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Bladder cancer (BC) is fatal during muscle invasion and treatment progress is limited. In this study, we aimed to construct and validate basement membrane (BM)-associated gene prognosis to predict BC progression and tumor immune infiltration correlation. We choreographed BM-related genes in the Cancer Genome Atlas (TCGA) database using COX regression and least absolute shrinkage and selection operator (LASSO) analysis, and the predictive value of BM-related genes was further validated by the GSE32548, GSE129845, and immunohistochemistry staining. All analyses were performed with R-version 4.2.2, and its appropriate packages. Three genes were identified to construct a gene signature to predictive of BC prognosis. We divided the TCGA database into 2 groups, and patients in the high-risk group had worse overall survival (OS) than those in the low-risk group. In GSE32548, we confirmed that patients in the high-risk group had a poorer prognosis compared to those in the low-risk group in terms of OS. Immunohistochemical staining of EPEMP1, GPC2, and ITGA3 showed significantly higher expression at the protein level in BC tissues than in normal tissues. The Spearman analysis showed risk score was positively correlated with B cell naïve, Macrophages M2, and Mast cells resting. stromal score, immune score, and ESTIMATE scores were significantly higher in the high-risk group. drugs sensitivity analysis showed IC50 of Cisplatin, Gemcitabine, and Methotrexate in the high-risk group was significantly higher than that in the low-risk group. We identified 3 prognostic genes from a novel perspective of BM genes as effective risk stratification tools for BC patients.
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Membrana Basal , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patología , Pronóstico , Membrana Basal/inmunología , Membrana Basal/patología , Masculino , Femenino , Biomarcadores de Tumor/genética , Persona de Mediana Edad , Anciano , Regulación Neoplásica de la Expresión GénicaRESUMEN
Purpose: The purpose of this study was to investigate the ocular morphological characteristics of Col4a3-/- mice as a model of Alport syndrome (AS) and the potential pathogenesis. Methods: The expression of collagen IV at 8, 12, and 21 weeks of age was evaluated by immunohistochemistry in wild-type (WT) and Col4a3-/- mice. Hematoxylin and eosin (H&E) staining and thickness measurements were performed to assess the thickness of anterior lens capsule and retina. Ultrastructure analysis of corneal epithelial basement membrane, anterior lens capsule, internal limiting membrane (ILM), and retinal pigment epithelium (RPE) basement membrane was performed using transmission electron microscopy. Finally, Müller cell activation was evaluated by glial fibrillary acidic protein (GFAP) expression. Results: Collagen IV was downregulated in the corneal epithelial basement membrane and ILM of Col4a3-/- mice. The hemidesmosomes of Col4a3-/- mice corneal epithelium became flat and less electron-dense than those of the WT group. Compared with those of the WT mice, the anterior lens capsules of Col4a3-/- mice were thinner. Abnormal structure was detected at the ILM Col4a3-/- mice, and the basal folds of the RPE basement membrane in Col4a3-/- mice were thicker and shorter. The retinas of Col4a3-/- mice were thinner than those of WT mice, especially within 1000 µm away from the optic nerve. GFAP expression enhanced in each age group of Col4a3-/- mice. Conclusions: Our results suggested that Col4a3-/- mice exhibit ocular anomalies similar to patients with AS. Additionally, Müller cells may be involved in AS retinal anomalies. Translational Relevance: This animal model could provide an opportunity to understand the underlying mechanisms of AS ocular disorders and to investigate potential new treatments.
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Membrana Basal , Colágeno Tipo IV , Modelos Animales de Enfermedad , Ratones Noqueados , Nefritis Hereditaria , Animales , Nefritis Hereditaria/patología , Nefritis Hereditaria/genética , Nefritis Hereditaria/metabolismo , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Colágeno Tipo IV/deficiencia , Ratones , Membrana Basal/metabolismo , Membrana Basal/patología , Membrana Basal/ultraestructura , Epitelio Pigmentado de la Retina/patología , Epitelio Pigmentado de la Retina/metabolismo , Epitelio Pigmentado de la Retina/ultraestructura , Microscopía Electrónica de Transmisión , Ratones Endogámicos C57BL , Cápsula del Cristalino/metabolismo , Cápsula del Cristalino/patología , Cápsula del Cristalino/ultraestructura , Epitelio Corneal/patología , Epitelio Corneal/ultraestructura , Epitelio Corneal/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteína Ácida Fibrilar de la Glía/genética , Retina/patología , Retina/metabolismo , Retina/ultraestructura , Autoantígenos/genética , Autoantígenos/metabolismo , Células Ependimogliales/patología , Células Ependimogliales/metabolismo , Células Ependimogliales/ultraestructura , Inmunohistoquímica , MasculinoRESUMEN
The basement membrane zone is the interface between the epidermis and dermis, and it is disrupted in several skin conditions. Here, we report the results of a comprehensive investigation into the structural and molecular factors of the basement membrane zone in vitiligo, a dermatological disorder characterised by depigmented patches on the skin. Using electron microscopy and immunofluorescence staining, we confirmed abnormal basement membrane zone morphology and disrupted basement membrane zone architecture in human vitiliginous skin. Furthermore, we identified elevated expression of matrix metalloproteinase 2 (MMP2) in human dermal fibroblasts as a key factor responsible for basement membrane zone matrix degradation. In our in vitro and ex vivo models, overexpression of MMP2 in fibroblasts led to basement membrane zone disruption and melanocyte disappearance. Importantly, we reveal that the loss of melanocytes in vitiligo is primarily linked to their weakened adhesion to the basement membrane, mediated by binding between integrin ß1 and laminin and discoidin domain receptor 1 and collagen IV. Finally, inhibition of matrix metalloproteinase 2 expression reversed depigmentation in a mouse model of vitiligo. In conclusion, our research shows the importance of basement membrane zone integrity in melanocyte residence and offers new avenues for therapeutic interventions to address this challenging skin condition. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Membrana Basal , Melanocitos , Vitíligo , Vitíligo/patología , Vitíligo/metabolismo , Melanocitos/patología , Melanocitos/metabolismo , Membrana Basal/patología , Membrana Basal/metabolismo , Humanos , Animales , Ratones , Metaloproteinasa 2 de la Matriz/metabolismo , Fibroblastos/patología , Fibroblastos/metabolismo , Masculino , Femenino , Modelos Animales de Enfermedad , Ratones Endogámicos C57BLRESUMEN
In all mammals, the basement membrane serves as a pivotal extracellular matrix. Hepatocellular carcinoma (HCC) is a challenge among numerous cancer types shaped by basement membrane-related genes (BMGs). Our research established an innovative prognostic model that is highly accurate in its prediction of HCC prognoses and immunotherapy efficacy to summarize the crucial role of BMGs in HCC. We obtained HCC transcriptome analysis data and corresponding clinical data from The Cancer Genome Atlas (TCGA). To augment our dataset, we incorporated 222 differentially expressed BMGs identified from relevant literature. A weighted gene coexpression network analysis (WGCNA) of 10158 genes demonstrated four modules that were connected to HCC. Additionally, 66 genes that are found at the intersection of BMGs and HCC-related genes were designated as hub HCC-related BMGs. MMP1, ITGA2, P3H1, and CTSA comprise the novel model that was engineered using univariate and multivariate Cox regression analysis. Furthermore, the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO) datasets encouraged the BMs model's validity. The overall survival (OS) of individuals with HCC may be precisely predicted in the TCGA and ICGC databases utilizing the BMs model. A nomogram based on the model was created in the TCGA database at similar time, and displayed a favorable discriminating ability for HCC. Particularly, when compared to the patients at an elevated risk, the patients with a low-risk profile presented different tumor microenvironment (TME) and hallmark pathways. Moreover, we discovered that a lower risk score of HCC patients would display a greater response to immunotherapy. Finally, quantitative real-time PCR (qRT-PCR) experiments were used to verify the expression patterns of BMs model. In summary, BMs model demonstrated efficacy in prognosticating the survival probability of HCC patients and their immunotherapeutic responsiveness.
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Membrana Basal , Carcinoma Hepatocelular , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/mortalidad , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/mortalidad , Membrana Basal/patología , Membrana Basal/metabolismo , Pronóstico , Perfilación de la Expresión Génica , Biomarcadores de Tumor/genética , Masculino , Femenino , Nomogramas , Redes Reguladoras de Genes , Bases de Datos Genéticas , TranscriptomaRESUMEN
BACKGROUND: This study sought to investigate the prognostic value of basement membrane (BM)-associated gene expressions in oral cancer. METHODS: We harvested and integrated data on BM-associated genes (BMGs), the oral cancer transcriptome, and clinical information from public repositories. After identifying differentially expressed BMGs, we used Cox and Lasso regression analyses to create a BMG-based risk score for overall survival at various intervals. We then validated this score using the GSE42743 cohort as a validation set. The prognostic potential of the risk scores and their relations to clinical features were assessed. Further, we conducted functional pathway enrichment, immune cell infiltration, and immune checkpoint analyses to elucidate the immunological implications and therapeutic potential of the BMG-based risk score and constituent genes. To confirm the expression levels of the BMG LAMA3 in clinical samples of oral cancer tissue, we performed quantitative real-time PCR (qRT-PCR) and immunohistochemical staining. RESULTS: The BMGs LAMA3, MMP14, and GPC2 demonstrated notable prognostic significance, facilitating the construction of a BMG-based risk score. A higher risk score derived from BMGs correlated with a poorer survival prognosis for oral cancer patients. Moreover, the risk-associated BMGs exhibited a significant relationship with immune function variability (P < 0.05), discrepancies in infiltrating immune cell fractions, and immune checkpoint expressions (P < 0.05). The upregulated expression levels of LAMA3 in oral cancer tissues were substantiated through qRT-PCR and immunohistochemical staining. CONCLUSION: The BMG-based risk score emerged as a reliable prognostic tool for oral cancer, meriting further research for validation and potential clinical application.
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Membrana Basal , Biomarcadores de Tumor , Neoplasias de la Boca , Humanos , Neoplasias de la Boca/genética , Neoplasias de la Boca/mortalidad , Neoplasias de la Boca/patología , Pronóstico , Membrana Basal/metabolismo , Membrana Basal/patología , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Transcriptoma , Femenino , Perfilación de la Expresión Génica , Masculino , Laminina/genéticaRESUMEN
The extracellular matrix surrounding the tumor undergoes changes in its organization during the metastasis process. The present study aims to quantify total collagen, collagen I (Col I) and collagen III (Col III), analyze the alignment of collagen fibers and assess the basement membrane integrity in samples from patients with metastatic and non-metastatic prostate cancer. Tissue samples from 60 patients were classified into groups based on prognostic parameters: better prognosis (n = 20), worse prognosis without metastasis (n = 23) and metastatic (n = 17). Picrosirius red with further analysis under polarizing microscope was used to quantify (with validation using immunohistochemistry) and analyze collagen alignment, and Periodic Acid Schiff staining was used to analyze the basement membrane integrity. The Col I/Col III ratio was found to be higher in the metastatic group than in the groups with better prognosis (p = 0.012) and worse prognosis without metastasis (p = 0.018). Basement membrane integrity constitution in malignant tumor tissue differed from that of adjacent non-tumor tissue (p < 0.001). Moreover, the worsening in the tumor tissue integrity was positively correlated with worse prognostic parameters. All in all, absence of Col III and basement membrane integrity might be indicators of poor prognosis in prostate cancer.
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Membrana Basal , Biomarcadores de Tumor , Colágeno Tipo III , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Membrana Basal/metabolismo , Membrana Basal/patología , Pronóstico , Biomarcadores de Tumor/metabolismo , Anciano , Colágeno Tipo III/metabolismo , Persona de Mediana Edad , Colágeno Tipo I/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/patologíaRESUMEN
Vascular endothelial cells (VECs) are key players in the formation of neovessels and tumor metastasis, the ultimate cause of the majority of cancer-related human death. However, the crosstalk between VECs and metastasis remain greatly elusive. Based on our finding that tumor-associated VECs present significant decrease of Nrdp1 protein which is closely correlated with higher metastatic probability, herein we show that the conditional medium from hypoxia-incubated cancer cells induces extensive Nrdp1 downregulation in human and mouse VECs by vascular endothelial growth factor (VEGF), which activates CHIP, followed by Nrdp1 degradation in ubiquitin-proteasome-dependent way. More importantly, lung metastases of cancer cells significantly increase in conditional VECs Nrdp1 knockout mice. Mechanically, Nrdp1 promotes degradation of Fam20C, a secretory kinase involved in phosphorylating numerous secreted proteins. Reciprocally, deficiency of Nrdp1 in VECs (ecNrdp1) results in increased secretion of Fam20C, which induces degradation of extracellular matrix and disrupts integrity of vascular basement membrane, thus driving tumor metastatic dissemination. In addition, specific overexpression of ecNrdp1 by Nrdp1-carrying adeno-associated virus or chemical Nrdp1 activator ABPN efficiently mitigates tumor metastasis in mice. Collectively, we explore a new mechanism for VEGF to enhance metastasis and role of Nrdp1 in maintaining the integrity of vascular endothelium, suggesting that ecNrdp1-mediated signaling pathways might become potential target for anti-metastatic therapies.
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Membrana Basal , Células Endoteliales , Ratones Noqueados , Metástasis de la Neoplasia , Factor A de Crecimiento Endotelial Vascular , Animales , Humanos , Ratones , Membrana Basal/metabolismo , Membrana Basal/patología , Línea Celular Tumoral , Células Endoteliales/metabolismo , Células Endoteliales/patología , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Epithelial cells adhere to a specialized extracellular matrix called the basement membrane which allows them to polarize and form epithelial tissues. The extracellular matrix provides essential physical scaffolding and biochemical and biophysical cues required for tissue morphogenesis, differentiation, function, and homeostasis. Epithelial cell adhesion to the extracellular matrix (i.e., basement membrane) plays a critical role in organizing epithelial tissues, separating the epithelial cells from the stroma. Epithelial cell detachment from the basement membrane classically results in death, though detachment or invasion through the basement membrane represents a critical step in carcinogenesis. Epithelial cells bind to the extracellular matrix via specialized matrix receptors, including integrins. Integrins are transmembrane receptors that form a mechanical linkage between the extracellular matrix and the intracellular cytoskeleton and are required for anchorage-dependent cellular functions such as proliferation, migration, and invasion. The role of integrins in the development, growth, and dissemination of multiple types of carcinomas has been investigated by numerous methodologies, which has led to great complexity. To organize this vast array of information, we have utilized the "Hallmarks of Cancer" from Hanahan and Weinberg as a convenient framework to discuss the role of integrins in the pathogenesis of cancers. This review explores this biology and how its complexity has impacted the development of integrin-targeted anti-cancer therapeutics.
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Adhesión Celular , Matriz Extracelular , Integrinas , Neoplasias , Humanos , Integrinas/metabolismo , Integrinas/genética , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/genética , Matriz Extracelular/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Animales , Membrana Basal/metabolismo , Membrana Basal/patología , Transducción de Señal , Movimiento Celular , Invasividad Neoplásica , Proliferación CelularRESUMEN
Focal segmental glomerulosclerosis (FSGS) lesions have been linked to variants in COL4A3/A4/A5 genes, which are also mutated in Alport syndrome. Although it could be useful for diagnosis, quantitative evaluation of glomerular basement membrane (GBM) type IV collagen (colIV) networks is not widely used to assess these patients. To do so, we developed immunofluorescence imaging for collagen α5(IV) and α1/2(IV) on kidney paraffin sections with Airyscan confocal microscopy that clearly distinguishes GBM collagen α3α4α5(IV) and α1α1α2(IV) as two distinct layers, allowing quantitative assessment of both colIV networks. The ratios of collagen α5(IV):α1/2(IV) mean fluorescence intensities (α5:α1/2 intensity ratios) and thicknesses (α5:α1/2 thickness ratios) were calculated to represent the levels of collagen α3α4α5(IV) relative to α1α1α2(IV). The α5:α1/2 intensity and thickness ratios were comparable across all 11 control samples, while both ratios were significantly and markedly decreased in all patients with pathogenic or likely pathogenic Alport COL4A variants, supporting validity of this approach. Thus, with further validation of this technique, quantitative measurement of GBM colIV subtype abundance by immunofluorescence, may potentially serve to identify the subgroup of patients with FSGS lesions likely to harbor pathogenic COL4A variants who could benefit from genetic testing.
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Glomeruloesclerosis Focal y Segmentaria , Nefritis Hereditaria , Humanos , Membrana Basal Glomerular/patología , Colágeno Tipo IV/genética , Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/patología , Parafina , Nefritis Hereditaria/diagnóstico , Nefritis Hereditaria/genética , Nefritis Hereditaria/patología , Membrana Basal/patologíaRESUMEN
BACKGROUND: To examine the effect of internal limiting membrane peeling on the inner retinal layers in patients without macular pathological condition. METHODS: A prospective nonrandomized trial of patients undergoing pars plana vitrectomy with internal limiting membrane peeling for pathologic condition outside the macula was performed. Optical coherence tomography including macular ganglion cell layer, inner plexiform layer, and peripapillary retinal nerve fiber layer imaging was performed before surgery, 1, 3, and 6 months postoperatively, and at the end of follow-up (ranges between 4 and 17 months). Patients with any macular pathological condition on optical coherence tomography before surgery were excluded. The main outcome measure was change in thickness of the ganglion cell layer and inner plexiform layer. RESULTS: Ten patients who underwent pars plana vitrectomy with internal limiting membrane peeling for macula-on retinal detachment were included in the analysis. The mean age was 55 years, and the mean follow up was 10.8 months. All patients completed at least two postoperative follow-up visits that included an optical coherence tomography as per the protocol (range 2-6 months). There was an immediate reduction in the global (G), inferotemporal, superotemporal, and superior (S) ganglion cell layer thickness at the first follow up as compared with the preoperative state ( P = 0.028, P = 0.027, P = 0.026, and P = 0.027 respectively). From the first follow-up visit onward until the final follow-up, the thinning persisted, although there was no further statistically significant thinning. CONCLUSION: Peeling of the internal limiting membrane causes significant ganglion cell layer thinning in maculae without pathologic condition before surgery. At up to 17 months of follow-up, this effect seems to be immediate and nonprogressive.
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Membrana Basal , Fibras Nerviosas , Células Ganglionares de la Retina , Tomografía de Coherencia Óptica , Agudeza Visual , Vitrectomía , Humanos , Tomografía de Coherencia Óptica/métodos , Vitrectomía/métodos , Femenino , Estudios Prospectivos , Masculino , Persona de Mediana Edad , Células Ganglionares de la Retina/patología , Membrana Basal/cirugía , Membrana Basal/patología , Anciano , Fibras Nerviosas/patología , Estudios de Seguimiento , Adulto , Desprendimiento de Retina/cirugía , Desprendimiento de Retina/diagnóstico , Membrana Epirretinal/cirugía , Membrana Epirretinal/diagnóstico , Mácula Lútea/patología , Mácula Lútea/diagnóstico por imagenRESUMEN
BACKGROUND: Cathepsins have been recently identified as a regulator in the activation of Th1 and Th17 cells, which play an important role in the pathogenesis of anti-glomerular basement membrane (GBM) disease. Whether cathepsins contribute to the development of anti-GBM disease through regulating the activation of CD4+ T cell is still unclear. METHODS: Rats with experimental anti-GBM disease was established by immunization with the nephritogenic T cell epitope α3127-148. E64d, a cysteine cathepsin inhibitor, was administered in vitro and vivo to evaluate the effect of cathepsins on regulating the activation of antigen specific T cells and the development of anti-GBM disease. RESULTS: In rats with experimental anti-GBM diseases, E64d treatment not only reduced the levels of proteinuria, serum creatinine and anti-GBM antibody, but also ameliorated the kidney injury with less glomerular IgG deposition, a lower percentage of crescents and less infiltration of CD4+ T cells, CD8+ T cells and macrophages, as well as a lower percentage of splenic Th1 cells. In vitro, E64d treatment could significantly reduce the production of IFN-γ in the supernatant which might be produced by the activation of Th1 cells after being recalled with the autoantigen α3127-148. We also found the CD4+ T cells of rats with anti-GBM disease had an increased expression of cathepsin L (Cts-L), and the percentage of CD4+ T cells with extracellular expression of Cts-L was obviously higher, indicating it as a potential key regulator. CONCLUSIONS: E64d might attenuate the development of anti-GBM disease by participating in the activation of Th1 cells, indicating it as a potential drug for anti-GBM disease in the future.
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Enfermedad por Anticuerpos Antimembrana Basal Glomerular , Leucina/análogos & derivados , Ratas , Animales , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/tratamiento farmacológico , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/patología , Células TH1/patología , Linfocitos T CD8-positivos , Autoantígenos , Catepsinas , Membrana Basal/patologíaRESUMEN
BACKGROUND: Short-chain fatty acids (SCFAs), as the link between gut microbiota and the immune system, had been reported to be protective in many autoimmune diseases by the modulation of T cell differentiation. The pathogenic role of autoreactive Th1 and Th17 cells and the protective role of Treg cells in the pathogenesis of anti-GBM disease have been fully demonstrated. Thus, the present study aimed to investigate the therapeutic effects of SCFAs in a rat model of anti-GBM disease. MATERIALS AND METHODS: Experimental anti-GBM disease was constructed by immunizing Wistar Kyoto rats with a nephrogenic T cell epitope α3127-148, and intervened by sodium acetate, sodium propionate, or sodium butyrate, 150 mM in the drinking water from day 0 to 42. Kidney injury was accessed by the biochemical analyzer, immunofluorescence, and immunohistochemistry. Antibody response was detected by ELISA. T cell clustering and proliferation were detected by flow cytometry. Human kidney 2 (HK2) cells were stimulated in vitro and cytokines were assessed by quantitative real-time PCR. RESULTS: Treatment with sodium acetate, sodium propionate, or sodium butyrate ameliorated the severity of kidney impairment in rats with anti-GBM glomerulonephritis. In the sodium butyrate-treated rats, the urinary protein, serum creatinine, and blood urea nitrogen levels were significantly lower; the percentage of crescent formation in glomeruli was significantly reduced; and the kidneys showed reduced IgG deposition, complement activation, T cell, and macrophage infiltration as well as the level of circulating antibodies against anti-α3(IV)NC1. The treatment of sodium butyrate reduced the α3127-148-specific T cell activation and increased the Treg cells differentiation and the intestinal beneficial bacteria flora. It also alleviated the damage of HK2 cells treated with inflammatory factors and complement. CONCLUSION: Treatment with SCFAs, especially butyrate, alleviated anti-GBM nephritis in rat model, indicating its potential therapeutic effects in clinical usage.
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Enfermedad por Anticuerpos Antimembrana Basal Glomerular , Ratas , Humanos , Animales , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/tratamiento farmacológico , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/etiología , Ácido Butírico , Acetato de Sodio , Propionatos/farmacología , Ratas Endogámicas WKY , Membrana Basal/metabolismo , Membrana Basal/patologíaRESUMEN
An effective nanotherapeutic transport from the vasculature to the tumour is crucial for cancer treatment with minimal side effects. Here we demonstrate that, in addition to the endothelial barrier, the tumour vascular basement membrane surrounding the endothelium acts as a formidable mechanical barrier that entraps nanoparticles (NPs) in the subendothelial void, forming perivascular NP pools. Breaking through this basement membrane barrier substantially increases NP extravasation. Using inflammation triggered by local hyperthermia, we develop a cooperative immunodriven strategy to overcome the basement membrane barrier that leads to robust tumour killing. Hyperthermia-triggered accumulation and inflammation of platelets attract neutrophils to the NP pools. The subsequent movement of neutrophils through the basement membrane can release the NPs entrapped in the subendothelial void, resulting in increased NP penetration into deeper tumours. We show the necessity of considering the tumour vascular basement membrane barrier when delivering nanotherapeutics. Understanding this barrier will contribute to developing more effective antitumour therapies.
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Neoplasias , Humanos , Membrana Basal/patología , Neoplasias/patología , Neutrófilos , Inflamación/patologíaRESUMEN
Atypical antiglomerular basement membrane (anti-GBM) nephritis can be defined as linear GBM staining for monotypic or polytypic immunoglobulin (Ig) by immunofluorescence (IF) without a diffuse crescentic pattern. We describe the clinicopathologic features of 6 patients (18 biopsies) in this first series of recurrent atypical anti-GBM nephritis after kidney transplantation. Recurrent glomerulonephritis occurred at a mean of 3.8 months posttransplant (range 1-7 months). Three index biopsies were for clinical indication, and 3 were protocol biopsies. Glomerular histologic changes were mild, with 2 showing segmental endocapillary hypercellularity, 1 focal glomerular microangiopathy, and the others no significant glomerular histologic changes. All 6 allografts showed monotypic linear glomerular Ig staining by IF: IgG kappa (n = 2), IgG lambda, IgA kappa, IgA lambda, and IgM lambda. Follow-up biopsies were available for 5 patients and showed similar histologic and IF findings without evidence of significant progression. No patients had detectable serum anti-GBM antibody or monoclonal proteins. The mean serum creatinine level on follow-up (24-62 months posttransplant) was 1.8 (range 0.93-2.77) mg/dL; no grafts were lost to recurrent disease. This series demonstrates that monotypic atypical anti-GBM recurs in the allograft and supports the idea that this disease is due to a circulating monoclonal protein.
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Glomerulonefritis , Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Membrana Basal/patología , Autoanticuerpos , Anticuerpos Monoclonales , Inmunoglobulina G , Inmunoglobulina ARESUMEN
Clinically, hemorrhages at the vitreoretinal interface have been termed as 'pre-retinal' in location. However, there is a careful distinction to be made between sub-hyaloid and sub-internal limiting membrane (ILM) planes of blood collection. In the past half-century, a body of literature has accrued on sub-internal limiting membrane hemorrhage. We characterize the etiopathological, clinical, anatomical, and imaging characteristics of this entity (often misconstrued as sub-hyaloid hemorrhage). Management decisions are briefly described, and a unifying term of sub-internal limiting membrane macular hemorrhage is proposed to aid in further research.
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Membrana Epirretinal , Perforaciones de la Retina , Humanos , Hemorragia Retiniana/diagnóstico , Hemorragia Retiniana/etiología , Vitrectomía/métodos , Retina/diagnóstico por imagen , Membrana Basal/cirugía , Membrana Basal/patología , Agudeza Visual , Membrana Epirretinal/cirugía , Perforaciones de la Retina/cirugíaRESUMEN
Combination therapy with glucocorticoids, cyclophosphamide, and plasmapheresis is recommended as the standard treatment for anti-glomerular basement membrane (anti-GBM) disease, but the prognosis of this disease remains poor. Several immunobiological agents have been administered or are expected to be useful for anti-GBM disease in light of refractory disease or the standard treatments' tolerability. Many data regarding the use of biologic agents for anti-GBM disease have accumulated, verifying the effectiveness and potential of biologic agents as a new treatment option for anti-GBM disease. Tumor necrosis factor (TNF) inhibitors were shown to be useful in animal studies, but these agents have no clinical use and were even shown to induce anti-GBM disease in several cases. Although the efficacy of the TNF-receptor antagonist has been observed in animal models, there are no published case reports of its clinical use. There are also no published reports of animal or clinical studies of anti-B-cell-activating factor, which is a member of the TNF family of agents. Anti-interleukin (IL)-6 antibodies have been demonstrated to have no effect on or to exacerbate nephritis in animal models. Anti-C5 inhibitor was observed to be useful in a few anti-GBM disease cases. Among the several immunobiological agents, only rituximab has been demonstrated to be useful in refractory or poor-tolerance patients or small uncontrolled studies. Rituximab is usually used in combination with steroids and plasma exchange and is used primarily as an alternative to cyclophosphamide, but there is insufficient evidence regarding the efficacy of rituximab for anti-GBM disease, and thus, randomized controlled studies are required.
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Enfermedad por Anticuerpos Antimembrana Basal Glomerular , Animales , Humanos , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/tratamiento farmacológico , Rituximab/uso terapéutico , Autoanticuerpos , Ciclofosfamida/uso terapéutico , Factores Biológicos , Membrana Basal/patologíaRESUMEN
Anti-glomerular basement membrane (anti-GBM) disease is typically characterized by autoimmunity against the α3 chain of type IV collagen. Rarely, circulating autoantibodies are not detected. These atypical cases follow a more indolent clinical course, and underlying mechanisms, including alternative target antigens, require investigation. In this issue of Kidney International, Kuang et al. describe a case of anti-GBM disease with autoantibodies against the GBM component laminin-521 and demonstrate that laminin-521 is pathogenic in a rat model of anti-GBM glomerulonephritis.
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Enfermedad por Anticuerpos Antimembrana Basal Glomerular , Glomerulonefritis , Ratas , Animales , Autoanticuerpos , Laminina , Riñón/patología , Colágeno Tipo IV , Membrana Basal/patología , AutoantígenosRESUMEN
Following allogenic hematopoietic stem cell transplantation (HSCT), graft-versus-host disease (GVHD) may develop which may affect several organs. Although the presence of nephrotic syndrome after HSCT is rare, sometimes it occurs in the setting of GVHD. The most common histological finding on kidney biopsy of patients with proteinuria owing to GVHD is membranous glomerulonephritis (MGN). However, reports of immune complex deposition in the tubular basement membrane (TBM) and glomerular basement membrane (GBM) are extremely rare. Herein we present a 65-year-old female with a history of HSCT at six years ago who was referred to Dr.Shariati Hospital in Tehran with nephrotic syndrome. Secondary serologic laboratory tests were all normal. The histopathologic study indicated diffuse GBM and TBM thickening, spike formation, infiltration of inflammatory mononuclear cells in tubulointerstitial area and acute tubular injury in light microscopy. Immunofluorescence staining showed immune complex deposits in GBM, mesangial cells, and TBM. DOI: 10.52547/ijkd.7550.
Asunto(s)
Glomerulonefritis Membranosa , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Síndrome Nefrótico , Femenino , Humanos , Anciano , Síndrome Nefrótico/etiología , Síndrome Nefrótico/complicaciones , Complejo Antígeno-Anticuerpo , Irán , Glomerulonefritis Membranosa/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Membrana Basal/patología , Enfermedad Injerto contra Huésped/complicaciones , Enfermedad Injerto contra Huésped/diagnósticoRESUMEN
BACKGROUND: Historically, due to the lack of distinct clinical symptoms, Alport syndrome, a hereditary kidney disease prevalent in children and a leading cause of kidney failure, has often been misdiagnosed as other kidney conditions. CASE DESCRIPTION: This article presents a comprehensive review and analysis of clinical data concerning a child diagnosed with Alport syndrome, where nephrotic syndrome served as the primary manifestation. The male child in this case exhibited symptoms starting at the age of 6, initially diagnosed as nephrotic syndrome. Consequently, oral steroid medication was administered, proving ineffective. Due to persistent proteinuria and microscopic hematuria, a renal biopsy was performed. Immunofluorescence staining revealed no abnormal expression of the α3, α4, and α5 chains of type IV collagen. Notably, electron microscopy revealed the basement membrane to be partially torn and arachnoid. Genetic testing indicated a hemizygous COL4A5 acceptor-splice-site mutation c.4707-1(IVS50)G > A, inherited from his mother. CONCLUSION: This specific mutated locus, being the first of its kind reported, adds valuable information to the existing gene mutation spectrum of Alport syndrome. Consequently, it emphasizes the importance for clinicians to deepen their understanding of rare kidney diseases, contributing to enhanced diagnostic accuracy and improved patient care.
Asunto(s)
Nefritis Hereditaria , Síndrome Nefrótico , Niño , Masculino , Humanos , Nefritis Hereditaria/diagnóstico , Nefritis Hereditaria/tratamiento farmacológico , Nefritis Hereditaria/genética , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/tratamiento farmacológico , Síndrome Nefrótico/metabolismo , Riñón/patología , Membrana Basal/metabolismo , Membrana Basal/patología , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismoRESUMEN
PURPOSE: This study aimed to determine closure rates of large idiopathic macular holes treated with pars plana vitrectomy and 360-degree pedicled inverted internal limiting membrane flap without face-down posturing and define visual improvement, types of macular hole closure, and external retina integrity as secondary outcomes. METHODS: This retrospective case series analyzed all patients who were treated by vitrectomy, 360-degree pedicled inverted internal limiting membrane flap, and gas tamponade, without face-down posturing postoperatively. Age, sex, time of visual acuity reduction, other ocular pathologies, and lens status were collected. The best-corrected visual acuity and optical coherence tomography results were recorded during pre- and postoperative follow-up examinations (15 days and 2 months after surgery). RESULTS: This study enrolled 20 eyes of 19 patients, and the mean age was 66 years. Optical coherence tomography performed 2 months after surgery revealed hole closure in 19 (95%) eyes. The median best-corrected visual acuity improved from +1.08 preoperatively to +0.66 LogMAR 2 months postoperatively (p<0.001), with a median of 20 letters of visual improvement (0.4 LogMAR) on the Early Treatment Diabetic Retinopathy Study chart. V (47.36%)- and U (52.63%)-types of closure were observed. CONCLUSION: The 360-degree pedicled inverted internal limiting membrane flap technique, without face-down posturing, provided a high closure rate (95%), external layer recovery, and V- and U-type foveal closure contours, in addition to visual improvement in most cases of large macular holes (even macular holes >650 µm). This technique may be a viable alternative to patients in whom traditional postoperative face-down positioning for large macular hole treatment is not possible.