Publications by authors named "Zihua Wang"

96 Publications

Rates of contributory de novo mutation in high and low-risk autism families.

Commun Biol 2021 09 1;4(1):1026. Epub 2021 Sep 1.

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA.

Autism arises in high and low-risk families. De novo mutation contributes to autism incidence in low-risk families as there is a higher incidence in the affected of the simplex families than in their unaffected siblings. But the extent of contribution in low-risk families cannot be determined solely from simplex families as they are a mixture of low and high-risk. The rate of de novo mutation in nearly pure populations of high-risk families, the multiplex families, has not previously been rigorously determined. Moreover, rates of de novo mutation have been underestimated from studies based on low resolution microarrays and whole exome sequencing. Here we report on findings from whole genome sequence (WGS) of both simplex families from the Simons Simplex Collection (SSC) and multiplex families from the Autism Genetic Resource Exchange (AGRE). After removing the multiplex samples with excessive cell-line genetic drift, we find that the contribution of de novo mutation in multiplex is significantly smaller than the contribution in simplex. We use WGS to provide high resolution CNV profiles and to analyze more than coding regions, and revise upward the rate in simplex autism due to an excess of de novo events targeting introns. Based on this study, we now estimate that de novo events contribute to 52-67% of cases of autism arising from low risk families, and 30-39% of cases of all autism.
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http://dx.doi.org/10.1038/s42003-021-02533-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410909PMC
September 2021

Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies.

Dev Cell 2021 Sep 4;56(17):2427-2439.e4. Epub 2021 Aug 4.

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address:

Aneuploidy is a ubiquitous feature of human tumors, but the acquisition of aneuploidy typically antagonizes cellular fitness. To investigate how aneuploidy could contribute to tumor growth, we triggered periods of chromosomal instability (CIN) in human cells and then exposed them to different culture environments. We discovered that transient CIN reproducibly accelerates the acquisition of resistance to anti-cancer therapies. Single-cell sequencing revealed that these resistant populations develop recurrent aneuploidies, and independently deriving one chromosome-loss event that was frequently observed in paclitaxel-resistant cells was sufficient to decrease paclitaxel sensitivity. Finally, we demonstrated that intrinsic levels of CIN correlate with poor responses to numerous therapies in human tumors. Our results show that, although CIN generally decreases cancer cell fitness, it also provides phenotypic plasticity to cancer cells that can allow them to adapt to diverse stressful environments. Moreover, our findings suggest that aneuploidy may function as an under-explored cause of therapy failure.
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http://dx.doi.org/10.1016/j.devcel.2021.07.009DOI Listing
September 2021

Novel Environmentally Friendly Waterborne Epoxy Coating with Long-Term Antiscaling and Anticorrosion Properties.

Langmuir 2021 08 27;37(31):9439-9450. Epub 2021 Jul 27.

Chemistry and Chemical Engineering College, Northeast Petroleum University, Daqing 163000, P. R. China.

Metal pipes in industrial production are exposed to various corrosive ions. The combined action of these ions with oxygen in water causes corrosion and contamination of the metal pipes and equipment. In addition, metallic ions in water react with anions to form scale on the surface of the metal, which significantly reduces the service life of the metal and equipment, resulting in safety hazards. Waterborne coatings have attracted tremendous attention due to the less negative impact on the environment, but their practical applications are severely restricted by poor barrier properties and poor mechanical durability. Herein, the barrier properties of water-based coatings are successfully improved by adding functional slow-release nanofillers, and the fillers also endow the coating with excellent antiscaling properties. A functional slow-release nanofiller (lecithin/SiO/HEDP) was prepared using HEDP (etidronic acid) as the scale inhibitor active material and SiO as the carrier, combined with a phospholipid membrane with slow-release permeability. With the addition of slow-release fillers, compared with the EP coating, the impedance modulus of composite coatings increases about 1 order of magnitude, the scale inhibition rate is as high as 80.7%, and the antiscaling life is double that of the coating without the phospholipid-coated filler. Thus, this study is expected to provide a new perspective for the preparation of new slow-release fillers and high-efficiency scale inhibitor coatings.
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http://dx.doi.org/10.1021/acs.langmuir.1c01124DOI Listing
August 2021

Transcriptome landscape of the late-stage alcohol-induced osteonecrosis of the human femoral head.

Bone 2021 09 18;150:116012. Epub 2021 May 18.

Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China; Laboratory of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China; National-Local Joint Engineering Laboratory for the Development of Orthopedic Implant Materials, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China. Electronic address:

Osteonecrosis resulting from heavy ethanol consumption is one of the major causes of nontraumatic osteonecrosis of the femoral head (ONFH). The underlying pathological and molecular mechanisms remain elusive. In this study, we performed deep RNA sequencing from femoral heads of patients diagnosed with late-stage alcohol-induced ONFH (AIONFH), other types of ONFH and traumatic injury (bone fracture). Genome-wide gene expression analyses identified 690 differentially expressed mRNAs in AIONFH. Gene annotation and pathway analyses revealed significant dysregulated genes involved in hemostasis, angiogenesis and bone remodeling processes from the late-stage AIONFH. Notably, ADH1B, which codes for one of the major alcohol dehydrogenases, is significantly upregulated in AIONFH samples. Further, we found that the ADH1B protein was primarily expressed in smooth muscle cells of the blood vessels, stromal cells and adipocytes of the femoral heads of AIONFH patients; but was absent in other ONFH samples. Our analyses also revealed unique long non-coding RNA (lncRNA) expression profiles and identified novel lncRNAs in AIONFH. In addition, we observed a close co-expression correlation between lncRNAs and mRNAs in AIONFH suggesting that cis-gene regulation represents a major mechanism of action of human femoral lncRNAs. Further, the expression signature of lncRNAs, but not mRNAs, distinguishes AIONFH from other types of ONFH. Taken together, our studies uncovered novel molecular signatures associated with late-stage AIONFH in which the dysregulation of several key signaling pathways within the femoral head may be involved in AIONFH. Subsequently, lncRNAs may serve as potential biomarkers for diagnosis and therapeutic treatment of AIONFH. Further studies are needed to confirm that ADH1B is specifically upregulated in AIONFH and not generally upregulated in patients who consume alcohol excessively.
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http://dx.doi.org/10.1016/j.bone.2021.116012DOI Listing
September 2021

Novel Peptide-Based Magnetic Nanoparticle for Mesenchymal Circulating Tumor Cells Detection.

Anal Chem 2021 04 31;93(14):5670-5675. Epub 2021 Mar 31.

CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China.

The monitoring of circulating tumor cells (CTCs) has recently served as a promising approach for assessing prognosis and evaluating cancer treatment. We have already developed a CTCs enrichment platform by EpCAM recognition peptide-functionalized magnetic nanoparticles ([email protected]). However, considering heterogeneous CTCs generated through epithelial-mesenchymal transition (EMT), mesenchymal CTCs would be missed with this method. Notably, N-cadherin, overexpressed on mesenchymal CTCs, can facilitate the migration of cancer cells. Hence, we screened a novel peptide targeting N-cadherin, NP, and developed a new CTCs isolation approach via [email protected] to complement EpCAM methods' deficiencies. [email protected] had a high capture efficiency (about 85%) of mesenchymal CTCs from spiked human blood. Subsequently, CTCs were captured and sequenced at the single-cell level via [email protected] and [email protected], RNA profiles of which showed that epithelial and mesenchymal subgroups could be distinguished. Here, a novel CTCs isolation platform laid the foundation for mesenchymal CTCs isolation and subsequent molecular analysis.
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http://dx.doi.org/10.1021/acs.analchem.1c00577DOI Listing
April 2021

Electrochemical sensor based on magnetic nanohybrids of multiple phthalocyanine doped ferrites/CMWCNTs for detection of rosmarinic acid.

Talanta 2021 May 2;226:122165. Epub 2021 Feb 2.

The Key Laboratory of Bioactive Materials Ministry of Education, College of Life Science, Nankai University, Weijin Road No.94, Tianjin, 300071, PR China. Electronic address:

Ferrites have attracted considerable attention in biosensor developments owing to their favorable electrochemical and magnetic properties. Speedy and trace analysis can be succeeded by the sensors based on magnetic nanohybrids. In this work, we reported a novel method for one-step synthesis of magnetic ferrites composed of Fe and phthalocyanine. After hybridization with carbonylated multi wall carbon nanotubes, a sensor based on FeO-Pc-CMWCNTs nanocomposites was fabricated for the detection of rosmarinic acid (RA), a bioactive phytochemical. The sensor can be constructed within 30s without any complicated process. A comparison of electrochemical activity between ZnFeO-Pc-CMWCNTs and FeO-Pc-CMWCNTs nanohybrids also has been accomplished in this work. Compared with ZnFeO-Pc-CMWCNTs based on commonly used ferrites, FeO-Pc-CMWCNTs/MGCE exhibited a higher catalytical ability for the detection of RA. The sensor modified with FeO-Pc-CMWCNTs displayed a low LOD of 0.182 μM with a wide linear range from 0.2 to 400 μM, which was 30 times more sensitive than the one based on ZnFeO-Pc-CMWCNTs. The obtained sensor also owned an excellent selectivity, reproducibility, repeatability, and stability, which made it achieve the measurements in plant sample and human serum.
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http://dx.doi.org/10.1016/j.talanta.2021.122165DOI Listing
May 2021

Ultrasensitive Gastric Cancer Circulating Tumor Cellular RNA Detection Based on a Molecular Beacon.

Anal Chem 2021 01 14;93(2):665-670. Epub 2020 Dec 14.

Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing 100142, China.

Gastric cancer (GC) is a major global cancer burden, and only HER2-targeted therapies have been approved in first line clinical therapy. CLDN18.2 has been regarded as a potential therapeutic target for gastrointestinal tumors, and global clinical trials have been in process. Hence, the precise, efficient, and noninvasive detection of CLDN18.2 expression is important for the effective application of this attractive target. A high similarity of protein sequence between CLDN18.1 and -18.2 made RNA become more suitable for the detection of CLDN18.2 expression. In this study, CLDN18.2 molecular beacon (MB) with a stem-loop hairpin structure was optimized by phosphorothioate and 2'--methyl for stability and efficiency. The MB could recognize RNA rapidly. Its resolution and selectivity has been verified in several model cells, demonstrating that MB can distinguish CLDN18.2 expression in several model cells. Furthermore, it was applied successfully to the circulating tumor cell (CTC) assay. The concordance in the expression of CLDN18.2 between CTCs and tissue biopsy is 100% (negative: 3 vs 3; positive: 7 vs 7), indicating that RNA detection in CTCs based on a MB will be a promising approach for searching potential patients to CLDN 18.2 targeted drug.
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http://dx.doi.org/10.1021/acs.analchem.0c04055DOI Listing
January 2021

A novel oriented immunosensor based on AuNPs-thionine-CMWCNTs and staphylococcal protein A for interleukin-6 analysis in complicated biological samples.

Anal Chim Acta 2020 Dec 16;1140:145-152. Epub 2020 Oct 16.

The Key Laboratory of Bioactive Materials Ministry of Education, College of Life Science, Nankai University, Weijin Road No.94, Tianjin, 300071, PR China. Electronic address:

Interleukin-6 (IL-6) is of high importance for disease diagnosis and prognosis in human health since it's a crucial component in immune homeostasis, hematopoiesis, and metabolism. Herein, an immunosensor has been developed for monitoring IL-6, which is fabricated by Au nanoparticles (Au NPs)-thionine (THI)-carboxylated multi walled carbon nanotubes (CMWCNTs) as the substrate with high conductivity. Staphylococcal protein A (SPA) could directionally capture antibody to reduce steric hindrance caused by random immobilization. Built upon the high efficiency of IL-6 antibody immobilization by the SPA on the sensing surface, the immunosensor exhibited a favorable activity for IL-6 detection. Under optimal conditions, the biosensor presented a LOD of 2.87 pg mL and a wide linear range from 0.01 ng mL to 800 ng mL in serum samples. Furthermore, the assembled sensor successfully quantified the IL-6 concentration in serum and different tissue lapping liquids (lung, heart, liver) from rats with myocardial infarction. The satisfactory performance of the proposed sensor not only broadens its application in clinical monitoring of IL-6 but also provides a novel approach to study inflammation in rats.
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http://dx.doi.org/10.1016/j.aca.2020.10.025DOI Listing
December 2020

Omentin-1 promotes mitochondrial biogenesis via PGC1α-AMPK pathway in chondrocytes.

Arch Physiol Biochem 2020 Sep 15:1-7. Epub 2020 Sep 15.

Department of Orthopaedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, China.

Objective: Omentin-1 is a newly discovered metabolic regulatory adipokine. Studies have shown that omentin-1 possesses pleiotropic effects in different types of cells. This study aims to investigate the regulation by omentin-1 on mitochondrial biogenesis in chondrocytes.

Methodology: C-28/I2 chondrocytes were treated with omentin-1 (150 and 300 ng/ml) for 24 h. The expression of mitochondrial regulators, markers and the DNA copy was assessed. The mitochondrial morphology was observed by electron microscopy. The mitochondrial respiratory rate and ATP production in chondrocytes were measured by cell lysates.

Results: Omentin-1 treatment up-regulated PGC-1α, NRF-1 and mitochondrial transcription factor A (TFAM) in cultured chondrocytes, indicating that omentin-1 could be involved in the regulation of mitochondrial function. Omentin-1 promoted mtDNA/nDNA and four mitochondrial genes (Tomm20, Tomm40, Timm9 and Atp5c1), mRNA transcripts as well as two mitochondrial protein expressions (SDHB and MTCO1). At a cellular level, omentin-1 enhanced the mitochondrial respiratory rate and ATP production. Mechanistically, we proved that omentin-1 increased AMPKα activation, and the blockage of AMPKα by its inhibitor compound C abolished the inductive effect of omentin-1 on PGC1α expression and mtDNA/nDNA ratio, indicating that the effect of omentin-1 is dependent on AMPKα activation.

Conclusion: Omentin-1 is a positive regulator of mitochondrial biogenesis in chondrocytes, and its action is dependent on the AMPK-PGC1α pathway. This study, therefore, implies that omentin-1 has the potential to remedy chondrocyte damage in the prevention and treatment of osteoarthritis.
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http://dx.doi.org/10.1080/13813455.2020.1819337DOI Listing
September 2020

A Novel CD133- and EpCAM-Targeted Liposome With Redox-Responsive Properties Capable of Synergistically Eliminating Liver Cancer Stem Cells.

Front Chem 2020 11;8:649. Epub 2020 Aug 11.

Key Laboratory of Brain Aging and Neurodegenerative Diseases of Fujian Provincial Universities and Colleges, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.

Cancer stem cells (CSCs) are a small subset of cells that sit atop the hierarchical ladder in many cancer types. Liver CSCs have been associated with high chemoresistance and recurrence rates in hepatocellular carcinoma (HCC). However, as of yet, no satisfactorily effective liver CSC-targeted treatment is available, which drove us to design and investigate the efficacy of a liposome-based delivery system. Here, we introduce a redox-triggered dual-targeted liposome, [email protected]/D, capable of co-delivering doxorubicin (Dox) and salinomycin (Sal) for the synergistic treatment of liver cancer. This system is based on the association of CD133- and EpCAM-targeted peptides to form Y-shaped CEP ligands that were anchored to the surface of the liposome and allowed the selective targeting of CD133 EpCAM liver CSCs. After arriving to the CSCs, the [email protected]/D liposome undergoes endocytosis to the cytoplasm, where a high concentration of glutathione (GSH) breaks its disulfide bonds, thereby degrading the liposome. This then induces a rapid release of Dox and Sal to synergistically inhibit tumor growth. Notably, this effect occurs through Dox-induced apoptosis and concurrent lysosomal iron sequestration by Sal. Interestingly, both and studies indicated that our GSH-responsive co-delivery system not only effectively enhanced CSC targeting but also eliminated the non-CSC faction, thereby exhibiting high antitumor efficacy. We believe that the smart liposome nanocarrier-based co-delivery system is a promising strategy to combat liver cancer, which may also lay the groundwork for more enhanced approaches to target other cancer types as well.
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http://dx.doi.org/10.3389/fchem.2020.00649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431664PMC
August 2020

Prediction of the Ki-67 marker index in hepatocellular carcinoma based on CT radiomics features.

Phys Med Biol 2020 12 18;65(23):235048. Epub 2020 Dec 18.

Department of Radiology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510180, People's Republic of China. Jinan University, Guangzhou 510632, Guangdong, People's Republic of China.

The noninvasive detection of tumor proliferation is of great value and the Ki-67 is a biomarker of tumor proliferation. We hypothesized that radiomics characteristics may be related to tumor proliferation. To evaluate whether computed tomography (CT) radiomics feature analyses could aid in assessing the Ki-67 marker index in hepatocellular carcinoma (HCC), we retrospectively analyzed preoperative CT findings of 74 patients with HCC. The texture feature calculations were computed from MaZda 4.6 software, and the sequential forward selection algorithm was used as the selection method. The correlation between radiomics features and the Ki-67 marker index, as well as the difference between low Ki-67 (<10%) and high Ki-67 (≥10%) groups were evaluated. A simple logistic regression model was used to evaluate the associations between texture features and high Ki-67, and receiver operating characteristic analysis was performed on important parameters to assess the ability of radiomics characteristics to distinguish the high Ki-67 group from the low Ki-67 group. Contrast, correlation, and inverse difference moment (IDM) were significantly different (P < 0.001) between the low and high Ki-67 groups. Contrast (odds ratio [OR] = 0.957; 95% confidence interval [CI]: 0.926-0.990, P = 0.01) and correlation (OR = 2.5☆105; 95% CI: 7.560-8.9☆109; P = 0.019) were considered independent risk factors for combined model building with logistic regression. Angular second moment (r = -0.285, P = 0.014), contrast (r = -0.449, P < 0.001), correlation (r = 0.552, P < 0.001), IDM (r = 0.458, P < 0.001), and entropy (r = 0.285, P = 0.014) strongly correlated with the Ki-67 scores. Contrast, correlation, and the combined predictor were predictive of Ki-67 status (P < 0.001), with areas under the curve ranging from 0.777 to 0.836. The radiomics characteristics of CT have potential as biomarkers for predicting Ki-67 status in patients with HCC. These findings suggest that the radiomics features of CT might be used as a noninvasive measure of cellular proliferation in HCC.
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http://dx.doi.org/10.1088/1361-6560/abac9cDOI Listing
December 2020

Construction of a novel bispecific fusion protein to enhance targeting for pancreatic cancer imaging.

Biomaterials 2020 10 30;255:120161. Epub 2020 May 30.

Department of Diagnostic Imaging, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. Electronic address:

Early detection and diagnosis are the most important endeavors for reducing associated morbidity and mortality of pancreatic ductal adenocarcinoma (PDAC). Developing molecular imaging probes that can specifically and effectively target cancer-associated biological pathways is one of the key points for sensitive and accurate diagnosis for PDAC. Herein, a small-sized, bispecific fusion protein constructed by genetic fusion of different binding domains of antibodies, termed Bi50, with enhanced targeting effect for PDAC is reported. Bi50 has excellent bispecific targeting for vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) simultaneously in vitro and in vivo. Additionally, Bi50 shows increased intratumoral permeability and enrichment characteristics in the tumor than the control protein, which is constructed directly connecting two individual Fabs. Moreover, Bi50 can not only target areas rich in vasculature but also bind with affinity to tumor parenchymal cells, achieving "multilevel" targeting effect. Our work demonstrates that the bispecific fusion protein Bi50 has great potential as an efficient, targeted molecular imaging probe.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120161DOI Listing
October 2020

Digital Subtraction Angiography and Magnetic Resonance Imaging-Based Staging of Circulatory Obstruction in the Femoral Head During Osteonecrosis of the Femoral Head Development.

Ann Plast Surg 2020 12;85(6):677-684

From the Department of Orthopedics.

Introduction: Nontraumatic osteonecrosis of the femoral head (NONFH) is a common and difficult disease in orthopedics. Magnetic resonance imaging (MRI) assessment of NONFH and bone marrow edema was combined with digital subtraction angiography (DSA) to evaluate the circulatory status of NONFH in different Association Research Circulation Osseous stages. Based on the circulatory obstruction status (venous stasis, arterial ischemia, and arterial occlusion), appropriate perioperative management was adopted to achieve hip joint preservation and effectively delay the time for total hip arthroplasty in young patients.

Methods: From January 2013 to March 2019, 41 orthopedic patients were evaluated for medical imaging. Sixty-one ONFH cases were enrolled. The inclusion criteria include: (1) Clear diagnosis of osteonecrosis of the femoral head. (2) No history of infection in the affected hip, no history of hip surgery, and no congenital hip diseases. The patients enrolled in this study were 8 women and 33 men between the ages of 19 and 64 years (mean, 39.25 ± 8.90 years). Preoperative X-ray, computed tomography, MRI, DSA, and histological data were taken.

Results: The combination of DSA and MRI can efficiently show blood supply changes in the femoral head of NONFH patients at different Association Research Circulation Osseous stages; and also can possibly reveal the causes and development of NONFH. Different stages of circulatory obstruction of the femoral head can be clearly distinguished and used to determine the required perioperative management, thus yielding successful surgical outcomes.

Conclusions: The existing classification systems do not fully reflect the progression of circulatory obstruction in ONFH. Each stage of NONFH development has its own characteristics circulatory obstruction. Early-stage NONFH displays characteristic venous stasis of the femoral head, whereas advanced stage NONFH is characterized by insufficient arterial blood supply to the femoral head. Corresponding NONFH treatment strategies should be considered based on their specific circulatory status. This work also provides guidance and recommendations for adopting corresponding femoral head preserving strategies for young patients in different NONFH circulatory status.
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http://dx.doi.org/10.1097/SAP.0000000000002424DOI Listing
December 2020

An MRI contrast agent based on a zwitterionic metal-chelating polymer for hepatorenal angiography and tumor imaging.

J Mater Chem B 2020 08;8(31):6956-6963

Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Bei Yi Jie 2, Zhong Guan Cun, Beijing 100190, China.

MRI contrast agents such as paramagnetic Gd(iii)-chelates, can improve the ability of MRI in differentiating diseased and healthy tissues, and have been widely used in clinical diagnosis. However, the enhancement effect of small molecular MRI contrast agents is unsatisfied due to their relative high rotation rates. Furthermore, the small molecular contrast agents also suffer from the short blood half-life and nonspecific extracellular diffusion in tissues, which also restricts their applications. To address these issues, we developed a macromolecular MRI contrast agent based on a zwitterionic metal-chelating polymer. Poly(acrylic acid) (PAA) was chosen as the main chain, and diethylenetriamine pentaacetic acid (DTPA) as the metal-chelating group was coupled through the carboxyl groups of PAA using diethylenetriamine (DET) as a linker. The macromolecular MRI contrast agent constructed by chelating with Gd3+ (Gd-PAA) exhibited a much higher longitudinal relaxation rate (r1) than the clinical contrast agent Gd-DTPA. Importantly, due to the stealth ability of the zwitterionic structure, Gd-PAA can reside in the blood long enough without any microvascular leakage in the extracellular space of normal tissues, which allows it to be used for precise blood MR imaging, such as hepatorenal angiography, but also for tumor imaging because of the enhanced permeability and retention (EPR) effecta. Besides, the result of long-term toxicity tests highlights the safety feature of the current contrast agent. Hence, the current contrast agent overcomes the defect of traditional small molecular Gd(iii)-based T1-weighted contrast agents and shows great prospects for future clinical applications.
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http://dx.doi.org/10.1039/d0tb00893aDOI Listing
August 2020

Clinical value of texture analysis in differentiation of urothelial carcinoma based on multiphase computed tomography images.

Medicine (Baltimore) 2020 May;99(18):e20093

Department of Radiology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology.

Identification of histologic grading of urothelial carcinoma still depends on histopathologic examination. As an emerging and promising imaging technology, radiomic texture analysis is a noninvasive technique and has been studied to differentiate various tumors. This study explored the value of computed tomography (CT) texture analysis for the differentiation of low-grade urothelial carcinoma (LGUC), high-grade urothelial carcinoma (HGUC), and their invasive properties.Radiologic data were analyzed retrospectively for 94 patients with pathologically proven urothelial carcinomas from November 2016 to April 2019. Pathologic examination demonstrated that tumors were: high grade in 43 cases, and low grade in 51 cases; and nonmuscle invasive (NMI) in 37 cases, and muscle invasive (MI) in 37 cases. Maximum tumor diameters on CT scan were manually outlined as regions of interest and 78 texture features were extracted automatically. Three-phasic CT images were used to measure texture parameters, which were compared with postoperative pathologic grading and invasive results. The independent sample t test or Mann-Whitney U test was used to compare differences in parameters. Receiver-operating characteristic curves for statistically significant parameters were used to confirm efficacy.Of the 78 features extracted from each phase of CT images, 26 (33%), 20 (26%), and 22 (28%) texture parameters were significant (P < .05) for differentiating LGUC from HGUC, while 19 (24%), 16 (21%), and 30 (38%) were significant (P < .05) for differentiating NMI from MI urothelial carcinoma. Highest areas the under curve for differentiating grading and invasive properties were obtained by variance (0.761, P < .001) and correlation (0.798, P < .001) on venous-phase CT images.Texture analysis has the potential to distinguish LGUC and HGUC, or NMI from MI urothelial carcinoma, before surgery.
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http://dx.doi.org/10.1097/MD.0000000000020093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440185PMC
May 2020

Open Reduction and Internal Fixation and Intraoperative Exploration of the Superior Retinacular Arterial System in Young Adults Garden III Femoral Neck Fracture: A 10 Case Report.

Ann Plast Surg 2020 05;84(5S Suppl 3):S222-S224

From the Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning.

At present, there is no uniform standard for the treatment of femoral neck fractures (FNFs) in young adults, and the current strategy is inclined to the native hip joint preservation. Femoral neck fractures in young adult are mostly caused by high-energy violence, and the blood supply of femoral head is severely damaged, which is prone to secondary femoral head avascular necrosis. In this article, we report 10 cases of young adult Garden III FNF treated with open reduction and internal fixation (ORIF) and microsurgical exploration of the superior retinacular vessels from 2015 to 2018, to more intuitively understand the involvement of superior retinacular vessels after displaced FNF in young adults. The results show that the SRA injury of Garden III FNF could be categorized into 3 types (type A-C), type A (6/10): the SRA vessels were kept intact, while they were pulled or compressed by displaced fracture fragment and could be revascularized by reduction; type B (3/10): the SRA vessels were avulsed with the superior retinaculum attachment avulsion fracture and could not be revascularized by reduction; and type C (1/10): the SRA vessels were ruptured, and the remnant of the vessel is present, which can be revascularized by vascular anastomosis. The previously mentioned results showed that the vascular damage of femoral head in Garden III FNF is quite complicated and might have the potential for being further classified into several subtypes.
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http://dx.doi.org/10.1097/SAP.0000000000002364DOI Listing
May 2020

Imaging and monitoring HER2 expression in breast cancer during trastuzumab therapy with a peptide probe Tc-HYNIC-H10F.

Eur J Nucl Med Mol Imaging 2020 10 13;47(11):2613-2623. Epub 2020 Mar 13.

Medical Isotopes Research Center and Department of Radiation Medicine, State Key Laboratory of Natural and Biomimetic Drugs, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.

Purpose: The novel molecular imaging probe Tc-HYNIC-H10F was developed for patient screening and efficacy monitoring of trastuzumab therapy by SPECT imaging of HER2 expression in breast cancer.

Methods: Tc-HYNIC-H10F was developed by labeling H10F peptide with Tc following an optimized protocol. Biodistribution and SPECT/CT were performed in mouse models bearing HER2-positive SK-BR3 and HER2-negative MDA-MB-231 human breast cancer xenografts, respectively. The treatment response to trastuzumab was monitored and quantified by SPECT/CT in two HER2-positive breast cancer models (SK-BR3 and MDA-MB-361). The preliminary clinical study was performed in two patients with breast cancer.

Results: SPECT/CT with Tc-HYNIC-H10F showed that the SK-BR3 tumors were clearly visualized, while the signals from MDA-MB-231 tumors were much lower. The tumor uptake of Tc-HYNIC-H10F could be blocked by excess unlabeled H10F peptide but not by excess trastuzumab. The growth of two HER2-positive tumors was prominently suppressed at day 11 post-treatment. However, SPECT/CT reflected much earlier therapy response at day 4 post-treatment. The HER2 expression in tumors of breast cancer patients could be detected by Tc-HYNIC-H10F SPECT/CT imaging.

Conclusions: Tc-HYNIC-H10F specifically accumulates in HER2-positive tumors. Compared with trastuzumab, Tc-HYNIC-H10F binds to a different domain of HER2 antigen, providing new opportunities to monitor HER2 expression levels before/during/after trastuzumab treatment for more effective personalized treatment.
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http://dx.doi.org/10.1007/s00259-020-04754-6DOI Listing
October 2020

Synergetic Tumor Probes for Facilitating Therapeutic Delivery by Combined-Functionalized Peptide Ligands.

Anal Chem 2020 04 5;92(8):5650-5655. Epub 2020 Mar 5.

School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, P. R. China.

Both targeting and penetrating ability are the key characteristics for tissue probing and precise delivery. To construct an efficient nano probing and delivery system toward human epidermal growth factor receptor 2 (HER2) positive cancer, we established a nano liposomal system functionalized with a newly screened HER2 targeting peptide (HP2, YDLKEPEH) and the cell-penetrating peptide TAT simultaneously. Compared with the monofunctionalized liposomal probes, the dual-functional ones demonstrated a synergetic effect in cell uptake, drug delivery, and in vivo imaging. The improved efficacy of the synergetic system provides a prospective strategy for cancer diagnosis and therapy.
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http://dx.doi.org/10.1021/acs.analchem.0c00440DOI Listing
April 2020

Single-Chromosomal Gains Can Function as Metastasis Suppressors and Promoters in Colon Cancer.

Dev Cell 2020 02;52(4):413-428.e6

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address:

High levels of cancer aneuploidy are frequently associated with poor prognosis. To examine the relationship between aneuploidy and cancer progression, we analyzed a series of congenic cell lines that harbor single extra chromosomes. We found that across 13 different trisomic cell lines, 12 trisomies suppressed invasiveness or were largely neutral, while a single trisomy increased metastatic behavior by triggering a partial epithelial-mesenchymal transition. In contrast, we discovered that chromosomal instability activates cGAS/STING signaling but strongly suppresses invasiveness. By analyzing patient copy-number data, we demonstrate that specific aneuploidies are associated with distinct outcomes, and the acquisition of certain aneuploidies is in fact linked with a favorable prognosis. Thus, aneuploidy is not a uniform driver of malignancy, and different aneuploidies can uniquely influence tumor progression. At the same time, the gain of a single chromosome is capable of inducing a profound cell state transition, thereby linking genomic plasticity, phenotypic plasticity, and metastasis.
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http://dx.doi.org/10.1016/j.devcel.2020.01.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354079PMC
February 2020

Multiplex accurate sensitive quantitation (MASQ) with application to minimal residual disease in acute myeloid leukemia.

Nucleic Acids Res 2020 04;48(7):e40

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

Measuring minimal residual disease in cancer has applications for prognosis, monitoring treatment and detection of recurrence. Simple sequence-based methods to detect nucleotide substitution variants have error rates (about 10-3) that limit sensitive detection. We developed and characterized the performance of MASQ (multiplex accurate sensitive quantitation), a method with an error rate below 10-6. MASQ counts variant templates accurately in the presence of millions of host genomes by using tags to identify each template and demanding consensus over multiple reads. Since the MASQ protocol multiplexes 50 target loci, we can both integrate signal from multiple variants and capture subclonal response to treatment. Compared to existing methods for variant detection, MASQ achieves an excellent combination of sensitivity, specificity and yield. We tested MASQ in a pilot study in acute myeloid leukemia (AML) patients who entered complete remission. We detect leukemic variants in the blood and bone marrow samples of all five patients, after induction therapy, at levels ranging from 10-2 to nearly 10-6. We observe evidence of sub-clonal structure and find higher target variant frequencies in patients who go on to relapse, demonstrating the potential for MASQ to quantify residual disease in AML.
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http://dx.doi.org/10.1093/nar/gkaa090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144909PMC
April 2020

Autism risk in offspring can be assessed through quantification of male sperm mosaicism.

Nat Med 2020 01 23;26(1):143-150. Epub 2019 Dec 23.

Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, USA.

De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father's sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment.
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http://dx.doi.org/10.1038/s41591-019-0711-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032648PMC
January 2020

Copolymerization of single-cell nucleic acids into balls of acrylamide gel.

Genome Res 2020 01 14;30(1):49-61. Epub 2019 Nov 14.

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.

We show the use of 5'-Acrydite oligonucleotides to copolymerize single-cell DNA or RNA into balls of acrylamide el (BAGs). Combining this step with split-and-pool techniques for creating barcodes yields a method with advantages in cost and scalability, depth of coverage, ease of operation, minimal cross-contamination, and efficient use of samples. We perform DNA copy number profiling on mixtures of cell lines, nuclei from frozen prostate tumors, and biopsy washes. As applied to RNA, the method has high capture efficiency of transcripts and sufficient consistency to clearly distinguish the expression patterns of cell lines and individual nuclei from neurons dissected from the mouse brain. By using varietal tags (UMIs) to achieve sequence error correction, we show extremely low levels of cross-contamination by tracking source-specific SNVs. The method is readily modifiable, and we will discuss its adaptability and diverse applications.
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http://dx.doi.org/10.1101/gr.253047.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961581PMC
January 2020

DNA copy number variations in children with vesicoureteral reflux and urinary tract infections.

PLoS One 2019 12;14(8):e0220617. Epub 2019 Aug 12.

Department of Pediatrics, Indiana University, Indianapolis, IN, United States of America.

Vesicoureteral reflux (VUR) is a complex, heritable disorder. Genome-wide linkage analyses of families affected by VUR have revealed multiple genomic loci linked to VUR. These loci normally harbor a number of genes whose biologically functional variant is yet to be identified. DNA copy number variations (CNVs) have not been extensively studied at high resolution in VUR patients. In this study, we performed array comparative genomic hybridization (aCGH) on a cohort of patients with a history of both VUR and urinary tract infection (UTI) with the objective of identifying genetic variations responsible for VUR and/or UTI susceptibility. UTI/VUR-associated CNVs were identified by aCGH results from the 192 Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) patients compared to 683 controls. Rare, large CNVs that are likely pathogenic and lead to VUR development were identified using stringent analysis criteria. Because UTI is a common affliction with multiple risk factors, we utilized standard analysis to identify potential disease-modifying CNVs that can contribute to UTI risk. Gene ontology analysis identified that CNVs in innate immunity and development genes were enriched in RIVUR patients. CNVs affecting innate immune genes may contribute to UTI susceptibility in VUR patients and may provide the first step in assisting clinical medicine in determining adverse outcome risk in children with VUR.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0220617PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690579PMC
March 2020

Comprehensive analyses of ZFP gene family and characterization of expression profiles during plant hormone response in cotton.

BMC Plant Biol 2019 Jul 23;19(1):329. Epub 2019 Jul 23.

College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, China.

Background: Zinc finger proteins (ZFPs) containing only a single zinc finger domain play important roles in the regulation of plant growth and development, as well as in biotic and abiotic stress responses. To date, the evolutionary history and functions of the ZFP gene family have not been identified in cotton.

Results: In this paper, we identified 29 ZFP genes in Gossypium hirsutum. This gene family was divided into seven subfamilies, 22 of which were distributed over 17 chromosomes. Bioinformatic analysis revealed that 20 GhZFP genes originated from whole genome duplications and two originated from dispersed duplication events, indicating that whole genome duplication is the main force in the expansion of the GhZFP gene family. Most GhZFP8 subfamily genes, except for GhZFP8-3, were highly expressed during fiber cell growth, and were induced by brassinosteroids in vitro. Furthermore, we found that a large number of GhZFP genes contained gibberellic acid responsive elements, auxin responsive elements, and E-box elements in their promoter regions. Exogenous application of these hormones significantly stimulated the expression of these genes.

Conclusions: Our findings reveal that GhZFP8 genes are involved in cotton fiber development and widely induced by auxin, gibberellin and BR, which provides a foundation for the identification of more downstream genes with potential roles in phytohormone stimuli, and a basis for breeding better cotton varieties in the future.
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http://dx.doi.org/10.1186/s12870-019-1932-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652020PMC
July 2019

A Novel Peptide Probe for Identification of PLS3-Expressed Cancer Cells.

Anal Chem 2019 08 24;91(15):9640-9647. Epub 2019 Jul 24.

CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience , National Center for Nanoscience and Technology of China , Beijing 100190 , China.

The T-plastin (PLS3) has a significant implication in epithelial-mesenchymal transition (EMT) and breast cancer prognosis. Using one-bead-one-compound library strategy, a novel peptide TP1 (KVKSDRVC) toward PLS3 was screened and exhibited the specificity for identifying PLS3-expressed cancer cells. Moreover, we found Fluorescein isothiocyanate-labeled TP1 (FITC-TP1) could act as a novel probe for EMT-induced cancer cells, preferentially in the leading edge. It also has satisfactory specificity for PLS3-expressed cancer cells spiked in the blood. FITC-TP1 was expected to become a diagnostic tool to identify PLS3-expressed circulating tumor cells and predict prognosis for patients with breast cancer in the future.
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http://dx.doi.org/10.1021/acs.analchem.9b01061DOI Listing
August 2019

Coordinatively Unsaturated Fe Based Activatable Probes for Enhanced MRI and Therapy of Tumors.

Angew Chem Int Ed Engl 2019 08 3;58(32):11088-11096. Epub 2019 Jul 3.

Department Key Laboratory of Colloid Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.

Exogenous Fe can be used for cancer magnetic resonance (MR) imaging and potentially for cancer treatment by a ferroptosis pathway or photothermal ablation. To achieve this, effective and accurate delivery of Fe to cancerous sites is critical, requiring a balance of release kinetics of Fe in tumorous and normal tissues. A nanoprobe is described consisting of upconversion luminescence (UCL) nanoparticles as a core and a coordinatively unsaturated Fe -containing Fe /gallic acid complex as a shell. Owing to the introduction of an unsaturated coordination structure, Fe in the nanoprobe can be released only in the tumor microenvironment in response to the lightly acidic pH. The multiple UCLs are used for quantitatively visualizing the release of Fe in vivo, whilst the release resultant serves as a photothermal agent. This nanoprobe exhibited ligand-free tumor targeting ability, activatable MR imaging performance, and efficacious therapeutic effects against tumors in vivo.
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http://dx.doi.org/10.1002/anie.201904880DOI Listing
August 2019

pH-Sensitive Ratiometric Fluorescent Probe for Evaluation of Tumor Treatments.

Materials (Basel) 2019 May 18;12(10). Epub 2019 May 18.

Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.

Determining therapeutic efficacy is critical for tumor precision theranostics. In order to monitor the efficacy of anti-cancer drugs (e.g., Paclitaxel), a pH-sensitive ratiometric fluorescent imaging probe was constructed. The pH-sensitive ratiometric fluorescent dye ANNA was covalently coupled to the N-terminal of the cell-penetrating TAT peptide through an amidation reaction (TAT-ANNA). The in vitro cellular experiments determined that the TAT-ANNA probe could penetrate the cell membrane and image the intracellular pH in real time. The in vivo experiments were then carried out, and the ratiometric pH response to the state of the tumor was recorded immediately after medication. The TAT-ANNA probe was successfully used to monitor the pharmacodynamics of anti-cancer drugs in vivo.
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http://dx.doi.org/10.3390/ma12101632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566363PMC
May 2019

MMP-2-Controlled Transforming Micelles for Heterogeneic Targeting and Programmable Cancer Therapy.

Theranostics 2019 28;9(6):1728-1740. Epub 2019 Feb 28.

CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China.

Herein, through the active-peptide-functionalization, we developed a nanoscale micelles system (named HEKM) which consists of tumor microenvironment-regulated shape-changing with specific recognition abilities for enhanced cellular targeting, internalization and therapy of heterogeneic tumors. As a result, HEKMs could recognize and bind the tumor heterogeneity marker EGFR-HER2 complex, which led to an enhanced tumor targeting effect. In particular, HEKMs could self-assemble into nanorods under normal physiological conditions while transform into nanospheres in the tumor extracellular microenvironment by a sensitive response to matrix metalloproteinase-2 (MMP-2). The nanorods could prolong the blood circulation time while the nanospheres could accelerate tissue penetration in tumors. dual-modal targeted imaging was realized by FRET-fluorophore conjugation and gadolinium loading in HEKMs. Tumor cell apoptosis was achieved by proapoptotic element integration. The and studies both demonstrated that these rationally designed, shape-changing and targeting micelles could achieve maximized drug efficacy and minimum side effects.
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http://dx.doi.org/10.7150/thno.30915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485184PMC
March 2020

Boosting the Theranostic Effect of Liposomal Probes toward Prominin-1 through Optimized Dual-Site Targeting.

Anal Chem 2019 06 5;91(11):7245-7253. Epub 2019 Apr 5.

CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience , National Center for Nanoscience and Technology of China , Beijing 100190 , China.

Ligand-targeting specific liposomal probes are increasingly used as imaging and delivery vehicles for in vivo diagnosis. Thereinto, the ligand variety and density profoundly affect the binding behaviors toward the target. The synergetic effect of different ligands could be achieved only when the optimized molecular-recognition configuration occurred. In this study, we construct a dual-peptides-targeting liposomal probe named BTLS that could synergistically bind two different sites of prominin-1, a cancer stem cell marker. At the distance of 11 Å between the two new peptides, ligands could insert into the hollow pocket of prominin-1 and BTLS could achieve the appropriate spatial structure, showing the strong binding affinity in both cellular and in vivo levels. It is indicated that the design of density-optimized peptide-targeted liposomes could be promising to maximize the multifunctional targeting effects on the cancer theranostics.
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http://dx.doi.org/10.1021/acs.analchem.9b00622DOI Listing
June 2019

Mesenchymal stem cell-loaded porous tantalum integrated with biomimetic 3D collagen-based scaffold to repair large osteochondral defects in goats.

Stem Cell Res Ther 2019 03 5;10(1):72. Epub 2019 Mar 5.

Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, NO. 6 Jiefang Street, Zhongshan District, Dalian, 116001, Liaoning, China.

Background: The body is unable to repair and regenerate large area bone defects. Moreover, the repair capacity of articular cartilage is very limited. There has long been a lack of effective treatments for osteochondral lesions. The engineered tissue with biphase synthetic for osteochondral repair has become one of the hot research fields over the past few years. In this study, an integrated biomanufacturing platform was constructed with bone marrow mesenchymal stem cells (BMSCs)/porous tantalum (pTa) associated with chondrocytes/collagen membranes (CM) to repair large osteochondral defects in load-bearing areas of goats.

Methods: Twenty-four goats with a large osteochondral defect in the femoral heads of the left hind legs were randomly divided into three groups: eight were treated with chondrocytes/CM-BMSCs/pTa, eight were treated with pure CM-pTa composite, and the other eight goats were untreated. The repair effect was assessed by X-ray, gross observation, and histomorphology for 16 weeks after the operation. In addition, the biocompatibility of chondrocytes/CM-BMSCs/pTa was observed by flow cytometry, CCK8, immunocytochemistry, and Q-PCR. The characteristics of the chondrocytes/CM-BMSCs/pTa were evaluated using both scanning electron microscopy and mechanical testing machine.

Results: The integrated repair material consists of pTa, injectable fibrin sealant, and CM promoted adhesion and growth of BMSCs and chondrocytes. pTa played an important role in promoting the differentiation of BMSCs into osteoblasts. Three-dimensional CM maintained the phenotype of chondrocytes successfully and expressed chondrogenic genes highly. The in vivo study showed that after 16 weeks from implantation, osteochondral defects in almost half of the femoral heads had been successfully repaired by BMSC-loaded pTa associated with biomimetic 3D collagen-based scaffold.

Conclusions: The chondrocytes/CM-BMSCs/pTa demonstrated significant therapeutic efficacy in goat models of large osteochondral defect. This provides a novel therapeutic strategy for large osteochondral lesions in load-bearing areas caused by severe injury, necrosis, infection, degeneration, and tumor resection with a high profile of safety, effectiveness, and simplicity.
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http://dx.doi.org/10.1186/s13287-019-1176-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402115PMC
March 2019
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