bluuebunny/crossref_metadata_2025_split huggingface dataset:
COMPARATIVE STUDY OF VARIATIONAL CHAOS INDICATORS AND ODEs' NUMERICAL INTEGRATORS
Authors: DARRIBA L. A. , MAFFIONE N. P. , CINCOTTA P. M. , GIORDANO C. M. 
Published: November 2012

The reader can find in the literature a lot of different techniques to study the dynamics of a given system and also, many suitable numerical integrators to compute them. Notwithstanding the recent work of [Maffione et al., 2011b] for mappings, a detailed comparison among the widespread indicators of chaos in a general system is still lacking. Such a comparison could lead to select the most efficient algorithms given a certain dynamical problem. Furthermore, in order to choose the appropriate numerical integrators to compute them, more comparative studies among numerical integrators are also needed. This work deals with both problems. We first extend the work of [Maffione et al., 2011b] for mappings to the 2D [Hénon & Heiles, 1964] potential, and compare several variational indicators of chaos: the Lyapunov Indicator (LI); the Mean Exponential Growth Factor of Nearby Orbits (MEGNO); the Smaller Alignment Index (SALI) and its generalized version, the Generalized Alignment Index (GALI); the Fast Lyapunov Indicator (FLI) and its variant, the Orthogonal Fast Lyapunov Indicator (OFLI); the Spectral Distance (D) and the Dynamical Spectra of Stretching Numbers (SSNs). We also include in the record the Relative Lyapunov Indicator (RLI), which is not a variational indicator as the others. Then, we test a numerical technique to integrate Ordinary Differential Equations (ODEs) based on the Taylor method implemented by [Jorba & Zou, 2005] (called taylor), and we compare its performance with other two well-known efficient integrators: the [Prince & Dormand, 1981] implementation of a Runge–Kutta of order 7–8 (DOPRI8) and a Bulirsch–Stöer implementation. These tests are run under two very different systems from the complexity of their equations point of view: a triaxial galactic potential model and a perturbed 3D quartic oscillator. We first show that a combination of the FLI/OFLI, the MEGNO and the GALI 2N succeeds in describing in detail most of the dynamical characteristics of a general Hamiltonian system. In the second part, we show that the precision of taylor is better than that of the other integrators tested, but it is not well suited to integrate systems of equations which include the variational ones, like in the computing of almost all the preceeding indicators of chaos. The result which induces us to draw this conclusion is that the computing times spent by taylor are far greater than the times consumed by the DOPRI8 and the Bulirsch–Stöer integrators in such cases. On the other hand, the package is very efficient when we only need to integrate the equations of motion (both in precision and speed), for instance to study the chaotic diffusion. We also notice that taylor attains a greater precision on the coordinates than either the DOPRI8 or the Bulirsch–Stöer.
DNMT3AMutations in Patients with Acute Myeloid Leukemia in South Brazil
Authors: Pezzi Annelise , Moraes Lauro , Valim Vanessa , Amorin Bruna , Melchiades Gabriela , Oliveira Fernanda , da Silva Maria Aparecida , Matte Ursula , Pombo-de-Oliveira Maria S. , Bittencourt Rosane , Daudt Liane , Silla Lúcia 
Published: November 2012

Acute myeloid leukemia (AML) is a complex and heterogeneous hematopoietic tissue neoplasm. Several molecular markers have been described that help to classify AML patients into risk groups. DNA methyltransferase 3A (DNMT3A) gene mutations have been recently identified in about 22% of AML patients and associated with poor prognosis as an independent risk factor. Our aims were to determine the frequency of somatic mutations in the geneDNMT3Aand major chromosomal translocations in a sample of patients with AML. We investigated in 82 samples of bone marrow from patients with AML for somatic mutations inDNMT3Agene by sequencing and sought major fusion transcripts by RT-PCR. We found mutations in theDNMT3Agene in 6 patients (8%); 3 were type R882H. We found fusion transcripts in 19 patients, namely, AML1/ETO (n=5; 6.1%), PML/RARα(n=12; 14.6%), MLL/AF9 (0; 0%), and CBFβ/MYH11 (n=2; 2.4%). The identification of recurrent mutations in theDNMT3Agene and their possible prognostic implications can be a valuable tool for making treatment decisions. This is the first study on the presence of somatic mutations of theDNMT3Agene in patients with AML in Brazil. The frequency of these mutations suggests a possible ethnogeographic variation.Erratum to “DNMT3AMutations in Patients with Acute Myeloid Leukemia in South Brazil”
RhoB Differentially Controls Akt Function in Tumor Cells and Stromal Endothelial Cells during Breast Tumorigenesis
Authors: Kazerounian Shiva , Gerald Damien , Huang Minzhou , Chin Y. Rebecca , Udayakumar Durga , Zheng Ningning , O'Donnell Rebekah K. , Perruzzi Carole , Mangiante Lee , Pourat Jacob , Phung Thuy L. , Bravo-Nuevo Arturo , Shechter Sharon , McNamara Stephanie , DuHadaway James B. , Kocher Olivier N. , Brown Lawrence F. , Toker Alex , Prendergast George C. , Benjamin Laura E. 
Published: November 2012

Abstract
Tumors are composed of cancer cells but also a larger number of diverse stromal cells in the tumor microenvironment. Stromal cells provide essential supports to tumor pathophysiology but the distinct characteristics of their signaling networks are not usually considered in developing drugs to target tumors. This oversight potentially confounds proof-of-concept studies and increases drug development risks. Here, we show in established murine and human models of breast cancer how differential regulation of Akt by the small GTPase RhoB in cancer cells or stromal endothelial cells determines their dormancy versus outgrowth when angiogenesis becomes critical. In cancer cells in vitro or in vivo, RhoB functions as a tumor suppressor that restricts EGF receptor (EGFR) cell surface occupancy as well as Akt signaling. However, after activation of the angiogenic switch, RhoB functions as a tumor promoter by sustaining endothelial Akt signaling, growth, and survival of stromal endothelial cells that mediate tumor neoangiogenesis. Altogether, the positive impact of RhoB on angiogenesis and progression supercedes its negative impact in cancer cells themselves. Our findings elucidate the dominant positive role of RhoB in cancer. More generally, they illustrate how differential gene function effects on signaling pathways in the tumor stromal component can complicate the challenge of developing therapeutics to target cancer pathophysiology. Cancer Res; 73(1); 50–61. ©2012 AACR.
S100A9 Is a Novel Ligand of EMMPRIN That Promotes Melanoma Metastasis
Authors: Hibino Toshihiko , Sakaguchi Masakiyo , Miyamoto Shoko , Yamamoto Mami , Motoyama Akira , Hosoi Junichi , Shimokata Tadashi , Ito Tomonobu , Tsuboi Ryoji , Huh Nam-ho 
Published: November 2012

Abstract
The calcium-binding proteins S100A8 and S100A9 can dimerize to form calprotectin, the release of which during tissue damage has been implicated in inflammation and metastasis. However, receptor(s) mediating the physiologic and pathophysiologic effects of this damage-associated “danger signal” are uncertain. In this study, searching for candidate calprotectin receptors by affinity isolation-mass spectrometry, we identified the cell surface glycoprotein EMMPRIN/BASIGIN (CD147/BSG). EMMPRIN specifically bound to S100A9 but not S100A8. Induction of cytokines and matrix metalloproteases (MMP) by S100A9 was markedly downregulated in melanoma cells by attenuation of EMMPRIN. We found that EMMPRIN signaling used the TNF receptor–associated factor TRAF2 distinct from the known S100-binding signaling pathway mediated by RAGE (AGER). S100A9 strongly promoted migration when EMMPRIN was highly expressed, independent of RAGE, whereas EMMPRIN blockade suppressed migration by S100A9. Immunohistologic analysis of melanomas revealed that EMMPRIN was expressed at both the invasive edge of lesions and the adjacent epidermis, where S100A9 was also strongly expressed. In epidermal-specific transgenic mice, tail vein–injected melanoma accumulated in skin expressing S100A9 but not S100A8. Together, our results establish EMMPRIN as a receptor for S100A9 and suggest the therapeutic use in targeting S100A9–EMMPRIN interactions. Cancer Res; 73(1); 172–83. ©2012 AACR.
Cisplatin Selects for Multidrug-Resistant CD133+ Cells in Lung Adenocarcinoma by Activating Notch Signaling
Authors: Liu Yu-Peng , Yang Chih-Jen , Huang Ming-Shyan , Yeh Chi-Tai , Wu Alexander T.H. , Lee Yu-Cheng , Lai Tsung-Ching , Lee Chien-Hsin , Hsiao Ya-Wen , Lu Jean , Shen Chia-Ning , Lu Pei-Jung , Hsiao Michael 
Published: November 2012

Abstract
Platinum-based chemotherapy is the first-line treatment for non–small cell lung cancer, but recurrence occurs in most patients. Recent evidence suggests that CD133+ cells are the cause of drug resistance and tumor recurrence. However, the correlation between chemotherapy and regulation of CD133+ cells has not been investigated methodically. In this study, we revealed that CD133+ lung cancer cells labeled by a human CD133 promoter–driven GFP reporter exhibited drug resistance and stem cell characteristics. Treatment of H460 and H661 cell lines with low-dose cisplatin (IC20) was sufficient to enrich CD133+ cells, to induce DNA damage responses, and to upregulate ABCG2 and ABCB1 expression, which therefore increased the cross-resistance to doxorubicin and paclitaxel. This cisplatin-induced enrichment of CD133+ cells was mediated through Notch signaling as judged by increased levels of cleaved Notch1 (NICD1). Pretreatment with the γ-secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butyl ester (DAPT), or Notch1 short hairpin RNAs (shRNA) remarkably reduced the cisplatin-induced enrichment of CD133+ cells and increased the sensitivity to doxorubicin and paclitaxel. Ectopic expression of NICD1 reversed the action of DAPT on drug sensitivity. Immunohistochemistry showed that CD133+ cells were significantly increased in the relapsed tumors in three of six patients with lung cancer who have received cisplatin treatment. A similar effect was observed in animal experiments as cisplatin treatment increased Notch1 cleavage and the ratio of CD133+ cells in engrafted tumors. Intratumoral injection of DAPT with cisplatin treatment significantly reduced CD133+ cell number. Together, our results showed that cisplatin induces the enrichment of CD133+ cells, leading to multidrug resistance by the activation of Notch signaling. Cancer Res; 73(1); 406–16. ©2012 AACR.
Combination Therapy Targeting the Chk1 and Wee1 Kinases Shows Therapeutic Efficacy in Neuroblastoma
Authors: Russell Mike R. , Levin Kirill , Rader JulieAnn , Belcastro Lili , Li Yimei , Martinez Daniel , Pawel Bruce , Shumway Stuart D. , Maris John M. , Cole Kristina A. 
Published: November 2012

Abstract
Neuroblastoma is uniquely sensitive to single-agent inhibition of the DNA damage checkpoint kinase Chk1, leading us to examine downstream effectors of this pathway and identify mitotic regulator Wee1 as an additional therapeutic target in this disease. Wee1 was overexpressed in both neuroblastoma cell lines and high-risk patient tumors. Genetic or pharmacologic abrogation of Wee1 signaling results in marked cytotoxicity in 10 of 11 neuroblastoma cell lines with a median IC50 of 300 nmol/L for the Wee1-selective small-molecule inhibitor MK-1775. Murine tumor lines derived from mice that were either heterozygous or homozygous for MycN were particularly sensitive to single-agent inhibition of Wee1 (IC50s of 160 and 62 nmol/L, respectively). Simultaneous pharmacologic inhibition of Chk1 and Wee1 acted in a synergistic fashion to further impede neuroblastoma cell growth in vitro, in a manner greater than the individual inhibitors either alone or combined with chemotherapy. Combination Chk1 and Wee1 inhibition also revealed in vivo efficacy in neuroblastoma xenografts. Taken together, our results show that neuroblastoma cells depend on Wee1 activity for growth and that inhibition of this kinase may serve as a therapeutic for patients with neuroblastoma. Cancer Res; 73(2); 776–84. ©2012 AACR.
A Multicenter, Phase I, Dose-Escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics of Etirinotecan Pegol in Patients with Refractory Solid Tumors
Authors: Jameson Gayle S. , Hamm John T. , Weiss Glen J. , Alemany Carlos , Anthony Stephen , Basche Michele , Ramanathan Ramesh K. , Borad Mitesh J. , Tibes Raoul , Cohn Allen , Hinshaw Ioana , Jotte Robert , Rosen Lee S. , Hoch Ute , Eldon Michael A. , Medve Robert , Schroeder Katrina , White Erica , Von Hoff Daniel D. 
Published: November 2012

Abstract
Purpose: This study was designed to establish the maximum tolerated dose (MTD) and to evaluate tolerability, pharmacokinetics, and antitumor activity of etirinotecan pegol.
Experimental Design: Patients with refractory solid malignancies were enrolled and assigned to escalating-dose cohorts. Patients received 1 infusion of etirinotecan pegol weekly 3 times every 4 weeks (w × 3q4w), or every 14 days (q14d), or every 21 days (q21d), with MTD as the primary end point using a standard 3 + 3 design.
Results: Seventy-six patients were entered onto 3 dosing schedules (58–245 mg/m2). The MTD was 115 mg/m2 for the w × 3q4w schedule and 145 mg/m2 for both the q14d and q21d schedules. Most adverse events related to study drug were gastrointestinal disorders and were more frequent at higher doses of etirinotecan pegol. Late onset diarrhea was observed in some patients, the frequency of which generally correlated with dose density. Cholinergic diarrhea commonly seen with irinotecan treatment did not occur in patients treated with etirinotecan pegol. Etirinotecan pegol administration resulted in sustained and controlled systemic exposure to SN-38, which had a mean half-life of approximately 50 days. Overall, the pharmacokinetics of etirinotecan pegol are predictable and do not require complex dosing adjustments. Confirmed partial responses were observed in 8 patients with breast, colon, lung (small and squamous cell), bladder, cervical, and neuroendocrine cancer.
Conclusion: Etirinotecan pegol showed substantial antitumor activity in patients with various solid tumors and a somewhat different safety profile compared with the irinotecan historical profile. The MTD recommended for phase II clinical trials is 145 mg/m2 q14d or q21d. Clin Cancer Res; 19(1); 268–78. ©2012 AACR.
The Critical Role of Dysregulated FOXM1–PLAUR Signaling in Human Colon Cancer Progression and Metastasis
Authors: Li Dawei , Wei Ping , Peng Zhihai , Huang Chen , Tang Huamei , Jia Zhiliang , Cui Jiujie , Le Xiangdong , Huang Suyun , Xie Keping 
Published: November 2012

Abstract
Purpose: The mammalian Forkhead Box (Fox) transcription factor FOXM1 is implicated in tumorigenesis including mouse intestinal cancer. However, the clinical significance of FOXM1 signaling in human colorectal cancer pathogenesis remains unknown.
Experimental Design: We investigated FOXM1 expression in 203 cases of primary colon cancer and matched normal colon tissue specimens and explored the underlying mechanisms of altered FOXM1 expression and the impact of this altered expression on colon cancer growth and metastasis using in vitro and animal models of colon cancer.
Results: We found weak expression of FOXM1 protein in the colon mucosa, whereas we observed strong FOXM1 expression in tumor-cell nuclei of colon cancer and lymph node metastases. A Cox proportional hazards model revealed that FOXM1 expression was an independent prognostic factor in multivariate analysis. Experimentally, overexpression of FOXM1 by gene transfer significantly promoted the growth and metastasis of colon cancer cells in orthotopic mouse models, whereas knockdown of FOXM1 expression by siRNA did the opposite. Promotion of colon tumorigenesis by FOXM1 directly and significantly correlated with activation of urokinase-type plasminogen activator receptor (PLAUR) expression and elevation of invasion and metastasis.
Conclusions: Given the importance of FOXM1 in regulation of the expression of genes key to cancer biology, dysregulated expression and activation of FOXM1 may play important roles in colon cancer progression and metastasis. Clin Cancer Res; 19(1); 62–72. ©2012 AACR.
Phosphoinositide 3-Kinase (PI3K) Pathway Alterations Are Associated with Histologic Subtypes and Are Predictive of Sensitivity to PI3K Inhibitors in Lung Cancer Preclinical Models
Authors: Spoerke Jill M. , O'Brien Carol , Huw Ling , Koeppen Hartmut , Fridlyand Jane , Brachmann Rainer K. , Haverty Peter M. , Pandita Ajay , Mohan Sankar , Sampath Deepak , Friedman Lori S. , Ross Leanne , Hampton Garret M. , Amler Lukas C. , Shames David S. , Lackner Mark R. 
Published: November 2012

Abstract
Purpose: Class 1 phosphatidylinositol 3-kinase (PI3K) plays a major role in cell proliferation and survival in a wide variety of human cancers. Here, we investigated biomarker strategies for PI3K pathway inhibitors in non–small-cell lung cancer (NSCLC).
Experimental Design: Molecular profiling for candidate PI3K predictive biomarkers was conducted on a collection of NSCLC tumor samples. Assays included comparative genomic hybridization, reverse-transcription polymerase chain reaction gene expression, mutation detection for PIK3CA and other oncogenes, PTEN immunohistochemistry, and FISH for PIK3CA copy number. In addition, a panel of NSCLC cell lines characterized for alterations in the PI3K pathway was screened with PI3K and dual PI3K/mTOR inhibitors to assess the preclinical predictive value of candidate biomarkers.
Results: PIK3CA amplification was detected in 37% of squamous tumors and 5% of adenocarcinomas, whereas PIK3CA mutations were found in 9% of squamous and 0% of adenocarcinomas. Total loss of PTEN immunostaining was found in 21% of squamous tumors and 4% of adenocarcinomas. Cell lines harboring pathway alterations (receptor tyrosine kinase activation, PI3K mutation or amplification, and PTEN loss) were exquisitely sensitive to the PI3K inhibitor GDC-0941. A dual PI3K/mTOR inhibitor had broader activity across the cell line panel and in tumor xenografts. The combination of GDC-0941 with paclitaxel, erlotinib, or a mitogen-activated protein–extracellular signal-regulated kinase inhibitor had greater effects on cell viability than PI3K inhibition alone.
Conclusions: Candidate biomarkers for PI3K inhibitors have predictive value in preclinical models and show histology-specific alterations in primary tumors, suggesting that distinct biomarker strategies may be required in squamous compared with nonsquamous NSCLC patient populations. Clin Cancer Res; 18(24); 6771–83. ©2012 AACR.
Randomized Comparison of Sevoflurane Versus Propofol to Reduce Perioperative Myocardial Ischemia in Patients Undergoing Noncardiac Surgery
Authors: Lurati Buse Giovanna A.L. , Schumacher Philippe , Seeberger Esther , Studer Wolfgang , Schuman Regina M. , Fassl Jens , Kasper Jorge , Filipovic Miodrag , Bolliger Daniel , Seeberger Manfred D. 
Published: November 2012

Background—
Volatile anesthetics provide myocardial preconditioning in coronary surgery patients. We hypothesized that sevoflurane compared with propofol reduces the incidence of myocardial ischemia in patients undergoing major noncardiac surgery.

Methods and Results—

We enrolled 385 patients at cardiovascular risk in 3 centers. Patients were randomized to maintenance of anesthesia with sevoflurane or propofol. We recorded continuous ECG for 48 hours perioperatively, measured troponin T and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) on postoperative days 1 and 2, and evaluated postoperative delirium by the Confusion Assessment Method. At 6 and 12 months, we contacted patients by telephone to assess major adverse cardiac events. The primary end point was a composite of myocardial ischemia detected by continuous ECG and/or troponin elevation. Additional end points were postoperative NT-proBNP concentrations, major adverse cardiac events, and delirium. Patients and outcome assessors were blinded. We tested dichotomous end points by χ
2
test and NT-proBNP by Mann–Whitney test on an intention-to-treat basis. Myocardial ischemia occurred in 75 patients (40.8%) in the sevoflurane and 81 (40.3%) in the propofol group (relative risk, 1.01; 95% confidence interval, 0.78–1.30). NT-proBNP release did not differ across allocation on postoperative day 1 or 2. Within 12 months, 14 patients (7.6%) suffered a major adverse cardiac event after sevoflurane and 17 (8.5%) after propofol (relative risk, 0.90; 95% confidence interval, 0.44–1.83). The incidence of delirium did not differ (11.4% versus 14.4%;
P
=0.379).

Conclusions—
Compared with propofol, sevoflurane did not reduce the incidence of myocardial ischemia in high-risk patients undergoing major noncardiac surgery. The sevoflurane and propofol groups did not differ in postoperative NT-proBNP release, major adverse cardiac events at 1 year, or delirium.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00286585.
Coronary Artery Bypass Surgery With or Without Mitral Valve Annuloplasty in Moderate Functional Ischemic Mitral Regurgitation
Authors: Chan K.M. John , Punjabi Prakash P. , Flather Marcus , Wage Riccardo , Symmonds Karen , Roussin Isabelle , Rahman-Haley Shelley , Pennell Dudley J. , Kilner Philip J. , Dreyfus Gilles D. , Pepper John R. 
Published: November 2012

Background—
The role of mitral valve repair (MVR) during coronary artery bypass grafting (CABG) in patients with moderate ischemic mitral regurgitation (MR) is uncertain. We conducted a randomized, controlled trial to determine whether repairing the mitral valve during CABG may improve functional capacity and left ventricular reverse remodeling compared with CABG alone.

Methods and Results—

Seventy-three patients referred for CABG with moderate ischemic MR and an ejection fraction >30% were randomized to receive CABG plus MVR (34 patients) or CABG only (39 patients). The study was stopped early after review of interim data. At 1 year, there was a greater improvement in the primary end point of peak oxygen consumption in the CABG plus MVR group compared with the CABG group (3.3 mL/kg/min versus 0.8 mL/kg/min;
P
<0.001). There was also a greater improvement in the secondary end points in the CABG plus MVR group compared with the CABG group: left ventricular end-systolic volume index, MR volume, and plasma B-type natriuretic peptide reduction of 22.2 mL/m
2
, 28.2 mL/beat, and 557.4 pg/mL, respectively versus 4.4 mL/m
2
(
P
=0.002), 9.2 mL/beat (
P
=0.001), and 394.7 pg/mL (
P
=0.003), respectively. Operation duration, blood transfusion, intubation duration, and hospital stay duration were greater in the CABG plus MVR group. Deaths at 30 days and 1 year were similar in both groups: 3% and 9%, respectively in the CABG plus MVR group, versus 3% (
P
=1.00) and 5% (
P
=0.66), respectively in the CABG group.

Conclusions—
Adding mitral annuloplasty to CABG in patients with moderate ischemic MR may improve functional capacity, left ventricular reverse remodeling, MR severity, and B-type natriuretic peptide levels, compared with CABG alone. The impact of these benefits on longer term clinical outcomes remains to be defined.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00413998.
Oxygen treatment is effective in migraine with autonomic symptoms
Authors: Jürgens Tim P , Schulte Laura H , May Arne 
Published: November 2012

Introduction While inhalation of high-flow 100% oxygen is highly effective in cluster headache, studies on its efficacy in migraine are sparse and controversial. Case We report the case of a 22-year-old patient with an eight-year history of strictly unilateral migraine without aura but cranial autonomic symptoms. She repeatedly responded completely to inhalation of high-flow pure oxygen within 15 min but suffered from recurrence of attacks within 30 min after discontinuation. Discussion In line with experimental animal studies, this case suggests a clinically relevant efficacy of inhaled oxygen in patients with migraine with accompanying cranial autonomic symptoms.