bluuebunny/crossref_metadata_2025 huggingface dataset:
A Review of In Vitro and In Vivo Studies on the Efficacy of Herbal Medicines for Primary Dysmenorrhea
Authors: Park Kyoung-Sun , Park Kang-In , Hwang Deok-Sang , Lee Jin-Moo , Jang Jun-Bock , Lee Chang-Hoon
Published: November 2014

Purpose. Primary dysmenorrhea (PD) is a common gynecological complaint among adolescent girls and women of reproductive age. This study aims to review the findings of published articles on the in vitro and in vivo efficacy of herbal medicines for PD. Methods. In vitro and in vivo studies of herbal compounds, individual herbal extracts, or herbal formula decoctions published from their inception to April 2014 were included in this review. Results. A total of 18 studies involving herbal medicines exhibited their inhibitory effect on PD. The majority of in vitro studies investigated the inhibition of uterine contractions. In vivo studies suggest that herbal medicines exert a peripheral analgesic effect and a possible anti‐inflammatory activity via the inhibition of prostaglandin (PG) synthesis. The mechanisms of herbal medicines for PD are associated with PG level reduction, suppression of cyclooxygenase‐2 expression, superoxide dismutase activation and malondialdehyde reduction, nitric oxide, inducible nitric oxide synthase, and nuclear factor‐kappa B reduction, stimulation of somatostatin receptor, intracellular Ca2+ reduction, and recovery of phospholipid metabolism. Conclusions. Herbal medicines are thought to be promising sources for the development of effective therapeutic agents for PD. Further investigations on the appropriate herbal formula and their constituents are recommended.
Speeds of Sound and Excess Molar Volume for Binary Mixture of 1,4-Dioxane with 1-Heptanol at Five Temperatures
Authors: Koneti Anil Kumar , Chintalapati Srinivasu
Published: November 2014

Speed of sound and density data for dilute liquid solutions of cyclic ether 1,4-dioxane with 1-heptanol was obtained using the Anton-Paar DSA 5000 at five temperatures  T = (298.15, 303.15, 308.15, 313.15, and 318.15) K at atmospheric pressure. The excess parameters were calculated from experimental data and fitted with a Redlich-Kister polynomial function and concluded the presence of weak molecular interactions.
Robust Tension Control of Strip for 5-Stand Tandem Cold Mills
Authors: Shafiei Behrooz , Ekramian Mohsen , Shojaei Khoshnam
Published: November 2014

Tandem cold rolling process is a nonlinear complex system with external and internal uncertainties and significant disturbances. The improvement in the quality of the final output depends on the control strategy of centerline thickness and interstand tension. This paper focuses on interstand tension control problem in 5-stand tandem cold rolling mills. Tension dynamics can be described by a nominal model perturbed by parametric uncertainties. In order to overcome the model uncertainties and external disturbances, suboptimalH∞andμcontrollers are proposed and the Hankel-norm approximation is used to reduce the order ofμcontroller. The performance of the proposed controllers is demonstrated by some simulations.
Analysis of Vehicle-Following Heterogeneity Using Self-Organizing Feature Maps
Authors: Yang Jie , Cheu Ruey Long , Guo Xiucheng , Romo Alicia
Published: November 2014

A self-organizing feature map (SOM) was used to represent vehicle-following and to analyze the heterogeneities in vehicle-following behavior. The SOM was constructed in such a way that the prototype vectors represented vehicle-following stimuli (the follower’s velocity, relative velocity, and gap) while the output signals represented the response (the follower’s acceleration). Vehicle trajectories collected at a northbound segment of Interstate 80 Freeway at Emeryville, CA, were used to train the SOM. The trajectory information of two selected pairs of passenger cars was then fed into the trained SOM to identify similar stimuli experienced by the followers. The observed responses, when the stimuli were classified by the SOM into the same category, were compared to discover the interdriver heterogeneity. The acceleration profile of another passenger car was analyzed in the same fashion to observe the interdriver heterogeneity. The distribution of responses derived from data sets of car-following-car and car-following-truck, respectively, was compared to ascertain inter-vehicle-type heterogeneity.
Safety Assessment of Dangerous Goods Transport Enterprise Based on the Relative Entropy Aggregation in Group Decision Making Model
Authors: Wu Jun , Li Chengbing , Huo Yueying
Published: November 2014

Safety of dangerous goods transport is directly related to the operation safety of dangerous goods transport enterprise. Aiming at the problem of the high accident rate and large harm in dangerous goods logistics transportation, this paper took the group decision making problem based on integration and coordination thought into a multiagent multiobjective group decision making problem; a secondary decision model was established and applied to the safety assessment of dangerous goods transport enterprise. First of all, we used dynamic multivalue background and entropy theory building the first level multiobjective decision model. Secondly, experts were to empower according to the principle of clustering analysis, and combining with the relative entropy theory to establish a secondary rally optimization model based on relative entropy in group decision making, and discuss the solution of the model. Then, after investigation and analysis, we establish the dangerous goods transport enterprise safety evaluation index system. Finally, case analysis to five dangerous goods transport enterprises in the Inner Mongolia Autonomous Region validates the feasibility and effectiveness of this model for dangerous goods transport enterprise recognition, which provides vital decision making basis for recognizing the dangerous goods transport enterprises.
Control of the Thermal Fractal Diffusion of Tightly Compressed Heterogeneous Layers of Thin Plates
Authors: Qiao Wei , Liu Shu-Tang , Sun Jie
Published: November 2014

As the thermal conductivity of thin plates composed of tightly compressed heterogeneous layers varies continuously in the form of an exponential function, we present a nonlinear dynamical model of the fractal growth of thermal diffusion. We also analyze the quantitative relationship between the probability of growth and the disturbance term, predict the control action of the environmental disturbance term on fractal growth, and use Matlab simulation to verify the control effectiveness of thermal fractal diffusion. The results facilitate the selection of appropriate control areas and control parameters for the thermal diffusion variable coefficients. In addition, variation in the fractal dimension reflects the influence of environmental disturbance on the complex process of thermal fractal diffusion.
Sol‐Gel Synthesis and Characterization of Cubic Bismuth Zinc Niobium Oxide Nanopowders
Authors: Perenlei Ganchimeg , Talbot Peter C. , Martens Wayde N.
Published: November 2014

Bismuth zinc niobium oxide (BZN) was successfully synthesized by a diol‐based sol‐gel reaction utilizing metal acetate and alkoxide precursors. Thermal analysis of a liquid suspension of precursors suggests that the majority of organic precursors decompose at temperatures up to 150°C, and organic free powders form above 350°C. The experimental results indicate that a homogeneous gel is obtained at about 200°C and then converts to a mixture of intermediate oxides at 350–400°C. Finally, single‐phased BZN powders are obtained between 500 and 900°C. The degree of chemical homogeneity as determined by X‐ray diffraction and EDS mapping is consistent throughout the samples. Elemental analysis indicates that the atomic ratio of metals closely matches a Bi1.5ZnNb1.5O7 composition. Crystallite sizes of the BZN powders calculated from the Scherrer equation are about 33–98 nm for the samples prepared at 500–700°C, respectively. The particle and crystallite sizes increase with increased sintering temperature. The estimated band gap of the BZN nanopowders from optical analysis is about 2.60–2.75 eV at 500‐600°C. The observed phase formations and measured results in this study were compared with those of previous reports.
Adaptive Fuzzy Fault-Tolerant Output Feedback Tracking Control of Uncertain Stochastic Nonlinear Systems with Unknown Time-Delay and Tracking Error Constrained
Authors: Sui Shuai , Tong Shaocheng , Li Yongming
Published: November 2014

The problem of tracking error constrained adaptive fuzzy output feedback control is investigated for a class of single-input and single-output (SISO) stochastic nonlinear systems with actuator faults, unknown time-delay, and unmeasured states. The considered faults are modeled as both loss of effectiveness and lock-in-place. The fuzzy logic systems are used to approximate the unknown nonlinear functions, and a fuzzy adaptive observer is designed for estimating the unmeasured states. By transforming the tracking errors into new virtual error variables and based on backstepping recursive design technique, a new fuzzy adaptive output feedback control method is developed. It is shown that all the signals of the resulting closed-loop system are bounded in probability and the tracking error remains an adjustable neighborhood of the origin within the prescribed bounds. The simulation results are provided to show the effectiveness of the proposed approach.
Leptomeningeal Dissemination in Gall Bladder Carcinoma: Sequelae of Long-Term Survival?
Authors: Goyal Shikha , Mohanti Bidhu Kalyan
Published: November 2014

Patients with gall bladder malignancies usually present at an advanced stage with less than 20% cases being resectable at presentation and over a half harbouring distant metastases to liver or paraaortic nodes. Long-term cure is uncommon and so is the presence of central nervous system metastases. We present the case of a middle-aged woman with adenocarcinoma gall bladder, treated with postoperative locoregional irradiation following simple cholecystectomy, who developed headache, backache, vision loss, and multiple joint pains six years following adjuvant therapy. A diagnosis of leptomeningeal carcinomatous meningitis was established with cerebrospinal fluid cytology positivity for carcinoma. She deteriorated on palliative cranial irradiation and was managed with best supportive care.
Neural Network Based Retrieval of Atmospheric Temperature Profile Using AMSU-A Observations
Authors: Gangwar R. K. , Mathur A. K. , Gohil B. S. , Basu Sujit
Published: November 2014

The present study describes artificial neural network (ANN) based approach for the retrieval of atmospheric temperature profiles from AMSU-A microwave temperature sounder. The nonlinear relationship between the temperature profiles and satellite brightness temperatures dictates the use of ANN, which is inherently nonlinear in nature. Since latitudinal variation of temperature is dominant one in the Earth’s atmosphere, separate network configurations have been established for different latitudinal belts, namely, tropics, mid-latitudes, and polar regions. Moreover, as surface emissivity in the microwave region of electromagnetic spectrum significantly influences the radiance (or equivalently the brightness temperature) at the satellite altitude, separate algorithms have been developed for land and ocean for training the networks. Temperature profiles from National Center for Environmental Prediction (NCEP) analysis and brightness temperature observations of AMSU-A onboard NOAA-19 for the year 2010 have been used for training of the networks. Further, the algorithm has been tested on the independent dataset comprising several months of 2012 AMSU-A observations. Finally, an error analysis has been performed by comparing retrieved profiles with collocated temperature profiles from NCEP. Errors in the tropical region are found to be less than those in the mid-latitude and polar regions. Also, in each region the errors over ocean are less than the corresponding ones over land.
Borderline Ovarian Tumors and Diagnostic Dilemma of Intraoperative Diagnosis: Could Preoperative He4 Assay and ROMA Score Assessment Increase the Frozen Section Accuracy? A Multicenter Case-Control Study
Authors: Gizzo Salvatore , Berretta Roberto , Di Gangi Stefania , Guido Maria , Zanni Giuliano Carlo , Franceschetti Ilaria , Quaranta Michela , Plebani Mario , Nardelli Giovanni Battista , Patrelli Tito Silvio
Published: November 2014

The aim of our study was to assess the value of a preoperative He4-serum-assay and ROMA-score assessment in improving the accuracy of frozen section histology in the diagnosis of borderline ovarian tumors (BOT). 113 women presenting with a unilateral ovarian mass diagnosed as serous/mucinous BOT at frozen-section-histology (FS) and/or confirmed on final pathology were recruited. Pathologists were informed of the results of preoperative clinical/instrumental assessment of all patients. For Group_A patients, additional information regarding He4, CA125, and ROMA score was available (in Group_B only CA125 was known). The comparison between Group A and Group B in terms of FS accuracy, demonstrated a consensual diagnosis in 62.8% versus 58.6% (P: n.s.), underdiagnosis in 25.6% versus 41.4% (P<0.05), and overdiagnosis in 11.6% versus 0% (P<0.01). Low FS diagnostic accuracy was associated with menopausal status (OR: 2.13), laparoscopic approach (OR: 2.18), mucinous histotype (OR: 2.23), low grading (OR: 1.30), and FIGO stage I (OR: 2.53). Ultrasound detection of papillae (OR: 0.29), septa (OR: 0.39), atypical vascularization (OR: 0.34), serum He4 assay (OR: 0.39), and ROMA score assessment (OR: 0.44) decreased the probability of underdiagnosis. A combined preoperative assessment through serum markers and ultrasonographic features may potentially reduce the risk of underdiagnosis of BOTs on FS while likely increasing the concomitant incidence of false-positive events.
A Multiobjective Programming Method for Ranking All Units Based on Compensatory DEA Model
Authors: Cheng Haifang , Zhang Yishi , Cai Jianhu , Huang Weilai
Published: November 2014

In order to rank all decision making units (DMUs) on the same basis, this paper proposes a multiobjective programming (MOP) model based on a compensatory data envelopment analysis (DEA) model to derive a common set of weights that can be used for the full ranking of all DMUs. We first revisit a compensatory DEA model for ranking all units, point out the existing problem for solving the model, and present an improved algorithm for which an approximate global optimal solution of the model can be obtained by solving a sequence of linear programming. Then, we applied the key idea of the compensatory DEA model to develop the MOP model in which the objectives are to simultaneously maximize all common weights under constraints that the sum of efficiency values of all DMUs is equal to unity and the sum of all common weights is also equal to unity. In order to solve the MOP model, we transform it into a single objective programming (SOP) model using a fuzzy programming method and solve the SOP model using the proposed approximation algorithm. To illustrate the ranking method using the proposed method, two numerical examples are solved.
Sources of Error in Substance Use Prevalence Surveys
Authors: Johnson Timothy P.
Published: November 2014

Population-based estimates of substance use patterns have been regularly reported now for several decades. Concerns with the quality of the survey methodologies employed to produce those estimates date back almost as far. Those concerns have led to a considerable body of research specifically focused on understanding the nature and consequences of survey-based errors in substance use epidemiology. This paper reviews and summarizes that empirical research by organizing it within a total survey error model framework that considers multiple types of representation and measurement errors. Gaps in our knowledge of error sources in substance use surveys and areas needing future research are also identified.
Determination of Sunset Yellow and Tartrazine in Food Samples by Combining Ionic Liquid-Based Aqueous Two-Phase System with High Performance Liquid Chromatography
Authors: Sha Ou , Zhu Xiashi , Feng Yanli , Ma Weixing
Published: November 2014

We proposed a simple and effective method, by coupling ionic liquid-based aqueous two-phase systems (IL-ATPSs) with high performance liquid chromatography (HPLC), for the analysis of determining tartrazine and sunset yellow in food samples. Under the optimized conditions, IL-ATPSs generated an extraction efficiency of 99% for both analytes, which could then be directly analyzed by HPLC without further treatment. Calibration plots were linear in the range of 0.01–50.0 μg/mL for both Ta and SY. The limits of detection were 5.2 ng/mL for Ta and 6.9 ng/mL for SY. This method proves successful for the separation/analysis of tartrazine and sunset yellow in soft drink sample, candy sample, and instant powder drink and leads to consistent results as obtained from the Chinese national standard method.
The Law of Iterated Logarithm for Autoregressive Processes
Authors: Wang Yan , Mao Mingzhi , Hu Xiaohua , He Tingting
Published: November 2014

This paper mainly discusses some dynamics asymptotic properties of autoregressive processes. By using the m‐dependence of random variables, we prove the least squares (LS) estimator of the unknown parameters satisfies the law of iterated logarithm.
Endodontic Treatment of a Mandibular Second Premolar with Three Roots and Three Canals
Authors: Paul Bonny , Dube Kavita
Published: November 2014

Complex root canal system with atypical variations is a common finding among mandibular premolars. Endodontic treatment in these teeth may not be successful due to the failure to recognise and treat multiple canals. This paper presents endodontic treatment of a mandibular second premolar with three roots and three canals.
Four-in-One Antibodies Have Superior Cancer Inhibitory Activity against EGFR, HER2, HER3, and VEGF through Disruption of HER/MET Crosstalk
Authors: Hu Shi , Fu Wenyan , Xu Weihao , Yang Yang , Cruz Melissa , Berezov Sandra D. , Jorissen Daniel , Takeda Hiroaki , Zhu Wangdong
Published: November 2014

The anti-HER receptor antibodies cetuximab, trastuzumab, and pertuzumab are used widely in clinic to treat metastatic cancer. However, activation of the extensive crosstalk among the HER receptors as well as other RTKs, particularly HER-MET crosstalk, has emerged as a likely source of drug resistance. In this study, we developed two new types of tetra-specific antibodies that recognize EGFR, HER2, HER3, and VEGF. These tetra-specific antibodies, termed FL518 (four-in-one antibody) and CRTB6 (tetra-specific, tetravalent antibody), not only inhibited signaling mediated by these receptors in vitro and in vivo but unexpectedly also disrupted HER-MET crosstalk. When compared with two-in-one antibodies and a series of bispecific antibodies in multiple tumor models, FL518 and CRTB6 were more broadly efficacious. We further showed that tetra-specific antibodies were far more effective than bispecific antibodies in inhibiting the growth of anti–HER-resistant cancer cells, which exhibited elevated levels of MET activation both in vitro and in vivo. Overall, our results establish a new principle to achieve combined HER inhibition and limit drug resistance using a single antibody. Cancer Res; 75(1); 159–70. ©2014 AACR.
Recurrent BRCA1 and BRCA2 Mutations in Mexican Women with Breast Cancer
Authors: Torres-Mejía Gabriela , Royer Robert , Llacuachaqui Marcia , Akbari Mohammad R. , Giuliano Anna R. , Martínez-Matsushita Louis , Angeles-Llerenas Angélica , Ortega-Olvera Carolina , Ziv Elad , Lazcano-Ponce Eduardo , Phelan Catherine M. , Narod Steven A.
Published: November 2014

Background: Germline mutations in the BRCA1 and BRCA2 genes confer an estimated 58% to 80% lifetime risk of breast cancer. In general, screening is done for cancer patients if a relative has been diagnosed with breast or ovarian cancer. There are few data on the prevalence of mutations in these genes in Mexican women with breast cancer and this hampers efforts to develop screening policies in Mexico.

Methods: We screened 810 unselected women with breast cancer from three cities in Mexico (Mexico City, Veracruz, and Monterrey) for mutations in BRCA1 and BRCA2, including a panel of 26 previously reported mutations.

Results: Thirty-five mutations were identified in 34 women (4.3% of total) including 20 BRCA1 mutations and 15 BRCA2 mutations. Twenty-two of the 35 mutations were recurrent mutations (62.8%). Only five of the 34 mutation carriers had a first-degree relative with breast cancer (three with BRCA1 and two with BRCA2 mutations).

Conclusion: These results support the rationale for a strategy of screening for recurrent mutations in all women with breast cancer in Mexico, as opposed to restricting screening to those with a sister or mother with breast or ovarian cancer.

Impact: These results will impact cancer genetic testing in Mexico and the identification of at-risk individuals who will benefit from increased surveillance. Cancer Epidemiol Biomarkers Prev; 24(3); 498–505. ©2014 AACR.
Endogenous Sex Hormones and Breast Density in Young Women
Authors: Jung Seungyoun , Stanczyk Frank Z. , Egleston Brian L. , Snetselaar Linda G. , Stevens Victor J. , Shepherd John A. , Van Horn Linda , LeBlanc Erin S. , Paris Kenneth , Klifa Catherine , Dorgan Joanne F.
Published: November 2014

Background: Breast density is a strong risk factor for breast cancer and reflects epithelial and stromal content. Breast tissue is particularly sensitive to hormonal stimuli before it fully differentiates following the first full-term pregnancy. Few studies have examined associations between sex hormones and breast density among young women.

Methods: We conducted a cross-sectional study among 180 women ages 25 to 29 years old who participated in the Dietary Intervention Study in Children 2006 Follow-up Study. Eighty-five percent of participants attended a clinic visit during their luteal phase of menstrual cycle. Magnetic resonance imaging measured the percentage of dense breast volume (%DBV), absolute dense breast volume (ADBV), and absolute nondense breast volume (ANDBV). Multiple-linear mixed-effect regression models were used to evaluate the association of sex hormones and sex hormone–binding globulin (SHBG) with %DBV, ADBV, and ANDBV.

Results: Testosterone was significantly positively associated with %DBV and ADBV. The multivariable geometric mean of %DBV and ADBV across testosterone quartiles increased from 16.5% to 20.3% and from 68.6 to 82.3 cm3, respectively (Ptrend ≤ 0.03). There was no association of %DBV or ADBV with estrogens, progesterone, non–SHBG-bound testosterone, or SHBG (Ptrend ≥ 0.27). Neither sex hormones nor SHBG was associated with ANDBV except progesterone; however, the progesterone result was nonsignificant in analysis restricted to women in the luteal phase.

Conclusions: These findings suggest a modest positive association between testosterone and breast density in young women.

Impact: Hormonal influences at critical periods may contribute to morphologic differences in the breast associated with breast cancer risk later in life. Cancer Epidemiol Biomarkers Prev; 24(2); 369–78. ©2014 AACR.
Preexisting MEK1P124 Mutations Diminish Response to BRAF Inhibitors in Metastatic Melanoma Patients
Authors: Carlino Matteo S. , Fung Carina , Shahheydari Hamideh , Todd Jason R. , Boyd Suzanah C. , Irvine Mal , Nagrial Adnan M. , Scolyer Richard A. , Kefford Richard F. , Long Georgina V. , Rizos Helen
Published: November 2014

Background: MEK1 mutations in melanoma can confer resistance to BRAF inhibitors, although preexisting MEK1P124 mutations do not preclude clinical responses. We sought to determine whether recurrent, preexisting MEK1P124 mutations affected clinical outcome in BRAF inhibitor–treated patients with melanoma.

Methods: Data from four published datasets were analyzed to determine whether preexisting MEK1P124 mutations affect radiologic response or progression-free survival (PFS) in patients with BRAFV600-mutant metastatic melanoma treated with vemurafenib or dabrafenib. The effects of MEK1P124 mutations on MAPK pathway activity and response to BRAF inhibition were also investigated in a series of cell models.

Results: In a pooled analysis of 123 patients, the presence of a pretreatment MEK1P124 mutation (N = 12, 10%) was associated with a poorer RECIST response (33% vs. 72% in MEK1P124Q/S vs. MEK1P124 wild-type, P = 0.018), and a shorter PFS (median 3.1 vs. 4.8 months, P = 0.004). Furthermore, MEK1P124Q/S mutations were shown to have independent kinase activity and introduction of these mutations into a BRAF-mutant melanoma cell line diminished inhibition of ERK phosphorylation by dabrafenib and enhanced clonogenic survival in the presence of dabrafenib compared with cells ectopically expressing wild-type MEK1. Consistent with these data, two BRAF-mutant cell lines with endogenous MEK1P124 mutations showed intermediate sensitivity to dabrafenib, but were highly sensitive to downstream inhibition of MEK or ERK.

Conclusion: Taken together, our data indicate that preexisting MEK1P124 mutations are associated with a reduced response to BRAF inhibitor therapy and identify a subset of patients with BRAF-mutant melanoma likely to benefit from combination therapies involving MEK or ERK inhibitors. Clin Cancer Res; 21(1); 98–105. ©2014 AACR.
Metabolic Imaging of Pancreatic Ductal Adenocarcinoma Detects Altered Choline Metabolism
Authors: Penet Marie-France , Shah Tariq , Bharti Santosh , Krishnamachary Balaji , Artemov Dmitri , Mironchik Yelena , Wildes Flonné , Maitra Anirban , Bhujwalla Zaver M.
Published: November 2014

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal disease that develops relatively symptom-free and is therefore advanced at the time of diagnosis. The absence of early symptoms and effective treatments has created a critical need for identifying and developing new noninvasive biomarkers and therapeutic targets.

Experimental Design: We investigated the metabolism of a panel of PDAC cell lines in culture and noninvasively in vivo with 1H magnetic resonance spectroscopic imaging (MRSI) to identify noninvasive biomarkers and uncover potential metabolic targets.

Results: We observed elevated choline-containing compounds in the PDAC cell lines and tumors. These elevated choline-containing compounds were easily detected by increased total choline (tCho) in vivo, in spectroscopic images obtained from tumors. Principal component analysis of the spectral data identified additional differences in metabolites between immortalized human pancreatic cells and neoplastic PDAC cells. Molecular characterization revealed overexpression of choline kinase (Chk)-α, choline transporter 1 (CHT1), and choline transporter–like protein 1 (CTL1) in the PDAC cell lines and tumors.

Conclusions: Collectively, these data identify new metabolic characteristics of PDAC and reveal potential metabolic targets. Total choline detected with 1H MRSI may provide an intrinsic, imaging probe–independent biomarker to complement existing techniques in detecting PDAC. The expression of Chk-α, CHT1, and CTL1 may provide additional molecular markers in aspirated cytological samples. Clin Cancer Res; 21(2); 386–95. ©2014 AACR.
A Phase I Trial of AT9283 (a Selective Inhibitor of Aurora Kinases) in Children and Adolescents with Solid Tumors: A Cancer Research UK Study
Authors: Moreno Lucas , Marshall Lynley V. , Pearson Andrew D.J. , Morland Bruce , Elliott Martin , Campbell-Hewson Quentin , Makin Guy , Halford Sarah E.R. , Acton Gary , Ross Philip , Kazmi-Stokes Shamim , Lock Victoria , Rodriguez Ana , Lyons John F. , Boddy Alan V. , Griffin Melanie J. , Yule Murray , Hargrave Darren
Published: November 2014

Purpose: A phase I trial of AT9283 (a multitargeted inhibitor of Aurora kinases A and B) was conducted in children and adolescents with solid tumors, to identify maximum-tolerated dose (MTD), safety, efficacy, pharmacokinetics, and pharmacodynamic (PD) activity.

Experimental Design: AT9283 was administered as a 72-hour continuous intravenous infusion every 3 weeks. A rolling-six design, explored six dose levels (7, 9, 11.5, 14.5, 18.5, and 23 mg/m2/d). Pharmacokinetic and PD assessments, included inhibition of phospho-histone 3 (pHH3) in paired skin punch biopsies.

Results: Thirty-three patients were evaluable for toxicity. There were six dose-limiting toxicities and the MTD was 18.5 mg/m2/d. Most common drug-related toxicities were hematologic (neutropenia, anemia, and thrombocytopenia in 36.4%, 18.2%, and 21.2% of patients), which were grade ≥3 in 30.3%, 6.1%, and 3% of patients. Nonhematologic toxicities included fatigue, infections, febrile neutropenia and ALT elevation. One patient with central nervous system–primitive neuroectodermal tumor (CNS-PNET) achieved a partial response after 16 cycles and 3 cases were stable for four or more cycles. Plasma concentrations were comparable with those in adults at the same dose level, clearance was similar although half-life was shorter (4.9 ± 1.5 hours, compared with 8.4 ± 3.7 hours in adults). Inhibition of Aurora kinase B was shown by reduction in pHH3 in 17 of 18 patients treated at ≥11.5 mg/m2/d.

Conclusion: AT9283 was well tolerated in children and adolescents with solid tumors with manageable hematologic toxicity. Target inhibition was demonstrated. Disease stabilization was documented in intracranial and extracranial pediatric solid tumors and a phase II dose determined. Clin Cancer Res; 21(2); 267–73. ©2014 AACR.
A Novel MAPK–microRNA Signature Is Predictive of Hormone-Therapy Resistance and Poor Outcome in ER-Positive Breast Cancer
Authors: Miller Philip C. , Clarke Jennifer , Koru-Sengul Tulay , Brinkman Joeli , El-Ashry Dorraya
Published: November 2014

Purpose: Hyperactivation of ERK1/2 MAPK (hMAPK) leads to loss of estrogen receptor (ER) expression and poor outcome in breast cancer. microRNAs (miRNA) play important regulatory roles and serve as biomarkers of disease. Here, we describe molecular, pathologic, and clinical outcome associations of an hMAPK–miRNA expression signature in breast cancer.

Experimental Design: An hMAPK–miRNA signature was identified, and associations of this signature with molecular and genetic alterations, gene expression, pathologic features, and clinical outcomes were determined in primary breast cancers from training data and validated using independent datasets. Univariate and multivariate analyses identified subsignatures associated with increased disease recurrence and poorer disease survival among ER-positive (ER+) patients, respectively.

Results: High-hMAPK–miRNA status significantly correlated with ER-negativity, enrichment for basal and HER2-subtypes, and reduced recurrence-free and disease-specific survival in publicly available datasets. A robust determination of a recurrence signature and a survival signature identified hMAPK–miRNAs commonly associated with poor clinical outcome, and specific subsets associated more closely with either disease recurrence or disease survival, especially among ER+ cancers of both luminal A and luminal B subtypes. Multivariate analyses indicated that these recurrence and survival signatures significantly associated with increased risk of disease-specific death and disease recurrence in ER+ cancer and ER+ cancers treated with hormone therapy.

Conclusions: We report an hMAPK–miRNA signature and two subsignatures derived from it that associate significantly with adverse clinical features, poor clinical outcome, and poor response to hormone therapy in breast cancer, thus identifying potential effectors of MAPK signaling, and novel predictive and prognostic biomarkers or therapeutic targets in breast cancer. Clin Cancer Res; 21(2); 373–85. ©2014 AACR.
Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer
Authors: Salz Tal , Deng Changwang , Pampo Christine , Siemann Dietmar , Qiu Yi , Brown Kevin , Huang Suming
Published: November 2014

Epigenetic alteration is a hallmark of all cancers. Such alterations lead to modulation of fundamental cancer-related functions, such as proliferation, migration, and invasion. In particular, methylation of Histone H3 Lysine 4 (H3K4), a histone mark generally associated with transcriptional activation, is altered during progression of several human cancers. While the depletion of H3K4 demethylases promotes breast cancer metastasis, the effect of H3K4 methyltransferases on metastasis is not clear. Nevertheless, gene duplications in the human SETD1A (hSETD1A) H3K4 methyltransferase are present in almost half of breast cancers. Herein, expression analysis determined that hSETD1A is upregulated in multiple metastatic human breast cancer cell lines and clinical tumor specimens. Ablation of hSETD1A in breast cancer cells led to a decrease in migration and invasion in vitro and to a decrease in metastasis in nude mice. Furthermore, a group of matrix metalloproteinases (including MMP2, MMP9, MMP12, MMP13, and MMP17) were identified which were downregulated upon depletion of hSETD1A and demonstrated a decrease in H3K4me3 at their proximal promoters based on chromatin immunoprecipitation analysis. These results provide evidence for a functional and mechanistic link among hSETD1A, MMPs, and metastasis in breast cancer, thereby supporting an oncogenic role for hSETD1A in cancer.

Implications: This study reveals that hSETD1A controls tumor metastasis by activating MMP expression and provides an epigenetic link among hSETD1A, MMPs, and metastasis of breast cancer. Mol Cancer Res; 13(3); 461–9. ©2014 AACR.
PD-L1 Expression in Melanocytic Lesions Does Not Correlate with the BRAF V600E Mutation
Authors: Rodić Nemanja , Anders Robert A. , Eshleman James R. , Lin Ming-Tseh , Xu Haiying , Kim Jung H. , Beierl Katie , Chen Shuming , Luber Brandon S. , Wang Hao , Topalian Suzanne L , Pardoll Drew M. , Taube Janis M.
Published: November 2014

PD-L1 expression in melanoma correlates with response to PD-1 pathway–blocking antibodies. Aberrant tumor-cell PD-L1 expression may be oncogene driven and/or induced by IFNγ. Melanomas express PD-L1 in association with tumor-infiltrating lymphocytes (TIL), but the potential contribution of the BRAF V600E mutation (BRAFmut) to induced PD-L1 expression has not been determined. Fifty-two archival melanocytic lesions were assessed for PD-L1 expression, TIL infiltration, and BRAFmut simultaneously. IFNγ-induced PD-L1 expression in cultured melanomas was assessed in parallel according to BRAF status. Melanocyte PD-L1 expression was observed in 40% of specimens, and BRAFmut was observed in 42% of specimens, but no significant concordance was found between these variables. Almost all melanocytes displaying PD-L1 expression were observed to be adjacent to TILs, irrespective of BRAF status. TIL− lesions were not more likely to be associated with BRAFmut, when compared with TIL+ lesions. Baseline expression of PD-L1 by melanoma cell lines was virtually nil, regardless of BRAFmut status, and the intensity of IFN-induced PD-L1 expression in melanoma cell lines likewise did not correlate with BRAF mutational status. PD-L1 expression in melanocytic lesions does not correlate with the BRAFmut. Thus, distinct populations of melanoma patients will likely benefit from BRAF inhibitors versus PD-1 pathway blockade. Cancer Immunol Res; 3(2); 110–5. ©2014 AACR.
Outcomes of Prenatally Diagnosed Lung Lesions in Multigestational Pregnancies
Authors: Vrecenak Jesse D. , Howell Lori J. , Khalek Nahla , Moldenhauer Julie S. , Johnson Mark Paul , Coleman Beverly G. , Victoria Teresa , Hedrick Holly L. , Peranteau William H. , Flake Alan W. , Adzick N. Scott
Published: November 2014

Background: The outcomes of prenatally diagnosed lung lesions in the context of multigestational pregnancies are unknown. Methods: Of 960 fetal lung lesion cases evaluated at a single tertiary center over 16 years, 30 occurred in multigestational pregnancies. We reviewed this series to aid in prenatal counseling of affected families and to provide prognostic information for decision making. Pre- and postnatal clinical characteristics were gathered for these pregnancies, and the morbidity and mortality were determined for both affected and normal fetuses, whether twins or triplets. Results: Mortality was found to be 3/30 (10%) for affected fetuses, and morbidity in normal co-twins was consistent with the degree of prematurity. No morbidity was seen in co-twins born at or after 36 weeks of gestation. Median gestational age at delivery was 35 5/7 weeks. Conclusions: Outcomes for the affected fetus correlate with the size and pathophysiologic consequences of the lesion and are not worse than previously reported outcomes for similar lesions in singleton pregnancies, while morbidity in the normal co-twin is consistent with prematurity related to the fetal age of the multiple gestation at delivery, irrespective of the fetal lung lesion.
Dysphagia and Factors Associated with Respiratory Infections in the First Week Post Stroke
Authors: Brogan Emily , Langdon Claire , Brookes Kim , Budgeon Charley , Blacker David
Published: November 2014

Background: Dysphagia occurs in approximately half of the stroke patients and is associated with respiratory infections; however, it is unclear what other factors contribute to an increased risk. This study aimed to provide evidence on factors associated with respiratory infections in the very acute stroke period. Methods: Retrospective review of 536 stroke patients admitted to Australian Hospitals in 2010. Data were collected on 37 clinical and demographic parameters. Univariable and multivariable logistic regression was performed. Results: The overall incidence of respiratory infection was 11%. On admission, requiring full assistance with mobility [OR 6.48, 95% CI 1.35, 31.16] and urinary incontinence [OR 3.21, 95% CI 1.16, 8.87] were associated with respiratory infections. During the first week post stroke nasogastric tubes (NGT) [OR 3.91, 95% CI 1.73, 8.80] and Nil By Mouth (NBM) [OR 5.62, 95% CI 1.54, 20.46] were associated with respiratory infections. Impaired GCS, ischaemic stroke and significantly impaired mobility were associated with swallowing difficulties. Conclusion: This study of a large cohort of acute stroke patients supports research indicating aspiration pneumonia is multifactorial in nature. NGT were associated with increased risk of respiratory infections and may contribute to infections by promoting oropharyngeal colonisation. Patients with severely impaired mobility were also at very high risk of respiratory infection.
Methodology and Design of a National Epidemiological Study on Adult Neuromuscular Disease
Authors: Lefter Stela , Hardiman Orla , Ryan Aisling M.
Published: November 2014

Background: There have been no previous population-based studies of adult neuromuscular disease (NMD) in the Republic of Ireland (RoI). This article describes methods and case-ascertainment strategies used to identify patients with inherited and acquired NMD for the purpose of obtaining the prevalence of these disorders in the RoI. Methods: This epidemiological study was conducted between January 2012 and January 2014. Prospective and retrospective (until 1990) case identification of adults with inherited and acquired NMD have been carried out. Multiple countrywide patient identification sources including neuromuscular clinics, hospital neurology databases, the hospital in-patient enquiry (HIPE) system of each hospital and the records of Muscular Dystrophy Ireland, a nonprofit organisation, were used. Results: In total, 3,724 potential cases were identified. Of these, 1,083 were excluded because 869 cases represented duplicates or triplicates, 133 were coded incorrectly in HIPE, 74 patients were deceased and 7 patients had moved out of the country. The highest number of cases was identified in neurology databases and HIPE (1,724 and 884, respectively). A total of 2,641 individuals fulfilled the inclusion criteria and were included in the study. Conclusion: Detailed epidemiological data of this nature is difficult to acquire in the current structure of the Irish health service, requiring multiple sources including input from voluntary patient organisations. The development of a national patient registry for some or all of these conditions would greatly facilitate standardised data recording, giving a true picture of the burden of neuromuscular diseases in a population.
Impact of Cell Arrangement of Pleural Effusion in Survival of Patients with Breast Cancer
Authors: Camillo Natália Dressler , dos Santos Giovana Tavares , Prolla João Carlos , Flôres Eliza Ribas da Silveira , Introíni Gisele Orlandi , Brackmann Rosicler Luzia , da Cruz Ivana Beatrice Mânica , Bica Claudia Giuliano
Published: November 2014

Objective: This study was performed to evaluate the potential influence of cytological differences between pleural effusions on the survival of women with metastatic breast cancer during 30 months of follow-up. Study Design: A hospital-based cohort study was performed. Pleural fluid cytology slides from patients with breast cancer were examined. Cases were grouped according to the pattern of tumor cells (spheroid and isolated), in order to access their prognostic value. Results: The study comprised 87 patients. An isolated cell pattern was associated with higher mortality 30 months after the pleural effusion when compared to a spheroid pattern (p = 0.038). Patients with an isolated cell pattern showed higher risk of dying than patients with spheroid formations. The relative risk after adjustment of intervening variables was 5.336 (95% CI 1.054-27.020). The presence of a triple-negative immunohistochemical pattern significantly increased the risk of mortality before 30 months. Conclusion: Pleural effusion with isolated malignant cells is associated with worse prognosis after 30 months of follow-up.
Endoscopic Ultrasonography for Tumor Node Staging and Vascular Invasion in Pancreatic Cancer: A Meta-Analysis
Authors: Li Jun-hui , He Rui , Li Yi-ming , Cao Gang , Ma Qing-yong , Yang Wen-bin
Published: November 2014

Background/Aims: The accurate staging of pancreatic cancer (PanCa) is crucial in the development of a stage-specific treatment plan for PanCa patients. We aimed to perform a meta-analysis of endoscopic ultrasonography (EUS) in the tumor node (TN) staging and evaluation of vascular invasion in PanCa. Methods: A meta-analysis of diagnostic accuracy parameters was performed to evaluate the EUS-based TN staging, and vascular invasion by PanCa was compared to the results of intraoperative staging or to the histopathology of resected specimens. Results: Twenty studies with 726 PanCa cases were identified from 281 articles. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were 0.72, 0.90, 6.27, 0.28, and 24.69, respectively, for T1-2 staging and 0.90, 0.72, 3.58, 0.16, and 24.69, respectively, for T3-4 staging. The overall sensitivity, specificity, PLR, NLR, and DOR were 0.62, 0.74, 2.54, 0.51, and 6.67, respectively, for N staging (positive vs. negative) and 0.87, 0.92, 7.16, 0.20, and 56.19, respectively, for vascular invasion. The area under the curve was 0.90, 0.90, 0.79, and 0.94 for T1-2 staging, T3-4 staging, N staging, and vascular invasion, respectively. Conclusions: EUS is a reliable and accurate diagnostic tool for the TN staging and evaluation of vascular invasion in PanCa. The nodal staging accuracy using EUS is less satisfactory. i 2014 S. Karger AG, Basel
Effectiveness of Sternocleidomastoid Flap Repair for Cervical Anastomotic Leakage after Esophageal Reconstruction
Authors: Nakajima Masanobu , Satomura Hitoshi , Takahashi Masakazu , Muroi Hiroto , Kuwano Hiroyuki , Kato Hiroyuki
Published: November 2014

Background/Aims: The purpose of this study was to investigate the effectiveness of sternocleidomastoid (SCM) flap repair for anastomotic leakage after esophagectomy. Methods: A refractory cutaneous fistula from the gastric stump developed in 8 patients with esophageal cancer who underwent esophagogastric anastomosis after esophagectomy. All patients underwent SCM flap repair. The cutaneous fistula was removed and resutured. The sternal head of the left SCM was dissected from the manubrium of the sternum and sutured onto the repaired gastric stump. Results: The operative duration was 80-220 min (median, 120 min). The amount of intraoperative bleeding ranged from 5 to 182 g (median, 15 g). The absence of recurrent anastomotic leakage was confirmed after the SCM flap repair in every patient. Oral intake was initiated 7-15 days (median, 10 days) after the repair operation without discomfort. Conclusions: SCM flap repair is an effective and minimally invasive treatment method for cervical anastomotic leakage after esophageal reconstruction. This method may be considered in patients with refractory leakage of the gastric stump after staple anastomosis. i 2014 S. Karger AG, Basel
Type 1 Idiopathic Macular Telangiectasia Associated with Type 3 Neovascularization
Authors: Tilleul Julien , Querques Giuseppe , Capuano Vittorio , Miere Alexandra , Srour Mayer , Souied Eric H.
Published: November 2014

Purpose: To report the case of a patient with unilateral idiopathic macular telangiectasia (IMT) associated with type 3 neovascularization. Methods: Observational case report. Results: We describe a case of an 85-year-old woman who presented at our department with a gradual vision loss in her left eye (LE). Her best-corrected visual acuity (BCVA) was 20/200 in the LE. Fundus examination showed 2 small hemorrhages located nasally to the LE fovea, as well as lipid exudates. Fluorescein angiography revealed early hyperfluorescence corresponding to the dilated capillaries. Spectral-domain optical coherence tomography (SD-OCT) showed several microaneurysms within the inner retinal layers. Late indocyanine green angiography revealed a focal hyperfluorescence corresponding to a type 3 neovascularization. No signs of IMT or type 3 neovascularization were detected in the right eye. Based on these findings, the patient was diagnosed with type 1 IMT and coincident type 3 neovascularization. The LE was treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections. Twenty-four months later, SD-OCT revealed regression of the exudative signs, and LE BCVA improved to 20/100. Conclusion: We describe the case of an unusual association between older-onset IMT and type 3 neovascularization, and subsequent regression by anti-VEGF injections. We propose a new IMT subtype called type 1C for this association. Further research must be done in order to establish the pathophysiologic mechanism and likelihood of this association.
Antepartum Ornithine Transcarbamylase Deficiency
Authors: Nakajima Hitoshi , Sasaki Yosuke , Maeda Tadashi , Takeda Masako , Hara Noriko , Nakanishi Kazushige , Urita Yoshihisa , Hattori Risa , Miura Ken , Taniguchi Tomoko
Published: November 2014

Ornithine transcarbamylase deficiency (OTCD) is the most common type urea cycle enzyme deficiencies. This syndrome results from a deficiency of the mitochondrial enzyme ornithine transcarbamylase, which catalyzes the conversion of ornithine and carbamoyl phosphate to citrullin. Our case was a 28-year-old female diagnosed with OTCD following neurocognitive deficit during her first pregnancy. Although hyperammonemia was suspected as the cause of the patient's mental changes, there was no evidence of chronic liver disease. Plasma amino acid and urine organic acid analysis revealed OTCD. After combined modality treatment with arginine, sodium benzoate and hemodialysis, the patient's plasma ammonia level stabilized and her mental status returned to normal. At last she recovered without any damage left.