Search Results (1,006)

Light-chain (AL) amyloidosis is a rare clonal plasma cell disorder that, if left untreated, carries a high risk of organ damage and mortality. Due to the rarity of the disease and the vulnerability of affected organ systems, treatment requires significant caution and nuance. As a plasma cell dyscrasia, AL amyloidosis treatment regimens are often adapted from those used for related disorders, particularly multiple myeloma. Despite substantial progress in research and drug development, optimal treatment strategies for relapsed/refractory (RR) AL amyloidosis remain unclear, and no FDA-approved therapies currently exist for this setting. B-cell maturation antigen (BCMA) has emerged as a promising immunotherapy target, with associated drug classes including antibody–drug conjugates, bispecific antibodies, and CAR-T cell therapies. These therapies have been extensively studied in relapsed/refractory multiple myeloma (RRMM) and are now being explored in the context of RR AL amyloidosis. This review summarizes the current literature on the efficacy and tolerability of BCMA-directed therapies in AL amyloidosis, with a particular emphasis on CAR-T cell therapy and offers comparisons to outcomes observed in RRMM. Full article

Coxsackievirus B3 (CV-B3) infection causes inflammatory conditions such as viral myocarditis and meningitis, and incidence rates are rising annually. While children are more likely to be affected by severe manifestations, the molecular basis of this age-dependent susceptibility is poorly understood. In this study, we used young Balb/c mice at three developmental stages (7-, 14-, and 30-day-old mice) to investigate CV-B3 pathogenesis. Our findings revealed that 7-day-old mice exhibited substantial infection susceptibility and pathological severity compared to older mice. Critically, an age-dependent analysis showed a progressive decline in the expression of CV-B3-binding Coxsackievirus and Adenovirus Receptor (CAR) splice variants (CAR1 and CAR2) at both the transcriptional and translational levels as the mice matured from 7 to 30 days. These receptor isoforms demonstrated a direct correlation with viral replication efficiency in younger hosts. Concurrently, aging was associated with a rise in non-binding CAR variants (CAR3 and CAR4). During CV-B3 infection, the abundance of CAR1/CAR2 in young mice facilitated accelerated viral proliferation, coupled with the hyperactivation of the NLRP3 inflammasome and the expansion of IL-17-producing γδT cells (γδT17 cells). This cascade triggered excessive production of proinflammatory cytokines (IL-1β, IL-18, and IL-17), culminating in pronounced inflammatory infiltrates within cardiac and cerebral tissues. These findings establish NLRP3 inflammasome dysregulation as a critical determinant of CV-B3-induced tissue damage and provide novel insights into the heightened susceptibility to CV-B infection during early life and its associated severe disease rates. Full article

The developmental processes of microglia follow a general pattern, from immature amoeboid (activated) cells to fully ramified (inactivated) surveilling microglia. However, little is known about the mechanisms controlling the transition of microglia from an activated to an inactivated state during brain development. Due to the complexity of microenvironmentally dynamic changes during neuronal differentiation, interactions between developing nerve cells and microglia might be involved in this process. Extracellular vesicles (EVs) are cell-released particles that serve as mediators of cellular crosstalk and regulation. Using neural progenitor cells (NPCs) and a long-term neuron culture system, we found that EVs derived from NPCs or developing neurons possessed differential capacity on the induction of microglial activation. The exposure of microglia to NPC- or immature neuron (DIV7)-derived EVs resulted in the higher expression of protein and mRNA of multiple inflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6), when compared with mature neuron-derived EVs. Exploration of the intracellular signaling pathways revealed that MAPK signaling, IκBα phosphorylation/degradation, and NF-κB p65 nuclear translocation were strongly induced in microglia treated with NPC- or immature neuron-derived EVs. Using a pharmacological approach, we further demonstrate that Toll-like receptor (TLR) 7-mediated activation of NF-κB and MAPK signaling cascades contribute to EV-elicited microglial activation. Additionally, the application of conditioned media derived from microglia treated with NPC- or immature neuron-derived EVs is found to promote the survival of late-developing dopaminergic neurons. Thus, our results highlight a novel mechanism used by NPCs and developing neurons to modulate the developmental phases and functions of microglia through EV secretion. Full article

This study evaluated the influence of different male date palm cultivars, distinguished by their chloroplast haplotypes, on pollen quality, pollination efficiency, metaxenia effects, and gene expression during fruit development. Chloroplast DNA analysis of 37 male trees revealed multiple haplotypes, from which cultivars B25, P8, C22, and B46 were selected for further investigation. Pollen viability varied significantly among cultivars, with P8 and B25 exhibiting the highest germination rates and pollen tube elongation, while C22 showed the lowest. These differences correlated with pollination success: P8 and B25 achieved fertilization rates near 99%, whereas C22 remained below 43%. Pollination outcomes also varied in fruit traits. Despite its low pollen performance, C22 induced the production of larger fruits at the Bleh (Kimri) stage, potentially due to compensatory physiological mechanisms. Phytochemical profiling revealed significant cultivar effects: fruits from B25-pollinated trees had with lower moisture and polyphenol content but the higher sugar levels and soluble solids, suggesting accelerated maturation. Ripening patterns confirmed this finding, with B25 promoting the earliest ripening and B46 causing the most delayed. Gene expression analysis supported these phenotypic differences. Fruits pollinated by P8, B25, and B46 exhibited elevated levels of cell-division-related transcripts, particularly the PdCD_1 gene (PDK_XM_008786146.4, a gene encoding a cell division control protein), which was most abundant in P8. In contrast, fruits from C22-pollinated trees had the lowest expression of growth-related genes, suggesting a shift toward cell expansion rather than division. Overall, the results show the critical role of male genotype in influencing fertilization outcomes and fruit development, offering valuable insights for targeted breeding strategies at enhancing date palm productivity and fruit quality. Full article

This study investigated the effects of Bothrops moojeni (B. moojeni) venom and its high- (HMM) and low-molecular mass (LMM) fractions on human osteoclast (OC) differentiation and function in vitro, aiming to identify novel therapeutics for bone disorders. Venom preparations were applied at 5 µg/mL (crude venom and HMM) or 1 µg/mL (LMM) from day 4 of peripheral blood mononuclear cell (PBMC) differentiation through terminal OC formation, enabling evaluation across early differentiation, fusion, and maturation stages. RNA sequencing revealed 7793 genes common to all experimental groups, with unique gene expression signatures of 149 (control), 221 (HMM), 248 (crude venom), and 60 (LMM) genes, reflecting distinct molecular responses. The negative control PBMC group exhibited 1013 unique genes enriched in immune-related pathways, consistent with their undifferentiated state. Crude venom induced the broadest transcriptional modulation, upregulating key fusion (CD47) and resorption (CTSK) genes, and altering markers of OC differentiation. The HMM fraction predominantly influenced inflammatory and osteoclastogenic pathways, notably TNF and NF-κB signaling, while the LMM fraction selectively regulated fusion-related genes (e.g., CD44) and immune pathways, indicating targeted modulation of OC activity. Cytokine profiling showed that crude venom and HMM suppressed osteoclastogenic cytokines such as IL-1β and IL-6, supporting their potential use in inflammatory bone diseases. Pathway enrichment analyses confirmed these differential effects on immune response and bone resorption mechanisms. Together, these results demonstrate that B. moojeni venom and its fractions differentially impact OC biology, with crude venom exerting broad effects and HMM and LMM fractions offering more specific modulation. Future studies will isolate bioactive components and assess therapeutic efficacy in animal models of osteoporosis and rheumatoid arthritis. Full article

Antibody-mediated rejection (ABMR) caused by donor-specific Abs (DSAs) is still the leading cause of late graft loss following clinical organ transplantation, and effective strategies to combat ABMR are still elusive. We previously showed that rIL-2 complexed with anti-IL-2 mAb clone JES6-1A12 (IL-2 cplx) leads to the selective expansion of regulatory T cells (Tregs) and the prolonged survival of MHC-mismatched skin allografts. Although the grafts were eventually rejected, mice failed to develop DSAs. Here, we investigated the impact of IL-2 cplx on the humoral response and germinal center (GC) reaction during allograft rejection. IL-2 cplx treatment prevents Bcl-6 upregulation, leading to suppressed development of GC T and B cells. The IL-2 cplx-induced impairment of GC development limits IgG allo-Ab production but allows for IgM synthesis. By employing a hapten–carrier system to investigate affinity maturation, we found that IL-2 cplx induces a distinct shift in specific Ab production favoring low-affinity IgM while simultaneously decreasing IgG responses. These findings illuminate the potential of IL-2 cplx therapy for inducing humoral tolerance, potentially paving the way for refining strategies aimed at preventing and treating ABMR. Full article

Cutaneous melanoma is an aggressive cancer with an increasing incidence worldwide, highlighting the need for research into its pathogenesis. The tumor microenvironment (TME) plays a critical role in melanoma progression and consists of cellular components and an extracellular matrix (ECM) rich in cytokines and signaling molecules. The most abundant stromal cells within the TME are cancer-associated fibroblasts (CAFs), which remodel the ECM and modulate immune responses. Among immune cells, tumor-associated macrophages (TAMs) predominate, and their polarization toward the M2 phenotype supports tumor progression. Tumor-infiltrating lymphocytes (TILs) have diverse functions, including cytotoxic T-cells, helper T-cells that modulate immune response, B-cells forming tertiary lymphoid structures (TLS), and regulatory T-cells with immunosuppressive properties. Dendritic cells (DCs) also play a complex role in the TME. A notable subpopulation are mature regulatory dendritic cells (mregDCs), which contribute to immune evasion. All of these TME components may drive tumorigenesis. Advancements in melanoma treatment—including immunotherapy and targeted therapies—have significantly improved outcomes in advanced-stage disease. In parallel, emerging approaches targeting the tumor microenvironment and gut microbiome, as well as personalized strategies such as neoantigen vaccines and cell-based therapies, are under active investigation and may further enhance therapeutic efficacy in the near future. Full article

B-cell maturation antigen (BCMA)-targeted therapies including both chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies (BsAbs), have revolutionized the treatment landscape for relapsed/refractory multiple myeloma (MM), offering both deep and durable responses, even in heavily pretreated patients. Despite these advances, most patients ultimately experience relapse. This is likely related to the development of resistance mechanisms that limit the long-term efficacy and durability of BCMA-targeted approaches. In this review, we examine the current landscape of BCMA-directed therapies, including Idecabtagene Vileucel, Ciltacabtagene Autoleucel, Teclistamab, and Elranatamab and explore the multifactorial mechanisms driving resistance. These mechanisms include tumor-intrinsic factors, host-related and tumor-extrinsic factors, and factors related to the tumor-microenvironment itself. We outline emerging strategies to overcome resistance, such as dual-targeting therapies, γ-secretase inhibitors, immune-checkpoint blockade, armored CAR T constructs, and novel combination regimens. Additionally, we discuss the role of therapy sequencing, emphasizing how prior exposure to BsAbs or CAR T-cell therapies may influence the efficacy of subsequent treatments. A deeper understanding of resistance biology, supported by integrated immune and genomic profiling, is essential to optimizing therapeutic durability and ultimately improve patient outcomes for patients with MM. Full article

Background/Objectives: Response to immune checkpoint inhibitors (ICIs) is associated with several biological pathways, including tumor immunogenicity and antitumor immunity. Identifying host factors involved in these pathways may guide personalized ICI treatment. Methods: We describe the application of chromatin conformation assays to blood from patients with advanced urothelial carcinoma from the phase 3 JAVELIN Bladder 100 trial (NCT02603432). This trial demonstrated a significant survival benefit with avelumab maintenance plus best supportive care (BSC) vs. BSC alone following non-progression with platinum-based chemotherapy as first-line therapy. Blood-based chromatin conformation markers (CCMs) were screened for associations with high/low immune effector gene expression in tumors and for interactions with outcomes and tumor mutation burden. Results: Candidate CCMs included genes involved in several immune response pathways, such as POU2F2, which encodes a transcription factor that regulates B-cell maturation. Conclusions: Our findings suggest that polygenic host factors may affect response to ICIs and support further investigation of chromatin conformation assays. Full article

The sodium–citrate cotransporter (NaCT) plays a crucial role in citrate transport during amelogenesis. Mutations in the SLC13A5 gene, which encodes the NaCT, cause early infantile epileptic encephalopathy 25 and amelogenesis imperfecta. We analyzed developing pig molars and determined that the citrate concentrations in secretory- and maturation-stage enamel are both 5.3 µmol/g, with about 95% of the citrate being bound to mineral. To better understand how citrate might enter developing enamel, we developed Slc13a5^Flag reporter mice that express NaCT with a C-terminal Flag-tag (DYKDDDDK) that can be specifically and accurately recognized by commercially available anti-Flag antibodies. The 24-base Flag coding sequence was located immediately upstream of the natural translation termination codon (TAG) and was validated by Sanger sequencing. The general development, physical activities, and reproductive outcomes of this mouse strain were comparable to those of the C57BL/6 mice. No differences were detected between the Slc13a5^Flag and wild-type mice. Tooth development was extensively characterized using dissection microscopy, bSEM, light microscopy, in situ hybridization, and immunohistochemistry. Tooth formation was not altered in any detectable way by the introduction of the Flag. The Slc13a5^Flag citrate transporter was observed on all outer membranes of secretory ameloblasts (distal, lateral, and proximal), with the strongest signal on the Tomes process, and was detectable in all but the distal membrane of maturation-stage ameloblasts. The papillary layer also showed positive immunostaining for Flag. The outer membrane of odontoblasts stained stronger than ameloblasts, except for the odontoblastic processes, which did not immunostain. As NaCT is thought to only facilitate citrate entry into the cell, we performed in situ hybridization that showed Ank is not expressed by secretory- or maturation-stage ameloblasts, ruling out that ANK can transport citrate into enamel. In conclusion, we developed Slc13a5^Flag reporter mice that provide specific and sensitive localization of a fully functional NaCT-Flag protein. The localization of the Slc13a5^Flag citrate transporter throughout the ameloblast membrane suggests that either citrate enters enamel by a paracellular route or NaCT can transport citrate bidirectionally (into or out of ameloblasts) depending upon local conditions. Full article

Background/Objectives: Fish eggs activated with UV-irradiated spermatozoa and exposed to the High Hydrostatic Pressure (HHP) shock to inhibit first cell cleavage develop as gynogenetic Doubled Haploids (DHs) that are fully homozygous individuals. Due to the expression of the recessive genes and side effects of the gamete treatment, survival of fish DHs is rather low, and most of the mitotic gynogenotes die before hatching. Nevertheless, as maternal gene products provided during oogenesis control the initial steps of embryonic development in fish, a maternal effect on the survival of gynogenotes needs to be also considered to affect efficiency of gynogenesis. Thus, the objective of this research was to apply an RNA-seq approach to discriminate transcriptional differences between rainbow trout (Oncorhynchus mykiss) eggs with varied abilities to develop after gynogenetic activation. Methods: Gynogenetic development of rainbow trout was induced in eggs originated from eight females. Maternal RNA was isolated and sequenced using RNA-Seq approach. Survival rates of gynogenotes and transcriptome profiles of eggs from different females were compared. Results: RNA-seq analysis revealed substantial transcriptional differences between eggs originated from different females, and a significant correlation between the ability of the eggs for gynogenesis and their transcriptomic profiles was observed. Genes whose expression was altered in eggs with the increased survival of DHs were mostly associated (GO BP) with the following biological processes: development, cell differentiation, cell migration and protein transport. Some of the genes are involved in the oocyte maturation (RASL11b), apoptosis (CASPASE 6, PGAM5) and early embryogenesis, including maternal to zygotic transition (GATA2). Conclusions: Inter-individual variation of the transcription of maternal genes correlated with the competence of eggs for gynogenesis suggest that at least part of the mortality of the rainbow trout DHs appear before activation of zygotic genome and expression of the lethal recessive traits. Full article

Precision medicine is transforming hematologic cancer care by tailoring treatments to individual patient profiles and moving beyond the traditional “one-size-fits-all” model. This review outlines foundational technologies, disease-specific advances, and emerging directions in precision hematology. The field is enabled by molecular profiling techniques, including next-generation sequencing (NGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), as well as epigenomic and proteomic analyses. Complementary tools such as liquid biopsy and minimal residual disease (MRD) monitoring have improved diagnosis, risk stratification, and therapeutic decision making. We discuss major molecular targets and personalized strategies across hematologic malignancies: FLT3 and IDH1/2 in acute myeloid leukemia (AML); Philadelphia chromosome–positive and Ph-like subtypes in acute lymphoblastic leukemia (ALL); BCR-ABL1 in chronic myeloid leukemia (CML); TP53 and IGHV mutations in chronic lymphocytic leukemia (CLL); molecular subtypes and immune targets in diffuse large B-cell lymphoma (DLBCL) and other lymphomas; and B-cell maturation antigen (BCMA) in multiple myeloma. Despite significant progress, challenges remain, including high costs, disparities in access, a lack of standardization, and integration barriers in clinical practice. However, advances in single-cell sequencing, spatial transcriptomics, drug repurposing, immunotherapies, pan-cancer trials, precision prevention, and AI-guided algorithms offer promising avenues to refine treatment and improve outcomes. Overcoming these barriers will be critical for ensuring the equitable and widespread implementation of precision medicine in routine hematologic oncology care. Full article

Background: The bone morphogenetic protein (BMP) signaling pathway is essential for lung development. BMP4, a key regulator, binds to type I (BMPR1) and type II (BMPR2) receptors to initiate downstream signaling. While the inactivation of Bmpr1a and Bmpr1b leads to tracheoesophageal fistulae, the role of BMPR2 mutations in lung epithelial development remains unclear. Methods: We generated induced pluripotent stem cells (iPSCs) from a patient carrying a BMPR2 mutation (c.631C>T), and gene-corrected isogenic controls were created using CRISPR/Cas9. These iPSCs were differentiated into lung progenitor cells and subsequently cultured to generate alveolar and airway organoids. The differentiation efficiency and epithelial lineage specification were assessed using immunofluorescence, flow cytometry, and qRT-PCR. Results: BMPR2-mutant iPSCs showed no impairment in forming a definitive or anterior foregut endoderm. However, a significant reduction in lung progenitor cell differentiation was observed. Further, while alveolar epithelial differentiation remained largely unaffected, airway organoids derived from BMPR2-mutant cells exhibited impaired goblet and ciliated cell development, with an increase in basal and club cell markers, indicating skewing toward undifferentiated airway cell populations. Conclusions: BMPR2 dysfunction selectively impairs late-stage lung progenitor specification and disrupts airway epithelial maturation, providing new insights into the developmental impacts of BMPR2 mutations. Full article

The aims of the present study were to analyze the taxonomic profile and to evaluate the functional effects of sheep FF cultivable microbiota on prepubertal lamb oocytes PLOs developmental potential. Ovarian FFs were recovered from slaughtered adult sheep via the aspiration of developing follicles and used for microbiota propagation. Bacterial pellets underwent 16S rRNA gene sequencing and targeted culturomics, whereas cell-free supernatants were used as supplements for the in vitro maturation (IVM) of slaughtered PLOs. For the first time, bacteria presence in adult sheep FF was detected, with the first report of Streptococcus infantarius subsp. infantarius (as a species) and Burkholderia cepacia (as a genus and species) in either animal or human FF. The short- and long-term effects of bacterial metabolites on PLO maturation and embryonic development were demonstrated. As short-term effects, the addition of FF microbiota metabolites did not affect the oocyte nuclear maturation and mitochondria distribution pattern, except in one of the examined supernatants, which reduced all quantitative bioenergetic/oxidative parameters. As long-term effects, one of them reduced the total cleavage rate after in vitro embryo culture (IVC). In conclusion, microbiota/bacteria are present in adult sheep FF and may influence reproductive outcomes in vitro. Future studies may reveal the beneficial in vitro effects using the microbiome from preovulatory follicles. Full article

Mature dendritic cells (DCs) are known to activate effector immune responses, whereas steady state immature DCs can induce tolerance. Several studies have targeted immature murine quiescent DCs in vivo with antigen, including donor alloantigens, for the induction of tolerance. Receptors expressed by specific DC subsets have been also targeted with antibodies linked with antigens to induce tolerance; for instance, in vivo targeting of the DCIR2⁺ DC subset with donor alloantigen resulted in long-term survival of heart and skin transplants. DCs also express sialic acid immunoglobulin-like lectin (Siglec) receptors, and these have been successfully targeted with myelin oligiodendrocyte glycoprotein (MOG) antigen to induce tolerance in experimental autoimmune encephalomyelitis (EAE). We investigated, in a mismatched model of skin transplant (B6K^d into B6 recipient mice), whether targeting a sialylated alloantigen K^d (Sia-K^d) to Siglecs on recipient DCs promoted transplant survival. The injection of α2,3 Sia-K^d into B6 recipient mice prior to B6K^d skin transplantation, by binding to Batf3 dependent DCs, resulted in prolonged skin graft survival and an increase in CD4⁺CD62L⁺Foxp3⁺ Tregs. Targeting Siglecs on DC subsets in vivo represents a novel way of improving transplant survival. Full article