bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Flattening
Authors: Kim Jungeun , Lee Jae-Gil , Lim Sungsu
Published: October 2016

Amulti-layer graphconsists of multiple layers of weighted graphs, where the multiple layers represent the different aspects of relationships. Considering multiple aspects (i.e., layers) together is essential to achieve a comprehensive and consolidated view. In this article, we propose a novel framework ofdifferential flattening, which facilitates the analysis of multi-layer graphs, and apply this framework to community detection. Differential flattening merges multiple graphs into a single graph such that the graph structure with the maximum clustering coefficient is obtained from the single graph. It has two distinct features compared with existing approaches. First, dealing with multiple layers is doneindependentlyof a specific community detection algorithm, whereas previous approaches rely on a specific algorithm. Thus, any algorithm for a single graph becomes applicable to multi-layer graphs. Second, the contribution of each layer to the single graph is determinedautomaticallyfor the maximum clustering coefficient. Since differential flattening is formulated by an optimization problem, the optimal solution is easily obtained by well-known algorithms such as interior point methods. Extensive experiments were conducted using the Lancichinetti-Fortunato-Radicchi (LFR) benchmark networks as well as the DBLP, 20 Newsgroups, and MIT Reality Mining networks. The results show that our approach of differential flattening leads to discovery of higher-quality communities than baseline approaches and the state-of-the-art algorithms.
On a New SDP-SOCP Method for Acoustic Source Localization Problem
Authors: Gao Mingjie , Yiu Ka-Fai Cedric , Nordholm Sven , Ye Yinyu
Published: October 2016

Acoustic source localization has many important applications. Convex relaxation provides a viable approach of obtaining good estimates very efficiently. There are two popular convex relaxation methods using either semi-definite programming (SDP) or second-order cone programming (SOCP). However, the performances of the methods have not been studied properly in the literature and there is no comparison in terms of accuracy and performance. The aims of this article are twofold. First of all, we study and compare several convex relaxation methods. We demonstrate, by numerical examples, that most of the convex relaxation methods cannot localize the source exactly, even in the performance limit when the time difference of arrival (TDOA) information is exact. In addressing this problem, we propose a novel mixed SDP-SOCP relaxation model and study the characteristics of the optimal solutions and its localizable region. Furthermore, an error correction scheme for the proposed SDP-SOCP model is developed so that exact localization can be achieved in the performance limit. Experimental data have been collected in a room with two different array configurations to demonstrate our proposed approach.
Damaris
Authors: Dorier Matthieu , Antoniu Gabriel , Cappello Franck , Snir Marc , Sisneros Robert , Yildiz Orcun , Ibrahim Shadi , Peterka Tom , Orf Leigh
Published: October 2016

With exascale computing on the horizon, reducing performance variability in data management tasks (storage, visualization, analysis, etc.) is becoming a key challenge in sustaining high performance. This variability significantly impacts the overall application performance at scale and its predictability over time.

In this article, we present Damaris, a system that leverages
dedicated cores
in multicore nodes to offload data management tasks, including I/O, data compression, scheduling of data movements, in situ analysis, and visualization. We evaluate Damaris with the CM1 atmospheric simulation and the Nek5000 computational fluid dynamic simulation on four platforms, including NICS’s Kraken and NCSA’s Blue Waters. Our results show that (1) Damaris fully hides the I/O variability as well as all I/O-related costs, thus making simulation performance predictable; (2) it increases the sustained write throughput by a factor of up to 15 compared with standard I/O approaches; (3) it allows almost perfect scalability of the simulation up to over 9,000 cores, as opposed to state-of-the-art approaches that fail to scale; and (4) it enables a seamless connection to the VisIt visualization software to perform in situ analysis and visualization in a way that impacts neither the performance of the simulation nor its variability.

In addition, we extended our implementation of Damaris to also support the use of
dedicated nodes
and conducted a thorough comparison of the two approaches—dedicated cores and dedicated nodes—for I/O tasks with the aforementioned applications.
Temporal Lossless and Lossy Compression in Wireless Sensor Networks
Authors: Li Yimei , Liang Yao
Published: October 2016

Energy efficiency is one of the most critical issues in the design and deployment of Wireless Sensor Networks (WSNs). Data compression is an important approach to reducing energy consumption of data gathering in multihop sensor networks. Existing compression algorithms only apply to either lossless or lossy data compression, but not to both. This article presents a generalized predictive coding framework for unified lossless and lossy data compression. In addition, we devise a novel algorithm for lossless compression to significantly improve data compression performance for various data collections and applications in WSNs. Rigorous simulations show our proposed framework and compression algorithm outperform several recent popular compression algorithms for WSNs such as Lossless Entropy Compression (LEC), S-Lempel-Ziv-Welch (LZW), and Lightweight Temporal Compression (LTC) using various real-world sensor datasets, demonstrating the merit of the proposed framework for unified temporal lossless and lossy data compression in WSNs.
Luzzu—A Methodology and Framework for Linked Data Quality Assessment
Authors: Debattista Jeremy , Auer SÖren , Lange Christoph
Published: October 2016

The increasing variety of Linked Data on the Web makes it challenging to determine the quality of this data and, subsequently, to make this information explicit to data consumers. Despite the availability of a number of tools and frameworks to assess Linked Data Quality, the output of such tools is not suitable for machine consumption, and thus consumers can hardly compare and rank datasets in the order of
fitness for use
. This article describes a conceptual methodology for assessing Linked Datasets, and Luzzu; a framework for Linked Data Quality Assessment. Luzzu is based on four major components: (1) an
extensible
interface for defining new quality metrics; (2) an
interoperable
, ontology-driven back-end for representing quality metadata and quality problems that can be re-used within different semantic frameworks; (3)
scalable
dataset processors for data dumps, SPARQL endpoints, and big data infrastructures; and (4) a
customisable
ranking algorithm taking into account user-defined weights. We show that Luzzu scales linearly against the number of triples in a dataset. We also demonstrate the applicability of the Luzzu framework by evaluating and analysing a number of statistical datasets against a variety of metrics. This article contributes towards the definition of a holistic data quality lifecycle, in terms of the co-evolution of linked datasets, with the final aim of improving their quality.
Towards More Accurate Statistical Profiling of Deployed schema.org Microdata
Authors: Meusel Robert , Ritze Dominique , Paulheim Heiko
Published: October 2016

Being promoted by major search engines such as Google, Yahoo!, Bing, and Yandex, Microdata embedded in web pages, especially using schema.org, has become one of the most important markup languages for the Web. However, deployed Microdata is very often not free from errors, which makes it difficult to estimate the data volume and create an accurate data profile. In addition, as the usage of global identifiers is not common, the real number of entities described by this format in the Web is hard to assess. In this article, we discuss how the subsequent application of data cleaning steps, such as duplicate detection and correction of common schema-based errors, leads to a more realistic view on the data, step by step. The cleaning steps applied include both heuristics for fixing errors as well as means to perform duplicate detection and duplicate elimination. Using the Web Data Commons Microdata corpus, we show that applying such quality improvement methods can essentially change the statistical profile of the dataset and lead to different estimates of both the number of entities as well as the class distribution within the data.
Industrial Scale Agile - from Craft to Engineering
Authors: Jacobson Ivar , Spence Ian , Seidewitz Ed
Published: October 2016

There are many, many ways to illustrate how fragile IT investments can be. You just have to look at the way that, even after huge investments in education and coaching, many organizations are struggling to broaden their agile adoption to the whole of their organization - or at the way other organizations are struggling to maintain the momentum of their agile adoptions as their teams change and their systems mature.
Adult expression of PGC-1α and -1β in skeletal muscle is not required for endurance exercise-induced enhancement of exercise capacity
Authors: Ballmann Christopher , Tang Yawen , Bush Zachary , Rowe Glenn C.
Published: October 2016

Exercise has been shown to be the best intervention in the treatment of many diseases. Many of the benefits of exercise are mediated by adaptions induced in skeletal muscle. The peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators has emerged as being key mediators of the exercise response and is considered to be essential for many of the adaptions seen in skeletal muscle. However, the contribution of the PGC-1s in skeletal muscle has been evaluated by the use of either whole body or congenital skeletal muscle-specific deletion. In these models, PGC-1s were never present, thereby opening the possibility to developmental compensation. Therefore, we generated an inducible muscle-specific deletion of PGC-1α and -1β (iMyo-PGC-1DKO), in which both PGC-1α and -β can be deleted specifically in adult skeletal muscle. These iMyo-PGC-1DKO animals were used to assess the role of both PGC-1α and -1β in adult skeletal muscle and their contribution to the exercise training response. Untrained iMyo-PGC-1DKO animals exhibited a time-dependent decrease in exercise performance 8 wk postdeletion, similar to what was observed in the congenital muscle-specific PGC-1DKOs. However, after 4 wk of voluntary training, the iMyo-PGC-1DKOs exhibited an increase in exercise performance with a similar adaptive response compared with control animals. This increase was associated with an increase in electron transport complex (ETC) expression and activity in the absence of PGC-1α and -1β expression. Taken together these data suggest that PGC-1α and -1β expression are not required for training-induced exercise performance, highlighting the contribution of PGC-1-independent mechanisms.
Molecular determinants of transport function in zebrafish Slc34a Na-phosphate transporters
Authors: Werner Andreas , Patti Monica , Zinad Hany S , Fearn Amy , Laude Alex , Forster Ian
Published: October 2016

The epithelial Na+-coupled phosphate cotransporter family Slc34a (NaPi-II) is well conserved in vertebrates and plays an essential role in maintaining whole body levels of inorganic phosphate (Pi). A three-dimensional model of the transport protein has recently been proposed with defined substrate coordination sites. Zebrafish express two NaPi-II isoforms with high sequence identity but a 10-fold different apparent Km for Pi ([Formula: see text]). We took advantage of the two zebrafish isoforms to investigate the contribution of specific amino acids to Pi coordination and transport. Mutations were introduced to gradually transform the low-affinity isoform into a high-affinity transporter. The constructs were expressed in Xenopus laevis oocytes and functionally characterized. Becaue the cotransport of Pi and Na involves multiple steps that could all influence [Formula: see text], we performed a detailed functional analysis to characterize the impact of the mutations on particular steps of the transport cycle. We used varying concentrations of the substrates Pi and its slightly larger analog, arsenate, as well as the cosubstrate, Na+. Moreover, electrogenic kinetics were performed to assess intramolecular movements of the transporter. All of the mutations were found to affect multiple transport steps, which suggested that the altered amino acids induced subtle structural changes rather than coordinating Pi directly. The likely positions of the critical residues were mapped to the model of human Slc34a, and their localization in relation to the proposed substrate binding pockets concurs well with the observed functional data.
Impaired urinary osteopontin excretion in Npt2a−/− mice
Authors: Caballero Daniel , Li Yuwen , Ponsetto Julian , Zhu Chuanlong , Bergwitz Clemens
Published: October 2016

Mutations in the renal sodium-dependent phosphate cotransporters NPT2a and NPT2c have been reported in patients with renal stone disease and nephrocalcinosis. Oral phosphate supplementation is currently thought to reduce risk by reversing the hypercalciuria, but the exact mechanism remains unclear and the relative contribution of modifiers of mineralization such as osteopontin ( Opn) to the formation of renal mineral deposits in renal phosphate wasting disorders has not been studied. We observed a marked decrease of renal gene expression and urinary excretion of Opn in Npt2a−/− mice, a mouse model of these disorders, at baseline. Following supplementation with phosphate Opn gene expression was restored to wild-type levels in Npt2a−/− mice; however, urine excretion of the protein remained low. To further investigate the role of Opn, we used a double-knockout strategy, which provides evidence that loss of Opn worsens the nephrocalcinosis and nephrolithiasis observed in these mice on a high-phosphate diet. These studies suggest that impaired Opn gene expression and urinary excretion in Npt2a−/− mice may be an additional risk factor for nephrolithiasis, and normalizing urine Opn levels may improve the therapy of phosphaturic disorders.
Outside the mainstream: novel collecting duct proteins regulating water balance
Authors: Rahman Shamma S. , Boesen Erika I.
Published: October 2016

Body water balance is critical to survival and, therefore, very tightly regulated by the hypothalamus and kidney. A key mechanism involved in this process, the arginine vasopressin-mediated phosphorylation and apical membrane insertion of aquaporin 2 in the collecting duct, has been extensively studied; however, with the increased availability of conditional knockout animals, several novel collecting duct proteins have recently been implicated in water homeostasis. In this Mini-Review, we briefly discuss these novel proteins and their roles in the regulation of water homeostasis.
Large Bowel Obstruction, a Delayed Complication of Severe Gallstone Pancreatitis
Authors: Lal Neeraj , Whiting John , Hejmadi Rahul , Raman Sudarsanam
Published: October 2016

Colonic complications are rare after acute pancreatitis but are associated with a high mortality. Possible complications include mechanical obstruction, ischaemic necrosis, haemorrhage, and fistula. We report a case of large bowel obstruction in a 31-year-old postpartum female, secondary to severe gallstone pancreatitis. The patient required emergency laparotomy and segmental bowel resection, as well as cholecystectomy. Presentation of obstruction occurs during the acute episode or can be delayed for several weeks. The most common site is the splenic flexure owing to its proximity to the pancreas. Initial management may be conservative, stenting, or surgical. CT is an acceptable baseline investigation in all cases of new onset bowel obstruction. Although bowel obstruction is a rare complication of pancreatitis, clinicians should be aware of it due to its high mortality. Obstruction can occur after a significant delay following the resolution of pancreatitis. Those patients with evidence of colonic involvement on pancreatic imaging warrant further large bowel evaluation. Bowel resection may be required electively or acutely. Colonic stenting has an increasing role in the management of large bowel obstruction but is a modality of treatment that needs further evaluation in this setting.
Orthodontic Protocol Using Mini-Implant for Class II Treatment in Patient with Special Needs
Authors: Carvalho Ferreira Fernando Pedrin , Barbosa Lima Anderson Paulo , de Paula Eliana de Cássia Molina , Ferreira Conti Ana Claudia de Castro , Valarelli Danilo Pinelli , de Almeida-Pedrin Renata Rodrigues
Published: October 2016

Improving facial and dental appearance and social interaction are the main factors for special needs (SN) patients to seek orthodontic treatment. The cooperation of SN patients and their parents is crucial for treatment success.Objective. To show through a case report the satisfactory results, both functional and esthetic, in patients with intellectual disability, congenital nystagmus, and severe scoliosis.Materials Used. Pendulum device with mini-implants as anchorage unit.Results. Improvement of facial and dental esthetics, correction of Class II malocclusion, and no root resorption shown in the radiographic follow-up.Conclusion. Knowing the limitations of SN patients, having a trained team, motivating and counting on the cooperation of parents and patients, and employing quick and low-cost orthodontic therapy have been shown to be the essential factors for treatment success.
The Connections of Pregnancy-, Delivery-, and Infant-Related Risk Factors and Negative Life Events on Postpartum Depression and Their Role in First and Recurrent Depression
Authors: Kettunen Pirjo , Koistinen Eeva , Hintikka Jukka
Published: October 2016

Introduction. The aim of this study is to assess how negative life events and adverse experiences with pregnancy, delivery, the infant(s), and breastfeeding cessation impact on postpartum depression (PPD), specifically in first lifetime and recurrent depression. Method. The study group comprised 104 mothers with a current episode of PPD and a control group of 104 mothers who did not have current PPD. The Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) was used for data collection. The course of the depression, adverse experiences, and breastfeeding were assessed by self-reports. Results. In age-adjusted multivariate analyses, mental and physical problems during pregnancy or delivery, postpartum problems with the infant and breastfeeding cessation, and negative life events during the previous 12 months were associated with postpartum depression. Eighteen percent (18%) of the mothers had first depression and 82% recurrent depression. Mental and physical problems during pregnancy or delivery were associated with both first lifetime and recurrent depression. Nevertheless, negative life events and infant/breastfeeding issues associated only with recurrent depression. Conclusion. Factors associated with pregnancy and delivery have an impact on PPD, but in recurrent depression other postnatal and psychosocial factors are also important risk factors.
Caspase‐3 Deletion Promotes Necrosis in Atherosclerotic Plaques of ApoE Knockout Mice
Authors: Grootaert Mandy O. J. , Schrijvers Dorien M. , Hermans Marthe , Van Hoof Viviane O. , De Meyer Guido R. Y. , Martinet Wim
Published: October 2016

Apoptosis of macrophages and vascular smooth muscle cells (VSMCs) in advanced atherosclerotic plaques contributes to plaque progression and instability. Caspase‐3, a key executioner protease in the apoptotic pathway, has been identified in human and mouse atherosclerotic plaques but its role in atherogenesis is not fully explored. We therefore investigated the impact of caspase‐3 deletion on atherosclerosis by crossbreeding caspase‐3 knockout (Casp3−/−) mice with apolipoprotein E knockout (ApoE−/−) mice. Bone marrow‐derived macrophages and VSMCs isolated from Casp3−/−ApoE−/− mice were resistant to apoptosis but showed increased susceptibility to necrosis. However, caspase‐3 deficiency did not sensitize cells to undergo RIP1‐dependent necroptosis. To study the effect on atherosclerotic plaque development, Casp3+/+ApoE−/− and Casp3−/−ApoE−/− mice were fed a western‐type diet for 16 weeks. Though total plasma cholesterol, triglycerides, and LDL cholesterol levels were not altered, both the plaque size and percentage necrosis were significantly increased in the aortic root of Casp3−/−ApoE−/− mice as compared to Casp3+/+ApoE−/− mice. Macrophage content was significantly decreased in plaques of Casp3−/−ApoE−/− mice as compared to controls, while collagen content and VSMC content were not changed. To conclude, deletion of caspase‐3 promotes plaque growth and plaque necrosis in ApoE−/− mice, indicating that this antiapoptotic strategy is unfavorable to improve atherosclerotic plaque stability.
Development of Hydrophilic Interaction Liquid Chromatography Method for the Analysis of Moxonidine and Its Impurities
Authors: Filipic Slavica , Elek Milica , Popović Marija , Nikolic Katarina , Agbaba Danica
Published: October 2016

Fast and simple hydrophilic interaction liquid chromatography (HILIC) method was developed and validated for the analysis of moxonidine and its four impurities (A, B, C, and D) in pharmaceutical dosage form. All experiments were performed on the Agilent Technologies 1200 high-performance liquid chromatography (HPLC) system using Zorbax RX-SIL, 250 mm × 4.6 mm, 5 μm column as stationary phase (T=25°C, F=1 mL/min, and λ=255 nm), and mixture of acetonitrile and 40 mM ammonium formate buffer (pH 2.8) 80 : 20 (v/v) as mobile phase. Under the optimal chromatographic conditions, selected by central composite design, separation and analysis of moxonidine and its four impurities are enabled within 12 minutes. Validation of the method was conducted in accordance with ICH guidelines. Based on the obtained results selectivity, linearity (r≥0.9976), accuracy (recovery: 93.66%–114.08%), precision (RSD: 0.56%–2.55%), and robustness of the method were confirmed. The obtained values of the limit of detection and quantification revealed that the method can be used for determination of impurities levels below 0.1%. Validated method was applied for determination of moxonidine and its impurities in commercially available tablet formulation. Obtained results confirmed that validated method is fast, simple, and reliable for analysis of moxonidine and its impurities in tablets.
Thermoregulatory Instability in Childhood: Linking the Normal Brain to Hypothalamic Storm
Authors: Alves Martins William , do Amaral Cristovam Rafael , Fussiger Helena , Maria Vedana Viviane , Hemb Marta
Published: October 2016

Central core temperature is tightly controlled by hypothalamic centers, a feature that makes sudden changes in body temperature very unusual. A dysfunction of these hypothalamic pathways leads to Shapiro’s syndrome, comprising spontaneous hypothermia, hyperhidrosis, and corpus callosum dysgenesis. Although it may affect any age, usually it presents in childhood. Variants to this syndrome with completely normal brain anatomy have been consistently reported, expanding the clinical spectrum of the syndrome. Herein, we report the case of a 4-year-old girl with Shapiro’s syndrome and unaffected corpus callosum.
Comparison of Bone Resorption Rates after Intraoral Block Bone and Guided Bone Regeneration Augmentation for the Reconstruction of Horizontally Deficient Maxillary Alveolar Ridges
Authors: Gultekin B. Alper , Bedeloglu Elcin , Kose T. Emre , Mijiritsky Eitan
Published: October 2016

Purpose. Bone atrophy after tooth loss may leave insufficient bone for implant placement. We compared volumetric changes after autogenous ramus block bone grafting (RBG) or guided bone regeneration (GBR) in horizontally deficient maxilla before implant placement. Materials and Methods. In this retrospective study, volumetric changes at RBG or GBR graft sites were evaluated using cone-beam computed tomography. The primary outcome variable was the volumetric resorption rate. Secondary outcomes were bone gain, graft success, and implant insertion torque. Results. Twenty-four patients (28 grafted sites) were included (GBR, 15; RBG, 13). One patient (RBG) suffered mucosal dehiscence at the recipient site 6 weeks after surgery, which healed spontaneously. Mean volume reduction in the GBR and RBG groups was 12.48 ± 2.67% and 7.20 ± 1.40%, respectively. GBR resulted in significantly more bone resorption than RBG (P<0.001). Mean horizontal bone gain and width after healing were significantly greater in the GBR than in the RBG group (P=0.002 and 0.005, resp.). Implant torque was similar between groups (P>0.05). Conclusions. Both RBG and GBR hard-tissue augmentation techniques provide adequate bone graft volume and stability for implant insertion. However, GBR causes greater resorption at maxillary augmented sites than RBG, which clinicians should consider during treatment planning.
An Unusual Suspect: Lymphoepithelial Cyst of the Pancreas
Authors: Adike Abimbola , Horsley-Silva Jennifer L. , Deval Neha , Conley Christopher R. , Lam-Himlin Dora M. , Nguyen Cuong C.
Published: October 2016

Lymphoepithelial cysts (LECs) of the pancreas are benign, rare pancreatic cysts that are found predominantly in men. These cysts can present as a diagnostic conundrum given their rarity and difficulty of distinguishing these cysts from those with malignant potential. We present an incidental case of a LEC in a middle-aged man.
A Complicated Course of Acute Viral Induced Pharyngitis, Icteric Hepatitis, Acalculous Cholecystitis, and Skin Rash
Authors: Sheybani Fereshte , Naderi HamidReza , Erfani Seddigheh Sadat , Gharib Masoumeh
Published: October 2016

This case reveals the complexities and challenges in the diagnosis of acute Epstein-Barr virus (EBV) infection, indicating the potential relationship between EBV infection and severe icteric hepatitis, acalculous cholecystitis, and lymphocytic vasculitis. We suggest including EBV infectious mononucleosis in the list of differential diagnoses when any of these clinical syndromes (or a combination thereof) occurs without apparent cause, especially in the presence of lymphocytosis. To our knowledge, this is the first report to suggest the possible role of EBV in the pathogenesis of cutaneous lymphocytic vasculitis. Also it is possible that EBV infection triggered the flare-up of the underlying rheumatologic disease. Therefore, it could be assumed that a part of the clinical syndrome (e.g., dermatologic manifestations) might be related to the flare-up of the underlying rheumatologic disease.
Massive Thrombosis of the Right Atrium Extended to the Superior Vena Cava at the Diagnosis of Acute Myeloid Leukemia
Authors: Houssou Bienvenu , Orou-Guiwa Gnon Gourou , Habbal Rachida , Qachouh Meryem , Quessar Asmaa
Published: October 2016

Introduction. Venous thromboembolic disease is a common complication found in 8% of patients with acute myeloid leukemia. The location at the right atrium is exceptional. These last fifty years, only 6 cases of thrombosis of the atrium in the diagnosis of acute myeloid leukemia were published on PubMed search engine. Case Presentation. 35-year-old farmer, who had been admitted by emergency department for superior vena cava syndrome and had a hyperleukocytic AML with complex karyotype associated with a significant thrombosis of the right atrium, extended all along the superior vena cava. He has been treated by the 2011 AML protocol using low molecular weight heparin and died from respiratory distress. Conclusions. If thrombosis is common in AML, the location in right atrium is rare. Its management requires surgery that is sometimes difficult to achieve.
The Case for Improved Interprofessional Care: Fatal Analgesic Overdose Secondary to Acute Dental Pain during Pregnancy
Authors: Lee Sarah K. Y. , Quinonez Rocio B. , Chuang Alice , Munz Stephanie M. , Dabiri Darya
Published: October 2016

Prenatal oral health extends beyond the oral cavity, impacting the general well-being of the pregnant patient and her fetus. This case report follows a 19-year-old pregnant female presenting with acute liver failure secondary to acetaminophen overdose for management of dental pain following extensive dental procedures. Through the course of her illness, the patient suffered adverse outcomes including fetal demise, acute kidney injury, spontaneous bacterial peritonitis, and septic shock before eventual death from multiple organ failure. In managing the pregnant patient, healthcare providers, including physicians and dentists, must recognize and optimize the interconnected relationships shared by the health disciplines. An interdisciplinary approach of collaborative and coordinated care, the timing, sequence, and treatment for the pregnant patient can be improved and thereby maximize overall quality of health. Continued efforts toward integrating oral health into general healthcare education through interprofessional education and practice are necessary to enhance the quality of care that will benefit all patients.
Ma Huang Tang Suppresses the Production and Expression of Inflammatory Chemokines via Downregulating STAT1 Phosphorylation in HaCaT Keratinocytes
Authors: Lim Hye-Sun , Seo Chang-Seob , Jin Seong-Eun , Yoo Sae-Rom , Lee Mee-Young , Shin Hyeun-Kyoo , Jeong Soo-Jin
Published: October 2016

Ma huang tang (MHT) is a traditional herbal medicine comprising six medicinal herbs and is used to treat influenza‐like illness. However, the effects of MHT on inflammatory skin diseases have not been verified scientifically. We investigated determining the inhibitory effects of MHT against inflammation responses in skin using HaCaT human keratinocyte cells. We found that MHT suppressed production of thymus and activation‐regulated chemokine (TARC/CCL17), macrophage‐derived chemokine (MDC/CCL22), regulated on activation of normal T‐cell expressed and secreted (RANTES/CCL5), and interleukin‐8 (IL‐8) in tumor necrosis factor‐α (TNF‐α) and interferon‐γ‐ (IFN‐γ‐) stimulated HaCaT cells. Consistently, MHT suppressed the mRNA expression of TARC, MDC, RANTES, and IL‐8 in TNF‐α and IFN‐γ‐stimulated cells. Additionally, MHT inhibited TNF‐α and IFN‐γ‐stimulated signal transducer and activator of transcription 1 (STAT1) phosphorylation in a dose‐dependent manner and nuclear translocation in HaCaT cells. Our finding indicates that MHT inhibits production and expression of inflammatory chemokines in the stimulated keratinocytes by downregulating STAT1 phosphorylation, suggesting that MHT may be a possible therapeutic agent for inflammatory skin diseases.
Applying Modelica Tools to System Dynamics Based Learning Games: Project Management Game
Authors: Miettinen Tuomas , Salmi Juho , Gupta Kunal , Koskela Jussi , Kauttio Janne , Karhela Tommi , Ruutu Sampsa
Published: October 2016

Learning simulation games are interactive simulations with game characteristics. This paper presents a learning simulation game for EPCM (engineering, procurement, and construction management) project management training. The simulation model utilises system dynamics, which is a methodology for understanding the behaviour of dynamic complex systems of different domains using modelling and simulation. The system dynamics model in turn uses the equation-based Modelica modelling language: a system dynamics model created with the graphical user interface is converted to a pure Modelica model. Two Modelica environments, namely, OpenModelica and the custom Modelica solver, have been used to simulate the generated Modelica model. The focus of this article is on how generic systems modelling and simulation platforms such as Modelica based environments can be utilised in developing a learning simulation game: what benefits do they bring and what disadvantages do they have? On the one hand, it is evaluated how the Modelica language as such is suitable for being used in a learning game development. On the other hand, the suitability of the selected implementation environments, that is, OpenModelica, the custom Modelica solver, Simantics, and Simupedia, is evaluated. The paper also shortly presents how the project management game was received by its players.
The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models
Authors: Zhang Sen , Anjum Rana , Squillace Rachel , Nadworny Sara , Zhou Tianjun , Keats Jeff , Ning Yaoyu , Wardwell Scott D. , Miller David , Song Youngchul , Eichinger Lindsey , Moran Lauren , Huang Wei-Sheng , Liu Shuangying , Zou Dong , Wang Yihan , Mohemmad Qurish , Jang Hyun Gyung , Ye Emily , Narasimhan Narayana , Wang Frank , Miret Juan , Zhu Xiaotian , Clackson Tim , Dalgarno David , Shakespeare William C. , Rivera Victor M.
Published: October 2016

Purpose: Non–small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK+) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Here, we report the structure and first comprehensive preclinical evaluation of the next-generation ALK TKI brigatinib.

Experimental Design: A kinase screen was performed to evaluate the selectivity profile of brigatinib. The cellular and in vivo activities of ALK TKIs were compared using engineered and cancer-derived cell lines. The brigatinib–ALK co-structure was determined.

Results: Brigatinib potently inhibits ALK and ROS1, with a high degree of selectivity over more than 250 kinases. Across a panel of ALK+ cell lines, brigatinib inhibited native ALK (IC50, 10 nmol/L) with 12-fold greater potency than crizotinib. Superior efficacy of brigatinib was also observed in mice with ALK+ tumors implanted subcutaneously or intracranially. Brigatinib maintained substantial activity against all 17 secondary ALK mutants tested in cellular assays and exhibited a superior inhibitory profile compared with crizotinib, ceritinib, and alectinib at clinically achievable concentrations. Brigatinib was the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses.

Conclusions: Brigatinib is a highly potent and selective ALK inhibitor. These findings provide the molecular basis for the promising activity being observed in ALK+, crizotinib-resistant patients with NSCLC being treated with brigatinib in clinical trials. Clin Cancer Res; 22(22); 5527–38. ©2016 AACR.
Enrolling Adolescents in Disease/Target-Appropriate Adult Oncology Clinical Trials of Investigational Agents
Authors: Chuk Meredith K. , Mulugeta Yeruk , Roth-Cline Michelle , Mehrotra Nitin , Reaman Gregory H.
Published: October 2016

The enrollment of adolescents with cancer in clinical trials is much lower than that of younger pediatric patients. For adolescents with “adult-type” cancers, lack of access to relevant trials is cited as one of the reasons for this discrepancy. Adolescents are generally not eligible for enrollment in adult oncology trials, and initial pediatric trials for many drugs are conducted years later, often after the drug is approved. As a result, accrual of adolescents to these trials may be slow due to off-label use, prospectively collected safety and efficacy data are lacking at the time of initial approval, and, most importantly, these adolescents have delayed access to effective therapies. To facilitate earlier access to investigational and approved drugs for adolescent patients with cancer, and because drug exposure is most often similar in adolescents and adults, we recommend the inclusion of adolescents (ages 12–17) in disease- and target-appropriate adult oncology trials. This approach requires careful monitoring for any differential safety signals, appropriate pharmacokinetic evaluations, and ensuring that ethical requirements are met. Inclusion of adolescents in adult oncology trials will require the cooperation of investigators, cooperative groups, industry, institutional review boards, and regulatory agencies to overcome real and perceived barriers. Clin Cancer Res; 23(1); 9–12. ©2016 AACR.
Mechanisms of Resistance to Antibody–Drug Conjugates
Authors: Loganzo Frank , Sung Matthew , Gerber Hans-Peter
Published: October 2016

Drug resistance limits the effectiveness of cancer therapies. Despite attempts to develop curative anticancer treatments, tumors evolve evasive mechanisms limiting durable responses. Hence, diverse therapies are used to attack cancer, including cytotoxic and targeted agents. Antibody–drug conjugates (ADC) are biotherapeutics designed to deliver potent cytotoxins to cancer cells via tumor-specific antigens. Little is known about the clinical manifestations of drug resistance to this class of therapy; however, recent preclinical studies reveal potential mechanisms of resistance. Because ADCs are a combination of antibody and small molecule cytotoxin, multifactorial modes of resistance are emerging that are inherent to the structure and function of the ADC. Decreased cell-surface antigen reduces antibody binding, whereas elevated drug transporters such as MDR1 and MRP1 reduce effectiveness of the payload. Inherent to the uniqueness of the ADC, other novel resistance mechanisms are emerging, including altered antibody trafficking, ADC processing, and intracellular drug release. Most importantly, the modular nature of the ADC allows components to be switched and replaced, enabling development of second-generation ADCs that overcome acquired resistance. This review is intended to highlight recent progress in our understanding of ADC resistance, including approaches to create preclinical ADC-refractory models and to characterize their emerging mechanisms of resistance. Mol Cancer Ther; 15(12); 2825–34. ©2016 AACR.
A Way Forward for Cancer Chemoprevention: Think Local
Authors: Al Rabadi Luai , Bergan Raymond
Published: October 2016

As cells progress through carcinogenesis, the associated exponential expansion of genetic and molecular aberrations and resultant heterogeneity make therapeutic success increasingly unattainable. Therapeutic intervention at early stages of carcinogenesis that occurs within the primary organ and in the face of a lower burden of molecular aberrations, constitutes a basic tenet of cancer chemoprevention, and provides a situation that favors a greater degree of therapeutic efficacy compared with that of advanced cancer. A longstanding barrier to chemoprevention relates to the requirement for essentially no systemic toxicity, and the fact that when large numbers of people are treated, the emergence of systemic toxicity is almost universal. A rational means to address this in fact relates to a second basic tenet of the chemopreventive strategy: the focus of therapeutic intervention is to disrupt a process that is in essence localized to a single organ. Based upon this consideration, a strategy which is based upon local delivery of therapeutics to an at-risk organ will achieve therapeutic efficacy while avoiding systemic delivery and its associated toxicity. This article will review the rationale for undertaking such an approach, describe successful clinical achievements based on this strategy, describe ongoing efforts to expand the impact of this approach, and together will highlight the high impact that this approach has already had on the field as well as its extremely high potential for future impact. Cancer Prev Res; 10(1); 14–35. ©2016 AACR.
Does the Number of Neoadjuvant Chemotherapy Cycles before Interval Debulking Surgery Influence Survival in Advanced Ovarian Cancer?
Authors: Akladios Cherif , Baldauf Jean-Jacques , Marchal Frederic , Hummel Michel , Rebstock Laure-Emilie , Kurtz Jean-Emmanuel , Petit Thierry , Afors Karolina , Mathelin Carole , Lecointre Lise , Schrot-Sanyan Stéphanie
Published: October 2016

Objective: To evaluate the overall survival (OS) of patients with initially inoperable advanced ovarian cancer, tubal carcinoma, or primary peritoneal carcinoma of stages III or IV undergoing neoadjuvant chemotherapy (NAC) followed by cytoreductive surgery, according to the number of cycles performed. Methods: This retrospective study was conducted in three main oncology centres in the east of France, reviewing the charts of all patients who underwent NAC between January 1, 1998 and October 31, 2012. We performed an OS analysis using multivariate Cox regression models adjusted for potential confounders. We also analysed progression-free survival (PFS) as well as chemotherapy- and surgery-related morbidity. Results: Of the 204 patients included, 75 (36.8%) underwent ≤4 NAC cycles and 129 (63.2%) ≥5 NAC cycles. Characteristic data were similar in the two groups. Five-year OS was 35.0 and 25.8%, respectively. This difference was non-significant [HR = 1.06 (0.70-1.59), p = 0.79]. We also found no differences in PFS or morbidity between the two groups. Conclusions: The number of NAC cycles does not seem to play a role in the OS of patients with advanced ovarian cancer. Further evidence and prospective data are needed to assess the value of a high/low number of NAC cycles among these patients.
Classical and Molecular Cytogenetics of the Panther Genet Genetta maculata (Mammalia, Carnivora, Viverridae)
Authors: Matoso Silva Raquel , Adega Filomena , Kjöllerström Helena J. , Labuschagne Kim , Kotze Antoinette , Fernandes Carlos , Chaves Raquel , do Mar Oom Maria
Published: October 2016

Genets (Genetta) are a genus of African mammalian carnivorans with 14 currently recognized species, although taxonomic uncertainties remain, particularly regarding the number of species within the large-spotted genet complex. This study presents the first banded karyotype and molecular cytogenetic analysis of a genetically identified panther genet, Genetta maculata, the most common and widespread taxon of the large-spotted genet complex, with a wide distribution in sub-Saharan Africa. Sampled in Gauteng Province, South Africa, it could be assigned to the subspecies G. m. letabae on geographic grounds and had a similar karyotype (2n = 52, FNa = 96) to those published for a panther genet from Ethiopia and for the West African large-spotted genet G. pardina. Notably, the specimen had a different autosomal morphology (2 acrocentric chromosomes) from that previously attributed to letabae (a single acrocentric chromosome), but the latter assignment was uncertain because the studied individuals were captive born and assigned based solely on a presumed origin in the former Transvaal Province of South Africa. Fluorescence in situ hybridization with a telomere repeat probe revealed the presence of telomeric sequences in the centromeres of most chromosomes, the so-called interstitial telomeric sites (ITSs). Since genets seem to have a unique, highly rearranged karyotype among feliforms and relatively low interspecific karyotypic variation, and considering the known instability of ITSs, we suggest that the large amount of ITSs found here might be due to evolutionarily recent extensive genomic rearrangements. This study provides cytogenetic information that contributes to our understanding of chromosomal variation and genomic rearrangements in genets, and valuable baseline data for future studies of karyotype evolution in carnivores in general and viverrids in particular.
Investigating the Genetic Basis of Social Conformity: The Role of the Dopamine Receptor 3 (DRD3) Gene
Authors: Zhao Chunli , Liu Jinting , Gong Pingyuan , Hu Jie , Zhou Xiaolin
Published: October 2016

Background: People often change their opinions or behavior to match the responses of others, a phenomenon known as social conformity. Conforming behavior varies substantially across individuals. However, little is known about the genetic basis underlying individual differences in social conformity. A recent study demonstrated an association between enhanced dopaminergic function and increased conforming behavior. Given the effect of the dopamine receptor 3 gene (DRD3) Ser9Gly polymorphism (rs6280) on dopamine release in the striatum, this study investigated to what extent this polymorphism affects conforming behavior. Methods: We categorized Han Chinese individuals according to the polymorphism and tested them with a facial-attractiveness rating task. Results: We found that individuals with a greater number of the Gly alleles, which are related to an increased dopamine release in the striatum, were more susceptible to social influence and more likely to change their ratings to match those of other people. Conclusions: This finding demonstrates the importance of DRD3 Ser9Gly as a genetic basis for social conformity and in predicting individual differences in social learning.
Multiplex Ligation-Dependent Probe Amplification Accurately Detects Turner Syndrome in Girls with Short Stature
Authors: Grandone Anna , Del Vecchio Blanco Francesca , Torella Annalaura , Caruso Manuela , De Luca Filippo , Di Mase Raffaella , Messina Maria Francesca , Salerno Maria Carolina , Sallemi Alessia , Perone Lucia , Marzuillo Pierluigi , Miraglia Del Giudice Emanuele , Nigro Vincenzo , Perrone Laura
Published: October 2016

Aims: We aimed at evaluating a standard multiplex ligation-dependent probe amplification (MLPA) probe set for the detection of aneuploidy to diagnose Turner syndrome (TS). We first fixed an MLPA ratio cutoff able to detect all cases of TS in a pilot TS group. We then tested this value on a second group of TS patients and a short-stature population to measure specificity and sensitivity. Methods: 15 TS patients with X mosaicism or X structural abnormalities (Pilot TS Group), 45 TS karyotype-assessed patients (TS Group), and 74 prepubertal female patients with apparent idiopathic short stature (Short-Stature Group) were enrolled. All subjects underwent MLPA and karyotype analysis. In the TS and Short-Stature Groups, MLPA testing was performed in blind. Results: The choice of an MLPA threshold ratio of 0.76 for at least 1 probe allowed us to detect all TS cases, including mosaicisms. Sensitivity and specificity were 100% (CI 95%, 0.92-1) and 88.89% (CI 95%, 0.79-0.94), respectively. The positive predictive value was 88.5%, and the negative predictive value was 100%. MLPA detected the presence of Y chromosome material in 2 patients. Conclusion: MLPA is an accurate and inexpensive tool to screen for TS in girls with short stature. A customized MLPA kit may be useful for the screening of an even larger population.