The United States and Canadian Academy of Pathology Lippincott Williams and Wilkins publishes Laboratory Investigation

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		HEMATOPORPHYRIN DETECTS EARLY ATHEROSCLEROSIS: The continuous breakdown of hemoglobin and other heme containing proteins liberates abundant hematoporphyrin derivatives. In large measure these derivatives are efficiently metabolized; but a small percentage linger and accumulate in lipid-rich tissues. Thus, it has long been appreciated that hematoporphyrin derivatives accumulate in atheromas, certain tumors, and other tissues. Another very convenient property of such derivatives is that, upon excitation with ultraviolet light, they yield a red fluorescence that shifts to longer wavelengths as a function of the hydrophobicity of their environment. This property can be used to probe the microenvironemnt of the accumulated hematoporphyrin. In this issue, Machida and colleagues study the fluorescent emission of hematoporphyrin accumulated in the atheromas of a series of human aortas, and carefully correlate these findings with other measures of lesional progression (Lab Invest 1999;79:733\N746). Their findings reveal nicely the increasing accumulation of lipid and micellar structures and their increasing concentration into the core of the plaque as lesions progress. Although these observations have been made by other techniques and are well known, what is remarkable is that Machida et al demonstrate that these changes can be detected in situ (and potentially in vivo) entirely noninvasively by fluorescent ratio imaging. This opens the possibly, as the authors suggest, that it might be possible in the future to identify, using minimally invasive techniques in vivo, those lesions most prone to rupture and thrombosis. Fluorescence Spectroscopic and Histochemical Analysis Using Hematoporphyrin as a Microenvironmental Probe for Atherosclerotic Change in the Human Aorta Minoru Machida, Kohji Kameyama, Goro Asano, and Tatsuo Kumazaki METAPLASTIC MUCOSA IN CHRONIC GASTRITIS AND CARCINOMA: Chronic gastritis with intestinal metaplasia is a known risk factor for gastric cancer, and dysplasia arising in this background is the route for malignant transformation. However, the high prevalence of chronic gastritis in adults (exceeding 50\% in some populations) makes difficult any rational approach to screening for dysplasia. There is thus considerable value in gaining insights into the transition from mucosa-at-risk to dysplasia/carcinoma in the gastric mucosa. The predominant approach to such investigations is analysis of gene expression and regulation, based on the premise that changes in the nuclear cell cycle represent the causal events in onset of neoplasia. An alternative approach, used successfully by Ray et al in an analysis of dysplasia in Barrett\'s esophagus (Lab Invest 1997;77:503\N511), is to examine the cellular phenotype of neoplastic cells. There is elegant logic in this approach, because nuclear changes result in alterations in the cell phenotype, including loss of polarity and altered intercellular signalling and cell adhesion properties. The practice of histopathology is based on assessment of phenotype, not genotype. Therefore, it may be possible to evaluate the mucosa-at-risk on the basis of proteins expressed elsewhere in the cell, rather than the nucleus. In this issue, the same group (Schmidt et al) has examined expression of the trefoil peptide spasmolytic polypeptide (SP) in metaplastic, dysplastic, and malignant gastric mucosa (Lab Invest 1999;79:639\N646). Trefoil peptides are small secretory proteins characterized by three intrachain disulfide bonds forming a trefoil motif. They are abundantly expressed on mucosal surfaces, especially of the gastrointestinal tract. Their expression is up-regulated in pathologic conditions such as ulceration, metaplasia, and neoplasia. Helicobacter felis infection in laboratory mice leads to a profound gastropathy with mucous cell hyperplasia, oxyntic atrophy, and marked expansion of a metaplastic epithelial cell lineage strongy expressing SP (Fox et al, Gastroenterology 1996,110:155\N166). Schmidt et al now demonstrate that SP-expressing metaplastic mucosa (SPEM) was present in 68% of gastric biopsies from human patients infected with Helicobacter pylori,but is absent in patients without H. pylori infection. The SPEM lineage also was identified in 91\% of gastric resections for adenocarcinoma, typically located in mucosa adjacent to the carcinoma or in areas of dysplasia. A strong association between the SPEM lineage with both chronic gastritis with H. pylori infection and gastric adenocarcinoma is thus demonstrated. Although this study does not prove any causal associations, the identification of an aberrant cell lineage expressing SP raises the possibility that this phenotypic change is a link between chronic gastritis and dysplasia leading to gastric adenocarcinoma. In particular, besides evaluating the potential diagnostic utility of this marker protein, investigation of the aberrant cellular expression of this trefoil peptide may provide clues regarding how chronic extracellular H. pylori infection increases the risk of intracellular malignant transformation within the gastric mucosa. Identification of a Metaplastic Cell Lineage Associated with Human Gastric Adenocarcinoma P. Henry Schmidt, Jeffrey R. Lee, Viren Joshi, Raymond J. Playford, Richard Poulsom, Nicholas A. Wright, and James R. Goldenring PRION PROTEIN IS REQUIRED FOR PURKINJE CELL DEVELOPMENT: Understanding the etiology of the spongiform encephalopathies and many other neurodegenerative disorders is proving to be one of modern medicine's most difficult and controversial challenges. Increasing evidence indicates that many of these diseases may be so-called protein folding disorders that result from the accumulation in the CNS of abnormally folded and degradation resistant proteins. In the so-called CAG repeat disorders (eg, Huntington's disease), the accumulation of excessively long polyglutamine protein tails leads to their inefficient processing and pathologic accumulation in neurons. Alzheimer's patients accumulate amyloid after inappropriate cleavage of its precursor protein (APP). In the prion diseases, it appears that the underlying event is the accumulation of abnormal protease-resistant protein (PrPSc). This abnormal form appears to nucleate its own propagation by a post-translational modification of the normal prion protein (PrP C). However, the mechanisms of cell injury in the prion diseases and the normal functions of prion protein have remained uncertain. One possibility is that, as with other protein folding diseases, it is the accumulation of the abnormally folded product per se that leads to neuronal toxicity; alternatively, the presence of the PrPSc protein itself may act in a dominant negative way to block the normal action of PrP C. In this issue, Dr. Prusiner and his colleagues present persuasive evidence that the loss of PrPC function prevents Purkinje cell development in PrPC (\-/\-) animals, and that this phenotype can be rescued by restoration of wild-type PrPC (Lab Invest 1999;79:689\N698). These are important observations and clearly indicate that, regardless of any toxicity that might arise from PrP accumulation, the loss of PrPC function is in itself toxic. A Mouse Prion Protein Transgene Rescues Mice Deficient for the Prion Protein Gene from Purkinje Cell Degeneration and Demyelination Noriyuki Nishida, Patrick Tremblay, Tetsuo Sugimoto, Kazuto Shigematsu, Susumu Shirabe, Chris Petromilli, Susanne Pilkuhn Erpel, Ryota Nakaoke, Ryuichiro Atarashi, Takeshi Houtani, Marilyn Torchia, Suehiro Sakaguchi, Stephen J. DeArmond, Stanley B. Prusiner, and Shigeru Katamine THE CONSEQUENCES OF THE POWER TO STAY: Stabilization of the myc protein may be a hereto unknown mechanism to generate a superactive function of the myc gene product involved in malignant transformation. Myc is a nuclear phosphoprotein that has regulatory roles in cell cycle, cell immortality/apoptosis, and cell differentiation. Its function as a transcription factor seems to be regulated by the formation of heterodimers with other proteins such as max. Recent reports indicate that myc is one of the downstream genes controlled by the beta-catenin/Tcf-4 bipartite transcription factor, the terminal component of the Wnt/Wng pathway. Disruption of the Wnt transduction cascade by mutation of the APC or beta-catenin genes can lead to the overexpression of myc seen in colorectal tumors. The data presented here by Albalwi et al (Lab Invest 1999;79:707\N716) indicate that the levels of myc protein are significantly higher in the cells of malignant lymphomas than in normal lymphoid cells. The study is performed by using semiquantitative fluorescence analysis of RNA levels (using FISH) and protein (using immunofluorescence). The somewhat unexpected finding is that the major differences are observed not at the mRNA level but at the protein level. The authors therefore conclude that in non-Hodgkin's lymphomas, stabilization of the myc protein may lead to increased myc function that in turn contributes to malignant transformation of the lymphoid cells. By studying paired tissue biopsies obtained at the low grade and high grade stages of evolution of the tumors, they present evidence that the stabilization occurs early and is not likely to be implicated in the progression of the tumors. The fact that the levels of protein are lower in proliferative benign lymphoid tissues suggest that the observations are not simply explained by cell proliferation and that the stabilization of myc may well be important in the physiopathology of a subgroup of non\NHodgkin\'s malignant lymphomaIf these findings are confirmed, it will be interesting to learn how wdespread this phenomenon may be in other tumors and whether the increased levels of myc result from decreased degradation or increased rate of synthesis. Semi-Quantitative Fluorescence In Situ Hybridization Analysis Indicates that the myc Protein Is Consistently Stabilized Both Before and After Transformation of Low-Grade Follicular Center to High-Grade Diffuse Large Cell Lymphoma Mohammed Albalwi, David W. Hammond, John R. Goepel, Rachael E. Hough, and Malcolm H. Goyns