Search

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]

Post-allogeneic hematopoietic cell transplant (HCT) immunosuppression regimens are given as graft-versus-host disease (GVHD) prophylaxis. Most GVHD prophylaxis regimens are based on calcineurin inhibitors (CNIs). Unfortunately, CNIs are associated with significant associated morbidity, frequently cannot be tolerated, and often need to be discontinued. There is no consensus as to which alternative immunosuppression should be used in cases where CNIs have to be permanently discontinued. Cytotoxic T-lymphocyte-associated protein 4-immunoglobulin (CTLA4-Ig) blocking agents are well tolerated and have been used extensively in patients with autoimmune disease and as post-transplant immunosuppression. There are two CTLA4-Ig agents: belatacept and abatacept. Belatacept is routinely used in adult kidney transplantation to prevent rejection and abatacept has been approved by the Food and Drug Administration (FDA) for GVHD prophylaxis in patients undergoing a matched or one allele-mismatched unrelated allogenic HCT. Herein, we describe a case in which abatacept was given off-label to replace tacrolimus GVHD prophylaxis in a patient with neurotoxicity undergoing haploidentical HCT. This case suggests that CTLA4-Ig blockade may be a good alternative to a CNI in cases where the CNI needs to be discontinued and warrants further investigation.

Brown and brown-like adipose tissues have attracted significant attention for their role in metabolism and therapeutic potential in diabetes and obesity. Despite compelling evidence of an interplay between adipocytes and lymphocytes, the involvement of these tissues in immune responses remains largely unexplored. This study explicates a newfound connection between neuroinflammation and brown- and bone marrow adipose tissue. Leveraging the use of [18F]F-AraG, a mitochondrial metabolic tracer capable of tracking activated lymphocytes and adipocytes simultaneously, we demonstrate, in models of glioblastoma and multiple sclerosis, the correlation between intracerebral immune infiltration and changes in brown- and bone marrow adipose tissue. Significantly, we show initial evidence that a neuroinflammation-adipose tissue link may also exist in humans. This study proposes the concept of an intricate immuno-neuro-adipose circuit, and highlights brown- and bone marrow adipose tissue as an intermediary in the communication between the immune and nervous systems. Understanding the interconnectedness within this circuitry may lead to advancements in the treatment and management of various conditions, including cancer, neurodegenerative diseases and metabolic disorders.

Myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukaemia (AML) are neoplastic haematopoietic cell proliferations that are diagnosed and classified based on a combination of morphological, clinical and genetic features. Specifically, the percentage of myeloblasts in the blood and bone marrow is a key feature that has historically separated MDS from AML and, together with several other morphological parameters, defines distinct disease entities within MDS. Both MDS and AML have recurrent genetic abnormalities that are increasingly influencing their definitions and subclassification. For example, in 2022, two new MDS entities were recognised based on the presence of SF3B1 mutation or bi‐allelic TP53 abnormalities. Genomic information is more objective and reproducible than morphological analyses, which are subject to interobserver variability and arbitrary numeric cut‐offs. Nevertheless, the integration of genomic data with traditional morphological features in myeloid neoplasm classification has proved challenging by virtue of its sheer complexity; gene expression and methylation profiling also can provide information regarding disease pathogenesis, adding to the complexity. New machine‐learning technologies have the potential to effectively integrate multiple diagnostic modalities and improve on historical classification systems. Going forward, the application of machine learning and advanced statistical methods to large patient cohorts can refine future classifications by advancing unbiased and robust previously unrecognised disease subgroups. Future classifications will probably incorporate these newer technologies and higher‐level analyses that emphasise genomic disease entities over traditional morphologically defined entities, thus promoting more accurate diagnosis and patient risk stratification. [ABSTRACT FROM AUTHOR]

Introduction: Immune checkpoint blockade (ICB) immunotherapy has revolutionized cancer treatment, demonstrating exceptional clinical responses in a wide range of cancers. Despite the success, a significant proportion of patients still fail to respond, highlighting the existence of unappreciated mechanisms of immunotherapy resistance. Delineating such mechanisms is paramount to minimize immunotherapy failures and optimize the clinical benefit. Methods: In this study, we treated tumour-bearing mice with PD-L1 blockage antibody (aPD-L1) immunotherapy, to investigate its effects on cancer-induced emergency myelopoiesis, focusing on bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs). We examined the impact of aPD-L1 treatment on HSPC quiescence, proliferation, transcriptomic profile, and functionality. Results: Herein, we reveal that aPD-L1 in tumour-bearing mice targets the HSPCs in the BM, mediating their exit from quiescence and promoting their proliferation. Notably, disruption of the PDL1/PD1 axis induces transcriptomic reprogramming in HSPCs, observed in both individuals with Hodgkin lymphoma (HL) and tumour-bearing mice, shifting towards an inflammatory state. Furthermore, HSPCs from aPDL1-treated mice demonstrated resistance to cancer-induced emergency myelopoiesis, evidenced by a lower generation of MDSCs compared to control-treated mice. Discussion: Our findings shed light on unrecognized mechanisms of action of ICB immunotherapy in cancer, which involves targeting of BM-driven HSPCs and reprogramming of cancer-induced emergency myelopoiesis. [ABSTRACT FROM AUTHOR]

Radiation‐induced lung injury (RILI) is frequently observed in patients undergoing radiotherapy for thoracic malignancies, constituting a significant complication that hampers the effectiveness and utilization of tumor treatments. Ionizing radiation exerts both direct and indirect detrimental effects on cellular macromolecules, including DNA, RNA and proteins, but the impact of oxidized RNA in RILI remains inadequately explored. Mesenchymal stem cells (MSCs) can repair injured tissues, and the reparative potential and molecular mechanism of MSCs in treating RILI remains incompletely understood. This study aimed to investigate the therapeutic effects and mechanisms of action of three distinct sources of MSCs, including human umbilical cord mesenchymal stem cells (UCMSCs), bone marrow mesenchymal stem cells (BMSCs), and adipose‐derived stem cells (ADSCs), in thoracically irradiated mice. Comparative analysis revealed that all three types of MSCs exhibited the ability to mitigate radiation‐induced inflammatory infiltration, alveolar hemorrhage, and alveolar wall thickening in the lung tissue of the mice. MSCs also attenuated RILI by decreasing inflammatory factors, upregulating anti‐inflammatory factor expression, and reducing collagen accumulation. Immunohistochemical results showed that all three MSCs reduced radiation‐induced cell apoptosis and promoted the regeneration of lung tissue cells. The analysis of malondialdehyde (MDA) and 8‐hydroyguanosine (8‐OHG) content indicated that MSCs possess reparative properties against radiation‐induced oxidative damage in lung tissue. The study provides evidence that UCMSCs are a more appropriate therapeutic option for RILI compared to BMSCs and ADSCs. Additionally, MSCs effectively reduce the accumulation of oxidized RNA in RILI, thereby, presenting a unique avenue for investigating the underlying mechanism of MSC‐based treatment for RILI. [ABSTRACT FROM AUTHOR]

Background: Though 60–80% of hospitalized patients have an intravascular device placed during hospitalization, there is a substantial risk of complication related to the placement, maintenance and removal of these devices. The objectives of this study were to describe vascular access device use, device complications and lumen dysfunction. Methods: An observational cohort study was conducted over a 4.5 years period, in two quaternary, university-affiliated paediatric intensive care units (ICU). Eligible patients were admitted to either the paediatric or cardiac ICU and had one or more vascular access devices in-situ at the time of enrolment. Vascular access devices were defined as any external connection directly into the circulation including peripheral and central veins, arteries or bone marrow. Consistent with practice in the studied ICUs removal of peripheral catheters was regarded as due to dysfunction or complication. Results: 220 patients, 683 devices and 924 lumens were observed. The device complication rate was 21% and the lumen complication rate was 25%. The median duration without complication was 18 days for arterial catheters, 14 days for central venous catheters; 13 days for peripherally inserted central catheters and 4 days for peripheral intravenous catheters. On one third of all patient days, the volume of fluid administered to maintain VADs was equal to or greater than 20% of the total hourly total fluid intake. Conclusion: Approximately 1 in 5 vascular devices had one or more complications in ICU, most devices continued to be used without removal, and some complications resolved. The implications of the fluids infused to maintain device function warrants further study, as do strategies to resolve or limit the their complications in children. [ABSTRACT FROM AUTHOR]

The specific mechanisms underlying bacteria‐triggered cell death and osteogenic dysfunction in host bone marrow mesenchymal stem cells (BMSCs) remain unclear, posing a significant challenge to the repair of infected bone defects. This study identifies ferroptosis as the predominant cause of BMSCs death in the infected bone microenvironment. Mechanistically, the bacteria‐induced activation of the innate immune response in BMSCs leads to upregulation and phosphorylation of interferon regulatory factor 7 (IRF7), thus facilitating IRF7‐dependent ferroptosis of BMSCs through the transcriptional upregulation of acyl‐coenzyme A synthetase long‐chain family member 4 (ACSL4). Moreover, it is found that intervening in ferroptosis can partially rescue cell injuries and osteogenic dysfunction. Based on these findings, a hydrogel composite 3D‐printed scaffold is designed with reactive oxygen species (ROS)‐responsive release of antibacterial quaternized chitosan and sustained delivery of the ferroptosis inhibitor Ferrostatin‐1 (Fer‐1), capable of eradicating pathogens and promoting bone regeneration in a rat model of infected bone defects. Together, this study suggests that ferroptosis of BMSCs is a promising therapeutic target for infected bone defect repair. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are highly effective in the treatment of acute liver failure (ALF). The efficacy of MSCs is closely related to the inflammatory environment. Therefore, we investigated the functional changes of MSCs in response to interleukin‐33 (IL‐33) stimulation. The results showed that bone marrow mesenchymal stem cells (BMSCs) pretreated with IL‐33 had increased CCR2 expression, targeted CCL2 in the injured liver tissue, and improved the migration ability. Under LPS stimulation, the NF‐κB pathway of BMDM was activated, and its phenotype polarized to the M1‐type, while BMSCs pretreated with IL‐33 inhibited the NF‐κB pathway and enhanced M2 macrophage polarization. The M2‐type macrophages could further inhibit hepatocytes inflammation, reduce hepatocytes apoptosis, and promote hepatocytes repair. These results suggest that IL‐33 can enhance the efficacy of BMSCs in ALF and provide a new strategy for cell therapy of liver diseases. [ABSTRACT FROM AUTHOR]

The mixture cure rate model (MCM) is the most widely used model for the analysis of survival data with a cured subgroup. In this context, the most common strategy to model the cure probability is to assume a generalized linear model with a known link function, such as the logit link function. However, the logit model can only capture simple effects of covariates on the cure probability. In this article, we propose a new MCM where the cure probability is modeled using a decision tree-based classifier and the survival distribution of the uncured is modeled using an accelerated failure time structure. To estimate the model parameters, we develop an expectation maximization algorithm. Our simulation study shows that the proposed model performs better in capturing nonlinear classification boundaries when compared to the logit-based MCM and the spline-based MCM. This results in more accurate and precise estimates of the cured probabilities, which in-turn results in improved predictive accuracy of cure. We further show that capturing nonlinear classification boundary also improves the estimation results corresponding to the survival distribution of the uncured subjects. Finally, we apply our proposed model and the EM algorithm to analyze an existing bone marrow transplant data. [ABSTRACT FROM AUTHOR]

Background: By interacting with bone marrow mesenchymal stem cells (BMSCs) and regulating their function through exosomes, bone macrophages play crucial roles in various bone-related diseases. Research has highlighted a notable increase in the number of M1 macrophages in glucocorticoid-associated osteonecrosis of the femoral head (GA-ONFH). Nevertheless, the intricate crosstalk between M1 macrophages and BMSCs in the glucocorticoid-stimulated environment has not been fully elucidated, and the underlying regulatory mechanisms involved in the occurrence of GA-ONFH remain unclear. Methods: We employed in vivo mouse models and clinical samples from GA-ONFH patients to investigate the interactions between M1 macrophages and BMSCs. Immunofluorescence staining was used to assess the colocalization of M1 macrophages and BMSCs. Flow cytometry and transcriptomic analysis were performed to evaluate the impact of exosomes derived from normal (n-M1) and glucocorticoid-stimulated M1 macrophages (GC-M1) on BMSC differentiation. Additionally, miR-1a-3p expression was altered in vitro and in vivo to assess its role in regulating adipogenic differentiation. Results: In vivo, the colocalization of M1 macrophages and BMSCs was observed, and an increase in M1 macrophage numbers and a decrease in bone repair capabilities were further confirmed in both GA-ONFH patients and mouse models. Both n-M1 and GC-M1 were identified as contributors to the inhibition of osteogenic differentiation in BMSCs to a certain extent via exosome secretion. More importantly, exosomes derived from GC-M1 macrophages exhibited a heightened capacity to regulate the adipogenic differentiation of BMSCs, which was mediated by miR-1a-3p. In vivo and in vitro, miR-1a-3p promoted the adipogenic differentiation of BMSCs by targeting Cebpz and played an important role in the onset and progression of GA-ONFH. Conclusion: We demonstrated that exosomes derived from GC-M1 macrophages disrupt the balance between osteogenic and adipogenic differentiation in BMSCs, contributing to the pathogenesis of GA-ONFH. Inhibiting miR-1a-3p expression, both in vitro and in vivo, significantly mitigates the preferential adipogenic differentiation of BMSCs, thus slowing the progression of GA-ONFH. These findings provide new insights into the regulatory mechanisms underlying GA-ONFH and highlight potential therapeutic targets for intervention. [ABSTRACT FROM AUTHOR]

Objective: To summarize the clinical features, imaging characteristics, and surgical diagnosis and treatment experience of mediastinal extramedullary hematopoiesis. Methods: By summarizing and analyzing the case data and reviewing the literature, one case of posterior mediastinal extramedullary hematopoiesis on thoracoscopic biopsy in our department was summarized. Conclusion: Posterior mediastinal extramedullary hematopoiesis is a response to failure of bone marrow erythropoiesis, which is relatively rare clinically, and diagnosis requires a combination of patient history and imaging, puncture biopsy or thoracoscopic excisional biopsy can provide a pathological diagnosis, and surgical complete resection is the main treatment modality. [ABSTRACT FROM AUTHOR]

Recent research indicates that mesenchymal stem cells (MSCs), known for their anti‐inflammatory and anti‐infectious properties, could be a promising alternative for treating inflammatory diseases such as inflammatory bowel disease (IBD). This study examined how MSCs and their derivatives, when cocultured with interleukin‐1β (IL‐1β)‐stimulated Caco‐2 cells, affect the expression of genes related to inflammation, microbes, and apoptosis. In the experiment, Caco‐2 cells were exposed to 10 ng/mL of IL‐1β for 24 h. MSCs were sourced from human bone marrow, adipose tissue (AD‐MSC), and menstrual blood. These MSCs and their conditioned medium (CM) were then cocultured with the IL‐1β‐induced Caco‐2 cells. After 48 h, gene expression levels were analyzed using real‐time PCR, and the data were statistically evaluated using T‐tests, U‐Mann–Whitney, and Tukey's post hoc analyses. The results indicated that IL‐1β at 10 ng/mL was the optimal concentration for inducing Caco‐2 cells with the highest viability and minimal damage. Among the MSCs tested, AD‐MSCs were the most effective in regulating gene expression. Specifically, AD‐MSC treatment significantly reduced the mRNA expression of TNF‐α and IL‐1β, both of which are crucial in sustaining inflammatory responses (p ≤ 0.05). This study concludes that AD‐MSCs have superior effects compared to other MSC sources in modulating genes associated with inflammation, antibacterial effects, and apoptosis in an in vitro model of IBD using Caco‐2 cells. [ABSTRACT FROM AUTHOR]

Background: There is a need for therapies that can mitigate bone marrow dysfunction and organ toxicity that occur following myeloablative injury and reduced intensity conditioning regimens used in patients undergoing bone marrow transplantation (BMT). The pathogenesis of adverse effects from BMT conditioning has been linked to injury to the vascular endothelium, bone marrow (BM), and other organs. Objective: To evaluate the impact of the thrombopoietin mimetic drug JNJ-26366821 (TPOm) on BM vascular recovery in mice undergoing myeloablative radiation conditioning followed by BMT. Study design: TPOm (doses: 0 µg, 300 µg, 1000 µg per Kg body weight) was administered on Days 0 and 7 after BMT, in mice receiving a total body irradiation (TBI) conditioning regimen (5.5 Gy x 2) before congenic BMT. BM donner cell engraftment was analyzed using flow cytometry on Days 7, 14, and 30 post-BMT. The morphological and biophysical properties of the BM vasculature were evaluated by intravital multiphoton microscopy (MPM) and immunofluorescence confocal imaging. Herein, morphological properties involve microvascular density (MVD), vessel diameter, and vascular area, while biophysical properties include transfer rate (Ktrans) of contrast within the BM vascular niche, as well as the fractional volume (vec) of extracellular extravascular tissue (EES). Results: No significant difference in donor chimerism was observed at days 7, 14, and 30 post-BMT, between TPOm and PBS-treated mice. TPOm intervention improved BM vasculature regeneration in transplanted mice. The MVD, Ktrans, and BM vasculature as well as vascular endothelial growth factor receptor-2 (VEGFR2) in the BM, showed a dose dependent improvement inmice treated with TPOm. On day 14 post-BMT, the group receiving 1000 µg/Kg TPOm showed significant shifts (p-value < 0.05) in MVD, Ktrans, and VEGFR2 expression from their corresponding control types (TPOm dose 0 µg) towards levels comparable to healthy controls. Conclusion: TPOm intervention augments BM vascular structure and function, which may be important for hematopoietic recovery and bone marrow function in radiation conditioned hematopoietic stem cell transplant patients, in addition to enhancing platelet recovery. day 14 post-BMT, the group receiving 1000 µg/Kg TPOm showed significant shifts (p-value < 0.05) in MVD, Ktrans, and VEGFR2 expression from their corresponding control types (TPOm dose 0 µg) towards levels comparable to healthy controls. Conclusion: TPOm intervention augments BM vascular structure and function, which may be important for hematopoietic recovery and bone marrow function in radiation conditioned hematopoietic stem cell transplant patients, in addition to enhancing platelet recovery. [ABSTRACT FROM AUTHOR]

To prevent infection by respiratory viruses and consequently limit virus circulation, vaccines need to promote mucosal immunity. The extent to which the currently used messenger RNA (mRNA)–based COVID-19 vaccines induce mucosal immunity remains poorly characterized. We evaluated mucosal neutralizing antibody responses in a cohort of 183 individuals. Participants were sampled at several time points after primary adenovirus vector–based or mRNA-based COVID-19 vaccination and after mRNA-based booster vaccinations. Our findings revealed that repeated vaccination with mRNA boosters promoted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies in nasal secretions. Nasal and serum neutralizing antibody titers of both IgG and IgA isotypes correlated to one another. We investigated the source of these mucosal antibodies in a mouse model wherein mice received repeated mRNA vaccines for SARS-CoV-2. These experiments indicated that neutralizing antibody–producing cells reside in the spleen and bone marrow, whereas no proof of tissue homing to the respiratory mucosa was observed, despite the detection of mucosal antibodies. Serum transfer experiments confirmed that circulating antibodies were able to migrate to the respiratory mucosa. Collectively, these results demonstrate that, especially upon repeated vaccination, the currently used COVID-19 mRNA vaccines can elicit mucosal neutralizing antibodies and that vaccination might also stimulate mucosal immunity induced by previous SARS-CoV-2 infection. Moreover, migration of circulating antibodies to the respiratory mucosa might be a main mechanism. These findings advance our understanding of mRNA vaccine–induced immunity and have implications for the design of vaccine strategies to combat respiratory infections. Editor's summary: mRNA vaccines for SARS-CoV-2 elicit robust antibody responses in the circulation, which aid in protection from severe disease. However, the extent to which mRNA vaccines, which are delivered intramuscularly, can elicit mucosal immune responses is unclear. In a pair of papers, Declercq et al. and Lasrado et al. come to distinct conclusions. Using human nasal swab samples in both studies, Declercq et al. show that repeated vaccination for SARS-CoV-2 promotes neutralizing antibodies in the nose, whereas Lasrado et al. observed no obvious increase in neutralizing antibody titers after booster vaccination. These differing results may be due to the number of SARS-CoV-2 vaccinations or exposures, time since last exposure, and experimental approaches, but this pair of papers underscores the need to better understand the mucosal immune response in humans. —Courtney Malo [ABSTRACT FROM AUTHOR]

Introduction: The utilization of denosumab in treating osteoporosis highlights promising prospects for osteoporosis intervention guided by gene targets. While omics-based research into osteoporosis pathogenesis yields a plethora of potential gene targets for clinical transformation, identifying effective gene targets has posed challenges. Methods: We first queried the omics data of osteoporosis clinical samples on PubMed, used International Mouse Phenotyping Consortium (IMPC) to screen differentially expressed genes, and conducted preliminary functional verification of candidate genes in human Saos2 cells through osteogenic differentiation and mineralization experiments. We then selected the candidate genes with the most significant effects on osteogenic differentiation and further verified the osteogenic differentiation and mineralization functions in mouse 3T3-E1 and bone marrow mesenchymal stem cells (BMSC). Finally, we used RNA-seq to explore the regulation of osteogenesis by the target gene. Results: We identified PPP2R2A, RRBP1, HSPB6, SLC22A15, ADAMTS4, ATP8B1, CTNNB1, ROBO1, and EFR3B, which may contribute to osteoporosis. ROBO1 was the most significant regulator of osteogenesis in both human and mouse osteoblast. The inhibitory effect of Robo1 knockdown on osteogenic differentiation may be related to the activation of inflammatory signaling pathways. Conclusion: Our study provides several novel molecular mechanisms involved in the pathogenesis of osteoporosis. ROBO1 is a potential target for osteoporosis intervention. [ABSTRACT FROM AUTHOR]

Distraction osteogenesis (DO) is a valuable surgical method for limb lengthening and bone defect correction, but its lengthy consolidation phase presents challenges. The accordion technique (AT), involving compression and distraction of bone segments, has shown potential for enhancing healing. This study aimed to investigate the effectiveness of the AT conducted at three different time points (distraction phase, early consolidation phase, or late consolidation phase) compared to conventional DO in a mouse osteotomy model. Healing was evaluated using in vivo microCT, histology, and computational modeling. Results showed that bridging frequency, BV, and callus tissue composition were similar between conventional DO and late consolidation AT. In contrast, distraction phase AT led to delayed healing at day 15 with a 72% reduction in BV compared to DO, but no significant differences by the endpoint. Early consolidation AT showed significantly impaired healing compared to DO, with only 29% of mice achieving bony bridging, and significantly reduced bone marrow area of the endpoint callus. In silico modeling was generally predictive of in vivo findings and suggested that application of the AT during early consolidation results in destruction of newly-formed vascular tissue. Overall, no benefit was observed for the AT compared to conventional DO with the parameters employed in this study. [ABSTRACT FROM AUTHOR]

Objectives: Good's syndrome (GS) is a rare secondary immunodeficiency which is characterized by hypogammaglobulinemia and thymoma. This study aims to investigate the expression and distribution of B cells in thymoma tissue, given that B cells had been found to be reduced or absent in peripheral blood or bone marrow. Methods: This study retrospectively analyzed thymoma tissues from 5 GS patients at the First Affiliated Hospital of Wenzhou Medical University and Zhejiang Provincial People's Hospital. Tissues from 20 patients with simple thymoma were used as controls. Immunohistochemistry analyses were performed to detect the markers CD19, CD20, PAX5 and CD138 to evaluate the expression of B cells or plasma cells. Results: Compared to the control group, 4 GS patients exhibited a complete absence of B cells in their thymoma tissue, while 1 GS patient exhibited a notable reduction in B cells. The expression levels of CD19, CD20 and PAX5 in the thymoma tissues of GS patients were dramatically lower than those in the control group (0 vs. 85%, 20 vs. 85%, 20 vs. 85%, respectively; P < 0.05). However, no significant difference was observed in the expression frequency of CD138 between the thymoma tissues of the two groups (0 vs. 30%, P > 0.05). Conclusion: This is the first report of B cell deficiency in 5 thymoma tissues of GS patients. [ABSTRACT FROM AUTHOR]

Monocytes directly contribute to atherosclerosis development by their recruitment to plaques in which they differentiate into macrophages. In the present study, we ask how modulating monocyte glucose metabolism could affect their homeostasis and their impact on atherosclerosis. Here we investigate how circulating metabolites control monocyte behavior in blood, bone marrow and peripheral tissues of mice. We find that serum glucose concentrations correlate with monocyte numbers. In diet-restricted mice, monocytes fail to metabolically reprogram from glycolysis to fatty acid oxidation, leading to reduced monocyte numbers in the blood. Mechanistically, Glut1-dependent glucose metabolism helps maintain CD115 membrane expression on monocytes and their progenitors, and regulates monocyte migratory capacity by modulating CCR2 expression. Results from genetic models and pharmacological inhibitors further depict the relative contribution of different metabolic pathways to the regulation of CD115 and CCR2 expression. Meanwhile, Glut1 inhibition does not impact atherosclerotic plaque development in mouse models despite dramatically reducing blood monocyte numbers, potentially due to the remaining monocytes having increased migratory capacity. Together, these data emphasize the role of glucose uptake and intracellular glucose metabolism in controlling monocyte homeostasis and functions. Monocytes participate in plaque formation, and adapt to metabolic changes to alter their functions. Here the authors show, using genetic mouse models and functional analyses, that Glut1-mediated glucose metabolism is important for regulating monocyte homeostasis and migration, but curiously has no impact on atherosclerotic plaque formation. [ABSTRACT FROM AUTHOR]

Osteopetrosis is an inherited metabolic disease, characterized by increased bone density and narrow marrow cavity. Patients with severe osteopetrosis exhibit abnormal bone brittleness, anemia, and infection complications, which commonly cause death within the first decade of life. Pathologically, osteopetrosis impairs not only the skeletal system, but also the hemopoietic and immune systems during development, while the underlying osteoimmunological mechanisms remain unclear. Osteoclastic mutations are regarded as the major causes of osteopetrosis, while osteoclast non-autonomous theories have been proposed in recent years with unclear underlying mechanisms. Retinoic acid (RA), the metabolite of Vitamin A, is an essential requirement for skeletal and hematopoietic development, through the activation of retinoic acid signaling. RA can relieve osteopetrosis symptoms in some animal models, while its effect on bone health is still controversial and the underlying mechanisms remain unclear. In this study, we constructed an osteoblast-specific inhibitory retinoic acid signaling mouse model and surprisingly found it mimicked the symptoms of osteopetrosis found in clinical cases: dwarfism, increased imperfectly-formed trabecular bone deposition with a reduced marrow cavity, thin cortical bone with a brittle skeleton, and hematopoietic and immune dysfunction. Micro-CT, the three-point bending test, and histological analysis drew a landscape of poor bone quality. Single-cell RNA sequencing (scRNA-seq) of the femur and RNA-seq of osteoblasts uncovered an atlas of pathological skeletal metabolism dysfunction in the mutant mice showing that osteogenesis was impaired in a cell-autonomous manner and osteoclastogenesis was impaired via osteoblast-osteoclast crosstalk. Moreover, scRNA-seq of bone marrow and flow cytometry of peripheral blood, spleen, and bone marrow uncovered pathology in the hematopoietic and immune systems in the mutant mice, mimicking human osteopetrosis. Results showed that hematopoietic progenitors and B lymphocyte differentiation were affected and the osteoblast-dominated cell crosstalk was impaired, which may result from transcriptional impairment of the ligands Pdgfd and Sema4d. In summary, we uncovered previously unreported pathogenesis of osteopetrosis-like disorder in mice with skeletal, hematopoietic, and immune system dysfunction, which was induced by the inhibition of retinoic acid signaling in osteoblasts, and sheds new insights into a potential treatment for osteopetrosis. [ABSTRACT FROM AUTHOR]

Introduction: Despite the improvement in survival in acute lymphoblastic leukemia (ALL), there are still cases with evasion of chemotherapy-induced apoptosis. The IKK/ NF-kB signaling pathway contributes to antiapoptotic gene expression. Pentoxifylline (PTX) inhibits IkB phosphorylation, blocking NF-kB and antiapoptotic activity. Methods: We conducted a randomized, double-blind clinical trial on pediatric ALL patients undergoing induction therapy, assigning them to PTX or placebo group. Bone marrow aspirates were obtained on days 1, 8, 15, and 22. Apoptosis was assessed using Annexin-V/propidium iodide. Results: Results indicated that the PTX group exhibited higher apoptosis on day- 8 (41.3% vs. 19.4%, p =0.029) and day-15 (35.0% vs. 14.2%, p <0.01). On day-8, the PTX group displayed an MRD of 0.25% vs. 18.2% (p <0.01) in placebo group; on day-15, the PTX group demonstrated an MRD of 0.09% vs. 1.4% (p =0.02). Patients achieving an MRD <0.01% on day-8 demonstrated a 3-year Overall Survival (OS) of 81.6% vs. 58.3% (p =0.03); on day-15, patients with MRD <0.01% had a 3-year OS of 77.9% vs. 54.5% (p =0.03). The PTX group achieved an MRD of <0.01% earlier on days-8 and 15, along with a higher apoptosis rate, indicating a more favorable therapeutic response. In the entire cohort, patients achieving MRD <0.01% on day-8 or 15 displayed superior OS. Conclusion: Our study demonstrates that PTX enhances apoptosis and reduces MRD in pediatric acute lymphoblastic leukemia patients. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT02451774. [ABSTRACT FROM AUTHOR]

Serine and folate metabolism play critical roles in erythroid development in both embryonic and adult mice; however, the precise roles of these metabolic pathways in erythropoiesis and the pathophysiology of anemia remain inadequately characterized in the literature. To delineate the contributions of serine and folate metabolism to erythroid differentiation, we focused on serine hydroxymethyltransferase 2 (SHMT2), a key regulatory enzyme within these metabolic pathways. Using gene-editing techniques, we created fetal and adult mouse models with targeted deletion of Shmt2 in the hematopoietic system. Our findings demonstrated that the deletion of Shmt2 within the hematopoietic system led to the distinctive anemia phenotype in both fetal and adult mice. Detailed progression analysis of anemia revealed that Shmt2 deletion exerts stage-specific effects on the development and maturation of erythroid cells. Specifically, Shmt2 deficiency promoted erythroid differentiation in the R2 (CD71+ Ter119−) cell population residing in the bone marrow while concurrently inhibiting the proliferation and erythroid differentiation of the R3 (CD71+ Ter119+) cell population. This disruption resulted in developmental arrest at the R3 stage, significantly contributing to the anemia phenotype observed in the models. This study elucidates the critical role of Shmt2 in erythroid development within the hematopoietic system, highlighting the underlying mechanisms of erythroid developmental arrest associated with Shmt2 loss. [ABSTRACT FROM AUTHOR]

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome that can occur either in genetically predisposed individuals (primary HLH) or in particular conditions in immunocompromised patients (secondary HLH). Secondary HLH is very rare among solid organ transplant recipients, especially in lung transplant recipients, for whom its prognosis is dismal. Case Report: We report an exceptional case of HLH occurring unusually late following lung transplantation. At 11 years after transplantation, the patient, aged 67 years, presented with pancytopenia, fever, hyperferritinemia, and hypertriglyceridemia, along with splenomegaly. Exhaustive serological and PCR tests ruled out active infection. Bone marrow aspirates showed signs of hemophagocytosis, and bone marrow biopsy was suggestive of posttransplant lymphoproliferative disorder (PTLD). Timely treatment with etoposide and corticosteroids led to a transient improvement in the patient's clinical condition, and rituximab was initiated as a treatment for PTLD. Unfortunately, pancytopenia persisted for weeks, and the patient died from refractory septic shock, despite appropriate intravenous antibiotics. Autopsy revealed lymphoid infiltration of the mediastinal lymph nodes, liver and bone marrow, with some lymphocytes expressing CD3. A final diagnosis of Ann-Arbor stage IV non-EBVmediated monomorphic T-cell PTLD was established. Conclusions: This case report highlights a very unusual and fatal presentation of HLH in a lung transplant recipient, secondary to a T-cell PTLD. Indeed, HLH is typically seen as infection-related and reported to occur in the initial months following transplantation. To date, no guidelines or consensus exist regarding the management of immunosuppression regimen in solid organ transplantation. [ABSTRACT FROM AUTHOR]

Quantitative systems toxicology (QST) models are increasingly being applied for predicting and understanding toxicity liabilities in pharmaceutical research and development. A European Federation of Pharmaceutical Industries and Associations (EFPIA)‐wide survey was completed by 15 companies. The results provide insights into the current use of QST models across the industry. 73% of responding companies with more than 10,000 employees utilize QST models. The most applied QST models are for liver, cardiac electrophysiology, and bone marrow/hematology. Responders indicated particular interest in QST models for the central nervous system (CNS), kidney, lung, and skin. QST models are used to support decisions in both preclinical and clinical stages of pharmaceutical development. The survey suggests high demand for QST models and resource limitations were indicated as a common obstacle to broader use and impact. Increased investment in QST resources and training may accelerate application and impact. Case studies of QST model use in decision‐making within EFPIA companies are also discussed. This article aims to (i) share industry experience and learnings from applying QST models to inform decision‐making in drug discovery and development programs, and (ii) share approaches taken during QST model development and validation and compare these with recommendations for modeling best practices and frameworks proposed in the literature. Discussion of QST‐specific applications in relation to these modeling frameworks is relevant in the context of the recently proposed International Council for Harmonization (ICH) M15 guideline on general principles for Model‐Informed Drug Development (MIDD). [ABSTRACT FROM AUTHOR]

Background: The optimal regimen for 177Lu-labeled prostate-specific membrane antigen-targeted radioligand therapy, including treatment intervals, remains under study, with evidence suggesting shorter intervals could benefit patients with high disease volume and rapid progression. This retrospective analysis evaluated treatment toxicity, PSA response, PSA-progression-free survival (PSA-PFS), and overall survival (OS) in matched cohorts of mCRPC patients receiving 177Lu-PSMA-RLT at 4-week versus 6-week intervals. Results: A PSA response (PSA decline ≥ 50%) was achieved in 47.8% and 21.7% of patients in the 4-week and 6-week treatment interval groups, respectively (p = 0.12). There was a trend towards longer PSA-PFS in the 4-week group compared to the 6-week group (median PSA-PFS, 26.0 weeks vs. 18.0 weeks; HR 0.6; p = 0.2). Although not statistically significant, there was a trend towards shorter OS in the 4-week group compared to the 6-week group (median OS, 15.1 months vs. 18.4 months; HR 1.3; p = 0.5). The 4-week group had a significantly greater decrease in leucocyte and platelet counts compared to the 6-week group (38.5% vs. 18.2% and 26.7% vs. 10.7%; p = 0.047 and p = 0.02). Severe adverse events were modest in both groups. Conclusions: Intensifying treatment intervals from 6 weeks to 4 weeks showed some improvements in PSA response and PSA-PFS for mCRPC patients, but did not significantly affect OS. Additionally, bone marrow reserve was significantly reduced with the intensified regimen. Therefore, the overall benefit remains uncertain, and further prospective studies are needed to compare 4-week and 6-week intervals regarding toxicity, treatment response, and outcome. [ABSTRACT FROM AUTHOR]

Introduction: NPM1‐mutated (NPM1mut) myeloid neoplasms (MNs) with <20% bone marrow (BM) blasts (NPM1mut MNs<20) are uncommon, and their classification remains inconsistent. Methods: The clinicopathologic features of 54 patients with NPM1mut MNs <20 were evaluated and compared with wild‐type NPM1 MNs <20 and NPM1mut MNs≥20, respectively. Results: NPM1mut MNs had similar features regardless of blast percentage, except for higher IDH2 (29% vs 7%, p =.023) and FLT3 (70% vs 11%, p <.001) frequency in patients with ≥20% BM blasts. Thirty‐three (61%) patients with NPM1mut MNs <20 received low‐intensity chemotherapy (LIC) and 12 (22%) received intensive chemotherapy (IC). Higher complete remission rates (75% vs 27%, p =.006) and median overall survival (mOS) (not reached vs 30.4 months, p =.06) were observed with IC compared to LIC. Young patients (age <60 years) did not reach mOS either when treated with LIC or IC. Stem cell transplant was associated with increased survival only in patients treated with LIC (HR, 0.24; p =.025). No differences in mOS were observed by BM blast strata (32.2 months, not reached and 46.9 months for <10%, 10%–19%, and ≥20% blasts, p =.700) regardless of treatment modality (LIC: p =.900; IC: p =.360). Twenty‐three patients (43%) with NPM1mut MNs <20 had marrow blast progression to ≥20%. Conclusions: Overall, NPM1mut MNs define a unique entity independent of BM blast percentage. NPM1 mutations define a unique leukemia entity regardless of bone marrow blast percentage. Patients with NPM1‐mutated myeloid neoplasms benefit from intensive chemotherapy approaches even in the setting of low bone marrow blast percentage. [ABSTRACT FROM AUTHOR]

Our previous research revealed a close association between the acetylation of peroxisome proliferator-activated receptor γ (PPARγ) histone H3K27 and the adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). We preliminarily explored the epigenetic mechanism of steroid-induced avascular necrosis of the femoral head (SANFH) development, but the specific histone deacetylase (HDAC) involved in this regulatory process remains unknown. In this study, we combined cell, animal, and clinical specimen experiments to screen for specific HDAC genes that could regulate BMSC adipogenic differentiation and to explore their roles. The results showed that dexamethasone (DEX) significantly exacerbated the imbalance between the adipogenic and osteogenic differentiation of BMSCs, and there were differences in HDAC expression in the adipogenic differentiation cell models, with histone deacetylase 10 (HDAC10) showing the most significant decrease in expression. Subsequent use of a chromatin immunoprecipitation assay kit and quantitative polymerase chain reaction (ChIP‒qPCR) revealed a decrease in HDAC10 expression at predicted potential sites within the PPARγ promoter, indicating a significant decrease in HDAC10 enrichment in the PPARγ promoter region of BMSCs, thereby promoting sustained PPARγ expression. Additionally, immunohistochemistry of samples collected from mice and humans with SANFH and normal femoral heads revealed an imbalance between adipogenic and osteogenic differentiation in the necrotic area of femoral heads, with a significant decrease in the relative expression of HDAC10 in the necrotic area of femoral heads with SANFH. In summary, we speculate that HDAC10 affects the progression of SANFH by regulating BMSC adipogenic differentiation, a process possibly related to PPARγ histone acetylation. These findings provide a promising direction for the treatment of SANFH. [ABSTRACT FROM AUTHOR]

Case presentation: A 47-year-old Asian woman was admitted with worsening chest tightness and dyspnea for 10 days. Computed tomography (CT) showed changes in the trachea and segmental bronchi. Pulmonary function results suggestive of severe obstructive ventilatory dysfunction. Bronchoscopic findings showed the presence of multiple nodular lesions in the patient's trachea and left and right main bronchi. Bronchoscopic biopsy, lymph node biopsy and bone marrow aspiration flow cytometry test results led to a definitive diagnosis of chronic lymphocytic leukemia (CLL), staged as Binet stage B and Rai stage 2. [ABSTRACT FROM AUTHOR]

Neutrophil subsets endowed with regulatory/suppressive properties are widely regarded as deleterious immune cells that can jeopardize antitumoral response and/or antimicrobial resistance. Here, we describe a sizeable fraction of neutrophils characterized by the expression of programmed death-ligand 1 (PD-L1) in biological fluids of humans and mice with severe viral respiratory infections (VRI). Biological and transcriptomic approaches indicated that VRI-driven PD-L1+ neutrophils are endowed with potent regulatory functions and reduced classical antimicrobial properties, as compared to their PD-L1-counterpart. VRI-induced regulatory PD-L1+ neutrophils were generated remotely in the bone marrow in an IFN dependent manner and were quickly mobilized into the inflamed lungs where they fulfilled their maturation. Neutrophil depletion and PD-L1 blockade during experimental VRI resulted in higher mortality, increased local inflammation, and reduced expression of resolving factors. These findings suggest that PD-L1+ neutrophils are important players in disease tolerance by mitigating local inflammation during severe VRI and that they may constitute relevant targets for future immune interventions. [ABSTRACT FROM AUTHOR]

Background: Error-corrected next-generation sequencing (ecNGS) technologies have enabled the direct evaluation of genome-wide mutations after exposure to mutagens. Previously, we reported an ecNGS methodology, Hawk-Seq™, and demonstrated its utility in evaluating mutagenicity. The evaluation of technical transferability is essential to further evaluate the reliability of ecNGS-based assays. However, cutting-edge sequencing platforms are continually evolving, which can affect the sensitivity of ecNGS. Therefore, the effect of differences in sequencing instruments on mutation data quality should be evaluated. Results: We assessed the performance of four sequencing platforms (HiSeq2500, NovaSeq6000, NextSeq2000, and DNBSEQ-G400) with the Hawk-Seq™ protocol for mutagenicity evaluation using DNA samples from mouse bone marrow exposed to benzo[a]pyrene (BP). The overall mutation (OM) frequencies per 106 bp in vehicle-treated samples were 0.22, 0.36, 0.46, and 0.26 for HiSeq2500, NovaSeq6000, NextSeq2000, and DNBSEQ-G400, respectively. The OM frequency of NextSeq2000 was significantly higher than that of HiSeq2500, suggesting the difference to be based on the platform. The relatively higher value in NextSeq2000 was a consequence of the G:C to C:G mutations in NextSeq2000 data (0.67 per 106 G:C bp), which was higher than the mean of the four platforms by a ca. of 0.25 per 106 G:C bp. A clear dose-dependent increase in G:C to T:A mutation frequencies was observed in all four sequencing platforms after BP exposure. The cosine similarity values of the 96-dimensional trinucleotide mutation patterns between HiSeq and the three other platforms were 0.93, 0.95, and 0.92 for NovaSeq, NextSeq, and DNBSeq, respectively. These results suggest that all platforms can provide equivalent data that reflect the characteristics of the mutagens. Conclusions: All platforms sensitively detected mutagen-induced mutations using the Hawk-Seq™ analysis. The substitution types and frequencies of the background errors differed depending on the platform. The effects of sequencing platforms on mutagenicity evaluation should be assessed before experimentation. [ABSTRACT FROM AUTHOR]

Purpose: The current study aims to investigate the significance of N6-methyladenosine (m6A) methylationrelated genes in the clinical prognosis of childhood relapsed B-cell acute lymphoblastic leukemia (B-ALLL) patient. Methods: Transcriptome data and corresponding clinical data on m6A methylation-related genes (including 20 genes) were obtained from the Therapeutically Applicable Research To Generate Effective Treatments (TARGET) database. Results: The bone marrow (BM) samples of 134 newly diagnosed (naive) and 116 relapsed B-ALL from TARGET were enrolled in the current study. Three genes (FTO, HNRNPC, RBM15B) showed significant up-regulation in relapsed B-ALL compared with that in naive B-ALL.The three genes had a significantly worse survival (P < 0.05). The LASSO Cox regression model was used to select the most predictive genes as prognostic indicators, and YTHDC1 and FTO were identified as prognostic factors for relapsed B-ALL. Finally, the results of multivariate regression analysis showed that the risk score of m6A methylation-related genes was an independent prognostic factor in relapsed B-ALL (P < 0.05). Conclusion: We found that the expression levels of m6A methylation-related genes were different in naive and relapsed patients with B-ALL and correlated with survival and prognosis.This implies that m6A methylation-related genes may be promising prognostic indicators or therapeutic targets for relapsed B-ALL. [ABSTRACT FROM AUTHOR]

AbstractMiRNAs 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]

Background: The inflammatory microenvironment plays an essential role in bone healing after fracture. The signaling lymphocytic activation molecule family (SLAMF) members deeply participate in inflammatory response and make a vast difference. Methods: We identified SLAMF8 in GEO datasets (GSE129165 and GSE176086) and co-expression analyses were performed to define the relationships between SLAMF8 and osteogenesis relative genes (RUNX2 and COL1A1). In vitro, we established SLAMF8 knockdown and overexpression mouse bone marrow mesenchymal stem cells (mBMSCs) lines. qPCR, Western blot, ALP staining, ARS staining, Oil Red O staining and Immunofluorescence analyses were performed to investigate the effect of SLAMF8 in mBMSCs osteogenesis and adipogenesis. In vivo, mice femoral fracture model was performed to explore the function of SLAMF8. Results: SLAMF8 knockdown significantly suppressed the expression of osteogenesis relative genes (RUNX2, SP7 and COL1A1), ALP activity and mineral deposition, but increased the expression of adipogenesis relative genes (PPARγ and C/EBPα). Additionally, SLAMF8 overexpression had the opposite effects. The role SLAMF8 played in mBMSCs osteogenic and adipogenic differentiation were through S100A6 and Wnt/β-Catenin signaling pathway. Moreover, SLAMF8 overexpression mBMSCs promoted the healing of femoral fracture. Conclusions: SLAMF8 promotes osteogenesis and inhibits adipogenesis of mBMSCs via S100A6 and Wnt/β-Catenin signaling pathway. SLAMF8 overexpression mBMSCs effectively accelerate the healing of femoral fracture in mice. [ABSTRACT FROM AUTHOR]

Summary Shwachman–Diamond syndrome represents a clinically and genetically heterogeneous disorder. We report on an infant with a very severe, fatal clinical course caused by biallelic EFL1 variants: c.89A>G, p.(His30Arg), and c.2599A>G, p.(Asn867Asp). Functional analysis of patient‐derived B‐lymphoblastoid and SV40‐transformed fibroblast cell lines suggests that the compound heterozygous EFL1 variants impaired mature ribosome formation leading to compromised protein synthesis, ultimately resulting in a severe form of Shwachman–Diamond syndrome. [ABSTRACT FROM AUTHOR]

Tumor progress and tumor‐associated osteolysis are two key issues of breast cancer bone metastasis, which makes it challenging for bone metastasis treatment. To settle these two issues concurrently, a versatile semiconducting nanointegrator (termed as SPNCpG/Ca) containing semiconducting polymer nanoparticle (SPN), Ca2+ and cytosine‐phosphate‐guanine (CpG) oligonucleotides conjugated on the surface via a singlet oxygen (1O2)‐responsive linker, is designed. The antitumor effect can be triggered with X‐ray irradiation as an adjuvant, in which SPN works as a radiosensitizer to produce 1O2 for radiotherapy and controlled release of CpG via disrupting 1O2‐responsive linkers. The Ca2+ accumulation via SPNCpG/Ca delivering causes tumor cell death and the released CpG activates immune response to realize immunotherapy. The combinational action of radiotherapy, Ca2+ overloading, and immunotherapy results in complete clearance of metastatic tumor cells in 4T1 breast cancer‐based bone metastasis mouse models. Furthermore, Ca2+ can accelerate osteogenesis of bone marrow mesenchymal stem cells while CpG inhibits osteoclast differentiation in the bone metastasis microenvironment to alleviate osteolysis, which synergistically contributes to repair of tumor‐associated bone destruction. SPNCpG/Ca represents a versatile therapeutic nanosystem with the abilities to treat bone metastasis and repair tumor‐associated bone destruction, providing a new tactic for bone metastasis therapy. [ABSTRACT FROM AUTHOR]

Background: This study investigated the factors influencing treatment continuity and bone marrow suppression in whole-brain and whole-spinal cord radiotherapy for medulloblastoma, providing a clinical reference for mitigating the impact of hematological suppression on radiotherapy continuity. Methods: A retrospective analysis was conducted on patients with medulloblastoma who underwent craniospinal irradiation (CSI) radiotherapy at our hospital between August 2019 and December 2023. According to the inclusion and exclusion criteria, a total of 87 patients were enrolled. The bone marrow suppression status, clinical data, and radiotherapy dose data of the enrolled patients were recorded, and correlation analyses were performed. Based on the correlation results, further group comparisons were subsequently conducted. Results: Overall, 22.99% (20 out of 87) of the patients experienced treatment interruption (median duration, 6.5 [5, 8] days), typically during the 12th (7.5, 14.75) radiotherapy session. Treatment continuity was weakly correlated with age and treatment modality, and the timing of interruptions was weakly correlated with dosage and treatment modality. Bone marrow suppression severity was weakly correlated with age, body mass index (BMI), and treatment modality. Treatment modality and age were found to be independent predictors of treatment continuity and the degree of bone marrow suppression, respectively. Subgroup comparisons revealed differences in the severity of bone marrow suppression, grade of hematological toxicity, and timing of interruption depending on the treatment modality, dosage, and sex (P <.05). Conclusions: Timely monitoring of hematological changes, especially in the middle and posterior segments after radiotherapy, is crucial. Treatment with helical tomotherapy, male sex, younger age, and lower BMI during radiotherapy are indicators of greater clinical attention. [ABSTRACT FROM AUTHOR]

Certain immune cells, including neutrophils, macrophages, dendritic cells, B cells, Breg cells, CD4+ T cells, CD8+ T cells, and Treg cells, establish enduring residency within the bone marrow. Their distinctive interactions with hematopoiesis and the bone marrow microenvironment are becoming increasingly recognized alongside their multifaceted immune functions. These cells play a dual role in shaping hematopoiesis. They directly influence the quiescence, self-renewal, and multi-lineage differentiation of hematopoietic stem and progenitor cells through either direct cell-to-cell interactions or the secretion of various factors known for their immunological functions. Additionally, they actively engage with the cellular constituents of the bone marrow niche, particularly mesenchymal stem cells, endothelial cells, osteoblasts, and osteoclasts, to promote their survival and contribute to tissue repair, thereby fostering a supportive environment for hematopoietic stem and progenitor cells. Importantly, these bone marrow immune cells function synergistically, both locally and functionally, rather than in isolation. In summary, immune cells residing in the bone marrow are pivotal components of a sophisticated network of regulating hematopoiesis. [ABSTRACT FROM AUTHOR]

MRD2STOP is a pragmatic trial evaluating maintenance therapy cessation guided by measurable residual disease (MRD) negativity in multiple myeloma (MM). Eligible patients had previous MRD < 10−5, received ≥1 year of maintenance, and were prospectively confirmed to have undetectable disease by positron emission tomography, bone marrow (BM) flow cytometry (limit of detection [LoD] 10−5), and BM clonoSEQ (LoD 10−6). BM aspirates enriched for CD138+ cells were analyzed by clonoSEQ to achieve MRD 10−7 sensitivity. We evaluated the incidence of disease resurgence and progression-free survival (PFS), stratified by 10−7 status. Forty-seven patients discontinued maintenance after a median of 36 months. Baseline MRD ≥ 10−7 was observed in 19% (9/47). The median follow-up post-discontinuation was 30 months. Disease resurgence (MRD 10 ≥ −6) occurred in 11 patients, including 5 disease progressions. One patient died from a second cancer. The estimated 3-year cumulative incidence of disease resurgence was 20% for patients with baseline MRD < 10−7 compared to 75% for MRD ≥ 10−7 (HR 7.8, 95% CI 2.2-27.6, p = 0.001). Baseline MRD ≥ 10−7 was associated with inferior PFS compared to MRD < 10−7 (HR 10.1, 95% CI 1.6–62.3; 3-year PFS 49% vs 92%). Maintenance discontinuation in patients with MM and MRD < 10−6 led to low rates of disease resurgence. MRD < 10−7 may be a superior cessation threshold, requiring further validation. [ABSTRACT FROM AUTHOR]

Bone marrow cellular therapy has undergone a remarkable evolution, significantly impacting the treatment of musculoskeletal disorders. This review traces the historical trajectory from early mythological references to contemporary scientific advancements. The groundbreaking work of Friedenstein in 1968, identifying fibroblast colony-forming cells in bone marrow, laid the foundation for future studies. Caplan's subsequent identification of mesenchymal stem cells (MSCs) in 1991 highlighted their differentiation potential and immunomodulatory properties, establishing them as key players in regenerative medicine. Contemporary research has focused on refining techniques for isolating and applying bone marrow-derived MSCs. These cells have shown promise in treating conditions like osteonecrosis, osteoarthritis, and tendon injuries thanks to their ability to promote tissue repair, modulate immune responses, and enhance angiogenesis. Clinical studies have demonstrated significant improvements in pain relief, functional recovery, and tissue regeneration. Innovations such as the ACH classification system and advancements in bone marrow aspiration methods have standardized practices, improving the consistency and efficacy of these therapies. Recent clinical trials have validated the therapeutic potential of bone marrow-derived products, highlighting their advantages in both surgical and non-surgical applications. Studies have shown that MSCs can reduce inflammation, support bone healing, and enhance cartilage repair. However, challenges remain, including the need for rigorous characterization of cell populations and standardized reporting in clinical trials. Addressing these issues is crucial for advancing the field and ensuring the reliable application of these therapies. Looking ahead, future research should focus on integrating bone marrow-derived products with other regenerative techniques and exploring non-surgical interventions. The continued innovation and refinement of these therapies hold promise for revolutionizing the treatment of musculoskeletal disorders, offering improved patient outcomes, and advancing the boundaries of medical science. [ABSTRACT FROM AUTHOR]

Autoimmune polyglandular syndrome 1 (APS1) is an autosomal recessive disorder due to biallelic pathogenic variants in the autoimmune regulator (AIRE) gene that manifests with chronic mucocutaneous candidiasis, primary hypoparathyroidism, and adrenal insufficiency. We report a 39-year-old woman with APS1 who developed partial lipodystrophy during adulthood. She presented with diaper rashes, oral thrush, and tetany during infancy due to candidiasis and hypoparathyroidism. During childhood, she developed hypothyroidism, primary adrenal insufficiency, and ovarian insufficiency. At age 14, she received a sibling-matched allogenic bone marrow transplant due to multiple antibiotic-refractory fungal infections. At age 35, her serum triglycerides were 914 mg/dL (10.32 mmol/L) and she had loss of subcutaneous fat from the upper and lower extremities and hips. A whole-body dual-energy x-ray absorptiometry revealed lower-extremity fat at less than the first percentile. Whole-exome sequencing on DNA extracted from saliva revealed pathogenic variants, p.Leu28Pro and p.Arg257* in AIRE but none in the known lipodystrophy genes. Phage-immunoprecipitation-sequencing revealed the presence of autoantibodies to MAGEB1, MAGEB4, and RFX6, which have been previously reported in APS1. Our case suggests that patients with APS1 may develop partial lipodystrophy due to autoantibodies against novel adipocyte-expressed proteins. A causal relationship of high levels of autoantibodies in our patient to adipose tissue–expressed ODC1, NUCKS1, or FNBP1L and lipodystrophy remains uncertain. [ABSTRACT FROM AUTHOR]

Background: Bone marrow stimulation (BMS) has been proposed to augment healing at the time of arthroscopic rotator cuff repair (ARCR) by creating several bone marrow vents in the footprint of the rotator cuff, allowing mesenchymal stem cells, platelets, and growth factors to cover the area as a "crimson duvet." Purpose: To perform a meta-analysis of randomized controlled trials (RCTs) to compare the outcomes after BMS and a control for those undergoing ARCR. Study Design: Meta-analysis; Level of evidence, 1. Methods: A literature search of 3 databases was performed based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RCTs comparing BMS and a control for ARCR were included. Clinical outcomes were compared, and a P value <.05 was considered to be statistically significant. Results: A total of 7 RCTs with 576 patients were included. Overall, 18.8% of patients treated with BMS and 21.0% of patients treated with a control had a retear (I 2 = 43%; P =.61). With BMS, the mean Constant score was 88.2, and with the control, the mean Constant score was 86.7 (P =.12). Additionally, there was no significant difference in the American Shoulder and Elbow Surgeons score (94.3 vs 93.2, respectively; P =.31) or visual analog scale score (0.9 vs 0.9, respectively; P =.89). Conclusion: The level 1 evidence in the literature did not support BMS as a modality to improve retear rates or clinical outcomes after ARCR. [ABSTRACT FROM AUTHOR]

Introduction: Donor leucocyte survival following red blood cell (RBC) transfusion, known as transfusion‐associated microchimerism (TAM), can occur in some patients. In Australia, despite the introduction of leucocyte filtration (leucodepletion) during RBC manufacture, TAM has been detected in adult trauma patients. However, the incidence of TAM in Australian pediatric patients has not been analyzed. Methods: Patients aged 0–16 years were recruited across two cohorts. Retrospective participants had RBC transfusion between January 1, 2002 and November 15, 2017 and prospective participants received RBC transfusion between December 1, 2016 and November 25, 2020. Twelve bi‐allelic insertion/deletion (InDel) polymorphisms were used to detect microchimerism amplification patterns using real‐time PCR (RT‐PCR) and droplet digital PCR (ddPCR). Results: Of the retrospective cohort (n = 40), six patients showed amplification of InDel sequences indicating potential microchimerism. For three patients, minor InDel sequences were detected using RT‐PCR only, two patients had minor InDel amplification using ddPCR only, and one patient had minor InDel amplification that was confirmed using both techniques. Amplification of minor sequences occurred in three patients who had received a bone marrow transplant in addition to RBC transfusion. In the prospective cohort (n = 25), no InDel amplification indicating potential microchimerism was detected using RT‐PCR. Discussion: Cell‐based therapies had been administered in three patients where microchimerism amplification patterns were detected. Three patients have microchimerism that may be attributed to RBC transfusion. In prospective patients, who received leucodepleted and gamma‐irradiated RBC units, no potential microchimerism amplification were detected. ddPCR may be a suitable technique for TAM analysis but requires further evaluation. [ABSTRACT FROM AUTHOR]

Erythroid enucleation, the penultimate step in mammalian erythroid terminal differentiation, is a unique cellular process by which red blood cells (erythrocytes) remove their nucleus and accompanying nuclear material. This complex, multi-stage event begins with chromatin compaction and cell cycle arrest and ends with generation of two daughter cells: a pyrenocyte, which contains the expelled nucleus, and an anucleate reticulocyte, which matures into an erythrocyte. Although enucleation has been compared to asymmetric cell division (ACD), many mechanistic hallmarks of ACD appear to be absent. Instead, enucleation appears to rely on mechanisms borrowed from cell migration, endosomal trafficking and apoptosis, as well as unique cellular interactions within the microenvironment. In this Cell Science at a Glance article and the accompanying poster, we summarise current insights into the morphological features and genetic drivers regulating the key intracellular events that culminate in erythroid enucleation and engulfment of pyrenocytes by macrophages within the bone marrow microenvironment. [ABSTRACT FROM AUTHOR]

Exosomes are bilayer lipid bodies and contain a variety of bioactive molecules such as proteins, lipids, and nucleic acids, and so forth. Exosomes derived from solid tumors may play critical roles in tumor development and immune evasion. However, the underlying effects of tumor‐derived exosomes on immune function in modulating intercellular crosstalk within the bone marrow niche during acute myeloid leukemia (AML) development and immune evasion remain largely elusive. In this study, we aimed to explore the role of AML‐exos in AML immune evasion. First, we isolated tumor‐derived exosomes from AML cells (AML‐exos) and revealed the presence of programmed cell death ligand‐1 (PD‐L1) protein in AML‐exos. Next, we demonstrated that AML‐exos can directly suppress the activation of natural killer (NK) cells and inhibit the cytotoxicity of NK cells, probably through activating the programmed cell death‐1 (PD‐1)/PD‐L1 pathway. Furthermore, the inhibitory effect of AML‐exos on NK cells could be alleviated by either PD‐L1 inhibitor or antagonist. In summary, we demonstrated that AML‐exos possess a PD‐L1‐dependent tumor‐promoting effect which may contribute to immune tolerance in antitumor therapy, but blocking the PD‐1/PD‐L1 pathway may alleviate the tumor immunosuppression induced by AML‐exos. Our findings in this study may offer a new immunotherapy strategy to cure AML. Highlights: Programmed cell death ligand‐1 (PD‐L1) is present in acute myeloid leukemia (AML) cell‐derived exosomes (AML‐exos).AML‐exos suppress natural killer (NK) cell activation and inhibit NK cell cytotoxicity.Blocking PD‐1/PD‐L1 pathway alleviates the tumor immunosuppression by AML‐exos.AML‐exos impact the NK cells mainly through PD‐1/PD‐L1 pathway. [ABSTRACT FROM AUTHOR]

Summary: Bone marrow endothelial progenitor cells (BM EPCs) are crucial in supporting haematopoietic regeneration, while the BM EPCs of haematological patients with chemotherapy‐induced thrombocytopenia (CIT) are unavoidably damaged. Therefore, the present study aimed to examine the effect of thrombopoietin (TPO) on the recovery of BM EPCs of CIT patients and to identify the underlying mechanisms. The cell functions were determined by 1,1'‐dioctadecyl‐3,3,3',3'‐tetramethylindocarbocyanine perchlorate (Dil)–acetylated low‐density lipoprotein (Dil‐Ac‐LDL) uptake and fluorescein isothiocyanate (FITC)‐labeled Ulex europaeus agglutinin‐I (FITC‐UEA‐I) binding assay, as well as proliferation, migration and tube formation experiments. Endothelial cells were transfected with METTL16 lentivirus, followed by methylated RNA immunoprecipitation sequencing. Zebrafish with vascular defect was used as the in vivo model. TPO significantly improved the quantity and functions of BM EPCs from CIT patients in vitro and restored the subintestinal vein area of zebrafish with vascular defect in vivo. Mechanically, TPO enhanced the BM EPC functions through Akt signal mediated by METTL16, which was downregulated in BM EPCs of CIT patients and involved in the regulation of endothelial functions. The present study demonstrates that TPO improves the recovery of BM EPCs from CIT patients with haematological malignancies via METTL16/Akt signalling, which provides new insights into the role of TPO in treating CIT in addition to direct megakaryopoiesis. [ABSTRACT FROM AUTHOR]

Summary: Recent evidence suggests that immune thrombocytopenia (ITP), a common bleeding disorder, is linked to an imbalance in macrophage polarization and impaired bone marrow mesenchymal stem cells (BMSCs). However, the relationship between macrophage polarization imbalance and functional defects in BMSCs, as well as the involvement of associated molecules in BMSCs' defects, is not well understood. This study aimed to investigate the regulatory effects of high mobility group protein 1 (HMGB1) on the physiological functions of BMSCs, specifically in relation to macrophage polarization imbalance. Patients with ITP showed dysregulation in monocyte/macrophage polarization and impaired BMSCs function. HMGB1 was found to have a negative impact on the ability of BMSCs to regulate the imbalance in macrophage polarization, especially when inflammatory factors are present. The MyD88‐dependent pathway downstream of BMSCs was found to be significantly enhanced with HMGB1 treatment. Furthermore, treatment with toll‐like receptor 4 (TLR4) inhibitors successfully restored the regulatory capacity of BMSCs in ameliorating macrophage polarization imbalance and effectively inhibited the activation of the MyD88‐dependent pathway. Meanwhile, infusion of si‐TLR4‐BMSCs reversed HMGB1‐induced platelet dysfunction and reduced over‐polarization to M1‐like macrophages in the ITP mouse model. Consequently, targeting the HMGB1‐TLR4 pathway could be a potential approach to restore the immunoregulatory function of BMSCs. [ABSTRACT FROM AUTHOR]

Summary: Diagnosis of essential thrombocythaemia (ET) is challenging in patients lacking JAK2/CALR/MPL mutations. In a retrospective evaluation of 320 patients with 'triple‐negative thrombocytosis', we assessed utility of bone marrow histology (90.9% of patients) and myeloid gene panel (MGP, 55.6%). Supportive histology ('myeloproliferative neoplasm‐definite/probable', 36.8%) was associated with higher platelet counts and varied between centres. 14.6% MGP revealed significant variants: 3.4% JAK2/CALR/MPL and 11.2% other myeloid genes. Final clinical diagnosis was strongly predicted by histology, not MGP. 23.7% received cytoreduction (17.6% under 60 years). Real‐world 'triple‐negative' ET diagnosis currently depends heavily on histology; we advocate caution in MGP‐negative cases and that specific guidelines are needed. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor (CAR) T‐cell therapies have increased the patients with relapsed/refractory multiple myeloma (RRMM) in whom standard electrophoretic techniques fail to detect the M‐protein. Quantitative immunoprecipitation mass spectrometry (QIP‐MS) can accurately measure serum M‐protein with high sensitivity, and identify interferences caused by therapeutic monoclonal antibodies. Here, we investigate the outcome of QIP‐MS in 33 patients treated with the academic BCMA‐directed CAR T‐cell ARI0002h (Cesnicabtagene Autoleucel). QIP‐MS offered more detailed insights than serum immunofixation (sIFE), identifying glycosylated M‐proteins and minor additional peaks. Moreover, the potential interferences owing to daratumumab or tocilizumab treatments were successfully detected. When analysing different assay platforms during patient's monitoring after ARI0002h administration, we observed that QIP‐MS showed a high global concordance (78.8%) with sIFE, whereas it was only moderate (55.6%) with bone marrow (BM)‐based next‐generation flow cytometry (NGF). Furthermore, QIP‐MS consistently demonstrated the lowest negativity rate across the different timepoints (27.3% vs. 60.0% in months 1 and 12, respectively). Patients with QIP‐MS(+)/BM‐based NGF(−) showed a non‐significant shorter median progression free survival than those with QIP‐MS(−)/BM‐based NGF(−). In summary, we show the first experience to our knowledge demonstrating that QIP‐MS could be particularly useful as a non‐invasive technique when evaluating response after CAR T‐cell treatment in MM. [ABSTRACT FROM AUTHOR]

Summary: Inherited bone marrow failure syndromes (IBMFS) pose significant diagnostic challenges due to overlapping symptoms and variable expressivity, despite evolving genomic insights. The study aimed to elucidate the genomic landscape among 130 Korean patients with IBMFS. We conducted targeted next‐generation sequencing (NGS) and clinical exome sequencing (CES) across the cohort, complemented by whole genome sequencing (WGS) and chromosomal microarray (CMA) in 12 and 47 cases, respectively, with negative initial results. Notably, 50% (n = 65) of our cohort achieved a genomic diagnosis. Among these, 35 patients exhibited mutations associated with classic IBMFSs (n = 33) and the recently defined IBMFS, aplastic anaemia, mental retardation and dwarfism syndrome (AmeDS, n = 2). Classic IBMFSs were predominantly detected via targeted NGS (85%, n = 28) and CES (88%, n = 29), whereas AMeDS was exclusively identified through CES. Both CMA and WGS aided in identifying copy number variations (n = 2) and mutations in previously unexplored regions (n = 2). Additionally, 30 patients were diagnosed with other congenital diseases, encompassing 13 distinct entities including inherited thrombocytopenia (n = 12), myeloid neoplasms with germline predisposition (n = 8), congenital immune disorders (n = 7) and miscellaneous genomic conditions (n = 3). CES was particularly effective in revealing these diverse diagnoses. Our findings underscore the significance of comprehensive genomic analysis in IBMFS, highlighting the need for ongoing exploration in this complex field. [ABSTRACT FROM AUTHOR]