Browse Articles

Harnessing the CD2 axis to broaden and enhance the efficacy of CAR T-cell therapies

Abstract Patients with T-cell lymphomas and leukemias have overall poor outcomes because of the lack of targeted and effective treatments, particularly in the relapsed and refractory settings. The development of chimeric antigen receptor (CAR) T cells against T-cell neoplasms is limited by a lack of discriminating T-cell antigens that allow for effective antitumor responses while preventing CAR T-cell fratricide. We hypothesized that targeting CD2, a pan–T-cell antigen, with anti-CD2 CAR T cells engineered to lack CD2 expression (CART2) would improve manufacturability and preclinical efficacy. Optimized CD2-knockout CART2 cells, generated using CRISPR-Cas9, eradicated primary patient-derived CD2+ hematological neoplasms in vitro and in vivo, secreted effector cytokines, and exhibited adequate proliferative capacity. Nevertheless, CD2 has a key costimulatory function, and its deletion could lead to CAR T-cell dysfunction. Therefore, we tested the role of the CD2:CD58 axis in CAR T cells, using the anti-CD19 CART models. We demonstrate that CD2 loss attenuates CART19 efficacy by reducing avidity for tumor antigen, costimulation, and ultimately in vivo activity. Analogously, we show that tumor CD58 loss reduces CART19 efficacy. To overcome this issue, we developed a novel programmed cell death protein 1 (PD-1):CD2 switch receptor that rescues intracellular CD2 signaling, particularly when programmed death-ligand 1 is engaged, thereby improving in vivo outcomes. Collectively, we studied the role of CD2 both as a target for CAR T-cell therapy and as a critical costimulatory protein, whose signaling can be rescued using the PD-1:CD2 switch receptor. This receptor can be incorporated into CAR T cells and provides an effective strategy to overcome CD2-signaling deficiencies.

Your nose contains multitudes — of long-lived immune cells

Correction: Evidence of microalgal isotopic fractionation through enrichment of depleted uranium

Folded domains impose structural heterogeneity and attenuated dynamics in biomolecular condensates

Size-independent, between-individual variability in feed ingestion rate in European seabass (Dicentrarchus labrax)

Understanding between-individual variability in energy acquisition is essential for elucidating many ecological processes in wild fish populations and for enhancing the efficiency of aquaculture production. This study explores whether individual variations in feed ingestion rates among group-reared fish can arise from intrinsic fish-specific, size-independent factors. Specifically, we quantify the residual variability in ingestion rate (i.e., the variability beyond body size effects and extrinsic influences) to assess the role of context-independent, stable, intrinsic behavioural differences that may lead to feeding hierarchies. We monitored the individual feeding behaviour of 48 European seabass adult females ( Dicentrarchus labrax) externally tagged reared in sea cages (6 cages housing 8 fish each) under three feeding levels (two cages per level) over four months. Across 8 repeated feeding trials per cage, fish were offered feed pellets one at a time using an automated feeder, and their individual pellet consumption were video recorded. Using a Bayesian statistical model, we evaluated the fish-specific probability of pellet consumption as a function of body size, temperature, anthropogenic stress and feeding level, while accounting for variation across individuals and feeding trials. Our results showed: i) a substantial and consistent between-individual variability in ingestion rates across feeding trials, and ii) a relevant negative effect of anthropogenic stress on feeding activity. Notably, individual-specific effects, independent of body size and external variables, accounted for over 70% of the variance in ingestion rate, suggesting that intrinsic and stable behavioural differences, indicative of fish behavioural types, may play a central role in shaping feeding hierarchies.

Transient aberrant plasma cells in a young patient with chronic inflammatory disease

Combining ability and molecular marker approach for developing early maturing high yielding hybrid rice

Regional drying over the Western U.S. driven by enhanced atmospheric subsidence amid global moistening from 1980 to 2020

Abstract As the global climate has warmed anthropogenically over the past decades, the atmosphere across most of the globe has experienced significant moistening, except for a “moistening hole” (MH) -like change over the Western U.S. This regional anomaly since 1980 is at odds with the forced response of climate models to global warming in this region. Here, through analysis of a wide array of observations and water-tagging enabled simulations, we find that atmospheric forcing originating from the North Pacific contributes to the MH. A barotropic high-pressure circulation trend over the North Pacific, driven by observed sea surface temperature cooling in the tropical Eastern Pacific, enhances atmospheric sinking over the Western U.S. through equatorward cold air advection. This intensified atmospheric descent suppresses precipitation and weakens land-sourced evaporation, which are critical for replenishing atmospheric moisture in the region. We suggest that focusing on low-frequency changes of atmospheric vertical motion may offer insights into assessing and projecting climate stress and drought risks posed by long-term atmospheric moisture deficits in arid regions.

The physical and psychological well-being after a pulmonary embolism across age and comorbidities – Evidence from focus group interviews

Background Few studies have investigated the psychological and physical consequences of having experienced a pulmonary embolism (PE), and most patients with PE are not offered proper follow-up. Objective To gain qualitative insight into the physical and psychological well-being across age and comorbidities and to investigate the patients need for rehabilitative strategies in patients with PE. Methods Qualitative data was obtained through focus group interviews. Patients were recruited from an outpatient thrombosis clinic at Herlev and Gentofte hospital in Denmark, based on the principles of maximum variation strategy which included age, concomitant disease, risk factors for pulmonary embolism (pregnancy, infection, cancer, and recurrence). Data was analysed using inductive thematic analysis. Results Six focus group interviews were conducted with a total of 17 participants being interviewed. Results showed that a significant degree of symptoms was experienced after PE. The emotional reactions experienced was largely affected by disease experience, and varied according to age, cancer status and PE in relation to pregnancy. Anticoagulation therapy was perceived as a life saver, yet it also contributed to a perception of being chronically ill, illustrating a medication conundrum. Lastly, confusion and frustration regarding follow-up care was prominent with a perception of limited guidance and limited information about potential rehabilitation strategies following PE. Conclusion This study showed that the patients’ experiences, worries and needs are different according to age and comorbidities, which indicates that interventions aimed at improving outcomes for these patients should be targeted accordingly.

Nikiforow S, Mahadeo K, Chaganti S, et al. Subgroup analysis based on prior treatment from the phase 3 allele study of tabelecleucel for epstein-barr virus-driven post-transplant lymphoproliferative disease [abstract]. <i>Blood.</i> 2025;146(suppl 1):1934.

Microbial hockey: bacteria can spin a ‘puck’ just by swimming

Non-equilibrium snapshots of ligand efficacy at the μ-opioid receptor

Characteristics of functional bacteria involved in carbon, nitrogen and sulfur cycles in PM2.5 under different meteorological conditions

Beyond metabolic dormancy: metabolic rewiring in bacterial persistence

Correction: A systematic review and meta-analysis of adolescent nutrition in Ethiopia: Transforming adolescent lives through nutrition (TALENT) initiative

Understanding how a highly prevalent <i>GRK5</i> polymorphism affects platelets and enhances thrombotic risk

Abstract Inherited genetic variants that modulate platelet function contribute significantly to thrombotic disorders, yet their mechanisms and clinical implications remain underexplored. Two genome-wide association studies identified an A→G variant (rs10886430) in the first intron of G protein–coupled receptor kinase 5 (GRK5), found in homozygosity in ∼5 million Americans. The homozygous GRK5 GG genotype is associated with an increased risk of stroke and venous thromboembolism, but the mechanistic link between this variant and thrombotic risk has remained unclear. To investigate this, we identified 3 GG individuals. GRK5 protein levels in GG platelets were 90% lower than in AA controls. The significant reduction in GRK5 levels in GG platelets led to elevated platelet responsiveness to thrombin and a protease-activated receptor 1 (PAR1) agonist but not a PAR4 agonist. These findings were corroborated in GRK5˗/˗ induced pluripotent stem cell–derived megakaryocytes, transgenic Grk5-deficient murine platelets, and AA platelets exposed to a GRK5 inhibitor. We demonstrated that PAR1 internalization was reduced in GG platelets, leading to enhanced PAR1 signaling. Under venous shear in an endothelialized microfluidic system, GG platelets exhibited increased accumulation, which was reversed by PAR1 inhibition with vorapaxar. In an arterial murine thrombosis model following human platelet infusion, GG platelets also showed enhanced thrombus formation in vivo. This study provides, to our knowledge, the first experimental evidence directly linking a highly prevalent human GRK5 variant to defective PAR1 regulation and increased thrombotic risk. Together, these findings establish that the GRK5 GG genotype confers increased thrombotic potential through impaired PAR1 desensitization, providing mechanistic insight that connects human genetics, thrombin receptor signaling, and thrombotic disease.

Characteristics and immune dynamics of peripheral blood immune cells and cytokines in individuals with chronic hepatitis B virus infection

Electrically reconfigurable extended lasing state in an organic liquid-crystal microcavity

Abstract Small-footprint, low-power, and reprogrammable arrays of coupled coherent emitters are highly sought in modern nanophotonics. Among existing solutions, only inorganic semiconductor microcavities operating in a strong light-matter coupling regime exhibit controlled on-chip interaction between individual coherent states, predominantly at cryogenic temperatures. Here, we demonstrate electrically controlled in-plane interaction between optically reconfigurable spatially separated lasing states, operating at room temperature in the weak light-matter coupling regime. An organic liquid crystal-filled microcavity is introduced as a new material platform where a spatially extended coherent lasing state, or “supermode", appears due to the blueshift-induced near-field transverse coupling between distinct spatially pumped states. We demonstrate a wide-range microscale control of supermode near- and far-field with on-chip phase-locking tuning functionality. We realize electrical control over the interaction strength between lasing states and corresponding mutual coherence going beyond nearest neighbours, and a spin-selective directional coupling regime by using a photonic analogue of the Rashba-Dresselhaus spin-orbit interaction.

LungNet: Leveraging state-space models with SE-enhanced skip connections for precise CT-based lung lesion segmentation

Lung cancer, which accounted for 2.48 million new cases and 1.82 million deaths worldwide in 2022, continues to be the most lethal cancer across the globe, underscoring the urgent demand for more advanced diagnostic tools. Although computed tomography (CT) imaging has long been central to lung cancer detection, the heterogeneous and complex characteristics of lung lesions make accurate segmentation particularly challenging. Current deep learning methods face a critical bottleneck: convolutional neural networks (CNNs) often struggle to capture long-range dependencies due to limited receptive fields, while Transformer-based architectures incur prohibitive computational costs when processing high-resolution CT volumes. Furthermore, standard skip connections in traditional UNet models frequently introduce redundant noise, leading to the dilution of subtle lesion features. To address these specific technical gaps, we introduce a novel deep learning framework that integrates Mamba state-space models with an improved UNet architecture. In this design, to mitigate feature redundancy, Squeeze-and-Excitation networks are embedded into skip connections, while auxiliary losses are introduced to address the degradation of shallow features and capture fine-grained lesion features across varied morphologies. Such a framework not only accommodates the intricate differences in lesion size, shape, and spatial distribution but also achieves a balance between global context modeling and linear computational efficiency. By uniting the local feature extraction strengths of convolutional layers with the long-range dependency modeling power of state-space models, our approach achieves more precise delineation of lung lesion boundaries. Extensive experiments conducted on multiple datasets provide compelling evidence of the method’s effectiveness: it attains state-of-the-art segmentation accuracy and demonstrates significant promise for enhancing early detection, ongoing disease monitoring, and treatment planning in lung cancer patients. This advancement delivers a robust solution for the inherently complex task of lung lesion segmentation. Moreover, because lung cancer treatment is costly and insurance coverage plays a decisive role in distributing expenses, the study’s outcomes also carry considerable implications for the insurance sector.

How I treat breakthrough thrombosis in patients with cancer

Abstract Patients with cancer face an increased risk of venous thromboembolism (VTE), and breakthrough thrombosis despite anticoagulation, with a 6-month cumulative incidence of 5% to 8%. The management of these events is challenging. Confirming suspected breakthrough thrombosis requires imaging review, ideally by comparison with postindex baseline studies, because residual thrombus is common and may mimic recurrence. When breakthrough thrombosis is confirmed, several potential contributing factors should be assessed. Nonadherence is common among patients undergoing anticoagulation and should be evaluated through detailed medication history. Measurement of drug-specific plasma levels, when available, may assist in confirming nonadherence. In patients on low-molecular-weight heparin (LMWH), underlying prothrombotic conditions such as heparin-induced thrombocytopenia or acquired antithrombin deficiency must also be considered. For patients receiving oral anticoagulants, drug-drug interactions and impaired gastrointestinal absorption should be excluded. Therapeutic strategies are guided by limited evidence, primarily from observational studies. Current practice generally favors switching to therapeutic LMWH if the patient was on oral anticoagulation, escalating LMWH dosing by 25% to 33% if already on therapeutic LMWH, or increasing LMWH to weight-adjusted therapeutic dose if treatment was subtherapeutic. Despite treatment adjustments, recurrence and bleeding risks remain substantial. In this review, we outline common clinical scenarios of breakthrough thrombosis in patients with cancer and critically appraise the available evidence to inform treatment decisions.