Faculty Bibliography
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156
Irsogladine maleate inhibits angiogenesis in wild-type and plasminogen activator-deficient mice
BACKGROUND: The activation of the zymogen plasminogen to the serine protease plasmin by urokinase-type (uPA) and tissue-type (tPA) plasminogen activators (PA) is an important event in a variety of physiologic and pathophysiologic processes in mammals. Enhanced PA activity occurs during angiogenesis and has been correlated in vitro and in vivo with increased tumor aggressiveness and is an indicator of poor prognosis in a variety of tumors in humans. Preliminary studies suggest that the antiulcer drug irsogladine maleate (IM) diminishes PA activity in vitro and may inhibit angiogenesis in vivo. To define the precise mechanism of angiogenesis inhibition by IM in vivo, we tested the ability of IM to blunt angiogenesis in a mouse cornea neovascularization model performed in wild-type and PA-knockout mice. METHODS: Three days prior to pellet implantation, groups of C57Bl/6 wild-type, uPA-deficient (upA-/-), and tPA-deficient (tPA-/-) mice received IM (300 mg/kg), IM (500 mg/kg), or vehicle (0.5% carboxymethylcellulose) via oral gavage. After 3 days of treatment, hydron polymer-coated pellets of sucrose aluminum sulfate containing 100 ng of basic fibroblast growth factor (bFGF) were inserted into surgically created pockets in the cornea of each mouse. On postoperative day 6, the neovascularization of each cornea was evaluated by a blinded observer using slit lamp microscopy and photographed. Angiogenesis was quantified by calculating vascular area (mm2) +/- SEM using a modified formula for a half ellipse that incorporates calibrated vessel measurements [Vessel length (mm) x Clock hours x pi x 0.2]. RESULTS: IM treatment (300 and 500 mg/kg/day) resulted in a dose-dependent reduction of angiogenesis in wild-type mice by 21 and 45.3% (P < 0.02, P < 0.001), in tPA-deficient mice by 42.6 and 46% (P < 0.001, P < 0.001), and in uPA-deficient mice by 27.2 and 46% (P < 0.05, p < 0.001), respectively. No quantitative differences in neovascularization were observed in either treatment group between transgenic mouse strains. No toxicity was noted in any group. CONCLUSION: IM inhibits bFGF-induced angiogenesis in wild-type, tPA-knockout, and uPA-knockout mice. The observation that IM significantly diminishes angiogenesis in both PA-deficient mice and wild-type mice suggests that the mechanism of action of IM may be independent of plasminogen activation.
PMID: 9733598
ISSN: 0022-4804
CID: 12076
Randomized, double-blind, clinical trial of a polyvalent melanoma vaccine in patients with stage III melanoma [Meeting Abstract]
ISI:000072738200183
ISSN: 0022-202x
CID: 53522
Poly(ADP-ribose) polymerase in human breast cancer: a case-control analysis
The importance of a genetic polymorphism (A/B allele) of poly(ADP-ribose) polymerase (PARP) pseudogene on chromosome 13q34-qter, and PARP enzyme activities in the development of human breast cancer were evaluated in a cancer case-control study. A total of 309 Caucasian women (> or = 50 years old) were evaluated for the PARP genotype, 70 of whom had histologically confirmed breast cancer, 128 women with benign breast diseases as study controls, and 111 reference controls. Age was significantly associated with case-control status (p < 0.0001), but family history of breast cancer, age at menarche, age at first live birth and parity were not. The frequency of the PARP B allele was similar in breast cancer cases (0.14), study controls (0.13), and reference controls (0.15). In a subset of 14 breast cancer cases and 32 study controls, the mean PARP enzyme activities (induced by H2O2 or oligonucleotide) were observed to be lower in cancer cases; an age-adjusted odds ratio of 3.40 (95% confidence interval = 0.70-19.54) for the below-median oligonucleotide-induced PARP was suggestive of an association. In subjects with the AB or BB genotype, the mean H2O2-induced PARP enzyme activity was significantly higher (p = 0.02, adjusted for case-control status and age) compared with that in subjects with the AA genotype. These findings indicate that: (a) the genetic polymorphism of the PARP pseudogene on chromosome 13 is not associated with the development of breast cancer in our study population; (b) oligonucleotide-induced PARP activity may be useful for identifying postmenopausal women at increased risk for breast cancer; and (c) there is a possible functional link between the genotype of the PARP pseudogene and enzyme activation
PMID: 9295059
ISSN: 0960-314x
CID: 25128
Stimulation of CD8+ T cell responses to MAGE-3 and MART-1 by immunization to a shed antigen melanoma vaccine [Meeting Abstract]
ISI:A1997WP04000134
ISSN: 0022-202x
CID: 53215
Urokinase-type plasminogen activator-deficient mice are predisposed to staphylococcal botryomycosis, pleuritis, and effacement of lymphoid follicles
Urokinase-type plasminogen activator (uPA) is thought to be an important mediator in the proteolytic degradation of extracellular matrix components observed in a wide variety of normal physiological and pathological conditions. However, the phenotype of a recently developed strain of urokinase-deficient (uPA-/-) mice appears to be normal when maintained under ideal nonstressful conditions. We report an outbreak of botryomycosis, an unusual staphylococcal infection, in a colony of uPA-deficient mice. A detailed histological examination of these uPA-deficient animals also revealed a variety of previously unreported phenotypic abnormalities such as pleuritis and the effacement of lymphoid follicles in the regional lymph nodes and spleen. Additional phenotypic abnormalities such as dystrophic calcifications and rectal prolapse were also observed in the uPA-deficient population. These abnormalities were also noted in ostensibly healthy uPA-deficient animals. Botryomycosis did not affect a colony of wild-type (uPA+/+) animals maintained concurrently under identical conditions in the same room. The peculiar predisposition of the uPA-deficient animals to this rare bacterial infection and the development of phenotypic abnormalities associated with the targeted disruption the uPA gene suggests that uPA contributes significantly to the cutaneous microenvironment and is additional evidence of the extensive involvement of the plasminogen activators in mammalian physiology
PMCID:1858536
PMID: 9006351
ISSN: 0002-9440
CID: 12426
A polyvalent melanoma vaccine induces MAGE-3 and MART-1/Melan-A specific CD8+ T cell responses that correlate with clinical outcome [Meeting Abstract]
A critical requirement to use tumor antigens as vaccines is that they stimulate CD8+ T cell responses. In this study, we tested the ability of a shed, polyvalent, melanoma antigen vaccine to induce such responses to the melanoma-associated antigens, MAGE-3 and MART-1/Melan-A. Fifteen HLA-A2+ patients with resected malignant melanoma were immunized to the vaccine sc every 2-3 weeks x 4, and monthly thereafter. CD8+ T cells in peripheral blood reacting to HLA-A2 restricted epitopes on MAGE-3 (FLWGPRALV) and/or MART-1/Melan-A (AAGIGILTV) were quantitated directly using a filter spot assay at baseline and following 4 immunizations. Vaccine immunization induced CD8+ T cells reacting specifically to one or both of these antigens in 9 (60%) patients. These cells were CD8+ and HLA-A2 restricted, as reactivity was abrogated by monoclonal antibodies to CD8 and to class I HLA, but not by anti-CD4. The CD8+ T cells were specifically directed to these antigens, as they did not react to the same targets pulsed with a control HLA-A2 restricted peptide recognized by T cells. All responding patients remained recurrence-free during a follow-up of 12-21 months, whereas melanoma recurred within 3-5 months in non-responders. The differences in outcome were unrelated to differences in disease-severity or overall immunological competence between CD8+ T cell responders and non-responders. These results demonstrate that a polyvalent vaccine can stimulate a CD8+ T cell response to MAGE-3 and MART-1/Melan-A in humans, and suggest that the responses are protective and surrogate markers of vaccine efficacy. (C) American Society of Clinical Oncology 1997
ORIGINAL:0014208
ISSN: 0736-7589
CID: 6031
Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction
Background Antiplatelet therapy with aspirin and systematic anticoagulation with warfarin reduce cardiovascular morbidity and mortality after myocardial infarction when given alone. In the Coumadin Aspirin Reinfarction Study (CARS), we aimed to find out whether a combination of low-dose warfarin and low-dose aspirin would give superior results to standard aspirin monotherapy without excessive bleeding risk. Methods We used a randomised double-blind study design. At 293 sites, we randomly assigned 8803 patients who had had myocardial infarction, treatment with 160 mg aspirin, 3 mg warfarin with 80 mg aspirin, or 1 mg warfarin with 80 mg aspirin. Patients took a single tablet daily, and attended for prothrombin time (PT) measurements at weeks 1, 2, 3, 4, 6, and 12, and then every 3 months. Patients were followed up for a maximum of 33 months (median 14 months). Findings The primary event was first occurrence of reinfarction, non-fatal ischaemic stroke, or cardiovascular death. 1-year life-table estimates for the primary event were 8.6% (95% Cl 7.6-9.6) for 160 mg aspirin, 8.4% (7.4-9.4) for 3 mg warfarin with 80 mg aspirin, and 8.8% (7.6-10) for 1 mg warfarin with 80 mg aspirin. Primary comparisons were done with all follow-up data. The relative risk of the primary event for the 160 mg aspirin group compared with the 3 mg warfarin with 80 mg aspirin group was 0.95 (0.81-1.12, p=0.57). For spontaneous major haemorrhage (not procedure related), 1-year life-table estimates were 0.74% (0.43-1.1) in the 160 mg aspirin group and 1.4% (0.94-1.8) in the 3 mg warfarin with 80 mg aspirin group (p=0.014 log rank on follow-up). For the 3382 patients assigned 3 mg warfarin with 80 mg aspirin, the INR results were: at week 1 (n=2985) median 1.51 (IQR 1.23-2.13); at week 4 (n=2701) 1.27 (1.13-1.64); at month 6 (n=2145) 1.19 (1.08-1.44). Interpretation Low, fixed-dose warfarin (1 mg or 3 mg) combined with low-dose aspirin (80 mg) in patients who have had myocardial infarction does not provide clinical benefit beyond that achievable with 160 mg aspirin monotherapy. $$:
ISI:A1997XQ24800008
ISSN: 0140-6736
CID: 130406
Morphological and biological characteristics of mammogram-detected invasive breast cancer
Thirty-nine mammographically detected, (M-detected) small invasive carcinomas of the breast (< or = 5 mm) were compared with 78 consecutive clinical cancers (> or = 10 mm) for a variety of morphological and biological markers of prognostic importance. There were more tubular carcinomas in the M-detected group (12.8% v 3.8%), but this did not reach statistical significance. Incidences of other histological types were similar. The types of associated in situ component were similar in the two groups. M-detected cancers were of lower overall grade (P < .001), lower architectural and nuclear grades (P = .0164 and P < .0001 respectively), and had fewer mitotic cells (P < .0001). None showed positive lymph nodes (P < .0001). Estrogen and progesterone receptor expression was similar in both groups. M-detected cancers expressed p53 nuclear protein less frequently than clinical cancers (P = .0398), had lower levels of microvessel density (P = .0001), and were more often diploid (P = .0131). S-phase of diploid tumors in the two groups was similar, but S-phase of aneuploid tumors was lower in the M-detected group (P = .0057). Ki67 expression was lower in M-detected cancers (P < .0001). In conclusion, M-detected small breast cancers, although invasive, represent an evolutionary phase of breast cancer that generally lacks morphological and biologic markers of aggressive behavior. The presence or absence of these markers, collectively, may explain the influence of tumor size on survival in patients with breast cancer
PMID: 8816890
ISSN: 0046-8177
CID: 7020
Induction of primary cutaneous melanocytic neoplasms in urokinase-type plasminogen activator (uPA)-deficient and wild-type mice: cellular blue nevi invade but do not progress to malignant melanoma in uPA-deficient animals
Evidence suggests that the plasminogen activators (PAs), in particular urokinase-type PA (uPA), play a pivotal role in tumor invasion and metastasis. We studied the contribution of the PAs to the malignant phenotype through the chemical induction of melanocytic neoplasms in uPA-deficient mice. Primary tumors were induced and promoted concurrently in 35 uPA-/- deficient and 35 uPA+/+ wild-type mice using a single application of 7,12-dimethylbenz(a)anthracene followed by repetitive applications of croton oil. Animals were sacrificed at 60-day intervals for 1 year. At necropsy, the four largest pigmented lesions in each animal were excised, characterized histologically, and evaluated microscopically for evidence of invasion. The regional lymph nodes, lungs, and solid abdominal visceral organs were sectioned and examined microscopically for evidence of metastatic disease. Cellular blue nevi were induced in 100% of uPA-/- and uPA+/+ promoted animals. Although a reduction in the radial and vertical progression of these lesions was noted in the uPA-deficient mice compared with the wild-type group, more than 95% of cellular blue nevi induced in both groups of animals invaded the underlying tissues. These lesions did not metastasize to the regional lymph nodes. Malignant melanoma arose in 5 of 35 (14.3%) of promoted wild-type mice. These tumors were locally aggressive, produced tissue-type PA, but were not metastatic to the regional nodes, lungs, or abdominal viscera. These results indicate that the invasive capability of melanocytic lesions may depend more on tissue-type PA than uPA activity. No melanomas were induced in the uPA-/- mice. The resistance of the uPA -/- strain to melanoma induction suggests that uPA contributes to malignant progression. We propose that the absence of uPA negatively affects tumorigenesis by decreasing the liberation and availability of growth factors such as basic fibroblast growth factor
PMID: 8758932
ISSN: 0008-5472
CID: 12575
The management of pigmented lesions of the nail bed
Pigmented lesions of the nail bed, especially without a history of trauma, represent a diagnostic challenge to the clinician. These lesions are often categorized as melanonychia striata (MS), which refers to any linear tan-brown-black pigmentation of the nail bed. The differential diagnosis of MS includes subungual hematomas, onchomycosis nigricans, junctional nevi, melanoma in situ (MIS), and malignant melanoma (MM). Our algorithm at the New York University (NYU) Medical Center for the treatment of pigmented lesions of the nail bed is presented. A histopathologic diagnosis with any evidence of melanocytic atypia, however subtle, requires absolute confirmation by complete excision. The absence of a clear margin or recurrence requires total nail bed excision and reconstruction using a full-thickness graft. The diagnosis of MIS is similarly treated. The surgical management of subungual MM is discussed. All cases of MM of the hand treated at NYU were reviewed. In all, 30 patients were treated from 1982 to 1995. Follow-up ranged from 6 months to 13 years. In our series, there were 8 cutaneous and 22 subungual melanomas. There was a marked delay in treatment of both groups, with subungual melanomas more often erroneously treated as other pathology prior to correct diagnosis. The 5-year survival rate was 100% for patients with cutaneous lesions, but only 80% for those with the subungual variety. There was a statistical difference in the depths of the lesions (subungual, 3.68 mm; cutaneous, 1.36 mm) with a p-value of 0.008. The role of elective lymph node dissection in the absence of clinical metastases as well as intraoperative sentinel lymphatic mapping remains controversial and is discussed
PMID: 8863970
ISSN: 0148-7043
CID: 12566
