bluuebunny/crossref_metadata_2025_split huggingface dataset:
EGFR mutation testing in NSCLC: Patterns of care and outcomes in Western Australia
Authors: WEBB Suzanne , THOMAS Marc , METCALF Cecily , SEGAL Amanda , NOWAK Anna K , BENTEL Jacqueline , MILLWARD Michael 
Published: February 2009

AbstractAims:  This study evaluated the EGFR mutation status, administration of gefitinib or erlotinib and outcomes of patients assessed for EGFR mutations since the commencement of testing in Western Australia.Methods:  A retrospective study identified patients with NSCLC who undergone EGFR mutation testing in the Department of Anatomical Pathology, Royal Perth Hospital, Western Australia from March 2005 until May 2007. Patient characteristics, cancer history, treatment, outcomes and survival were collected from the medical records and pathology reports.Results:  Tumor samples from 64 patients were sequenced for mutations in exons 18–21 EGFR and, of these, 53 patients with NSCLC were included in the analysis. The mean age at diagnosis was 61 years (range 19–80) and most of the tumor samples tested were from female patients (76%). Overall 36% of patients tested were mutation‐positive with 95% of mutations occurring in exons 19 or 21. A total of 63% of mutation‐positive and 18% of mutation‐negative patients were treated with gefitinib or erlotinib. Of these, 83% of patients whose tumors had an EGFR mutation had a favorable response following treatment, compared to 17% of mutation‐negative patients. The duration of treatment was longer in mutation‐positive patients (mean 30 weeks vs 9 weeks).Conclusion:  EGFR mutation testing is not routinely performed in NSCLC in Western Australia. Referral for testing is at the discretion of the treating physician, accounting for the high proportion of women and adenocarcinoma histology. Selection of mutation‐positive tumors for treatment with gefitinib or erlotinib is associated with good responses to treatment. This study supports the use of gefitinib or erlotinib in routine clinical practice in patients with NSCLC carrying an EGFR mutation.
Vulnerability in Research: Individuals with Limited Financial and/or Social Resources
Authors: Grady Christine 
Published: February 2009

Vulnerability in research is often understood as a diminished ability to protect one's own interests, manifested by a compromised capacity to give informed or voluntary consent. Certain groups of people are thought to be more vulnerable than others and therefore are at risk of being exploited or mistreated in research. Accordingly, the federal regulations call for additional safeguards to protect vulnerable groups.There remains some ambiguity and contradiction, however, regarding what groups are vulnerable in research and why,3 since the available codes of research ethics and regulations describe many groups as vulnerable. When so many groups are considered vulnerable, but no specification is offered as to how they are vulnerable or what particular protections are appropriate, the possibility of meaningful safeguards is diminished. In addition, current concepts of vulnerability are usually applied to whole groups of people, without distinguishing between individuals in a group who might truly have a compromised capacity to protect their own interests from those who do not.
The Vulnerability of the Very Sick
Authors: Menikoff Jerry 
Published: February 2009

Suppose that someone has a serious illness. The illness will likely lead to significant disabilities, and may even cause death. Existing treatments are unsatisfactory. The patient learns about a clinical trial, in which some allegedly promising new treatment for that illness is being tested.Such seriously ill patients for whom existing treatments are unsatisfactory have sometimes been categorized as medically vulnerable in the literature. Should these patients indeed be considered vulnerable subjects and be provided with special protections? And if the answer is yes, then what are those special protections? This article explores the possible answers to these questions.The federal regulations for the protection of research subjects have several provisions addressing the concept of vulnerability. The three subparts Subparts B (pregnant women, fetuses, and neonates), C (prisoners), and D (children) deal with specific categories of vulnerable subjects, but do relatively little to address broader issues relating to vulnerability that might apply to a category such as the medically vulnerable. The Common Rule (Subpart A) is the only section containing general discussions of vulnerability.
Prejudice and the Medical Profession: A Five-Year Update
Authors: Clark Peter A. 
Published: February 2009

Over the past decades the mortality rate in the United States has decreased and life expectancy has increased. Yet a number of recent studies have drawn Americans attention to the fact that racial and ethnic disparities persist in health care. It is clear that the U.S. health care system is not only flawed for many reasons including basic injustices, but may be the cause of both injury and death for members of racial and ethnic minorities.In 2002, an Institute of Medicine (IOM) report requested by Congress listed more than 100 studies documenting a wide range of disparities in the United States health care system. This report found that people belonging to racial and ethnic minorities often receive lower quality of health care than do people of European descent, even when their medical insurance coverage and income levels are the same as that of the latter.
Africa's Linguistic Diversity
Authors: Sands Bonny 
Published: February 2009

AbstractAfrican language classification in the latter half of the 20th century has been dominated by Joseph Greenberg's work classifying African languages into four linguistic genetic groupings: Afroasiatic, Niger‐Kordofanian, Nilo‐Saharan, and Khoisan. Current research indicates that there are a minimum of 20 unrelated African language families or isolates. Africa's linguistic diversity will remain poorly documented unless significant efforts are made to document some of the continent's most endangered, underdescribed languages and language families.
Characterizing the Structure and Photocycle of PR 2D Crystals with CD and FTIR Spectroscopy†
Authors: Schäfer Gabriela , Shastri Sarika , Verhoefen Mirka‐Kristin , Vogel Vitali , Glaubitz Clemens , Wachtveitl Josef , Mäntele Werner 
Published: February 2009

AbstractWe present here a study on proteorhodopsin (PR) 2D crystals with analytical ultracentrifugation, circular dichroism and Fourier transform infrared (FTIR) spectroscopy. The aim of our experiments was to test the activity of 2D crystal sample preparations and to gain further insight in PR structure, stability and function with these techniques. Our results demonstrate higher stability compared to detergent‐solubilized or reconstituted samples. For different pH values, low pH 2D crystals tend to form bigger aggregates and are less stable than at basic pH. The pH 9 sample shows a sharp phase transition during heat denaturation and there is also evidence for protein–protein interaction due to the close proximity of the proteins in the 2D crystals. In the FTIR measurements at cryogenic temperatures (77 K), we characterized the first step in the PR photocycle. At pH 9, the K intermediate could be observed and the samples showed no orientation effects. At pH 5, we could trap the K/L intermediate, characterized by its negative IR signal at 1741 cm−1. In rapid‐scan FTIR experiments, we could also identify the M intermediate of the photocycle at basic pH. We conclude that the PR 2D crystals exhibit a fully functional photocycle and are therefore well suited for further studies on the proton transport mechanism of PR.
Genesis and Mixing/Mingling of Mafic and Felsic Magmas of Back‐Arc Granite: Miocene Tsushima Pluton, Southwest Japan
Authors: Shin Ki‐Cheol , Kurosawa Masanori , Anma Ryo , Nakano Takanori 
Published: February 2009

AbstractThe Middle Miocene Tsushima granite pluton is composed of leucocratic granites, gray granites and numerous mafic microgranular enclaves (MME). The granites have a metaluminous to slightly peraluminous composition and belong to the calc‐alkaline series, as do many other coeval granites of southwestern Japan, all of which formed in relation to the opening of the Sea of Japan. The Tsushima granites are unique in that they occur in the back‐arc area of the innermost Inner Zone of Southwest Japan, contain numerous miarolitic cavities, and show shallow crystallization (2–6 km deep), based on hornblende geobarometry. The leucocratic granite has higher initial 87Sr/86Sr ratios (0.7065–0.7085) and lower εNd(t) (−7.70 to −4.35) than the MME of basaltic–dacitic composition (0.7044–0.7061 and −0.53 to −5.24), whereas most gray granites have intermediate chemical and Sr–Nd isotopic compositions (0.7061–0.7072 and −3.75 to −6.17). Field, petrological, and geochemical data demonstrate that the Tsushima granites formed by the mingling and mixing of mafic and felsic magmas. The Sr–Nd–Pb isotope data strongly suggest that the mafic magma was derived from two mantle components with depleted mantle material and enriched mantle I (EMI) compositions, whereas the felsic magma formed by mixing of upper mantle magma of EMI composition with metabasic rocks in the overlying lower crust. Element data points deviating from the simple mixing line of the two magmas may indicate fractional crystallization of the felsic magma or chemical modification by hydrothermal fluid. The miarolitic cavities and enrichment of alkali elements in the MME suggest rapid cooling of the mingled magma accompanied by elemental transport by hydrothermal fluid. The inferred genesis of this magma–fluid system is as follows: (i) the mafic and felsic magmas were generated in the mantle and lower crust, respectively, by a large heat supply and pressure decrease under back‐arc conditions induced by mantle upwelling and crustal thinning; (ii) they mingled and crystallized rapidly at shallow depths in the upper crust without interaction during the ascent of the magmas from the middle to the upper crust, which (iii) led to fluid generation in the shallow crust. The upper mantle in southwest Japan thus has an EMI‐like composition, which plays an important role in the genesis of igneous rocks there.
DNA barcoding of the endemic New Zealand leafroller moth genera, Ctenopseustis and Planotortrix
Authors: LANGHOFF PIA , AUTHIER ASTRID , BUCKLEY THOMAS R. , DUGDALE JOHN S. , RODRIGO ALLEN , NEWCOMB RICHARD D. 
Published: February 2009

AbstractMolecular techniques such as DNA barcoding have become popular in assisting species identification especially for cryptic species complexes. We have analysed data from a 468‐bp region of the mitochondrial cytochrome oxidase subunit I (COI) gene from 200 specimens of 12 species of endemic New Zealand leafroller moths (Tortricidae) from the genera Planotortrix and Ctenopseustis to assess whether the DNA barcoding region can distinguish these species. Among the 200 sequences analysed, 72 haplotypes were recovered, with each genus forming a separate major clade. Maximum likelihood phylogenetic methods were used to test whether species fell into reciprocally monophyletic clades. The optimal phylogeny showed that four species within the genus Ctenopseustis (C. obliquana, C. herana, C. filicis and C. fraterna) and three within Planotortrix (P. octo, P. excessana and P. avicenniae) are polyphyletic. Shimodaira–Hasegawa tests rejected a null hypothesis of monophyly for the species C. obliquana, C. herana, P. octo and P. excessana. Comparisons of within and between species levels of sequence divergence for the same set of seven species showed cases where maximum levels of within‐species divergence were greater than some levels of between‐species divergence. DNA barcoding using this region of the COI gene is able to distinguish the two genera and some species within each genus; however, many species cannot be identified using this method. Finally, we discuss the possible reasons for this polyphyly, including incomplete lineage sorting, introgression, horizontal gene transfer and incorrect taxonomy.
New polymorphic microsatellite loci in the house sparrow, Passer domesticus
Authors: GARNIER S. , DURAND P. , ARNATHAU C. , RISTERUCCI A. M. , ESPARZA‐SALAS R. , CELLIER‐HOLZEM E. , SORCI G. 
Published: February 2009

AbstractWe developed 13 new polymorphic microsatellite loci in the house sparrow (Passer domesticus), which exhibited from 2 to 15 alleles. Observed and expected heterozygosities ranged from 0.17 to 0.77 and from 0.35 to 0.85, respectively. We detected no linkage disequilibrium between loci. Allele frequencies supported Hardy–Weinberg equilibrium for 8 loci out of 13 after Bonferroni correction. Combined with loci previously isolated in the house sparrow, these new microsatellite markers provide valuable tools to study population genetics of this species.
KINALYZER, a computer program for reconstructing sibling groups
Authors: ASHLEY M. V. , CABALLERO I. C. , CHAOVALITWONGSE W. , DASGUPTA B. , GOVINDAN P. , SHEIKH S. I. , BERGER‐WOLF T. Y. 
Published: February 2009

AbstractA software suite KINALYZER reconstructs full‐sibling groups without parental information using data from codominant marker loci such as microsatellites. KINALYZER utilizes a new algorithm for sibling reconstruction in diploid organisms based on combinatorial optimization. KINALYZER makes use of a Minimum 2‐Allele Set Cover approach based on Mendelian inheritance rules and finds the smallest number of sibling groups that contain all the individuals in the sample. Also available is a ‘Greedy Consensus’ approach that reconstructs sibgroups using subsets of loci and finds the consensus of the partial solutions. Unlike likelihood methods for sibling reconstruction, KINALYZER does not require information about population allele frequencies and it makes no assumptions regarding the mating system of the species. KINALYZER is freely available as a web‐based service.
Isolation and characterization of microsatellite loci in the plant‐ant Pseudomyrmex ferrugineus (Formicidae: Pseudomyrmecinae) and cross‐testing for two congeneric species
Authors: KAUTZ STEFANIE , SCHMID VOLKER S. , TRINDL ANDREAS , HEINZE JÜRGEN , BALLHORN DANIEL J. , HEIL MARTIN 
Published: February 2009

AbstractTo investigate the population structure of the obligate plant‐ant Pseudomyrmex ferrugineus, we developed primers for 12 microsatellite loci. We tested the variability of the markers on 11 individuals from each of two populations (totalling 22 individuals) and found two to 12 alleles per locus and population. No deviations from Hardy–Weinberg equilibrium were detected. Observed and expected heterozygosities at each locus ranged from 0.00 to 0.50 and from 0.08 to 0.46, respectively. We also investigated suitability of these primers in two congeneric species.
Isolation of nine nuclear microsatellites in the common Mediterranean sea urchin, Paracentrotus lividus (Lamarck)
Authors: CALDERÓN I. , TURON X. , PASCUAL M. 
Published: February 2009

AbstractNine polymorphic microsatellite loci were isolated and characterized for the edible common sea urchin Paracentrotus lividus. Loci were obtained from two genomic libraries enriched with different di‐, tri‐ and tetranucleotides. Most microsatellites obtained were imperfect dinucleotides. Allelic variation was screened for a total of 56 individuals from two populations from North‐Western Mediterranean. Microsatellites showed a number of alleles ranging from 13 to 35. Linkage disequilibrium was not detected between any pair of loci, and all loci showed a significant departure from Hardy–Weinberg equilibrium which is not likely to be the result of null alleles, suggesting that demographic features may be acting upon this commercially interesting species.
EphA2 Reexpression Prompts Invasion of Melanoma Cells Shifting from Mesenchymal to Amoeboid-like Motility Style
Authors: Parri Matteo , Taddei Maria Letizia , Bianchini Francesca , Calorini Lido , Chiarugi Paola 
Published: February 2009

Abstract
Eph tyrosine kinases instruct cell for a repulsive behavior, regulating cell shape, adhesion, and motility. Beside its role during embryogenesis, neurogenesis, and angiogenesis, EphA2 kinase is frequently up-regulated in tumor cells of different histotypes, including prostate, breast, colon, and lung carcinoma, as well as melanoma. Although a function in both tumor onset and metastasis has been proposed, the role played by EphA2 is still debated. Here, we showed that EphA2 reexpression in B16 murine melanoma cells, which use a defined mesenchymal invasion strategy, converts their migration style from mesenchymal to amoeboid-like, conferring a plasticity in tumor cell invasiveness. Indeed, in response to reexpression and activation of EphA2, melanoma cells activate a nonproteolytic invasive program that proceeds through the activation of cytoskeleton motility, the retraction of cell protrusions, a Rho-mediated rounding of the cell body, and squeezing among three-dimensional matrix, giving rise to successful lung and peritoneal lymph node metastases. Our results suggest that, among the redundant mechanisms operating in tumor cells to penetrate the anatomic barriers of host tissues, EphA2 plays a pivotal role in the adaptive switch in migration pattern and mechanism, defining and distinguishing tumor cell invasion strategies. Thus, targeting EphA2 might represent a future approach for the therapy of cancer dissemination. [Cancer Res 2009;69(5):2072–81]
Unsupervised Analysis of Transcriptomic Profiles Reveals Six Glioma Subtypes
Authors: Li Aiguo , Walling Jennifer , Ahn Susie , Kotliarov Yuri , Su Qin , Quezado Martha , Oberholtzer J. Carl , Park John , Zenklusen Jean C. , Fine Howard A. 
Published: February 2009

Abstract
Gliomas are the most common type of primary brain tumors in adults and a significant cause of cancer-related mortality. Defining glioma subtypes based on objective genetic and molecular signatures may allow for a more rational, patient-specific approach to therapy in the future. Classifications based on gene expression data have been attempted in the past with varying success and with only some concordance between studies, possibly due to inherent bias that can be introduced through the use of analytic methodologies that make a priori selection of genes before classification. To overcome this potential source of bias, we have applied two unsupervised machine learning methods to genome-wide gene expression profiles of 159 gliomas, thereby establishing a robust glioma classification model relying only on the molecular data. The model predicts for two major groups of gliomas (oligodendroglioma-rich and glioblastoma-rich groups) separable into six hierarchically nested subtypes. We then identified six sets of classifiers that can be used to assign any given glioma to the corresponding subtype and validated these classifiers using both internal (189 additional independent samples) and two external data sets (341 patients). Application of the classification system to the external glioma data sets allowed us to identify previously unrecognized prognostic groups within previously published data and within The Cancer Genome Atlas glioblastoma samples and the different biological pathways associated with the different glioma subtypes offering a potential clue to the pathogenesis and possibly therapeutic targets for tumors within each subtype. [Cancer Res 2009;69(5):2091–9]
Regulatory T Cells Recruited through CCL22/CCR4 Are Selectively Activated in Lymphoid Infiltrates Surrounding Primary Breast Tumors and Lead to an Adverse Clinical Outcome
Authors: Gobert Michael , Treilleux Isabelle , Bendriss-Vermare Nathalie , Bachelot Thomas , Goddard-Leon Sophie , Arfi Vanessa , Biota Cathy , Doffin Anne Claire , Durand Isabelle , Olive Daniel , Perez Solène , Pasqual Nicolas , Faure Christelle , Ray-Coquard Isabelle , Puisieux Alain , Caux Christophe , Blay Jean-Yves , Ménétrier-Caux Christine 
Published: February 2009

Abstract
Immunohistochemical analysis of FOXP3 in primary breast tumors showed that a high number of tumor-infiltrating regulatory T cells (Ti-Treg) within lymphoid infiltrates surrounding the tumor was predictive of relapse and death, in contrast to those present within the tumor bed. Ex vivo analysis showed that these tumor-infiltrating FOXP3+ T cells are typical Treg based on their CD4+CD25highCD127lowFOXP3+ phenotype, their anergic state on in vitro stimulation, and their suppressive functions. These Ti-Treg could be selectively recruited through CCR4 as illustrated by (a) selective blood Treg CCR4 expression and migration to CCR4 ligands, (b) CCR4 down-regulation on Ti-Treg, and (c) correlation between Ti-Treg in lymphoid infiltrates and intratumoral CCL22 expression. Importantly, in contrast to other T cells, Ti-Treg are selectively activated locally and proliferate in situ, showing T-cell receptor engagement and suggesting specific recognition of tumor-associated antigens (TAA). Immunohistochemical stainings for ICOS, Ki67, and DC-LAMP show that Ti-Treg were close to mature DC-LAMP+ dendritic cells (DC) in lymphoid infiltrates but not in tumor bed and were activated and proliferating. Furthermore, proximity between Ti-Treg, CD3+, and CD8+ T cells was documented within lymphoid infiltrates. Altogether, these results show that Treg are selectively recruited within lymphoid infiltrates and activated by mature DC likely through TAA presentation, resulting in the prevention of effector T-cell activation, immune escape, and ultimately tumor progression. This study sheds new light on Treg physiology and validates CCR4/CCL22 and ICOS as therapeutic targets in breast tumors, which represent a major health problem. [Cancer Res 2009;69(5):2000–9]
Telomere Dysfunction and DNA-PKcs Deficiency: Characterization and Consequence
Authors: Williams Eli S. , Klingler Rebekah , Ponnaiya Brian , Hardt Tanja , Schrock Evelin , Lees-Miller Susan P. , Meek Katheryn , Ullrich Robert L. , Bailey Susan M. 
Published: February 2009

Abstract
The mechanisms by which cells accurately distinguish between DNA double-strand break (DSB) ends and telomeric DNA ends remain poorly defined. Recent investigations have revealed intriguing interactions between DNA repair and telomeres. We were the first to report a requirement for the nonhomologous end-joining (NHEJ) protein DNA-dependent protein kinase (DNA-PK) in the effective end-capping of mammalian telomeres. Here, we report our continued characterization of uncapped (as opposed to shortened) dysfunctional telomeres in cells deficient for the catalytic subunit of DNA-PK (DNA-PKcs) and shed light on their consequence. We present evidence in support of our model that uncapped telomeres in this repair-deficient background are inappropriately detected and processed as DSBs and thus participate not only in spontaneous telomere-telomere fusion but, importantly, also in ionizing radiation–induced telomere-DSB fusion events. We show that phosphorylation of DNA-PKcs itself (Thr-2609 cluster) is a critical event for proper telomere end-processing and that ligase IV (NHEJ) is required for uncapped telomere fusion. We also find uncapped telomeres in cells from the BALB/c mouse, which harbors two single-nucleotide polymorphisms that result in reduced DNA-PKcs abundance and activity, most markedly in mammary tissue, and are both radiosensitive and susceptible to radiogenic mammary cancer. Our results suggest mechanistic links between uncapped/dysfunctional telomeres in DNA-PKcs–deficient backgrounds, radiation-induced instability, and breast cancer. These studies provide the first direct evidence of genetic susceptibility and environmental insult interactions leading to a unique and ongoing form of genomic instability capable of driving carcinogenesis. [Cancer Res 2009;69(5):2100–7]