bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hybrid binary rewriting for memory access instrumentation
Authors: Roy Amitabha , Hand Steven , Harris Tim 
Published: July 2011

Memory access instrumentation is fundamental to many applications such as software transactional memory systems, profiling tools and race detectors. We examine the problem of efficiently instrumenting memory accesses in x86 machine code to support software transactional memory and profiling. We aim to automatically instrument all shared memory accesses in critical sections of x86
binaries
, while achieving overhead close to that obtained when performing manual instrumentation at the source code level.

The two primary options in building such an instrumentation system are static and dynamic binary rewriting: the former instruments binaries at link time before execution, while the latter binary rewriting instruments binaries at runtime. Static binary rewriting offers extremely low overhead but is hampered by the limits of static analysis. Dynamic binary rewriting is able to use runtime information but typically incurs higher overhead. This paper proposes an alternative: hybrid binary rewriting. Hybrid binary rewriting is built around the idea of a persistent instrumentation cache (PIC) that is associated with a binary and contains instrumented code from it. It supports two execution modes when using instrumentation: active and passive modes. In the active execution mode, a dynamic binary rewriting engine (PIN) is used to intercept execution, and generate instrumentation into the PIC, which is an on-disk file. This execution mode can take full advantage of runtime information. Later, passive execution can be used where instrumented code is executed out of the PIC. This allows us to attain overheads similar to those incurred with static binary rewriting.
This instrumentation methodology enables a variety of static and dynamic techniques to be applied. For example, in passive mode, execution occurs directly from the original executable save for regions that require instrumentation. This has allowed us to build a low-overhead transactional memory profiler. We also demonstrate how we can use the combination of static and dynamic techniques to eliminate instrumentation for accesses to locations that are thread-private.
New Strategies in Overcoming Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Cancer
Authors: Oxnard Geoffrey R. , Arcila Maria E. , Chmielecki Juliann , Ladanyi Marc , Miller Vincent A. , Pao William 
Published: July 2011

Abstract
The management of non–small cell lung carcinoma (NSCLC) has been transformed by the observation that lung adenocarcinomas harboring mutations in epidermal growth factor receptor (EGFR) are uniquely sensitive to EGFR tyrosine kinase inhibitors (TKI). In these patients, acquired resistance to EGFR-TKI develops after a median of 10 to 14 months, at which time the current standard practice is to switch to conventional cytotoxic chemotherapy. Several possible mechanisms for acquired resistance have been identified, the most common being the development of an EGFR T790M gatekeeper mutation in more than 50% of cases. In this review, we discuss recent advances in the understanding of acquired TKI resistance in EGFR-mutant lung cancer and review therapeutic progress with second generation TKIs and combinations of targeted therapies. Clin Cancer Res; 17(17); 5530–7. ©2011 AACR.
Genetic Variation Predicting Cisplatin Cytotoxicity Associated with Overall Survival in Lung Cancer Patients Receiving Platinum-Based Chemotherapy
Authors: Tan Xiang-Lin , Moyer Ann M. , Fridley Brooke L. , Schaid Daniel J. , Niu Nifang , Batzler Anthony J. , Jenkins Gregory D. , Abo Ryan P. , Li Liang , Cunningham Julie M. , Sun Zhifu , Yang Ping , Wang Liewei 
Published: July 2011

Abstract
Purpose: Inherited variability in the prognosis of lung cancer patients treated with platinum-based chemotherapy has been widely investigated. However, the overall contribution of genetic variation to platinum response is not well established. To identify novel candidate single nucleotide polymorphisms (SNP)/genes, we carried out a genome-wide association study (GWAS) for cisplatin cytotoxicity by using lymphoblastoid cell lines (LCL), followed by an association study of selected SNPs from the GWAS with overall survival (OS) in lung cancer patients.
Experimental Design: A GWAS for cisplatin was conducted with 283 ethnically diverse LCLs. A total of 168 top SNPs were genotyped in 222 small cell lung cancer (SCLC) and 961 non-SCLC (NSCLC) patients treated with platinum-based therapy. Association of the SNPs with OS was determined by using the Cox regression model. Selected candidate genes were functionally validated by siRNA knockdown in human lung cancer cells.
Results: Among 157 successfully genotyped SNPs, 9 and 10 SNPs were top SNPs associated with OS for patients with NSCLC and SCLC, respectively, although they were not significant after adjusting for multiple testing. Fifteen genes, including 7 located within 200 kb up or downstream of the 4 top SNPs and 8 genes for which expression was correlated with 3 SNPs in LCLs were selected for siRNA screening. Knockdown of DAPK3 and METTL6, for which expression levels were correlated with the rs11169748 and rs2440915 SNPs, significantly decreased cisplatin sensitivity in lung cancer cells.
Conclusions: This series of clinical and complementary laboratory-based functional studies identified several candidate genes/SNPs that might help predict treatment outcomes for platinum-based therapy of lung cancer. Clin Cancer Res; 17(17); 5801–11. ©2011 AACR.
Forced Dimerization Increases the Activity of ΔEGFR/EGFRvIII and Enhances Its Oncogenicity
Authors: Hwang Yeohyeon , Chumbalkar Vaibhav , Latha Khatri , Bogler Oliver 
Published: July 2011

Abstract
Delta epidermal growth factor receptor (ΔEGFR), an in-frame deletion mutant of the extracellular ligand-binding domain, which occurs in about 30% of glioblastoma, is a potent oncogene that promotes tumor growth and progression. The signaling of ΔEGFR is ligand-independent and low intensity, allowing it to evade the normal mechanisms of internalization and degradation by the endocytic machinery and hence is persistent. The basis of the oncogenic potential of ΔEGFR remains incompletely understood, including whether dimerization plays an important role in its signal and whether its oncogenic potential is dependent on its relatively low intensity, when compared with the acutely activated wild-type receptor. To examine these two important questions, we have generated a chimeric ΔEGFR that allows forced dimerization via domains derived from variants of the FKBP12 protein that are brought together by FK506 derivatives. Forced dimerization of chimeric ΔEGFR significantly increased the intensity of its signal, as measured by receptor phosphorylation levels, suggesting that the naturally occurring ΔEGFR does not form strong or stable dimers as part of its low level signal. Interestingly, the increased activity of dimerized, chimeric ΔEGFR did not promote receptor internalization, implying that reduced rate of endocytic downregulation of ΔEGFR is an inherent characteristic. Significantly, forced dimerization enhanced the oncogenic signal of the receptor, implying that the ΔEGFR is a potent oncogene despite, not because of its low intensity. Mol Cancer Res; 9(9); 1199–208. ©2011 AACR.
Coxibs and Other Nonsteroidal Anti-Inflammatory Drugs in Animal Models of Cancer Chemoprevention
Authors: Fischer Susan M. , Hawk Ernest T. , Lubet Ronald A. 
Published: July 2011

Abstract
Coxibs, including celecoxib, and other nonsteroidal anti-inflammatory drugs (NSAID), including aspirin, are among the most promising cancer chemopreventive agents in development today. This article examines the data on the efficacy of these agents in animal model studies of cancer prevention carried out by the authors. The studies evaluated here are restricted to our rodent models of colon/intestinal, bladder, and nonmelanoma skin cancer, in which celecoxib and other NSAIDs were administered as either cancer preventive or therapeutic agents. These studies may shed light on several questions. Is celecoxib unique compared with other NSAIDs, and if so, what implications would this have for human use? Are standard NSAIDs (which inhibit both COX-1 and COX-2) as effective as celecoxib in animal studies? Is the efficacy of celecoxib in particular or NSAIDs in general due to their off-target effects or to their effects on COX-1 and COX-2? What is the likely efficacy of low-dose aspirin? Some questions raised by human trials and epidemiology are discussed and related to our observations in animal model studies. We also discuss the problem of cardiovascular (CV) events associated with coxibs and certain other NSAIDs and whether results in animal models are predictive of efficacy in humans. On the basis of epidemiologic studies and its CV profile, aspirin seems to be the most promising NSAID for preventing human colorectal, bladder, and skin cancer, although the animal data for aspirin are less clear. A comprehensive understanding of the results of coxibs and other NSAIDs in animal studies may help inform and shape human trials of these commonly employed, relatively inexpensive, and highly effective compounds. Cancer Prev Res; 4(11); 1728–35. ©2011 AACR.
Characterization of New Founder Alu-Mediated Rearrangements in MSH2 Gene Associated with a Lynch Syndrome Phenotype
Authors: Pérez-Cabornero Lucia , Borrás Flores Ester , Sanz Mar Infante , Sampedro Eladio Velasco , Becares Alberto Acedo , Aras Enrique Lastra , González Jorge Cuevas , Riu Marta Pineda , Asensio Teresa Ramón y Cajal , Munar Gabriel Capellá , Pino Cristina Miner , Domínguez Mercedes Durán 
Published: July 2011

Abstract
It has been reported that large genomic deletions in the MLH1 and MSH2 genes are a frequent cause of Lynch syndrome in certain populations. Here, a cohort has been screened and two new founder rearrangements have been found in the MSH2 gene. These mutations have been characterized by break point determination, haplotype analysis, and genotype–phenotype correlation. Mutations have been identified in the MLH1, MSH2, and MSH6 genes in 303 subjects from 160 suspected Lynch syndrome unrelated families. All subjects were tested using heteroduplex analysis by capillary array electrophoresis. Multiplex ligation-dependent probe amplification was used to detect rearrangements in mutation-negative index patients and confirmed by reverse transcriptase PCR. The break point of the deletions was further characterized by the array comparative genomic hybridization method. Immunohistochemical staining and microsatellite instability were studied in tumor samples. Hereditary nonpolyposis colorectal cancer–related phenotypes were evaluated. More than 16% (24 of 160) of the families had pathogenic mutations (8 MLH1, 15 MSH2, and 1 MSH6). Twelve of these families (50%) are carriers of a novel mutation. Seven of the 15 positive MSH2 families (47%) are carriers of a rearrangement. The exon 7 deletion and exon 4 to 8 deletion of MSH2 are new founder mutations. The segregation of a common haplotype, a similar phenotype, and anticipation effects were observed in these families. These findings will greatly simplify the diagnosis, counseling, and clinical care in suspected Lynch syndrome families and not just in specific geographic areas, so wide distribution may be explained by migration patterns. Cancer Prev Res; 4(10); 1546–55. ©2011 AACR.
Improved Late Survival and Disability After Stroke With Therapeutic Anticoagulation for Atrial Fibrillation
Authors: Hannon Niamh , Callaly Elizabeth , Moore Alan , Ní Chróinín Danielle , Sheehan Órla , Marnane Michael , Merwick Áine , Kyne Lorraine , Duggan Joseph , McCormack Patricia M.E. , Dolan Eamon , Crispino-O'Connell Gloria , Harris Dawn , Horgan Gillian , Williams David , Kelly Peter J. 
Published: July 2011

Background and Purpose—
Although therapeutic anticoagulation improves early (within 1 month) outcomes after ischemic stroke in hospital-admitted patients with atrial fibrillation, no information exists on late outcomes in unselected population-based studies, including patients with all stroke (ischemic and hemorrhagic).

Methods—
We identified patients with atrial fibrillation and stroke in a prospective, population-based study in North Dublin. Clinical characteristics, stroke subtype, stroke severity (National Institutes of Health Stroke Scale), prestroke antithrombotic medication, and International Normalized Ratio (INR) at onset were documented. Modified Rankin Scale (mRS) score was measured before stroke and at 7, 28, and 90 days; 1 year; and 2 years after stroke.

Results—

One hundred seventy-five patients had atrial fibrillation–associated stroke and medication data at stroke onset (159 ischemic, 16 hemorrhagic); 17% of those with ischemic stroke were anticoagulated before stroke (27 of 159.) On multivariable analysis, therapeutic INR was associated with improved late survival after ischemic stroke (adjusted 2-year odds ratio for death=0.08; 95% CI, 0.01 to 0.78;
P
=0.03). This survival benefit persisted when patients with hemorrhagic stroke were included (2-year survival; 70.5% therapeutic INR, 14.3% nontherapeutic INR; log-rank
P
<0.001; odds ratio for death=0.27; 95% CI, 0.09 to 0.88;
P
=0.03). Admission INR was inversely correlated with early and late modified Rankin Scale score (2-year Spearman ρ=−0.65;
P
<0.0003). An INR of 2 to 3 at ischemic stroke onset was associated with greater early (72 hours to 28 days) modified Rankin Scale score improvement (
P
=0.04) and good functional outcome (modified Rankin Scale score=0 to 2) at 1 year (adjusted odds ratio=4.8; 95% CI, 1.45 to 23.8;
P
=0.04).

Conclusions—
In addition to improving short-term outcome in selected hospital-treated patient groups, therapeutic anticoagulation may provide important benefits for long-term stroke outcomes in unselected populations.
Stroke Declines From Third to Fourth Leading Cause of Death in the United States
Authors: Towfighi Amytis , Saver Jeffrey L. 
Published: July 2011

Background and Purpose—
Stroke recently declined from the third to the fourth leading cause of death in the United States, its first rank transition among sources of American mortality in nearly 75 years.

Methods—
This is a narrative review supplemented by new analyses of Centers for Disease Control and Prevention National Vital Statistics Reports from 1931 to 2008.

Results—
Historically, stroke transitioned from the second to the third leading cause of death in the United States in 1937, but stroke death rates were essentially stable from 1930 to 1960. Then a long, great decline began, moderate in the 1960s, precipitous in the 1970s and 1980s, and moderate again in the 1990s and 2000s. By 2008, age-adjusted annual death rates from stroke were three fourths less than the historic 1931 to 1960 norm (40.6 versus 175.0 per 100 000). Total actual stroke deaths in the United States declined from a high of 214 000 in 1973 to 134 000 in 2008. Improved stroke prevention, through control of hypertension, hyperlipidemia, and tobacco, contributed most greatly to the mortality decline with a lesser but still substantial contribution of improved acute stroke care. Persisting challenges include race–ethnicity, sex, and geographic disparities in stroke mortality; the burden of stroke disability; the expanding obesity epidemic and aging of the US population; and the epidemic of cerebrovascular disease in low- and middle-income countries worldwide.

Conclusions—
The recent rank decline of stroke among leading causes of American death is testament to a half century of societal progress in cerebrovascular disease prevention and acute care. Renewed commitments are needed to preserve and broaden this historic achievement.
Malacia, inflammation and bronchoalveolar lavage culture in children with persistent respiratory symptoms
Authors: De Baets F. , De Schutter I. , Aarts C. , Haerynck F. , Van daele S. , De Wachter E. , Malfroot A. , Schelstraete P. 
Published: July 2011

In children with persistent respiratory symptoms despite regular anti-asthma inhalation treatment, diagnostic investigations to exclude underlying disease are warranted.124 children were prospectively enrolled, and 24-h oesophageal pH measurement and fibreoptic bronchoscopy with bronchoalveolar lavage (BAL) were performed. BAL fluid (BALF) was processed for neutrophil counting and bacterial culture. Inflammation of the respiratory mucosa was assessed.A structural abnormality of the central airways was found in 47% of subjects (40% females). In 19% of subjects, neither anatomical anomalies nor inflamed respiratory mucosa were observed, whereas in 64%, definite macroscopic mucosal inflammation was observed. Inflammation of the respiratory mucosa was associated with a significantly higher percentage of neutrophils in the BALF: median (interquartile range) 48 (14–82)% compared with 7 (0–16)% (p<0.025). A positive BALF culture was found in 62% of the infants with mucosal inflammation compared with 25% in the group without inflammation (p<0.016). 56% of the BALF samples were positive for bacterial culture.In children with persistent respiratory symptoms, nearly half have anatomical anomalies of the central airways. In 62% of the children with mucosal inflammation, a positive BAL culture and a significantly higher percentage of BALF neutrophils were detected.
Anti-reflux surgery in lung transplant recipients: outcomes and effects on quality of life
Authors: Robertson A.G.N. , Krishnan A. , Ward C. , Pearson J.P. , Small T. , Corris P.A. , Dark J.H. , Karat D. , Shenfine J. , Griffin S.M. 
Published: July 2011

Fundoplication may improve survival after lung transplantation. Little is known about the effects of fundoplication on quality of life in these patients. The aim of this study was to assess the safety of fundoplication in lung transplant recipients and its effects on quality of life.Between June 1, 2008 and December 31, 2010, a prospective study of lung transplant recipients undergoing fundoplication was undertaken. Quality of life was assessed before and after surgery. Body mass index (BMI) and pulmonary function were followed up.16 patients, mean±sdage 38±11.9 yrs, underwent laparoscopic Nissen fundoplication. There was no peri-operative mortality or major complications. Mean±sdhospital stay was 2.6±0.9 days. 15 out of 16 patients were satisfied with the results of surgery post fundoplication. There was a significant improvement in reflux symptom index and DeMeester questionnaires and gastrointestinal quality of life index scores at 6 months. Mean BMI decreased significantly after fundoplication (p=0.01). Patients operated on for deteriorating lung function had a statistically significant decrease in the rate of lung function decline after fundoplication (p=0.008).Laparoscopic fundoplication is safe in selected lung transplant recipients. Patient benefit is suggested by improved symptoms and satisfaction. This procedure is acceptable, improves quality of life and may reduce deterioration of lung function.
Mutation screening of the RNF8, UBC13 and MMS2 genes in Northern Finnish breast cancer families
Authors: Vuorela Mikko , Pylkäs Katri , Winqvist Robert 
Published: July 2011

Abstract

Background
Currently known susceptibility genes such as BRCA1 and BRCA2 explain less than 25% of familial aggregation of breast cancer, which suggests the involvement of additional susceptibility genes. RNF8, UBC13 and MMS2 are involved in the DNA damage response pathway and play important roles in BRCA1-mediated DNA damage recognition. Based on the evidence that several players in the ubiquitin-mediated BRCA1-dependent DDR seem to contribute to breast cancer predisposition, RNF8, UBC13 and MMS2 were considered plausible candidate genes for susceptibility to breast cancer.

Methods
The entire coding region and splice junctions of RNF8, UBC13 and MMS2 genes were screened for mutations in affected index cases from 123 Northern Finnish breast cancer families by using conformation sensitive gel electrophoresis, high resolution melting (HRM) analysis and direct sequencing.

Results
Mutation analysis revealed several changes in RNF8 and UBC13, whereas no aberrations were observed in MMS2. None of the found sequence changes appeared to associate with breast cancer susceptibility.

Conclusions
The present data suggest that mutations in RNF8, UBC13 and MMS2 genes unlikely make any sizeable contribution to breast cancer predisposition in Northern Finland.
Target-selective joint polymerase chain reaction: A robust and rapid method for high-throughput production of recombinant monoclonal antibodies from single cells
Authors: Yoshioka Megumi , Kurosawa Nobuyuki , Isobe Masaharu 
Published: July 2011

AbstractBackgroundDuring the development of a therapeutic antibody, large numbers of monoclonal antibodies are required to screen for those that are best suited for the desired activity. Although the single cell-based immunoglobulin variable gene cloning technique is a powerful tool, the current methods remain an obstacle to the rapid production of large numbers of recombinant antibodies.ResultsWe have developed a novel overlap extension polymerase chain reaction, the target-selective joint polymerase chain reaction (TS-jPCR), and applied it to the generation of linear immunoglobulin gene expression constructs. TS-jPCR is conducted using a PCR-amplified immunoglobulin variable gene and an immunoglobulin gene-selective cassette (Ig-cassette) that contains all essential elements for antibody expression and overlapping areas of immunoglobulin gene-specific homology. The TS-jPCR technique is simple and specific; the 3'-random nucleotide-tailed immunoglobulin variable gene fragment and the Ig-cassette are assembled into a linear immunoglobulin expression construct, even in the presence of nonspecifically amplified DNA. We also developed a robotic magnetic beads handling instrument for single cell-based cDNA synthesis to amplify immunoglobulin variable genes by rapid amplification of 5' cDNA ends PCR. Using these methods, we were able to produce recombinant monoclonal antibodies from large numbers of single plasma cells within four days.ConclusionOur system reduces the burden of antibody discovery and engineering by rapidly producing large numbers of recombinant monoclonal antibodies in a short period of time.
Chronic administration of palmitoleic acid reduces insulin resistance and hepatic lipid accumulation in KK-Ay Mice with genetic type 2 diabetes
Authors: Yang Zhi-Hong , Miyahara Hiroko , Hatanaka Akimasa 
Published: July 2011

Abstract
Background
Studies have demonstrated the beneficial effect of palmitoleic acid (C16:1 n-7) on reducing muscle insulin resistance and preventing beta-cell apoptosis. However, the effect of palmitoleic acid on diabetes remains to be elucidated. The aim of this study was to examine the antidiabetic effect of palmitoleic acid in KK-Ay mice, a spontaneous model for studies of obese type 2 diabetes with low insulin sensitivity.

Methods
KK-Ay mice were orally administered vehicle, 300 mg/kg of palmitoleic acid, or 300 mg/kg of palmitic acid (C16:0) on a daily basis for 4 weeks.

Results
Palmitoleic acid reduced body weight increase, ameliorated the development of hyperglycemia and hypertriglyceridemia, and improved insulin sensitivity. In addition, hepatic characteristics were significantly affected, as weight of the liver and hepatic triglyceride levels were lower in the palmitoleic acid group when compared to the control (vehicle and palmitic acid groups). Oil red O staining clearly indicated reduced hepatic lipid accumulation in response to palmitoleic acid. Furthermore, palmitoleic acid down-regulated mRNA expressions of proinflammatory adipocytokine genes (TNFα and resistin) in white adipose tissue and lipogenic genes (SREBP-1, FAS, and SCD-1) in liver.

Conclusions
These results suggest that palmitoleic acid improves hyperglycemia and hypertriglyceridemia by increasing insulin sensitivity, in part owing to suppressing proinflammatory gene expressions and improving hepatic lipid metabolism in diabetic mice.