bluuebunny/crossref_metadata_2025 huggingface dataset:
A Critical Review on Solid Desiccant-Based Hybrid Cooling Systems
Authors: Jani D. B. , Mishra M. , Sahoo P. K.
Published: May 2017

The present review provides scientific and technical support on how solid desiccant-based hybrid cooling can be a supplement to the commonly used vapor compression-based traditional air-conditioning systems to provide the indoor thermal comfort to the occupants. The existing design of standalone vapor compression system needs to be modified by integrating it with the solid desiccant-based dehumidification system to achieve better performance and economic feasibility by handling humidity and temperature separately especially in case of hot humid conditions. The present study is undertaken by considering variety of aspects including background and need for alternative cooling systems, system configuration as well as operational modes and current status of desiccant-based hybrid cooling technology. The review work also indicates that the technology of desiccant-based hybrid cooling has a great potential to provide thermal comfort especially in hot humid climate at the expense of lower energy consumption as compared to traditional cooling systems.
A Risk-Scoring Feedback Model for Webpages and Web Users Based on Browsing Behavior
Authors: Neria Michal Ben , Yacovzada Nancy-Sarah , Ben-Gal Irad
Published: May 2017

It has been claimed that many security breaches are often caused by vulnerable (naïve) employees within the organization [Ponemon Institute LLC 2015a]. Thus, the weakest link in security is often not the technology itself but rather the people who use it [Schneier 2003]. In this article, we propose a machine learning scheme for detecting risky webpages and risky browsing behavior, performed by naïve users in the organization. The scheme analyzes the interaction between two modules: one represents naïve users, while the other represents risky webpages. It implements a feedback loop between these modules such that if a webpage is exposed to a lot of traffic from risky users, its “risk score” increases, while in a similar manner, as the user is exposed to risky webpages (with a high “risk score”), his own “risk score” increases. The proposed scheme is tested on a real-world dataset of HTTP logs provided by a large American toolbar company. The results suggest that a feedback learning process involving webpages and users can improve the scoring accuracy and lead to the detection of unknown malicious webpages.
Novice Java Programming Mistakes
Authors: Brown Neil C. C. , Altadmri Amjad
Published: May 2017

Teaching is the process of conveying knowledge and skills to learners. It involves preventing misunderstandings or correcting misconceptions that learners have acquired. Thus, effective teaching relies on solid knowledge of the discipline, but also a good grasp of where learners are likely to trip up or misunderstand. In programming, there is much opportunity for misunderstanding, and the penalties are harsh: failing to produce the correct syntax for a program, for example, can completely prevent any progress in learning how to program. Because programming is inherently computer-based, we have an opportunity to automatically observe programming behaviour -- more closely even than an educator in the room at the time. By observing students’ programming behaviour, and surveying educators, we can ask: do educators have an accurate understanding of the mistakes that students are likely to make? In this study, we combined two years of the Blackbox dataset (with more than 900 thousand users and almost 100 million compilation events) with a survey of 76 educators to investigate which mistakes students make while learning to program Java, and whether the educators could make an accurate estimate of which mistakes were most common. We find that educators’ estimates do not agree with one another or the student data, and discuss the implications of these results.
Automated Generation of Erotetic Search Scenarios
Authors: Chlebowski Szymon , Komosinski Maciej , Kups Adam
Published: May 2017

This article concerns automated generation and processing of
erotetic search scenarios
(ESSs). ESSs are formal constructs characterized in Inferential Erotetic Logic that enable finding possible answers to a posed question by decomposing it into auxiliary questions. The first part of this work describes a formal account on ESSs. The formal approach is then applied to automatically generate ESSs, and the resulting scenarios are evaluated according to a number of criteria. These criteria are subjected to discordance analysis that reveals their mutual relationships. Finally, knowledge concerning relationships between different values of evaluation criteria is extracted by applying Apriori—an association rules mining algorithm. The proposed approach of integration of formal erotetic logic with computational tools provides extensive insight into the former and helps with the development of efficient ESSs.
Drawing strategies for communication planning
Authors: King Abigail Selzer , Moore Kristen R. , Edlin Ashley Hardage , Frankel Sophie
Published: May 2017

Simple drawing tasks are effective for evaluating the many options communicators have during early design stages. These drawing strategies leverage the metaphoric meanings of basic geometric shapes, not complex artistic illustration, to represent ideas while they are in development. Our paper supports this perspective by linking previous research on sketching, collaboration, and ideation to identify a specific approach to this kind of drawing that we term Geometric Page Forms. To further illustrate the value of these strategies, we give an example of how technical communicators used drawing during a workshop to develop communication solutions explaining complex information about sun block efficacy.
Making practice-level struggles visible
Authors: Rose Emma , Tenenberg Josh
Published: May 2017

Teaching user experience (UX) can be challenging due to the situated, complex, and messy nature of the work. However, the complexity of UX in practice is often invisible to students learning these methods and practices for the first time in class. In this article, we present findings from a study of rhetorical strategies of UX practitioners and pair them with strategies for teaching UX to students. While previous work on teaching UX reflects current practices in the classroom or reflections of practitioners, this study demonstrates the benefits of researching existing industry practices in order to inform pedagogy.
Spike-timing-dependent plasticity in lower-limb motoneurons after human spinal cord injury
Authors: Urbin M. A. , Ozdemir Recep A. , Tazoe Toshiki , Perez Monica A.
Published: May 2017

Recovery of lower-limb function after spinal cord injury (SCI) likely depends on transmission in the corticospinal pathway. Here, we examined whether paired corticospinal-motoneuronal stimulation (PCMS) changes transmission at spinal synapses of lower-limb motoneurons in humans with chronic incomplete SCI and aged-matched controls. We used 200 pairs of stimuli where corticospinal volleys evoked by transcranial magnetic stimulation (TMS) over the leg representation of the motor cortex were timed to arrive at corticospinal-motoneuronal synapses of the tibialis anterior (TA) muscle 2 ms before antidromic potentials evoked in motoneurons by electrical stimulation of the common peroneal nerve (PCMS+) or when antidromic potentials arrived 15 or 28 ms before corticospinal volleys (PCMS−) on separate days. Motor evoked potentials (MEPs) elicited by TMS and electrical stimulation were measured in the TA muscle before and after each stimulation protocol. After PCMS+, the size of MEPs elicited by TMS and electrical stimulation increased for up to 30 min in control and SCI participants. Notably, this was accompanied by increases in TA electromyographic activity and ankle dorsiflexion force in both groups, suggesting that this plasticity has functional implications. After PCMS−, MEPs elicited by TMS and electrical stimulation were suppressed if afferent input from the common peroneal nerve reduced TA MEP size during paired stimulation in both groups. In conclusion, PCMS elicits spike-timing-dependent changes at spinal synapses of lower-limb motoneurons in humans and has potential to improve lower-limb motor output following SCI.

NEW & NOTEWORTHY Approaches that aim to enhance corticospinal transmission to lower-limb muscles following spinal cord injury (SCI) are needed. We demonstrate that paired corticomotoneuronal stimulation (PCMS) can enhance plasticity at spinal synapses of lower-limb motoneurons in humans with and without SCI. We propose that PCMS has potential for improving motor output in leg muscles in individuals with damage to the corticospinal tract.
Rapid accumulation of inhibition accounts for saccades curved away from distractors
Authors: Kehoe Devin H. , Fallah Mazyar
Published: May 2017

In this research article, we propose a novel, noninvasive approach to behaviorally model the time course of competitive oculomotor processing. Our results highly resembled those from previously published neurophysiological experiments utilizing similar oculomotor processing contexts, thus validating our approach. Furthermore, this methodology provided new insights into the underlying neural mechanism subserving oculomotor processing given that we applied it to a context with which the neural mechanism is more contentious, and the results clearly favored one view.
Minimally Invasive Percutaneous Nephrolithotomy versus Retrograde Intrarenal Surgery for Upper Urinary Stones: A Systematic Review and Meta-Analysis
Authors: Jiang Hongyang , Yu Zhe , Chen Liping , Wang Tao , Liu Zhuo , Liu Jihong , Wang Shaogang , Ye Zhangqun
Published: May 2017

Minimally invasive percutaneous nephrolithotomy (mini-PCNL) and retrograde intrarenal surgery (RIRS) are both alternatives for PCNL to treat renal calculi. This study is aimed at comparing the stone-free rate (SFR) and other surgery parameters of two approaches for treating upper urinary calculi. We performed this meta-analysis in September 2016 by searching studies about mini-PCNL and RIRS for treating upper urinary calculi in various databases, and RevMan v.5.3 was applied. Three randomized controlled trials and ten nonrandomized trials were included, involving a total of 1317 patients. Meta-analysis showed that mini-PCNL group led to a higher SFR [odds ratio: 1.96; 95% confidence interval: 1.46–2.64; P<0.00001] but brought a larger postoperative decrease in hemoglobin levels compared with RIRS. RIRS provided a shorter hospital time. There was no significant difference in operation time. Higher postoperative complications were detected in the mini-PCNL, but the difference was not significant. Grade I and III complications did not vary between two procedures, but grade II complications were of lower incidence in RIRS group. In the light of these results, compared with RIRS, mini-PCNL provided significantly higher SFR and efficiency quotient for managing calculi; however, it resulted in higher incidence of postoperative complications, larger hemoglobin drops, and longer hospital stay.
Use of Chlorothiazide in the Management of Central Diabetes Insipidus in Early Infancy
Authors: Raisingani Manish , Palliyil Gopi Resmy , Shah Bina
Published: May 2017

Management of central diabetes insipidus in infancy is challenging. The various forms of desmopressin, oral, subcutaneous, and intranasal, have variability in the duration of action. Infants consume most of their calories as liquids which with desmopressin puts them at risk for hyponatremia and seizures. There are few cases reporting chlorothiazide as a temporizing measure for central diabetes insipidus in infancy. A male infant presented on day of life 30 with holoprosencephaly, cleft lip and palate, and poor weight gain to endocrine clinic. Biochemical tests and urine output were consistent with central diabetes insipidus. The patient required approximately 2.5 times the normal fluid intake to keep up with the urine output. Patient was started on low renal solute load formula and oral chlorothiazide. There were normalization of serum sodium, decrease in fluid intake close to 1.3 times the normal, and improved urine output. There were no episodes of hyponatremia/hypernatremia inpatient. The patient had 2 episodes of hypernatremia in the first year of life resolving with few hours of hydration. Oral chlorothiazide is a potential bridging agent for treatment of central DI along with low renal solute load formula in early infancy. It can help achieve adequate control of DI without wide serum sodium fluctuations.
Construct, Face, and Content Validation on Voxel-Man® Simulator for Otologic Surgical Training
Authors: Varoquier M. , Hoffmann C. P. , Perrenot C. , Tran N. , Parietti-Winkler C.
Published: May 2017

Objective. To assess the face, content, and construct validity of the Voxel-Man TempoSurg Virtual Reality simulator. Participants and Methods. 74 ear, nose, and throat (ENT) surgeons participated. They were assigned to one of two groups according to their level of expertise: the expert group (n=16) and the novice group (n=58). The participants performed four temporal bone dissection tasks on the simulator. Performances were assessed by a global score and then compared to assess the construct validity of the simulator. Finally, the expert group assessed the face and content validity by means of a five-point Likert-type scale. Results. experienced surgeons performed better (p<.01) and faster (p<.001) than the novices. However, the groups did not differ in terms of bone volume removed (p=.11) or number of injuries (p=.37). 93.7% of experienced surgeons stated they would recommend this simulator for anatomical learning. Most (87.5%) also thought that it could be integrated into surgical training. Conclusion. The Voxel-Man TempoSurg Virtual Reality simulator constitutes an interesting complementary tool to traditional teaching methods for training in otologic surgery.
Serum Vaspin Concentration in Elderly Type 2 Diabetes Mellitus Patients with Differing Body Mass Index: A Cross-Sectional Study
Authors: Yang Wei , Li Yun , Tian Tian , Wang Li
Published: May 2017

Aims. This study was to evaluate the association of serum vaspin concentrations with body mass index (BMI) among elderly patients (>60 years old). Methods. A total of 227 elderly individuals included 76 healthy with normal glucose tolerance, which divided into normal weight control (BMI < 25, n=38) and overweight or obese control (BMI ≥ 25, n=38) subgroups, and 150 T2DM patients, which divided into normal weight diabetes (BMI < 25, n=55), overweight diabetes (30 > BMI ≥ 25, n=52), and obese diabetes (BMI ≥ 30, n=43) subgroups. Relevant parameters were matched for age and gender ratio. Serum vaspin concentrations were measured by enzyme-linked immunosorbent assay. Results. Serum vaspin concentration was significantly higher in the T2DM than the healthy (451.9±32.6 versus 284.2±21.7, P<0.01). In the diabetic patients, the vaspin concentration was significantly higher in the obese group than the normal weight group (498.2±17.1 versus 382.1±21.3, P<0.05). In addition, the concentration of vaspin in normal weight T2DM was higher than in healthy control group with normal weight (382.1±21.3 versus 192.5±45.2, P<0.05). Multiple regression analysis revealed that BMI was independent factors influencing the serum vaspin concentration in all participants. Conclusion. Vaspin may play an important compensatory role in obesity and insulin resistance in elderly people. The clinical trial registration number is ChiCTR-OPC-14005698.
Existence and Uniqueness of Positive and Bounded Solutions of a Discrete Population Model with Fractional Dynamics
Authors: Macías-Díaz J. E.
Published: May 2017

We depart from the well-known one-dimensional Fisher’s equation from population dynamics and consider an extension of this model using Riesz fractional derivatives in space. Positive and bounded initial-boundary data are imposed on a closed and bounded domain, and a fully discrete form of this fractional initial-boundary-value problem is provided next using fractional centered differences. The fully discrete population model is implicit and linear, so a convenient vector representation is readily derived. Under suitable conditions, the matrix representing the implicit problem is an inverse-positive matrix. Using this fact, we establish that the discrete population model is capable of preserving the positivity and the boundedness of the discrete initial-boundary conditions. Moreover, the computational solubility of the discrete model is tackled in the closing remarks.
Perovskite Thin Film Solar Cells Based on Inorganic Hole Conducting Materials
Authors: Zhang Pan-Pan , Zhou Zheng-Ji , Kou Dong-Xing , Wu Si-Xin
Published: May 2017

Organic-inorganic metal halide perovskites have recently shown great potential for application, due to their advantages of low-cost, excellent photoelectric properties and high power conversion efficiency. Perovskite-based thin film solar cells have achieved a power conversion efficiency (PCE) of up to 20%. Hole transport materials (HTMs) are one of the most important components of perovskite solar cells (PSCs), having functions of optimizing interface, adjusting the energy match, and helping to obtain higher PCE. Inorganic p-type semiconductors are alternative HTMs due to their chemical stability, higher mobility, high transparency in the visible region, and applicable valence band (VB) energy level. This review analyzed the advantages, disadvantages, and development prospects of several popular inorganic HTMs in PSCs.
Prophet: A Context-Aware Location Privacy-Preserving Scheme in Location Sharing Service
Authors: Qu Jiaxing , Zhang Guoyin , Fang Zhou
Published: May 2017

Location sharing service has become an indispensable part in mobile social networks. However, location sharing may introduce a new class of privacy threats ranging from localizing an individual to profiling and identifying him based on the places he shared. Although users may avoid releasing geocontent in sensitive locations, it does not necessarily prevent the adversary from inferring users’ privacy through space-temporal correlations and historical information. In this paper, we design a Prophet framework, which provides an effective security scheme for users sharing their location information. First, we define fingerprint identification based on Markov chain and state classification to describe the users’ behavior patterns. Then, we propose a novel location anonymization mechanism, which adopts a ε-indistinguishability strategy to protect user’s sensitive location information published. Finally, experimental results are given to illustrate good performance and effectiveness of the proposed scheme.
Nonlinear Output Regulation with Input Delay and Application in AHV Attitude Control
Authors: Cai Liang , Wu Qingxian
Published: May 2017

Time delay phenomena exist almost everywhere in the actual world and are especially important in the control of an AHV. The small time delay usually ignored in control may cause quite obvious errors in the flight trajectory tracking, because of the extremely high flight speed. In this paper, a new framework of solving a nonlinear input delay regulation problem is proposed for the first time, which is comprised of nonlinear damping controllers, nonlinear disturbance observers, and a nonlinear time delay predictor-based compensator, under the proved separation principle. Then the attitude tracking control of an AHV with a known time-varying input delay is studied based on the proposed design framework. Simulation results show the advantage of the proposed control method.
Bound for the 2-Page Fixed Linear Crossing Number of Hypercube Graph via SDP Relaxation
Authors: Suebsriwichai A. , Mouktonglang T.
Published: May 2017

The crossing number of graph G is the minimum number of edges crossing in any drawing of G in a plane. In this paper we describe a method of finding the bound of 2-page fixed linear crossing number of G. We consider a conflict graph G′ of G. Then, instead of minimizing the crossing number of G, we show that it is equivalent to maximize the weight of a cut of G′. We formulate the original problem into the MAXCUT problem. We consider a semidefinite relaxation of the MAXCUT problem. An example of a case where G is hypercube is explicitly shown to obtain an upper bound. The numerical results confirm the effectiveness of the approximation.
Improving the Morphology of the Perovskite Absorber Layer in Hybrid Organic/Inorganic Halide Perovskite MAPbI3 Solar Cells
Authors: Ogundana I. J. , Foo S. Y.
Published: May 2017

Recently, perovskite solar cells have attracted tremendous attention due to their excellent power conversion efficiency, low cost, simple fabrications, and high photovoltaic performance. Furthermore, the perovskite solar cells are lightweight and possess thin film and semitransparency. However, the nonuniformity in perovskite layer constitutes a major setback to the operation mechanism, performance, reproducibility, and degradation of perovskite solar cells. Therefore, one of the main challenges in planar perovskite devices is the fabrication of high quality films with controlled morphology and least amount of pin-holes for high performance thin film perovskite devices. The poor reproducibility in perovskite solar cells hinders the accurate fabrication of practical devices for use in real world applications, and this is primarily as a result of the inability to control the morphology of perovskites, leading to large variability in the characteristics of perovskite solar cells. Hence, the focus of research in perovskites has been mostly geared towards improving the morphology and crystallization of perovskite absorber by selecting the optimal annealing condition considering the effect of humidity. Here we report a controlled ambient condition that is necessary to grow uniform perovskite crystals. A best PCE of 7.5% was achieved along with a short-circuit current density of 15.2 mA/cm2, an open-circuit voltage of 0.81 V, and a fill factor of 0.612 from the perovskite solar cell prepared under 60% relative humidity.
Phase I and Preliminary Phase II Study of TRC105 in Combination with Sorafenib in Hepatocellular Carcinoma
Authors: Duffy Austin G. , Ma Chi , Ulahannan Susanna V. , Rahma Osama E. , Makarova-Rusher Oxana , Cao Liang , Yu Yunkai , Kleiner David E. , Trepel Jane , Lee Min-Jung , Tomita Yusuke , Steinberg Seth M. , Heller Theo , Turkbey Baris , Choyke Peter L. , Peer Cody J. , Figg William D. , Wood Brad J. , Greten Tim F.
Published: May 2017

Purpose: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including that of hepatocellular carcinoma (HCC), and is associated with poor prognosis. Endoglin is essential for angiogenesis, and its expression is induced by hypoxia and VEGF pathway inhibition. TRC105 is a chimeric IgG1 CD105 mAb that inhibits angiogenesis and causes antibody-dependent cellular cytotoxicity and apoptosis of proliferating endothelium.

Experimental Design: Patients with HCC (Child–Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, and 15 mg/kg every 2 weeks given with sorafenib 400 mg twice daily. Correlative biomarkers included DCE-MRI and plasma levels of angiogenic factors, including soluble endoglin. Pharmacokinetics were assessed in serum.

Results: Twenty-six patients were enrolled, of whom 25 received treatment, 15 with cirrhosis. Hep B/C: 3/15; M:F 19:6; mean age of 60 (range, 18–76); 1 DLT (grade 3 AST) occurred at 10 mg/kg. The most frequent toxicity was low-grade epistaxis, a known toxicity of TRC105. One patient experienced an infusion reaction and was replaced. One patient with coronary stenosis developed a fatal myocardial infarction, and one patient developed G3 cerebral tumor hemorrhage. MTD was not established and DL4 (15 mg/kg) was expanded. The overall response rate in 24 evaluable patients at all 4 dose levels was 21% [95% confidence interval (CI), 7.1–42.2], and 25% (95% CI, 8.7–49.1) in patients with measureable disease. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median progression-free survival (PFS) for 24 patients evaluable for PFS was 3.8 months (95% CI, 3.2–5.6 months); median overall survival was 15.5 months (95% CI, 8.5–26.3 months).

Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity to date (PR rate 25%) was observed, and the study is now continuing to recruit in the phase II stage as a multicenter study to confirm activity of the combination. Clin Cancer Res; 23(16); 4633–41. ©2017 AACR.
Cell-Free DNA from Ascites and Pleural Effusions: Molecular Insights into Genomic Aberrations and Disease Biology
Authors: Husain Hatim , Nykin David , Bui Nam , Quan Daniel , Gomez German , Woodward Brian , Venkatapathy Sumathi , Duttagupta Radha , Fung Eric , Lippman Scott M. , Kurzrock Razelle
Published: May 2017

Collection of cell-free DNA (cfDNA) from the blood of individuals with cancer has permitted noninvasive tumor genome analysis. Detection and characterization of cfDNA in ascites and pleural effusions have not yet been reported. Herein, we analyzed cfDNA in the ascites and pleural effusions from six individuals with metastatic cancer. In all cases, cfDNA copy number variations (CNV) were discovered within the effusate. One individual had a relevant alteration with a high copy amplification in EGFR in a never smoker with lung cancer, who showed only MDM2 and CDK4 amplification in a prior tissue biopsy. Another subject with metastatic breast cancer had cytology-positive ascites and an activating PIK3CA mutation identified in the tissue, blood, and ascites collectively. This individual had tumor regression after the administration of the mTOR inhibitor everolimus and had evidence of chromotripsis from chromosomal rearrangements noted in the cell-free ascitic fluid. These results indicate that cfDNA from ascites and pleural effusions may provide additional information not detected with tumor and plasma cell-free DNA molecular characterization, and a context for important insights into tumor biology and clonal dynamic change within primary tumor and metastatic deposits. Mol Cancer Ther; 16(5); 948–55. ©2017 AACR.
Abstract A09: The role of pre-mRNA splicing factor in Glioblastoma Multiforme by regulating EGFRvIII
Authors: Oh Young Taek , Hong Jun Hee , Park Jong Bae
Published: May 2017

Glioblastoma (GBM) heterogeneity in the genomic and phenotypic properties has potentiated personalized approach against specific therapeutic targets of each GBM patient. Therefore, there is a critical unmet need to predict therapeutic responses for individual patients. There is 50% of GBM patient has EGFR over-expression and mutation. Because of this reason, there are various EGFRvIII target inhibitor for GBM patient. However, the efficacy of EGFRvIII specific drugs is not good because of autophosphorylation. We found Tra2β, which is pre-mRNA splicing factor, can bind in first intron and there are 9 consensus sequences. Because of EGFRvIII has deletion of second exon, Tra2β can regulate the expression of EGFRvIII. We validated low WTAP expression level in differentiated GBM stem cells, and confirmed the tumorigenic function of Tra2β in GBM cells. Furthermore, we are going to find the mechanism of Tra2β that can regulated by CDC-like kinase. As a result, we connected Tra2β function and EGFR specific drug resistance problem. This study could be helpful on personalized treatment approach based on genetic characteristics of each GBM could make better treatment outcomes of GBMs.

Citation Format: Young Taek Oh, Jun Hee Hong, Jong Bae Park. The role of pre-mRNA splicing factor in Glioblastoma Multiforme by regulating EGFRvIII. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A09.
Abstract A23: AMPK's role in glioblastoma survival: An insight into its regulation on transcription factors and mTOR
Authors: Chhipa Rishi Raj , Dasgupta Biplab
Published: May 2017

AMP kinase (AMPK) is an evolutionarily conserved enzyme required for adaptive responses to various physiological and pathological conditions. The multisubunit structure and sensitivity to various stresses confer complexity to AMPK function which scores beyond energy sensing. Here we show that inhibition of AMPK reduces viability of patient-derived primary Glioblastoma Multiforme (GBM) lines and tumors. We demonstrate that primary GBM cells coopt the AMPK-CREB1 pathway to coordinate global bioenergetics program through control of the transcription factors HIF1alpha and GABPA. But a growing number of AMPK activators are being developed to treat human diseases such as cancer and diabetes. This may be because AMPK activity can inhibit biosynthetic kinases like mammalian target of rapamycin (mTOR) and acetyl Co-A carboxylase (ACC). We found that AMPK silencing in glioma cells did not affect mTOR or downstream targets. AMPK is not absolutely necessary for mTOR inhibition, suggesting that in certain contexts, activated AMPK and mTOR may coexist. Indeed, this is what we observed in glioblastoma suggesting that basally active AMPK may not be sufficient to put a brake on mTOR. Further analysis of our preliminary data from primary tumor cells on Cap-dependent and well reported procancer IRES dependent translation under tumor microenvironment context will demonstrate significance of AMPK in translational machinery in GBM and will benefit in finding new therapeutic targets.

Citation Format: Rishi Raj Chhipa, Biplab Dasgupta. AMPK's role in glioblastoma survival: An insight into its regulation on transcription factors and mTOR. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A23.
Abstract A39: Expression of DNA methylation-related proteins in metastatic breast cancer
Authors: Yukyung Lee , Eun-Sol Kim , Seung Koo Ja
Published: May 2017

Purpose: To investigate the expressions of methylation-related proteins (5-methylcytosine [5-meC] and DNA [cytosine-5-]-methyltransferase 1 [DNMT1]) in metastatic breast cancers of variable sites and their associations with clinicopathologic factors.

Methods: A total of 126 metastatic breast cancers (31, 36, 11, and 48 bone, brain, liver, and lung metastases, respectively) were made into tissue microarrays, and immunohistochemical staining was performed for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER-2), Ki-67, 5-meC, and DNMT1. Molecular classification was made on the basis of the immunohistochemical staining results of ER, PR, HER-2, and Ki-67, as luminal A, luminal B, HER-2-positive, and triple-negative breast cancers.

Results: Methylation-related proteins were differentially expressed based on the metastatic sites. Tumoral and stromal 5-meC showed the lowest expression in bone metastases (P < 0.001), while tumoral DNMT1 showed the lowest expression in bone metastases and the highest expression in brain metastases (P < 0.001). Expression of DNMT1 correlated with ER-negativity (P = 0.004), PR-negativity (P = 0.011), HER-2-positivity (P = 0.016), higher Ki-67 labeling indices (P = 0.016), and non-luminal A type (P = 0.017). Univariate analysis revealed that DNMT1-positivity was associated with shorter overall survival in patients with bone (P = 0.017) and lung metastases (P = 0.028).

Conclusion: In metastatic breast cancer, methylation-related proteins are differentially expressed according to the metastatic sites. Tumoral and stromal 5-meC showed the lowest expression in bone metastases, while tumoral DNMT1 expression was low in bone metastases and the highest in brain metastases.

Citation Format: Lee Yukyung, Kim Eun-Sol, Koo Ja Seung. Expression of DNA methylation-related proteins in metastatic breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A39.
Abstract B06: Translational control of mitochondria through mTORC1/4E-BP signaling pathway
Authors: Morita Masahiro , Prudent Julien , McBride Heidi , Bergeron John , Sonenberg Nahum
Published: May 2017

mRNA translation is the most energy consuming process in the cell. Translation and energy metabolism are dysregulated in a variety of diseases including cancer. However, the mechanisms which coordinate translation and energy metabolism remain largely unknown. The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) stimulates mRNA translation and other anabolic processes in response to a variety of extracellular signals and intracellular cues (e.g., growth factors, nutrients, oxygen), ultimately accelerating cellular growth and proliferation. mTORC1 is frequently hyper-activated in a series of cancer, thereby it is targeted for the cancer treatment.

We previously carried out a genome-wide polysome profiling analysis using mTORC1 inhibitors, such as rapamycin and active-site mTOR inhibitors. These experiments revealed that mRNAs whose translation is regulated by mTORC1 are enriched in those encoding mitochondrial proteins. Here, by using a combination of pharmacological, genetic, biochemical and metabolomic approaches, we demonstrate that mTORC1 modulates mitochondrial functions and dynamics through translational regulation of mRNAs encoding mitochondrial proteins. Mechanistically, we indicate that the effects of mTORC1 on mitochondria are mediated by the eukaryotic translation initiation factor 4E (eIF4E) binding proteins (4E-BPs). Stimulation of translation of mitochondria-related mRNAs engendered an increase in ATP production, which is required as an energy source for translation.

These data support a feed-forward loop model, whereby the mTORC1/4E-BP pathway promotes translation of mitochondria-related mRNAs to increase mitochondrial ATP production to meet the high energy demand of protein synthesis in proliferating cells. This represents a novel paradigm for understanding how cellular energy homeostasis is maintained via direct coordination of energy consumption (translation) and energy production (ATP production in mitochondrion). Thereby, our findings provide a new mechanism linking aberrant mTOR signaling to conditions of abnormal cellular energy metabolism such as neoplasia. In this presentation, we will introduce our recent data and discuss the role of mTORC1/4E-BP signaling pathway on mitochondrial function, cellular metabolism and proliferation.

Citation Format: Masahiro Morita, Julien Prudent, Heidi McBride, John Bergeron, Nahum Sonenberg. Translational control of mitochondria through mTORC1/4E-BP signaling pathway. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B06.
Abstract B28: Discovery of 2-acetylpyridine-[N-(3-hydroxy-2-naphthoyl)]hydrazone analogs as glycine N-methyltransferase (GNMT) inducers for the treatment of hepatocellular carcinoma (HCC)
Authors: Tzeng Cherng-Chyi , Tseng Chih-Hua , Chen Yeh-Long
Published: May 2017

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third most common cause of cancer mortality. Because of the late diagnosis, poor treatment options and high recurrence, the incidence still nearly equals to the mortality rate. Therefore, the discovery of novel therapeutic agents and/or drug combination strategies is urgently needed. Glycine N-methyltransferase (GNMT) is a tumor suppressor gene for HCC. Literatures revealed that the expression of GNMT is significantly down-regulated in HCC patients. Therefore, discovery of small molecule compounds that are able to enhance GNMT expression will have important implications for the treatment of HCC. Recently, we have identified a small molecule, 2-acetylpyridine-[N-(3-hydroxy-2-naphthoyl)]hydrazone (1), as a hit from a collective drug library containing more than 20,000 compounds using a GNMT gene expression-oriented screen platform. Preliminary results indicated that compound 1 is capable of inducing GNMT expression strongly with 7.57 folds to control in 2.5 micromole.

In order to discover novel lead compounds based on the initial hit, we have synthesized more than 100 analogs of compound 1 and evaluated for their effects on GNMT promoter activity. Results indicated certain newly synthesized compounds are more active than compound 1. A comprehensive Structure-activity relationships (SAR) study will be presented.

Citation Format: Cherng-Chyi Tzeng, Chih-Hua Tseng, Yeh-Long Chen. Discovery of 2-acetylpyridine-[N-(3-hydroxy-2-naphthoyl)]hydrazone analogs as glycine N-methyltransferase (GNMT) inducers for the treatment of hepatocellular carcinoma (HCC). [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B28.
Abstract B45: Insights into the anti-prostate cancer activity of pterostilbene
Authors: Tolba Mai F. , Omar Hany A.
Published: May 2017

Castration-resistant prostate cancer (PC) is one of the most challenging cancers with limited therapeutic options. Angiogenesis is a key mechanism required for the progression of advanced metastatic stage of PC. Interference with angiogenesis halts prostate tumor progression and metastases. Estrogen receptor alpha (ER-α) is upregulated in PC compared to normal tissues. ER-α is implicated in tumor angiogenesis through activating vascular endothelial growth factor (VEGF) transcription. Pterostilbene (PT) is an active component of blueberries that exhibits anti-proliferative and antimetastatic effects in PC. The impact of PT on pro-angiogenic signals is not known. The current study tested the hypothesis that PT exhibits sensitizes prostate cancer (PC) cells to chemotherapy. We also examined the underlying mechanisms by which PT exhibits cytotoxic effects in PC with special emphasis on ER-α, Akt activity and angiogenesis signals. PT is cytotoxic against LNCaP, DU-145 and PC-3 with IC50 of 33.76, 41.17 and 58.9 µM. PT synergized doxorubicin in both LNCaP and PC-3 cells. Molecular docking indicated that PT interacts with ER-α active site with a comparable affinity to estradiol. Since, ER-α is implicated in the progression of PC. The effect of PT on PC migration and invasion was investigated and results showed significant reduction in both functions. PT suppressed ER-α expression, ER-α(Ser-167) and Akt(Ser473) phosphorylations in PC-3 cells. PT opposed the release of the pro-angiogenic growth factors VEGF, IGF-1 and TGF-β by 41.5, 36.5 and 28.8% (P<0.05). Our findings suggest that PT could serve as a promising antiangiogenic therapy/ adjuvant for the management of advanced stage PC.

Citation Format: Mai F. Tolba, Hany A. Omar. Insights into the anti-prostate cancer activity of pterostilbene. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B45.
Abstract IA21: New technologies to monitor and understand RNA-binding proteins in cancer cells
Authors: Hentze Matthias W.
Published: May 2017

Based on the development of “RNA interactome capture”, we recently discovered that hundreds of cellular proteins, previously well known for other biological functions, also unexpectedly bind RNA (termed “enigmRBPs” for enigmatic RNA-Binding Proteins) (1-4). Since many enigmRBPs are conserved from yeast to humans, their existence raises pressing questions—for benign as well as for cancer cells.

One of the most stunning surprises was the discovery that almost all enzymes of the glycolytic pathway are conserved as enigmRBPs. Overall, more than 50 metabolic enzymes were found to bind RNA. Could the combination of enzymatic and RNA-binding functions represent a general biological principle for coordination between gene expression and metabolism? (5,6). Applying a newly developed technique, RBDmap, to identify the RNA-binding domains of enigmRBPs, we uncovered new RNA-binding architectures yielding functional insights (7). Integrating all information, we discuss a possible new function for genomes in addition to their classical role in driving protein biosynthesis via mRNAs, rRNAs, and tRNAs and their associated modifying and regulatory RNAs. I will also reflect on how RNA interactome capture and RBDmap can advance our understanding of cancer cell biology.

(1) Castello et al., Cell 149, 1393-1406, 2012

(2) Castello et al., Nature Protoc. 8, 491-500, 2013

(3) Kwon et al., Nature Struc. Mol. Biol. 20, 1122-1132, 2013

(4) Beckmann et al., Nature Communications, 2015

(5) Hentze and Preiss, TiBS 35, 423-426, 2010

(6) Castello et al., Trends in Endocrin. Metab., 2015

(7) Castello et al., Mol. Cell, 2016

Citation Format: Matthias W. Hentze. New technologies to monitor and understand RNA-binding proteins in cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA21.
Abstract PR06: PTEN-mTOR pathway serves as a guardian of ribosomal DNA
Authors: Xu Baoshan , Li Hua , Perry John , Harris Bethany , Slaughter Brian , Unruh Jay , Singh Vijay Pratap , Zakari Musinu , McDowell William , Li Linheng , Gerton Jennifer L.
Published: May 2017

Ribosomal DNA is one of the most variable regions in the human genome with respect to copy number, yet we know virtually nothing about what governs its copy number, stability, and sequence. Ribosomal DNA is present in many tandem repeats that are incredibly important because 1) they encode the template for the RNA component of ribosomes, 2) they organize large parts of nearly every human chromosome and 3) they can titrate factors involved in chromosomal processes, with profound impact on DNA replication, repair, and gene expression. We applied computational and droplet digital PCR approaches to explore rDNA copy number in normal and cancer states in human and mouse genomes. We find that the copy number is similar between tissues from the same mouse, and is similar within inbred mouse strains, but can vary widely between individuals in an outbred strain. PTEN is a tumor suppressor and negative regulator of mTOR activity that is critical for genome stability. We find that hematopoietic stem cells from a PTEN-/- mouse model for leukemia have lower rDNA copy number than normal tissue, associated with hypersensitivity to DNA damage. Remarkably, analysis of three human cancer genome projects reveals low rDNA copy number relative to matched normal tissue. Our analysis reveals a genomic signature associated with hyperactive mTOR in osteosarcoma that includes loss of rDNA copies accompanied by an increase in sequence heterogeneity, as well as additional genes that co-vary in copy number. PTEN-mTOR may normally contribute to maintenance of ribosomal DNA.

This abstract is also being presented as Poster A38.

Citation Format: Baoshan Xu, Hua Li, John Perry, Bethany Harris, Brian Slaughter, Jay Unruh, Vijay Pratap Singh, Musinu Zakari, William McDowell, Linheng Li, Jennifer L. Gerton. PTEN-mTOR pathway serves as a guardian of ribosomal DNA. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr PR06.
Abstract B44: Emerging targets from Cancer Dependency Map v0.1
Authors: Vazquez Francisca , Tsherniak Aviad , Weir Barbara , Montgomery Phil , Cowley Glenn , Gill Stanley , Kryukov Gregory , Pantel Sasha , Harrington Will , Burger Mike , Meyers Robin , Ali Levi , Goodale Amy , Lee Yenarae , Garraway Levi , Boehm Jesse , Root David , Golub Todd , Hahn William
Published: May 2017

Precision Cancer Medicine requires the identification of vulnerabilities linked to genetic features of tumors. Recent studies utilizing highly annotated small molecule collections to assess dependencies across hundreds of genomically annotated cell lines have demonstrated the potential for such large-scale preclinical “Dependency Map” projects. We have undertaken a complementary approach using genetic perturbation tools (RNAi and CRISPR-Cas9 based loss-of-function viability screens), to systematically catalog preferential genetic dependencies and markers that predict response. These efforts are providing a foundation for the discovery of novel targets poised for early therapeutic discovery projects together with patient populations that may be enriched for responders to such therapies.

Here, we present results from our initial Cancer Dependency Map consisting of RNAi loss-of-function screens across 503 cell lines, including both solid and hematopoietic tumors. We discovered 43 genes whose mutation or copy number creates a cancer dependency (oncogene addiction) including a novel dependency on the small GTPase, GNAI2 in Diffuse large B-cell Lymphoma. We discovered 142 genes in which elevated levels of expression create a dependency (gene addiction), a group of genes highly enriched for master regulator transcription factors such as SOX10, SPDEF, PAX8 and HNF1B. We discovered 474 genes for which hemizygous copy number creates a dependency (CYCLOPS genes), a group of genes highly enriched for members of macromolecular protein complexes including the spliceosome and proteasome. Finally, we discovered 171 genes that become a dependency when a redundant functional paralog is lost in cancer cells (redundant essentials). We demonstrate the mechanistic basis behind one such redundant essential dependency relationship in which promoter methylation of the UBB ubiquitin gene eliminates a compensatory mechanism leading to a novel vulnerability on the suppression of the UBC ubiquitin gene.

These observations begin to provide an initial census, categorization and prioritization of robust cancer dependencies and support the potential impact for expanding early efforts to develop dependency maps of cancer.

Citation Format: Francisca Vazquez, Aviad Tsherniak, Barbara Weir, Phil Montgomery, Glenn Cowley, Stanley Gill, Gregory Kryukov, Sasha Pantel, Will Harrington, Mike Burger, Robin Meyers, Levi Ali, Amy Goodale, Yenarae Lee, Levi Garraway, Jesse Boehm, David Root, Todd Golub, William Hahn. Emerging targets from Cancer Dependency Map v0.1. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B44.