Molecular mechanisms of the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced inverted U-shaped dose responsiveness in anchorage independent growth and cell proliferation of human breast epithelial cells with stem cell characteristics

Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has a variety of carcinogenic and noncarcinogenic effects in experimental animals, its role in human carcinogenicity remain controversial. A simian virus 40-immortalized cell line from normal human breast epithelial cells with stem cells and luminal characteristics (M13SV1) was used to study whether TCDD can induce AIG positive colony formation and cause increased cell numbers in a inverted U-shaped dose–response manner. TCDD activated Akt, ERK2, and increased the expression of CYP1A1, PAI-2, IL-lb mRNA, and ERK2 protein levels. TCDD was able to increased phosphorylation and expression of ERK2 in same dose–response manner as AIG positive colony formation. Thus, TCDD induced tumorigenicity in M13SV1, possibly through the phosphorylation of ERK2 and/or Akt. Further, cDNA microarray with 7448 sequence-verified clones was used to profile various gene expression patterns after treatment of TCDD. Three clear patterns could be delineated: genes that were dose-dependently up-regulated, genes expressed in either U-shape and/or inverted U-shape. The fact that these genes are intrinsically related to breast epithelial cell proliferation and survival clearly suggests that they may be involved in the TCDD-induced breast tumorigenesis.     

A Biomathematical Modeling Approach to Explain the Phenomenon of Radiation Hormesis

This study presents an improved version of a published biomathematical model, the Random Coincidence Model-Radiation Adapted (RCM-RA). That model describes how cancer mortality increases as dose rate increases in the high-dose rate range, as well as how mortality decreases as dose rate increases in the low-dose rate range. It was assumed that low-dose rates of ionizing radiation induce cellular defense mechanisms that also prevent or repair endogenous DNA damage caused by natural cell metabolism. The model presented describes the development of cancer by a phase of initiation that consists of a series of DNA lesions in the critical regions of tumor-associated genes such as proto-oncogenes or tumor-suppressor genes. Initiated cells can divide and form a clone of initiated cells. This clonal growth is called promotion and leads to premalignant cells. Premalignant clones can sustain further genomic damage that may lead to a malignant cell and ultimately a malignant tumor. The model thereby shares structural features with Moolgavkar's two-stage clonal expansion model. It was tested on published, U-shaped data of radon exposure in U.S. homes. The model correctly reflects the ratio of endogenous DNA damage to radiation-induced damage.     

Hormesis: from mainstream to therapy

This issue of the Journal of Cell Communication and Cell Signaling on hormetic mechanisms represents an important step in the evolution of the hormesis dose response concept. Since its modern resurgence in the late 1970s the widespread occurrence of hormesis has been in search of its underlying mechanisms. The present integrative set of papers builds upon significant recent advances in the elucidation of hormetic mechanisms and provides the reader with a deep and extensive view of the concept of hormesis from a broad range of researcher perspectives and in many biomedical applications.     

Functional conservation of hematopoietic factors in Drosophila and vertebrates

The GATA, Friend of GATA, and Runt homology domain protein families function during hematopoiesis to promote progenitor cell development and regulate lineage commitment and differentiation. The hematopoietic functions of these factors have been remarkably conserved across taxonomic groups, ranging from flies to humans. Furthermore, aspects of hematopoiesis and hemocyte function appear to be conserved. Thus, comparative studies using Drosophila and vertebrate models should enhance our understanding of blood cell development.     

Molecular mechanisms of the 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced inverted U-shaped dose responsiveness in anchorage independent growth and cell proliferation of human breast epithelial cells with stem cell characteristics

Although 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has a variety of carcinogenic and noncarcinogenic effects in experimental animals, its role in human carcinogenicity remain controversial. A simian virus 40-immortalized cell line from normal human breast epithelial cells with stem cells and luminal characteristics (M13SV1) was used to study whether TCDD can induce AIG positive colony formation and cause increased cell numbers in a inverted U-shaped dose–response manner. TCDD activated Akt, ERK2, and increased the expression of CYP1A1, PAI-2, IL-lb mRNA, and ERK2 protein levels. TCDD was able to increased phosphorylation and expression of ERK2 in same dose–response manner as AIG positive colony formation. Thus, TCDD induced tumorigenicity in M13SV1, possibly through the phosphorylation of ERK2 and/or Akt. Further, cDNA microarray with 7448 sequence-verified clones was used to profile various gene expression patterns after treatment of TCDD. Three clear patterns could be delineated: genes that were dose-dependently up-regulated, genes expressed in either U-shape and/or inverted U-shape. The fact that these genes are intrinsically related to breast epithelial cell proliferation and survival clearly suggests that they may be involved in the TCDD-induced breast tumorigenesis.     

β-Barrel topology of Alzheimer's β-amyloid ion channels

Emerging evidence supports the ion channel mechanism for Alzheimer's disease pathophysiology wherein small β-amyloid (Aβ) oligomers insert into the cell membrane, forming toxic ion channels and destabilizing the cellular ionic homeostasis. Solid-state NMR-based data of amyloid oligomers in solution indicate that they consist of a double-layered β-sheets where each monomer folds into β-strand-turn-β-strand and the monomers are stacked atop each other. In the membrane, Aβ peptides are proposed to be β-type structures. Experimental structural data available from atomic force microscopy (AFM) imaging of Aβ oligomers in membranes reveal heterogeneous channel morphologies. Previously, we modeled the channels in a non-tilted organization, parallel with the cross-membrane normal. Here, we modeled a β-barrel-like organization. β-Barrels are common in transmembrane toxin pores, typically consisting of a monomeric chain forming a pore, organized in a single-layered β-sheet with antiparallel β-strands and a right-handed twist. Our explicit solvent molecular dynamics simulations of a range of channel sizes and polymorphic turns and comparisons of these with AFM image dimensions support a β-barrel channel organization. Different from the transmembrane β-barrels where the monomers are folded into a circular β-sheet with antiparallel β-strands stabilized by the connecting loops, these Aβ barrels consist of multimeric chains forming double β-sheets with parallel β-strands, where the strands of each monomer are connected by a turn. Although the Aβ barrels adopt the right-handed β-sheet twist, the barrels still break into heterogeneous, loosely attached subunits, in good agreement with AFM images and previous modeling. The subunits appear mobile, allowing unregulated, hence toxic, ion flux.     

China's U-Shaped Line in the South China Sea Revisited

Despite its existence on the Chinese maps for more than six decades, the U-shaped line, as a traditional maritime boundary line of China in the South China Sea, has never received a wide recognition in the world community, much less by the other claimant states in the South China Sea. The U-shaped line is a legal conundrum not only for China but also for the world community, particularly after the map with the U-shaped line, together with China's Notes Verbale with respect to the claims to the outer continental shelves made by Malaysia and Vietnam, were submitted to the UN Commission on the Limits of Continental Shelf in May 2009. This article discusses China's recent practice relating to the U-shaped line as well as the external factors that affect the validity of the line and tries to unravel the legal puzzle posed by the line.     

Stress amplifications in dental non-carious cervical lesions

This study aims to investigate the influence of the presence, shape and depth of NCCLs on the mechanical response of a maxillary second premolar subjected to functional and non-functional occlusal loadings using 3-D finite element (FE) analysis. A three-dimensional model of a maxillary second premolar and its supporting bone was constructed based on the contours of their cross-sections. From the sound model, cervical defects having either V- or U-shapes, as found clinically, were subtracted in three different depths. The models were loaded with 105 N to simulate normal chewing forces according to a functional occlusal loading (F1) vertically applied and two non-functional loadings (F2 and F3) obliquely oriented. Two alveolar bone crest heights were tested. Ansys™ FE software was used to compute stress distributions and maximum principal stress for each of the models. The presence of a lesion had no effect on the overall stress distribution of the system, but affected local stress concentrations. Non-functional loadings exhibited tensile stresses concentrating at the cervical areas and root surfaces, while the functional loading resulted in homogeneous stress distributions within the tooth. V-shaped lesions showed higher stress levels concentrated at the zenith of the lesion, whereas in U-shaped defect stresses concentrated over a wider area. As the lesions advanced in depth, the stress was amplified at their deepest part. A trend of stress amplification was observed with decreasing bone height. These results suggest a non-linear lesion progression with time, with the progression rate increasing with patient's age (deeper lesions and lower bone support).