bluuebunny/crossref_metadata_2025 huggingface dataset:
Paraoxonase-1 Inhibits Oxidized Low-Density Lipoprotein-Induced Metabolic Alterations and Apoptosis in Endothelial Cells: A Nondirected Metabolomic Study
Authors: García-Heredia Anabel , Marsillach Judit , Rull Anna , Triguero Iris , Fort Isabel , Mackness Bharti , Mackness Michael , Shih Diana M. , Joven Jorge , Camps Jordi
Published: May 2013

We studied the influence of PON1 on metabolic alterations induced by oxidized LDL when incubated with endothelial cells. HUVEC cells were incubated with native LDL, oxidized LDL, oxidized LDL plus HDL from wild type mice, and oxidized LDL plus HDL from PON1-deficient mice. Results showed alterations in carbohydrate and phospholipid metabolism and increased apoptosis in cells incubated with oxidized LDL. These changes were partially prevented by wild type mouse HDL, but the effects were less effective with HDL from PON1-deficient mice. Our results suggest that PON1 may play a significant role in endothelial cell survival by protecting cells from alterations in the respiratory chain induced by oxidized LDL. These results extend current knowledge on the protective role of HDL and PON1 against oxidation and apoptosis in endothelial cells.
A Method for Simulating Burr Type III and Type XII Distributions through -Moments and -Correlations
Authors: Pant Mohan D. , Headrick Todd C.
Published: May 2013

This paper derives the Burr Type III and Type XII family of distributions in the contexts of univariate -moments and the -correlations. Included is the development of a procedure for specifying nonnormal distributions with controlled degrees of -skew, -kurtosis, and -correlations. The procedure can be applied in a variety of settings such as statistical modeling (e.g., forestry, fracture roughness, life testing, operational risk, etc.) and Monte Carlo or simulation studies. Numerical examples are provided to demonstrate that -moment-based Burr distributions are superior to their conventional moment-based analogs in terms of estimation and distribution fitting. Evaluation of the proposed procedure also demonstrates that the estimates of -skew, -kurtosis, and -correlation are substantially superior to their conventional product moment-based counterparts of skew, kurtosis, and Pearson correlations in terms of relative bias and relative efficiency—most notably when heavy-tailed distributions are of concern.
Evaluation of the Diagnostic Power of Thermography in Breast Cancer Using Bayesian Network Classifiers
Authors: Nicandro Cruz-Ramírez , Efrén Mezura-Montes , María Yaneli Ameca-Alducin , Enrique Martín-Del-Campo-Mena , Héctor Gabriel Acosta-Mesa , Nancy Pérez-Castro , Alejandro Guerra-Hernández , Guillermo de Jesús Hoyos-Rivera , Rocío Erandi Barrientos-Martínez
Published: May 2013

Breast cancer is one of the leading causes of death among women worldwide. There are a number of techniques used for diagnosing this disease: mammography, ultrasound, and biopsy, among others. Each of these has well-known advantages and disadvantages. A relatively new method, based on the temperature a tumor may produce, has recently been explored: thermography. In this paper, we will evaluate the diagnostic power of thermography in breast cancer using Bayesian network classifiers. We will show how the information provided by the thermal image can be used in order to characterize patients suspected of having cancer. Our main contribution is the proposal of a score, based on the aforementioned information, that could help distinguish sick patients from healthy ones. Our main results suggest the potential of this technique in such a goal but also show its main limitations that have to be overcome to consider it as an effective diagnosis complementary tool.
An Efficient Resource Management Protocol for Handling Small Resource in Wireless Sensor Networks
Authors: Cho Wan-Hee , Kim Jiho , Song Ohyoung
Published: May 2013

Wireless sensor nodes with single chips may have insufficient resources for certain applications. We propose a resource management protocol for applications with constrained resources to improve effectiveness by borrowing resources from a resource management server.
Thoracic Primitive Neuroectodermal Tumor: An Unusual Case and Literature Review
Authors: Kalkan Kubra Erol , Bilici Ahmet , Selcukbiricik Fatih , Unver Nurcan , Yuksel Mahmut
Published: May 2013

We describe herein a rare case of a primary primitive neuroectodermal tumor (PNET) in the mediastinum of a 75-year-old man. Grossly, the tumor was located in the left upper anterior mediastinum. Transcutaneous fine-needle biopsy (TCNB) revealed small round-cell proliferation. The expression immunohistochemical analysis was confirmed the diagnosis of PNET. He was successfully treated with chemotherapy and is alive with no sign of recurrence for 17 months after the diagnosis.
The Control of Mesenchymal Stromal Cell Osteogenic Differentiation through Modified Surfaces
Authors: Logan Niall , Brett Peter
Published: May 2013

Stem cells continue to receive widespread attention due to their potential to revolutionise treatments in the fields of both tissue engineering and regenerative medicine. Adult stem cells, specifically mesenchymal stromal cells (MSCs), play a vital role in the natural events surrounding bone healing and osseointegration through being stimulated to differentiate along their osteogenic lineage and in doing so, they form new cortical and trabecular bone tissue. Understanding how to control, manipulate, and enhance the intrinsic healing events modulated through osteogenic differentiation of MSCs by the use of modified surfaces and biomaterials could potentially advance the fields of both orthopaedics and dentistry. This could be by either using surface modification to generate greater implant stability and more rapid healing following implantation or the stimulation of MSCsex vivofor reimplantation. This review aims to gather publications targeted at promoting, enhancing, and controlling the osteogenic differentiation of MSCs through biomaterials, nanotopographies, and modified surfaces for use in implant procedures.
Weight-Selected Attribute Bagging for Credit Scoring
Authors: Li Jianwu , Wei Haizhou , Hao Wangli
Published: May 2013

Assessment of credit risk is of great importance in financial risk management. In this paper, we propose an improved attribute bagging method, weight-selected attribute bagging (WSAB), to evaluate credit risk. Weights of attributes are first computed using attribute evaluation method such as linear support vector machine (LSVM) and principal component analysis (PCA). Subsets of attributes are then constructed according to weights of attributes. For each of attribute subsets, the larger the weights of the attributes the larger the probabilities by which they are selected into the attribute subset. Next, training samples and test samples are projected onto each attribute subset, respectively. A scoring model is then constructed based on each set of newly produced training samples. Finally, all scoring models are used to vote for test instances. An individual model that only uses selected attributes will be more accurate because of elimination of some of redundant and uninformative attributes. Besides, the way of selecting attributes by probability can also guarantee the diversity of scoring models. Experimental results based on two credit benchmark databases show that the proposed method, WSAB, is outstanding in both prediction accuracy and stability, as compared to analogous methods.
Life-Threatening Rupture of a False Aneurysm after Femoral Arterial Catheterization: Unexpected Delay after a Common Procedure
Authors: Renner Julie , Pasquier Pierre , Falzone Elisabeth , Rozwadowski Faye , Mérat Stéphane
Published: May 2013

We report the case of a 79-year-old patient who presented with a femoral iatrogenic pseudoaneurysm of delayed and unusual onset with immediately life-threatening massive bleeding. Ultrasound is the method of choice for the diagnosis of pseudo aneurysm. If there is not spontaneous closure, ultrasound-guided compression repair, minimally invasive percutaneous treatments, and surgical repair are the three therapeutic options.
The Protective Effect of Fasudil on the Structure and Function of Cardiac Mitochondria from Rats with Type 2 Diabetes Induced by Streptozotocin with a High-Fat Diet Is Mediated by the Attenuation of Oxidative Stress
Authors: Guo Rong , Liu Baoxin , Zhou Shunping , Zhang Buchun , Xu Yawei
Published: May 2013

Dysfunction of cardiac mitochondria appears to play a substantial role in cardiomyopathy or myocardial dysfunction and is a promising therapeutic target for many cardiovascular diseases. We investigated the effect of the Rho/Rho-associated protein kinase (ROCK) inhibitor fasudil on cardiac mitochondria from rats in which diabetes was induced by a combination of streptozotocin (STZ) and a sustained high-fat diet. Eight weeks after diabetes was induced by a single intraperitoneal injection of 50 mg/kg STZ followed by a sustained high-fat diet, either fasudil (5 mg/kg bid) or equivalent volumes of saline (control) were administered over four weeks. Fasudil significantly protected against the histopathologic changes of cardiac mitochondria in diabetic rats. Fasudil significantly reduced the abundances of the Rho A, ROCK 1, and ROCK 2 proteins, restored the activities of succinate dehydrogenase (SDH) and monoamine oxidase (MAO) in cardiac mitochondria, inhibited the opening of the mitochondrial permeability transition pore, and decreased the total antioxidant capacity, as well as levels of malonyldialdehyde, hydroxy radical, reduced glutathione, and superoxide dismutase in heart. Fasudil improved the structures of cardiac mitochondria and increased both SDH and MAO activities in cardiac mitochondria. These beneficial effects may be associated with the attenuation of oxidative stress caused by fasudil treatment.
Placental Vacuolar ATPase Function Is a Key Link between Multiple Causes of Preeclampsia
Authors: Zhang Dongxin , Ye Duyun , Chen Hongxiang
Published: May 2013

Preeclampsia, a relatively common pregnancy disorder, is one of the major causes of maternal and fetal morbidity and mortality. Despite numerous research, the etiology of this syndrome remains not well understood as the pathogenesis of preeclampsia is complex, involving interaction between genetic, immunologic, and environmental factors. Preeclampsia, originating in placenta abnormalities, is induced by the circulating factors derived from the abnormal placenta. Recent work has identified various molecular mechanisms related to placenta development, including renin-angiotensin system, 1, 25-dihydroxyvitamin D, and lipoxin A4. Interestingly, advances suggest that vacuolar ATPase, a key molecule in placentation, is closely associated with them. Therefore, this intriguing molecule may represent an important link between various causes of preeclampsia. Here, we review that vacuolar ATPase works as a key link between multiple causes of preeclampsia and discuss the potential molecular mechanisms. The novel findings outlined in this review may provide promising explanations for the causation of preeclampsia and a rationale for future therapeutic interventions for this condition.
First Description of a Primitive Neuroectodermal Tumor Arising in the Nose
Authors: Rizk Habib , Khazzaka Aline , Sebaaly Amer , Cherfan Maguy , Tomb Roland , Sarkis Riad
Published: May 2013

We report the case of a 12-year-old girl, who consulted us with one-year history of an 8 mm nose lesion that was painless and firm upon palpation. The lesion was resected conservatively. Immunohistochemistry was in favor of a primitive neuroectodermal tumor (PNET)/Ewing’s sarcoma lesion, excluding epithelial, lymphoid, and other tumors. After a second resection, our patient was referred to chemotherapy and has already undergone 9 cycles out of 14. The patient is to date with no evidence of persistent or recurrent disease. To our knowledge, this is the first description of a PNET arising in the nose.
Scattering Analysis of a Compact Dipole Array with Series and Parallel Feed Network including Mutual Coupling Effect
Authors: Sneha H. L. , Singh Hema , Jha R. M.
Published: May 2013

The current focus in defense arena is towards the stealth technology with an emphasis to control the radar cross-section (RCS). The scattering from the antennas mounted over the platform is of prime importance especially for a low-observable aerospace vehicle. This paper presents the analysis of the scattering cross section of a uniformly spaced linear dipole array. Two types of feed networks, that is, series and parallel feed networks, are considered. The total RCS of phased array with either kind of feed network is obtained by following the signal as it enters through the aperture and travels through the feed network. The RCS estimation of array is done including the mutual coupling effect between the dipole elements in three configurations, that is, side-by-side, collinear, and parallel-in-echelon. The results presented can be useful while designing a phased array with optimum performance towards low observability.
Cone Beam Computed Tomography Evaluation of the Diagnosis, Treatment Planning, and Long-Term Followup of Large Periapical Lesions Treated by Endodontic Surgery: Two Case Reports
Authors: Shekhar Vijay , Shashikala K.
Published: May 2013

The aim of this case report is to present two cases where cone beam computed tomography (CBCT) was used for the diagnosis, treatment planning, and followup of large periapical lesions in relation to maxillary anterior teeth treated by endodontic surgery. Periapical disease may be detected sooner using CBCT, and their true size, extent, nature, and position can be assessed. It allows clinician to select the most relevant views of the area of interest resulting in improved detection of periapical lesions. CBCT scan may provide a better, more accurate, and faster method to differentially diagnose a solid (granuloma) from a fluid-filled lesion or cavity (cyst). In the present case report, endodontic treatment was performed for both the cases followed by endodontic surgery. Biopsy was done to establish the confirmatory histopathological diagnosis of the periapical lesions. Long-term assessment of the periapical healing following surgery was done in all the three dimensions using CBCT and was found to be more accurate than IOPA radiography. It was concluded that CBCT was a useful modality in making the diagnosis and treatment plan and assessing the outcome of endodontic surgery for large periapical lesions.
Nonlocal Adaptive Image Denoising Model
Authors: Sun Xiaoli , Xu Chen , Li Min
Published: May 2013

When denoising with the method of Weickert’s anisotropic diffusion equation, the textures and details will be compromised. A fidelity term is added to Weickert’s equation, and the coefficient of fidelity term will vary adaptively with the instant image, which makes the diffusion term and the fidelity term come to a better compromise. Otherwise, when deciding the edge directions, because of the strong smoothness of linear Gaussian function, a few other edge directions hiding in the main direction will be lost. To preserve these detailed edge directions, Gaussian kernel is substituted for nonlinear wavelet threshold. In addition, in order to preserve the textures and details as much as possible, a nonlocal diffusion tensor was introduced, and the two eigenvalues are reset by combining the two methods: edge-enhancing diffusion and coherence-enhancing diffusion. Experiments show that the new model has an obvious effect on preserving textures and details.
Power Optimization of Tilted Tomlinson-Harashima Precoder in MIMO Channels with Imperfect Channel State Information
Authors: Bizaki Hossein Khaleghi , Hojaghan Morteza Khaleghi , Razavizadeh Seyyed Mohammad
Published: May 2013

This paper concentrates on the designing of a robust Tomlinson-Harashima Precoder (THP) over multiple-input multiple-output (MIMO) channels in wireless communication systems with assumption of imperfect channel state information (CSI) at the transmitter side. With the assumption that the covariance matrix of channel estimation error is available at the transmitter side, we design a THP that presents robustness against channel uncertainties. In the proposed robust THP, the transmit power is further minimized by using the Tilted constellation concept. This power minimization reduces the interchannel Interference (ICI) between subchannels and, furthermore, recovers some part of the THP's power loss. The bit error rate (BER) of the proposed system is further improved by using a power loading technique. Finally, the simulation results compare the performance of our proposed robust THP with a conventional MIMO-THP.
Verification of Opacity and Diagnosability for Pushdown Systems
Authors: Kobayashi Koichi , Hiraishi Kunihiko
Published: May 2013

In control theory of discrete event systems (DESs), one of the challenging topics is the extension of theory of finite-state DESs to that of infinite-state DESs. In this paper, we discuss verification of opacity and diagnosability for infinite-state DESs modeled by pushdown automata (called here pushdown systems). First, we discuss opacity of pushdown systems and prove that opacity of pushdown systems is in general undecidable. In addition, a decidable class is clarified. Next, in diagnosability, we prove that under a certain assumption, which is different from the assumption in the existing result, diagnosability of pushdown systems is decidable. Furthermore, a necessary condition and a sufficient condition using finite-state approximations are derived. Finally, as one of the applications, we consider data integration using XML (Extensible Markup Language). The obtained result is useful for developing control theory of infinite-state DESs.
Collapse of a Relativistic Self-Gravitating Star with Radial Heat Flux: Impact of Anisotropic Stresses
Authors: Sharma Ranjan , Das Shyam
Published: May 2013

We develop a simple model for a self-gravitating spherically symmetric relativistic star which begins to collapse from an initially static configuration by dissipating energy in the form of radial heat flow. We utilize the model to show how local anisotropy affects the collapse rate and thermal behavior of gravitationally evolving systems.
Detection of Neoplastic Gastric Lesions Using Capsule Endoscopy: Pilot Study
Authors: Jun Byoung Yeon , Lim Chul-Hyun , Lee Wook Hyun , Kim Jin Su , Park Jae Myung , Lee In Seok , Kim Sang Woo , Choi Myung-Gyu
Published: May 2013

Objectives. Capsule endoscopy is relatively noninvasive method and its use extends from the small bowel to the esophagus and colon. The aim of this study was to evaluate the feasibility and acceptability of capsule endoscopy for neoplastic gastric lesions.Methods. Capsule endoscopy (Pillcam ESO) was performed within 48 hours of esophagogastroduodenoscopy for eight patients who were diagnosed with gastric cancers, the size of which were less than 4 cm and who presented written consent. Patients changed position in a specified designed sequence every 30 seconds after capsule ingestion. Position change was repeated with ingestion of an effervescent agent. The rate of detection of intragastric lesions, observation of normal gastric anatomy and patient satisfaction between capsule endoscopy and esophagogastroduodenoscopy were compared.Results. Capsule endoscopy found four out of eight gastric lesions. The gastroesophageal junction was observed in seven of the eight cases, pyloric ring in five of the eight cases, and gastric angle in four of the eight cases. The patient satisfaction assessment questionnaire rated capsule endoscopy significantly higher than upper endoscopy in all categories.Conclusions. Capsule endoscopy was less effective than esophagogastroduodenoscopy and showed limited value in this feasibility study.
The Use of Sumudu Transform for Solving Certain Nonlinear Fractional Heat-Like Equations
Authors: Atangana Abdon , Kılıçman Adem
Published: May 2013

We make use of the properties of the Sumudu transform to solve nonlinear fractional partial differential equations describing heat-like equation with variable coefficients. The method, namely, homotopy perturbation Sumudu transform method, is the combination of the Sumudu transform and the HPM using He’s polynomials. This method is very powerful, and professional techniques for solving different kinds of linear and nonlinear fractional differential equations arising in different fields of science and engineering.
What Are the Molecules Involved in Regulatory T-Cells Induction by Dendritic Cells in Cancer?
Authors: Ramos Rodrigo Nalio , Moraes Cristiano Jacob de , Zelante Bruna , Barbuto José Alexandre M.
Published: May 2013

Dendritic cells (DCs) are essential for the maintenance of homeostasis in the organism, and they do that by modulating lymphocyte priming, expansion, and response patterns according to signals they receive from the environment. The induction of suppressive lymphocytes by DCs is essential to hinder the development of autoimmune diseases but can be reverted against homeostasis when in the context of neoplasia. In this setting, the induction of suppressive or regulatory T cells contributes to the establishment of a state of tolerance towards the tumor, allowing it to grow unchecked by an otherwise functional immune system. Besides affecting its local environment, tumor also has been described as potent sources of anti-inflammatory/suppressive factors, which may act systemically, generating defects in the differentiation and maturation of immune cells, far beyond the immediate vicinity of the tumor mass. Cytokines, as IL-10 and TGF-beta, as well as cell surface molecules like PD-L1 and ICOS seem to be significantly involved in the redirection of DCs towards tolerance induction, and recent data suggest that tumor cells may, indeed, modulate distinct DCs subpopulations through the involvement of these molecules. It is to be expected that the identification of such molecules should provide molecular targets for more effective immunotherapeutic approaches to cancer.
Comparison of Efficiencies of Michigan Neuropathy Screening Instrument, Neurothesiometer, and Electromyography for Diagnosis of Diabetic Neuropathy
Authors: Mete Turkan , Aydin Yusuf , Saka Mustafa , Cinar Yavuz Halise , Bilen Sule , Yalcin Yavuz , Arli Berna , Berker Dilek , Guler Serdar
Published: May 2013

Aim. This study compares the effectiveness of Michigan Neuropathy Screening Instrument (MNSI), neurothesiometer, and electromyography (EMG) in detecting diabetic peripheral neuropathy in patients with diabetes type 2.Materials and Methods. 106 patients with diabetes type 2 treated at the outpatient clinic of Ankara Numune Education and Research Hospital Department of Endocrinology between September 2008 and May 2009 were included in this study. Patients were evaluated by glycemic regulation tests, MNSI (questionnaire and physical examination), EMG (for detecting sensorial and motor defects in right median, ulnar, posterior tibial, and bilateral sural nerves), and neurothesiometer (for detecting alterations in cold and warm sensations as well as vibratory sensations).Results. According to the MNSI score, there was diabetic peripheral neuropathy in 34 (32.1%) patients (score ≥2.5). However, when the patients were evaluated by EMG and neurothesiometer, neurological impairments were detected in 49 (46.2%) and 79 (74.5%) patients, respectively.Conclusion. According to our findings, questionnaires and physical examination often present lower diabetic peripheral neuropathy prevalence. Hence, we recommend that in the evaluation of diabetic patients neurological tests should be used for more accurate results and thus early treatment options to prevent neuropathic complications.
On the Geometry of the Movements of Particles in a Hamilton Space
Authors: Coken A. Ceylan , Ayhan Ismet
Published: May 2013

We studied on the differential geometry of the Hamilton space including trajectories of the motion of particles exposed to gravitational fields and the cotangent bundle.
Bovine Papillomavirus Type 2 Infection and Microscopic Patterns of Urothelial Tumors of the Urinary Bladder in Water Buffaloes
Authors: Maiolino Paola , Özkul Ayhan , Sepici-Dincel Aylin , Roperto Franco , Yücel Gözde , Russo Valeria , Urraro Chiara , Lucà Roberta , Riccardi Marita Georgia , Martano Manuela , Borzacchiello Giuseppe , Esposito Iolanda , Roperto Sante
Published: May 2013

Microscopic patterns of thirty-four urothelial tumors of the urinary bladder of water buffaloes from the Marmara and Black Sea Regions of Turkey are here described. All the animals grazed on lands rich in bracken fern. Histological diagnosis was assessed using morphological parameters recently suggested for the urinary bladder tumors of cattle. Papillary carcinoma was the most common neoplastic lesion (22/34) observed in this study, and low-grade carcinoma was more common (seventeen cases) than high-grade carcinoma (five cases). Papilloma, papillary urothelial neoplasm of low malignant potential (PUNLMP), and invasive carcinomas were less frequently seen. Carcinoma in situ (CIS) was often detected associated with some papillary and invasive carcinomas. De novo (primary) CIS was rare representing 3% of tumors of this series. A peculiar feature of the most urothelial tumors was the presence in the tumor stroma of immune cells anatomically organized in tertiary lymphoid organs (TLOs). Bovine papillomavirus type-2 (PV-2) E5 oncoprotein was detected by molecular and immunohistochemistry procedures. Early protein, E2, and late protein, L1, were also detected by immunohistochemical studies. Morphological and molecular findings show that BPV-2 infection contributes to the development of urothelial bladder carcinogenesis also in water buffaloes.
Characterization of Radium Sulphate
Authors: Hedström Hanna , Persson Ingmar , Skarnemark Gunnar , Ekberg Christian
Published: May 2013

This paper examines the crystal structure of radium sulphate and compares its structure to barium sulphate, strontium sulphate, and lead sulphate. The radium sulphate powder was measured by both powder X-ray diffraction and EXAFS. The unit cell was determined to be orthorhombic, belonging to thePnma(no. 62) space group with the cell parametersa=9.07 Å,b=5.52 Å,c=7.28 Å, andV=364.48 Å3. These data support the fact that radium sulphate is isostructural with barium, strontium, and lead sulphate. The bond distances were determined using EXAFS. The mean Ra–O and S–O bond distances were found to be 2.96(2) Å and 1.485(8) Å, respectively, and the Ra–O–S bond angle was127(2)∘. Findings of EXAFS data are quite consistent and support the XRD data. These findings show that it is possible for radium to coprecipitate with barium, strontium, and lead in sulphate media to form a substitutional solid solution.
Ludwig’s Angina: The Original Angina
Authors: Kassam Karim , Messiha Ashraf , Heliotis Manolis
Published: May 2013

Ludwig’s angina was first detailed by the German surgeon Wilhelm Friedrich von Ludwig in 1836. We present a case which needed awake fibreoptic intubation due to severe trismus and a prolonged period intubated in the Intensive Care Unit after incision and drainage of neck spaces and removal of his lower wisdom teeth. He was finally discharged a week after admission and followed up in the outpatient clinic. The case is presented with clinical photographs and a video of the fibreoptic intubation to illustrate the airway.
Lineage Relationship of Gleason Patterns in Gleason Score 7 Prostate Cancer
Authors: Kovtun Irina V. , Cheville John C. , Murphy Stephen J. , Johnson Sarah H. , Zarei Shabnam , Kosari Farhad , Sukov William R , Karnes R. Jeffrey , Vasmatzis George
Published: May 2013

Gleason score 7 (GS7) prostate cancer [tumors with both Gleason patterns 3 (GP3) and 4 (GP4)] portends a significantly more aggressive tumor than Gleason score 6 (GS6). It is, therefore, critical to understand the molecular relationship of adjacent GP3 and GP4 tumor cell populations and relate molecular abnormalities to disease progression. To decipher molecular relatedness, we used laser capture microdissection (LCM) and whole-genome amplification (WGA) to separately collect and amplify DNA from adjacent GP3 and GP4 cell populations from 14 cases of GS7 prostate cancer. We then carried out massively parallel mate-pair next generation sequencing (NGS) to examine the landscape of large chromosomal alterations. We identified four to 115 DNA breakpoints in GP3 and 17 to 480 in GP4. Our findings indicate that while GP3 and GP4 from the same tumor each possess unique breakpoints, they also share identical ones, indicating a common origin. Approximately 300 chromosomal breakpoints were localized to the regions affected in at least two tumors, whereas more than 3,000 were unique within the set of 14 tumors. TMPRSS2–ERG was the most recurrent rearrangement present in eight cases, in both GP3 and GP4. PTEN rearrangements were found in five of eight TMPRSS2–ERG fusion–positive cases in both GP3 and GP4. Hierarchical clustering analysis revealed that GP3 has greater breakpoint similarity to its partner GP4 compared with GP3 from different patients. We show evidence that LCM, WGA, and NGS of adjacent tumor regions provide an important tool in deciphering lineage relationships and discovering chromosomal alterations associated with tumor progression. Cancer Res; 73(11); 3275–84. ©2013 AACR.
Visualizing Inhibition of Nucleosome Mobility and Transcription by Cisplatin–DNA Interstrand Crosslinks in Live Mammalian Cells
Authors: Zhu Guangyu , Song Lina , Lippard Stephen J.
Published: May 2013

Cisplatin is a widely used anticancer drug that acts by binding DNA and causing the formation of intrastrand and interstrand (ICL) crosslinks, but the precise downstream effects of the latter damage are not well understood. In this study, we investigated the influence of cisplatin ICLs on synthetic nucleosomes that were platinated in a site-specific manner in vitro and on gene transcription in live mammalian cells. Nucleosome core particles that we constructed contained site-specific cisplatin 5′-d(G*pC)/5′-d(G*pC) ICLs, where the asterisk denotes the platinated nucleoside, to examine the influence of platinum lesions on the dynamic behavior of nucleosomes in solution. A cisplatin ICL, but not a 1,2-d(GpG) crosslink, significantly inhibited ATP-independent histone octamer-DNA sliding. We also used a novel linearization-recircularization strategy described here to synthesize mammalian expression vectors containing site-specific cisplatin ICLs. Plasmid vectors were tested in live mammalian cells to study the transcription inhibition effects of cisplatin ICLs in the context of two different repair backgrounds. Cisplatin ICLs inhibit transcription as effectively as 1,2-d(GpG) crosslinks. We determined that nucleotide excision repair plays a key role in the removal of cisplatin ICLs, acting in a replication-independent fashion. We also found that loss of mismatch repair function dramatically attenuates the transcription inhibition effects by cisplatin ICLs but not 1,2-d(GpG) intrastrand crosslinks. Our results revealed the unique properties of cisplatin ICLs on nucleosome mobility and on transcription, and they defined how these adducts act in a manner completely different from that used for cisplatin 1,2-d(GpG) crosslinks. These new findings provide direct support for a role of ICLs in the pharmacologic activities of cisplatin, despite the lower frequency of their formation. Cancer Res; 73(14); 4451–60. ©2013 AACR.
Synergistic Effects of Metformin Treatment in Combination with Gefitinib, a Selective EGFR Tyrosine Kinase Inhibitor, in LKB1 Wild-type NSCLC Cell Lines
Authors: Morgillo Floriana , Sasso Ferdinando Carlo , Della Corte Carminia Maria , Vitagliano Donata , D'Aiuto Elena , Troiani Teresa , Martinelli Erika , De Vita Ferdinando , Orditura Michele , De Palma Raffaele , Ciardiello Fortunato
Published: May 2013

Purpose: EGF receptor (EGFR) tyrosine kinase inhibitors (TKI) have been found to be effective against lung cancer, but clinical resistance to these agents has developed as their usage has increased. Metformin is a widely used antidiabetic drug and also displays significant growth-inhibitory and proapoptotic effects in several cancer models, alone or in combination with chemotherapeutic drugs.

Experimental Design: The effects of gefitinib, a selective EGFR-TKI, and metformin on a panel of non–small cell lung cancer (NSCLC) cell lines were assessed by using MTT, bromide assay, flow cytometry, anchorage-independent growth, coimmunoprecipitation, and Western blot analysis.

Results: The combination of metformin with gefitinib induced a strong antiproliferative and proapoptotic effect in NSCLC cell lines that harbored wild-type LKB1 gene. Treatment with metformin as single agent, however, induced an activation and phosphorylation of mitogen-activated protein kinase (MAPK) through an increased C-RAF/B-RAF heterodimerization. The inhibition of EGFR phosphorylation and of downstream signaling by adding gefitinib to metformin treatment abrogated this phenomenon and induced a strong apoptotic effect in vitro and in vivo.

Conclusions: Metformin and gefitinib are synergistic in LKB1 wild-type NSCLC cells. However, further studies are required to investigate better the effect of metformin action on the RAS/RAF/MAPK pathway and the best context in which to use metformin in combination with molecular targeted agents. Clin Cancer Res; 19(13); 3508–19. ©2013 AACR.
Anti-HDGF Targets Cancer and Cancer Stromal Stem Cells Resistant to Chemotherapy
Authors: Zhao Jun , Ma Mark Z. , Ren Hening , Liu Zhenqiu , Edelman Martin J. , Pan Hong , Mao Li
Published: May 2013

Purpose: Approximately one third of the patients with advanced non–small cell lung carcinoma (NSCLC) will initially respond to platinum-based chemotherapy, but virtually all tumors will progress (acquired resistance). The remainder will progress during initial treatment (primary resistance). In this study, we test whether the treatment can be improved by inhibiting hepatoma-derived growth factor (HDGF).

Experimental Design: Thirteen primary NSCLC heterotransplant models were used to test four treatment regimens, including platinum-based chemotherapy with and without bevacizumab (VEGF-neutralizing antibody) or HDGF-H3 (HDGF-neutralizing antibody) and chemotherapy with bevacizumab and HDGF-H3. Expression of stem cell–related genes was measured using quantitative reverse transcription PCR (qRT-PCR) and immunohistochemistry.

Results: Among 13 primary NSCLC heterotransplant models, three (23%) responded to chemotherapy but all relapsed within 20 days. The residual tumors after response to the chemotherapy exhibited an increased expression in 51 (61%) of 84 genes related with stem cell proliferation and maintenance, particularly those in Notch and Wnt pathways, suggesting enrichment for stem cell populations in the residual tumors. Interestingly, tumors from two of three models treated with HDGF-H3, bevacizumab, and chemotherapy combination did not relapse during 6 months of posttreatment observation. Importantly, this treatment combination substantially downregulated expression levels in 57 (68%) of 84 stem cell–related genes, including 34 (67%) of 51 genes upregulated after the chemotherapy.

Conclusion: These data support the hypothesis that cancer stem cells (CSC) are a mechanism for chemotherapy resistance and suggest HDGF may be a target for repressing CSCs to prevent relapse of NSCLC sensitive to chemotherapy. Clin Cancer Res; 19(13); 3567–76. ©2013 AACR.
Downregulation of miR-452 Promotes Stem-Like Traits and Tumorigenicity of Gliomas
Authors: Liu Liping , Chen Kun , Wu Jueheng , Shi Ling , Hu Bo , Cheng Shiyuan , Li Mengfeng , Song Libing
Published: May 2013

Purpose: miR-452 is reported to be required for neural crest stem cell differentiation during neural crest development. However, the biologic role of miR-452 in gliomas remains unclear. The aim of the present study was to evaluate the effect of miR-452 on the stem-like properties and tumorigenesis of glioma cells.

Experimental Design: The expression of miR-452 was examined in glioma cells and glioma tissues using real-time PCR. The effects of miR-452 on stem-like traits and tumorigenesis were investigated in vitro and in vivo using patient-derived glioma cells and glioma cell lines. Western blotting and luciferase reporter assays were conducted to examine the negative regulation of Bmi-1, LEF1, and TCF4 by miR-452. The methylation of the miR-452 promoter region was examined by bisulfite genomic sequencing PCR.

Results: miR-452 was markedly downregulated in glioma cells and clinical glioma tissues. miR-452 levels were inversely correlated with World Health Organization (WHO) grades and patient survival. miR-452 directly targeted and suppressed multiple stemness regulators, including Bmi-1, LEF1, and TCF4, resulting in reduced stem-like traits and tumorigenesis of glioma cells in vitro and in vivo. Furthermore, we showed that downregulation of miR-452 in gliomas was caused by hypermethylation of its promoter region.

Conclusions: Downregulation of miR-452 plays an important role in promoting the stem-like traits and tumorigenesis of gliomas and may represent a novel prognostic biomarker and therapeutic target for the disease. Clin Cancer Res; 19(13); 3429–38. ©2013 AACR.
PG545, an Angiogenesis and Heparanase Inhibitor, Reduces Primary Tumor Growth and Metastasis in Experimental Pancreatic Cancer
Authors: Ostapoff Katherine T. , Awasthi Niranjan , Kutluk Cenik Bercin , Hinz Stefan , Dredge Keith , Schwarz Roderich E. , Brekken Rolf A.
Published: May 2013

Aggressive tumor progression, metastasis, and resistance to conventional therapies lead to an extremely poor prognosis for pancreatic ductal adenocarcinoma (PDAC). Heparanase, an enzyme expressed by multiple cell types, including tumor cells in the tumor microenvironment, has been implicated in angiogenesis and metastasis, and its expression correlates with decreased overall survival in PDAC. We evaluated the therapeutic potential of PG545, an angiogenesis and heparanase inhibitor, in experimental PDAC. PG545 inhibited the proliferation, migration, and colony formation of pancreatic cancer cells in vitro at pharmacologically relevant concentrations. Heparanase inhibition also reduced the proliferation of fibroblasts but had only modest effects on endothelial cells in vitro. Furthermore, PG545 significantly prolonged animal survival in intraperitoneal and genetic models (mPDAC: LSL-KrasG12D; Cdkn2alox/lox; p48Cre) of PDAC. PG545 also inhibited primary tumor growth and metastasis in orthotopic and genetic endpoint studies. Analysis of tumor tissue revealed that PG545 significantly decreased cell proliferation, increased apoptosis, reduced microvessel density, disrupted vascular function, and elevated intratumoral hypoxia. Elevated hypoxia is a known driver of collagen deposition and tumor progression; however, tumors from PG545-treated animals displayed reduced collagen deposition and a greater degree of differentiation compared with control or gemcitabine-treated tumors. These results highlight the potent antitumor activity of PG545 and support the further exploration of heparanase inhibitors as a potential clinical strategy for the treatment of PDAC. Mol Cancer Ther; 12(7); 1190–201. ©2013 AACR.
Pulmonary Hypertension Risk in Patients with Hemoglobin H Disease: Low Incidence and Absence of Correlation with Splenectomy
Authors: Yin Xiao-Lin , Zhang Xin-Hua , Wu Zhi-Kui , Zhao Dong-Hai , Zhou Ya-Li , Yu Yue-Hua , Liu Tie-Niu , Fang Su-Ping , Zhou Tian-Hong , Wang Li , Huang Jie
Published: May 2013

Pulmonary hypertension (PHT) is a common complication for patients with β thalassemia intermediate (TI), especially splenectomized patients. However, the frequency and risk factors of PHT in patients with hemoglobin H (HbH) disease is unknown. The purpose of this study was to identify the prevalence of PHT risk manifested as tricuspid regurgitant jet velocity (TRV) ≥2.5 m/s in patients with HbH disease and its correlation with splenectomy. One hundred and ninety-eight patients with HbH disease who visited the 303rd Hospital of the People's Liberation Army (Nanning, China) were investigated. Thirteen subjects (6.5%) were diagnosed as having a risk of PHT. Regression analyses showed that the prevalence of PHT risk was correlated only with age (r = 0.195, p = 0.006) and not with splenectomy. The risk of PHT in patients older than 35 years was 5.7 times (range 1.8-18.6) greater than that for patients younger than 35 years. For splenectomized patients compared to those with HbH disease, patients with TI had a higher frequency of PHT risk, higher nucleated red blood cell counts (46.03 ± 41.11 × 109/l vs. 0.18 ± 1.19 × 109/l, p < 0.001) and a higher platelet counts (837.6 ± 178.9 × 109/l vs. 506.7 ± 146.2 × 109/l, p < 0.001). PHT risk is low in patients with HbH disease and does not correlate with splenectomy. Patients older than 35 years should be monitored regularly.
Emotion Regulation Skills Training Enhances the Efficacy of Inpatient Cognitive Behavioral Therapy for Major Depressive Disorder: A Randomized Controlled Trial
Authors: Berking Matthias , Ebert David , Cuijpers Pim , Hofmann Stefan G.
Published: May 2013

Background: Deficits in emotion regulation skills are possible factors maintaining major depressive disorder (MDD). Therefore, the aim of the study was to test whether integrating a systematic emotion regulation training (ERT) enhances the efficacy of routine inpatient cognitive behavioral therapy (CBT) for MDD. Methods: In a prospective randomized controlled trial, 432 inpatients meeting criteria for MDD were assigned to receive either routine CBT or CBT enriched with an intense emotion regulation skills training (CBT-ERT). Results: Participants in the CBT-ERT condition demonstrated a significantly greater reduction in depression (response rates - CBT: 75.5%, CBT-ERT: 84.9%; remission rates - CBT: 51.1%, CBT-ERT: 65.1%). Moreover, CBT-ERT participants demonstrated a significantly greater reduction of negative affect, as well as a greater increase of well-being and emotion regulation skills particularly relevant for mental health. Conclusions: Integrating strategies that target emotion regulation skills improves the efficacy of CBT for MDD.
Dialectical Behaviour Therapy for Post-traumatic Stress Disorder after Childhood Sexual Abuse in Patients with and without Borderline Personality Disorder: A Randomised Controlled Trial
Authors: Bohus Martin , Dyer Anne S. , Priebe Kathlen , Krüger Antje , Kleindienst Nikolaus , Schmahl Christian , Niedtfeld Inga , Steil Regina
Published: May 2013

Background: Post-traumatic stress disorder (PTSD) with co-occurring severe psychopathology such as borderline personality disorder (BPD) is a frequent sequel of childhood sexual abuse (CSA). CSA-related PTSD has been effectively treated through cognitive-behavioural treatments, but it remains unclear whether success can be achieved in patients with co-occurring BPD. The aim of the present study was to determine the efficacy of a newly developed modular treatment programme (DBT-PTSD) that combines principles of dialectical behaviour therapy (DBT) and trauma-focused interventions. Methods: Female patients (n = 74) with CSA-related PTSD were randomised to either a 12-week residential DBT-PTSD programme or a treatment-as-usual wait list. About half of the participants met the criteria for co-occurring BPD. Individuals with ongoing self-harm were not excluded. The primary outcomes were reduction of PTSD symptoms as assessed by the Clinician-Administered PTSD Scale (CAPS) and by the Posttraumatic Stress Diagnostic Scale (PDS). Hierarchical linear models were used to compare improvements across treatment groups. Assessments were carried out by blinded raters at admission, at end of treatment, and at 6 and 12 weeks post-treatment. Results: Under DBT-PTSD the mean change was significantly greater than in the control group on both the CAPS (33.16 vs. 2.08) and the PDS (0.70 vs. 0.14). Between-group effect sizes were large and highly significant. Neither a diagnosis of BPD nor the severity or the number of BPD symptoms was significantly related to treatment outcome. Safety analyses indicated no increase in dysfunctional behaviours during the trial. Conclusion: DBT-PTSD is an efficacious treatment of CSA-related PTSD, even in the presence of severe co-occurring psychopathology such as BPD.
Insight in Psychotic Disorder: Relation with Psychopathology and Frontal Lobe Function
Authors: Kumar Atmesh , Sharma Pranjal , Das Shyamanta , Nath Kamal , Talukdar Uddip , Bhagabati Dipesh
Published: May 2013

Background/Aims: Through conceptualising poor insight in psychotic disorders as a form of anosognosia, frontal lobe dysfunction is often ascribed a vital role in its pathogenesis. The objective of this study was to compare the relation of insight in patients with psychotic illness to that of psychopathology and frontal lobe function. Methods: Forty patients with psychotic disorder were selected from those attending the Department of Psychiatry in a tertiary care teaching hospital. The evaluation of insight was carried out using the Schedule for Assessment of Insight (SAI), that of frontal lobe function by the Frontal Assessment Battery (FAB) and psychopathology by the Brief Psychiatric Rating Scale (BPRS). The correlation coefficients were determined. Results: A negative correlation between SAI and BPRS scores means that the BPRS score is opposite to SAI scores. When the SAI total score was compared with the FAB total score, the correlation coefficient demonstrated a positive correlation. Better insight predicted lesser psychopathology and also that poor insight would exist with greater psychopathology. Better insight predicted a higher functional status of frontal lobes and prefrontal cortex in particular. Conclusion: Insight deficits in schizophrenia and other psychotic illnesses are multidimensional. Integration of different aetiological factors like biological, psychopathological, environmental ones and others are necessary for a better understanding of insight in psychosis.
Psychosis in Neurosyphilis - Clinical Aspects and Implications
Authors: Friedrich F. , Aigner M. , Fearns N. , Friedrich M.E. , Frey R. , Geusau A.
Published: May 2013

Background: The World Health Organization estimates that 10-12 million new syphilis infections occur each year. Without treatment, years to decades after initial infection, 30% of affected individuals may develop tertiary syphilis, which can manifest as neurosyphilis. The aim of this review is to evaluate the research literature examining the psychopathological manifestations of psychosis in association with neurosyphilis. Method: The authors performed a systematic electronic search for published studies (1995-2012). The following databases were used: Medline, Embase and the Cochrane Library as well as the search engines Scopus and Google Scholar. Results: 61 articles were used for detailed analysis. Psychotic symptoms due to neurosyphilis are numerous and can inform differential diagnosis for many psychotic manifestations according to ICD-10 or DSM-IV. Conclusion: Due to our results, current epidemiological data, and the difficulties in differential diagnosis of neurosyphilis, routine screening tests are still recommended in the psychiatric field. Long-term psychiatric input, with periodic syphilis titre controls, seems indicated in individuals affected by neurosyphilis with psychiatric symptoms. Furthermore, individuals with mental health problems may be at higher risk of acquiring syphilis.