Advancement on the pathogenesis of hereditary multiple exostoses / 中华骨科杂志

Hereditary multiple exostoses (HME) are benign bone tumors characterized by autosomal dominant inheritance, which can cause skeletal malformation in adolescents, seriously affecting the body's aesthetic and motor functions. Currently, there are no guidelines for diagnosing and treating HME, and the main treatment is surgical treatment to remove the tumor and correct the deformity. However, osteochondroma is multiple and difficult to be completely resected. Therefore, more and more scholars are exploring the method of conservative treatment. However, the current understanding of the pathogenesis of HME is limited, and there are no safe and effective drugs in the clinic. Most hypotheses regarding the pathogenesis of HME are based on genetic mutations. Patients with HME may have EXT tumor suppressor gene mutations and function loss caused by secondary mutations such as loss of gene heterozygosity, which ultimately induce abnormal proliferation and differentiation of cartilage in growth plates. Abnormal EXT gene expression causes a decrease in the level of heparan sulphate (HS), leading to abnormalities in multiple molecular pathways that regulate the development and differentiation of growth plate chondrocytes, which together participate in the entire process of HME development and progression. This paper reviews the relevant studies on the pathogenesis of HME in recent years, in order to better understand the pathological process of HME, provide a theoretical basis for the diagnosis and treatment of HME, and also provide ideas for the development of drugs targeting HME.

Mucopolisacaridosis III. Revisión bibliográfica / Mucopolysaccharidosis III. Bibliographic review

Mucopolisacaridosis de tipo III es una enfermedad rara, con una incidencia de 1 en 70 000 nacidos vivos, es la más frecuente dentro del grupo de Mucopolisacaridosis y se produce por un defecto en la vía del metabolismo del heparan sulfato. Se caracteriza por afectar a mayor profundidad el sistema nervioso central, el paciente tiene un desarrollo normal hasta aproximadamente los 1 a 3 años de edad y posteriormente empieza con deterioro progresivo, cursa con retraso del desarrollo, alteración del comportamiento y trastorno del sueño agregándose déficit motor y cuadros infecciosos, culminando en un estado de postración. La esperanza de vida oscila entre los 20 a 30 años, aunque depende del fenotipo y la principal causa de muerte fue la neumonía. El diagnóstico definitivo se consigue mediante pruebas genómicas y ensayo enzimático. No cuenta con tratamiento curativo, únicamente con paliación y soporte ante las complicaciones que va desarrollando

Mucopolysaccharidosis III is a rare disease, with an incidence of 1 in 70 000 live births, it is the most frequent within the group of Mucopolysaccharidosis and is caused by a defect in the heparan sulfate metabolism pathway. It is characterized by affecting the central nervous system in greater depth, the patient has a normal development until approximately 1 to 3 years of age and later begins with progressive deterioration, courses with developmental delay, behavioral alteration and sleep disorder, adding motor deficits and infectious pictures, culminating in a state of prostration. Life expectancy ranges from 20 to 30 years, although it depends on the phenotype, and the main cause of death is pneumonia. Definitive diagnosis is achieved by genomic tests and enzymatic assay. It does not have curative treatment, only palliation and support in the face of the complications that it develops.

Genetic mutation analysis in three pedigrees with hereditary multiple exostosis / 中华检验医学杂志

Objective:To detect the pathogenic gene of the three pedigrees with hereditary multiple exostosis, and to provide evidences for genetic counselling and prenatal diagnosis.Methods:The three families were admitted to the Institute of Medical Genetics of Henan Provincial People′s Hospital due to hereditary multiple exostosis from January 2018 to December 2020. Detail medical history and the blood samples of the family members were collected after they signed the informed consent forms. The pathological mutations were selected from the proband using whole exome sequencing (WES). Sanger sequencing was used to conduct the co-segregation analysis of the family members. The pathogenicity of the mutation was analyzed in combination with ACMG guidelines.Results:The EXT1 gene c.1056+2T>C mutation, c.369dupA (p.G124fs) mutation and the EXT2 gene c.1171C>T (p.Q391*) mutation were detected in the probands through whole exome sequencing. The same mutations were found in the patients from these three families, while the mutation was not detected among the healthy family members. These variations have co-segregated with the disease phenotype. According to ACMG guidelines, all mutations in these three families meet the criteria of pathogenic variations. Conclusion:The EXT1 gene c.1056+2T>C mutation, c.369dupA (p.G124fs) mutation and the EXT2 gene c.1171C>T (p.Q391*) mutation were identified to be responsible for hereditary multiple exostosis in these families.

Glycomics expression analysis of sulfated glycosaminoglycans of human colorectal cancer tissues and non-neoplastic mucosa by electrospray ionization mass spectrometry / Análise da expressão de glicosaminoglicanos sulfatados no tecido humano neoplásico colorretal e na mucosa não neoplásica por espectrometria de massa por ionização por electrospray

ABSTRACT Objective To determine the presence of glycosaminoglycans in the extracellular matrix of connective tissue from neoplastic and non-neoplastic colorectal tissues, since it has a central role in tumor development and progression. Methods Tissue samples from neoplastic and non-neoplastic colorectal tissues were obtained from 64 operated patients who had colorectal carcinoma with no distant metastases. Expressions of heparan sulphate, chondroitin sulphate, dermatan sulphate and their fragments were analyzed by electrospray ionization mass spectrometry, with the technique for extraction and quantification of glycosaminoglycans after proteolysis and electrophoresis. The statistical analysis included mean, standard deviation, and Student’st test. Results The glycosaminoglycans extracted from colorectal tissue showed three electrophoretic bands in agarose gel. Electrospray ionization mass spectrometry showed characteristic disaccharide fragments from glycosaminoglycans, indicating their structural characterization in the tissues analyzed. Some peaks in the electrospray ionization mass spectrometry were not characterized as fragments of sugars, indicating the presence of fragments of the protein structure of proteoglycans generated during the glycosaminoglycan purification. The average amount of chondroitin and dermatan increased in the neoplastic tissue compared to normal tissue (p=0.01). On the other hand, the average amount of heparan decreased in the neoplastic tissue compared to normal tissue (p= 0.03). Conclusion The method allowed the determination of the glycosaminoglycans structural profile in colorectal tissue from neoplastic and non-neoplastic colorectal tissue. Neoplastic tissues showed greater amounts of chondroitin sulphate and dermatan sulphate compared to non-neoplastic tissues, while heparan sulphate was decreased in neoplastic tissues.

RESUMO Objetivo Determinar a presença de glicosaminoglicanos na matriz extracelular do tecido conjuntivo colorretal neoplásico e não neoplásico, tendo em vista seu papel central no desenvolvimento e na progressão dos tumores. Métodos Amostras de tecidos colorretais neoplásicos e não neoplásicos foram obtidas de 64 pacientes operados com carcinoma colorretal sem metástases a distância. As expressões de heparan sulfato, sulfato de condroitina e sulfato de dermatan e seus fragmentos foram analisadas por espectrometria de massa por ionização por electrospray, com técnica de extração e quantificação de glicosaminoglicanos após proteólise e eletroforese. Para análise estatística, utilizaram-se média, desvio padrão e teste t de Student. Resultados Em gel de agarose, os glicosaminoglicanos extraídos de tecido colorretal mostraram três bandas eletroforéticas. A espectrometria de massa por ionização por electrospray mostrou fragmentos de dissacarídeos característicos de glicosaminoglicanos e indicou sua característica estrutural. Alguns picos na espectrometria de massa por ionização por electrospray não foram caracterizados como fragmentos de açúcares, sugerindo a presença de fragmentos de proteínas estruturais dos proteoglicanos, formadas durante a purificação dos glicosaminoglicanos. A quantidade média de condroitina e dermatan aumentou no tecido neoplástico em relação ao tecido normal (p=0,01). Por outro lado, a quantidade média de heparan foi menor no tecido neoplásico em relação ao tecido normal (p=0,03). Conclusão O método empregado permitiu determinar o perfil estrutural dos glicosaminoglicanos nas amostras. Tecidos neoplásicos apresentaram maiores quantidades de sulfato de condroitina e sulfato de dermatan em comparação com os não neoplásicos, enquanto o sulfato de heparan foi encontrado em menores quantidades nos tecidos neoplásicos.

Effect of systemic heparan sulfate haploinsufficiency on steady state hematopoiesis and engraftment of hematopoietic stem cells.

Heparan sulfate (HS) proteoglycans on stromal and hematopoietic stem/progenitor cells (HSPC) help form the stem cell niche, co-localize molecules that direct stem cell fate, and modulate HSPC homing and retention. Inhibition of HS function mobilizes marrow HSPC. In vitro, HSPC maintenance is influenced by stromal HS structure and concentration. Because inhibition of HS activity or synthesis may be developed for HSPC transplantation, it is important to examine if systemic HS deficiency influences hematopoiesis in vivo. In a transgenic mouse model of HS haploinsufficiency, we examined endogenous hematopoiesis and engraftment of allogeneic bone marrow. Endogenous hematopoiesis was normal except gender-specific alterations in peripheral blood monocyte and platelet counts. Donor engraftment was achieved in all mice following myeloablative irradiation, but HS deficiency in the stromal microenvironment, on HSPC, or both (the 3 test conditions), was associated with a trend towards lower donor engraftment percentage in the bone marrow. Following non-myeloablative irradiation, competitive engraftment was achieved in 22% of mice in the test conditions, vs 50% of control animals (P = 0.03). HS deficiency did not re-direct donor engraftment from bone marrow to spleen or liver. Normal HS levels in the stromal microenvironment and HSPC are required for HSPC engraftment following non-myeloablative conditioning.

Heparanase accelerates angiogenesis after cerebral ischemia / 国际脑血管病杂志

Heparanase (Hpa) is the only β-D-glucuronidase of degading heparan sulfate proteoglycans in the body of mammalian.Studies have confirmed that Hpa accelerates angiogenesis in multiple physiopathological processes; however there are still a few studies about the expression and role of Hpa after cerebral ischemia.This article mainly introduces the relation between Hpa and angiogenesis after cerebral ischemia.

Effects of Low-Molecular-Weight Heparin on Respiratory Syncytial Virus Nephropathy in Rats / 实用儿科临床杂志

0.05).3.Under light microscope, there was no change of the glomeruli detected in all of the LMWH-treated groups compared with the controls,while congestion and swel-ling in part glomeruli of group RSV were observed significantly. 4.Under electron microscope,glomerular structures of the LMWH-treated groups were almost normal compared with the control, while extensive foot process effacement was observed in group RSV under an electron microscope. 5.RSV RNA signal expressed weaker in the LMWH-treated groups than in group RSV.Conclusions Positive charged RSV destroys the glome-rular filtration barrier through its electrostatic interaction with the negative charged heparan sulfate(HS) of GBM. LMWH, as the analog of HS, charged with anion, competes with GBM HS to combine with RSV to keep the glomeruli from being infected and destroyed, and then reduce the proteinuria.