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1.
Artigo em Inglês | MEDLINE | ID: mdl-34519889

RESUMO

PURPOSE: Without a standard test for pancreatic carcinomas, this highly lethal disease is normally diagnosed at its advanced stage, leading to a low survival rate of patients. Trophoblast cell-surface antigen 2 (Trop-2), a transmembrane glycoprotein, is associated with cell proliferation and highly expressed in most of solid epithelial tumors, including pancreatic cancer. A non-invasive method of imaging Trop-2 would greatly benefit clinical diagnosis and monitoring of pancreatic cancer. In the current study, 89Zr-labeled anti-Trop-2 antibody (AF650) was recruited for the systemic evaluation of Trop-2 as an immunoPET target for pancreatic cancer imaging. METHODS: AF650 was conjugated with desferrioxamine (DFO) and then radiolabeled with 89Zr. Trop-2 expression levels were determined in three pancreatic cancer cell lines (BxPC-3, MIA PaCa-2, and AsPC-1) via western blot, flow cytometry, saturation binding assay, and immunofluorescence staining. The targeting capacity of 89Zr-DFO-AF650 was evaluated in mouse models with subcutaneous xenograft of pancreatic cancers via PET imaging and bio-distribution studies. In addition, a Trop-2-positive orthotopic cancer model was recruited for further validating the targeting specificity of 89Zr-DFO-AF650. RESULTS: BxPC-3 cells expressed high levels of Trop-2, while AsPC-1 and MIA PaCa-2 cells expressed low levels of Trop-2. Additionally, 89Zr-DFO-AF650 exhibited high specificity to Trop-2 in BxPC-3 cells (Kd = 22.34 ± 2.509 nM). In subcutaneous xenograft models, about 28.8 ± 7.63%ID/g tracer accumulated in the BxPC-3 tumors at 120 h post injection, which was much higher than those reaching MIA PaCa-2 (6.76 ± 2.08%ID/g) and AsPC-1 (3.51 ± 0.69%ID/g) tumors (n = 4). More importantly, 89Zr-DFO-AF650 could efficiently distinguish primary tumors in the orthotopic BxPC-3 cancer model, showing high correlation between PET imaging and bio-distribution and sensitivity. CONCLUSIONS: 89Zr-DFO-AF650 can be effectively used to detect pancreatic cancer via Trop-2-mediated immunoPET in vivo, clearly revealing the great potential of Trop-2-based non-invasive imaging in pancreatic cancer detection and treatment monitoring.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34512928

RESUMO

In our previous work, we developed an automated tool, AutoVEM, for real-time monitoring the candidate key mutations and epidemic trends of SARS-CoV-2. In this research, we further developed AutoVEM into AutoVEM2. AutoVEM2 is composed of three modules, including call module, analysis module, and plot module, which can be used modularly or as a whole for any virus, as long as the corresponding reference genome is provided. Therefore, it's much more flexible than AutoVEM. Here, we analyzed three existing viruses by AutoVEM2, including SARS-CoV-2, HBV and HPV-16, to show the functions, effectiveness and flexibility of AutoVEM2. We found that the N501Y locus was almost completely linked to the other 16 loci in SARS-CoV-2 genomes from the UK and Europe. Among the 17 loci, 5 loci were on the S protein and all of the five mutations cause amino acid changes, which may influence the epidemic traits of SARS-CoV-2. And some candidate key mutations of HBV and HPV-16, including T350G of HPV-16 and C659T of HBV, were detected. In brief, we developed a flexible automated tool to analyze candidate key mutations and epidemic trends for any virus, which would become a standard process for virus analysis based on genome sequences in the future.

3.
Mol Pharm ; 18(9): 3544-3552, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34482695

RESUMO

Maternal embryo leucine zipper kinase (MELK) is a serine/threonine kinase and is highly expressed in triple-negative breast cancer (TNBC). This study aimed to develop a 18F-radiolabeled tracer based on the structure of a small-molecule MELK inhibitor OTSSP167 and evaluate its application for PET imaging of MELK expression in TNBC. OTSSP167 was modified with ethylene glycol to adjust its pharmacokinetics and was then radiolabeled with 18F to obtain [18F]F-ET-OTSSP167 at a labeling yield of 7.14 ± 2.19% and a molar activity of 16.23 ± 1.13 MBq/nmol. In vitro binding assays showed differentiated binding affinities of [18F]F-ET-OTSSP167 in different breast cancer cell lines, with high uptake in MDA-MB-231 (mild MELK expression) and low uptake in MCF-7 (negative MELK expression). PET imaging revealed that MDA-MB-231 tumors could be clearly delineated in vivo, while low tracer uptake was observed in MCF-7 tumors. These findings were confirmed by ex vivo biodistribution studies and were consistent with the immunohistochemistry and tissue staining results. Tracer accumulation in MDA-MB-231 tumors was significantly inhibited by excess amounts of OTSSP167, indicating high specificity of the tracer. In summary, [18F]F-ET-OTSSP167, an easily-prepared probe, can be used to visualize MELK positive tumors, demonstrating its promising clinical potential in selecting patients for MELK inhibitor therapy.

4.
Theranostics ; 11(18): 9177-9179, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34522233

RESUMO

Ideal nuclear imaging tracers should exhibit high target uptake and low background signal. Traditional renal scintigraphy and SPECT scans examine kidney function via static or dynamic tracing of radioactive probes in the kidneys. The lack of tracer affinity to specific biological processes and high background uptake from urinary excretion have added many difficulties to precision renal diagnosis. In this issue of Theranostics, Jin and colleagues innovatively devised a recombinant probe for preferential kidney imaging through targeting of tubular neonatal Fc receptor and proximal tubular basement membrane for sustained tubular reabsorption and accumulation. This work has broad implications regarding how an in depth understanding of physiology and pathology may be of service for tracer development, renal diagnosis, and disease theranostics.

5.
Pharmaceutics ; 13(8)2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34452187

RESUMO

Highly efficient drug delivery systems with excellent tumor selectivity and minimal toxicity to normal tissues remain challenging for tumor treatment. Although great effort has been made to prolong the blood circulation and improve the delivery efficiency to tumor sites, nanomedicines are rarely approved for clinical application. Bacteria have the inherent properties of homing to solid tumors, presenting themselves as promising drug delivery systems. Escherichia coli Nissle 1917 (EcN) is a commonly used probiotic in clinical practice. Its facultative anaerobic property drives it to selectively colonize in the hypoxic area of the tumor for survival and reproduction. EcN can be engineered as a bacteria-based microrobot for molecular imaging, drug delivery, and gene delivery. This review summarizes the progress in EcN-mediated tumor imaging and therapy and discusses the prospects and challenges for its clinical application. EcN provides a new idea as a delivery vehicle and will be a powerful weapon against cancer.

6.
J Nanostructure Chem ; : 1-19, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34367531

RESUMO

Silver nanowires (AgNWs), as one-dimensional nanometallic materials, have attracted wide attention due to the excellent electrical conductivity, transparency and flexibility, especially in flexible and stretchable electronics. However, the microscopic discontinuities require AgNWs be attached to some carrier for practical applications. Relative to the preparation method, how to integrate AgNWs into the flexible matrix is particularly important. In recent years, plenty of papers have been published on the preparation of conductors based on AgNWs, including printing techniques, coating techniques, vacuum filtration techniques, template-assisted assembly techniques, electrospinning techniques and gelating techniques. The aim of this review is to discuss different assembly method of AgNW-based conducting film and their advantages. Conducting films based on silver nanowires (AgNWs) have been reviewed with a focus on their assembly and their advantages.

7.
Can J Gastroenterol Hepatol ; 2021: 8882129, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34222137

RESUMO

Background: One of the microRNAs (miRNAs) known to be associated with cancer development is miR-607. The aim of this study is to investigate the clinical significance and diagnostic and prognostic value of miR-607 and to explore its potential role in pancreatic ductal adenocarcinoma (PDAC). Methods: The expression levels of miR-607 were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). The correlation between miR-607 expression and clinical characteristics was analyzed by the Chi-square test. Overall survival (OS) and progression-free survival (PFS) were evaluated via the Kaplan-Meier method, and the association between miR-607 expression and OS was investigated by the Cox proportional hazard analysis. The diagnostic value was estimated via receiver operating characteristic (ROC) curve analysis. The effect of miR-607 overexpression on cell migration, invasion, and epithelial-mesenchymal transition (EMT) was determined by wound-healing, Transwell invasion, and Western blotting assays. Results: miR-607 levels were downregulated in PDAC tumor tissues compared with normal tissues. Also, low miR-607 levels were observed in serum samples from PDAC patients than that in healthy controls. The miR-607 level was found to be closely correlated with lymphatic metastasis and liver metastasis, perineural invasion, and OS and PFS, and the low miR-607 level was an independent prognostic factor for the poor OS of PDAC patients. Furthermore, the area under the curve (AUC) of serum miR-607 for discriminating PDAC patients was 0.785 with a sensitivity of 0.647 and a specificity of 0.772, which was better than those for CA19-9 (AUC: 0.702, sensitivity: 0.607, specificity: 0.736) and CEA (AUC: 0.648, sensitivity: 0.542, specificity: 0.670). The AUC (0.863), sensitivity (0.766), and specificity (0.831) of their combination in the diagnosis of PDAC were better than those for alone. Moreover, ectopic overexpression of miR-607 could inhibit cell migration and invasion of BxPc-3 and PANC-1 cells by decreasing EMT ability. Conclusions: Low serum miR-607 level may serve as a potential diagnostic and prognostic biomarker through regulation of tumor metastasis in PDAC patients.


Assuntos
Carcinoma Ductal Pancreático , MicroRNAs , Neoplasias Pancreáticas , Biomarcadores Tumorais/sangue , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/sangue , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Prognóstico
8.
Theranostics ; 11(14): 6800-6817, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093854

RESUMO

Chimeric antigen receptor T cell (CAR-T) therapy is a new and effective form of adoptive cell therapy that is rapidly entering the mainstream for the treatment of CD19-positive hematological cancers because of its impressive effect and durable responses. Huge challenges remain in achieving similar success in patients with solid tumors. The current methods of monitoring CAR-T, including morphological imaging (CT and MRI), blood tests, and biopsy, have limitations to assess whether CAR-T cells are homing to tumor sites and infiltrating into tumor bed, or to assess the survival, proliferation, and persistence of CAR-T cells in solid tumors associated with an immunosuppressive microenvironment. Radionuclide-based molecular imaging affords improved CAR-T cellular visualization and therapeutic monitoring through either a direct cellular radiolabeling approach or a reporter gene imaging strategy, and endogenous cell imaging is beneficial to reflect functional information and immune status of T cells. Focusing on the dynamic monitoring and precise assessment of CAR-T therapy, this review summarizes the current applications of radionuclide-based noninvasive imaging in CAR-T cells visualization and monitoring and presents current challenges and strategic choices.


Assuntos
Antígenos de Neoplasias/imunologia , Imunoterapia Adotiva/métodos , Imagem Molecular/métodos , Neoplasias/diagnóstico por imagem , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T/imunologia , Microambiente Tumoral , Animais , Genes Reporter , Humanos , Camundongos , Radioisótopos , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Tomografia Computadorizada por Raios X , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Nanobiotechnology ; 19(1): 151, 2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34022897

RESUMO

BACKGROUD: Colon cancer contributes to high mortality rates as the result of incomplete resection in tumor surgery. Multimodal imaging can provide preoperative evaluation and intraoperative image-guiding. As biocompatible nanocarriers, extracellular vesicles hold great promise for multimodal imaging. In this study, we aim to synthesized an extracellular vesicles-based nanoprobe to visualize colon cancer with positron-emission tomography/computed tomography (PET/CT) and near-infrared fluorescence (NIRF) imaging, and investigated its utility in image-guided surgery of colon cancer in animal models. RESULTS: Extracellular vesicles were successfully isolated from adipose-derived stem cells (ADSCs), and their membrane vesicles were observed under TEM. DLS detected that the hydrodynamic diameters of the extracellular vesicles were approximately 140 nm and the zeta potential was - 7.93 ± 0.24 mV. Confocal microscopy showed that extracellular vesicles had a strong binding ability to tumor cells. A click chemistry-based pre-targeting strategy was used to achieve PET imaging in vivo. PET images and the biodistribution results showed that the best pre-targeting time was 20 h, and the best imaging time was 2 h after the injection of 68 Ga-L-NETA-DBCO. The NIRF images showed that the tumor had clear images at all time points after administration of nanoparticles and the Tumor/Muscle ratio peaked at 20 h after injection. Our data also showed that both PET/CT and NIRF imaging clearly visualized the orthotopic colon cancer models, providing preoperative evaluation. Under real-time NIRF imaging, the tumor location and tumor boundary could be clearly observed. CONCLUSIONS: In brief, this novel nanoprobe may be useful for multi-modal imaging of colon cancer and NIRF image-guided surgery. More importantly, this study provides a new possibility for clinical application of extracellular vesicles as nanocarriers.

10.
Adv Sci (Weinh) ; 8(10): 2001879, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34026426

RESUMO

Lymphoma is a heterogeneous disease with varying clinical manifestations and outcomes. Many subtypes of lymphoma, such as Burkitt's lymphoma and diffuse large B cell lymphoma, are highly aggressive with dismal prognosis even after conventional chemotherapy and radiotherapy. As such, exploring specific biomarkers for lymphoma is of high clinical significance. Herein, a potential marker, CD38, is investigated for differentiating lymphoma. A CD38-targeting monoclonal antibody (mAb, daratumumab) is then radiolabeled with Zr-89 and Lu-177 for theranostic applications. As the diagnostic component, the Zr-89-labeled mAb is highly specific in delineating CD38-positive lymphoma via positron emission tomography (PET) imaging, while the Lu-177-labeled mAb serves well as the therapeutic component to suppress tumor growth after a one-time administration. These results strongly suggest that CD38 is a lymphoma-specific marker and prove that 89Zr/177Lu-labeled daratumumab facilitates immunoPET imaging and radioimmunotherapy of lymphoma in preclinical models. Further clinical evaluation and translation of this CD38-targeted theranostics may be of significant help in lymphoma patient stratification and management.

11.
Nano Lett ; 21(11): 4692-4699, 2021 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-34029471

RESUMO

Theranostic nanoparticles hold the potential to greatly improve cancer management by providing personalized medicine. Although many theranostic nanoconstructs have been successful in preclinical studies, clinical translation is still hampered by their limited targeting capability and lack of successful therapeutic efficacy. We report the use of novel ultrasmall porous silica nanoparticles (UPSN) with enhanced in vivo pharmacokinetics such as high target tissue accumulation (12% ID/g in the tumor) and evasion from the reticuloendothelial system (RES) organs. Herein, UPSN is conjugated with the isotopic pair 90/86Y, enabling both noninvasive imaging as well as internal radiotherapy. In vivo PET imaging demonstrates prolonged blood circulation and excellent tumor contrast with 86Y-DOTA-UPSN. Tumor-to-muscle and tumor-to-liver uptake values were significantly high (12.4 ± 1.7 and 1.5 ± 0.5, respectively), unprecedented for inorganic nanomaterials. 90Y-DOTA-UPSN significantly inhibits tumor growth and increases overall survival, indicating the promise of UPSN for future clinical translation as a cancer theranostic agent.


Assuntos
Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Humanos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Porosidade , Medicina de Precisão , Dióxido de Silício
12.
Artigo em Inglês | MEDLINE | ID: mdl-33841748

RESUMO

With the global epidemic of SARS-CoV-2, it is important to effectively monitor the variation, haplotype subgroup epidemic trends and key mutations of SARS-CoV-2 over time. This is of great significance to the development of new vaccines, the update of therapeutic drugs, and the improvement of detection methods. The AutoVEM tool developed in the present study could complete all mutations detections, haplotypes classification, haplotype subgroup epidemic trends and candidate key mutations analysis for 131,576 SARS-CoV-2 genome sequences in 18 hours on a 1 core CPU and 2GB RAM computer. Through haplotype subgroup epidemic trends analysis of 131,576 genome sequences, the great significance of the previous 4 specific sites (C241T, C3037T, C14408T and A23403G) was further revealed, and 6 new mutation sites of highly linked (T445C, C6286T, C22227T, G25563T, C26801G and G29645T) were discovered for the first time that might be related to the infectivity, pathogenicity or host adaptability of SARS-CoV-2. In brief, we proposed an integrative method and developed an efficient automated tool to monitor haplotype subgroup epidemic trends and screen for the candidate key mutations in the evolution of SARS-CoV-2 over time for the first time, and all data could be updated quickly to track the prevalence of previous key mutations and new candidate key mutations because of high efficiency of the tool. In addition, the idea of combinatorial analysis in the present study can also provide a reference for the mutation monitoring of other viruses.

13.
Eur J Nucl Med Mol Imaging ; 48(9): 2737-2748, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33537836

RESUMO

PURPOSE: We dual-labeled an intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody (mAb) and evaluated its effectiveness for lesion detection and surgical navigation in pancreatic ductal adenocarcinoma (PDAC) via multiple noninvasive imaging approaches, including positron emission tomography (PET), near-infrared fluorescence (NIRF), and Cerenkov luminescence imaging (CLI). METHODS: ICAM-1 expression in PDAC cell lines (BxPC-3 and AsPC-1) was assessed via flow cytometry and immunofluorescent staining. An ICAM-1 mAb labeled by IRDye 800CW and radionuclide zirconium-89 (denoted as [89Zr]Zr-DFO-ICAM-1-IR800) was synthesized. Its performance was validated via in vivo comparative PET/NIRF/CLI and biodistribution (Bio-D) studies in nude mice bearing subcutaneous BxPC-3/AsPC-1 tumors or orthotopic BxPC-3 tumor models using nonspecific IgG as an isotype control tracer. RESULTS: ICAM-1 expression was strong in the BxPC-3 and minimal in the AsPC-1 cell line. Both multimodality imaging and Bio-D data exhibited more prominent uptake of [89Zr]Zr-DFO-ICAM-1-IR800 in BxPC-3 tumors than in AsPC-1 tumors. The uptake of [89Zr]Zr-DFO-IgG-IR800 in BxPC-3 tumors was similar to that of [89Zr]Zr-DFO-ICAM-1-IR800 in AsPC-1 tumors. These results demonstrate the desirable affinity and specificity of [89Zr]Zr-DFO-ICAM-1-IR800 compared to [89Zr]Zr-DFO-IgG-IR800. Orthotopic BxPC-3 tumor foci could also be clearly delineated by [89Zr]Zr-DFO-ICAM-1-IR800. An intermodal match was achieved in the ICAM-1-targeted immunoPET/NIRF/CLI. The positive expression levels of ICAM-1 in BxPC-3 tumor tissue were further confirmed by immunohistopathology. CONCLUSION: We successfully developed a dual-labeled ICAM-1-targeted tracer for PET/NIRF/CLI of PDAC that can facilitate better diagnosis and intervention of PDAC upon clinical translation.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Carcinoma Ductal Pancreático/diagnóstico por imagem , Linhagem Celular Tumoral , Molécula 1 de Adesão Intercelular , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Distribuição Tecidual , Zircônio
14.
Eur J Nucl Med Mol Imaging ; 48(10): 3228-3237, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33609152

RESUMO

PURPOSE: To conduct a head-to-head comparison of the diagnostic ability of 68Ga-DOTA-FAPI-04 (68Ga-FAPI) and 18F-FDG PET/MR in nasopharyngeal carcinoma (NPC) patients. METHODS: Patients diagnosed with NPC were prospectively enrolled. All patients underwent head-and-neck 68Ga-FAPI PET/MR and 18F-FDG PET/MR within 1 week. Primary tumor, lymph node numbers, and tracer uptake were compared by SUVmax and visual evaluation. The primary tumor volumes derived from 68Ga-FAPI, 18F-FDG PET, and MRI were also compared. RESULTS: Fifteen patients were enrolled from June to August 2020. Both 68Ga-FAPI and 18F-FDG PET had 100% detection rate of the primary tumor. The 68Ga-FAPI SUVmax of primary tumors (13.87 ± 5.13) was lower than that of 18F-FDG (17.73 ± 6.84), but the difference was not significant (p = 0.078). Compared with 18F-FDG, 68Ga-FAPI PET improved the delineation of skull-base invasion in eight out of eight patients and intracranial invasion in four out of four patients. When 25%SUVmax of 68Ga-FAPI or 20%SUVmax of 18F-FDG was utilized as a threshold for determining tumor volume, it was highly consistent with MRI. 18F-FDG PET detected much more positive lymph nodes than 68Ga-FAPI (100 vs 48). The SUVmax of 48 paired lymph nodes was significantly lower on 68Ga-FAPI than 18F-FDG (8.67 ± 3.88 vs 11.79 ± 6.17, p < 0.001). Additionally, 68Ga-FAPI further detected four highly suspected small, distant metastases in three patients. Compared with 18F-FDG, 68Ga-FAPI changed overall staging in six of fifteen patients, with three patients being up-staged, and three down-staged. CONCLUSION: 68Ga-FAPI outperforms 18F-FDG in delineating the primary tumor and detecting suspected distant metastases, particularly in the evaluation of skull-base and intracranial invasion, suggesting 68Ga-FAPI hybrid PET/MR has the potential to serve as a single-step staging modality for patients with NPC. However, its value regarding lymph node and distant metastases evaluation needs further study. TRIAL REGISTRATION: NCT04554719. Registered September 8, 2020 - retrospectively registered, http://clinicaltrails.gov/show/NCT04554719.


Assuntos
Fluordesoxiglucose F18 , Neoplasias Nasofaríngeas , Radioisótopos de Gálio , Humanos , Imageamento por Ressonância Magnética , Carcinoma Nasofaríngeo/diagnóstico por imagem , Neoplasias Nasofaríngeas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Prospectivos , Quinolinas
15.
J Healthc Eng ; 2021: 6656204, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33628404

RESUMO

With the close integration of science and technology and health, the broad application prospects of healthy interconnection bring revolutionary changes to health services. Health and medical wearable devices can collect real-time data related to user health, such as user behavior, mood, and sleep, which have great commercial and social value. Healthcare wearable devices, as important network nodes for health interconnection, connect patients and hospitals with the Internet of Things and sensing technology to form a huge medical network. As wearable devices can also collect user data regardless of time and place, uploading data to the cloud can easily make the wearable device's system vulnerable to attacks and data leakage. Defects in technology can sometimes cause problems such as lack of control over data flow links in wearable devices, and data and privacy leaks are more likely to occur. In this regard, how to ensure the data security and user privacy while using healthcare wearable devices to collect data is a problem worth studying. This article investigates data from healthcare wearable devices, from technical, management, and legal aspects, and studies data security and privacy protection issues for healthcare wearable devices to protect data security and user privacy and promote the sustainable development of the healthcare wearable device industry and the scientific use of data collection.

16.
Bioconjug Chem ; 32(7): 1306-1314, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-33475350

RESUMO

The overexpression of CD146 in breast cancer is considered a hallmark of tumor progression and metastasis, particularly in triple negative breast cancer. Aimed at imaging differential CD146 expressions in breast cancer, a noninvasive method for predictive prognosis and diagnosis was investigated using a 64Cu-labeled CD146-specific monoclonal antibody, YY146. CD146 expression was screened in human breast cancer cell lines using Western blotting. Binding ability was evaluated using flow cytometry and immunofluorescent staining. YY146 was conjugated with 1,4,7-triazacyclononane-triacetic acid (NOTA) and radiolabeled with 64Cu following standard procedures. Serial PET or PET/CT imaging was performed in orthotopic and metastatic breast cancer tumor models. Biodistribution was performed after the final time point of imaging. Finally, tissue immunofluorescent staining and hematoxylin and eosin (H&E) staining were performed on tumor tissues. The MDA-MB-435 cell line showed the highest CD146 expression level, whereas MCF-7 had the lowest level at the cellular level. ImmunoPET showed that MDA-MB-435 orthotopic tumors had high and clear radioactive accumulation after the administration of 64Cu-NOTA-YY146. The tumor uptake of 64Cu-NOTA-YY146 in MDA-MB-435 was significantly higher than that in MCF-7 and nonspecific IgG control groups (P < 0.01). Biodistribution verified the PET imaging results. For metastatic models, 64Cu-NOTA-YY146 allowed for the visualization of high radioactivity accumulation in metastatic MDA-MB-435 tumors, which was confirmed by ex vivo biodistribution of lung tissues. H&E staining proved the successful building of metastatic tumor models. Immunofluorescent staining verified the differential expression of CD146 in orthotopic tumors. Therefore, 64Cu-NOTA-YY146 could be used as an immunoPET probe to visualize CD146 in the breast cancer model and is potentially useful for cancer diagnosis, prognosis prediction, and monitoring therapeutic response.

17.
J Nucl Med ; 62(3): 372-378, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32826320

RESUMO

CD20-overexpressed non-Hodgkin lymphoma typically indicates progressive malignancy. Obinutuzumab is a next-generation Food and Drug Administration-approved humanized monoclonal antibody that targets CD20. Previous studies with 89Zr-labeled obinutuzumab have successfully imaged CD20 in vivo. However, delayed tumor uptake and increased radioactive exposure caused by long blood circulation limit its clinical translation. This study aimed to develop 64Cu-labeled F(ab')2 fragments of obinutuzumab for imaging CD20 in lymphoma xenograft tumor models. Methods: F(ab')2 fragments were produced from obinutuzumab using an IgG-degrading enzyme of Streptococcus pyogenes (IdeS) enzyme and purified with protein A beads. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and high-performance liquid chromatography were performed to evaluate the products and their stability. F(ab')2 products were conjugated with p-SCN-Bn-NOTA (NOTA) for 64Cu radiolabeling. Western blotting was performed to screen the CD20 expression levels of lymphoma cells. Enzyme-linked immunosorbent assay, flow cytometry, and confocal imaging were used to test the binding affinity in vitro. Serial PET imaging and biodistribution studies in subcutaneous lymphoma-bearing mice were performed using 64Cu-NOTA-F(ab')2-obinutuzumab or 64Cu-NOTA-F(ab')2-IgG. Results: F(ab')2-obinutuzumab and F(ab')2-IgG produced by the IdeS digestion system were confirmed with sodium dodecyl sulfate polyacrylamide gel electrophoresis and high-performance liquid chromatography. The radiochemical purity of 64Cu-labeled F(ab')2 fragments was no less than 98%, and the specific activity was 56.3 ± 7.9 MBq/mg (n = 6). Among the 5 lymphoma cell lines, Ramos showed the strongest expression of CD20, and CLL-155 showed the lowest, as confirmed by enzyme-linked immunosorbent assay, flow cytometry, and confocal imaging. PET imaging revealed rapid and sustained tumor uptake of 64Cu-NOTA-F(ab')2-obinutuzumab in Ramos tumor-bearing mice. The peak tumor uptake (9.08 ± 1.67 percentage injected dose per gram of tissue [%ID/g]) in the Ramos model was significantly higher than that in the CCL-155 model (2.78 ± 0.62 %ID/g) or the 64Cu-NOTA-F(ab')2-IgG control (1.93 ± 0.26 %ID/g, n = 4, P < 0.001). The tumor-to-blood and tumor-to-muscle ratios were 7.3 ± 1.6 and 21.9 ± 9.0, respectively, at 48 h after injection in the 64Cu-NOTA-F(ab')2-obinutuzumab group. Of the measured off-target organs, the kidneys showed the highest uptake. Ex vivo immunofluorescent staining verified the differential CD20 expression in the Ramos and CCL-155 tumor models. Conclusion: This study demonstrated that 64Cu-NOTA-F(ab')2-obinutuzumab had a rapid and sustained tumor uptake in CD20-positive lymphoma with high contrast, which could enable noninvasive evaluation of CD20 levels in the clinic.


Assuntos
Anticorpos Monoclonais Humanizados/imunologia , Antígenos CD20/metabolismo , Radioisótopos de Cobre/química , Regulação Neoplásica da Expressão Gênica , Fragmentos Fab das Imunoglobulinas/química , Linfoma/metabolismo , Animais , Antígenos CD20/imunologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Humanos , Marcação por Isótopo , Linfoma/diagnóstico por imagem , Masculino , Camundongos
18.
J Clin Lab Anal ; 35(1): e23587, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32960485

RESUMO

OBJECTIVE: Long noncoding RNAs (lncRNAs) are involved in the proliferation, migration, and invasion of tumors. In the current study, our aim was to explore the role of lncRNA plasmacytoma variant translocation gene 1 (PVT1) in osteosarcoma. METHODS: Quantitative real-time reverse transcription-polymerase chain reaction was used to detect the expression of lncRNA PVT1 in osteosarcoma tissues and cells. The relationship between lncRNA PVT1 expression status and the prognosis of patients with osteosarcoma was analyzed. The effect of lncRNA PVT1 on the malignant biological behavior of osteosarcoma cells in vitro was also analyzed. RESULTS: LncRNA PVT1 was upregulated in osteosarcoma. High lncRNA PVT1 expression indicated poor prognosis in patients with osteosarcoma. In vitro knockdown of lncRNA PVT1 inhibited the proliferation, migration, and invasion ability of osteosarcoma cells. In addition, we confirmed that lncRNA PVT1 affected the epithelial-mesenchymal transition of osteosarcoma cells. CONCLUSION: LncRNA PVT1 is a potential therapeutic target for osteosarcoma.

19.
Appl Bionics Biomech ; 2020: 8841400, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33273965

RESUMO

This paper proposes a bionic flexible wrist parallel mechanism to simulate human wrist joints, which is characterized by a rope-driven, compression spring-supported hybrid mechanism. Specifically, to realize the movement of the wrist mechanism, a parallel structure is adopted to support the mobile platform and is controlled by a cable, which plays the role of wrist muscles. Because the compression spring is elastic, it is difficult to directly solve inverse kinematics. To address this problem, the external force acting on the moving platform is firstly equivalent to the vector force and torque at the center of the moving platform. Then, based on inverse kinematic and static analyses, the inverse motion of the robot model can be solved according to the force and torque balance conditions and the lateral spring bending equation of the compression spring. In order to verify the proposed method, kinematics, statics, and parallel mechanism workspace are further analyzed by the software MATLAB. The obtained results demonstrate the effectiveness and feasibility of the designed parallel mechanism. This work offers new insights into the parallel mechanism with flexible joints in replicating the movements of the human wrist, thus promoting the development of rehabilitation robots and rope-driven technology to some extent.

20.
J Virol ; 94(24)2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-32999030

RESUMO

Porcine reproductive and respiratory syndrome virus (PRRSV) infection eliminates production of type I interferons (IFNs) in host cells, which triggers an antiviral immune response through the induction of downstream IFN-stimulated genes (ISGs), thus escaping the fate of host-mediated clearance. The IFN-induced transmembrane 3 (IFITM3) has recently been identified as an ISG and plays a pivotal role against enveloped RNA viruses by restricting cell entry. However, the role of IFITM3 in PRRSV replication is unknown. The present study demonstrated that overexpression of IFITM3 suppresses PRRSV replication, while silencing of endogenous IFITM3 prominently promoted PRRSV replication. Additionally, it was shown that IFITM3 undergoes S-palmitoylation and ubiquitination modification, and both posttranslational modifications contribute to the anti-PRRSV activity of IFITM3. Further study showed that PRRSV particles are transported into endosomes and then into lysosomes during the early stages of infection, and confocal microscopy results revealed that PRRSV particles are transported to IFITM3-positive cellular vesicles. By using a single virus particle fluorescent labeling technique, we confirmed that IFITM3 can restrict PRRSV membrane fusion by inducing accumulation of cholesterol in cellular vesicles. Additionally, we found that both endogenous and exogenous IFITM3 are incorporated into newly producing PRRS virions and diminish viral intrinsic infectivity. By using cell coculture systems, we found that IFITM3 effectively restricted PRRSV intercellular transmission, which may have been caused by disrupted membrane fusion and reduced viral infectivity. In conclusion, our results demonstrate, for the first time, that swine IFITM3 interferes with the life cycle of PRRSV, and possibly other enveloped arteritis viruses, at multiple steps.IMPORTANCE Porcine reproductive and respiratory syndrome (PRRS), which is caused by PRRS virus (PRRSV), is of great economic significance to the swine industry. Due to the complicated immune escape mechanisms of PRRSV, there are no effective vaccines or therapeutic drugs currently available against PRRS. Identification of cellular factors and underlying mechanisms that establish an effective antiviral state against PRRSV can provide unique strategies for developing antiviral vaccines or drugs. As an interferon (IFN)-stimulated gene, the role of IFN-induced transmembrane 3 (IFITM3) in PRRSV infection has not been reported as of yet. In the present study, it was shown that IFITM3 can exert a potent anti-PRRSV effect, and PRRS virions are trafficked to IFITM3-containing cell vesicles, where viral membrane fusion is impaired by cholesterol accumulation that is induced by IFITM3. Additionally, both endogenous and exogenous IFITM3 are incorporated into newly assembled progeny virions, and this decreased their intrinsic infectivity.


Assuntos
Interferon Tipo I/metabolismo , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia , Proteínas Virais/metabolismo , Internalização do Vírus , Animais , Linhagem Celular , Colesterol/metabolismo , Endossomos/metabolismo , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Lisossomos/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Síndrome Respiratória e Reprodutiva Suína/imunologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Suínos , Vírion/metabolismo , Montagem de Vírus , Replicação Viral
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