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1.
Transl Oncol ; 44: 101937, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38547613

RESUMEN

BACKGROUND: Soft tissue sarcoma, a malignant tumor arising from mesenchymal tissues with poor prognosis. 5'-Nucleotidase Domain Containing 2 (NT5DC2) is a novel oncogene, and the precise involvement of NT5DC2 in soft tissue sarcoma were still undefined. Hence, our study aims to investigate NT5DC2 functions in soft tissue sarcoma progression. METHODS: The tumor immune single-cell hub 2 (TISCH2) website, The Cancer Genome Atlas (TCGA) pan-cancer or sarcoma and Gene Expression Omnibus (GEO, GSE21122) databases were applied to visualize the NT5DC2 status in the sarcoma databases. The NT5DC2 protein expression in sarcoma tissues in our hospital was detected by using immunohistochemistry (IHC) and analyzed the associations between NT5DC2 expression and clinicopathological parameters. Real-time quantitative polymerase chain reaction (RT-qPCR), colony formation, 5-ethynyl-2'-deoxyuridine (EdU) assay, wound healing, transwell, flow cytometry and xenograft model were used to elucidate the effects of NT5DC2 downregulated by lentivirus in sarcoma cell. RESULTS: The TISCH2 website detection found that NT5DC2 expression is enriched in malignant cells in sarcoma single-cell database. Furthermore, the TCGA-sarcoma database indicated that NT5DC2 expression correlates with metastasis, positive margin status, prognosis, and diagnostic value. Additionally, IHC staining showed that 40 % of soft tissue sarcoma patients present high expression of NT5DC2, and NT5DC2 upregulation is closely associated with poor prognosis. Functional verification analysis further revealed that downregulating NT5DC2 expression can suppress sarcoma progression through the ECM-receptor interaction pathway. CONCLUSION: Low expression of NT5DC2 predicts a favorable prognosis in soft tissue sarcoma, and downregulated NT5DC2 expression can suppress sarcoma cell progression through the ECM-receptor interaction pathway.

2.
Clin Transl Med ; 14(2): e1586, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38372422

RESUMEN

BACKGROUND: Osteosarcoma (OSA) presents a clinical challenge and has a low 5-year survival rate. Currently, the lack of advanced stratification models makes personalized therapy difficult. This study aims to identify novel biomarkers to stratify high-risk OSA patients and guide treatment. METHODS: We combined 10 machine-learning algorithms into 101 combinations, from which the optimal model was established for predicting overall survival based on transcriptomic profiles for 254 samples. Alterations in transcriptomic, genomic and epigenomic landscapes were assessed to elucidate mechanisms driving poor prognosis. Single-cell RNA sequencing (scRNA-seq) unveiled genes overexpressed in OSA cells as potential therapeutic targets, one of which was validated via tissue staining, knockdown and pharmacological inhibition. We characterized changes in multiple phenotypes, including proliferation, colony formation, migration, invasion, apoptosis, chemosensitivity and in vivo tumourigenicity. RNA-seq and Western blotting elucidated the impact of squalene epoxidase (SQLE) suppression on signalling pathways. RESULTS: The artificial intelligence-derived prognostic index (AIDPI), generated by our model, was an independent prognostic biomarker, outperforming clinicopathological factors and previously published signatures. Incorporating the AIDPI with clinical factors into a nomogram improved predictive accuracy. For user convenience, both the model and nomogram are accessible online. Patients in the high-AIDPI group exhibited chemoresistance, coupled with overexpression of MYC and SQLE, increased mTORC1 signalling, disrupted PI3K-Akt signalling, and diminished immune infiltration. ScRNA-seq revealed high expression of MYC and SQLE in OSA cells. Elevated SQLE expression correlated with chemoresistance and worse outcomes in OSA patients. Therapeutically, silencing SQLE suppressed OSA malignancy and enhanced chemosensitivity, mediated by cholesterol depletion and suppression of the FAK/PI3K/Akt/mTOR pathway. Furthermore, the SQLE-specific inhibitor FR194738 demonstrated anti-OSA effects in vivo and exhibited synergistic effects with chemotherapeutic agents. CONCLUSIONS: AIDPI is a robust biomarker for identifying the high-risk subset of OSA patients. The SQLE protein emerges as a metabolic vulnerability in these patients, providing a target with translational potential.


Asunto(s)
Neoplasias Óseas , Osteosarcoma , Escualeno-Monooxigenasa , Humanos , Inteligencia Artificial , Biomarcadores , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/genética , Fosfatidilinositol 3-Quinasas , Pronóstico , Proteínas Proto-Oncogénicas c-akt , Escualeno-Monooxigenasa/genética , Escualeno-Monooxigenasa/metabolismo
3.
Chemistry ; 30(24): e202304209, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38372165

RESUMEN

It is challenging to realize the selective C-C bond cleavage of lignin ß-O-4 linkages for production of high-value aromatic chemicals due to its intrinsic inertness and complex structure. Here we report a light-driven, chlorine-radical-based protocol to realize the oxidative C-C bond cleavage in various lignin model compounds catalyzed by commercially available TPT and CaCl2, achieving high conversion and good to high product yields at room temperature. Mechanistic studies reveal that the preferential activation of Cß-H bond facilitates the oxidation and C-C bond cleavage of lignin ß-O-4 model via chlorine radical. Furthermore, this method is also applicable to the depolymerization of natural lignin extracts, furnishing the aromatic oxygenates from the cleavage of Cα-Cß bonds. This study provides experimental foundations to the depolymerization and valorization of lignin into high value-added aromatic compounds.

4.
Front Bioeng Biotechnol ; 11: 1289363, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38116196

RESUMEN

Background: Prostheses for the reconstruction of periacetabular bone tumors are prone to instigate stress shielding. The purpose of this study is to design 3D-printed prostheses with topology optimization (TO) for the reconstruction of periacetabular bone tumors and to add porous structures to reduce stress shielding and facilitate integration between prostheses and host bone. Methods: Utilizing patient CT data, we constructed a finite element analysis (FEA) model. Subsequent phases encompassed carrying out TO on the designated area, utilizing the solid isotropic material penalization model (SIMP), and this optimized removal area was replaced with a porous structure. Further analyses included preoperative FEA simulations to comparatively evaluate parameters, including maximum stress, stress distribution, strain energy density (SED), and the relative micromotion of prostheses before and after TO. Furthermore, FEA based on patients' postoperative CT data was conducted again to assess the potential risk of stress shielding subsequent to implantation. Ultimately, preliminary follow-up findings from two patients were documented. Results: In both prostheses, the SED before and after TO increased by 143.61% (from 0.10322 to 0.25145 mJ/mm3) and 35.050% (from 0.30964 to 0.41817 mJ/mm3) respectively, showing significant differences (p < 0.001). The peak stress in the Type II prosthesis decreased by 10.494% (from 77.227 to 69.123 MPa), while there was no significant change in peak stress for the Type I prosthesis. There were no significant changes in stress distribution or the proportion of regions with micromotion less than 28 µm before and after TO for either prosthesis. Postoperative FEA verified results showed that the stress in the pelvis and prostheses remained at relatively low levels. The results of follow-up showed that the patients had successful osseointegration and their MSTS scores at the 12th month after surgery were both 100%. Conclusion: These two types of 3D-printed porous prostheses using TO for periacetabular bone tumor reconstruction offer advantages over traditional prostheses by reducing stress shielding and promoting osseointegration, while maintaining the original stiffness of the prosthesis. Furthermore, in vivo experiments show that these prostheses meet the requirements for daily activities of patients. This study provides a valuable reference for the design of future periacetabular bone tumor reconstruction prostheses.

5.
Drug Dev Res ; 84(8): 1751-1763, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37784254

RESUMEN

Osteosarcoma is a prevalent malignant bone tumor with a poor prognosis. Mothers against decapentaplegic homolog 3 (Smad3) present as a therapeutic target in antitumor treatment, whereas its functions in the osteosarcoma have not been well explored. In the current study, we aimed to investigate the effects of Smad3 in the progression of osteosarcoma. The tumor immune single-cell hub 2 website was used for graph-based visualization of Smad3 status in osteosarcoma single-cell database. Western Blot was applied to detect the expression of Smad3 protein in cell lines. Colony formation and cell counting kit-8 assays were used to evaluate cell proliferation. Transwell and wound healing assays were used to detect the migration and invasion abilities of cells. Cell apoptosis rates and cell cycle changes were explored by using flow cytometry analysis. The xenograft tumor growth model was applied to explore the effect in tumor growth after Smad3 blockage in vivo. Moreover, to confirm the potential mechanism of Smad3's effects on osteosarcoma, bioinformatics analysis was performed in TARGET-Osteosarcoma and GSE19276 databases. Our study found that the Smad3 protein is overexpressed in 143B and U2OS cells, suppressing the expression of Smad3 protein in osteosarcoma cells by Smad3 target inhibitor (E)-SIS3 or lentivirus can inhibit the proliferation, migration, invasion, promote cell apoptosis, arrest cell G1 cycle in osteosarcoma cells in vitro, and suppress tumor growth in vivo. Furthermore, the bioinformatics analysis demonstrated that high expression of Smad3 is closely associated with low immune status in TARGET-Osteosarcoma and GSE19276 databases. Our study suggested that Smad3 could contribute positively to osteosarcoma progression via the regulation of tumor immune microenvironment, and Smad3 may represent as an valuable potential therapeutic target in osteosarcoma therapy.


Asunto(s)
Neoplasias Óseas , Osteosarcoma , Humanos , Proteína smad3 , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/metabolismo , Osteosarcoma/patología , Apoptosis , Ciclo Celular , Proliferación Celular , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Línea Celular Tumoral , Movimiento Celular , Microambiente Tumoral
6.
Front Bioeng Biotechnol ; 11: 1153394, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37187886

RESUMEN

Background: Acetabular metastasis is a type of metastatic bone cancer, and it mainly metastasizes from cancers such as lung cancer, breast cancer, and renal carcinoma. Acetabular metastasis often causes severe pain, pathological fractures, and hypercalcemia which may seriously affect the quality of life of acetabular metastasis patients. Due to the characteristics of acetabular metastasis, there is no most suitable treatment to address it. Therefore, our study aimed to investigate a novel treatment technique to relieve these symptoms. Methods: Our study explored a novel technique to reconstruct the stability of the acetabular structure. A surgical robot was used for accurate positioning and larger-bore cannulated screws were accurately inserted under the robot's guidance. Then, the lesion was curetted and bone cement was injected through a screw channel to further strengthen the structure and kill tumor cells. Results: A total of five acetabular metastasis patients received this novel treatment technique. The data relating to surgery were collected and analyzed. The results found that this novel technique can significantly reduce operation time, intraoperative bleeding, visual analogue score scores, Eastern Cooperative Oncology Group scores, and postoperative complications (e.g., infection, implant loosening, hip dislocation) after treatment. Follow-up time ranged from 3 months to 6 months, and the most recent follow-up results showed that all patients survived and no acetabular metastasis progressed in any of the patients after surgery. Conclusion: Surgical robot-assisted tripod percutaneous reconstruction combined with the bone cement filling technique may be a novel and suitable treatment in acetabular metastasis patients. Our study may provide new insights into the treatment of acetabular metastasis.

7.
Biomed Res Int ; 2021: 8410317, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33997042

RESUMEN

OBJECTIVE: (1) To propose a novel technique named thoracic extensive laminoplasty (TELP) in curing severe thoracic ligamentum flavum ossification (STOLF) and (2) to compare outcomes between TELP and laminectomy in curing STOLF. METHODS: Cases with fused or tuberous STOLF (Sato classification) treated from Jan 2015 to Jan 2017 were reviewed and divided into the TELP group (G1) and laminectomy group (G2) according to their surgical management. Data on demographics, complications, pre- and postoperative symptoms, residual spinal canal area (RSCA-1), residual spinal cord area (RSCA-2), modified Japanese Orthopedic Association score (mJOA), and health-related quality of life (HRQOL, based on the SF-36) were collected. RESULTS: Fifty-nine G1 and sixty-two G2 patients were enrolled. No significant differences in demographic data or preoperative data of RSCA-1, RSCA-2, mJOA, or HRQOL were observed between the two groups (p > 0.05). Patients in G1 and G2 showed similar postoperative improvements in RSCA-1 and RSCA-2 at the final follow-up (p > 0.05). However, patients in G1 showed higher postoperative improvements in mJOA (OR = 2.706, 95% CI: 1.279~5.727, p = 0.008) at the final follow-up. Patients in G1 also showed higher postoperative improvements in HRQOL than patients in G2 (p < 0.05) at the final follow-up, and patients with more severe STOLF presented with better improvements in HRQOL in G1 (p < 0.05). Dural laceration and cerebrospinal fluid leakage were observed in seven G2 patients, and no complications were found in G1 patients after surgery. CONCLUSION: TELP is a novel, effective, and safer surgical technique in treating STOLF and could be a substitute for traditional laminectomy.


Asunto(s)
Laminectomía , Laminoplastia , Ligamento Amarillo/cirugía , Osificación del Ligamento Longitudinal Posterior/cirugía , Enfermedades de la Columna Vertebral/cirugía , Estudios de Casos y Controles , Femenino , Humanos , Laminectomía/efectos adversos , Laminectomía/métodos , Laminoplastia/efectos adversos , Laminoplastia/métodos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Calidad de Vida
8.
Theranostics ; 10(19): 8619-8632, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32754267

RESUMEN

Numerous factors have been claimed to play important roles in colorectal cancer (CRC) tumorigenesis, including myeloid-derived suppressor cells (MDSCs) and other immune cells, cytokines, and chemokines; however, the precise mechanisms of colorectal tumorigenesis remain elusive, and there is a lack of effective preventive treatments. Here, we investigated the role of complement system, a key regulator of immune surveillance and homeostasis, in colorectal tumorigenesis. Methods: The prototypical CRC model was induced by combined administration of azoxymethane (AOM)/ dextran sulfate sodium (DSS) in Wild-type (WT), C3-, C5-, C5ar1-, and C5ar2-deficient mice. Using flow cytometry, immunohistochemical staining and multiplex bead assay, we profiled the immune cells, cytokines and chemokines. Bone marrow transplantation was employed to determine the contribution of immune cells in colorectal tumorigenesis. Further, we used C5aR1 antagonist PMX205 to investigate the protective role in colorectal tumorigenesis. Results: Complement was extensively activated in inflamed tissues of AOM/DSS-induced murine CRC model, leading to multifaceted consequences. The deficiency of complement C5 or especially C5ar1, but not C3 almost completely prevented CRC tumorigenesis. C5a/C5aR1 signaling recruited MDSCs into the inflamed colorectum to impair CD8+ T cells, and modulated the production of critical cytokines and chemokines, thus initiating CRC. Moreover, the C5aR1 antagonist PMX205 strongly impeded colorectal tumorigenesis. Bone marrow transplantation further revealed that C5aR1 expression by immune cells was critical for colorectal tumorigenesis. Conclusion: Our study identifies C5a/C5aR1 signaling as a vital immunomodulatory program in CRC tumorigenesis and suggests a feasible preventive strategy.


Asunto(s)
Azoximetano/efectos adversos , Linfocitos T CD8-positivos/metabolismo , Colitis/complicaciones , Neoplasias Colorrectales/inmunología , Sulfato de Dextran/efectos adversos , Receptor de Anafilatoxina C5a/genética , Animales , Trasplante de Médula Ósea , Colitis/inducido químicamente , Colitis/genética , Colitis/inmunología , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/terapia , Complemento C3/genética , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Inactivación de Genes , Masculino , Ratones , Péptidos Cíclicos/administración & dosificación , Péptidos Cíclicos/farmacología
9.
J Med Genet ; 57(6): 405-413, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32381728

RESUMEN

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a genetically heterogeneous disease characterised by three-dimensional deformity of the spine in the absence of a congenital spinal anomaly or neurological musculoskeletal disorder. The clinical variability and incomplete penetrance of some genes linked with AIS indicate that this disease constitutes an oligogenic trait. OBJECTIVE: We aimed to explore the oligogenic nature of this disease and identify novel AIS genes. METHODS: We analysed rare damaging variants within AIS-associated genes by using exome sequencing in 40 AIS trios and 183 sporadic patients. RESULTS: Multiple variants within AIS-associated genes were identified in eight AIS trios, and five individuals harboured rare damaging variants in the FLNB gene. The patients showed more frequent oligogenicity than the controls. In the gene-based burden test, the top signal resided in FLNB. In functional studies, we found that the AIS-associated FLNB variants altered the protein's conformation and subcellular localisation and its interaction with other proteins (TTC26 and OFD1) involved in AIS. The most compelling evidence of an oligogenic basis was that the number of rare damaging variants was recognised as an independent prognostic factor for curve progression in Cox regression analysis. CONCLUSION: Our data indicate that AIS is an oligogenic disease and identify FLNB as a susceptibility gene for AIS.


Asunto(s)
Filaminas/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Escoliosis/genética , Adolescente , Niño , Exoma/genética , Femenino , Filaminas/ultraestructura , Pruebas Genéticas , Variación Genética/genética , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Conformación Proteica , Proteínas/genética , Escoliosis/patología , Secuenciación del Exoma
10.
Transl Cancer Res ; 9(3): 1795-1805, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35117527

RESUMEN

BACKGROUND: Osteosarcoma (OS) is among the most prevalent forms of malignant tumors seen in children and teenagers. Early metastasis is a hallmark of OS, and it is therefore important to find new and more effective treatment targets to improve the survival time of patients with the disease. High mobility group N (HMGNs) is a family of proteins that contributes to the development of a number of different tumors. In particular, HMGN2 was found in our earlier study to be an anti-tumor factor and was seen to impede the metastasis of OS when it was overexpressed. This study aims to further investigate the potential of HMGN2 in anti-tumor treatment. METHODS: We overexpressed HMGN2 in 293FT cells via transfection with recombinant lentiviruses and purified HMGN2 protein with flag tags to treat OS cell lines. The cellular location of exogenous HMGN2 was detected by immunocytochemistry, and wound healing and transwell assays were used to study differences in the rates of migration and invasion of cells between each group. RESULTS: We found that exogenous HMGN2 enters OS cells in a concentration-dependent manner and inhibits the migration and invasion of OS cells, and exogenous HMGN2 regulates the expression of matrix metalloproteinase 2 (MMP2) and MMP9 in OS cells. CONCLUSIONS: Our results demonstrated that exogenous HMGN2 plays a role in inhibiting OS metastasis, which could act as a basis for new ideas for future anti-tumor therapy research.

11.
Eur Spine J ; 28(9): 1977-1986, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31079250

RESUMEN

PURPOSE: To determine the relationship between the bone formation-related functions of GPR126 and the structural asymmetry of spine in adolescent idiopathic scoliosis (AIS). METHODS: Vertebral body samples were obtained from 51 AIS patients during spinal surgery between October 2014 and November 2017, and the expression pattern of GPR126 in the convex/concave sides of AIS spine was identified by RT-qPCR. Next, we explored the bone formation-related functions of GPR126 by knocking down and overexpressing GPR126 in human mesenchymal stem cells (hMSC) and further performing osteogenic differentiation. We also applied overexpression of N-terminal fragments derived from GPR126 (GPR126-NTFs) and osteogenic differentiation experiments to determine the functional part of GPR126 in skeletal development. RESULTS: We provided evidence that GPR126 showed a marked convex/concave asymmetric expression in the spine of AIS. Further RNA detection found that exon6-included transcripts of GPR126 (GPR126-exon6in) were significantly higher expressed in the convex side of AIS patients. Knocking down of GPR126 accelerated ossification of hMSCs during osteogenic differentiation, and overexpression of GPR126-exon6in delayed this process. Overexpression of GPR126-NTFs revealed that NTF is a functional fragment and exon6-included NTF (NTF-exon6in) delayed ossification of hMSCs. CONCLUSION: Our findings indicated that GPR126-NTFs play a role in skeletal development, and the inclusion/exclusion of exon6 may regulate the bone formation-related functions of GPR126. The convex/concave asymmetric expression of GPR126-exon6in may be an important factor in abnormal bone formation of AIS. These slides can be retrieved under Electronic Supplementary Material.


Asunto(s)
Anomalías Musculoesqueléticas/metabolismo , Receptores Acoplados a Proteínas G/biosíntesis , Escoliosis/metabolismo , Adolescente , Diferenciación Celular/fisiología , Células Cultivadas , Niño , Femenino , Regulación de la Expresión Génica/fisiología , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/patología , Anomalías Musculoesqueléticas/genética , Anomalías Musculoesqueléticas/patología , Osteogénesis/genética , Osteogénesis/fisiología , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiología , Escoliosis/genética , Escoliosis/patología , Escoliosis/cirugía , Columna Vertebral/patología , Columna Vertebral/fisiopatología
12.
Biomed Res Int ; 2019: 4678969, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30886859

RESUMEN

Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity disease in adolescents but its etiology and pathogenesis are still unclear. The current study aims to identify the relationship between single nucleotide polymorphisms (SNPs) of G protein-coupled receptor 126 (GPR126) gene and AIS predisposition. GPR126 contains 26 exons and alternative splicing of exon 6 and exon 25 produces 4 protein-coding transcripts. We genotyped SNPs of GPR126 gene around exon 6 and exon 25 in 131 Chinese AIS patients and 132 healthy controls and provided evidence that SNP rs41289839 G>A is strongly associated with AIS susceptibility. Linkage disequilibrium analysis suggests that rs41289839 and other AIS-related SNPs were in strong LD. Next, we demonstrated that rs41289839 G>A inhibits the inclusion of exon 6 during alternative splicing, resulting in a decreased expression level of exon 6-included transcript (GPR126-exon6in) relative to the exon 6 excluded transcript (GPR126-exon6ex) by minigene assay. Chondrogenic differentiation experiment showed that GPR126-exon6in has a high expression level relative to GPR126-exon6ex during chondrogenic differentiation of hMSCs. Our findings indicate that newly discovered SNP is related to cartilage development and may provide valuable insights into the etiology and pathogenesis of adolescent idiopathic scoliosis.


Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Receptores Acoplados a Proteínas G/genética , Escoliosis/genética , Adolescente , Adulto , Anciano , Alelos , Cartílago/metabolismo , Cartílago/patología , Diferenciación Celular/genética , Niño , Condrogénesis/genética , Exones/genética , Femenino , Genotipo , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Escoliosis/fisiopatología , Adulto Joven
13.
World Neurosurg ; 126: e173-e180, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30797914

RESUMEN

OBJECTIVE: To determine the safety and effectiveness of the combined halo gravity traction and dual growing rod technique in achieving and maintaining scoliosis correction while allowing spinal growth. METHODS: From January 2014 to July 2017, 11 patients with dystrophic neurofibromatosis type 1 (NF1)-associated scoliosis, including 7 men and 4 women, underwent combined halo gravity traction and dual growing rod technique procedures. Diagnoses were all dystrophic NF1-associated scoliosis. Patients with a Cobb angle of major curve >60° and flexibility of spine <30% were included in our research. Analysis included age at the time of treatment, levels of instrumentation, number and frequency of lengthening, lengthening distance, and complications. The changes in Cobb angle of scoliosis and T1-S1 length of spine over the treatment period were measured by radiographic evaluation. RESULTS: The average age of treated patients was 7.2 years (range, 5-9 years). Growing rods were lengthened every 6 months through exposure. The mean number of times of lengthening was 3.9 (range, 3-5). The distance of each extension was 1.6 cm (range, 1.0-2.0 cm). The Cobb angle was corrected 41.7% on average after traction, 48.4% after initial surgery, and 53.3% at the last follow-up. T1-S1 length increased 3.4 cm (range, 1.2-5.1 cm) on average over a mean treatment period of 2.2 years, with an average of 1.5 cm/y (range, 0.5-2.3 cm/y). During the treatment period, complication of hook dislodgement occurred in 1 of 11 patients (9.1%). CONCLUSIONS: The combined halo gravity traction and dual growing rod technique can safely and effectively correct NF1-associated scoliosis. This is an ongoing study that requires long-term follow-up.


Asunto(s)
Fijadores Externos , Distrofias Musculares/etiología , Distrofias Musculares/terapia , Neurofibromatosis 1/complicaciones , Escoliosis/etiología , Escoliosis/terapia , Tracción/métodos , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Masculino , Distrofias Musculares/diagnóstico por imagen , Neurofibromatosis 1/diagnóstico por imagen , Aparatos Ortopédicos , Escoliosis/diagnóstico por imagen , Tracción/instrumentación , Resultado del Tratamiento
14.
Biomed Res Int ; 2019: 5630124, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31930127

RESUMEN

Osteosarcoma is one of the most common malignant tumors in children and adolescents and is characterized by early metastasis. High-mobility group N (HMGN) domains are involved in the development of several tumors. Our previous study found that HMGN5 is highly expressed in osteosarcoma tissues and knockdown of HMGN5 inhibits migration and invasion of U-2 OS and Saos-2 cells. A hypoxic environment is commonly found in solid tumors such as osteosarcoma and is likely to be associated with tumor metastasis, so we further explored the relationship between HMGN5 and the hypoxic environment. Hypoxia-inducible factor 1A (HIF1A) is an adaptive factor in the hypoxic environment. We found that HIF1A and HMGN5 were upregulated in osteosarcoma (OS) cells cultured in the hypoxic environment, and the results of overexpression and knockdown experiments showed that HIF1A upregulated the transcription factor GATA1 and further promoted the expression of HMGN5. In addition, MMP2 and MMP9 were subsequently upregulated through the c-jun pathway, and finally, this promoted the migration and invasion of OS cells. It is suggested that HMGN5 may be an important downstream factor for HIF1A to promote osteosarcoma metastasis. It has an important clinical significance for the selection of therapeutic targets for osteosarcoma.


Asunto(s)
Factor de Transcripción GATA1/genética , Proteínas HMGN/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Hipoxia/genética , Metástasis de la Neoplasia/genética , Osteosarcoma/genética , Transactivadores/genética , Línea Celular Tumoral , Movimiento Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Hipoxia/patología , Metástasis de la Neoplasia/patología , Osteosarcoma/patología , Regulación hacia Arriba/genética
15.
RSC Adv ; 8(50): 28376-28385, 2018 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-35542465

RESUMEN

Prolinamides with double-H potential were prepared and employed as organocatalysts in asymmetric aldol reactions. The catalyst with adamantane showed improved catalytic activity, which was further enhanced by using brine as the solvent. A series of aldol reactions in brine at 0 °C provided good yields (up to 98%) with high diastereoselectivities (>99 : 1) and enantioselectivities (>99%). The prepared catalyst was adsorbed by a nanofibrous film of poly(AN-MA-ß-CD) via host-guest interaction in the reaction system. The catalyst was separated from the film by applying ultrasound, with a total recovery of 96.2%. The catalyst was reused up to five times without a significant change in diastereoselectivity and enantioselectivity.

16.
Biomed Res Int ; 2018: 3476425, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30627550

RESUMEN

Coronal decompensation is a common complication in Lenke 1 or 2 AIS patients after selective thoracic fusion (STF). However, the majority who developed immediately postoperative coronal decompensation experienced improvement and the related factors are not fully understood. The aim of this retrospective study was to investigate the prevalence of coronal imbalance in patients with Lenke 1 or 2 AIS and to explore radiological factors associated with spontaneous correction of coronal balance after surgery. Lenke 1 or 2 AIS patients receiving STF in our center from January 2013 to March 2015 were analyzed. Anteroposterior and lateral films were evaluated before surgery, at 1 month's and 2 years' follow-up. Patients were divided into 2 groups according to whether coronal imbalance occurred in the early postoperative period (1 month). Various radiological parameters as well as Scoliosis Research Society-22 were statistically compared between groups. Coronal decompensation was observed in 33 patients preoperatively, in 48 patients immediately postoperatively, and in 2 patients at final follow-up. Lowermost instrumented vertebra (LIV) disc angle (0.9° vs. 6.7°, p=0.019) and LIV- C7 plumb line and central sacral vertical line (CSVL) (-3.4mm vs. -13.7mm, p=0.020) increased in the final follow-up in the imbalanced group of type A modifier. The magnitude of lumbar curve was greater in the imbalanced group of type B or C modifier in the early postoperative period (19.5° vs. 12.6°, p=0.006; 25.5° vs. 13.7°, p<0.01), and this difference disappeared in the final follow-up. No differences in SRS-22 outcome scores were noted between groups in different time. Coronal imbalance was frequently detected immediately after STF in Lenke 1 or 2 AIS patients, with type C modifier slightly higher than A or B. Distal adding-on may help compensate for coronal imbalance in patients with type A modifier, while spontaneous correction of lumbar curve attributes to the improvement of coronal imbalance in patients with type B or C modifier.


Asunto(s)
Complicaciones Posoperatorias , Escoliosis , Fusión Vertebral/efectos adversos , Vértebras Torácicas , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Complicaciones Posoperatorias/diagnóstico por imagen , Complicaciones Posoperatorias/fisiopatología , Prevalencia , Estudios Retrospectivos , Escoliosis/diagnóstico por imagen , Escoliosis/fisiopatología , Escoliosis/cirugía , Vértebras Torácicas/diagnóstico por imagen , Vértebras Torácicas/fisiopatología , Vértebras Torácicas/cirugía
17.
Sci Rep ; 7(1): 416, 2017 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-28341864

RESUMEN

Chemotherapy is an important treatment modality for osteosarcoma. However, it often fails because of chemoresistance, especially multidrug resistance. Previously, we found several genes were involved in chemoresistance development. In this report, we used high-throughput microRNA (miRNA) expression analysis to reveal that expression of miR-140-5p was associated with chemosensitivity in osteosarcoma. The exact roles of miR-140-5p in the chemoresistance of osteosarcoma were then investigated, we found that knockdown of miR-140-5p enhanced osteosarcoma cells resistance to multiple chemotherapeutics while overexpression of miR-140-5p sensitized tumors to chemotherapy in vitro. Moreover, in vivo, knockdown of miR-140-5p also increased the osteosarcoma cells resistance to chemotherapy. Luciferase assay and Western blot analysis showed that HMGN5 was the direct target of miR-140-5p which could positively regulated autophagy. Silencing these target genes by siRNA or inhibition of autophagy sensitized osteosarcoma cells to chemotherapy. These findings suggest that a miR-140-5p/HMGN5/autophagy regulatory loop plays a critical role in chemoresistance in osteosarcoma. In conclusion, our data elucidated that miR-140-5p promoted autophagy mediated by HMGN5 and sensitized osteosarcoma cells to chemotherapy. These results suggest a potential application of miR-140-5p in overall survival, chemoresistance prognosis and treatment.


Asunto(s)
Autofagia , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Proteínas HMGN/metabolismo , MicroARNs/metabolismo , Osteosarcoma/genética , Transactivadores/metabolismo , Adolescente , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Femenino , Humanos , Masculino , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/metabolismo , Adulto Joven
18.
Sci Rep ; 6: 34643, 2016 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-27698377

RESUMEN

Ankylosing spondylitis (AS) is a chronic axial spondyloarthritis (SpA) resulting in back pain and progressive spinal ankyloses. Currently, there are no effective therapeutics targeting AS largely due to elusive pathogenesis mechanisms, even as potential candidates such as HLA-B27 autoantigen have been identified. Herein, we employed a proteoglycan (PG)-induced AS mouse model together with clinical specimens, and found that the complement system was substantially activated in the spinal bone marrow, accompanied by a remarkable proportion alteration of neutrophils and macrophage in bone marrow and spleen, and by the significant increase of TGF-ß1 in serum. The combined treatment with a bacteria-derived complement inhibitor Efb-C (C-terminal of extracellular fibrinogen-binding protein of Staphylococcus aureus) remarkably retarded the progression of mouse AS by reducing osteoblast differentiation. Furthermore, we demonstrated that two important modulators involved in AS disease, TGF-ß1 and RANKL, were elevated upon in vitro complement attack in osteoblast and/or osteoclast cells. These findings further unravel that complement activation is closely related with the pathogenesis of AS, and suggest that complement inhibition may hold great potential for AS therapy.


Asunto(s)
Antiinflamatorios/farmacología , Dolor de Espalda/tratamiento farmacológico , Proteínas Bacterianas/farmacología , Proteínas del Sistema Complemento/genética , Espondilitis Anquilosante/tratamiento farmacológico , Animales , Dolor de Espalda/inducido químicamente , Dolor de Espalda/inmunología , Dolor de Espalda/patología , Médula Ósea/efectos de los fármacos , Médula Ósea/inmunología , Médula Ósea/patología , Diferenciación Celular/efectos de los fármacos , Proteínas del Sistema Complemento/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Regulación de la Expresión Génica , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/patología , Ratones , Neutrófilos/efectos de los fármacos , Neutrófilos/inmunología , Neutrófilos/patología , Osteoblastos/efectos de los fármacos , Osteoblastos/inmunología , Osteoblastos/patología , Cultivo Primario de Células , Proteoglicanos/administración & dosificación , Ligando RANK/genética , Ligando RANK/inmunología , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/patología , Espondilitis Anquilosante/inducido químicamente , Espondilitis Anquilosante/inmunología , Espondilitis Anquilosante/patología , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/inmunología
19.
Immunobiology ; 221(11): 1293-303, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27316715

RESUMEN

As a potent effector of innate immunity, the complement system has been shown to be involved in the pathogenesis of inflammatory bowel disease (IBD). However, the role of the membrane attack complex (MAC) in the development of IBD is still largely unknown. Here, we used C6-deficient mice in which MAC formation was blocked due to the absence of C6 to develop an acute colitis model by the administration of dextran sulfate sodium (DSS). The results showed that DSS-induced colitis was aggravated in C6-deficient mice compared with wild-type (WT) mice, as represented by the markedly greater weight loss, higher disease activity index (DAI), shortened colon length, more severe histological injury with increased epithelial ulcerations, and massively increased infiltration of leukocytes accompanied by much higher myeloperoxidase (MPO) levels in local inflammatory colonic sites. In addition, the DSS-induced colitis in C6-deficient mice could be significantly ameliorated by the exogenous C6 from WT sera. Furthermore, the significantly enhanced production of pro-inflammatory mediators, including IL-1ß, IL-6, CXCL-1, CCL-3, TGF-ß1 and IL-17F, was also observed in C6-deficient mice. Unexpectedly, the aggravated colitis in C6-deficient mice may be not due to the increase of lipopolysaccharide (LPS) levels in serum. Overall, we demonstrated that MAC exerts a protective role in acute colitis, strongly highlighting the host defense function of the complement system.


Asunto(s)
Colitis/etiología , Complemento C6/deficiencia , Sulfato de Dextran/efectos adversos , Susceptibilidad a Enfermedades , Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/inmunología , Animales , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colitis/patología , Complemento C6/administración & dosificación , Complemento C6/inmunología , Complejo de Ataque a Membrana del Sistema Complemento/inmunología , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Proteínas del Sistema Complemento/inmunología , Proteínas del Sistema Complemento/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Enfermedades por Deficiencia de Complemento Hereditario , Humanos , Mediadores de Inflamación/metabolismo , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Leucocitos/inmunología , Leucocitos/metabolismo , Leucocitos/patología , Ratones , Ratones Noqueados
20.
Oncol Rep ; 35(1): 275-83, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26549292

RESUMEN

Osteosarcoma is the most common human primary malignant bone tumor and recurrences are common due to the development of chemoresistance. However, the underlying molecular mechanism for chemoresistance remains unclear. Recent studies demonstrated that miR-146b-5p, an important regulator in tumorigenesis, was involved in chemoresistance in thyroid cancer, lymphoma. Thus, to confirm the role of miR­146b-5p in osteosarcoma, the study was divided into three steps: first, miR-146b-5p in paired samples were assessed using a quantitative real-time PCR (qRT-PCR) assay from osteosarcoma patients. Second, to confirm the role of miR-146b-5p, we applied lentivirus system to overexpression and knockdown of miR-146b-5p, respectively, in MG-63 osteosarcoma cell line. Third, luciferase assays were performed to determine whether Wnt/ß-catenin pathway participated in the role of miR-146b-5p on chemoresistance. As a result, miR-146b-5p was highly expressed in human osteosarcoma tissues and an elevated expression of miR-146b-5p was observed in human osteosarcoma tissues after chemotherapy. Furthermore, it was shown that miR-146b-5p overexpression promoted migration and invasiveness. miR-146b-5p overexpression also increased resistance to chemotherapy. Moreover, knockdown of miR-146b-5p substantially inhibited migration and invasion of osteosarcoma cells as well as rendered them significantly more sensitive to chemotherapy. Results of western blot assay indicated that miR-146b-5p increased MMP-16 protein expression and showed a decrease of ZNRF3 protein. Whereas, IWR-1-endo, an inhibitor of Wnt/ß-catenin, suppressed the decrease in apoptosis of osteosarcoma cells caused by miR-146b-5p overexpression. These results indicated that miR-146b-5p promoted proliferation, migration and invasiveness. It also increased resistance to chemotherapy through the regulation of ZNRF3, and suggested novel potential therapeutic targets for the treatment of osteosarcoma.


Asunto(s)
Neoplasias Óseas/genética , Resistencia a Antineoplásicos , MicroARNs/genética , Osteosarcoma/genética , Ubiquitina-Proteína Ligasas/genética , Regiones no Traducidas 3' , Línea Celular Tumoral , Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Humanos , MicroARNs/metabolismo , Invasividad Neoplásica , Metástasis de la Neoplasia
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