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Objective: To review studies on digital medicine in cardiovascular diseases (CVD), discuss its development process, knowledge structure and research hotspots, and provide a perspective for researchers in this field. Methods: The relevant literature in recent 20 years (January 2004 to October 2022) were retrieved from the Web of Science Core Collection (WoSCC). CiteSpace was used to demonstrate our knowledge of keywords, co-references and speculative frontiers. VOSviewer was used to chart the contributions of authors, institutions and countries and incorporates their link strength into the table. Results: A total of 5265 English articles in set timespan were included. The number of publications increased steadily annually. The United States (US) produced the highest number of publications, followed by England. Most publications were from Harvard Medicine School, followed by Massachusetts General Hospital and Brigham Women's Hospital. The most authoritative academic journal was JMIR mHealth and uHealth. Noseworthy PA may have the highest influence in this intersected field with the highest number of citations and total link strength. The utilization of wearable mobile devices in the context of CVD, encompassing the identification of risk factors, diagnosis and prevention of diseases, as well as early intervention and remote management of diseases, has been widely acknowledged as a knowledge base and an area of current interest. To investigate the impact of various digital medicine interventions on chronic care and assess their clinical effectiveness, examine the potential of machine learning (ML) in delivering clinical care for atrial fibrillation (AF) and identifying early disease risk factors, as well as explore the development of disease prediction models using neural networks (NNs), ML and unsupervised learning in CVD prognosis, may emerge as future trends and areas of focus. Conclusion: Recently, there has been a significant surge of interest in the investigation of digital medicine in CVD. This initial bibliometric study offers a comprehensive analysis of the research landscape pertaining to digital medicine in CVD, thereby furnishing related scholars with a dependable reference to facilitate further progress in this domain.
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Brown fat adipose tissue (BAT) is a therapeutic potential target to improve obesity, diabetes and cold acclimation in mammals. During the long-term cold exposure, the hyperplastic sympathetic network is crucial for BAT the maintain the highly thermogenic status. It has been proved that the sympathetic nervous drives the thermogenic activity of BAT via the release of norepinephrine. However, it is still unclear that how the thermogenic BAT affects the remodeling of the hyperplastic sympathetic network, especially during the long-term cold exposure. Here, we showed that following long-term cold exposure, SCD1-mediated monounsaturated fatty acid biosynthesis pathway was enriched, and the ratios of monounsaturated/saturated fatty acids were significantly up-regulated in BAT. And SCD1-deficiency in BAT decreased the capacity of cold acclimation, and suppressed long-term cold mediated BAT thermogenic activation. Furthermore, by using thermoneutral exposure and sympathetic nerve excision models, we disclosed that SCD1-deficiency in BAT affected the thermogenic activity, depended on sympathetic nerve. In mechanism, SCD1-deficiency resulted in the unbalanced ratio of palmitic acid (PA)/palmitoleic acid (PO), with obviously higher level of PA and lower level of PO. And PO supplement efficiently reversed the inhibitory role of SCD1-deficiency on BAT thermogenesis and the hyperplastic sympathetic network. Thus, our data provided insight into the role of SCD1-mediated monounsaturated fatty acids metabolism to the interaction between thermogenic activity BAT and hyperplastic sympathetic networks, and illustrated the critical role of monounsaturated fatty acids biosynthetic pathway in cold acclimation during the long-term cold exposure.
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Tecido Adiposo Marrom , Termogênese , Animais , Tecido Adiposo Marrom/metabolismo , Termogênese/fisiologia , Sistema Nervoso Simpático , Obesidade/metabolismo , Ácidos Graxos Monoinsaturados/metabolismo , Temperatura Baixa , MamíferosRESUMO
After Clostridium tetani infects the human body, it propagates under anaerobic conditions and produces tetanus neurotoxin (TeNT). TeNT can affect the central nervous system, inhibit the release of neurotransmitters, and result in respiratory failure, which are the root causes of death in tetanus patients. Identifying monoclonal antibodies (mAbs) targeting TeNT with neutralizing activity is urgently needed for the prevention and treatment of tetanus infection. In this study, through immunizing BALB/c mice with tetanus toxoid (TT), we obtained six positive hybridoma cell lines (1A7, 2C7, 3A7, 3H4, 4C1, and 4E12). Antibody isotyping showed that the antibodies are all of the IgG1/κ subclass. Ascites fluid was prepared by allogeneic ascites induction and the antibodies were purified through protein G affinity chromatography columns. Purities of the produced murine mAbs were all greater than 95%. All six antibodies bound to linear epitopes, among which 3A7 bound to the TeNT/L domain and the other five antibodies bound to the TeNT/Hc domain. Moreover, the affinity constants of these six antibodies against the antigen were all in the nanomolar range, and the affinity of 4E12 antibody reached the picomolar range. Results from toxin-neutralization assays in mice showed that 2C7 antibody delayed animal death, while 1A7, 3A7, 3H4, and 4E12 antibodies conferred partial protection. Additionally, 4C1 antibody offered complete protection, as 200 µg of 4C1 antibody fully protected against toxin challenge with 10 LD50 of TeNT and had a window period of 1 h. Antibody epitope grouping results revealed that the binding epitopes of 4C1 antibody were different from those of the other five antibodies. When 4C1 antibody was used in combination with another antibody, the neutralizing activities of antibodies were all evidently enhanced. Specifically, 4C1 combined with 3A7 antibody led to the greatest improvement in neutralizing activities, and 20 µg antibodies total (10 + 10 µg) fully protected against toxin challenge with 10 LD50. When 4E12, 3A7, and 4C1 antibodies were used in combination, 18 µg antibodies total (6 + 6 + 6 µg) completely neutralized 10 LD50 toxin. The present study derived murine mAbs with neutralizing activities and laid the foundation for follow-up therapeutic drug development for TeNT poisoning as well as establishment of TeNT detection methods.
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Toxina Tetânica , Tétano , Humanos , Camundongos , Animais , Toxina Tetânica/metabolismo , Tétano/prevenção & controle , Anticorpos Neutralizantes , Ascite , Anticorpos Monoclonais , Epitopos , Camundongos Endogâmicos BALB CRESUMO
Numerous studies have examined the effects of lead (Pb) on cognitive ability. It is essential for the brain to maintain its functions through the differentiation of neural stem cells into various types of cells. Despite this, it remains unclear how Pb exposure affects neural stem cells and how it does, so the Pb-exposed mice were treated with the Notch inhibitor DAPT after we established the Pb exposure models. Neuronal stem cells and autophagy were assessed by immunofluorescence staining and western blot. The microbiota of the feces was also analyzed using the 16S rRNA amplicon sequencing technique. In this study, we found that Pb exposure caused neural injuries and deficits in neural stem cells, whereas DAPT rescued the damage. With DAPT, Pb-induced autophagy was partially reversed. Exposure to Pb also reduced inflammation and damaged gut barrier function. Furthermore, Pb exposure led to low bacterial diversity, an increase in pathogen abundance, and an unusual mode of interaction. Taken together, this study revealed that damages in neural stem cells contributed largely to cognitive impairment during Pb exposure, and this process was partially dependent on the Notch pathway and gut dysbiosis.
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Chumbo , Células-Tronco Neurais , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Eixo Encéfalo-Intestino , Chumbo/toxicidade , Camundongos , Células-Tronco Neurais/metabolismo , Inibidores da Agregação Plaquetária/farmacologia , RNA Ribossômico 16S/genética , RNA Ribossômico 16S/metabolismo , Transdução de SinaisRESUMO
Lead exposure may weaken the ability of learning and memory in the nervous system through mitochondrial paramorphia and dysfunction. However, the underlying mechanism has not been fully elucidated. In our works, with SD rats, primary culture of hippocampal neuron and PC12 cell line model were built up and behavioral tests were performed to determine the learning and memory insults; Western blot, immunological staining, and electron microscope were then conducted to determine endoplasmic reticulum stress and mitochondrial paramorphia and dysfunction. Co-immunoprecipitation were performed to investigate potential protein-protein interaction. The results show that lead exposure may cripple rats' learning and memory capability by inducing endoplasmic reticulum stress and mitochondrial paramorphia and dysfunction. Furthermore, we clarify that enhanced MFN2 ubiquitination degradation mediated by PINK1 may account for mitochondrial paramorphia and endoplasmic reticulum stress. Our work may provide important clues for research on the mechanism of how Pb exposure leads to nervous system damage.
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Chumbo , Síndromes Neurotóxicas , Animais , Apoptose , Estresse do Retículo Endoplasmático , Chumbo/metabolismo , Chumbo/toxicidade , Mitocôndrias/metabolismo , Síndromes Neurotóxicas/metabolismo , Proteínas Quinases/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Environmental hypoxic hazard has increasingly become a global public health issue, with impelling evidences supporting the relation between hypoxia and cognitive disorders. As a potent stressor, hypoxia causes mitochondrial dysfunction with insufficient energy production, thus the formation of brain memory disorder. Yet, the underlying molecular mechanism/s against hypoxia induced injury have yet to be identified. Here, we report that cold inducible RNA binding protein (Cirbp) attenuates hypoxia induced insufficient energy production and oxidative stress. Further analyses show that Cirbp sustains protein levels of respiratory chain complexes II (SDHB) and IV (MT-CO1), and directly binds the 3'UTR of Atp5g3 to control mitochondrial homeostasis and ATP biogenesis upon hypoxic stress. Altogether, our data establish Cirbp as a critical protective factor against hypoxic health hazard and provide novel insights into its latent regulation network.
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Hipóxia , Proteínas de Ligação a RNA , Encéfalo/metabolismo , Humanos , Transtornos da Memória , Mitocôndrias/metabolismo , Proteínas de Ligação a RNA/metabolismoRESUMO
Hypobaric hypoxia (HH) is a typical characteristic of high altitude environment and causes a spectrum of pathophysiological effects, including headaches, gliovascular dysfunction and cognitive retardation. Here, we sought to understand the mechanisms underlying cognitive deficits under HH exposure. Our results showed that hypobaric hypoxia exposure impaired cognitive function and suppressed dendritic spine density accompanied with increased neck length in both basal and apical hippocampal CA1 region neurons in mice. The expression of PSD95, a vital synaptic scaffolding molecule, is down-regulated by hypobaric hypoxia exposure and post-transcriptionally regulated by cold-inducible RNA-binding protein (Cirbp) through 3'-UTR region binding. PSD95 expressing alleviates hypoxia-induced dendritic spine morphology changes of hippocampal neurons and memory deterioration. Moreover, overexpressed Cirbp in hippocampus rescues HH-induced abnormal expression of PSD95 and attenuates hypoxia-induced dendritic spine injury and cognitive retardation. Thus, our findings reveal a novel mechanism that Cirbp-PSD-95 axis appears to play an essential role in HH-induced cognitive dysfunction in mice.
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Doença da Altitude/fisiopatologia , Região CA1 Hipocampal/patologia , Transtornos Cognitivos/prevenção & controle , Espinhas Dendríticas/ultraestrutura , Proteína 4 Homóloga a Disks-Large/fisiologia , Proteínas de Ligação a RNA/fisiologia , Regiões 3' não Traduzidas , Animais , Aprendizagem da Esquiva , Sequência de Bases , Células Cultivadas , Transtornos Cognitivos/etiologia , Proteína 4 Homóloga a Disks-Large/biossíntese , Proteína 4 Homóloga a Disks-Large/genética , Regulação da Expressão Gênica , Genes Reporter , Vetores Genéticos/administração & dosagem , Transtornos da Memória/etiologia , Transtornos da Memória/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Teste do Labirinto Aquático de Morris , Neurônios/fisiologia , Neurônios/ultraestrutura , Teste de Campo Aberto , Proteínas de Ligação a RNA/biossíntese , Proteínas de Ligação a RNA/genética , Distribuição Aleatória , Proteínas Recombinantes de Fusão/metabolismoRESUMO
Purpose: The authors aimed to identify Notch signaling pathway gene mutations as a prognostic biomarker for bladder cancer. Methods: First, critical Notch signaling pathway genes were screened using The Cancer Genome Atlas and validation sets. Second, immune infiltration, protein-protein interaction network, Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analysis analyses were performed. Finally, potential immunotherapy drug targets were screened using T-cell receptors, B-cell receptors and CERES scores for bladder cancer. Results: The NOTCH7 gene was identified, with a significant difference in immune infiltration level between mutant and wild type in bladder cancer, mainly related to T cells. NOTCH7 was an immunotherapy prognostic factor, and IRF1 and B2M were the potential drug targets for NOTCH7 mutation in bladder cancer. Conclusion: NOTCH7 gene mutation can be used as an immunotherapy biomarker for bladder cancer.
Lay abstract Studies have shown that 43% of bladder cancer patients harbor somatic mutations in genes associated with the Notch signaling pathway. However, it is not clear whether these mutations impact the efficacy of immunotherapy in bladder cancer patients. In the present study, the authors aimed to elucidate whether Notch signaling pathway gene mutations are effective biomarkers for predicting immunotherapy response and prognosis in patients with bladder cancer. Results of the present study suggested that seven genes CNTN6, CREBBP, EP300, NCOR1, NCOR2, NOTCH2 and SPEN involved in the Notch signaling pathway can be used to predict the response of patients to immunotherapy. In addition, IRF1 and B2M can act as combination drug targets with these seven genes.
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Mutação , Receptores Notch/genética , Neoplasias da Bexiga Urinária/genética , Humanos , Imunoterapia , Prognóstico , Mapas de Interação de Proteínas , Transdução de Sinais/fisiologia , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/terapiaRESUMO
Previous studies reported perturbed expressing of X-linked inhibitor of apoptosis protein (XIAP) under lead (Pb) exposure. However, researches on XIAP expression mainly focused on its transcriptional and post-translational regulation, rarely involving post-transcriptional mechanism manipulated by certain indispensable microRNAs (miRNAs). Interestingly, we unveiled that miR-106b-5p, a widely expressed miRNA in various tissues, is up-regulated by Pb2+-induced stress. Moreover, we found a binding site for miR-106b-5p in the 3'-UTR of xiap mRNA using bioinformatics analysis, and provided the evidences that miR-106b-5p can interact and function with this regulatory region via luciferase reporter assay. Our results further showed that miR-106b-5p down-regulates XIAP protein level, and suppression of miR-106b-5p reverses the decrease in both XIAP level and cell viability in Pb2+-treated HT-22 and PC12 cells. In brief, we identified a novel function of miR-106b-5p in the post-transcriptional regulation of XIAP expression associated with Pb neurotoxicity.
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Poluentes Ambientais/toxicidade , Chumbo/toxicidade , MicroRNAs , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Camundongos , RNA Mensageiro/metabolismo , Ratos , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genéticaRESUMO
Cold exposure stress causes hypothermia, cognitive impairment, liver injury, and cardiovascular diseases, thereby increasing morbidity and mortality. Paradoxically, cold acclimation is believed to confer metabolic improvement to allow individuals to adapt to cold, harsh conditions and to protect them from cold stress-induced diseases. However, the therapeutic strategy to enhance cold acclimation remains less studied. Here, we demonstrate that the mitochondrial-derived peptide MOTS-c efficiently promotes cold adaptation. Following cold exposure, the improvement of adipose non-shivering thermogenesis facilitated cold adaptation. MOTS-c, a newly identified peptide, is secreted by mitochondria. In this study, we observed that the level of MOTS-c in serum decreased after cold stress. MOTS-c treatment enhanced cold tolerance and reduced lipid trafficking to the liver. In addition, MOTS-c dramatically upregulated brown adipose tissue (BAT) thermogenic gene expression and increased white fat "browning". This effect might have been mediated by MOTS-c-activated phosphorylation of the ERK signaling pathway. The inhibition of ERK signaling disturbed the up-regulatory effect of MOTS-c on thermogenesis. In summary, our results indicate that MOTS-c treatment is a potential therapeutic strategy for defending against cold stress by increasing the adipose thermogenesis via the ERK pathway.
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Resposta ao Choque Frio/efeitos dos fármacos , Hipotermia/tratamento farmacológico , Peptídeos/administração & dosagem , Peptídeos/sangue , Termogênese/efeitos dos fármacos , Adaptação Fisiológica/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotermia/sangue , Hipotermia/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Peptídeos/farmacologia , Fosforilação/efeitos dos fármacosRESUMO
Objective. In China, the method of clearing heat and removing dampness medicine of Chinese traditional medicine has been widely used on gout. However, the clinical effects are various and not summarized systematically. Methods. In this study, a large number of randomized controlled clinical trials were reviewed and analyzed and the clinical efficacy and adverse reactions of traditional Chinese medicine with clearing heat and removing dampness effects for the treatment of gout were systematically evaluated. A comprehensive search of databases including pubMed, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database, Wanfang Data, and SinoMed was performed. Results. There are 69 randomized controlled trials with 5915 sample sizes meeting the criteria in the study. The results of the meta-analysis indicate that the effects of clearing heat and removing dampness medicine were slightly better than western medicine in the treatment of gout based on the following parameters: serum uric acid (standardized mean difference (SMD):-62.14, 95% confidence interval (CI): -78.12 to-46.15), C reactive protein (SMD: -4.21, 95% CI: -6.19 to -2.23), erythrocyte sedimentation rate (SMD: -6.23, 95% CI: -8.39 to-4.06), and overall clinical response (relative risk (RR): 1.11, 95% CI: 1.08 to 1.15) and, in the profile of adverse drug reactions, the clearing heat and removing dampness medicine showed less adverse reactions than traditional Western medicine (RR: 0.18, 95% CI: 0.10 to 0.32). Conclusions. Through a systemic evaluation of the clinical efficacy of the clearing heat and removing dampness medicine of traditional Chinese medicine and western medicine on gout, the clearing heat and removing dampness medicine and western medicine possessed similar clinical efficacy, but traditional Chinese medicine treatments are superior to western medicine in controlling adverse reactions.
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Trans-ferulic acid-4-ß-glucoside (C16H20O9, TFA-4ß-G) is a monomer extracted from the Chinese medicine called radix aconiti carmichaeli (Fuzi). To date, research on this substance is lacking. Here, we found that trans-ferulic acid-4-ß-glucoside effectively promoted cold acclimatization in mice via increased heat production and alleviation of oxidative stress in a cold environment. Thus, our work indicates that ferulic acid-4-ß-glucoside is a potential therapeutic candidate for prevention and treatment of cold stress injury.
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Resposta ao Choque Frio/efeitos dos fármacos , Glucosídeos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Termogênese/genética , Aclimatação/efeitos dos fármacos , Aconitum/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/fisiologia , Animais , Temperatura Baixa/efeitos adversos , Resposta ao Choque Frio/fisiologia , Ácidos Cumáricos/metabolismo , Ácidos Cumáricos/uso terapêutico , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/uso terapêutico , Glucosídeos/uso terapêutico , Humanos , Camundongos , Termogênese/efeitos dos fármacosRESUMO
Anion- and solvent-induced single-crystal-to-single-crystal transformation within an iron(II) triazole system has been generated from {[Fe(TPPT)2Cl2]·CHCl3} n (1a) to [Fe(TPPT)(C2O4)0.5Cl(H2O)] n (1b). Luminescence studies indicated that the resultant 1b can be considered as a promising luminescent probe for CrO42- and cyano molecules.
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BACKGROUND: The aim of this study is to evaluate the diagnostic value of prostate-specific antigen density (PSAD) test in detecting prostate cancer. METHODS: We searched public databases including PubMed, Medline, Springer, Elsevier Science Direct, Cochrane Library, and Google scholar before June 2015. In this meta-analysis, specificity, positive LR, negative LR, and dOR of PSAD test in patients with prostate cancer were analyzed from published studies. We applied Meta-DiSc 1.4 and Stata 11.0 software to the meta-analysis. RESULTS: A total of 11 separate studies consisting of 1821 participants were considered in the meta-analysis. The results of this meta-analysis indicated that sensitivity, specificity, positive Likelihood Ratio (LR), negative LR, and Diagnostic Odds Ratio (dOR) of PSAD test for prostate cancer were 0.73 (95% CI = 0.69 to 0.78), 0.64 (95% CI = 0.61 to 0.66), 2.13 (95% CI = 1.64 to 2.76), 0.45 (95% CI = 0.35 to 0.57), and 5.87 (95% CI = 4.42 to 7.81), respectively. It also showed that the AUC and Q* index were 0.77 and 0.71, respectively. The results of the Egger's linear regression test showed that no publication bias existed (p > 0.05). CONCLUSIONS: In general, our results show that specificity, positive LR, negative LR, dOR, the area under the curve (AUC), and Q * index of PSAD test may be appropriate for detecting prostate cancer.
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Antígenos de Neoplasias/sangue , Proteínas de Neoplasias/sangue , Neoplasias da Próstata/diagnóstico , Idoso , Área Sob a Curva , Distribuição de Qui-Quadrado , Proteínas Ligadas por GPI/sangue , Humanos , Funções Verossimilhança , Modelos Lineares , Masculino , Razão de Chances , Valor Preditivo dos Testes , Prognóstico , Neoplasias da Próstata/sangue , Neoplasias da Próstata/terapia , Curva ROCRESUMO
OBJECTIVE: To evaluate the feasibility and possibility of wrapping ureter by a pedicled gastrocolic omentum flap combined with an artificial ureter external scaffold to prevent stoma stenosis in rabbit after ureterocutaneostomy. METHODS: Forty male New Zealand rabbits were involved in this study. For application of ureterocutaneostomy, the right ureter was wrapped by a pedicled gastrocolic omentum flap and combined with application of an artificial external scaffold, which served as experimental side. Traditional ureterocutaneostomy was applied in left ureter (control side). All rabbits were killed after 1 month, and the kidney, ureter and abdominal segment ureter were collected to study the morphological and pathological changes by using HE staining, Masson staining, immunohistochemistry staining and microvessel density (MVD) study. RESULTS: HE staining showed that renal medullary tubular dilatation, large number of collagen deposition, renal glomerular and renal tubular atrophy. Glomerular vascular leaves and interstitial fibrosis were detected in the kidney of control side. However, these abnormities in the kidney of experimental side were significantly alleviated compared to control side. The hydronephrosis and ureterectasia in the experimental side were dramatically attenuated compared to control side. Fibrosis in ureter around stoma and stoma stenosis were prevented by wrapping ureter by a pedicled gastrocolic omentum flap combined with an artificial external scaffold. CONCLUSION: In this study, we have demonstrated that wrapping ureter by a pedicled gastrocolic omentum flap combined with an artificial external scaffold is capable of preventing stoma stenosis in rabbit after ureterocutaneostomy, which provided a new method and theoretical basis for clinical application in the future.
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Hidronefrose , Omento/cirurgia , Complicações Pós-Operatórias , Estomas Cirúrgicos/efeitos adversos , Derivação Urinária , Animais , Constrição Patológica/etiologia , Constrição Patológica/patologia , Constrição Patológica/prevenção & controle , Modelos Animais de Doenças , Hidronefrose/etiologia , Hidronefrose/prevenção & controle , Modelos Anatômicos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Coelhos , Retalhos Cirúrgicos , Ureter/cirurgia , Derivação Urinária/efeitos adversos , Derivação Urinária/métodosRESUMO
BACKGROUND: Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are widely used for EGFR mutated non-small-cell lung cancer (NSCLC) patients, tumor sample availability and heterogeneity of the tumor remain challenging for physicians' selection of these patients. Here, we developed a serum proteomic classifier based on matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) to predict the clinical outcome of patients treated with EGFR-TKIs. METHOD: A total of 68 patients were included in this study. All patients received EGFR-TKIs as second or third line treatment and blood samples were collected before treatment. Using magnetic bead assisted serum peptide capture coupled to MALDI-TOF-MS, pretreatment serum from 24 NSCLC patients was analyzed to develop a proteomic classifier (training set). In a blinded test set with 44 patients, each sample was classified into "good" or "poor" groups using this classifier. Survival analysis of each group was done based on this classification. RESULT: A 3-peptide proteomic classifier was developed from the training set. In the testing set, the classifier was able to distinguish patients of "good" or "poor" outcomes with 93% accuracy, sensitivity, and specificity. The overall survival and progression free survival of the predicted good group were found to be significantly longer than the poor group, not only in the whole population but also in certain subgroups, such as pathological adenocarcinoma and nonsmokers. With respect to the tumor samples available for EGFR mutation detection, all eight EGFR mutant tumors and three of the 12 wild type EGFR tumors were classified as good while nine of the 12 wild type EGFR tumors were classified as poor. CONCLUSION: The current study has shown that a proteomic classifier can predict the outcome of patients treated with EGFR-TKIs and may aid in patient selection in the absence of available tumor tissue. Further studies are necessary to confirm these findings.
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The unfavorable pharmacokinetics and low tumor specificity hampered the potential clinical utility of Onconase, a promising modality in anticancer treatment with unique targets and novel mechanism of action. In this study, a modular and multi-stage drug delivery system (DDS) that can break down organ (renal accumulation), cellular (cancer cell specific uptake) and sub-cellular (endosomal escape) level barriers encountered by Onconase during its long journey from injection site to the cytoplasm of cancer cell was designed. Human serum albumin fusion extended the half-life of Onconase and significantly decreased its kidney accumulation. Epithelial cell adhesion molecular (EpCAM) specific antibody fragment appending enhanced binding and internalization of Onconase toward EpCAM positive cancer cell and increased its tumor accumulation and retention. Tethering Onconase to its carrier by cleavable disulfide linker prompted endosomal escape and restored its cytotoxicity. In vivo antitumor efficacy assay in human tumor xenograft model revealed that only when the entire organ, cellular and sub-cellular level barriers had been broken down, will Onconase turn into a potent antitumor agent.
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Antineoplásicos/administração & dosagem , Citosol/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Ribonucleases/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Feminino , Células HT29 , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Testes de Função Renal , Fígado/efeitos dos fármacos , Fígado/metabolismo , Testes de Função Hepática , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos BALB C , Pichia/genética , Proteínas Recombinantes de Fusão/genética , Ribonucleases/genética , Ribonucleases/farmacocinética , Ribonucleases/farmacologia , Ribonucleases/toxicidade , Fatores de Tempo , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Human serum albumin (HSA) fusion (Albufusion) technology has evolved to be a general strategy to increase the in vivo half-lives of therapeutic proteins. However, because of the steric hindrance effect of HSA, conventional Albufusion technology improves the pharmacokinetics (PK) at the cost of pharmacodynamics (PD). To achieve balanced PK and PD of interferon-α2b (IFN-α2b) and HSA fusion protein, protease cleavage sites or disulfide linkage that enabled releasing of intact IFN-α2b with full activity was introduced between these two moieties. Nonreleasable and releasable fusion proteins showed similar cell surface receptor binding affinities; however, releasable fusion proteins exhibited release efficiency proportional increase of in vitro antiviral and antiproliferative activities. The release rate also had a profound impact on the in vivo pharmaceutical properties of fusion proteins. Releasable fusion proteins with intermediate release rate had the most balanced PK and PD, which translated into improved therapeutic efficacy in the HT29 human colon cancer xenograft model. Releasable Albufusion (rAlbufusion) allows tailored design of the PK/PD profile and greatly extends the utility of conventional Albufusion technology.
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Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antivirais/farmacocinética , Interferon-alfa/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Proteínas Recombinantes de Fusão/uso terapêutico , Albumina Sérica/metabolismo , Animais , Antineoplásicos/metabolismo , Antivirais/metabolismo , Antivirais/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Ensaio de Imunoadsorção Enzimática , Feminino , Células HT29 , Humanos , Interferon-alfa/farmacocinética , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , Camundongos , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/farmacocinética , Albumina Sérica/genética , Vesiculovirus/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: An important characteristic of renal cell carcinomas and adrenal tumors is that these tumors may expand into the renal vein and inferior vena cava, and transform into tumor thrombi. This study was to evaluate the use of piggyback liver transplant techniques for surgical management of urological tumors with inferior vena cava tumor thrombus. METHODS: Nineteen patients with renal cell carcinomas or adrenal tumors with inferior vena cava tumor thrombus were treated from November 1995 to April 2008. Their ages ranged from 29 years to 76 years (mean 54 years). The extent of tumor thrombus was infrahepatic (level I) in 2, retrohepatic (level II) in 7, suprahepatic (level III) in 6, and intra-atrial (level IV) in 4 patients. We used cardiopulmonary bypass with deep hypothermic circulatory arrest to remove the thrombi in 3 cases of level IV and in 2 cases of level III. In all level II, 4 level III, and 2 level IV cases, we used piggyback liver transplant techniques to mobilize the liver off of the inferior vena cava and to separate the inferior vena cava from the posterior abdominal wall. RESULTS: Mean operative time was 5.1 hours, mean estimated blood loss was 2289 ml and mean blood transfusion was 12.84 U. One patient with adrenal cortical carcinoma and level IV thrombus died in the immediate postoperative period. Three patients were lost to follow up, and the other 15 survivors were followed from 5 months to 56 months. Eight of these 15 patients died due to metastasis; however 7 were still alive at the last follow-up. CONCLUSIONS: An aggressive surgical approach is the only hope for curing patients diagnosed with urological tumors combined with inferior vena cava tumor thrombus. The use of piggyback liver transplant techniques to mobilize the liver off of the inferior vena cava provides excellent exposure of the inferior vena cava. Patients with a level II or level III inferior vena cava thrombus may be treated without using cardiopulmonary bypass.
Assuntos
Neoplasias das Glândulas Suprarrenais/cirurgia , Carcinoma de Células Renais/cirurgia , Transplante de Fígado/métodos , Veia Cava Inferior/patologia , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Carcinoma de Células Renais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Células Neoplásicas CirculantesRESUMO
Calcineurin inhibitors (CNIs) are playing an important role in preventing acute rejection in renal transplantation; however, their nephrotoxicity may impact long-term renal allograft survival. Several CNI-sparing regimens (such as CNI-avoidance or CNI-minimization) have shown at least comparable efficacy with standard-dose CNI regimens. Research continues to achieve the "best" balance between efficacy and toxicity of available immunosuppressive regimens.