Comprehensive transcriptomic analysis of cell lines as models of primary tumors across 22 tumor types.

Cancer cell lines are a cornerstone of cancer research but previous studies have shown that not all cell lines are equal in their ability to model primary tumors. Here we present a comprehensive pan-cancer analysis utilizing transcriptomic profiles from The Cancer Genome Atlas and the Cancer Cell Line Encyclopedia to evaluate cell lines as models of primary tumors across 22 tumor types. We perform correlation analysis and gene set enrichment analysis to understand the differences between cell lines and primary tumors. Additionally, we classify cell lines into tumor subtypes in 9 tumor types. We present our pancreatic cancer results as a case study and find that the commonly used cell line MIA PaCa-2 is transcriptionally unrepresentative of primary pancreatic adenocarcinomas. Lastly, we propose a new cell line panel, the TCGA-110-CL, for pan-cancer studies. This study provides a resource to help researchers select more representative cell line models

Accurate masses and radii of normal stars: modern results and applications

This paper presents and discusses a critical compilation of accurate, fundamental determinations of stellar masses and radii. We have identified 95 detached binary systems containing 190 stars (94 eclipsing systems, and alpha Centauri) that satisfy our criterion that the mass and radius of both stars be known to 3% or better. To these we add interstellar reddening, effective temperature, metal abundance, rotational velocity and apsidal motion determinations when available, and we compute a number of other physical parameters, notably luminosity and distance. We discuss the use of this information for testing models of stellar evolution. The amount and quality of the data also allow us to analyse the tidal evolution of the systems in considerable depth, testing prescriptions of rotational synchronisation and orbital circularisation in greater detail than possible before. The new data also enable us to derive empirical calibrations of M and R for single (post-) main-sequence stars above 0.6 M(Sun). Simple, polynomial functions of T(eff), log g and [Fe/H] yield M and R with errors of 6% and 3%, respectively. Excellent agreement is found with independent determinations for host stars of transiting extrasolar planets, and good agreement with determinations of M and R from stellar models as constrained by trigonometric parallaxes and spectroscopic values of T(eff) and [Fe/H]. Finally, we list a set of 23 interferometric binaries with masses known to better than 3%, but without fundamental radius determinations (except alpha Aur). We discuss the prospects for improving these and other stellar parameters in the near future.Comment: 56 pages including figures and tables. To appear in The Astronomy and Astrophysics Review. Ascii versions of the tables will appear in the online version of the articl

Predictability of evolutionary trajectories in fitness landscapes

Experimental studies on enzyme evolution show that only a small fraction of all possible mutation trajectories are accessible to evolution. However, these experiments deal with individual enzymes and explore a tiny part of the fitness landscape. We report an exhaustive analysis of fitness landscapes constructed with an off-lattice model of protein folding where fitness is equated with robustness to misfolding. This model mimics the essential features of the interactions between amino acids, is consistent with the key paradigms of protein folding and reproduces the universal distribution of evolutionary rates among orthologous proteins. We introduce mean path divergence as a quantitative measure of the degree to which the starting and ending points determine the path of evolution in fitness landscapes. Global measures of landscape roughness are good predictors of path divergence in all studied landscapes: the mean path divergence is greater in smooth landscapes than in rough ones. The model-derived and experimental landscapes are significantly smoother than random landscapes and resemble additive landscapes perturbed with moderate amounts of noise; thus, these landscapes are substantially robust to mutation. The model landscapes show a deficit of suboptimal peaks even compared with noisy additive landscapes with similar overall roughness. We suggest that smoothness and the substantial deficit of peaks in the fitness landscapes of protein evolution are fundamental consequences of the physics of protein folding.Comment: 14 pages, 7 figure

Diel variations in cell division and biomass production of Emiliania huxleyi — Consequences for the calculation of physiological cell parameters

Cell division of the coccolithophore Emiliania huxleyi and other phytoplankton typically becomes entrained to diel light/dark cycles under laboratory conditions, with division occurring primarily during dark phases and production occurring during light phases. Under these conditions, increases in cell and biomass concentrations deviate from exponential functions on time scales < 24 h. These deviations lead to significant diel variations in common measurements of phytoplankton physiology such as cellular quotas of particulate organic and inorganic carbon (POC, PIC) and their production rates. Being time-dependent, only the temporal mean of the various values during the day are comparable between experiments. Deviations from exponential growth furthermore imply that increases in cell and biomass concentrations cannot be expressed by the daily growth rate μ24 h (typically determined from daily increments in cell concentrations). Consequently, conventional calculations of production as the product of a cellular quota (e.g., POC quota) and μ24 h are mathematically incorrect. To account for this, we here describe short-term changes in cell and biomass concentrations of fast -dividing, dilute-batch cultures of E. huxleyi grown under a diel light/dark cycle using linear regression. Based on the derived models, we present calculations for daily means of cellular quotas and production rates. Conventional (time-specific) measurements of cellular quotas and production differ from daily means by up to 65% in our example and, under some circumstances, cause false “effects” of treatments. Intending to reduce errors in ecophysiological studies, we recommend determining daily means—mathematically or by adjusting the experimental setup or sampling times appropriately

Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer

Pre-clinical and retrospective studies of patients using statins to reduce plasma cholesterol have suggested that statins may be useful to treat cancer. However, prospective clinical trials have yet to demonstrate significant efficacy. We have previously shown that this is in part because a hydrophobic statin with a long half-life is necessary. Pitavastatin, the only statin with this profile, has not undergone clinical evaluation in oncology. The target of pitavastatin, hydroxymethylglutarate coenzyme-A reductase (HMGCR), was found to be over-expressed in all ovarian cancer cell lines examined and upregulated by mutated TP53, a gene commonly altered in ovarian cancer. Pitavastatin-induced apoptosis was blocked by geranylgeraniol and mevalonate, products of the HMGCR pathway, confirming that pitavastatin causes cell death through inhibition of HMGCR. Solvent extracts of human and mouse food were also able to block pitavastatin-induced apoptosis, suggesting diet might influence the outcome of clinical trials. When nude mice were maintained on a diet lacking geranylgeraniol, oral pitavastatin caused regression of Ovcar-4 tumour xenografts. However, when the animal diet was supplemented with geranylgeraniol, pitavastatin failed to prevent tumour growth. This suggests that a diet containing geranylgeraniol can limit the anti-tumour activity of pitavastatin and diet should be controlled in clinical trials of statins

PCV13 induced IgG responses in serum associate with serotype-specific IgG in the lung

Pneumococcal conjugate vaccine efficacy is lower for non-invasive pneumonia than invasive disease. In this study, participants were vaccinated with PCV13 or HepA (control). Bronchoalveolar lavage samples were taken between 2-6 months and serum at 4- and 7-weeks post vaccination. In the lung, anti-capsular IgG levels were higher in the PCV13 group compared to control for all serotypes, except 3 and 6B. Systemically, IgG levels were elevated in the PCV group at 4-weeks for all serotypes, except 3. IgG in BAL and serum positively correlated for nearly all serotypes. PCV13 shows poor immunogenicity to serotype 3, implying lack of protective efficacy. Clinical trial registration with ISRCTN: 4534043

Genomes in turmoil: quantification of genome dynamics in prokaryote supergenomes

Background: Genomes of bacteria and archaea (collectively, prokaryotes) appear to exist in incessant flux, expanding via horizontal gene transfer and gene duplication, and contracting via gene loss. However, the actual rates of genome dynamics and relative contributions of different types of event across the diversity of prokaryotes are largely unknown, as are the sizes of microbial supergenomes, i.e. pools of genes that are accessible to the given microbial species.Results: We performed a comprehensive analysis of the genome dynamics in 35 groups (34 bacterial and one archaeal) of closely related microbial genomes using a phylogenetic birth-and-death maximum likelihood model to quantify the rates of gene family gain and loss, as well as expansion and reduction. The results show that loss of gene families dominates the evolution of prokaryotes, occurring at approximately three times the rate of gain. The rates of gene family expansion and reduction are typically seven and twenty times less than the gain and loss rates, respectively. Thus, the prevailing mode of evolution in bacteria and archaea is genome contraction, which is partially compensated by the gain of new gene families via horizontal gene transfer. However, the rates of gene family gain, loss, expansion and reduction vary within wide ranges, with the most stable genomes showing rates about 25 times lower than the most dynamic genomes. For many groups, the supergenome estimated from the fraction of repetitive gene family gains includes about tenfold more gene families than the typical genome in the group although some groups appear to have vast, 'open' supergenomes.Conclusions: Reconstruction of evolution for groups of closely related bacteria and archaea reveals an extremely rapid and highly variable flux of genes in evolving microbial genomes, demonstrates that extensive gene loss and horizontal gene transfer leading to innovation are the two dominant evolutionary processes, and yields robust estimates of the supergenome size

Human cooperation in groups: variation begets variation

Many experiments on human cooperation have revealed that individuals differ systematically in their tendency to cooperate with others. It has also been shown that individuals condition their behaviour on the overall cooperation level of their peers. Yet, little is known about how individuals respond to heterogeneity in cooperativeness in their neighbourhood. Here, we present an experimental study investigating whether and how people respond to heterogeneous behaviour in a public goods game. We find that a large majority of subjects does respond to heterogeneity in their group, but they respond in quite different ways. Most subjects contribute less to the public good when the contributions of their peers are more heterogeneous, but a substantial fraction of individuals consistently contributes more in this case. In addition, we find that individuals that respond positively to heterogeneity have a higher general cooperation tendency. The finding that social responsiveness occurs in different forms and is correlated with cooperativeness may have important implications for the outcome of cooperative interactions

Spontaneous ventral urethral fistula in a young diabetic man: a case report

We present the first case reported in the medical literature of a patient with a spontaneous ventral urethral fistula accompanied by severe infection due to diabetes mellitus. A 34-year-old man with poor controlled adult-onset diabetes mellitus was admitted to our hospital with a large subcutaneous abscess involving the complete penis, scrotum and perineum. The patient did not report any history of any penile trauma or local infection but has experienced transient swelling of the perineal region following urination. Initial surgical treatment consisted of surgical debridement of necrotic tissue. At this time reconstructive surgery was impossible and a suprapubic cystostomy was performed. After 4 months of suprapubic urinary diversion the urethral fistula resolved and function of external genitalia was reestablished. In a follow-up period of 40 months no recurrence occurred. Spontaneous diabetes-associated ventral urethral fistulas are extremely rare and we are not aware of any other published case report

What's in a name; Genetic structure in Solanum section Petota studied using population-genetic tools

Background - The taxonomy and systematic relationships among species of Solanum section Petota are complicated and the section seems overclassified. Many of the presumed (sub)species from South America are very similar and they are able to exchange genetic material. We applied a population genetic approach to evaluate support for subgroups within this material, using AFLP data. Our approach is based on the following assumptions: (i) accessions that may exchange genetic material can be analyzed as if they are part of one gene pool, and (ii) genetic differentiation among species is expected to be higher than within species. Results - A dataset of 566 South-American accessions (encompassing 89 species and subspecies) was analyzed in two steps. First, with the program STRUCTURE 2.2 in an 'unsupervised' procedure, individual accessions were assigned to inferred clusters based on genetic similarity. The results showed that the South American members of section Petota could be arranged in 16 clusters of various size and composition. Next, the accessions within the clusters were grouped by maximizing the partitioning of genetic diversity among subgroups (i.e., maximizing Fst values) for all available individuals of the accessions (2767 genotypes). This two-step approach produced an optimal partitioning into 44 groups. Some of the species clustered as genetically distinct groups, either on their own, or combined with one or more other species. However, accessions of other species were distributed over more than one cluster, and did not form genetically distinct units. Conclusions - We could not find any support for 43 species (almost half of our dataset). For 28 species some level of support could be found varying from good to weak. For 18 species no conclusions could be drawn as the number of accessions included in our dataset was too low. These molecular data should be combined with data from morphological surveys, with geographical distribution data, and with information from crossing experiments to identify natural units at the species level. However, the data do indicate which taxa or combinations of taxa are clearly supported by a distinct set of molecular marker data, leaving other taxa unsupported. Therefore, the approach taken provides a general method to evaluate the taxonomic system in any species complex for which molecular data are available