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Optimizing prostate cancer suicide gene therapy using herpes simplex virus thymidine kinase active site variants 总被引:1,自引:0,他引:1
Pantuck AJ Matherly J Zisman A Nguyen D Berger F Gambhir SS Black ME Belldegrun A Wu L 《Human gene therapy》2002,13(7):777-789
The herpes simplex virus (HSV) thymidine kinase gene (tk) forms the basis of a widely used strategy for suicide gene therapy. A library of HSV thymidine kinase enzyme (TK) active site mutants having different affinities for guanosine analog prodrugs was developed. We sought to determine the optimal combination of tk variant and prodrug specifically for prostate cancer gene therapy, using in vitro and in vivo studies of adenovirally infected CL1, DU-145, and LNCaP tumor lines carrying wild-type tk, tk30, tk75, and sr39tk mutants expressed by a strong, constitutive cytomegalovirus promoter and treated with ganciclovir and acyclovir. In vitro experiments involving prostate cancer (CaP) cell line infection were carried out with a broad range of prodrug concentrations, and cell killing was determined by limiting dilution (colony-forming), MTT, and propidium iodide assays. In vivo studies based on CL1-GFP xenograft experiments were carried out to examine the ability of each TK variant to prevent tumor formation and to inhibit tumor growth and development of metastases in established orthotopic and subcutaneous tumors in SCID mice. Both in vitro and in vivo studies suggest improved killing with the sr39tk variant. Thus, the results suggest that the use of sr39tk in future trials of prostate cancer tk suicide gene therapy may be beneficial. 相似文献
105.
Innate and adaptive lymphocytes employ diverse effector programs that provide optimal immunity to pathogens and orchestrate tissue homeostasis, or conversely can become dysregulated to drive progression of chronic inflammatory diseases. Emerging evidence suggests that CD4+ T helper cell subsets and their innate counterparts, the innate lymphoid cell family, accomplish these complex biological roles by selectively programming their cellular metabolism in order to instruct distinct modules of lymphocyte differentiation, proliferation, and cytokine production. Further, these metabolic pathways are significantly influenced by tissue microenvironments and disease states. Here, we summarize our current knowledge on how cell-intrinsic metabolic factors modulate the context-dependent bioenergetic pathways that govern innate and adaptive lymphocytes. Further, we propose that a greater understanding of these pathways may lead to the identification of unique features in each population and provoke the development of novel therapeutic strategies to modulate lymphocytes in health and disease. 相似文献
106.
Claus Niederau Jürgen Müller Amnon Sonnenberg Theodor Scholten Joachim Erckenbrecht Wolf-P. Fritsch Theodor Brüuster Georg Strohmeyer 《Journal of clinical ultrasound : JCU》1983,11(1):23-27
To determine the average diameter and the upper normal limit of the common bile duct in healthy man, 830 blood donors were examined by ultrasound. The mean diameter was 2.5 ± 1.1 mm (SD) at the porta hepatis and 2.8 ± 1.2 mm (SD) at the widest point, the regression coefficient between both diameters being r = 0.84. None of the healthy subjects had a diameter larger than 7 mm at any site, and in 95% of all subjects the diameters were less than 4 mm at both sites of measurement. The diameters were significantly correlated with age (r = 0.16) and weight (r = 0.11), but not with sex, height, and body surface area. In 73 patients with cholelithiasis and in 55 patients after cholecystectomy, all of whom lacked clinical or laboratory signs of biliary obstruction, the average diameters at the porta hepatis were 3.8 ± 2.0 mm and 5.2 ± 2.3 mm, and at the widest point 4.8 ± 2.2 mm and 6.2 ± 2.5 mm, respectively. It is concluded that a common bile duct with any sonographic diameter larger than 4 mm should be followed closely and evaluated further with clinical examinations such as intravenous cholangiography unless cholecystectomy has been performed. 相似文献
107.
A single amino acid alteration in cytoplasmic domain determines IL-2 promoter activation by ligation of CD28 but not inducible costimulator (ICOS) 总被引:8,自引:0,他引:8 下载免费PDF全文
Harada Y Ohgai D Watanabe R Okano K Koiwai O Tanabe K Toma H Altman A Abe R 《The Journal of experimental medicine》2003,197(2):257-262
The CD28 family molecules, CD28, and inducible costimulator (ICOS) all provide positive costimulatory signals. However, unlike CD28, ICOS does not costimulate IL-2 secretion. The YMNM motif that exists in the CD28 cytoplasmic domain is a known binding site for phosphatidylinositol 3-kinase (PI3-K) and Grb2. ICOS possesses the YMFM motif in the corresponding region of CD28 that binds PI3-K but not Grb2. We postulated that the reason that ICOS does not have the ability to induce IL-2 production is because it fails to recruit Grb2. To verify this hypothesis, we generated a mutant ICOS gene that contains the CD28 YMNM motif and measured IL-2 promoter activation after ICOS ligation. The results indicated that ICOS became competent to activate the IL-2 promoter by this single alteration. Further analysis demonstrated that Grb2 binding to ICOS was sufficient to activate the NFAT/AP-1 site in the IL-2 promoter and that the cytoplasmic domain of CD28 outside of the YMNM motif is required for activation of the CD28RE/AP-1 and NF-kappaB sites. Together, these observations lead us to believe that the difference of a single amino acid, which affects Grb2 binding ability, may define a functional difference between the CD28- and ICOS-mediated costimulatory signals. 相似文献
108.
Evaluating real-life clinical and economical burden of amphotericin-B deoxycholate adverse reactions
Horwitz E Shavit O Shouval R Hoffman A Shapiro M Moses AE 《International journal of clinical pharmacy》2012,34(4):611-617
Background Amphotericin-B (AMB) is associated with toxicity such as renal impairment, hypokalemia and infusion-related events (IRE). With the advent of AMB lipid formulations and newer antifungal drugs, presenting improved safety profiles, it was suggested that using the conventional deoxycholate (AMB-D) formulation should no longer be regarded acceptable. Objectives Evaluation of real-life incidence of AMB-D-related adverse-drug effects (ADE) and associated costs. Setting Hadassah Hebrew University Medical Center, Jerusalem, Israel, a tertiary 1,100-bed teaching hospital. Methods A 1-year single-center prospective observational study following all patients administered AMB-D. Various parameters related to AMB-D administration were recorded. Main outcome measures Subsequent ADE-related events, discontinuations, switch to alternative antifungals and related resource-utilization were monitored. Results Among 119 patients (60 children, 59 adults) receiving AMB-D, serum creatinine doubling from baseline, hypokalemia and IRE occurred in 14.3?% (15?% in children, 13.6?% in adults), 16.8?% (16.6?% in children, 16.9?% in adults) and 10.9?% (10?% in children, 11.8?% in adults), respectively. AMB-D was discontinued due to an ADE in 12.6?% of patients (6.7?% in children, 18.6?% in adults). The total annual cost associated with AMB-D use was ?58,600. Conclusion The clinical as well as economic burden of AMB-D associated ADE, as observed in real-life settings, appears to be manageable. Considering the significant cost implications associated, as suggested by simulated evaluation of an overall theoretic replacement of AMB-D by an equivalent volume of alternative antifungals, total abandonment of AMB-D appears unjustified. 相似文献
109.
Umberto Capitanio Nazareno Suardi Shahrokh F. Shariat Yair Lotan Ganesh S. Palapattu Patrick J. Bastian Amit Gupta Amnon Vazina Mark Schoenberg Seth P. Lerner Arthur I. Sagalowsky Pierre I. Karakiewicz 《BJU international》2009,103(10):1359-1362
OBJECTIVE
To identify the likelihood of finding one or more positive lymph nodes (LNs) according to the number of LNs removed at radical cystectomy (RC), as the number of LNs removed affects disease progression and survival after RC.PATIENTS AND METHODS
Between 1984 and 2003, 731 assessable patients had RC and bilateral pelvic lymphadenectomy at three different institutions. ROC curve coordinates were used to determine the probability of identifying one or more positive LNs according to the total number of removed LNs.RESULTS
Of the 731 patients, 174 (23.8%) had LNs metastases. The mean (median, range) number of LNs removed was 18.7 (17, 1–80). The ROC coordinate‐based plots of the number of removed LNs and the probability of finding one or more LNs metastases indicated that removing 45 LNs yielded a 90% probability. Conversely, removing either 15 or 25 LNs indicated, respectively, 50% and 75% probability of detecting one or more LNs metastases.CONCLUSIONS
These data indicate that removing 25 LNs might represent the lowest threshold for the extent of lymphadenectomy at RC. Our findings confirm the importance of an extended lymph node dissection. 相似文献110.
Christine Stroh D. Birk R. Flade- Kuthe M. Frenken B. Herbig S. Höhne H. Köhler V. Lange K. Ludwig R. Matkowitz G. Meyer P. Pick Th. Horbach S. Krause L. Schäfer M. Schlensak E. Shang T. Sonnenberg M. Susewind H. Voigt R. Weiner S. Wolff A. M. Wolf U. Schmidt F. Meyer H. Lippert Th. Manger 《Obesity surgery》2009,19(7):928-936
Background Since January 1st, 2005, the current situation for bariatric surgery has been examined by means of a voluntary quality assurance
study in Germany with a multicenter design in which 38 hospitals and surgical departments participated. The data are registered
in cooperation with the Institute of Quality Assurance in Surgery at the Otto-von-Guericke University of Magdeburg (Germany).
Methods Data describing peri-interventional characteristics were prospectively documented in an internet online data registry. All
primary bariatric procedures performed since January 1st, 2005, were registered. In addition, reoperations in patients who
had previously undergone primary surgical intervention were included. As a representative excerpt from the overall prospective
multicenter observational study on obesity surgery, data on the type, regimen, and time course of deep venous thrombosis (DVT)
prophylaxis were documented. From the number and spectrum of complications, the incidences of clinically manifest DVT or pulmonary
embolism (PE) were derived during the in-hospital course and follow-up in conjunction with the type of surgical procedure
and body mass index (BMI).
Results Overall, 3,122 bariatric procedures were performed at 38 German hospitals between January 2005 and December 2007. These procedures
were subdivided into 2,869 primary operations and 253 revisions (sex ratio, male to female = 25.6:74.4%). The average BMI
of all patients was 48.5 kg/m2 in 2005, 48.4 kg/m2 in 2006, and 48.0 kg/m2 in 2007. In 2005 and 2006, gastric banding (GB)
was the most commonly performed operation, followed by Roux-en-Y gastric bypass (RYGBP). In 2007, RYGBP was carried out in
42.1% of all bariatric procedures. Interestingly, the incidence of deep venous thrombosis (DVT) was only 0.06%, whereas PE
occurred in 0.06% of patients only after hospital discharge. The DVT prophylaxis protocol used has been changed for the last
2 years: the majority of patients with a BMI above 50 kg/m2 received low-molecular-weight heparin twice a day.
Conclusion In Germany, a trend from GB to sleeve gastrectomy (SG) and malabsorptive approach has been evaluated. This trend is associated
with differences of the DVT prophylaxis regimen in the profile of bariatric surgical patients depending on BMI and the type
of bariatric procedure. Despite the low incidence of DVT and pulmonary embolism (PE) detected, there is a lack of evidence
on a reasonable regimen for sufficient DVT prophylaxis in bariatric surgery; instead, there are only recommendations from
the guidelines and statements of a specific medical society. Therefore, prospective studies are necessary to determine the
optimal DVT prophylaxis for bariatric surgical patients as well as obese patients undergoing surgery. 相似文献