Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 30
Filtrar
1.
Int J Biol Sci ; 17(15): 4285-4304, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34803498

RESUMO

Circular RNAs (circRNAs) is a novel class of non-coding RNAs resulting from the non-canonical splicing of linear pre-mRNAs. However, the role of circRNAs in gastric cancer (GC) remains indistinct. This study aims to explore their potential modulation in GC and its prognostic value. We first screen for circRNA expression patterns in GC through GC and adjacent noncancerous tissues by microarray. Based on the bioinformatics analysis of the microarray data, we screened out a novel circRNA, circ-PTPDC1. Then we demonstrated that circ-PTPDC1 was up-regulated in GC cells, tissues, and serum. Its overexpression was positively correlated with age, invasion depth, advanced clinical stages, and worse survival in patients with GC. We further revealed that circ-PTPDC1 promotes the proliferation, migration, and invasion of GC cell lines via sponging miR-139-3p by regulating ELK1. Importantly, we identified that circ-PTPDC1 promotes tumor upgrowth and metabasis in vivo. Additionally, we established its prognostic prediction model based on the follow-up data of the patients. Our study revealed a novel regulatory mechanism and a comprehensive landscape of circ-PTPDC1 in GC, suggesting that circ-PTPDC1 has the potential to be a biomarker for early detection and prognostic prediction of GC.

2.
Cancers (Basel) ; 13(21)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34771548

RESUMO

OBJECTIVES: As diagnosis and treatment guidelines for bone sarcomas continue updating, it is important to examine whether, when, and which kinds of patients have had a survival improvement over the last four decades. METHODS: This cohort study included 9178 patients with primary bone and joint sarcomas from 1 January 1980 to 31 December 2018 using data from Surveillance, Epidemiology and End Results (SEER)-9 Registries. The follow-up period was extended to November 2020. Patients were divided by decade into four time periods: 1980-1989, 1990-1999, 2000-2009, and 2010-2018. The primary endpoint was bone sarcomas-specific mortality (CSM). The 5-year bone sarcomas-specific survival (CSS) rate was determined stratified by demographic, neoplastic, temporal, economic, and geographic categories. The associations between time periods and CSM were examined using a multivariable Cox regression model, with reported hazard ratio (HR) and 95% confidence interval (CI). RESULTS: The 5-year CSS rate for bone sarcomas was 58.7%, 69.9%, 71.0%, and 69.2%, in the 1980s, 1990s, 2000s, and 2010s, respectively. Older age, male gender, tumor sites at pelvic bones, sacrum, coccyx and associated joints, as well as vertebral column, osteosarcoma and Ewing tumor, and residence in non-metropolitan areas were independently associated with higher CSM risk. After adjusting for the covariates above, patients in the 1990s (HR = 0.74, 95% CI = 0.68-0.82), 2000s (HR = 0.71, 95% CI = 0.65-0.78), and 2010s (HR = 0.68, 95% CI = 0.62-0.76) had significantly lower CSM risks than patients in the 1980s. However, patients in the 2000s and 2010s did not have lower CSM risks than those in the 1990s (both p > 0.05). CONCLUSIONS: Although bone sarcomas survival has significantly improved since 1990, it almost halted over the next three decades. Bone sarcomas survival should improve over time, similar to common cancers. New diagnostic and therapeutic strategies such as emerging immune and targeted agents are warranted to overcome this survival stalemate.

3.
Front Cell Dev Biol ; 9: 694363, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34568317

RESUMO

Research on molecular targeted therapy of tumors is booming, and novel targeted therapy drugs are constantly emerging. Small molecule targeted compounds, novel targeted therapy drugs, can be administered orally as tablets among other methods, and do not draw upon genes, causing no immune response. It is easily structurally modified to make it more applicable to clinical needs, and convenient to promote due to low cost. It refers to a hotspot in the research of tumor molecular targeted therapy. In the present study, we review the current Food and Drug Administration (FDA)-approved use of small molecule targeted compounds in tumors, summarize the clinical drug resistance problems and mechanisms facing the use of small molecule targeted compounds, and predict the future directions of the evolving field.

4.
Cell Mol Biol Lett ; 26(1): 34, 2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315404

RESUMO

Burn injury is one of the potential causes of heterotopic ossification (HO), which is a rare but debilitating condition. The incidence ranges from 3.5 to 5.6 depending on body area. Burns that cover a larger percentage of the total body surface area (TBSA), require skin graft surgeries, or necessitate pulmonary intensive care are well-researched risk factors for HO. Since burns initiate such complex pathophysiological processes with a variety of molecular signal changes, it is essential to focus on HO in the specific context of burn injury to define best practices for its treatment. There are numerous key players in the pathways of burn-induced HO, including neutrophils, monocytes, transforming growth factor-ß1-expressing macrophages and the adaptive immune system. The increased inflammation associated with burn injuries is also associated with pathway activation. Neurological and calcium-related contributions are also known. Endothelial-to-mesenchymal transition (EMT) and vascularization are known to play key roles in burn-induced HO, with hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) as potential initiators. Currently, non-steroidal anti-inflammatory drugs (NSAIDs) and radiotherapy are effective prophylaxes for HO. Limited joint motion, ankylosis and intolerable pain caused by burn-induced HO can be effectively tackled via surgery. Effective biomarkers for monitoring burn-induced HO occurrence and bio-prophylactic and bio-therapeutic strategies should be actively developed in the future.

5.
Carcinogenesis ; 42(9): 1196-1207, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216208

RESUMO

tRNA-derived fragments (tRFs) are a novel class of small non-coding RNAs whose biological roles are not well defined. Here, using multiple approaches, we investigated its role in human triple-negative breast cancer (TNBC). Our genome-wide transcriptome analysis of small non-coding RNAs revealed that tRFLys-CTT-010 was significantly increased in human TNBC. It promoted TNBC proliferation and migration. It also closely associated with starch and sucrose metabolism pathways (Kyoto Encyclopedia of Genes and Genomes analysis) and positively regulated the expression of glucose-6-phosphatase catalytic subunit (G6PC), one of the related genes in the pathway. G6PC, a complex of glucose-6-phosphatase in gluconeogenesis and glycogenolysis, is upregulated in human TNBC samples. Further studies demonstrated that overexpression of G6PC in tRFLys-CTT-010 inhibitor-transfected TNBC cell lines can reverse malignant biological behavior and knockdown of G6PC in TNBC cell lines inhibited tumor progression and reversed the oncogenic function of tRFLys-CTT-010. In addition, tRFLys-CTT-010 interacted with G6PC to regulate cellular lactate production and glycogen consumption, resulting in cell survival and proliferation. Thus, fine-tuning glucose metabolism and the tRFLys-CTT-010/G6PC axis may provide a therapeutic target for TNBC treatment.

7.
Cell Adh Migr ; 15(1): 140-151, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34057025

RESUMO

LncRNA plays a critical role in tumor progression. However, the role it executes in breast cancer is still unclear. Here, we report a newly discovered lncRNA, ENST00000508435, which could be remarkably up-regulated in breast cancer cells and tissues. We found that the expression of ENST00000508435 was positively correlated with tumor size, lymph node metastasis and HER2. More interesting, overexpression of ENST00000508435 significantly increased cell migration, while specific knockdown led to the opposite. RNA pull-down and RNA immunoprecipitation assays demonstrated that ENST00000508435 could directly bind to FXR1 to promote tumor metastasis. ENST00000508435 and FXR1 were positively correlated. FXR1 was also significantly up-regulated in breast tumors. Taken together, we propose that ENST00000508435 regulates FXR1 to promote breast cancer metastasis.

8.
Mol Ther Oncolytics ; 21: 183-206, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34027052

RESUMO

Cancer has become one of the greatest threats to human health, and new technologies are urgently needed to further clarify the mechanisms of cancer so that better detection and treatment strategies can be developed. At present, extensive genomic analysis and testing of clinical specimens shape the insights into carcinoma. Nevertheless, carcinoma of humans is a complex ecosystem of cells, including carcinoma cells and immunity-related and stroma-related subsets, with accurate characteristics obscured by extensive genome-related approaches. A growing body of research shows that sequencing of single-cell RNA (scRNA-seq) is emerging to be an effective way for dissecting human tumor tissue at single-cell resolution, presenting one prominent way for explaining carcinoma biology. This review summarizes the research progress of scRNA-seq in the field of tumors, focusing on the application of scRNA-seq in tumor circulating cells, tumor stem cells, tumor drug resistance, the tumor microenvironment, and so on, which provides a new perspective for tumor research.

9.
Cancers (Basel) ; 13(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33921187

RESUMO

BACKGROUND: Undifferentiated pleomorphic sarcomas (UPS) were one of the most common soft tissue sarcomas. As UPS had relatively high potentials of recurrence and metastasis, we designed two nomograms to better predict the overall survival (OS) and time to recurrence (TTR) for patients who underwent primary surgery. METHODS: The data of UPS patients who underwent primary surgery were extracted from Shanghai Cancer Center, Fudan University. Multivariate analyses were performed using Cox proportional hazards regression to identify independent prognostic factors. Kaplan-Meier analysis was used to compare differences for patients who underwent primary surgery in OS and TTR. Nomograms were designed with the help of R software and validated using calibration curves and receiver operating characteristic curves (ROC). RESULTS: Kaplan-Meier curves showed that patients with older ages (p = 0.0024), deeper locations (p = 0.0422), necrosis (p < 0.0001), G3 French Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) classification (p < 0.0001), higher Ki-67 (p < 0.0001), higher mitotic index (p < 0.0001), R1/R2 resections (p = 0.0002) and higher invasive depth (p = 0.0099) had shorter OS than the other patients while patients with older ages (p = 0.0108), necrosis (p = 0.0001), G3 FNCLCC classification (p < 0.0001), higher Ki-67 (p = 0.0006), higher mitotic index (p < 0.0001) and R1/R2 resections (p < 0.0001) had shorter TTR compared with those without. Multivariate analyses demonstrated that mitotic rates and surgical margin were independent factors for TTR while age and invasive depth were independent factors for OS. Three parameters were adopted to build the nomograms for 3- and 5-year OS and TTR. The Area Under Curve (AUC) of this nomogram at 3- and 5-year TTR reached 0.802, 0.814, respectively, while OS reached 0.718, 0.802, respectively. Calibration curves for the prediction of 3- and 5-year OS and TTR showed excellent agreement between the predicted and the actual survival outcomes. CONCLUSIONS: Some important parameters could be used to predict the outcome of individual UPS patients such as mitotic age, rates, surgical margin, and invasive depth. We developed two accurate and practicable nomograms that could predict 3- and 5-year OS and TTR for UPS patients, which could be involved in the modern medical decision-making process.

10.
Theranostics ; 11(8): 3868-3881, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33664867

RESUMO

Rationale: Osteosarcoma (OS), the most common type of bone tumor, which seriously affects the patients' limb function and life quality. OS has a strong tendency of lung metastasis, and the five-year survival rate of patients with metastatic osteosarcoma is less than 20%. Thus, new treatment targets and strategies are urgently needed. Methods: The expression of the histone demethylase KDM6B and H3K27me3 levels in OS specimens were analyzed using quantitative PCR and immunohistochemical assays. The biological functions of KDM6B were determined using in vitro transwell, wound healing assays, and an in vivo orthotopic injection-induced lung metastasis model. Subsequently, chromatin immunoprecipitation sequencing (ChIP-seq) combined with transcriptomic RNA sequencing (RNA-seq), and subsequent ChIP-qPCR, western blot, and aerobic glycolysis assays were used to explore the mechanism of KDM6B function and validate the candidate target gene of KDM6B. Results: KDM6B expression was significantly upregulated in OS patients, and high KDM6B expression was associated with poorer prognosis in OS patients. Targeting KDM6B significantly inhibited OS cell migration in vitro and lung metastasis in vivo. RNA-seq and ChIP-seq analysis revealed that KDM6B increases lactate dehydrogenase LDHA expression in OS cells by directly mediating H3K27me3 demethylation. The phenotypes of inhibited cell metastasis in KDM6B-knockdown OS cells was reversed upon overexpression of LDHA. Finally, a small molecule inhibitor targeting KDM6B significantly inhibited OS cell migration in vitro and lung metastasis in vivo. Conclusions: Collectively, we elucidated that upregulated KDM6B facilitates tumor metastasis in OS via modulating LDHA expression. Our findings deepen the recognition of OS metastasis mechanism and suggest that KDM6B might be a new potential therapeutic target for the treatment of OS (especially highly metastatic OS).


Assuntos
Neoplasias Ósseas/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , L-Lactato Desidrogenase/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Osteossarcoma/metabolismo , Osteossarcoma/secundário , Animais , Benzazepinas/farmacologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Técnicas de Silenciamento de Genes , Código das Histonas/genética , Humanos , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/genética , Neoplasias Pulmonares/genética , Camundongos , Camundongos Nus , Terapia de Alvo Molecular , Osteossarcoma/genética , Medicina de Precisão , Prognóstico , Pirimidinas/farmacologia , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Biochem Biophys Res Commun ; 550: 77-83, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33689883

RESUMO

Osteosarcoma (OS) is the most common type of bone tumor that seriously affects limb function and induces great pain in patients. Lung metastasis and chemotherapy resistance are two key issues leading to the poor prognosis of OS patients, therefore new treatment targets and strategies are urgently needed. In our study, we uncovered the role of histone demethylase KDM4A in regulating OS cell ferroptosis and tumor progression. KDM4A was significantly upregulated in OS specimens and high KDM4A expression was associated with poorer prognosis in OS patients. Our data indicated that targeting KDM4A significantly increased OS cell death, enhanced cisplatin response, and attenuated migration ability in vitro. KDM4A depletion dramatically inhibited tumor progression and lung metastasis of OS in vivo Further experiments confirmed that KDM4A knockdown promoted OS cell ferroptosis, a special non-apoptotic form of cell death. KDM4A regulates SLC7A11 transcription and OS cell ferroptosis by controlling H3K9me3 demethylation in the promoter region of SLC7A11. Our findings deepened the recognition of epigenetic regulatory mechanism in OS tumorigenesis, chemoresistance, and metastasis, suggesting that KDM4A activity may be a potential therapeutic target for future OS treatment.


Assuntos
Sistema y+ de Transporte de Aminoácidos/genética , Desmetilação , Ferroptose , Histonas/química , Histonas/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Osteossarcoma/metabolismo , Animais , Carcinogênese , Morte Celular , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Ferroptose/genética , Técnicas de Silenciamento de Genes , Humanos , Histona Desmetilases com o Domínio Jumonji/deficiência , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica/genética , Osteossarcoma/genética , Osteossarcoma/patologia , Prognóstico , Regulação para Cima
12.
Signal Transduct Target Ther ; 5(1): 256, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33139693

RESUMO

Coronavirus disease-2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection is spreading globally and poses a huge threat to human health. Besides common respiratory symptoms, some patients with COVID-19 experience gastrointestinal symptoms, such as diarrhea, nausea, vomiting, and loss of appetite. SARS-CoV-2 might infect the gastrointestinal tract through its viral receptor angiotensin-converting enzyme 2 (ACE2) and there is increasing evidence of a possible fecal-oral transmission route. In addition, there exist multiple abnormalities in liver enzymes. COVID-19-related liver injury may be due to drug-induced liver injury, systemic inflammatory reaction, and hypoxia-ischemia reperfusion injury. The direct toxic attack of SARS-CoV-2 on the liver is still questionable. This review highlights the manifestations and potential mechanisms of gastrointestinal and hepatic injuries in COVID-19 to raise awareness of digestive system injury in COVID-19.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Infecções por Coronavirus/epidemiologia , Gastroenteropatias/epidemiologia , Hepatopatias/epidemiologia , Pneumonia Viral/epidemiologia , Enzima de Conversão de Angiotensina 2 , COVID-19 , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/virologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Fezes/virologia , Gastroenteropatias/complicações , Gastroenteropatias/genética , Gastroenteropatias/virologia , Trato Gastrointestinal/lesões , Trato Gastrointestinal/patologia , Trato Gastrointestinal/virologia , Humanos , Fígado/fisiopatologia , Fígado/virologia , Hepatopatias/genética , Hepatopatias/patologia , Hepatopatias/virologia , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/genética , Pneumonia Viral/patologia , Pneumonia Viral/virologia
13.
Aging (Albany NY) ; 12(18): 18436-18452, 2020 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-32979259

RESUMO

Tendon-derived stem cells (TSCs) play a primary role in tendon physiology, pathology, as well as tendon repair and regeneration after injury. TSCs are often exposed to mechanical loading-related cellular stresses such as oxidative stress, resulting in loss of stemness and multipotent differentiation potential. Cytoprotective autophagy has previously been identified as an important mechanism to protect human TSCs (hTSCs) from oxidative stress induced impairments. In this study, we found that high-mobility AT-hook 2 (HMGA2) overexpression protects hTSCs against H2O2-induced loss of stemness through autophagy activation. Evidentially, H2O2 treatment increases the expression of Nudt21, a protein critical to polyadenylation site selection in alternative polyadenylation (APA) of mRNA transcripts. This leads to increased cleavage and polyadenylation of HMGA2 3'-UTR at the distal site, resulting in increased HMGA2 silencing by the microRNA let-7 and reduced HMGA2 expression. In conclusion, Nudt21-regulated APA of HMGA2 3'-UTR and subsequent HMGA2 downregulation mediates oxidative stress induced hTSC impairments.

15.
J Diabetes Complications ; 34(8): 107611, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32402839

RESUMO

BACKGROUND: This study will explore the effectiveness and safety of autologous PRP in the treatment of patients with DFU. METHODS: The electronic databases of PubMed, EMBASE, BIOSIS, Cochrane central, and Google Scholar internet were searched updated on Jan 30, 2020. Evaluated outcomes included rate of complete ulcer healing, time to healing and adverse events. Statistical analysis was performed with RevMan 5.0 software and STATA 10.0 software. RESULTS: Ten RCTs with 456 patients were included in this study. The meta-analysis showed a higher complete ulcer healing rate (RR = 1.32, 95% CI 1.06 to 1.65, P = 0.01, I2 = 57%), a shorter healing time (MD = -23.42, 95% CI -37.33 to -9.51, P = 0.01, I2 = 78%), with no increasing the incidence of adverse events (RR = 0.48, 95% CI 0.22 to 1.05, P = 0.75, I2 = 0%) in PRP group compared with control. Mixed evidence was seen for publication bias, but analyses by using the trim-and-fill method did not appreciably alter results. CONCLUSION: Our findings suggest that autologous PRP may improve the complete ulcer healing rate, shorten the healing time, with no increasing the incidence of adverse events.


Assuntos
Transfusão de Sangue Autóloga , Pé Diabético/terapia , Transfusão de Plaquetas , Plasma Rico em Plaquetas , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
Nat Commun ; 10(1): 2935, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270335

RESUMO

Trace elements play important roles in human health, but little is known about their functions in humoral immunity. Here, we show an important role for iron in inducing cyclin E and B cell proliferation. We find that iron-deficient individuals exhibit a significantly reduced antibody response to the measles vaccine when compared to iron-normal controls. Mice with iron deficiency also exhibit attenuated T-dependent or T-independent antigen-specific antibody responses. We show that iron is essential for B cell proliferation; both iron deficiency and α-ketoglutarate inhibition could suppress cyclin E1 induction and S phase entry of B cells upon activation. Finally, we demonstrate that three demethylases, KDM2B, KDM3B and KDM4C, are responsible for histone 3 lysine 9 (H3K9) demethylation at the cyclin E1 promoter, cyclin E1 induction and B cell proliferation. Thus, our data reveal a crucial role of H3K9 demethylation in B cell proliferation, and the importance of iron in humoral immunity.


Assuntos
Linfócitos B/imunologia , Proliferação de Células , Histonas/química , Histonas/imunologia , Imunidade Humoral , Lisina/imunologia , Animais , Linfócitos B/química , Linfócitos B/citologia , Ciclo Celular , Células Cultivadas , Ciclina E/genética , Ciclina E/imunologia , Desmetilação , Proteínas F-Box/genética , Proteínas F-Box/imunologia , Histonas/genética , Ferro/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/imunologia , Ativação Linfocitária , Lisina/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/imunologia , Regiões Promotoras Genéticas , Linfócitos T/citologia , Linfócitos T/imunologia
17.
Cell Death Dis ; 10(2): 65, 2019 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-30683853

RESUMO

Osteosarcoma (OS) is a primary malignant bone tumour. However, the genetic basis for the pathogenesis of OS remains elusive. In this study, we uncovered the role of the histone methyltransferase NSD2 in regulating tumourigenesis and chemosensitivity in OS. We show that NSD2 knockdown leads to increased apoptosis in OS cells in vitro and in vivo. Additionally, NSD2 knockdown significantly enhances the efficacy of cisplatin against OS cells and accordingly inhibits properties associated with cancer stem cells (CSCs). Furthermore, RNA sequencing (RNAseq) and Gene Ontology (GO) analysis revealed that NSD2 promotes transcription of genes associated with negative regulation of apoptotic signalling pathways and CSC properties. The results of chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR) assays indicated that NSD2 knockdown leads to decreased H3K36me2 modification at BCL2 and SOX2 loci, thus inhibiting the transcription of these two genes that are closely correlated with apoptosis, CSC properties and chemosensitivity in OS cells. Pathway analysis demonstrated that the ERK and AKT pathways mediate the regulation of OS progression and chemosensitivity by NSD2. Overall, our study is the first to uncover the function of NSD2 in OS chemosensitivity. NSD2 regulates the expression of the apoptosis regulatory proteins BCL2 and SOX2 through the ERK and AKT pathways. Our results suggest that NSD2 is a new target for combined chemotherapy and is a prognostic factor for OS.


Assuntos
Apoptose/genética , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Histona-Lisina N-Metiltransferase/genética , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Proteínas Repressoras/genética , Adolescente , Adulto , Idoso , Animais , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Criança , Cisplatino/uso terapêutico , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Osteossarcoma/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Fatores de Transcrição SOXB1/genética , Transdução de Sinais/genética , Transfecção , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto Jovem
18.
Cell Death Dis ; 9(2): 144, 2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29396550

RESUMO

Recombinant human bone morphogenetic protein-2 (rhBMP-2) is widely used in the clinic for bone defect reconstruction because of its powerful osteoinductive capacity. However, commercially available rhBMP-2 requires a high concentration in the clinical setting for consistent bone formation. A high dose of rhBMP-2 induces a promising bone formation yield but also leads to inflammation-related events, deteriorated bone quality, and fatty tissue formation. We hypothesize that the seemingly contradictory phenomenon of coformation of new bone and excessive adipose tissue in rhBMP-2-induced bone voids may be associated with interleukin-6 (IL-6), which is significantly elevated after application of rhBMP-2/absorbable collagen sponge (rhBMP-2/ACS). Here, we show that IL-6 injection enhances new bone regeneration and induces excessive adipose tissue formation in an rhBMP-2/ACS-induced ectopic bone formation model in rats. In vitro data further show that IL-6 and its soluble receptor sIL-6R synergistically augment rhBMP-2-induced osteogenic and adipogenic differentiation of human BMSCs (hBMSCs) by promoting cell surface translocation of BMPR1A and then amplifying BMPR1A-mediated BMP/Smad and p38 MAPK pathways, respectively. Our study suggests elevated IL-6 may be responsible for coformation of new bone and excessive adipose tissue in rhBMP-2-induced bone voids.


Assuntos
Adipogenia/efeitos dos fármacos , Proteína Morfogenética Óssea 2/farmacologia , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Interleucina-6/farmacologia , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologia , Adulto , Animais , Regeneração Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Animais , Modelos Biológicos , Ratos Endogâmicos Lew , Receptores de Interleucina-6/metabolismo , Proteínas Recombinantes/farmacologia , Proteínas Smad/metabolismo , Adulto Jovem , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Sci Rep ; 7(1): 18038, 2017 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-29269864

RESUMO

The in vivo bioreactor principle, which focuses on using the body as a living bioreactor to cultivate stem cells, bioscaffolds, and growth factors and leveraging the body's self-regenerative capacity to regenerate new tissue, has been considered a potential approach for bone defect reconstruction. The histological characteristics of the periosteum allow it to possess a remarkable capacity to induce bone growth and remodeling, making it suitable as an in vivo bioreactor strategy for bone graft prefabrication. The present study was designed to prefabricate vascularized bone grafts using pedicled periosteal flaps and decellularized bone matrix (DBM) scaffolds in a rabbit model. The muscular pouches created in the femoral muscle were acted as a control. Our histological results revealed that both the periosteal flap group and muscular pouch group induced bone tissue formation on the DBM surface at both 8 and 16 weeks postoperatively. However, micro-computed tomography (microCT) scanning, biomechanical, and histomorphometric findings indicated that bone grafts from the periosteal flap group showed larger bone mass, faster bone formation rates, higher vascular density, and stronger biomechanical properties than in the muscular pouch group. We suggest that using the pedicled periosteal flap as an in vivo bioreactor is a promising approach for functional bone graft prefabrication.


Assuntos
Reatores Biológicos , Regeneração Óssea/fisiologia , Transplante Ósseo/métodos , Osteogênese/fisiologia , Retalhos Cirúrgicos , Engenharia Tecidual/métodos , Animais , Matriz Óssea/fisiologia , Coelhos , Microtomografia por Raio-X
20.
Oncotarget ; 8(46): 80651-80665, 2017 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-29113333

RESUMO

Excessive skin scars due to elective operations or trauma represent a challenging clinical problem. Pathophysiology of hypertrophic scars entails a prolonged inflammatory and proliferative phase of wound healing. Over expression of TGF-ß1 and COX-2 play key regulatory roles of the aberrant fibrogenic responses and proinflammatory mediators. When we silenced TGF-ß1 and COX-2 expression simultaneously in primary human fibroblasts, a marked increase in the apoptotic cell population occurred in contrast to those only treated with either TGF-ß1 or COX-2 siRNA alone. Furthermore, using human hypertrophic scar and skin graft implant models in mice, we observed significant size reductions of the implanted tissues following intra-scar administration of TGF-ß1/COX-2 specific siRNA combination packaged with Histidine Lysine Polymer (HKP). Gene expression analyses of those treated tissues revealed silencing of the target gene along with down regulations of pro-fibrotic factors such as α-SMA, hydroxyproline acid, Collagen 1 and Collagen 3. Using TUNEL assay detection, we found that the human fibroblasts in the implanted tissues treated with the TGF-ß1/COX-2siRNAs combination exhibited significant apoptotic activity. Therefore we conclude that a synergistic effect of the TGF-ß1/COX-2siRNAs combination contributed to the size reductions of the hypertrophic scar implants, through activation of fibroblast apoptosis and re-balancing between scar tissue deposition and degradation.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...