bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ploidy and Large-Scale Genomic Instability Consistently Identify Basal-like Breast Carcinomas with BRCA1/2 Inactivation
Authors: Popova Tatiana , Manié Elodie , Rieunier Guillaume , Caux-Moncoutier Virginie , Tirapo Carole , Dubois Thierry , Delattre Olivier , Sigal-Zafrani Brigitte , Bollet Marc , Longy Michel , Houdayer Claude , Sastre-Garau Xavier , Vincent-Salomon Anne , Stoppa-Lyonnet Dominique , Stern Marc-Henri 
Published: August 2012

Abstract
BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define a signature of BRCA1-associated genomic instability. Large-scale state transitions (LST), defined as chromosomal break between adjacent regions of at least 10 Mb, were found to be a robust indicator of BRCA1 status in this setting. Two major ploidy-specific cutoffs in LST distributions were sufficient to distinguish highly rearranged BLCs with 85% of proven BRCA1-inactivated cases from less rearranged BLCs devoid of proven BRCA1-inactivated cases. The genomic signature we defined was validated in a second independent series of 55 primary BLC cases and 17 BLC-derived tumor cell lines. High numbers of LSTs resembling BRCA1-inactivated BLC were observed in 4 primary BLC cases and 2 BLC cell lines that harbored BRCA2 mutations. Overall, the genomic signature we defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy). This assay may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer. Cancer Res; 72(21); 5454–62. ©2012 AACR.
Sorafenib Inhibits Hypoxia-Inducible Factor-1α Synthesis: Implications for Antiangiogenic Activity in Hepatocellular Carcinoma
Authors: Liu Li-ping , Ho Rocky L. K. , Chen George G. , Lai Paul B. S. 
Published: August 2012

Abstract
Purpose: The overexpression of hypoxia-inducible factor 1α (HIF-1α) is a common finding in hepatocellular carcinoma (HCC), and it leads to angiogenesis and poor prognosis. Sorafenib, a multikinase inhibitor, has shown significant improvement in survival in patients with advanced HCC in clinical trials. However, the mechanisms that account for the antiangiogenic efficiency of sorafenib have not been fully elucidated. The present study aims to explore the effect of sorafenib on HIF-1α expression and activation in HCC cells and xenografts.
Experimental Design: HCC cells and xenografts were treated with sorafenib or vehicles. Western blotting and quantitative PCR array were used to determine protein and mRNA expression, respectively. HIF-1α activity, de novo protein synthesis, and VEGF secretions were determined using assay kits.
Results: Sorafenib dose dependently decreased the hypoxia-induced accumulation and activation of HIF-1α protein. Further analysis revealed that such reduction of HIF-1α was associated with the inhibition of HIF-1α protein synthesis rather than the promotion of HIF-1α protein degradation or the reduction of HIF-1α mRNA. Moreover, the phosphorylation levels of mTOR, extracellular signal-regulated kinase (ERK), p70S6K, RP-S6, 4E-BP1, and eIF4E were significantly suppressed by sorafenib. In vivo studies further confirmed the inhibitory effect of sorafenib on the expression of HIF-1α and VEGF proteins, leading to a decrease in tumor vascularization and growth of the xenografts.
Conclusions: Sorafenib-mediated inhibition of HIF-1α synthesis is associated with previously undefined pathways in which mTOR/p70S6K/4E-BP1 and ERK phosphorylation are downregulated. Our preclinical data expand our understanding of sorafenib's antiangiogenic mechanism of action by inhibiting HIF-1α and VEGF protein expression. Clin Cancer Res; 18(20); 5662–71. ©2012 AACR.
Carfilzomib and ONX 0912 Inhibit Cell Survival and Tumor Growth of Head and Neck Cancer and Their Activities Are Enhanced by Suppression of Mcl-1 or Autophagy
Authors: Zang Yan , Thomas Sufi M. , Chan Elena T. , Kirk Christopher J. , Freilino Maria L. , DeLancey Hannah M. , Grandis Jennifer R. , Li Changyou , Johnson Daniel E. 
Published: August 2012

Abstract
Purpose: Carfilzomib is a selective, irreversible inhibitor of the chymotrypsin-like activity of the proteasome and is undergoing clinical evaluation in myeloma. ONX 0912 (oprozomib) is an orally bioavailable derivative. The activities of carfilzomib and ONX 0912 against solid tumor malignancies are less well understood. We investigated the impact and mechanisms of action of carfilzomib and ONX 0912 in preclinical models of head and neck squamous cell carcinoma (HNSCC).
Experimental Design: The effects of carfilzomib and ONX 0912 on HNSCC cell survival and xenograft tumor growth were evaluated. The impact and mechanisms of both agents on apoptosis and autophagy induction were also investigated. The contribution of the unfolded protein response (UPR) to autophagy induction and the role of autophagy in attenuating HNSCC cell death were determined.
Results: Carfilzomib and ONX 0912 potently induced apoptosis in HNSCC cell lines via upregulation of pro-apoptotic Bik. Upregulation of Mcl-1 by these agents served to dampen their efficacies. Carfilzomib and ONX 0912 also induced autophagy, mediated, in part, by activation of the UPR pathway involving upregulation of ATF4 transcription factor. Autophagy induction served a prosurvival role. Oral administration of ONX 0912 inhibited the growth of HNSCC xenograft tumors in a dose-dependent manner.
Conclusions: These results show that carfilzomib and ONX 0912 are potently active against HNSCC cells, and the activities of these agents can be enhanced via suppression of Mcl-1 or inhibition of autophagy. Oral ONX 0912 exhibits in vivo activity against HNSCC tumors and may represent a useful therapeutic agent for this malignancy. Clin Cancer Res; 18(20); 5639–49. ©2012 AACR.
Loss of the Malignant Phenotype of Human Neuroblastoma Cells by a Catalytically Inactive Dominant-Negative hTERT Mutant
Authors: Samy Mona , Gattolliat Charles-Henry , Pendino Frédéric , Hillion Josette , Nguyen Eric , Bombard Sophie , Douc-Rasy Sétha , Bénard Jean , Ségal-Bendirdjian Evelyne 
Published: August 2012

Abstract
Telomerase, a ribonucleoprotein complex mainly composed of the reverse transcriptase catalytic subunit (human telomerase reverse transcriptase, hTERT) and the RNA component (hTR), is a key enzyme of cancer progression. That aggressive stage 4-neuroblastoma expressed high levels of telomerase activity, whereas favorable tumors had no or little telomerase expression and activity, prompted us to investigate the role of this enzyme in this tumor model of altered proliferation, neuronal differentiation, and apoptosis. A human MYCN-amplified neuroblastoma cell line (IGR-N-91) was engineered to stably express either the normal hTERT protein (WT-hTERT) or a catalytically inactive dominant-negative mutant of this protein (DN-hTERT). We showed that DN-hTERT expression inhibited the endogenous hTERT in the malignant neuroblasts without telomere shortening nor loss of in vitro proliferative capacity. Importantly, DN-hTERT expression induced major changes in cell morphology of neuroblasts that switched them from a neuronal to a substrate adherent phenotype, which was more prone to apoptosis and lost their tumorigenic properties in nude mice. These biologic effects arose from modifications in the expression of genes involved in both apoptosis and neuroblastoma biology. Taken together these results highlighted the functional relevance of noncanonical functions of hTERT in the determination of neuroblast cell fate. Therefore, our results envision new therapeutic strategies for metastatic neuroblastoma therapeutic management. Mol Cancer Ther; 11(11); 2384–93. ©2012 AACR.
Stromal Platelet-Derived Growth Factor Receptor α (PDGFRα) Provides a Therapeutic Target Independent of Tumor Cell PDGFRα Expression in Lung Cancer Xenografts
Authors: Gerber David E. , Gupta Puja , Dellinger Michael T. , Toombs Jason E. , Peyton Michael , Duignan Inga , Malaby Jennifer , Bailey Timothy , Burns Colleen , Brekken Rolf A. , Loizos Nick 
Published: August 2012

Abstract
In lung cancer, platelet-derived growth factor receptor α (PDGFRα) is expressed frequently by tumor-associated stromal cells and by cancer cells in a subset of tumors. We sought to determine the effect of targeting stromal PDGFRα in preclinical lung tumor xenograft models (human tumor, mouse stroma). Effects of anti-human (IMC-3G3) and anti-mouse (1E10) PDGFRα monoclonal antibodies (mAb) on proliferation and PDGFRα signaling were evaluated in lung cancer cell lines and mouse fibroblasts. Therapy studies were conducted using established PDGFRα-positive H1703 cells and PDGFRα-negative Calu-6, H1993, and A549 subcutaneous tumors in immunocompromised mice treated with vehicle, anti-PDGFRα mAbs, chemotherapy, or combination therapy. Tumors were analyzed for growth and levels of growth factors. IMC-3G3 inhibited PDGFRα activation and the growth of H1703 cells in vitro and tumor growth in vivo, but had no effect on PDGFRα-negative cell lines or mouse fibroblasts. 1E10 inhibited growth and PDGFRα activation of mouse fibroblasts, but had no effect on human cancer cell lines in vitro. In vivo, 1E10-targeted inhibition of murine PDGFRα reduced tumor growth as single-agent therapy in Calu-6 cells and enhanced the effect of chemotherapy in xenografts derived from A549 cells. We also identified that low expression cancer cell expression of VEGF-A and elevated expression of PDGF-AA were associated with response to stromal PDGFRα targeting. We conclude that stromal PDGFRα inhibition represents a means for enhancing control of lung cancer growth in some cases, independent of tumor cell PDGFRα expression. Mol Cancer Ther; 11(11); 2473–82. ©2012 AACR.
Diagnostic and Prognostic Performance of Myeloperoxidase Plasma Levels Compared With Sensitive Troponins in Patients Admitted With Acute Onset Chest Pain
Authors: Rudolph Volker , Keller Till , Schulz Andreas , Ojeda Francisco , Rudolph Tanja K. , Tzikas Stergios , Bickel Christoph , Meinertz Thomas , Münzel Thomas , Blankenberg Stefan , Baldus Stephan 
Published: August 2012

Background—
Activation of leukocytes with release of myeloperoxidase (MPO) has been linked to acute coronary disease. To date, studies investigating the diagnostic and prognostic performance of circulating MPO in patients with chest pain (CP) are mainly retrospective, of low size, and lack a cut-off value for MPO. Herein, we prospectively assess the diagnostic and prognostic properties of MPO compared with sensitive troponin I (sTNI) in patients admitted to the emergency room with CP.

Methods and Results—
One thousand, eight hundred and eighteen consecutive patients (mean age, 61.4±13.5 years; 33.6% female) admitted for CP underwent determination of MPO, sTnI, and B-natriuretic peptide plasma levels at admission and 3 hours and 6 hours thereafter. A cut-off for MPO was defined in 5000 population-based subjects. Baseline MPO levels were elevated in patients with acute myocardial infarction compared with patients with noncoronary CP. For all time-points accuracy of MPO was inferior to sTNI for predicting AMI. The sensitivity of MPO to diagnose AMI at presentation was 73.5% compared with 90.7% for sTNI, and the specificity of MPO was 45.5% as opposed to 90.2%. B-natriuretic peptide levels also failed to demonstrate independent diagnostic information. Both MPO and B-natriuretic peptide were predictive for increased risk of adverse events at 30 days and 6 months, whereas their predictive value was weakened after covariate adjustment.

Conclusions—
The data demonstrate that MPO and B-natriuretic peptide fail to provide incremental information for patients with acute onset CP when added to sensitive troponin. However, there is a potential value for both biomarkers as prognostic markers.
Spongious Hypertrophic Cardiomyopathy in Patients With Mutations in the Four-and-a-Half LIM Domain 1 Gene
Authors: Binder Josepha S. , Weidemann Frank , Schoser Benedikt , Niemann Markus , Machann Wolfram , Beer Meinrad , Plank Gernot , Schmidt Albrecht , Bisping Egbert , Poparic Ivana , Lafer Ingrid , Stojakovic Tatjana , Quasthoff Stefan , Vincent John B. , Rienmueller Rainer , Speicher Michael R. , Berghold Andrea , Pieske Burkert , Windpassinger Christian 
Published: August 2012

Background—

X-linked myopathy with postural muscle atrophy is a novel X-linked myopathy caused by mutations in the four-and-a-half LIM domain 1 gene (FHL1). Cardiac involvement was suspected in initial publications. We now systematically analyzed the association of the
FHL1
genotype with the cardiac phenotype to establish a potential cardiac involvement in the disease.

Methods and Results—

Seventeen male patients and 23 female mutation carriers were compared with healthy controls. Every patient underwent a comprehensive clinical and cardiovascular workup. ECG abnormalities occurred frequently in affected males and were less frequent in heterozygous females. Both male and female mutation carriers had increased myocardial mass (affected males=115.1±25.3 g/m
2
; heterozygous females=95.1±19.6 g/m
2
; controls=89.0±15.6 g/m
2
and 72.6±12.6 g/m
2
; respectively) with increased wall thickness (typically midventricular and apical segments) mainly in affected males. Longitudinal systolic function was reduced in affected males (radial systolic strain: affected males=24.6±11.8%; male controls=43.2±14.8%;
P
=0.002). Diastolic dysfunction occurred in both affected males and heterozygous females. Cardiac MRI revealed a morphological hallmark of X-linked myopathy with postural muscle atrophy; a characteristic spongious structure and replacement fibrosis indicated by late enhancement could be detected in most affected males. X-linked myopathy with postural muscle atrophy was associated with reduced exercise capacity in affected males but not in heterozygous female mutation carriers.

Conclusions—
X-linked myopathy with postural muscle atrophy patients consistently showed electrical, functional, and characteristic morphological cardiac abnormalities that translate into reduced exercise capacity. Reduced systolic and diastolic function is associated with a novel type of spongious hypertrophic cardiomyopathy. An unexpected finding was that some cardiac abnormalities were also present in heterozygous female mutation carriers.
Pooled DNA Resequencing of 68 Myocardial Infarction Candidate Genes in French Canadians
Authors: Beaudoin Mélissa , Lo Ken Sin , N’Diaye Amidou , Rivas Manuel A. , Dubé Marie-Pierre , Laplante Nathalie , Phillips Michael S. , Rioux John D. , Tardif Jean-Claude , Lettre Guillaume 
Published: August 2012

Background—

Familial history is a strong risk factor for coronary artery disease (CAD), especially for early-onset myocardial infarction (MI). Several genes and chromosomal regions have been implicated in the genetic cause of coronary artery disease/MI, mostly through the discovery of familial mutations implicated in hyper-/hypocholesterolemia by linkage studies and single nucleotide polymorphisms by genome-wide association studies. Except for a few examples (eg,
PCSK9
), the role of low-frequency genetic variation (minor allele frequency [MAF]) ≈0.1%−5% on MI/coronary artery disease predisposition has not been extensively investigated.

Methods and Results—
We selected 68 candidate genes and sequenced their exons (394 kb) in 500 early-onset MI cases and 500 matched controls, all of French-Canadian ancestry, using solution-based capture in pools of nonindexed DNA samples. In these regions, we identified 1852 single nucleotide variants (695 novel) and captured 85% of the variants with MAF≥1% found by the 1000 Genomes Project in Europe-ancestry individuals. Using gene-based association testing, we prioritized for follow-up 29 low-frequency variants in 8 genes and attempted to genotype them for replication in 1594 MI cases and 2988 controls from 2 French-Canadian panels. Our pilot association analysis of low-frequency variants in 68 candidate genes did not identify genes with large effect on MI risk in French Canadians.

Conclusions—
We have optimized a strategy, applicable to all complex diseases and traits, to discover efficiently and cost-effectively DNA sequence variants in large populations. Resequencing endeavors to find low-frequency variants implicated in common human diseases are likely to require very large sample size.
Exome Sequencing Identifies 2 Rare Variants for Low High-Density Lipoprotein Cholesterol in an Extended Family
Authors: Reddy M.V. Prasad Linga , Iatan Iulia , Weissglas-Volkov Daphna , Nikkola Elina , Haas Blake E. , Juvonen Miina , Ruel Isabelle , Sinsheimer Janet S. , Genest Jacques , Pajukanta Päivi 
Published: August 2012

Background—
Exome sequencing is a recently implemented method to discover rare mutations for Mendelian disorders. Less is known about its feasibility to identify genes for complex traits. We used exome sequencing to search for rare variants responsible for a complex trait, low levels of serum high-density lipoprotein cholesterol (HDL-C).

Methods and Results—
We conducted exome sequencing in a large French-Canadian family with 75 subjects available for study, of which 27 had HDL-C values less than the fifth age-sex-specific population percentile. We captured ≈50 Mb of exonic and transcribed sequences of 3 closely related family members with HDL-C levels less than the fifth age-sex percentile and sequenced the captured DNA. Approximately 82 000 variants were detected in each individual, of which 41 rare nonsynonymous variants were shared by the sequenced affected individuals after filtering steps. Two rare nonsynonymous variants in the ATP-binding cassette, subfamily A (ABC1), member 1 (ABCA1), and lipoprotein lipase genes predicted to be damaging were investigated for cosegregation with the low HDL-C trait in the entire extended family. The carriers of either variant had low HDL-C levels, and the individuals carrying both variants had the lowest HDL-C values. Interestingly, the ABCA1 variant exhibited a sex effect which was first functionally identified, and, subsequently, statistically demonstrated using additional French-Canadian families with ABCA1 mutations.

Conclusions—
This complex combination of 2 rare variants causing low HDL-C in the extended family would not have been identified using traditional linkage analysis, emphasizing the need for exome sequencing of complex lipid traits in unexplained familial cases.
National Survey of Hospital Strategies to Reduce Heart Failure Readmissions
Authors: Kociol Robb D. , Peterson Eric D. , Hammill Bradley G. , Flynn Kathryn E. , Heidenreich Paul A. , Piña Ileana L. , Lytle Barbara L. , Albert Nancy M. , Curtis Lesley H. , Fonarow Gregg C. , Hernandez Adrian F. 
Published: August 2012

Background—
Reducing 30-day heart failure readmission rates is a national priority. Yet, little is known about how hospitals address the problem and whether hospital-based processes of care are associated with reductions in readmission rates.

Methods and Results—

We surveyed 100 randomly selected hospitals participating in the Get With the Guidelines-Heart Failure quality improvement program regarding common processes of care aimed at reducing readmissions. We grouped processes into 3 domains (ie, inpatient care, discharge and transitional care, and general quality improvement) and scored hospitals on the basis of survey responses using processes selected a priori. We used linear regression to examine associations between these domain scores and 30-day risk-standardized readmission rates. Of the 100 participating sites, 28% were academic centers and 64% were community hospitals. The median readmission rate among participating sites (24.0%; 95% CI, 22.6%–25.7%) was comparable with the national average (24.6%; 23.5–25.9). Sites varied substantially in care processes used for inpatient care, education, discharge process, care transitions, and quality improvement. Overall, neither inpatient care nor general quality improvement domains were associated with 30-day readmission rates. Hospitals in the lowest readmission rate quartile had modestly higher discharge and transitional care domain scores (
P
=0.03).

Conclusions—
A variety of strategies are used by hospitals in an attempt to improve 30-day readmission rates for patients hospitalized with heart failure. Although more complete discharge and transitional care processes may be modestly associated with lower 30-day readmission rates, most current strategies are not associated with lower readmission rates.
The Rule of Law and the Enforcement of the Law
Authors: Goldín Liliana , Dowdall Courtney 
Published: August 2012

Research with hundreds of mostly indigenous Maya workers in the export processing plants (maquilas) of highland Guatemala has revealed a disconnect between working conditions in the factories, perceived rights, national and international labor laws, and law enforcement. Because of this disjunction, efforts to address the plight of workers must engage the complex conditions of the current labor regimes. Maquilas operate in contexts that are virtually exempt from regulation and conflate national and global orders, precluding a clear perspective on issues of rights and legal claims. In the new geographies of power, workers in transnational factories fall into the interstices between state and nonstate spaces and lose their rights and entitlements in the process. Investigaciones en torno a cientos de trabajadores, en su mayor parte indígenas mayas, en las maquilas del altiplano guatemalteco revelan profundas discrepancias entre las condiciones laborales en las fábricas, los derechos presuntamente establecidos, una gama de leyes nacionales e internacionales a las cuales se suscribe Guatemala, y los sistemas de tutela y aplicación de la ley. Dadas estas divergencias, cualquier esfuerzo por atender las condiciones de los trabajadores tiene que tomar en cuenta el complejo entorno de los actuales regímenes laborales. Las maquilas operan en contextos prácticamente exentos de regulación y entremezclan el orden nacional y global, impidiendo una visión clara sobre los derechos y reclamos legales. En las nuevas geografías de poder, los trabajadores de las fábricas transnacionales desaparecen en los intersticios entre el espacio estatal y espacios no estatales, dando lugar a una pérdida de derechos y situaciones vagas dentro del marco de la ley.
The People, Not the Movement
Authors: Frajman Eduardo 
Published: August 2012

The social mobilization against the Central American Free Trade Agreement (CAFTA) in Costa Rica between 2002 and 2007 was the strongest of any nation associated with the treaty. The popular opposition was able to delay for years and nearly stop its ratification. It did so by amassing support from the public at large and, in preparation for a national referendum, adopting a strategy of complete decentralization and horizontal, voluntary work at the grassroots level. This strategy ultimately led to a loss of the battle against the agreement, but it avoided costly clashes over leadership and forced the Costa Rican government to become more open and transparent vis-à-vis the popular organizations and the public. La movilización social costarricense contra el CAFTA entre 2002 y 2007 fue la más contundente en cualquier país asociado al tratado. La oposición popular logró detener el proyecto por varios años y casi evita su ratificación. Su éxito se basó en el apoyo general del público y, en preparación para un referendo nacional, la adopción de una estrategia descentralizada y horizontal fundamentada en el voluntariado de grupos de base. Esta estrategia finalmente resultó en la pérdida de la batalla contra el tratado, pero evitó costosas desavenencias en torno al liderazgo y obligó al gobierno costarricense a abrirse y dar cuentas más transparentes a las organizaciones populares y el público en general.