Search Results (1,205)

The therapeutic landscape of adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is undergoing a paradigm shift, driven by the development of immunotherapy-based “chemo-free” and “chemo-light’ regimens. These strategies aim to achieve high efficacy with reduced toxicity, particularly in older adults who may not tolerate intensive chemotherapy. In Philadelphia chromosome-positive (Ph+) BCP-ALL, the incorporation of ABL tyrosine kinase inhibitors (TKIs) with blinatumomab (CD3/CD19 bispecific T-cell engager) has shown remarkable efficacy, with some studies reporting molecular response rates in the range of 90–100% and long-term survival exceeding 80% without the need for intensive chemotherapy or allogeneic hematopoietic cell transplantation (allo-HCT). In Philadelphia-negative (Ph−) BCP- ALL, an immunotherapy-based combination of blinatumomab and inotuzumab ozogamicin (anti-CD22 antibody-drug conjugate) has demonstrated high rates of complete remission and measurable residual disease (MRD) negativity, with manageable toxicity. While chimeric antigen receptor (CAR) T-cell therapy remains a transformative option for relapsed/refractory B-ALL, its integration into frontline treatment is still under investigation. Ongoing trials are evaluating the optimal sequencing and combinations of these agents and their potential to obviate the need for chemotherapy and/or allo-HCT in selected patients. As evidence continues to accumulate, chemo-free and chemo-light regimens, incorporating minimal chemotherapy with targeted agents to balance efficacy and reduced toxicity, are poised to redefine the standard of care for adults BCP-ALL, offering the possibility of durable remissions with reduced treatment-related morbidity. Full article

Retinoic acid (RA) plays a key role in mucosal immune regulation and tolerance, with implications for inflammatory bowel disease (IBD). However, its effects have not been extensively studied in humanized in vitro models that recapitulate epithelial–immune interactions. We established a 3D in vitro small intestinal model composed of three epithelial cell types, naïve CD4⁺ T cells, and monocyte/dendritic cell (M/DC) precursors derived from CD34⁺ umbilical cord blood hematopoietic stem/progenitor cells. The epithelial microenvironment strongly suppressed monocyte/DC differentiation and T cell activation, indicating a regulatory role of epithelial-derived signals. Retinoic acid (RA) priming of M/DC precursors induced CD103⁺CD11b⁺Sirp1α⁻ regulatory DCs and promoted a shift from naive to memory-type T cells. Upon addition of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β), the model mimicked an inflamed intestinal state, resulting in CD14⁺CD16⁺ inflammatory monocytes and increased T cell activation (CD25⁺CD69⁺). RA-primed DCs modestly counterbalanced T cell activation and IBD-like responses, even under inflammatory conditions. Flow cytometry and clustering analysis revealed distinct immune cell phenotypes depending on RA exposure and cytokine context. This model provides a reproducible and physiologically relevant human system to study RA-mediated immune programming in the intestinal mucosa and may support the development of novel therapeutic strategies for IBD and related inflammatory conditions. Statistical differences were evaluated using ANOVA with Tukey’s post-hoc test (n = 4; p < 0.05). Full article

This study investigated the expression of immune checkpoint molecules on CD4⁺ and CD4⁻ NKT cell subpopulations throughout healthy pregnancy trimesters and in non-pregnant condition to understand their role in maternal–fetal immunotolerance. Using flow cytometry, we found that CD4⁻ NKT cells significantly outnumbered CD4⁺ NKT cells in all investigated groups. In the case of the immune checkpoint molecules, PD-1 receptor expression was significantly lower in CD4⁻ NKT cells compared to CD4⁺ counterpart cells only in non-pregnant women, while the PD-L1 ligand expression on CD4⁺ NKT cells significantly decreased in the third trimester. In contrast, LAG-3 and Galectin-3 expressions remained stable across all subsets and trimesters. For the TIGIT/CD226 axis, CD226 expression was significantly higher in CD4⁺ NKT cells in the third trimester and in non-pregnant women. The two ligands CD112 and CD155 were consistently lower on CD4⁻ NKT cells across all groups. The activating receptor NKG2D was significantly higher on CD4⁻ NKT cells in all examined cohorts. These findings suggest that CD4⁺ NKT cells tend towards a more tolerogenic phenotype, while CD4⁻ NKT cells maintain a balanced cytotoxic potential with reduced immunoregulation function. The dynamic regulation of immune checkpoints on NKT cell subsets, particularly the downregulation of PD-L1 and CD226 in late pregnancy, highlights their fine-tuned role in balancing maternal–fetal immune tolerance with readiness for parturition. Full article

As chemical messengers, phytohormones can enhance the tolerance of plants to stress caused by toxic elements (TEs) such as cadmium (Cd), lead (Pb), and zinc (Zn). This study investigated the combined toxicity of Cd, Pb, and Zn, and its impact on stress phytohormones (jasmonates, salicylic acid, and abscisic acid), in oat (Avena sativa L.) using anthropogenically contaminated soil in a 4-week pot experiment. The uptake of TEs by the roots increased in the multi-contaminated soil, while Zn was the only TE to be translocated to the leaves. The toxic effect of the TEs was assessed in terms of plant growth, revealing a decline in leaf dry biomass, whereas the impact on the roots was insignificant. These findings align with the levels of stress phytohormones. An increase in bioactive forms of stress phytohormones in leaves due to TEs indicates TE toxicity and leaf sensitivity. Conversely, low levels of these phytohormones, along with crosstalk between them, suggest reduced defense against TEs in the roots. The abundance of stress phytohormones declined in the following order: salicylic acid > jasmonates > abscisic acid. These results help to understand the mechanism by which plants respond to TEs, particularly their combined toxicity. Full article

Background/Objectives: Normal-weight obesity describes those with a normal body mass index (BMI) and high body fat percent. Older adults with normal-weight obesity (NWO-O) are at increased risk for cardiovascular disease (CVD), but underlying mechanisms remain unclear. This pilot study examined whether NWO-O had an unfavorable cardiometabolic response to acute high-fat meal intake compared to normal BMI, low body fat percent individuals that were both older (NWL-O) and younger (NWL-Y). Methods: Participants (N = 29) with a normal BMI were grouped as follows: NWL-Y (18–35 years, low body fat percent; n = 12), NWL-O (≥60 years, low body fat percent; n = 9), and NWO-O (≥60 years, high body fat percent; n = 8). All participants completed an abbreviated fat tolerance test (75 g fat). Fasting and 4 h blood samples were collected to measure lipids (triglycerides and high-density lipoprotein cholesterol [HDL-C]), biomarkers of intestinal permeability (lipopolysaccharide binding protein [LBP] and soluble cluster of differentiation [sCD14]), and the inflammatory marker interleukin (IL)-6. Results: NWO-O had higher percent, absolute, and trunk fat compared to NWL-Y and NWL-O (p’s ≤ 0.01). Conversely, percent lean mass was lower in NWO-O versus both NWL groups (p’s ≤ 0.01). NWO-O had higher fasting triglycerides than NWL-Y (p < 0.05), but all groups were in the clinically normal range on average (≤107 mg/dL). However, NWO-O had higher 4 h triglycerides (239.4 ± 101.0 mg/dL) compared to NWL-Y and NWL-O (p < 0.01), consistent with an adverse response. The absolute change in triglycerides was higher in NWO-O relative to NWL-Y (p < 0.01), but not compared to NWL-O (p = 0.06). Fasting IL-6 was higher in NWO-O relative to NWL-Y (p < 0.05). Fasting and 4 h sCD14 were similarly higher in NWL-O and NWO-O versus NWL-Y (p’s < 0.01). Conclusions: NWO-O had an exaggerated postprandial triglyceride response compared to younger and similar-aged NWL individuals, which could reflect hepatic very low-density lipoprotein overproduction or impaired triglyceride clearance. Future work should continue to investigate the role of postprandial dyslipidemia in NWO-O’s reported CVD risk. Full article

Twenty-nine sediment samples were collected from Hurghada Bay, a highly impacted coastal area along the Northern Red Sea of Egypt, to evaluate environmental quality and human-induced effects on benthic ostracods. As potential bioindicators, benthic ostracods are highly responsive to environmental disturbances, with pollution leading to reduced abundance, lower diversity, and increased opportunistic taxa. To investigate the link between ostracod assemblages and sediment contamination, we measured the concentrations of eight heavy metals (Cu, Cd, Zn, Pb, As, Cr, Ni, and Mn) using inductively coupled plasma–atomic emission spectrometry (ICP-AES). Multivariate statistical analyses identified three distinct ostracod assemblages distributed across three station groups with varying pollution levels. Group I, associated with offshore stations, exhibited low to moderate heavy metal (HM) concentrations and high ostracod abundance and was dominated by Moosella striata, Hiltermannicythere rubrimaris, Ruggieria danielopoli, Neonesidea schulzi, and Paranesidea fracticorallcola, where the water depth and sand content are the main controlling factors. In contrast, Group II, corresponding to stations with the highest HMs and total organic matter (TOM), was dominated by pollution-tolerant species Jugosocythereis borchersi, Cyprideis torosa, Alocopocythere reticulata, and, to a lesser extent, Ghardaglaia triebeli, with reduced ostracod density and diversity. Group III, characterized by stations influenced by the mud-controlling factor, had the lowest HMs and was dominated by pollution-sensitive species Xestoleberis rhomboidei, Paranesidea fortificata, and Loxocorniculum ghardaquensis. These findings highlight the ecological risks posed by HM pollution and emphasize the urgent need for pollution mitigation strategies and continued monitoring to preserve the Red Sea’s benthic biodiversity. Full article

Arbuscular mycorrhizal fungi (AMF) demonstrate considerable potential for remediating soils contaminated with heavy metals. However, comprehensive research examining the effects of cadmium (Cd) contamination on AMF communities in paddy fields remains scarce, constraining their broader application in such environments. In this study, high-throughput sequencing was utilized to assess AMF community structure in paddy soils subjected to five distinct levels of Cd contamination. The study also explored the effect of different soil properties on AMF community dynamics. A total of 188 AMF taxa were identified across all soil samples, spanning four families. The Claroideoglomeraceae family emerged as the predominant group, exhibiting notable Cd tolerance. While elevated Cd concentrations inhibited the AMF community structure, lower concentrations increased the α-diversity of the community. Furthermore, soil-available phosphorus, calcium levels, and pH were found to be critical factors driving shifts in AMF community structure. Redundancy analysis explicitly quantified the relative strength of environmental factors, demonstrating that phosphorus and pH directly influenced the AMF community structure through significant effects, while Cd and calcium exerted their influence via indirect or nonlinear pathways. Given the relative abundance advantage of Claroideoglomeraceae in Cd-contaminated environments and its positive correlation with Cd concentration, we hypothesize that this group may exhibit Cd tolerance. Therefore, it could be considered a potential candidate species for prioritization in future field inoculation trials, and its practical application potential should be further validated. Full article

Systematic Background/Objectives: Type 1 diabetes mellitus (T1DM) is an autoimmune condition in which pancreatic β-cells are selectively destroyed, predominantly by autoreactive T lymphocytes. Despite decades of research, the achievement of durable immune tolerance remains elusive. This review presents a historically grounded and forward-looking perspective on the evolution of immunotherapy in T1DM, from early immunosuppressive interventions to advanced precision-based cellular approaches. Specifically, we focus on systemic immunosuppressants (e.g., corticosteroids, cyclosporine), monoclonal antibodies (e.g., anti-CD3, anti-IL-1, anti-TNF), regulatory cell-based approaches (e.g., Tregs, CAR-Tregs, MDSCs), and β-cell replacement strategies using stem cell-derived islets. Methods: We analyzed major clinical and translational milestones in immunotherapy for T1DM, with particular attention to the transition from broad immunosuppression to targeted modulation of immune pathways. Emerging data on cell-based therapies, artificial intelligence (AI)-driven stratification, and personalized intervention timing have been incorporated to provide a comprehensive overview of current and future directions. Results: Initial therapies such as corticosteroids and cyclosporine offered proof-of-concept for immune modulation, yet suffered from relapse and toxicity. The introduction of monoclonal antibodies (e.g., teplizumab) marked a shift toward immune-specific intervention, particularly in stage 2 preclinical T1DM. More recent approaches include low-dose IL-2, checkpoint modulation, and antigen-specific tolerance strategies. Cellular therapies such as Treg adoptive transfer, chimeric antigen receptor Tregs (CAR-Tregs), and stem cell-derived islet replacements (e.g., VX-880) have shown promise in preserving β-cell function and modulating autoimmunity. Myeloid-derived suppressor cells (MDSCs), although still preclinical, represent a complementary avenue for immune tolerance induction. Concurrently, AI-based models are emerging as tools to stratify risk and personalize immunotherapeutic timing, enhancing trial design and outcome prediction. Conclusions: In conclusion, the historical progression from broad immunosuppression to precision-driven strategies underscores the importance of stage-specific, mechanism-based interventions in T1DM. The convergence of targeted biologics, regenerative cell therapies, and β-cell replacement approaches, supported by AI-enabled patient stratification, offers a realistic path toward durable immune tolerance and functional β-cell preservation. Continued integration of these modalities, coupled with rigorous long-term evaluation, will be essential to transform these scientific advances into sustained clinical benefit. Full article

One hundred presumptive Pseudomonas isolates, recovered from 15 sites impacted by anthropogenic activity in the Foggia district (Italy), were screened for key adaptive and functional traits important for environmental applications. The isolates were phenotypically characterized for their ability to grow under combined pH (5.0–8.0) and temperature (15–37 °C) conditions, to produce proteolytic enzymes, pigments, and exopolysaccharides, and to tolerate SDS. Moreover, the resistance to six environmentally relevant heavy metals (Cd, Co, Cu, Ni, Zn, As) was qualitatively assessed. The results highlighted wide inter-strain variability, with distinct clusters of isolates showing unique combinations of stress tolerance, enzymatic potential, and resistance profile. PERMANOVA analysis revealed significant effects of both the isolation site and the metal type, as well as their interaction, on the observed resistance patterns. A subset of isolates showed co-tolerance to elevated temperatures and heavy metals. These findings offer an initial yet insightful overview of the adaptive diversity of soil-derived Pseudomonas, laying the groundwork for the rational selection of strains for bioaugmentation in contaminated soils. Full article

Wild edible mushrooms are increasingly recognised for their nutritional and therapeutic potential, owing to their richness in bioactive compounds and antioxidant properties. This study assessed the chemical composition, antioxidant capacity, and bioaccumulation of heavy metals (Cd, Pb, Ni) in Boletus edulis, Imleria badia, and Leccinum scabrum collected from two forested regions of north-western Poland differing in anthropogenic influence and soil characteristics. The analysis encompassed structural polysaccharides (β- and α-glucans, chitin), carotenoids, L-ascorbic acid, phenolic and organic acids. B. edulis exhibited the highest β-glucan and lycopene contents, but also the greatest cadmium accumulation. I. badia was distinguished by elevated ascorbic and citric acid levels and the strongest DPPH radical scavenging activity, while L. scabrum showed the highest ABTS and FRAP antioxidant capacities and accumulated quinic acid and catechin. Principal component analysis indicated strong correlations between antioxidant activity and phenolic acids, while cadmium levels were inversely associated with antioxidant potential and positively correlated with chitin. Although all metal concentrations remained within EU food safety limits, B. edulis showed consistent cadmium bioaccumulation. From a practical perspective, the results highlight the importance of species selection and sourcing location when considering wild mushrooms for consumption or processing, particularly in the context of nutritional value and contaminant load. Importantly, regular or excessive consumption of B. edulis may result in exceeding the tolerable weekly intake (TWI) levels for cadmium and nickel, which warrants particular attention from a food safety perspective. These findings underscore the influence of species-specific traits and environmental conditions on mushroom biochemical profiles and support their potential as functional foods, provided that metal contents are adequately monitored. Full article

Multiple myeloma (MM) is predominantly a disease of the elderly. In recent years, a surge of highly effective plasma cell therapies has revolutionized the care of elderly multiple myeloma (MM) patients, for whom frailty and age-related competing causes of mortality determine management. Traditionally, the treatment of newly diagnosed elderly patients has centered on doublet or triplet combinations composed of immunomodulators (IMIDs), proteasome inhibitors (PIs), anti-CD38 monoclonal antibodies (mAbs), and corticosteroids producing median progression-free survival (PFS) rates between 34 and 62 months. However, recently, a series of large phase III clinical trials examining quadruplet regimens of PIs, IMIDs, corticosteroids, and anti-CD38 mAbs have shown exceptional outcomes, with median PFS exceeding 60 months, albeit with higher rates of peripheral neuropathy (≥Grade 2: 27% vs. 10%) when PIs and IMIDs are combined, and infections (≥Grade 3: 40% vs. 29–41%) with the addition of anti-CD38mAbs. The development of T-cell redirecting therapies including T-cell engagers (TCEs) and CAR-T cells has further expanded the therapeutic arsenal. TCEs have shown exceptional activity in relapsed disease and are being explored in the newly diagnosed setting with promising early results. However, concerns remain regarding the logistical challenges of step-up dosing, which often necessitates inpatient admission, the infectious risks, and the financial burden associated with TCEs in elderly patients. CAR-T, the most potent commercially available therapy for MM, offers the potential of a ‘one and done’ approach. However, its application to elderly patients has been tempered by significant concerns of cytokine release syndrome, early and delayed neurological toxicity, and its overall tolerability in frail patients. Robust data in frail patients are still needed. How CAR-T and TCEs will be sequenced among the growing therapeutic armamentarium for elderly MM patients remains to be determined. This review explores the safety, efficacy, cost, and logistical barriers associated with the above treatments in elderly MM patients. Full article

Freshwater salinization, an escalating global environmental stressor, poses a significant threat to freshwater biodiversity, including fish communities. This study investigates the grass carp (Ctenopharyngodon idellus), a species with the highest aquaculture output in China, to elucidate the molecular underpinnings of its physiological adaptations to fluctuating salinity gradients. We used high-throughput mRNA sequencing and differential gene expression profiling to analyze transcriptional dynamics in intestinal and kidney tissues of grass carp exposed to heterogeneous salinity stressors. Concurrent serum biochemical analyses showed salinity stress significantly increased Na⁺, Cl⁻, and osmolarity, while decreasing lactate and glucose. Salinity stress exerted a profound impact on the global transcriptomic landscape of grass carp. A substantial number of co-regulated differentially expressed genes (DEGs) in kidney and intestinal tissues were enriched in immune and metabolic pathways. Specifically, genes associated with antigen processing and presentation (e.g., cd4-1, calr3b) and apoptosis (e.g., caspase17, pik3ca) exhibited upregulated expression, whereas genes involved in gluconeogenesis/glycolysis (e.g., hk2, pck2) were downregulated. KEGG pathway enrichment analyses revealed that metabolic and cellular structural pathways were predominantly enriched in intestinal tissues, while kidney tissues showed preferential enrichment of immune and apoptotic pathways. Rigorous validation of RNA-seq data via qPCR confirmed the robustness and cross-platform consistency of the findings. This study investigated the core transcriptional and physiological mechanisms regulating grass carp’s response to salinity stress, providing a theoretical foundation for research into grass carp’s resistance to salinity stress and the development of salt-tolerant varieties. Full article

Glutathione peroxidase (GPX) is crucial in mediating plant responses to abiotic stresses. In this study, bioinformatics methods were used to identify the GPX gene family in quinoa. A total of 15 CqGPX genes were identified at the quinoa genome level and conducted preliminary analysis on their protein characteristics, chromosome distribution, gene structure, conserved domain structure, cis-acting elements, and expression patterns. Phylogenetic analysis showed that the GPX genes of quinoa, Arabidopsis, soybean, rice, and maize were divided into three groups. Most of the CqGPXs had the three characteristic conserved motifs and other conserved sequences and amino acid residues. Six types of cis-acting elements were identified in the CqGPX gene promoter, with stress and hormone response-related cis-acting elements constituting the two main categories. Additionally, the expression patterns of CqGPX genes across various tissues and their responses to treatments with NaCl, PEG, CdCl₂, and H₂O₂ were also investigated. The qRT-PCR results showed significant differences in the expression levels of the CqGPX genes under stress treatment at different time points. Consistently, the activity of glutathione peroxidase enzymes increased under stresses. Heterologous expression of CqGPX4 and CqGPX15 conferred stress tolerance to E. coli. This study will provide a reference for exploring the function of CqGPX genes. Full article

Cadmium (Cd) is a highly toxic heavy metal that can greatly affect crops and pose a threat to food security. Plant growth-promoting rhizobacteria (PGPR) are capable of alleviating the harm of Cd to crops. In this research, a Cd-tolerant PGPR strain was isolated and screened from the root nodules of semi-wild soybeans. The strain was identified as Pseudomonas sp. strain KM25 by 16S rRNA. Strain KM25 has strong Cd tolerance and can produce indole-3-acetic acid (IAA) and siderophores, dissolve organic and inorganic phosphorus, and has 1-aminocyclopropane-1-carboxylate (ACC) deaminase activity. Under Cd stress, all growth indicators of soybean seedlings were significantly inhibited. After inoculation with strain KM25, the heavy metal stress of soybeans was effectively alleviated. Compared with the non-inoculated group, its shoot height, shoot and root dry weight, fresh weight, and chlorophyll content were significantly increased. Strain KM25 increased the superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) activities of soybean seedlings, reduced the malondialdehyde (MDA) content, increased the Cd content in the roots of soybeans, and decreased the Cd content in the shoot parts. In addition, inoculation treatment can affect the community structure of endophytic bacteria in the roots of soybeans under Cd stress, increasing the relative abundance of Proteobacteria, Bacteroidetes, Sphingomonas, Rhizobium, and Pseudomonas. This study demonstrates that strain KM25 is capable of significantly reducing the adverse effects of Cd on soybean plants while enhancing their growth. Full article

Despite targeting mainly the respiratory tract, SARS-CoV-2 disrupts T cell homeostasis in ways that may explain both acute lethality and long-term immunological consequences. In this study, we aimed to evaluate the T-cell-mediated chain of immunity and formation of TCR via TREC assessment in COVID-19 and long COVID (LC). For this study, we collected 231 blood samples taken from patients with acute COVID-19 (n = 71), convalescents (n = 51), people diagnosed with LC (n = 63), and healthy volunteers (n = 46). With flow cytometry, we assessed levels of CD4+ and CD8+ minor T cell subpopulations (i.e., naïve, central and effector memory cells (CM and EM), Th1, Th2, Th17, Tfh, Tc1, Tc2, Tc17, Tc17.1, and subpopulations of effector cells (pE1, pE2, effector cells)). Additionally, we measured TREC levels. We found distinct changes in immune cell distribution—whilst distribution of major subpopulations of T cells was similar between cohorts, we noted that COVID-19 was associated with a decrease in naïve Th and CTLs, an increase in Th2/Tc2 lymphocyte polarization, an increase in CM cells, and a decrease in effector memory cells 1,3, and TEMRA cells. LC was associated with naïve CTL increase, polarization towards Th2 population, and a decrease in Tc1, Tc2, Em2, 3, 4 cells. We also noted TREC correlating with naïve cells subpopulations. Our findings suggest ongoing immune dysregulation, possibly driven by persistent antigen exposure or tissue migration of effector cells. The positive correlation between TREC levels and naïve T cells in LC patients points to residual thymic activity. The observed Th2/Th17 bias supports the hypothesis that LC involves autoimmune mechanisms, potentially driven by molecular mimicry or loss of immune tolerance. Full article