bluuebunny/crossref_metadata_2025 huggingface dataset:
Review of Nonlinear Analysis and Modeling of Steel and Composite Structures
Authors: Thai Huu-Tai , Nguyen Trung-Kien , Lee Seunghye , Patel Vipulkumar Ishvarbhai , Vo Thuc P.
Published: March 2020

Structural steel frames exhibit significantly geometric and material nonlinearities which can be captured using the second-order inelastic analysis, also known as advanced analysis. Current specifications of most modern steel design codes, e.g. American code AISC360, European code EC3, Chinese code GB50017 and Australian code AS4100 permit the use of advanced analysis methods for the direct design of steel structures to avoid tedious member capacity checks. In the past three decades, a huge number of advanced analysis and modeling methods have been developed to predict the behavior of steel and composite frames. This paper presents a comprehensive review of their developments, which focus on beam-column elements with close attention to the way to capture geometric and material nonlinearity effects. A brief outline of analysis methods and analysis tools for frames was presented in the initial part of the paper. This was followed by a discussion on the development of displacement-based, force-based and mixed beam elements with distributed plasticity and concentrated plasticity models. The modeling of frames subjected to fire and explosion was also discussed. Finally, a review of the beam-column models for composite structures including concrete-filled steel tubular (CFST) columns, composite beams and composite frames was presented.
Dynamics of drainage under stochastic rainfall in river networks
Authors: Ramirez Jorge M , Constantinescu Corina
Published: March 2020

We consider a linearized dynamical system modeling the flow rate of water along the rivers and hillslopes of an arbitrary watershed. The system is perturbed by a random rainfall in the form of a compound Poisson process. The model describes the evolution, at daily time scales, of an interconnected network of linear reservoirs and takes into account the differences in flow celerity between hillslopes and streams as well as their spatial variation. The resulting stochastic process is a piece-wise deterministic Markov process of the Orstein–Uhlembeck type. We provide an explicit formula for the Laplace transform of the invariant density of streamflow in terms of the geophysical parameters of the river network and the statistical properties of the precipitation field. As an application, we include novel formulas for the invariant moments of the streamflow at the watershed’s outlet, as well as the asymptotic behavior of extreme discharge events, and conditions for the statistical scaling of streamflow with respect to Horton order.
Strong solutions to the density-dependent incompressible Cahn–Hilliard–Navier–Stokes system
Authors: Zhao Xiaopeng
Published: March 2020

We study the density-dependent incompressible Cahn–Hilliard–Navier–Stokes system, which describes a two-phase flow of two incompressible fluids with different densities. We establish the local existence and uniqueness of strong solutions to the initial value problem in a bounded domain, when the initial density function enjoys a positive lower bound.
Edge version of metric dimension for the families of grid graphs and generalized prism graphs
Authors: Nasir Ruby , Zahid Zohaib , Zafar Sohail
Published: March 2020

The minimum edge version of metric basis is the smallest set [Formula: see text] of edges in a connected graph [Formula: see text] such that for every pair of edges [Formula: see text] [Formula: see text][Formula: see text] there exists an edge [Formula: see text] [Formula: see text][Formula: see text] for which [Formula: see text] [Formula: see text] [Formula: see text] holds. In this paper, the families of grid graphs and generalized prism graphs have been studied for edge version of metric dimension. Edge version of metric dimension is found to be constant for both families of graphs.
Model-Checking on Ordered Structures
Authors: Eickmeyer Kord , Heuvel Jan van den , Kawarabayashi Ken-Ichi , Kreutzer Stephan , Mendez Patrice Ossona De , Pilipczuk Michał , Quiroz Daniel A. , Rabinovich Roman , Siebertz Sebastian
Published: March 2020

We study the model-checking problem for first- and monadic second-order logic on finite relational structures. The problem of verifying whether a formula of these logics is true on a given structure is considered intractable in general, but it does become tractable on interesting classes of structures, such as on classes whose Gaifman graphs have bounded treewidth. In this article, we continue this line of research and study model-checking for first- and monadic second-order logic in the presence of an ordering on the input structure. We do so in two settings: the general ordered case, where the input structures are equipped with a fixed order or successor relation, and the order-invariant case, where the formulas may resort to an ordering, but their truth must be independent of the particular choice of order. In the first setting we show very strong intractability results for most interesting classes of structures. In contrast, in the order-invariant case we obtain tractability results for order-invariant monadic second-order formulas on the same classes of graphs as in the unordered case. For first-order logic, we obtain tractability of successor-invariant formulas on classes whose Gaifman graphs have bounded expansion. Furthermore, we show that model-checking for order-invariant first-order formulas is tractable on coloured posets of bounded width.
A Memristor-Based Compressive Sampling Encoder with Dynamic Rate Control for Low-Power Video Streaming
Authors: Qian Fengyu , Gong Yanping , Wang Lei
Published: March 2020

Image sensors are widely used in various applications. With the increasing requirement for high resolutions and frame rates, power consumption has become a critical issue, which limits the use of image sensors in mobile devices and IoT applications. Compressive sensing (CS) techniques can achieve a sub-Nyquist sampling rate to reduce the power consumption in hardware circuits. Currently, most compressive measurements are implemented in digital CMOS circuits, leading to high hardware complexity and power consumption, as well as the limited sampling speed. Furthermore, CS applications with large image sizes are usually based on block-wise methods, which require real-time rate controls during practical operations. In this article, we propose a memristor-based CS encoder that can be integrated with conventional image sensors to achieve high performance with low power consumption and hardware overheads. A self-adaptive compressing rate control mechanism is also devised to maximize the performance of the proposed technique. Simulation results of wireless video streaming demonstrate the advantages of the proposed technique.
Preliminary results from a survey to measure the benefits of accessibility and universal design topics in course curricula
Authors: Kramer Howard
Published: March 2020

This paper discusses the preliminary results from a national survey conducted by the University of Colorado Boulder to gauge the student benefits of taking accessibility and Universal Design topics in post-secondary courses. About a dozen programs and schools with a focus on Computer Science, Digital Media, Environmental Design, or other technical or design-related programs, agreed to distribute the survey to their current students and recent graduates. To date we have received 114 responses. Students who had taken these topics overwhelmingly rated these topics as either crucial (48.3%) or very valuable (31.7%). The results of this preliminary survey support the idea that including courses with these topics has notable work or career benefits, including finding employment. 42% of those taking courses with these topics reported some type of benefit in the area of work. Five individuals (or about 10%) of individuals who took these topics mentioned either that it specifically helped or possibly helped them to obtain a particular job or that it directed their career path.
Usability evaluation of captions for people who are deaf or hard of hearing
Authors: Kafle Sushant , Huenerfauth Matt
Published: March 2020

Many Deaf and Hard-of-Hearing (DHH) individuals across the world benefit from various captioning services for accessing information existing in the form of speech. Today, the Automatic Speech Recognition (ASR) technology has the potential to replace the existing human-provided services for captioning due to their lowered cost of operation and ever-increasing accuracy. However, as with most automatic systems, ASR technology is still not fully perfect --- which leads to issues in terms of its trust and acceptance when focusing on building a human-free service of communication for these users. Thus, there is a need for evaluating the usability these systems with the users before deploying them into the real-world. Yet, most researchers lack access to sufficient DHH users for extrinsic, empirical studies of these automatic captioning systems. This articles presents our work on the development of automatic caption quality evaluation metric which we design and validate through studies and real-world observations with DHH users.
Early adopters of a low vision head-mounted assistive technology
Authors: Zolyomi Annuska , Snyder Jaime
Published: March 2020

Early adopters of emerging technology offer unique insights into the benefits and hurdles of using technology in daily life. We interviewed early adopters of a head-mounted assistive device for low vision called eSight 2.0 and client-facing employees of the company that produced the device in order to better understand the ways that daily use of the technology can help us understand social implications of digitally enhanced vision. These interviews probed personal and professional experiences for social and emotional impacts associated with adoption of this type of low-vision assistive technology. From our interviews, four themes emerged: 1) assessing the value of assistive technology in real life, 2) negotiating social engagement, 3) boundaries of sight, and 4) attitudes toward and expectations of technology. We introduce the concept of multiplicities of vision to highlight that sight is not one thing for all people in all situations. We argue that individuals with low vision who use assistive technology have skilled vision that is neither fully-human nor fully-digital, but rather, assembled through a combination of social and technical affordances. We propose that instead of seeing low-vision users through a deficit model of sight, human-computer interaction designers have more to gain by viewing people with low vision as individuals with expertise in skilled vision that is both socially and technologically mediated.
Plea Bargaining, Conviction Without Trial, and the Global Administratization of Criminal Convictions
Authors: Langer Máximo
Published: March 2020

This article documents the diffusion of plea bargaining and other mechanisms to reach criminal convictions without a trial and argues that their spread implies what this article terms an administratization of criminal convictions in many corners of the world. Criminal convictions have been administratized in two ways: ( a) Trial-avoiding mechanisms have given a larger role to nonjudicature, administrative officials in the determination of who gets convicted and for which crimes, and ( b) these decisions are made in proceedings that do not include a trial with its attached defendants’ rights. The article also proposes a way this phenomenon could be quantitatively measured by articulating the rate of administratization of criminal convictions, a metric to allow for comparison among different jurisdictions. The article then presents cross-national data from 26 jurisdictions on their rate of administratization of criminal convictions and different hypotheses that may help explain variation across jurisdictions on this rate.
The effects of estradiol are modulated in a tissue-specific manner in mice with inducible inactivation of ERα after sexual maturation
Authors: Ohlsson Claes , Farman Helen H. , Gustafsson Karin L. , Wu Jianyao , Henning Petra , Windahl Sara H. , Sjögren Klara , Gustafsson Jan-Åke , Movérare-Skrtic Sofia , Lagerquist Marie K.
Published: March 2020

Mouse models with lifelong inactivation of estrogen receptor-α (ERα) show that ERα is the main mediator of estrogenic effects in bone, thymus, uterus, and fat. However, ERα inactivation early in life may cause developmental effects that confound the adult phenotypes. To address the specific role of adult ERα expression for estrogenic effects in bone and other nonskeletal tissues, we established a tamoxifen-inducible ERα-inactivated model by crossing CAGG-Cre-ER and ERαflox/flox mice. Tamoxifen-induced ERα inactivation after sexual maturation substantially reduced ERα mRNA levels in cortical bone, trabecular bone, thymus, uterus, gonadal fat, and hypothalamus, in CAGG-Cre-ERαflox/flox (inducible ERαKO) compared with ERαflox/flox (control) mice. 17β-estradiol (E2) treatment increased trabecular bone volume fraction (BV/TV), cortical bone area, and uterine weight, while it reduced thymus weight and fat mass in ovariectomized control mice. The estrogenic responses were substantially reduced in inducible ERαKO mice compared with control mice on BV/TV (−67%), uterine weight (−94%), thymus weight (−70%), and gonadal fat mass (−94%). In contrast, the estrogenic response on cortical bone area was unaffected in inducible ERαKO compared with control mice. In conclusion, using an inducible ERαKO model, not confounded by lack of ERα during development, we demonstrate that ERα expression in sexually mature female mice is required for normal E2 responses in most, but not all, tissues. The finding that cortical, but not trabecular bone, responds normally to E2 treatment in inducible ERαKO mice strengthens the idea of cortical and trabecular bone being regulated by estrogen via different mechanisms.
Effect of Qihuang Decoction Combined with Enteral Nutrition on Postoperative Gastric Cancer of Nutrition and Immune Function
Authors: Yu Qing-sheng , Zheng Zhou , Peng Hui , Shen Yi , Liu Ju-da , Zhou Fu-hai
Published: March 2020

Objective. Early nutritional support in patients with gastric cancer can improve their nutritional status, but the impact on immune function has not been confirmed. This study aimed to analyze the effects of Qihuang decoction combined with enteral nutrition on nutrition and the immune function of postoperative gastric cancer. Methods. 120 patients with postoperative gastric cancer in the study group and 117 in the control group were selected as the study subjects from our hospital at random. Indications of nutrition and immune and the rates of complications were compared the day before surgery and 1, 3, 7, and 14 days after surgery. Results. Indications of nutrition except hemoglobin (HB) in the study group were significantly higher than those before operation and the albumin (ALB) and prealbumin (TP) were significantly increased 7 and 14 days after surgery (P < 0.001 and P < 0.001 versus P < 0.001 and P < 0.001) and the protein (PA) 3, 7, and 14 days after surgery (P = 0.011, P = 0.002, and P = 0.022) in the study group compared to those in the control group. Cellular and humoral immunity indications in the study group are significantly higher than those before operation compared to those in the control group, and the CD3+, CD4+, and CD4+/CD8+ were significantly increased 7 and 14 days after surgery (P = 0.027 and P < 0.001 versus P = 0.008 and P < 0.001 versus P = 0.010 and P < 0.001) and IgA, IgG, and IgM 3, 7, and 14 days after surgery in the study group (P < 0.001, P < 0.001, and P < 0.001 versus P < 0.001, P < 0.002, and P < 0.001 versus P < 0.001, P < 0.001, and P < 0.001). The complications such as abdominal, lung, wound, and urinary infection were also significantly decreased (; ; ; ). Conclusions. Qihuang decoction combined with enteral nutrition can promote the absorption of enteral nutrition with improving the immune and reducing complications of infection.
Urinary I-FABP, L-FABP, TFF-3, and SAA Can Diagnose and Predict the Disease Course in Necrotizing Enterocolitis at the Early Stage of Disease
Authors: Coufal Stepan , Kokesova Alena , Tlaskalova-Hogenova Helena , Frybova Barbora , Snajdauf Jiri , Rygl Michal , Kverka Miloslav
Published: March 2020

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease affecting mainly preterm newborns. It is characterized by unexpected onset and rapid progression with specific diagnostic signs as pneumatosis intestinalis or gas in the portal vein appearing later in the course of the disease. Therefore, we analyzed diagnostic and prognostic potential of the markers of early NEC pathogenesis, such as excessive inflammatory response (serum amyloid A (SAA)) and gut epithelium damage (intestinal and liver fatty acid-binding protein (I-FABP and L-FABP, respectively) and trefoil factor-3 (TFF-3)). We used ELISA to analyze these biomarkers in the urine of patients with suspected NEC, either spontaneous or surgery-related, or in infants without gut surgery (controls). Next, we compared their levels with the type of the disease (NEC or sepsis) and its severity. Already at the time of NEC suspicion, infants who developed NEC had significantly higher levels of all tested biomarkers than controls and higher levels of I-FABP and L-FABP than those who will later develop sepsis. Infants who will develop surgery-related NEC had higher levels of I-FABP and L-FABP than those who will develop sepsis already during the first 6 hours after the abdominal surgery. I-FABP was able to discriminate between infants who will develop NEC or sepsis and the SAA was able to discriminate between medical and surgical NEC. Moreover, the combination of TFF-3 with I-FABP and SAA could predict pneumatosis intestinalis, and the combination of I-FABP, L-FABP, and SAA could predict gas in the portal vein or long-term hospitalization and low SAA predicts early full enteral feeding. Thus, these biomarkers may be useful not only in the early, noninvasive diagnostics but also in the subsequent NEC management.
The Diethylcarbamazine Delays and Decreases the NETosis of Polymorphonuclear Cells of Humans with DM Type 2
Authors: Segoviano-Ramirez Juan C. , Lopez-Altamirano Daniel F. , Garcia-Juarez Jaime , Aguirre-Garza Juan E. S. , Cárdenas-Estrada Eloy , Ancer-Rodriguez Jesús
Published: March 2020

Type 2 diabetes mellitus (DM2) is a disease that reports high morbidity and mortality rates worldwide. Between its complications, one of the most important is the development of plantar ulcers. The role of the polymorphonuclear cells (PMNs) is affected by metabolic diseases like DM2. Fifteen years ago, reports about a new mechanism of innate immune response where PMNs generate some kind of webs with their chromatin were published. This mechanism was called NETosis. Also, some researchers have demonstrated that NETosis is responsible for the delay of the ulcer healing both in patients with DM2 and in animal models of DM2. Purified PMNs from healthy and DM2 human volunteers were incubated with diethylcarbamazine (DEC) and then induced to NETosis using phorbol 12-myristate 13-acetate (PMA). In a randomized blind study model, the NETosis was documented by confocal microscopy. On microphotographs, the area of each extracellular neutrophil trap (NET) formed at different times after stimuli with PMA was bounded, and the intensity of fluorescence (IF) from the chromatin dyed with 4′,6-diamidino-2-phenylindole dihydrochloride (DAPI) was quantified. PMNs from healthy volunteers showed the development of NETs at expected times according to the literature. The same phenomenon was seen in cultures of PMNs from metabolically controlled DM2 volunteers. The use of DEC one hour before of the challenge with PMA delayed the NETosis in both groups. The semiquantitative morphometric analysis of the IF from DAPI, as a measure of PMN’s capacity to forming NETs, is consistent with these results. The ANOVA test demonstrated that NETosis was lower and appeared later than expected time, both in PMNs from healthy (p≤0.000001) and from DM2 (p≤0.000477) volunteers. In conclusion, the DEC delays and decreases the NETosis by PMNs from healthy as well as DM2 people.
Validation of the Arabic Version of the Epworth Sleepiness Scale among the Yemeni Medical Students
Authors: Attal Bothaina Ahemd , Al-Ammar Fawziah Kassim , Bezdan Mohammed
Published: March 2020

The study was conducted with the aim to assess the psychometric measures of an adapted Arabic version of the Epworth Sleepiness Scale (ESS) among medical students at Sana’a University, Yemen. The cross-sectional study targeted 360 students (males: 176; females: 184) from the preclinical 3rd year (N: 197) and the final clinical year (N: 163). Participants self-filled an Arabic and slightly modified version of the 8-item Epworth Sleepiness Scale. Exploratory Principal Component Analysis (PCA) and Confirmatory Factor Analyses (CFA) were conducted on two equal subsets of the sample (N: 180 each). The PCA yielded a two-dimension model subsequently confirmed by factor analysis. The first dimension was grouped on three items while the second dimension had five items reflecting the respondents’ propensity to sleep during “interactive situations” and “sitting and lying,” respectively. The model had an acceptable goodness of fit measures for the overall ESS (CMINDF=2.362, CFI=0.91, IFI=0.92) and acceptable reliability indicators (factor 1 α=0.65, factor 2 α=0.62). However, due to weak variance explanation (0.07) of item 6 (sitting and talking) in factor 1, analysis was repeated excluding this item. The 7-item model was also two-dimensional, valid, and reliable. The reliability indicators were acceptable with α=0.65 for factor 1 (4 items of interactive situations) and 0.62 for factor 2 (3 items of sitting) and overall α=0.68. Overall, the ESS is a useful tool. Factor analysis produced a two-factor model of 7 items with good validity and reasonable reliability that can be used in diagnosing daytime sleepiness among young Yemeni adults.
Hemodialysis Increases the Risk of Lower Gastrointestinal Bleeding and Angiodysplasia Bleeding: A Nationwide Population Study
Authors: Tsai Tzung-Jiun , Chen Wen-Chi , Huang Yu-Tung , Yang Yi-Hsin , Feng I-Che , Wu Wen-Chieh , Hu Huang-Ming , Wu Deng-Chyang , Hsu Ping-I
Published: March 2020

Background. Patients with chronic kidney disease (CKD) with or without hemodialysis were considered to have bleeding tendency and higher risk for gastrointestinal (GI) bleeding. Previous studies had documented that hemodialysis may increase the gastroduodenal ulcer bleeding. Few studies evaluated the relationship between CKD and lower GI bleeding. Materials and Methods. An observational cohort study design was conducted. The end-stage renal disease (ESRD) patients receiving regular hemodialysis (dialysis CKD), CKD patients without dialysis (dialysis-free CKD), and controls were selected from 1 million randomly sampled subjects in the National Health Insurance Research Database of Taiwan. These three group subjects were matched by age, sex, comorbidity, and enrollment time in a 1 : 2 : 2 ratio. The Cox proportional hazard regression models were used to identify the potential risk factors for lower gastrointestinal bleeding. Results. Dialysis CKD patients (n=574) had a higher incidence of lower GI bleeding than dialysis-free CKD patients (n=1148) and control subjects (n=1148) (12.9% vs. 3.6% and 2.8%; both P<0.001). Multivariate analysis showed that extreme old age (age≥85), male gender, dialysis-free CKD, and dialysis CKD were independent factors of lower GI bleeding. Additionally, dialysis CKD patients also had a higher incidence of angiodysplasia bleeding compared to dialysis-free CKD patients and control subjects (1.1% vs. 0.1% and 0.1%, respectively; both P=0.003). Conclusion. Hemodialysis may have higher risk of lower GI bleeding and angiodysplasia bleeding.
The Association of Sleep Duration and the Use of Electronic Cigarettes, NHANES, 2015-2016
Authors: Wiener R. Constance , Waters Christopher , Bhandari Ruchi , Trickett Shockey Alcinda K. , Alshaarawy Omayma
Published: March 2020

Introduction. The unknown effects of electronic cigarettes are public health concerns. One potential effect of electronic cigarette fluid constituents, such as nicotine, may influence sleep. The purpose of this study is to determine if there is an association between sleep duration and electronic cigarette use. Methods. A retrospective, cross-sectional study was conducted using National Health and Nutrition Examination Survey (NHANES) 2015-2016. Variables of interest included responses to questions concerning electronic cigarette use, hours of sleep, and other variables associated with sleep. Data analyses were conducted with the Rao-Scott chi square test and logistic regression. Results. This study was conducted on 2889 participants, aged 18-65 years, of whom 50.7% were female. Using a bivariate analyses of electronic cigarette usage and sleep duration, participants who never used an electronic cigarette were more likely to have appropriate sleep durations as compared with participants who were currently using electronic cigarettes (P<0.0001). After adjusting for sociodemographic variables and cigarette smoking, current electronic cigarette use was associated with higher odds of less sleep duration (adjusted odds ratio=1.82; 95% CI: 1.18, 2.79; P=0.0075). Conclusions. Participants currently using electronic cigarettes are more likely to have less sleep as compared to participants who have never used electronic cigarettes. Implications. With sleep time duration being a major factor for proper body function and repair, this study can serve as confirmation that the use of electronic cigarettes is not a harmless health behavior.
Monosomic Loss of MIR15A/MIR16-1 Is a Driver of Multiple Myeloma Proliferation and Disease Progression
Authors: Chesi Marta , Stein Caleb K. , Garbitt Victoria M. , Sharik Meaghen E. , Asmann Yan W. , Bergsagel Matteo , Riggs Daniel L. , Welsh Seth J. , Meermeier Erin W. , Kumar Shaji K. , Braggio Esteban , Bergsagel P. Leif
Published: March 2020

The most common genetic abnormality in multiple myeloma is the deletion of chromosome 13, seen in almost half of newly diagnosed patients. Unlike chronic lymphocytic leukemia, where a recurrent minimally deleted region including MIR15A/MIR16-1 has been mapped, the deletions in multiple myeloma predominantly involve the entire chromosome and no specific driver gene has been identified. Additional candidate loci include RB1 and DIS3, but while biallelic deletion of RB1 is associated with disease progression, DIS3 is a common essential gene and complete inactivation is not observed. The Vk*MYC transgenic mouse model of multiple myeloma spontaneously acquires del(14), syntenic to human chromosome 13, and Rb1 complete inactivation, but not Dis3 mutations. Taking advantage of this model, we explored the role in multiple myeloma initiation and progression of two candidate loci on chromosome 13: RB1 and MIR15A/MIR16-1. Monoallelic deletion of Mir15a/Mir16-1, but not Rb1, was sufficient to accelerate the development of monoclonal gammopathy in wild-type mice and the progression of multiple myeloma in Vk*MYC mice, resulting in increased expression of Mir15a/Mir16-1 target genes and plasma cell proliferation, which was similarly observed in patients with multiple myeloma.

Significance:

In the absence of a defined, minimally deleted region the significance of del(13) in multiple myeloma has remained controversial. Here we show that haploinsufficiency of Mir15a/Mir16-1, but not Rb1, upregulates the cell cycle–regulatory network, inducing monoclonal gammopathy in mice and promoting multiple myeloma progression in both mice and men.

See related commentary by Walker, p. 16.

This article is highlighted in the In This Issue feature, p. 5
Harmonizing Cell-Free DNA Collection and Processing Practices through Evidence-Based Guidance
Authors: Greytak Sarah R. , Engel Kelly B. , Parpart-Li Sonya , Murtaza Muhammed , Bronkhorst Abel J. , Pertile Mark D. , Moore Helen M.
Published: March 2020

Circulating cell-free DNA (cfDNA) is rapidly transitioning from discovery research to an important tool in clinical decision making. However, the lack of harmonization of preanalytic practices across institutions may compromise the reproducibility of cfDNA-derived data and hamper advancements in cfDNA testing in the clinic. Differences in cellular genomic contamination, cfDNA yield, integrity, and fragment length have been attributed to different collection tube types and anticoagulants, processing delays and temperatures, tube agitation, centrifugation protocols and speeds, plasma storage duration and temperature, the number of freeze-thaw events, and cfDNA extraction and quantification methods, all of which can also ultimately impact subsequent downstream analysis. Thus, there is a pressing need for widely applicable standards tailored for cfDNA analysis that include all preanalytic steps from blood draw to analysis. The NCI's Biorepositories and Biospecimen Research Branch has developed cfDNA-specific guidelines that are based upon published evidence and have been vetted by a panel of internationally recognized experts in the field. The guidelines include optimal procedures as well as acceptable alternatives to facilitate the generation of evidence-based protocols by individual laboratories and institutions. The aim of the document, which is entitled “Biospecimen Evidence-based Best Practices for Cell-free DNA: Biospecimen Collection and Processing,” is to improve the accuracy of cfDNA analysis in both basic research and the clinic by improving and harmonizing practices across institutions.
Phase I Dose-Escalation and -Expansion Study of Telisotuzumab (ABT-700), an Anti–c-Met Antibody, in Patients with Advanced Solid Tumors
Authors: Strickler John H. , LoRusso Patricia , Salgia Ravi , Kang Yoon-Koo , Yen Chia Jui , Lin Chia-Chi , Ansell Peter , Motwani Monica , Wong Shekman , Yue Huibin , Wang Lan , Reilly Edward , Afar Daniel , Naumovski Louie , Ramanathan Ramesh K.
Published: March 2020

This first-in-human phase I study evaluated the pharmacokinetics, safety, and preliminary efficacy of telisotuzumab, formerly called ABT-700, an antagonistic antibody directed against c-Met. For dose escalation (3+3 design), 3 to 6 patients with advanced solid tumors were enrolled into four dose cohorts (5–25 mg/kg). In the dose-expansion phase, a subset of patients was prospectively selected for MET amplification (FISH screening). Patients received telisotuzumab intravenously on day 1 every 21 days. For dose expansion, 15 mg/kg was chosen as the dose on the basis of safety, pharmacokinetics, and other data from the escalation cohorts. Forty-five patients were enrolled and received at least one dose of telisotuzumab (dose escalation, n = 15; dose expansion, n = 30). Telisotuzumab showed a linear pharmacokinetics profile; peak plasma concentration was proportional to dose level. There were no acute infusion reactions and no dose-limiting toxicities were observed. The most common treatment-related adverse events included hypoalbuminemia (n = 9, 20.0%) and fatigue (n = 5, 11.1%). By Response Evaluation Criteria In Solid Tumors (RECIST), 4 of 10 (40.0%) patients with MET-amplified tumors had confirmed partial response in target lesions (one ovarian, two gastric, and one esophageal), two (20.0%) had stable disease, three (30.0%) had progressive disease; one patient was unable to be evaluated. Among patients with nonamplified tumors (n = 35), no objective responses were observed; however, 11 patients had stable disease per RECIST criteria. In conclusion, telisotuzumab has an acceptable safety profile with clinical activity observed in patients with MET-amplified advanced solid tumors.
TCF21 Promotes Luminal-Like Differentiation and Suppresses Metastasis in Bladder Cancer
Authors: Mokkapati Sharada , Porten Sima P. , Narayan Vikram M. , Lim Amy H. , Jayaratna Isuru S. , Roth Beat , Cheng Tiewei , Navai Neema , Wszolek Matthew , Melquist Jonathan , Manyam Ganiraju , Choi Woonyoung , Broom Bradley , Pretzsch Shanna , Czerniak Bogdan , McConkey David J. , Dinney Colin P. N.
Published: March 2020

Little is known regarding the subclone evolution process in advanced bladder cancer, particularly with respect to the genomic alterations that lead to the development of metastatic lesions. In this project, we identify gene expression signatures associated with metastatic bladder cancer through mRNA expression profiling of RNA isolated from 33 primary bladder cancer and corresponding lymph node (LN) metastasis samples. Gene expression profiling (GEP) was performed on RNA isolated using the Illumina DASL platform. We identified the developmental transcription factor TCF21 as being significantly higher in primary bladder cancer compared with LN metastasis samples. To elucidate its function in bladder cancer, loss- and gain-of-function experiments were conducted in bladder cancer cell lines with high and low expression of TCF21, respectively. We also performed GEP in bladder cancer cell lines following TCF21 overexpression. We identified 2,390 genes differentially expressed in primary bladder cancer and corresponding LN metastasis pairs at an FDR cutoff of 0.1 and a fold change of 1. Among those significantly altered, expression of TCF21 was higher in the primary tumor compared with LN metastasis. We validated this finding with qPCR and IHC on patient samples. Moreover, TCF21 expression was higher in luminal cell lines and knockdown of TCF21 increased invasion, tumor cell dissemination, and metastasis. In contrast, overexpression of TCF21 in highly metastatic basal bladder cancer cell lines decreased their invasive and metastatic potential.

Implications:

TCF21 is differentially overexpressed in primary bladder cancer compared with matched LN metastasis, with in vitro and in vivo studies demonstrating a metastasis suppressor function of this transcription factor.
Chronische myeloische Leukämie: TKI-Behandlung bei hohem kardiovaskulärem Risiko
Authors: Link Hartmut
Published: March 2020

Cardiovascular (CV) adverse events are considered common complications of ponatinib treatment. Recently, it has been demonstrated that ponatinib dose reductions in definite settings can obtain optimal responses and lower ponatinib-related CV events. In this study, we describe the management of 5 patients with chronic myeloid leukemia treated with ponatinib, from second to fourth line of tyrosine kinase inhibitor therapy, carrying high pre-ponatinib CV risk, who obtained optimal molecular response and developed no CV adverse event during follow-up. Among these 5 patients, 2 had diagnosis of ischemic heart disease and underwent percutaneous angioplasty, 2 had type 2 diabetes and arterial hypertension, and 1 had only arterial hypertension. Median follow-up for ponatinib therapy is 1,039 days (34.6 months). Median dosage administered is 30 mg a day. SCORE charts were used to estimate risk of CV death in 10 years and Charlson Comorbidity Index was applied to estimate age-adjusted risk of death related to comorbidities. Strict cardiologic follow-up (complete evaluation every 3 to 6 months) and maximum effort in the control of CV modifiable risk factors are strongly recommended in the management of ponatinib treatment in patients at high risk for CV events and may allow the use of ponatinib in patients belonging to CV risk category.
ДОСЛІДЖЕННЯ ГІПОЛІПІДЕМІЧНОЇ ДІЇ ПРИ КУРСОВОМУ ПРИЗНАЧЕННІ ЕКСТРАКТІВ ТРАВИ Verbena officinalis L.
Authors: Posatska N. M. , Grytsyk A. R. , Struk О. А. , Ivanochko V. M. , Klymenko A. O.
Published: March 2020

Мета роботи. Дослідження впливу екстрактів трави Verbena officinalis L. на рівень ліпідів в крові піддослідних тварин на моделі атеросклеротичної гіперліпідемії. Матеріали і методи. Дослідження впливу екстрактів трави Verbena officinalis L. на рівень фракцій ліпідів у крові піддослідних білих щурів проводили в умовах тритонової моделі гіперліпідемії. Про фармакотерапевтичну ефективність досліджуваних екстрактів робили висновок на основі біохімічних, морфологічних та гістологічних показників. Результати й обговорення. Отримані результати вивчення біохімічних показників крові щурів свідчать, що при курсовому, протягом 10 днів, введенні стандартизованих екстрактів трави Verbena officinalis L. тваринам із модельованою тритоном WR-1339 атеросклеротичною гіперліпідемією, спостерігалося зниження рівня ліпідного складу крові. Висновки. В результаті вивчення динаміки біохімічних показників крові щурів із атеросклеротичною гіперліпідемією, змодельованою тритоном WR-1339, при курсовому призначенні екстрактів із трави  Verbena officinalis L. встановлено, що застосування екстрактів  зменшує рівень ліпідів крові, а саме загальних ліпідів, β-ліпопротеїнів, тригліцеролів, загального холестеролу, а також показників загального протеїну, сечовини, АлАТ і АсАТ. Найбільш виражену дію проявляє водно-спиртовий екстракт трави Verbena officinalis L.
ХРОМАТОГРАФІЧНИЙ ПРОФІЛЬ ГІДРОКСИКОРИЧНИХ КИСЛОТ СУХОГО ЕКСТРАКТУ ПАГОНІВ ЧОРНИЦІ
Authors: Vronska L. V.
Published: March 2020

Мета роботи. Вивчення профілю гідроксикоричних кислот сухого екстракту пагонів чорниці методом високоефективної рідинної хроматографії.

Матеріали і методи. Матеріалом для дослідження були сухі екстракти пагонів чорниці, отримані методом дробної мацерації з подрібнених пагонів чорниці вітчизняного походження за допомогою спиртово-водного екстрагенту із різним вмістом етанолу. Для ідентифікації гідроксикоричних кислот застосовували стандартні зразки гідроксикоричних кислот (Sigma-Aldrich, Fluka). ВЕРХ-дослідження проводили на рідинному хроматографі з детектором діодною матрицею («Waters 2960», США). Використовували хроматографічну колонку XTerra C18 («Waters», США) розміром 250х4,6 мм (5 мкм) при температурі (25±1) ºС.

Результати й обговорення. ВЕРХ-профілі сухого екстракту пагонів чорниці містили хроматографічні піки, що відповідали часу утримування хлорогенової, кофейної, ферулової, транс-п-кумарової і 3-гідроксикоричної кислот. Шляхом аналізу їхніх електронних спектрів поглинання було підтверджено присутність лише хлорогенової і кофейної кислот. Речовина з відносним часом утримування 4,2 (відносно хлорогенової кислоти) характеризується спектром поглинання ідентичним спектрові хлорогенової кислоти, що вказує на приналежність цієї речовини до гідроксикоричних кислот. ВЕРХ-профіль екстракту містить хроматографічні піки трьох речовин, спектри поглинання яких є подібними зі спектром транс-п-кумарової кислоти. Ймовірно, вони можуть належати до ізомерів чи похідних цієї кислоти. Були проведені ВЕРХ-дослідження профілів гідроксикоричних кислот сухих екстрактів, отриманих за допомогою екстрагентів із різним вмістом етанолу. Було встановлено, що вміст кофейної кислоти в сухому екстракті підвищується, а вміст хлорогенової знижується зі зменшенням вмісту етанолу в екстрагенті. Це, ймовірно, пов’язано з інтенсифікацією процесів гідролізу хлорогенової кислоти до кофейної. Це спонукає до глибшого вивчення даного процесу як з метою оптимізації технології, так дослідження стабільності й умов зберігання готового екстракту.

Висновки. Для ідентифікації сухого екстракту пагонів чорниці доцільно застосувати метод хроматографічного «відбитка» шляхом виявлення у ВЕРХ-профілях екстракту, отриманого при довжині хвилі детектування 270 і 330 нм хлорогенової, кофейної, невідомої гідроксикоричної (відносний час утримування 4,2 відносно хлорогенової кислоти) та похідних транс-п-кумарової кислот. Одночасно з дослідженням ВЕРХ профілів необхідне порівняння спектрів поглинання речовин із відповідними часами утримування. Зважаючи на високий вміст окремих гідроксикоричних кислот (хлорогенової, кофейної), вміст окремо взятої кислоти чи/або суми гідроксикоричних кислот, у перерахунку на хлорогенову, необхідно обрати як один із кількісних критеріїв якості сухого екстракту.
MAIN INDIVIDUAL AND TYPOLOGICAL PARAMETERS OF HIGHER NERVOUS ACTIVITY IN YOUNG PEOPLE OF DIFFERENT SOMATOTYPE WITH NORMAL AND HIGH BLOOD PRESSURE
Authors: Vadzyuk S. N. , Horban L. I. , Papinko I. Ya.
Published: March 2020

Background. The individual and typological features of the central nervous system are interpreted as highly genetically determined. Each somatotype is characterized by morphofunctional features of the activity of different systems, including the circulatory system.

Objective. The aim of the research was to study the features of the main individual and typological parameters of higher nervous activity in persons of different somatotype with normal and high blood pressure (BP).

Methods. In the control group of the surveyed patients the BP value corresponded to the optimal level according to the WHO classification (125 people). The second group consisted of individuals, whose systolic blood pressure exceeded 130 mmHg at the time of the study and (or) diastolic – 85 mmHg (135 people). Somatotyping technique by Carter and Heath was used. Functional mobility (FMNP) and strength of nervous processes (SNP) were determined using the Diagnost-1 program (Makarenko and Lizogub).

Results. In the individuals with predominance of ecto- and mesomorphic somatotype component, higher levels of major nervous processes were reported in response to strenuous processing of information, which was associated with more advanced mechanisms of information processing, its neurophysiological support. In people with endomorphic somatotype the lower levels of FMNP and SNP were clearly detected that could indicate that the speed characteristics of the nervous processes in them are at a lower level.

Conclusions. In normal blood pressure, the highest indicator of FMNP was found in the individuals with predominance of ecto- and mesomorphic component. In the group with high blood pressure, the indicator at the level below the average was in endomorphs. Predominance of the ectomorphic component tended to increase in the surveyed, and in the mesomorphs was at the average level. The lowest level of SNP was found in the individuals with endomorphic somatotype of both groups.
IMPACT OF NITRIC OXIDE SYNTHESIS MODULATORS ON THE CYTOKINES PROFILE IN EXPERIMENTAL ANTIPHOSPHOLIPID SYNDROME
Authors: Yaremchuk O. Z. , Posokhova K. A. , Kuzmak I. P. , Kulitska M. I. , Shevchuk О. О. , Volska A. S. , Lykhatskyi P.H.
Published: March 2020

Background.  Antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of specific antibodies. Objective. The aim of the study was to investigate the effect of combined use of L-arginine and aminoguanidine on cytokine profile (IL-1β, IL-6, TNF-α, IL-4, IL-10) in experimental APS. Methods. The study was performed on BALB/c female mice. L-arginine (25 mg/kg) and aminoguanidine (10 mg/kg) were used for correction. Serum cytokines concentrations were assessed using an ELISA test. Results. It was found that in APS the concentration of proinflammatory cytokines IL-1β, IL-6 and TNF-a increases in 3.2, 2.3 and 4.5 times respectively, compare to the control. At the same time a decrease of the IL-4 and IL-10 in 1.9 and 2.2 times was evidenced. Aminoguanidine, a selective iNOS inhibitor, caused a significant decrease of TNF-α by 57% (p<0.001), but there were no changes in IL-1β, IL-6, IL-4 and IL-10 compare to the APS-group. L-arginine combined with aminoguanidine caused a significant decrease in the concentration of IL-1β by 30% (p<0.01), IL-6 – by 16% (p<0.05), TNF-a – by 59% (p<0.001) compare to the control. At the same time, the concentration of IL-4 increased by 35% (p <0.01), IL-10 – by 25% (p<0.005). Conclusions. Combined use of the precursor of the NO synthesis L-arginine and aminoguanidine, a selective iNOS inhibitor, leads to a decrease in the concentrations of IL-1β, IL-6, TNF-a and an increase of IL-4 and IL-10 compare to the group of the BALB/c mice with APS and the group of animals administered with aminoguanidine.
GOUT AND NONALCOHOLIC FATTY LIVER DISEASE: EFFECT OF ENTEROSORPTION’S ADDITION TO COMMON TREATMENT
Authors: Mudra U. O.
Published: March 2020

Background. Gout is still one of the major health problems despite significant advances in treatment in recent years. It has been proved that pathogenetic mechanisms of development and progression of gout are associated with nonalcoholic fatty liver disease. Complex pathogenic treatment of patients aimed at different parts of the pathological process has recently been supplemented with the enterosorbents.

Objective. The aim of the research is to study the clinical features of gout with concomitant nonalcoholic fatty liver disease (NAFLD) and to evaluate the effect of carbon enterosorbent on its course.

Methods. 123 patients were involved in the study. They were divided into 2 groups: group 1 included patients with gout without liver damage, and group 2 included patients with concomitant NAFLD. Each of these groups was divided into subgroups, in which the patients received carbon enterosorbent carboline plus basic treatment. The control group consisted of 30 healthy persons. Anamnesis, physical examination, uric acid (UA), C-reactive protein (CRP) content, erythrocyte sedimentation rate (ESR) in serum were determined. Gout activity was evaluated using the Gout Activity Score (GAS).

Results. Basic treatment in combination with carbon enterosorbent contributed to faster cure of intoxication, pain and joint syndromes, as well as decrease of the inflammatory process activity.

Conclusions. The course of gout in the patients with concomitant NAFLD is more severe. Adding of carbon granular enterosorbent carboline in the complex treatment of patients with gout with or without concomitant NAFLD in the exacerbation phase contributes to a faster cureing dynamics of clinical and laboratory manifestations of the disease.
YOUDEN'S TEST FOR CHROMATOGRAPHIC DETERMINATION OF ENALAPRIL IN PHARMACEUTICALS
Authors: Logoyda L. S.
Published: March 2020

Background. Robustness tests were firstly introduced for avoiding problems in interlaboratory studies and identifying the factors potentially responsible. A robustness test performing in late validation procedure involves the possibility that when the method is established not robust, it should be redeveloped and optimized. At this stage much effort has been made and money spent for optimization and validation, and therefore avoiding this would be great.

Objective. The aim of the study was to consider the robustness of HPLC determination of enalapril (in tablets) by the Youden’s test.

Methods. Youden’s test was chosen as an efficient method to assess the robustness among all analytical methods that is by means of an experiment design, which involved seven analytical parameters combined in eight tests. In previous studies, we evaluated the chromatographic method robustness to quantify enalapril (in tablets) by Youden’s test.

Results. According to the Youden’s test criteria, HPLC method proved to be greatly robust regarding the enalapril content in introduction of variation of seven analytic parameters. The lowest variation in enalapril content was 0.91 %, when Grace Platinumр C8 EPS column (4.6 mm i.d. X 250 mm, 5 μm) was used. A holistic approach concerning simultaneous innovations in particle technology and instrument design was endeavored for the first time to meet and tackle the analytical laboratory issues. This was aimed at promoting success of analytical scientists as well as profitability and productiveness of business.

 Conclusion. The Youden’s test has been proved to be an efficient and useful tool for evaluation of robustness of enalapril HPLC assay.