Tipifarnib, an orally bioavailable inhibitor of farnesyl transferase, has activity in hematologic malignancies, but the dose required to achieve the proposed biologic end point, inhibition of ...farnesylation, is unknown.
The impact on post-translational farnesylation was assessed in 42 patients with refractory hematologic malignancies and bone marrow involvement. Tipifarnib was taken orally for 21 days of a 28-day cycle. For cycle 1, patients were randomly assigned to one of four dose levels: 100 mg bid, 200 mg bid, 300 mg bid, and 600 mg bid. In cycle 1, peripheral blood and bone marrow mononuclear cells were analyzed for inhibition of HDJ2 prenylation by Western blot analysis at baseline and on day 21.
Twenty-three patients were assessable for analysis of HDJ2 prenylation before and after therapy. Inhibition of farnesylation was noted at all dose levels, although the highest level of inhibition was noted at the 300-mg-bid dose. The inhibition of farnesylation in the peripheral blood correlated with the inhibition in the bone marrow (r = 0.62). Of the 26 patients assessable for clinical activity after cycle 1, three patients had a significant decrease in total blasts count (acute myeloid leukemia in two patients, and chronic myelogenous leukemia in one patient). The inhibition of farnesylation was greater in the three responders than the nonresponders (P = .03).
Farnesylation as measured by HDJ2 analysis was inhibited at all dose levels administered. Clinical activity may correlate with the degree of farnesylation inhibition, rather than dose of tipifarnib, and escalation beyond 300 mg bid might not result in additional clinical activity.
Cerebral ischemia has been proposed as a contributing mechanism to secondary neuronal injury after intracerebral hemorrhage (ICH). The search for surrogate parameters that allow treatment ...stratification for spontaneous ICH continues. We sought to assess the presence and prognostic effect of perihemorrhagic ischemic changes and hypoperfusion in a prospective stroke MRI study.
We performed stroke MRI in 32 patients with hyperacute ICH (mean, 16.9+/-17.2 mL) within 6 hours after symptom onset (mean, 3.1+/-1.3 hours). Clinical data at baseline (National Institutes of Health Stroke Scale) and on day 90 (Barthel Index, modified Rankin Scale) were assessed. Perihemorrhagic perfusion- and diffusion-weighted imaging changes were assessed in a 1-cm-wide area around the clot.
Despite a mild perihemorrhagic mean transit time prolongation of 0.7+/-1.1 second, there were no significant perihemorrhagic apparent diffusion coefficient or mean transit time changes indicating irreversible ischemia or hypoperfusion. ICH size, time to imaging, or clinical severity at baseline or outcome were not reflected by changes of relative apparent diffusion coefficient or perfusion-weighted imaging. ICH size correlated with baseline clinical severity (r=0.51, P=0.005). There was a significant association (P=0.0494) and a significant negative correlation (r=-0.468, P=0.0103) of perihemorrhagic perfusion change with time from symptom onset not associated with ICH size.
Perihemorrhagic hypoperfusion probably is a consequence of reduced metabolic demand (diaschisis) rather than a sign of ischemia. We found no evidence for a perihemorrhagic and potentially salvageable ischemic penumbra in hyperacute ICH. Further studies should address metabolic, toxic, apoptotic, and microvascular aspects.
We present Sloan Digital Sky Survey (SDSS) photometry and spectroscopy in the fields of 27 gamma‐ray bursts observed bySwift, including bursts localized bySwift,HETE‐2, andINTEGRAL, after 2004 ...December. After this bulk release, we plan to provide individual releases of similar data shortly after the localization of future bursts falling in the SDSS survey area. These data provide a solid basis for the astrometric and photometric calibration of follow‐up afterglow searches and monitoring. Furthermore, the images provided with this release will allow observers to find transient objects up to a magnitude fainter than is possible with Digitized Sky Survey images.
We describe the results of two placebo-controlled trials (MIL-1077 and MIL-1078) designed to evaluate the clinical efficacy of oral milrinone administered together with converting enzyme inhibitors ...to patients with congestive heart failure. Although these trials were terminated prematurely, they provide the only controlled data regarding the effect of oral milrinone on exercise capacity in patients receiving converting enzyme inhibitors. Of the 254 patients randomized, 140 completed one of the trials or reached an end point and are the basis of this report. In both trials, there was a clear trend for an increase in exercise capacity in the milrinone-treated patients (+ 26 ± 8% vs. +5 ± 7% in MIL-1077 and + 11 ± 5% vs. + 2 ± 4% in MIL-1078). Symptoms of congestive heart failure were decreased in one trial but not the other. Quality of life, as assessed by a questionnaire, was not effected in either trial. There was an increased incidence of adverse events in milrinone-treated patients. Adverse events related primarily to hypotension and vasodilation led to discontinuation of drug in 18 milrinone-treated patients vs. 1 placebo-treated patient. Milrinone had little or no proarrhythmic effect and cardiovascular deaths were distributed equally between the milrinone and placebo groups. These data suggest that when used in combination with a converting enzyme inhibitor, oral milrinone improves exercise capacity but is associated with a high incidence of adverse events that appear to be related to excessive vasodilation.
Health care decisionmakers face increasing pressure to use health care resources more efficiently, but the information they need to assess policy options often is unavailable or not disseminated in a ...useful form. Findings from stakeholder meetings and a survey of private-sector health care decisionmakers in California begin to identify high-priority issues, the perceived adequacy of current information, and preferred formats and other desired attributes of research. This is a first step in establishing a systematic approach to linking the information priorities of private-sector decisionmakers with those who fund and conduct research.
Experiments involving overexpression of Ski have suggested that this gene is involved in neural tube development and muscle differentiation. In agreement with these findings, Ski−/− mice display a ...cranial neural tube defect that results in exencephaly and a marked reduction in skeletal muscle mass. Here we show that the penetrance and expressivity of the phenotype changes when the null mutation is backcrossed into the C57BL6/J background, with the principal change involving a switch from a neural tube defect to midline facial clefting. Other defects, including depressed nasal bridge, eye abnormalities, skeletal muscle defects and digit abnormalities, show increased penetrance in the C57BL6/J background. These phenotypes are interesting because they resemble some of the features observed in individuals diagnosed with 1p36 deletion syndrome, a disorder caused by monosomy of the short arm of human chromosome 1p (refs. 6-9). These similarities prompted us to re-examine the chromosomal location of human SKI and to determine whether SKI is included in the deletions of 1p36. We found that human SKI is located at distal 1p36.3 and is deleted in all of the individuals tested so far who have this syndrome. Thus, SKI may contribute to some of the phenotypes common in 1p36 deletion syndrome, and particularly to facial clefting.
OBJECTIVE: Adiponectin influences insulin sensitivity (Ssubscript I) and fat oxidation. Little is known about changes in adiponectin with changes in the fat content of eucaloric diets. We ...hypothesized that dietary fat content may influence adiponectin according to an individual's Ssubscript I. RESEARCH METHODS AND PROCEDURES: We measured changes in adiponectin, insulin, glucose, and leptin in response to high-fat (HF) and low-fat (LF) eucaloric diets in lean (n = 10) and obese (n = 11) subjects. Obese subjects were further subdivided in relation to a priori Ssubscript I. RESULTS: We found significantly higher insulin, glucose, and leptin and lower adiponectin in obese vs. lean subjects during both HF and LF. The mean group values of these measurements, including adiponectin (lean, HF 21.9 ± 9.8; LF, 20.8 ± 6.6; obese, HF 10.0 ± 3.3; LF, 9.5 ± 2.3 ng/mL; mean ± SD), did not significantly change between HF and LF diets. However, within the obese group, the insulin-sensitive subjects had significantly higher adiponectin during HF than did the insulin-resistant subjects. Additionally, the change in adiponectin from LF to HF diet correlated positively with the obese subjects' baseline Ssubscript I. DISCUSSION: Although in lean and obese women, group mean values for adiponectin did not change significantly with a change in fat content of a eucaloric diet, a priori measured Ssubscript I in obese subjects predicted an increase in adiponectin during the HF diet; this may be a mechanism that preserves Ssubscript I in an already obese group.
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