Search Results (3,404)

Background/Objectives: Multiple myeloma (MM) is an incurable plasma cell neoplasm in which diagnosis and prognostication rely on invasive bone marrow examinations that may not capture biological heterogeneity across different disease sites. There is a clinical need for non-invasive biomarkers that can accurately predict treatment outcomes. Methods: We performed a global proteomic profiling of bone marrow-derived extracellular vesicles (EVs) from nine MM patients and ten controls. A total of 8839 proteins were identified, of which 14 met predefined selection criteria. These candidates were quantified in serum-derived EVs using targeted proteomic analysis. Prognostic relevance of selected proteins was evaluated in newly diagnosed MM (NDMM) patients treated with daratumumab-containing frontline regimens (n = 26) and healthy individuals (n = 60). Progression-free survival (PFS) was analyzed using univariable and multivariable models. Results: IL5RA (p = 0.003) and BCMA (p < 0.001) were significantly elevated in serum EVs from MM patients compared with controls. Higher serum EV-IL5RA and EV-BCMA were associated with a trend toward shorter PFS. Combined assessment of these biomarkers enabled clear stratification of MM patients into three prognostic groups, including a cohort with markedly inferior outcomes, with a 20-month PFS of 0 (p = 0.001). In multivariable analysis, the combined serum EV-IL5RA and EV-BCMA signature suggests an independent prognostic potential (HR = 38.49 [95% CI, 1.51–47.79], p = 0.015). Conclusions: Serum EV-IL5RA and EV-BCMA are novel non-invasive biomarkers, measurable through routine blood testing, with strong potential to improve risk stratification in NDMM patients in the era of daratumumab-based frontline therapy. Full article

FAM3A, FAM3B, FAM3C and FAM3D are members of the “family with sequence similarity 3” (FAM3) gene family, an emerging class of cytokine-like proteins with a unique structural globular β-β-α fold and distinct biological functions. With widespread expression in tissue, organs and in many cell types, their specific roles in human diseases have been the focus of much research. FAM3A acts as a positive regulator of metabolic health, typically activating canonical pro-survival and metabolic pathways. FAM3B, also called PANDER (PANcreatic DERived Factor), exerts critical physiological functions in the regulation of glycemic levels via promotion of hepatic glucose production and pancreatic β-cell insulin secretion. FAM3C, also named ILEI (Interleukin-like EMT inducer), is involved as an inducer of epithelial–mesenchymal transition (EMT) and cancer metastasis, as well as osteoblast differentiation and bone mineralization. FAM3D is a gut-secreted protein and potential regulator of gastrointestinal homeostasis and microbiota-induced inflammation. Here we provide an overview of previous studies supporting that FAM3 proteins act through putative membrane receptors and co-partners, including fibroblast growth factor receptor (FGFR), leukemia inhibitory factor receptor (LIFR), formyl peptide receptor (FPR1/2), to activate diverse downstream signaling pathways on different cellular contexts. Basic and clinical studies suggest that the FAM3 family influences both obesity, diabetes, and other metabolic disorders; thus, its expression may have diagnostic potential. The differential and often cancer-specific expression patterns make members of the FAM3 family promising candidates for biomarkers and therapeutic targets of some types of neoplasia. Full article

Radiation-induced bone injury, characterized by oxidative stress damage and impaired osteogenesis, lacks effective treatments. Exosome-based therapies have recently emerged as a safe and effective modality for radiation damage, and their functional capacity can be further potentiated through tailored preconditioning strategies—such as nanoparticle induction or physical stimulation. This study developed a novel exosome-based therapy by preconditioning bone marrow mesenchymal stem cells (BMSCs) with Iron oxide (Fe₃O₄) magnetic nanoparticles (MNPs, 50 µg/mL) and a static magnetic field (SMF, 100 mT). Exosomes derived from these preconditioned cells (BMSC-Fe₃O₄-SMF-Exos) exhibited enhanced yield and dual functionality. In irradiated BMSCs, BMSC-Fe₃O₄-SMF-Exos significantly promoted osteogenic differentiation, restoring alkaline phosphatase activity, mineralization, and expression of RUNX2, OCN, and COL1A1. They concurrently alleviated oxidative stress by scavenging reactive oxygen species, reducing malondialdehyde, and boosting superoxide dismutase activity. Mechanistically, miR-429 was found to be highly enriched in BMSC-Fe₃O₄-SMF-Exos, which directly targeted Noggin (NOG). Our functional validation experiments also confirmed that overexpression of miR-429 could inhibit NOG, alleviate oxidative stress and rescue the osteogenic differentiation of irradiated BMSCs. In conclusion, exosomes derived from preconditioning BMSCs with Fe₃O₄ MNPs and SMF mitigate radiation-induced damage via the miR-429/NOG pathway, presenting a promising cell-free strategy for bone regeneration. Full article

Background: Bone and soft tissue sarcomas, while rare, making up less than 2% of adult cancers with an incidence below 5 per 100,000 annually, present a significant challenge due to their varied and often obscure pathology. Additionally, the absence of global sarcoma awareness contributes to delayed interventions, necessitating more-aggressive treatments and increasing mortality risks. Conversely, cancers such as breast and colon have seen improved outcomes through effective screening and early-management strategies. Methods: In this cross-sectional study, out of the total number of participants approached, using a preset questionnaire, by trained medical students to participate in this study, 626 met the inclusion criteria. The questionnaire started with an informed consent process followed by a set of questions regarding sociodemographic characteristics and lifestyle. Subsequently, the questionnaire delved into their understanding and awareness of bone and soft tissue sarcomas, focusing on risk factors, recognizable signs and symptoms, and tendencies regarding health-seeking behavior. Results: In this study with 626 participants, demographic insights showed a young cohort, with 43.5% between 21 and 30 years, and a male predominance of 60.1%. Risk factor awareness was moderate; genetics and smoking were recognized as primary risks for sarcomas. Participants showed limited awareness of sarcoma signs, symptoms, and management, with a substantial percentage unsure about the most at-risk age group, gender differences in risk, and recognizability of symptoms. Barriers to seeking medical care included a passive attitude towards healthcare, fear, and accessibility issues. Most participants had limited knowledge of sarcomas, with 58% unaware of risk factors and 72.3% of signs and symptoms. Conclusions: This study emphasizes the necessity for targeted interventions to bridge the knowledge gap and promote early detection practices, which could significantly impact the prognosis of sarcoma patients. Full article

Paediatric osteoarticular infections (OAIs) encompass a heterogeneous group of musculoskeletal infections associated with acute septic complications, prolonged morbidity and potentially long-term sequelae. Over the past two decades, advances in microbiological diagnostics—particularly nucleic acid amplification assays—have refined the aetiological understanding of OAIs and started a new therapeutic debate regarding the most appropriate routes of antibiotic administration. Clinicians now evaluate which children can be treated safely using oral antibiotics from the outset (oral-first), which require an initial intravenous (IV) phase before a step-down to oral therapy, and which will need IV therapy all along their care pathway. Treatment debates are particularly relevant in contexts involving constrained healthcare resources and limited hospital bed availability. This narrative review summarises the essential prerequisites for prescribing oral antibiotic therapy for paediatric OAIs and proposes a pharmacokinetic/pharmacodynamic (PK/PD) framework for guiding clinical decision-making. Key considerations include: pathogen identification and resistance profiling; contemporary bacteriological epidemiology; the comparative effectiveness of IV versus oral therapy; the availability of active oral antibiotics and their penetration into bone and joint compartments; achieving adequate systemic exposure and hitting PK/PD targets after oral administration; and the clinical limitations of oral antibiotic therapy, including patient selection criteria. We argue that oral-first and early-switch strategies are best framed as structured selection processes that integrate clinical severity and source control, pathogen/minimal inhibitory concentration constraints, the feasibility of attaining PK/PD targets orally and the reliability of follow-up. No single strategy should be seen as a universal default strategy. Full article

Loss of myelinating oligodendrocytes and myelin impairs motor and cognitive functions. Transplantation of autologous oligodendrocyte precursors (OPCs) holds promise for treatment of such diseases, but a protocol to derive human OPCs from a safe, ethical and accessible cell source with the rapidity required to catch the therapeutic window remains to be found. Although we previously generated myelinating glia from rat bone marrow stromal cells (BMSCs), it remains unknown if clinically sourced human BMSCs (hBMSCs) share the same potential. Moreover, whether the multipotency of BMSCs results from diverse progenitors preexisting in the bone marrow or from a single multipotent progenitor population remains unaddressed. Single-cell RNA sequencing data revealed a CD90^hiEGFR⁺PDGFRA⁺ pre-OPC-like subpopulation within hBMSCs. With a small-molecule-based (virus-free and supporting-cell-free) two-step induction protocol designed to expand this pre-OPC population, we generated functional OPCs with high purity in eight days. These derived OPCs showed phenotypic transcriptomes and immunoprofiles. They were also capable of myelinating naked axons when transplanted into myelin-deficient shiverer mice. Results highlight how targeted enrichment and maturation of specific progenitor subpopulations within hBMSCs allows rapid induction of desired cell types. These results place hBMSCs as a robust source of OPCs, unlocking the possibility for cell transplantation therapy for myelin deficiency in the central nervous system. Full article

(1) Background: The search for new polymodal antioxidants to correct oxidative stress of various origins and its consequences remains one of the most pressing and rapidly developing areas of biomedical research. (2) Methods: Hydrogen peroxide and hydroxyl radical detection, induced luminescence assay, ELISA for 8-oxoguanine detection, animal survival, blood cell count, micronucleus test, and PCR were used. (3) Results: 2R,3R-trans-dihydroquercetin (DHQ) was shown to reduce the amount of hydrogen peroxide and hydroxyl radicals formed during water radiolysis, leading to reduced damage to biomolecules. DHQ is a radioprotector, most effective at a dose of 300 mg/kg administered 15 min before radiation exposure. The dose reduction factor is 1.22. DHQ administration reduces the severity of radiation-induced leukopenia and thrombopenia by protecting red bone marrow cells. The mechanism of DHQ’s radioprotective action is fundamentally different from that of classical stress response inducers and is based on the normalization of the target cell transcriptional profile, rather than its hyperstimulation. (4) Conclusions: DHQ’s ability to restore the expression of antioxidant defense, DNA repair, and apoptotic genes to physiological levels under radiation exposure allows it to be considered a promising pharmacological agent for the correction of radiation-induced damage to normal tissues. Full article

Background and Objectives: Osteonecrosis of the jaw (ONJ) occurring after infection with SARS-CoV-2 has emerged as an increasingly reported complication in the post-COVID-19 era. Post-COVID-19 osteonecrosis of the jaw (PC-ONJ) has been described in association with both COVID-19-associated mucormycosis (CAM) and non-fungal phenotypes. This narrative review aims to synthesize and critically analyze the available evidence regarding terminology and classification, epidemiology and risk factors, pathophysiological mechanisms, clinical and imaging characteristics, diagnostic challenges, and management strategies relevant to oral and maxillofacial surgery practice. Materials and Methods: An extensive literature search was conducted in the PubMed/MEDLINE, Scopus, Web of Science, ScienceDirect, and Google Scholar databases. The search targeted peer-reviewed publications published between 2020 and 2025, reflecting the post-pandemic emergence of this clinical spectrum. Original studies, systematic and narrative reviews, multicenter case series, consensus guidelines, and well-documented case reports were considered. Results: Available data, largely derived from case reports and small series, demonstrate a predominance of maxillary involvement and frequent association with diabetes mellitus and systemic corticosteroid therapy. Proposed mechanisms include COVID-19-associated endothelial dysfunction, microvascular thrombosis, immune dysregulation, metabolic imbalance, and treatment-related effects. Clinically, patients may present with persistent orofacial pain, tooth mobility, exposed or probeable bone, and frequent sinonasal extension, with symptoms sometimes preceding bone exposure. Diagnostic challenges arise from the overlap with medication-related osteonecrosis of the jaw (MRONJ), osteoradionecrosis (ORN), and chronic osteomyelitis. Imaging is essential for assessing disease extent but remains insufficient for etiologic differentiation, making histopathological examination and targeted microbiological investigations necessary, particularly to exclude invasive fungal infection. Conclusions: Management must be etiology-driven. CAM requires urgent antifungal therapy combined with surgical debridement, whereas non-fungal forms are generally managed with conservative surgery and appropriate antimicrobial stewardship. Standardized diagnostic criteria and prospective multicenter studies are needed to reduce nosological ambiguity and optimize clinical decision-making in this emerging post-viral condition. Full article

Background: Genetic causes of growth failure should be suspected in patients born small for gestational age (SGA) who fail to show postnatal catch-up growth, present with severe short stature (SS), and exhibit a poor or absent response to growth hormone (rhGH) therapy. Mutations in the insulin-like growth factor 1 receptor (IGF1R) gene are associated with impaired growth, intrauterine growth restriction (IUGR), low birth weight and/or length, and postnatal SS. Case Description: A 9-year-old boy, born SGA for birth length, was evaluated for severe SS. Common causes of SS were excluded. At 9 years and 7 months of age, his height was 112.6 cm (−3.99 SDS), weight 18 kg (−3.79 SDS), and BMI 14.2 kg/m² (−1.8 SDS); pubertal development was Tanner stage 1. The target height was 158 cm (−2.62 SDS). Bone age was delayed by approximately one year compared with chronological age. Serum IGF-1 levels were within the upper-normal range for age. GH therapy (0.035 mg/kg/day) was initiated due to the lack of catch-up growth in an SGA subject. After three years of treatment, the height gain was only 0.5 SDS. IGF-1 levels showed a transient treatment-related increase, followed by persistent normalization during ongoing therapy. Next-generation sequencing (NGS) analysis identified novel heterozygous paternal nonsense variant in the IGF1R gene: c.3498C>G (p.Tyr1166Ter). At 12 years of age, impaired fasting glucose and reduced glucose tolerance were detected; consequently, it was decided to discontinue rhGH therapy, also in light of the IGF1R mutation and the lack of height recovery. Conclusions: This case underlines the critical role of genetic testing in the evaluation of patients born SGA. The coexistence of SGA status and an IGF1R gene mutation may provide a clear explanation for both the poor response to rhGH therapy and the increased risk of alterations in glucose metabolism. An extensive narrative review of the literature on growth outcomes and glucose metabolism abnormalities during GH treatment in SGA patients carrying IGF1R variants was also performed. Full article

The 2025 approval of the selective NaV1.8 blocker suzetrigine for acute pain marked a pivotal advance in analgesic drug development. Yet the subsequent failure of Vertex’s next-generation NaV1.8 inhibitor VX993 to demonstrate clinical analgesia underscores enduring challenges in translating mechanistic promise into patient benefit. This review examines why promising targets and compounds, spanning NaV and TRP channels, often falter and outlines a path toward more reliable target selection and validation. I first summarize the pain pathway, from nociceptor transduction through spinal processing to cortical perception, emphasizing how inflammation and peripheral sensitization reshape excitability. Historically serendipitous, pain drug discovery now prioritizes molecular precision. Most approved chronic pain therapies act in the CNS and are limited by modest efficacy and adverse effects. Nociceptor-enriched targets (NaV1.7/1.8/1.9; TRP channels) remain attractive, yet redundancy among NaV subtypes and the necessity of blocking targets at the correct anatomical sites complicate translation. Human genetics and multi-omics provide a powerful, unbiased engine for target discovery. Rare high-impact variants offer strong causal hypotheses, while common polygenic contributions illuminate broader susceptibility. Large biobanks increasingly reveal a mismatch between legacy pain targets and genetically supported candidates across neuronal and non-neuronal cells. Human DRG transcriptomics highlight NaV channel redundancy. Human in vitro electrophysiology and PK/PD analyses show suzetrigine achieves ~90–95% NaV1.8 engagement, yet neurons can still fire unless additional channels are blocked. Species differences and drug distribution (including BBB/PNS penetration and P-gp efflux) critically influence efficacy; centrally accessible blockade (e.g., for NaV1.7 or TRPA1) may be necessary to achieve robust analgesia, challenging peripherally restricted strategies. Osteoarthritis illustrates how obesity-driven metabolic inflammation, synovial immune activation, subchondral bone remodeling, and specific nociceptor subtypes converge to drive mechanical pain. Multi-omic integration across diseased human tissues can pinpoint causal processes and cell types, enabling more selective and safer target choices. I propose a practical framework for target validation that integrates: (i) rigorous human genetic support; (ii) cell-type and site-of-action mapping; (iii) human-relevant electrophysiology and PK/PD with verified target engagement; (iv) species-appropriate models; (v) consideration of modality (small molecule, biologic, RNA, targeted protein degradation). Advancing genetically and anatomically aligned targets, tested at the right sites and exposures, offers the best path to genuinely effective, better-tolerated pain therapeutics. Full article

Background/Objectives: FcγRIIIA presents a single nucleotide polymorphism at position 158 (V/F), which affects its binding affinity to the fragment crystallizable (Fc) of antibodies (Abs). In the presence of immune complexes, FcγRIIIA can mediate the inflammatory signaling, severity of bone disease, and osteoclastogenic activity. Based on this functional relevance, we hypothesized that the FcγRIIIA F158V polymorphism may influence the clinical presentation of multiple myeloma (MM). Methods: FcγRIIIA F158V genotyping was performed on genomic DNA extracted from peripheral blood samples of patients affected by MM or asymptomatic conditions named MGUS and SMM. We compared the allele frequency of FcγRIIIA-F158V polymorphism in 72 MM, 42 MGUS and 31 SMM and evaluated the association with clinical features and occurrence of high-risk chromosome abnormalities. Targeted NGS mutation analysis was performed on genomic DNA isolated from purified CD138⁺ bone marrow plasma cells (BMPCs) of 41 patients, to evaluate the association between somatic mutations and the FcγRIIIA F158V genotype. Results: the FcγRIIIA-158 V/V homozygous genotype was associated with high-risk cytogenetics, anemia, high beta-2 microglobulin levels, and more than 10 osteolytic lesions. V/V homozygous genotype was significantly associated with at least one mutation in RAS pathway genes (N-RAS, K-RAS or B-RAF). In the immune microenvironment, patients carrying the V/V homozygous genotype had a higher percentage of CD14⁺CD16⁺⁺ non-conventional inflammatory monocytes than the V/F or FF genotype. Conclusions: Our study contributes to a better understanding of the interactions between genetic variants, tumor microenvironment, and therapeutic response in plasma cell dyscrasias, to identify molecular biomarkers for precision medicine in MM, MGUS and SMM. Full article

Background/Objectives: Sarcopenia (SP) and osteoporosis (OP) are common yet underrecognized complications of liver cirrhosis, contributing to increased morbidity and mortality. Their coexistence, termed osteosarcopenia (OS), represents a compounded musculoskeletal impairment. Insulin-like growth factor 1 (IGF-1), synthesized in the liver, has been implicated in muscle and bone metabolism. This study aimed to assess the prevalence and association of laboratory and clinical parameters with SP, OP, and OS in cirrhotic patients, with a focus on IGF-1 deficiency and their impact on mortality. Methods: This cross-sectional study included 100 cirrhotic patients at a tertiary center. Sarcopenia was diagnosed using CT-derived L3 skeletal muscle index and osteoporosis via the DEXA scan. IGF-1 levels and metabolic parameters were measured. Multivariate logistic regression identified laboratory and clinical factors associated with musculoskeletal complications. However, due to the cross-sectional design, causal relationships could not be inferred. Results: SP, OP, and OS were present in 41%, 22%, and 11% of patients, respectively. IGF-1 levels were significantly lower in patients with SP, OP, and OS (p < 0.05) and were independently associated with increased risk of SP (OR = 1.797, p = 0.006), OP (OR = 1.873, p = 0.045), and OS (OR = 2.326, p = 0.003). Mortality rates were significantly higher among patients with OS (72.7%), OP (77.3%), and SP (56.1%). OS conferred the highest adjusted mortality risk (OR = 2.739, p = 0.009), followed by SP (OR = 2.278, p = 0.015) and OP (OR = 1.958, p = 0.036). Conclusions: Musculoskeletal complications are highly prevalent and predictive of mortality in cirrhosis. IGF-1 deficiency is a strong independent biomarker for SP, OP, and OS. Routine screening and early intervention targeting IGF-1 pathways and nutrition may improve outcomes in this population. Full article

Histone deacetylase 6 (HDAC6), a member of the class IIb HDAC family, plays a crucial role in epigenetic regulation and cytoskeletal dynamics, while participating in host anti-infective immune responses. However, its precise functions and mechanisms during Chlamydia muridarum (C. muridarum) infection remain incompletely defined. Our study demonstrated that C. muridarum respiratory infection upregulates HDAC6 expression at the infection site and in immune organs. Comparative analysis of wild-type (WT) and HDAC6-deficient (HDAC6^−/−) mice in this infection model revealed that HDAC6 deficiency exacerbates disease progression, including significant weight loss, severe pulmonary inflammation, and impaired C. muridarum clearance. Relative to WT mice, HDAC6^−/− mice exhibited elevated Signal Transducer and Activator of Transcription 6 (Stat6) and GATA Binding Protein 3 (Gata3) mRNA expression, enhanced pathological Th2 responses with increased IL-4 secretion, and no significant differences in protective Th1 or Th17 responses following C. muridarum infection. Concurrently, these mice displayed enhanced M2 macrophage polarization, as evidenced by upregulated CD206 and Arg-1 expression, whereas M1 marker expression remained unchanged. The vitro studies confirmed that HDAC6^−/− bone marrow-derived macrophages (BMDMs) promote M2 polarization, characterized by increased Arg-1, IL-10, and TGF-β production, and further co-culture experiments showed that C. muridarum -stimulated HDAC6^−/− BMDMs drive Th2 differentiation. These findings elucidate the critical role of HDAC6 in regulating Th2-M2 immune responses during C. muridarum respiratory infection and suggest targeted modulation of HDAC6 as a novel therapeutic strategy for chlamydial respiratory infection. Full article

Chronic alcohol consumption increases the risk of osteoporosis and fracture by disrupting bone remodeling, in part by enhancing osteoclastogenesis. However, the cellular mechanisms underlying this process remain incompletely defined. We analyzed scRNA-seq data from osteoclasts differentiated in vitro from bone marrow mononuclear cells obtained from macaques following 12 months of chronic ethanol or isocaloric control solution consumption. Module scoring, trajectory inference with generalized additive modeling (tradeSeq), and CellChat-based analyses of intercellular communication were applied to uncover ethanol-induced changes in metabolic reprogramming, lineage progression, and signaling network dynamics. Module scoring indicated metabolic reprogramming toward oxidative phosphorylation, with reduced glycolytic, migratory, and phagocytic activities. Pseudotime analysis revealed accelerated osteoclast lineage commitment, broader intermediate differentiation states, and stabilization of mature osteoclasts. CellChat analysis showed globally amplified intercellular signaling, with mature osteoclasts functioning as dominant communication hubs sustained by autocrine feedback. Together, chronic alcohol consumption rewired osteoclastogenesis through early fate priming, metabolic adaptation, and hierarchical remodeling of intercellular communication, promoting enhanced osteoclastogenesis. These findings provide mechanistic insight into alcohol-induced bone pathology and highlight potential targets for therapeutic intervention. Full article

Background/Objectives: Atraumatic electrode array insertion should be targeted in cochlear implantation. Robotic insertion is used in many centers worldwide. Our objective was to evaluate manual electrode placement and robot-assisted placement using RobOtol^® on human temporal bones (TBs), in terms of endocochlear trauma and completion of insertion. Methods: Sixteen TBs originating from eight bodies were implanted with Medel-FLEX24 electrodes through the round window. The right TB was implanted manually, while the left TB of the same body was implanted using RobOtol^® for electrode insertion. Results were analyzed through micro-computed tomography imaging. No statistical analysis was used, given the small sample size; a descriptive interpretation of micro-CT scans was rather preferred. Results: In the “manual group”, there were two cases (25%) of insertion trauma: elevation of basilar membrane at basal turn (Eshraghi-stage-1). In the “robotic group”, there were two cases (25%) of insertion trauma: one case of elevation of basilar membrane at the middle turn (Eshraghi-stage-1) and one case of dislocation of all electrodes in scala vestibuli (Eshraghi-stage-3). There were six cases (75%) of incomplete insertion in the “manual group” and four cases (50%) of incomplete insertion in the “robotic group”. Conclusions: Both techniques of electrode placement yielded fairly similar results, in terms of endocochlear trauma and completion of insertion. New larger-scale cadaveric and clinical studies are needed to determine the possible benefit of robot-assisted electrode insertion in cochlear implantation. Full article