bluuebunny/crossref_metadata_2025 huggingface dataset:
A Study of Smoothing Methods for Language Models Applied to Ad Hoc Information Retrieval
Authors: Zhai Chengxiang , Lafferty John
Published: August 2017

Language modeling approaches to information retrieval are attractive and promising because they connect the problem of retrieval with that of language model estimation, which has been studied extensively in other application areas such as speech recognition. The basic idea of these approaches is to estimate a language model for each document, and then rank documents by the likelihood of the query according to the estimated language model. A core problem in language model estimation is smoothing, which adjusts the maximum likelihood estimator so as to correct the inaccuracy due to data sparseness. In this paper, we study the problem of language model smoothing and its influence on retrieval performance. We examine the sensitivity of retrieval performance to the smoothing parameters and compare several popular smoothing methods on different test collection.
From Information Security Awareness to Reasoned Compliant Action
Authors: Bauer Stefan , Bernroider Edward W.N.
Published: August 2017

Despite the importance of information security, far too many organizations, in particular banks, are facing behavioral information security incidents. In the context given by the headquarters of a large European banking organization, this single case study investigates whether individual behavioral compliance with the information security policy is influenced by accumulated security information and information security awareness embedded within the theory of reasoned action in an extended norms approach. We collected empirical data through a three-staged process in which we conducted semi-structured interviews, implemented a survey to test the developed research hypotheses, and engaged in interactive presentations to discuss the results. In particular, the qualitative interviews strengthened internal validity of survey constructs related to neutralization techniques and internal channel use for information acquisition. We found that the attitude toward information security policy compliance, and not only social norms but also personal norms related to neutralization techniques, are all significant variables potentially mitigating the knowing-doing gap reported in related information security research. Besides emphasizing the importance of extended norms, which should be accounted for in information security awareness programs, we also highlight the use of internal and external channels to acquire information as initial drivers of awareness. The empirical findings provide implications to practice and advance theoretical development by generally supporting the developed model that accounts for compliant information security behavior at an international bank.
Strategic Insights into Localizing Web Communications
Authors: Singh Nitish , Park Ji Eun , Chun Wootae , Moura Francisco Tigre , Kim Seung H.
Published: August 2017

The objectives of this study are firstly, to explore cultural values of South Korean websites; secondly, to investigate whether multinational companies take a standardized global web strategy or culturally localize website contents for foreign markets; and lastly, to examine whether a regionalized web strategy can be used for countries that have low cultural distance. Content analysis was conducted to measure and explore website localization efforts by South Korean local companies, and U.S. and Japanese multinational enterprises in their home markets as well as in their host markets when localizing web content for South Korean B-to-C e-commerce markets. The findings from the study revealed that Korean cultural values are reflected on their local websites, that U.S. multinational firms are not culturally adapting their websites for Korean consumers, and that Japanese multinational corporations follow a standardized website strategy for Korean online shoppers.
Detection of maltodextrin and its discrimination from sucrose are independent of the T1R2 + T1R3 heterodimer
Authors: Smith Kimberly R. , Spector Alan C.
Published: August 2017

Maltodextrins, such as Maltrin and Polycose, are glucose polymer mixtures of varying chain lengths that are palatable to rodents. Although glucose and other sugars activate the T1R2 + T1R3 “sweet” taste receptor, recent evidence from T1R2- or T1R3-knockout (KO) mice suggests that maltodextrins, despite their glucose polymer composition, activate a separate receptor mechanism to generate a taste percept qualitatively distinguishable from that of sweeteners. However, explicit discrimination of maltodextrins from prototypical sweeteners has not yet been psychophysically tested in any murine model. Therefore, mice lacking T1R2 + T1R3 and wild-type controls were tested in a two-response taste discrimination task to determine whether maltodextrins are 1) detectable when both receptor subunits are absent and 2) perceptually distinct from that of sucrose irrespective of viscosity, intensity, and hedonics. Most KO mice displayed similar Polycose sensitivity as controls. However, some KO mice were only sensitive to the higher Polycose concentrations, implicating potential allelic variation in the putative polysaccharide receptor or downstream pathways unmasked by the absence of T1R2 + T1R3. Varied Maltrin and sucrose concentrations of approximately matched viscosities were then presented to render the oral somatosensory features, intensity, and hedonic value of the solutions irrelevant. Although both genotypes competently discriminated Maltrin from sucrose, performance was apparently driven by the different orosensory percepts of the two stimuli in control mice and the presence of a Maltrin but not sucrose orosensory cue in KO mice. These data support the proposed presence of an orosensory receptor mechanism that gives rise to a qualitatively distinguishable sensation from that of sucrose.
Altered tactile sensitivity in children with attention-deficit hyperactivity disorder
Authors: Puts Nicolaas A. J. , Harris Ashley D. , Mikkelsen Mark , Tommerdahl Mark , Edden Richard A. E. , Mostofsky Stewart H.
Published: August 2017

Attention-deficit hyperactivity disorder (ADHD) is characterized by an inability to concentrate, heightened activity, and hypermotoric behavior, but sensory (e.g., tactile) problems are common. The literature on tactile impairments in ADHD is limited, with most work employing clinical observations or questionnaires. We studied tactile processing in children with ADHD and hypothesized that children with ADHD would show reduced performance in tasks closely linked to inhibition. Sixty-seven children with ADHD and 62 typically developing children (TDC) performed a battery of tasks grouped in domains: simple and choice reaction time; static and dynamic detection threshold (probing feedforward inhibition); amplitude discrimination without adaptation and with dual and single-site adaptation (probing lateral inhibition and adaptation); sequential and simultaneous frequency discrimination (previously linked to GABA); and temporal order judgment with and without a synchronous carrier stimulus. Children with ADHD could discriminate different amplitudes without adaptation, suggesting lateral inhibition is intact, but were negatively affected in all adaptation conditions, whereas TDC were only affected during single-site adaptation. Children with ADHD also showed normal frequency discrimination. Children with ADHD showed slower reaction times and higher detection threshold, likely driven by IQ and inattention, because reaction time and detection thresholds correlated with IQ and subtle motor signs. Children with ADHD showed a pattern of altered tactile processing on specific tasks, suggesting that higher cognitive function and cortical mechanisms related to adaptation are affected in ADHD, but no clear conclusion can be drawn toward impaired inhibition.

NEW & NOTEWORTHY This manuscript presents the first tactile psychophysical study testing different aspects of tactile processing in attention-deficit hyperactivity disorder (ADHD), using large cohort sizes of 67 children with ADHD and 65 Typically Developing Children. This study demonstrates impaired tactile processing in children with ADHD, on some, but not all tasks (showing this is not just due to attention), related to impaired cortical mechanisms. Furthermore, both IQ and soft motor skill abnormalities (common in ADHD) are correlated with tactile abnormalities.
Theta-frequency selectivity in the somatic spike-triggered average of rat hippocampal pyramidal neurons is dependent on HCN channels
Authors: Das Anindita , Narayanan Rishikesh
Published: August 2017

The ability to distill specific frequencies from complex spatiotemporal patterns of afferent inputs is a pivotal functional requirement for neurons residing in networks receiving frequency-multiplexed inputs. Although the expression of theta-frequency subthreshold resonance is established in hippocampal pyramidal neurons, it is not known if their spike initiation dynamics manifest spectral selectivity, or if their intrinsic properties are tuned to process gamma-frequency inputs. Here, we measured the spike-triggered average (STA) of rat hippocampal pyramidal neurons through electrophysiological recordings and quantified spectral selectivity in their spike initiation dynamics and their coincidence detection window (CDW). Our results revealed strong theta-frequency selectivity in the STA, which was also endowed with gamma-range CDW, with prominent neuron-to-neuron variability that manifested distinct pairwise dissociations and correlations with different intrinsic measurements. Furthermore, we demonstrate that the STA and its measurements substantially adapted to the state of the neuron defined by its membrane potential and to the statistics of its afferent inputs. Finally, we tested the effect of pharmacologically blocking the hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels on the STA and found that the STA characteristic frequency reduced significantly to the delta-frequency band after HCN channel blockade. This delta-frequency selectivity in the STA emerged in the absence of subthreshold resonance, which was abolished by HCN channel blockade, thereby confirming computational predictions on the dissociation between these two forms of spectral selectivity. Our results expand the roles of HCN channels to theta-frequency selectivity in the spike initiation dynamics, apart from underscoring the critical role of interactions among different ion channels in regulating neuronal physiology.

NEW & NOTEWORTHY We had previously predicted, using computational analyses, that the spike-triggered average (STA) of hippocampal neurons would exhibit theta-frequency (4–10 Hz) spectral selectivity and would manifest coincidence detection capabilities for inputs in the gamma-frequency band (25–150 Hz). Here, we confirmed these predictions through direct electrophysiological recordings of STA from rat CA1 pyramidal neurons and demonstrate that blocking HCN channels reduces the frequency of STA spectral selectivity to the delta-frequency range (0.5–4 Hz).
Multiple spatial representations interact to increase reach accuracy when coordinating a saccade with a reach
Authors: Vazquez Yuriria , Federici Laura , Pesaran Bijan
Published: August 2017

Reaching is an essential behavior that allows primates to interact with the environment. Precise reaching to visual targets depends on our ability to localize and foveate the target. Despite this, how the saccade system contributes to improvements in reach accuracy remains poorly understood. To assess spatial contributions of eye movements to reach accuracy, we performed a series of behavioral psychophysics experiments in nonhuman primates ( Macaca mulatta). We found that a coordinated saccade with a reach to a remembered target location increases reach accuracy without target foveation. The improvement in reach accuracy was similar to that obtained when the subject had visual information about the location of the current target in the visual periphery and executed the reach while maintaining central fixation. Moreover, we found that the increase in reach accuracy elicited by a coordinated movement involved a spatial coupling mechanism between the saccade and reach movements. We observed significant correlations between the saccade and reach errors for coordinated movements. In contrast, when the eye and arm movements were made to targets in different spatial locations, the magnitude of the error and the degree of correlation between the saccade and reach direction were determined by the spatial location of the eye and the hand targets. Hence, we propose that coordinated movements improve reach accuracy without target foveation due to spatial coupling between the reach and saccade systems. Spatial coupling could arise from a neural mechanism for coordinated visual behavior that involves interacting spatial representations.

NEW & NOTEWORTHY How visual spatial representations guiding reach movements involve coordinated saccadic eye movements is unknown. Temporal coupling between the reach and saccade system during coordinated movements improves reach performance. However, the role of spatial coupling is unclear. Using behavioral psychophysics, we found that spatial coupling increases reach accuracy in addition to temporal coupling and visual acuity. These results suggest that a spatial mechanism to couple the reach and saccade systems increases the accuracy of coordinated movements.
The temporal stability of visuomotor adaptation generalization
Authors: Zhou Weiwei , Fitzgerald Justin , Colucci-Chang Katrina , Murthy Karthik G. , Joiner Wilsaan M.
Published: August 2017

Movement adaptation in response to systematic motor perturbations exhibits distinct spatial and temporal properties. These characteristics are typically studied in isolation, leaving the interaction largely unknown. Here we examined how the temporal decay of visuomotor adaptation influences the spatial generalization of the motor recalibration. First, we quantified the extent to which adaptation decayed over time. Subjects reached to a peripheral target, and a rotation was applied to the visual feedback of the unseen motion. The retention of this adaptation over different delays (0–120 s) 1) decreased by 29.0 ± 6.8% at the longest delay and 2) was represented by a simple exponential, with a time constant of 22.5 ± 5.6 s. On the basis of this relationship we simulated how the spatial generalization of adaptation would change with delay. To test this directly, we trained additional subjects with the same perturbation and assessed transfer to 19 different locations (spaced 15° apart, symmetric around the trained location) and examined three delays (~4, 12, and 25 s). Consistent with the simulation, we found that generalization around the trained direction (±15°) significantly decreased with delay and distance, while locations >60° displayed near-constant spatiotemporal transfer. Intermediate distances (30° and 45°) showed a difference in transfer across space, but this amount was approximately constant across time. Interestingly, the decay at the trained direction was faster than that based purely on time, suggesting that the spatial transfer of adaptation is modified by concurrent passive (time dependent) and active (movement dependent) processes.

NEW & NOTEWORTHY Short-term motor adaptation exhibits distinct spatial and temporal characteristics. Here we investigated the interaction of these features, utilizing a simple motor adaptation paradigm (recalibration of reaching arm movements in response to rotated visual feedback). We examined the changes in the spatial generalization of motor adaptation for different temporal manipulations and report that the spatiotemporal generalization of motor adaptation is generally local and is influenced by both passive (time dependent) and active (movement dependent) learning processes.
Altered modulation of sensorimotor rhythms with chronic paralysis
Authors: Foldes Stephen T. , Weber Douglas J. , Collinger Jennifer L.
Published: August 2017

After paralysis, the disconnection between the cortex and its peripheral targets leads to neuroplasticity throughout the nervous system. However, it is unclear how chronic paralysis specifically impacts cortical oscillations associated with attempted movement of impaired limbs. We hypothesized that μ- (8–13 Hz) and β- (15–30 Hz) event-related desynchronization (ERD) would be less modulated for individuals with hand paralysis due to cervical spinal cord injury (SCI). To test this, we compared the modulation of ERD from magnetoencephalography (MEG) during attempted and imagined grasping performed by participants with cervical SCI ( n = 12) and able-bodied controls ( n = 13). Seven participants with tetraplegia were able to generate some electromyography (EMG) activity during attempted grasping, whereas the other five were not. The peak and area of ERD were significantly decreased for individuals without volitional muscle activity when they attempted to grasp compared with able-bodied subjects and participants with SCI,with some residual EMG activity. However, no significant differences were found between subject groups during mentally simulated tasks (i.e., motor imagery) where no muscle activity or somatosensory consequences were expected. These findings suggest that individuals who are unable to produce muscle activity are capable of generating ERD when attempting to move, but the characteristics of this ERD are altered. However, for people who maintain volitional muscle activity after SCI, there are no significant differences in ERD characteristics compared with able-bodied controls. These results provide evidence that ERD is dependent on the level of intact muscle activity after SCI.

NEW & NOTEWORTHY Source space MEG was used to investigate sensorimotor cortical oscillations in individuals with SCI. This study provides evidence that individuals with cervical SCI exhibit decreased ERD when they attempt to grasp if they are incapable of generating muscle activity. However, there were no significant differences in ERD between paralyzed and able-bodied participants during motor imagery. These results have important implications for the design and evaluation of new therapies, such as motor imagery and neurofeedback interventions.
Bifurcation and Global Dynamics of a Leslie-Gower Type Competitive System of Rational Difference Equations with Quadratic Terms
Authors: Hadžiabdić V. , Kulenović M. R. S. , Pilav E.
Published: August 2017

We investigate global dynamics of the following systems of difference equations xn+1=xn/A1+B1xn+C1yn, yn+1=yn2/A2+B2xn+C2yn2, n=0,1,…, where the parameters A1, A2, B1, B2, C1, and C2 are positive numbers and the initial conditions x0 and y0 are arbitrary nonnegative numbers. This system is a version of the Leslie-Gower competition model for two species. We show that this system has rich dynamics which depends on the part of parametric space.
Arthroscopically Assisted Coracoclavicular Fixation Using a Single Flip Button Device Technique: What Are the Main Factors Affecting the Maintenance of Reduction?
Authors: Lee Yong-Beom , Kim Jeehyoung , Lee Ho-Won , Kim Byung-Su , Yoon Won-Yong , Yoo Yon-Sik
Published: August 2017

Background. Among coracoclavicular (CC) fixation techniques, the use of flip button device was demonstrated to have successful outcomes with the advantage of being able to accommodate an arthroscopic procedure. Purpose. This study was conducted to investigate the factors associated with loss of fixation after arthroscopically assisted CC fixation using a single flip button device for acromioclavicular (AC) joint dislocations. Materials and Methods. We enrolled a total of 47 patients (35 men and 12 women). Plain radiography was performed at a mean of 24 months postoperatively to evaluate the final radiological outcome. The primary outcome measure was a long-term reduction of the AC joint for at least 24 months. Results. We found that 29 patients had a high quality reduction (61.7%) and 18 patients had a low quality reduction (38.3%) in initial postoperative CT findings. Our study showed that the duration (5 days) from injury to treatment and the quality of initial postoperative reduction were significantly associated with the maintenance of reduction at final follow-up. Conclusion. Our study showed that maintaining stable reduction after arthroscopically assisted CC fixation using a single flip button device technique is difficult especially in patients who received delayed treatment or whose initial reduction quality was poor.
Polar Value Analysis of Low to Moderate Astigmatism with Wavefront-Guided Sub-Bowman Keratomileusis
Authors: Yan Pisong , Du Zhiyu , Zhang Yu
Published: August 2017

Purpose. To evaluate the astigmatic outcomes of wavefront-guided sub-Bowman keratomileusis (WFG-SBK) for low to moderate myopic astigmatism.Methods. This study enrolled 100 right eyes from 100 patients who underwent WFG-SBK for the correction of myopia and astigmatism. The polar value method was performed with anterior and posterior corneal astigmatism measured with Scheimpflug camera combined with Placido corneal topography (Sirius, CSO) and refractive astigmatism preoperatively and 1 month, 3 months, and 6 months postoperatively.Results. Similar results for surgically induced astigmatism (SIA) and error of the procedure in both anterior corneal astigmatism (ACA) and total ocular astigmatism (TOA). There was a minor undercorrection of the cylinder in both ACA and TOA. Posterior corneal astigmatism (PCA) showed no significant change.Conclusions. Wavefront-guided SBK could provide good astigmatic outcomes for the correction of low to moderate myopic astigmatism. The surgical effects were largely attributed to the astigmatic correction of the anterior corneal surface. Posterior corneal astigmatism remained unchanged even after WFG-SBK for myopic astigmatism. Polar value analysis can be used to guide adjustments to the treatment cylinder alongside a nomogram designed to optimize postoperative astigmatic outcomes in myopic WFG-SBK.
Research on Fault Diagnosis for Pumping Station Based on T-S Fuzzy Fault Tree and Bayesian Network
Authors: Bi Zhuqing , Li Chenming , Li Xujie , Gao Hongmin
Published: August 2017

According to the characteristics of fault diagnosis for pumping station, such as the complex structure, multiple mappings, and numerous uncertainties, a new approach combining T-S fuzzy gate fault tree and Bayesian network (BN) is proposed. On the one hand, traditional fault tree method needs the logical relationship between events and probability value of events and can only represent the events with two states. T-S fuzzy gate fault tree method can solve these disadvantages but still has weaknesses in complex reasoning and only one-way reasoning. On the other hand, the BN is suitable for fault diagnosis of pumping station because of its powerful ability to deal with uncertain information. However, it is difficult to determine the structure and conditional probability tables of the BN. Therefore, the proposed method integrates the advantages of the two methods. Finally, the feasibility of the method is verified through a fault diagnosis model of the rotor in the pumping unit, the accuracy of the method is verified by comparing with the methods based on traditional Bayesian network and BP neural network, respectively, when the historical data is sufficient, and the results are more superior to the above two when the historical data is insufficient.
Standardized Kaempferia parviflora Extract Inhibits Intrinsic Aging Process in Human Dermal Fibroblasts and Hairless Mice by Inhibiting Cellular Senescence and Mitochondrial Dysfunction
Authors: Park Ji-Eun , Woo Seon Wook , Kim Mi-Bo , Kim Changhee , Hwang Jae-Kwan
Published: August 2017

Intrinsic skin aging is a complex biological phenomenon mainly caused by cellular senescence and mitochondrial dysfunction. This study evaluated the inhibitory effect of Kaempferia parviflora Wall ex. Baker ethanol extract (KPE) on H2O2‐stimulated cellular senescence and mitochondrial dysfunction both in vitro and in vivo. KPE significantly increased cell growth and suppressed senescence‐associated β‐galactosidase activation. KPE inhibited the expression of cell‐cycle inhibitors (p53, p21, p16, and pRb) and stimulated the expression of cell‐cycle activators (E2F1 and E2F2). H2O2‐induced hyperactivation of the phosphatidylinositol 3‐kinase/protein kinase B (AKT) signaling pathway was suppressed by KPE through regulated expression of forkhead box O3a (FoxO3a) and mammalian target of rapamycin (mTOR). KPE attenuated inflammatory mediators (interleukin‐6 (IL‐6), IL‐8, nuclear factor kappa B (NF‐κB), and cyclooxygenase‐2 (COX‐2)) and increased the mRNA expression of PGC‐1α, ERRα, NRF1, and Tfam, which modulate mitochondrial biogenesis and function. Consequently, reduced ATP levels and increased ROS level were also reversed by KPE treatment. In hairless mice, KPE inhibited wrinkle formation, skin atrophy, and loss of elasticity by increasing the collagen and elastic fibers. The results indicate that KPE prevents intrinsic aging process in hairless mice by inhibiting cellular senescence and mitochondrial dysfunction, suggesting its potential as a natural antiaging agent.
IL-10-Producing B Cells Suppress Effector T Cells Activation and Promote Regulatory T Cells in Crystalline Silica-Induced Inflammatory Response In Vitro
Authors: Lu Yiping , Liu Fangwei , Li Chao , Chen Ying , Weng Dong , Chen Jie
Published: August 2017

Long-term exposure to crystalline silica leads to silicosis, which is characterized by persistent lung inflammation and lung fibrosis. Multiple immune cells have been demonstrated to participate in crystalline silica-induced immune responses. Our previous study indicated that B10 could control lung inflammation through modulating the Th balance in experimental silicosis in mice. However, the regulatory mechanism of B10 on CD4+ T cells is still unclear. MACS-sorted CD19+ B cells from the three different groups were cultured with CD4+ T cells either with or without transwell insert plates to evaluate the effects of B10 on CD4+ T cells, including Teff and Treg. B10 was eliminated by anti-CD22 application in vivo. Flow cytometry was used to test the frequencies of CD4+ T cells, and the expressions of the related cytokines were detected by real-time PCR and CBA. Insufficient B10 elevated the levels of proinflammatory cytokines and promoted Th responses in a way independent upon cell-cell contact in the Teff and B cell coculture system. B10 could both increase Treg activity and enhance conversion of Teff into Treg. Our findings demonstrated that B10 could affect Th responses by the release of IL-10, enhancing Treg functions and converting Teff into Treg.
Cryosurgery as an Option for the Treatment of Vascular Lesions of the Oral Cavity
Authors: Nogueira Pedro Thalles Bernardo de Carvalho , Remigio Mariana Maria Castro Jatobá , Queiroz Andreza Maria Correia de , Silva Andréia Aparecida da , Filho José Rodrigues Laureano
Published: August 2017

Cryosurgery is a treatment modality consisting in the destruction of tissue by the application of extremely low temperatures. This causes irreversible damage to cellular metabolism, leading to tissue destruction within minutes, a mechanism that may be beneficial when used in diseased tissues. Because cryosurgery is effective, simple, and easy to perform, it has been used in the treatment of lesions in both medical and dental fields. This technique provides many advantages, such as easy operation, absence of intraoperative bleeding, and low infection rate. We report the case of a patient with a hemangiomatous lesion of the oral cavity who was treated with liquid nitrogen spray cryosurgery, with successful results at 18-month follow-up.
An Endoscopic Nasomediastinal Approach to a Mediastinal Abscess Developing after Zenker’s Diverticulectomy
Authors: Altintoprak Fatih , Gundogdu Kemal , Eminler Ahmet Tarik , Parlak Erkan , Cakmak Guner , Uzunoglu Mustafa Yener
Published: August 2017

Zenker’s diverticulum is the most frequent symptomatic diverticulum of the esophagus, but the prevalence is <0.1%. The optimal treatment is surgery. Here, we present a nasomediastinal drainage approach to treatment of a mediastinal abscess, developing in the late postoperative period and attributable to leakage from the staple line.
An Investigation on Self-Compacting Concrete Using Ultrafine Natural Steatite Powder as Replacement to Cement
Authors: Kumar P. , Sudalaimani K. , Shanmugasundaram M.
Published: August 2017

An experimental investigation was made on flow properties and compressive strength of self-compacting concrete (SCC) with ultrafine natural steatite powder (UFNSP) as replacement to cement. The tests were conducted on specimens with 5%, 10%, 15%, 20%, and 25% of replacement of UFNSP to the weight of cement and compared to the control specimens. The flow properties of all specimens were tested and checked for their limit with the existing guidelines. The compressive strength test was done on all specimens for strength of 7 days, 14 days, 28 days, and 56 days. The hardened samples were tested for their microstructural behavior and the elements Mg, Ca, and Si were mapped. Through mapping, the formations of M-S-H along with C-S-H are observed. The results show that the addition of UFNSP influences the flow property, by reducing the flow, and increases the compressive strength till 20% replacement. Further the addition of UFNSP increases the denseness of microstructure of the specimens thus resulting in the strength increment.
Sharp Refinements for the Inverse Sine Function Related to Shafer‐Fink’s Inequality
Authors: Bercu Gabriel
Published: August 2017

The aim of our work is to give new sharp refinements of Shafer‐Fink’s inequality, using suitable changes of variables.
Robust Circle Detection Using Harmony Search
Authors: Fourie Jaco
Published: August 2017

Automatic circle detection is an important element of many image processing algorithms. Traditionally the Hough transform has been used to find circular objects in images but more modern approaches that make use of heuristic optimisation techniques have been developed. These are often used in large complex images where the presence of noise or limited computational resources make the Hough transform impractical. Previous research on the use of the Harmony Search (HS) in circle detection showed that HS is an attractive alternative to many of the modern circle detectors based on heuristic optimisers like genetic algorithms and simulated annealing. We propose improvements to this work that enables our algorithm to robustly find multiple circles in larger data sets and still work on realistic images that are heavily corrupted by noisy edges.
Mitochondrial Superoxide Increases Age-Associated Susceptibility of Human Dermal Fibroblasts to Radiation and Chemotherapy
Authors: Mapuskar Kranti A. , Flippo Kyle H. , Schoenfeld Joshua D. , Riley Dennis P. , Strack Stefan , Hejleh Taher Abu , Furqan Muhammad , Monga Varun , Domann Frederick E. , Buatti John M. , Goswami Prabhat C. , Spitz Douglas R. , Allen Bryan G.
Published: August 2017

Elderly cancer patients treated with ionizing radiation (IR) or chemotherapy experience more frequent and greater normal tissue toxicity relative to younger patients. The current study demonstrates that exponentially growing fibroblasts from elderly (old) male donor subjects (70, 72, and 78 years) are significantly more sensitive to clonogenic killing mediated by platinum-based chemotherapy and IR (∼70%–80% killing) relative to young fibroblasts (5 months and 1 year; ∼10%–20% killing) and adult fibroblasts (20 years old; ∼10%–30% killing). Old fibroblasts also displayed significantly increased (2–4-fold) steady-state levels of O2•−, O2 consumption, and mitochondrial membrane potential as well as significantly decreased (40%–50%) electron transport chain (ETC) complex I, II, IV, V, and aconitase (70%) activities, decreased ATP levels, and significantly altered mitochondrial structure. Following adenoviral-mediated overexpression of SOD2 activity (5–7-fold), mitochondrial ETC activity and aconitase activity were restored, demonstrating a role for mitochondrial O2•− in these effects. Old fibroblasts also demonstrated elevated levels of endogenous DNA damage that were increased following treatment with IR and chemotherapy. Most importantly, treatment with the small-molecule, superoxide dismutase mimetic (GC4419; 0.25 μmol/L) significantly mitigated the increased sensitivity of old fibroblasts to IR and chemotherapy and partially restored mitochondrial function without affecting IR or chemotherapy-induced cancer cell killing. These results support the hypothesis that age-associated increased O2•− and resulting DNA damage mediate the increased susceptibility of old fibroblasts to IR and chemotherapy that can be mitigated by GC4419. Cancer Res; 77(18); 5054–67. ©2017 AACR.
Glesatinib Exhibits Antitumor Activity in Lung Cancer Models and Patients Harboring MET Exon 14 Mutations and Overcomes Mutation-mediated Resistance to Type I MET Inhibitors in Nonclinical Models
Authors: Engstrom Lars D. , Aranda Ruth , Lee Matthew , Tovar Elizabeth A. , Essenburg Curt J. , Madaj Zachary , Chiang Harrah , Briere David , Hallin Jill , Lopez-Casas Pedro P. , Baños Natalia , Menendez Camino , Hidalgo Manuel , Tassell Vanessa , Chao Richard , Chudova Darya I. , Lanman Richard B. , Olson Peter , Bazhenova Lyudmilla , Patel Sandip Pravin , Graveel Carrie , Nishino Mizuki , Shapiro Geoffrey I. , Peled Nir , Awad Mark M. , Jänne Pasi A. , Christensen James G.
Published: August 2017

Purpose: MET exon 14 deletion (METex14 del) mutations represent a novel class of non–small cell lung cancer (NSCLC) driver mutations. We evaluated glesatinib, a spectrum-selective MET inhibitor exhibiting a type II binding mode, in METex14 del–positive nonclinical models and NSCLC patients and assessed its ability to overcome resistance to type I MET inhibitors.

Experimental Design: As most MET inhibitors in clinical development bind the active site with a type I binding mode, we investigated mechanisms of acquired resistance to each MET inhibitor class utilizing in vitro and in vivo models and in glesatinib clinical trials.

Results: Glesatinib inhibited MET signaling, demonstrated marked regression of METex14 del-driven patient-derived xenografts, and demonstrated a durable RECIST partial response in a METex14 del mutation-positive patient enrolled on a glesatinib clinical trial. Prolonged treatment of nonclinical models with selected MET inhibitors resulted in differences in resistance kinetics and mutations within the MET activation loop (i.e., D1228N, Y1230C/H) that conferred resistance to type I MET inhibitors, but remained sensitive to glesatinib. In vivo models exhibiting METex14 del/A-loop double mutations and resistance to type I inhibitors exhibited a marked response to glesatinib. Finally, a METex14 del mutation-positive NSCLC patient who responded to crizotinib but later relapsed, demonstrated a mixed response to glesatinib including reduction in size of a MET Y1230H mutation-positive liver metastasis and concurrent loss of detection of this mutation in plasma DNA.

Conclusions: Together, these data demonstrate that glesatinib exhibits a distinct mechanism of target inhibition and can overcome resistance to type I MET inhibitors. Clin Cancer Res; 23(21); 6661–72. ©2017 AACR.
Overcoming Acquired Resistance to AZD9291, A Third-Generation EGFR Inhibitor, through Modulation of MEK/ERK-Dependent Bim and Mcl-1 Degradation
Authors: Shi Puyu , Oh You-Take , Deng Liang , Zhang Guojing , Qian Guoqing , Zhang Shuo , Ren Hui , Wu Grant , Legendre Benjamin , Anderson Emily , Ramalingam Suresh S. , Owonikoko Taofeek K. , Chen Mingwei , Sun Shi-Yong
Published: August 2017

Purpose: The mechanisms accounting for anticancer activity of AZD9291 (osimertinib or TAGRISSO), an approved third-generation EGFR inhibitor, in EGFR-mutant non–small cell lung cancer (NSCLC) cells and particularly for the subsequent development of acquired resistance are unclear and thus are the focus of this study.

Experimental Design: AZD9219-resistant cell lines were established by exposing sensitive cell lines to AZD9291. Protein alterations were detected with Western blotting. Apoptosis was measured with annexin V/flow cytometry. Growth-inhibitory effects of tested drugs were evaluated in vitro with cell number estimation and colony formation assay and in vivo with mouse xenograft models. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. Gene knockdown were achieved with siRNA or shRNA.

Results: AZD9291 potently induced apoptosis in EGFR-mutant NSCLC cell lines, in which ERK phosphorylation was suppressed accompanied with Bim elevation and Mcl-1 reduction likely due to enhanced Mcl-1 degradation and increased Bim stability. Blocking Bim elevation by gene knockdown or enforcing Mcl-1 expression attenuated or abolished AZD9291-induced apoptosis. Moreover, AZD9291 lost its ability to modulate Bim and Mcl-1 levels in AZD9291-resistant cell lines. The combination of a MEK inhibitor with AZD9291 restores the sensitivity of AZD9291-resistant cells including those with C797S mutation to undergo apoptosis and growth regression in vitro and in vivo.

Conclusions: Modulation of MEK/ERK-dependent Bim and Mcl-1 degradation critically mediates sensitivity and resistance of EGFR-mutant NSCLC cells to AZD9291 and hence is an effective strategy to overcome acquired resistance to AZD9291. Clin Cancer Res; 23(21); 6567–79. ©2017 AACR.
In Silico Systems Biology Analysis of Variants of Uncertain Significance in Lynch Syndrome Supports the Prioritization of Functional Molecular Validation
Authors: Borras Ester , Chang Kyle , Pande Mala , Cuddy Amanda , Bosch Jennifer L. , Bannon Sarah A. , Mork Maureen E. , Rodriguez-Bigas Miguel A. , Taggart Melissa W. , Lynch Patrick M. , You Y. Nancy , Vilar Eduardo
Published: August 2017

Lynch syndrome (LS) is a genetic condition secondary to germline alterations in the DNA mismatch repair (MMR) genes with 30% of changes being variants of uncertain significance (VUS). Our aim was to perform an in silico reclassification of VUS from a large single institutional cohort that will help prioritizing functional validation. A total of 54 VUS were detected with 33 (61%) novel variants. We integrated family history, pathology, and genetic information along with supporting evidence from eight different in silico tools at the RNA and protein level. Our assessment allowed us to reclassify 54% (29/54) of the VUS as probably damaging, 13% (7/54) as possibly damaging, and 28% (15/54) as probably neutral. There are more than 1,000 VUS reported in MMR genes and our approach facilitates the prioritization of further functional efforts to assess the pathogenicity to those classified as probably damaging. Cancer Prev Res; 10(10); 580–7. ©2017 AACR.
Effect of Green Tea Supplements on Liver Enzyme Elevation: Results from a Randomized Intervention Study in the United States
Authors: Yu Zheming , Samavat Hamed , Dostal Allison M. , Wang Renwei , Torkelson Carolyn J. , Yang Chung S. , Butler Lesley M. , Kensler Thomas W. , Wu Anna H. , Kurzer Mindy S. , Yuan Jian-Min
Published: August 2017

Liver injury effects of green tea–based products have been reported in sporadic case reports. However, no study has examined systematically such adverse effects in an unbiased manner. We examined the potential effects of a high, sustained oral dose of green tea extract (GTE) on liver injury measures in a randomized, placebo-controlled, double-blinded phase II clinical trial, which enrolled 1,075 women with the original aim to assess the effect of daily GTE consumption for 12 months on biomarkers of breast cancer risk. The current analysis examined the effect of GTE consumption on liver injury in 1,021 participants (513 in GTE and 508 in placebo arm) with normal baseline levels of liver enzymes. Among women in the GTE arm, alanine aminotransferase (ALT) increased by 5.4 U/L [95% confidence interval (CI), 3.6–7.1] and aspartate aminotransferase increased by 3.8 U/L (95% CI, 2.5–5.1), which were significantly higher than those among women in the placebo arm (both P < 0.001). Overall, 26 (5.1%) women in GTE developed moderate or more severe abnormalities in any liver function measure during the intervention period, yielding an OR of 7.0 (95% CI, 2.4–20.3) for developing liver function abnormalities as compared with those in the placebo arm. ALT returned to normal after dechallenge and increased again after one or more rechallenges with GTE. The rise–fall pattern of liver enzyme values following the challenge–dechallenge cycles of GTE consumption strongly implicates the effect of high-dose GTE on liver enzyme elevations. Cancer Prev Res; 10(10); 571–9. ©2017 AACR.
Acne Fulminans: Treatment Experience from 26 Patients
Authors: Massa António F. , Burmeister Lena , Bass Dirk , Zouboulis Christos C.
Published: August 2017

Background /Aim: Acne fulminans is a rare form of acne vulgaris with acute clinical deterioration including systemic signs. Etiopathogenesis and management remain largely unknown. Our aim is to assess the efficacy of a combined therapeutic regimen of systemic isotretinoin and prednisolone following the recent concepts of acne pathogenesis and drug kinetics. Methods: A prospective case series was recruited over 15 years. Isotretinoin 0.5 mg/kg bw/d (0.25-0-0.25) and prednisolone 30 mg/d (10-10-10) were administered concomitantly with prednisolone being tapered after that time. The overall efficacy was evaluated at month 1 and every month thereafter. Daily drug doses were split to reduce the risk for adverse effects. Results: 26 patients (20 male, 77%) at a mean age of 19 years and a history of acne vulgaris of 3.2 years presented acutely necrotic and ulcerating skin papules (100%), fever (45%), arthralgia (38.5%), leukocytosis (88.5%) and elevated erythrocyte sedimentation rate (100%). After one month of treatment resolution of systemic signs was achieved in all patients and a >50% skin lesion improvement in 17 patients (65%). Conclusion: The concomitant administration of isotretinoin (0.5 mg/kg bw/d, 0.25-0-0.25) and prednisolone 30 mg/d (10-10-10) is able to resolve systemic signs and markedly improve skin lesions in 65% of the patients at one month.
NICU Human Milk Dose and 20-Month Neurodevelopmental Outcome in Very Low Birth Weight Infants
Authors: Patra Kousiki , Hamilton Matthew , Johnson Tricia J. , Greene Michelle , Dabrowski Elizabeth , Meier Paula P. , Patel Aloka L.
Published: August 2017

Background: The association between human milk (HM) feeding in the NICU and neurodevelopmental (ND) outcome in very low birth weight (VLBW) infants is unclear. Limitations of previous studies include a lack of exact estimates of HM dose and of generalizability to minority populations. Objective: To determine the impact on ND outcome of an exact dose of HM received in the NICU in a diverse, contemporary cohort of VLBW infants. Methods: We included 430 VLBW infants born in the period 2008-2012 for whom the mean daily dose (DD) of HM received during the stay in the NICU (NICU HM-DD) was calculated prospectively from the daily nutritional intake from admission to discharge. Outcomes included Bayley-III index scores at 20 months' corrected age (CA) as assessed upon ND follow-up, which were collected retrospectively. Multivariable linear regression analyses controlled for neonatal and social risk factors. Results: Each 10 mL/kg/day increase in NICU HM-DD was associated with a 0.35 increase in cognitive index score (95% CI [0.03-0.66], p = 0.03), but no significant associations were detected for the language or motor indices. Conclusions: There is a significant dose-dependent association between NICU HM intake and cognitive scores at 20 months' CA. Further follow-up will determine whether these findings persist at school age, and could help alleviate the special-education and health-care burden in this population.
Vitrectomy, Inner Limiting Membrane Peel, and Gas Tamponade in the Management of Traumatic Paediatric Macular Holes: A Case Series of 13 Patients
Authors: Brennan Nicholas , Reekie Ian , Khawaja Anthony P. , Georgakarakos Nikolaos , Ezra Eric
Published: August 2017

Purpose: To review the outcomes of pars plana vitrectomy, internal limiting membrane (ILM) peel, and gas tamponade in the management of traumatic paediatric macular holes. Methods: Retrospective case series of children undergoing vitrectomy, ILM peel, and gas tamponade for traumatic macular hole between March 2007 and July 2014. Main outcome measures were postoperative visual acuity at 3 and 12 months, anatomic closure rate, and surgical complications. Results: Anatomic macular hole closure was achieved in 12 (92.3%) of 13 cases. Mean preoperative logMAR visual acuity was 0.91 (95% CI 0.65-1.17) with improvement postoperatively to 0.54 (95% CI 0.43-0.64) at 3 months (p = 0.002) and 0.50 (95% CI 0.39-0.60) at 12 months (p = 0.002). There were no perioperative complications. Conclusion: Pars plana vitrectomy and ILM peel is an effective management option for paediatric macular holes.
A Potential Role for the NOD1 Variant (rs6958571) in Gram-Positive Blood Stream Infection in ELBW Infants
Authors: Sampath Venkatesh , Mulrooney Neil , Patel Aloka L. , Cohen Jonathan , Zhang Liyun , Garland Jeffery , Lavoie Pascal M. , Dagle John , Simpson Pippa
Published: August 2017

Background: The genetic basis of sepsis susceptibility in preterm infants remains understudied. Herein, we investigated the nucleotide binding-oligomerization domain (NOD)-like receptor (NLR) family of immune receptors as putative loci for preterm sepsis susceptibility. Objective: To determine whether single nucleotide polymorphisms (SNPs) in NLR genes are associated with blood stream infections (BSI) in premature infants. Methods: An international cohort of infants with gestational age (GA) <35 weeks were genotyped for SNPs in the ATG16L1, CARD8, NLRP3, NOD2, and NOD1 genes. χ2 and logistic regression analyses were used to examine relationships between NLR variants and BSI. Results: Among 764 infants, 138 developed BSI, 113 had gram-positive bacterial (GPB) BSI, and 28 had gram-negative bacterial (GNB) BSI. Infants with BSI had a lower birth weight and GA (p < 0.001), but did not differ in gender, race, or chorioamnionitis. NLR variants were not associated with GPB or GNB BSI in the entire cohort. The CC genotype of the NOD1 SNP (rs6958571) was associated with increased GPB BSI in extremely low birth weight (ELBW, birth weight <1,000 g) infants (OR = 3.3, 95% CI: 1.4-7.5, p = 0.003, n = 362) and in Caucasian infants (OR = 2.5, 95% CI: 1.2-5.4, p = 0.016, n = 535). Regression models adjusting for clinical variables identified ELBW status and the NOD1 CC genotype as risk factors for GPB BSI in Caucasian infants. Conclusions: In this study investigating relationships between NLR variants and sepsis in infants with GA <35 weeks, the NOD1 (rs6958571) SNP was associated with GPB BSI in Caucasian infants and ELBW infants. Replication of our results in an independent cohort would support a role for NLR variants in determining sepsis risk in ELBW infants.