bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intracytoplasmic Copper Homeostasis Controls Cytochrome
c
Oxidase Production
Authors: Ekici Seda , Turkarslan Serdar , Pawlik Grzegorz , Dancis Andrew , Baliga Nitin S. , Koch Hans-Georg , Daldal Fevzi 
Published: January 2014

ABSTRACT

Copper is an essential micronutrient used as a metal cofactor by a variety of enzymes, including cytochrome
c
oxidase (Cox). In all organisms from bacteria to humans, cellular availability and insertion of copper into target proteins are tightly controlled due to its toxicity. The major subunit of Cox contains a copper atom that is required for its catalytic activity. Previously, we identified CcoA (a member of major facilitator superfamily transporters) as a component required for
cbb
3
-type Cox production in the Gram-negative, facultative phototroph
Rhodobacter capsulatus
. Here, first we demonstrate that CcoA is a cytoplasmic copper importer. Second, we show that bypass suppressors of a
ccoA
deletion mutant suppress
cbb
3
-Cox deficiency by increasing cellular copper content and sensitivity. Third, we establish that these suppressors are single-base-pair insertion/deletions located in
copA
, encoding the major P1B-type ATP-dependent copper exporter (CopA) responsible for copper detoxification. A
copA
deletion alone has no effect on
cbb
3
-Cox biogenesis in an otherwise wild-type background, even though it rescues the
cbb
3
-Cox defect in the absence of CcoA and renders cells sensitive to copper. We conclude that a hitherto unknown functional interplay between the copper importer CcoA and the copper exporter CopA controls intracellular copper homeostasis required for
cbb
3
-Cox production in bacteria like
R. capsulatus
.

IMPORTANCE
Copper (Cu) is an essential micronutrient required for many processes in the cell. It is found as a cofactor for heme-copper containing cytochrome
c
oxidase enzymes at the terminus of the respiratory chains of aerobic organisms by catalyzing reduction of dioxygen (O
2
) to water. Defects in the biogenesis and copper insertion into cytochrome
c
oxidases lead to mitochondrial diseases in humans. This work shows that a previously identified Cu transporter (CcoA) is a Cu importer and illustrates the link between two Cu transporters, the importer CcoA and the exporter CopA, required for Cu homeostasis and Cu trafficking to cytochrome
c
oxidase in the cell.
microRNA-148a Is a Prognostic oncomiR That Targets MIG6 and BIM to Regulate EGFR and Apoptosis in Glioblastoma
Authors: Kim Jungeun , Zhang Ying , Skalski Michael , Hayes Josie , Kefas Benjamin , Schiff David , Purow Benjamin , Parsons Sarah , Lawler Sean , Abounader Roger 
Published: January 2014

Abstract
Great interest persists in useful prognostic and therapeutic targets in glioblastoma. In this study, we report the definition of miRNA (miR)-148a as a novel prognostic oncomiR in glioblastoma. miR-148a expression was elevated in human glioblastoma specimens, cell lines, and stem cells (GSC) compared with normal human brain and astrocytes. High levels were a risk indicator for glioblastoma patient survival. Functionally, miR-148a expression increased cell growth, survival, migration, and invasion in glioblastoma cells and GSCs and promoted GSC neurosphere formation. Two direct targets of miR-148a were identified, the EGF receptor (EGFR) regulator MIG6 and the apoptosis regulator BIM, which rescue experiments showed were essential to mediate the oncogenic activity of miR-148a. By inhibiting MIG6 expression, miR-148a reduced EGFR trafficking to Rab7-expressing compartments, which includes late endosomes and lysosomes. This process coincided with reduced degradation and elevated expression and activation of EGFR. Finally, inhibition of miR-148a strongly suppressed GSC and glioblastoma xenograft growth in vivo. Taken together, our findings provide a comprehensive analysis of the prognostic value and oncogenic function of miR-148a in glioblastoma, further defining it as a potential target for glioblastoma therapy. Cancer Res; 74(5); 1541–53. ©2014 AACR.
Id2 Mediates Oligodendrocyte Precursor Cell Maturation Arrest and Is Tumorigenic in a PDGF-Rich Microenvironment
Authors: Havrda Matthew C. , Paolella Brenton R. , Ran Cong , Jering Karola S. , Wray Christina M. , Sullivan Jaclyn M. , Nailor Audrey , Hitoshi Yasuyuki , Israel Mark A. 
Published: January 2014

Abstract
Maturation defects occurring in adult tissue progenitor cells have the potential to contribute to tumor development; however, there is little experimental evidence implicating this cellular mechanism in the pathogenesis of solid tumors. Inhibitor of DNA-binding 2 (Id2) is a transcription factor known to regulate the proliferation and differentiation of primitive stem and progenitor cells. Id2 is derepressed in adult tissue neural stem cells (NSC) lacking the tumor suppressor Tp53 and modulates their proliferation. Constitutive expression of Id2 in differentiating NSCs resulted in maturation-resistant oligodendroglial precursor cells (OPC), a cell population implicated in the initiation of glioma. Mechanistically, Id2 overexpression was associated with inhibition of the Notch effector Hey1, a bHLH transcription factor that we here characterize as a direct transcriptional repressor of the oligodendroglial lineage determinant Olig2. Orthotopic inoculation of NSCs with enhanced Id2 expression into brains of mice engineered to express platelet-derived growth factor in the central nervous system resulted in glioma. These data implicate a mechanism of altered NSC differentiation in glioma development and characterize a novel mouse model that reflects key characteristics of the recently described proneural subtype of glioblastoma multiforme. Such findings support the emerging concept that the cellular and molecular characteristics of tumor cells are linked to the transformation of distinct subsets of adult tissue progenitors. Cancer Res; 74(6); 1822–32. ©2014 AACR.
Invasive Lobular Carcinoma Cell Lines Are Characterized by Unique Estrogen-Mediated Gene Expression Patterns and Altered Tamoxifen Response
Authors: Sikora Matthew J. , Cooper Kristine L. , Bahreini Amir , Luthra Soumya , Wang Guoying , Chandran Uma R. , Davidson Nancy E. , Dabbs David J. , Welm Alana L. , Oesterreich Steffi 
Published: January 2014

Abstract
Invasive lobular carcinoma (ILC) is a histologic subtype of breast cancer that is frequently associated with favorable outcomes, as approximately 90% of ILC express the estrogen receptor (ER). However, recent retrospective analyses suggest that patients with ILC receiving adjuvant endocrine therapy may not benefit as much as patients with invasive ductal carcinoma. On the basis of these observations, we characterized ER function and endocrine response in ILC models. The ER-positive ILC cell lines MDA MB 134VI (MM134) and SUM44PE were used to examine the ER-regulated transcriptome via gene expression microarray analyses and ER ChIP-Seq, and to examine response to endocrine therapy. In parallel, estrogen response was assessed in vivo in the patient-derived ILC xenograft HCI-013. We identified 915 genes that were uniquely E2 regulated in ILC cell lines versus other breast cancer cell lines, and a subset of these genes were also E2 regulated in vivo in HCI-013. MM134 cells were de novo tamoxifen resistant and were induced to grow by 4-hydroxytamoxifen, as well as other antiestrogens, as partial agonists. Growth was accompanied by agonist activity of tamoxifen on ER-mediated gene expression. Though tamoxifen induced cell growth, MM134 cells required fibroblast growth factor receptor (FGFR)-1 signaling to maintain viability and were sensitive to combined endocrine therapy and FGFR1 inhibition. Our observation that ER drives a unique program of gene expression in ILC cells correlates with the ability of tamoxifen to induce growth in these cells. Targeting growth factors using FGFR1 inhibitors may block survival pathways required by ILC and reverse tamoxifen resistance. Cancer Res; 74(5); 1463–74. ©2014 AACR.
Frequent Overexpression of HMGA2 in Human Atypical Teratoid/Rhabdoid Tumor and Its Correlation with let-7a3/let-7b miRNA
Authors: Zhang Keqiang , Gao Hanlin , Wu Xiwei , Wang Jinhui , Zhou Wendi , Sun Guihua , Wang Jinghan , Wang Yafan , Mu Bing , Kim Charles , Chu Peiguo , Ho Donald M. , Ann David K. , Wong Tai-Tong , Yen Yun 
Published: January 2014

Abstract
Purpose: Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive pediatric malignancies characterized by biallelic inactivation of the SMARCB1 tumor suppressor gene. We searched for novel genomic aberrations by investigating the copy number and expression alterations of let-7a3/let-7b microRNA (miRNA) and correlated these with expression of high-mobility group AT-hook 2 (HMGA2) oncoprotein, a target of let-7 miRNA family, in 18 AT/RT samples to elucidate potential roles of HMGA2 in the pathogenesis of AT/RT.
Experimental Design: Genomic aberrations, let-7a3/let-7b miRNA and HMGA2 expression in AT/RT tissues were identified using quantitative PCR, reverse transcription PCR (RT-PCR), and immunohistochemistry. The impact of let-7b miRNA on HMGA2 expression and the malignant potential of human rhabdoid tumor cell G401 (SMARCB1−/−) were investigated by antisense inhibition and ectopic overexpression studies.
Results: The copy number of let-7a3/let-7b miRNA was substantially decreased in 4 of 11 AT/RT samples. A significantly inverse correlation between let-7a3/let-7b miRNA expression and HMGA2 mRNA expression was observed in AT/RT tissues (R = −0.34; P &lt; 0.05). Immunohistochemistry analysis demonstrated that HMGA2 was highly overexpressed in 83.3% (15 of 18) of AT/RT tissues. Restoration of let-7 miRNA or knockdown of HMGA2 expression significantly suppressed proliferation and colony formation, and almost abolished the invasive potential of G401 cells.
Conclusion: Reduction of let-7a3/let-7b miRNA may be one of mechanisms leading to overexpression of HMGA2 in AT/RT tissues. HMGA2 oncoprotein plays critical roles in the pathogenesis of AT/RT development; and reconstitution of let-7 miRNA or knockdown of HMGA2 oncoprotein may provide a novel therapeutic strategy for the treatment of patients with AT/RT. Clin Cancer Res; 20(5); 1179–89. ©2014 AACR.
LINE-1 Hypomethylation, DNA Copy Number Alterations, and CDK6 Amplification in Esophageal Squamous Cell Carcinoma
Authors: Baba Yoshifumi , Watanabe Masayuki , Murata Asuka , Shigaki Hironobu , Miyake Keisuke , Ishimoto Takatsugu , Iwatsuki Masaaki , Iwagami Shiro , Yoshida Naoya , Oki Eiji , Sakamaki Kentaro , Nakao Mitsuyoshi , Baba Hideo 
Published: January 2014

Abstract
Purpose: Global DNA hypomethylation plays a crucial role in genomic instability and carcinogenesis. DNA methylation of the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of the global DNA methylation level, and is attracting interest as a useful marker for predicting cancer prognosis. Our previous study using more than 200 esophageal squamous cell carcinoma (ESCC) specimens demonstrated the significant relationship between LINE-1 hypomethylation and poor prognosis. However, the mechanism by which LINE-1 hypomethylation affects aggressive tumor behavior has yet to be revealed.
Experimental Design: To examine the relationship between LINE-1 hypomethylation and DNA copy number variations, we investigated LINE-1–hypomethylated and LINE-1–hypermethylated ESCC tumors by comparative genomic hybridization array.
Results: LINE-1–hypomethylated tumors showed highly frequent genomic gains at various loci containing candidate oncogenes such as CDK6. LINE-1 methylation levels were significantly associated with CDK6 mRNA and CDK6 protein expression levels in ESCC specimens. In our cohort of 129 patients with ESCC, cases with CDK6-positive expression experienced worse clinical outcome compared with those with CDK6-negative expression, supporting the oncogenic role of CDK6 in ESCC. In addition, we found that the prognostic impact of LINE-1 hypomethylation might be attenuated by CDK6 expression.
Conclusion: LINE-1 hypomethylation (i.e., global DNA hypomethylation) in ESCC might contribute to the acquisition of aggressive tumor behavior through genomic gains of oncogenes such as CDK6. Clin Cancer Res; 20(5); 1114–24. ©2014 AACR.
Interactions of Hormone Replacement Therapy, Body Weight, and Bilateral Oophorectomy in Breast Cancer Risk
Authors: Cui Yong , Deming-Halverson Sandra L. , Beeghly-Fadiel Alicia , Lipworth Loren , Shrubsole Martha J. , Fair Alecia M. , Shu Xiao-Ou , Zheng Wei 
Published: January 2014

Abstract
Purpose: To examine potential modifying effects of body weight and bilateral oophorectomy on the association of hormone replacement therapy (HRT) with risk of breast cancer, overall and by subtypes according to status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2) among postmenopausal women.
Experimental Design: This analysis included 2,510 postmenopausal white women recruited in the Nashville Breast Health Study, a population-based case–control study of breast cancer. Multivariable logistic regression was used to estimate ORs and 95% confidence intervals (CI) for associations between HRT use and risk of breast cancer overall and by subtypes, adjusted for age and education.
Results: Among women with natural menopause and body mass index (BMI) &lt; 25 kg/m2, ever-use of HRT was associated with increased breast cancer risk (OR, 1.95; 95% CI, 1.32–2.88). Risk was elevated with duration of HRT use (P for trend = 0.002). Similar association patterns were found for ER+, ER+PR+, and luminal A cancer subtypes but not ER−, ER−PR−, and triple-negative cancer. In contrast, ever-HRT use in overweight women (BMI ≥ 25 kg/m2) showed no association with risk of breast cancer overall or by subtypes; interaction tests for modifying effect of BMI were statistically significant. Ever-HRT use was associated with decreased breast cancer risk (OR, 0.70; 95% CI, 0.38–1.31) among women with prior bilateral oophorectomy but elevated risk (OR, 1.45; 95% CI, 0.92–2.29) among those with hysterectomy without bilateral oophorectomy (P for interaction = 0.057). Similar associations were seen for virtually all breast cancer subtypes, although interaction tests were statistically significant for ER+ and luminal A only.
Conclusion: Body weight and bilateral oophorectomy modify associations between HRT use and breast cancer risk, especially the risk of hormone receptor–positive tumors. Clin Cancer Res; 20(5); 1169–78. ©2014 AACR.
Hedgehog–GLI Signaling Inhibition Suppresses Tumor Growth in Squamous Lung Cancer
Authors: Huang Lingling , Walter Vonn , Hayes D. Neil , Onaitis Mark 
Published: January 2014

Abstract
Purpose: Lung squamous cell carcinoma (LSCC) currently lacks effective targeted therapies. Previous studies reported overexpression of Hedgehog (HH)–GLI signaling components in LSCC. However, they addressed neither the tumor heterogeneity nor the requirement for HH–GLI signaling. Here, we investigated the role of HH–GLI signaling in LSCC, and studied the therapeutic potential of HH–GLI suppression.
Experimental Design: Gene expression datasets of two independent LSCC patient cohorts were analyzed to study the activation of HH–GLI signaling. Four human LSCC cell lines were examined for HH–GLI signaling components. Cell proliferation and apoptosis were assayed in these cells after blocking the HH–GLI pathway by lentiviral-shRNA knockdown or small-molecule inhibitors. Xenografts in immunodeficient mice were used to determine the in vivo efficacy of GLI inhibitor GANT61.
Results: In both cohorts, activation of HH–GLI signaling was significantly associated with the classical subtype of LSCC. In cell lines, genetic knockdown of Smoothened (SMO) produced minor effects on cell survival, whereas GLI2 knockdown significantly reduced proliferation and induced extensive apoptosis. Consistently, the SMO inhibitor GDC-0449 resulted in limited cytotoxicity in LSCC cells, whereas the GLI inhibitor GANT61 was very effective. Importantly, GANT61 demonstrated specific in vivo antitumor activity in xenograft models of GLI+ cell lines.
Conclusion: Our studies demonstrate an important role for GLI2 in LSCC, and suggest GLI inhibition as a novel and potent strategy to treat a subset of patients with LSCC. Clin Cancer Res; 20(6); 1566–75. ©2014 AACR.
BRAFV600E Cooperates with PI3K Signaling, Independent of AKT, to Regulate Melanoma Cell Proliferation
Authors: Silva Jillian M. , Bulman Christina , McMahon Martin 
Published: January 2014

Abstract
Mutationally activated BRAFV600E cooperates with PTEN silencing in the conversion of normal melanocytes to metastatic melanoma cells, but the mechanism underlying this cooperation is poorly understood. Here, the consequences of pharmacologic blockade of BRAFV600E or phosphoinositide 3-kinase (PI3K) signaling were explored using pathway-targeted inhibitors and a panel of human BRAF-mutated melanoma-derived cell lines. Blockade of BRAFV600E → MEK1/2 → ERK1/2 or class I PI3K inhibited melanoma proliferation, whereas inhibition of AKT had only modest effects, even in cells with mutated or amplified AKT. Although single-agent inhibition of either BRAFV600E or PI3K signaling elicited antiproliferative effects, combinatorial inhibition was more potent. Analysis of signaling downstream of BRAFV600E or PI3K revealed that these pathways cooperated to regulate protein synthesis through AKT-independent, mTOR complex 1 (mTORC1)-dependent effects on p70S6K, ribosomal protein S6, and 4E-BP1 phosphorylation. Moreover, inhibition of mTORC1/2 inhibited cell proliferation as profoundly as single-agent inhibition of either BRAFV600E or PI3K signaling. These data reveal a mechanism by which BRAFV600E and PI3K signaling cooperate to regulate melanoma proliferation through AKT-independent effects on protein translation. Furthermore, this study provides a potential foundation for pathway-targeted combination therapy designed to enhance the therapeutic benefit to patients with melanoma that contain combined alterations in BRAF and PI3K signaling.
Implications: PI3K, but not AKT, represent potential targets for melanoma therapy. Mol Cancer Res; 12(3); 447–63. ©2014 AACR.
How Accurate Is the Eyeball Test?
Authors: Jain Renuka , Duval Sue , Adabag Selcuk 
Published: January 2014

Background—
In the era of increasing percutaneous treatment options for heart disease, the estimation of surgical risk has become a key factor in selecting optimal treatment strategies. Surgical risk has historically been estimated by physician’s subjective assessment and more recently by statistical risk estimates.

Methods and Results—

We studied 5099 consecutive patients who underwent cardiac surgery at Minneapolis Veterans Affairs Medical Center between 1993 and 2010. Operative mortality risk was estimated statistically by the Veterans Affairs mortality risk estimate and subjectively by cardiac surgeons before surgery. Observed mortality rate was 3.3% (168 deaths) at 1 month, 7.1% (360 deaths) at 1 year, and 18.5% (942 deaths) at 5 years after surgery. Physician’s risk estimate (mean [SD], 5.6% [4.4]) and statistical risk estimate (4.3% [5.1]) had modest correlation (c-index, 0.56;
P
<0.001). Both methods modestly overestimated operative mortality risk. Statistical risk estimate was significantly better than physician’s risk estimate in separating patients who died from those who survived at 30 days (c-index, 0.78 versus 0.73;
P
=0.003), at 1 year (c-index, 0.72 versus 0.61;
P
<0.001), and at 5 years (c-index, 0.72 versus 0.64;
P
<0.001) after surgery. Physician’s risk estimate was higher than statistical risk estimate in all subgroups except high-risk patients.

Conclusions—
In patients undergoing cardiac surgery, statistical risk estimate is a better method to predict operative and long-term mortality compared with physician’s subjective risk estimate. However, both methods modestly overestimate actual operative mortality risk.
Peripheral Arterial Testing Before Lower Extremity Amputation Among Medicare Beneficiaries, 2000 to 2010
Authors: Vemulapalli Sreekanth , Greiner Melissa A. , Jones W. Schuyler , Patel Manesh R. , Hernandez Adrian F. , Curtis Lesley H. 
Published: January 2014

Background—
Despite mild reductions in rates of lower extremity amputation over the past decade, few data exist on the use of arterial testing in patients before amputation.

Methods and Results—

Using Medicare claims from 2000 through 2010, we examined rates of preamputation arterial testing between 0 to 12 and 0 to 24 months before amputation. We used multivariable, modified Poisson regression models to identify patient and clinical predictors of preamputation arterial testing. The main outcome measures were rates of preamputation arterial testing. Among 17 463 patients undergoing nontraumatic amputation, 68.4% underwent some type of arterial testing. Of these patients, 47.5% underwent ankle-brachial index measurement, 38.7% duplex ultrasound, 31.1% invasive angiography, 6.7% computed tomographic angiography, and 5.6% magnetic resonance angiography. Temporal analysis revealed an increase in testing from 65.7% in 2002 to 69.2% in 2010 (
P
<0.001). The use of preamputation arterial testing varied significantly by location of amputation and was lowest for foot amputation (62.5%), followed by above-knee amputation (69.0%) and below-knee amputation (76.7%;
P
<0.001). After multivariable adjustment, older age, male sex, black race, renal disease, diabetes mellitus, known peripheral arterial disease, evaluation by a vascular specialist, and living in the East North Central region were associated with greater rates of preamputation arterial testing.

Conclusions—
Rates of evaluation for peripheral arterial disease before amputation were low, and testing varied by patient, provider, and regional characteristics.
Using Internally Developed Risk Models to Assess Heterogeneity in Treatment Effects in Clinical Trials
Authors: Burke James F. , Hayward Rodney A. , Nelson Jason P. , Kent David M. 
Published: January 2014

Background—
Recent proposals suggest that risk-stratified analyses of clinical trials be routinely performed to better enable tailoring of treatment decisions to individuals. Trial data can be stratified using externally developed risk models (eg, Framingham risk score), but such models are not always available. We sought to determine whether internally developed risk models, developed directly on trial data, introduce bias compared with external models.

Methods and Results—
We simulated a large patient population with known risk factors and outcomes. Clinical trials were then simulated by repeatedly drawing from the patient population assuming a specified relative treatment effect in the experimental arm, which either did or did not vary according to a subject’s baseline risk. For each simulated trial, 2 internal risk models were developed on either the control population only (internal controls only) or the whole trial population blinded to treatment (internal whole trial). Bias was estimated for the internal models by comparing treatment effect predictions to predictions from the external model. Under all treatment assumptions, internal models introduced only modest bias compared with external models. The magnitude of these biases was slightly smaller for internal whole trial models than for internal controls only models. Internal whole trial models were also slightly less sensitive to bias introduced by overfitting and less sensitive to falsely identifying the existence of variability in treatment effect across the risk spectrum compared with internal controls only models.

Conclusions—
Appropriately developed internal models produce relatively unbiased estimates of treatment effect across the spectrum of risk. When estimating treatment effect, internally developed risk models using both treatment arms should, in general, be preferred to models developed on the control population.