Columnar cell lesions of the breast: The missing link in breast cancer progression? A morphological and molecular analysis

Columnar cell lesions (CCLs) of the breast are a spectrum of lesions that have posed difficulties to pathologists for many years, prompting discussion concerning their biologic and clinical significance. We present a study of CCL in context with hyperplasia of usual type (HUT) and the more advanced lesions ductal carcinoma in situ (DCIS) and invasive ductal carcinoma. A total of 81 lesions from 18 patients were subjected to a comprehensive morphologic review based upon a modified version of Schnitt's classification system for CCL, immunophenotypic analysis (estrogen receptor [ER], progesterone receptor [PgR], Her2/neu, cytokeratin 5/6 [CK5/6], cytokeratin 14 [CK14], E-cadherin, p53) and for the first time, a whole genome molecular analysis by comparative genomic hybridization. Multiple CCLs from 3 patients were studied in particular detail, with topographic information and/or showing a morphologic spectrum of CCL within individual terminal duct lobular units. CCLs were ER an PgR positive, CK5/6 and CK14 negative, exhibit low numbers of genetic alterations and recurrent 16q loss, features that are similar to those of low grade in situ and invasive carcinoma. The molecular genetic profiles closely reflect the degree of proliferation and atypia in CCL, indicating some of these lesions represent both a morphologic and molecular continuum. In addition, overlapping chromosomal alterations between CCL and more advanced lesions within individual terminal duct lobular units suggest a commonality in molecular evolution. These data further support the hypothesis that CCLs are a nonobligate, intermediary step in the development of some forms of low grade in situ and invasive carcinoma. Copyright: © 2005 Lippincott Williams & Wilkins, Inc.

Microstructure of MmM(5)/Mg multi-layer hydrogen storage films prepared by magnetron sputtering

Multi-layer hydrogen storage thin films with Mg and MmNi(3.5)(CoAlMn)(1.5) (here Mm denotes La-rich mischmetal) as alternative layers were prepared by direct current magnetron sputtering. Transmission electron microscopy investigation shows that the microstructure of the MmNi(3.5)(CoAlMn)(1.5) and Mg layers are significantly different although their deposition conditions are the same. The MmNi(3.5)(CoAlMn)(1.5) layer is composed of two regions: one is an amorphous region approximately 4 nm thick at the bottom of the layer and the other is a nanocrystalline region on top of the amorphous region. The Mg layer is also composed of two regions: one is a randomly orientated nanocrystalline region 50 nm thick at the bottom of the layer and the other is a columnar crystallite region on top of the nanocrystalline region. These Mg columnar crystallites have their [001] directions parallel to the growth direction and the average lateral size of these columnar crystallites is about 100 nm. A growth mechanism of the multi-layer thin films is discussed based on the experiment results. Wiley-Liss, Inc.

Transgenic mice that express Cre recombinase in osteoclasts

To study the physiological control of osteoclasts, the bone resorbing cells, we generated transgenic mice carrying the Cre recombinase gene driven by either the tartrate-resistant acid phosphatase (TRAP) or cathepsin K (Ctsk) promoters. TRAP-Cre and Ctsk-Cre transgenic mouse lines were characterized by breeding with LacZ ROSA 26 (R26R) reporter mice and immunohistochemistry for Cre recombinase. The Cre transgene was functional in all lines, with Cre-mediated recombination occurring primarily in the long bones, vertebrae, ribs, and calvaria. Histological analyses of the bones demonstrated that functional Cre protein was present in 1) osteoclasts (Ctsk-Cre); 2) osteoclasts, columnar proliferating, and hypertrophic chondrocytes (TRAP-Cre line 4); and 3) round proliferating chondrocytes (TRAP-Cre line 3). In conclusion, we generated transgenic mouse lines that will enable the deletion of floxed target genes in osteoclasts, which will be valuable tools for studying the regulation of osteoclast function. (C) 2004 Wiley-Liss, Inc.

Use of X-radiographs to distinguish members of the Montastraea annularis reef-coral species complex

Recent work suggests the Montastraea annularis species complex consists of at least three species, which can be distinguished qualitatively in the field using features related to colony growth (e.g. overall growth form. bumpiness, growth along the colony edge). However, when whole colonies are not available and surfaces are eroded, identification becomes problematic when relying on such characteristics. Characters based on internal skeletal structures are less prone to loss due to taphonomic processes. Previous work has shown that internal corallite architectural features measured in transverse thin sections can be used to distinguish species. To determine whether internal colony-level features measured on X-radiographs can be used. eight characters related to corallite budding and accretionary growth were measured on specimens representing three modern members of the M. annularis species complex (M. annularis, M. flaveolata and M. franksi), as well as two fossil forms (columnar and organ-pipe). All eight characters showed significant differences among species. Discriminant function analysis using seven of these characters resulted in distinct species groupings In canonical scores plots and a 100% classification success for specimens from Panama. These results suggest that measurements made on X-radiographs provide a useful tool for quantitatively distinguishing members of the M. annularis complex as well as between other massive reef corals.

Overlapping species boundaries and hybridization within the Monastraea "annularis" reef coral complex in the Pleistocene of the Bahama Islands

Recent molecular analyses indicate that many reef coral species belong to hybridizing species complexes or "syngameons." Such complexes consist of numerous genetically distinct-species or lineages, which periodically split and/or fuse as they extend through time. During splitting and fusion, morphologic intermediates form and species overlap. Here we focus on processes associated with lineage fusion, specifically introgressive hybridization, and the recognition of such hybridization in the fossil record. Our approach involves comparing patterns of ecologic and morphologic overlap in genetically characterized modern species with fossil representatives of the same or closely related species. We similarly consider the long-term consequences of past hybridization on the structure of modern-day species boundaries. Our study involves the species complex Montastraea annularis s.l. and is based in the Bahamas, where, unlike other Caribbean locations, two of the three members of the complex today are not genetically distinct. We measured and collected colonies along linear transects across Pleistocene reef terraces of last interglacial age (approximately 125 Ka) on the islands of San Salvador, Andros, and Great Inagua. We performed quantitative ecologic and morphologic analyses of the fossil data, and compared patterns of overlap among species with data from modern localities where species are and are not genetically distinct. Ecologic and morphologic analyses reveal "moderate" overlap (>10%, but statistically significant differences) and sometimes "high" overlap (no statistically significant differences) among Pleistocene growth forms (= "species"). Ecologic analyses show that three species (massive, column, organ-pipe) co-occurred. Although organ-pipes had higher abundances in patch reef environments, columnar and massive species exhibited broad, completely overlapping distributions and had abundances that were not related to reef environment. For morphometric analyses, we used multivariate discriminant analysis on landmark data and linear measurements. The results show that columnar species overlap "moderately" with organ-pipe and massive species. Comparisons with genetically characterized colonies from Panama show that the Pleistocene Bahamas species have intermediate morphologies, and that the observed "moderate" overlap differs from the morphologic separation among the three modern species. In contrast, massive and columnar species from the Pleistocene of the Dominican Republic comprise distinct morphologic clusters, similar to the modern species; organ-pipe species exhibit "low" overlap (

Molecular evolution of breast cancer

Molecular analysis of invasive breast cancer and its precursors has furthered our understanding of breast cancer progression. In the past few years, new multi-step pathways of breast cancer progression have been delineated through genotypic-phenotypic correlations. Nuclear grade, more than any other pathological feature, is strongly associated with the number and pattern of molecular genetic abnormalities in breast cancer cells. Thus, there are two distinct major pathways to the evolution of low- and high-grade invasive carcinomas: whilst the former consistently show oestrogen receptor (ER) and progesterone receptor (PgR) positivity and 16q loss, the latter are usually ER/PgR-negative and show Her-2 over-expression/amplification and complex karyotypes. The boundaries between the evolutionary pathways of well-differentiated/low-grade ductal and lobular carcinomas have been blurred, with changes in E-cadherin expression being one of the few distinguishing features between the two. In addition, lesions long thought to be precursors of breast carcinomas, such as hyperplasia of usual type, are currently considered mere risk indicators, whilst columnar cell lesions are now implicated as non-obligate precursors of atypical ductal hyperplasia (ADH) and well-differentiated ductal carcinoma in situ (DCIS). However, only through the combination of comprehensive morphological analysis and cutting-edge molecular tools can this knowledge be translated into clinical practice and patient management. Copyright (C) 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley Sons, Ltd.

The molecular genetics of breast cancer: The contribution of comparative genomic hybridization

Comparative genomic hybridization (CGH) has been the technique of choice over the last 10 years for mapping DNA copy number changes in human tumors. Here we review the literature to demonstrate how CGH has contributed to the comprehension of molecular aspects of breast tumorigenesis. At least two distinct molecular pathways of breast cancer have been characterized that show a strong correlation with histological grade. It seems that grade I invasive ductal carcinomas (IDCs) arise from well-differentiated ductal carcinoma in situ (DCIS), whereas grade III IDCs come from poorly differentiated DCIS. In addition, dedifferentiation from a low- to a high-grade breast cancer has proven an unlikely phenomenon. CGH has been instrumental in dissecting distinct molecular pathways toward breast malignancy and in establishing a direct relationship between genotype and clinical pathological features. (C) 2005 Elsevier GrnbH. All rights reserved.

Microstructure of MmM(5)/Mg multi-layer films prepared by magnetron sputtering

Microstructure of MmNi(3.5)(CoAlMn)(1.5)/Mg (here Mm denotes La-rich mischmetal) multi-layer hydrogen storage thin films prepared by direct current magnetron sputtering was investigated by cross-sectional transmission electron microscopy (XTEM). It was shown that the MMM5 layers are composed of two regions: an amorphous region with a thickness of similar to 4nm at the bottom of the layers and a randomly orientated nanocrystallite region on the top of the amorphous region and the Mg layers consist of typical columnar crystallite with their [001] direction nearly parallel to the growth direction. The mechanism for the formation of the above microstructure characteristics in the multi-layer thin films has been proposed. Based on the microstructure feature of the multi-layer films, mechanism for the apparent improvement of hydrogen absorption/desorption kinetics was discussed. (c) 2005 Elsevier B.V. All rights reserved.

Adenocarcinoma of colon differentiating as dome epithelium of gut-associated lymphoid tissue

Aims: An early adenocarcinoma of the ascending colon was confined to a mass of gut-associated lymphoid tissue (GALT). The first description of an adenocarcinoma of colon differentiating as dome epithelium is presented. Methods and results: A plaque-like carcinoma was identified opposite the ileocaecal valve in an asymptomatic 56-year-old man with a family history of colorectal cancer. Malignant epithelium was confined to a mass of GALT filling but limited to the submucosa, Characterization of the neoplasm was undertaken by means of mucin histochemistry, immunohistochemistry, electron microscopy and assessment of DNA microsatellite instability status. The malignant epithelium comprised well differentiated columnar cells with a microvillous brush border and expressing MUC1, but no goblet cells or expression of MUC2. The demonstration of focal clusters of intraepithelial B-lymphocytes supported the presence of functioning M-cells within the malignant neoplasm. The cancer was DNA microsatellite stable despite the finding of tumour infiltrating lymphocytes. Conclusions: There is evidence for the origin of colorectal neoplasia from dome epithelium in both experimental models and microreconstruction studies of early adenomas in nonpolypotic human colorectal mucose, It is suggested that the lymphocyte-rich subset of colorectal cancer that expresses MUC1 but not MUC2 may be differentiating as dome epithelium of gut-associated lymphoid tissue.