Los restos de Sus scrofa (Artiodactyla, Mammalia) del yacimiento Pleistoceno de Pinilla del Valle (Madrid, España)

A morphologic and biometric study has been carried out on the fossil remains of Suidae derived from the first phase of excavation (1980-1989) at the late Pleistocene paleontological site of Cueva del Camino near Pinilla del Valle, north of Madrid. The material consists in 47 remains belonging to a minimum of 6 individuals. The results allow identifying the presence of the wild boar Sus scrofa, whose anatomical characteristics are compared with material from various European Pleistocene sites as well as present-day specimens. From the material obtained is this first phase of excavation stands out several cranial remains, because they are very scarce in coeval European sites, and are not recorded so far in other Spanish sites. The record of Sus scrofa agrees with the palaeoecological and palaeoenvironmental inferences displayed by previous studies from the whole faunal assemblage of the Cueva del Camino site.Se ha llevado a cabo un estudio morfológico y biométrico de los restos fósiles de Suidos excavados en el yacimiento del Pleistoceno superior de la Cueva del Camino, en el término de Pinilla del Valle (Madrid), comparándolos con los restos de otros yacimientos y con especímenes actuales. El material extraído comprende 47 elementos pertenecientes a un mínimo de 6 individuos, destacando la presencia de restos craneales, muy poco frecuentes en los yacimientos europeos de esta época, y ausentes en yacimientos españoles. Se han comprobado en los restos los caracteres anatómicos típicos de Sus scrofa, confirmándose las condiciones paleoambientales obtenidas del conjunto de la fauna

On the expanding terminology in the GPCR field: The meaning of receptor mosaics and receptor heteromers

The oligomerization of G protein-coupled receptors (GPCRs) is a fact that deserves further attention as increases both the complexity and diversity of the receptor-mediated signal transduction, thus enriching the cell signaling. Consequently, in the present review we tackle among others the problems concerning the terminology used to describe aspects surrounding the GPCRs oligomerization phenomenon. Therefore, the theoretical implications of the GPCR oligomerization will be briefly discussed together with possible implications of this phenomenon especially for new strategies in drug development

Development of clinically relevant in vivo metastasis models using human bone discs and breast cancer patient-derived xenografts

Background Late-stage breast cancer preferentially metastasises to bone; despite advances in targeted therapies, this condition remains incurable. The lack of clinically relevant models for studying breast cancer metastasis to a human bone microenvironment has stunted the development of effective treatments for this condition. To address this problem, we have developed humanised mouse models in which breast cancer patient-derived xenografts (PDXs) metastasise to human bone implants with low variability and high frequency. Methods To model the human bone environment, bone discs from femoral heads of patients undergoing hip replacement surgery were implanted subcutaneously into NOD/SCID mice. For metastasis studies, 7 patient-derived xenograft tumours (PDX: BB3RC32, ER+ PR+ HER2−; BB2RC08, ER+ PR+ ER2−; BB6RC37, ER− PR− HER2− and BB6RC39, ER+ PR+ HER2+), MDA-MB-231-luc2, T47D-luc2 or MCF7-Luc2 cells were injected into the 4th mammary ducts and metastases monitored by luciferase imaging and confirmed on histological sections. Bone integrity, viability and vascularisation were assessed by uCT, calcein uptake and histomorphometry. Expression profiling of genes/proteins during different stages of metastasis were assessed by whole genome Affymetrix array, real-time PCR and immunohistochemistry. Importance of IL-1 was confirmed following anakinra treatment. Results Implantation of femoral bone provided a metabolically active, human-specific site for tumour cells to metastasise to. After 4 weeks, bone implants were re-vascularised and demonstrated active bone remodelling (as evidenced by the presence of osteoclasts, osteoblasts and calcein uptake). Restricting bone implants to the use of subchondral bone and introduction of cancer cells via intraductal injection maximised metastasis to human bone implants. MDA-MB-231 cells specifically metastasised to human bone (70% metastases) whereas T47D, MCF7, BB3RC32, BB2RC08, and BB6RC37 cells metastasised to both human bone and mouse bones. Importantly, human bone was the preferred metastatic site especially from ER+ PDX (100% metastasis human bone compared with 20–75% to mouse bone), whereas ER-ve PDX developed metastases in 20% of human and 20% of mouse bone. Breast cancer cells underwent a series of molecular changes as they progressed from primary tumours to bone metastasis including altered expression of IL-1B, IL-1R1, S100A4, CTSK, SPP1 and RANK. Inhibiting IL-1B signalling significantly reduced bone metastasis. Conclusions Our reliable and clinically relevant humanised mouse models provide significant advancements in modelling of breast cancer bone metastasis

Investigating the Role of Guanosine on Human Neuroblastoma Cell Differentiation and the Underlying Molecular Mechanisms

Neuroblastoma arises from neural crest cell precursors failing to complete the process of differentiation. Thus, agents helping tumor cells to differentiate into normal cells can represent a valid therapeutic strategy. Here, we evaluated whether guanosine (GUO), a natural purine nucleoside, which is able to induce differentiation of many cell types, may cause the differentiation of human neuroblastoma SH-SY5Y cells and the molecular mechanisms involved. We found that GUO, added to the cell culture medium, promoted neuron-like cell differentiation in a time- and concentration-dependent manner. This effect was mainly due to an extracellular GUO action since nucleoside transporter inhibitors reduced but not abolished it. Importantly, GUO-mediated neuron-like cell differentiation was independent of adenosine receptor activation as it was not altered by the blockade of these receptors. Noteworthy, the neuritogenic activity of GUO was not affected by blocking the phosphoinositide 3-kinase pathway, while it was reduced by inhibitors of protein kinase C or soluble guanylate cyclase. Furthermore, the inhibitor of the enzyme heme oxygenase-1 but not that of nitric oxide synthase reduced GUO-induced neurite outgrowth. Interestingly, we found that GUO was largely metabolized into guanine by the purine nucleoside phosphorylase (PNP) enzyme released from cells. Taken together, our results suggest that GUO, promoting neuroblastoma cell differentiation, may represent a potential therapeutic agent; however, due to its spontaneous extracellular metabolism, the role played by the GUO-PNP-guanine system needs to be further investigated

Guanine inhibits the growth of human glioma and melanoma cell lines by interacting with GPR23

Guanine-based purines (GBPs) exert numerous biological effects at the central nervous system through putative membrane receptors, the existence of which is still elusive. To shed light on this question, we screened orphan and poorly characterized G protein-coupled receptors (GPRs), selecting those that showed a high purinoreceptor similarity and were expressed in glioma cells, where GBPs exerted a powerful antiproliferative effect. Of the GPRs chosen, only the silencing of GPR23, also known as lysophosphatidic acid (LPA) 4 receptor, counteracted GBP-induced growth inhibition in U87 cells. Guanine (GUA) was the most potent compound behind the GPR23-mediated effect, acting as the endpoint effector of GBP antiproliferative effects. Accordingly, cells stably expressing GPR23 showed increased sensitivity to GUA. Furthermore, while GPR23 expression was low in a hypoxanthine-guanine phosphoribosyl-transferase (HGPRT)-mutated melanoma cell line showing poor sensitivity to GBPs, and in HGPRT-silenced glioma cells, GPR23-induced expression in both cell types rescued GUA-mediated cell growth inhibition. Finally, binding experiments using [H-3]-GUA and U87 cell membranes revealed the existence of a selective GUA binding (K-D = 29.44 & PLUSMN; 4.07 nM; Bmax 1.007 & PLUSMN; 0.035 pmol/mg prot) likely to GPR23. Overall, these data suggest GPR23 involvement in modulating responses to GUA in tumor cell lines, although further research needs to verify whether this receptor mediates other GUA effects

Metabolismo proteico en ratas con resección intestinal. Influencia de los triglicéridos de cadena media y del ácido ursodeoxicólico

The effects of different types of diet and resecting 50% of the distal small intestine on the digestive and metabolic utilization of protein were studied in resected rats and sham-operated controls, one month and three months after the operation. Intestinal resection led to a deterioration in digestive utilization of protein, which improved with time (3 months postsurgery). A qualitative change in the dietary fat source from 100% olive oil to equal parts of medium chain triglycerides, sunflower seed oil and olive oil favored digestive utilization of protein as recordered 1 month after surgery. However, the beneficial effects were maintaned at 3 months in resected rats given dietary fat in the form of 100% olive oil or if the modificate diet is additionate of ursodeoxycholic acid.Se estudia en ratas adultas controles "falsamente operadas" y con resección del 50% de intestino delgado distal, el efecto de dicha resección y de la administración de distintos tipos de dieta sobre la utilización nutritiva de la proteína, cuando han transcurrido un mes y tres meses después de la resección. La resección intestinal conlleva a un deterioro de la utilización digestiva de la proteína, al mes de la intervención; este deterioro es paliado con el transcurso del tiempo. La modificación de la calidad lipídica por sustitución de 2/3 de aceite de oliva por triglicéridos de cadena media (MCT) a partes iguales, mejora la utilización digestiva de la proteína al mes de la intervención quirúrgica. Sin embargo, este efecto beneficioso se manifiesta a los tres meses de la resección cuando las ratas tienen como aporte lipídico sólo aceite de oliva o bien si la dieta modificada es adicionada de ácido ursodeoxicólico

Efecto de la resección intestinal de los triglicéridos de cadena media y del ácido ursodeoxicólico sobre la utilización nutritiva del Calcio, Fósforo y Magnesio en ratas

Se estudia el efecto de la resección intestinal y de la administración de dos tipos de dieta sobre la utilización nutritiva de calcio, fósforo y magnesio en ratas controles "falsamente operadas" y con resección del 50% de intestino delgado distal al mes y a los tres meses de la intervención quirúrgica. La exclusión del 50% de intestino delgado distal conduce a un descenso en la utilización digestiva de calcio, fósforo y magnesio, reflejándose en el contenido mineral del hueso. A los tres meses de haber practicado la resección, la utilización nutritiva de calcio no se recupera, en cambio mejora la eficacia digestiva de fósforo y el aprovechamiento digestivo y metabólico de magnesio. La dieta que contiene triglicéridos de cadena media (MCT) y aceite de girasol en sustitución de 2/3 de aceite de oliva adicionada de ácido ursodeoxicólico, eleva la absorción de fósforo y magnesio cuando es ingerida por ratas resecadas durante un mes. A los tres meses de haber practicado la resección, el suministro de la misma dieta mejora la utilización digestiva y metabólica de calcio. En relación al fósforo, la mejor utilización nutritiva encontrada al mes, se hace aún más patente a los tres meses.The nutntIve utilization of calcium, phosphorus and magnesium was studied in adult rats in which 50% of the distal small intestine (DSI) had been resected and in sham-operated controls one month and three months after the operation. Resection of half the DSI reduced the digestive utilization of Ca, P. and Mg as reflected by mineral content in bone. Three months after resec tion, nutritive utilizatíon of Ca had still not recovered; in contrast digestive utilization of P and nutritive utilization of Mg were seen to recover by three months postsurgery. When dietary fat was supplied as equal parts of medium chain trig Iycerides, sunflower seed oil and olive oil instead of lOO%·'oÍive 01-1,' additionate of ursodeoxycholic acid, P and Mg absorption were ' en'hanced in resected rats after one month. After a period of three months durin& which res'ected rats were given the same diet, digestive and metabolic utilization of Ca improve. In relation to P, the better nutritive utilization found one month after resection is more notable at three months

Metabolismo proteico en ratas con resección intestinal. Influencia de los triglicéridos de cadena media y del ácido ursodeoxicólico

Se estudia en ratas adultas controles "falsamente operadas" y con resección del 50% de intestino delgado distal, el efecto de dicha resección y de la administración de distintos tipos de dieta sobre la utilización nutritiva de la proteína, cuando han transcurrido un mes y tres meses después de la resección. La resección intestinal conlleva a un deterioro de la utilización digestiva de la proteína, al mes de la intervención; este deterioro es paliado con el trans curso del tiempo. La modificación de la calidad lipídica por sustitución de 2/3 de aceite de oliva por triglicéridos de cadena media (MCT) a partes iguales, mejora la utilización digestiva de la proteína al mes de la intervención quirúrgica. Sin embargo, este efecto beneficioso se manifiesta a los tres meses de la resección cuando las ratas tienen como aporte lipídico sólo aceite de oliva o bien si la dieta modificada es adicionada de ácido ursodeoxicólico.The effects of different types of diet and resecting 50% of the distal small intestine on the digestive and metabolic utilization of protein were studied in resected rats and sham-operated controls, one month and three months after the operation. Intestinal resection led to a deterioration in digestive utilization of protein, which improved with time (3 months postsurgery). A qualitative change in the dietary fat source from 100% olive oil to equal parts of medium chain trig\ycerides, sunflower seed oil and olive oil favored digestive utilization of protein as recordered 1 month after surgery. However, the beneficial effects were maintaned at 3 months in resected rats given dietary fat in the form of 100% olive oil or if the modificate diet is additionate of ursodeoxycholic acid

Efecto de la resección intestinal de los triglicéridos de cadena media y del ácido ursodeoxicólico sobre la utilización nutritiva del Calcio, Fósforo y Magnesio en ratas

The nutritive utilization of calcium, phosphorus and magnesium was studied in adult rats in which 50% of the distal small intestine (DSI) had been resected and in sham-operated controls one month and three months after the operation. Resection of half the DSI reduced the digestive utilization of Ca, P. and Mg as reflected by mineral content in bone. Three months after resection, nutritive utilizatíon of Ca had still not recovered; in contrast digestive utilization of P and nutritive utilization of Mg were seen to recover by three months postsurgery. When dietary fat was supplied as equal parts of medium chain triglycerides, sunflower seed oil and olive oil instead of 100% olive oil, additionate of ursodeoxycholic acid, P and Mg absorption were enhanced in resected rats after one month. After a period of three months during which resected rats were given the same diet, digestive and metabolic utilization of Ca improve. In relation to P, the better nutritive utilization found one month after resection is more notable at three months.Se estudia el efecto de la resección intestinal y de la administración de dos tipos de dieta sobre la utilización nutritiva de calcio, fósforo y magnesio en ratas controles "falsamente operadas" y con resección del 50% de intestino delgado distal al mes y a los tres meses de la intervención quirúrgica. La exclusión del 50% de intestino delgado distal conduce a un descenso en la utilización digestiva de calcio, fósforo y magnesio, reflejándose en el contenido mineral del hueso. A los tres meses de haber practicado la resección, la utilización nutritiva de calcio no se recupera, en cambio mejora la eficacia digestiva de fósforo y el aprovechamiento digestivo y metabólico de magnesio. La dieta que contiene triglicéridos de cadena media (MCT) y aceite de girasol en sustitución de 2/3 de aceite de oliva adicionada de ácido ursodeoxicólico, eleva la absorción de fósforo y magnesio cuando es ingerida por ratas resecadas durante un mes. A los tres meses de haber practicado la resección, el suministro de la misma dieta mejora la utilización digestiva y metabólica de calcio. En relación al fósforo, la mejor utilización nutritiva encontrada al mes, se hace aún más patente a los tres meses

Adenosine receptor heteromers and their integrative role in striatal function

By analyzing the functional role of adenosine receptor heteromers, we review a series of new concepts that should modify our classical views of neurotransmission in the central nervous system (CNS). Neurotransmitter receptors cannot be considered as single functional units anymore. Heteromerization of neurotransmitter receptors confers functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. Some of these characteristics can be used as a 'biochemical fingerprint' to identify neurotransmitter receptor heteromers in the CNS. This is exemplified by changes in binding characteristics that are dependent on coactivation of the receptor units of different adenosine receptor heteromers. Neurotransmitter receptor heteromers can act as 'processors' of computations that modulate cell signaling, sometimes critically involved in the control of pre- and postsynaptic neurotransmission. For instance, the adenosine A1-A2A receptor heteromer acts as a concentration-dependent switch that controls striatal glutamatergic neurotransmission. Neurotransmitter receptor heteromers play a particularly important integrative role in the 'local module' (the minimal portion of one or more neurons and/or one or more glial cells that operates as an independent integrative unit), where they act as processors mediating computations that convey information from diverse volume-transmitted signals. For instance, the adenosine A2A-dopamine D2 receptor heteromers work as integrators of two different neurotransmitters in the striatal spine module