bluuebunny/crossref_metadata_2025 huggingface dataset:
A New Quasi 3D Nonlocal Plate Theory for Vibration and Buckling of FGM Nanoplates
Authors: Sobhy Mohammed , Radwan Ahmed F.
Published: February 2017

This paper presents the analyses of free vibration and buckling of functionally graded (FG) nanoplates in thermal environment by using a new quasi-3D nonlocal hyperbolic plate theory in which both shear and normal strains are included. The nonlocal equations of motion for the present problem are derived from Hamilton’s principle. For simply-supported boundary conditions, Navier’s approach is utilized to solve the motion equations. Eringen’s nonlocal theory is employed to capture the effect of the nonlocal parameter on natural frequency and buckling of the FGM nanoplates. Numerical results of the present formulation are compared with those predicted by other theories available in the open literature to explain the accuracy of the suggested theory that contains the shear deformation and thickness stretching. Other numerical examples are also presented to show the influences of the nonlocal coefficient, power law index and geometrical parameters on the vibration and buckling load of FGM nanoplates.
Effects caused by antiferroelectric nanodomains in PZT-based coarse-grained ceramics with compositions from the morphotropic boundary region
Authors: Ishchuk V. M. , Kuzenko D. V. , Sobolev V. L.
Published: February 2017

Presented results demonstrate importance of taking into account such a phenomenon as the solid solution decomposition at the boundaries separating coexisting phases in lead zirconate-titanate-based solid solutions with compositions belonging to the morphotropic boundary region of the “temperature–composition” phase diagram. It is shown that in the local decomposition of solid solutions in the vicinity of the boundaries separating the tetragonal and rhombohedral phases in lead zirconate-titanate-based solid solutions lead to the changes of the solid solution’s chemical composition and to the formation of segregates. It is also shown that the proper thermoelectric treatment of samples containing these segregates can give substantially higher values of piezoelectric parameters in the lead zirconate-titanate-based compounds.
The Blackwater gold-spessartine-pyrolusite glacial dispersal train, British Columbia, Canada: Influence of sampling depth on indicator mineralogy and geochemistry
Authors: Averill Stuart A.
Published: February 2017

A comprehensive program of indicator mineral and geochemical sampling of both oxidized and unoxidized till at the glaciated Blackwater Au-Ag deposit in the interior of south-central British Columbia, Canada has provided key insights into glacial and post-glacial dispersal patterns that can be used to explore other glaciated regions more effectively.

The Blackwater deposit is located on the northeastern slope of Mount Davidson and is completely covered by till that was deposited by NE-flowing ice. Only the sulphide-depleted supergene cap of the deposit was exposed to the ice. Indicator mineral sampling of C-horizon till on the mountain slope identified a 1.3 km wide gold grain dispersal train that extends
c.
3 km glacially down-ice and 200 vertical metres down-slope from the deposit. The till within this train contains from 10 to 641 gold grains, dominantly of 25 µm size, per 10 kg of its <2 mm matrix. As well, the 0.25 – 0.5 mm fraction contains up to 25 000 grains per sample of spessartine garnet derived from the hypogene alteration envelope of the Blackwater deposit, increasing the probable detectable length of the train to 10 km. Geochemically, in the <0.063 mm fraction of the till, the detectable length of the train is reduced to <1 km, with the best indicator elements being Au and Zn.

In drill holes, the host till is oxidized to a depth of 2 – 5 m. It thickens markedly downslope from a few metres to
c.
100 m. The gold-spessartine dispersal train thickens sympathetically to nearly 30 m and also ascends progressively within the till section. Gold grain and spessartine levels in the unoxidized till at depth are similar to those in the oxidized till at surface but the unoxidized till also contains up to 60 000 grains per sample of metal-rich pyrolusite derived from supergene cap of the Blackwater deposit.
Techniques to determine the kinematics of synsedimentary normal faults and implications for fault growth models
Authors: Jackson Christopher A.-L. , Bell Rebecca E. , Rotevatn Atle , Tvedt Anette B. M.
Published: February 2017

Normal faults grow via a sympathetic increase in their displacement and length (‘isolated model’) or by rapid establishment of their near-final length prior to significant displacement accumulation (‘constant-length model’). The isolated model has dominated the structural geology literature for >30 years, although some 3D seismic data-based studies support the constant-length model. Because they make different predictions regarding rift development, and earthquake size and recurrence intervals in areas of continental extension, it is critical to test these models with data from natural examples. Here we outline a range of techniques that constrain the kinematics of synsedimentary normal faults and thus test competing fault growth models. We then apply these techniques to three seismically imaged faults, showing that, in general, they grew in accordance with the constant-length model, although periods of relatively minor tip propagation and coeval displacement accumulation, characteristics more consistent with the isolated model, also occurred. We argue that analysis of growth strata represents the best way to test competing fault growth models; most studies utilizing this approach support the constant-length fault model, suggesting it may be more widely applicable than is currently assumed. It is plausible that the very early development of large faults is, however, characterized by the development of faults that, pre-linkage, grow in accordance with the isolated model; we may simply lack the data resolution, especially in the subsurface, to resolve this very early stage of fault growth.
Aquaporin-2 membrane targeting: still a conundrum
Authors: Olesen Emma T. B. , Fenton Robert A.
Published: February 2017

The targeting of the water channel aquaporin-2 (AQP2) to the apical plasma membrane of kidney collecting duct principal cells is regulated mainly by the antidiuretic peptide hormone arginine vasopressin (AVP). This process is of crucial importance for the maintenance of body water homeostasis. In this brief review we assess the role of cyclic adenosine monophosphate (cAMP) and discuss the emerging concept that type 2 AVP receptor (V2R)-mediated AQP2 trafficking is cAMP-independent.
An Improved Traveling‐Wave‐Based Fault Location Method with Compensating the Dispersion Effect of Traveling Wave in Wavelet Domain
Authors: Jia Huibin
Published: February 2017

The fault generated transient traveling waves are wide band signals which cover the whole frequency range. When the frequency characteristic of line parameters is considered, different frequency components of traveling wave will have different attenuation values and wave velocities, which is defined as the dispersion effect of traveling wave. Because of the dispersion effect, the rise or fall time of the wavefront becomes longer, which decreases the singularity of traveling wave and makes it difficult to determine the arrival time and velocity of traveling wave. Furthermore, the dispersion effect seriously affects the accuracy and reliability of fault location. In this paper, a novel double‐ended fault location method has been proposed with compensating the dispersion effect of traveling wave in wavelet domain. From the propagation theory of traveling wave, a correction function is established within a certain limit band to compensate the dispersion effect of traveling wave. Based on the determined arrival time and velocity of traveling wave, the fault distance can be calculated precisely by utilizing the proposed method. The simulation experiments have been carried out in ATP/EMTP software, and simulation results demonstrate that, compared with the traditional traveling‐wave fault location methods, the proposed method can significantly improve the accuracy of fault location. Moreover, the proposed method is insensitive to different fault conditions, and it is adaptive to both transposed and untransposed transmission lines well.
Solitary Endobronchial Papilloma with Malignant Transformation and Concomitant TB Infection: Case Report and Literature Review
Authors: Ghobain Mohammed Al
Published: February 2017

We are reporting a case of solitary endobronchial papilloma located in posterior segment of the left upper lobe of the lung with malignant transformation and negative human papilloma virus (HPV) strains in a 40-year-old Saudi nonsmoker man. The patient had a concomitant tuberculosis (TB) infection. The patient received appropriate treatment in the form of anti-TB medication and surgical resection of the squamous cell carcinoma followed by chemotherapy. There was no evidence of tumor recurrence, resulting in a complete cure. We are reporting the case as well as a literature review related to the topic.
Competition between High‐Speed Rail and Airline Based on Game Theory
Authors: Jiang Xiushan , Zhang Xi , Lu Wanwan , Zhang Lei , Chen Xiqun
Published: February 2017

The coexistence of high‐speed rail (HSR) and airline in a busy transportation corridor generates competition between the two transportation modes. An unfair competition between HSR and airline not only reduces both revenues, but also triggers a series of social problems. Based on generalized costs, this paper proposes combining an improved gray prediction model, modified gravity model, and Logit model to predict the average passenger flow, induced passenger flow, and transfer passenger flow. According to the predicted results, we establish a game model that considers different stages of the HSR development. For demonstrative purposes, the approach is applied to an empirical study in China, that is, the competition between Beijing‐Shenyang HSR and airline. Malignant fare war will make both parties lose out. Either mode that improves service quality will generate more revenue. If both parties improve the level of service, all incomes of the HSR, airline, and community increase. Results show the HSR contribution is greater than the airline in the case study.
Modeling Kelvin–Helmholtz Instability in Soft X-Ray Solar Jets
Authors: Zhelyazkov Ivan , Chandra Ramesh , Srivastava Abhishek K.
Published: February 2017

Development of Kelvin–Helmholtz (KH) instability in solar coronal jets can trigger the wave turbulence considered as one of the main mechanisms of coronal heating. In this review, we have investigated the propagation of normal MHD modes running on three X-ray jets modeling them as untwisted and slightly twisted moving cylindrical flux tubes. The basic physical parameters of the jets are temperatures in the range of 5.2–8.2 MK, particle number densities of the order of109 cm−3, and speeds of 385, 437, and 532 km s−1, respectively. For small density contrast between the environment and a given jet, as well as at ambient coronal temperature of 2.0 MK and magnetic field around 7 G, we have obtained that the kink (m=1) mode propagating on moving untwisted flux tubes can become unstable in the first and second jets at flow speeds of≅348 and 429 km s−1, respectively. The KH instability onset in the third jet requires a speed of≅826 km s−1, higher than the observed one. The same mode, propagating in weakly twisted flux tubes, becomes unstable at flow speeds of≅361 km s−1for the first and of 443 km s−1for the second jet. Except the kink mode, the twisted moving flux tube supports the propagation of higher (m>1) MHD modes that can become unstable at accessible jets’ speeds.
Intelligent Machine Vision Based Modeling and Positioning System in Sand Casting Process
Authors: Butt Shahid Ikramullah , Asgher Umer , Mushtaq Umar , Ahmed Riaz , Zhang Faping , Ayaz Yasar , Jamil Mohsin , Amjad Muhammad Kamal
Published: February 2017

Advanced vision solutions enable manufacturers in the technology sector to reconcile both competitive and regulatory concerns and address the need for immaculate fault detection and quality assurance. The modern manufacturing has completely shifted from the manual inspections to the machine assisted vision inspection methodology. Furthermore, the research outcomes in industrial automation have revolutionized the whole product development strategy. The purpose of this research paper is to introduce a new scheme of automation in the sand casting process by means of machine vision based technology for mold positioning. Automation has been achieved by developing a novel system in which casting molds of different sizes, having different pouring cup location and radius, position themselves in front of the induction furnace such that the center of pouring cup comes directly beneath the pouring point of furnace. The coordinates of the center of pouring cup are found by using computer vision algorithms. The output is then transferred to a microcontroller which controls the alignment mechanism on which the mold is placed at the optimum location.
Triethylenetetramine Synergizes with Pharmacologic Ascorbic Acid in Hydrogen Peroxide Mediated Selective Toxicity to Breast Cancer Cell
Authors: Wang Lianlian , Luo Xiaofang , Li Cong , Huang Yubing , Xu Ping , Lloyd-Davies Laetitia H. , Delplancke Thibaut , Peng Chuan , Gao Rufei , Qi Hongbo , Tong Chao , Baker Philip
Published: February 2017

Breast cancer is characterized by overexpression of superoxide dismutase (SOD) and downregulation of catalase and more resistance to hydrogen peroxide (H2O2) than normal cells. Thus, relatively high H2O2 promotes breast cancer cell growth and proliferation. However, excessive intracellular H2O2 leads to death of breast cancer cells. In cancer cells, high level ascorbic acid (Asc) is able to be autoxidized and thus provides an electron to oxygen to generate H2O2. In the present study, we demonstrated that triethylenetetramine (TETA) enhances Asc autoxidation and thus elevates H2O2 production in MCF‐7 cells. Furthermore, Asc/TETA combination significantly impaired cancer cell viability, while having much milder effects on normal cells, indicating Asc/TETA could be a promising therapy for breast cancer. Moreover, SOD1 and N‐acetyl‐L‐cysteine failed to improve MCF‐7 cells viability in the presence of Asc/TETA, while catalase significantly inhibited the cytotoxicity of Asc/TETA to breast cancer cells, strongly suggesting that the selective cytotoxicity of Asc/TETA to cancer cells is H2O2‐dependent. In addition, Asc/TETA induces RAS/ERK downregulation in breast cancer cells. Animal studies confirmed that Asc/TETA effectively suppressed tumor growth in vivo. In conclusion, TETA synergizes pharmacologic Asc autoxidation and H2O2 overproduction in breast cancer cells, which suppresses RAS/ERK pathway and results in apoptosis.
Bose-Einstein Condensate Dark Matter Halos Confronted with Galactic Rotation Curves
Authors: Dwornik M. , Keresztes Z. , Kun E. , Gergely L. Á.
Published: February 2017

We present a comparative confrontation of both the Bose-Einstein Condensate (BEC) and the Navarro-Frenk-White (NFW) dark halo models with galactic rotation curves. We employ 6 High Surface Brightness (HSB), 6 Low Surface Brightness (LSB), and 7 dwarf galaxies with rotation curves falling into two classes. In the first class rotational velocities increase with radius over the observed range. The BEC and NFW models give comparable fits for HSB and LSB galaxies of this type, while for dwarf galaxies the fit is significantly better with the BEC model. In the second class the rotational velocity of HSB and LSB galaxies exhibits long flat plateaus, resulting in better fit with the NFW model for HSB galaxies and comparable fits for LSB galaxies. We conclude that due to its central density cusp avoidance the BEC model fits better dwarf galaxy dark matter distribution. Nevertheless it suffers from sharp cutoff in larger galaxies, where the NFW model performs better. The investigated galaxy sample obeys the Tully-Fisher relation, including the particular characteristics exhibited by dwarf galaxies. In both models the fitting enforces a relation between dark matter parameters: the characteristic density and the corresponding characteristic distance scale with an inverse power.
Fatigue Design Evaluation of Railway Bogie with Full-Scale Fatigue Test
Authors: Seo Jung-Won , Hur Hyun-Moo , Jun Hyun-Kyu , Kwon Seok-Jin , Lee Dong-Hyeong
Published: February 2017

The bogie frame of a railway is an important structural member for the support of vehicle loading. In general, more than 25 years’ durability is necessary. Much study has been carried out in experimental and theoretical domains on the prediction of the structural integrity of the bogie frame. The objective of this paper is to estimate the structural integrity of the bogie frame of an electric railcar. Strength analysis has been performed by finite element analysis. From this analysis, stress concentration areas were investigated. To evaluate the loading conditions, dynamic stress was measured by strain gauge. It has been found that the stress and strain due to the applied loads were multiaxial conditions according to the location of the strain gauge. Fatigue strength evaluations of the bogie frame were performed to investigate the effect of a multiaxial load through the employment of a critical plane approach.
Reduced Need for Rescue Antiemetics and Improved Capacity to Eat in Patients Receiving Acupuncture Compared to Patients Receiving Sham Acupuncture or Standard Care during Radiotherapy
Authors: Enblom Anna , Steineck Gunnar , Hammar Mats , Börjeson Sussanne
Published: February 2017

Objective. To evaluate if consumption of emesis‐related care and eating capacity differed between patients receiving verum acupuncture, sham acupuncture, or standard care only during radiotherapy. Methods. Patients were randomized to verum (n = 100) or sham (n = 100) acupuncture (telescopic blunt sham needle) (median 12 sessions) and registered daily their consumption of antiemetics and eating capacity. A standard care group (n = 62) received standard care only and delivered these data once. Results. More patients in the verum (n = 73 of 89 patients still undergoing radiotherapy; 82%, Relative Risk (RR) 1.23, 95% Confidence Interval (CI) 1.01–1.50) and the sham acupuncture group (n = 79 of 95; 83%, RR 1.24, CI 1.03–1.52) did not need any antiemetic medications, as compared to the standard care group (n = 42 out of 63; 67%) after receiving 27 Gray dose of radiotherapy. More patients in the verum (n = 50 of 89; 56%, RR 1.78, CI 1.31–2.42) and the sham acupuncture group (n = 58 of 94 answering patients; 62%, RR 1.83, CI 1.20–2.80) were capable of eating as usual, compared to the standard care group (n = 20 of 63; 39%). Conclusion. Patients receiving acupuncture had lower consumption of antiemetics and better eating capacity than patients receiving standard antiemetic care, plausible by nonspecific effects of the extra care during acupuncture.
Visual Display of 5p-arm and 3p-arm miRNA Expression with a Mobile Application
Authors: Pan Chao-Yu , Kuo Wei-Ting , Chiu Chien-Yuan , Lin Wen-chang
Published: February 2017

MicroRNAs (miRNAs) play important roles in human cancers. In previous studies, we have demonstrated that both 5p-arm and 3p-arm of mature miRNAs could be expressed from the same precursor and we further interrogated the 5p-arm and 3p-arm miRNA expression with a comprehensive arm feature annotation list. To assist biologists to visualize the differential 5p-arm and 3p-arm miRNA expression patterns, we utilized a user-friendly mobile App to display. The Cancer Genome Atlas (TCGA) miRNA-Seq expression information. We have collected over 4,500 miRNA-Seq datasets from 15 TCGA cancer types and further processed them with the 5p-arm and 3p-arm annotation analysis pipeline. In order to be displayed with the RNA-Seq Viewer App, annotated 5p-arm and 3p-arm miRNA expression information and miRNA gene loci information were converted into SQLite tables. In this distinct application, for any given miRNA gene, 5p-arm miRNA is illustrated on the top of chromosome ideogram and 3p-arm miRNA is illustrated on the bottom of chromosome ideogram. Users can then easily interrogate the differentially 5p-arm/3p-arm expressed miRNAs with their mobile devices. This study demonstrates the feasibility and utility of RNA-Seq Viewer App in addition to mRNA-Seq data visualization.
Assessing Survival and Grading the Severity of Complications in Octogenarians Undergoing Pulmonary Lobectomy
Authors: Feczko Andrew , McKeown Elizabeth , Wilson Jennifer L. , Louie Brian E. , Aye Ralph W. , Gorden Jed A. , Vallières Eric , Farivar Alexander S.
Published: February 2017

Introduction. Octogenarians are at increased risk for complications after lung resection. With alternatives such as radiation, understanding the risks of surgery and associated survival are valuable. Data grading the severity of complications and long-term survival in this population is lacking. We reviewed our experience with lobectomy in octogenarians, grading complications using a validated thoracic morbidity and mortality schema. Methods. We retrospectively reviewed consecutive patients aged ≥80 undergoing lobectomy between 2004 and 2012. Demographics, clinical/pathologic stage, complications, recurrence, and mortality were collected. Complications were graded by the Seely thoracic morbidity and mortality model. Results. 45 patients (mean age 82.2 years) were analyzed. The majority of patients (28/45, 62%) were clinical stage IA/IB. 62% (28/45) of patients experienced a complication. Only 15.6% (7/45) were considered significantly morbid (≥ grade IIIB) per the Seely model. Perioperative mortality was 2% and half of patients were living at a follow-up of 53 months. Overall five-year survival was 52%. Conclusions. In carefully selected octogenarians, lobectomy carries a 15.6% rate of significantly morbid complications with encouraging overall survival. These data provide the basis for a more complete discussion with patients regarding lobectomy for lung cancer.
Prevalence of Skin Sensitization to Pollen of Date Palm in Marrakesh, Morocco
Authors: Serhane Hind , Amro Lamyae , Sajiai Hafsa , Alaoui Yazidi Abdelhaq
Published: February 2017

Background. Date palm’s pollen has been identified as a source of allergy; the rate of sensitization of this pollen is between 6 and 29%. Objective. To determine the prevalence of sensitization to date palm in Marrakesh and to identify the clinical profile. Patients and Methods. This study is based on a questionnaire and the prick test on 7 allergens, in population aged 5 years and above with clinical symptoms suggesting allergic diseases, from November 2012 to February 2013 in Marrakech. Results. We included 468 patients (women: 79.5%). The prick tests were considered interpretable in 467 cases. The prevalence of skin sensitization to pollen of date palm was 6.6%. The 31 cases of sensitization to date palm involved 7 men and 24 women with an average age of 37.5 years. Cutaneous monosensitization to date palm’s pollen was observed in 2 cases. Asthma, rhinitis, and conjunctivitis were recorded, respectively, in 48.4%, 93.5%, and 67.7%. Conclusion. Skin sensitization to pollen of date palm does not seem unusual among allergic patients in Marrakech and is comparable to that found in Casablanca (7%), Barcelona (6.6%), and Cartagena (6.1%).
An Asymptotic-Numerical Hybrid Method for Solving Singularly Perturbed Linear Delay Differential Equations
Authors: Cengizci Süleyman
Published: February 2017

In this work, approximations to the solutions of singularly perturbed second-order linear delay differential equations are studied. We firstly use two-term Taylor series expansion for the delayed convection term and obtain a singularly perturbed ordinary differential equation (ODE). Later, an efficient and simple asymptotic method so called Successive Complementary Expansion Method (SCEM) is employed to obtain a uniformly valid approximation to this corresponding singularly perturbed ODE. As the final step, we employ a numerical procedure to solve the resulting equations that come from SCEM procedure. In order to show efficiency of this numerical-asymptotic hybrid method, we compare the results with exact solutions if possible; if not we compare with the results that are obtained by other reported methods.
Dirichlet Forms Constructed from Annihilation Operators on Bernoulli Functionals
Authors: Wang Caishi , Wang Beiping
Published: February 2017

The annihilation operators on Bernoulli functionals (Bernoulli annihilators, for short) and their adjoint operators satisfy a canonical anticommutation relation (CAR) in equal-time. As a mathematical structure, Dirichlet forms play an important role in many fields in mathematical physics. In this paper, we apply the Bernoulli annihilators to constructing Dirichlet forms on Bernoulli functionals. Let w be a nonnegative function on N. By using the Bernoulli annihilators, we first define in a dense subspace of L2-space of Bernoulli functionals a positive, symmetric, bilinear form Ew associated with w. And then we prove that Ew is closed and has the contraction property; hence, it is a Dirichlet form. Finally, we consider an interesting semigroup of operators associated with w on L2-space of Bernoulli functionals, which we call the w-Ornstein-Uhlenbeck semigroup, and, by using the Dirichlet form, Ew we show that the w-Ornstein-Uhlenbeck semigroup is a Markov semigroup.
Treatment Algorithm for Chronic Idiopathic Constipation and Constipation-Predominant Irritable Bowel Syndrome Derived from a Canadian National Survey and Needs Assessment on Choices of Therapeutic Agents
Authors: Tse Yvonne , Armstrong David , Andrews Christopher N. , Bitton Alain , Bressler Brian , Marshall John , Liu Louis W. C.
Published: February 2017

Background. Chronic idiopathic constipation (CIC) and constipation-predominant irritable bowel syndrome (IBS-C) are common functional lower gastrointestinal disorders that impair patients’ quality of life. In a national survey, we aimed to evaluate (1) Canadian physician practice patterns in the utilization of therapeutic agents listed in the new ACG and AGA guidelines; (2) physicians satisfaction with these agents for their CIC and IBS-C patients; and (3) the usefulness of these new guidelines in their clinical practice. Methods. A 9-item questionnaire was sent to 350 Canadian specialists to evaluate their clinical practice for the management of CIC and IBS-C. Results. The response rate to the survey was 16% (n=55). Almost all (96%) respondents followed a standard, stepwise approach for management while they believed that only 24% of referring physicians followed the same approach. Respondents found guanylyl cyclase C (GCC) agonist most satisfying when treating their patients. Among the 69% of respondents who were aware of published guidelines, only 50% found them helpful in prioritizing treatment choices and 69% of respondents indicated that a treatment algorithm, applicable to Canadian practice, would be valuable. Conclusion. Based on this needs assessment, a treatment algorithm was developed to provide clinical guidance in the management of IBS-C and CIC in Canada.
Potential Antitumor Effect of Harmine in the Treatment of Thyroid Cancer
Authors: Ruan Shu , Jia Feng , Li Jianbo
Published: February 2017

Thyroid cancer is one of the most common types of cancer in endocrine system. In latest studies, harmine has been proved to inhibit the growth of several cancers in vitro and in vivo. In the current study, we evaluated the in vitro and in vivo anticancer efficiency of harmine against thyroid cancer cell line TPC‐1. The in vitro cytotoxicity of harmine evaluated by XTT assay indicated that harmine suppressed the proliferation of TPC‐1 cells in a dose‐ and time‐dependent manner. Moreover, harmine dose‐dependently induced apoptosis of TPC‐1 cells through regulating the ratio of Bcl‐2/Bax. The colony forming ability of TPC‐1 cells was also time‐dependently inhibited by harmine. The inhibitory effects of harmine on migration and invasion of TPC‐1 cells were studied by wound scratching and Transwell assays. In vivo evaluation showed that harmine effectively inhibited the growth of thyroid cancer in a dose‐dependent manner in nude mice. Therefore, harmine might be a promising herbal medicine in the therapy of thyroid cancer and further efforts are needed to explore this therapeutic strategy.
Advanced Interval Type-2 Fuzzy Sliding Mode Control for Robot Manipulator
Authors: Hwang Ji-Hwan , Kang Young-Chang , Park Jong-Wook , Kim Dong W.
Published: February 2017

In this paper, advanced interval type-2 fuzzy sliding mode control (AIT2FSMC) for robot manipulator is proposed. The proposed AIT2FSMC is a combination of interval type-2 fuzzy system and sliding mode control. For resembling a feedback linearization (FL) control law, interval type-2 fuzzy system is designed. For compensating the approximation error between the FL control law and interval type-2 fuzzy system, sliding mode controller is designed, respectively. The tuning algorithms are derived in the sense of Lyapunov stability theorem. Two-link rigid robot manipulator with nonlinearity is used to test and the simulation results are presented to show the effectiveness of the proposed method that can control unknown system well.
Unsteady Helical Flows of a Size-Dependent Couple-Stress Fluid
Authors: Rubbab Qammar , Mirza Itrat Abbas , Siddique Imran , Irshad Saadia
Published: February 2017

The helical flows of couple-stress fluids in a straight circular cylinder are studied in the framework of the newly developed, fully determinate linear couple-stress theory. The fluid flow is generated by the helical motion of the cylinder with time-dependent velocity. Also, the couple-stress vector is given on the cylindrical surface and the nonslip condition is considered. Using the integral transform method, analytical solutions to the axial velocity, azimuthal velocity, nonsymmetric force-stress tensor, and couple-stress vector are obtained. The obtained solutions incorporate the characteristic material length scale, which is essential to understand the fluid behavior at microscales. If characteristic length of the couple-stress fluid is zero, the results to the classical fluid are recovered. The influence of the scale parameter on the fluid velocity, axial flow rate, force-stress tensor, and couple-stress vector is analyzed by numerical calculus and graphical illustrations. It is found that the small values of the scale parameter have a significant influence on the flow parameters.
Antiemetic and Myeloprotective Effects of Rhus verniciflua Stoke in a Cisplatin‐Induced Rat Model
Authors: Kim Hyo-Seon , Kim Hyeong-Geug , Im Hwi-Jin , Lee Jin-Seok , Lee Sung-Bae , Kim Won-Yong , Lee Hye-Won , Lee Sam-Keun , Byun Chang Kyu , Son Chang-Gue
Published: February 2017

Rhus verniciflua Stoke has been commonly used in traditional medicine to treat gastrointestinal (GI) dysfunction diseases. In order to investigate pharmacological properties of Rhus verniciflua Stoke water extract (RVX) on cisplatin‐induced amnesia, RVX (0, 25, 50, or 100 mg/kg) was orally administrated for five consecutive days after a single intraperitoneal injection of cisplatin (6 mg/kg) to SD rat. Cisplatin injection significantly increased the kaolin intake (emesis) but reduced the normal diet intake (anorexia) whereas the RVX treatment significantly improved these abnormal diet behaviors at both the acute and delayed phase. The serotonin concentration and the related gene expressions (5‐HT3 receptors and SERT) in small intestine tissue were abnormally altered by cisplatin injection, which were significantly attenuated by the RVX treatment. Histological findings of gastrointestinal tracts, as well as the proteins level of proinflammatory cytokines (TNF‐α, IL‐6, and IL‐1β), revealed the beneficial effect of RVX on cisplatin‐induced gastrointestinal inflammation. In addition, RVX significantly improved cisplatin‐induced myelosuppression, as evidenced by the observation of leukopenia and by histological examinations in bone marrow. Our findings collectively indicated Rhus verniciflua Stoke improved the resistance of rats to chemotherapy‐related adverse effects in the gastrointestinal track and bone marrow.
CT Perfusion as an Early Biomarker of Treatment Efficacy in Advanced Ovarian Cancer: An ACRIN and GOG Study
Authors: Ng Chaan S. , Zhang Zheng , Lee Susanna I. , Marques Helga S. , Burgers Kyle , Su Feng , Bauza Joseph , Mannel Robert S. , Walker Joan L. , Huh Warner King , Rubin Stephen C. , DiSilvestro Paul , Martin Lainie P. , Chan John K. , Bookman Michael A. , Coleman Robert L. , Lee Ting-Yim
Published: February 2017

Purpose: ACRIN 6695 was a feasibility study investigating whether CT perfusion (CTP) biomarkers are associated with progression-free survival (PFS) at 6 months (PFS-6) in patients with advanced ovarian cancer who were treated with carboplatin and either dose-dense (weekly) or conventional (3-weekly) paclitaxel, with optional bevacizumab in the prospective phase III GOG-0262 trial.

Experimental Design: ACRIN 6695 recruited participants with residual disease after primary cytoreductive surgery or planned interval cytoreduction following neoadjuvant therapy, to undergo CTP studies before (T0), 3 weeks (T1), and 4 weeks (T2) after chemotherapy initiation. Tumor blood flow (BF) and blood volume (BV) were derived with commercial software. Fisher exact tests assessed the associations of CTP biomarkers changes from T0 to T2 dichotomized at zero with PFS-6 and overall radiographic response rate, while Cox regression assessed the associations between CTP biomarker changes and PFS and overall survival (OS). Bonferroni correction was used to account for multiple comparisons.

Results: Seventy-six of 120 enrolled patients from 19 centers were evaluable with a median age of 61 years. BV increase was significantly associated with lower chance of PFS-6 (P = 0.028), while BF achieves borderline significance (P = 0.053). In addition, BF increase was associated with shorter PFS (HR 2.9, 95% CI, 1.3–6.4, P = 0.008) and remained significant after adjusting for age, change in tumor volume, and surgery status (P = 0.007). Neither BF nor BV changes were significantly associated with treatment response rate or OS.

Conclusions: Early CTP biomarkers measurement may provide early prognostic information for PFS in newly diagnosed ovarian cancer. Clin Cancer Res; 23(14); 3684–91. ©2017 AACR.
Exposure–Response Analysis of Alvocidib (Flavopiridol) Treatment by Bolus or Hybrid Administration in Newly Diagnosed or Relapsed/Refractory Acute Leukemia Patients
Authors: LaCerte Carl , Ivaturi Vijay , Gobburu Joga , Greer Jacqueline M. , Doyle L. Austin , Wright John J. , Karp Judith E. , Rudek Michelle A.
Published: February 2017

Purpose: To elucidate any differences in the exposure–response of alvocidib (flavopiridol) given by 1-hour bolus or a hybrid schedule (30-minute bolus followed by a 4-hour infusion) using a flavopiridol/cytosine arabinoside/mitoxantrone sequential protocol (FLAM) in patients with acute leukemia. The hybrid schedule was devised to be pharmacologically superior in chronic leukemia based on unbound exposure.

Experimental Design: Data from 129 patients in three FLAM studies were used for pharmacokinetic/pharmacodynamic modeling. Newly diagnosed (62%) or relapsed/refractory (38%) patients were treated by bolus (43%) or hybrid schedule (57%). Total and unbound flavopiridol concentrations were fit using nonlinear mixed-effect population pharmacokinetic methodologies. Exposure–response relationships using unbound flavopiridol AUC were explored using recursive partitioning.

Results: Flavopiridol pharmacokinetic parameters were estimated using a two-compartment model. No pharmacokinetic covariates were identified. Flavopiridol fraction unbound was 10.9% and not different between schedules. Partitioning found no association between dosing schedule and clinical response. Clinical response was associated with AUC ≥ 780 h*ng/mL for newly diagnosed patients and AUC ≥ 1,690 h*ng/mL for relapsed/refractory patients. Higher exposures were not associated with increases in severe adverse events (≥ grade 3).

Conclusions: Pharmacokinetic modeling showed no difference in flavopiridol plasma protein binding for bolus versus hybrid dosing. Further trials in newly diagnosed patients with acute leukemia should utilize the bolus FLAM regimen at the MTD of 50 mg/m2/day. Trials in relapsed/refractory patients should use the hybrid dosing schedule at the MTD (30/60 mg/m2/day) to achieve the higher exposures required for maximal efficacy in this population. Clin Cancer Res; 23(14); 3592–600. ©2017 AACR.
Anti-Cytokine Strategies beyond Anti-Tumour Necrosis Factor-α Therapy: Pathophysiology and Clinical Implications
Authors: Rogler Gerhard , Biedermann Luc , Scharl Michael
Published: February 2017

Cytokines are small proteins produced by a broad range of cells important in cell signaling. They include interleukins, but also chemokines, interferons, and tumor necrosis factors (TNF). They play an important role for communication between cells of the innate and adaptive immune system. The cytokine network is complex and, therefore, therapeutic interventions are difficult. The first anti-cytokine strategy successfully introduced into IBD therapy was the neutralization of TNF by antibodies. Beyond targeting this cytokine anti-IL-23 strategies were demonstrated to be of therapeutic benefit in IBD. Anti-IL-6 strategies seem to have clinical potential but also cause some risk for the patient due to the lack of CRP increase upon severe inflammation. JAK inhibitors target the intracellular signaling of several cytokine receptors and represent a promising class of broader and somewhat unspecific anti-cytokine strategies. Many other anti-cytokine approaches have failed due to the redundant nature of the cytokine network. Whether further anti-cytokines strategies have potential for IBD treatment may be evaluated in future studies.
Leukocyte Anti-Trafficking Strategies: Current Status and Future Directions
Authors: Sands Bruce E.
Published: February 2017

Background: In inflammatory bowel diseases (IBD), a pivotal step in the initiation and perpetuation of mucosal inflammation entails the recruitment of inflammatory leukocytes to the gut. Understanding the carefully coordinated series of molecular events that culminate in the recruitment of leukocytes to the gut has resulted in novel interventions with new capabilities in treating both Crohn's disease and ulcerative colitis. Key Messages: Natalizumab, an anti-α4 integrin antibody, was the first agent to demonstrate the efficacy of this approach for the induction and maintenance of response and remission in Crohn's disease. Widespread adoption was mitigated by the previously unknown risk of progressive multifocal leukoencephalopathy (PML) with this approach. Current approaches employ a more selective inhibition of adhesion molecules targeting the gut to avoid broad suppression of surveillance for JC virus, the causal pathogen of PML. Subsequently, vedolizumab, a humanized anti-α4β7 integrin antibody, has demonstrated efficacy in patients with IBD and has an excellent safety profile. To date, there have been no cases of PML in patients treated with vedolizumab, suggesting that this more selective agent does not have the same risk for PML as natalizumab. Other agents target β7 integrin (etrolizumab) and mucosal addressin cellular adhesion molecule-1, the endothelial ligand of α4β7 integrin. Efforts to inhibit the chemokine receptor CCR9 using the agent CCX282-B in Crohn's disease were not successful. An orally administered anti-α4 integrin compound showed some promise in a phase 2 trial but raises concern for PML. Finally, the S1P1 receptor agonist ozanimod showed promise in early trials in ulcerative colitis. Conclusions: In summary, anti-trafficking agents have the potential to provide safe and effective therapy for IBD, and are a burgeoning class of novel agents.
Pathogenesis of Intestinal Fibrosis in Inflammatory Bowel Disease and Perspectives for Therapeutic Implication
Authors: Bettenworth Dominik , Rieder Florian
Published: February 2017

Background: Intestinal fibrosis with stricture formation is a common feature of inflammatory bowel disease (IBD) and leads to a significantly impaired quality of life in affected patients, intestinal obstruction as well as to the need for surgical intervention. This constitutes a major treatment challenge. Key Messages: Fibrosis results from the response of gut tissue to the insult inflicted by chronic inflammation. Similarly to what occurs in other organs, the underlying fibrogenic mechanisms are complex and dynamic, involving multiple cell types, interrelated cellular events, and a large number of soluble factors. Owing to a breakdown of the epithelial barrier in IBD, luminal bacterial products leak into the interstitium and induce an innate immune response mediated by the activation of both immune and non-immune cells. Other environmental factors as well as chronic inflammation will certainly impact the quality and quantity of intestinal fibrosis. Finally, the composition of the intestinal extracellular matrix is dramatically altered in chronic gut inflammation and actively promotes fibrosis through its mechanical properties. The conventional view that intestinal fibrosis is an inevitable and irreversible process is gradually changing in light of an improved understanding of the cellular and molecular mechanisms that underline its pathogenesis. In addition, clinical observations in patients who undergo strictureplasty have shown that stricture formation is reversible. Conclusions: Identification of the unique mechanisms of intestinal fibrogenesis should create a practical framework to target and block specific fibrogenic pathways, estimate the risk of fibrotic complications, permit the detection of early fibrotic changes and, eventually, allow the development of treatment methods customized to each patient's type and degree of intestinal fibrosis.
Measurement of Fibrosis in Crohn's Disease Strictures with Imaging and Blood Biomarkers to Inform Clinical Decisions
Authors: Higgins Peter D.R.
Published: February 2017

Background: Distinguishing fibrosis from inflammation in an intestinal stricture in Crohn's disease is quite difficult. The absence of signs of inflammation on CT or MRI does not prove the absence of inflammation, as most strictures have a mix of fibrosis and inflammation. Identifying refractory fibrosis and distinguishing the patients who will respond to anti-inflammatory therapy from those who will require surgery are important clinical requirements, and several new technologies in imaging and serum biomarkers are being applied to this problem. Key Messages: Delayed gadolinium enhancement of a Crohn's disease stricture on MRI can reliably identify severe fibrosis, and may be helpful in deciding which patients will require surgery. However, this approach does not appear to be able to identify patients with mild or moderate fibrosis. New imaging technologies, including T2/magnetization transfer MRI, shear wave velocity ultrasound, and photoacoustic imaging, offer promising animal data that could prove to accurately assist clinical decision making. Glyoproteomics has identified hepatic growth factor alpha and cartilage oligomeric matrix protein as possible serum biomarkers to detect and measure intestinal fibrosis. The presence of upstream small bowel dilation >3.5 cm or a platelet/albumin ratio >150 helps in identifying Crohn's disease patients at high risk of stricture resection in the next 2 years. Conclusions: Imaging and biomarker technologies to measure intestinal fibrosis are rapidly evolving, and could soon provide valuable information for clinical decision making for patients with intestinal strictures from Crohn's disease
What Should Be Done in Inflammatory Bowel Disease Patients with Prior Malignancy?
Authors: Cosnes Jacques
Published: February 2017

Background: Treatment of inflammatory bowel disease (IBD) in patients with prior malignancy is challenging because therapeutic immunosuppression required for controlling IBD activity may increase the risk of cancer recurrence. Key Messages: Contrary to the observations in the post-transplant population, retrospective observational studies of IBD patients with prior malignancy have not demonstrated that immunosuppressive drugs increased significantly the risk of new or recurrent cancer. However, these studies are highly biased and do not permit the use of these drugs. Factors like the time since treatment completion, severity, and subtype of prior cancer should be weighed along with the current IBD activity before choosing the best therapeutic strategy. In practice, most cases of prior cancer require a delay of at least 2 years before starting or resuming immunosuppressants, including anti-TNF agents. This delay should be extended to 5 years in cancer with a high risk of recurrence including cancer of the urinary tract, gastrointestinal cancer, leukemias, and multiple myeloma. A special attention should be paid to cancers with a high risk of late metastasis (breast, melanoma, renal cell carcinoma). Enteral nutrition, Budesonide, mesalamine, and limited intestinal resection should be considered following the completion of cancer treatment and prior to the safe initiation of immunosuppressive treatment for IBD. Thiopurines should be avoided in case of prior Epstein-Barr virus-related lymphoma, HPV-related carcinomas, and cancer of the urinary tract. Methotrexate and anti-TNF agents seem to be safe except for the risk of recurrent melanoma for the latter. Conclusion: IBD patients with prior malignancy should benefit from individual decisions made on a case-by-case basis.
Promises and Dangers of Combination Therapy
Authors: Kruis Wolfgang , Nguyen Phuong G. , Morgenstern Julia
Published: February 2017

The efficiency of the existing methods of treating inflammatory bowel disease (IBD) is limited. There are 2 ways to address this problem - either create new treatment modalities or optimize current therapies. Optimisation may be accomplished by using combinations of established therapeutic strategies. With regard to topically acting compounds such as 5-aminosalicylic acid, combining oral and rectal preparations is a commonly used method. Another commonly used combination is anti-tumor necrosis factor (TNF)-α antibody modalities together with immunosuppressants (thiopurines, methotrexate). Several aspects favour those combinations such as increased effectivity, prevention of immunogenicity and perhaps less adverse events. Currently, discussion on directly additive therapeutic effects is in progress, which have been demonstrated in some clinical trials. As on date, the combination of infliximab with azathioprine is most likely the most effective treatment of Crohn's disease. On the other hand, a combination therapy with both compounds affecting the immune system has, of course, risks. For sure, the frequency with which serious infectious complications are arising is increasing. Furthermore, the number of patients experiencing malignancies such as hepato-splenic lymphoma or melanoma is strongly suspected to be on the rise. In summary, combinations of current treatments for IBD are widely established. Various strategies have been studied and significant improvements of therapeutic effects have been demonstrated. Unfortunately, some of those proven combinations increase therapeutic risks, for example, increase the frequency of serious infections and also of some malignancies. Therefore, great caution has to be exercised when applying combination therapies.