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1.
Leuk Lymphoma ; : 1-9, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722601

RESUMO

The association between serum albumin level and clinical outcomes has been reported for several hematological malignancies. Our study aimed to identify the relationship between serum albumin level at the time of diagnosis and subsequent clinical outcomes in patients with newly diagnosed acute myeloid leukemias (AMLs) other than acute promyelocytic leukemias (APLs). A total of 243 patients with de novo non-M3 AML were enrolled in this study. Variables including gender, age, serum albumin, white blood cell (WBC) count, hemoglobin (Hb), platelet (PLT) count, blasts at peripheral blood (PB) and bone marrow (BM), immunophenotype and cytogenetics at diagnosis, BM response after one course of chemotherapy and hematopoietic stem cell transplantation (HSCT) treatment were studied. We found that normal albumin level (serum albumin >3.5 g/dL) was significantly associated with superior overall survival (HR = 0.375, p < .001) and leukemia-free survival (HR = 0.411, p < .001). These results demonstrate that albumin could serve as a simple, cheap, and objective prognostication factor in refinement of AML regimens.

2.
Hepatology ; 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31692012

RESUMO

BACKGROUND AND AIMS: Aristolochic acid (AA) exposure has been statistically associated with human liver cancers. However, direct evidence of AA exposure-induced liver cancer is absent. This study aims to establish a direct causal relationship between AA exposure and liver cancers based on a mouse model and then explores the AA-mediated genomic alterations that could be implicated in human cancers with AA-associated mutational signature. APPROACH AND RESULTS: We subjected mice, including phosphatase and tensin homolog (Pten)-deficient ones, to aristolochic acid I (AAI) alone or a combination of AAI and CCl4 . Significantly, AAI exposure induced mouse liver cancers, including hepatocellular carcinoma (HCC) and combined HCC and intrahepatic cholangiocarcinoma, in a dose-dependent manner. Moreover, AAI exposure also enhanced tumorigenesis in these CCl4 -treated or Pten-deficient mice. AAI led to DNA damage and AAI-DNA adduct that could initiate liver cancers through characteristic adenine-to-thymine transversions, as indicated by comprehensive genomic analysis, which revealed recurrent mutations in Harvey rat sarcoma virus oncogene. Interestingly, an AA-associated mutational signature was mainly implicated in human liver cancers, especially from China. Moreover, we detected the AAI-DNA adduct in 25.8% (16/62) of paratumor liver tissues from randomly selected Chinese patients with HCC. Furthermore, based on phylogenetic analysis, the characteristic mutations were found in the initiating malignant clones in the AA-implicated mouse and human liver cancers where the mutations of tumor protein p53 and Janus kinase 1 were prone to be significantly enriched in the AA-affected human tumors. CONCLUSIONS: This study provides evidence for AA-induced liver cancer with the featured mutational processes during malignant clonal evolution, laying a solid foundation for the prevention and diagnosis of AA-associated human cancers, especially liver cancers.

3.
Macromol Rapid Commun ; : e1900492, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31693258

RESUMO

Fibers have traditionally been made through melt or solution processes from macromolecules. Most of these fibers have crystalline domains where the segregation of different crystalline features is extremely difficult due to the statistical nature of the formation and growth of these domains. A fibrous nano-crystalline sandwich is reported where distinctly different crystalline regions are formed in layers along the continuous fiber direction during the spinning process and locked in place. This approach employs side-by-side bicomponent nanofiber electrospinning where the components are the enantiomeric pair of poly(l-lactic acid) and poly(d-lactic acid). The formation of the poly(lactic acid) (PLA) stereo-complexes at the junction interphase of the two components is demonstrated through diffusion, which subsequently crystallize into continuous sandwich domains. The stereo-complex crystalline core in the fiber possesses a melting point 50 °C higher than, and properties substantially different from, the regular PLAs at the fringe areas of the fiber. This nano-crystalline sandwich fiber structure can be scaled to the micrometers in a commercial bicomponent process.

4.
Blood ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31697824

RESUMO

Antigen escape relapse has emerged as a major challenge for long-term disease control post CD19-directed therapies, to which dual-targeting of CD19 and CD22 has been proposed as a potential solution. Between March 2016 and January 2018, we conducted a pilot study in 89 patients, who had refractory/relapsed B-cell malignancies, to evaluate the efficacy and safety of sequential infusion of anti-CD19 and anti-CD22, two single-specific, third-generation chimeric antigen receptor-engineered (CAR19/22) T-cell "cocktail". Among the 51 patients with acute lymphoblastic leukemia, the minimal residual disease-negative response rate was 96.0% (95% confidence interval (CI), 86.3 to 99.5). With a median follow-up of 16.7 months (range, 1.3 to 33.3), the median progression-free survival (PFS) was 13.6 months (95% CI, 6.5 to not reached, NR), and the median overall survival (OS) was 31.0 months (95% CI, 10.6 to NR). Among the 38 patients with non-Hodgkin lymphoma, the overall response rate was 72.2% (95% CI, 54.8 to 85.8), with a complete response rate of 50.0% (95% CI, 32.9 to 67.1). With a median follow-up of 14.4 months (range, 0.4 to 27.4), the median PFS was 9.9 months (95% CI, 3.3 to NR), and the median OS was 18.0 months (95% CI, 6.1 to NR). Antigen loss relapse occurred in one patient during follow-up. High-grade cytokine release syndrome and neurotoxicity occurred in 22.4% and 1.12% patients, respectively. All except one were reversible. Our results indicated that sequential infusion of CAR19/22 T-cell was safe, efficacious, and may have reduced the rate of antigen escape relapse in B-cell malignancies. ChiCTR, number ChiCTR-OPN-16008526.

5.
Biomed Pharmacother ; 121: 109566, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31698268

RESUMO

Oxidative stress is a crucial pathogenic factor in osteoporosis. Autophagy is a cellular self-digestion process that can selectively remove damaged organelles under oxidative stress, and thus presents a potential therapeutic target against osteoporosis. Monotropein is an iridoid glycoside which can increase osteoblastic bone formation and be applied for medicinal purpose in China. The aim of this work is to investigate whether autophagy participates the protection effects of monotropein in osteoblasts under oxidative stress and the possible mechanism of such involvement. Here, monotropein was capable of inhibiting the H2O2-induced reactive oxygen species generation in osteoblasts. Monotropein induced autophagy and protected osteoblasts from cytotoxic effects of H2O2, as assessed by viability assays, apoptosis and western blotting. Moreover, it significantly attenuated H2O2-evoked oxidative stress as measured by malondialdehyde, catalase, and superoxide dismutase levels. Importantly, monotropein reduced the phosphorylation of protein kinase B (Akt), mammalian target of rapamycin (mTOR) and its two downstream proteins (p70S6K and 4EBP1). The autophagy level increased in osteoblasts treated with monotropein as represented by an increased in both Beclin1 expression and the LC3-II/LC3-I ratio. However, the Akt activator (SC79) and mTOR activator (MHY1485) suppressed the autophagy level induced by monotropein in H2O2-treated cells. Consequently, the antioxidant effects of monotropein were mediated, at least in part, by enhancing autophagy through the Akt/mTOR pathway. These results suggested that monotropein might be a promising candidate for osteoporosis treatment.

6.
Mikrochim Acta ; 186(11): 738, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31676959

RESUMO

The peroxidase-like activity of hollow Prussian Blue nanocubes (hPBNCs) is used, in combination with the enzyme alcohol oxidase (AOx), in a colorimetric ethanol assay. Different from other nanozymes, the large cavity structure of the hPBNCs provides a larger surface and more binding sites for AOx to be bound on their surface or in the pores. This extremely enhances the sensitivity of the assay system. In the presence of ethanol, AOx is capable of catalyzing the oxidation of alcohols to aldehydes, accompanied by the generation of hydrogen peroxide (H2O2). The hPBNCs act as peroxidase mimics and then can catalyze the oxidation of 3,3'5,5'-tetramethylbenzidine (TMB) by H2O2, resulting in a color change of the solution from colorless to blue with a strong absorption at 652 nm. The lower detection limit for ethanol is 1.41 µg∙mL-1. Due to the high catalytic activity of hPBNCs in weakly acidic and neutral solutions, the system was successfully applied to the determination of ethanol in mice blood. This is critically important for studying the alcohol consumption and monitoring the ethanol toxicokinetics. Graphical abstract Schematic representation of hollow Prussian Blue nanocubes (hPBNCs) used as both a peroxidase mimetic and as a carrier for alcohol oxidase. Utilizing hPBNCs along with the ethanol conversion enzyme, a sensitive colorimetric assay for ethanol was developed and applied to blood samples with satisfactory results.

7.
J Control Release ; 316: 359-380, 2019 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-31682912

RESUMO

Curcumin (Cur), a natural compound from Curcuma longa Linn, has various of pharmacological activities such as anti-cancer, anti-inflammatory, anti-oxidant, anti-Alzheimer, anti-microbial and more. Curcumin also has nephroprotective, hepatoprotective, neuroprotective, antirheumatic and cardioprotective effects. However, its low aqueous solubility inhibits the oral bioavailability of curcumin. As well, curcumin can be metabolized rapidly by intestinal tract which can also result in low oral bioavailability. In fact, the bioavailability of curcumin is low even through intraveneous administration routes. Various of pharmaceutical strategies for oral administration including solid dispersions, nano/microparticles, polymeric micelles, nanosuspensions, lipid-based nanocarriers, cyclodextrins, conjugates, polymorphs have been developed in order to improve the oral bioavailability of curcumin. These pharmaceutical strategies can increase the solubility of curcumin, improve the intestinal stability of curcumin, change the absorption route of curcumin and allow for coadministration with other adjuvants. Here we discuss efficacy studies in vitro and in vivo of curcumin nanoformulations, as well as human clinical trials.

8.
Am J Transl Res ; 11(10): 6701, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31737221

RESUMO

[This corrects the article on p. 3375 in vol. 11, PMID: 31312351.].

9.
Hum Genomics ; 13(1): 56, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31744542

RESUMO

BACKGROUND: Coronary artery disease (CAD) including acute myocardial infarction (AMI) is a common complex disease caused by atherosclerosis. Vascular epithelial growth factor receptor-1 (VEGFR-1) stimulates angiogenesis and vascular permeability, and functions as a decoy to sequester VEGF and prevent initiation of intracellular signaling. VEGFR-1 knockout mice exhibit significantly higher mortality due to heart failure, cardiac hypertrophy, and cardiac dysfunction. An evident increase in macrophage infiltration and cardiac fibrosis are also observed after transverse aortic constriction. Therefore, VEGFR-1 gene variants may be involved in CAD. In this study, VEGFR-1 gene promoter was genetically and functionally analyzed in large cohorts of AMI patients and ethnic-matched controls. RESULTS: A total of 16 DNA sequence variants (DSVs) including six single-nucleotide polymorphisms (SNPs) were found in the VEGFR-1 gene promoter and 5'-untranslated region. Five novel DSVs and one SNP were only identified in AMI patients group. These DSVs and SNP significantly altered the transcriptional activity of the VEGFR-1 gene promoter in both HEK-293 and H9c2 cells (P < 0.05). Further electrophoretic mobility shift assay indicated that the DSVs and SNPs evidently affected the binding of transcription factors. CONCLUSIONS: The genetic variants in VEGFR-1 gene identified in AMI patients may alter the transcriptional activity of the VEGFR-1 gene promoter and change VEGFR-1 level, contributing to AMI development.

10.
New Phytol ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31667846

RESUMO

Basic helix-loop-helix (bHLH) proteins are involved in transcriptional networks controlling a number of biological processes in plants. However, little is known on the roles of bHLH proteins in cotton fiber development so far. Here, we show that a cotton bHLH protein (GhFP1) positively regulates fiber elongation. GhFP1 transgenic cotton and Arabidopsis plants were generated to study how GhFP1 regulates fiber cell elongation. Fiber length of the transgenic cotton overexpressing GhFP1 was significantly longer than that of wild type, whereas suppression of GhFP1 expression hindered fiber elongation. Furthermore, overexpression of GhFP1 in Arabidopsis promoted trichome development. Expressions of the brassinosteroid (BR)-related genes were remarkably up-regulated in fibers of GhFP1 overexpression cotton, but down-regulated in GhFP1-silenced fibers. BR content in the transgenic fibers was significantly altered, relative to that in wild type. Moreover, GhFP1 protein could directly bind to the promoters of GhDWF4 and GhCPD to activate expressions of these BR-related genes. Thus, our data suggest that GhFP1 as a positive regulator participates in controlling fiber elongation by activating BR biosynthesis and signaling. Additionally, homodimerization of GhFP1 may be essential for its function, and interaction between GhFP1 and other cotton bHLH proteins may interfere with its DNA-binding activity.

11.
BMC Genomics ; 20(1): 861, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31726988

RESUMO

BACKGROUND: Elymus sibiricus is an ecologically and economically important perennial, self-pollinated, and allotetraploid (StStHH) grass, widely used for forage production and animal husbandry in Western and Northern China. However, it has low seed yield mainly caused by seed shattering, which makes seed production difficult for this species. The goals of this study were to construct the high-density genetic linkage map, and to identify QTLs and candidate genes for seed-yield related traits. RESULTS: An F2 mapping population of 200 individuals was developed from a cross between single genotype from "Y1005" and "ZhN06". Specific-locus amplified fragment sequencing (SLAF-seq) was applied to construct the first genetic linkage map. The final genetic map included 1971 markers on the 14 linkage groups (LGs) and was 1866.35 cM in total. The length of each linkage group varied from 87.67 cM (LG7) to 183.45 cM (LG1), with an average distance of 1.66 cM between adjacent markers. The marker sequences of E. sibiricus were compared to two grass genomes and showed 1556 (79%) markers mapped to wheat, 1380 (70%) to barley. Phenotypic data of eight seed-related traits (2016-2018) were used for QTL identification. A total of 29 QTLs were detected for eight seed-related traits on 14 linkage groups, of which 16 QTLs could be consistently detected for two or three years. A total of 6 QTLs were associated with seed shattering. Based on annotation with wheat and barley genome and transcriptome data of abscission zone in E. sibiricus, we identified 30 candidate genes for seed shattering, of which 15, 7, 6 and 2 genes were involved in plant hormone signal transcription, transcription factor, hydrolase activity and lignin biosynthetic pathway, respectively. CONCLUSION: This study constructed the first high-density genetic linkage map and identified QTLs and candidate genes for seed-related traits in E. sibiricus. Results of this study will not only serve as genome-wide resources for gene/QTL fine mapping, but also provide a genetic framework for anchoring sequence scaffolds on chromosomes in future genome sequence assembly of E. sibiricus.

12.
Ann Nutr Metab ; : 1-11, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31739307

RESUMO

BACKGROUND/AIMS: Metabolic syndrome (MetS) and its metabolic components, the common risk factors, may be involved in the development and progression of decreased estimated glomerular filtration rate (eGFR). The aim of this study was to examine the association of MetS and its metabolic components with eGFR status and severity among Chinese adults. METHODS: The population-based, cross-sectional study recruited a total of 33,300 Chinese adults (aged ≥18 years) from 4 study community sites in Songjiang District, Shanghai, between June 2016 and December 2017. Decreased eGFR was defined as a value of eGFR below 60 mL/min/1.73 m2. Weighted multiple logistic regression models were used to examine the association of MetS and its components with eGFR status and severity. RESULTS: After adjusting for potential confounders, subjects with MetS had an increased risk of decreased eGFR with an adjusted OR of 1.76 (95% CI 1.53-2.01), and subjects with increasing numbers of MetS components had a gradually increased risk for decreased eGFR (p trend <0.001). The multivariable-adjusted ORs (95% CI) of decreased eGFR were 1.66 (1.44-1.93) for abdominal obesity, 1.37 (1.18-1.60) for elevated triglycerides, 1.13 (0.96-1.33) for reduced high-density lipoprotein cholesterol, 0.84 (0.72-0.98) for elevated fasting glucose, and 1.92 (1.57-2.35) for elevated blood pressure (BP). Furthermore, these associations remained in most of the subgroups analyses. Significant associations between elevated BP and the risks of mildly, moderately, and severely decreased eGFR were also found. CONCLUSIONS: MetS was independently associated with an increased risk of decreased eGFR, and individual components of MetS each play a different role in decreased eGFR. Elevated BP may be an important risk factor for the progression of renal dysfunction or even chronic kidney disease.

13.
Artigo em Inglês | MEDLINE | ID: mdl-31760167

RESUMO

Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) play crucial roles as signaling mediators for the TNF receptor (TNFR) superfamily and the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamily. TRAFs collectively play important roles in multiple biological processes and organismal immunity. However, systematic identification of the TRAF gene family in teleost fish has not yet been reported, and there is little available information about its roles in innate immunity in Chinese tongue sole (Cynoglossus semilaevis), an aquaculture fish of high economic value. In the present study, we identified and characterized seven TRAF genes, namely, CsTRAF2a, CsTRAF2b, CsTRAF3, CsTRAF4, CsTRAF5, CsTRAF6 and CsTRAF7, in Chinese tongue sole, and the complete ORFs of the CsTRAFs were cloned. Sequence analysis revealed various genomic structures of the CsTRAFs and showed that they contain typical conserved domains compared with mammalian TRAFs. Phylogenetic analysis indicated the evolutionary relationships of TRAF family members in teleost fish and revealed an absence of TRAF1 in most species and TRAF5 in some species of teleosts. Analysis of the gene structures and motifs showed the diversity and distribution of exon-intron structures and conserved motifs in Chinese tongue sole and several other teleost species. Real-time quantitative PCR was used to investigate the expression patterns of CsTRAF genes in tissues of healthy fish and in the gills, livers and spleens of fish after bacterial infection with Vibrio harveyi. The results indicate that only CsTRAF2a is relatively highly expressed in the brain and that the other CsTRAFs are highly expressed in immune-related tissues and may participate in the immune response after infection with pathogenic bacteria. Functional analysis of CsTRAF3, CsTRAF4 and CsTRAF6 revealed that only CsTRAF6 could strongly activate the NF-кB pathway after overexpression of CsTRAF3, CsTRAF4 and CsTRAF6 in HEK-293T cells. This systematic analysis provided valuable information about the diverse roles of TRAFs in the innate immune response to pathogenic bacterial infection in teleost fish and will contribute to the functional characterization of CsTRAF genes in further research.

14.
Waste Manag ; 102: 380-390, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31733562

RESUMO

The gas and oil product derived from municipal solid waste (MSW) pyrolysis was upgraded by utilizing the interaction between the volatile compounds and the char and the mechanism involved is explored. The influences of operation parameters, including interaction temperature, char/volatiles mass ratio (C/V) and gas hourly space velocity (GHSV) of the volatiles on the distribution and property of the upgraded products were investigated. The results showed that the higher interaction temperature, higher C/V and lower GHSV favored the conversion of condensable volatiles into gas products, thus increasing the gas yield in the outlet stream. The highest gas yield (44.14 wt%) was obtained at 700 °C with the natural C/V ratio (0.8) and GHSV, which was twice of the gas yield in the volatiles. The chemical energy portion of gas increased to 8065 kJ/kgMSW from 3209 kJ/kgMSW at this condition. Syngas with H2/CO molar ratio of around 2 can be obtained at 700 °C with C/V ratio of 0.8 or at 600 °C with higher C/V ratios (C/V = 1.5-2.2). Oxygenates and acidity of the reformed oil products decreased; but monoaromatics and light polyaromatics concentration increased greatly. Heavy polycyclic aromatic hydrocarbons (PAHs) in the liquid products were degraded after volatiles/hot char interaction. Suitable conditions can be varied and recommended for obtaining different desired high-quality products based on this process.

15.
Curr HIV/AIDS Rep ; 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31776975

RESUMO

PURPOSE OF REVIEW: To describe HIV epidemic and interventions for improving HIV continuum of care in China. RECENT FINDINGS: The reported HIV epidemic has been continuously increasing, partially due to the expansion of active HIV testing campaign. Public health intervention programs have been effective in containing HIV spread among former plasma donors and people who inject drugs (PWID), but more infections occur among heterosexual men and women and young men who have sex with men. Of 1.25 million Chinese people are living with HIV, one-third do not know their status. About two-thirds of diagnosed individuals have used antiretroviral therapy (ART) and two-thirds of those on ART have achieved viral suppression, but some risk groups such as PWID have lower rates. The national free ART program has reduced adult and pediatric mortality and reduced heterosexual transmission. China faces great challenges to reduce HIV sexual transmission, improve the HIV continuum of care, and close the gaps to the UNAIDS Three "90" Targets.

16.
Nat Neurosci ; 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31570863

RESUMO

It was recently reported that a magnetic actuator, Magneto, can control neuronal firings at magnetic strength as low as 50 mT (ref. 1), offering an exciting non-invasive approach to manipulating neuronal activity in a variety of research and clinical applications. We investigated whether Magneto can be used to manipulate electric properties of Purkinje cells in the cerebellum, which play critical roles in motor learning and emotional behaviors2. Surprisingly, we found that the application of a magnetic field did not change any electrical properties of Purkinje cells expressing Magneto, raising serious doubt about the previous claim that Magneto can readily be used as a magnetic actuator1.

17.
Wei Sheng Yan Jiu ; 48(4): 577-582, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31601338

RESUMO

OBJECTIVE: To investigate the correlation between the polymorphisms of(brain derived neurotrophic factor, BDNF)BDNF gene rs11030104 and rs2030324 and executive function in children with attention deficit hyperactivity disorder(ADHD). METHODS: A total of 206 ADHD children and 212 control children were enrolled in the study. Five mL peripheral venous blood was extracted from each subject and genomic DNA was extracted. The genotypes of rs11030104 and rs2030324 loci were genotyped by PCR/sequencing. The selection was tested by Wisconsin Classification Card Test, Stroop Color-Word Task, Reaction/Nonresponse Task and Stop Signal Task. RESULTS: The distribution of rs2030324 locus gene frequency was different between ADHD group and control group. G allele was the risk factor of ADHD(χ~2=4. 481, P=0. 034; OR=1. 520, 95%CI 1. 031-2. 243); rs11030101 locus gene frequency distribution and genotype distribution had statistical significance between the two groups, and A allele was related to ADHD susceptibility(OR=1. 601, 95%CI 1. 052-2. 436). The error interference score of Stroop test in ADHD group was higher than that in control group(P<0. 05), but there was no significant difference in response time interference score between the two groups(P>0. 05). The SCWT scores of different genotypes of BDNF rs2030324 in ADHD group were different. Compared with AA type and AG type, the SCWT error interference scores of GG type ADHD patients were higher. There was no significant difference among rs11030101 genotypes. The WCST scores of ADHD group were lower than those of control group. The variation of Go/no-go scores in ADHD group was higher than that of control group in missed count, mistaken count and correct reaction time. The variation of SST and correct reaction time in ADHD group were higher than that of control group, but the genotype distribution of rs11030104 and rs2030324 loci had no significant correlation with WCST, Go/no-go and SST scores. CONCLUSION: Children with ADHD have executive dysfunction. ADHD children with BDNF rs2030324 GG genotype showed poor Stroop executive function.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Criança , Função Executiva , Frequência do Gene , Humanos , Polimorfismo de Nucleotídeo Único
18.
Dig Dis Sci ; 64(11): 3357, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31630342

RESUMO

The Editor-in-Chief has retracted this article [1] because Figure 8 overlaps with Figure 6b of [2] and Figure 6 overlaps with Figure 3 of [3] and Figure 3 of [4].

19.
J Cell Biol ; 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619485

RESUMO

The primary cilium is a sensory organelle that protrudes from the cell surface. Primary cilia undergo dynamic transitions between assembly and disassembly to exert their function in cell signaling. In this study, we identify the small GTPase Rab7 as a novel regulator of cilia disassembly. Depletion of Rab7 potently induced spontaneous ciliogenesis in proliferating cells and promoted cilia elongation during quiescence. Moreover, Rab7 performs an essential role in cilia disassembly; knockdown of Rab7 blocked serum-induced ciliary resorption, and active Rab7 was required for this process. Further, we demonstrate that Rab7 depletion significantly suppresses cilia tip excision, referred to as cilia ectocytosis, which has been identified as required for cilia disassembly. Mechanically, the failure of F-actin polymerization at the site of excision of cilia tips caused suppression of cilia ectocytosis on Rab7 depletion. Overall, our results suggest a novel function for Rab7 in regulating cilia ectocytosis and cilia disassembly via control of intraciliary F-actin polymerization.

20.
J Pathol ; 2019 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-31621921

RESUMO

The genetics underlying thyroid cancer dedifferentiation is only partly understood and has not yet been characterized using comprehensive pan-genomic analyses. We investigated a unique case with synchronous follicular thyroid carcinoma (FTC), poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC), as well as regional lymph node metastases from the PDTC and ATC from a single patient using whole-genome sequencing (WGS). The FTC displayed mutations in CALR, RB1 and MSH2 and the PDTC exhibited mutations in TP53, DROSHA, APC, TERT and additional DNA repair genes - associated with an immense increase in subclonal somatic mutations. All components displayed an overrepresentation of C>T transitions with associated microsatellite instability (MSI) in the PDTC and ATC, with borderline MSI in the FTC. Clonality analyses pinpointed a shared ancestral clone enriched for mutations in TP53-associated regulation of DNA repair and identified important sub-clones for each tumour component already present in the corresponding preceding lesion. This genomic characterization of the natural progression of thyroid cancer reveals several novel genes of interest for future studies. Moreover, the findings support the theory of a stepwise dedifferentiation process and suggest that defects in DNA repair could play an important role in the clonal evolution of thyroid cancer. This article is protected by copyright. All rights reserved.

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