Mouse models of uveal melanoma: Strengths,weaknesses, and future directions

Uveal melanoma is the most common primary malignancy of the eye, and a number of discoveries in the last decade have led to a more thorough molecular characterization of this cancer. However, the prognosis remains dismal for patients with metastases, and there is an urgent need to identify treatments that are effective for this stage of disease. Animal models are important tools for preclinical studies of uveal melanoma. A variety of models exist, and they have specific advantages, disadvantages, and applications. In this review article, these differences are explored in detail, and ideas for new models that might overcome current challenges are proposed.     

Strengths and weaknesses of immunotherapy for advanced non-small-cell lung cancer: a meta-analysis of 12 randomized controlled trials

Background

Lung cancer is one of the leading causes of cancer death worldwide. Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Immunotherapy has yielded no consistent benefit to date for those patients. Assessing the objective efficacy and safety of immunotherapy for advanced NSCLC patients will help to instruct the future development of immunotherapeutic drugs.

Methodology and Principal Findings

We performed a meta-analysis of 12 randomized controlled trials including 3134 patients (1570 patients in the immunotherapy group and 1564 patients in the control group) with histologically confirmed stage IIIA, IIIB, or IV NSCLC. The analysis was executed with efficacy end points regarding overall survival (OS), progression-free survival (PFS), complete response (CR), partial response (PR), and total effective rate. Overall unstratified OS, PFS, PR, and total effective rate were significantly improved in advanced NSCLC patients in the immunotherapy group (P = 0.0007, 0.0004, 0.002, 0.003, respectively), whereas CR was not improved (P = 0.97). Subgroup analysis showed that monoclonal antibody (mAb) immunotherapy significantly improved the PFS, PR, and total effective rate and showed a trend of improving OS of advanced NSCLC patients compared with the control group, with one kind of adverse event being significantly dominant. Compared with the control group, the vaccine subgroup showed no significant difference with regard to serious adverse events, whereas cytokine immunotherapy significantly induced three kinds of serious adverse events.

Conclusions

Immunotherapy works efficiently on advanced NSCLC patients. Of several immunotherapies, mAb therapy may be a potential immunotherapy for advanced NSCLC patients, and become a standard complementary therapeutic approach in the future if the issues concerning toxicity and allergenicity of mAbs have been overcome.     

Strengths and weaknesses of museum and national survey data sets for predicting regional species richness: comparative and combined approaches

We compiled three independent data sets of bird species occurrences in northeastern Colorado to test how predicted species richness compared to a combined analysis using all the data. The first data set was a georeferenced regional museum data set from two major repositories — the Denver Museum of Nature, and the Science and University of Colorado Museum. The two national survey data sets were the Breeding Bird Survey (summer), and the Great Backyard Bird Count (winter). Resulting analyses show that the museum data sets give richness estimates closest to the combined data set while exhibiting a skewed abundance distribution, whereas survey data sets do not accurately estimate overall richness even though they contain far more records. The combined data set allows the strengths of one data set to augment weaknesses in others. It is likely some museum data sets display skewed abundance distributions due to collectors’ potentially self‐selecting under‐represented species over common ones.     

Strengths and weaknesses in the long-term sustainability of two sympatric seabreams (Argyrops spinifer and Rhabdosargus haffara,Sparidae)

Argyrops spinifer and Rhabdosargus haffara are two sympatric seabream species making important contributions to fisheries landings in the western Arabian/Persian Gulf. We identified the strengths and weaknesses in the long-term sustainability of A. spinifer and R. haffara stocks by integrating multiple sources of data, including fisheries catch and effort statistics, life history traits, scientific trawl surveys and historical length frequency distribution. Four strengths were identified in A. spinifer: wide distribution of juveniles, positive association to the network of de facto fishing exclusion areas created by hundreds of oil-gas facilities, early maturation and the existence of large and old individuals. A. spinifer suffers from two potential weaknesses: slow growth rate and higher exploitation pressure on the small-sized individuals. R. haffara, on the other hand, has a strength of having a short life span and a fast growth rate, characteristics that make it robust to unfavourable conditions. R. haffara suffers from two weaknesses: the lack of association to the oil and gas facilities, and the preference for nearshore shallow waters with stronger negative anthropogenic impacts. Identified strengths and weaknesses of these two sparids provided a preliminary assessment about their long-term sustainability, as well as a roadmap about how to develop different management strategies to meet specific objectives.     

Strengths abd weaknesses of the reef guild concepts and quantitative data: Application to the upper Capitan-massive community (Permian), Guadalupe Mountains, New Mexico-Texas

Summary Analyses of large acatate sheet tracings, close-up photos and 105 sub-horizontal quadrat surfaces at four localities near the base of the Guadalupe Mountains Escarpment indicate that the biotic framework of the upper Capitan reef was built by about 35 species: one codiacean (Eugonophyllum sp.), 17 calcisponges, 9 bryozoans, one richthofenid brachipod, some crinoid (known only from columns), 4 Problematica and microbes. This widespread fossil community included members of the Constructor, Baffler and Binder Guilds. A re-evaluation of the Guild Concept (Fagerstrom, 1987, 1991) highlights the validity of the functional roles of the Constructor and Binder Guilds for reef construction. Members of the Baffler Guild, however, need to be revised and an interpretation of microbial micrite and cryptic biota remains controversial. Open surface phylloid algal and cryptic sponge-bryozoan dominated sub-communities were of only local importance. The upper Capitanmassive differs from its Permian conterparts in the low diversity and areal cover of the frame-building biota, low micrite content and abundant micro-frameworks, i.e, intergrown small sponges, Problematica and syndepositional cements (botryoidal and isopachous, fibrous calcite). Quantitative areal cover data were assessed at various scales. Large acetate sheets generally have low coverage of macro-biota (5.4%). By contrast, analysis of small areas of local high areal cover (selected acetate sheet quadrats, subvertical photographs, and quadrat samples: 15–21%) provide detailed insights into clustered patches forming the inital reef framework. Both data sets provide useful clues for an integrated approach to framework assessment. Mean acetate sheet data are limited by their somewhat generalized pattern, while small investigation areas may overemphasize local variation. Erect and pendant sponges with solitary, sub-cylindrical and multi-branche/clonal forms, were the predominant initial frame-builders in both open surface and cryptic habitats. Selective larval recruitment of erects sponges to firm substrates produced continous upward accretion of the initial framework. On open surfaces and in pores formed by tabular sponges and fenestrate bryozoans, erect and pendant sponges were supported in their hydrodynamically unstable growth position by encrusters, chieflyArchaeolithoporelle hidensis, Shamovella obscura, an unnamed tubular organism, and microbes. Subsequent growth ofArchaeolithoporella hidensis, microbial crusts and syndepositional cements on the outer walls of live sponges would have impeded ambient water circulation and may have led to ‘creeping sponge death by suffocation’ or complete encrustation after death. Filling of pores in the initial and encrusted reef framework by internal sediment (packstone-grainstone; derived from the framework and the back-reef shelf/platform) and voluminous syndepositional marine-phreatic cements completed the framebuilding process.     

Coding for pathology tests - strengths and weaknesses

Laboratory professionals will increasingly find themselves called upon to assist with the coding of pathology test requests and reported results in the era of the e-Health Record (EHR). EHR users from outside pathology, including patients and clinicians, will expect seamless integration of pathology services, and question variations in test nomenclature, units, reference intervals, and interpretive comments. Scientists and pathologists will need to be ready to work with colleagues outside their traditional scientific disciplines, along with IT and terminology experts, to resolve illogical historical variations, highlight differences that might endanger patient safety, and help lay the foundations for evolving e-health systems that enhance healthcare without eroding the interpretive value of pathology reports from different laboratories. An overview of medical terminologies and Australasian eHealth harmonisation programs is also provided.     

Current methods of gene prediction,their strengths and weaknesses

While the genomes of many organisms have been sequenced over the last few years, transforming such raw sequence data into knowledge remains a hard task. A great number of prediction programs have been developed that try to address one part of this problem, which consists of locating the genes along a genome. This paper reviews the existing approaches to predicting genes in eukaryotic genomes and underlines their intrinsic advantages and limitations. The main mathematical models and computational algorithms adopted are also briefly described and the resulting software classified according to both the method and the type of evidence used. Finally, the several difficulties and pitfalls encountered by the programs are detailed, showing that improvements are needed and that new directions must be considered.     

Strengths and limitations of genetic models of ADHD

The cause and pathophysiology of attention-deficit hyperactivity disorder (ADHD) are unknown, but compelling evidence suggests an involvement of genetic factors. While dopamine is believed to play a major role in ADHD, the role for norepinephrine and serotonin systems has also been indicated. Mutant mice are valuable tools to dissect the contribution of specific neurotransmitter systems to brain dysfunction and particularly useful to decode complex multi-transmitter interaction that is critical to the pathophysiology of ADHD. Genetically altered mice provided also an opportunity to test experimentally the role of novel candidate genes for this disorder identified in genetic clinical studies. While it is clear that no rodent model would be able to recapitulate fully the complex nature of ADHD, certain endophenotypes could be reasonably well mimicked in these models. Multiple studies have reported associations between polymorphisms in dopamine transporter (DAT) gene and ADHD. Although the functional consequences of these associations are still unclear, it is believed that alterations in DAT-mediated processes might contribute to the pathogenesis of ADHD. Mice lacking the dopamine transporter have elevated dopaminergic tone and represent a genetic animal model in which certain endophenotypes of ADHD can be recapitulated. These mutants as well as other mouse models of DAT dysfunction provided an opportunity to investigate the neuronal circuitry and molecular mechanisms involved in the inhibitory action of psychostimulants on hyperactivity. Several additional knockout and transgenic mouse models have been proposed to model ADHD. Strengths and limitations of currently available genetic mouse models of ADHD are discussed.     

Strengths and limitations of the neurosphere culture system

After the initial reports of free-floating cultures of neural stem cells termed neurospheres (1,2), a wide array of studies using this promising culture system emerged. In theory, this was a nearperfect system for large-scale production of neural cells for use in cell replacement therapies and to assay for and characterize neural stem cells. More than a decade later, after rigorous scrutiny and ample experimental testing of the neurosphere culture system, it has become apparent that the culture system suffers from several disadvantages, and its usefulness is limited for several applications. Nevertheless, the bulk of high-quality research produced over the last decade has also shown that under the right circumstances and for the appropriate purposes, neurospheres hold up to their initial promise. This article discusses the pros and cons of the neurosphere culture system regarding its three major applications: as an assay for neural stem cells, as a model system for neurogenesis and neural development, and for expansion of neural stem cells for transplantation purposes.