Purpose: Protein farnesylation by farnesyltransferase (FTase) is required for membrane localization and effective signal transduction by G-proteins, including Ras. Lonafarnib inhibits FTase and has shown antitumor activity in both preclinical and clinical settings. As disturbances in Ras signaling pathways have been implicated in the pathogenesis of transitional cell carcinoma (TCC), the antitumor activity of lonafarnib was studied in a National Cancer Institute of Canada Clinical Trials Group Phase II trial in patients with previously treated TCC.Patients and Methods: Patients had at least 1 prior chemotherapy regimen for advanced unresectable or metastatic TCC, or recurrence less than I year after adjuvant or neoadjuvant chemotherapy. Lonafarnib was given at a dose of 200 mg PO twice daily continuously, with cycles repeated every 4 weeks.Results: Between December 1999 and December 2000, 19 eligible patients were enrolled at 8 National Cancer Institute of Canada Clinical Trials Group centers. Median time on treatment was 7.1 weeks (range, 0.6-23.9). Drug-related Grade 3 toxicities included fatigue, anorexia, nausea, confusion, dehydration, muscle weakness, depression, headache, and dyspnea. Five patients discontinued the study protocol due to toxicity. No responses were observed in 10 patients who were evaluable. Of 9 patients not evaluable for response, 5 had symptomatic progression, fulfilling multinomial criteria to stop the Study after the first Stage.Conclusion: No single-agent activity of lonafarnib was observed in this study of patients with aggressive TCC failing prior chemotherapy. (c) 2005 Elsevier Inc. All rights reserved.

It is common practice to assess the average effect of some type of announcement on stock prices by performing event studies on a large sample of firms and then averaging or otherwise combining the results. One benefit of this procedure is that the event window length can be standardized across observations because the errors from having too long or short an event window should have a small impact on the average by the Law of Large Numbers. Here, we examine various potential rules for determining the length of an event window when looking at a limited number of observations. We find that rules based on continuing price movements yield window lengths that correlate with the "size" of the news, as measured by the magnitude of earnings surprises, while a rule based on abnormally high volume does not have this property.

From the Publisher:All the essential information needed to take full advantage of Microsoft's newest Web development platform. What is ASP.NET ASP.NET is a revolutionary new programming framework that enables the rapid development of powerful web applications and services. Part of the emerging Microsoft .NET Platform, it provides the easiest and most scalable way to build, deploy and run distributed web applications that can target any browser or device. ASP.NET (formerly referred to as ASP+) is more than the next version of Active Server Pages (ASP); it is a unified Web development platform that provides the services necessary for developers to build enterprise-class Web applications. ASP.NET Web Developer's Guide will teach Web developers to quickly and easily build solutions for the Microsoft .NET platform. Programmers who are expert in asp and other languages will find this book invaluable. Features: This book will appeal to all web developers - regardless of what language they are using or what platform they will be using You can take it with you. The book comes packaged with Syngress' revolutionary wallet-sized CD containing a printable HTML version of the book, all of the source code examples and demos of popular ASP.NET programming tools Comprehensive Coverage of the Entire .net Framework for B2B commerce About the Author Jeremy Faircloth (CCNA, MCSE, MCP+I, A+) is a Systems Analyst for Gateway, Inc. In this position, he develops and maintains enterprise-wide client/server and Web-based technologies. As a Systems Analyst with over 10 years of real-world IT experience, he has become an expert in many areas of IT including Web development, database administration, enterprise security, network design, and project management. Mesbah Ahmed (PhD and MS, Industrial Engineering) is a Professor of Information Systems at the University of Toledo. In addition to teaching and research, he provides technical consulting and training for IT and manufacturing industries in Ohio and Michigan. His consulting experience includes systems design and implementation projects with Ford Motors, Dana Corporation, Riverside Hospital, Sears, and others. Currently, he provides IT training in the areas of Java Server, XML, and .NET technologies. He teaches graduate level courses in Database Systems, Manufacturing Systems, and Application Development in Distributed and Web Environment. Recently, he received the University of Toledo Outstanding Teaching award, and the College of Business Graduate Teaching Excellence award. He has published many research articles in academic journals such as Decision Sciences, Information & Management, Naval Research Logistic Quarterly, Journal of Operations Management, IIE Transaction, and International Journal of Production Research. Chris Garrett is the Technical Manager for a large European Web agency. He has been working with Internet technologies since 1994 and has provided technical and new media expertise for some of the world聮s biggest brands. Chris Payne, author of Teach Yourself ASP.NET in 21 Days, is the Co-Founder and CIO of Enfused Media, Inc., which designs and develops applications to automate and facilitate business processes. Chris has taught ASP and solution techniques through articles and tutorials. Jonothon Ortiz is Vice President of Xnext, Inc. in Winter Haven, FL. Xnext, Inc. is a small, privately owned company that develops Web sites and applications for prestigious companies such as the New York Times. Wei Meng Lee is Series Editor for Syngress Publishing's .NET Developer Series. He is currently lecturing at The Center for Computer Studies, Ngee Ann Polytechnic, Singapore. Wei Meng is actively involved in Web development work and conducts training for Web developers and Visual Basic programmers. He has co-authored two books on WAP. He holds a bachelor聮s degree in Information Systems and Computer Science from the National University of Singapore. The first book in the .NET series, VB.NET Developer聮s Guide (ISBN: 1-928994-48-2), is currently available from Syngress Publishing.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Diastolic function of the left ventricle (LV) is principally assessed by analysis of the Doppler velocity flow profiles at the mitral orifice (MO). Assuming the mitral valve is not obstructed, early and late diastolic inflow are influenced not only by the left atrium but also by the LV. We hypothesized that recording of diastolic flow velocity profiles in the mid LV might contribute additional information on the response of the ventricle to filling in diastole. In 58 normal subjects, the differences at the MO and midventricular (MV) levels between the R–E interval (the time in milliseconds from the peak of the R wave of the electrocardiogram to the peak of the early diastolic filling wave), the R–D interval (the time in milliseconds from the peak of the R wave to the beginning of the early diastolic flow wave), and the D–E interval (the time in milliseconds from the onset to the peak of the early diastolic flow wave) were quite small, averaging 13 ± 17, −21 ± 27, and −7 ± 16 ms, respectively (mean ± SD). At the MO, the E/A velocity ratio averaged 1.6/1, whereas it was significantly greater at the MV level 2.1/1 (p <0.001) due to a relatively greater decrease in the A-wave velocity (37%) compared with the decrease in peak E-wave velocity (18%). The peak A-wave velocity occurred before the R wave (average 44 ± 19 ms at the MO and 43 ± 24 ms at the MV level). Abnormal patterns involving both early and late diastole were observed with left ventricular hypertrophy and systolic dysfunction. The method is simple and therefore adaptable for routine clinical practice. Importantly, early diastolic left ventricular function can be assessed in patients in atrial fibrillation as well as sinus rhythm.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A previously described cembranolide diterpene from Lobophytum cristagalli was identified as a potent (IC50 0.15 μM) inhibitor of farnesyl protein transferase (FPT). The compound showed selectivity for FPT as compared to the closely related enzyme geranylgeranyl protein transferase-1 (IC50 5.3 μM). Kinetic evaluation suggests that this compound competes with the protein/peptide farnesyl acceptor substrate, and not with farnesyl pyrophosphate for inhibition of FPT.

SCH 58450, a novel secondary metabolite possessing the 6a,12a:7,12.diepoxybenz[a]anthracene ring system, has been isolated from a Streptomyces sp. SCH 58450 inhibits farnesyl protein transferase with an IC50 of 29 μM, and shows 25 fold selectivity for farnesyl protein transferase over geranylgeranyl protein transferase-1.

An increase in the pulmonary capillary wedge pressure (PAWP) has been shown to impact on the inherent relationship between the pulmonary arterial compliance (PAC) and pulmonary vascular resistance (PVR), thus augmenting the pulsatile relative to the resistive load of the right ventricle. However, the PAWP comprises the integration of both the steady and the pulsatile pressure components. We sought to address the differential impact of the these distinct PAWP components on the PAC–PVR relationship in a cohort of patients with heart failure. The study population consisted of 192 patients with hemodynamic findings diagnostic for heart failure. Off-line analysis was performed using the MATLAB software. The steady and pulsatile PAWP components were calculated as mid-A pressure and mean pressure during the V-wave oscillation, respectively. The PAC and PVR were hyperbolically and inversely associated and the subgroup of patients with PAWP above the median (>18 mm Hg) displayed a significant left and downward shift of the curve fit (P < .001). The shift in the PAC–PVR fit between patients with higher versus low steady PAWP was not significant (P = .43). In contrast, there was a significant downward and leftward shift of the PVR–PAC curve fit for the subgroup with a higher pulsatile PAWP (P < .001). Furthermore, only the pulsatile PAWP was significantly associated with the time-constant of the pulmonary circulation, assessed as the PAC × PVR product (P < .001).In patients with heart failure, the pulsatile rather than the steady PAWP component stands for the previously documented shift of the PAC–PVR relationship occurring at an elevated PAWP.

Left ventricular (LV) hypertrophy is common in end-stage renal disease, yet the factors associated with its development are poorly understood. LV mass index was determined by echocardiography in 78 patients who had been treated by dialysis for at least 3 months. A significant relation was evident between anemia and LV hypertrophy. The mean LV mass index was 158 ± 6 g/m2 (mean ± standard error) in patients in the lowest quartile of serum hemoglobin and 140 ± 10, 132 ± 7 and 120 ±8 g/m2 in the second, third and uppermost quartiles, respectively (p = 0.005). This relation persisted after adjusting for systolic blood pressure, treatment mode and suspected coronary artery disease. Forty-eight patients had paired studies. In these, LV mass index increased as hemoglobin decreased (coefficient = −0.81 g/m2/g/liter, p < 0.025). These data indicate that anemia contributes to the development of LV hypertrophy in patients with endstage renal disease.

Cardiovascular diseases account for the greatest number of deaths among uremic patients.1,2 Most attention has focused on atherosclerosis, with opinion divided as to whether it is accelerated by uremia.3,4 Although a “uremic dilated cardiomyopathy” has been reported, its cause and prevalence remain obscure.5 In contrast, concentric left ventricular (LV) hypertrophy is known to occur more often in patients treated with dialysis, although apparently little attention has been paid to its possible clinical significance.6,7 This report was designed to (1) determine the prevalence of LV hypertrophy in patients treated with dialysis, (2) examine the clinical factors that may be responsible for its presence, and (3) determine whether LV hypertrophy was associated with increased mortality. Because blood pressure (BP) is likely to be involved in the pathogenesis of LV hypertrophy, the study was conducted in patients treated with continuous ambulatory peritoneal dialysis because such patients are free of the marked swings in BP that frequently accompany the relatively rapid intravascular volume changes with hemodialysis, and accurate tracking of BP is therefore possible.

This report tests the hypothesis that, in early diastole, motion of the anterior left atrial wall corresponds to the motion that can be observed in the contiguous posterior wall of the aortic root. To test this hypothesis, we examined the effects of mitral stenosis, exercise in normals, exercise induced left ventricular ischemia, left ventricular hypertrophy and left ventricular dysfunction on this slope. Each altered early diastolic atrioventricular interaction as predicted and therefore, the early diastolic motion of the anterior left atrial wall does appear to be mirrored by the early diastolic slope of the posterior wall of the aortic root. Consequently, if interpreted in the clinical context, measurement of early diastolic slope of the posterior wall of the aortic root may serve as a useful guide to separate patients with severe from those with mild mitral stenosis.

Twenty-two patients with advanced prostatic carcinoma were subjected either to orchiectomy (group I, n = 5) or to chronic administration of a gonadotropin releasing hormone agonistic analogue D, Ser (TBU)6, des Gly-NH2(10) LHRH nonapeptide (HOE 766) (group 2, n = 17). Plasma testosterone was similar in both groups prior to treatment (group 1: 636 +/- 129.29, group 2: 580.85 +/- 37.57; X +/- SE). The levels attained in group I were significantly lower (P less than .05) than those of group 2 through eight weeks of follow-up but were similar by the third month. Prostatic size (cm2) as estimated by transabdominal ultrasonography did not differ between the two groups prior to treatment (group 1: 23.6 +/- 3.35, group 2: 21.4 +/- 1.97; X +/- SE). Both therapies resulted in a decrease of prostatic size that was significantly more pronounced (P less than .05) in group I compared with group 2 by the first and third month; by the six month, there was no statistical difference in the prostatic size attained with either therapeutic modality. Persistent suppression of prostatic size was documented in all patients of group 2 chronically (up to 24 months) treated with HOE 766 even when there was evidence of uninhibited or progressive bony metastases. The above data 1) indicate the efficacy of the HOE 766 in inducing medical castration and prostatic shrinkage in advanced carcinoma of the prostate, 2) document the usefulness of transabdominal ultrasound in the follow-up of such patients, and 3) suggest a relationship between the rapidity of tumor shrinkage and Leydig cell suppression.