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1.
Endocr Relat Cancer ; 27(3): 153-162, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31905165

RESUMO

HER2-positive breast cancer is a biologically and clinically heterogeneous disease. Based on the expression of hormone receptors (HR), breast tumors can be further categorized into HR positive and HR negative. Here, we elucidated the comprehensive somatic mutation profile of HR+ and HR- HER2-positive breast tumors to understand their molecular heterogeneity. In this study, 64 HR+/HER2+ and 43 HR-/HER2+ stage I-III breast cancer patients were included. Capture-based targeted sequencing was performed using a panel consisting of 520 cancer-related genes, spanning 1.64 megabases of the human genome. A total of 1119 mutations were detected among the 107 HER2-positive patients. TP53, CDK12 and PIK3CA were the most frequently mutated, with mutation rates of 76, 61 and 49, respectively. HR+/HER2+ tumors had more gene amplification, splice site and frameshift mutations and a smaller number of missense, nonsense and insertion-deletion mutations than HR-/HER2+ tumors. In KEGG analysis, HR+/HER2+ tumors had more mutations in genes involved in homologous recombination (P = 0.004), TGF-beta (P = 0.007) and WNT (P = 0.002) signaling pathways than HR-/HER2+ tumors. Moreover, comparative analysis of our cohort with datasets from The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium revealed the distinct somatic mutation profile of Chinese HER2-positive breast cancer patients. Our study revealed the heterogeneity of somatic mutations between HR+/HER2+ and HR-/HER2+ in Chinese breast cancer patients. The distinct mutation profile and related pathways are potentially relevant in the development of optimal treatment strategies for this subset of patients.

2.
Chin Med J (Engl) ; 132(20): 2476-2484, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31613820

RESUMO

OBJECTIVE: Secreted modular calcium-binding proteins (SMOCs) are extracellular glycoproteins of the secreted protein, acidic, and rich in cysteine-related modular calcium-binding protein family and include two isoforms, SMOC1 and SMOC2, in humans. Functionally, SMOCs bind to calcium for various cell functions. In this review, we provided a summary of the most recent advancements in and findings of SMOC1 and SMOC2 in development, homeostasis, and disease states. DATA SOURCES: All publications in the PubMed database were searched and retrieved (up to July 24, 2019) using various combinations of keywords searching, including SMOC1, SMOC2, and diseases. STUDY SELECTION: All original studies and review articles of SMOCs in human diseases and embryo development written in English were retrieved and included. RESULTS: SMOC1 and SMOC2 regulate embryonic development, cell homeostasis, and disease pathophysiology. They play an important role in the regulation of cell cycle progression, cell attachment to the extracellular matrix, tissue fibrosis, calcification, angiogenesis, birth defects, and cancer development. CONCLUSIONS: SMOC1 and SMOC2 are critical regulators of many cell biological processes and potential therapeutic targets for the control of human cancers and birth defects.

3.
Aging (Albany NY) ; 11(18): 7525-7536, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31548433

RESUMO

Increasing evidence has revealed that microRNAs (miRNAs) play vital roles in breast cancer (BC) prognosis. Thus, we aimed to identify recurrence-related miRNAs and establish accurate risk stratification system in BC patients. A total of 381 differentially expressed miRNAs were confirmed by analyzing 1044 BC tissues and 102 adjacent normal samples from The Cancer Genome Atlas (TCGA). Then, based on the association between each miRNAs and disease-free survival (DFS), we identified miRNA recurrence-related signature to construct a novel prognostic nomogram using Cox regression model. Target genes of the four miRNAs were analyzed via Gene Ontology and KEGG pathway analyses. Time-dependent receiver operating characteristic analysis indicated that a combination of the miRNA signature and tumor-node-metastasis (TNM) stage had better predictive performance than that of TNM stage (0.710 vs 0.616, P<0.0001). Furthermore, risk stratification analysis suggested that the miRNA-based model could significantly classify patients into the high- and low-risk groups in the two cohorts (all P<0.0001), and was independent of other clinical features. Functional enrichment analysis demonstrated that the 46 target genes mainly enrichment in important cell biological processes, protein binding and cancer-related pathways. The miRNA-based prognostic model may facilitate individualized treatment decisions for BC patients.

4.
Ann Transl Med ; 7(8): 179, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31168460

RESUMO

Background: The complexity of breast cancer at the clinical, morphological and genomic levels has been extensively studied in the western population. However, the mutational genomic profiles in Chinese breast cancer patients have not been explored in any detail. Methods: We performed targeted sequencing using a panel consisting of 33 breast cancer-related genes to investigate the genomic landscape of 304 consecutive treatment-naïve Chinese breast cancer patients at Guangdong Provincial People's Hospital (GDPH), and further compared the results to those in 453 of Caucasian breast cancer patients from The Cancer Genome Atlas (TCGA). Results: The most frequently mutated gene was TP53 (45%), followed by PIK3CA (44%), GATA3 (18%), MAP3K1 (10%), whereas the copy-number amplifications were frequently observed in genes of ERBB2 (24%), MYC (23%), FGFR1 (13%) and CCND1 (10%). Among the 8 most frequently mutated or amplified genes, at least one driver was identifiable in 87.5% (n=267) of our GDPH cohort, revealing the significant contribution of these known driver genes in the development of Chinese breast cancer. Compared to TCGA data, the median age at diagnosis in our cohort was significantly younger (48 vs. 58 years; P<0.001), while the distribution of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) statuses were similar. The largest difference occurred in HR+/HER2- subtype, where 8 of the 10 driver genes compared had statistically significant differences in their frequency, while there were differences in 2 of 10 driver genes among the TNBC and HR+/HER2+ group, but none in the HR-/HER2+ patients in our cohort compared to the TCGA data. Collectively, the most significant genomic difference was a significantly higher prevalence for TP53 and AKT1 in Chinese patients. Additionally, more than half of TP53-mutation HR+/HER2- Chinese patients (~60%) are likely to harbor more severe mutations in TP53, such as nonsense, indels, and splicing mutations. Conclusions: We elucidated the mutational landscape of cancer genes in Chinese breast cancer and further identified significant genomic differences between Asian and Caucasian patients. These results should improve our understanding of pathogenesis and/or metastatic behavior of breast cancer across races/ethnicities, including a better selection of targeted therapies.

5.
Biochem Biophys Res Commun ; 501(1): 266-272, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29729271

RESUMO

BACKGROUND: Fat grafting is a commonly used procedure; however, the mechanisms that regulate graft outcomes are not clear. Estrogen has been associated with vascularization, inflammation and fat metabolism, yet its role in fat grafting is unclear. METHODS: Mice were implanted with 17ß-estradiol pellets (high estrogen, HE), underwent ovariectomy (low estrogen level, OVX) or sham surgery (normal estrogen level, CON). 45 days later, inguinal fat of mice was autografted subcutaneously. At 1, 2, 4, and 12 weeks post-transplantation, grafts were dissected, weighed, and assessed for histology, angiogenesis and inflammation level. RESULTS: Serum estrogen level correlated to estrogen manipulation. 12 weeks after autografting, the retention rate was significantly higher in the OVX (79% ± 30%) than in the HE (16% ± 8%) and CON (35% ± 13%) groups. OVX-grafts had the least necrosis and most hypertrophic fat. OVX recruited the most pro-inflammatory macrophages and demonstrated a faster dead tissue removal process, however a higher fibrogenic tendency was found in this group. HE grafts had the most Sca1+ local stem cells and CD31 + capillary content; however, with a low level of acute inflammation and insufficient adipokine PPAR-γ expression, their retention rate was impaired. CONCLUSIONS: Elevated serum estrogen increased stem cell density and early vascularization; however, by inhibiting the early inflammation, it resulted in delayed necrotic tissue removal and finally led to impaired adipose restoration. A low estrogen level induced favorable inflammation status and adipocyte hypertrophy to improve fat graft retention, but a continuing decreased estrogen level led to fat graft fibrosis.


Assuntos
Tecido Adiposo/transplante , Estrogênios/sangue , Macrófagos/citologia , Adipócitos/citologia , Adipogenia , Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/citologia , Animais , Autoenxertos , Crescimento Celular , Proliferação de Células , Estradiol/administração & dosagem , Estradiol/sangue , Estrogênios/deficiência , Feminino , Fibrose , Sobrevivência de Enxerto , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica , Ovariectomia , Células-Tronco/citologia
6.
Wound Repair Regen ; 25(6): 923-932, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29240284

RESUMO

Conditioned medium (CM) is a new treatment modality in regenerative medicine and has shown a successful outcome in wound healing. We recently introduced extracellular matrix/stromal vascular fraction gel (ECM/SVF-gel), an adipose-derived stem cell and adipose native extracellular matrix-enriched product for cytotherapy. This study aimed to evaluate the effect of CM from ECM/SVF-gel (Gel-CM) on wound healing compared with the conventional CM from adipose tissue (Adi-CM) and stem cell (SVF-CM). In vitro wound healing effect of three CMs on keratinocytes and fibroblasts was evaluated in terms of proliferation property, migratory property, and extracellular matrix production. In vivo, two full-thickness wounds were created on the back of each mice. The wounds were randomly divided to receive Gel-CM, Adi-CM, SVF-CM, and PBS injection. Histologic observations and collagen content of wound skin were made. Growth factors concentration in three CMs was further quantified. In vitro, Gel-CM promoted the proliferation and migration of keratinocytes and fibroblasts and enhanced collagen I synthesis in fibroblasts compared to Adi-CM and SVF-CM. In vivo, wound closure was faster, and dermal and epidermal regeneration was improved in the Gel-CM-treated mice compared to that in Adi-CM and SVF-CM-treated mice. Moreover, The growth factors concentration (i.e., vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor, and transforming growth factor-ß) in Gel-CM were significantly higher than those in Adi-CM and SVF-CM. Gel-CM generated under serum free conditions significantly enhanced wound healing effect compared to Adi-CM and SVF-CM by accelerating cell proliferation, migration, and production of ECM. This improved trophic effect may be attributed to the higher growth factors concentration in Gel-CM. Gel-CM shows potential as a novel and promising alternative to skin wound healing treatment. But limitations include the safety and immunogenicity studies of Gel-CM still remain to be clearly clarified and more data on mechanism study are needed.


Assuntos
Meios de Cultivo Condicionados/farmacologia , Matriz Extracelular , Fibroblastos/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Pele/efeitos dos fármacos , Células-Tronco , Células Estromais , Cicatrização/efeitos dos fármacos , Tecido Adiposo/citologia , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/biossíntese , Colágeno Tipo I/efeitos dos fármacos , Meios de Cultivo Condicionados/metabolismo , Modelos Animais de Doenças , Fator 2 de Crescimento de Fibroblastos/metabolismo , Géis , Fator de Crescimento de Hepatócito/metabolismo , Técnicas In Vitro , Camundongos , Pele/lesões , Pele/patologia , Fator de Crescimento Transformador beta/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Oncol Lett ; 7(2): 349-356, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24396446

RESUMO

Perioperative corticosteroid administration is a controversial therapy for improving the short-term prognosis following surgery. The objective of the current meta-analysis was to evaluate the effects of the perioperative use of corticosteroids during esophagectomy for esophageal carcinoma. A comprehensive study was performed using references selected from the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE (Ovid databases), EMBASE and three Chinese databases (Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure and VIP Database for Chinese Technical Periodicals). Eligible studies were restricted to randomized clinical trials that reported data from patients undergoing esophagectomy. In addition, treated groups of patients received perioperative corticosteroid administration and control groups received a placebo infusion, such as saline water. The studies evaluated the incidence of postoperative complications and the variation of inflammatory mediators. All extracted data underwent meta-analysis using Review Manager 5.1 software. Only six studies were eligible for selection. The following parameters were found to be reduced following the use of methylprednisolone: Interleukin (IL)-6 immediately following surgery and on postoperative days (PODs) 1 and 3; IL-8 immediately following surgery; and PaO2/FiO2 on POD 3. Moreover, organ failure, cardiovascular complications and pulmonary morbidity were all reduced in patients with corticosteroid usage. Certain factors showed no significant differences between the treated and control groups, including IL-8 on POD 1, IL-6 prior to surgery and on POD 5, PaO2/FiO2 following surgery, mortality, anastomotic leakage, severe infection and renal and hepatic failure. Prophylactic administration of methylprednisolone during the perioperative period may reduce the incidence of specific types of postoperative complications and inhibit the postoperative inflammatory reaction. Additional randomized controlled trials must be performed.

8.
Pak J Med Sci ; 30(6): 1377-82, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25674142

RESUMO

OBJECTIVE: Evidence-based medicine offers explicit methods to evaluate the evidence grades of literature. However, evidence grades do not meet all the practical needs of physicians. This study is aimed to develop a convenient method for evaluating the clinical value of medical literature from the perspective of the clinician. METHODS: A literature applicability equation was formulated through the Delphi method and the analytic hierarchy process. A consistency check was used to ascertain the efficacy of the formula. Three senior clinicians assessed 30 articles based on their clinical experiences and subjective opinions, while one independent researcher performed independent assessments of the applicability of 30 articles using the evaluation formula. RESULTS: The literature applicability equation was Y = 3.93X1 + 11.78X2 + 14.83X3 + 44.53X4 + 24.93X5, where Y = literature applicability, X1 = years since publication, X2 = target question covered or not, X3 = sample size, X4 = study type, and X5 = journal quality. Consistency index (CI) values for the first-level indicator ("literature applicability") and the second-level indicators ("pertinence and timeliness" and "quality of results") were 0.0325, 0.0012, and 0.0001, respectively. The weights used to calculate the matrix indicators had satisfactory accordance (random coincidence coefficient = 0.056). A consistency check for the efficacy of the formula revealed kappa = 0.749 and P < .001. Conclusion : The developed and validated literature applicability evaluation formula may be a useful and convenient tool for identifying clinically valuable medical literature.

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