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Despite the various treatments proposed with barrier membranes, one of the main challenges for guided bone regeneration (GBR) is maintaining space for large defects and ensuring an adequate blood supply. The presented feasibility case series aims to introduce an original titanium frame (TF) design, customized for each defect, as a modification of well-known principles and materials for GBR to achieve an enhanced and more predictable horizontal and vertical bone augmentation. Three patients with significant horizontal defects were treated with pre-trimmed TFs to create needed space, and then a 50/50 mixture of autograft and bovine xenograft was placed and covered with a collagen membrane. After 8 months of healing, the sites were reopened, and the titanium screws were removed with the frame. An average of 8.0 ± 1.0 mm of horizontal and 3.0 ± 0.0 mm of vertical bone gain were achieved at the time of reentry and implant placement surgery. Bone core biopsy sample was obtained during the implant placement. Histomorphometric analysis revealed that 42.8% of the sample was new vital bone, 18.8% was residual bone graft particles, and 38.4% was bone marrow-like structures. After 3 to 4 months from implant placement, the implants were restored with provisional crowns and then finalized with zirconia screw-retained crowns. This case series suggests that GBR utilizing TFs with or without collagen membranes can be considered a suitable approach for horizontal and vertical bone augmentation. However, based on only three reported cases, the results should be carefully interpreted. [ABSTRACT FROM AUTHOR]

We took a systems approach to the analysis of macrophage phenotype in regenerative and fibrotic volumetric muscle loss outcomes in mice together with analysis of systemic inflammation and of other leukocytes in the muscle, spleen, and bone marrow. Differences in expression of macrophage phenotype markers occurred as early as day 1, persisted to at least day 28, and were associated with increased numbers of leukocytes in the muscle and bone marrow, increased pro-inflammatory marker expression in splenic macrophages, and changes in the levels of pro-inflammatory cytokines in the blood. The most prominent differences were in muscle neutrophils, which were much more abundant in fibrotic outcomes compared to regenerative outcomes at day 1 after injury. However, neutrophil depletion had little to no effect on macrophage phenotype or on muscle repair outcomes. Together, these results suggest that the entire system of immune cell interactions must be considered to improve muscle repair outcomes. [ABSTRACT FROM AUTHOR]

Skin infiltration by neutrophils is a hallmark of the chronic inflammatory skin disease psoriasis, yet the mechanisms underlying neutrophil recruitment and positioning in chronically inflamed skin remain poorly understood. In this study, we demonstrate the significant impact of a total genetic deficiency of secretory leukocyte protease inhibitor (SLPI) on neutrophil migration in mouse skin. Without SLPI, neutrophils displayed an unconventional migratory pattern, characterized by altered interactions with vessel walls and reduced efficiency in extravasating from blood vessels into skin tissue during the early stages of experimental psoriasis. This was associated with changes in tissue motility, positioning neutrophils farther from the skin entry vessels and closer to the skin surface. Neutrophil diapedesis was partially dependent on SLPI within the neutrophils themselves. The impact of SLPI on neutrophil movement was further supported by the increased migration of human neutrophils in the presence of neutrophil-penetrant recombinant SLPI. Additionally, our data suggest that neutrophils with varying capacities for vessel wall interaction are released from the bone marrow into circulation in an SLPI-dependent manner. These findings establish a role for SLPI in regulating the spatiotemporal infiltration of neutrophils into the skin in psoriasis, highlighting its relevance to psoriasis pathophysiology. [ABSTRACT FROM AUTHOR]

AbstractMeasurable residual disease (MRD) is critical in guiding therapeutic strategies for B-cell acute lymphoblastic leukemia (B-ALL). This study evaluated the performance of a novel next-generation sequencing-based Celemics IGH assay (CM-IGH; Celemics, Seoul, Korea) compared with the LymphoTrack® IGH FR1 assay (LT-IGH; Invivoscribe Technologies, USA) and multiparameter flow cytometry (MFC). A total of 31 diagnostic and 60 follow-up bone marrow aspirate samples, all from the same 31 pediatric patients with B-ALL, were analyzed using the CM-IGH and LT-IGH assays on the MiSeq platform, as well as MFC according to EuroFlow guidelines. Initial IGH clonality was detected in 83.9% of CM-IGH samples and 90.3% of LT-IGH samples (p = 0.060). MRD positivity rates in follow-up samples were 74.5% for CM-IGH, 61.1% for LT-IGH, and 56.7% for MFC. CM-IGH showed concordance rates of 78.3% with LT-IGH and 68.1% with MFC, while LT-IGH demonstrated an 81.5% concordance rate with MFC. The correlation coefficients (r) of MRD levels were 0.831 between CM-IGH and LT-IGH, 0.702 between CM-IGH and MFC, and 0.776 between LT-IGH and MFC. The CM-IGH assay demonstrates substantial concordance with LT-IGH and MFC in detecting MRD in pediatric patients with B-ALL, highlighting the complementary value of IGH clonality assays and MFC. [ABSTRACT FROM AUTHOR]

Objective: The mechanism of glioma development has been extensively explored and comprehension of the exosomal microRNA-142-3p/growth factor independent-1 (miR-142-3p/GFI1) axis in glioma is still at an initial stage. Therein, the conducted work goes toward ascertaining the role of the bone marrow mesenchymal stem cells-derived exosomes (BMSCs-Exos)/miR-142-3p/GFI1 axis in glioma development. Methods: Cancer tissues from patients with glioma and normal brain tissues from those who underwent surgery for traumatic brain injury were collected. miR-142-3p and GFI1 expression in tissues and cells were measured. Exos derived from BMSCs carrying miR-142-3p were cocultured with glioma cells to observe the effects of exosomal miR-142-3p on glioma cell invasion, migration, and apoptosis. The targeting relationship of miR-142-3p and GFI1 was validated. A series of rescue assays were conducted to further investigate whether GFI1 is implicated in the exosomal miR-142-3p-mediated regulation of glioma cell invasion, migration, and apoptosis. Results: miR-142-3p was low-expressed in glioma tissues and cells, and the low expression had an association with unwanted prognosis. Exos-shuttled miR-142-3p suppressed the migration and invasion, while promoting apoptosis of glioma cells. Further investigation revealed that GFI1 was a direct target of miR-142-3p, and re-expression of GFI1 neutralized the inhibitory effects of exosomal miR-142-3p. Conclusion: Exosomal miR-142-3p suppressed glioma cell migration and invasion and stimulated apoptosis by targeting GFI1. [ABSTRACT FROM AUTHOR]

Background: The study aims were to systematically review and analyze preclinical research on the efficacy of exosomes derived from various mesenchymal stem cell sources (MSC-exos) for the treatment of spinal cord contusion injury (SCI) in small animal models. Methods: We conducted a systematic search of PubMed, Embase and Google Scholar databases from their inception through February 29, 2024, to identify eligible English-language studies based on predefined inclusion and exclusion criteria. Two independent investigators performed literature screening, data extraction and bias assessment. Results: A total of 235 rats were used to assess locomotor recovery at the initial assessment, and exhibited significant improvement in hind limb movement in those treated with exosomes, as indicated by a statistically significant increase in Basso-Beattie-Bresnahan (BBB) scores (MD: 1.26, 95% CI: 1.14–1.38, p < 0.01) compared to the controls. This trend persisted in final assessment data across 21 studies, with pooled analysis confirming similar results (MD: 1.56, 95% CI: 1.43–1.68, p < 0.01). Funnel plot analysis indicated asymmetry in the pooled BBB scores at both baseline and endpoint assessments, suggesting potential publication bias. Exosomes were derived from bone marrow, adipose tissue, umbilical cord or human placental MSCs. Meta-analysis results showed no statistically significant differences in therapeutic efficacy among these MSC-exos sources at various treatment time points. Conclusion: MSC-exos demonstrated considerable promise in improving motor function in SCI-affected rats, with bone marrow MSC-derived exosomes having particularly notable effectiveness. [ABSTRACT FROM AUTHOR]

Background: Neutrophil granulocytes are important parts of the defence against bacterial infections. Their action is a two-edged sword, the mediators killing the intruding bacteria are at the same time causing tissue damage. Neutrophil activation is part of the dysregulated immune response to infection defining sepsis and neutrophil elastase is one of the powerful proteases causing both effects and damage. Inhibition of neutrophil elastase has been tried in sepsis and ARDS, so far with inconclusive results. Methods: We used positron emission tomography (PET) combined with computed tomography (CT) and the selective and specific neutrophil elastase inhibitor PET-tracer [11C]GW457427 ([11C]NES), in an intensive care unit porcine Escherichia coli sepsis model with the primary aim to visualise the biodistribution of neutrophil elastase in the initial acute phase of the septic reaction. Repeated PET–CT investigations were performed before and after induction of sepsis. Results: At baseline [11C]NES uptake was found in the bone marrow, spleen and liver. The uptake in the bone marrow was markedly increased two hours into the sepsis, whereas in spleen and liver the uptake was not as markedly changed compared to baseline. At 4 h after the sepsis induction [11C]NES in the bone marrow decreased while the uptake increased in the spleen, liver and lungs. Conclusion: The neutrophil elastase PET-tracer [11C]NES is a novel and unique instrument to study the acute innate neutrophil immune response in sepsis and associated vital organ failure. We here present images and quantitative data of the neutrophil elastase distribution the first hours of acute experimental sepsis. Surprisingly, a pronounced increase of neutrophil elastase was found in the bone marrow 2 h into the sepsis reaction followed at 4 h by increase in the liver, spleen and lungs and a concomitant reduction of the tracer uptake in bone marrow. [ABSTRACT FROM AUTHOR]

Polymorphonuclear neutrophils (PMNs), the most abundant leukocytes circulating in human blood, are pivotal players in the innate immune system. In recent years, PMNs have gained increasing recognition for their significant involvement in the pathogenesis of a wide array of human diseases, including sepsis, pulmonary conditions, autoimmune disorders, and various cancers. Due to their terminally differentiated state, PMNs possess a short lifespan and exhibit limited proliferative potential, which makes continuous replenishment from the bone marrow essential for maintaining immune homeostasis. This demand underscores the need for efficient, reliable, and robust methods of PMN production. In this study, we evaluated three forward programming protocols and one directed differentiation protocol aimed at generating PMNs from human pluripotent stem cells (hPSCs). We analyzed not only their differentiation efficiency but also the transcriptomic profiles and functional capabilities of the resulting PMNs. Our findings revealed that both the forward programming method and the directed differentiation approach can successfully generate functional PMNs. Furthermore, by fine-tuning the culture media at various stages during forward programming, we identified an optimal protocol that significantly enhances hematopoietic differentiation potential and promotes the functional maturity of the neutrophils. [ABSTRACT FROM AUTHOR]

Background: Steroid-resistant asthma (SRA) is a form of asthma resistant to corticosteroid therapy, which is characterized by the presence of neutrophil-predominant inflammatory response and neutrophil extracellular traps (NETs) formation. Hyssopus cuspidatus Boriss., a traditional Uyghur medicine, is known for its efficacy in treating inflammatory lung conditions such as asthma. However, the therapeutic impact and underlying mechanisms of Hyssopus cuspidatus Boriss.'s volatile oil (HVO) in SRA have not been fully elucidated. Methods: This study established an ovalbumin/lipopolysaccharide (OVA/LPS)-induced SRA mice model to evaluate the therapeutic effect of HVO on SRA. UPLC-QE-Orbitrap-MS was applied to analyze the serum compositions of HVO. Network pharmacology and molecular docking were employed to uncover the complex mechanisms of HVO in treating SRA and predict potential effective compounds in HVO. Furthermore, in vivo studies in SRA mice and in vitro studies using HL-60 cells and bone marrow neutrophils were conducted to validate the mechanism. Results: HVO could significantly ameliorate OVA/LPS-induced SRA symptoms, including airway hyperresponsiveness, airway inflammation, mucus overproduction and airway remodeling. 41 prototype compounds, 65 Phase I metabolites and 50 Phase II metabolites were identified in serum-containing HVO. The integration of network pharmacology with experimental validation revealed that HVO can inhibit the formation of NETs by targeting neutrophil elastase, thereby exerting a therapeutic influence on SRA. Meanwhile, molecular docking results showed that 3-methoxy-4-hydroxy mandelonitrile, 1,2,3,4-tetrahydro-1,5,7-trimethyl-naphthalene, cis-calamenene and aristol-1(10)-en-9-yl isovalerate may be the therapeutic compounds of HVO in treating SRA. Conclusion: These findings suggest that HVO is a promising therapeutic candidate for neutrophil-dominant SRA by targeting NETs formation. [ABSTRACT FROM AUTHOR]

Neutrophils are rapidly recruited to sites of infection, injury, or to immune complexes. Upon arrival, they initiate degranulation, release reactive oxygen species (ROS), and/or nuclear extracellular traps (NETs) to eliminate invading microorganisms, clear debris, or remove abnormal immunoglobulins. While these processes ideally trigger healing and a return to balance, overshooting neutrophil function can lead to life-threatening infections such as sepsis or persistent inflammation observed in various autoimmune diseases. However, recent evidence highlights a phenotypic and functional heterogeneity of neutrophils that extends well beyond their traditional - potentially harmful- role as first responders. For example, neutrophils regulate ongoing inflammation by modulating macrophage function through efferocytosis, T cell responses by antigen presentation and the release of cytokines. The factors that induce neutrophil differentiation into activating or regulatory phenotypes remain poorly defined. Here, we hypothesize that intracellular components that have been released into the extracellular space could contribute to the phenotypic heterogeneity of neutrophils. To find out, we used nanoparticles composed of intracellular proteins (cell-derived nanoparticles, CDNPs) and analyzed their effects on cultured murine bone marrow neutrophils (BMN). We observed that CDNPs activate BMN transiently with an increase in the expression of CD11b without triggering classical effector functions. Additionally, CDNPs induce the secretion of IL-10, shift PMA-induced cell death toward apoptosis, and increase the expression of CD80. Mechanistically, our findings indicate that 26% of BMNs ingest CDNPs. These BMNs preferentially express CD54+, fail to migrate toward CXCL12, exhibit diminished responses to LPS, and undergo apoptosis. These data identify CDNPs as biomaterials that modulate neutrophil behavior by fine-tuning the expression of CD11b and CD80. [ABSTRACT FROM AUTHOR]

Men develop larger infarct sizes than women after a myocardial infarction (MI), but the mechanism underlying this sex difference is unknown. Here, we demonstrated that blood neutrophil counts post-MI were higher in male than female mice. Castration-induced testosterone deficiency reduced blood neutrophil counts to the level in females and increased survival post-MI. These effects were mimicked by Osterix-directed ablation of the androgen receptor in bone marrow (BM). Mechanistically, androgens downregulated the leukocyte retention factor CXCL12 in BM stromal cells. Post-hoc analysis of clinical trial data showed that neutrophilia was greater in men than women after reperfusion of first-time ST-elevation MI, and tocilizumab, an interleukin-6 receptor inhibitor, reduced blood neutrophil counts and infarct size to a greater extent in men than women. Our work reveals a previously unknown mechanism connecting testosterone with neutrophilia and MI injury via BM and identifies the importance of considering sex when developing anti-inflammatory strategies to treat MI. Men develop larger myocardial infarction (MI) sizes than women. Here, the authors show that male sex and testosterone, via bone marrow stroma, exacerbates MI-induced neutrophilia and cardiac injury and that response to anti-inflammatory treatment in MI is greater in men than women [ABSTRACT FROM AUTHOR]

Background: Natural killer cells, an important component of the innate immune system, can directly recognize and lyse virally infected or transformed cells. However, NK cells fail to restrain the growth of malignancies, such as B-cell acute lymphoblastic leukemia (B-ALL). The molecular genetics of NK cells in the B-ALL bone marrow microenvironment and the mechanisms underlying the inhibited function of NK cells at the single-cell level remain largely elusive. Methods: In this study, we studied the frequency and absolute number of NK cells in peripheral blood samples collected from 43 healthy volunteers and 104 pediatric B-ALL patients diagnosed at Hunan Children's Hospital. We also analyzed published single-cell RNA sequencing (scRNAseq) data from B-ALL and normal bone marrow samples using unsupervised clustering. Our findings were further validated using bulk transcriptomic data and clinical data from a cohort of 139 B-ALL bone marrow samples. Results: We found that the frequency and number of NK cells were significantly decreased in the bone marrow and peripheral blood of B-ALL patients. In-depth analysis of scRNAseq data identified 12 NK cell clusters. Among them, the C2 cluster, which is present in healthy bone marrow but reduced in B-ALL bone marrow, displays overexpression of a transcription factor KLF2 and a significant downregulation of the "leukocyte proliferation" pathway. Furthermore, we found that the expression of KLF2 in B-ALL at diagnosis was positively correlated with the percentage of leukemia cells and the positive rate of minimal residual disease (MRD), indicating that KLF2 is a marker of poor prognosis. Conclusion: There are dramatic differences at the single-cell level in the transcriptomics of NK cells between healthy donors and B-ALL patients. A transcription factor, KLF2, which is enriched in the C2 cluster of NK cells, has been suggested to regulate the proliferation of NK cells and is associated with poor prognosis of pediatric B-ALL. [ABSTRACT FROM AUTHOR]

Murine double minute 2 (MDM2) inhibitors have shown promising activity in TP53-wild type tumors and are under active investigation across a spectrum of malignancies. Herein, we report a 51-year-old female with MDM2-amplified, TP53-wild type adenoid cystic carcinoma who was treated with a MDM2 inhibitor and developed persistent pancytopenia despite drug discontinuation. Her pancytopenia was associated with 20 distinct pathogenic TP53 mutations in peripheral blood and bone marrow not present in drug-resistant tumor tissue. Plasma TP53 mutations were similarly detected among 4 other patients treated at our institution, with the number of mutations correlating strongly with duration of treatment. This case suggests that MDM2 inhibitors are associated with TP53 clonal hematopoiesis, which may confer a risk of subsequent myeloid malignancy. As multiple MDM2 inhibitor trials are ongoing, our findings underscore the need for further investigation into the potential long-term deleterious effects of these inhibitors in the hematopoietic stem and progenitor compartment. [ABSTRACT FROM AUTHOR]

Although both central and peripheral inflammation have been observed consistently in depression, the relationship between the two remains obscure. Extra-axial immune cells may play a role in mediating the connection between central and peripheral immunity. This study investigates the potential roles of calvarial bone marrow and parameningeal spaces in mediating interactions between central and peripheral immunity in depression. PET was used to measure regional TSPO expression in the skull and parameninges as a marker of inflammatory activity. This measure was correlated with brain TSPO expression and peripheral cytokine concentrations in a cohort enriched for heightened peripheral and central immunity comprising 51 individuals with depression and 25 healthy controls. The findings reveal a complex relationship between regional skull TSPO expression and both peripheral and central immunity. Facial and parietal skull bone TSPO expression showed significant associations with both peripheral and central immunity. TSPO expression in the confluence of sinuses was also linked to both central and peripheral immune markers. Group-dependent elevations in TSPO expression within the occipital skull bone marrow were also found to be significantly associated with central inflammation. Significant associations between immune activity within the skull, parameninges, parenchyma and periphery highlight the role of the skull bone marrow and venous sinuses as pivotal sites for peripheral and central immune interactions. [ABSTRACT FROM AUTHOR]

Objectives This study aimed to evaluate the relationship between the degree of bone marrow involvement, hematological parameters, and 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography/computed tomography (PET/CT) data in patients diagnosed with multiple myeloma. Methods A total of 71 patients [19 females, 52 males, mean age 67 (36-83) years] who were diagnosed with multiple myeloma between 2014 and 2021, had not received any treatment yet, and underwent 18F-FDG-PET/CT for staging were included in the study. Results No significant correlation was observed between bone marrow standardized uptake value (SUV)max and plasma cell infiltration (p=0.07). However, we found that patients with visually increased bone marrow counts also had higher plasma cell infiltration rates (p=0.037). No significant correlation was found between plasma cell infiltration rates and bone marrow SUVmax and systemic inflammatory index (SII) (p=0.187 and p=0.446, respectively). However, there was a significant correlation between the SUVmax of lytic lesions showing increased 18F-FDG uptake in bone and SII (p=0.025, r=0.330). Conclusion We believe that 18F-FDG PET/CT may be an advantage over bone marrow biopsy in the diagnosis and evaluation of multiple myeloma recurrence and may prevent repeated bone marrow biopsies. Keywords:Multiple myeloma, 18F-FDG PET/CT, plasma cell infiltration rate, systemic immune-inflammatory index: [ABSTRACT FROM AUTHOR]

The issue of a possible association between Shwachman-Diamond Syndrome and diabetes has been debated for many years. This review updates the Italian Shwachman-Diamond registry, confirming our previous findings that suggest that these patients might be at higher risk of developing diabetes, particularly type 1. These data are of relevance in the clinical follow-up of patients in everyday life, emphasizing the need for early diagnosis and timely intervention. [ABSTRACT FROM AUTHOR]

Sarcoid-like reaction (SLR) has been reported in patients with solid tumor malignancies, lymphomas, and patients receiving immunotherapy. SLR is often incidentally found during positron emission tomography/computed tomography scans as hilar and/or mediastinal lymphadenopathy. SLR has also been found in the lung, spleen, bone marrow, and skin. Biopsy of these lesions shows noncaseating granulomas. When systemic criteria are not met for sarcoidosis, these noncaseating granulomas are termed SLR. We present the first case in the literature of a case of orbital SLR in a patient with concomitant diffuse large B-cell lymphoma and inverted papilloma of the maxillary sinus. This case highlights the importance of including malignancy in the differential for the presence of a noncaseating granuloma in the orbit. [ABSTRACT FROM AUTHOR]

Acute manifestations of sickle cell disease (SCD) are numerous and multisystemic. Cerebral fat embolism (CFE) is a rare but serious complication of SCD caused by bone marrow necrosis (BMN) during vaso-occlusive crises (VOC). We present the case of a 41-year-old man with SCD who developed severe VOC and multi-organ dysfunction. He subsequently experienced neurological deterioration with decreased consciousness and diffuse encephalopathy on serial electroencephalograms. Bone marrow aspiration confirmed BMN. Brain MRI revealed extensive diffuse leukoencephalopathy, vasogenic and cytotoxic edema in the white matter, patchy edema in the cranial vault bone marrow on fat-suppressed FLAIR sequence (a finding consistent with the confirmed BMN), and multiple cerebral microbleeds on susceptibility-weighted imaging consistent with CFE. The management of acute neurological complications of SCD varies depending on the specific complication. Brain MRI plays a crucial role in the accurate diagnosis of these complications to guide appropriate treatment. [ABSTRACT FROM AUTHOR]

Introduction: The influence of patient age on the clinical outcome of surgically treated osteochondral lesions of the talus (OCT) is controversial. Aim of this study was to evaluate the 24 months follow-up data of the German Cartilage Registry (KnorpelRegister DGOU, GCR) regarding the influence of patient age on clinical outcomes after surgical OCT treatment. Materials and methods: 303 patients met the inclusion criteria and were divided into patients < 40 years (27.1 ± 5.8 years, n = 177) and patients ≥ 40 years (50.8 ± 7.4 years, n = 126). Pre- and postoperative FAOS total scores, subscores and ΔFAOS for most frequent surgical techniques (bone marrow stimulation, matrix-augmented bone marrow stimulation, matrix-augmented bone marrow stimulation with additional bone grafting) and lesion size characteristics were evaluated for both groups. ANOVA analysis with post hoc Duncan test was applied for statistical analysis. Results: Both patients < 40 years and patients ≥ 40 years benefit from surgical treatment of OCT showing significant changes from pre- to postoperative FAOS total score (63.8 ± 20.3 to 81.5 ± 17.8 in patients < 40 years, p < 0.001; 57.3 ± 20.1 to 74.9 ± 21.6 in patients ≥ 40 years, p < 0.001) and subscores. Younger patient group tended to higher pre- and postoperative scores. ΔFAOS was not different between both groups. Older patient group had significantly higher lesion size area and volume; proportion of additional bone grafting was increased. Conclusion: Results of surgical therapy of OCTs are independent from patient age. There is no superiority of a specific surgical technique depending on patient age. [ABSTRACT FROM AUTHOR]

The hematopoietic system is the primary target of benzene exposure. Whether peripheral blood miRNA can serve as sensitive biomarkers for benzene-induced hematopoietic damage has attracted considerable attention. This study focuses on exploring the role of miR-451a and miR-486-5p in benzene-induced erythroid damage and assessing their potential as biomarkers of benzene-induced hematotoxicity. Animal experiments and human studies were conducted to reveal expression patterns of miR-451a and miR-486-5p in bone marrow and peripheral blood after benzene exposure, along with their correlations with erythrocyte indices. In C57BL/6J mice exposed to benzene, the expression levels of miR-451a and miR-486-5p in bone marrow decreased, which also positively correlated with red blood cell count (RBC), hemoglobin (Hb), and hematocrit (HCT). Conversely, in peripheral blood of C57BL/6J mice, the expression levels of the two miRNAs increased and showed a negative correlation with the three erythroid indices. Subsequent validation in bone marrow samples of chronic benzene poisoning patients and peripheral blood of workers from petrochemical plant confirmed significant correlations between miR-451a and miR-486-5p expression levels and red blood cell parameters. Furthermore, receiver operator characteristic (ROC) curve analyses revealed that miR-451a emerged as a potential biomarker for benzene-induced hematotoxicity, exhibiting superior discriminatory power compared to miR-486-5p and conventional erythroid indices. Additionally, in vitro experiments using K562 cells revealed differential regulatory effects of benzene metabolite hydroquinone (HQ) on miR-451a expression based on erythroid differentiation status. These findings emphasized the important role of miR-451a and miR-486-5p in benzene-induced erythrogenesis disruption, offering valuable insights for biomarker development and therapeutic interventions. [ABSTRACT FROM AUTHOR]

The increasing use of SARS-CoV-2 mRNA vaccines has raised concerns about their potential toxicological effects, necessitating further investigation to ensure their safety. To address this issue, we aimed to evaluate the toxicological effects of SARS-CoV-2 mRNA vaccine candidates formulated with four different types of lipid nanoparticles in ICR mice, focusing on repeated doses and administration routes. We conducted an extensive analysis in which mice received the mRNA vaccine candidates intramuscularly (50 μg/head) twice at 2-week intervals, followed by necropsy at 2 and 14 dpsi (days post-secondary injection). In addition, we performed a repeated dose toxicity test involving three, four, or five doses and compared the toxicological outcomes between intravenous and intramuscular routes. Our findings revealed that all vaccine candidates significantly induced SARS-CoV-2 spike protein-specific IgG and T cell responses. However, at 2 dpsi, there was a notable temporary decrease in lymphocyte and reticulocyte counts, anemia-related parameters, and significant increases in cardiac damage markers, troponin-I and NT-proBNP. Histopathological analysis revealed severe inflammation and necrosis at the injection site, decreased erythroid cells in bone marrow, cortical atrophy of the thymus, and increased spleen cellularity. While most toxicological changes observed at 2 dpsi had resolved by 14 dpsi, spleen enlargement and injection site damage persisted. Furthermore, repeated doses led to the accumulation of toxicity, and different administration routes resulted in distinct toxicological phenotypes. These findings highlight the potential toxicological risks associated with mRNA vaccines, emphasizing the necessity to carefully consider administration routes and dosage regimens in vaccine safety evaluations, particularly given the presence of bone marrow and immune organ toxicity, which, though eventually reversible, remains a serious concern. [ABSTRACT FROM AUTHOR]

Objective: Sepsis is a syndrome of the systemic inflammatory response caused by infection that can endanger a patient's life. The aim of this study was to explore the molecular mechanism by which bone marrow mesenchymal stem cells-derived exosomes (BMSCs-exo) carrying miR-20a-5p regulate the progression of sepsis. Methods: Clinical samples from sepsis patients were collected. Mouse and cell models of sepsis were induced by lipopolysaccharide (LPS). The levels of related genes and proteins were determined by RT‒qPCR, Western blotting and ELISA. CCK-8 and flow cytometry assays were used to assess cell viability, apoptosis, and markers of macrophage polarization. Results: In septic patients, miR-20a-5p levels were significantly lower and CXCL12 expression was significantly increased. After LPS induction, M2 polarization of macrophages was significantly reduced, the level of inflammatory factors was increased, and apoptosis was increased. The addition of BMSCs-exo increased the miR-20a-5p level and decreased the expression of CXCL12 in macrophages, thereby promoting macrophage M2 polarization and reducing the levels of inflammatory factors. Conclusion: This study demonstrated for the first time that BMSCs-exo promoted the polarization of M2 macrophages through the miR-20a-5p/CXCL12 axis, thus alleviating the development of sepsis. These findings provide a new theoretical basis for the targeted treatment of sepsis with exosomes or miR-20a-5p. [ABSTRACT FROM AUTHOR]

MiRNAs have been identified as participants in leukemogenesis by controlling several cellular functions, such as differentiation, proliferation, and apoptosis. Their role in myelodysplastic neoplasms (MDS) pathogenesis is researched due to implementations in early identification, classification, and therapeutical options. IPSS-R, being the most widely used MDS classification, underestimates early biological events that can alter the disease's prognosis. The purpose of this study is to determine whether miRNA levels are aligned to MDS risk stratification groups and can therefore be used as diagnostic biomarkers. To evaluate miRNAs as possible biomarkers, we measured the levels of miR-181a-2-3p, miR-124-3p, miR-550a-3p, miR-155-5p, miR-151a-3p, and miR-125b-5p by a quantitative real-time PCR in bone marrow samples of 41 MDS patients. In conclusion, in myeloid malignancies, genomic characteristics may provide a wider apprehension of its clinical course and prognosis. MiRNAs constitute a possible diagnostic biomarker and therapeutic target, allowing intermediate-risk patients that express high levels of specific miRNAs to be re-classified and receive more advanced therapeutic agents. In our study, an association between high levels of miRNAs and worsening outcomes is established, supporting the need for further incorporation of molecular data into currently used classification systems. [ABSTRACT FROM AUTHOR]

Objective: To examine the association between medial meniscal extrusion and structural progression in adults with symptomatic knee osteoarthritis (OA). Methods: This prospective cohort study examined 176 participants with symptomatic knee OA recruited into a randomised controlled trial. The participants underwent magnetic resonance imaging (MRI) of the study knee at baseline and approximately 2 years later. Meniscal extrusion, tibial cartilage volume, and tibiofemoral bone marrow lesions (BMLs) were measured from MRI using validated methods. Results: Participants with medial meniscal extrusion ≥ 3 mm had a higher prevalence of lateral tibiofemoral BMLs at baseline (OR = 2.21, 95% CI 1.06–4.61, p = 0.035), and those with medial meniscal extrusion 2–3 mm had a higher likelihood of lateral BML worsening over 2 years (OR = 3.76, 95% CI 1.35–10.52, p = 0.011), compared with those with medial meniscal extrusion < 2 mm. Participants with stable medial meniscal extrusion had a lower likelihood of lateral BML worsening compared with those with regression of medial meniscal extrusion over 2 years (OR = 0.20, 95% CI 0.07–0.56, p = 0.002). There were no associations between medial meniscal extrusion and tibial cartilage volume or medial tibiofemoral BMLs. Conclusions: Our study showed associations between medial meniscal extrusion and baseline prevalence and worsening over 2 years of lateral tibiofemoral BMLs in people with symptomatic knee OA. Although the reasons for the lack of associations in the medial compartment are not clear, our results suggest a role of medial meniscal extrusion in predicting structural progression in lateral knee OA and that meniscal extrusion might be a potential target in the management of knee OA. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a leading cause of pain, functional impairment, and disability in older adults. However, there are no effective treatments to delay and reverse OA. Magnetic resonance imaging (MRI) can assess structural abnormalities of OA by directly visualizing damage and inflammatory reactions within the tissues and detecting abnormal signals in the subchondral bone marrow region. While some studies have shown that bone marrow lesions (BMLs) are one of the early signs of the development of OA and predict structural and symptomatic progression of OA, others claimed that BMLs are prevalent in the general population and have no role in the progression of OA. In this narrative review, we screened and summarized studies with different designs that evaluated the association of BMLs with joint symptoms and structural abnormalities of OA. We also discussed whether BMLs may serve as an imaging biomarker and a treatment target for OA based on existing clinical trials. [ABSTRACT FROM AUTHOR]

• The neuro-mesenchymal units regulate bone marrow B cell development mainly via the norepinephrine-Cxcl12 pathway. • Targeting these neuro-mesenchymal units not only restored B cell development but also alleviated anxiety-like behavior in the mice. • Anxiety disorders can create a vicious cycle, perpetuating ongoing mental and immunological damage and ultimately leading to irreversible harm. The reduction in B lymphocytes observed in individuals with anxiety disorders may compromise antiviral responses, yet the precise mechanisms behind this decline remain unclear. While elevated glucocorticoid levels have been suggested as contributing factors, anxiety disorders are associated with diminished glucocorticoid signaling. Given that autonomic nervous system dysfunction is a hallmark of anxiety disorders, we established an anxiety-related behavior mouse model by stimulating C1 neurons in the rostral ventrolateral medulla. Using this model, we confirmed that sustained activation of sympathetic nerves can disrupt adaptive immunity, particularly affecting the development of B cells. The underlying mechanism involves the control of B cell development through neuro-mesenchymal units within the bone marrow, with mesenchyme-derived CXCL12 playing a pivotal role in this regulatory process. Intriguingly, targeting these neuro-mesenchymal units not only restored B cell development but also alleviated anxiety-like behavior in the mice. Our study provides compelling evidence regarding the regulatory role of neuro-mesenchymal units in the development of B cells within the bone marrow. Additionally, our findings suggest that anxiety disorders can create a vicious cycle, perpetuating ongoing mental and immunological damage and ultimately leading to irreversible harm. To break this cycle, it is essential to focus on the dysfunction of immune cells and strive to restore immune homeostasis in individuals suffering from anxiety disorders. [ABSTRACT FROM AUTHOR]

Purpose: Obesity increases colon cancer risk that has been previously linked to marrow-derived myeloid cells. We previously demonstrated that exercise training (EX) prevents colon cancer initiation, potentially through reduced myelopoiesis. However, it remains unknown whether early myeloid cell accumulation and inflammation in the colon precedes carcinogenesis with high-fat diet (HFD)-induced obesity, and if EX can attenuate these effects. We hypothesized that obesity would promote colon carcinogenesis that was preceded by myeloid cell accumulation and inflammation that would be attenuated by EX. Methods: C57BL/6 mice were randomized to a HFD or control (CON) diet for 8 weeks. The HFD mice switched to CON diet and all mice were given intraperitoneal injections of azoxymethane (AOM) to induce colon cancer and randomized into EX or sedentary (SED) conditions. Results: HFD mice developed more aberrant crypt foci (ACF), a marker for early carcinogenesis, compared with CON (P < 0.01), and EX developed fewer ACF compared with SED (P < 0.0001). Marrow-derived (P < 0.001) CD206+ macrophages were elevated in HFD compared with CON at study week 16 (P < 0.01). Marrow-derived CD206− macrophages (P < 0.05) and marrow-derived (P < 0.05) CD206+ macrophages were more abundant in HFD compared with CON at study week 42. EX did not alter colon immune cell populations. β-catenin protein was higher in HFD compared with CON at study week 42 (P < 0.05), and STAT3 protein content was lower at study week 28 with EX compared with SED (P < 0.05). Conclusions: The results suggest that obesity promotes colon ACF formation, potentially through early inflammatory myeloid cell accumulation. Despite attenuating ACF, EX did not alter myeloid cell accumulation in the colon, suggesting that EX inhibits ACF formation through alternative mechanisms which may include reduced β-catenin and STAT3 signaling. [ABSTRACT FROM AUTHOR]

Innate training of macrophages can be beneficial for the clearance of pathogens. However, for certain chronic conditions, innate training can have detrimental effects due to an excessive production of pro-inflammatory cytokines. Obesity is a condition that is associated with a range of increased pro-inflammatory training stimuli including the free fatty acid palmitate. Mesenchymal stromal cells (MSCs) are powerful immunomodulators and known to suppress inflammatory macrophages via a range of soluble factors. We show that palmitate training of murine bone-marrow-derived macrophages and human monocyte-derived macrophages (MDMs) results in an increased production of TNFα and IL-6 upon stimulation with lipopolysaccharide and is associated with epigenetic remodeling. Palmitate training led to metabolic changes, however, MSCs did not alter the metabolic profile of human MDMs. Using a transwell system, we demonstrated that human bone marrow MSCs block palmitate training in both murine and human macrophages suggesting the involvement of secreted factors. MSC disruption of the training process occurs through more than one pathway. Suppression of palmitate-enhanced TNFα production is associated with cyclooxygenase-2 activity in MSCs, while secretion of interleukin-1 receptor antagonist by MSCs is required to suppress palmitate-enhanced IL-6 production in MDMs. [Display omitted] • Palmitate drives trained immunity in human macrophages dependent on epigenetic remodeling. • Palmitate training promotes an M2 phenotypic switch with CD206 expression. • MSCs suppress palmitate training pro-inflammatory cytokine production by macrophages. • MSCs do not alter palmitate training-induced M2 phenotypic switch. • MSCs block palmitate training of macrophages via COX-2 and IL-1Ra. [ABSTRACT FROM AUTHOR]

The immune system is regulated by dendritic cells (DCs), which are highly specialized cells for presenting antigens. They are thought of as natural sentinels that start the immune response triggered by naive T cells against invasive infections. DCs participate in the initial stage of muscle damage in conjunction with monocytes, macrophages, and myogenic cells. The goal of this study was to determine whether DCs might mitigate tissue damage and aid in the regeneration of the gastrocnemius muscle following envenomation with Bothrops jararacussu venom (BjV). Mature bone marrow dendritic cells (BMDCs) were used to treat mice in an experimental envenomation model with BjV by activation with lipopolysaccharide (LPS). BMDCs were injected into the gastrocnemius muscle at the same site of the BjV injury, in a single dose, 3 h after envenomation, and envenoming effects were observed at different periods for 7 days. In both untreated (NT) and treated (T) groups tissue necrosis, leukocyte influx, and hemorrhage at the injury site were observed. Results showed an increase in serum and tissue CK as well as IL-6, TNF-α, and IL-1β release in the first hours after envenoming. In contrast, after treatment with BMDCs results obtained demonstrated an attenuated local effect with a small leukocyte influx, decreased or non-existent necrosis and hemorrhage, as well as a reduction in both serum and tissue CK levels as well as cytokine release and, consequently, the onset of a moderate regenerative process. The present study's findings concluded that BjV causes a severe inflammatory reaction at the site of injury and that treating envenoming with BMDCs in the muscle was crucial for minimizing damage to the muscle and the inflammatory reaction and promoting the early onset of the tissue repair process. • BjV induces myonecrosis and local inflammation. • BMDCs therapy promote muscle regeneration of envenomated animals. • BMDCs played an important role attenuating inflammation and local damage. [ABSTRACT FROM AUTHOR]