bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular simulation strategies for the discovery of selective inhibitors of β-catenin
Authors: Saranyadevi S. , Shanthi V.
Published: May 2020

Tumor dissemination and relapse in lung cancer were found to be due to the existence of cancer stem cells. In particular, the [Formula: see text]-catenin pathway is found to be one of the crucial pathways in maintaining the stem-like properties of the cells. Thus, targeting the [Formula: see text]-catenin family of proteins is a significant therapeutic route in the treatment of lung cancer. Therefore, in the present study, a pharmacophore-based drug repurposing approach was accomplished to pinpoint potent [Formula: see text]-catenin inhibitors from the DrugBank database. Primarily, ligand-based pharmacophore hypothesis (AAHHR) was generated using existing [Formula: see text]-catenin inhibitors available in the literature and utilized for library screening. Subsequently, the inhibitory activity of the screened compounds was examined by the hierarchical docking process and the Prime MM-GBSA algorithm. Moreover, quantum chemical calculations and molecular dynamics simulations were executed to analyze the inhibitory effects of the screened hit molecule. The results indicate that hit molecule, DB08047 was found to possess better binding free energy, favorable ligand strain energy, satisfactory pharmacokinetic properties and superior free energy landscape profile. Eventually, the pIC[Formula: see text] values of the lead compounds were predicted by the AutoQSAR algorithm. It is noteworthy to mention that DB08047 was found to possess pyrazole scaffolds which could downregulate [Formula: see text]-catenin pathway and thus facilitate the controlled cell growth/inhibit tumor growth.
MUC1 contributes to goblet cell metaplasia and MUC5AC expression in response to cigarette smoke in vivo
Authors: Kato Kosuke , Chang Eugene H. , Chen Yin , Lu Wenju , Kim Marianne M. , Niihori Maki , Hecker Louise , Kim Kwang Chul
Published: May 2020

Goblet cell metaplasia (GCM) and mucin overproduction are a hallmark of chronic rhinosinusitis (CRS) and chronic obstructive pulmonary disease (COPD). In the airways, cigarette smoke (CS) induces activation of the epidermal growth factor receptor (EGFR) leading to GCM and overexpression of the gel-forming mucin MUC5AC. Although previous studies have demonstrated that a membrane-bound mucin, MUC1, modulates the activation of CS-induced EGFR, the role of MUC1 in CS-induced GCM and mucin overproduction has not been explored. In response to CS exposure, wild-type (WT) rats displayed Muc1 translocation from the apical surface of airway epithelium to the intracellular compartment of hyperplastic intermediate cells, EGFR phosphorylation, GCM, and Muc5ac overproduction. Similarly, human CRS sinonasal tissues demonstrated hyperplasia of intermediate cells enriched with MUC1 in the intracellular compartment, which was accompanied by GCM and increased MUC5AC expression. To further evaluate the role of Muc1 in vivo, a Muc1 knockout (KO) rat (MUC in humans and Muc in animals) was developed. In contrast to WT littermates, Muc1-KO rats exhibited no activation of EGFR, and were protected from GCM and Muc5ac overproduction. Genetic knockdown of MUC1 in human lung or Muc1 knockout in primary rat airway epithelial cells led to significantly diminished EGF-induced MUC5AC production. Together, these findings suggest that MUC1-dependent EGFR activation mediates CS-induced GCM and mucin overproduction. Strategies designed to suppress MUC1-dependent EGFR activation may provide a novel therapeutic approach for treating mucin hypersecretion in CRS and COPD.
Treatment of COVID-19-exacerbated asthma: should systemic corticosteroids be used?
Authors: Kumar Kartik , Hinks Timothy S. C. , Singanayagam Aran
Published: May 2020

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a new rapidly spreading infectious disease. Current guidance from the World Health Organization (WHO) highlights asthmatics as a high-risk group for severe illness from COVID-19. Viruses are common triggers of asthma exacerbations and the current SARS-CoV-2 pandemic raises several questions regarding the optimum management strategies. Here, we discuss the contentious issue of whether the mainstay therapy systemic corticosteroids should be used in the routine management of COVID-19-associated asthma exacerbations. Recent guidance from the WHO has advised against the use of corticosteroids if COVID-19 is suspected due to concerns that these agents may impair protective innate antiviral immune responses. This may not be appropriate in the unique case of asthma exacerbation, a syndrome associated with augmented type 2 inflammation, a disease feature that is known to directly inhibit antiviral immunity. Corticosteroids, through their suppressive effects on type 2 inflammation, are thus likely to restore impaired antiviral immunity in asthma and, in contrast to non-asthmatic subjects, have beneficial clinical effects in the context of SARS-CoV-2 infection.
Differential and synergistic roles of 17β-estradiol and progesterone in modulating adult female rat nucleus accumbens core medium spiny neuron electrophysiology
Authors: Proaño Stephanie B. , Krentzel Amanda A. , Meitzen John
Published: May 2020

This research indicates that estradiol and progesterone act both differentially and synergistically to modulate neuron physiology in the nucleus accumbens core. These actions by specific hormones provide key data indicating the endocrine mechanisms underlying how the estrous cycle modulates neuron physiology in this region. Overall, these data reinforce that hormones are an important influence on neural physiology.
BRAFV600E expression in neural progenitors results in a hyperexcitable phenotype in neocortical pyramidal neurons
Authors: Goz Roman U. , Akgül Gülcan , LoTurco Joseph J.
Published: May 2020

This study is the first to report the cell autonomous effects of BRAFV600E mutations on the intrinsic neuronal excitability. We show that BRAFV600E alters multiple electrophysiological parameters in neocortical neurons. Similar excitability changes did not occur in cells neighboring BRAFV600E-expressing neurons, after overexpression of wild-type BRAF transgenes, or after introduction of mutations affecting the mammalian target of rapamycin (mTOR) or the catalytic subunit of phosphoinositide 3-kinase (PIK3CA). We conclude that BRAFV600E causes a distinct, cell autonomous, highly excitable neuronal phenotype when introduced somatically into neocortical neuronal progenitors.
Timing of response onset and offset in macaque V4: stimulus and task dependence
Authors: Zamarashkina Polina , Popovkina Dina V. , Pasupathy Anitha
Published: May 2020

In the primate visual cortex, both the magnitude of the neuronal response and its timing can carry important information about the visual world, but studies typically focus only on response magnitude. Here, we examine the onset and offset latency of the responses of neurons in area V4 of awake, behaving macaques across several experiments, in the context of a variety of stimuli and task paradigms. Our results highlight distinct contributions of stimuli and tasks to V4 response latency. We found that response onset latencies are shorter than typically cited (median = 75.5 ms), supporting a role for V4 neurons in rapid object and scene recognition functions. Moreover, onset latencies are longer for smaller stimuli and stimulus outlines, consistent with the hypothesis that longer latencies are associated with higher spatial frequency content. Strikingly, we found that onset latencies showed no significant dependence on stimulus occlusion, unlike in inferotemporal cortex, nor on task demands. Across the V4 population, onset latencies had a broad distribution, reflecting the diversity of feedforward, recurrent and feedback connections that inform the responses of individual neurons. Response offset latencies, on the other hand, displayed the opposite tendency in their relationship to stimulus and task attributes: they are less influenced by stimulus appearance, but are shorter in guided saccade tasks compared to fixation tasks. The observation that response latency is influenced by stimulus- and task-associated factors emphasizes a need to examine response timing alongside firing rate in determining the functional role of area V4.
Mixed slip-trip perturbation training for improving reactive responses in people with chronic stroke
Authors: Dusane Shamali , Bhatt Tanvi
Published: May 2020

Block perturbation training led to development of favorable reactive responses to counteract treadmill-based, slip-like and trip-like stance perturbations among people with chronic stroke. During mixed block, previously acquired adaptive changes in reactive responses from slip-block training were not maintained, probably due to interference offered by trip block. Instead, on trip-like perturbations, trip block-induced adaptation was maintained and continued to show further improvement. Our findings might provide future direction for designing effective mixed perturbation training paradigms to counteract both opposing perturbation types.
Molecular Physiology and Pathophysiology of Bilirubin Handling by the Blood, Liver, Intestine, and Brain in the Newborn
Authors: Hansen Thor W. R. , Wong Ronald J. , Stevenson David K.
Published: May 2020

Bilirubin is the end product of heme catabolism formed during a process that involves oxidation-reduction reactions and conserves iron body stores. Unconjugated hyperbilirubinemia is common in newborn infants, but rare later in life. The basic physiology of bilirubin metabolism, such as production, transport, and excretion, has been well described. However, in the neonate, numerous variables related to nutrition, ethnicity, and genetic variants at several metabolic steps may be superimposed on the normal physiological hyperbilirubinemia that occurs in the first week of life and results in bilirubin levels that may be toxic to the brain. Bilirubin exists in several isomeric forms that differ in their polarities and is considered a physiologically important antioxidant. Here we review the chemistry of the bilirubin molecule and its metabolism in the body with a particular focus on the processes that impact the newborn infant, and how differences relative to older children and adults contribute to the risk of developing both acute and long-term neurological sequelae in the newborn infant. The final section deals with the interplay between the brain and bilirubin and its entry, clearance, and accumulation. We conclude with a discussion of the current state of knowledge regarding the mechanism(s) of bilirubin neurotoxicity.
Endoscopic Detorsion Results in Sigmoid Volvulus: Single-Center Experience
Authors: Firat Necattin , Mantoglu Baris , Ozdemir Kayhan , Muhtaroglu Ali , Akin Emrah , Celebi Fehmi , Fatih Altintoprak
Published: May 2020

Endoscopic detorsion is the first-line recommended treatment modality in sigmoid volvulus patients who have no peritoneal irritation signs on admission. In this paper, we present the results of endoscopic detorsion procedures applied at the time of presentation with the diagnosis of sigmoid volvulus and review the current literature about this topic.
The Effect of Training and Testing Process on Machine Learning in Biomedical Datasets
Authors: Uçar Muhammed Kürşad , Nour Majid , Sindi Hatem , Polat Kemal
Published: May 2020

Training and testing process for the classification of biomedical datasets in machine learning is very important. The researcher should choose carefully the methods that should be used at every step. However, there are very few studies on method choices. The studies in the literature are generally theoretical. Besides, there is no useful model for how to select samples in the training and testing process. Therefore, there is a need for resources in machine learning that discuss the training and testing process in detail and offer new recommendations. This article provides a detailed analysis of the training and testing process in machine learning. The article has the following sections. The third section describes how to prepare the datasets. Four balanced datasets were used for the application. The fourth section describes the rate and how to select samples at the training and testing stage. The fundamental sampling theorem is the subject of statistics. It shows how to select samples. In this article, it has been proposed to use sampling methods in machine learning training and testing process. The fourth section covers the theoretic expression of four different sampling theorems. Besides, the results section has the results of the performance of sampling theorems. The fifth section describes the methods by which training and pretest features can be selected. In the study, three different classifiers control the performance. The results section describes how the results should be analyzed. Additionally, this article proposes performance evaluation methods to evaluate its results. This article examines the effect of the training and testing process on performance in machine learning in detail and proposes the use of sampling theorems for the training and testing process. According to the results, datasets, feature selection algorithms, classifiers, training, and test ratio are the criteria that directly affect performance. However, the methods of selecting samples at the training and testing stages are vital for the system to work correctly. In order to design a stable system, it is recommended that samples should be selected with a stratified systematic sampling theorem.
Grain Consumption Forecasting: One Modified MLR Model Combined with Time Series Forecasting Theory
Authors: Zhu Chunhua , Wang Jiaojiao , Tian Jiake
Published: May 2020

In the classical multivariate prediction model, most research studies focused on the selection of relevant behaviour factors and the stability of historical data for improving the predicting accuracy of the main behaviour factor, and the historical data of the main behaviour factor have never been considered as one relevant behaviour factor, which in fact can be the first key impact factor; besides, the historical data can directly predict the main behaviour in the time series forecasting model, such as the ARIMA model. In this paper, one modified MLR model combined with time series forecasting theory is presented and applied in grain consumption forecasting. In the proposed model, to improve the current grain consumption forecasting, how to select impact factors is also discussed by combining the grey relational degree and Pearson correlation coefficient with given weights, and the optimal preprocessing parameter by the moving average filtering is computed for eliminating the abnormal points and stabilizing the data. Finally, the selected main impact factors are inputted to the proposed modified MLR model for forecasting grain consumption. Simulation results have shown that the five-year mean absolute percentage error of ration and feed grain is 2.34% and 3.27%, respectively, and the prediction accuracy has improved up to 2 times compared with the BP model and LSTM model. Moreover, the robustness of the model is verified by prediction analysis at different time intervals of historical data.
Clinicopathologic Features and Outcome of Adenocarcinoma of the Anal Canal: A Population-Based Study
Authors: Gogna Shekhar , Bergamaschi Roberto , Kajmolli Agon , Gachabayov Mahir , Rojas Aram , Samson David , Latifi Rifat , Dong Xiang Da
Published: May 2020

Background. Anal canal adenocarcinoma (AA) is an uncommon tumor of the gastrointestinal tract. We seek to provide a detailed description of the incidence, demographics, and outcome of this rare tumor in the United States. Methods. The data on anal canal adenocarcinoma from SEER Program, between 1973–2015, were extracted. We analyzed the incidence rates by demographics and tumor characteristics, followed by analysis of its impact on survival. Results. The incidence of AA increased initially by 4.03% yearly from 1973 to 1985 but had a modest decline of 0.32% annually thereafter. The mean age for diagnosis of AA was 68.12 ± 14.02 years. Males outnumbered females by 54.8 to 45.2%. Tumors were mostly localized on presentation (44.4%) and moderately differentiated (41.1%). Age generally correlated with poor overall cancer survival. However, young patients (age <40 years) also showed poor long-term survival. Patients with localized disease and well-differentiated tumors showed better survival outcomes. Surgical intervention improved survival significantly as compared to patients who did not (116.7 months vs 42.7 months, p<0.01). Conclusions. Anal canal adenocarcinoma demonstrated a poor bimodal cancer-free survival in both younger and older patient groups. Surgery significantly improves odds of survival and should be offered to patients amenable to intervention.
The Neuroprotective Effects of Astragaloside IV against H2O2-Induced Damage in SH-SY5Y Cells are Associated with Synaptic Plasticity
Authors: Song Zurong , Tao Ali
Published: May 2020

The aim of this study was to investigate whether the neuroprotective effects of astragaloside IV (AS-IV) against hydrogen peroxide (H2O2)-induced damage on human neuroblastoma cell line (SH-SY5Y) are associated with synaptic plasticity. The concentration screening of AS-IV and H2O2 on SH-SY5Y cells and the protective effects of AS-IV on SH-SY5Y cells under H2O2 stress were all determined by MTT assay. The expression of postsynaptic density 95 (PSD-95) and growth-associated protein 43 (GAP-43) were measured by western blot (WB) and inmunofluorescence staining assay under the same treatment conditions. According to the MTT results, the concentration of H2O2 at 50 μmol/L for 3 h was used for the cell damage model, and various concentrations of AS-IV (0.1, 0.2, 0.3, and 0.4 μmol/L) were used to affect SH-SY5Y cells. The MTT results showed that pretreatment of SH-SY5Y cells with AS-IV (0.1, 0.2, 0.3, and 0.4 μmol/L) attenuated the damage induced by H2O2 (50 μmol/L, 51.62% cell viability) and increased cell viability to 64.19, 63.48, 65.86, and 65.81%, respectively. Western blot analysis and immunofluorescence staining showed that the protective effects of AS-IV against SH-SY5Y cell damage caused by H2O2 resulted in reduced expression of PSD-95 and increased expression of GAP-43 in comparison with the H2O2 treatment group. The conclusion shows that AS-IV protected SH-SY5Y cells and enhanced their viability under H2O2 stress. AS-IV may facilitate presynaptic and postsynaptic plasticity to exert protective effects against oxidative damage of SH-SY5Y cells.
New Method for OC Relay Coordination
Authors: Kamoona Ameer Aqeel , Najm alfadli Ahmed , Alshabeeb Israa Ali
Published: May 2020

Protection relays design and manufacture have arrived to a new level of advancement; hence, numerical relays have appeared recently. They combine all the functions of monitoring, control, and protection in one device. Also these relays have the ability to communicate with each other to share statuses and orders using GOOSE (generic object‐oriented substation events) messages based on communication protocols such as IEC61850. In this paper, a proposed method for overcurrent (OC) relay coordination has been introduced based on numerical relay features of several setting groups and communication capability. This work supposes that the coordination between feeder, bus section, and incomer protection relays, in a substation of single busbar configuration with bus sectionalizer (i.e., bus section), depends on the status of the bus section circuit breaker (CB) as a criterion for determining active relay setting group, to achieve a faster tripping action. ETAP has been used as a simulation software environment. And the simulation results show the advantages of the proposed method in reducing the time needed by the relay to clear the electrical fault. Siemens SIPROTEC series have been used as an example of numerical relays, specifically 7SJ64 as OC relay, which exists in the ETAP library.
AKNA Is a Potential Prognostic Biomarker in Gastric Cancer and Function as a Tumor Suppressor by Modulating EMT‐Related Pathways
Authors: Wang Gang , Sun Dan , Li Wenhui , Xin Yan
Published: May 2020

The AT‐hook transcription factor, AKNA, is a nuclear protein that affects a few physiological and pathological processes including cancer. Here, we investigated the role of AKNA in gastric cancer (GC). By using quantitative real‐time polymerase chain reaction (qRT‐PCR) and Western blot assays, AKNA was found deregulated in both GC cell lines and 32 paired GC tissues. Subsequently, Kaplan‐Meier analysis and clinicopathological analysis were conducted using both 32 GC cases’ data above and RNA‐Seq data of AKNA in 354 GC patients and the corresponding clinical‐pathological data obtained from The Cancer Genome Atlas (TCGA), and AKNA expression was found closely related to location, metastasis, and TNM staging of GC. Then, the potential molecular mechanisms of AKNA in GC were explored by gene set enrichment analysis (GSEA), qRT‐PCR, and Western blot assays. AKNA was found to be a hub gene related to homotypic cell to cell adhesion, regulation of cell to cell adhesion, leukocyte cell to cell adhesion, and regulation of T cell proliferation in GC. GO analysis revealed that AKNA involved in the regulation of epithelial‐mesenchymal transition (EMT)‐related pathways including chemokine signaling pathway, cytokine to cytokine receptor interaction, cell adhesion molecules, and jak‐stat signaling pathway in GC. To explore the regulation of AKNA expression, Targetscan and TargetMiner were used to predict the possible miRNA which targeted AKNA and found the expression of AKNA was negatively correlated to miR‐762 which could be sponged by circTRNC18. In conclusion, AKNA could function as a tumor suppressor by modulating EMT‐related pathways in GC. The expression of AKNA might be regulated by circTRNC18/miR‐762 axis. AKNA could serve as a potential biomarker and an effective target for GC diagnosis and therapy.
An Analysis of the Allometric and Multifractal Features of a Development in the Urban-Rural Area in the Lower Reaches of the Yangtze River: 2012 Cross-Sectional Data of Four Provinces and One City
Authors: Song Zhi-jun , Chen Yi , Li Yun , Zhao Xin
Published: May 2020

The provinces of Jiangsu, Anhui, Jiangxi, and Zhejiang and the city of Shanghai in the lower reaches of the Yangtze River forming a concentrated distribution area of developed cities and rich villages in China are so called “the four provinces and one city,” which have experienced rapid and typical urban-rural development. By drawing on the perspective of allometric growth, this paper conducts fundamental analysis and multifractal analysis of 52 prefecture-level cities in four provinces and one city in the lower reaches of the Yangtze River. Fundamental analysis shows that there are different patterns of allometric growth in various areas of the region, as well as the emergence of diffusion in fundamental activities and of polarisation in advanced activities. Multifractal analysis also shows that the comprehensive regional development is dominated by large- and medium-sized cities, but various fields have different fractal spectrums and form six interrelated urban-rural integration modes. The multiple spatial dissymmetry disclosed in the analysis also shows that each field had its own allometric growth features during the regional development. This paper adopts the fitting function and the relevant parameters of the fractal dimension to quantify the evolution in particular fields. Analysis shows that the developments in prefecture-level cities are different and represent the regional evolution status; the urban-rural development in metropolises and small- and medium-sized cities is nonmainstream.
Study on Cargo Products’ Layout Optimization of Truck Railway Line
Authors: Liu Jie , He ShiWei , Zhang Meng
Published: May 2020

Cargo products’ layout is one of the problems that needs an important decision in freight railroads. The purpose of optimization of the cargo products’ layout on railway lines is to make a rational cargo products’ plan to satisfy customers’ diversified transport demands. In this paper, a service network is designed using the method of node splitting. Then, an optimized model is built for the products’ layout problem on busy main railway lines. The immune clone-variable neighborhood algorithm is used to solve the model. Finally, a numerical example is given to verify the model and algorithm. The result shows that the model and algorithm are of good practical applicability.
Existence of Solutions for Fractional Boundary Value Problems with a Quadratic Growth of Fractional Derivative
Authors: Li Yaning , Zhang Quanguo , Sun Baoyan
Published: May 2020

In this paper, we deal with two fractional boundary value problems which have linear growth and quadratic growth about the fractional derivative in the nonlinearity term. By using variational methods coupled with the iterative methods, we obtain the existence results of solutions. To the best of the authors’ knowledge, there are no results on the solutions to the fractional boundary problem which have quadratic growth about the fractional derivative in the nonlinearity term.
Evaluation on Filter Performance of Variational Mode Decomposition and Its Application in Separating Closely Spaced Modes
Authors: Gu Wenjing , Zhou Li
Published: May 2020

The equivalent filter characteristics of variational mode decomposition (VMD) are fully evaluated when applied to the fractional Gaussian noise (fGn) and the application in separating closely spaced modes of vibration system is performed in this paper. VMD is a newly proposed signal decomposition technique, which nonrecursively decomposes a signal into a given number of subsignals (modes), and each mode is mostly compact around a center pulsation. The filter performance of VMD is largely dependent on the constraint parameter and the initialization of center frequencies. In order to extract the desired modes, criteria for the determination of decomposition parameters are established. The initial center frequencies could be simply determined by prior estimated modal frequencies of the analyzed signal, while the constraint parameter is optimized utilizing a genetic algorithm (GA). A two-degree-of-freedom parametric system is considered to evaluate the capability of VMD in the separation of closely spaced modes. Compared with the noise-assisted versions of empirical mode decomposition (EMD) and wavelet packet transform (WPT), the parameter-optimized VMD can successfully separate the closely spaced modes while recovering the most modal information simultaneously. When introduced to the ground vibration test (GVT) of a horizontal tail, the proposed method successfully extracted the first five oscillation modes and identified the modal parameters accurately.
The Era of COVID-19 and the Rise of Science Collectivism in Cancer Research
Authors: Janowitz Tobias , Tuveson David A.
Published: May 2020

The coronavirus SARS-CoV-2 has created a global pandemic that has killed more than a quarter million people since December 2019, halted commerce, and disrupted our ability to research cancer in the laboratory and clinic and care for our patients. A return to a functioning society can be facilitated by the active participation of cancer researchers to diagnose and treat SARS-CoV-2–infected patients, and the direct and indirect benefits of our involvement cannot be overstated.
Biocompatibility and Therapeutic Effect of 3 Intra-Tympanic Drug Delivery Vehicles in Acute Acoustic Trauma
Authors: Park Mina , Hwang Yu-Jung , Noh Tae-Soo , Woo Shin-Wook , Park Ji-Hoon , Park Seung Hun , Kim Moon Suk , Suh Myung-Whan
Published: May 2020

Introduction: The aim of this study was to assess the biocompatibility of several intra-tympanic (IT) drug delivery vehicles and to compare hearing outcomes. Materials and Methods: After acute acoustic trauma, rats were treated with IT 10 mg/mL dexamethasone phosphate (D) and divided into the following groups for drug delivery: saline + D (n = 15), hyaluronic acid (HA) + D (n = 17), and methoxy polyethylene glycol-b-polycaprolactone block copolymer (MP) + D (n = 24). Results: No inflammation was found in the saline + D or HA + D groups. The duration of vehicle/drug persistence in the bulla was significantly longer for the MP + D (47.5 days) and HA + D groups (1.8 days) than for the saline + D group (<1 day). The tympanic membrane was significantly thicker in the MP + D group than in the saline + D and HA + D groups. The proportion of ears with good hearing outcome was significantly higher (63.6%) in the HA + D group than in the MP + D group. The number of hair cells in the hearing loss (HL) control group was significantly lower than in the MP + D group. Discussion/Conclusion: HA shows great potential as a biocompatible vehicle for D delivery via the IT route, without an inflammatory reaction and with better hearing outcomes. Considering inflammation and hearing, MP may not be a good candidate for IT drug delivery.
Management of a 75-Year-Old Lady with Refractory Chronic Myelogenous Leukemia
Authors: Sobash Philip T. , Guddati Achuta K. , Kota Vamsi
Published: May 2020

Chronic myelogenous leukemia (CML) is a hematopoietic disorder caused by the BCR/ABL gene or Philadelphia chromosome. The first Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor for treatment of CML was imatinib in 2001. Since then, multiple therapies, such as nilotinib, dasatinib, bosutinib, and, more recently, ponatinib, have made their way as viable treatment options for first-line and secondary therapies. Most patients tend to respond to first-line treatment. Although there is a subset of patients who do not achieve complete molecular response with first line, newer options have proven beneficial. As we progress through therapies, there still remain some patients who do not adequately respond to current available therapies. The treatment options and guidelines become more difficult in such situations, not only with respect to cost but also patient quality of life and satisfaction. We discuss a 75-year-old white female with CML, who has had multiple therapies with hematological remission but has never achieved complete molecular remission, currently on bosutinib and tolerating it well.
Covered Metal Stent after Dysfunction of Uncovered Stents for Palliation of Gastrointestinal Malignant Obstruction
Authors: Patita Marta , Castro Rui , Libânio Diogo , Bastos Rui Pedro , Silva Rui , Dinis-Ribeiro Mário , Pimentel-Nunes Pedro
Published: May 2020

Background: Self-expanding metal stents (SEMS) have been used for the palliative treatment of malignant gastrointestinal tract obstruction. However, restenosis or incomplete expansion of a first stent is a frequent complication, and the effectiveness of reintervention with placement of a second stent is still controversial. Objective: To evaluate the clinical outcomes of covered SEMS (cSEMS) placement after dysfunction of uncovered SEMS (uSEMS) by the stent-in-stent technique. Patients and Methods: We retrospectively studied a consecutive series of patients receiving palliative treatment for malignant gastrointestinal obstruction with cSEMS placement after uSEMS dysfunction in a tertiary center from January 2013 to August 2018. Technical and clinical success, time of patency, and adverse events were analyzed. Results: Twelve patients were included; their mean age was 60 ± 9 years. Eleven patients had gastric outlet obstruction, and 1 patient had compression of the transverse colon due to gastric neoplasia. In 5 cases, there was absence of early clinical success with uSEMS and stent dysfunction in 7 cases (median patency time: 81 days). There was 100% technical success and 91.7% clinical success after cSEMS placement. There were no adverse events nor need for reintervention. The median patency time after placement of both stents was 163 days (vs. 71 days with the initial stent). Conclusion: cSEMS placement after uSEMS dysfunction is technically feasible and a clinically effective treatment for patients with recurrent malignant gastrointestinal obstruction, with good stent patency in the medium/long term. This approach seems to be safe and without increase in adverse effects.
A Monocentric, Retrospective Analysis of 61 Patients with Generalized Granuloma Annulare
Authors: Nordmann Thierry M. , Kim Joo-Ri , Dummer Reinhard , Anzengruber Florian
Published: May 2020

Background: Granuloma annulare is a chronic noninfectious granulomatous skin condition with variable clinical presentations. Generalized granuloma annulare, defined as widespread disease with >10 skin lesions, accounts for 15% of all cases. Numerous associated diseases have been controversially discussed, most importantly diabetes mellitus, dyslipidemia, thyroid disease, malignancy and systemic infections. Objectives: The objective of our study is to describe disease characteristics, treatment outcome and associated diseases in patients treated at the Department of Dermatology of the University Hospital Zurich during the last 20 years. Methods: The hospital database was searched for patients with generalized granuloma annulare in the last 20 years (January 1, 1998, to December 31, 2017). Overall, 61 patients, 14 males and 47 females, were included in our study. The mean age was 58 years at first consultation. The diagnosis was verified clinically and histologically. Results: Generalized granuloma annulare occurred at a mean age of 55 years, more commonly in females. Pruritus was absent in 51% of all patients. Metabolic diseases including diabetes mellitus, hypercholesterinemia and hypertriglyceridemia were present in 10.5, 8.2 and 4.9%, respectively. Thyroid disease was present in 9.8% and malignant disease in 23%, including colorectal cancer, lymphoproliferative disease, squamous cell carcinoma of the esophagus, basal cell carcinoma and gynecological malignancy. Therapy was initiated in 92%, while second- and third-line therapy was performed in 70 and 39%, respectively. Benefit during therapy (e.g., full and partial remission) was achieved in 39.3% during first-line, in 39.4% during second-line and in 33.8% during third-line treatment. Topical corticosteroids were the most commonly prescribed treatment, mostly leading to stable disease (46.6%). Combined full and partial remission occurred in a large proportion of patients receiving UVA1 (45%), PUVA (63.6%) and intralesional triamcinolone acetonide (100%). Conclusions: Generalized granuloma annulare is a mostly asymptomatic and benign disease with a strong tendency for treatment resistance. We suggest to screen all patients for dyslipidemia, thyroid disease and malignant disease. While randomized trials are needed, we suggest topical corticosteroids as the first-line treatment, intralesional triamcinolone acetonide for persistent solitary lesions and, if further treatment is needed, UVA1 or PUVA.
Binaural Interaction in Tinnitus Patients
Authors: Gabr Takwa A. , Lasheen Reham M.
Published: May 2020

The auditory brainstem response (ABR) is a commonly used objective clinical measure for hearing evaluation. It can be also used to draw conclusions about the functioning of distinct stages of the auditory pathway including the binaural processing stages using the binaural interaction component (BIC) of the ABR. Objective: To study binaural processing in normal hearing subjects complaining of tinnitus. Methods: Sixty cases with bilateral normal peripheral hearing were included in this work, divided into 2 groups, i.e., group 1 (comprised of 30 healthy subjects representing the control group) and group 2 (comprised of 30 subjects with tinnitus representing the study group). All of the subjects were submitted to a basic audiological evaluation (including pure tone audiometry, speech audiometry, and immittancemetry) and ABR audiometry recorded in monaural and then binaural conditions. Results: In monaural recording, the tinnitus group showed significantly delayed latencies of waves I, III, and V in addition to significantly reduced wave I and III amplitudes when compared with the controls. Similar significant findings were found when binaural ABR responses were compared between both groups. Comparing BIC between both groups showed significant earlier BIC for latencies of waves I and V in the control group, while the BIC for amplitudes showed similar results in both groups. Conclusions: These finding suggest the presence of binaural processing deficits in tinnitus patients at different levels along the ascending auditory pathway.
Sigmoid Volvulus with Widespread Bowel Ischemia after Endoscopic Reduction Successfully Treated with Elective Laparoscopic Surgery
Authors: Yasuda Koji , Oura Shoji , Kashu Nozomi , Yoshitake Hiroyuki , Takami Tomoya , Shintani Hiroshi , Kataoka Naoki , Yamaguchi Tomoyuki , Makimoto Shinichiro
Published: May 2020

An 87-year-old man complaining of abdominal distention was referred to our hospital. Plain radiograph and enhanced computed tomography (CT) showed a dilated sigmoid colon with a coffee bean sign, leading to the diagnosis of sigmoid volvulus. Based on symptoms and the CT and laboratory test findings, we initially treated the patient with endoscopic reduction, resulting in successful reduction of the sigmoid volvulus with widespread presumed mucosal ischemia. Due both to the lack of emerging symptoms suggesting colon perforation and to the laboratory test findings after endoscopic reduction, we treated the patient without further urgent surgical intervention. Two months later, the patient underwent successful elective laparoscopic surgery with a redundant sigmoid colon resection and a functional end-to-end anastomosis. He has been well without any events for 20 months. Conservative treatment with careful observation should be taken into consideration in the treatment of sigmoid volvulus with mild to moderate ischemia after endoscopic reduction.
Literacy Profile of Children with Language Impairment: Evidence from an Alphasyllabary
Authors: Tiwari Shivani , Karanth Prathibha , Suresh Kiran , Krishnan Gopee
Published: May 2020

Background: Most of the evidence explaining the language-literacy link is derived from children learning to read and write alphabetic orthography. Aim: This study investigated the literacy deficits in children learning to read Kannada, a Dravidian language that employs an alphasyllabary. Methods: A group of 15 children with language impairment (CwLI) was compared with two groups of control (age- and language-matched) participants on a range of literacy measures. Results: The results showed that, compared to the age-matched group, the CwLI group performed significantly poorer on reading (words and nonwords) and written spelling tasks. However, the performance on akshara (the written symbol in the alphasyllabary) recognition task was comparable between groups. Similarly, comparison of the CwLI group with the language-matched control group revealed poorer performance in the former group on most literacy measures but not the akshara recognition task. Akshara recognition emerged as the most significant predictor of literacy performance in children learning to read and write the Kannada alphasyllabary. Detailed analyses of the written spelling errors unveiled several unique error types in the language-impaired group. Conclusion: The findings of our study revealed both orthography-independent and orthography-dependent deficits in the literacy skills of CwLI mastering the Kannada alphasyllabary.
Mythen der Klinischen Psychologie und Psychotherapie: Entwicklung und Erprobung eines Fragebogens zur standardisierten Erfassung
Authors: Jungmann Stefanie M. , Witthöft Michael
Published: May 2020

Hintergrund: Mythen im Sinne von wissenschaftlich nicht haltbaren Aussagen sind im Bereich der Klinischen Psychologie und Psychotherapie weitverbreitet und können erhebliche Auswirkungen haben (z.B. Stigmatisierung, unwirksame/potenziell schädliche Behandlungen). Im deutschsprachigen Raum sind Mythen bislang wenig erforscht, und es existiert kein validierter Fragebogen spezifisch zur Erfassung von Mythen der Klinischen Psychologie/Psychothe­rapie. Die Studie verfolgte das Ziel, einen Fragebogen zu ­Mythen der Klinischen Psychologie und Psychotherapie (FMKPP) zu entwickeln und an zwei Stichproben (Allgemeinbevölkerung, Studierende) einer ersten psychometrischen Prüfung zu unterziehen. Zudem wurden Zusammenhänge mit Persönlichkeitsmerkmalen, Absorption und Unsicherheitsintoleranz geprüft. Methode: An einer Stichprobe der Allgemeinbevölkerung (n = 286) sowie Studierenden (n = 368) wurden mittels einer Hauptkomponentenanalyse die Faktorstruktur untersucht, eine Itemanalyse durchgeführt sowie Korrelationen mit Fragebögen zu dispositionellen Merkmalen berechnet. Ergebnisse: Der FMKPP zeigte die drei Faktoren: “Mythen zur Wirksamkeit von Psychotherapie”, “Mythen zu psychischen Störungen/Prozessen in der Psychotherapie” und “Mythen bezüglich der Funktionsweise des Gedächtnisses”. Die Reliabilitäten (McDonalds ω) lagen zwischen 0,50 und 0,75. Erwartungskonform zeigte der FMKPP signifikant positive Zusammenhänge mit Absorption und Unsicherheitsintoleranz. Schlussfolgerung: Vor dem Hintergrund einer ersten psychometrischen Prüfung sollten die Reliabilität sowie die Validität einzelner Items in zukünftigen Studien untersucht werden. Die Assoziation mit Unsicherheitsintoleranz könnte eine Funktion von Mythen im Sinne der Erhöhung von Sicherheit und Vorhersagbarkeit indizieren.
Opportunistic and Serious Infections in Patients with Neuroendocrine Tumors Treated with Everolimus: A Multicenter Study of Real-World Patients
Authors: Mauro Carine , de Jesus Victor Hugo Fonseca , Barros Milton , Costa Frederico Perego , Weschenfelder Rui F. , D'Agustini Nathalia , Angel Martin , Luca Romina , Nuñez Jose Eduardo , O'Connor Juan Manuel , Riechelmann Rachel P.
Published: May 2020

Introduction: The incidence of infections is poorly studied in patients with neuroendocrine tumors (NET) treated with everolimus outside of clinical trials. We aimed to evaluate the frequency of and risk factors for opportunistic infections (Opl) or any serious infection in eligible patients. Methods: This was a retrospective multicenter study of a Latin American cohort of consecutive patients with advanced NET treated with everolimus. Duration of everolimus, comorbidities, Charlson comorbidity score, type of prior treatment, institution, and concurrent immunosuppressive conditions were tested for possible associations with serious (grade 3–5) infections in univariate and multivariable logistic regression models. Results: One hundred eleven patients from 5 centers were included. The median duration of everolimus was 8.9 months. After a median follow-up of 32.9 months, 34 patients (30.6%; 95% CI 22.2–40.1) experienced infections of any grade, with 24 (21.6%; 95% CI 14.8–30.4) having a serious infection and 7 (6.3%; 95% CI 2.6–12.6) having at least 1 OpI (Candida sp., Toxoplasma gondi, Pneumocystis sp., Herpes sp., and Cryptococcus sp.). Four patients (3.6%) died from infections, but only 2 deaths (1.8%) were deemed to be related to everolimus. The multivariable analysis identified everolimus duration (every 6-month increase; OR = 1.28; 95% CI 1.02–1.60; p = 0.03) as an independent risk factor for serious infection. Conclusion: Infections are more frequent in NET patients using everolimus than previously reported in clinical trials. Patients on everolimus should be closely monitored for infections, especially those receiving it for several months.
Bone Metastases in Neuroendocrine Tumors: Molecular Pathogenesis and Implications in Clinical Practice
Authors: Cives Mauro , Pellè Eleonora , Rinzivillo Maria , Prosperi Daniela , Tucci Marco , Silvestris Franco , Panzuto Francesco
Published: May 2020

Skeletal colonization is often regarded as a rare event in patients with neuroendocrine tumors (NETs) although both national registries and retrospective series report an incidence of bone metastases as high as 20% in subjects with advanced disease. While the biological mechanisms leading to bone metastatic colonization in NETs have been poorly investigated so far, key steps of osteotropic mechanisms, including the epithelial-to-mesenchymal transition, preparation of the premetastatic niche, migration of circulating tumor cells towards the bone marrow as well as the resulting alterations of the skeletal metabolism, are likely to operate also during the development of NET bone metastases. The skeleton involvement by NETs has a detrimental impact on both quality of life and patients’ prognosis, leading to pain in the majority of symptomatic subjects. While it is currently unclear whether or not the earlier recognition of bone involvement by PET/CT imaging techniques employing 68Ga-DOTA-conjugated peptides might improve outcomes through the exploitation of timely treatments, the management of bone-colonizing NETs is today based only on clinical experience from other osteotropic tumors. Here, we summarize the fundamental molecular mechanisms driving bone colonization and revisit both established and novel treatments for patients with bone metastatic NETs.
Dietary Intakes of Eggs and Cholesterol in Relation to All‐Cause and Heart Disease Mortality: A Prospective Cohort Study
Authors: Xia Peng‐Fei , Pan Xiong‐Fei , Chen Chen , Wang Yi , Ye Yi , Pan An
Published: May 2020

Background

The aim of this study was to identify associations between dietary intakes of eggs and cholesterol and all‐cause and heart disease mortality in a
US
population.

Methods and Results

Data from the National Health and Nutrition Examination Survey 1999–2014 were used in this study, which included 37 121 participants ≥20 years of age. Dietary information was assessed via 24‐hour dietary recalls at baseline. Mortality status was documented until December 31, 2015. Cox proportional hazards models were used to examine the associations between dietary intakes of eggs and cholesterol and all‐cause and heart disease mortality. During a median follow‐up of 7.8 years, 4991 deaths were documented, including 870 deaths from heart disease. No significant association was observed between additional daily consumption of half an egg and all‐cause mortality (multivariable‐adjusted hazard ratio, 1.04; 95% CI, 0.96–1.13), or heart disease mortality (0.96; 0.80–1.14). Each 50‐mg/day increase of cholesterol intake was inversely associated with all‐cause mortality among participants with daily intake <250 mg (0.87; 0.77–0.98), but positively associated with all‐cause mortality among participants with daily intake ≥250 mg (1.07; 1.01–1.12). No significant association was found between dietary cholesterol intake and heart disease mortality.

Conclusions

No significant association was found between egg consumption and mortality in
US
adults. The association between dietary cholesterol intake and all‐cause mortality depended on the baseline intake levels, with an inverse association in those with lower intake levels (<250 mg/day) but a positive association in those with higher intake levels (≥250 mg/day).