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Biomedical subjects

S Rosenberg

Publications and source records attributed to S Rosenberg.

At least 37 records · Page 2Linked to original sources
PubMed2000

Nonproteolytic role for the urokinase receptor in cellular migration in vivo.

The urokinase receptor (uPAR) binds and localizes urokinase activity at cellular surfaces, facilitating fibrinolysis and cellular migration at sites of tissue injury. uPAR also participates in cellular signaling and regulates integrin-dependent adhesion and migration in vitro. We now report evidence that uPAR occupancy regulates cellular migration in vivo in the absence of functional urokinase. Recombinant murine KC (1.5 microg), a potent neutrophil chemoattractant, was delivered to the lungs of wild-type, urokinase-deficient or uPAR-deficient mice 18 h after intraperitoneal injection of 200 microg human immunoglobulin G (IgG) or a fusion protein composed of an amino-terminal receptor-binding fragment of urokinase and a human IgG Fc fragment (GFD-Fc). Whole lung lavage for recovery of leukocytes was performed 4 h later. KC treatment resulted in a 100-fold increase in lavage neutrophils. GFD-Fc injection resulted in >50% reduction in neutrophil influx in both wild-type and urokinase-deficient animals but had no effect on uPAR -/- mice. A concomitant reduction in alveolar protein leakage but no change in numbers of circulating neutrophils accompanied this attenuated inflammatory response. The reduction in neutrophil influx induced by GFD-Fc is thus related to uPAR occupancy and yet not due to disruption of uPAR-mediated proteolysis. These observations verify that protease-independent functions of uPAR operate in vivo and identify uPAR as a potential target for regulation of inflammatory processes characterized by neutrophil-mediated injury.

Administration, Intranasal↗
PubMed1999

Potent inhibitors of protein farnesyltransferase: heteroarenes as cysteine replacements.

Synthesis and biological evaluation of heteroarenes as reduced cysteine replacements are described. Of the heteroaryl groups examined with respect to FT inhibitor FTI-276 (1), pyridyl was the replacement found to be most effective. Substitutions at C4 of the pyridyl moiety did not affect the in vitro activity. Compound 9a was found to have moderate in vivo bioavailability.

3T3 Cells↗
PubMed1999

Enhanced expression of a transmembrane phosphotyrosine phosphatase (LAR) in keratoconus cultures and corneas.

The purpose of the study was to identify genes that are differentially expressed in normal versus keratoconus corneas. Total RNA isolated from corneal stromal cell cultures was reverse-transcribed and then amplified by the polymerase chain reaction (PCR) using defined, arbitrary primers. The products were displayed on polyacrylamide gels and bands that were differentially expressed were excised, re-amplified and subcloned. The resulting clones were sequenced and utilized as probes for Northern blots with cultured cell RNA or Southern blots of corneal cDNA. One of the products that appeared to be more highly expressed in keratoconus cultures and corneas displayed 100% homology with leukocyte common antigen related protein (LAR), a transmembrane phosphotyrosine phosphatase. Western analyses and immunohistochemistry with monoclonal and/or polyclonal antibodies to LAR were used to examine keratocyte cultures and fresh frozen normal, keratoconus and pseudophakic bullous corneas. We identified a gene product with 100% homology to LAR that is expressed at the RNA level in keratoconus corneas and cell cultures but is found only at low or undetectable levels in normal cultures and normal and pseudophakic bullous keratopathy (PBK) corneas. By Western blotting and immunofluorescence with specific LAR antibodies, the protein was identified in keratoconus stromal cell cultures but not in normal cultures. When fresh frozen tissue was examined, LAR protein was localized to numerous stromal cells throughout central keratoconus corneas, while no central staining was seen in normal or bullous keratopathy corneas. LAR, a transmembrane phosphotyrosine phosphatase, is more highly expressed in keratoconus corneas and stromal cell cultures as demonstrated by differential display, Northern analyses, immunohistochemistry and Western blotting.

Adolescent↗
PubMed1999

Treatment of multicentric Castleman's disease complicated by the development of non-Hodgkin's lymphoma with high-dose chemotherapy and autologous peripheral stem-cell support.

BACKGROUND: Castleman's disease or angiofollicular lymph node hyperplasia is a rare entity with a localized/unicentric or a generalized/multicentric presentation. While surgery is curable for most localized presentations, there is limited information regarding the optimal management of the multicentric type. The latter type is associated with a poor prognoses and can be associated with the development of lymphoma and infections. PATIENTS AND METHODS: In this report we describe a case of multicentric Castleman's disease who failed steroids and chemotherapy and developed a follicular mixed lymphoma. He was treated with high-dose chemotherapy with autologous stem-cell support and remains disease at four years of follow-up. CONCLUSIONS: A long-term durable remission may be possible with high dose chemotherapy with stem-cell support. This treatment modality should be considered an option in the management of multicentric Castleman's disease.

Adult↗
PubMed1999

Semirational design of a potent, artificial agonist of fibroblast growth factor receptors.

Fibroblast growth factors (FGFs) are being investigated in human clinical trials as treatments for angina, claudication, and stroke. We designed a molecule structurally unrelated to all FGFs, which potently mimicked basic FGF activity, by combining domains that (1) bind FGF receptors (2) bind heparin, and (3) mediate dimerization. A 26-residue peptide identified by phage display specifically bound FGF receptor (FGFR) 1c extracellular domain but had no homology with FGFs. When fused with the c-jun leucine zipper domain, which binds heparin and forms homodimers, the polypeptide specifically reproduced the mitogenic and morphogenic activities of basic FGF with similar potency (EC50 = 240 pM). The polypeptide required interaction with heparin for activity, demonstrating the importance of heparin for FGFR activation even with designed ligands structurally unrelated to FGF. Our results demonstrate the feasibility of engineering potent artificial agonists for the receptor tyrosine kinases, and have important implications for the design of nonpeptidic ligands for FGF receptors. Furthermore, artificial FGFR agonists may be useful alternatives to FGF in the treatment of ischemic vascular disease.

3T3 Cells↗
PubMed1999

Urokinase receptor antagonists: discovery and application to in vivo models of tumor growth.

Urokinase receptor antagonists based on the growth factor domains of both human and murine urokinase which show sub-nanomolar affinities for their homologous receptors have been expressed as recombinant proteins. Further modification of these molecules by preparing fusions with the constant region of human IgG has led to molecules with high affinities and long in vivo half-lives. Smaller peptidic inhibitors have been obtained by a combination of bacteriophage display and peptide analog synthesis. All of these molecules inhibit the binding of the growth factor domain of uPA to the uPA receptor and enhance binding of the uPA receptor to vitronectin. Protein uPA receptor antagonists were tested in an in vivo tumor model using the human breast carcinoma MDAmb231 in immunodeficient mice. Both human and murine receptor antagonists showed significant inhibition of primary tumor growth, demonstrating that in vivo, both tumor and stromal cell uPA receptor dependent plasminogen activation can modulate tumor growth.

Amino Acid Sequence↗
PubMed1999

Immune selection after antigen-specific immunotherapy of melanoma.

BACKGROUND: Melanoma antigen (MA)-specific vaccination strongly enhances antitumor reactivity in vivo and is capable of producing strong cytotoxic T lymphocyte responses in vitro. Furthermore, specific human leukocyte antigen-restricted T cell activation is hypothesized to occur in response to peptide-based immunotherapy, which may lead to the preferential killing of tumor cells bearing the relevant MA. The development of melanoma antigen-loss variants may subsequently occur in vivo. METHODS: Analysis of 532 melanoma lesions from 204 patients was performed on fine-needle aspiration biopsy specimens. Lesions were graded for the expression of the MAs gp100 and MART-1 with use of immunocytochemistry. A total of 351 melanoma lesions were divided into cohorts on the basis of the treatment received. The pretreatment group (n = 175) consisted of lesions obtained before any form of gp100 immunotherapy, with the posttreatment group (n = 176) consisting of lesions obtained after vaccination with a modified gp100 epitope, gp209-2M +/- interleukin 2 (IL-2). RESULTS: The percentage of lesions not expressing the gp100 antigen is greater than the percentage not expressing MART-1 (26% vs 14%). The frequency of lesions with high expression (> 75%) of gp100 significantly decreased with therapy (47% vs 34%) and conversely negative lesions increased (18% vs 29%). Treatment of lesions with peptide alone (no IL-2) revealed a significant decrease in gp100 expression (47% vs 32%), enhanced with the addition of IL-2 to therapy (47% vs 35%). The expression of MART-1 remained essentially unchanged unless IL-2 was added (54% vs 54%, MART-1 peptide alone, 54% vs 43%, MART-1 peptide + IL-2). Of 94 patients (181 lesions) assessed for gp100 expression before treatment, 10 patients responded to therapy. Pretreatment lesions in responding patients expressed some level of gp100 in all cases compared with 27% of nonresponding lesions, which were negative for gp100 expression. CONCLUSIONS. This study indirectly demonstrates that vaccination with an MA-derived peptide can result in immune selection in vivo. Furthermore, it provides strong immunologic evidence for the specificity of MA vaccines and to the relevance of MA expression in predicting the response to vaccination.

Antigens, Neoplasm↗
PubMed1999

Outcomes after laser stapedotomy with and without preservation of the stapedius tendon.

Our goal was to investigate the postoperative differences in hearing between patients who had their stapedius tendon sacrificed and those whose stapedius tendon was preserved during laser stapes surgery for otosclerosis. To that end, we performed a retrospective review by mailing extensive questionnaires to patients who had been operated on between 1994 and 1997. We also performed routine and special audiometric testing to augment the subjective data. Seventy-nine of 124 questionnaires (64%) were returned. Of the respondents, 75 patients had undergone additional pre- and/or postoperative audiometric testing, including tests to evaluate "hearing in noise" and to determine the "uncomfortable loudness level" (dynamic range). We found no statistically significant differences between the two groups with respect to their subjective responses and their audiologic test results. The responses to the questionnaire indicated that in most cases, hearing was improved by stapes surgery. We conclude that the stapedius tendon should be preserved whenever possible during stapes surgery, provided that it does not jeopardize the exposure or outcome.

Adult↗
PubMed1998

Potent and selective non-cysteine-containing inhibitors of protein farnesyltransferase.

Potent and selective non-thiol-containing inhibitors of protein farnesyltransferase are described. FTI-276 (1) was transformed into pyridyl ether analogue 19. The potency of pyridyl ether 19 was improved by modification of the biphenyl core to that of an o-tolyl substituted biphenyl core to give 29. In addition to 0.4 nM in vitro potency, 29 displayed 350 nM potency in whole cells as the parent carboxylic acid. The o-tolyl biphenyl core dramatically and unexpectedly enhanced the potency of other compounds as exemplified by 46, 47, 48, and 49.

3T3 Cells↗
PubMed1998

Receptor-independent role of urokinase-type plasminogen activator in pericellular plasmin and matrix metalloproteinase proteolysis during vascular wound healing in mice.

It has been proposed that the urokinase receptor (u-PAR) is essential for the various biological roles of urokinase-type plasminogen activator (u-PA) in vivo, and that smooth muscle cells require u-PA for migration during arterial neointima formation. The present study was undertaken to evaluate the role of u-PAR during this process in mice with targeted disruption of the u-PAR gene (u-PAR-/-). Surprisingly, u-PAR deficiency did not affect arterial neointima formation, neointimal cell accumulation, or migration of smooth muscle cells. Indeed, topographic analysis of arterial wound healing after electric injury revealed that u-PAR-/- smooth muscle cells, originating from the uninjured borders, migrated over a similar distance and at a similar rate into the necrotic center of the wound as wild-type (u-PAR+/+) smooth muscle cells. In addition, u-PAR deficiency did not impair migration of wounded cultured smooth muscle cells in vitro. There were no genotypic differences in reendothelialization of the vascular wound. The minimal role of u-PAR in smooth muscle cell migration was not because of absent expression, since wild-type smooth muscle cells expressed u-PAR mRNA and functional receptor in vitro and in vivo. Pericellular plasmin proteolysis, evaluated by degradation of 125I-labeled fibrin and activation of zymogen matrix metalloproteinases, was similar for u-PAR-/- and u-PAR+/+ cells. Immunoelectron microscopy of injured arteries in vivo revealed that u-PA was bound on the cell surface of u-PAR+/+ cells, whereas it was present in the pericellular space around u-PAR-/- cells. Taken together, these results suggest that binding of u-PA to u-PAR is not required to provide sufficient pericellular u-PA-mediated plasmin proteolysis to allow cellular migration into a vascular wound.

Animals↗
PubMed1998

Modification of a receptor-binding surface of epidermal growth factor (EGF): analogs with enhanced receptor affinity at low pH or at neutrality.

Six mutants of human epidermal growth factor (EGF), which carry single point substitutions within a surface patch proposed to juxtapose the bound receptor, were prepared and characterized for receptor affinity and mitogenicity. Receptor affinities relative to EGF are G12Q > H16D > Y13W > Q43A approximately = H16A approximately = EGF >> L15A. Notably, the reduced receptor affinity of mutant L15A indicates that Leu15 probably contributes substantially to receptor binding whereas unaltered receptor affinities observed for analogs H16A and Q43A indicate that neither His16 nor Gln43 contributes significantly to this interaction. On the other hand, the observed enhanced receptor affinities of analogs G12Q, Y13W and H16D highlight surface loci where additional productive receptor-binding contacts can be introduced. Interestingly, at acidic pH analog H16A reveals substantially greater receptor affinity than that of EGF, a property which may offer enhanced therapeutic utility in acidic environments in vivo.

Amino Acid Sequence↗
PubMed1998

Tracing the textures of an ethical relation to the dead: trauma, witnessing, and the "Montreal massacre".

This essay offers a consideration of English-language feminist memorial discourse as this has been sedimenting in Canada since the 1989 murder of 14 women at Ecole Polytechnique. The author suggests that remembrance now, almost a decade after the murders, exceeds the terms offered by a politic in which the living and the dead are connected through feminist alignment ["it could have been me"]. In its place, the author argues that there is a binding relation to the dead that is forged through understanding the murders as an event of historical trauma and rupture. She then contemplates and explores the implications of this rethinking of an ethics of relation through a situated analysis of annual memorial vigils.

Adult↗
PubMed1998

Dexamethasone inner ear perfusion for the treatment of Meniere's disease: a prospective, randomized, double-blind, crossover trial.

OBJECTIVE: To investigate the benefits of intratympanic administration of dexamethasone in the treatment of unilateral Meniere's disease, with particular attention to the symptoms of hearing loss and tinnitus. STUDY DESIGN: A prospective, randomized, double-blind, crossover study comparing improvements in hearing loss, tinnitus, aural fullness, and caloric vestibular response secondary to intratympanic dexamethasone and sodium hyaluronate injection versus placebo consisting of saline and sodium hyaluronate. SETTING: A private otology/neurotology practice. PATIENTS: Twenty patients diagnosed with either definite or probable Meniere's disease as defined by the American Academy of Otolaryngology Head and Neck Surgery Committee on Hearing and Equilibrium. All patients were < or =21 years old and were not receiving any other form of treatment for their Meniere's disease. Each patient's primary symptoms of concern were hearing loss, aural fullness, and roaring tinnitus. INTERVENTIONS: Three consecutive daily administrations of intratympanic dexamethasone or placebo to the involved ear. MAIN OUTCOME MEASURES: Changes in audiometric pure-tone averages, speech reception thresholds, caloric vestibular responses, scores on the tinnitus handicap inventories, questionnaires, and telephone interview responses. RESULTS: No significant changes were observed in any measured parameter. Patients were unable to consistently identify which medication was dexamethasone and which was placebo. CONCLUSIONS: Intratympanic administration of dexamethasone in a group of patients with unilateral Meniere's disease (Shea's stage IV) showed no benefit over placebo for the treatment of hearing loss and tinnitus.

Adult↗
PubMed1998

First records of Hyalomma aegyptium (Acari: Ixodida: Ixodidae) from the Russian spur-thighed tortoise, Testudo graeca nikolskii, with an analysis of tick population dynamics.

During the fall of 1995 and the spring of 1996, 77 statistically comparable tick collections, comprising 792 specimens, were made from adults of the Russian spur-thighed tortoise, Testudo graeca nikolskii, at 4 sites along Russia's Black Sea coast. These are the first tick collections reported from T. g. nikolskii since its recognition as a taxonomic entity. All ticks were determined to be Hyalomma (Hyalomma) aegyptium, a common tortoise parasite in southern Russia that in 1930 was erroneously designated the type of subgenus Hyalommasta. Male ticks were recovered from more tortoises (67) than were females (57) or immatures (14), and nymphs were seen only in the fall. Significantly more ticks parasitized male tortoises than females, perhaps because males of T. g. nikolskii have larger home ranges. However, no functional relationship was found between tortoise ventral surface area and degree of tick infestation. Like other tortoise ticks, H. aegyptium is expected to decline in concert with its increasingly threatened hosts.

Animals↗
PubMed1997

Laser-assisted otoendoscopy.

In order to determine if laser tympanostomy is a useful adjunct to middle ear endoscopy, a retrospective case review of 95 patients over 18 years of age and requiring middle ear endoscopy was conducted in a tertiary referral center. The review revealed that clear, rapid visualization of the middle ear structures was accomplished with minimal complications. The tympanic membrane usually healed after the procedure. We conclude that laser tympanostomy safely provides a middle ear opening which streamlines the procedure by providing a bloodless field, and by greatly reducing the need for frequent cleaning of the endoscopic lens.

Adolescent↗