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1.
Acta Histochem ; 122(8): 151647, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33130420

RESUMO

BACKGROUND: Accumulating evidence has suggested that long noncoding RNAs (lncRNAs) are involved in the progression of types of human cancers. It has been known that exosomes can mediate cell-cell crosstalk by transferring lncRNAs in tumor progression. This study aimed to investigate the role of exosomal lncRNA HEIH on cisplatin (DDP) resistance in tongue squamous cell carcinoma (TSCC). METHODS: The expression of HEIH in human oral keratinocytes cell line (HOK), DDP-sensitive TSCC cell line (SCC4/S) and DDP-resistant TSCC cell line (SCC4/DDP) was measured. SCC4/S and SCC4/DDP cells were transfected with sh-HEIH to examine TSCC cell proliferation and apoptosis. The DDP-resistant exosomes were extracted and identified. The expression of miR­3619-5p and TDGF in DDP-sensitive recipient cells was determined. The binding capacity between HEIH and miR­3619-5p, along with miR­3619-5p and TDGF was verified. RESULTS: HEIH expression was significantly upregulated in SCC4/DDP cells. Downregulation of HEIH inhibited DDP resistance and cell proliferation and promoted cell apoptosis. HEIH acted as a competing endogenous RNA (ceRNA) for miR­3619-5p to upregulate HDGF expression. Exosomal HEIH promoted cell proliferation and drug resistance and inhibited cell apoptosis by sponging miR­3169-5p and upregulating HDGF. CONCLUSION: Exosomal HEIH acted as a ceRNA for miR­3619-5p to upregulate HDGF, thereby promoting DDP resistance in TSCC cells.

2.
Cancer Manag Res ; 12: 5293-5299, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32753948

RESUMO

Purpose: This study aimed to retrospectively analyze the failure patterns and clinical outcomes in patients with locally advanced cervical esophageal carcinoma (CEC) after definitive radiotherapy (RT), and illustrate the mapping of regional failures. Patients and Methods: We reviewed 82 patients with CEC confirmed as squamous cell carcinoma who had completed definitive RT from August 2008 to December 2017. Data on clinical characteristics were collected from the medical records system. Patterns of treatment failures and the survival follow-up were analyzed. Results: The median age was 58 (38-78) years. In 37 patients, the lesions were limited to the cervical esophagus, while in the remaining 45 patients, the disease got beyond the cervical esophagus (pharynx or thoracic esophagus involved). While 10 patients had stage Ⅱ disease, 72 had stage III disease. The completed median dose for 95% PGTV and 95% PTV was 66 Gy and 58 Gy. While the median follow-up was 27.6 months, the median progression-free survival (PFS) and overall survival (OS) was 16.1 and 28.3 months, respectively. The 3-year PFS and OS was 30.3% and 45.3%, respectively. Treatment failures were reported in 55 patients, of which 22, 8, 7, 9, 2, 3, and 4 patients had developed local, regional, distant, local-regional, regional-distant, local-distant and local-regional-distant failure, respectively. Of the 41 relapsed nodal sites, 28 were located "in-field" whereas 1 was "marginal" and 12 were "out-field". The most frequent regional relapses were at level VIb, IV and the upper-middle mediastinum. Conclusion: Regional recurrences focused on lower neck and upper-middle mediastinum, and mainly "in-field", after definitive RT in patients with CEC.

3.
Emerg Microbes Infect ; 9(1): 1194-1205, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32397909

RESUMO

Enterovirus A71 (EV-A71), a positive-stranded RNA virus of the Picornaviridae family, may cause neurological complications or fatality in children. We examined specific factors responsible for this virulence using a chemical genetics approach. Known compounds from an anti-EV-A71 herbal medicine, Salvia miltiorrhiza (Danshen), were screened for anti-EV-A71. We identified a natural product, rosmarinic acid (RA), as a potential inhibitor of EV-A71 by cell-based antiviral assay and in vivo mouse model. Results also show that RA may affect the early stage of viral infection and may target viral particles directly, thereby interfering with virus-P-selectin glycoprotein ligand-1 (PSGL1) and virus-heparan sulfate interactions without abolishing the interaction between the virus and scavenger receptor B2 (SCARB2). Sequencing of the plaque-purified RA-resistant viruses revealed a N104K mutation in the five-fold axis of the structural protein VP1, which contains positively charged amino acids reportedly associated with virus-PSGL1 and virus-heparan sulfate interactions via electrostatic attraction. The plasmid-derived recombinant virus harbouring this mutation was confirmed to be refractory to RA inhibition. Receptor pull-down showed that this non-positively charged VP1-N104 is critical for virus binding to heparan sulfate. As the VP1-N104 residue is conserved among different EV-A71 strains, RA may be useful for inhibiting EV-A71 infection, even for emergent virus variants. Our study provides insight into the molecular mechanism of virus-host interactions and identifies a promising new class of inhibitors based on its antiviral activity and broad spectrum effects against a range of EV-A71.

4.
Chem Commun (Camb) ; 56(43): 5827-5830, 2020 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-32329494

RESUMO

Thrombin activates protease-activated receptor-1 (PAR-1) through binding to exosite I and the active site to promote tumor growth. We have developed a new class of anti-cancer glyco-peptides to target exosite I selectively without affecting the active-site-mediated coagulation activity and showed the importance of glycans for the stability and anti-cancer activity of the glyco-peptides.

5.
Thorac Cancer ; 11(3): 754-761, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32012484

RESUMO

BACKGROUND: There is no consensus on the definition or recommended radiotherapy treatment of ultracentral non-small cell lung cancer (NSCLC). Here, we report our institution's experience in treating ultracentral lung cancer patients with stereotactic ablative radiotherapy (SABR) of 60 Gy in eight fractions. METHODS: We retrospectively reviewed the outcomes of 21 ultracentral NSCLC patients treated with 60 Gy SABR in eight fractions. We defined ultracentral lung cancer as the planning target volume (PTV) directly abutting or overlapping central structures, including the proximal bronchial tree, heart, and great vessels but not the esophagus. The Kaplan-Meier method was used to estimate overall survival (OS), progression-free survival (PFS) and local control (LC). Toxicity was scored per the CTCAE v4.03. RESULTS: The median follow-up time was 15 months, and the median OS was 15 months. The one- and two-year OS rates were 87.5% and 76.6%, respectively. The one- and two-year PFS rates were 71.1% and 64.0%, respectively. The one- and two-year LC rates were 92.9% and 92.9%, respectively. The rate of grade 2 treatment-related toxicities was 19.1%. There was no grade ≥ 3 treatment-related toxicity. CONCLUSION: SABR of 60 Gy in eight fractions is feasible for ultracentral NSCLC.

6.
Clin Exp Rheumatol ; 38(4): 713-723, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31694750

RESUMO

OBJECTIVES: Rheumatoid arthritis (RA) is a systematic autoimmune disease that cardinally affects the joints and other organs. Many people all over the world are suffering from the disease and no effective treatment has been established. Fibroblast-like synoviocytes (FLSs) play a critical role in the occurrence and development of RA. Long non-coding RNA Fer-1-like protein 4 (FER1L4) has been reported to participate in various cancers as a tumour suppressor. However, its clinical significance and biological role in RA is completely unknown. METHODS: RT-qPCR or FISH were used to examine the expression of FER1L4 NLRC5, FER1L4 and inflammatory cytokine levels in synovial tissues (STs) from patients with RA or RA FLSs. Western blot was applied to examine the expression of NLRC5 and inflammatory cytokine levels in synovial tissues (STs) from patients with RA or RA FLSs. BrdU staining and MTT assay were used to examine the cell proliferation ability. The methylation-specific PCR was performed to analyse the methylation levels. RESULTS: The level of FER1L4 significantly reduced in STs and FLSs, whereas the nucleotide oligomerisation domain-like receptors 5 (NLRC5) levels were increased. Overexpression of FER1L4 can decreased the level of NLRC5 and inflammatory cytokine level. The FER1L4 gene promoter was significantly methylated in RA STs and FLSs. More importantly, treatment with methylation inhibitor 5-aza-2-deoxycytidine (5-azadC) inhibited hypermethylation of FER1L4 promoter and the expression of NLRC5. CONCLUSIONS: These results indicated that FER1L4 regulates RA via targeting NLRC5 potentially. Therefore, this study may provide a candidate therapeutic target for RA.


Assuntos
Artrite Reumatoide , RNA Longo não Codificante , Sinoviócitos , Proliferação de Células , Células Cultivadas , Fibroblastos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Membrana Sinovial
7.
Zhongguo Fei Ai Za Zhi ; 22(11): 696-701, 2019 Nov 20.
Artigo em Chinês | MEDLINE | ID: mdl-31771738

RESUMO

BACKGROUND: The standard treatment for locally advanced non-small cell lung cancer (NSCLC) is radiotherapy concurrent with chemotherapy, but the survival was not satisfied. With the development of intensity modulated radiotherapy, simultaneous integrated boost technique (SIB) becomes the research direction of locally advanced NSCLC. The aim of this study is to investigate the efficacy and safety of SIB intensity modulated radiotherapy technique for locally advanced NSCLC. METHODS: We retrospectively reviewed the clinical data of locally advanced NSCLC who were treated with radiotherapy by SIB technique in Peking University Cancer Hospital from June 2015 to December 2018. Kaplan-Meier method was used for analysis. RESULTS: Ninty-three patients were included in the analysis. After a median follow-up of 34.23 months, 3-year overall survival (OS), progression-free survival (PFS), local-recurrence free survival (LRFS) and metastasis free survival (MFS) rates were 53.0%, 37.0%, 50.5% and 50.5%, respectively. The incidence of grade ≥3 esophagitis was 5.4%. There were 2 (2.2%) patients experiencing grade ≥3 radiation-related pneumonia. CONCLUSIONS: Radiation with SIB intensity modulated radiotherapy technique is effective and safe for patients with locally advanced NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Radioterapia de Intensidade Modulada/métodos , Adulto , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radioterapia de Intensidade Modulada/efeitos adversos , Estudos Retrospectivos , Segurança , Análise de Sobrevida
8.
J Vis Exp ; (150)2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31498313

RESUMO

The presence of cancer stem cells (CSCs) has been associated with relapse or poor outcomes after radiotherapy. Studying radioresistant CSCs may provide clues to overcoming radioresistance. Voltage-gated calcium channel α2δ1 subunit isoform 5 has been reported as a marker for radioresistant CSCs in non-small cell lung cancer (NSCLC) cell lines. Using calcium channel α2δ1 subunit as an example of a CSC marker, methods to study the radiosensitivity of CSCs in NSCLC cell lines are presented. CSCs are sorted with putative markers by flow cytometry, and the self-renewal capacity of sorted cells is evaluated by sphere formation assay. Colony formation assay, which determines how many cells lose the ability to generate descendants forming the colony after a certain dose of radiation, is then performed to assess the radiosensitivity of sorted cells. This manuscript provides initial steps for studying the radiosensitivity of CSCs, which establishes the basis for further understanding of the underlying mechanisms.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Recidiva Local de Neoplasia/radioterapia , Células-Tronco Neoplásicas/patologia , Tolerância a Radiação , Radioterapia/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/patologia , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos da radiação , Ensaio Tumoral de Célula-Tronco
9.
Vasc Endovascular Surg ; 53(8): 644-648, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31455177

RESUMO

OBJECTIVE: Stenting is the preferred treatment for iliac vein lesions. For the treatment of occlusions in the junction of the iliac vein and the inferior vena cava (IVC), the stent needs to be positioned in the IVC to cover the lesion. However, the pathological changes in the contralateral iliac vein due to stent coverage on its ostium remain unclear. We observed the patency of the contralateral iliac vein via animal experiments. METHODS: The stents were placed in the left iliac vein and extended into the IVC in 8 beagle dogs. Doppler ultrasonography, angiography, and histopathological examination were used to assess the patency and histopathological changes in the contralateral iliac vein. RESULTS: Angiography showed patency of the contralateral iliac vein and no sign of thrombosis or stenosis. Twelve months after stenting, Doppler ultrasonography showed a stenotic change in the ostium of the contralateral iliac vein. The histopathological examination showed that the stent strut at the ostium of the contralateral iliac vein was mostly covered by the intima, and the cross-sectional stenosis rate was greater than 60%. CONCLUSIONS: The coverage of the iliac vein stent on the ostium of the contralateral iliac vein does not cause complete occlusion of the contralateral vein but can cause significant stenosis at the ostium of the contralateral iliac vein, which is considered to be a potential risk factor for thrombosis.


Assuntos
Procedimentos Endovasculares/instrumentação , Veia Ilíaca/fisiopatologia , Stents , Grau de Desobstrução Vascular , Remodelação Vascular , Veia Cava Inferior/fisiopatologia , Animais , Constrição Patológica , Cães , Procedimentos Endovasculares/efeitos adversos , Veia Ilíaca/diagnóstico por imagem , Veia Ilíaca/ultraestrutura , Masculino , Modelos Animais , Neointima , Fatores de Tempo , Veia Cava Inferior/diagnóstico por imagem , Veia Cava Inferior/ultraestrutura
10.
JAMA Netw Open ; 2(5): e190103, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31099859

RESUMO

Importance: Although thoracic twice-daily radiotherapy (TDRT) is one of the standards of care for small cell lung cancer, its association with brain metastases remains unknown. Objective: To investigate the association of TDRT vs once-daily radiotherapy (ODRT) with brain metastases after prophylactic cranial irradiation in patients with small cell lung cancer. Design, Setting, and Participants: In this multicenter cohort study, data on 778 consecutive patients with small cell lung cancer who had undergone thoracic radiotherapy (609 received ODRT and 169 received TDRT), chemotherapy, and prophylactic cranial irradiation were retrieved from the databases of 8 hospitals in China between July 1, 2003, and June 30, 2016. A 1:1 propensity score matching approach was used to control for confounding between the ODRT and TDRT groups. Confounding covariates included 8 demographic variables and 8 treatment-related covariates. Data analysis was conducted from November 1, 2017, to May 31, 2018, and reanalyzed for revision. Exposures: The ODRT group received 50 to 66 Gy given in 25 to 33 fractions. The TDRT group received 45 Gy given in 30 fractions. Main Outcomes and Measures: The primary end point was brain metastases. Secondary end points included progression-free survival and overall survival. Results: Of the 778 patients (median age, 55 years [interquartile range, 48-61 years]), 204 were women and 574 were men. At a median follow-up of 23.6 months (interquartile range, 14.2-38.2 months), 131 patients (16.8%) experienced brain metastases. The rate of brain metastasis at 3 years in the TDRT group was significantly higher than in the ODRT group (26.0% vs 16.9%; hazard ratio, 1.55; 95% CI, 1.06-2.26; P = .03). Of the 338 matched patients (169 in the ODRT group vs 169 in the TDRT group), 60 (17.8%) experienced brain metastases, with a rate at 3 years of 14.9% in the ODRT group vs 26.0% in the TDRT group (hazard ratio, 1.71; 95% CI, 1.02-2.88; P = .04). Progression-free survival was similar in both the whole cohort and the matched cohort. Median overall survival in the ODRT group tended to be significantly longer than in the TDRT group after matching (47.2 vs 32.8 months; hazard ratio, 1.41; 95% CI, 0.99-2.01; P = .06). Conclusions and Relevance: In this study, patients with small cell lung cancer who received thoracic TDRT appeared to have a higher risk of brain metastases than those who received ODRT, which supports the need for further prospective randomized clinical trials, especially in China and other parts of Asia.


Assuntos
Neoplasias Encefálicas/secundário , Neoplasias Pulmonares/radioterapia , Carcinoma de Pequenas Células do Pulmão/radioterapia , Idoso , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/radioterapia , Irradiação Craniana/efeitos adversos , Relação Dose-Resposta à Radiação , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/mortalidade
11.
J Neurosurg ; : 1-9, 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31003211

RESUMO

OBJECTIVEAlthough glucose metabolism reengineering is a typical feature of various tumors, including glioma, key regulators of glycolytic reprogramming are still poorly understood. The authors sought to investigate whether glycolysis inhibition by microRNA (miR)-448 increases radiosensitivity in glioma cells.METHODSThe authors used glioma tissue samples from glioma patients, cells from glioblastoma (GBM) cell lines and normal human astrocyte cells, and subcutaneous tumor-bearing U87 cells in mice to examine the effects of signaling regulation by miR-448 in the response of glioma tissues and cells to radiation treatment. Techniques used for investigation included bioinformatics analyses, biochemical assays, luciferase reporter assays, and establishment of subcutaneous tumors in a mouse model. Glucose consumption, LDH activity, and cellular ATP were measured to determine the ability of glioma cells to perform glycolysis. Expression of HIF-1α was measured as a potential target gene of miR-448 in glycolysis.RESULTSmiR-448 was detected and determined to be significantly downregulated in both glioma tissues from glioma patients and GBM cell lines. Furthermore, miR-448 acted as a tumor-inhibiting factor and suppressed glycolysis in glioma by negatively regulating the activity of HIF-1α signaling and then interfering with its downstream regulators relative to glycolysis, HK1, HK2, and LDHA. Interestingly, overexpression of miR-448 increased the x-radiation sensitivity of glioma cells. Finally, in in vivo experiments, subcutaneous tumor-bearing U87 cells in a mouse model verified that high expression of miR-448 also enhanced glioma radiosensitivity via inhibiting glycolytic factors.CONCLUSIONSmiR-448 can promote radiosensitivity by inhibiting HIF-1α signaling and then negatively controlling the glycolysis process in glioma. A newly identified miR-448-HIF-1α axis acts as a potentially valuable therapeutic target that may be useful in overcoming radioresistance in glioma treatment.

12.
Biomed Pharmacother ; 110: 528-536, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30530288

RESUMO

Thyroid cancer keeps rapidly increasing worldwide and the most frequent type is papillary thyroid carcinoma (PTC). MicroRNAs (miRNAs) are proved dysregulated in many types of malignancies, including thyroid cancer. Although miR-let-7e has been implicated in several types of cancer regulation, relatively little is known about the function of miR-let-7e in PTC. In this study, we showed that the overexpression of miR-let-7e or knockdown of high mobility group box 1 (HMGB1) inhibited cell migration and invasion. MiR-let-7e downregulates HMGB1 expression by directly targeting the HMGB1 3'-UTR. Furthermore, HMGB1 reintroduction reversed the anti-proliferation, anti-migration, and anti-invasion roles of miR-let-7e. miR-let-7e might function as a tumor suppressor in papillary thyroid carcinoma through HMGB1. Therefore, our study demonstrates that miR-let-7e plays an important role in papillary thyroid carcinoma progression and might represent a new potential therapeutic target for treatment.


Assuntos
Movimento Celular/fisiologia , Regulação Neoplásica da Expressão Gênica , Proteína HMGB1/biossíntese , MicroRNAs/biossíntese , Câncer Papilífero da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Animais , Linhagem Celular Tumoral , Proteína HMGB1/antagonistas & inibidores , Proteína HMGB1/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia
13.
Clin Lung Cancer ; 19(4): e399-e404, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29519614

RESUMO

PURPOSE: Stereotactic ablative body radiotherapy (SABR) represents an exciting, tolerable, and highly effective form of radiotherapy. Ongoing investigations into the interactions between radiotherapy and the immune system have uncovered new mechanisms that can be exploited to improve efficacy. We determined whether baseline or posttreatment immune parameters could predict disease control and toxicity in stage I non-small-cell lung cancer (NSCLC) patients treated with SABR. PATIENTS AND METHODS: Peripheral blood samples were collected from 62 patients 24 hours before treatment and within 4 weeks after treatment for lymphocyte subset count analysis. All peripheral blood samples were analyzed by flow cytometry. Associated parameters were evaluated to determine their association with progression-free survival (PFS) and symptomatic radiation pneumonitis (grade 2 or higher). The survival rates were estimated with Kaplan-Meier and multivariable analyses using binary logistic regression analysis or a Cox proportional hazards model. RESULTS: At a median follow-up time of 36.0 months, the PFS rates for years 1, 2, and 3 were 91.0%, 82.5%, and 48.9%, respectively. The multivariable logistic regression analysis showed that only proportion of lung receiving 20 Gy of radiotherapy (odds ratio = 1.41; 95% confidence interval, 1.05-1.87; P = .023) and mean lung dose (odds ratio = 2.02; 95% confidence interval, 1.16-3.53; P = .016) were associated with symptomatic radiation pneumonitis (grade 2 or higher). Moreover, the immune parameters had no predictive value. In the multivariable Cox regression analysis, an elevated posttreatment cytotoxic CD8+ T-cell level was an independent prognostic factor for longer PFS in stage I NSCLC (hazard ratio, 1.16; 95% confidence interval, 1.01-1.28; P = .01). CONCLUSION: A higher posttreatment cytotoxic CD8+ T-cell level was predictive of better PFS in stage I NSCLC patients receiving SABR. Thus, enhancing tumor antigen-specific cellular immunity by combining radiotherapy and immunotherapy might be a crucial strategy for improving survival in these patients.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/radioterapia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Pneumonite por Radiação/imunologia , Radiocirurgia/efeitos adversos , Radiocirurgia/métodos , Estudos Retrospectivos , Subpopulações de Linfócitos T/imunologia , Resultado do Tratamento
14.
Cell Oncol (Dordr) ; 41(1): 25-33, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29076027

RESUMO

PURPOSE: Exosomal miRNAs that play an important role in cell-cell communication have attracted major attention as potential diagnostic and prognostic biomarkers for various cancers. The aim of this study was to determine the diagnostic/prognostic significance of serum exosomal miR-301a in glioma patients. METHODS: Quantitative real-time PCR was used to determine the serum exosomal expression levels of miR-301a. Kaplan-Meier survival analyses, Cox regression analyses and ROC working curve analyses were applied to assess the diagnostic and prognostic values of miR-301a in glioma patients. Also, several in vitro assays were used, including proliferation, invasion and cell signaling assays. RESULTS: First, we established that serum exosomal miR-301a extracted from grade IV glioblastoma (GBM) patients was biologically active, i.e., promoted the proliferation and invasion of glioma-derived H4 cells. Subsequently, we found that serum exosomal miR-301a levels were significantly up-regulated in glioma patients compared to healthy controls. Additionally, we found that increased serum exosomal miR-301a levels were correlated with ascending pathological grades and lower Karnofsky performance status (KPS) scores. Importantly, we also found that the serum exosomal miR-301a levels were significantly reduced after surgical resection of primary tumors and increased again during GBM recurrence. Kaplan-Meier analysis of patients with an advanced pathological grade (III or IV) and an increased serum exosomal miR-301a level revealed a longer overall survival (OS) compared to those with a lower level (p < 0.01). Both univariate and multivariate Cox regression analyses confirmed that serum exosomal miR-301a levels are independently associated with OS. Finally, we found that miR-301a may activate the AKT and FAK signaling pathways by down regulating PTEN. CONCLUSIONS: Our data indicate that serum exosomal miR-301a levels may reflect the cancer-bearing status and pathological changes in glioma patients. Serum exosomal miR-301a expression may serve as a novel biomarker for glioma diagnosis and as a prognostic factor for advanced grade disease.


Assuntos
Neoplasias Encefálicas/diagnóstico , Exossomos/genética , Glioma/diagnóstico , MicroRNAs/sangue , Adulto , Idoso , Biomarcadores Tumorais/sangue , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Proliferação de Células , Feminino , Glioma/sangue , Glioma/mortalidade , Glioma/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , PTEN Fosfo-Hidrolase/metabolismo , Prognóstico , Curva ROC
15.
PLoS One ; 12(3): e0174561, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28362827

RESUMO

Alzheimer's disease (AD) is the most common dementia affecting tens of million people worldwide. The primary neuropathological hallmark in AD is amyloid plaques composed of amyloid-ß peptide (Aß). Several familial mutations found in Aß sequence result in early onset of AD. Previous studies showed that the mutations located at N-terminus of Aß, such as the English (H6R) and Tottori (D7N) mutations, promote fibril formation and increase cytotoxicity. However, A2T mutant located at the very N-terminus of Aß shows low-prevalence incidence of AD, whereas, another mutant A2V causes early onset of AD. To understand the molecular mechanism of the distinct effect and develop new potential therapeutic strategy, here, we examined the effect of full-length and N-terminal A2V/T variants to wild type (WT) Aß40 by fibrillization assays and NMR studies. We found that full-length and N-terminal A2V accelerated WT fibrillization and induced large chemical shifts on the N-terminus of WT Aß, whereas, full-length and N-terminal A2T retarded the fibrillization. We further examined the inhibition effect of various N-terminal fragments (NTFs) of A2T to WT Aß. The A2T NTFs ranging from residue 1 to residue 7 to 10, but not 1 to 6 or shorter, are capable to retard WT Aß fibrillization and rescue cytotoxicity. The results suggest that in the presence of full-length or specific N-terminal A2T can retard Aß aggregation and the A2T NTFs can mitigate its toxicity. Our results provide a novel targeting site for future therapeutic development of AD.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Dicroísmo Circular , Humanos , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Transmissão , Espectroscopia de Infravermelho com Transformada de Fourier
16.
Medicine (Baltimore) ; 96(8): e5943, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28225485

RESUMO

We investigate the impact of magnetic resonance (MR) on the staging and radiotherapy planning for patients with nonsmall cell lung cancer (NSCLC).A total of 24 patients with NSCLC underwent MRI, which was fused with radiotherapy planning CT using rigid registration. Gross tumor volume (GTV) was delineated not only according to CT image alone (GTVCT), but also based on both CT and MR image (GTVCT/MR). For each patient, 2 conformal treatment plans were made according to GTVCT and GTVCT/MR, respectively. Dose-volume histograms (DVH) for lesion and normal organs were generated using both GTVCT and GTVCT/MR treatment plans. All patients were irradiated according to GTVCT/MR plan.Median volume of the GTVCT/MR and GTVCT were 105.42 cm and 124.45 cm, respectively, and the mean value of GTVCT/MR was significantly smaller than that of GTVCT (145.71 ±â€Š145.04 vs 174.30 ±â€Š150.34, P < 0.01). Clinical stage was modified in 9 patients (37.5%). The objective response rate (ORR) was 83.3% and the l-year overall survival (OS) was 87.5%.MR is a useful tool in radiotherapy treatment planning for NSCLC, which improves the definition of tumor volume, reduces organs at risk dose and does not increase the local recurrence rate.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Imagem por Ressonância Magnética/métodos , Estadiamento de Neoplasias , Planejamento da Radioterapia Assistida por Computador/métodos , Carga Tumoral , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Adenocarcinoma/radioterapia , Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Feminino , Seguimentos , Humanos , Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Radioterapia Conformacional/métodos , Radioterapia Guiada por Imagem/métodos , Análise de Sobrevida , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
17.
Zhongguo Fei Ai Za Zhi ; 20(1): 28-34, 2017 Jan 20.
Artigo em Chinês | MEDLINE | ID: mdl-28103970

RESUMO

BACKGROUND: Twice-daily radiation concurrent with chemotherapy is one of the standard methods for limited-stage small cell lung cancer. The study was to evaluate the feasibility of chemotherapy concurrent with dose-escalating twice-daily radiotherapy by simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) approach in patients with limited-stage small cell lung cancer. METHODS: Patients with limited-stage small cell lung cancer were included, treated with twice-daily radiotherapy by SIB-IMRT concurrent with chemotherapy of etoposide plus cisplatin. Dose escalation was conducted by "classical" 3+3 methods with three patients enrolled in each dose level. The therapeutic gross tumor volume (GTV) was treated according to three consecutive dose levels i.e., 45 Gy at 1.5 Gy twice daily, 50 Gy at 1.67 Gy twice daily and 54 Gy at 1.8 Gy twice daily. The planning target volume (PTV) received a dose of 45 Gy delivered in 30 fractions of 1.5 Gy. The primary endpoints were acute toxicities. The secondary endpoints included overall survival (OS), progression-free survival (PFS) and loco-regional failure-free survival (LRFFS) at 1-year of follow-up. RESULTS: Twenty men and six women were included. The median age was 52 (30-68) months. 12 patients experienced grade 2 acute esophagitis, and 1 patient developed grade 3 acute esophagitis. Only 3 patients developed Grade 2 pneumonitis. Grade 3 or higher radiation-related pneumonia was not observed. None died of treatment-related causes. With median follow-up of 11.2 months (3.2-36.2 months), 1-year OS, PFS and LRFFS were 89.0%, 51.0% and 85.0%, respectively. CONCLUSIONS: Dose escalation for twice-daily radiation concurrent with chemotherapy in LS-SCLC has been safely achieved up to 54 Gy for GTV using SIB-IMRT technique.


Assuntos
Quimiorradioterapia/métodos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Radioterapia de Intensidade Modulada , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/terapia , Adulto , Idoso , Quimiorradioterapia/efeitos adversos , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Relação Dose-Resposta à Radiação , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Masculino , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/efeitos adversos , Segurança , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/radioterapia , Fatores de Tempo
18.
Zhongguo Fei Ai Za Zhi ; 20(1): 55-60, 2017 Jan 20.
Artigo em Chinês | MEDLINE | ID: mdl-28103974

RESUMO

BACKGROUND: Concurrent twice-daily radiotherapy with chemotherapy of EP regimen is one of the current standard treatments for limited-stage small cell lung cancer. However, the safely tolerated dose of standard chemotherapy for Chinese patients is not decided. This study was to evaluate the toxicity and the maximum tolerated dose (MTD) of etoposide and cisplatin concurrent with thoracic radiation therapy for patients with limited-stage small cell lung cancer. METHODS: Patients with histologically proven limited-stage small cell lung cancer (LS-SCLC) were eligible. The patients underwent thoracic radiotherapy (45 Gy, 1.5 Gy bid, 30 fractions for 3 weeks) delivered concurrently with etoposide (100 mg/m2 iv, days 1-3) and cisplatin dose escalating from the two levels ( 70 mg/m2 and 75 mg/m2 on d1). The primary endpoints were hematologic toxicities during treatment. The secondary endpoints were non-hematologic toxicities, overall survival (OS) and progression-free survival (PFS). According to Common Terminology Criteria for Adverse Events 4.0 (CTC-AE 4.0), maximum tolerant dosage (MTD) was defined as the highest safely tolerated dose at which no more than one patient out of six experiences dose-limiting toxicity (Grades 4 hematologic), with the next higher dose having at least two out of six patients experience dose-limiting toxicity. RESULTS: From January 2013 to August 2016, 20 patients were enrolled in this study. The median age was 49.5 (30-68). After the first 6 patients were enrolled in Arm 1 (70 mg/m2 on d1), one patient had Grade 4 neutropenia. Another 14 patients were enrolled in Arm 2 (75 mg/m2 on d1), one patient had Grade 4 neutropenia. The MTD was determined to be etoposide (100 mg/m2 iv, d1-d3) and cisplatin dose (75 mg/m2 on d1). 4 patients had ≥Grade 3 neutropenia and 1 patients had ≥Grade 3 acute esophagitis in Arm 1. 10 patients had ≥Grade 3 neutropenia and no patient had ≥Grade 3 acute esophagitis in Arm 2. All patients with a median follow-up time was 9.0 months, median OS and PFS were not achieved, 1-year OS and PFS were 91% and 61%, respectively. CONCLUSIONS: The MTD of RT with concurrent chemotherapy of EP regimen for patients with LS-SCLC was etoposide (100 mg/m2 iv, d1-d3) and cisplatin dose (75 mg/m2 on d1).
.


Assuntos
Quimiorradioterapia/métodos , Cisplatino/uso terapêutico , Etoposídeo/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/radioterapia , Adulto , Idoso , Quimiorradioterapia/efeitos adversos , Cisplatino/efeitos adversos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Etoposídeo/efeitos adversos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Segurança , Resultado do Tratamento , Adulto Jovem
19.
J Plant Biol ; 60(5): 506-512, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30310351

RESUMO

Plant shoot stem cell pool is constantly maintained by a negative feedback loop through peptide-receptor mediated signaling pathway. CLAVATA3 (CLV3) encode a 96 amino-acid protein which is processed to 12-amino-acid or arabinosylated 13-amino-acid peptides, acting as a ligand signal to regulate stem cell homeostasis in the shoot apical meristem (SAM). Although arabinosylated 13-amino-acid CLV3 peptide (CLV3p) shows more significant binding affinity to its receptors and biological activities in the SAM, the physiological function of two mature forms of CLV3p remained an unresolved puzzle in the past decade due to the technical difficulties of arabinosylation modification in the peptide synthesis. Here, we analyzed the role of two mature CLV3 peptides with newly synthesized arabinosylated peptide. Beside shoot meristem phenotypes, arabinosylated CLV3p showed the conventional trait of CLV2-dependent root growth inhibition. Moreover, both 12-amino-acid and arabinosylated 13-amino-acid CLV3 peptides have analogous activities in shoot stem cell signaling. Notably, we demonstrated that non-arabinosylated 12-amino acid CLV3p can affect shoot stem cell signaling at the physiological level unlike previously suggested (Ohyama et al., 2009; Shinohara and Matsubayashi, 2013; Shinohara and Matsubayashi, 2015). Therefore, these results support the physiological role of the 12-amino-acid CLV3p in shoot stem cell signaling in the deficient condition of arabinosylated 13-amino-acid CLV3p in Arabidopsis thaliana.

20.
ACS Chem Neurosci ; 7(8): 1097-106, 2016 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-27227450

RESUMO

Amyloid-ß (Aß), the main constituent in senile plaques found in the brain of patients with Alzheimer's disease (AD), is considered as a causative factor in AD pathogenesis. The clinical examination of the brains of patients with AD has demonstrated that caspase-3 colocalizes with senile plaques. Cellular studies have shown that Aß can induce neuronal apoptosis via caspase-3 activation. Here, we performed biochemical and in silico studies to investigate possible direct effect of Aß on caspase-3 to understand the molecular mechanism of the interaction between Aß and caspase-3. We found that Aß conformers can specifically and directly sequester caspase-3 activity in which freshly prepared Aß42 is the most potent. The inhibition is noncompetitive, and the C-terminal region of Aß plays an important role in sequestration. The binding of Aß to caspase-3 was examined by cross-linking and proteolysis and by docking and all-atom molecular dynamic simulations. Experimental and in silico results revealed that Aß42 exhibits a higher binding affinity than Aß40 and the hydrophobic C-terminal region plays a key role in the caspase-Aß interaction. Overall, our study describes a novel mechanism demonstrating that Aß sequesters caspase-3 activity via direct interaction and facilitates future therapeutic development in AD.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Caspase 3/química , Caspase 3/metabolismo , Fragmentos de Peptídeos/química , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/ultraestrutura , Precursor de Proteína beta-Amiloide/genética , Animais , Caspase 3/efeitos dos fármacos , Linhagem Celular Tumoral , Simulação por Computador , Modelos Animais de Doenças , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Simulação de Acoplamento Molecular , Mutação/genética , Neuroblastoma/patologia , Fragmentos de Peptídeos/farmacologia , Placa Amiloide/metabolismo , Presenilina-1/genética , Proteínas tau/genética
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