RESUMO
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and its prognosis remains poor. Although growing numbers of studies have verified the involvement of circular RNAs (circRNAs) in various cancer types, their specific functions in ICC remain elusive. Herein, a circRNA, circUGP2 is identified by circRNA sequencing, which is downregulated in ICC tissues and correlated with patients' prognosis. Moreover, circUGP2 overexpression suppresses tumor progression in vitro and in vivo. Mechanistically, circUGP2 functions as a transcriptional co-activator of PURB over the expression of ADGRB1. It can also upregulate ADGRB1 expression by sponging miR-3191-5p. As a result, ADGRB1 prevents MDM2-mediated p53 polyubiquitination and thereby activates p53 signaling to inhibit ICC progression. Based on these findings, circUGP2 plasmid is encapsulated into a lipid nanoparticle (LNP) system, which has successfully targeted tumor site and shows superior anti-tumor effects. In summary, the present study has identified the role of circUGP2 as a tumor suppressor in ICC through regulating ADGRB1/p53 axis, and the application of LNP provides a promising translational strategy for ICC treatment.
RESUMO
In 2022, the U.S. Food and Drug Administration approved a total of 16 marketing applications for small molecule drugs, which not only provided dominant scaffolds but also introduced novel mechanisms of action and clinical indications. The successful cases provide valuable information for optimizing efficacy and enhancing pharmacokinetic properties through strategies like macrocyclization, bioequivalent group utilization, prodrug synthesis, and conformation restriction. Therefore, gaining an in-depth understanding of the design principles and strategies underlying these drugs will greatly facilitate the development of new therapeutic agents. This review focuses on the research and development process of these newly approved small molecule drugs including drug design, structural modification, and improvement of pharmacokinetic properties to inspire future research in this field.
RESUMO
In 2023, the U.S. Food and Drug Administration has approved 55 novel medications, consisting of 17 biologics license applications and 38 new molecular entities. Although the biologics license applications including antibody and enzyme replacement therapy set a historical record, the new molecular entities comprising small molecule drugs, diagnostic agent, RNA interference therapy and biomacromolecular peptide still account for over 50 % of the newly approved medications. The novel and privileged scaffolds derived from drugs, active molecules and natural products are consistently associated with the discovery of new mechanisms, the expansion of clinical indications and the reduction of side effects. Moreover, the structural modifications based on the promising scaffolds can provide the clinical candidates with the improved biological activities, bypass the patent protection and greatly shorten the period of new drug discovery. Therefore, conducting an appraisal of drug approval experience and related information will expedite the identification of more potent drug molecules. In this review, we comprehensively summarized the pertinent information encompassing the clinical application, mechanism, elegant design and development processes of 28 small molecule drugs, and expected to provide the promising structural basis and design inspiration for pharmaceutical chemists.
Assuntos
Aprovação de Drogas , United States Food and Drug Administration , Humanos , Estados Unidos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Estrutura MolecularRESUMO
CAPZA2 encodes the α2 subunit of CAPZA, which is vital for actin polymerization and depolymerization in humans. However, understanding of diseases associated with CAPZA2 remains limited. To date, only three cases have been documented with neurodevelopmental abnormalities such as delayed motor development, speech delay, intellectual disability, hypotonia, and a history of seizures. In this study, we document a patient who exhibited seizures, mild intellectual disability, and impaired motor development yet did not demonstrate speech delay or hypotonia. The patient also suffered from recurrent instances of respiratory infections, gastrointestinal and allergic diseases. A novel de novo splicing variant c.219+1 G > A was detected in the CAPZA2 gene through whole-exome sequencing. This variant led to exon 4 skipping in mRNA splicing, confirmed by RT-PCR and Sanger sequencing. To our knowledge, this is the third study on human CAPZA2 defects, documenting the fourth unambiguously diagnosed case. Furthermore, this splicing mutation type is reported here for the first time. Our research offers additional support for the existence of a CAPZA2-related non-syndromic neurodevelopmental disorder. Our findings augment our understanding of the phenotypic range associated with CAPZA2 deficiency and enrich the knowledge of the mutational spectrum of the CAPZA2 gene.
Assuntos
Proteína de Capeamento de Actina CapZ , Deficiências do Desenvolvimento , Epilepsia , Heterozigoto , Hipotonia Muscular , Mutação , Pré-Escolar , Feminino , Humanos , Masculino , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Epilepsia/genética , Sequenciamento do Exoma , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Hipotonia Muscular/genética , Hipotonia Muscular/patologia , Fenótipo , Splicing de RNA/genética , Proteína de Capeamento de Actina CapZ/genéticaRESUMO
BACKGROUND & AIMS: Apolipoprotein A-1 (ApoA-1), the main apolipoprotein of high-density lipoprotein, has been well studied in the area of lipid metabolism and cardiovascular diseases. In this project, we clarify the function and mechanism of ApoA-1 in liver regeneration. METHODS: Seventy percent of partial hepatectomy was applied in male ApoA-1 knockout mice and wild-type mice to investigate the effects of ApoA-1 on liver regeneration. D-4F (ApoA-1 mimetic peptide), autophagy activator, and AMPK activator were used to explore the mechanism of ApoA-1 on liver regeneration. RESULTS: We demonstrated that ApoA-1 levels were highly expressed during the early stage of liver regeneration. ApoA-1 deficiency greatly impaired liver regeneration after hepatectomy. Meanwhile, we found that ApoA-1 deficiency inhibited autophagy during liver regeneration. The activation of autophagy protected against ApoA-1 deficiency in inhibiting liver regeneration. Furthermore, ApoA-1 deficiency impaired autophagy through AMPK-ULK1 pathway, and AMPK activation significantly improved liver regeneration. The administration of D-4F could accelerated liver regeneration after hepatectomy. CONCLUSIONS: These findings suggested that ApoA-1 played an essential role in liver regeneration through promoting autophagy in hepatocytes via AMPK-ULK1 pathway. Our findings enrich the understanding of the underlying mechanism of liver regeneration and provide a potential therapeutic strategy for liver injury.
Assuntos
Proteínas Quinases Ativadas por AMP , Apolipoproteína A-I , Animais , Masculino , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Apolipoproteína A-I/metabolismo , Apolipoproteína A-I/farmacologia , Autofagia , Fígado/metabolismo , Regeneração HepáticaRESUMO
OBJECTIVES: To study the intellectual level and the factors influencing the intelligence in children aged 6-16 years with attention deficit hyperactivity disorder (ADHD). METHODS: A retrospective study was conducted on 2 861 children who were diagnosed with ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition between October 2014 and September 2022 at Henan Children's Hospital. The Wechsler Intelligence Scale for Children-Fourth Edition was used to assess the intellectual levels of the ADHD children. Based on intelligence quotient (IQ) scores, the intellectual levels were classified into five categories: borderline (70-79), low average (80-89), average (90-109), high average (110-119), and superior (≥120). The intellectual levels among the children of different genders, grades, and parental education levels were compared. RESULTS: Among the 2 861 ADHD children, 569 (19.89%) were classified as borderline, 846 (29.57%) as low average, 1 304 (45.58%) as average, 111 (3.88%) as high average, and 31 (1.08%) as superior. The boys had lower scores in working memory, processing speed, and overall IQ than the girls (P<0.05). There were significant differences in perceptual reasoning, working memory, processing speed, and overall IQ scores among different grade groups (P<0.05). The scores in language comprehension, perceptual reasoning, working memory, processing speed, and overall IQ were found to be associated with parental education level in ADHD children (P<0.05). CONCLUSIONS: The proportion of ADHD children with low average and borderline intellectual levels is relatively high. The IQ level of ADHD children is influenced by gender, grade level and parental education level.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Humanos , Masculino , Criança , Feminino , Estudos Retrospectivos , Inteligência , Testes de Inteligência , CogniçãoRESUMO
Chronic inflammation, through a variety of mechanisms, plays a key role in the occurrence and development of digestive system malignant tumors (DSMTs). In this study, we feature and provide a comprehensive understanding of DSMT prevention strategies based on preventing or controlling chronic inflammation. The development and evaluation of cancer prevention strategies is a longstanding process. Cancer prevention, especially in the early stage of life, should be emphasized throughout the whole life course. Issues such as the time interval for colon cancer screening, the development of direct-acting antiviral drugs for liver cancer, and the Helicobacter pylori vaccine all need to be explored in long-term, large-scale experiments in the future.
RESUMO
BACKGROUND AND AIMS: Apolipoprotein A-1 (ApoA-1), the major apolipoprotein of high-density lipoprotein, plays anti-atherogenic role in cardiovascular diseases and exerts anti-inflammation effect in various inflammatory and infectious diseases. However, the role and mechanism of ApoA-1 in hepatic ischaemia-reperfusion (I/R) injury is unknown. METHODS: In this study, we measured ApoA-1 expression in human liver grafts after transplantation. Mice partial hepatic I/R injury model was made in ApoA-1 knockout mice, ApoA-1 mimetic peptide D-4F treatment mice and corresponding control mice to examine the effect of ApoA-1 on liver damage, inflammation response and cell death. Primary hepatocytes and macrophages were isolated for in vitro study. RESULTS: The results showed that ApoA-1 expression was down-regulated in human liver grafts after transplantation and mice livers subjected to hepatic I/R injury. ApoA-1 deficiency aggravated liver damage and inflammation response induced by hepatic I/R injury. Interestingly, we found that ApoA-1 deficiency increased pyroptosis instead of apoptosis during acute phase of hepatic I/R injury, which mainly occurred in macrophages rather than hepatocytes. The inhibition of pyroptosis compensated for the adverse impact of ApoA-1 deficiency. Furthermore, the up-regulated pyroptosis process was testified to be mediated by ApoA-1 through TLR4-NF-κB pathway and TLR4 inhibition significantly improved hepatic I/R injury. In addition, we confirmed that D-4F ameliorated hepatic I/R injury. CONCLUSIONS: Our study has identified the protective role of ApoA-1 in hepatic I/R injury through inhibiting pyroptosis in macrophages via TLR4-NF-κB pathway. The effect of ApoA-1 may provide a novel therapeutic approach for hepatic I/R injury.
Assuntos
Hepatopatias , Traumatismo por Reperfusão , Humanos , Camundongos , Animais , NF-kappa B/metabolismo , Apolipoproteína A-I/farmacologia , Apolipoproteína A-I/metabolismo , Apolipoproteína A-I/uso terapêutico , Piroptose , Receptor 4 Toll-Like , Transdução de Sinais , Fígado/metabolismo , Hepatopatias/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/metabolismo , Macrófagos/metabolismoRESUMO
The antiviral drug remdesivir has been used to treat the growing number of coronavirus disease 2019 (COVID-19) patients. However, the drug is mainly excreted through urine and feces and introduced into the environment to affect non-target organisms, including fish, which has raised concerns about potential ecotoxicological effects on aquatic organisms. Moreover, studies on the ecological impacts of remdesivir on aquatic environments have not been reported. Here, we aimed to explore the toxicological impacts of microinjection of remdesivir on zebrafish early embryonic development and larvae and the associated mechanism. We found that 100 µM remdesivir delayed epiboly and impaired convergent movement of embryos during gastrulation, and dose-dependent increases in mortality and malformation were observed in remdesivir-treated embryos. Moreover, 10-100 µM remdesivir decreased blood flow and swimming velocity and altered the behavior of larvae. In terms of molecular mechanisms, 80 differentially expressed genes (DEGs) were identified by transcriptome analysis in the remdesivir-treated group. Some of these DEGs, such as manf, kif3a, hnf1ba, rgn, prkcz, egr1, fosab, nr4a1, and ptgs2b, were mainly involved in early embryonic development, neuronal developmental disorders, vascular disease and the blood flow pathway. These data reveal that remdesivir can impair early embryonic development, blood flow and behavior of zebrafish embryos/larvae, probably due to alterations at the transcriptome level. This study suggests that it is important to avoid the discharge of remdesivir to aquatic ecosystems and provides a theoretical foundation to hinder remdesivir-induced ecotoxicity to aquatic environments.
Assuntos
Tratamento Farmacológico da COVID-19 , Poluentes Químicos da Água , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Animais , Ecossistema , Embrião não Mamífero , Fator 1-beta Nuclear de Hepatócito/metabolismo , Fator 1-beta Nuclear de Hepatócito/farmacologia , Larva , Poluentes Químicos da Água/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismoRESUMO
The purpose of the present study was to investigate whether catalpol exhibited neuroprotective effects in chronic unpredictable mild stress (CUMS) mice through oxidative stress-mediated nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin-domain-containing 3 (NLRP3) inflammasome and neuroinflammation. Deficits in behavioral tests, including open field test (OFT), forced swim test (FST), and elevated plus-maze test (EPM), were ameliorated following catalpol administration. To study the potential mechanism, western blots, quantitative real-time PCR (qRT-PCR) analysis and immunofluorescence imaging were performed on the hippocampus samples. We found that the defects of behavioral tests induced by CUMS could be reversed by the absence of NLRP3 and NLRP3 inflammasome might be involved in the antidepressant effects of catalpol on CUMS mice. Similar to the NLRP3 inflammasome, the expression of interleukin-1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), and inducible nitride oxide synthase (iNOS) were increased after CUMS. The current study demonstrated that catalpol possessed anti-inflammatory effect on CUMS mice and inhibited microglial polarization to the M1 phenotype. In addition, the activity of mitochondrial oxidative stress might be involved in the NLRP3 activation, which was proved by the downregulation of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and cleaved IL-1ß, after the administration of mitochondrion-targeted antioxidant peptide SS31. Taken together, we provided evidence that catalpol exhibited antidepressive effects on CUMS mice possibly via the oxidative stress-mediated regulation of NLRP3 and neuroinflammation.
Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Depressão/tratamento farmacológico , Glucosídeos Iridoides , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo , Estresse Psicológico/complicações , Estresse Psicológico/tratamento farmacológicoRESUMO
Currently, the controversy regarding the expression profile and function of BUB1B in different malignancies still exist. In this project, we aimed to explore the role and molecular mechanism of BUB1B in the progression of extrahepatic cholangiocarcinoma (ECC). The expression levels of BUB1B in human ECC were evaluated by immunohistochemistry, western blot, and real-time PCR. The role and mechanism of BUB1B in CCA cell proliferation and invasion were investigated in both in vitro and in vivo functional studies. To indicate the clinical significance, a tissue microarray was performed on 113 ECC patients, followed by univariate and multivariate analyses. The expression of BUB1B was increased in both human CCA tissues and CCA cells. Results from loss-of-function and gain-of-function experiments suggested that the inhibition of BUB1B decreased the proliferation and invasiveness of CCA cells in vitro and in vivo, while overexpression of BUB1B achieved the opposite effect. Furthermore, the activation of c-Jun N-terminal kinase-c-Jun (JNK)-c-Jun pathway was regulated by BUB1B. BUB1B regulated the proliferation and invasiveness of CAA cells in a JNK-c-Jun-dependent manner. Clinically, ECC patients with BUB1B high expression had worse overall survival and recurrence-free survival than those with BUB1B low expression. Multivariate analysis identified that BUB1B was an independent predictor for postoperative recurrence and overall survival of ECC patients. In conclusion, BUB1B promoted ECC progression via JNK/c-Jun pathways. These findings suggested that BUB1B could be a potential therapeutic target and a biomarker for predicting prognosis for ECC patients.
Assuntos
Neoplasias dos Ductos Biliares/genética , Proteínas de Ciclo Celular/metabolismo , Colangiocarcinoma/genética , Proteínas Serina-Treonina Quinases/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Sistema de Sinalização das MAP Quinases , PrognósticoRESUMO
Background: MicroRNAs (miRNAs) play important roles in the occurrence and development of cancers. In this project, we aimed to explore the role and molecular mechanism of mir-30a-5p in cholangiocarcinoma (CCA). Materials and Methods: The expression profile and clinical significance of miR-30a-5p in CCA patients were investigated in 31 ICC and 52 ECC patients respectively. The role and mechanism of miR-30a-5p in CCA cells were investigated by up-regulating and inhibiting miR-30a-5p expression in vitro functional study. Results: The expression of miR-30a-5p was increased in both CCA tissues and cells. The inhibition of miR-30a-5p decreased cell proliferation and induced cell apoptosis while overexpression of miR-30a-5p achieved the opposite effect. Furthermore, SOCS3 was down-regulated in ICC and ECC tissues and negatively regulated by miR-30a-5p. Dual-luciferase reporter assay revealed that co-transfection of miR-30a-5p significantly inhibited the activity of firefly luciferase reporter carrying the wild-type 3'UTR of SOCS3. The inhibition of SOCS3 could largely rescue the inhibitory effect of miR-30a-5p inhibition on CCA cells proliferation. In clinical, up-regulated miR-30a-5p expression was correlated with large tumor size in both ICC and ECC cohorts. Conclusions: miR-30a-5p promoted CCA cells proliferation through targeting SOCS3. These findings suggested that miR-30a-5p could be a potential therapeutic target.
RESUMO
OBJECTIVES: Our previous study showed that aldose reductase (AR) played key roles in fatty liver ischemia-reperfusion (IR) injury by regulating inflammatory response and energy metabolism. Here, we aim to investigate the role and mechanism of AR in the regeneration of normal and fatty livers after liver surgery. METHODS: The association of AR expression with liver regeneration was studied in the rat small-for-size liver transplantation model and the mice major hepatectomy and hepatic IR injury model with or without fatty change. The direct role and mechanism of AR in liver regeneration was explored in the AR knockout mouse model. RESULTS: Delayed regeneration was detected in fatty liver after liver surgery in both rat and mouse models. Furthermore, the expression of AR was increased in liver after liver surgery, especially in fatty liver. In a functional study, the knockout of AR promoted liver regeneration at day 2 after major hepatectomy and IR injury. Compared to wild-type groups, the expressions of cyclins were increased in normal and fatty livers of AR knockout mice. AR inhibition increased the expressions of PPAR-α and PPAR-γ in both normal liver and fatty liver groups after major hepatectomy and IR injury. In addition, the knockout of AR promoted the expressions of SDHB, AMPK, SIRT1, and PGC1-α and PPAR. CONCLUSIONS: The knockout of AR promoted the regeneration of normal and fatty livers through regulating energy metabolism. AR may be a new potential therapeutic target to accelerate liver regeneration after surgery.
Assuntos
Aldeído Redutase/antagonistas & inibidores , Metabolismo Energético , Inibidores Enzimáticos/farmacologia , Regeneração Hepática/fisiologia , Trifosfato de Adenosina/metabolismo , Aldeído Redutase/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Ciclinas/metabolismo , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Fígado Gorduroso/enzimologia , Fígado Gorduroso/patologia , Fígado Gorduroso/fisiopatologia , Hepatectomia , Fígado/patologia , Fígado/fisiopatologia , Fígado/cirurgia , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Biogênese de Organelas , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Regulação para Cima/efeitos dos fármacosRESUMO
OBJECTIVE: To study the relationship between serum microRNA-122 (miR-122) and insulin resistance in obese children. METHODS: Forty-seven children with severely obesity aged 7-14 years and 45 age- and gender matched healthy children with normal weight (control group) were enrolled. The levels of height, weight, waistline, hip circumference, fasting blood glucose (FBG), fasting insulin (FINS), triglyceride (TG), total cholesterol (TC), free fatty acid (FFA), interleukin-6 (IL-6) and miR-122 in the two groups were measured. Body mass index (BMI), waist-hip ratio (WHR) and insulin resistance index (HOMA-IR) were calculated. RESULTS: Compared with the control group, the height, weight, BMI, WHR, FINS, HOMA-IR, TG, FFA, IL-6, and miR-122 levels in the obese group were significantly increased (P<0.05). MiR-122 levels in the obese group were positively correlated with FINS, HOMA-IR and IL-6 levels (r=0.408, 0.442, and 0.464 respectively, P<0.05). The changes of miR-122 have a linear regression relationship with IL-6 (b'=0.318, P<0.05). CONCLUSIONS: The elevated serum miR-122 levels may be correlated with insulin resistance in obese children. The mechanism needs to be further studied.
Assuntos
Resistência à Insulina , MicroRNAs/genética , Adolescente , Glicemia , Índice de Massa Corporal , Criança , Humanos , Insulina , Obesidade , Relação Cintura-QuadrilRESUMO
OBJECTIVES: This study was conducted in order to establish and validate a radiomics model for predicting lymph node (LN) metastasis of intrahepatic cholangiocarcinoma (IHC) and to determine its prognostic value. METHODS: For this retrospective study, a radiomics model was developed in a primary cohort of 103 IHC patients who underwent curative-intent resection and lymphadenectomy. Radiomics features were extracted from arterial phase computed tomography (CT) scans. A radiomics signature was built based on highly reproducible features using the least absolute shrinkage and selection operator (LASSO) method. Multivariate logistic regression analysis was adopted to establish a radiomics model incorporating radiomics signature and other independent predictors. Model performance was determined by its discrimination, calibration, and clinical usefulness. The model was internally validated in 52 consecutive patients. RESULTS: The radiomics signature comprised eight LN-status-related features and showed significant association with LN metastasis in both cohorts (p < 0.001). A radiomics nomogram that incorporates radiomics signature and CA 19-9 level showed good calibration and discrimination in the primary cohort (AUC 0.8462) and validation cohort (AUC 0.8921). Promisingly, the radiomics nomogram yielded an AUC of 0.9224 in the CT-reported LN-negative subgroup. Decision curve analysis confirmed the clinical utility of this nomogram. High risk for metastasis portended significantly lower overall and recurrence-free survival than low risk for metastasis (both p < 0.001). The radiomics nomogram was an independent preoperative predictor of overall and recurrence-free survival. CONCLUSIONS: Our radiomics model provided a robust diagnostic tool for prediction of LN metastasis, especially in CT-reported LN-negative IHC patients, that may facilitate clinical decision-making. KEY POINTS: ⢠The radiomics nomogram showed good performance for prediction of LN metastasis in IHC patients, particularly in the CT-reported LN-negative subgroup. ⢠Prognosis of high-risk patients remains dismal after curative-intent resection. ⢠The radiomics model may facilitate clinical decision-making and define patient subsets benefiting most from surgery.
Assuntos
Neoplasias dos Ductos Biliares/diagnóstico , Ductos Biliares Intra-Hepáticos/diagnóstico por imagem , Colangiocarcinoma/secundário , Linfonodos/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Colangiocarcinoma/diagnóstico , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
Purpose To evaluate a radiomics model for predicting lymph node (LN) metastasis in biliary tract cancers (BTCs) and to determine its prognostic value for disease-specific and recurrence-free survival. Materials and Methods For this retrospective study, a radiomics model was developed on the basis of a primary cohort of 177 patients with BTC who underwent resection and LN dissection between June 2010 and December 2016. Radiomic features were extracted from portal venous CT scans. A radiomics signature was built on the basis of reproducible features by using the least absolute shrinkage and selection operator method. Multivariable logistic regression model was adopted to establish a radiomics nomogram. Nomogram performance was determined by its discrimination, calibration, and clinical usefulness. The model was internally validated in 70 consecutive patients with BTC between January 2017 and February 2018. Results The radiomics signature, composed of three LN-status-related features, was associated with LN metastasis in primary and validation cohorts (P < .001). The radiomics nomogram that incorporated radiomics signature and CT-reported LN status showed good calibration and discrimination in primary cohort (area under the curve, 0.81) and validation cohort (area under the curve, 0.80). Patients at high risk of LN metastasis portended lower disease-specific and recurrence-free survival than did those at low risk after surgery (both P < .001). High-risk LN metastasis was an independent preoperative predictor of disease-specific survival (hazard ratio, 3.37; P < .001) and recurrence-free survival (hazard ratio, 1.98; P = .003). Conclusion A radiomics model derived from portal phase CT of the liver has good performance for predicting lymph node metastasis in biliary tract cancer and may help to improve clinical decision making. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Laghi and Voena in this issue.
Assuntos
Neoplasias do Sistema Biliar , Metástase Linfática/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Neoplasias do Sistema Biliar/diagnóstico por imagem , Neoplasias do Sistema Biliar/epidemiologia , Neoplasias do Sistema Biliar/mortalidade , Neoplasias do Sistema Biliar/patologia , Intervalo Livre de Doença , Feminino , Humanos , Fígado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Curva ROC , Estudos RetrospectivosRESUMO
BACKGROUND: The diagnosis of postoperative cognitive dysfunction (POCD) requires complicated neuropsychological testing and is often delayed. Possible biomarkers for early detection or prediction are essential for the prevention and treatment of POCD. Preoperative screening of salivary cortisol levels may help to identify patients at elevated risk for POCD. METHODS: One hundred twenty patients >60 years of age and undergoing major noncardiac surgery underwent neuropsychological testing 1 day before and 1 week after surgery. Saliva samples were collected in the morning and the evening 1 day before surgery. POCD was defined as a Z-score of ≤-1.96 on at least 2 different tests. The primary outcome was the presence of POCD. The primary objective of this study was to assess the relationship between the ratio of AM (morning) to PM (evening) salivary cortisol levels and the presence of POCD. The secondary objective was to assess the relationship between POCD and salivary cortisol absolute values in the morning or in the evening. RESULTS: POCD was observed in 17.02% (16 of 94; 95% confidence interval [CI], 9.28%-24.76%) of patients 1 week after the operation. A higher preoperative AM/PM salivary cortisol ratio predicted early POCD onset (odds ratio [OR], 1.56; 95% CI, 1.20-2.02; P = .001), even after adjusting for the Mini-Mental Sate Examination score (odds ratio, 1.55; 95% CI, 1.19-2.02; P = .001). The area under the receiver operating characteristic curve for the salivary cortisol AM/PM ratio in individuals with POCD was 0.72 (95% CI, 0.56-0.88; P = .006). The optimal cutoff value was 5.69, with a sensitivity of 50% and specificity of 91%. CONCLUSIONS: The preoperative salivary cortisol AM/PM ratio was significantly associated with the presence of early POCD. This biomarker may have potential utility for screening patients for an increased risk and also for further elucidating the etiology of POCD.
Assuntos
Disfunção Cognitiva/metabolismo , Hidrocortisona/metabolismo , Complicações Pós-Operatórias/metabolismo , Cuidados Pré-Operatórios/tendências , Saliva/metabolismo , Idoso , Ritmo Circadiano/fisiologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/psicologia , Feminino , Humanos , Hidrocortisona/análise , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/psicologia , Valor Preditivo dos Testes , Cuidados Pré-Operatórios/métodos , Cuidados Pré-Operatórios/psicologia , Saliva/químicaRESUMO
BACKGROUND: This study aimed to compare clinical outcomes of the middle hepatic vein (MHV)-oriented versus conventional hemihepatectomy for perihilar cholangiocarcinoma (PHC). METHODS: From 2008 to 2017, medical records of patients undergoing hemihepatectomy with caudate lobectomy for advanced PHC were reviewed retrospectively. MHV-oriented hepatectomy was defined as full exposure of the MHV on the dissection plane. Predictors of morbidity and survival were identified. RESULTS: A total of 125 patients were enrolled. MHV-oriented and conventional hepatectomies were performed in 44 and 81 patients, respectively. The curative resection rate, blood loss, transfusion, and survival were comparable between two groups; however, severe morbidity rate was significantly lower in the MHV-oriented group (9.1% vs 38.3%, P < 0.001). MHV-oriented approach was an independent predictor of severe morbidity, as were the age, bilirubin level, and blood transfusion. Severe morbidity was associated with significantly decreased overall survival and recurrence-free survival (RFS) (median 29.0 vs 46.9 months, P = 0.011 and 20.3 vs 31.1 months, P = 0.003, respectively). Multivariate analysis revealed that severe morbidity independently predicted shorter RFS (P = 0.025). CONCLUSIONS: MHV-oriented approach for advanced PHC is safe and associated with a significant decrease in severe morbidity. Severe morbidity adversely affects survival after surgery; therefore, optimal preoperative preparation and MHV-oriented hepatectomy with meticulous dissection remain of critical importance.
Assuntos
Neoplasias dos Ductos Biliares/cirurgia , Hepatectomia/mortalidade , Veias Hepáticas/cirurgia , Tumor de Klatskin/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/patologia , Feminino , Seguimentos , Veias Hepáticas/patologia , Humanos , Tumor de Klatskin/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
To protect against oxidative stress-induced apoptosis in lens epithelial cells is a potential strategy in preventing cataract formation. The present study aimed at studying the protective effect and underlying mechanisms of p-coumaric acid (p-CA) on hydrogen peroxide- (H2O2-) induced apoptosis in human lens epithelial (HLE) cells (SRA 01-04). Cells were pretreated with p-CA at a concentration of 3, 10, and 30 µM before the treatment of H2O2 (275 µM). Results showed that pretreatment with p-CA significantly protected against H2O2-induced cell death in a dose-dependent manner, as well as downregulating the expressions of both cleaved caspase-3 and cleaved caspase-9 in HLE cells. Moreover, p-CA also greatly suppressed H2O2-induced intracellular ROS production and mitochondrial membrane potential loss and elevated the activities of T-SOD, CAT, and GSH-Px of H2O2-treated cells. As well, in vitro study showed that p-CA also suppressed H2O2-induced phosphorylation of p-38, ERK, and JNK in HLE cells. These findings demonstrate that p-CA suppresses H2O2-induced HLE cell apoptosis through modulating MAPK signaling pathways and suggest that p-CA has a potential therapeutic role in the prevention of cataract.
Assuntos
Apoptose/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Propionatos/farmacologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Catalase/metabolismo , Células Cultivadas , Ácidos Cumáricos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Cristalino/citologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Propionatos/química , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismoRESUMO
BACKGROUND: The authors previously reported that noncoding microRNA miR-219-5p is down-regulated in the spinal cord in a nociceptive state. The ventral tegmental area also plays critical roles in modulating nociception, although the underlying mechanism remains unknown. The authors hypothesized that miR-219-5p in the ventral tegmental area also may modulate nociception. METHODS: The authors studied the bidirectional regulatory role of ventral tegmental area miR-219-5p in a rat complete Freund's adjuvant model of inflammatory nociception by measuring paw withdrawal latencies. Using molecular biology technologies, the authors measured the effects of astroglial coiled-coil and C2 domain containing 1A/nuclear factor κB cascade and dopamine neuron activity on the down-regulation of ventral tegmental area miR-219-5p-induced nociceptive responses. RESULTS: MiR-219-5p expression in the ventral tegmental area was reduced in rats with thermal hyperalgesia. Viral overexpression of ventral tegmental area miR-219-5p attenuated complete Freund's adjuvant-induced nociception from 7 days after complete Freund's adjuvant injection (paw withdrawal latencies: 6.09 ± 0.83 s vs. 3.96 ± 0.76 s; n = 6/group). Down-regulation of ventral tegmental area miR-219-5p in naïve rats was sufficient to induce thermal hyperalgesia from 7 days after lentivirus injection (paw withdrawal latencies: 7.09 ± 1.54 s vs. 11.75 ± 2.15 s; n = 8/group), which was accompanied by increased glial fibrillary acidic protein (fold change: 2.81 ± 0.38; n = 3/group) and reversed by intraventral tegmental area injection of the astroglial inhibitor fluorocitrate. The nociceptive responses induced by astroglial miR-219-5p down-regulation were inhibited by interfering with astroglial coiled-coil and C2 domain containing 1A/nuclear factor-κB signaling. Finally, pharmacologic inhibition of ventral tegmental area dopamine neurons alleviated this hyperalgesia. CONCLUSIONS: Down-regulation of astroglial miR-219-5p in ventral tegmental area induced nociceptive responses are mediated by astroglial coiled-coil and C2 domain containing 1A/nuclear factor-κB signaling and elevated dopamine neuron activity.