bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined mineralocorticoid and glucocorticoid deficiency is caused by a novel founder nicotinamide nucleotide transhydrogenase mutation that alters mitochondrial morphology and increases oxidative stress
Authors: Weinberg-Shukron Ariella , Abu-Libdeh Abdulsalam , Zhadeh Fouad , Carmel Liran , Kogot-Levin Aviram , Kamal Lara , Kanaan Moien , Zeligson Sharon , Renbaum Paul , Levy-Lahad Ephrat , Zangen David 
Published: June 2015

BackgroundFamilial glucocorticoid deficiency (FGD) reflects specific failure of adrenocortical glucocorticoid production in response to adrenocorticotropic hormone (ACTH). Most cases are caused by mutations encoding ACTH-receptor components (MC2R, MRAP) or the general steroidogenesis protein (StAR). Recently, nicotinamide nucleotide transhydrogenase (NNT) mutations were found to cause FGD through a postulated mechanism resulting from decreased detoxification of reactive oxygen species (ROS) in adrenocortical cells.Methods and resultsIn a consanguineous Palestinian family with combined mineralocorticoid and glucocorticoid deficiency, whole-exome sequencing revealed a novel homozygous NNT_c.598 G>A, p.G200S, mutation. Another affected, unrelated Palestinian child was also homozygous for NNT_p.G200S. Haplotype analysis showed this mutation is ancestral; carrier frequency in ethnically matched controls is 1/200. Assessment of patient fibroblasts for ROS production, ATP content and mitochondrial morphology showed that biallelic NNT mutations result in increased levels of ROS, lower ATP content and morphological mitochondrial defects.ConclusionsThis report of a novel NNT mutation, p.G200S, expands the phenotype of NNT mutations to include mineralocorticoid deficiency. We provide the first patient-based evidence that NNT mutations can cause oxidative stress and both phenotypic and functional mitochondrial defects. These results directly demonstrate the importance of NNT to mitochondrial function in the setting of adrenocortical insufficiency.
Distal access using hyperflexible atraumatic distal tip with optimized proximal stability of the Benchmark intracranial guide catheter for the treatment of cerebral vascular diseases: a technical note
Authors: Chandran Arun , Puthuran Mani , Eldridge Paul R , Nahser Hans C 
Published: June 2015

BackgroundA stable guide catheter position within the intracranial vasculature is critical for safe, successful endovascular treatment.ObjectiveTo present ourinitial experience with the 0.071 inch inner diameter Benchmark guide catheter used in the treatment of intracranial cerebrovascular pathologies, demonstrating its safety and efficacy.MethodsWe retrospectively reviewed use of the Benchmark guide catheter from September through December 2014 in the management of various neuroendovascular intracranial pathologies. Clinical performance and complication rates were evaluated, with particular consideration of vessel tortuosity. A total of 62 Benchmarks were used, 47 in the anterior circulation, 10 in the posterior circulation, 4 in the external carotid, and 1 in the venous sinus. The five cases with access to the external carotid and venous sinus were excluded.ResultsThe Benchmark was able to cross at least one 90° turn in 49 (86%) of the 57 patients. Reversal of the catheter was seen in 15% of 47 anterior circulation cases (4 at one 90° turn; 3 at two 90° turns). We report no complications of dissection or thromboembolic events. All guide catheter positions were safely achieved over a 0.035 Terumo stiff glidewire without need for an inner smaller lumen guide catheter for navigation.ConclusionsBenchmark is a new guide catheter, with an ideal combination of both hyperflexible, atraumatic distal tip and optimized proximal shaft support to provide stable 6F primary access for a successful neurointerventional procedure. Benchmark can be easily, safely, and consistently positioned in a desired location within intracranial arteries providing a stable position for intervention and adequate angiography.
The nature of stress state: numerical and laboratory experiments and some field observations
Authors: Harper T. R. , Hagan J. T. 
Published: June 2015

Abstract
Simulations of the stress state in a region of discontinuously fractured rock revealed a strongly heterogeneous, self-organized stress distribution displaying internally balanced strains and corresponding energy storage. The explicit simulations follow a sequence which may be inferred to be irreversible and strongly dependent on interaction between fractures, implying a time-dependency. The state of the simulated reservoir displays a sensitivity characteristic of marginal stability. These numerical observations are compared with new and previous laboratory and field experiments spanning a wide range of size, stress magnitude and stress difference. The characteristics of the state of the simulated reservoir, laboratory samples and field behaviour are found to be consistent with the numerical predictions. A stress memory is evident. This supports previous conclusions that the concept of stress state as uniform, constant and resulting from averaged values of stresses or displacements, presently applied at remote and artificial boundaries, is grossly oversimplified and flawed.
Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals
Authors: Cedervall Jessica , Zhang Yanyu , Huang Hua , Zhang Lei , Femel Julia , Dimberg Anna , Olsson Anna-Karin 
Published: June 2015

Abstract
Cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions. However, the basis for such effects, associated with either primary or metastatic tumors, are generally poorly understood. In this study, we show how heart and kidney vascular function is impaired by neutrophils that accumulate in those tissues as a result of tumor formation in two different transgenic mouse models of cancer (RIP1-Tag2 model of insulinoma and MMTV-PyMT model of breast cancer). Neutrophil depletion by systemic administration of an anti-Gr1 antibody improved vascular perfusion and prevented vascular leakage in kidney vessels. We also observed the accumulation of platelet–neutrophil complexes, a signature of neutrophil extracellular traps (NET), in the kidneys of tumor-bearing mice that were completely absent from healthy nontumor-bearing littermates. NET accumulation in the vasculature was associated with upregulation of the proinflammatory adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the proinflammatory cytokines IL1β, IL6, and the chemokine CXCL1. Administering DNase I to dissolve NETs, which have a high DNA content, restored perfusion in the kidney and heart to levels seen in nontumor-bearing mice, and also prevented vessel leakage in the blood vasculature of these organs. Taken together, our findings strongly suggest that NETs mediate the negative collateral effects of tumors on distal organs, acting to impair vascular function, and to heighten inflammation at these sites. Cancer Res; 75(13); 2653–62. ©2015 AACR.
EGF Receptor Promotes Prostate Cancer Bone Metastasis by Downregulating miR-1 and Activating TWIST1
Authors: Chang Yung-Sheng , Chen Wei-Yu , Yin Juan Juan , Sheppard-Tillman Heather , Huang Jiaoti , Liu Yen-Nien 
Published: June 2015

Abstract
Dysregulation of the EGFR signaling axis enhances bone metastases in many solid cancers. However, the relevant downstream effector signals in this axis are unclear. miR-1 was recently shown to function as a tumor suppressor in prostate cancer cells, where its expression correlated with reduced metastatic potential. In this study, we demonstrated a role for EGFR translocation in regulating transcription of miR-1-1, which directly targets expression of TWIST1. Consistent with these findings, we observed decreased miR-1 levels that correlated with enhanced expression of activated EGFR and TWIST1 in a cohort of human prostate cancer specimens and additional datasets. Our findings support a model in which nuclear EGFR acts as a transcriptional repressor to constrain the tumor-suppressive role of miR-1 and sustain oncogenic activation of TWIST1, thereby leading to accelerated bone metastasis. Cancer Res; 75(15); 3077–86. ©2015 AACR.
EGFR Mutation Status and First-Line Treatment in Patients with Stage III/IV Non–Small Cell Lung Cancer in Germany: An Observational Study
Authors: Schuette Wolfgang , Schirmacher Peter , Eberhardt Wilfried Ernst Erich , Fischer Juergen R. , von der Schulenburg J.-Matthias Graf , Mezger Joerg , Schumann Christian , Serke Monika , Zaun Silke , Dietel Manfred , Thomas Michael 
Published: June 2015

Abstract
Introduction: EGFR mutations confer sensitivity to EGFR tyrosine kinase inhibitors (TKI) in advanced non–small cell lung cancer (NSCLC). We investigated the clinicopathologic characteristics associated with EGFR mutations and their impact on real-world treatment decisions and outcomes in Caucasian patients with advanced NSCLC.
Methods: REASON (NCT00997230) was a noninterventional multicenter study in patients (≥18 years) with stage IIIb/IV NSCLC, who were candidates for EGFR mutation testing and first-line systemic treatment, but not eligible for surgery or radiotherapy. Patients were followed up according to normal clinical practice and assessed for primary (correlation of mutation status with baseline characteristics) and secondary endpoints (first-line treatment decision).
Results: Baseline data were obtained for 4,200 patients; 4,196 fulfilled the inclusion criteria; EGFR mutations were detected in 431 patients; no EGFR mutations were detected in 3,590 patients; mutation status was not evaluable in 175 patients. In multivariate analysis, the odds of EGFR mutations were significantly higher (P &lt; 0.0001) in females versus males (odds ratio: 1.85; 95% confidence interval, 1.48–2.32), never-smokers versus smokers (3.64; 2.91–4.56), and patients with adenocarcinoma versus other histologic subtypes (2.94; 2.17–4.08). The most commonly prescribed first-line systemic treatments were: EGFR-TKIs in EGFR mutation–positive NSCLC (56.6%) and combination chemotherapy in EGFR mutation–negative NSCLC (78.5%).
Conclusions: This represents the largest dataset for EGFR mutations in Caucasian patients and shows EGFR mutations to be most prevalent in females with adenocarcinoma who had never smoked.
Impact: These findings add to our understanding of the prognostic and predictive factors of NSCLC, supporting future improved treatment selection. Cancer Epidemiol Biomarkers Prev; 24(8); 1254–61. ©2015 AACR.
Gallbladder Cancer Incidence and Mortality, United States 1999–2011
Authors: Henley S. Jane , Weir Hannah K. , Jim Melissa A. , Watson Meg , Richardson Lisa C. 
Published: June 2015

Abstract
Background: Gallbladder cancer is a rare cancer with unusual distribution, and few population-based estimates for the United States have been published.
Methods: Using population-based cancer incidence and mortality data, we examined U.S. gallbladder cancer incidence and death rates for 2007–2011 and trends for 1999–2011.
Results: During 2007 to 2011, approximately 3,700 persons were diagnosed with primary gallbladder cancer (rate = 1.13 cases per 100,000) and 2,000 died from the disease (rate = 0.62 deaths per 100,000) each year in the United States. Two thirds of gallbladder cancer cases and deaths occurred among women. Gallbladder cancer incidence and death rates were three times higher among American Indian and Alaska Native persons than non-Hispanic white persons. By state, gallbladder cancer incidence and death rates ranged by about 2-fold. During 1999 to 2011, gallbladder cancer incidence rates decreased among women but remained level among men; death rates declined among women but stabilized among men after declining from 1999 to 2006. Gallbladder cancer incidence rates increased in some subgroups, notably among black persons, those aged &lt;45 years, and for endocrine tumors.
Conclusions: Data from U.S. population-based cancer registries confirm that gallbladder cancer incidence and death rates are higher among women than men, highest among American Indian and Alaska Native persons, and differ by region. While overall incidence and death rates decreased during 1999 to 2011, incidence rates increased among some small subgroups.
Impact: Surveillance of gallbladder cancer incidence and mortality, particularly to monitor increases in subgroups, may provide clues to etiology and stimulate further research. Cancer Epidemiol Biomarkers Prev; 24(9); 1319–26. ©2015 AACR.
Secreted Frizzled-Related Protein 3 (SFRP3) Is Required for Tumorigenesis of PAX3–FOXO1-Positive Alveolar Rhabdomyosarcoma
Authors: Kephart Julie J.G. , Tiller Rosanne G.J. , Crose Lisa E.S. , Slemmons Katherine K. , Chen Po-Han , Hinson Ashley R. , Bentley Rex C. , Chi Jen-Tsan Ashley , Linardic Corinne M. 
Published: June 2015

Abstract
Purpose: Rhabdomyosarcoma (RMS) is a soft tissue sarcoma associated with the skeletal muscle lineage. Of the two predominant subtypes, known as embryonal (eRMS) and alveolar (aRMS), aRMS has the poorer prognosis, with a five-year survival rate of &lt;50%. The majority of aRMS tumors express the fusion protein PAX3–FOXO1. As PAX3–FOXO1 has proven chemically intractable, this study aims to identify targetable proteins that are downstream from or cooperate with PAX3–FOXO1 to support tumorigenesis.
Experimental Design: Microarray analysis of the transcriptomes of human skeletal muscle myoblasts expressing PAX3–FOXO1 revealed alteration of several Wnt pathway gene members, including secreted frizzled related protein 3 (SFRP3), a secreted Wnt pathway inhibitor. Loss-of-function using shRNAs against SFRP3 was used to interrogate the role of SFRP3 in human aRMS cell lines in vitro and conditional murine xenograft systems in vivo. The combination of SFRP3 genetic suppression and the chemotherapeutic agent vincristine was also examined.
Results: In vitro, suppression of SFRP3 inhibited aRMS cell growth, reduced proliferation accompanied by a G1 arrest and induction of p21, and induced apoptosis. In vivo, doxycycline-inducible suppression of SFRP3 reduced aRMS tumor growth and weight by more than three-fold, in addition to increasing myogenic differentiation and β-catenin signaling. The combination of SFRP3 suppression and vincristine was more effective at reducing aRMS cell growth in vitro than either treatment alone, and ablated tumorigenesis in vivo.
Conclusions: SFRP3 is necessary for the growth of human aRMS cells both in vitro and in vivo and is a promising new target for investigation in aRMS. Clin Cancer Res; 21(21); 4868–80. ©2015 AACR.
Autocrine Activation of CHRM3 Promotes Prostate Cancer Growth and Castration Resistance via CaM/CaMKK–Mediated Phosphorylation of Akt
Authors: Wang Naitao , Yao Ming , Xu Jin , Quan Yizhou , Zhang Kaiqing , Yang Ru , Gao Wei-Qiang 
Published: June 2015

AbstractPurpose: Although a previous study reported nerve ending–derived acetylcholine promoted prostate cancer invasion and metastasis by regulating the microenvironment of cancer cells, the present study aims to determine whether there is autocrine cholinergic signaling in prostate epithelial cells that promotes prostate cancer growth and castration resistance.Experimental design: In this study, IHC was performed to detect protein expression in mouse prostate tissue sections and human prostate cancer tissue sections. Subcutaneously and orthotopically xenografted tumor models were established to evaluate the functions of autocrine cholinergic signaling in regulating prostate cancer growth and castration resistance. Western blotting analysis was performed to assess the autocrine cholinergic signaling–induced signaling pathway.Results: We found the expression of choline acetyltransferase (ChAT), the secretion of acetylcholine and the expression of CHRM3 in prostate epithelial cells, supporting the presence of autocrine cholinergic signaling in the prostate epithelium. In addition, we found that CHRM3 was upregulated in clinical prostate cancer tissues compared with adjacent non-cancer tissues. Overexpression of CHRM3 or activation of CHRM3 by carbachol promoted cell proliferation, migration, and castration resistance. On the contrary, blockading CHRM3 by shRNA or treatment with darifenacin inhibited prostate cancer growth and castration resistance both in vitro and in vivo. Furthermore, we found that autocrine cholinergic signaling caused calmodulin/calmodulin–dependent protein kinase kinase (CaM/CaMKK)–mediated phosphorylation of Akt.Conclusions: These findings suggest that blockade of CHRM3 may represent a novel adjuvant therapy for castration-resistant prostate cancer. Clin Cancer Res; 21(20); 4676–85. ©2015 AACR.
Exome Sequencing Reveals AMER1 as a Frequently Mutated Gene in Colorectal Cancer
Authors: Sanz-Pamplona Rebeca , Lopez-Doriga Adriana , Paré-Brunet Laia , Lázaro Kira , Bellido Fernando , Alonso M. Henar , Aussó Susanna , Guinó Elisabet , Beltrán Sergi , Castro-Giner Francesc , Gut Marta , Sanjuan Xavier , Closa Adria , Cordero David , Morón-Duran Francisco D. , Soriano Antonio , Salazar Ramón , Valle Laura , Moreno Victor 
Published: June 2015

Abstract
Purpose: Somatic mutations occur at early stages of adenoma and accumulate throughout colorectal cancer progression. The aim of this study was to characterize the mutational landscape of stage II tumors and to search for novel recurrent mutations likely implicated in colorectal cancer tumorigenesis.
Experimental Design: The exomic DNA of 42 stage II, microsatellite-stable colon tumors and their paired mucosae were sequenced. Other molecular data available in the discovery dataset [gene expression, methylation, and copy number variations (CNV)] were used to further characterize these tumors. Additional datasets comprising 553 colorectal cancer samples were used to validate the discovered mutations.
Results: As a result, 4,886 somatic single-nucleotide variants (SNV) were found. Almost all SNVs were private changes, with few mutations shared by more than one tumor, thus revealing tumor-specific mutational landscapes. Nevertheless, these diverse mutations converged into common cellular pathways, such as cell cycle or apoptosis. Among this mutational heterogeneity, variants resulting in early stop codons in the AMER1 (also known as FAM123B or WTX) gene emerged as recurrent mutations in colorectal cancer. Losses of AMER1 by other mechanisms apart from mutations such as methylation and copy number aberrations were also found. Tumors lacking this tumor suppressor gene exhibited a mesenchymal phenotype characterized by inhibition of the canonical Wnt pathway.
Conclusions: In silico and experimental validation in independent datasets confirmed the existence of functional mutations in AMER1 in approximately 10% of analyzed colorectal cancer tumors. Moreover, these tumors exhibited a characteristic phenotype. Clin Cancer Res; 21(20); 4709–18. ©2015 AACR.
A Novel Pharmacologic Activity of Ketorolac for Therapeutic Benefit in Ovarian Cancer Patients
Authors: Guo Yuna , Kenney S. Ray , Cook Linda , Adams Sarah F. , Rutledge Teresa , Romero Elsa , Oprea Tudor I. , Sklar Larry A. , Bedrick Edward , Wiggins Charles L. , Kang Huining , Lomo Lesley , Muller Carolyn Y. , Wandinger-Ness Angela , Hudson Laurie G. 
Published: June 2015

Abstract
Purpose: We previously identified the R-enantiomer of ketorolac as an inhibitor of the Rho-family GTPases Rac1 and Cdc42. Rac1 and Cdc42 regulate cancer-relevant functions, including cytoskeleton remodeling necessary for tumor cell adhesion and migration. This study investigated whether administration of racemic (R,S) ketorolac after ovarian cancer surgery leads to peritoneal distribution of R-ketorolac, target GTPase inhibition in cells retrieved from the peritoneal cavity, and measureable impact on patient outcomes.
Experimental Design: Eligible patients had suspected advanced-stage ovarian, fallopian tube or primary peritoneal cancer. Secondary eligibility was met when ovarian cancer was confirmed and optimally debulked, an intraperitoneal port was placed, and there were no contraindications for ketorolac administration. R- and S-ketorolac were measured in serum and peritoneal fluid, and GTPase activity was measured in peritoneal cells. A retrospective study correlated perioperative ketorolac and ovarian cancer–specific survival in ovarian cancer cases.
Results: Elevated expression and activity of Rac1 and Cdc42 was detected in ovarian cancer patient tissues, confirming target relevance. Ketorolac in peritoneal fluids was enriched in the R-enantiomer and peritoneal cell GTPase activity was inhibited after ketorolac administration when R-ketorolac was at peak levels. After adjusting for age, AJCC stage, completion of chemotherapy, and neoadjuvant therapy, women given perioperative ketorolac had a lower hazard of death (HR, 0.30; 95% confidence interval, 0.11–0.88).
Conclusions: Ketorolac has a novel pharmacologic activity conferred by the R-enantiomer and R-ketorolac achieves sufficient levels in the peritoneal cavity to inhibit Rac1 and Cdc42, potentially contributing to the observed survival benefit in women who received ketorolac. Clin Cancer Res; 21(22); 5064–72. ©2015 AACR.
Left Ventricular Early Inflow–Outflow Index: A Novel Echocardiographic Indicator of Mitral Regurgitation Severity
Authors: Lee Ming‐Ming , Salahuddin Ayesha , Garcia Mario J. , Spevack Daniel M. 
Published: June 2015

Background

No gold standard currently exists for quantification of mitral regurgitation (
MR
) severity. Classification by echocardiography is based on integrative criteria using color and spectral Doppler and anatomic measurements. We hypothesized that a simple Doppler left ventricular early inflow–outflow index (
LVEIO
), based on flow velocity into the left ventricle (
LV
) in diastole and ejected from the
LV
in systole, would add incrementally to current diagnostic criteria.
LVEIO
was calculated by dividing the mitral E‐wave velocity by the
LV
outflow velocity time integral.

Methods and Results

Transthoracic echocardiography reports from Montefiore Medical Center and its referring clinics from July 1, 2011, to December 31, 2011 (n=11 235) were reviewed. The
MR
severity reported by a cardiologist certified by the National Board of Echocardiography was used as a reference standard. Studies reporting moderate or severe
MR
(n=550) were reanalyzed to measure effective regurgitant orifice area by the proximal isovelocity surface area method, vena contracta width,
MR
jet area, and left‐sided chamber volumes.
LVEIO
was 9.3±3.9, 7.0±3.2, and 4.2±1.7 among those with severe, moderate, and insignificant
MR
, respectively (
ANOVA
P
<0.001). By receiver operating characteristic analysis, area under the curve for
LVEIO
was 0.92 for severe
MR
. Those with
LVEIO
≥8 were likely to have severe
MR
(likelihood ratio 26.5), whereas those with
LVEIO
≤4 were unlikely to have severe
MR
(likelihood ratio 0.11).
LVEIO
performed better in those with normal
LV ejection fraction
(≥50%) compared with those with reduced
LV ejection fraction
(<50%) (area under the curve 0.92 versus 0.80,
P
<0.001). By multivariate logistic regression analysis,
LVEIO
was independently associated with severe
MR
when compared with
vena contracta
width,
MR
jet area, and
effective regurgitant orifice area measured
by
the proximal isovelocity surface area method
.

Conclusion

LVEIO
is a simple‐to‐use echocardiographic parameter that accurately identifies severe
MR
, particularly in patients with normal
LV ejection fraction
.