Search Results (131)

Recently, there has been great interest in AI-based approaches for de novo design of novel drug candidates. However, the generation of useful lead drug candidate compounds requires more than predicting engagement with the desired protein target. Candidate molecules must also be anchored in the real world of medicinal chemistry for their synthesis and modification as well as satisfying multiple drug development-related criteria. Here, we present Nevermore, an AI target-conditioned, database-grounded workflow for prioritizing candidate ligands from large compound libraries. Nevermore uses a geometry-aware protein–ligand affinity oracle to score target-specific binding and perform sparse integer edits in count-based Morgan fingerprint space. Nevermore then retrieves the most structurally similar molecules from public chemical databases. This design enables multi-objective search over predicted affinity and absorption, distribution, metabolism, excretion, and toxicity (ADMET) proxies while keeping all candidates anchored to valid database compounds. We evaluated Nevermore’s performance across three biologically distinct targets: Menin, a protein-interaction target relevant to leukemia; SARS-CoV-2 M^pro, a viral cysteine protease relevant to antiviral discovery; and epidermal growth factor receptor (EGFR), a kinase-superfamily oncology target with extensive experimentally tested compounds. Nevermore retrieved candidate sets with favorable predicted affinity–property trade-offs. These results support database-grounded fingerprint steering as a practical computational strategy for lead prioritization and for generating testable molecular hypotheses, although the prioritized candidates remain predictions, requiring follow-up experimental validation. Full article

Growth hormone-releasing hormone (GHRH) antagonists have displayed anti-neoplastic activity against a multitude of cancers in vitro, as well as in vivo, via xenografted tumors in nude mice. Following a successful demonstration of GHRH antagonists treating non-Hodgkin’s lymphoma and the discovery of GHRH mRNA and peptide products in immune cells, GHRH antagonism was explored in acute myeloid leukemia (AML), a disease characterized by a malignant expansion of immature myeloid progenitors, and poor 5-year survival. Targeted therapies have yielded breakthroughs in treatment response and overall survival, such as all-trans retinoic acid/arsenic trioxide (ATRA/ATO) for acute promyelocytic leukemia (APL), or FLT3 inhibitors, IDH inhibitors, and menin inhibitors for AML harboring actionable genetic lesions. However, therapeutic resistance remains a major barrier to durable remission. GHRH receptor (GHRH-R) has been reported in several experimental models of AML, including drug-resistant sublines. Significant time- and dose-dependent reduction in leukemic growth was observed in vitro and in vivo following MIA-602 treatment. FLT3 inhibitor resistance has been associated with activation of PI3K/AKT, ERK/MAPK, inflammatory, stromal, and apoptotic escape pathways. The documented effects of GHRH-R antagonism raise the possibility that it could influence signaling networks relevant to therapeutic resistance in AML. This hypothesis remains speculative; to date no studies have stratified AML by FLT3 status in the context of GHRH-R expression or GHRH antagonism, and there is currently no evidence that MIA-602 directly alters FLT3 receptor signaling or inhibitor sensitivity. Full article

Background: Evidence on the role of synthetic biomimetic bone substitutes in the surgical management of proximal humerus fractures remains limited. This study aimed to evaluate the clinical, radiographic, and safety outcomes of a porous hydroxyapatite bone substitute used as an adjunct to locking-plate fixation in proximal humerus fractures with metaphyseal bone loss. Methods: We performed a retrospective comparative cohort study including 45 patients treated with locking-plate fixation and porous hydroxyapatite scaffold augmentation and 40 comparable control patients treated with locking-plate fixation without scaffold augmentation. Patients were evaluated clinically and radiographically at 1, 3, 6, and 12 months after surgery. Functional outcome was assessed with the Constant–Murley Score (CMS), and pain was assessed using the Visual Analogue Scale (VAS). Longitudinal changes over time were analyzed using mixed-effects models for repeated measures. Results: CMS improved progressively over follow-up, whereas VAS pain scores decreased significantly over time. No cases of device migration or radiographic resorption were observed during follow-up. Adverse events were recorded, but no complication was considered directly attributable to the implanted biomaterial. Functional recovery and pain reduction followed a similar trajectory in both groups, with no significant group-by-time interaction. Conclusions: In this retrospective series, graft augmentation with a porous hydroxyapatite scaffold during locking-plate fixation of proximal humerus fractures with bone void was associated with progressive functional improvement and pain reduction, without evident device-related safety concerns. Owing to the retrospective, non-randomized design, limited sample size, potential selection bias, and incomplete follow-up in part of the cohort, these findings should be interpreted as supportive of feasibility and short- to mid-term safety rather than as definitive evidence of biomaterial efficacy. Level of Evidence: Level III, retrospective cohort study. Full article

Background: Differentiation therapy is a cornerstone in treating hematologic malignancies, particularly acute myeloid leukemia (AML). Differentiation agents target molecular defects blocking myeloid differentiation. However, rapid differentiation can precipitate a life-threatening complication, differentiation syndrome (DS). DS manifests with fever, pulmonary infiltrates, pleural or pericardial effusions, hypotension, and organ dysfunction, often mimicking sepsis or infection. Early recognition in the emergency department (ED) is critical to mitigate morbidity and mortality. This review aims to provide emergency clinicians with practical strategies for the timely identification and management of DS in patients undergoing differentiation therapy. Discussion: Suspicion for DS should be heightened in patients with acute promyelocytic leukemia (M3 AML) who recently started induction chemotherapy, including all-trans retinoic acid or arsenic trioxide, and in those with non-M3 AML receiving differentiation agents (i.e., isocitrate dehydrogenase inhibitors, menin inhibitors, FMS-like tyrosine kinase 3 inhibitors). Imaging can identify pulmonary infiltrates, effusions, and other cardiopulmonary manifestations. Laboratory workups should include complete blood counts with differentials, serum chemistries, cardiac biomarkers, and sepsis panels to exclude infection. Electrocardiography is advised for patients on QT-prolonging agents. Management emphasizes prompt initiation of high-dose corticosteroids and supportive measures such as blood pressure support, intravascular volume optimization, and oxygen therapy or ventilatory support. Multidisciplinary coordination with oncology, hematology, and critical care teams is important to tailor plans and monitor complications. Conclusions: DS represents a diagnostic challenge in the ED due to its nonspecific presentation and mimicry of infection. A high index of suspicion, combined with targeted imaging, laboratory evaluation, and early corticosteroid therapy, can improve outcomes. Full article

Among the transcriptional dependencies that sustain leukemic identity in acute myeloid leukemia (AML), the menin–KMT2A chromatin complex has emerged as a central regulatory node. The scaffold protein menin, encoded by MEN1, facilitates transcriptional activation of HOX and MEIS family genes during normal hematopoietic development. In AML, this physiologic and developmentally regulated role is co-opted to sustain constitutive HOX/MEIS-driven programs that block differentiation and maintain leukemic potential. Although dependency on menin is most clearly established in KMT2A-rearranged and NPM1-mutated AML, this vulnerability appears to arise from a shared transcriptional state characterized by persistent HOX activation rather than from any single genetic alteration. Pharmacologic disruption of the menin-KMT2A interaction collapses stemness-associated transcriptional networks, promotes myeloid differentiation, and attenuates leukemic self-renewal. Clinical activity observed with menin inhibitors provides translational validation of this dependency and establishes menin inhibition as a differentiation-based therapeutic strategy. In this review, we examine the molecular basis of menin-dependent transcriptional regulation in AML and its implications for therapeutic targeting with menin inhibitors and resistance to therapy. Full article

In this Reply, we address the criticisms raised by Franzini, Valdenassi, and Chirumbolo concerning our study on the effects of ozonized saline solution (O3SS) on microglial polarization and endothelial responses in vitro. We clarify that the primary aim of the original work was mechanistic, relying on rigorously controlled cellular models that are universally recognized as essential preclinical tools in translational medicine. We reaffirm the validity of our experimental approach, including the preparation and characterization of O3SS based on empirically validated methodologies, direct ozone quantification, and standardized protocols consistent with the existing literature and clinical practice. Concerns regarding ozone chemistry, dose relevance, and hypochlorite formation are addressed through analytical validation, biological threshold considerations, and the use of certified assays. We further justify the choice of BV2 microglia and HUVEC cells as established and widely used models for investigating inflammatory and vascular pathways under reproducible conditions. Statistical analyses, gene expression interpretation, and the absence of comparative pharmacological agents are discussed in the context of the study’s focused objectives. Finally, we place our findings within the established framework of ozone as an indirect pro-oxidant that elicits adaptive redox signaling (“oxidative eustress”), emphasizing the translational relevance of in vitro systems for elucidating early mechanistic events. Overall, we maintain that our study provides a robust, balanced, and evidence-based contribution to the understanding of ozone-derived redox biology. Full article

Deformation monitoring of bridges is essential to ensure the structural integrity and serviceability of these critical civil infrastructures. In this context, geodetic measurements using total stations and 3D terrestrial laser scanning (TLS) surveys can provide accurate and reliable data. Multitemporal geodetic observations from total stations enable the tracking of displacements at discrete points, whereas TLS surveys allow for the extension of deformation analysis to entire surfaces. Both techniques can achieve comparable millimeter-level precision. These methods were applied to monitor the deformation of the Ponte della Costituzione (PdC), the most recent pedestrian arch bridge spanning the Grand Canal in Venice (Italy). A total station was used to measure the displacements of six control points installed on structurally significant locations of the bridge. Between 3 October 2023 and 2 February 2026, 28 multitemporal measurement campaigns were conducted. In addition, four TLS surveys, using two different laser scanners, were carried out on 1 August 2025 and 2 February 2026, in order to capture conditions corresponding to maximum annual thermal deformation. The results derived from geodetic measurements reveal a strong correlation among: (i) variations in the distance between the abutments (on the order of 6–7 mm); (ii) vertical displacements of the central upper points of the arch (ranging from 9 to 12 cm); and (iii) fluctuations in ambient temperature. TLS data highlighted a spatially homogeneous deformation pattern extending from the crown of the arch to the abutments, demonstrating that longitudinal displacements affect the entire lateral structure. Mid-term deformation analysis over the two-year period from 6 February 2024 to 2 February 2026 indicates displacement rates of approximately 1.4 mm/year for increasing separation between the abutments and 16.2 mm/year for the decrease in elevation of the central arch point. However, these trends are significantly influenced by environmental temperature variations, as evidenced by an estimated temperature change rate of −3.5 °C/year over the same period. Therefore, continued deformation monitoring of the PdC bridge is recommended in the coming years, particularly in light of ongoing climate change and the associated increase in temperature variability. Full article

After many years of stagnation in the treatment of acute myeloid leukemia (AML), there is currently a rapid move towards personalized medicine. Improvements in molecular diagnostics, risk assessment tools, targeted therapies, overall patient fitness assessments, and quality-of-life assessments have significantly changed how patients are treated. Genetic and molecular analyses, risk and health assessments, and measurable residual disease (MRD) monitoring are now integral to the treatment plan for evaluating patient responses and recurrence. In this regard, lower-intensity treatments are provided to older or unfit individuals. On the other hand, younger patients are usually subjected to curative therapies such as intensive chemotherapy to induce remission. Depending on their fitness and disease risk, they can be considered for hematopoietic cell transplantation, which is done after close observation for MRD. In addition, newer therapeutic drugs and immunotherapy techniques are being applied for patient management. Tremendous strides have been made in improving the efficiency of treatment programs in the relatively new area of personalized AML therapy, with a focus on functionality. Full article

Background: Chromosomal rearrangements involving lysine methyltransferase 2A (KMT2A) define a genetically distinct subset of acute myeloid leukemia (AML) in 10% of cases in adult patients; the frequency of KMT2A-r is higher in pediatric AML. Translocations involving the KMT2A locus at chromosome 11q23 result in the formation of a chimeric oncogene partner, where the N-terminal part of KMT2A is fused to a variety of translocation partners. The leukemogenic activity of KMT2A-fusion partners is related to their capacity to hyperactivate the expression of HOX-A and MEIS1 target genes, which stimulate the proliferation of hematopoietic stem cells. The oncogenic activity of KMT2A fusion proteins requires the binding with Menin, and this interaction can be targeted pharmacologically by small molecules acting as potent and selective Menin inhibitors. Methods: A search of the literature showed a marked development of experimental studies exploring the molecular pathogenesis of AML with KMT2A-r and of clinical studies evaluating new induction intensive treatments and the development of a targeted therapy based on Menin inhibitors. Results and Conclusions: In the present review article, we summarize our current understanding of the biology of KMT2A-r in AML development and the recent consistent progress made in the treatment of KMT2A-r AML through new chemotherapy regimens and targeted therapy using Menin inhibitors. However, the prognosis of older KMT2A-r AML patients remains poor and could be improved by drug combination studies including Menin inhibitors. Many encouraging observations derived from ongoing clinical trials with Menin inhibitors need to be confirmed through randomized clinical trials. Full article

Menin, the product of the Multiple Endocrine Neoplasia type 1 (MEN1) gene, is a scaffold protein, the lack of which leads to the development of a tumor syndrome primarily affecting endocrine organs. Although it is classified as an oncosuppressor, menin is a ubiquitous protein whose expression is also abundant in non-endocrine tissues such as the central nervous system, where knowledge of menin’s role still remains limited. In this article, we aim to draw attention to an underestimated clinical aspect of MEN1 syndrome, i.e., the psychological/psychiatric manifestations, in which menin deficiency could have an important function. Our aim is to highlight that a multidisciplinary team caring for patients with MEN1 throughout their lives should include professionals such as psychologists and psychiatrists in order to better manage any mental illness associated with the syndrome and to further improve the patient’s quality of life. Full article

For decades, induction treatment of acute myeloid leukemia consisted of intensive chemotherapy for induction. High relapse rates and severe toxicity resulted in a five-year overall survival of ~30%. In patients ineligible for intensive treatment, hypomethylating agents (HMA) could be administered but generally failed to induce durable remissions. These limitations have driven the development of targeted drugs and less toxic therapeutic regimens. In the past decade, fourteen new agents have gained FDA and/or EMA approval, including small-molecule inhibitors targeting FLT3, IDH1, IDH2, BCL-2, menin, and the hedgehog pathway, as well as a CD33-directed antibody-drug conjugate. The combination of targeted drugs with intensive chemotherapy or HMA has resulted in improved remission rates and prolonged survival in certain patient subpopulations. However, many promising combinations are currently being evaluated in randomized trials and are not yet available in clinical routine. A combination that has become standard of care is HMA plus venetoclax for patients unfit for intensive chemotherapy, achieving high remission rates with relatively manageable toxicity. Moreover, targeted drugs directed against FLT3 and IDH1 have been approved in combination with intensive chemotherapy and HMA, respectively. Clinical decision-making requires rapid molecular diagnostic testing, assessment of a patient’s fitness for intensive chemotherapy, and management of toxicities and drug interactions. This narrative review, illustrated with patient vignettes, summarizes currently available therapies, guides through the latest trials on frontline combinations in AML, and provides a preview of how the therapeutic landscape may evolve in the near future. Full article

Acute myeloid leukemia (AML) is a molecularly heterogeneous neoplasm of hematopoietic stem and progenitor cells. The advent of high-resolution genomic sequencing has uncovered several genetic drivers of AML which spurred a surge of therapies that target the disease at a mutational, clonal, or epigenetic level. Currently, the molecular profiling of AML patients before treatment is commonplace and crucial for ensuring that patients receive the most optimal therapy for any driver mutations they may have. Here, we detail the current targeted therapies available for AML: specifically, those targeting the BCL2 family (venetoclax), FLT3 (midostaurin, gilteritinib, quizartinib), IDH1/2 (enasidenib, ivosidenib), and MENIN (revumenib, ziftomenib). In addition, we outline potential mechanisms of resistance against these therapies, as well as efforts being taken to prevent or bypass them. Full article

The development of targeted treatments, including inhibitors of BCL-2, FLT3, IDH1/2, and menin, has significantly expanded the therapeutic landscape of acute myeloid leukemia (AML), offering more personalized and molecularly driven treatment approaches. Despite these advances, achieving durable responses represents a major challenge, limited by the emergence of intrinsic and acquired resistance to targeted agents. This review summarizes the current understanding of the cellular and molecular mechanisms underlying resistance to targeted therapies in AML. Key mechanisms include acquired mutations that alter the drug target, other co-occurring genetic and epigenetic alterations, activation of bypass signaling pathways, and metabolic reprogramming. Furthermore, the role of clonal heterogeneity and the bone marrow microenvironment in the development of resistance is increasingly recognized. In addition, we discuss emerging strategies aiming at overcoming resistance, such as combination treatments and novel inhibitors designed to target resistant clones. Finally, this review highlights the critical need for mechanism-driven therapeutic design in order to achieve sustained responses and improve long-term outcomes in patients with AML. Full article

Background/Objectives: Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy with historically poor outcomes, particularly among older adults and patients harboring high-risk molecular features. Advances in genomic profiling have enabled the development of targeted therapies, reshaping treatment algorithms beyond conventional cytarabine-anthracycline induction and hypomethylating agent-based regimens. This review summarizes current evidence and emerging therapeutic strategies across four evolving areas: menin inhibition, FLT3 inhibition, IDH inhibition and treatment approaches for TP53-mutated AML. Methods: We reviewed published clinical trials, preclinical studies, and ongoing clinical trials evaluating targeted therapies in AML. Emphasis was placed on agents with regulatory approval or substantial clinical development, including menin inhibitors, FLT3 inhibitors, IDH inhibitors and novel therapies directed at TP53-mutated disease. Mechanistic data, response rates, survival outcomes, and resistance patterns were analyzed to provide an updated overview of therapeutic progress. Results: Menin inhibitors have demonstrated significant activity in NPM1-mutated and KMT2A-rearranged AML, with agents such as revumenib and ziftomenib producing meaningful remission rates and ongoing studies exploring combination strategies to mitigate resistance. FLT3 inhibitors, including midostaurin, gilteritinib, and quizartinib, have improved survival in FLT3-mutated AML, while emerging evidence supports potential benefit in selected FLT3–wild-type disease based on FLT3-like gene expression signatures. IDH inhibitors, namely ivosidenib and enasidenib, have provided increased efficacy in AML patients carrying these mutations. Questions still remain regarding their efficacy in contrast to venetoclax which has been shown to be particularly effective against this population. In contrast, TP53-mutated AML remains a therapeutic challenge: although hypomethylating-agent/venetoclax-based regimens yield improved initial responses, remissions are generally short-lived and overall survival remains poor. Early-phase therapies, including p53 reactivators and multi-kinase inhibitors, show preclinical promise but lack definitive clinical efficacy to date. Conclusions: Targeted therapies have improved outcomes in molecularly defined subsets of AML, with menin, IDH and FLT3 inhibitors representing major advances. However, TP53-mutated AML continues to carry a dismal prognosis, underscoring the need for more effective therapeutic strategies. Continued biomarker-driven research, novel drug combinations, and mechanistic insights will be essential to further refine AML treatment and improve long-term survival across disease subsets. Full article