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Between a clot and a hard place: role of FXIa inhibition
UVB-induced Ca2+ signaling orchestrates PPP3CA-AFF4 axis to promote cancer stem cell plasticity in melanoma
A quantitative definition of the clinical manifestations of GATA2 deficiency in adults
Germline GATA2 deficiency is a pleiotropic condition 1-8 characterized by numerous phenotypes, including monocytopenia, immunodeficiency, microbial susceptibilities, and high rates of myeloid malignancies 1,8. Accurate curation of germline GATA2 variants is critical for patient care and requires well-defined phenotypes associated with GATA2 deficiency. The many phenotypes attributed to the condition render a simple description of GATA2 deficiency difficult, complicating the development of GATA2 variant curation rules. Therefore, the Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) sought to define GATA2 deficiency based on a statistical comparison of phenotype data. To do so, the MM-VCEP systematically analyzed phenotype data and applied statistical comparisons to define the phenotypic features of GATA2 deficiency to inform germline variant curation. The MM-VCEP assembled an international cohort of 339 people with clinically diagnosed GATA2 deficiency from 16 centers in seven countries. The 73 phenotypes of these individuals were compared statistically to those of control participants from the UK Biobank (UKBB). We compared single phenotypes as well as combinations of two, three, and four phenotypes in people with clinically diagnosed GATA2 deficiency to UKBB controls. We defined GATA2 deficiency as any of the 2,903 combinations of two or three phenotypes with log10Odds Ratio ≥3 (OR ≥ 1000). This definition of GATA2 deficiency will inform gene-specific phenotypic criteria used in GATA2 variant curation guidelines that will facilitate standardized variant curation by clinical laboratories worldwide.
Evidence of predation events by marine mammals at offshore wind farms
Abstract Anthropogenic structures in the marine environment alter the availability and distribution of food for marine animals with potential consequences for individual fitness, population and community dynamics. Knowledge of how marine mammals’ behaviour or foraging activities are influence by existing wind farms is essential to predict the effect of future large-scale renewable energy development on local or regional populations. During acoustic tracking of demersal gadoid fish at two offshore wind farms in Scotland, six Atlantic cod were predated by a marine mammal close to or in the vicinity of turbine foundations. The distinct change in the temperature, depth and movement pattern of the acoustic tags allowed estimations of the time and location of predation (and likely predator) and provided details of post consumption behaviour. The detection of tags (predator) at multiple turbines within a relatively short period, post consumption, suggests the targeted use of turbine foundations as foraging sites where prey fish are known to aggregate. Moreover, the bias in predation of cod over haddock, and evidence for the cod being of higher energetic quality, provide rare evidence for prey selection by a marine mammal predator(s). These data provide further evidence for how wind farms and other introduced structures influence the behaviour of marine mammals with potential consequences for individuals and populations through changes in the distribution of prey. The ultimate consequences are to be determined but need consideration with the continued development of offshore wind farm sites.
Renin-angiotensin-aldosterone system inhibition exacerbates anemia in sickle cell disease
Abstract Renin-angiotensin-aldosterone system inhibitors (RAASi) are suggested for treating albuminuria in patients with sickle cell disease (SCD). RAASi may exacerbate anemia in the general population and those with diabetes through unclear mechanisms. The impact of RAASi on anemia in chronic hemolytic disorders, such as SCD, is unknown. In a cross-sectional analysis of 658 Walk-PHaSST participants, RAASi use was independently associated with lower hemoglobin concentrations, adjusting for age, sex, SCD genotype, estimated glomerular filtration rate, and erythroid-stimulating agent and hydroxyurea use (β, −0.46 ± 0.21; P = .032). In 2 longitudinal cohorts (University of Illinois Chicago, n = 24; multicenter losartan clinical trial, n = 32), RAASi therapy led to a reduction in hemoglobin concentrations compared with pretreatment values by −0.44 ± 0.14 g/dL (P = .006) and −0.53 ± 0.17 g/dL (P = .005), respectively. SCD mice treated with losartan demonstrated lower hemoglobin concentrations after 6 and 14 weeks (P< .001) and lower absolute reticulocyte counts by 14 weeks (P = .03) vs control mice without changes in circulating erythropoietin, interleukin-12p70 (IL-12p70), IL-3, or insulin-like growth factor 1 levels. Bone marrow cells from losartan-treated SCD mice had lower colony-forming units (P ≤ .09) with rescue of erythroid colony formation after exogenous erythropoietin supplementation (P = .02). Bone marrow histopathology demonstrated reduced erythroid relative to myeloid ratios in losartan-treated vs untreated SCD mice. Hemoglobin levels should be closely monitored when using RAASi in this high-risk population.
Investigation of cold flow field characteristics in strut–cavity integrated afterburner
Mosunetuzumab plus polatuzumab vedotin for relapsed/refractory MCL after BTK inhibitor therapy: a phase 2 study
Abstract Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), especially those progressing after Bruton tyrosine kinase (BTK) inhibitor and/or chimeric antigen receptor (CAR) T-cell therapy and those with high-risk features, have poor outcomes. The bispecific antibody, mosunetuzumab, combined with the antibody-drug conjugate (ADC), polatuzumab vedotin (Mosun-Pola), targets CD20 and CD79b via independent cell-killing mechanisms. In this multicenter phase 2 study, patients with MCL who had received ≥2 previous lines of therapy, including a BTK inhibitor, were enrolled. Patients received outpatient fixed-duration mosunetuzumab subcutaneously (17 cycles), with cycle 1 step-up dosing to mitigate cytokine release syndrome (CRS), and polatuzumab vedotin (1.8 mg/kg IV) for 6 cycles. The primary end point was centrally assessed best objective response rate. A total of 42 patients with a median of 3 previous therapies were enrolled; 26% had previous CAR T-cell therapy. A number of patients had MCL with high-risk features (Ki-67 of ≥50%, 67%; blastoid/pleomorphic morphology, 38%; TP53 aberration, 48%). Objective response occurred in 88.1% of evaluable patients (95% confidence interval [CI], 74.4-96.0) and complete response in 78.6% (95% CI, 63.2-89.7). With a median follow-up of 15.9 months, median progression-free survival was 18.6 months (95% CI, 13.9 to not estimable). Consistent efficacy was observed in high-risk subgroups. CRS occurred in 42.9% of patients and was limited to grade 1/2 events. Mosun-Pola achieved high complete remission rates while maintaining a manageable safety profile in patients with R/R MCL exhibiting high-risk features. This is, to our knowledge, the first bispecific-ADC combination therapy study in MCL. This trial was registered at www.clinicaltrials.gov as #NCT03671018.
Evaluation of aspirin resistance and its association with TBXA2R and ABCB1 polymorphisms in patients with acute coronary syndrome: a single-center case-control study
Single-day nonactivated IL-18–armed CAR T cells establish a durable, stemlike state with enhanced persistence
Abstract Chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment of B-cell malignancies, yet challenges including manufacturing delays, T-cell exhaustion, and limited persistence impede broader clinical success. Here, we report the single-day production of nonactivated CAR T cells engineered to secrete interleukin-18 (IL-18), a proinflammatory cytokine that enhances T-cell function. These nonactivated CART19-IL-18 cells (IL-18–secreting anti-CD19 CAR T cells) exhibit robust antitumor efficacy across xenograft models of lymphoma, leukemia, and pancreatic cancer. IL-18 expression enhances the functional advantages of naïve-like nonactivated CAR T cells, resulting in improved persistence, metabolic fitness, and resistance to exhaustion. Single-cell transcriptomic analysis revealed upregulation of IL7R, KLF2, and MCL1, alongside suppression of inhibitory checkpoint genes such as PDCD1, TOX, and HAVCR2. Metabolomic profiling demonstrated enhanced mitochondrial bioenergetics, with increased spare respiratory capacity and accumulation of α-ketoglutarate, malate, and spermine. Functional in vitro and in vivo profiling demonstrated enhanced per-cell cytotoxicity and in vivo durability. We complemented these studies with single-cell transcriptomic and metabolomic analyses to define CAR T-cell biological states beyond what is captured by xenograft tumor clearance. This IL-18–enhanced, activation-free CAR T-cell product offers a clinically actionable platform with the potential to reduce vein-to-vein time while improving product potency and persistence, providing a rationale for clinical testing in patients with tumors refractory to standard CAR T-cell therapy.
A degradation index model for maintenance prediction run-to-failure in production systems
Abstract Timely asset maintenance remains a critical challenge in Industry 4.0 environments. Predictive Maintenance aims to anticipate failures and estimate Remaining Useful Life (RUL), enabling cost reduction and minimizing production downtime. However, real-world industrial scenarios are often characterized by noisy telemetry data, incomplete information about operating conditions, and weak degradation signals, which limit the effectiveness of conventional data-driven approaches. This paper proposes a methodology for RUL prediction under such challenging conditions, leveraging raw sensor telemetry without requiring detailed knowledge of machine operating characteristics. The approach introduces a novel Degradation Index, combined with a Health Index, to better represent degradation patterns. Additionally, signal preprocessing techniques, including Savitzky–Golay and Kalman filters, are applied to mitigate noise and improve data quality. The methodology integrates statistical analysis, similarity-based pattern extraction, and machine learning techniques, including Convolutional Neural Networks and Long Short-Term Memory models, for feature selection and prediction. Experiments conducted on real-world industrial datasets demonstrate that the proposed approach significantly improves prediction performance, achieving high accuracy and enabling failure anticipation up to five days in advance. The results highlight the importance of feature engineering and signal processing in PdM applications, showing that combining degradation modeling with deep learning yields robust, generalizable RUL predictions, even in noisy, partially observed environments.
Chromatin’s compass
Organic-rich carbonate characteristics and depositional settings of the Late Jurassic Lam Member in the Shabwah depression, southeastern Yemen
Boosting HSC functions: <scp>l</scp> -carnitine takes center stage
Development and validation of supervised machine learning models for the non-invasive screening of osteosarcopenia: Bushehr Elderly Health (BEH) program
LCK-targeting molecular glues overcome resistance to inhibitor-based therapy in T-cell acute lymphoblastic leukemia
Abstract Drug resistance is a major challenge in cancer therapy, especially in hematologic malignancies in which kinase inhibitors have transformed treatment yet are frequently undermined by drug resistance. Although targeted protein degradation (TPD) offers a mechanistically distinct mode of action compared with inhibition-based therapeutic therapies, the potential value of TPD in drug-resistant blood cancer remains unclear. Here, we report the discovery of cereblon (CRBN)–recruiting molecular glue degraders (MGDs) targeting lymphocyte-specific tyrosine kinase (LCK), an oncogenic kinase in T-cell acute lymphoblastic leukemia (T-ALL). By high-throughput screening and medicinal chemistry optimization, we developed a series of MGDs that induced CRBN-dependent degradation of LCK as well as potent cytotoxicity in T-ALL in vitro. Structure-activity relationship analysis and ternary complex modeling revealed a noncanonical degron at the LCK-CRBN interface involving the G-loop, whose mutation disrupts this interaction. Unlike inhibitors and inhibitor-based proteolysis-targeting chimeras, these MGDs engage LCK in regions distal to the ATP-binding site, and thus their activities in T-ALL are not affected by gatekeeper LCK mutations that drive resistance to inhibitor-based therapeutics. Taken together, our data highlight the potential of LCK-targeting MGDs as a strategy to overcome kinase inhibitor resistance in T-ALL, offering a framework for targeting kinase dependencies in drug-refractory hematologic malignancies more broadly.
Oral administration of a xanthine oxidoreductase inhibitor suppresses retinal degeneration and preserves ocular ATP levels
T-ALL micro(RNA)management: miR-15b and -16-2 join the team
Experimental evidence on response rates and data measurement in phone versus online surveys
<scp>l</scp> -Carnitine regulates regeneration of human hematopoietic stem and progenitor cells
Abstract Understanding how metabolism governs human hematopoietic stem cells (HSCs) function is essential for advancing regenerative therapies, yet direct metabolic profiling of human HSCs has been limited by their extreme scarcity and the technical limitations of conventional methods. Here, we applied a low-input mass spectrometry–based metabolomics platform, optimized for rare cell populations, to generate metabolic profiles of 13 immunophenotypically defined hematopoietic cell types from adult human bone marrow. Using as few as ∼10 000 cells per sample, we detected &gt;80 metabolites and uncovered both conserved metabolic programs in primitive hematopoietic stem and progenitor cells (HSPCs) and lineage-specific metabolic specializations. Of note, we identified l-carnitine–driven fatty acid oxidation as a key metabolic feature supporting HSPC function. Mechanistically, l-carnitine activates the peroxisome proliferator-activated receptor alpha–transcription factor EB signaling axis, promoting mitochondrial metabolism and autophagy to preserve regenerative capacity. Functional assays in primary CD34+ HSPCs derived from healthy donors or patients with aplastic anemia confirm that l-carnitine supplementation improves stem cell function ex vivo and in vivo. This work provides a foundation for human hematopoietic metabolism and reveals a targetable metabolic circuit governing HSPC regenerative fitness with therapeutic potential for improving stem cell–based interventions.