bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolic Reprogramming by Dual AKT/ERK Inhibition through Imipridones Elicits Unique Vulnerabilities in Glioblastoma
Authors: Ishida Chiaki T. , Zhang Yiru , Bianchetti Elena , Shu Chang , Nguyen Trang T.T. , Kleiner Giulio , Sanchez-Quintero Maria J. , Quinzii Catarina M. , Westhoff Mike-Andrew , Karpel-Massler Georg , Prabhu Varun V. , Allen Joshua E. , Siegelin Markus D. 
Published: July 2018

Abstract
Purpose: The goal of this study is to enhance the efficacy of imipridones, a novel class of AKT/ERK inhibitors that displayed limited therapeutic efficacy against glioblastoma (GBM).
Experimental Design: Gene set enrichment, LC/MS, and extracellular flux analyses were used to determine the mechanism of action of novel imipridone compounds, ONC206 and ONC212. Orthotopic patient-derived xenografts were utilized to evaluate therapeutic potency.
Results: Imipridones reduce the proliferation of patient-derived xenograft and stem-like glioblastoma cell cultures in vitro and in multiple xenograft models in vivo. ONC212 displayed the highest potency. High levels of c-myc predict susceptibility to growth inhibition and apoptosis induction by imipridones and increased host survival in orthotopic patient-derived xenografts. As early as 1 hour, imipridones elicit on-target inhibition, followed by dephosphorylation of GSK3β at serine 9. GSK3β promotes phosphorylation of c-myc at threonine 58 and enhances its proteasomal degradation. Moreover, inhibition of c-myc by BRD4 antagonists sensitizes for imipridone-induced apoptosis in stem-like GBM cells in vitro and in vivo. Imipridones affect energy metabolism by suppressing both glycolysis and oxidative phosphorylation, which is accompanied by a compensatory activation of the serine-one carbon-glycine (SOG) pathway, involving the transcription factor ATF4. Interference with the SOG pathway through novel inhibitors of PHGDH results in synergistic cell death induction in vitro and in vivo.
Conclusions: These results suggest that c-myc expression predicts therapeutic responses to imipridones and that imipridones lead to suppression of tumor cell energy metabolism, eliciting unique metabolic vulnerabilities that can be exploited for clinical relevant drug combination therapies. Clin Cancer Res; 24(21); 5392–406. ©2018 AACR.
Elevated miR-182-5p Associates with Renal Cancer Cell Mitotic Arrest through Diminished MALAT-1 Expression
Authors: Kulkarni Priyanka , Dasgupta Pritha , Bhat Nadeem S. , Shahryari Varahram , Shiina Marisa , Hashimoto Yutaka , Majid Shahana , Deng Guoren , Saini Sharanjot , Tabatabai Z. Laura , Yamamura Soichiro , Tanaka Yuichiro , Dahiya Rajvir 
Published: July 2018

Abstract
The molecular heterogeneity of clear cell renal carcinoma (ccRCC) makes prediction of disease progression and therapeutic response difficult. Thus, this report investigates the functional significance, mechanisms of action, and clinical utility of miR-182-5p and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1/NEAT2), a long noncoding RNA (lncRNA), in the regulation of kidney cancer using human kidney cancer tissues as well as in vitro and in vivo model systems. Profiling of miR-182-5p and MALAT-1 in human renal cancer cells and clinical specimens was done by quantitative real-time PCR (qPCR). The biological significance was determined by series of in vitro and in vivo experiments. The interaction between miR-182-5p and MALAT-1 was investigated using luciferase reporter assays. In addition, the effects of miR-182-5p overexpression and MALAT-1 downregulation on cell-cycle progression were assessed in ccRCC cells. The data indicate that miR-182-5p is downregulated in ccRCC; the mechanism being CpG hypermethylation as observed from 5-Aza CdR treatment that decreased promoter methylation and expression of key methylation regulatory genes like DNMT1, DNMT3a, and DNMT3b. Overexpression of miR-182-5p–inhibited cell proliferation, colony formation, apoptosis, and led to G2–M-phase cell-cycle arrest by directly targeting MALAT-1. Downregulation of MALAT-1 led to upregulation of p53, downregulation of CDC20, AURKA, drivers of the cell-cycle mitotic phase. Transient knockdown of MALAT-1 mimicked the effects of miR-182-5p overexpression. Finally, overexpression of miR-182-5p decreased tumor growth in mice, compared with controls; thus, demonstrating its antitumor effect in vivo.
Implications: This is the first study that offers new insight into role of miR-182-5p/MALAT-1 interaction on inhibition of ccRCC progression. Mol Cancer Res; 16(11); 1750–60. ©2018 AACR.
Molecular Portrait of Hypoxia in Breast Cancer: A Prognostic Signature and Novel HIF-Regulated Genes
Authors: Ye I. Chae , Fertig Elana J. , DiGiacomo Josh W. , Considine Michael , Godet Inês , Gilkes Daniele M. 
Published: July 2018

Abstract

Intratumoral hypoxia has been associated with invasion, metastasis, and treatment failure, prompting the need for a global characterization of the response to hypoxic conditions. The current study presents the results of a large-scale RNA sequencing (RNA-seq) effort, analyzing 31 breast cancer cell lines representative of breast cancer subtypes or normal mammary epithelial (NME) cells exposed to control tissue culture conditions (20% O2) or hypoxic conditions (1% O2). The results demonstrate that NME have a stronger response to hypoxia both in terms of number of genes induced by hypoxia as well as level of expression. A conserved 42-gene hypoxia signature shared across PAM50 subtypes and genes that are exclusively upregulated in Luminal A, Luminal B, and normal-like mammary epithelial cells is identified. The 42-gene expression signature is enriched in a subset of basal-like cell lines and tumors and differentiates survival among patients with basal-like tumors. Mechanistically, the hypoxia-inducible factors (HIF-1 and/or HIF-2) mediate the conserved hypoxic response. Also, four novel hypoxia-regulated and HIF-1–responsive genes were identified as part of the conserved signature. This dataset provides a novel resource to query transcriptional changes that occur in response to hypoxia and serves as a starting point for a clinical assay to aid in stratifying patients that would benefit from hypoxia-targeted therapies, some of which are currently in clinical trials.

Implications:
RNA-seq of 31 breast cancer cells exposed to control or hypoxic conditions reveals a conserved genomic signature that contains novel HIF-regulated genes and is prognostic for the survival of patients with triple-negative breast cancer.
An Ultrasound Study of the Development of Lingual Coarticulation during Childhood
Authors: Zharkova Natalia 
Published: July 2018

AbstractBackground/Aims: There is growing evidence that coarticulation development is protracted and segment-specific, and yet very little information is available on the changes in the extent of coarticulation across different phonemes throughout childhood. This study describes lingual coarticulatory patterns in 6 age groups of Scottish English-speaking children between 3 and 13 years old. Methods: Vowelon-consonant anticipatory coarticulation was analysed using ultrasound imaging data on tongue shape from 4 consonants that differ in the degree of constraint, i.e., the extent of articulatory demand, on the tongue. Results: Consonant-specific age-related patterns are reported, with consonants that have more demands on the tongue reaching adolescent-like levels of coarticulation in older age groups. Within-speaker variability in tongue shape decreases with increasing age. Conclusion: Reduced coarticulation in the youngest age group may be due to insufficient tongue differentiation. Immature patterns for lingual consonants in 5- to 11-year-olds are explained by the goal of producing the consonant target overriding the goal of coarticulating the consonant with the following vowel.
Assessing Decision Timing and Seasonal Climate Forecast Needs of Winter Wheat Producers in the South-Central United States
Authors: Klemm Toni , McPherson Renee A. 
Published: July 2018

AbstractAgricultural decision-making that adapts to climate variability is essential to global food security. Crop production can be severely impacted by drought, flood, and heat, as seen in recent years in parts of the United States. Seasonal climate forecasts can help producers reduce crop losses, but many nationwide, publicly available seasonal forecasts currently lack relevance for agricultural producers, in part because they do not reflect their decision needs. This study examines the seasonal forecast needs of winter wheat producers in the southern Great Plains to understand what climate information is most useful and what lead times are most relevant for decision-making. An online survey of 119 agricultural advisers, cooperative extension agents in Oklahoma, Kansas, Texas, and Colorado, was conducted and gave insights into producers’ preferences for forecast elements, what weather and climate extremes have the most impact on decision-making, and the decision timing of major farm practices. The survey participants indicated that winter wheat growers were interested not only in directly modeled variables, such as total monthly rainfall, but also in derived elements, such as consecutive number of dry days. Moreover, these agricultural advisers perceived that winter wheat producers needed seasonal climate forecasts to have a lead time of 0–2.5 months—the planning lead time for major farm practices, like planting or harvesting. A forecast calendar and monthly rankings for forecast elements were created that can guide forecasters and advisers as they develop decision tools for winter wheat producers and that can serve as a template for other time-sensitive decision tools developed for stakeholder communities.
Assessment of Radiative Forcing by Light-Absorbing Particles in Snow from In Situ Observations with Radiative Transfer Modeling
Authors: McKenzie Skiles S. , Painter Thomas H. 
Published: July 2018

Abstract
It is well established that episodic deposition of dust on mountain snow reduces snow albedo and impacts snow hydrology in the western United States, particularly in the Colorado Rockies, which are headwaters for the Colorado River. Until recently the snow observations needed to physically quantify radiative forcing (RF) by dust on snow were lacking, and analysis of impacts used a semiempirical relationship between snow optical properties and observed surface reflectance. Here, we present a physically based daily time series of RF by dust and black carbon (BC) in snow at Senator Beck Basin Study Area, Colorado. Over the 2013 ablation season (March–May), a snow–aerosol radiative transfer model was forced with near daily measured snow property inputs (density, effective grain size, and dust/BC concentrations) and validated with coincidentally measured spectral albedo. Over the measurement period, instantaneous RF by dust and BC in snow ranged from 0.25 to 525 W m−2, with daily averages ranging from 0 to 347 W m−2. Dust dominated particulate mass, accounting for more than 90% of RF. The semiempirical RF values, which constitute the continuous long-term record, compared well to the physically based RF values; over the full time series, daily reported semiempirical RF values were 8 W m−2 higher on average, with a root-mean-square difference of 16 W m−2.
Incidence of Vestibular Schwannoma in Taiwan from 2001 to 2012: A Population-Based National Health Insurance Study
Authors: Koo Malcolm , Lai Jen-Tsung , Yang Edward Yih-Liang , Liu Tien-Chen , Hwang Juen-Haur 
Published: July 2018

Objectives: Vestibular schwannomas, also known as acoustic neuromas, are slow-growing tumors that may lead to asymmetric hearing loss, unilateral tinnitus, and vertigo. Population-based data are lacking regarding the incidence of vestibular schwannoma in Asian populations. The aim of this study was to investigate the incidence of vestibular schwannoma in Taiwan using data from a population-based health claim database. Subjects and Methods: Patients aged 20 years and over with incident cases of vestibular schwannoma between January 1, 2001, and December 31, 2012, were identified from the Longitudinal Health Insurance Database 2000 of the National Health Insurance Research Database (NHIRD), Taiwan, based on the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code 225.1. Only those patients who had received a magnetic resonance imaging scan prior to the diagnosis of vestibular schwannoma were considered as definitive cases. Results: 206 cases of vestibular schwannoma were identified during the interval 2001 to 2012. The overall annual incidence was 2.66 per 100 000 persons (95% confidence interval, 2.32-3.05). The annual incidence rate varied throughout the study period, ranging from 1.74 to 3.72 per 100 000 persons. The highest incidence rate of 4.86 per 100 000 persons was observed in the age group of 60 to 69 years. Conclusions: Based on data from the NHIRD in Taiwan for the years 2001 to 2012, the average annual incidence rate of vestibular schwannoma was found to be 2.66 per 100 000 persons.
Crowdsourced Measurement of Reaction Times to Audiovisual Stimuli With Various Degrees of Asynchrony
Authors: Bazilinskyy Pavlo , Winter Joost de 
Published: July 2018

Objective: This study was designed to replicate past research concerning reaction times to audiovisual stimuli with different stimulus onset asynchrony (SOA) using a large sample of crowdsourcing respondents. Background: Research has shown that reaction times are fastest when an auditory and a visual stimulus are presented simultaneously and that SOA causes an increase in reaction time, this increase being dependent on stimulus intensity. Research on audiovisual SOA has been conducted with small numbers of participants. Method: Participants ( N = 1,823) each performed 176 reaction time trials consisting of 29 SOA levels and three visual intensity levels, using CrowdFlower, with a compensation of US$0.20 per participant. Results were verified with a local Web-in-lab study ( N = 34). Results: The results replicated past research, with a V shape of mean reaction time as a function of SOA, the V shape being stronger for lower-intensity visual stimuli. The level of SOA affected mainly the right side of the reaction time distribution, whereas the fastest 5% was hardly affected. The variability of reaction times was higher for the crowdsourcing study than for the Web-in-lab study. Conclusion: Crowdsourcing is a promising medium for reaction time research that involves small temporal differences in stimulus presentation. The observed effects of SOA can be explained by an independent-channels mechanism and also by some participants not perceiving the auditory or visual stimulus, hardware variability, misinterpretation of the task instructions, or lapses in attention. Application: The obtained knowledge on the distribution of reaction times may benefit the design of warning systems.
Rhythmic auditory stimulation for reduction of falls in Parkinson’s disease: a randomized controlled study
Authors: Thaut Michael H , Rice Ruth R , Braun Janzen Thenille , Hurt-Thaut Corene P , McIntosh Gerald C 
Published: July 2018

Objective: To test whether rhythmic auditory stimulation (RAS) training reduces the number of falls in Parkinson’s disease patients with a history of frequent falls. Design: Randomized withdrawal study design. Subjects: A total of 60 participants (aged 62–82 years) diagnosed with idiopathic Parkinson’s disease (Hoehn and Yahr stages III or IV) with at least two falls in the past 12 months. Intervention: Participants were randomly allocated to two groups and completed 30 minutes of daily home-based gait training with metronome click–embedded music. The experimental group completed 24 weeks of RAS training, whereas the control group discontinued RAS training between weeks 8 and 16. Main measures: Changes in clinical and kinematic parameters were assessed at baseline, weeks 8, 16, and 24. Results: Both groups improved significantly at week 8. At week 16—after the control group had discontinued training—significant differences between groups emerged including a rise in the fall index for the control group ( M = 10, SD = 6). Resumption of training reduced the number of falls so that group differences were no longer significant at week 24 ( Mexperimental = 3, SD = 2.6; Mcontrol = 5, SD = 4.4; P > 0.05). Bilateral ankle dorsiflexion was significantly correlated with changes in gait, fear of falling, and the fall index, indicating ankle flexion as a potential kinematic mechanism RAS addresses to reduce falls. Conclusion: RAS training significantly reduced the number of falls in Parkinson’s disease and modified key gait parameters, such as velocity and stride length.
Failures in dual-task obstacle crossing could predict risk of future fall in independent ambulatory individuals with spinal cord injury
Authors: Amatachaya Sugalya , Srisim Kitiyawadee , Thaweewannakij Thiwabhorn , Arrayawichanon Preeda , Amatachaya Pipatana , Mato Lugkana 
Published: July 2018

Objective: To determine whether cognitive-motor interference using ability of dual-task obstacle crossing could predict a risk of fall in 90 ambulatory individuals with spinal cord injury. Design: Six-month prospective study. Setting: A rehabilitation center and community hospitals. Subjects: Independent ambulatory individuals with spinal cord injury. Main outcome measures: Subjects were interviewed and evaluated for personal characteristics, dual-task obstacle crossing ability, and functional ability using the 10 Meter Walk Test, Timed Up and Go Test, and Five Times Sit-to-Stand Test. Then they were prospectively monitored for fall data every month for six months in total. Results: A total of 90 chronic ambulatory individuals with spinal cord injury with an average age of 52.51 ± 13.43 years, who mostly had mild lesion severity ( n = 71, 79%) and walked with a walking device ( n = 54, 60%) completed in the study. More than one-third of the subjects ( n = 32, 36%) failed in dual-task obstacle crossing. The failures were obviously associated with the fall (unadjusted odds ratio = 7.07, P < 0.002, power = 1.000). Conclusion: Cognitive-motor interference is important for ambulatory individuals with spinal cord injury, as it could detect those with low functional ability and risk of future falls.
Acute inhalation toxicity study of n-heneicosane and its combination with diflubenzuron: An attracticide of Aedes aegypti
Authors: Gautam Anshoo , Singh Deeksha , Shrivastava Peeyush , Vijayaraghavan R 
Published: July 2018

Objective: Combination of an oviposition pheromone and an insect growth regulator for the control of vectors is an effective approach. There is a need for toxicological evaluation before its introduction. The present study evaluates the acute inhalation toxicity of n-heneicosane and its combination with diflubenzuron in a head-only inhalation exposure chamber made of glass. Materials and methods: A head-only inhalation exposure chamber made of glass (volume: 3.5 l) was used for exposing four rats at a time. A glass nebulizer was used for aerosolization of n-heneicosane and its combination with diflubenzuron (1:10 w/w). Nebulization pressure was 10 and 15 psi and the air flow of exposure the chamber was adjusted to 30 lpm. Male Wistar rats were acclimatized in whole body plethysmographs that were connected to volumetric flow pressure transducers by silicon tubes. The transducers were connected to an amplifier and a digitized response was recorded through an oscillograph and personal computers. Respiratory variables were recorded online. After inhalation exposure, various other parameters like survival, body weight, organ body weight index and biochemical changes were recorded for analysis. Results and discussion: Particle size determination proved that the aerosol particles were within the respirable range. LC50 of n-heneicosane and its combination with diflubenzuron was found to be more than 5 g/m3. There were minimal changes observed during exposure to n-heneicosane and also its combination with diflubenzuron on the respiratory variables. The changes were not consistent with the dose. Conclusion: n-Heneicosane and its combination with diflubenzuron showed low mammalian toxicity.
jAVANT-GARDE: A Cross-Platform Serious Game for an Introduction to Programming With Java
Authors: Galgouranas Stefanos , Xinogalos Stelios 
Published: July 2018

Background. Programming is widely known to be a cognitively demanding field. Learning programming can be a strenuous task without the proper guidance and methodology. Students often face difficulties in understanding even the most basic and fundamental concepts of programming, leading to their confusion and disappointment. Serious games for programming have the potential to alleviate students’ difficulties with programming. Aim. This article introduces a new serious game named jAVANT-GARDE which aims to educate the player on the basic concepts of programming and object-oriented programming through Java. By design, the game is suitable for everyone, even for players with no previous knowledge of programming. This article aims to present important information regarding the design, implementation and pilot evaluation of jAVANT-GARDE. Method. The game was evaluated by 42 high school students (age 16-17) in terms of perceived player experience and short-term learning. The participants played the game for one hour in the school lab and then answered a questionnaire based on the MEEGA+ framework. Results. Students evaluated positively the game in terms of its usability, confidence in playing the game, challenge, satisfaction, fun, focused attention and relevance. Moreover, the majority of students stated that would prefer learning programming with this game to learning through other teaching methods. Conclusions. The results of the pilot study and students’ replies in the questionnaire are rather positive. This gives us the initiative to proceed with studying the effect of the game in long-term learning of programming concepts.
Age- and Gender-Specific Normative Values for the Self-Reported Foot and Ankle Score (SEFAS)
Authors: Cöster Maria C. , Rosengren Björn E. , Karlsson Magnus K. , Carlsson Åke 
Published: July 2018

Background: The Self-Reported Foot and Ankle Score (SEFAS) is a foot- and ankle-specific patient-reported outcome measurement (PROM) score that has been validated with good results for a variety of foot and ankle disorders. SEFAS is sensitive detecting improvement or deterioration after surgery. However, normative values, required to put a specific patient’s summary score into perspective, are lacking. Methods: In this report, we included 396 population-based men and 383 women (43% of the invited individuals), age 20-89 years, who had completed the SEFAS questionnaire and questions regarding anthropometrics and health. We used Mann-Whitney U test to test gender differences and Spearman correlation coefficients to determine any association between SEFAS score and age. We present gender-specific median SEFAS scores with range and 5th to 95th percentiles and mean with standard deviation. Results: The SEFAS normative values were median 48 in men (range 11-48), 5th to 95th percentiles 31 to 48 and mean 45 ± 6, and in women, median 47 (range 6-48), 5th to 95th percentiles 23 to 48 and mean 43 ± 8 (gender comparison P < .001). SEFAS normative values correlated inversely with age (r = −0.12, P < .001). Conclusion: In the general population, older age was associated with lower SEFAS value, and men had higher values than women. The population-based normative SEFAS values provided in this study can facilitate quantification of disability related to foot and ankle with and without surgery in the foot and ankle. Level of Evidence: Level II, prospective comparative study.