bluuebunny/crossref_metadata_2025 huggingface dataset:
Does prey size matter? Novel observations of feeding in the leatherback turtle (
Dermochelys coriacea
) allow a test of predator–prey size relationships
Authors: Fossette Sabrina , Gleiss Adrian C. , Casey James P. , Lewis Andrew R. , Hays Graeme C.
Published: November 2011

Optimal foraging models predict that large predators should concentrate on large prey in order to maximize their net gain of energy intake. Here, we show that the largest species of sea turtle,
Dermochelys coriacea
, does not strictly adhere to this general pattern. Field observations combined with a theoretical model suggest that a 300 kg leatherback turtle would meet its energetic requirements by feeding for 3–4 h a day on 4 g jellyfish, but only if prey were aggregated in high-density patches. Therefore, prey abundance rather than prey size may, in some cases, be the overriding parameter for foraging leatherbacks. This is a classic example where the presence of small prey in the diet of a large marine predator may reflect profitable foraging decisions if the relatively low energy intake per small individual prey is offset by high encounter rates and minimal capture and handling costs. This study provides, to our knowledge, the first quantitative estimates of intake rate for this species.
Effects of surface microtopography on the assembly of the osteoclast resorption apparatus
Authors: Geblinger Dafna , Zink Christian , Spencer Nicholas D. , Addadi Lia , Geiger Benjamin
Published: November 2011

Bone degradation by osteoclasts depends on the formation of a sealing zone, composed of an interlinked network of podosomes, which delimits the degradation lacuna into which osteoclasts secrete acid and proteolytic enzymes. For resorption to occur, the sealing zone must be coherent and stable for extended periods of time. Using titanium roughness gradients ranging from 1 to 4.5 µmRaas substrates for osteoclast adhesion, we show that microtopographic obstacles of a length scale well beyond the range of the ‘footprint’ of an individual podosome can slow down sealing-zone expansion. A clear inverse correlation was found between ring stability, structural integrity and sealing-zone translocation rate. Direct live-cell microscopy indicated that the expansion of the sealing zone is locally arrested by steep, three-dimensional ‘ridge-like barriers’, running parallel to its perimeter. It was, however, also evident that the sealing zone can bypass such obstacles, if pulled by neighbouring regions, extending through flanking, obstacle-free areas. We propose that sealing-zone dynamics, while being locally regulated by surface roughness, are globally integrated via the associated actin cytoskeleton. The effect of substrate roughness on osteoclast behaviour is significant in relation to osteoclast function under physiological and pathological conditions, and may constitute an important consideration in the design of advanced bone replacements.
Helmholtz and the British scientific elite: From force conservation to energy conservation
Authors: Cahan David
Published: November 2011

This article discusses the close relationship that developed during the 1850s and 1860s between Hermann von Helmholtz (1821–94), one of the leading German scientists during the second half of the nineteenth century, and the British scientific elite generally. It focuses especially on the importance of the law of conservation of energy to both sides of that relationship as the law emerged and became popularized. In presenting this Anglo-German relationship, the article relates Helmholtz's friendships or acquaintanceships with numerous members of the British elite, including William Thomson, John Tyndall, Henry Enfield Roscoe, Michael Faraday, Edward Sabine, Henry Bence Jones, George Gabriel Stokes, James Clerk Maxwell, Peter Guthrie Tait, George Biddell Airy and James Thomson. It suggests that the building of these social relationships helped create a sense of trust between Helmholtz and the British elite that, in turn, eased the revision of the understanding of the law of conservation of force into that of energy and consolidated its acceptance, and that laid the personal groundwork for Helmholtz's future promotion of Maxwell's electromagnetic theory in Germany and for Anglo-German agreements in electrical metrology.
The Adenomatous polyposis coli tumour suppressor is essential for Axin complex assembly and function and opposes Axin's interaction with Dishevelled
Authors: Mendoza-Topaz Carolina , Mieszczanek Juliusz , Bienz Mariann
Published: November 2011

Most cases of colorectal cancer are linked to mutational inactivation of the Adenomatous polyposis coli (APC) tumour suppressor. APC downregulates Wnt signalling by enabling Axin to promote the degradation of the Wnt signalling effector β-catenin (Armadillo in flies). This depends on Axin's DIX domain whose polymerization allows it to form dynamic protein assemblies (‘degradasomes’). Axin is inactivated upon Wnt signalling, by heteropolymerization with the DIX domain of Dishevelled, which recruits it into membrane-associated ‘signalosomes’. How APC promotes Axin's function is unclear, especially as it has been reported that APC's function can be bypassed by overexpression of Axin. Examiningapcnull mutantDrosophilatissues, we discovered that APC is required for Axin degradasome assembly, itself essential for Armadillo downregulation. Degradasome assembly is also attenuated inAPCmutant cancer cells. Notably, Axin becomes prone to Dishevelled-dependent plasma membrane recruitment in the absence of APC, indicating a crucial role of APC in opposing the interaction of Axin with Dishevelled. Indeed, co-expression experiments reveal that APC displaces Dishevelled from Axin assemblies, promoting degradasome over signalosome formation in the absence of Wnts. APC thus empowers Axin to function in two ways—by enabling its DIX-dependent self-assembly, and by opposing its DIX-dependent copolymerization with Dishevelled and consequent inactivation.
Variation in annual and lifetime reproductive success of lance-tailed manakins: alpha experience mitigates effects of senescence on siring success
Authors: DuVal Emily H.
Published: November 2011

The causes of variation in individual reproductive success over a lifetime are not well understood. In long-lived vertebrates, reproductive output usually increases during early adulthood, but it is difficult to disentangle the roles of development and learning on this gain of reproductive success. Lekking lance-tailed manakins provide an opportunity to separate these processes, as the vast majority of male reproduction occurs after a bird obtains alpha status and maintains a display area in the lek, but the age at which males achieve alpha status varies widely. Using 11 years of longitudinal data on age, social status and genetic siring success, I assessed the factors influencing variation in siring success by individuals over their lifetimes. The data show increases in annual reproductive success with both age and alpha experience. At advanced ages, these gains were offset by senescence in fecundity. Individual ontogeny, rather than compositional change of the population, generated a nonlinear relationship of breeding tenure with lifetime success; age of assuming alpha status was unrelated to tenure as a breeder, or success in the alpha role. Importantly, these findings suggest that social experience can mitigate the negative effects of senescence in older breeders.
Evolution of spur-length diversity in
Aquilegia
petals is achieved solely through cell-shape anisotropy
Authors: Puzey Joshua R. , Gerbode Sharon J. , Hodges Scott A. , Kramer Elena M. , Mahadevan L.
Published: November 2011

The role of petal spurs and specialized pollinator interactions has been studied since Darwin.
Aquilegia
petal spurs exhibit striking size and shape diversity, correlated with specialized pollinators ranging from bees to hawkmoths in a textbook example of adaptive radiation. Despite the evolutionary significance of spur length, remarkably little is known about
Aquilegia
spur morphogenesis and its evolution. Using experimental measurements, both at tissue and cellular levels, combined with numerical modelling, we have investigated the relative roles of cell divisions and cell shape in determining the morphology of the
Aquilegia
petal spur. Contrary to decades-old hypotheses implicating a discrete meristematic zone as the driver of spur growth, we find that
Aquilegia
petal spurs develop via anisotropic cell expansion. Furthermore, changes in cell anisotropy account for 99 per cent of the spur-length variation in the genus, suggesting that the true evolutionary innovation underlying the rapid radiation of
Aquilegia
was the mechanism of tuning cell shape.
An ecological approach to assessing the epidemiology of antimicrobial resistance in animal and human populations
Authors: Mather Alison E. , Matthews Louise , Mellor Dominic J. , Reeve Richard , Denwood Matthew J. , Boerlin Patrick , Reid-Smith Richard J. , Brown Derek J. , Coia John E. , Browning Lynda M. , Haydon Daniel T. , Reid Stuart W. J.
Published: November 2011

We examined long-term surveillance data on antimicrobial resistance (AMR) inSalmonellaTyphimurium DT104 (DT104) isolates from concurrently sampled and sympatric human and animal populations in Scotland. Using novel ecological and epidemiological approaches to examine diversity, and phenotypic and temporal relatedness of the resistance profiles, we assessed the more probable source of resistance of these two populations. The ecological diversity of AMR phenotypes was significantly greater in human isolates than in animal isolates, at the resolution of both sample and population. Of 5200 isolates, there were 65 resistance phenotypes, 13 unique to animals, 30 unique to humans and 22 were common to both. Of these 22, 11 were identified first in the human isolates, whereas only five were identified first in the animal isolates. We conclude that, while ecologically connected, animals and humans have distinguishable DT104 communities, differing in prevalence, linkage and diversity. Furthermore, we infer that the sympatric animal population is unlikely to be the major source of resistance diversity for humans. This suggests that current policy emphasis on restricting antimicrobial use in domestic animals may be overly simplistic. While these conclusions pertain to DT104 in Scotland, this approach could be applied to AMR in other bacteria–host ecosystems.
Invasive rats and recent colonist birds partially compensate for the loss of endemic New Zealand pollinators
Authors: Pattemore David E. , Wilcove David S.
Published: November 2011

Reported declines of pollinator populations around the world have led to increasing concerns about the consequences for pollination as a critical ecosystem function and service. Pollination could be maintained through compensation if remaining pollinators increase their contribution or if novel species are recruited as pollinators, but empirical evidence of this compensation is so far lacking. Using a natural experiment in New Zealand where endemic vertebrate pollinators still occur on one offshore island reserve despite their local extinction on the adjacent North Island, we investigated whether compensation could maintain pollination in the face of pollinator extinctions. We show that two recently arrived species in New Zealand, the invasive ship rat (
Rattus rattus
) and the recent colonist silvereye (
Zosterops lateralis
; a passerine bird), at least partly maintain pollination for three forest plant species in northern New Zealand, and without this compensation, these plants would be significantly more pollen-limited. This study provides empirical evidence that widespread non-native species can play an important role in maintaining ecosystem functions, a role that needs to be assessed when planning invasive species control or eradication programmes.
Amino acids 473V and 598P of PB1 from an avian-origin influenza A virus contribute to polymerase activity, especially in mammalian cells
Authors: Xu Chen , Hu Wei-Bin , Xu Ke , He Yun-Xia , Wang Tong-Yan , Chen Ze , Li Tian-Xian , Liu Jin-Hua , Buchy Philippe , Sun Bing
Published: November 2011

It has been reported that the avian-origin influenza A virus PB1 protein (avian PB1) enhances influenza A virus polymerase activity in mammalian cells when it replaces the human-origin PB1 protein (human PB1). Characterization of the amino acid residues that contribute to this enhancement is needed. In this study, it was found that PB1 from an avian-origin influenza A virus [A/Cambodia/P0322095/2005, H5N1 (Cam)] could enhance the polymerase activity of an attenuated human isolated virus, A/WSN/33, carrying the PB2 K627E mutation (WSN627E) in vitro. Furthermore, 473V and 598P in the Cam PB1 were identified as the residues responsible for this enhanced activity. The results from recombinant virus experiments demonstrated the contribution of PB1 amino acids 473V and 598P to polymerase activity in mammalian cells and in mice. Interestingly, 473V is conserved in pH1N1 viruses from the 2009 pandemic. Substitution of 473V by leucine in pH1N1 PB1 led to a decreased viral polymerase activity and a lower growth rate in mammalian cells, suggesting that the PB1 473V also plays a role in maintaining efficient virus replication of the pH1N1 virus. Thus, it was concluded that two amino acids in avian-origin PB1, 473V and 598P, contribute to the polymerase activity of the H5N1 virus, especially in mammalian cells, and that 473V in PB1 also contributes to efficient replication of the pH1N1 strain.
Differences in the mechanism of inoculation between a semi-persistent and a non-persistent aphid-transmitted plant virus
Authors: Moreno Aranzazu , Tjallingii W. Freddy , Fernandez-Mata Gabriela , Fereres Alberto
Published: November 2011

Inoculation of the semi-persistent cauliflower mosaic virus (CaMV, genus Caulimovirus) is associated with successive brief (5–10 s) intracellular stylet punctures (pd) when aphids probe in epidermal and mesophyll cells. In contrast to non-persistent viruses, there is no evidence for which of the pd subphases (II-1, II-2 and II-3) is involved in the inoculation of CaMV. Experiments were conducted using the electrical penetration graph (EPG) technique to investigate which particular subphases of the pd are associated with the inoculation of CaMV to turnip by its aphid vector Brevicoryne brassicae. In addition, the same aphid species/test plant combination was used to compare the role of the pd subphases in the inoculation of the non-persistent turnip mosaic virus (TuMV, genus Potyvirus). Inoculation of TuMV was found to be related to subphase II-1, confirming earlier results, but CaMV inoculation appeared to be related exclusively to subphase II-2 instead. The mechanism of CaMV inoculation and the possible nature of subphase II-2 are discussed in the scope of our findings.
Bystander Position Taking in School Bullying: The Role of Positive Identity, Self-Efficacy, and Self-Determination
Authors: Tsang Sandra K. M. , Hui Eadaoin K. P. , Law Bella C. M.
Published: November 2011

School bullying has become an explicit, burgeoning problem challenging the healthy development of children and adolescents in Hong Kong. Many bullying prevention and intervention programs focus on victims and bullies, with bystanders treated as either nonexistent or irrelevant. This paper asserts that bystanders actually play pivotal roles in deciding whether the bullying process and dynamics are benign or adversarial. Bystanders' own abilities and characteristics often influence how they respond to victims and bullies. “P.A.T.H.S. to Adulthood: A Jockey Club Youth Enhancement Scheme” (P.A.T.H.S. = Positive Adolescent Training through Holistic Social Programmes) is an evidence-based positive youth development program which shows that primary intervention programs have constructive impacts on junior secondary school students' beliefs and behavior. This paper asserts that intrapsychic qualities, namely identity, self-efficacy, and self-determination, greatly influence how bystanders react in school bullying situations. The paper also explains how classroom-based educational programs based on the P.A.T.H.S. model have been designed to help junior secondary school students strengthen these characteristics, so that they can be constructive bystanders when they encounter school bullying.
Preparation of high-quality next-generation sequencing libraries from picogram quantities of target DNA
Authors: Parkinson Nicholas J. , Maslau Siarhei , Ferneyhough Ben , Zhang Gang , Gregory Lorna , Buck David , Ragoussis Jiannis , Ponting Chris P. , Fischer Michael D.
Published: November 2011

New sequencing technologies can address diverse biomedical questions but are limited by a minimum required DNA input of typically 1 μg. We describe how sequencing libraries can be reproducibly created from 20 pg of input DNA using a modified transpososome-mediated fragmentation technique. Resulting libraries incorporate in-line bar-coding, which facilitates sample multiplexes that can be sequenced using Illumina platforms with the manufacturer's sequencing primer. We demonstrate this technique by providing deep coverage sequence of the Escherichia coli K-12 genome that shows equivalent target coverage to a 1-μg input library prepared using standard Illumina methods. Reducing template quantity does, however, increase the proportion of duplicate reads and enriches coverage in low-GC regions. This finding was confirmed with exhaustive resequencing of a mouse library constructed from 20 pg of gDNA input (about seven haploid genomes) resulting in ∼0.4-fold statistical coverage of uniquely mapped fragments. This implies that a near-complete coverage of the mouse genome is obtainable with this approach using 20 genomes as input. Application of this new method now allows genomic studies from low mass samples and routine preparation of sequencing libraries from enrichment procedures.
Experimental and theoretical electron-density study of three isoindole derivatives: topological and Hirshfeld surface analysis of weak intermolecular interactions
Authors: Chęcińska Lilianna , Grabowsky Simon , Małecka Magdalena , Rybarczyk-Pirek Agnieszka J. , Jóźwiak Andrzej , Paulmann Carsten , Luger Peter
Published: November 2011

A combined experimental and theoretical study of three isoindole derivatives was made on the basis of a topological analysis of their electron-density distributions. Experimental electron densities were determined from high-resolution X-ray diffraction data sets measured with synchrotron radiation at 100 K, whereas theoretical calculations were performed using DFT methods at the B3LYP\6-311++G(3df,3pd) level of approximation. Both experimental and theoretical models are in good agreement with each other. Since the analysed structures possess a variety of hydrogen-bonding interactions, weak intermolecular contacts of C—H...C(π), C,N(π)...C,N(π) and H...H types were subject to our special interest and are discussed in detail. They were characterized quantitatively and qualitatively by topological properties using Bader's Atoms in Molecules theory and by mapping the electron-density distribution, electrostatic potential and a geometric function on the Hirshfeld surface. This way the forces and directions of intermolecular interactions as present on the molecular surfaces were depicted and described. These interactions not only guide crystal packing, but are likewise important for recognition processes involving (aza)isoindole fragments in a biological environment.
Stacking faults and superstructures in a layered brownmillerite
Authors: Krüger H. , Stöber S. , Welberry T. R. , Withers R. L. , Fitz Gerald J. D.
Published: November 2011

Single crystals of Ca4Fe2Mn0.5Ti0.5O9 have been synthesized using a flux method. The structural characterization using single-crystal X-ray diffraction revealed the space group Amma and unit-cell dimensions of a = 5.3510 (6), b = 26.669 (3), c = 5.4914 (6) Å. The structure is isotypic with Sr3NdFe3O9 [Barrier et al. (2005). Chem. Mater. 17, 6619–6623] and exhibits separated brownmillerite-type layers. One-dimensional diffuse scattering shows that the unit cell is doubled along c by alternating the intra-layer order of tetrahedral chains, causing stacking faults along the b direction. A computer simulation was performed, proving that the observed intensity variations along the diffuse scattering rods originates from two different local structures depending on the configuration of the tetrahedral chains. Selected-area electron diffraction experiments exhibit well ordered regions characterized by satellite reflections corresponding to two different superstructures. Both superstructures can be described using the superspace group A21/m(0βγ)0s, with γ = 0.5 and β ≃ 0.27 or β = 0.
Structural study of piracetam polymorphs and cocrystals: crystallography redetermination and quantum mechanics calculations
Authors: Tilborg Anaëlle , Jacquemin Denis , Norberg Bernadette , Perpète Eric , Michaux Catherine , Wouters Johan
Published: November 2011

Pharmaceutical compounds are mostly developed as solid dosage forms containing a single-crystal form. It means that the selection of a particular crystal state for a given molecule is an important step for further clinical outlooks. In this context, piracetam, a pharmaceutical molecule known since the sixties for its nootropic properties, is considered in the present work. This molecule is analyzed using several experimental and theoretical approaches. First, the conformational space of the molecule has been systematically explored by performing a quantum mechanics scan of the two most relevant dihedral angles of the lateral chain. The predicted stable conformations have been compared to all the reported experimental geometries retrieved from the Cambridge Structural Database (CSD) covering polymorphs and cocrystals structures. In parallel, different batches of powders have been recrystallized. Under specific conditions, single crystals of polymorph (III) of piracetam have been obtained, an outcome confirmed by crystallographic analysis.
Circular dichroism beamline B23 at the Diamond Light Source
Authors: Hussain Rohanah , Jávorfi Tamás , Siligardi Giuliano
Published: November 2011

Synchrotron radiation circular dichroism (SRCD) is a well established technique in structural biology. The first UV-VIS beamline, dedicated to circular dichroism, at Diamond Light Source Ltd, a third-generation synchrotron facility in south Oxfordshire, UK, has recently become operational and it is now available for the user community. Herein the main characteristics of the B23 SRCD beamline, the ancillary facilities available for users, and some of the recent advances achieved are summarized.
Global and local hard X-ray tomography of a centimeter-size tumor vessel tree
Authors: Lang Sabrina , Dominietto Marco , Cattin Philippe , Ulmann-Schuler Alexandra , Weitkamp Timm , Müller Bert
Published: November 2011

The visualization of the vascular network in tumors down to the smallest vessels requires high spatial resolution and reasonable contrast. Stained corrosion casts of the microvasculature network guarantee superior X-ray absorption contrast and highest reproduction fidelity. Tomography of a centimeter-size tumor, however, is unfeasible at the spatial resolution needed to reveal the smallest vessels. Therefore, local tomography has been performed to visualize the smallest capillaries within the region of interest. These three-dimensional data show the detailed morphology, but the reconstructed absorption coefficients obtained in local tomography differ substantially from the absorption coefficients retrieved from the less detailed global tomography data. This paper deals with the adaptation of local tomography data using the global data and considers two-parameter histogram matching of the radiographs, sinogram extension, and multi-parameter cupping correction. It is demonstrated that two-parameter histogram matching of the radiographs already provides reasonable agreement. The change of the lens in front of the detector's camera, however, significantly affects the obtained local X-ray absorption coefficients in the tomograms predominantly owing to the dissimilar point-spread functions of the two configurations used, and much less to the fact that one of the data sets was acquired in a local geometry.
Notch1 promotes glioma cell migration and invasion by stimulating β‐catenin and NF‐κB signaling via AKT activation
Authors: Zhang Xiaohua , Chen Tao , Zhang Jiannan , Mao Qin , Li Shanquan , Xiong Wenhao , Qiu Yongming , Xie Qiuling , Ge Jianwei
Published: November 2011

The Notch signaling pathway has been implicated in both developmental processes and tumorigenesis. Aberrant Notch signaling has been repeatedly demonstrated to facilitate the proliferation and survival of glioma cells by regulating downstream effectors or other signaling pathways. In glioblastoma multiforme specimens from 59 patients, Notch1 was highly expressed in tumor tissues compared with normal brain tissues, and this expression was correlated with elevated AKT phosphorylation and Snail expression. Increased nuclear localization of β‐catenin and p50 as well as enhanced IKKα/AKT interaction were also observed in glioma tissues. In U87MG cells, the activation of Notch1 by DLL4 stimulation or by the overexpression of Notch intracellular domain (NICD) resulted in AKT activation and thereby promoted β‐catenin activity and NF‐κB signaling. Inhibition of EGFR partially blocked the β‐catenin and NF‐κB signaling stimulated by Notch1 activation. Furthermore, NICD overexpression in U87MG cells led to the upregulated expression of several metastasis‐associated molecules, which could be abrogated by the knockdown of either β‐catenin or p50. In U87MG and U251 cells, DLL4‐induced cellular migration and invasion could be inhibited by either β‐catenin or a p50 inhibitor. Collectively, these results indicate that Notch activation could stimulate β‐catenin and NF‐κB signaling through AKT activation in glioma cells. Thus, Notch activation‐stimulated β‐catenin and NF‐κB signaling synergistically promote the migratory and invasive properties of glioma cells. (Cancer Sci 2012; 103: 181–190)
α‐Lipoic acid prevents mild portal endotoxaemia‐induced hepatic inflammation and β cell dysfunction
Authors: Tian Yu‐Feng , Hsieh Chang‐Hsun , Hsieh Yen‐Ju , Chen Yu‐Ting , Peng Yi‐Jen , Hsieh Po‐Shiuan
Published: November 2011

Eur J Clin Invest 2012; 42 (6): 637–648

Background  This study was undertaken to evaluate the preventive effect of α‐lipoic acid (LA) on chronic mild portal endotoxaemia‐mediated subacute hepatic inflammation and pancreatic β cell dysfunction in rats.

Materials and methods  Male Sprague–Dawley rats were randomly assigned into four groups: those with intraportal vehicle (saline) or low‐dose lipopolysaccharide (LPS) (0·42 ng/kg/min) infusion, combined with oral administration of vehicle or LA, a potent antioxidant (60 mg/kg/day) for 4 weeks. The hyperglycaemic clamp and euglycaemic clamp techniques were used to access the glucose‐stimulated insulin secretion and systemic insulin sensitivity in vivo.

Results  Body weight, fasting plasma glucose and insulin were not different among groups. In rats with chronic intraportal LPS infusion, plasma C‐reactive protein, amylase, superoxide levels, the contents of thiobarbituric acid‐reactive substance, tumour necrosis factor α and interleukin 6 in liver and pancreas and also the gene expression of Toll‐like receptor 4 in liver were significantly increased as compared with those with LA cotreatment. The histopathological examination showed that inflammatory changes were clearly visible in liver and pancreatic islets of LPS‐infused rats and rarely observed in those cotreated with LA. In addition, low‐dose intraportal LPS infusion also significantly impaired glucose‐stimulated insulin secretion but not affect the systemic insulin sensitivity and metabolic clearance rate of insulin. LA administration markedly reversed LPS‐induced β cell dysfunction.

Conclusions  α‐Lipoic acid cotreatment could significantly prevent mild portal endotoxaemia‐induced chronic hepatic inflammation and impaired pancreatic insulin secretion in absence of changing systemic insulin resistance.
Heterogeneous amplification of ERBB2 in primary lesions is responsible for the discordant ERBB2 status of primary and metastatic lesions in gastric carcinoma
Authors: Kim Min A , Lee Hyuk‐Joon , Yang Han‐Kwang , Bang Yung‐Jue , Kim Woo Ho
Published: November 2011

Kim M A, Lee H‐J, Yang H‐K, Bang Y‐J & Kim W H  (2011) Histopathology59, 822–831

Heterogeneous amplification of ERBB2 in primary lesions is responsible for the discordant ERBB2 status of primary and metastatic lesions in gastric carcinoma

Aims:  To determine the extent of HER2 homogeneity/heterogeneity in primary versus metastatic gastric carcinoma (GC).

Materials and results:  The human epidermal growth factor receptor 2 (HER2) status in primary and metastatic lesions was evaluated by immunohistochemistry (IHC) and fluorescence in‐situ hybridization (FISH). Four separate cohorts consisting of primary GC alone or primary GC paired with metastatic lesions were examined. In the FISH analysis of 325 primary GCs, eight cases (2.5%) showed amplification with a heterogeneous pattern, whereas 27 cases (8.3%) showed amplification with a homogeneous pattern, and in this cohort the discordant:concordant FISH ratio based on examination of three different areas in each primary lesion was 0.30:1. FISH testing using 250 paired primary and metastatic lesions revealed seven cases (2.8%) with discordant amplification. In metastatic disease positive conversion occurred in six cases (2.4%), whereas negative conversion happened in one case (0.4%). The discordant:concordant ratio of primary versus secondary lesions was 0.23:1. When the seven discordant cases were re‐evaluated using whole sections of primary GCs, six showed a heterogeneous pattern of amplification.

Conclusions:  These findings suggest that the discordant HER2 amplification observed in metastatic lesions is explained substantially by heterogeneity within primary tumours.
An immunohistochemical analysis‐based decision tree model for estimating the risk of lymphatic metastasis in pN0 squamous cell carcinomas of the lung
Authors: Liu Yu , Lin Dongmei , Xiao Ting , Ma Ying , Hu Zhi , Zheng Hongwei , Zheng Shan , Liu Yan , Li Min , Li Lin , Cao Yan , Guo Suping , Han Naijun , Di Xuebing , Zhang Kaitai , Cheng Shujun , Gao Yanning
Published: November 2011

Liu Y, Lin D, Xiao T, Ma Y, Hu Z, Zheng H, Zheng S, Liu Y, Li M, Li L, Cao Y, Guo S, Han N, Di X, Zhang K, Cheng S & Gao Y  (2011) Histopathology  59, 882–891

An immunohistochemical analysis‐based decision tree model for estimating the risk of lymphatic metastasis in pN0 squamous cell carcinomas of the lung

Aims:  Lung cancer patients within the pN0 category have a significantly different outcome. The aim of this study was to develop a mathematical model to assist in predicting the prognosis of pN0 lung squamous cell carcinoma (SCC).

Methods and results:  Twenty‐three proteins were examined by immunohistochemical (IHC) analysis on primary tumour tissues from 319 lung SCC patients. In a training group, using IHC data, a recursive partitioning decision tree (RP‐DT) was used to build a model for estimating the risk for lymphatic metastasis. This model was then validated in a test cohort. Of 23 proteins, 8 (matrix metallopeptidase 1, metalloproteinase inhibitor 1, Ras GTPase‐activating‐like protein IQGAP1, targeting protein for Xklp2, urokinase‐type plasminogen activator, cathepsin D, fascin, polymeric immunoglobulin receptor/secretory component) were selected, and generated a tree model in a training group of 255 patients to classify them as at high or low risk of lymphatic invasion, with accuracy of 78.0% (compared to histopathological diagnosis), sensitivity of 83.0% and specificity of 70.3%. When the tree model was applied to the test group, the accuracy, sensitivity and specificity were 76.6%, 76.0% and 76.9%, respectively. The performance of this mathematical model was substantiated further in 34 ‘problematic’ stage I/pN0 patients by survival analysis.

Conclusions:  The RP‐DT model, constructed with eight protein markers for estimating lymphatic metastasis risk in pN0 lung SCC, is clinically feasible and practical, using IHC data from the primary tumour.
Pulmonary capillary haemangiomatosis‐like lesions in severely congested lungs
Authors: Matsukuma Susumu , Sato Kimiya
Published: November 2011

Matsukuma S & Sato K (2011) Histopathology59, 876–881

Pulmonary capillary haemangiomatosis‐like lesions in severely congested lungs

Aims:  To elucidate the nature of capillary alterations in the severe form of pulmonary venous congestion (SPVC).

Methods and results:  Post‐mortem lungs from 52 patients with left‐sided cardiac failure were examined, including 31 cases of valvular heart disease and 21 cases of cardiomyopathy. Six post‐mortem lungs (six of 52, 11.5%) had patchy lesions composed of markedly widened alveolar walls containing numerous dilated capillaries. These features strikingly mimicked pulmonary capillary haemangiomatosis (PCH). Moreover, one (one of 52, 1.9%) lung showed numerous fibrous micronodules containing capillaries with or without ossification, associated with prominent capillary sprouts, suggesting capillary varicose changes. No pathological features suggesting plexiform angiopathy or veno‐occlusive disease were found. Ultrastructural examination revealed occasional interposition of swollen endothelial cells in the thickened basement membranes of the pulmonary capillaries.

Conclusion:  PCH‐like lesions can occur infrequently as an incidental finding in SPVC, rarely accompanying ossifying fibrocapillary micronodules. These lesions are considered to be a secondary form of PCH, representing severely tortuous and proliferative capillary changes rather than neoplasia.
Human epidermal growth factor receptor 2 testing in gastric carcinoma: issues related to heterogeneity in biopsies and resections*
Authors: Lee Stephen , de Boer Willem Bastiaan , Fermoyle Soraya , Platten Michael , Kumarasinghe Marian Priyanthi
Published: November 2011

Lee S, de Boer W B, Fermoyle S, Platten M & Kumarasinghe M P  (2011) Histopathology59, 832–840

Human epidermal growth factor receptor 2 testing in gastric carcinoma: issues related to heterogeneity in biopsies and resections

Aims:  To assess human epidermal growth factor receptor 2 (HER2) status and heterogeneity using immunohistochemistry (IHC) and silver in‐situ hybridization (SISH) in gastric carcinoma and dysplasia, and to correlate HER2 status between biopsy and resection specimens of gastric carcinoma.

Methods and results:  Immunohistochemistry for HER2 was performed in 178 cases of gastric carcinoma, and SISH in cases showing at least 1+ reaction. HER2 positivity [European Medicines Agency (EMA) guidelines] was identified in 20.2% of carcinomas and 12.9% of high‐grade dysplasia, and HER2 heterogeneity noted in 50% and 33% of these cases, respectively. IHC negative/positive reactivity and SISH results were concordant in 96.2%. SISH amplification was seen in 35.3% of IHC 2+ and in a case with previously unrecognized staining pattern. Concordance of IHC HER2 status on biopsies and gastrectomies was seen in 74.1%. False negative IHC results on either the biopsy or gastrectomy were seen in 19.4% of HER2 amplified cases.

Conclusions:  Human epidermal growth factor receptor 2 status in gastric carcinoma is comparable to previous studies with good concordance between IHC and SISH; all IHC 2+ and unusual patterns should be assessed with ISH studies; heterogeneity of tumour HER2 overexpression/amplification is common with possible implications for HER2 testing; and HER2 overexpression appears sufficiently specific to be considered a potential diagnostic biomarker of dysplasia.
Evaluation of a hormone receptor‐positive ovarian carcinoma subtype with a favourable prognosis by determination of progesterone receptor and oestrogen receptor 1 mRNA expression in formalin‐fixed paraffin‐embedded tissue
Authors: Sinn Bruno V , Darb‐Esfahani Silvia , Wirtz Ralph M , Budczies Jan , Sehouli Jalid , Chekerov Radoslav , Dietel Manfred , Denkert Carsten
Published: November 2011

Sinn B V, Darb‐Esfahani S, Wirtz R M, Budczies J, Sehouli J, Chekerov R, Dietel M & Denkert C  (2011) Histopathology  59, 918–927

Evaluation of a hormone receptor‐positive ovarian carcinoma subtype with a favourable prognosis by determination of progesterone receptor and oestrogen receptor 1 mRNA expression in formalin‐fixed paraffin‐embedded tissue

Aims:  In vitro and epidemiological studies indicate an essential role for progesterone in the aetiology and progression of ovarian carcinoma. The aim of this study was to examine the prognostic role of progesterone receptor (PR) protein and mRNA expression.

Methods and results:  PR expression was examined by immunohistochemistry (n = 143) and kinetic reverse transcription–polymerase chain reaction (RT–PCR) from formalin‐fixed and paraffin‐embedded tissue (n = 55). PR mRNA and protein expression correlated (P < 0.0001). PR mRNA was a positive predictor for overall and progression‐free survival (P = 0.0005 and P < 0.0001, respectively). Protein expression was also prognostic (P = 0.015 and P = 0.0011, respectively), whereas only PR mRNA retained its prognostic value on multivariate analysis (P = 0.04). PR mRNA was still a positive prognostic marker among oestrogen receptor 1 (ESR1) mRNA‐positive tumours (P= 0.0007) and survival was best in patients with PR‐ and ESR1‐positive phenotypes (P = 0.0155 and P = 0.0016, respectively).

Conclusion:  Expression of PR and ESR1 defines a subgroup of ovarian carcinomas with a favourable prognosis. PR and ESR1 mRNA expression analysis is a sensitive, quantitative and easy‐to‐perform high‐throughput analytical tool for the identification of this subgroup and could be predictive in clinical trials focused on patients with potential benefit from hormonal treatment.
Nuclear atypia grading score is a useful prognostic factor in papillary gastric adenocarcinoma
Authors: Nakashima Yuichiro , Yao Takashi , Hirahashi Minako , Aishima Shinichi , Kakeji Yoshihiro , Maehara Yoshihiko , Tsuneyoshi Masazumi
Published: November 2011

Nakashima Y, Yao T, Hirahashi M, Aishima S, Kakeji Y, Maehara Y & Tsuneyoshi M  (2011) Histopathology59, 841–849

Nuclear atypia grading score is a useful prognostic factor in papillary gastric adenocarcinoma

Aims:  To investigate nuclear atypical in papillary gastric adenocarcinoma (PGA).

Method and results:  Hundred cases of PGA were classified into two groups according to nuclear pleomorphism and nuclear polarity; these groups were designated as high nuclear grade and low nuclear grade. Correlations between nuclear grade and clinicopathological features were evaluated for prognostic value. In order to evaluate which types of biological factors influence nuclear atypia, the expression of gastric‐type mucin phenotype, p53, HER2 and Ki‐67 detected by immunohistochemistry and DNA ploidy detected by laser scanning cytometry. The high nuclear grade group correlated with deeper wall invasion, the presence of lymphatic and venous invasion and the positivity of lymph node metastasis. High nuclear grade was an independent prognostic factor for disease‐free survival. Moreover, significant correlations were observed between high nuclear grade and positivity of gastric‐type mucin phenotype, p53 and HER2 and DNA aneuploidy.

Conclusion:  Nuclear grade could be a new and useful morphological predictor for high malignant potential in PGA.
Unexplained fetal death has a biological signature of maternal anti‐fetal rejection: chronic chorioamnionitis and alloimmune anti‐human leucocyte antigen antibodies
Authors: Lee JoonHo , Romero Roberto , Dong Zhong , Xu Yi , Qureshi Faisal , Jacques Suzanne , Yoo Wonsuk , Chaiworapongsa Tinnakorn , Mittal Pooja , Hassan Sonia S. , Kim Chong Jai
Published: November 2011

Lee J, Romero R, Dong Z, Xu Y, Qureshi F, Jacques S, Yoo W, Chaiworapongsa T, Mittal P, Hassan S S & Kim C J  (2011) Histopathology  59, 928–938

Unexplained fetal death has a biological signature of maternal anti‐fetal rejection: chronic chorioamnionitis and alloimmune anti‐human leucocyte antigen antibodies

Aims:  Chronic chorioamnionitis is a histological manifestation of maternal anti‐fetal cellular rejection. As failure of graft survival is the most catastrophic event in organ transplantation, we hypothesized that fetal death could be a consequence of maternal rejection. The aim of this study was to assess whether there is evidence of cellular and antibody‐mediated rejection in fetal death.

Methods and results:  Placental histology was reviewed for the presence of chronic chorioamnionitis in unexplained preterm fetal death (n = 30) and preterm live birth (n = 103). Amniotic fluid CXCL10 concentrations were measured with a specific immunoassay. Chronic chorioamnionitis was more frequent in fetal death than in live birth (60.0% versus 37.9%; P < 0.05) and fetal death had a higher median amniotic fluid CXCL10 concentration than live birth (2.0 versus 1.8 ng/ml, P < 0.05), after adjusting for gestational age at amniocentesis. Maternal anti‐human leucocyte antigen class II panel‐reactive seropositivity determined by flow cytometry was higher in fetal death compared to live birth (35.7% versus 10.9%; P < 0.05).

Conclusions:  Chronic chorioamnionitis is a common pathologic feature in unexplained preterm fetal death. This novel finding suggests that cellular and antibody‐mediated anti‐fetal rejection of the mother is associated with fetal death (graft failure) in human pregnancy.
Invasion in tidal zones on complex coastlines: modelling larvae of the non‐native Manila clam, Ruditapes philippinarum, in the UK
Authors: Herbert Roger J. H. , Willis Jay , Jones Elfed , Ross Kathryn , Hübner Ralf , Humphreys John , Jensen Antony , Baugh John
Published: November 2011

Aim  To evaluate whether natural larval transport and behaviour alone can explain the pattern of invasion and establishment of the non‐indigenous Manila clam, Ruditapes philippinarum (Adams & Reeve, 1850), and its spread beyond the point of introduction in the UK.

Location  The study is focused on Poole Harbour, south England, the point of introduction of the Manila clam in the UK.

Methods  We use fine‐resolution hydrodynamic models coupled with a water salinity model and an individual behaviour model of Manila clam larvae. The model was informed by experimental studies on the vertical response of larvae to salinity and field studies of the species in its natural and new environments.

Results  Variations in the behavioural response of larvae to salinity in the model considerably affected the retention of clam larvae within the harbour. High levels of predicted larval retention occurred in two of five zones in the harbour when the salinity target was set at 17 practical salinity units. Persistently high densities of adult clams and recruits are accurately predicted in these regions.

Main conclusions  Even within a relatively small region such as Poole Harbour, there is both localized retention of larvae or ‘closed’ areas and areas that are considerably more ‘open’ and potentially connected. The behavioural response of larvae to salinity significantly affected the degree of retention and ‘openness’ of the harbour to this species. Although, through natural transport, larvae could theoretically reach the next available habitat within the duration of their pelagic stage our study indicates that areas of sufficiently reduced salinity may be necessary for sufficient retention, recruitment and establishment of new adult populations in estuaries. High resolution hydrodynamic models, coupled with larval behaviour, can accurately simulate and predict biological invasion along complex coastlines and contribute to risk assessment of the introduction of non‐indigenous species for aquaculture and spatial management of marine protection.
Baby oil therapy for uremic pruritus in haemodialysis patients
Authors: Lin Tzu‐Chen , Lai Yu‐Hung , Guo Su‐Er , Liu Chin‐Fang , Tsai Jer‐Chia , Guo How‐Ran , Hsu Hsin‐Tien
Published: November 2011

Aims.  The purpose of this study was to investigate the effectiveness of chilled/un‐chilled baby oil therapy for treating uremic pruritus in haemodialysis patients.

Background.  Uremic pruritus affects 50–90% of haemodialysis patients, which makes it one of the most common medical problems in this population. Pruritus can cause skin infection, desquamation, pathological skin change, sleep disorder, anxiety, depression and social dysfunction.

Design.  A prospective, pretest—post‐test quasi‐experimental design was used.

Methods.  Haemodialysis patients with uremic pruritus were recruited and randomly assigned to one of three groups: experimental group 1 (chilled baby oil treatment; n = 30), experimental group 2 (un‐chilled baby oil treatment; n = 31) and a control group (routine care only; n = 32). Participants in experimental group 1 and experimental group 2 were treated with chilled and un‐chilled baby oil, respectively, for 15 minutes at least once daily for three weeks. The control group received no intervention other than standard care. Data collection included demographic data and itch severity. Medical records were also reviewed.

Results.  The baseline characteristics of subjects in this study were as follows: 59% were male, mean age was 61·88 (SD 12·7) years, mean duration of haemodialysis was 5·31 years, mean duration of uremic pruritus was 40·58 (SD 37·8) months and mean intensity of uremic pruritus was mild. The anti‐pruritic effects were significantly larger in subjects treated with either chilled or un‐chilled baby oil than in those who received routine care. Anti‐pruritic effects did not significantly differ between experimental group 1 and experimental group 2.

Conclusions.  The study confirmed that, for relieving pruritus in haemodialysis patients, either chilled or un‐chilled baby oil is as effective as moisturising lotions and cooling soothing agents.

Relevance to clinical practice.  Applying baby oil is a simple, safe, inexpensive and easily administered treatment for itchy skin in haemodialysis patients. By preventing or reducing uremic pruritus, baby oil treatment may also improve quality of life in this patient group.
Development of neutralizing antibody responses in muskellunge, Esox masquinongy (Mitchill), experimentally exposed to viral haemorrhagic septicaemia virus (genotype IVb)
Authors: Millard E V , Faisal M
Published: November 2011

A complement‐dependent 50% plaque neutralization test was used to assess the neutralizing antibody response in sera of muskellunge, Esox masquinongy, experimentally infected with viral haemorrhagic septicaemia virus (VHSV, genotype IVb) by immersion. Groups of muskellunge were challenged with varying concentrations of VHSV: Group 1 with 102 plaque‐forming units (pfu) mL−1, Group 2 with 4 × 103 pfu mL−1, Group 3 with 105 pfu mL−1 and Group 4 with 0 pfu mL−1. The fish were held at a temperature of 11 ± 1 °C and were sampled over a 20‐week period. Neutralizing antibodies were not detected in sera of any of the negative control fish throughout the study. Low neutralizing titres were detected in Groups 1–3 by 6 days post‐infection (p.i.). Neutralizing titres of <80 were not detected again until 3, 4 and 7 weeks p.i. for Groups 2, 3 and 1, respectively, with peak titres for those groups occurring 16, 11 and 17 weeks p.i., respectively. VHSV was detected in serum for up to 11 weeks p.i. Results of this study show that survivors can be detected by a serological technique, despite being virus negative. This may benefit the investigation of VHSV IVb distribution in the Great Lakes and the study of host immune responses to this emerging sublineage.