Tumor growth instability and the onset of invasion

Motivated by experimental observations, we develop a mathematical model of chemotactically directed tumor growth. We present an analytical study of the model as well as a numerical one. The mathematical analysis shows that: (i) tumor cell proliferation by itself cannot generate the invasive branching behaviour observed experimentally, (ii) heterotype chemotaxis provides an instability mechanism that leads to the onset of tumor invasion and (iii) homotype chemotaxis does not provide such an instability mechanism but enhances the mean speed of the tumor surface. The numerical results not only support the assumptions needed to perform the mathematical analysis but they also provide evidence of (i), (ii) and (iii). Finally, both the analytical study and the numerical work agree with the experimental phenomena.Comment: 12 pages, 8 figures, revtex

When the optimal is not the best: parameter estimation in complex biological models

Background: The vast computational resources that became available during the past decade enabled the development and simulation of increasingly complex mathematical models of cancer growth. These models typically involve many free parameters whose determination is a substantial obstacle to model development. Direct measurement of biochemical parameters in vivo is often difficult and sometimes impracticable, while fitting them under data-poor conditions may result in biologically implausible values. Results: We discuss different methodological approaches to estimate parameters in complex biological models. We make use of the high computational power of the Blue Gene technology to perform an extensive study of the parameter space in a model of avascular tumor growth. We explicitly show that the landscape of the cost function used to optimize the model to the data has a very rugged surface in parameter space. This cost function has many local minima with unrealistic solutions, including the global minimum corresponding to the best fit. Conclusions: The case studied in this paper shows one example in which model parameters that optimally fit the data are not necessarily the best ones from a biological point of view. To avoid force-fitting a model to a dataset, we propose that the best model parameters should be found by choosing, among suboptimal parameters, those that match criteria other than the ones used to fit the model. We also conclude that the model, data and optimization approach form a new complex system, and point to the need of a theory that addresses this problem more generally

An HST Search for Lyman Continuum Emission From Galaxies at z=1.1--1.4

If enough of their Lyman limit continuum escapes, star-forming galaxies could be significant contributors to the cosmic background of ionizing photons. To investigate this possibility, we obtained the first deep imaging in the far ultraviolet of eleven bright blue galaxies at intermediate redshift (z=1.1--1.4). NO Lyman continuum emission was detected. Sensitive, model-independent, upper limits of typically 2 x 10**-19 erg/sec/cm2/Ang were obtained for the ionizing flux escaping from these normal galaxies. This corresponds to lower limits on the observed ratio of 1500 to 700Ang flux of 150 up to 1000. Based on a wide range of stellar synthesis models, this suggests that less than 6%, down to less than 1%, of the available ionizing flux emitted by hot stars is escaping these galaxies. The magnitude of this spectral break at the Lyman l imit confirms that the basic premise of `Lyman break' searches for galaxies at high redshift can also be applied at intermediate redshifts. This implies that the integrated contribution of galaxies to the UV cosmic background at z around 1.2 is less than 15%, and may be less than 2%.Comment: 20 manuscript pages, which includes two tables and two figures. To be published in 1 December 2003 issue of The Astrophysical Journa

Measurements of scattering and absorption in mammalian cell suspensions

During the past several years a range of spectroscopies, including fluorescence and elastic-scatter spectroscopy, have been investigated for optically based detection of cancer and other tissue pathologies. Both elastic-scatter and fluorescence signals depend, in part, on scattering and absorption properties of the cells in the tissue. Therefore an understanding of the scattering and absorption properties of cells is a necessary prerequisite for understanding and developing these techniques. Cell suspensions provide a simple model with which to begin studying the absorption and scattering properties of cells. In this study we have made preliminary measurements of the scattering and absorption properties of suspensions of mouse mammary carcinoma cells (EMT6) over a broad wavelength range (380 nm to 800 nm)

The transcriptomic evolution of mammalian pregnancy:gene expression innovations in endometrial stromal fibroblasts

The endometrial stromal fibroblast (ESF) is a cell type present in the uterine lining of therian mammals. In the stem lineage of eutherian mammals, ESF acquired the ability to differentiate into decidual cells in order to allow embryo implantation. We call the latter cell type “neo-ESF” in contrast to “paleo-ESF” which is homologous to eutherian ESF but is not able to decidualize. In this study, we compare the transcriptomes of ESF from six therian species: Opossum (Monodelphis domestica; paleo-ESF), mink, rat, rabbit, human (all neo-ESF), and cow (secondarily nondecidualizing neo-ESF). We find evidence for strong stabilizing selection on transcriptome composition suggesting that the expression of approximately 5,600 genes is maintained by natural selection. The evolution of neo-ESF from paleo-ESF involved the following gene expression changes: Loss of expression of genes related to inflammation and immune response, lower expression of genes opposing tissue invasion, increased markers for proliferation as well as the recruitment of FOXM1, a key gene transiently expressed during decidualization. Signaling pathways also evolve rapidly and continue to evolve within eutherian lineages. In the bovine lineage, where invasiveness and decidualization were secondarily lost, we see a re-expression of genes found in opossum, most prominently WISP2, and a loss of gene expression related to angiogenesis. The data from this and previous studies support a scenario, where the proinflammatory paleo-ESF was reprogrammed to express anti-inflammatory genes in response to the inflammatory stimulus coming from the implanting conceptus and thus paving the way for extended, trans-cyclic gestation

Prognostic factors for tumour response, progression-free survival and toxicity in metastatic colorectal cancer patients given irinotecan (CPT-11) as second-line chemotherapy after 5FU failure

Our purpose was to determine, in patients with metastatic colorectal carcinoma treated with irinotecan single-agent after 5-FU failure, the most significant predictive parameters for tumour response, progression-free survival and toxicity. Between October 1992 and April 1995, 455 patients with 5-FU resistant metastatic colorectal carcinoma entered four consecutive phase II trials. The first two studies assessed tumour response, the other two were randomized studies which assessed the efficacy of racecadotril to prevent irinotecan-induced diarrhoea. Due to homogeneous main eligibility criterias, data from those studies could be pooled for statistical analysis. Potential clinical and biological predictive factors (PF) for toxicity, tumour growth control, e.g. response or stabilization and progression-free survival (PFS), were studied in multivariate analysis. 363 patients were evaluable for response, 432 were evaluable for PFS, 368 for neutropenia and 416 for delayed diarrhoea, respectively. Normal baseline haemoglobin level (Hb), time since diagnosis of colorectal carcinoma, grade 3 or 4 neutropenia or diarrhoea at first cycle and a low number of organs involved were the most PF for tumour growth control (P< 0.05). Significant prognostic variables for PFS were WHO Performance Status, liver and lymph-node involvement, time since diagnosis, age and CEA value (P≤ 0.02). Six groups of patients based on the number of unfavourable prognostic factors are presented. Baseline bilirubin, haemoglobin level, number of organs involved and time from diagnosis were PF for neutropenia; PS, serum creatinine, leukocyte count, time from 5-FU progression and prior abdominopelvic irradiation were PF for delayed diarrhoea (P≤ 0.05). These PF should help clinicians to anticipate for a given patient the probability to observe a response/stabilization or a toxicity. These results should also be prospectively confirmed in ongoing or future trials using irinotecan, both as a single agent and in combination with other drugs. © 2000 Cancer Research Campaig

Massive stars and the energy balance of the interstellar medium. II. The 35 solar mass star and a solution to the "missing wind problem"

We continue our numerical analysis of the morphological and energetic influence of massive stars on their ambient interstellar medium for a 35 solar mass star that evolves from the main sequence through red supergiant and Wolf-Rayet phases, until it ultimately explodes as a supernova. We find that structure formation in the circumstellar gas during the early main-sequence evolution occurs as in the 60 solar mass case but is much less pronounced because of the lower mechanical wind luminosity of the star. Since on the other hand the shell-like structure of the HII region is largely preserved, effects that rely on this symmetry become more important. At the end of the stellar lifetime 1% of the energy released as Lyman continuum radiation and stellar wind has been transferred to the circumstellar gas. From this fraction 10% is kinetic energy of bulk motion, 36% is thermal energy, and the remaining 54% is ionization energy of hydrogen. The sweeping up of the slow red supergiant wind by the fast Wolf-Rayet wind produces remarkable morphological structures and emission signatures, which are compared with existing observations of the Wolf-Rayet bubble S308. Our model reproduces the correct order of magnitude of observed X-ray luminosity, the temperature of the emitting plasma as well as the limb brightening of the intensity profile. This is remarkable, because current analytical and numerical models of Wolf-Rayet bubbles fail to consistently explain these features. A key result is that almost the entire X-ray emission in this stage comes from the shell of red supergiant wind swept up by the shocked Wolf-Rayet wind rather than from the shocked Wolf-Rayet wind itself as hitherto assumed and modeled. This offers a possible solution to what is called the ``missing wind problem'' of Wolf-Rayet bubbles.Comment: 52 pages, 20 figures, 2 tables, accepted for publication in the Astrophysical Journa

Ranking ligand affinity for the DNA minor groove by experiment and simulation

The structural and thermodynamic basis for the strength and selectivity of the interactions of minor-groove binders (MGBs) with DNA is not fully understood. In 2003 we reported the first example of a thiazole containing MGB that bound in a phase shifted pattern that spanned 6 base-pairs rather than the usual 4 (for tricyclic distamycin-like compounds). Since then, using DNA footprinting, nuclear magnetic resonance spectroscopy, isothermal titration calorimetry and molecular dynamics, we have established that the flanking bases around the central 4 being read by the ligand have subtle effects on recognition. We have investigated the effect of these flanking sequences on binding and the reasons for the differences and established a computational method to rank ligand affinity against varying DNA sequences

A phenomenological approach to the simulation of metabolism and proliferation dynamics of large tumour cell populations

A major goal of modern computational biology is to simulate the collective behaviour of large cell populations starting from the intricate web of molecular interactions occurring at the microscopic level. In this paper we describe a simplified model of cell metabolism, growth and proliferation, suitable for inclusion in a multicell simulator, now under development (Chignola R and Milotti E 2004 Physica A 338 261-6). Nutrients regulate the proliferation dynamics of tumor cells which adapt their behaviour to respond to changes in the biochemical composition of the environment. This modeling of nutrient metabolism and cell cycle at a mesoscopic scale level leads to a continuous flow of information between the two disparate spatiotemporal scales of molecular and cellular dynamics that can be simulated with modern computers and tested experimentally.Comment: 58 pages, 7 figures, 3 tables, pdf onl