5,370 results on '"GPI-Linked Proteins"'
Search Results
2. Relationship between circulating serum omentin-1 levels and nascent metabolic syndrome in patients with hypertension
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Gokay Nar, Sara Cetin Sanlialp, and Rukiye Nar
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Adult ,Male ,medicine.medical_specialty ,Adipokine ,Adipocytokine ,GPI-Linked Proteins ,Gastroenterology ,General Biochemistry, Genetics and Molecular Biology ,Coronary artery disease ,Plasma ,Insulin resistance ,Lectins ,Diabetes mellitus ,Internal medicine ,medicine ,Insulin ,Humans ,adipokines ,Coronary-Artery-Disease ,Triglycerides ,Metabolic Syndrome ,business.industry ,Area under the curve ,General Medicine ,Overweight ,Middle Aged ,medicine.disease ,Obesity ,Adipose-Tissue ,Glucose ,Cardiovascular Diseases ,Hypertension ,Cytokines ,Female ,Insulin Resistance ,Metabolic syndrome ,business ,Body mass index ,Biomarkers - Abstract
The prevalence of metabolic syndrome (MetS) is more common in patients with hypertension and is associated with an increased risk of target organ damage and/or cardiovascular disease (CVD). Omentin-1 is a beneficial adipokine considered to play a role in MetS and MetS-related states such as obesity, diabetes, and coronary artery disease. The aim of this study was to determine the relationship between circulating omentin-1 levels and MetS uncomplicated by diabetes or CVD (nascent MetS) in patients with hypertension. In this study, 110 patients (54 men, 49%; average age: 49.72±11.32 years) treated for hypertension but without overt diabetes and/or CVD were enrolled. 66 patients were stratified into MetS (+) (group 1) and 44 patients into MetS (−) (group 2) according to the American Heart Association/National Heart, Lung, and Blood Institute criteria. The triglyceride glucose (TyG) index was used to assess insulin resistance. Circulating omentin-1 levels in venous blood samples were measured by an ELISA kit. Circulating omentin-1 levels in patients with MetS were significantly lower than in patients without MetS (46.35 ng/mL (42.70–57.70 ng/mL) vs 130.95 ng/mL (62.83–236.48 ng/mL), p
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- 2022
3. The impact of omentin-1 gene polymorphisms (rs2274907 and rs2274908) on serum lipid concentrations and coronary artery disease in a sample of Iraqi individuals (A pilot study)
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Thekra Abdul-Jabr, Teba Jabir Mirza, Abeer Ghassan Mahdi, Majid Kadhum Hussain, Khalid Ibrahim Amber, and Muna Abdulridha Al-Barqaawi
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Adult ,Linkage disequilibrium ,medicine.medical_specialty ,Genotype ,Clinical Biochemistry ,Population ,Pilot Projects ,Single-nucleotide polymorphism ,Coronary Artery Disease ,GPI-Linked Proteins ,Polymorphism, Single Nucleotide ,Linkage Disequilibrium ,Polymorphism (computer science) ,Lectins ,Internal medicine ,medicine ,Humans ,SNP ,education ,Genotyping ,Aged ,education.field_of_study ,business.industry ,Haplotype ,General Medicine ,Middle Aged ,Lipids ,Endocrinology ,Cytokines ,business - Abstract
BACKGROUND Coronary artery disease (CAD) is the primary cause of death worldwide. It is mainly caused by atherosclerosis that initiates from a genetic-environmental interaction. Studies highlighted the association of numerous gene polymorphisms with CAD. Omentin-1 is secreted from visceral adipose tissues, intestine, and others; it has anti-inflammatory and insulin sensitivity improving roles. AIM To explore the association of the omentin-1 gene polymorphisms (rs2274907 and rs2274908) with serum lipid concentrations and CAD in a sample of the Iraqi population. METHODS A case-control study was followed, in which CAD patients were analyzed versus a group of healthy persons. Serum lipid concentrations were measured by enzymatic methods. Genotyping of the omentin-1 gene for rs2274907 SNP was achieved by ARMS-PCR, while for rs2274908 SNP by allele-specific PCR (AS-PCR) techniques. RESULTS Atherogenic serum lipid concentrations increased significantly in CAD patients relative to the control group. Genotyping of the omentin-1 gene for rs2274907 SNP revealed a significant (OR = 4.11, P = 0.035) elevation of the AT genotype carriers in CAD versus the control groups. The genotype analysis of the rs2274908 SNP failed to exhibit a significant variation. The two analyzed SNPs were indicated to be in linkage disequilibrium (r = 0.772, P
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- 2022
4. Massive digital gene expression analysis reveals different predictive profiles for immune checkpoint inhibitor therapy between adenocarcinoma and squamous cell carcinoma of advanced lung cancer
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Tomoko Yoshida, Kazuhiko Takeda, Toshihiko Kaneda, Hiroaki Yanagimoto, Takao Yoshida, Kayoko Kibata, Koji Tsuta, Takayasu Kurata, and Hiroshige Yoshioka
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Adult ,Male ,Cancer Research ,Lung Neoplasms ,Immune checkpoint inhibitors ,Programmed Cell Death 1 Receptor ,Gene Expression ,Adenocarcinoma ,GPI-Linked Proteins ,Antigens, CD ,Antigens, Neoplasm ,Predictive Value of Tests ,Carcinoma, Non-Small-Cell Lung ,Proto-Oncogene Proteins ,Gene expression ,medicine ,Biomarkers, Tumor ,Genetics ,Humans ,Basal cell ,RNA, Messenger ,Anti PD-1 antibody ,Lung cancer ,Immune Checkpoint Inhibitors ,HLA-DP beta-Chains ,RC254-282 ,Adaptor Proteins, Signal Transducing ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Middle Aged ,medicine.disease ,Cadherins ,Neoplasm Proteins ,Treatment Outcome ,Nivolumab ,Oncology ,Drug Resistance, Neoplasm ,Cancer research ,Carcinoma, Squamous Cell ,Female ,Advanced non-small cell lung cancer ,business ,Apoptosis Regulatory Proteins ,Transcriptome - Abstract
Background Immune checkpoint inhibitors prolong the survival of non-small cell lung cancer (NSCLC) patients. Although it has been acknowledged that there is some correlation between the efficacy of anti-programmed cell death-1 (PD-1) antibody therapy and immunohistochemical analysis, this technique is not yet considered foolproof for predicting a favorable outcome of PD-1 antibody therapy. We aimed to predict the efficacy of nivolumab based on a comprehensive analysis of RNA expression at the gene level in advanced NSCLC. Methods This was a retrospective study on patients with NSCLC who were administered nivolumab at the Kansai Medical University Hospital. To identify genes associated with response to anti-PD-1 antibodies, we grouped patients into responders (complete and partial response) and non-responders (stable and progressive disease) to nivolumab therapy. Significant genes were then identified for these groups using Welch’s t-test. Results Among 42 analyzed cases (20 adenocarcinomas and 22 squamous cell carcinomas), enhanced expression of MAGE-A4, BBC3, and OTOA genes was observed in responders with adenocarcinoma, and enhanced expression of DAB2, HLA-DPB,1 and CDH2 genes was observed in responders with squamous cell carcinoma. Conclusions This study predicted the efficacy of nivolumab based on a comprehensive analysis of mRNA expression at the gene level in advanced NSCLC. We also revealed different gene expression patterns as predictors of the effectiveness of anti PD-1 antibody therapy in adenocarcinoma and squamous cell carcinoma.
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- 2022
5. Suppression of tumor metastasis by a RECK-activating small molecule
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Yoko Yoshida, Kanako Yuki, Shingo Dan, Kanami Yamazaki, and Makoto Noda
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Male ,Mice, Inbred BALB C ,Multidisciplinary ,Lung Neoplasms ,Science ,Kruppel-Like Transcription Factors ,GPI-Linked Proteins ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,Mice ,Genes, Reporter ,Cell Line, Tumor ,Animals ,Humans ,Medicine ,Drug Screening Assays, Antitumor ,Neoplasm Metastasis ,Promoter Regions, Genetic ,Transcription Factors - Abstract
RECK encodes a membrane-anchored protease-regulator which is often downregulated in a wide variety of cancers, and reduced RECK expression often correlates with poorer prognoses. In mouse models, forced expression of RECK in tumor xenografts results in suppression of tumor angiogenesis, invasion, and metastasis. RECK mutations, however, are rare in cancer genomes, suggesting that agents that re-activate dormant RECK may be of clinical value. We found a potent RECK-inducer, DSK638, that inhibits spontaneous lung metastasis in our mouse xenograft model. Induction of RECK expression involves SP1 sites in its promoter and may be mediated by KLF2. DSK638 also upregulates MXI1, an endogenous MYC-antagonist, and inhibition of metastasis by DSK638 is dependent on both RECK and MXI1. This study demonstrates the utility of our approach (using a simple reporter assay followed by multiple phenotypic assays) and DSK638 itself (as a reference compound) in finding potential metastasis-suppressing drugs.
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- 2022
6. A highly-specific fully-human antibody and CAR-T cells targeting CD66e/CEACAM5 are cytotoxic for CD66e-expressing cancer cells in vitro and in vivo
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Guillermo Calero, Sandra Vergara, Cynthia Adams, Alex Conard, Rieko Ishima, Du-San Baek, John W. Mellors, Ye-Jin Kim, and Dimiter S. Dimitrov
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Male ,Cancer Research ,medicine.drug_class ,medicine.medical_treatment ,Antineoplastic Agents ,GPI-Linked Proteins ,Monoclonal antibody ,Immunotherapy, Adoptive ,Mice ,Prostate cancer ,Prostate ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Cell Proliferation ,Receptors, Chimeric Antigen ,biology ,Chemistry ,Antibodies, Monoclonal ,Prostatic Neoplasms ,Immunotherapy ,medicine.disease ,Chimeric antigen receptor ,Antibodies, Anti-Idiotypic ,Carcinoembryonic Antigen ,Gene Expression Regulation, Neoplastic ,Neuroendocrine Tumors ,Prostatic Neoplasms, Castration-Resistant ,medicine.anatomical_structure ,Oncology ,Immunoglobulin G ,Cancer cell ,Cancer research ,biology.protein ,Antibody - Abstract
Neuro-endocrine prostate cancer (NEPC) accounts for about 20% of lethal metastatic castration-resistant prostate cancer (CRPC). NEPC has the most aggressive biologic behavior of all prostate cancers and is associated with poor patient outcome. Effective treatment for NEPC is not available because NEPC exhibit distinct cell-surface expression profiles compared to other types of prostate cancer. Recently, the carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) (known as CEA or CD66e) was suggested to be a specific surface protein marker for NEPC. Therefore, we identified a new, fully-human anti-CEACAM5 monoclonal antibody, 1G9, which bound to the most proximal membrane domains, A3 and B3, of CEACAM5 with high affinity and specificity. It shows no off-target binding to other CEACAM family members, membrane distal domains of CEACAM5, or 5800 human membrane proteins. IgG1 1G9 exhibited CEACAM5-specific ADCC activity toward CEACAM5-positive prostate cancer cells in vitro and in vivo. Chimeric antigen receptor T cells (CAR-T) based on scFv 1G9 induced specific and strong antitumor activity in a mouse model of prostate cancer. Our results suggest that IgG1 and CAR-T cells based on 1G9 are promising candidate therapeutics for CEACAM5-positive NEPC and other cancers.
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- 2022
7. A novel circular RNA circ_HN1/miR-628-5p/Ecto-5’-nucleotidase competing endogenous RNA network regulates gastric cancer development
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Jianmin Zhang, Mingbo Cao, Fang Wang, and Haihui Zhang
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Male ,cerna crosstalk ,Cell ,Bioengineering ,Biology ,medicine.disease_cause ,GPI-Linked Proteins ,Applied Microbiology and Biotechnology ,circ_hn1 ,Circular RNA ,Stomach Neoplasms ,Cell Line, Tumor ,microRNA ,medicine ,Gene silencing ,Humans ,RNA, Neoplasm ,nt5e ,5'-Nucleotidase ,Aged ,Competing endogenous RNA ,Cell growth ,gastric cancer ,Cancer ,General Medicine ,RNA, Circular ,Middle Aged ,medicine.disease ,Neoplasm Proteins ,MicroRNAs ,medicine.anatomical_structure ,Cancer research ,Female ,Carcinogenesis ,mir-628-5p ,TP248.13-248.65 ,Research Article ,Research Paper ,Biotechnology - Abstract
The competing endogenous RNA (ceRNA) activity of circular RNAs (circRNAs) has been implicated in the development of gastric cancer. Here, we sought to explore the ceRNA function of circRNA Jupiter microtubule associated homolog 1 (circ_HN1) in gastric tumorigenesis. Circ_HN1, microRNA (miR)-628-5p, and NT5E expression levels were quantified by qRT-PCR and western blot. Dual-luciferase reporter assays were used to assess the direct relationship between miR-628-5p and circ_HN1 or NT5E. Our data showed that circ_HN1 expression was enhanced in human gastric cancer. Depletion of circ_HN1 impeded cell proliferation, spheroid formation, invasion, and migration and promoted apoptosis in vitro, as well as diminished tumor growth in vivo. NT5E was a downstream effector of circ_HN1 function. NT5E was targeted and inhibited by miR-628-5p through the perfect complementary site in NT5E 3ʹUTR, and circ_HN1 affected NT5E expression through miR-628-5p competition. Moreover, depletion of miR-628-5p reversed the effects of circ_HN1 silencing on regulating cell functional behaviors. Our findings identify a novel ceRNA network, the circ_HN1/miR-628-5p/NT5E axis, for the oncogenic activity of circ_HN1 in gastric cancer, highlighting circ_HN1 inhibition as a promising targeted treatment against gastric cancer.
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- 2021
8. Exploring Spike Protein as Potential Target of Novel Coronavirus and to Inhibit the Viability Utilizing Natural Agents
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Sisir Nandi, Anil Saxena, Asha Gummadi, and Harekrishna Roy
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Clinical Biochemistry ,Disease ,Biology ,GPI-Linked Proteins ,medicine.disease_cause ,Antiviral Agents ,Virus ,Drug Discovery ,medicine ,Humans ,Receptor ,Gene ,Coronavirus ,Pharmacology ,Biological Products ,SARS-CoV-2 ,Activator (genetics) ,COVID-19 ,Lipid bilayer fusion ,Virology ,Antigens, Surface ,Spike Glycoprotein, Coronavirus ,Molecular Medicine ,Spike (software development) ,Angiotensin-Converting Enzyme 2 ,Protein Binding - Abstract
Background: By the end of 2019, the sudden outbreak of the novel coronavirus disease (COVID-19) has become a global threat. It is called COVID-19 because it was caused by the novel coronavirus (SARS-COV-2) in 2019. A total of 1.9 M deaths and 87.9 M cases have been reported all over the world, where 49M cases have recovered so far. Scientists are working hard to find chemotherapeutics and vaccines for COVID-19. Mutations in SARS-CoV-2 have been observed in a combination of several hazardous stresses, making them more resistant and beneficial. So to break down the viral system, the disease targets are examined. Objective: In today's review, a comprehensive study of spike protein explains the main purpose of the novel coronavirus and how to prevent the spread of the disease virus cross-transmission from infected to a healthy person. Methods: Covid-19 has already been declared a pandemic by the World Health Organization (WHO) due to its result in causing death and severe illness globally. SARS-CoV-2 is highly contagious; however, the intermediate host of the novel coronavirus is not clear. To explore the mechanisms of disease, one of the viral targets, such as the spike protein that binds to human cells and causes the disease by altering its genetic structure which is considered along with potential inhibitors. Results: It has been shown that the interaction of receptor-binding domain (RBD) protein of SARS- CoV-2 spike and the angiotensin-converting enzyme 2 (ACE2) host receptor and further replication of coronavirus spike protein causes its invasion in the host cell. The human Lymphocyte antigen 6 complex, Locus E (LY6E), inhibits the entry of CoV into host cells by interfering with the human gene, inducing spike protein-mediated membrane fusion. Some natural formulations have also been shown to prevent spike protein from binding to the host cell. Conclusion: With the development of the LY6E gene activator that can inhibit spike protein- ACE2-mediated membrane fusion, new opportunities for SARS-CoV-2 treatment may emerge. Existing antiviral fusion inhibitors and natural compounds targeting spike resistance can serve as a template for further SARS-CoV-2 drug formulation.
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- 2021
9. CircDLGAP4 overexpression relieves oxygen-glucose deprivation-induced neuronal injury by elevating NEGR1 through sponging miR-503-3p
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Xiaohui Xu, Lingling Qiu, Hui Chen, Jinfeng He, and Yongjun Tao
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Programmed cell death ,Histology ,Physiology ,Cell Adhesion Molecules, Neuronal ,Cell ,GPI-Linked Proteins ,Flow cytometry ,medicine ,Humans ,Viability assay ,Cell damage ,Neurons ,Reporter gene ,Gene knockdown ,Neuronal growth regulator 1 ,medicine.diagnostic_test ,Chemistry ,RNA, Circular ,Cell Biology ,General Medicine ,medicine.disease ,Molecular biology ,SAP90-PSD95 Associated Proteins ,Oxygen ,MicroRNAs ,Glucose ,medicine.anatomical_structure - Abstract
Circular RNAs (circRNAs) have been reported to play vital regulatory roles in human diseases. However, the functions of circRNAs in ischemic stroke (IS) are limited. In this study, we aimed to explore the functions and mechanisms of circRNA DLG associated protein 4 (circDLGAP4) in IS development. Oxygen-glucose deprivation (OGD)-treated HCN-2 cells were used to mimic IS environment in vitro. Quantitative real-time polymerase chain reaction (qRT-PCR) assay was used to detect the levels of circDLGAP4, microRNA-503-3p (miR-503-3p) and neuronal growth regulator 1 (NEGR1) mRNA. RNase R assay was conducted to analyze the stability of circDLGAP4. Cell Counting Kit-8 (CCK-8) assay and flow cytometry analysis were adopted for cell viability and death, respectively. Western blot assay was performed for protein levels. Enzyme-linked immunosorbent assay (ELISA) kits were used to examine the concentrations of inflammatory cytokines. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay and RNA pull-down assay were employed to analyze the relationships among circDLGAP4, miR-503-3p and NEGR1. CircDLGAP4 level was declined in HCN-2 cells after OGD treatment. CircDLGAP4 overexpression promoted cell viability and suppressed cell death and inflammatory cytokine concentrations in OGD-treated HCN-2 cells. CircDLGAP4 acted as the sponge for miR-503-3p and the impacts of circDLGAP4 overexpression on cell viability, death and inflammation in OGD-treated HCN-2 cells were reversed by miR-503-3p elevation. Furthermore, NEGR1 was the target gene of miR-503-3p. MiR-503-3p inhibition ameliorated OGD-induced HCN-2 cell impairments, but NEGR1 knockdown abolished the effects. CircDLGAP4 alleviated OGD-induced HCN-2 cell damage by regulating miR-503-3p/NEGR1 axis.
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- 2021
10. Changes of omentin-1 and chemerin during 4 weeks of lifestyle intervention and 1 year follow-up in children with obesity
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Wolfgang Koenig, Monika Siegrist, Nicolas Vogg, Melanie Heitkamp, Martin Halle, Bernhard Haller, Isabell Braun, and Helmut Langhof
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Male ,Pediatric Obesity ,medicine.medical_specialty ,Adolescent ,Adipokine ,Overweight ,GPI-Linked Proteins ,Critical Care and Intensive Care Medicine ,Body Mass Index ,Behavior Therapy ,Weight loss ,Lectins ,Internal medicine ,Weight Loss ,medicine ,Humans ,Chemerin ,Child ,Life Style ,Randomized Controlled Trials as Topic ,Nutrition and Dietetics ,Anthropometry ,Adiponectin ,biology ,business.industry ,Cardiometabolic Risk Factors ,medicine.disease ,Obesity ,Obesity Management ,Treatment Outcome ,Cohort ,biology.protein ,Cytokines ,Female ,Chemokines ,medicine.symptom ,business ,Risk Reduction Behavior ,Follow-Up Studies - Abstract
Data about the influence of short-term lifestyle intervention in children with obesity on long-term follow-up body weight, adipokines and cardiometabolic risk parameters is scarce.In a subgroup of the LOGIC-trial (Long-term Effects of Lifestyle Intervention in Obesity and Genetic Influence in Children), we assessed anthropometry (BMI, BMI-SDS (Standard Deviation Score), adipokines (omentin-1, chemerin, leptin, adiponectin) and cardiometabolic risk parameters, (e.g. hsCRP) in children with overweight/obesity after 4 weeks of lifestyle intervention (n = 156, 14.0 ± 1.8 yrs) and after one year follow-up (n = 50). Data were compared to normal weight children (JuvenTUM school cohort; n = 152, 13.3 ± 0.7 yrs).Short-term lifestyle intervention was associated with a significant reduction in BMI and BMI-SDS (p 0.001), with significant reductions in hsCRP, leptin, and chemerin levels, and an increase in adiponectin and omentin-1 levels (p 0.001 for all). After one year follow-up a significant reduction in BMI and BMI-SDS was observed in children from the LOGIC-trial (p 0.001). Improvements in adiponectin (p = 0.025) and chemerin levels (p = 0.027) were seen in children with clear weight loss success (BMI-SDS reduction ≥ 0.2), whereas children with no or only mild weight loss success showed an increase in leptin levels (p 0.001). An increase in omentin-1 levels was observed after 1 year independent of weight change (p 0.001).Effects of short-term weight reduction on mean BMI and BMI-SDS persist over one year. Improvements in omentin-1 levels were independent of short-term or long-term weight loss.ClinicalTrials.gov: LOGIC-trial: NCT01067157, JuvenTUM-trial: NCT00988754.
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- 2021
11. Complementary Transcriptomic and Proteomic Analysis in the Substantia Nigra of Parkinson’s Disease
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Fan-Mei Meng, Jing-Tao Zhang, Yi-Jing Zhou, Zhao-Qing Niu, Bao-Hua Dong, and Ai-Qin Dong
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Medicine (General) ,Parkinson's disease ,Article Subject ,Clinical Biochemistry ,Vesicular Transport Proteins ,Substantia nigra ,Computational biology ,Biology ,GPI-Linked Proteins ,Proteomics ,SCNA ,Pathogenesis ,Transcriptome ,R5-920 ,Genetics ,medicine ,Cluster Analysis ,Humans ,RNA, Messenger ,Molecular Biology ,Gene ,Calcium-Binding Proteins ,Biochemistry (medical) ,Proteins ,Parkinson Disease ,General Medicine ,medicine.disease ,Substantia Nigra ,Acetylcholinesterase ,Cell aging ,Research Article - Abstract
Parkinson’s disease (PD) is a disease that involves brain damage and is associated with neuroinflammation, mitochondrial damage, and cell aging. However, the pathogenic mechanism of PD is still unknown. Sequencing data and proteomic data can describe the fluctuation of molecular abundance in diseases at the mRNA level and protein level, respectively. In order to explore new targets in the pathogenesis of PD, the study analyzed molecular changes from the database by combining transcriptomic and proteomic analysis. Differentially expressed genes and differentially abundant proteins were summarized and analyzed. Enrichment and cluster analysis emphasized the importance of neurotransmitter release, mitochondrial damage, and vesicle transport. The molecular network revealed a subnetwork of 9 molecules related to SCNA and TH and revealed hub gene with differential expression at both mRNA and protein levels. It found that ACHE and CADPS could be used as new targets in PD, emphasizing that impaired nerve signal transmission and vesicle transport affect the pathogenesis of PD. Our research emphasized that the joint analysis and verification of transcriptomics and proteomics were devoted to understanding the comprehensive views and mechanism of pathogenesis in PD.
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- 2021
12. Serum Proteomics and Plasma Fibulin-3 in Differentiation of Mesothelioma From Asbestos-Exposed Controls and Patients With Other Pleural Diseases
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John G. Edwards, Matthew Neilson, Davand Sharma, Fiona T. Thomson, Carol McCormick, Caroline Kelly, Euan J. Cameron, Seamus Grundy, Stephen R. L. Clark, Samantha Hinsley, David Breen, Angela Wright, Dipak Mukherjee, Crispin J. Miller, Rachel Ostroff, Alan Hart-Thomas, J Holme, Mohammed Munavvar, Ioannis Psallidas, Giles Cox, Holly Hall, Rakesh Panchal, Nick A Maskell, Rehan Naseer, Matthew Evison, Leigh Alexander, Laura Alexander, Mahendran Chetty, Alina Ionescu, S. Tsim, Elankumaran Paramasivam, Kevin G. Blyth, Ann Shaw, Douglas Grieve, Anthony J. Chalmers, and C Daneshvar
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Mesothelioma ,Proteomics ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,Pleural Neoplasms ,GPI-Linked Proteins ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Mesothelin ,SOMAscan ,Retrospective Studies ,Extracellular Matrix Proteins ,biology ,business.industry ,Calcium-Binding Proteins ,Area under the curve ,Asbestos ,Retrospective cohort study ,Fibulin-3 ,Biomarker ,medicine.disease ,Primary tumor ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cohort ,biology.protein ,Biomarker (medicine) ,Original Article ,Translational Oncology ,business ,Blood sampling - Abstract
Introduction:\ud Malignant pleural mesothelioma (MPM) is difficult to diagnose. An accurate blood biomarker could prompt specialist referral or be deployed in future screening. In earlier retrospective studies, SOMAscan proteomics (Somalogic, Boulder, CO) and fibulin-3 seemed highly accurate, but SOMAscan has not been validated prospectively and subsequent fibulin-3 data have been contradictory.\ud \ud Methods:\ud A multicenter prospective observational study was performed in 22 centers, generating a large intention-to-diagnose cohort. Blood sampling, processing, and diagnostic assessment were standardized, including a 1-year follow-up. Plasma fibulin-3 was measured using two enzyme-linked immunosorbent assays (CloudClone [used in previous studies] and BosterBio, Pleasanton, CA). Serum proteomics was measured using the SOMAscan assay. Diagnostic performance (sensitivity at 95% specificity, area under the curve [AUC]) was benchmarked against serum mesothelin (Mesomark, Fujirebio Diagnostics, Malvern, PA). Biomarkers were correlated against primary tumor volume, inflammatory markers, and asbestos exposure.\ud \ud Results:\ud A total of 638 patients with suspected pleural malignancy (SPM) and 110 asbestos-exposed controls (AECs) were recruited. SOMAscan reliably differentiated MPM from AECs (75% sensitivity, 88.2% specificity, validation cohort AUC 0.855) but was not useful in patients with differentiating non-MPM SPM. Fibulin-3 (by BosterBio after failed CloudClone validation) revealed 7.4% and 11.9% sensitivity at 95% specificity in MPM versus non-MPM SPM and AECs, respectively (associated AUCs 0.611 [0.557–0.664], p = 0.0015) and 0.516 [0.443–0.589], p = 0.671), both inferior to mesothelin. SOMAscan proteins correlated with inflammatory markers but not with asbestos exposure. Neither biomarker correlated with tumor volume.\ud \ud Conclusions:\ud SOMAscan may prove useful as a future screening test for MPM in asbestos-exposed persons. Neither fibulin-3 nor SOMAscan should be used for diagnosis or pathway stratification.
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- 2021
13. Machine learning identification of specific changes in myeloid cell phenotype during bloodstream infections
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Gosset, Christian, Foguenne, Jacques, Simul, Mickaël, Tomsin, Olivier, Ammar, Hayet, Layios, Nathalie, Massion, Paul B., Damas, Pierre, and Gothot, André
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Adult ,Male ,Critical Care ,Science ,Predictive medicine ,Interleukin-3 Receptor alpha Subunit ,Lipopolysaccharide Receptors ,Bacteremia ,Predictive markers ,GPI-Linked Proteins ,Dendritic cells ,Article ,Monocytes ,Immunophenotyping ,Machine Learning ,Sepsis ,Humans ,Myeloid Cells ,Flow cytometry ,Monocytes and macrophages ,Aged ,Inflammation ,Macrophages ,Receptors, IgG ,Middle Aged ,Intensive Care Units ,Phenotype ,ROC Curve ,Area Under Curve ,Medicine ,Female ,Infection ,Algorithms ,Biomarkers ,Granulocytes - Abstract
The early identification of bacteremia is critical for ensuring appropriate treatment of nosocomial infections in intensive care unit (ICU) patients. The aim of this study was to use flow cytometric data of myeloid cells as a biomarker of bloodstream infection (BSI). An eight-color antibody panel was used to identify seven monocyte and two dendritic cell subsets. In the learning cohort, immunophenotyping was applied to (1) control subjects, (2) postoperative heart surgery patients, as a model of noninfectious inflammatory responses, and (3) blood culture-positive patients. Of the complex changes in the myeloid cell phenotype, a decrease in myeloid and plasmacytoid dendritic cell numbers, increase in CD14+CD16+ inflammatory monocyte numbers, and upregulation of neutrophils CD64 and CD123 expression were prominent in BSI patients. An extreme gradient boosting (XGBoost) algorithm called the “infection detection and ranging score” (iDAR), ranging from 0 to 100, was developed to identify infection-specific changes in 101 phenotypic variables related to neutrophils, monocytes and dendritic cells. The tenfold cross-validation achieved an area under the receiver operating characteristic (AUROC) of 0.988 (95% CI 0.985–1) for the detection of bacteremic patients. In an out-of-sample, in-house validation, iDAR achieved an AUROC of 0.85 (95% CI 0.71–0.98) in differentiating localized from bloodstream infection and 0.95 (95% CI 0.89–1) in discriminating infected from noninfected ICU patients. In conclusion, a machine learning approach was used to translate the changes in myeloid cell phenotype in response to infection into a score that could identify bacteremia with high specificity in ICU patients.
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- 2021
14. Water jet-assisted lipoaspiration and Sepax cell separation system for the isolation of adipose stem cells with high adipogenic potential
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Mikael Wiberg, Paul J. Kingham, Maria Brohlin, Peyman Kelk, Rebecca Wiberg, Anne Therese Lauvrud, and Rojda Gümüscü
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Adult ,medicine.medical_specialty ,Angiogenesis ,Cell- och molekylärbiologi ,Cell ,Gene Expression ,Neovascularization, Physiologic ,Adipose tissue ,CD146 Antigen ,Cell Separation ,Fatty Acid-Binding Proteins ,GPI-Linked Proteins ,Stem cell marker ,adipogenesis ,Colony-Forming Units Assay ,angiogenesis ,chemistry.chemical_compound ,Lipectomy ,stem cells ,Adipocyte ,Humans ,Medicine ,CD90 ,5'-Nucleotidase ,Cell Proliferation ,Adipogenesis ,Glucose Transporter Type 4 ,business.industry ,Stem Cells ,Kirurgi ,Endoglin ,Cell Differentiation ,differentiation ,Middle Aged ,Surgery ,Cell biology ,medicine.anatomical_structure ,Adipose Tissue ,chemistry ,Thy-1 Antigens ,CD146 ,Female ,Adiponectin ,Stem cell ,business ,Cell and Molecular Biology ,fat grafting - Abstract
Summary Introduction Water jet-assisted liposuction has gained popularity due to favourable fat grafting outcomes. In this study, we compared stem cells obtained from fat isolated with manual or the water jet-assisted procedure. Methods Liposuction of abdominal fat was performed using the two methods on each donor (n = 10). Aspirate samples were collagenase digested and the isolated cells seeded in vitro prior to proliferation, adipogenic differentiation and angiogenic activity analyses. Results Cells from either procedure proliferated at similar rates and exhibited a similar colony-forming ability. The cells expressed stem cell markers CD73, CD90 and CD105. In the water jet cell preparations, there were higher numbers of cells expressing CD146. Robust adipogenic differentiation was observed in cultures expanded from both manual and water jet lipoaspirates. Gene analysis showed higher expression of the adipocyte markers aP2 and GLUT4 in the adipocyte-differentiated water jet cell preparations, and ELISA indicated increased secretion of adiponectin from these cells. Both cell groups expressed vasculogenic factors and the water jet cells promoted the highest levels of in vitro angiogenesis. Given these positive results, we further characterised the water jet cells when prepared using an automated closed cell processing unit, the Sepax-2 system (Cytiva). The growth and stem cell properties of the Sepax-processed cells were similar to the standard centrifugation protocol, but there was evidence for greater adipogenic differentiation in the Sepax-processed cells. Conclusions Water jet lipoaspirates yield cells with high adipogenic potential and angiogenic activity, which may be beneficial for use in cell-assisted lipotransfers.
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- 2021
15. CD177 modulates the function and homeostasis of tumor-infiltrating regulatory T cells
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Zheng Wang, Dorina Avram, Xin Zhang, Ryan Kolb, Ajaykumar Vishwakarma, Hongrui Xiang, Xuefeng Wu, Xian Huang, Katherine N. Gibson-Corley, Umasankar De, Andrew P. Voigt, Julia Klesney-Tait, Myung-Chul Kim, Dongyang Wang, Song Guo Zheng, Mingjia Li, Rhonda Bacher, Weizhou Zhang, Gaurav Pandey, Nicholas Borcherding, Jiajia Hu, Jian Tang, Haoyang Zhuang, Jinke Cheng, Yuwen Zhu, Daohong Zhou, Jinglu Lu, Theodore T. Drashansky, Paige Kluz, Kawther K. Ahmed, Yousef Zakharia, Zhengting Wang, Hua Liu, Eric Y. Helm, and Jinsong Lu
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Isoantigens ,Cell type ,Transcription, Genetic ,Carcinogenesis ,medicine.medical_treatment ,Science ,Population ,Systems analysis ,General Physics and Astronomy ,Receptors, Cell Surface ,chemical and pharmacologic phenomena ,GPI-Linked Proteins ,T-Lymphocytes, Regulatory ,Article ,General Biochemistry, Genetics and Molecular Biology ,Lymphocytes, Tumor-Infiltrating ,Immune system ,medicine ,Animals ,Homeostasis ,Humans ,education ,Carcinoma, Renal Cell ,Mice, Knockout ,education.field_of_study ,Multidisciplinary ,Base Sequence ,Chemistry ,Gene Expression Profiling ,RNA ,Cancer ,hemic and immune systems ,Regulatory T cells ,General Chemistry ,Immunotherapy ,Prognosis ,medicine.disease ,Kidney Neoplasms ,In vitro ,Gene Expression Regulation, Neoplastic ,Gene regulation in immune cells ,Cancer research ,Tumour immunology ,Single-Cell Analysis - Abstract
Regulatory T (Treg) cells are one of the major immunosuppressive cell types in cancer and a potential target for immunotherapy, but targeting tumor-infiltrating (TI) Treg cells has been challenging. Here, using single-cell RNA sequencing of immune cells from renal clear cell carcinoma (ccRCC) patients, we identify two distinct transcriptional fates for TI Treg cells, Fate-1 and Fate-2. The Fate-1 signature is associated with a poorer prognosis in ccRCC and several other solid cancers. CD177, a cell surface protein normally expressed on neutrophil, is specifically expressed on Fate-1 TI Treg cells in several solid cancer types, but not on other TI or peripheral Treg cells. Mechanistically, blocking CD177 reduces the suppressive activity of Treg cells in vitro, while Treg-specific deletion of Cd177 leads to decreased tumor growth and reduced TI Treg frequency in mice. Our results thus uncover a functional CD177+ TI Treg population that may serve as a target for TI Treg-specific immunotherapy., Regulatory T (Treg) cells are important modulators of the tumor microenvironment. Here the authors perform transcriptome profiling of immune cells from patients with renal clear cell carcinoma to find a Treg signature that correlates with poorer prognosis, with CD177 being implicated as the main mediator for related alterations in Treg activity and tumor outcome.
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- 2021
16. Human neutrophil antigen 2 sequence‐based typing: Joining the hunt for the <scp>CD177</scp> answer
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Elizabeth Wroe, Anthony Poles, Leigh Keen, and Tom Browne
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Isoantigens ,Mutation ,Neutropenia ,Neutrophils ,Null (mathematics) ,Infant, Newborn ,Receptors, Cell Surface ,Exons ,Hematology ,General Medicine ,Biology ,GPI-Linked Proteins ,medicine.disease ,medicine.disease_cause ,Isoantibodies ,Exon ,Antigen ,Polymorphism (computer science) ,Immunology ,medicine ,Humans ,Genotyping - Abstract
BACKGROUND AND OBJECTIVES Isoantibodies to human neutrophil antigen 2 (CD177) have been associated with several clinical conditions but to date the molecular basis for altered or non-expression has not been determined. Reliance on phenotyping and crossmatch to investigate these neutropenic clinical cases are inconvenient for the patients and demanding of resources within the laboratory. Therefore, a molecular approach has been introduced to address both issues. MATERIALS AND METHODS A DNA panel of 100 randomly selected blood donors were collected and supplemented with 18 DNA samples from blood donors previously shown to be CD177 null. All DNA samples were sequence-based typed for all exons and observed polymorphisms recorded. The DNA from two families previously investigated for neonatal alloimmune neutropenia due to CD177 isoantibodies were also analysed. RESULTS The incidence of CD177 null could be associated with a known exon 7 single-nucleotide polymorphism in 16/21 known CD177 null samples, which is consistent with previously published findings. Two additional mutations that may lead to null expression were also identified, of which one may be novel. In both family investigations, this same mutation could also be observed in the maternal DNA sample. CONCLUSION Based on these observations, introduction of CD177 genotyping into routine use would identify null expression in over 75% (16/21) of associated cases. In turn, this could significantly reduce the need for supplementary testing and associated inconvenience to patients while permitting increased efficiency of laboratory testing. An added benefit would potentially elucidate other clinically relevant mutations and associated antigenic targets.
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- 2021
17. The Role of Change Rates of CYFRA21-1 and CEA in Predicting Chemotherapy Efficacy for Non-Small-Cell Lung Cancer
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Ming Chen, Tongwei Zhao, and Guangyun Mao
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Male ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,Article Subject ,medicine.medical_treatment ,Computer applications to medicine. Medical informatics ,R858-859.7 ,GPI-Linked Proteins ,General Biochemistry, Genetics and Molecular Biology ,Carcinoembryonic antigen ,Antigens, Neoplasm ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,medicine ,Humans ,Stage (cooking) ,Lung cancer ,Aged ,Retrospective Studies ,Keratin-19 ,Chemotherapy ,General Immunology and Microbiology ,Receiver operating characteristic ,biology ,business.industry ,Applied Mathematics ,Computational Biology ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Carcinoembryonic Antigen ,Chemotherapy cycle ,Treatment Outcome ,ROC Curve ,Modeling and Simulation ,Linear Models ,biology.protein ,Female ,Non small cell ,business ,Progressive disease ,Research Article - Abstract
Background. Cytokeratin 19 fragment 21-1 (CYFRA21-1) and carcinoembryonic antigen (CEA) are effective prognostic biomarkers for lung cancer. This study investigated the predictive effects of change rates of CYFRA21-1 and CEA before and after the first cycles of chemotherapy on advanced IIIb/IIIc or IV stage non-small-cell lung cancer (NSCLC) patients. Methods. Data of 103 NSCLC patients who received chemotherapy in Zhejiang Provincial People’s Hospital from February 2018 to November 2020 were retrospectively analyzed. All patients received platinum doublet chemotherapy for at least 2 cycles. CYFRA21-1 and CEA levels of patients were detected before and after the first chemotherapy cycle, respectively. After the second cycle, the efficacy was evaluated, and patients were divided into the disease control (DC) and progressive disease (PD) groups. The generalized linear model (GLM) and linear trend test assessed the relationship between change rates of CYFRA21-1 and CEA levels and chemotherapeutic efficacy before and after chemotherapy. Moreover, the receiver operating characteristic (ROC) curve determined the predictive value of change rates of CYFRA21-1 and CEA on chemotherapeutic efficacy. Results. After the second chemotherapeutic cycle, there were 92 patients in the DC group and 11 in the PD group. GLM and linear trend test both indicated that change rates of CYFRA21-1 and CEA were inversely correlated with chemotherapeutic efficacy for NSCLC. Change rates of CYFRA21-1 and CEA were used to predict area under the ROC curve of chemotherapeutic efficacy (0.87, 0.71-1.00), which is better than single index prediction of CYFRA21-1 (0.71, 0.49-0.94) or CEA change rate (0.85, 0.69-1.00) ( p < 0.001 ). Conclusion. Before and after chemotherapy of the first cycle for advanced NSCLC patients, combining serum CYFRA21-1 and CEA levels could increase sensitivity and specificity to predict the chemotherapeutic efficacy and guide the following therapy of advanced NSCLC patients.
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- 2021
18. Significant differences in FcγRIIa, FcγRIIIa and FcγRIIIb genes polymorphism and anti-malarial IgG subclass pattern are associated with severe Plasmodium falciparum malaria in Saudi children
- Author
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Ahmad Al-Bawab, Themer H. Alenazi, Amre Nasr, Ayman M. Salah, Osama Hamid, Emad Masuadi, Ahmad Aljada, H.A. Elsheikh, and Amir Abushouk
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Male ,Falciparum ,Plasmodium ,RC955-962 ,Saudi Arabia ,Infectious and parasitic diseases ,RC109-216 ,GPI-Linked Proteins ,Subclass ,Saudi ,IgG subclass ,Polymorphism (computer science) ,Arctic medicine. Tropical medicine ,Genotype ,parasitic diseases ,medicine ,Humans ,Malaria, Falciparum ,Child ,Children ,Polymorphism, Genetic ,biology ,business.industry ,Research ,Receptors, IgG ,Plasmodium falciparum ,medicine.disease ,biology.organism_classification ,Malaria ,Infectious Diseases ,Parasitology ,Immunoglobulin G ,Immunology ,Humoral immunity ,AMA-1 ,biology.protein ,Female ,Antibody ,business - Abstract
Background The FcγRs genotypes have been reported to play a key role in the defence against malaria parasites through both cellular and humoral immunity. This study aimed to investigate the possible correlation between FcγR (IIa, IIIa, and IIIb) genes polymorphism and the clinical outcome for anti‐malarial antibody response of Plasmodium falciparum infection among Saudi children. Methods A total of 600 volunteers were enrolled in this study, including 200 malaria-free control (MFC) subjects, 218 patients with uncomplicated malaria (UM) and 182 patients with severe malaria (SM). The FcγR genotypes were analysed using PCR amplification methods, and measurements of immunoglobulin were determined using enzyme-linked immunosorbent assay (ELISA) technique. Results The data revealed that the FcγRIIa-R/R131 showed a statistically significant association with SM patients when compared to UM patients. Furthermore, higher levels of IgG1, IgG2, and IgG4 were associated with the FcγRIIa-H/H131 genotype among UM patients. Although the FcγRIIa-F/V176 genotype was not associated with UM, it showed a significant association with severe malaria. Interestingly, the FcγRIIIa-V/V176 genotype offered protection against SM. Moreover, SM patients carrying the FcγRIIIa-F/F genotype showed higher levels of AMA-1-specific IgG2 and IgG4 antibodies. The FcγRIIIb-NA1/NA1 and FcγRIIIb-NA2/NA2 genotypes did not show significant differences between the UM and the MFC groups. However, the genotype FcγRIIIb-NA2/NA2 was statistically significantly associated with SM patients. Conclusions The data presented in this study suggest that the influence of the FcγRIIa-R/R131, FcγRIIIa-F/F176 and FcγRIIIb-NA2/NA2 genotypes are statistically significantly associated with SM patients. However, the FcγRIIa-H/H13 and FcγRIIIa-V/V176 genotypes have demonstrated a protective effect against SM when compared to UM patients. The impact of the FcyR (IIa, IIIa and IIIb) gene variants and anti-malaria IgG subclasses play an important role in susceptibility to malaria infection and disease outcome in Saudi children.
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- 2021
19. Lepidium meyenii Supplemented Diet Modulates Neurobehavioral and Biochemical Parameters in Mice Fed High-Fat High-Sugar Diet
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Adejoke Y. Onaolapo, Abiola Alawode, Anthony Tope Olofinnade, and Olakunle J. Onaolapo
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Male ,medicine.medical_specialty ,Antioxidant ,Dietary Sugars ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Diet, High-Fat ,GPI-Linked Proteins ,medicine.disease_cause ,Lepidium ,Lipid peroxidation ,Mice ,chemistry.chemical_compound ,Functional Food ,Memory ,Internal medicine ,Diabetes mellitus ,medicine ,Animals ,Immunology and Allergy ,Maze Learning ,Metabolic Syndrome ,Behavior, Animal ,medicine.diagnostic_test ,Lepidium meyenii ,business.industry ,Brain ,medicine.disease ,Animal Feed ,Grooming ,Acetylcholinesterase ,Diet ,Disease Models, Animal ,Oxidative Stress ,Endocrinology ,chemistry ,Inflammation Mediators ,Metabolic syndrome ,Lipid profile ,business ,Biomarkers ,Oxidative stress - Abstract
Background: Metabolic syndrome has been associated with an increased risk of cardiovascular disease, diabetes mellitus, and neurodegenerative disorders. Known side-effects of currently- available drugs necessitate the search for possibly better treatment options. Objective: This study examined the effects of dietary lepidium meyenii (MACA) supplementation on neurobehaviour, metabolic profile, levels of inflammatory markers, and oxidative stress parameters in a mouse model of metabolic syndrome. Methods: Mice were randomly assigned into 8 groups of ten animals each. Groups consist of standard diet (SD) control, high fat/high sugar (HFHS) control and three groups each of lepidium meyenii incorporated into either SD or HFHS diet at 0.1, 0.2 and 0.4%. Mice were fed for seven weeks, and body weight was measured weekly. Open-field behaviors and radial-arm/Y-maze spatial memory were scored at the end of the study. Twenty-four hours after the last behavioral test, fasting blood glucose levels were estimated. Animals were then euthanized, and blood was drawn for estimation of serum lipid profile. Whole brains were excised, weighed and homogenized to estimate the levels of lipid peroxidation, inflammatory markers, antioxidant status, and acetylcholinesterase activity. Results: MACA-supplemented diet was associated with a decrease in body weight gain, an increase in food intake (at lower concentrations), suppression of grooming behavior, and decrease in acetylcholinesterase activity. MACA-supplement also reversed HFHS-induced memory impairment, anxiety, hyperglycaemia, lipid derangement, oxidative stress, and derangement of inflammatory markers. Conclusion: Dietary supplementation with MACA shows beneficial effects in mitigating the effects of metabolic syndrome on the brain in mice.
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- 2021
20. NT5E mutation in sisters who underwent aortic valve replacements for aortic stenosis
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Tetsuro Uchida, Tadashi Kaname, Nobuyoshi Azuma, Atsushi Yamashita, Ai Ishizawa, and Mitsuaki Sadahiro
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Pulmonary and Respiratory Medicine ,Aortic valve ,medicine.medical_specialty ,Gene mutation ,GPI-Linked Proteins ,NT5E ,Aortic valve replacement ,Internal medicine ,medicine ,Humans ,5'-Nucleotidase ,Adult Cardiac ,business.industry ,Calcinosis ,Aortic Valve Stenosis ,medicine.disease ,Stenosis ,medicine.anatomical_structure ,Bypass surgery ,Aortic Valve ,Heart Valve Prosthesis ,Mutation ,cardiovascular system ,Cardiology ,Female ,Surgery ,Aortic valve calcification ,Cardiology and Cardiovascular Medicine ,business ,Calcification - Abstract
Background and Aims: Mutations of the NT5E gene encoding the cluster of differentiation 73 (CD73) protein have been found in patients with characteristic calcification of joints and arteries (CALJA). CD73 plays a protective role against aortic valve calcification and its deletion results in aortic valve calcification. However, there have been no reports of a patient with CALJA with aortic stenosis. Methods: We describe two extremely rare cases of two sisters with identical NT5E gene mutation patterns, both of whom presented severe aortic stenosis and limb ischemia. Genetic examination for definitive diagnosis was also performed in both patients. Results: Both patients underwent aortic valve replacement and bilateral distal arterial bypass surgeries successfully. They were genetically diagnosed with CALJA based on the NT5E mutation. Conclusions: NT5E mutation should be considered in patients requiring aortic valve replacement for a calcified aortic valve and bypass surgery for specific calcified and occluded arteries.
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- 2021
21. Mesothelin is Commonly Expressed in Pancreatic Adenocarcinoma but Unrelated to Cancer Aggressiveness
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Frank Jacobsen, Sören Weidemann, Michael Neipp, Ulf Nahrstedt, Jakob R. Izbicki, Till S. Clauditz, Eike Burandt, Christian Bernreuther, Ronald Simon, Daniel Perez, Till Krech, Hamid Mofid, Stefan Steurer, Thies Daniels, Andreas H. Marx, and Kristina Jansen
- Subjects
0301 basic medicine ,Cancer Research ,endocrine system diseases ,Adenocarcinoma ,GPI-Linked Proteins ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Pancreatic cancer ,Biomarkers, Tumor ,Humans ,Medicine ,Mesothelin ,Tissue microarray ,biology ,business.industry ,Cancer ,General Medicine ,medicine.disease ,Immunohistochemistry ,Pancreatic Neoplasms ,030104 developmental biology ,Oncology ,Tissue Array Analysis ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Pancreatitis ,Cancer biomarkers ,business - Abstract
Data on Mesothelin expression in human normal and cancerous tissues is controversial. We employed immunohistochemistry on a tissue microarray from 599 pancreatic cancers and 12 large tissue sections of pancreatitis. Mesothelin expression was highest in pancreatic adenocarcinomas (89%) and adenocarcinomas of the ampulla Vateri (79%), infrequent in pancreatitis and absent in 6 acinus cell carcinomas and normal pancreas. Mesothelin expression was unrelated to pathological tumor stage, grade, metastasis, and tumor infiltrating CD8+ lymphocytes. In conclusion, pancreatic cancer may be ideally suited for putative anti-mesothelin therapies, and mesothelin may represent a suitable biomarker for pancreatic cancer diagnosis, especially on small biopsies.
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- 2021
22. Artificial intelligence and placental DNA methylation: newborn prediction and molecular mechanisms of autism in preterm children
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Buket Aydas, Ray O. Bahado-Singh, Sangeetha Vishweswaraiah, and Uppala Radhakrishna
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Autism Spectrum Disorder ,Placenta ,GPI-Linked Proteins ,behavioral disciplines and activities ,Epigenesis, Genetic ,chemistry.chemical_compound ,Pregnancy ,Artificial Intelligence ,mental disorders ,Humans ,Medicine ,Epigenetics ,Autistic Disorder ,Epigenomics ,Genetics ,Membrane Glycoproteins ,Heterogeneous group ,Mechanism (biology) ,business.industry ,Neuropeptides ,Infant, Newborn ,Obstetrics and Gynecology ,DNA Methylation ,medicine.disease ,chemistry ,Autism spectrum disorder ,Pediatrics, Perinatology and Child Health ,DNA methylation ,Autism ,Female ,business ,Biomarkers ,DNA - Abstract
Autism Spectrum Disorder (ASD) represents a heterogeneous group of disorders with a complex genetic and epigenomic etiology. DNA methylation is the most extensively studied epigenomic mechanism and correlates with altered gene expression. Artificial intelligence (AI) is a powerful tool for group segregation and for handling the large volume of data generated in omics experiments.We performed genome-wide methylation analysis for differential methylation of cytosine nucleotide (CpG) was performed in 20 postpartum placental tissue samples from preterm births. Ten newborns went on to develop autism (Autistic Disorder subtype) and there were 10 unaffected controls. AI including Deep Learning (AI-DL) platforms were used to identify and rank cytosine methylation markers for ASD detection. Ingenuity Pathway Analysis (IPA) to identify genes and molecular pathways that were dysregulated in autism.We identified 4870 CpG loci comprising 2868 genes that were significantly differentially methylated in ASD compared to controls. Of these 431 CpGs met the stringent EWAS threshold (The present study provides substantial evidence that epigenetic differences in placental tissue are associated with autism development and raises the prospect of early and accurate detection of the disorder.
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- 2021
23. CD16xCD33 Bispecific Killer Cell Engager (BiKE) as potential immunotherapeutic in pediatric patients with AML and biphenotypic ALL
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Angela R. Manser, DA Vallera, Titus Vatrin, Florian Babor, Jeffrey S. Miller, Sarah B. Reusing, Sanil Bhatia, Markus Uhrberg, and Martin Felices
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Cytotoxicity, Immunologic ,Research Report ,Cancer Research ,CD3 ,medicine.medical_treatment ,Sialic Acid Binding Ig-like Lectin 3 ,Immunology ,CD33 ,HL-60 Cells ,NK cells ,Hematopoietic stem cell transplantation ,GPI-Linked Proteins ,Lymphocyte Activation ,Cell Line ,Cell Line, Tumor ,hemic and lymphatic diseases ,Antibodies, Bispecific ,Humans ,Immunology and Allergy ,Medicine ,Cytotoxic T cell ,Acute leukemia ,biology ,business.industry ,Receptors, IgG ,Correction ,Chimeric antigen receptor ,Killer Cells, Natural ,Leukemia, Myeloid, Acute ,Oncology ,Granzyme ,Perforin ,Biphenotypic ALL ,Cancer research ,biology.protein ,Immunotherapy ,Antibody therapy ,BiKE ,Bispecific antibodies ,business - Abstract
Similar to pediatric acute myeloid leukemia (AML) the subgroup of biphenotypic acute lymphoblastic leukemia (ALL) is a rare complex entity with adverse outcome, characterized by the surface expression of CD33. Despite novel and promising anti-CD19 targeted immunotherapies such as chimeric antigen receptor T cells and bispecific anti-CD19/CD3 antibodies, relapse and resistance remain a major challenge in about 30% to 60% of patients. To investigate the potential role of the fully humanized bispecific antibody CD16 × CD33 (BiKE) in children with CD33+ acute leukemia, we tested whether the reagent was able to boost NK cell effector functions against CD33+ AML and biphenotypic ALL blasts. Stimulation of primary NK cells from healthy volunteers with 16 × 33 BiKE led to increased cytotoxicity, degranulation and cytokine production against CD33+ cell lines. Moreover, BiKE treatment significantly increased degranulation, IFN-γ and TNF-α production against primary ALL and AML targets. Importantly, also NK cells from leukemic patients profited from restoration of effector functions by BiKE treatment, albeit to a lesser extent than NK cells from healthy donors. In particular, those patients with low perforin and granzyme expression showed compromised cytotoxic function even in the presence of BiKE. In patients with intrinsic NK cell deficiency, combination therapy of CD16xCD33 BiKE and allogeneic NK cells might thus be a promising therapeutic approach. Taken together, CD16xCD33 BiKE successfully increased NK cell effector functions against pediatric AML and biphenotypic ALL blasts and constitutes a promising new option for supporting maintenance therapy or “bridging” consolidation chemotherapy before hematopoietic stem cell transplantation. Supplementary Information The online version contains supplementary material available at 10.1007/s00262-021-03008-0.
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- 2021
24. A Novel Color-Coded Liver Metastasis Mouse Model to Distinguish Tumor and Adjacent Liver Segment
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Jun Yamamoto, Bernhard B. Singer, Siamak Amirfakhri, Thinzar M. Lwin, Michael A. Turner, Yoshihiko Tashiro, Hiroto Nishino, Robert M. Hoffman, Hannah M. Hollandsworth, and Michael Bouvet
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Pathology ,Colorectal cancer ,Medizin ,Metastasis ,Mice ,Liver metastases ,chemistry.chemical_compound ,0302 clinical medicine ,Monoclonal ,Nude mouse model ,Cancer ,Color-coded fluorescence imaging ,biology ,Liver Disease ,Liver segment ,Liver Neoplasms ,Optical Imaging ,Antibodies, Monoclonal ,Molecular Imaging ,Colon cancer ,Colo-Rectal Cancer ,Liver ,030220 oncology & carcinogenesis ,Injections, Intravenous ,Colonic Neoplasms ,030211 gastroenterology & hepatology ,Fluorescent tumor-specific antibody ,Antibody ,Intravenous ,Biotechnology ,Indocyanine Green ,medicine.medical_specialty ,Liver tumor ,medicine.drug_class ,Clinical Sciences ,Color ,GPI-Linked Proteins ,Monoclonal antibody ,Article ,Antibodies ,Injections ,03 medical and health sciences ,medicine ,Animals ,Humans ,Hepatectomy ,Fluorescent Dyes ,business.industry ,medicine.disease ,Xenograft Model Antitumor Assays ,Carcinoembryonic Antigen ,CEACAM ,chemistry ,biology.protein ,Surgery ,Digestive Diseases ,Ligation ,business ,Indocyanine green - Abstract
Background It is difficult to distinguish between a tumor and its liver segment with traditional use of indocyanine green (ICG) alone. In the present study, a method was used to limit ICG to the liver segment adjacent to a tumor. A spectrally-distinct fluorescently-labeled tumor-specific antibody against human carcinoembryonic antigen-related cell-adhesion molecules was used to label the metastatic tumor in a patient-derived orthotopic xenograft mouse model to enable color-coded visualization and distinction of a colon-cancer liver metastases and its adjacent liver segment. Materials and Methods Nude mice received surgical orthotopic implantation in the liver of colon-cancer liver metastases derived from two patients. An anti- carcinoembryonic antigen-related cell-adhesion molecules monoclonal antibody (mAb 6G5j) was conjugated to a near-infrared dye IR700DX (6G5j-IR700DX). After three weeks, mice received 6G5j-IR700DX via tail-vein injection 48 hours before surgery. ICG was intravenously injected after ligation of the left or left lateral Glissonean pedicle resulting in labeling of the segment with preserved blood-flow in the liver. Imaging was performed with the Pearl Trilogy and FLARE Imaging Systems. Results The metastatic liver tumor had a clear fluorescence signal due to selective tumor targeting by 6G5j-IR700DX, which was imaged on the 700 nm channel. The adjacent liver segment, with preserved blood-flow in the liver, had a clear fluorescence ICG 800 nm signal, while the left or left lateral segment had no fluorescence signal. Overlay of the images showed clear color-coded differentiation between the tumor fluorescing at 700 nm and the adjacent liver segment fluorescing at 800 nm. Conclusions Color-coding of a liver tumor and uninvolved liver segment has the potential for improved liver resection.
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- 2021
25. Prevalence of mesothelin expression in peritoneal disease from colorectal and appendiceal cancers
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Sergei Tatishchev, Dong H. Yoon, Mariun Philip N. Duldulao, Ahmad M. Ibrahim, Joongho Shin, and Sang W. Lee
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Male ,Pathology ,medicine.medical_specialty ,Peritoneal metastasis ,Colorectal cancer ,Cell ,Adenocarcinoma ,GPI-Linked Proteins ,Biomarkers, Tumor ,Prevalence ,Humans ,Medicine ,Mesothelin ,Peritoneal Neoplasms ,Aged ,biology ,business.industry ,General Medicine ,Odds ratio ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Staining ,medicine.anatomical_structure ,Appendiceal Neoplasms ,Oncology ,Case-Control Studies ,biology.protein ,Female ,Surgery ,Peritoneal diseases ,Colorectal Neoplasms ,business ,Immunostaining - Abstract
BACKGROUND Mesothelin is a cell surface glycoprotein overexpressed in 28%-58% of colorectal cancer (CRC). We hypothesized that CRC mesothelin expression contributes to peritoneal spread and that it is selectively overexpressed in those with peritoneal metastasis versus distant metastasis. METHODS This case-controlled study involved mesothelin immunohistochemistry staining of tumor specimens from patients with metastatic CRC/appendiceal cancers between 2017 and 2019. Staining reactivity was graded from trace to 4+ (low ≤1+; high >1+). Staining patterns were characterized on global (focal/patchy/diffuse) and cellular (apical/cytoplasmic) levels. Immunostaining of normal mesothelial cells served as internal control. RESULTS Thirty-one patients were identified: 11 peritoneal (study) and 20 distant metastasis (control). The control group did not include appendiceal cancers. The study group had greater proportion of high staining reactivity (55% vs. 5%; odds ratio [OR] = 20.4, 95% confidence interval [CI] 1.96-211.8). The study group had more diffuse (36% vs. 0%; OR = 22.2, 95% CI 1.1-465.3) and cytoplasmic staining patterns (73% vs. 28%; OR = 6.9, 95% CI 1.3-37.2). CONCLUSION Mesothelin expression is higher in CRC/appendiceal cancers with peritoneal metastasis than those with distant metastasis. Immunohistochemistry staining patterns suggestive of propensity towards peritoneal metastasis include diffuse and cytoplasmic staining. Mesothelin may be a potential target for novel treatments of CRC/appendiceal carcinoma with peritoneal involvement.
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- 2021
26. Differential <scp>DNA</scp> methylation and <scp>mRNA</scp> transcription in gingival tissues in periodontal health and disease
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Per Hoffmann, Steven C. Y. Chen, Panos N. Papapanou, Fatemeh Momen-Heravi, Hyunjin Kim, and Moritz Kebschull
- Subjects
Homeodomain Proteins ,Periodontium ,Periodontitis ,Promoter ,Methylation ,DNA Methylation ,Biology ,GPI-Linked Proteins ,medicine.disease ,Gingivitis ,Molecular biology ,Article ,CpG site ,DNA methylation ,medicine ,Humans ,Periodontics ,RNA, Messenger ,Epigenetics ,medicine.symptom ,DNA microarray ,Cell Adhesion Molecules ,Transcription Factors - Abstract
AIM We investigated differential DNA methylation in gingival tissues in periodontal health, gingivitis, and periodontitis, and its association with differential mRNA expression. MATERIALS AND METHODS Gingival tissues were harvested from individuals and sites with clinically healthy and intact periodontium, gingivitis, and periodontitis. Samples were processed for differential DNA methylation and mRNA expression using the IlluminaEPIC (850 K) and the IlluminaHiSeq2000 platforms, respectively. Across the three phenotypes, we identified differentially methylated CpG sites and regions, differentially expressed genes (DEGs), and genes with concomitant differential methylation at their promoters and expression were identified. The findings were validated using our earlier databases using HG-U133Plus2.0Affymetrix microarrays and Illumina (450 K) methylation arrays. RESULTS We observed 43,631 differentially methylated positions (DMPs) between periodontitis and health, and 536 DMPs between gingivitis and health (FDR
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- 2021
27. Novel fusion genes in spindle cell rhabdomyosarcoma: The spectrum broadens
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Jaylou Velez-Torres, Elizabeth A Montgomery, Andrew E. Rosenberg, Julio A. Diaz-Perez, and Diego Montoya-Cerrillo
- Subjects
Adult ,Male ,Cancer Research ,Oncogene Proteins, Fusion ,Cell Adhesion Molecules, Neuronal ,Caveolin 1 ,Cell ,GPI-Linked Proteins ,Fusion gene ,Nuclear Receptor Coactivator 2 ,Young Adult ,HMGA2 ,Rhabdomyosarcoma ,Genetics ,medicine ,Humans ,Myeloid Ecotropic Viral Integration Site 1 Protein ,Spindle cell rhabdomyosarcoma ,Gene ,Heterogeneous group ,biology ,HMGA2 Protein ,Sarcoma ,Middle Aged ,Proto-Oncogene Proteins c-met ,Prognosis ,medicine.disease ,Molecular analysis ,medicine.anatomical_structure ,biology.protein ,Cancer research ,Female ,E1A-Associated p300 Protein ,Transcription Factors - Abstract
Rhabdomyosarcoma (RMS) encompasses a heterogeneous group of tumors with striated muscle differentiation. RMSs are classified as alveolar, embryonal, spindle cell /sclerosing and pleomorphic types and molecular analysis of these tumors has identified aberrations that are useful in their further subclassification. Spindle cell rhabdomyosarcoma (SpRMS) is uncommon and has been described with VGLL2 fusions, EWSR1/FUS-TFCP2 rearrangements, and myoD1 mutations - the mutations are associated with significantly different prognoses. Also, the NCOA2-MEIS1 fusion gene was recently described in two primary intraosseous RMS that contained spindle cell components. Herein, we report three cases of SpRMS harboring different novel fusion genes, one possessing EP300-VGLL3, a second with NCOA2-MEIS1 and CAV1-MET, and the third case had HMGA2-NEGR1 and multiple amplified genes. This article is protected by copyright. All rights reserved.
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- 2021
28. Downregulation of NKG2DLs by TGF-β in human lung cancer cells
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Chi-Dug Kang, Jae-Ho Bae, You-Soo Park, Woo-Chang Son, Ho-Jung Choi, Hae-Ryung Cho, and Young Shin Lee
- Subjects
Cytotoxicity, Immunologic ,0301 basic medicine ,Lung Neoplasms ,medicine.medical_treatment ,Immunology ,Cell ,Down-Regulation ,GPI-Linked Proteins ,NKG2D ligands ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Downregulation and upregulation ,Immune Tolerance ,medicine ,Humans ,Galunisertib ,Lung cancer ,biology ,Chemistry ,Research ,Intracellular Signaling Peptides and Proteins ,Transforming growth factor beta ,Adenocarcinoma, Bronchiolo-Alveolar ,RC581-607 ,medicine.disease ,Killer Cells, Natural ,Matrix metalloproteinase ,030104 developmental biology ,medicine.anatomical_structure ,Cytokine ,A549 Cells ,030220 oncology & carcinogenesis ,Cancer cell ,Quinolines ,Cancer research ,biology.protein ,Intercellular Signaling Peptides and Proteins ,Pyrazoles ,Tumor Escape ,Immunologic diseases. Allergy - Abstract
BackgroundTransforming growth factor beta (TGF-β) is a typical immuno-inhibitory cytokine and highly secreted by lung cancer cells. It was supposed that its immunosuppressive effects to NK cell might be related with the altered expression of activating and inhibitory molecules in lung cancer cells. In this study, we examined the expression of NKG2DLs, PD-L1 and PD-L2 in lung cancer cells after treatment of TGF-β and a TGF-β inhibitor, Galunisertib (LY2157299).ResultsTGF-β reduced the level of surface proteins of five NKG2DLs without altered transcription levels in lung cancer cells. Galunisertib reversed the effect of TGF-β on the expression of NKG2DLs. Since MMP inhibitors, MMPi III and MMP2 inhibitor I, restored the reduced expression of NKG2DLs after treatment of TGF-β, it was thought that TGF-β induced the expression of MMP2 which facilitated the shedding of the NKG2DLs in cancer cells. However, the expression of PD-L1, L2 were not changed by treatment with TGF-β or Galunisertib.ConclusionsTherefore, inhibition of TGF-β might reverse the immunosuppressive status on immune cells and restore NK cell mediated anticancer immune responses by upregulation of NKG2DLs in cancer cells.
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- 2021
29. Activin receptor-like kinase 4 haplodeficiency alleviates the cardiac inflammation and pacing-induced ventricular arrhythmias after myocardial infarction
- Author
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Qian Wang, Yudong Fei, Xingxing Cai, Yi-Gang Li, Yuli Yang, Jianwen Hou, Wei Li, and Zhixing Wei
- Subjects
Cardiac function curve ,Aging ,medicine.medical_specialty ,Chemokine ,CD14 ,Lipopolysaccharide Receptors ,Myocardial Infarction ,Inflammation ,Stimulation ,macrophage ,GPI-Linked Proteins ,Peripheral blood mononuclear cell ,ALK4 ,Mice ,Internal medicine ,Medicine ,Macrophage ,Animals ,Humans ,Myocardial infarction ,ventricular arrhythmia ,Mice, Knockout ,biology ,business.industry ,Macrophages ,Receptors, IgG ,Cardiac Pacing, Artificial ,Arrhythmias, Cardiac ,Cell Biology ,medicine.disease ,Healthy Volunteers ,Mice, Inbred C57BL ,Myocarditis ,Endocrinology ,inflammation ,Echocardiography ,biology.protein ,Cytokines ,medicine.symptom ,business ,Activin Receptors, Type I ,Research Paper - Abstract
Background: Inflammation process is an important determinant for subsequent changes in cardiac function and remodeling after acute myocardial infarction (MI). Recent studies have implicated that ALK4 haplodeficiency improves cardiac function after MI. However, it remains unknown if the beneficial effects are partly attributed to ALK4 haplodeficiency-induced modulation on inflammatory response in the inflammatory phase of MI. In this research, we aimed to explore the mechanism of ALK4 haplodeficiency in the inflammatory stage of MI. Methods: ALK4, CD16, and CD14 were detected in peripheral blood mononuclear cells (PBMCs) isolated from MI patients and healthy volunteers. ALK4 haplodeficiency (ALK4+/-) mice and wild-type (WT) littermates were randomly divided into the sham group and the MI group. Inflammation cytokines and chemokines were measured. Echocardiography and intracardiac electrophysiological recordings were performed on the 3rd day and the 7th day after MI operation. ALK4 expression and inflammation cytokines were also detected in LPS- or IL-4-stimulated bone marrow-derived macrophages (BMDM) from the ALK4+/- mice and WT littermates. Results: ALK4 gene expression in circulating monocytes of MI patients was higher than that in those of healthy volunteers. Cardiac inflammation and vulnerability of ventricular arrhythmia after acute myocardial injury are significantly alleviated in ALK4+/- mice as compared to WT littermates. On the 3rd day post-MI, the level of M1 macrophages were decreased in ALK4+/- mice as compared to WT littermates, while the level of M2 macrophages were increased on the 7th day post-MI. BMDM isolated from ALK4+/- mice displayed reduced secretion of pro-inflammation cytokines after stimulation by LPS in hypoxic condition and increased secretion of anti-inflammation cytokines after stimulation by IL-4. As a result, the haplodeficiency of ALK4 might be responsible for reduced inflammation response in the post-MI stage. Conclusions: ALK4 haplodeficiency reduces cardiac inflammation, improves cardiac function, and finally reduces the vulnerability of ventricular arrhythmia in the inflammatory stage after MI.
- Published
- 2021
30. Eradicating mesothelin-positive human gastric and pancreatic tumors in xenograft models with optimized anti-mesothelin antibody–drug conjugates from synthetic antibody libraries
- Author
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Michael Hsiao, Jhih-Wei Jian, Chiao-Yun Hsieh, Yong Alison Wang, Yueh-Liang Tsou, Chia-Ning Shen, Yu Chung-Ming, Hung-Ju Hsu, Hong-Sen Chen, Kuo Wei-Ying, Fei-Hung Hung, Tung Chao-Ping, Chi-Yung Chen, Hung-Pin Peng, Pei-Hsun Tsai, Simon Shih-Hsien Chuang, An-Suei Yang, Chiu Yi-Kai, Su-I Lin, and Yu-Chuan Huang
- Subjects
Male ,0301 basic medicine ,Immunoconjugates ,medicine.medical_treatment ,Mice, SCID ,Protein Engineering ,Targeted therapy ,Mice ,0302 clinical medicine ,Mice, Inbred NOD ,Pancreatic tumor ,Molecular Targeted Therapy ,Multidisciplinary ,biology ,Chemistry ,Tumor Burden ,Synthetic antibody ,Treatment Outcome ,Mesothelin ,030220 oncology & carcinogenesis ,Injections, Intravenous ,Heterografts ,Medicine ,Antibody ,Science ,Drug development ,GPI-Linked Proteins ,Article ,03 medical and health sciences ,Stomach Neoplasms ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Mesothelin Positive ,Molecular engineering ,Cancer ,medicine.disease ,Complementarity Determining Regions ,Xenograft Model Antitumor Assays ,Pancreatic Neoplasms ,body regions ,Disease Models, Animal ,030104 developmental biology ,Immunoglobulin G ,Cancer research ,biology.protein - Abstract
Mesothelin (MSLN) is an attractive candidate of targeted therapy for several cancers, and hence there are increasing needs to develop MSLN-targeting strategies for cancer therapeutics. Antibody–drug conjugates (ADCs) targeting MSLN have been demonstrated to be a viable strategy in treating MSLN-positive cancers. However, developing antibodies as targeting modules in ADCs for toxic payload delivery to the tumor site but not to normal tissues is not a straightforward task with many potential hurdles. In this work, we established a high throughput engineering platform to develop and optimize anti-MSLN ADCs by characterizing more than 300 scFv CDR-variants and more than 50 IgG CDR-variants of a parent anti-MSLN antibody as candidates for ADCs. The results indicate that only a small portion of the complementarity determining region (CDR) residues are indispensable in the MSLN-specific targeting. Also, the enhancement of the hydrophilicity of the rest of the CDR residues could drastically increase the overall solubility of the optimized anti-MSLN antibodies, and thus substantially improve the efficacies of the ADCs in treating human gastric and pancreatic tumor xenograft models in mice. We demonstrated that the in vivo treatments with the optimized ADCs resulted in almost complete eradication of the xenograft tumors at the treatment endpoints, without detectable off-target toxicity because of the ADCs’ high specificity targeting the cell surface tumor-associated MSLN. The technological platform can be applied to optimize the antibody sequences for more effective targeting modules of ADCs, even when the candidate antibodies are not necessarily feasible for the ADC development due to the antibodies’ inferior solubility or affinity/specificity to the target antigen.
- Published
- 2021
31. Extensive variation in the intelectin gene family in laboratory and wild mouse strains
- Author
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Patricia A. Castillo, Kristian K. Ullrich, Alex Bevin-Holder, Edward J. Hollox, Charles L. Bevins, Eric B. Nonnecke, Bo Lönnerdal, Faisal Almalki, and Linda Odenthal-Hesse
- Subjects
Glycan ,Evolution ,Sequence analysis ,1.1 Normal biological development and functioning ,Pseudogene ,Science ,Immunology ,Messenger ,Intelectin ,Inbred C57BL ,GPI-Linked Proteins ,Article ,Evolution, Molecular ,Mice ,03 medical and health sciences ,Underpinning research ,Lectins ,Gene expression ,Genetics ,Animals ,Humans ,2.1 Biological and endogenous factors ,Gene family ,RNA, Messenger ,Aetiology ,Gene ,Phylogeny ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Innate immune system ,biology ,030302 biochemistry & molecular biology ,Gastroenterology ,Molecular ,Mice, Inbred C57BL ,biology.protein ,RNA ,Cytokines ,Medicine ,Generic health relevance ,Laboratories ,Biotechnology - Abstract
Intelectins are a family of multimeric secreted proteins that bind microbe-specific glycans. Both genetic and functional studies have suggested that intelectins have an important role in innate immunity and are involved in the etiology of various human diseases, including inflammatory bowel disease. Experiments investigating the role of intelectins in human disease using mouse models are limited by the fact that there is not a clear one-to-one relationship between intelectin genes in humans and mice, and that the number of intelectin genes varies between different mouse strains. In this study we show by gene sequence and gene expression analysis that human intelectin-1 (ITLN1) has multiple orthologues in mice, including a functional homologue Itln1; however, human intelectin-2 has no such orthologue or homologue. We confirm that all sub-strains of the C57 mouse strain have a large deletion resulting in retention of only one intelectin gene, Itln1. The majority of laboratory strains have a full complement of six intelectin genes, except CAST, SPRET, SKIVE, MOLF and PANCEVO strains, which are derived from different mouse species/subspecies and encode different complements of intelectin genes. In wild mice, intelectin deletions are polymorphic in Mus musculus castaneus and Mus musculus domesticus. Further sequence analysis shows that Itln3 and Itln5 are polymorphic pseudogenes due to premature truncating mutations, and that mouse Itln1 has undergone recent adaptive evolution. Taken together, our study shows extensive diversity in intelectin genes in both laboratory and wild-mice, suggesting a pattern of birth-and-death evolution. In addition, our data provide a foundation for further experimental investigation of the role of intelectins in disease.
- Published
- 2021
32. AMP hydrolysis reduction in blood plasma of breast cancer elderly patients after different treatments
- Author
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Barbara Zanesco Moehlecke, Ana Paula Franco Lambert, Angélica Regina Cappellari, Carolina Aiko Moriguchi, Liliana Rockenbach, Daiana Renck, Fernanda Valente Gheler, Julia Brandt de Souza, Fernanda Bueno Morrone, Paula Engroff, and Renan Oliveira de Melo
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Clinical Biochemistry ,Breast Neoplasms ,Pharmacology ,GPI-Linked Proteins ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Adenine nucleotide ,Blood plasma ,Biomarkers, Tumor ,medicine ,Humans ,Prospective cohort study ,5'-Nucleotidase ,Molecular Biology ,Aged ,Aged, 80 and over ,business.industry ,Hydrolysis ,Cancer ,Cell Biology ,General Medicine ,Middle Aged ,medicine.disease ,Metastatic breast cancer ,Adenosine Monophosphate ,Neoplasm Proteins ,Radiation therapy ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,business - Abstract
Adenine nucleotides are important signaling molecules that mediate biological functions in many conditions, including cancer. The enzymes CD39 and CD73 produce adenosine in the extracellular milieu that has a very important role in tumor development. This study aimed to evaluate nucleotide hydrolysis in the plasma blood of breast cancer elderly patients. In this prospective cohort study, we investigated the ectonucleotidases activity in breast cancer elderly patients, at the moment of diagnosis and after treatment. Control group consisted of elderly women without cancer diagnostic. The nucleotide hydrolysis assay was performed by the malachite green method and used ATP, ADP, or AMP as substrates. Paired t test or Wilcoxon rank-sum test was used. Our data showed that breast cancer patients presented high levels of ATP and AMP hydrolyses when compared to control group at the moment of diagnosis. When analyzing the differences between the samples at the time of diagnostic and 6 months after treatment, we observed a significant reduction on CD73 activity after all treatments used: surgery, chemotherapy, radiotherapy, or hormone therapy. The results with APCP, a specific CD73 inhibitor, showed that the AMP hydrolysis was inhibited in all conditions evaluated. We observed a diminished ADPase activity in the patients without metastasis when compared to metastatic breast cancer patients. The results showed that AMP hydrolysis was reduced in the blood plasma of breast cancer elderly patients after different treatments. This study strengthens the potential role of CD73 enzyme as a biomarker for breast cancer treatment response.
- Published
- 2021
33. Dihydroartemisinin regulates apoptosis, migration, and invasion of ovarian cancer cells via mediating RECK
- Author
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Weili Yang, Jingfei Zheng, Fang Zhang, and Xuehe Li
- Subjects
0301 basic medicine ,endocrine system diseases ,medicine.medical_treatment ,Gene Expression ,Dihydroartemisinin ,Apoptosis ,Vimentin ,RM1-950 ,GPI-Linked Proteins ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Invasion ,Western blot ,Ovarian cancer ,Cell Movement ,Glioma ,Tumor Cells, Cultured ,medicine ,Humans ,Neoplasm Invasiveness ,RECK ,Ovarian Neoplasms ,Pharmacology ,medicine.diagnostic_test ,biology ,medicine.disease ,Artemisinins ,Up-Regulation ,030104 developmental biology ,biology.protein ,Cancer research ,Molecular Medicine ,Female ,Therapeutics. Pharmacology ,Wound healing ,030217 neurology & neurosurgery ,Phytotherapy - Abstract
Background Dihydroartemisinin (DHA) possesses an inhibitory effect on ovarian cancer and promotes reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression in glioma cells. This study explored the role of DHA and RECK on ovarian cancer. Methods The RECK level in ovarian cancer was analyzed under GEPIA 2 database and proved by RT-qPCR. After being treated with DHA or infected with siRECK lentivirus, the viability, apoptosis, migration, and invasion of ovarian cancer cells were evaluated by CCK-8, flow cytometry, wound healing, and transwell assays. Also, the expressions of factors related to apoptosis and epithelial-mesenchymal transition were measured by Western blot or RT-qPCR. Results DHA-treatment weakened the viability, migration, invasion, and enhanced apoptosis of ovarian cancer cells. DHA also down-regulated the levels of Bcl-2, N-cadherin, and Vimentin, and up-regulated the levels of Bax, C-caspase-3 and E-cadherin in ovarian cancer cells. RECK was lowly expressed in both ovarian cancer tissues and cells. siRECK not only had an effect opposite to DHA on the viability, apoptosis, migration, invasion, and related-factors of ovarian cancer cells but also offset the effect of DHA on ovarian cancer cells. Conclusion DHA regulated apoptosis, migration, and invasion of ovarian cancer cells via mediating RECK.
- Published
- 2021
34. FLA14 is required for pollen development and preventing premature pollen germination under high humidity in Arabidopsis
- Author
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Youjian Yu, Sue Lin, Jiashu Cao, Yingjing Miao, and Li Huang
- Subjects
0106 biological sciences ,0301 basic medicine ,Stamen ,Arabidopsis ,Plant Science ,medicine.disease_cause ,GPI-Linked Proteins ,01 natural sciences ,03 medical and health sciences ,Gene Expression Regulation, Plant ,Pollen ,medicine ,Gametogenesis ,Intine formation ,biology ,Arabidopsis Proteins ,Research ,Cell Membrane ,Botany ,Water ,food and beverages ,biology.organism_classification ,Plants, Genetically Modified ,Microspore development ,Sexual reproduction ,Cell biology ,High humidity ,Protein Transport ,030104 developmental biology ,Germination ,Fasciclin-like arabinogalactan proteins ,Pollen germination ,QK1-989 ,Ectopic expression ,Silique ,010606 plant biology & botany - Abstract
Background As an important subfamily of arabinogalactan proteins (AGPs), fasciclin-like AGPs (FLAs) contribute to various aspects of growth, development and adaptation, yet their function remains largely elusive. Despite the diversity of FLAs, only two members, Arabidopsis FLA3 and rice MTR1, are reported to be involved in sexual reproduction. In this study, another Arabidopsis FLA-encoding gene, FLA14, was identified, and its role was investigated. Results Arabidopsis FLA14 was found to be a pollen grain-specific gene. Expression results from fusion with green fluorescent protein showed that FLA14 was localized along the cell membrane and in Hechtian strands. A loss-of-function mutant of FLA14 showed no discernible defects during male gametogenesis, but precocious pollen germination occurred inside the mature anthers under high moisture conditions. Overexpression of FLA14 caused 39.2% abnormal pollen grains with a shrunken and withered appearance, leading to largely reduced fertility with short mature siliques and lower seed set. Cytological and ultramicroscopic observation showed that ectopic expression of FLA14 caused disruption at the uninucleate stage, resulting in either collapsed pollen with absent intine or pollen of normal appearance but with a thickened intine. Conclusions Taken together, our data suggest a role for FLA14 in pollen development and preventing premature pollen germination inside the anthers under high relative humidity in Arabidopsis.
- Published
- 2021
35. Single-cell immune checkpoint landscape of PBMCs stimulated with Candida albicans
- Author
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Xiao Liu, Ruoyu Li, Yi Zhang, Tianyu Liang, Jin Shao, Panpan Liang, Weiwei Deng, Yufang Liu, Kai Zhang, Yubo Ma, Zhen Su, and Wenling Han
- Subjects
0301 basic medicine ,Epidemiology ,animal diseases ,medicine.medical_treatment ,Cell ,Programmed Cell Death 1 Receptor ,CD8-Positive T-Lymphocytes ,Monocytes ,Drug Discovery ,Candida albicans ,CTLA-4 Antigen ,RNA-Seq ,Hepatitis A Virus Cellular Receptor 2 ,Sorting Nexins ,biology ,Candidiasis ,Immunosuppression ,General Medicine ,bioinformatics ,Lymphocyte Activation Gene 3 Protein ,Killer Cells, Natural ,Infectious Diseases ,medicine.anatomical_structure ,Antigens, Surface ,Cytokines ,immunotherapy ,Single-Cell Analysis ,Research Article ,Signal Transduction ,Single-cell RNA-sequencing ,030106 microbiology ,Immunology ,chemical and pharmacologic phenomena ,Tumor immunity ,GPI-Linked Proteins ,Microbiology ,Peripheral blood mononuclear cell ,03 medical and health sciences ,Immune system ,Antigens, CD ,Virology ,medicine ,Humans ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Ubiquitins ,Immunotherapy ,Dendritic Cells ,biochemical phenomena, metabolism, and nutrition ,immune checkpoints ,biology.organism_classification ,Immune Checkpoint Proteins ,Immune checkpoint ,030104 developmental biology ,Exoribonucleases ,Leukocytes, Mononuclear ,bacteria ,Parasitology ,Transcriptome - Abstract
Immune checkpoints play various important roles in tumour immunity, which usually contribute to T cells’ exhaustion, leading to immunosuppression in the tumour microenvironment. However, the roles of immune checkpoints in infectious diseases, especially fungal infection, remain elusive. Here, we reanalyzed a recent published single-cell RNA-sequencing (scRNA-seq) data of peripheral blood mononuclear cells (PBMCs) stimulated with Candida albicans (C. albicans), to explore the expression patterns of immune checkpoints after C. albicans bloodstream infection. We characterized the heterogeneous pathway activities among different immune cell subpopulations after C. albicans infection. The CTLA-4 pathway was up-regulated in stimulated CD4+ and CD8+ T cells, while the PD-1 pathway showed high activity in stimulated plasmacytoid dendritic cell (pDC) and monocytes. Importantly, we found that immunosuppressive checkpoints HAVCR2 and LAG3 were only expressed in stimulated NK and CD8+ T cells, respectively. Their viabilities were validated by flow cytometry. We also identified three overexpressed genes (ISG20, LY6E, ISG15) across all stimulated cells. Also, two monocyte-specific overexpressed genes (SNX10, IDO1) were screened out in this study. Together, these results supplemented the landscape of immune checkpoints in fungal infection, which may serve as potential therapeutic targets for C. albicans infection. Moreover, the genes with the most relevant for C. albicans infection were identified in this study.
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- 2021
36. Omentin-1: Protective impact on ischemic stroke via ameliorating atherosclerosis
- Author
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Jiabei Zhang, Xin Li, Yuyang Zhang, and Shiyi Lin
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Nitric Oxide Synthase Type III ,p38 mitogen-activated protein kinases ,Clinical Biochemistry ,Pharmacology ,GPI-Linked Proteins ,Biochemistry ,Brain Ischemia ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,0302 clinical medicine ,Enos ,Lectins ,Humans ,Medicine ,Protein kinase A ,Protein kinase B ,Ischemic Stroke ,NADPH oxidase ,biology ,business.industry ,Biochemistry (medical) ,AMPK ,General Medicine ,Atherosclerosis ,biology.organism_classification ,Stroke ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Cytokines ,Signal transduction ,business ,Proto-Oncogene Proteins c-akt - Abstract
Omentin-1, a newly identified adipokine, has recently been revealed as a novel biomarker for ischemic stroke (IS). Low circulating omentin-1 levels could indicate a high risk of IS, and elevated omentin-1 levels exert a favorable impact on cerebral ischemia. Furthermore, omentin-1 has anti-atherosclerotic, anti-inflammatory, and cardiovascular protective capabilities through the intracellular Akt/AMP-activated protein kinase (AMPK)/ nuclear factor-κB (NF-κB) and certain protein kinase (ERK, JNK, and p38) signaling pathways. Omentin-1 also alleviates endothelial cell dysfunction, improves revascularization via the Akt-endothelial nitric-oxide synthase (eNOS) regulatory axis, promotes endothelium-dependent vasodilation through endothelium-derived NO in an eNOS fashion, and inhibits VSMC proliferation by means of AMPK/ERK signaling pathways, VSMC migration via inactivation of the NADPH oxidase (NOX)/ROS/p38/HSP27 pathways and artery calcification via the PI3K-Akt pathway. These findings indicate that omentin-1 may be a negative mediator of IS. Pharmacologically, several lines of clinical evidence indicate that metformin and statins could elevate omentin-1 levels, although the specific mechanism has not been precisely delineated until now. This study is the first to summarize the comprehensive mechanisms between omentin-1 and atherosclerosis and to review the shielding effect of omentin-1 on IS. We shed light on omentin-1 as a novel therapeutic target for combating IS.
- Published
- 2021
37. Omentin attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-knockout mice
- Author
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Yasuko K Bando, Rei Shibata, Tomonobu Takikawa, Yuta Ozaki, Koji Ohashi, Lixin Fang, Noriyuki Ouchi, Katsuhiro Kato, Yuuki Shimizu, Hiroshi Kawanishi, Hayato Ogawa, Mikito Takefuji, Toyoaki Murohara, Naoya Otaka, and Mizuho Hiramatsu-Ito
- Subjects
0301 basic medicine ,Genetically modified mouse ,medicine.medical_specialty ,Vascular smooth muscle ,Physiology ,Adipokine ,Adipose tissue ,030204 cardiovascular system & hematology ,GPI-Linked Proteins ,Mice ,03 medical and health sciences ,Apolipoproteins E ,0302 clinical medicine ,Adipokines ,Lectins ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Protein kinase B ,Mice, Knockout ,business.industry ,Angiotensin II ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Matrix Metalloproteinase 9 ,Knockout mouse ,Cytokines ,Matrix Metalloproteinase 2 ,Tumor necrosis factor alpha ,Cardiology and Cardiovascular Medicine ,business ,Proto-Oncogene Proteins c-akt ,Aortic Aneurysm, Abdominal - Abstract
Aims Abdominal aortic aneurysm (AAA) is an increasing and life-threatening disease. Obesity contributes to an increased risk of AAA. Omentin is a circulating adipokine, which is downregulated in obese complications. Here, we examined whether omentin could modulate angiotensin (Ang) II-induced AAA formation in apolipoprotein E-knockout (apoE-KO) mice. Methods and results apoE-KO mice were crossed with transgenic mice expressing the human omentin gene in fat tissue (OMT-Tg mice) to generate apoE-KO/OMT-Tg mice. apoE-KO/OMT-Tg and apoE-KO mice were subjected to continuous Ang II infusion by using osmotic mini pumps. apoE-KO/OMT-Tg mice exhibited a lower incidence of AAA formation and a reduced maximal diameter of AAA compared with apoE-KO mice. apoE-KO/OMT-Tg mice showed attenuated disruption of medial elastic fibres in response to Ang II compared with apoE-KO mice. apoE-KO/OMT-Tg mice also displayed reduced expression levels of matrix metalloproteinase (MMP) 9, MMP2, and pro-inflammatory genes in aortic walls compared with apoE-KO mice. Furthermore, systemic administration of omentin also attenuated AAA formation and disruption of medial elastic fibres in response to Ang II in apoE-KO mice. Treatment of human monocyte-derived macrophages with omentin protein attenuated expression of MMP9 and pro-inflammatory mediators, and MMP9 activation after stimulation with lipopolysaccharide. Treatment of human vascular smooth muscle cells (VSMCs) with omentin protein reduced expression and activation of MMP2 after stimulation with tumour necrosis factor α. Omentin treatment increased phosphorylation levels of Akt in human macrophages and VSMCs. The suppressive effects of omentin on MMP9 and MMP2 expression were reversed by inhibition of integrin-αVβ3/PI3-kinase/Akt signalling in macrophages and VSMCs, respectively. Conclusion These data suggest that omentin acts as an adipokine that can attenuate Ang II-induced development of AAA through suppression of MMP9 and MMP2 expression and inflammatory response in the vascular wall.
- Published
- 2021
38. Sex-specific prognostic effect of CD66b-positive tumor-infiltrating neutrophils (TANs) in gastric and esophageal adenocarcinoma
- Author
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Aylin Pamuk, Wolfgang Schroeder, Jan Rehkaemper, Hakan Alakus, Thomas Zander, Reinhard Buettner, Atakan Görkem Barutcu, Josef Rueschoff, Heike Löser, Sebastian Klein, Christiane Bruns, Jennifer Quantius, Alexander Quaas, Birgid Schoemig-Markiefka, Axel M. Hillmer, and Florian Gebauer
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Esophageal Neoplasms ,Neutrophils ,medicine.medical_treatment ,Stomach neoplasms ,Subgroup analysis ,Adenocarcinoma ,GPI-Linked Proteins ,Gastroenterology ,Cohort Studies ,Antigens, CD ,Surgical oncology ,Germany ,Internal medicine ,medicine ,Humans ,Esophagus ,Neoadjuvant therapy ,Tumor microenvironment ,business.industry ,Gender ,Gender Identity ,Cancer ,General Medicine ,Middle Aged ,Esophageal cancer ,Prognosis ,medicine.disease ,Combined Modality Therapy ,Survival Analysis ,Neoadjuvant Therapy ,medicine.anatomical_structure ,Oncology ,Cohort ,Original Article ,Female ,business ,Cell Adhesion Molecules - Abstract
Background Tumor-associated neutrophils (TANs) have recently been identified as a relevant component of the tumor microenvironment (TME) in solid tumors. Within the TME TANs mediate either tumor-promoting or tumor-inhibiting activities. So far, their prognostic relevance remains to be determined. This study aims to evaluate the prognostic relevance of TANs in different molecular subtypes of gastric and esophageal adenocarcinoma. Methods We analyzed a total of 1118 Caucasian patients divided into gastric adenocarcinoma (n = 458) and esophageal adenocarcinoma cohort (n = 660) of primarily resected and neoadjuvant-treated individuals. The amount of CD66b + TANs in the tumor stroma was determined using quantitative image analysis and correlated to both molecular, as well as clinical data. Results An accumulation of TANs in the tumor stroma of gastric carcinomas was associated to a significant favorable prognosis (p = 0.026). A subgroup analysis showed that this effect was primarily related to the molecular chromosomal instable subtype (CIN) of gastric carcinomas (p = 0.010). This was only observed in female patients (p = 0.014) but not in male patients (p = 0.315). The same sex-specific effect could be confirmed in adenocarcinomas of the esophagus (p = 0.027), as well as in female individuals after receiving neoadjuvant therapy (p = 0.034). Conclusions Together, we show a sex-specific prognostic effect of TANs in gastric cancer within a Caucasian cohort. For the first time, we showed that this sex-specific prognostic effect of TANs can also be seen in esophageal cancer.
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- 2021
39. Circular RNA circ_ASAP2 regulates drug sensitivity and functional behaviors of cisplatin-resistant gastric cancer cells by the miR-330-3p/NT5E axis
- Author
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Ruijie Wang, Jie Ma, Junkai Lin, Yongjun Sun, Ping Song, Dawei Sun, Lujing Shi, Shijun Liu, Hongtao Li, and Ziwen Wang
- Subjects
Male ,Cancer Research ,endocrine system diseases ,Cell ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,GPI-Linked Proteins ,Flow cytometry ,Inhibitory Concentration 50 ,Mice ,Cell Movement ,Stomach Neoplasms ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Pharmacology (medical) ,5'-Nucleotidase ,Cell Proliferation ,Pharmacology ,Cisplatin ,Mice, Inbred BALB C ,Gene knockdown ,medicine.diagnostic_test ,Chemistry ,Cell growth ,Cell Cycle ,GTPase-Activating Proteins ,RNA, Circular ,Cell cycle ,MicroRNAs ,medicine.anatomical_structure ,Oncology ,Drug Resistance, Neoplasm ,Cancer cell ,Cancer research ,Female ,medicine.drug - Abstract
This study aims to explore the biological actions of circular RNA (circRNA) ArfGAP with SH3 domain, ankyrin repeat and PH domain 2 (circ_ASAP2, circ_0006089) in cisplatin (DDP) resistance of gastric cancer. Circ_ASAP2, ecto-5'-nucleotidase (NT5E) and miR-330-3p were quantified by quantitative real-time PCR or western blot. The measurements of the IC50 value and cell proliferation were done using 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay. Cell colony formation, cell cycle distribution, apoptosis, migration and invasion were evaluated by the colony formation, flow cytometry and transwell assays. Dual-luciferase reporter assay was performed to confirm the targeted relationship between different molecules. The role of circ_ASAP2 in tumor growth was gauged by in vivo animal studies. Circ_ASAP2 and NT5E were overexpressed in DDP-resistant gastric cancer tissues and cells. Knockdown of circ_ASAP2 promoted DDP sensitivity, apoptosis and repressed proliferation, migration and invasion of DDP-resistant gastric cancer cells in vitro and diminished tumor growth in vivo. Moreover, NT5E was a downstream effector of circ_ASAP2 in regulating cell DDP sensitivity and functional behaviors. Mechanistically, circ_ASAP2 directly bound to miR-330-3p to promote NT5E expression. Furthermore, circ_ASAP2 modulated cell DDP sensitivity and functional behaviors by targeting miR-330-3p. Knockdown of circ_ASAP2 promoted DDP sensitivity and suppressed malignant behaviors of DDP-resistant gastric cancer cells through targeting the miR-330-3p/NT5E axis.
- Published
- 2021
40. Incorporation of a Novel CD16-Specific Single-Domain Antibody into Multispecific Natural Killer Cell Engagers With Potent ADCC
- Author
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Seung-Hwan Lee, Michael J. Lowden, Dong-Hyeon Jo, Shannon Ryan, Greg Hussack, Henk van Faassen, Shalini Raphael, Kevin A. Henry, and C. Roger MacKenzie
- Subjects
medicine.medical_treatment ,Pharmaceutical Science ,02 engineering and technology ,030226 pharmacology & pharmacy ,Jurkat Cells ,Mice ,0302 clinical medicine ,Cancer immunotherapy ,Neoplasms ,Antibodies, Bispecific ,Drug Discovery ,Antibody-dependent cell-mediated cytotoxicity ,biology ,Chemistry ,Degranulation ,hemic and immune systems ,021001 nanoscience & nanotechnology ,Killer Cells, Natural ,medicine.anatomical_structure ,bispecific NK cell engager ,Molecular Medicine ,Biological Assay ,Immunotherapy ,Antibody ,0210 nano-technology ,Camelids, New World ,CD16 ,Recombinant Fusion Proteins ,Primary Cell Culture ,VHH ,chemical and pharmacologic phenomena ,GPI-Linked Proteins ,CD19 ,Natural killer cell ,03 medical and health sciences ,Protein Domains ,Antigen ,Antigens, Neoplasm ,medicine ,Animals ,Humans ,single-domain antibody ,cancer immunotherapy ,Receptors, IgG ,Antibody-Dependent Cell Cytotoxicity ,Single-Domain Antibodies ,natural killer cell ,Molecular biology ,Macaca fascicularis ,nanobody ,Single-domain antibody ,biology.protein - Abstract
Multispecific antibodies that bridge immune effector and tumor cells have shown promising preclinical and clinical efficacies. Here, we isolated and characterized novel llama single-domain antibodies (sdAbs) against CD16. One sdAb, NRC-sdAb048, bound recombinant human and cynomolgus monkey CD16 ectodomains with equivalent affinity (KD: 1 nM) but did not recognize murine CD16. Binding was similar for human CD16a expressed on NK cells and CD16b (NA2) expressed on neutrophils but dramatically weaker (KD: ∼6 μM) for the CD16b (NA1) allotype. The sdAb stained primary human peripheral blood NK cells. Irrespective of fusion orientation and linker length, bispecific sdAb–sdAb and sdAb–scFv dimers (anti-CD16/EGFR, anti-CD16/HER2, and anti-CD16/CD19) retained full binding affinity for each target, coengaged both antigens simultaneously, elicited ADCC against target antigen-expressing tumor cells in a reporter bioassay, and triggered target-specific activation and degranulation of primary NK cells as measured via interferon-γ and CD107a expression. These molecules may have applications in cancer immunotherapy.
- Published
- 2021
41. Methylation of NRN1 is a novel synthetic lethal marker of PI3K‐Akt‐mTOR and ATR inhibitors in esophageal cancer
- Author
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James G. Herman, Wushuang Du, Lidong Wang, Shunchang Jiao, Aiai Gao, Lirong Zhang, and Mingzhou Guo
- Subjects
Genetics, Genomics and Proteomics ,Male ,0301 basic medicine ,Cancer Research ,DNA Repair ,Esophageal Neoplasms ,Cell ,Apoptosis ,Ataxia Telangiectasia Mutated Proteins ,Mice ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Cell Movement ,DNA damage repair ,ATR inhibitor ,Promoter Regions, Genetic ,PI3K signaling ,Phosphoinositide-3 Kinase Inhibitors ,Aged, 80 and over ,DNA methylation ,Chemistry ,TOR Serine-Threonine Kinases ,Age Factors ,Wnt signaling pathway ,General Medicine ,Methylation ,Middle Aged ,Esophageal cancer ,Prognosis ,Tumor Burden ,medicine.anatomical_structure ,Oncology ,Pyrazines ,030220 oncology & carcinogenesis ,Heterografts ,Original Article ,Female ,Esophageal Squamous Cell Carcinoma ,Adult ,Alcohol Drinking ,DNA repair ,NRN1 ,Mice, Nude ,GPI-Linked Proteins ,03 medical and health sciences ,Cell Line, Tumor ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,PI3K/AKT/mTOR pathway ,Aged ,Cell Proliferation ,Cell growth ,Neuropeptides ,Original Articles ,medicine.disease ,030104 developmental biology ,Cancer research ,Pyrazoles ,Proto-Oncogene Proteins c-akt ,Neoplasm Transplantation ,DNA Damage - Abstract
Wnt, PI3K‐Akt‐mTOR, and NF‐κB pathways were reported to be involved in DNA damage repair (DDR). DDR‐deficient cancers become critically dependent on backup DNA repair pathways. Neuritin 1 (NRN1) is reported to be involved in PI3K‐Akt‐mTOR, and its role in DDR remains unclear. Methylation‐specific PCR, siRNA, flow cytometry, esophageal cancer cell lines, and xenograft mouse models were used to examine the role of NRN1 in esophageal cancer. The expression of NRN1 is frequently repressed by promoter region methylation in human esophageal cancer cells. NRN1 was methylated in 50.4% (510/1012) of primary esophageal cancer samples. NRN1 methylation is associated significantly with age (P, The combination of NVP‐BEZ235 and VE‐822 increased cytotoxicity in NRN1 methylated esophageal cancer cells. Methylation of NRN1 is a novel synthetic lethal marker for PI3K‐Akt‐mTOR and ATR inhibitors in human esophageal cancer.
- Published
- 2021
42. Repulsive Guidance Molecule-a and Central Nervous System Diseases
- Author
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Hang Li, Jinzhou Feng, Jinhua Tang, Jun Yang, Lu Ju, and Xiaopeng Zeng
- Subjects
Biomedical Research ,Neurogenesis ,Central nervous system ,Nerve Tissue Proteins ,Review Article ,GPI-Linked Proteins ,General Biochemistry, Genetics and Molecular Biology ,Pathogenesis ,Mice ,Central Nervous System Diseases ,medicine ,Animals ,Humans ,Spinal cord injury ,Cell Proliferation ,Neuromyelitis optica ,General Immunology and Microbiology ,business.industry ,Multiple sclerosis ,Membrane Proteins ,General Medicine ,Repulsive guidance molecule A ,medicine.disease ,Neural stem cell ,Rats ,medicine.anatomical_structure ,Medicine ,Axon guidance ,business ,Neuroscience ,Signal Transduction - Abstract
Repulsive guidance molecule-a (RGMa) is a member of glycosylphosphatidylinositol- (GPI-) anchored protein family, which has axon guidance function and is widely involved in the development and pathological processes of the central nervous system (CNS). On the one hand, the binding of RGMa and its receptor Neogenin can regulate axonal guidance, differentiation of neural stem cells into neurons, and the survival of these cells; on the other hand, RGMa can inhibit functional recovery of CNS by inhibiting axonal growth. A number of studies have shown that RGMa may be involved in the pathogenesis of CNS diseases, such as multiple sclerosis, neuromyelitis optica spectrum diseases, cerebral infarction, spinal cord injury, Parkinson’s disease, and epilepsy. Targeting RGMa can enhance the functional recovery of CNS, so it may become a promising target for the treatment of CNS diseases. This article will comprehensively review the research progression of RGMa in various CNS diseases up to date.
- Published
- 2021
43. Mesothelin is a novel cell surface disease marker and potential therapeutic target in acute myeloid leukemia
- Author
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Anilkumar Gopalakrishnapillai, Todd A. Alonzo, Soheil Meshinchi, Min Xu, Steven M. Kornblau, Lisa Broderson, E. Anders Kolb, Timothy J. Triche, Jenny L. Smith, Sonali P. Barwe, Quy Le, Michael R. Loken, Amanda R. Leonti, Colin Correnti, Laura Pardo, Cassie K. Chou, Robert B. Gerbing, Allison Kaeding, Rhonda E. Ries, Katherine Tarlock, and Thao T. Tang
- Subjects
Myeloid ,GPI-Linked Proteins ,Flow cytometry ,Young Adult ,In vivo ,hemic and lymphatic diseases ,medicine ,Humans ,Mesothelin ,Child ,Myeloid Neoplasia ,medicine.diagnostic_test ,biology ,business.industry ,Myeloid leukemia ,Hematology ,medicine.disease ,Reverse transcription polymerase chain reaction ,Leukemia, Myeloid, Acute ,Leukemia ,KMT2A ,medicine.anatomical_structure ,biology.protein ,Cancer research ,business - Abstract
In an effort to identify acute myeloid leukemia (AML)-restricted targets for therapeutic development in AML, we analyzed the transcriptomes of 2051 children and young adults with AML and compared the expression profile with normal marrow specimens. This analysis identified a large cohort of AML-restricted genes with high expression in AML, but low to no expression in normal hematopoiesis. Mesothelin (MSLN), a known therapeutic target in solid tumors, was shown to be highly overexpressed in 36% of the AML cohort (range, 5-1077.6 transcripts per million [TPM]) and virtually absent in normal marrow (range, 0.1-10.7 TPM). We verified MSLN transcript expression by quantitative reverse transcription polymerase chain reaction, confirmed cell surface protein expression on leukemic blasts by multidimensional flow cytometry, and demonstrated that MSLN expression was associated with promoter hypomethylation. MSLN was highly expressed in patients with KMT2A rearrangements (P < .001), core-binding factor fusions [inv(16)/t(16;16), P < .001; t(8;21), P < .001], and extramedullary disease (P = .001). We also demonstrated the presence of soluble MSLN in diagnostic serum specimens using an MSLN-directed enzyme-linked immunosorbent assay. In vitro and in vivo preclinical efficacy of the MSLN-directed antibody-drug conjugates (ADCs) anetumab ravtansine and anti-MSLN–DGN462 were evaluated in MSLN+ leukemia cell lines in vitro and in vivo, as well as in patient-derived xenografts. Treatment with ADCs resulted in potent target-dependent cytotoxicity in MSLN+ AML. In this study, we demonstrate that MSLN is expressed in a significant proportion of patients with AML and holds significant promise as a diagnostic and therapeutic target in AML, and that MSLN-directed therapeutic strategies, including ADCs, warrant further clinical investigation.
- Published
- 2021
44. The 'Intermediate' CD14 + CD16 + monocyte subpopulation plays a role in IVIG responsiveness of children with Kawasaki disease
- Author
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Yi Seul Kim, Hwa Jin Cho, Seung-Jung Kee, Hyun Yang, Kisoo Ha, Katrina K Ki, Insu Choi, and In Seok Jeong
- Subjects
0301 basic medicine ,Male ,IVIG-resistant ,Lipopolysaccharide Receptors ,Diseases of the musculoskeletal system ,Pediatrics ,Biomarkers, Pharmacological ,Monocytes ,0302 clinical medicine ,hemic and lymphatic diseases ,Immunology and Allergy ,Medicine ,IVIG responsiveness ,biology ,Immunoglobulins, Intravenous ,Flow Cytometry ,Pathophysiology ,medicine.anatomical_structure ,Treatment Outcome ,Child, Preschool ,Cohort ,Female ,Antibody ,Research Article ,medicine.medical_specialty ,Fever ,CD14 ,CD16 ,Mucocutaneous Lymph Node Syndrome ,GPI-Linked Proteins ,RJ1-570 ,Immunophenotyping ,03 medical and health sciences ,Rheumatology ,Internal medicine ,Humans ,Immunologic Factors ,030203 arthritis & rheumatology ,Kawasaki disease ,business.industry ,Monocyte ,Receptors, IgG ,Intermediate monocyte ,Patient Acuity ,Immunity ,medicine.disease ,030104 developmental biology ,RC925-935 ,Pediatrics, Perinatology and Child Health ,Immunology ,biology.protein ,business - Abstract
Background Kawasaki disease (KD) is an acute, self-limited febrile illness of unknown cause. Intravenous immunoglobulin (IVIG)-resistance are related to greater risk for permanent cardiac complications. We aimed to determine the correlation between monocytes and the phenotype of KD in relation to IVIG responsiveness in children. Materials and methods The study cohort included 62 patients who were diagnosed with KD, 20 non febrile healthy controls (NFC), and 15 other febrile controls (OFC). In all enrolled patients, blood was taken at least 4 times and laboratory tests were performed. In addition, subtypes of monocytes were characterized via flow cytometry. Results The numbers of intermediate monocytes were significantly lower in IVIG-resistant group compared to IVIG-responsive group before IVIG infusion (p p value of 0.03. Conclusions CD14 + CD16 + intermediate monocyte may play an important role in IVIG responsiveness among KD children. Low starting levels of intermediate monocytes, followed by a dramatic increase post-IVIG infusion during acute phase of KD are associated with IVIG-resistance. Functional studies on intermediate monocyte may help to reveal the pathophysiology.
- Published
- 2021
45. Neuritin inhibits astrogliosis to ameliorate diabetic cognitive dysfunction
- Author
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Hongli Zhou, Zuo Zhang, and Jiyin Zhou
- Subjects
Lipopolysaccharides ,STAT3 Transcription Factor ,0301 basic medicine ,medicine.medical_specialty ,Hippocampus ,030209 endocrinology & metabolism ,neuritin ,Hippocampal formation ,GPI-Linked Proteins ,Stat3 Signaling Pathway ,Diabetes Complications ,Cerebellar Cortex ,Mice ,03 medical and health sciences ,astrocyte ,0302 clinical medicine ,Endocrinology ,Diabetic Neuropathies ,Downregulation and upregulation ,Internal medicine ,Animals ,Humans ,Medicine ,Cognitive Dysfunction ,Gliosis ,Molecular Biology ,Neurons ,Neuronal Plasticity ,business.industry ,Research ,diabetic cognitive dysfunction ,Neuropeptides ,Janus Kinase 2 ,medicine.disease ,JAK2/STAT3 signaling pathway ,Rats ,Astrogliosis ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Astrocytes ,Synaptic plasticity ,medicine.symptom ,business ,Astrocyte - Abstract
Earlier, it was shown that reversing the downregulation of neuritin expression in the brain improves central neuropathy in diabetic rats. We investigated the protective mechanism of neuritin in diabetic cognitive dysfunction via astrocytes. Further, the impact of the overexpression of neuritin in the cortex and the hippocampus on diabetic cognitive dysfunction and astrogliosis in type 2 diabetic (db/db) mice was assessed. Antagonists were used to inhibit the JAK2/STAT3 signaling pathway in U-118MG, an astrocyte cell line. Immunofluorescence, Western blotting, and real-time PCR were performed. Neuritin overexpression in the hippocampus of db/db mice significantly ameliorated cognitive dysfunction, hippocampal neuronal impairment, and synaptic plasticity deterioration, and inhibited astrogliosis and the JAK2/STAT3 signaling pathway in the hippocampus. Neuritin suppressed the JAK2/STAT3 signaling pathway to inhibit lipopolysaccharide-induced gliosis in U-118MG cells. It was observed that neuritin regulates the JAK2/STAT3 signaling pathway in astrocytes to inhibit astrogliosis and improve diabetic cognitive dysfunction.
- Published
- 2021
46. Human SND2 mediates ER targeting of GPI‐anchored proteins with low hydrophobic GPI attachment signals
- Author
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Tetsuya Hirata, Yi-Shi Liu, Xiao-Dong Gao, Xin-Yu Guo, Morihisa Fujita, Taroh Kinoshita, and Jing Yang
- Subjects
Signal peptide ,Glycosylphosphatidylinositols ,Biophysics ,Gene Expression ,CD59 Antigens ,CD59 ,Protein Sorting Signals ,Endoplasmic Reticulum ,GPI-Linked Proteins ,medicine.disease_cause ,Biochemistry ,03 medical and health sciences ,Protein Domains ,Antigens, CD ,Structural Biology ,Protein targeting ,Genetics ,medicine ,Humans ,Receptor ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Signal recognition particle ,Er targeting ,CD55 Antigens ,Chemistry ,Arsenite Transporting ATPases ,Endoplasmic reticulum ,030302 biochemistry & molecular biology ,Membrane Proteins ,Cell Biology ,Gpi anchored protein ,Neoplasm Proteins ,Cell biology ,carbohydrates (lipids) ,Protein Transport ,HEK293 Cells ,lipids (amino acids, peptides, and proteins) ,Hydrophobic and Hydrophilic Interactions ,SEC Translocation Channels ,Protein Binding - Abstract
Over 100 glycosylphosphatidylinositol-anchored proteins (GPI-APs) are encoded in the mammalian genome. It is not well understood how these proteins are targeted and translocated to the endoplasmic reticulum (ER). Here, we reveal that many GPI-APs, such as CD59, CD55, and CD109, utilize human SND2 (hSND2)-dependent ER targeting machinery. We also found that signal recognition particle receptors seem to cooperate with hSND2 to target GPI-APs to the ER. Both the N-terminal signal sequence and C-terminal GPI attachment signal of GPI-APs contribute to ER targeting via the hSND2-dependent pathway. Particularly, the hydrophobicity of the C-terminal GPI attachment signal acts as the determinant of hSND2 dependency. Our results explain the route and mechanism of the ER targeting of GPI-APs in mammalian cells.
- Published
- 2021
47. Alleviation of colonic inflammation by Lypd8 in a mouse model of inflammatory bowel disease
- Author
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Tetsuya Iida, Chiao-Ching Hsu, Ryu Okumura, Daisuke Motooka, Reo Sasaki, Kiyoshi Takeda, and Shota Nakamura
- Subjects
0301 basic medicine ,Colon ,Immunology ,Motility ,Inflammation ,Diet, High-Fat ,GPI-Linked Proteins ,Inflammatory bowel disease ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Immunology and Allergy ,Intestinal Mucosa ,Colitis ,biology ,business.industry ,Dextran Sulfate ,Mucous membrane ,Inflammatory Bowel Diseases ,General Medicine ,medicine.disease ,biology.organism_classification ,Gastrointestinal Microbiome ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Dysbiosis ,Female ,030211 gastroenterology & hepatology ,medicine.symptom ,business ,Bacteria - Abstract
Dysfunction of the intestinal mucosal barrier causes inflammatory bowel diseases (IBDs). Indeed, mucosal barrier impairment in the gut of IBD patients results from decreased expression of barrier molecules. Ly6/Plaur domain containing 8 (Lypd8) segregates microbiota from the colonic epithelial layer. In this study, we found that Lypd8−/− mice, in which flagellated bacteria invaded the mucosal surface of the colon, developed spontaneous colitis when dysbiosis was induced by a high-fat diet (HFD). On the basis of this finding, we assessed whether the application of human LYPD8 (hLYPD8) protein exhibiting the glycan-dependent inhibition of bacterial motility is effective in a colitis model. Oral and anal treatments with hLYPD8 protein ameliorate dextran sulfate sodium-induced colitis and HFD-induced colitis in Lypd8−/− mice. These results indicate a therapeutic potential of hLYPD8 protein supplementation for IBD.
- Published
- 2021
48. Serum soluble mesothelin-related protein (SMRP) and fibulin-3 levels correlate with baseline malignant pleural mesothelioma (MPM) tumor volumes but are not useful as biomarkers of response in an immunotherapy trial
- Author
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Steven M. Albelda, Andrew R. Haas, Daniel H. Sterman, Keith A. Cengel, Charles B. Simone, Ian Berger, Sharyn I. Katz, Leonid Roshkovan, Evan W. Alley, and Joseph S. Friedberg
- Subjects
Adult ,Mesothelioma ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Pleural Neoplasms ,medicine.medical_treatment ,GPI-Linked Proteins ,Serology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Biomarkers, Tumor ,Humans ,Medicine ,Mesothelin ,Prospective Studies ,Chemotherapy ,biology ,business.industry ,Calcium-Binding Proteins ,Mesothelioma, Malignant ,Immunotherapy ,medicine.disease ,Tumor Burden ,Fibulin ,Clinical trial ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cohort ,biology.protein ,business - Abstract
Objectives Soluble mesothelin-related protein (SMRP) and fibulin-3 serum levels may serve as diagnostic and prognostic biomarkers of malignant pleural mesothelioma (MPM). Here, we evaluate these markers for correlation to tumor volume, prognosis and response assessment in a clinical trial of immunogene therapy in combination with chemotherapy. Materials and methods Serial serum levels of SMRP and fibulin-3 were measured in adult patients with biopsy-proven MPM enrolled in two prospective clinical trials. Pre-therapy computed tomography (CT) measurements of tumor burden were calculated and correlated with pre-therapy serum SMRP and fibulin-3 levels in these two trials. Serological data were also correlated with radiological assessment of response using Modified RECIST criteria over the first 6 months of intrapleural delivery of adenovirus-IFN alpha (Ad.IFN-α) combined with chemotherapy. Results A cohort of 58 patients who enrolled in either a photodynamic therapy trial or immunotherapy clinical trial had available imaging and SMRP serological data for analysis of whom 45 patients had serological fibulin-3 data. The cohort mean total tumor volume was 387 cm3 (STD 561 cm3). Serum SMRP was detectable in 57 of 58 patients (mean 3.8 nM, STD 6.0). Serum fibulin-3 was detected in 44 of 45 patients (mean 23 ng/mL, STD 14). At pre-therapy baseline in these two trials, there was a strong correlation between tumor volume and serum SMRP levels (r = 0.61, p Conclusions Although our data show correlations of SMRP and fibulin-3 with initial tumor volumes as measured by CT scanning, the use of SMRP and fibulin-3 as serological biomarkers in the immunotherapy trial were not useful in following tumor response longitudinally.
- Published
- 2021
49. Lysine acetylation of NKG2D ligand Rae-1 stabilizes the protein and sensitizes tumor cells to NKG2D immune surveillance
- Author
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Shulin Li, Qingnan Zhao, Jiemiao Hu, and Xueqing Xia
- Subjects
0301 basic medicine ,Nucleocytoplasmic Transport Proteins ,Cancer Research ,medicine.medical_treatment ,media_common.quotation_subject ,chemical and pharmacologic phenomena ,GPI-Linked Proteins ,Article ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Nuclear Matrix-Associated Proteins ,Cell Line, Tumor ,Neoplasms ,medicine ,Humans ,p300-CBP Transcription Factors ,Internalization ,media_common ,Protein Stability ,Chemistry ,Lysine ,Intracellular Signaling Peptides and Proteins ,Cancer ,Acetylation ,hemic and immune systems ,Immunotherapy ,medicine.disease ,NKG2D ,Survival Analysis ,In vitro ,HEK293 Cells ,030104 developmental biology ,Oncology ,PCAF ,NK Cell Lectin-Like Receptor Subfamily K ,Tissue Array Analysis ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Tumor Escape ,Neoplasm Transplantation - Abstract
Shedding, loss of expression, or internalization of natural killer group 2, member D (NKG2D) ligands from the tumor cell surface leads to immune evasion, which is associated with poor prognosis in patients with cancer. In many cancers, matrix metalloproteinases cause the proteolytic shedding of NKG2D ligands. However, it remained unclear how to protect NKG2D ligands from shedding. Here, we showed that the shedding of the mouse NKG2D ligand Rae-1 can be prevented by two critical acetyltransferases, GCN5 and PCAF, which acetylate the lysine residues of Rae-1 to avoid shedding both in vitro and in vivo. In contrast, mutations at lysines 80 and 87 of Rae-1 abrogated this acetylation and thereby desensitized tumor cells to NKG2D-dependent immune surveillance. Notably, the protein levels of GCN5 correlated with the expression levels of the human NKG2D ligand ULPB1 in a human tumor tissue microarray and, more importantly, with prolonged overall survival in many cancers. Our results suggest that the acetylation of Rae-1 protein at lysines 80 and 87 by GCN5 and PCAF protects Rae-1 from shedding so as to activate NKG2D-dependent immune surveillance. This discovery may shed light on new targets for NKG2D immunotherapy in cancer treatment.
- Published
- 2021
50. Predicting anthropometric and metabolic traits with a genetic risk score for obesity in a sample of Pakistanis
- Author
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Adil Anwar Bhatti and Sobia Rana
- Subjects
Adult ,0301 basic medicine ,Multifactorial Inheritance ,Adolescent ,Molecular biology ,Cell Adhesion Molecules, Neuronal ,Science ,Common Obesity ,Alpha-Ketoglutarate-Dependent Dioxygenase FTO ,Overweight ,Biology ,GPI-Linked Proteins ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Linear regression ,Genetics ,medicine ,Humans ,Body Weights and Measures ,Pakistan ,Obesity ,Genetic risk ,Child ,Genetic Association Studies ,Multidisciplinary ,Brain-Derived Neurotrophic Factor ,Genetic Variation ,Membrane Proteins ,Middle Aged ,Anthropometry ,medicine.disease ,Phenotype ,030104 developmental biology ,Polygenic trait ,Receptor, Melanocortin, Type 4 ,Medicine ,medicine.symptom ,rs6265 ,030217 neurology & neurosurgery - Abstract
Obesity is an outcome of multiple factors including environmental and genetic influences. Common obesity is a polygenic trait indicating that multiple genetic variants act synergistically to influence its expression. We constructed a genetic risk score (GRS) based on five genetic variants (MC4R rs17782313, BDNF rs6265, FTO rs1421085, TMEM18 rs7561317, and NEGR1 rs2815752) and examined its association with obesity-related traits in a sample of Pakistanis. The study involved 306 overweight/obese (OW/OB) and 300 normal-weight (NW) individuals. The age range of the study participants was 12–63 years. All anthropometric and metabolic parameters were measured for each participant via standard procedures and biochemical assays, respectively. The genetic variants were genotyped by allelic discrimination assays. The age- and gender-adjusted associations between the GRS and obesity-related anthropometric and metabolic measures were determined using linear regression analyses. The results showed that OW/OB individuals had significantly higher mean ranks of GRS than NW individuals. Moreover, a significant association of the GRS with obesity-related anthropometric traits was seen. However, the GRS did not appear to affect any obesity-related metabolic parameter. In conclusion, our findings indicate the combined effect of multiple genetic variants on the obesity-related anthropometric phenotypes in Pakistanis.
- Published
- 2021
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