bluuebunny/crossref_metadata_2025 huggingface dataset:
Pregnancy duration and endometrial cancer risk: nationwide cohort study
Authors: Husby Anders , Wohlfahrt Jan , Melbye Mads
Published: August 2019

Objective

To explore the association between pregnancy duration and risk of endometrial cancer.

Design

Nationwide register based cohort study.

Setting

Denmark.

Participants

All Danish women born from 1935 to 2002.

Main outcome measures

Relative risk (incidence rate ratio) of endometrial cancer by pregnancy number, type, and duration, estimated using log-linear Poisson regression.

Results

Among 2 311 332 Danish women with 3 947 650 pregnancies, 6743 women developed endometrial cancer during 57 347 622 person years of follow-up. After adjustment for age, period, and socioeconomic factors, a first pregnancy was associated with a noticeably reduced risk of endometrial cancer, whether it ended in induced abortion (adjusted relative risk 0.53 (95% confidence interval 0.45 to 0.64) or childbirth (0.66, 0.61 to 0.72). Each subsequent pregnancy was associated with an additional reduction in risk, whether it ended in induced abortion (0.81, 0.77 to 0.86) or childbirth (0.86, 0.84 to 0.89). Duration of pregnancy, age at pregnancy, spontaneous abortions, obesity, maternal birth cohort, fecundity, and socioeconomic factors did not modify the results.

Conclusions

The risk of endometrial cancer is reduced regardless of whether a pregnancy ends shortly after conception or at 40 weeks of gestation. This reduction in risk could be explained by a biological process occurring within the first weeks of pregnancy, as pregnancies ending in induced abortions were associated with similar reductions in risk as pregnancies ending in childbirth.
Potential of perennial cereal rye for perennial grain production in Manitoba
Authors: Cattani Douglas J.
Published: August 2019

Perennial cereal rye (Secale cereale L. × Secale montanum Guss.) has been utilized for forage production and this study investigated its perennial grain production potential in Manitoba. Two seeding years at Carman, MB, showed poor winter survival and high ergot occurrence. Therefore, this species is not recommended for grain production in Manitoba.
Classical and quantum cosmological solutions in Bianchi type-I metric with fermionic field and relativistic fluid in Schutz’s formalism
Authors: Ribas Marlos O. , Devecchi Fernando P. , Kremer Gilberto M.
Published: August 2019

A model for an anisotropic pre-inflationary universe described by the Bianchi type-I metric is developed. A relativistic fluid of the Schutz formalism and a self-interacting fermionic field are considered as sources of the gravitational field. The classical analysis is based on the Hamiltonian formalism written in terms of the Misner variables and it is shown that the fluid degrees of freedom can be embodied by a conformal time variable. The three classical scale factors are obtained as functions of the conformal time. The quantum analysis follows from the de Broglie–Bohm formalism applied to the wave function which is a solution of the Wheeler–DeWitt equation and the three scale factors are also determined as functions of the conformal time. While the classical expressions for the scale factors show a singularity when the conformal time vanishes, their quantum expressions exhibit bouncing behavior. It is possible to adjust the behavior of the classical and quantum scale factors as functions of the conformal time so that they have a common isotropic behavior at late times with a dilution of the quantum effects.
(1+1)-dimensional Dirac oscillator with deformed algebra with minimal uncertainty in position and maximal in momentum
Authors: Stetsko M. M.
Published: August 2019

[Formula: see text]-dimensional Dirac oscillator with minimal uncertainty in position and maximal in momentum is investigated. To obtain energy spectrum, SUSY QM technique is applied. It is shown that the Dirac oscillator has two branches of spectrum, the first one gives the standard spectrum of the Dirac oscillator when the parameter of deformation goes to zero and the second branch does not have nondeformed limit. Maximal momentum brings an upper bound for the energy and it gives rise to the conclusion that the energy spectrum contains a finite number of eigenvalues. We also calculate partition function for the spectrum of the first type. The partition function allows us to derive thermodynamic functions of the oscillator which are obtained numerically.
Casimir effect and Stefan–Boltzmann law in Yang–Mills theory at finite temperature
Authors: Santos A. F. , Khanna Faqir C.
Published: August 2019

A non-Abelian gauge theory describes the strong interactions among particles with the commutator of generators are nonzero. An [Formula: see text] gauge theory describes the interactions that lead to nuclear forces among particles. The Lagrangian density refers to fermions with color and flavor and the gauge field quanta implying gluons. The gauge theory is treated at finite temperature using the Thermo Field Dynamics (TFD). Using self-interaction of gluons, the Stefan–Boltzmann law and the Casimir effect are calculated at finite temperature. An appendix is attached to give a response of a massless quarks in gauge theory.
Structural, elastic and electronic properties of new superhard orthorhombic C28
Authors: Zhang Rui , Wei Qun , Wei Bing , Yang Ruike , Cheng Ke , Zhang Meiguang , Yan Haiyan , Chen Qinghua , Xue Minhua
Published: August 2019

The structural, mechanical and electronic properties of recently reported superhard material C[Formula: see text] are studied by first-principles calculations. The unit cell of C[Formula: see text] is composed of 28 carbon atoms and all sp3 hybridized bonds. From 0 GPa to 100 GPa, C[Formula: see text] satisfies the mechanical stability criteria and the phonon spectrum of C[Formula: see text] has no imaginary frequency, which means that C[Formula: see text] is mechanically and dynamically stable. The results of hardness calculated show that C[Formula: see text] is a potential superhard material with the Vickers hardness of 84.0 GPa. By analyzing the elastic anisotropy, we found that elastic anisotropy of C[Formula: see text] increases with pressure. The calculations of band structure demonstrates that C[Formula: see text] is an indirect bandgap semiconductor with the gap of 4.406 eV. These analyses demonstrate C[Formula: see text] is a superhard semiconductor material.
Density functional study on electric structure and optical properties in Na-doped 3C-SiC
Authors: Lu Xuefeng , Luo Jianhua , Yang Panfeng , Zhao Tingting , Ren Junqiang , Guo Xin
Published: August 2019

Structural stability along with the electronic and the optical properties of intrinsic 3C-SiC, [Formula: see text] and [Formula: see text] are studied by the first-principles calculations. [Formula: see text] system possesses the most considerate stability with lowest binding energy [Formula: see text] and formation energy [Formula: see text] compared to [Formula: see text]. It is observed that the non-filled impurity energy levels in the vicinity of the Fermi level can subsequently give rise to an enhancement of electrical conductivity of 3C-SiC. Through the analysis of charge difference density maps, it is found that covalence of bonds between the Na atom and nearby C atom reduces in varying degrees. In different concentrations of Na doping systems, especially for the supercell of [Formula: see text], the real and imaginary parts of the dielectric constant are visibly added in the energy range of 0–0.5 eV, demonstrating that the dielectric loss property of the 3C-SiC is improved evidently. These features confirm that the Na-doped 3C-SiC semiconductor is propitious to the wide application of 3C-SiC in the field of absorbing materials.
Characteristics of the lump, lumpoff and rouge wave solutions in a (3+1)-dimensional generalized potential Yu–Toda–Sasa–Fukuyama equation
Authors: Li Zhi-Qiang , Tian Shou-Fu , Wang Hui , Yang Jin-Jie , Zhang Tian-Tian
Published: August 2019

In this work, we consider a (3[Formula: see text]+[Formula: see text]1)-dimensional generalized nonlinear evolution equation, which can be reduced to the potential Yu–Toda–Sasa–Fukuyama (YTSF) equation. We establish the more general lump solutions of the equation and discover its propagation path. It is interesting that we study the case where the lump wave is cut by one stripe wave. In this case, we obtain the lumpoff solution. Furthermore, the special rogue wave is generated by the collision of the lump wave and a couple of stripe soliton waves. The time and position it generates can be determined by tracking the propagation path of the lump wave. Finally, some graphical analysis of the solutions are presented to better understand the dynamic behavior of these waves.
21-Carbaporphyrin: a cyclopentadiene moiety entrapped into a porphyrin scaffold
Authors: Berlicka Anna , Latos-Grażyński Lechosław
Published: August 2019

This minireview underscores the chemistry of 21-carbaporphyrins containing a plain cyclopentadiene moiety. Thus the cyclopentadiene incorporation afforded two 21-carbaporphyrin series represented by meso-tetraaryl-21-carbaporphyrin and [Formula: see text]-alkylated 21-carbaporphyrin with their properties evidently controlled by the nature of perimeter substitution. The synthetic strategy, physicochemical characterization and some insight in coordination properties of 21-carbaporphyrins have been illustrated. The formation of palladium(II), rhodium(III) and gold(III) meso-tetraaryl-21-carbaporphyrins via unprecedented intramolecular contractions of meta-benzi- or para-benziporphyrins has been also addressed.
Spectroscopic characterization of the heme binding (GAF) domain of two sensor kinases from Methanosarcina acetivorans
Authors: Fiege Kerstin , Twittenhoff Christian , Kwiatkowski Kathrin , Frankenberg-Dinkel Nicole
Published: August 2019

The sensor kinases MsmS and RdmS from the methanogenic archaeon Methanosarcina acetivorans are multidomain proteins containing a covalently linked heme cofactor. This cofactor is connected via a single cysteine residue in a GAF domain. Although both proteins were shown to display a redox-dependent control of the downstream kinase module, this property appears to be independent of the heme cofactor. We therefore envision an additional sensor role for the heme cofactor. In order to learn more about the heme binding pocket and its constitution, UV-vis spectroscopy in combination with site-directed mutagenesis was performed on the isolated heme-binding sGAF2 domain and the full-length protein. The data indicate a 6-coordinated heme with a proximal histidine ligand and a smaller ligand, likely a water molecule on the distal site. The latter is also thought to be the sensory site and is shown to easily undergo ligand exchange.
Chiral carbazole-based porphyrins showing absorption and circular dichroism in the near-infrared region
Authors: Maeda Chihiro , Ema Tadashi
Published: August 2019

Chiral carbazole-based porphyrins were synthesized for the first time via the incorporation of hydrobenzoin units at the thiophene moieties. They showed absorption and circular dichroism in the near-infrared (NIR) region. The NIR absorption was further red-shifted by solvent-induced aggregation.
Corporate Financial Disclosure Measurement in the Empirical Accounting Literature: A Review Article
Authors: Hassan Omaima A. G. , Marston Claire
Published: August 2019

This paper develops a framework for corporate financial disclosure measurement to identify and evaluate common measures of financial disclosure employed in prior empirical accounting studies. It identifies two approaches: (i) a disclosure-based approach that investigates actual disclosure, operationalizes the concept of disclosure in terms of its main dimensions such as the quantity and quality of disclosure, and develops methods to measure them such as the disclosure index and textual analysis, and (ii) a non-disclosure-based approach that uses the values of some observable variables to proxy for disclosure such as market-based disclosure measures. The study also discusses some empirical challenges related to causal claims and the extent to which the reliability and validity of these different measures of disclosure are tested. The purposes of this review are (i) to help future researchers identify exemplars and select or develop their own suitable disclosure measures, and (ii) to identify measurement issues relating to corporate financial disclosure and provide avenues for future research.
Company stock rewards on the evaluation of investor’s remuneration package with stochastic income
Authors: Moalosi-Court Kebareng I. , Lungu Edward M. , Offen Elias R.
Published: August 2019

We consider a risk averse investor as are who has a bond, is rewarded with [Formula: see text] units of company stock option and is endowed with stochastic income. First, we derive and analyzes the optimal investment threshold and investment value function of the investor. Second, we determine a remuneration package and the utility indifference pricing of this risk averse investor and analyze the results for two utility functions; the exponential and logarithmic utilities. From these results, we conclude that the more units of company stock the investor receives, the higher the chances of increasing the total wealth or profit.
Wave Propagation Through Dense Vertical Cylinder Arrays: 3D Experimental Study
Authors: Arnaud Gwendoline , Rey Vincent , Touboul Julien , Sous Damien
Published: August 2019

The purpose of this research work is to study the diffraction of surface gravity waves propagating through rectangular porous medium in three dimensions. The considered porous structure consists of dense arrays of surface piercing vertical cylinders. Experiments for different regular wave conditions have been carried out, especially for three-wave frequencies. The experimental data of wave refraction–diffraction and reflection have been compared to computed results from potential linear theory solved with an integral matching method. Comparison with a previous 2D study about wave propagation through porous medium in a 10 m long wave flume is also discussed in order to highlight the refraction–diffraction effect due to the porous structure.
Gneisses (
Serizzo
and
Beola
) of the Verbano–Cusio–Ossola District (Piedmont, northern Italy): possible candidates for designation as Global Heritage Stone Resources
Authors: Cavallo Alessandro , Dino Giovanna Antonella , Primavori Piero
Published: August 2019

The Verbano–Cusio–Ossola quarrying district (Piedmont, northern Italy) produces many different ornamental stones (granites, gneisses, marbles); two important categories are represented by
Serizzo
and
Beola
gneisses. The
Serizzo
, a group of foliated orthogneisses, is the most important and extensively exploited ornamental stone, largely used to produce columns since the end of fifteenth century and used for many parts of the Duomo di Milano.
Beola
is the name of a group of heterogeneous orthogneisses with mylonitic foliation and strong mineralogical lineation, easy to split into thin slabs with hammer and chisel, occurring in the middle Ossola Valley. The quarries of
Beola
are probably the oldest of the Ossola Valley (since the Roman period), and the
Beola
trade probably started at the end of the thirteenth century. In general,
Beola and Serizzo
gneisses have been used for ornamental purposes and for the construction of churches, palaces and monuments, widely documented in many towns and villages of the Ossola Valley and in northern Italy. This contribution reviews the history and distinctiveness of these materials, their importance in local and national culture, and their present international diffusion. Both stones are recommended as Global Heritage Stone Resources within a Global Heritage Stone Province.
Experimental Studies of Evolution and Eco-Evo Dynamics in Guppies (Poecilia reticulata)
Authors: Reznick David N. , Travis Joseph
Published: August 2019

Guppies in Trinidad range across aquatic environments with fish communities that vary in risk of predation. These communities are often discrete, separated by waterfalls, with high-predation communities downstream and low-predation communities upstream. This gradient is repeated in many rivers; in each one, we see the same divergence between guppy populations in life history, behavior, morphology, and physiology. We have shown that the agent of selection on the life history, behavior, and physiology in low-predation communities is high population density and the cascade of ecological effects that stems from it. In effect, guppy populations modify their ecosystem and, in so doing, impose selection on themselves and shape their own evolution, which further changes the ecosystem. Evolution unfolds rapidly in this system, which has enabled us to study the dynamics of the process, not just its end points. Those studies enable us to answer some very general questions in ecology and evolutionary biology.
Periodicity, time constants of drainage, and the mechanical determinants of peak cardiac output during exercise
Authors: Magder Sheldon , Famulari Gabriel , Gariepy Brian
Published: August 2019

To analyze mechanical adaptations that must occur in the cardiovascular system to reach the high cardiac outputs known to occur at peak aerobic performance, we adapted a computational model of the circulation by adding a second parallel venous compartment as proposed by August Krogh in 1912. One venous compartment has a large compliance and slow time constant of emptying; it is representative of the splanchnic circulation. The other has a low compliance and fast time constant of emptying and is representative of muscle beds. Fractional distribution between the two compartments is an important determinant of cardiac output. Parameters in the model were based on values from animal and human studies normalized to a 70 kg male. The baseline cardiac output was set at 5 L/min, and we aimed for 25 L/min at peak exercise with a fractional flow to the peripheral-muscle region of 90%. Finally, we added the equivalent of a muscle pump. Adjustments in circuit and cardiac parameters alone increased cardiac output to only 15.6 L/min because volume accumulated in the muscle compartment and limited a higher cardiac output. Addition of muscle contractions decompressed the muscle region and allowed cardiac output to increase to 23.4 L/min. The pulsatility of blood flow imposes important constraints on the adaptations of cardiac and circulatory functions because it fixes the times for filling and emptying. Flow is further limited by the limits of cardiac filling on each beat. Muscle contractions play a key role by decompressing volume that would otherwise accumulate in the muscle vasculature and by decreasing the time for stroke return to the right ventricle.

NEW & NOTEWORTHY We used a computational model of the circulation and previous human and animal data to model mechanical changes in the heart and circulation that are needed to reach the known high cardiac output at peak aerobic exercise. Key points are that time constants of drainage of circulatory compartments put limits on peak flow in a pulsatile system. Muscle contractions increase the rate of return to the heart and by doing so prevent accumulation of volume in the muscle compartment and greatly increase circulatory capacity.
Immunity, Hypoxia, and Metabolism–the Ménage à Trois of Cancer: Implications for Immunotherapy
Authors: Riera-Domingo Carla , Audigé Annette , Granja Sara , Cheng Wan-Chen , Ho Ping-Chih , Baltazar Fátima , Stockmann Christian , Mazzone Massimiliano
Published: August 2019

It is generally accepted that metabolism is able to shape the immune response. Only recently we are gaining awareness that the metabolic crosstalk between different tumor compartments strongly contributes to the harsh tumor microenvironment (TME) and ultimately impairs immune cell fitness and effector functions. The major aims of this review are to provide an overview on the immune system in cancer; to position oxygen shortage and metabolic competition as the ground of a restrictive TME and as important players in the anti-tumor immune response; to define how immunotherapies affect hypoxia/oxygen delivery and the metabolic landscape of the tumor; and vice versa, how oxygen and metabolites within the TME impinge on the success of immunotherapies. By analyzing preclinical and clinical endeavors, we will discuss how a metabolic characterization of the TME can identify novel targets and signatures that could be exploited in combination with standard immunotherapies and can help to predict the benefit of new and traditional immunotherapeutic drugs.
Nephrotic Syndrome due to Focal Segmental Glomerulosclerosis Complicating Sjögren’s Syndrome: A Case Report and Literature Review
Authors: Kurihara Shigekazu , Harada Makoto , Ichikawa Tohru , Ehara Takashi , Kobayashi Mamoru
Published: August 2019

Background. Renal tubular acidosis and tubulointerstitial nephritis constitute the primary renal complications associated with Sjögren’s syndrome (SjS), and glomerulonephritis and nephrotic syndrome are rare. Case Presentation. A 79-year-old Japanese woman presented with bilateral leg edema and weight gain and was diagnosed with nephrotic syndrome. In addition, she reported a 5-year history of dryness of mouth and was diagnosed with SjS. Renal biopsy revealed segmental glomerulosclerosis, with some specimens showing collapse of the glomerular capillary loops, proliferation of glomerular epithelial cells, and sclerotic lesions at the tubular poles, without spike formation, double contour lesions, or any other changes of the glomerular basement membrane. Immunofluorescence staining showed no immune complex (immunoglobulin IgG, IgA, or IgM) or complement (C3) deposition in the glomerular capillary walls. Based on these findings, she was diagnosed with focal segmental glomerulosclerosis (FSGS). The administration of steroid and cyclosporine achieved complete remission of nephrotic syndrome. Conclusion. Although glomerular diseases are rare, a variety of glomerular lesions including FSGS are reported in patients with SjS. Therefore, renal biopsy is warranted in patients with SjS presenting with severe urinary abnormalities.
Modelling of Asphalt’s Adhesive Behaviour Using Classification and Regression Tree (CART) Analysis
Authors: Arifuzzaman Md , Gazder Uneb , Alam Md Shah , Sirin Okan , Mamun Abdullah Al
Published: August 2019

The modification by polymers and nanomaterials can significantly improve different properties of asphalt. However, during the service life, the oxidation affects the constituents of modified asphalt and subsequently results in deviation from the desired properties. One of the important properties affected due to oxidation is the adhesive properties of modified asphalt. In this study, the adhesive properties of asphalt modified with the polymers (styrene-butadiene-styrene and styrene-butadiene) and carbon nanotubes were investigated. Asphalt samples were aged in the laboratory by simulating the field conditions, and then adhesive properties were evaluated by different tips of atomic force microscopy (AFM) following the existing functional group in asphalt. Finally, a predictive modelling and machine learning technique called the classification and regression tree (CART) was used to predict the adhesive properties of modified asphalt subjected to oxidation. The parameters that affect the behaviour of asphalt have been used to predict the results using the CART. The results obtained from CART analysis were also compared with those from the regression model. It was observed that the CART analysis shows more explanatory relationships between different variables. The model can predict accurately the adhesive properties of modified asphalts considering the real field oxidation and chemistry of asphalt at a nanoscale.
A Lightweight API-Based Approach for Building Flexible Clinical NLP Systems
Authors: Shen Zhengru , van Krimpen Hugo , Spruit Marco
Published: August 2019

Natural language processing (NLP) has become essential for secondary use of clinical data. Over the last two decades, many clinical NLP systems were developed in both academia and industry. However, nearly all existing systems are restricted to specific clinical settings mainly because they were developed for and tested with specific datasets, and they often fail to scale up. Therefore, using existing NLP systems for one’s own clinical purposes requires substantial resources and long-term time commitments for customization and testing. Moreover, the maintenance is also troublesome and time-consuming. This research presents a lightweight approach for building clinical NLP systems with limited resources. Following the design science research approach, we propose a lightweight architecture which is designed to be composable, extensible, and configurable. It takes NLP as an external component which can be accessed independently and orchestrated in a pipeline via web APIs. To validate its feasibility, we developed a web-based prototype for clinical concept extraction with six well-known NLP APIs and evaluated it on three clinical datasets. In comparison with available benchmarks for the datasets, three high F1 scores (0.861, 0.724, and 0.805) were obtained from the evaluation. It also gained a low F1 score (0.373) on one of the tests, which probably is due to the small size of the test dataset. The development and evaluation of the prototype demonstrates that our approach has a great potential for building effective clinical NLP systems with limited resources.
Association of Patients’ Characteristics with Acupuncture Treatment Outcomes in Treating Bell’s Palsy: Results from a Randomised Controlled Trial
Authors: Xiao Xianjun , Zheng Qianhua , Shi Yunzhou , Zhang Leixiao , Zhao Ling , Zhou Siyuan , Zhang Wei , Cao Wei , Liu Ying , Li Ying
Published: August 2019

Background. Acupuncture has been found to be effective for treating Bell’s palsy (BP). However, which class of BP patients will have a better response to acupuncture remains uncertain and requires investigation. Methods. We performed a secondary analysis of a multicenter, randomized, controlled trial. BP patients were randomly divided into five acupuncture treatment groups. The degree of facial nerve recovery was assessed according to the House–Brackmann grading system (HB grade). Grade I was defined as complete recovery (CR), and grades II–VI were defined as incomplete recovery (IR). The relevant patient characteristics were collected and compared between CR and IR groups by univariate and logistic regression analyses. Results. Eight-hundred twenty-six subjects were analyzed. Among these, 698 (85%) subjects had a good prognosis. No significant difference in the effectiveness of the five treatments was observed (all P>0.05). The likelihood of IR increased by 2.2% with each one-year increase in age (odds ratio (OR) 1.022, 95% confidence interval (CI) 1.005–1.038; P=0.009). The likelihood of IR increased by 9% with each kg/m2 increase in BMI (OR 1.090, 95% CI 1.019–1.165; P=0.012). The likelihood of IR at the recovery stage was higher than that at the acute stage (OR 7.996, 95% CI 4.570–13.991; P<0.001), and the likelihood of IR of patients with lesions at or above the chorda tympani was higher than that of patients with lesions below the chorda tympani (OR 1.989, 95% CI 1.256–3.150; P=0.003). The likelihood of IR increased by 281.7% with each unit increase in the HB grade (OR 2.817, 95% CI 2.113–3.756; P<0.001). Conclusions. Younger patients at the acute stage of the disease with low BMIs, low initial HB grades, and lesions below the chorda tympani were more likely to respond to acupuncture.
Estimation of Additional Equivalent Damping Ratio of the Damped Structure Based on Energy Dissipation
Authors: Hu Xiuyan , Chen Qingjun , Weng Dagen , Zhang Ruifu , Ren Xiaosong
Published: August 2019

In the design of damped structures, the additional equivalent damping ratio (EDR) is an important factor in the evaluation of the energy dissipation effect. However, previous additional EDR estimation methods are complicated and not easy to be applied in practical engineering. Therefore, in this study, a method based on energy dissipation is developed to simplify the estimation of the additional EDR. First, an energy governing equation is established to calculate the structural energy dissipation. By means of dynamic analysis, the ratio of the energy consumed by dampers to that consumed by structural inherent damping is obtained under external excitation. Because the energy dissipation capacity of the installed dampers is reflected by the additional EDR, the abovementioned ratio can be used to estimate the additional EDR of the damped structure. Energy dissipation varies with time, which indicates that the ratio is related to the duration of ground motion. Hence, the energy dissipation during the most intensive period in the entire seismic motion duration is used to calculate the additional EDR. Accordingly, the procedure of the proposed method is presented. The feasibility of this method is verified by using a single‐degree‐of‐freedom system. Then, a benchmark structure with dampers is adopted to illustrate the usefulness of this method in practical engineering applications. In conclusion, the proposed method is not only explicit in the theoretical concept and convenient in application but also reflects the time‐varying characteristic of additional EDR, which possesses the value in practical engineering.
Application of Factorial and Doehlert Designs for the Optimization of the Simultaneous Separation and Determination of Antimigraine Drugs in Pharmaceutical Formulations by RP-HPLC-UV
Authors: Jebali Sami , Belgacem Chaouki , Louhaichi Mohamed Radhouen , Bahri Senda , Latrous El Atarche Latifa
Published: August 2019

A sensitive, precise, accurate, and specific isocratic reversed-phase high-performance liquid chromatographic (RP-HPLC) method for the simultaneous separation and determination of zolmitriptan, naratriptan, dihydroergotamine, ketotifen, and pizotifen in pharmaceutical formulations has been developed and validated. An experimental design was applied for the optimization of the chromatographic parameters. A two-level full factorial 2k was used for studying the interaction between the variables to be optimized: the percentage of acetonitrile in the mobile phase, mobile-phase pH, nature of the buffer, and column oven temperature. The most significant parameters are the percentage of acetonitrile and the mobile-phase pH. These significant parameters were optimized using the Doehlert matrix. The optimum separation was achieved by means of a Waters XBridge C18 column (250 mm × 4.6 mm, 5 μm) with a mobile phase consisting of acetonitrile and a 10 mM sodium perchlorate buffer (38 : 62, v/v) at a flow rate of 1.0 mL·min−1 and UV detection at 220 nm. The selectivity, method linearity, accuracy, and precision were examined as part of the method validation. The described method shows excellent linearity over a range of 30 to 70 μg·mL−1 for all compounds with correlation coefficients higher than 0.995. The standard deviations of the intraday and interday precision were between 0.75 and 1.94%. The validated method was successfully applied to perform routine analysis of these compounds in different pharmaceutical products such as syrups and tablets. In the presence of some preservatives, it was found that there were no peaks at the related peak locations.
ERBB3 and IGF1R Signaling Are Required for Nrf2-Dependent Growth in KEAP1-Mutant Lung Cancer
Authors: Vartanian Steffan , Lee James , Klijn Christiaan , Gnad Florian , Bagniewska Maria , Schaefer Gabriele , Zhang Donglu , Tan Jenille , Watson Sara A. , Liu Liling , Chen Honglin , Liang Yuxin , Watanabe Colin , Cuellar Trinna , Kan David , Hartmaier Ryan J. , Lau Ted , Costa Michael R. , Martin Scott E. , Merchant Mark , Haley Benjamin , Stokoe David
Published: August 2019

Mutations in KEAP1 and NFE2L2 (encoding the protein Nrf2) are prevalent in both adeno and squamous subtypes of non–small cell lung cancer, as well as additional tumor indications. The consequence of these mutations is stabilized Nrf2 and chronic induction of a battery of Nrf2 target genes. We show that knockdown of Nrf2 caused modest growth inhibition of cells growing in two-dimension, which was more pronounced in cell lines expressing mutant KEAP1. In contrast, Nrf2 knockdown caused almost complete regression of established KEAP1-mutant tumors in mice, with little effect on wild-type (WT) KEAP1 tumors. The strong dependency on Nrf2 could be recapitulated in certain anchorage-independent growth environments and was not prevented by excess extracellular glutathione. A CRISPR screen was used to investigate the mechanism(s) underlying this dependence. We identified alternative pathways critical for Nrf2-dependent growth in KEAP1-mutant cell lines, including the redox proteins thioredoxin and peroxiredoxin, as well as the growth factor receptors IGF1R and ERBB3. IGF1R inhibition was effective in KEAP1-mutant cells compared with WT, especially under conditions of anchorage-independent growth. These results point to addiction of KEAP1-mutant tumor cells to Nrf2 and suggest that inhibition of Nrf2 or discrete druggable Nrf2 target genes such as IGF1R could be an effective therapeutic strategy for disabling these tumors.

Significance:

This study identifies pathways activated by Nrf2 that are important for the proliferation and tumorigenicity of KEAP1-mutant non–small cell lung cancer.
Crizotinib inMET-Deregulated orROS1-Rearranged Pretreated Non–Small Cell Lung Cancer (METROS): A Phase II, Prospective, Multicenter, Two-Arms Trial
Authors: Landi Lorenza , Chiari Rita , Tiseo Marcello , D'Incà Federica , Dazzi Claudio , Chella Antonio , Delmonte Angelo , Bonanno Laura , Giannarelli Diana , Cortinovis Diego Luigi , de Marinis Filippo , Borra Gloria , Morabito Alessandro , Gridelli Cesare , Galetta Domenico , Barbieri Fausto , Grossi Francesco , Capelletto Enrica , Minuti Gabriele , Mazzoni Francesca , Verusio Claudio , Bria Emilio , Alì Greta , Bruno Rossella , Proietti Agnese , Fontanini Gabriella , Crinò Lucio , Cappuzzo Federico
Published: August 2019

Purpose:

MET-deregulated NSCLC represents an urgent clinical need because of unfavorable prognosis and lack of specific therapies. Although recent studies have suggested a potential role for crizotinib in patients harboring MET amplification or exon 14 mutations, no conclusive data are currently available. This study aimed at investigating activity of crizotinib in patients harboring MET or ROS1 alterations.

Patients and Methods:

Patients with pretreated advanced NSCLC and evidence of ROS1 rearrangements (cohort A) or MET deregulation (amplification, ratio MET/CEP7 >2.2 or MET exon 14 mutations, cohort B) were treated with crizotinib 250 mg twice daily orally. The coprimary endpoint was objective response rate in the two cohorts.

Results:

From December 2014 to March 2017, 505 patients were screened and a total of 52 patients (26 patients per cohort) were enrolled onto the study. At data cutoff of September 2017, in cohort A, objective response rate was 65%, and median progression-free survival and overall survival were 22.8 months [95% confidence interval (CI) 15.2–30.3] and not reached, respectively. In cohort B, objective response rate was 27%, median progression-free survival was 4.4 months (95% CI 3.0–5.8), and overall survival was 5.4 months (95% CI, 4.2–6.5). No difference in any clinical endpoint was observed between MET-amplified and exon 14–mutated patients. No response was observed among the 5 patients with cooccurrence of a second gene alteration. No unexpected toxicity was observed in both cohorts.

Conclusions:

Crizotinib induces response in a fraction of MET-deregulated NSCLC. Additional studies and innovative therapies are urgently needed.
RETRACTED: CDX1 Expression Induced by CagA-Expressing Helicobacter pylori Promotes Gastric Tumorigenesis
Authors: Choi Sang Il , Yoon Changhwan , Park Mi Ree , Lee DaHyung , Kook Myeong-Cherl , Lin Jian-Xian , Kang Jun Hyuk , Ashktorab Hassan , Smoot Duane T. , Yoon Sam S. , Cho Soo-Jeong
Published: August 2019

Intestinal-type gastric cancer often results from Helicobacter pylori infection through intestinal metaplasia, a transdifferentiated premalignant phenotype. Because H. pylori virulence factor CagA has been associated with aberrant expression of the transcription factor CDX1, which regulates intestinal differentiation, we explored its relationship with H. pylori infection and function during gastric carcinogenesis in normal gastric epithelial cells and gastric cancer cell lines. Infection of HFE 145 cells with CagA+ H. pylori increased expression of CDX1, as well as the epithelial-to-mesenchymal transition (EMT) markers Snail and Slug, increased invasion and migration, but those effects were not found in HFE 145 cells infected with CagA-deficient H. pylori. CDX1 overexpression increased expression of the intestinal markers Villin, sucrose isomaltase (SI), and MUC2, induced spheroid formation, and enhanced expression of the stem cell markers CD44, SOX2, Oct4, and Nanog, while CDX1 knockdown inhibited proliferation and intestinal stemness. Treatment of CDX1-expressing cells with metformin, an antidiabetic drug known to decrease the risk of gastric cancer, decreased expression of EMT and stemness markers, and reduced spheroid formation. In a murine xenograft model, combining metformin or shCDX1 with cisplatin reduced tumor growth, increased caspase-3 cleavage, and reduced expression of CD44 and MMP-9 to a greater degree than cisplatin alone. Patients with more advanced intestinal metaplasia staging exhibited higher CDX1 expression than those with earlier intestinal metaplasia staging (P = 0.039), and those with H. pylori tended to have more CDX1 expression than noninfected patients (P = 0.061). Finally, human tissue samples with higher CDX1 levels showed prominent CD44/SOX2 expression. Our findings indicate CagA+ H. pylori–induced CDX1 expression may enhance gastric cancer tumorigenesis and progression, and support therapeutic targeting of CDX1 in gastric cancer.

Implications:

This study shows that CDX1 contributes to the tumorigenesis and progression of gastric cancer and suggests the potential of targeting CDX1 to treat this malignancy.
P-Mail: The Information Highway of Nocturnal, but Not Diurnal or Cathemeral, Strepsirrhines
Authors: Drea Christine M. , Goodwin Thomas E. , delBarco-Trillo Javier
Published: August 2019

Scent marking is a well-established, but highly variable, mode of communication among strepsirrhine primates. We begin by reviewing this literature, focusing on nocturnal species. Our understanding about the information content of scent signals and the factors driving species diversity remains incomplete, owing to difficulties in acquiring comparative chemical data. We therefore re-examine such a data set, representing the richness and relative abundance of volatile organic compounds (VOCs) in the urine of 12 species (from Galagidae, Lorisidae, Daubentoniidae, Cheirogaleidae, Indriidae, and Lemuridae), to explore differences between nocturnal, diurnal and cathemeral species. As predicted by the variable importance of urine marking across species, the urine of nocturnal strepsirrhines contained the most VOCs and putative semiochemicals, differed significantly in composition from that of diurnal and cathemeral species and showed the strongest species scent “signatures.” Relevant to retracing the evolutionary trajectory of cathemeral strepsirrhines, nocturnal and diurnal species were most differentiated in their VOCs, with cathemeral species being intermediary, but more closely aligned with diurnal species. These data support cathemerality as an ancient expansion of diurnal animals into a nocturnal niche. Consideration of the traits and variables associated with olfactory communication offers a profitable new way for examining species diversity and patterns of evolutionary change.
Predictors of Risk and Success of Obesity Surgery
Authors: Nickel Felix , de la Garza Javier R. , Werthmann Fabian S. , Benner Laura , Tapking Christian , Karadza Emir , Wekerle Anna-Laura , Billeter Adrian T. , Kenngott Hannes G. , Fischer Lars , Müller-Stich Beat Peter
Published: August 2019

Background: Obesity surgery has proven successful for weight loss and the resolution of comorbidities. There is, however, little evidence on its success and the risk of complications when considering age of onset of obesity (AOO), years of obesity (YOO), preoperative body mass index (BMI), Edmonton obesity staging system (EOSS) score, and age as possible predictors of weight loss, the resolution of comorbidities, and the risk of complications. Methods: Patients who underwent Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (LSG) from a prospective database were analyzed. Multiple regression analyses were used to predict comorbidities and their resolution, percentage excess weight loss (%EWL) and total weight loss (%TWL) 12 months after surgery, and the risk of complications using the predictors AOO, YOO, age, EOSS, and BMI. Results: 180 patients aged 46.8 ± 11.1 years with a preoperative BMI 49.5 ± 7.5 were included. The number of preoperative comorbidities was higher with older age (β = 0.054; p = 0.023) and a greater BMI (β = 0.040; p = 0.036) but was not related to AOO and YOO. Patients with AOO as a child or adolescent were more likely to have an EOSS score of ≥2. Greater preoperative BMI was negatively associated with %EWL (β = –1.236; p < 0.001) and older age was negatively associated with %TWL (β = –0.344; p = 0.020). Postoperative complications were positively associated with EOSS score (odds ratio [OR] 1.147; p = 0.042) and BMI (OR 1.010; p = 0.020), but not with age. AOO and YOO were not related to postoperative outcome. Conclusion: Greater BMI was associated with a lower %EWL and age was associated with a low %TWL. YOO and AOO did not influence outcome. Age, BMI, and EOSS score were the most important predictors for risk and success after obesity surgery. Surgery should be performed early enough for optimal outcomes.
Species Boundaries within Morphologically Cryptic Galagos: Evidence from Acoustic and Genetic Data
Authors: Pozzi Luca , Disotell Todd R. , Bearder Simon K. , Karlsson Johan , Perkin Andrew , Gamba Marco
Published: August 2019

Describing primate biodiversity is one of the main goals in primatology. Species are the fundamental unit of study in phylogeny, behaviour, ecology and conservation. Identifying species boundaries is particularly challenging for nocturnal taxa where only subtle morphological variation is present. Traditionally, vocal signals have been used to identify species within nocturnal primates: species-specific signals often play a critical role in mate recognition, and they can restrict gene flow with other species. However, little research has been conducted to test whether different “acoustic forms” also represent genetically distinct species. Here, we investigate species boundaries between two putative highly cryptic species of Eastern dwarf galagos (Paragalago cocosand P. zanzibaricus). We combined vocal and genetic data: molecular data included the complete mitochondrial cytochrome b gene (1,140 bp) for 50 samples across 11 localities in Kenya and Tanzania, while vocal data comprised 221 vocalisations recorded across 8 localities. Acoustic analyses showed a high level of correct assignation to the putative species (approx. 90%), while genetic analyses identified two separate clades at the mitochondrial level. We conclude that P. cocos and P. zanzibaricus represent two valid cryptic species that probably underwent speciation in the Late Pliocene while fragmented in isolated populations in the eastern forests.
Echolocation in a Nocturnal Primate?
Authors: Gursky Sharon
Published: August 2019

Recently it has been noted that Gursky’s spectral tarsier emits ultrasonic calls. Because high-frequency sounds are capable of travelling only short distances, their function is limited by the distance the sound can be discerned. One possible function for these short-distance, high-frequency sounds is that they might be used by the tarsiers to navigate throughout their environment. I conducted this study at Tangkoko Nature Reserve in Sulawesi, Indonesia, from May to August 2017. Using the focal follows, I recorded the start of each locomotor activity to the nearest second. I also simultaneously recorded all ultrasonic vocalisations that the focal individual emitted using a Wildlife Acoustics Ultrasonic Song Meter BAT3. Approximately 42% of the ultrasonic calls that I recorded during this study were given within 1 s prior to engaging in locomotor activity. The tarsiers gave statistically more ultrasonic calls during locomotion than during other behaviours (rest, forage and social). Four types of ultrasonic calls were given while locomoting: whistles, doubles, trills and frequency-modulated calls. Of these, the trill and the frequency-modulated call were only given during locomotion, and trills were only given prior to leaping. These results preliminarily suggest that the tarsiers do use ultrasonic calls for navigation. Studying echolocation in organisms closely related to bats is critical for understanding the evolution of echolocation.
Low Geographic and Subspecific Variation in the Loud Call of the Widespread and Phenotypically Cryptic Northern Lesser Galago (Galago senegalensis) Suggests Taxonomic Uniformity
Authors: Svensson Magdalena S. , Butynski Thomas M. , de Jong Yvonne A. , Bearder Simon K. , Schneiderová Irena , Nijman Vincent
Published: August 2019

Like other nocturnal primates, many species of galago (Galagidae) are phenotypically cryptic, making their taxonomic status difficult to resolve. Recent taxonomic work has disentangled some of the confusion. This has resulted in an increase in the number of recognised galago species. The most widespread galago species, and indeed the most widespread nocturnal primate, is the northern lesser galago (Galago senegalensis) whose geographic range stretches >7,000 km across Africa. Based on morphology, 4 subspecies are currently recognised: G. s. senegalensis, G. s. braccatus, G. s. sotikae and G. s. dunni. We explore geographic and subspecific acoustic variation in G. senegalensis, testing three hypotheses: isolation by distance, genetic basis, and isolation by barrier. There is statistical support for isolation by distance for 2 of 4 call parameters (fundamental frequency and unit length). Geographic distance explains a moderate amount of the acoustic variation. Discriminant function analysis provides some degree of separation of geographic regions and subspecies, but the percentage of misdesignation is high. Despite having (putative) parapatric geographic ranges, the most pronounced acoustic differences are between G. s. senegalensis and G. s. dunni. The findings suggest that the Eastern Rift Valley and Niger River are significant barriers for G. senegalensis. The acoustic structures of the loud calls of 121 individuals from 28 widespread sites are not significantly different. Although this makes it unlikely that additional unrecognised species occur within G. senegalensis at the sites sampled, vast areas of the geographic range remain unsampled. We show that wide-ranging species do not necessarily exhibit large amounts of variation in their vocal repertoire. This pattern may also be present in nocturnal primates with smaller geographic ranges.