AmpClass: an Antimicrobial Peptide Predictor Based on Supervised Machine Learning.

In the last decades, antibiotic resistance has been considered a severe problem worldwide. Antimicrobial peptides (AMPs) are molecules that have shown potential for the development of new drugs against antibiotic-resistant bacteria. Nowadays, medicinal drug researchers use supervised learning methods to screen new peptides with antimicrobial potency to save time and resources. In this work, we consolidate a database with 15945 AMPs and 12535 non-AMPs taken as the base to train a pool of supervised learning models to recognize peptides with antimicrobial activity. Results show that the proposed tool (AmpClass) outperforms classical state-of-the-art prediction models and achieves similar results compared with deep learning models.

Structural basis for the ligand promiscuity of the hydroxamate siderophore binding protein FtsB from Streptococcus pyogenes.

Pathogenic bacteria must secure the uptake of nutritional metals such as iron for their growth, making their import systems attractive targets for the development of new antimicrobial modalities. In the pathogenic bacterium Streptococcus pyogenes, the iron uptake system FtsABCD transports iron encapsulated by siderophores of the hydroxamate class. However, the inability of S. pyogenes to produce these metabolites makes the biological and clinical relevance of this route unresolved. Herein, we demonstrated that the periplasmic binding protein FtsB recognizes not only the hydroxamate siderophore ferrichrome, as previously documented, but also ferrioxamine E (FOE), ferrioxamine B (FOB), and bisucaberin (BIS), each of them with high affinity (nM level). Up to seven aromatic residues in the binding pocket accommodate the variable backbones of the different siderophores through CH-π interactions, explaining ligand promiscuity. Collectively, our observations revealed how S. pyogenes exploits the diverse xenosiderophores produced by other microorganisms as iron sources to secure this precious nutrient.

Two-Decade Retrospective Analysis of Endogenous Endophthalmitis in Spain and Mexico: A Comprehensive Study.

Objectives: The aim of this study was to investigate endogenous endophthalmitis (EE) in Spain and Mexico, focusing on microbial patterns, antibiotic resistance, infection sources, risk factors, and patient outcomes. Methods: Over 20 years, 705 endophthalmitis cases were reviewed, and we identified 78 cases of EE in Santiago de Compostela, Spain, and Mexico City, Mexico. Microbial etiology, infection sources, antibiotic resistance, and treatment outcomes were compared between patients from Spain and Mexico. Results: Among the 78 EE cases, 47 (60.25%) were from Spain and primarily had bacterial infections (57.1%, mainly Staphylococcus and Streptococcus). In contrast, 31 cases (39.74%) were from Mexico and had a higher prevalence of fungal infections, particularly Candida (47.1%). Diabetes mellitus was a significant risk factor, and was more common in Mexico (61.3%) than in Spain (37.0%). The Spanish cohort exhibited notable antibiotic resistance, especially in Staphylococcus. Treatment typically involved systemic and intraocular antibiotics, with vitrectomy performed in 61.5% cases. Post-treatment, bacterial infections had higher success rates (approximately 50%) compared with fungal infections (approximately 30%). Evisceration was necessary in 9% cases, and the overall mortality rate was approximately 4.4%; it was slightly higher in Mexico than in Spain. Conclusions: The study highlights significant regional differences in EE between Spain and Mexico, particularly regarding microbial etiology and antibiotic resistance. The findings emphasize the need to adapt healthcare practices to specific regions to improve EE treatment outcomes, underscoring the importance of ongoing research and interregional collaboration to better understand and manage this complex condition.

Factors Affecting on Environmental Strategy in SMEs manufacturing Firms of a developing country: Mediating role of Green Employee Behavior.

Background: Sustainability in small and medium-sized enterprises (SMEs) which engage heavily in manufacturing provides them with an essential platform for implementing environmental strategy, which is aimed at reducing environmental damage and promoting environmental protection. This study aims to examine the impact of the reduction in resource use, the greening of processes and products on environmental strategy and the mediating role of green employee behaviour. Methods: Primary data gathered with the help of questionnaires from employees of SMEs manufacturing in developing countries, Pakistan. The research gathered data from 211 participants by applying a pre-tested instrumental questionnaire and structural equation modelling (SEM) for data analysis. Results: The results confirmed all direct effects, including a reduction in resource use, the greening of processes and products and green employee behaviour of environmental strategies in small and medium manufacturing firms. Also, confirmed partial mediation effect of green employee behavior between greening of processes and products and environmental strategy. Conclusion: The current study clearly showed the need for programs and infrastructures that support resource reduction and greening businesses in SMEs. Companies' implementation of green processes and technologies allows SMEs to take an environmentally responsible stand and become part of the movement toward sustainability. The research stresses the importance of green employee conduct as a mediator, the central point being the individual employee being engaged and aware of the subject and willing to participate in environmentally friendly practices. Therefore, small and medium enterprises should enlighten their staff to practice green behaviour, give them what they need and empower them to be change drivers that will trigger sustainability throughout the organisations.

Lights and Shadows of Bacillus Calmette-Guérin (BCG)-exposed and BCG-unresponsive Definitions: A Practical Overview.

According to the current definitions of recurrence of non-muscle-invasive bladder cancer after bacillus Calmette-Guérin (BCG), patients in the BCG-exposed and late relapse categories might benefit from further instillations. Patients with BCG-unresponsive disease could be included in clinical trials, but otherwise radical cystectomy is the preferred treatment. BCG-intolerant disease still represents an area of debate, with limited evidence regarding the best treatment for these patients.

A Comprehensive Review of Silver and Gold Nanoparticles as Effective Antibacterial Agents.

The increasing threat from antibiotic-resistant bacteria has necessitated the development of novel methods to counter bacterial infections. In this context, the application of metallic nanoparticles (NPs), especially gold (Au) and silver (Ag), has emerged as a promising strategy due to their remarkable antibacterial properties. This review examines research published between 2006 and 2023, focusing on leading journals in nanotechnology, materials science, and biomedical research. The primary applications explored are the efficacy of Ag and Au NPs as antibacterial agents, their synthesis methods, morphological properties, and mechanisms of action. An extensive review of the literature on NPs synthesis, morphology, minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and effectiveness against various Gram(+/-) bacteria confirms the antibacterial efficacy of Au and Ag NPs. The synthesis methods and characteristics of NPs, such as size, shape, and surface charge, are crucial in determining their antibacterial activity, as these factors influence their interactions with bacterial cells. Furthermore, this review underscores the urgent necessity of standardizing synthesis techniques, MICs, and reporting protocols to enhance the comparability and reproducibility of future studies. Standardization is essential for ensuring the reliability of research findings and accelerating the clinical application of NP-based antimicrobial approaches. This review aims to propel NP-based antimicrobial strategies by elucidating the properties that enhance the antibacterial activity of Ag and Au NPs. By highlighting their inhibitory effects against various bacterial strains and relatively low cytotoxicity, this work positions Ag and Au NPs as promising materials for developing antibacterial agents, making a significant contribution to global efforts to combat antibiotic-resistant pathogens.

Description of lesions in lambs intoxicated with sodium selenite included in intraruminal boluses: Lambs intoxicated with selenium.

Selenium is an essential micronutrient for ruminants, which participates in the optimal functioning of proteins and enzymes that can combat oxidative stress in the body; however, its toxicity is documented in different species. The objective of this work was to describe macroscopic and microscopic lesions in lambs intoxicated with selenium administered through intraruminal boluses. The main lesions at necropsy were pulmonary oedema; the myocardial surface presented multifocal pale areas; the thyroid and thymus glands were decreased in size, and areas of necrosis, haemorrhage and hyperkeratosis were observed in the reticulum and rumen. At the microscopic level, congestion, haemorrhage, oedema and hyaline membranes were observed in the lung; hepatic congestion, haemorrhage, degeneration and necrosis; degeneration and necrosis of the reticulum mucosa, as well as areas of hyperplasia and hyperkeratosis; myocardial degeneration, necrosis and fibrosis; congestion, haemorrhage, degeneration and renal tubular necrosis; thyroid follicular atrophy and thymic cortical atrophy. This study evidenced the main lesions related to selenium poisoning in lambs supplemented with the mineral through intraruminal boluses.

Integrated sustainability assessment of wood building products: The case of larch and chestnut cascading systems in Northern Italy.

Wood is increasingly being appreciated in construction due to its valuable environmental attributes. This paper explores the environmental and market performance of two wood supply chains in Northern Italy. Larch and chestnut wood are extracted and processed to obtain beams, planks, MDF panels and energy. LCA is performed to evaluate the environmental impacts of 1m3 of extracted wood through a cradle-to-gate approach. Then, a biogenic carbon analysis is carried out using the EN 16449:2014 standard including a comparison of different end-of-life treatments. Also, OSB is proposed as an alternative path for wood chips and contrasted to the current energy scenario. Moreover, solid wood beams and planks are compared with engineered wood products (EWPs). Lastly, a market analysis is conducted to assess the market trends of the different wood products studied. The LCA shows similar results for both wood species across most impact categories, with slightly higher values for the chestnut system. Most impacts are related to the production of MDF boards and the energy valorization of wood chips. Biogenic carbon analysis shows a negative balance of emissions with -314 and -205 kg of CO2 eq for larch and chestnut, respectively. It also suggests that OSB manufacturing can be a valuable alternative to the energy use of wood chips and that the end-of-life treatment with better results is recycling. The comparison of beams and planks with engineered wood products supports that solid wood poses a better environmental alternative in similar applications. Market analysis shows stagnation in the apparent consumption of wood products in the European market and a slight growth in the Italian one between 2018 and 2022. Overall, the systems studied suggest that the potential environmental benefits of using wood in construction are not being matched by current market trends.

Tomorrow Never Comes: The Risks of Procrastination for Adolescent Health.

This study explores the relationship between procrastination and declining healthy habits among adolescents, a topic lacking systematic reviews in the existing literature. The primary purpose is to lay the groundwork for promoting mental health and preventing procrastination as risky behavior. This systematic review examined five areas related to procrastination and its influence on healthy lifestyle habits in adolescents: technology and procrastination; sleep and procrastination; academic procrastination; and the COVID-19 pandemic. The findings highlight that technology misuse is linked with procrastination; adolescents tend to procrastinate when going to sleep; academic procrastination negatively impacts long-term educational achievements, and the COVID-19 pandemic has exacerbated this phenomenon. Ultimately, it is concluded that procrastination is related to all these aspects and has detrimental effects on adolescents' physical and psychological development.

Is Nasal Dysbiosis a Required Component for Neuroinflammation in Major Depressive Disorder?

Human microbiota is known to influence immune and cerebral responses by direct and/or indirect mechanisms, including hypothalamic-pituitary-adrenal axis signaling, activation of neural afferent circuits to the brain, and by altering the peripheral immune responses (cellular and humoral immune function, circulatory inflammatory cells, and the production of several inflammatory mediators, such as cytokines, chemokines, and reactive oxygen species). The inflammatory responses in the nasal mucosa (rhinitis) or paranasal sinuses (chronic rhinosinusitis) are dual conditions related with a greater risk for developing depression. In the nasal cavity, anatomic components of the olfactive function are in direct contact with the CNS through the olfactory receptors, neurons, and axons that end in the olfactory bulb and the entorhinal cortex. Local microbiome alterations (dysbiosis) are linked to transepithelial translocation of microorganisms and their metabolites, which disrupts the epithelial barrier and favors vascular permeability, increasing the levels of several inflammatory molecules (both cytokines and non-cytokine mediators: extracellular vesicles (exosomes) and neuropeptides), triggering local inflammation (rhinitis) and the spread of these components into the central nervous system (neuroinflammation). In this review, we discuss the role of microbiota-related immunity in conditions affecting the nasal mucosa (chronic rhinosinusitis and allergic rhinitis) and their relevance in major depressive disorders, focusing on the few mechanisms known to be involved and providing some hypothetical proposals on the pathophysiology of depression.

Alternative splicing of BAZ1A in colorectal cancer disrupts the DNA damage response and increases chemosensitization.

Bromodomain Adjacent to Zinc Finger Domain 1A (BAZ1A) is a critical regulator of chromatin remodeling. We sought to clarify the roles of BAZ1A in the etiology of colorectal cancer, including the mechanisms of its alternatively spliced variants. Public databases were examined and revealed high BAZ1A expression in the majority of colorectal cancer patients, which was corroborated in a panel of human colon cancer cell lines. BAZ1A silencing reduced cell viability and increased markers of DNA damage, apoptosis, and senescence, along with the downregulation of Wnt/ß-catenin signaling. The corresponding molecular changes resulted in tumor growth inhibition when BAZ1A-knockout cells were implanted into nude mice. In rescue experiments, a short isoform of BAZ1A that was associated with alternative splicing by the DBIRD complex failed to restore DNA repair activity in colon cancer cells and maintained chemosensitivity to phleomycin treatment, unlike the full-length BAZ1A. A working model proposes that a buried domain in the N-terminus of the BAZ1A short isoform lacks the ability to access linker DNA, thereby disrupting the activity of the associated chromatin remodeling complexes. Given the current interest in RNA splicing deregulation and cancer etiology, additional mechanistic studies are warranted with new lead compounds targeting BAZ1A, and other members of the BAZ family, with a view to improved therapeutic interventions.

Single cell RNA sequencing of human FAPs reveals different functional stages in Duchenne muscular dystrophy.

Background: Duchenne muscular dystrophy is a genetic disease produced by mutations in the dystrophin gene characterized by early onset muscle weakness leading to severe and irreversible disability. Muscle degeneration involves a complex interplay between multiple cell lineages spatially located within areas of damage, termed the degenerative niche, including inflammatory cells, satellite cells (SCs) and fibro-adipogenic precursor cells (FAPs). FAPs are mesenchymal stem cell which have a pivotal role in muscle homeostasis as they can either promote muscle regeneration or contribute to muscle degeneration by expanding fibrotic and fatty tissue. Although it has been described that FAPs could have a different behavior in DMD patients than in healthy controls, the molecular pathways regulating their function as well as their gene expression profile are unknown. Methods: We used single-cell RNA sequencing (scRNAseq) with 10X Genomics and Illumina technology to elucidate the differences in the transcriptional profile of isolated FAPs from healthy and DMD patients. Results: Gene signatures in FAPs from both groups revealed transcriptional differences. Seurat analysis categorized cell clusters as proliferative FAPs, regulatory FAPs, inflammatory FAPs, and myofibroblasts. Differentially expressed genes (DEGs) between healthy and DMD FAPs included upregulated genes CHI3L1, EFEMP1, MFAP5, and TGFBR2 in DMD. Functional analysis highlighted distinctions in system development, wound healing, and cytoskeletal organization in control FAPs, while extracellular organization, degradation, and collagen degradation were upregulated in DMD FAPs. Validation of DEGs in additional samples (n = 9) using qPCR reinforced the specific impact of pathological settings on FAP heterogeneity, reflecting their distinct contribution to fibro or fatty degeneration in vivo. Conclusion: Using the single-cell RNA seq from human samples provide new opportunities to study cellular coordination to further understand the regulation of muscle homeostasis and degeneration that occurs in muscular dystrophies.

Attenuated mutants of Salmonella enterica Typhimurium mediate melanoma regression via an immune response.

The lack of effective treatment options for an increasing number of cancer cases highlights the need for new anticancer therapeutic strategies. Immunotherapy mediated by Salmonella enterica Typhimurium is a promising anticancer treatment. Candidate strains for anticancer therapy must be attenuated while retaining their antitumor activity. Here, we investigated the attenuation and antitumor efficacy of two S. enterica Typhimurium mutants, ΔtolRA and ΔihfABpmi, in a murine melanoma model. Results showed high attenuation of ΔtolRA in the Galleria mellonella model, and invasion and survival in tumor cells. However, it showed weak antitumor effects in vitro and in vivo. Contrastingly, lower attenuation of the attenuated ΔihfABpmi strain resulted in regression of tumor mass in all mice, approximately 6 days after the first treatment. The therapeutic response induced by ΔihfABpmi was accompanied with macrophage accumulation of antitumor phenotype (M1) and significant increase in the mRNAs of proinflammatory mediators (TNF-α, IL-6, and iNOS) and an apoptosis inducer (Bax). Our findings indicate that the attenuated ΔihfABpmi exerts its antitumor activity by inducing macrophage infiltration or reprogramming the immunosuppressed tumor microenvironment to an activated state, suggesting that attenuated S. enterica Typhimurium strains based on nucleoid-associated protein genes deletion could be immunotherapeutic against cancer.

Adipose Tissue Dysfunction and the Role of Adipocyte-Derived Extracellular Vesicles in Obesity and Metabolic Syndrome.

Obesity is a major public health issue that is associated with metabolic diseases including diabetes mellitus type 2 and metabolic syndrome. This pathology leads to detrimental cardiovascular health and secondary effects, such as lipotoxicity, inflammation, and oxidative stress. Recently, extracellular vesicles (EVs) have been highlighted as novel players participating in human physiology and pathophysiology. In obesity, adipose tissue is related to the active shedding of adipocyte-derived extracellular vesicles (AdEVs). The current review explores and highlights the role of AdEVs and their cargo in obesity and metabolic syndrome. AdEVs are proposed to play an important role in obesity and its comorbidities. AdEVs are biological nanoparticles mainly shed by visceral and subcutaneous adipose tissue, acting in physiological and pathophysiological conditions, and also carrying different cargo biomolecules, such as RNA, microRNA (miRNA), proteins, and lipids, among others. RNA and miRNA have local and systemic effects affecting gene expression in target cell types via paracrine and endocrine actions. State of the art analyses identified some miRNAs, such as miR-222, miR-23b, miR-4429, miR-148b, and miR-4269, that could potentially affect cell pathways involved in obesity-related comorbidities, such as chronic inflammation and fibrosis. Similarly, AdEVs-proteins (RBP4, perilipin-A, FABP, mimecan, TGFBI) and AdEVs-lipids (sphingolipids) have been linked to the obesity pathophysiology. The current knowledge about AdEVs along with further research would support and reveal novel pathways, potential biomarkers, and therapeutic options in obesity.

Clinically Relevant Topics and New Tendencies in Childhood Nutrition during the First 2 Years of Life: A Survey among Primary Care Spanish Paediatricians.

A multicenter cross-sectional study was conducted among 245 experienced Spanish paediatricians, who completed an online survey based on clinically relevant topics in nutrition during the first two years of life and their recommendations to parents in daily clinical practice. Most participants advise about the choking risk associated with baby-led weaning (BLW) and more than 60% consider that infants can receive an insufficient variety and quantity of nutrients with this practice. The general opinion is that there is a lack of evidence for delaying the introduction of gluten and other allergenic foods in the complementary feeding of healthy infants. Most participants agree/strongly agree that two servings of dairy products are the adequate daily amount in a diversified diet and 93.4% disagree/strongly disagree with the use of vegetal beverages under 1 year of life. There is a general agreement to avoid added salt and sugar before 12 months of life, the consideration that organic foods do not have a better nutritional profile than non-organic ones, and the limitations of vegetarian diets especially for adequate provision of micronutrients. Overall, there is an adequate knowledge of the new trends by paediatricians and younger ones seemed more in favor of them and interested in receiving more information on most topics.

Duodeno-ileal diversion with self-forming magnets in a sutureless neodymium anastomosis procedure (SNAP) for weight recidivism after sleeve gastrectomy: feasibility and 9-month results.

BACKGROUND: The sleeve gastrectomy (SG) has become the most common bariatric procedure worldwide. However, insufficient weight loss or weight recidivism is frequent, which may require effective and safe revisional procedures. OBJECTIVE: To determine the technical feasibility and safety of a minimally invasive, duodeno-ileal side-to-side anastomosis using a Sutureless Neodymium Anastomosis Procedure (SNAP) for patients with weight recidivism or inadequate weight loss following SG. METHODS: This is a prospective, single-arm, open-label pilot study that enrolled patients with obesity to assist in weight reduction following an SG performed > 12 months prior. For the SNAP, self-assembling magnets were deployed into the ileum (laparoscopically) and duodenum (per-oral endoscopy). Magnets were coupled under laparoscopic and fluoroscopic guidance to create a compression anastomosis. The primary endpoints were technical feasibility, weight loss, and rate of serious adverse events (SAEs). RESULTS: Successful duodeno-ileal diversions were created with SNAP in 27 participants (mean age: 50.6 ± 9.1, mean BMI: 38.1 ± 4.6 kg/m2) with no device-related serious adverse events. Upper endoscopy at 3 months confirmed patent, healthy anastomoses in all patients. At 9 months, patients (n = 24) experienced 11.9 ± 6.2%, 14.5 ± 10.8%, and 17.0 ± 13.9% TBWL at 3, 6, and 9 months, respectively. There were no device-related SAEs. CONCLUSION: The SNAP is technically feasible and relatively safe, with all patients presenting widely patent anastomosis at 3 months. Patients experienced a progressive, clinically meaningful weight loss. Further studies are needed to confirm our findings.

Epigenetic regulation of major histocompatibility complexes in gastrointestinal malignancies and the potential for clinical interception.

BACKGROUND: Gastrointestinal malignancies encompass a diverse group of cancers that pose significant challenges to global health. The major histocompatibility complex (MHC) plays a pivotal role in immune surveillance, orchestrating the recognition and elimination of tumor cells by the immune system. However, the intricate regulation of MHC gene expression is susceptible to dynamic epigenetic modification, which can influence functionality and pathological outcomes. MAIN BODY: By understanding the epigenetic alterations that drive MHC downregulation, insights are gained into the molecular mechanisms underlying immune escape, tumor progression, and immunotherapy resistance. This systematic review examines the current literature on epigenetic mechanisms that contribute to MHC deregulation in esophageal, gastric, pancreatic, hepatic and colorectal malignancies. Potential clinical implications are discussed of targeting aberrant epigenetic modifications to restore MHC expression and 0 the effectiveness of immunotherapeutic interventions. CONCLUSION: The integration of epigenetic-targeted therapies with immunotherapies holds great potential for improving clinical outcomes in patients with gastrointestinal malignancies and represents a compelling avenue for future research and therapeutic development.

Intraepithelial CD15 infiltration identifies high-grade anal dysplasia in people with HIV.

Men who have sex with men (MSM) with HIV are at high risk for squamous intraepithelial lesion (SIL) and anal cancer. Identifying local immunological mechanisms involved in the development of anal dysplasia could aid treatment and diagnostics. Here, we studied 111 anal biopsies obtained from 101 MSM with HIV, who participated in an anal screening program. We first assessed multiple immune subsets by flow cytometry, in addition to histological examination, in a discovery cohort. Selected molecules were further evaluated by immunohistochemistry in a validation cohort. Pathological samples were characterized by the presence of resident memory T cells with low expression of CD103 and by changes in natural killer cell subsets, affecting residency and activation. Furthermore, potentially immunosuppressive subsets, including CD15+CD16+ mature neutrophils, gradually increased as the anal lesion progressed. Immunohistochemistry verified the association between the presence of CD15 in the epithelium and SIL diagnosis for the correlation with high-grade SIL. A complex immunological environment with imbalanced proportions of resident effectors and immune-suppressive subsets characterized pathological samples. Neutrophil infiltration, determined by CD15 staining, may represent a valuable pathological marker associated with the grade of dysplasia.

The impact of clinical genome sequencing in a global population with suspected rare genetic disease.

There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9-3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1-∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5-1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.

Intensive induction chemotherapy vs hypomethylating agents in combination with venetoclax in NPM1-mutant AML.

ABSTRACT: Although intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remission among older patients with nucleophosmin 1 (NPM1) mutations. Whether IC or HMA/VEN is superior in patients aged ≥60 years with NPM1-mutant AML is unknown. We performed an international, multicenter retrospective cohort study of 221 patients (147 IC and 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR) (defined as CR + CR with incomplete count recovery) rate was similar for IC and HMA/VEN (cCR, 85% vs 74%; P = .067). Although overall survival (OS) was favorable with IC in unselected patients compared with HMA/VEN (24-month OS, 59% [95% confidence interval (CI), 52-69%] vs 38% [95% CI, 27-55%]; P = .013), it was not statistically different among patients aged 60-75 years (60% [95% CI, 52-70%] vs 44% [95% CI, 29-66%]; P = .069) and patients who received an allogeneic stem cell transplant (70% [95% CI, 58-85%] vs 66% [95% CI, 44-100%]; P = .56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS, 65% [95% CI, 56-74%] with IC vs 40% [95% CI, 26-60%] with HMA/VEN; P = .009) and without FLT3 internal tandem duplication mutations might benefit from IC compared with HMA/VEN (24-month OS, 68% [95% CI, 59-79%] vs 43% [95% CI, 29-63%]; P = .008). In multivariable analysis, OS was not statistically different between patients treated with IC and HMA/VEN (hazard ratio for death with HMA/VEN vs IC, 0.71; 95% CI, 0.40-1.27; P = .25).