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Left bundle branch pacing (LBBP) has proven to be an alternative method for delivering physiological pacing to achieve electrical synchrony of the left ventricle (LV), especially in patients with atrioventricular block and left bundle branch block (LBBB). However, it is unclear whether it still achieved in patients whose left bundle branch (LBB) has had surgery-induced damage. The Morrow operation (Morrow septal myectomy) is regarded as one of the most effective treatments for hypertrophic obstructive cardiomyopathy (HOCM). The surgery resects small sections of muscle tissue in the proximal ventricular septum nearby or contains the LBB, which means that physical damage to the LBB is almost inevitable. Approximately 2%-12% of patients may need pacemaker implanted after Morrow surgery. LBBP is a feasible and effective method for achieving electric resynchronization of LBBB compared to right ventricular pacing (RVB). Nevertheless, there is a dearth of data on LBBP in third-degree atrioventricular block (AVB) following Morrow surgery. We report a case of successful LBBP in those patients.
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OBJECTIVES: This study aims to investigate the influence of glucose regulated protein (GRP) 78 on osteoblast differentiation in periodontal ligament fibroblasts (PDLFs) under cyclic mechanical stretch and determine the underlying mechanism. METHODS: FlexCell 5000 cell mechanical device was applied to simulate the stress environment of orthodontic teeth. GRP78High and GRP78Low subpopulation were obtained by flow sorting. Gene transfection was performed to knockdown GRP78 and c-Src expression and overexpress c-Src. Western blot analysis was used to detect the protein expression of Runt-related gene 2 (RUNX2), Osterix, osteocalcin (OCN), and osteopontin (OPN). Immunoprecipitation assay was used to determine the interaction of GRP78 with c-Src. The formation of cellular mineralized nodules was determined by alizarin red staining. RESULTS: GRP78 was heterogeneously expressed in PDLFs, and GRP78High and GRP78Low subpopulations were obtained by flow sorting. The osteogenic differentiation ability and phosphorylation level of c-Src kinase in the GRP78High subpopulation were significantly increased compared with those in GRP78Low subpopulation after cyclic mechanical stretch (P<0.05). GRP78 interacted with c-Src in PDLFs. The overexpression c-Src group showed significantly increased osteogenic differentiation ability than the vector group (P<0.05), and the sic-Src group showed significantly decreased osteogenic differentiation ability (P<0.05) after cyclic mechanical stretch. CONCLUSIONS: GRP78 upregulates c-Src expression by interacting with c-Src kinase and promotes osteogenic differentiation under cyclic mechanical stretch in PDLFs.
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Diferenciación Celular , Proteínas de Choque Térmico , Osteoblastos , Ligamento Periodontal , Proteínas Proto-Oncogénicas pp60(c-src) , Transducción de Señal , Estrés Mecánico , Humanos , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Proteína Tirosina Quinasa CSK/metabolismo , Chaperón BiP del Retículo Endoplásmico/metabolismo , Fibroblastos/metabolismo , Proteínas de Choque Térmico/metabolismo , Osteoblastos/metabolismo , Osteocalcina/metabolismo , Osteogénesis , Osteopontina/metabolismo , Ligamento Periodontal/metabolismo , Ligamento Periodontal/citología , Fosforilación , Familia-src Quinasas/metabolismo , Proteínas Proto-Oncogénicas pp60(c-src)/metabolismoRESUMEN
BACKGROUND: Vesicle-associated membrane protein 7 (VAMP7) plays oncogenic roles in cancers. However, its clinical significance in breast cancer (BC) tissues remains unknown. OBJECTIVE: To elucidate the clinical implications of VAMP7, as well as its involvement in the tumor microenvironment and molecular pathways of breast cancer. METHODS: BC (n=100) and non-cancerous breast tissues (n= 100) were collected for an immunohistochemical experiment (1:200). The protein expression level of VAMP7 was determined by using a semi-quantitative scoring method. High-throughput RNA-sequencing data of BC tissues were analyzed to confirm the mRNA expression trend of VAMP7. Additionally, the largest BC prognosis cohort data were collected to mine the potential impact VAMP7 has on BC progression. The association between VAMP7 and the microenvironment of BC was evaluated by using a CIBERSORT algorithm. Moreover, we explored the co-expressed molecular mechanisms of VAMP7 in BC by calculating Pearson correlation coefficients and overexpressed genes. Finally, the biological mechanism underlying the relationship between VAMP7 and the key pathways was also explored using gene set enrichment analysis (GSEA). Potential therapeutic strategies were predicted targeting VAMP7. RESULTS: VAMP7 protein was significantly over-expressed in BC tissue than that in controls (p< 0.001). Compared with 459 normal breast tissues and 113 non-cancerous breast tissues, the expression level of VAMP7 mRNA was significantly increased in 1111 BC tissues. CD4+T cells, macrophages, and naïve B cells had a higher infiltration rate in BC tissues with high VAMP7 expression, while regulatory T cells and CD8+T cells had a lower infiltration rate. Over-expressed VAMP7 was associated with macrophages activation and transition from M1 to M2 polarization. Upregulated VAMP7 could predicted poorer OS, DMFS, PPS, and RFS outcomes. Upregulated VAMP7 co-expressed genes were significantly enriched in the cell cycle checkpoints. GSEA confirmed that over-expressed VAMP7 are markedly associated with functional enrichment in cell cycle related categories, including mitotic spindle, G2M checkpoint, and E2F targets. KU-55933 was predicted as a putative therapeutic drug for BC targeting VAMP7. CONCLUSIONS: VAMP7 was upregulated in BC tissue and correlated with poor prognosis of BC patients. VAMP7 may promote BC progression by targeting the cell cycle pathway.
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Neoplasias de la Mama , Proteínas R-SNARE , Regulación hacia Arriba , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Femenino , Proteínas R-SNARE/genética , Proteínas R-SNARE/metabolismo , Microambiente Tumoral , Pronóstico , Persona de Mediana Edad , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión GénicaRESUMEN
Enterovirus A71 (EV-A71) is one of the main pathogens causing hand, foot, and mouth disease (HFMD) outbreaks in Asian children under 5 years of age. In severe cases, it can cause neurological complications and be life-threatening. In this study, 200 newly sequenced EV-A71 whole-genome sequences were combined with 772 EV-A71 sequences from GenBank for large-scale analysis to investigate global EV-A71 epidemiology, phylogeny, and Bayesian phylodynamic characteristics. Based on the phylogenetic analysis of the EV-A71 3Dpol region, six new evolutionary lineages (lineages B, J, K, O, P, and Q) were found in this study, and the number of evolutionary lineages was expanded from 11 to 17. Temporal dynamics and recombination breakpoint analyses based on genotype C revealed that recombination of nonstructural protein-coding regions, including 3Dpol, is an important reason for the emergence of new lineages. The EV-A71 epidemic in the Asia-Pacific region is complex, and phylogeographic analysis found that Vietnam played a key role in the spread of subgenotypes B5 and C4. The origin of EV-A71 subgenotype C4 in China is East China, which is closely related to the prevalence of subgenotype C4 in the south and throughout China. Selection pressure analysis revealed that, in addition to VP1 amino acid residues VP1-98 and VP1-145, which are associated with EV-A71 pathogenicity, amino acid residues VP1-184 and VP1-249 were also positively selected, and their functions still need to be determined by biology and immunology. This study aimed to provide a solid theoretical basis for EV-A71-related disease surveillance and prevention, antiviral research, and vaccine development through a comprehensive analysis. IMPORTANCE EV-A71 is one of the most important pathogens causing HFMD outbreaks; however, large-scale studies of EV-A71 genomic epidemiology are currently lacking. In this study, 200 new EV-A71 whole-genome sequences were determined. Combining these with 772 EV-A71 whole-genome sequences in the GenBank database, the evolutionary and transmission characteristics of global and Asian EV-A71 were analyzed. Six new evolutionary lineages were identified in this study. We also found that recombination in nonstructural protein-coding regions, including 3Dpol, is an important cause for the emergence of new lineages. The results provided a solid theoretical basis for EV-A71-related disease surveillance and prevention, antiviral research, and vaccine development.
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Enterovirus Humano A , Infecciones por Enterovirus , Enterovirus , Enfermedad de Boca, Mano y Pie , Niño , Humanos , Preescolar , Enterovirus/genética , Enfermedad de Boca, Mano y Pie/epidemiología , Enterovirus Humano A/genética , Filogenia , Teorema de Bayes , Infecciones por Enterovirus/epidemiología , Asia/epidemiología , Antígenos Virales , Genómica , Antivirales , AminoácidosRESUMEN
Anti-angiogenic medicines have been evaluated as anticancer therapies, however, their use remains limited in clinical practice due to associated adverse effects. Asiatic acid (AA) is known to have broad-spectrum anticancer properties, however, its effects on angiogenesis in breast cancer remain to be fully established. In this study, we analyzed the inhibitory effects of AA on angiogenesis using human umbilical vein endothelial cells (HUVECs) cultured in vitro and on the growth and metastasis of a subcutaneous breast cancer 4T1 tumor model and a lung metastasis model in vivo. AA significantly inhibited HUVECs proliferation, migration, and tube formation in vitro. In vivo, AA significantly reduced the microvascular density and blood vascular permeability in breast cancer tumors and inhibited growth and lung metastasis. AA inhibited the expression of vascular endothelial growth factor (VEGF) in HUVECs and subsequently downregulated the phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) and its downstream target proteins including ERK1/2, Src, and FAK. These results indicate that AA significantly inhibits angiogenesis and blood vessel permeability through the VEGF/VEGFR2 signal axis to inhibit the growth and metastasis of breast cancer. Our data strongly demonstrate the potential applications of AA in the treatment of breast cancer.
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Neoplasias de la Mama , Factor A de Crecimiento Endotelial Vascular , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Neoplasias de la Mama/tratamiento farmacológico , Permeabilidad Capilar , Movimiento Celular , Proliferación Celular , Femenino , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Ratones , Neovascularización Patológica/tratamiento farmacológico , Triterpenos Pentacíclicos , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Asiatic acid (AA) has been shown to induce apoptotic death in a range of cancers, but the mechanisms whereby it can inhibit tongue cancer growth have yet to be clarified. Herein, we explored the effects of AA on tongue cancer cells and found that it induced their apoptotic death in vitro and in vivo, while additionally impairing xenograft tumor growth in vivo. From a mechanistic perspective, AA treatment was associated with increases in levels of calcium and the calcium- dependent protease calpain, and it further induced endoplasmic reticulum (ER) stress and consequent Grp78-related IRE1α and JNK phosphorylation, ultimately driving caspase-3 activation and apoptotic death. Together, these results highlight AA as a promising tool for the therapeutic treatment of tongue cancer in clinical practice.
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PURPOSE: To investigate the effect of Met kinase inhibitor BMS-777607 on proliferation and apoptosis of tongue squamous cell carcinoma cell line CAL27. METHODS: The effect of BMS-777607 on proliferation of CAL27 was detected by MTT method, clone formation assay and EdU cell imaging. Morphological changes of apoptosis of CAL27 cells induced by BMS-777607 were observed by Heochst33342 staining. JC-1 staining was used to detect the changes of mitochondrial membrane potential of CAL27 cells treated with BMS-777607. Western blot was used to detect the effect of BMS-777607 on the expression of proliferation protein Akt, p-Akt and apoptosis-related proteins Bcl-2, Cleaved caspase-3, Bax and Parp in CAL27 cells. The data were analyzed using SPSS 22.0 software package. RESULTS: BMS-777607 inhibited proliferation and promoted apoptosis of CAL27 cells in a concentration-dependent mannerï¼Pï¼0.05ï¼. It also inhibited the expression of Bcl-2 and p-Akt and promoted the expression of Bax, Cleaved caspase-3 and Parp protein (Pï¼0.05). CONCLUSIONS: BMS-777607 can inhibit proliferation and promote apoptosis of CAL27 cells.
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Carcinoma de Células Escamosas , Neoplasias de la Lengua , Aminopiridinas , Apoptosis , Proteínas Reguladoras de la Apoptosis , Carcinoma de Células Escamosas/metabolismo , Caspasa 3/farmacología , Caspasa 3/uso terapéutico , Línea Celular Tumoral , Proliferación Celular , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt , Proteínas Proto-Oncogénicas c-bcl-2/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/uso terapéutico , Piridonas , Lengua , Neoplasias de la Lengua/tratamiento farmacológico , Proteína X Asociada a bcl-2/farmacologíaRESUMEN
The subgenotype B5 of EV-A71 is a widely circulating subgenotype that frequently spreads across the globe. Several outbreaks have occurred in nations, such as Malaysia, Thailand, Vietnam, and Japan. Appearing first in Taiwan, China, the subgenotype has been frequently reported in mainland of China even though no outbreaks have been reported so far. The current study reconstructed the migration of the B5 subgenotype of EV-A71 in China via phylogeographical analysis. Furthermore, we investigated its population dynamics in order to draw more credible inferences. Following a dataset cleanup of B5 subgenotype of EV-A71, we detected earlier B5 subgenotypes of EV-A71 sequences that had been circulating in Malaysia and Singapore since the year 2000, which was before the 2003 outbreak that occurred in Sarawak. The Bayesian inference indicated that the most recent common ancestor of B5 subgenotype EV-A71 appeared in September, 1994 (1994.75). With respect to the overall prevalence, geographical reconstruction revealed that the B5 subgenotype EV-A71 originated singly from single-source cluster and subsequently developed several active lineages. Based on a large amount of data that was accumulated, we conclude that the appearance of the B5 subgenotype of EV-A71 in mainland of China was mainly due to multiple migrations from different origins.
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Enterovirus Humano A , Infecciones por Enterovirus , Enfermedad de Boca, Mano y Pie , Teorema de Bayes , China/epidemiología , Humanos , Japón , Filogenia , Singapur , Taiwán , Tailandia , Vietnam/epidemiologíaRESUMEN
OBJECTIVE: This study aims to study the effect of the enhancer of zeste homolog 2 (EZH2) inhibitor GSK126 on the proliferation and apoptosis of human tongue squamous cell carcinoma cells in vitro and explore its related mechanisms in order to obtain insights into the clinical treatment of tongue squamous cell carcinoma. METHODS: Different concentrations of GSK126 were applied to CAL-27 cells of tongue squamous cell carcinoma, and the effects of drugs on cell proliferation were detected through methyl thiazolyl tetrazolium (MTT) assay, colony formation assay, and 5-ethynyl-2'-deoxyuridine (EdU) fluorescence staining. Hoechst33342 fluorescence staining and the JC-1 method were used in observing apoptosis. The expression levels of extracellular regulated protein kinases (ERK), phospho-extracellular regulated protein kinases (p-ERK), Bax, Bcl-2, and Cleaved caspase-9 in Cal-27 cells were detected through Western blot. RESULTS: GSK126 inhibited CAL-27 cell proliferation and promoted apoptosis. GSK126 down-regulated the expression of p-ERK and Bcl-2 and increased the expression of Bax and Cleaved caspase-9 (P<0.05). CONCLUSIONS: GSK126 can inhibit the proliferation of CAL-27 cells in tongue squamous cell carcinoma and promote its apoptosis, and the related mechanism may be associated with the inhibition of the MEK/ERK signaling pathway and activation of the Bax/Bcl-2 pathway.
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Apoptosis , Carcinoma de Células Escamosas , Neoplasias de la Lengua , Carcinoma de Células Escamosas/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular , Proteína Potenciadora del Homólogo Zeste 2 , Humanos , Indoles , Piridonas , Neoplasias de la Lengua/tratamiento farmacológicoRESUMEN
Pheochromocytoma is a neuroendocrine tumor of the adrenal gland that secretes excess amount of catecholamine, which in turn leads to extremely varied clinical manifestations, such as hypertension, headache, sweating and palpitations. This eventually leads to delay or mistakes in diagnosing the disease. This could be fatal due to misdiagnosis as it receives a totally different treatment. We herein reported a case of pheochromocytoma with recurrent ventricular tachycardia. A literature review was conducted to investigate the clinical features of these patients.
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Neoplasias de las Glándulas Suprarrenales , Feocromocitoma , Taquicardia Ventricular , Neoplasias de las Glándulas Suprarrenales/complicaciones , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Catecolaminas , Electrocardiografía , Humanos , Feocromocitoma/complicaciones , Feocromocitoma/diagnóstico , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/etiologíaRESUMEN
BACKGROUND: Coxsackievirus B3 (CV-B3) is usually associated with aseptic meningitis and myocarditis; however, the association between CV-B3 and hand, foot, and mouth disease (HFMD) has not been clearly demonstrated, and the phylogenetic dynamics and transmission history of CV-B3 have not been well summarized. METHOD: Two HFMD outbreaks caused by CV-B3 were described in Hebei Province in 2012 and in Shandong Province in 2016 in China. To analyze the epidemiological features of two CV-B3 outbreaks, a retrospective analysis was conducted. All clinical specimens from CV-B3 outbreaks were collected and disposed according to the standard procedures supported by the WHO Global Poliovirus Specialized Laboratory. EV genotyping and phylogenetic analysis were performed to illustrate the genetic characteristics of CV-B3 in China and worldwide. RESULTS: Two transmissible lineages (lineage 2 and 3) were observed in Northern China, which acted as an important "reservoir" for the transmission of CV-B3. Sporadic exporting and importing of cases were observed in almost all regions. In addition, the global sequences of CV-B3 showed a tendency of geographic-specific clustering, indicating that geographic-driven adaptation plays a major role in the diversification and evolution of CV-B3. CONCLUSIONS: Overall, our study indicated that CV-B3 is a causative agent of HFMD outbreak and revealed the phylogenetic dynamics of CV-B3 worldwide, as well as provided an insight on CV-B3 outbreaks for effective intervention and countermeasures.
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Enterovirus Humano B/genética , Enterovirus Humano B/patogenicidad , Enfermedad de Boca, Mano y Pie/epidemiología , Enfermedad de Boca, Mano y Pie/virología , Evolución Biológica , China/epidemiología , Análisis por Conglomerados , Infecciones por Coxsackievirus/epidemiología , Brotes de Enfermedades , Enterovirus Humano B/fisiología , Humanos , Filogenia , Estudios RetrospectivosRESUMEN
When a quantum system is driven slowly through a parametric cycle in a degenerate Hilbert space, the state would acquire a non-Abelian geometric phase, which is stable and forms the foundation for holonomic quantum computation (HQC). However, in the adiabatic limit, the environmental decoherence becomes a significant source of errors. Recently, various nonadiabatic holonomic quantum computation (NHQC) schemes have been proposed, but all at the price of increased sensitivity to control errors. Alternatively, there exist theoretical proposals for speeding up HQC by the technique of "shortcut to adiabaticity" (STA), but no experimental demonstration has been reported so far, as these proposals involve a complicated control of four energy levels simultaneously. Here, we propose and experimentally demonstrate that HQC via shortcut to adiabaticity can be constructed with only three energy levels, using a superconducting qubit in a scalable architecture. With this scheme, all holonomic single-qubit operations can be realized nonadiabatically through a single cycle of state evolution. As a result, we are able to experimentally benchmark the stability of STA+HQC against NHQC in the same platform. The flexibility and simplicity of our scheme makes it also implementable on other systems, such as nitrogen-vacancy center, quantum dots, and nuclear magnetic resonance. Finally, our scheme can be extended to construct two-qubit holonomic entangling gates, leading to a universal set of STAHQC gates.
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Enterovirus B80 (EV-B80) is a newly identified serotype belonging to the enterovirus B species. To date, only two full-length genomic sequences of EV-B80 are available in GenBank, and few studies on EV-B80 have been conducted in China or worldwide. More information and research on EV-B80 is needed to assess its genetic characteristics, phylogenetic relationships, and association with enteroviral diseases. In this study, we report the phylogenetic characteristics of three Xinjiang EV-B80 strains and one Tibet EV-B80 strain in China. The full-length genomic sequences of four strains show 78.8-79% nucleotide identity and 94-94.2% amino acid identity with the prototype of EV-B80, indicating a tendency for evolution. Based on a maximum likelihood phylogenetic tree based on the entire VP1 region, three genotypes (A-C) were defined, revealing the possible origin of EV-B80 strains in the mainland of China. Recombination analysis revealed intraspecies recombinations in all four EV-B80 strains in nonstructural regions along with two recombination patterns. Due to the geographic factor, the coevolution of EV-B strains formed two different patterns of circulation. An antibody seroprevalence study against EV-B80 in two Xinjiang prefectures also showed that EV-B80 strains were widely prevalent in Xinjiang, China, compared to other studies on EV-B106 and EV-B89. All four EV-B80 strains are not temperature sensitive, showing a higher transmissibility in the population. In summary, this study reports the full-length genomic sequences of EV-B80 and provides valuable information on global EV-B80 molecular epidemiology.
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Infecciones por Enterovirus/epidemiología , Enterovirus/genética , Evolución Molecular , Genoma Viral , Anticuerpos Antivirales/sangre , Preescolar , China/epidemiología , Enterovirus/aislamiento & purificación , Infecciones por Enterovirus/sangre , Heces/virología , Geografía , Humanos , Lactante , Recién Nacido , Filogenia , ARN Viral/genética , Recombinación Genética , Análisis de Secuencia de ADN , Estudios Seroepidemiológicos , SerogrupoRESUMEN
A central task towards building a practical quantum computer is to protect individual qubits from decoherence while retaining the ability to perform high-fidelity entangling gates involving arbitrary two qubits. Here we propose and demonstrate a dephasing-insensitive procedure for storing and processing quantum information in an all-to-all connected superconducting circuit involving multiple frequency-tunable qubits, each of which can be controllably coupled to any other through a central bus resonator. Although it is generally believed that the extra frequency tunability enhances the control freedom but induces more dephasing impact for superconducting qubits, our results show that any individual qubit can be dynamically decoupled from dephasing noise by applying a weak continuous and resonant driving field whose phase is reversed in the middle of the pulse. More importantly, we demonstrate a new method for realizing a two-qubit phase gate with inherent dynamical decoupling via the combination of continuous driving and qubit-qubit swapping coupling. We find that the weak continuous driving fields not only enable the conditional dynamics essential for quantum information processing, but also protect both qubits from dephasing during the gate operation.
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Signal transducer and activator of transcription 3 (STAT3) have roles in various cellular processes, including angiogenesis, apoptosis, cell cycle progression, cell migration and drug resistance. To clarify the effects of STAT3 in colorectal cancer (CRC) cells and the underlying molecular mechanisms, STAT3 was directly silenced, and the effects of STAT3 silencing on cell proliferation, apoptosis and growth with phenotype-associated molecules were examined.pSH1-Si-STAT3 was successfully transfected into the CRC HCT-116 and SW480 cell lines, which was verified by GFP tagging under a fluorescence microscope. An MTT assay revealed that the proliferation of both cell lines that were transfected with pSH1-Si-STAT3 was significantly suppressed in comparison with the control and mock (P<0.05). Acridine orange/ethidium bromide staining and flow cytometry indicated that the transfected cell lines had a significantly higher rate of apoptosis than the control- and mock-treated cells (P<0.05). STAT3-silienced cells were also significantly arrested at the G2/M stage compared with the cells that were transfected with control and mock plasmids (P<0.05). At the mRNA level, the expression of STAT3 and survivin was significantly downregulated (P<0.05), but p53 and caspase-3 were significantly upregulated (P<0.05). The significantly different patterns of expression were observed in western blot analysis (P<0.05). The findings of the present study indicate that STAT3 silencing may suppress the proliferation and growth of CRC cells, and induce their apoptosis by upregulating the expression of survivin, p53 and caspase-3. Therefore, STAT3 may be a good candidate for CRC gene therapy.
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BACKGROUND: Erlotinib is a commonly used molecular-targeted drug for the treatment of tongue cancer. However, the development of acquired resistance to erlotinib hampers its therapeutic use. MATERIALS AND METHODS: To analyze the erlotinib resistance, long-term and short term survival assay were used to compare the resistance between parental and resistant tongue cancer cells. Flow cytometry, Hochest staining and western blot were used to analyze the apoptosis among the cells. Moreover, Transwell and wound healing assay were used to compare the invasion ability of the cells. To deeply explore the drug resistance in vivo, orthotopic tumor studies were applied. Finally, to explain the mechanism of c-met in erlotinib resistance, shRNA against c-met was used to down-regulate the expression of c-met. And SU11274 also used in orthotopic model. RESULTS: We established erlotinib-resistant human tongue cancer cell line by chronic exposure of TCA-8113 cells to increasing concentrations of erlotinib and determined the role of c-MET and EGFR in the development of acquired resistance. We found a significant increase in the phosphorylation of c-MET and an obvious decrease of the phosphorylation of EGFR in erlotinib-resistant cells. Our results also revealed that inhibition of c-MET alone with SU11274 exerted an inhibitory effect on the proliferation of erlotinib-resistant cells in the short term; however, it failed to sustain the inhibitory effect in the long term. Simultaneous inhibition of c-MET and EGFR significantly inhibited the proliferation of erlotinib-resistant cells in both a short and long period. Furthermore, we explored the underlying mechanism and found that treatment of erlotinib-resistant cells with SU11274 or shRNA against c-MET induced the phosphorylation of EGFR. Moreover, our results demonstrated that simultaneous inhibition of c-MET and EGFR significantly inhibited the migration and invasion of erlotinib-resistant cells. CONCLUSION: Taken together, our results suggested that c-MET is involved in acquired drug resistance to erlotinib and that cotargeting of EGFR and c-MET could overcome acquired resistance to erlotinib and inhibit the invasion and metastasis of erlotinib-resistant cells.
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Anyons are quasiparticles occurring in two dimensions, whose topological properties are believed to be robust against local perturbations and may hold promise for fault tolerant quantum computing. Here we present an experiment of demonstrating the path independent nature of anyonic braiding statistics with a superconducting quantum circuit, which represents a 7-qubit version of the toric code model. We dynamically create the ground state of the model, achieving a state fidelity of 0.688±0.015 as verified by quantum state tomography. Anyonic excitations and braiding operations are subsequently implemented with single-qubit rotations. The braiding robustness is witnessed by looping an anyonic excitation around another one along two distinct, but topologically equivalent paths: Both reveal the nontrivial π-phase shift, the hallmark of Abelian 1/2 anyons, with a phase accuracy of â¼99% in the Ramsey-type interference measurement.
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Enterovirus A90 (EV-A90) is a novel serotype of enterovirus A species that is rarely reported. Here, we isolated five enteroviruses from patients with acute flaccid paralysis in Hotan and Kashgar cities in Xinjiang, China that were identified as EV-A90 by molecular typing. The VP1 sequences of these Xinjiang EV-A90 strains showed 88.4-89% nucleotide sequence identity to the prototype EV-A90 strain; however, genome analysis indicated complex recombination events in P2 and P3 regions. Next, the seroprevalence of EV-A90 was examined in 49 serum specimens collected in Hotan and Kashgar, and 37.5% were EV-A90 antibody positive (>1:8), with a geometric mean titre (GMT) of 1:10.47. The low positive rate and GMT suggest a low-level EV-A90 epidemic in Xinjiang. Two of the five Xinjiang EV-A90 strains were temperature sensitive, and three were temperature resistant, and a comparative genomics analysis suggested that an amino acid substitution (H1799Y) in the 3Dpol region was related to temperature sensitivity. Although the epidemic strength is low, some EV-A90 strains were temperature resistant, which is suggestive of strong virulence and transmission capacity. This study expanded the number of EV-A90 in GenBank and provided basic data that may be useful for studying the molecular epidemiology of EV-A90.
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Anticuerpos Antivirales/sangre , Antígenos Virales/inmunología , Infecciones por Enterovirus/epidemiología , Enterovirus/genética , Enterovirus/inmunología , Evolución Molecular , Genoma Viral , Anticuerpos Antivirales/inmunología , Antígenos Virales/genética , China/epidemiología , Enterovirus/clasificación , Enterovirus/aislamiento & purificación , Infecciones por Enterovirus/sangre , Infecciones por Enterovirus/inmunología , Infecciones por Enterovirus/virología , Humanos , Tipificación Molecular , Pruebas de Neutralización , Filogenia , ARN Viral/genética , Estudios SeroepidemiológicosRESUMEN
The law of statistical physics dictates that generic closed quantum many-body systems initialized in nonequilibrium will thermalize under their own dynamics. However, the emergence of many-body localization (MBL) owing to the interplay between interaction and disorder, which is in stark contrast to Anderson localization, which only addresses noninteracting particles in the presence of disorder, greatly challenges this concept, because it prevents the systems from evolving to the ergodic thermalized state. One critical evidence of MBL is the long-time logarithmic growth of entanglement entropy, and a direct observation of it is still elusive due to the experimental challenges in multiqubit single-shot measurement and quantum state tomography. Here we present an experiment fully emulating the MBL dynamics with a 10-qubit superconducting quantum processor, which represents a spin-1/2 XY model featuring programmable disorder and long-range spin-spin interactions. We provide essential signatures of MBL, such as the imbalance due to the initial nonequilibrium, the violation of eigenstate thermalization hypothesis, and, more importantly, the direct evidence of the long-time logarithmic growth of entanglement entropy. Our results lay solid foundations for precisely simulating the intriguing physics of quantum many-body systems on the platform of large-scale multiqubit superconducting quantum processors.
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LATS1 is a serine/threonine kinase of the Hippo signaling pathway that phosphorylates and inactivates transcriptional co-activators YAP1 and WWTR1. To investigate roles of LATS1 expression in head and neck squamous cell carcinomas (HNSCCs), we transfected LATS1-expressing plasmid into B88 cells and examined the phenotypes and their relevant molecules. LATS1 expression was analyzed using immunohistochemistry on tissue microarray, Oncomine, and TCGA databases. LATS1 overexpression was found to suppress growth, migration and invasion, and induce apoptosis, G2 arrest, and mesenchymal to epithelial transition (MET) (P < 0.05). Both increased expression of P21, Bax, and E-cadherin and decreased expression of Cyclin B1, D1, Bcl-2, and MMPs. Twist and N-cadherin were detected in B88 transfectants, in comparison to mock and control by Western blot. Nuclear LATS1 expression was weaker in primary cancers than in normal squamous tissue and dysplasia (P < 0.05) but versa for cytoplasmic counterpart (P < 0.05). Cytoplasmic LATS1 expression was positively correlated with lymph node metastasis (P < 0.05). Survival analysis showed that differentiation degree was an independent factor of long overall and relapse-free survival of HNSCC patients (P < 0.05). According to bioinformatics analysis, we found upregulated LATS1 mRNA expression in HNSCCs (P < 0.05). Cox proportional hazards model indicated that perineural invasion and distant metastasis were independent prognostic factors for overall survival of HNSCC (P < 0.05). These findings suggest nucleocytoplasmic translocation of LATS1 protein and upregulated expression of LATS1 mRNA during tumorigenesis of HNSCC. LATS1 mRNA overexpression may reverse aggressive phenotypes of HNSCC cells, as a gene therapy target.