Facilitates Chromatin Transcription Complex Is an “Accelerator” of Tumor Transformation and Potential Marker and Target of Aggressive Cancers

SummaryThe facilitates chromatin transcription (FACT) complex is involved in chromatin remodeling during transcription, replication, and DNA repair. FACT was previously considered to be ubiquitously expressed and not associated with any disease. However, we discovered that FACT is the target of a class of anticancer compounds and is not expressed in normal cells of adult mammalian tissues, except for undifferentiated and stem-like cells. Here, we show that FACT expression is strongly associated with poorly differentiated aggressive cancers with low overall survival. In addition, FACT was found to be upregulated during in vitro transformation and to be necessary, but not sufficient, for driving transformation. FACT also promoted survival and growth of established tumor cells. Genome-wide mapping of chromatin-bound FACT indicated that FACT’s role in cancer most likely involves selective chromatin remodeling of genes that stimulate proliferation, inhibit cell death and differentiation, and regulate cellular stress responses

Does Precision Imaging (PI) improve image quality in breast ultrasound?

Objective To determine the effect of the PI speckle reduction algorithm on image quality in breast ultrasound. Introduction Ultrasound is an integral tool used to identify breast cancer specifically in populations with mammographically dense breasts. One of the drawbacks of ultrasound is its tendency to produce a grainy image due to speckle noise. A granulated image is generally held to be of poorer quality, and this interference makes image contrast and spatial resolution difficult to appreciate. Not only does this reduce the quality of the image, but it also makes lesion characterization particularly difficult. Image enhancement methods that boost detection of low contrast objects, small high contrast targets and small differences in image brightness require investigation. Precision Imaging (PI) introduced by Toshiba is a post-processing speckle reduction algorithm. Toshiba claims that its software improves diagnostic confidence through enhanced structure definition and reduced noise (Azar, 2011; Toshiba, 2009) Material and methods The images included in this research were patients aged from 20 to 85 years who attended The Sydney Breast Clinic from October 2010 to July 2011. The commercial ultrasound scanner used for image acquisition was the Toshiba AplioMX, Model SSA-780A, (Toshiba Medical Systems, Otawara-shi, Tochigi-ken, Japan) with compact linear transducers 15-7MHz (PLT-1204BT) and 12-5 MHz (PLT-805AT). The image considered to best represent the area of interest was recorded without PI (L0), then with all other 3 levels of PI, namely Precision 1 (L1), Precision 2 (L2) and Precision 3 (L3). 247 sets of de-annotated images (92 with normal breast parenchyma and 155 showing benign lesions) were selected. The images were evaluated by one radiologist and five sonographers dedicated to breast imaging. They scored each lesion from 1 and 4 with 1 being the most preferred image and 4 being the least preferred. Results The Friedman test showed overall that the results were significant in favour of more speckle reduced images. That is, all except one observer preferred L2 PI and L3 PI. A Wilcoxon T paired analysis also demonstrated a statistically significant difference (p<0.001). Conclusion Image quality can be improved with an increased PI level, and the majority of observers prefer the most speckle-reduced image over others

Model characteristics of physical, functional readiness, psycho-emotional state and competitive activity of weightlifters in dynamics of four years

The article considers the indices of studying all sides of readiness among weightlifters for model characteristics formation according to kinds of training. The results of the held research works in dynamics of several years help to choose the average values depending on weightlifters’ level of readiness, experience and age. The research work examined the cadets, who go in for kettlebell lifting at Tyumen Higher Military –Engineering Command School. We defined the level of weightlifters’ physical, functional, psycho-emotional readiness, working capacity and the indices of competitive activity. We analyzed four years of sports training among weightlifters. The article defines model values of the studied indices within the range of their deviations in the studied groups. The indices of the competitive exercise are distributed as phase, advanced and etalon model values. We substantiated the necessity to study model characteristics as the base for an effective training process correction at all stages of training. The held analysis helps to reveal that during recent years technical indices significantly increased. It proves the increased functional abilities of highly-qualified weightlifters, their physical readiness and the attention paid by coaches to this side of sports training

TGF-β signaling promotes tumor vasculature by enhancing the pericyte-endothelium association

Abstract Background The breast cancer microenvironment promotes tumor vascularization through the complex interactions involving tumor-associated fibroblasts (TAFs). Emerging data indicate that TAFs increase production and signaling by TGF-β cytokines, while the role of TGF-β signaling in the regulation of tumor blood vessels is not fully understood. The current study presents evidence that TAFs enhance the organization of tumor blood capillaries, and TGF-β signaling plays an important role in this response. Methods Tumor vascularization was studied in xenograft models of breast carcinoma cells, alone and in combination with fibroblasts. TGF-β signaling in breast cancer cells was modulated by expression of kinase-inactive TGFBR1-K232R (dnTGFBR1) or constitutive-active TGFBR1-T204D (caTGFBR1) receptor mutants. The architecture of tumor blood capillaries was assessed by immune-histochemical analysis of endothelium and pericytes. The role of TGF-β-Smad signaling in fibronectin expression was examined using adenoviral transduction of signaling components. Results Our studies revealed that TAFs significantly increase the lumen size of blood microvessels. Inactivation of TGF-β signaling in tumor cells by dnTGFBR1 reduced the microvessel density and lumen sizes, decreasing tumor growth. In contrast, caTGFBR1-tumors exhibited greater vessel density and lumen sizes. Tumors with inactive dnTGFBR1 showed lower amounts of TAFs, while caTGFBR1 increased amounts of TAFs compared to the control. Inspection of pericytes and endothelial cells in tumor vasculature revealed that TAFs enhanced vessel coverage by pericytes, vascular cells supporting capillaries. This effect was impaired in dnTGFBR1-tumors, whereas active caTGFBR1 enhanced the association of pericytes with endothelium. Accordingly, dnTGFBR1-tumors exhibited the presence of hemorrhages, a sign of fragile blood vessels. Biochemical analysis showed that TGFBR1-SMAD signaling up-regulates fibronectin, a prominent regulator of endothelium-pericyte interactions. Conclusions The current study indicates that tumor-fibroblast crosstalk enhances tumor vascularization by increasing the pericyte-endothelium association via a mechanism involving the TGFβ-fibronectin axis. The tumor-fibroblast model represents a useful system for dissecting the complex interactions governing tumor angiogenesis and developing new approaches to therapeutic targeting tumor vasculature

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Additional file 5: of TGF-β signaling promotes tumor vasculature by enhancing the pericyte-endothelium association

Figure S5. Immunoblotting of fibronectin and alpha-catenin in whole-cell lysates from wild-type and Smad3-deficient MEFs treated with 2 ng/ml TGF-β1 for 24 h. (TIF 262 kb

Additional file 6: of TGF-β signaling promotes tumor vasculature by enhancing the pericyte-endothelium association

Figure S6. Detection of Fibronectin and endothelial markers in normal breast and carcinoma tissues: (A-B) Immunostaining of fibronectin FN1 in normal breast (top) and breast carcinoma tissues (bottom), bar size (A) 200 μm and (B) 50 μm. (C-D) Immunostaining of breast carcinoma tissues for endothelial markers CD31 and CD105, bar size 200 μm. Panels in (D) show enlargements of highlighted areas, bar size 50 μm. The images were obtained from the Human Protein Atlas ( www.proteinatlas.org ), Uhlen M, Zhang C, Lee S, Sjöstedt E, Fagerberg L, Bidkhori G, et al... A pathology atlas of the human cancer transcriptome. Science. 2017;357(6352) [49]. (TIF 4246 kb

Additional file 1: of TGF-β signaling promotes tumor vasculature by enhancing the pericyte-endothelium association

Figure S1. (A) Proliferative Ki67 index shows percentage of Ki67-positive cells measured from three fields in three tumors/group at × 600 magnification. Bars show the mean number of positive cells per field, NS - no statistical significance. (B) TUNEL (terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling) staining of tumor xenografts. Images were taken at 200× magnification and TUNEL-positive cells were counted from the periphery in three fields in three tumors/group; total cell numbers/group n = 2796; 2962; 2923; 2528. Bars show the mean number of positive cells per field, NS - no statistical significance. (C) TUNEL-positive areas in the tumor core relative to total area of the tumor. Images were taken at × 40 magnification, 6 tumors in EGFP and 5 tumors in dnTGFBR1 groups; *, P < 0.05; **, P < 0.01;***, P < 0.001. (TIF 1356 kb