Citations

Purpose: To evaluate the antitumor activity, safety, immune response, and replication of CI-1042 (ONYX-015), an E1B 55-kd gene-deleted replication-selective adenovirus, administered intravenously to patients with metastatic colorectal cancer Patients and Methods: Eighteen patients with metastatic colorectal cancer for whom prior chemotherapy failed were enrolled onto an open-label, multicenter, phase II study. CI-1042 was administered intravenously at a dose of 2 × 1012 viral particles every 2 weeks. Patients were evaluated for tumor response and toxicity; in addition, blood samples were taken for adenovirus DNA and neutralizing antibody analysis. Results: Common toxicities included flu-like symptoms, nausea, and emesis. All 18 patients eventually were removed from study because of progressive disease. Seven patients were assessed as having stable disease after 2 months of treatment, whereas two patients were considered to have stable disease after 4 months. Detectable circulating CI-1042 DNA was identified in 36% of patients 72 hours after last infusion, which is suggestive of ongoing viral replication. Conclusion: In this phase II study, intravenous CI-1042 was administered safely to patients with advanced colorectal cancer. Toxicity was manageable, consisting primarily of flu-like symptoms. Stable disease was experienced by seven patients for 11 to 18 weeks.

Purpose: To investigate the effect of granulocyte colony-stimulating factor (G-CSF) on hematopoietic toxicities, supportive care requirements, time to complete intensive therapy, and event-free survival (EFS) and overall survival (OS) in children with high-risk acute lymphoblastic leukemia (HR-ALL). Patients and Methods: A total of 287 children with HR-ALL were randomly assigned to intensive chemotherapy regimens (New York I [NY I] or NY II) as part of the Children’s Cancer Group (CCG)-1901 protocol. The induction phases consisted of five drugs (vincristine, prednisone, l-asparaginase, daunorubicin, and cyclophosphamide). Initial consolidation comprised six-agent chemotherapy combined with 18 Gy of total-brain irradiation. Patients were randomly assigned to receive G-CSF (5 μg/kg/day) during either induction or initial consolidation. A crossover study analysis was done on the 259 patients who completed both phases of therapy. Results: The mean time to neutrophil recovery (≥ 0.5 × 109/L) was reduced with G-CSF (16.7 v 19.1 days, P = .0003); however, patients who received G-CSF did not have significantly reduced episodes of febrile neutropenia (149 v 164, P = .41), positive blood cultures (57 v 61, P = .66), or serious infections (75 v 79, P = .62). Hospitalization (14.0 v 13.9 days, P = .87) and induction therapy completion times (NY I, 30.3 v 31.3 days, P = .11; NY II, 33.4 v 32.3 days, P = .40) were not significantly altered. There were no differences in 6-year EFS (P = .24) or OS (P = .54) between patients receiving or not receiving G-CSF on CCG-1901, NY I and NY II. Conclusion: Children with high-risk ALL do not appear to benefit from prophylactic G-CSF.

Atherosclerosis is the major cause of adult mortality in the developed world, and a significant contributor to atherosclerotic plaque progression involves smooth muscle cell recruitment to the intima of the vessel wall. Controversy currently exists on the exact origin of these recruited cells. Here we use sex-mismatched bone marrow transplant subjects to show that smooth muscle cells throughout the atherosclerotic vessel wall can derive from donor bone marrow. We demonstrate extensive recruitment of these cells in diseased compared with undiseased segments and exclude cell–cell fusion events as a cause for this enrichment. These data have broad implications for our understanding of the cellular components of human atherosclerotic plaque and provide a potentially novel target for future diagnostic and therapeutic strategies.

Background— Validation of in-hospital mortality models after percutaneous coronary interventions using multicenter data remains limited. Methods and Results— This study evaluated whether multivariable mortality models developed during the pre-stent era by New York State, American College of Cardiology (ACC)–National Cardiovascular Data Registry, Northern New England Cooperative Group, Cleveland Clinic Foundation, and the University of Michigan are relevant in patients undergoing percutaneous coronary intervention in the 1997 to 1999 National Heart, Lung, and Blood Institute Dynamic Registry. Of 4448 Dynamic Registry patients, 73% received ≥1 stent and 28% received a IIB/IIIA receptor inhibitor. In-hospital mortality occurred in 64 patients (1.4%). The New York state model predicted mortality in 69 patients (1.5%; 95% confidence bounds [CI], 0.89% to 1.70%); Northern New England predicted mortality in 60 patients (1.3%; 95% CI, 1.0% to 1.7%); and Cleveland Clinic predicted mortality in 76 patients (1.7%; 95% CI, 1.3% to 2.1%). Among high-risk subgroups, with these 3 models, observed and predicted in-hospital mortality rates in general were not different. The other 2 models yielded different results. The University of Michigan predicted fewer deaths (n=47; 1.1%; 95% CI, 0.7% to 1.3%), and the ACC Registry model predicted 603 deaths (13.5%; 95% CI, 12.6% to 14.4%). Using the ACC Registry model, predicted mortality was higher than observed in each subgroup. Conclusions— Application of 5 mortality risk models developed from different data sets to patients undergoing percutaneous coronary intervention in the Dynamic Registry predicted, in 3 models, mortality rates that were not significantly different than those observed. In both high and low risk subgroups, the University of Michigan slightly underpredicted mortality, and the ACC Registry predicted significantly higher mortality than that observed.

ABSTRACT γ‐Secretase cleavage is the final proteolytic step that releases the amyloid β‐peptide (Aβ) from the amyloid β‐protein precursor (APP). Significant evidence indicates that the presenilins (PS) are catalytic components of a high molecular weight γ‐secretase complex. The glycoprotein nicastrin was recently identified as a functional unit of this complex based on 1) binding to PS and 2) the ability to modulate Aβ production following mutation of a conserved DYIGS region. In contrast to the initial report, we find that overexpression of wild‐type (WT) nicastrin increases Aβ production, whereas DYIGS mutations (MT) have little or no effect. The increase in Aβ production is associated with an increase in γ‐secretase activity but not with a detectable increase in PS1 levels. Subcellular fractionation studies show that WT but not MT nicastrin matures into buoyant membrane fractions enriched in γ‐secretase activity. These data support the hypothesis that nicastrin is an essential component of the γ‐secretase complex. The finding that WT nicastrin overexpression can increase γ‐secretase activity without altering levels of the presumed catalytic component (PS) of the enzyme may point to a role for nicastrin in facilitating cleavage by regulating substrate interactions with the γ‐secretase complex.

Multivesicular bodies are late endosomal compartments containing lumenal vesicles that are formed by inward budding of the limiting endosomal membrane. In the yeast Saccharomyces cerevisiae, integral membrane proteins are sorted into the lumenal vesicles of multivesicular bodies, and this process requires the class E subset of VPS genes. We show that one of the class E VPS genes, BRO1/VPS31, encodes a cytoplasmic protein that associates with endosomal compartments. The dissociation of Bro1 from endosomes requires another class E Vps protein, Vps4, which is an ATPase that also regulates the endosomal dissociation of ESCRT-III, a complex of four class E Vps proteins (Vps2, Vps20, Vps24 and Snf7/Vps32) that oligomerize at the endosomal membrane. We also show that the endosomal association of Bro1 is specifically dependent on one of the ESCRT-III components, Snf7. Our data suggest that the function of Bro1 in the MVB pathway takes place on endosomal membranes and occurs in concert with or downstream of the function of the ESCRT-III complex.