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Model selection based on experimental data is an important challenge in biological data science. Particularly when collecting data is expensive or time-consuming, as it is often the case with clinical trial and biomolecular experiments, the problem of selecting information-rich data becomes crucial for creating relevant models. We identify geometric properties of input data that result in an unique algebraic model, and we show that if the data form a staircase, or a so-called linear shift of a staircase, the ideal of the points has a unique reduced Gröbner basis and thus corresponds to a unique model. We use linear shifts to partition data into equivalence classes with the same basis. We demonstrate the utility of the results by applying them to a Boolean model of the well-studied lac operon in E. coli.
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Modelos Biológicos , Algoritmos , Bases de Dados Factuais , Escherichia coli/genética , Escherichia coli/metabolismo , Óperon Lac , Modelos Lineares , Conceitos Matemáticos , Biologia de SistemasRESUMO
RATIONALE: We observed that the accuracy and precision of magnesium (Mg) isotope analyses could be affected if the room temperature oscillated during measurements. To achieve high-quality Mg isotopic data, it is critical to evaluate how the unstable room temperature affects Mg isotope measurements by multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS). METHODS: We measured the Mg isotopes for the reference material DSM-3 using MC-ICP-MS under oscillating room temperatures in spring. For a comparison, we also measured the Mg isotopes under stable room temperatures, which were achieved by the installation of an improved temperature control system in the laboratory. RESULTS: The δ26 Mg values measured under oscillating room temperatures have a larger deviation (δ26 Mg from -0.09 to 0.08, with average δ26 Mg = 0.00 ± 0.08) than those measured under a stable room temperature (δ26 Mg from -0.03 to 0.03, with average δ26 Mg = 0.00 ± 0.02) using the same MC-ICP-MS system. CONCLUSIONS: The room temperature variation can influence the stability of MC-ICP-MS. Therefore, it is critical to keep the room temperature stable to acquire high-precision and accurate isotopic data when using MC-ICP-MS, especially when using the sample-standard bracketing (SSB) correction method.
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STUDY OBJECTIVE: To investigate whether the addition of S-ketamine to patient-controlled hydromorphone analgesia decreases postoperative moderate-to-severe pain and improves the quality of recovery (QoR) in patients undergoing thoracoscopic lung surgery. DESIGN: Single-center prospective randomized double-blinded controlled trial. SETTING: Tertiary university hospital. PATIENTS: 242 patients undergoing thoracoscopic lung surgery. INTERVENTIONS: Patients were randomized to receive intravenous patient-controlled analgesia (IV-PCA) with hydromorphone alone or hydromorphone combined with S-ketamine (0.5 mg/kg/48 h, 1 mg/kg/48 h, or 2 mg/kg/48 h). MEASUREMENTS: Primary outcome was proportion of patients with moderate-to-severe pain. (numerical rating scale [NRS] pain scores ≥4 when coughing) within 2 days after surgery. Postoperative QoR scores and other prespecified outcomes were also recorded. MAIN RESULTS: Of 242 enrolled patients, 220 were included in the final analysis. The results demonstrated that the incidence of postoperative moderate-to-severe pain was significantly different between the hydromorphone group and combined S-ketamine group (absolute difference, 27.9%; 95% confidence interval [CI], 11.7% to 42.1%; P < 0.001). Patients who received S-ketamine had lower NRS pain scores at rest and when coughing on postoperative day 1 (POD1; median difference 1 and 1, P < 0.001) and postoperative day 2 (POD2; median difference 1 and 1, P < 0.001). The QoR-15 scores were higher in the combined S-ketamine group on POD1 (mean difference 6, P < 0.001) and POD2 (mean difference 6, P < 0.001) than in the hydromorphone group. A higher dose of S-ketamine was associated with deeper sedation. No differences were detected in the other safety outcomes. CONCLUSIONS: Addition of S-ketamine to IV-PCA hydromorphone significantly reduced the incidence of postoperative moderate-to-severe pain and improved the QoR in patients undergoing thoracoscopic lung surgery. TRIAL REGISTRATION: Chinese Clinical Trail Register (identifier: ChiCTR2200058890).
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Analgesia Controlada pelo Paciente , Hidromorfona , Humanos , Analgesia Controlada pelo Paciente/métodos , Analgésicos Opioides/efeitos adversos , Hidromorfona/efeitos adversos , Pulmão/cirurgia , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/prevenção & controle , Estudos Prospectivos , Método Duplo-CegoRESUMO
The synergistic effects of ultrafine grinding and enzymolysis (cellulase and Laccase hydrolysis) alone or combined with carboxymethylation or acetylation on the hypoglycemic and antioxidant activities of oil palm kernel fibre (OPKEF) were studied for the first time. After these synergistic modifications, the microstructure of OPKEF became more porous, and its soluble fibre and total polyphenols contents, and surface area were all improved (P < 0.05). Superfine-grinding and enzymolysis combined with carboxymethylation treated OPKEF exhibited the highest viscosity (13.9 mPaâs), inhibition ability to glucose diffusion (38.18%), and water-expansion volume (3.58 mLâg-1). OPKEF treated with superfine-grinding and enzymolysis combined with acetylation showed the highest surface hydrophobicity (50.93) and glucose adsorption capacity (4.53 µmolâg-1), but a lower α-amylase-inhibition ability. Moreover, OPKEF modified by superfine-grinding and enzymolysis had the highest inhibiting activity against α-amylase (25.78%). Additionally, superfine-grinding and enzymolysis combined with carboxymethylation or acetylation both improved the content and antioxidant activity of OPEKF's bounding polyphenols (P < 0.05).
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Antioxidantes , Hipoglicemiantes , Antioxidantes/química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Acetilação , Óleo de Palmeira/química , alfa-Amilases/química , alfa-Amilases/metabolismo , Lacase/química , Lacase/metabolismo , Metilação , Celulase/química , Celulase/metabolismo , Hidrólise , Viscosidade , Sementes/química , Manipulação de Alimentos , Polifenóis/química , Polifenóis/farmacologiaRESUMO
INTRODUCTION: Postoperative pulmonary complications (PPCs) occur after up to 60% of non-cardiac thoracic surgery (NCTS), especially for multimorbid elderly patients. Nevertheless, current risk prediction models for PPCs have major limitations regarding derivation and validation, and do not account for the specific risks of NCTS patients. Well-founded and externally validated models specific to elderly NCTS patients are warranted to inform consent and treatment decisions. METHODS AND ANALYSIS: We will develop, internally and externally validate a multivariable risk model to predict 30-day PPCs in elderly NCTS patients. Our cohort will be generated in three study sites in southern China with a target population of approximately 1400 between October 2021 and December 2023. Candidate predictors have been selected based on published data, clinical expertise and epidemiological knowledge. Our model will be derived using the combination of multivariable logistic regression and bootstrapping technique to lessen predictors. The final model will be internally validated using bootstrapping validation technique and externally validated using data from different study sites. A parsimonious risk score will then be developed on the basis of beta estimates derived from the logistic model. Model performance will be evaluated using area under the receiver operating characteristic curve, max-rescaled Brier score and calibration slope. In exploratory analysis, we will also assess the net benefit of Probability of PPCs Associated with THoracic surgery in elderly patients score in the complete cohort using decision curve analysis. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Institutional Review Board of the Affiliated Cancer Hospital and Institute of Guangzhou Medical University, the Second Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine and the University of Hongkong-Shenzhen Hospital, respectively. The final risk prediction model will be published in an appropriate journal and further disseminated as an online calculator or nomogram for clinical application. Approved and anonymised data will be shared. TRIAL REGISTRATION NUMBER: ChiCTR2100051170.
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Cirurgia Torácica , Procedimentos Cirúrgicos Torácicos , Humanos , Idoso , Estudos de Coortes , Pulmão/cirurgia , Fatores de Risco , Procedimentos Cirúrgicos Torácicos/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologiaRESUMO
Mesenchymal stromal/stem cells (MSCs) typically require significant ex vivo expansion to achieve the high cell numbers required for research and clinical applications. However, conventional MSC culture on planar (2D) plastic surfaces has been shown to induce MSC senescence and decrease cell functionality over long-term proliferation, and usually, it has a high labor requirement, a high usage of reagents, and therefore, a high cost. In this Review, we describe current MSC-based therapeutic strategies and outline the important factors that need to be considered when developing next-generation cell expansion platforms. To retain the functional value of expanded MSCs, ex vivo culture systems should ideally recapitulate the components of the native stem cell microenvironment, which include soluble cues, resident cells, and the extracellular matrix substrate. We review the interplay between these stem cell niche components and their biological roles in governing MSC phenotype and functionality. We discuss current biomimetic strategies of incorporating biochemical and biophysical cues in MSC culture platforms to grow clinically relevant cell numbers while preserving cell potency and stemness. This Review summarizes the current state of MSC expansion technologies and the challenges that still need to be overcome for MSC clinical applications to be feasible and sustainable.
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Biomimética , Células-Tronco Mesenquimais , Matriz Extracelular/metabolismo , Fenótipo , Células-Tronco Mesenquimais/metabolismoRESUMO
The highly organized extracellular matrix (ECM) of musculoskeletal tissues, encompassing tendons, ligaments and muscles, is structurally anisotropic, hierarchical and multi-compartmental. These features collectively contribute to their unique function. Previous studies have investigated the effect of tissue-engineered scaffold anisotropy on cell morphology and organization for musculoskeletal tissue repair and regeneration, but the hierarchical arrangement of ECM and compartmentalization are not typically replicated. Here, we present a method for multi-compartmental scaffold design that allows for physical mimicry of the spatial architecture of musculoskeletal tissue in regenerative medicine. This design is based on an ECM-inspired macromolecule scaffold. Polycaprolactone (PCL) scaffolds were fabricated with aligned fibers by electrospinning and mechanical stretching, and then surface-functionalized with the cell-supporting ECM protein molecule, tropoelastin (TE). TE was attached using two alternative methods that allowed for either physisorption or covalent attachment, where the latter was achieved by plasma ion immersion implantation (PIII). Aligned fibers stimulated cell elongation and improved cell alignment, in contrast to randomly oriented fibers. TE coatings bound by physisorption or covalently following 200 s PIII treatment promoted fibroblast proliferation. This represents the first cytocompatibility assessment of novel PIII-treated TE-coated PCL scaffolds. To demonstrate their versatility, these 2D anisotropic PCL scaffolds were assembled into 3D hierarchical constructs with an internally compartmentalized structure to mimic the structure of musculoskeletal tissue.
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Strategies to promote rapid formation of functional endothelium are required to maintain blood fluidity and regulate smooth muscle cell proliferation in synthetic vascular conduits. In this work, we explored the biofunctionalization of silk biomaterials with recombinantly expressed domain V of human perlecan (rDV) to promote endothelial cell interactions and the formation of functional endothelium. Perlecan is essential in vascular development and homeostasis and rDV has been shown to uniquely support endothelial cell, while inhibiting smooth muscle cell and platelet interactions, both key contributors of vascular graft failure. rDV was covalently immobilized on silk using plasma immersion ion implantation (PIII), a simple one-step surface treatment process which enables strong immobilization in the absence of chemical cross-linkers. rDV immobilization on surface-modified silk was assessed for amount, orientation, and bio-functionality in terms of endothelial cell interactions and functional endothelial layer formation. rDV immobilized on PIII-treated silk (rDV-PIII-silk) supported rapid endothelial cell adhesion, spreading, and proliferation to form functional endothelium, as evidenced by the expression of vinculin and VE-cadherin markers. Taken together, the results provide evidence for the potential of rDV-PIII-silk as a biomimetic vascular graft material.
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Materiais Biocompatíveis , Seda , Humanos , Seda/química , Imersão , Adesão Celular , Prótese Vascular , Proteínas da Matriz Extracelular , EndotélioRESUMO
Mesenchymal stem cells (MSCs) used for clinical applications require in vitro expansion to achieve therapeutically relevant numbers. However, conventional planar cell expansion approaches using tissue culture vessels are inefficient, costly, and can trigger MSC phenotypic and functional decline. Here we present a one-step dry plasma process to modify the internal surfaces of three-dimensional (3D) printed, high surface area to volume ratio (high-SA:V) porous scaffolds as platforms for stem cell expansion. To address the long-lasting challenge of uniform plasma treatment within the micrometre-sized pores of scaffolds, we developed a packed bed plasma immersion ion implantation (PBPI3) technology by which plasma is ignited inside porous materials for homogeneous surface activation. COMSOL Multiphysics simulations support our experimental data and provide insights into the role of electrical field and pressure distribution in plasma ignition. Spatial surface characterisation inside scaffolds demonstrates the homogeneity of PBPI3 activation. The PBPI3 treatment induces radical-containing chemical structures that enable the covalent attachment of biomolecules via a simple, non-toxic, single-step incubation process. We showed that PBPI3-treated scaffolds biofunctionalised with fibroblast growth factor 2 (FGF2) significantly promoted the expansion of MSCs, preserved cell phenotypic expression, and multipotency, while reducing the usage of costly growth factor supplements. This breakthrough PBPI3 technology can be applied to a wide range of 3D polymeric porous scaffolds, paving the way towards developing new biomimetic interfaces for tissue engineering and regenerative medicine.
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INTRODUCTION: Postoperative delirium (POD) is a common and distressing complication after thoracic surgery. S-ketamine has neuroprotective properties as a dissociative anaesthetic. Emerging literature has indicated that S-ketamine can reduce cognitive impairment in patients with depression. However, the role of S-ketamine in preventing POD remains unknown. Therefore, this study aims to evaluate the effect of intraoperative prophylactic S-ketamine compared with that of dexmedetomidine on the incidence of POD in elderly patients undergoing non-cardiac thoracic surgery. METHODS AND ANALYSIS: This will be a randomised, double-blinded, placebo-controlled, positive-controlled, non-inferiority trial that enrolled patients aged 60-90 years undergoing thoracic surgery. The patients will be randomly allocated in a ratio of 1:1:1 to S-ketamine, dexmedetomidine or normal saline placebo groups using computer-generated randomisation with a block size of six. The primary outcome will be the incidence of POD within 4 days after surgery and this will be assessed using a 3-Minute Diagnostic Confusion Assessment Method two times per day. The severity and duration of POD, the incidence of emergence delirium, postoperative pain, quality of sleep, cognitive function, and the plasma concentrations of acetylcholine, brain-derived neurotrophic factor, tumour necrosis factor-α and incidence of adverse events will be evaluated as secondary outcomes. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Institutional Review Board of the Cancer Hospital and the Institute of Guangzhou Medical University (ZN202119). At the end of the trial, we commit to making a public disclosure available, regardless of the outcome. The public disclosure will include a publication in an appropriate journal and an oral presentation at academic meetings. TRIAL REGISTRATION NUMBER: ChiCTR2100052750 (NCT05242692).
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Delírio , Dexmedetomidina , Cirurgia Torácica , Idoso , Cognição , Delírio/diagnóstico , Delírio/etiologia , Delírio/prevenção & controle , Dexmedetomidina/uso terapêutico , Método Duplo-Cego , Estudos de Equivalência como Asunto , Humanos , Ketamina , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Drought is the most serious natural disaster causing severe damage to agriculture. Drought impacts on rice (Oryza sativa) production present a major threat to future global food security. In this paper, the Environmental Policy Integrated Climate (EPIC) model was used to simulate the growth of rice, in different periods (short-term (2019-2039), medium-term (2040-2069), long-term (2070-2099)), based on multiple Representative Concentration Pathways (RCP) scenarios. Drought intensity and rice physical vulnerability curves were assessed, based on the output parameters of EPIC, to evaluate global rice yield risk, due to drought. The results show that the average expected loss rate of global rice yield may reach 13.1% (±0.4%) in the future. The high-risk area of rice drought is mainly located in the north of 30°N. The fluctuation of rice drought risk and the proportion of increased risk areas will increase significantly. About 77.6% of the changes in rice drought risk are explained by variations in shortwave radiation (r = 0.88). Projections show that the average value of daily shortwave radiation increases by 1 W/m2 during the rice growth period, accompanied by an expected rice yield loss rate of about 12.7%. The rice drought risk methods presented in this paper provide plausible estimates of forecasting future drought risk under climate change, and address challenges of sparse data; we believe these methods can be applied to decisions for reducing drought-related crop losses and ensuring global food security.
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Secas , Oryza , Agricultura , Mudança Climática , Medição de RiscoRESUMO
AIM: The aim of this study was to evaluate the anti-inflammatory effects and underlying mechanism of naloxone on lipopolysaccharide- (LPS-) induced neuronal inflammation and microglial activation. METHODS: LPS-treated microglial BV-2 cells and mice were used to investigate the anti-inflammatory effects of naloxone. RESULTS: The results showed that naloxone dose-dependently promoted cell proliferation in LPS-induced BV-2 cells, downregulated the expression of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) and proinflammatory enzymes iNOS and COX-2 as well as the expression of free radical molecule NO, and reduced the expression of Iba-1-positive microglia in LPS-stimulated BV-2 cells and mouse brain. Moreover, naloxone improved LPS-induced behavior degeneration in mice. Mechanically, naloxone inhibited LPS-induced activation in the ATP-sensitive potassium (KATP) channel. However, the presence of glibenclamide (Glib), an antagonist of KATP channel, ameliorated the suppressive effects of naloxone on inflammation and microglial activation. CONCLUSION: Naloxone prevented LPS-induced neuroinflammation and microglial activation partially through the KATP channel. These findings might highlight the potential of naloxone in neuroinflammation therapy.
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Inflamação/prevenção & controle , Canais KATP/antagonistas & inibidores , Microglia/efeitos dos fármacos , Naloxona/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Comportamento Animal/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Biologia Computacional , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lipopolissacarídeos/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Microglia/metabolismo , Microglia/patologia , Antagonistas de Entorpecentes/farmacologia , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/prevenção & controleRESUMO
BACKGROUND: 18F-FDG PET/CT metabolic parameters have been applied as prognostic factors in multi-malignancies. However, the role in locally advanced pancreatic cancer (LAPC) was not confirmed. In this study, we investigated the prognostic value of 18F-FDG PET/CT metabolic parameters in LAPC patients treated with stereotactic body radiation therapy (SBRT). METHODS: Seventy three LAPC patients who received SBRT therapy and pre-treatment 18F-FDG PET/CT imaging from January 2012 to January 2016 were included in this retrospective study. The study aim was to evaluate the relationship between metabolic parameters with clinical factors, and the value of metabolic parameters in the prognosis of LAPC. The median of parameters was set as the cut-off value for statistical analysis. Univariate survival analysis was performed by the Kaplan Meier method and log-rank test, and multivariate analysis was carried out by a Cox proportional hazards model. RESULTS: Patients with lymph node metastasis or longer tumor diameters were associated with higher TLG (P < 0.05). Univariate analysis showed MTV, TLG, radiotherapy dose and chemotherapy were significantly associated with disease progression-free survival (PFS) and overall survival (OS) (P < 0.05). Lymph node metastasis and tumor longest diameter were associated with OS. Multivariate analysis demonstrated TLG, radiotherapy dose, and chemotherapy were independent factors of PFS and OS (HR: 2.307, 0.591, 0.572 and 2.145, 0.480, 0.471, P < 0.05). CONCLUSIONS: TLG was found to be the independent prognostic factor of OS and PFS. Among clinical factors, radiotherapy dose and chemotherapy were independent prognostic factors of OS and PFS.
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Fluordesoxiglucose F18 , Neoplasias Pancreáticas/radioterapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Radiocirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Glicólise , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Estudos RetrospectivosRESUMO
Stereotactic body radiation therapy (SBRT) has emerged to be a preference treatment for locally advanced pancreatic cancer (LAPC) patients. In this study, we aimed to investigate the prognostic roles of F-FDG PET/CT metabolic parameters and clinical figures in LAPC patients underwent chemo-SBRT combined therapy.During January 2013 to January 2017, 23 LAPC patients who underwent F-FDG PET/CT within 2 weeks before treatment were recruited and retrospectively analyzed. Maximum standardized uptake values (SUVmax), SUVmean, metabolic tumor volume (MTV), total lesion glycolysis (TLG), chemoradiotherapy (CRT) sequence, and relevant clinical figures were grouped upon the median values, then analyzed by Kaplan-Meier method and Cox proportional hazard models for their prognostic evaluation.The median overall survival (OS) and progression-free survival (PFS) of all patients were 16.7 months and 11.3 months, respectively. According to the statistic results, the longest diameter of tumor (LDT), MTV, TLG, and CRT sequence were associated with OS (all Pâ<.05). Among which, LDT and MTV were proved to be the independent prognostic factors for OS (hazard ratio [HR]: 3.437, 3.015, both Pâ<.05). Additionally, LDT and CRT sequence were found associated with PFS (both Pâ<.05), and CRT sequence was the independent prognostic factor for PFS in chemo-SBRT treated LAPC patients (HR: 0.130, Pâ<.05).For LAPC patients received chemotherapy and SBRT combined therapy, MTV and LDT showed independent prognostic values for OS. Meanwhile, CRT sequence was an independent PFS prediction factor.
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Neoplasias Pancreáticas/diagnóstico por imagem , Neoplasias Pancreáticas/mortalidade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/estatística & dados numéricos , Adulto , Idoso , Antineoplásicos/uso terapêutico , Terapia Combinada , Feminino , Fluordesoxiglucose F18 , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/terapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Compostos Radiofarmacêuticos , Radiocirurgia/mortalidade , Taxa de Sobrevida , Resultado do Tratamento , Carga TumoralRESUMO
AIM: To explore the diagnostic value of the cross-modality fusion images provided by positron emission tomography/computed tomography (PET/CT) and contrast-enhanced CT (CECT) for pancreatic cancer (PC). METHODS: Data from 70 patients with pancreatic lesions who underwent CECT and PET/CT examinations at our hospital from August 2010 to October 2012 were analyzed. PET/CECT for the cross-modality image fusion was obtained using TureD software. The diagnostic efficiencies of PET/CT, CECT and PET/CECT were calculated and compared with each other using a χ(2) test. P < 0.05 was considered to indicate statistical significance. RESULTS: Of the total 70 patients, 50 had PC and 20 had benign lesions. The differences in the sensitivity, negative predictive value (NPV), and accuracy between CECT and PET/CECT in detecting PC were statistically significant (P < 0.05 for each). In 15 of the 31 patients with PC who underwent a surgical operation, peripancreatic vessel invasion was verified. The differences in the sensitivity, positive predictive value, NPV, and accuracy of CECT vs PET/CT and PET/CECT vs PET/CT in diagnosing peripancreatic vessel invasion were statistically significant (P < 0.05 for each). In 19 of the 31 patients with PC who underwent a surgical operation, regional lymph node metastasis was verified by postsurgical histology. There was no statistically significant difference among the three methods in detecting regional lymph node metastasis (P > 0.05 for each). In 17 of the 50 patients with PC confirmed by histology or clinical follow-up, distant metastasis was confirmed. The differences in the sensitivity and NPV between CECT and PET/CECT in detecting distant metastasis were statistically significant (P < 0.05 for each). CONCLUSION: Cross-modality image fusion of PET/CT and CECT is a convenient and effective method that can be used to diagnose and stage PC, compensating for the defects of PET/CT and CECT when they are conducted individually.
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Meios de Contraste , Tomografia Computadorizada Multidetectores , Imagem Multimodal/métodos , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Pancreáticas/cirurgia , Valor Preditivo dos Testes , Interpretação de Imagem Radiográfica Assistida por Computador , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: The overexpression of gelatinases, that is, matrix metalloproteinase MMP2 and MMP9, has been associated with tumor progression, invasion, and metastasis. To image MMP2 in tumors, we developed a novel ligand termed [18F]AlF-NOTA-C6, with consideration that: c(KAHWGFTLD)NH2 (herein, C6) is a selective gelatinase inhibitor; Cy5.5-C6 has been visualized in many in vivo tumor models; positron emission tomography (PET) has a higher detection sensitivity and a wider field of view than optical imaging; fluorine-18 (18F) is the optimal PET radioisotope, and the creation of a [18F]AlF-peptide complex is a simple procedure. METHODS: C6 was conjugated to the bifunctional chelator NOTA (1, 4, 7-triazacyclononanetriacetic acid) for radiolabeling [18F]AlF conjugation. The MMP2-binding characteristics and tumor-targeting efficacy of [18F]AlF-NOTA-C6 were tested in vitro and in vivo. RESULTS: The non-decay corrected yield of [18F]AlF-NOTA-C6 was 46.2-64.2%, and the radiochemical purity exceeded 95%. [18F]AlF-NOTA-C6 was favorably retained in SKOV3 and PC3 cells, determined by cell uptake. Using NOTA-C6 as a competitive ligand, the uptake of [18F]AlF-NOTA-C6 in SKOV3 cells decreased in a dose-dependent manner. In biodistribution and PET imaging studies, higher radioactivity concentrations were observed in tumors. Pre-injection of C6 caused a marked reduction in tumor tissue uptake. Immunohistochemistry showed MMP2 in tumor tissues. CONCLUSIONS: [18F]AlF-NOTA-C6 was easy to synthesize and has substantial potential as an imaging agent that targets MMP2 in tumors.
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Radioisótopos de Flúor/administração & dosagem , Compostos Heterocíclicos/administração & dosagem , Metaloproteinase 2 da Matriz/metabolismo , Linhagem Celular Tumoral , Compostos Heterocíclicos com 1 Anel , Humanos , Ligantes , Peptídeos/administração & dosagem , Tomografia por Emissão de Pósitrons/métodos , Radioquímica/métodos , Distribuição TecidualRESUMO
INTRODUCTION: Elevated levels of gelatinases (matrix metalloproteinases 2/9, i.e., MMP2 and MMP9) are associated with tumor progression, invasion and metastasis, so these enzymes are potential targets for tumor imaging. The peptide c(KAHWGFTLD)NH2 (herein, C6) is a selective gelatinase inhibitor. Cy5.5-C6 has been visualized in many tumor models in vivo. However, the sensitivity and penetrance of optical imaging are poor. It is well known that positron emission tomography (PET) has a high detection sensitivity and Gallium-68 ((68)Ga) is an optimal PET radioisotope. Thus, in the present study, we developed a novel ligand, (68)Ga-NOTA-C6, to image MMP2 activity in tumors. METHODS: C6 was conjugated with the bifunctional chelator NOTA (1,4,7-triazacyclononanetriacetic acid) and labeled with (68)Ga. In vitro uptake and binding analyses were performed by using SKOV3 cell lines, coincubating with or without the MMP inhibitor doxycycline. The biodistribution and PET imaging were conducted on SKOV3 ovarian tumor models. MMP2 expression in tumors was analyzed by immunohistochemistry (IHC). RESULTS: The non-decay corrected yield of (68)Ga-NOTA-C6 was 61.8%-63.3%. (68)Ga-NOTA-C6 was stable in both physiological saline and human serum. The uptake of (68)Ga-NOTA-C6 in SKOV3 cells increased with time, and could be blocked by doxycycline in a dose dependent manner. The results of biodistribution and PET imaging showed that high radioactivity concentrations of (68)Ga-NOTA-C6 occurred in tumors. The ratios of tumor to blood, muscle and ovary and oviduct at 30, 60 and 120min p.i. were 2.78±0.54, 3.86±0.65, 0.48±0.14, and 1.73±0.36, 10.31±3.12, 1.22±0.10, and 2.50±0.78, 7.03±1.85, 0.97±0.25, respectively. The tracer was excreted mainly through the renal system, as evidenced by high levels of radioactivity in the kidneys. These data support the possibility of using (68)Ga-NOTA-C6 in PET to visualize tumors that overexpress MMP2. CONCLUSIONS: (68)Ga-NOTA-C6 is a potential radiopharmaceutical for the imaging of in vivo MMP2 activity in tumors.