Browse Articles

Time of day of CAR T-cell infusion and outcomes in large B-cell lymphoma

Abstract Circadian rhythms orchestrate immune activation and effector function, yet whether within-day timing influences chimeric antigen receptor (CAR) T-cell therapy outcomes remains unknown. We conducted an international, multicenter retrospective study of 1052 adults with relapsed or refractory large B-cell lymphoma treated with CD19-directed CAR T-cell therapy across 7 centers (2017-2025). The median infusion time was 11:48 am (interquartile range, 11:06 am to 12:45 pm). Each hour later in infusion time was associated with an increased risk of progression, relapse, or death (hazard ratio, 1.11; 95% confidence interval, 1.03-1.20; P = .004) after adjustment for center, product, and key clinical variables. One-year progression-free survival (PFS) was 51.4% for early (before 12:00 noon) infusion vs 35.2% for late (at or after 12:00 noon) infusion, whereas overall survival was similar between groups. The PFS benefit was driven by lower relapse and higher complete response rates in the early infusion group. Although no differences were observed in immune toxicities, late infusion correlated with higher peak inflammatory markers and reduced day 7 CAR T-cell expansion. Together, these findings suggest that the timing of CAR T-cell infusion may influence therapeutic efficacy and support prospective evaluation of circadian-informed delivery strategies.

Fish meal replacement with poultry byproduct and black soldier fly larvae proteins: effects on growth, flesh quality, bioactivity, and physiological responses of Nile tilapia

Abstract The demand for fishmeal is increasing, but its supply is stagnating or even declining. There is an urgent need to find an eco-friendly and cost-effective alternative protein source. This study evaluated poultry by-product and insect meal as alternatives to fishmeal for the health performance and bioactivity of Nile tilapia. A Nile tilapia fry was divided into four groups with three replicates (No = 168). The first group was fed a basal diet containing 20% fishmeal (T FM ). The second, third, and fourth groups received a basal diet where the fishmeal was substituted with poultry by-product meal (T PM ), insect meal from Hermetia illucens (T IM ), and a mixture of poultry by-product and insect meal (T MIX ), respectively. The overall growth performance data indicated that T FM and T IM significantly achieved the highest growth rates and feed utilization ( P  < 0.05). The T IM diet significantly exhibited the highest total phenolic content, and both T IM and T FM showed superior antioxidant activity in fish muscle. There were no abnormal hematological or serum biochemical parameters observed in Nile tilapia fed insect meal and/or poultry by-product. The fish fillet samples from all groups were microbiologically safe for human consumption. Fish fed T IM displayed the lowest levels of TNF-α and the highest levels of IL-10 ( P  < 0.05). All the groups exhibited normal architecture of the internal organs. The significantly highest recorded absorption surface area was found in both T FM and T IM diets ( P  < 0.05). The NF-κB immunostaining showed no significant changes among experimental groups ( P  > 0.05). Based on this study, it can be suggested that the insect meal can be a sustainable and cost-effective substitute for conventional fishmeal in aquaculture feed formulations.

DC-CD4 bispecific tolerogenic nanovesicles induce antigen-specific regulatory T cells and ameliorate collagen-induced arthritis in mice

Myofibrillar protein accumulation but reduced protein synthesis in PDCD4-depleted myotubes

Skeletal muscle is critical to whole-body functionality and homeostasis. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient/growth-factor sensitive positive regulator of skeletal muscle mass. Amongst other substrates, mTORC1 phosphorylates the ribosomal protein S6 kinase (S6K1). Activated S6K1 acts through multiple effectors, including programmed cell death 4 (PDCD4), to promote mRNA translation and protein synthesis. Much of what is known about PDCD4 is in non-muscle cells. We previously demonstrated that the effect of PDCD4 differs between myoblasts and myotubes. Here, we showed that PDCD4 depletion in myotubes enhanced myotube diameter (+36%) and accumulation of myofibrillar proteins (+163–237%). These effects occurred along with increased phosphorylation of AKT ser473 (+85%) and of the mTORC1 substrate S6K1 thr389 (+152%), but protein synthesis was suppressed. There was increased phosphorylation of FoxO3a ser253 (+250%) and a corresponding reduction in the expression of the muscle protein ubiquitin ligase MuRF1 (–44%), but there was no significant effect on measures of proteolysis or autophagy. In starved myotubes treated with the proteasome inhibitor MG132, accumulation of ubiquitinated proteins was attenuated in PDCD4-depleted cells. PDCD4 depletion did not augment sarcoplasmic reticulum (SR) Ca 2+ release capacity but was associated with reduced ATP and intracellular amino acid levels. Finally, AKT inhibition partially attenuated the effect of PDCD4 depletion on myofibrillar protein abundance. In summary, myofibrillar protein accumulation in PDCD4-depleted myotubes did not lead to improved intracellular Ca 2+ handling, likely due to reduced energy level. Our data point to a pivotal role for PDCD4 in regulating myotube size.

Outcomes of BCP-ALL with hypodiploidy or <i>BCR</i> :: <i>ABL1</i> fusion in children undergoing allogeneic HSCT: results from the FORUM study

Abstract Hypodiploid and BCR::ABL1+ B-cell precursor acute lymphoblastic leukemia (BCP-ALL) confers a high risk of disease relapse. We investigated post–hematopoietic stem cell transplantation (HSCT) outcomes within the prospective FORUM trial, comparing outcomes among these genetic subgroups with those of patients without these lesions. The use of pre- and post-HSCT add-on treatments, including tyrosine kinase inhibitors (TKI) and immunotherapies, was also assessed. Multivariate analysis evaluated associations with overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR). The FORUM trial enrolled 741 patients aged ≥4 years with BCP-ALL who underwent HSCT from HLA-matched donors (2013-2023). The 3-year OS and EFS did not differ significantly between patients with BCR::ABL1 fusion, hypodiploidy, and neither of these 2 genetic lesions. However, patients with hypodiploid BCP-ALL in second complete remission (CR2) showed inferior OS and EFS, driven by higher nonrelapse mortality (NRM), which occurred exclusively in near-diploid cases. No NRM occurred in severe hypodiploid cases conditioned with total body irradiation. Minimal residual disease (MRD) positivity at transplant predicted worse OS, EFS, and CIR in all genetic groups. Patients with hypodiploid BCP-ALL were difficult to salvage after relapse, even with chimeric antigen receptor T-cell therapy. By contrast, BCR::ABL1+ patients had favorable outcomes, even when MRD positive before HSCT. Prophylactic TKI use after HSCT improved EFS and reduced CIR. BCR::ABL1+ patients who received a transplant in CR2 had a 3-year OS of 96%. In conclusion, the standardized FORUM protocol yielded comparable outcomes across genetic subgroups. Posttransplant TKI maintenance improved outcomes in BCR::ABL1+ BCP-ALL. This trial was registered at www.clinicaltrials.gov as #NCT01949129 and at www.clinicaltrialsregister.eu as #EudraCT2012-0032-22.

A potential of serum anti-C1P IgG antibodies as biomarkers in differential diagnosis of relapsing-remitting multiple sclerosis

Abstract There is a growing interest in the role of sphingolipids in the background of multiple sclerosis (MS). The goal of this study was to evaluate the serum levels of antibodies against ceramide-1-phosphate (C1P) subclasses and their relationships with clinical status in MS. The study groups comprised 39 patients with relapsing-remitting MS (RRMS), 26 patients with other neurological diseases (OND) and 12 healthy subjects (HS). Anti-C1P IgG levels in serum were determined using ELISA test. Levels of anti-C18:0-C1P and anti-C24:1-C1P IgG were significantly increased ( p  = 0.003; p  &lt; 0.0001, respectively) in RRMS compared to HS, while anti-C16:0-C1P and anti-C24:0-C1P IgG – significantly lower p  &lt; 0.0001 in RRMS compared to OND, with large effect size ( r  ≥ 0.5) in all above cases. In both settings the acceptable discriminatory performance for RRMS subtype from HS (AUC = 78.1%, 95% CI 66.1–90.4 and AUC = 76.9%, 95% CI 60.3–93.6, respectively) as well as from OND (AUC = 79.8%, 95% CI 68.2–91.4 and AUC = 94.2%, 95% CI 88.6–99.8, accordingly) by receiver operating curve (ROC) was shown. Validation of ROC by cluster analysis confirmed the ability of these anti-C1P IgG panels to discriminate between the study groups. No relationships were found between levels of antibodies in the anti-C1P IgG panel in RRMS group and disease duration, degree of disability or Link index. These findings highlight the relevant role of C1P as a target and/or mediator of autoimmune response in MS and potential value of anti-C1P antibodies as biomarkers in differential diagnosis of this disease.

Low-intensity focused ultrasound-activated piezoelectric gel bandage for diabetic wound repair and neuropathic pain relief

Evidence of allocentric spatial learning in male rats with large lesions of the hippocampus

The hippocampus (HPC) is the neural substrate of viewpoint-invariant cognitive maps, also known as allocentric spatial representations. Lesions of the HPC disrupt performance on allocentric tasks like the Morris Water Task (MWT), in which rodents must learn and recall the location of a platform submerged within a circular pool. Success in finding the hidden platform from any start point requires integrating multiple types of information, such as discerning its location relative to fixed (allocentric) environmental cues. Rats with HPC lesions, however, may show improvement in the MWT over repeated swim trials by resorting to alternative search strategies based on body-centered (egocentric) cues. Here, we investigated whether HPC lesion size correlates with allocentric impairments in the MWT. Using swim path classification alongside standard performance measures, we analyzed an archival dataset of 53 HPC lesion and 15 control rats trained under the same protocol. All rats showed evidence of learning, but the HPC group demonstrated impairment relative to the control group. Further analysis revealed that control rats shifted to a persistent allocentric search strategy by the fifth trial. The HPC rats shifted to persistent strategy use by the sixth trial, but not necessarily to an egocentric strategy. Interestingly, a subset of the HPC rats developed and maintained an allocentric strategy. Performance was not correlated with lesion size. These findings suggest that a subgroup of rats with HPC lesions, even nearly complete ones, can learn and remember allocentric spatial information in the MWT. This highlights the potential role of other brain regions in supporting spatial learning and memory in the absence of the HPC.

Novel strategies targeting mutant calreticulin in essential thrombocythemia and myelofibrosis

Abstract The discovery of calreticulin (CALR) mutations in patients with myeloproliferative neoplasms (MPNs) has paved the way for the elucidation of a unique disease mechanism that is particularly well suited to targeting by biologics. All MPN-associated pathogenic CALR mutations are characterized by a frameshift, resulting in translation of the same neoantigen peptide. This neoantigen directly activates the thrombopoietin receptor, leading to uncontrolled neoplastic cell proliferation. Current therapeutic approaches for MPNs are focused primarily on blood count control. Furthermore, current approaches are neither disease modifying nor clonally selective. However, because the mutant CALR neoantigen peptide is functional and not expressed in normal physiology, it is an ideal drug target. Here, we review the structure and function of mutant CALR, including the subtle yet clinically and therapeutically relevant differences between the 2 most commonly occurring types of mutation. We also review the current therapeutic landscape for CALR-mutated MPNs, highlighting the areas in which current approaches are inadequate. Finally, we review ongoing clinical and preclinical experimental approaches for targeting mutant CALR in MPNs in a clonally selective manner using monoclonal antibodies, bispecific antibodies, cancer vaccination, chimeric antigen receptor T cells, and antibody-drug conjugates. Taken together, we expect that ongoing developments in mutant CALR–targeted therapeutics will lead to promising novel strategies for long-term disease control.

Polymers with purpose: molecules can squirm free of the pack

A method for multi-criteria decision making with probabilistic linguistic term based on cloud TOPSIS

Effects of similarity networks in graph-based multi-omics classification

Accurate classification of disease subtypes is a fundamental requirement of precision medicine especially for complex and heterogeneous conditions such as breast cancer and Alzheimer’s disease. Recent advances in graph-based deep learning have shown strong potential in multi-omics integration by modeling inter-sample relationships through similarity networks. Yet, the question of how best to construct these networks remains an open and underexplored challenge. In this work, we present a systematic evaluation of six distinct similarity network construction strategies including Cosine Similarity, Cosine Distance, RBF-based measures, and two hybrid combinations leveraging a graph convolutional network (GCN) integrated with a view correlation discovery network (VCDN) framework for multi-omics disease classification. Using two benchmark datasets (BRCA and ROSMAP), we assessed the impact of each method on classification performance, variance across runs, and statistical robustness. Surprisingly, our results demonstrate that Cosine Similarity outperforms all other metrics, consistently achieving the highest accuracy, F1-score, and AUC, while also showing the lowest standard deviation across cross-validation splits. Despite the growing popularity of kernel-based and hybrid similarity designs, our findings highlight the unique effectiveness of simple angular similarity in capturing biologically meaningful structure in high-dimensional omics data. In our study, we showed that simple yet biologically meaningful similarity measures like Cosine Similarity can outperform more complex techniques in accuracy, consistency, and clarity. This insight sets the stage for building more effective and interpretable graph-based models to support precision medicine.

Brexucabtagene autoleucel for BTKi-naive relapsed/refractory mantle cell lymphoma: primary analysis of ZUMA-2 cohort 3

Abstract Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for adults with relapsed/refractory (R/R) mantle cell lymphoma (MCL) based on the ZUMA-2 cohort 1 (ClinicalTrials.gov identifier: NCT02601313) study in which brexu-cel demonstrated a 93% objective response rate (ORR) and 67% complete response (CR) rate in patients with R/R MCL and previous BTKi therapy (N = 60). Here, we report the primary results of ZUMA-2 cohort 3 (brexu-cel in patients with BTKi-naive R/R MCL). Adults received brexu-cel at 2 × 106 anti-CD19 CAR T cells per kilogram. The primary end point was ORR assessed by independent radiology review committee (IRRC). As of 26 November 2023, 95 patients were enrolled, and 86 received brexu-cel; median follow-up was 15.5 months. The primary end point was met, with a 91% ORR (95% confidence interval [CI], 82.5-95.9; P&amp;lt; .0001; N = 86) and a CR rate of 73% (95% CI, 62.6-82.2). Estimated 12-month progression-free survival (PFS), duration of response, and overall survival (OS) rates were 75%, 80%, and 90%, respectively. Among 95 enrolled patients, the ORR was 82%, the CR rate was 66%, and the 12-month PFS and OS rates (95% CI) were 73% (62.1-80.8) and 85% (75.6-90.7), respectively. Most patients (88%) experienced treatment-related grade ≥3 adverse events, including 4 treatment-related grade 5 events. Consistent with cohort 1, brexu-cel demonstrated a high ORR and similar safety profile. These results support the continued use of brexu-cel in patients with R/R MCL, and consideration in some patients without previous BTKi therapy who have high-risk disease. This trial was registered at clinicaltrials.gov as #NCT04880434.

Reproductive strategies of the most geographically isolated Trachylepis support predictions of the island syndrome

Genetic merit of sires for ad libitum residual feed intake has no adverse effects on carcass and ham quality traits of restricted-fed heavy pigs

This study evaluated the influence of sire genetic merit for residual feed intake (RFI) on carcass and ham quality traits in heavy pigs raised under the restricted feeding conditions typical of Protected Designation of Origin dry-cured ham production. A total of 417 purebred C21 Goland pigs, offspring of 23 sires, were randomly assigned to ad libitum , restricted medium-protein, or restricted low-protein dietary treatments. Sire breeding values (EBV) for RFI were estimated using RFI records of ad libitum -fed progeny between 96 and 161 kg body weight. Sires were classified into three RFI groups: low EBV (LRFI), medium EBV (MRFI), and high EBV (HRFI). Effects of RFI sire groups were estimated on traits recorded on the restricted-fed progeny. Progeny of LRFI sires exhibited differences in carcass traits, including a significantly higher carcass weight gain (+0.03 kg/day, corresponding to +7.3%; p&lt; 0.01) and increased green ham yield (+1.3%, p &lt; 0.05), compared to those of HRFI sires. LRFI progeny showed no differences in ham fat depth, but exhibited improved subcutaneous fat quality, including higher saturation (increased stearic acid, reduced linoleic acid and polyunsaturated fatty acids) and lower iodine number, as well as firmer subcutaneous fat. No variation in ham weight loss during dry-curing was observed across RFI sire groups. These findings suggest that selection for improved RFI does not significantly compromise carcass and dry-cured ham quality in restricted-fed heavy pigs. Incorporating RFI into selection objectives for sire lines could therefore provide a viable strategy for balancing production efficiency and product quality in heavy pig systems. These findings apply to restricted-fed heavy pigs of the population studied, and potential genotype × feeding regime interactions may limit direct extrapolation to other genetic backgrounds or production systems.

Immune thrombocytopenia in patients treated with immune checkpoint inhibitors

Abstract Immune checkpoint inhibitor–associated immune thrombocytopenia (ICI-ITP) has been described in case reports and small case series, but comprehensive data on its incidence, risk factors, clinical features, treatment, and outcomes are lacking. We reviewed medical records of all adults initiating ICI therapy between 2016 and 2023 at 29 US hospitals across 7 major cancer centers to identify patients with ICI-ITP. Multivariable logistic regression was used to identify risk factors, and Cox modeling was performed to assess the association between ICI-ITP, its severity, and mortality. Among 86 467 patients, ICI-ITP occurred in 214 (0.25%). Independent risk factors included lower baseline platelet count, combination ICI therapy, stage IV cancer, and additional immune-related adverse events. ICI-ITP occurred at a median of 8 weeks (interquartile range [IQR], 4-18) after ICI initiation, with a median nadir platelet count of 41 × 109/L (IQR, 17 × 109/L to 64 × 109/L). Patients were treated with glucocorticoids (n = 106 [49.5%]), immune globulin (n = 39 [18.2%]), and thrombopoietin receptor agonists (n = 29 [13.6%]). Recovery occurred in 161 patients (75.2%) at a median of 2.3 weeks (IQR, 1.0-5.3). Of 76 patients rechallenged with ICIs, 23 (30.3%) developed recurrent ICI-ITP. ICI-ITP and its severity were associated with higher all-cause mortality, with a nearly threefold increase in risk among patients with severe ICI-ITP than those without ICI-ITP (adjusted hazard ratio, 2.96 [95% confidence interval, 2.14-4.08]). These findings establish ICI-ITP as a rare but clinically significant complication of ICI therapy, provide, to our knowledge, the first large-scale description of its risk factors and clinical course, and underscore the importance of timely recognition and management.

A prospective study on the predictive value of the modified Glasgow prognostic score in non-small cell lung cancer treated with radiation therapy

“It makes me feel so much safer”: Sexual and gender minority community perspectives on telehealth use and implications for future practice

Introduction Telehealth has the potential to expand access to care, though barriers including insurance coverage, technology literacy, and personal preferences have been described since the pandemic induced uptick. Sexual and gender minoritized individuals (SGMs) face unique challenges which make telehealth a particularly promising care option. Regardless of population needs, research efforts looking at experiences and opportunities following multiple years of use are missing from the literature. Given that telehealth is here to stay, this study explores telehealth experiences, barriers, and preferences of SGM individuals 4 + years after rapid uptick to inform future efforts for the community. Methods Participants were recruited from an observational cohort study of SGM individuals. Eligible participants consented to follow-up contact and had previously used telehealth. Semi-structured interviews (N = 21) were conducted between March and April of 2024, covering telehealth use, barriers, and future directions. Interviews were recorded, transcribed, and thematically analyzed using a directed content analysis approach informed by prior literature. Coding was completed iteratively by four authors, with themes refined through group consensus, resulting in final recommendations for improving telehealth practice and engagement among SGM populations. Results The majority of participants were White (52%), cisgender men (90%) with at least some college education (90%), employed full-time (73%), and residing in the southern U.S (57%). Participants highlighted telehealth’s benefits, including provider accessibility, convenience, and comfort discussing sexual health needs with affirming clinicians. They found telehealth particularly useful for medication management, mental health, and sexual health services. They also emphasized the importance of promoting telehealth as providing privacy, security, and culturally competent care, findings which underscore their utilization motivators and shed light on unique needs of the population. Participants recommended improvement opportunities, such as creating/expanding directories of LGBTQ + -friendly providers and increasing/tailoring community-targeted marketing through social media and physical spaces. Discussion and conclusion We interviewed a diverse group of SGM-identifying telehealth users to explore their experiences with telehealth-based care. Participants expressed ongoing interest in telehealth overall, but conversations highlighted future opportunities and provided clear next steps for research, practice, and marketing. Our findings provide valuable insight for the next era of telehealth use.

Modulators of the hepcidin pathway in polycythemia vera and myelofibrosis

Abstract The peptide hepcidin is produced by the liver and serves as the central negative regulator of iron trafficking. Recently, drugs that affect the hepcidin pathway have been evaluated as potential treatment options for both controlling the degree of erythrocytosis in patients with polycythemia vera (PV) as well as correcting anemia associated with myelofibrosis (MF). Under normal conditions, increased hepcidin levels limit iron absorption from the gastrointestinal tract and iron recycling from liver and splenic macrophages, thus decreasing plasma iron levels and restricting iron availability for erythropoiesis. In PV, however, unrestricted erythropoiesis occurs despite low systemic iron levels. Because hepcidin levels are relatively low in patients with PV, hepcidin agonists (rusfertide, divesiran, sapablursen) are undergoing clinical development to control PV-associated erythrocytosis, thereby reducing the need for therapeutic phlebotomies and myelosuppressive therapeutic options. By contrast, hepcidin levels are increased in patients with MF leading to the trapping of iron in tissue macrophages, which creates a picture that resembles anemia of chronic inflammation. A number of strategies to lower hepcidin levels (the Janus kinase 2 inhibitors pacritinib and momelotinib, anti-hemojuvelin monoclonal antibody DISC-0974C) are currently undergoing clinical development to make systemic iron available for erythropoiesis and alleviate the degree of MF-associated anemia. These new therapeutic options that modulate iron trafficking in patients with PV and MF represent the application of greater knowledge of iron trafficking to create novel therapeutic options to treat patients with hematological malignancies.

Interpretable machine learning for thermoelectric materials design with Kolmogorov–Arnold networks

Abstract The discovery of high-performance thermoelectric materials requires models that are both accurate and interpretable. Traditional machine learning approaches, while effective at property prediction, often act as black boxes and provide limited physical insight. In this work, we introduce Kolmogorov–Arnold Networks (KANs) for the prediction of thermoelectric properties, focusing on the Seebeck coefficient and band gap. Compared to multilayer perceptrons (MLPs), KANs achieve comparable predictive accuracy while offering explicit symbolic representations of structure-property relationships. This dual capability enables both reliable predictions and physically interpretable functional forms, providing insight into the governing mechanisms of thermoelectric behaviour. Benchmarking against literature baselines highlights their robustness and generalisability, demonstrating that KANs constitute a practical framework for reverse engineering materials with targeted thermoelectric performance and bridging the gap between predictive power and scientific interpretability.