Browse Articles

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 &amp;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.

Exercise trainingin home-based pulmonary rehabilitationforchronic obstructive pulmonary disease:Asystematic review and meta-analysis

Chen L, Monti S, Juszczynski P, et al. SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma, <i>Blood</i> . 2008;111(4):2230-2237.

Impact of polygeneration topology on the technoeconomic performance of green hydrogen production utilizing integrated CPVT systems

Abstract This paper presents a year-long hour-by-hour dynamic comparative analysis of solar-driven polygeneration configurations at three Egyptian Sea coast locations — Hurghada, Suez, and Port Said. A MATLAB/SIMSCAPE computational framework is developed and validated, coupling a concentrating parabolic trough collector (PTC) to two receiver technologies: a conventional concentrating photovoltaic-thermal (CPVT), receiver-A, and a high-efficiency GaInP/GaInAs/Ge triple-junction photovoltaic-thermal (C3JT), receiver-B. Both are integrated with proton exchange membrane (PEM) electrolyzer and multi-effect evaporation (MEE) desalination units. Four configurations are evaluated: Polygeneration-I (Cases I-A and I-B) producing hydrogen and freshwater, and Polygeneration-II (Cases II-A and II-B) producing hydrogen and exporting electricity. The results show that the C3JT architecture consistently outperforms CPVT by 57.1–57.7% in annual hydrogen production across all configurations and locations. A global minimum levelized cost of hydrogen (LCOH) of 2.909 USD/kg is achieved by Case II-B at Hurghada, representing a 32.6% reduction relative to the Polygeneration-I CPVT baseline (Case I-A) at the same location. MEE thermal integration introduces an energy partitioning trade-off that reduces system-to-hydrogen HHV efficiency to 4.53–7.43% across Polygeneration-I configurations, yet this is more than offset by freshwater revenue credits in the economic framework. The results also demonstrate the economic viability of concentrating solar polygeneration in Egypt without requiring gigawatt-scale deployment.

Discovery and preclinical activity of the menin-KMT2A inhibitor ziftomenib in acute leukemia models

Abstract The protein-protein interaction between menin and KMT2A (histone lysine methyltransferase 2A) plays a critical role in acute leukemia with KMT2A rearrangements, nucleophosmin 1 (NPM1) mutations, and nucleoporin 98 rearrangements and represents an emerging opportunity for therapeutic intervention. Here, we report the development and comprehensive evaluation of the activity of ziftomenib as an orally bioavailable, highly potent, and selective small-molecule inhibitor of the menin-KMT2A interaction. In leukemia cells and primary patient samples with the menin-KMT2A dependency, ziftomenib profoundly inhibited proliferation, reduced clonogenic potential, and induced differentiation, which was associated with strong downregulation of the menin-KMT2A target genes, including MEIS1, HOXA9, and HOXB2. In xenografts and patient-derived xenograft models of KMT2A-rearranged leukemia, ziftomenib induced leukemia regression or reduced leukemia burden, accompanied by a pronounced reduction in the menin-KMT2A target genes. We next assessed ziftomenib against 4 MEN1 (gene encoding menin) mutants (T349M, M327I, G331R, G331D) associated with clinical resistance to another menin inhibitor, revumenib. Ziftomenib retained antileukemic activity against T349M mutant cells and demonstrated low nanomolar potency (50% growth inhibition ≤ 25nM) against G331R cells, despite several-fold reduced potency relative to MEN1 wild-type cells, whereas the M327I and G331D mutants were resistant. The crystal structures of ziftomenib in complex with menin wild-type, T349M, or G331R mutants revealed a similar binding mode of ziftomenib to these menin variants, rationalizing the potent inhibitory activity toward these mutants. Ziftomenib has recently received US Food and Drug Administration approval for adult patients with NPM1-mutated acute myeloid leukemia and continues to be evaluated clinically in leukemias with NPM1 or KMT2A alterations, both as monotherapy and in combinations.

OCT angiography vessel density loss and rates of visual field progression in glaucoma and glaucoma suspects

Abstract To evaluate the relationship between rates of retinal vessel density (VD) loss and rates of central and peripheral standard automated perimetry (SAP) progression. In this prospective cohort study, 116 eyes (85 glaucoma, 31 suspects) from 60 participants (mean age 68.6 ± 7.6 years) were followed at 4-month intervals. Participants underwent comprehensive ophthalmic evaluation, blood pressure assessment, SAP, and optical coherence tomography angiography (OCTA) of the optic nerve head (ONH) and peripapillary retina. OCTA scans (4.5 × 4.5 mm) were centered on the ONH, and VD was quantified using a custom fractal analysis algorithm. Over 33.3 ± 6.6 months, eyes completed an average of 7.9 ± 2.0 SAP and OCTA exams. The median SAP MD slope was 0.19 dB/year (range –2.99 to 2.74 dB/year), with 4.3% of eyes showing moderate to fast progression (≤ –0.50 dB/year). Faster SAP deterioration, across MD, central 5°, central 10°, and peripheral MS, was significantly associated with faster RPC VD loss (β = –1.63 to –2.17%/year; all p  ≤ 0.01) after adjusting for confounding factors. Rates of RPC VD loss measured by OCTA are strongly correlated with both central and peripheral SAP progression, supporting RPC VD loss as a biomarker associated with glaucomatous functional decline in this predominantly mild, slow-progressing cohort.

Two birds with one stone: faster, fitter CAR T cells