bluuebunny/crossref_metadata_2025_split huggingface dataset:
In-depth investigation of the molecular pathogenesis of bladder cancer in a unique 26-year old patient with extensive multifocal disease: a case report
Authors: Zuiverloon Tahlita CM , Abas Cheno S , van der Keur Kirstin A , Vermeij Marcel , Tjin Stephen S , van Tilborg Angela G , Busstra Martijn , Zwarthoff Ellen C 
Published: February 2010

Abstract

Background
The molecular characteristics and the clinical disease course of bladder cancer (BC) in young patients remain largely unresolved. All patients are monitored according to an intensive surveillance protocol and we aim to gain more insight into the molecular pathways of bladder tumors in young patients that could ultimately contribute to patient stratification, improve patient quality of life and reduce associated costs. We also determined whether a biomarker-based surveillance could be feasible.

Case Presentation
We report a unique case of a 26-year-old Caucasian male with recurrent non-muscle invasive bladder tumors occurring at a high frequency and analyzed multiple tumors (maximal pTaG2) and urine samples of this patient. Analysis included FGFR3 mutation detection, FGFR3 and TP53 immunohistochemistry, mircosatellite analysis of markers on chromosomes 8, 9, 10, 11 and 17 and a genome wide single nucleotide polymorphism-array (SNP). All analyzed tumors contained a mutation in FGFR3 and were associated with FGFR3 overexpression. None of the tumors showed overexpression of TP53. We found a deletion on chromosome 9 in the primary tumor and this was confirmed by the SNP-array that showed regions of loss on chromosome 9. Detection of all recurrences was possible by urinary FGFR3 mutation analysis.

Conclusions
Our findings would suggest that the BC disease course is determined by not only a patient's age, but also by the molecular characteristics of a tumor. This young patient contained typical genetic changes found in tumors of older patients and implies a clinical disease course comparable to older patients. We demonstrate that FGFR3 mutation analysis on voided urine is a simple non-invasive method and could serve as a feasible follow-up approach for this young patient presenting with an FGFR3 mutant tumor.
Medical student engagement and leadership within a new learning community
Authors: Bicket Mark , Misra Satish , Wright Scott M , Shochet Robert 
Published: February 2010

Abstract

Background
Many medical schools are establishing learning communities to foster cohesion among students and to strengthen relationships between students and faculty members. Emerging learning communities require nurturing and attention; this represents an opportunity wherein medical students can become involved as leaders. This study sought to understand issues related to active involvement among students who chose to become highly engaged in a newly developed learning community.

Methods
Between April and June 2008, 36 students who assumed leadership roles within the Colleges Program were queried electronically with open-ended questions about their engagement. Qualitative analysis of the written responses was independently performed by two investigators; coding was compared for agreement. Content analysis identified major themes.

Results
35 students (97%) completed the questionnaire. Motives that emerged as reasons for getting involved included: endorsing the need for the program; excitement with the start-up; wanting to give back; commitment to institutional excellence; and collaboration with talented peers and faculty. Perceived benefits were grouped under the following domains: connecting with others; mentoring; learning new skills; and recognition. The most frequently identified drawbacks were the time commitment and the opportunity costs. Ideas for drawing medical students into new endeavors included: creating defined roles; offering a breadth of opportunities; empowering students with responsibility; and making them feel valued.

Conclusions
Medical students were drawn to and took on leadership roles in a medical school curricular innovation. This example may prove helpful to others hoping to engage students as leaders in learning communities at their schools or those wishing to augment student involvement in other programs.
A role for NRAGE in NF-κB activation through the non-canonical BMP pathway
Authors: Matluk Nicholas , Rochira Jennifer A , Karaczyn Aldona , Adams Tamara , Verdi Joseph M 
Published: February 2010

Abstract

Background
Previous studies have linked neurotrophin receptor-interacting MAGE protein to the bone morphogenic protein signaling pathway and its effect on p38 mediated apoptosis of neural progenitor cells via the XIAP-Tak1-Tab1 complex. Its effect on NF-κB has yet to be explored.

Results
Herein we report that NRAGE, via the same XIAP-Tak1-Tab1 complex, is required for the phosphorylation of IKK -α/β and subsequent transcriptional activation of the p65 subunit of NF-κB. Ablation of endogenous NRAGE by siRNA inhibited NF-κB pathway activation, while ablation of Tak1 and Tab1 by morpholino inhibited overexpression of NRAGE from activating NF-κB. Finally, cytokine profiling of an NRAGE over-expressing stable line revealed the expression of macrophage migration inhibitory factor.

Conclusion
Modulation of NRAGE expression revealed novel roles in regulating NF-κB activity in the non-canonical bone morphogenic protein signaling pathway. The expression of macrophage migration inhibitory factor by bone morphogenic protein -4 reveals novel crosstalk between an immune cytokine and a developmental pathway.
Alteration of Primary Afferent Activity following Inferior Alveolar Nerve Transection in Rats
Authors: Nakagawa Kazuharu , Takeda Mamoru , Tsuboi Yoshiyuki , Kondo Masahiro , Kitagawa Junichi , Matsumoto Shigeji , Kobayashi Azusa , Sessle Barry J , Shinoda Masamichi , Iwata Koichi 
Published: February 2010

Background: In order to evaluate the neural mechanisms underlying the abnormal facial pain that may develop following regeneration of the injured inferior alveolar nerve (IAN), the properties of the IAN innervated in the mental region were analyzed. Results: Fluorogold (FG) injection into the mental region 14 days after IAN transection showed massive labeling of trigeminal ganglion (TG). The escape threshold to mechanical stimulation of the mental skin was significantly lower (i.e. mechanical allodynia) at 11–14 days after IAN transection than before surgery. The background activity, mechanically evoked responses and afterdischarges of IAN Aδ-fibers were significantly higher in IAN-transected rats than naive. The small/medium diameter TG neurons showed an increase in both tetrodotoxin (TTX)-resistant (TTX-R) and -sensitive (TTX-S) sodium currents ( INa) and decrease in total potassium current, transient current ( IA) and sustained current ( IK) in IAN-transected rats. The amplitude, overshoot amplitude and number of action potentials evoked by the depolarizing pulses after 1 μM TTX administration in TG neurons were significantly higher, whereas the threshold current to elicit spikes was smaller in IAN-transected rats than naive. Resting membrane potential was significantly smaller in IAN-transected rats than that of naive. Conclusions: These data suggest that the increase in both TTX-S INa and TTX-R INa and the decrease in IA and Ik in small/medium TG neurons in IAN-transected rats are involved in the activation of spike generation, resulting in hyperexcitability of Aδ-IAN fibers innervating the mental region after IAN transection.
Akt activity protects rheumatoid synovial fibroblasts from Fas-induced apoptosis by inhibition of Bid cleavage
Authors: García Samuel , Liz Myriam , Gómez-Reino Juan J , Conde Carmen 
Published: February 2010

Abstract
Introduction
Synovial hyperplasia is a main feature of rheumatoid arthritis pathology that leads to cartilage and bone damage in the inflamed joints. Impaired apoptosis of resident synoviocytes is pivotal in this process. Apoptosis resistance seems to involve defects in the extrinsic and intrinsic apoptotic pathways. The aim of this study was to investigate the association of PI3Kinase/Akt and the mitochondrial apoptotic pathway in the resistance of rheumatoid arthritis (RA) fibroblast like synovial cells (FLS) to Fas-mediated apoptosis.

Methods
Apoptosis was assessed by ELISA quantification of nucleosomal release, Hoechst staining and activated caspase-3/7 measure in cultured RA FLS stimulated with anti-Fas antibody. Two Phosphoinositol-3-kinase/protein Kinase B (PI3 Kinase) inhibitors, Wortmannine and LY294002, were used before anti-Fas stimulation. Proapoptotic BH3 interacting domain death agonist (Bid) was suppressed in RA FLS by small interfering RNA (siRNA) transfection. Bid was overexpressed by transfection with the pDsRed2-Bid vector. Phosphorylated Akt, caspase-9, and Bid expression were analysed by western blot.

Results
PI3 kinase inhibition sensitizes RA FLS to Fas-induced apoptosis by increasing cleavage of Bid protein. Bid suppression completely abrogated Fas-induced apoptosis and Bid overexpression highly increased apoptotic rate of RA FLS in association with cleavage of caspase-9.

Conclusions
In RA FLS, phosphorylation of Akt protects against Fas-induced apoptosis through inhibition of Bid cleavage. The connection between the extrinsic and the intrinsic apoptotic pathways are critical in this Fas- mediated apoptosis and points to PI3Kinase as potential therapeutic target for RA.
Identification of functional modules that correlate with phenotypic difference: the influence of network topology
Authors: Hung Jui-Hung , Whitfield Troy W , Yang Tun-Hsiang , Hu Zhenjun , Weng Zhiping , DeLisi Charles 
Published: February 2010

AbstractOne of the important challenges to post-genomic biology is relating observed phenotypic alterations to the underlying collective alterations in genes. Current inferential methods, however, invariably omit large bodies of information on the relationships between genes. We present a method that takes account of such information - expressed in terms of the topology of a correlation network - and we apply the method in the context of current procedures for gene set enrichment analysis.
The physiology of climate change: how potentials for acclimatization and genetic adaptation will determine ‘winners’ and ‘losers’
Authors: Somero G. N. 
Published: February 2010

SUMMARYPhysiological studies can help predict effects of climate change through determining which species currently live closest to their upper thermal tolerance limits, which physiological systems set these limits, and how species differ in acclimatization capacities for modifying their thermal tolerances. Reductionist studies at the molecular level can contribute to this analysis by revealing how much change in sequence is needed to adapt proteins to warmer temperatures — thus providing insights into potential rates of adaptive evolution — and determining how the contents of genomes — protein-coding genes and gene regulatory mechanisms — influence capacities for adapting to acute and long-term increases in temperature. Studies of congeneric invertebrates from thermally stressful rocky intertidal habitats have shown that warm-adapted congeners are most susceptible to local extinctions because their acute upper thermal limits (LT50 values) lie near current thermal maxima and their abilities to increase thermal tolerance through acclimation are limited. Collapse of cardiac function may underlie acute and longer-term thermal limits. Local extinctions from heat death may be offset by in-migration of genetically warm-adapted conspecifics from mid-latitude ‘hot spots’, where midday low tides in summer select for heat tolerance. A single amino acid replacement is sufficient to adapt a protein to a new thermal range. More challenging to adaptive evolution are lesions in genomes of stenotherms like Antarctic marine ectotherms, which have lost protein-coding genes and gene regulatory mechanisms needed for coping with rising temperature. These extreme stenotherms, along with warm-adapted eurytherms living near their thermal limits, may be the major ‘losers’ from climate change.
Challenges in predicting climate and environmental effects on vector-borne disease episystems in a changing world
Authors: Tabachnick W. J. 
Published: February 2010

SUMMARY
Vector-borne pathogens cause enormous suffering to humans and animals. Many are expanding their range into new areas. Dengue, West Nile and Chikungunya have recently caused substantial human epidemics. Arthropod-borne animal diseases like Bluetongue, Rift Valley fever and African horse sickness pose substantial threats to livestock economies around the world. Climate change can impact the vector-borne disease epidemiology. Changes in climate will influence arthropod vectors, their life cycles and life histories, resulting in changes in both vector and pathogen distribution and changes in the ability of arthropods to transmit pathogens. Climate can affect the way pathogens interact with both the arthropod vector and the human or animal host. Predicting and mitigating the effects of future changes in the environment like climate change on the complex arthropod—pathogen—host epidemiological cycle requires understanding of a variety of complex mechanisms from the molecular to the population level. Although there has been substantial progress on many fronts the challenges to effectively understand and mitigate the impact of potential changes in the environment on vector-borne pathogens are formidable and at an early stage of development. The challenges will be explored using several arthropod-borne pathogen systems as illustration, and potential avenues to meet the challenges will be presented.
Physiological climatic limits inDrosophila: patterns and implications
Authors: Hoffmann A. A. 
Published: February 2010

SUMMARYPhysiological limits determine susceptibility to environmental changes, and can be assessed at the individual, population or species/lineage levels. Here I discuss these levels in Drosophila, and consider implications for determining species susceptibility to climate change. Limits at the individual level in Drosophila depend on experimental technique and on the context in which traits are evaluated. At the population level, evidence from selection experiments particularly involving Drosophila melanogaster indicate high levels of heritable variation and evolvability for coping with thermal stresses and aridity. An exception is resistance to high temperatures, which reaches a plateau in selection experiments and has a low heritability/evolvability when temperatures are ramped up to a stressful level. In tropical Drosophila species, populations are limited in their ability to evolve increased desiccation and cold resistance. Population limits can arise from trait and gene interactions but results from different laboratory studies are inconsistent and likely to underestimate the strength of interactions under field conditions. Species and lineage comparisons suggest phylogenetic conservatism for resistance to thermal extremes and other stresses. Plastic responses set individual limits but appear to evolve slowly in Drosophila. There is more species-level variation in lower thermal limits and desiccation resistance compared with upper limits, which might reflect different selection pressures and/or low evolvability. When extremes are considered, tropical Drosophila species do not appear more threatened than temperate species by higher temperatures associated with global warming, contrary to recent conjectures. However, species from the humid tropics may be threatened if they cannot adapt genetically to drier conditions.
Deforestation and avian infectious diseases
Authors: Sehgal R. N. M. 
Published: February 2010

SUMMARY
In this time of unprecedented global change, infectious diseases will impact humans and wildlife in novel and unknown ways. Climate change, the introduction of invasive species, urbanization, agricultural practices and the loss of biodiversity have all been implicated in increasing the spread of infectious pathogens. In many regards, deforestation supersedes these other global events in terms of its immediate potential global effects in both tropical and temperate regions. The effects of deforestation on the spread of pathogens in birds are largely unknown. Birds harbor many of the same types of pathogens as humans and in addition can spread infectious agents to humans and other wildlife. It is thought that avifauna have gone extinct due to infectious diseases and many are presently threatened, especially endemic island birds. It is clear that habitat degradation can pose a direct threat to many bird species but it is uncertain how these alterations will affect disease transmission and susceptibility to disease. The migration and dispersal of birds can also change with habitat degradation, and thus expose populations to novel pathogens. Some recent work has shown that the results of landscape transformation can have confounding effects on avian malaria, other haemosporidian parasites and viruses. Now with advances in many technologies, including mathematical and computer modeling, genomics and satellite tracking, scientists have tools to further research the disease ecology of deforestation. This research will be imperative to help predict and prevent outbreaks that could affect avifauna, humans and other wildlife worldwide.
Crucial knowledge gaps in current understanding of climate change impacts on coral reef fishes
Authors: Wilson S. K. , Adjeroud M. , Bellwood D. R. , Berumen M. L. , Booth D. , Bozec Y.-Marie , Chabanet P. , Cheal A. , Cinner J. , Depczynski M. , Feary D. A. , Gagliano M. , Graham N. A. J. , Halford A. R. , Halpern B. S. , Harborne A. R. , Hoey A. S. , Holbrook S. J. , Jones G. P. , Kulbiki M. , Letourneur Y. , De Loma T. L. , McClanahan T. , McCormick M. I. , Meekan M. G. , Mumby P. J. , Munday P. L. , Öhman M. C. , Pratchett M. S. , Riegl B. , Sano M. , Schmitt R. J. , Syms C. 
Published: February 2010

SUMMARY
Expert opinion was canvassed to identify crucial knowledge gaps in current understanding of climate change impacts on coral reef fishes. Scientists that had published three or more papers on the effects of climate and environmental factors on reef fishes were invited to submit five questions that, if addressed, would improve our understanding of climate change effects on coral reef fishes. Thirty-three scientists provided 155 questions, and 32 scientists scored these questions in terms of: (i) identifying a knowledge gap, (ii) achievability, (iii) applicability to a broad spectrum of species and reef habitats, and (iv) priority. Forty-two per cent of the questions related to habitat associations and community dynamics of fish, reflecting the established effects and immediate concern relating to climate-induced coral loss and habitat degradation. However, there were also questions on fish demographics, physiology, behaviour and management, all of which could be potentially affected by climate change. Irrespective of their individual expertise and background, scientists scored questions from different topics similarly, suggesting limited bias and recognition of a need for greater interdisciplinary and collaborative research. Presented here are the 53 highest-scoring unique questions. These questions should act as a guide for future research, providing a basis for better assessment and management of climate change impacts on coral reefs and associated fish communities.
Insect overwintering in a changing climate
Authors: Bale J. S. , Hayward S. A. L. 
Published: February 2010

SUMMARYInsects are highly successful animals inhabiting marine, freshwater and terrestrial habitats from the equator to the poles. As a group, insects have limited ability to regulate their body temperature and have thus required a range of strategies to support life in thermally stressful environments, including behavioural avoidance through migration and seasonal changes in cold tolerance. With respect to overwintering strategies, insects have traditionally been divided into two main groups: freeze tolerant and freeze avoiding, although this simple classification is underpinned by a complex of interacting processes, i.e. synthesis of ice nucleating agents, cryoprotectants, antifreeze proteins and changes in membrane lipid composition. Also, in temperate and colder climates, the overwintering ability of many species is closely linked to the diapause state, which often increases cold tolerance ahead of temperature-induced seasonal acclimatisation. Importantly, even though most species can invoke one or both of these responses, the majority of insects die from the effects of cold rather than freezing. Most studies on the effects of a changing climate on insects have focused on processes that occur predominantly in summer (development, reproduction) and on changes in distributions rather than winter survival per se. For species that routinely experience cold stress, a general hypothesis would be that predicted temperature increases of 1°C to 5°C over the next 50-100 years would increase winter survival in some climatic zones. However, this is unlikely to be a universal effect. Negative impacts may occur if climate warming leads to a reduction or loss of winter snow cover in polar and sub-polar areas, resulting in exposure to more severe air temperatures, increasing frequency of freeze—thaw cycles and risks of ice encasement. Likewise, whilst the dominant diapause-inducing cue (photoperiod) will be unaffected by global climate change, higher temperatures may modify normal rates of development, leading to a decoupling of synchrony between diapause-sensitive life-cycle stages and critical photoperiods for diapause induction. In terms of climate warming and potential heat stress, the most recent predictions of summer temperatures in Europe of 40°C or higher in 50-75 years, are close to the current upper lethal limit of some insects. Long-term data sets on insect distributions and the timing of annual migrations provide strong evidence for ‘positive’ responses to higher winter temperatures over timescales of the past 20-50 years in North America, Europe and Asia.
Variation in the heat shock response and its implication for predicting the effect of global climate change on species' biogeographical distribution ranges and metabolic costs
Authors: Tomanek L. 
Published: February 2010

SUMMARYThe preferential synthesis of heat shock proteins (Hsps) in response to thermal stress [the heat shock response (HSR)] has been shown to vary in species that occupy different thermal environments. A survey of case studies of aquatic (mostly marine) organisms occupying stable thermal environments at all latitudes, from polar to tropical, shows that they do not in general respond to heat stress with an inducible HSR. Organisms that occupy highly variable thermal environments (variations up to &gt;20°C), like the intertidal zone, induce the HSR frequently and within the range of body temperatures they normally experience, suggesting that the response is part of their biochemical strategy to occupy this thermal niche. The highest temperatures at which these organisms can synthesize Hsps are only a few degrees Celsius higher than the highest body temperatures they experience. Thus, they live close to their thermal limits and any further increase in temperature is probably going to push them beyond those limits. In comparison, organisms occupying moderately variable thermal environments (&lt;10°C), like the subtidal zone, activate the HSR at temperatures above those they normally experience in their habitats. They have a wider temperature range above their body temperature range over which they can synthesize Hsps. Contrary to our expectations, species from highly (in comparison with moderately) variable thermal environments have a limited acclimatory plasticity. Due to this variation in the HSR, species from stable and highly variable environments are likely to be more affected by climate change than species from moderately variable environments.