RESUMEN
PURPOSE: Despite the generally favourable prognoses observed in patients with ALK-positive non-small cell lung cancer (NSCLC), there remains significant variability in clinical outcomes. The objective of this study is to enhance patient stratification by examining both the specific sites of gene fusion and the presence of co-occurring mutations. METHODS: We collected retrospective clinical and pathological data on ALK-positive patients with locally advanced or metastatic disease. ALK fusion variants and concomitant mutations were identified through next-generation sequencing technology. We then assessed treatment efficacy via tumor response and survival metrics. RESULTS: This study included a total of 59 patients, with 49 harboring echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusions and 10 presenting with rare fusions. The median follow-up period was 33 months. Clinical outcomes between non-EML4-ALK and EML4-ALK patients were comparable. Among the EML4-ALK cohort, patients with longer variants (v1, v2, v8) demonstrated superior progression-free survival (PFS) (median PFS: 34 months vs. 11 months; hazard ratio [HR]: 2.28; P = 0.05) compared to those with shorter variants (v3, v5). Furthermore, patients treated with second-generation ALK inhibitors (ALKi) displayed a progression-free survival advantage (median PFS: not reached [NR] vs. 9 months; HR: 5.37; P = 0.013). Baseline TP53 co-mutation were linked with a substantially shorter OS (median OS,37 months vs. NR; HR 2.74; P = 0.047). CONCLUSIONS: In ALK+ NSCLC, longer EML4-ALK variants correlate with improved prognosis and enhanced response to second-generation ALKi, while TP53 co-mutations indicate a negative prognosis.
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Quinasa de Linfoma Anaplásico , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Mutación , Proteínas de Fusión Oncogénica , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Quinasa de Linfoma Anaplásico/genética , Estudios Retrospectivos , Anciano , Adulto , Proteínas de Fusión Oncogénica/genética , Proteína p53 Supresora de Tumor/genética , Supervivencia sin Progresión , Pronóstico , China , Pueblos del Este de AsiaRESUMEN
PURPOSE: This study aimed to identify the impact of epidermal growth factor receptor (EGFR) T790M mutations on clinical characteristics and prognosis. METHODS: Retrospective analyses were conducted on the differences on clinicopathological features and prognosis between primary and acquired T790M mutations. Subgroup analyses were performed for primary T790M coexisting with other mutations. RESULTS: Patients with primary T790M mutations showed a 60.53% (23/38) incidence of concurrent L858R mutations, 18.42% (7/38) for 19del mutations and a 21.05% (8/38) occurrence of brain metastases. Conversely, those with acquired T790M mutations demonstrated respective frequencies of 36.53% (61/167), 58.68% (98/167) and 44.31% (74/167), with all comparisons yielding p < 0.05. The median overall survival differed significantly between the two groups, with a duration of 33 months for patients with primary T790M mutations as compared to 48 months for those with acquired mutations (p = 0.030). Notably, among patients with L858R co-mutations, when treated with third-generation EGFR-TKIs, those with acquired T790M mutations experienced a significantly prolonged median time to treatment failure compared to those with primary mutations (17 months vs. 9 months, p = 0.009). CONCLUSION: Patients with primary T790M have unique molecular features and had worse prognosis compared with acquired T790M. Resistance to third-generation EGFR-TKIs seems to be associated with the presence of EGFR co-mutations.
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Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Mutación , Humanos , Receptores ErbB/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Masculino , Femenino , Estudios Retrospectivos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Pronóstico , Persona de Mediana Edad , Anciano , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/mortalidad , Anciano de 80 o más Años , Inhibidores de Proteínas Quinasas/uso terapéutico , Tasa de SupervivenciaRESUMEN
BACKGROUND: Osteoporosis attacks approximately 10% of the population worldwide. Sika Deer (Cervus nippon), one of China's precious traditional medicinal animals, has been widely recorded in ancient Chinese medical books and claimed for centuries to have numerous medical benefits including bone strengthening. This study aimed to find the use of Sika Deer bone in treating osteoporosis according to traditional records and to investigate the protective effect of Sika Deer bone polypeptide extract on glucocorticoidinduced osteoporosis (GIOP) in rats. RESULTS: Sika Deer bone polypeptide extract could increase serum Ca2+ and BGP, decrease serum P3+, ALP, PTH, and CT, but had no effect on serum NO in rats with GIOP. The immunohistochemical iNOS results of the rats' distal femur were negative in each group. Besides the model group, the eNOS color reaction in osteoblasts was strongly positive in the other three groups. CONCLUSIONS: Sika Deer bone polypeptide extract can improve pathological changes in the microstructure and stimulate the expression of eNOS in osteoblasts. The protective effect on bone might be mediated by eNOS-dependent NO generation.
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Animales , Masculino , Ratas , Osteoporosis/prevención & control , Péptidos/farmacología , Huesos/metabolismo , Ciervos , Osteoblastos , Dexametasona , Ratas Wistar , Óxido Nítrico Sintasa de Tipo III/efectos de los fármacosRESUMEN
The development of chemotherapy resistance significantly impairs the efficiency of chemotherapy, but the underlying mechanisms of chemotherapy resistance in gastric cancer (GC) are complicated and still need to be further explored. Here, we aimed to reveal the effects of miR-4290/PDK1 (pyruvate dehydrogenase kinase 1) axis on chemotherapy resistance of GC in vitro. The expression patterns of miR-4290 in GC tissues and cell lines were determined by real-time quantitative PCR. Kaplan-Meier was used to assess the relationship between miR-4290 expression levels and patients' overall survival. CCK-8 and flow cytometry technologies were applied to detect cell proliferation and apoptosis. The luciferase gene reporter assay was used to evaluate the interaction between miR-4290 and PDK1. miR-4290 was lowly expressed in GC tissues and cell lines, which was closely associated with the shorter overall survival of GC patients. miR-4290 mimics significantly inhibited cell proliferation and induced cell apoptosis, as well as induced a significant reduction in the expression of PDK1. Moreover, miR-4290 significantly inhibited glycolysis and decreased the IC50 value to cisplatin in SGC7901 cells, whereas these effects were abolished and cell apoptosis was promoted when PDK1 was overexpressed. In conclusion, this study revealed that miR-4290 suppressed PDK1-mediated glycolysis to enhance the sensitivity of GC cells to cisplatin.
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Cisplatino/farmacología , Resistencia a Antineoplásicos/genética , Glucólisis/genética , MicroARNs/metabolismo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Neoplasias Gástricas/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica , Humanos , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , TransfecciónRESUMEN
The development of chemotherapy resistance significantly impairs the efficiency of chemotherapy, but the underlying mechanisms of chemotherapy resistance in gastric cancer (GC) are complicated and still need to be further explored. Here, we aimed to reveal the effects of miR-4290/PDK1 (pyruvate dehydrogenase kinase 1) axis on chemotherapy resistance of GC in vitro. The expression patterns of miR-4290 in GC tissues and cell lines were determined by real-time quantitative PCR. Kaplan-Meier was used to assess the relationship between miR-4290 expression levels and patients' overall survival. CCK-8 and flow cytometry technologies were applied to detect cell proliferation and apoptosis. The luciferase gene reporter assay was used to evaluate the interaction between miR-4290 and PDK1. miR-4290 was lowly expressed in GC tissues and cell lines, which was closely associated with the shorter overall survival of GC patients. miR-4290 mimics significantly inhibited cell proliferation and induced cell apoptosis, as well as induced a significant reduction in the expression of PDK1. Moreover, miR-4290 significantly inhibited glycolysis and decreased the IC50 value to cisplatin in SGC7901 cells, whereas these effects were abolished and cell apoptosis was promoted when PDK1 was overexpressed. In conclusion, this study revealed that miR-4290 suppressed PDK1-mediated glycolysis to enhance the sensitivity of GC cells to cisplatin.
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Humanos , Neoplasias Gástricas/metabolismo , Cisplatino/farmacología , Resistencia a Antineoplásicos/genética , MicroARNs/metabolismo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , Glucólisis/genética , Transfección , Regulación Neoplásica de la Expresión Génica , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Reacción en Cadena en Tiempo Real de la Polimerasa , Citometría de Flujo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/genéticaRESUMEN
The aim of this study was to evaluate the impact and mechanism of co-blocking of costimulatory signals CD28-B7-CD40-CD40L during immune allograft rejection. Forty-eight recipient rabbits were prepared as a high-risk corneal allograft model. After surgery, the animals were randomly divided into: control group, MR1 group, anti-B7 group, and co-blocking group (n=12, each group). Subconjunctival injection was first performed on the allograft surgery day until post-surgery day five. Four weeks later, or when immune rejection occurred, the cornea was sampled to detect and analyze the gene spectrum. The survival time in the co-blocking group was significantly longer than that in the other three groups (p < 0.05). Gene expression analysis revealed that the expression of genes associated with immune rejection, interleukin (IL)-1α, IL-1ß, intercellular cell adhesion molecule-1, and IL-2 was down-regulated in the co-blocking group, while IL-10 was up-regulated, but the changes in nuclear factor-κB and interferon-γ were not significant. In conclusion, the co-blocking of costimulatory signals can significantly reduce genes that promote corneal allograft rejection. The inhibition of corneal allograft rejection gene expression was significantly enhanced. These gene expression results can explain the conclusion of previous work at the genetic level.
RESUMEN
Obesity and its consequent type 2 diabetes are significant threats to global health. Emerging evidence indicates that ginsenosides from ginseng (Panax ginseng) have anti-diabetic activity. We hypothesized that ginsenosides Rg1 could suppress dietary-induced obesity and improve obesity-related glucose metabolic disorders. Our results showed that ginsenoside Rg1 attenuated dietary-induced body weight gain and fat accumulation in white adipocyte tissue of mice fed a high-fat diet. Furthermore, we found that ginsenosides Rg1 not only decreased fasting glucose concentration and the 2-h postprandial glucose concentration, but also improved insulin resistance and glucose intolerance in those mice. Ginsenoside Rg1 also activated the AMPK pathway in vitro and in vivo and increased plasma membrane translocation of GLUT4 in C2C12 skeletal muscle cells. In conclusion, our observations suggested that ginsenoside Rg1 inhibited dietary-induced obesity and improved obesity-related insulin resistance and glucose intolerance by activation of the AMPK pathway.
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Dieta Alta en Grasa , Ginsenósidos/farmacología , Trastornos del Metabolismo de la Glucosa/prevención & control , Obesidad/complicaciones , Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Trastornos del Metabolismo de la Glucosa/etiología , Trastornos del Metabolismo de la Glucosa/metabolismo , Resistencia a la Insulina , Masculino , Ratones , Obesidad/metabolismo , Transducción de Señal , Factores de TiempoRESUMEN
Obesity and its consequent type 2 diabetes are significant threats to global health. Emerging evidence indicates that ginsenosides from ginseng (Panax ginseng) have anti-diabetic activity. We hypothesized that ginsenosides Rg1 could suppress dietary-induced obesity and improve obesity-related glucose metabolic disorders. Our results showed that ginsenoside Rg1 attenuated dietary-induced body weight gain and fat accumulation in white adipocyte tissue of mice fed a high-fat diet. Furthermore, we found that ginsenosides Rg1 not only decreased fasting glucose concentration and the 2-h postprandial glucose concentration, but also improved insulin resistance and glucose intolerance in those mice. Ginsenoside Rg1 also activated the AMPK pathway in vitro and in vivo and increased plasma membrane translocation of GLUT4 in C2C12 skeletal muscle cells. In conclusion, our observations suggested that ginsenoside Rg1 inhibited dietary-induced obesity and improved obesity-related insulin resistance and glucose intolerance by activation of the AMPK pathway.
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Animales , Masculino , Ratones , Dieta Alta en Grasa , Ginsenósidos/farmacología , Trastornos del Metabolismo de la Glucosa/prevención & control , Obesidad/complicaciones , Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Trastornos del Metabolismo de la Glucosa/etiología , Trastornos del Metabolismo de la Glucosa/metabolismo , Resistencia a la Insulina , Obesidad/metabolismo , Transducción de Señal , Factores de TiempoRESUMEN
PURPOSE:: To evaluate the effect of hyperin in cisplatin-induced liver injury in mice. METHODS:: Mice were pretreated with hyperin at doses of 25 mg/kg and 50 mg/kg, respectively, for six days, and intraperitoneal injection of cisplatin (40 mg/kg) was administrated one hour after the final intragastrication of hyperin. Twenty-four hours later, blood and liver were collected for further research. RESULTS:: A single injection of cisplatin (40 mg/kg) for 24 h significantly increased serum alanine and aspartate aminotransferases (ALT/AST) and gamma glutamyl transferase (GGT) activities, whileas hyperin reversed cisplatin-induced such increases. Liver histopathological examination further demonstrated the protection of hyperin against cisplatin-induced liver injury. Further results showed hyperin reversed cisplatin-induced the increase in content of malondialdehyde (MDA) and the decrease in level of total antioxidant capacity (T-AOC) in liver. Moreover, hyperin increased the levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), glutathione-s transferase (GST) in cisplatin-induced liver. CONCLUSION:: Hyperin inhibits cisplatin-induced hepatic oxidative stress, which contributes greatly to the amelioration of cisplatin-induced liver injury in mice.
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Antineoplásicos/efectos adversos , Antioxidantes/farmacología , Aspartato Aminotransferasas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Cisplatino/efectos adversos , Quercetina/análogos & derivados , gamma-Glutamiltransferasa/metabolismo , Alanina Transaminasa/metabolismo , Animales , Antioxidantes/uso terapéutico , Catalasa/análisis , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Cisplatino/antagonistas & inhibidores , Glutatión/análisis , Glutatión Peroxidasa/análisis , Glutatión Transferasa/análisis , Peroxidación de Lípido , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Masculino , Malondialdehído/análisis , Ratones Endogámicos ICR , Estrés Oxidativo/efectos de los fármacos , Quercetina/farmacología , Quercetina/uso terapéutico , Distribución Aleatoria , Valores de Referencia , Reproducibilidad de los Resultados , Superóxido Dismutasa/análisis , Resultado del TratamientoRESUMEN
Purpose: To evaluate the effect of hyperin in cisplatin-induced liver injury in mice. Methods: Mice were pretreated with hyperin at doses of 25 mg/kg and 50 mg/kg, respectively, for six days, and intraperitoneal injection of cisplatin (40 mg/kg) was administrated one hour after the final intragastrication of hyperin. Twenty-four hours later, blood and liver were collected for further research. Results: A single injection of cisplatin (40 mg/kg) for 24 h significantly increased serum alanine and aspartate aminotransferases (ALT/AST) and gamma glutamyl transferase (GGT) activities, whileas hyperin reversed cisplatin-induced such increases. Liver histopathological examination further demonstrated the protection of hyperin against cisplatin-induced liver injury. Further results showed hyperin reversed cisplatin-induced the increase in content of malondialdehyde (MDA) and the decrease in level of total antioxidant capacity (T-AOC) in liver. Moreover, hyperin increased the levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), glutathione-s transferase (GST) in cisplatin-induced liver. Conclusion: Hyperin inhibits cisplatin-induced hepatic oxidative stress, which contributes greatly to the amelioration of cisplatin-induced liver injury in mice.(AU)
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Animales , Ratas , Ratones/lesiones , Ratones/fisiología , Enfermedad Hepática Inducida por Sustancias y Drogas/rehabilitación , Enfermedad Hepática Inducida por Sustancias y Drogas/veterinaria , Heparina/administración & dosificación , Estrés OxidativoRESUMEN
Abstract Purpose: To evaluate the effect of hyperin in cisplatin-induced liver injury in mice. Methods: Mice were pretreated with hyperin at doses of 25 mg/kg and 50 mg/kg, respectively, for six days, and intraperitoneal injection of cisplatin (40 mg/kg) was administrated one hour after the final intragastrication of hyperin. Twenty-four hours later, blood and liver were collected for further research. Results: A single injection of cisplatin (40 mg/kg) for 24 h significantly increased serum alanine and aspartate aminotransferases (ALT/AST) and gamma glutamyl transferase (GGT) activities, whileas hyperin reversed cisplatin-induced such increases. Liver histopathological examination further demonstrated the protection of hyperin against cisplatin-induced liver injury. Further results showed hyperin reversed cisplatin-induced the increase in content of malondialdehyde (MDA) and the decrease in level of total antioxidant capacity (T-AOC) in liver. Moreover, hyperin increased the levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), glutathione-s transferase (GST) in cisplatin-induced liver. Conclusion: Hyperin inhibits cisplatin-induced hepatic oxidative stress, which contributes greatly to the amelioration of cisplatin-induced liver injury in mice.
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Animales , Masculino , Quercetina/análogos & derivados , Aspartato Aminotransferasas/metabolismo , Cisplatino/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Antineoplásicos/efectos adversos , Antioxidantes/farmacología , Quercetina/uso terapéutico , Quercetina/farmacología , Valores de Referencia , Peroxidación de Lípido , Catalasa/análisis , Distribución Aleatoria , Reproducibilidad de los Resultados , Cisplatino/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacos , Alanina Transaminasa/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Glutatión/análisis , Glutatión Peroxidasa/análisis , Glutatión Transferasa/análisis , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Malondialdehído/análisis , Ratones Endogámicos ICR , Antioxidantes/uso terapéuticoRESUMEN
One Gram-negative, aerobic, motile, rod-shaped bacterium, designated as FH14T, was isolated from nodules of Phaseolus vulgaris grown in Hidalgo State of Mexico. Results based upon 16S rRNA gene (≥99.8 % similarities to known species), concatenated sequence (recA, atpD and glnII) analysis of three housekeeping genes (≤93.4 % similarities to known species) and average nucleotide identity (ANI) values of genome sequence (ranged from 87.6 to 90.0 % to related species) indicated the distinct position of strain FH14T within the genus Rhizobium. In analyses of symbiotic genes, only nitrogen fixation gene nifH was amplified that had nucleotide sequence identical to those of the bean-nodulating strains in R. phaseoli and R. vallis, while nodulation gene nodC gene was not amplified. The failure of nodulation to its original host P. vulgaris and other legumes evidenced the loss of its nodulation capability. Strain FH14T contained summed feature 8 (C18:1 ω6c/C18:1 ω7c, 59.96 %), C16:0 (10.6 %) and summed feature 2 (C12:0 aldehyde/unknown 10.928, 10.24 %) as the major components of cellular fatty acids. Failure to utilize alaninamide, and utilizing L-alanine, L-asparagine and γ-amino butyric acid as carbon source, distinguished the strain FH14T from the type strains for the related species. The genome size and DNA G+C content of FH14T were 6.94 Mbp and 60.8 mol %, respectively. Based on those results, a novel specie in Rhizobium, named Rhizobium hidalgonense sp. nov., was proposed, with FH14T (=HAMBI 3636T = LMG 29288T) as the type strain.