bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Ancestry Is not Associated with Breast Cancer Recurrence or Survival in U.S. Latina Women Enrolled in the Kaiser Permanente Pathways Study
Authors: Engmann Natalie J. , Ergas Isaac J. , Yao Song , Kwan Marilyn L. , Roh Janise M. , Ambrosone Christine B. , Kushi Lawrence H. , Fejerman Laura 
Published: September 2017

Abstract
Background: The U.S. Hispanic/Latino population is heterogeneous both socioculturally and by the proportion of European, Indigenous American, and African ancestry of the regions from which individuals originate. A previous study reported that genetic ancestry was associated with breast cancer survival among Latinas, independent of sociodemographic and tumor characteristics, suggesting that a genetic factor associated with ancestry may affect breast cancer survival.
Methods: We evaluated the association of genetic ancestry with breast cancer outcomes among 506 Latina women with invasive breast cancer in the Pathways Study, a cohort study within Kaiser Permanente, an integrated health care delivery system. Proportional hazards models were used to assess the effect of ancestry on breast cancer recurrence (53 events), breast cancer–specific mortality (31 events) and all-cause mortality (54 events), with a mean follow-up time of 6 years.
Results: Indigenous American ancestry was not associated with breast cancer recurrence [HR = 1.00 per 10% increase; 95% confidence interval (CI), 0.86–1.16], breast cancer mortality (HR = 0.95; 95% CI, 0.77–1.17), or all-cause mortality (HR = 0.93; 95% CI, 0.80–1.08). Adjustment for sociodemographic variables, tumor characteristics, and treatment did not alter the associations.
Conclusions: Our results suggest that previously reported differences in breast cancer survival by genetic ancestry may be overcome by improving health care access and/or quality.
Impact: Improving health care access and quality may reduce breast cancer disparities among U.S. Latinas. Cancer Epidemiol Biomarkers Prev; 26(9); 1466–9. ©2017 AACR.
No Association of Vitamin D Pathway Genetic Variants with Cancer Risks in a Population-Based Cohort of German Older Adults
Authors: Ordóñez-Mena José Manuel , Schöttker Ben , Saum Kai U. , Holleczek Bernd , Burwinkel Barbara , Wang Thomas J. , Brenner Hermann 
Published: September 2017

Abstract
Background: Several investigations assessed the association of vitamin D receptor (VDR) SNPs with cancer risk. Less is known about the implications of other vitamin D pathway SNPs on cancer risk.
Methods: In a population-based cohort study of 9,949 German older adults, we used Cox regression to assess the association of 6 SNPs in the VDR, vitamin D–binding protein (GC), 7-dehydrocholesterol reductase (DHCR7), vitamin D 25-hydroxylase (CYP2R1), and vitamin D 24-hydroxylase (CYP24A1) genes with total and site-specific cancer incidence endpoints.
Results: Overall, no association of SNPs with cancer incidence endpoints was observed, except for a genotype score based on SNPs associated with lower 25(OH)D, which was associated with higher lung cancer risk [HR, 1.20; 95% confidence intervals (CI), 1.03–1.39], although this was no longer significant after correcting for multiple testing.
Conclusions: Our data provide little to no evidence of a major influence of vitamin D genetic predisposition on cancer risks.
Impact: Large-scale genetic epidemiology consortia and meta-analysis of smaller published studies are needed to verify a potential modest influence of genetic variation in the association of vitamin D with the risk of cancer. Cancer Epidemiol Biomarkers Prev; 26(9); 1459–61. ©2017 AACR.
Challenges and Opportunities in Adapting Clinical Trial Design for Immunotherapies
Authors: Siu Lillian L. , Ivy S. Percy , Dixon Erica L. , Gravell Amy E. , Reeves Steven A. , Rosner Gary L. 
Published: September 2017

AbstractImmunotherapy adds an exciting new dimension to the treatment of cancer, joining other approaches as a key pillar in the oncotherapeutics armamentarium. Immuno-oncology agents harbor unique mechanisms of antitumor activity by leveraging the host immune system, which may result in response patterns, resistance kinetics, and toxicity profiles that differ from other systemic therapies. These features have led to many discussions on ways to optimally integrate immunotherapy into cancer clinical trials. This overview provides an introduction to the four CCR Focus articles that ensue, with special thoughts paid to clinical trial endpoints, biomarker development and validation, combination strategies, and limitations that arise with increasing use of these agents. In addition, this overview examines design concepts that may be applied to invigorate clinical trials and to maximize their impact in the immuno-oncology era. Clin Cancer Res; 23(17); 4950–8. ©2017 AACR.See all articles in this CCR Focus section, “Clinical Trial Design Considerations in the Immuno-oncology Era.”
NAD Synthesis Pathway Interference Is a Viable Therapeutic Strategy for Chondrosarcoma
Authors: Peterse Elisabeth F.P. , van den Akker Brendy E.W.M. , Niessen Bertine , Oosting Jan , Suijker Johnny , de Jong Yvonne , Danen Erik H.J. , Cleton-Jansen Anne-Marie , Bovée Judith V.M.G. 
Published: September 2017

Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) and nicotinic acid phosphoribosyltransferase (NAPRT) are rate-limiting enzymes in the NAD+ synthesis pathway. Chondrosarcoma is a malignant cartilage forming bone tumor, in which mutations altering isocitrate dehydrogenase-1 and -2 (IDH1 and IDH2) activity have been identified as potential driver mutations. Vulnerability for NAD+ depletion has been reported for IDH1/2-mutant cells. Here, the potency of NAMPT inhibitors as a treatment of chondrosarcoma was explored. Eleven chondrosarcoma cell lines were treated with NAMPT inhibitors, in which the effect on cell viability, colony formation, and 3D collagen invasion was assessed. The expression level of NAMPT and NAPRT transcripts in chondrosarcoma cells was determined by qRT-PCR. Methylation of the NAPRT promoter was evaluated using a previously published dataset of genome-wide methylation. In addition, a methylation dataset was used to determine methylation of the NAPRT promoter in 20 IDH1/2-mutated cartilage tumors. Chondrosarcoma cells showed a dose-dependent decrease in cell viability, 3D collagen invasion, and colony formation upon treatment with NAMPT inhibitors, in which nearly half of the cell lines demonstrated absolute IC50s in the low nanomolar range. Increasing IC50s correlated to increasing NAPRT expression levels and decreasing NAPRT promoter methylation. No correlation between IDH1/2 mutation status and sensitivity for NAMPT inhibitors was observed. Strikingly, higher methylation of the NAPRT promoter was observed in high-grade versus low-grade chondrosarcomas. In conclusion, this study identified NAMPT as a potential target for treatment of chondrosarcoma.
Implications: Chondrosarcoma patients, especially those of high histologic grade with lower expression and hypermethylation of NAPRT, may benefit from inhibition of the NAD synthesis pathway. Mol Cancer Res; 15(12); 1714–21. ©2017 AACR.
Reversion Mutations with Clinical Use of PARP Inhibitors: Many Genes, Many Versions
Authors: Domchek Susan M. 
Published: September 2017

Abstract
Summary: Reversion mutations associated with PARP inhibitor resistance have been identified in tumors with RAD51C, RAD51D, and PALB2 as well as BRCA1 and BRCA2 mutations. Multiple different reversion mutations can occur in a single patient, and they can be detected by analysis of circulating cell-free DNA. Cancer Discov; 7(9); 937–9. ©2017 AACR.
See related article by Kondrashova et al., p. 984.
See related article by Quigley et al., p. 999.
See related article by Goodall et al., p. 1006.
Crônicas e cartas como laboratório multidisciplinar: a infância como tópos e o esboço de um éthos da província no Modernismo brasileiro
Authors: Dias Silvana Moreli Vicente 
Published: September 2017

Pretende-se, aqui, discutir como a “infância” é dimensionada como tópos literário e se entrelaça com as perspectivas provinciana e brasileira a partir da correspondência pessoal e da obra publicada de escritores regionalista- modernistas nordestinos, tais como Gilberto Freyre, Jorge de Lima, José Lins do Rego e Manuel Bandeira. Arquivos da vida privada abrangem documentos plurais e heterogêneos, em meio aos quais as cartas ocupam espaço privilegiado como centro irradiador de relações intertextuais amplas. Veremos, assim, dispositivos afetivos e intelectuais na construção de imagens contraditórias da infância, da família e da província, sedimentadas a partir de um diálogo tenso, por exemplo, entre rural e urbano, público e privado, província e metrópole, tradição e vanguarda.
Large-Scale Analysis of Determinants, Stability, and Heritability of High-Density Lipoprotein Cholesterol Efflux Capacity
Authors: Koekemoer Andrea L. , Codd Veryan , Masca Nicholas G.D. , Nelson Christopher P. , Musameh Muntaser D. , Kaess Bernhard M. , Hengstenberg Christian , Rader Daniel J. , Samani Nilesh J. 
Published: September 2017

Objective—
Cholesterol efflux capacity (CEC) has emerged as a biomarker of coronary artery disease risk beyond plasma high-density lipoprotein (HDL) cholesterol (HDL-C) level. However, the determinants of CEC are incompletely characterized. We undertook a large-scale family-based population study to identify clinical, biochemical, and HDL particle parameter determinants of CEC, characterize reasons for the discordancy with HDL-C, quantify its heritability, and assess its stability over 10 to 12 years.

Approaches and Results—

CEC was quantified in 1988 individuals from the GRAPHIC (Genetic Regulation of Arterial Pressure of Humans in the Community) cohort, comprising individuals from 2 generations from 520 white nuclear families. Serum lipid and lipoprotein levels were determined by ultracentrifugation or nuclear magnetic resonance and HDL particle size and number quantified by nuclear magnetic resonance. Ninety unrelated individuals had repeat CEC measurements in samples collected after 10 to 12 years. CEC was positively correlated with HDL-C (
R
=0.62;
P
<0.0001). Among clinical and biochemical parameters, age, systolic blood pressure, alcohol consumption, serum albumin, triglycerides, phospholipids, and lipoprotein(a) were independently associated with CEC. Among HDL particle parameters, HDL particle number, particle size, and apolipoprotein A-II level were independently associated with CEC. Serum triglyceride level partially explained discordancy between CEC and HDL-C. CEC measurements in samples collected 10 to 12 years apart were strongly correlated (
r
=0.73;
P
<0.0001). Heritability of CEC was 0.31 (
P
=3.89×10
−14
) without adjustment for HDL-C and 0.13 (
P
=1.44×10
−3
) with adjustment.

Conclusions—
CEC is a stable trait over time, is influenced by specific clinical, serum, and HDL particle parameters factors beyond HDL-C, can be maintained in persons with a low plasma HDL-C by elevated serum triglyceride level, and is modestly independently heritable.
Variability in Total Cholesterol Is Associated With the Risk of End-Stage Renal Disease
Authors: Kim Mee Kyoung , Han Kyungdo , Koh Eun Sil , Kim Hun-Sung , Kwon Hyuk-Sang , Park Yong-Moon , Yoon Kun-Ho , Lee Seung-Hwan 
Published: September 2017

Objective—
Recent data suggest that visit-to-visit variability of cholesterol is associated with cardiovascular events. We evaluated the role of lipid variability as a determinant of end-stage renal disease (ESRD).

Approach and Results—
Using nationally representative data from the Korean National Health Insurance System, 8 493 277 subjects who were free of ESRD and who underwent ≥3 health examinations during 2005 to 2010 were followed to the end of 2015. Total cholesterol (TC) variability was measured using the coefficient of variation, SD, and the variability independent of the mean. The primary outcome was the development of ESRD, defined as a combination of the relevant disease code and the initiation of renal replacement therapy. There were 11 247 cases of ESRD during a median follow-up of 6.1 years. There was a graded association between a higher TC variability and incident ESRD. In the multivariable adjusted model, the hazard ratios and 95% confidence intervals comparing the highest versus lowest quartiles of coefficient of variation of TC were 2.66 (95% confidence interval, 2.52–2.82). The results were consistent when the variability of TC was modeled using SD and variability independent of the mean and were independent of preexisting chronic kidney disease.

Conclusions—
Increasing TC variability was associated with an increasing incidence of ESRD.
Exercise-Induced Changes in Glucose Metabolism Promote Physiological Cardiac Growth
Authors: Gibb Andrew A. , Epstein Paul N. , Uchida Shizuka , Zheng Yuting , McNally Lindsey A. , Obal Detlef , Katragadda Kartik , Trainor Patrick , Conklin Daniel J. , Brittian Kenneth R. , Tseng Michael T. , Wang Jianxun , Jones Steven P. , Bhatnagar Aruni , Hill Bradford G. 
Published: September 2017

Background:
Exercise promotes metabolic remodeling in the heart, which is associated with physiological cardiac growth; however, it is not known whether or how physical activity–induced changes in cardiac metabolism cause myocardial remodeling. In this study, we tested whether exercise-mediated changes in cardiomyocyte glucose metabolism are important for physiological cardiac growth.

Methods:
We used radiometric, immunologic, metabolomic, and biochemical assays to measure changes in myocardial glucose metabolism in mice subjected to acute and chronic treadmill exercise. To assess the relevance of changes in glycolytic activity, we determined how cardiac-specific expression of mutant forms of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase affect cardiac structure, function, metabolism, and gene programs relevant to cardiac remodeling. Metabolomic and transcriptomic screenings were used to identify metabolic pathways and gene sets regulated by glycolytic activity in the heart.

Results:

Exercise acutely decreased glucose utilization via glycolysis by modulating circulating substrates and reducing phosphofructokinase activity; however, in the recovered state following exercise adaptation, there was an increase in myocardial phosphofructokinase activity and glycolysis. In mice, cardiac-specific expression of a kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase transgene (Glyco
Lo
mice) lowered glycolytic rate and regulated the expression of genes known to promote cardiac growth. Hearts of Glyco
Lo
mice had larger myocytes, enhanced cardiac function, and higher capillary-to-myocyte ratios. Expression of phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in the heart (Glyco
Hi
mice) increased glucose utilization and promoted a more pathological form of hypertrophy devoid of transcriptional activation of the physiological cardiac growth program. Modulation of phosphofructokinase activity was sufficient to regulate the glucose–fatty acid cycle in the heart; however, metabolic inflexibility caused by invariantly low or high phosphofructokinase activity caused modest mitochondrial damage. Transcriptomic analyses showed that glycolysis regulates the expression of key genes involved in cardiac metabolism and remodeling.

Conclusions:
Exercise-induced decreases in glycolytic activity stimulate physiological cardiac remodeling, and metabolic flexibility is important for maintaining mitochondrial health in the heart.
High Perforin‐Positive Cardiac Cell Infiltration and Male Sex Predict Adverse Long‐Term Mortality in Patients With Inflammatory Cardiomyopathy
Authors: Escher Felicitas , Kühl Uwe , Lassner Dirk , Stroux Andrea , Gross Ulrich , Westermann Dirk , Pieske Burkert , Poller Wolfgang , Schultheiss Heinz‐Peter 
Published: September 2017

Background

The authors analyzed the effects of perforin‐dependent infiltration on long‐term mortality in patients with inflammatory cardiomyopathy (
CM
i). We previously demonstrated that left ventricular function deteriorates and progresses to substantial cardiac dysfunction in patients with perforin‐positive cardiac cell infiltration.

Methods and Results

Between 2003 and 2013, 2389 consecutive patients with clinically suspected
CM
i who underwent endomyocardial biopsies were enrolled. Endomyocardial biopsies were performed at first admission after exclusion of ischemic or valvular heart disease, and
CM
i was confirmed in 1717 patients. Follow‐up was up to 10.1 years (median 0.47 years; interquartile range, 0.03–2.56 years) and information on vital status was obtained from official resident data files. Multivariable statistical analysis was conducted for all patients with CMi regarding significant predictors of all‐cause mortality or need for heart transplantation. Multiple Cox regression analysis revealed perforin above the calculated cutoff point of 2.9 cells/mm² as a strong predictor of impaired survival with a hazard ratio of 1.881 (95%
confidence interval
, 1.177–3.008;
P
=0.008), independent of left ventricular function and other myocardial inflammation markers (
CD
3, macrophage‐1 antigen, leukocyte function–associated antigen‐1, human leukocyte antigen‐1, and intercellular cell adhesion molecule‐1). Unexpectedly, male sex emerged as another strong adverse predictor of survival in
CM
i (hazard ratio, 1.863;
confidence interval
, 1.096–3.168 [
P
=0.022]). Whereas left ventricular ejection fraction course is adversely affected by myocardial perforin, multivariate analysis indicates that left ventricular ejection fraction explains only part of the observed overall mortality.

Conclusions

High perforin‐positive cardiac cell infiltration and male sex are independent adverse predictors of long‐term mortality in
CM
i. Furthermore, exact quantification of immunohistochemically detected infiltrates is necessary to assess the prognosis.
Childhood Age and Associations Between Childhood Metabolic Syndrome and Adult Risk for Metabolic Syndrome, Type 2 Diabetes Mellitus and Carotid Intima Media Thickness: The International Childhood Cardiovascular Cohort Consortium
Authors: Koskinen Juha , Magnussen Costan G. , Sinaiko Alan , Woo Jessica , Urbina Elaine , Jacobs David R. , Steinberger Julia , Prineas Ronald , Sabin Matthew A. , Burns Trudy , Berenson Gerald , Bazzano Lydia , Venn Alison , Viikari Jorma S.A. , Hutri‐Kähönen Nina , Raitakari Olli , Dwyer Terence , Juonala Markus 
Published: September 2017

Background
There is paucity of knowledge concerning the specific age in youth when the associations of metabolic syndrome (MetS) begin to be operative. Thus, we investigated the relation of age to the associations of childhood MetS with adult MetS, type 2 diabetes mellitus and high carotid intima‐media thickness.

Methods and Results
Five thousand eight‐hundred three participants were analyzed in 4 cohort studies (Cardiovascular Risk in Young Finns, Bogalusa Heart Study, Princeton Lipid Research Study, Insulin Study). International cutoffs and previously used 75th percentile cutoffs were used for children to define MetS and its components. Mean follow‐up period was 22.3 years. Logistic regression was used to calculate risk ratios and 95% confidence intervals. Childhood MetS and overweight were associated with over 2.4‐fold risk for adult MetS from the age of 5 years onward. Risk for type 2 diabetes mellitus was increased from the age of 8 (risk ratio, 2.6–4.1; 95% confidence interval, 1.35–6.76 and 1.12–7.24, respectively) onward for the 2 childhood MetS criteria based on international cut‐off values and for childhood overweight. Risk for high carotid intima‐media thickness was significant at ages 11 to 18 years in relation to childhood MetS or overweight (risk ratio, 2.44–4.22; 95% confidence interval, 1.55–3.55 and 2.55–5.66, respectively). Continuous childhood MetS score was associated with adult MetS from the age of 5, with type 2 diabetes mellitus from the age of 14 and with high carotid intima‐media thickness from the age of 11 years onward.

Conclusions
Adult MetS was predicted by MetS in childhood beginning at age 5. However, adult type 2 diabetes mellitus and subclinical atherosclerosis were not predicted by childhood data until after age 8. Body mass index measurement alone at the same age points provided similar findings.
Predictors of Intramyocardial Hemorrhage After Reperfused ST‐Segment Elevation Myocardial Infarction
Authors: Amier Raquel P. , Tijssen Ruben Y. G. , Teunissen Paul F. A. , Fernández‐Jiménez Rodrigo , Pizarro Gonzalo , García‐Lunar Inés , Bastante Teresa , van de Ven Peter M. , Beek Aernout M. , Smulders Martijn W. , Bekkers Sebastiaan C. A. M. , van Royen Niels , Ibanez Borja , Nijveldt Robin 
Published: September 2017

Background

Findings from recent studies show that microvascular injury consists of microvascular destruction and intramyocardial hemorrhage (
IMH
). Patients with ST‐segment elevation myocardial infarction (
STEMI
) with
IMH
show poorer prognoses than patients without
IMH
. Knowledge on predictors for the occurrence of
IMH
after
STEMI
is lacking. The current study aimed to investigate the prevalence and extent of
IMH
in patients with STEMI and its relation with periprocedural and clinical variables.

Methods and Results

A multicenter observational cohort study was performed in patients with successfully reperfused
STEMI
with cardiovascular magnetic resonance examination 5.5±1.8 days after percutaneous coronary intervention. Microvascular injury was visualized using late gadolinium enhancement and T2‐weighted cardiovascular magnetic resonance imaging for microvascular obstruction and
IMH
, respectively. The median was used as the cutoff value to divide the study population with presence of
IMH
into mild or extensive
IMH
. Clinical and periprocedural parameters were studied in relation to occurrence of
IMH
and extensive
IMH
, respectively. Of the 410 patients, 54% had
IMH
. The presence of
IMH
was independently associated with anterior infarction (odds ratio, 2.96; 95%
CI
, 1.73–5.06 [
P
<0.001]) and periprocedural glycoprotein
II
b/
III
a inhibitor treatment (odds ratio, 2.67; 95%
CI
, 1.49–4.80 [
P
<0.001]). Extensive
IMH
was independently associated with anterior infarction (odds ratio, 3.76; 95%
CI
, 1.91–7.43 [
P
<0.001]). Presence and extent of
IMH
was associated with larger infarct size, greater extent of microvascular obstruction, larger left ventricular dimensions, and lower left ventricular ejection fraction (all
P
<0.001).

Conclusions

Occurrence of
IMH
was associated with anterior infarction and glycoprotein
II
b/
III
a inhibitor treatment. Extensive
IMH
was associated with anterior infarction.
IMH
was associated with more severe infarction and worse short‐term left ventricular function in patients with STEMI.