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1.
PLoS One ; 19(6): e0301223, 2024.
Article in English | MEDLINE | ID: mdl-38837964

ABSTRACT

New immune checkpoints are emerging in a bid to improve response rates to immunotherapeutic drugs. The adenosine A2A receptor (A2AR) has been proposed as a target for immunotherapeutic development due to its participation in immunosuppression of the tumor microenvironment. Blockade of A2AR could restore tumor immunity and, consequently, improve patient outcomes. Here, we describe the discovery of a potent, selective, and tumor-suppressing antibody antagonist of human A2AR (hA2AR) by phage display. We constructed and screened four single-chain variable fragment (scFv) libraries-two synthetic and two immunized-against hA2AR and antagonist-stabilized hA2AR. After biopanning and ELISA screening, scFv hits were reformatted to human IgG and triaged in a series of cellular binding and functional assays to identify a lead candidate. Lead candidate TB206-001 displayed nanomolar binding of hA2AR-overexpressing HEK293 cells; cross-reactivity with mouse and cynomolgus A2AR but not human A1, A2B, or A3 receptors; functional antagonism of hA2AR in hA2AR-overexpressing HEK293 cells and peripheral blood mononuclear cells (PBMCs); and tumor-suppressing activity in colon tumor-bearing HuCD34-NCG mice. Given its therapeutic properties, TB206-001 is a good candidate for incorporation into next-generation bispecific immunotherapeutics.


Subject(s)
Adenosine A2 Receptor Antagonists , Receptor, Adenosine A2A , Humans , Animals , Receptor, Adenosine A2A/metabolism , Receptor, Adenosine A2A/immunology , HEK293 Cells , Mice , Adenosine A2 Receptor Antagonists/pharmacology , Adenosine A2 Receptor Antagonists/therapeutic use , Single-Chain Antibodies/immunology , Single-Chain Antibodies/pharmacology , Macaca fascicularis , Peptide Library
2.
Heliyon ; 10(5): e27107, 2024 Mar 15.
Article in English | MEDLINE | ID: mdl-38434265

ABSTRACT

TTMV::RARA is a recently reported fusion gene associated with acute promyelocytic leukemia (APL), caused by the integration of torque teno mini virus (TTMV) genomic fragments into the second intron of the RARA gene. Currently, there have been only six documented cases, with clinical presentations showing significant variability. Although initial responses to all-trans retinoic acid (ATRA) treatment may be observed in patients with TTMV::RARA-APL, the overall prognosis remains unfavorable among infrequent reported cases. This article presents a pediatric case that manifested as PML::RARA-negative APL with central nervous system involvement at onset. The patient experienced both intramedullary and extramedullary relapse one year after undergoing allogeneic hematopoietic stem cell transplantation. Upon identification as TTMV::RARA-APL and subsequent administration of two rounds of ATRA-based treatment, the patient rapidly developed multiple RARA ligand-binding domain mutations and demonstrated extensive resistance to ATRA and various other therapeutic interventions. Additionally, the patient experienced ARID1A mutant clone expansion and progressed MYC-targeted gene activation. This case represents the first documentation of extramedullary involvement at both the initial diagnosis and relapse stages, emphasizing the intricate clinical features and challenges associated with the rapid accumulation of multiple ATRA-resistant mutations in TTMV::RARA-APL, characterizing it as a distinct and complex sub-entity of atypical APL.

3.
Hematol Oncol ; 42(2): e3256, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38367260

ABSTRACT

This study aimed to investigate the clinical characteristics and prognosis of Runt-related transcription factor 1 (RUNX1) mutant acute myeloid leukemia (AML) patients by comparing the features of AML patients with or without RUNX1 mutation. We retrospectively analyzed 180 AML patients including 36 AML patients with mutant RUNX1(AML-RUNX1mut ) and 144 AML patients with wild-type RUNX1(AML-RUNX1wt ) were selected using the case-pair method(1:4). Compared to AML-RUNX1wt , AML-RUNX1mut showed higher frequency of ASXL1 (p < 0.001), SRSF2 (p < 0.001), BCORL1 (p < 0.001), RAS (p = 0.010) mutations, and absent NPM1 mutations (p = 0.022). The 3-year overall survival (OS) and disease-free survival (DFS) of AML-RUNX1mut and AML-RUNX1wt were 73.1% versus 68.0% (p = 0.64) and 80.7% versus 71.6% (p = 0.37), respectively. AML-RUNX1mut receiving allogeneic hematopoietic cell transplantation (allo-HSCT) showed better survival than those who did not receive allo-HSCT (3-year OS, 84.3% vs. 52.7%; p = 0.006). Multivariate analysis showed that EZH2 mutation (p = 0.003), white blood cell (WBC) ≥30 × 109 /L (p = 0.036) and age ≥60 years (p = 0.038) were significant independent risk factors for inferior OS of AML-RUNX1mut ; WBC ≥30 × 109 /L (p = 0.013) and DNMT3A mutation (p = 0.045) were significant independent risk factors for shorter DFS of AML-RUNX1mut . In conclusion, AML-RUNX1mut showed unique clinical characteristics, but the survival between AML-RUNX1mut and AML-RUNX1wt were comparable. EZH2 co-mutation, DNMT3A co-mutation, old age and high WBC count were associated with inferior survival of AML-RUNX1mut . Allo-HSCT can significantly improve the prognosis of AML-RUNX1mut .


Subject(s)
Core Binding Factor Alpha 2 Subunit , Leukemia, Myeloid, Acute , Humans , Middle Aged , Core Binding Factor Alpha 2 Subunit/genetics , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Mutation , Nucleophosmin , Prognosis , Retrospective Studies
4.
Psicol Reflex Crit ; 36(1): 31, 2023 Oct 26.
Article in English | MEDLINE | ID: mdl-37880429

ABSTRACT

OBJECTIVE: To provide a scientifc tool, the Temptations to Try Smoking Scale (TTSS) is introduced to evaluate its reliability and validity in preventing and intervening Chinese adolescents from smoking temptations. METHODS: A questionnaire, including the TTSS, the Chinese version of the Decisional Balance Scale (CDBS), the Adolescent Smoking Curiosity Scale (ASCOS), and the Sensation-Seeking Scale (SSS), is used to test 1195 Chinese adolescent volunteers (214 of them are retested after 1 month). If all six items in the TTSS are retained, the exploratory factor analysis (EFA) reveals that the TTSS exhibits a structure of two factors: positive social and curiosity/stress. RESULTS: The confrmatory factor analysis (CFA) shows that the two-factor model of the TTSS has the ftting indices χ2/df = 2.35, RMSEA = 0.06, and CFI = 0.99, which are better than those of its single-factor model. The total scores of the TTSS, positive social, and curiosity/stress are positively correlated with the scores of Pros, ASCOS, TAS, and Dis of SSS but negatively correlated with the Cons, hereby exhibiting good criterion-related validity. The internal consistency coefcient of the TTSS is 0.89, and the retest reliability is 0.90. CONCLUSION: Therefore, the TTSS has good reliability and validity for Chinese adolescents and can be used as an efective tool to evaluate adolescents' smoking temptations in China.

6.
Diabetes ; 72(9): 1320-1329, 2023 09 01.
Article in English | MEDLINE | ID: mdl-37358194

ABSTRACT

Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic ß-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can cause brain damage or death. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the ß-cell ATP-sensitive potassium channel (KATP), are unresponsive to diazoxide, the only U.S. Food and Drug Administration-approved medical therapy and require pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent that inhibits insulin secretion in both HI and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein-coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1-/- mice, and in islets from an infant with HI, and increased plasma glucose levels and decreased the insulin to glucose ratio in Sur1-/- mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism. ARTICLE HIGHLIGHTS: Patients with the most common and severe form of diazoxide-unresponsive congenital hyperinsulinism (HI) require a pancreatectomy. Other second-line therapies are limited in their use because of severe side effects and short half-lives. Therefore, there is a critical need for better therapies. Studies with the glucagon-like peptide 1 receptor (GLP-1R) antagonist, avexitide (exendin-(9-39)), have demonstrated that GLP-1R antagonism is effective at lowering insulin secretion and increasing plasma glucose levels. We have optimized a GLP-1R antagonist antibody with more potent blocking of GLP-1R than avexitide. This antibody therapy is a potential novel and effective treatment for HI.


Subject(s)
Congenital Hyperinsulinism , Glucagon-Like Peptide-1 Receptor , Hyperinsulinism , Animals , Mice , Antibodies/therapeutic use , Blood Glucose , Congenital Hyperinsulinism/drug therapy , Congenital Hyperinsulinism/genetics , Diazoxide/pharmacology , Glucagon-Like Peptide 1 , Glucagon-Like Peptide-1 Receptor/antagonists & inhibitors , Hyperinsulinism/immunology , Hyperinsulinism/therapy , Mutation , Sulfonylurea Receptors/genetics
7.
Blood Adv ; 7(13): 3099-3112, 2023 07 11.
Article in English | MEDLINE | ID: mdl-36912760

ABSTRACT

The effect of aerobic glycolysis remains elusive in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Increasing evidence has revealed that dysregulation of deubiquitination is involved in glycolysis, by targeting glycolytic rate-limiting enzymes. Here, we demonstrated that upregulated deubiquitinase ubiquitin-specific peptidase 1 (USP1) expression correlated with poor prognosis in pediatric primary T-ALL samples. USP1 depletion abolished cellular proliferation and attenuated glycolytic metabolism. In vivo experiments showed that USP1 suppression decreased leukemia progression in nude mice. Inhibition of USP1 caused a decrease in both mRNA and protein levels in lactate dehydrogenase A (LDHA), a critical glycolytic enzyme. Moreover, USP1 interacted with and deubiquitinated polo-like kinase 1 (PLK1), a critical regulator of glycolysis. Overexpression of USP1 with upregulated PLK1 was observed in most samples of patients with T-ALL. In addition, PLK1 inhibition reduced LDHA expression and abrogated the USP1-mediated increase of cell proliferation and lactate level. Ectopic expression of LDHA can rescue the suppressive effect of USP1 silencing on cell growth and lactate production. Pharmacological inhibition of USP1 by ML323 exhibited cell cytotoxicity in human T-ALL cells. Taken together, our results demonstrated that USP1 may be a promising therapeutic target in pediatric T-ALL.


Subject(s)
L-Lactate Dehydrogenase , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Animals , Child , Humans , Mice , Cell Line, Tumor , Disease Progression , Glycolysis/genetics , L-Lactate Dehydrogenase/genetics , Lactate Dehydrogenase 5/metabolism , Lactates , Mice, Nude , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , T-Lymphocytes/metabolism , Ubiquitin-Specific Proteases/metabolism , Polo-Like Kinase 1
8.
Front Neurol ; 14: 1295051, 2023.
Article in English | MEDLINE | ID: mdl-38322794

ABSTRACT

Objective: Some previous studies have suggested a potential link between stroke and gastroesophageal reflux disease (GERD). We used a two-sample bidirectional Mendelian randomization (MR) method to explore the causal relationship between stroke and GERD. Design: Summary-level data derived from the published genome-wide association studies (GWAS) were employed for analyses. Single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for stroke (n = 446,696) and its common subtypes ischemic stroke (IS) (n = 440,328), large vessel stroke (LVS) (n = 410,484), small vessel stroke (SVS) (n = 198,048), and cardioembolic stroke (CES) (n = 413,304) were obtained from the MEGASTROKE consortium. The data on intracerebral hemorrhage (ICH) (n = 721,135) come from the UK Biobank. Instrumental variables (IVs) for lacunar stroke (LS) (n = 474,348) and GERD (n = 602,604) were screened from publicly available genetic summary data. The inverse variance weighted (IVW) method was used as the main MR method. Pleiotropy was detected by the MR-Egger intercept test, MR pleiotropy residual sum and outlier, and leave-one-out analysis. Cochran Q statistics were used as supplements to detect pleiotropy. Results: We found that GERD can causally increase the risk of stroke [IVW odds ratio (OR): 1.22, 95% confidence interval (CI): 1.13-1.32, p = 1.16 × 10-6] and its common subtypes IS (OR: 1.19, 95% CI: 1.10-1.30, p = 3.22 × 10-5), LVS (OR: 1.49, 95% CI: 1.21-1.84, p = 1.47 × 10-4), and LS (OR: 1.20, 95% CI: 1.001-1.44, p = 0.048). Several important risk factors for stroke have also been implicated in the above causal relationship, including type 2 diabetes, sleep apnea syndrome, high body mass index, high waist-to-hip ratio, and elevated serum triglyceride levels. In reverse MR analysis, we found that overall stroke (OR: 1.09, 95% CI: 1.004-1.19, p = 0.039) and IS (OR: 1.10, 95% CI: 1.03-1.17, p = 0.007) have the causal potential to enhance GERD risk. Conclusion: This MR study provides evidence supporting a causal relationship between GERD and stroke and some of its common subtypes. We need to further explore the interconnected mechanisms between these two common diseases to better prevent and treat them.

9.
Psicol. reflex. crit ; 36: 31, 2023. tab, graf
Article in English | LILACS-Express | LILACS, Index Psychology - journals | ID: biblio-1529272

ABSTRACT

Abstract Objective To provide a scientifc tool, the Temptations to Try Smoking Scale (TTSS) is introduced to evaluate its reliability and validity in preventing and intervening Chinese adolescents from smoking temptations. Methods A questionnaire, including the TTSS, the Chinese version of the Decisional Balance Scale (CDBS), the Adolescent Smoking Curiosity Scale (ASCOS), and the Sensation-Seeking Scale (SSS), is used to test 1195 Chinese adolescent volunteers (214 of them are retested after 1 month). If all six items in the TTSS are retained, the exploratory factor analysis (EFA) reveals that the TTSS exhibits a structure of two factors: positive social and curiosity/stress. Results The confrmatory factor analysis (CFA) shows that the two-factor model of the TTSS has the ftting indices χ2/df = 2.35, RMSEA = 0.06, and CFI = 0.99, which are better than those of its single-factor model. The total scores of the TTSS, positive social, and curiosity/stress are positively correlated with the scores of Pros, ASCOS, TAS, and Dis of SSS but negatively correlated with the Cons, hereby exhibiting good criterion-related validity. The internal consistency coefcient of the TTSS is 0.89, and the retest reliability is 0.90. Conclusion Therefore, the TTSS has good reliability and validity for Chinese adolescents and can be used as an efective tool to evaluate adolescents' smoking temptations in China.

10.
Hum Exp Toxicol ; 41: 9603271211064537, 2022.
Article in English | MEDLINE | ID: mdl-35195477

ABSTRACT

Arsenic trioxide (ATO) has been found to be effective in acute promyelocytic leukemia. However, ATO-induced severe cardiotoxicity limits its clinical application. To date, the mechanisms of ATO-induced cardiotoxicity remain unclear. It is hypothesized that ferroptosis may trigger ATO-induced cardiotoxicity; however, this has not yet been investigated. To clarify this hypothesis, rat cardiomyocyte H9c2 cells were treated with ATO with or without ferrostain-1 (Fer-1). The results indicated that ATO exposure induced H9c2 cell death and apoptosis, and the ferroptosis inhibitor Fer-1, administered for 24 h before ATO exposure, suppressed ATO-induced cell death, and apoptosis, as determined by Annexin V-APC/7-AAD apoptosis assay. Furthermore, Fer-1 displayed a cardioprotective effect through inhibiting the ATO-induced production of intracellular reactive oxygen species, improving the ATO-induced loss of the mitochondrial membrane potential, alleviating hyperactive endoplasmic reticulum stress, and alleviating the ATO-induced impairment in autophagy in H9c2 cells. Overall, the cardioprotective effect of Fer-1 against ATO-induced cell injury implies that ATO may trigger ferroptosis to induce cardiotoxicity. These findings lay the foundation for exploring the potential value of ferroptosis inhibitors against ATO-induced cardiotoxicity in the future.


Subject(s)
Arsenic Trioxide/toxicity , Cardiotoxicity/etiology , Cardiotoxicity/physiopathology , Cell Death/drug effects , Cells, Cultured/drug effects , Ferroptosis/drug effects , Myocytes, Cardiac/drug effects , Animals , Humans , Rats
11.
MAbs ; 14(1): 2002236, 2022.
Article in English | MEDLINE | ID: mdl-34967699

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an evolving global public health crisis in need of therapeutic options. Passive immunization of monoclonal antibodies (mAbs) represents a promising therapeutic strategy capable of conferring immediate protection from SARS-CoV-2 infection. Herein, we describe the discovery and characterization of neutralizing SARS-CoV-2 IgG and VHH antibodies from four large-scale phage libraries. Each library was constructed synthetically with shuffled complementarity-determining region loops from natural llama and human antibody repertoires. While most candidates targeted the receptor-binding domain of the S1 subunit of SARS-CoV-2 spike protein, we also identified a neutralizing IgG candidate that binds a unique epitope on the N-terminal domain. A select number of antibodies retained binding to SARS-CoV-2 variants Alpha, Beta, Gamma, Kappa and Delta. Overall, our data show that synthetic phage libraries can rapidly yield SARS-CoV-2 S1 antibodies with therapeutically desirable features, including high affinity, unique binding sites, and potent neutralizing activity in vitro, and a capacity to limit disease in vivo.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , Cell Surface Display Techniques , Immunoglobulin G/immunology , Peptide Library , SARS-CoV-2/immunology , Single-Domain Antibodies/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Neutralizing/genetics , Antibodies, Neutralizing/metabolism , Antibodies, Neutralizing/pharmacology , Antibodies, Viral/genetics , Antibodies, Viral/metabolism , Antibody Specificity , Binding Sites, Antibody , COVID-19/metabolism , COVID-19/prevention & control , COVID-19/virology , Chlorocebus aethiops , Disease Models, Animal , Epitopes , Female , Host-Pathogen Interactions , Immunoglobulin G/genetics , Immunoglobulin G/metabolism , Immunoglobulin G/pharmacology , Mesocricetus , SARS-CoV-2/pathogenicity , Single-Domain Antibodies/genetics , Single-Domain Antibodies/metabolism , Single-Domain Antibodies/pharmacology , Vero Cells
12.
ACS Omega ; 6(43): 29215-29222, 2021 Nov 02.
Article in English | MEDLINE | ID: mdl-34746610

ABSTRACT

Myristic acid-palmitic acid-tetradecanol/expanded graphite (MA-PA-TD/EG) and myristic acid-stearic acid-lauric acid/ expanded graphite (MA-SA-LA/EG) were obtained. MA-PA-TD/EG and MA-SA-LA/EG for the optimum mass ratio of 8:1 were investigated by DSC, FT-IR, TG, and SEM, and it was shown that MA-PA-TD and MA-SA-LA phase change materials were evenly distributed in expanded graphite through capillary force. Phase transition temperatures of MA-PA-TD/EG and MA-SA-LA/EG before and after cooling and heating cycles were 34.14, 34.39 °C and 30.21, 30.33 °C, respectively, and MA-PA-TD/EG and MA-SA-LA/EG had good stability. On the other hand, MA-PA-TD/EG was 67% faster than that of MA-PA-TD during solid-liquid phase change, and MA-SA-LA/EG was 63% faster than that of MA-SA-LA. Meanwhile, MA-PA-TD/EG and MA-SA-LA/EG had good thermal stability and heat storage according to thermogravimetric experiments. Therefore, MA-PA-TD/EG and MA-SA-LA/EG are suitable for practical application in buildings.

13.
Pharmacogenomics ; 22(17): 1135-1142, 2021 11.
Article in English | MEDLINE | ID: mdl-34747637

ABSTRACT

Aim: To evaluate the associations between human leukocyte antigen (HLA)-DRB1 variants and the rs6021191 variant in nuclear factor of activated T cells 2 (NFATC2) with PEG-asparaginase hypersensitivity in children with acute lymphoblastic leukemia (ALL) treated according to the Chinese Children Leukemia Group (CCLG) ALL 2018 protocol. Methods:HLA-DRB1 genotyping was performed using a PCR sequence-based typing (SBT) method. NFATC2 rs6021191 was genotyped applying TaqMan Genotyping Assay. Results: T-ALL and higher risk groups were at higher risk for PEG-asparaginase hypersensitivity. No association was found between NFATC2 rs6021191 and PEG-asparaginase hypersensitivity. HLA-DRB1*16:02 variant was associated with PEG-asparaginase allergy both in univariate and multivariate logistic regression analysis. Conclusion: Our results confirm that variations in HLA-DRB1 might influence the development of asparaginase hypersensitivity.


Subject(s)
Asparaginase/adverse effects , Drug Hypersensitivity/etiology , HLA-DRB1 Chains/genetics , Polyethylene Glycols/adverse effects , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Child , Child, Preschool , Drug Hypersensitivity/genetics , Female , Genotype , Humans , Infant , Male , NFATC Transcription Factors/genetics
14.
J Clin Oncol ; 39(28): 3161-3170, 2021 10 01.
Article in English | MEDLINE | ID: mdl-34077242

ABSTRACT

PURPOSE: Arsenic combined with all-trans retinoic acid (ATRA) is the standard of care for adult acute promyelocytic leukemia (APL). However, the safety and effectiveness of this treatment in pediatric patients with APL have not been reported on the basis of larger sample sizes. METHODS: We conducted a multicenter trial at 38 hospitals in China. Patients with newly diagnosed APL were stratified into two risk groups according to baseline WBC count and FLT3-ITD mutation. ATRA plus arsenic trioxide or oral arsenic without chemotherapy were administered to the standard-risk group, whereas ATRA, arsenic trioxide, or oral arsenic plus reduced-dose anthracycline were administered to the high-risk group. Primary end points were event-free survival and overall survival at 2 years. RESULTS: We enrolled 193 patients with APL. After a median follow-up of 28.9 months, the 2-year overall survival rate was 99% (95% CI, 97 to 100) in the standard-risk group and 95% (95% CI, 90 to 100) in the high-risk group (P = .088). The 2-year event-free survival was 97% (95% CI, 93 to 100) in the standard-risk group and 90% (95% CI, 83 to 96) in the high-risk group (P = .252). The plasma levels of arsenic were significantly elevated after treatment, with a stable effective level ranging from 42.9 to 63.2 ng/mL during treatment. In addition, plasma, urine, hair, and nail arsenic levels rapidly decreased to normal 6 months after the end of treatment. CONCLUSION: Arsenic combined with ATRA is effective and safe in pediatric patients with APL, although long-term follow-up is still needed.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Arsenic Trioxide/administration & dosage , Leukemia, Promyelocytic, Acute/drug therapy , Tretinoin/administration & dosage , Adolescent , Anthracyclines/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Arsenic Trioxide/adverse effects , Child , Child, Preschool , China , Female , Humans , Infant , Leukemia, Promyelocytic, Acute/diagnosis , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/mortality , Male , Progression-Free Survival , Time Factors , Tretinoin/adverse effects
15.
MAbs ; 13(1): 1893425, 2021.
Article in English | MEDLINE | ID: mdl-33706686

ABSTRACT

G protein-coupled receptors (GPCRs) are a group of seven-transmembrane receptor proteins that have proven to be successful drug targets. Antibodies are becoming an increasingly promising modality to target these receptors due to their unique properties, such as exquisite specificity, long half-life, and fewer side effects, and their improved pharmacokinetic and pharmacodynamic profiles compared to peptides and small molecules, which results from their more favorable biodistribution. To date, there are only two US Food and Drug Administration-approved GPCR antibody drugs, namely erenumab and mogamulizumab, and this highlights the challenges encountered in identifying functional antibodies against GPCRs. Utilizing Twist's precision DNA writing technologies, we have created a GPCR-focused phage display library with 1 × 1010 diversity. Specifically, we mined endogenous GPCR binding ligand and peptide sequences and incorporated these binding motifs into the heavy chain complementarity-determining region 3 in a synthetic antibody library. Glucagon-like peptide-1 receptor (GLP-1 R) is a class B GPCR that acts as the receptor for the incretin GLP-1, which is released to regulate insulin levels in response to food intake. GLP-1 R agonists have been widely used to increase insulin secretion to lower blood glucose levels for the treatment of type 1 and type 2 diabetes, whereas GLP-1 R antagonists have applications in the treatment of severe hypoglycemia associated with bariatric surgery and hyperinsulinomic hypoglycemia. Here we present the discovery and creation of both antagonistic and agonistic GLP-1 R antibodies by panning this GPCR-focused phage display library on a GLP-1 R-overexpressing Chinese hamster ovary cell line and demonstrate their in vitro and in vivo functional activity.


Subject(s)
Antibodies, Monoclonal/pharmacology , Blood Glucose/drug effects , Cell Surface Display Techniques , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptide-1 Receptor/antagonists & inhibitors , Glycemic Control , Hypoglycemic Agents/pharmacology , Incretins/pharmacology , Peptide Library , Animals , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/metabolism , Antibodies, Monoclonal/pharmacokinetics , Binding Sites, Antibody , Biomarkers/blood , Blood Glucose/metabolism , CHO Cells , Cricetulus , Glucagon-Like Peptide-1 Receptor/genetics , Glucagon-Like Peptide-1 Receptor/metabolism , High-Throughput Screening Assays , Hypoglycemic Agents/metabolism , Hypoglycemic Agents/pharmacokinetics , Incretins/genetics , Incretins/metabolism , Incretins/pharmacokinetics , Ligands , Male , Mice, Inbred C57BL , Protein Interaction Domains and Motifs , Rats, Sprague-Dawley
16.
ACS Omega ; 6(9): 6144-6152, 2021 Mar 09.
Article in English | MEDLINE | ID: mdl-33718705

ABSTRACT

Energy has become the key material basis of social development. In this work, liquid capric acid-paraffin was evenly adsorbed in the pore structure of expanded graphite (EG) by a physical adsorption method, and the new composite phase change material of capric acid-paraffin/expanded graphite (CA-P/EG) was prepared. The Fourier transform infrared (FT-IR) curves of CA-P/EG composites did not change after 1000 cycles, and there was no new characteristic absorption peak, indicating that CA-P/EG composites have good chemical stability. The results showed that the optimum content of CA-P/EG in a phase change energy storage gypsum board was 20%, and the wet bending strength and compressive strength were 2.42 and 6.45 MPa, respectively. The water absorption was 16.37%, and the apparent density was 1.410 g/cm3. In addition, the melting and freezing temperatures were 26.40 and 23.10 °C, and the latent heats of melting and freezing were 27.20 and 25.69 J/g, respectively. It was found that the gypsum board has excellent thermal stability after 400 times of melting-freezing cycling and that the heat storage capacity increases with the increase of the CA-P/EG content and the thickness of the gypsum board.

17.
RSC Adv ; 11(40): 24938-24948, 2021 Jul 13.
Article in English | MEDLINE | ID: mdl-35481044

ABSTRACT

Two kinds of CA-SA-based ternary phase change materials (PCMs), namely, capric acid-stearic acid-palmitic acid (CA-SA-PA) and capric acid-stearic acid-octadecanol (CA-SA-OD), were prepared by the melting-blending method. By the step cooling curve method, the optimum mass ratio of the two PCMs were determined to be CA : SA : PA = 77.4 : 8.6 : 14.0 and CA : SA : OD = 81.9 : 9.1 : 9.0, and the crystallization temperatures were 19.20 °C and 23.90 °C, respectively. The phase transition temperatures as measured by DSC were 18.60 °C and 24.82 °C, and the latent heat of phase transition were 129.15 J g-1 and 161.74 J g-1, respectively. The results are in good agreement with those measured by the step cooling curve method. The chemical and crystalline properties of the two PCMs were analyzed by FT-IR and XRD. It was found that CA-SA is combined with PA or OD by physical action, and the components have good compatibility and form a good eutectic structure. In addition, the results of heat storage and heat release experiments and the 500 times of accelerated melting-solidification cycling test showed that the two kinds of PCMs have good heat resistance and thermal reliability. Therefore, the prepared CA-SA-PA and CA-SA-OD have good performance and great application potential in building energy saving and solar energy utilization.

18.
ACS Omega ; 5(42): 27522-27529, 2020 Oct 27.
Article in English | MEDLINE | ID: mdl-33134715

ABSTRACT

A new composite phase change material of capric acid-palmitic acid/expanded graphite (CA-PA/EG) with the optimum mass ratio of EG equated to 8:1 was prepared by the physical adsorption method. It was observed that the eutectic point of CA-PA binary system was reached at 22.1 °C, and CA-PA was uniformly distributed into the pores of EG by physical interaction. The melting and freezing temperatures of CA-PA/EG obtained by differential scanning calorimeter (DSC) were 23.05 and 20.82 °C, respectively, while the corresponding latent heats were 139.7 and 131.8 J/g, respectively. It had good thermal and chemical stability, and there was almost no leakage of liquid binary phase change materials after 1000 melting-freezing cycles. According to the experimental results of the thermogravimetry (TG) analyzer as well as heat storage and release, CA-PA/EG has excellent thermal reliability and heat resistance and the high thermal conductivity of EG promotes the thermal energy storage and release rate of CA-PA. Thus, CA-PA/EG is suitable as a phase change energy storage material for building energy conservation.

19.
Pediatr Hematol Oncol ; 36(7): 399-409, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31530209

ABSTRACT

We studied the outcomes of children with APL treated by the Beijing Children's Hospital's (BCH) acute promyelocytic leukemia (APL) 2005 protocol (BCH-APL2005). The clinical data of 77 patients enrolled from January 2005 to June 2015 were analyzed retrospectively. The hematologic complete remission (CR) rate and overall survival (OS) rate were evaluated between standard-risk (SR) and high-risk (HR) groups. Prognostic factors and complications were investigated in these two groups. CR in the SR and HR groups was 96.4% (54/56) and 85.7% (18/21), respectively, while the 10-year OS was 94.6% (53/56) and 76.2% (16/21), respectively. The cumulative incidence of early death was 6.5% (5/77), and the SR and HR groups were 1.8% (1/56) and 19.0% (4/21), respectively. Only two patients relapsed, and the relapse rate was 2.6% (2/77). According to Kaplan-Meier analysis, the SR group had a significantly better long-term survival than HR counterparts (p= .016). Initial leukocyte count was the only prognostic factor (p= .016) by univariate analysis, while other factors, such as FLT3-ITD and platelet count, had no correlation with prognosis. In addition, early deaths were mainly due to intracranial hemorrhage. Although the combination of all-trans retinoic acid (ATRA) and chemotherapy can improve the outcome of APL patients, the early deaths and anthracycline-related cardiac toxicity were relatively higher in our study. Current efforts focus on reducing or even avoiding chemotherapy in APL children and rest on the frontline regimen of intravenous arsenic trioxide or oral realgar-indigo naturalis formula plus ATRA, which is the direction for APL treatment.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/mortality , Child , Child, Preschool , China , Disease-Free Survival , Female , Follow-Up Studies , Humans , Leukemia, Promyelocytic, Acute/blood , Leukocyte Count , Male , Platelet Count , Survival Rate
20.
DNA Cell Biol ; 37(4): 287-290, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29350547

ABSTRACT

Macroautophagy, hereafter autophagy, is a catabolic process that is important for maintaining cellular homeostasis. It can also be used by cells to remove intracellular microbial pathogens. However, the studies on hepatitis C virus (HCV) in recent years indicated that this virus could regulate this cellular pathway and use it to enhance its replication. HCV could temporally control the autophagic flux and use the autophagic membranes for the assembly of its RNA replication complex. In this report, we will discuss the biogenesis of autophagosomes induced by HCV and how HCV uses this autophagic pathway for its RNA replication.


Subject(s)
Autophagy/physiology , Hepacivirus/metabolism , RNA, Viral/physiology , Autophagosomes , Autophagy/immunology , DNA Replication , Hepacivirus/pathogenicity , Humans , Phagosomes/metabolism , RNA, Viral/genetics , RNA, Viral/metabolism , Virus Replication/genetics , Virus Replication/physiology
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