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1.
J Am Heart Assoc ; 9(9): e014920, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32349637

RESUMO

Background Although multiple signaling cascades and molecules contributing to the pathophysiological process have been studied, the treatments for stroke against present targets have not acquired significant clinical progress. Although CARD3 (caspase activation and recruitment domain 3) protein is an important factor involved in regulating immunity, inflammation, lipid metabolism, and apoptosis, its role in cerebral stroke is currently unknown. Methods and Results Using a mouse model of ischemia-reperfusion (I-R) injury based on transient blockage of the middle cerebral artery, we have found that CARD3 expression is upregulated in a time-dependent manner during I-R injury. Further animal study revealed that, relative to control mice, CARD3-knockout mice exhibited decreased inflammatory response and neuronal apoptosis, with reduced infarct volume and lower neuropathological scores. In contrast, neuron-specific CARD3-overexpressing transgenic (CARD3-TG) mice exhibited increased I-R induced injury compared with controls. Mechanistically, we also found that the activation of TAK1 (transforming growth factor-ß-activated kinase 1) was enhanced in CARD3-TG mice. Furthermore, the increased inflammation and apoptosis seen in injured CARD3-TG brains were reversed by intravenous administration of the TAK1 inhibitor 5Z-7-oxozeaenol. Conclusions These results indicate that CARD3 promotes I-R injury via activation of TAK1, which not only reveals a novel regulatory axis of I-R induced brain injury but also provides a new potential therapeutic approach for I-R injury.

2.
Thorac Cancer ; 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286013

RESUMO

Here, we describe a novel method using microwave ablation (MWA) guided by electromagnetic navigation bronchoscopy (ENB) and video-assisted thoracoscopic surgery (VATS) for simultaneous treatment of multiple high-risk pulmonary nodules in a 47-year-old woman. After the ENB registration process, the operator delivered the locatable electromagnetic probe to the target in the right upper lobe following the navigational route. MWA was performed after an antenna was passed into the lesion through the working channel. The wedge resection of the left upper lobe and lower lobe and the lingual segment resection were performed by VATS. The pathological diagnoses was adenocarcinoma in situ (AIS) of the right upper lobe lesion, AIS of the left upper lobe, minimally invasive adenocarcinoma of the left lower lobe lesion and chronic inflammation of the lingular segment. MWA guided by ENB combined with VATS is an alternative treatment strategy to deal with multiple pulmonary nodules at the same stage of the operation.

3.
Int J Biol Sci ; 16(9): 1551-1562, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32226301

RESUMO

As one of the most common malignant tumors worldwide, hepatocellular carcinoma (HCC) is known for its poor prognosis due to diagnosis only in advanced stages. Nearly 50% of the patients with the first diagnosis of HCC die within a year. Currently, the advancements in the integration of omics information have begun to transform the clinical management of cancer patients. Molecular profiling for HCC patients is in general obtained from resected tumor materials or biopsies. However, the resected tumor tissue is limited and can only be obtained through surgery, so that dynamic monitoring of patients cannot be performed. Compared to invasive procedures, circulating tumor DNA (ctDNA) has been proposed as an alternative source to perform molecular profiling of tumor DNA in cancer patients. The detection of abnormal forms of circulating cell-free DNA (cfDNA) that originate from cancer cells (ctDNA) provides a novel tool for cancer detection and disease monitoring. This may also be an opportunity to optimize the early diagnosis of HCC. In this review, we summarized the updated methods, materials, storage of sampling, detection techniques for ctDNA and the comparison of the applications among different biomarkers in HCC patients. In particular, we analyzed ctDNA studies dealing with copy number variations, gene integrity, mutations (RAS, TERT, CTNNB1, TP53 and so on), DNA methylation alterations (DBX2, THY1, TGR5 and so on) for the potential utility of ctDNA in the diagnosis and management of HCC. The biological functions and correlated signaling pathways of ctDNA associated genes (including MAPK/RAS pathway, p53 signaling pathway and Wnt-ß catenin pathway) are also discussed and highlighted. Thus, exploration of ctDNA/cfDNA as potential biomarkers may provide a great opportunity in future liquid biopsy applications for HCC.

4.
Anal Biochem ; 600: 113746, 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32333904

RESUMO

Metabolite profiling in anaerobic alkane biodegradation plays an important role in revealing activation mechanisms. Apart from alkylsuccinates, which are considered to be the usual biomarkers via fumarate addition, the downstream metabolites of C-skeleton rearrangement can also be regarded as biomarkers. However, it is difficult to detect intermediate metabolites in both environmental samples and enrichment cultures, resulting in lacking direct evidence to prove the occurrence of fumarate addition pathway. In this work, a synthetic method of rearrangement metabolites was established. Four compounds, namely, propylmalonic acid, 2-(2-methylbutyl)malonic acid, 2-(2-methylpentyl)malonic acid and 2-(2-methyloctyl)malonic acid, were synthesized and determined by four derivatization approaches. Besides, their mass spectra were obtained. Four characteristic ions were observed at m/z 133 + 14n, 160 + 28n, 173 + 28n and [M - (45 + 14n)]+ (n = 0 and 2 for ethyl and n-butyl esters, respectively). For methyl esterification, mass spectral features were m/z 132, 145 and [M - 31]+, while for silylation, fragments were m/z 73, 147, 217, 248, 261 and [M - 15]+. These data provide basis on identification of potential rearrangement metabolites in anaerobic alkane biodegradation via fumarate addition.

5.
Microb Biotechnol ; 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32202696

RESUMO

The uncomposted faeces of dairy cow are usually stacked on cow breeding farms, dried under natural conditions and then used as cow bedding material or they may be continuously piled up. However, no information is available to evaluate variations in the human and animal pathogen genes and antibiotic resistance during the accumulation of fresh faeces of dairy cow to manure. Here, we present the metagenomic analysis of fresh faeces and manure from a dairy farm in Ning Xia, showing a unique enrichment of human and animal pathogen genes and antibiotic resistance genes (ARGs) in manure. We found that manure accumulation could significantly increase the diversity and abundance of the pathogenic constituents. Furthermore, pathogens from manure could spread to the plant environment and enphytotic pathogens could affect the yield and quality of crops during the use of manure as a fertilizer. Levels of virulence genes and ARGs increased with the enrichment of microbes and pathogens when faeces accumulated to manure. Accumulated manure was also the transfer station of ARGs to enrich the ARGs in the environment, indicating the ubiquitous presence of environmental antibiotic resistance genes. Our results demonstrate that manure accumulation and usage without effective manure management is an unreasonable approach that could enrich pathogenic microorganisms and ARGs in the environment. The manure metagenome structure allows us to appreciate the overall influence and interaction of animal waste on water, soil and other areas impacted by faecal accumulation and the factors that influence pathogen occurrence in products from dairy cows.

6.
BMC Genomics ; 21(1): 216, 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32151239

RESUMO

BACKGROUND: All retroviruses, including human immunodeficiency virus (HIV), must integrate a DNA copy of their genomes into the genome of the infected host cell to replicate. Although integrated retroviral DNA, known as a provirus, can be found at many sites in the host genome, integration is not random. The adaption of linker-mediated PCR (LM-PCR) protocols for high-throughput integration site mapping, using randomly-sheared genomic DNA and Illumina paired-end sequencing, has dramatically increased the number of mapped integration sites. Analysis of samples from human donors has shown that there is clonal expansion of HIV infected cells and that clonal expansion makes an important contribution to HIV persistence. However, analysis of HIV integration sites in samples taken from patients requires extensive PCR amplification and high-throughput sequencing, which makes the methodology prone to certain specific artifacts. RESULTS: To address the problems with artifacts, we use a comprehensive approach involving experimental procedures linked to a bioinformatics analysis pipeline. Using this combined approach, we are able to reduce the number of PCR/sequencing artifacts that arise and identify the ones that remain. Our streamlined workflow combines random cleavage of the DNA in the samples, end repair, and linker ligation in a single step. We provide guidance on primer and linker design that reduces some of the common artifacts. We also discuss how to identify and remove some of the common artifacts, including the products of PCR mispriming and PCR recombination, that have appeared in some published studies. Our improved bioinformatics pipeline rapidly parses the sequencing data and identifies bona fide integration sites in clonally expanded cells, producing an Excel-formatted report that can be used for additional data processing. CONCLUSIONS: We provide a detailed protocol that reduces the prevalence of artifacts that arise in the analysis of retroviral integration site data generated from in vivo samples and a bioinformatics pipeline that is able to remove the artifacts that remain.

7.
Gastroenterology ; 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32060001

RESUMO

BACKGROUND AND AIMS: Glypican 3 (GPC3) is an oncofetal antigen involved in Wnt-dependent cell proliferation that is highly expressed in hepatocellular carcinoma (HCC). We investigated whether the functions of chimeric antigen receptors (CARs) that target GPC3 are affected by their antibody-binding properties. METHODS: We collected peripheral blood mononuclear cells from healthy donors and patients with HCC and used them to create CAR T cells, based on the humanized YP7 (hYP7) and HN3 antibodies, which have high affinities for the C-lobe and N-lobe of GPC3, respectively. NOD/SCID/IL-2Rgcnull (NSG) mice were given intraperitoneal injections of luciferase-expressing (Luc) Hep3B or HepG2 cells and after xenograft tumors formed, mice were given injections of saline or untransduced T cells (controls), or CAR (HN3) T cells or CAR (hYP7) T cells. In other NOD/SCID/IL-2Rgcnull (NSG) mice, HepG2-Luc or Hep3B-Luc cells were injected into liver, and after orthotopic tumors formed, mice were given 1 injection of CAR (hYP7) T cells or CD19 CAR T cells (control). We developed droplet digital polymerase chain reaction and genome sequencing methods to analyze persistent CAR T cells in mice. RESULTS: Injections of CAR (hYP7) T cells eliminated tumors in 66% of mice by week 3, whereas CAR (HN3) T cells did not reduce tumor burden. Mice given CAR (hYP7) T cells remained tumor free after re-challenge with additional Hep3B cells. The CAR T cells induced perforin- and granzyme-mediated apoptosis and reduced levels of active ß-catenin in HCC cells. Mice injected with CAR (hYP7) T cells had persistent expansion of T cells and subsets of polyfunctional CAR T cells via antigen-induced selection. These T cells were observed in the tumor microenvironment and spleen for up to 7 weeks after CAR T-cell administration. Integration sites in pre-infusion CAR (HN3) and CAR (hYP7) T cells were randomly distributed, whereas integration into NUPL1 was detected in 3.9% of CAR (hYP7) T cells 5 weeks after injection into tumor-bearing mice and 18.1% of CAR (hYP7) T cells at week 7. There was no common site of integration in CAR (HN3) or CD19 CAR T cells from tumor-bearing mice. CONCLUSIONS: In mice with xenograft or orthoptic liver tumors, CAR (hYP7) T cells eliminate GPC3-positive HCC cells, possibly by inducing perforin- and granzyme-mediated apoptosis or reducing Wnt signaling in tumor cells. GPC3-targeted CAR T cells might be developed for treatment of patients with HCC.

8.
Int J Radiat Oncol Biol Phys ; 107(1): 194-201, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31987963

RESUMO

PURPOSE: The various microenvironments that exist within the brain combined with the invasive nature of glioblastoma (GBM) creates the potential for a topographic influence on tumor cell radiosensitivity. The aim of this study was to determine whether specific brain microenvironments differentially influence tumor cell radioresponse. METHODS AND MATERIALS: GBM stem-like cells were implanted into the right striatum of nude mice. To measure radiosensitivity, proliferation status of individual tumor cells was determined according to the incorporation of 5-chloro-2'-deoxyuridine delivered at 4, 12, and 20 days after brain irradiation. As an additional measure of radiosensitivity, the percentage of human cells in the right hemisphere and the olfactory bulb were defined using digital droplet polymerase chain reaction. Targeted gene expression profiling was accomplished using NanoString analysis. RESULTS: Tumor cells were detected throughout the striatum, corpus callosum, and olfactory bulb. After an initial loss of proliferating tumor cells in the corpus callosum and striatum after irradiation, there was only a minor recovery by 20 days. In contrast, the proliferation of tumor cells located in the olfactory bulb began to recover at 4 days and returned to unirradiated levels by day 12 postirradiation. The percentage of human cells in the right hemisphere and the olfactory bulb after irradiation also suggested that the tumor cells in the olfactory bulb were relatively radioresistant. Gene expression profiling identified consistent differences between tumor cells residing in the olfactory bulb and those in the right hemisphere. CONCLUSIONS: These results suggest that the olfactory bulb provides a radioresistant niche for GBM cells.

9.
Viruses ; 12(2)2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31991737

RESUMO

Combination antiretroviral therapy (cART) controls but does not eradicate HIV infection; HIV persistence is the principal obstacle to curing infections. The proportion of defective proviruses increases during cART, but the dynamics of this process are not well understood, and a quantitative analysis of how the proviral landscape is reshaped after cART is initiated is critical to understanding how HIV persists. Here, we studied longitudinal samples from HIV infected individuals undergoing long term cART using multiplexed Droplet Digital PCR (ddPCR) approaches to quantify the proportion of deleted proviruses in lymphocytes. In most individuals undergoing cART, HIV proviruses that contain gag are lost more quickly than those that lack gag. Increases in the fraction of gag-deleted proviruses occurred only after 1-2 years of therapy, suggesting that the immune system, and/or toxicity of viral re-activation helps to gradually shape the proviral landscape. After 10-15 years on therapy, there were as many as 3.5-5 times more proviruses in which gag was deleted or highly defective than those containing intact gag. We developed a provirus-specific ddPCR approach to quantify individual clones. Investigation of a clone of cells containing a deleted HIV provirus integrated in the HORMAD2 gene revealed that the cells underwent a massive expansion shortly after cART was initiated until the clone, which was primarily in effector memory cells, dominated the population of proviruses for over 6 years. The expansion of this HIV-infected clone had substantial effects on the overall proviral population.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/genética , HIV-1/isolamento & purificação , Leucócitos Mononucleares/virologia , Provírus/isolamento & purificação , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/virologia , Proteínas de Ciclo Celular/genética , DNA Viral/sangue , DNA Viral/genética , Vírus Defeituosos/genética , Genes gag , Repetição Terminal Longa de HIV , HIV-1/efeitos dos fármacos , Humanos , Memória Imunológica , Reação em Cadeia da Polimerase Multiplex , Provírus/genética , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/virologia , Fatores de Tempo , Resultado do Tratamento , Carga Viral
10.
Chemosphere ; 239: 124685, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31521928

RESUMO

This review provides a summary of the levels and profiles of PCDD/Fs throughout China, as reported in peer reviewed literatures since 1997. The literature shows that PCDD/Fs are widespread in various environmental media including air, water, sediment, and soil. PCDD/Fs concentrations in air were relatively low in most regions, with only a few areas considered polluted. Many studies reported seasonal trends, with higher and lower concentrations in winter and summer, respectively. We analyzed the factors affecting the concentrations of dioxins in air and summarized the causes of seasonal changes. As hydrophobic organic compounds, PCDD/Fs readily accumulate in sediments. The distribution of dioxins in sediment in Bohai Sea area was mainly introduced and the factors affecting concentrations of dioxins were studied. The levels of dioxins in soil in different regions varied greatly, with higher levels in areas close to pollution sources. We examined the dioxins concentrations in soil in places where the levels were very low (including the Tibet Plateau and other remote areas), contaminated areas, and other areas. Apart from the contaminated areas, the dioxins concentrations in soil were low. The results of the relatively low number of studies that have investigated PCDD/Fs in water have reported no obvious pollution in some waters, apart from Dongting Lake. PCDD/Fs levels across China are similar to those worldwide. Point sources, mainly related to local geographic, economic, and historical factors, were the most common source of contamination. E-waste dismantling and chemical production has the greatest impact on PCDD/Fs in different media.


Assuntos
Dibenzofuranos Policlorados/análise , Monitoramento Ambiental/métodos , Poluição Ambiental/análise , Dibenzodioxinas Policloradas/análise , Poluentes Químicos da Água/análise , China , Sedimentos Geológicos/química , Lagos/química , Solo/química , Tibet
11.
J Neurosurg ; : 1-8, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31881540

RESUMO

OBJECTIVE: Superficial temporal artery-middle cerebral artery (STA-MCA) bypass is a common approach for treating moyamoya disease (MMD); however, the selection of recipient vessels is still controversial, and its relationship with postoperative cerebral hyperperfusion (CHP) has not been revealed. The aim of the study was to investigate the relationship between the hemodynamic sources of the recipient parasylvian cortical arteries (PSCAs) and the occurrence of postoperative CHP. METHODS: The authors retrospectively analyzed the clinical data from 68 adult patients (75 hemispheres) with MMD who underwent STA-MCA bypass. Based on their hemodynamic sources from the MCA and non-MCAs, the PSCAs were classified as M-PSCAs and non-M-PSCAs, and their distributional characteristics were studied. Moreover, the patients' demographics, incidence of postoperative CHP, and post- and preoperative relative cerebral blood flow values were examined. RESULTS: The digital subtraction angiography analysis demonstrated that 40% (30/75) of the recipient PSCAs had no hemodynamic relationship with the MCA. The post- and preoperative relative cerebral blood flow values of the M-PSCA group were significantly higher than those of the non-M-PSCA group (p < 0.001). Multivariate analysis revealed that the hemodynamic source of PSCAs from the MCA was significantly associated with the development of focal (p = 0.003) and symptomatic (p = 0.021) CHP. Twelve (85.7%) of the 14 patients with symptomatic CHP and all 4 (100%) patients with postoperative hemorrhage were from the M-PSCA group. CONCLUSIONS: This study revealed that direct anastomoses of PSCAs with anterograde hemodynamic sources from the MCA had a high risk of postoperative CHP during STA-MCA bypass in adult patients with MMD.

12.
Proc Natl Acad Sci U S A ; 116(51): 25891-25899, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31776247

RESUMO

Understanding HIV-1 persistence despite antiretroviral therapy (ART) is of paramount importance. Both single-genome sequencing (SGS) and integration site analysis (ISA) provide useful information regarding the structure of persistent HIV DNA populations; however, until recently, there was no way to link integration sites to their cognate proviral sequences. Here, we used multiple-displacement amplification (MDA) of cellular DNA diluted to a proviral endpoint to obtain full-length proviral sequences and their corresponding sites of integration. We applied this method to lymph node and peripheral blood mononuclear cells from 5 ART-treated donors to determine whether groups of identical subgenomic sequences in the 2 compartments are the result of clonal expansion of infected cells or a viral genetic bottleneck. We found that identical proviral sequences can result from both cellular expansion and viral genetic bottlenecks occurring prior to ART initiation and following ART failure. We identified an expanded T cell clone carrying an intact provirus that matched a variant previously detected by viral outgrowth assays and expanded clones with wild-type and drug-resistant defective proviruses. We also found 2 clones from 1 donor that carried identical proviruses except for nonoverlapping deletions, from which we could infer the sequence of the intact parental virus. Thus, MDA-SGS can be used for "viral reconstruction" to better understand intrapatient HIV-1 evolution and to determine the clonality and structure of proviruses within expanded clones, including those with drug-resistant mutations. Importantly, we demonstrate that identical sequences observed by standard SGS are not always sufficient to establish proviral clonality.

13.
Phys Chem Chem Phys ; 21(47): 25976-25981, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31637392

RESUMO

Organometallic compounds constitute a very large group of substances that contain at least one metal-to-carbon bond in which the carbon is part of an organic group. They have played a major role in the development of the science of chemistry. These compounds are used to a large extent as catalysts (substances that increase the rate of reactions without themselves being consumed) and as intermediates in the laboratory and in industry. Recently, novel quantum phenomena such as topological insulators and superconductors were also suggested in these materials. However, there has been no report on the experimental exploration of the topological state. Evidence for superconductivity from the zero-resistivity state in any organometallic compound has not been achieved yet, though much effort has been made. Here we report the experimental realization of superconductivity with a critical temperature of 3.6 K in a potassium-doped organometallic compound, i.e. tri-o-tolylbismuthine, with evidence of both the Meissner effect and the zero-resistivity state through dc and ac magnetic susceptibility measurements. The obtained superconducting parameters classify this compound as a type-II superconductor. The benzene ring is identified to be the essential superconducting unit in such a phenyl organometallic compound. The superconducting phase and its composition are determined by combined studies of X-ray diffraction and theoretical calculations as well as Raman spectroscopy measurements. These findings enrich the applications of organometallic compounds in superconductivity and add a new electron-acceptor family of organic superconductors. This work also points to a large pool for finding superconductors from organometallic compounds.

14.
BMC Genomics ; 20(1): 758, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640549

RESUMO

BACKGROUND: The mesocotyl connects the coleoptilar node and the basal part of the seminal root of maize (Zea mays) seedling. The mesocotyl pushes the shoot of the seedling out of the soil during seed germination; thus, its growth is highly related to deep-sowing tolerance. Although many studies on the maize mesocotyl have been carried out at physiological and molecular levels, the proteomic changes associated with cellular and physiological activities during mesocotyl growth are still unknown. RESULTS: In the present study, the maize hybrid Zhengdan 958 was used to study mesocotyl growth and accompanying protein changes. The dark-grown etiolated mesocotyls exhibited a slow-fast-slow feature, with significant changes in the levels of indole-3-acetic acid (IAA) and cellulose and the activity of peroxidase (POD). In particular, POD activity increased with mesocotyl growth, showing higher activity at the mature (lower) end of the mesocotyl. For the proteomic analysis, soluble proteins were extracted from etiolated mesocotyls dark-grown for 48 h, 84 h, and 132 h, corresponding to the initial, rapid, and slow growth periods, respectively, and subjected to separation by two-dimensional gel electrophoresis (2-DE). As a result, 88 differentially abundant proteins (DAPs) were identified using MALDI-TOF-TOF analysis. At 48 h, most DAPs were stress proteins, heat shock proteins and storage proteins; at 84 h, oxidation/reduction proteins, carbohydrate biogenesis-related proteins and cytoskeleton-related proteins were highly accumulated; at 132 h, the most striking DAPs were those involved in the synthesis and modification of the cell wall and the biogenesis of carbohydrates. Gene ontology (GO) analysis showed that changes in the abundance and proportion of DAPs were consistent with cellular and physiological activities and biological processes during mesocotyl growth. The accumulation of nine DAPs of interest was verified by immunoblotting and RT-qPCR. CONCLUSIONS: The present study revealed that the protein patterns in 2-D gels differed greatly with mesocotyl growth. At different growth periods, a specific set of DAPs participate in various biological processes and underlie the cellular and physiological activities of the mesocotyl. These results contributed to the understanding of mesocotyl growth and the cultivation of maize lines with deep-sowing tolerance.


Assuntos
Proteínas de Plantas/metabolismo , Plântula/crescimento & desenvolvimento , Plântula/metabolismo , Zea mays , Agricultura , Celulose/metabolismo , Eletroforese em Gel Bidimensional , Estiolamento , Ácidos Indolacéticos/metabolismo , Peroxidases/metabolismo , Proteínas de Plantas/genética , Brotos de Planta/crescimento & desenvolvimento , Brotos de Planta/metabolismo , Proteômica , RNA Mensageiro/metabolismo , Zea mays/crescimento & desenvolvimento , Zea mays/metabolismo
15.
Cancer Res ; 79(23): 6032-6043, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31615806

RESUMO

A consequence of the intratumor heterogeneity (ITH) of glioblastoma (GBM) is the susceptibility to treatment-driven evolution. To determine the potential of radiotherapy to influence GBM evolution, we used orthotopic xenografts initiated from CD133+ GBM stem-like cells (GSC). Toward this end, orthotopic xenografts grown in nude mice were exposed to a fractionated radiation protocol, which resulted in a significant increase in animal survival. Brain tumors from control and irradiated mice were then collected at morbidity and compared in terms of growth pattern, clonal diversity, and genomic architecture. In mice that received fractionated radiation, tumors were less invasive, with more clearly demarcated borders and tumor core hypercellularity as compared with controls, suggesting a fundamental change in tumor biology. Viral integration site analysis indicated a reduction in clonal diversity in the irradiated tumors, implying a decrease in ITH. Changes in clonal diversity were not detected after irradiation of GSCs in vitro, suggesting that the radiation-induced reduction in ITH was dependent on the brain microenvironment. Whole-exome sequencing revealed differences in mutation patterns between control and irradiated tumors, which included modifications in the presence and clonality of driver mutations associated with GBM. Moreover, changes in the distribution of mutations as a function of subpopulation size between control and irradiated tumors were consistent with subclone expansion and contraction, that is, subpopulation evolution. Taken together, these results indicate that radiation drives the evolution of the GSC-initiated orthotopic xenografts and suggest that radiation-driven evolution may have therapeutic implications for recurrent GBM. SIGNIFICANCE: Radiation drives the evolution of glioblastoma orthotopic xenografts; when translated to the clinic, this may have therapeutic implications for recurrent tumors.

16.
iScience ; 19: 256-266, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31400748

RESUMO

How cells adapt to oncogenic transformation-associated cellular stress and become fully transformed is still unknown. Here we identified a novel GGCT-regulated glutathione (GSH)-reactive oxygen species (ROS) metabolic pathway in oncogenic stress alleviation. We identified GGCT as a target of oncogenic Ras and that it is required for oncogenic Ras-induced primary mouse cell proliferation and transformation and in vivo lung cancer formation in the LSL-Kras G12D mouse model. However, GGCT deficiency is compatible with normal mouse development, suggesting that GGCT can be a cancer-specific therapeutic target. Genetically amplified GGCT locus further supports the oncogenic driving function of GGCT. In summary, our study not only identifies an oncogenic function of GGCT but also identifies a novel regulator of GSH metabolism, with implications for further understanding of oncogenic stress and cancer treatment.

18.
Plant Cell Environ ; 42(12): 3355-3371, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31429107

RESUMO

Starch is the major form of carbohydrate storage in plants and exists as discrete starch granules (SGs). Isolation of high-quality SGs in different plant tissues is a prerequisite for studying the roles of SGs during plant growth, development, and responses to abiotic stress. However, it is difficult to isolate transitory SGs from leaves and storage SGs from pollen grains due to their small sizes and low quantities. Herein, we develop a novel method for isolating SGs by using the aqueous two-phase system (ATS) of ethanol/NaH2 PO4 . The ATS method efficiently separated SGs from contaminants based on their differences in density, solubility, and polarity. Using this method, we first isolated and purified three kinds of SGs from maize seeds, pollen, and leaves. The biochemical, microscopic, and proteomic analyses demonstrated the high purity of the isolated SGs. Proteomic analysis revealed distinct differences in SG-bound proteins between seed SGs and pollen SGs. As a simple, rapid, and low-cost method, the ATS-based method exhibits highly universal and reproducible results for starch-containing tissues in various plant species.

19.
Data Brief ; 25: 104329, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31453300

RESUMO

This data article quantifies the extent of shared bicycle riding risks for shared-bicycle riders in urban China. The data were collected through a WeChat-based online survey, with a valid sample of 1960 respondents. It reports the basic descriptive statistics through eight tables concerning various unsafe shared bicycle riding behaviors, and complete frequency data from riders concerning eight unsafe riding behaviors. The data can be used for comparisons with other studies using the same outcome measures, which are valuable to generate specialized and targeted solutions to reduce unsafe riding behaviors. For further information, please refer to the full article entitled "Unsafe riding behaviors of shared-bicycle riders in urban China: A retrospective survey".(Wu et al., 2019).

20.
Semin Cancer Biol ; 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31445220

RESUMO

More than 70% of gastrointestinal (GI) cancers are diagnosed with metastases, leading to poor prognosis. For some cancer patients with limited sites of metastatic tumors, the term oligometastatic disease (OMD) has been coined as opposed to systemic polymetastasis (PMD) disease. Stephan Paget first described an organ-specific pattern of metastasis in 1889, now known as the "seed and soil" theory where distinct cancer types are found to metastasize to different tumor-specific sites. Our understanding of the biology of tumor metastasis and specifically the molecular mechanisms driving their formation are still limited, in particular, as it relates to the genesis of oligometastasis. In the following review, we discuss recent advances in general understanding of this metastatic behavior including the role of specific signaling pathways, various molecular features and biomarkers, as well as the interaction of carcinoma cells with their tissue microenvironments (both primary and metastatic niches). The unique features that underlie OMD provide potential targets for localized therapy. As it relates to clinical practice, OMD is emerging as treatable with surgical resection and/or other local therapy options. Strategies currently being applied in the clinical management of OMD will be discussed including surgical, radiation-based therapy, ablation procedures, and the results of emerging clinical trials involving immunotherapy.

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