The tripartite motif protein TRIM24 (tripartite motif-containing 24) has been found to play distinct roles in tumor development and progression, according to different tumor contexts. However, it remains elusive whether TRIM24 plays a role in malignant gliomas that are the most common and deadly primary brain tumors in adults. We report here that TRIM24 expression is positively correlated with glioma malignancy and is negatively associated with prognosis of patients with newly diagnosed glioblastoma, which is the most malignant form of gliomas but displays highly heterogeneous clinical outcome. The multivariate Cox regression analysis demonstrates the independent predictive value of TRIM24 expression level for overall and progression-free survival. Knockdown of TRIM24 suppresses cell proliferation, cell cycle progression, clone formation and in vivo tumor development, whereas overexpression of TRIM24 promotes cell growth. Chromatin immunoprecipitation, real-time reverse transcription-PCR and mutation analyses demonstrate that TRIM24 binds to the PIK3CA promoter via its PHD-Bromo domain to activate the transcription of PIK3CA gene, thus enhancing phosphatidylinositide 3-kinase (PI3K)/Akt signaling. The pan-PI3K inhibitor LY294002 and small interfering RNA targeting PIK3CA both abrogate the growth-promoting effect of TRIM24. Moreover, TRIM24 regulates the expression of DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) through PI3K/Akt/nuclear factor-κB signaling transduction and enhances resistance to temozolomide, the standard chemotherapeutic agent for glioblastoma. Finally, glioblastoma patients with low TRIM24 expression benefit from chemotherapy, whereas those with high TRIM24 expression do not have such benefit. Our results suggest that TRIM24 might serve as a potential prognostic marker and therapeutic target for the management of malignant gliomas.

Follistatin is a secreted protein that binds activin in vitro and in vivo and thereby inhibits its biological functions. Recently, related human and murine genes, designated follistatin-related gene (FLRG), were identified, and their products were shown to bind activin with high affinity. In this study we further characterized the murine FLRG protein, and we analyzed its tissue-specific expression and regulation in comparison with those of follistatin. Transient expression of the mouse FLRG protein in COS-1 cells revealed that the FLRG cDNA encodes a secreted glycoprotein. FLRG mRNA was expressed at high levels in the lung, the testis, the uterus and, particularly, the skin. Immunohistochemistry revealed the presence of FLRG in the basement membrane between the dermis and the epidermis and around blood vessels. FLRG mRNA expression was induced in keratinocytes by keratinocyte growth factor, epidermal growth factor and transforming growth factor-1, and in fibroblasts by platelet-derived growth factor and epidermal growth factor. The induction was more rapid, but weaker, than that of follistatin. Most interestingly, both follistatin and FLRG were expressed during the wound healing process, but their distribution within the wound was different. The different expression pattern of FLRG and follistatin and their differential regulation suggest different functions of these activin-binding proteins in vivo.

We investigated the impact of bone marrow-derived mesenchymal stem cells (BM-MSCs) alone or in combination with hepatocyte growth factor (HGF) transplantation via noninfarct-relative artery in a swine myocardial infarction (MI) model. Donor BM-MSCs were derived in vitro from swine auto-bone marrow cultures labeled by bromodeoxyuridine (BrdU) incorporation. Host MI swine model was created by ligating the distal left anterior descending artery. After 4 weeks, age-matched male MI swines were used for the transplantation. Male MI swines were transfused via noninfarctrelative artery with vehicle (control, n ¼ 6) or BrdU-labeled BM-MSCs (5 Â 10 6 ) alone (MSCs, n ¼ 6) or BrdU-labeled BM-MSCs (5 Â 10 6 ) combined with HGF (4 Â 10 9 PFU) (MSCs+HGF, n ¼ 6). To evaluate the collateral artery growth (Rentrop) and cardiac perfusion in these animals, gate cardiac perfusion imaging and coronary angiography were performed before and 4 weeks after transplantation, respectively. To assess the contribution of donor-originated cells in stimulation of cardiomyocyte regeneration and angiogenesis, immunohistochemistry for BrdU and a-smooth muscle actin (a-SMA) and quantitative image analysis were performed at 4 weeks after transplantation. The results are as follows: (1) BrdU-positive cells were detected in host myocardium in both MSCs and MSCs+HGF groups, but not in the vehicle group.Most BrdU-positive cells expressed myosin heavy chain b.(2) a-SMA -positive arteriole densities in the infarcted border area and infarcted area were increased significantly in both transplantation groups compared with the vehicle group. (3) Gate cardiac perfusion imaging demonstrated that the cardiac perfusion was significantly improved in transplantation groups compared with the vehicle group. (4) Ejection fraction and a-SMA-positive arteriole densities were increased significantly in both transplantation groups compared with the vehicle group. However, there was no difference in ejection fraction and a-SMA-positive arteriole densities between the MSCs group and the MSCs+HGF group. Growth of collateral arteries was not detected by coronary angiography in all three groups. In conclusion, the current study indicates that BMMSCs transplantation via noninfarct-relative artery stimulates cardiomyocyte regeneration and angiogenesis and improves cardiac function, but does not stimulate collateral artery growth. BM-MSCs transplantation combined with HGF therapy is not superior to BM-MSCs alone transplantation. BM-MSCs transplantation via noninfarct-relative artery may be an alternative for those patients who cannot be transplanted via infarct-relative artery in clinical practice. Gene Therapy (2006) 13, 1564-1568.

DNA vaccination is an attractive approach for eliciting antigen-specific immunity. In this study, we used magnetosomes (bacterial magnetic particles, BMPs) as carriers of a recombinant DNA composed of a secondary lymphoid tissue chemokine, human papillomavirus type E7 (HPV-E7) and Ig-Fc fragment (pSLC-E7-Fc) to generate a gene vaccine (BMP-V) for tumour immunotherapy. The results indicate that BMPs linked to DNA more efficiently in phosphate-buffered saline (pH=4–5) than in physiological saline. Efficient transfection of BMP-V in vitro and in vivo was achieved when a 600-mT static magnetic field was applied for 10 min. In a mouse tumour model, subcutaneous injection of BMP-V (5 μg, × 3 at 4-day intervals) plus magnetic exposure elicited systemic HPV-E7-specific immunity leading to significant tumour inhibition. The treated mice tolerated BMP-V immunisation well with no toxic side effects, as shown by histopathological examinations of major internal organs. Taken together, these results suggest that BMP can be used as a gene carrier to elicit a systemic immune response.

Submucosal tunneling endoscopic resection is a safe and efficient technique for treating multiple esophageal SMTs originating from MP layer, which can avoid patients suffering repeated resections.

No abstract

tion of many types of cells. For instance, activins increase Activin A is an autocrine inhibitor of initiation of DNA the number of gonadotrophs in pituitary, 7 promote erythroid synthesis in rat hepatocytes. The present study was condifferentiation, 8 support neural cell survival, 9 and induce ducted to characterize the cell-surface receptors for acmesoderm during embryonal development. 10 They elicit tivin A in cultured rat hepatocytes by measuring 125 Because follistatin is synthesized in hepatocytes in response tivin receptors, respectively. Another band with a molecto growth stimulation, 16 the activin-follistatin system plays ular weight of 180 kd was also found, which may reprea vital role in the regulation of growth of hepatocytes. While sent the type III activin receptor. When hepatocytes all of these studies have helped to elucidate the biological were cultured with epidermal growth factor (EGF), both effects of activin A in hepatocytes, the receptor system for high-and low-affinity binding sites increased at 12 hours activin A in hepatocytes remains largely uncharacterized. b D ). 3,4 Hence, the struc-chymal liver cells were isolated according to the methods described ture of activins is more complex than ever thought. Being by Berry and Friend. 17 Briefly, the liver was first perfused via the discovered by virtue of their capacity to stimulate production portal vein with Ca 2/ -free Krebs-Ringer bicarbonate buffer, followed of follicle-stimulating hormone from pituitary gland, 5,6 it is by the same buffer containing 1.25 mmol/L Ca 2/ , 0.05% collagenase, and 0.005% trypsin inhibitor. The liver was then removed, minced, now well known that activins have widespread anatomical and the dispersed cells were filtered through nylon mesh. Isolated distribution and are implicated in the regulation of many hepatocytes were allowed to attach to collagen-coated dishes in apbiological processes, including proliferation and differentiapropriate densities in Williams' medium E supplemented with 10 nmol/L dexamethasone, 1 nmol/L insulin, 10% fetal calf serum, streptomycin, and penicillin. Cells were allowed to attach for 3 hours and were then washed. The medium was changed to serum-free Williams' Abbreviations: mRNA, messenger RNA; EGF, epidermal growth factor. medium containing 1 nmol/L dexamethasone, 0.1 nmol/L insulin, From the 1 Department of Cell Biology, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, and 2 Fourth Department of Internal Medicine, University and 0.01% bovine serum albumin, and various additions were made.of Tokyo School of Medicine, Tokyo, Japan.Incubation was performed at 37ЊC under a humidified condition of Received September 11, 1995; accepted April 18, 1996. 95% air and 5% CO 2 .

Introduction: Controlling blood pressure is a key aspect of cardiovascular disease prevention, but current levels of blood pressure control are suboptimal. Self-management of hypertension might lead to better control but is under researched. This study aimed to evaluate whether self-management of hypertension results in better control of blood pressure.Methods: Inclusion criteria were age 35-85, treated hypertension (2 or fewer antihypertensives) but not controlled below 140/90 mmHg at baseline. Participants were randomised to usual care or self-management. Self-management comprised home blood pressure monitoring with telemonitoring and self-titration of anti hypertensive medication following a plan predetermined by their general practitioner. The primary end point was change in mean systolic blood pressure (mmHg) between baseline and follow up at six and twelve months. Analysis was by intention to treat without imputation.Results: 527 patients were recruited from 24 UK general practices and 480(92%) were available for follow up after one year. Reduction in systolic blood pressure was significantly greater in the self-management group compared to usual care after both six months (3.7 mmHg, 95% CI 0.8-6.6, p ¼ 0.013) and 12 months (5.4 mmHg, 2.4-8.5, p < 0.001). Reduction in diastolic blood pressure was also significantly greater for self-management after 12 months (2.7mmHg 1.1-4.2, p ¼ 0.001) but not six months (1.3mmHg, À0.3-2.6, p ¼ 0.108). Results were similar regardless of age, sex, baseline blood pressure or the presence of a co-morbidity. Patients who self managed increased their antihypertensive medication more than those following usual care 2.1(1.9-2.3) vs 1.7(1.5-1.9) medications. Patients who self-managed were no more anxious and had no more side effects than those that did not.Conclusions: Self-management of hypertension results in significant and worthwhile reductions in blood pressure which are maintained after twelve months. This reduction appears to be due to the increase in the number of anti-hypertensive drugs. Whilst not all patients will wish to self manage, it represents an important new option when blood pressure is not well controlled.Background: Microalbuminuria is an early sign of diabetic nephropathy and increased cardiovascular risk. We investigated whether early treatment with an angiotensin receptor blocker (ARB) in diabetic subjects with normal albumin excretion delays the occurrence of microalbuminuria and concomitantly recorded cardiovascular and renal events.