Biomedical subjects

S E Raper

Publications and source records attributed to S E Raper.

77 records · Page 5Linked to original sources

PubMed1984

Transport of epidermal growth factor by rat liver: evidence for a nonlysosomal pathway.

Epidermal growth factor (EGF), circulating in the blood, is taken up by rat liver hepatocytes by means of specific and saturable receptor-mediated endocytosis. These experiments were undertaken to determine (a) the transport pathway(s) of EGF taken up by rat liver and (b) the effects of lysosomal inhibition on its transport. 125I-EGF was injected into rat portal veins, and bile samples were collected and analyzed for both total and immunoprecipitable radioactivity. In addition, the livers were examined by electron microscopic autoradiography. Some animals received injections of chloroquine before surgery, to disrupt lysosomal function. The results indicate that most of the EGF taken up by the hepatocytes is transported to lysosomes and degraded. However, a small but significant percentage of endocytosed EGF is transported by a pathway independent of the lysosomal system, resulting in secretion of intact EGF: (a) Both degraded and immunoprecipitable EGF are secreted into bile. (b) Immunoprecipitable radioactivity peaks at 20 min after EGF injection, whereas degradation-associated radioactivity does not peak until 40 min postinjection. (c) EGF isolated from bile is specifically taken up by isolated hepatocytes in monolayer culture, indicating that it is still recognizable by the EGF receptor. (d) When the lysosomal system is inhibited with chloroquine, secretion of degraded EGF is significantly inhibited, whereas the amount of intact EGF secreted into bile is unchanged. The utilization by liver of a dual transport process for EGF represents an unusual system of intracellular ligand processing, whose physiological significance has yet to be determined.

Animals↗

PubMed1982

Technical accuracy and clinical efficacy of thoracic computed tomography.

The technical accuracy and clinical efficacy of thoracic CAT scans in 302 surgical patients were retrospectively reviewed. We conclude that thoracic CAT scans should be ordered selectively since the technical accuracy of existing radiographic studies in detecting disease is equally high (greater than 90 percent) and the clinical efficacy does not differ substantially (less than 16 percent). The accuracy of CAT scans in staging carcinoma (the extent of the lesion or nodes) is only 58 percent. The technical limitations of these scans include (1) a lack of specificity because of the high incidence of false-positive lymph nodes, (2) a low or unreliable yield from needle aspiration, and (3) unreliable findings due to altered anatomy by previous treatment or associated disease. Surgical treatment regarding operability and resectability should not be solely based on CAT scans. These scans appear to be a useful screening test for chronic vascular disease and localization of obscure thoracic infections.

False Positive Reactions↗

PubMedDate not supplied

Cellular immunity delimits adenoviral gene therapy strategies for the treatment of neoplastic diseases.

BACKGROUND: Adenoviral gene therapy is a promising new approach for the treatment of neoplastic diseases. To design rational clinical trials and distinguish the effects of therapeutic transgene expression from those caused by viral infection alone, the immune response to the vector must be understood. In these experiments, we further define cellular immunity to recombinant adenovirus. METHODS: The immune response to hepatic adenoviral gene transfer was studied in infected mice by depleting T cells with an anti-CD3 antibody, measuring splenocyte cytokine production, determining the impact of transgene expression on inflammation, and assessing liver MHC protein expression. RESULTS: The cellular immune response to recombinant adenovirus is (1) averted by T lymphocyte depletion, (2) marked by a TH1 response with increased IL-2 production, (3) directed against both the transgene product and viral proteins, and (4) associated with increased hepatocyte MHC Class I expression. CONCLUSIONS: It is necessary to take into consideration the constraints imposed by the immunogenicity of recombinant adenovirus and its transient transgene expression in the clinical application of adenoviral gene transfer for the treatment of cancer.

Adenoviruses, Human↗

PubMedDate not supplied

Cell transplantation in liver-directed gene therapy.

Somatic cell gene therapy is a new field of biomedical research that encompasses a variety of traditional basic research and clinical disciplines. This new approach to therapeutics has the potential to prevent, treat, or cure a variety of inherited and acquired diseases. Two divergent strategies of hepatocyte transplantation are being employed in animal models and clinical trials in an attempt to correct genetic deficiencies. Allogeneic hepatocyte transplantation has two main advantages over autologous cell transplantation. First, invasive surgical procedures are not required in the recipient. Second, allogeneic cells can be administered repetitively, so that multiple harvests are not necessary. The major drawbacks to allogeneic hepatocyte transplants are rejection and the risks of immunosuppression. Although there is no clinical experience with the treatment of genetic disease by allogeneic hepatocyte transplantation, a variety of animal models have been characterized, including the Gunn rat (UDP-glucuronosyl transferase deficient), the Nagase analbuminemic rat, and the Watanabe heritable hyperlipidemic rabbit (LDL receptor deficient). The use of genetically corrected autologous cells represents a different and more elegant approach to the correction of inherited disease. A segment of liver is harvested from the affected individual. Recombinant retroviruses are used to transduce normal genes--with a variety of promoter/enhancer constructs--into the patients own hepatocytes. The genetically corrected hepatocytes are then transplanted back into the patient. This approach, known as ex vivo gene therapy, eliminates the risk of rejection and the need for immunosuppression. The safety and efficacy of this approach has been proven in a variety of preclinical animals models, including Watanabe rabbits, dogs, and Papio spp. A clinical trial for the treatment of familial hypercholesterolemia is currently in progress. A number of approaches for the reintroduction of hepatocytes into the recipient have been proposed, including catheter-mediated delivery into the inferior mesenteric vein, the umbilical vein, or into the spleen. Candidate diseases, which are likely to result in the first clinical trials include familial hypercholesterolemia, ornithine transcarbamylase deficiency, Crigler-Najjar syndrome, alpha 1-antitrypsin deficiency, and phenylketonuria.

Animals↗

PubMedDate not supplied

Efficacy of two comparative antibiotic regimens in the treatment of serious intra-abdominal infections: results of a multicenter study.

A multicenter, open-label randomized trial was conducted to evaluate the efficacy and tolerability of monotherapy with imipenem-cilastatin (I-C) compared with combination therapy with clindamycin and an aminoglycoside (C+A) for treatment of 117 patients with serious intra-abdominal infections. Fifty-three patients (45%) received I-C and 64 patients (55%) received C+A. The overall clinical success rate was 96.2% for the I-C patients and 92.2% for the C+A patients. Clinical failure rates were 3.8% and 7.8%, respectively (P = NS). Eradication or suppression of pathogens was observed in 81.8% and 82.2% of patients, respectively. Uniform bacteriologic response was observed among all infection subgroups. Fourteen of 145 patients experienced adverse symptoms, including six of 66 (9.1%) monotherapy patients and eight of 79 (10.1%) combination-therapy patients (P = NS). The results of this study demonstrate that I-C monotherapy was as effective as C+A combination therapy for the treatment of serious intra-abdominal infections, regardless of the site or severity of infection or the clinical status of the patient. Both regimens also were found to be comparable in tolerability.

Abdomen↗