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Biomedical subjects

R J Epstein

Publications and source records attributed to R J Epstein.

At least 19 recordsLinked to original sources
PubMed1997

Reduced ability of transforming growth factor-alpha to induce EGF receptor heterodimerization and downregulation suggests a mechanism of oncogenic synergy with ErbB2.

The epidermal growth factor receptor (EGFR) is activated by a variety of ligands including EGF and transforming growth factor-alpha (TGFalpha), whereas no ligand for the homologous ErbB2 oncoprotein has yet been identified. Here we use both an ErbB2 phosphoantibody (aPY1222) and an activation-specific EGFR antibody to show that low concentrations of EGF induce more efficient tyrosine phosphorylation of ErbB2 in A431 cells than does equimolar TGFalpha, while EGFR is more potently activated by TGFalpha. Co-precipitation studies confirm that heterodimerization of activated EGFR and transphosphorylated ErbB2 is readily induced by EGF but not TGFalpha. EGFR downregulation is also more efficiently induced by EGF, suggesting that ligand-dependent modification of ErbB2 may be required to terminate EGFR signalling in cells expressing both receptor types. These findings indicate that EGF and TGFalpha differ in their abilities to induce tyrosine phosphorylation and heterodimerization of ErbB2, and raise the possibility that ErbB2 exerts its oncogenic effect in part by impairing TGFalpha-dependent EGFR downregulation.

Antibodies↗
PubMed1996

Active minimisation of radiation scatter during breast radiotherapy: management implications for young patients with good-prognosis primary neoplasms.

BACKGROUND AND PURPOSE: Radiotherapy is used to reverse or prevent local tumour growth but is also a carcinogen in its own right. A recent audit of post-radiotherapy second malignancies in this institution revealed a striking preponderance of tumours originating near the outside edge of the treatment field. Since this finding suggests the existence of a critical subtherapeutic dose range predisposing to tumourigenesis, we attempted to define and reduce this radiation scatter dose. MATERIALS AND METHODS: We undertook a dosimetric review of 6 MV scatter from a linear accelerator in sites matching the putative tumourigenic region, and then extended this analysis to patients and tissue phantoms. RESULTS: A wide range of radiation scatter doses was confirmed-for example, doses 3 cm from the field edge varied from 1.7 to 22% of the therapeutic dose depending upon the field parameters. Scatter doses were then assessed in a sample of eight patients undergoing standard breast radiotherapy. Contralateral breast sites 4-12 cm from the midline received 4-10% of the therapeutic dose, or 200-500 cGy for a 50 Gy treatment, approximating historical estimates of the tumourigenic range. The deep component of this scatter dose from medial field breast irradiation was reduced 19% simply by replacing the 15 degrees medial tangential field wedge with a 30 degrees lateral wedge. Other manoeuvres which reduced contralateral breast dose by up to 46% included making the posterior field edges co-planar and shielding the breast during medial field irradiation. CONCLUSIONS: These results suggest that the risk of radiogenic second malignancies could be significantly decreased by careful attention to the treatment details. Greater awareness of these measures may prove particularly relevant to the conservative management of young patients with good-prognosis breast neoplasms such as ductal carcinoma in situ.

Breast↗
PubMed1996

Endocrine treatment of cancer.

Cancer has been treated by hormonal manipulation for over 100 years. Although therapeutic progress during this period has resulted mainly from clinical observation, more rational treatment approaches are now emerging from insights into the molecular basis of hormone-responsiveness. Among these are the recognition that hormonal signalling effects are transduced via specific receptor proteins, and the possibility that tumour lysis by hormonal therapies is effected by triggering of a programmed cell death pathway. Clinical progress has already been achieved through basic advances: receptor assays, for example, now permit prediction of treatment benefit in various settings. However, much remains to be learned about the mechanism and application of hormonal anticancer treatments.

Antineoplastic Agents, Hormonal↗
PubMed1995

Preferential detection of catalytically inactive c-erbB-2 by antibodies to unphosphorylated peptides mimicking receptor tyrosine autophosphorylation sites.

The c-erbB-2 tyrosine kinase is often overexpressed in human breast cancer, but correlations of receptor expression with tumour behaviour have proven elusive in patients without metastases at diagnosis. To address the possibility that receptor function may be more informative than expression, we previously developed function-specific c-erbB-2 antibodies using synthetic tyrosine-phosphorylated peptide immunogens (Epstein et al., Proc. Natl. Acad. Sci. USA 1992; 89: 10435-10439). Here the converse approach has been taken to determine the functional status of c-erbB-2 receptors detected by antibodies to dephosphorylated (dep) autophosphorylation sequences. In contrast to antiphosphopeptide (apt) antibodies, dep antibodies to the Tyr1248 autophosphorylation site exhibited preferential, but not exclusive, binding to tyrosine-dephosphorylated c-erbB-2. Consistent with this, catalytically active and inactive receptors could not be clearly distinguished by in vitro autophosphorylation experiments in which c-erbB-2 was immunoprecipitated using a monoclonal Tyr1248 dep antibody. A dep antiserum recognizing autophosphorylation sites N-terminal to Tyr1248 exclusively recognized tyrosine-dephosphorylated c-erbB-2 following antibody preabsorption with homologous phosphopeptides. Although indirect, these data are consistent with a model of sequential c-erbB-2 autophosphorylation in which Tyr1248 is the final residue modified. Moreover, since many studies of c-erbB-2 expression have used antibodies to dephosphorylated autophosphorylation sites, these results caution against automatically equating such receptor immunoreactivity with in vivo function or clinical significance.

Absorption↗
PubMed1995

Routine or delayed axillary dissection for primary breast cancer?

Prophylactic lymph node excision has long been recommended for preventing axillary recurrence of primary breast cancer, and has more recently gained support from the finding that adjuvant systemic therapy preferentially benefits patients with axillary node metastases. Despite these justifications, medical opinion in many communities has become deeply polarised over the merits of routine axillary dissection. A factor likely to be contributing to this split is the popularity of prescribing adjuvant systemic therapy (usually tamoxifen) on an expectant basis. Since there has been no controlled assessment of the net benefits of axillary dissection in patients receiving routine adjuvant systemic therapy--followed where necessary by delayed ("salvage") axillary treatment--objective data are urgently needed. If no substantial benefit is lost by replacing routine with delayed dissection, a small but significant improvement in quality of life could be expected for the majority of breast cancer patients.

Axilla↗
PubMed1995

Circumscribed posterior keratoconus.

BACKGROUND: Posterior keratoconus is characterized by an internal protrusion of the posterior corneal surface and associated localized or diffuse stromal thinning. Two cases of circumscribed (localized) posterior keratoconus are presented that are representative of the spectrum of the anomaly. CONCLUSIONS: The clinical and histological appearance of posterior keratoconus and its differential diagnosis from other corneal ectasias and developmental anomalies are reviewed to enable the eye care practitioner to better diagnose and manage this rare anterior segment disorder.

Anterior Eye Segment↗
PubMed1993

Six authors in search of a citation: villains or victims of the Vancouver convention?

OBJECTIVES: To analyse trends in the number of authors per article over the past 10 years. DESIGN: Analysis of articles from random volumes of eight biomedical journals. SUBJECTS: Cell, Nature, Proceedings of the National Academy of Sciences USA (PNAS), Journal of Clinical Investigation (JCI), Biochemical and Biophysical Research Communications (BBRC), Journal of Clinical Oncology (JCO), New England Journal of Medicine (NEJM), Lancet. MAIN OUTCOME MEASURES: Median and modal numbers of authors. RESULTS: All journals except Cell and Nature showed a trend towards increasing authorship numbers over the study period. The trend was most noticeable in journals such as JCO which feature clinical research. General medical journals (Lancet, NEJM) with a median of six to seven authors per article published far fewer seven author than six author studies, which suggests that author number may be influenced by the Vancouver convention which precludes citation of more than six authors. CONCLUSIONS: The phenomenon of expanding authorship in biomedical journal articles is not explained by the hypothesis that newer research technologies have necessitated more extensive collaboration. Rather, the data suggest that conferral of authorship may sometimes have a volitional component which contributes to rising author numbers. It is proposed that replacement of the Vancouver convention with a "first author, last author" citation system may help stem this rise in author numbers.

Authorship↗
PubMed1993

Histopathology of acute intraoperative suprachoroidal hemorrhage associated with transscleral intraocular lens fixation.

An 83-year-old hypertensive female had penetrating keratoplasty with insertion of a transsclerally fixated posterior chamber intraocular lens for pseudophakic corneal edema associated with a closed-loop, semiflexible anterior chamber intraocular lens. An acute intraoperative suprachoroidal hemorrhage developed five minutes after passage of the transscleral sutures. The eye became blind and painful and was enucleated three weeks later. Histopathologic examination showed an idiopathic suprachoroidal hemorrhage with no evidence of disruption of the ciliary body vasculature. Acute intraocular hemorrhage resulting from a needle pass through the highly vascularized ciliary body has been a greatly feared, though as yet unreported, complication of this procedure. Damage to the anterior uveal circulation was not implicated as a cause of the hemorrhage in this case.

Acute Disease↗
PubMed1992

Synthetic phosphopeptide immunogens yield activation-specific antibodies to the c-erbB-2 receptor.

We inoculated rabbits with synthetic phosphopeptides, duplicating a major autophosphorylation site of the c-erbB-2 protooncogene product. The rabbits produced antisera that, after reverse immunoaffinity purification, selectively recognize the erbB-2 protein in its enzymatically active configuration. These anti-phosphopeptide antisera identify a subset of erbB-2-positive human cell lines wherein the protein is constitutively active as a tyrosine kinase. Synthetic phosphopeptides incorporating informative protein phosphorylation sites may prove useful for generating antibodies that indicate the activation state of additional tyrosine kinases and perhaps other proteins phosphorylated on serine and threonine residues.

Animals↗
PubMed1992

Suppression of corneal neovascularization with cyclosporine.

We sought to determine if cyclosporine, which has been shown to suppress corneal allograft rejection, could also suppress corneal neovascularization induced by interleukin 2. Thirty A/J mice were treated with daily intramuscular injections of cyclosporine (25 mg/kg in olive oil) for 3 days before and 2 weeks following the intrastromal injection of 0.5 microL (5 IU) of recombinant mouse interleukin 2. Controls received intramuscular injections of olive oil. The mean area of corneal neovascularization 4, 8, and 12 weeks after injection was 9.2, 9.1, and 9.2 mm2, respectively, in controls, and 5.0, 5.2, and 5.2 mm2 in cyclosporine-treated mice (P less than .02; Student's t test). Cyclosporine causes a significant reduction in interleukin 2-induced corneal neovascularization that may, in part, account for its ability to prolong corneal allograft survival in high-risk cases.

Animals↗
PubMed1992

Does the breast cancer dollar make sense?

The past decade has witnessed a transformation of breast cancer management. Innovative developments such as widespread mammographic screening, breast-conserving approaches to primary disease and adjuvant systemic therapy have improved the quality of breast cancer care in the community. These and other therapeutic developments have been accompanied by substantial increases in consumption of health care resources. With the exception of adjuvant systemic therapy for node-positive disease, the evidence that such increases have been associated with commensurate improvements in disease outcome is weak. Indefinite continuation of this trend may prove incompatible with socioeconomic realities.

Adult↗