The bone marrow microenvironment is critical for the maintenance and functionality of stem/progenitor cells,which are essential for bone development and regeneration.However,the composition and potential use of bone m...The bone marrow microenvironment is critical for the maintenance and functionality of stem/progenitor cells,which are essential for bone development and regeneration.However,the composition and potential use of bone marrow interstitial fluid have not been well explored.In this study,we report the role of neonatal bovine bone marrow interstitial fluid(NBIF)in enhancing the bone regeneration capacity of human bone marrow mesenchymal stem cells(hBMSCs).Unlike adult bovine bone marrow interstitial fluid(ABIF),NBIF-fed hBMSCs exhibit enhanced self-renewal and osteogenic potential and bone marrow homing ability,along with transcriptome changes as compared to hBMSCs cultured in standard fetal bovine serum(FBS)supplemented medium.Mass spectrometry analysis reveals that multiple secreted factors associated with tissue repair and bone development are enriched in NBIF compared to FBS and ABIF.The combined use of NBIF-enriched Nerve Growth Factor(NGF),Lactoferrin(LTF),and High Mobility Group Protein B1(HMGB1),together with Insulin-Like Growth Factor 1(IGF1)for culturing hBMSCs in the presence of FBS can enhance osteogenic potential and bone marrow homing ability,mimicking NBIF's effects.These findings highlight the role of interstitial fluid in the bone marrow microenvironment and its potential to optimize stem cell-based therapies.展开更多
BACKGROUND Thrombotic microangiopathy(TMA)is an acute syndrome characterized by microangiopathic hemolytic anemia,thrombocytopenia,and multi-organ dysfunction due to the microcirculation of platelet thrombi.Cancer-ass...BACKGROUND Thrombotic microangiopathy(TMA)is an acute syndrome characterized by microangiopathic hemolytic anemia,thrombocytopenia,and multi-organ dysfunction due to the microcirculation of platelet thrombi.Cancer-associated TMA is a rare and fatal complication,which often occurs during cancer remission.It is frequently misdiagnosed because of limited clinical awareness.CASE SUMMARY A middle-aged female patient presented to our clinic with a 15-days history of back pain,15 months post-gastrectomy.Cancer-associated TMA was confirmed through bone marrow aspiration,biopsy,and imaging.The patient received intermittent transfusions,fluids,nutrition,and microcirculation therapy with partial coagulation improvement.The family refused intensive care unit admission and plasma exchange,preferring palliative care.The patient died of cerebral hemorrhage and herniation due to disease progression.This case indicates that TMA may serve as an early manifestation of various malignancies,particularly gastric cancer.However,it is often misdiagnosed.Its pathogenesis is not well understood and needs to be further investigated.Currently,no standardized treatment have been developed.Plasma exchange is the only intervention available,though other therapies may also be effective.CONCLUSION In this case of gastric signet-ring cell carcinoma complicated by TMA,the patient achieved transient remission with supportive care but died following treatment discontinuation.Further studies are needed to elucidate the pathological mechanisms and therapeutic strategies for cancer-associated TMA.展开更多
BACKGROUND Knee osteoarthritis(OA)is a degenerative joint disease traditionally viewed through the lens of cartilage degradation.However,emerging evidence positions subchondral bone pathology-particularly bone marrow ...BACKGROUND Knee osteoarthritis(OA)is a degenerative joint disease traditionally viewed through the lens of cartilage degradation.However,emerging evidence positions subchondral bone pathology-particularly bone marrow lesions(BMLs)-as a key contributor to pain,progression,and structural deterioration.Mesenchymal stem cell exhaustion within the osteoarthritic subchondral zone further impairs intrinsic repair mechanisms,reinforcing the rationale for biologic interventions.AIM To evaluate the clinical efficacy of bone marrow aspirate concentrate(BMAC)therapy for knee OA,comparing subchondral vs intra-articular delivery routes,and elucidating the therapeutic impact on symptom relief and structural preservation.METHODS Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines,five clinical studies were included-comprising three randomized controlled trials and two prospective cohorts-with pooled data from 298 knees.Data on functional outcomes,imaging findings,and progression to total knee arthroplasty(TKA)were extracted and qualitatively synthesized.RESULTS Subchondral BMAC injections demonstrated superior improvements compared to intra-articular injection or placebo:Knee Injury and Osteoarthritis Outcome Score improved from 49.1±1.9 to 61.2±6.3 at 12 months(P<0.05),Knee Society Score increased from 57±12 to 87.3±12 at two years,and Western Ontario and McMaster Universities Arthritis Index scores showed significant improvement favoring combined approaches.Magnetic resonance imaging analyses revealed mean BML volume regression of 2.1 cm3,with 80%of knees avoiding TKA over 13-year follow-up.Magnetic resonance imaging analyses revealed regression of BMLs and increased cartilage preservation in subchondral-treated knees.Long-term data indicated delayed progression to TKA and biomechanical improvements(e.g.,Hip-Knee-Ankle angle correction).No major adverse events were reported.CONCLUSION Targeting subchondral bone with BMAC addresses underlying OA pathology and may offer disease-modifying potential beyond symptom relief.These findings support a paradigm shift toward whole-joint biologic therapy,positioning the subchondral matrix as a therapeutic epicenter in OA management.展开更多
Bone marrow lesions(BML)are early signs of osteoarthritis(OA)and are strongly correlated with the deterioration of cartilage lesions.Single-cell RNA sequencing(scRNA-seq)analyses were performed on BM from non-BML and ...Bone marrow lesions(BML)are early signs of osteoarthritis(OA)and are strongly correlated with the deterioration of cartilage lesions.Single-cell RNA sequencing(scRNA-seq)analyses were performed on BM from non-BML and BML areas and articular cartilage from intact and damaged areas to explore BML landscape and BML-cartilage crosstalk.We revealed the immune landscape of BM in non-BML and BML,and the transition to pro-inflammatory states of clusters in BMLs,such as classical monocytes and nonclassical monocytes.Non-classical monocytes have high inflammation,OA gene signatures,and senescence scores,and are potential primary clusters promoting OA progression.Histological signs of OA related to the cellular landscape in damaged cartilage were identified,including PreFC exhaustion.The BM-cartilage crosstalk at the cell-cell interaction(CCIs)level and the TNF signal transmitted by non-classical monocytes are the critical CCIs in BML-induced cartilage damage,and PreFC is one of the primary receivers of the signal.We further validated the higher senescence level of non-classical monocyte and FC-2 in OA mice,compared with classical monocyte and PreFC,respectively.Transcription factor 7 like 2(TCF7L2)was identified as a shared transcription factor in the senescence of monocytes and chondrocytes,facilitating the development of the senescence-associated secretory phenotype(SASP).Therefore,senescent non-classical monocytes promote BMLs and inflammation and senescence of chondrocytes by modulating BML–cartilage crosstalk in OA,with TCF7L2 serving as a regulator.展开更多
Bone resorption by osteoclasts is a critical step in bone remodeling,a process important for maintaining bone homeostasis and repairing injured bone.We previously identified a bone marrow mesenchymal subpopulation,mar...Bone resorption by osteoclasts is a critical step in bone remodeling,a process important for maintaining bone homeostasis and repairing injured bone.We previously identified a bone marrow mesenchymal subpopulation,marrow adipogenic lineage precursors(MALPs),and showed that its production of RANKL stimulates bone resorption in young mice using Adipoq-Cre.To exclude developmental defects and to investigate the role of MALPs-derived RANKL in adult bone,we generated inducible reporter mice(Adipoq-CreER Tomato)and RANKL deficient mice(Adipoq-CreER RANKLflox/flox,iCKO).Single cell-RNA sequencing data analysis and lineage tracing revealed that Adipoq+cells contain not only MALPs but also some mesenchymal progenitors capable of osteogenic differentiation.In situ hybridization showed that RANKL mRNA is only detected in MALPs,but not in osteogenic cells.RANKL deficiency in MALPs induced at 3 months of age rapidly increased trabecular bone mass in long bones as well as vertebrae due to diminished bone resorption but had no effect on the cortical bone.Ovariectomy(OVX)induced trabecular bone loss at both sites.RANKL depletion either before OVX or at 6 weeks post OVX protected and restored trabecular bone mass.Furthermore,bone healing after drill-hole injury was delayed in iCKO mice.Together,our findings demonstrate that MALPs play a dominant role in controlling trabecular bone resorption and that RANKL from MALPs is essential for trabecular bone turnover in adult bone homeostasis,postmenopausal bone loss,and injury repair.展开更多
Cardiac arrest can lead to severe neurological impairment as a result of inflammation,mitochondrial dysfunction,and post-cardiopulmonary resuscitation neurological damage.Hypoxic preconditioning has been shown to impr...Cardiac arrest can lead to severe neurological impairment as a result of inflammation,mitochondrial dysfunction,and post-cardiopulmonary resuscitation neurological damage.Hypoxic preconditioning has been shown to improve migration and survival of bone marrow–derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest,but the specific mechanisms by which hypoxia-preconditioned bone marrow–derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown.To this end,we established an in vitro co-culture model of bone marrow–derived mesenchymal stem cells and oxygen–glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis,possibly through inhibition of the MAPK and nuclear factor κB pathways.Subsequently,we transplanted hypoxia-preconditioned bone marrow–derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia.The results showed that hypoxia-preconditioned bone marrow–derived mesenchymal stem cells significantly reduced cardiac arrest–induced neuronal pyroptosis,oxidative stress,and mitochondrial damage,whereas knockdown of the liver isoform of phosphofructokinase in bone marrow–derived mesenchymal stem cells inhibited these effects.To conclude,hypoxia-preconditioned bone marrow–derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest,and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.展开更多
Knee osteoarthritis(OA)is a debilitating condition with limited long-term treatment options.The therapeutic potential of mesenchymal stem cells(MSCs),particularly those derived from bone marrow aspirate concentrate,ha...Knee osteoarthritis(OA)is a debilitating condition with limited long-term treatment options.The therapeutic potential of mesenchymal stem cells(MSCs),particularly those derived from bone marrow aspirate concentrate,has garnered attention for cartilage repair in OA.While the iliac crest is the traditional site for bone marrow harvesting(BMH),associated morbidity has prompted the exploration of alternative sites such as the proximal tibia,distal femur,and proximal humerus.This paper reviews the impact of different harvesting sites on mesenchymal stem cell(MSC)yield,viability,and regenerative potential,emphasizing their relevance in knee OA treatment.The iliac crest consistently offers the highest MSC yield,but alternative sites within the surgical field of knee procedures offer comparable MSC characteristics with reduced morbidity.The integration of harvesting techniques into existing knee surgeries,such as total knee arthroplasty,provides a less invasive approach while maintaining thera-peutic efficacy.However,variability in MSC yield from these alternative sites underscores the need for further research to standardize techniques and optimize clinical outcomes.Future directions include large-scale comparative studies,advanced characterization of MSCs,and the development of personalized harvesting strategies.Ultimately,the findings suggest that optimizing the site of BMH can significantly influence the quality of MSC-based therapies for knee OA,enhancing their clinical utility and patient outcomes.展开更多
目的探讨双能量CT Bone Marrow Edema(骨髓水肿)定量评估肋骨骨折演变时间节点的价值。方法收集60例双能量CT扫描的胸部外伤患者,利用CT Bone Marrow Edema技术,标准化定量肋骨骨折处骨髓水肿区域及骨折两侧1 cm处正常区域骨髓CT值,得...目的探讨双能量CT Bone Marrow Edema(骨髓水肿)定量评估肋骨骨折演变时间节点的价值。方法收集60例双能量CT扫描的胸部外伤患者,利用CT Bone Marrow Edema技术,标准化定量肋骨骨折处骨髓水肿区域及骨折两侧1 cm处正常区域骨髓CT值,得到三期骨髓水肿标准化CT值增量与VNCa标准化CT值增量。对数值变量行统计学描述,并对三期骨髓水肿标准化CT值增量、VNCa标准化CT值增量进行各自组间比较及两两间比较,对有差异的组别行诊断效能比较,由接受者工作特征(ROC)曲线下面积(AUC)进行评估,并计算Cut-off值。结果三期骨髓水肿标准化CT值增量及VNCa标准化CT值增量组间均有统计学意义(H=10.788,p=0.005;F=115.787,p=0.000),其中,软骨痂期(纤维性骨痂期)与硬骨痂-重塑期骨髓水肿标准化CT值增量有统计学意义(H=54.958,p=0.003),其余两两间无统计学意义(分别为H=-25.603,p=0.183;H=29.354,p=0.113)。而三期VNCa标准化CT值增量两两间均有统计学意义(P均为0.000)。ROC曲线鉴别软骨痂期(纤维性骨痂期)与硬骨痂-重塑期骨髓水肿标准化CT值增量曲线下面积为0.652,Cut-off值为81.575 Hu,鉴别血肿炎症机化期与软骨痂期(纤维性骨痂期)VNCa标准化CT值增量曲线下面积为0.668,Cut-off值为55.700 Hu,鉴别软骨痂期(纤维性骨痂期)与硬骨痂-重塑期VNCa标准化CT值增量曲线下面积为0.905,Cut-off值为37.625 Hu。结论通过双能量CT Bone Marrow Edema可定量评估肋骨骨折演变时间节点,骨折时间演变的标准化CT值增量差异性可为法医鉴定骨折处于不同时间段提供理论依据。通过标准化CT值增量Cut-off值可一定程度上预测骨折所处时间阶段,为法医在鉴定肋骨骨折方面提供定量依据。展开更多
Bone marrow edema syndrome (BMES), is a rare and self-limiting condition characterized by localized bone pain and transient marrow edema visible on MRI. BMES has been increasingly associated with specific cutaneous ma...Bone marrow edema syndrome (BMES), is a rare and self-limiting condition characterized by localized bone pain and transient marrow edema visible on MRI. BMES has been increasingly associated with specific cutaneous manifestations that may hold diagnostic and prognostic significance. Patients with BMES have reported localized erythema, dermal thickening, and induration overlying the affected joints, which are hypothesized to reflect microvascular compromise and inflammatory processes within the bone and adjacent soft tissues. Dermatologic signs are likely linked to regional hyperemia, venous stasis, and cytokine-mediated inflammation, paralleling the pathophysiological mechanisms underlying intraosseous edema. Elevated intraosseous pressure in BMES may disrupt local perfusion, resulting in ischemia-reperfusion injury and subsequent vascular leakage, which manifests in visible cutaneous changes. Pro-inflammatory mediators, such as interleukin-1β and vascular endothelial growth factor (VEGF), central to BMES pathogenesis, may exacerbate endothelial activation, and dermal involvement. Histopathologic studies of affected skin have revealed perivascular lymphocytic infiltration and increased dermal vascularity, further supporting the theory of a shared ischemic and inflammatory pathway between bone and skin. Although MRI remains the gold standard for BMES diagnosis, recognition of these cutaneous manifestations could expedite orthopedic referral and intervention, especially in cases where imaging is delayed or symptoms are ambiguous. Current treatment options, including bisphosphonates, prostacyclin analogs, and offloading of weight bearing, may benefit from integration with dermatologic strategies to alleviate localized cutaneous symptoms and improve patient comfort. Evaluating the molecular and vascular links between BMES and its cutaneous manifestations provides an opportunity to refine diagnostic protocols and therapeutic approaches, offering a comprehensive understanding of the systemic interplay between dermal and skeletal pathophysiology, and optimizing clinical outcomes for patients affected by BMES.展开更多
Objective:The effectiveness of chemotherapy is affected by tumor heterogeneity and drug resistance mechanisms;however,there are certain limitations.Electroacupuncture can regulate the tumor immune response and restore...Objective:The effectiveness of chemotherapy is affected by tumor heterogeneity and drug resistance mechanisms;however,there are certain limitations.Electroacupuncture can regulate the tumor immune response and restore bone marrow hematopoietic function,which is affected by chemotherapy.This study investigated the efficacy and mechanism of electroacupuncture combined with cisplatin in the treatment of non-small-cell lung cancer mice.Methods:To establish a mouse model of non-small-cell lung cancer,gene sequencing combined with bioinformatics analysis,flow cytometry,and liquid-phase chips was used to observe the expression of immune cells and related factors in the mouse tumor microenvironment.Flow cytometry was used to observe subpopulations of mouse bone marrow hematopoietic stem cells and progenitor cells.PAC1 receptor agonists were used to observe mouse tumor immunity and bone marrow hematopoiesis-related indicators.Results:The combination of electroacupuncture with high-and low-dose chemotherapy had a better tumor-suppressive effect.Electroacupuncture can affect the gene expression profile of immune cells,especially the expression levels of Ccr1,Cxcr5,Zbp1,and CamkIIα,and increases the levels of interferon-γ(IFN-γ)and interleukin(IL)-2 protein,upregulating the levels of cytokines Ccl4,Ccl3,and IL-6 in the tumor tissue.Additionally,electroacupuncture enhanced the infiltration of CD8+T cells,dendritic cells,and M1-type macrophages at the tumor site,and reduced the proportion of Th17 and Treg cells.Furthermore,electroacupuncture remodels the bone marrow hematopoietic microenvironment after chemotherapy by increasing the number of bone marrow hematopoietic stem cell subsets,leukocytes,and subpopulations in the peripheral blood.PAC1 receptor agonists have similar effects to those of electroacupuncture on hematopoietic protection and tumor immunity after chemotherapy.Conclusions:Electroacupuncture may improve chemotherapy-induced bone marrow suppression,reshape the tumor microenvironment immune response affected by chemotherapy,and change the tumor immune microenvironment to an anti-tumor mode by regulating tumor local immune-related cytokines.The PAC1 receptor may be a drug target for the treatment of myelosuppression and immunosuppression in patients with tumors.展开更多
BACKGROUND Bone marrow transplantation(BMT)is a breakthrough procedure for patients with hematological and oncological conditions,particularly when all other treat-ments fail.Its indications vary between patients and ...BACKGROUND Bone marrow transplantation(BMT)is a breakthrough procedure for patients with hematological and oncological conditions,particularly when all other treat-ments fail.Its indications vary between patients and settings,and its outcomes depend on the donor type,transplantation facility,and center expertise.In coun-tries where transplantation facilities are lacking,sending patients abroad for transplantation might be a safe and effective alternative to leaving the patient to face eventual disease morbidity or even mortality if the procedure is not per-formed locally.However,studies evaluating BMT abroad are scarce.AIM To assess the clinical characteristics of patients who underwent BMT overseas and analyze the factors affecting their survival outcomes.METHODS We conducted a retrospective cohort study of all Bahraini pediatric patients who underwent BMT between 2013 and 2024.Medical records from Salmaniya Medical Complex and Overseas Treatment Office were reviewed.Patient demographics,RESULTS Of the 75 listed patients,62(82.7%)underwent BMT and were included,10(13.3%)did not,and 3(4.0%)were awaiting transplantation.Most patients were male(n=33,53.2%).The mean age at transplantation was 7.8±4.9 years.The main indication for treatment was acute myeloid leukemia(AML)(n=15,36.6%).Six patients(9.7%)required re-transplantation.Of the 68 transplants,60(88.2%)involved conditioning,mostly a combination of fludarabine and total body irradiation(n=7,11.7%).Most patients underwent allogeneic transplantation(n=48,77.4%),primarily from related donors(n=47/48,97.9%).The most common complication was infection(n=51,79.7%).Follow-up averaged 3.3±2.5 years.The overall survival rate was 77.4%.Survival odds were better for non-AML patients and Middle Eastern centers(P=0.015 and P=0.032,respectively).CONCLUSION Bahraini males with AML primarily underwent allogeneic BMT.Non-AML patients and those transplanted in the Middle East had better survival rates,despite high complication rates.展开更多
BACKGROUND Although limited clinical evidence exists,such as case reports of azoospermia treatment in humans using bone marrow aspirate concentrate(BMAC)injection,these findings provide a compelling foundation for exp...BACKGROUND Although limited clinical evidence exists,such as case reports of azoospermia treatment in humans using bone marrow aspirate concentrate(BMAC)injection,these findings provide a compelling foundation for exploring mesenchymal stem cell therapy in male infertility.AIM To evaluate the safety and efficacy of autologous BMAC injection into human testis for men with severe oligospermia or azoospermia over the existing standard of care pharmacotherapy and lifestyle modifications.METHODS We included patients diagnosed with male infertility of the age group between 35–45 years in this trial comparing BMAC injection therapy with pharmacotherapy and lifestyle modifications over a 6-month follow-up period.Semen analysis was used to evaluate the efficacy of the interventions analyzed.RESULTS We enrolled 30 patients in the trial with 10 patients in each arm of the trial.Compared to the baseline,neither the BMAC group(P=0.139)or pharmacotherapy group(P=0.056)nor the lifestyle modification group(P=0.112)demonstrated a statistically significant increase in sperm count at 6 months.However,the BMAC group demonstrated a significant increase in sperm count(mean 19.2 million;P=0.001)compared to the pharmacotherapy group(mean 3.5 million)and lifestyle modification group(mean 2.2 million)at 6 months.Significant improvement was noted in the motility grade(P<0.001)only in the BMAC group while no changes were noted in the other groups.CONCLUSION This trial highlights the potential of autologous BMAC as a promising therapeutic option for male infertility.Despite the absence of significant changes within individual treatment arms,BMAC therapy demonstrated superior efficacy in improving both sperm count and motility compared to standard pharmacotherapy and lifestyle modifications.These findings underscore the potential role of regenerative medicine in addressing severe oligospermia and azoospermia,warranting further research to solidify its clinical applicability.展开更多
BACKGROUND Knee osteoarthritis(OA)imposes a substantial burden through pain,functional limitation,and progressive cartilage loss.Bone marrow aspirate concentrate(BMAC)has emerged as a promising regenerative therapy fo...BACKGROUND Knee osteoarthritis(OA)imposes a substantial burden through pain,functional limitation,and progressive cartilage loss.Bone marrow aspirate concentrate(BMAC)has emerged as a promising regenerative therapy for OA due to its rich composition of mesenchymal stromal cells(MSCs)and bioactive factors.While intra-articular BMAC injections provide short-term symptomatic relief,recent literature suggests that targeting the subchondral bone—an area crucial to OA progression—may offer superior and longer-lasting clinical benefits.AIM To compares the outcomes of subchondral vs intra-articular BMAC injections in patients with primary knee OA.METHODS In this unicentric,double-blinded,randomized controlled trial,30 patients with radiologically confirmed primary knee OA(Kellgren-Lawrence grades II and III)will be equally randomized to receive either subchondral(Group A)or intra-articular(Group B)BMAC injections.BMAC will be harvested from the posterior iliac crest,processed using a standardized centrifugation protocol to yield a product with>85%cell viability,and administered under image guidance.The primary outcome is the change in pain intensity at 12 months as measured by the Visual Analog Scale(VAS).Secondary outcomes include functional improvement assessed by Knee Injury and Osteoarthritis Outcome Score(KOOS),International Knee Documentation Committee(IKDC),and Western Ontario and McMaster Universities Arthritis Index(WOMAC)scores,structural changes evaluated through advanced magnetic resonance imaging using(MRI)the whole-organ MRI Score,and safety as determined by the incidence of adverse events.RESULTS This study aims to evaluate pain reduction at 12 months post-injection,using the VAS as the primary outcome.Secondary outcomes include functional improvement(KOOS,WOMAC,IKDC),cartilage regeneration(T2 cartigram),adverse event incidence,patient satisfaction(standardized questionnaires,Likert scale),and quality of life(EQ-5D).Ethical considerations follow the Declaration of Helsinki and Good Clinical Practice,with institutional review board approval and participant informed consent ensured.Confidentiality and data security comply with regulations,and a data safety monitoring board oversees trial safety.Results will be shared via peer-reviewed journals,presentations at international orthopedic conferences,and detailed summaries for stakeholders and participants.The trial is registered under clinical trial registry of India/2024/04/065284.Findings emphasize patient-centered advancements in knee osteoarthritis management.CONCLUSION This trial aims to refine regenerative strategies for knee OA by comparing subchondral vs intra-articular BMAC injections,addressing long-term efficacy,safety,and treatment standardization to guide targeted interventions.This trial will provide critical insights into the comparative efficacy and safety of subchondral vs intra-articular BMAC injections in treating primary knee OA.展开更多
BACKGROUND Epilepsy is a prevalent chronic neurological disorder affecting 50 million individuals globally,with temporal lobe epilepsy(TLE)being the most common form.Despite advances in antiepileptic drug development,...BACKGROUND Epilepsy is a prevalent chronic neurological disorder affecting 50 million individuals globally,with temporal lobe epilepsy(TLE)being the most common form.Despite advances in antiepileptic drug development,over 30%of patients suffer from drug-resistant epilepsy,which can lead to severe cognitive impairments and adverse psychosocial outcomes.AIM To explore the role of bone marrow mesenchymal stem cell(BMSC)-derived exosomal miR-203 in the regulation of neuroinflammation in a mouse model of epilepsy,providing a theoretical basis for the development of targeted microRNA delivery therapies for drug-resistant epilepsy.METHODS Adult male C57BL/6 mice were divided into a control group and a TLE model of 30 mice each,and the TLE model group was established by injecting kainic acid.BMSCs were isolated from the mice,and exosomes were purified using ultracentrifugation.Exosomal miR-203 was identified and characterized using highthroughput sequencing and quantitative reverse-transcription polymerase chain reaction.The uptake of exosomes by hippocampal neurons and the subsequent effects on neuroinflammatory markers were assessed using in vitro cell culture models.RESULTS Exosomal miR-203 exhibited a significant upregulation in BMSCs derived from epileptic mice.In vitro investigations demonstrated the efficient internalization of these exosomes by hippocampal neurons,resulting in downregulation of suppressor of cytokine signaling 3 expression and activation of the nuclear factor kappaB pathway,ultimately leading to enhanced secretion of pro-inflammatory cytokines.CONCLUSION Our study identifies exosomal miR-203 as a key regulator of neuroinflammation in a mouse model of epilepsy.The findings suggest that targeting miR-203 may offer a novel therapeutic strategy for epilepsy by modulating the suppression of cytokine signaling 3/nuclear factor kappaB pathway,thus providing a potential avenue for the development of cell-free therapeutics.展开更多
BACKGROUND Pathological calcification is a common feature of many diseases.Calcifying nanoparticles(CNPs)are considered potential inducers of this abnormal calcification,but their specific effects on bone marrow mesen...BACKGROUND Pathological calcification is a common feature of many diseases.Calcifying nanoparticles(CNPs)are considered potential inducers of this abnormal calcification,but their specific effects on bone marrow mesenchymal stem cells(BMSCs)remain unclear.BMSCs are key cells in bone formation and repair,and their aberrant apoptosis and calcification are closely related to disease progression.AIM To explore whether CNPs can induce apoptosis and calcification in BMSCs and analyzed the relationship between these processes.The differential effects of CNPs and nanoscale hydroxyapatites(nHAPs)in inducing apoptosis and calcification in BMSCs were also compared.METHODS CNPs obtained in the early stage were identified by electron microscopy and particle size analysis.BMSCs were cultured with various treatments,including different concentrations of nHAPs,CNPs[2 McFarland(MCF)turbidity,4 MCF,6 MCF],and a transforming growth factor(TGF)-βinhibitor(SB431542)for 72 hours.The isolated CNPs exhibited the expected sizes and shapes.RESULTS Exposure to CNPs and nHAPs suppressed cell proliferation and promoted apoptosis in a concentration-dependent manner,with CNPs exhibiting significantly stronger effects.Alizarin Red staining indicated an increase in calcium deposition with exposure to increasing concentrations of nHAPs and CNPs.Quantitative reverse-transcription polymerase chain reaction results indicated that medium concentrations of nHAPs and CNPs significantly enhanced the expression of pro-apoptotic and pro-calcification markers,whereas the expression of anti-apoptotic Bcl-2 was reduced compared with untreated controls.Western blotting results showed that medium concentrations of CNPs and nHAPs increased the expression of osteopontin,bone morphogenetic protein-2,TGF-β/Smad,Bax,and caspase-3 and decreased Bcl-2 expression compared with controls.CONCLUSION CNPs and nHAPs induced apoptosis and calcification in BMSCs,with CNPs being the most potent.Additionally,the TGF-βinhibitor SB431542 significantly reduced the occurrence of apoptosis and calcification.A correlation was found between apoptosis and calcification,which is likely mediated through the TGF-β/Smad signaling pathway.展开更多
OBJECTIVE:To investigate the effect of Shisiwei Jianzhong decoction(十四味建中汤,SJD)on non-severe aplastic anemia(NSAA).METHODS:Bone marrow mesenchymal stem cells(BMSCs)were isolated from bone marrow samples of 15 NS...OBJECTIVE:To investigate the effect of Shisiwei Jianzhong decoction(十四味建中汤,SJD)on non-severe aplastic anemia(NSAA).METHODS:Bone marrow mesenchymal stem cells(BMSCs)were isolated from bone marrow samples of 15 NSAA patients and 3 healthy controls.Cells were treated with gradient concentrations of SJD,and a portion was transfected with a vector overexpressing the nuclear factor of activated T cells,cytoplasmic 4(NFATC4).Cell viability and apoptosis were detected by cell counting kit-8 and flow cytometry,respectively.After adipogenic differentiation induction,lipid droplet formation in BMSCs was examined by Oil Red O staining.The expression of NFATC4,peroxisome proliferator-activated receptor gamma(PPARG),fatty acid-binding protein 4(FABP4),peroxisome proliferator-activated receptor-gamma coactivator(PGC-1α),and acetylated PGC-1αwas measured by quantitative real-time polymerase chain reaction or Western blot.RESULTS:SJD significantly increased the viability and decreased the apoptosis of NSAA-derived BMSCs.It also dose-dependently inhibited lipid droplet formation and decreased the expression of PPARG and FABP4 in NSAA-derived BMSCs.NFATC4 expression was higher in patients with NSAA than in healthy controls,and SJD downregulated its expression.NFATC4 overexpression reversed the inhibitory effect of SJD on adipogenic differentiation.Additionally,SJD promoted the deacetylation of PGC-1αin NSAA-derived BMSCs,which was also partially eliminated by NFATC4 overexpression.CONCLUSIONS:SJD inhibits adipogenic differentiation of BMSCs through downregulating NFATC4,thereby contributing to the remission of NSAA.展开更多
Background:Primary bone marrow diffuse large B-cell lymphoma(PBM-DLBCL)represents an uncommon yet clinically aggressive hematologic malignancy.Despite its significant clinical impact,this entity lacks standardized dia...Background:Primary bone marrow diffuse large B-cell lymphoma(PBM-DLBCL)represents an uncommon yet clinically aggressive hematologic malignancy.Despite its significant clinical impact,this entity lacks standardized diagnostic criteria in current WHO classifications.Methods:We performed a retrospective analysis of 55 PBM-DLBCL cases from our institutional database and published literature(2001–2022)to characterize disease features and identify prognostic factors,with particular focus on assessing how different treatment regimens influence therapeutic efficacy and long-term outcomes.Results:The data suggested a potential link between international prognostic index(IPI)scores and poorer survival,albeit without conclusive statistical evidence(p 0.05).Treatment=response emerged as a significant prognostic factor,and patients with complete response(CR)demonstrating superior survival in Cox univariate and multivariate analysis(p 0.001).Intensive therapeutic regimens were associated with<improved clinical outcomes compared to conventional therapies.While incorporating rituximab into conventional chemotherapy regimens has demonstrated superior clinical outcomes compared to chemotherapy alone in PBM-DLBCL patients.Conclusion:Our findings highlight the aggressive nature of PBM-DLBCL and underscore the importance of early recognition,risk stratification,and optimized treatment selection for this rare disease entity.展开更多
Tumor-associated neutrophils(TANs)exhibit highly func-tional heterogeneity across cancers.Although TANs pro-mote inflammatory responses and contribute to tumor clearance,they frequently undergo context-dependent repro...Tumor-associated neutrophils(TANs)exhibit highly func-tional heterogeneity across cancers.Although TANs pro-mote inflammatory responses and contribute to tumor clearance,they frequently undergo context-dependent reprogramming within the tumor microenvironment(TME)into highly immunosuppressive phenotypes that facilitate cancer dissemination and immunotherapy resist-ance1,2.We contend that an underappreciated,upstream determinant of this divergence is the maturation stage of TANs3,4.The developmental stage of TANs determines the migration patterns and constrains the functional capacity,and the developmental stage also constrains the extent of TME-driven re-education,together shaping pro-or anti-tu-mor outcomes3-5.In this Perspective,we place maturation at the core of TAN biology and discuss current definitions for TAN developmental stages and the measurable mark-ers that researchers and clinicians can use(Figure 1).In addition,spatial and temporal transitions in TAN matu-ration stages and the factors that govern these transitions are elucidated.We explain how maturation status shapes TAN function and articulate the key differences between mouse and human TAN maturation systems to highlight the value of human immune system(HIS)mouse models.Based on this framework,functional biomarkers and signa-tures of TAN maturation are introduced and we show how to embed them into patient stratification and longitudinal monitoring.Finally,we outline immunotherapy strategies targeting TAN maturation,selecting interventions guided by maturation markers to reinforce treatment benefits for cancer patients.展开更多
<strong>Introduction:</strong> Bone marrow aspiration and biopsies are carried out principally to permit cytological assessment of marrow. The procedure is also indicated for immunophenotypic, cytogenetic,...<strong>Introduction:</strong> Bone marrow aspiration and biopsies are carried out principally to permit cytological assessment of marrow. The procedure is also indicated for immunophenotypic, cytogenetic, molecular and other specialized investigations. The skill to perform bone marrow aspirate and biopsy is usually acquired by the medical personnel through apprenticeship during their training. The training includes performing the procedure, indications, contraindications, and associated hazards. Moi Teaching and Referral Hospital (MTRH) being a specialized Hospital in Western Kenya has several staff trained on performing the procedure. <strong>Objective:</strong> To assess the performance of bone marrow procedure by clinicians at a teaching and referral hospital. <strong>Materials and </strong><strong>methods: </strong>A descriptive cross-sectional study was done involving 40 clinicians working in the hematology clinic and medical wards from June to December 2019. A structured questionnaire was used to collect the data and data analysis was done using frequency tables. Approval to carry out the study was sought from the institutional IRB. <strong>Results:</strong> Patients attended to were predominantly adults 33 (83%). The superior posterior iliac crest was the commonest site for the procedure and disposable needles were routinely used in 33 (83%) of the patients. Pain and excessive bleeding 18 (45%) were the commonest complications associated with the procedure. <strong>Conclusion:</strong> Most of the clinicians involved doing the procedure were residents/registrars. Most of the patients attended to were adults (83%) and majority of the clinicians performed the procedure on the posterior iliac site (96%) using disposable needles (83%). Local anesthesia was commonly used during the procedure (88%). The common complications associated with the bone marrow procedure were pain and excessive bleeding (45%).展开更多
Nerve guidance conduits(NGCs)effectively support and guide the regeneration of injured nerves.However,traditional NGCs often lack essential growth factors and fail to create a biomimetic microenvironment conducive to ...Nerve guidance conduits(NGCs)effectively support and guide the regeneration of injured nerves.However,traditional NGCs often lack essential growth factors and fail to create a biomimetic microenvironment conducive to nerve regrowth.This study develops a highly bionic nerve guidance conduit(HB-NGC)using hybrid high-voltage electrotechnologies that integrate electrospinning with electrohydrodynamic(EHD)printing.The outer layer consists of electrospun polycaprolactone fibers loaded with carboxyl-multi-walled carbon nanotubes,while the inner layer is composed of highly aligned polycaprolactone fibers created by EHD printing.The tubular core of the HB-NGC is filled with hyaluronic acid methacryloyl(HAMA)hydrogel encapsulating bone marrow mesenchymal stem cells(BMSCs).This highly biomimetic NGC is conductive,capable of guiding axon growth,and sustainably releases growth factors,effectively mimicking the structure,function,and characteristics of natural peripheral nerves.Its distinctive architectural layers provide an exceptional bionic microenvironment by restoring physical pathways,facilitating electrical signal conduction,and supplying an extracellular matrix(ECM)environment enriched with essential growth factors.Additionally,the HB-NGC’s morphology,along with its physicochemical and mechanical properties,effectively bridges the gap between severed nerve ends.In vivo animal studies validate the HB-NGC’s effectiveness,highlighting its significant potential to enhance peripheral nerve regeneration.展开更多
基金financially supported by the Guangzhou National Laboratory(grant#GZNL2025C02022,A.M.#QNPG2317,J.Z.)partially by the National Natural Science Foundation of China(31988101)。
文摘The bone marrow microenvironment is critical for the maintenance and functionality of stem/progenitor cells,which are essential for bone development and regeneration.However,the composition and potential use of bone marrow interstitial fluid have not been well explored.In this study,we report the role of neonatal bovine bone marrow interstitial fluid(NBIF)in enhancing the bone regeneration capacity of human bone marrow mesenchymal stem cells(hBMSCs).Unlike adult bovine bone marrow interstitial fluid(ABIF),NBIF-fed hBMSCs exhibit enhanced self-renewal and osteogenic potential and bone marrow homing ability,along with transcriptome changes as compared to hBMSCs cultured in standard fetal bovine serum(FBS)supplemented medium.Mass spectrometry analysis reveals that multiple secreted factors associated with tissue repair and bone development are enriched in NBIF compared to FBS and ABIF.The combined use of NBIF-enriched Nerve Growth Factor(NGF),Lactoferrin(LTF),and High Mobility Group Protein B1(HMGB1),together with Insulin-Like Growth Factor 1(IGF1)for culturing hBMSCs in the presence of FBS can enhance osteogenic potential and bone marrow homing ability,mimicking NBIF's effects.These findings highlight the role of interstitial fluid in the bone marrow microenvironment and its potential to optimize stem cell-based therapies.
基金Supported by the Research Project for Clinical Research on Precision Diagnosis and Innovative Treatment of Bone Marrow Failure,No.2024YFC2510500Jiangsu Provincial Traditional Chinese Medicine Science and Technology Development Plan,No.YB2020102Nantong Municipal Health Commission Research Project,No.QN2023007.
文摘BACKGROUND Thrombotic microangiopathy(TMA)is an acute syndrome characterized by microangiopathic hemolytic anemia,thrombocytopenia,and multi-organ dysfunction due to the microcirculation of platelet thrombi.Cancer-associated TMA is a rare and fatal complication,which often occurs during cancer remission.It is frequently misdiagnosed because of limited clinical awareness.CASE SUMMARY A middle-aged female patient presented to our clinic with a 15-days history of back pain,15 months post-gastrectomy.Cancer-associated TMA was confirmed through bone marrow aspiration,biopsy,and imaging.The patient received intermittent transfusions,fluids,nutrition,and microcirculation therapy with partial coagulation improvement.The family refused intensive care unit admission and plasma exchange,preferring palliative care.The patient died of cerebral hemorrhage and herniation due to disease progression.This case indicates that TMA may serve as an early manifestation of various malignancies,particularly gastric cancer.However,it is often misdiagnosed.Its pathogenesis is not well understood and needs to be further investigated.Currently,no standardized treatment have been developed.Plasma exchange is the only intervention available,though other therapies may also be effective.CONCLUSION In this case of gastric signet-ring cell carcinoma complicated by TMA,the patient achieved transient remission with supportive care but died following treatment discontinuation.Further studies are needed to elucidate the pathological mechanisms and therapeutic strategies for cancer-associated TMA.
文摘BACKGROUND Knee osteoarthritis(OA)is a degenerative joint disease traditionally viewed through the lens of cartilage degradation.However,emerging evidence positions subchondral bone pathology-particularly bone marrow lesions(BMLs)-as a key contributor to pain,progression,and structural deterioration.Mesenchymal stem cell exhaustion within the osteoarthritic subchondral zone further impairs intrinsic repair mechanisms,reinforcing the rationale for biologic interventions.AIM To evaluate the clinical efficacy of bone marrow aspirate concentrate(BMAC)therapy for knee OA,comparing subchondral vs intra-articular delivery routes,and elucidating the therapeutic impact on symptom relief and structural preservation.METHODS Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines,five clinical studies were included-comprising three randomized controlled trials and two prospective cohorts-with pooled data from 298 knees.Data on functional outcomes,imaging findings,and progression to total knee arthroplasty(TKA)were extracted and qualitatively synthesized.RESULTS Subchondral BMAC injections demonstrated superior improvements compared to intra-articular injection or placebo:Knee Injury and Osteoarthritis Outcome Score improved from 49.1±1.9 to 61.2±6.3 at 12 months(P<0.05),Knee Society Score increased from 57±12 to 87.3±12 at two years,and Western Ontario and McMaster Universities Arthritis Index scores showed significant improvement favoring combined approaches.Magnetic resonance imaging analyses revealed mean BML volume regression of 2.1 cm3,with 80%of knees avoiding TKA over 13-year follow-up.Magnetic resonance imaging analyses revealed regression of BMLs and increased cartilage preservation in subchondral-treated knees.Long-term data indicated delayed progression to TKA and biomechanical improvements(e.g.,Hip-Knee-Ankle angle correction).No major adverse events were reported.CONCLUSION Targeting subchondral bone with BMAC addresses underlying OA pathology and may offer disease-modifying potential beyond symptom relief.These findings support a paradigm shift toward whole-joint biologic therapy,positioning the subchondral matrix as a therapeutic epicenter in OA management.
基金supported by the Nature Science Foundation of Zhejiang Province(grant no.LD22C060002)National Science Foundation of China(grant no.82274547,82474240)+2 种基金Zhejiang Provincial Medical and Health Science and Technology Fund(grant no.2024KY1223)Research Project of Zhejiang Chinese Medical University(grant no.2023JKZKTS34)Project of Chunyan Special Fund for Chinese Medicine Development of Zhejiang Chinese Medical University(grant no.CY202305)。
文摘Bone marrow lesions(BML)are early signs of osteoarthritis(OA)and are strongly correlated with the deterioration of cartilage lesions.Single-cell RNA sequencing(scRNA-seq)analyses were performed on BM from non-BML and BML areas and articular cartilage from intact and damaged areas to explore BML landscape and BML-cartilage crosstalk.We revealed the immune landscape of BM in non-BML and BML,and the transition to pro-inflammatory states of clusters in BMLs,such as classical monocytes and nonclassical monocytes.Non-classical monocytes have high inflammation,OA gene signatures,and senescence scores,and are potential primary clusters promoting OA progression.Histological signs of OA related to the cellular landscape in damaged cartilage were identified,including PreFC exhaustion.The BM-cartilage crosstalk at the cell-cell interaction(CCIs)level and the TNF signal transmitted by non-classical monocytes are the critical CCIs in BML-induced cartilage damage,and PreFC is one of the primary receivers of the signal.We further validated the higher senescence level of non-classical monocyte and FC-2 in OA mice,compared with classical monocyte and PreFC,respectively.Transcription factor 7 like 2(TCF7L2)was identified as a shared transcription factor in the senescence of monocytes and chondrocytes,facilitating the development of the senescence-associated secretory phenotype(SASP).Therefore,senescent non-classical monocytes promote BMLs and inflammation and senescence of chondrocytes by modulating BML–cartilage crosstalk in OA,with TCF7L2 serving as a regulator.
基金supported by NIH grants NIH/NIA R01AG069401(to L.Q.)NIH/NHLBI U54HL165442(to K.T.)P30AR069619(to Penn Center for Musculoskeletal Disorders).
文摘Bone resorption by osteoclasts is a critical step in bone remodeling,a process important for maintaining bone homeostasis and repairing injured bone.We previously identified a bone marrow mesenchymal subpopulation,marrow adipogenic lineage precursors(MALPs),and showed that its production of RANKL stimulates bone resorption in young mice using Adipoq-Cre.To exclude developmental defects and to investigate the role of MALPs-derived RANKL in adult bone,we generated inducible reporter mice(Adipoq-CreER Tomato)and RANKL deficient mice(Adipoq-CreER RANKLflox/flox,iCKO).Single cell-RNA sequencing data analysis and lineage tracing revealed that Adipoq+cells contain not only MALPs but also some mesenchymal progenitors capable of osteogenic differentiation.In situ hybridization showed that RANKL mRNA is only detected in MALPs,but not in osteogenic cells.RANKL deficiency in MALPs induced at 3 months of age rapidly increased trabecular bone mass in long bones as well as vertebrae due to diminished bone resorption but had no effect on the cortical bone.Ovariectomy(OVX)induced trabecular bone loss at both sites.RANKL depletion either before OVX or at 6 weeks post OVX protected and restored trabecular bone mass.Furthermore,bone healing after drill-hole injury was delayed in iCKO mice.Together,our findings demonstrate that MALPs play a dominant role in controlling trabecular bone resorption and that RANKL from MALPs is essential for trabecular bone turnover in adult bone homeostasis,postmenopausal bone loss,and injury repair.
基金supported by the Natural Science Fund of Fujian Province,No.2020J011058(to JK)the Project of Fujian Provincial Hospital for High-level Hospital Construction,No.2020HSJJ12(to JK)+1 种基金the Fujian Provincial Finance Department Special Fund,No.(2021)848(to FC)the Fujian Provincial Major Scientific and Technological Special Projects on Health,No.2022ZD01008(to FC).
文摘Cardiac arrest can lead to severe neurological impairment as a result of inflammation,mitochondrial dysfunction,and post-cardiopulmonary resuscitation neurological damage.Hypoxic preconditioning has been shown to improve migration and survival of bone marrow–derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest,but the specific mechanisms by which hypoxia-preconditioned bone marrow–derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown.To this end,we established an in vitro co-culture model of bone marrow–derived mesenchymal stem cells and oxygen–glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis,possibly through inhibition of the MAPK and nuclear factor κB pathways.Subsequently,we transplanted hypoxia-preconditioned bone marrow–derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia.The results showed that hypoxia-preconditioned bone marrow–derived mesenchymal stem cells significantly reduced cardiac arrest–induced neuronal pyroptosis,oxidative stress,and mitochondrial damage,whereas knockdown of the liver isoform of phosphofructokinase in bone marrow–derived mesenchymal stem cells inhibited these effects.To conclude,hypoxia-preconditioned bone marrow–derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest,and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.
文摘Knee osteoarthritis(OA)is a debilitating condition with limited long-term treatment options.The therapeutic potential of mesenchymal stem cells(MSCs),particularly those derived from bone marrow aspirate concentrate,has garnered attention for cartilage repair in OA.While the iliac crest is the traditional site for bone marrow harvesting(BMH),associated morbidity has prompted the exploration of alternative sites such as the proximal tibia,distal femur,and proximal humerus.This paper reviews the impact of different harvesting sites on mesenchymal stem cell(MSC)yield,viability,and regenerative potential,emphasizing their relevance in knee OA treatment.The iliac crest consistently offers the highest MSC yield,but alternative sites within the surgical field of knee procedures offer comparable MSC characteristics with reduced morbidity.The integration of harvesting techniques into existing knee surgeries,such as total knee arthroplasty,provides a less invasive approach while maintaining thera-peutic efficacy.However,variability in MSC yield from these alternative sites underscores the need for further research to standardize techniques and optimize clinical outcomes.Future directions include large-scale comparative studies,advanced characterization of MSCs,and the development of personalized harvesting strategies.Ultimately,the findings suggest that optimizing the site of BMH can significantly influence the quality of MSC-based therapies for knee OA,enhancing their clinical utility and patient outcomes.
文摘目的探讨双能量CT Bone Marrow Edema(骨髓水肿)定量评估肋骨骨折演变时间节点的价值。方法收集60例双能量CT扫描的胸部外伤患者,利用CT Bone Marrow Edema技术,标准化定量肋骨骨折处骨髓水肿区域及骨折两侧1 cm处正常区域骨髓CT值,得到三期骨髓水肿标准化CT值增量与VNCa标准化CT值增量。对数值变量行统计学描述,并对三期骨髓水肿标准化CT值增量、VNCa标准化CT值增量进行各自组间比较及两两间比较,对有差异的组别行诊断效能比较,由接受者工作特征(ROC)曲线下面积(AUC)进行评估,并计算Cut-off值。结果三期骨髓水肿标准化CT值增量及VNCa标准化CT值增量组间均有统计学意义(H=10.788,p=0.005;F=115.787,p=0.000),其中,软骨痂期(纤维性骨痂期)与硬骨痂-重塑期骨髓水肿标准化CT值增量有统计学意义(H=54.958,p=0.003),其余两两间无统计学意义(分别为H=-25.603,p=0.183;H=29.354,p=0.113)。而三期VNCa标准化CT值增量两两间均有统计学意义(P均为0.000)。ROC曲线鉴别软骨痂期(纤维性骨痂期)与硬骨痂-重塑期骨髓水肿标准化CT值增量曲线下面积为0.652,Cut-off值为81.575 Hu,鉴别血肿炎症机化期与软骨痂期(纤维性骨痂期)VNCa标准化CT值增量曲线下面积为0.668,Cut-off值为55.700 Hu,鉴别软骨痂期(纤维性骨痂期)与硬骨痂-重塑期VNCa标准化CT值增量曲线下面积为0.905,Cut-off值为37.625 Hu。结论通过双能量CT Bone Marrow Edema可定量评估肋骨骨折演变时间节点,骨折时间演变的标准化CT值增量差异性可为法医鉴定骨折处于不同时间段提供理论依据。通过标准化CT值增量Cut-off值可一定程度上预测骨折所处时间阶段,为法医在鉴定肋骨骨折方面提供定量依据。
文摘Bone marrow edema syndrome (BMES), is a rare and self-limiting condition characterized by localized bone pain and transient marrow edema visible on MRI. BMES has been increasingly associated with specific cutaneous manifestations that may hold diagnostic and prognostic significance. Patients with BMES have reported localized erythema, dermal thickening, and induration overlying the affected joints, which are hypothesized to reflect microvascular compromise and inflammatory processes within the bone and adjacent soft tissues. Dermatologic signs are likely linked to regional hyperemia, venous stasis, and cytokine-mediated inflammation, paralleling the pathophysiological mechanisms underlying intraosseous edema. Elevated intraosseous pressure in BMES may disrupt local perfusion, resulting in ischemia-reperfusion injury and subsequent vascular leakage, which manifests in visible cutaneous changes. Pro-inflammatory mediators, such as interleukin-1β and vascular endothelial growth factor (VEGF), central to BMES pathogenesis, may exacerbate endothelial activation, and dermal involvement. Histopathologic studies of affected skin have revealed perivascular lymphocytic infiltration and increased dermal vascularity, further supporting the theory of a shared ischemic and inflammatory pathway between bone and skin. Although MRI remains the gold standard for BMES diagnosis, recognition of these cutaneous manifestations could expedite orthopedic referral and intervention, especially in cases where imaging is delayed or symptoms are ambiguous. Current treatment options, including bisphosphonates, prostacyclin analogs, and offloading of weight bearing, may benefit from integration with dermatologic strategies to alleviate localized cutaneous symptoms and improve patient comfort. Evaluating the molecular and vascular links between BMES and its cutaneous manifestations provides an opportunity to refine diagnostic protocols and therapeutic approaches, offering a comprehensive understanding of the systemic interplay between dermal and skeletal pathophysiology, and optimizing clinical outcomes for patients affected by BMES.
基金supported by the National Key Research and Development Program of China(2022YFC3500404)the Natural Science Foundation of China(NSFC)(81704146,82205310)+1 种基金the Research Program Project of Tianjin Education Commission(2021KJ120)the National College Student Innovation and Entrepreneurship Training Program(202410063009)。
文摘Objective:The effectiveness of chemotherapy is affected by tumor heterogeneity and drug resistance mechanisms;however,there are certain limitations.Electroacupuncture can regulate the tumor immune response and restore bone marrow hematopoietic function,which is affected by chemotherapy.This study investigated the efficacy and mechanism of electroacupuncture combined with cisplatin in the treatment of non-small-cell lung cancer mice.Methods:To establish a mouse model of non-small-cell lung cancer,gene sequencing combined with bioinformatics analysis,flow cytometry,and liquid-phase chips was used to observe the expression of immune cells and related factors in the mouse tumor microenvironment.Flow cytometry was used to observe subpopulations of mouse bone marrow hematopoietic stem cells and progenitor cells.PAC1 receptor agonists were used to observe mouse tumor immunity and bone marrow hematopoiesis-related indicators.Results:The combination of electroacupuncture with high-and low-dose chemotherapy had a better tumor-suppressive effect.Electroacupuncture can affect the gene expression profile of immune cells,especially the expression levels of Ccr1,Cxcr5,Zbp1,and CamkIIα,and increases the levels of interferon-γ(IFN-γ)and interleukin(IL)-2 protein,upregulating the levels of cytokines Ccl4,Ccl3,and IL-6 in the tumor tissue.Additionally,electroacupuncture enhanced the infiltration of CD8+T cells,dendritic cells,and M1-type macrophages at the tumor site,and reduced the proportion of Th17 and Treg cells.Furthermore,electroacupuncture remodels the bone marrow hematopoietic microenvironment after chemotherapy by increasing the number of bone marrow hematopoietic stem cell subsets,leukocytes,and subpopulations in the peripheral blood.PAC1 receptor agonists have similar effects to those of electroacupuncture on hematopoietic protection and tumor immunity after chemotherapy.Conclusions:Electroacupuncture may improve chemotherapy-induced bone marrow suppression,reshape the tumor microenvironment immune response affected by chemotherapy,and change the tumor immune microenvironment to an anti-tumor mode by regulating tumor local immune-related cytokines.The PAC1 receptor may be a drug target for the treatment of myelosuppression and immunosuppression in patients with tumors.
文摘BACKGROUND Bone marrow transplantation(BMT)is a breakthrough procedure for patients with hematological and oncological conditions,particularly when all other treat-ments fail.Its indications vary between patients and settings,and its outcomes depend on the donor type,transplantation facility,and center expertise.In coun-tries where transplantation facilities are lacking,sending patients abroad for transplantation might be a safe and effective alternative to leaving the patient to face eventual disease morbidity or even mortality if the procedure is not per-formed locally.However,studies evaluating BMT abroad are scarce.AIM To assess the clinical characteristics of patients who underwent BMT overseas and analyze the factors affecting their survival outcomes.METHODS We conducted a retrospective cohort study of all Bahraini pediatric patients who underwent BMT between 2013 and 2024.Medical records from Salmaniya Medical Complex and Overseas Treatment Office were reviewed.Patient demographics,RESULTS Of the 75 listed patients,62(82.7%)underwent BMT and were included,10(13.3%)did not,and 3(4.0%)were awaiting transplantation.Most patients were male(n=33,53.2%).The mean age at transplantation was 7.8±4.9 years.The main indication for treatment was acute myeloid leukemia(AML)(n=15,36.6%).Six patients(9.7%)required re-transplantation.Of the 68 transplants,60(88.2%)involved conditioning,mostly a combination of fludarabine and total body irradiation(n=7,11.7%).Most patients underwent allogeneic transplantation(n=48,77.4%),primarily from related donors(n=47/48,97.9%).The most common complication was infection(n=51,79.7%).Follow-up averaged 3.3±2.5 years.The overall survival rate was 77.4%.Survival odds were better for non-AML patients and Middle Eastern centers(P=0.015 and P=0.032,respectively).CONCLUSION Bahraini males with AML primarily underwent allogeneic BMT.Non-AML patients and those transplanted in the Middle East had better survival rates,despite high complication rates.
文摘BACKGROUND Although limited clinical evidence exists,such as case reports of azoospermia treatment in humans using bone marrow aspirate concentrate(BMAC)injection,these findings provide a compelling foundation for exploring mesenchymal stem cell therapy in male infertility.AIM To evaluate the safety and efficacy of autologous BMAC injection into human testis for men with severe oligospermia or azoospermia over the existing standard of care pharmacotherapy and lifestyle modifications.METHODS We included patients diagnosed with male infertility of the age group between 35–45 years in this trial comparing BMAC injection therapy with pharmacotherapy and lifestyle modifications over a 6-month follow-up period.Semen analysis was used to evaluate the efficacy of the interventions analyzed.RESULTS We enrolled 30 patients in the trial with 10 patients in each arm of the trial.Compared to the baseline,neither the BMAC group(P=0.139)or pharmacotherapy group(P=0.056)nor the lifestyle modification group(P=0.112)demonstrated a statistically significant increase in sperm count at 6 months.However,the BMAC group demonstrated a significant increase in sperm count(mean 19.2 million;P=0.001)compared to the pharmacotherapy group(mean 3.5 million)and lifestyle modification group(mean 2.2 million)at 6 months.Significant improvement was noted in the motility grade(P<0.001)only in the BMAC group while no changes were noted in the other groups.CONCLUSION This trial highlights the potential of autologous BMAC as a promising therapeutic option for male infertility.Despite the absence of significant changes within individual treatment arms,BMAC therapy demonstrated superior efficacy in improving both sperm count and motility compared to standard pharmacotherapy and lifestyle modifications.These findings underscore the potential role of regenerative medicine in addressing severe oligospermia and azoospermia,warranting further research to solidify its clinical applicability.
文摘BACKGROUND Knee osteoarthritis(OA)imposes a substantial burden through pain,functional limitation,and progressive cartilage loss.Bone marrow aspirate concentrate(BMAC)has emerged as a promising regenerative therapy for OA due to its rich composition of mesenchymal stromal cells(MSCs)and bioactive factors.While intra-articular BMAC injections provide short-term symptomatic relief,recent literature suggests that targeting the subchondral bone—an area crucial to OA progression—may offer superior and longer-lasting clinical benefits.AIM To compares the outcomes of subchondral vs intra-articular BMAC injections in patients with primary knee OA.METHODS In this unicentric,double-blinded,randomized controlled trial,30 patients with radiologically confirmed primary knee OA(Kellgren-Lawrence grades II and III)will be equally randomized to receive either subchondral(Group A)or intra-articular(Group B)BMAC injections.BMAC will be harvested from the posterior iliac crest,processed using a standardized centrifugation protocol to yield a product with>85%cell viability,and administered under image guidance.The primary outcome is the change in pain intensity at 12 months as measured by the Visual Analog Scale(VAS).Secondary outcomes include functional improvement assessed by Knee Injury and Osteoarthritis Outcome Score(KOOS),International Knee Documentation Committee(IKDC),and Western Ontario and McMaster Universities Arthritis Index(WOMAC)scores,structural changes evaluated through advanced magnetic resonance imaging using(MRI)the whole-organ MRI Score,and safety as determined by the incidence of adverse events.RESULTS This study aims to evaluate pain reduction at 12 months post-injection,using the VAS as the primary outcome.Secondary outcomes include functional improvement(KOOS,WOMAC,IKDC),cartilage regeneration(T2 cartigram),adverse event incidence,patient satisfaction(standardized questionnaires,Likert scale),and quality of life(EQ-5D).Ethical considerations follow the Declaration of Helsinki and Good Clinical Practice,with institutional review board approval and participant informed consent ensured.Confidentiality and data security comply with regulations,and a data safety monitoring board oversees trial safety.Results will be shared via peer-reviewed journals,presentations at international orthopedic conferences,and detailed summaries for stakeholders and participants.The trial is registered under clinical trial registry of India/2024/04/065284.Findings emphasize patient-centered advancements in knee osteoarthritis management.CONCLUSION This trial aims to refine regenerative strategies for knee OA by comparing subchondral vs intra-articular BMAC injections,addressing long-term efficacy,safety,and treatment standardization to guide targeted interventions.This trial will provide critical insights into the comparative efficacy and safety of subchondral vs intra-articular BMAC injections in treating primary knee OA.
文摘BACKGROUND Epilepsy is a prevalent chronic neurological disorder affecting 50 million individuals globally,with temporal lobe epilepsy(TLE)being the most common form.Despite advances in antiepileptic drug development,over 30%of patients suffer from drug-resistant epilepsy,which can lead to severe cognitive impairments and adverse psychosocial outcomes.AIM To explore the role of bone marrow mesenchymal stem cell(BMSC)-derived exosomal miR-203 in the regulation of neuroinflammation in a mouse model of epilepsy,providing a theoretical basis for the development of targeted microRNA delivery therapies for drug-resistant epilepsy.METHODS Adult male C57BL/6 mice were divided into a control group and a TLE model of 30 mice each,and the TLE model group was established by injecting kainic acid.BMSCs were isolated from the mice,and exosomes were purified using ultracentrifugation.Exosomal miR-203 was identified and characterized using highthroughput sequencing and quantitative reverse-transcription polymerase chain reaction.The uptake of exosomes by hippocampal neurons and the subsequent effects on neuroinflammatory markers were assessed using in vitro cell culture models.RESULTS Exosomal miR-203 exhibited a significant upregulation in BMSCs derived from epileptic mice.In vitro investigations demonstrated the efficient internalization of these exosomes by hippocampal neurons,resulting in downregulation of suppressor of cytokine signaling 3 expression and activation of the nuclear factor kappaB pathway,ultimately leading to enhanced secretion of pro-inflammatory cytokines.CONCLUSION Our study identifies exosomal miR-203 as a key regulator of neuroinflammation in a mouse model of epilepsy.The findings suggest that targeting miR-203 may offer a novel therapeutic strategy for epilepsy by modulating the suppression of cytokine signaling 3/nuclear factor kappaB pathway,thus providing a potential avenue for the development of cell-free therapeutics.
基金Supported by the Project of Xinjiang Production and Construction Corps,No.2022ZD090the Project of Xinjiang Production and Construction Corps-Young Science and Technology Innovation Talents,No.2023CB008-31+2 种基金The First Affiliated Hospital of Shihezi University Medical College,Doctoral Fund Project,No.BS202207Talent Development Fund-Tianshan Talents,No.CZ0012192024 National Health Commission Central Asian High-Incidence Prevention and Control Key Laboratory,No.KF202405.
文摘BACKGROUND Pathological calcification is a common feature of many diseases.Calcifying nanoparticles(CNPs)are considered potential inducers of this abnormal calcification,but their specific effects on bone marrow mesenchymal stem cells(BMSCs)remain unclear.BMSCs are key cells in bone formation and repair,and their aberrant apoptosis and calcification are closely related to disease progression.AIM To explore whether CNPs can induce apoptosis and calcification in BMSCs and analyzed the relationship between these processes.The differential effects of CNPs and nanoscale hydroxyapatites(nHAPs)in inducing apoptosis and calcification in BMSCs were also compared.METHODS CNPs obtained in the early stage were identified by electron microscopy and particle size analysis.BMSCs were cultured with various treatments,including different concentrations of nHAPs,CNPs[2 McFarland(MCF)turbidity,4 MCF,6 MCF],and a transforming growth factor(TGF)-βinhibitor(SB431542)for 72 hours.The isolated CNPs exhibited the expected sizes and shapes.RESULTS Exposure to CNPs and nHAPs suppressed cell proliferation and promoted apoptosis in a concentration-dependent manner,with CNPs exhibiting significantly stronger effects.Alizarin Red staining indicated an increase in calcium deposition with exposure to increasing concentrations of nHAPs and CNPs.Quantitative reverse-transcription polymerase chain reaction results indicated that medium concentrations of nHAPs and CNPs significantly enhanced the expression of pro-apoptotic and pro-calcification markers,whereas the expression of anti-apoptotic Bcl-2 was reduced compared with untreated controls.Western blotting results showed that medium concentrations of CNPs and nHAPs increased the expression of osteopontin,bone morphogenetic protein-2,TGF-β/Smad,Bax,and caspase-3 and decreased Bcl-2 expression compared with controls.CONCLUSION CNPs and nHAPs induced apoptosis and calcification in BMSCs,with CNPs being the most potent.Additionally,the TGF-βinhibitor SB431542 significantly reduced the occurrence of apoptosis and calcification.A correlation was found between apoptosis and calcification,which is likely mediated through the TGF-β/Smad signaling pathway.
基金Supported by Zhejiang Province Traditional Chinese Medicine Science and Technology Plan Project:Research on the Mechanism of Shisiwei Jianzhong Decoction in Treating Non-severe Aplastic Anemia with Kidney Yang Deficiency Based on the C Vactivated T Nuclear Factor(NFATc4)(2020ZB086)Zhejiang Province Traditional Chinese Medicine Science and Technology Youth Talent Plan Project:Study on the Academic thought and Clinical Application of Professor Zhou Yuhong in the Treatment of Chronic Aplastic Anemia(2021ZQ029)。
文摘OBJECTIVE:To investigate the effect of Shisiwei Jianzhong decoction(十四味建中汤,SJD)on non-severe aplastic anemia(NSAA).METHODS:Bone marrow mesenchymal stem cells(BMSCs)were isolated from bone marrow samples of 15 NSAA patients and 3 healthy controls.Cells were treated with gradient concentrations of SJD,and a portion was transfected with a vector overexpressing the nuclear factor of activated T cells,cytoplasmic 4(NFATC4).Cell viability and apoptosis were detected by cell counting kit-8 and flow cytometry,respectively.After adipogenic differentiation induction,lipid droplet formation in BMSCs was examined by Oil Red O staining.The expression of NFATC4,peroxisome proliferator-activated receptor gamma(PPARG),fatty acid-binding protein 4(FABP4),peroxisome proliferator-activated receptor-gamma coactivator(PGC-1α),and acetylated PGC-1αwas measured by quantitative real-time polymerase chain reaction or Western blot.RESULTS:SJD significantly increased the viability and decreased the apoptosis of NSAA-derived BMSCs.It also dose-dependently inhibited lipid droplet formation and decreased the expression of PPARG and FABP4 in NSAA-derived BMSCs.NFATC4 expression was higher in patients with NSAA than in healthy controls,and SJD downregulated its expression.NFATC4 overexpression reversed the inhibitory effect of SJD on adipogenic differentiation.Additionally,SJD promoted the deacetylation of PGC-1αin NSAA-derived BMSCs,which was also partially eliminated by NFATC4 overexpression.CONCLUSIONS:SJD inhibits adipogenic differentiation of BMSCs through downregulating NFATC4,thereby contributing to the remission of NSAA.
基金supported by grants from the Jinling Hospital Affiliated to Medical School of Nanjing University(2023LCZLXB055).
文摘Background:Primary bone marrow diffuse large B-cell lymphoma(PBM-DLBCL)represents an uncommon yet clinically aggressive hematologic malignancy.Despite its significant clinical impact,this entity lacks standardized diagnostic criteria in current WHO classifications.Methods:We performed a retrospective analysis of 55 PBM-DLBCL cases from our institutional database and published literature(2001–2022)to characterize disease features and identify prognostic factors,with particular focus on assessing how different treatment regimens influence therapeutic efficacy and long-term outcomes.Results:The data suggested a potential link between international prognostic index(IPI)scores and poorer survival,albeit without conclusive statistical evidence(p 0.05).Treatment=response emerged as a significant prognostic factor,and patients with complete response(CR)demonstrating superior survival in Cox univariate and multivariate analysis(p 0.001).Intensive therapeutic regimens were associated with<improved clinical outcomes compared to conventional therapies.While incorporating rituximab into conventional chemotherapy regimens has demonstrated superior clinical outcomes compared to chemotherapy alone in PBM-DLBCL patients.Conclusion:Our findings highlight the aggressive nature of PBM-DLBCL and underscore the importance of early recognition,risk stratification,and optimized treatment selection for this rare disease entity.
基金funded by grants from the National Natural Science Foundation of China(Grant Nos.82373263 and 82403835)the National Key Research and Development Program of China(Grant No.2023YFC2506400)+2 种基金China Postdoctoral Science Foundation(Grant No.2024M751405)Jiangsu Provincial Natural Science Foundation Youth Project(Grant No.BK20240247)General Project of Nanjing Health Science and Technology Development Program(Grant No.YKK24084).
文摘Tumor-associated neutrophils(TANs)exhibit highly func-tional heterogeneity across cancers.Although TANs pro-mote inflammatory responses and contribute to tumor clearance,they frequently undergo context-dependent reprogramming within the tumor microenvironment(TME)into highly immunosuppressive phenotypes that facilitate cancer dissemination and immunotherapy resist-ance1,2.We contend that an underappreciated,upstream determinant of this divergence is the maturation stage of TANs3,4.The developmental stage of TANs determines the migration patterns and constrains the functional capacity,and the developmental stage also constrains the extent of TME-driven re-education,together shaping pro-or anti-tu-mor outcomes3-5.In this Perspective,we place maturation at the core of TAN biology and discuss current definitions for TAN developmental stages and the measurable mark-ers that researchers and clinicians can use(Figure 1).In addition,spatial and temporal transitions in TAN matu-ration stages and the factors that govern these transitions are elucidated.We explain how maturation status shapes TAN function and articulate the key differences between mouse and human TAN maturation systems to highlight the value of human immune system(HIS)mouse models.Based on this framework,functional biomarkers and signa-tures of TAN maturation are introduced and we show how to embed them into patient stratification and longitudinal monitoring.Finally,we outline immunotherapy strategies targeting TAN maturation,selecting interventions guided by maturation markers to reinforce treatment benefits for cancer patients.
文摘<strong>Introduction:</strong> Bone marrow aspiration and biopsies are carried out principally to permit cytological assessment of marrow. The procedure is also indicated for immunophenotypic, cytogenetic, molecular and other specialized investigations. The skill to perform bone marrow aspirate and biopsy is usually acquired by the medical personnel through apprenticeship during their training. The training includes performing the procedure, indications, contraindications, and associated hazards. Moi Teaching and Referral Hospital (MTRH) being a specialized Hospital in Western Kenya has several staff trained on performing the procedure. <strong>Objective:</strong> To assess the performance of bone marrow procedure by clinicians at a teaching and referral hospital. <strong>Materials and </strong><strong>methods: </strong>A descriptive cross-sectional study was done involving 40 clinicians working in the hematology clinic and medical wards from June to December 2019. A structured questionnaire was used to collect the data and data analysis was done using frequency tables. Approval to carry out the study was sought from the institutional IRB. <strong>Results:</strong> Patients attended to were predominantly adults 33 (83%). The superior posterior iliac crest was the commonest site for the procedure and disposable needles were routinely used in 33 (83%) of the patients. Pain and excessive bleeding 18 (45%) were the commonest complications associated with the procedure. <strong>Conclusion:</strong> Most of the clinicians involved doing the procedure were residents/registrars. Most of the patients attended to were adults (83%) and majority of the clinicians performed the procedure on the posterior iliac site (96%) using disposable needles (83%). Local anesthesia was commonly used during the procedure (88%). The common complications associated with the bone marrow procedure were pain and excessive bleeding (45%).
基金supported by the Natural Science Foundation of Hebei Province of China(Nos.H2020202002 and H2023202001)the Natural Science Foundation of Tianjin City of China(No.24JCQNJC01180)Science Research Project of Hebei Educational Department(No.BJK2023034).
文摘Nerve guidance conduits(NGCs)effectively support and guide the regeneration of injured nerves.However,traditional NGCs often lack essential growth factors and fail to create a biomimetic microenvironment conducive to nerve regrowth.This study develops a highly bionic nerve guidance conduit(HB-NGC)using hybrid high-voltage electrotechnologies that integrate electrospinning with electrohydrodynamic(EHD)printing.The outer layer consists of electrospun polycaprolactone fibers loaded with carboxyl-multi-walled carbon nanotubes,while the inner layer is composed of highly aligned polycaprolactone fibers created by EHD printing.The tubular core of the HB-NGC is filled with hyaluronic acid methacryloyl(HAMA)hydrogel encapsulating bone marrow mesenchymal stem cells(BMSCs).This highly biomimetic NGC is conductive,capable of guiding axon growth,and sustainably releases growth factors,effectively mimicking the structure,function,and characteristics of natural peripheral nerves.Its distinctive architectural layers provide an exceptional bionic microenvironment by restoring physical pathways,facilitating electrical signal conduction,and supplying an extracellular matrix(ECM)environment enriched with essential growth factors.Additionally,the HB-NGC’s morphology,along with its physicochemical and mechanical properties,effectively bridges the gap between severed nerve ends.In vivo animal studies validate the HB-NGC’s effectiveness,highlighting its significant potential to enhance peripheral nerve regeneration.
