bluuebunny/crossref_metadata_2025 huggingface dataset:
Can the Second to Fourth Digit Ratio (2D : 4D) Be a Marker to Determine Ankylosing Spondylitis Disease Activity?
Authors: Uğur Sevcan , Çay Hasan Fatih , Sezer İlhan , Kaçar Cahit
Published: February 2019

Objective. The length ratio of the index finger (2D) to the ring finger (4D) (2D : 4D ratio) is considered a biomarker of prenatal sex hormone exposure. The 2D : 4D ratio is influenced by prenatal androgen and estrogen levels. Because ankylosing spondylitis (AS) influences men more frequently and severely than women, androgens are proposed to be related to AS pathogenesis. Estrogens have immune-modulating effects and reduce AS disease activity. The aim of this study was to assess the relationship between 2D : 4D ratio and AS disease activity.Material and Methods. In this study, 167 (43 female) patients diagnosed with AS were studied. The lengths of the second and fourth fingers were measured using a digital caliper. The 2D : 4D ratio was found by dividing the length of the second finger by the length of the fourth finger. AS disease activity was assessed with the Turkish version of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). AS functional status was assessed with Bath Ankylosing Spondylitis Functional Index (BASFI). L-Schober, tragus to wall distance, finger to floor distance, and chest expansion were used to evaluate mobility.Results. In female patients, the right hand 2D : 4D ratios were higher than those in male patients. Biologic drug use was more frequent in males. The BASDAI scores were higher in female patients than in male patients. There were significant negative correlations between right and left hand 2D : 4D ratio and BASFI and BASDAI in female patients. There was no significant correlation between the 2D : 4D ratio and BASFI or BASDAI in male patients. We found a positive correlation between L-Schober and right hand 2D : 4D and a negative correlation between the left hand 2D : 4D ratio and finger to floor distance in female patients with AS.Conclusion. The 2D : 4D ratio of the right and left hand was low in female patients with high BASFI and BASDAI and low spinal mobility (L-Schober) was also linked to low female 2D : 4D. The lack of strong associations between 2D : 4D and AS in male patients may have resulted from their higher use of biologics.
Robust Prediction Algorithm Based on a General EIV Model for Multiframe Transformation
Authors: Yao Lihui , Lin Peng , Gao Jingxiang , Liu Chao
Published: February 2019

In modern geodesy, there are cases in which the target frame is unique and there is more than one source frame. Helmert transformations, which are extensively used to solve transformation parameters, can be separately solved between the target frame and one of the source frames. However, this is not globally optimal, even though each transformation is locally optimal on its own. Additionally, this also generates the problem of multiple solutions in the noncommon station of the target frame. Moreover, least squares solutions can cause estimation value distortion, with a gross error existing in observations. Thus, in this paper, Helmert transformations among three frames, that is, one target frame and two source frames, are studied as an example. A robust prediction algorithm based on the general errors‐in‐variables prediction algorithm and the robust estimation is derived in detail and is applied to achieve multiframe total transformation. Furthermore, simulation experiments were conducted and the results validated the superiority of the proposed total transformation method over classical separate approaches.
Dipeptidyl Peptidase 4 Activity Is Related to Body Composition, Measures of Adiposity, and Insulin Resistance in Subjects with Excessive Adiposity and Different Degrees of Glucose Tolerance
Authors: Silva Júnior Wellington S. , Souza Maria das Graças C. , Nogueira Neto José Firmino , Bouskela Eliete , Kraemer-Aguiar Luiz Guilherme
Published: February 2019

Background. The enzyme dipeptidyl peptidase 4 (DPP4) has been recently recognized as an adipo-myokine. However, studies that associate its constitutive activity with body composition, anthropometry, and insulin resistance (IR) are very scarce and included only healthy people. Methods. First, we investigated the relationships of constitutive DPP4 activity, body composition (assessed by bioelectrical impedance analysis), and measures of adiposity and IR in fifty-two subjects of both sexes, 18-50 years, and BMI ≥25.0 kg/m2 who comprised three groups according to glucose tolerance. Additionally, we evaluated associations among DPP4 activity and adipokines, gut peptides, and biochemical variables at fasting and 30 and 60 min after a standardized meal intake. Results. DPP4 activity was no different among the three groups. At fasting, pooled analysis showed it was positively correlated with measures of central adiposity, such as WC (P=0.011) and WHR (P=0.009), and with all measures of IR, but inversely related to indexes of general adiposity, such as fat mass percentage (P=0.014) and BAI (P=0.0003). DPP4 activity was also associated with lean mass (r=0.57, P<0.0001). After meal intake, DPP4 activity remained significantly associated with insulin, leptin, and resistin. In multiple regression analysis, BAI, WHR, percent lean mass, HOMA-IR, and leptin influenced DPP4 activity and explained approximately 26% of the variance on it. Conclusions. Constitutive DPP4 activity is positively associated with lean mass, central adiposity, and IR and negatively to general adiposity. Furthermore, it seems to be influenced by body composition and IR and could also be viewed as an adipo-myokine in subjects with excessive adiposity and different stages of glucose tolerance.
Sensor Fault Diagnosis and Fault‐Tolerant Control for Non‐Gaussian Stochastic Distribution Systems
Authors: Wang Hao , Yao Lina
Published: February 2019

A sensor fault diagnosis method based on learning observer is proposed for non‐Gaussian stochastic distribution control (SDC) systems. First, the system is modeled, and the linear B‐spline is used to approximate the probability density function (PDF) of the system output. Then a new state variable is introduced, and the original system is transformed to an augmentation system. The observer is designed for the augmented system to estimate the fault. The observer gain and unknown parameters can be obtained by solving the linear matrix inequality (LMI). The fault influence can be compensated by the fault estimation information to achieve fault‐tolerant control. Sliding mode control is used to make the PDF of the system output to track the desired distribution. MATLAB is used to verify the fault diagnosis and fault‐tolerant control results.
Two‐Phase Incremental Kernel PCA for Learning Massive or Online Datasets
Authors: Zhao Feng , Rekik Islem , Lee Seong-Whan , Liu Jing , Zhang Junying , Shen Dinggang
Published: February 2019

As a powerful nonlinear feature extractor, kernel principal component analysis (KPCA) has been widely adopted in many machine learning applications. However, KPCA is usually performed in a batch mode, leading to some potential problems when handling massive or online datasets. To overcome this drawback of KPCA, in this paper, we propose a two‐phase incremental KPCA (TP‐IKPCA) algorithm which can incorporate data into KPCA in an incremental fashion. In the first phase, an incremental algorithm is developed to explicitly express the data in the kernel space. In the second phase, we extend an incremental principal component analysis (IPCA) to estimate the kernel principal components. Extensive experimental results on both synthesized and real datasets showed that the proposed TP‐IKPCA produces similar principal components as conventional batch‐based KPCA but is computationally faster than KPCA and its several incremental variants. Therefore, our algorithm can be applied to massive or online datasets where the batch method is not available.
The Influence of Blood Glucose Meter Resistance Variation on the Performance of a Biosensor with a Gold-Coated Circuit Board
Authors: Kim Kun-Yong , Chang Ho , Lee Win-Der , Cai Yi-Fan , Chen You-Jia
Published: February 2019

In this study, a novel gold-coated test strip for blood glucose measurement has been designed. Such gold-coated test strip is feasible for mass production to achieve economies of scale. Cyclic voltammetry was applied to test strips to undergo electrochemical reaction under a potential range of ±0.4 V. Glucose oxidase (GOD) was added into K3[Fe(CN)6]. When glucose oxidase undergoes electrochemical reaction, the medium, K3[Fe(CN)6], will act as an electron acceptor, causing the electrodes on the test strip to generate a pair of clear anodic and reductive peaks. The maximum of the anodic and reductive peaks can be used as reference to adjust the resistance of the blood glucose meter. The experimental results show that by adjusting the resistance of the blood glucose meter, the accuracy of blood glucose meter reading can be tuned and blood glucose reading can be stabilized. Therefore, when the resistance of the blood glucose meter is at 2.4 KΩ, the standard deviation (STD) and coefficient of variation (CV) of the test strip are lower than those of the test strips measured at resistances of 2.2 KΩ and 2.6 KΩ. It has been proved in this study that adjusting the resistance of the blood glucose meter can optimize the chemical reaction on gold-coated test strips as well as its reading. This method can also be applied to tune the accuracy of readings for test strips coated with other materials.
Tunable Piezophotonic Effect on Core-Shell Nanoparticles Prepared by Laser Ablation in Liquids under External Voltage
Authors: Kodeary A. K. , Hamidi S. M.
Published: February 2019

We report an experimental study on the piezophotonic effect of gold and lead zirconate titanate (PbZrTiO3) nanoparticles (NPs) and also their core-shell nanostructures prepared by the laser ablation in liquid method. To obtain these NPs and composite materials, the targets were immersed in deionized water and a polymeric solution of polyvinyl pyrrolidone (PVP) under Nd:YAG laser pulses irradiation. Linear and nonlinear properties of these NPs were studied by optical spectroscopy and the Z-scan technique. Furthermore, tunable nonlinear properties of the NPs were measured under an external electric field under illumination to investigate the piezophotonic effect. Our results show that, at the interface of PZT and Au, due to the Schottky barrier, we have electron/hole recombination prevention, which leads to efficient enhancement in the nonlinear properties.
Prevalence and Determinants of Diabetic Foot Ulcers and Lower Extremity Amputations in Three Selected Tertiary Hospitals in Ghana
Authors: Atosona Ambrose , Larbie Christopher
Published: February 2019

Background. The occurrence and complications of diabetes are increasing worldwide. This study examined the prevalence and determinants of diabetic foot ulcers and lower extremity amputations in three selected tertiary hospitals in Ghana. Methods. A cross-sectional multicenter study involving 100 subjects was carried out. Subjects were selected through simple random sampling from three selected tertiary hospitals in Ghana. A structured questionnaire was used to document information on sociodemographic, medical history, lifestyle, and physical characteristics of subjects. Foot ulcers and lower extremity amputations were also investigated. Total cholesterol, triglycerides, low-density lipoproteins, high-density lipoproteins, serum urea, serum creatinine, and estimated glomerular filtration rate of subjects were assessed. Data analysis was done using SPSS version 22. Results. The study revealed that 31% and 69% were males and females, respectively, with a mean age of 53.8±13.8 years. Among the patients, 11% had diabetic foot ulcers whilst 3% had lower extremity amputations. In the multivariate binary logistic regression analysis, previous history of foot ulcers (OR=40.4, 95% CI=5.5-299.9) and foot deformities (OR=14.4, 95% CI=1.3-161.2) were identified as independent predictors of diabetic foot ulcers. Foot deformity (p=0.043) and serum urea (p=0.002) were associated with diabetic lower extremity amputations in the univariate analysis. Conclusion. This study showed that the prevalences of diabetic foot ulcers and lower extremity amputations are high among diabetes patients. Foot deformities and previous history of foot ulcers are determinants of diabetic foot ulcers. Foot deformity and serum urea are associated with diabetic lower extremity amputations.
Validity and Reliability of Upper Limb Functional Assessment Using the Microsoft Kinect V2 Sensor
Authors: Cai Laisi , Ma Ye , Xiong Shuping , Zhang Yanxin
Published: February 2019

Objective. To quantify the concurrent accuracy and the test-retest reliability of a Kinect V2-based upper limb functional assessment system. Approach. Ten healthy males performed a series of upper limb movements, which were measured concurrently with Kinect V2 and the Vicon motion capture system (gold standard). Each participant attended two testing sessions, seven days apart. Four tasks were performed including hand to contralateral shoulder, hand to mouth, combing hair, and hand to back pocket. Upper limb kinematics were calculated using our developed kinematic model and the UWA model for Kinect V2 and Vicon. The interdevice coefficient of multiple correlation (CMC) and the root mean squared error (RMSE) were used to evaluate the validity of the kinematic waveforms. Mean absolute bias and Pearson’s r correlation were used to evaluate the validity of the angles at the points of target achieved (PTA) and the range of motion (ROM). The intersession CMC and RMSE and the intraclass correlation coefficient (ICC) were used to assess the test-retest reliability of Kinect V2. Main Results. Both validity and reliability are found to be task-dependent and plane-dependent. Kinect V2 had good accuracy in measuring shoulder and elbow flexion/extension angular waveforms (CMC>0.87), moderate accuracy of measuring shoulder adduction/abduction angular waveforms (CMC=0.69-0.82), and poor accuracy of measuring shoulder internal/external angles (CMC<0.6). We also found high test-retest reliability of Kinect V2 in most of the upper limb angular waveforms (CMC=0.75-0.99), angles at the PTA (ICC=0.65-0.91), and the ROM (ICC=0.68-0.96). Significance. Kinect V2 has great potential as a low-cost, easy implemented device for assessing upper limb angular waveforms when performing functional tasks. The system is suitable for assessing relative within-person change in upper limb motions over time, such as disease progression or improvement due to intervention.
MicroRNA-224 Promotes Tumorigenesis through Downregulation of Caspase-9 in Triple-Negative Breast Cancer
Authors: Zhang Li , Zhang Xin , Wang Xin , He Miao , Qiao Shixing
Published: February 2019

Triple-negative breast cancer (TNBC) harbors genetic heterogeneity and generally has more aggressive clinical outcomes. As such, there is urgency in identifying new prognostic targets and developing novel therapeutic strategies. In this study, miR-224 was overexpressed in breast cancer cell lines and TNBC primary cancer samples. Knockdown of miR-224 in MDA-MB-231 cancer cells reduced cell proliferation, migration, and invasion. Through integrating in silico prediction algorithms with KEGG pathway and Gene Ontology analyses, CASP9 was identified to be a potential target of miR-224. miR-224 knockdown significantly increased CASP9 transcript and protein levels. Furthermore, luciferase reporter assays confirmed a direct interaction of miR-224 with CASP9. Our findings have demonstrated that the miR-224/CASP9 axis plays an important role in TNBC progression, providing evidence in support of a promising therapeutic strategy for this disease.
Super Broadband-Sensitive Upconversion in Tm and Ni Codoped Perovskites
Authors: Luitel Hom Nath , Mizuno Shintaro , Takeda Yasuhiko
Published: February 2019

We investigated broadband-sensitive upconversion (UC) processes in a series of Tm- and Ni-sensitized ABO3 (A = Ca/Sr/Ba and B = Ti/Zr/Hf) perovskites. We have designed combinations of the sensitizers and host cations such that super broad solar radiation ranging from 900 nm to nearly 2000 nm can be efficiently upconverted to 800 nm and shorter wavelengths. The Ni2+ ions located at the center of O2− octahedra absorbed photons in the 900–1500 nm range and transferred those energies to the nearby Tm3+ ions. The Tm3+ ions upconverted those energies at 800 nm, along with the energies absorbed by themselves in the 1100–1250 and 1550–2000 nm ranges, exhibiting super broadband sensitivity. Among the ABO3:Tm, Ni (A = Ca/Sr/Ba and B = Ti/Zr/Hf) upconverters, CaTiO3:Tm, Ni exhibited the best performance due to its most distorted crystal structure, which intensified the emission and absorption extents by increasing the optical transition probabilities of Tm3+ and Ni2+ ions. Introduction of alkali ions at the Ca2+ sites and Nb5+ ions at the Ti4+ sites intensified the UC emission by many folds, mainly due to a charge balance mechanism. At the same time, bigger and smaller codoped alkali ions created an asymmetric crystal field around the active ions and further enhanced the UC emission. Importantly, the upconverted photons are within the absorption edges of GaAs, Cu2ZnSnS4, and dye-sensitized solar cells making wider applications of these upconverters besides crystalline Si solar cells.
Air Ultrasonic Signal Localization with a Beamforming Microphone Array
Authors: Movahed Ali , Waschkies Thomas , Rabe Ute
Published: February 2019

Nondestructive testing methods are used to inspect and test materials and components for discontinuities or differences in mechanical characteristics. Phased array signal processing techniques have been widely used in different applications, but less research has been conducted on contactless nondestructive testing with passive arrays. This paper presents an application of beamforming techniques analysis using a passive synthetic microphone array to calculate the origin and intensity of sound waves in the ultrasonic frequency range. Acoustic cameras operating in the audible frequency range are well known. In order to conduct measurements in higher frequencies, the arrangement of microphones in an array has to be taken into consideration. This arrangement has a strong influence on the array properties, such as its beam pattern, its dynamics, and its susceptibility to spatial aliasing. Based on simulations, optimized configurations with 16, 32, and 48 microphones and 20 cm diameter were implemented in real experiments to investigate the array resolution and localize ultrasonic sources at 75 kHz signal frequency. The results show that development of an ultrasonic camera to localize ultrasonic sound sources is beneficial.
Oxidative Stress in Animal Models of Acute and Chronic Renal Failure
Authors: Gyurászová Marianna , Kovalčíková Alexandra Gaál , Renczés Emese , Kmeťová Katarína , Celec Peter , Bábíčková Janka , Tóthová Ľubomíra
Published: February 2019

Introduction. Kidney disease is a worldwide health and economic burden, with rising prevalence. The search for biomarkers for earlier and more effective disease screening and monitoring is needed. Oxidative stress has been linked to both, acute kidney injury (AKI) and chronic kidney disease (CKD). The aim of our study was to investigate whether the concentrations of systemic markers of oxidative stress and antioxidant status are affected by AKI and CKD, and to identify potential biomarkers.Methods. In adult male Wistar rats, AKI was induced by bilateral nephrectomy, and CKD was induced by 5/6 nephrectomy. Blood was collected 48 hours after surgery in AKI and 6 months after surgery in CKD. Advanced oxidation protein products (AOPP), thiobarbituric acid reactive substances (TBARS), advanced glycation end products (AGEs), fructosamine, total antioxidant capacity (TAC), and ferric reducing antioxidant power (FRAP) were measured.Results. Impaired renal function was confirmed by high concentrations of plasma creatinine and urea in AKI and CKD animals. AOPP and fructosamine were higher by 100% and 54% in AKI, respectively, and by 100% and 199% in CKD, respectively, when compared to corresponding control groups. Similarly, there was approximately a twofold increase in AGEs (by 92%) and TAC (by 102%) during AKI. In CKD, concentrations of FRAP, as an antioxidative status marker, were doubled (by 107%) when compared to the control group, but concentration of TAC, another marker of antioxidative status, did not differ between the groups.Conclusions. AKI and CKD led to increased systemic oxidative stress. AOPP and fructosamine could be considered potential biomarkers for both, acute and chronic kidney damage. On the other hand, AGEs, TAC, and FRAP seem to be disease specific, which could help to differentiate between acute and chronic kidney injuries. However, this needs further validation in clinical studies.
Induced Choquet Integral Aggregation Operators with Single‐Valued Neutrosophic Uncertain Linguistic Numbers and Their Application in Multiple Attribute Group Decision‐Making
Authors: Zhao Shuping , Wang Dong , Changyong Liang , Lu Wenxing
Published: February 2019

For real decision‐making problems, aggregating the attributes which have interactive or correlated characteristics by traditional aggregation operators is unsuitable. Thus, applying Choquet integral operator to approximate and simulate human subjective decision‐making process, in which independence among the input arguments is not necessarily assumed, would be suitable. Moreover, using single‐valued neutrosophic uncertain linguistic sets (SVNULSs) can express the indeterminate, inconsistent, and incomplete information better than FSs and IFSs. In this paper, we studied the MAGDM problems with SVNULSs and proposed two single‐valued neutrosophic uncertain linguistic Choquet integrate aggregation operators where the interactions phenomena among the attributes or the experts are considered. First, the definition, operational rules, and comparison method of single‐valued neutrosophic uncertain linguistic numbers (SVNULNs) are introduced briefly. Second, induced single‐valued neutrosophic uncertain linguistic Choquet ordered averaging (I‐SVNULCA) operator and induced single‐valued neutrosophic uncertain linguistic Choquet geometric (I‐SVNULCG) operator are presented. Moreover, a few of its properties are discussed. Further, the procedure and algorithm of MAGDM based on the above single‐valued neutrosophic uncertain linguistic Choquet integral operator are proposed. Finally, in the illustrative example, the practicality and effectiveness of the proposed method would be demonstrated.
Critical Challenges for BIM Adoption in Small and Medium‐Sized Enterprises: Evidence from China
Authors: Li Pengfei , Zheng Shengqin , Si Hongyun , Xu Ke
Published: February 2019

Building information modelling (BIM) is a set of technologies that aim to increase interorganisational and cross‐disciplinary collaboration in the architecture, engineering, and construction (AEC) industries to promote productivity and the quality of design, construction, and maintenance stages of a building. Studies on BIM adoption in small and medium‐sized enterprises (SMEs) have remained an under‐represented area. It is necessary to understand the main challenges hindering the adoption of BIM in SMEs and to consider corresponding strategies that can be applied in order to obtain further understanding of BIM in SMEs. On the basis of literature review and interview, stakeholder‐associated factors were identified from a network perspective, and the social network analysis (SNA) method was applied to determine the interconnections between the influencing factors and links in BIM adoption in SMEs. Eventually, 10 critical factors and 10 crucial links were selected and divided into six challenges. Corresponding strategies, including cultivating the BIM perception of SMEs, integrated project delivery, strengthening the legal environment for BIM adoption in SMEs, and developing native software and standards and cloud‐based technology, were proposed to mitigate these challenges. The strategies may help practitioners gain an in‐depth understanding of BIM adoption in SMEs from a stakeholder‐oriented perspective.
Green Analytical Methods for the Separation of Seven Antihistamines: Application in Separation of Azelastine and Related Impurities in Nasal Solution
Authors: da Costa Lucas Maciel , Oliveira de Almeida Leite Heitor , Kassab Nájla Mohamad , Singh Anil Kumar
Published: February 2019

Antihistamines are widely used to alleviate the symptoms caused by allergic reactions. Most of these drugs have zwitteriónicas and/or amphoteric characteristics, which confer additional analytical challenges. This work aimed to develop a single eco-friendly and efficient chromatographic methods for analysis of seven antihistamines, namely, azelastine HCl, desloratadine, ebastine, fexofenadine HCl, ketotifen, loratadine, and olopatadine HCl. The separations were obtained using RP C-18 LUNA (150x4.6mm, 5 μm) column. The mobile phase consisted of acetonitrile and acidified water (pH 2.1) in the following proportion: 15:85, v/v for desloratadine, 25:75, v/v for ketotifen and olopatadine, 32:68, v/v for fexofenadine, 35:65, v/v for azelastine and loratadine, and 45:55, v/v for ebastine. All separations were obtained in less than 7.0 min. A prototype method was fully validated and applied in the assay of azelastine HCl in nasal solutions. The proposed methods for analysis of seven antihistamines are highly efficient, selective, and sensitive. Moreover, all methods can be considered excellent in terms of greenness, with total organic residue < 2.5 mL/analysis. An improved gradient method is also described for separation of azelastine HCl and its related impurities.
Vibration Suppression Control of a Flexible Gantry Crane System with Varying Rope Length
Authors: Nguyen Tung Lam , Do Trong Hieu , Nguyen Hong Quang
Published: February 2019

The paper presents a control approach to a flexible gantry crane system. From Hamilton’s extended principle the equations of motion that characterized coupled transverse-transverse motions with varying rope length of the gantry is obtained. The equations of motion consist of a system of ordinary and partial differential equations. Lyapunov’s direct method is used to derive the control located at the trolley end that can precisely position the gantry payload and minimize vibrations. The designed control is verified through extensive numerical simulations.
Global Fault-Tolerant Control of Underactuated Aerial Vehicles with Redundant Actuators
Authors: Yu Yushu , Dong Yiqun
Published: February 2019

In this paper, we consider the fault-tolerant control problem for aerial vehicles with redundant actuators. The redundant actuator brings difficulty in fault identification and isolation. Active fault-tolerant control is adopted in this paper as it can detect actuator fault. The entire proposed fault-tolerant control algorithm contains a baseline controller, the fault detection and isolation scheme, and the controller reconstruction module. A robust parameter identification method is designed to identify the torque and thrust generated by the actuators. The feasibility of isolating the fault for the redundant actuators is analyzed through mathematical proof. Through the analysis, the practical fault isolation algorithm is also proposed. Two typical aerial vehicles with redundant actuators, an eight-rotor aircraft and a hexa-rotor aircraft, are adopted in numerical simulations to verify the effectiveness of the proposed fault-tolerant control approach.
A Phase I, Open-Label, Multicenter, Dose-escalation Study of the Oral Selective FGFR Inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene Alterations
Authors: Voss Martin H. , Hierro Cinta , Heist Rebecca S. , Cleary James M. , Meric-Bernstam Funda , Tabernero Josep , Janku Filip , Gandhi Leena , Iafrate A. John , Borger Darrell R. , Ishii Nobuya , Hu Youyou , Kirpicheva Yulia , Nicolas-Metral Valerie , Pokorska-Bocci Anna , Vaslin Chessex Anne , Zanna Claudio , Flaherty Keith T. , Baselga Jose
Published: February 2019

Purpose:

To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor.

Patients and Methods:

This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1–3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks.

Results:

A total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with FGFR fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of ≤30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day.

Conclusions:

Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.
Bad to the Bone: The Role of the Insulin-Like Growth Factor Axis in Osseous Metastasis
Authors: Rieunier Guillaume , Wu Xiaoning , Macaulay Valentine M. , Lee Adrian V. , Weyer-Czernilofsky Ulrike , Bogenrieder Thomas
Published: February 2019

Bone metastases are a frequent complication of cancer that are associated with considerable morbidity. Current treatments may temporarily palliate the symptoms of bone metastases but often fail to delay their progression. Bones provide a permissive environment because they are characterized by dynamic turnover, secreting factors required for bone maintenance but also stimulating the establishment and growth of metastases. Insulin-like growth factors (IGF) are the most abundant growth factors in bone and are required for normal skeletal development and function. Via activation of the IGF-1 receptors (IGF-1R) and variant insulin receptors, IGFs promote cancer progression, aggressiveness, and treatment resistance. Of specific relevance to bone biology, IGFs contribute to the homing, dormancy, colonization, and expansion of bone metastases. Furthermore, preclinical evidence suggests that tumor cells can be primed to metastasize to bone by a high IGF-1 environment in the primary tumor, suggesting that bone metastases may reflect IGF dependency. Therapeutic targeting of the IGF axis may therefore provide an effective method for treating bone metastases. Indeed, anti–IGF-1R antibodies, IGF-1R tyrosine kinase inhibitors, and anti–IGF-1/2 antibodies have demonstrated antitumor activity in preclinical models of prostate and breast cancer metastases, either alone or in combination with other agents. Several studies suggest that such treatments can inhibit bone metastases without affecting growth of the primary tumor. Although previous trials of anti–IGF-1R drugs have generated negative results in unselected patients, these considerations suggest that future clinical trials of IGF-targeted agents may be warranted in patients with bone metastases.
Molecular Characterization of Prostate Cancer with Associated Gleason Score Using Mass Spectrometry Imaging
Authors: Randall Elizabeth C. , Zadra Giorgia , Chetta Paolo , Lopez Begona G.C. , Syamala Sudeepa , Basu Sankha S. , Agar Jeffrey N. , Loda Massimo , Tempany Clare M. , Fennessy Fiona M. , Agar Nathalie Y.R.
Published: February 2019

Diagnosis of prostate cancer is based on histologic evaluation of tumor architecture using a system known as the “Gleason score.” This diagnostic paradigm, while the standard of care, is time-consuming, shows intraobserver variability, and provides no information about the altered metabolic pathways, which result in altered tissue architecture. Characterization of the molecular composition of prostate cancer and how it changes with respect to the Gleason score (GS) could enable a more objective and faster diagnosis. It may also aid in our understanding of disease onset and progression. In this work, we present mass spectrometry imaging for identification and mapping of lipids and metabolites in prostate tissue from patients with known prostate cancer with GS from 6 to 9. A gradient of changes in the intensity of various lipids was observed, which correlated with increasing GS. Interestingly, these changes were identified in both regions of high tumor cell density, and in regions of tissue that appeared histologically benign, possibly suggestive of precancerous metabolomic changes. A total of 31 lipids, including several phosphatidylcholines, phosphatidic acids, phosphatidylserines, phosphatidylinositols, and cardiolipins were detected with higher intensity in GS (4+3) compared with GS (3+4), suggesting they may be markers of prostate cancer aggression. Results obtained through mass spectrometry imaging studies were subsequently correlated with a fast, ambient mass spectrometry method for potential use as a clinical tool to support image-guided prostate biopsy.

Implications:

In this study, we suggest that metabolomic differences between prostate cancers with different Gleason scores can be detected by mass spectrometry imaging.
Therapeutic Targeting of CD146/MCAM Reduces Bone Metastasis in Prostate Cancer
Authors: Zoni Eugenio , Astrologo Letizia , Ng Charlotte K.Y. , Piscuoglio Salvatore , Melsen Janine , Grosjean Joël , Klima Irena , Chen Lanpeng , Snaar-Jagalska Ewa B. , Flanagan Kenneth , van der Pluijm Gabri , Kloen Peter , Cecchini Marco G. , Kruithof-de Julio Marianna , Thalmann George N.
Published: February 2019

Prostate Cancer is the most common cancer and the second leading cause of cancer-related death in males. When prostate cancer acquires castration resistance, incurable metastases, primarily in the bone, occur. The aim of this study is to test the applicability of targeting melanoma cell adhesion molecule (MCAM; CD146) with a mAb for the treatment of lytic prostate cancer bone metastasis. We evaluated the effect of targeting MCAM using in vivo preclinical bone metastasis models and an in vitro bone niche coculture system. We utilized FACS, cell proliferation assays, and gene expression profiling to study the phenotype and function of MCAM knockdown in vitro and in vivo. To demonstrate the impact of MCAM targeting and therapeutic applicability, we employed an anti-MCAM mAb in vivo. MCAM is elevated in prostate cancer metastases resistant to androgen ablation. Treatment with DHT showed MCAM upregulation upon castration. We investigated the function of MCAM in a direct coculture model of human prostate cancer cells with human osteoblasts and found that there is a reduced influence of human osteoblasts on human prostate cancer cells in which MCAM has been knocked down. Furthermore, we observed a strongly reduced formation of osteolytic lesions upon bone inoculation of MCAM-depleted human prostate cancer cells in animal model of prostate cancer bone metastasis. This phenotype is supported by RNA sequencing (RNA-seq) analysis. Importantly, in vivo administration of an anti-MCAM human mAb reduced the tumor growth and lytic lesions. These results highlight the functional role for MCAM in the development of lytic bone metastasis and suggest that MCAM is a potential therapeutic target in prostate cancer bone metastasis.

Implications:

This study highlights the functional application of an anti-MCAM mAb to target prostate cancer bone metastasis.
Immune Profiling and Quantitative Analysis Decipher the Clinical Role of Immune-Checkpoint Expression in the Tumor Immune Microenvironment of DLBCL
Authors: Xu-Monette Ziju Y. , Xiao Min , Au Qingyan , Padmanabhan Raghav , Xu Bing , Hoe Nicholas , Rodríguez-Perales Sandra , Torres-Ruiz Raul , Manyam Ganiraju C. , Visco Carlo , Miao Yi , Tan Xiaohong , Zhang Hongwei , Tzankov Alexandar , Wang Jing , Dybkær Karen , Tam Wayne , You Hua , Bhagat Govind , Hsi Eric D. , Ponzoni Maurilio , Ferreri Andrés J.M. , Møller Michael B. , Piris Miguel A. , van Krieken J. Han , Winter Jane N. , Westin Jason R. , Pham Lan V. , Medeiros L. Jeffrey , Rassidakis George Z. , Li Yong , Freeman Gordon J. , Young Ken H.
Published: February 2019

PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for 13 types of cancers and are being studied in diffuse large B-cell lymphoma (DLBCL), the most common aggressive B-cell lymphoma. However, whether both PD-1 and CTLA-4 checkpoints are active and clinically significant in DLBCL is unknown. Whether PD-1 ligands expressed by tumor cells or by the microenvironment of DLBCL are critical for the PD-1 immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with de novo DLBCL using a MultiOmyx immunofluorescence platform and simultaneously quantitated expression/coexpression of 13 immune markers to identify prognostic determinants. In both training and validation cohorts, results demonstrated a central role of the tumor immune microenvironment, and when its functionality was impaired by deficiency in tumor-infiltrating T cells and/or natural killer cells, high PD-1 expression (but not CTLA-4) on CD8+ T cells, or PD-L1 expression on T cells and macrophages, patients had significantly poorer survival after rituximab–CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. In contrast, tumor-cell PD-L2 expression was associated with superior survival, as well as PD-L1+CD20+ cells proximal (indicates interaction) to PD-1+CD8+ T cells in patients with low PD-1+ percentage of CD8+ T cells. Gene-expression profiling results suggested the reversibility of T-cell exhaustion in PD-1+/PD-L1+ patients with unfavorable prognosis and implication of LILRA/B, IDO1, CHI3L1, and SOD2 upregulation in the microenvironment dysfunction with PD-L1 expression. This study comprehensively characterized the DLBCL immune landscape, deciphered the differential roles of various checkpoint components in rituximab–CHOP resistance in DLBCL patients, and suggests targets for PD-1/PD-L1 blockade and combination immunotherapies.
Análise da resposta cartesiana acerca de como pode a alma mover o corpo na Correspondência com Elisabeth
Authors: Laporta Beatriz
Published: February 2019

Trata-se de abordar uma das questões com mais desdobramentos que já foram dirigidas à filosofia cartesiana, a saber, como pode a alma mover o corpo, na carta endereçada a Elisabeth de 21 de maio de 1643. Issoexige uma reflexão sobre como Descartes estabeleceu com tanta segurança a ordem das razões nas Meditações, e como colocou a união substancial dentro dela, pois na Correspondência afirmou-se que essa união não pode ser entendida pela razão.
O conceito de substância e seus desdobramentos: uma visão geral da metafísica de Leibniz
Authors: Frohlich Victor
Published: February 2019

Pretende-se investigar os elementos centrais do conceito de substância no pensamento de Gottfried Wilhelm Leibniz, tomando a complexidade de tal conceito e suas diversas formulações como prerrogativa para analisar os diversos textos do autor, observando os caminhos argumentativos trilhados nessas obras e o desenvolvimento de outros de seus temas centrais e conceitos chaves — notavelmente, a harmonia preestabelecida e o papel de Deus em sua cosmologia. Parte-se, também, da premissa de que a heterogeneidade e a polissemia conceitual do autor podem ser tomadas como qualidades de um sistema de particular riqueza filosófica, que não se apresenta em um único texto dito “canônico” do autor.
Maria Cora, de Machado de Assis, e o primado da vontade sobre o intelecto em Arthur Schopenhauer
Authors: Souza Allan Alves de
Published: February 2019

Este artigo pretende analisar os tormentos psíquicos do protagonista de Maria Cora (1906), de Machado de Assis, a partir da ótica da filosofia de Arthur Schopenhauer. Exímio leitor do filósofo alemão e criador de uma literatura que suporta investigação filosófica, analisaremos de que forma os aspectos implícitos no sofrimento da personagem poderiam ser transpostos à literatura machadiana por meio das reflexões metafísicas e psicológicas de Schopenhauer.
A verdade como poder, o poder como verdade: os procedimentos da subjetivação cristã sob a ótica de Michel Foucault - parte 1
Authors: Teixeira Lucas Carvalho Lima
Published: February 2019

O objetivo de uma primeira dimensão deste trabalho é perscrutar a análise feita por Foucault acerca do arcabouço prático-discursivo presente na montagem do sujeito cristão tal como elaborado por Tertuliano e Cassiano. As investigações do pensador francês, especialmente aquelas encontradas em Do governo dos vivos (1979-1980), convidam o leitor a conceber a produção do poder não como instância abstrata e soberana ao modelo tradicional, porém como manifestação contínua e circular da própria verdade, verdade que produz e expressa, por sua vez, a constituição subjetiva mesma dos homens. Para Foucault, portanto, o poder no Ocidente foi edificado à maneira de um regime de verdade, ou, ainda, um regime de veridição. Aqui, a manifestação do poder é imediatamente uma manifestação da verdade e da subjetividade. Que alcance têm, na tradição ocidental, as raízes da civilização moderna? Que tipo de procedimentos e dispositivos estão implicados em sua atividade? Buscaremos as respostas para esses questionamentos, no nível de fundamentação, nas malhas da subjetivação cristã; a expressão contemporânea deste dispositivo, contudo, restará a uma segunda dimensão deste trabalho, pautada no encontro com as pesquisas de Nascimento da biopolítica (1978-1979).
Direct Visualization of the His Bundle Pacing Lead Placement by 3-Dimensional Electroanatomic Mapping
Authors: Orlov Michael V. , Koulouridis Ioannis , Monin AJ , Casavant David , Maslov Mikhail , Erez Aharon , Hicks Amy , Aoun Joe , Wylie John V.
Published: February 2019

Background:

His bundle pacing (HBP) remains technically challenging and is currently guided by electrograms and 2-dimensional fluoroscopy. Our objective was to describe a new technique for HBP directly guided by electroanatomic mapping (EAM).

Methods:

Twenty-eight patients were included. The atrioventricular septum was mapped via EAM, and His bundle (HB) electrograms, selective, and nonselective HB capture sites were tagged. Pacing leads were connected to EAM, navigated to tagged HB target sites and deployed. Intracardiac electrograms and pacing parameters were recorded. Lead location was tagged on the cloud of HB sites, which was divided into 3 arbitrary segments. In 5 patients, atrioventricular nodal ablation was performed with direct visualization of the HBP lead by EAM.

Results:

Reproducible navigation of the pacing lead to predetermined HBP locations guided by EAM was achieved in all patients. The lead was successfully deployed in 25 patients. HB cloud area was 360 (212) mm
2
. There was no correlation between HBP threshold and lead location on the His cloud. The intracardiac electrograms atrial/ventricular ratio at the lead deployment site correlated with its EAM position on the His cloud (
P
=0.045). Procedure, fluoroscopy, and mapping times were 116.0 (38.8), 8.6 (6.3), and 9.0 (11.4) minutes, respectively. HBP threshold at implant was 1.5 (2.3) V at 1.5 (1.0) ms. Distance between HB lead and ablation sites was 10.0 (1.3) mm in patients undergoing atrioventricular nodal ablation.

Conclusions:

Direct guidance of HBP by EAM allows for direct visualization of the pacing lead on the HB cloud and reproducible navigation to predetermined HB capture sites. Intracardiac electrograms atrial/ventricular ratio at the lead deployment site correlates with His cloud location. EAM can be applied during standard HBP procedures or combined with atrioventricular nodal ablation.
Genomic Reorganization of Lamin-Associated Domains in Cardiac Myocytes Is Associated With Differential Gene Expression and DNA Methylation in Human Dilated Cardiomyopathy
Authors: Cheedipudi Sirisha M. , Matkovich Scot J. , Coarfa Cristian , Hu Xin , Robertson Matthew J. , Sweet Mary , Taylor Matthew , Mestroni Luisa , Cleveland Joseph , Willerson James T. , Gurha Priyatansh , Marian Ali J.
Published: February 2019

Rationale:

LMNA (Lamin A/C), a nuclear membrane protein, interacts with genome through lamin-associated domains (LADs) and regulates gene expression. Mutations in the
LMNA
gene cause a diverse array of diseases, including dilated cardiomyopathy (DCM). DCM is the leading cause of death in laminopathies.

Objective:

To identify LADs and characterize their associations with CpG methylation and gene expression in human cardiac myocytes in DCM.

Methods and Results:

LMNA chromatin immunoprecipitation-sequencing, reduced representative bisulfite sequencing, and RNA-sequencing were performed in 5 control and 5 LMNA-associated DCM hearts. LADs were identified using enriched domain detector program. Genome-wide 331±77 LADs with an average size of 2.1±1.5 Mbp were identified in control human cardiac myocytes. LADs encompassed ≈20% of the genome and were predominantly located in the heterochromatin and less so in the promoter and actively transcribed regions. LADs were redistributed in DCM as evidenced by a gain of 520 and loss of 149 genomic regions. Approximately, 4500 coding genes and 800 long noncoding RNAs, whose levels correlated with the transcript levels of coding genes in cis, were differentially expressed in DCM. TP53 (tumor protein 53) was the most prominent among the dysregulated pathways. CpG sites were predominantly hypomethylated genome-wide in controls and DCM hearts, but overall CpG methylation was increased in DCM. LADs were associated with increased CpG methylation and suppressed gene expression. Integrated analysis identified genes whose expressions were regulated by LADs or CpG methylation, or by both, the latter pertained to genes involved in cell death, cell cycle, and metabolic regulation.

Conclusions:

LADs encompass ≈20% of the genome in human cardiac myocytes comprised several hundred coding and noncoding genes. LADs are redistributed in LMNA-associated DCM in association with markedly altered CpG methylation and gene expression. Thus, LADs through genomic alterations contribute to the pathogenesis of DCM in laminopathies.
Drawing to Extend Waddington's Epigenetic Landscape
Authors: Anderson Gemma , Verd Berta , Jaeger Johannes
Published: February 2019

The authors, an artist, a mathematician and a biologist, describe their collaboration examining the potential of drawing to further the understanding of biological processes. As a case study, this article considers C.H. Waddington's powerful visual representation of the “epigenetic landscape,” whose purpose is to unify research in genetics, embryology and evolutionary biology. The authors explore the strengths and limitations of Waddington's landscape and attempt to transcend the latter through a collaborative series of exploratory images. Through careful description of this drawing process, the authors touch on its epistemological consequences for all participants.