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1.
Cancers (Basel) ; 12(4)2020 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-32244657

RESUMEN

A hypercoagulable state may either underlie or frankly accompany cancer disease at its onset or emerge in course of cancer development. Whichever the case, hypercoagulation may severely limit administration of cancer therapies, impose integrative supporting treatments and finally have an impact on prognosis. Within a flourishing research pipeline, a recent study of stage I-IIA breast cancer patients has allowed the development of a prognostic model including biomarkers of coagulation activation, which efficiently stratified prognosis of patients in the study cohort. We are now validating our risk assessment tool in an independent cohort of 108 patients with locally advanced breast cancer with indication to neo-adjuvant therapy followed by breast surgery. Within this study population, we will use our tool for risk assessment and stratification in reference to 1. pathologic complete response rate at definitive surgery, intended as our primary endpoint, and 2. rate of thromboembolic events, intended as our secondary endpoint. Patients' screening and enrollment procedures are currently in place. The trial will be shortly enriched by experimental tasks centered on next-generation sequencing techniques for identifying additional molecular targets of treatments which may integrate current standards of therapy in high-risk patients.

2.
J Transl Med ; 16(1): 129, 2018 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-29769125

RESUMEN

BACKGROUND: Cancer and coagulation activation are tightly related. The extent to which factors related to both these pathologic conditions concur to patient prognosis intensely animates the inherent research areas. The study herein presented aimed to the development of a tool for the assessment and stratification of risk of death and disease recurrence in early breast cancer. METHODS: Between 2008 and 2010, two hundreds thirty-five (N: 235) patients diagnosed with stage I-IIA breast cancer were included. Data on patient demographics and clinic-pathologic features were collected in course of face-to-face interviews or actively retrieved from clinical charts. Plasma levels of plasminogen activator inhibitor type 1 (PAI-1), fragment 1 + 2 (F1 + 2), thrombin antithrombin complex (TAT), factor VIII (FVIII), and D-dimer (DD) were measured at breast cancer diagnosis and prior to any therapeutic procedure, including breast surgery. The risk of death was computed in terms of overall survival (OS), which was the primary outcome. For a subset of patients (N = 62), disease free survival (DFS) was also assessed as a measure of risk of disease recurrence. RESULTS: Median follow up was 95 months (range 6-112 months). Mean age at diagnosis was 60.3 ± 13.4 years. Cancer cases were more commonly intraductal carcinomas (N: 204; 86.8%), pT1 (131; 55.7%), pN0 (141; 60%) and G2 (126; 53.6%). Elevated levels of PAI-1 (113; 48.1%) represented the most frequent coagulation abnormality, followed by higher levels of F1 + 2 (97; 41.3%), DD (63; 27.0%), TAT (34; 40%), and FVIII (29; 12.3%). In univariate models of OS, age, pT, DD, FVIII were prognostically relevant. In multivariate models of OS, age (p = 0.043), pT (p = 0.001), levels of DD (p = 0.029) and FVIII (p = 0.087) were confirmed. In the smaller subgroup of 62 patients, lymph node involvement, percent expression of estrogen receptors and levels of FVIII impacted DFS significantly. CONCLUSIONS: We developed a risk assessment tool for OS including patient- and cancer-related features along with biomarkers of coagulation activation in a cohort of early BC patients. Further studies are warranted to validate our prognostic model in the early setting and eventually extend its application to risk evaluation in the advanced setting for breast and other cancers.


Asunto(s)
Coagulación Sanguínea , Neoplasias de la Mama/sangre , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/patología , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Factores de Riesgo , Análisis de Supervivencia
3.
Sci Rep ; 7(1): 10597, 2017 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-28878375

RESUMEN

Evidence on everolimus in breast cancer has placed hyperglycemia among the most common high grade adverse events. Anthropometrics and biomarkers of glucose metabolism were investigated in a observational study of 102 postmenopausal, HR + HER2- metastatic breast cancer patients treated with everolimus-exemestane in first and subsequent lines. Best overall response (BR) and clinical benefit rate (CBR) were assessed across subgroups defined upon fasting glucose (FG) and body mass index (BMI). Survival was estimated by Kaplan-Meier method and log-rank test. Survival predictors were tested in Cox models. Median follow up was 12.4 months (1.0-41.0). The overall cohort showed increasing levels of FG and decreasing BMI (p < 0.001). Lower FG fasting glucose at BR was more commonly associated with C/PR or SD compared with PD (p < 0.001). We also observed a somewhat higher BMI associated with better response (p = 0.052). More patients in the lowest FG category achieved clinical benefit compared to the highest (p < 0.001), while no relevant differences emerged for BMI. Fasting glucose at re-assessment was also predictive of PFS (p = 0.037), as confirmed in models including BMI and line of therapy (p = 0.049). Treatment discontinuation was significantly associated with changes in FG (p = 0.014). Further research is warranted to corroborate these findings and clarify the underlying mechanisms.


Asunto(s)
Glucemia , Índice de Masa Corporal , Neoplasias de la Mama/sangre , Neoplasias de la Mama/diagnóstico , Ayuno/sangre , Anciano , Androstadienos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Everolimus , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Pronóstico , Resultado del Tratamiento
4.
PLoS One ; 10(4): e0124213, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25910078

RESUMEN

Testicular vasculogenesis is one of the key processes regulating male gonad morphogenesis. The knowledge of the molecular cues underlining this phenomenon is one of today's most challenging issues and could represent a major contribution toward a better understanding of the onset of testicular morphogenetic disorders. R-spondin 1 has been clearly established as a candidate for mammalian ovary determination. Conversely, very little information is available on the expression and role of R-spondin 1 during testicular morphogenesis. This study aims to clarify the distribution pattern of R-spondin 1 and other partners of its machinery during the entire period of testicular morphogenesis and to indicate the role of this system in testicular development. Our whole mount immunofluorescence results clearly demonstrate that R-spondin 1 is always detectable in the testicular coelomic partition, where testicular vasculature is organized, while Dickkopf-1 is never detectable in this area. Moreover, organ culture experiments of embryonic male UGRs demonstrated that Dickkopf-1 acted as an inhibitor of testis vasculature formation. Consistent with this observation, real-time PCR analyses demonstrated that DKK1 is able to slightly but significantly decrease the expression level of the endothelial marker Pecam1. The latter experiments allowed us to observe that DKK1 administration also perturbs the expression level of the Pdgf-b chain, which is consistent with some authors' observations relating this factor with prenatal testicular patterning and angiogenesis. Interestingly, the DKK1 induced inhibition of testicular angiogenesis was rescued by the co-administration of R-spondin 1. In addition, R-spondin 1 alone was sufficient to enhance, in culture, testicular angiogenesis.


Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/genética , Testículo/embriología , Testículo/metabolismo , Trombospondinas/genética , beta Catenina/genética , Animales , Apoptosis , Movimiento Celular/genética , Proliferación Celular , Células Endoteliales/metabolismo , Expresión Génica , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Masculino , Ratones , Morfogénesis/genética , Neovascularización Fisiológica/genética , Regiones Promotoras Genéticas , Transporte de Proteínas , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Trombospondinas/metabolismo , beta Catenina/metabolismo
5.
Biomed Res Int ; 2014: 904396, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25140323

RESUMEN

The study of how mechanical forces may influence cell behavior via cytoskeleton remodeling is a relevant challenge of nowadays that may allow us to define the relationship between mechanics and biochemistry and to address the larger problem of biological complexity. An increasing amount of literature data reported that microgravity condition alters cell architecture as a consequence of cytoskeleton structure modifications. Herein, we are reporting the morphological, cytoskeletal, and behavioral modifications due to the exposition of a seminoma cell line (TCam-2) to simulated microgravity. Even if no differences in cell proliferation and apoptosis were observed after 24 hours of exposure to simulated microgravity, scanning electron microscopy (SEM) analysis revealed that the change of gravity vector significantly affects TCam-2 cell surface morphological appearance. Consistent with this observation, we found that microtubule orientation is altered by microgravity. Moreover, the confocal analysis of actin microfilaments revealed an increase in the cell width induced by the low gravitational force. Microtubules and microfilaments have been related to autophagy modulation and, interestingly, we found a significant autophagic induction in TCam-2 cells exposed to simulated microgravity. This observation is of relevant interest because it shows, for the first time, TCam-2 cell autophagy as a biological response induced by a mechanical stimulus instead of a biochemical one.


Asunto(s)
Citoesqueleto de Actina/metabolismo , Autofagia , Microtúbulos/metabolismo , Seminoma/metabolismo , Ingravidez , Citoesqueleto de Actina/ultraestructura , Línea Celular Tumoral , Humanos , Masculino , Microtúbulos/ultraestructura , Seminoma/ultraestructura
6.
Eur J Nutr ; 53(2): 421-31, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-23754570

RESUMEN

BACKGROUND AND AIM: Breast cancer remains a leading cause of mortality among women. In metastasis, cascade migration of cancer cells and invasion of extracellular matrix (ECM) represent critical steps. Urokinase-type plasminogen activator (uPA), as well as metalloproteinases MMP-2 and MMP-9, strongly contribute to ECM remodelling, thus becoming associated with tumour migration and invasion. In addition, the high expression of cytoskeletal (CSK) proteins, as fascin, has been correlated with clinically aggressive metastatic tumours, and CSK proteins are thought to affect the migration of cancer cells. Consumption of fruits and vegetables, characterized by high procyanidin content, has been associated to a reduced mortality for breast cancer. Therefore, we investigated the biological effect of grape seed extract (GSE) on the highly metastatic MDA-MB231 breast cancer cell line, focusing on studying GSE ability in inhibiting two main metastatic processes, i.e., cell migration and invasion. METHODS: After MDA-MB231 breast cancer cells stimulated with GSE migration and invasion were evaluated by means of trans-well assays and uPA as well as MMPs activity was detected by gelatin zymography. Fascin, ß-catenin and nuclear factor-κB (NF-κB) expression were determined using western blot technique. ß-Catenin localization was observed by confocal microscopy. RESULTS: We observed that high concentrations of GSE inhibited cell proliferation and apoptosis. Conversely, low GSE concentration decreased cell migration and invasion, likely by hampering ß-catenin expression and localization, fascin and NF-κB expression, as well as by decreasing the activity of uPA, MMP-2 and MMP-9. CONCLUSIONS: These results make GSE a powerful candidate for developing preventive agents against cancer metastasis.


Asunto(s)
Neoplasias de la Mama/patología , Movimiento Celular/efectos de los fármacos , Extracto de Semillas de Uva/farmacología , Invasividad Neoplásica/prevención & control , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/química , Proteínas Portadoras/análisis , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Metaloproteinasas de la Matriz/efectos de los fármacos , Metaloproteinasas de la Matriz/metabolismo , Proteínas de Microfilamentos/análisis , FN-kappa B/análisis , Activador de Plasminógeno de Tipo Uroquinasa/efectos de los fármacos , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , beta Catenina/análisis
7.
Biodivers Conserv ; 23(14): 3657-3671, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-26321799

RESUMEN

Scientific studies reveal significant consequences of climate change for nature, from ecosystems to individual species. Such studies are important factors in policy decisions on forest conservation and management in Europe. However, while research has shown that climate change research start to impact on European conservation policies like Natura 2000, climate change information has yet to translate into management practices. This article contributes to the on-going debates about science-society relations and knowledge utilization by exploring and analysing the interface between scientific knowledge and forest management practice. We focus specifically on climate change debates in conservation policy and on how managers of forest areas in Europe perceive and use climate change ecology. Our findings show that forest managers do not necessarily deny the potential importance of climate change for their management practices, at least in the future, but have reservations about the current usefulness of available knowledge for their own areas and circumstances. This suggests that the science-management interface is not as politicized as current policy debates about climate change and that the use of climate change ecology is situated in practice. We conclude the article by discussing what forms of knowledge may enable responsible and future oriented management in practice focusing specifically on the role of reflexive experimentation and monitoring.

8.
PLoS One ; 8(10): e76192, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24098438

RESUMEN

Seminoma is one of the most common Testicular Germ Cell Tumours that originates during embryonic development due to an alteration of the local niche that in turn results in a delayed or blocked differentiation of Primordial Germ Cells. The block of differentiation is actually a common way to develop cancer disease as postulated by the "embryonic rest theory of cancer". In agreement with this theory different studies have demonstrated that embryonic cues display the capacity of reprogramming aggressive cancer cells towards a less aggressive phenotype. Herein we investigate the ability of a culture medium added with 10% egg albumen (EW, Egg White) to modulate seminoma cell phenotype and behaviour, by ensuring a proper set of morphogenetic signals. We chose to use the TCam-2 seminoma cell line that has been established as the only available cell line, obtained from a primary testicular seminoma. EW is able to: 1) modify TCam-2 cell spreading rate and cell-substrate adhesion without affecting proliferation and survival indexes; 2) modulate TCam-2 actin distribution pattern increasing cortical localization of actin filaments; 3) increase TCam-2 cell-cell junction capability; 4) decrease both chemo-sensitive and collective TCam-2 migratory behaviour. According to these observations morphometric fractal analysis revealed the ability of EW to increase Circularity and Solidity parameters and, consequently, to decrease Fractal dimension. Prompted by these observations we hypothesize that EW treatment could rescue, at least in part, the neoplastic-metastatic behaviour of seminoma cells.


Asunto(s)
Proteínas del Huevo/farmacología , Seminoma/metabolismo , Seminoma/patología , Neoplasias Testiculares/metabolismo , Neoplasias Testiculares/patología , Actinas/metabolismo , Animales , Cadherinas/metabolismo , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Conexina 43/metabolismo , Clara de Huevo , Adhesiones Focales/efectos de los fármacos , Humanos , Integrina beta1/metabolismo , Uniones Intercelulares/metabolismo , Uniones Intercelulares/ultraestructura , Masculino , Seminoma/genética , Neoplasias Testiculares/genética , Vinculina/metabolismo , beta Catenina/metabolismo
9.
Biol Reprod ; 87(6): 146, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23077169

RESUMEN

The hepatocyte growth factor (HGF) is a pleiotropic cytokine and a well-known regulator of mouse embryonic organogenesis. In previous papers, we have shown the expression pattern of HGF and its receptor, C-MET, during the different stages of testis prenatal development. We demonstrated that C-MET is expressed in fetal Leydig cells (FLCs) and that HGF stimulates testosterone secretion in organ culture of late fetal testes. In the present study, we analyzed the proliferation rate, apoptotic index, and differentiation of FLCs in testicular organ culture of 17.5 days postcoitum (17.5 dpc) embryos to clarify the physiological role of HGF in late testis organogenesis. Based on our data, we conclude the following: 1) HGF acts as an antiapoptotic factor that is able to reduce the number of apoptotic FLCs and testicular caspase-3 active fragment; 2) HGF does not affect FLC proliferation; 3) HGF significantly increases expression of insulin-like 3 (INSL3), a marker of Leydig cell terminal differentiation, without affecting 3beta-hydroxysteroid dehydrogenase (3betaHSD) expression; 4) HGF significantly decreases the expression of nestin, a marker of Leydig cell progenitors; and 5) HGF significantly increases the number of fully developed FLCs. Taken together, these observations demonstrate that HGF is able to act in vitro as a survival and differentiation factor in FLC population.


Asunto(s)
Diferenciación Celular , Factor de Crecimiento de Hepatocito/metabolismo , Células Intersticiales del Testículo/citología , Organogénesis , Proteínas Proto-Oncogénicas c-met/metabolismo , Transducción de Señal , Testículo/embriología , Animales , Apoptosis , Biomarcadores/metabolismo , Caspasa 3/metabolismo , Proliferación Celular , Supervivencia Celular , Factor de Crecimiento de Hepatocito/genética , Proteínas de Filamentos Intermediarios/metabolismo , Células Intersticiales del Testículo/enzimología , Células Intersticiales del Testículo/metabolismo , Masculino , Ratones , Ratones Endogámicos , Proteínas del Tejido Nervioso/metabolismo , Nestina , Técnicas de Cultivo de Órganos , Fragmentos de Péptidos/metabolismo , Proteínas Proto-Oncogénicas c-met/genética , ARN Mensajero/metabolismo , Testículo/citología , Testículo/metabolismo
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