bluuebunny/crossref_metadata_2025 huggingface dataset:
Hardware software co-design in Haskell
Authors: Aronsson Markus , Sheeran Mary
Published: November 2017

We present a library in Haskell for programming Field Programmable Gate Arrays (FPGAs), including hardware software co-design. Code for software (in C) and hardware (in VHDL) is generated from a single program, along with the code to support communication between hardware and software. We present type-based techniques for the simultaneous implementation of more than one embedded domain specific language (EDSL). We build upon a generic representation of imperative programs that is loosely coupled to instruction and expression types, allowing the individual parts to be developed and improved separately. Code generation is implemented as a series of translations between progressively smaller, typed EDSLs, safeguarding against errors that arise in untyped translations. Initial case studies show promising performance.
Locus coeruleus phasic discharge is essential for stimulus-induced gamma oscillations in the prefrontal cortex
Authors: Neves Ricardo M. , van Keulen Silvia , Yang Mingyu , Logothetis Nikos K. , Eschenko Oxana
Published: November 2017

The locus coeruleus (LC) noradrenergic (NE) neuromodulatory system is critically involved in regulation of neural excitability via its diffuse ascending projections. Tonic NE release in the forebrain is essential for maintenance of vigilant states and increases the signal-to-noise ratio of cortical sensory responses. The impact of phasic NE release on cortical activity and sensory processing is less explored. We previously reported that LC microstimulation caused a transient desynchronization of population activity in the medial prefrontal cortex (mPFC), similar to noxious somatosensory stimuli. The LC receives nociceptive information from the medulla and therefore may mediate sensory signaling to its forebrain targets. Here we performed extracellular recordings in LC and mPFC while presenting noxious stimuli in urethane-anesthetized rats. A brief train of foot shocks produced a robust phasic response in the LC and a transient change in the mPFC power spectrum, with the strongest modulation in the gamma (30–90 Hz) range. The LC phasic response preceded prefrontal gamma power increase, and cortical modulation was proportional to the LC excitation. We also quantitatively characterized distinct cortical states and showed that sensory responses in both LC and mPFC depend on the ongoing cortical state. Finally, cessation of the LC firing by bilateral local iontophoretic injection of clonidine, an α2-adrenoreceptor agonist, completely eliminated sensory responses in the mPFC without shifting cortex to a less excitable state. Together, our results suggest that the LC phasic response induces gamma power increase in the PFC and is essential for mediating sensory information along an ascending noxious pathway.

NEW & NOTEWORTHY Our study shows linear relationships between locus coeruleus phasic excitation and the amplitude of gamma oscillations in the prefrontal cortex. Results suggest that the locus coeruleus phasic response is essential for mediating sensory information along an ascending noxious pathway.
Stable Dyonic Thin-Shell Wormholes in Low-Energy String Theory
Authors: Övgün Ali , Jusufi Kimet
Published: November 2017

Considerable attention has been devoted to the wormhole physics in the past 30 years by exploring the possibilities of finding traversable wormholes without the need for exotic matter. In particular, the thin-shell wormhole formalism has been widely investigated by exploiting the cut-and-paste technique to merge two space-time regions and to research the stability of these wormholes developed by Visser. This method helps us to minimize the amount of the exotic matter. In this paper, we construct a four-dimensional, spherically symmetric, dyonic thin-shell wormhole with electric charge Q, magnetic charge P, and dilaton charge Σ, in the context of Einstein-Maxwell-dilaton theory. We have applied Darmois-Israel formalism and the cut-and-paste method by joining together two identical space-time solutions. We carry out the dyonic thin-shell wormhole stability analyses by using a linear barotropic gas, Chaplygin gas, and logarithmic gas for the exotic matter. It is shown that, by choosing suitable parameter values as well as equation of state parameter, under specific conditions, we obtain a stable dyonic thin-shell wormhole solution. Finally, we argue that the stability domain of the dyonic thin-shell wormhole can be increased in terms of electric charge, magnetic charge, and dilaton charge.
Desmoplastic Small Round Blue Cell Tumor: A Review of Treatment and Potential Therapeutic Genomic Alterations
Authors: Bulbul Ajaz , Fahy Bridget Noel , Xiu Joanne , Rashad Sadaf , Mustafa Asrar , Husain Hatim , Hayes-Jordan Andrea
Published: November 2017

Desmoplastic small round blue cell tumors (DSRCTs) originate from a cell with multilineage potential. A molecular hallmark of DSRCT is the EWS-WT1 reciprocal translocation. Ewing sarcoma and DSRCT are treated similarly due to similar oncogene activation pathways, and DSRCT has been represented in very limited numbers in sarcoma studies. Despite aggressive therapy, median survival ranges from 17 to 25 months, and 5-year survival rates remain around 15%, with higher survival reported among those undergoing removal of at least 90% of tumor in the absence of extraperitoneal metastasis. Almost 100% of these tumors contain t(11;22) (p13;q12) translocation, and it is likely that EWS-WT1 functions as a transcription factor possibly through WT1 targets. While there is no standard protocol for this aggressive disease, treatment usually includes the neoadjuvant HD P6 regimen (high-dose cyclophosphamide, doxorubicin, and vincristine (HD-CAV) alternating with ifosfamide and etoposide (IE) chemotherapy combined with aggressively attempted R0 resection). We aimed to review the molecular characteristics of DSRCTs to explore therapeutic opportunities for this extremely rare and aggressive cancer type.
Case Report of Foreign Body Stuck in Esophagus with Failure of Endoscopic Management in a Man with a History of Pica
Authors: Mulinder Holly , Ammann Allison , Puckett Yana , Dissanaike Sharmila
Published: November 2017

This is a case report of foreign body ingestion in a 55-year-old intellectually disabled man with a history of pica and previous removal of ten plastic gloves from his rectum four months prior to this presentation. The patient presented after ingesting plastic gloves which formed large, rigid esophageal and gastric bezoars that were not amenable to endoscopic removal. An exploratory laparotomy and gastrostomy was performed, and a 10 × 4.5 × 2 cm gastric bezoar consisting of rigid plastic gloves was removed without complication. Special considerations must be taken when considering the ingestion of nonfood items in the intellectually disabled population as these cases may not present classically with symptoms of a gastric bezoar.
Coexistence of GH-Producing Pituitary Macroadenoma and Meningioma in a Patient with Multiple Endocrine Neoplasia Type 1 with Hyperglycemia and Ketosis as First Clinical Sign
Authors: Herrero-Ruiz A. , Villanueva-Alvarado H. S. , Corrales-Hernández J. J. , Higueruela-Mínguez C. , Feito-Pérez J. , Recio-Cordova J. M.
Published: November 2017

We present the clinical case of a patient who was admitted with an onset of diabetes mellitus (DM) with associated ketosis and whose clinical, hormonal, and radiological evolution revealed the presence of primary hyperparathyroidism, pancreatic neuroendocrine tumor, and GH-producing pituitary macroadenoma in the context of multiple endocrine neoplasia type 1 (MEN1). DM is relatively common in cases of acromegaly, but it is not generally associated with ketosis. Simultaneously, the patient presented a meningioma, which is associated with pituitary macroadenoma only in extremely rare cases.
Breast Cancer Status in Iran: Statistical Analysis of 3010 Cases between 1998 and 2014
Authors: Akbari Mohammad Esmaeil , Sayad Soheila , Sayad Saed , Khayamzadeh Maryam , Shojaee Leila , Shormeji Zeynab , Amiri Mojtaba
Published: November 2017

Background. Breast cancer is the 5th leading cause of cancer death in Iranian women. This study analyzed 3010 women with breast cancer that had been referred to a cancer research center in Tehran between 1998 and 2014. Methods. In this retrospective study, we analyzed 3010 breast cancer cases with 32 clinical and paraclinical attributes. We checked the data quality rigorously and removed any invalid values or records. The method was data mining (problem definition, data preparation, data exploration, modeling, evaluation, and deployment). However, only the descriptive analyses’ results of the variables are presented in this article. To our knowledge, this is the most comprehensive study on breast cancer status in Iran. Results. A typical Iranian breast cancer patient has been a 40–50-year-old married woman with two children, who has a high school diploma and no history of abortion, smoking, or diabetes. Most patients were estrogen and progesterone receptor positive, human epidermal growth factor (HER) negative, and P53 negative. Most cases were detected in stage 2 with intermediate grade. Conclusion. This study revealed original findings which can be used in national policymaking to find the best early detection method and improve the care quality and breast cancer prevention in Iran.
The Relationship between Dental Follicle Width and Maxillary Impacted Canines’ Descriptive and Resorptive Features Using Cone-Beam Computed Tomography
Authors: Dağsuyu İlhan Metin , Okşayan Rıdvan , Kahraman Fatih , Aydın Mehmet , Bayrakdar İbrahim Şevki , Uğurlu Mehmet
Published: November 2017

Objectives. To assess the relationship between dental follicle width and maxillary impacted canines’ descriptive and resorptive features with three-dimensional (3D) cone-beam computed tomography (CBCT). Methods. The study comprised 102 patients with cone-beam computed tomography 3D images and a total of 140 impacted canines. The association between maxillary impacted canine dental follicle width and the variables of gender, impaction side (right and left), localization of impacted canine (buccal, central, and palatal), and resorption of the adjacent laterals was compared. Measurements were analyzed with Student’s t-test, Kruskal-Wallis test, and Mann–Whitney U statistical test. Results. According to gender, no statistically significant differences were found in the follicle size of the maxillary impacted canine between males and females (p>0.05). Widths of the follicles were determined for the right and left impaction sides, and no statistically significant relation was found (p>0.05). There were statistically significant differences between root resorption degrees of lateral incisors and maxillary impacted canine follicle width (p<0.05). Statistically significant higher follicle width values were present in degree 2 (mild) resorption than in degree 1 (no) and degree 3 (moderate) resorption samples (p<0.05). Conclusions. No significant correlation was found between follicle width and the variables of gender, impaction side, and localization of maxillary impacted canines. Our study could not confirm that increased dental follicle width of the maxillary impacted canines exhibited more resorption risk for the adjacent lateral incisors.
Fas-Related Apoptosis of Peritoneal Fluid Macrophages in Endometriosis Patients: Understanding the Disease
Authors: Gogacz Marek , Gałczyński Krzysztof , Wojtaś Małgorzata , Winkler Izabela , Adamiak Aneta , Romanek-Piva Katarzyna , Rechberger Tomasz , Kotarski Jan
Published: November 2017

Recent studies of the peritoneal cavity environment in endometriosis demonstrate quantitative and qualitative changes in the cells responsible for cell-mediated immunity. Such changes may have led to disturbances in the surveillance, recognition, and destruction of misplaced endometrial cells and might have, in fact, brought about the disease. The aim of the study was to assess CD95 (Fas) expression on (activated) peritoneal fluid (PF) macrophages, as well as to ascertain soluble Fas (sFas) concentration in the PF of endometriosis patients, as compared to the nonendometriotic group. The concentration of leukocytes in the PF, the percentage of cells expressing CD45+/CD14+, and the percentage of PF macrophages expressing the HLA-DR antigen were significantly higher in patients with stages I and II endometriosis. The percentage of Fas- (CD95+-) expressing macrophages was significantly higher in all stages of the disease, in comparison with controls. Moreover, the concentration of sFas in the PF of patients with moderate and severe endometriosis was significantly higher, as compared to the reference group. The high number of immune cells in PF in early stage endometriosis and their increased susceptibility to apoptosis confirm the role of the impaired peritoneal environment and immune defects in the development and progression of the disease.
Applications of the g-Drazin Inverse to the Heat Equation and a Delay Differential Equation
Authors: Abdeljabbar Alrazi , Tran Trung Dinh
Published: November 2017

We consider applications of the g-Drazin inverse to some classes of abstract Cauchy problems, namely, the heat equation with operator coefficient and delay differential equations in Banach space.
Effects of Astaxanthin on Reverse Cholesterol Transport and Atherosclerosis in Mice
Authors: Zou Tang-Bin , Zhu Shan-Shan , Luo Fei , Li Wei-Qiao , Sun Xue-Rong , Wu Hong-Fu
Published: November 2017

High plasma level of HDL-cholesterol (HDL-C) has been consistently associated with a decreased risk of atherosclerosis (AS); thus, HDL-C is considered to be an antiatherogenic lipoprotein. The development of novel therapies to enhance the atheroprotective properties of HDL may have the possibility of further reducing the residual AS risk. Reverse cholesterol transport (RCT) is believed to be a primary atheroprotective activity of HDL, which has been shown to promote the efflux of excess cholesterol from macrophage-derived foam cells via ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), and scavenger receptor class B type I (SR-BI) and then transport it back to the liver for excretion into bile and eventually into the feces. In the current study, we investigated the effects of astaxanthin on RCT and AS progression in mice. The results showed that short- and long-term supplementation of astaxanthin promote RCT in C57BL/6J and ApoE−/−mice, respectively. Moreover, astaxanthin can relieve the plaque area of the aortic sinus and aortic cholesterol in mice. These findings suggest that astaxanthin is beneficial for boosting RCT and preventing the development of AS.
An Unconventional Finite Difference Scheme for Modified Korteweg-de Vries Equation
Authors: Koroglu Canan , Aydin Ayhan
Published: November 2017

A numerical solution of the modified Korteweg-de Vries (MKdV) equation is presented by using a nonstandard finite difference (NSFD) scheme with theta method which includes the implicit Euler and a Crank-Nicolson type discretization. Local truncation error of the NSFD scheme and linear stability analysis are discussed. To test the accuracy and efficiency of the method, some numerical examples are given. The numerical results of NSFD scheme are compared with the exact solution and a standard finite difference scheme. The numerical results illustrate that the NSFD scheme is a robust numerical tool for the numerical integration of the MKdV equation.
Amelioration of Scopolamine‐Induced Learning and Memory Impairment by α‐Pinene in C57BL/6 Mice
Authors: Lee Gil-Yong , Lee Chan , Park Gyu Hwan , Jang Jung-Hee
Published: November 2017

Increasing evidence suggests that neurodegenerative disorders such as Alzheimer’s disease (AD) are mediated via disruption of cholinergic neurons and enhanced oxidative stress. Therefore, attention has been focused on searching for antioxidant phytochemicals for the prevention and/or treatment of AD through their ability to fortify cholinergic function and antioxidant defense capacity. In this study, we have investigated the neuroprotective effect of α‐pinene (APN) against learning and memory impairment induced by scopolamine (SCO, 1 mg/kg, i.p.), a muscarinic receptor antagonist in C57BL/6 mice. Administration of APN (10 mg/kg, i.p.) significantly improved SCO‐induced cognitive dysfunction as assessed by Y‐maze and passive avoidance tests. In Morris water‐maze test, APN effectively shortened the mean escape latency to find the hidden platform during training days. To further elucidate the molecular mechanisms underlying the neuroprotective effect of APN, the expression of proteins involved in the acetylcholine metabolism and antioxidant system was examined. Particularly, APN treatment increased mRNA expression of choline acetyltransferase in the cortex and protein levels of antioxidant enzymes such as heme oxygenase‐1 and manganese superoxide dismutase in the hippocampus via activation of NF‐E2‐related factor 2. These findings suggest the possible neuroprotective potentials of APN for the management of dementia with learning and memory loss.
Red Wine Age Estimation by the Alteration of Its Color Parameters: Fourier Transform Infrared Spectroscopy as a Tool to Monitor Wine Maturation Time
Authors: Basalekou M. , Pappas C. , Kotseridis Y. , Tarantilis P. A. , Kontaxakis E. , Kallithraka S.
Published: November 2017

Color, phenolic content, and chemical age values of red wines made from Cretan grape varieties (Kotsifali, Mandilari) were evaluated over nine months of maturation in different containers for two vintages. The wines differed greatly on their anthocyanin profiles. Mid-IR spectra were also recorded with the use of a Fourier Transform Infrared Spectrophotometer in ZnSe disk mode. Analysis of Variance was used to explore the parameter’s dependency on time. Determination models were developed for the chemical age indexes using Partial Least Squares (PLS) (TQ Analyst software) considering the spectral region 1830–1500 cm−1. The correlation coefficients (r) for chemical age index i were 0.86 for Kotsifali (Root Mean Square Error of Calibration (RMSEC) = 0.067, Root Mean Square Error of Prediction (RMSEP) = 0,115, and Root Mean Square Error of Validation (RMSECV) = 0.164) and 0.90 for Mandilari (RMSEC = 0.050, RMSEP = 0.040, and RMSECV = 0.089). For chemical age index ii the correlation coefficients (r) were 0.86 and 0.97 for Kotsifali (RMSEC 0.044, RMSEP = 0.087, and RMSECV = 0.214) and Mandilari (RMSEC = 0.024, RMSEP = 0.033, and RMSECV = 0.078), respectively. The proposed method is simpler, less time consuming, and more economical and does not require chemical reagents.
1H‐NMR Based Serum Metabolomics Study to Investigate Hepatoprotective Effect of Qin‐Jiao on Carbon Tetrachloride‐Induced Acute Hepatotoxicity in Rats
Authors: Li Zeyun , Li Ying , Lu Lingpan , Yang Zhiheng , Xue Wenhua , Tian Xin , Zhang Xiaojian
Published: November 2017

Gentiana macrophylla Radix, commonly known as Qin‐Jiao (QJ), was recorded alone to treat jaundice in Compendium of Materia Medica and has been frequently prescribed for treatment of liver disease in China. However, the underlying mechanism remains unknown. In the present work, QJ of 1,2 g/kg or silybin of 40 mg/kg (positive control) was orally given to rats for 7 days to verify the protective effect on acute liver damage induced by tetrachloride (CCl4). Together with serum biochemistry and histopathological examination, 1H‐NMR based metabolomics work was carried out to investigate the efficacy. It turned out that QJ of 2 g/kg exerted comparable protective effect with positive control and partially recovered disturbed metabolism by CCl4. Multivariate analysis was conducted and metabolites altered significantly among groups were assigned and discussed, including betaine, glucose, lactate, creatine, and LDL/VLDL. Metabolic regulations involved in QJ or silybin treatment were as follows: tricarboxylic acid (TCA) cycle, synthesis of LDL/VLDL, and gluconeogenesis were enhanced, while betaine metabolism, glycolysis, creatine metabolism, synthesis of ketone bodies, amino acids metabolism, and β‐oxidation of fatty acids were suppressed. For the first time hepatoprotective effect of QJ on acute liver damage was revealed by 1H‐NMR based metabolomics, prompting understanding of the underlying mechanism.
Detailed Componential Characterization of Extractable Species with Organic Solvents from Wheat Straw
Authors: Lu Yong-Chao , Lu Yao , Lu Zhao-Lin , Wei Xian-Yong
Published: November 2017

Componential analysis of extractives is important for better understanding the structure and utilization of biomass. In this investigation, wheat straw (WS) was extracted with petroleum ether (PE) and carbon disulfide (CS2) sequentially, to afford extractable fractionsEFPEandEFCS2, respectively. Detailed componential analyses ofEFPEandEFCS2were carried out with Fourier transform infrared (FTIR) spectroscopy, gas chromatography/mass spectrometry (GC/MS), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), energy dispersive spectrometry (EDS), and electron probe microanalysis (EPMA). Total extractives were quantified 4.96% by weight compared to the initial WS sample. FTIR and GC/MS analyses results showed that PE was effective for the extraction of ketones and waxes derived compounds; meanwhile CS2preferred ketones and other species with higher degrees of unsaturation. Steroids were enriched intoEFPEandEFCS2with considerable high relative contents, namely, 64.52% and 79.58%, respectively. XPS analysis showed that most of the C atoms in extractives were contained in the structures of C-C, C-COOR, and C-O. TEM-EDS and EPMA analyses were used to detect trace amount elements, such as Al, Si, P, S, Cl, and Ca atoms. Detailed characterization of extractable species from WS can provide more information on elucidation of extractives in biomass.
Induction of Reactive Intermediates and Autophagy-Related Proteins upon Infection of Macrophages withRhodococcus equi
Authors: Chandramani-Shivalingappa Prashanth , Bhandari Mahesh , Wiechert Sarah A. , Gilbertie Jessica , Jones Douglas E. , Sponseller Brett A.
Published: November 2017

Rhodococcus equi (R. equi)is an intracellular macrophage-tropic pathogen with potential for causing fatal pyogranulomatous pneumonia in foals between 1 and 6 months of age. In this study, we sought to determine whether infection of macrophages withR. equicould lead to the induction of autophagy. Murine bone marrow derived macrophages (BMDM) were infected withR. equifor various time intervals and analyzed for upregulation of autophagy proteins and accumulation of autophagosomes relative to uninfected controls. Western blot analysis showed a progressive increase in LC3-II and Beclin1 levels in a time-dependent manner. The functional accumulation of autophagosomes detected with monodansylcadaverine further supported the enhanced induction of autophagy in BMDM infected withR. equi. In addition, infection of BMDM withR. equiinduced generation of reactive oxygen species (ROS) in a time-dependent manner. These data are consistent with reports documenting the role of ROS in induction of autophagy and indicate that the infection of macrophages byR. equielicits innate host defense mechanisms.
Development of Fault Identification System for Electric Servo Actuators of Multilink Manipulators Using Logic-Dynamic Approach
Authors: Filaretov V. , Zuev A. , Zhirabok A. , Protsenko A.
Published: November 2017

This paper presents the method of synthesis of faults identification systems for electric servo actuators of multilink manipulators. These actuators are described by nonlinear equations with significantly changing coefficients. The proposed method is based on logic-dynamic approach for design of diagnostic observers for fault detection and isolation. An advantage of this approach is that it allows studying systems with nonsmooth nonlinearities by linear methods only. For solving the task of faults identification, a residual signal feedback was proposed to be used for observers. The efficiency of the proposed fault identification system was confirmed by results of simulation.
Decision Matrix Analysis of Impact Sounding Test Method to Determine Interlayer Condition of Concrete Bridge Deck
Authors: Rosales Cristina Amor , Lee Hyun Jong , Kim Wonjae , Park Chang kyu
Published: November 2017

This study focused on the analysis of the frequency spectra of impact sounding test performed on composite slabs with different interlayer condition. Distinct and consistent characteristics of the frequency spectra were observed from the impact signals. The consistency of results for bonding condition at varying temperature was also investigated. Results of laboratory tests were compared to different bonding condition observed in the field. Finally, a proposed decision matrix analysis was presented and successfully identified the interface bonding condition. The proposed decision matrix is composed of four zones characterizing each interlayer condition based on the features of impact signals. Field and laboratory assessment conform to decision matrix result.
Acquired von Willebrand Disease Associated with Monoclonal Gammopathy of Unknown Significance
Authors: Basnet Sijan , Lin Catherine , Dhital Rashmi , Mir Izza , Mohanty Elan , Tharu Biswaraj , Ghimire Sushil , Poudel Dilli Ram
Published: November 2017

We present a case of a 79-year-old male who presented with retroperitoneal hematoma a week after motor vehicle accident. Prior history and family history of bleeding were nonsignificant. His activated partial thromboplastin time was found to be prolonged in the emergency department. Further workup with coagulation studies showed decreased factor VIII, vWF antigen, and vWF:ristocetin cofactor assay, and negative Bethesda assay, indicating acquired von Willebrand disease. Immunofluorescence to find an underlying etiology was suggestive of MGUS. Management of AvWD depends on controlling active bleeding and treating the underlying cause. He was treated with factor VIII, haemate-p, rituximab, two cycles of IVIg, and three weeks of oral steroids.
A Containerized Software System for Generation, Management, and Exploration of Features from Whole Slide Tissue Images
Authors: Saltz Joel , Sharma Ashish , Iyer Ganesh , Bremer Erich , Wang Feiqiao , Jasniewski Alina , DiPrima Tammy , Almeida Jonas S. , Gao Yi , Zhao Tianhao , Saltz Mary , Kurc Tahsin
Published: November 2017

Well-curated sets of pathology image features will be critical to clinical studies that aim to evaluate and predict treatment responses. Researchers require information synthesized across multiple biological scales, from the patient to the molecular scale, to more effectively study cancer. This article describes a suite of services and web applications that allow users to select regions of interest in whole slide tissue images, run a segmentation pipeline on the selected regions to extract nuclei and compute shape, size, intensity, and texture features, store and index images and analysis results, and visualize and explore images and computed features. All the services are deployed as containers and the user-facing interfaces as web-based applications. The set of containers and web applications presented in this article is used in cancer research studies of morphologic characteristics of tumor tissues. The software is free and open source. Cancer Res; 77(21); e79–82. ©2017 AACR.
An Accessible Proteogenomics Informatics Resource for Cancer Researchers
Authors: Chambers Matthew C. , Jagtap Pratik D. , Johnson James E. , McGowan Thomas , Kumar Praveen , Onsongo Getiria , Guerrero Candace R. , Barsnes Harald , Vaudel Marc , Martens Lennart , Grüning Björn , Cooke Ira R. , Heydarian Mohammad , Reddy Karen L. , Griffin Timothy J.
Published: November 2017

Proteogenomics has emerged as a valuable approach in cancer research, which integrates genomic and transcriptomic data with mass spectrometry–based proteomics data to directly identify expressed, variant protein sequences that may have functional roles in cancer. This approach is computationally intensive, requiring integration of disparate software tools into sophisticated workflows, challenging its adoption by nonexpert, bench scientists. To address this need, we have developed an extensible, Galaxy-based resource aimed at providing more researchers access to, and training in, proteogenomic informatics. Our resource brings together software from several leading research groups to address two foundational aspects of proteogenomics: (i) generation of customized, annotated protein sequence databases from RNA-Seq data; and (ii) accurate matching of tandem mass spectrometry data to putative variants, followed by filtering to confirm their novelty. Directions for accessing software tools and workflows, along with instructional documentation, can be found at z.umn.edu/canresgithub. Cancer Res; 77(21); e43–46. ©2017 AACR.
LesionTracker: Extensible Open-Source Zero-Footprint Web Viewer for Cancer Imaging Research and Clinical Trials
Authors: Urban Trinity , Ziegler Erik , Lewis Rob , Hafey Chris , Sadow Cheryl , Van den Abbeele Annick D. , Harris Gordon J.
Published: November 2017

Oncology clinical trials have become increasingly dependent upon image-based surrogate endpoints for determining patient eligibility and treatment efficacy. As therapeutics have evolved and multiplied in number, the tumor metrics criteria used to characterize therapeutic response have become progressively more varied and complex. The growing intricacies of image-based response evaluation, together with rising expectations for rapid and consistent results reporting, make it difficult for site radiologists to adequately address local and multicenter imaging demands. These challenges demonstrate the need for advanced cancer imaging informatics tools that can help ensure protocol-compliant image evaluation while simultaneously promoting reviewer efficiency. LesionTracker is a quantitative imaging package optimized for oncology clinical trial workflows. The goal of the project is to create an open source zero-footprint viewer for image analysis that is designed to be extensible as well as capable of being integrated into third-party systems for advanced imaging tools and clinical trials informatics platforms. Cancer Res; 77(21); e119–22. ©2017 AACR.
The Cancer Genomics Cloud: Collaborative, Reproducible, and Democratized—A New Paradigm in Large-Scale Computational Research
Authors: Lau Jessica W. , Lehnert Erik , Sethi Anurag , Malhotra Raunaq , Kaushik Gaurav , Onder Zeynep , Groves-Kirkby Nick , Mihajlovic Aleksandar , DiGiovanna Jack , Srdic Mladen , Bajcic Dragan , Radenkovic Jelena , Mladenovic Vladimir , Krstanovic Damir , Arsenijevic Vladan , Klisic Djordje , Mitrovic Milan , Bogicevic Igor , Kural Deniz , Davis-Dusenbery Brandi
Published: November 2017

The Seven Bridges Cancer Genomics Cloud (CGC; www.cancergenomicscloud.org) enables researchers to rapidly access and collaborate on massive public cancer genomic datasets, including The Cancer Genome Atlas. It provides secure on-demand access to data, analysis tools, and computing resources. Researchers from diverse backgrounds can easily visualize, query, and explore cancer genomic datasets visually or programmatically. Data of interest can be immediately analyzed in the cloud using more than 200 preinstalled, curated bioinformatics tools and workflows. Researchers can also extend the functionality of the platform by adding their own data and tools via an intuitive software development kit. By colocalizing these resources in the cloud, the CGC enables scalable, reproducible analyses. Researchers worldwide can use the CGC to investigate key questions in cancer genomics. Cancer Res; 77(21); e3–6. ©2017 AACR.
The Mouse Tumor Biology Database: A Comprehensive Resource for Mouse Models of Human Cancer
Authors: Krupke Debra M. , Begley Dale A. , Sundberg John P. , Richardson Joel E. , Neuhauser Steven B. , Bult Carol J.
Published: November 2017

Research using laboratory mice has led to fundamental insights into the molecular genetic processes that govern cancer initiation, progression, and treatment response. Although thousands of scientific articles have been published about mouse models of human cancer, collating information and data for a specific model is hampered by the fact that many authors do not adhere to existing annotation standards when describing models. The interpretation of experimental results in mouse models can also be confounded when researchers do not factor in the effect of genetic background on tumor biology. The Mouse Tumor Biology (MTB) database is an expertly curated, comprehensive compendium of mouse models of human cancer. Through the enforcement of nomenclature and related annotation standards, MTB supports aggregation of data about a cancer model from diverse sources and assessment of how genetic background of a mouse strain influences the biological properties of a specific tumor type and model utility. Cancer Res; 77(21); e67–70. ©2017 AACR.
The ISB Cancer Genomics Cloud: A Flexible Cloud-Based Platform for Cancer Genomics Research
Authors: Reynolds Sheila M. , Miller Michael , Lee Phyliss , Leinonen Kalle , Paquette Suzanne M. , Rodebaugh Zack , Hahn Abigail , Gibbs David L. , Slagel Joseph , Longabaugh William J. , Dhankani Varsha , Reyes Madelyn , Pihl Todd , Backus Mark , Bookman Matthew , Deflaux Nicole , Bingham Jonathan , Pot David , Shmulevich Ilya
Published: November 2017

The ISB Cancer Genomics Cloud (ISB-CGC) is one of three pilot projects funded by the National Cancer Institute to explore new approaches to computing on large cancer datasets in a cloud environment. With a focus on Data as a Service, the ISB-CGC offers multiple avenues for accessing and analyzing The Cancer Genome Atlas, TARGET, and other important references such as GENCODE and COSMIC using the Google Cloud Platform. The open approach allows researchers to choose approaches best suited to the task at hand: from analyzing terabytes of data using complex workflows to developing new analysis methods in common languages such as Python, R, and SQL; to using an interactive web application to create synthetic patient cohorts and to explore the wealth of available genomic data. Links to resources and documentation can be found at www.isb-cgc.org. Cancer Res; 77(21); e7–10. ©2017 AACR.
Novel SEC61G–EGFR Fusion Gene in Pediatric Ependymomas Discovered by Clonal Expansion of Stem Cells in Absence of Exogenous Mitogens
Authors: Servidei Tiziana , Meco Daniela , Muto Valentina , Bruselles Alessandro , Ciolfi Andrea , Trivieri Nadia , Lucchini Matteo , Morosetti Roberta , Mirabella Massimiliano , Martini Maurizio , Caldarelli Massimo , Lasorella Anna , Tartaglia Marco , Riccardi Riccardo
Published: November 2017

The basis for molecular and cellular heterogeneity in ependymomas of the central nervous system is not understood. This study suggests a basis for this phenomenon in the selection for mitogen-independent (MI) stem-like cells with impaired proliferation but increased intracranial tumorigenicity. MI ependymoma cell lines created by selection for EGF/FGF2-independent proliferation exhibited constitutive activation of EGFR, AKT, and STAT3 and sensitization to the antiproliferative effects of EGFR tyrosine kinase inhibitors (TKI). One highly tumorigenic MI line harbored membrane-bound, constitutively active, truncated EGFR. Two EGFR mutants (ΔN566 and ΔN599) were identified as products of intrachromosomal rearrangements fusing the 3′ coding portion of the EGFR gene to the 5′-UTR of the SEC61G, yielding products lacking the entire extracellular ligand-binding domain of the receptor while retaining the transmembrane and tyrosine kinase domains. EGFR TKI efficiently targeted ΔN566/ΔN599-mutant–mediated signaling and prolonged the survival of mice bearing intracranial xenografts of MI cells harboring these mutations. RT-PCR sequencing of 16 childhood ependymoma samples identified SEC61G–EGFR chimeric mRNAs in one infratentorial ependymoma WHO III, arguing that this fusion occurs in a small proportion of these tumors. Our findings demonstrate how in vitro culture selections applied to genetically heterogeneous tumors can help identify focal mutations that are potentially pharmaceutically actionable in rare cancers. Cancer Res; 77(21); 5860–72. ©2017 AACR.
WebMeV: A Cloud Platform for Analyzing and Visualizing Cancer Genomic Data
Authors: Wang Yaoyu E. , Kutnetsov Lev , Partensky Antony , Farid Jalil , Quackenbush John
Published: November 2017

Although large, complex genomic datasets are increasingly easy to generate, and the number of publicly available datasets in cancer and other diseases is rapidly growing, the lack of intuitive, easy-to-use analysis tools has remained a barrier to the effective use of such data. WebMeV (http://mev.tm4.org) is an open-source, web-based tool that gives users access to sophisticated tools for analysis of RNA-Seq and other data in an interface designed to democratize data access. WebMeV combines cloud-based technologies with a simple user interface to allow users to access large public datasets, such as that from The Cancer Genome Atlas or to upload their own. The interface allows users to visualize data and to apply advanced data mining analysis methods to explore the data and draw biologically meaningful conclusions. We provide an overview of WebMeV and demonstrate two simple use cases that illustrate the value of putting data analysis in the hands of those looking to explore the underlying biology of the systems being studied. Cancer Res; 77(21); e11–14. ©2017 AACR.
miR-519d Promotes Melanoma Progression by Downregulating EphA4
Authors: Hua Kuo-Tai , Hong Jin-Bong , Sheen Yi-Shuan , Huang Hsin-Yi , Huang Yi-Ling , Chen Jau-Shiuh , Liao Yi-Hua
Published: November 2017

Increasing evidence suggests that there is a unique cell subpopulation in melanoma that can form nonadherent melanospheres in serum-free stem cell medium, mimicking aggressive malignancy. Using melanospheres as a model to investigate progression mechanisms, we found that miR-519d overexpression was sufficient to promote cell proliferation, migration, invasion, and adhesion in vitro and lung metastatic capability in vivo. The cell adhesion receptor EphA4 was determined to be a direct target of miR-519d. Forced expression of EphA4 reversed the effects of miR-519d overexpression, whereas silencing of EphA4 phenocopied the effect of miR-519d. Malignant progression phenotypes were also affected at the level of epithelial-to-mesenchymal transition and the ERK1/2 signaling pathway inversely affected by miR-519d or EphA4 expression. In clinical specimens of metastatic melanoma, we observed significant upregulation of miR-519d and downregulation of EphA4, in the latter case correlated inversely with overall survival. Taken together, our results suggest a significant functional role for miR-519d in determining EphA4 expression and melanoma progression.

Significance: These results suggest a significant role for miR-519d in determining expression of a pivotal cell adhesion molecule that may impact risks of malignant progression in many cancers. Cancer Res; 78(1); 216–29. ©2017 AACR.
A Population of Heterogeneous Breast Cancer Patient-Derived Xenografts Demonstrate Broad Activity of PARP Inhibitor in BRCA1/2 Wild-Type Tumors
Authors: Evans Kurt W. , Yuca Erkan , Akcakanat Argun , Scott Stephen M. , Arango Natalia Paez , Zheng Xiaofeng , Chen Ken , Tapia Coya , Tarco Emily , Eterovic Agda K. , Black Dalliah M. , Litton Jennifer K. , Yap Timothy A. , Tripathy Debu , Mills Gordon B. , Meric-Bernstam Funda
Published: November 2017

Background: Breast cancer patients who do not respond to neoadjuvant therapy have a poor prognosis. There is a pressing need for novel targets and models for preclinical testing. Here we report characterization of breast cancer patient-derived xenografts (PDX) largely generated from residual tumors following neoadjuvant chemotherapy.

Experimental Design: PDXs were derived from surgical samples of primary or locally recurrent tumors. Normal and tumor DNA sequencing, RNASeq, and reverse phase protein arrays (RPPA) were performed. Phenotypic profiling was performed by determining efficacy of a panel of standard and investigational agents.

Results: Twenty-six PDXs were developed from 25 patients. Twenty-two were generated from residual disease following neoadjuvant chemotherapy, and 24 were from triple-negative breast cancer (TNBC). These PDXs harbored a heterogeneous set of genomic alterations and represented all TNBC molecular subtypes. On RPPA, PDXs varied in extent of PI3K and MAPK activation. PDXs also varied in their sensitivity to chemotherapeutic agents. PI3K, mTOR, and MEK inhibitors repressed growth but did not cause tumor regression. The PARP inhibitor talazoparib caused dramatic regression in five of 12 PDXs. Notably, four of five talazoparib-sensitive models did not harbor germline BRCA1/2 mutations, but several had somatic alterations in homologous repair pathways, including ATM deletion and BRCA2 alterations.

Conclusions: PDXs capture the molecular and phenotypic heterogeneity of TNBC. Here we show that PARP inhibition can have activity beyond germline BRCA1/2 altered tumors, causing regression in a variety of molecular subtypes. These models represent an opportunity for the discovery of rational combinations with targeted therapies and predictive biomarkers. Clin Cancer Res; 23(21); 6468–77. ©2017 AACR.
Focal Transplantation of Aberrant Glial Cells Carrying the SOD1G93A Mutation into Rat Spinal Cord Induces Extensive Gliosis
Authors: Ibarburu Sofía , Trias Emiliano , Lago Natalia , Peluffo Hugo , Barreto-Núñez Romina , Varela Valentina , Beckman Joseph S. , Barbeito Luis
Published: November 2017

Objective: We aimed to determine the potential of aberrant glial cells (AbAs) isolated from the spinal cord of adult SOD1G93A symptomatic rats to induce gliosis and neuronal damage following focal transplantation into the lumbar spinal cord of wild-type rats. Methods: AbAs were obtained from the spinal cords of SOD1G93A symptomatic rats. One hundred thousand cells were injected using a glass micropipette into the lumbar spinal cords (L3-L5) of syngeneic wild-type adult rats. Equal volumes of culture medium or wild-type neonatal microglia were used as controls. Seven days after transplantation, immunohistochemistry analysis was carried out using astrocytic and microglia cell markers. Transplanted SOD1G93A AbAs were recognized by specific antibodies to human SOD1 (hSOD1) or misfolded human SOD1. Results: Seven days after transplantation, AbAs were mainly detected in the medial region of the lumbar ventral horn as a well-limited cell cluster formed at the site of injection by their immunoreactivity to either misfolded SOD1 or normally folded hSOD1. Compared with controls, transplanted AbAs were surrounded by marked microgliosis and reactive astrocytes. Marked microgliosis was observed to extend bilaterally up to the cervical cord. Motor neurons close to AbA transplants were surrounded by activated glial cells and displayed ubiquitin aggregation. Conclusions: AbAs bearing mutant SOD1G93A have the potential to induce neuroinflammation along the spinal cord and incipient damage to the motor neurons. The emergence of AbAs during amyotrophic lateral sclerosis pathogenesis may therefore be a mechanism to boost neuroinflammation and spread motor neuron damage along the neuroaxis.
A New Baltic Population-Specific Human Genetic Marker in the PMCA4 Gene
Authors: Stavusis Janis , Inashkina Inna , Lace Baiba , Pelnena Dita , Limborska Svetlana , Khrunin Andrey , Kucinskas Vaidutis , Krumina Astrida , Piekuse Linda , Zorn Branko , Fodina Violeta , Punab Margus , Erenpreiss Juris
Published: November 2017

Objectives: The PMCA gene family consists of 4 genes and at least 21 splice variants; among these, the Ca2+ ATPase 4 (PMCA4) gene encodes a plasma membrane protein abundantly expressed in several tissues, including the kidney, heart, and sperm. Knockout of PMCA4 causes infertility due to immotile sperm in mouse models. We therefore investigated variants in this gene for potential association with infertility in groups of Estonian (n = 191) and Latvian (n = 92) men with reduced sperm motility. Methods: All exons, exon-intron boundaries, 5′ and 3′ untranslated regions, and the promoter region of the PMCA4 gene were analysed by direct sequencing for a group of Estonian infertile men. Genotyping of guanine and adenine alleles of rs147729934 was performed, using a custom-designed TaqMan® probe for a group of Latvian infertile men as well as additional groups from Latvia and several groups of people with proven ethnicity from the Baltic region. Results: Although we did not identify any significant associations between variants in the gene and infertility, our results indicated that in all studied Latvian and Estonian groups the adenine allele of the variant rs147729934 was present at a higher frequency than expected. Analysis of additional samples indicated that the adenine allele of rs147729934 likely originated once in the modern-day Baltic or western Russia area, as the frequency of the minor adenine allele observed in this region is remarkably higher than that in the general European population. Conclusions: Our results revealed no significant difference in frequencies of genetic variants in PMCA4 gene between men with normal and those with reduced sperm motility. The adenine allele of the variant rs147729934 is potentially an informative tool for future population studies concerning ancient Baltic and Finno-Ugric history.
Impact of Altered WNT2B Expression on Bladder Wall Fibroblasts: Implications for Apoptosis Regulation in the Stroma of the Lower Urinary Tract
Authors: Worst Thomas Stefan , Daskalova Kristina , Steidler Annette , Berner-Leischner Karin , Röth Ralph , Niesler Beate , Kriegmair Maximilian C. , Erben Philipp , Pfalzgraf Daniel
Published: November 2017

Background: Little is known about the role of WNT signalling in pathological processes involving the urinary tract stroma. Here the impact of WNT signalling on bladder wall fibroblasts (BWFs) was studied using integrated expression profiling. Material and Methods: WNT ligand and downstream WNT pathway component expression was profiled in human BWFs using qRT-PCR. Highly expressed WNT2B was knocked down using siRNA in BWFs. The expression of 730 mRNAs and 800 miRNAs was analyzed on the nCounter MAX platform in #WNT2B and control transfected BWFs. qRT-PCR was used for validation in vitro and in matched scar and healthy bladder wall tissue samples of 12 patients with vesico-urethral anastomotic stricture (VUAS). Results: Thirteen genes and 9 miRNAs showed differential expression in #WNT2B cells. Among these were TNFSF10, a key apoptosis inductor, (0.22fold, p = 0.011) and miR-1246 (36.2fold, p = 0.031). miRNA target prediction indicated TNFSF10 to be regulated by miR-1246. qRT-PCR analysis confirmed differential expression of miR-1246 and TNFSF10 in #WNT2B BWFs. Furthermore, TNFSF10 was significantly underexpressed in VUAS tissue (p = 0.009). Conclusion: Perturbation of WNT signalling results in an altered expression of the apoptosis inductor TNFSF10. Similar changes are observed in VUAS. Further studies investigating the crosslink between WNT signalling and apoptosis regulation in the urinary tract stroma are warranted.