Role of transforming growth factor-α in von Hippel– Lindau (VHL)−/− clear cell renal carcinoma cell proliferation: A possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis

Mutations of the VHL tumor suppressor gene occur in patients with VHL disease and in the majority of sporadic clear cell renal carcinomas (VHL−/− RCC). Loss of VHL protein function is associated with constitutive expression of mRNAs encoding hypoxia-inducible proteins, such as vascular endothelial growth factor. Overproduction of angiogenic factors might explain why VHL−/− RCC tumors are so highly vascularized, but whether this overproduction is sufficient for oncogenesis still remains unknown. In this report, we examined the activity of transforming growth factor-α (TGF-α), another VHL-regulated growth factor. We show that TGF-α mRNA and protein are hypoxia-inducible in VHL−/− RCC cells expressing reintroduced VHL. In addition to its overexpression by VHL−/− RCC cells, TGF-α can also act as a specific growth-stimulatory factor for VHL−/− RCC cells expressing reintroduced wild-type VHL, as well as primary renal proximal tubule epithelial cells, the likely site of origin of RCC. This role is in contrast to those of other growth factors overexpressed by VHL−/− RCC cells, such as vascular endothelial growth factor and TGF-β1, which do not stimulate RCC cell proliferation. A TGF-α-specific antisense oligodeoxynucleotide blocked TGF-α production in VHL−/− RCC cells, which led to the dependence of those cells on exogenous growth factors to sustain growth in culture. Growth of VHL−/− RCC cells was also significantly reduced by a drug that specifically inhibits the epidermal growth factor receptor, the receptor through which TGF-α stimulates proliferation. These results suggest that the generation of a TGF-α autocrine loop as a consequence of VHL inactivation in renal proximal tubule epithelial cells may provide the uncontrolled growth stimulus necessary for the initiation of tumorigenesis.

High-sensitivity array analysis of gene expression for the early detection of disseminated breast tumor cells in peripheral blood

Early detection is an effective means of reducing cancer mortality. Here, we describe a highly sensitive high-throughput screen that can identify panels of markers for the early detection of solid tumor cells disseminated in peripheral blood. The method is a two-step combination of differential display and high-sensitivity cDNA arrays. In a primary screen, differential display identified 170 candidate marker genes differentially expressed between breast tumor cells and normal breast epithelial cells. In a secondary screen, high-sensitivity arrays assessed expression levels of these genes in 48 blood samples, 22 from healthy volunteers and 26 from breast cancer patients. Cluster analysis identified a group of 12 genes that were elevated in the blood of cancer patients. Permutation analysis of individual genes defined five core genes (P ≤ 0.05, permax test). As a group, the 12 genes generally distinguished accurately between healthy volunteers and patients with breast cancer. Mean expression levels of the 12 genes were elevated in 77% (10 of 13) untreated invasive cancer patients, whereas cluster analysis correctly classified volunteers and patients (P = 0.0022, Fisher's exact test). Quantitative real-time PCR confirmed array results and indicated that the sensitivity of the assay (1:2 × 108 transcripts) was sufficient to detect disseminated solid tumor cells in blood. Expression-based blood assays developed with the screening approach described here have the potential to detect and classify solid tumor cells originating from virtually any primary site in the body.

Adaptation of the bovine spongiform encephalopathy agent to primates and comparison with Creutzfeldt– Jakob disease: Implications for human health

There is substantial scientific evidence to support the notion that bovine spongiform encephalopathy (BSE) has contaminated human beings, causing variant Creutzfeldt–Jakob disease (vCJD). This disease has raised concerns about the possibility of an iatrogenic secondary transmission to humans, because the biological properties of the primate-adapted BSE agent are unknown. We show that (i) BSE can be transmitted from primate to primate by intravenous route in 25 months, and (ii) an iatrogenic transmission of vCJD to humans could be readily recognized pathologically, whether it occurs by the central or peripheral route. Strain typing in mice demonstrates that the BSE agent adapts to macaques in the same way as it does to humans and confirms that the BSE agent is responsible for vCJD not only in the United Kingdom but also in France. The agent responsible for French iatrogenic growth hormone-linked CJD taken as a control is very different from vCJD but is similar to that found in one case of sporadic CJD and one sheep scrapie isolate. These data will be key in identifying the origin of human cases of prion disease, including accidental vCJD transmission, and could provide bases for vCJD risk assessment.

Occurrence of two somatostatin variants in the frog brain: characterization of the cDNAs, distribution of the mRNAs, and receptor-binding affinities of the peptides.

In tetrapods, only one gene encoding a somatostatin precursor has been identified so far. The present study reports the characterization of the cDNA clones that encode two distinct somatostatin precursors in the brain of the frog Rana ridibunda. The cDNAs were isolated by using degenerate oligonucleotides based on the sequence of the central region of somatostatin to screen a frog brain cDNA library. One of the cDNAs encodes a 115-amino acid protein (prepro-somatostatin-14; PSS1) that exhibits a high degree of structural similarity with the mammalian somatostatin precursor. The other cDNA encodes a 103-amino acid protein (prepro-[Pro2, Met13]somatostatin-14; PSS2) that contains the sequence of the somatostatin analog (peptide SS2) at its C terminus, but does not exhibit appreciable sequence similarity with PSS1 in the remaining region. In situ hybridization studies indicate differential expression of the PSS1 and PSS2 genes in the septum, the lateral part of the pallium, the amygdaloid complex, the posterior nuclei of the thalamus, the ventral hypothalamic nucleus, the torus semicircularis and the optic tectum. The somatostatin variant SS2 was significantly more potent (4-6 fold) than somatostatin itself in displacing [125I-Tyr0, D-Trp8] somatostatin-14 from its specific binding sites. The present study indicates that the two somatostatin variants could exert different functions in the frog brain and pituitary. These data also suggest that distinct genes encoding somatostatin variants may be expressed in the brain of other tetrapods.

Adaptación del BRIEF ("Behavior Rating Inventory of Executive Function") a población española y su utilidad para el diagnóstico del trastorno por déficit de atención-hiperactividad subtipos inatento y combinado

La valoración de las funciones ejecutivas tiene una especial dificultad cuando se intenta llevar a cabo mediante un enfoque tradicional de pruebas neuropsicológicas. Este aspecto es especialmente relevante en la evaluación de funciones ejecutivas en población pediátrica, lo que propició el desarrollo de cuestionarios de conducta como el Behavior Rating Inventory of Executive Function (BRIEF), con el fin de convertirse en una medida ecológica de las alteraciones de funciones ejecutivas. Resulta necesario realizar una adaptación completa de una prueba psicométrica para que ésta pueda ser utilizada en una población diferente para la cual fue diseñada. El BRIEF ha sido utilizado para la valoración de las alteraciones ejecutivas en numerosas patologías, pero destacan los estudios realizados en niños con Trastorno por Déficit de Atención - Hiperactividad (TDAH). El TDAH presenta alteraciones neuropsicológicas que implican especialmente a las funciones ejecutivas, lo que justifica el uso de la prueba en esta patología. Incluso, algunas de las teorías más importantes sobre TDAH apuntan a las alteraciones en inhibición como el síntoma nuclear del trastorno. La existencia de dos subtipos principales en el TDAH (subtipo predominantemente inatento y combinado) podría implicar un patrón diferente de alteraciones ejecutiva en cada tipo. OBJETIVOS: Se presentan dos objetivos principales: 1) Adaptación del BRIEF a población española, y 2) Estudio del perfil diferencial del BRIEF entre los subtipos inatento y combinado del TDAH...

Jamaica, 1763 (Image 1 of 4) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: This map of the island of Jamaica; laid down from the papers and under the direction of Henry Moore, Esqr.; His Majesty's Lieutenant Governor and Commander in Chief of that island, in the years 1756, 57, 58, 59, 60 & 61; & from a great number of actual surveys performed by the publishers is humbly inscribed by his lordship's most obedient & most humble servants, Thos. Craskell, engineer, Jas. Simpson, surveyor. It was published by D. Fournier in 1763. Scale [ca 1:200,000]. This layer is image 1 of 4 total images of the four sheet map, representing the southwest portion of the map.The image inside the map neatline is georeferenced to the surface of the earth and fit to the Jamaica Grid projected coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as towns, villages, and other human settlements, roads, drainage, selected buildings, ground cover, shoreline features, and more. Relief shown pictorially. Includes also illustrations.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

Jamaica, 1763 (Image 2 of 4) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: This map of the island of Jamaica; laid down from the papers and under the direction of Henry Moore, Esqr.; His Majesty's Lieutenant Governor and Commander in Chief of that island, in the years 1756, 57, 58, 59, 60 & 61; & from a great number of actual surveys performed by the publishers is humbly inscribed by his lordship's most obedient & most humble servants, Thos. Craskell, engineer, Jas. Simpson, surveyor. It was published by D. Fournier in 1763. Scale [ca 1:200,000]. This layer is image 2 of 4 total images of the four sheet map, representing the southeast portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Jamaica Grid projected coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as towns, villages, and other human settlements, roads, drainage, selected buildings, ground cover, shoreline features, and more. Relief shown pictorially. Includes also illustrations.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

Jamaica, 1763 (Image 3 of 4) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: This map of the island of Jamaica; laid down from the papers and under the direction of Henry Moore, Esqr.; His Majesty's Lieutenant Governor and Commander in Chief of that island, in the years 1756, 57, 58, 59, 60 & 61; & from a great number of actual surveys performed by the publishers is humbly inscribed by his lordship's most obedient & most humble servants, Thos. Craskell, engineer, Jas. Simpson, surveyor. It was published by D. Fournier in 1763. Scale [ca 1:200,000]. This layer is image 3 of 4 total images of the four sheet map, representing the northeast portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Jamaica Grid projected coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as towns, villages, and other human settlements, roads, drainage, selected buildings, ground cover, shoreline features, and more. Relief shown pictorially. Includes also illustrations.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

Jamaica, 1763 (Image 4 of 4) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: This map of the island of Jamaica; laid down from the papers and under the direction of Henry Moore, Esqr.; His Majesty's Lieutenant Governor and Commander in Chief of that island, in the years 1756, 57, 58, 59, 60 & 61; & from a great number of actual surveys performed by the publishers is humbly inscribed by his lordship's most obedient & most humble servants, Thos. Craskell, engineer, Jas. Simpson, surveyor. It was published by D. Fournier in 1763. Scale [ca 1:200,000]. This layer is image 4 of 4 total images of the four sheet map, representing the northwest portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Jamaica Grid projected coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as towns, villages, and other human settlements, roads, drainage, selected buildings, ground cover, shoreline features, and more. Relief shown pictorially. Includes also illustrations.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

County of Cornwall, Jamaica, 1763 (Image 1 of 4) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: This map of the county of Cornwall, in the island of Jamaica; laid down from the papers, under the direction of, Henry Moore, Esqr., His Majesty's Lieutenant Governor, and Commander in Chief of that island, in the years 1756, 57, 58, 59, 60 & 61, & from a great number of actual surveys performed by the publishers is humbly inscribed by his lordship's most obedient & humble servants, Thos. Craskell, engineer, Jas. Simpson, surveyor. It was published by D. Fournier in 1763. Scale [ca. 1:95,000]. This layer is image 1 of 4 total images of the four sheet source map, representing the southwest portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Jamaica Grid projected coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as towns, villages, and other human settlements, roads, parish boundaries, drainage, selected buildings and names of landowners, ground cover, shoreline features, shoals, channels, anchorage points, and more.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

County of Cornwall, Jamaica, 1763 (Image 2 of 4) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: This map of the county of Cornwall, in the island of Jamaica; laid down from the papers, under the direction of, Henry Moore, Esqr., His Majesty's Lieutenant Governor, and Commander in Chief of that island, in the years 1756, 57, 58, 59, 60 & 61, & from a great number of actual surveys performed by the publishers is humbly inscribed by his lordship's most obedient & humble servants, Thos. Craskell, engineer, Jas. Simpson, surveyor. It was published by D. Fournier in 1763. Scale [ca. 1:95,000]. This layer is image 2 of 4 total images of the four sheet source map, representing the southeast portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Jamaica Grid projected coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as towns, villages, and other human settlements, roads, parish boundaries, drainage, selected buildings and names of landowners, ground cover, shoreline features, shoals, channels, anchorage points, and more.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

County of Cornwall, Jamaica, 1763 (Image 3 of 4) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: This map of the county of Cornwall, in the island of Jamaica; laid down from the papers, under the direction of, Henry Moore, Esqr., His Majesty's Lieutenant Governor, and Commander in Chief of that island, in the years 1756, 57, 58, 59, 60 & 61, & from a great number of actual surveys performed by the publishers is humbly inscribed by his lordship's most obedient & humble servants, Thos. Craskell, engineer, Jas. Simpson, surveyor. It was published by D. Fournier in 1763. Scale [ca. 1:95,000]. This layer is image 3 of 4 total images of the four sheet source map, representing the northeast portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Jamaica Grid projected coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as towns, villages, and other human settlements, roads, parish boundaries, drainage, selected buildings and names of landowners, ground cover, shoreline features, shoals, channels, anchorage points, and more.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

County of Cornwall, Jamaica, 1763 (Image 4 of 4) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: This map of the county of Cornwall, in the island of Jamaica; laid down from the papers, under the direction of, Henry Moore, Esqr., His Majesty's Lieutenant Governor, and Commander in Chief of that island, in the years 1756, 57, 58, 59, 60 & 61, & from a great number of actual surveys performed by the publishers is humbly inscribed by his lordship's most obedient & humble servants, Thos. Craskell, engineer, Jas. Simpson, surveyor. It was published by D. Fournier in 1763. Scale [ca. 1:95,000]. This layer is image 4 of 4 total images of the four sheet source map, representing the northwest portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Jamaica Grid projected coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as towns, villages, and other human settlements, roads, parish boundaries, drainage, selected buildings and names of landowners, ground cover, shoreline features, shoals, channels, anchorage points, and more. This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

County of Middlesex, Jamaica, 1763 (Image 1 of 4) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: This map of the county of Middlesex in the island of Jamaica; laid down from the papers, and under the direction of Henry Moore, Esqr., His Majesty's Lieutenant Governor and Commander in Chief of that island, in the years 1756, 57, 58, 60, & 61 and from a great number of actual surveys performed by the publishers is humbly inscribed by his lordship's most obedient & most humble servants, Thos. Craskell, engineer, Jas. Simpson, surveyor. It was published by D. Fournier in 1763. Scale [ca. 1:95,000]. The layer is image 1 of 4 total images of the four sheet map, representing the southeast portion of the map.The image inside the map neatline is georeferenced to the surface of the earth and fit to the Jamaica Grid projected coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as towns, villages, and other human settlements, roads, parish boundaries, drainage, selected buildings and names of landowners, ground cover, shoreline features, shoals, channels, anchorage points, and more.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

County of Middlesex, Jamaica, 1763 (Image 2 of 4) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: This map of the county of Middlesex in the island of Jamaica; laid down from the papers, and under the direction of Henry Moore, Esqr., His Majesty's Lieutenant Governor and Commander in Chief of that island, in the years 1756, 57, 58, 60, & 61 and from a great number of actual surveys performed by the publishers is humbly inscribed by his lordship's most obedient & most humble servants, Thos. Craskell, engineer, Jas. Simpson, surveyor. It was published by D. Fournier in 1763. Scale [ca. 1:95,000]. The layer is image 2 of 4 total images of the four sheet map, representing the southwest portion of the map. The image inside the map neatline is georeferenced to the surface of the earth and fit to the Jamaica Grid projected coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as towns, villages, and other human settlements, roads, parish boundaries, drainage, selected buildings and names of landowners, ground cover, shoreline features, shoals, channels, anchorage points, and more.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.