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RATIONALE: Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and aggressive gynecological tumor. We retrospectively analyzed the clinical manifestations and imaging findings of this patient and analyzed the relevant literature, with the aim of improving the ability of radiologists to differentiate SCCOHT from other ovarian tumors. PATIENT CONCERNS: We report a case of 36-year-old woman who was diagnosed with SCCOHT. MRI suggested a malignant tumor of the left ovary. The immunohistochemical markers shows SMARCA4 negativity. Notably, hypercalcemia was not detected. Microscopically, it was consistent with the large-cell variants. LESSIONS: Despite its rarity, SCCOHT should still be considered in the differential diagnosis of ovarian malignancies. When a young female patient presents with a large unilateral tumor on MRI with a predominant solid component and significant enhancement on the contrast enhanced scans, along with hypercalcemia, SCCOHT should be considered.
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Carcinoma de Células Pequenas , Hipercalcemia , Imageamento por Ressonância Magnética , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/diagnóstico , Adulto , Hipercalcemia/etiologia , Hipercalcemia/diagnóstico por imagem , Carcinoma de Células Pequenas/diagnóstico por imagem , Carcinoma de Células Pequenas/diagnóstico , Imageamento por Ressonância Magnética/métodos , Diagnóstico DiferencialRESUMO
Traditional antibody-drug conjugates (ADCs) mainly suppress tumor growth through either chemotherapy with cytotoxic payloads or immunotherapy with immuno-modulators. However, a single therapeutic modality may limit their exploration. Herein, we developed a new type of drug conjugate termed CAR-EDC (CAR-M-derived exosome-drug conjugate) by using CAR-exosomes from CAR-M cells as the targeting drug carrier that contains a high level of CXCL10. CAR-exosomes could significantly enhance the immunological activation and migratory capacity of T lymphocytes and promote their differentiation into CD8+ T cells. It also increased the proportion of M1 macrophages. The CAR-EDC, covalently loaded with SN-38, was internalized into Raji cells through endocytosis mediated by the CAR molecules. It exerted excellent antitumor activity in vivo by virtue of not only chemotherapy by SN38 but also immunotherapy by CXCL10-mediated antitumor immunity. Generally, this study provides an exosome-drug conjugate system with enhanced antitumor effects over traditional ADCs through the synergism of chemotherapy and immunotherapy.
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The signal transducer and activator of transcription 3 (STAT3) has been established as a crucial drug target in the development of antitumor agents. In this study, a series of 21 derivatives of the STAT3 inhibitor napabucasin were designed and synthesized. Through preliminary screening against tumor cell lines, SZ6 emerged as the most potent compound with half maximal inhibitory concentration (IC50) values of 46.3 nM, 66.4 nM, and 53.8 nM against HCT116, HepG2, and Hela cells respectively. Furthermore, SZ6 effectively suppressed tumor invasion and migration in HCT116 cell assays by inducing S-phase arrest and apoptosis through inhibition of Protein Kinase B (PKB/AKT) activity and induction of reactive oxygen species (ROS). The mechanism underlying SZ6's action involves inhibition of STAT3 phosphorylation, which was confirmed by western blotting analysis. Additionally, surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA) demonstrated direct binding between SZ6 and STAT3. Notably, in vivo studies revealed that SZ6 significantly inhibited tumor growth without any observed organ toxicity. Collectively, these findings identify SZ6 as a promising STAT3 inhibitor for colorectal cancer treatment.
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Antineoplásicos , Apoptose , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Fator de Transcrição STAT3 , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Animais , Tiazóis/farmacologia , Tiazóis/química , Tiazóis/síntese química , Camundongos , Naftoquinonas/farmacologia , Naftoquinonas/síntese química , Naftoquinonas/química , Camundongos Nus , Camundongos Endogâmicos BALB C , Movimento Celular/efeitos dos fármacos , BenzofuranosRESUMO
Colorectal cancer (CRC) is trending to be a major health problem throughout the world. Therapeutics with dual modes of action have shown latent capacity to create ideal anti-tumor activity. Signal transducer and activator of transcription 3 (STAT3) has been proved to be a potential target for the development of anti-colon cancer drug. In addition, modulation of tumor redox homeostasis through deploying exogenous reactive oxygen species (ROS)-enhancing agents has been widely applied as anti-tumor strategy. Thus, simultaneously targeting STAT3 and modulation ROS balance would offer a fresh avenue to combat CRC. In this work, we designed and synthesized a novel series of isoxazole-fused quinones, which were evaluated for their preliminary anti-proliferative activity against HCT116 cells. Among these quinones, compound 41 exerted excellent in vitro anti-tumor effect against HCT116 cell line with an IC50 value of 10.18 ± 0.4 nM. Compound 41 was proved to bind to STAT3 by using Bio-Layer Interferometry (BLI) assay, and can significantly inhibit phosphorylation of STAT3. It also elevated ROS of HCT116 cells by acting as a substrate of NQO1. Mitochondrial dysfunction, apoptosis, and cell cycle arrest, which was caused by compound 41, might be partially due to the inhibition of STAT3 phosphorylation and ROS production induced by 41. Moreover, it exhibited ideal anti-tumor activity in human colorectal cancer xenograft model and good safety profiles in vivo. Overall, this study provided a novel quinone derivative 41 with excellent anti-tumor activity by inhibiting STAT3 and elevating ROS level, and gave insights into designing novel anti-tumor therapeutics by simultaneously modulation of STAT3 and ROS.
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Antineoplásicos , Apoptose , Proliferação de Células , Neoplasias Colorretais , Ensaios de Seleção de Medicamentos Antitumorais , Isoxazóis , Quinonas , Espécies Reativas de Oxigênio , Fator de Transcrição STAT3 , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Animais , Isoxazóis/farmacologia , Isoxazóis/química , Isoxazóis/síntese química , Quinonas/farmacologia , Quinonas/química , Quinonas/síntese química , Apoptose/efeitos dos fármacos , Estrutura Molecular , Camundongos , Relação Dose-Resposta a Droga , Células HCT116 , Camundongos Nus , Camundongos Endogâmicos BALB CRESUMO
Inflammatory bowel disease (IBD) is a chronic immune-mediated disease associated with a high recurrence rate and an elevated risk of colon cancer. In this study, we screened a bioactive compound library using a luciferase reporter assay and identified the compound TAK875 as a novel inhibitor of signal transducer and activator of transcription 3 (STAT3). Surface plasmon resonance analysis, differential scanning fluorimetry, and isothermal titration calorimetry demonstrated that TAK875 directly bound to recombinant STAT3. TAK875 suppressed the lipopolysaccharide (LPS)-induced release of nitric oxide, inducible nitric oxide synthase, and inflammatory factors in RAW264.7 cells, likely by inhibiting STAT3 phosphorylation. In addition, TAK875 inhibited the differentiation of CD4+ T cells into T-helper 17 cells, which may partially account for its anti-inflammatory effect. TAK875 also alleviated the LPS-induced accumulation of intracellular reactive oxygen species, thus displaying its antioxidant effects. Finally, we demonstrated its satisfactory anti-inflammatory effect in a dextran sulfate sodium-induced mouse model of ulcerative colitis. In conclusion, this study presented TAK875 as a novel STAT3 inhibitor and demonstrated its anti-inflammatory and antioxidant effects both in vitro and in vivo.
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Doenças Inflamatórias Intestinais , Fator de Transcrição STAT3 , Transdução de Sinais , Animais , Camundongos , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Lipopolissacarídeos , NF-kappa B/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidoresRESUMO
Background: Although high-flow humidified oxygen therapy (HFNC) has emerged as an important treatment for respiratory failure, few studies have reported on whether HFNC is appropriate for patients with hypoxemia after cardiac surgery, and the clinical efficacy of HFNC in patients undergoing cardiac surgery is unclear. Objective: To investigate the clinical effect of HFNC after cardiac surgery. Methods: Convenience sampling was used to select 76 patients who underwent invasive mechanical ventilation and oxygen therapy after valve replacement or coronary artery bypass grafting from July 2019 to June 2021. The patients were divided into the routine group and the HFNC group according to the oxygen therapy provided after the operation. The patients in the routine group (N = 38) were treated with oxygen inhalation by face mask after the operation, while those in the HFNC group (N = 38) were treated with HFNC via nasal cavity. The arterial partial pressure of oxygen (PaO2), the arterial partial pressure of carbon dioxide (PaCO2) and the oxygenation index (OI) were observed and compared between the two groups at 6 h, 12 h and 24 h after treatment. The sputum viscosity, incidence of second intubation and the intensive care unit (ICU) stay time were evaluated. Results: The difference in PaCO2 between the two groups was statistically significant at 24 h after treatment (p < 0.05). The PaO2 in the HFNC group was significantly higher than in the routine group at 24 h after treatment, and the OI of the routine group was lower than in the HFNC group at 6 h, 12 h and 24 h after treatment (p < 0.05). The sputum viscosity in the HFNC group was better than in the routine group at 12 h and 24 h after treatment. The second intubation rate and ICU stay time in the HFNC group were lower than in the routine group (p < 0.05). Conclusion: Compared with conventional mask oxygen inhalation, HFNC can effectively reduce sputum viscosity, improve oxygenation, reduce the incidence of repeated intubation and meet patients' comfort needs. It is an advantageous respiratory support strategy for patients after cardiac surgery compared with invasive mechanical ventilation to oxygen therapy and is beneficial to the recovery of cardiopulmonary function.
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PURPOSE: We have developed a new pharmaceutical, ibandronic acid (IBA), and preliminarily demonstrated that it is an efficient bisphosphonate for the diagnosis and treatment of bone metastases. This study aims to examine the biodistribution and internal dosimetry of the diagnostic 68 Ga-DOTA-IBA in patients. PATIENTS AND METHODS: 68 Ga-DOTA-IBA was intravenously injected based on 1.81-2.57 MBq/Kg into 8 patients with bone metastases. Each patient underwent 4 sequential static whole-body PET scans at 0.1, 0.45, 0.8, and 1.8 hours after injection. The acquisition time for each scan was 20 minutes with 10 bed positions. Image registrations and volume of interest delineation were first performed on Hermes, whereas percentage injected activity (%IA), absorbed dose, and effective dose were measured for source organs, using OLINDA/EXM v2.0. Dosimetrics for the bladder was based on a bladder voiding model. RESULTS: No adverse effects were observed on all patients. After the injection, 68 Ga-DOTA-IBA rapidly accumulated in bone metastases and cleared from nonbone tissues, as indicated by visual analysis and %IA measured on the sequential scans. High activity uptake was presented in the expected target organs, that is, bone, red marrow, and the drug-excretion organs such as kidneys and bladder. The mean total body effective dose is 0.022 ± 0.002 mSv/MBq. CONCLUSIONS: 68 Ga-DOTA-IBA has high bone affinity and is promising in the diagnosis of bone metastases. Dosimetric results show that the absorbed doses for critical organs and total body are within the safety limit and with high bone retention. It also has the potential to be used in 177 Lu-therapy as a theranostic pair.
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Neoplasias Ósseas , Tomografia por Emissão de Pósitrons , Humanos , Ácido Ibandrônico , Distribuição Tecidual , Tomografia por Emissão de Pósitrons/métodos , Radiometria , Neoplasias Ósseas/diagnóstico por imagemRESUMO
We previously established a hepatocellular carcinoma (HCC) targeting system of conditionally replicative adenovirus (CRAd) delivered by human umbilical cord-derived mesenchymal stem cells (HUMSCs). However, this system needed to be developed further to enhance the antitumor effect and overcome the limitations caused by the alpha-fetoprotein (AFP) heterogeneity of HCC. In this study, a bispecific T cell engager (BiTE) targeting programmed death ligand 1 controlled by the human telomerase reverse transcriptase promoter was armed on the CRAd of the old system. It was demonstrated on orthotopic transplantation model mice that the new system had a better anti-tumor effect with no more damage to extrahepatic organs and less liver injury, and the infiltration and activation of T cells were significantly enhanced in the tumor tissues of the model mice treated with the new system. Importantly, we confirmed that the new system eliminated the AFP-negative cells on AFP heterogeneous tumor models efficiently. Conclusion: Compared with the old system, the new system provided a more effective and safer strategy against HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Células-Tronco Mesenquimais , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , alfa-Fetoproteínas/genética , alfa-Fetoproteínas/metabolismo , Adenoviridae/genética , Linfócitos T , Vetores Genéticos/genética , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologiaRESUMO
Introduction: Zinc finger and SCAN domain-containing protein 18 (ZSCAN18) has been investigated as a putative biomarker of multiple human cancers. However, the expression profile, epigenetic modification, prognostic value, transcription regulation, and molecular mechanism of ZSCAN18 in breast cancer (BC) remain unknown. Methods: In the study, we present an integrated analysis of ZSCAN18 in BC based on public omics datasets with the use of multiple bioinformatics tools. Genes potentially regulated through restoration of ZSCAN18 expression in MDA-MB-231 cells were investigated to identify pathways associated with BC. Results: We observed that ZSCAN18 was downregulated in BC and mRNA expression was significantly correlated with clinicopathological parameters. Low expression of ZSCAN18 was found in the HER2-positive and TNBC subtypes. High expression of ZSCAN18 was associated with good prognosis. As compared to normal tissues, the extent of ZSCAN18 DNA methylation was greater with fewer genetic alterations in BC tissues. ZSCAN18 was identified as a transcription factor that might be involved in intracellular molecular and metabolic processes. Low ZSCAN18 expression was associated with the cell cycle and glycolysis signaling pathway. Overexpression of ZSCAN18 inhibited mRNA expression of genes associated with the Wnt/ß-catenin and glycolysis signaling pathways, including CTNNB1, BCL9, TSC1, and PFKP. ZSCAN18 expression was negatively correlated with infiltrating B cells and dendritic cells (DCs), as determined by the TIMER web server and reference to the TISIDB. ZSCAN18 DNA methylation was positively correlated with activated B cells, activated CD8+ and CD4+ T cells, macrophages, neutrophils, and activated DCs. Moreover, five ZSCAN18-related hub genes (KDM6B, KAT6A, KMT2D, KDM1A, and HSPBP1) were identified. ZSCAN18, ZNF396, and PGBD1 were identified as components of a physical complex. Conclusion: ZSCAN18 is a potential tumor suppressor in BC, as expression is modified by DNA methylation and associated with patient survival. In addition, ZSCAN18 plays important roles in transcription regulation, the glycolysis signaling pathway, and the tumor immune microenvironment.
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Neoplasias da Mama , Dedos de Zinco , Feminino , Humanos , Proteínas Adaptadoras de Transdução de Sinal , Biomarcadores , Neoplasias da Mama/genética , Metilação de DNA , Histona Acetiltransferases , Histona Desmetilases , Histona Desmetilases com o Domínio Jumonji , RNA Mensageiro , Microambiente TumoralRESUMO
The activating receptor natural killer group 2D (NKG2D) expressed by Natural killer (NK) cells functions as a "master-switch" in governing the awakening status of NK cells. The NKG2D-mediated cytotoxicity has been declared to be related with the expression levels of NKG2D ligands (NKG2DLs) expressed on tumor cells. Therefore, selective induction of NKG2DLs could be a reliable approach to enhance the efficacy of NK cell-mediated immunotherapy. Our existing study demonstrated that Ciclopirox Olamine (CPX), an off-patent antifungal agent, effectively elevated the expression of NKG2DLs on leukemia cells and sensitized leukemia cells to NK-cell mediated cytolysis. Induction of ROS production and AKT phosphorylation by CPX is essential for the up-regulation of NKG2DLs expressions. Inhibition of AKT by using AKT inhibitor MK2206 decreased both NKG2DLs expressions and NK cell cytotoxicity. These data indicated that increased sensitivity of CPX-treated leukemia cells to NK cell cytolysis was attributed to higher NKG2DLs expressions, resulting from activated AKT signaling pathway. Our findings support the ongoing development of CPX as an anti-tumor agent and suggest its promising immunotherapeutic value in the medication of leukemia.
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Leucemia , Proteínas Proto-Oncogênicas c-akt , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ciclopirox/farmacologia , Ciclopirox/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Células Matadoras Naturais/metabolismo , Transdução de Sinais , Leucemia/tratamento farmacológico , Leucemia/metabolismo , Linhagem Celular TumoralRESUMO
ABSTRACT: External ear melanomas are relatively rare and usually occur in the regions of helix and ear lobes. Rarer still are primary melanomas of the external auditory canal. We report findings of melanoma of the external auditory canal on 68 Ga-FAPI PET/CT in a 56-year-old man who presented with sharp pain in the external auditory canal for 7 months.
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Melanoma , Neoplasias Cutâneas , Masculino , Humanos , Pessoa de Meia-Idade , Meato Acústico Externo/diagnóstico por imagem , Meato Acústico Externo/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Melanoma/diagnóstico por imagem , Melanoma/patologia , Neoplasias Cutâneas/patologia , Radioisótopos de Gálio , Fluordesoxiglucose F18 , Melanoma Maligno CutâneoRESUMO
A novel class of quinoxaline-arylfuran derivatives were designed, synthesized, and preliminarily evaluated for their antiproliferative activities in vitro against several cancer cell lines and normal cells. The representative derivative QW12 exerts a potent antiproliferative effect against HeLa cells (IC50 value of 10.58 µM), through inducing apoptosis and triggering ROS generation and the accumulation of HeLa cells in vitro. Western blot analysis showed that QW12 inhibits STAT3 phosphorylation (Y705) in a dose-dependent manner. The BLI experiment directly demonstrated that QW12 binds to the STAT3 recombination protein with a KD value of 67.3 µM. Furthermore, molecular docking investigation showed that QW12 specifically occupies the pY+1 and pY-X subpocket of the SH2 domain, thus blocking the whole transmission signaling process. In general, these findings indicated that the study of new quinoxaline-aryfuran derivatives as inhibitors of STAT3 may lead to new therapeutic medical applications for cancer in the future.
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A series of novel naphthoquinone-furan-2-cyanoacryloyl hybrids were designed; they were synthesized and preliminarily evaluated for their anti-proliferative activities in vitro against several cancer cell lines and normal cells. The most potent compound, 5c, inhibited the proliferation of HeLa cells (IC50 value of 3.10 ± 0.02 µM) and colony survival, and it induced apoptosis while having relatively weaker effects on normal cells. Compound 5c also triggered ROS generation and accumulation, thus partially contributing to the observed cell apoptosis. A Western blotting analysis demonstrated that compound 5c inhibited the phosphorylation of STAT3. Furthermore, a biolayer interferometry (BLI) analysis confirmed that compound 5c had a direct effect on STAT3, with a KD value of 13.0 µM. Molecular docking showed that 5c specifically occupied the subpockets in the SH2 domain, thereby blocking the whole transmission signaling process. Overall, this study provides an important structural reference for the development of effective antitumor agents.
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The tea plant is a kind of ammonium-preferring crop, but the mechanism whereby ammonium (NH4 +) regulate its growth is not well understood. The current study focused on the effects of NH4 + on tea plants. Transcriptomic analysis was performed to investigate the early- and late-stage NH4 + deprivation and resupply in tea plants shoots. Through short- and long-term NH4 + deficiency, the dynamic response to NH4 + stress was investigated. The most significant effects of NH4 + deficiency were found to be on photosynthesis and gene ontology (GO) enrichment varied with the length of NH4 + deprivation. Enriched KEGG pathways were also different when NH4 + was resupplied at different concentrations which may indicate reasons for tolerance of high NH4 + concentration. Using weighted gene co-expression network analysis (WGCNA), modules related to significant tea components, tea polyphenols and free amino acids, were identified. Hence, NH4 + could be regarded as a signaling molecule with the response of catechins shown to be higher than that of amino acids. The current work represents a comprehensive transcriptomic analysis of plant responses to NH4 + and reveals many potential genes regulated by NH4 + in tea plants. Such findings may lead to improvements in nitrogen efficiency of tea plants.
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Crop rotation is a typical agronomic practice to mitigate soil deterioration caused by continuous cropping. However, the mechanisms of soil biotic and abiotic factors in response to different cropping patterns in acidic and polyphenol-rich tea nurseries remain unclear. In this study, the composition and function of microbial communities were comparatively investigated in soils of tea seedlings continuously planted for 2 years (AC: autumn-cutting; SC: summer-cutting) and in soils rotation with strawberries alternately for 3 years (AR: autumn-cutting). The results showed that AR significantly improved the survival of tea seedlings but greatly reduced the contents of soil polyphenols. The lower soil polyphenol levels in AR were associated with the decline of nutrients (SOC, TN, Olsen-P) availability, which stimulates the proliferation of nutrient cycling-related bacteria and mixed-trophic fungi, endophytic fungi and ectomycorrhizal fungi, thus further satisfying the nutrient requirements of tea seedlings. Moreover, lower levels of polyphenols facilitated the growth of plant beneficial microorganisms (Bacillus, Mortierella, etc.) and suppressed pathogenic fungi (Pseudopestalotiopsis, etc.), creating a more balanced microbial community that is beneficial to plant health. Our study broadens the understanding of the ecological role of plant secondary metabolites and provides new insights into the sustainability of tea breeding.
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Multiple myeloma (MM) is a B-cell malignancy for which new treatments are urgently needed. Redirecting the activity of T cells by bispecific antibodies against tumor cells is a potent approach. The B-cell maturation antigen (BCMA) is a highly plasma cell-selective protein and therefore is an ideal therapeutic target for T-cell redirecting therapies. The main objective of this work is to target the BCMA by generating BCMA-specific murine monoclonal antibody and construct a cluster of differentiation 3 (CD3)/BCMA-directed tandem diabodies (Tandab). In brief, using standard hybridoma technology, we developed a novel BCMA-specific monoclonal antibody (clone 69G8), that specifically bind with BCMA+ cell lines and MM patient sample; whereas BCMA- cells were not recognized. For T cells by bispecific antibodies application, we constructed a Tandab (CD3/BCMA) simultaneously targeting both CD3 and BCMA and our studies demonstrated that Tandab (CD3/BCMA) was functional with specific binding capability both for CD3+ cells and BCMA+ cells. It induced selective, dose-dependent lysis of BCMA+ cell lines, activation of T cells, release of cytokines and T-cell proliferation; whereas BCMA- cells were not affected. Furthermore, we demonstrated that Tandab activity correlates with BCMA expression, with higher potency observed in highly BCMA expressing tumor cells. In vivo, the purified Tandab (CD3/BCMA) significantly inhibited the tumor growth in a subcutaneous NCI-H929 xenograft model. Taken together, these results show that the Tandab (CD3/BCMA) displays potent and selective anti-MM activities and represents a promising immunotherapeutic for the treatment of MM.
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Anticorpos Biespecíficos , Mieloma Múltiplo , Animais , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antígenos CD , Antígeno de Maturação de Linfócitos B , Humanos , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Linfócitos TRESUMO
Nitrogen plays an important role in plant growth and development, with different nitrogen forms also having an impact on carbon/nitrogen metabolism. Unlike most plants, tea plants prefer ammonium over nitrate. In this paper, we focused on how different nitrogen sources regulate the carbon/nitrogen metabolism in tea plants. Tea seedlings of 'Longjing 43' were cultivated hydroponically in four different solutions (zero-nitrogen, only NH4+, only NO3- and mixed nitrogen (NH4+: NO3- = 1:1). We analyzed characteristic components of tea plants and related genes in carbon and nitrogen metabolism. Tea polyphenols and catechins representing carbon pool, increased when NO3- was supplied as the nitrogen source, and similar findings were recorded in the zero-nitrogen treatment. The expression of most catechins biosynthesis-related genes was up regulated under NO3- and zero-N treatment, that was associated with tea polyphenols and catechins changes. Compared with NO3- as the nitrogen source, NH4+ and mixed nitrogen treatments had a positive effect on the accumulation of amino acids, especially theanine, glutamate and arginine, and these components contribute to the freshness flavor of tea. The expression of ammonium-assimilation genes was also up-regulated with NH4+ supply. Under mixed nitrogen treatment, the ratio of total polyphenols to free amino acids (PP/AA) was between sole NH4+ and NO3- supply. Therefore, compared with single nitrogen source, carbon and nitrogen metabolism of tea plant was more balanced under mixed nitrogen treatment. The results suggested that NO3- as the nitrogen source promoted the biosynthesis of catechins enriching the carbon pool, whereas NH4+ supply was more conducive to nitrogen metabolism, indicating that different nitrogen sources could affect the carbon and nitrogen balance.
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Camellia sinensis , Camellia sinensis/genética , Carbono , Expressão Gênica , Nitratos , Nitrogênio , CháRESUMO
The aim of this work is to discover the inhibitory mechanism of tea peptides and to analyse the affinities between the peptides and the angiotensin-converting enzyme (ACE) as well as the stability of the complexes using in vitro and in silico methods. Four peptide sequences identified from tea, namely peptides I, II, III, and IV, were used to examine ACE inhibition and kinetics. The half maximal inhibitory concentration (IC50) values of the four peptides were (210.03±18.29), (178.91±5.18), (196.31±2.87), and (121.11±3.38) µmol/L, respectively. The results of Lineweaver-Burk plots showed that peptides I, II, and IV inhibited ACE activity in an uncompetitive manner, which requires the presence of substrate. Peptide III inhibited ACE in a non-competitive manner, for which the presence of substrate is not necessary. The docking simulations showed that the four peptides did not bind to the active sites of ACE, indicating that the four peptides are allosteric inhibitors. The binding free energies calculated from molecular dynamic (MD) simulation were -72.47, -42.20, -52.10, and -67.14 kcal/mol (1 kcal=4.186 kJ), respectively. The lower IC50 value of peptide IV may be attributed to its stability when docking with ACE and changes in the flexibility and unfolding of ACE. These four bioactive peptides with ACE inhibitory ability can be incorporated into novel functional ingredients of black tea.
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Inibidores da Enzima Conversora de Angiotensina/farmacologia , Peptídeos/química , Peptidil Dipeptidase A/química , Chá , Sítio Alostérico , Animais , Domínio Catalítico , Alimentos , Ligação de Hidrogênio , Concentração Inibidora 50 , Cinética , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Peptidil Dipeptidase A/metabolismo , CoelhosRESUMO
ABSTRACT: Inflammatory myofibroblastic tumor is an uncommon mesenchymal neoplasm, which can be seen in any anatomic region from the central nervous system to the gastrointestinal tract. Herein, we report the 68Ga-FAPI PET/CT findings in a 49-year-old man with mesenteric inflammatory myofibroblastic tumor.
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Neoplasias , Quinolinas , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia ComputadorizadaRESUMO
ABSTRACT Objective: To investigate the association between plasma Hydrogen Sulfide (H2S) levels and visceral fat area (VFA) among Chinese young men. Subjects and methods: This cross-sectional study involved 156 Chinese male subjects, aged 18-45 years, who visited the First Hospital of Qinhuangdao (Hebei, China) in 2014 for annual health check-up. Participants were categorized into: low (VFA < 75.57 cm2), medium (75.57 cm2 ≤ VFA<100.37 cm2), and high (VFA ≥ 100.37 cm2) (n = 52/group). We estimated VFA and plasma H2S levels by using bioelectrical impedance analysis and a fluorescence probe-based approach, respectively. The associations of H2S with VFA and obesity anthropometric measures were assessed. Results: In the high VFA group, the body mass index (BMI, 30.4 ± 2.45 kg/m2), total body fat (TBF, 27.9 ± 3.23 kg), plasma H2S (3.5 μmol/L), free fatty acid (FFA, 0.6 ± 0.24 mmol/L), triglyceride (TG, 2.0 mmol/L), and total cholesterol (TC, 5.5 ± 1.02 mmol/L) levels were significantly higher than that of those of the low and medium VFA groups, respectively (P < 0.05). Plasma H2S levels were found to be inversely correlated with VFA, TBF, waist circumference, BMI, FFA, LnFINS, LnHOMA-IR, LnTG, TC, and LDL-C (P < 0.05). Multiple backward stepwise regression analysis revealed an inverse correlation of plasma H2S levels with FFA (β = −0.214, P = 0.005) and VFA (β = −0.429, P < 0.001), independent of adiposity measures and other confounding factors. Conclusion: VFA was independently and inversely associated with plasma H2S levels among Chinese young men. Therefore, determining plasma H2S levels could aid in the assessment of abnormal VAT distribution.