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1.
Planta Med ; 88(11): 891-898, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34521132

RESUMEN

The lichen compound protolichesterinic acid (PA) has an anti-proliferative effect against several cancer cell lines of different origin. This effect cannot be explained by the known inhibitory activity of PA against 5- and 12-lipoxygenases. The aim was therefore to search for mechanisms for the anti-proliferative activity of PA. Two cancer cell lines of different origin, both sensitive to anti-proliferative effects of PA, were selected for this study, T-47D from breast cancer and AsPC-1 from pancreatic cancer. Morphological changes were assessed by transmission electron microscopy, HPLC coupled with TOF spectrometry was used for metabolomics, mitochondrial function was measured using the Agilent Seahorse XFp Real-time ATP assay and glucose/lactate levels by radiometry. Levels of glutathione, NADP/NADPH and reactive oxygen species [ROS] were measured by luminescence. Following exposure to PA both cell lines showed structural changes in mitochondria that were in line with a measured reduction in oxidative phosphorylation and increased glycolysis. These changes were more marked in T-47D, which had poorer mitochondrial function at baseline. PA was processed and expelled from the cells via the mercapturic pathway, which consumes glutathione. Nevertheless, glutathione levels were increased after 24 hours of exposure to PA, implying enhanced synthesis. Redox balance was not much affected and ROS levels were not increased. We conclude that PA is metabolically processed and expelled from cells, leading indirectly to increased glutathione levels with minimal effects on redox balance. The most marked effect was on mitochondrial structure and metabolic function implying that effects of PA may depend on mitochondrial fitness.


Asunto(s)
Líquenes , Neoplasias , 4-Butirolactona/análogos & derivados , Proliferación Celular , Glutatión/metabolismo , Líquenes/química , Oxidación-Reducción , Fosforilación Oxidativa , Especies Reactivas de Oxígeno/metabolismo
2.
Pharmacoepidemiol Drug Saf ; 28(4): 471-478, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30565786

RESUMEN

PURPOSE: Increased expression of Vacuolar-type H+ ATPases (V-ATPases), in the plasma membrane of cancer cells has been suggested to contribute to the development of aggressive cancer phenotypes by promoting acidic tumor microenvironments. Accumulating data suggest that proton pump inhibitors (PPIs) may elicit a chemopreventive effect via V-ATPase inhibition in some cancers, but evidence is still limited. Therefore, we aimed to explore a potential preventive role of PPIs in this study. METHODS: In this population-based case-control study, we identified incident cases of breast cancer (n = 1739), prostate cancer (n = 1897), and malignant melanoma (n = 385) in Iceland between 2005 and 2014 from the Icelandic Cancer Registry. We assessed varying levels of PPI use through record linkages to the Icelandic Medicines Registry. For each case, we selected up to 10 age-matched, sex-matched, and calendar-matched population controls using risk-set sampling. Using conditional logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) controlling for NSAID use. RESULTS: Adjusted ORs associated with ever use of PPIs were 1.03 (95% CI: 0.92-1.16) for breast cancer, 1.12 (95% CI: 1.00-1.25) for prostate cancer, and 0.84 (95% CI: 0.69-1.12) for malignant melanoma. Analyses of high use of PPIs (≥1000 DDDs) yielded ORs of 0.97 (95% CI: 0.78-1.19), 1.20 (0.99-1.47), and 0.59 (0.40-1.13) for breast cancer, prostate cancer, and malignant melanoma, respectively. Analyses of cumulative exposure to PPIs did not support a dose-response relationship for any of the three cancer types. CONCLUSIONS: Our findings do not support a chemopreventive effect of PPI use on breast cancer, prostate cancer, or malignant melanoma.


Asunto(s)
Neoplasias de la Mama/epidemiología , Melanoma/epidemiología , Neoplasias de la Próstata/epidemiología , Inhibidores de la Bomba de Protones/administración & dosificación , Neoplasias Cutáneas/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/prevención & control , Estudios de Casos y Controles , Femenino , Humanos , Islandia/epidemiología , Modelos Logísticos , Masculino , Melanoma/prevención & control , Persona de Mediana Edad , Oportunidad Relativa , Neoplasias de la Próstata/prevención & control , Sistema de Registros/estadística & datos numéricos , Factores de Riesgo , Neoplasias Cutáneas/prevención & control , Microambiente Tumoral/efectos de los fármacos , ATPasas de Translocación de Protón Vacuolares/antagonistas & inhibidores , ATPasas de Translocación de Protón Vacuolares/metabolismo , Adulto Joven
3.
Mar Drugs ; 15(2)2017 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-28241423

RESUMEN

Twenty-eight sponge specimens were collected at a shallow water hydrothermal vent site north of Iceland. Extracts were prepared and tested in vitro for cytotoxic activity, and eight of them were shown to be cytotoxic. A mass spectrometry (MS)-based metabolomics approach was used to determine the chemical composition of the extracts. This analysis highlighted clear differences in the metabolomes of three sponge specimens, and all of them were identified as Haliclona (Rhizoniera) rosea (Bowerbank, 1866). Therefore, these specimens were selected for further investigation. Haliclona rosea metabolomes contained a class of potential key compounds, the 3-alkyl pyridine alkaloids (3-APA) responsible for the cytotoxic activity of the fractions. Several 3-APA compounds were tentatively identified including haliclamines, cyclostellettamines, viscosalines and viscosamines. Among these compounds, cyclostellettamine P was tentatively identified for the first time by using ion mobility MS in time-aligned parallel (TAP) fragmentation mode. In this work, we show the potential of applying metabolomics strategies and in particular the utility of coupling ion mobility with MS for the molecular characterization of sponge specimens.


Asunto(s)
Alcaloides/toxicidad , Respiraderos Hidrotermales/química , Metaboloma/efectos de los fármacos , Poríferos/efectos de los fármacos , Poríferos/metabolismo , Piridinas/toxicidad , Alcaloides/química , Animales , Haliclona/química , Haliclona/metabolismo , Islandia , Metabolómica/métodos , Piridinas/química , Piridinas/metabolismo , Compuestos de Piridinio/química , Compuestos de Piridinio/metabolismo , Agua/química
4.
Invest New Drugs ; 30(2): 425-34, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-20960027

RESUMEN

Aurora kinases play a vital part in successful mitosis and cell division. Aberrant Aurora-A and -B expression is commonly seen in various types of tumors. Small molecule Aurora inhibitors have already entered clinical trials. Aurora-A amplification has been shown to be associated with breast tumors from BRCA2-mutation carriers and such patients might therefore be candidates for treatment with Aurora kinase inhibitors. There is a need to identify markers that can predict sensitivity to Aurora inhibition. In this study sensitivity to the inhibitor ZM447439 was tested on a panel of 15 non-malignant and malignant epithelial cell lines that differed with respect to BRCA2 and p53 status and related to level of Aurora kinase expression. The IC(50) value for cell survival ranged from 1.9-8.1 µM and was not related to presence or absence of BRCA2 mutation. The levels of Aurora-A and -B expression correlated with each other but sensitivity towards ZM447439 did not correlate with levels of Aurora-A and -B mRNA expression, alone. Cells treated with the Aurora kinase inhibitor completed mitosis but cytokinesis was inhibited resulting in polyploidy and multinucleation. Different levels of polyploidy could not be fully explained by defects in p53. Only cell lines with a combination of high Aurora-A and -B expression, BRCA2 mutation and p53 defects showed more sensitivity towards Aurora inhibition than other cell lines. In conclusion, BRCA2-mutated cells showed variable sensitivity towards Aurora kinase inhibition. The level of sensitivity could not be predicted by Aurora expression levels alone but BRCA2 mutated tumors with high Aurora expression and non-functional p53 are likely candidates for treatment with Aurora inhibitors.


Asunto(s)
Antineoplásicos/farmacología , Proteína BRCA2/genética , Benzamidas/farmacología , Neoplasias de la Mama/enzimología , Mutación , Neoplasias Pancreáticas/enzimología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Quinazolinas/farmacología , Aurora Quinasas , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Tamaño de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citocinesis/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Concentración 50 Inhibidora , Mitosis/efectos de los fármacos , Terapia Molecular Dirigida , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Ploidias , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , ARN Mensajero/metabolismo , Transfección , Proteína p53 Supresora de Tumor/genética
5.
Planta Med ; 78(5): 448-54, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22331811

RESUMEN

Macrocyclic bisbibenzyls are a class of characteristic compounds, exclusively produced by liverworts. They are attracting increasing attention due to their wide range of biological activities, including antibacterial, antifungal, and antioxidative properties as well as cytotoxicity. Marchantin A is a cyclic bisbibenzyl that has previously been isolated from Marchantia polymorpha and other liverwort species and has been shown to exert cytotoxic effects. In the present study we found that the Icelandic M. polymorpha species produces marchantin A and through an in vitro cell growth inhibition assay, marchantin A was shown to induce a reduction in cell viability of breast cancer cell lines A256 (IC50 = 5.5 µM), MCF7 (IC50 = 11.5 µM), and T47D (IC50 = 15.3 µM). The effect was considerably increased in all cell lines in a synergistic manner when the Aurora-A kinase inhibitor MLN8237 was added simultaneously. Fluorescence microscopy confirmed the antimicrotubular effect of marchantin A, and cell cycle analysis indicated enhanced cell division failure when combining this mitotic-spindle inhibitor with the checkpoint modulator.


Asunto(s)
Azepinas/farmacología , Bibencilos/farmacología , Éteres Cíclicos/farmacología , Marchantia/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Moduladores de Tubulina/farmacología , Aurora Quinasas , Azepinas/química , Bibencilos/química , Bibencilos/aislamiento & purificación , División Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , ADN de Neoplasias/análisis , ADN de Neoplasias/genética , Sinergismo Farmacológico , Éteres Cíclicos/química , Éteres Cíclicos/aislamiento & purificación , Femenino , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinas/química , Moduladores de Tubulina/química , Moduladores de Tubulina/aislamiento & purificación
6.
Genes Chromosomes Cancer ; 50(11): 930-9, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21910159

RESUMEN

Routinely used prognostic factors fail to predict clinical outcome in a significant proportion of breast cancer patients, implying that they can not detect some important biological characteristics. Chromosomal changes have been described in breast carcinomas for many years but their significance is not clear. We compared chromosomal changes with clinico-pathological characteristics and clinical outcome in 203 breast cancer patients with a follow-up of 9-18 years. Combining data from classical cytogenetics and flow cytometry revealed chromosomal abnormalities in 142 cases (70%). Of these, 51 (35.9%) contained two or more cytogenetically abnormal clones. Polyclonality was significantly associated with poor breast-cancer-specific survival (P = 0.03) within 5 years, independent of tumor size, lymph node metastases, and hormone receptors. Specific changes were similar to those previously described, but a new finding was a significant association between del 3p12p21 and poor survival. Polyclonality was significantly associated with TP53-mutations but not with a germline BRCA2 mutation. Less than one third of the polyclonal samples were identified by flow cytometry alone. Cytogenetic changes were detected in 17 out of 114 samples from non-tumorous tissue (15%), two of them identical with a clone in the corresponding tumor. Several samples contained clearly unrelated clones within the tumor and outside, implying either multifocal origin or early divergence. In conclusion, the common deletion on Chromosome 3p12p21 was associated with poor clinical outcome. Chromosomal polyclonality is common in breast carcinomas and predicts poor survival. Polyclonality was poorly detected by one-sample flow cytometry. Multiple sampling might improve the detection rate.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Adulto , Anciano , Anciano de 80 o más Años , Proteína BRCA2/genética , Distribución de Chi-Cuadrado , Aberraciones Cromosómicas , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Cariotipificación , Persona de Mediana Edad , Análisis Multivariante , Factores de Riesgo , Proteína p53 Supresora de Tumor/genética
7.
Dent J (Basel) ; 10(9)2022 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-36135171

RESUMEN

The malignant potential of oral lichen planus (OLP) has been discussed and disputed for decades. The lesions are often characterized by strong expression of the TP53 protein in the basal layer of the mucosa. In 2002, we reported the presence of TP53 mutations in nine out of 27 OLP lesions tested. At follow-up in 2009, one case of oral squamous cell cancer (OSCC) had occurred in a different site six years later. In contrast, in another case, TP53 mutation persisted for years without malignant transformation. In a longitudinal study of eight selected patients with OSCC or different pre-malignant lesions, it was concluded that TP53 mutations could occur early or late in the development of OSCC. A follow-up in the present, almost 20 years later, revealed that one further case of OSCC had occurred in a TP53-mutated case of OLP, 21 years after the first sample was taken, again in a different site. With this second case, this small study now points towards a risk of developing OSCC in TP53-mutated OLP lesions. A review of recent literature indicates a growing consensus that OLP should be regarded as a potentially pre-malignant lesion. Several protein markers have been studied, but none proved useful for prediction of malignant progression. The great majority of published studies are retrospective, and it has been suggested that multi-centre prospective studies will be needed to reach a definitive answer on the malignant potential of OLP, and particularly, to identify contributing factors. Screening for TP53 mutations could help to identify the subgroup of OLP patients that is truly at risk of developing oral cancer.

8.
Dalton Trans ; 51(34): 13119-13128, 2022 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-35975724

RESUMEN

Organotin complexes are studied as promising alternatives to the anticancer drug cisplatin. We report two monoorganotin(IV) complexes based on a dibenzyl phosphinoyldithioformate (H-DBPTF) ligand, containing either bromide (Sn-DBPTF-1) or chloride (Sn-DBPTF-2) anions. The complexes were characterized by standard analytical techniques and the structural details of these complexes were elucidated by single crystal X-ray diffraction. Sn-DBPTF-1 was cytotoxic at IC50 <10 µg mL-1 against cancer cell lines A549 (lung cancer), Aspc-1 (pancreatic cancer), OVCAR-3 (ovarian cancer), T-47D (breast cancer) and HCT116 (colon cancer), and breast epithelial stem cell line D492. The non-tumorigenic breast epithelial cell line MCF-10 was less sensitive at IC50 = 22 µg mL-1. Sn-DBPTF-2 had limited cytotoxic effect at IC50 13-37 µg mL-1. Sn-DBPTF-1 induced apoptosis and double-strand DNA breaks. Cell cycle arrest in G2 occurred in HCT116 and accumulation in G1 in Aspc-1. The results indicate that the basic effect of Sn-DBPTF-1 is to induce DNA damage, leading to apoptosis and cell cycle arrest depending on the cell line.


Asunto(s)
Antineoplásicos , Neoplasias Ováricas , Femenino , Humanos , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Estaño/farmacología
9.
Eur J Haematol ; 86(5): 396-404, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21342269

RESUMEN

BACKGROUND: In Iceland, eight families have been identified with multiple cases of monoclonal gammopathies (MG) and other lymphoproliferative diseases. In one of these families with several cases of monoclonal gammopathy of undetermined significance (MGUS) and Waldenströms macroglobulinemia, in vitro stimulation with poke-weed mitogen revealed hyper-responsive B cells showing increased immunoglobulin production in one-third of disease-free family members. DESIGN AND METHODS: In this study, the families were further traced and the list of names produced was compared with The Icelandic Cancer Registry (ICR) to find all recent cases of lymphoproliferative diseases. First-degree relatives and descendants older than 20yrs of age (n=350) were selected for screening for paraprotein. Selected family members were tested for B-cell hyper-responsiveness and the lymphocyte phenotype was analysed by flow cytometry. RESULTS: Comparison of the total list of 4370 family members with the ICR revealed 22 new cases and screening for serum paraprotein identified nine new cases of MG, eight being first-degree relatives of known probands. Sixty cases of lymphoproliferative diseases are currently known within the eight families, five of them containing both IgG/A and IgM disorders. Twelve hyper-responders (HR) were identified in four families, eight from one family, of whom four were known already. Stimulated B cells from HR had a significantly higher proportion of CD27(+) memory/plasma cells than controls. CONCLUSION: Identification of new affected family members by screening confirms a hereditary predisposition to B-cell proliferative diseases. Contrary to most studies, IgG/A and IgM disorders occurred together in five families. In four families, enhanced B-cell responsiveness was found in healthy subjects clustered around cases.


Asunto(s)
Linfocitos B/inmunología , Paraproteinemias/genética , Paraproteinemias/inmunología , Adulto , Anciano , Estudios de Casos y Controles , Familia , Femenino , Predisposición Genética a la Enfermedad , Humanos , Islandia , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/inmunología , Masculino , Persona de Mediana Edad , Gammopatía Monoclonal de Relevancia Indeterminada/genética , Gammopatía Monoclonal de Relevancia Indeterminada/inmunología , Mieloma Múltiple/genética , Mieloma Múltiple/inmunología , Paraproteínas/genética , Paraproteínas/inmunología , Linaje , Sistema de Registros , Macroglobulinemia de Waldenström/genética , Macroglobulinemia de Waldenström/inmunología , Adulto Joven
10.
BMC Cell Biol ; 11: 34, 2010 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-20492670

RESUMEN

BACKGROUND: In cytokinesis, when the cleavage furrow has been formed, the two centrioles in each daughter cell separate. It has been suggested that the centrioles facilitate and regulate cytokinesis to some extent. It has been postulated that termination of cytokinesis (abscission) depends on the migration of a centriole to the intercellular bridge and then back to the cell center. To investigate the involvement of centrioles in cytokinesis, we monitored the movements of centrioles in three mammalian epithelial cell lines, HeLa, MCF 10A, and the p53-deficient mouse mammary tumor cell line KP-7.7, by time-lapse imaging. Centrin1-EGFP and alpha-Tubulin-mCherry were co-expressed in the cells to visualize respectively the centrioles and microtubules. RESULTS: Here we report that separated centrioles that migrate from the cell pole are very mobile during cytokinesis and their movements can be characterized as 1) along the nuclear envelope, 2) irregular, and 3) along microtubules forming the spindle axis. Centriole movement towards the intercellular bridge was only seen occasionally and was highly cell-line dependent. CONCLUSIONS: These findings show that centrioles are highly mobile during cytokinesis and suggest that the repositioning of a centriole to the intercellular bridge is not essential for controlling abscission. We suggest that centriole movements are microtubule dependent and that abscission is more dependent on other mechanisms than positioning of centrioles.


Asunto(s)
Centriolos/metabolismo , Células Epiteliales/metabolismo , Microtúbulos/metabolismo , Animales , Biomarcadores/metabolismo , Proteínas de Unión al Calcio/metabolismo , Centriolos/ultraestructura , Proteínas Cromosómicas no Histona/metabolismo , Citocinesis , Células Epiteliales/ultraestructura , Células HeLa , Humanos , Mamíferos , Ratones , Microscopía , Microtúbulos/ultraestructura , Tubulina (Proteína)/metabolismo
11.
Planta Med ; 76(10): 969-74, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20143294

RESUMEN

The lichen compound usnic acid is used for its antimicrobial activities in cosmetic products and is also a component of slimming agents. Its effect against cancer cells was first noted over 30 years ago. In this study possible mechanisms of this effect were investigated using two human cell lines, the breast cancer cell line T-47D and the pancreatic cancer cell line Capan-2. Pure (+)-usnic acid from CLADONIA ARBUSCULA and (-)-usnic acid from ALECTORIA OCHROLEUCA were shown to be equally effective inhibitors of DNA synthesis, with IC (50) 4.2 microg/mL and 4.0 microg/mL for (+) and (-)-usnic acid against T-47D, and 5.3 microg/mL and 5.0 microg/mL against Capan-2, respectively. Flow cytometric analysis confirmed the inhibited entry into the S-phase and showed reduction in cell size. Classical apoptosis, as assessed by TUNEL staining, was not observed. Necrosis, measured by LDH release, was seen only in Capan-2 after exposure for 48 hours. Staining with the mitochondrial dye JC-1 demonstrated dose-dependent loss of mitochondrial membrane potential following treatment with usnic acid in both cell lines. In conclusion, usnic acid had a marked inhibitory effect on growth and proliferation of two different human cancer cell lines and led to loss of mitochondrial membrane potential. Cell survival was little affected; late necrosis was seen in one of the cell lines. No difference was noted between the two enantiomers.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Benzofuranos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Líquenes/química , Neoplasias Pancreáticas/tratamiento farmacológico , Extractos Vegetales/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Bencimidazoles , Benzofuranos/uso terapéutico , Neoplasias de la Mama/patología , Carbocianinas , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , ADN/biosíntesis , Relación Dosis-Respuesta a Droga , Femenino , Citometría de Flujo , Humanos , Concentración 50 Inhibidora , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Necrosis , Neoplasias Pancreáticas/patología , Fitoterapia , Extractos Vegetales/uso terapéutico
12.
PLoS One ; 15(4): e0231289, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32287294

RESUMEN

Breast cancer (BC) is the most prevalent type of cancer in women in western countries. BC mortality has not declined despite early detection by screening, indicating the need for better informed treatment decisions. Therefore, a novel noninvasive diagnostic tool for BC would give the opportunity of subtype-specific treatment and improved prospects for the patients. Heterogeneity of BC tumor subtypes is reflected in the expression levels of enzymes in lipid metabolism. The aim of the study was to investigate whether the subtype defined by the transcriptome is reflected in the lipidome of BC cell lines. A liquid chromatography mass spectrometry (LC-MS) platform was applied to analyze the lipidome of six cell lines derived from human BC cell lines representing different BC subtypes. We identified an increased abundance of triacylglycerols (TG) ≥ C-48 with moderate or multiple unsaturation in fatty acyl chains and down-regulated ether-phosphatidylethanolamines (PE) (C-34 to C-38) in cell lines representing estrogen receptor and progesterone receptor positive tumor subtypes. In a cell line representing HER2-overexpressing tumor subtype an elevated expression of TG (≤ C-46), phosphatidylcholines (PC) and PE containing short-chained (≤ C-16) saturated or monounsaturated fatty acids were observed. Increased abundance of PC ≥ C-40 was found in cell lines of triple negative BC subtype. In addition, differences were detected in lipidomes within these previously defined subtypes. We conclude that subtypes defined by the transcriptome are indeed reflected in differences in the lipidome and, furthermore, potentially biologically relevant differences may exist within these defined subtypes.


Asunto(s)
Neoplasias de la Mama/clasificación , Neoplasias de la Mama/metabolismo , Metabolismo de los Lípidos , Lipidómica/métodos , Línea Celular Tumoral , Femenino , Humanos , Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , Triglicéridos/metabolismo
13.
Basic Clin Pharmacol Toxicol ; 126(6): 484-491, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31872571

RESUMEN

Proton pump inhibitors (PPIs) are commonly used drugs among cancer patients. Due to conflicting reports on their safety, we aimed to determine whether PPI use is associated with mortality among prostate cancer patients. In this population-based cohort study, we identified incident diagnoses of prostate cancer between 2007 and 2012 (n = 1058). Follow-up was from 12 months after diagnosis until death, emigration or end the of study. Post-diagnosis use was defined as ≥2 filled prescriptions following diagnosis. We used time-dependent Cox proportional hazard regression models to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer-specific and all-cause mortality associated with post-diagnosis use of PPIs. We identified 347 (32.8%) post-diagnosis PPI users and 711 (67.2%) non-users after diagnosis. Of the 347 patients using PPIs after diagnosis, 59 (17.0%) died due to any cause and 22 (6.3%) due to prostate cancer, compared with 144 (20.3%) and 76 (10.7%) among non-users after diagnosis, respectively. Post-diagnosis PPI use was not associated with prostate cancer-specific mortality (HR 0.88; 95% CI: 0.52-1.48) or all-cause mortality (HR 1.02; 95% CI: 0.73-1.43). Contrary to a previous report, this study did not find evidence of an association between post-diagnosis PPI use and mortality among prostate cancer patients.


Asunto(s)
Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/mortalidad , Inhibidores de la Bomba de Protones/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Humanos , Islandia/epidemiología , Masculino , Persona de Mediana Edad , Inhibidores de la Bomba de Protones/efectos adversos , Factores de Riesgo
14.
Int J Cancer ; 124(12): 2923-8, 2009 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-19330837

RESUMEN

According to the leading hypothesis on testicular cancer (TC) etiology exposure to a specific pattern of steroid hormones in utero, in particular, to high levels of estrogens and low levels of androgens is the major determinant of TC risk in the offspring. We performed a case-referent study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of maternal endogenous steroid hormones with regard to the risk of TC. TC cases and referents were aged between 0 and 25 years. For each case-index mother pair, three or four matched referent-referent mother pairs were identified using national population registries. First trimester or early second trimester sera were retrieved from the index mothers of 73 TC cases and 286 matched referent mothers, and were tested for dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, estradiol, estrone, and sex hormone binding globulin (SHBG). Offspring of mothers with high DHEAS levels had a significantly decreased risk of TC (OR for highest vs. lowest DHEAS quartile, 0.18 (95% CI 0.06-0.58). In contrast, offspring of mothers with high androstenedione levels had an increased risk of TC (OR 4.1; 95% CI 1.2-12.0). High maternal total estradiol level also tended to be associated with an increased risk of TC in the offspring (OR 32; 95% CI 0.98-1,090). We report the first direct evidence that interplay of maternal steroid hormones in the early pregnancy is important in the etiology of TC in the offspring.


Asunto(s)
Hormonas Esteroides Gonadales/sangre , Efectos Tardíos de la Exposición Prenatal/epidemiología , Neoplasias Testiculares/epidemiología , Adolescente , Adulto , Androstenodiona/sangre , Estudios de Casos y Controles , Niño , Preescolar , Sulfato de Deshidroepiandrosterona/sangre , Estradiol/sangre , Estrona/sangre , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Embarazo , Medición de Riesgo , Factores de Riesgo , Globulina de Unión a Hormona Sexual/análisis , Testosterona/sangre , Adulto Joven
15.
Clin Lymphoma Myeloma ; 9(1): 27-9, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19362965

RESUMEN

The medical literature contains reports of around 130 families with two or more cases of MM, MGUS, or WM. An Icelandic family with multiple cases of MGUS, WM, and lymphoma was first described in 1978. In vitro testing of peripheral blood lymphocytes revealed increased production of immunoglobulins in response to poke-weed mitogen in 10 out of 35 family members, referred to as hyperresponders (HR). Enhanced B-cell survival after stimulation was associated with prolonged expression of Bcl-2. A population-based cancer registry study of 218 MM patients identified 7 additional families. Nine new cases of monoclonal gammopathy were detected by the screening of 350 family members. Further testing confirmed previously identified HR in the originally described family as well as detecting new cases. Only two HR were found in the recently identified families. The long-term aim is to identify the genetic background(s) and biology predisposing to the emergence of a persistent clone of immunoglobulin-producing cells.


Asunto(s)
Mieloma Múltiple/genética , Paraproteinemias/genética , Macroglobulinemia de Waldenström/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino
16.
Sci Rep ; 9(1): 1055, 2019 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-30705290

RESUMEN

The MITF transcription factor is a master regulator of melanocyte development and a critical factor in melanomagenesis. The related transcription factors TFEB and TFE3 regulate lysosomal activity and autophagy processes known to be important in melanoma. Here we show that MITF binds the CLEAR-box element in the promoters of lysosomal and autophagosomal genes in melanocytes and melanoma cells. The crystal structure of MITF bound to the CLEAR-box reveals how the palindromic nature of this motif induces symmetric MITF homodimer binding. In metastatic melanoma tumors and cell lines, MITF positively correlates with the expression of lysosomal and autophagosomal genes, which, interestingly, are different from the lysosomal and autophagosomal genes correlated with TFEB and TFE3. Depletion of MITF in melanoma cells and melanocytes attenuates the response to starvation-induced autophagy, whereas the overexpression of MITF in melanoma cells increases the number of autophagosomes but is not sufficient to induce autophagic flux. Our results suggest that MITF and the related factors TFEB and TFE3 have separate roles in regulating a starvation-induced autophagy response in melanoma. Understanding the normal and pathophysiological roles of MITF and related transcription factors may provide important clinical insights into melanoma therapy.


Asunto(s)
Melanoma/metabolismo , Factor de Transcripción Asociado a Microftalmía/metabolismo , Autofagia/genética , Autofagia/fisiología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Células HEK293 , Humanos , Immunoblotting , Lisosomas/metabolismo , Melanocitos/metabolismo , Melanoma/genética , Factor de Transcripción Asociado a Microftalmía/genética , Reacción en Cadena en Tiempo Real de la Polimerasa
17.
APMIS ; 116(9): 816-22, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-19024602

RESUMEN

During recent decades the incidence of testicular cancer (TC) has increased rapidly around the world. Associated exogenous etiological factors might therefore be identifiable. We performed a case-control study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of congenital or neonatal infections with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) as risk factors of TC in the offspring. For each case-index mother pair, three or four matched control-control mother pairs were identified using national population registries. First trimester sera were retrieved from the index mothers of 66 TC cases and 258 matched control mothers, and were tested for antibodies to EBV and CMV. High level of maternal EBV IgG antibodies was associated with significantly increased risk of TC in the offspring (odds ratio (OR), 2.50; 95% confidence interval (CI), 1.15, 5.40), especially with risk of non-seminoma TC (OR, 2.73; 950% CI, 1.25, 5.99) and non-seminoma TC diagnosed under 8 years of age (OR, 2.72; 95% CI, 1.05, 7.04). In contrast, offspring of CMV IgG-seropositive mothers had a decreased risk of TC diagnosed under 8 years of age (OR, 0.35; 95% CI, 0.14, 0.89). Our results suggest that EBV and CMV infections may be associated with TC.


Asunto(s)
Infecciones por Citomegalovirus/epidemiología , Citomegalovirus/crecimiento & desarrollo , Infecciones por Virus de Epstein-Barr/epidemiología , Herpesvirus Humano 4/crecimiento & desarrollo , Neoplasias Testiculares/virología , Adolescente , Adulto , Anticuerpos Antivirales/sangre , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Infecciones por Citomegalovirus/sangre , Infecciones por Citomegalovirus/virología , Ensayo de Inmunoadsorción Enzimática , Infecciones por Virus de Epstein-Barr/sangre , Infecciones por Virus de Epstein-Barr/virología , Europa (Continente)/epidemiología , Femenino , Humanos , Inmunoglobulina G/sangre , Transmisión Vertical de Enfermedad Infecciosa , Masculino , Persona de Mediana Edad , Embarazo , Estudios Seroepidemiológicos , Neoplasias Testiculares/epidemiología , Adulto Joven
18.
Int J Biochem Cell Biol ; 103: 99-104, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30114482

RESUMEN

Epithelial to mesenchymal transition (EMT) is a developmental event characterized by phenotypic switching from a polarized epithelial phenotype to an unpolarized mesenchymal phenotype. Changes to plasma membrane function accompany EMT yet the differences in lipid composition of cells that have undergone EMT are relatively unexplored. To address this the lipidome of two cell models of EMT in breast epithelial tissue, D492 and HMLE, were analyzed by untargeted LC-MS. Detected masses were identified and their abundance was compared through multivariate statistical analysis. Considerable concordance was observed in eight lipid components between epithelial and mesenchymal cells in both cell models. Specifically, an increase in phosphatidylcholine and triacylglycerol were found to accompany EMT while phosphatidylcholine- and phosphatidylethanolamine plasmalogens, as well as diacylglycerols decreased. The most abundant fatty acid lengths were C16 and C18 but mesenchymal cells had on average shorter and more unsaturated fatty acids. The results are consistent with enhanced cell mobility post EMT and reflect a consequence of oxidative stress pre- and post EMT in breast epithelial tissue.


Asunto(s)
Transición Epitelial-Mesenquimal , Ácidos Grasos/metabolismo , Metabolismo de los Lípidos , Glándulas Mamarias Humanas/metabolismo , Plasmalógenos/metabolismo , Células Epiteliales/citología , Femenino , Humanos , Glándulas Mamarias Humanas/citología
19.
Therap Adv Gastroenterol ; 11: 1756284818777943, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29872455

RESUMEN

BACKGROUND: The use of proton-pump inhibitors (PPIs) has grown worldwide, and there are concerns about increased unsubstantiated long-term use. The aim of the study was to describe the real-world use of PPIs over the past decade in an entire national population. METHODS: This was a nationwide population-based drug-utilization study. Patterns of outpatient PPI use among adults in Iceland between 2003 and 2015 were investigated, including annual incidence and prevalence, duration of use, and dose of tablet used (lower versus higher), as well as the proportion of PPI use attributable to gastroprotection. RESULTS: We observed 1,372,790 prescription fills over the entire study period, of which 95% were for higher-dose PPIs. Annual incidence remained stable across time (3.3-4.1 per 100 persons per year), while the annual prevalence increased from 8.5 per 100 persons to 15.5 per 100 persons. Prevalence increased with patient age and was higher among women than men. Duration of treatment increased with patients' age (36% of users over 80 years remained on treatment after 1 year compared with 13% of users aged 19-39 years), and was longer among those initiating on a higher dose compared with a lower dose. The proportion of PPI users concurrently using nonsteroidal anti-inflammatory drugs decreased over the study period, while the proportion concurrently using acetylsalicylic acid, oral anticoagulants, or platelet inhibitors increased. CONCLUSIONS: In this nationwide study, a considerable increase in overall outpatient use of PPIs over a 13-year period was observed, particularly among older adults. Patients were increasingly treated for longer durations than recommended by clinical guidelines and mainly with higher doses.

20.
Haematologica ; 92(8): 1131-4, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17650445

RESUMEN

The aim of this study was to examine the natural history of monoclonal gammopathy using a retrospective approach and a long observation period. Protein electrophoresis (PE) and immunofixation (IF) was performed on frozen prediagnosis serum samples from 65 multiple myeloma (MM) and 10 Waldenström's macroglobulinemia (WM) cases. Paraprotein was found in 28% and 46% of the samples from cases using PE and IF respectively. The type of paraprotein was IgA in 33.4% of cases, IgG in 57%, and IgM in 8.5%. Excluding light chain or non-secretory disease, 72 % of MM cases had a prodromal MGUS phase within 10 years of diagnosis MM and WM were preceded by MGUS in at least half of the cases, confirming the premalignant nature of this condition.


Asunto(s)
Paraproteinemias/epidemiología , Lesiones Precancerosas/epidemiología , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Islandia/epidemiología , Inmunoglobulina A/análisis , Inmunoglobulina G/análisis , Inmunoglobulina M/análisis , Masculino , Persona de Mediana Edad , Mieloma Múltiple/epidemiología , Proteínas de Mieloma/análisis , Paraproteinemias/sangre , Paraproteinemias/tratamiento farmacológico , Paraproteínas/análisis , Lesiones Precancerosas/sangre , Lesiones Precancerosas/tratamiento farmacológico , Estudios Retrospectivos , Factores de Tiempo , Macroglobulinemia de Waldenström/sangre , Macroglobulinemia de Waldenström/tratamiento farmacológico , Macroglobulinemia de Waldenström/epidemiología
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