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Biomedical subjects

C R Taylor

Publications and source records attributed to C R Taylor.

At least 163 records · Page 9Linked to original sources
PubMed1989

Are pancarcinoma T and Tn differentiation antigens?

Human fetal tissues were studied for presence of immunoreactive Thomsen-Friedenreich (T) and Tn epitopes (EPs) using well-defined anti-T and anti-Tn rodent monoclonal antibodies. T and Tn are universal (pan) carcinoma (CA) markers that are occluded in normal postfetal tissues except in some immunoprivileged enclaves. Immunohistochemical methods using avidin-biotin immunoperoxidase for staining were employed. Tissues between 45 and 117 days after ovulation were studied. In most instances, anti-T and anti-Tn antibodies showed similar immunoreactivity as demonstrated by positive immunohistochemical staining. The most intense staining was in epithelial and mesothelial components; the mesenchyme stained more faintly. All human sera have anti-T and anti-Tn antibodies, stimulated largely by intestinal flora. The presence of immunoreactive T and Tn during an early phase of fetal development, as shown here, and their known absence in noncarcinomatous postfetal tissues suggests that T and Tn, in addition to their association with CA, are stage-specific oncofetal antigens in pretolerogenic differentiation phases.

Antigens, Differentiation↗
PubMed1989

Tumor necrosis treatment of ME-180 human cervical carcinoma model with 131I-labeled TNT-1 monoclonal antibody.

In contrast to normal tissues, many malignant tumors contain a high proportion of dead and dying cells. The loss of membrane integrity that accompanies cellular degeneration permits macromolecules, including antibodies, to freely enter the cell cytoplasm. Based upon these observations, it was hypothesized that monoclonal antibodies to intracellular antigens, which are integral structural components and are retained by degenerating cells, may be used to target a wide range of human malignancies. Previous studies by our laboratory utilizing these principles have demonstrated the feasibility of imaging four different histological types of human cancer in a nude mouse model, using monoclonal antibodies directed against insoluble intranuclear antigens. The present study describes the application of this approach, designated tumor necrosis treatment, for the radioimmunotherapy of transplantable ME-180 human cervical carcinomas in the nude mouse. Groups of tumor-bearing nude mice received three weekly treatments of 150 or 300 microCi of 131I-labeled experimental (TNT-1) or control (Lym-1) monoclonal antibodies. Detailed biodistribution data, dosimetric evaluations, and therapeutic results are presented to demonstrate the effective and preferential targeting of 131I-labeled TNT-1 monoclonal antibody within the tumor. In the experimental groups, the dose delivered to the tumor was sufficient to induce clinical regressions in 88% of treated animals, without evidence of toxicity to normal tissues. Complete regressions were obtained in 25% of the mice treated with high dose TNT-1. Microscopic examination of the implantation sites of these mice demonstrated the presence of acute radiation damage and residual keratin-positive tumor cells showing marked evidence of degeneration. Dosimetric data obtained over the 3-week treatment period showed that, unlike control treated mice, which received approximately 500 cGy each week, the experimental animals received increasing doses of radiolabeled antibody with each treatment (averages for weeks 1, 2, and 3: 1066, 2046, and 2476 cGy, respectively). In accordance with these data, enhanced imaging and therapeutic responses were observed with each therapeutic dose in the TNT-1-treated groups, compared with controls. These results indicate that TNT-1 therapy produces an ever expanding population of TNT-1-positive targets in the tumor as a result of the centrifugal killing of adjacent viable tumor cells. To help illustrate these results, a four-compartment model of the dose distribution kinetics of TNT-1 is presented for discussion with respect to the possible application of this method for the imaging and treatment of cancer in

Animals↗
PubMed1989

Reactivity of a human monoclonal antibody against carcinomas and other lesions of the colon.

To identify tumor-associated antigens that may be immunogenic to man, human monoclonal antibodies (human mAb) were generated by fusing nonsecreting mouse myeloma cells with lymphocytes from regional mesenteric nodes of patients with adenocarcinomas of the colon. One IgG1 human mAb, designated as 14-31-10, was identified by its reactivity against human tumor xenografts. We have studied the reactivity of mAb 14-31-10 with formalin-fixed, paraffin-embedded specimens of human colon. A total of 86 cases were studied, including normal adult and fetal colons, adenocarcinomas of the colon, and a variety of colonic inflammatory diseases and preneoplastic lesions. Intense reactivity was found in 15 of 18 adenocarcinomas of the colon, but not in 10 specimens of normal adult or 4 specimens of fetal colonic mucosa. Interestingly, in four cases of carcinoma, reactivity was also observed in histologically normal mucosa situated 10 cm or more from the primary lesion. On the other hand, no staining was detected in any of the 16 inflammatory lesions. Of the 38 preneoplastic lesions, only 6 showed staining by the mAb: 1 of 5 benign tubular adenomatous polyps, 3 of 9 villous adenomas and tubovillous polyps, 1 of 5 specimens of ulcerative colitis and 1 of 19 specimens of familial polyposis. However, the intensity of staining was only moderate in those cases. Our data, therefore, suggest that the epitope identified by the human mAb 14-31-10 shows preferential expression in preneoplastic and neoplastic lesions of the colon, and in ostensibly normal mucosa at some distance from a primary colonic carcinoma. In all instances, the staining was cytoplasmic, suggesting a cytoplasmic or internal membrane location of the target antigen. This antigen appeared to be distinct from carcinoembryonic antigen, since staining by 14-31-10 was consistently different from that of a mouse monoclonal antibody to carcinoembryonic antigen in serial sections of the same specimens. The restricted reactivity of 14-31-10 suggests its potential application in immunohistochemistry. Moreover, the epitope identified by mAb 14-31-10 may be expressed during the progression of normal mucosa to neoplasia.

Animals↗
PubMed1989

Total muscle mitochondrial volume in relation to aerobic capacity of horses and steers.

The relationship between maximal oxygen consumption rate (VO2max) and mitochondrial content of skeletal muscles was examined in horses and steers (n = 3 each). Samples of the heart left ventricle, diaphragm, m. vastus medialis, m. semitendinosus, m. cutaneous thoracicus and m. masseter, as well as samples of muscles collected in a whole-body sampling procedure, were analyzed by electron microscopy. VO2max per kilogram body mass was 2.7 x greater in horses than steers. This higher VO2max was in proportion to the higher total volume of mitochondria in horse versus steer muscle when analyzed from the whole-body samples and from the locomotor muscle samples. In non-locomotor muscles, total mitochondrial volume was greater in horses than steers, but not in proportion to their differences in VO2max. The VO2max of the mitochondria was estimated to be close to 4.5 ml O2.ml-1 mitochondria in both species. It is concluded that in a comparison of a highly aerobic to a less aerobic mammalian species of similar body size, a higher oxidative potential may be found in all muscles of the more aerobic species. This greater oxidative potential is achieved by a greater total volume of skeletal muscle mitochondria.

Animals↗
PubMed1989

High rate of O2 consumption in exercising foxes: large PO2 difference drives diffusion across the lung.

The fox has one of the highest mass specific rates of maximal oxygen consumption (VO2max/Mb) that has been measured, yet its specific pulmonary diffusing capacity (DLO2/Mb, measured morphometrically) is similar to that of most mammalian species. It achieves a high O2 flux per unit DLO2 with a large partial pressure difference driving O2 diffusion from alveolar gas to capillary blood (PAO2-PbO2). This paper explores the mechanisms that the fox utilizes to achieve this large pressure difference and the extent to which it exploits its structural diffusing capacity. Foxes were exercised on a treadmill at maximal rates of O2 uptake. The following parameters were measured or calculated: arterial and mixed venous PO2, PCO2, pH and O2 concentration of the blood, cardiac output, hemoglobin concentration and O2 equilibrium curve of the blood, and morphometric estimates of pulmonary capillary volume and pulmonary diffusing capacity for O2. These data were used to calculate pulmonary capillary transit time and the time course of the change in O2 concentration and PO2 of the blood as it transits the lung. The fox has a morphometric pulmonary diffusing capacity of 0.098 ml O2.sec-1.mm Hg-1.kg-1. At VO2 max (3.6 ml O2.sec-1.kg-1) the fox hyperventilates, resulting in a high PAO2 (124 mm Hg); it also maintains a low PbO2 (88 mm Hg) by having a short transit time (0.13 sec) due to a high specific cardiac output (25 ml.sec-1.kg-1). Our calculations indicate that at VO2max the fox uses almost all of the pulmonary capillary transit time for O2 equilibration, in contrast to other species.

Animals↗
PubMed1989

Biochemical and immunological characterizations of antigens recognised by human monoclonal antibodies.

The lymphocytes from lymph nodes of six patients with metastatic mammary carcinomas were hybridised by fusion with a non-secreting variant of murine myeloma cells. Hybrid cells producing human immunoglobulin were detected by screening of culture supernatants using a solid-phase enzyme-linked immunosorbent assay for human IgG or IgM. Reactivity of human immunoglobulins to breast tumour cells was assessed by an indirect immunoperoxidase staining of fresh-frozen breast carcinoma sections. In the initial screening, the tissues used were those removed from the patients who acted as source of lymphocytes for fusion. The hybrid-cells, after repeated cloning, were stable for secretion of immunoglobulins. A total of 14 immunoglobulin G and 51 immunoglobulin M human monoclonal antibodies, showing variable reactivity to mammary carcinoma cells in tissue sections by an indirect immunoperoxidase staining method, were obtained. Two immunoglobulin G monoclonal antibodies (designated HMA-29 and HMA-31) were selected on the basis of their strong reactivity to the tumour cells and utilised to identify their corresponding antigens. The antibodies quantitatively discriminated, as expressed by the degree of staining, malignant from normal or benign mammary epithelia in freshly frozen or formalin-fixed breast tissues. The antibodies also showed reactivity to malignant cells of colon, stomach and lung and to normal cells lining the renal tubules and surface epithelium of colon. As revealed by blocking experiments, the epitopes recognised by these antibodies were not expressed on carcinoembryonic antigens, erythrocytes, lymphocytes, glycoproteins from milk-fat-globule membrane or keratins. The antibody HMA-29 immunoprecipitated a phosphoprotein (Mr = 29,000), and antibody HMA-31 two protein components (Mr = 31,000 and 34,000), from lysates of intrinsically labelled human mammary carcinoma cell line (MCF7). Neither of these proteins were present in detectable amounts in an intrinsically labelled melanoma cell line. Immunoblocking and immunoprecipitation experiments suggested that epitopes recognised by these two antibodies are dissimilar and are expressed on different molecules. The antibodies appear to be useful for functional characterisation of those antigens which are present in elevated levels in malignant compared with normal mammary epithelia.

Antibodies, Monoclonal↗
PubMed1989

Oxygen transport during exercise in large mammals. I. Adaptive variation in oxygen demand.

This study investigated mechanisms used by horses and steers to increase O2 uptake and delivery (VO2) from resting to maximal rates and identified the mechanisms that enable horses to achieve higher maximal rates of O2 consumption (VO2max) than steers. VO2 and circulatory variables were measured while Standardbred trotting horses and steers (450-kg body mass) stood quietly and ran on a treadmill at speeds up to those eliciting VO2max. As VO2 increased in both species, heart rate and circulating hemoglobin (Hb) concentration increased, thereby increasing O2 delivery by the circulation, while cardiac stroke volume remained unchanged. At VO2max arterial PCO2 increased from its resting value in horses but was unchanged in steers, and arterial PO2 decreased in both species. Although the horses hypoventilated and were hypoxemic at VO2max, no significant decrease in arterial Hb saturation occurred. VO2max of the horses was 2.6 times higher than that of the steers and was associated with a 100% larger cardiac output, 100% larger stroke volume, and 40% higher Hb concentration, whereas heart rates at VO2max were identical in the two species. The higher cardiac output of the horses at VO2max resulted from a 1.2-fold higher mean arterial pressure and 1.6-fold lower peripheral tissue resistance (associated with a larger skeletal muscle capillary bed). Both the magnitude of the difference in VO2max between horses and steers and the mechanisms used to achieve it are the same as observed in smaller pairs of mammalian species with large variation in aerobic capacity.

Adaptation, Physiological↗
PubMed1989

Oxygen transport during exercise in large mammals. II. Oxygen uptake by the pulmonary gas exchanger.

Because the maximal rate of O2 consumption (VO2max) of the horse is 2.6 times larger than that of steers of equal size, we wondered whether their pulmonary gas exchanger is proportionately larger. Three Standardbred racehorses [body mass (Mb) = 447 kg] and three domestic steers (Mb = 474 kg) whose cardiovascular function at VO2max had been thoroughly studied (Jones et al. J. Appl. Physiol. 67: 862-870, 1989) were used to study their lungs by morphometry. The basic morphometric parameters were similar in both species. The nearly 2 times larger lung volumes of the horses caused the gas exchange surfaces and capillary blood volume to be 1.6 to 1.8 times larger. Morphometric pulmonary diffusing capacity was 2 times larger in the horse than in the steer; the 2.6-fold greater rate of O2 uptake thus required the alveolar-capillary PO2 difference to be 1.3 times larger in the horse than in the steer. Combining physiological and morphometric data, we calculated capillary transit time at VO2max to be 0.4-0.5 s. Bohr integration showed capillary blood to be equilibrated with alveolar air after 75 and 58% of transit time in horses and steers, respectively; horses maintain a smaller degree of redundancy in their pulmonary gas exchanger.

Animals↗
PubMed1989

Blood gas measurements during exercise: errors due to temperature correction.

This study assessed the degree to which correcting blood gas measurements to rectal temperature (Tre) rather than to the temperatures at which gas exchange occurs [pulmonary arterial (Tpa) or intramuscular (Tm)] introduces errors into blood gas analysis of exercising mammals. Horses and steers weighing 450 kg were run on a treadmill at speeds up to those eliciting maximal rates of O2 consumption (VO2max), and temperatures were measured in various body compartments. In both species Tpa rose faster than Tre during the run, the degree of dissociation being a function of exercise intensity and duration. Tm was measured only in horses, and it rose faster than Tpa during the run and decreased more slowly postrun. Correcting blood gas values measured at an analyzer temperature of 37 degrees C to Tre without accounting for transient increases during the run of Tpa and Tm that were never reflected in Tre significantly biased estimates of blood gases. The biased estimates erroneously indicated that both species experienced more severe hypoxemia than they actually did at VO2max and masked the hypercapnia experienced by the horses at VO2max.

Animals↗
PubMed1989

LN-6: a monoclonal antibody to vimentin expressed in non-hematopoietic mesenchymal cells and derived tumors and reactive in B5-fixed, paraffin-embedded tissues.

We generated a monoclonal antibody (MAb), designated LN-6, directed against human vimentin, which retains its immunoreactivity in B5-fixed, paraffin-embedded tissues. Like other anti-vimentin MAb, LN-6 was found to be reactive with a wide spectrum of human sarcomas and normal cells of mesenchymal derivation. However, unlike other similar reagents, LN-6 was unreactive with normal and malignant human lymphoid cells and therefore displays a more restricted immunoreactivity. Because of its ability to stain routinely processed pathological tissues and its marked reactivity with human sarcomas, LN-6 is a unique reagent for the immunohistochemical diagnosis of human cancer.

Animals↗
PubMed1988

Nuclear reactivity for estrogen. A possible diagnostic tool in differentiating colon cancer metastases in the ovary from primary mucinous ovarian tumors.

Tissue distribution of carcinoembryonic antigen (CEA) and estrogen was analyzed in eight primary ovarian mucinous carcinomas, three primary mucinous colonic cancers, and four ovarian metastatic lesions from colonic and pancreatic adenocarcinomas. Primary ovarian mucinous carcinomas and metastatic colonic carcinomas had similar localization of CEA within the epithelial cytoplasm. Estrogen localization, in contrast, was shown within the epithelial nuclei of seven of eight primary ovarian mucinous tumors; whereas the nuclei of metastatic and primary mucinous colonic carcinomas did not have intranuclear estrogen. The cytoplasm and the stroma of both primary ovarian and metastatic colonic carcinomas stained for estrogen.

Biomarkers, Tumor↗
PubMed1988

A novel method for the detection of necrotic lesions in human cancers.

Data are presented in support of the hypothesis that malignant tumors, containing abnormally permeable, degenerating cells, can be selectively detected using monoclonal antibodies to intracellular antigens. Biodistribution, imaging, and autoradiographic studies were performed in nude mice transplanted with four different human tumor cell lines to demonstrate the binding of radiolabeled antinuclear monoclonal antibodies within bulky tumors containing necrotic lesions. For these studies, two monoclonal antibodies, designated TNT-1 (IgG2a) and TNT-2 (IgM) were chosen since they were found to bind to abundant nuclear antigens which are retained in permeable, dying cells. F(ab')2 fragments prepared by pepsin digestion were radiolabeled with iodine-125 or iodine-131 by the iodogen method for i.v. administration. Biodistribution studies in nontumor-bearing BALB/c mice at various time intervals revealed normal patterns of antibody excretion with no accumulation of antibody in healthy organs. In contrast, biodistribution studies performed on Day 3 in tumor-bearing nude mice showed high tumor to organ ratios in those animals bearing necrotic tumors. Necrotic regions dissected at necropsy gave tumor to blood ratios as high as 131:1. Transplants having little demonstrable necrosis were found to have low tumor to blood ratios (0.4:1). Sequential imaging studies confirmed the high tumor-to-organ ratios and showed positive tumor imaging as early as 4 h. Autoradiographic studies of excised tumors showed the presence of label selectively in necrotic areas with preferential labeling over the nuclei of degenerating cells. Because of the universal presence of these nuclear antigens and the known prevalence of necrosis in tumors, this approach may be of value for the imaging and treatment of a wide variety of cancers in humans.

Animals↗
PubMed1988

IL-4 regulates differentiation and proliferation of human precursor B cells.

The mechanism by which precursor and pre-B cells undergo differentiation is unclear; however, it is known that growth factors play an important role in this maturation process. The lymphokine, IL-4 has been shown to increase expression of class II Ag on B cells and induce B cell proliferation. In the murine system, IL-4 induced differentiation of precursor B cells into pre-B cells. In order to analyze growth factors on B cell development we have established an in vitro culture system for human bone marrow cells. We found that in the presence of IL-4, normal human precursor and pre-B cells can be induced to differentiate in the absence of cell proliferation with four days of culture. Furthermore, IL-4 depressed proliferation induced by supernatant from a T cell line. The differentiation was measured by an increase in both the number of cytoplasmic mu and surface IgM-positive cells. The effect of IL-4 on precursor and pre-B cell differentiation was detected as soon as 14 h of exposure to the lymphokine in the absence of an adherent feeder layer. These data suggest that IL-4 directly affects the differentiation process of normal human precursor and pre-B cells, and may antagonistically affect cell proliferation.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1988

Distinguishing tumour cells of mammary from extramammary Paget's disease using antibodies to two different glycoproteins from human milk-fat-globule membrane.

The purpose of this study was to investigate the histogenesis of Paget's cells of mammary and extramammary Paget's disease. Accordingly, rabbit antibodies to two glycoproteins, purified from human milk-fat-globule membrane and designated MFGM-gp 70 and MFGM-gp 155, were used to study the presence and patterns of distribution of these glycoproteins in formalin-fixed and paraffin-embedded tissue sections by an indirect immunoperoxidase staining method. Both antibodies recognized epitopes which are located on the protein domain of the molecules. MFGM-gp 70 as shown to be localized on the apical plasma membrane of luminal epithelial cells of all ducts and lobules of the mammary gland; it was also present in normal apocrine but not eccrine sweat glands coils and ducts in skin. MFGM-gp 155 was present on the apical plasma membrane of the cells of lobules and terminal ducts, but not larger ducts of mammary gland, normal apocrine and eccrine sweat glands coils and ducts, or sebaceous glands in skin. Neither of the antibodies reacted with keratinocytes or melanocytes. Under similar conditions, the antibodies to MFGM-gp 70 reacted with Paget's cells of 8 of 8 cases of mammary disease and 6 of 8 cases of extramammary disease. By contrast, MFGM-gp 155 was localized in Paget's cells of 7 of 8 cases of mammary disease but none of the 8 cases of extramammary disease. The underlying tumour cells of infiltrating ductal breast carcinoma, where one was present, consistently showed reactivity with antibodies to MFGM-gp 70 and MFGM-gp 155. These findings lend additional support to the postulates that (a) Paget's cells in the breast originate in most cases from neoplastic mammary epithelial cells and (b) mammary and extramammary Paget cells, although morphologically similar, differ in expressing MFGM-gp 155.

Antibodies↗
PubMed1988

Diagnostic imaging of hepatocellular carcinoma: progress in noninvasive tissue characterization.

Hepatocellular carcinoma (HCC), a common malignancy in the United States with poor prognosis, must be differentiated from hemangioma, focal fat, metastases, and regenerating nodules. Serum alpha-fetoprotein (AFP) levels are not a sensitive method for detection of HCC. High resolution ultrasound has been highly effective in detecting HCC in Japan and Taiwan. Doppler ultrasound can be used to increase the specificity. We review the roles of angiography, computed tomography (CT), and magnetic resonance, to conclude that the Japanese experience has demonstrated the efficacy of screening for HCC in the population at risk using serum AFP and ultrasound with the addition of dynamic CT and angiography where indicated. The continuing poor prognosis of patients with HCC in the United States suggests a failure to apply these methods for the early detection of HCC.

Angiography↗