Biomedical subjects
Lowell E Schnipper
Publications and source records attributed to Lowell E Schnipper.
Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred.
PURPOSE: Members of a family with hereditary gastrointestinal stromal tumors (GISTs) and a germline KIT oncogene mutation were evaluated for other potential syndrome manifestations. A tumor from the proband was analyzed to compare features with sporadic GISTs. PATIENTS AND METHODS: Members of a kindred in which six relatives in four consecutive generations comprised an autosomal dominant pattern of documented GISTs and cutaneous lesions underwent physical examination, imaging studies, and germline KIT analysis. A recurrent GIST from the proband was studied using microarray, karyotypic, immunohistochemical, and immunoblotting techniques. RESULTS: In addition to evidence of multiple GISTs, lentigines, malignant melanoma, and an angioleiomyoma were identified in relatives. A previously reported gain-of-function missense mutation in KIT exon 11 (T --> C) that results in a V559A substitution within the juxtamembrane domain was identified in three family members. The proband's recurrent gastric GIST had a 44,XY-14,-22 karyotype and immunohistochemical evidence of strong diffuse cytoplasmic KIT expression without expression of actin, desmin, or S-100. Immunoblotting showed strong expression of phosphorylated KIT and downstream signaling intermediates (AKT and MAPK) at levels comparable with those reported in sporadic GISTs. cDNA array profiling demonstrated clustering with sporadic GISTs, and expression of GIST markers comparable to sporadic GISTs. CONCLUSION: These studies provide the first evidence that gene expression and mechanisms of cytogenetic progression and cell signaling are indistinguishable in familial and sporadic GISTs. Current investigations of molecularly targeted therapies in GIST patients provide opportunities to increase the understanding of features of the hereditary syndrome, and risk factors and molecular pathways of the neoplastic phenotypes.
The costs of conducting clinical research.
PURPOSE: Physicians frequently receive payment for enrolling subjects onto clinical trials. Some view these payments as conflicts of interest. Others contend that these payments are necessary reimbursements for conducting clinical research. We evaluated the clinical and nonclinical hours and costs associated with conducting a mock phase III clinical research trial. METHODS: We collected data from representatives of 21 clinical sites, on the numbers of hours associated with 13 activities necessary to the conduct of clinical research. The hours were based on enrolling 20 patients in a 12-month randomized placebo-controlled trial of a new chemotherapeutic agent. The outcome measures were disease progression and quality-of-life reports. These costs were evaluated for both government and pharmaceutical industry-sponsored trials. RESULTS: On average, 4,012 hours (range, 1,512 to 13,319 hours) were required for a government-sponsored trial, and 3,998 hours (range: 1735 to 15,699) were required for a pharmaceutical industry-sponsored trial involving 20 subjects with 17 office visits, or approximately 200 hours per subject. Thirty-two percent of the hours were devoted to nonclinical activities, such as institutional review board submission and completion of clinical reporting forms. On average, excluding overhead expenses, it cost slightly more than 6,094 dollars (range, 2,098 dollars to 19,285 dollars) per enrolled subject for an industry-sponsored trial, including 1,999 dollars devoted to nonclinical costs. CONCLUSION: Based on the results of our mock trial, the time required for nontreatment trial activities is considerable, and the associated costs are substantial.
In vitro and in vivo induction of antiangiogenic activity by plasminogen activators and captopril.
BACKGROUND: Many antiangiogenic molecules are proteolytically cleaved from larger plasma proteins. For example, plasminogen activators cleave plasminogen into plasmin, and plasmin is converted into angiostatin in the presence of sulfhydryl donors. We thus investigated whether the antiangiogenic activity in plasma could be increased by treatment with recombinant tissue plasminogen activator (rt-PA) and the sulfhydryl donor captopril. METHODS: Human plasma was treated with rt-PA (10 micro g/mL) and/or captopril (1 micro M). Angiogenesis was measured in vitro by human endothelial cell tube formation and endothelial cell proliferation and in vivo in mice with the Matrigel plug assay. Angiostatin was removed from treated plasma by affinity chromatography, immunoprecipitation, or ion-exchange chromatography, and the antiangiogenic activity of the depleted plasma was assessed by tube formation. Three cancer patients were treated with rt-PA and captopril, and their pretreatment and post-treatment plasmas were tested for antiangiogenic activity in vitro. RESULTS: Angiogenesis in vitro was stimulated by untreated plasma and inhibited by plasma that had been treated with rt-PA and captopril but was not affected by treatment with rt-PA and/or captopril alone. In vivo angiogenesis in Matrigel plugs was substantially lower in mice treated with rt-PA and captopril than in untreated control mice. Antiangiogenic activity in treated plasma was largely retained after angiostatin was removed: treated plasma inhibited angiogenesis by 64.3% (95% confidence interval [CI] = 46.4% to 82.2%), relative to untreated plasma, and treated plasma depleted of angiostatin by affinity chromatography or immunoprecipitation inhibited angiogenesis by 65.1% (95% CI = 53.8% to 76.4%) or 63.7% (95% CI = 50.9% to 76.5%), respectively. Antiangiogenic activity of plasma from three cancer patients was higher after treatment with rt-PA and captopril than before such treatment. CONCLUSION: Treatment with rt-PA and captopril induced antiangiogenic activity in vitro and in vivo that appears to be independent of angiostatin.
Cancer survivorship issues for minority and underserved populations.
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A model state act to authorize and regulate physician-assisted suicide.
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