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Biomedical subjects

P M Anderson

Publications and source records attributed to P M Anderson.

At least 37 records · Page 2Linked to original sources
PubMed1999

Muscle as the primary site of urea cycle enzyme activity in an alkaline lake-adapted tilapia, Oreochromis alcalicus grahami.

The tilapia fish Oreochromis alcalicus grahami from Kenya has adapted to living in waters at pH 10.5 by excreting the end product of nitrogen metabolism as urea rather than as ammonia directly across the gills as occurs in most fish. The level of activity in liver of the first enzyme in the urea cycle pathway, carbamoyl-phosphate synthetase III (CPSase III), is too low to account for the observed high rates of urea excretion. We report here the surprising finding that CPSase III and all other urea cycle enzyme activities are present in muscle of this species at levels more than sufficient to account for the rate of urea excretion; in addition, the basic kinetic properties of the CPSase III appear to be different from those of other known type III CPSases. The sequence of the CPSase III cDNA is reported as well as the finding that glutamine synthetase activity is present in liver but not in muscle. This unusual form of adaptation may have occurred because of the apparent impossibility of packaging the needed amount of urea cycle enzymes in liver.

Adaptation, Physiological↗
PubMed1999

Educating medical students for work in culturally diverse societies.

CONTEXT: Recent attention has focused on whether government health service institutions, particularly in the United Kingdom, reflect cultural sensitivity and competence and whether medical students receive proper guidance in this area. OBJECTIVE: To systematically identify educational programs for medical students on cultural diversity, in particular, racial and ethnic diversity. DATA SOURCES: The following databases were searched: MEDLINE (1963-August 1998); Bath International Data Service (BIDS) Institute for Scientific Information science and social science citation indexes (1981-August 1998); BIDS International Bibliography for the Social Sciences (1981-August 1998); and the Educational Resources Information Centre (1981-August 1998). In addition, the following online data sets were searched: Kings Fund; Centre for Ethnic Relations, University of Warwick; Health Education Authority; European Research Centre on Migration and Ethnic Relations, University of Utrecht; International Centre for Intercultural Studies, University of London; the Refugee Studies Programme, University of Oxford. Medical education and academic medicine journals (1994-1998) were searched manually and experts in medical education were contacted. STUDY SELECTION: Studies included in the analysis were articles published in English before August 1998 that described specific programs for medical students on racial and ethnic diversity. Of 1456 studies identified by the literature search, 17 met the criteria. Two of the authors performed the study selection independently. DATA EXTRACTION: The following data were extracted: publication year, program setting, student year, whether a program was required or optional, the teaching staff and involvement of minority racial and ethnic communities, program length, content and teaching methods, student assessment, and nature of program evaluation. DATA SYNTHESIS: Of the 17 selected programs, 13 were conducted in North America. Eleven programs were exclusively for students in years 1 or 2. Fewer than half (n = 7) the programs were part of core teaching. Only 1 required program reported that the students were assessed on the session in cultural diversity. CONCLUSIONS: Our study suggests that there is limited information available on an increasingly important subject in medical education. Further research is needed to identify effective components of educational programs on cultural diversity and valid methods of student assessment and program evaluation.

Cultural Diversity↗
PubMed1999

Aerosol granulocyte macrophage-colony stimulating factor: a low toxicity, lung-specific biological therapy in patients with lung metastases.

The objective was to study the feasibility of granulocyte macrophage-colony stimulating factor (GM-CSF) delivery to the lung using an aerosol in humans. A Phase I dose escalation study provided GM-CSF at three dose levels as a twice-a-day (BID) x 7 days schedule. Pulmonary functions were monitored using a remote spirometry device. Blood counts were checked at the beginning and end of each week of GM-CSF nebulization. If no toxicity was encountered, patients rested for 7 days and then were treated at the next dose level. Six of seven patients were successfully dose escalated from 60 microg/dose BID x 7 days, to 120 microg/dose BID x 7 days, then 240 microg/dose BID x 7 days. No toxicity was seen. Comparison of day 0 and day 7 blood leukocyte counts showed no significant increases in either leukocyte numbers or percentage of neutrophils. Pulmonary functions test changes were minor. No significant change in forced vital capacity, FEV1, peak flow, or FEF 25-75 related to either time or dose level was observed. One patient's lung metastases progressed. The other five patients received an additional 2-6 months of intermittent aerosol GM-CSF at dose level 3 without side effects. One patient with Ewing's sarcoma has a complete response, and a patient with melanoma had a partial response; the other three had stabilization of pulmonary metastases for 2-6 months. Aerosol delivery of GM-CSF is feasible, safe, and possibly effective. Aerosol cytokine delivery may achieve effective immunological activation against cancer in the lung and is worthy of further study.

Administration, Inhalation↗
PubMed1998

Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy.

BACKGROUND: Mouth sores and/or difficulty swallowing are common and painful consequences of cytotoxic chemotherapy for cancer. In previous studies oral glutamine was found to protect animals from the effects of whole abdominal radiation and methotrexate-induced enteritis. Glutamine also was found to reduce oral mucositis in a nonrandomized pilot study in humans. Therefore, the authors attempted to determine the efficacy of oral glutamine in a randomized, double blind, crossover trial in cancer patients receiving chemotherapy. METHODS: Twenty-four patients (16 children and 8 adults) received glutamine or placebo (glycine) suspension (2 g amino acid/M2/dose twice daily) to swish and swallow on days of chemotherapy administration and for at least 14 additional days. Patients completed a calendar indicating days of mouth pain associated with each chemotherapy course and the effect of mouth pain on oral intake. RESULTS: Paired data indicated significant amelioration of stomatitis associated with glutamine administration after chemotherapy. The duration of mouth pain was 4.5 days less in chemotherapy courses in which glutamine supplementation was compared with placebo (Wilcoxon's signed rank test, P=0.0005). The severity of oral pain also was reduced significantly when glutamine was provided with chemotherapy (the amount of days mucositis restricted oral intake to soft foods [> or =Grade 2; Modified Eastern Cooperative Oncology Group grading system] was 4 days less with glutamine compared with placebo; Wilcoxon's signed rank test, P=0.002). CONCLUSIONS: Low dose oral glutamine supplementation during and after chemotherapy significantly reduced both the duration and severity of chemotherapy-associated stomatitis. Oral glutamine appears to be a simple and useful measure to increase the comfort of many patients at high risk of developing mouth sores as a consequence of intensive cancer chemotherapy.

Administration, Oral↗
PubMed1998

Nitrogen excretion and expression of carbamoyl-phosphate synthetase III activity and mRNA in extrahepatic tissues of largemouth bass (Micropterus salmoides).

Low levels of all of the enzymes required for urea synthesis via the urea cycle, including mitochondrial glutamine- and acetylglutamate-dependent carbamoyl-phosphate synthetase III (CPSase III) and cytosolic glutamine synthetase, are known to be present in liver of the teleost fish largemouth bass (Micropterus salmoides). The levels of these enzymes are higher than those in most other teleosts, but they are significantly lower than the levels present in liver of ureoosmotic elasmobranchs. The purpose of this study was to assess the physiological role of CPSase III in the context of urea synthesis in adult bass. The results showed that urea-N accounts for about 30% of the total nitrogen (ammonia-N plus urea-N) excreted under control conditions. The rate of urea-N excretion did not increase in response to exposure to 1 mM NH4Cl (3 days) or 0.25 mM NH4Cl (12 days) in the external water, except for a transient increase after a day or two of exposure. CPSase III activity in liver also did not increase in response to exposure to ammonia. Adult largemouth bass, while apparently ureogenic, are primarily ammonotelic and remain so even in the presence of relatively high concentrations of ammonia in the external environment. The total units of CPSase III activity in liver are not sufficient to account for the quantity of urea that is excreted. However, CPSase III and ornithine carbamoyltransferase (OCTase) activities were found to be present in intestinal tissue and, unexpectedly, in muscle tissue. The total units of CPSase III and OCTase in muscle, intestine, and liver appear to be sufficient to account for the observed rate of urea excretion. The sequence of CPSase III cDNA was determined, which permitted the use of ribonuclease protection assays to demonstrate the presence of CPSase III mRNA in these tissues.

Amino Acid Sequence↗
PubMed1998

N-acetyl-L-glutamate and the urea cycle in gulf toadfish (Opsanus beta) and other fish.

Carbamoyl phosphate synthetase I (CPSase I) catalyzes the first reaction of the urea cycle in mammalian ureotelic species. The positive allosteric cofactor N-acetyl-L-glutamate (AGA) is required for CPSase I activity and is important for regulation of the urea cycle. A similar enzyme, CPSase III, catalyzes this reaction in fish; CPSase III differs from CPSase I in that it utilizes glutamine as the nitrogen-donating substrate instead of ammonia. AGA also stimulates the CPSase III-catalyzed reaction, but is not absolutely required for activity if the glutamine concentration is high. There has been no report of the presence or function of AGA in fish. Here we report that AGA is present in those species and tissues of fish that have significant levels of CPSase III and urea cycle activity; the levels of AGA were higher in liver of adult gulf toadfish (Opsanus beta) and spiny dogfish shark (Squalus acanthias), both of which have high CPSase III activity, than in bass (Micropterus salmoides) or trout (Oncorhynchus mykiss), which have much lower or no CPSase III activity, respectively. In the toadfish the levels of AGA in liver and muscle tissue were considerably higher in the fed than in the fasting state, as is observed in mammalian species; in liver, but not in muscle, the level of AGA increased when the toadfish were confined (stressed), which has been shown to induce a ureotelic response. Toadfish muscle had CPSase III and ornithine carbamoyltransferase activities; the increase in AGA concentration in muscle when fed suggests that the presence of these first two enzymes of the urea cycle in muscle may be physiologically significant. The results indicate that the fish investigated have physiologically significant levels of AGA and that the levels correlate with parameters related to urea cycle activity.

Animals↗
PubMed1998

Effect of low-dose oral glutamine on painful stomatitis during bone marrow transplantation.

Painful oral mucositis is a common complication after bone marrow transplantation (BMT). Glutamine is a nutrient for rapidly dividing cells and the major energy source for intestinal epithelium. This study tested whether an oral glutamine preparation could decrease the severity of oral mucositis in patients undergoing BMT. Glutamine or a placebo (glycine) were administered from admission until day +28 in 193 BMT patients in a randomized, double-blind, placebo-controlled study at a dose of 1.0 g amino acid/m2/dose swish and swallow four times a day. In autologous BMT patients (n = 87) glutamine was associated with significantly less mouth pain by self report and by opiate use (5.0+/-6.2 days of morphine for glutamine vs 10.3+/-9.8 days for placebo; P= 0.005). Matched sibling BMT patients had no effect by self report and an increased duration of opiate use (23.2+/-5.7 days for glutamine vs 16.3+/-8.3 days for placebo) (P = 0.002). However, day 28 survival of allogeneic patients was improved by glutamine. No significant differences in TPN use, rate of relapse or progression of malignancy, parenteral antibiotic use, acute or chronic GVHD, or days of hospitalization were observed in either autologous or allogeneic recipients. No toxicity of glutamine was observed. We conclude that oral glutamine can decrease the severity and duration of oropharyngeal mucositis in autologous BMT patients but not in allogeneic BMT patients, possibly due to interaction with methotrexate.

Administration, Oral↗
PubMed1997

A phase I/IB trial of murine monoclonal anti-GD2 antibody 14.G2a plus interleukin-2 in children with refractory neuroblastoma: a report of the Children's Cancer Group.

BACKGROUND: The murine monoclonal antibody (MoAb) 14.G2a recognizes GD2, a disialoganglioside expressed in tumors of neuroectodermal origin, and facilitates antibody dependent cellular cytotoxicity (ADCC) in vitro. When given in vivo, interleukin-2 (IL-2) can increase ADCC by enhancing the activity and number of circulating lymphocytes. METHODS: Thirty-three pediatric patients with GD2 positive malignancies, ranging in age from 2 to 17 years (median, 9.9 years), received IL-2 and 14.G2a in this Phase I/IB study of the Children's Cancer Group (CCG) and were monitored for toxicities and response to therapy. Seven of these patients also received granulocyte-macrophage-colony stimulating factor. RESULTS: The maximum tolerated dose (MTD) of 14.G2a with IL-2 was 15 mg/m2/day. The most prevalent Grade 3-4 toxicities were generalized pain (n = 14 [42%]) and fever without documented infection (n = 17 [52%]). IL-2 was thought to be the causative agent in most cases of fever. Toxicities attributed to 14.G2a included pain, allergic or anaphylactic reactions, and rash. Human antimouse antibodies were demonstrated in 9 of 21 evaluated patients. One patient with neuroblastoma had a partial response, and one patient with osteosarcoma had a complete response. Immunocytology demonstrated that the number of neuroblastoma cells in bone marrow decreased in three patients. CONCLUSIONS: The murine MoAb 14.G2a was well tolerated at the MTD and appeared to have some antitumor activity. Further development of this approach will involve additional engineered forms of the antibody as well as testing in the adjuvant and minimal residual disease setting.

Adjuvants, Immunologic↗
PubMed1997

Chimeric CLL-1 antibody fusion proteins containing granulocyte-macrophage colony-stimulating factor or interleukin-2 with specificity for B-cell malignancies exhibit enhanced effector functions while retaining tumor targeting properties.

Although monoclonal antibody (MoAb) therapy of the human malignant lymphomas has shown success in clinical trials, its full potential for the treatment of hematologic malignancies has yet to be realized. To expand the clinical potential of a promising human-mouse chimeric antihuman B-cell MoAb (chCLL-1) constructed using the variable domains cloned from the murine Lym-2 (muLym-2) hybridoma, fusion proteins containing granulocyte-macrophage colony-stimulating factor (GM-CSF) (chCLL-1/GM-CSF) or interleukin (IL)-2 (chCLL-1/IL-2) were generated and evaluated for in vitro cytotoxicity and in vivo tumor targeting. The glutamine synthetase gene amplification system was employed for high level expression of the recombinant fusion proteins. Antigenic specificity was confirmed by a competition radioimmunoassay against ARH-77 human myeloma cells. The activity of chCLL-1/GM-CSF was established by a colony formation assay, and the bioactivity of chCLL-1/IL-2 was confirmed by supporting the growth of an IL-2-dependent T-cell line. Antibody-dependent cellular cytotoxicity against ARH-77 target cells demonstrated that both fusion proteins mediate enhanced tumor cell lysis by human mononuclear cells. Finally, biodistribution and imaging studies in nude mice bearing ARH-77 xenografts indicated that the fusion proteins specifically target the tumors. These in vitro and in vivo data suggest that chCLL-1/GM-CSF and chCLL-1/IL-2 have potential as immunotherapeutic reagents for the treatment of B-cell malignancies.

Animals↗
PubMed1997

Interleukin-2 liposome inhalation therapy is safe and effective for dogs with spontaneous pulmonary metastases.

BACKGROUND: Systemic in vivo toxicity of interleukin-2 (IL-2) has been problematic. Antineoplastic activity of IL-2 has been modest. The authors have previously demonstrated the biologic activity and safety of aerosols of IL-2 liposomes in normal dogs. They now report objective regression of naturally occurring pulmonary metastases in dogs after 1 month of nebulized IL-2 liposome therapy. METHODS: Dogs with pulmonary metastases (n = 7) and primary lung carcinoma (n = 2) were treated with aerosols of IL-2 liposomes. Response to therapy was monitored with serial chest radiographs. Effector populations, collected by bronchoalveolar lavage (BAL) and from heparinized whole blood, were assessed for cell type, immunophenotype, and tumor cytolytic activity. Immunogenicity of human IL-2 and human serum albumin (HSA) in dogs was assessed by immunofluorescence assay. RESULTS: Two of four dogs with metastatic pulmonary osteosarcoma had complete regression of metastases; the regression remained stable for more than 12 and more than 20 months, respectively. One of two dogs with lung carcinoma had stabilization of disease for more than 8 months; the other had disease progression. Toxicity was minimal. BAL cell numbers increased more than fourfold (P = 0.01) and included significantly greater proportions and total numbers of eosinophils (P = 0.006) and lymphocytes (P = 0.008). Mean BAL effector lytic activity was significantly greater after 15 days of IL-2 liposome inhalation compared with pretreatment activity (P = 0.01); however, mean BAL lytic activity decreased after 30 days and was no longer significantly greater than pretreatment BAL lytic activity. No allergic reactions were associated with inhaled IL-2 liposome therapy. Canine antibodies against human IL-2 and HSA were detected in all dogs. CONCLUSIONS: Pet dogs with naturally occurring pulmonary metastases and primary lung carcinomas accepted inhalation treatments easily. Nontoxic and effective treatment of pulmonary metastases of osteosarcoma is possible with nebulized IL-2 liposomes.

Aerosols↗
PubMed1997

Expression of carbamoyl-phosphate synthetase III mRNA during the early stages of development and in muscle of adult rainbow trout (Oncorhynchus mykiss).

It has been reported that the activities of the urea cycle-related enzymes ornithine carbamoyltransferase and carbamoyl-phosphate synthetase III (CPSase III) are induced during early life stages of ammonotelic rainbow trout (Oncorhynchus mykiss), suggesting that the urea cycle may play a physiological role in early development in teleost fish (Wright, P. A., Felskie, A., and Anderson, P. M. (1995) J. Exp. Biol. 198, 127-135). CPSase III cDNA prepared from embryo mRNA was sequenced, confirming the existence of the CPSase III gene in trout and its expression. The deduced amino acid sequence of the CPSase III is homologous to other CPSases. Supporting evidence for the expression of CPSase III activity in trout embryos was obtained by demonstrating expression of CPSase III mRNA as early as day 3 post-fertilization, reaching a maximum at 10-14 days, declining to a minimum at day 70, and then increasing to a relatively constant level from days 90 to 110 (relative to total RNA). Unexpectedly, in tissues of adult and fingerling trout, CPSase III mRNA was found to be present in muscle but not in other tissues, including liver. This finding was confirmed by assay of extracts, which showed CPSase III and ornithine carbamoyltransferase activity in muscle but not in other tissues. The pyrimidine nucleotide pathway-related CPSase II mRNA was expressed in all tissues.

Amino Acid Sequence↗
PubMed1997

Antitumor mechanisms of attenuated Salmonella typhimurium containing the gene for human interleukin-2: a novel antitumor agent?

Currently, there is no long-term effective treatment for unresectable hepatic malignancies. Salmonella species are known to naturally track to the liver during active infection. To develop a biological vector for delivery of interleukin-2 (IL-2) to the liver for antitumor purposes, the thi 4550 attenuated strain of Salmonella typhimurium was used as a vector for IL-2. The gene for human IL-2 was cloned into plasmid pYA292 and inserted into the attenuated S typhimurium and renamed (thi 4550(pIL-2)]. MCA-38 murine adenocarcinoma cells were injected intrasplenically into C57BL/6 mice to produce hepatic metastases that were subsequently enumerated after 12 days. We previously have demonstrated that the thi 4550(pIL-2) produces biologically active IL-2 and that a single gavage feeding of 10(7) thi 4550(pIL-2) significantly reduced the number of hepatic metastases when compared with animals fed salmonella lacking the IL-2 gene or nontreated controls. The aims of the current studies were to determine which host effector cell populations were responsible for the antitumor effect seen with thi 4550(pIL-2) by depletion of natural killer (NK), cytotoxic T lymphocytes (CD8+), T helper (CD4+) cells, and Kupffer cells. Multiple experiments were conducted for each host effector cell population depleted. We found a consistent reduction in the mean number of hepatic metastases in animals fed thi 4550(pIL-2) (55.6 metastases; n = 54) when compared with controls (162.3 metastases; n = 53) (P < .0001). Depletion of NK cells and CD8+ T cells significantly inhibited the antitumor effect of thi 4550(pIL-2) (analysis of variance [ANOVA], P < .01). Elimination of CD4+ T cells and Kupffer cells had no significant impact on the antitumor effect of thi 4550(pIL-2) (ANOVA, P value was not significant). Salmonella IL-2 may represent a novel form of in vivo biotherapy for unresectable hepatic malignancies that employs the oral route of administration. Furthermore, both NK cells or CD8+ cells are required for the antitumor effect seen while CD4+ T cells and Kupffer cells do not appear to be as essential.

Adenosarcoma↗
PubMed1997

Patterns of hepatic and splenic colonization by an attenuated strain of Salmonella typhimurium containing the gene for human interleukin-2: a novel anti-tumor agent.

Currently, there is no effective treatment for unresectable hepatic malignancies. Salmonella sp. are known to naturally track to the liver during active infection. A live biological vector was developed for delivery of Interleukin-2 (IL-2) to the liver for anti-tumor purposes. The avirulent and highly immunogenic c4550 strain of Salmonella typhimurium was used to express the IL-2 protein [renamed c4550(pIL-2)]. We have previously demonstrated that the c4550(pIL-2) produces biologically active IL-2 (up to 46.2 IU/ml) and that a single gavage feeding of 10(7) colony forming units (cfu) of c4550(pIL-2) significantly reduced the number of hepatic metastases when compared to animals fed salmonella lacking the IL-2 gene or non-treated controls. The goal of the current studies was to determine the pattern of splenic and hepatic colonization of Salmonella-IL2. Hepatic and splenic colonization was determined following administration of 10(7) cfu of c4550(pIL-2) and c4550(pYA292) via a single gavage feeding to C57BL/6 mice. Five experiments of antibiotic regimen administration were conducted where splenic and hepatic homogenates were cultured after 14 days of parenteral and/or oral antibiotics. The natural history of hepatic and splenic colonization was also determined for animals without antibiotic treatment. Despite administration of various antibiotic regimens using different routes, eradication of salmonella with and without IL-2 was not achieved. Salmonella, however, was not cultured from hepatic and splenic tissue at 4 months after a single gavage feeding of salmonella with no specific treatment. In conclusion, oral administration of c4550(pIL-2) may represent a novel form of in vivo biotherapy for unresectable hepatic malignancies. Antibiotics do not accelerate eradication of this bacteria and it appears that c4550(pIL-2) follows the natural pathophysiological of salmonella infection in which eradication from the splenic and hepatic tissue occurs over a period of 2-4 months.

Animals↗
PubMed1997

Nebulized interleukin 2 liposomes: aerosol characteristics and biodistribution.

Although interleukin 2 (IL-2) has been associated with modest anti-tumour responses in man, treatment-related toxicity has limited its widespread use. The local delivery of liposomal formulations of interleukin 2 to the lung as aerosols has been demonstrated to be non-toxic, biologically active, and associated with regression of spontaneous pulmonary metastases in dogs. This study was undertaken to evaluate the physical and biological characteristics of nebulized interleukin 2 liposomes. The aerosol droplet size distribution and the physical stability of interleukin 2 liposomes were examined in-vitro using an Andersen cascade impactor and studies of liposome entrapment of interleukin 2 before and after nebulization. The biological stability of interleukin 2 liposomes after nebulization was demonstrated using the CTLL-2 bioassay for interleukin 2. In-vivo studies of pulmonary biodistribution and clearance of inhaled technetium (99mTc)-labelled interleukin 2 liposomes were undertaken in a normal dog. Aerosols of free interleukin 2 and of interleukin 2 liposomes were compared in both in-vitro and in-vivo experiments. The mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of interleukin 2 liposomes were 1.98 microns and 2.02, respectively. Independent analysis of aerosol particle-size distribution using the constitutive components of the interleukin 2 liposomes (interleukin 2: lipid:HSA) demonstrated a close correlation of size distributions (r = 0.9445; P < 0.001). The entrapment of interleukin 2 in liposomes was 93 +/- 4.3% before nebulization and 90 +/- 8.9% after. After delivery to an anaesthetized dog, interleukin 2 liposome aerosols were deposited evenly throughout the lung (mean +/- s.d. central lung-to-peripheral lung deposition was 1.12 +/- 0.03). After approximately 24 h inhalation, interleukin 2 liposomes were retained within the lung and were taken up in part by the spleen. The results of this study are indicative of the stability of this interleukin 2 liposome formulation to nebulization. Such nebulization might be an attractive immunotherapeutic strategy for treatment of pulmonary metastases and primary lung cancers.

Aerosols↗
PubMed1997

Mechanical response of an artery using a standard nonlinear solid.

INTRODUCTION: The stress and deformation in an artery are determined from an axisymmetric analysis of thick-walled cylinder with a time-dependent internal pressure. The purpose is to understand how different constitutive, loading, and geometric conditions affect the stress and deformation state within the artery. MATERIALS AND METHODS: The equilibrium, compatibility, and constitutive equations are applied at N discretized points in the arterial wall, in an efficient scheme using Mathcad software on a desktop computer. The constitutive equations are a modification to a standard linear solid, so that one of the linear elements is nonlinear, and so that the 3-D response is anisotropic and dissipates energy only under deviatoric (shearing) stress states. Solution at each successive time increment requires inversion of a 6N by 6N matrix. RESULTS: The model reproduces experimental stress relaxation data with a correlation coefficient of 0.985 and can reproduce quasi-static stress strain data with equal accuracy. Features such as conditioning of the tissue are understood in terms of the time-dependent properties of the tissue. CONCLUSION: The program can produce transient and steady-state responses that closely mimic tissue response. The analysis allows for quick and stable determination of the stress and strain states for a variety of loading conditions.

Arteries↗
PubMed1996

A chimeric Lym-1/interleukin 2 fusion protein for increasing tumor vascular permeability and enhancing antibody uptake.

A murine antihuman B-cell monoclonal antibody, Lym-1, has shown considerable promise for the treatment of human malignant lymphomas. To enhance its clinical potential, a genetically engineered fusion protein consisting of a chimeric Lym-1 (chLym-1) and interleukin 2 (IL-2) was tested for mediating cytotoxicity, increasing vasopermeability, and enhancing antibody uptake in human malignant lymphomas. The chLym-1/IL-2 fusion protein, which was expressed initially in a baculovirus system and more recently in the glutamine synthetase gene amplification system, was shown to be processed and assembled into a normal immunoglobulin monomer with two IL-2 molecules per antibody. It was found to be equivalent to the chLym-1 antibody in antigen-binding specificity and relative affinity. In addition, it maintains IL-2 cytokine activity as demonstrated by support of T-cell proliferation. Moreover, in antibody-dependent cellular cytotoxicity assays against Raji target cells, chLym-1/IL-2 had approximately 2-fold and 4-fold higher cytotoxicity than chLym-1 and murine Lym-1, respectively. Used as a pretreatment, chLym-1/IL-2 enhances the uptake of chLym-1 at the tumor site by altering the permeability of tumor vessels producing tumor:normal organ ratios of 420:1 for blood and 1708:1 for muscle at 3 days. The in vitro and in vivo activities of chLym-1/IL-2, therefore, suggest that this genetically engineered antibody fusion protein may represent a new immunotherapeutic reagent for the treatment of human malignant lymphomas.

Animals↗