Applications of quantitative digital image analysis to breast cancer research

Our studies of radiogenic carcinogenesis in mouse and human models of breast cancer are based on the view that cell phenotype, microenvironment composition, communication between cells and within the microenvironment are important factors in the development of breast cancer. This is complicated in the mammary gland by its postnatal development, cyclic evolution via pregnancy and involution, and dynamic remodeling of epithelial-stromal interactions, all of which contribute to breast cancer susceptibility. Microscopy is the tool of choice to examine cells in context. Specific features can be defined using probes, antibodies, immunofluorescence, and image analysis to measure protein distribution, cell composition, and genomic instability in human and mouse models of breast cancer. We discuss the integration of image acquisition, analysis, and annotation to efficiently analyze large amounts of image data. In the future, cell and tissue image-based studies will be facilitated by a bioinformatics strategy that generates multidimensional databases of quantitative information derived from molecular, immunological, and morphological probes at multiple resolutions. This approach will facilitate the construction of an in vivo phenotype database necessary for understanding when, where, and how normal cells become cancer.     

Cancer risk related to mammary gland structure and development

The breast undergoes dramatic changes in size, shape, and function in association with growth, reproduction, and post-menopausal regression. Those changes impact women's lifetime breast cancer risk. An early first full-term pregnancy exerts a protective effect, emphasizing the need for understanding the role of reproductive influences on breast development and on cancer initiation and progression, and providing a paradigm for developing preventive strategies based on physiological principles. Even though the cause of breast cancer and the ultimate mechanisms through which an early pregnancy protects from cancer development remain largely unknown, a likely explanation for this protection has been provided by experimental in vivo and in vitro models. These studies have led to the conclusions that cancer initiation requires the interaction of a carcinogen with an undifferentiated and highly proliferating mammary epithelium, whereas differentiation of the mammary gland inhibits carcinogenic initiation. The process of mammary gland differentiation is the result of complex interactions of ovarian, pituitary, and placental hormones, which in turn induce inhibition of cell proliferation, downregulation of estrogen and progesterone receptors, activation of specific genes, such as inhibin, mammary derived growth factor inhibitor and a serpin-like gene, and expression of extracellular matrix proteins in the normal breast. Cell immortalization and transformation are associated with the expression of ferritin H and S100P protein, which serve as markers of cancer initiation. Comparative studies of normal and neoplastic breast development have unraveled similarities with experimental models that validate the extrapolation of findings for testing hypotheses on the initiation and progression of breast cancer.     

Human, rhesus macaque, and feline sequences highly similar to mouse mammary tumor virus sequences

Sequences highly similar (>95%) to the mouse mammary tumor virus (MMTV) env gene have been amplified from human DNA samples, including DNA samples from patients with breast cancer (BC) and persons who did not have BC. The sequences from human DNA were distinct from the MMTV sequences used as controls in these PCR reactions, indicating that these results are not simply due to contamination. In addition to both, mouse and human-related sequences were also amplified from some monkey and cat genomic DNA samples. These products were shown to be distinct from, but highly related to, the MMTV env gene, whereas, testing of other sources (lambda phage, snake, cockroach, sea urchin, chicken, or dog) demonstrated no specific amplification. A sequence 90% similar to the MMTV group antigen gene (gag) was amplified from cat DNA. These results indicate that DNA from vertebrate species other than rodents, including some but not all humans, monkeys, and cats, can contain sequences closely related to MMTV.     

GND accumulation in bi-crystal deformation: Crystal plasticity analysis and comparison with experiments

A three-dimensional, large deformation crystal plasticity model is presented in which the lengthscale effect is incorporated through the explicit coupling of the density of geometrically necessary dislocations (GNDs) with the crystallographic slip rule.The channel-die bi-crystal compression tests carried out by Sun et al. [1998. Mesoscale investigation of the deformation field of an aluminium bicrystal. Scripta Material 39(4/5), 501-508; Sun, S., Adams, B.L., King, W.E., et al., 2000. Observations of lattice curvature near the interface of a deformed aluminium bicrystal. Philosophical Magazine 80 (1), 9-25] have been assessed and the crystal plasticity model has been employed to predict the distributions of GNDs local to the grain boundary. Quantitative comparisons of the predicted distributions with those determined experimentally show reasonable agreement. The qualitative comparisons of crystal reorientation predicted by the model with those observed by Zaefferer et al. [2003. On the influence of the grain boundary misorientation on the plastic deformation of aluminium bicrystals. Acta Materialia 51, 4719-4735] show good agreement. Further analyses of the bi-crystal have been carried out both with and without the development of GNDs. The results show that the crystal re-orientations local to the grain boundary are different if GND accumulation is included, suggesting that conventional, non-lengthscale crystal plasticity models are unlikely to be capable of capturing correctly the deformations arising at grain boundaries.     

Mammary epithelial stem cells

It has recently been shown that the progeny from a single cell may comprise the epithelial population of a fully developed lactating mammary outgrowth in mice. Serial transplantation of epithelial fragments from this clonally derived gland demonstrates that the subsequently generated outgrowths are also comprised of progeny from the original antecedent. All epithelial cell types were found to be present within these clonal normal populations including luminal, myoepithelial, ductal, and lobule-committed epithelial progenitors and fully competent mammary epithelial stem cells. These observations demonstrate the presence of multipotent tissue-specific epithelial stem cells among the parenchyma of the murine mammary gland. Similarly, genetic analysis of contiguous portions of individual human mammary ducts within the same breast indicates their clonal derivation. Here, we discuss the properties, location, division-potential, senescence, and plasticity associated with mammary epithelial stem cells and present the developing evidence for their presence in human breast and their important role in the risk for breast cancer development. Further, we review the present morphologic and genetic evidence for the characterization of specific stem cell markers and lineage-limited progenitor cells in human and rodent mammary epithelium. Microsc. Res. Tech. 52:190-203, 2001. Published 2001 Wiley-Liss, Inc.     

Protein kinases in mammary gland development and cancer

Protein kinases, the enzymes responsible for phosphorylation of a wide variety of proteins, are the largest class of genes known to regulate growth, development, and neoplastic transformation of mammary gland. Mammary gland growth and maturation consist of a series of highly ordered events involving interactions among several distinct cell types that are regulated by complex interactions among many steroid hormones and growth factors. The mammary gland is one of the few organ systems in mammals that complete their morphologic development postnatally during two discrete physiologic states, puberty and pregnancy. Thus, the mammary gland is an excellent model for studying normal development and the early steps of tumor formation. The susceptibility of the mammary gland to tumorigenesis is influenced by its normal development, particularly during stages of puberty and pregnancy. Numerous experimental and epidemiological studies have suggested that specific details in the development of the mammary gland play a critical role in breast cancer risk. Mammary gland development is characterized by dynamic changes in the expression and functions of protein kinases. Perturbations in the regulated expression or function of protein kinases or their associated signaling pathways can lead to malignant transformation of the breast. For example, overexpression of several receptor-tyrosine kinases, including human epidermal growth factor receptor and HER2/Neu, has been shown to contribute to the development of breast cancer. Since receptor-tyrosine kinases regulate several essential processes such as mitogenesis, motility, invasion, cell survival, and angiogenesis, targeting receptor-tyrosine kinases may have important implications in designing strategies against breast cancer.     

Application of the singularity function method to semi-infinite orthotropic rectangular plates on an elastic foundation

The singularity function method is applied to solve the structural problems of semi-infinite orthotropic rectangular plates on a Winker-type elastic foundation. Previous application by Selek et al. (Int. J. Mech. Sci., 25 (1983) 397) of the singularity function to plates on an elastic foundation was limited only to isotropic cases. Foundation-free orthotropic plate problems have been previously solved Adewale et al. (Int. J. Mech. Sci., 31 (1989) 853). In this paper, the singularity function method technique is extended to orthotropic rectangular plate on Winkler-type foundation. The isotropic rectangular plate results of Selek et al. (Int. J. Mech. Sci., 25 (1983) 397) and the foundation-free orthotropic rectangular plate results provided by Adewale et al. (Int. J. Mech. Sci., 31 (1989) 853) are recovered as special cases.     

Novel combination of orientation measurements and transmission microscopy for experimental determination of grain boundary miller indices in silicon and other semiconductors

The determination of grain boundary planes in multicrystalline material has only been restricted to transmission electron microscope investigations (Jang et al., 1992; Elgat et al., 1985) or to metallograpical investigations of the grain boundary (Randle et al., 1993). The first method is expensive, and both are complex and time consuming in grain boundary preparation. This paper proposes the determination of grain boundary planes in semiconductor wafer by a combined application of Electron Back Scatter Diffraction and Infrared Transmission Microscopy. In particular, the new method is demonstrated with directional solidificated multicrystalline silicon.     

BI-RADS联合UE技术对小乳腺癌的诊断价值分析

目的 分析乳腺影像报告与数据系统(BI-RADS)联合超声弹性成像(UE)技术对小乳腺癌的诊断价值.方法 以我院乳腺科2018年1月～2020年2月收治的274例乳腺肿块患者为研究对象,所有患者均进行病理检查,根据病理检查结果分为乳腺增生患者(165例)和小乳腺癌(109例)患者,比较乳腺增生患者和小乳腺癌患者BI-R...     

图像处理和特征分析在评估乳腺癌近期发病风险中的应用

图像处理和特征分析在乳腺癌早期诊断中发挥着重要作用。为了将一个基于左右乳腺X光片图像密度特征不对称性的图像特征分析方法应用于乳腺癌近期发病风险的预测,训练开发了一个以多图像特征相融合的人工智能分辨模型来预测每个妇女在近期(比如,在最近一次的良性检测以后2年之内)由医学影像检测出来的早期癌症的风险程度。介绍这一个新癌症风险预测模型的基本原理,演示一个新型的人机交互式的计算机辅助图像特征分析和计算的工作平台。初步实验证明,应用这一个基于医学图像特征定量分析的模型能够取得比采用现行其他已知的乳腺癌风险因子有着显著提高的对于近期乳腺癌发病风险的预测精度,这将为建立更有效的个性化乳腺癌普查提供依据和帮助。     

Molecular markers and therapeutic targets in ductal carcinoma in situ

Ductal carcinoma in situ (DCIS) of the breast is a premalignant condition which accounts for approximately 20% of all new breast cancers and up to 40% of neoplastic lesions detected by mammographic screening. Since recurrence is common after DCIS treated with breast conservation surgery, there is a need to determine molecular factors that predict recurrence. In parallel with this and with the finding that oestrogen receptor (ER) positive breast cancer can be prevented with anti-oestrogens, there have been recent advances in the understanding of the molecular biology of DCIS. Receptor coexpression in DCIS has been determined largely by immunohistochemistry. Animal models have provided evidence for the signalling pathways involved in the regulation and dysregulation of proliferation and apoptosis in both normal breast and in situ cancer. ER-negative DCIS has been shown to be hormone-independent. Blockade of the pathways involved in cell proliferation in ER-negative DCIS is possible and will be necessary to prevent ER-negative breast cancers if the goal of breast cancer chemoprevention is to be realistically achieved.     

Labelled-replica techniques: post-shadow labelling of intramembrane particles in freeze-fracture replicas

Three methods are described for direct post-fracture, post-shadow labelling of individual classes of intramembrane particles (IMPs) in freeze-fracture replicas of biological membranes. The P-face IMPs corresponding to the acetylcholine receptor complexes (AChRs) of vertebrate neuroeffector junctions are identified by post-replication labelling with ferritin-antibody complexes and with neurotoxin-biotin-avidin-colloidal gold affinity ligands. (The freeze-etch nomenclature of Branton et al., 1975, is used in this report.) These post-shadow labelling techniques resemble conventional en bloc labelling techniques except that the labelling reagents must penetrate a thin but discontinuous layer of platinum superimposed on the molecules of interest. In the ‘sectioned labelled-replica technique’, the replicated and labelled tissues are stained, embedded in plastic and sectioned parallel to the replica-tissue interfaces. In the direct ‘labelled-replica techniques’, the replicated and labelled samples are freeze-dried or critical point dried, the labelled surfaces are stabilized by carbon coating, and the underlying tissues are dissolved, allowing the labelled-replicas to be examined as conventional freeze-fracture replicas. The unshadowed side of each AChR IMP is shown to retain sufficient biochemical information to permit both immunospecific and neurotoxin specific labelling despite formaldehyde fixation, freezing, fracturing, platinum shadowing, and thawing in aqueous media. A new mixed ferricyanide-osmium staining method reveals electron opaque structures spanning the membrane bilayer in the same size, number and distribution as the labelled IMPs. These experiments demonstrate the feasibility of identifying individual IMPs in freeze-fracture replicas and may allow the identification of specific membrane lesions in human disease.     

Comparison of multiaxial fatigue damage models under variable amplitude loading

Based on the cycle counting method of Wang and Brown and on the linear accumulation damage rule of Miner, four multiaxial fatigue damage models without any weight factors proposed by Pan et al., Varvani-Farahani, Shang and Wang, and Shang et al. are used to compute fatigue damage. The procedure is evaluated using the low cycle fatigue experimental data of 7050-T7451 aluminum alloy and En15R steel under tension/torsion variable amplitude loading. The results reveal that the procedure is convenient for engineering design and application, and that the four multiaxial fatigue damage models provide good life estimates.     

The in situ architecture of Escherichia coli ribosomal RNA derived by electron spectroscopic imaging and three-dimensional reconstruction

The structures of the large and small ribosomal subunits of Escherichia coli were reconstructed using spectroscopic electron microscopy and quaternion-assisted angular reconstitution to resolutions of better than 4 nm. In addition, the distributions of phosphorus within these complexes were reconstructed. The three-dimensional reconstruction of the distribution of this atomic element is an extension of microanalysis (in two dimensions) for phosphorus identification and mapping, as a signature of the arrangement of the phosphate backbones of the constituent ribosomal RNAs. The results on both the phosphorus reconstructions and the total reconstructions (protein and ribosomal RNA) reveal several passageways through both subunits. The structures correspond favourably with other independent reconstructions of the whole E. coli ribosome from cryoelectron micrographs and their accompanying models of translation (Frank et al ., Nature , 376, 441–444, 1995; Stark et al ., Structure , 3, 815–821, 1995). The overall reconstructions in conjunction with the phosphorus (rRNA) distributions are the first to be achieved synchronously for this nucleoprotein complex.     

Of mice, cats, and men: is human breast cancer a zoonosis?

Mouse mammary tumor virus (MMTV), a member of the betaretroviridae, is the most common cause of breast cancer (BC) in mice. MMTV is transmitted in mice both in the germline as endogenous proviruses and exogenously as infectious virions. Here, we review a variety of evidence accumulated for six decades that has suggested that a human homologue of MMTV may exist. The findings include recent studies from several independent laboratories that have detected sequences very closely related to MMTV in DNA isolated from human BC tumors. Other laboratories, however, have failed to detect the MMTV-related sequences in human DNA samples, and conclusive evidence for a human mammary tumor virus has been elusive. We also reviewed additional studies, suggesting that betaretroviruses are present in a much wider range of species than previously known, including rodents, felines, and primates. The observation that a subset of cats may be infected with a close homologue of MMTV may be of epidemiological significance for human BC. Cats may become infected by MMTV from mice, and in turn may transmit the virus to humans, possibly after selection for variants with an expanded host range.     

Experimental milling moment model in orthogonal cutting condition: to an accurate energy balance

The control of cutting energy parameters is essential to optimize the cutting condition during the milling process. Our previous works (Cahuc et al., Int J Adv Manuf Technol 18(9):648?C656, 2001; Darnis et?al. 2000) have shown the existence of the six components of the cutting mechanical actions. Thus, the influence of geometric and kinematic parameters on the six components must be quantified. Based on the experimental approach explained in our last works (Albert et al., 2008a, b), this study proposes an energetic criterion characterizing the cutting moment in orthogonal cutting condition. Then, the energy balance has to take into account the cutting moment, highlighting the utility of this criterion. Therefore, the cutting moment model proposed allows an accurate evaluation of the energy balance and the mechanical actions (forces and moments) applied to the workpiece. Consequently, the cutting parameters can be chosen in order to optimize the cutting power consumption.     

Object-oriented graphical modeling of FMSs

Presented in the article is a method for constructing a graphical model of an FMS by using a new modeling tool called JR-net (Job Resource relation-net). JR-net is an object-oriented graphical tool for modeling automated manufacturing systems (AMSs), such as FMSs, FASs, and AS/RSs. As with the object-oriented modeling paradigm of Rumbaugh et al. (1991), the JR-net modeling framework supports the three stages of models: static layout model (object model); job flow model (functional model); and supervisory control model (dynamic model). In this article, the existing JR-net structure (Park 1992, Han et al., 1995) is extended further to make it a graphical tool for FMS modeling. Using the extended JR-net, a step-by-step procedure for constructing a graphical model of FMSs is presented. Also addressed are issues of classifying FMSs in terms of their generic functions and of utilizing the JR-net model of FMSs.     

A note on “A multi-objective genetic algorithm for solving assembly line balancing problem”

Assembly line balancing has a considerable place in industrial importance. Hence, a lot of researchers are interested in this subject and several papers have been published so far. Many exact, heuristic, metaheuristic, and hybrid approaches have been used to solve this type of problems. Recently Ponnanbalam et al. (Int J Adv Manuf Technol 16:341–352, 2000) have considered a multi-objective genetic algorithm utilizing several simple heuristic rules for solving the simple assembly line balancing problems, one of these rules was “rank positional weight (RPW)” originally published in Helgeson and Birnie (J Ind Eng 12(6):394–398, 1961). Through providing two possible justifications, this note suggests that the mentioned rule can be mistakenly utilized and some revisions in Ponnanbalam et al. (Int J Adv Manuf Technol 16:341–352, 2000) seem to be necessary.     

Angiogenesis in breast cancer: the role of transforming growth factor beta and CD105

The progression of breast cancer depends on the establishment of a neovasculature, by a process called angiogenesis. Angiogenesis is an invasive cellular event that requires the co-ordination of numerous molecules including growth factors and their receptors, extracellular proteins, adhesion molecules, and proteolytic enzymes. TGFbeta has emerged to be a major modulator of angiogenesis by regulating endothelial cell proliferation, migration, extracellular matrix (ECM) metabolism, and the expression of adhesion molecules. It is a potent growth inhibitor of normal mammary epithelial cells and a number of breast cancer cell lines. It seems that TGFbeta exerts pleiotropic effects in the oncogenesis of breast cancers in a contextual manner, i.e., it suppresses tumourigenesis at an early stage by direct inhibition of angiogenesis and tumour cell growth. However, over-production of TGFbeta by an advanced tumour may accelerate disease progression through indirect stimulation of angiogenesis and immune suppression. The cell membrane antigen CD105 (endoglin) binds TGFbeta1 and TGFbeta3 and is preferentially expressed in angiogenic vascular endothelial cells. The reduction of CD105 levels in HUVEC leads to in vitro angiogenesis inhibition and massive cell mortality in the presence of TGFbeta1. CD105 null mice die in utero with impaired vasculature, indicating the pivotal role of CD105 in vascular development. The administration of an immunotoxin-conjugate, mab to CD105, induces long-term and complete regression of breast cancer growth in SCID mice. Therefore, CD105 is a promising vascular target for antiangiogenic therapy.