bluuebunny/crossref_metadata_2025 huggingface dataset:
Constrained Point Set Embedding of a Balanced Binary Tree
Authors: Rajabi-Alni Fatemeh , Bagheri Alireza
Published: May 2015

Given an undirected planar graph G with n vertices and a set S of n points inside a simple polygon P, a point-set embedding of G on S is a planar drawing of G such that each vertex is mapped to a distinct point of S and the edges are polygonal chains surrounded by P. A special case of the embedding problem is that in which G is a balanced binary tree. In this paper, we present a new algorithm for embedding an n-vertex balanced binary tree BBT on a set S of n points inside a simple m-gon P in O(m4/3+ϵ + nlog2 n + m log n) time with at most O(m) bends per edge.
New Self-Stabilizing Algorithms for Minimal Weakly Connected Dominating Sets
Authors: Ding Yihua , Wang James Z. , Srimani Pradip K.
Published: May 2015

In this paper, we propose two new self-stabilizing algorithms, MWCDS-C and MWCDS-D, for minimal weakly connected dominating sets in an arbitrary connected graph. Algorithm MWCDS-C stabilizes in O(n4) steps using an unfair central daemon and space requirement at each node is O(log n) bits at each node for an arbitrary connected graph with n nodes; it uses a designated node while other nodes are identical and anonymous. Algorithm MWCDS-D stabilizes using an unfair distributed daemon with identical time and space complexities, but it assumes unique node IDs. In the literature, the best reported stabilization time for a minimal weakly connected dominating set algorithm is O(nmA) under a distributed daemon [1], where m is the number of edges and A is the number of moves to construct a breadth-first tree.
Random Models and Analyses for Chemical Graphs
Authors: Kouri Tina M. , Pascua Daniel , Mehta Dinesh P.
Published: May 2015

This paper describes a random model for chemical graphs that captures the notion of valence along with algorithms to generate chemical graphs using this model. An approach for computing the probability that a particular chemical graph is generated under this model is provided. The model is also used to provide theoretical bounds on the accuracy of a class of canonical labeling algorithms for a class of hydrocarbons.
Homotopy groups and periodic geodesics of closed 4-manifolds
Authors: Basu Samik , Basu Somnath
Published: May 2015

Given a simply connected, closed 4-manifold, we prove that the homotopy groups of such a manifold are determined by its second Betti number, and the ranks of the homotopy groups can be explicitly calculated. We show that for a generic metric on such a smooth 4-manifold with second Betti number at least three the number of geometrically distinct periodic geodesics of length at most l grows exponentially as a function of l.
Detectors for collider experiments at the luminosity frontier
Authors: Križan Peter
Published: May 2015

In experiments at the luminosity frontier, New Physics is being searched for in precision studies of rare processes. The most important example of such an effort is experiments at B factories and super B factories. While B factories have fully established the CKM quark transition matrix as the only source of CP violation in the Standard Model, the next generation of B factories, the so-called super B factories, will look for departures from the Standard Model. To collect a 50 times larger data sample, needed to reach the required sensitivity, a substantial B factory upgrade is being carried out. The SuperKEKB accelerator complex is designed for an increase in luminosity by a factor of 40. The upgraded Belle II spectrometer is being constructed to operate at considerably higher event rates, as well as higher backgrounds, accompanied by an increase in occupancy and radiation damage. Higher event rates also require substantial modifications in the trigger scheme, data acquisition system and computing. The paper discusses the detectors at B factories, the motivation for SuperKEKB/Belle II, the super B factory at KEK, as well as the requirements for the new accelerator and for the new detector. The present status of the project will be presented together with plans for the future. We will also discuss its competition, the LHCb experiment at the LHC.
Texture Image Segmentation Using Affinity Propagation and Spectral Clustering
Authors: Du Hui , Wang Yuping , Dong Xiaopan
Published: May 2015

Clustering is a popular and effective method for image segmentation. However, existing cluster methods often suffer the following problems: (1) Need a huge space and a lot of computation when the input data are large. (2) Need to assign some parameters (e.g. number of clusters) in advance which will affect the clustering results greatly. To save the space and computation, reduce the sensitivity of the parameters, and improve the effectiveness and efficiency of the clustering algorithms, we construct a new clustering algorithm for image segmentation. The new algorithm consists of two phases: coarsening clustering and exact clustering. First, we use Affinity Propagation (AP) algorithm for coarsening. Specifically, in order to save the space and computational cost, we only compute the similarity between each point and its t nearest neighbors, and get a condensed similarity matrix (with only t columns, where t << N and N is the number of data points). Second, to further improve the efficiency and effectiveness of the proposed algorithm, the Self-tuning Spectral Clustering (SSC) is used to the resulted points (the representative points gotten in the first phase) to do the exact clustering. As a result, the proposed algorithm can quickly and precisely realize the clustering for texture image segmentation. The experimental results show that the proposed algorithm is more efficient than the compared algorithms FCM, K-means and SOM.
Novel Synthesis Methodology for Fault Tolerant Reversible Circuits by Bounded Model Checking for Linear Temporal Logic
Authors: Li Ming-Cui , Zhou Ri-Gui
Published: May 2015

Reversible circuit is of interest due to the characteristics of low energy consumption. This paper proposes a new scheme for synthesizing fault tolerant reversible circuits. A two-step method is put forward to convert an irreversible function into a parity-preserving reversible circuit. By introducing model checking for linear temporal logic, we construct a finite state machine to synthesize small reversible gates from elementary 1-qubit and 2-qubit gates, which is more automatic than the methods proposed previously. Constrains are increased so as to reduce the synthesis time in the two step method. The parity-preserving gate constructed by the two-step method has characteristics of low quantum cost because the quantum representation obtained from the counterexample for a given function in each step has the minimum quantum cost. In order to further reduce the quantum cost and decrease the synthesis time, the semi parity-preserving gates are put forward for the first time. These gates are parity-preserving when the auxiliary input is set to 0 and opposite parity when 1. Maintaining good robustness of the system in performing specific function, semi parity-preserving gate is conducive to detecting the stuck-at fault and partial gate fault in reversible circuits. The innovation of this paper is introducing the formal method to synthesis small fault tolerant gate, so as to construct the circuit with robust (semi) parity-preserving gates.
Using Cascaded Non-Identical CIC Sections to Improve Insertion Loss
Authors: Stošić Biljana P. , Pavlović Vlastimir D.
Published: May 2015

A novel class of cascaded-integrator-comb (CIC) filter functions, which preserve the CIC filter simplicity avoiding the multipliers, is proposed in this paper. The proposed class is designed using several cascaded non-identical CIC sections. The paper provides its non-recursive and recursive forms, as well as frequency response. Compared with classical CIC finite impulse response (FIR) filters designed novel class shows excellent performances in term of insertion loss in stopband and selectivity. To verify the behavior of the proposed novel class of CIC FIR filter functions, several illustrative examples are provided. Also, comparisons of the novel filter class with existing classical CIC structures and some recent improvements given in the literature are provided. For the same level of a constant group delay of 31.5 s, a classical CIC filter function has insertion loss of 115.176 dB, and proposed novel filter function has 136.757 dB. It has achieved significant improvement of 21.581 dB or approximately about 20%.
A polynomial class of u(2) algebras
Authors: Daoud Mohammed , Chung Won Sang
Published: May 2015

A r-parameter u{κ1,κ2,…,κr}(2) algebra is introduced. Finite unitary representations are investigated. This polynomial algebra reduces via a contraction procedure to the generalized Weyl–Heisenberg algebra 𝒜{κ1,κ2,…,κr} [M. Daoud and M. Kibler, J. Phys. A: Math. Theor.45 (2012) 244036]. A pair of nonlinear (quadratic) bosons of type 𝒜κ ≡ 𝒜{κ1=κ,κ2=0,…,κr=0} is used to construct, à la Schwinger, a one parameter family of (cubic) uκ(2) algebra. The corresponding Hilbert space is constructed. The analytical Bargmann representation is also presented.
Study of Omnidirectional Reflection Bandgap Extension in One-Dimensional Quasi-Periodic Metallic Photonic Crystal
Authors: Xiao Xuyang , Chen Runping
Published: May 2015

The reflection properties of light wave propagation in one-dimensional quasi-periodic metallic photonic crystal (PC) are comprehensively analyzed by transfer matrix method. In this work, we form a Fibonacci sequence quasi-periodic PC composed of metal and dielectric. The results demonstrate that the reflection stop band is strongly dependent on the periodic structure, metal thickness and incident angle. For this structure, the reflection stop band ranges from the visible light region to near-infrared region. Compared with the periodic metallic PC, the reflection stop bandwidth of our structure is wider. When the metal thickness increases, the reflection stop band is significantly enlarged. Furthermore, the reflection stop bandwidth slowly gets narrow and shifts to short wavelength region with the increase of incidence angle. Considering TE and TM wave at all incident angles, there is an omnidirectional reflection bandgap with width of 241nm for our investigated quasi-periodic metal PC.
Two-dimensional finite element model to study temperature distribution in peripheral regions of extended spherical human organs involving uniformly perfused tumors
Authors: Makrariya Akshara , Adlakha Neeru
Published: May 2015

Temperature as an indicator of tissue response is widely used in clinical applications. In view of above a problem of temperature distribution in peripheral regions of extended spherical organs of a human body like, human breast involving uniformly perfused tumor is investigated in this paper. The human breast is assumed to be spherical in shape with upper hemisphere projecting out from the trunk of the body and lower hemisphere is considered to be a part of the body core. The outer surface of the breast is assumed to be exposed to the environment from where the heat loss takes place by conduction, convection, radiation and evaporation. The heat transfer from core to the surface takes place by thermal conduction and blood perfusion. Also metabolic activity takes place at different rates in different layers of the breast. An elliptical-shaped tumor is assumed to be present in the dermis region of human breast. A finite element model is developed for a two-dimensional steady state case incorporating the important parameters like blood flow, metabolic activity and thermal conductivity. The triangular ring elements are employed to discretize the region. Appropriate boundary conditions are framed using biophysical conditions. The numerical results are used to study the effect of tumor on temperature distribution in the region.
Can an earthquake of M
w
∼9 occur in the Himalayan region?
Authors: Gupta H. K. , Gahalaut V. K.
Published: May 2015

It has been suggested that all of the Earth's subduction zones are capable of producing an M
w
∼9 earthquake. Such a possibility has also been suggested for the Himalayan collisional arc. We examined recent and historical earthquakes in the Himalayan region and suggest that, in the past few hundred years, only great earthquakes (M
w
∼8) have occurred in the region, the largest being the 1950 Assam earthquake with M
w
8.6. Several aseismic ridges segment the Himalayan arc and these appear to have limited the extent of rupture in earthquakes of the past 200 years. There is also evidence of distributed deformation and out-of-sequence thrusting, where only part of the detachment participates in the accommodation of the convergence. We concluded that, although it is unlikely that an M
w
∼9 earthquake could occur in the Himalaya, from the hazard point of view a great earthquake of M
w
∼8 anywhere along the Himalayan arc could kill about one million people in the Himalaya and adjoining Indo-Ganga plains. As an example, a scenario developed for a hypothetical M
w
8 earthquake occurring in the middle of the night at Mandi, close to the epicentre of the 1905 Kangra earthquake, predicts an estimated loss of one million human lives.
Lipotoxic Stress Induces Pancreaticβ-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System
Authors: Litwak Sara A. , Wali Jibran A. , Pappas Evan G. , Saadi Hamdi , Stanley William J. , Varanasi L. Chitra , Kay Thomas W. H. , Thomas Helen E. , Gurzov Esteban N.
Published: May 2015

Pancreaticβ-cell loss induced by saturated free fatty acids (FFAs) is believed to contribute to type 2 diabetes. Previous studies have shown induction of endoplasmic reticulum (ER) stress, increased ubiquitinated proteins, and deregulation of the Bcl-2 family in the pancreas of type 2 diabetic patients. However, the precise mechanism ofβ-cell death remains unknown. In the present study we demonstrate that the FFA palmitate blocks the ubiquitin-proteasome system (UPS) and causes apoptosis through induction of ER stress and deregulation of Bcl-2 proteins. We found that palmitate and the proteasome inhibitor MG132 induced ER stress inβ-cells, resulting in decreased expression of the prosurvival proteins Bcl-2, Mcl-1, and Bcl-XL, and upregulation of the prodeath BH3-only protein PUMA. On the other hand, pharmacological activation of the UPS by sulforaphane ameliorated ER stress, upregulated prosurvival Bcl-2 proteins, and protectedβ-cells from FFA-induced cell death. Furthermore, transgenic overexpression of Bcl-2 protected islets from FFA-induced cell deathin vitroand improved glucose-induced insulin secretionin vivo. Together our results suggest that targeting the UPS and Bcl-2 protein expression may be a valuable strategy to preventβ-cell demise in type 2 diabetes.
The Value of Circulating Nogo-B for Evaluating Hepatic Functional Reserve in Patients with Cirrhosis
Authors: Wen Maoyao , Men Ruoting , Yang Zongze , Dan Xuelian , Wu Wenchao , Liu Xiaojing , Yang Li
Published: May 2015

Objective. To examine Nogo-B in liver tissues and plasma of patients with liver cirrhosis and associate them with various clinical parameters.Materials and Methods. Nogo-B protein expression was examined by immunohistochemistry in 24 human fibrotic/cirrhotic liver specimens and 10 healthy controls. We determined plasma Nogo-B levels by enzyme-linked immunosorbent assay in 301 patients with liver cirrhosis and 153 healthy controls, and then analyzed various clinical parameters.Results. Nogo-B was mainly expressed in nonparenchymal cells in the liver and was marked increased in liver with significant fibrosis/cirrhosis compared to controls. Moreover, Metavir F4 showed a higher level of expression than F2. Plasma Nogo-B levels were significantly higher in cirrhotic patients than in healthy controls and were the highest in Child-Pugh class C patients. Plasma Nogo-B levels were positively correlated with Child-Pugh scores. However, there was no relationship between plasma Nogo-B levels and etiology of liver diseases, ALT, AST, platelet counts, and the severity of esophagogastric varices.Conclusions. Nogo-B is mainly expressed in hepatic nonparenchymal cells and is present in plasma. Abnormally high plasma levels of Nogo-B are associated with hepatic cirrhosis and Child-Pugh score, but not correlated with the grade of liver inflammation or portal hypertension. Plasma Nogo-B may be a novel surrogate marker to reflect liver function reserve.
Visceral Kaposi’s Sarcoma Presenting as Upper Gastrointestinal Bleeding
Authors: Hauser Naomi , McKenzie Devon , Fonseca Xavier , Orsini Jose
Published: May 2015

Since the advent of highly active antiretroviral therapy (HAART), the incidence of acquired immunodeficiency syndrome- (AIDS-) related Kaposi’s sarcoma (KS) has decreased dramatically. While cutaneous KS is the most common and well-known manifestation, knowledge of alternative sites such as the gastrointestinal (GI) tract is important. GI-KS is particularly dangerous because of its potential for serious complications including perforation, obstruction, or bleeding. We report a rare case of GI-KS presenting as upper GI bleeding in a human immunodeficiency virus- (HIV-) infected transgendered individual. Prompt diagnosis and early initiation of therapy are the cornerstones for management of this potentially severe disease.
A Case Report of Long-Term Survival following Hepatic Arterial Infusion ofL-Folinic Acid Modulated 5-Fluorouracil Combined with Intravenous Irinotecan and Cetuximab Followed by Hepatectomy in a Patient with Initially Unresectable Colorectal Liver Metastases
Authors: Van Bael Kobe , Jansen Yanina , Seremet Teofila , Engels Benedikt , Delvaux Georges , Neyns Bart
Published: May 2015

A 43-year-old women admitted to our hospital for weight loss, anorexia, and abdominal pain was diagnosed with sigmoid neoplasm and multiple bilobar liver metastases. This patient received six cycles of systemic FOLFOX prior to a laparoscopically assisted anterior resection of the rectosigmoid for a poorly differentiated invasive adenocarcinoma T2N2M1, K-RAS negative (wild type). Hepatic arterial infusion (HAI) ofL-folinic acid modulated 5-fluorouracil (LV/5-FU) with intravenous (iv) irinotecan (FOLFIRI) and cetuximab as adjuvant therapy resulted in a complete metabolic response (CR) with CEA normalization. A right hepatectomy extended to segment IV was performed resulting in (FDG-)PET negative remission for 7 months. Solitary intrahepatic recurrence was effectively managed by local radiofrequent ablation following 6c FOLFIRI plus cetuximab iv. Multiple lung lesions and recurrence of pulmonary and local lymph node metastases were successfully treated with fractionated stereotactic radiotherapy (50 Gy) and iv LV/5-FU/oxaliplatin (FOLFOX) plus cetuximab finally switched to panitumumab with CR as a result. At present the patient is in persistent complete remission of her stage IV colorectal cancer, more than 5 years after initial diagnosis of the advanced disease. Multidisciplinary treatment with HAI of chemotherapy (LV/5-FU + CPT-11) plus EGFR-inhibitor can achieve CR of complex unresectable LM and can even result in hepatectomy with possible long-term survival.
Stability of Nonhyperbolic Equilibrium Solution of Second Order Nonlinear Rational Difference Equation
Authors: Atawna S. , Abu-Saris R. , Ismail E. S. , Hashim I.
Published: May 2015

This is a continuation part of our investigation in which the second order nonlinear rational difference equation xn+1=(α+βxn+γxn-1)/(A+Bxn+Cxn-1), n=0,1,2,…, where the parameters A≥0 and B, C, α, β, γ are positive real numbers and the initial conditions x-1, x0 are nonnegative real numbers such that A+Bx0+Cx-1>0, is considered. The first part handled the global asymptotic stability of the hyperbolic equilibrium solution of the equation. Our concentration in this part is on the global asymptotic stability of the nonhyperbolic equilibrium solution of the equation.
Antioxidant Activity and Total Phenolic and Flavonoid Content of Various Solvent Extracts fromIn VivoandIn VitroGrownTrifolium pratenseL. (Red Clover)
Authors: Khorasani Esmaeili Arash , Mat Taha Rosna , Mohajer Sadegh , Banisalam Behrooz
Published: May 2015

In the present study the extracts ofin vivoandin vitrogrown plants as well as callus tissue of red clover were tested for their antioxidant activities, using different extraction solvent and different antioxidant assays. The total flavonoid and phenolic contents as well as extraction yield of the extracts were also investigated to determine their correlation with the antioxidant activity of the extracts. Among all the tested extracts the highest amounts of total phenolic and total flavonoids content were found in methanol extract ofin vivogrown plants. The antioxidant activity of tested samples followed the orderin vivoplant extract > callus extract >in vitroextract. The highest reducing power, 2,2-azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical scavenging, and chelating power were found in methanol extracts ofin vivogrown red clover, while the chloroform fraction ofin vivogrown plants showed the highest 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, superoxide anion radical scavenging and hydrogen peroxide scavenging compared to the other tested extracts. A significant correlation was found between the antioxidant activity of extracts and their total phenolic and total flavonoid content. According to the findings, the extract ofin vitroculture of red clover especially the callus tissue possesses a comparable antioxidant activity to thein vivocultured plants’ extract.
Estimation of Evolutionary Spectra of Monitored Seismic Ground Motions by Transformation of Correlation Functions
Authors: Xu Zhifeng , Li Li , Hu Liang
Published: May 2015

Spatially varying seismic ground motions recorded by distributed structural health monitoring systems (SHMS) can be used to improve the performances of civil engineering structures, necessitating estimation of the evolutionary power spectral density as an indispensable procedure for utilizing records of SHMS. This paper proposes a method for the estimation of evolutionary power spectral density of a nonstationary process by transforming the correlation functions of its sample time histories. First, the background of the theory of evolutionary power spectral density is reviewed in detail. Relationship between the EPSD and the correlation function of a reference stationary process is then established. Formulas are derived for estimating this correlation function directly from nonstationary sample time histories so that the EPSD can be obtained. The implementation procedure of the proposed method is also detailed. Finally, a numerical example is presented, which validates the proposed method, demonstrates its application for SHMS, and displays its capabilities by comparison with the traditional method.
Facial Characteristics and Olfactory Dysfunction: Two Endophenotypes Related to Nonsyndromic Cleft Lip and/or Palate
Authors: Roosenboom J. , Saey I. , Peeters H. , Devriendt K. , Claes P. , Hens G.
Published: May 2015

Evidence exists for the presence of a specific facial phenotype in nonaffected first-degree relatives of persons with CL/P. An increased risk for olfactory dysfunction has also been reported in CL/P-relatives. These phenotypic features can probably be explained via the presence of CL/P-related susceptibility genes. We aimed at confirming the occurrence of these endophenotypic traits in first-degree CL/P-relatives, and we investigated the link between the facial phenotype and the smell capacity in this group. We studied the facial morphology of 88 nonaffected first-degree relatives of patients with CL/P and 33 control subjects without family history of facial clefting by 3D surface imaging and a spatially dense analysis of the images. Smell testing was performed in 30 relatives and compared with 23 control subjects. Nonaffected relatives showed midface retrusion, hypertelorism, and olfactory dysfunction, compared to controls. In addition, we show for the first time that olfactory dysfunction in relatives is correlated to a smaller upper nasal region. This might be explained by a smaller central olfactory system. The different facial morphology in the relatives with olfactory impairment as compared to the total group may be an illustration of the contribution of different genetic backgrounds to the occurrence of CL/P via different biological pathways.
Approximative Compactness and Radon-Nikodym Property inw∗Nearly Dentable Banach Spaces and Applications
Authors: Shang Shaoqiang , Cui Yunan
Published: May 2015

Authors definew∗nearly dentable Banach space. Authors study Radon-Nikodym property, approximative compactness and continuity metric projector operator inw∗nearly dentable space. Moreover, authors obtain some examples ofw∗nearly dentable space in Orlicz function spaces. Finally, by the method of geometry of Banach spaces, authors give important applications ofw∗nearly dentability in generalized inverse theory of Banach space.
Microcystins Induces Vascular Inflammation in Human Umbilical Vein Endothelial Cells via Activation of NF‐κB
Authors: Shi Jun , Zhou Jie , Zhang Min
Published: May 2015

Microcystins (MCs) produced by toxic cyanobacteria cause serious water pollution and public health hazard to humans and animals. However, direct molecular mechanisms of MC‐LR in vascular endothelial cells (ECs) have not been understood yet. In this study, we investigated whether MC‐LR induces vascular inflammatory process in cultured human umbilical vein endothelial cells (HUVECs). Our data demonstrated that MC‐LR decreased HUVECs proliferation and tube formation and enhanced apoptosis. MC‐LR also induced intracellular reactive oxygen species formation (ROS) in HUVECs. The MC‐LR directly stimulated phosphorylation of NF‐κB. Furthermore, MC‐LR also increased cell adhesion molecules (ICAM‐1 and VCAM‐1) expression in HUVECs. Taken together, the present data suggested that MC‐LR induced vascular inflammatory process, which may be closely related to the oxidative stress, NF‐κB activation, and cell adhesion molecules expression in HUVECs. Our findings may highlight that MC‐LR causes potential damage to blood vessels.
Drug Redeployment to Kill Leukemia and Lymphoma Cells by Disrupting SCD1-Mediated Synthesis of Monounsaturated Fatty Acids
Authors: Southam Andrew D. , Khanim Farhat L. , Hayden Rachel E. , Constantinou Julia K. , Koczula Katarzyna M. , Michell Robert H. , Viant Mark R. , Drayson Mark T. , Bunce Chris M.
Published: May 2015

The redeployed drug combination of bezafibrate and medroxyprogesterone acetate (designated BaP) has potent in vivo anticancer activity in acute myelogenous leukemia (AML) and endemic Burkitt lymphoma (eBL) patients; however, its mechanism-of-action is unclear. Given that elevated fatty acid biosynthesis is a hallmark of many cancers and that these drugs can affect lipid metabolism, we hypothesized that BaP exerts anticancer effects by disrupting lipogenesis. We applied mass spectrometry–based lipidomics and gene and protein expression measurements of key lipogenic enzymes [acetyl CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), and stearoyl CoA desaturase 1 (SCD1)] to AML and eBL cell lines treated with BaP. BaP treatment decreased fatty acid and phospholipid biosynthesis from 13C D-glucose. The proportion of phospholipid species with saturated and monounsaturated acyl chains was also decreased after treatment, whereas those with polyunsaturated chains increased. BaP decreased SCD1 protein levels in each cell line (0.46- to 0.62-fold; P < 0.023) and decreased FASN protein levels across all cell lines (0.87-fold decrease; P = 1.7 × 10−4). Changes to ACC1 protein levels were mostly insignificant. Supplementation with the SCD1 enzymatic product, oleate, rescued AML and e-BL cells from BaP cell killing and decreased levels of BaP-induced reactive oxygen species, whereas supplementation with the SCD1 substrate (and FASN product), palmitate, did not rescue cells. In conclusion, these data suggest that the critical anticancer actions of BaP are decreases in SCD1 levels and monounsaturated fatty acid synthesis. To our knowledge, this is the first time that clinically available antileukemic and antilymphoma drugs targeting SCD1 have been reported. Cancer Res; 75(12); 2530–40. ©2015 AACR.
Functional Variants in Notch Pathway Genes NCOR2, NCSTN, and MAML2 Predict Survival of Patients with Cutaneous Melanoma
Authors: Zhang Weikang , Liu Hongliang , Liu Zhensheng , Zhu Dakai , Amos Christopher I. , Fang Shenying , Lee Jeffrey E. , Wei Qingyi
Published: May 2015

Background: The Notch signaling pathway is constitutively activated in human cutaneous melanoma to promote growth and aggressive metastatic potential of primary melanoma cells. Therefore, genetic variants in Notch pathway genes may affect the prognosis of cutaneous melanoma patients.

Methods: We identified 6,256 SNPs in 48 Notch genes in 858 cutaneous melanoma patients included in a previously published cutaneous melanoma genome-wide association study dataset. Multivariate and stepwise Cox proportional hazards regression and false-positive report probability corrections were performed to evaluate associations between putative functional SNPs and cutaneous melanoma disease-specific survival. Receiver operating characteristic curve was constructed, and area under the curve was used to assess the classification performance of the model.

Results: Four putative functional SNPs of Notch pathway genes had independent and joint predictive roles in survival of cutaneous melanoma patients. The most significant variant was NCOR2 rs2342924 T>C (adjusted HR, 2.71; 95% confidence interval, 1.73–4.23; Ptrend = 9.62 × 10−7), followed by NCSTN rs1124379 G>A, NCOR2 rs10846684 G>A, and MAML2 rs7953425 G>A (Ptrend = 0.005, 0.005, and 0.013, respectively). The receiver operating characteristic analysis revealed that area under the curve was significantly increased after adding the combined unfavorable genotype score to the model containing the known clinicopathologic factors.

Conclusions: Our results suggest that SNPs in Notch pathway genes may be predictors of cutaneous melanoma disease-specific survival.

Impact: Our discovery offers a translational potential for using genetic variants in Notch pathway genes as a genotype score of biomarkers for developing an improved prognostic assessment and personalized management of cutaneous melanoma patients. Cancer Epidemiol Biomarkers Prev; 24(7); 1101–10. ©2015 AACR.
Creation of a Human Secretome: A Novel Composite Library of Human Secreted Proteins: Validation Using Ovarian Cancer Gene Expression Data and a Virtual Secretome Array
Authors: Vathipadiekal Vinod , Wang Victoria , Wei Wei , Waldron Levi , Drapkin Ronny , Gillette Michael , Skates Steven , Birrer Michael
Published: May 2015

Purpose: To generate a comprehensive “Secretome” of proteins potentially found in the blood and derive a virtual Affymetrix array. To validate the utility of this database for the discovery of novel serum-based biomarkers using ovarian cancer transcriptomic data.

Experimental Design: The secretome was constructed by aggregating the data from databases of known secreted proteins, transmembrane or membrane proteins, signal peptides, G-protein coupled receptors, or proteins existing in the extracellular region, and the virtual array was generated by mapping them to Affymetrix probeset identifiers. Whole-genome microarray data from ovarian cancer, normal ovarian surface epithelium, and fallopian tube epithelium were used to identify transcripts upregulated in ovarian cancer.

Results: We established the secretome from eight public databases and a virtual array consisting of 16,521 Affymetrix U133 Plus 2.0 probesets. Using ovarian cancer transcriptomic data, we identified candidate blood-based biomarkers for ovarian cancer and performed bioinformatic validation by demonstrating rediscovery of known biomarkers including CA125 and HE4. Two novel top biomarkers (FGF18 and GPR172A) were validated in serum samples from an independent patient cohort.

Conclusions: We present the secretome, comprising the most comprehensive resource available for protein products that are potentially found in the blood. The associated virtual array can be used to translate gene-expression data into cancer biomarker discovery. A list of blood-based biomarkers for ovarian cancer detection is reported and includes CA125 and HE4. FGF18 and GPR172A were identified and validated by ELISA as being differentially expressed in the serum of ovarian cancer patients compared with controls. Clin Cancer Res; 21(21); 4960–9. ©2015 AACR.
Inhibition of Survivin with YM155 Induces Durable Tumor Response in Anaplastic Thyroid Cancer
Authors: Mehta Amit , Zhang Lisa , Boufraqech Myriem , Liu-Chittenden Yi , Zhang Yaqin , Patel Dhaval , Davis Sean , Rosenberg Avi , Ylaya Kris , Aufforth Rachel , Li Zhuyin , Shen Min , Kebebew Electron
Published: May 2015

Purpose: Anaplastic thyroid cancer (ATC) is a rare but lethal malignancy without any effective therapy. The aim of this study is to use a high-throughput drug library screening to identify a novel therapeutic agent that targets dysregulated genes/pathways in ATC.

ExperimentalDesign: We performed quantitative high-throughput screening (qHTS) in ATC cell lines using a compound library of 3,282 drugs. Dysregulated genes in ATC were analyzed using genome-wide expression analysis and immunohistochemistry in human ATC tissue samples and ATC cell lines. In vitro and in vivo studies were performed for determining drug activity, effectiveness of targeting, and the mechanism of action.

Results: qHTS identified 100 active compounds in three ATC cell lines. One of the most active agents was the first-in-class survivin inhibitor YM155. Genome-wide expression analysis and immunohistochemistry showed overexpression of survivin in human ATC tissue samples, and survivin was highly expressed in all ATC cell lines tested. YM155 significantly inhibited ATC cellular proliferation. Mechanistically, YM155 inhibited survivin expression in ATC cells. Furthermore, YM155 treatment reduced claspin expression, which was associated with S-phase arrest in ATC cells. In vivo, YM155 significantly inhibited growth and metastases and prolonged survival.

Conclusions: Our data show that YM155 is a promising anticancer agent for ATC and that its target, survivin, is overexpressed in ATC. Our findings support the use of YM155 in clinical trials as a therapeutic option in advanced and metastatic ATC. Clin Cancer Res; 21(18); 4123–32. ©2015 AACR.
Differential Expression of Immune-Regulatory Genes Associated with PD-L1 Display in Melanoma: Implications for PD-1 Pathway Blockade
Authors: Taube Janis M. , Young Geoffrey D. , McMiller Tracee L. , Chen Shuming , Salas January T. , Pritchard Theresa S. , Xu Haiying , Meeker Alan K. , Fan Jinshui , Cheadle Chris , Berger Alan E. , Pardoll Drew M. , Topalian Suzanne L.
Published: May 2015

Purpose: Blocking the immunosuppressive PD-1/PD-L1 pathway has antitumor activity in multiple cancer types, and PD-L1 expression on tumor cells and infiltrating myeloid cells correlates with the likelihood of response. We previously found that IFNG (interferon-gamma) was overexpressed by tumor-infiltrating lymphocytes in PD-L1+ versus PD-L1(−) melanomas, creating adaptive immune resistance by promoting PD-L1 display. This study was undertaken to identify additional factors in the PD-L1+ melanoma microenvironment coordinately contributing to immunosuppression.

Experimental Design: Archived, formalin-fixed paraffin-embedded melanoma specimens were assessed for PD-L1 protein expression at the tumor cell surface with IHC. Whole-genome expression analysis, quantitative (q)RT-PCR, IHC, and functional in vitro validation studies were used to assess factors differentially expressed in PD-L1+ versus PD-L1(−) melanomas.

Results: Functional annotation clustering based on whole-genome expression profiling revealed pathways upregulated in PD-L1+ melanomas, involving immune cell activation, inflammation, and antigen processing and presentation. Analysis by qRT-PCR demonstrated overexpression of functionally related genes in PD-L1+ melanomas, involved in CD8+ T-cell activation (CD8A, IFNG, PRF1, and CCL5), antigen presentation (CD163, TLR3, CXCL1, and LYZ), and immunosuppression [PDCD1 (PD-1), CD274 (PD-L1), and LAG3, IL10]. Functional studies demonstrated that some factors, including IL10 and IL32-gamma, induced PD-L1 expression on monocytes but not tumor cells.

Conclusions: These studies elucidate the complexity of immune checkpoint regulation in the tumor microenvironment, identifying multiple factors likely contributing to coordinated immunosuppression. These factors may provide tumor escape mechanisms from anti–PD-1/PD-L1 therapy, and should be considered for cotargeting in combinatorial immunomodulation treatment strategies. Clin Cancer Res; 21(17); 3969–76. ©2015 AACR.
Increasing Efforts to Reduce Cervical Cancer through State-Level Comprehensive Cancer Control Planning
Authors: Meyerson Beth E. , Zimet Gregory D. , Multani Gurprit S. , Levell Caleb , Lawrence Carrie A. , Smith Jennifer S.
Published: May 2015

Reducing cervical cancer disparities in the United States requires intentional focus on structural barriers such as systems and policy that impact access to human papillomavirus (HPV) vaccination, cervical cancer screening, and treatment. Such changes are difficult and often politicized. State comprehensive cancer control (CCC) plans are vehicles that, if designed well, can help build collective focus on structural changes. Study objectives were to identify the prioritization of cervical cancer in state CCC plans, the conceptualization of HPV within these plans, and the focus of plans on structural changes to reduce cervical cancer disparities. Data were gathered by systematic content analysis of CCC plans from 50 states and the District of Columbia from February–June 2014 for evidence of cervical cancer prioritization, conceptualization of HPV, and focus on structural barriers to cervical cancer vaccination, screening or treatment. Findings indicate that prioritization of cervical cancer within state CCC plans may not be a strong indicator of state efforts to reduce screening and treatment disparities. While a majority of plans reflected scientific evidence that HPV causes cervical and other cancers, they did not focus on structural elements impacting access to evidence-based interventions. Opportunities exist to improve state CCC plans by increasing their focus on structural interventions that impact cervical cancer prevention, detection, and treatment, particularly for the 41% of plans ending in 2015 and the 31% ending between 2016 and 2020. Future studies should focus on the use of policy tools in state CCC plans and their application to cervical cancer prevention and treatment. Cancer Prev Res; 8(7); 636–41. ©2015 AACR.
Coexistence of Calcification, Intraplaque Hemorrhage and Lipid Core within the Asymptomatic Atherosclerotic Carotid Plaque: The Rotterdam Study
Authors: van den Bouwhuijsen Quirijn J.A. , Bos Daniel , Ikram M. Arfan , Hofman Albert , Krestin Gabriel P. , Franco Oscar H. , van der Lugt Aad , Vernooij Meike W.
Published: May 2015

Background: There is a growing amount of evidence suggesting that the composition of carotid atherosclerotic plaques may be of clinical relevance. Yet, little is known on the coexistence of potentially vulnerable and stabilizing components within asymptomatic plaques. Therefore, in this study we set out to investigate the coexistence of intraplaque calcification, hemorrhage and lipid core within the carotid artery using a multi-modality imaging approach. Methods: In 329 subjects from the population-based Rotterdam Study, all with ultrasound-confirmed carotid wall thickening, we performed a multi-detector CT and a high-resolution MRI of the carotid artery bifurcation at both sides. On the CT examinations, we quantified the volume of intraplaque calcification, and using the MRI examinations we rated the presence of intraplaque hemorrhage and of lipid core. In total, we investigated 611 carotid arteries with plaques. With logistic regression models we investigated the relationship of calcification volume - as a potential stabilizing component - with the presence of potential vulnerable components (intraplaque hemorrhage and lipid core) within each carotid plaque. We adjusted all analyses for age, sex and maximal plaque thickness. Next, we stratified on degree of stenosis (≤ or >30%) to evaluate effect modification by atherosclerotic burden. Results: We found that a larger calcification volume was associated with a higher prevalence of intraplaque hemorrhage, and a lower prevalence of lipid core (fully-adjusted odds ratio (OR) per standard deviation (SD) increase in calcification volume: 2.04 (95% confidence intervals (CI): 1.49; 2.78) and 0.72 (95% CI: 0.58; 0.90), respectively). Stratification on the degree of stenosis showed no difference in the association between calcification volume and hemorrhage over strata, while the relationship between a larger calcification volume and a lower prevalence of lipid seemed more pronounced in persons with a high degree of stenosis. Conclusions: In this population-based setting, we found that there is a complex relationship between calcification, intraplaque hemorrhage and lipid core within the carotid atherosclerotic plaque. Plaques with a higher load of calcification contain more often hemorrhagic components, but less often lipid core. Our results suggest that both in small and large plaques, intraplaque calcification may not be a stabilizing factor per se. These findings create an urge for conducting prospective studies investigating the interrelation of these different plaque components with regard to future cerebrovascular events.
Stroke-Risk Factors Differ between Rural and Urban Communities: Population Survey in Central Uganda
Authors: Nakibuuka Jane , Sajatovic Martha , Nankabirwa Joaniter , Furlan Anthony J. , Kayima James , Ddumba Edward , Katabira Elly , Byakika-Tusiime Jayne
Published: May 2015

Background: Socioeconomic transition is changing stroke risk factors in Sub-Saharan Africa. This study assessed stroke-risk factors and their associated characteristics in urban and rural Uganda. Methods: We surveyed 5,420 urban and rural participants and assessed the stroke-risk factor prevalence and socio-behavioural characteristics associated with risk factors. Results: Rural participants were older with higher proportions of men and fewer poor compared to urban areas. The most prevalent modifiable stroke-risk factors in all areas were hypertension (27.1% rural and 22.4% urban, p = 0.004), overweight and obesity (22.0% rural and 42% urban, p < 0.0001), and elevated waist hip ratio (25.8% rural and 24.1% urban, p = 0.045). Diabetes, smoking, physical inactivity, harmful alcohol consumption were found in ≤5%. Age, family history of hypertension, and waist hip ratio were associated with hypertension in all, while BMI, HIV were associated with hypertension only in urban dwellers. Sex and family history of hypertension were associated with BMI in all, while age, socio-economic status and diabetes were associated with BMI only in urban dwellers. Conclusions: The prevalence of stroke-risk factors of diabetes, smoking, inactivity and harmful alcohol consumption was rare in Uganda. Rural dwellers belonging to a higher age group tended to be with hypertension and elevated waist hip ratio. Unlike high-income countries, higher socioeconomic status was associated with overweight and obesity.
Patients’ and Providers’ Perspectives of a Polypill Strategy to Improve Cardiovascular Prevention in Australian Primary Health Care
Authors: Liu Hueiming , Massi Luciana , Laba Tracey-Lea , Peiris David , Usherwood Tim , Patel Anushka , Cass Alan , Eades Anne-Marie , Redfern Julie , Hayman Noel , Howard Kirsten , Brien Jo-anne , Jan Stephen
Published: May 2015

Background—

This study explores health provider and patient attitudes toward the use of a cardiovascular polypill as a health service strategy to improve cardiovascular prevention.

Methods and Results—

In-depth, semistructured interviews (n=94) were conducted with health providers and patients from Australian general practice, Aboriginal community-controlled and government-run Indigenous Health Services participating in a pragmatic randomized controlled trial evaluating a polypill-based strategy for high-risk primary and secondary cardiovascular disease prevention. Interview topics included polypill strategy acceptability, factors affecting adherence, and trial implementation. Transcribed interview data were analyzed thematically and interpretively. Polypill patients commented frequently on cost-savings, ease, and convenience of a daily-dosing pill. Most providers considered a polypill strategy to facilitate improved patient medication use. Indigenous Health Services providers and indigenous patients thought the strategy acceptable and beneficial for indigenous patients given the high disease burden. Providers noted the inflexibility of the fixed dose regimen, with dosages sometimes inappropriate for patients with complex management considerations. Future polypill formulations with varied strengths and classes of medications may overcome this barrier. Many providers suggested the polypill strategy, in its current formulations, might be more suited to high-risk primary prevention patients.

Conclusions—

The polypill strategy was generally acceptable to patients and providers in cardiovascular prevention. Limitations to provider acceptability of this particular polypill were revealed, as was a perception it might be more suitable for high-risk primary prevention patients, though future combinations could facilitate its use in secondary prevention. Participants suggested a polypill-based strategy as particularly appropriate for lowering the high cardiovascular burden in indigenous populations.

Clinical Trial Registration—

URL:
http://www.anzctr.org.au
. ANZCTRN: 12608000583347.
Pulmonary Congestion at Rest and Abnormal Ventilation During Exercise in Chronic Systolic Heart Failure
Authors: Malfatto Gabriella , Caravita Sergio , Giglio Alessia , Rossi Jessica , Perego Giovanni B. , Facchini Mario , Parati Gianfranco
Published: May 2015

Background

In patients with chronic heart failure, abnormal ventilation at cardiopulmonary testing (expressed by minute ventilation‐to‐carbon dioxide production, or
VE
/
VCO
2
slope, and resting end‐tidal
CO
2
pressure) may derive either from abnormal autonomic or chemoreflex regulation or from lung dysfunction induced by pulmonary congestion. The latter hypothesis is supported by measurement of pulmonary capillary wedge pressure, which cannot be obtained routinely but may be estimated noninvasively by measuring transthoracic conductance (thoracic fluid content 1/kΩ) with impedance cardiography.

Methods and Results

Preliminarily, in 9 patients undergoing invasive hemodynamics during cardiopulmonary testing, we demonstrated a significant relationship between
VE
/
VCO
2
slope and resting end‐tidal
CO
2
pressure with baseline and peak pulmonary capillary wedge pressure. Later, noninvasive hemodynamic evaluation by impedance cardiography was performed before cardiopulmonary testing in 190 patients with chronic systolic heart failure and normal lung function (aged 67±3 years, 71% with ischemia, ejection fraction 32±7%, 69% with implantable cardioverter‐defibrillator or cardiac resynchronization therapy). In this group, we determined the relationship between abnormal ventilation (
VE
/
VCO
2
slope and resting end‐tidal
CO
2
pressure) and transthoracic conductance. In the whole population, thoracic fluid content values were significantly related to
VE
/
VCO
2
slope (
R
=0.63,
P
<0.0001) and to resting end‐tidal
CO
2
pressure (
R
=−0.44,
P
<0.001).

Conclusions

In patients with chronic heart failure, abnormal ventilation during exercise may be related in part to pulmonary congestion, as detected by resting baseline impedance cardiography.