8 research outputs found
Las met谩stasis 贸seas del c谩ncer
Las met谩stasis 贸seas representan un problema cl铆nico devastador en las neoplasias m谩s frecuentes,
especialmente en el mieloma m煤ltiple, mama, pr贸stata, y pulm贸n. Las consecuencias incluyen dolores refractarios a analg茅sicos convencionales, osteolisis que conlleva en ocasiones compresi贸n medular, fracturas patol贸gicas, y trastornos metab贸licos. Recientes avances en el diagn贸stico mediante t茅cnicas de imagen, as铆 como diversas t茅cnicas bioqu铆micas, han favorecido un certero diagn贸stico y seguimiento. El aumento de la supervivencia se ha mejorado mediante una aproximaci贸n multimodal en los tratamientos con la combinaci贸n de la inhibici贸n de la osteolisis, la cirug铆a ortop茅dica profil谩ctica y la radioterapia. Recientes progresos en la investigaci贸n b谩sica han determinado la huella molecular de met谩stasis de un tumor capaz de predecir su proclividad metast谩sica. La investigaci贸n b谩sica favorecer谩 un conocimiento de los mecanismos b谩sicos y llevar谩 a elucidar dianas moleculares que favorecer谩n el desarrollo de f谩rmacos capaces de prevenir,
amortiguar o bloquear el proceso metast谩tico.Bone metastases represent a devastating clinical problem in the most frequent neoplasies, especially in multiple myeloma, tumours breast, prostate and lung. The consequences include pain which is refractory to conventional analgesics, osteolysis often leading to bone-marrow compression and pathological fractures, and metabolic disorders. Recent advances in diagnosis using imaging techniques as well as different biochemical techniques have helped accurate diagnosis and follow-up. The increase in survival has improved through a multimodal approach combining, inhibition of osteolysis, with prophylactic orthopaedic surgery and radiation
therapy. Recent advances in basic research have determined the molecular metastatic that can predict its proclivity to metastasize. Basic research will improve understanding of the basic mechanisms and lead to the clarification of molecular targets that will help in the development of medicines capable of preventing, decreasing or blocking the metastatic process
Glutamatergic pallidothalamic projections and their implications in the pathophysiology of Parkinson's disease
GABAergic projections emitted from the entopeduncular nucleus (ENT) and the substantia nigra pars reticulata (SNr) innervate different thalamic nuclei and they are known to be hyperactive after dopaminergic depletion. Here we show that isoform 2 of the vesicular glutamate transporter (VGLUT2) is expressed by neurons in the ENT nucleus but not in the SNr. Indeed, dual in situ hybridization demonstrated that the ENT nucleus contains two different subpopulations of projection neurons, one single-expressing GAD65/67 mRNAs and another one that co-expresses either of the GAD isoforms together with VGLUT2 mRNA. Unilateral dopaminergic depletion induced marked changes in pallidothalamic-projecting neuron gene expression, resulting in increased expression of GAD65/67 mRNAs together with a clear down-regulation of VGLUT2 mRNA expression. Our results indicate that the increased thalamic inhibition typical of dopamine depletion might be explained by a synergistic effect of increased GABA outflow coupled to decreased glutamate levels, both neurotransmitters coming from ENT neurons
Glutamatergic pallidothalamic projections and their implications in the pathophysiology of Parkinson's disease
GABAergic projections emitted from the entopeduncular nucleus (ENT) and the substantia nigra pars reticulata (SNr) innervate different thalamic nuclei and they are known to be hyperactive after dopaminergic depletion. Here we show that isoform 2 of the vesicular glutamate transporter (VGLUT2) is expressed by neurons in the ENT nucleus but not in the SNr. Indeed, dual in situ hybridization demonstrated that the ENT nucleus contains two different subpopulations of projection neurons, one single-expressing GAD65/67 mRNAs and another one that co-expresses either of the GAD isoforms together with VGLUT2 mRNA. Unilateral dopaminergic depletion induced marked changes in pallidothalamic-projecting neuron gene expression, resulting in increased expression of GAD65/67 mRNAs together with a clear down-regulation of VGLUT2 mRNA expression. Our results indicate that the increased thalamic inhibition typical of dopamine depletion might be explained by a synergistic effect of increased GABA outflow coupled to decreased glutamate levels, both neurotransmitters coming from ENT neurons
Las met谩stasis 贸seas del c谩ncer
Las met谩stasis 贸seas representan un problema cl铆nico devastador en las neoplasias m谩s frecuentes,
especialmente en el mieloma m煤ltiple, mama, pr贸stata, y pulm贸n. Las consecuencias incluyen dolores refractarios a analg茅sicos convencionales, osteolisis que conlleva en ocasiones compresi贸n medular, fracturas patol贸gicas, y trastornos metab贸licos. Recientes avances en el diagn贸stico mediante t茅cnicas de imagen, as铆 como diversas t茅cnicas bioqu铆micas, han favorecido un certero diagn贸stico y seguimiento. El aumento de la supervivencia se ha mejorado mediante una aproximaci贸n multimodal en los tratamientos con la combinaci贸n de la inhibici贸n de la osteolisis, la cirug铆a ortop茅dica profil谩ctica y la radioterapia. Recientes progresos en la investigaci贸n b谩sica han determinado la huella molecular de met谩stasis de un tumor capaz de predecir su proclividad metast谩sica. La investigaci贸n b谩sica favorecer谩 un conocimiento de los mecanismos b谩sicos y llevar谩 a elucidar dianas moleculares que favorecer谩n el desarrollo de f谩rmacos capaces de prevenir,
amortiguar o bloquear el proceso metast谩tico.Bone metastases represent a devastating clinical problem in the most frequent neoplasies, especially in multiple myeloma, tumours breast, prostate and lung. The consequences include pain which is refractory to conventional analgesics, osteolysis often leading to bone-marrow compression and pathological fractures, and metabolic disorders. Recent advances in diagnosis using imaging techniques as well as different biochemical techniques have helped accurate diagnosis and follow-up. The increase in survival has improved through a multimodal approach combining, inhibition of osteolysis, with prophylactic orthopaedic surgery and radiation
therapy. Recent advances in basic research have determined the molecular metastatic that can predict its proclivity to metastasize. Basic research will improve understanding of the basic mechanisms and lead to the clarification of molecular targets that will help in the development of medicines capable of preventing, decreasing or blocking the metastatic process
Receptor of Activated Protein C Promotes Metastasis and Correlates with Clinical Outcome in Lung Adenocarcinoma
Receptor of Activated Protein C Promotes Metastasis and Correlates with Clinical Outcome in Lung Adenocarcinoma
RATIONALE: Efficient metastasis requires survival and adaptation of tumor cells to stringent conditions imposed by the extracellular milieu. Identification of critical survival signaling pathways in tumor cells might unveil novel targets relevant in disease progression.
OBJECTIVES: To investigate the contribution of activated protein C (APC) and its receptor (EPCR) in animal models of lung cancer metastasis and in patients with lung adenocarcinoma.
METHODS: Signaling pathway triggered by APC/EPCR and its relevance in apoptosis was studied in vitro. Functional significance was assessed by silencing and blocking antibodies in several in vivo models of lung cancer metastasis. We examined EPCR levels using a microarray dataset of 107 patients. Immunohistochemical analysis was performed in an independent cohort of 295 patients with lung adenocarcinoma.
MEASUREMENTS AND MAIN RESULTS: The effects of APC binding to EPCR rapidly triggered Akt and ERK signaling pathways, leading to attenuated in vitro apoptosis. In vivo, silencing of EPCR expression or blocking APC/EPCR interaction reduced homing resulting in impaired prometastatic activity. Moreover, overexpression of EPCR induced an increase metastatic activity to target organs. Analysis of clinical samples showed a robust association between high EPCR levels and poor prognosis particularly in stage I patients.
CONCLUSIONS: EPCR and its ligand APC promote cell survival that contributes to tumor cell endurance to stress favoring prometastatic activity of lung adenocarcinoma (ADC). EPCR/APC is a novel target of relevance in the clinical outcome of early-stage lung cancer
Receptor of Activated Protein C Promotes Metastasis and Correlates with Clinical Outcome in Lung Adenocarcinoma
RATIONALE: Efficient metastasis requires survival and adaptation of tumor cells to stringent conditions imposed by the extracellular milieu. Identification of critical survival signaling pathways in tumor cells might unveil novel targets relevant in disease progression.
OBJECTIVES: To investigate the contribution of activated protein C (APC) and its receptor (EPCR) in animal models of lung cancer metastasis and in patients with lung adenocarcinoma.
METHODS: Signaling pathway triggered by APC/EPCR and its relevance in apoptosis was studied in vitro. Functional significance was assessed by silencing and blocking antibodies in several in vivo models of lung cancer metastasis. We examined EPCR levels using a microarray dataset of 107 patients. Immunohistochemical analysis was performed in an independent cohort of 295 patients with lung adenocarcinoma.
MEASUREMENTS AND MAIN RESULTS: The effects of APC binding to EPCR rapidly triggered Akt and ERK signaling pathways, leading to attenuated in vitro apoptosis. In vivo, silencing of EPCR expression or blocking APC/EPCR interaction reduced homing resulting in impaired prometastatic activity. Moreover, overexpression of EPCR induced an increase metastatic activity to target organs. Analysis of clinical samples showed a robust association between high EPCR levels and poor prognosis particularly in stage I patients.
CONCLUSIONS: EPCR and its ligand APC promote cell survival that contributes to tumor cell endurance to stress favoring prometastatic activity of lung adenocarcinoma (ADC). EPCR/APC is a novel target of relevance in the clinical outcome of early-stage lung cancer
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field