bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional brain responses associated with thermogenic and psychogenic sweating events in humans
Authors: Farrell Michael J. , Trevaks David , Taylor Nigel A. S. , McAllen Robin M.
Published: August 2015

Sweating events occur in response to mental stress (psychogenic) or with increased body temperature (thermogenic). We previously found that both were linked to activation of common brain stem regions, suggesting that they share the same output pathways: a putative common premotor nucleus was identified in the rostral-lateral medulla (Farrell MJ, Trevaks D, Taylor NA, McAllen RM. Am J Physiol Regul Integr Comp Physiol 304: R810–R817, 2013). We therefore looked in higher brain regions for the neural basis that differentiates the two types of sweating event. Previous work has identified hemispheric activations linked to psychogenic sweating, but no corresponding data have been reported for thermogenic sweating. Galvanic skin responses were used to measure sweating events in two groups of subjects during either psychogenic sweating ( n = 11, 35.3 ± 11.8 yr) or thermogenic sweating ( n = 11, 34.4 ± 10.2 yr) while regional brain activation was measured by BOLD signals in a 3-Tesla MRI scanner. Common regions activated with sweating events in both groups included the anterior and posterior cingulate cortex, insula, premotor cortex, thalamus, lentiform nuclei, and cerebellum ( Pcorrected < 0.05). Psychogenic sweating events were associated with significantly greater activation in the dorsal midcingulate cortex, parietal cortex, premotor cortex, occipital cortex, and cerebellum. No hemispheric region was found to show statistically significantly greater activation with thermogenic than with psychogenic sweating events. However, a discrete cluster of activation in the anterior hypothalamus/preoptic area was seen only with thermogenic sweating events. These findings suggest that the expected association between sweating events and brain regions implicated in “arousal” may apply selectively to psychogenic sweating; the neural basis for thermogenic sweating events may be subcortical.
Mobile Localization Based on Received Signal Strength and Pearson's Correlation Coefficient
Authors: Liu Huiyu , Zhang Yunzhou , Su Xiaolin , Li Xintong , Xu Ning
Published: August 2015

Being applicable for almost every scenario, mobile localization based on cellular network has gained increasing interest in recent years. Since received signal strength indication (RSSI) information is available in all mobile phones, RSSI-based techniques have become the preferred method for GSM localization. Although the GSM standard allows for a mobile phone to receive signal strength information from up to seven base stations (BSs), most of mobile phones only use the information of the associated cell as its estimated position. Therefore, the accuracy of GSM localization is seriously limited. In this paper, an algorithm for GSM localization is proposed with RSSI and Pearson's correlation coefficient (PCC). The information of seven cells, including the serving cell and six neighboring cells, is used to accurately estimate the mobile location. With redundant information, the proposed algorithm restrains the error of Cell-ID and shows good robustness against environmental change. Without any additional device or prior statistical knowledge, the proposed algorithm is implementable on common mobile devices. Furthermore, in the practical test, its maximum error is below 550 m, which is 100 m better than that of Cell-ID, and the mean error is below 150 m, which is 250 m better than Cell-ID.
Chemical Composition and Vasorelaxant and Antispasmodic Effects of Essential Oil fromRosa indicaL. Petals
Authors: Rasheed Hafiz Majid , Khan Taous , Wahid Fazli , Khan Rasool , Shah Abdul Jabbar
Published: August 2015

Rosa indicaL. belongs to the family Rosaceae and is locally known as gulaab. It has different traditional uses in cardiovascular and gastrointestinal disorders but there is no scientific data available in this regard. Therefore, the basic aim of this study was to explore the chemical composition and gastrointestinal and cardiovascular effects of the essential oil obtained fromR. indica. The chemical composition of the essential oil was investigated using gas chromatography-mass spectrometry (GC-MS) technique. The cardiovascular and gastrointestinal effects were investigated using electrophysiological measurements. The GC-MS analysis of the essential oil showed various chemical components including acetic acid, mercaptohexyl ester, butanoic acid, 2-methyl-5-oxo-1-cyclopentene-1-yl ester, artemiseole, methyl santonilate, isosteviol, caryophyllene oxide, pentyl phenyl acetate, dihydromyrcene, 1,5-octadecadien, octadecanoic acid, ethyl ester, palmitic acid (2-phenyl-1,3-dioxolan-4-yl methyl ester), santolina epoxide, and 9-farnesene. The electrophysiological measurements revealed that essential oil was more potent against K+(80 mM) than phenylephrine precontractions using isolated rabbit aorta preparations. In isolated rabbit jejunum preparations, it showed more potency against high K+induced contractions than spontaneous contractions. Considering these evidences, it can be concluded thatR. indicaessential oil may work as a complementary and alternative medicine in gastrointestinal and cardiovascular diseases.
Increasing Understanding in Children of Depressed Parents: Predictors and Moderators of Intervention Response
Authors: Gladstone Tracy R. G. , Forbes Peter W. , Diehl Anne , Beardslee William R.
Published: August 2015

We evaluated predictors and moderators of differential response to two family-based depression prevention programs for families with a depressed parent: a clinician-facilitated intervention and a lecture group intervention. Individual and family level variables were examined using regression analyses with generalized estimating equations. For the outcome of child understanding of depression, parental changes in child-related behaviors and attitudes predicted greater child understanding (p<0.001). For the parent outcome of behavior and attitude change, across intervention conditions, younger parent age (p<0.05), female parent gender (p<0.01), more chronic and severe parental depression history (p<0.05), lower SES (p<0.05), and single-parent status (p<0.05) were associated with better outcomes across conditions. Effect sizes were moderate, ranging from 0.4 to 0.7 SD. Family and marital functioning were not found to be predictors of any outcomes. When both parents were depressed at baseline, there was no difference in the clinician- versus lecture-based approach, and when only the father was depressed, families reported more changes with the clinician condition than with the lecture condition (p<0.05). Findings from this study can help identify intervention strategies that are appropriate for different types of at-risk individuals and families.
Near-Infrared Transcranial Radiation for Major Depressive Disorder: Proof of Concept Study
Authors: Cassano Paolo , Cusin Cristina , Mischoulon David , Hamblin Michael R. , De Taboada Luis , Pisoni Angela , Chang Trina , Yeung Albert , Ionescu Dawn F. , Petrie Samuel R. , Nierenberg Andrew A. , Fava Maurizio , Iosifescu Dan V.
Published: August 2015

Transcranial near-infrared radiation (NIR) is an innovative treatment for major depressive disorder (MDD), but clinical evidence for its efficacy is limited. Our objective was to investigate the tolerability and efficacy of NIR in patients with MDD. We conducted a proof of concept, prospective, double-blind, randomized study of 6 sessions of NIR versus sham treatment for patients with MDD, using a crossover design. Four patients with MDD with mean age 47 ± 14 (SD) years (1 woman and 3 men) were exposed to irradiance of 700 mW/cm2and a fluence of 84 J/cm2for a total NIR energy of 2.40 kJ delivered per session for 6 sessions. Baseline mean HAM-D17scores decreased from 19.8 ± 4.4 (SD) to 13 ± 5.35 (SD) after treatment (t=7.905;df=3;P=0.004). Patients tolerated the treatment well without any serious adverse events. These findings confirm and extend the preliminary data on NIR as a novel intervention for patients with MDD, but further clinical trials are needed to better understand the efficacy of this new treatment. This trial is registered with ClinicalTrials.govNCT01538199.
Groundwater Recharge and Hydrogeochemical Evolution in Leizhou Peninsula, China
Authors: Lu Yintao , Tang Changyuan , Chen Jianyao , Chen Junhong
Published: August 2015

An analysis of the stable isotopes and the major ions in the surface water and groundwater in the Leizhou Peninsula was performed to identify the sources and recharge mechanisms of the groundwater. In this study, 70 water samples were collected from rivers, a lake, and pumping wells. The surface water was considered to have a lower salinity than the groundwater in the region of study. The regression equations forδD andδ18O for the surface water and the groundwater are similar to those for precipitation, indicating meteoric origins. TheδD andδ18O levels in the groundwater ranged from −60‰; to −25‰; and −8.6‰; to −2.5‰, respectively, and were lower than the stable isotope levels from the winter and spring precipitation. The groundwater in the southern area was classified as the Ca2+-Mg2+-HCO3--type, whereas the groundwater in the northern area included three types (Na+-Cl−-type, Ca2+-Mg2+-HCO3--type, and Ca2+-Mg2+-Cl−-type), indicating rapid and frequent water-rock exchange in the region. A reasonable conclusion is that the groundwater chemistry is dominated by rock weathering and rainwater of local origin, which are influenced by seawater carried by the Asian monsoon.
A Collaborative Self-Governing Privacy-Preserving Wireless Sensor Network Architecture Based on Location Optimization for Dynamic Service Discovery in MANET Environment
Authors: Gao Cong , Ma Jianfeng , Zhang Shangwei
Published: August 2015

Due to the characteristics of a MANET, none of the existing solutions for service discovery work well in decentralized mobile environments. In this paper, we propose a collaborative self-governing privacy-preserving wireless sensor network architecture to address the issue of service discovery in MANET environment. The proposed architecture is able to dynamically adjust the working modes between directory-based and directory-less modes according to the network status of a MANET. The dynamic network status of a MANET is monitored by a wireless sensor network. Two location optimization algorithms are developed for topology control and the preservation of user location privacy. Simulation results show that the proposed architecture can greatly improve the performance of service discovery.
Hypergame Theory: A Model for Conflict, Misperception, and Deception
Authors: Kovach Nicholas S. , Gibson Alan S. , Lamont Gary B.
Published: August 2015

When dealing with conflicts, game theory and decision theory can be used to model the interactions of the decision-makers. To date, game theory and decision theory have received considerable modeling focus, while hypergame theory has not. A metagame, known as a hypergame, occurs when one player does not know or fully understand all the strategies of a game. Hypergame theory extends the advantages of game theory by allowing a player to outmaneuver an opponent and obtaining a more preferred outcome with a higher utility. The ability to outmaneuver an opponent occurs in the hypergame because the different views (perception or deception) of opponents are captured in the model, through the incorporation of information unknown to other players (misperception or intentional deception). The hypergame model more accurately provides solutions for complex theoretic modeling of conflicts than those modeled by game theory and excels where perception or information differences exist between players. This paper explores the current research in hypergame theory and presents a broad overview of the historical literature on hypergame theory.
Respiratory Failure in an Adolescent with Primary Cardiac Sarcoma
Authors: Angeli Daniel , Angeli Stephen J.
Published: August 2015

We report a case of progressive respiratory failure secondary to primary cardiac sarcoma masquerading as primary lung disease. An 18-year-old female presented to our hospital emergency department with progressive cough, dyspnea, and hemoptysis. She was treated for primary lung infection without improvement and had respiratory failure with endotracheal intubation by the third hospital day. An “intermediate” plasma brain natriuretic protein (BNP) of 216 pg/mL did not raise concerns about a heart failure diagnosis and may have delayed the correct diagnosis. Computed tomography of the chest with intravenous contrast was performed on the fifth hospital day and revealed a cardiac mass. A transthoracic echocardiogram confirmed a large left atrial mass that was obstructing mitral inflow. She was transferred to a tertiary center for emergency cardiac surgery. Primary cardiac tumors are a rare and treatable cause of heart failure in adolescent and young adult patients. Presentation can be confused with primary lung disease and must be suspected early. Plasma BNP cutoff levels used in the adult population should not be extrapolated to adolescents, as levels, both normal and abnormal, are significantly lower in this group of patients.
Silent Spontaneous Uterine Rupture at 36 Weeks of Gestation
Authors: Woo J. Y. , Tate L. , Roth S. , Eke A. C.
Published: August 2015

Introduction.Silent spontaneous rupture of the uterus before term, with extrusion of an intact amniotic sac and delivery of a healthy neonate, with no maternal or neonatal morbidity or mortality is very rare. Very few cases have been reported in literature.Case Presentation.We report a case of silent spontaneous uterine rupture, found during a scheduled repeat cesarean section at 36 weeks of gestation. Patient had history of two prior classical cesarean sections. She underwent cesarean section, with delivery of a healthy male infant. She had a good postoperative recovery and was discharged on postoperative day 3.Conclusion.Silent spontaneous rupture of the uterus before term with extrusion of an intact amniotic sac is rare. A high index of suspicion and good imaging during pregnancy are important in making this diagnosis.
Efficacy of Multiple Micronutrients Fortified Milk Consumption on Iron Nutritional Status in Moroccan Schoolchildren
Authors: El Menchawy Imane , El Hamdouchi Asmaa , El Kari Khalid , Saeid Naima , Zahrou Fatima Ezzahra , Benajiba Nada , El Harchaoui Imane , El Mzibri Mohamed , El Haloui Noureddine , Aguenaou Hassan
Published: August 2015

Iron deficiency constitutes a major public health problem in Morocco, mainly among women and children. The aim of our paper is to assess the efficacy of consumption of multiple micronutrients (MMN) fortified milk on iron status of Moroccan schoolchildren living in rural region. Children (N=195), aged 7 to 9 y, were recruited from schools and divided into two groups: the nonfortified group (NFG) received daily a nonfortified Ultra-High-Temperature (UHT) milk and the fortified group received (FG) daily UHT milk fortified with multiple micronutrients including iron sulfate. Blood samples were collected at baseline (T0) and after 9 months (T9). Hemoglobin (Hb) was measuredin situby Hemocue device; ferritin and C Reactive Protein were assessed in serum using ELISA and nephelometry techniques, respectively. Results were considered significant when thepvalue was <0.05. At T9 FG showed a reduction of iron deficiency from 50.9% to 37.2% (p=0.037). Despite the low prevalence of iron deficiency anemia (1.9%); more than 50% of children in our sample suffered from iron deficiency at baseline. The consumption of fortified milk reduced the prevalence of iron deficiency by 27% in schoolchildren living in high altitude rural region of Morocco.Clinical Trial Registration.Our study is registered in the Pan African Clinical Trial Registry with the identification numberPACTR201410000896410.
A Study of Isothermal Curing of PMI Using DMA
Authors: Zhang Jing , Ye Rui , Zou Jun , Tang Jijun , Wang Hongliang
Published: August 2015

The isothermal curing of polymethacrylimide (PMI) is studied through the use of dynamic mechanical analysis (DMA). Based on the growth rate of measured dynamic mechanical property, the relative conversion is defined to investigate the evolution of storage modulusE′at different curing temperatures. Hsich’s nonequilibrium thermodynamic fluctuation theory, Avrami equation, and isoconversional methods are used to analyze isothermal cure kinetics of PMI. The results show that there are different increase modes ofE′at low temperature range and high temperature range, respectively. In low temperature range, the relative conversion curves include a transitional stage which is found to be strongly frequency-dependent, but this stage is not observed in the relative conversion curve in high temperature range. During the isothermal curing process, the relative evolution ofE′can be described by Hsich’s nonequilibrium thermodynamic fluctuation theory and Avrami equation. Moreover, the values and evolutions of activation energy are different in two temperature ranges, which suggest that the curing mechanism probably has changed.
Kinematics Modeling and Simulation of a Bionic Fish Tail System Based on Linear Hypocycloid
Authors: Wang Shu-yan , Zhu Jun , Wang Xin-guo , Li Qin-feng , Zhu Hui-yun
Published: August 2015

Kinematics and simulation study on a two-joint linear hypocycloid tail driving system composed of a special planetary gear system and a linkage mechanism are conducted in this paper. First, the composition and working principle of the linear hypocycloid tail transmission system are introduced and analyzed. Second, the kinematics study on the transmission mechanism is conducted with graphical method of vector equation. The relationships between the caudal peduncle stroke, the tail fin swing angle, and the phase difference with structure parameters are studied, and further optimization of structure sizes (i.e., linkage length, sun gear’s diameter, the intersection angle between planet gears, etc.) is developed. At last, simulation and comparative study on a biofish in sample parameters with a live fish of Carp is conducted in MATLAB. The study would serve for underwater vehicles thruster design and its mechanism.
A Self-Adaptive and Link-Aware Beaconless Forwarding Protocol for VANETs
Authors: Li Changle , Chen Yun , Han Xiaolei , Zhu Lina
Published: August 2015

With the development of networks, Vehicular Ad-hoc Networks (VANETs) which act as the emerging application enhance the potential power of networks on the traffic safety and the entertainment. However, the high mobility and the dynamic nature of VANETs lead to the unreliable link which causes unreachable transmission and degrades the performance of the routing protocol in terms of the quality of experience (QoE). To provide a reliable routing for the data transmission, a self-adaptive and link-aware beaconless forwarding (SLBF) protocol is proposed. Based on the receiver based forwarding (RBF) scheme, SLBF designs a self-adaptive forwarding zone which is used to make the candidate nodes accurate. Furthermore, it proposes a comprehensive algorithm to calculate the waiting time by taking the greedy strategy, link quality, and the traffic load into account. With the NS-2 simulator, the performance of SLBF is demonstrated. The results show that the SLBF makes a great improvement in the delivery ratio, the end-to-end delay, and the average hops.
LTTng CLUST: A System-Wide Unified CPU and GPU Tracing Tool for OpenCL Applications
Authors: Couturier David , Dagenais Michel R.
Published: August 2015

As computation schemes evolve and many new tools become available to programmers to enhance the performance of their applications, many programmers started
to look towards highly parallel platforms such as Graphical Processing Unit (GPU). Offloading computations that can take advantage of the architecture of the GPU
is a technique that has proven fruitful in recent years. This technology enhances the speed and responsiveness of applications. Also, as a side effect, it reduces the
power requirements for those applications and therefore extends portable devices battery life and helps computing clusters to run more power efficiently.
Many performance analysis tools such as LTTng, strace and SystemTap already allow Central Processing Unit (CPU) tracing and help programmers to use CPU resources more efficiently. On the GPU side, different tools such as Nvidia’s Nsight, AMD’s CodeXL, and third party TAU and VampirTrace allow tracing Application Programming Interface (API) calls and OpenCL kernel execution. These tools are useful but are completely
separate, and none of them allow a unified CPU-GPU
tracing experience. We propose an extension to the existing scalable
and highly efficient LTTng tracing platform to allow
unified tracing of GPU along with CPU’s full tracing
capabilities.
Morphological Retrospective Study of Peritoneal Biopsies from Patients with Encapsulating Peritoneal Sclerosis: Underestimated Role of Adipocytes as New Fibroblasts Lineage?
Authors: Tooulou Monika , Demetter Pieter , Hamade Anwar , Keyzer Caroline , Nortier Joëlle L. , Pozdzik Agnieszka A.
Published: August 2015

Background. Encapsulating peritoneal sclerosis (EPS) is a rare but serious complication of peritoneal dialysis (PD). Besides the endothelial-to-mesenchymal transition (EMT), recently peritoneal adipocytes emerged as a potential source of fibrosis. We performed immunohistochemistry to approach EMT and to localize peritoneal adipocytes in peritoneal biopsies from PD-related EPS patients.Material and Methods. We investigated tissue expression of podoplanin, cytokeratin AE1/AE3 (mesothelium), calretinin (adipocytes), alpha-smooth muscle actin [α-SMA] (mesenchymal cells), interstitial mononuclear cell inflammation, and neoangiogenesis (CD3, CD4, CD8, CD20, CD68, and CD31 immunostainings, resp.).Results. Three patients (1 man/2 women; 17, 64, and 39 years old, resp.) developed EPS after 21, 90, and 164 months of PD therapy. In patients with EPS, we observed (1) loss of AE1/AE3 cytokeratin+ mesothelial cells without any evidence of migration into the interstitium, (2) disappearance of adipose tissue, (3) diffuse infiltration of calretinin+ cells in the areas of submesothelial fibrosis with a huge number ofα-SMA and calretinin+ fusiform cells, and (4) increased vascular density.Conclusion. We report that the involvement of EMT in peritoneal fibrosis is difficult to demonstrate and that the calretinin+ adipocytes might be an underestimated component and a new source of myofibroblasts in peritoneal remodeling during PD-related EPS.
SH3BGRL3 Protein as a Potential Prognostic Biomarker for Urothelial Carcinoma: A Novel Binding Partner of Epidermal Growth Factor Receptor
Authors: Chiang Cheng-Yao , Pan Chin-Chen , Chang Hong-Yi , Lai Ming-Derg , Tzai Tzong-Shin , Tsai Yuh-Shyan , Ling Pin , Liu Hsiao-Sheng , Lee Bi-Fang , Cheng Hong-Ling , Ho Chung-Liang , Chen Shu-Hui , Chow Nan-Haw
Published: August 2015

Purpose: Mass spectrometry–based biomarker discovery has clinical benefit. To identify novel biomarkers for urothelial carcinoma, we performed quantitative proteomics on pooled urine pairs from patients with and without urothelial carcinoma.

Experimental Design: Shot-gun proteomics using liquid chromatography-tandem mass spectrometry and stable isotope dimethyl labeling identified 219 candidate proteins. The potential implication of SH3 domain binding glutamic acid-rich protein like 3 (SH3BGRL3) was examined by immunoblotting of the urine (n = 13) and urothelial tumors (n = 32). Additional immunohistochemistry was performed on bladder cancer array (n = 1145) and correlated with tumor aggressiveness. Then, biologic functions and signaling pathways of SH3BGRL3 were explored using stable cell lines.

Results: The detectable urine SH3BGRL3 in patients with urothelial carcinoma was positively associated with higher histologic grading and muscle invasiveness of urothelial carcinoma. SH3BGRL3 is expressed in 13.9% (159/1145) of bladder cancer cohort and is positively associated with muscle invasion (P = 0.0028). SH3BGRL3 expression is associated with increased risk of progression in patients with nonmuscle-invasive bladder cancer (P = 0.032). SH3BGRL3 expression is significantly associated with a high level of epidermal growth factor receptor (EGFR) in bladder cancer (P < 0.0001). SH3BGRL3 promotes the epithelial–mesenchymal transition, cell migration, and proliferation of urothelial carcinoma in vitro. SH3BGRL3 interacts with phosphor-EGFR at Y1068, Y1086, and Y1173 through Grb2 by its proline-rich motif, and activates the Akt-associated signaling pathway.

Conclusions: Evaluation of SH3BGRL3 expression status or urine content may identify a subset of patients with bladder cancer who may require more intensive treatment. SH3BGRL3 deserves further investigation as a cotargeting candidate for designing EGFR-based cancer therapies. Clin Cancer Res; 21(24); 5601–11. ©2015 AACR.
Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2
Authors: Smith Bryan D. , Kaufman Michael D. , Leary Cynthia B. , Turner Benjamin A. , Wise Scott C. , Ahn Yu Mi , Booth R. John , Caldwell Timothy M. , Ensinger Carol L. , Hood Molly M. , Lu Wei-Ping , Patt Tristan W. , Patt William C. , Rutkoski Thomas J. , Samarakoon Thiwanka , Telikepalli Hanumaiah , Vogeti Lakshminarayana , Vogeti Subha , Yates Karen M. , Chun Lawrence , Stewart Lance J. , Clare Michael , Flynn Daniel L.
Published: August 2015

Altiratinib (DCC-2701) was designed based on the rationale of engineering a single therapeutic agent able to address multiple hallmarks of cancer (1). Specifically, altiratinib inhibits not only mechanisms of tumor initiation and progression, but also drug resistance mechanisms in the tumor and microenvironment through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 (KDR) kinases. This profile was achieved by optimizing binding into the switch control pocket of all three kinases, inducing type II inactive conformations. Altiratinib durably inhibits MET, both wild-type and mutated forms, in vitro and in vivo. Through its balanced inhibitory potency versus MET, TIE2, and VEGFR2, altiratinib provides an agent that inhibits three major evasive (re)vascularization and resistance pathways (HGF, ANG, and VEGF) and blocks tumor invasion and metastasis. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood–brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases. Mol Cancer Ther; 14(9); 2023–34. ©2015 AACR.
Abstract AS03: Epithelial-mesenchymal transition driven by transcriptional feedback loops contributes to intertumoral molecular heterogeneity in the metastasis and relapse of epithelial ovarian cancer
Authors: Chung VY , Tan M , Tan TZ , Kuay KT , Ye J , Thiery JP , Huang RY
Published: August 2015

Epithelial ovarian cancer (EOC) is highly heterogeneous with five molecular subgroups, Epi-A, Epi-B, Mes, Stem-A and Stem-B, being identified. The mechanisms behind the clonal evolution and intertumoral molecular heterogeneity are not fully elucidated. Previously, we performed EOC profiling meta-analysis to identify epithelial-mesenchymal transition (EMT) as the crucial mechanism for molecular heterogeneity. Transcription factors SNAI1, SNAI2, ZEB1, ZEB1, TWIST1, and GRHL2 were identified as crucial regulators for the Mes subtype which has undergone EMT. Here, we utilized three in-vitro EOC cell lines, PEO1, OVCA420, and OVCA429, to model the EMT-driven clonal evolution by manipulating the expression levels of these EMT transcriptional regulators. We analysed the molecular subtypes of matched primary tumor versus peritoneal metastases. Six out of 11 pairs showed concordant molecular subtypes. We also analysed a dataset of matched primary tumor versus omental metastases. Four out of 9 pairs showed concordant molecular subtypes. Among the 10 pairs showing a shift of molecular subtypes, 5 out of 5 omental metastases were designated as Mes. The variation in the evolution of molecular heterogeneity can be explained by the differences in the EMT transcriptional cross-regulation of the in-vitro models. Manipulating EMT regulators in PEO1 did not induce any transcriptional cross-regulation with no molecular subtype switching observed. However, manipulating EMT regulators in OVCA420 and OVCA429 caused hierarchical transcriptional control and feedback loop regulation, respectively. The OVCA429 model showed molecular subtype switch from Epi-A to Mes. In conclusion, the heterogeneity caused by EMT-driven clonal evolution is the consequence of transcriptional feedback loops of EMT regulators.

Citation Format: Chung VY, Tan M, Tan TZ, Kuay KT, Ye J, Thiery JP & Huang RY. Epithelial-mesenchymal transition driven by transcriptional feedback loops contributes to intertumoral molecular heterogeneity in the metastasis and relapse of epithelial ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS03.
Abstract AS05: Metabolomic signatures in sera from early stage ovarian cancer patients
Authors: Gaul David A. , Jones Christina M. , Monge Maria Eugenia , Tran Long Q. , Matzuk Martin M. , McDonald John F. , Fernandez Facundo M.
Published: August 2015

PURPOSE: Lack of symptoms as well as the deficiency of highly specific biomarkers has resulted in only a quarter of ovarian cancer cases being diagnosed in stage I. Early detection combined with conventional therapies has resulted in 5-year survival rates up to 90%, while 5-year overall survival is less than 30% for women with advanced stage ovarian cancer. An effective screening strategy for early diagnosis would be particularly advantageous for ovarian cancer patients. Investigation into characteristic metabolomic patterns for disease has the potential to detect changes in cells, tissues, and biofluids that can aid in diagnosis at an early stage.

METHODS: Serum samples were collected from early-stage serous papillary or endometrioid ovarian cancer (n=26) and normal patients (n=40) and analyzed using ultra high performance liquid chromatography coupled with high resolution mass spectrometry (UPLC-MS) and tandem mass spectrometry (MS/MS). Metabolites were extracted from blood serum by precipitating proteins with methanol, lyophilization, and solvent reconstitution prior to MS analysis in both positive and negative electrospray ionization modes. Metabolic features were extracted with MZmine software. Untargeted multivariate statistical analysis employing support vector machine (SVM) learning methods, genetic algorithms and recursive feature elimination (RFE) selected a panel of metabolites that differentiates between the age-matched samples with better than 92% sensitivity and 91% specificity in all cases tested.

RESULTS: Comparison of metabolic phenotypes of ovarian cancer with normal metabolic signatures revealed unique metabolite patterns for ovarian cancer. From multivariate statistical analysis, panels consisting of 17-35 metabolic features from serum samples were found to differentiate between early stage cancer and normal with very high accuracy, sensitivity, and specificity.

CONCLUSIONS: Poor early diagnosis complicates collection of large patient cohorts for more detailed studies. Our preliminary work demonstrated that metabolites in serum samples may be useful for detecting early-stage ovarian cancer and support conducting larger, more focused studies.

(Grant support: Marsha Rivkin Ovarian Cancer Challenge Grant; Ovarian Cancer Research Fund (OCRF))

Citation Format: David A. Gaul, Christina M. Jones, Maria Eugenia Monge, Long Q. Tran, Martin M. Matzuk, John F. McDonald*, Facundo M. Fernandez*. Metabolomic signatures in sera from early stage ovarian cancer patients [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS05.
Abstract AS06: Development and characterization of an oviduct-specific model of high-grade serous carcinoma
Authors: Zhai Yali , Wu Rong , Hu Tom C. , Fearon Eric R. , Cho Kathleen R.
Published: August 2015

Recent studies suggest the most common and lethal type of “ovarian” cancer, high-grade serous carcinoma (HGSC), often arises from fallopian tube epithelium rather than the ovarian surface epithelium. Their intraperitoneal location and microscopic size make it very difficult to screen for, or study the biology of early tubal lesions in humans, as most are discovered incidentally in women with hereditary predisposition to ovarian cancer who elect prophylactic salpingo-oophorectomy for cancer risk-reduction. Although most cases of pelvic HGSC probably originate in the fallopian tube, roughly one-third lack evidence of tubal origin. These cases may arise from ectopic tubal-type epithelium (endosalpingiosis) present in the ovary, peritoneum, or at other sites. Mouse models that closely mimic the genetics and biology of human HGSCs may be useful for clarifying how tubal and non-tubal pelvic HGSCs develop and progress.

We have developed transgenic (Ovgp1-iCreERT2) mice allowing conditional (tamoxifen [TAM]-inducible) expression of Cre recombinase exclusively in the oviductal epithelium, using a single transgene. Using double transgenic Ovgp1-iCreERT2;R26LSL-eYFP mice in which TAM treatment activates eYFP reporter protein expression in oviductal epithelial cells, we have shown that tubal-type inclusion glands (endosalpingiosis) expressing both eYFP and OVGP1 are present in a subset of murine ovaries following treatment with TAM. The findings suggest that oviductal epithelium can detach from the oviduct and traffic to the ovaries, where it implants through breaks in the OSE and maintains its tubal-type differentiation. Preliminary data also suggest that the frequency of ovarian endosalpingiosis increases over time and by superovulating the mice. The latter finding raises the possibility that at least some of the protective effects of high parity and oral contraceptive use on human ovarian cancer risk is related to reduced likelihood of acquiring endosalpingiosis from which “ovarian” HGSCs may eventually arise.

We have further shown that Ovgp1-iCreERT2;Trp53fl/fl;Brca1fl/fl mice develop oviductal lesions identical to human serous tubal intraepithelial carcinomas (STICs) after TAM treatment and have identified additional genetic alterations that cooperate with Trp53 and Brca1 inactivation in oviductal HGSC pathogenesis in our model system. Murine models of HGSC that recapitulate their human tumor counterparts provide excellent in vivo systems with which to define the cellular and molecular events associated with HGSC development and progression.

Citation Format: Yali Zhai, Rong Wu, Tom C. Hu, Eric R. Fearon, Kathleen R. Cho. Development and characterization of an oviduct-specific model of high-grade serous carcinoma [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS06.
Abstract AS15: DNA promoter hypermethylation of HIST1H2BB as a diagnostic and prognostic biomarker for ovarian cancer
Authors: Valle Blanca L. , Kuhn Elisabetta , Sidransky David , Guerrero-Preston Rafael
Published: August 2015

Background: Until recently, epithelial ovarian cancers were thought to arise from the ovarian surface epithelial cells. However, recent studies suggest that the majority of high grade serous carcinomas (HGSCs) arise from lesions in the fallopian tubes. DNA promoter hypermethylation of certain genes is often an early event in tumorigenesis, and it can be detected in blood and other bodily fluids, making it a feasible biomarker strategy for early detection of tumors.

Purpose of study: Therefore, we sought to determine the methylation profile of HGSCs as compared to fallopian tube epithelium. Using the Infinium HumanMethylation 450 Array, that permits to quantitatively assess over 450,000 methylation sites, within and outside of CpG islands and more than 20,000 genes per sample, at single-nucleotide resolution, we have obtained the genome-wide methylation profile of HGSC and fallopian tubal epithelium. We conducted a pilot study by comparing the global methylation in 12 HGSC tissue samples to 15 fallopian tube epithelium samples. In addition, we compared the methylation profile among long-term survivors (more than 5 years) and short-term survivors (2-3 years) of HGSCs.

Results: Our results identified the HIST1H2BB promoter as the most differentially methylated region when comparing HGSC with normal fallopian tube samples. Furthermore, we also found that HIST1H2BB is differentially methylated in HGSC patients with long-term survival when compared to patients with short-term survival.

Conclusions: Taken together, these results support the potential of HIST1H2BB promoter hypermethylation as a diagnostic and prognostic biomarker. Our findings could lead to the development of a biomarker for the diagnosis and/or prognosis of ovarian cancer and could contribute to the current understanding of the mechanisms of progression in ovarian cancer.

Citation Format: Blanca L. Valle, Elisabetta Kuhn, David Sidransky, Rafael Guerrero-Preston. DNA promoter hypermethylation of HIST1H2BB as a diagnostic and prognostic biomarker for ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS15.
Abstract AS18: The somatic mutational landscape of endometriosis associated ovarian cancers and precursor lesions
Authors: Anglesio Michael S , Bashashati Ali , Wang Yikan , Ha Gavin , Senz Janine , Yang Winnie , Kalloger Steve E , Prentice Leah M , Yanagida Satoshi , Salamanca Clara , Soukhatcheva Galina , Kazernis Anthony , Chang Hector , Mes-Mason Anne-Marie , Okamoto Aikou , Marra Marco A , Gilks Blake , Shah Sohrab P , Huntsman David G
Published: August 2015

Introduction: Clear Cell ovarian carcinomas (CCC) represent 10% of ovarian carcinomas, with outcomes for high-stage significantly worse than high-grade serous form. The complete mutational landscape, the molecular basis of the transformation of endometriosis, the putative precursor, and patterns of clonal evolution in CCC are not well understood.

Methods: Whole genome sequencing and gene expression profiling was done to uncover somatic alterations and measure effects on transcriptional networks. Targeted deep sequencing of primary tumors, metastases and endometriosis was also performed and statistical modeling approaches were used to validate mutations, quantify clonal diversity, and trace patterns of selection.

Results: Mutations in ARID1A (11/19) and PIK3CA (8/19) were by far the most frequent aberrations seen. Three other SWI/SNF components also showed somatic alteration: two in non-ARID1A mutant cases and a truncating mutation of ARID1B in an ARID1A-null case. Amongst 24 significant “candidate drivers” impacting expression, five “cancer genes” have been previously described: PIK3CA, ARID1A, CTNNB1, TP53, and PPP2R1A. We observed no association between PIK3CA or ARID1A status with disease stage, genomic instability, or mutation load. Deep sequencing data suggested multiple clones in every case. In cases with matching precursor lesions, we observed multiple mutations in at least one such lesion. In precursor lesions where tumor-matched somatic mutations were observed, ARID1A and PIK3CA mutations were also always present, if observed in the matched tumor.

Conclusions: ARID1A and PIK3CA mutations appear as early and histo-type defining events in CCC. Pattern of endometriosis transformation can be associated with somatic mutations in all cases, including histologically “Atypical” and non-atypical endometriosis. Finally, patterns of mutational conservation across the series of precursor lesions may present an opportunity for early screening of endometriosis tissues as an indicator of transformation potential.

Citation Format: Michael S Anglesio, Ali Bashashati, Yikan Wang, Gavin Ha, Janine Senz, Winnie Yang, Steve E Kalloger, Leah M Prentice, Satoshi Yanagida, Clara Salamanca, Galina Soukhatcheva, Anthony Kazernis, Hector Chang, Anne-Marie Mes-Mason, Aikou Okamoto, Marco A Marra, Blake Gilks, Sohrab P Shah, David G Huntsman. The somatic mutational landscape of endometriosis associated ovarian cancers and precursor lesions [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS18.
Abstract AS19: The role of the receptor tyrosine kinase AXL in an immunocompetent mouse model of invasive endometrioid ovarian cancer
Authors: Fuh Katherine , Rankin Erinn , Wu Colleen , Diep Anh , Giaccia Amato J.
Published: August 2015

Objective: To evaluate the role of AXL in an immunocompetent model of ovarian cancer metastasis.

Methods: Immunohistochemical staining of ovarian cancer tissue microarrays of advanced stage, high-grade epithelial ovarian cancer specimens for AXL expression was performed and correlated with overall survival. Metastatic endometrioid ovarian cancer was generated through intrabursal AdCre-infected LSL-K-rasG12D/+Ptenfl/fl mouse model. LSL-K-rasG12D/+Ptenfl/fl Axl+/+ and LSL-K-rasG12D/+Ptenfl/flAxl−/−were used to evaluate the role of AXL. Necropsy was performed to evaluate burden of the primary and metastatic tumors. Hematoxylin and eosin (H&E) staining was used to confirm tumor formation or lack of tumor. Western blotting was performed to evaluate protein expression.

Results: Of the 80 patient-derived primary ovarian tumor specimens, 76% (61) of advanced stage, high-grade epithelial ovarian cancer specimens had 3+ transmembrane AXL staining whereas 24% (19) of advanced stage, high-grade epithelial ovarian cancer specimens had no AXL staining. When correlated with overall survival, patients with tumors that had no AXL expression had a median survival of 53 months vs. 45 months for those with 3+AXL expression (p=0.12). The majority of intrabursal AdCre-infected LSL-K-rasG12D/+Ptenfl/fl Axl+/+ mice had primary (78%) and metastatic tumor formation (86%) whereas the majority of LSL-K-rasG12D/+Ptenfl/flAxl−/− had primary tumor formation (64%) but few had metastatic tumors (28%) (p<0.05). There was no difference in primary tumor weight between the two groups: 120mg for Axl+/+ vs. 110mg for Axl−/−. Metastatic tumors were microscopic and therefore unable to be resected and weighed prior to identification by H&E staining. Western blotting of primary and metastatic tumors from LSL-KrasG12D/+Ptenfl/fl Axl+/+ showed high AXL expression compared to no AXL expression in the ovaries of normal mice.

Conclusions: AXL expression in advanced stage epithelial ovarian cancer correlated with lower overall survival. Primary ovarian and metastatic tumors in this intrabursal AdCre-infected LSL-K-rasG12D/+Ptenfl/fl mouse model express AXL. Deletion of the receptor tyrosine kinase, AXL, in this conditional genetically engineered mouse model of endometrioid ovarian cancer resulted in inhibition of metastatic tumor formation. AXL is a critical factor driving metastasis in this immunocompetent murine model of metastatic ovarian cancer.

Citation Format: Katherine Fuh, Erinn Rankin, Colleen Wu, Anh Diep, Amato J. Giaccia. The role of the receptor tyrosine kinase AXL in an immunocompetent mouse model of invasive endometrioid ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS19.
Abstract AS28: Phase Ib/II with expansion of patients at the mtd study of olaparib plus weekly (metronomic) carboplatin and paclitaxel in relapsed ovarian cancer
Authors: Rivkin SE , Iriarte D , Sloan H , Wiseman C , Moon J
Published: August 2015

BACKGROUND: To establish the maximum-tolerated dose (MTD) and evaluate dose-limiting toxicities (DLTs) and response to therapy of combination therapy with carboplatin/paclitaxel and olaparib, an oral tablet inhibitor of poly ADP ribose polymerase (PARP), in advanced (Stage III or IV) relapsed ovarian cancer.

METHODS: Eligibility required measurable disease, adequate organ function and ECOG performance status of ≤ 2. Patients had to have failed first line platinum containing chemotherapy. All patients were tested for BRCA 1 and 2 mutations. Patients received the metronomic therapy of paclitaxel 60mg/m2 IV and carboplatin AUC 2 IV weekly, 3 weeks out of 4 and increasing doses of olaparib until the maximum tolerated dose was obtained. Olaparib started at 50 mg bid administered orally for 3 consecutive days (D1-D3), every week for each cycle. Patients were assessed for toxicity and response according to the protocol. Patients received combination therapy until DLT or disease progression.

RESULTS: The maximum tolerated dose was found to be olaparib 150 mg bid administered orally, three (D1-D3) consecutive days of each week of each cycle. Total number of patients enrolled in the phase 1b part of this study was 14. Median age was 58 (range 42-77). The median number of prior therapeutic regimens was 4 (range 3-8). Median number of cycles on study to date is 9.3 and the mean is 7.3. There were no grade 4 toxicities. The most common grade 3 toxicities were neutropenia (11), leukopenia (7), lymphopenia (4), anemia (4), fatigue (1) and MDS (1). There was no evidence of GI, cardiac, hepatic, pulmonary or dermatologic toxicities in any of these patients. Two patients had an allergic reaction prior to participating in the trial and once enrolled were desensitized to carboplatin for each study visit. One patient had a mild allergic reaction to the chemotherapy on trial, but did not require desensitization. 4 patients had a complete response (CR), 3 had partial response (PR), 3 had stable disease (SD), 2 had progressive disease (PD) and 2 were not evaluable. Of the 4 CR's three were BRCA mutant and 1 had no known BRCA mutation. Of the PD's one was BRCA mutant.

CONCLUSION: Olaparib, an oral tablet can be safely administered with a weekly regimen of carboplatin and paclitaxel in heavily pretreated, ovarian cancer patients. This is early preliminary data. This study is ongoing with a planned total expansion of 40 additional patients at the MTD.

Citation Format: Rivkin SE, Iriarte D, Sloan, H, Wiseman, C, Moon J,. Phase Ib/II with expansion of patients at the mtd study of olaparib plus weekly (metronomic) carboplatin and paclitaxel in relapsed ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS28.