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1.
Cancer Med ; 8(12): 5673-5686, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31369215

RESUMO

INTRODUCTION: Targeted therapies are based on specific gene alterations. Various specimen types have been used to determine gene alterations, however, no systemic comparisons have yet been made. Herein, we assessed alterations in selected cancer-associated genes across varying sample sites in lung cancer patients. MATERIALS AND METHODS: Targeted deep sequencing for 48 tumor-related genes was applied to 153 samples from 55 lung cancer patients obtained from six sources: Formalin-fixed paraffin-embedded (FFPE) tumor tissues, pleural effusion supernatant (PES) and pleural effusion cell sediments (PEC), white blood cells (WBCs), oral epithelial cells (OECs), and plasma. RESULTS: Mutations were detected in 96% (53/55) of the patients and in 83% (40/48) of the selected genes. Each sample type exhibited a characteristic mutational pattern. As anticipated, TP53 was the most affected sequence (54.5% patients), however this was followed by NOTCH1 (36%, across all sample types). EGFR was altered in patient samples at a frequency of 32.7% and KRAS 10.9%. This high EGFR/ low KRAS frequency is in accordance with other TCGA cohorts of Asian origin but differs from the Caucasian population where KRAS is the more dominant mutation. Additionally, 66% (31/47) of PEC samples had copy number variants (CNVs) in at least one gene. Unlike the concurrent loss and gain in most genes, herein NOTCH1 loss was identified in 21% patients, with no gain observed. Based on the relative prevalence of mutations and CNVs, we divided lung cancer patients into SNV-dominated, CNV-dominated, and codominated groups. CONCLUSIONS: Our results confirm previous reports that EGFR mutations are more prevalent than KRAS in Chinese lung cancer patients. NOTCH1 gene alterations are more common than previously reported and reveals a role of NOTCH1 modifications in tumor metastasis. Furthermore, genetic material from malignant pleural effusion cell sediments may be a noninvasive manner to identify CNV and participate in treatment decisions.

2.
Int J Cancer ; 145(9): 2547-2557, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30919951

RESUMO

The liquid biopsy is being integrated into cancer diagnostics and surveillance. However, critical questions still remain, such as how to precisely evaluate cancer mutation burden and interpret the corresponding clinical implications. Herein, we evaluated the role of peripheral blood cell-free DNA (cfDNA) in characterizing the dynamic mutation alterations of 48 cancer driver genes from cervical cancer patients. We performed targeted deep sequencing on 93 plasma cfDNA from 57 cervical cancer patients and from this developed an algorithm, allele fraction deviation (AFD), to monitor in an unbiased manner the dynamic changes of genomic aberrations. Differing treatments, including chemotherapy (n = 22), radiotherapy (n = 14) and surgery (n = 15), led to a significant decrease in AFD values (Wilcoxon, p = 0.029). The decrease of cfDNA AFD values was accompanied by shrinkage in the size of the tumor in most patients. However, in a subgroup of patients where cfDNA AFD values did not reflect a reduction in tumor size, there was a detection of progressive disease (metastasis). Furthermore, a low AFD value at diagnosis followed a later increase of AFD value also successfully predicted relapse. These results show that plasma cfDNA, together with targeted deep sequencing, may help predict treatment response and disease development in cervical cancer.

3.
EBioMedicine ; 41: 120-133, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30799199

RESUMO

BACKGROUND: Differential gene expression patterns are commonly used as biomarkers to predict treatment responses among heterogeneous tumors. However, the link between response biomarkers and treatment-targeting biological processes remain poorly understood. Here, we develop a prognosis-guided approach to establish the determinants of treatment response. METHODS: The prognoses of biological processes were evaluated by integrating the transcriptomes and clinical outcomes of ~26,000 cases across 39 malignancies. Gene-prognosis scores of 39 malignancies (GEO datasets) were used for examining the prognoses, and TCGA datasets were selected for validation. The Oncomine and GEO datasets were used to establish and validate transcriptional signatures for treatment responses. FINDINGS: The prognostic landscape of biological processes was established across 39 malignancies. Notably, the prognoses of biological processes varied among cancer types, and transcriptional features underlying these prognostic patterns distinguished response to treatment targeting specific biological process. Applying this metric, we found that low tumor proliferation rates predicted favorable prognosis, whereas elevated cellular stress response signatures signified resistance to anti-proliferation treatment. Moreover, while high immune activities were associated with favorable prognosis, enhanced lipid metabolism signatures distinguished immunotherapy resistant patients. INTERPRETATION: These findings between prognosis and treatment response provide further insights into patient stratification for precision treatments, providing opportunities for further experimental and clinical validations. FUND: National Natural Science Foundation, Innovative Research Team in University of Ministry of Education of China, National Key Research and Development Program, Natural Science Foundation of Guangdong, Science and Technology Planning Project of Guangzhou, MRC, CRUK, Breast Cancer Now, Imperial ECMC, NIHR Imperial BRC and NIH.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Neoplasias/genética , Transcriptoma , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Conjuntos de Dados como Assunto , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Resultado do Tratamento
4.
J Clin Invest ; 129(3): 1030-1046, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30688660

RESUMO

Chronic stress triggers activation of the sympathetic nervous system and drives malignancy. Using an immunodeficient murine system, we showed that chronic stress-induced epinephrine promoted breast cancer stem-like properties via lactate dehydrogenase A-dependent (LDHA-dependent) metabolic rewiring. Chronic stress-induced epinephrine activated LDHA to generate lactate, and the adjusted pH directed USP28-mediated deubiquitination and stabilization of MYC. The SLUG promoter was then activated by MYC, which promoted development of breast cancer stem-like traits. Using a drug screen that targeted LDHA, we found that a chronic stress-induced cancer stem-like phenotype could be reversed by vitamin C. These findings demonstrated the critical importance of psychological factors in promoting stem-like properties in breast cancer cells. Thus, the LDHA-lowering agent vitamin C can be a potential approach for combating stress-associated breast cancer.

5.
Cancer Commun (Lond) ; 38(1): 56, 2018 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-30231942

RESUMO

BACKGROUND: Breast cancer stem cells (BCSCs) are considered responsible for cancer relapse and drug resistance. Understanding the identity of BCSCs may open new avenues in breast cancer therapy. Although several discoveries have been made on BCSC characterization, the factors critical to the origination of BCSCs are largely unclear. This study aimed to determine whether genomic mutations contribute to the acquisition of cancer stem-like phenotype and to investigate the genetic and transcriptional features of BCSCs. METHODS: We detected potential BCSC phenotype-associated mutation hotspot regions by using whole-genome sequencing on parental cancer cells and derived serial-generation spheres in increasing order of BCSC frequency, and then performed target deep DNA sequencing at bulk-cell and single-cell levels. To identify the transcriptional program associated with BCSCs, bulk-cell and single-cell RNA sequencing was performed. RESULTS: By using whole-genome sequencing of bulk cells, potential BCSC phenotype-associated mutation hotspot regions were detected. Validation by target deep DNA sequencing, at both bulk-cell and single-cell levels, revealed no genetic changes specifically associated with BCSC phenotype. Moreover, single-cell RNA sequencing showed profound transcriptomic variability in cancer cells at the single-cell level that predicted BCSC features. Notably, this transcriptomic variability was enriched during the transcription of 74 genes, revealed as BCSC markers. Breast cancer patients with a high risk of relapse exhibited higher expression levels of these BCSC markers than those with a low risk of relapse, thereby highlighting the clinical significance of predicting breast cancer prognosis with these BCSC markers. CONCLUSIONS: Transcriptomic variability, not genetic mutations, distinguishes BCSCs from non-BCSCs. The identified 74 BCSC markers have the potential of becoming novel targets for breast cancer therapy.

6.
Genetics ; 210(2): 547-558, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30076202

RESUMO

Investigation of spontaneous mutations by next-generation sequencing technology has attracted extensive attention lately due to the fundamental roles of spontaneous mutations in evolution and pathological processes. However, these studies only focused on the mutations accumulated through many generations during long-term (possibly be years of) culturing, but not the freshly generated mutations that occur at very low frequencies. In this study, we established a molecularly barcoded deep sequencing strategy to detect low abundant spontaneous mutations in genomes of bacteria cell cultures. Genome-wide spontaneous mutations in 15 Escherichia coli cell culture samples were defined with a high confidence (P < 0.01). We also developed a hotspot-calling approach based on the run-length encoding algorithm to find the genomic regions that are vulnerable to the spontaneous mutations. The hotspots for the mutations appeared to be highly conserved across the bacteria samples. Further biological annotation of these regions indicated that most of the spontaneous mutations were located at the repeat domains or nonfunctional domains of the genomes, suggesting the existence of mechanisms that could somehow prevent the occurrence of mutations in crucial genic areas. This study provides a more faithful picture of mutation occurrence and spectra in a single expansion process without long-term culturing.

7.
Molecules ; 22(4)2017 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-28368360

RESUMO

A new triflavanoid, kandelin B-5 (1), was isolated from the rhizomes of Smilax china L., together with six known phenylpropanoid substituted flavan-3-ols (2-7), nine flavonoids (8-16), two stilbenoids (17, 18), and two other compounds (19, 20). The structure of compound 1 was determined on the basis of 1D, 2D NMR and HR-ESI-MS data, as well as chemical method. Compounds 2-5, 8-12, 15, 17, and 19 were evaluated for anti-inflammatory activity. Only compounds 10, 15 and 17 showed slightly IL-1ß expression inhibitory activities on LPS induced THP-1 cells, with inhibition rate of 15.8%, 37.3%, and 35.8%, respectively, at concentration of 50 µg/mL.


Assuntos
Anti-Inflamatórios/farmacologia , Flavonoides/farmacologia , Extratos Vegetais/farmacologia , Rizoma/química , Smilax/química , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Linhagem Celular , Citocinas/biossíntese , Flavonoides/química , Flavonoides/isolamento & purificação , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação
8.
Nat Prod Res ; 31(13): 1495-1500, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28081652

RESUMO

A new dimeric stilbene, gnetifolin P (1), was isolated from the lianas of Gnetum parvifolium, together with seven known compounds 2-8. The structure of compound 1 was determined by extensive NMR and HRESIMS data analyses, and quantum chemical calculations. All the compounds were evaluated for their anti-inflammatory activity. Compounds 1 and 6 inhibited the expression of IL-1ß on LPS induced THP-1 cells with the inhibition rate of 35.78 and 64.67%, respectively, at concentration of 25 µg/mL.


Assuntos
Anti-Inflamatórios/isolamento & purificação , Gnetum/química , Estilbenos/isolamento & purificação , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Linhagem Celular , Humanos , Interleucina-1beta/antagonistas & inibidores , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Estilbenos/química , Estilbenos/farmacologia
9.
Nan Fang Yi Ke Da Xue Xue Bao ; 36(2): 260-4, 2016 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-26922027

RESUMO

OBJECTIVE: To evaluate the effect of sodium tanshinone IIA sulfonate (STS) in preventing postoperative peritoneal adhesions in rats and explore the mechanisms. METHODS: Sixty SD rats were randomized into 4 equal groups, including a blank control group, adhesion model group, and high-, moderate-, and low-dose STS-treated groups, and were subjected to injuries of the parietal peritoneum and cecum to induce peritoneal adhesions, followed by intraperitoneal administration of saline and STS at the doses of 20, 10, and 5 mg/kg for 7 consecutive days, respectively. Another 15 untreated rats served as the blank control group. The adhesion scores in each group were recorded after the treatments; the activity of tissue-type plasminogen activator (tPA) in peritoneal lavage fluid was measured, tPA/PAI-1 protein ratio in the peritoneal tissue was determined by ELISA, and the expressions of TGF-ß1 and collagen I were detected by immunohistochemistry. The anastomotic healing model was used to assess the impact of STS on wound healing. RESULTS: Intraperitoneal administration of STS effectively prevented peritoneal adhesion without affecting anastomotic healing in the rats. Compared with the adhesion model group, the STS-treated groups showed increased peritoneal lavage fluid tPA activity and tPA/PAI-1 ratio in the ischemic tissues with lowered TGF-ß1 and collagen I expressions in the ischemic tissues. CONCLUSIONS: Intraperitoneal administration of STS can prevent peritoneal adhesion and enhance local fibrinolysis in rats, and these effects may be mediated by TGF-ß signaling pathway.


Assuntos
Fibrinólise , Peritônio/patologia , Fenantrenos/farmacologia , Aderências Teciduais/prevenção & controle , Animais , Ceco/lesões , Ceco/patologia , Colágeno Tipo I/metabolismo , Injeções Intraperitoneais , Peritônio/lesões , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Complicações Pós-Operatórias/prevenção & controle , Ratos , Ratos Sprague-Dawley , Ativador de Plasminogênio Tecidual/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Cicatrização
10.
Nan Fang Yi Ke Da Xue Xue Bao ; 34(2): 236-40, 2014 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-24589604

RESUMO

OBJECTIVE: To study the mechanism that mediates the therapeutic effect of the bioactive fraction of Baqia (Smilax china) on chronic pelvic inflammatory disease (CPID). METHODS: Seventy rats were randomized into CPID model group, sham-operated group, normal control group, Jingangteng capsule group, and high-, medium-, and low-dose Baqia groups. Rat models of CPID were established by inducing chemical burns of the uterus and corresponding treatments were administered. After 14 days of treatment, the rat uterus was observed for swelling and inhibition rate, and the expressions of tumor necrosis factor-α (TNF-α) and interleukin-4 (IL-4) in the uterine tissues were determined using enzyme-linked immunosorbent assay. RESULTS: The bioactive fraction of Baqia at the 3 doses obviously reduced the inflammatory cells in the endometrium, promoted epithelial cell proliferation, and ameliorated congestion and edema of the serosa. High and medium doses of Baqia bioactive fraction significantly decreased uterus swelling rate of the rats (P<0.01). All the 3 doses of the Baqia bioactive fraction obviously decreased uterine TNF-α content (P<0.01) and significantly increased uterine IL-4 expression level (P<0.05), and IL-4 up-regulation was especially obvious in high and medium dose groups (P<0.01). CONCLUSION: Baqia bioactive fraction can ameliorate uterine swelling, lower uterine TNF-α and increase IL-4 expressions in rats with CPID, which may be a pharmacological mechanism underlying its therapeutic effect on CPID and cervical adhesion.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Interleucina-4/metabolismo , Doença Inflamatória Pélvica/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Útero/efeitos dos fármacos , Animais , Doença Crônica , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Doença Inflamatória Pélvica/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Smilax/química , Útero/metabolismo
11.
Nan Fang Yi Ke Da Xue Xue Bao ; 33(1): 145-9, 2013 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-23353177

RESUMO

OBJECTIVE: To determine the effective fraction of Smilax for treatment of chronic pelvic inflammatory disease (CPID) by pharmacodynamic screening as the basis for further development of sarsaparilla preparations. METHODS: The chemical fractions of Smilax were administered intragastrically in rat models of CPID induced by injecting phenol mucilage into the uterus to observe the therapeutic effects. The anti-inflammatory effects of different extract fractions from Smilax were tested in mice with xylene-induced ear edema and in rats with cotton-ball-induced granuloma. RESULTS: High-dose ethyl acetate extract of Smilax could obviously inhibit uterus inflammation in rats with CPID, showing also strong anti-inflammatory effects against ear edema in mice and granuloma in rats (P<0.01). The moderate dose of ethyl acetate extract also obviously ameliorated the inflammation. Both the ethyl acetate extract fraction and the total extract fraction of Smilax showed anti-inflammatory effects, while the former produced strong effects while the latter has only weak actions. CONCLUSION: The ethyl acetate extract fraction of Smilax is the effective fraction to produce anti-inflammatory and anti-CPID effects.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Doença Inflamatória Pélvica/tratamento farmacológico , Smilax , Animais , Anti-Inflamatórios/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Feminino , Camundongos , Camundongos Endogâmicos , Ratos , Ratos Sprague-Dawley
12.
Rev Sci Instrum ; 84(12): 123107, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24387420

RESUMO

We investigated the fiber Bragg grating (FBG) thermal response in space vacuum thermal environment. The FBGs were packaged with 6061-T6 aluminum. The liquid nitrogen immersion experiment results show that its wavelength shift standard deviation is 0.76 pm for 217 h. The combination effect of vacuum and cryogenic temperature was studied by thermal cycling process in space environment simulator. The FBG sensors show accuracy better than 2% full scale, and the hysteresis errors are below 1%. It proves that these metal packaged FBG sensors can survive and meet the requirement of space measurement.

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