bluuebunny/crossref_metadata_2025_split huggingface dataset:
Establishment of phosphatidylinositol 3‐kinase inhibitor‐resistant cancer cell lines and therapeutic strategies for overcoming the resistance
Authors: Isoyama Sho , Dan Shingo , Nishimura Yumiko , Nakamura Naoki , Kajiwara Gensei , Seki Mariko , Irimura Tatsuro , Yamori Takao 
Published: August 2012

Acquired resistance is a major obstacle for conventional cancer chemotherapy, and also for some of the targeted therapies approved to date. Long‐term treatment using protein tyrosine kinase inhibitors (TKIs), such as gefitinib and imatinib, gives rise to resistant cancer cells carrying a drug‐resistant gatekeeper mutation in the kinase domain of the respective target genes, EGFR and BCR–ABL. As for the phosphatidylinositol 3‐kinase inhibitors (PI3Kis), little is known about their acquired resistance, although some are undergoing clinical trials. To address this issue, we exposed 11 human cancer cell lines to ZSTK474, a PI3Ki we developed previously, for a period of more than 1 year in vitro. Consequently, we established ZSTK474‐resistant cells from four of the 11 cancer cell lines tested. The acquired resistance was not only to ZSTK474 but also to other PI3Kis. None of the PI3Ki‐resistant cells, however, contained any mutation in the kinase domain of the PIK3CA gene. Instead, we found that insulin‐like growth factor 1 receptor (IGF1R) was overexpressed in all four resistant cells. Interestingly, targeted knockdown of IGF1R expression using specific siRNAs or inhibition of IGF1R using IGF1R‐TKIs reversed the acquired PI3Ki resistance. These results suggest that long‐term treatment with PI3Kis may cause acquired resistance, and targeting IGF1R is a promising strategy to overcome the resistance.
Restructuring the Sea: profound shifts in the world's most invaded marine ecosystem
Authors: Edelist Dor , Rilov Gil , Golani Daniel , Carlton James T. , Spanier Ehud 
Published: August 2012

AbstractAimWe examine fish invasions in the south‐eastern Mediterranean as a model system for the invasibility of open coasts and provide perspectives through a review of global marine fish invasions.LocationSouth‐eastern Mediterranean (Levant Sea).MethodsWe compare historical (1990–1994) and modern (2008–2011) trawl surveys from the Mediterranean continental shelf and upper slope of Israel to evaluate the relative abundance and biomass of Indo‐Pacific fishes and their impact on diversity and trophic level (TrL). We examine resultant changes in community composition by both univariate and multivariate analyses, and compliment this study with a critical global review of open coast marine fish invasions.ResultsA staggering 55 Indo‐Pacific fish species have established permanent populations in the Mediterranean in the last 142 years, more than any other marine ecosystem. This process is accelerating with 13 of 27 new arrivals having established in the 21st century alone. Invasive fish biomass and abundance proportions in the shallow open coast have doubled in just two decades and today the Levantine ecosystem is dominated by non‐native species. This proliferation has resulted in significant declines of some indigenous species, some to near extirpation levels.Main conclusionsHere, we show that non‐estuarine ecosystems are much more susceptible to large‐scale invasion pressures than previously thought. Our results place invasion in the same category with overexploitation, habitat destruction and pollution, processes normally considered as much more critical perturbations to coastal fish communities. We propose that despite these irreversible alterations, invasions have masked overall TrL changes and diversity declines by replacing native fish with invasives of similar ecological position. As species extirpations increase, we anticipate further declines in indigenous biomass, abundance and diversity in the Mediterranean Sea.
Deposition of superparamagnetic iron‐oxide nanoparticles in axillary sentinel lymph nodes following subcutaneous injection
Authors: Johnson Laura , Pinder Sarah E , Douek Michael 
Published: August 2012

AimsSuperparamagnetic iron oxide nanoparticle (SPIO)‐enhanced axillary lymph node magnetic resonance imaging (MRI) has the potential to supersede sentinel lymph node (SLN) biopsy in the management of early breast cancer with in vivo pre‐operative metastasis detection. We evaluated the distribution and extent of SPIOs within the SLN and its impact on routine histological assessment.Methods and resultsA total of 131 SLNs from 51 consecutive patients with breast cancer were examined histologically following subcutaneous injection of 2–4 ml SPIOs. SLNs were identified intra‐operatively using the combined technique. Ex vivo histological analysis was performed and the distribution of SPIOs assessed using standard haematoxylin and eosin staining. SPIO distribution was predominantly within lymph node sinuses (81%); fewer nodes contained iron in the subcapsular space (24%) and parenchyma (14%). In 58%, SPIOs were sequestered in macrophages. SPIOs were not seen within the areas of nodes containing metastases, but was seen surrounding the metastases.ConclusionsFollowing subcutaneous injection of SPIOs, iron deposition is found predominantly in sinuses and the subcapsular space and is not found in areas containing metastases. This reinforces the notion that high resolution SPIO‐enhanced MRI has the potential for in vivo metastasis in the SLN in breast cancer. Routine histological examination was unaffected.
A record‐linkage study of drug‐related death and suicide after hospital discharge among drug‐treatment clients inScotland, 1996–2006
Authors: Merrall Elizabeth L. C. , Bird Sheila M. , Hutchinson Sharon J. 
Published: August 2012

AbstractAimsTo investigate the relationship between time after hospital discharge and drug‐related death (DRD) and suicide among drug users inScotland, while controlling for potential confounders.DesignCohort study.Setting and participantsThe 69 457 individuals who registered for drug treatment in Scotland during 1April 1996–31March 2006.MeasurementsTime‐at‐risk was from the date of an individual's first attendance at drug treatment services after 1April 1996 until the earlier date of death or end‐of‐study, 31March 2006, and was categorized according to time since the most recent hospitalization, as during hospitalization, within 28 days, 29–90 days, 91 days to 1 year and >1 year since discharge from most recent hospital stay versus ‘never admitted’ (reference).FindingsTime‐periods soon after discharge were associated with increased risk ofDRD.DRDrates per 1000 person‐years were: 87 (95%CI: 72–103) during hospitalization, 21 (18–25) within 28 days, 12 (10–15) during 29–90 days and 8.5 (7.5–9.5) during 91 days to 1 year after discharge versus 4.2 (3.7–4.7) when >1 year after most recent hospitalization and 1.9 (1.7–2.1) for those never admitted. Adjusted hazard ratios by time since hospital discharge (versus never admitted) were: 9.6 (95%CI: 8–12) within 28 days, 5.6 (4.6–6.8) during days 29–90, thereafter 4.0 (3.5–4.7) and 2.3 (2.0–2.7) when >1 year. Non‐drug‐related suicides were less frequent thanDRDs(269 versus 1383) but a similar risk pattern was observed.ConclusionsIn people receiving treatment for drug dependence, discharge from a period of hospitalization marks the start of a period of heightened vulnerability to drug‐related death.
Predicted metabolic drug clearance with increasing adult age
Authors: Polasek Thomas M. , Patel Farhaan , Jensen Berit P. , Sorich Michael J. , Wiese Michael D. , Doogue Matthew P. 
Published: August 2012

AimTo determine the effect of increasing adult age on predicted metabolic drug clearance.MethodPredicted metabolic drug clearances (CLPT) were determined using in vitro‐in vivo extrapolation coupled with physiological‐based pharmacokinetic modelling and simulation (IVIVE‐PBPK) in Simcyp®. Simulations were conducted using CYP‐selective ‘probe’ drugs with subjects in 5 year age groups (20–25 to 90–95 years). CLPT values were compared with human pharmacokinetic data stratified according to age (young = 20–40 years and elderly = 65–85 years) and gender. Age‐related changes in the physiological parameters used for IVIVE of CLPT were described.ResultsPredicted metabolic drug clearances decreased with increasing adult age to approximately 65–70 years: caffeine from 1.5 to 1.0 ml min−1 kg−1 (a 33% decrease), S‐warfarin from 0.100 to 0.064 ml min−1 kg−1 (36%), S‐mephenytoin from 4.1 to 2.5 ml min−1 kg−1 (39%), desipramine from 10.6 to 7.3 ml min−1 kg−1 (31%) and midazolam from 5.4 to 3.9 ml min−1 kg−1 (27%). Except for S‐mephenytoin, predictions were within 3.5‐fold of clearances from clinical studies when stratified by age and gender. A trend towards higher CLPT was observed in females, but this was only statistically significant in larger virtual trials. Physiological parameters that determine CLPT decreased with increasing adult age: mean microsomal protein g–1 of liver, liver weight, hepatic blood flow and human serum albumin concentration.ConclusionDecreased metabolic clearance in the elderly was predicted by Simcyp® and was generally consistent with limited clinical data for four out of five drugs studied and the broader literature for drugs metabolized by CYP enzymes. IVIVE‐PBPK may be increasingly useful in predicting metabolic drug clearance in the elderly.
Characterization of the interaction between astrocytes and encephalitogenic lymphocytes during the development of experimental autoimmune encephalitomyelitis (EAE) in mice
Authors: Yang J F , Tao H Q , Liu Y M , Zhan X X , Liu Y , Wang X Y , Wang J H , Mu L L , Yang L L , Gao Z M , Kong Q F , Wang G Y , Han J H , Sun B , Li H L 
Published: August 2012

SummaryThe nature of pathogenic mechanisms associated with the development of multiple sclerosis (MS) have long been debated. However, limited research was conducted to define the interplay between infiltrating lymphocytes and resident cells of the central nervous system (CNS). Data presented in this report describe a novel role for astrocyte-mediated alterations to myelin oligodendrocyte glycoprotein (MOG)35–55-specific lymphocyte responses, elicited during the development of experimental autoimmune encephalitomyelitis (EAE). In-vitro studies demonstrated that astrocytes inhibited the proliferation and interferon (IFN)-γ, interleukin (IL)-4, IL-17 and transforming growth factor (TGF)-β secretion levels of MOG35–55-specific lymphocytes, an effect that could be ameliorated by astrocyte IL-27 neutralization. However, when astrocytes were pretreated with IFN-γ, they could promote the proliferation and secretion levels of MOG35–55-specific lymphocytes, coinciding with apparent expression of major histocompatibility complex (MHC)-II on astrocytes themselves. Quantitative polymerase chain reaction (qPCR) demonstrated that production of IL-27 in the spinal cord was at its highest during the initial phases. Conversely, production of IFN-γ in the spinal cord was highest during the peak phase. Quantitative analysis of MHC-II expression in the spinal cord showed that there was a positive correlation between MHC-II expression and IFN-γ production. In addition, astrocyte MHC-II expression levels correlated positively with IFN-γ production in the spinal cord. These findings suggested that astrocytes might function as both inhibitors and promoters of EAE. Astrocytes prevented MOG35–55-specific lymphocyte function by secreting IL-27 during the initial phases of EAE. Then, in the presence of higher IFN-γ levels in the spinal cord, astrocytes were converted into antigen-presenting cells. This conversion might promote the progression of pathological damage and result in a peak of EAE severity.
Reduced expression of galectin-1 and galectin-9 by leucocytes in asthma patients
Authors: Sanchez-Cuellar S , de la Fuente H , Cruz-Adalia A , Lamana A , Cibrian D , Giron R M , Vara A , Sanchez-Madrid F , Ancochea J 
Published: August 2012

Summary
Accumulating evidence shows that galectins play roles in the initiation and resolution phases of inflammatory responses by promoting anti- or proinflammatory effects. This study investigated the presence of three members of the galectin family (galectin-1, -3 and -9) in induced sputum samples of asthma patients, as well as their possible implication in the immunopathogenesis of human asthma. Levels of interleukin (IL)-5, IL-13, and galectins were determined in leucocytes isolated from induced sputum samples by reverse transcription–polymerase chain reaction (RT–PCR) immunofluorescence and flow cytometry. High levels of IL-5 and IL-13 mRNA were detected in sputum cells from asthma patients. In parallel, immunoregulatory proteins galectin-1 and galectin-9 showed a reduced expression on macrophages from sputum samples compared with cells from healthy donors. In-vitro immunoassays showed that galectin-1 and galectin-9, but not galectin-3, are able to induce the production of IL-10 by peripheral blood mononuclear cells from healthy donors. These findings indicate that macrophages from sputum samples of asthma patients express low levels of galectin-1 and galectin-9, favouring the exacerbated immune response observed in this disease.
Epitope recognition patterns of thyroglobulin antibody in sera from patients with Hashimoto's thyroiditis on different thyroid functional status
Authors: Liu M , Zhao L , Gao Y , Huang Y , Lu G , Guo X 
Published: August 2012

SummaryThyroglobulin antibody (TgAb) is a diagnostic serological marker of Hashimoto's thyroiditis (HT). The pathogenesis of HT progression from euthyroidism to hypothyroidism is still not clear. Epitope recognition patterns of TgAb have been shown to be different in individuals who are euthyroid or who have clinical disease. The aim of our study was to investigate the role of thyroglobulin (Tg) epitope specificities in HT progression. Sera from 107 patients with newly diagnosed HT were collected and divided into three groups: patients with hypothyroidism (H, n = 39), subclinical hypothyroidism (sH, n = 31) and euthyroidism (Eu, n = 37). A panel of Tg murine monoclonal antibodies (mAb: PB2, 5E6, 1D4, 5F9, Tg6) and a hircine pAb (N15) were employed as the probe antibodies to define the antigenic determinants recognized by HT sera on competitive enzyme-linked immunosorbent assays (ELISAs). Eight of 39 sera samples in H and seven of 31 in sH inhibited PB2 binding, respectively, whereas none did in Eu. The ratio of sera samples, inhibiting PB2 binding in Eu, was significantly lower than that in H (P = 0·011) and in sH (P = 0·008). For N15, five of 39 sera samples in H, six of 31 in sH and 15 of 37 in Eu inhibited its binding, respectively. The ratio of sera samples, inhibiting N15 binding in Eu, was significantly higher than that in H (P = 0·013). Our study demonstrated that HT patients in different thyroid functional status exhibited different Tg epitope recognition patterns. Epitope patterns of TgAb might be used as a prediction marker of HT progression.
Schistosoma mansonitetraspanning orphan receptor (SmTOR): a new vaccine candidate against schistosomiasis
Authors: Lochmatter C , Schneider C L , Ingram K , Keiser J , Schifferli J A 
Published: August 2012

SummaryOne approach to fight against schistosomiasis is to develop an efficient vaccine. Schistosoma mansoni tetraspanning orphan receptor (SmTOR) might be a vaccine candidate, as it is a tegument membrane protein expressed most highly in cercariae. In this study we characterized the recombinant first extracellular domain of SmTOR (rSmTORed1) as having the expected property to bind C2 of complement similarly to a smaller peptide of the same domain, and to produce specific and high-titre antibodies in BALB/c mice immunized using complete Freund's adjuvant/incomplete Freund's adjuvant (CFA/IFA). Immunization was protective against parasite infection, as demonstrated by a significant decrease in worm burden in immunized BALB/c mice versus the control groups over two independent trials [64 and 45% reduction for mean adult worm burden in immunized versus phosphate-bufferd saline (PBS) injected mice]. Interestingly, infection by itself did not lead to the generation of anti-rSmTORed1 antibodies, corresponding to the low frequency of specific anti-rSmTORed1 antibodies detected in the sera of patients infected with S. mansoni (2/20; 10%). These data suggest that, as opposed to the natural infection during which SmTOR induces antibodies only rarely, immunization with its smaller first extracellular domain might be more efficient.
Phenotypic plasticity and evolutionary demographic responses to climate change: taking theory out to the field
Authors: Chevin Luis‐Miguel , Collins Sinéad , Lefèvre François 
Published: August 2012

Summary

Rapid climate change both imposes strong selective pressures on natural populations – potentially reducing their growth rate and causing genetic evolution – and affects the physiology and development of individual organisms. Understanding and predicting the fates of populations under global change, including extinctions and geographical range shifts, requires analysing the interplay of these processes, which has long been a grey area in evolutionary biology.
We review recent theory on the interaction of phenotypic plasticity, genetic evolution and demography in environments that change in time or space. We then discuss the main limitations of the models and the difficulties in testing theoretical predictions in the wild, notably regarding changes in phenotypic selection, the evolution of (co)variances of reaction norm parameters, and transient dynamics.
We use two landmark examples of physiological responses to climate change –trees facing drier climate and extreme temperatures, and marine phytoplankton under rising CO2 – to highlight relatively neglected questions and indicate the theoretical and empirical challenges that they raise. These examples illustrate notably that age‐specific patterns of plasticity and selection on the one hand, and changes in community interactions and functioning on the other hand, need to be further investigated theoretically and empirically for a better understanding of evolutionary demographic responses to climate change in the wild.
Quality of raw and smoked fillets from clinically healthy Atlantic salmon, Salmo salar L., following an outbreak of pancreas disease (PD)
Authors: Taksdal T , Wiik‐Nielsen J , Birkeland S , Dalgaard P , Mørkøre T 
Published: August 2012

AbstractPancreas disease (PD) is a viral disease of farmed salmonid fish, which causes huge economic losses. Pathological changes in skeletal muscle, pancreas and heart are hallmarks of PD. Stakeholders in the fish‐smoking industry have claimed that fillets from PD‐affected Atlantic salmon, Salmo salar L., are of poor quality. We therefore examined harvest‐ready, clinically healthy Atlantic salmon from a population of fish previously affected by PD. Histopathological changes in skeletal muscle tissues ranged from minor to severe. Fillet quality measurements showed that fish with severe skeletal muscle changes provided a paler raw fillet and a yellowish and harder cold‐smoked fillet than normal. PD had no significant effect on fillet gaping, bacteriological quality or off‐odour development during storage. An unexpected finding was a significant subendocardial fibrosis in 23% of the PD‐affected fish. The latter may indicate susceptibility to stress‐related heart failure.
SolTrack: an automatic video processing software for in situ interface tracking
Authors: GRIESSER S. , PIERER R. , REID M. , DIPPENAAR R. 
Published: August 2012

SummaryHigh‐Resolution in situ observation of solidification experiments has become a powerful technique to improve the fundamental understanding of solidification processes of metals and alloys. In the present study, high‐temperature laser‐scanning confocal microscopy (HTLSCM) was utilized to observe and capture in situ solidification and phase transformations of alloys for subsequent post processing and analysis. Until now, this analysis has been very time consuming as frame‐by‐frame manual evaluation of propagating interfaces was used to determine the interface velocities. SolTrack has been developed using the commercial software package MATLAB and is designed to automatically detect, locate and track propagating interfaces during solidification and phase transformations as well as to calculate interfacial velocities. Different solidification phenomena have been recorded to demonstrate a wider spectrum of applications of this software. A validation, through comparison with manual evaluation, is included where the accuracy is shown to be very high.
The EAGR box structure: a motif involved in mycoplasma motility
Authors: Calisto Bárbara M. , Broto Alícia , Martinelli Luca , Querol Enrique , Piñol Jaume , Fita Ignacio 
Published: August 2012

SummaryMycoplasma genitalium is an emerging human pathogen with the smallest genome found among self‐replicating organisms. M. genitalium presents a complex cytoskeleton with a differentiated protrusion known as the terminal organelle. This polar structure plays a central role in functions essential for the virulence of the microorganism, such as motility and cell‐host adhesion. A well‐conserved Enriched in Aromatic and Glycine Residues motif, the EAGR box, is present in many of the proteins found in the terminal organelle. We determined the crystal structure of the globular domain from M. genitalium MG200 that contains an EAGR box. This structural information is the first at near atomic resolution for the components of the terminal organelle. The structure revealed a dimer stabilized by a compact hydrophobic core that extends throughout the dimer interface. Monomers present a new fold that contains an accurate intra‐subunit symmetry relating two conspicuous hairpins. Some features, such as the domain plasticity and the presence and organization of the intra‐ and inter‐subunit symmetry axes, support a role for the EAGR box in protein–protein interactions. Genetic, biochemical and microcinematography analyses of MG200 variants lacking the EAGR box containing domain confirm the relevant and specific association of this domain with cell motility.
A complex network of small non‐coding RNAs regulate motility in Escherichia coli
Authors: De Lay Nicholas , Gottesman Susan 
Published: August 2012

SummarySmall Hfq‐dependent non‐coding regulatory RNAs (sRNAs) that alter mRNA stability and expression by pairing with target mRNAs have increasingly been shown to be important in influencing the behaviour of bacteria. In Escherichia coli, flhD and flhC, which encode the master regulator of flagellar synthesis, are co‐transcribed from a promoter that is regulated by multiple transcription factors that respond to different environmental cues. Here, we show that the 5′ untranslated region (5′ UTR) of the flhDC mRNA also serves as a hub to integrate additional environmental cues into the decision to make flagella. Four sRNAs, ArcZ, OmrA, OmrB and OxyS, negatively regulated and one sRNA, McaS, positively regulated motility and flhDC expression by base‐pairing with the 5′ UTR of this mRNA. Another sRNA, MicA, positively regulated motility independent of regulation of flhDC. Furthermore, we demonstrate that the regulation of motility by the ArcB/A two component system is in part due to its regulation of ArcZ. flhDC is the first mRNA that has been shown to be both positively and negatively regulated by direct pairing to sRNAs. Moreover, both positive regulation by McaS and negative regulation by ArcZ require the same binding site in the flhDC mRNA.