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1.
Cancer Lett ; 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31678168

RESUMO

Sustained angiogenesis and increased PD-L1 expression on endothelial and carcinoma cells contribute toward fostering an immunosuppressive microenvironment suitable for tumor growth. PD-L1+ CTCs were reported to associate with poor prognosis in NSCLC patients. However, whether or not aneuploid circulating tumor endothelial cells (CTECs) express PD-L1, then serve as a surrogate biomarker to evaluate immunotherapy efficacy remains unknown. In this study, a novel SE-iFISH strategy was established to comprehensively quantify a full spectrum of aneuploid CTCs and CTECs in advanced NSCLC patients subjected to second-line anti-PD-1 (nivolumab) immunotherapy. In situ co-detection of diverse subtypes of aneuploid CTCs and CTECs expressing PD-L1 and Vimentin was performed. Clinical study demonstrated that significant amounts of PD-L1+ aneuploid CTCs and CTECs could be detected in histopathologic hPD-L1- patients. In contrast to decreased PD-L1+ CTCs, the number of multiploid PD-L1+ CTECs (≥tetrasomy 8) undergoing karyotype shifting increased in patients along with tumor progression following anti-PD-1 treatment. PD patients with multiploid PD-L1+ CTECs had a significantly shorter PFS compared to those without PD-L1+ CTECs. In carcinoma patients, aneuploid CTCs and CTECs may exhibit a functional interplay with respect to tumor angiogenesis, progression, metastasis, and response to immunotherapy.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31646374

RESUMO

OBJECTIVE: To investigate the presence of vimentin expression in CTCs and its clinical relevance in patients with advanced lung cancer. METHODS: Peripheral blood was obtained from 61 treatment-naive patients with advanced lung cancer. Subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) platform was applied to identify, enumerate and characterize CTCs based on cell size, aneuploidy of chromosome 8 (Chr8) and vimentin expression. Quantification and analysis of CTCs were performed on patients before chemotherapy administration and after two cycles of therapy. RESULTS: Before treatment, CTCs were detected in 60 (98.4%) patients, small cell CTCs (≤ 5 µm of WBCs) accounted for 52.8% of the absolute CTCs number, while 12 (19.7%) of the included patients had detectable vimentin-positive CTCs (vim+ CTCs). Liver metastases were reported in 7 (11.5%) patients and were significantly correlated to the presence of Vim+ CTCs (p = 0.002), with a high positivity rate of 71.4% (5/7). Vim+ CTCs were mostly in small cell size and Chr8 aneuploidy (77.0% and 82.05%, respectively). Baseline small cell CTCs ≥ 2/6 ml, triploid CTCs ≥ 2/6 ml, Vim+ CTCs ≥ 1/6 ml were found to significantly correlate with poor progression-free survival (PFS) (p = 0.017, p = 0.009 and p = 0.001, respectively). After adjusting for clinically significant factors, baseline Vim+ CTCs ≥ 1/6 ml was the only independent predictor of poor PFS [hazard ratio (HR):2.756, 95% confidence interval (CI): 1.239-6.131; p = 0.013]. CONCLUSIONS: This study demonstrates an important morphologic, karyotypic and phenotypic CTCs heterogeneity in advanced lung cancer patients. The majority of Vim+ CTCs are in small size and Chr8 aneuploidy. Baseline presence of Vim+ CTCs is correlated with liver metastases and may help predict poor PFS.

3.
J Am Coll Cardiol ; 74(19): 2365-2375, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31487545

RESUMO

BACKGROUND: Low detection and nonadherence are major problems in current management approaches for patients with suspected atrial fibrillation (AF). Mobile health devices may enable earlier AF detection and improved AF management. OBJECTIVES: This study sought to investigate the effectiveness of AF screening in a large population-based cohort using smart device-based photoplethysmography (PPG) technology, combined with a clinical care AF management pathway using a mobile health approach. METHODS: AF screening was performed with smart devices using PPG technology, which were made available for the population ≥18 years of age across China. Monitoring for at least 14 days with a wristband (Honor Band 4) or wristwatch (Huawei Watch GT, Honor Watch, Huawei Technologies Co., Ltd., Shenzhen, China) was allowed. The patients with "possible AF" episodes using the PPG algorithm were further confirmed by health providers among the MAFA (mobile AF app) Telecare center and network hospitals, with clinical evaluation, electrocardiogram, or 24-h Holter monitoring. RESULTS: There were 246,541 individuals who downloaded the PPG screening app, and 187,912 individuals used smart devices to monitor their pulse rhythm between October 26, 2018, and May 20, 2019. Among those with PPG monitoring (mean age 35 years, 86.7% male), 424 (of 187,912, 0.23%) (mean age 54 years, 87.0% male) received a "suspected AF" notification. Of those effectively followed up, 227 individuals (of 262, 87.0%) were confirmed as having AF, with the positive predictive value of PPG signals being 91.6% (95% confidential interval [CI]: 91.5% to 91.8%). Both suspected AF and identified AF markedly increased with age (p for trend <0.001), and individuals in Northeast China had the highest proportion of detected AF of 0.28% (95% CI: 0.20% to 0.39%). Of the individuals with identified AF, 216 (of 227, 95.1%) subsequently entered a program of integrated AF management using a mobile AF application; approximately 80% of high-risk patients were successfully anticoagulated. CONCLUSIONS: Based on the present study, continuous home monitoring with smart device-based PPG technology could be a feasible approach for AF screening. This would help efforts at screening and detection of AF, as well as early interventions to reduce stroke and other AF-related complications. (Mobile Health [mHealth] Technology for Improved Screening, Patient Involvement and Optimizing Integrated Care in Atrial Fibrillation [MAFA II]; ChiCTR-OOC-17014138).

4.
Science ; 365(6459): 1301-1305, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31488703

RESUMO

We report a robust, versatile approach called CRISPR live-cell fluorescent in situ hybridization (LiveFISH) using fluorescent oligonucleotides for genome tracking in a broad range of cell types, including primary cells. An intrinsic stability switch of CRISPR guide RNAs enables LiveFISH to accurately detect chromosomal disorders such as Patau syndrome in prenatal amniotic fluid cells and track multiple loci in human T lymphocytes. In addition, LiveFISH tracks the real-time movement of DNA double-strand breaks induced by CRISPR-Cas9-mediated editing and consequent chromosome translocations. Finally, by combining Cas9 and Cas13 systems, LiveFISH allows for simultaneous visualization of genomic DNA and RNA transcripts in living cells. The LiveFISH approach enables real-time live imaging of DNA and RNA during genome editing, transcription, and rearrangements in single cells.

5.
Mol Med Rep ; 20(1): 455-462, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180535

RESUMO

Acute lung injury (ALI) is a major cause of morbidity and mortality globally, and is characterized by widespread inflammation in the lungs. Increased production of reactive oxygen species is hypothesized to be associated with ALI. Matrine and lycopene are active products present in traditional Chinese medicine. Matrine is an effective inhibitor of inflammation, whereas lycopene decreases lipid peroxidation. Therefore, it was hypothesized that combinatorial treatment with matrine and lycopene may provide synergistic protection against ALI. In the present study, mice were treated with dexamethasone (DEX; 5 mg/kg), matrine (25 mg/kg), lycopene (100 mg/kg), and matrine (25 mg/kg) + lycopene (100 mg/kg) for 7 days prior to injury induction using lipopolysaccharide (LPS; 5 mg/kg) for 6 h. Lung tissues were collected following the sacrifice of the mice and hematoxylin and eosin staining was used for histological analysis. Malondialdehyde (MDA), glutathione (GSH) and myeloperoxidas (MPO) levels were examined by respective kits. The expressions of interleukin­6 (IL­6) and tumor necrosis factor­α (TNF­α) were evaluated by ELISA. The expressions of IκBα and NF­κB p65 were examined by reverse transcription­quantitative polymerase chain reaction, western blotting and immunohistochemistry. The results indicated that the combined treatment exhibited a similar effect to DEX, both of which attenuated lung structural injuries, downregulated the expressions of IL­6, TNF­α, MPO and MDA, and upregulated that of GSH. Furthermore, the combined treatment and DEX inhibited NF­κB p65 activation. The present study revealed that combined treatment with matrine and lycopene exhibited protective effects on an LPS­induced mouse model of ALI, suggesting that they may serve as a potential alternative to glucocorticoid therapy for ALI.

6.
J Cell Mol Med ; 23(8): 5087-5097, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31124603

RESUMO

Krüppel-like transcription factor (KLF) family is involved in tumorigenesis in different types of cancer. However, the importance of KLF family in gastric cancer is unclear. Here, we examined KLF gene expression in five paired liver metastases and primary gastric cancer tissues by RT-PCR, and immunohistochemistry was used to study KLF8 expression in 206 gastric cancer samples. The impact of KLF8 expression on glycolysis, an altered energy metabolism that characterizes cancer cells, was evaluated. KLF8 showed the highest up-regulation in liver metastases compared with primary tumours among all KLF members. Higher KLF8 expression associated with larger tumour size (P < 0.001), advanced T stage (P = 0.003) and N stage (P < 0.001). High KLF8 expression implied shorter survival outcome in both TCGA and validation cohort (P < 0.05). Silencing KLF8 expression impaired the glycolysis rate of gastric cancer cells in vitro. Moreover, high KLF8 expression positively associated with SUVmax in patient samples. KLF8 activated the GLUT4 promoter activity in a dose-dependent manner (P < 0.05). Importantly, KLF8 and GLUT4 showed consistent expression patterns in gastric cancer tissues. These findings suggest that KLF8 modulates glycolysis by targeting GLUT4 and could serve as a novel biomarker for survival and potential therapeutic target in gastric cancer.

7.
J BUON ; 24(2): 549-554, 2019 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31128004

RESUMO

PURPOSE: In this study we examined the anticancer effects of methanolic root extract of Prunella Vulgaris (PVE) against the MCF-5 breast cancer (BC) cell line along with its mode of action. METHODS: The proliferation rate of the MCF-5 cells was assessed by MTT assay. Apoptosis was confirmed by acridine orange (AO)/ethidium bromide (EB) and annexin V/propidium iodide (PI) staining. DNA damage was checked by comet assay. Cell cycle analysis was performed by flow cytometry. Protein expression was determined by western blotting. In vivo evaluation of the extract was carried out in xenografted tumor mice models. RESULTS: PVE inhibited the growth of the MCF-5 cells and exhibited an IC50 value of 25 µg/ml. The investigation of underlying mechanism revealed that PVE triggered apoptotic cell death of the MCF-5 cells which was also associated with enhancement of the expression of Bax and decrease in the expression of Bcl-2. PVE also caused arrest of the cells in the G2/M phase of the cell cycle and also exerted the anti-angiogenic effects. In vivo evaluation of PVE showed that it could inhibit the tumor weight and volume, suggestive of the anticancer potential of PVE. CONCLUSION: The root extract of Prunella vulgaris in this study was shown to exert potent anticancer effects in MCF-7 human BC cells both in vitro and in vivo, accompanied with apoptosis induction, inhibition of angiogenesis, cell cycle arrest, and modulation of PI3K/AKT signaling pathway.

8.
Molecules ; 24(7)2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30987000

RESUMO

The stability of gossypol was investigated by the spectroscopic method. Gossypol was dissolved in three different solvents (CHCl3, DMSO, and CH3OH) under different storage conditions (dark and with nitrogen protection, natural light and with nitrogen protection, ambient air conditions) for different time intervals (0 days, 3 days, 5 days, 7 days, 15 days, 30 days, and 45 days) at room temperature. Then, the stability of gossypol was investigated by ¹H NMR, UV-vis, and HPLC-QTOF-MS spectrometry. Results showed that gossypol existed in aldehyde-aldehyde form in chloroform within five days. Then, both aldehyde-aldehyde and lactol-lactol tautomeric forms existed and maintained a stable solution for 45 days. Gossypol dissolved in methanol mainly existed in aldehyde-aldehyde form. Only a tiny amount of lactol-lactol was found in freshly prepared methanol solution. Gossypol was found to only exist in lactol-lactol form between 30-45 days. Gossypol existed in aldehyde-aldehyde, lactol-lactol, and ketol-ketol forms in dimethyl sulfoxide, and there was a competitive relationship between aldehyde-aldehyde and lactol-lactol form during the 45 days. Among all the solvents and conditions studied, gossypol was found to be highly stable in chloroform. Under the tested conditions, the natural light and atmospheric oxygen had little effect on its stability. Although the spectroscopy data seemed to be changed over time in the three different solvents, it was actually due to the tautomeric transformation rather than molecular decomposition.


Assuntos
Gossipol/química , Cromatografia Líquida de Alta Pressão/métodos , Espectroscopia de Ressonância Magnética/métodos , Estrutura Molecular
9.
Chem Biol Interact ; 306: 29-38, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30954463

RESUMO

Resveratrol, found in variety of plants, is a natural stilbene structure polyphenol. It has various pharmacological effects, such as antioxidation, anti-aging, anti-inflammation, anti-cancer, antiobesity, anti-diabetes, cardioprotection, neuroprotection. Recently, anti-leukemia activities of resveratrol has been studied extensively via its effects on a variety of biological processes involving cell proliferation, apoptosis, autophagy. Current treatments of leukemia mainly rely on intensive chemotherapy or hematopoietic stem cell transplantation, however, these treatments are still with poor survival and high treatment-related mortality. Therefore, it is extremely needed to find relatively non-toxic medicines with minimal side effects but sufficient therapeutic efficacy. Resveratrol is one such potential candidate owing to its reported anti-leukemia effect. In this review, we summarized resveratrol's discovery, sources and isolation methods, administration methods, effects in different types of leukemia, pharmacokinetics and toxicities, aiming to exploit resveratrol as a potential drug candidate for anti-leukemia.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Descoberta de Drogas , Leucemia/tratamento farmacológico , Resveratrol/farmacologia , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/química , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Humanos , Leucemia/patologia , Resveratrol/efeitos adversos , Resveratrol/química
10.
J Exp Clin Cancer Res ; 38(1): 67, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744690

RESUMO

BACKGROUND: Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved intracellular mechanism for lysosomal degradation of damaged cellular components. The specific degradation of nuclear components by the autophagy pathway is called nucleophagy. Most studies have focused on autophagic turnover of cytoplasmic materials, and little is known about the role of autophagy in the degradation of nuclear components. METHODS: Human MDA-MB-231 and MCF-7 breast cancer cell lines were used as model systems in vitro. Induction of nucleophagy by nuclear DNA leakage was determined by western blot and immunofluorescence analyses. The interaction and colocalization of LC3 and lamin A/C was determined by immunoprecipitation and immunofluorescence. The role of the SUMO E2 ligase, UBC9, on the regulation of SUMOylation of lamin A/C and nucleophagy was determined by siRNA silencing of UBC9, and analyzed by immunoprecipitation and immunofluorescence. RESULTS: DNA damage induced nuclear accumulation of UBC9 ligase which resulted in SUMOylation of lamin A/C and that SUMOylation of this protein was required for the interaction between the autophagy protein LC3 and lamin A/C, which was required for nucleophagy. Knockdown of UBC9 prevented SUMOylation of lamin A/C and LC3-lamin A/C interaction. This attenuated nucleophagy which degraded nuclear components lamin A/C and leaked nuclear DNA mediated by DNA damage. CONCLUSIONS: Our findings suggest that nuclear DNA leakage activates nucleophagy through UBC9-mediated SUMOylation of lamin A/C, leading to degradation of nuclear components including lamin A/C and leaked nuclear DNA.


Assuntos
Núcleo Celular/metabolismo , Dano ao DNA , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , Laminas/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo , Células A549 , Autofagia/fisiologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Células HEK293 , Células Hep G2 , Humanos , Laminas/genética , Células MCF-7 , Microscopia Confocal , Sumoilação , Enzimas de Conjugação de Ubiquitina/genética
11.
Cytokine ; 115: 8-12, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30616035

RESUMO

OBJECTIVE: To evaluate whether the macrophage migration inhibitory factor (MIF) level in serum of ischemic stroke patients was associated with their clinical severity and early outcome. METHODS: During February 2017-March 2018, consecutive patients admitted to our hospital because of first-ever ischemic stroke were identified. The prognostic value of MIF was set for predicting the outcome of these patients at discharge. The results were compared with existing methods, including National Institutes of Health Stroke Scale (NIHSS) score and validated indicators. RESULTS: 289 patients were enrolled. The serum level of all patients was determined (median: 20.6 ng/ml). At admission, 131 patients (45.3%) were evaluated as minor stroke (NIHSS < 5). When serum level of MIF was increased by each 1 ng/ml, the unadjusted and adjusted risk of moderate-to-high clinical severity was elevated by 5% (OR = 1.05 [95% CI: 1.01-1.09], P = 0.006) and 3% (1.03 [1.00-1.08], P = 0.02), respectively. At discharge, 82 patients (28.4%) had poor functional outcomes. The median serum level of MIF was lower in group with good outcomes than that observed in poor outcomes (19.4[15.8-24.2] vs. 24.0[19.9-29.4] ng/ml; P < 0.001). When serum level of MIF was increased by each 1 ng/ml, the unadjusted and adjusted risk of poor outcomes was elevated by 9% (1.09 [1.05-1.13], P < 0.001) and 6% (1.06 [1.02-1.10], P < 0.01), respectively. CONCLUSIONS: High MIF levels are independently related to the moderate to high clinical severity in ischemic stroke patients, as well as the poor outcome at discharge.

12.
Small ; 15(3): e1804318, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30556315

RESUMO

A significant development in the design of a NiCo2 S4 3D hierarchical hollow nanoarrow arrays (HNA)-based supercapacitor binder free electrode assembled by 1D hollow nanoneedles and 2D nanosheets on a Ni foam collector through controlling ionic liquid 1-octyl-3-methylimidazolium chloride ([OMIm]Cl) concentration is reported. The unique NiCo2 S4 -HNA electrode acquires high specific capacity (1297 C g-1 at 1 A g-1 , 2.59 C cm-2 at 2 mA cm-2 ), excellent rate capability (maintaining 73.0% at 20 A g-1 ), and long operational life (maintaining 92.4% after 10 000 cycles at 5 A g-1 ), which are superior to those for 1D hollow nanoneedle arrays (HNN) and 2D porous nanoflake arrays (PNF). The outstanding electrochemical performance is attributed to the novel 3D structure with large specific surface, hollow cores, high porosity as well as stable architecture. In addition, a hybrid supercapacitor applying 3D NiCo2 S4 -HNA as the positive electrode and active carbon as the negative electrode exhibits a high energy density of 42.5 Wh kg-1 at a power density of 2684.2 W kg-1 in an operating voltage of 1.6 V. Robust cycling stability is also expressed with 84.9% retention after repeating 10 000 cycles at 5 A g-1 , implying their great potential in superior-performance supercapacitors.

13.
Nucleic Acids Res ; 2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30335176

RESUMO

Dynamics of nucleosome positioning affects chromatin state, transcription and all other biological processes occurring on genomic DNA. While MNase-Seq has been used to depict nucleosome positioning map in eukaryote in the past years, nucleosome positioning data is increasing dramatically. To facilitate the usage of published data across studies, we developed a database named nucleosome positioning map (NucMap, http://bigd.big.ac.cn/nucmap). NucMap includes 798 experimental data from 477 samples across 15 species. With a series of functional modules, users can search profile of nucleosome positioning at the promoter region of each gene across all samples and make enrichment analysis on nucleosome positioning data in all genomic regions. Nucleosome browser was built to visualize the profiles of nucleosome positioning. Users can also visualize multiple sources of omics data with the nucleosome browser and make side-by-side comparisons. All processed data in the database are freely available. NucMap is the first comprehensive nucleosome positioning platform and it will serve as an important resource to facilitate the understanding of chromatin regulation.

14.
Sci Rep ; 8(1): 15602, 2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30349053

RESUMO

Arsenic resistance protein 2 (Ars2) is a component of the nuclear RNA cap-binding complex (CBC) that is important for some microRNA biogenesis and it is critical for cell proliferation and tumorigenicity. However, mechanism of Ars2-regulated cellular proliferation and tumorigenicity in glioblastoma has not been fully understood. Western blotting was used to detect the expressions of Ars2, p53, p21, and cleavage/activation of caspases-3 (C-Caspase 3). Microarray and Quantitative Real-time PCR (qRT-PCR) were performed to identify the Ars2-regulated microRNAs. Apoptosis assessed by flow cytometry analysis was used to evaluate the role of Ars2 in cells proliferation. The lentivirus-mediated gene knockdown approach was conducted to determine the function of Ars2. The orthotopic glioblastoma xenograft was used to demonstrate the role of Ars2 in glioblastoma growth in vivo. The high expression of Ars2 was observed in several glioblastoma cell lines and was significantly associated with poorer overall survival. Importantly, the overexpression of Ars2 promoted cell proliferation and colony formation in glioblastoma cells, whereas the depletion of Ars2 inhibited cell proliferation, colony formation, and tumor growth. Mechanistic study revealed that knockdown of Ars2 reduced the expression levels of miR-6798-3p, which was responsible for the up-regulation of p53 and p21, leading to apoptosis. Furthermore, the knockdown of Ars2 suppressed tumor growth in orthotopic glioblastoma xenograft model and significantly prolonged the survival time of the tumor-bearing mice. These findings identify a critical role for Ars2 in regulation of proliferation and tumorigenicity in glioblastoma and suggest that Ars2 could be a critical therapeutic target for glioblastoma intervention.

15.
Cancer Manag Res ; 10: 4279-4286, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30349362

RESUMO

Background: Postoperative management and survival of gastric cancer is mainly determined by pathologic TNM stage. However, gastric cancer is a heterogeneity group, and the survival is quite different even when they are in the same TNM stage. Moreover, TNM stage system does not grasp other important clinicopathologic factors to determine the survival. The aim of the present study is to propose and validate prognostic score based on age, tumor size, and grade. Materials and methods: Patients diagnosed with gastric cancer in the Surveillance, Epidemiology, and End Results database from 1988 to 2012 were included in the present study. Kaplan-Meier methods were adopted and multivariable Cox regression models were built for the analysis of long-term survival outcomes and risk factors. Results: A total of 26,091 eligible patients diagnosed with noncardia gastric cancer were included in the study. In the univariate and multivariate survival analysis, age at diagnosis, tumor grade, and tumor size were validated as independent prognostic factors (P<0.05). Then, we proposed a prognostic score calculated from the number of risk factors, with 0, 1, and 2 points each given for favorable, intermediate, and poor prognostic categories of age (≤50, 50-70, and >70), grade (well, moderate, and poor differentiation), and size (≤3, 3-6, ≥7 cm). The prognostic score was verified as independent predictor in both univariate and multivariate survival analyses (P<0.001). In addition, nomograms on cause-specific survival were established according to prognostic factor and all other significant factors, and c-index was 0.715 (95% CI: 0.706-0.725). Conclusion: Prognostic score based on age, tumor size, and grade is an independent predictor of survival after gastrectomy. The novel prognostic score can improve the accuracy of prediction for current TNM stage system. Patients who are with a high prognostic score should undergo extensive follow-up after surgery.

16.
Cell ; 175(5): 1405-1417.e14, 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30318144

RESUMO

Programmable control of spatial genome organization is a powerful approach for studying how nuclear structure affects gene regulation and cellular function. Here, we develop a versatile CRISPR-genome organization (CRISPR-GO) system that can efficiently control the spatial positioning of genomic loci relative to specific nuclear compartments, including the nuclear periphery, Cajal bodies, and promyelocytic leukemia (PML) bodies. CRISPR-GO is chemically inducible and reversible, enabling interrogation of real-time dynamics of chromatin interactions with nuclear compartments in living cells. Inducible repositioning of genomic loci to the nuclear periphery allows for dissection of mitosis-dependent and -independent relocalization events and also for interrogation of the relationship between gene position and gene expression. CRISPR-GO mediates rapid de novo formation of Cajal bodies at desired chromatin loci and causes significant repression of endogenous gene expression over long distances (30-600 kb). The CRISPR-GO system offers a programmable platform to investigate large-scale spatial genome organization and function.

17.
Cell Stem Cell ; 23(5): 758-771.e8, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30318302

RESUMO

Comprehensive identification of factors that can specify neuronal fate could provide valuable insights into lineage specification and reprogramming, but systematic interrogation of transcription factors, and their interactions with each other, has proven technically challenging. We developed a CRISPR activation (CRISPRa) approach to systematically identify regulators of neuronal-fate specification. We activated expression of all endogenous transcription factors and other regulators via a pooled CRISPRa screen in embryonic stem cells, revealing genes including epigenetic regulators such as Ezh2 that can induce neuronal fate. Systematic CRISPR-based activation of factor pairs allowed us to generate a genetic interaction map for neuronal differentiation, with confirmation of top individual and combinatorial hits as bona fide inducers of neuronal fate. Several factor pairs could directly reprogram fibroblasts into neurons, which shared similar transcriptional programs with endogenous neurons. This study provides an unbiased discovery approach for systematic identification of genes that drive cell-fate acquisition.

18.
Genome Biol ; 19(1): 159, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30296940

RESUMO

Pooled CRISPR screens allow researchers to interrogate genetic causes of complex phenotypes at the genome-wide scale and promise higher specificity and sensitivity compared to competing technologies. Unfortunately, two problems exist, particularly for CRISPRi/a screens: variability in guide efficiency and large rare off-target effects. We present a method, CRISPhieRmix, that resolves these issues by using a hierarchical mixture model with a broad-tailed null distribution. We show that CRISPhieRmix allows for more accurate and powerful inferences in large-scale pooled CRISPRi/a screens. We discuss key issues in the analysis and design of screens, particularly the number of guides needed for faithful full discovery.

19.
Int Immunopharmacol ; 64: 183-191, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30195109

RESUMO

Idiopathic Pulmonary fibrosis is a disease with high morbidity and mortality. Therefore, the development of new drugs is imperative. Gallic acid derivative is a derivative of Gallic acid that can be extracted from Chinese herbal medicine. In previous experiments, we found that Gallic acid derivative played dual roles in inflammatory and antioxidant activities. Meanwhile, Gallic acid derivative could inhibit the proliferation of lung fibroblast. In the present study, we investigated the function of Gallic acid derivative in inhibiting lung fibrosis. 5 mg/kg of bleomycin was administered to mice by a single intratracheal instillation. Three dosages of Gallic acid derivative (75 mg/kg, 150 mg/kg, 300 mg/kg) and Pirfenidone (80 mg/kg) were given to mice for 21 day. Gallic acid derivative treatment significantly reduced lung histological changes and decreased inflammatory cell infiltration. The content of collagen decreased with the decrease of hydroxyproline level. Analogously, the expression of alpha smooth muscle actin was reduced. Gallic acid derivative enhanced the antioxidant status, but reduced the expression of interleukin 6, NADPH oxidase-4. Our study proved that Gallic acid derivative reduced inflammation activation to some extent and could exert its effects through transforming growth factor ß1/Smad2 signaling pathway and balancing NOX4/Nrf2.

20.
Chemosphere ; 212: 438-446, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30153616

RESUMO

H2O2- and PDS-based reactions are two typical advanced oxidation processes (AOPs) with different adaptive pH ranges. However, the underlying mechanisms that caused the distinct applicability of these two AOPs have rarely been explored. Herein, a comparative study of H2O2/PDS-based AOPs employing pyrite as a catalyst to degrade acetaminophen (ACT) was reported. The poor ACT degradation in H2O2/pyrite under alkaline conditions was proven to be caused by a lack of OH production instead of by the weaker oxidation property of OH. The continuous exposure surface behavior induced by the intense acid-production reaction between PDS and pyrite prevented the coverage of iron-containing compounds on the pyrite surface. Therefore, the adaptive pH range in PDS/pyrite could extend from 4 to 10, in contrast to the narrow effective pH range of 4-6 in H2O2/pyrite. Oxidant consumption indicated that H2O2/pyrite possesses a higher oxidation efficiency than PDS/pyrite. The homogenous catalytic effect was non-negligible in PDS/pyrite, whereas heterogeneous catalytic oxidation dominated H2O2/pyrite under acidic conditions. The quenching experiment and electron spin resonance (ESR) spectroscopy demonstrated that the dominant radical species in H2O2/PDS-based AOPs via pyrite at a pH of 4 were OH and OH/SO4-, respectively, thus causing different degradation pathways of ACT. In addition, a higher proportion of S consumption was found in H2O2/pyrite, indicating that sulfur also plays a role during the catalytic reaction. The distinct surface reactions between pyrite and H2O2/PDS led to different water treatment applications.


Assuntos
Acetaminofen/metabolismo , Recuperação e Remediação Ambiental/métodos , Peróxido de Hidrogênio/química , Ferro/química , Sulfetos/química , Catálise , Oxirredução , Purificação da Água
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