Steady late quaternary slip rate on the Cinarcik section of the North Anatolian fault near Istanbul, Turkey

The distribution of plate motion between multiple fault strands and how this distribution may evolve remain poorly understood, despite the key implications for seismic hazards. The North Anatolian Fault in northwest Turkey is a prime example of a multistranded continental transform. Here we present the first constraints on late Quaternary slip rates on its northern branch across the Cinarcik Basin in the eastern Marmara Sea. We use both deep penetration and high‐resolution multichannel seismic reflection data with a stratigraphic age model to show that a depocenter has persisted near the fault bend responsible for that transform basin. Successively older depocenters have been transported westward by fault motion relative to Eurasia, indicating a uniform right‐lateral slip rate of 18.5 mm/yr over the last 500,000 years, compared to overall GPS rates (23–24 mm/yr). Thus, the northern branch has slipped at a nearly constant rate and has accounted for most of the relative plate motion between Eurasia and Anatolia since ~0.5 Ma

The Role of EZH2 in the Regulation of the Activity of Matrix Metalloproteinases in Prostate Cancer Cells

Degradation of the extracellular matrix (ECM), a critical step in cancer metastasis, is determined by the balance between MMPs (matrix metalloproteinases) and their inhibitors TIMPs (tissue inhibitors of metalloproteinases). In cancer cells, this balance is shifted towards MMPs, promoting ECM degradation. Here, we show that EZH2 plays an active role in this process by repressing the expression of TIMP2 and TIMP3 in prostate cancer cells. The TIMP genes are derepressed by knockdown of EZH2 expression in human prostate cancer cells but repressed by overexpression of EZH2 in benign human prostate epithelial cells. EZH2 catalyzes H3K27 trimethylation and subsequent DNA methylation of the TIMP gene promoters. Overexpression of EZH2 confers an invasive phenotype on benign prostate epithelial cells; however, this phenotype is suppressed by cooverexpression of TIMP3. EZH2 knockdown markedly reduces the proteolytic activity of MMP-9, thereby decreasing the invasive activity of prostate cancer cells. These results suggest that the transcriptional repression of the TIMP genes by EZH2 may be a major mechanism to shift the MMPs/TIMPs balance in favor of MMP activity and thus to promote ECM degradation and subsequent invasion of prostate cancer cells

Therapeutic Hemoglobin Levels after Gene Transfer in β-Thalassemia Mice and in Hematopoietic Cells of β-Thalassemia and Sickle Cells Disease Patients

Preclinical and clinical studies demonstrate the feasibility of treating β-thalassemia and Sickle Cell Disease (SCD) by lentiviral-mediated transfer of the human β-globin gene. However, previous studies have not addressed whether the ability of lentiviral vectors to increase hemoglobin synthesis might vary in different patients

An example of secondary fault activity along the North Anatolian Fault on the NE Marmara Sea Shelf, NW Turkey

Seismic data on the NE Marmara Sea Shelf indicate that a NNE-SSW-oriented buried basin and ridge system exist on the sub-marine extension of the Paleozoic Rocks delimited by the northern segment of the North Anatolian Fault (NS-NAF), while seismic and multi-beam bathymetric data imply that four NW-SE-oriented strike-slip faults also exist on the shelf area. Seismic data indicate that NW-SE-oriented strike-slip faults are the youngest structures that dissect the basin-ridge system. One of the NW-SE-oriented faults (F1) is aligned with a rupture of the North Anatolian Fault (NAF) cutting the northern slope of the Cinarcik Basin. This observation indicates that these faults have similar characteristics with the NS-NAF along the Marmara Sea. Therefore, they may have a secondary relation to the NAF since the principle deformation zone of the NAF follows the Marmara Trough in that region. The seismic energy recorded on these secondary faults is much less than that on the NAF in the Marmara Sea. These faults may, however, produce a large earthquake in the long term

Evidence for widespread creep on the flanks of the Sea of Marmara transform basin from marine geophysical data

"Wave" fields have long been recognized in marine sediments on the flanks of basins and oceans in both tectonically active and inactive environments. The origin of "waves" (hereafter called undulations) is controversial; competing models ascribe them to depositional processes, gravity-driven downslope creep or collapse, and/or tectonic shortening. Here we analyze pervasive undulation fields identified in swath bathymetry and new high-resolution multichannel seismic (MCS) reflection data from the Sea of Marmara, Turkey. Although they exhibit some of the classical features of sediment waves, the following distinctive characteristics exclude a purely depositional origin: (1) parallelism between the crests of the undulations and bathymetric contours over a wide range of orientations, (2) steep flanks of the undulations (up to ∼40°), and (3) increases in undulations amplitude with depth. We argue that the undulations are folds formed by gravity-driven downslope creep that have been augmented by depositional processes. These creep folds develop over long time periods (≥0.5 m.y.) and stand in contrast to geologically instantaneous collapse. Stratigraphic growth on the upslope limbs indicates that deposition contributes to the formation and upslope migration of the folds. The temporal and spatial evolution of the creep folds is clearly related to rapid tilting in this tectonically active transform basin

TIMP-2 Fusion Protein with Human Serum Albumin Potentiates Anti-Angiogenesis-Mediated Inhibition of Tumor Growth by Suppressing MMP-2 Expression

TIMP-2 protein has been intensively studied as a promising anticancer candidate agent, but the in vivo mechanism underlying its anticancer effect has not been clearly elucidated by previous works. In this study, we investigated the mechanism underlying the anti-tumor effects of a TIMP-2 fusion protein conjugated with human serum albumin (HSA/TIMP-2). Systemic administration of HSA/TIMP-2 effectively inhibited tumor growth at a minimum effective dose of 60 mg/kg. The suppressive effect of HSA/TIMP-2 was accompanied by a marked reduction of in vivo vascularization. The anti-angiogenic activity of HSA/TIMP-2 was directly confirmed by CAM assays. In HSA/TIMP-2-treated tumor tissues, MMP-2 expression was profoundly decreased without a change in MT1-MMP expression of PECAM-1-positive cells. MMP-2 mRNA was also decreased by HSA/TIMP-2 treatment of human umbilical vein endothelial cells. Zymographic analysis showed that HSA/TIMP-2 substantially decreased extracellular pro-MMP-2 activity (94–99% reduction) and moderately decreased active MMP-2 activity (10–24% reduction), suggesting MT1-MMP-independent MMP-2 modulation. Furthermore, HSA/TIMP-2 had no effect on in vitro active MMP-2 activity and in vivo MMP-2 activity. These studies show that HSA/TIMP-2 potentiates anti-angiogenic activity by modulating MMP-2 expression, but not MMP-2 activity, to subsequently suppress tumor growth, suggesting an important role for MMP-2 expression rather than MMP-2 activity in anti-angiogenesis

Matrix metalloproteinases in human melanoma cell lines and xenografts: increased expression of activated matrix metalloproteinase-2 (MMP-2) correlates with melanoma progression

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in tumour progression and metastasis. In this study, we investigated the in vitro and in vivo expression patterns of MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1 and TIMP-2 mRNA and protein in a previously described human melanoma xenograft model. This model consists of eight human melanoma cell lines with different metastatic behaviour after subcutaneous (s.c.) injection into nude mice. MMP-1 mRNA was detectable in all cell lines by reverse transcription polymerase chain reaction (RT-PCR), but the expression was too low to be detected by Northern blot analysis. No MMP-1 protein could be found using Western blotting. MMP-2 mRNA and protein were present in all cell lines, with the highest expression of both latent and active MMP-2 in the highest metastatic cell lines MV3 and BLM. MMP-3 mRNA was expressed in MV3 and BLM, and in the non-metastatic cell line 530, whereas MMP-3 protein was detectable only in MV3 and BLM. None of the melanoma cell lines expressed MMP-9. TIMP-1 and TIMP-2 mRNA and protein, finally, were present in all cell lines. A correlation between TIMP expression level and metastatic capacity of cell lines, however, was lacking. MMP and TIMP mRNA and protein expression levels were also studied in s.c. xenograft lesions derived from a selection of these cell lines. RT-PCR analysis revealed that MMP-1 mRNA was present in MV3 and BLM xenografts, and to a lesser extent in 530. Positive staining for MMP-1 protein was found in xenograft lesions derived from both low and high metastatic cell lines, indicating an in vivo up-regulation of MMP-1. MMP-2 mRNA was detectable only in xenografts derived from the highly metastatic cell lines 1F6m, MV3 and BLM. In agreement with the in vitro results, the highest levels of both latent and activated MMP-2 protein were observed in MV3 and BLM xenografts. With the exception of MMP-9 mRNA expression in 530 xenografts, MMP-3, MMP-9, and TIMP-1 mRNA and protein were not detectable in any xenograft, indicating a down-regulated expression of MMP-3 and TIMP-1 in vivo. TIMP-2 mRNA and protein were present in all xenografts; interestingly, the strongest immunoreactivity of tumour cells was found at the border of necrotic areas. Our study demonstrates that of all tested components of the matrix metalloproteinase system, only expression of activated MMP-2 correlates with increased malignancy in our melanoma xenograft model, corroborating an important role of MMP-2 in human melanoma invasion and metastasis. © 1999 Cancer Research Campaig

Organotypic modelling as a means of investigating epithelial-stromal interactions during tumourigenesis

The advent of co-culture approaches has allowed researchers to more accurately model the behaviour of epithelial cells in cell culture studies. The initial work on epidermal modelling allowed the development of reconstituted epidermis, growing keratinocytes on top of fibroblasts seeded in a collagen gel at an air-liquid interface to generate terminally differentiated 'skin equivalents'. In addition to developing ex vivo skin sheets for the treatment of burns victims, such cultures have also been used as a means of investigating both the development and repair of the epidermis, in more relevant conditions than simple two-dimensional culture, but without the use of animals. More recently, by varying the cell types used and adjusting the composition of the matrix components, this physiological system can be adapted to allow the study of interactions between tumour cells and their surrounding stroma, particularly with regards to how such interactions regulate invasion. Here we provide a summary of the major themes involved in tumour progression and consider the evolution of the approaches used to study cancer cell behaviour. Finally, we review how organotypic models have facilitated the study of several key pathways in cancer development and invasion, and speculate on the exciting future roles for these models in cancer research