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PubMed1995

Intratumoral DNA heterogeneity of small hepatocellular carcinoma.

BACKGROUND: Intratumoral DNA heterogeneity provides important information regarding biologic and clinical behavior. The purpose of this study was to evaluate the incidence of DNA heterogeneity in small hepatocellular carcinoma (HCC) nodules. METHODS: The DNA content of 28 surgically resected small HCC nodules (< or = 3.0 cm) was measured using flow cytometry of fresh or frozen samples taken from different parts of each nodule with reference to the macroscopic features. RESULTS: Of the 28 small HCC nodules, 14 (50.0%) had only DNA diploid stemline characteristics. Five nodules (17.9%) manifested DNA diploid and DNA aneuploidy within the same tumor. Of the remaining nine nodules (32.1%) that showed only DNA aneuploidy, two contained tumor tissues with apparently different DNA content. Thus, DNA heterogeneity was found in 7 (25.0%) of 28 nodules. DNA heterogeneity correlated well with macroscopic histologic features. All four early HCC were composed of only DNA diploid cells, whereas three of six nodule-in-nodule lesions were composed of DNA heterogeneous cells, in which the inner obviously cancerous nodule showed DNA aneuploidy and the outer well differentiated HCC portion demonstrated DNA diploid. Four of 18 overt HCC nodules showed DNA heterogeneity; 2 of these 4 nodules showed both diploid and aneuploid peaks, and the other 2 two showed different aneuploid peaks within the same nodule. CONCLUSIONS: DNA heterogeneity correlating with macroscopic features is found frequently even in small HCC nodules. Therefore, multiple sampling based on macroscopic features is required for the accurate assessment of DNA ploidy, particularly when the information about DNA ploidy is used as a prognostic indicator.

Aged↗
PubMed2007

A comparison of heterogeneity variance estimators in combining results of studies.

For random effects meta-analysis, seven different estimators of the heterogeneity variance are compared and assessed using a simulation study. The seven estimators are the variance component type estimator (VC), the method of moments estimator (MM), the maximum likelihood estimator (ML), the restricted maximum likelihood estimator (REML), the empirical Bayes estimator (EB), the model error variance type estimator (MV), and a variation of the MV estimator (MVvc). The performance of the estimators is compared in terms of both bias and mean squared error, using Monte Carlo simulation. The results show that the REML and especially the ML and MM estimators are not accurate, having large biases unless the true heterogeneity variance is small. The VC estimator tends to overestimate the heterogeneity variance in general, but is quite accurate when the number of studies is large. The MV estimator is not a good estimator when the heterogeneity variance is small to moderate, but it is reasonably accurate when the heterogeneity variance is large. The MVvc estimator is an improved estimator compared to the MV estimator, especially for small to moderate values of the heterogeneity variance. The two estimators MVvc and EB are found to be the most accurate in general, particularly when the heterogeneity variance is moderate to large.

Bias↗
PubMed1992

Spontaneous sarcoplasmic reticulum Ca2+ release leads to heterogeneity of contractile and electrical properties of the heart.

The cytosolic Ca2+ (Cai) oscillation generated by the sarcoplasmic reticulum (SR) in response to an action potential (AP) occurs relatively synchronously within and among cells. The SR can also generate spontaneous Cai oscillations (S-CaOs), i.e., not triggered by sarcolemmal depolarization. The local increase in Cai due to S-CaOs is equivalent to that induced by an AP. Heterogeneity of diastolic Cai caused by asynchronous S-CaOs among cells within myocardial tissue leads to heterogeneous myofilament activation, the summation of which produces a Ca(2+)-dependent component to diastolic tone. The local increases in Cai due to S-CaOs also cause oscillatory sarcolemmal depolarizations due to Ca2+ modulation of the Na/Ca exchanger and of non-specific cation channels. Thus, inhomogeneous levels of diastolic Cai may lead to heterogeneity in cell coupling and thus may also affect the impulse conduction. The magnitude of the S-CaOs induced diastolic tonus and membrane depolarization varies with the extent to which S-CaOs are synchronized; partially synchronized S-CaOs following an AP induced SR Ca2+ release produce an aftercontraction and after depolarization. When local S-CaOs is sufficiently synchronized within the cell the resultant depolarization summates and can be sufficient to trigger spontaneous AP. Inhomogeneity of diastolic SR Ca2+ loading and sarcomere lengths within individual cardiac cells due to S-CaOs leads to inhomogeneous systolic Cai levels and sarcomere length inhomogeneities in response a subsequent AP; this heterogeneity compromises the systolic contraction amplitude. Heterogeneity of systolic Cai among cells due to diastolic S-CaOs also leads to heterogeneity of AP repolarization times, due, to heterogeneous Cai modulation of the Na/Ca exchanger, the non-specific cation channel and of the L type sarcolemmal Ca2+ channel. S-CaOs occurrence during a long AP plateau may also modulate the removal of voltage inactivation of L type Ca2+ channels and affect the likelihood of the occurrence of "early after depolarizations." Thus, as a single entity, S-CaOs may be implicated in diverse manifestations of heart failure--impaired systolic performance, increased diastolic tonus and an increased probability for the occurrence of arrhythmias.

Animals↗
PubMed1995

Effect of tissue heterogeneity on quantification in positron emission tomography.

As a result of the limited spatial resolution of positron emission tomographic scanners, the measurements of physiological parameters are compromised by tissue heterogeneity. The effect of tissue heterogeneity on a number of parameters was studied by simulation and an analytical method. Five common tracer models were assessed. The input and tissue response functions were assumed to be free from noise and systematic errors. The kinetic model was assumed to be perfect. Two components with different kinetics were mixed in different proportions and contrast with respect to the model parameters. Different experimental protocols were investigated. Of three methods investigated for the measurement of cerebral blood flow (CBF) (steady state, dynamic, integral), the second one was least sensitive to errors caused by tissue heterogeneity and the main effect was an underestimation of the distribution volume. With the steady state method, errors in oxygen extraction fraction caused by tissue heterogeneity were always found to be less than the corresponding errors in CBF. For myocardial blood flow the steady state method was found to perform better than the bolus method. The net accumulation of substrate (i.e. rCMRglc in the case of glucose analogs) was found to be comparatively insensitive to tissue heterogeneity. Individual rate constants such as k2 and k3 for efflux and metabolism of the substrate in the pool of unmetabolized substrate in the tissue, respectively, were found to be more sensitive. In studies of radioligand binding, using only tracer doses, the effect of tissue heterogeneity on the parameter kon.Bmax could be considerable. In studies of radioligand binding using a protocol with two experiments, one with high and one with low specific activity, Bmax was found to be insensitive while Kd was very sensitive to tissue heterogeneity.

Body Water↗
PubMed2004

How do grazers affect periphyton heterogeneity in streams?

The effects of grazing by stream invertebrates on algal biomass and spatial heterogeneity were tested experimentally in flow-through microcosms with natural substrates (rocks). One experiment tested the effects of fixed densities of three species of grazers (the caddisfly Allomyia sp. and two mayflies, Epeorus deceptivus and Baetis bicaudatus) on periphyton. Baetis was tested with and without chemical cues from fish predators, which reduced grazer foraging activity to levels similar to the less mobile mayfly (Epeorus). Mean algal biomass (chlorophyll a; chl a) was reduced in grazer treatments compared to ungrazed controls, but there were no differences among grazer treatments. Algal heterogeneity (Morisita index) increased with grazer mobility, with the highest heterogeneity occurring in the Baetis-no fish treatment (most mobile grazer) and the lowest in the caddisfly treatment (most sedentary grazer). A second experiment used a three factorial design, and tested whether initial resource distribution (homogeneous vs. heterogeneous), Baetis density (high vs. low) and fish odor (present vs. absent) affected grazer impact on algal resources. Abundances of Baetis and chl a on individual rocks were recorded to explore the mechanisms responsible for the observed distributions of algae. Initial resource heterogeneity was maintained despite being subjected to grazing. Mean chl a was highest in controls, as in experiment I, and effects of Baetis on algal biomass increased with grazer density. There were no fish effects on algal biomass and no effects of grazer density or fish on algal heterogeneity. At the scale of individual rocks Baetis was unselective when food was homogeneously distributed, but chose high-food rocks when it was heterogeneously distributed. Results of these mechanistic experiments showed that Baetis can track resources at the scale of single rocks; and at moderate densities mobile grazers could potentially maintain periphyton distributions observed in natural streams.

Animals↗
PubMed2006

Biomass responses to elevated CO2, soil heterogeneity and diversity: an experimental assessment with grassland assemblages.

While it is well-established that the spatial distribution of soil nutrients (soil heterogeneity) influences the competitive ability and survival of individual plants, as well as the productivity of plant communities, there is a paucity of data on how soil heterogeneity and global change drivers interact to affect plant performance and ecosystem functioning. To evaluate the effects of elevated CO(2), soil heterogeneity and diversity (species richness and composition) on productivity, patterns of biomass allocation and root foraging precision, we conducted an experiment with grassland assemblages formed by monocultures, two- and three-species mixtures of Lolium perenne, Plantago lanceolata and Holcus lanatus. The experiment lasted for 90 days, and was conducted on microcosms built out of PVC pipe (length 38 cm, internal diameter 10 cm). When nutrients were heterogeneously supplied (in discrete patches), assemblages exhibited precise root foraging patterns, and had higher total, above- and belowground biomass. Greater aboveground biomass was observed under elevated CO(2). Species composition affected the below:aboveground biomass ratio and interacted with nutrient heterogeneity to determine belowground and total biomass. Species richness had no significant effects, and did not interact with either CO(2) or nutrient heterogeneity. Under elevated CO(2) conditions, the two- and three-species mixtures showed a clear trend towards underyielding. Our results show that differences among composition levels were dependent on soil heterogeneity, highlighting its potential role in modulating diversity-productivity relationships.

Analysis of Variance↗
PubMed1983

Expression of defined idiotypes throughout the BALB/c anti-fluorescyl antibody response: affinity and idiotype analyses of heterogeneous antibodies.

Heterogeneous BALB/c anti-fluorescyl antibodies were shown to display increases (greater than 50-fold) in binding affinity from the primary through the tertiary responses. The structural basis of such affinity maturation and the diversity exhibited by anti-fluorescyl antibodies was examined by idiotypic analysis using a panel of anti-idiotype reagents specific for seven different monoclonal antifluorescyl antibodies. Because these clones exhibited binding affinities characteristic of a secondary or hyperimmune response, it was possible to examine the mechanism of affinity maturation by determining the prevalence of the seven idiotypes (Id-4-4-20, Id-20-19-1, Id-20-20-3, Id-6-10-6, Id-20-4-4, Id-4-6-10 and Id-6-19-1) in specifically purified heterogeneous preparations with low (i.e. primary response) or high (i.e. secondary and tertiary responses) binding affinities. Four of the idiotypes were not detected in heterogeneous preparations and thus each represented less than 0.1% of the total anti-fluorescein repertoire. Although results indicated that each of three other clones expressed unique or private idiotypic determinants not present in the heterogeneous population, these idiotypes (Id-4-4-20, Id-6-10-6, Id-6-19-1) were detected and ranged from approximately 0.2 to 2.0% of the repertoire. However, results indicated that each clone expressed unique or private idiotypic determinants not present in the heterogeneous population. Determinants expressed by such high-affinity monoclonal antibodies were expressed equally in all heterogeneous preparations examined. Because those determinants which were expressed were found in either low- or high-affinity heterogeneous antibodies, it is likely that the higher affinities exhibited by monoclonal antibodies derived from a secondary response are associated with unique idiotypic determinants which were not detected in polyclonal preparations. Hence, the process of affinity maturation may find as its structural correlate a mechanism such as somatic mutation which generates individual or unique idiotypes.

Animals↗
PubMed1995

The case for heterogeneity in the etiology of schizophrenia.

To confirm etiological heterogeneity, it is required that schizophrenic patients may be separated into at least two classes having different known etiologies and, perhaps, different pathophysiological signatures. In contrast, the homogeneity hypothesis asserts that there is a single necessary and sufficient cause or configuration of causes of schizophrenia. Because the link between phenotypic heterogeneity and etiological heterogeneity is tenuous, attempts to use purely phenotypic data to infer etiologic heterogeneity must be viewed cautiously. We examined three candidate causes for schizophrenia: genes, obstetric complications and viral infection. Cytogenetic studies show that some rare cases of schizophrenia are due to gross abnormalities of chromosomes. As for the large majority of schizophrenic patients, the candidate cause data most certainly reject the most parsimonious version of the hypothesis of etiological homogeneity: that all schizophrenia is caused by exactly the same pattern of genetic mutations, birth related complications and exposure to the same viral infections. We conclude that the heterogeneity debate should consider the possibility of rewording the question: 'Heterogeneity: yes or no?' to 'Heterogeneity: how much?'

Chromosome Aberrations↗
PubMed2006

Evolution of pathogens towards low R0 in heterogeneous populations.

Maximization of the basic reproduction ratio or R(0) is widely believed to drive the emergence of novel pathogens. The presence of exploitable heterogeneities in a population, such as high variance in the number of potentially infectious contacts, increases R(0) and thus pathogens that can exploit heterogeneities in the contact structure have an advantage over those that do not. However, exploitation of heterogeneities results in a more rapid depletion of the potentially susceptible neighbourhood for an infected host. Here a simple model of pathogen evolution in a heterogeneous environment is developed and placed in the context of HIV transmission. In this model, it is shown that pathogens may evolve towards lower R(0), even if this results in pathogen extinction. For sufficiently high transmissibility, two locally stable strategies exist for an evolving pathogen, one that exploits heterogeneities and results in higher R(0), and one that does not, and results in lower R(0). While the low R(0) strategy is never evolutionarily stable, invading strains with higher R(0) will also converge to the low R(0) strategy if not sufficiently different from the resident strain. Heterogenous transmission is increasingly recognized as fundamental to epidemiological dynamics and the evolution of pathogens; here, it is shown that the ability to exploit heterogeneity is a strategy that can itself evolve.

Disease Outbreaks↗
PubMed2005

The spatial and temporal heterogeneity of regional ventilation: comparison of measurements by two high-resolution methods.

High-resolution estimates of ventilation distribution in normal animals utilizing deposition of fluorescent microsphere aerosol (FMS technique) demonstrate substantial ventilation heterogeneity, but this finding has not been confirmed by an independent method. Five supine anesthetized sheep were used to compare the spatial and temporal heterogeneity of regional ventilation measured by both the FMS technique and by a ventilation model utilizing the data from computed tomography images of xenon gas washin (CT/Xe technique). An aerosol containing 1 microm fluorescent microspheres (FMS) was administered via a mechanical ventilator delivering a 2-s end-inspiration hold during each breath. Following the aerosol administration, sequential CT images of a transverse lung slice were acquired during each end-inspiration hold during washin of a 65% Xenon/35% oxygen gas mixture (CT/Xe technique). Four paired FMS and CT/Xe measurements were done at 30 min intervals, after which the animals were sacrificed. The lungs were extracted, air-dried and sliced in 1cm transverse sections. The lung section corresponding to the CT image was cut into 1 cm3 cubes, with notation of spatial coordinates. The individual cubes were soaked in solvent and the four fluorescent signals were measured with a fluorescence spectrophotometer. The color signals were normalized by the mean signal for all pieces and taken as the FMS estimate of ventilation heterogeneity. The CT images were clustered into 1 cm3 voxels and the rate of increase in voxel density was used to calculate voxel ventilation utilizing the model of . The regional ventilation voxel measurements were normalized by the mean value to give a CT/Xe estimate of ventilation heterogeneity comparable to the normalized FMS measurements. The overall of heterogeneity of ventilation at the 1 cm3 level of resolution was comparable by both techniques, with substantial differences among animals (coefficient of variation ranging from 37% to 74%). The repeated within-animal measurements by both techniques gave consistent values. Both techniques showed comparable large-scale distribution of regional ventilation in the caudal lobes of the supine animals. There were appreciable differences in the temporal variability of ventilation among animals. This study provides an independent confirmation of the scale-dependent heterogeneity of ventilation described by previous FMS aerosol studies of ventilation heterogeneity.

Animals↗
PubMed2002

pH Heterogeneity of human and rabbit atherosclerotic plaques; a new insight into detection of vulnerable plaque.

BACKGROUND: Atherosclerotic plaques are heterogeneous with respect to inflammation, calcification, vascularity, oxygen, and temperature. We hypothesized that they also vary in pH and measured pH in living human carotid endarterectomized atherosclerotic plaques (CEA), Watanabe heritable hyperlipidemic (WHHL) rabbit aortas and human umbilical arteries (HUA). METHODS AND RESULTS: We measured pH of CEA of 48 patients, nine WHHL rabbit aortas and 11 HUA specimens (as controls) using a glass type microelectrode mounted on a micromanipulator in a 37 degrees C incubator. We also used single emission and also dual emission fluorescence ratio imaging microscopy employing pH-sensitive probes to confirm pH heterogeneity. Mean pH measured at 415 points of CEA was 7.55+/-0.32; at 275 points of WHHL rabbit aortas it was 7.40+/-0.43; and in 233 points of HUA it was 7.24+/-0.1. In CEA, pH of yellow (lipid-rich) areas was significantly lower than pH in calcified areas (7.15+/-0.01 vs. 7.73+/-0.01, P<0.0001). The coefficients of variation (heterogeneity) of pH in CEA, WHHL rabbit aortas, and HUA were 0.038+/-0.010, 0.039+/-0.007, and 0.009+/-0.003, respectively (P=0.0001). Fluorescence microscopic imaging confirmed pH heterogeneity in both humans and rabbits but not in HUA. In a variance components analysis 82% of the heterogeneity was due to the within-plaque variation and 2% was attributable to between-plaque variation. CONCLUSIONS: Our findings support the hypothesis of pH heterogeneity in plaques, and suggest a possible role for detecting low pH in the detection of plaque vulnerability. The source of pH heterogeneity particularly acidic pH, its impact on the stability of plaques and its potential clinical utility in locating vulnerable plaques remain to be evaluated.

Animals↗
PubMed2003

Characterization of hepatic parenchymous perfusion heterogeneity and regional flow kinetics after porcine liver transplantation.

BACKGROUND: In clinical practice, a heterogeneous hepatic tissue microperfusion (MC) is often observed after liver resection or transplantation (LTx). Nevertheless this hepatic perfusion phenomenon has never been really quantified with respect to its anatomic distribution and time course in detail. The aim of the study was to characterize liver perfusion heterogeneity and local flow kinetics both in the physiological situation and after standardized ischemia and reperfusion using an established model of porcine LTx. METHODS: Regional distribution of hepatic MC in healthy native porcine livers (control group; n = 8) was analyzed in comparison with data derived 60 min, 24 h, and 72 h after porcine LTx (transplantation group; n = 8 each subgroup; cold ischemia time: 5.7 +/- 1.2 h). MC was measured with implanted thermal diffusion electrodes (TD). Flow in hepatic artery and portal vein was continuously detected by ultrasonic probes. For standardization of measurement localizations, porcine liver lobes were divided anatomically into three horizontal layers (cranial, medial, caudal), defining 12 distinct hepatic measurement regions. RESULTS: In the control group, a homogenous liver MC with a mean flow of 81.6 +/- 13.9 ml/100 g/min was detected in all regions. After LTx, a marked MC heterogeneity was noted 60 min after reperfusion. MC rehomogenization was first documented within horizontal liver planes 24 h later. Comparison of MC between planes showed persisting heterogeneity with a significant intralober drop of mean MC in the cranio-caudal direction. Complete MC rehomogenization (both between horizontal and vertical liver planes) was detected 72 h after reperfusion. Still, an overall reduction of mean liver perfusion by about 15% was existent. CONCLUSIONS: A homogenous tissue perfusion was observed in healthy porcine livers. In contrast, marked heterogeneity of hepatic MC was detected after LTx. Heterogeneity presents as a very dynamic and temporary phenomenon. Early horizontal flow rehomogenization and reconstitution of normal blood flow, particularly primarily in the cranial liver layers, appear to be characteristic features during early flow reconstitution after postischemic reperfusion. Due to heterogeneity and time-dependent flow dynamics, measurement of MC volumes at single hepatic regions may not always allow a valid characterization of liver perfusion quality during the first 24 h after postischemic reperfusion.

Animals↗
PubMed2001

Variable-density groundwater flow and solute transport in heterogeneous porous media: approaches, resolutions and future challenges.

In certain hydrogeological situations, fluid density variations occur because of changes in the solute or colloidal concentration, temperature, and pressure of the groundwater. These include seawater intrusion, high-level radioactive waste disposal, groundwater contamination, and geothermal energy production. When the density of the invading fluid is greater than that of the ambient one, density-driven free convection can lead to transport of heat and solutes over larger spatial scales and significantly shorter time scales than compared with diffusion alone. Beginning with the work of Lord Rayleigh in 1916, thermal and solute instabilities in homogeneous media have been studied in detail for almost a century. Recently, these theoretical and experimental studies have been applied in the study of groundwater phenomena, where the assumptions of homogeneity and isotropy rarely, if ever, apply. The critical role that heterogeneity plays in the onset as well as the growth and/or decay of convective motion is discussed by way of a review of pertinent literature and numerical simulations performed using a variable-density flow and solute transport numerical code. Different styles of heterogeneity are considered and range from continuously "trending" heterogeneity (sinusoidal and stochastic permeability distributions) to discretely fractured geologic media. Results indicate that both the onset of instabilities and their subsequent growth and decay are intimately related to the structure and variance of the permeability field. While disordered heterogeneity tends to dissipate convection through dispersive mixing, an ordered heterogeneity (e.g., sets of vertical fractures) allows instabilities to propagate at modest combinations of fracture aperture and separation distances. Despite a clearer understanding of the processes that control the onset and propagation of instabilities, resultant plume patterns and their migration rates and pathways do not appear amenable to prediction at present. The classical Rayleigh number used to predict the occurrence of instabilities fails, in most cases, when heterogeneous conditions prevail. The incorporation of key characteristics of the heterogeneous permeability field into relevant stability criteria and numerical models remains a challenge for future research.

Chemical Phenomena↗
PubMed2003

Socio-economic and demographic variation in health and in its measures: the issue of reporting heterogeneity.

True health state is an unobservable concept. Researchers and practitioners now have access to a large variety of tools to measure the health state and health related quality of life by self-reports. Socio-demographic variation in these measures is usually interpreted as variation in health. However, building on several measures simultaneously (multiple indicators), true health might be better represented, so that socio-demographic variation in any indicator can be decomposed into variation in the estimated true health, and measure-specific variation, holding true health constant. The latter variation is referred to as "reporting heterogeneity". Using structural equations models, the paper provides an empirical assessment of reporting heterogeneity in three popular measures of health and health related quality of life: the number of chronic conditions (CHRON), the SF-36 instrument and the visual analogue rating scale. Considering a large array of socio-economic and demographic characteristics from an Israeli health survey, the results indicate the existence of age-related reporting heterogeneity in the CHRON; income-related heterogeneity in the rating scale measure; and age, sex, income, ethnic origin and religiosity-related reporting heterogeneity in the SF-36 tool, in particular in its mental component scale. The main implication of reporting heterogeneity on the common uses of self-reported health measures is the need to adjust the measures not only for the determinants of health but also for the determinants of reporting heterogeneity.

Chronic Disease↗
PubMed1999

Time factors in larynx tumor radiotherapy: lag times and intertumor heterogeneity in clinical datasets from four centers.

PURPOSE: To use the time-dependent linear-quadratic model, both in the standard form and in a form modified to incorporate intertumor heterogeneity, in a reanalysis of 4 datasets for larynx tumor control, to provide more representative and direct estimates of the lag period, the time factor (lambda/alpha), and the clonogen population inactivation dose ([lnk]/alpha). METHODS AND MATERIALS: The data comprised 2,225 patients treated in Edinburgh (UK), Glasgow (UK), Manchester (UK), or Toronto (Canada), with tumor control assessed after at least 2 years. Heterogeneity in each series was taken into account using the coefficient of variation (CV) of the clonogen radiosensitivity (alpha). Maximum likelihood techniques were used to provide best estimates of the parameters, and also direct estimation of the more stable parameter ratios of interest. RESULTS: The use of different heterogeneity factors for the different series allowed common dose/time parameters to be fitted across all four series in a way not possible using the standard model, enabling the inherent effect of heterogeneity in flattening dose-response curves and in reducing time factors to be separated from the underlying more-representative values. Radiosensitivity CVs were calculated to be 30% (Edinburgh), 36% (Glasgow), 40% (Manchester), and 71% (Toronto). The lag phase was 32 days (95% CL 20-38 days) which was longer than the value of 23 days (11-36 days) deduced using the standard model without the heterogeneity parameter. The time factor was 1.2 (0.8-2.2) Gy/day, again greater than the value of 0.80 (0.54-1.41) Gy/day derived using the standard model. Similar larger time factors and longer lag periods could be reproduced using the standard model either by using a parameterization based on parameter ratios, or by omitting the discordant Toronto data and refitting just the data from the three UK centers. CONCLUSION: It was concluded that the heterogeneity model provides a better representation of the time factor for tumor control when data are analyzed comprising different stages of disease treated at different centers. The model allows different amounts of heterogeneity in different series, which tend to flatten dose-responses curves and reduce time factors, to be taken in to account. Also, direct maximum likelihood estimates can be made of the lag period, the time factor (lambda/alpha), and the fractionation sensitivity (beta/alpha), as well as the clonogen population inactivation dose (lnk)/alpha. Values of these parameter ratios are more robust and stable than the individual parameter values. The results of the present analysis using a total of 2,225 patients from four centers indicate that the average lag period may be somewhat longer and the average time factor somewhat greater (and the 95% confidence limits of the time factor exclude previous estimates), than the values deduced previously using simpler models and more diverse multi-center datasets.

Dose-Response Relationship, Radiation↗
PubMed2001

Microvascular permeability to macromolecules in human melanoma xenografts assessed by contrast-enhanced MRI--intertumor and intratumor heterogeneity.

Several novel macromolecular anticancer agents have fallen short of expectations owing to inadequate and heterogeneous uptake in tumor tissue. In the present work, contrast-enhanced magnetic resonance imaging was used to measure the intertumor and intratumor heterogeneity in the effective microvascular permeability constant, P(eff), of an 82 kDa macromolecule in an attempt to identify possible causes of the inadequate and heterogeneous uptake. Tumors of two human melanoma xenograft lines (A-07 and R-18) were included in the study. Human serum albumin with 30 gadopentetate dimeglumine units per molecule was used as a model molecule of macromolecular therapeutic agents. P(eff) was measured in manually defined regions of interest, corresponding to a whole tumor (ROI(WHOLE)) or to subregions of a tumor (ROIs(SUB)). The P(eff) of the ROI(WHOLE) of individual tumors ranged from 1.4 x 10(-7) cm/s to 2.8 x 10(-7) cm/s (A-07) and from 7.7 x 10(-8) cm/s to 3.2 x 10(-7) cm/s (R-18). P(eff) decreased with increasing tumor volume in R-18, but was independent of tumor volume in A-07. The intratumor heterogeneity in P(eff) exceeded the intertumor heterogeneity in both tumor lines. Some ROIs(SUB) showed P(eff) values that were similar to or slightly higher than the P(eff) values of albumin in normal tissues. Our observations suggest that inadequate and heterogeneous uptake of macromolecular therapeutic agents in tumor tissue is partly a result of low and heterogeneous microvascular permeability. However, the microvascular wall is probably not the major transport barrier to macromolecules in A-07 and R-18 tumors, as most individual tumors and individual tumor subregions showed high P(eff) values, i.e. values that are up to 10-fold higher than those of normal tissues.

Animals↗
PubMedDate not supplied

Effects of ammonia and glucosamine on the heterogeneity of erythropoietin glycoforms.

Recombinant human erythropoietin (EPO) is a glycoprotein produced as a therapeutic agent from mammalian cell cultures for the treatment of anemia associated with severe kidney damage. The EPO structure has a high glycan content which is essential for bioactivity but shows considerable molecular heterogeneity. The cell culture conditions that affect the heterogeneity of the glycoforms of EPO are not well understood. However, the accumulation of ammonia in culture is one factor that has been associated with an enhanced heterogeneity of glycoforms. In this report we investigate the metabolic perturbations associated with ammonia and glucosamine that may give rise to an altered pattern of EPO glycosylation. Recombinant human erythropoietin was synthesized in serum-free cultures of transfected Chinese hamster ovary (CHO) cells. The molecular heterogeneity of erythropoietin was increased by supplementation of cultures with either ammonia or glucosamine. The enhanced molecular heterogeneity was shown to be due to variable glycosylation that resulted in EPO with an enhanced molecular weight and isoelectric point range. Enzymatic removal of the glycan moiety of EPO in all cases resulted in a single molecular form with a molecular weight of 18 000, which corresponded to non-glycosylated EPO. The variable glycosylation was consistent with reduced sialylation and antennarity of the carbohydrate structures present on the three N-linked sites of EPO. In the presence of ammonia (>30 mM) the proportion of tetrasialylated and tetraantennary glycan structures were reduced by 73% and 57%, respectively, as determined by HPLC analysis. Such changes were also observed, although to a lesser extent (41% and 37%), by an increase in the glucosamine concentration (>10 mM) in the medium. The enhanced heterogeneity of the glycan structures coincided with a significant increase in the intracellular UDP-N-acetylhexosamine (UDP-GNAc) pool. The measured UDP-GNAc level was up to 2 orders of magnitude higher in the presence of either glucosamine or ammonia. However, the changes in the glycosylation profiles induced by either glucosamine or ammonia were significantly different even at the same intracellular UDP-GNAc concentration. This suggests that the enhanced EPO heterogeneity could not be mediated solely by the increased UDP-GNAc level. Glucosamine (but not ammonia) was shown to cause significant inhibition of glucose transport into the cells, which could induce a different pattern of primary metabolism.

Ammonia↗
PubMed1985

Heterogeneous expression of cell-surface antigens in normal epithelia and their tumours, revealed by monoclonal antibodies.

Most monoclonal antibodies that have been raised to human epithelial tumours bind to only some of the cells in a tumour, showing that tumour cells are very heterogeneous in their expression of antigens. Normal epithelia show the same heterogeneity of antigen expression, as also do cell lines and clones of epithelial cells in culture. It is not related to the mitotic cell cycle. Many, probably most of the antigenic determinants to which the antibodies bind are carbohydrate structures. It is not clear whether variations in antigen expression reflect variations in the differentiated state of the cells or merely variations in the carbohydrate structures on otherwise identical cells, nor is ir clear whether antibodies could be made that bind to all tumour cells by avoiding antibodies to carbohydrate structures. The normal and apparently reversible nature of this heterogeneity of antigen expression conflicts with conventional views that heterogeneity among cells of a tumour is due to permanent genetic change. The heterogeneity within normal clones suggests that cloning is not an adequate way to study heterogeneity in tumour cells. The implications of heterogeneous expression of antigens within tumours for therapeutic and diagnostic application of antibodies are discussed.

Antibodies, Monoclonal↗