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1.
Inorg Chem ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31794201

RESUMO

Utilizing the oxygen-bridged 5,5'-oxidiisophthalic acid (H4L) linker, one Co(II)-based 3D porous MOF {[Co5(L)2(OH)2(OH2)2(H2O)4]·2DMF·H2O}n (1) with pentanuclear [Co5(µ3-OH)2(µ2-OH2)2]8+ cluster was prepared. The glassy carbon electrode was modified by 1, and the obtained electrode revealed electrocatalytic performance for glucose oxidation. The porous MOF matrix is beneficial for dispersing Ag nanoparticles evenly in the interior cages or channels, so Ag@1 composite composed of both Ag nanoparticles and MOF was further prepared through deposition-reduction method to enhance electrocatalytic activity. The result demonstrates that the glucose oxidation by Ag@1 was greatly increased with low detection limit (1.32 µM) and good selectivity and sensitivity (0.135 µA µM-1), which promote the application of MOF-template porous composites as advanced electrochemical sensor materials. Furthermore, 1 shows an interesting magnetic spin-glass slow dynamics for the existing of peculiar pentanuclear Co(II) clusters.

2.
Biochimie ; 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31786229

RESUMO

Changes in brain energy metabolism in diabetes mellitus, including increased insulin resistance and mitochondrial dysfunction, are critically involved in diabetes-related neurodegeneration, and associate with early cognitive impairment as well. The aim of this study is to detect the specific phosphorylated-Thr485- AMP-activated protein kinase (AMPK-α2), regulated by cyclin-dependent kinase 5 (Cdk5) paly the inhibitory functional role of AMPK-α2, Which is maybe the link to the accelelated diabetic brain damage progression. Here, we used GK rats, the type 2 diabetic animal model for in vivo studies and performed In vitro kinase assay, high glucose treatment, -phosphorylated mutation and protein expression in both HEK-293T and HT-22 cell lines. In vitro, the results show that murine wild-type AMPK-α2 was phosphorylated by Cdk5 at a (S/T)PX(K/H/R) phosphorylation consensus sequence, which was associated with decreased AMPK-α2 activity. Surprisingly, mutation of Thr485 to alanine in AMPK-α2 results in the abolished Cdk5 effects, demonstrating that Thr485-phosphorylation is critical to AMPK-α2 inhibition by Cdk5. In addition, these alterations in AMPK-α2-phosphorylation and -activity induced by Cdk5 is specific at Thr485. Furthermore, in GK rats, the increased phosphorylated- Thr 485 of AMPK-α2 results in the decreased AMPK-α2 activity, which is correlated with the apoptosis of neurons in hippocamps. After high glucose treatment, the decreased survival showed in AMPK-α2T485A HT-22 cells compared to AMPK-α2WT. The down-regulated of p-CREB, SNAP25, synaptophysin as well as synapsin-1were shown in both GK rats and HT-22 cell line. Meanwhile, pre-treated with either the specific Cdk5-inhibitor (roscovitine) or the antidiabetic AMPK-α2-inhibitor (metformin) could restore the alterations in neuronal protein expression. Our results suggest that Cdk5-mediated phosphorylated- Thr485 in AMPK-α2 may be involved in the pathogenesis of diabetic brain damage.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31793764

RESUMO

Herein, a new porous Zn(II)-based metal-organic framework (MOF 1) has been prepared, the structure of which featured a twofold entangled motif based on two typical secondary building units (SBUs). The gas sorption studies indicated that MOF 1 may be explored as a useful platform to encapsulate metallic nanoparticles. Then the Au@1 composite has been prepared via a facile incorporation method without extra reducing agents. The Au@1 composite has been fully characterized by HRTEM, SEM-EDX, PXRD, gas sorption, XPS, ICP, etc. Catalytic experiments showed that the Au@1 composite had a perfect catalytic performance in CO2 fixation for epoxides with different substituents under mild conditions.

4.
Theriogenology ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31711699

RESUMO

Reproductive traits are important factors in sheep production. The Booroola fecundity (FecB) gene-the first major gene for prolificacy identified in sheep-has a positive effect on ovulation rates and litter size under natural reproductive conditions. However, the effect of the FecB gene on reproductive performance under assisted reproduction, which uses many artificial hormones, remains unclear. In the present study, we evaluated the effect of FecB (BMPR-1B mutation) on reproductive performance under assisted reproduction, and examined offspring body weight at birth and weaning and survival rate at weaning. There were no differences among three genotype groups (homozygous carrier, BB; heterozygous carrier, B+; non-carrier, ++) in terms of estrus detection rate, time to estrus onset, or estrus duration following estrus synchronization (P > 0.05). The pregnancy rates at 60 d were similar among three genotype groups after artificial insemination (P > 0.05). However, the B allele had an additive effect on litter size (one copy resulted in an increase of 0.88 lambs and two copies produced an additional 0.41 lambs; P < 0.01), and increased lambing and fecundity rates (P < 0.01). After multiple ovulation, the average numbers of recovered embryos per ewe were 9.16 ±â€¯0.79, 8.20 ±â€¯0.77, and 8.44 ±â€¯0.61 in the BB, B+, and ++ ewes, respectively (P > 0.05). There were no differences in the fertilization rate or numbers of grade 1-2 embryos among different groups (P > 0.05). The birth and weaning weights of lambs from BB and B+ ewes were lower than those of lambs born from ++ ewes (P < 0.01) owing to the high fecundity. The survival rate of lambs at weaning did not differ among groups (P > 0.05). Our results indicated that the presence of the B allele had an additive effect on litter size after artificial insemination, but it did not influence the parameters of estrus synchronization and multiple ovulation. Furthermore, the higher prolificacy in ewes carrying the B allele was associated with a reduction in offspring body weight at birth and weaning.

5.
Genes (Basel) ; 10(11)2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31739500

RESUMO

While methods for detecting SNVs and indels in circulating tumor DNA (ctDNA) with hybridization capture-based next-generation sequencing (NGS) have been available, copy number variations (CNVs) detection is more challenging. Here, we present a method enabling CNV detection from a 150-gene panel using a very low amount of ctDNA. First, a read depth-based CNV estimation method without a paired blood sample was developed and cfDNA sequencing data from healthy people were used to build a panel of normal (PoN) model. Then, in silico and in vitro simulations were performed to define the limit of detection (LOD) for EGFR, ERBB2, and MET. Compared to the WES results of the 48 samples, the concordance rate for EGFR, ERBB2, and MET CNVs was 78%, 89.6%, and 92.4%, respectively. In another cohort profiled with the 150-gene panel from 5980 lung cancer ctDNA samples, we detected the three genes' amplification with comparable population frequency with other cohorts. One lung adenocarcinoma patient with MET amplification detected by our method reached partial response to crizotinib. These findings show that our ctDNA CNV detection pipeline can detect CNVs with high specificity and concordance, which enables CNV calling in a non-invasive way for cancer patients when tissues are not available.

6.
Chaos ; 29(11): 113104, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31779366

RESUMO

A novel scheme to optimize the adaptive transmit waveform of chaotic multiple-input multiple-output (MIMO) radar is developed. The main objective of this work is to achieve high ability in target discrimination by using a Dirichlet process mixture model (DPMM)-based clustering method based on nonparametric Bayesian theory and to improve the capability of target detection by minimizing the mean square error of radar channel response via Kalman filtering (KF) technique. The two stages are the discrimination of multiple range-extended targets and the optimization of the adaptive chaos-based waveform for transmission. The adaptive chaotic MIMO waveform optimization scheme overcomes the problem of target discrimination and detection in an intelligent transportation system, where there is a need for extracting the feature of target information achieved from vehicle-mounted sensor. As the number of iterations increases, simulation experiments demonstrate better target discrimination capability provided by the proposed DPMM-KF technique as compared with the traditional waveform design method. In addition, the proposed DPMM-KF technique leads to improved target detection probability and receiver operating characteristics in the interference environment.

7.
Chem Asian J ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31782903

RESUMO

Three new isostructural 3D lanthanide metal-organic frameworks (Ln-MOFs), {H[LnL(H2O)]·2H2O}n (1-Ln) (Ln = Eu3+, Gd3+ and Tb3+) based on infinite lanthanide-carboxylate chains were constructed by employing an ether O separated 5,5'-oxydiisophthalic acid (H4L) ligand under the solverthermal reaction. 1-Eu and 1-Tb exhibit strong red and green emission, respectively, through antenna effect, as demonstrated through combing calculation and experimental results. Moreover, a series of dichromatic doped 1-EuxTby MOFs were fabricated by introducing different concentrations of Eu3+ and Tb3+ ions, displaying an unusual variation of luminescent colors from green, yellow, orange to red. 1-Eu with the channels decorated by ether O atoms and the open metal sites displays good performance for CO2 capture and conversion between CO2 and epoxides into cyclic carbonates.

8.
Blood Adv ; 3(21): 3379-3392, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31698466

RESUMO

Induction of fetal hemoglobin (HbF) via clustered regularly interspaced short palindromic repeats/Cas9-mediated disruption of DNA regulatory elements that repress γ-globin gene (HBG1 and HBG2) expression is a promising therapeutic strategy for sickle cell disease (SCD) and ß-thalassemia, although the optimal technical approaches and limiting toxicities are not yet fully defined. We disrupted an HBG1/HBG2 gene promoter motif that is bound by the transcriptional repressor BCL11A. Electroporation of Cas9 single guide RNA ribonucleoprotein complex into normal and SCD donor CD34+ hematopoietic stem and progenitor cells resulted in high frequencies of on-target mutations and the induction of HbF to potentially therapeutic levels in erythroid progeny generated in vitro and in vivo after transplantation of hematopoietic stem and progenitor cells into nonobese diabetic/severe combined immunodeficiency/Il2rγ-/-/KitW41/W41 immunodeficient mice. On-target editing did not impair CD34+ cell regeneration or differentiation into erythroid, T, B, or myeloid cell lineages at 16 to 17 weeks after xenotransplantation. No off-target mutations were detected by targeted sequencing of candidate sites identified by circularization for in vitro reporting of cleavage effects by sequencing (CIRCLE-seq), an in vitro genome-scale method for detecting Cas9 activity. Engineered Cas9 containing 3 nuclear localization sequences edited human hematopoietic stem and progenitor cells more efficiently and consistently than conventional Cas9 with 2 nuclear localization sequences. Our studies provide novel and essential preclinical evidence supporting the safety, feasibility, and efficacy of a mechanism-based approach to induce HbF for treating hemoglobinopathies.

9.
J Zhejiang Univ Sci B ; 20(12): 945-959, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31749342

RESUMO

BACKGROUND: The shortage of donor corneas is a severe global issue, and hence the development of corneal alternatives is imperative and urgent. Although attempts to produce artificial cornea substitutes by tissue engineering have made some positive progress, many problems remain that hamper their clinical application worldwide. For example, the curvature of tissue-engineered cornea substitutes cannot be designed to fit the bulbus oculi of patients. OBJECTIVE: To overcome these limitations, in this paper, we present a novel integrated three-dimensional (3D) bioprinting-based cornea substitute fabrication strategy to realize design, customized fabrication, and evaluation of multi-layer hollow structures with complicated surfaces. METHODS: The key rationale for this method is to combine digital light processing (DLP) and extrusion bioprinting into an integrated 3D cornea bioprinting system. A designable and personalized corneal substitute was designed based on mathematical modelling and a computer tomography scan of a natural cornea. The printed corneal substitute was evaluated based on biomechanical analysis, weight, structural integrity, and fit. RESULTS: The results revealed that the fabrication of high water content and highly transparent curved films with geometric features designed according to the natural human cornea can be achieved using a rapid, simple, and low-cost manufacturing process with a high repetition rate and quality. CONCLUSIONS: This study demonstrated the feasibility of customized design, analysis, and fabrication of a corneal substitute. The programmability of this method opens up the possibility of producing substitutes for other cornea-like shell structures with different scale and geometry features, such as the glomerulus, atrium, and oophoron.

10.
Cutis ; 104(3): E11-E15, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31675404

RESUMO

The expanding use of novel targeted anticancer agents such as sorafenib has led to an increasing number of dermatologic adverse events. Although cutaneous adverse events are commonly described in patients taking sorafenib, there are few reports describing psoriasis secondary to this medication. In this report, we describe 3 patients with sorafenib-induced psoriasiform drug eruption and review the available literature of similar patient cases. Our findings highlight shared characteristics among affected patients and potential treatment options for patients in whom sorafenib cannot be discontinued. Increased awareness of such drug eruptions and management options is critical to prevent suboptimal dosing and decreased quality of life.

11.
J Clin Nurs ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31715048

RESUMO

AIMS AND OBJECTIVES: This study was designed to explore the psychological processes experienced by nursing students caring for suicidal patients during their first psychiatric clinical practicum. BACKGROUND: Nursing students expressed fear when caring for patients who presented with suicidal behaviors. Yet, there is a lack of research exploring nursing students' feelings and thoughts when caring for suicidal patients. DESIGN: A grounded theory study. METHODS: A theoretical sample of 22 undergraduate nursing students who had cared for suicidal patients for at least five days during their psychiatric clinical practicum. Data were collected from 2016 to 2017, in three universities in Taiwan, using a semi-structured interview and constant comparative analysis. COREQ reporting guidelines were utilized. RESULTS: Four categories emerged depicting the psychological processes and revealing that the student nurses navigated four phases when caring for patients exhibiting suicidal behaviors. The phases were: (1) apprehension and fear; involving students being frightened about patients attempting suicide; (2) frustration and powerlessness: concerning students finding it challenging to focus on changing patients' suicidal ideations; (3) support and catharsis: covering the students having to ask for psychological support from other people and explore their painful emotions; (4) confidence and empathy: meaning that the students incorporated enhanced confidence and cultivated advanced empathy, leading to the integration of competent care competencies toward suicidal patients. CONCLUSIONS: Findings could help nursing teachers to understand students' psychological processes when caring for suicidal patients. Teachers could provide appropriate support to help reduce students' negative thoughts and feelings and increase their care-competencies when nursing suicidal patients during their psychiatric clinical practicum. RELEVANCE TO CLINICAL PRACTICE: Clinical nurse teachers could support and facilitate students to develop their competencies and confidence as they negotiate the four phases and, actually, complete their internship goals on their clinical practicums.

12.
Medicine (Baltimore) ; 98(48): e18000, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770212

RESUMO

RATIONALE: Bladder cancer (BC) is commonly diagnosed in the urinary system and the most common subtype is transitional urothelial carcinoma (TCC). Even with the best treatment, tumor recurrence and metastases always occur. While clinicians commonly observe the metastases to pelvic lymph nodes, liver, lung, and bone, it may infrequently spread to some uncommon locations. PATIENT CONCERNS: The patient was a 67-year-old man with a diagnosis of high-grade TCC with squamous differentiation in the bladder and prostate. Subsequently, radical cystoprostatectomy, adjuvant radiotherapy, and chemotherapy were performed. However, he felt intermittent right scrotal pain about 1 year later. DIAGNOSIS: Ultrasound strongly suggested a testicular neoplasm of right testis, but the left was normal. INTERVENTIONS: The patient underwent a right radical orchiectomy and histopathology confirmed testicular metastatic neoplasm from bladder. Moreover, further examination with positron emission tomography revealed no visible distant spread of the urothelial carcinoma. OUTCOMES: No signs of tumor recurrence or distant metastasis were visible under follow-up 1 year after radical orchiectomy. LESSONS: Testicular mass may be metastatic tumor during follow-up for patients who were diagnosed as BC, especially for TCC with variant histology. The reason of this could be explained of residual micrometastases after surgery and need more examination to discover local micrometastases to apply more aggressive treatment.

13.
Artigo em Inglês | MEDLINE | ID: mdl-31589799

RESUMO

A series of supramolecular assemblies of types [Ag8 (L)4 ](PF6 )8 and [Ag4 (L)2 ](PF6 )4 , obtained from the tetraphenylethylene (TPE) bridged tetrakis(1,2,4-triazolium) salts H4 -L(PF6 )4 and AgI ions, is described. The assembly type obtained dependends on the N-wingtip substituents of H4 -L(PF6 )4 . Changes in the lengths of the N4-wingtip substituents enables controlled formation of assemblies with either [Ag4 (L)2 ](PF6 )4 or [Ag8 (L)4 ](PF6 )8 stoichiometry. The molecular structures of selected [Ag8 (L)4 ](PF6 )8 and [Ag4 (L)2 ](PF6 )4 assemblies were determined by X-ray diffraction analyses. While H4 -L(PF6 )4 does not exhibit fluorescence in solution, their tetra-NHC (NHC=N-heterocyclic carbene) assemblies do upon NHC-metal coordination. Upon irradiation, all assemblies undergo a light-induced, supramolecule-to-supramolecule structural transformation by an oxidative photocyclization involving phenyl groups of the TPE core, resulting in a significant change of the luminescence properties.

14.
Inorg Chem ; 58(20): 13969-13978, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31577144

RESUMO

A series of isomorphic lanthanide metal-organic frameworks (Ln-MOFs), {[Ln(L)(H2O)2]·5H2O}n (1-Ln, where Ln = Eu, Tb, Gd, and EuxTb1-x), have been synthesized by a rigid 1,3-bis(3,5-dicarboxyphenyl)imidazolium chloride (H4L+Cl-) ligand and Ln3+ ions via a solvothermal method. Single-crystal X-ray diffraction indicated that 1-Ln exhibited similar three-dimensional porous frameworks with one-dimensional channels decorated by the uncoordinated carboxylate oxygen atoms. The luminescent sensing studies indicated that 1-Eu is an outstanding reusable luminescent probe suitable for the simultaneous detection of Cr2O72-, CrO42-, and MnO4- ions in an aqueous solution. Remarkably, the different proportions of Eu3+ and Tb3+ can be combined into the same Ln-MOF to yield a new series of differently doped 1-EuxTb1-x MOFs. At the same excitation wavelength, they generated dual-emission peaks of Eu3+ and Tb3+ to show a gradual change in luminous color between yellow-green, yellow, orange, orange-red, and red. On the basis of the excellent optical properties of 1-Ln complexes, they can be employed as promising luminescent probe and multicolor tunable photoluminescence materials.

15.
Medicine (Baltimore) ; 98(42): e17538, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626116

RESUMO

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine carcinoma of the skin. The available reports of MCC in Asia are limited; in this study, we report the largest series of MCC in Taiwan to date.The series is composed by 24 pathologically proven MCC cases, which were retrospectively reviewed in Chang Gung Memorial Hospital in Taiwan between 2000 and 2018.The tumor occurred predominantly in men (80%) and in the elderly (median 74.8 years). Twenty-one patients had locoregional MCC and 3 had metastatic MCC at the time of diagnosis. Patients with pathologically proven negative nodes by sentinel lymph node biopsy (SLNB) showed better survival time than those without SLNB in 16 clinically node-negative MCC cases undergoing primary surgery. Salvage surgery for loco-regional recurrence lengthened the survival time and possibly cured recurrent MCC. Palliative chemotherapy with cisplatin and etoposide showed a response rate of 25%, progression-free survival of 3.6 months, and overall survival of 14.8 months in 4 metastatic/recurrent MCC. Avelumab treatment was effective in 1 patient, who achieved a durable disease control.This observational cohort of MCC patients in Taiwan suggests aggressive surgical intervention including wide excision and lymph node management, salvage operation is critical for early MCC patients, and palliative chemotherapy and immunotherapy showed their efficacy for advanced MCC patients.


Assuntos
Carcinoma de Célula de Merkel/mortalidade , Neoplasias Cutâneas/mortalidade , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Célula de Merkel/patologia , Carcinoma de Célula de Merkel/terapia , Feminino , Humanos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Estudos Retrospectivos , Terapia de Salvação/estatística & dados numéricos , Biópsia de Linfonodo Sentinela/estatística & dados numéricos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Taiwan/epidemiologia
16.
Genes (Basel) ; 10(10)2019 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-31569425

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer. The five-year survival rate of PDAC is very low (less than 8%), which is associated with the late diagnosis, high metastatic potential, and resistance to therapeutic agents. The identification of better prognostic or therapeutic biomarker may have clinical benefits for PDAC treatment. SMAD4, a central mediator of transforming growth factor beta (TGFß) signaling pathway, is considered a tumor suppressor gene. SMAD4 inactivation is frequently found in PDAC. However, its role in prognosis and therapeutics of PDAC is still unclear. In this study, we applied bioinformatics approaches, and integrated publicly available resources, to investigate the role of SMAD4 gene deletion in PDAC. We found that SMAD4 deletion was associated with poorer disease-free, but not overall, survival in PDAC patients. Cancer hallmark enrichment and pathway analysis suggested that the upregulation of cell cycle-related genes in SMAD4-deleted PDAC. Chemotherapy response profiling of PDAC cell lines and patient-derived organoids revealed that SMAD4-deleted PDAC was sensitive to gemcitabine, the first-line treatment for PDAC, and specific cell cycle-targeting drugs. Taken together, our study provides an insight into the prognostic and therapeutic roles of SMAD4 gene deletion in PDAC, and SMAD4 gene copy numbers may be used as a therapeutic biomarker for PDAC treatment.

17.
Small ; 15(46): e1903725, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31599490

RESUMO

Lithium (sodium)-metal batteries are the most promising batteries for next-generation electrical energy storage due to their high volumetric energy density and gravimetric energy density. However, their applications have been prevented by uncontrollable dendrite growth and large volume expansion during the stripping/plating process. To address this issue, the key strategy is to realize uniform lithium (sodium) deposition during the stripping/plating process. Herein, a thin lithiophilic layer consisting of RuO2 particles anchored on brush-like 3D carbon cloth (RuO2 @CC) is prepared by a simple solution-based method. After infusion of Li, the RuO2 @CC transfers to Li-Ru@CC. Ru nanoparticles not only play a role in leading Li+ (Na+ ) to plate on the 3D carbon framework, but also lower local current density because of the good electrical conductivity. Furthermore, density functional theory calculations demonstrate that Ru metal, the reaction product of alkali metal and Ru, can lead Li+ to plate evenly around carbon fiber owing to the strong binding energy with Li+ . The Li-Ru@CC anode shows ultralong cycle life (1500 h at 5 mA cm-2 ). The full cell of Li-Ru@CC|LiFePO4 exhibits lower polarization (90% capacity retention after 650 cycles). In addition, sodium metal batteries based on Na-Ru@CC anodes can achieve similar improvement.

18.
Chem Commun (Camb) ; 55(91): 13689-13692, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31657391

RESUMO

In this work, we demonstrate the design and fabrication of a series of cylinder-like, hexazido-terminated MI-CNHC (M = Ag, Au) complexes. Moreover, we present for the first time a process-tracing and aggregation-induced emission (AIE) study of a covalent postassembly modification (PAM) process of the AuI-CNHC cylinders, highlighting the excellent versatility and complexity of functionalised poly-NHC compounds as a new type of molecular platform for novel applications.

20.
Biomolecules ; 9(9)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505885

RESUMO

Although chemotherapy for treating colorectal cancer has had some success, drug resistance and metastasis remain the major causes of death for colorectal cancer patients. MicroRNA-21-5p (hereafter denoted as miR-21) is one of the most abundant miRNAs in human colorectal cancer. A Kaplan-Meier survival analysis found a negative prognostic correlation of miR-21 and metastasis-free survival in colorectal cancer patients (The Cancer Genome Atlas Colon Adenocarcinoma/TCGA-COAD cohort). To explore the role of miR-21 overexpression in drug resistance, a stable miR-21-overexpressing clone in a human DLD-1 colorectal cancer cell line was established. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) cell viability assay found that miR-21 overexpression induced drug resistance to topoisomerase inhibitors (SN-38, doxorubicin, and etoposide/VP-16). Mechanistically, we showed that miR-21 overexpression reduced VP-16-induced apoptosis and concomitantly enhanced pro-survival autophagic flux without the alteration of topoisomerase expression and activity. Bioinformatics analyses suggested that miR-21 overexpression induced genetic reprogramming that mimicked the gene signature of topoisomerase inhibitors and downregulated genes related to the proteasome pathway. Taken together, our results provide a novel insight into the role of miR-21 in the development of drug resistance in colorectal cancer.

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