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[en] The in vitro radiosensitivity of fibroblasts derived from patients undergoing radiotherapy has been investigated by a number of groups for possible prediction of normal tissue effects. Some studies have suggested a weak correlation between radiosensitivity and late normal tissue effects, such as fibrosis, but others have not. One possible reason may be that radiosensitivity in vivo is not always reflected by radiosensitivity in vitro. We are investigating whether heterogeneity in the normal tissue response of individual soft tissue sarcoma patients receiving pre-operative radiotherapy can be assessed by determining the number of micronuclei (DNA damage) in fibroblasts obtained and assayed directly from their skin after irradiation. The micronuclei are counted in binucleate cells in primary cultures of the fibroblasts at 72 hrs after treatment with cytochalasin B. This endpoint is dose responsive and in rats we have demonstrated that the presence of micronuclei can be detected months after irradiation. The assay can thus provide data for fibroblasts irradiated with fractionated doses in situ in tissue or for fibroblasts irradiated in vitro following outgrowth from the tissue. We have demonstrated that fibroblasts obtained directly from irradiated skin at surgery (approx 5-6 weeks after the end of radiotherapy) from a small number of soft tissue sarcoma patients given nominally similar preoperative irradiation (50Gy in 20 fractions to the tumor) show significant variability in response. Estimates of radiation dose to the skin have suggested that much of this variability may be dose related but further studies are underway with skin samples from regions given carefully measured doses. Comparisons with micronucleus formation for fibroblasts from the same patient irradiated in vitro are also underway. Our results demonstrate that DNA damage in fibroblasts in irradiated tissue can be assessed directly ex vivo and that DNA damage can be detected at 1-2 months after irradiation
[en] A second patient, XP-CS-2, has been discovered with both xeroderma pigmentosum and Cockayne syndrome. His fibroblasts have 30% of the normal rate of uv-induced unscheduled DNA synthesis. His fibroblasts were fused with those from each of the xeroderma pigmentosum groups A through G. His cells complemented every cell line, since in each case there were obtained multinucleate cells which had a normal amount of uv-induced unscheduled DNA synthesis. Since the XP-CS-2 cells complement all the currently established xeroderma pigmentosum complementation groups, this new XP-CS patient is in a new group which we designate group H. 10 references, 1 figure
[en] Highlights: • miRNAs could regulate Cyclins and CDKs by targeting their promoters. • Perl programming was used to identify putative targets of miRNA in promoters. • miR-1273g-3p and miR-619-5p showed significance with longest seed sequence matches. • Through CDK10, CDK11 and Cyclin, these two miRNAs could regulate cell cycle during megakaryopoiesis. The distinct process of megakaryopoiesis requires occurrence of endomitosis for polyploidization of the megakaryocytes. Although, Cyclins, CDKs and have been described to regulate endomitosis, the exact mechanism still remains an enigma. miRNA which were otherwise known as post transcriptional gene silencers are now emerging with various non-canonical functions including gene regulation at pre-transcriptional level by miRNA binding at promoter region. Out of the many processes they regulate, miRNA have been manifested to play a role in megakaryocyte differentiation. In this study an attempt has been made to identify miRNA that could regulate cell cycle genes (Cyclins and CDKs) by targeting their promoters, during megakaryopoiesis. A new computational algorithm was implemented using Perl programming to identify putative targets of miRNA in CDK and Cyclin promoters. Perl script was also used to check nuclear localizing miRNA based on the presence of a consensus sequence. Real-time PCR was performed to analyze the expression of miRNA and their predicted targets in Dami vs. PMA treated Dami cells. Putative targets of miRNAs with longest, high complementarity matches in CDK/Cyclin promoters were obtained. We identified two significant miRNA, miR-1273g-3p and miR-619-5p with longest seed sequence matches. We further identified three main targets (CDK10, CDK11, Cyclin F) through which these two miRNA could regulate cell cycle during megakaryopoiesis. Our results reinforce the role of promoting targeting miRNA in regulation of cell cycle through certain CDK/Cyclins to support the process of endomitosis during megakaryopoiesis.
[en] This paper relates ultrasound-induced changes in bone cell function to quantitative data assessing the level of several interaction mechanisms within the exposure environment. Characterisation of ultrasound fields in terms of resultant levels of heating, cavitation and acoustic streaming may provide a novel means of accurately assessing the likelihood of biological effects in vitro
[en] Cells in many organs exist in both proliferating and quiescent states. Proliferating cells are more radio-sensitive, DNA damage pathways including p53 pathway are activated to undergo either G1/S or G2/M arrest to avoid entering S and M phase with DNA damage. Our results showed that quiescence does not affect irradiation response of key proteins involved in stress and DNA damage at least in normal fibroblasts, providing a better understanding of the radiation response in quiescent cells, which is crucial for tissue repair and regeneration
[en] Cell shape is known to have profound effects on a number of cell behaviors. In this paper we have studied its role in cell migration through modeling the effect of cell shape on the cell traction force distribution, the traction force dependent stability of cell adhesion and the matrix rigidity dependent traction force formation. To quantify the driving force of cell migration, a new parameter called the motility factor, that takes account of the effect of cell shape, matrix rigidity and dynamic stability of cell adhesion, is proposed. We showed that the motility factor depends on the matrix rigidity in a biphasic manner, which is consistent with the experimental observations of the biphasic dependence of cell migration speed on the matrix rigidity. We showed that the cell shape plays a pivotal role in the cell migration behavior by regulating the traction force at the cell front and rear. The larger the cell polarity, the larger the motility factor is. The keratocyte-like shape has a larger motility factor than the fibroblast-like shape, which explains why keratocyte has a much higher migration speed. The motility factor might be an appropriate parameter for a quantitative description of the driving force of cell migration. (paper)
[en] In this study, we investigated whether the GLP-1RA, liraglutide, affected differentiation of C3H10T1/2 mesenchymal stem cells (MSCs) to mature brown adipocytes and involvement of PI3K/AKT/mTOR signaling pathway in this process.
[en] Angiopoietin (Ang)-1 and Ang-2 interact in angiogenesis to activate the Tie-2 receptor, which may be involved in new vessel maturation and regression. Mast cells (MCs) are also involved in formation of new blood vessels and angiogenesis. The present study was designed to test whether MCs can mediate angiogenesis in myocardial microvascular endothelial cells (MMVECs). Using a rat MMVEC and MC co-culture system, we observed that Ang-1 protein levels were very low even though its mRNA levels were increased by MCs. Interestingly, MCs were able to enhance migration, proliferation, and capillary-like tube formation, which were associated with suppressed Ang-2 protein expression, but not Tie-2 expression levels. These MCs induced effects that could be reversed by either tryptase inhibitor [N-tosyl-L-lysine chloromethyl ketone (TLCK)] or chymase inhibitor (N-tosyl-L-phenylalanyl chloromethyl ketone), with TLCK showing greater effects. In conclusion, our data indicated that MCs can interrupt neovessel maturation via suppression of the Ang-2/Tie-2 signaling pathway