bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal changes and consistency in male physical and behavioural traits have implications for mating success in the grey seal (Halichoerus grypus)
Authors: Lidgard D.C. , Bowen W.D. , Boness D.J. 
Published: June 2012

We examined age-related changes and consistency in physical and behavioural traits of 20 male grey seals ( Halichoerus grypus (Fabricius, 1791)) and implications for a proxy of mating success (number of oestrous females attended) over four successive breeding seasons on Sable Island, Canada. Across the study, young males (10–15 years) gained body mass, while old males (23–31 years) lost body mass. Body length was an important determinant of tenure (time spent at a site among females) and males of all ages exhibited a high level of consistency in duration of tenure (r = 0.40–0.50). In young males, our proxy of success showed a strong relationship with arrival body mass and also exhibited a high level of consistency (r = 0.50). None of the physical traits measured explained variation in success by exhibiting mating tactics that did not involve tenure, which is likely due to the opportunistic nature of those tactics. Whereas young male grey seals exhibited age-dependent improvements in success owing to changes in their physical state, later in life physical traits were less influential and suggest that nonphysical traits may compensate for a deteriorating physical state and its impact on male success.
Dispersal, home-range size, and habitat use of an endangered land snail, the Oregon forestsnail (Allogona townsendiana)
Authors: Edworthy A.B. , Steensma K.M.M. , Zandberg H.M. , Lilley P.L. 
Published: June 2012

Terrestrial molluscs have declined globally, often as a result of habitat loss and fragmentation. Many land snails are poor dispersers and exist in isolated habitat patches. The Oregon forestsnail ( Allogona townsendiana (I. Lea, 1838)) coincides with the most densely populated region of British Columbia and is listed as endangered in Canada. To investigate the dispersal distances and habitat-use patterns of Oregon forestsnails, we tagged and tracked 21 adult snails at Langley, British Columbia, for up to 3 years (2005–2008). The maximum daily dispersal distance for a snail was 4.5 m and the maximum displacement that we observed for a snail was 32.2 m during 3 years. Snails occupied home-range areas of 18.4–404.4 m2, often overlapping both forest and meadow habitat. Their home-range sizes were smaller in habitats with high availability of stinging nettle ( Urtica dioica L.), which may be an indicator of high-quality habitat. Our results suggest that the Oregon forestsnail is a relatively sedentary species with limited dispersal ability in its adult stage. Although Oregon forestsnails are likely unable to colonize suitable habitat independently, remnant forest–meadow mosaic patches such as our study site provide valuable habitat for Oregon forestsnail, which are supplementary to large tracts of intact forest where most of their populations are found.
The Vitamin E Analogue α-TEA Stimulates Tumor Autophagy and Enhances Antigen Cross-Presentation
Authors: Li Yuhuan , Hahn Tobias , Garrison Kendra , Cui Zhi-Hua , Thorburn Andrew , Thorburn Jacqueline , Hu Hong-Ming , Akporiaye Emmanuel T. 
Published: June 2012

Abstract
The semisynthetic vitamin E derivative alpha-tocopheryloxyacetic acid (α-TEA) induces tumor cell apoptosis and may offer a simple adjuvant supplement for cancer therapy if its mechanisms can be better understood. Here we report that α-TEA also triggers tumor cell autophagy and that it improves cross-presentation of tumor antigens to the immune system. α-TEA stimulated both apoptosis and autophagy in murine mammary and lung cancer cells and inhibition of caspase-dependent apoptosis enhanced α-TEA–induced autophagy. Cell exposure to α-TEA generated double-membrane–bound vesicles indicative of autophagosomes, which efficiently cross-primed antigen-specific CD8+ T cells. Notably, vaccination with dendritic cells pulsed with α-TEA–generated autophagosomes reduced lung metastases and increased the survival of tumor-bearing mice. Taken together, our findings suggest that both autophagy and apoptosis signaling programs are activated during α-TEA–induced tumor cell killing. We suggest that the ability of α-TEA to stimulate autophagy and enhance cross-priming of CD8+ T cells might be exploited as an adjuvant strategy to improve stimulation of antitumor immune responses. Cancer Res; 72(14); 3535–45. ©2012 AACR.
Trifunctional Bispecific Antibodies Induce Tumor-Specific T Cells and Elicit a Vaccination Effect
Authors: Eissler Nina , Ruf Peter , Mysliwietz Josef , Lindhofer Horst , Mocikat Ralph 
Published: June 2012

AbstractA major goal of tumor immunotherapy is the induction of long-lasting systemic T-cell immunity. Bispecific antibodies (bsAbs) that lack the immunoglobulin Fc region confer T–cell-mediated killing of tumor cells but do not induce long-term memory. In contrast, trifunctional bsAbs comprise an appropriate Fc region and, therefore, not only recruit T cells but also accessory cells that bear activating Fcγ receptors (FcγR), providing additional T–cell-activating signals and securing presentation of tumor-derived antigens to T cells. In this study, we show that trifunctional bsAbs induce a polyvalent T-cell response and, therefore, a vaccination effect. Mice were treated with melanoma cells and with a trifunctional bsAb directed against the melanoma target antigen ganglioside GD2 in addition to murine CD3. The trifunctional bsAb activated dendritic cells and induced a systemic immune response that was not replicated by treatment with the F(ab′)2-counterpart lacking the Fc region. Restimulation of spleen and lymph node cells in vitro yielded T-cell lines that specifically produced interferon-γ in response to tumor. In addition, trifunctional bsAb-induced T cells recognized various specific peptides derived from melanoma-associated antigens. Moreover, these polyvalent responses proved to be tumor-suppressive and could not be induced by the corresponding bsF(ab′)2-fragment. Taken together, our findings provide preclinical proof of concept that trifunctional bsAbs can induce tumor-specific T cells with defined antigen specificity. Cancer Res; 72(16); 3958–66. ©2012 AACR.
Improved Statistical Modeling of Tumor Growth and Treatment Effect in Preclinical Animal Studies with Highly Heterogeneous Responses In Vivo
Authors: Laajala Teemu D. , Corander Jukka , Saarinen Niina M. , Mäkelä Katja , Savolainen Saija , Suominen Mari I. , Alhoniemi Esa , Mäkelä Sari , Poutanen Matti , Aittokallio Tero 
Published: June 2012

Abstract
Purpose: Preclinical tumor growth experiments often result in heterogeneous datasets that include growing, regressing, or stable growth profiles in the treatment and control groups. Such confounding intertumor variability may mask the true treatment effects especially when less aggressive treatment alternatives are being evaluated.
Experimental design: We developed a statistical modeling approach in which the growing and poorly growing tumor categories were automatically detected by means of an expectation-maximization algorithm coupled within a mixed-effects modeling framework. The framework is implemented and distributed as an R package, which enables model estimation and statistical inference, as well as statistical power and precision analyses.
Results: When applied to four tumor growth experiments, the modeling framework was shown to (i) improve the detection of subtle treatment effects in the presence of high within-group tumor variability; (ii) reveal hidden tumor subgroups associated with established or novel biomarkers, such as ERβ expression in a MCF-7 breast cancer model, which remained undetected with standard statistical analysis; (iii) provide guidance on the selection of sufficient sample sizes and most informative treatment periods; and (iv) offer flexibility to various cancer models, experimental designs, and treatment options. Model-based testing of treatment effect on the tumor growth rate (or slope) was shown as particularly informative in the preclinical assessment of treatment alternatives based on dietary interventions.
Conclusions: In general, the modeling framework enables identification of such biologically significant differences in tumor growth profiles that would have gone undetected or had required considerably higher number of animals when using traditional statistical methods. Clin Cancer Res; 18(16); 4385–96. ©2012 AACR.
Promising Personalized Therapeutic Options for Diffuse Large B-cell Lymphoma Subtypes with Oncogene Addictions
Authors: Steinhardt James J. , Gartenhaus Ronald B. 
Published: June 2012

Abstract
Currently, two major classification systems segregate diffuse large B-cell lymphoma (DLBCL) into subtypes based on gene expression profiles and provide great insights about the oncogenic mechanisms that may be crucial for lymphomagenesis as well as prognostic information regarding response to current therapies. However, these current classification systems primarily look at expression and not dependency and are thus limited to inductive or probabilistic reasoning when evaluating alternative therapeutic options. The development of a deductive classification system that identifies subtypes in which all patients with a given phenotype require the same oncogenic drivers, and would therefore have a similar response to a rational therapy targeting the essential drivers, would significantly advance the treatment of DLBCL. This review highlights the putative drivers identified as well as the work done to identify potentially dependent populations. These studies integrated genomic analysis and functional screens to provide a rationale for targeted therapies within defined populations. Personalizing treatments by identifying patients with oncogenic dependencies via genotyping and specifically targeting the responsible drivers may constitute a novel approach for the treatment of DLBCL. Clin Cancer Res; 18(17); 4538–48. ©2012 AACR.
Genetic Variation Within the Interleukin-1 Gene Cluster and Ischemic Stroke
Authors: Olsson Sandra , Holmegaard Lukas , Jood Katarina , Sjögren Marketa , Engström Gunnar , Lövkvist Håkan , Blomstrand Christian , Norrving Bo , Melander Olle , Lindgren Arne , Jern Christina 
Published: June 2012

Background and Purpose—

Evidence is emerging that inflammation plays a key role in the pathophysiology of ischemic stroke (IS). The aim of this study was to investigate whether genetic variation in the interleukin-1α, interleukin-1β, and interleukin-1 receptor antagonist genes (
IL1A, IL1B
, and
IL1RN
) is associated with IS and/or any etiologic subtype of IS.

Methods—
Twelve tagSNPs were analyzed in the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS), which comprises 844 patients with IS and 668 control subjects. IS subtypes were defined according to the Trial of Org 10172 in Acute Stroke Treatment criteria in SAHLSIS. The Lund Stroke Register and the Malmö Diet and Cancer study were used as a replication sample for overall IS (in total 3145 patients and 1793 control subjects).

Results—

The single nucleotide polymorphism rs380092 in
IL1RN
showed an association with overall IS in SAHLSIS (OR, 1.21; 95% CI, 1.02–1.43;
P
=0.03), which was replicated in the Lund Stroke Register and the Malmö Diet and Cancer study sample. An association was also detected in all samples combined (OR, 1.12; 95% CI, 1.04–1.21;
P
=0.03). Three single nucleotide polymorphisms in
IL1RN
(including rs380092) were nominally associated with the subtype of cryptogenic stroke in SAHLSIS, but the statistical significance did not remain after correction for multiple testing. Furthermore, increased plasma levels of interleukin-1 receptor antagonist were observed in the subtype of cryptogenic stroke compared with controls.

Conclusion—

This comprehensive study, based on a tagSNP approach and replication, presents support for the role of
IL1RN
in overall IS.
C1-Inhibitor Protects From Brain Ischemia-Reperfusion Injury by Combined Antiinflammatory and Antithrombotic Mechanisms
Authors: Heydenreich Nadine , Nolte Marc W. , Göb Eva , Langhauser Friederike , Hofmeister Marion , Kraft Peter , Albert-Weissenberger Christiane , Brede Marc , Varallyay Csanad , Göbel Kerstin , Meuth Sven G. , Nieswandt Bernhard , Dickneite Gerhard , Stoll Guido , Kleinschnitz Christoph 
Published: June 2012

Background and Purpose—
Inflammation and thrombosis are pathophysiological hallmarks of ischemic stroke still unamenable to therapeutic interventions. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is involved in stroke development. C1-inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-inhibitor in models of ischemic stroke.

Methods—
Male and female C57Bl/6 mice and rats of different ages were subjected to middle cerebral artery occlusion and treated with C1-inhibitor after 1 hour or 6 hours. Infarct volumes and functional outcomes were assessed between day 1 and day 7, and findings were validated by magnetic resonance imaging. Blood–brain barrier damage, thrombus formation, and the local inflammatory response were determined poststroke.

Results—
Treatment with 15.0 U C1-inhibitor, but not 7.5 U, 1 hour after stroke reduced infarct volumes by ≈60% and improved clinical scores in mice of either sex on day 1. This protective effect was preserved at later stages of infarction as well as in elderly mice and in another species, ie, rats. Delayed C1-inhibitor treatment still improved clinical outcome. Blood–brain barrier damage, edema formation, and inflammation were significantly lower compared with controls. Moreover, C1-inhibitor showed strong antithrombotic effects.

Conclusions—
C1-inhibitor is a multifaceted antiinflammatory and antithrombotic compound that protects from ischemic neurodegeneration in clinically meaningful settings.
Prevalence and Management of Helminthiasis among Underfives Living with HIV/AIDS at Amana Hospital, Tanzania
Authors: Mwambete Kennedy D. , Tunzo Jones , Justin-Temu Mary 
Published: June 2012

Objective: This was a cross-sectional study intended to assess the prevalence and management of helminthiasis (HL) among underfives living with HIV/AIDS (ULHA). Methodology: Clinical histories of ULHA were scrutinized for HIV/AIDS status, antiretroviral therapy (ART), HL prevalence, and their management. Results: About 364 ULHA were studied, 213 (58.5%) were girls and 151 (41.5%) were boys. Of the 364 ULHA, 171 (47.5%) had HL and 64.3% were treated with albendazole (ABZ). Trichuriasis was ascribed to 23.6% of HL. Majority (72.5%) of ULHA had a CD4 count below 200 cells/mm3. Direct association was observed between CD4 counts and HL. About 55% ULHA were on lamivudine (3TC)-stavudine (d4T)-nevirapine (NVP; LSN) combination therapy. The ABZ-LSN combination was frequently used for HIV/AIDS and HL management. Conclusion: High prevalence of HL and vivid correlation between HIV status and HL were observed. The LSN-ABZ combination was frequently employed for management of HIV/AIDS and HL. We recommended prompt diagnosis of HL to avoid acceleration of HIV infection to AIDS.
ER stress and autophagy: new discoveries in the mechanism of action and drug resistance of the cyclin-dependent kinase inhibitor flavopiridol
Authors: Mahoney Emilia , Lucas David M. , Gupta Sneha V. , Wagner Amy J. , Herman Sarah E. M. , Smith Lisa L. , Yeh Yuh-Ying , Andritsos Leslie , Jones Jeffrey A. , Flynn Joseph M. , Blum Kristie A. , Zhang Xiaoli , Lehman Amy , Kong Hui , Gurcan Metin , Grever Michael R. , Johnson Amy J. , Byrd John C. 
Published: June 2012

Abstract
Cyclin dependent kinase (CDK) inhibitors, such as flavopiridol, demonstrate significant single-agent activity in chronic lymphocytic leukemia (CLL), but the mechanism of action in these nonproliferating cells is unclear. Here we demonstrate that CLL cells undergo autophagy after treatment with therapeutic agents, including fludarabine, CAL-101, and flavopiridol as well as the endoplasmic reticulum (ER) stress-inducing agent thapsigargin. The addition of chloroquine or siRNA against autophagy components enhanced the cytotoxic effects of flavopiridol and thapsigargin, but not the other agents. Similar to thapsigargin, flavopiridol robustly induces a distinct pattern of ER stress in CLL cells that contributes to cell death through IRE1-mediated activation of ASK1 and possibly downstream caspases. Both autophagy and ER stress were documented in tumor cells from CLL patients receiving flavopiridol. Thus, CLL cells undergo autophagy after multiple stimuli, including therapeutic agents, but only with ER stress mediators and CDK inhibitors is autophagy a mechanism of resistance to cell death. These findings collectively demonstrate, for the first time, a novel mechanism of action (ER stress) and drug resistance (autophagy) for CDK inhibitors, such as flavopiridol in CLL, and provide avenues for new therapeutic combination approaches in this disease.
The rhesus macaque is three times as diverse but more closely equivalent in damaging coding variation as compared to the human
Authors: Yuan Qiaoping , Zhou Zhifeng , Lindell Stephen G , Higley J Dee , Ferguson Betsy , Thompson Robert C , Lopez Juan F , Suomi Stephen J , Baghal Basel , Baker Maggie , Mash Deborah C , Barr Christina S , Goldman David 
Published: June 2012

Abstract

Background
As a model organism in biomedicine, the rhesus macaque (Macaca mulatta) is the most widely used nonhuman primate. Although a draft genome sequence was completed in 2007, there has been no systematic genome-wide comparison of genetic variation of this species to humans. Comparative analysis of functional and nonfunctional diversity in this highly abundant and adaptable non-human primate could inform its use as a model for human biology, and could reveal how variation in population history and size alters patterns and levels of sequence variation in primates.

Results
We sequenced the mRNA transcriptome and H3K4me3-marked DNA regions in hippocampus from 14 humans and 14 rhesus macaques. Using equivalent methodology and sampling spaces, we identified 462,802 macaque SNPs, most of which were novel and disproportionately located in the functionally important genomic regions we had targeted in the sequencing. At least one SNP was identified in each of 16,797 annotated macaque genes. Accuracy of macaque SNP identification was conservatively estimated to be >90%. Comparative analyses using SNPs equivalently identified in the two species revealed that rhesus macaque has approximately three times higher SNP density and average nucleotide diversity as compared to the human. Based on this level of diversity, the effective population size of the rhesus macaque is approximately 80,000 which contrasts with an effective population size of less than 10,000 for humans. Across five categories of genomic regions, intergenic regions had the highest SNP density and average nucleotide diversity and CDS (coding sequences) the lowest, in both humans and macaques. Although there are more coding SNPs (cSNPs) per individual in macaques than in humans, the ratio of dN/dS is significantly lower in the macaque. Furthermore, the number of damaging nonsynonymous cSNPs (have damaging effects on protein functions from PolyPhen-2 prediction) in the macaque is more closely equivalent to that of the human.

Conclusions
This large panel of newly identified macaque SNPs enriched for functionally significant regions considerably expands our knowledge of genetic variation in the rhesus macaque. Comparative analysis reveals that this widespread, highly adaptable species is approximately three times as diverse as the human but more closely equivalent in damaging variation.
Development of efficient catharanthus roseus regeneration and transformation system using agrobacterium tumefaciens and hypocotyls as explants
Authors: Wang Quan , Xing Shihai , Pan Qifang , Yuan Fang , Zhao Jingya , Tian Yuesheng , Chen Yu , Wang Guofeng , Tang Kexuan 
Published: June 2012

Abstract

Background
As a valuable medicinal plant, Madagascar periwinkle (Catharanthus roseus) produces many terpenoid indole alkaloids (TIAs), such as vindoline, ajamlicine, serpentine, catharanthine, vinblastine and vincristine et al. Some of them are important components of drugs treating cancer and hypertension. However, the yields of these TIAs are low in wild-type plants, and the total chemical synthesis is impractical in large scale due to high-cost and their complicated structures. The recent development of metabolic engineering strategy offers a promising solution. In order to improve the production of TIAs in C. roseus, the establishment of an efficient genetic transformation method is required.

Results
To develop a genetic transformation method for C. roseus, Agrobacterium tumefaciens strain EHA105 was employed which harbors a binary vector pCAMBIA2301 containing a report β-glucuronidase (GUS) gene and a selectable marker neomycin phosphotransferase II gene (NTPII). The influential factors were investigated systematically and the optimal transformation condition was achieved using hypocotyls as explants, including the sonication treatment of 10 min with 80 W, A. tumefaciens infection of 30 min and co-cultivation of 2 d in 1/2 MS medium containing 100 μM acetosyringone. With a series of selection in callus, shoot and root inducing kanamycin-containing resistance media, we successfully obtained stable transgenic regeneration plants. The expression of GUS gene was confirmed by histochemistry, polymerase chain reaction, and genomic southern blot analysis. To prove the efficiency of the established genetic transformation system, the rate-limiting gene in TIAs biosynthetic pathway, DAT, which encodes deacetylvindoline-4-O-acetyltransferase, was transferred into C. roseus using this established system and 9 independent transgenic plants were obtained. The results of metabolite analysis using high performance liquid chromatography (HPLC) showed that overexpression of DAT increased the yield of vindoline in transgenic plants.

Conclusions
In the present study, we report an efficient Agrobacterium-mediated transformation system for C. roseus plants with 11% of transformation frequency. To our knowledge, this is the first report on the establishment of A. tumefaciens mediated transformation and regeneration of C. roseus. More importantly, the C. roseus transformation system developed in this work was confirmed in the successful transformation of C. roseus using a key gene DAT involved in TIAs biosynthetic pathway resulting in the higher accumulation of vindoline in transgenic plants.