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RATIONALE AND OBJECTIVES: This study aims to investigate the role of a flourine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) multimodal radiomics model in predicting the status of human epidermal growth factor receptor 2 (HER2) expression preoperatively in cases of gastric adenocarcinoma. MATERIALS AND METHODS: This retrospective study included 133 patients with gastric adenocarcinoma who were classified into training (n = 93) and validation (n = 40) cohorts in a ratio of 7:3. Features were selected using Least Absolute Shrinkage and Selection Operator and Extreme Gradient Boosting (XGBoost) methods; further, prediction models were constructed using logistic regression and XGBoost. These models were evaluated and validated using area under the curve (AUC), decision curves, and calibration curves to select the best-performing model. RESULTS: Six different models were established to predict HER2 expression. Among these, the comprehensive model, which integrates seven clinical features, one CT feature, and five PET features, demonstrated AUC values of 0.95 (95% confidence interval [CI]: 0.89-1.00) and 0.76 (95% CI: 0.52-1.00) in the training and validation cohorts, respectively. Compared with other models, this model exhibited a superior net benefit on the decision curve and demonstrated good alignment agreement with the observed values on the calibration curve. Based on these findings, we constructed a nomogram for visualizing the model, providing a noninvasive preoperative method for predicting HER2 expression. CONCLUSION: The preoperative 18F-FDG PET/CT multimodal radiomics model can effectively predict HER2 expression in patients with gastric adenocarcinoma, thereby guiding clinical decision-making and advancing the field of precision medicine.
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Adenocarcinoma , Fluorodesoxiglucosa F18 , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos , Receptor ErbB-2 , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Femenino , Masculino , Persona de Mediana Edad , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/metabolismo , Receptor ErbB-2/metabolismo , Estudios Retrospectivos , Anciano , Adulto , Valor Predictivo de las PruebasRESUMEN
OBJECTIVE: The present study investigated the predictive diseases progression value of preoperative fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in patients with local advanced cervical cancer (LACC). METHODS: In total, 267 patients [median age 58 (range: 27-85) years old] with LACC underwent 18F-FDG PET/CT prior to any treatment. The maximum standardized uptake values (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary lesion and metastatic lymph nodes were measured on PET/CT and correlated with clinicopathological features and progression-free survival (PFS). RESULTS: The median follow-up was 36.52 (range: 3.09-61.29) months. During the observation period, 80 (30.0%) patients exhibited disease progression. Univariate analysis showed that FIGO stage, concurrent chemoradiotherapy (CRT), serum level of carcinoembryonic antigen (CEA) and squamous cell carcinoma antigen (SCC-Ag), primary tumor MTV (pMTV) and TLG (pTLG), lymph nodes SUVmax (nSUVmax) and TLG (nTLG), and total metabolic activity (sMTV, sTLG) were associated with PFS. nSUVmax ≥ 5.29, CEA ≥ 7.11 ng/ml and deficiency of concurrent CRT were independent risk factor for PFS (p = 0.006, p = 0.008, p = 0.014). The 3-year PFS for patients with high nSUVmax were 42.2% compared to 56.3% for low nSUVmax values. CONCLUSION: Pretreatment cervical and lymph nodes metabolic parameters were associated with PFS in patients with LACC.
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Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias del Cuello Uterino , Femenino , Humanos , Persona de Mediana Edad , Adulto , Anciano , Anciano de 80 o más Años , Fluorodesoxiglucosa F18 , Neoplasias del Cuello Uterino/diagnóstico por imagen , Neoplasias del Cuello Uterino/terapia , Antígeno Carcinoembrionario , Supervivencia sin Progresión , Radiofármacos , Progresión de la Enfermedad , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Carga Tumoral , Pronóstico , Estudios RetrospectivosRESUMEN
The initial interaction mechanism is very important for the design and safety of nano-scale composite energetic materials composed of ammonium dinitramide (ADN) and nitrocellulose (NC). The thermal behaviors of ADN, NC and an NC/ADN mixture under different conditions were studied by using differential scanning calorimetry (DSC) with sealed crucibles, an accelerating rate calorimeter (ARC), a self-developed gas pressure measurement instrument and a DSC-thermogravimetry (TG)-quadrupole mass spectroscopy (MS)-Fourier transform infrared spectroscopy (FTIR) combined technique. The results show that the exothermic peak temperature of the NC/ADN mixture shifted forward greatly in both open and closed circumstances compared to those of NC or ADN. After 585.5 min under quasi-adiabatic conditions, the NC/ADN mixture stepped into the self-heating stage at 106.4 °C, which was much less than the initial temperatures of NC or ADN. The significant reduction in net pressure increment of NC, ADN and the NC/ADN mixture under vacuum indicates that ADN initiated the interaction of NC with ADN. Compared to gas products of NC or ADN, two new kinds of oxidative gases O2 and HNO2 appeared for the NC/ADN mixture, while NH3 and aldehyde disappeared. The mixing of NC with ADN did not change the initial decomposition pathway of either, but NC made ADN more inclined to decompose into N2O, which resulted in the formation of oxidative gases O2 and HNO2. The thermal decomposition of ADN dominated the initial thermal decomposition stage of the NC/ADN mixture, followed by the oxidation of NC and the cation of ADN.
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BACKGROUND: Immunotherapy targeting PD-1/PD-L1 has been proven to be effective for cervical cancer treatment. To explore non-invasive examinations for assessing the PD-L1 status in cervical cancer, we performed a retrospective study to investigate the predictive value of 18F-FDG PET/CT. METHODS: The correlations between PD-L1 expression, clinicopathological characteristics and 18F-FDG PET/CT metabolic parameters were evaluated in 74 cervical cancer patients. The clinicopathological characteristics included age, histologic type, tumor differentiation, FIGO stage and tumor size. The metabolic parameters included maximum standard uptake (SUVmax), mean standard uptake (SUVmean), total lesion glycolysis (TLG) and tumor metabolic volume (MTV). RESULTS: In univariate analysis, SUVmax, SUVmean, TLG, tumor size and tumor differentiation were obviously associated with PD-L1 status. SUVmax (rs = 0.42) and SUVmean (rs = 0.40) were moderately positively correlated with the combined positive score (CPS) for PD-L1 in Spearman correlation analysis. The results of multivariable analysis showed that the higher SUVmax (odds ratio = 2.849) and the lower degree of differentiation (Odds Ratio = 0.168), the greater probability of being PD-L1 positive. The ROC curve analysis demonstrated that when the cut-off values of SUVmax, SUVmean and TLG were 10.45, 6.75 and 143.4, respectively, the highest accuracy for predicting PD-L1 expression was 77.0%, 71.6% and 62.2%, respectively. The comprehensive predictive ability of PD-L1 expression, assessed by combining SUVmax with tumor differentiation, showed that the PD-L1-negative rate was 100% in the low probability group, whereas the PD-L1-positive rate was 84.6% in the high probability group. In addition, we also found that the H-score of HIF-1α was moderately positively correlated with PD-L1 CPS (rs = 0.51). CONCLUSIONS: The SUVmax and differentiation of the primary lesion were the optimum predictors for PD-L1 expression in cervical cancer. There was a great potential for 18F-FDG PET/CT in predicting PD-L1 status and selecting cervical cancer candidates for PD1/PD-L1 immune checkpoint therapy.
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Nanoscale composite energetic materials (CEMs) based on oxidizer and fuel have potential advantages in energy adjustment and regulation through oxygen balance (OB) change. The micro- and nanosized fibers based on nano nitrocellulose (NC)-ammonium dinitramide (ADN) were prepared by the electrospinning technique, and the morphology, thermal stability, combustion behaviors, and mechanical sensitivity of the fibers were characterized by means of scanning electron microscope (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), gas pressure measurement of thermostatic decomposition, laser ignition, and sensitivity tests. The results showed that the prepared fibers with fluffy 3D macrostructure were constructed by the overlap of micro/nanofibers with the energetic particles embedded in the NC matrix. The first exothermic peak temperature (Tp) of the samples containing ADN decreased by 10.1 °C at most compared to that of ADN, and the pressure rise time of all the samples containing ADN moved forward compared to that of the sample containing NC only. Furthermore, ADN can decrease the ignition delay time of NC-based fibers under atmosphere at room temperature from 33 ms to 9 ms and can enhance the burning intensity of NC-based fibers under normal pressure. In addition, compared to the single high explosive CL-20 or RDX, the mechanical sensitivities of the composite materials containing high explosive CL-20 or RDX were much decreased. The positive oxygen balance of ADN and the intensive interactions between ADN and NC can reduce the ignition delay time and promote the burning reaction intensity of NC-based composite fibers, while the mechanical sensitivities of composite fibers could be improved.
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In the field of energy-containing materials, the modification of nanoaluminum powders has been widely studied. However, in modified experimental design, the lack of theoretical prediction usually leads to long experimental cycles and high resource consumption. To this end, this study evaluated the process and effect of dopamine (PDA)- and polytetrafluoroethylene (PTFE)-modified nanoaluminum powders based on molecular dynamics (MD). Through the calculation of the coating stability, compatibility, and oxygen barrier performance of the modified material, the modification process and effect were explored from a microscopic point of view. The results showed that the adsorption of PDA on the nanoaluminum was the most stable, and the binding energy was 463.03 kcal·mol-1. PDA and PTFE with different ratios are compatible systems at 350 K, and the best compatibility ratio is 10 wt % PTFE/90 wt % PDA. The 90 wt % PTFE/10 wt % PDA bilayer model has the best barrier performance for oxygen molecules in a wide temperature range. The calculated results of the coating stability agree with the experiments, and it is pointed out that it is feasible to evaluate the modification effect in advance by MD simulation. In addition, the simulation results concluded that the double-layered PDA and PTFE have better oxygen barrier properties. Compatibility can be used only to determine whether phase separation occurs between mixtures and is not directly related to the dense mixing of polymers and the barrier properties of small gas molecules. The simulation provided in this article can predict the experimental results and provide theoretical guidance for coating modification experiments in order to reduce unnecessary experiments, shorten the experimental cycle, and reduce costs.
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Studying how to improve the performance of illuminating agents to meet the requirements of ammunition miniaturization of great importance. In this study, a simple method for increasing light radiation intensity through the adding of metal oxides was developed and tested. Results revealed that the metal oxides had a very strong effect on the light radiation intensity of the reaction system. Optical radiation intensity increased by 17.8%, - 5.4% and 25.9% after the addition 5% of MgO, Al2O3 and BaO to the Ba(NO3)2/Mg reaction system, respectively. This phenomenon may be related to the light radiation characteristics and reactivity of the metal oxide itself, as well as the temperature at which the added metal oxide can be excited to radiate light intensity.
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The effects of different types of nano-sized metal particles, such as aluminum (nAl), zirconium (nZr), titanium (nTi), and nickel (nNi), on the properties of a variety of solid rocket propellants (composite, fuel-rich, and composite modified double base (CMDB)) were analyzed and compared with those of propellants loaded with micro-sized Al (mAl) powder. Emphasis was placed on the investigation of burning rate, pressure exponent (n), and hazardous properties, which control whether a propellant can be adopted in solid rocket motors. It was found that nano-sized additives can affect the combustion behavior and increase the burning rate of propellants. Compared with the corresponding micro-sized ones, the nano-sized particles promote higher impact sensitivity and friction sensitivity. In this paper, 101 references are enclosed.
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The reactions of the concerted HO2 elimination from alkyl peroxy radicals and the ß-scission of the C-OOH bond from hydroperoxy alkyl radicals, which lead to the formation of olefins and HO2 radicals, are two important reaction classes that compete with the second O2 addition step of hydroperoxy alkyl radicals, which are responsible for the chain branching in the low-temperature oxidation of normal alkyl cycloalkanes. These two reaction classes are also believed to be responsible for the negative temperature coefficient behavior due to the formation of the relatively unreactive HO2 radical, which has the potential to inhibit ignition of normal alkyl cycloalkanes. In this work, the kinetics of the above two reaction classes in normal alkyl cycloalkanes are studied, where reactions in the concerted elimination class are divided into subclasses depending upon the types of carbons from which the H atom is eliminated and the positions of the reaction center (on the alkyl side chain or on the cycle), and the reactions in the ß-scission reaction class are divided into subclasses depending upon the types of the carbons on which the radical is located and the positions of the reaction center. Energy barriers by using quantum chemical methods at the CBS-QB3 level, high-pressure-limit rate constants by using canonical transition state theory, and pressure-dependent rate constants at pressures from 0.01 to 100 atm by using Rice-Ramsberger-Kassel-Marcus/Master Equation theory are calculated for a representative set of reactions from methyl cyclohexane to n-butyl cyclohexane in each subclass, from which high-pressure-limit rate rules and pressure-dependent rate rules for each subclass are derived from the average rate constants of reactions within each subclass. A comparison of the rate constants for the reactions in the two reaction classes calculated in this work is made with the rate constants of the same reactions from available mechanisms published in the literature, where most of the rate constants are approximately estimated from analogous reactions in alkanes or small alkyl cyclohexanes, and it is found that a large difference may exist between them, indicating that the present work, which provides more accurate kinetic parameters and reasonable rate rules for these reaction classes, can be helpful to construct higher-accuracy mechanism models for normal alkyl cyclohexane combustion.
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The hydroperoxy alkyl radicals are important intermediates in the low-temperature combustion for normal-alkyl cycloalkanes, and the cyclization reactions of hydroperoxy alkyl radicals to form cyclic ethers are responsible for a major fraction of the OH formation, which has the potential to promote ignition. In most of the previous modeling studies for normal-alkyl cycloalkane combustion, the kinetic data of the cyclization reactions in the detailed combustion mechanism were mainly taken from the analogous reactions in cyclohexane, methyl cyclohexane, and alkanes in published literature studies. In this work, the kinetics of the cyclization reaction class of hydroperoxy alkyl radicals in normal-alkyl cycloalkanes is studied, where the reaction class is divided into subclasses depending upon the ring size of the transition states, the types of the carbons on which the -OOH site is located and the types of the carbons on which the radical site is located, and the positions of the cyclization (on the alkyl side chain, on the cycle, or between the alkyl side chain and the cycle). Energy barriers and high-pressure-limit site rate constants and pressure-dependent rates for reactions in all subclasses are calculated, and rate rules for all subclasses are developed. The high-pressure-limit rate constants are determined from CBS-QB3 electronic structure calculations combined with canonical transition-state theory calculations, and pressure-dependent rate constants are calculated by using the Rice-Ramsberger-Kassel-Marcus/Master Equation theory at pressures varying from 0.01 to 100 atm. Comparisons of the rate constants for cyclization reactions of hydroperoxy alkyl cyclohexylperoxy radicals calculated in this work with the values of the corresponding reactions in some of the popular combustion mechanisms show that it is unreasonable to use the kinetic data of analogous reactions in alkanes, cyclohexanes, or smaller normal-alkyl cyclohexanes. Therefore, the accurate kinetic calculations and the construction of rate rules for normal-alkyl cycloalkanes are necessary and significant for the reliable modeling of the low-temperature combustion of normal-alkyl cyclohexanes.
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As a hot research topic, nano-scale energetic materials have recently attracted much attention in the fields of propellants and explosives. The preparation of different types of nano-sized energetic materials were carried out, and the effects of nano-sized energetic materials (nEMs) on the properties of solid propellants and explosives were investigated and compared with those of micro-sized ones, placing emphasis on the investigation of the hazardous properties, which could be useable for solid rocket nozzle motor applications. It was found that the nano-sized energetic materials can decrease the impact sensitivity and friction sensitivity of solid propellants and explosives compared with the corresponding micro-sized ones, and the mechanical sensitivities are lower than that of micro-sized particles formulation. Seventy-nine references were enclosed.
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Based on molecular dynamic method, densities, mechanical behavior and mechanical performance of P(BAMO/ AMMO) (Polymer 1) and two novel modified P(BAMO/AMMO) (Polymer 2: containing amino group, Polymer 3: containing nitro group), and their effects on mechanical properties of four energetic materials are investigated, the main results are as follow: Polymer 2 (1.235 g/cm3, 240 ± 5 K) and Polymer 3: 1.281 g/cm3, 181 ± 3 K) possess higher densities and lower glass transition temperatures than Polymer 1 (1.229 g/cm3, 247 ± 4 K). The modification makes Polymer 1 difficult to expand, improves its mechanical properties, but has few effect on its diffusion coefficient at same temperature and state. In addition, three binders are compatible with TNT, HMX and CL-20, and may react with DNTF. All polymers particularly improve rigidity of four energetic materials, and enhance their ductility except Polymer 2 on TNT. The ability of Polymer 2 and Polymer 3 improving rigidity (except Polymer 3 on HMX) and ductility of TNT and HMX is inferior to that of Polymer 1, but it is contrary for CL-20 and DNTF (except Polymer 2 on rigidity of DNTF). Moreover, Polymer 2-based interfacial crystals exhibit higher rigidity than Polymer 3-based interfacial crystals.
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The cocrystallization of high-energy explosives has attracted great interests since it can alleviate to a certain extent the power-safety contradiction. 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaaza-isowurtzitane (CL-20), one of the most powerful explosives, has attracted much attention for researchers worldwide. However, the disadvantage of CL-20 has increased sensitivity to mechanical stimuli and cocrystallization of CL-20 with other compounds may provide a way to decrease its sensitivity. The intermolecular interaction of five types of CL-20-based cocrystal (CL-20/TNT, CL-20/HMX, CL-20/FOX-7, CL-20/TKX-50 and CL-20/DNB) by using molecular dynamic simulation was reviewed. The preparation methods and thermal decomposition properties of CL-20-based cocrystal are emphatically analyzed. Special emphasis is focused on the improved mechanical performances of CL-20-based cocrystal, which are compared with those of CL-20. The existing problems and challenges for the future work on CL-20-based cocrystal are discussed.
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Compuestos Aza/química , Sustancias Explosivas/química , Compuestos Heterocíclicos/química , Azocinas/química , Cristalización , Etilenos , Conformación Molecular , Simulación de Dinámica Molecular , Nitrocompuestos , Relación Estructura-Actividad , Trinitrotolueno/químicaRESUMEN
As one of the new types of functional materials, nano-sized composite energetic materials (nano-CEMs) possess many advantages and broad application prospects in the research field of explosives and propellants. The recent progress in the preparation and performance characterization of Al-based nano-CEMs has been reviewed. The preparation methods and properties of Al-based nano-CEMs are emphatically analyzed. Special emphasis is focused on the improved performances of Al-based nano-CEMs, which are different from those of conventional micro-sized composite energetic materials (micro-CEMs), such as thermal decomposition and hazardous properties. The existing problems and challenges for the future work on Al-based nano-CEMs are discussed.
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Glycogen synthase kinase-3ß (GSK-3ß) is a ubiquitously expressed serine/threonine kinase involved in a variety of functions ranging from the control of glycogen metabolism to transcriptional regulation. We recently demonstrated that GSK-3ß inhibition triggered ASK1-JNK-dependent apoptosis in human hepatocellular carcinoma (HCC) cells. However, the comprehensive picture of downstream GSK-3ß-regulated pathways/functions remains elusive. In this study, we showed that GSK-3ß was aberrantly activated in HCC. Pharmacological inhibition and genetic depletion of GSK-3ß suppressed the growth and induced caspase-dependent apoptosis in HCC cells. In addition, GSK-3ß inhibition-induced apoptosis through downregulation of c-FLIPL in HCC, which was caused by biogenesis of functional lysosomes and subsequently c-FLIPL translocated to lysosome for degradation. This induction of the lysosome-dependent c-FLIPL degradation was associated with nuclear translocation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis. Moreover, GSK-3ß inhibition-induced TFEB translocation acts through activation of AMPK and subsequently suppression of mTOR activity. Thus our findings reveal a novel mechanism by which inhibition of GSK-3ß promotes lysosome-dependent degradation of c-FLIPL. Our study shows that GSK-3ß may become a promising therapeutic target for HCC.
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Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/genética , Proteínas del Citoesqueleto/genética , Lisosomas/metabolismo , Proteínas Nucleares/genética , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Secuencia de Aminoácidos , Apoptosis/efectos de los fármacos , Apoptosis/genética , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Caspasa 3/genética , Caspasa 3/metabolismo , Línea Celular Tumoral , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Proteínas del Citoesqueleto/antagonistas & inhibidores , Proteínas del Citoesqueleto/metabolismo , Citosol/efectos de los fármacos , Citosol/metabolismo , Regulación de la Expresión Génica , Células Hep G2 , Humanos , Lisosomas/efectos de los fármacos , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/metabolismo , Estabilidad Proteica , Proteolisis , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Tiazoles/farmacología , Urea/análogos & derivados , Urea/farmacologíaRESUMEN
To discover small-molecule cancer immunotherapy candidates through targeting Indoleamine 2,3-dioxygenase 1 (IDO1), twenty-five new berberine (BBR) derivatives defined with substituents on position 3 or 9 were synthesized and examined for repression of IFN-γ-induced IDO1 promoter activities. Structure-activity relationship (SAR) indicated that large volume groups at the 9-position might be beneficial for potency. Among them, compounds 2f, 2i, 2n, 2o and 8b exhibited increased activities, with inhibition rate of 71-90% compared with BBR. Their effects on IDO1 expression were further confirmed by protein level as well. Furthermore, compounds 2i and 2n exhibited anticancer activity by enhancing the specific lysis of NK cells to A549 through IDO1, but not cytotoxicity. Preliminary mechanism revealed that both of them inhibited IFN-γ-induced IDO1 expression through activating AMPK and subsequent inhibition of STAT1 phosphorylation. Therefore, compounds 2i and 2n have been selected as IDO1 modulators for small-molecule cancer immunotherapy for next investigation.
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Berberina/farmacología , Inmunoterapia , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Neoplasias Pulmonares/terapia , Berberina/síntesis química , Berberina/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Neoplasias Pulmonares/metabolismo , Estructura Molecular , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Targeting the autophagic pathway is currently regarded as an attractive strategy for cancer drug discovery. Our previous work showed that IMB-6G is a novel N-substituted sophoridinic acid derivative with potent cytotoxicity against tumor cells, yet the effect of IMB-6G on autophagy and pancreatic cancer cell death remains unknown. Here, we show that IMB-6G inhibits the growth of MiaPaCa-2 and HupT-3 pancreatic cancer cells and induces caspase-mediated apoptosis, which is correlated with an accumulation of autophagic vacuoles. IMB-6G promotes autophagosome accumulation from the early stage of treatment but blocks autophagic flux in the degradation stage, mainly through attenuation of lysosomal cathepsin activity in pancreatic cancer cells. Moreover, IMB-6G triggers lysosomal membrane permeabilization (LMP), followed by cathepsin B/CTSB and cathepsin D/CTSD release from lysosomes into the cytoplasm. Inhibition of autophagosome formation with siRNA against autophagy protein 5 (Atg5) attenuates IMB-6G-induced LMP and apoptosis. Furthermore, cathepsin inhibitors relieve IMB-6G-induced apoptosis as well. Altogether, our findings demonstrate that IMB-6G is a novel autophagy inhibitor, which induces autophagy-dependent apoptosis through autophagosomal-cathepsin axis in pancreatic cancer cells and indicate the potential value of IMB-6G as a novel antitumor drug candidate.
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Antineoplásicos/farmacología , Apoptosis , Autofagia , Lisosomas/efectos de los fármacos , Compuestos de Mostaza Nitrogenada/farmacología , Neoplasias Pancreáticas/metabolismo , Proteína 5 Relacionada con la Autofagia/genética , Proteína 5 Relacionada con la Autofagia/metabolismo , Catepsinas/metabolismo , Línea Celular Tumoral , Humanos , Lisosomas/metabolismoRESUMEN
Sophoridinic acid derivatives have received considerable attentions for their potencies in cancer therapy. IMB-6G is a novel N-substituted sophoridinic acid derivative with potent cytotoxicity against tumor cells. In the present study, we explored the antitumor abilities of IMB-6G in human hepatocellular carcinoma (HCC) cells and investigated the underlying mechanisms. We found that IMB-6G inhibited cell growth and induced mitochondrial-dependent apoptosis in HepG2 and SMMC7721 cells. Analyses of the molecular mechanism of IMB-6G-induced apoptosis indicated IMB-6G induced endoplasmic reticulum (ER) stress activation. Incubation of HCC cells with IMB-6G induced increase in Bip and CHOP levels, which precede induction of apoptosis. Further study showed IMB-6G activated IRE1α and PERK pathways but did not stimulated ATF6 pathway in HCC cells. Moreover, silencing of IRE1α dramatically abrogated IMB-6G-induced pro-apoptotic ASK1-JNK signaling. Importantly, interruption of CHOP rendered HCC cells sensitive to IMB-6G-induced apoptosis via inactivation of Bim, PUMA and Bax. Thus, the IRE1α-ASK1 and PERK-CHOP pathways may be a novel molecular mechanism of IMB-6G-induced apoptosis. Collectively, our study demonstrates that IMB-6G induces ER stress-mediated apoptosis by activating IRE1α and PERK pathways. Our findings provide a rationale for the potential application of IMB-6G in HCC therapy.
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Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/patología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Endorribonucleasas/metabolismo , Compuestos de Mostaza Nitrogenada/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , eIF-2 Quinasa/metabolismo , Antineoplásicos/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Proliferación Celular/efectos de los fármacos , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , MAP Quinasa Quinasa Quinasa 5/metabolismo , Compuestos de Mostaza Nitrogenada/química , Transducción de Señal , Factor de Transcripción CHOP/metabolismo , Células Tumorales CultivadasRESUMEN
OBJECTIVE: To investigate the safety and efficacy of percutaneous incisional needle biopsy (PINB) in the parapharyngeal region under CT guide for highly suspicious nasopharyngeal carcinoma (NPC) or recurrence of NPC after radiotherapy. METHODS: PINB under CT guide was performed in 32 highly suspicious NPC or recurrence of NPC after radiotherapy through three puncture routes: posterolateral maxillary sinus fatty area, mandibular fossa area, and anterior-mastoid area. Specimens were fixed by 95% alcohol and then underwent pathologic examination. RESULTS: CT guided PINB was successfully performed in every patients with a technical successful rate of 100%. Definitive histopathologic diagnosis was obtained in 30 patients: squamous-cell carcinoma 21, undifferentiated carcinoma 5 and adenocarcinoma 4. The remaining two negative cases were confirmed as fibrosis after radiotherapy. Complications included persistent bleeding of puncture point in one patient and bloody sputum in 3 patients which subsided after symptomatic management. None of these patients was found to have symptoms of nerve injury caused by PINB procedure. CONCLUSION: The CT guided percutaneous incisional needle biopsy in parapharyngeal region through the above three puncture routes for highly suspicious nasopharyngeal carcinoma is safe, rapid and effective.