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Gas sensor-embedded smartphones would offer the opportunity of on-site tracking of gas molecules for various applications, for example, harmful air pollutant alarms or noninvasive assessment of health status. Nevertheless, high power consumption and difficulty in replacing malfunctioned sensors as well as limited space in the smartphone to host the sensor restrain the relevant advancements. In this article, we create a smartphone case-based sensing platform by integrating the functional units into a smartphone case, which performs a low detection limit of 117 ppb to acetone and high specificity. Particularly, dimming glass-regulated light fidelity (Li-Fi) communication is successfully developed, allowing the sensing platform to operate with relatively low power consumption (around 217 mW). Experimental proof on harmful gas sensing and potential clinic application is implemented with the sensing platform, demonstrating satisfactory sensing performance and acceptable health risk pre-warning accuracy (87%). Thus, the developed smartphone case-based sensing platform would be a good candidate for realizing harmful gas alarms and noninvasive assessment of health status.
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Acetona , SmartphoneRESUMO
BACKGROUND: Neuroblastoma (NB) is a common extracranial malignancy with high mortality in children. Recently, super-enhancers (SEs) have been reported to play a critical role in the tumorigenesis and development of NB via regulating a wide range of oncogenes Thus, the synthesis and identification of chemical inhibitors specifically targeting SEs are of great urgency for the clinical therapy of NB. This study aimed to characterize the activity of the SEs inhibitor GNE987, which targets BRD4, in NB. RESULTS: In this study, we found that nanomolar concentrations of GNE987 markedly diminished NB cell proliferation and survival via degrading BRD4. Meanwhile, GNE987 significantly induced NB cell apoptosis and cell cycle arrest. Consistent with in vitro results, GNE987 administration (0.25 mg/kg) markedly decreased the tumor size in the xenograft model, with less toxicity, and induced similar BRD4 protein degradation to that observed in vitro. Mechanically, GNE987 led to significant downregulation of hallmark genes associated with MYC and the global disruption of the SEs landscape in NB cells. Moreover, a novel candidate oncogenic transcript, FAM163A, was identified through analysis of the RNA-seq and ChIP-seq data. FAM163A is abnormally transcribed by SEs, playing an important role in NB occurrence and development. CONCLUSION: GNE987 destroyed the abnormal transcriptional regulation of oncogenes in NB by downregulating BRD4, which could be a potential therapeutic candidate for NB.
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Neuroblastoma(NB) is a common childhood solid tumor, and most patients in the high-risk group with MYCN gene amplification have a poor prognosis. Inhibition of bromodomain and extra terminal (BET) proteins has shown considerable promise in the investigation of MYCN-driven malignancies in recent years. MZ1 is a novel BET inhibitor that employs proteolytic-targeting chimera (PROTAC) technology for proteasomal degradation of target proteins and has shown excellent effects in some tumors, but its role in neuroblastoma remains poorly understood. Herein, we observed that MZ1 suppressed MYC-amplified NB cell proliferation and normal cell cycle, while simultaneously boosting cell apoptosis. MZ1 also provides a significant therapeutic impact in vivo. Mechanistically, MZ1 exhibits anti-tumor effect in NB cells by suppressing the expression of N-Myc or C-Myc as well as the MAPK signaling pathway. Overall, our data imply that MZ1 might be exploited as a possible therapeutic method for NB therapy.
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Proteínas de Ciclo Celular , Dipeptídeos , Compostos Heterocíclicos com 3 Anéis , Proteína Proto-Oncogênica N-Myc , Neuroblastoma , Fatores de Transcrição , Proteínas de Ciclo Celular/antagonistas & inibidores , Linhagem Celular Tumoral , Criança , Dipeptídeos/farmacologia , Regulação Neoplásica da Expressão Gênica , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismoRESUMO
Recent studies uncovered the emerging roles of SAPCD2 (suppressor anaphase-promoting complex domain containing 2) in several types of human cancer. However, the functions and underlying mechanisms of SAPCD2 in the progression of neuroblastoma (NB) remain elusive. Herein, through integrative analysis of public datasets and regulatory network of GSK-J4, a small-molecule drug with anti-NB activity, we identified SAPCD2 as an appealing target with a high connection to poor prognosis in NB. SAPCD2 promoted NB progression in vitro and in vivo. Mechanistically, SAPCD2 could directly bind to cytoplasmic E2F7 but not E2F1, alter the subcellular distribution of E2F7 and regulate E2F activity. Among the E2F family members, the roles of E2F7 in NB are poorly understood. We found that an increasing level of nuclear E2F7 was induced by SAPCD2 knockdown, thereby affecting the expression of genes involved in the cell cycle and chromosome instability. In addition, Selinexor (KTP-330), a clinically available inhibitor of exportin 1 (XPO1), could induce nuclear accumulation of E2F7 and suppress the growth of NB. Overall, our studies suggested a previously unrecognized role of SAPCD2 in the E2F signaling pathway and a potential therapeutic approach for NB, as well as clues for understanding the differences in subcellular distribution of E2F1 and E2F7 during their nucleocytoplasmic shuttling.
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Fator de Transcrição E2F7 , Neuroblastoma , Proteínas Nucleares , Transporte Ativo do Núcleo Celular , Ciclo Celular , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Fator de Transcrição E2F7/genética , Fator de Transcrição E2F7/metabolismo , Humanos , Neuroblastoma/genética , Neuroblastoma/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismoRESUMO
Tumor necrosis factor alpha (TNFα) is an important inflammatory factor. It plays a cardinal role in inflammatory synovitis and articular matrix degradation, and is, therefore, a prime target for directed immunotherapy in autoimmune diseases. In this study, we screened and isolated the B cells secreting anti-TNFα antibody from patients with rheumatoid arthritis. The heavy-chain and light-chain sequences of the antibody were cloned and used to generate a stable Chinese hamster ovary (CHO) cell line producing the antibody, which was named Haidalimumab. Haidalimumab showed a TNFα binding affinity comparable to that of the antibody Humira, which is the best TNF inhibitor on the market. Furthermore, Haidalimumab could effectively neutralize recombinant human tumor necrosis factor alpha (rhTNFα) toxicity in a C57BL/6 mouse model and showed significant therapeutic effect in a tumor necrosis factor transgenic (TNF-Tg) mouse arthritis model. In conclusion, we developed a high-affinity, fully human anti-TNFα antibody with low immunogenicity that could potentially have significant therapeutic applications in rheumatoid arthritis or other autoimmune diseases.Abbreviations: ELISAenzyme linked immunosorbent assayRArheumatoid arthritisSDS-PAGEsodium dodecyl sulfate polyacrylamide gel electrophoresisrhTNFαrecombinant human tumor necrosis factor-alphaEC50concentration for 50% of maximal effectTNF-Tg micetumor necrosis factor transgenic miceAMDactinomycin DMTTmethylthiazolyldiphenyl-tetrazolium bromidePBSphosphate-buffered saline.
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Anticorpos Monoclonais/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Células CHO , Cricetulus , Feminino , Humanos , Fatores Imunológicos/imunologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVE: Suppression of bromodomain and extra terminal (BET) proteins has a bright prospect to treat MYC-driven tumors. Bromodomain containing 4 (BRD4) is one of the BET proteins. ARV-825, consisting of a BRD4 inhibitor conjugated with a cereblon ligand using proteolysis-targeting chimera (PROTAC) technology, was proven to decrease the tumor growth effectively and continuously. Nevertheless, the efficacy and mechanisms of ARV-825 in gastric cancer are still poorly understood. METHODS: Cell counting kit 8 assay, lentivirus infection, Western blotting analysis, Annexin V/propidium iodide (PI) staining, RNA sequencing, a xenograft model, and immunohistochemistry were used to assess the efficacy of ARV-825 in cell level and animal model. RESULTS: The messenger RNA (mRNA) expression of BRD4 in gastric cancer raised significantly than those in normal tissues, which suggested poor outcome of patients with gastric cancer. ARV-825 displayed higher anticancer efficiency in gastric cancer cells than OTX015 and JQ1. ARV-825 could inhibit cell growth, inducing cell cycle block and apoptosis in vitro. ARV-825 induced degradation of BRD4, BRD2, BRD3, c-MYC, and polo-like kinase 1 (PLK1) proteins in four gastric cancer cell lines. In addition, cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP) was elevated. Knockdown or overexpression CRBN could increase or decrease, respectively, the ARV-825 IC50 of gastric cancer cells. ARV-825 reduced MYC and PLK1 expression in gastric cancer cells. ARV-825 treatment significantly reduced tumor growth without toxic side effects and downregulated the expression of BRD4 in vivo. CONCLUSIONS: High mRNA expression of BRD4 in gastric cancer indicated poor prognosis. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells via transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.
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BACKGROUND: Acute myeloid leukemia (AML) is a myeloid neoplasm accounts for 7.6% of hematopoietic malignancies. AML is a complex disease, and understanding its pathophysiology is contributing to the improvement in the treatment and prognosis of AML. In this study, we assessed the expression profile and molecular functions of CCAAT enhancer binding protein gamma (CEBPG), a gene implicated in myeloid differentiation and AML progression. METHODS: shRNA mediated gene interference was used to down-regulate the expression of CEBPG in AML cell lines, and knockdown efficiency was detected by RT-qPCR and western blotting. The effect of knockdown on the growth of AML cell lines was evaluated by CCK-8. Western blotting was used to detect PARP cleavage, and flow cytometry were used to determine the effect of knockdown on apoptosis of AML cells. Genes and pathways affected by knockdown of CEBPG were identified by gene expression analysis using RNA-seq. One of the genes affected by knockdown of CEBPG was Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1), a known repressor of translation. Knockdown of EIF4EBP1 was used to assess its potential role in AML progression downstream of CEBPG. RESULTS: We explored the ChIP-Seq data of AML cell lines and non-AML hematopoietic cells, and found CEBPG was activated through its distal enhancer in AML cell lines. Using the public transcriptomic dataset, the Cancer Cell Line Encyclopedia (CCLE) and western blotting, we also found CEBPG was overexpressed in AML. Moreover, we observed that CEBPG promotes AML cell proliferation by activating EIF4EBP1, thus contributing to the progression of AML. These findings indicate that CEBPG could act as a potential therapeutic target for AML patients. CONCLUSION: In summary, we systematically explored the molecular characteristics of CEBPG in AML and identified CEBPG as a potential therapeutic target for AML patients. Our findings provide novel insights into the pathophysiology of AML and indicate a key role for CEBPG in promoting AML progression.
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Neuroblastoma (NB) is a common pediatric malignancy associated with poor outcomes. Recent studies have shown that murine double minute2 homolog (MDM2) protein inhibitors are promising anticancer agents. MI-773 is a novel and specific antagonist of MDM2, however, the molecular mechanism of its anti-NB activity remains unclear. NB cell viability was measured by Cell Counting Kit-8 assay following MI-773 treatment. Cell cycle progression was analyzed using PI staining and apoptosis was assessed using Annexin V/PI staining. The molecular mechanisms by which MI-773 exerted its effects were investigated using a microarray. The results showed that disturbance of the MDM2/p53 axis by MI-773 resulted in potent suppression of proliferation, induction of apoptosis and cell cycle arrest in NB cells. In addition, microarray analysis showed that MI-773 led to significant downregulation of genes involved in the G2/M phase checkpoint and upregulation of hallmark gene associated with the p53 pathway. Meanwhile, knockdown of insulinoma-associated 1 decreased proliferation and increased apoptosis of NB cells. In conclusion, the present study demonstrated that MI-773 exhibited high selectivity and blockade affinity for the interaction between MDM2 and TP53 and may serve as a novel strategy for the treatment of NB.
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Paper-based immunoassays are effective methods that employ microfluidic paper-based analytical devices (µPADs) for the rapid, simple, and accurate quantification of analytes in point-of-care diagnosis. In this study, we developed a wax-printed multilayered µPAD for the colorimetric detection of carcinoembryonic antigen (CEA), where the device contained a movable and rotatable detection layer to allow the µPAD to switch the state of the sample solutions, i.e., flowing or storing in the sensing zones. A smartphone with a custom-developed program served as an automated colorimetric reader to capture and analyze images from the µPAD, before calculating and displaying the test results. After optimizing the crucial conditions for the assay, the proposed method exhibited a wide linear dynamic range from 0.5 to 70 ng/mL, with a low CEA detection limit of 0.015 ng/mL. The clinical performance of this method was successfully validated using 50 positive and 40 negative human serum samples, thereby demonstrating the high sensitivity of 98.0% and specificity of 97.5% in the detection of CEA. The proposed method is greatly simplified compared with the cumbersome steps required for traditional immunoassays, but without any loss of accuracy and stability, as well as reducing the time needed to detect CEA. Complex and bulky instruments are replaced with a smartphone. The proposed detection platform could potentially be applied in point-of-care testing. Graphical abstract.
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Antígeno Carcinoembrionário/sangue , Colorimetria/instrumentação , Papel , Smartphone , Antígeno Carcinoembrionário/análise , Desenho de Equipamento , Humanos , Imunoensaio/instrumentação , Limite de DetecçãoRESUMO
Inhibition of tumor vasculature is an effective strategy for cancer therapy. Angiostatin could suppress tumor growth and metastasis by binding and inhibiting F1F0 ATP synthase on the endothelial cell surface. We previously screened a monoclonal antibody (McAb, McAb178-5G10), which specifically bound to ATPase on the surface of cells and showed an angiostatin-like activity. Here, we further generated a panel of CHO-mAb subclone stable expressing a humanized chimeric antibody from hybridoma cell McAb178-5G10 by gene engineer. And then, we successfully expressed the humanized antibody Hai178 at high level in a 5-L wave bioreactor. The vitro results showed that Hai178 retained the specific binding and antitumor activity of murine antibody. Furthermore, Hai178 also had a tumor therapeutic effect in tumor xenografts. These results paved the way for Hai178 as a therapeutic antibody in clinic.