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Leukemic cells modulate the bone marrow microenvironment to enhance their survival. Lipolysis in bone marrow adipose tissue (BMAT) has emerged as a critical factor supporting leukemic cell survival, yet understanding its primary role in leukemia development remains limited. Fanconi anemia (FA), characterized by a predisposition to acute myeloid leukemia (AML) and hypersensitivity to environmental toxins, is a transitional model for studying leukemic transformation. İntegrated multi-omics analyses were conducted on BMAT-derived mesenchymal stem/stromal cells (MSCs) from healthy donors (HD), AML, and FA patients. These analyses revealed intricate interactions among genes, metabolites, and lipids. Particularly noteworthy were the effects observed following the inhibition of aryl hydrocarbon receptor (AhR) signaling by StemRegenin1 (SR1). BMAT-MSCs showed increased expression of epithelial-mesenchymal transition (EMT) genes in FA and AML, suggesting a potential shift towards cancer-associated fibroblasts in the dysregulated marrow microenvironment. Identification of potential circadian rhythm biomarkers ( NPAS2 , PER2 , BHLHE40 , PER3 , CIART ) in BMAT-MSCs indicates a link between related lipid metabolism genes (e.g., PTGS1 , PIK3R1 ) and SR1 treatment, implicating them in lipolysis processes. Dysregulation of circadian rhythm-related genes ( CIART , BHLHE40 , NPAS2 ) in AML BMAT-MSCs, along with changes in circulating lipid metabolites like palmitate suggests their role in shaping the leukemia microenvironment. Upregulation of FABP5 and CD36 suggests a novel molecular mechanism involving FABP5 in AhR-mediated circadian regulation and identifies CD36 as a potential partner for FABP5 in BMAT-MSCs. Overall, this study unveils the interplay between AhR signaling, circadian rhythm, and the leukemia microenvironment in BMAT-MSCs, offering new insights into leukemia pathogenesis and therapeutic opportunities.

Strongyloidiasis is a helminth infection where symptoms vary, and asymptomatic presentation is common. Chronic strongyloidiasis can cause a high mortality ‘hyper-infection’ in immunocompromised states. Understanding at risk populations and symptomology can guide screening and early treatment to reduce hyper-infection risk. A systematic review of studies describing patients in the UK with strongyloidiasis pooled a total of 1,308 patients. Weighted pooled prevalence (WPP) of asymptomatic cases was 27.7% (95% CI 17.1–39.5%, I2 = 92%, p < 0.01). At-risk populations included migrants, returning travellers and armed forces personnel. The most common symptoms reported were abdominal pain (WPP 32.1% (95% CI 20.5–44.8%), I2 = 93%, p < 0.01), rashes (WPP 38.4% (95% CI 13.1–67.7%), I2 = 99%, p < 0.01) and diarrhoea (WPP 12.6% (95% CI 6.7–19.9%), I2=70%, p = 0.03). Symptomatology varied with cohort characteristics. Although asymptomatic presentation is common, patients may present with abdominal pain, diarrhoea or rashes. A low threshold for screening symptomatic individuals in at-risk groups is required.

Background Autosomal recessive osteopetrosis is a genetically and phenotypically heterogeneous disease, caused by defects in osteoclast formation and function. The only available treatment is allogeneic stem cell transplantation that has still high morbidity and mortality. The goal of the present study was to generate iPSCs from bone marrow-derived MSCs of osteopetrosis patients with three most common mutations by using two different integration-free gene transfer methods and compare their efficiencies. The secondary objective was to select the most appropriate integration-free production method for our institutional iPSC bank using this rare disease as a prototype. Methods Two different integration-free gene transfer methods (episomal and Sendai viral vectors) were tested and compared on the same set of patient samples exhibiting three different mutations associated with osteopetrosis. Generated iPSCs were characterized by standard assays, including immunophenotyping, immunocytochemistry, RT-PCR, embryoid body, and teratoma assays. Karyotype analyses were performed to evaluate genetic stability. Results iPSC lines exhibiting typical ESC-like colony morphology were shown to express pluripotency markers by immunofluorescence staining. Over 90% of the cells were found positive for SSEA-4 and OCT3/4 and negative/weak positive for CD29 by flow cytometry. Immunohistochemical staining of teratoma and spontaneously differentiated embryoid body sections confirmed their trilineage differentiation potential. All iPSC lines expressed pluripotency-related genes. Karyotype analyses were found normal. Direct sequencing of PCR-amplified DNA showed that disease-related mutations were retained in the patient-specific iPSCs. Conclusion Generation of iPSC using SeV and episomal DNA vectors have several advantages over other methods like the ease of production, reliability, high efficiency, and safety, which is required for translational research. Furthermore, owing to the pluripotency and self-renewal capacity, patient-specific iPSCs seem to be ideal cell source for the modeling of a rare genetic bone disease like osteopetrosis to identify osteoclast defects, leading to clinical heterogeneity in osteopetrosis patients, especially among those with different mutations in the same gene.

Chronic skeletal muscle degeneration is characterized by fiber atrophy accompanied by deposition of extracellular matrix (ECM) components and fatty infiltration. Excessive accumulation of ECM leads to fibrosis via the contribution of fibro-adipogenic precursors (FAPs). Fibrosis also accompanies disuse atrophy and sarcopenia without significant inflammation. The present study aimed to comparatively analyze heterogeneous population of FAPs during acute injury and immobilization (tenotomy and denervation). The comparative analysis was accomplished based on the following 3 stromal cell subpopulations: i) CD140a (+) /Sca1 (+) ; ii) CD140a (+) /Sca1 (–) ; iii) CD140a (–) /Sca1 (+) . RNASeq analysis was employed to characterize and compare their quiescent and activated states. Whereas CD140a (-) /Sca1 (+) was the most predominant activated subpopulation in tenotomy, denervation stimulated the CD140a (+) /Sca1 (+) subpopulation. Immobilization models lacked myofiber damage and exhibited a minute increase in CD45 (+) cells, as compared to acute injury. Transcriptome analysis showed common and discordant regulation of ECM components, without profound proliferative activation. Herein, we suggest unique surface markers for further identification of the investigated cell subpopulations. FAP subpopulations show similar activation kinetics in an inflammatory environment but the present findings highlight the fact that inflammation may not be a prerequisite for FAP activation. Delayed proliferation kinetics indicate that signals beyond inflammation might trigger FAP activation, leading to irreversible stromal changes.

Purpose The ideal treatment of osteochondral defects is controversial. Regenerative treatment methods aim to produce ideal scaffolds using different biomaterials. Decellularized extracellular matrix (ECM) containing scaffolds are good options recently. Promising results have been reported with decellularized human omentum xenografts in animal models for tissue regeneration. Mesenchymal stem cells (MSCs) and growth factors also form other parts of the tissue engineering triad for cartilage regeneration The objective of this study is to evaluate the regenerative effects of the decellularised omentum-based scaffold, MSCs and platelet-rich plasma (PRP) in the rat knee articular cartilage model. To our knowledge, this study is the first to evaluate the combined effect of a decellularized human omentum composite scaffold, mesenchymal stem cells, and PRP on osteochondral defect repair. Methods Osteochondral defects were bilaterally created in the femoral trochlea of 42 rats. The animals were randomly divided into five groups: negative control (C), scaffold only (O), scaffold combined with mesenchymal stem cells (OM), scaffold combined with PRP (OP) and scaffold combined with both MSCs and PRP (OMP). At 12 weeks postoperatively, cartilage repair was assessed by macroscopic and histomorphometric evaluation. Results The O group ( p  = 0.022) and the OMP group ( p  = 0.001) showed higher scores than the C group macroscopically. No statistically significant differences were observed between the other group comparisons ( p  > 0.05). According to the total O’Driscoll evaluation scores, none of the experimental groups showed a significant improvement compared to the C group. However, the OMP group had significantly higher total scores than the group O ( p  = 0.002). According to the ICRS scoring system, the OMP application showed significantly better surface continuity ( p  = 0.0314), healthier calcified cartilage formation ( p  = 0.0327), and higher cell viability ( p  = 0.0029) compared to group O. The OM group demonstrated improved calcified cartilage structure compared to the O group ( p  = 0.0429). Conclusions The omentum-based scaffold, along with MSCs and PRP orthobiologic interventions applied in a single-dose, 12-week protocol, demonstrated limited efficacy in osteochondral defect regeneration. Level of evidence Level NA-Animal studies.

Background and AimsIn 2022, a patient suffered a fatal cardiac arrest following a ropivacaine overdose, attributed to inconsistent documentation. This tragedy exposed critical safety gaps in local anaesthetic (LA) administration, highlighting the need for standardised practices to prevent errors and improve patient safety. This project aimed to enhance LA safety at Medway Maritime Hospital by assessing LA types, dosing methods, and surgical team roles; standardising documentation and weight-based dosing; and improving communication through pre-surgical briefings.MethodsA two-cycle Plan-Do-Study-Act (PDSA) approach was used, beginning with a baseline audit via questionnaires (n=60). Interventions, aligned with the Royal College of Anaesthetists’ guidelines, included standardised notation by recording LA as ‘volume (ml) of solution (mg/ml) of named LA’; implementation of ideal body weight (IBW)-based dosing calculations; enhanced documentation to ensure LA administration was recorded in the care plan; and improved verification and communication through surgeon vial checks and mandatory pre-surgical brief discussions.ResultsLA documentation in care plans improved from 36% to 91% (+55%, p<0.001). IBW-based dosing compliance increased from 39% to 91% (+52%, p<0.001). Pre-surgical LA discussions rose from 83% to 100% (+17%, p=0.02). Across the two cycles, LA overdoses decreased from two to one, with no clinical impact identified.ConclusionsStatistical analysis confirmed significant improvements in LA safety, with p-values <0.05. The interventions effectively reduced documentation errors, dosing inconsistencies, and communication gaps, emphasising the importance of ongoing monitoring and training. Future efforts will focus on embedding these practices into routine workflows to ensure sustained improvements and safeguard patient safety across surgical units.

Secondary acute myeloid leukemia (sAML) may develop following a prior therapy or may evolve from an antecedent hematological disorder such as Fanconi Anemia (FA). Pathophysiology of leukemic evolution is not clear. Etoposide (Eto) is a chemotherapeutic agent implicated in development of sAML. FA is an inherited bone marrow (BM) failure disease characterized by genomic instability and xenobiotic susceptibility. Here, we hypothesized that alterations in the BM niche may play a critical/driver role in development of sAML in both conditions. Expression of selected genes involved in xenobiotic metabolism, DNA double-strand break response, endoplasmic reticulum (ER) stress, heat shock response and cell cycle regulation were determined in BM mesenchymal stem cells (MSCs) of healthy controls and FA patients at steady state and upon exposure to Eto at different concentrations and in recurrent doses. Expression of CYPA1 , p53, CCNB1, Dicer1, CXCL12, FLT3L and TGF-Beta genes were significantly downregulated in FA-MSCs compared with healthy controls. Eto exposure induced significant alterations in healthy BM-MSCs with increased expression of CYP1A1, GAD34, ATF4, NUPR1, CXCL12, KLF4, CCNB1 and nuclear localization of Dicer1 . Interestingly, FA-MSCs did not show significant alterations in these genes upon Eto exposure. As opposed to healthy MSCs DICER1 gene expression and intracellular localization was not altered on FA BM-MSCs after Eto treatment. These results showed that Eto is a highly potent molecule and has pleiotropic effects on BM-MSCs, FA cells show altered expression profile compared to healthy controls and Eto exposure on FA cells shows differential profile than healthy controls. Graphical abstract

Skeletal dysplasias, characterized by bone, cartilage, and connective tissue abnormalities, often arise due to disruptions in extracellular matrix (ECM) dynamics and growth factor-dependent signaling pathways. RSPRY1, a secreted protein with RING and SPRY domains, has been implicated in bone development, yet its exact role remains to be determined. RSPRY1 gene mutations are associated with spondyloepimetaphyseal dysplasia (SEMD), a rare skeletal disorder characterized by severe epiphyseal and metaphyseal deformities. This study aimed to determine the molecular and cellular mechanisms by which RSPRY1 deficiency affects skeletal homeostasis. Transcriptome analysis of fibroblasts from patients with homozygous RSPRY1 mutations showed there was significant enrichment of transforming growth factor beta (TGF-β) signaling and ECM-related pathways. Functional wound healing assays showed that RSPRY1 knockout fibroblasts exhibited enhanced motility, a phenotype that was abrogated in RSPRY1 + SMAD3 double knockout fibroblasts, highlighting the SMAD3-dependence of RSPRY1′s effects. The observed limited response to exogenous TGF-β in RSPRY1-deficient cells indicated that there was constitutive pathway activation. These findings show that RSPRY1 is a critical regulator of TGF-β signaling in ECM dynamics and cell motility, contributing to the pathophysiology of SEMD. An improvement in our understanding of the molecular roles of RSPRY1 might yield novel therapeutic strategies that target TGF-β signaling in patients with SEMD and other skeletal dysplasias.