Glucocorticoids are potent anti-inflammatory drugs, although their use is associated with severe side effects. Loading glucocorticoids into suitable nanocarriers can significantly reduce these undesirable effects. Macrophages play a crucial role in inflammation, making them strategic targets for glucocorticoid-loaded nanocarriers. The main objective of this study is to develop a glucocorticoid-loaded PLGA nanocarrier specifically targeting liver macrophages, thereby enabling the localized release of glucocorticoids at the site of inflammation. Dexamethasone acetate (DA)-loaded PLGA nanospheres designed for passive macrophage targeting are synthesized using the nanoprecipitation method. Two types of PLGA NSs in the size range of 100-300 nm are prepared, achieving a DA-loading efficiency of 19 %. Sustained DA release from nanospheres over 3 days is demonstrated. Flow cytometry analysis using murine bone marrow-derived macrophages demonstrates the efficient internalization of fluorescent dye-labeled PLGA nanospheres, particularly into pro-inflammatory macrophages. Significant down-regulation in pro-inflammatory cytokine genes mRNA is observed without apparent cytotoxicity after treatment with DA-loaded PLGA nanospheres. Subsequent experiments in mice confirm liver macrophage-specific nanospheres accumulation following intravenous administration using in vivo imaging, flow cytometry, and fluorescence microscopy. Taken together, the data show that the DA-loaded PLGA nanospheres are a promising drug-delivery system for the treatment of inflammatory liver diseases.

• MeSH
• Anti-Inflammatory Agents pharmacology   chemistry   MeSH
• Dexamethasone * pharmacology   chemistry   analogs & derivatives   MeSH
• Liver * drug effects   metabolism   MeSH
• Polylactic Acid-Polyglycolic Acid Copolymer * chemistry   MeSH
• Macrophages * drug effects   metabolism   MeSH
• Mice MeSH
• Nanospheres * chemistry   MeSH
• Drug Carriers chemistry   pharmacology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Inflammatory changes in perivascular adipose tissue are associated with atherosclerotic lesions in the adjacent artery and can also be used as a marker in patient workup. While adipocyte size is known to be closely related to adipose tissue dysfunction and inflammation, it has not been widely studied in perivascular adipose tissue obtained from healthy human subjects without clinical atherosclerosis. In this cross-sectional study, we addressed this issue by measuring adipocyte size and defining its relationship to cardiovascular risk factors in a healthy cohort of living kidney donors. The presence of cardiovascular risk factors was established by a standardized questionnaire, clinical measurements and body composition analyses. Adipocyte size was measured in the perivascular depot. The proportions of various macrophage subtypes were determined by flow cytometry. To confirm the results, the proportion of CD68 + macrophages was additionally assessed by immunohistochemistry. A correlation and principal component analyses were performed to explore associations. Adipocyte size in perivascular adipose tissue correlated with markers of lipid metabolism, inflammation, and glucose metabolism. Further, the positive correlation with the pro-inflammatory subpopulation of macrophages suggests a strong local effect of perivascular adipose tissue. Perivascular adipocyte size was associated with cardiovascular risk factors and markers of inflammation in a healthy cohort of living kidney donors. This further supports the local role of adipose tissue dysfunction and inflammation in early atherosclerosis development and detection.

• MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Lipids * MeSH
• Macrophages metabolism   MeSH
• Lipid Metabolism MeSH
• Cross-Sectional Studies MeSH
• Adipose Tissue metabolism   MeSH
• Adipocytes * metabolism   cytology   MeSH
• Cell Size MeSH
• Inflammation * metabolism   pathology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

From tumorigenesis to the establishment of local or metastatic high-grade tumours, an integral part of the cellular lifespan relies on various signalling pathways. Particular pathways that allow cells to proliferate by creating a network of new blood vessels have been documented, whereas other pathways are primarily involved with a migration to distant body parts, partially through the process of epithelial-mesenchymal transition (EMT). This review will discuss the different signalling pathways, such as TGF-β, Cripto-1, Wnt pathways, Hedgehog, Notch and NF-κB pathways, and how they promote tumour initiation and progression by influencing diverse cellular processes and EMT in general and in benign and malignant prostate tumours. This review will discuss only the critical pathways. Therefore, many other types of signalling pathways which are related to prostate cancer will not be discussed. Possibilities for further investigation will be mentioned, as many underlying mechanisms involved in these pathways have potential as targets in future tumour therapy. This review will also introduce some novel clinical trials relating to the inhibition of signalling pathways and their clinical outcomes.

• MeSH
• Epithelial-Mesenchymal Transition physiology   MeSH
• Humans MeSH
• Prostatic Neoplasms * pathology   metabolism   therapy   drug therapy   MeSH
• NF-kappa B metabolism   MeSH
• Hedgehog Proteins metabolism   MeSH
• Signal Transduction * physiology   MeSH
• Transforming Growth Factor beta metabolism   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

The eye represents a highly specialized organ, with its main function being to convert light signals into electrical impulses. Any damage or disease of the eye induces a local inflammatory reaction that could be harmful for the specialized ocular cells. Therefore, the eye developed several immunoregulatory mechanisms which protect the ocular structures against deleterious immune reactions. This protection is ensured by the production of a variety of immunosuppressive molecules, which create the immune privilege of the eye. In addition, ocular cells are potent producers of numerous growth and trophic factors which support the survival and regeneration of diseased and damaged cells. If the immune privilege of the eye is interrupted and the regulatory mechanisms are not sufficiently effective, the eye disease can progress and result in worsening of vision or even blindness. In such cases, external immunotherapeutic interventions are needed. One perspective possibility of treatment is represented by mesenchymal stromal/stem cell (MSC) therapy. MSCs, which can be administered intraocularly or locally into diseased site, are potent producers of various immunoregulatory and regenerative molecules. The main advantages of MSC therapy include the safety of the treatment, the possibility to use autologous (patient's own) cells, and observations that the therapeutic properties of MSCs can be intentionally regulated by external factors during their preparation. In this review, we provide a survey of the immunoregulatory and regenerative mechanisms in the eye and describe the therapeutic potential of MSC application for corneal damages and retinal diseases.

• MeSH
• Humans MeSH
• Mesenchymal Stem Cells * cytology   MeSH
• Retinal Diseases * therapy   MeSH
• Corneal Injuries * therapy   MeSH
• Mesenchymal Stem Cell Transplantation * methods   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

PURPOSE: Revision total hip arthroplasty (rTHA) is an increasingly common procedure due to the growing number of primary total hip arthroplasties (THAs) performed worldwide. This study evaluates the long-term implant survival, functional outcomes, and radiographic performance of cemented femoral stem (Beznoska s.r.o., Kladno, Czechia) in rTHA. METHODS: A retrospective analysis was conducted on 183 patients who underwent rTHA with cemented stem between March 2012 and December 2023. The mean follow-up duration was 71.26(± 39.31) months. Implant survival was analyzed using Kaplan-Meier survival estimates, and failure modes were assessed. Radiographic changes were classified using the Gruen Zones system. Functional outcomes were evaluated using the Harris Hip Score (HHS). Cox proportional hazard models were applied to identify prognostic factors influencing implant survival. RESULTS: The five-year implant survival rate was 98.1%, declining to 83.9% at twelve years. The overall failure rate was 3.83%, with periprosthetic infection (4 cases) being the most common cause, followed by aseptic loosening (2 cases). Radiographic changes were observed in 24.03% of cases, predominantly in Gruen Zones 2, 6, and 1. Functional outcomes were favorable, with a mean HHS of 81.28(± 5.74), comparable to outcomes reported for uncemented revision stems. Age, stem diameter, and stem length did not significantly impact implant survival. CONCLUSION: The cemented stem demonstrated favourable long-term survival, with high implant retention rates. Functional outcomes indicated overall satisfactory performance. Radiographic evaluation revealed localized changes around the implant, predominantly in Gruen Zones 2, 6, and 1. Implant failure was relatively rare, with periprosthetic infection being the most common cause.

• MeSH
• Cementation MeSH
• Adult MeSH
• Kaplan-Meier Estimate MeSH
• Bone Cements MeSH
• Hip Joint diagnostic imaging   surgery   MeSH
• Hip Prosthesis * adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Arthroplasty, Replacement, Hip * methods   instrumentation   adverse effects   MeSH
• Prosthesis Design MeSH
• Radiography MeSH
• Reoperation * MeSH
• Retrospective Studies MeSH
• Prosthesis Failure * MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

An increasing number of studies have characterized the bone as an endocrine organ, and that bone secreted factors may not only regulate local bone remodeling, but also other tissues and whole-body metabolic functions. The precise nature of these regulatory factors and their roles at bridging the bone, bone marrow adipose tissue, extramedullary body fat and whole-body energy homeostasis are being explored. In this study, we report that KIAA1199, a secreted factor produced from bone and bone marrow, previously described as an inhibitor of bone formation, also plays a role at promoting adipogenesis. KIAA1199-deficient mice exhibit reduced bone marrow adipose tissue, subcutaneous and visceral fat tissue mass, blood cholesterol, triglycerides, free fatty acids and glycerol, as well as improved insulin sensitivity in skeletal muscle, liver and fat. Moreover, these mice are protected from the detrimental effects of high-fat diet feeding, with decreased obesity, lower blood glucose and glucose tolerance, as well as decreased adipose tissue inflammation, insulin resistance and hepatic steatosis. In human studies, plasma levels of KIAA1199 or its expression levels in adipose tissue are positively correlated with insulin resistance and blood levels of cholesterol, triglycerides, free fatty acids, glycerol, fasting glucose and HOMA-IR. Mechanistically, KIAA1199 mediates its effects on adipogenesis through modulating osteopontin-integrin and AKT / ERK signaling. These findings provide evidence for the role of bone secreted factors on coupling bone, fat and whole-body energy homeostasis.

• MeSH
• Adipogenesis * physiology   MeSH
• Diet, High-Fat MeSH
• Energy Metabolism * MeSH
• Hyaluronoglucosaminidase MeSH
• Insulin Resistance MeSH
• Humans MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Obesity metabolism   MeSH
• Proteins * metabolism   MeSH
• Adipose Tissue metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

OBJECTIVES: This study aimed to investigate the associations between radiographic damage, serum biomarkers, and clinical assessments in Czech patients with hand osteoarthritis (HOA) over a five-year follow-up period. METHODS: The study cohort comprised 129 patients diagnosed with HOA, including 72 patients with an erosive subtype and 57 patients with a non-erosive subtype. Radiographs were evaluated using the Kallman scoring system by two independent readers. Blood samples were analysed for markers of dyslipidaemia, bone metabolism, and inflammation. Clinical assessments focused on symptom severity and functional impairment. We employed generalised additive modelling (GAM) to analyse the associations between the Kallman score, serum biomarkers and clinical outcomes. RESULTS: The Kallman score was consistently higher in the erosive subtype compared to the non-erosive subtype across all time points and demonstrated a positive correlation with age in both groups. We demonstrated significant positive associations between radiographic progression and erythrocyte sedimentation rate across both HOA subtypes. Additionally, positive associations with the number of swollen joints and health assessment questionnaire scores were observed in all HOA patients, particularly in those with non-erosive subtypes. In contrast, markers of dyslipidaemia (e.g. LDL‐c or atherogenic index) were negatively associated with radiographic progression. No biomarker reliably differentiated between the erosive and non-erosive subtypes. CONCLUSIONS: Our longitudinal study revealed a significant association between systemic/local inflammation, dyslipidaemia, functional impairment and structural progression in HOA. However, these findings warrant further validation through additional studies to confirm these associations.

• MeSH
• Biomarkers * blood   MeSH
• Time Factors MeSH
• Dyslipidemias * blood   diagnostic imaging   MeSH
• Functional Status MeSH
• Hand Joints * diagnostic imaging   MeSH
• Blood Sedimentation MeSH
• Middle Aged MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Inflammation Mediators blood   MeSH
• Osteoarthritis * diagnostic imaging   blood   MeSH
• Disability Evaluation MeSH
• Predictive Value of Tests MeSH
• Disease Progression * MeSH
• Radiography MeSH
• Aged MeSH
• Severity of Illness Index MeSH
• Inflammation blood   diagnostic imaging   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

The lateral line system enables fishes and aquatic-stage amphibians to detect local water movement via mechanosensory hair cells in neuromasts, and many species to detect weak electric fields via electroreceptors (modified hair cells) in ampullary organs. Both neuromasts and ampullary organs develop from lateral line placodes, but the molecular mechanisms underpinning ampullary organ formation are understudied relative to neuromasts. This is because the ancestral lineages of zebrafish (teleosts) and Xenopus (frogs) independently lost electroreception. We identified Bmp5 as a promising candidate via differential RNA-seq in an electroreceptive ray-finned fish, the Mississippi paddlefish (Polyodon spathula; Modrell et al., 2017, eLife 6: e24197). In an experimentally tractable relative, the sterlet sturgeon (Acipenser ruthenus), we found that Bmp5 and four other Bmp pathway genes are expressed in the developing lateral line, and that Bmp signalling is active. Furthermore, CRISPR/Cas9-mediated mutagenesis targeting Bmp5 in G0-injected sterlet embryos resulted in fewer ampullary organs. Conversely, when Bmp signalling was inhibited by DMH1 treatment shortly before the formation of ampullary organ primordia, supernumerary ampullary organs developed. These data suggest that Bmp5 promotes ampullary organ development, whereas Bmp signalling via another ligand(s) prevents their overproduction. Taken together, this demonstrates opposing roles for Bmp signalling during ampullary organ formation.

• MeSH
• Bone Morphogenetic Proteins * metabolism   genetics   MeSH
• Lateral Line System * embryology   metabolism   MeSH
• Fish Proteins metabolism   genetics   MeSH
• Fishes genetics   MeSH
• Signal Transduction * MeSH
• Gene Expression Regulation, Developmental MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH

PURPOSE: The AIEOP-BFM ALL 2009 protocol included, at the end of the induction phase, a randomized study of patients with high-risk (HR) ALL to investigate if an intensive exposure to pegylated L-asparaginase (PEG-ASNASE, 2,500 IU/sqm once a week × 4) on top of BFM consolidation phase IB allowed us to decrease minimal residual disease (MRD) and improve outcome. PATIENTS AND METHODS: A total of 1,097 patients presented, from June 2010 to February 2017, with one or more of the following HR criteria: KMT2A::AFF1 rearrangement, hypodiploidy, prednisone poor response, poor bone marrow response at day 15 (Flow MRD ≥10%), or no complete remission (CR) at the end of induction. Of them, 809 (85.1%) were randomly assigned to receive (404) or not receive (405) four weekly doses of PEG-ASNASE. RESULTS: By intention to treat (ITT) analysis, there was no significant difference in the proportion of patients with polimerase chain reaction MRD ≥5 × 10-4 at the end of phase IB in the experimental versus control arm (13.9% v 17.0%, P = .25). The 5-year event-free survival (median follow-up 6.3 years) by ITT in the experimental and control arms was 70.4% (2.3) versus 75.0% (2.2; P = .18), and the 5-year overall survival was 81.5% (2.0) versus 84.0% (1.9; P = .25), respectively. The corresponding 5-year cumulative incidence of death in CR was 9.5% (1.5) versus 5.7% (1.2; P = .08), and that of relapse was 17.7% (1.9) versus 17.2% (1.9), respectively (P = .94). Adverse reactions in phase IB occurred in 22.2% and 8.9% of patients in the experimental and control arm, respectively (P < .001). CONCLUSION: Additional PEG-ASNASE in phase IB did not translate into a benefit for decreasing relapse incidence but was associated with higher toxicity. Further improvements with conventional chemotherapy might be difficult in the context of intensive treatment protocols.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma * MeSH
• Asparaginase * MeSH
• Infant MeSH
• Humans MeSH
• Neoplasm Recurrence, Local drug therapy   MeSH
• Polyethylene Glycols MeSH
• Prednisone adverse effects   MeSH
• Disease-Free Survival MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Randomized Controlled Trials as Topic MeSH
• Recurrence MeSH
• Treatment Outcome MeSH
• Check Tag
• Infant MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial Protocol MeSH

SMARCB1-deficient sinonasal adenocarcinoma is a rare variant of SWI/SNF-deficient malignancies with SMARCB1 loss and adenocarcinoma features. More than 200 high-grade epithelial sinonasal malignancies were retrieved. A total of 14 cases exhibited complete SMARCB1 (INI1) loss and glandular differentiation. SMARCA2 and SMARCA4 were normal, except for one case with a loss of SMARCA2. Next-generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH) revealed an alteration in the SMARCB1 gene in 9/13 cases, while 2/13 were negative. Two tumors harbored SMARCB1 mutations in c.157C > T p.(Arg53Ter) and c.842G > A p.(Trp281Ter). One harbored ARID1B mutations in c.1469G > A p.(Trp490Ter) and MGA c.3724C > T p.(Arg1242Ter). Seven tumors had a SMARCB1 deletion. One carried an ESR1 mutation in c.644-2A > T, and another carried a POLE mutation in c.352_374del p.(Ser118GlyfsTer78). One case had a PAX3 mutation in c.44del p.(Gly15AlafsTer95). Histomorphology of SMARCB1-deficient adenocarcinoma was oncocytoid/rhabdoid and glandular, solid, or trabecular in 9/14 cases. Two had basaloid/blue cytoplasm and one showed focal signet ring cells. Yolk sac tumor-like differentiation with Schiller-Duval-like bodies was seen in 6/14 cases, with 2 cases showing exclusively reticular-microcystic yolk sac pattern. Follow-up of a maximum of 26 months (median 10 months) was available for 8/14 patients. Distant metastasis to the lung, liver, mediastinum, bone, and/or retroperitoneum was seen in 4/8 cases. Locoregional failure was seen in 75% of patients, with 6/8 local recurrences and 3 cervical lymph node metastases. At the last follow-up, 5 of 8 (62%) patients had died of their disease 2 to 20 months after diagnosis (median 8.2 months), and 3 were alive with the disease. The original diagnosis was usually high-grade non-intestinal-type adenocarcinoma or high-grade myoepithelial carcinoma. A correct diagnosis of these aggressive tumors could lead to improved targeted therapies with potentially better overall disease-specific survival.

• MeSH
• Adenocarcinoma * genetics   pathology   MeSH
• Diagnosis, Differential MeSH
• DNA-Binding Proteins genetics   deficiency   MeSH
• Adult MeSH
• SMARCB1 Protein * deficiency   genetics   MeSH
• In Situ Hybridization, Fluorescence MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation * MeSH
• Myoepithelioma * genetics   pathology   MeSH
• Biomarkers, Tumor genetics   MeSH
• Paranasal Sinus Neoplasms * genetics   pathology   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Neoplasm Grading MeSH
• Transcription Factors * genetics   deficiency   MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH