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In the published publication [...].
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Tumor cells stimulate local angiogenesis, resulting in their further multiplication and spread. Angiogenesis is a multifaceted process in which angiopoietins parti- cipate. Angiopoietin-1 (Ang-1) through its receptor Tie2 stimulates endothelial cell survival and the maintenance of the endothelial barrier. These phenomena can support tumour growth by promoting angiogenesis. On the other hand, overproduction of Ang-1 triggers endothelium stability and can lead to angiogenesis inhibition. Because of the ambiguous role of Ang-1, we decided to determine its clinical significance in patients with resectable NSCLC. In a group of 47 patients, tumours and the adjacent non-cancerous tissues were assessed for ANG-1 mRNA expression (using Q-RT-PCR analysis) and Ang-1 concentration (by enzyme-linked immunosorbent assay) together with clinical parameters and the five-year survival rate. ANG-1 expression and Ang-1 concentration were higher in tumour-free tissue, showing no differences between histological types of NSCLC, clinical stage or grading and seemed not to determine the five-year survival. ANG-1 expression and Ang-1 concentration in tumour and tumour-free tissues in patients with NSCLC seem not to be useful as factors supporting either diagnostics or prognosis.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Angiopoyetina 1/genética , Angiopoyetina 2/genética , Angiopoyetina 2/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neovascularización Patológica , Pronóstico , Receptor TIE-2/genética , Receptor TIE-2/metabolismoRESUMEN
By binding to the spliceosomal protein Snu66, the human ubiquitin-like protein Hub1 is a modulator of the spliceosome performance and facilitates alternative splicing. Small molecules that bind to Hub1 would be of interest to study the protein-protein interaction of Hub1/Snu66, which is linked to several human pathologies, such as hypercholesterolemia, premature aging, neurodegenerative diseases, and cancer. To identify small molecule ligands for Hub1, we used the interface analysis, peptide modeling of the Hub1/Snu66 interaction and the fragment-based NMR screening. Fragment-based NMR screening has not proven sufficient to unambiguously search for fragments that bind to the Hub1 protein. This was because the Snu66 binding pocket of Hub1 is occupied by pH-sensitive residues, making it difficult to distinguish between pH-induced NMR shifts and actual binding events. The NMR analyses were therefore verified experimentally by microscale thermophoresis and by NMR pH titration experiments. Our study found two small peptides that showed binding to Hub1. These peptides are the first small-molecule ligands reported to interact with the Hub1 protein.
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Empalme Alternativo , Empalmosomas , Humanos , Empalmosomas/metabolismo , Ubiquitinas/genética , Espectroscopía de Resonancia Magnética , Computadores , Unión Proteica , Ligandos , Sitios de UniónRESUMEN
The proteinprotein interaction of p53 and MDM2/X is a promising non genotoxic anticancer target. A rapid and efficient methodology was developed to synthesize the 2,30-bis(10H-indole) heterocyclic scaffold 2 as ester, acid and amide derivatives. Their binding affinity with MDM2 was evaluated using both fluorescence polarization (FP) assay and HSQC experiments, indicating good inhibition and a perfect starting point for further optimizations.
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Compuestos Heterocíclicos/química , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Sitios de Unión , Polarización de Fluorescencia , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/metabolismo , Indoles/química , Simulación del Acoplamiento Molecular , Dominios y Motivos de Interacción de Proteínas , Estructura Terciaria de Proteína , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Superior mesenteric artery syndrome is a condition caused by the compression of the third part of the duodenum between the superior mesenteric artery and the aorta. We present the clinical case of a patient, a female, 18 years old, with history of two days' evolution characterized by postprandial epigastric colic, accompanied by nausea and intractable vomiting. Applied conservative management was insufficient. The patient was successfully treated with open duodenojejunostomy.
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Síndrome de la Arteria Mesentérica Superior/diagnóstico , Síndrome de la Arteria Mesentérica Superior/cirugía , Adolescente , Duodenostomía , Femenino , Humanos , YeyunostomíaRESUMEN
Lung tissue is directly exposed to high oxygen pressure, as well as increased endogenous and exogenous oxidative stress. Reactive oxygen species (ROS) generated in these conditions play an important role in the initiation and promotion of neoplastic growth. In response to oxidative stress, the antioxidant activity increases and minimizes ROS-induced injury in experimental systems. The aim of the present study was to evaluate the activity of antioxidant enzymes, such as superoxide dismutase (SOD; isoforms: Cu/ZnSOD and MnSOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S-transferase (GST), along with the concentration of malondialdehyde (MDA) in tumor and adjacent noncancerous tissues of two histological types of NSCLC, i.e., adenocarcinoma and squamous cell carcinoma, collected from 53 individuals with surgically resectable NSCLC. MDA concentration was similar in tumors compared with adjacent noncancerous tissues. Tumor cells had low MnSOD activity, usually low Cu/ZnSOD activity, and almost always low catalase activity compared with those of the corresponding tumor-free lung tissues. Activities of GSH-related enzymes were significantly higher in tumor tissues, irrespective of the histological type of cancer. This pattern of antioxidant enzymes activity could possibly be the way by which tumor cells protect themselves against increased oxidative stress.
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Antioxidantes/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Neoplasias Pulmonares/enzimología , Proteínas de Neoplasias/metabolismo , Oxidorreductasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Femenino , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana EdadRESUMEN
USP2a is a deubiquitinating protease that rescues its target proteins from destruction by the proteasome by reversing the process of protein ubiquitination. USP2a shows oncogenic properties in vivo and has been found to be a specific activator of cyclin D1. Many types of cancers are addicted to cyclin D1 expression. Targeting USP2a is a promising strategy for cancer therapy but little progress has been made in the field of inhibition of USP2a. Using NMR-based fragment screening and biophysical binding assays, we have discovered small molecules that bind to USP2a. Iterations of fragment combination and structure-driven design identified two 5-(2-thienyl)-3-isoxazoles as the inhibitors of the USP2a-ubiquitin protein-protein interaction. The affinity of these molecules for the catalytic domain of USP2a parallels their ability to interfere with USP2a binding to ubiquitin in vitro. Altogether, our results establish the 5-(2-thienyl)-3-isoxazole pharmacophore as an attractive starting point for lead optimization.
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Endopeptidasas/metabolismo , Inhibidores Enzimáticos/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad , Ubiquitina TiolesterasaRESUMEN
USP2a is a deubiquitinase responsible for stabilization of cyclin D1, a crucial regulator of cell-cycle progression and a proto-oncoprotein overexpressed in numerous cancer types. Here we report that lithocholic acid (LCA) derivatives are inhibitors of USP proteins, including USP2a. The most potent LCA derivative, LCA hydroxyamide (LCAHA), inhibits USP2a, leading to a significant Akt/GSK3ß-independent destabilization of cyclin D1, but does not change the expression of p27. This leads to the defects in cell-cycle progression. As a result, LCAHA inhibits the growth of cyclin D1-expressing, but not cyclin D1-negative cells, independently of the p53 status. We show that LCA derivatives may be considered as future therapeutics for the treatment of cyclin D1-addicted p53-expressing and p53-defective cancer types.
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Ciclina D1/metabolismo , Endopeptidasas/metabolismo , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Ácido Litocólico/análogos & derivados , Dominio Catalítico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ciclina D1/antagonistas & inhibidores , Ciclina D1/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Cicloheximida/química , Cicloheximida/farmacología , Regulación hacia Abajo/efectos de los fármacos , Endopeptidasas/química , Endopeptidasas/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Células HCT116 , Humanos , Ácido Litocólico/farmacología , Células MCF-7 , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/deficiencia , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitina TiolesterasaRESUMEN
Telomerase, undetectable in normal somatic cells, plays a critical role in carcinogenesis of the majority of human tumors including lung carcinoma. The aim of our study was to determine human telomerase reverse transcriptase (hTERT) mRNA expression in patients with non-small cell lung cancer (NSCLC) in order to estimate its usefulness as diagnostic and/or prognostic factor. hTERT expression was analyzed in a group of 12 females and 28 males with NSCLC using Quantitative Real-Time Polymerase Chain Reaction (QRT-PCR method) in cancerous and non-cancerous lung tissues. Results were analyzed according to clinical data and one-, two-, and five-year survival rates. hTERT expression in the cancerous tissue was significantly higher than in the lung parenchyma free from neoplasm infiltration (p<0.05). There was no significant association between hTERT expression in the tumor tissue and age, gender, grading or clinical stage. A significant difference in hTERT expression between two types of histopathological patterns (adenocarcinoma and squamous cell carcinoma) was detected (p=0.01). No association between hTERT expression in NSCLC specimens and survival rates was found. hTERT mRNA detection by QRT-PCR in tumor and corresponding cancer-free tissues can be used as a diagnostic marker in patients with NSCLC, but seems not to be a prognostic factor.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Telomerasa/genética , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Anciano , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de SupervivenciaRESUMEN
The tumor suppressor protein p53, the "guardian of the genome", is inactivated in nearly all cancer types by mutations in the TP53 gene or by overexpression of its negative regulators, oncoproteins MDM2/MDMX. Recovery of p53 function by disrupting the p53-MDM2/MDMX interaction using small-molecule antagonists could provide an efficient nongenotoxic anticancer therapy. Here we present the syntheses, activities, and crystal structures of the p53-MDM2/MDMX inhibitors based on the 1,4,5-trisubstituted imidazole scaffold which are appended with aliphatic linkers that enable coupling to bioactive carriers. The compounds have favorable properties at both biochemical and cellular levels. The most effective compound 19 is a tight binder of MDM2 and activates p53 in cancer cells that express the wild-type p53, leading to cell cycle arrest and growth inhibition. Crystal structures reveal that compound 19 induces MDM2 dimerization via the aliphatic linker. This unique dimerization-binding mode opens new prospects for the optimization of the p53-MDM2/MDMX inhibitors and conjugation with bioactive carriers.
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Imidazoles/química , Imidazoles/farmacología , Mapas de Interacción de Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Simulación del Acoplamiento Molecular , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Unión Proteica/efectos de los fármacos , Multimerización de Proteína/efectos de los fármacosRESUMEN
INTRODUCTION: High telomerase activity has been detected in the majority of malignant neoplasms including lung cancer. The purpose of the study was to attempt to use telomerase activity as a prognostic factor in patients with non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: Telomerase activity was analyzed in 47 tissue specimens taken from patients with NSCLC. The control group consisted of 30 specimens of non-cancerous lung parenchyma. Telomerase activity was measured by means of the telomeric repeat amplification protocol (TRAP). RESULTS: Telomerase activity in the neoplastic tissue was significantly higher than in the lung parenchyma that was free from neoplastic infiltration. There was no significant association between telomerase activity and age, gender, tobacco smoking, histological type of the tumor, or staging (pTNM). No association was found between the level of telomerase activity in NSCLC specimens and the two-year survival rate of patients (p = 0.326). A higher level of telomerase activity in poorly differentiated tumors (G3) as compared to moderately differentiated tumors (G2) was detected (p = 0.008). A positive association was identified between telomerase activity in pulmonary parenchyma free from tumor infiltration and the presence of leukocyte infiltration (p = 0.0001). CONCLUSIONS: No association was found between the level of telomerase activity in NSCLC specimens and the two-year survival rate of patients. The study has revealed a positive association between telomerase activity and the grade of differentiation (G) in NSCLC.
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The p53 pathway is inactivated in almost all types of cancer by mutations in the p53 encoding gene or overexpression of the p53 negative regulators, Mdm2 and/or Mdmx. Restoration of the p53 function by inhibition of the p53-Mdm2/Mdmx interaction opens up a prospect for a nongenotoxic anticancer therapy. Here, we present the syntheses, activities, and crystal structures of two novel classes of Mdm2-p53 inhibitors that are based on the 3-pyrrolin-2-one and 2-furanone scaffolds. The structures of the complexes formed by these inhibitors and Mdm2 reveal the dimeric protein molecular organization that has not been observed in the small-molecule/Mdm2 complexes described until now. In particular, the 6-chloroindole group does not occupy the usual Trp-23 pocket of Mdm2 but instead is engaged in dimerization. This entirely unique binding mode of the compounds opens new possibilities for optimization of the Mdm2-p53 interaction inhibitors.
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4-Butirolactona/análogos & derivados , Mapas de Interacción de Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Pirroles/química , Pirroles/farmacología , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , 4-Butirolactona/química , 4-Butirolactona/farmacología , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Modelos Moleculares , Conformación Proteica , Multimerización de Proteína/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/química , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/química , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Cholelithiasis is diagnosed in 10% of the population of the USA and Western Europe. A rare but serious complication of cholelithiasis is the obstruction of the digestive tract caused by a gall-stone (Bernard syndrome). It can add up to 1-4% of the mechanical obstructions of a small intestine among the general population but it can result in nonstriangulational mechanical obstructions of a small intestine in 25% cases among the patients over the age of 65. 5 patients have undergone an operation due to a small intestine gall-stone ileus in years 2011-2013 (within 27 months) in the General Surgery Ward of the Beskid Oncology Center - Municipal Hospital. In 4 patients simple enterotomy with a gall-stone extraction was performed. In the fifth patient enterolitotomy was conducted together with cholecystectomy and fistulotomy.
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Cálculos Biliares/complicaciones , Cálculos Biliares/cirugía , Ileus/complicaciones , Ileus/cirugía , Obstrucción Intestinal/etiología , Obstrucción Intestinal/cirugía , Cálculos Biliares/diagnóstico , Humanos , Ileus/diagnóstico , Obstrucción Intestinal/diagnóstico , Factores de RiesgoRESUMEN
We report a case of patient with stage IIIb gastric cancer qualified for laparoscopy-assisted gastrectomy and our first impressions about this procedure. Total gastrectomy with complete omentectomy and extended lymphadenectomy (D2) was performed laparoscopically. The intestinal continuity was restored in a Roux-en-Y mode extracorporeally through the abdominal access system. The orogastric tube with anvil of the circular stapler was transorally introduced into the esophagus. Subsequently, intracorporeal stapling esophagojejunostomy was performed. There were no complications after the operation and the patient was discharged in good shape. Oncological radicality was sufficient and patient has undergone chemotherapy treatment.