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OBJECTIVE: Traditional knowledge-based and machine learning diagnostic decision support systems have benefited from integrating the medical domain knowledge encoded in the Unified Medical Language System (UMLS). The emergence of Large Language Models (LLMs) to supplant traditional systems poses questions of the quality and extent of the medical knowledge in the models' internal knowledge representations and the need for external knowledge sources. The objective of this study is three-fold: to probe the diagnosis-related medical knowledge of popular LLMs, to examine the benefit of providing the UMLS knowledge to LLMs (grounding the diagnosis predictions), and to evaluate the correlations between human judgments and the UMLS-based metrics for generations by LLMs. METHODS: We evaluated diagnoses generated by LLMs from consumer health questions and daily care notes in the electronic health records using the ConsumerQA and Problem Summarization datasets. Probing LLMs for the UMLS knowledge was performed by prompting the LLM to complete the diagnosis-related UMLS knowledge paths. Grounding the predictions was examined in an approach that integrated the UMLS graph paths and clinical notes in prompting the LLMs. The results were compared to prompting without the UMLS paths. The final experiments examined the alignment of different evaluation metrics, UMLS-based and non-UMLS, with human expert evaluation. RESULTS: In probing the UMLS knowledge, GPT-3.5 significantly outperformed Llama2 and a simple baseline yielding an F1 score of 10.9% in completing one-hop UMLS paths for a given concept. Grounding diagnosis predictions with the UMLS paths improved the results for both models on both tasks, with the highest improvement (4%) in SapBERT score. There was a weak correlation between the widely used evaluation metrics (ROUGE and SapBERT) and human judgments. CONCLUSION: We found that while popular LLMs contain some medical knowledge in their internal representations, augmentation with the UMLS knowledge provides performance gains around diagnosis generation. The UMLS needs to be tailored for the task to improve the LLMs predictions. Finding evaluation metrics that are aligned with human judgments better than the traditional ROUGE and BERT-based scores remains an open research question.
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The role of serum uric acid as a factor in the recurrence of ischemic stroke stays unclear. Several studies have examined the relationship between serum uric acid and recurrence of acute ischemic stroke, with various results. Therefore, we carried out a meta-analysis to have a look at the relationship between serum uric acid levels and the potential danger of stroke recurrence in patients with ischemic stroke. Relevant experiments have been recognized via looking out the electronic databases and conference sessions. This present study included a case-control study of the impact of uric acid on the recurrence of ischemic stroke. After the assessment of eligibility, this meta-analysis included four articles in which 2452 patients with ischemic stroke were tested for their level of serum uric acid. The results obtained from this meta-analysis confirmed that improved uric acid concentrations were extensively and independently related to an accelerated and higher risk of recurrent stroke. The pooled OR (95% CI) was 1.80 (1.47, 2.20) (p<0.001). Overall, this meta-analysis shows a relationship between uric acid concentration and stroke recurrence rate. Furthermore, high uric acid levels could enhance the recurrence rate of ischemic stroke.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Ácido Úrico , Estudios de Casos y Controles , Factores de RiesgoRESUMEN
Daily progress notes are a common note type in the electronic health record (EHR) where healthcare providers document the patient's daily progress and treatment plans. The EHR is designed to document all the care provided to patients, but it also enables note bloat with extraneous information that distracts from the diagnoses and treatment plans. Applications of natural language processing (NLP) in the EHR is a growing field with the majority of methods in information extraction. Few tasks use NLP methods for downstream diagnostic decision support. We introduced the 2022 National NLP Clinical Challenge (N2C2) Track 3: Progress Note Understanding - Assessment and Plan Reasoning as one step towards a new suite of tasks. The Assessment and Plan Reasoning task focuses on the most critical components of progress notes, Assessment and Plan subsections where health problems and diagnoses are contained. The goal of the task was to develop and evaluate NLP systems that automatically predict causal relations between the overall status of the patient contained in the Assessment section and its relation to each component of the Plan section which contains the diagnoses and treatment plans. The goal of the task was to identify and prioritize diagnoses as the first steps in diagnostic decision support to find the most relevant information in long documents like daily progress notes. We present the results of the 2022 N2C2 Track 3 and provide a description of the data, evaluation, participation and system performance.
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Registros Electrónicos de Salud , Almacenamiento y Recuperación de la Información , Humanos , Procesamiento de Lenguaje Natural , Personal de SaludRESUMEN
The meaningful use of electronic health records (EHR) continues to progress in the digital era with clinical decision support systems augmented by artificial intelligence. A priority in improving provider experience is to overcome information overload and reduce the cognitive burden so fewer medical errors and cognitive biases are introduced during patient care. One major type of medical error is diagnostic error due to systematic or predictable errors in judgement that rely on heuristics. The potential for clinical natural language processing (cNLP) to model diagnostic reasoning in humans with forward reasoning from data to diagnosis and potentially reduce cognitive burden and medical error has not been investigated. Existing tasks to advance the science in cNLP have largely focused on information extraction and named entity recognition through classification tasks. We introduce a novel suite of tasks coined as Diagnostic Reasoning Benchmarks, Dr.Bench, as a new benchmark for developing and evaluating cNLP models with clinical diagnostic reasoning ability. The suite includes six tasks from ten publicly available datasets addressing clinical text understanding, medical knowledge reasoning, and diagnosis generation. DR.BENCH is the first clinical suite of tasks designed to be a natural language generation framework to evaluate pre-trained language models for diagnostic reasoning. The goal of DR. BENCH is to advance the science in cNLP to support downstream applications in computerized diagnostic decision support and improve the efficiency and accuracy of healthcare providers during patient care. We fine-tune and evaluate the state-of-the-art generative models on DR.BENCH. Experiments show that with domain adaptation pre-training on medical knowledge, the model demonstrated opportunities for improvement when evaluated in DR. BENCH. We share DR. BENCH as a publicly available GitLab repository with a systematic approach to load and evaluate models for the cNLP community. We also discuss the carbon footprint produced during the experiments and encourage future work on DR.BENCH to report the carbon footprint.
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Inteligencia Artificial , Procesamiento de Lenguaje Natural , Humanos , Benchmarking , Solución de Problemas , Almacenamiento y Recuperación de la InformaciónRESUMEN
BACKGROUND: Titanium dioxide (TiO2), no matter in nanoscale or micron sizes, has been widely used in food industry as additives for decades. Given the potential impact of TiO2 on the gastrointestinal epithelial and parenchymal cells, including goblet cells, the public consumers may suffer the risk of diseases caused by its widespread dissemination in food products. We therefore set out to investigate the impact of TiO2 NPs on the course and prognosis of ulcerative colitis by oral gavaging TiO2 NPs at the doses levels of 0, 30, 100, and 300 mg/kg during the induction (7 days, from day 1 to day 7) and recovery (10 days, from day 8 to day 17) phases of colitis in mice. RESULTS: The ulcerative colitis (UC) disease model was established by administrating of 2.5% dextran sulfate sodium (DSS) solution. Our results show that TiO2 NPs significantly enhanced the severity of DSS-induced colitis, decreased the body weight, increased the disease activity index (DAI) and colonic mucosa damage index (CMDI) scores, shortened the colonic length, increased the inflammatory infiltration in the colon. The most significant changes occurred in the low dose (30 mg/kg) group of TiO2 NPs exposure during the development phase of UC and the high dose (300 mg/kg) group of TiO2 NPs during UC self-healing phase. Increased reactive oxygen species (ROS) level and upregulation of anti-oxidant enzymes including total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-PX) and catalase (CAT), demonstrate that the TiO2 NP exposure has triggered oxidative stress in mice. Moreover, the upregulation of caspase-1 mRNA and increased expression of thioredoxin interacting protein (TXNIP) further demonstrate the involvement of the ROS-TXNIP-NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway in aggravating the development of UC. CONCLUSION: Oral intake of TiO2 NPs could affect the course of acute colitis in exacerbating the development of UC, prolonging the UC course and inhibiting UC recovery.
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Colitis Ulcerosa , Colitis , Nanopartículas , Ratones , Animales , Colitis Ulcerosa/inducido químicamente , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Colitis/inducido químicamente , Colitis/metabolismo , Nanopartículas/toxicidad , Pronóstico , Ratones Endogámicos C57BL , Modelos Animales de EnfermedadRESUMEN
Printers can release numerous particles to contaminate indoor environments and pose health risks. Clarifying the exposure level and physicochemical properties of printer-emitted particles (PEPs) will help to evaluate the health risks of printer operator. In our study, the particles concentration in the printing shop was monitored in real time for a long time (12 h/day, total 6 days), and the PEPs were collected to characterize their physicochemical properties including shape, size and compositions. The result showed that the concentration of PEPs is closely related to the printing workload and the highest particle mass concentration of PM10 and PM2.5 was 212.73 µg m-3 and 91.48 µg m-3, respectively. The concentration of PM1 in the printing shop was in the range of 11.88-80.59 µg m-3 for mass value, and 174.83-1348.84 P cm-3 for count value which changed with the printing volume. The particle sizes of PEPs were less than 900 nm, 47.99% of PEPs was less than 200 nm, and 14.21% of the particles were at the nanoscale. PEPs contained 68.92% organic carbon (OC), 5.31% elemental carbon (EC), 3.17% metal elements, and 22.60% other inorganic additives, which contained more OC and metal elements than toners. Total polycyclic aromatic hydrocarbons (PAHs) levels were 18.95 ng/mg in toner and 120.70 ng/mg in PEPs. The carcinogenic risk of PAHs in PEPs was 1.40 × 10-7. These findings suggested future studies should pay more attention to the health effects of printing workers exposed to nanoparticles.
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Contaminantes Atmosféricos , Exposición Profesional , Humanos , Tamaño de la Partícula , Impresión , China , Impresión Tridimensional , Material Particulado/análisis , Contaminantes Atmosféricos/análisis , Monitoreo del AmbienteRESUMEN
Aldehyde dehydrogenase 6 family member A1 (ALDH6A1) is a highly conserved member of aldehyde dehydrogenase (ALDHs) family. Recent studies reveal that it broadly involved in tumorigenesis and drug metabolism in kinds of cancer. However, the critical role of ALDH6A1 in bladder cancer progression and cisplatin resistance of cancer cells are still poorly understood. In this study, we researched the significant function of ALDH6A1 in bladder cancer. Our results showed that ALDH6A1 exhibited a decreased expression in clinical bladder cancer tissues and bladder cancer cell lines. Stable ALDH6A1 knockdown not only could promote cell growth and colony formation in bladder cancer cells, but also enhance drug resistance to cisplatin treatment. On the contrary, we found the active transcript factor hepatocyte nuclear factor 4α (HNF4α, NR2A1) by alveriene could upregulate ALDH6A1 expression, significantly inhibit the cell growth and colony formation of bladder cancer cells, and improve cisplatin sensitivity of bladder cancer cells. Together, our results show that ALDH6A1 plays as a tumor suppressor in bladder cancer, which regulated by HNF4a. ALDH6A1 could be a promising diagnostic marker and treatment target in bladder cancer.
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Aldehído Oxidorreductasas/metabolismo , Antineoplásicos , Neoplasias de la Vejiga Urinaria , Aldehído Deshidrogenasa/genética , Familia de Aldehído Deshidrogenasa 1 , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Cisplatino/farmacología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/genética , Familia , Humanos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismoRESUMEN
Environmental pollution, especially particulate matter in the air, is a serious threat to human health. Long-term inhalation of particulate matter with a diameter < 2.5 µm (PM2.5) induced irreversible respiratory and lung injury. However, it is not clear whether temporary exposure to massive PM2.5 would result in epithelial damage and lung injury. More importantly, it is urgent to clarify the mechanisms of PM2.5 cytotoxicity and develop a defensive and therapeutic approach. In this study, we demonstrated that temporary exposure with PM2.5 induced lung epithelial cell apoptosis via promoting cytokines expression and inflammatory factors secretion. The cytotoxicity of PM2.5 could be alleviated by tussilagone (TSL), which is a natural compound isolated from the flower buds of Tussilago farfara. The mechanism study indicated that PM2.5 promoted the protein level of Hif-1α by reducing its degradation mediated by PHD2 binding, which furtherly activated NF-κB signaling and inflammatory response. Meanwhile, TSL administration facilitated the interaction of the Hif-1α/PHD2 complex and restored the Hif-1α protein level increased by PM2.5. When PHD2 was inhibited in epithelial cells, the protective function of TSL on PM2.5 cytotoxicity was attenuated and the expression of cytokines was retrieved. Expectedly, the in vivo study also suggested that temporary PM2.5 exposure led to acute lung injury. TSL treatment could effectively relieve the damage and decrease the expression of inflammatory cytokines by repressing Hif-1α level and NF-κB activation. Our findings provide a new therapeutic strategy for air pollution-related respiratory diseases, and TSL would be a potential preventive medicine for PM2.5 cytotoxicity.
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Lesión Pulmonar Aguda , Lesión Pulmonar , Sesquiterpenos , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/prevención & control , Humanos , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/prevención & control , FN-kappa B/metabolismo , Material Particulado/toxicidadRESUMEN
BACKGROUND: Previous work indicated that benzo[a]pyrene (B(a)P) exposure in utero might adversely affect neurodevelopment and cause Parkinson's Disease (PD)-like symptoms. However, the effect of utero exposure to B(a)P on PD-like α-synucleinopathy and the mechanism under are unclear. OBJECTIVE: The A53T human alpha-synuclein (α-syn) transgenic mice (M83+/-) were used in this study to gain insights into the role of B(a)P exposure in utero in the onset of α-syn pathology and neuronal damage. METHOD: Timed-pregnant M83+/- dams were exposed to 1) corn oil (vehicle) or 2) 5 mg/kg bw/d B(a)P or 3) 20 mg/kg bw/d B(a)P at gestational day 10-17 by oral gavage and then the SNCA transcription, α-syn accumulation and aggregation, neuroinflammation and nigral dopaminergic neurodegeneration of 60-day-old pups were evaluated. RESULT: SNCA mRNA and α-syn protein expression in the midbrain of 60 days adult mice were found to be remarkably elevated after B(a)P exposure in utero, the protein degradation capacity was injured (in 20 mg/kg dose group) and α-syn aggregation could be observed in the substantia nigra (SN); Enhanced Iba1 expression in the midbrain and microglial activation (in 20 mg/kg dose group) in the SN were also figured out; Besides, dopaminergic neurons in the SN of 60 days adult mice were significantly decreased. CONCLUSIONS: Our findings demonstrated that B(a)P exposure in utero could exacerbate α-syn pathology and induce activation of microglia which might further lead to dopaminergic neuronal loss in the SN.
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Benzo(a)pireno/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/genética , Sinucleinopatías/inducido químicamente , Sinucleinopatías/genética , alfa-Sinucleína/genética , Animales , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/genética , Enfermedad de Parkinson Secundaria/patología , Embarazo , Efectos Tardíos de la Exposición Prenatal/patología , Sinucleinopatías/patologíaRESUMEN
BACKGROUND: Keloid is troublesome for patients' skin appearance and mental health, although it is a benign tumor. Long noncoding RNA (lncRNA) troubling keloid is frequently reported. The purpose of this study was to investigate the role of lncRNA homeobox (HOX) A11 antisense (HOXA11-AS) and related action mechanisms during the development of keloid. METHODS: The expression of HOXA11-AS, miR-205-5p, and forkhead box M1 (FOXM1) was measured by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation or apoptosis was assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium (MTT) assay or flow cytometry assay. Cell migration and invasion were monitored by transwell assay. The protein levels of extracellular matrix (ECM) proteins (collagen I and collagen III), fibronectin, glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and FOXM1 were quantified by Western blot. Glycolysis processes were investigated by the glycolysis stress test, glucose consumption, and lactate production. The relationship between miR-205-5p and HOXA11-AS or FOXM1 was predicted by the online tool MIRcode or starBase v2.0 and verified by dual-luciferase reporter assay or RNA immunoprecipitation (RIP). RESULTS: HOXA11-AS and FOXM1 were significantly upregulated in keloid tissues and keloid fibroblasts, while miR-205-5p was downregulated. HOXA11-AS knockdown or miR-205-5p enrichment inhibited proliferation, migration, invasion, ECM accumulation, and glycolysis but accelerated apoptosis of keloid fibroblasts. MiR-205-5p was targeted by HOXA11-AS, and its inhibition overturned the effects of HOXA11-AS knockdown. Moreover, FOXM1 was a target of miR-205-5p, and HOXA11-AS regulated the expression of FOXM1 by adsorbing miR-205-5p. FOXM1 overexpression abolished the role of miR-205-5p enrichment. CONCLUSIONS: The HOXA11-AS-miR-205-5p-FOXM1 pathway may be an active mode in which HOXA11-AS participates in the progression of keloid.
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Proteína Forkhead Box M1/fisiología , Queloide/etiología , MicroARNs/fisiología , ARN Largo no Codificante/fisiología , Adulto , Progresión de la Enfermedad , Femenino , Regulación de la Expresión Génica , Humanos , Queloide/genética , Masculino , Persona de Mediana Edad , Transducción de Señal/fisiología , Adulto JovenRESUMEN
BACKGROUND: Coronavirus disease 2019 (COVID-19) has caused a global pandemic that has raised worldwide concern. This study aims to investigate the correlation between the extent of lung infection and relevant clinical laboratory testing indicators in COVID-19 and to analyse its underlying mechanism. METHODS: Chest high-resolution computer tomography (CT) images and laboratory examination data of 31 patients with COVID-19 were extracted, and the lesion areas in CT images were quantitatively segmented and calculated using a deep learning (DL) system. A cross-sectional study method was carried out to explore the differences among the proportions of lung lobe infection and to correlate the percentage of infection (POI) of the whole lung in all patients with clinical laboratory examination values. RESULTS: No significant difference in the proportion of infection was noted among various lung lobes (P > 0.05). The POI of total lung was negatively correlated with the peripheral blood lymphocyte percentage (L%) (r = - 0.633, P < 0.001) and lymphocyte (LY) count (r = - 0.555, P = 0.001) but positively correlated with the neutrophil percentage (N%) (r = 0.565, P = 0.001). Otherwise, the POI was not significantly correlated with the peripheral blood white blood cell (WBC) count, monocyte percentage (M%) or haemoglobin (HGB) content. In some patients, as the infection progressed, the L% and LY count decreased progressively accompanied by a continuous increase in the N%. CONCLUSIONS: Lung lesions in COVID-19 patients are significantly correlated with the peripheral blood lymphocyte and neutrophil levels, both of which could serve as prognostic indicators that provide warning implications, and contribute to clinical interventions in patients.
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COVID-19/diagnóstico por imagen , Pulmón/patología , Aprendizaje Automático , Adulto , Prueba de COVID-19 , Técnicas de Laboratorio Clínico , Estudios Transversales , Femenino , Humanos , Pulmón/diagnóstico por imagen , Pulmón/virología , Recuento de Linfocitos , Linfocitos/citología , Masculino , Persona de Mediana Edad , Neutrófilos/citología , Pandemias , Pronóstico , Índice de Severidad de la Enfermedad , Tomografía Computarizada por Rayos XRESUMEN
RN181, a RING finger domain-containing protein, is an E3 ubiquitin ligase. However, its biological function and clinical significance in cancer biology are obscure. Here, we report that RN181 expression is significantly down-regulated in 165 tumour tissues of gastric carcinoma (GC) versus adjacent non-tumour tissues, and inversely associated with tumour differentiation, tumour size, clinical stage, and patient's overall survival. Alterations of RN181 expression in GC cells by retrovirus-transduced up-regulation and down-regulation demonstrated that RN181 functions as a tumour suppressor to inhibit growth of GC in both in vitro culture and in vivo animal models by decreasing tumour cell proliferation and increasing tumour cell apoptosis. Cell cycle analysis revealed that RN181 controls the cell cycle transition from G1 to S phase. Mechanistic studies demonstrated that RN181 inhibits ERK/MAPK signalling, thereby regulating the activity of cyclin D1-CDK4, and consequently controlling progression in the cell cycle from G1 to S phase. Restoring CDK4 in GC cells rescued the inhibitory phenotype produced by RN181 in vitro and in vivo, suggesting a dominant role of CDK4 in control of the tumour growth by RN181. Importantly, RN181 expression is inversely correlated with the expression of cyclin D1 and CDK4 in GC clinical samples, substantiating the role of the RN181-cyclin D1/CDK4 pathway in control of the tumour growth of GC. Our results provide new insights into the pathogenesis and development of GC and rationale for developing novel intervention strategies against GC by disruption of ERK/MAPK-cyclin D1/CDK4 signalling. In addition, RN181 may serve as a novel biomarker for predicting clinical outcome of GC. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Apoptosis , Proliferación Celular , Ciclina D1/metabolismo , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Neoplasias Gástricas/enzimología , Proteínas Supresoras de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Línea Celular Tumoral , Ciclina D1/genética , Quinasa 4 Dependiente de la Ciclina/genética , Quinasas MAP Reguladas por Señal Extracelular/genética , Femenino , Puntos de Control de la Fase G1 del Ciclo Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Transducción de Señal , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Carga Tumoral , Proteínas Supresoras de Tumor/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Chemotherapy is still a standard treatment of unresectable bladder cancer or distant metastases. The chemotherapy resistance always occurs after a period of treatment indicating poor prognosis. The current study aimed to explore the molecular mechanism of chemoresistance in bladder cancer cells. The gene expression profiles of GSE77883, including three untreated T24 cells samples and three gemcitabine-resistant T24 cells samples, was downloaded from Gene Expression Omnibus database. The screening of differentially expressed genes (DEGs), gene function analysis, and interaction prediction between microRNAs (miRNAs) and DEGs were performed by R software. The protein-protein interaction (PPI) and miRNA-DEGs networks were constructed and visualized by Cytoscape software. Then, the small molecules, with potential synergistic or antagonistic effects to gemcitabine resistance, were identified using the Connectivity Map database. Finally, gemcitabine-resistant T24 cell line was established and key genes were validated by quantitative real-time polymerase chain reaction (qRT-PCR). In total, 536 upregulated and 513 downregulated genes were screened and mainly enriched in oxidative stress response and signaling pathways related to extracellular matrix-receptor interaction and focal adhesion. PPI network showed interleukin 6, tumor necrosis factor, kinesin family member 11, and BUB1 mitotic checkpoint serine/threonine kinase B were key genes. The miRNA-DEGs regulatory networks included 18 miRNAs and 185 DEGs, including miR-182-5p, miR-590-3p, miR-320a and serum- and glucocorticoid-regulated kinase 1 (SGK1). Then, the related key genes and miRNAs were confirmed by qRT-PCR. Furthermore, 81 small molecules with antagonistic or synergistic effect to GEM were screened. We have investigated the molecular mechanisms driving GEM-resistance in bladder cancer cells that would contribute to the development of chemotherapy for advanced bladder cancer.
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Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos , Redes Reguladoras de Genes , MicroARNs/genética , Neoplasias de la Vejiga Urinaria/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Bases de Datos Genéticas , Desoxicitidina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes/efectos de los fármacos , Humanos , Mapas de Interacción de Proteínas/efectos de los fármacos , ARN Mensajero/genética , Bibliotecas de Moléculas Pequeñas/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , GemcitabinaRESUMEN
BACKGROUND: Sorafenib is the only approved first line systemic therapy for advanced hepatocellular carcinoma (HCC) in the last decade. Tumour resistance to sorafenib has been of major obstacles to improve HCC patient survival. METHODS: We polarised THP-1 cells to M1 and M2 macrophages, performed various in vitro assays and developed sorafenib-resistant xenograft models to investigate the role of tumour-associated macrophages (TAM)-secreted molecules in HCC resistance to the targeted therapy. RESULTS: We demonstrated M2, but not M1, macrophages not only promote proliferation, colony formation and migration of hepatoma cells but also significantly confer tumour resistance to sorafenib via sustaining tumour growth and metastasis by secreting hepatocyte growth factor (HGF). HGF activates HGF/c-Met, ERK1/2/MAPK and PI3K/AKT pathways in tumour cells. Tumour-associated M2 macrophages were accumulated in sorafenib-resistance tumours more than in sorafenib-sensitive tumours in vivo and produced abundant HGF. HGF chemoattracts more macrophages migrated from surrounding area, regulates the distribution of M2 macrophages and increases hepatoma resistance to sorafenib in a feed-forward manner. CONCLUSIONS: Our results provide new insights into the mechanisms of sorafenib resistance in HCC and rationale for developing new trials by combining sorafenib with a potent HGF inhibitor such as cabozantinib to improve the first line systemic therapeutic efficacy.
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Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Factor de Crecimiento de Hepatocito/fisiología , Neoplasias Hepáticas/tratamiento farmacológico , Macrófagos/fisiología , Sorafenib/uso terapéutico , Línea Celular Tumoral , Resistencia a Antineoplásicos , Quinasas MAP Reguladas por Señal Extracelular/fisiología , Factor de Crecimiento de Hepatocito/antagonistas & inhibidores , Humanos , Fosfatidilinositol 3-Quinasas/fisiología , Proteínas Proto-Oncogénicas c-akt/fisiologíaRESUMEN
BACKGROUND: The role of long non-coding RNA (lncRNA) Minichromosome Maintenance Complex Component 3 Associated Protein (MCM3AP) Antisense RNA 1 (MCM3AP-AS1) has been analyzed in liver cancer. But its role in osteoarthritis (OA) is unknown. Through bioinformatics analysis, we predicted that MCM3AP-AS1 may interact with miR-142-3p, which is a major player in OA. This study aimed to investigate the roles of MCM3AP-AS1 in OA and to explore its interactions with microRNA miR-142-3p. METHODS: Differential expressions of MCM3AP-AS1 in OA patients and healthy participants were analyzed by performing quantitative PCR (qPCR). To analyze the relationship between MCM3AP-AS1 and miR-142-3p, human chondrocytes were transfected with MCM3AP-AS1 over-expression vector and miR-142-3p mimic. MCM3AP-AS1, miR-142-3p and high mobility group protein B1 (HMGB1) mRNA expression levels were measured by qPCR. RESULTS: We found that MCM3AP-AS1 was up-regulated in OA. Bioinformatics analysis showed that MCM3AP-AS1 may interact with miR-142-3p, which can inhibit the apoptosis of chondrocytes. In addition, over-expression of MCM3AP-AS1 and miR-142-3p failed to affect the expression of each other. Instead, MCM3AP-AS1 over-expression led to up-regulated expressions of HMGB1, which is a target of miR-142-3p. Lipopolysaccharide (LPS) treatment led to the up-regulated expressions of MCM3AP-AS1 in chondrocytes. In cell apoptosis assay, MCM3AP-AS1 and HMGB1 over-expression led to increased apoptotic rate of chondrocytes. MiR-142-3p over-expression played an opposite role and attenuated the effects of MCM3AP-AS1 over-expression. CONCLUSIONS: MCM3AP-AS1 may regulate miR-142-3p/HMGB1 to promote LPS-induced chondrocyte apoptosis.
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Acetiltransferasas/genética , Condrocitos/fisiología , Proteína HMGB1/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , MicroARNs/metabolismo , Osteoartritis/metabolismo , Anciano , Apoptosis , Estudios de Casos y Controles , Femenino , Humanos , Lipopolisacáridos , Masculino , Persona de Mediana EdadRESUMEN
Automatic joint detection is of vital importance for the teaching of robots before welding and the seam tracking during welding. For narrow butt joints, the traditional structured light method may be ineffective, and many existing detection methods designed for narrow butt joints can only detect their 2D position. However, for butt joints with narrow gaps and 3D trajectories, their 3D position and orientation of the workpiece surface are required. In this paper, a vision based detection method for narrow butt joints is proposed. A crosshair laser is projected onto the workpiece surface and an auxiliary light source is used to illuminate the workpiece surface continuously. Then, images with an appropriate grayscale distribution are grabbed with the auto exposure function of the camera. The 3D position of the joint and the normal vector of the workpiece surface are calculated by the combination of the 2D and 3D information in the images. In addition, the detection method is applied in a robotic seam tracking system for GTAW (gas tungsten arc welding). Different filtering methods are used to smooth the detection results, and compared with the moving average method, the Kalman filter can reduce the dithering of the robot and improve the tracking accuracy significantly.
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OBJECTIVE: This study was aimed to explore whether the omentin-1, a novel adipokine marker, could be a biomarker for stroke, as well as its association with stroke severity. METHODS: This study included 239 patients with ischemic stroke. The serum omentin-1 level was determined and the stroke was evaluated when the patients were hospitalized. The control groups consisted of 108 patients with matched age, gender and prior vascular risk factors and 120 health control with matched age and gender. The stroke severity was assessed with National Institutes of Health Stroke Scale (NIHSS) when the patients were hospitalized, and NIHSS scoreâ¯>â¯6 was evaluated as moderate-to-severe stroke. RESULTS: Omentin-1 level in serum samples of 239 stroke patients was determined, with the median value of 109.5â¯ng/ml [Inter Quartile Range (IQR), 78.4-142.9â¯ng/ml]. There was a negative relation between omentin-1 level and the infarct volume (râ¯=â¯-0.289, Pâ¯=â¯0.001). The level of omentin-1 was significantly reduced in stroke patients than that of in control group 1 [125.3 (IQR, 95.8-158.7); Pâ¯=â¯0.002] and control group 2 [146.5 (IQR, 116.2-177.3); Pâ¯<â¯0.001]. With the analysis of multivariate model, omentin-1 as a continuous variable was related to lowered stroke risk (odds ratios [OR] 0.994, 95% confidence interval (CI): 0.990-0.998; Pâ¯=â¯0.006). In addition, omentin-1 was an independent indicator for stroke severity (OR 0.992, 95% CI: 0.989-0.996). Levels of omentin-1 in the Q1 showed a relative risk of 2.66 (95% CI: 1.52-4.18) for moderate-to-severe stroke after adjusting for above possible confounders compared to reference category [Quartile (Q): 2-4]. CONCLUSION: The data indicated a negative relation between omentin-1 level and risk of ischemic stroke. The omentin-1 could be promising indicator of stroke and its severity.
Asunto(s)
Isquemia Encefálica/sangre , Citocinas/sangre , Lectinas/sangre , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/diagnóstico , Anciano , Biomarcadores/sangre , Isquemia Encefálica/diagnóstico , Diagnóstico Precoz , Femenino , Proteínas Ligadas a GPI/sangre , Humanos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
[This corrects the article DOI: 10.1186/s12935-017-0471-1.].
RESUMEN
Sauchinone is one of the active lignan isolated from Saururus chinensis, which has been considered to possess various pharmacological activities, such as antitumor, hepatoprotective, antioxidant, and anti-inflammatory effects. However, the functional roles of sauchinone in interleukin-1 beta (IL-1ß)-stimulated human osteoarthritis (OA) chondrocytes are still unknown. Thus, in this study, we investigated the anti-inflammatory effects of sauchinone in IL-1ß-stimulated chondrocytes. Our results demonstrated that sauchinone significantly attenuated NO and PGE2 production, as well as inhibited iNOS and COX-2 expression in IL-1ß-stimulated OA chondrocytes. In addition, sauchinone efficiently inhibited IL-1ß-induced MMP-3 and MMP-13 release in human OA chondrocytes. Furthermore, sauchinone significantly attenuated the activation of NF-κB in human OA chondrocytes. In conclusion, we showed for the first time that sauchinone inhibited inflammatory response in IL-1ß-stimulated human chondrocytes probably through inhibiting the activation of NF-κB signaling pathway. These data suggest that sauchinone may be a potential agent in the treatment of OA.