Designing optimal allocations for cancer screening using queuing network models

Cancer is one of the leading causes of death, but mortality can be reduced by detecting tumors earlier so that treatment is initiated at a less aggressive stage. The tradeoff between costs associated with screening and its benefit makes the decision of whom to screen and when a challenge. To enable comparisons across screening strategies for any cancer type, we demonstrate a mathematical modeling platform based on the theory of queuing networks designed for quantifying the benefits of screening strategies. Our methodology can be used to design optimal screening protocols and to estimate their benefits for specific patient populations. Our method is amenable to exact analysis, thus circumventing the need for simulations, and is capable of exactly quantifying outcomes given variability in the age of diagnosis, rate of progression, and screening sensitivity and intervention outcomes. We demonstrate the power of this methodology by applying it to data from the Surveillance, Epidemiology and End Results (SEER) program. Our approach estimates the benefits that various novel screening programs would confer to different patient populations, thus enabling us to formulate an optimal screening allocation and quantify its potential effects for any cancer type and intervention.     

Quantifying individual‐ and community‐level effects of competition using experimentally‐determined null species pools

Abstract. The effects of competition on individual fitness and species diversity were investigated in a first‐year old field by comparing the natural community to an experimentally‐determined null community. The species pool for the null community was estimated from low‐density plots, and hypothetical sample plots in the null community were constructed by random sampling from the species pool. Individual plants were larger in low‐density plots than control plots, indicating that competition reduced individual fitness. Competition appeared to reduce diversity in half the plots (i.e. species richness and diversity were lower than in hypothetical null community plots with the same number of individuals), but did not affect diversity in the other plots. However, the reduction in diversity could be explained as an artifact caused by spatial aggregation in control plots. The magnitude of the effects of competition on diversity did not change with plot density, and no species consistently increased or decreased in relative abundance as plot density increased. We conclude that competition had no effect on diversity in this community, despite the strong effect on individual growth.     

Pericellular coat of chick embryo chondrocytes: structural role of hyaluronate

Chondrocytes produce large pericellular coats in vitro that can be visualized by the exclusion of particles, e.g., fixed erythrocytes, and that are removed by treatment with Streptomyces hyaluronidase, which is specific for hyaluronate. In this study, we examined the kinetics of formation of these coats and the relationship of hyaluronate and proteoglycan to coat structure. Chondrocytes were isolated from chick tibia cartilage by collagenase-trypsin digestion and were characterized by their morphology and by their synthesis of both type II collagen and high molecular weight proteoglycans. The degree of spreading of the chondrocytes and the size of the coats were quantitated at various times subsequent to seeding by tracing phase-contrast photomicrographs of the cultures. After seeding, the chondrocytes attached themselves to the tissue culture dish and exhibited coats within 4 h. The coats reached a maximum size after 3-4 d and subsequently decreased over the next 2-3 d. Subcultured chondrocytes produced a large coat only if passaged before 4 d. Both primary and first passage cells, with or without coats, produced type II collagen but not type I collagen as determined by enzyme-linked immunosorbent assay. Treatment with Streptomyces hyaluronidase (1.0 mU/ml, 15 min), which completely removed the coat, released 58% of the chondroitin sulfate but only 9% of the proteins associated with the cell surface. The proteins released by hyaluronidase were not digestible by bacterial collagenase. Monensin and cycloheximide (0.01-10 microM, 48 h) caused a dose-dependent decrease in coat size that was linearly correlated to synthesis of cell surface hyaluronate (r = 0.98) but not chondroitin sulfate (r = 0.2). We conclude that the coat surrounding chondrocytes is dependent on hyaluronate for its structure and that hyaluronate retains a large proportion of the proteoglycan in the coat.     

A first attempt to bring computational biology into advanced high school biology classrooms

Computer science has become ubiquitous in many areas of biological research, yet most high school and even college students are unaware of this. As a result, many college biology majors graduate without adequate computational skills for contemporary fields of biology. The absence of a computational element in secondary school biology classrooms is of growing concern to the computational biology community and biology teachers who would like to acquaint their students with updated approaches in the discipline. We present a first attempt to correct this absence by introducing a computational biology element to teach genetic evolution into advanced biology classes in two local high schools. Our primary goal was to show students how computation is used in biology and why a basic understanding of computation is necessary for research in many fields of biology. This curriculum is intended to be taught by a computational biologist who has worked with a high school advanced biology teacher to adapt the unit for his/her classroom, but a motivated high school teacher comfortable with mathematics and computing may be able to teach this alone. In this paper, we present our curriculum, which takes into consideration the constraints of the required curriculum, and discuss our experiences teaching it. We describe the successes and challenges we encountered while bringing this unit to high school students, discuss how we addressed these challenges, and make suggestions for future versions of this curriculum.We believe that our curriculum can be a valuable seed for further development of computational activities aimed at high school biology students. Further, our experiences may be of value to others teaching computational biology at this level. Our curriculum can be obtained at http://ecsite.cs.colorado.edu/?page_id=149#biology or by contacting the authors.     

Flow cytometry isolation and improved visualization of sorted mouse chromosomes. Purification of chromosomes X and ISO-1 from cell lines with Robertsonian translocations

While analysis and sorting of human chromosomes by flow cytometry has been widely used, isolation of a pure mouse chromosome remains very difficult, since most murine chromosomes are quite similar in size. To overcome this problem, we have analysed mouse cell lines having either Robertsonian translocations or isochromosomes. The resulting metacentric chromosomes are very different in size and in morphology from normal mouse acrocentric chromosomes. These characteristics have been analysed by computer-monitored flow cytometry, facilitated by improvements in the chromosome extraction procedure. Signals characteristic of the iso-lq chromosome in cell line PCC4 azaR1, and of the normal X chromosome in the mouse strain 22CD have thus been obtained. These chromosomes have been sorted and can be easily recognized by fluorescence microscopy when collected onto serum-albumin-coated microscope slides. The technical modifications made, coupled with the existence of a great diversity of metacentric chromosomes resulting from Robertsonian translocations, should allow the purification of a number of different mouse chromosomes.     

Biochemical Aspects of Fumaric Acid Accumulation by Rhizopus arrhizus

The accumulation and excretion of fumaric acid, and to a lesser extent malic and succinic acids, by Rhizopus arrhizus occurs under aerobic conditions in a high-glucose medium containing a limiting amount of nitrogen and a neutralizing agent (CaCO₃). An overall four-carbon dicarboxylic acid molar yield of up to 145% (moles of acid produced per mole of glucose utilized) is obtained after incubation for 4 to 5 days. Evidence is presented that fumarate is synthesized from pyruvate via a carboxylation reaction yielding oxaloacetate, which is then converted to malate and further on to fumarate via the reductive reactions of the tricarboxylic acid cycle. The possible formation of fumarate from the normal (oxidative) operation of the tricarboxylic acid cycle was not excluded by the data. Yield, ¹³C nuclear magnetic resonance, and enzymatic activity studies were carried out in a strain of R. arrhizus which produces high levels of fumarate from glucose and carbonate. The observed high fumarate molar yield (greater than 100%) can therefore be explained in terms of the carboxylation of pyruvate and the operation of the reductive reactions of the tricarboxylic acid cycle under aerobic conditions.