bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cellular trafficking of lipoteichoic acid and Toll-like receptor 2 in relation to signaling; role of CD14 and CD36
Authors: Nilsen Nadra J , Deininger Susanne , Nonstad Unni , Skjeldal Frode , Husebye Harald , Rodionov Dmitrii , von Aulock Sonja , Hartung Thomas , Lien Egil , Bakke Oddmund , Espevik Terje 
Published: May 2008

AbstractLipoteichoic acid (LTA) is a central inducer of inflammatory responses caused by Gram-positive bacteria, such as Staphylococcus aureus, via activation of TLR2. Localization of TLR2 in relation to its coreceptors may be important for function. This study explores the signaling, uptake, and trafficking pattern of LTA in relation to expression of TLR2 and its coreceptors CD36 and CD14 in human monocytes. We found TLR2 expressed in early endosomes, late endosomes/lysosomes, and in Rab-11-positive compartments but not in the Golgi apparatus or endoplasmic reticulum (ER). Rapid internalization of fluorescently labeled LTA was observed in human monocytes, colocalizing with markers for early and late endosomes, lysosomes, ER, and Golgi network. Blocking CD14 and CD36 with antibodies inhibited LTA binding and LTA-induced TNF release from monocytes, emphasizing an important role for both molecules as coreceptors for TLR2. Importantly, blocking CD36 did not affect TNF release induced by N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2R,S)-propyl]-(R)-cysteinyl-seryl-(lysyl)3-lysine or LPS. Expression of CD14 markedly enhanced LTA binding to the plasma membrane and also enhanced NF-κB activation. LTA internalization, but not NF-κB activation, was inhibited in Dynamin-I K44A dominant-negative transfectants, suggesting that LTA is internalized by receptor-mediated endocytosis but that internalization is not required for signaling. In fact, immobilizing LTA and thereby inhibiting internalization resulted in enhanced TNF release from monocytes. Our results suggest that LTA signaling preferentially occurs at the plasma membrane, is independent of internalization, and is facilitated by CD36 and CD14 as coreceptors for TLR2.
Efficacy and Safety of Lapatinib As First-Line Therapy for ErbB2-Amplified Locally Advanced or Metastatic Breast Cancer
Authors: Gomez Henry L. , Doval Dinesh C. , Chavez Miguel A. , Ang Peter C.-S. , Aziz Zeba , Nag Shona , Ng Christina , Franco Sandra X. , Chow Louis W.C. , Arbushites Michael C. , Casey Michelle A. , Berger Mark S. , Stein Steven H. , Sledge George W. 
Published: May 2008

Purpose This study ( EGF20009 ) assessed the efficacy and tolerability of two lapatinib administration schedules as first-line monotherapy in women with ErbB2-amplified locally advanced or metastatic breast cancer. Patients and Methods Patients with ErbB2-amplified, locally advanced or metastatic breast cancer previously untreated in the metastatic setting were randomly assigned to one of two lapatinib dose cohorts and received either 1,500 mg once daily or 500 mg twice daily. Clinical response was assessed at weeks 8 and 12 and every 12 weeks thereafter. Results A total of 138 patients were treated with lapatinib for a median of 17.6 weeks. The overall response rate (complete response [CR] plus partial response [PR]) was 24% in the intent-to-treat population, and 31% of patients derived clinical benefit (CR, PR, or stable disease for ≥ 24 weeks). The median time to response was 7.9 weeks, and the progression-free survival rates at 4 and 6 months were 63% and 43%, respectively. The most common lapatinib-related adverse events (AEs) were diarrhea, rash, pruritus, and nausea, and these events were primarily grade 1 or 2. There were no significant differences in clinical activity or the AE profile between the dosing schedules. Conclusion Lapatinib demonstrated clinical activity and was well tolerated as first-line therapy in ErbB2-amplified locally advanced or metastatic breast cancer. This study supports further evaluation of lapatinib in first-line and early-stage ErbB2-overexpressing breast cancer.
First-Line Gefitinib in Patients With Advanced Non–Small-Cell Lung Cancer Harboring SomaticEGFRMutations
Authors: Sequist Lecia V. , Martins Renato G. , Spigel David , Grunberg Steven M. , Spira Alexander , Jänne Pasi A. , Joshi Victoria A. , McCollum David , Evans Tracey L. , Muzikansky Alona , Kuhlmann Georgiana L. , Han Moon , Goldberg Jonathan S. , Settleman Jeffrey , Iafrate A. John , Engelman Jeffrey A. , Haber Daniel A. , Johnson Bruce E. , Lynch Thomas J. 
Published: May 2008

PurposeSomatic mutations in the epidermal growth factor receptor (EGFR) correlate with increased response in patients with non–small-cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). The multicenter iTARGET trial prospectively examined first-line gefitinib in advanced NSCLC patients harboring EGFR mutations and explored the significance of EGFR mutation subtypes and TKI resistance mechanisms.Patients and MethodsChemotherapy-naïve patients with advanced NSCLC with ≥ 1 clinical characteristic associated with EGFR mutations underwent direct DNA sequencing of tumor tissue EGFR exons 18 to 21. Patients found to harbor any EGFR mutation were treated with gefitinib 250 mg/d until progression or unacceptable toxicity. The primary outcome was response rate.ResultsNinety-eight patients underwent EGFR screening and mutations were detected in 34 (35%). EGFR mutations were primarily exon 19 deletions (53%) and L858R (26%) though 21% of mutation-positive cases had less common subtypes including exon 20 insertions, T790M/L858R, G719A, and L861Q. Thirty-one patients received gefitinib. The response rate was 55% (95% CI, 33 to 70) and median progression-free survival was 9.2 months (95% CI, 6.2 to 11.8). Therapy was well tolerated; 13% of patients had grade 3 toxicities including one grade 3 pneumonitis. Two patients with classic activating mutations exhibited de novo gefitinib resistance and had concurrent genetic anomalies usually associated with acquired TKI resistance, specifically the T790M EGFR mutation and MET amplification.ConclusionFirst-line therapy with gefitinib administered in a genotype-directed fashion to patients with advanced NSCLC harboring EGFR mutations results in very favorable clinical outcomes with good tolerance. This strategy should be compared with combination chemotherapy, the current standard of care.
Distinct Clinical and Prognostic Features of Infiltrating Lobular Carcinoma of the Breast: Combined Results of 15 International Breast Cancer Study Group Clinical Trials
Authors: Pestalozzi Bernhard C. , Zahrieh David , Mallon Elizabeth , Gusterson Barry A. , Price Karen N. , Gelber Richard D. , Holmberg Stig B. , Lindtner Jurij , Snyder Raymond , Thürlimann Beat , Murray Elizabeth , Viale Giuseppe , Castiglione-Gertsch Monica , Coates Alan S. , Goldhirsch Aron 
Published: May 2008

Purpose To determine how patients with infiltrating lobular carcinoma (ILC) differ from patients with the more common infiltrating ductal carcinoma (IDC) with regard to patient and tumor factors, local treatment, and patterns of recurrence. Patients and Methods Twelve thousand two hundred six breast cancer patients entered onto 15 International Breast Cancer Study Group trials between 1978 and 2002 were categorized as having ILC, IDC, or other/mixed types. Results Seven hundred sixty-seven tumors (6.2%) were classified as ILC, 8,607 (70.5%) were classified as IDC, and 2,832 (23.2%) were classified as other. The analysis is limited to the 9,374 patients categorized as either pure IDC or ILC. The median follow-up time was 13 years. Compared with IDC, ILC was associated with older age; larger, better differentiated, and estrogen receptor (ER)–positive tumors; and less vessel invasion. Mastectomy was used more frequently for ILC (P < .01). There was a significant (P < .01) early advantage in disease-free survival and overall survival for the ILC cohort followed by a significant (P < .01) late advantage for the IDC cohort after 6 and 10 years, respectively. Similar patterns were observed in cohorts defined by ER status. ILC was associated with an increased incidence of bone events but a decrease in regional and lung events (all P < .01). Conclusion ILC is more than a histologic variant of breast cancer. The diagnosis of ILC carries distinct prognostic and biologic implications.
Hydrogen Content, Preoxidation, and Cooling Scenario Effects on Post-Quench Microstructure and Mechanical Properties of Zircaloy-4 and M5® Alloys in LOCA Conditions
Authors: Brachet J.-C. , Vandenberghe-Maillot V. , Portier L. , Gilbon D. , Lesbros A. , Waeckel N. , Mardon J.-P. 
Published: May 2008

AbstractPrevious papers pointed out the influence of long-term service exposures on the thermal-mechanical behavior of Zr alloys in LOCA conditions and, especially, the impact of in-service hydrogen pick-up on post-quench mechanical properties. Moreover, the oxide layer grown under in-service conditions was occasionally expected to have a protective effect against high temperature oxidation. Finally, the oxygen and hydrogen distributions within the prior-β layer appear as a key parameter with regard to the residual ductility of the alloy, especially as a function of the cooling scenario. The objective of the study presented here was to further investigate the influence of these parameters on the post-quench mechanical properties. Unirradiated Zircaloy-4 and M5® cladding tubes were consequently hydrided up to different concentration levels, then oxidized at high temperature (1000–1200°C) up to at least 10 % measured equivalent cladding reacted (ECR) and directly quenched to room temperature (RT). Ring compression tests (RCT), 3-point bending tests (3PBT) at RT and 135°C, as well as impact tests at RT were then performed to determine the evolution of the post-quench mechanical properties of Zircaloy-4 and M5® alloys with H content. Similarly, specimens preoxidized out-of-pile were also submitted to high temperature oxidation and direct quench, as well as to post-quench ring compression tests. Along with calculations of oxygen diffusion in the metal, results from those tests allowed us to estimate the assumed protective effect of the pretransient oxide layer. Finally, using specimens in the as-received condition or hydrided to typical end-of-life H contents, the effect of temperature history after oxidation at 1200°C was studied, i.e., at the end of the high temperature isothermal oxidation, samples were either submitted to direct quenching to RT or to slow cooling to different final quenching temperatures. It was thus demonstrated that the cooling scenario has a significant impact on the post-quench mechanical properties. All test samples were investigated by means of fractographic examinations to assess the type of failure mode. Moreover, a deep metallurgical analysis has been performed: SEM and image analysis were used for accurate phase thickness measurements, nuclear and electron microprobes for quantitative mapping of hydrogen and oxygen. It proved that the oxygen and hydrogen contents and their distribution in the prior-β layer have a first-order influence on the residual ductility. From all the results obtained on as-received and hydrided samples directly quenched from the oxidation temperature, it was then possible to derive a relationship between structural parameters, i.e., oxygen and hydrogen contents and thickness of the prior-β layer, and the post-quench impact properties at RT.
Genome Integrity Is Regulated by theCaenorhabditis elegansRad51D Homologrfs-1
Authors: Yanowitz Judith L 
Published: May 2008

AbstractMultiple mechanisms ensure genome maintenance through DNA damage repair, suppression of transposition, and telomere length regulation. The mortal germline (Mrt) mutants in Caenorhabditis elegans are defective in maintaining genome integrity, resulting in a progressive loss of fertility over many generations. Here I show that the high incidence of males (him)-15 locus, defined by the deficiency eDf25, is allelic to rfs-1, the sole rad-51 paralog group member in C. elegans. The rfs-1/eDf25 mutant displays a Mrt phenotype and mutant animals manifest features of chromosome fusions prior to the onset of sterility. Unlike other Mrt genes, rfs-1 manifests fluctuations in telomere lengths and functions independently of telomerase. These data suggest that rfs-1 is a novel regulator of genome stability.
Evidence on the Molecular Basis of the Ac/ac Adaptive Cyanogenesis Polymorphism in White Clover (Trifolium repens L.)
Authors: Olsen Kenneth M , Hsu Shih-Chung , Small Linda L 
Published: May 2008

Abstract
White clover is polymorphic for cyanogenesis, with both cyanogenic and acyanogenic plants occurring in nature. This chemical defense polymorphism is one of the longest-studied and best-documented examples of an adaptive polymorphism in plants. It is controlled by two independently segregating genes: Ac/ac controls the presence/absence of cyanogenic glucosides; and Li/li controls the presence/absence of their hydrolyzing enzyme, linamarase. Whereas Li is well characterized at the molecular level, Ac has remained unidentified. Here we report evidence that Ac corresponds to a gene encoding a cytochrome P450 of the CYP79D protein subfamily (CYP79D15), and we describe the apparent molecular basis of the Ac/ac polymorphism. CYP79D orthologs catalyze the first step in cyanogenic glucoside biosynthesis in other cyanogenic plant species. In white clover, Southern hybridizations indicate that CYP79D15 occurs as a single-copy gene in cyanogenic plants but is absent from the genomes of ac plants. Gene-expression analyses by RT–PCR corroborate this finding. This apparent molecular basis of the Ac/ac polymorphism parallels our previous findings for the Li/li polymorphism, which also arises through the presence/absence of a single-copy gene. The nature of these polymorphisms may reflect white clover's evolutionary origin as an allotetraploid derived from cyanogenic and acyanogenic diploid progenitors.
Hsp90/Hsp70 Chaperone Machine Regulation of the Saccharomyces MAL-Activator As Determined in Vivo Using Noninducible and Constitutive Mutant Alleles
Authors: Ran Fulai , Bali Mehtap , Michels Corinne A 
Published: May 2008

Abstract
The Hsp90/Hsp70 chaperone machine is an essential regulator of cell growth and division. It is required for activation of select client proteins, chiefly protein kinases and transcription activators and thus plays a major role in regulating intracellular signaling and gene expression. This report demonstrates, in vivo, the association of the Saccharomyces cerevisiae maltose-responsive transcription activator Mal63 (MAL-activator) with the yeast Hsp70 (Ssa1), Hsp90 (Hsp82), and Hop (Sti1) homologs, using a collection of inducible, constitutive, and noninducible alleles. Each class of mutant activator forms a distinctly different stable multichaperone complex in the absence of maltose. Inducible Mal63p associates with Ssa1, Hsp82, and Sti1 and is released in the presence of maltose. Noninducible mal63 mutant proteins bind to Ssa1 alone and do not stably associate with Hsp82 or Sti1. Constitutive MAL-activators bind well to Hsp82 and poorly to Ssa1 and Sti1, but deletion of STI1 restores Ssa1 binding. Taken together, Mal63p regulation requires the formation of Hsp90/Hsp70 subcomplexes comparable to, yet distinct from those observed with previously characterized Hsp90 clients including glucocorticoid receptor and yeast Hap1p. Thus, comparative studies of different client proteins highlight functional diversity in the operation of the Hsp90/Hsp70 chaperone machine.
High Rates of “Unselected” Aneuploidy and Chromosome Rearrangements intel1 mec1Haploid Yeast Strains
Authors: Vernon Michael , Lobachev Kirill , Petes Thomas D 
Published: May 2008

AbstractThe yeast TEL1 and MEC1 genes (homologous to the mammalian ATM and ATR genes, respectively) serve partially redundant roles in the detection of DNA damage and in the regulation of telomere length. Haploid yeast tel1 mec1 strains were subcultured nonselectively for ∼200 cell divisions. The subcultured strains had very high rates of chromosome aberrations: duplications, deletions, and translocations. The breakpoints of the rearranged chromosomes were within retrotransposons (Ty or δ-repeats), and these chromosome aberrations nonrandomly involved chromosome III. In addition, we showed that strains with the hypomorphic mec1-21 allele often became disomic for chromosome VIII. This property of the mec1-21 strains is suppressed by a plasmid containing the DNA2 gene (located on chromosome VIII) that encodes an essential nuclease/helicase involved in DNA replication and DNA repair.
Mechanisms of Rad52-Independent Spontaneous and UV-Induced Mitotic Recombination inSaccharomyces cerevisiae
Authors: Coïc Eric , Feldman Taya , Landman Allison S , Haber James E 
Published: May 2008

AbstractIn wild-type diploid cells, heteroallelic recombination between his4A and his4C alleles leads mostly to His+ gene conversions that have a parental configuration of flanking markers, but ∼22% of recombinants have associated reciprocal crossovers. In rad52 strains, gene conversion is reduced 75-fold and the majority of His+ recombinants are crossover associated, with the largest class being half-crossovers in which the other participating chromatid is lost. We report that UV irradiating rad52 cells results in an increase in overall recombination frequency, comparable to increases induced in wild-type (WT) cells, and surprisingly results in a pattern of recombination products quite similar to RAD52 cells: gene conversion without exchange is favored, and the number of 2n − 1 events is markedly reduced. Both spontaneous and UV-induced RAD52-independent recombination depends strongly on Rad50, whereas rad50 has no effect in cells restored to RAD52. The high level of noncrossover gene conversion outcomes in UV-induced rad52 cells depends on Rad51, but not on Rad59. Those outcomes also rely on the UV-inducible kinase Dun1 and Dun1's target, the repressor Crt1, whereas gene conversion events arising spontaneously depend on Rad59 and Crt1. Thus, there are at least two Rad52-independent recombination pathways in budding yeast.
Caenorhabditis elegansGenes Required for the Engulfment of Apoptotic Corpses Function in the Cytotoxic Cell Deaths Induced by Mutations inlin-24andlin-33
Authors: Galvin Brendan D , Kim Saechin , Horvitz H Robert 
Published: May 2008

AbstractTwo types of cell death have been studied extensively in Caenorhabditis elegans, programmed cell death and necrosis. We describe a novel type of cell death that occurs in animals containing mutations in either of two genes, lin-24 and lin-33. Gain-of-function mutations in lin-24 and lin-33 cause the inappropriate deaths of many of the Pn.p hypodermal blast cells and prevent the surviving Pn.p cells from expressing their normal developmental fates. The abnormal Pn.p cells in lin-24 and lin-33 mutant animals are morphologically distinct from the dying cells characteristic of C. elegans programmed cell deaths and necrotic cell deaths. lin-24 encodes a protein with homology to bacterial toxins. lin-33 encodes a novel protein. The cytotoxicity caused by mutation of either gene requires the function of the other. An evolutionarily conserved set of genes required for the efficient engulfment and removal of both apoptotic and necrotic cell corpses is required for the full cell-killing effect of mutant lin-24 and lin-33 genes, suggesting that engulfment promotes these cytotoxic cell deaths.
Degradation of Functional Triose Phosphate Isomerase Protein UnderliessugarkillPathology
Authors: Seigle Jacquelyn L , Celotto Alicia M , Palladino Michael J 
Published: May 2008

AbstractTriose phosphate isomerase (TPI) deficiency glycolytic enzymopathy is a progressive neurodegenerative condition that remains poorly understood. The disease is caused exclusively by specific missense mutations affecting the TPI protein and clinically features hemolytic anemia, adult-onset neurological impairment, degeneration, and reduced longevity. TPI has a well-characterized role in glycolysis, catalyzing the isomerization of dihydroxyacetone phosphate (DHAP) to glyceraldehyde-3-phosphate (G3P); however, little is known mechanistically about the pathogenesis associated with specific recessive mutations that cause progressive neurodegeneration. Here, we describe key aspects of TPI pathogenesis identified using the TPIsugarkill mutation, a Drosophila model of human TPI deficiency. Specifically, we demonstrate that the mutant protein is expressed, capable of forming a homodimer, and is functional. However, the mutant protein is degraded by the 20S proteasome core leading to loss-of-function pathogenesis.
Tidal Volume Threshold for Colorimetric Carbon Dioxide Detectors Available for Use in Neonates
Authors: Garey Donna M. , Ward Raymond , Rich Wade , Heldt Gregory , Leone Tina , Finer Neil N. 
Published: May 2008

OBJECTIVE. Colorimetric carbon dioxide detectors are used for confirmation of endotracheal intubation. The colorimetric carbon dioxide detectors that are used for neonates are labeled for use with infants and small children &gt;1 and &lt;15 kg. The objective of this study was to determine the minimal tidal volume that causes a breath-to-breath color change on 2 colorimetric carbon dioxide detectors.METHODS. Using an artificial-lung model, we determined the tidal volume threshold of 2 colorimetric carbon dioxide detectors (Pedi-Cap [Nellcor, Pleasanton, CA] or Mini StatCO2 [Mercury Medical, Clearwater, FL]) during ventilation with a T-piece resuscitator or neonatal ventilator. Digital video recordings of the colorimetric carbon dioxide detectors were made during 20 seconds of ventilation at each tidal volume. Seven clinicians who were blinded to the tidal volume reviewed the videos in random order and graded the color change to determine adequacy for clinical application.RESULTS. The Mini StatCO2 tidal volume threshold was 0.83 mL, and the Pedi-Cap tidal volume threshold was 1.08 mL.CONCLUSIONS. The lung model revealed that the tidal volume threshold for the tested colorimetric carbon dioxide detectors is less than the expected tidal volume of a 400-g infant and suggests that these devices are appropriate for use with any neonate to confirm intubation.