CVEs with TKIs, including dasatinib, bosutinib, imatinib, and nilotinib. These agents were discontinued, and treatment was switched to asciminib, a novel agent that targets the myristoyl pocket of the BCR::ABL1 protein distinct from the ATP-binding site targeted by conventional TKIs. This treatment was well tolerated without any CVEs. Given its minimal off-target activity and lower reported incidence of CVEs, asciminib may offer a viable and safer therapeutic option for CML patients with advanced cardiovascular comorbidities, including those awaiting heart transplantation.

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is a fundamental intracellular mechanism that mediates cytokine and growth factor signaling. Dysregulation of this pathway through genetic mutations, polymorphisms, or persistent activation has been strongly associated with autoimmune diseases, inflammatory disorders, and a wide range of hematologic and solid malignancies. Consequently, the JAK/STAT pathway has emerged as a major therapeutic and diagnostic target in precision medicine. This review synthesizes evidence from experimental, translational, and clinical studies addressing the molecular structure, activation mechanisms, and regulatory control of JAK and STAT proteins. Aberrant JAK/STAT signaling contributes significantly to the pathogenesis of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, as well as malignancies including myeloproliferative neoplasms, lymphomas, and breast cancer. Somatic mutations, transcriptional activation signatures, and phosphorylated STAT proteins serve as valuable diagnostic and prognostic biomarkers. JAK inhibitors, including ruxolitinib and tofacitinib, demonstrate clinical efficacy; however, treatment resistance, adverse effects, and incomplete disease modification remain significant challenges. The involvement of JAK/STAT signaling in metabolic, cardiovascular, and neuroinflammatory diseases remains insufficiently explored. Predictive biomarkers for patient stratification and long-term treatment outcomes are not yet fully established. This review is limited by reliance on heterogeneous published data and the scarcity of long-term clinical trials validating biomarker utility and resistance mechanisms. This review uniquely integrates the molecular structure, regulatory mechanisms, diagnostic biomarkers, therapeutic targeting, and resistance mechanisms of the JAK/STAT pathway across autoimmune diseases and malignancies. The JAK/STAT pathway is a central regulator of immune and inflammatory signaling with broad clinical relevance. The continued integration of molecular diagnostics, novel STAT-targeted agents, and combination therapies is essential for improving therapeutic precision and clinical outcomes.

Doxorubicin (DOX) is widely used as a chemotherapeutic agent for both hematologic and solid tumors and is a reasonable candidate for glioma treatment. However, its effectiveness is hindered by significant toxicity and drug resistance. Moreover, the presence of the blood-brain barrier (BBB) brings a crucial challenge to glioma therapy. In response, a GSH-responsive and actively targeted nanoprodrug delivery system (cRGD/PSDOX-Cur@NPs) are developed. In this system, a disulfide bond-bridged DOX prodrug (PEG-SS-DOX) is designed to release specifically in the high glutathione (GSH) tumor environment, markedly reducing the cardiotoxicity associated with DOX. To further address DOX resistance, curcumin, serving as a P-glycoprotein (P-gp) inhibitor, effectively increased cellular DOX concentration. Consequently, cRGD/PSDOX-Cur@NPs exhibited synergistic anti-tumor effects in vitro. Furthermore, in vivo experiments validated the superior BBB penetration and brain-targeting abilities of cRGD/PSDOX-Cur@NPs, showcasing the remarkable potential for treating both subcutaneous and orthotopic gliomas. This research underscores that this nanoprodrug delivery system presents a novel approach to inhibiting glioma while addressing resistance and systemic toxicity.

Ibrutinib and acalabrutinib are first- and next-generation Bruton Tyrosine Kinase inhibitors (BTKi), respectively, approved for chronic lymphocytic leukemia (CLL). Ibrutinib has been associated with cardiovascular events, including atrial fibrillation (AF) and hypertension. Acalabrutinib has demonstrated non-inferior progression-free survival than ibrutinib in relapsed/refractory CLL patients, with a lower cardiovascular event incidence. These adverse events seem to be derived from off-targets rather than BTK inhibition. Machine learning algorithms were applied to identify targets likely to trigger AF and hypertension in simulated CLL patients receiving acalabrutinib or ibrutinib. Common ibrutinib and acalabrutinib off-targets showed association with AF through structural remodeling and electrophysiology/ectopic activity mechanisms (TEC and ERBB4). There was association with hypertension through inflammation (ERBB4) and oxidative stress and endothelial dysfunction (ERBB4 and RIPK2). Ibrutinib-specific off-targets showed association with AF through structural remodeling (HCK, FGR, LYN, FYN, YES1, and FLT3) and electrophysiology activity (LYN and SRC), and with hypertension through inflammation (LCK, JAK3, and FLT3) and oxidative stress and endothelial dysfunction (ERBB2, BLK, SRC, and CSK). No acalabrutinib-specific off-targets were identified for AF or hypertension. This study supports that BTKi off-target selectivity may justify the different AF and hypertension incidences, suggesting their association with several ibrutinib-specific off-targets and identifying no acalabrutinib-specific ones.

FLT3 is mainly expressed in immune and various cancer cells and is a drug target for acute myeloid leukemia (AML). Recently, FLT3 has also been identified as a potential target for treating chronic pain. Most FLT3 inhibitors (FLT3i) identified to date, including approved drugs such as gilteritinib, midostaurin, ponatinib, quizartinib, and FLT3i in clinical trials, such as quizartinib and crenolanib, also inhibit closely-related kinases that are important for immune (c-KIT), cardiovascular (KDR/VEGFR2, FGFR, PDGFR) or kidney (RET) functions. While the aforementioned FLT3i may increase survival rates in AML, they are neither ideal for AML maintenance therapy nor for non-oncology applications, such as for the treatment of chronic pain, due to their promiscuous inhibition of many kinase anti-targets. Here, we report the identification of new FLT3i compounds that have low activities against kinases that have traditionally been difficult to differentiate from FLT3 inhibition, such as KDR/VEGFR, FGFR, PGFR, c-KIT, and RET. These selective compounds could be valuable chemical probes for studying FLT3 biology in the context of chronic pain and/or may represent good starting points to develop well-tolerated FLT3 therapeutics for non-oncology indications or for maintenance therapy for AML.

Molecular docking is a computational technique that predicts the binding affinity of ligands to receptor proteins. Although it has potential uses in nutraceutical research, it has developed into a formidable tool for drug development. Bioactive substances called nutraceuticals are present in food sources and can be used in the management of diseases. Finding their molecular targets can help in the creation of disease-specific new therapies. The purpose of this review was to explore molecular docking's application to the study of dietary supplements and disease management. First, an overview of the fundamentals of molecular docking and the various software tools available for docking was presented. The limitations and difficulties of using molecular docking in nutraceutical research are also covered, including the reliability of scoring functions and the requirement for experimental validation. Additionally, there was a focus on the identification of molecular targets for nutraceuticals in numerous disease models, including those for sickle cell disease, cancer, cardiovascular, gut, reproductive, and neurodegenerative disorders. We further highlighted biochemistry pathways and models from recent studies that have revealed molecular mechanisms to pinpoint new nutraceuticals' effects on disease pathogenesis. It is convincingly true that molecular docking is a useful tool for identifying the molecular targets of nutraceuticals in the management of diseases. It may offer information about how nutraceuticals work and support the creation of new therapeutics. Therefore, molecular docking has a bright future in nutraceutical research and has a lot of potentials to lead to the creation of brand-new medicines for the treatment of disease.

Our aim was to gain deeper insight into the genetic susceptibility of iron deficiency anemia (IDA). We performed the first multi-ancestry meta-analysis of genome-wide association study (GWAS), which included 113 055 IDA cases and 1 783 936 healthy controls. Through multi-ancestry meta-analysis, 31 risk loci were identified, alongside 703 candidate genes indicated and 47 genes prioritized for IDA. Heritability analyses demonstrated that the liability scale heritability was 3.1% ± 0.2%, whereas an estimated 43.92 million effective sample size would be required to explain 90% of the phenotypic variance. Gene enrichment analysis, gene-set analyses, and genetic correlation studies revealed that IDA-related genes were enriched in whole blood, influenced the role of HFE (hemochromatosis gene) in regulating systemic iron homeostasis, and showed positive correlations with inflammatory diseases, psychological diseases, and cardiovascular diseases. Finally, gene-based prioritized analysis and gene-drug interaction analysis identified some potential targets (e.g., BLK), while drug repurposing approaches highlighted exploratory drug candidates (e.g., folic acid) for IDA. We identified 31 novel risk loci for IDA and further characterized its genetic architecture.

Activating mutations of Src homology-2 domain-containing protein tyrosine phosphatase-2 (Shp2) cause multiple childhood conditions for which there is an unmet therapeutic need, including juvenile myelomonocytic leukemia (JMML) and Noonan syndrome. SFX-01, an α-cyclodextrin-stabilized sulforaphane complex currently in clinical development, covalently adducts cysteine residues. Using unbiased proteomics, its protein targets were identified, including Shp2. SFX-01 induced an inhibitory dithiolethione modification at the Shp2 active site cysteine. Importantly, in a transgenic mouse model of human Noonan syndrome with hyperactive D61G Shp2, SFX-01 concomitantly normalized their phosphatase activity and myeloid cell count. Furthermore, SFX-01 also attenuated JMML human patient-derived hematopoietic stem cell proliferation that was linked to STAT1 signaling and decreased cyclin D1 expression, resulting in cell-cycle arrest. We conclude that SFX-01 is an activating mutant Shp2 inhibitor and may offer beneficial effects in patients with JMML or Noonan syndrome.

Cardiotoxicity has emerged as a serious outcome catalyzed by various therapeutic targets in the field of cancer treatment, which includes chemotherapy, radiation, and targeted therapies. The growing significance of cancer drug-induced cardiotoxicity (CDIC) and radiation-induced cardiotoxicity (CRIC) necessitates immediate attention. This article intricately unveils how cancer treatments cause cardiotoxicity, which is exacerbated by patient-specific risks. In particular, drugs like anthracyclines, alkylating agents, and tyrosine kinase inhibitors pose a risk, along with factors such as hypertension and diabetes. Mechanistic insights into oxidative stress and topoisomerase-II-B inhibition are crucial, while cardiac biomarkers show early damage. Timely intervention and prompt treatment, especially with specific agents like dexrazoxane and beta-blockers, are pivotal in the proactive management of CDIC.

While it is widely accepted that intravenous (IV) iron improves functional capacity, symptoms, and cardiovascular outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF) diagnosed with iron deficiency (ID), three recently published cardiovascular outcome trials (AFFIRM-AHF, IRONMAN and HEART-FID) of IV iron supplementation in HF failed to demonstrate a significant benefit on their respective primary endpoints. Dosing of IV iron after the initial correction of baseline ID&#xa0;-&#xa0;by design or as a result of trial circumstances&#xa0;-&#xa0;was relatively low (i.e. <500&#x2009;mg/year). The primary objective of the FAIR-HF2 trial is to evaluate the treatment effect of ferric carboxymaltose (FCM) compared with placebo in ambulatory patients with HFrEF using a higher dose of IV iron during follow-up (i.e. >1000&#x2009;mg/year). The second objective of the study is to create prospective evidence for patients fulfilling the new definition of ID for patients with HF, i.e. for those with a transferrin saturation&#x2009;<20%. FAIR-HF2 is an investigator-initiated, multicentre, randomized, double-blind, placebo-controlled trial that has recruited 1105 patients with chronic HF with a left ventricular ejection fraction of &#x2264;45% and concomitant ID, defined as serum ferritin <100&#x2009;ng/ml or serum ferritin 100-299&#x2009;ng/ml with a transferrin saturation&#x2009;<20%. Patients were consented and randomized to receive either IV FCM (treatment) or saline (placebo). During an estimated median follow-up of over 2&#x2009;years, patients underwent a placebo-controlled repletion and maintenance phase, with an initial iron supplementation of up to 2000&#x2009;mg, followed by 500&#x2009;mg every 4&#x2009;months unless stop criteria of haemoglobin >16&#x2009;mg/dl or serum ferritin >800&#x2009;ng/ml are met on repeat visits. The trial will evaluate three primary hypotheses: (i) time to first event of cardiovascular death or hospitalization for HF, (ii) the rate of total (first and recurrent) HF hospitalizations (both analysed in the full study population), and (iii) the time to first event of cardiovascular death or hospitalization for HF in patients with a transferrin saturation&#x2009;<20% at baseline. The familywise type I error rate across the three primary endpoint hypotheses will be controlled using the Hochberg procedure (alpha 0.05). The FAIR-HF2 will evaluate the efficacy of FCM in patients with HFrEF in improving cardiovascular outcomes by utilizing a more aggressive approach towards iron supplementation ensuring prevention of transitional ID after initial repletion targets have been met.

Backgrounds/Objectives: Abnormal platelet functions are associated with human morbidity and mortality. Platelets have emerged as critical regulators of numerous physiological and pathological processes beyond their established roles in hemostasis and thrombosis. Maintaining physiological platelet function is essential to hemostasis and preventing platelet-associated diseases such as cardiovascular disease, cancer metastasis, immune disorders, hypertension, diabetes, sickle cell disease, inflammatory bowel disease, sepsis, rheumatoid arthritis, myeloproliferative disease, and Alzheimer's disease. Platelets become hyperactive in obesity, diabetes, a sedentary lifestyle, hypertension, pollution, and smokers. Platelets, upon activation, can trawl leukocytes and progenitor cells to the vascular sites. Platelets release various proinflammatory, anti-inflammatory, and angiogenic factors and shed microparticles in the circulation, thus promoting pathological reactions. These platelet-released factors also maintain sustained activation, further impacting these disease processes. Although the mechanisms are unknown, multiple stimuli induce platelet hyperreactivity but involve the early pathways of platelet activation. The exact mechanisms of how hyperactive platelets contribute to these diseases are still unclear, and antiplatelet strategies are inevitable for preventing these diseases. Reducing platelet function during the early stages could significantly impact these diseases. However, while this is potentially a worthwhile intervention, using antiplatelet drugs to limit platelet function in apparently healthy individuals without cardiovascular disease is not recommended due to the increased risk of internal bleeding, resistance, and other side effects. The challenge for therapeutic intervention in these diseases is identifying factors that preferentially block specific targets involved in platelets' complex contribution to these diseases while leaving their hemostatic function at least partially intact. Since antiplatelet drugs such as aspirin are not recommended as primary preventives, it is essential to use alternative safe platelet inhibitors without side effects. A systematic search of the PUBMED database from 2000 to 2023 was conducted using the selected keywords: "functional foods", "polyphenols", "fatty acids", "herbs", fruits and vegetables", "cardioprotective agents", "plant", "platelet aggregation", "platelet activation", "clinical and non-clinical trial", "randomized", and "controlled". Potent natural antiplatelet factors have been described, including omega-3 fatty acids, polyphenols, and other phytochemicals. Antiplatelet bioactive compounds in food that can prevent platelet hyperactivity and thus may prevent several platelet-mediated diseases, including cardiovascular disease. This narrative review describes the work during 2000-2023 in developing functional foods from natural sources with antiplatelet effects.

Hyperproliferation of myeloid and erythroid cells in myeloproliferative neoplasms (MPN) driven by the JAK2-V617F mutation is associated with altered metabolism. Given the central role of glutamine in anabolic and catabolic pathways, we examined the effects of pharmacologically inhibiting glutaminolysis, that is, the conversion of glutamine (Gln) to glutamate (Glu), using CB-839, a small molecular inhibitor of the enzyme glutaminase (GLS). We show that CB-839 strongly reduced the mitochondrial respiration rate of bone marrow cells from JAK2-V617F mutant (VF) mice, demonstrating a marked dependence of these cells on Gln-derived ATP production. Consistently, in&#xa0;vivo treatment with CB-839 normalized blood glucose levels, reduced splenomegaly and decreased erythrocytosis in VF mice. These effects were more pronounced when CB-839 was combined with the JAK1/2 inhibitor ruxolitinib or the glycolysis inhibitor 3PO, indicating possible synergies when cotargeting different metabolic and oncogenic pathways. Furthermore, we show that the inhibition of glutaminolysis with CB-839 preferentially lowered the proportion of JAK2-mutant hematopoietic stem cells (HSCs). The total number of HSCs was decreased by CB-839, primarily by reducing HSCs in the G1 phase of the cell cycle. CB-839 in combination with ruxolitinib also strongly reduced myelofibrosis at later stages of MPN. In line with the effects shown in mice, proliferation of CD34+ hematopoietic stem and progenitor cells from polycythemia vera patients was inhibited by CB-839 at nanomolar concentrations. These data suggest that inhibiting GLS alone or in combination with inhibitors of glycolysis or JAK2 inhibitors represents an attractive new therapeutic approach to MPN.

Acute myeloid leukemia (AML) remains a devastating hematologic malignancy with persistently high early mortality, particularly among older adults and socioeconomically or geographically disadvantaged populations. Despite therapeutic progress&#x2014;from cytarabine&#x2013;anthracycline induction to targeted inhibitors&#x2014;global disparities persist in diagnosis, treatment access, and supportive care. Among the most underrecognized inequities lies the burden of cardio-thrombotic complications, which disproportionately affect patients with limited access to cardiovascular monitoring or individualized treatment optimization. Anthracyclines induce dose-dependent myocardial injury in up to 20% of patients, while endothelial dysfunction, platelet activation, and inflammatory hypercoagulability amplify the risk of venous and arterial thromboses. These toxicities not only worsen morbidity but also lead to dose reductions, therapy interruptions, and inferior remission outcomes&#x2014;amplifying survival gaps across populations. Yet, most AML protocols prioritize cytotoxic efficacy over cardio-oncologic safety, perpetuating a structural disparity in comprehensive cancer care. This work integrates mechanistic, clinical, and translational dimensions to construct a unified framework for addressing the cardio-thrombotic burden in AML therapy. We highlight the biological convergence of oxidative stress, mitochondrial dysfunction, endothelial injury, platelet activation, and NET-driven thromboinflammation&#x2014;factors often magnified in resource-limited settings lacking early biomarker surveillance. We further propose precision-guided innovations, including biomarker-based risk stratification, machine learning&#x2013;driven prediction models, and functionalized nanomedicine or platelet-hitchhiking drug delivery systems, as equitable solutions to bridge this cardio-onco gap. By conceptualizing cardio-thrombotic injury as both a biological and systemic disparity, our study reframes AML care within an integrative cardio-onco-hematology paradigm aimed at achieving therapeutic equity and improving survival across diverse patient populations.

Asciminib, a novel allosteric BCR::ABL1 inhibitor, targets the ABL1 myristoyl pocket to potentially reduce toxicity and enhance efficacy. It is approved for Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CML-CP) in patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs) or those with the T315I mutation. This retrospective analysis evaluated patients with CML treated with asciminib under a managed-access program across eight Israeli centers from July 2019 to August 2022. We assessed treatment responses, toxicities, event-free survival (EFS), and overall survival (OS) using Kaplan-Meier methods. The study included 30 patients who had received a median of three prior TKIs, with 73% starting asciminib due to intolerance. After a median follow-up of 7.1&#x2009;months, 85% of those without prior complete cytogenetic response (CCyR) achieved CCyR, and 60% previously not in major molecular response (MMR) attained MMR. Resistance was rare (10%), with no cardiovascular events reported despite high baseline comorbidity (73%). Median EFS was 47&#x2009;months; median OS was not reached. Asciminib demonstrates significant efficacy and tolerability in heavily pretreated patients with CML-CP, with no new cardiovascular events observed. Further long-term studies are necessary to explore its full cardiovascular impact.

Dupilumab is a monoclonal antibody which selectively targets T2 inflammation by binding the IL-4 and 13 receptor and blocking its contribution to the immune activation. Clinical trials and real-life studies on severe asthma and nasal polyps patients have reported blood eosinophils fluctuation over the treatment course. In the present narrative review the authors aim to provide a practical perspective on the recent evidence related to hypereosinophilia occurring during dupilumab therapy in respiratory indications, its underlying mechanisms, frequency, and clinical relevance, and to critically revise the currently proposed approaches to its management. Eosinophils increase is in most cases transient, spontaneously resolving, without any clinical relevance and no impact on efficacy. In fact, dupilumab safety profile is overall comparable with the other monoclonal antibody of the same drug class. Blood eosinophil count itself should not preclude dupilumab prescription, neither lead to dupilumab discontinuation, especially in the presence of ascertained drug efficacy and in the absence of signs suggesting a eosinophils-related complication. However, an extensive diagnostic work-up and regular follow-up monitoring is indicated, especially in patients with increased baseline eosinophils and coexisting nasal polyps and asthma.

Acute leukaemia is a highly aggressive malignancy with significant unmet therapeutic needs, partly due to epigenetic dysregulation. Here, we uncover deoxynucleotidyl transferase terminal-interacting protein 1 (DNTTIP1) within the mitotic deacetylase complex (MiDAC) as a previously unrecognised epigenetic regulator crucial for leukaemic cell survival and elucidate its mechanistic and translational significance. Using cellular, biochemical, and genetic perturbations, coupled with validation in multiple in vivo leukaemia mouse models, we characterised DNTTIP1's role in acute leukaemia. An integrated multi-omics analysis incorporating RNA-seq, cleavage under targets and tagmentation (CUT&Tag) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) revealed that DNTTIP1 recruits histone deacetylase 1/2 (HDAC1/2) to silence BCL2-modifying factor (BMF) and drive leukaemogenesis, validated by chromatin immunoprecipitation quantitative PCR (ChIP-qPCR). Drug synergy assays identify poly(ADP-ribose) polymerase (PARP)/HDAC/BCL2 inhibitor combinatorial efficacy. DNTTIP1 depletion impaired MiDAC recruitment in acute leukaemia, leading to histone H3 lysine 27 (H3K27) hyperacetylation at the BMF promoter and reactivating this effector. Upregulated BMF disrupted BCL2-mediated survival, triggering coordinated autophagy and apoptosis. Combined HDAC1/2 and BCL2 inhibition exerts synergistic anti-leukaemic effects, a therapeutic strategy currently under clinical evaluation. Further, PARP inhibition profoundly enhanced this synergy by impairing DNA damage repair, unveiling a novel triple-combination strategy. Our work defines the DNTTIP1&#x2012;HDAC1/2&#x2012;BMF axis as a pivotal epigenetic vulnerability in acute leukaemia and provides preclinical rationale for targeting this axis. These findings offer a validated biological framework for advancing this targeted combination therapy into clinical trials. DNTTIP1 is overexpressed in acute leukaemia and associated with poor prognosis. DNTTIP1 acts as a scaffold for the MiDAC complex, recruiting HDAC1/2 to silence BMF and inhibit leukaemic cell death. Pharmacological disruption of the DNTTIP1-HDAC1/2-BMF axis impairs leukaemogenesis.