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Various vaccine strategies have been proposed in response to the global COVID-19 pandemic, each with unique strategies for eliciting immune responses. Here, we developed nanoparticle vaccines by covalently conjugating the self-assembled 24-mer ferritin to the receptor binding domain (RBD) and/or heptad repeat (HR) subunits of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) spike (S) protein. Compared to monomer vaccines, nanoparticle vaccines elicited more robust neutralizing antibodies and cellular immune responses. RBD and RBD-HR nanoparticle vaccinated hACE2 transgenic mice vaccinated with RBD and/or RBD-HR nanoparticles exhibited reduced viral load in the lungs after SARS-CoV-2 challenge. RBD-HR nanoparticle vaccines also promoted neutralizing antibodies and cellular immune responses against other coronaviruses. The nanoparticle vaccination of rhesus macaques induced neutralizing antibodies, and T and B cell responses prior to boost immunization; these responses persisted for more than three months. RBD- and HR-based nanoparticles thus present a promising vaccination approach against SARS-CoV-2 and other coronaviruses.
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Proteínas Bacterianas/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/inmunología , Ferritinas/inmunología , Helicobacter pylori/metabolismo , Proteínas Recombinantes de Fusión/inmunología , SARS-CoV-2/fisiología , Glicoproteína de la Espiga del Coronavirus/inmunología , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Antivirales/metabolismo , Proteínas Bacterianas/química , Vacunas contra la COVID-19/química , Ferritinas/química , Humanos , Macaca mulatta , Ratones , Ratones Endogámicos BALB C , Nanopartículas/química , Pandemias , Unión Proteica , Glicoproteína de la Espiga del Coronavirus/química , VacunaciónRESUMEN
BACKGROUND: This study aimed to explore potential indicators associated with the neoadjuvant efficacy of TCbHP regimen (taxane, carboplatin, trastuzumab, and pertuzumab) in HER2 + breast cancer (BrCa) patients. METHODS: A total of 120 plasma samples from 40 patients with HER2 + BrCa were prospectively collected at three treatment times of neoadjuvant therapy (NAT) with TCbHP regimen. Serum metabolites were analyzed based on LC-MS and GC-MS data. Random forest was used to establish predictive models based on pre-therapeutic differentially expressed metabolites. Time series analysis was used to obtain potential monitors for treatment response. Transcriptome analysis was performed in nine available pretherapeutic specimens of core needle biopsies. Integrated analyses of metabolomics and transcriptomics were also performed in these nine patients. qRT-PCR was used to detect altered genes in trastuzumab-sensitive and trastuzumab-resistant cell lines. RESULTS: Twenty-one patients achieved pCR, and 19 patients achieved non-pCR. There were significant differences in plasma metabolic profiles before and during treatment. A total of 100 differential metabolites were identified between pCR patients and non-pCR patients at baseline; these metabolites were markedly enriched in 40 metabolic pathways. The area under the curve (AUC) values for discriminating the pCR and non-PCR groups from the NAT of the single potential metabolite [sophorose, N-(2-acetamido) iminodiacetic acid, taurine and 6-hydroxy-2-aminohexanoic acid] or combined panel of these metabolites were greater than 0.910. Eighteen metabolites exhibited potential for monitoring efficacy. Several validated genes might be associated with trastuzumab resistance. Thirty-nine altered pathways were found to be abnormally expressed at both the transcriptional and metabolic levels. CONCLUSION: Serum-metabolomics could be used as a powerful tool for exploring informative biomarkers for predicting or monitoring treatment efficacy. Metabolomics integrated with transcriptomics analysis could assist in obtaining new insights into biochemical pathophysiology and might facilitate the development of new treatment targets for insensitive patients.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Terapia Neoadyuvante , Metabolómica , Trastuzumab , BiomarcadoresRESUMEN
Due to the intrinsic flame-retardant, eutectic electrolytes are considered a promising candidate for sodium-metal batteries (SMBs). However, the high viscosity and ruinous side reaction with Na metal anode greatly hinder their further development. Herein, based on the Lewis acid-base theory, a new eutectic electrolyte (EE) composed of sodium bis(trifluoromethanesulfonyl)imide (NaTFSI), succinonitrile (SN), and fluoroethylene carbonate (FEC) is reported. As a strong Lewis base, the âC≡N group of SN can effectively weaken the interaction between Na+ and TFSI-, achieving the dynamic equilibrium and reducing the viscosity of EE. Moreover, the FEC additive shows a low energy level to construct thicker and denser solid electrolyte interphase (SEI) on the Na metal surface, which can effectively eliminate the side reaction between EE and Na metal anode. Therefore, EE-1:6 + 5% FEC shows high ionic conductivity (2.62 mS cm-1) and ultra-high transference number of Na+ (0.96). The Na||Na symmetric cell achieves stable Na plating/stripping for 1100 h and Na||Na3V2(PO4)3/C cell shows superior long-term cycling stability over 2000 cycles (99.1% retention) at 5 C. More importantly, the Na||NVP/C pouch cell demonstrates good cycling performance of 102.1 mAh g-1 after 135 cycles at 0.5 C with an average coulombic efficiency of 99.63%.
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A rational design of high-efficiency electrocatalysts and thus achieving sensitive electrochemical sensing remains a great challenge. In this work, single-atom indium anchored on nitrogen-doped carbon (In1-N-C) with an In-N4 configuration is prepared successfully through a high-temperature annealing strategy; the product can serve as an advanced electrocatalyst for sensitive electrochemical sensing of dopamine (DA). Compared with In nanoparticle catalysts, In1-N-C exhibits high catalytic performance for DA oxidation. The theoretical calculation reveals that In1-N-C has high adsorption energy for hydroxy groups and a low energy barrier in the process of DA oxidation compared to In nanoparticles, indicating that In1-N-C with atomically dispersed In-N4 sites possesses enhanced intrinsic activity. An electrochemical sensor for DA detection is established as a concept application with high sensitivity and selectivity. Furthermore, we also verify the feasibility of In1-N-C catalysts for the simultaneous detection of uric acid, ascorbic acid, and DA. This work extends the application prospect of p-block metal single-atom catalysts in electrochemical sensing.
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Dopamina , Nanopartículas , Indio , Técnicas Electroquímicas/métodos , Carbono , Ácido AscórbicoRESUMEN
Noncovalent modification of carbon materials with redox-active organic molecules has been considered as an effective strategy to improve the electrochemical performance of supercapacitors. However, their low loading mass, slow electron transfer rate, and easy dissolution into the electrolyte greatly limit further practical applications. Herein, this work reports dual molecules (1,5-dihydroxyanthraquinone (DHAQ) and 2,6-diamino anthraquinone (DAQ)) cooperatively confined in-between edge-oxygen-rich graphene sheets as high-performance electrodes for supercapacitors. Cooperative electrostatic-interaction on the edge-oxygen sites and π-π interaction in-between graphene sheets lead to the increased loading mass and structural stability of dual molecules. Moreover, the electron tunneling paths constructed between edge-oxygen groups and dual molecules can effectively boost the electron transfer rate and redox reaction kinetics, especially at ultrahigh current densities. As a result, the as-obtained electrode exhibits a high capacitance of 507 F g-1 at 0.5 A g-1 , and an unprecedented rate capability (203 F g-1 at 200 A g-1 ). Moreover, the assembled symmetrical supercapacitor achieves a high energy density of 17.1 Wh kg-1 and an ultrahigh power density of 140 kW kg-1 , as well as remarkable stability with a retention of 86% after 50 000 cycles. This work may open a new avenue for the efficient utilization of organic materials in energy storage and conversion.
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It is commonly known that the MAPK pathway is involved in translating environmental inputs, regulating downstream reactions, and maintaining the intrinsic dynamic balance. Numerous essential elements and regulatory processes are included in this pathway, which are essential to its functionality. Among these, MAP3K4, a member of the serine/threonine kinases family, plays vital roles throughout the organism's life cycle, including the regulation of apoptosis and autophagy. Moreover, MAP3K4 can interact with key partners like GADD45, which affects organism's growth and development. Notably, MAP3K4 functions as both a tumor promotor and suppressor, being activated by a variety of factors and triggering diverse downstream pathways that differently influence cancer progression. The aim of this study is to provide a brief overview of physiological functions of MAP3K4 and shed light on its contradictory roles in tumorigenesis.
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Breast cancer is the leading cause of cancer-related death among women globally. Immunotherapy has emerged as a major milestone in contemporary oncology. This study aims to conduct a bibliometric analysis in the field of immunotherapy for breast cancer, providing a comprehensive overview of the current research status, identifying trends and hotspots in research topics. We searched and retrieved data from the Web of Science Core Collection, and performed a bibliometric analysis of publications on immunotherapy for breast cancer from 2013 to 2022. Current status and hotspots were evaluated by co-occurrence analysis using VOSviewer. Evolution and bursts of knowledge base were assessed by co-citation analysis using CiteSpace. Thematic evolution by bibliometrix package was used to discover keywords trends. The attribution and collaboration of countries/regions, institutions and authors were also explored. A total of 7,975 publications were included. In co-occurrence analysis of keywords, 6 major clusters were revealed: tumor microenvironment, prognosis biomarker, immune checkpoints, novel drug delivery methods, immune cells and therapeutic approaches. The top three most frequently mentioned keywords were tumor microenvironment, triple-negative breast cancer, and programmed cell death ligand 1. The most productive country, institution and author were the USA (2926 publications), the University of Texas MD Anderson Cancer Center (219 publications), and Sherene Loi (28 publications), respectively. There has been a rapid growth in studies on immunotherapy for breast cancer worldwide. This research area has gained increasing attention from different countries and institutions. With the rising incidence of breast cancer, immunotherapy represents a research field of significant clinical value and potential.
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Inmunoterapia , Neoplasias de la Mama Triple Negativas , Femenino , Humanos , Neoplasias de la Mama Triple Negativas/terapia , Bibliometría , Sistemas de Liberación de Medicamentos , Instituciones de Salud , Microambiente TumoralRESUMEN
Solid polymer electrolytes are considered among the most promising candidates for developing practical solid-state sodium batteries. However, moderate ionic conductivity and narrow electrochemical windows hinder their further application. Herein, inspired by the Na+/K+ conduction in biological membranes, we report a (-COO-)-modified covalent organic framework (COF) as a Na-ion quasi-solid-state electrolyte with sub-nanometre-sized Na+ transport zones (6.7-11.6 Å) created by adjacent -COO- groups and COF inwalls. The quasi-solid-state electrolyte enables selective Na+ transport along specific areas that are electronegative with sub-nanometre dimensions, resulting in a Na+ conductivity of 1.30×10-4 S cm-1 and oxidative stability of up to 5.32 V (versus Na+/Na) at 25 ± 1 °C. Testing the quasi-solid-state electrolyte in Na||Na3V2(PO4)3 coin cell configuration demonstrates fast reaction dynamics, low polarization voltages, and a stable cycling performance over 1000 cycles at 60 mA g-1 and 25 ± 1 °C with a 0.0048% capacity decay per cycle and a final discharge capacity of 83.5 mAh g-1.
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Oncogene induced senescence is a tumor suppressing defense mechanism, in which the cell cycle-dependent protein kinase (CDK) inhibitor p16INK4A (encoded by the CDKN2A gene) plays a key role. We previously reported that a transcriptional co-activator chromodomain helicase DNA binding protein 7 (CHD7) mediates oncogenic ras-induced senescence by inducing transcription of the p16INK4A gene. In the current study, we identified myeloid zinc finger 1 (MZF1) as the transcriptional factor that recruits CHD7 to the p16INK4A promoter, where it mediates oncogenic ras-induced p16INK4A transcription and senescence through CHD7, in primary human cells from multiple origins. Moreover, the expression of MZF1 is induced by oncogenic ras in senescent cells through the c-Jun and Ets1 transcriptional factors upon their activation by the Ras-Raf-1-MEK-ERK signaling pathway. In non-small cell lung cancer (NSCLC) and pancreatic adenocarcinoma (PAAD) where activating ras mutations occur frequently, reduced MZF1 expression is observed in tumors, as compared to corresponding normal tissues, and correlates with poor patient survival. Analysis of single cell RNA-sequencing data from PAAD patients revealed that among the tumor cells with normal RB expression levels, those with reduced levels of MZF1 are more likely to express lower p16INK4A levels. These findings have identified novel signaling components in the pathway that mediates induction of the p16INK4A tumor suppressor and the senescence response, and suggested that MZF1 is a potential tumor suppressor in at least some cancer types, the loss of which contributes to the inactivation of the p16INK4A/RB pathway and disruption of senescence in tumor cells with intact RB.
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Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Animales , Células Cultivadas , Humanos , Ratones , Ratones Noqueados , Oncogenes , Factores de TranscripciónRESUMEN
The SARS-CoV-2 Delta (B.1.617.2) strain is a variant of concern (VOC) that has become the dominant strain worldwide in 2021. Its transmission capacity is approximately twice that of the original strain, with a shorter incubation period and higher viral load during infection. Importantly, the breakthrough infections of the Delta variant have continued to emerge in the first-generation vaccine recipients. There is thus an urgent need to develop a novel vaccine with SARS-CoV-2 variants as the major target. Here, receptor binding domain (RBD)-conjugated nanoparticle vaccines targeting the Delta variant, as well as the early and Beta/Gamma strains, are developed. Under both a single-dose and a prime-boost strategy, these RBD-conjugated nanoparticle vaccines induce the abundant neutralizing antibodies (NAbs) and significantly protect hACE2 mice from infection by the authentic SARS-CoV-2 Delta strain, as well as the early and Beta strains. Furthermore, the elicitation of the robust production of broader cross-protective NAbs against almost all the notable SARS-CoV-2 variants including the Omicron variant in rhesus macaques by the third re-boost with trivalent vaccines is found. These results suggest that RBD-based monovalent or multivalent nanoparticle vaccines provide a promising second-generation vaccine strategy for SARS-CoV-2 variants.
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COVID-19 , Nanopartículas , Animales , Anticuerpos ampliamente neutralizantes , COVID-19/prevención & control , Macaca mulatta/metabolismo , Ratones , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Vacunas ConjugadasRESUMEN
Since the outbreak of coronavirus disease 2019 (COVID-19), it has become a global pandemic. The spike (S) protein of etiologic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specifically recognizes human angiotensin-converting enzyme 2 (hACE2) as its receptor, which is recently identified as an interferon (IFN)-stimulated gene. Here, we find that hACE2 exists on the surface of exosomes released by different cell types, and the expression of exosomal hACE2 is increased by IFNα/ß treatment. In particular, exosomal hACE2 can specifically block the cell entry of SARS-CoV-2, subsequently inhibit the replication of SARS-CoV-2 in vitro and ex vivo. Our findings have indicated that IFN is able to upregulate a viral receptor on the exosomes which competitively block the virus entry, exhibiting a potential antiviral strategy.
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Enzima Convertidora de Angiotensina 2/metabolismo , Exosomas/metabolismo , Interferón-alfa/farmacología , Interferón beta/farmacología , SARS-CoV-2/fisiología , Internalización del Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Enzima Convertidora de Angiotensina 2/genética , Animales , Chlorocebus aethiops , Exosomas/genética , Exosomas/virología , Células HEK293 , Humanos , Ratones , Ratones Transgénicos , Células VeroRESUMEN
Metastases are the main cause of cancer-related mortality in breast cancer. Although significant progress has been made in the field of tumor metastasis, the exact molecular mechanisms involved in tumor metastasis are still unclear. Here, we report that ATOH8-V1, a novel isoform of ATOH8, is highly expressed in breast cancer and is a negative prognostic indicator of survival for patients. Forced expression of ATOH8-V1 dramatically enhances, while silencing of ATOH8-V1 decreases the metastasis of breast cancer cell lines. Moreover, ATOH8-V1 directly binds to the RhoC promoter and stimulates the expression of RhoC, which in turn enhances the metastasis of breast cancer. Altogether, our data demonstrate that ATOH8-V1 is a novel pro-metastatic factor that enhances cancer metastasis, suggesting that ATOH8-V1 is a potential therapeutic target for treatment of metastatic cancers.
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Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Neoplasias de la Mama/genética , Regulación Neoplásica de la Expresión Génica , Proteína rhoC de Unión a GTP/genética , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Humanos , Estimación de Kaplan-Meier , Ratones , Persona de Mediana Edad , Invasividad Neoplásica/genética , Pronóstico , Isoformas de Proteínas/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Hepatocellular carcinoma (HCC), the most common primary liver cancer, relies on the formation of new blood vessel for growth and frequent intrahepatic and extrahepatic metastasis. Therefore, it is important to explore the underlying molecular mechanisms of tumor angiogenesis of HCC. Recently, microRNAs have been shown to modulate angiogenic processes by modulating the expression of critical angiogenic factors. However, the potential roles of tumor-derived exosomal microRNAs in regulating tumor angiogenesis remain to be elucidated. In this study, our miRNome sequencing demonstrated that miR-1290 was overexpressed in HCC patient serum-derived exosomes, and we found that delivery of miR-1290 into human endothelial cells enhanced their angiogenic ability. Our results further revealed that SMEK1 is a direct target of miR-1290 in endothelial cells. MiR-1290 exerted its proangiogenic function, at least in part, by alleviating the inhibition of VEGFR2 phosphorylation done by SMEK1. Collectively, our findings provide evidence that miR-1290 is overexpressed in HCC and promotes tumor angiogenesis via exosomal secretion, implicating its potential role as a therapeutic target for HCC.
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When recruited to promoters, histone 3 lysine 4 (H3K4) methyltransferases KMT2 (KMT2A-D) activate transcription by opening chromatin through H3K4 methylation. Here, we report that KMT2 mutations occur frequently in non-small cell lung cancer (NSCLC) and are associated with high mutation loads and poor survival. KMT2C regulated DNA damage responses (DDR) through direct recruitment to DNA damage sites by Ago2 and small noncoding DNA damage response RNA, where it mediates H3K4 methylation, chromatin relaxation, secondary recruitment of DDR factors, and amplification of DDR signals along chromatin. Furthermore, by disrupting homologous recombination (HR)-mediated DNA repair, KMT2C/D mutations sensitized NSCLC to Poly(ADP-ribose) polymerase inhibitors (PARPi), whose efficacy is unclear in NSCLC due to low BRCA1/2 mutation rates. These results demonstrate a novel, transcription-independent role of KMT2C in DDR and identify high-frequency KMT2C/D mutations as much-needed biomarkers for PARPi therapies in NSCLC and other cancers with infrequent BRCA1/2 mutations. SIGNIFICANCE: This study uncovers a critical role for KMT2C in DDR via direct recruitment to DNA damage sites, identifying high-frequency KMT2C/D mutations as biomarkers for response to PARP inhibition in cancer.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Daño del ADN , Proteínas de Unión al ADN/metabolismo , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Mutación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Animales , Apoptosis , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular , Proteínas de Unión al ADN/genética , Femenino , Recombinación Homóloga , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Pronóstico , Tasa de Supervivencia , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
CD8+ T cells are major components of adaptive immunity and confer robust protective cellular immunity, which requires adequate T-cell numbers, targeted migration, and efficient T-cell proliferation. Altered CD8+ T-cell homeostasis and impaired proliferation result in dysfunctional immune response to infection or tumorigenesis. However, intrinsic factors controlling CD8+ T-cell homeostasis and immunity remain largely elusive. Here, we demonstrate the prominent role of Brd4 on CD8+ T cell homeostasis and immune response. By upregulating Myc and GLUT1 expression, Brd4 facilitates glucose uptake and energy production in mitochondria, subsequently supporting naïve CD8+ T-cell survival. Besides, Brd4 promotes the trafficking of naïve CD8+ T cells partially through maintaining the expression of homing receptors (CD62L and LFA-1). Furthermore, Brd4 is required for CD8+ T cell response to antigen stimulation, as Brd4 deficiency leads to a severe defect in clonal expansion and terminal differentiation by decreasing glycolysis. Importantly, as JQ1, a pan-BRD inhibitor, severely dampens CD8+ T-cell immune response, its usage as an anti-tumor agent or latency-reversing agent for human immunodeficiency virus type I (HIV-1) should be more cautious. Collectively, our study identifies a previously-unexpected role of Brd4 in the metabolic regulation of CD8+ T cell-mediated immune surveillance and also provides a potential immunomodulation target.
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Antígenos Virales/inmunología , Linfocitos T CD8-positivos/virología , Proliferación Celular , Activación de Linfocitos , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/inmunología , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Traslado Adoptivo , Animales , Azepinas/farmacología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/trasplante , Proliferación Celular/efectos de los fármacos , Chlorocebus aethiops , Modelos Animales de Enfermedad , Transportador de Glucosa de Tipo 1/genética , Transportador de Glucosa de Tipo 1/metabolismo , Glucólisis , Interacciones Huésped-Patógeno , Activación de Linfocitos/efectos de los fármacos , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/metabolismo , Virus de la Coriomeningitis Linfocítica/patogenicidad , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/genética , Mitocondrias/inmunología , Mitocondrias/metabolismo , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/genética , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Triazoles/farmacología , Células VeroRESUMEN
Asymmetric supercapacitors (ASCs) show promising potential for electrochemical energy storage applications. However, the energy density of ASCs is limited by the poor electrochemical performance of anodes. To achieve high-performance ASCs, herein, Fe2O3 nanotubes constructed from Fe2O3 nanoneedles were fabricated by employing MnO2 nanotubes as a self-sacrificing template, and then a layer of polypyrrole (PPy) was coated through an in situ chemical oxidative polymerization method to enhance their performance. The electrochemical tests indicate that the resultant PPy-coated Fe2O3 nanotubes (Fe2O3@PPy) exhibit a high areal capacitance of 530 mF cm-2 at 1 mA cm-2 and good cycling stability, which are superior to those of the Fe2O3 nanotubes. The superior performance of the Fe2O3@PPy nanotubes can be attributed to the synergistic effect between the PPy shell and Fe2O3 core, in which the conducting PPy shell not only works as a superhighway for charge transport, but also stabilizes the Fe2O3 nanotubes during charge-discharge processes. When the Fe2O3@PPy nanotubes were assembled with MnO2 nanotubes, the as-assembled ASCs possess a high cell voltage of 2.0 V and deliver a high energy density of up to 51.2 Wh kg-1 at a power density of 285.4 W kg-1 with an excellent cycling stability (83.5% capacitance retention over 5000 cycles).
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Long-lived plasma cells (LLPCs) are robust specialized antibody-secreting cells that mainly stay in the bone marrow and can persist a lifetime. As they can be generated by inducing the differentiation of B-lymphocytes, we investigated the possibility that human LLPCs might be engineered to express α-PD-1 monoclonal antibody to substitute recombinant α-PD-1 antitumor immunotherapy. To this end, we inserted an α-PD-1 cassette into the GAPDH locus through Cas9/sgRNA-guided specific integration in B-lymphocytes, which was mediated by an integrase-defective lentiviral vector. The edited B cells were capable of differentiating into LLPCs both in vitro and in vivo. Transcriptional profiling analysis confirmed that these cells were typical LLPCs. Importantly, these cells secreted de novo antibodies persistently, which were able to inhibit human melanoma growth via an antibody-mediated checkpoint blockade in xenograft-tumor mice. Our work suggests that the engineered LLPCs may be utilized as a vehicle to constantly produce special antibodies for long-term cellular immunotherapy to eradicate tumors and cellular reservoirs for various pathogens including human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV).
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Anticuerpos Monoclonales/inmunología , Sistemas CRISPR-Cas , Inmunoterapia/métodos , Células Plasmáticas/inmunología , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Animales , Anticuerpos Monoclonales/biosíntesis , Anticuerpos Monoclonales/genética , Linfocitos B/citología , Linfocitos B/inmunología , Diferenciación Celular/inmunología , Línea Celular Tumoral , Células HEK293 , Humanos , Ratones , Células Plasmáticas/citología , Linfocitos T/inmunología , TransgenesRESUMEN
While mechanisms for metastasis were extensively studied in cancer cells from patients with detectable tumors, pathways underlying metastatic dissemination from early lesions before primary tumors appear are poorly understood. Her2 promotes breast cancer early dissemination by suppressing p38, but how Her2 downregulates p38 is unclear. Here, we demonstrate that in early lesion breast cancer models, Her2 inhibits p38 by inducing Skp2 through Akt-mediated phosphorylation, which promotes ubiquitination and proteasomal degradation of Tpl2, a p38 MAP3K. The early disseminating cells are Her2+Skp2highTpl2lowp-p38lowE-cadherinlow in the MMTV-Her2 breast cancer model. In human breast carcinoma, high Skp2 and low Tpl2 expression are associated with the Her2+ status; Tpl2 expression positively correlates with that of activated p38; Skp2 expression negatively correlates with that of Tpl2 and activated p38. Moreover, the Her2-Akt-Skp2-Tpl2-p38 axis plays a key role in the disseminating phenotypes in early lesion breast cancer cells; inhibition of Tpl2 enhances early dissemination in vivo. These findings identify the Her2-Akt-Skp2-Tpl2-p38 cascade as a novel mechanism mediating breast cancer early dissemination and a potential target for novel therapies targeting early metastatic dissemination.
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Neoplasias de la Mama/patología , Quinasas Quinasa Quinasa PAM/metabolismo , Sistema de Señalización de MAP Quinasas/genética , Proteínas Proto-Oncogénicas/metabolismo , Receptor ErbB-2/metabolismo , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Animales , Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Línea Celular Tumoral , Movimiento Celular/genética , Conjuntos de Datos como Asunto , Supervivencia sin Enfermedad , Células Epiteliales , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Transgénicos , Metástasis de la Neoplasia/patología , Cultivo Primario de Células , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Cancer can metastasize from early lesions without detectable tumors. Despite extensive studies on metastasis in cancer cells from patients with detectable primary tumors, mechanisms for early metastatic dissemination are poorly understood. Her2 promotes breast cancer early dissemination by inhibiting p38, but the downstream pathway in this process was unknown. Using early lesion breast cancer models, we demonstrate that the effect of p38 suppression by Her2 on early dissemination is mediated by MK2 and heat shock protein 27 (Hsp27). The early disseminating cells in the MMTV-Her2 breast cancer model are Her2highp-p38lowp-MK2lowp-Hsp27low, which also exist in human breast carcinoma tissues. Suppression of p38 and MK2 by Her2 reduces MK2-mediated Hsp27 phosphorylation, and unphosphorylated Hsp27 binds to ß-catenin and enhances its phosphorylation by Src, leading to ß-catenin activation and disseminating phenotypes in early lesion breast cancer cells. Pharmacological inhibition of MK2 promotes, while inhibition of a p38 phosphatase Wip1 suppresses, early dissemination in vivo. These findings identify Her2-mediated suppression of the p38-MK2-Hsp27 pathway as a novel mechanism for cancer early dissemination, and provide a basis for new therapies targeting early metastatic dissemination in Her2+ breast cancer.