Humans and animals undergo ageing, and although their primary cells undergo cellular senescence in culture, the relationship between these two processes is unclear. Here we show that γ-H2AX foci ...(γ-foci), which reveal DNA double-strand breaks (DSBs), accumulate in senescing human cell cultures and in ageing mice. They colocalize with DSB repair factors, but not significantly with telomeres. These cryptogenic γ-foci remain after repair of radiation-induced γ-foci, suggesting that they may represent DNA lesions with unrepairable DSBs. Thus, we conclude that accumulation of unrepairable DSBs may have a causal role in mammalian ageing.
E-cadherin is a cell-cell adhesion molecule that acts as a suppressor of cancer cell invasion and its expression is downregulated in many advanced, poorly differentiated, human cancers. In this ...study, we found that the expression of DLC1 (deleted in liver cancer 1) tumor-suppressor gene in metastatic prostate carcinoma (PCA) cells increased the expression of E-cadherin and resulted in an elevated rate of cell-cell aggregation as measured by aggregation assay. DLC1-mediated increase in E-cadherin expression was not dependent on α-catenin, a DLC1-binding protein associated with E-cadherin, and/or cellular density. The increase of E-cadherin expression occurred at mRNA level and relied on DLC1 RhoGAP function, leading to suppression of high level of RhoA-GTP and RhoC-GTP activity in metastatic PCA cells. Application of Rho/ROCK inhibitors produced the same effect as introduction of DLC1. Knocking down of RhoA produced a moderate increase in E-cadherin whereas knocking down of RhoC resulted in a significant increase of E-cadherin. Downregulation of E-cadherin caused by constitutively active RhoA(V14) and RhoC(V14) could not be reversed by expression of DLC1 in DLC1-negative cell line. DLC1-mediated suppression of metastatic PCA cells invasion was comparable with the one associated with ectopic E-cadherin expression, or caused by suppression of Rho pathway either by Rho/ROCK inhibitors, or by shRNA repression. This study demonstrates that DLC1 expression positively regulates E-cadherin and suppresses highly metastatic PCA cell invasion by modulating Rho pathway, which appears as a feasible therapeutic target in cancers with high activity of RhoGTPases.
The critical 8p22 tumor suppressor deleted in liver cancer 1 (DLC1) is frequently inactivated by aberrant CpG methylation and/or genetic deletion and implicated in tumorigeneses of multiple tumor ...types. Here, we report the identification and characterization of its new isoform, DLC1 isoform 4 (DLC1-i4). This novel isoform encodes an 1125-aa (amino acid) protein with distinct N-terminus as compared with other known DLC1 isoforms. Similar to other isoforms, DLC1-i4 is expressed ubiquitously in normal tissues and immortalized normal epithelial cells, suggesting a role as a major DLC1 transcript. However, differential expression of the four DLC1 isoforms is found in tumor cell lines: Isoform 1 (longest) and 3 (short thus probably nonfunctional) share a promoter and are silenced in almost all cancer and immortalized cell lines, whereas isoform 2 and 4 utilize different promoters and are frequently downregulated. DLC1-i4 is significantly downregulated in multiple carcinoma cell lines, including 2/4 nasopharyngeal, 8/16 (50%) esophageal, 4/16 (25%) gastric, 6/9 (67%) breast, 3/4 colorectal, 4/4 cervical and 2/8(25%) lung carcinoma cell lines. The functional DLC1-i4 promoter is within a CpG island and is activated by wild-type p53. CpG methylation of the DLC1-i4 promoter is associated with its silencing in tumor cells and was detected in 38-100% of multiple primary tumors. Treatment with 5-aza-2'-deoxycytidine or genetic double knockout of DNMT1 and DNMT3B led to demethylation of the promoter and reactivation of its expression, indicating a predominantly epigenetic mechanism of silencing. Ectopic expression of DLC1-i4 in silenced tumor cells strongly inhibited their growth and colony formation. Thus, we identified a new isoform of DLC1 with tumor suppressive function. The differential expression of various DLC1 isoforms suggests interplay in modulating the complex activities of DLC1 during carcinogenesis.
Chalcogenide phase change materials (PCMs) are truly remarkable compounds whose unique switchable optical and electronic properties have fueled an explosion of emerging applications in electronics ...and photonics. Key to any application is the ability of PCMs to reliably switch between crystalline and amorphous states over a large number of cycles. While this issue has been extensively studied in the case of electronic memories, current PCM-based photonic devices show limited endurance. This review discusses the various parameters that impact crystallization and re-amorphization of several PCMs, their failure mechanisms, and formulate design rules for enhancing cycling durability of these compounds.
Display omitted
•A water-based ferrofluid was irradiated with photons and electrons.•The dose was that usually involved in radiation therapy of human subjects (50 Gy).•Electron irradiation induced ...minor change in the colloidal stability of ferrofluid.•Magnetic heating of ferrofluid at 100 kHz is not affected by irradiation.•Magnetic hyperthermia can be applied in the same time period as radiation therapy.
The paper reports on the effect of therapeutic-like irradiation of a water based magnetic fluid with magnetite particles double-surfacted with oleic acid on its magnetic heating characteristics. To assess the effect of irradiation, a quantity of the initial sample was retained as the reference sample. The other part of the ferrofluid was irradiated with a photon beam (with the energy of 10 MeV and the dose of 50 Gy) and with an electron beam (of the energy of 9 MeV and the dose of 50 Gy).
The frequency dependence of the complex magnetic permeability, μ(ω) = μ′(ω)-i μ″(ω), was affected only in the case of the electron irradiated sample and over the approximate range of 10–100 kHz.
The dynamic light scattering investigation revealed a small increase of the average of the size of light scattering entities and of the polydispersity index of the sample irradiated with electrons compared to the reference sample.
Magnetic heating experiments, performed at the frequency of 100 kHz and with various amplitudes of magnetic field, H, (of 25, 50, 75 and 100 Oe) did not reveal significant difference in the heating rate values of the reference sample and of the irradiated samples. Therefore, magnetic hyperthermia can be involved in the therapy plan, in the same period of time as the radiation therapy, provided at the frequency of the alternating magnetic field larger than the frequency corresponding to the Brownian relaxation peak.
DLC1 (deleted in liver cancer 1), which encodes a Rho GTPase-activating protein (Rho-GAP), is a potent tumor suppressor gene that is frequently inactivated in several human cancers. DLC1 is a ...multidomain protein that has been shown previously to bind members of the tensin gene family. Here we show that p120Ras-GAP (Ras-GAP; also known as RASA1) interacts and extensively colocalizes with DLC1 in focal adhesions. The binding was mapped to the SH3 domain located in the N terminus of Ras-GAP and to the Rho-GAP catalytic domain located in the C terminus of the DLC1. In vitro analyses with purified proteins determined that the isolated Ras-GAP SH3 domain inhibits DLC1 Rho-GAP activity, suggesting that Ras-GAP is a negative regulator of DLC1 Rho-GAP activity. Consistent with this possibility, we found that ectopic overexpression of Ras-GAP in a Ras-GAP-insensitive tumor line impaired the growth-suppressing activity of DLC1 and increased RhoA activity in vivo. Our observations expand the complexity of proteins that regulate DLC1 function and define a novel mechanism of the cross talk between Ras and Rho GTPases.1R01CA129610
The organization and replication of DNA render fragile sites (FSs) prone to breakage, recombination as well as becoming preferential targets for mutagens–carcinogens and integration of oncogenic ...viruses. For many years, attempts to link FSs and cancer generated mostly circumstantial evidence. The discoveries that chromosome translocations, amplification of proto-oncogenes, deletion of tumor suppressor genes, and integration of oncogenic viruses all result from the specific breakage of genomic DNA at FSs, however, have provided compelling support for such a link, further suggesting a causative role for FSs in cancer.
► TCO thin films were grown by PLD on PET substrate at low temperature. ► We found that the quality of TCO on PET substrate depends on the target–substrate distance. ► TCO with high transparency ...(>95%) and reduced electrical resistivity (∼5×10−4Ωcm) were obtained. ► Optimized TCO films deposited on PET were free of any cracks.
The influence of target–substrate distance during pulsed laser deposition of indium zinc oxide (IZO), indium tin oxide (ITO) and aluminium-doped zinc oxide (AZO) thin films grown on polyethylene terephthalate (PET) substrates was investigated. It was found that the properties of such flexible transparent conductive oxide (TCO)/PET electrodes critically depend on this parameter. The TCO films that were deposited at distances of 6 and 8cm exhibited an optical transmittance higher than 90% in the visible range and electrical resistivities around 5×10−4Ωcm. In addition to these excellent electrical and optical characteristics the films grown at 8cm distance were homogenous, smooth, adherent, and without cracks or any other extended defects, being suitable for opto-electronic device applications.
A number of genetic mutations have been identified in human breast cancers, yet the specific combinations of mutations required in concert to form breast carcinoma cells remain unknown. One approach ...to identifying the genetic and biochemical alterations required for this process involves the transformation of primary human mammary epithelial cells (HMECs) to carcinoma cells through the introduction of specific genes. Here we show that introduction of three genes encoding the SV40 large-T antigen, the telomerase catalytic subunit, and an H-Ras oncoprotein into primary HMECs results in cells that form tumors when transplanted subcutaneously or into the mammary glands of immunocompromised mice. The tumorigenicity of these transformed cells was dependent on the level of ras oncogene expression. Interestingly, transformation of HMECs but not two other human cell types was associated with amplifications of the c-myc oncogene, which occurred during the in vitro growth of the cells. Tumors derived from the transformed HMECs were poorly differentiated carcinomas that infiltrated through adjacent tissue. When these cells were injected subcutaneously, tumors formed in only half of the injections and with an average latency of 7.5 weeks. Mixing the epithelial tumor cells with Matrigel or primary human mammary fibroblasts substantially increased the efficiency of tumor formation and decreased the latency of tumor formation, demonstrating a significant influence of the stromal microenvironment on tumorigenicity. Thus, these observations establish an experimental system for elucidating both the genetic and cell biological requirements for the development of breast cancer.
PDF
