Browse Articles

Antigen-boosted CD4CAR T cells fail to expand or control viremia in multiple nonhuman primate models of HIV

Abstract Chimeric antigen receptor T (CAR T)-cell therapy has demonstrated curative potential in B-cell malignancies; yet, translating this success to chronic infections such as HIV remains a major challenge. In people living with HIV who are receiving suppressive antiretroviral therapy (ART), low-antigen levels limit CAR T-cell expansion and persistence. We previously reported data from a pilot study suggesting that HIV-targeted CD4CAR T cells could overcome this barrier through exogenous antigen supplementation, leading to robust in vivo expansion. Here we sought to comprehensively confirm and expand on those findings. We tested a broad array of strategies to enhance CD4CAR T-cell efficacy, including CRISPR-Cas9-mediated gene editing of immune checkpoint and HIV-associated genes, single and pooled competitive infusions of engineered CAR T cells, distinct CAR constructs incorporating either CD28 or 4-1BB costimulatory domains, and exogenous antigen boosting. We also developed highly sensitive droplet digital polymerase chain reaction assays to quantify CAR T-cell frequency and to corroborate the flow cytometry–based quantification of CD4CAR T-cell expansion. We evaluated these new approaches across multiple nonhuman primate (NHP) models of HIV, including both simian immunodeficiency virus– and simian-human immunodeficiency virus–infected, ART-suppressed NHPs. Although CD4CAR T-cell products exhibited antigen-specific proliferation and cytotoxicity ex vivo, they failed to expand, persist, or control viremia in vivo. We were also unable to confirm the previously observed CD4CAR T-cell expansions from our earlier studies, which have been retracted. Together, these data highlight the need for alternative strategies to potentiate anti-HIV CD4CAR T cells in the immunocompetent setting.

Antitumor efficacy of cobalt–zinc ferrite nanoparticles on MCF-7 cell line and Ehrlich ascites carcinoma bearing mice

Abstract Cobalt–zinc ferrite nanoparticles (Co 1−x Zn x Fe 2 O 4 ; x = 0, 0.35) were synthesized using a flash-combustion method and characterized by FTIR and SEM to evaluate their structural and surface properties. This study investigated the in vitro and in vivo antitumor efficacy of cobalt ferrite nanoparticles (CF NPs). In vitro, human breast cancer cells (MCF-7) were used to determine cytotoxicity (IC 50 ), apoptosis, and cell cycle effects. The IC 50 of CF NPs was 144 µg/mL. Treatment with 1/10 IC 50 increased necrotic, early apoptotic, and late apoptotic cell populations to 7.2%, 9.5%, and 12.6%, respectively. CF NPs arrested the cell cycle at sub-G1 and G2/M phases, while IC 50 of cisplatin was 11.25 µg/mL. Treatment with1/10 IC 50 arrested the cell cycle at S and G2/M phases. For in vivo analysis, forty female albino mice (CD-1) were divided into four groups. Tumor induction was performed using Ehrlich ascites carcinoma (EAC) cells (1 × 10 6 /mouse). After 24 h, mice received either cisplatin (2 mg/kg) or CF NPs (150 mg/kg; 1/10 LD 50 ). After 14 days, CF NP treatment significantly reduced body weight gain, tumor volume (44%), tumor cell count (28%), and viable tumor cells (30%). Additionally, CF NPs improved hematological parameters, liver and kidney function, and restored normal histological architecture of hepatic and renal tissues. CF NPs exhibit significant antitumor activity both in vitro and in vivo by inducing apoptosis, suppressing tumor growth, and improving biochemical and histopathological parameters, supporting their potential as a promising adjunct in cancer nanotherapy.

Photobiomodulation for pain management during placement of the copper T 380 intrauterine device: Protocol for a randomized, double-blind controlled trial

Introduction Unplanned pregnancy remains a critical public health issue in Brazil that affects up to 65% of women in some regions and increases the incidence of both unsafe abortions and maternal mortality. Although the copper intrauterine device (IUD) is a highly effective, long-acting contraceptive method, its rate of use remains low in Brazil (only 4.4% of women of reproductive age). One of the primary barriers is the pain experienced during placement of the device, which discourages adherence. Although multiple social and cultural determinants influence IUD uptake, insertion-related pain constitutes a modifiable, procedure-specific factor that may directly affect both pain perception and anticipatory discomfort. Conventional pain management strategies, such as anti-inflammatories and local anesthetics, have produced inconsistent results. Photobiomodulation (PBM) is a non-invasive therapy with anti-inflammatory and analgesic properties that has shown promise in managing pelvic pain in contexts such as labor. Methods and analysis The proposed randomized, double-blind clinical trial will investigate the effectiveness of PBM at reducing pain during the placement of the copper T 380 IUD. Seventy-two women will be randomly allocated to either an active PBM group (n = 36) or sham PBM control group (n = 36). In all participants, the standard IUD placement protocol will follow the guidelines of the Brazilian Ministry of Health. Pain will be assessed using the Visual Analog Scale (VAS) at multiple time points: during each step of insertion (Pozzi clamp, hysterometry, IUD placement) as well as 5 min, 15 min, 24 hours, and 48 hours post-procedure. The secondary outcomes will be analgesic use, anxiety levels (GAD-7), quality of life (WHOQOL-100), satisfaction with the procedure, and adverse effects. Ethics and dissemination. This clinical trial received approval from the Research Ethics Committee of the Mandaqui Hospital Complex (process: 7.367.867) and was registered in ClinicalTrials.gov (NCT06984796). Statistical analyses will be conducted using SPSS v24.0, with a significance level of 5%. Either parametric or nonparametric tests will be applied, depending on the data distribution. Kaplan-Meier curves will be used to assess time to pain resolution. The results will be disseminated through peer-reviewed publications.

Morphologic and flow cytometric features of menin inhibitor–induced pseudoprogression in <i>KMT2A</i> -rearranged acute myeloid leukemia

Subbrow blepharoplasty reveals a natural eyelid crease with appropriate skin removal

Knowledge, attitude, and practice about e-cigarettes among university students: A comparative study between Afghanistan, the Netherlands, and Turkey

Background The rise in e-cigarette use among young adults has raised significant public health concerns. Initially introduced as a harm-reduction tool, e-cigarettes have increasingly become a popular alternative to traditional smoking. However, misconceptions about their safety, social acceptability, and long-term health effects persist among university students. Methods This study adopts an analytical cross-sectional design and employs a foundational approach by administering an online questionnaire. The study uses a quantitative methodology to explore universities students’ knowledge, attitudes, and perceptions regarding e-cigarettes. Data collection was facilitated through a survey distributed via Google Forms, and statistical analysis was performed using SPSS (Statistical Package for the Social Sciences) 26 to identify significant associations. Results The findings revealed that 54.2% of students reported using e-cigarettes, with a higher prevalence among those with close friends or family members who smoked. Knowledge about e-cigarettes was generally low, with 56.2% demonstrating poor understanding, particularly regarding the health risks and regulatory status of e-cigarettes. Attitudes were largely negative, with 73.4% expressing concerns about vaping, though 62.7% believed it was more socially acceptable than traditional smoking. Peer influence was a major factor, as 74.6% of e-cigarette users had close friends who also vaped. A significant association was found between smoking tobacco and e-cigarette use (p = 0.00), indicating a trend of dual-use rather than e-cigarettes serving as a quitting tool. Conclusion The study highlights a critical gap in e-cigarette knowledge and a strong influence of social and environmental factors on vaping behaviors. Despite negative attitudes toward vaping, its perceived social acceptability remains high. Public health interventions should focus on targeted educational campaigns, peer-led awareness programs, and regulatory measures to address misconceptions and reduce e-cigarette use among young adults.

The GATA1 N terminus coordinates metabolic reprogramming in erythropoiesis

Abstract Mutations in GATA1 that cause skipping of exon 2, which encodes the N terminus, are associated with the myeloid leukemia of Down syndrome and Diamond-Blackfan anemia (DBA). To elucidate the molecular function of this N-terminal region, we used single-cell RNA sequencing (scRNA-seq) on fetal liver cells from Gata1-mutant embryos that express only the short isoform of GATA1 (GATA1s) lacking the N terminus of full-length GATA1 (GATA1FL). scRNA-seq revealed defects in erythropoiesis and aberrant upregulation of glycolytic genes, including PKM, which encodes pyruvate kinase to catalyze the final and irreversible step of glycolysis. Using precision nuclear run-on sequencing and cleavage under targets and release using nuclease (CUT&amp;RUN) after acute GATA1 deletion in erythroid cells, we identified PKM as a direct target of GATA1. Substitution of GATA1FL with GATA1s induced histone lactylation at the PKM promoter, increased pyruvate kinase M (PKM) expression and activity, and enhanced glycolytic flux in erythroid progenitors, without affecting mitochondrial respiration. Importantly, PKM expression is also significantly elevated in patients with DBA with RPS19 mutations, which is associated with reduced levels of GATA1, further supporting a link between GATA1s-driven defective erythropoiesis and dysregulated glycolysis. Together, these findings reveal that GATA1 controls not only heme metabolism but also glycolytic reprogramming.

Unintended tripping of healthy parallel lines during single-line-to-ground faults: field evidence and mitigation

Retraction: Digital economy, scientific and technological innovation, and high-quality economic development: A mediating effect model based on the spatial perspective

Unlocking the locking secret behind FNAlT

H2O2 repurposes plant O2 sensing to regulate post-hypoxia responses

Abstract Understanding plant molecular responses to flooding is crucial for strategies to increase resilience. Plants respond to submergence-induced low oxygen (hypoxia) through decreased plant cysteine oxidase (PCO) activity, which stabilizes group VII ethylene response factors (ERFVIIs), master regulators of metabolic and anatomic acclimation responses 1–4 . Rapid reoxygenation on desubmergence induces a burst of reactive oxygen species (ROS) generation and metabolic reconfiguration 5,6 ; however, how plants mitigate this post-hypoxic stress to facilitate submergence recovery has remained unknown. Here we report that ERFVIIs are also important in post-submergence recovery, remaining stable upon reoxygenation through ROS-mediated PCO inhibition. Stabilized ERFVIIs are retained at hypoxia-responsive promoters, becoming repressors of typical hypoxia marker genes but upregulators of genes involved in ROS homeostasis and oxidative stress protection. Our findings suggest that PCOs and ERFVIIs integrate signals from both oxygen and ROS to coordinate ERFVII stability through submergence-induced hypoxia and desubmergence stress to promote plant survival and recovery.

A fully-CMOS spiking LIF neuron implementation for optimized STDP learning on memristor

Expression of Concern: Economic policy uncertainty, intra-industry trade, and China’s mechanical and electrical product exports

CD117-targeted HCT preconditioning in AML and MDS

Development and evaluation of an effective solubility prediction model for pharmaceuticals in organic solvents using machine learning based on eXtreme Gradient Boosting

Abstract In this work, we have examined the predictive capability of a machine leaning model based on the XGBoost framework as regards the solubility of active pharmaceutical ingredient-like molecules in organic solvents over a wide range of temperatures. A total of 30 binary mixtures has been investigated. The dataset was divided in two sets, with one set for training, testing and validation including solubility data for four solute compounds (butyl paraben, fenofibrate, risperidone, fenoxycarb) consisting of a total of 224 data points, and the second set used for prediction consisting of the solubility data for butamben, with 50 data points in total. The calculated root mean square errors (RMSLE) for the calculated solubility (train, test, validation) were 0.05, 0.09, 0.13 and 0.15, respectively, while the average RMSLE for the predicted solubility of butamben was 0.41. A total of 10 descriptors were considered in this work, comprising parameters for solute (heat of fusion, melting temperature, heat capacity and Hansen solubility parameter), two descriptors representing the solvent (dielectric constant and boiling temperature) as well as temperature, and drug and solvent names. The temperature-dependence of solubility has been captured accurately by setting a constraint on the XGBoost algorithm. A comparison between the performance of the machine learning model proposed and evaluated in this work, and the semi-predictive Flory-Huggins and the temperature-dependent NRTL-SAC models on the other hand, shows that for all the studied compounds, the machine learning model can deliver significantly improved capability to model as well as predict solubility.

‘The world is just so fast, and I’m not fast… it’s just really, really difficult to keep up’: A qualitative exploration of the lived experience of adults with Developmental Coordination Disorder

Background Developmental Coordination Disorder (DCD) is an under-recognised neurodevelopmental condition impacting 5–6% of the population. There is a growing evidence base showing the deleterious impacts of poor motor skill development, however there is a distinct lack of research gathering in-depth insights which explore the impact of DCD within both childhood and adulthood. Methods Ten online lived experience interviews were undertaken with adults who have a diagnosis of DCD/ Dyspraxia (8 females, 2 males), lasting between 30 minutes and one hour. Participants were recruited both nationally and internationally. Lived experience interviews focused on experiences in primary care, education, friendships, wellbeing, employment and romantic relationships. Data were transcribed and analysed using inductive thematic analysis. Results Emergent themes highlighted a major lack of societal awareness in all life domains, which often led to participants facing difficulties navigating health, education and workplace systems for support, resulting in relative abandonment and a lack of validation within their lived experience of DCD. Conclusion Individuals with DCD often report feeling alone, isolated and misunderstood in a world which presents challenges for them across all aspects of life. There is an urgent need for the profile of DCD to be raised by insider voices as for many, DCD often transcends diagnostic criteria to wider challenges, for example executive functioning. Fundamentally, more needs to be done to ensure a lifespan approach to DCD, to allow greater opportunities for adults with a diagnosis to thrive alongside their ‘neurotypical’ peers.

How I treat HLH-like toxicities after immune effector cell therapy

Abstract Breakthroughs in cancer immunotherapy have redefined patient care, ushering in a new era of therapeutic modalities, chimeric antigen receptor T cells (CAR-T), and bispecific T-cell engagers, among others. Hemophagocytic lymphohistiocytosis (HLH)–like toxicities triggered by these immunotherapies are increasingly recognized as part of a broader category of hyperinflammatory syndromes. The recently defined immune effector cell–associated HLH-like syndrome (IEC-HS), characterized by hallmark clinical and biochemical features of secondary HLH, is both clinically and temporally distinct from cytokine release syndrome (CRS), typically emerging as CRS subsides or after it has resolved. In contrast, in CRS with multiorgan dysfunction (CRS-MOD), HLH-like manifestations often appear with worsening CRS and progress through standard CRS-directed therapy. Importantly, CRS-MOD is to be differentiated from the acute hyperferritinemia and transient organ toxicities seen with CRS, which often responds to standard CRS management. Clinically differentiating these HLH-like syndromes remains challenging; however, their shared pathophysiology has contributed to an evolving landscape of therapeutic strategies. Given the association of HLH-like toxicities with poor outcomes, enhanced recognition, comprehensive diagnostic approaches, and early intervention strategies may improve outcomes, preserving the potential benefit of the therapies patients are receiving. In this article, we highlight our collective approach in managing 2 recognized CAR-associated HLH-like toxicity syndromes, CRS-MOD and IEC-HS, and provide an overview of the current treatment landscape.

Influence of wind barrier configuration on driving space over bridge decks: A PIV-based parametric study

Impact of depression and anxiety on health-related quality of life changes over time within individuals with rheumatoid arthritis or inflammatory bowel disease: A prospective Canadian cohort study

Objectives In individuals with rheumatoid arthritis (RA), inflammatory bowel disease (IBD), or primary depressive or anxiety disorders without RA or IBD (DEP/ANX) we aimed to evaluate between-person and within-person changes in physical and mental health-related quality of life (HRQoL) over time. We also aimed to compare the impacts of depression and anxiety symptoms on HRQoL, and to examine the roles of physical and cognitive functioning, fatigue, physical comorbidities, and disease activity, on HRQoL over time. Methods As part of a single centre prospective cohort study, individuals with RA (n = 154), IBD (n = 247), or DEP/ANX (n = 306) recruited between November 2014 and July 2016 were seen annually for 3 years. Participants reported symptoms of depression and anxiety (Hospital Anxiety and Depression Scale), fatigue (Daily Fatigue Impact Scale), HRQoL (RAND-36), and completed functional assessments (physical: nine-hole peg test, timed 25-foot walk test; cognition: Symbol Digit Modalities Test). Generalized linear models with generalized estimating equations tested between-person and within-person associations of depression and anxiety with HRQoL in covariate-adjusted models that included socio-demographic characteristics, health status and medication use. Physical (PCS-36) and mental (MCS-36) HRQoL were assessed separately and comparatively for RA, IBD and DEP/ANX. Results RA participants were older than IBD or DEP/ANX participants [mean age = 59.49(11.66), 47.45(14.80), 43.87(12.94)]. Most participants (&gt;85%) reported meaningful changes in HRQoL. After adjustment, within-person increased depressive and anxiety symptoms were associated with reduced MCS-36 [depression: −7.91 (−9.45, −6.36), anxiety: −5.62 (−6.85, −4.39)]. Increased fatigue and worse cognition were associated with reduced PCS-36 [−0.33 (−0.38, −0.28); −0.31 (−0.64, 0.022)]. After adjustment, increased physical function, IBD or DEP/ANX diagnosis were associated with higher PCS-36 [1.47 (0.63, 2.30); 2.84 (1.60, 4.08); 5.23 (3.92, 6.55)]. Conclusions Variations in depression, anxiety, fatigue, cognition, and physical function are associated with HRQoL fluctuations in people with RA, IBD and DEP/ANX, highlighting the importance of addressing these issues while treating disease.

Thrombotic thrombocytopenic purpura: celebrating 25 years of ADAMTS13

Abstract Thrombotic thrombocytopenic purpura (TTP) was first described just over a century ago, and it is now 25 years since the identification of ADAMTS13 as the enzyme deficient in both antibody-mediated immune TTP (iTTP) and congenital TTP (cTTP). The discovery of ADAMTS13 has been fundamental to the vast improvement seen in TTP outcomes. Understanding the interaction between ADAMTS13, platelets, and von Willebrand factor led to the development of clinical ADAMTS13 assays, and therefore quicker and accurate diagnosis, but also, critically, to novel therapies and monitoring of treatment. Landmark additions to iTTP therapy have included anti-CD20 treatment with rituximab, in both the acute and elective settings, and the use of the nanobody caplacizumab in acute TTP. In cTTP, the use of ADAMTS13 replacement is playing a role in reducing end-organ damage and morbidity, with recombinant ADAMTS13 (rADAMTS13) now representing the gold standard for cTTP. The ability to measure response to treatment by monitoring ADAMTS13 activity has underpinned these treatment advances, and allowed clinicians to tailor immunosuppressive treatment for iTTP and rADAMTS13 dosing in cTTP. Looking forward, there are many avenues for future development, with potential expansion of rADAMTS13 to treat iTTP, new, quicker assays to improve diagnosis, monitoring, and immunomodulatory therapeutic advancement, all underpinned by ADAMTS13. Future endeavors for the role of ADAMTS13 in other thrombotic indications open further exciting opportunities.