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1.
Theranostics ; 11(10): 4672-4687, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754020

RESUMO

Rationale: Oxaliplatin-induced peripheral neuropathy (OIPN) is a common adverse effect that causes delayed treatment and poor prognosis among colorectal cancer (CRC) patients. However, its mechanism remains elusive, and no effective treatment is available. Methods: We employed a prospective cohort study of adult patients with pathologically confirmed stage III CRC receiving adjuvant chemotherapy with an oxaliplatin-based regimen for investigating OIPN. To further validate the clinical manifestations and identify a potential therapeutic strategy, animal models, and in vitro studies on the mechanism of OIPN were applied. Results: Our work found that (1) consistent with clinical findings, OIPN was observed in animal models. Targeting the enzymatic activity of cathepsin S (CTSS) by pharmacological blockade and gene deficiency strategy alleviates the manifestations of OIPN. (2) Oxaliplatin treatment increases CTSS expression by enhancing cytosol translocation of interferon response factor 1 (IRF1), which then facilitates STIM-dependent store-operated Ca2+ entry homeostasis. (3) The cytokine array demonstrated an increase in anti-inflammatory cytokines and suppression of proinflammatory cytokines in mice treated with RJW-58. (4) Mechanistically, inhibiting CTSS facilitated olfactory receptors transcription factor 1 release from P300/CBP binding, which enhanced binding to the interleukin-10 (IL-10) promoter region, driving IL-10 downstream signaling pathway. (5) Serum CTSS expression is increased in CRC patients with oxaliplatin-induced neurotoxicity. Conclusions: We highlighted the critical role of CTSS in OIPN, which provides a therapeutic strategy for the common adverse side effects of oxaliplatin.

2.
ChemSusChem ; 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33783971

RESUMO

The electroreduction of CO 2 into highly value-added fuel, HCOOH, has been considered as a perfect approach to converse renewable energy and mitigate environmental crisis. SnO 2 electrode is one of the promising candidates to electrocatalytically convert CO 2 to HCOOH, but its poor stability limits its future development and application. Here in this work, highly stable SnO 2 /Bi 2 O 3 oxide catalysts were obtained by distributing SnO 2 nanoparticles on the surface of Bi 2 O 3 sheets. The XPS spectra revealed an interfacial electronic transportation from Bi 2 O 3 sheets to SnO 2 nanoparticles, which made SnO 2 rich of electrons. The strong interfacial interaction protected the active sites of SnO 2 from self-reduction in CO 2 electroreduction reaction (CO 2 RR), stabilizing SnO 2 species in the composite catalyst even after long-time working. Calculations based on density functional theory signified that the existence of Bi 2 O 3 favored the adsorption of HCOO* intermediate, improved the CO 2 conversion to HCOOH on SnO 2 /Bi 2 O 3 interface. As a result, the SnO 2 /Bi 2 O 3 catalyst achieved high performance on CO 2 RR (the highest FE C1 value of 90% at -1.0 V vs RHE), suppressing H 2 evolution reaction (HER) at high potentials. In particular, the selectivity of HCOOH remained above 76% in a wide potential window (from -1.0 to -1.4 V vs RHE) and a long duration (12 h).

3.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(3): 279-282, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33691922

RESUMO

OBJECTIVE: To study the clinical features of vesicoureteral reflux (VUR) in children with neurogenic bladder (NB), and to provide a reference for its early diagnosis and treatment. METHODS: Clinical data were collected from 26 children with NB and urinary tract infection who were admitted to the Department of Pediatric Nephrology from January 2014 to December 2019. According to the presence or absence of VUR, the children were divided into a VUR group with 11 children and a non-VUR group with 15 children. Clinical features were compared between the two groups. RESULTS: Compared with the non-VUR group, the VUR group had a significantly higher proportion of children with non-Escherichia coli urinary tract infection, hydronephrosis (the severity of hydronephrosis increased with the grade of VUR), abnormal 99mTc-DMSA renal scanning findings, elevated ratios of urinary albumin, urinary IgG and urinary transferrin to creatinine, increased residual urine volume, and increased detrusor leak point pressure (P < 0.05). CONCLUSIONS: When NB children have the clinical manifestations of non-Escherichia coli urinary tract infection, hydronephrosis, abnormal 99mTc-DMSA renal scanning findings, glomerular proteinuria, increased bladder residual urine volume, and high detrusor leak point pressure, such children may already have VUR, and so diagnosis and intervention should be performed as early as possible.


Assuntos
Bexiga Urinaria Neurogênica , Infecções Urinárias , Refluxo Vesicoureteral , Criança , Creatinina , Humanos , Lactente , Cintilografia , Bexiga Urinaria Neurogênica/etiologia , Infecções Urinárias/diagnóstico por imagem , Infecções Urinárias/etiologia , Refluxo Vesicoureteral/diagnóstico , Refluxo Vesicoureteral/diagnóstico por imagem
4.
ACS Appl Mater Interfaces ; 13(10): 11621-11630, 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33656313

RESUMO

Magnetic-activated cell sorting (MACS) is an affinity-based technique used to separate cells according to the presence of specific markers. Current MACS systems generally require an antigen to be expressed at the cell surface; these antigen-presenting cells subsequently interact with antibody-labeled magnetic particles, facilitating separation. Here, we present an alternative MACS method based on coiled-coil peptide interactions. We demonstrate that HeLa, CHO, and NIH3T3 cells can either incorporate a lipid-modified coiled-coil-forming peptide into their membrane, or that the cells can be transfected with a plasmid containing a gene encoding a coiled-coil-forming peptide. Iron oxide particles are functionalized with the complementary peptide and, upon incubation with the cells, labeled cells are facilely separated from nonlabeled populations. In addition, the resulting cells and particles can be treated with trypsin to facilitate detachment of the cells from the particles. Therefore, our new MACS method promotes efficient cell sorting of different cell lines, without the need for antigen presentation, and enables simple detachment of the magnetic particles from cells after the sorting process. Such a system can be applied to rapidly developing, sensitive research areas, such as the separation of genetically modified cells from their unmodified counterparts.

5.
BMC Cancer ; 21(1): 217, 2021 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-33653301

RESUMO

BACKGROUND: Certain sequences of genomic mutations can lead to cancer formation and affect treatment outcomes and drug resistance. We constructed a cancer evolutionary tree using bulk-targeted deep sequencing to explore the impact of sequential and co-occurring somatic mutations on patients with stage III colorectal cancer (CRC). METHODS: A total of 108 stage III CRC patients from National Cheng Kung University Hospital (NCKUH) were recruited for this study between Jan. 2014 and Jan. 2019. Clinical information and tumor-targeted deep sequencing data were collected. Phylogenetic trees were reconstructed for evolutionary trajectories. We used a machine learning model for survival analysis. RESULTS: Six sequential somatic mutations stratified patients into seven subgroups based on survival. Patients carrying sequential germline followed by DNA damage response-related ATM or BRCA2 somatic mutations or non-TP53, APC somatic mutations had a better outcome than those without such mutations. The 4-year recurrence-free survival (RFS) probability was 88% in the low-risk group (G1) and 46% in the high-risk group (G2) (log-rank p-value 2e-05). The predictive efficacy by the area under the curve (AUC) was 0.73, 0.7, 0.797, and 0.88 at 2, 4, 6, and 8 years, respectively. The mutation status of mismatch repair (MMR) genes was not associated with RFS. Different genomic features were found between the groups. The orders of APC, KRAS and APC, BRCA2 sequential somatic mutations were associated with clinical outcomes. The occurrence of somatic mutations in BRCA2, such as TP53 somatic mutations, affected recurrence-free survival. CONCLUSIONS: According to the evolution model, DNA damage response (DDR)-related ATM or BRCA2 somatic mutations are promising biomarkers for assessing the response of stage III CRC patients to oxaliplatin-based chemotherapy. The sequential order and co-occurring DDR somatic mutations are associated with recurrence-free survival.

6.
Ultrasound Med Biol ; 47(5): 1261-1268, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33541751

RESUMO

We aimed to explore the value of contrast-enhanced ultrasound (CEUS) of the pleural cavity in locating catheters and identifying fibrous septa and to compare CEUS with multiple existing methods. We included 304 participants whose pleural effusion could not continue to be drained and compared the catheter-localization capabilities of empirical diagnosis, B-mode ultrasound with normal saline and CEUS, with computed tomography as the reference standard. CEUS performed the best (accuracy, 100%; sensitivity, 100%; specificity, 100%), followed by B-mode ultrasound with normal saline (accuracy, 77.78%; sensitivity, 62.5%; specificity, 100%), and finally empirical diagnosis (accuracy, 54.17%; sensitivity, 66.67%; specificity, 33.33%). The capabilities of CEUS and computed tomography to identify fibrous septa were evaluated, with B-mode ultrasound as the reference, and CEUS (accuracy, 100%; sensitivity, 100%; specificity, 100%) was superior to computed tomography (accuracy, 82.41%; sensitivity, 26.09%; specificity, 97.65%). Overall, CEUS can accurately locate catheters and identify fibrous septa, with performance superior to existing methods.

7.
Infection ; 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33543403

RESUMO

OBJECTIVE: The diagnosis of superficial tuberculous lymphadenitis (TBLN) remains difficult due to low detection rate of etiology. To increase the diagnostic value for TBLN, contrast-enhanced ultrasound (CEUS) guided core biopsy was introduced to obtain the specimen followed by Xpert MTB/RIF (Xpert) and other methods testing and to explore the optimum diagnostic pattern for TBLN in China. METHODS: A prospective study was performed on patients with suspected superficial TBLN. All patients underwent CEUS-guided core biopsy from which specimens were tested by histopathology, Xpert, acid-fast bacilli (AFB), and MGIT960 culture (MGIT960), respectively. The diagnostic values were calculated and compared. RESULTS: A total of 328 patients were included the study, 272 were diagnosed as TBLN (254 definite TB, 18 probable TB) and 56 cases with Non-TBLN, and 100% (272/272) of TBLN patients obtained diagnosis sampled by CEUS-guided core biopsy. The overall sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of comprehensive diagnosis on the specimens by CEUS-guided core biopsy for TBLN were 100% ( 272/272, 95% CI 98.26-100.00), 94.64% (53/56, 95% CI 84.20-98.61), 98.91% (272/275, 95% CI 96.58-99.72), and 100% (53/53, 95% CI 91.58-100%), respectively. Xpert obtained 93.31% (237/254) of etiology detection rate on the specimens sampling by CEUS-guided biopsy. The etiology detection rate was associated with histopathological caseous necrosis. CONCLUSIONS: Current examinations on specimens by CEUS-guided core biopsy can achieve a high diagnostic efficacy for TBLN. Pathological differentiation of CEUS-guided biopsy tissue, then followed by Xpert, may be the best pattern for the diagnosis of TBLN in high TB burden areas.

8.
Cancer Sci ; 2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33609307

RESUMO

Non-small-cell lung cancer (NSCLC), with an aggressive biological behavior, is one of the most diagnosed cancers. Tumor-associated inflammatory cells play important roles in the interaction between chronic inflammation and lung cancer. However, the mechanisms involved are far from defined. In the present study, by developing an orthotopic NSCLC mouse model on the basis of chronic inflammation, we proved that inflammatory microenvironment accelerated growth of orthotopic xenografts in vivo. Tumor associated macrophages (TAMs) the most abundant population of inflammatory cells were identified. Treatment of macrophage conditional medium (MCM) promoted growth and migration of NSCLC cells. By using bioinformatics analysis, we identified down-regulated PP2Ac expression in NSCLC cells upon treatment of MCM. We further confirmed that this down-regulation was executed through NF-κB pathway dependent manner. Since IKK has been proved to be a substrate of PP2Ac, inhibition on PP2Ac could result in an amplification of NF-κB pathway signaling. Overexpression of PP2Ac, or the dominant negative forms of IKK or IκB, attenuated the acceleration on growth and metastasis by MCM. By using bioinformatics analysis, we further identified CXCL1 and COL6A1 could be downstreams of NF-κB/PP2Ac pathway. Luciferase assay and ChIP assay further confirmed location of response elements on the promoter regions of CXCL1 and COL6A1. Elevated CXCL1 facilitated angiogenesis, while up-regulated COL6A1 promoted proliferation and migration.

9.
J Assist Reprod Genet ; 38(3): 587-594, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33471230

RESUMO

PURPOSE: To provide a comprehensive analysis of mtDNA quantity in D5 and D6 blastocysts, as well as a further insight to the origin of delayed blastocyst development. METHODS: A retrospective cohort analysis of 829 D5 and 472 D6 blastocysts from 460 patients who underwent in vitro fertilization (IVF) with next-generation sequencing (NGS)-based preimplantation genetic testing for aneuploidy (PGT-A). The quantity of trophectoderm mtDNA was extrapolated from the NGS data, followed by the analysis of mean mtDNA levels between D5 and D6 blastocysts of the same ploidy (aneuploid/euploid) and transfer outcomes (positive/negative clinical pregnancy). RESULTS: D5 blastocysts had significantly higher euploidy rate and clinical pregnancy rate when compared with D6 blastocysts. The proportion of blastocysts derived from patients ≧ 40 years old were similar between the D5 and D6 cohorts. When blastocysts with identical ploidy were analyzed, the D5 cohorts all had significantly higher mean mtDNA levels than their D6 counterparts. Similarly, when embryo transfers with identical outcome were analyzed, the D5 cohorts also had significantly higher mean mtDNA levels than the D6 cohorts. Trophectoderm mtDNA level was independent of maternal age and blastocyst morphology grades. CONCLUSIONS: Our data provided further evidence D5 blastocysts contained significantly greater mtDNA quantity than D6 blastocysts, and mtDNA quantity could be a key factor that affects the development rate of blastocysts. Furthermore, one must avoid using an arbitrary threshold when incorporating mtDNA quantity into the embryo selection criteria, as the observed value may have vastly different clinical implication when blastulation rate is also considered.

10.
Nat Commun ; 12(1): 51, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397955

RESUMO

Identifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin-Sca1+c-Kit+ CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Inibidores de Proteínas Quinases/farmacologia , Ubiquitina Tiolesterase/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteínas de Fusão bcr-abl , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Camundongos Knockout , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiofenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína 1 de Ligação a Y-Box/metabolismo , Proteínas ras/metabolismo
11.
Redox Biol ; 40: 101865, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33493903

RESUMO

Association of both iron/hepcidin and apolipoprotein E (ApoE) with development of Alzheimer disease (AD) and atherosclerosis led us to hypothesize that ApoE might be required for body iron homeostasis. Here, we demonstrated that ApoE knock-out (KO) induced a progressive accumulation of iron with age in the liver and spleen of mice. Subsequent investigations showed that the increased iron in the liver and spleen was due to phosphorylated extracellular regulated protein kinases (pERK) mediated up-regulation of transferrin receptor 1 (TfR1), and nuclear factor erythroid 2-related factor-2 (Nrf2)-dependent down-regulation of ferroportin 1. Furthermore, replenishment of ApoE could partially reverse the iron-related phenotype in ApoE KO mice. The findings imply that ApoE may be essential for body iron homeostasis and also suggest that clinical late-onset diseases with unexplained iron abnormality may partly be related to deficiency or reduced expression of ApoE.

12.
Hum Genomics ; 15(1): 3, 2021 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431054

RESUMO

BACKGROUND: Functional disruptions by large germline genomic structural variants in susceptible genes are known risks for cancer. We used deletion structural variants (DSVs) generated from germline whole-genome sequencing (WGS) and DSV immune-related association tumor microenvironment (TME) to predict cancer risk and prognosis. METHODS: We investigated the contribution of germline DSVs to cancer susceptibility and prognosis by silicon and causal inference models. DSVs in germline WGS data were generated from the blood samples of 192 cancer and 499 non-cancer subjects. Clinical information, including family cancer history (FCH), was obtained from the National Cheng Kung University Hospital and Taiwan Biobank. Ninety-nine colorectal cancer (CRC) patients had immune response gene expression data. We used joint calling tools and an attention-weighted model to build the cancer risk predictive model and identify DSVs in familial cancer. The survival support vector machine (survival-SVM) was used to select prognostic DSVs. RESULTS: We identified 671 DSVs that could predict cancer risk. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) of the attention-weighted model was 0.71. The 3 most frequent DSV genes observed in cancer patients were identified as ADCY9, AURKAPS1, and RAB3GAP2 (p < 0.05). The DSVs in SGSM2 and LHFPL3 were relevant to colorectal cancer. We found a higher incidence of FCH in cancer patients than in non-cancer subjects (p < 0.05). SMYD3 and NKD2DSV genes were associated with cancer patients with FCH (p < 0.05). We identified 65 immune-associated DSV markers for assessing cancer prognosis (p < 0.05). The functional protein of MUC4 DSV gene interacted with MAGE1 expression, according to the STRING database. The causal inference model showed that deleting the CEP72 DSV gene affect the recurrence-free survival (RFS) of IFIT1 expression. CONCLUSIONS: We established an explainable attention-weighted model for cancer risk prediction and used the survival-SVM for prognostic stratification by using germline DSVs and immune gene expression datasets. Comprehensive assessments of germline DSVs can predict the cancer risk and clinical outcome of colon cancer patients.

13.
Front Med (Lausanne) ; 7: 556818, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33304910

RESUMO

Background: Coronavirus disease (COVID-19) has swept around the globe and led to a worldwide catastrophe. Studies examining the disease progression of patients with non-severe disease on admission are scarce but of profound importance in the early identification of patients at a high risk of deterioration. Objectives: To elucidate the differences in clinical characteristics between patients with progressive and non-progressive COVID-19 and to determine the risk factors for disease progression. Study design: Clinical data of 365 patients with non-severe COVID-19 from 1 January 2020 to 18 March 2020 were retrospectively collected. Patients were stratified into progressive and non-progressive disease groups. Univariate and multivariate logistic regression analyses were performed to determine the independent risk factors for disease progression. Results: Compared with patients with non-progressive disease, those who progressed to severe COVID-19 were older and had significantly decreased lymphocyte and eosinophil counts; increased neutrophil and platelet counts; lower albumin levels; higher levels of lactate dehydrogenase, C-reactive protein (CRP), creatinine, creatinine kinase, and urea nitrogen; and longer prothrombin times. Hypertension, fever, fatigue, anorexia, bacterial coinfection, bilateral patchy shadowing, antibiotic and corticosteroid administration, and oxygen support had a significantly higher incidence among patients with progressive disease. A significantly longer duration of hospital stay was also observed in patients with progressive disease. Bilateral patchy shadowing (OR = 4.82, 95% CI: 1.33-17.50; P = 0.017) and elevated levels of creatinine (OR =6.24, 95% CI: 1.42-27.40; P = 0.015), and CRP (OR = 7.28, 95% CI: 2.56-20.74; P < 0.001) were independent predictors for disease progression. Conclusion: The clinical characteristics of patients with progressive and non-progressive COVID-19 were significantly different. Bilateral patchy shadowing and increased levels of creatinine, and CRP were independent predictors of disease progression.

14.
Brief Bioinform ; 2020 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-33190153

RESUMO

Several studies to date have proposed different types of interpreters for measuring the degree of pathogenicity of variants. However, in predicting the disease type and disease-gene associations, scholars face two essential challenges, namely the vast number of existing variants and the existence of variants which are recognized as variant of uncertain significance (VUS). To tackle these challenges, we propose algorithms to assign a significance to each gene rather than each variant, describing its degree of pathogenicity. Since the interpreters identified most of the variants as VUS, most of the gene scores were identified as uncertain significance. To predict the uncertain significance scores, we design two matrix factorization-based models: the common latent space model uses genomics variant data as well as heterogeneous clinical data, while the single-matrix factorization model can be used when heterogeneous clinical data are unavailable. We have managed to show that the models successfully predict the uncertain significance scores with low error and high accuracy. Moreover, to evaluate the effectiveness of our novel input features, we train five different multi-label classifiers including a feedforward neural network with the same feature set and show they all achieve high accuracy as the main impact of our approach comes from the features. Availability: The source code is freely available at https://github.com/sabdollahi/CoLaSpSMFM.

15.
Front Oncol ; 10: 588557, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33194745

RESUMO

Many studies failed to demonstrate benefit from the addition of targeted agents to current standard adjuvant FOLFOX chemotherapy in stage III colorectal cancer (CRC) patients. Intratumor heterogeneity may foster the resistant subclones and leads to cancer recurrence. Here, we built a cancer evolution model and applied machine learning analysis to identify potential therapeutic targets. Among 78 CRC cases, whole-genome (WGS) and deep targeted sequencing data generated from paired blood and primary tumor were used for phylogenetic tree reconstruction. Genetic alterations in the PI3K/AKT, and RTK oncogenic signaling pathways were commonly detected in founding clones. The dominant subclones frequently exhibited dysregulations in the TP53, FBXW7/NOTCH1 tumor suppression, and DNA repair pathways. Fourteen genetic mutations were simultaneously selected by random forest and LASSO methods. The logistic regression model had better accuracy (79%), precision (70%), and recall (65%) and area under the curve (AUC) (82%) for cancer recurrence prediction. Three genes, including MYO18A in the founding clone, FBXW7, and ATM in the dominant subclone, affected the prognosis were selected simultaneously by different feature sets. The in vitro studies, HCT-116 cells transfected with MYO18A siRNA demonstrated a significant reduction in cell migration activity by 20-40%. These results indicate that MYO18A plays a crucial role in the migration of human CRC cells. The cancer evolution model revealed the critical mutations in the founding and dominant subclones. They can be used to predict clinical outcomes and the development of novel therapeutic targets for stage III CRC.

16.
Ann Transl Med ; 8(20): 1305, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33209885

RESUMO

Background: Hepatocellular carcinoma (HCC) is the fourth most common malignant tumor in China. Temozolomide (TMZ) is a common chemotherapy drug which can effectively kill HCC cells in vitro. However, it is possible that HCC cells possess intrinsic resistance to TMZ. A key mechanism of TMZ resistance is the overexpression of O6-methylguanine-DNA methyltransferase (MGMT). Studies have shown that MAPK may be related to MGMT expression, U0126 is a highly selective inhibitor of MEK1 and MEK2, which were crucial molecule in cascade of mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) pathway. Sorafenib was another widely applicated target drug in HCC which could inhibit multiple kinases including MAPK/ERK. This research was aimed to investigate the efficacy of MAPK/ERK inhibitor U0126 and sorafenib combine with TMZ in the treatment of HCC. Methods: In HCC cells, MAPK/ERK signaling pathway was blocked by U0126 and sorafenib. The effect of blocking MAPK/ERK signaling pathway on TMZ-induced cytotoxicity was evaluated by MTT assay, flow cytometry and TUNEL assay. DNA damage protein and the expression of MGMT were detected by Western-blot. After the downregulation of MAPK/ERK signaling pathway, MGMT mRNA expression and the protein expression of MGMT were quantified by quantitative real-time polymerase chain reaction (RT-qPCR) and immunofluorescence assay, respectively. HepG2 cells were transfected with an MGMT over expression plasmid. After transfection, the effect of U0126 on TMZ-induced cytotoxicity was evaluated by MTT and Western-Blot in MGMT OE cells. The influence of Sorafenib on TMZ-induced cytotoxicity to HCC cells was also detected by MTT assay. Results: U0126 can enhance the chemosensitivity of HCC cells to TMZ. At the same time, we also found that U0126 increases the damage to DNA caused by TMZ in HepG2 cells. Moreover, the results from RT-qPCR and Western blot showed that U0126 downregulated MGMT mRNA and MGMT protein expression via blocking MAPK/ERK pathway. Furthermore, after transfection with an MGMT expression plasmid, overexpression of MGMT restored U0126-induced chemosensitivity to TMZ in HCC cells. Sorafenib can also increase the chemosensitivity of HCC cells to TMZ. Conclusions: Our studies suggest great clinical potential for the utilization of combined U0126 and TMZ in patients with advanced HCC.

17.
Sci Rep ; 10(1): 19695, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33184436

RESUMO

Bladder cancer is one of the most common cancers worldwide. The immune response and immune cell infiltration play crucial roles in tumour progression. Immunotherapy has delivered breakthrough achievements in the past decade in bladder cancer. Differentially expressed genes and immune-related genes (DEIRGs) were identified by using the edgeR package. Gene ontology annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for functional enrichment analysis of DEIRGs. Survival-associated IRGs were identified by univariate Cox regression analysis. A prognostic model was established by univariate COX regression analysis, and verified by a validation prognostic model based on the GEO database. Patients were divided into high-risk and low-risk groups based on the median risk score value for immune cell infiltration and clinicopathological analyses. A regulatory network of survival-associated IRGs and potential transcription factors was constructed to investigate the potential regulatory mechanisms of survival-associated IRGs. Nomogram and ROC curve to verify the accuracy of the model. Quantitative real-time PCR was performed to validate the expression of relevant key genes in the prognostic model. A total of 259 differentially expressed IRGs were identified in the present study. KEGG pathway analysis of IRGs showed that the "cytokine-cytokine receptor interaction" pathway was the most significantly enriched pathway. Thirteen survival-associated IRGs were selected to establish a prognostic index for bladder cancer. In both TCGA prognostic model and GEO validation model, patients with high riskscore had worse prognosis compared to low riskscore group. A high infiltration level of macrophages was observed in high-risk patients. OGN, ELN, ANXA6, ILK and TGFB3 were identified as hub survival-associated IRGs in the network. EBF1, WWTR1, GATA6, MYH11, and MEF2C were involved in the transcriptional regulation of these survival-associated hub IRGs. The present study identified several survival-associated IRGs of clinical significance and established a prognostic index for bladder cancer outcome evaluation for the first time.

18.
Dalton Trans ; 49(44): 15750-15757, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33146211

RESUMO

Developing highly efficient photocatalysts is of crucial importance to solve the energy crisis and global warming issues. In this work, a P-doped polymeric carbon nitride (CN) photocatalyst was synthesized by one-step copolymerization of guanidine hydrochloride and phosphonitrilic chloride trimer. The doping of P in CN was found to alter the electronic structure, enhance the charge separation and transfer, and promote the CO2 adsorption and activation, making it an efficient CO2 photoreduction catalyst. At the optimized P dose, the CO evolution amount on P-doped CN reached 0.349 µmol (30 mg, 3 h), which was 3.5 times that of pure CN. The process of CO2 photoreduction on P-doped CN was investigated by in situ FTIR analysis, revealing that P doping could promote the formation of a CO2- intermediate. A possible mechanism has been proposed, which may provide new insights into the effect of non-metal element doping in CN on its CO2 photocatalytic reduction performance.

19.
Sensors (Basel) ; 20(21)2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33138043

RESUMO

In this work, Ga2O3 films were deposited on sapphire substrates using a plasma-enhanced atomic layer deposition system with trimethylgallium precursor and oxygen (O2) plasma. To improve the quality of Ga2O3 films, they were annealed in an O2 ambient furnace system for 15 min at 700, 800, and 900 °C, respectively. The performance improvement was verified from the measurement results of X-ray diffraction, X-ray photoelectron spectroscopy, and photoluminescence spectroscopy. The optical bandgap energy of the Ga2O3 films decreased with an increase of annealing temperatures. Metal-semiconductor-metal ultraviolet C photodetectors (MSM UVC-PDs) with various Ga2O3 active layers were fabricated and studied in this work. The cut-off wavelength of the MSM UVC-PDs with the Ga2O3 active layers annealed at 800 °C was 250 nm. Compared with the performance of the MSM UVC-PDs with the as-grown Ga2O3 active layers, the MSM UVC-PDs with the 800 °C-annealed Ga2O3 active layers under a bias voltage of 5 V exhibited better performances including photoresponsivity of 22.19 A/W, UV/visible rejection ratio of 5.98 × 104, and detectivity of 8.74 × 1012 cmHz1/2W-1.

20.
J Med Internet Res ; 22(10): e19878, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33001832

RESUMO

BACKGROUND: As the COVID-19 epidemic increases in severity, the burden of quarantine stations outside emergency departments (EDs) at hospitals is increasing daily. To address the high screening workload at quarantine stations, all staff members with medical licenses are required to work shifts in these stations. Therefore, it is necessary to simplify the workflow and decision-making process for physicians and surgeons from all subspecialties. OBJECTIVE: The aim of this paper is to demonstrate how the National Cheng Kung University Hospital artificial intelligence (AI) trilogy of diversion to a smart quarantine station, AI-assisted image interpretation, and a built-in clinical decision-making algorithm improves medical care and reduces quarantine processing times. METHODS: This observational study on the emerging COVID-19 pandemic included 643 patients. An "AI trilogy" of diversion to a smart quarantine station, AI-assisted image interpretation, and a built-in clinical decision-making algorithm on a tablet computer was applied to shorten the quarantine survey process and reduce processing time during the COVID-19 pandemic. RESULTS: The use of the AI trilogy facilitated the processing of suspected cases of COVID-19 with or without symptoms; also, travel, occupation, contact, and clustering histories were obtained with the tablet computer device. A separate AI-mode function that could quickly recognize pulmonary infiltrates on chest x-rays was merged into the smart clinical assisting system (SCAS), and this model was subsequently trained with COVID-19 pneumonia cases from the GitHub open source data set. The detection rates for posteroanterior and anteroposterior chest x-rays were 55/59 (93%) and 5/11 (45%), respectively. The SCAS algorithm was continuously adjusted based on updates to the Taiwan Centers for Disease Control public safety guidelines for faster clinical decision making. Our ex vivo study demonstrated the efficiency of disinfecting the tablet computer surface by wiping it twice with 75% alcohol sanitizer. To further analyze the impact of the AI application in the quarantine station, we subdivided the station group into groups with or without AI. Compared with the conventional ED (n=281), the survey time at the quarantine station (n=1520) was significantly shortened; the median survey time at the ED was 153 minutes (95% CI 108.5-205.0), vs 35 minutes at the quarantine station (95% CI 24-56; P<.001). Furthermore, the use of the AI application in the quarantine station reduced the survey time in the quarantine station; the median survey time without AI was 101 minutes (95% CI 40-153), vs 34 minutes (95% CI 24-53) with AI in the quarantine station (P<.001). CONCLUSIONS: The AI trilogy improved our medical care workflow by shortening the quarantine survey process and reducing the processing time, which is especially important during an emerging infectious disease epidemic.


Assuntos
Inteligência Artificial , Betacoronavirus , Quarentena , Adulto , Infecções por Coronavirus , Feminino , Hospitais de Isolamento , Humanos , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral , Quarentena/métodos , Inquéritos e Questionários , Taiwan/epidemiologia
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