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Biomedical subjects

J M Taylor

Publications and source records attributed to J M Taylor.

At least 109 records · Page 6Linked to original sources
PubMed1997

Annexin I in fibrotic rat lung and cultured lung fibroblasts following irradiation.

Radiation-induced lung fibrosis is a result of collagen accumulation in the interstitium, partly due to increased collagen synthesis by fibroblasts. One feature of active collagen synthesis is increased membrane trafficking in the fibroblasts. A group of proteins called annexins is believed to play a regulatory role in membrane fusion and exocytosis. Therefore, increased annexin activity might be expected in the fibrotic lung. We tested this hypothesis by measuring annexin I levels, hydroxyproline content and ultrastructural changes in radiation-induced pulmonary fibrosis in rat. Three months after a single exposure to 30 Gy of X-rays to the right hemithorax, the right lung of the rat was atrophied and fibrotic with a concomitant increase in size of the shielded left lung. Electron micrographs revealed that the irradiated lung was ladened with interstitial collagen fibrils, with increased number of fibroblasts amongst them. Hydroxyproline concentration in the irradiated lung was nearly twice that in the sham-irradiated lung. Annexin I in the irradiated lung, on the other hand, was markedly reduced, and barely detectable on immunoblots. Since increased annexin I might precede enhanced collagen production, we also measured annexin I levels in rat lungs 3 days after 30 Gy irradiation and correlated that with hydroxyproline concentration. We found no appreciable difference in annexin I levels and hydroxyproline content between sham-irradiated and irradiated lungs at 3 days. To determine whether annexin I levels in cultured fibroblasts were altered by irradiation, we assayed annexin I in cultured rat lung fibroblasts 3 days after 0.10 Gy exposure, with concomitant measurement of 14C-proline incorporation. The annexin I level in fibroblasts irradiated with 10 Gy X-rays was 55% higher than in sham-irradiated fibroblasts. However, incorporation of 14C-proline into collagenase-sensitive macromolecules in the culture medium and extracellular matrix was not different between these two groups of cells. These data demonstrate a radiation-induced increase in immunoreactive annexin I in cultured lung fibroblasts, but fail to support the hypothesis of a positive correlation between annexin I concentration and fibrosis in irradiated rat lung.

Animals↗
PubMed1997

Effects of elevated CO(2) on chloroplast components, gas exchange and growth of oak and cherry.

Specific chloroplast proteins, gas exchange and dry matter production in oak (Quercus robur L.) seedlings and clonal cherry (Prunus avium L. x pseudocerasus Lind.) plants were measured during 19 months of growth in climate-controlled greenhouses at ambient (350 vpm) or elevated (700 vpm) CO(2). In both species, the elevated CO(2) treatment increased the PPFD saturated-rate of photosynthesis and dry matter production. After two months at elevated CO(2), Prunus plants showed significant increases in leaf (55%) and stem (61%) dry mass but not in root dry mass. However, this initial stimulation was not sustained: treatment differences in net assimilation rate (A) and plant dry mass were less after 10 months of growth than after 2 months of growth, suggesting acclimation of A to elevated CO(2) in Prunus. In contrast, after 10 months of growth at elevated CO(2), leaf dry mass of Quercus increased (130%) along with shoot (356%) and root (219%) dry mass, and A was also twice that of plants grown and measured at ambient CO(2). The amounts of Rubisco and the thylakoid-bound protein cytochrome f were higher in Quercus plants grown for 19 months in elevated CO(2) than in control plants, whereas in Prunus there was less Rubisco in plants grown for 19 months in elevated CO(2) than in control plants. Exposure to elevated CO(2) for 10 months resulted in increased mean leaf area in both species and increased abaxial stomatal density in Quercus. There was no change in leaf epidermal cell size in either species in response to the elevated CO(2) treatment. The lack of acclimation of photosynthesis in oak grown at elevated CO(2) is discussed in relation to the production and allocation of dry matter. We propose that differences in carbohydrate utilization underlie the differing long-term CO(2) responses of the two species.

Journal Article↗
PubMed1997

Dependence of the hazard of AIDS on markers.

OBJECTIVE: To investigate the dependence of the hazard of symptomatic AIDS on various markers using a non-parametric method. The markers we consider are measures of time (time since infection and calendar date), measures of immune function (numbers and percentage of CD4 T cells) and serological activation markers (neopterin and beta 2-microglobulin). METHODS: We adapted a non-parametric statistical method to estimate the hazard of AIDS. We considered both univariate analyses, in which each marker was considered separately and bivariate analyses of pairs of markers. CONCLUSIONS: Using data from 356 seroconverters from the Multicenter AIDS Cohort Study, we found that in the univariate analyses the hazard of AIDS is dependent on all markers, with the strongest dependence for CD4 count and CD4 percentage. In the bivariate analyses we found that the time since infection is of little importance in determining the hazard of AIDS if the CD4 count or percentage are known, and is of minor additional value if one of the serological markers is known. In contrast, we found that both beta 2-microglobulin and neopterin do add some additional information to the hazard of AIDS if CD4 count or CD4 percentage are known.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Effects of nucleotide changes on the ability of hepatitis delta virus to transcribe, process, and accumulate unit-length, circular RNA.

The circular RNA genome of hepatitis delta virus (HDV) can fold into an unbranched rodlike structure. We mutagenized the two ends of this structure and assayed the effects on the ability of the genomes to replicate and accumulate processed RNA transcripts in transfected cells. The top end, defined as that nearest to the 5' end of the putative mRNA for delta antigen, was much more sensitive than the other end, defined as the bottom. Most of the 22 mutants made at the bottom were able to accumulate RNA as well as the wild type. For deletions extending as close as 2 nucleotides (nt) from the predicted domains needed for the two ribozymes, the accumulation levels dropped to <0.1%. In one mutant, 13 nt of HDV was replaced with 57 nt of non-HDV sequences, and accumulation was at 20% of the wild-type level, consistent with the potential of HDV to act as a vector. However, after replacement with a second sequence, accumulation dropped to 1%. For most of the 14 mutants made at the top of the rod, we observed dramatic inhibitory effects. For example, after removal of 3 bp from the stem adjacent to the terminal loop, accumulation dropped to <0.06% of the wild-type genome level. The top region that we considered was adjacent to both the 5' end of the putative mRNA and the domain that has been proposed to contain a promoter for RNA-directed RNA synthesis. The RNA accumulation abilities of certain mutants were tested under additional different experimental conditions. It was found that after longer times, some mutants began to catch up with the wild type. Also, it was found that certain top mutants gave much greater levels of accumulation when transfected into cells containing the small delta antigen. One interpretation of these data is that certain features at the top of the rod are needed for the accumulation of essential delta antigen mRNA species.

Animals↗
PubMed1997

A role for the ETS domain transcription factor PEA3 in myogenic differentiation.

Activation of adult myoblasts called satellite cells during muscle degeneration is an important aspect of muscle regeneration. Satellite cells are believed to be the only myogenic stem cells in adult skeletal muscle and the source of regenerating muscle fibers. Upon activation, satellite cells proliferate, migrate to the site of degeneration, and become competent to fuse and differentiate. We show here that the transcription factor polyomavirus enhancer activator 3 (PEA3) is expressed in adult myoblasts in vitro when they are proliferative and during the early stages of differentiation. Overexpression of PEA3 accelerates differentiation, whereas blocking of PEA3 function delays myoblast fusion. PEA3 activates gene expression following binding to the ets motif most efficiently in conjunction with the transcription factor myocyte enhancer factor 2 (MEF2). In vivo, PEA3 is expressed in satellite cells only after muscle degeneration. Taken together, these results suggest that PEA3 is an important regulator of activated satellite cell function.

Animals↗
PubMed1997

Hepatic lipase is abundant on both hepatocyte and endothelial cell surfaces in the liver.

The cellular location of hepatic lipase was investigated in transgenic rabbits that expressed human hepatic lipase in the liver. The binding of monoclonal antibodies to human hepatic lipase, as detected by either fluorescence-tagged or gold-conjugated secondary antibodies, showed that hepatic lipase was concentrated at the surfaces of hepatic sinusoids. This distribution was the same as observed in the human liver. At the ultrastructural level, immunogold labeling of the space of Disse showed hepatic lipase on both lumenal and sublumenal surfaces of rabbit liver sinusoidal endothelial cells. An equivalent amount of hepatic lipase also was found on the external surfaces of hepatocyte microvilli in the space of Disse, as well as in the interhepatocyte spaces. The distribution suggests that a majority of the hepatic lipase produced by the liver is associated with hepatocyte surfaces, consistent with the functions of this enzyme in lipoprotein metabolism.

Animals↗
PubMed1997

A stochastic model for the analysis of bivariate longitudinal AIDS data.

We present a model for multivariate repeated measures that incorporates random effects, correlated stochastic processes, and measurement errors. The model is a multivariate generalization of the model for univariate longitudinal data given by Taylor, Cumberland, and Sy (1994, Journal of the American Statistical Association 89, 727-736). The stochastic process used in this paper is the multivariate integrated Ornstein-Uhlenbeck (OU) process, which includes Brownian motion and a random effects model as special limiting cases. This process is an underlying continuous-time autoregressive order [AR(1)] process for the derivatives of the multivariate observations. The model allows unequally spaced observations and missing values for some of the variables. We analyze CD4 T-cell and beta-2-microglobulin measurements of the seroconverters at multiple time points from the Los Angeles section of the Multicenter AIDS Cohort Study. The model allows us to investigate the relationship between CD4 and beta-2-microglobulin through the correlations between their random effects and their serial correlation. The data suggest that CD4 and beta-2-microglobulin follow a bivariate Brownian motion process. The fit of the model implies that an increase in beta-2-microglobulin is associated with a decrease in future CD4 but not vice versa, agreeing with immunologic postulates about the relationship between these two variables.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Incidence and kinetics of distant metastases in patients with operable breast cancer.

The purpose of this paper is to evaluate the incidence and kinetics of distant metastases in operable breast cancer and to relate these estimates to various tumor and patient characteristics. The records of 309 consecutive patients with operable breast cancer in stage T1-4N0-1M0 were reviewed, and the incidence of distant metastases (DM) and death due to DM were evaluated. 195 patients had positive axillary nodes with the following distribution of the number of nodes: 45% had 1-2 node, 16% had 3-4 nodes, 14% and 25% had 5-7 and more nodes, respectively. All patients were treated with radical mastectomy with axillary nodes dissection (the only treatment in 39% of cases). In 198 cases radical mastectomy was combined with radiotherapy and/or chemotherapy given pre- or postoperatively. Hormonal treatment was given in 27% of cases. Minimum follow-up was 10 years. Distant metastases were found in 150 cases (49%) and in 78 cases (25%) they developed early, during the first 18 months follow-up. Average rate of DM in N0 cases was 25%. Number of involved nodes and extracapsular invasion were found significant and independent prognostic factors. High risk (50%) of DM and death due to DM correlate with age < 40 y, premenopausal status, tumor stage > or = T3, more than 2 axillary nodes and/or extracapsular invasion. The linearity of the curves for freedom from DM and for freedom from death due to the DM suggest uniform distribution of progression rates with a median value for halving time for freedom from early DM of about 8 months, and of about 40 months for freedom from the DM occurring later than 18 months, being for whole group an average of 20 months. High incidence of DM is a significant cause of poor long-term survival. Early appearance (< 18 month follow-up) of about half of the DM suggests that they are already present as subclinical micrometastases at the time of initial loco-regional treatment. The time of appearance of distant metastases is consistent with a wide range of metastatic cell burdens among patients. Systemic therapy, at least for selected group of patients, might decrease the incidence of DM and improve long-term results.

Adenocarcinoma↗
PubMed1996

Receptor and membrane interaction sites on Gbeta. A receptor-derived peptide binds to the carboxyl terminus.

The functional organization of Gbetagamma is poorly understood. Regions of bovine brain Gbetagamma that interact with a photoaffinity derivative of an alpha2-adrenergic receptor-derived peptide from the third intracellular loop (diazopyruvoyl-modified peptide Q (DAP-Q)) and a hydrophobic membrane probe (3-trifluoromethyl-3-(m-iodophenyl)diazirine (TID)) were examined. We previously showed that DAP-Q cross-links to specific, competable sites on both the alpha and beta subunits of Go/Gi but not on the gamma subunit and that betagamma subunit was required for stimulation of Go/Gi GTPase activity (Taylor, J. M., Jacob Mosier, G. G., Lawton, R. G., Remmers, A. E., and Neubig, R. R. (1994) J. Biol. Chem. 269, 27618-27624). Similarly, we show here that the membrane-associated photoprobe [125I]TID labels alpha and beta but not gamma. We have now mapped the sites of incorporation of DAP-Q and TID into the beta subunit. TID labels both the 14-kDa amino-terminal and the 23-kDa carboxyl-terminal fragments from a partial tryptic digest of beta while DAP-Q labels only the carboxyl-terminal fragment. Further mapping with endopeptidase Lys C reveals substantial labeling of multiple fragments by TID while DAP-Q labels predominantly a approximately 6-kDa fragment within the carboxyl-terminal 60 amino acids of beta1. Thus, regions within the 7th (or possibly 6th) WD-40 repeat of the beta subunit of G protein interact with the receptor-derived peptide while membrane interaction involves multiple sites throughout the beta subunit.

Animals↗
PubMed1996

Models for residual time to AIDS.

The distributions of the time from Human Immunodeficiency Virus (HIV) infection to the onset of Acquired Immune Deficiency Syndrome (AIDS) and of the residual time to AIDS diagnosis are important for modeling the growth of the AIDS epidemic and for predicting onset of the disease in an individual. Markers such as CD4 counts carry valuable information about disease progression and therefore about the two survival distributions. Building on the framework set out by Jewell and Kalbfleisch (1992), we study these two survival distributions based on stochastic models for the marker process (X(t)) and a marker-dependent hazard (h(.)). We examine various plausible CD4 marker processes and marker-dependent hazard functions for AIDS proposed in recent literature. For a random effects plus Brownian motion marker process X(t) = (a + bt + BM(t))4, where a has a normal distribution, b < 0 is an unknown parameter and BM(t) is Brownian motion, and marker-dependent hazard h(X(t)), we prove that, given CD4 cell count X(t), the residual time to AIDS distribution does not depend on the time since infection t. Using simulation and numerical integration, we find the marginal incubation period distribution, the marginal hazard and the residual time distribution for several combinations of marker processes and marker-dependent hazards. An example using data from the Multicenter AIDS Cohort Study is given. A simple regression model relating the cube root of residual time to AIDS to CD4 count is suggested.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Randomized clinical trial on accelerated 7 days per week fractionation in radiotherapy for head and neck cancer. Preliminary report on acute toxicity.

PURPOSE: Toxicity of an accelerated 7 days per week fractionation schedule (arm A) was evaluated and compared with a conventional 5 days per week treatment (arm B) in a randomized trial. MATERIALS AND METHODS: Forty-four patients with squamous cell carcinoma of the head and neck in stage T2-4Nzero-1Mzero were included in the study. Total dose and dose per fraction of 2.0 Gy given once-a-day at 24 h intervals were the same in both arms of the trial. The only difference was the overall treatment time being 5 weeks in arm A and 7 weeks in arm B. RESULTS: Analysis of severe mucosal reactions shows significant difference between arm A and B, with regard to both maximum score and duration of severe mucositis. Confluent mucositis (score > 15 according to the Dische system) lasting longer than 3 weeks developed in 48% of patients in arm A and only in 5% in arm B. In group A seven (30%) late effects (osteo- and soft tissue necrosis) occurred during 7-12 month follow-up with two reactions (10%) in group B being suspected as late effects. There was significant association between acute reactions and late effects in arm A, suggesting that the late effects are consequential. CONCLUSION: The high incidence of severe acute reactions and consequential late effects suggests that the accelerated treatment in arm A (using daily fractions of 2.0 Gy, 7 days per week) gives unacceptable toxicity.

Acute Disease↗
PubMed1996

Influence of selection bias on dose-time analysis: a theoretical investigation.

BACKGROUND AND PURPOSE: We investigate the effect of patient selection factors on the interpretation of dose-time analyses of retrospective head and neck data treated with external beam radiation therapy. MATERIALS AND METHODS: We use a computer simulation model to ascertain the influence of individualizing the fractionation regimen on the estimated steepness of dose-response and time-response estimates, on the probability of local control and on the validity of statistical tests and confidence intervals. We assume that the total dose and overall treatment time for each patient are altered by consideration of three possible factors, the pre treatment size of the tumor, the response of the tumor to therapy or the amount of acute effects. RESULTS: We find that individualizing treatment leads to very small improvements in the local control rate, but substantial biases in the estimates of the doubling time and the effective D0 value. Patient selection also compromises the validity of confidence intervals and tests. Despite this selection bias our results suggest that if there were no real effect of treatment time then the influence of individualizing treatments would not cause treatment time to be found to be as important as it has been shown to be in many studies. CONCLUSIONS: Assuming the fundamental radiobiological assumptions in the model are appropriate, individual alterations of the fractionation schedule due to the response to therapy can compromise the interpretation of dose-time analyses of retrospective data, without giving much improvement in the control rate.

Bias↗
PubMed1996

Injury-specific cytotoxic response of tumor cells and endothelial cells.

Cytotoxicity indicated by increased release of prelabeled 51chromium (51Cr) and lactate dehydrogenase (LDH) was studied in human prostate cancer and melanoma cells in cell culture following irradiation or exposure to several injurious substances. These changes were compared to those observed in bovine aortic endothelial cells (BAEC) subjected to identical treatments. Further, the effect of irradiation on plasminogen activator (PA) secretion from prostate cancer cells, and the effect of glycine on radiation-induced cytotoxicity in BAEC were also investigated. Radiation, lipopolysaccharide and xanthine/xanthine oxidase stimulated no release of 51Cr or LDH from tumor cells, while these treatments induced a dose- and time-related loss of those cytotoxic indicators from BAEC. Protease, elastase and Triton X-100 incited loss of 51Cr and LDH from all three cell types. Radiation, lipopolysaccharide and xanthine/xanthine oxidase have been shown to cause cell injury via a common pathogenic pathway of oxidant generation. Tumor cells appear quite resistant to oxidant stress. Cell damage precipitated by protease, elastase and Triton probably involves hydrolysis of proteins and phospholipids in the cell membrane, leading to an increased leakage of intracellular proteins such as LDH and those bound with 51Cr. Radiation caused a dose- and time-related reduction in the secretion of PA from prostate cancer cells. PA is alleged to play a role in tumor metastasis; the reduced secretion could be another beneficial effect of radiation, in addition to interruption of cell proliferation, in the impediment of tumor growth and spread. Glycine diminished cytotoxic injury of BAEC inflicted by radiation. This amino acid may prove useful in offering a degree of protection of normal tissue against radiation associated side-effects.

Animals↗
PubMed1996

Improved models of tumour cure.

The standard mechanistic model for the probability of tumour cure (the "Poisson model') is based on the assumption that the number of surviving clonogens at the end of treatment follows a Poisson distribution from tumour to tumour. This assumption is not correct, however, if proliferation of tumour clonogens occurs during treatment, as would be expected in general during a fractionated course of radiotherapy. In the present study, the possible magnitude of the error in the Poisson model was investigated for tumours treated with either conventional fractionation or split-course therapy. An example is presented in which the Poisson model has an absolute error of nearly 100%, predicting a cure rate of 0% when in fact the cure rate was close to 100%. The largest errors in the Poisson model found in this study were for very small tumours (approximately 100 clonogens), but for larger tumours (> or = 10(6) clonogens), the Poisson model may still be highly inaccurate, predicting a cure rate that differs from the actual cure rate by as much as 40%. Three new tumour-cure models are proposed (the GS, PS, and GS+ models), and their accuracy is also investigated. Two of these (the GS and PS models) are better than the Poisson model for the clinically relevant cases tested here. The third model, the GS+ model, consistently produced the most accurate estimate of the tumour cure rate, but has more limited use than the GS and PS models because it is more highly parametrized. It is demonstrated here that no tumour-cure model based on the effective clonogen doubling time will be perfectly accurate in all cases, since the cure rate depends on the details of the cell kinetics contributing to the effective doubling time.

Clone Cells↗
PubMed1996

Replacing time since human immunodeficiency virus infection by marker values in predicting residual time to acquired immunodeficiency syndrome diagnosis. Multicenter AIDS Cohort Study.

It is widely assumed that the time since human immunodeficiency virus (HIV) infection is an important indicator of HIV disease stage, yet for most infected individuals the date of infection is unknown. We consider whether marker values, such as CD4 lymphocyte number or percent and levels of serum beta2 microglobulin or serum neopterin, render time since infection unimportant for predicting the residual time to acquired immunodeficiency syndrome (AIDS) diagnosis. The Multicenter AIDS Cohort Study (MACS) contains a subsample of homosexual men whose date of HIV seroconversion is known within +/-6 months and who provide data for this analysis. From this subsample, we extract two overlapping data subsets. The first subset consists of 370 persons whose 3,723 study visits include complete data on the cellular markers CD4 lymphocyte number and percent for a period of 9 years. The second consists of 272 persons whose 1,593 visits include complete information on cellular markers and on the serological markers beta2-microglobulin and neopterin for a period of 5 1/2 years. We model the residual time to AIDS diagnosis with a regression model, in which cellular and serologic markers are the explanatory covariates (independent variables) and the residual time to AIDS is the responses variable (dependent variable). A robust estimate of the variance-covariance matrix corrects for the dependence of repeated measurements in the same individual. In the case of CD4 number and percent, the results indicate that time since infection is of none or at most little importance if the marker value is known, suggesting that time since infection can be adequately replaced by the combination of marker values. However, the serological markers alone do not eliminate the importance of the time since infection.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Normal range estimation for repeated immunologic measures.

A method for estimating a normal range from a set of immunologic measurements on control subjects when there may be more than one observation per subject is described. The method is nonparametric, makes efficient use of all observations, and is very simple to apply. It is illustrated on a set of 152 CD38 measurements from 58 healthy men.

ADP-ribosyl Cyclase↗
PubMed1996

Redistribution of the delta antigens in cells replicating the genome of hepatitis delta virus.

When the small form of the delta antigen (deltaAg-S) was expressed from a cDNA expression plasmid and subsequently detected by immunofluorescence, it was found localized to the nucleoli. However, if the cDNA was cotransfected with a cDNA expressing a mutated hepatitis delta virus (HDV) genome that could only replicate by using the deltaAg-S provided by the first plasmid, then most of the deltaAg-S was redistributed to the nucleoplasm, largely to specific discrete nucleoplasmic sites or speckles; this pattern was stable for at least 50 days after transfection. These speckles coincided with those detected with an antibody to SC35, an essential non-small nuclear ribonucleoprotein splicing factor. Others have shown that SC35 speckles correspond to active sites of DNA-directed transcription by RNA polymerase II and also of RNA processing. We also found, in contrast to the cotransfections with the mutant HDV and the deltaAg-S provided in trans, that cells transfected with wild-type HDV showed a variable pattern of staining. The SC35-like speckle pattern of accumulation of delta antigen deltaAg was maintained for only 6 days, after which the pattern began to change. By 18 days posttransfection, a variety of different deltaAg staining patterns were observed. This pattern of change occurs at a time when the large form of the delta antigen deltaAg-L appears and HDV RNA synthesis begins to shut down. Our studies therefore support the interpretation that HDV RNA and deltaAg-S accumulate at SC35 speckle sites in the nucleoplasm. We speculate that these may be the sites at which HDV RNA is transcribed by RNA polymerase II and/or sites of HDV RNA processing. Furthermore, when deltaAg-L, as well as other mutant deltaAg accumulate, the speckle association is disrupted, thereby stopping HDV RNA replication.

Amino Acid Sequence↗