bluuebunny/crossref_metadata_2025 huggingface dataset:
Distribution of Number, Location of Pain and Comorbidities, and Determinants of Work Limitations among Firefighters
Authors: Nazari Goris , Osifeso Temitope A. , MacDermid Joy C.
Published: November 2020

Introduction. The unique demands of firefighting results in acute, recurrent, or chronic pain complications. We aimed to describe the percentage distribution of number and location of painful sites among FFs and determine whether work limitations differed based on the number or location of painful sites, age, and/or sex. Methods. About 325 firefighters completed a work limitation questionnaire (WLQ-26) and a checklist to indicate painful regions of the body using either a paper format or an online survey. A one-way ANOVA was employed to analyze the transformed work limitation scores; this was a two-sided test with a significance level of <0.05, to determine if work limitations differed among firefighters based on the number or location of painful sites, age, and/or sex. Results. The data analyzed consisted of 325 (

men
=
216

,

women
=
109

) FFs in total. The percentage distribution of the number of painful sites in our study cohort was 43% no pain, 17% one painful site, 19% two painful sites, and 21% three or more painful sites. The percentage distribution of the locations of painful sites was 43% no pain, 41% spine, 9% lower extremity, and 7% upper extremity. An estimated 31% of FFs (

n
=
102

) reported non-MSK comorbidities with 23% (

n
=
76

) reporting at least one non-MSK comorbidity and 8% (

n
=
26

) reported having two or more comorbidities.

FFs
>
45
 
years

of age experienced more physical work limitations than

FFs
≤
45
years

(mean difference: 0.74/10; 95% CI .19-1.29;

p
=
0.008

). Conclusions. The majority of firefighters reported having at least one painful site and indicated the spine as the most common painful location. Age, the number of painful sites, and location of pain were identified as a potential contributor to physical/mental and work output limitations.
Mibefradil and Flunarizine, Two T-Type Calcium Channel Inhibitors, Protect Mice against Lipopolysaccharide-Induced Acute Lung Injury
Authors: Wan Limei , Wu Weibin , Jiang Shunjun , Wan Shanhe , Meng Dongmei , Wang Zhipeng , Zhang Jiajie , Wei Li , Yu Pengjiu
Published: November 2020

Recent studies have illuminated that blocking Ca2+ influx into effector cells is an attractive therapeutic strategy for lung injury. We hypothesize that T-type calcium channel may be a potential therapeutic target for acute lung injury (ALI). In this study, the pharmacological activity of mibefradil (a classical T-type calcium channel inhibitor) was assessed in a mouse model of lipopolysaccharide- (LPS-) induced ALI. In LPS challenged mice, mibefradil (20 and 40 mg/kg) dramatically decreased the total cell number, as well as the productions of TNF-α and IL-6 in bronchoalveolar lavage fluid (BALF). Mibefradil also suppressed total protein concentration in BALF, attenuated Evans blue extravasation, MPO activity, and NF-κB activation in lung tissue. Furthermore, flunarizine, a widely prescripted antimigraine agent with potent inhibition on T-type channel, was also found to protect mice against lung injury. These data demonstrated that T-type calcium channel inhibitors may be beneficial for treating acute lung injury. The important role of T-type calcium channel in the acute lung injury is encouraged to be further investigated.
New Exact Solutions of Kolmogorov Petrovskii Piskunov Equation, Fitzhugh Nagumo Equation, and Newell-Whitehead Equation
Authors: Chu Yu-Ming , Javeed Shumaila , Baleanu Dumitru , Riaz Sidra , Rezazadeh Hadi
Published: November 2020

This work presents the new exact solutions of nonlinear partial differential equations (PDEs). The solutions are acquired by using an effectual approach, the first integral method (FIM). The suggested technique is implemented to obtain the solutions of space-time Kolmogorov Petrovskii Piskunov (KPP) equation and its derived equations, namely, Fitzhugh Nagumo (FHN) equation and Newell-Whitehead (NW) equation. The considered models are significant in biology. The KPP equation describes genetic model for spread of dominant gene through population. The FHN equation is imperative in the study of intercellular trigger waves. Similarly, the NW equation is applied for chemical reactions, Faraday instability, and Rayleigh-Benard convection. The proposed technique FIM can be applied to find the exact solutions of PDEs.
Synthesis, Characterization, Cyclic Voltammetry, and Biological Studies of Co(II), Ni(II), and Cu(II) Complexes of a Tridentate Schiff Base, 1-((E)-(2-Mercaptophenylimino) Methyl) Naphthalen-2-ol (H2L1)
Authors: Kuate Maurice , Conde Mariam Asseng , Ngandung Mainsah Evans , Paboudam Awawou G. , Tchieno Francis Merlin M. , Ketchemen Kevin I. Y. , Tonle Kenfack Ignas , Ndifon Peter T.
Published: November 2020

A novel tridentate Schiff base, 1-((E)-(2-mercaptophenylimino) methyl) naphthalen-2-ol (H2L1), was synthesized by the condensation reaction of 2-hydroxy-1-naphthaldehyde with 2-aminothiophenol in absolute ethanol. The resulting ligand was reacted with Co(II), Ni(II), and Cu(II) ions to obtain tetrahedral CoL1, NiL1, and square planar CuL1 complexes. The Schiff base and its metal complexes were characterized using 1H-NMR, microanalysis, FT-IR, UV-visible, and mass spectroscopy (ESI-MS). All the compounds are soluble in DMSO and DMF. Spectroscopic studies show that the ligand coordinates to the metal center through the azomethine nitrogen, naphthoxide oxygen, and thiophenoxide sulfur to form a tridentate chelate system. Conductance measurements show that these compounds are molecular in solution. Cyclic voltammetry studies show Co(III)/Co(II) and Cu(II)/Cu(I) redox systems to be quasi-reversible involving a monoelectronic transfer while Ni(III)/Ni(II) was irreversible. In vitro antibacterial and antifungal activity against five bacterial strains (Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis, and Proteus mirabilis) and five fungal strains (Candida albicans, Candida glabrata, Candida tropicalis, Candida krusei, and Candida parapsilosis) showed no antifungal activity but moderate antibacterial activity on E. coli, S. aureus, P. aeruginosa, and P. mirabilis bacterial strains. Antioxidant studies reveal that the ligand and its Cu(II) complex are more potent than Co(II) and Ni(II) complexes to eliminate free radicals.
Comparative Reliability Assessment of Tooth Volume Measurement with Different Three‐Dimensional Imaging Software
Authors: Rasheed Tara Ali , Shehab Al Hamdany Afrah Khazal , Rauf Aras Maruf
Published: November 2020

Objective. To evaluate the in vivo tooth volume through VRMesh and 3Matic programs and to compare the measurements to the physical volume. So, the aim of the study was to ensure the reliability and sensitivity of the three‐dimensional software (VRMesh and 3Matic) in measuring tooth volume. Material and Methods. The volume of 26 extracted upper first premolars from orthodontic patients who had CBCT before orthodontic treatment were measured. Two different commercial programs, which were VRMesh and 3Matic, were used to calculate the volume of the segmented upper first premolar from CBCT. The in vivo tooth volume was compared to the physical tooth volume to examine the accuracy of the two software in measuring the tooth volume. Results. The difference between the mean of the in vivo and in vitro tooth volume measurements was too small, making it clinically nonsignificant. ANOVA test was used as a statistical tool, and no statistically significant difference was noticed among the measurements. The values were normally distributed when tested for normality by Kolmogorov‐Smirnov and Shapiro‐Wilk test. P value less than or equal to 0.05 (P ≤ 0.05) was considered statistically significant. Conclusion. The assessment of the in vivo tooth volume measurement with different three‐dimensional imaging software (VRMesh and 3Matic) programs in comparison with the tooth physical volume is reliable. The use of a mouse pen during the refining stage of the segmentation may have increased the accuracy of the procedure. The determined in vivo tooth volumes are dependable and can be applied in orthodontic diagnosis and treatment planning.
Identification and Expression Analysis of Sugar Transporter Gene Family in Aspergillus oryzae
Authors: Lv Gongbo , Jiang Chunmiao , Liang Tiantian , Tu Yayi , Cheng Xiaojie , Zeng Bin , He Bin
Published: November 2020

Sugar transporter (SUT) genes are associated with multiple physiological and biochemical processes in filamentous fungi, such as the response to various stresses. However, limited systematic analysis and functional information of SUT gene family have been available on Aspergillus oryzae (A. oryzae). To investigate the potential roles of SUTs in A. oryzae, we performed an integrative analysis of the SUT gene family in this study. Based on the conserved protein domain search, 127 putative SUT genes were identified in A. oryzae and further categorized into eight distinct subfamilies. The result of gene structure and conserved motif analysis illustrated functional similarities among the AoSUT proteins within the same subfamily. Additionally, expression profiles of the AoSUT genes at different growth stages elucidated that most of AoSUT genes have high expression levels at the stationary phase while low in the adaptive phase. Furthermore, expression profiles of AoSUT genes under salt stress showed that AoSUT genes may be closely linked to salt tolerance and involved in sophisticated transcriptional process. The protein-protein interaction network of AoSUT propounded some potentially interacting proteins. A comprehensive overview of the AoSUT gene family will offer new insights into the structural and functional features as well as facilitate further research on the roles of AoSUT genes in response to abiotic stresses.
Utilizing Technology-Enabled Intervention to Improve Blood Glucose Self-Management Outcome in Type 2 Diabetic Patients Initiated on Insulin Therapy: A Retrospective Real-World Study
Authors: Lin Jian , Li Xia , Jiang Shan , Ma Xiao , Yang Yuxin , Zhou Zhiguang
Published: November 2020

Background. The aim of this study was to assess the benefits of a mobile-enabled app through Lilly Connected Care Program (LCCP) in achieving blood glucose control and adhering to self-monitoring of blood glucose in patients with type 2 diabetes mellitus (T2DM). Methods. This retrospective study included T2DM patients who were initiated on insulin therapy (mostly premixed insulin) after failure to respond to oral antidiabetic drugs. Patients were provided with glucometers enabled with synchronous data transmission to healthcare providers and family members. The primary objective was to assess the benefits of LCCP based on changes in fasting blood glucose (FBG) and postprandial glucose (PPG) levels from baseline to 12 weeks. Paired t-test was used to assess the change in blood glucose (BG) from baseline to week 12. Results. In total, 14,085 T2DM patients were recruited. Compared with baseline, significant reductions in FBG and PPG were evident at week 12 (FBG: -0.39 mmol/L; PPG: −0.79 mmol/L; both

P
<
0.001

). Furthermore, at week 12, the proportion of patients attaining a target glucose level of FBG <7.0 mmol/L and PPG <10.0 mmol/L was 25.37% and 59.68%, respectively, with a statistically significant increase compared with that at baseline (6.74% and 45.59%, respectively, both

P
<
0.001

). The frequent monitoring of patients could gain a higher target achievement of FBG (28.1% vs 24.2%) and PPG (64.4% vs 55.1%) than the occasional monitoring patients. Additionally, the incidence of hypoglycemia gradually decreased and was significantly lower than the baseline level. Conclusions. In T2DM patients with poor glycemic control, the application of mobile enabled intervention (LCCP) along with insulin significantly reduced the hypoglycemia while improving glycemic control during period of naïve initiating insulin therapy. Additionally, the high frequency of BG self-monitoring was associated with better glycemic control.
Identification of Genetic Biomarkers for Diagnosis of Myocardial Infarction Compared with Angina Patients
Authors: Zhang Yuanyuan , Tian Chunyang , Liu Xuejian , Zhang He
Published: November 2020

Background. Myocardial infarction (MI) is the most terrible appearance of cardiovascular disease. The incidence of heart failure, one of the complications of MI, has increased in the past few decades. Therefore, the identification of MI from angina patients and the determination of new diagnoses and therapies of MI are increasingly important. The present study was aimed at identifying differentially expressed genes and miRNAs as biomarkers for the clinical and prognosis factors of MI compared with angina using microarray data analysis. Methods. Differentially expressed miRNAs and genes were manifested by GEO2R. The biological function of differentially expressed genes (DEGs) was examined by GO and KEGG. The construction of a protein-protein network was explored by STRING. cytoHubba was utilized to screen hub genes. Analysis of miRNA-gene pairs was executed by the miRWalk 3.0 database. The miRNA-target pairs overlapped with hub genes were seen as key genes. Logistic regressive analysis was performed by SPSS. Results. A number of 779 DEGs were recorded. The biological function containing extracellular components, signaling pathways, and cell adhesion was enriched. Twenty-four hub genes and three differentially expressed miRNAs were noted. Eight key genes were demonstrated, and 6 out of these 8 key genes were significantly related to clinical and prognosis factors following MI. Conclusions. CALCA, CDK6, MDM2, NRXN1, SOCS3, VEGFA, SMAD4, NCAM1, and hsa-miR-127-5p were thought to be potential diagnosis biomarkers for MI. Meanwhile, CALCA, CDK6, NRXN1, SMAD4, SOCS3, and NCAM1 were further identified to be potential diagnosis and therapy targets for MI.
The Role of Peer Mentors in Promoting Knowledge and Skills Development in Graduate Education
Authors: Lorenzetti Diane L. , Nowell Lorelli , Jacobsen Michele , Lorenzetti Liza , Clancy Tracey , Freeman Georgina , Oddone Paolucci Elizabeth
Published: November 2020

The objective of this study was to explore the role of peer mentorship in facilitating graduate student resiliency, knowledge acquisition, and development of academic competencies. We conducted a qualitative case study, using in-person interview data from sixty-two students recruited from four professional faculties (Education, Medicine, Nursing, and Social Work) at a large Canadian University. We identified four broad themes derived from a thematic and constant comparative analysis of interview data: (1) knowledge sharing, (2) skills development, (3) academic milestones, and (4) program supports. Graduate students reported that peer mentorship promoted the development of learning environments that emphasized community, collaboration, and shared purpose. Students believed that peer mentors facilitated their access to essential procedural and disciplinary knowledge and helped them to develop academic and research skills and achieve key academic milestones. While the majority of the students interviewed had not participated in any formal peer-mentoring program, they recommended that any future program incorporate mentorship training and include access to collaborative spaces and targeted opportunities for students to develop these relationships.
Multiple Firing Patterns in Coupled Hindmarsh-Rose Neurons with a Nonsmooth Memristor
Authors: Shi Xuerong , Wang Zuolei
Published: November 2020

A model is introduced by coupling two three-dimensional Hindmarsh-Rose models with the help of a nonsmooth memristor. The firing patterns dependent on the external forcing current are explored, which undergo a process from adding-period to chaos. The stability of equilibrium points of the considered model is investigated via qualitative analysis, from which it can be gained that the model has diversity in the number and stability of equilibrium points for different coupling coefficients. The coexistence of multiple firing patterns relative to initial values is revealed, which means that the referred model can appear various firing patterns with the change of the initial value. Multiple firing patterns of the addressed neuron model induced by different scales are uncovered, which suggests that the discussed model has a multiscale effect for the nonzero initial value.
A Smart Cache Content Update Policy Based on Deep Reinforcement Learning
Authors: Li Lincan , Kwong Chiew Foong , Liu Qianyu , Wang Jing
Published: November 2020

This paper proposes a DRL-based cache content update policy in the cache-enabled network to improve the cache hit ratio and reduce the average latency. In contrast to the existing policies, a more practical cache scenario is considered in this work, in which the content requests vary by both time and location. Considering the constraint of the limited cache capacity, the dynamic content update problem is modeled as a Markov decision process (MDP). Besides that, the deep Q-learning network (DQN) algorithm is utilised to solve the MDP problem. Specifically, the neural network is optimised to approximate the

Q

value where the training data are chosen from the experience replay memory. The DQN agent derives the optimal policy for the cache decision. Compared with the existing policies, the simulation results show that our proposed policy is 56%–64% improved in terms of the cache hit ratio and 56%–59% decreased in terms of the average latency.
In Situ Curing of a Polymer Film for Light‐Proof Coring of Deep Rocks with Preservation of Rock Quality and Moisture
Authors: Zhao Zhiyu , Xie Heping , Liu Tao , Wu Yifan
Published: November 2020

Deep in situ rock mechanic is of great significance for deep foundation research and engineering application. In order to explore the deep in situ mechanical law, it is necessary to maintain the in situ environment, which means to achieve fidelity coring. However, at present, there is a lack of method of deep rocks with quality‐preserving, moisture‐preserving, and light‐proof to obtain deep rock specimens, making it difficult to obtain in situ scientific information of the core. In this study, we developed a novel in situ quality‐preserving coring method of deep rocks based on an in situ film‐forming process. In this method, a solution was covered on the core, and then a sealing polymer film was formed through crosslinking reaction. Organic montmorillonite and carbon black functional fillers were incorporated to further reduce the O2 and water vapor permeability and light transmittance of the polymer sealing film. The sealing film was characterized by Fourier transform infrared spectroscopy, X‐ray diffraction, and scanning electron microscopy. Compared to the neat silicone rubber film, the O2 and water vapor permeability and light transmittance of the sealing film were reduced by 81.2%, 84.4%, and 100%, respectively. In addition, the mechanical and thermal stability of the sealing film was excellent; it showed an elongation at a break of 98.0% and a tensile strength of 0.857 MPa. Moreover, a simulator was developed and the sealing film showed an excellent quality‐preserving ability on the rock specimens. The significant improvement demonstrated that the method developed in this research may open up new opportunities for the development of the in situ quality‐preserving coring method of deep rocks and construction of deep in situ rock mechanics.
Ventricular Rupture due to Myocardial Infarction without Obstructive Coronary Artery Disease
Authors: Lapp Hendrik , Keßler Marcel , Rock Thomas , Schmid Franz X. , Shin Dong-In , Bufe Alexander , Klues Heinrich G. , Blockhaus Christian
Published: November 2020

An 87-year-old woman presenting with myocardial infarction and ST-segment elevation in the electrocardiogram suffered from pericardial effusion due to left ventricular rupture. After ruling out obstructive coronary artery disease and aortic dissection, she underwent cardiac surgery showing typical infarct-macerated myocardial tissue in situ. This case shows that even etiologically unclear and small-sized myocardial infarctions can cause life-threatening mechanical complications.
Impact of Smart City Planning and Construction on Economic and Social Benefits Based on Big Data Analysis
Authors: Zhao Zihan , Zhang Yuhan
Published: November 2020

With the progress of urbanization, urban management is facing a series of challenges in the new situation. The scale of the city is growing, urban management problems are increasingly prominent, the urban population is showing a rapid growth trend, and various elements of urban infrastructure management, such as rapid growth and urban expansion, have increased the load of urban infrastructure. To make overall planning for urban transportation, municipal administration, economic industry, and public service, intelligent urban planning and construction came into being. Big data technology provides important support for the construction and development of smart city, which is not only an effective means to improve the design of smart city, but also the premise for the development of smart city. Therefore, this paper first introduces the characteristics of smart city, analyses the application of big data technology in smart city design, and finally evaluates the impact of smart city planning and construction based on big data on economic and social benefits.
Long-Range Scalar Forces in Five-Dimensional General Relativity
Authors: Williams L. L.
Published: November 2020

We present new results regarding the long-range scalar field that emerges from the classical Kaluza unification of general relativity and electromagnetism. The Kaluza framework reproduces known physics exactly when the scalar field goes to one, so we studied perturbations of the scalar field around unity, as is done for gravity in the Newtonian limit of general relativity. A suite of interesting phenomena unknown to the Kaluza literature is revealed: planetary masses are clothed in scalar field, which contributes 25% of the mass-energy of the clothed mass; the scalar potential around a planet is positive, compared with the negative gravitational potential; at laboratory scales, the scalar charge which couples to the scalar field is quadratic in electric charge; a new length scale of physics is encountered for the static scalar field around an electrically-charged mass,

L

s

=

μ

0

Q

2

/
M

; the scalar charge of elementary particles is proportional to the electric charge, making the scalar force indistinguishable from the atomic electric force. An unduly strong electrogravitic buoyancy force is predicted for electrically-charged objects in the planetary scalar field, and this calculation appears to be the first quantitative falsification of the Kaluza unification. Since the simplest classical field, a long-range scalar field, is expected in nature, and since the Kaluza scalar field is as weak as gravity, we suggest that if there is an error in this calculation, it is likely to be in the magnitude of the coupling to the scalar field, not in the existence or magnitude of the scalar field itself.
The Use of System Dynamics Methodology in Building a COVID-19 Confirmed Case Model
Authors: Mohd Yusoff Mohd Izhan
Published: November 2020

Researchers used a hybrid model (a combination of health resource demand model and disease transmission model), Bayesian model, and susceptible-exposed-infectious-removed (SEIR) model to predict health service utilization and deaths and mixed-effect nonlinear regression. Further, they used the mixture model to predict the number of confirmed cases and deaths or to predict when the curve would flatten. In this article, we show, through scenarios developed using system dynamics methodology, besides close to real-world results, the detrimental effects of ignoring social distancing guidelines (in terms of the number of people infected, which decreased as the percentage of noncompliance decreased).
An Improved Cooperative Control Method for Hybrid Unmanned Aerial-Ground System in Multitasks
Authors: Ni Jianjun , Tang Min , Chen Yinan , Cao Weidong
Published: November 2020

The cooperative control in complex multitasks using unmanned aerial vehicle and unmanned ground vehicle (UAV/UGV) is an important and challenging issue in the multirobot cooperative field. The main goal of the task studied in this paper is to minimize the time and energy consumed by the system to complete the assigned tasks. In this paper, a complex multitask problem using the hybrid UAV/UGV system is studied, which is divided into three stages, namely, the stage of finding the optimal locations of the relay stations for the UGV; the stage of solving the path planning problem for the UGV; and the stage of the task assignment for multi-UAVs. Furthermore, an improved integrated method is proposed to deal with the cooperative control problems in these three stages. Firstly, an adaptive clustering method is proposed to determine the locations of the UGV relay stations, and then an improved cuckoo search algorithm is used to find the shortest path for the UGV. Finally, a grouping method is presented to solve the multitask allocation problem of UAVs, based on an improved dynamic programming algorithm. In addition, some simulations are carried out and the results show that the proposed method has better performance when it comes to the time and energy consumption and can effectively guide the hybrid UAV/UGV system to carry out the complex multitasks.
Nest Sidecar Savings: Lecciones para Chile de la estrategia de “frascos” para promover el ahorro previsional voluntario en el Reino Unido
Authors: Fuentes Contreras Olga , Garcia Huitron Manuel , López Fernando
Published: November 2020

Este artículo describe el programa de ahorro voluntario “Sidecar Savings” y su experiencia con la implementación de la versión piloto de “Jars” (Frascos). En un solo producto, Jars combina una cuenta de ahorro de emergencia, que no tiene restricciones para el retiro de fondos, y una cuenta de ahorro previsional tradicional que no permite retiros. Esta innovación apunta a mejorar el bienestar de las personas promoviendo la acumulación de ahorro que les permita abordar de mejor manera sus necesidades de corto y largo plazo. En relación al caso chileno, surgen dos ideas. Primero, el producto “Jars” presenta elementos que permitirían mejorar el  diseño del Ahorro Previsional Voluntario Colectivo (APVC). Segundo, la creación de una unidad de inteligencia pensional similar al “Nest Insight” contribuiría a mejorar el desarrollo y testeo de iniciativas orientadas a aumentar el ahorro y mejorar las pensiones.
Loss of Aurora Kinase Signaling Allows Lung Cancer Cells to Adopt Endoreplication and Form Polyploid Giant Cancer Cells That Resist Antimitotic Drugs
Authors: Tagal Vural , Roth Michael G.
Published: November 2020

Polyploid giant cancer cells (PGCC) are common in tumors and have been associated with resistance to cancer therapy, tumor relapse, malignancy, immunosuppression, metastasis, cancer stem cell production, and modulation of the tumor microenvironment. However, the molecular mechanisms that cause these cells to form are not yet known. In this study, we discover that Aurora kinases are synergistic determinants of a switch from the proliferative cell cycle to polyploid growth and multinucleation in lung cancer cell lines. When Aurora kinases were inhibited together, lung cancer cells uniformly grew into multinucleated PGCCs. These cells adopted an endoreplication in which the genome replicates, mitosis is omitted, and cells grow in size. Consequently, such cells continued to safely grow in the presence of antimitotic agents. These PGCC re-entered the proliferative cell cycle and grew in cell number when treatment was terminated. Thus, PGCC formation might represent a fundamental cellular response to Aurora kinase inhibitors and contributes to therapy resistance or tumor relapse.

Significance:

These findings provide a novel insight about how cancer cells respond to Aurora kinase inhibitors and identify a new mechanism responsible for resistance to these agents and other antimitotic drugs.
YAP/TAZ Transcriptional Coactivators Create Therapeutic Vulnerability to Verteporfin in EGFR-mutant Glioblastoma
Authors: Vigneswaran Krishanthan , Boyd Nathaniel H. , Oh Se-Yeong , Lallani Shoeb , Boucher Andrew , Neill Stewart G. , Olson Jeffrey J. , Read Renee D.
Published: November 2020

Purpose:

Glioblastomas (GBMs), neoplasms derived from glia and neuroglial progenitor cells, are the most common and lethal malignant primary brain tumors diagnosed in adults, with a median survival of 14 months. GBM tumorigenicity is often driven by genetic aberrations in receptor tyrosine kinases, such as amplification and mutation of EGFR.

Experimental Design:

Using a Drosophila glioma model and human patient–derived GBM stem cells and xenograft models, we genetically and pharmacologically tested whether the YAP and TAZ transcription coactivators, effectors of the Hippo pathway that promote gene expression via TEA domain (TEAD) cofactors, are key drivers of GBM tumorigenicity downstream of oncogenic EGFR signaling.

Results:

YAP and TAZ are highly expressed in EGFR-amplified/mutant human GBMs, and their knockdown in EGFR-amplified/mutant GBM cells inhibited proliferation and elicited apoptosis. Our results indicate that YAP/TAZ-TEAD directly regulates transcription of SOX2, C-MYC, and EGFR itself to create a feedforward loop to drive survival and proliferation of human GBM cells. Moreover, the benzoporphyrin derivative verteporfin, a disruptor of YAP/TAZ-TEAD–mediated transcription, preferentially induced apoptosis of cultured patient-derived EGFR-amplified/mutant GBM cells, suppressed expression of YAP/TAZ transcriptional targets, including EGFR, and conferred significant survival benefit in an orthotopic xenograft GBM model. Our efforts led us to design and initiate a phase 0 clinical trial of Visudyne, an FDA-approved liposomal formulation of verteporfin, where we used intraoperative fluorescence to observe verteporfin uptake into tumor cells in GBM tumors in human patients.

Conclusions:

Together, our data suggest that verteporfin is a promising therapeutic agent for EGFR-amplified and -mutant GBM.
Proteogenomic Analysis of Salivary Adenoid Cystic Carcinomas Defines Molecular Subtypes and Identifies Therapeutic Targets
Authors: Ferrarotto Renata , Mitani Yoshitsugu , McGrail Daniel J. , Li Kaiyi , Karpinets Tatiana V. , Bell Diana , Frank Steven J. , Song Xingzhi , Kupferman Michael E. , Liu Bin , Lee J. Jack , Glisson Bonnie S. , Zhang Jianhua , Aster Jon C. , Lin Shiaw-Yih , Futreal P. Andrew , Heymach John V. , El-Naggar Adel K.
Published: November 2020

Purpose:

Salivary gland adenoid cystic carcinoma (ACC) has heterogeneous clinical behavior. Currently, all patients are treated uniformly, and no standard-of-care systemic therapy exists for metastatic ACC. We conducted an integrated proteogenomic analyses of ACC tumors to identify dysregulated pathways and propose a classification with therapeutic implications.

Experimental Design:

RNA/DNA sequencing of 54 flash-frozen salivary ACCs and reverse phase protein array (RPPA) in 38 specimens were performed, with validation by Western blotting and/or IHC. Three independent ACC cohorts were used for validation.

Results:

Both unbiased RNA sequencing (RNA-seq) and RPPA analysis revealed two molecular subtypes: ACC-I (37%) and ACC-II (63%). ACC-I had strong upregulation of MYC, MYC target genes, and mRNA splicing, enrichment of NOTCH-activating mutations, and dramatically worse prognosis. ACC-II exhibited upregulation of TP63 and receptor tyrosine kinases (AXL, MET, and EGFR) and less aggressive clinical course. TP63 and MYC were sufficient to assign tumors to ACC subtypes, which was validated in one independent cohort by IHC and two additional independent cohorts by RNA-seq. Furthermore, IHC staining for MYC and P63 protein levels can be used to identify ACC subtypes, enabling rapid clinical deployment to guide therapeutic decisions. Our data suggest a model in which ACC-I is driven by MYC signaling through either NOTCH mutations or direct amplification, which in turn suppress P63 signaling observed in ACC-II, producing unique therapeutic vulnerabilities for each subtype.

Conclusions:

Cooccurrence of multiple actionable protein/pathways alterations in each subtype indicates unique therapeutic vulnerabilities and opportunities for optimal combination therapy for this understudied and heterogeneous disease.
A Prospective Validation and Observer Performance Study of a Deep Learning Algorithm for Pathologic Diagnosis of Gastric Tumors in Endoscopic Biopsies
Authors: Park Jeonghyuk , Jang Bo Gun , Kim Yeong Won , Park Hyunho , Kim Baek-hui , Kim Myeung Ju , Ko Hyungsuk , Gwak Jae Moon , Lee Eun Ji , Chung Yul Ri , Kim Kyungdoc , Myung Jae Kyung , Park Jeong Hwan , Choi Dong Youl , Jung Chang Won , Park Bong-Hee , Jung Kyu-Hwan , Kim Dong-Il
Published: November 2020

Purpose:

Gastric cancer remains the leading cause of cancer-related deaths in Northeast Asia. Population-based endoscopic screenings in the region have yielded successful results in early detection of gastric tumors. Endoscopic screening rates are continuously increasing, and there is a need for an automatic computerized diagnostic system to reduce the diagnostic burden. In this study, we developed an algorithm to classify gastric epithelial tumors automatically and assessed its performance in a large series of gastric biopsies and its benefits as an assistance tool.

Experimental Design:

Using 2,434 whole-slide images, we developed an algorithm based on convolutional neural networks to classify a gastric biopsy image into one of three categories: negative for dysplasia (NFD), tubular adenoma, or carcinoma. The performance of the algorithm was evaluated by using 7,440 biopsy specimens collected prospectively. The impact of algorithm-assisted diagnosis was assessed by six pathologists using 150 gastric biopsy cases.

Results:

Diagnostic performance evaluated by the AUROC curve in the prospective study was 0.9790 for two-tier classification: negative (NFD) versus positive (all cases except NFD). When limited to epithelial tumors, the sensitivity and specificity were 1.000 and 0.9749. Algorithm-assisted digital image viewer (DV) resulted in 47% reduction in review time per image compared with DV only and 58% decrease to microscopy.

Conclusions:

Our algorithm has demonstrated high accuracy in classifying epithelial tumors and its benefits as an assistance tool, which can serve as a potential screening aid system in diagnosing gastric biopsy specimens.
Expression of β-1,4-galactosyltransferases during Aging in Caenorhabditis elegans
Authors: Kremer Jennifer , Brendel Cornelia , Mack Elisabeth Karin Maria , Mack Hildegard Isolde Dietlinde
Published: November 2020

Background: Altered plasma activity of β-1,4-galac­tosyl­transferases (B4GALTs) is a novel candidate biomarker of human aging. B4GALT1 is assumed to be largely responsible for this activity increase, but how it modulates the aging process is unclear at present. Objectives: To determine how expression of B4GALT1 and other B4GALT enzymes changes during aging of an experimentally tractable model organism, Caenorhabditis elegans. Methods: Targeted analysis of mRNA levels of all 3 C. elegans B4GALT family members was performed by qPCR in wild-type and in long-lived daf-2 (insulin/IGF1-like receptor)-deficient or germline-deficient animals. Results: bre-4 (B4GALT1/2/3/4) is the only B4GALT whose expression increases during aging in wild-type worms. In addition, bre-4 levels also rise during aging in long-lived daf-2-deficient worms, but not in animals that are long-lived due to the lack of germline stem cells. On the other hand, expression of sqv-3 (B4GALT7) and of W02B12.11 (B4GALT5/6) appears decreased or constant, respectively, in all backgrounds during aging. Conclusions: The age-dependent bre-4 mRNA increase in C. elegans parallels the age-dependent B4GALT activity increase in humans and is consistent with C. elegans being a suitable experimental organism to define potentially conserved roles of B4GALT1 during aging.
Gender Dysphoria Disrupting the Course of Treatment of a Recurrent Juvenile Granulosa Cell Tumor in an Adolescent Female: A Case Report
Authors: Kwiatkowska Agnieszka , Kułak Krzysztof , Wertel Iwona
Published: November 2020

We present the case of an adolescent female patient with gender dysphoria (GD) who was diagnosed with a recurrent ovarian neoplasm – juvenile granulosa cell tumor (JGCT). The 17-year-old female patient presented multiple endocrine pathologies and a recurrent JGCT. During the surgery qualification process, the patient admitted having identified herself as a male. The patient reported being uncomfortable with her body and with the expected roles of her assigned gender. Due to that, the patient requested a total hysterectomy with a bilateral salpingo-oophorectomy. As a minor, she required the permission of her parents, which was not granted. The patient underwent several specialist consultations, after which she agreed to the unilateral removal of tumor-changed pathologies and additional hormonal, psychological, and psychiatric diagnostics. To the best of our knowledge, this is the first detailed report of co-occurrence of GD spectrum disorders and JGCT in an adolescent female. This case contains many therapeutic and ethical problems regarding both physical and mental health. It should be noted that adolescents with GD spectrum rarely develop persistent transsexuality. Modulations from developmental psychology, psychotherapy, family dynamics, hormonal treatment, and the removal of JGCT in the presented case may have potential therapeutic implications for GD.
A Case of Sporadic Cerebral Small Vessel Disease in an Identical Twin
Authors: van den Brink Hilde , Weaver Nick A. , Biessels Geert Jan
Published: November 2020

Sporadic cerebral small vessel disease (cSVD) is primarily attributed to heritability and vascular risk factors. Still, our understanding of the causative factors in cSVD lesion burden in the brain is far from complete. This is exemplified by this case of identical twins with remarkably similar vascular risk profiles, where one twin had developed severe cSVD on neuroimaging with cognitive deficits, while the other twin had no cSVD. This case highlights the need to search for further causes of cSVD, also beyond genetic and conventional vascular risk factors. Identification of other potential risk factors or disease mechanisms should be a priority for cSVD research to improve our understanding, prevention and treatment of this common cause of vascular brain injury with major clinical consequences.
Short- and Long-Term Outcomes of Simultaneous Hepatic Artery Resection and Reconstruction for Perihilar Cholangiocarcinoma
Authors: Shindo Yoshitaro , Kobayashi Shogo , Wada Hiroshi , Tokumitsu Yukio , Matsukuma Satoshi , Matsui Hiroto , Nakajima Masao , Yoshida Shin , Iida Michihisa , Suzuki Nobuaki , Takeda Shigeru , Hoshii Yoshinobu , Eguchi Hidetoshi , Nagano Hiroaki
Published: November 2020

Introduction: Because surgical resection with simultaneous hepatic artery (HA) resection and reconstruction for perihilar cholangiocarcinoma (PHC) is technically demanding, the surgical indication for this challenging procedure is controversial. Thus, this study aimed to evaluate the efficacy of simultaneous HA resection and reconstruction for PHC. Methods: Between January 2002 and January 2018, 13 patients with PHC underwent surgical intervention with simultaneous resection and reconstruction of the HA at Yamaguchi University Hospital (Ube, Japan) and Osaka University Hospital (Suita, Japan). Results: There were 2 cases (15.4%) of 90-day postoperative mortality. Nine patients (69.2%) developed major postoperative complications (Clavien-Dindo classification ≥IIIa). Curative resections (R0) were achieved in 8 cases (61.5%). The median survival time (MST) and 1- and 3-year survival rates after resection (including in-hospital deaths) were 20.9 months and 61.5 and 10.3%, respectively. The MST and 1- and 2-year survival rates of 8 patients who underwent R0 resection were significantly better than those of the other 5 patients (24.2 vs. 10.2 months, 75.0 vs. 40.0%, and 50.0 vs. 0.0%, respectively, p = 0.0228). Conclusions: Simultaneous HA resection and reconstruction is technically possible and may provide long-term survival in selected patients with locally advanced PHC.
Expression of the Peptidase “Fibroblast Activation Protein” on Decidual Stromal Cells Facilitating Tissue Remodeling
Authors: Segerer Sabine E. , Bartmann Catharina , Schwab Michael , Kämmerer Ulrike
Published: November 2020

Introduction: Expression of fibroblast activation protein (FAP) has been detected in activated fibroblasts participating in injury response, fibrotic and inflammatory conditions, and tumorigenesis. Human endometrium is equally characterized by rapid tissue remodeling events due to the reproductive tasks comprising the activity of proteolytic enzymes. Objective: We therefore hypothesized that FAP-positive fibroblasts could also be involved in physiological processes requiring tissue remodeling, such as decidualization during early pregnancy. Methods/Results: The expression of FAP was analyzed by immunohistochemistry in frozen sections of decidual tissue from early pregnancy (gestational weeks: 6–12). All tissue samples clearly displayed a strong expression of FAP on the surface of stromal fibroblasts. Additionally, the percentage of FAP-positive fibroblasts freshly isolated from the decidua of the corresponding gestational weeks was calculated by applying FACS analysis. Decidual fibroblasts of different gestational weeks showed a significant decrease in FAP expression between the 6th and 7th weeks of gestation, which was followed by a steady slow reconstitution. By analyzing the expression of cytokines, chemokines, and growth factors of isolated FAP-positive decidual fibroblasts, we detected high levels of monocyte-attracting chemokines (growth-related oncogene alpha and monocyte chemoattractant protein-1 and -2), granulocyte-attracting chemokines (e.g., IL-8), proinflammatory factors (IL-1α and tumor necrosis factor alpha), and angiogenic substances (e.g., vascular endothelial growth factor and IL-8), which all promote an optimal microenvironment for implantation and growth of the conceptus. Conclusions: Our data demonstrate that the healthy early pregnancy decidua is characterized by a general occurrence of FAP-positive fibroblasts possibly participating in active tissue remodeling during implantation.
Treatment of Chemotherapy-Induced Subungual Pyogenic Granuloma with Topical Timolol Solution
Authors: Williams Natalie M. , Morrison Brian W.
Published: November 2020

Introduction: Subungual pyogenic granuloma (PG) can be caused by numerous medications including chemotherapeutic agents. These lesions grow rapidly, oftentimes causing significant pain and bleeding, prompting patients to seek treatment. The management of subungual PG ranges from topical steroids to surgical excision. However, patients with chemotherapy-induced PGs are prone to developing multiple or recurrent lesions. Therefore, finding a therapeutic option that effectively eliminates the tumor and prevents the need for repeated procedural interventions is important. The use of topical β-adrenergic antagonists has been reported to be effective in regressing cutaneous PG. Case Presentation: In this report, we present a case of chemotherapy-induced subungual PG of the toenail arising in a 62-year-old woman that was successfully treated with topical timolol solution. Conclusion: This case highlights the promising use of timolol solution for therapeutically challenging PGs, such as those of subungual regions. This option may be particularly useful for individuals who are vulnerable to multiple PGs secondary to chemotherapy who wish to avoid repeated procedural interventions.
Deployment of a New CRRT/PIRRT Device during the COVID-19 Pandemic Emergency: Organizational Challenges and Implementation Results
Authors: Yessayan Lenar T. , Heung Michael , Girard Francine A. , Shaikhouni Salma , Szamosfalvi Balazs
Published: November 2020

Introduction: The coronavirus disease 2019 (COVID-19) pandemic led to increased demand nationwide for dialysis equipment, including supplies and machines. To meet the demand in our institution, our surge plan included rapid mobilization of a novel continuous renal replacement treatment (CRRT) machine named SAMI. The SAMI is a push-pull filtration enhanced dialysis machine that can conjugate extremely high single-pass solute removal efficiency with very precise fluid balance control. Material and Methods: Machine assembly was conducted on-site by local biomedical engineers with remote assistance by the vendor. One 3-h virtual training session of 3 dialysis nurses was conducted before SAMI deployment. The SAMI was deployed in prolonged intermittent replacement therapy (PIRRT) mode to maximize patients covered per machine per day. Live on-demand vendor support was provided to troubleshoot any issues for the first few cases. After 4 weeks of the SAMI implementation, data on treatments with the SAMI were collected, and a questionnaire was provided to the nurse trainees to assess device usability. Results: On-site installation of the SAMI was accomplished with remote assistance. Delivery of remote training was successfully achieved. 23 PIRRT treatments were conducted in 10 patients. 7/10 of patients had CO­VID-19. The median PIRRT dose was 50 mL/kg/h (IQR [interquartile range] 44 – 62 mL/kg/h), and duration of the treatment was 8 h (IQR 6.3 – 8 h). Solute control was adequate. The user response was favorable to the set of usability questions involving user interface, on-screen instructions, machine setup, troubleshooting, and the ease of moving the machine. Conclusion: Assembly of the SAMI and training of nurses remotely are possible when access to vendor employees is restricted during states of emergency. The successful deployment of the SAMI in our institution during the pandemic with only 3-h virtual training supports that operating the SAMI is simple and safe.
Population Bias in Polygenic Risk Prediction Models for Coronary Artery Disease
Authors: Gola Damian , Erdmann Jeanette , Läll Kristi , Mägi Reedik , Müller-Myhsok Bertram , Schunkert Heribert , König Inke R.
Published: November 2020

Background:

Individual risk prediction based on genome-wide polygenic risk scores (PRSs) using millions of genetic variants has attracted much attention. It is under debate whether PRS models can be applied—without loss of precision—to populations of similar ethnic but different geographic background than the one the scores were trained on. Here, we examine how PRS trained in population-specific but European data sets perform in other European subpopulations in distinguishing between coronary artery disease patients and healthy individuals.

Methods:

We use data from UK and Estonian biobanks (UKB, EB) as well as case-control data from the German population (DE) to develop and evaluate PRS in the same and different populations.

Results:

PRSs have the highest performance in their corresponding population testing data sets, whereas their performance significantly drops if applied to testing data sets from different European populations. Models trained on DE data revealed area under the curves in independent testing sets in DE: 0.6752, EB: 0.6156, and UKB: 0.5989; trained on EB and tested on EB: 0.6565, DE: 0.5407, and UKB: 0.6043; trained on UKB and tested on UKB: 0.6133, DE: 0.5143, and EB: 0.6049.

Conclusions:

This result has a direct impact on the clinical usability of PRS for risk prediction models using PRS: a population effect must be kept in mind when applying risk estimation models, which are based on additional genetic information even for individuals from different European populations of the same ethnicity.