Cancer Pharmacogenomics May Require Both Qualitative and Quantitative Approaches

Resistance to chemotherapy is a major cause of mortality in patients receiving treatment for most types of cancer, and overcoming drug resistance has become an important focus of current research. A major clinical challenge is the fact that most anticancer drugs have a narrow therapeutic range, that is, their effective dose is relatively close to that associated with substantial toxicity. Significant advances have been achieved in event-free survival of patients with many types of cancer (most dramatically childhood acute lymphoblastic leukemia, ALL) through a better understanding of the pathobiology of human cancers, the cellular mechanisms of cancer chemotherapy, and the determinants of inter-individual differences in drug effects and treatment response. It is anticipated that expanding our knowledge of these areas will lead to the development of new anticancer agents and to more effective use of existing cancer chemotherapy. Pharmacogenomics research aims to elucidate the genetics determinants of drug efficacy and toxicity. Results of recent studies indicate that both qualitative and quantitative genomic analyses may be required for precise pharmacogenomic characterization of some types of human cancer.     

Flexibility of Continental Navigation and Migration in European Mallards

The ontogeny of continent-wide navigation mechanisms of the individual organism, despite being crucial for the understanding of animal movement and migration, is still poorly understood. Several previous studies, mainly conducted on passerines, indicate that inexperienced, juvenile birds may not generally correct for displacement during fall migration. Waterbirds such as the mallard (Anas platyrhynchos, Linnaeus 1758) are more flexible in their migration behavior than most migratory songbirds, but previous experiments with waterbirds have not yet allowed clear conclusions about their navigation abilities. Here we tested whether immature mallard ducks correct for latitudinal displacement during fall migration within Europe. During two consecutive fall migration periods, we caught immature females on a stopover site in southeast Sweden, and translocated a group of them ca. 1,000 km to southern Germany. We followed the movements of the ducks via satellite GPS-tracking and observed their migration decisions during the fall and consecutive spring migration. The control animals released in Ottenby behaved as expected from banding recoveries: they continued migration during the winter and in spring returned to the population’s breeding grounds in the Baltics and Northwest Russia. Contrary to the control animals, the translocated mallards did not continue migration and stayed at Lake Constance. In spring, three types of movement tactics could be observed: 61.5% of the ducks (16 of 26) stayed around Lake Constance, 27% (7 of 26) migrated in a northerly direction towards Sweden and 11.5% of the individuals (3 of 26) headed east for ca. 1,000 km and then north. We suggest that young female mallards flexibly adjust their migration tactics and develop a navigational map that allows them to return to their natal breeding area.     

A Comparison of Qualitative and Quantitative Methodological Approaches to Characterizing the Dorsal Side of the Scapula in Hominoidea and Its Relationship to Locomotion

Hominoidea have adapted to various forms of locomotion, each of which has specific requirements that are reflected in the shape of the scapula. We compared several qualitative and quantitative methods for characterizing the dorsal side of the scapula to detect morphological differences that reflect the adaptations of the scapula to locomotor behaviors. Our sample included 55 specimens of Hominoidea, representing five genera, including Homo, focusing specifically on the relative sizes of the scapular supraspinous and infranspinous fossae. In addition, we weighed the supraspinatus and infraspinatus muscles of 23 of the specimens to examine the feasibility of extrapolating muscle characteristics from osteological data. Our findings confirmed that the five genera exhibit significant differences in the relative size of the supraspinous and the infraspinous fossae that are related to their forms of locomotion. The supraspinous fossa was relatively small in Homo and Pongo but large in Pan, Gorilla, and Hylobates. The analysis of muscle weights showed that a substantial amount of information about soft tissues is lost in osteological analyses, leading us to recommend caution when drawing conclusions regarding forms of locomotion based only on osteological analyses.     

Approaches to Recording Drug Allergies in Electronic Health Records: Qualitative Study

Background

Drug allergy represent an important subset of adverse drug reactions that is worthy of attention because many of these reactions are potentially preventable with use of computerised decision support systems. This is however dependent on the accurate and comprehensive recording of these reactions in the electronic health record. The objectives of this study were to understand approaches to the recording of drug allergies in electronic health record systems.

Materials and Methods

We undertook a case study comprising of 21 in-depth interviews with a purposefully selected group of primary and secondary care clinicians, academics, and members of the informatics and drug regulatory communities, observations in four General Practices and an expert group discussion with 15 participants from the Allergy and Respiratory Expert Resource Group of the Royal College of General Practitioners.

Results

There was widespread acceptance among healthcare professionals of the need for accurate recording of drug allergies and adverse drug reactions. Most drug reactions were however likely to go unreported to and/or unrecognised by healthcare professionals and, even when recognised and reported, not all reactions were accurately recorded. The process of recording these reactions was not standardised.

Conclusions

There is considerable variation in the way drug allergies are recorded in electronic health records. This limits the potential of computerised decision support systems to help alert clinicians to the risk of further reactions. Inaccurate recording of information may in some instances introduce new problems as patients are denied treatments that they are erroneously believed to be allergic to.     

Heritability of a Quantitative and Qualitative Protease Inhibitor Polymorphism in Nicotiana attenuata

Abstract: Many plant species contain chemical defenses that protect them against herbivores. Despite the benefit of these chemical defenses, not all individuals contain high levels of these compounds. In the native tobacco Nicotiana attenuata we found that plants from three natural populations differed considerably in their ability to produce trypsin protease inhibitors (PIs), which are defensive proteins that reduce herbivore damage to plants. Plants from a Utah (U) population produced high levels, whereas plants from Arizona (A) contained no detectable PI levels. Californian (C) plants had intermediate levels. The PI-producing U and C plants thus differ quantitatively from each other, whereas they both differ qualitatively from PI-deficient A plants. Here we analyze how PI production is inherited in N. attenuata with the ultimate goal of better understanding how the quantitative and qualitative differences between the three populations have evolved. Using a series of classical crossing designs, we determined that the ability to produce PIs is inherited as a dominant Mendelian trait. PI-deficient plants contain two non-functional recessive alleles, whereas heterozygous plants or homozygous dominant plants both are able to produce PIs. Similarly, the level of constitutive PIs may be determined by its genotype, either by an interaction between a functional and a non-functional allele in heterozygotes, or by a factor on the PI allele itself in homozygous C plants. Based on these data and on previous studies with A and U plants we postulate that the PI-deficient A plants may have originated from a mutant that lost its ability to produce PIs. The fitness loss due to reduced herbivore resistance may be offset by the fitness gain associated with increased competitive ability, a trade-off which may maintain this mutation in the Arizona population.     

Identifying Factors to Improve Oral Cancer Screening Uptake: A Qualitative Study

Aims

To engage with high risk groups to identify knowledge and awareness of oral cancer signs and symptoms and the factors likely to contribute to improved screening uptake.

Methods

Focus group discussions were undertaken with 18 males; 40+ years of age; smokers and/or drinkers (15+ cigarettes per day and/or 15+ units of alcohol per week), irregular dental attenders living in economically deprived areas of Teesside.

Results

There was a striking reported lack of knowledge and awareness of oral cancer and its signs and symptoms among the participants. When oral/mouth cancer leaflets produced by Cancer Research UK were presented to the participants, they claimed that they would seek help on noticing such a condition. There was a preference to seek help from their general practitioner rather than their dentist due to perceptions that a dentist is ‘inaccessible’ on a physical and psychological level, costly, a ‘tooth specialist’ not a ‘mouth specialist’, and also not able to prescribe medication and make referrals to specialists. Interestingly, none of the 18 participants who were offered a free oral cancer examination at a dental practice took up this offer.

Conclusions

The uptake of oral cancer screening may be improved by increasing knowledge of the existence and signs and symptoms of oral cancer. Other factors that may increase uptake are increased awareness of the role of dentists in diagnosing oral cancer, promotion of oral cancer screening by health professionals during routine health checks, and the use of a “health” screening setting as opposed to a “dental” setting for such checks.     

Effect of Geolocators on Migration and Subsequent Breeding Performance of a Long-Distance Passerine Migrant

Geolocators are small light-weight data loggers used to track individual migratory routes, and their use has increased exponentially in birds. However, the effects of geolocators on individual performance are still poorly known. We studied geolocator effects on a long-distance migrating passerine bird, the northern wheatear (Oenanthe oenanthe L.). We asked the general question of whether geolocators affect migratory behaviour and subsequent reproductive performance of small passerines by comparing arrival time, breeding time, breeding success and survival of geolocator versus control birds of known identity and breeding history. During two years geolocator birds (n=37) displayed a lower apparent survival (30%) as compared to controls (45%, n=164). Furthermore, returning geolocator birds (n=12) arrived on average 3.5 days later, started laying eggs 6.3 days later, and had lower nest success (25%) than control birds (78%). Our results suggest that geolocators affect migratory performance with carry-over effects to the timing of breeding and reproductive success in the subsequent breeding season. We discuss the implications of such geolocator effects for the study of migratory strategies of small passerines in general and suggest how to identify and investigate such effects in the future.     

Quantitative Analysis of Bacterial Migration in Chemotaxis

THERE are a number of parallels between the chemotactic response of bacteria and the process of chemoreception in higher organisms^{1, 2}. Because of this analogy, the chemotactic response presents an unusual opportunity in a simple system for delineating some of the features of a receptor system. Adler and co-workers^3–5, for example, have made particularly important advances in studies on Escherichia coli which indicate that (a) the galactose binding protein^{6, 7} is the receptor which triggers the chemotactic response⁵ and (b) the response occurs with non-metabolizableanalogues of galactose³.     

Quantitative Analysis of Approaches to Measure Cooperative Phosphate Release in Polymerized Actin

We use stochastic simulations that treat several experimental probes of actin dynamics to explore the extent to which phosphate dissociation in filamentous actin may be cooperative. Phosphate time-courses from polymerization and copolymerization experiments of ATP- and ADP-actin are studied, including the effects of variations in filament-number concentration as well as single-filament depolymerization time-courses. We find that highly cooperative models are consistent with the treated experimental data. We also find that some types of experiments that are believed to provide strong constraints on the cooperativity of actin hydrolysis models do not provide such constraints.     

Tuberculosis in Migrant Populations. A Systematic Review of the Qualitative Literature

Background

The re-emergence of tuberculosis (TB) in low-incidence countries and its disproportionate burden on immigrants is a public health concern posing specific social and ethical challenges. This review explores perceptions, knowledge, attitudes and treatment adherence behaviour relating to TB and their social implications as reported in the qualitative literature.

Methods

Systematic review in four electronic databases. Findings from thirty selected studies extracted, tabulated, compared and synthesized.

Findings

TB was attributed to many non-exclusive causes including air-born transmission of bacteria, genetics, malnutrition, excessive work, irresponsible lifestyles, casual contact with infected persons or objects; and exposure to low temperatures, dirt, stress and witchcraft. Perceived as curable but potentially lethal and highly contagious, there was confusion around a condition surrounded by fears. A range of economic, legislative, cultural, social and health system barriers could delay treatment seeking. Fears of deportation and having contacts traced could prevent individuals from seeking medical assistance. Once on treatment, family support and “the personal touch” of health providers emerged as key factors facilitating adherence. The concept of latent infection was difficult to comprehend and while TB screening was often seen as a socially responsible act, it could be perceived as discriminatory. Immigration and the infectiousness of TB mutually reinforced each another exacerbating stigma. This was further aggravated by indirect costs such as losing a job, being evicted by a landlord or not being able to attend school.

Conclusions

Understanding immigrants’ views of TB and the obstacles that they face when accessing the health system and adhering to a treatment programme-taking into consideration their previous experiences at countries of origin as well as the social, economic and legislative context in which they live at host countries- has an important role and should be considered in the design, evaluation and adaptation of programmes.     

动物学定量与定性资料分析中的常见错误

合理选择正确的统计方法是提高科研工作质量和可信度的关键.然而有些科研工作所采用的统计方法往往不合理,甚至是错误的.例如,常常忽视定量资料中t-检验和方差分析的前提条件--正态性、方差齐性.对单因素多水平的定量资料直接使用组间两两比较的t-检验;对定性资料中列联表的分析一律通用Pearson χ~2检验,包括对Pearson χ~2检验结果的理解出现偏差,从而做出错误的推论.本文对国内一些动物学研究论文中所采用的具体统计方法提出辨析.     

Qualitative and Quantitative Assay of Trichothecin: a Mycotoxin Produced by Trichothecium roseum

A method for quantitative determination of trichothecin in crude culture filtrates was presented. The method utilized an agar diffusion bioassay against Candida albicans, a colorimetric test involving a halochromatic reaction with sulfuric acid, and subsequent formation of blue color with methanol, and thin-layer chromatography of trichothecin and its dinitrophenylhydrazine derivative. A positive result in all three systems confirmed the presence of trichothecin. Quantitative results were generally in close agreement.     

Quantitative Exposure-Response Assessment Approaches to Evaluate Acute Inhalation Toxicity of Phosgene

Phosgene has been a long-term subject of toxicological research due to its widespread use, high toxicity, and status as a model of chemically induced lung injury. To take advantage of the abundant data set for the acute inhalation toxicity of phosgene, methods for exposure-response analysis that use more data than the traditional no-observed-adverse-effect level approach were used to perform an exposure-response assessment for phosgene. Categorical regression is particularly useful for acute exposures due to the ability to combine studies of various exposure durations, and thus provide estimates of effect severity for a range of both exposure concentrations and durations. Results from the categorical regression approach were compared to those from parametric curve fitting models (i.e., benchmark concentration models) that make use of information from an entire dose-response, but only for one exposure duration. While categorical regression analysis provided results that were comparable to benchmark concentration results, categorical regression provides an improvement over that technique by accounting for the effects of both exposure concentration and duration on response. The other major advantage afforded by categorical regression is the ability to combine studies, allowing the quantitative use of a larger data set, which increases confidence in the final result.     

Plant Innate Immune Response: Qualitative and Quantitative Resistance

Plant diseases, caused by microbes, threaten world food, feed, and bioproduct security. Plant resistance has not been effectively deployed to improve resistance in plants for lack of understanding of biochemical mechanisms and genetic bedrock of resistance. With the advent of genome sequencing, the forward and reverse genetic approaches have enabled deciphering the riddle of resistance. Invading pathogens produce elicitors and effectors that are recognized by the host membrane-localized receptors, which in turn induce a cascade of downstream regulatory and resistance metabolite and protein biosynthetic genes (R) to produce resistance metabolites and proteins, which reduce pathogen advancement through their antimicrobial and cell wall enforcement properties. The resistance in plants to pathogen attack is expressed as reduced susceptibility, ranging from high susceptibility to hypersensitive response, the shades of gray. The hypersensitive response or cell death is considered as qualitative resistance, while the remainder of the reduced susceptibility is considered as quantitative resistance. The resistance is due to additive effects of several resistance metabolites and proteins, which are produced through a network of several hierarchies of plant R genes. Plants recognize the pathogen elicitors or receptors and then induce downstream genes to eventually produce resistance metabolites and proteins that suppress the pathogen advancement in plant. These resistance genes (R), against qualitative and quantitative resistance, can be identified in germplasm collections and replaced in commercial cultivars, if nonfunctional, based on genome editing to improve plant resistance.     

Qualitative and Quantitative Interactions between Microphytobenthos and Herbivorous Meiofauna on a Brackish Intertidal Mudflat

Micro- and meiofauna are the predominant consumers of diatoms on a brackish intertidal mudflat. The impact of grazing on the benthic diatom populations was studied by field observations and feeding experiments on a few abundant members of the community. Only small fractions of the microphytobenthic biomass and production are converted by herbivores. A hypothesis is presented explaining the growth kinetics and productivity of diatom populations and the inefficient transfer of carbon into herbivore foodchains. Data on feeding rate and population dynamics of the nematode species, Eudiplogaster pararmatus, are discussed in view of the seasonal succession of edible diatom species.     

Quantitative Assessment of Human Neutrophil Migration Across a Cultured Bladder Epithelium

The recruitment of immune cells from the periphery to the site of inflammation is an essential step in the innate immune response at any mucosal surface. During infection of the urinary bladder, polymorphonuclear leukocytes (PMN; neutrophils) migrate from the bloodstream and traverse the bladder epithelium. Failure to resolve infection in the absence of a neutrophilic response demonstrates the importance of PMN in bladder defense. To facilitate colonization of the bladder epithelium, uropathogenic Escherichia coli (UPEC), the causative agent of the majority of urinary tract infections (UTIs), dampen the acute inflammatory response using a variety of partially defined mechanisms. To further investigate the interplay between host and bacterial pathogen, we developed an in vitro model of this aspect of the innate immune response to UPEC. In the transuroepithelial neutrophil migration assay, a variation on the Boyden chamber, cultured bladder epithelial cells are grown to confluence on the underside of a permeable support. PMN are isolated from human venous blood and are applied to the basolateral side of the bladder epithelial cell layers. PMN migration representing the physiologically relevant basolateral-to-apical direction in response to bacterial infection or chemoattractant molecules is enumerated using a hemocytometer. This model can be used to investigate interactions between UPEC and eukaryotic cells as well as to interrogate the molecular requirements for the traversal of bladder epithelia by PMN. The transuroepithelial neutrophil migration model will further our understanding of the initial inflammatory response to UPEC in the bladder.     

Qualitative and Quantitative Protein Complex Prediction Through Proteome-Wide Simulations

Despite recent progress in proteomics most protein complexes are still unknown. Identification of these complexes will help us understand cellular regulatory mechanisms and support development of new drugs. Therefore it is really important to establish detailed information about the composition and the abundance of protein complexes but existing algorithms can only give qualitative predictions. Herein, we propose a new approach based on stochastic simulations of protein complex formation that integrates multi-source data—such as protein abundances, domain-domain interactions and functional annotations—to predict alternative forms of protein complexes together with their abundances. This method, called SiComPre (Simulation based Complex Prediction), achieves better qualitative prediction of yeast and human protein complexes than existing methods and is the first to predict protein complex abundances. Furthermore, we show that SiComPre can be used to predict complexome changes upon drug treatment with the example of bortezomib. SiComPre is the first method to produce quantitative predictions on the abundance of molecular complexes while performing the best qualitative predictions. With new data on tissue specific protein complexes becoming available SiComPre will be able to predict qualitative and quantitative differences in the complexome in various tissue types and under various conditions.