Deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis.

PTPRD encodes the protein tyrosine phosphatase receptor type D and is frequently inactivated across many human cancers. Despite its frequent inactivation, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo. PTPRD is located on chromosome 9p, as is CDKN2A, and the two loci are frequently deleted together. Here, we show that co-deletion of Ptprd and Cdkn2a cooperate to accelerate tumorigenesis. Interestingly,heterozygous loss of Ptprd was sufficient to promote tumorigenesis in our model, suggesting that Ptprd may be a haploinsufficient tumor suppressor. The loss of Ptprd resulted in changes to the tumor spectrum in mice and increased the frequency of lymphomas. In total, we reveal that Ptprd is a tumor suppressor that can promote tumorigenesis in concert with Cdkn2a loss.

Loss of the tyrosine phosphatase PTPRD leads to aberrant STAT3 activation and promotes gliomagenesis.

PTPRD, which encodes the protein tyrosine phosphatase receptor-δ, is one of the most frequently inactivated genes across human cancers, including glioblastoma multiforme (GBM). PTPRD undergoes both deletion and mutation in cancers, with copy number loss comprising the primary mode of inactivation in GBM. However, it is unknown whether loss of PTPRD promotes tumorigenesis in vivo, and the mechanistic basis of PTPRD function in tumors is unclear. Here, using genomic analysis and a glioma mouse model, we demonstrate that loss of Ptprd accelerates tumor formation and define the oncogenic context in which Ptprd loss acts. Specifically, we show that in human GBMs, heterozygous loss of PTPRD is the predominant type of lesion and that loss of PTPRD and the CDKN2A/p16(INK4A) tumor suppressor frequently co-occur. Accordingly, heterozygous loss of Ptprd cooperates with p16 deletion to drive gliomagenesis in mice. Moreover, loss of the Ptprd phosphatase resulted in phospho-Stat3 accumulation and constitutive activation of Stat3-driven genetic programs. Surprisingly, the consequences of Ptprd loss are maximal in the heterozygous state, demonstrating a tight dependence on gene dosage. Ptprd loss did not increase cell proliferation but rather altered pathways governing the macrophage response. In total, we reveal that PTPRD is a bona fide tumor suppressor, pinpoint PTPRD loss as a cause of aberrant STAT3 activation in gliomas, and establish PTPRD loss, in the setting of CDKN2A/p16(INK4A) deletion, as a driver of glioma progression.

Metabolic interactions between vitamin A and conjugated linoleic acid.

Lipid-soluble molecules share several aspects of their physiology due to their common adaptations to a hydrophilic environment, and may interact to regulate their action in a tissue-specific manner. Dietary conjugated linoleic acid (CLA) is a fatty acid with a conjugated diene structure that is found in low concentrations in ruminant products and available as a nutritional supplement. CLA has been shown to increase tissue levels of retinol (vitamin A alcohol) and its sole specific circulating carrier protein retinol-binding protein (RBP or RBP4). However, the precise mechanism of this action has not been elucidated yet. Here, we provide a summary of the current knowledge in this specific area of research and speculate that retinol and CLA may compete for catabolic pathways modulated by the activity of PPAR-α and RXR heterodimer. We also present preliminary data that may position PPAR-α at the crossroads between the metabolism of lipids and vitamin A.

Regional density of glial cells in the rat corpus callosum.

Axons and glial cells are the main components of white matter. The corpus callosum (CC) is the largest white matter tract in mammals; in rodents, 99% of the cells correspond to glia after postnatal day 5 (P5). The area of the CC varies through life and regional differences related to the number of axons have been previously described. Whether glial cell density varies accordingly is unknown; thus the aim of this study was to estimate glial cell density for the genu, body and splenium -the three main regions of CC-, of P6 and P30 rats. Here we report that the density of CC glial cells reduced by ~10% from P6 to P30. Even so, the density of astrocytes showed a slight increase (+6%), probably due to differentiation of glioblasts. Interestingly, glial cell density decreased for the genu (-21%) and the body (-13%), while for the splenium a minor increase (+5%) was observed. The astrocyte/glia ratio increased (from P6 to P30) for the genu (+27%), body (+17%) and splenium (+4%). Together, our results showed regional differences in glial cell density of the CC. Whether this pattern is modified in some neuropathologies remains to be explored.

Regional density of glial cells in the rat corpus callosum

Axons and glial cells are the main components of white matter. The corpus callosum (CC) is the largest white matter tract in mammals; in rodents, 99% of the cells correspond to glia after postnatal day 5 (P5). The area of the CC varies through life and regional differences related to the number of axons have been previously described. Whether glial cell density varies accordingly is unknown; thus the aim of this study was to estimate glial cell density for the genu, body and splenium -the three main regions of CC-, of P6 and P30 rats. Here we report that the density of CC glial cells reduced by ~10% from P6 to P30. Even so, the density of astrocytes showed a slight increase (+6%), probably due to differentiation of glioblasts. Interestingly, glial cell density decreased for the genu (-21%) and the body (-13%), while for the splenium a minor increase (+5%) was observed. The astrocyte/glia ratio increased (from P6 to P30) for the genu (+27%), body (+17%) and splenium (+4%). Together, our results showed regional differences in glial cell density of the CC. Whether this pattern is modified in some neuropathologies remains to be explored.

Protein tyrosine phosphatase receptor delta acts as a neuroblastoma tumor suppressor by destabilizing the aurora kinase A oncogene.

BACKGROUND: Protein tyrosine phosphatase receptor delta (PTPRD) is a member of a large family of protein tyrosine phosphatases which negatively regulate tyrosine phosphorylation. Neuroblastoma is a major childhood cancer arising from precursor cells of the sympathetic nervous system which is known to acquire deletions and alterations in the expression patterns of PTPRD, indicating a potential tumor suppressor function for this gene. The molecular mechanism, however, by which PTPRD renders a tumor suppressor effect in neuroblastoma is unknown. RESULTS: As a molecular mechanism, we demonstrate that PTPRD interacts with aurora kinase A (AURKA), an oncogenic protein that is over-expressed in multiple forms of cancer, including neuroblastoma. Ectopic up-regulation of PTPRD in neuroblastoma dephosphorylates tyrosine residues in AURKA resulting in a destabilization of this protein culminating in interfering with one of AURKA's primary functions in neuroblastoma, the stabilization of MYCN protein, the gene of which is amplified in approximately 25 to 30% of high risk neuroblastoma. CONCLUSIONS: PTPRD has a tumor suppressor function in neuroblastoma through AURKA dephosphorylation and destabilization and a downstream destabilization of MYCN protein, representing a novel mechanism for the function of PTPRD in neuroblastoma.

Hepatic retinol secretion and storage are altered by dietary CLA: common and distinct actions of CLA c9,t11 and t10,c12 isomers.

Conjugated linoleic acid (CLA) is a polyunsaturated fatty acid obtained from ruminant products. Previous studies in rats and pigs showed that a dietary equimolar mixture of c9,t11 and t10,c12 CLA isomers induces changes in serum and tissue levels of retinoids (vitamin A derivatives). However, the mechanism(s) responsible for these actions remain(s) unexplored. Given the numerous crucial biological functions regulated by retinoids, it is key to establish whether the perturbations in retinoid metabolism induced by dietary CLA mediate some of the beneficial effects associated with intake of this fatty acid or, rather, have adverse consequences on health. To address this important biological question, we began to explore the mechanisms through which dietary CLA alters retinoid metabolism. By using enriched preparations of CLA c9,t11 or CLA t10,c12, we uncoupled the effects of these two CLA isomers on retinoid metabolism. Specifically, we show that both isomers induce hepatic retinyl ester accumulation. However, only CLA t10,c12 enhances hepatic retinol secretion, resulting in increased serum levels of retinol and its specific carrier, retinol-binding protein (RBP). Dietary CLA t10,c12 also redistributes retinoids from the hepatic stores toward the adipose tissue and possibly stimulates hepatic retinoid oxidation. Using mice lacking RBP, we also demonstrate that this key protein in retinoid metabolism mediates hepatic retinol secretion and its redistribution toward fat tissue induced by CLA t10,c12 supplementation.

Well-being and family support among elderly rural Mexicans in the context of migration to the United States.

OBJECTIVE: To explore perceptions of well-being, family support, and economic resources in relation to level of contact with migration to the U.S. among a sample of elderly males from rural Mexico. METHOD: The snowballing technique was used to obtain a sample of 372 participants. Four groups were created according to the level of contact with migration among older adults and their children. RESULTS: Greater level of contact with migration was associated with a higher likelihood that an older adult was literate, married or living with someone, self-employed, and retired or pensioned. In addition, greater level of contact with migration to the U.S. was associated with a higher level of perceived well-being, family support, and economic security. DISCUSSION: Elderly, rural Mexican men with a greater degree of contact with migration to the U.S. seem to have more security and well-being in their old age.

["Damage, not age, is what makes a person old": ageing and health in rural males]. / "No hacen viejos los años, sino los daños": envejecimiento y salud en varones rurales.

OBJECTIVE: To analyze the social factors associated with the health status of elderly men, 60 years and older, who live in poverty in the rural areas of Mexico. MATERIAL AND METHODS: A cross-sectional, descriptive study was conducted between February and October 2002, in a convenience sample of 392 elderly men residing in rural areas of the states of Guerrero, Morelos and Jalisco states. A validated questionnaire was applied to collect data on sociodemographic characteristics, general wellbeing, health problems, food consumption, and some indicators of mental health, personal strength and social support. Data analysis was performed with the SPSS v. 11. software, to obtain chi-squared tests; food intake measures were analized with one-way ANOVA. RESULTS: Study subjects were married or were widowers and had six children on average. A higher proportion of the elderly men of Morelos state reported to have suffered more illnesses and a higher consumption of alcohol when compared to the other two state groups. Sixty percent of the men in the study used both home remedies and medication for their health problems. More than one half of them did not receive adequate social support from their families. CONCLUSIONS: The results of this study suggest that the process of ageing among rural elderly men is perceived as a burden, mainly because of the context of poverty in which they live. The lack of appropriate income and access to health services through adequate pension and retirement plans for the elderly poor is a problem that requires immediate attention.

"No hacen viejos los años, sino los daños": envejecimiento y salud en varones rurales / Ageing and health among rural men

OBJETIVO: Analizar los factores sociales asociados al estado de salud de hombres mayores de 60 años que viven en contextos de pobreza en áreas rurales de México. MATERIAL Y MÉTODOS: De febrero a octubre de 2002 se llevó a cabo un estudio transversal, descriptivo, con una muestra intencional de 392 adultos mayores residentes de zonas rurales de los estados de Guerrero, Morelos y Jalisco, utilizando un cuestionario especialmente diseñado y piloteado con anterioridad. Las variables de estudio incluyeron características sociodemográficas, bienestar generalizado, problemas de salud, consumo de algunos alimentos y algunos indicadores de salud mental, fuerza personal y apoyo social. Utilizando el paquete estadístico SPSS v. II.I se llevaron a cabo pruebas de Ji cuadrada de Pearson para variables categóricas; para analizar el consumo diferencial de alimentos se hicieron pruebas de ANOVA de una vía. RESULTADOS: Los ancianos de este estudio eran casados o viudos y tenían un promedio de seis hijos. Los ancianos de Morelos informaron haber padecido un mayor número de enfermedades y haber tenido un consumo más alto de bebidas alcohólicas, en comparación con los ancianos de los otros dos estados. De la muestra total, 60 por ciento notificaron el uso tanto de remedios caseros como de medicamentos para aliviar sus malestares de salud. Más de la mitad no recibía apoyo familiar adecuado. CONCLUSIONES: Los resultados de este estudio sugieren que el proceso de envejecimiento entre los hombres participantes es percibido como una carga, fundamentalmente debido al contexto de pobreza en que viven. La falta de ingresos suficientes y acceso a servicios de salud a través de planes de pensión y jubilación adecuados para los ancianos que viven en pobreza, es un problema que requiere de atención inmediata.