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BACKGROUND: The comparative effectiveness of volatile anaesthesia and total intravenous anaesthesia (TIVA) in terms of patient outcomes after cardiac surgery remains a topic of debate. METHODS: Multicentre randomised trial in 16 tertiary hospitals in China. Adult patients undergoing elective cardiac surgery were randomised in a 1:1 ratio to receive volatile anaesthesia (sevoflurane or desflurane) or propofol-based TIVA. The primary outcome was a composite of predefined major complications during hospitalisation and mortality 30 days after surgery. RESULTS: Of the 3123 randomised patients, 3083 (98.7%; mean age 55 yr; 1419 [46.0%] women) were included in the modified intention-to-treat analysis. The composite primary outcome was met by a similar number of patients in both groups (volatile group: 517 of 1531 (33.8%) patients vs TIVA group: 515 of 1552 (33.2%) patients; relative risk 1.02 [0.92-1.12]; P=0.76; adjusted odds ratio 1.05 [0.90-1.22]; P=0.57). Secondary outcomes including 6-month and 1-yr mortality, duration of mechanical ventilation, length of ICU and hospital stay, and healthcare costs, were also similar for the two groups. CONCLUSIONS: Among adults undergoing cardiac surgery, we found no difference in the clinical effectiveness of volatile anaesthesia and propofol-based TIVA. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-IOR-17013578).
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Anestésicos por Inhalación , Anestésicos Intravenosos , Procedimientos Quirúrgicos Cardíacos , Desflurano , Complicaciones Posoperatorias , Propofol , Humanos , Propofol/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Procedimientos Quirúrgicos Cardíacos/mortalidad , Anestésicos Intravenosos/efectos adversos , Anestésicos por Inhalación/efectos adversos , Anciano , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/prevención & control , Adulto , Sevoflurano/efectos adversos , Anestesia Intravenosa/métodos , China/epidemiología , Tiempo de Internación/estadística & datos numéricos , Anestesia por Inhalación/métodos , Anestesia por Inhalación/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: It is imperative to develop novel therapeutics to overcome chemoresistance, a significant obstacle in the clinical management of prostate cancer (PCa) and other cancers. METHODS: A phenotypic screen was performed to identify novel inhibitors of chemoresistant PCa cells. The mechanism of action of potential candidate(s) was investigated using in silico docking, and molecular and cellular assays in chemoresistant PCa cells. The in vivo efficacy was evaluated in mouse xenograft models of chemoresistant PCa. RESULTS: Nicardipine exhibited high selectivity and potency against chemoresistant PCa cells via inducing apoptosis and cell cycle arrest. Computational, molecular, and cellular studies identified nicardipine as a putative inhibitor of embryonic ectoderm development (EED) protein, and the results are consistent with a proposed mechanism of action that nicardipine destabilised enhancer of zeste homologue 2 (EZH2) and inhibited key components of noncanonical EZH2 signalling, including transducer and activator of transcription 3, S-phase kinase-associated protein 2, ATP binding cassette B1, and survivin. As a monotherapy, nicardipine effectively inhibited the skeletal growth of chemoresistant C4-2B-TaxR tumours. As a combination regimen, nicardipine synergistically enhanced the in vivo efficacy of docetaxel against C4-2 xenografts. CONCLUSION: Our findings provided the first preclinical evidence supporting nicardipine as a novel EED inhibitor that has the potential to be promptly tested in PCa patients to overcome chemoresistance and improve clinical outcomes.
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Nicardipino , Neoplasias de la Próstata , Animales , Humanos , Masculino , Ratones , Apoptosis , Línea Celular Tumoral , Docetaxel/farmacología , Docetaxel/uso terapéutico , Nicardipino/farmacología , Nicardipino/uso terapéutico , Complejo Represivo Polycomb 2 , Neoplasias de la Próstata/tratamiento farmacológicoRESUMEN
BACKGROUND: Androgen deprivation therapy (ADT) is the mainstay of treatment for castration-resistant prostate cancer (CRPC). Unfortunately, although ADT initially prolongs survival, most patients relapse and develop resistance. Clinical failure of these treatments in CRPC highlights the urgent need to develop novel strategies to more effectively block androgen receptor (AR) signaling and target other oncogenic factors responsible for ADT resistance. METHODS: We developed a small-molecule compound LG1836 and investigated the in vitro and in vivo activity of LG1836 against CRPC in cellular and animal models. RESULTS: LG1836 exhibits potent in vitro cytotoxicity in CRPC cells. Mechanistic studies demonstrated that LG1836 inhibits the expression of AR and AR variant 7, partially mediated via proteasome-dependent protein degradation. LG1836 also suppresses survivin expression and effectively induces apoptosis in CRPC cells. Significantly, as a single agent, LG1836 is therapeutically efficacious in suppressing the in vivo growth of CRPC in the subcutaneous and intraosseous models and extends the survival of tumor-bearing mice. CONCLUSIONS: These preclinical studies indicate that LG1836 is a promising lead compound for the treatment of CRPC.
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Piperidinas/farmacología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/farmacología , Antagonistas de Receptores Androgénicos/farmacología , Animales , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Procesos de Crecimiento Celular/efectos de los fármacos , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Masculino , Ratones , Ratones Desnudos , Ratones SCID , Neoplasias de la Próstata Resistentes a la Castración/patología , Distribución Aleatoria , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/metabolismo , Survivin/antagonistas & inhibidores , Survivin/biosíntesis , Ubiquitinación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A simple and sensitive liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed and validated for determination of two highly lipophilic anticancer drug candidates, LG1980 and GH501, in rat plasma and tissues (liver, kidney and femur bones). LG1980 and GH501 were extracted from rat plasma and tissue homogenates using liquid-liquid extraction. The method provided a linear range of 1.0-200.0 ng/mL for GH501 in plasma and LG1980 in plasma and liver. For both analytes in other tissue homogenates the linear range was 2.0-400.0 ng/mL. The method was validated with precision within 15% relative standard deviation, accuracy within 15% relative error and a consistent recovery. This method has been successfully applied in two preclinical studies for LG1980 and GH501 to determine their concentrations in rat plasma, liver, kidney and bone over 24 h after intravenous injection of compounds.
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Antineoplásicos/análisis , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Animales , Antineoplásicos/sangre , Antineoplásicos/química , Antineoplásicos/farmacocinética , Interacciones Hidrofóbicas e Hidrofílicas , Riñón/química , Límite de Detección , Modelos Lineales , Hígado/química , Masculino , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Distribución TisularRESUMEN
The translation initiation factor eIF4E mediates a rate-limiting process that drives selective translation of many oncongenic proteins such as cyclin D1, survivin and VEGF, thereby contributing to tumour growth, metastasis and therapy resistance. As an essential regulatory hub in cancer signalling network, many oncogenic signalling pathways appear to converge on eIF4E. Therefore, targeting eIF4E-mediated cap-dependent translation is considered a promising anticancer strategy. This paper reviews the strategies that can be used to target eIF4E, highlighting agents that target eIF4E activity at each distinct level.
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Antineoplásicos/uso terapéutico , Factor 4E Eucariótico de Iniciación/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica , Neoplasias/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Animales , Ciclina D1/genética , Ciclina D1/metabolismo , Compuestos Epoxi/uso terapéutico , Factor 4E Eucariótico de Iniciación/genética , Factor 4E Eucariótico de Iniciación/metabolismo , Humanos , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Macrólidos/uso terapéutico , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/metabolismo , Biosíntesis de Proteínas , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Ribavirina/uso terapéutico , Sirolimus/uso terapéutico , Survivin , Tiazoles/uso terapéutico , Triterpenos/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Aberrant expression of EGF receptors has been associated with hormone-refractory and metastatic prostate cancer (PCa). However, the molecular mechanism for EGF signaling in promoting PCa metastasis remains elusive. Using experimental models of PCa metastasis, we demonstrated that EGF could induce robust epithelial-mesenchymal transition (EMT) and increase invasiveness. Interestingly, EGF was found to be capable of promoting protein turnover of epithelial protein lost in neoplasm (EPLIN), a putative suppressor of EMT and tumor metastasis. Mechanistic study revealed that EGF could activate the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade. Pharmacological inhibition of the ERK1/2 pathway effectively antagonized EGF-induced EPLIN degradation. Two serine residues, i.e. serine 362 and serine 604, were identified as putative ERK1/2 phosphorylation sites in human EPLIN, whose point mutation rendered resistance to EGF-induced protein turnover. This study elucidated a novel molecular mechanism for EGF regulation of EMT and invasiveness in PCa cells, indicating that blockade of EGF signaling could be beneficial in preventing and retarding PCa metastasis at early stages.
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Proteínas del Citoesqueleto/metabolismo , Factor de Crecimiento Epidérmico/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Metástasis de la Neoplasia , Proteínas de Neoplasias/metabolismo , Neoplasias de la Próstata/genética , Línea Celular Tumoral , Movimiento Celular , Proteínas del Citoesqueleto/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Genes Reporteros , Humanos , Masculino , Proteínas de Neoplasias/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Proteolisis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , TransfecciónRESUMEN
Bone metastasis of breast cancer typically leads to osteolysis, which causes severe pathological bone fractures and hypercalcemia. Bone homeostasis is skillfully regulated through osteoblasts and osteoclasts. Bone loss with bone metastasis of breast cancer may be due to both activation of osteoclastic bone resorption and suppression of osteoblastic bone formation. This study was undertaken to determine whether the novel curcumin analogue UBS109 has preventive effects on bone loss induced by breast cancer cell bone metastasis. Nude mice were inoculated with breast cancer MDA-MB-231 bone metastatic cells (10(6) cells/mouse) into the head of the right and left tibia. One week after inoculation, the mice were treated with control (vehicle), oral administration (p.o.) of UBS109 (50 or 150 mg/kg body weight), or intraperitoneal administration (i.p.) of UBS109 (10 or 20 mg/kg body weight) once daily for 5 days per week for 7 weeks. After UBS109 administration for 7 weeks, hind limbs were assessed using an X-ray diagnosis system and hematoxylin and eosion staining to determine osteolytic destruction. Bone marrow cells obtained from the femurs and tibias were cultured to estimate osteoblastic mineralization and osteoclastogenesis ex vivo and in vitro. Remarkable bone loss was demonstrated in the tibias of mice inoculated with breast cancer MDA-MB-231 bone metastatic cells. This bone loss was prevented by p.o. administration of UBS109 (50 and 150 mg/kg body weight) and i.p. treatment of UBS109 (10 and 20 mg/kg) in vivo. Culture of bone marrow cells obtained from the bone tissues of mice with breast cancer cell bone metastasis showed suppressed osteoblastic mineralization and stimulated osteoclastogenesis ex vivo. These changes were not seen after culture of the bone marrow cells obtained from mice treated with UBS109. Moreover, UBS109 was found to stimulate osteoblastic mineralization and suppress lipopolysaccharide (LPS)-induced osteoclastogenesis in bone marrow cells obtained from normal nude mice in vitro. These findings suggest that the novel curcumin analogue UBS109 prevents breast cancer cell bone metastasis-induced bone loss by stimulating osteoblastic mineralization and suppressing osteoclastogenesis.
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Neoplasias Óseas/prevención & control , Neoplasias Óseas/secundario , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Osteoblastos/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Piperidonas/farmacología , Piridinas/farmacología , Animales , Resorción Ósea/patología , Resorción Ósea/prevención & control , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Ratones Desnudos , Metástasis de la Neoplasia , Osteoblastos/patología , Osteoclastos/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
China is a major player in the marine fish trade. The price prediction of marine fish is of great significance to socio-economic development and the fisheries industry. However, due to the complexity and uncertainty of the marine fish market, traditional forecasting methods often struggle to accurately predict price fluctuations. Therefore, this study adopts an intelligent combination model to enhance the accuracy of food product price prediction. Firstly, three decomposition methods, namely empirical wavelet transform, singular spectrum analysis, and variational mode decomposition, are applied to decompose complex original price series. Secondly, a combination of bidirectional long short-term memory artificial neural network, extreme learning machine, and exponential smoothing prediction methods are applied to the decomposed results for cross-prediction. Subsequently, the predicted results are input into the PSO-CS intelligence algorithm for weight allocation and to generate combined prediction results. Empirical analysis is conducted using data illustrating the daily sea purchase price of larimichthys crocea in Ningde City, Fujian Province, China. The combination prediction accuracy with PSO-CS weight allocation is found to be higher than that of single model predictions, yielding superior results. With the implementation of weight allocation intelligent combinatorial modelling, the prediction of marine fish prices demonstrates higher accuracy and stability, enabling better adaptation to market changes and price fluctuations.
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EED within the PRC2 complex is crucial for chromatin regulation particularly in tumor development, making its inhibition a promising epigenetic therapeutic strategy. Significant advancement in PRC2 inhibitor development has been achieved with an approved EZH2 inhibitor in the market and with others in the clinical trials. However, current EZH2 inhibitors are limited to specific blood cancers and encounter therapeutic resistance. EED stabilizes PRC2 complex and enhances its activity through unique allosteric mechanisms, thereby acting as both a scaffold protein and a recognizer of H3K27me3 making it an attractive drug target. This review provides an overview of epigenetic therapeutic strategies targeting EED, including allosteric inhibitors, PPI inhibitors, and PROTACs, together with brief discussions on the relevant challenges, opportunities, and future directions.
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Epigénesis Genética , Complejo Represivo Polycomb 2 , Humanos , Complejo Represivo Polycomb 2/antagonistas & inhibidores , Complejo Represivo Polycomb 2/metabolismo , Epigénesis Genética/efectos de los fármacos , Animales , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Terapia Molecular Dirigida , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Regulación Alostérica/efectos de los fármacosRESUMEN
BACKGROUND: Docetaxel treatment is the only first-line chemotherapy with a survival benefit in metastatic castration-resistant prostate cancer (PCa). Nonetheless, most patients become docetaxel resistant and inevitably progress with no cure. In this study, we investigated the potential of pomegranate extract (PE) in targeting metastatic castration-resistant PCa and improving docetaxel chemotherapy. METHODS: The in vitro and in vivo effect of POMx, a PE formula currently approved for clinical trials, in metastatic castration-resistant PCa cells was evaluated in experimental models. RESULTS: We demonstrated that POMx exhibited potent in vitro cytotoxicity in metastatic castration-resistant PCa cells. Mechanistic studies identified survivin as a novel molecular target that may mediate the anti-cancer activity of POMx, presumably through the inhibition of signal transducer and activator of transcription 3. The in vivo administration of POMx treatment effectively inhibited survivin, induced apoptosis, retarded C4-2 tumor growth in skeleton and significantly enhanced the efficacy of docetaxel in athymic nude mice. CONCLUSION: These results provide the first preclinical evidence that POMx may be effective in treating metastatic castration-resistant PCa and enhancing the efficacy of docetaxel chemotherapy. Prostate © 2013 Wiley Periodicals, Inc.
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BACKGROUND: Cabazitaxel (Jevtana) has been approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, most patients progress and become chemoresistant, which remains a major challenge in the management of advanced PCa. In this study, we investigated whether genistein, an isoflavone abundant in soy products, could sensitize mCRPC cells to cabazitaxel treatment in experimental models. METHODS: The in vitro and in vivo effect of genistein in enhancing the response of mCRPC cells to cabazitaxel chemotherapy was evaluated in experimental models. RESULTS: Genistein increases the expression of pro-apoptotic protein Bax, activates apoptotic signals, and enhances the response to cabazitaxel treatment in mCRPC cells. In a PC3-luciferase xenograft model, the combined treatment with genistein and cabazitaxel significantly retarded the growth of mCRPC when compared to vehicle control, cabazitaxel, or genistein. Tissue staining confirmed the in vivo effect of genistein on the induction of Bax and activation of apoptosis. CONCLUSION: This study provided the first preclinical evidence supporting that genistein could be beneficial in improving cabazitaxel chemotherapy in mCRPC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proliferación Celular/efectos de los fármacos , Genisteína/uso terapéutico , Próstata/efectos de los fármacos , Neoplasias de la Próstata/tratamiento farmacológico , Taxoides/uso terapéutico , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Genisteína/farmacología , Humanos , Masculino , Ratones , Ratones Desnudos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Próstata/metabolismo , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Taxoides/farmacología , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Chemoresistance is a major obstacle in the clinical management of metastatic, castration-resistant prostate cancer (PCa). It is imperative to develop novel strategies to overcome chemoresistance and improve clinical outcomes in patients who have failed chemotherapy. Using a two-tier phenotypic screening platform, we identified bromocriptine mesylate as a potent and selective inhibitor of chemoresistant PCa cells. Bromocriptine effectively induced cell cycle arrest and activated apoptosis in chemoresistant PCa cells but not in chemoresponsive PCa cells. RNA-seq analyses revealed that bromocriptine affected a subset of genes implicated in the regulation of the cell cycle, DNA repair, and cell death. Interestingly, approximately one-third (50/157) of the differentially expressed genes affected by bromocriptine overlapped with known p53-p21- retinoblastoma protein (RB) target genes. At the protein level, bromocriptine increased the expression of dopamine D2 receptor (DRD2) and affected several classical and non-classical dopamine receptor signal pathways in chemoresistant PCa cells, including adenosine monophosphate-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor kappa B (NF-κB), enhancer of zeste homolog 2 (EZH2), and survivin. As a monotherapy, bromocriptine treatment at 15 mg/kg, three times per week, via the intraperitoneal route significantly inhibited the skeletal growth of chemoresistant C4-2B-TaxR xenografts in athymic nude mice. In summary, these results provided the first preclinical evidence that bromocriptine is a selective and effective inhibitor of chemoresistant PCa. Due to its favorable clinical safety profiles, bromocriptine could be rapidly tested in PCa patients and repurposed as a novel subtype-specific treatment to overcome chemoresistance.
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Neurofilament light chain (NfL) levels have proved to be a good biomarker in cerebrospinal fluid (CSF) correlating with the degree of neuronal injury and neurodegeneration. However, little is known about the value of plasma neurofilament light chain (pNfL) levels in predicting the clinical prognosis of patients with acute cerebral infarction. This study aimed to explore whether pNfL could be used as a biomarker to predict the severity of the outcomes of acute ischemic stroke (AIS). Patients with AIS were included from the Department of Neurology of the First People's Hospital of Bengbu City from January 2018 to May 2019, as well as health control (HC). The plasma levels of NfL in patients with AIS (n = 60) at 2 days, 7 days, and 6 months after stroke, as well as in HCs (n = 60) were measured by electrochemiluminescence immunoassay(ECL) on the Meso Scale Discovery platform. Stroke severity was analyzed at admission using the National Institutes of Health Stroke Scale score. Functional outcomes were assessed at different times using the modified Rankin Scale (mRS) and Barthel Index. The mean level of pNfL in patients with ischemic stroke (IS) at 2 days (225.86 pg/L) after stroke was significantly higher than that in HC (107.02 pg/L) and gradually increased 7 days after stroke (316.23 pg/L) (P < .0001). The mean level of pNfL in patients with IS at 6 months after stroke was 173.38 pg/L, which was still significantly higher than that of HC. The levels of pNfL at 7 days after stroke independently predicted modified Rankin Scale scores (mRS) (R = 0.621, P < .001), Barthel Index (R = -0.716, P < .001), and National Institutes of Health Stroke Scale (R = -0.736, P < .001). The diagnostic severity and prognosis were evaluated by ROC curve, an area under the receiver operator curve of 0.812 (P = .001, 95% CI: 0.69-0.93) at 7 days. Plasma NfL levels reflect neuronal injury after AIS. It changes with time and has a certain relationship with prognosis and may be a promising biomarker for predicting the severity of neuroaxonal injury in patients with acute IS.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Biomarcadores , Isquemia Encefálica/diagnóstico , Humanos , Filamentos Intermedios , Accidente Cerebrovascular/diagnóstico , Estados UnidosRESUMEN
A series of nanosized (Fe3-xMnx)1-δO4 (x = 0, 0.2, 0.5, and 0.8) were synthesized for elemental mercury capture from the flue gas. Cation vacancies on (Fe3-xMnx)1-δO4 can provide the active sites for elemental mercury adsorption, and Mn(4+) cations on (Fe3-xMnx)1-δO4 may be the oxidizing agents for elemental mercury oxidization. With the increase of Mn content in the spinel structure, the percents of Mn(4+) cations and cation vacancies on the surface increased. As a result, elemental mercury capture by (Fe3-xMnx)1-δO4 was obviously promoted with the increase of Mn content. (Fe2.2Mn0.8)1-δO4 showed an excellent capacity for elemental mercury capture (>1.5 mg g(-1) at 100-300 °C) in the presence of SO2 and HCl. Furthermore, (Fe2.2Mn0.8)1-δO4 with the saturation magnetization of 45.6 emu g(-1) can be separated from the fly ash using magnetic separation, leaving the fly ash essentially free of sorbent and adsorbed Hg. Therefore, nanosized (Fe2.2Mn0.8)1-δO4 may be a promising sorbent for the control of elemental mercury emission.
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Mercurio/química , Nanopartículas , Adsorción , Contaminación del Aire/prevención & control , Ceniza del Carbón , Gases/química , Magnetismo , Oxidación-ReducciónRESUMEN
Confucius said, "Good tools are prerequisite to the successful execution of a job". Among his many groundbreaking achievements, Dr. Leland W. K. Chung established several widely used prostate cancer (PCa) cell lines, including C4-2, C4-2B, and ARCaP. These cellular models have been pivotal tools to enhance our understanding of the biology of PCa progression and assist in the discovery of new strategies to treat metastatic, castration-resistant PCa. Recent studies in the ARCaP PCa progression model uncovered epithelial protein lost in neoplasm (EPLIN), an actin-binding protein with an indispensable role in the maintenance of epithelial structures, as a negative regulator of epithelial-mesenchymal transition. Clinical evidence further supports the potential role of EPLIN in controlling metastasis in PCa and other solid tumors. In this article, we review the current understanding of the biology of EPLIN and the ARCaP model in the discovery of new agents for the prevention and treatment of PCa metastasis.
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The polycomb repressive complex 2 (PRC2) can methylate at lysine 27 of histone H3 at the trimethylation level (H3K27me3). This leads to gene silencing and is known to be dysregulated in many cancers. PRC2 is made up of three core subunits: EZH2, SUZ12, and EED. EED is essential for the regulation of PRC2 function by binding to H3K27me3. Targeting the allosteric site within EED offers new strategies to disrupt the PRC2 activity. In this minireview, we summarize some of the recent developments in small molecules that target EED and its interaction with other core proteins in the PRC2 complex.
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Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Complejo Represivo Polycomb 2/antagonistas & inhibidores , Sitio Alostérico , Animales , Histonas/química , Histonas/metabolismo , Humanos , Metilación , Complejo Represivo Polycomb 2/química , Complejo Represivo Polycomb 2/metabolismoRESUMEN
Bone metastasis is a frequent and lethal complication of many cancer types (i.e., prostate cancer, breast cancer, and multiple myeloma), and a cure for bone metastasis remains elusive. To recapitulate the process of bone metastasis and understand how cancer cells metastasize to bone, intracardiac injection and intracaudal arterial animal models were developed. The intratibial injection animal model was established to investigate the communication between cancer cells and the bone microenvironment and to mimic the setting of prostate cancer patients with bone metastasis. Given that detailed protocols of intratibial injection and its quantitative analysis are still insufficient, in this protocol, we provide hands-on procedures for how to prepare cells, perform the tibial injection, monitor tibial tumor growth, and quantitatively evaluate the tibial tumors in pathological samples. This manuscript provides a ready-to-use experimental protocol for investigating cancer cell behaviors in bone and developing novel therapeutic strategies for bone metastatic cancer patients.
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Despite the recent successes in siRNA therapeutics, targeted delivery beyond the liver remains the major hurdle for the widespread application of siRNA in vivo. Current cationic liposome or polymer-based delivery agents are restricted to the liver and suffer from off-target effects, poor clearance, low serum stability, and high toxicity. In this study, we genetically engineered a non-cationic non-viral tumor-targeted universal siRNA nanocarrier (MW 26 KDa). This protein nanocarrier consists of three function domains: a dsRNA binding domain (dsRBD) (from human protein kinase R) for any siRNA binding, 18-histidine for endosome escape, and two RGD peptides at the N- and C-termini for targeting tumor and tumor neovasculature. We showed that cloned dual-RGD-dsRBD-18his (dual-RGD) protein protects siRNA against RNases, induces effective siRNA endosomal escape, specifically targets integrin αvß3 expressing cells in vitro, and homes siRNA to tumors in vivo. The delivered siRNA leads to target gene knockdown in the cell lines and tumor xenografts with low toxicity. This multifunctional and biomimetic siRNA carrier is biodegradable, has low toxicity, is suitable for mass production by fermentation, and is serum stable, holding great potential to provide a widely applicable siRNA carrier for tumor-targeted siRNA delivery.
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Neurite outgrowth involves reciprocal signaling interactions between tumor cells and nerves where invading tumor cells have acquired the ability to respond to pro-invasive signals within the nerve environment. Neurite outgrowth could serve as a mechanism leading to invasion of cancer cells into the nerve sheath and subsequent metastasis. Snail transcription factor can promote migration and invasion of prostate cancer cells. We hypothesized that prostate cancer cell interaction with nerve cells will be mediated by Snail expression within prostate cancer cells. For this study we utilized various prostate cancer cell lines: C4-2 non-silencing (NS, control); C4-2 Snail shRNA, (stable Snail knockdown); LNCaP Neo (empty vector control) and LNCaP Snail (stably over-expressing Snail). Cancer cell adhesion and migration towards nerve cells (snF96.2 or NS20Y) was examined by co-culture assays. Conditioned media (CM) collected from C4-2 cells was cultured with nerve cells (PC-12 or NS20Y) for 48 h followed by qualitative or quantitative neurite outgrowth assay. Our results showed that cancer cells expressing high levels of Snail (LNCaP Snail/C4-2 NS) displayed significantly higher migration adherence to nerve cells, compared to cells with lower levels of Snail (LNCaP Neo/C4-2 Snail shRNA). Additionally, LNCaP Snail or C4-2 NS (Snail-high) CM led to a higher neurite outgrowth compared to the LNCaP Neo or C4-2 Snail shRNA (Snail-low). In conclusion, Snail promotes migration and adhesion to nerve cells, as well as neurite outgrowth via secretion of soluble factors. Therefore, targeting cancer cell interaction with nerves may contribute to halting prostate cancer progression/metastasis.
Asunto(s)
Proyección Neuronal/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Factores de Transcripción de la Familia Snail/genética , Factores de Transcripción de la Familia Snail/metabolismo , Animales , Adhesión Celular/genética , Comunicación Celular/genética , Línea Celular , Movimiento Celular/genética , Proliferación Celular/genética , Silenciador del Gen , Humanos , Masculino , Ratones , Neuronas/metabolismo , Neoplasias de la Próstata/patología , RatasRESUMEN
A major challenge to the treatment of advanced prostate cancer (PCa) is the development of resistance to androgen-deprivation therapy (ADT) and chemotherapy. It is imperative to discover effective therapies to overcome drug resistance and improve clinical outcomes. We have developed a novel class of silicon-containing compounds and evaluated the anticancer activities and mechanism of action using cellular and animal models of drug-resistant PCa. Five organosilicon compounds were evaluated for their anticancer activities in the NCI-60 panel and established drug-resistant PCa cell lines. GH1504 exhibited potent in vitro cytotoxicity in a broad spectrum of human cancer cells, including PCa cells refractory to ADT and chemotherapy. Molecular studies identified several potential targets of GH1504, most notably androgen receptor (AR), AR variant 7 (AR-v7) and survivin. Mechanistically, GH1504 may promote the protein turnover of AR, AR-v7 and survivin, thereby inducing apoptosis in ADT-resistant and chemoresistant PCa cells. Animal studies demonstrated that GH1504 effectively inhibited the in vivo growth of ADT-resistant CWR22Rv1 and chemoresistant C4-2B-TaxR xenografts in subcutaneous and intraosseous models. These preclinical results indicated that GH1504 is a promising lead that can be further developed as a novel therapy for drug-resistant PCa.