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This Month in AJP |
Shortened Telomeres Are Early Lesions in Human Pancreatic Ductal Adenocarcinoma, Detectable in Intraepithelial Neoplasia
Telomeres are DNA repeat sequences present at the ends of chromosomes. Telomeres shorten with each cell division and maintain the integrity of chromosomes by preventing fusion that leads to the formation of ring and dicentric chromosomes. Telomerase activity is generally undetectable in normal tissues but may be activated in tumors. Tjarda van Heek et al (Am J Pathol 2002, 161:1541–1547) hypothesized that critically short telomeres may cause chromosomal instability in pancreatic ductal adenocarcinomas. They reasoned that telomere shortening may be present in non-invasive precursor lesions for these tumors referred to as PanIN (pancreatic intraepithelial neoplasia). They measured telomere length by in situ hybridization in archival samples of 82 PanIN lesions with different histological grades, selected from pancreatic adenocarcinomas or chronic pancreatitis specimens. Telomere shortening was detected in 96% of the PanIN lesions, compared to adjacent normal tissues and was present in 91% of PanIN-1A, the earliest identifiable lesion. Reduction of telomere length was present in PanIN lesions in chronic pancreatitis but was absent in inflammatory or atrophic ductal lesions. Telomere shortening in PanIN lesions did not correlate with an increase in cell proliferation suggesting that telomere shortening is a very early abnormality that may predispose precursor lesions to progress into ductal adenocarcinomas in the human pancreas.
Isolation of Living Neurons from Brain Autopsy Tissues
The study of neuron biology would be greatly enhanced if it were possible to isolate living neurons from human brains and place them in culture. Although some attempts have been made to isolate living human neurons, they have not been successful. Konishi et al (Am J Pathol 2002, 161:1567–1576) describe a new technique for the isolation of living neurons from brains of elderly humans obtained at autopsy. The post-mortem interval was short, averaging 2.6 hours. The cells were obtained from the parietal cortex by separation through density gradients followed by immunomagnetic sorting using a DNA-linker technique. The fractionated cell preparations contained neurons (approximately 80% purity) with glutamate and GABA neurotransmitter phenotypes. In culture, the cells maintained viability and calcium influx for at least 2 weeks. The technique described by Konishi et al opens the way to the study of the molecular mechanisms of neuronal abnormalities using relatively pure cultures of human neurons.
L-Selectin and ICAM-1 Are Required for Development of Pulmonary Fibrosis
Pulmonary fibrosis develops as a consequence of asbestosis and connective tissue diseases as well as a primary, "idiopathic" disease. The molecular and cellular mechanisms that lead to pulmonary fibrosis are not well known and the use of immunosuppressive therapy has generally poor results. Intratracheal administration of bleomycin in mice causes an initial inflammatory response with leukocyte recruitment followed by a fibrotic reaction. For this reason, bleomycin lung injury has been used as a model to study the pathogenesis of pulmonary fibrosis. Hamaguchi et al (Am J Pathol 2002, 161:1607–1618) studied whether bleomycin-induced lung injury would be modified in knockout mice deficient in L-selectin or ICAM-1 and in mice deficient in both genes. In either L-selectin or ICAM-1 knockout mice, collagen deposition 16 days after administration of bleomycin was inhibited and was virtually eliminated in L-selectin/ICAM-1 double transgenic mice. Decreased collagen production was associated with reduced leukocyte infiltration and low expression of pro-inflammatory cytokines and TGFß1. These studies demonstrate that the adhesion molecules L-selectin and ICAM-1 play a key role in the development of pulmonary fibrosis.
Intracellular Accumulation of ß-Amyloid 42 Precedes Plaque Formation in Alzheimer’s Disease
The formation of extracellular plaques with deposition of ß-amyloid (Aß) is generally described as the most characteristic lesion of Alzheimer’s disease. Nevertheless, the extent to which plaques contribute to the pathogenesis and progression of the disease has not been established. Other studies have demonstrated that Aß can accumulate intraneuronally and cause severe behavioral and functional alterations before the appearance of Aß plaques. Aß42, an Aß form that is increased in familial Alzheimer’s disease and in Down’s syndrome, accumulates in pyramidal neurons in patients with early cognitive defects. Takahashi et al (Am J Pathol 2002, 161:1869–1879) studied the subcellular localization of Aß42 in human brains from patients with Alzheimer’s disease and in brains of mice with mutations associated with the disease. Both in human Alzheimer’s and in the transgenic brains, Aß42 accumulated in multivesicular bodies within pre- and particularly, in post-synaptic compartments. Intracellular deposition of Aß42 was accompanied by abnormal synaptic morphology and preceded the formation of Aß plaques. These results demonstrate that intracellular accumulation of Aß plays an important role in the pathogenesis of Alzheimer’s disease and that it occurs before plaque formation.
A New Animal Model to Study Phosphate Metabolism and Bone Development
Rickets and osteomalacia are bone diseases occurring respectively in children and adults most commonly as a consequence of vitamin-D-deficient diets and limited exposure to sunlight. Less frequently, these conditions may result from phosphate depletion. The condition known as X-linked hypophosphatemia (XLH) is a familial disease involving a defect in the phosphate-regulating gene Phex. The disease is characterized by rickets or osteomalacia, dwarfism, hypophosphatemia, and elevated serum alkaline phosphatase. Phex acts by repressing phosphate resorption by the kidney. Defects in the gene cause a decrease in extracellular calcium and phosphate with reduced mineralization of bone. Two strains of mice with deletions involving Phex have already been described. Carpinelli et al (Am J Pathol 2002, 161:1925–1933) identified, using random mutations induced by ethyl-nitrosourea, a strain of mice harboring a point mutation in the Phex gene that causes splicing abnormalities (skipping of exon8) in the gene. These animals have hypophosphatemia and skeletal abnormalities with the features of rickets. This animal model should prove to be of great value for the analysis of phosphate metabolism and bone development.
Guanylate Binding Protein-1 (GBP-1) Expression Is a Marker for Endothelial Cells Activated by Inflammatory Cytokines
Endothelial cell activation occurs in inflammatory processes, atherosclerosis, and tumor angiogenesis. Activation results in proliferation, apoptosis, adhesiveness, and chemotaxis and may be mediated by angiogenic growth factors and inflammatory cytokines. GBP-1 has intrinsic GTPase activity and together with GBP-2 is the most abundant protein induced by interferon-
. GBP-1 acts as an antiproliferative agent on endothelial cells exposed to inflammatory cytokines. Using a monoclonal antibody against GBP-1, Lubeseder-Martellato (Am J Pathol 2002, 161:1749–1759) show that GBP-1 is highly induced in vascular endothelial cells exposed to inflammatory cytokines such as interferon-, IL-1
, IL-1ß, and TNF, but not other cytokines. Expression of GBP-1, which is undetectable in normal skin, was greatly induced in psoriasis and Kaposi’s sarcoma. The data indicate that GBP-1 may be a marker for endothelial cells activated by inflammatory cytokines.
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