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Multidrug-resistant (MDR) bacteria are important public health problems. Antibiotic susceptibility testing (AST) currently uses time-consuming culture-based procedures, which cause treatment delays and increased mortality. We developed a machine learning model using Acinetobacter baumannii as an example to explore a fast AST approach using metagenomic next-generation sequencing (mNGS) data. The key genetic characteristics associated with antimicrobial resistance (AMR) were selected through a least absolute shrinkage and selection operator (LASSO) regression model based on 1,942 A. baumannii genomes. The mNGS-AST prediction model was accordingly established, validated, and optimized using read simulation sequences of clinical isolates. Clinical specimens were collected to evaluate the performance of the model retrospectively and prospectively. We identified 20, 31, 24, and 3 AMR signatures of A. baumannii for imipenem, ceftazidime, cefepime, and ciprofloxacin, respectively. Four mNGS-AST models had a positive predictive value (PPV) greater than 0.97 for 230 retrospective samples, with negative predictive values (NPVs) of 100% (imipenem), 86.67% (ceftazidime), 86.67% (cefepime), and 90.91% (ciprofloxacin). Our method classified antibacterial phenotypes with an accuracy of 97.65% for imipenem, 96.57% for ceftazidime, 97.64% for cefepime, and 98.36% for ciprofloxacin. The average reporting time of mNGS-based AST was 19.1 h, in contrast to the 63.3 h for culture-based AST, thus yielding a significant reduction of 44.3 h. mNGS-AST prediction results coincided 100% with the phenotypic AST results when testing 50 prospective samples. The mNGS-based model could be used as a rapid genotypic AST approach to identify A. baumannii and predict resistance and susceptibility to antibacterials and could be applicable to other pathogens and facilitate rational antimicrobial usage.
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Acinetobacter baumannii , Anti-Infecciosos , Estudos Retrospectivos , Cefepima , Ceftazidima , Estudos Prospectivos , Antibacterianos/farmacologia , Imipenem , Ciprofloxacina , Farmacorresistência Bacteriana Múltipla/genética , Sequenciamento de Nucleotídeos em Larga Escala , Testes de Sensibilidade MicrobianaRESUMO
BACKGROUND: Application of mesenchymal stem cell-derived exosomes (MSC-EXO) has emerged as a novel therapeutic strategy for myocardial infarction (MI). Our previous study showed that pretreatment with hemin, a potent heme oxygenase-1 (HO-1) inducer, enhanced the cardioprotective effects of MSCs in a mouse model of MI. This study aimed to investigate the therapeutic effects of EXO derived from hemin-pretreated MSCs (Hemin-MSC-EXO) in MI and explore the potential mechanisms. METHODS: MSC-EXO and Hemin-MSC-EXO were collected and characterized. MSC-EXO and Hemin-MSC-EXO were intramuscularly injected into the peri-infarct region in a mouse model of MI. Heart function of mice was assessed by echocardiography. The mitochondrial morphology of neonatal mice cardiomyocytes (NMCMs) under serum deprivation and hypoxic (SD/H) conditions was examined by Mitotracker staining. The cellular senescence of NMCMs was determined by senescence-associated-ß-galactosidase assay. A loss-of-function approach was adopted to determine the role of Hemin-MSC-exosomal-miR-183-5p in the regulation of cardiomyocyte senescence RESULTS: EXO were successfully isolated from the supernatant of MSCs and Hemin-pretreated MSCs. Compared with MSC-EXO, injection of Hemin-MSC-EXO significantly improved cardiac function and reduced fibrosis. Both MSC-EXO and Hemin-MSC-EXO ameliorated cardiomyocyte senescence and mitochondrial fission in vitro and in vivo, and the latter exhibited better protective effects. MicroRNA sequencing revealed a higher level of miR-183-5p in Hemin-MSC-EXO than in MSC-EXO. MiR-183-5p knockdown partially abrogated the protective effects of Hemin-MSC-EXO in attenuating mitochondrial fission and cellular senescence of cardiomyocytes induced by SD/H. High mobility group box-1 (HMGB1) abundance was lower in Hemin-MSC-EXO-treated than MSC-EXO-treated mouse hearts, and HMGB1 was identified as one of the potential target genes of miR-183-5p. Mechanistically, Hemin-MSC-EXO inhibited SD/H-induced cardiomyocyte senescence partially by delivering miR-183-5p into recipient cardiomyocytes via regulation of the HMGB1/ERK pathway. Furthermore, knockdown of miR-183-5p reduced the Hemin-MSC-EXO-mediated cardioprotective effects in a mouse model of MI. CONCLUSION: Our results reveal that Hemin-MSC-EXO are superior to MSC-EXO in treating MI. Exosomal miR-183-5p mediates, at least partially, the cardioprotective effects of Hemin-MSC-EXO by inhibiting cardiomyocyte senescence via regulation of the HMGB1/ERK pathway. This study highlights that MSC-EXO have high translational value in repairing cardiac dysfunction following infarction.
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Cardiotônicos , Exossomos , Hemina/farmacologia , Células-Tronco Mesenquimais/química , Infarto do Miocárdio/metabolismo , Animais , Cardiotônicos/química , Cardiotônicos/farmacologia , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismoRESUMO
Single layer MoS2 is an ideal material for the emerging field of "valleytronics" in which charge carrier momentum can be finely controlled by optical excitation. This system is also known to exhibit strong many-body interactions as observed by tightly bound excitons and trions. Here we report direct measurements of valley relaxation dynamics in single layer MoS2, by using ultrafast transient absorption spectroscopy. Our results show that strong Coulomb interactions significantly impact valley population dynamics. Initial excitation by circularly polarized light creates electron-hole pairs within the K-valley. These excitons coherently couple to dark intervalley excitonic states, which facilitate fast electron valley depolarization. Hole valley relaxation is delayed up to about 10 ps due to nondegeneracy of the valence band spin states. Intervalley biexciton formation reveals the hole valley relaxation dynamics. We observe that biexcitons form with more than an order of magnitude larger binding energy compared to conventional semiconductors. These measurements provide significant insight into valley specific processes in 2D semiconductors. Hence they could be used to suggest routes to design semiconducting materials that enable control of valley polarization.
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OBJECTIVES: To examine the feasibility of three-dimensional computed tomography (3D-CT) image fusion in facilitating assessment of the ablative margin (AM) after radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). METHODS: This study involved 75 patients with solitary HCC who underwent RFA. The AM was evaluated using 3D-CT image fusion. All cases were categorized into two groups based on the extent of the AM: in Group A, sufficient AM was obtained, which was greater than or equal to 5 mm; in Group B, the lesion was also ablated successfully, but a 5 mm AM was not obtained. RESULTS: 3D-CT Image Fusion was performed on 36 and 39 patients in Group A and Group B, respectively. The 1, 3, 5 year RFS was 87.6%, 63.2%, 50.6% for Group A, and 77.2%, 51.5%, 35.6% for Group B, respectively (P = 0.042); the corresponding OS was 94.3%, 73.8%, 64.6%, and 86.2%, 60.5%, 47.6%, respectively (P = 0.046). Multivariate analysis showed that the AM (P = 0.048, HR = 2.15, 95% CI 1.01-4.60) and Pre-NLR were independent prognostic factors for PFS. CONCLUSIONS: 3D-CT image fusion is a feasible and useful method to evaluate the AM after RFA of HCC.
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Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/cirurgia , Ablação por Cateter , Imageamento Tridimensional/métodos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/cirurgia , Tomografia Computadorizada Multidetectores/métodos , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Adulto , Idoso , Carcinoma Hepatocelular/mortalidade , Ablação por Cateter/efeitos adversos , Ablação por Cateter/mortalidade , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasia Residual , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
PURPOSE: To investigate the association between cholelithiasis and risk of pancreatic cancer (PaC). METHODS: We identified eligible studies in MEDLINE and EMBASE up to August 1, 2013 and the reference lists of original studies and review articles on this topic. Summary relative risks (SRRs) with their 95 % confidence intervals (CIs) were calculated with a random-effects model. RESULTS: Twenty-one studies (15 case-control studies, 6 cohort studies) met eligibility criteria. The current data suggest that cholelithiasis is associated with a 25 % excess risk of PaC (SRRs = 1.25, 95 % CI 1.10-1.41; test for heterogeneity p = 0.006, I (2) = 47.6 %). In subgroup analysis of timing of exposure, seven of eight studies in patients whose diagnosis of cholelithiasis made more than specified year (5, 3, 2, or 1 year) prior to cancer diagnosis showed no association for PaC, while all three studies in patients diagnosed less than specified year before cancer diagnosis showed a positive association. There was no publication bias in the present meta-analysis. CONCLUSION: This meta-analysis supports the hypothesis that a history of cholelithiasis may significantly increase PaC risk, particularly in Asian countries. However, the positive association disappeared over time, suggesting that cholelithiasis may be the early symptoms of PaC.
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Colelitíase/complicações , Neoplasias Pancreáticas/epidemiologia , Ásia/epidemiologia , Estudos de Casos e Controles , Estudos de Coortes , Humanos , Neoplasias Pancreáticas/etiologia , Medição de Risco , Fatores de RiscoRESUMO
Although mitochondrial aldehyde dehydrogenase 2 (ALDH2) is involved in aging and aging-related diseases, its role in the regulation of human mesenchymal stem cell (MSC) senescence has not been investigated. This study aimed to determine the role of ALDH2 in regulating MSC senescence and illustrate the potential mechanisms. MSCs were isolated from young (YMSCs) and aged donors (AMSCs). Senescence-associated ß-galactosidase (SA-ß-gal) staining and Western blotting were used to assess MSC senescence. Reactive oxygen species (ROS) generation and mitochondrial membrane potential were determined to evaluate mitochondrial function. We showed that the expression of ALDH2 increased alongside cellular senescence of MSCs. Overexpression of ALDH2 accelerated YMSC senescence whereas down-regulation alleviated premature senescent phenotypes of AMSCs. Transcriptome and biochemical analyses revealed that an elevated ROS level and mitochondrial dysfunction contributed to ALDH2 function in MSC senescence. Using molecular docking, we identified interferon regulatory factor 7 (IRF7) as the potential target of ALDH2. Mechanistically, ectopic expression of ALDH2 led to mitochondrial dysfunction and accelerated senescence of MSCs by increasing the stability of IRF7 through a direct physical interaction. These effects were partially reversed by knockdown of IRF7. These findings highlight a crucial role of ALDH2 in driving MSC senescence by regulating mitochondrial homeostasis, providing a novel potential strategy against human aging-related diseases.
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Aortic aneurysm and dissection (AAD) is a cardiovascular disease that poses a severe threat to life and has high morbidity and mortality rates. Clinical and animal-based studies have irrefutably shown that fluoroquinolones, a commonly prescribed antibiotic for treating infections, significantly increase the risk of AAD. Despite this, the precise mechanism by which fluoroquinolones cause AAD remains unclear. Therefore, this study aims to investigate the molecular mechanism and role of Ciprofloxacin definitively-a type of fluoroquinolone antibiotic-in the progression of AAD. Aortic transcriptome data were collected from GEO datasets to detect the genes and pathways expressed differently between healthy donors and AAD patients. Human primary Vascular Smooth Muscle Cells (VSMCs) were isolated from the aorta. After 72 h of exposure to 110ug/ml Ciprofloxacin or 100 nmol/L AngII, either or combined, the senescent cells were identified through SA-ß-gal staining. MitoTracker staining was used to examine the morphology of mitochondria in each group. Cellular Reactive Oxygen Species (ROS) levels were measured using MitoSox and DCFH-DA staining. Western blot assay was performed to detect the protein expression level. We conducted an analysis of transcriptome data from both healthy donors and patients with AAD and found that there were significant changes in cellular senescence-related signaling pathways in the latter group. We then isolated and identified human primary VSMCs from healthy donors (control-VSMCs) and patients' (AAD-VSMCs) aortic tissue, respectively. We found that VSMCs from patients exhibited senescent phenotype as compared to control-VSMCs. The higher levels of p21 and p16 and elevated SA-ß-gal activity demonstrated this. We also found that pretreatment with Ciprofloxacin promoted angiotensin-II-induced cellular senescence in control-VSMCs. This was evidenced by increased SA-ß-gal activity, decreased cell proliferation, and elevation of p21 and p16 protein levels. Additionally, we found that Angiotensin-II (AngII) induced VSMC senescence by promoting ROS generation. We used DCFH-DA and mitoSOX staining to identify that Ciprofloxacin and AngII pretreatment further elevated ROS levels than the vehicle or alone group. Furthermore, JC-1 staining showed that mitochondrial membrane potential significantly declined in the Ciprofloxacin and AngII combination group compared to others. Compared to the other three groups, pretreatment of Ciprofloxacin plus AngII could further induce mitochondrial fission, demonstrated by mitoTracker staining and western blotting assay. Mechanistically, we found that Ciprofloxacin impaired the balance of mitochondrial fission and fusion dynamics in VSMCs by suppressing the phosphorylation of AMPK signaling. This caused mitochondrial dysfunction and ROS generation, thereby elevating AngII-induced cellular senescence. However, treatment with the AMPK activator partially alleviated those effects. Our data indicate that Ciprofloxacin may accelerate AngII-induced VSMC senescence through modulating AMPK/ROS signaling and, subsequently, hasten the progression of AAD.
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Aortic aneurysm/dissection (AAD) poses a life-threatening cardiovascular emergency with complex mechanisms and a notably high mortality rate. Zebrafish (Danio rerio) serve as valuable models for AAD due to the conservation of their three-layered arterial structure and genome with that of humans. However, the existing studies have predominantly focused on larval zebrafish, leaving a gap in our understanding of adult zebrafish. In this study, we utilized ß-Aminopropionic Nitrile (BAPN) impregnation to induce AAD in both larval and adult zebrafish. Following induction, larval zebrafish exhibited a 28% widening of the dorsal aortic diameter (p < 0.0004, n = 10) and aortic arch malformations, with a high malformation rate of 75% (6/8). Conversely, adult zebrafish showed a 41.67% (5/12) mortality rate 22 days post-induction. At this time point, the dorsal aortic area had expanded by 2.46 times (p < 0.009), and the vessel wall demonstrated significant thickening (8.22 ± 2.23 µM vs. 26.38 ± 10.74 µM, p < 0.05). Pathological analysis revealed disruptions in the smooth muscle layer, contributing to a 58.33% aneurysm rate. Moreover, the expression levels of acta2, tagln, cnn1a, and cnn1b were decreased, indicating a weakened contractile phenotype. Transcriptome sequencing showed a significant overlap between the molecular features of zebrafish tissues post-BAPN treatment and those of AAD patients. Our findings present a straightforward and practical method for generating AAD models in both larval and adult zebrafish using BAPN.
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Abdominal Aortic Aneurysm (AAA) is a life-threatening vascular disease characterized by the weakening and ballooning of the abdominal aorta, which has no effective therapeutic approaches due to unclear molecular mechanisms. Using single-cell RNA sequencing, we analyzed the molecular profile of individual cells within control and AAA abdominal aortas. We found cellular heterogeneity, with increased plasmacytoid dendritic cells and reduced endothelial cells and vascular smooth muscle cells (VSMCs) in AAA. Up-regulated genes in AAA were associated with muscle tissue development and apoptosis. Genes controlling VSMCs aberrant switch from contractile to synthetic phenotype were significantly enriched in AAA. Additionally, VSMCs in AAA exhibited cell senescence and impaired oxidative phosphorylation. Similar observations were made in a mouse model of AAA induced by Angiotensin II, further affirming the relevance of our findings to human AAA. The concurrence of gene expression changes between human and mouse highlighted the impairment of oxidative phosphorylation as a potential target for intervention. Nicotinamide phosphoribosyltransferase (NAMPT, also named VISFATIN) signaling emerged as a signature event in AAA. NAMPT was significantly downregulated in AAA. NAMPT-extracellular vesicles (EVs) derived from mesenchymal stem cells restored NAMPT levels, and offered protection against AAA. Furthermore, NAMPT-EVs not only repressed injuries, such as cell senescence and DNA damage, but also rescued impairments of oxidative phosphorylation in both mouse and human AAA models, suggesting NAMPT supplementation as a potential therapeutic approach for AAA treatment. These findings shed light on the cellular heterogeneity and injuries in AAA, and offered promising therapeutic intervention for AAA treatment.
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Background: Complicated appendicitis, a potentially life-threatening condition, is common. However, the diagnosis of this condition is mainly based on physician's experiences and advanced diagnostic equipment. This study built and validated machine learning models to facilitate the detection of complicated appendicitis. Methods: A retrospective cohort study was conducted based on medical charts of all patients undergoing a laparoscopic appendectomy at a city hospital during 2016-2020. The synthetic minority over-sampling technique (SMOTE) was used to adjust for the imbalance. Multiple classification approaches were used to train and validate models including support vector machine (SVM), decision tree (DT), K-nearest neighbor (KNN), logistic regression (LR), artificial neural network (ANN), and gradient boosting (GB). Results: Among 1,950 patients included in the data analysis, there were 483 patients identified as having complicated appendicitis (24.8%). Based on data without SMOTE adjustment for imbalance, the accuracy levels and AUCs were high in all models using different parameters, ranging from 0.687 to 0.815. After adjusting for imbalance data using SMOTE, AUC and accuracy levels in the models using imbalance adjusted data were higher. Of these, the GB had all AUC and accuracy values of approximately 0.8 or more in both adjusted and unadjusted data. Conclusions: Machine learning approaches including SVM, DT, logistic, KNN, ANN, and GB have a high level of validity in classifying patients with complicated appendicitis and patients without complicated appendicitis. Among these, GB had the highest level of validity and should be used or further validated. Our study indicates the beneficial potentials of machine learning techniques in a clinical setting in general and in the diagnosis of complicated appendicitis in particular.
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Apendicite , Humanos , Apendicite/diagnóstico , Apendicite/cirurgia , Vietnã , Estudos Retrospectivos , Aprendizado de Máquina , Redes Neurais de Computação , Máquina de Vetores de SuporteRESUMO
The cellular senescence of mesenchymal stem cells (MSCs) limits their application in regenerative medicine. This study aimed to clarify the role of TNF receptor-associated factor 3 interacting protein 2 (TRAF3IP2), a pro-inflammatory cytoplasmic adaptor protein, in regulating MSC senescence and to explore the potential mechanisms. Methods: MSC senescence was determined by senescence-associated ß-galactosidase (SA-ß-gal) staining. The expression of TRAF3IP2 and senescence-related proteins was detected by Western blotting. The nicotinamide adenine dinucleotide (NAD+) level and nicotinamide phosphoribosyl transferase (NAMPT) expression in MSCs was measured. Results: Compared with that in MSCs isolated from young donors (YMSCs), the expression of TRAF3IP2 was greatly increased in MSCs derived from aged donors (AMSCs). Overexpression of TRAF3IP2 accelerated YMSC senescence whereas downregulation significantly rescued cellular senescence. The protein level of NAMPT and the level of NAD+ were significantly decreased in AMSCs compared with YMSCs. Mechanistically, TRAF3IP2 induced MSC senescence via downregulation of NAMPT expression and NAD + level by inhibiting the AMPK signaling pathway. These effects were partially reversed by treatment with an AMPK or NAMPT activator. Conclusion: We revealed that TRAF3IP2 accelerated MSC senescence via downregulation of NAMPT-mediated NAD biosynthesis by mediation of the AMPK pathway, highlighting a novel means to rejuvenate senescent MSCs.
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PURPOSE: Metabolic acidosis as one of the most common perioperative complications has been associated with increased risks for poor prognosis. Routine monitoring methods include blood gas analysis and electrocardiogram, which are limited by time delay effects. And the existing intravital imaging modalities are difficult to achieve in one step. Here, we present a dual-wavelength photoacoustic imaging approach to overcome this dilemma. The aim of this study was to develop a rapid approach for intensive monitoring of acid-base imbalance and cerebral oxygen metabolism. PROCEDURES: We characterized the cerebrovascular structure by label-free dual-wavelength (532 and 559 nm) photoacoustic microscopy in healthy and diabetic mouse models with metabolic acidosis. Concurrently, we developed a single-vessel analysis method to accurately delineate the differential responses of small vessels and quantify the cerebral oxygenation following experimental alteration of pH. RESULTS: We demonstrated that there was an increasing trend in changes of vascular measurements (density, diameter, and relative hemoglobin concentration) and cerebral microvascular oxygen metabolism with the aggravation of acidosis. Furthermore, we established a clinical nomogram for the diagnosis of disease severity and yielded good discrimination ability with area under the curve of 0.920-0.967 and accuracy of 81.9-93.0%. The nomogram was also validated well in the diabetic mouse model with metabolic acidosis. CONCLUSIONS: Our photoacoustic imaging approach has great potential for rapid detection of metabolic acidosis and brain oxygen metabolism, which could potentially be applied as a bedside monitoring method for brain protection and timely treatment of acid-base abnormalities.
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Acidose , Técnicas Fotoacústicas , Camundongos , Animais , Encéfalo/metabolismo , Acidose/diagnóstico por imagem , Microscopia , Oxigênio/metabolismo , Técnicas Fotoacústicas/métodosRESUMO
Although mesenchymal stem cell- (MSC-) based therapy has shown promising results for myocardial infarction (MI), low cell survival heavily limits its beneficial effects. Apelin plays an essential regulatory role in cell proliferation. This study was aimed at determining whether Apelin-13 pretreatment could improve the survival of MSCs in the ischemic heart and enhance their cardioprotective efficacy against MI. MSCs were pretreated with or without Apelin-13 for 24 hours and then exposed to serum deprivation and hypoxia (SD/H) for 48 hours. The mitochondrial morphology of MSCs was assessed by MitoTracker staining. The apoptosis of MSCs was determined by TUNEL staining. The level of mitochondrial reactive oxygen species (ROS) of MSCs was detected by Mito-Sox staining. MSCs and Apelin-13-pretreated MSCs were transplanted into the peri-infarct region in a mouse MI model. Apelin-13 pretreatment protected MSCs against SD/H-induced mitochondrial fragmentation and apoptosis. Apelin-13 pretreatment reduced ROS generation induced by SD/H in MSCs. Furthermore, Apelin-13 pretreatment enhanced the angiogenesis of MSCs under SD/H conditions. Mechanistically, Apelin-13 pretreatment inhibited SD/H-induced MSC apoptosis by downregulating mitochondrial fission via activation of the ERK pathway, and these effects were partially abrogated by ERK inhibitor U0126. Apelin-13 pretreatment promoted the survival of MSCs in the ischemic heart. Moreover, transplantation with Apelin-13-pretreated MSCs improved heart function and increased angiogenesis accompanied by decreased fibrosis compared with MSC transplantation at 28 days following MI. These findings reveal that pretreatment with Apelin-13 improves MSCs survival and enhances their therapeutic efficacy for MI. Our study provides a novel approach to improve MSC-based therapy for cardiovascular disease.
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INTRODUCTION: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Up to now, many genes associated with HCC have not yet been identified. In this study, we screened the HCC-related genes through the integrated analysis of the TCGA database, of which the potential biomarkers were also further validated by clinical specimens. The discovery of potential biomarkers for HCC provides more opportunities for diagnostic indicators or gene-targeted therapies. METHODS: Cancer-related genes in The Cancer Genome Atlas (TCGA) HCC database were screened by a random forest (RF) classifier based on the RF algorithm. Proteins encoded by the candidate genes and other associated proteins obtained via protein-protein interaction (PPI) analysis were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The newly identified genes were further validated in the HCC cell lines and clinical tissue specimens by Western blotting, immunofluorescence, and immunohistochemistry (IHC). Survival analysis verified the clinical value of genes. RESULTS: Ten genes with the best feature importance in the RF classifier were screened as candidate genes. By comprehensive analysis of PPI, GO and KEGG, these genes were confirmed to be closely related to HCC tumors. Representative NOX4 and FLVCR1 were selected for further validation by biochemical analysis which showed upregulation in both cancer cell lines and clinical tumor tissues. High expression of NOX4 or FLVCR1 in cancer cells predicts low survival. CONCLUSION: Herein, we report that NOX4 and FLVCR1 are promising biomarkers for HCC that may be used as diagnostic indicators or therapeutic targets.
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INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. COPD results from chronic inflammation of the lungs. Current treatments, including physical and chemical therapies, provide limited results. Stem cells, particularly mesenchymal stem cells (MSCs), are used to treat COPD. Here, we evaluated the safety and efficacy of umbilical cord-derived (UC)-MSCs for treating COPD. METHODS: Twenty patients were enrolled, 9 at stage C and 11 at stage D per the Global Initiative for Obstructive Lung Disease (GOLD) classification. Patients were infused with 106 cells/kg of expanded allogeneic UC-MSCs. All patients were followed for 6 months after the first infusion. The treatment end-point included a comprehensive safety evaluation, pulmonary function testing (PFT), and quality-of-life indicators including questionnaires, the 6-min walk test (6MWT), and systemic inflammation assessments. All patients completed the full infusion and 6-month follow-up. RESULTS: No infusion-related toxicities, deaths, or severe adverse events occurred that were deemed related to UC-MSC administration. The UC-MSC-transplanted patients showed a significantly reduced Modified Medical Research Council score, COPD assessment test, and number of exacerbations. However, the forced expiratory volume in 1 s, C-reactive protein, and 6MWT values were nonsignificantly reduced after treatment (1, 3, and 6 months) compared with those before the treatment. CONCLUSION: Systemic UC-MSC administration appears to be safe in patients with moderate-to-severe COPD, can significantly improve their quality of life, and provides a basis for subsequent cell therapy investigations. TRIAL REGISTRATION: ISRCTN, ISRCTN70443938. Registered 06 July 2019.
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Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Transplante de Células-Tronco Mesenquimais/métodos , Doença Pulmonar Obstrutiva Crônica/terapia , Transplante Homólogo/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
BACKGROUND: Rap1GAP, a member of the family of GTPase-activating proteins, is reported to be involved in cancer development and progression. OBJECTIVE: The study aimed to investigate the expression and prognostic value of Rap1GAP in gastric cancer patients. METHODS: Real-time quantitative polymerase chain reaction and western blotting were performed to examine Rap1GAP expression in tumorous and matched adjacent non-tumorous gastric tissues. Immunohistochemical staining was used to analyze Rap1GAP expression in 456 gastric cancer tissues. The correlation between Rap1GAP expression level and clinicopathological features as well as gastric cancer prognosis was analyzed. RESULTS: Rap1GAP expression was remarkably decreased in tumor tissues at mRNA (p= 0.012) and protein (p= 0.034) level. Clinicopathological analysis revealed that low Rap1GAP expression was significantly correlated with tumor size (p= 0.033), histological grade (p= 0.034), T classification (p= 0.012), N classification (p= 0.006) and clinical stage (p= 0.005). Kaplan-Meier survival analysis revealed the association between low Rap1GAP expression and poor survival in gastric cancer patients. Furthermore, multivariate Cox regression analysis showed that Rap1GAP expression was an independent prognostic factor (p= 0.02). CONCLUSION: Rap1GAP may play a significant role in gastric cancer progression and act as a valuable prognostic marker for gastric cancer.
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Biomarcadores Tumorais , Proteínas Ativadoras de GTPase/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Adulto , Idoso , Transformação Celular Neoplásica/genética , Feminino , Seguimentos , Proteínas Ativadoras de GTPase/metabolismo , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Neoplasias Gástricas/metabolismo , Carga TumoralRESUMO
OBJECTIVE: To investigate the association between serum concentration of insulin-like growth factor (IGF) and the risk of pancreatic cancer (PaC). METHODS: We identified eligible studies in Medline and EMBASE databases (no reference trials from 2014 to 2016) in addition to the reference lists of original studies and review articles on this topic. A summary of relative risks with 95% confidence intervals (CI) was calculated using a random-effects model. The heterogeneity between studies was assessed using Cochran Q and I² statistics. RESULTS: Ten studies (seven nested case-control studies and three retrospective case-control studies) were selected as they met our inclusion criteria in this meta-analysis. All these studies were published between 1997 and 2013. The current data suggested that serum concentrations of IGF-I, IGF-II and insulin-like growth factor binding protein-3 (IGFBP-3)in addition to the IGF-I/IGFBP-3 ratio were not associated with an increased risk of PaC (Summary relative risks (SRRs) = 0.92, 95% CI: 0.67-1.16 for IGF-I; SRRs = 0.84, 95% CI: 0.54-1.15 for IGF-II; SRRs = 0.93, 95% CI: 0.69-1.17 for IGFBP-3; SRRs = 0.97, 95% CI: 0.71-1.23 for IGF-I/IGFBP-3 ratio). There was no publication bias in the present meta-analysis. CONCLUSION: Serum concentrations of IGF-I, IGF-II, IGFBP-1 and IGFBP-3 as well as the IGF-I/IGFBP-3 ratio were not associated with increased risk of PaC.
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Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like II/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Pancreáticas/sangue , Humanos , Neoplasias Pancreáticas/etiologia , Fatores de RiscoRESUMO
Considering mucin 1-variable number tandem repeat (MUC1-VNTRn) as a novel target for pancreatic cancer immunotherapy, the present study aimed to screen and identify the pVAX1-MUC1-VNTRn DNA vaccine with the strongest immunogenicity. Following construction of a pVAX1-MUC1-VNTRn plasmid, immature dendritic cells (DCs) were subjected to transfection, and mature DCs were then co-cultured with autologous T-cells. The numbers of cytotoxic T lymphocytes (CTLs) secreting interferon (IFN)-γ were determined using an enzyme-linked immunospot assay, and CytoTox® was also used to examine the MUC1-VNTRn-specific Lethal effect of CTLs on Capan2 cells. Additional in vivo experiments in mice were performed to confirm the antitumor effect of the DNA vaccine candidate. The present study successfully constructed the pVAX1-MUC1-VNTRn plasmid, which expresses the target protein in eukaryotic cells. Additionally, upon uptake of the pVAX1-MUC1-VNTRn plasmid, the immature DCs differentiated into mature DCs. The levels of the DC surface molecules cluster of differentiation (CD) 80, CD86, human leukocyte antigen-antigen D related, interleukin (IL)-12, IL-17 and IFN-γ were significantly higher, while the levels of IL-10 and IL-14 were lower, in mature DCs of the stimulated groups compared with the immature DCs of the non-stimulated groups (all P<0.01). In addition, the MUC1-VNTR6 and MUC1-VNTR9 groups, in which DCs were capable of activating autologous T-cells, showed increased IFN-γ-producing T-cells compared with the other groups (strong MUC1-VNTR1, weak VNTR1, VNTR3, VNTR4 and MUC1-cDNA groups; all P<0.001). In addition, the Lethal effect of CTLs on Capan2 cells in these two groups was stronger compared with the other groups (all P<0.001). Furthermore, the induced protective and therapeutic immune responses in mouse experiments showed that the pVAX1-MUC1-VNTR6DNA vaccine likely possessed the strongest immunogenicity, and its ability to inhibit panc02-MUC1 tumor growth was superior to other DNA vaccines (P<0.01). The present study provides compelling evidence that pVAX1-MUC1-VNTRn has the potential to express the target protein in eukaryotic cells, and thatpVAX1-MUC1-VNTR6 was characterized by the strongest Lethal effect in both in vivo and in vitro experiments.
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We investigated the incidence, perioperative risk factors, and outcomes of postoperative acute kidney injury (AKI) in neurosurgical critically ill patients. A prospective multicenter cohort study was conducted, enrolling adult patients who underwent neurosurgical procedure and admitted to the neurosurgical intensive care units (ICU). Postoperative AKI was diagnosed within 7 days after surgery based on the Kidney Disease Improving Global Outcomes criteria. Of 624 enrolled patients, postoperative AKI occurred in 84 patients. AKI was associated with increased rates of ICU and in-hospital mortality, postoperative renal replacement therapy, postoperative tracheotomy, and postoperative tracheal reintubation. Patients who developed AKI had higher total ICU costs, prolonged length of hospital and ICU stay, and longer duration of postoperative mechanical ventilation. Multivariate analysis identified postoperative reoperation (adjusted odds ratio [OR] 5.70 [95% CI, 1.61-20.14]), postoperative concentration of serum cystatin C (adjusted OR 4.53 [95% CI, 1.98-10.39]), use of mannitol during operation (adjusted OR 1.97 [95% CI, 1.13-3.43]), postoperative APACHE II score (adjusted OR 1.11 [95% CI, 1.06-1.16]), and intraoperative estimated blood loss (adjusted OR 1.04 [95% CI, 1.00-1.08]) as independent risk factors for postoperative AKI. Postoperative AKI in neurosurgical critically ill cohort is prevalent and associated with adverse in-hospital outcomes.
Assuntos
Injúria Renal Aguda/fisiopatologia , Estado Terminal/mortalidade , Procedimentos Neurocirúrgicos/efeitos adversos , Complicações Pós-Operatórias/fisiopatologia , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Adulto , Idoso , Feminino , Mortalidade Hospitalar , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Respiração Artificial , Fatores de RiscoRESUMO
In this study, the complete mitochondrial genome sequence of Japanese macaque, Macaca fuscata fuscata, with the total length of 16,565 bp, is determined for the first time. This mitogenome harbors 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and 1 control region (D-loop). The overall base composition is A (31.7%), C (30.5%), G (12.9%), and T (24.9%), so the slight A-T bias (56.6%) was detected. Most of the genes are distributed on H-strand, except for the ND6 subunit gene and eight tRNA genes. The complete mitochondrial genome sequence reported here will provide new genetic resource to uncover the monkey's evolution.