bluuebunny/crossref_metadata_2025_split huggingface dataset:
A BRCA1deficient-like signature is enriched in breast cancer brain metastases and predicts DNA damage-induced poly (ADP-ribose) polymerase inhibitor sensitivity
Authors: McMullin Ryan P , Wittner Ben S , Yang Chuanwei , Denton-Schneider Benjamin R , Hicks Daniel , Singavarapu Raj , Moulis Sharon , Lee Jeongeun , Akbari Mohammad R , Narod Steven A , Aldape Kenneth D , Steeg Patricia S , Ramaswamy Sridhar , Sgroi Dennis C 
Published: March 2014

Abstract
Introduction
There is an unmet clinical need for biomarkers to identify breast cancer patients at an increased risk of developing brain metastases. The objective is to identify gene signatures and biological pathways associated with human epidermal growth factor receptor 2-positive (HER2+) brain metastasis.

Methods
We combined laser capture microdissection and gene expression microarrays to analyze malignant epithelium from HER2+ breast cancer brain metastases with that from HER2+ nonmetastatic primary tumors. Differential gene expression was performed including gene set enrichment analysis (GSEA) using publicly available breast cancer gene expression data sets.

Results
In a cohort of HER2+ breast cancer brain metastases, we identified a gene expression signature that anti-correlates with overexpression of BRCA1. Sequence analysis of the HER2+ brain metastases revealed no pathogenic mutations of BRCA1, and therefore the aforementioned signature was designated BRCA1 Deficient-Like (BD-L). Evaluation of an independent cohort of breast cancer metastases demonstrated that BD-L values are significantly higher in brain metastases as compared to other metastatic sites. Although the BD-L signature is present in all subtypes of breast cancer, it is significantly higher in BRCA1 mutant primary tumors as compared with sporadic breast tumors. Additionally, BD-L signature values are significantly higher in HER2-/ER- primary tumors as compared with HER2+/ER + and HER2-/ER + tumors. The BD-L signature correlates with breast cancer cell line pharmacologic response to a combination of poly (ADP-ribose) polymerase (PARP) inhibitor and temozolomide, and the signature outperformed four published gene signatures of BRCA1/2 deficiency.

Conclusions
A BD-L signature is enriched in HER2+ breast cancer brain metastases without pathogenic BRCA1 mutations. Unexpectedly, elevated BD-L values are found in a subset of primary tumors across all breast cancer subtypes. Evaluation of pharmacological sensitivity in breast cancer cell lines representing all breast cancer subtypes suggests the BD-L signature may serve as a biomarker to identify sporadic breast cancer patients who might benefit from a therapeutic combination of PARP inhibitor and temozolomide and may be indicative of a dysfunctional BRCA1-associated pathway.
Prolyl-4-hydroxylase domain 3 (PHD3) is a critical terminator for cell survival of macrophages under stress conditions
Authors: Swain Lija , Wottawa Marieke , Hillemann Annette , Beneke Angelika , Odagiri Haruki , Terada Kazutoyo , Endo Motoyoshi , Oike Yuichi , Farhat Katja , Katschinski Dörthe M 
Published: March 2014

AbstractOn a molecular level, cells sense changes in oxygen availability through the PHDs, which regulate the protein stability of the α-subunit of the transcription factor HIF. Especially, PHD3 has been additionally associated with apoptotic cell death. We hypothesized that PHD3 plays a role in cell-fate decisions in macrophages. Therefore, myeloid-specific PHD3−/− mice were created and analyzed. PHD3−/− BMDM showed no altered HIF-1α or HIF-2α stabilization or increased HIF target gene expression in normoxia or hypoxia. Macrophage M1 and M2 polarization was unchanged likewise. Compared with macrophages from WT littermates, PHD3−/− BMDM exhibited a significant reduction in TUNEL-positive cells after serum withdrawal or treatment with stauro and SNAP. Under the same conditions, PHD3−/− BMDM also showed less Annexin V staining, which is representative for membrane disruption, and indicated a reduced early apoptosis. In an unbiased transcriptome screen, we found that Angptl2 expression was reduced in PHD3−/− BMDM under stress conditions. Addition of rAngptl2 rescued the antiapoptotic phenotype, demonstrating that it is involved in the PHD3-mediated response toward apoptotic stimuli in macrophages.
Michigan Oncology Medical Home Demonstration Project: First-Year Results
Authors: Kuntz Gordon , Tozer Jane , Snegosky Jeff , Fox John , Neumann Kurt 
Published: March 2014

Purpose: The Michigan Oncology Medical Home Demonstration Project (MOMHDP) is an innovative multipractice oncology medical home model, supported by payment reform. Sponsored by Priority Health, Physician Resource Management, and ION Solutions, MOMHDP includes four oncology practices and 29 physicians. Methods: Oncology practices used existing technologies, with MOMHDP providing evidence-based treatment guideline selection and compliance tracking, automated physician order entry, a patient portal, symptom management/standardized nurse triage, and advance care planning. To support changes in care and administrative models and to focus on quality, MOMHDP modifies provider payments. The program replaces the average sales price payment methodology with a drug acquisition reimbursement plus a care management fee, calculated to increase total drug reimbursement. Additionally, it reimburses for chemotherapy and treatment planning and advance care planning consultation. There is also a shared savings opportunity. MOMHDP will be enhanced in its second year to include a survivorship program, patient distress screening, imaging guidelines, and standardized patient satisfaction surveys. Priority Health patients receiving chemotherapy for a cancer diagnosis were recruited to the program. Results for this group were compared with a control group of patients from a prior period. Results: In addition to the financial results, the project also accomplished the following: (1) adherence to practice-selected guidelines, (2) institution of advance care planning, (3) effective and standardized symptom management; and (4) payment reform. Conclusion: We have identified a number of critical success factors: strong payer/provider collaboration built on trust through transparent use and cost data; timing of clinical standardization must come from the practices, so they can effectively absorb new approaches; having comprehensive, written program documentation and consistently applied training facilitate practice understanding; existing, off-the-shelf technologies help control costs; independent clinical, administrative, and technical coordination improves provider/payer collaboration; everything takes longer than anticipated, including practice commitment, contracting, and technology implementation. Practices are willing to take on clinical standardization with payment reform. Neither practice size nor technology platform variation was a barrier to participation or success in the project. These results represent preliminary reporting from the first multipractice oncology medical home in the United States, to our knowledge, with payer support that includes payment reform. The results are promising, and the concept warrants further study, review, and reporting. [Table: see text]
LETM1 haploinsufficiency causes mitochondrial defects in Wolf-Hirschhorn syndrome patient cells: implications for dissecting underlying pathomechanisms in this condition
Authors: Hart Lesley , Rauch Anita , Carr Antony M. , Vermeesch Joris R. , O'Driscoll Mark 
Published: March 2014

Abstract
Wolf-Hirschhorn syndrome (WHS) represents an archetypical example of a contiguous gene deletion disorder; a condition comprising a complex set of developmental phenotypes with a multigenic origin. Epileptic seizures, intellectual disability, growth restriction, motor delay and hypotonia are significant co-morbidities in WHS. Haploinsufficiency of LETM1, which encodes an mitochondrial inner membrane protein functioning in ion transport, has been proposed as an underlying pathomechanism; principally for seizures but also for other core features of WHS including growth and motor delay. Growing evidence derived from several model organisms suggests that reduced LETM1 expression is associated with some element of mitochondrial dysfunction. Surprisingly, LETM1-dependent mitochondrial functional deficits have not previously been described in cells from WHS patients. Here, using a unique panel of WHS patient-derived cell lines with differing sized deletions incorporating LETM1 or not, we show for the first time, that LETM1 expression is reduced in mitochondria isolated from WHS patient cells. Further, we show that this is associated with distinct mitochondrial phenotypes including altered intracellular [Ca2+] levels, dysfunctional mitochondrial transition pore opening along with hyperpolarization and superoxide leakage from resting mitochondria. Interestingly, we find that these phenotypes segregate with seizures in our WHS cohort. Our findings identify novel cellular phenotypes in WHS attributable to a 50% reduction in LETM1 expression levels; phenotypes which may underlie and/or contribute to some of the core clinical features of this condition.
Mouse models of telomere dysfunction phenocopy skeletal changes found in human age-related osteoporosis
Authors: Brennan Tracy A. , Egan Kevin P. , Lindborg Carter M. , Chen Qijun , Sweetwyne Mariya T. , Hankenson Kurt D. , Xie Sharon X. , Johnson Frederick B. , Pignolo Robert J. 
Published: March 2014

AbstractA major challenge in the elderly is osteoporosis and the high risk of fracture. Telomere dysfunction is a cause of cellular senescence and telomere shortening which occurs with age in cells from most human tissues, including bone. Telomere defects contribute to the pathogenesis of two progeroid disorders characterized by premature osteoporosis, Werner syndrome and dyskeratosis congenital. It is hypothesized that telomere shortening contributes to bone aging. Using mice with disrupted telomere maintenance mechanisms, including mutants in Werner helicase (Wrn-/-), telomerase (Terc-/-) and Wrn-/- Terc-/- double mutants, we evaluated their skeletal phenotypes as models for human bone aging. Compared to young wild-type (WT) mice, micro-computerized tomography analysis revealed that young Terc-/- and Wrn-/-Terc-/- mice have decreased trabecular bone volume, trabecular number and trabecular thickness, as well as increased trabecular spacing. In cortical bone, young Terc-/- and Wrn-/-Terc-/- mice have increased cortical thinning, and increased porosity relative to age-matched WT mice. These trabecular and cortical changes were accelerated with age in Terc-/- and Wrn-/-Terc-/- mice compared to older WT mice. Histological quantification of osteoblasts in aged mice showed a similar number of osteoblasts in all genotypes; however, significant decreases in osteoid, mineralization surface, mineral apposition rate and bone formation rate in older Terc-/- and Wrn-/-Terc-/- bone suggest that osteoblast dysfunction is a prominent feature of precocious aging in these mice. Except in the Wrn-/- single mutant, osteoclast number did not increase in any genotype. Significant alterations in mechanical parameters (structure model index, degree of anistrophy, and moment of inertia) of the Terc-/- and Wrn-/-Terc-/- femurs compared to WT mice were also observed. Young Wrn-/-Terc-/- mice had a statistically significant increase in bone marrow fat content compared to young WT mice, which remained elevated in aged double mutants. Taken together, our results suggest that Terc-/- and Wrn-/-Terc-/- mutants recapitulate the human bone aging phenotype and are useful models for studying age-related osteoporosis.
RUNX2 in subtype specific breast cancer and mammary gland differentiation
Authors: McDonald Laura , Ferrari Nicola , Terry Anne , Bell Margaret , Mohammed Zahra M. , Orange Clare , Jenkins Alma , Muller William J. , Gusterson Barry A. , Neil James C. , Edwards Joanne , Morris Joanna S. , Cameron Ewan R. , Blyth Karen 
Published: March 2014

AbstractRUNX2, a master regulator of osteogenesis, is oncogenic in the lymphoid lineage however little is known about its role in epithelial cancers. Upregulation of RUNX2 in cell lines correlates with increased invasiveness and the capacity to form osteolytic disease in models of breast and prostate cancer. However, most studies have analysed the effects of this gene in a limited number of cell lines and its role in primary breast cancer has not been resolved. Using a human tumour tissue microarray, we show that high RUNX2 expression is significantly associated with ER/PR/HER2-negative breast cancers and that patients with high RUNX2 expression have a poorer survival rate than those with negative/low expression. We confirm RUNX2 as a gene which has a potentially important functional role in triple negative breast cancer. To investigate the role of this gene in breast cancer, we made a transgenic model where Runx2 is specifically expressed in murine mammary epithelium under the control of the MMTV-promoter. We show that ectopic Runx2 perturbs normal development in pubertal and lactating animals, delaying ductal elongation and inhibiting lobular alveolar differentiation. We also show that the Runx2 transgene elicits age-related, pre-neoplastic changes in the mammary epithelium of older transgenic animals, suggesting that elevated RUNX2 expression renders such tissue more susceptible to oncogenic changes and providing further evidence that this gene may have an important, context-dependent role in breast cancer.
Evolutionary capacity of upper thermal limits: beyond single trait assessments
Authors: Blackburn Shaun , Kellmermann Vanessa , van Heerwaarden Belinda , Sgrò Carla M. 
Published: March 2014

Abstract
Thermal tolerance is an important factor influencing the distribution of ectotherms, but we still have limited understanding of the ability of species to evolve different thermal limits. Recent studies suggest that species may have limited capaity to evolve higher themal limits in response to slower, more ecologically relevant rates of warming. However these conclusions are based on univarite estimates of adaptive capacity. To test these findings within an explicitly multivariate context, we used a paternal half-sibling breeding design to estimate the multivariate evolutionary potential for upper thermal limits in Drosophila melanogaster. We assessed heat tolerance using static (basal and hardened) and ramping assays. Additive genetic variances were significantly different from zero only for the static measures of heat tolerance. Our G matrix analysis revealed that any response to selection for increased heat tolerance will largely be driven by static basal and hardened heat tolerance, with minimal contribution from ramping heat tolerance. These results suggest that the capacity to evolve upper thermal limits in nature may depend on the type of thermal stress experienced.
The cost of muscle power production: muscle oxygen consumption per unit work increases at low temperatures inXenopus laevisDaudin
Authors: Seebacher Frank , Tallis Jason A. , James Rob S. 
Published: March 2014

AbstractMetabolic energy (ATP) supply to muscle is essential to support activity and behaviour. It is expected therefore that there is strong selection to maximise muscle power output for a given rate of ATP use. However, the viscosity and stiffness of muscle increases with a decrease in temperature, which means that more ATP may be required to achieve a given work output. Here we test the hypothesis that ATP use increases at lower temperatures for a given power output in Xenopus laevis. To account for temperature variation at different time scales, we considered the interaction between acclimation for four weeks (to 15°C or 25°C) and acute exposure to these temperatures. Cold acclimated frogs had greater sprint speed at 15°C than warm acclimated animals. However, acclimation temperature did not affect isolated gastrocnemius muscle biomechanics. Isolated muscle produced greater tetanus force, faster isometric force generation and relaxation, and generated more work loop power at 25°C than at 15°C acute test temperature. Oxygen consumption of isolated muscle at rest did not change with test temperature, but oxygen consumption while muscle was performing work was significantly higher at 15oC than at 25°C, regardless of acclimation conditions. Muscle therefore consumed significantly more oxygen at 15°C for a given work output than at 25°C, and plastic responses did not modify this thermodynamic effect. The metabolic cost of muscle performance and activity therefore increased with a decrease in temperature. To maintain activity across a range of temperature, animals must increase ATP production or face an allocation trade-off at lower temperatures. Our data demonstrate the potential energetic benefits of warming up muscle before activity, which is seen in diverse groups of animals such as bees that warm flight muscle before take-off, and humans performing warm ups before exercise.
Computational Study on the Mechanism of the Electron-Transfer-Induced Repair of the (6–4) T–T Photoproduct of DNA by Photolyase: Possibility of a Radical Cation Pathway
Authors: Matsubara Toshiaki , Araida Nozomi , Hayashi Daichi , Yamada Hatsumi 
Published: March 2014

Abstract
The oxetane and the non-oxetane mechanisms of the electron-transfer-driven repair of the (6–4) T–T photolesion of DNA by photolyase are examined by density functional theory (B3LYP). We calculated the radical cation pathway in addition to the radical anion and the neutral pathways for both mechanisms in order to assess the possibility of the radical cation pathway, because relatively large energy barriers have been found for the radical anion pathway. As a result, the radical anion pathway showed a large energy barrier in both the oxetane and the non-oxetane mechanisms in agreement with previous calculations. However, it was found that the radical cation pathway of the oxetane mechanism has a realistic low energy barrier. This advantage of the radical cation pathway was ascribed to the position of the radical before the formation of the oxetane and the stability of the oxetane in energy.
FTIR spectroscopic prediction of Klason and acid soluble lignin variation in Norway spruce cutting clones
Authors: Raiskila Sanni , Pulkkinen Minna , Laakso Tapio , Fagerstedt Kurt , Löija Mia , Mahlberg Riitta , Paajanen Leena , Ritschkoff Anne-Christine , Saranpää Pekka 
Published: March 2014

Our purpose was to develop a FTIR spectroscopic method to be used to determine the lignin content in a large number of samples and to apply this method studying variation in sapwood and heartwood lignin content between three fast-growing cutting clones grown in three sites. Models were estimated with 18 samples and tested with 6 samples for which the Klason ligninÂ +Â acid soluble lignin content had been determined. Altogether 272 candidate models were built with all-subset regressions from the principal components estimated from differently treated transmission spectra of the samples; the spectra were recorded on KBr pellets of sieved and unsieved unextracted wood powder and subjected to four different preprocessings and two different wavenumber selection schemes. The final model showed an adequate fit in the estimation data (R =â0.74) as well as a good prediction performance in the test data (R =â0.90). This model was based on the wavenumber range of 1850â500 cm of the line-subtraction-normalised spectra recorded from sieved samples. The model was used to predict lignin content in 64 samples of the same material. One of the clones had a slightly lower sapwood lignin content than the two other clones. The fertile growing site with fast growing trees showed slightly higher sapwood lignin content compared with the other two sites. The model was also used to predict the lignin content in the earlywood of 45 individual annual rings. Variation between individual stems and between annual rings was found to be large. No correlation was found between the lignin content and density of earlywood.22Pâ1
Quantum cascade lasers (QCL) for active hyperspectral imaging
Authors: Yang Quankui , Fuchs Frank , Wagner Joachim 
Published: March 2014

Abstract
There is an increasing demand for wavelength agile laser sources covering the mid-infrared (MIR, 3.5–12 µm) wavelength range, among others in active imaging. The MIR range comprises a particularly interesting part of the electromagnetic spectrum for active hyperspectral imaging applications, due to the fact that the characteristic ‘fingerprint’ absorption spectra of many chemical compounds lie in that range. Conventional semiconductor diode laser technology runs out of steam at such long wavelengths. For many applications, MIR coherent light sources based on solid state lasers in combination with optical parametric oscillators are too complex and thus bulky and expensive. In contrast, quantum cascade lasers (QCLs) constitute a class of very compact and robust semiconductor-based lasers, which are able to cover the mentioned wavelength range using the same semiconductor material system. In this tutorial, a brief review will be given on the state-of-the-art of QCL technology. Special emphasis will be addressed on QCL variants with well-defined spectral properties and spectral tunability. As an example for the use of wavelength agile QCL for active hyperspectral imaging, stand-off detection of explosives based on imaging backscattering laser spectroscopy will be discussed.
Correlative evidence for competition between Fucus serratus and the introduced chlorophyte Codium fragile subsp. fragile on the southwest coast of Norway
Authors: Armitage Caroline S. , Sjøtun Kjersti , Jensen Knut Helge 
Published: March 2014

Abstract
The distribution of Codium fragile subsp. fragile and the native canopy-forming alga Fucus
serratus was recorded at 51 sites in a 20 km long, sheltered region on the southwest coast of Norway. The purpose of the study was to examine if these species are potentially competing and how their distributions are related to wave-exposure and substrate. Codium fragile subsp. fragile was patchily distributed, a pattern which appears to have been sustained over time since its introduction to this area. It was almost always observed growing below mean low water, in the low intertidal and shallow subtidal. Both substrate type and wave-exposure influenced the vertical distribution of C. fragile subsp. fragile; growth occurred higher on the shore at sheltered sites and deeper in the subtidal on stony substrate. Its vertical range of growth overlapped with that of F. serratus and, when C. fragile subsp. fragile was abundant, F. serratus tended to grow higher on the shore and at lower abundances. This suggests that C. fragile subsp. fragile is affecting F. serratus in this area through competition, but only in the lower portion of the fucoid’s vertical range and only at sites favorable for its own growth with regard to shelter and substrate.
The ‘Learner Corpus Research, Cognitive Linguistics and Second Language Acquisition’ nexus: a SWOT analysis
Authors: De Knop Sabine , Meunier Fanny 
Published: March 2014

AbstractThe introductory chapter of this special issue on ‘Learner Corpus Research, Cognitive Linguistics and Second Language Acquisition’ addresses the strengths, weaknesses, opportunities and potential threats of using both learner corpora and Cognitive Linguistics to research second language acquisition. We also discuss some terminological issues related to the notion of second language acquisition. Finally, we present the various chapters included in the volume and explain how each of them concretely articulates the connections between the three disciplines under analysis.