bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of Malaria and Associated Knowledge, Attitude, and Practice among Suspected Patients in Bahir Dar Zuria District, Northwest Ethiopia
Authors: Dejazmach Zelalem , Alemu Getaneh , Yimer Mulat , Tegegne Banchamlak , Getaneh Abel
Published: October 2021

Background. Control and prevention activities have brought substantial decline of malaria incidence in the last two decades in Ethiopia. However, lack of local data on the disease transmission and community knowledge, attitude, and practice about malaria are thought to reverse the trend of malaria in certain areas. Therefore, assessment of the prevalence and community awareness towards malaria plays pivotal role for the success of malaria control and prevention. Objective. To assess malaria prevalence and knowledge, attitude, and practice about malaria among febrile patients in Bahir Dar Zuria district, Northwest Ethiopia. Methods. A facility based crosssectional study was conducted from January to March 2020 among 149 febrile patients attending selected health centers in Bahir Dar Zuria district. Data about knowledge, attitude, and practice about malaria were collected using semistructured questionnaire. Blood sample from each participant was tested for Plasmodium species through malaria rapid diagnostic tests and blood film microscopy. Data were analyzed using statistical software for social sciences version 20. Results. Among 149 participants, 22 (14.8%) were positive for Plasmodium infection at least by one diagnostic methods. Prevalence of P. falciparum and P. vivax was 3.4% and 10.1%, respectively, while that of mixed infection was 1.3%. From the total study participants, 29.5% have good knowledge, 77.2% have positive attitude, and 34.9% have good practice towards malaria. Statistically significant associations were observed on knowledge with age group (X2 = 10.377, P = 0.035), educational level (X2 = 15.075, P = 0.001), family size (X2 = 7.601, P = 0.022), attitude level and practice level. Participants with family size < 5 were 6.841 (95% CI: 2.570‐18.206, P ≤ 0.001) times more likely to have negative attitude as compared to those with family size ≥ 5. Conclusions. Prevalence of malaria in the study area was relatively high. Study participants had encouraging attitude; however, their knowledge and practice towards malaria were poor. Therefore, the existing malaria control activities should be supplemented with continuous health educations, aware the community, and ensure participation in the control and prevention activities.
An Efficient PCA‐GA‐HKSVM‐Based Disease Diagnostic Assistant
Authors: Jerop Brenda , Segera Davies Rene
Published: October 2021

Disease diagnosis faces challenges such as misdiagnosis, lack of diagnosis, and slow diagnosis. There are several machine learning techniques that have been applied to address these challenges, where a set of symptoms is applied to a classification model that predicts the presence or absence of a disease. To improve on the performance of these techniques, this paper presents a technique which involves feature selection using principal component analysis (PCA), a hybrid kernel‐based support vector machine (HKSVM) classification model and hyperparameter optimization using genetic algorithm (GA). The HKSVM in this paper introduces a new way of combining three kernels: Radial basis function (RBF), linear, and polynomial. Combining local (RBF) and global (linear and polynomial) kernels has the effect of improved model performance. This is because the local kernels are better able to distinguish points closer to each other while the global kernels are more suited to distinguish points that are far away from each other. The PCA‐GA‐HKSVM is used on 7 different medical datasets, with two datasets being multiclass datasets and 5 datasets being binary. Performance evaluation metrics used were accuracy, precision, and recall. It was observed that the PCA‐GA‐HKSVM offered better performance than the single kernel support vector machines (SVMs).
Construction of Modularized English Teaching Platform for Multimedia Wireless Network Based on NS2 Simulation Software
Authors: Li Wei , Wang Xin
Published: October 2021

Using the NS2 network simulation tool to teach the “wireless network” course can enhance students’ understanding of wireless network protocols through visualization and can also improve students’ ability to analyze problems hands on. We built a multimedia wireless network modularized English teaching platform based on NS2 simulation software; made full use of the rich components and network resources provided by NS2 to achieve a high degree of code reuse and reduce the time for developing simulation codes; designed the overall framework of this multimedia wireless network modular English teaching platform based on the B/S structure; and solved the weight coefficient and importance value of the learning input evaluation index, based on the feedback elite teaching optimization algorithm, the improved teaching formula, the increase in the number of exchanges, and the improvement in the learner’s performance. The experimental results show that the LEACH and LEACH-C protocols of the clustered NS2 simulation software have more surviving nodes most of the time, which indicates that the clustering routing protocol has better performance.
PRMT7: A Pivotal Arginine Methyltransferase in Stem Cells and Development
Authors: Wang Bingyuan , Zhang Mingrui , Liu Zhiguo , Mu Yulian , Li Kui
Published: October 2021

Protein arginine methylation is a posttranslational modification catalyzed by protein arginine methyltransferases (PRMTs), which play critical roles in many biological processes. To date, nine PRMT family members, namely, PRMT1, 2, 3, 4, 5, 6, 7, 8, and 9, have been identified in mammals. Among them, PRMT7 is a type III PRMT that can only catalyze the formation of monomethylarginine and plays pivotal roles in several kinds of stem cells. It has been reported that PRMT7 is closely associated with embryonic stem cells, induced pluripotent stem cells, muscle stem cells, and human cancer stem cells. PRMT7 deficiency or mutation led to severe developmental delay in mice and humans, which is possibly due to its crucial functions in stem cells. Here, we surveyed and summarized the studies on PRMT7 in stem cells and development in mice and humans and herein provide a discussion of the underlying molecular mechanisms. Furthermore, we also discuss the roles of PRMT7 in cancer, adipogenesis, male reproduction, cellular stress, and cellular senescence, as well as the future perspectives of PRMT7-related studies. Overall, PRMT7 mediates the proliferation and differentiation of stem cells. Deficiency or mutation of PRMT7 causes developmental delay, including defects in skeletal muscle, bone, adipose tissues, neuron, and male reproduction. A better understanding of the roles of PRMT7 in stem cells and development as well as the underlying mechanisms will provide information for the development of strategies for in-depth research of PRMT7 and stem cells as well as their applications in life sciences and medicine.
Optimization and Mechanical Characteristics of Spatial Arc Antislide Pile
Authors: Deng You-Sheng , Peng Cheng-Pu , Liu Jun-Cong , Li Ling-Tao , Fu Yun-Bo
Published: October 2021

To improve the stress state of traditional antislide pile and utilize the stable soil on both sides of a landslide and slope foot, a spatial arc antislide pile supporting structure was proposed. Based on numerical calculation, a parametric study was conducted to assess the influence of the rise‐span ratio on the stress state of the supporting structure, the displacement of the pile top, and the earth pressure in the front of the pile. The optimal rise‐span ratio was 3‐16 according to the numerical simulation results. An indoor model test at the optimal rise‐span ratio was carried out, recording the pile strain and the earth pressure in front of the pile. The results showed that some indices increased with the increase in rise‐span ratio, such as the load transferred to the pile at the arch foot, the bending moment of the piles, the displacement of the pile top, and the earth pressure; within a certain depth near the pile top, the soil in front of the pile is loose during the loading processes, and the earth pressure at the range was zero. The overall safety factors of the four supporting models were 2.42, 2.66, 2.78, and 2.84, respectively, which can satisfy the requirements for practical engineering. The test results verify the feasibility and rationality of the spatial arc antislide pile supporting structure, which can provide a new idea for landslide treatment.
Research on Slope Stability Evaluation Based on Improved Set Pair Analysis Method: A Case of Tonglvshan Open‐Pit Mine
Authors: Yang Xiaojie , Hao Zhenli , Ma Gaotong , Li Gan
Published: October 2021

In this paper, combined with fuzzy analytic hierarchy process (FAHP), information entropy theory, and set pair analysis (SPA) theory, an improved set pair analysis model (EFAHP‐SPA) for open‐pit mine slope stability evaluation based on entropy method and FAHP is proposed. Taking the east‐side slope of Tonglvshan north open‐pit mine in Daye as an example, the proposed method is verified. First, an open‐pit mine slope stability evaluation index system with 14 indicators in 4 categories, namely the topography and geomorphology, geological structure, hydrogeology, and other factors, have been constructed. Second, the objective weight and subjective weight of each evaluation index are calculated by entropy and fuzzy analytic hierarchy process, and then the comprehensive weight of the evaluation index is estimated based on subjective weight and objective weight. Afterward, the single‐index connection degree between the evaluation index and the evaluation standard of the secondary subsystem is evaluated considering the improved set pair analysis theory, and the comprehensive connection degree of the system is obtained by combining it with the comprehensive weight of each evaluation index. Finally, the confidence criterion is established to discern the risk grade of slope stability in the east‐side slope of the north open pit in Daye Tonglvshan mine. Moreover, case studies and comparisons of the proposed model with fuzzy comprehensive evaluation method and Entropy‐SPA model were performed to confirm the validity and reliability. The results show that the evaluation results of the proposed EFAHP‐SPA model are consistent with the actual situation of open‐pit mines and the evaluation results of entropy‐SPA model and are somewhat different from those of fuzzy comprehensive evaluation method. It indicates that the proposed EFAHP‐SPA evaluation model can objectively evaluate the slope stability of the open‐pit mine.
Some New Observations on Wijsman

ℐ

2

-Lacunary Statistical Convergence of Double Set Sequences in Intuitionistic Fuzzy Metric Spaces
Authors: Kişi Ömer
Published: October 2021

In this study, we investigate the notions of the Wijsman

ℐ

2

-statistical convergence, Wijsman

ℐ

2

-lacunary statistical convergence, Wijsman strongly

ℐ

2

-lacunary convergence, and Wijsman strongly

ℐ

2

-Cesàro convergence of double sequence of sets in the intuitionistic fuzzy metric spaces (briefly, IFMS). Also, we give the notions of Wijsman strongly

ℐ
2
∗

-lacunary convergence, Wijsman strongly

ℐ

2

-lacunary Cauchy, and Wijsman strongly

ℐ
2
∗

-lacunary Cauchy set sequence in IFMS and establish noteworthy results.
Enhancing Human-Computer Interaction in Digital Repositories through a MCDA-Based Recommender System
Authors: Troussas Christos , Krouska Akrivi , Sgouropoulou Cleo
Published: October 2021

Digital repositories contain a large amount of content, which is available to heterogeneous groups of people. As such, in many cases people encounter difficulties in finding specific content which is related to their preferences. In view of this compelling need and towards advancing human-computer interaction, this paper presents a recommender system which is incorporated in a digital repository. The recommender system is designed using multiple-criteria decision analysis (MCDA) and more specifically the weighted sum model (WSM) in order to refine the delivered content to the users. It also considers several users’ characteristics (their preferences as depicted by the content they visited or searched and by the frequency of searches/visits) and features of the content (content types and traffic). The recommender system outputs the suggestions of content to users based on their preferences and interests. The presented recommender system was evaluated by real users, and the results show a high degree of accuracy in the recommended content and satisfaction by users.
[Retracted] Protein Arginine Methyltransferase 5 Promotes the Migration of AML Cells by Regulating the Expression of Leukocyte Immunoglobulin‐Like Receptor B4
Authors: Zhao Lu , Cheng Bingqing , Xiong Jie , Ma Dan , Liu Xin , Wang Li , Zhang Xi , Wang Jishi
Published: October 2021

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults with poor prognosis. Especially for AML‐M5 type, due to the strong cell migration ability, the possibility of extramedullary invasion is large and widespread, which leads to poor therapeutic effect. Previous studies have found that protein arginine methyltransferase 5 (PRMT5) could promote the proliferation and differentiation of leukemic cells in AML, but its regulation on the invasive ability of AML cells remains unclear. This study was designed to explore the role of PRMT5 in regulating the invasion of AML cells and to investigate the mechanisms. Patient samples were collected for detection of PRMT5 expression level. AML cells were used for exploring the function of PRMT5. The results of clinical samples showed that the expression of PRMT5 was significantly increased in newly diagnosed and recurrent AML patients, and the expression of leukocyte immunoglobulin‐like receptor B4 (LILRB4) was positively correlated with the level of PRMT5. In the cell experiment in vitro, we found that when PRMT5 was knocked down, the invasion, migration, and adhesion capacities of MV‐4‐11 cells and THP‐1 cells were decreased, and the mRNA and protein levels of LILRB4 were also decreased. Moreover, we screened related signaling pathways and found that PRMT5 affected the expression of downstream LILRB4 by activating mTOR pathway, which in turn enhanced the invasive ability of AML cells. Taken together, PRMT5 plays an important role in the invasion of AML, which acts via regulating the expression of LILRB4. PRMT5 could act as a potential therapeutic candidate for AML.
Botanical Drug Puerarin Ameliorates Liposaccharide‐Induced Depressive Behaviors in Mice via Inhibiting RagA/mTOR/p70S6K Pathways
Authors: Zhao Jia , Jia Yizhen , Zhao Wei , Chen Huixin , Zhang Xiuying , Ngo Fung Yin , Luo Dan , Song Youqiang , Lao Lixing , Rong Jianhui
Published: October 2021

Background. The depressive symptom hallmarks the progression of the neurodegenerative diseases, especially Alzheimer’s disease. Bacterial infection is related to inflammation and depression. The present project thereby examined whether botanical drug puerarin could attenuate liposaccharide‐ (LPS‐) induced depressive behaviors in mice. Methods. Adult male C57BL/6N mice were sequentially treated with LPS and puerarin and evaluated for the depressive behaviors by tail suspension test and forced swim test. The brain tissues were profiled for the molecular targets of puerarin by next‐generation RNA sequencing technique. Candidate targets were further verified in LPS‐treated mice, neural stem cells, and highly differentiated PC12 cell line. Results. Puerarin ameliorated LPS‐induced depression in the mice. RNA sequencing profiles revealed that puerarin altered the expression of 16 genes while markedly downregulated Ras‐related GTP‐binding protein A (RagA) in LPS‐treated mice. The effect of puerarin on RagA expression was confirmed by immunostaining, Western blot, and quantitative real‐time PCR (qRT‐PCR). Biochemical studies showed that puerarin inhibited RagA/mTOR/p70S6K pathway, attenuated the accumulation of mTORC1 in close proximity to lysosome, and reduced the production of proinflammatory cytokines. Conclusions. Botanical drug puerarin attenuated inflammation and depressive behaviors in LPS‐challenged mice by inhibiting RagA/mTOR/p70S6K pathways. Puerarin may be a lead compound for the new antidepressant drugs.
Association between Neutrophil Gelatinase‐Associated Lipocalin and Fetal Hemoglobin Levels in Patients with Type 2 Diabetes Mellitus
Authors: Choi Jong Weon , Lee Moon Hee , Fujii Tatsuyoshi
Published: October 2021

The effect of neutrophil gelatinase‐associated lipocalin (NGAL) on fetal hemoglobin (HbF) levels in diabetic patients is rarely investigated. This study is aimed at investigating the possible association between NGAL and HbF levels in type 2 diabetes mellitus (T2DM). A total of 160 patients with T2DM and 61 healthy individuals were evaluated. NGAL, HbF, tumor necrosis factor‐α (TNF‐α), interleukin‐5 (IL‐5), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and urine albumin levels were measured. HbF levels were significantly higher in patients with elevated NGAL than in those without elevated NGAL (1.44% versus 0.94%, P = 0.001). High HbF was 2.3 times more prevalent in patients with elevated NGAL than in those without elevated NGAL. In addition, NGAL, TNF‐α, and IL‐5 levels were significantly higher in patients with high HbF than in those with low HbF; however, there was no significant difference in HbA1c and FPG levels between the two groups. HbF was positively correlated with NGAL (r = 0.275, P < 0.001), TNF‐α (r = 0.256, P < 0.001), and IL‐5 (r = 0.212, P < 0.001), but not with HbA1c and FPG. An elevated NGAL level led to a 1.27‐fold increase in the prevalence of high HbF (odds ratio: 1.27, 95% CI: 1.03–2.51, and P < 0.001). The diagnostic efficacy of NGAL to identify an elevated HbF level was superior to that of HbA1c (area under the curve: 0.697, 95% CI: 0.609–0.786 versus 0.584, 95% CI: 0.488–0.681, and P = 0.022). In conclusion, enhanced NGAL production may be closely linked to elevated HbF in conjunction with proinflammatory cytokines in patients with T2DM.
Multidisciplinary Approach for Full-Mouth Rehabilitation of a Young Adult Patient with Ameloblastoma
Authors: Liao Hung-Yi , Chen May-Show , Yang Ya-Fen , Liao Pei-Bang , Feng Sheng-Wei , Juan Po-kai
Published: October 2021

Ameloblastoma is a benign but locally invasive neoplasm of the odontogenic epithelium that tends to grow slowly in the mandible or maxilla. It can be highly destructive to the surrounding dental anatomy and can cause death by progressive spread to nearby vital structures in rare cases. Marginal resection is the most effective method of eliminating the tumor, but treatment can further contribute to oral and dental deformity and malfunction. This clinical report describes the dental rehabilitation of a young adult patient diagnosed with ameloblastoma and underwent preliminary marsupialization, segmental mandibulectomy, and fibula free flap reconstruction, followed by mandibular dental implant placements. Orthodontic and rapid palatal expansion for maxillary arch correction was also performed. The treatment goal of regaining dental function and a satisfactory appearance was accomplished.
Kinetics of Neutralizing Antibody Response Underscores Clinical COVID-19 Progression
Authors: Lei Qing , Hou Hongyan , Yu Caizheng , Zhang Yandi , Ndzouboukou Jo-Lewis Banga , Lin Xiaosong , Yao Zongjie , Fu Hui , Sun Ziyong , Wang Feng , Fan Xionglin
Published: October 2021

Background. Neutralizing antibody (nAb) response is generated following infection or immunization and plays an important role in the protection against a broad of viral infections. The role of nAb during clinical progression of coronavirus disease 2019 (COVID-19) remains little known. Methods. 123 COVID-19 patients during hospitalization in Tongji Hospital were involved in this retrospective study. The patients were grouped based on the severity and outcome. The nAb responses of 194 serum samples were collected from these patients within an investigation period of 60 days after the onset of symptoms and detected by a pseudotyped virus neutralization assay. The detail data about onset time, disease severity and laboratory biomarkers, treatment, and clinical outcome of these participants were obtained from electronic medical records. The relationship of longitudinal nAb changes with each clinical data was further assessed. Results. The nAb response in COVID-19 patients evidently experienced three consecutive stages, namely, rising, stationary, and declining periods. Patients with different severity and outcome showed differential dynamics of the nAb response over the course of disease. During the stationary phase (from 20 to 40 days after symptoms onset), all patients evolved nAb responses. In particular, high levels of nAb were elicited in severe and critical patients and older patients (≥60 years old). More importantly, critical but deceased COVID-19 patients showed high levels of several proinflammation cytokines, such as IL-2R, IL-8, and IL-6, and anti-inflammatory cytokine IL-10 in vivo, which resulted in lymphopenia, multiple organ failure, and the rapidly decreased nAb response. Conclusion. Our results indicate that nAb plays a crucial role in preventing the progression and deterioration of COVID-19, which has important implications for improving clinical management and developing effective interventions.
Two-Layer Optimization Algorithm for Multi-UAV Conflict Resolution considering Individual Fairness
Authors: Gan Xusheng , Zhang Honghong , Wu Yarong , Sun Jingjuan , Zhao Guhao , Lin Fugen
Published: October 2021

In order to solve the unfair individual payment costs problem in the low-altitude unmanned aerial vehicle (UAV) conflict resolution process, a multi-UAV conflict resolution algorithm based on the cooperative game concept “coalition complaint value” is proposed. Firstly, based on the low-altitude multi-UAV conflict scene characteristics, according to the “coalition complaint value” concept, the UAV conflict resolution payment matrix is established. Secondly, combined with the advantages of the artificial potential field (APF) method and the genetic algorithm (GA), a hybrid solution strategy for conflict resolution based on APF-GA is proposed. The final simulation results show that the APF-GA hybrid solution strategy has the best efficiency by combining the three evaluation indicators of calculation time, feasibility, and system efficiency. The reliability of the proposed algorithm is verified based on the Monte Carlo algorithm. The solution strategy based on the cooperative game “coalition complaint value” can improve individual fairness to a certain extent. At the same time, it can achieve the rapid planning goal with priority drones at the expense of a small amount of overall benefits.
Computational Analysis of Missense Variants in the Human Transmembrane Protease Serine 2 (TMPRSS2) and SARS‐CoV‐2
Authors: Saih Asmae , Bouqdayr Meryem , Baba Hanâ , Hamdi Salsabil , Moussamih Samya , Bennani Houda , Saile Rachid , Wakrim Lahcen , Kettani Anass
Published: October 2021

The human transmembrane protease serine 2 (TMPRSS2) protein plays an important role in prostate cancer progression. It also facilitates viral entry into target cells by proteolytically cleaving and activating the S protein of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). In the current study, we used different available tools like SIFT, PolyPhen2.0, PROVEAN, SNAP2, PMut, MutPred2, I‐Mutant Suite, MUpro, iStable, ConSurf, ModPred, SwissModel, PROCHECK, Verify3D, and TM‐align to identify the most deleterious variants and to explore possible effects on the TMPRSS2 stability, structure, and function. The six missense variants tested were evaluated to have deleterious effects on the protein by SIFT, PolyPhen2.0, PROVEAN, SNAP2, and PMut. Additionally, V160M, G181R, R240C, P335L, G432A, and D435Y variants showed a decrease in stability by at least 2 servers; G181R, G432A, and D435Y are highly conserved and identified posttranslational modifications sites (PTMs) for proteolytic cleavage and ADP‐ribosylation using ConSurf and ModPred servers. The 3D structure of TMPRSS2 native and mutants was generated using 7 meq as a template from the SwissModeller group, refined by ModRefiner, and validated using the Ramachandran plot. Hence, this paper can be advantageous to understand the association between these missense variants rs12329760, rs781089181, rs762108701, rs1185182900, rs570454392, and rs867186402 and susceptibility to SARS‐CoV‐2.
Persistence and Changing Distribution of Leishmaniases in Kenya Require a Paradigm Shift
Authors: Ouma Francan F. , Mulambalah Chrispinus S.
Published: October 2021

Background. Leishmaniases present a major global public health problem, being responsible for between 40,000 and 50,000 deaths annually. The resultant morbidity affects the economic productivity and quality of life of individuals in endemic regions. As zoonotic disease(s), leishmaniases have become persistent with intermittent transmission and a tendency to disappear and reemerge, straining the fragile healthcare infrastructure in Kenya. There is a need to better understand disease(s) dynamics in Kenya. Objectives of the study. The status of leishmaniases in Kenya was reviewed to refocus and influence the attention of the scientific community and intervention strategies/policies on this persistent public health problem. Methodology. Electronic and manual literature were searched for relevant scholarly peer-reviewed published articles on leishmaniases. Literatures were obtained from PubMed, Medline, EBSCO, Host, ScienceDirect, and Google Scholar. Findings. The diseases are reported to be persistent as emerging and reemerging within and outside traditional endemic regions. Cutaneous leishmaniasis (CL) has maintained restricted foci in Nyandarua, Baringo, Nakuru counties, and Mount Elgon area in Bungoma County. Visceral leishmaniasis (VL) was most prevalent with cases in Baringo, Turkana, West Pokot, Isiolo, Kitui, Meru, Machakos, Marsabit, and Wajir counties. New VL cases/foci reported in formerly nonendemic regions/beyond traditional foci of Garissa and Mandera counties. Diagnostics, management, and control strategies have remained unchanged even in the face of changing disease epidemiology. Conclusion. Leishmaniases are emerging and reemerging persistent infections in remote rural settings in Kenya. The adopted intervention strategies have not been effective over the years, and this has led to disease spread to formerly nonendemic areas of Kenya. The diseases spread have been further enhanced by population growth and movement, environmental and climate changes, and social conflicts. It is evident that without a paradigm shift in control methods, diagnostic techniques, and treatment protocols, the diseases may spread to even more areas in the country.
Patterns of Carbon-Bound Exogenous Compounds in Patients with Lung Cancer and Association with Disease Pathophysiology
Authors: Kunzke Thomas , Prade Verena M. , Buck Achim , Sun Na , Feuchtinger Annette , Matzka Marco , Fernandez Isis E. , Wuyts Wim , Ackermann Maximilian , Jonigk Danny , Aichler Michaela , Schmid Ralph A. , Eickelberg Oliver , Berezowska Sabina , Walch Axel
Published: October 2021

Asymptomatic anthracosis is the accumulation of black carbon particles in adult human lungs. It is a common occurrence, but the pathophysiologic significance of anthracosis is debatable. Using in situ high mass resolution matrix-assisted laser desorption/ionization (MALDI) fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry imaging analysis, we discovered noxious carbon-bound exogenous compounds, such as polycyclic aromatic hydrocarbons (PAH), tobacco-specific nitrosamines, or aromatic amines, in a series of 330 patients with lung cancer in highly variable and unique patterns. The characteristic nature of carbon-bound exogenous compounds had a strong association with patient outcome, tumor progression, the tumor immune microenvironment, programmed death-ligand 1 (PD-L1) expression, and DNA damage. Spatial correlation network analyses revealed substantial differences in the metabolome of tumor cells compared with tumor stroma depending on carbon-bound exogenous compounds. Overall, the bioactive pool of exogenous compounds is associated with several changes in lung cancer pathophysiology and correlates with patient outcome. Given the high prevalence of anthracosis in the lungs of adult humans, future work should investigate the role of carbon-bound exogenous compounds in lung carcinogenesis and lung cancer therapy.

Significance:

This study identifies a bioactive pool of carbon-bound exogenous compounds in patient tissues associated with several tumor biological features, contributing to an improved understanding of drivers of lung cancer pathophysiology.
Temporal Muscle Thickness as a Prognostic Marker in Patients with Newly Diagnosed Glioblastoma: Translational Imaging Analysis of the CENTRIC EORTC 26071–22072 and CORE Trials
Authors: Furtner Julia , Weller Michael , Weber Michael , Gorlia Thierry , Nabors Burt , Reardon David A. , Tonn Joerg C. , Stupp Roger , Preusser Matthias
Published: October 2021

Purpose:

To investigate the prognostic relevance of temporal muscle thickness (TMT) as a surrogate parameter of skeletal muscle status in patients with newly diagnosed glioblastoma.

Experimental Design:

We assessed TMT in cranial MRI of 755 patients enrolled in the CENTRIC EORTC 26071–22072 study (n = 508) and CORE study (n = 247). We used predefined sex-specific TMT cut-off values to categorize “patients at risk of sarcopenia” and “patients with normal muscle status” at baseline. Furthermore, we categorized patients according to the extent of TMT loss over time. Associations with progression-free survival (PFS) and overall survival (OS) were evaluated using the Cox model adjusted for other exploratory variables.

Results:

Patients at risk of sarcopenia (CENTRIC; n = 158/508, 31.1%; CORE; n = 87/247, 35.2%) at baseline had significantly higher risk of progression and death than patients with normal muscle status in both study cohorts [CENTRIC: PFS = HR 0.16; 95% confidence interval (CI), 0.12–0.21; P < 0.001; OS = HR 0.341; 95% CI, 0.27–0.44; P < 0.001; CORE: PFS = HR 0.29; 95% CI, 0.21–0.39; P < 0.001; OS = HR, 0.365; 95% CI, 0.27–0.49; P < 0.001]. Similar results were obtained in multivariate Cox models adjusted for other important prognostic parameters. The extent of TMT loss over time showed a significant inverse correlation with median OS times in patients at risk for sarcopenia (CENTRIC: P < 0.001; CORE: P = 0.005), but not in patients with normal baseline muscle mass (CENTRIC: P = 0.538; CORE: P = 0.28).

Conclusions:

TMT identifies ambulatory patients with newly diagnosed glioblastoma at risk for progressive sarcopenia and adverse outcomes. Early intervention may prevent skeletal muscle loss and improve patient outcome.
Differences in Prostate Cancer Genomes by Self-reported Race: Contributions of Genetic Ancestry, Modifiable Cancer Risk Factors, and Clinical Factors
Authors: Stopsack Konrad H. , Nandakumar Subhiksha , Arora Kanika , Nguyen Bastien , Vasselman Samantha E. , Nweji Barbara , McBride Sean M. , Morris Michael J. , Rathkopf Dana E. , Slovin Susan F. , Danila Daniel C. , Autio Karen A. , Scher Howard I. , Mucci Lorelei A. , Solit David B. , Gönen Mithat , Chen Yu , Berger Michael F. , Schultz Nikolaus , Abida Wassim , Kantoff Philip W.
Published: October 2021

Purpose:

Black men die from prostate cancer twice as often as White men, a disparity likely due to inherited genetics, modifiable cancer risk factors, and healthcare access. It is incompletely understood how and why tumor genomes differ by self-reported race and genetic ancestry.

Experimental Design:

Among 2,069 men with prostate cancer (1,841 self-reported White, 63 Asian, 165 Black) with access to clinical-grade sequencing at the same cancer center, prevalence of tumor and germline alterations was assessed in cancer driver genes reported to have different alteration prevalence by race.

Results:

Clinical characteristics such as prostate-specific antigen and age at diagnosis as well as cancer stage at sample procurement differed by self-reported race. However, most genomic differences persisted when adjusting for clinical characteristics. Tumors from Black men harbored fewer PTEN mutations and more AR alterations than those from White men. Tumors from Asian men had more FOXA1 mutations and more ZFHX3 alterations than White men. Despite fewer TP53 mutations, tumors from Black men had more aneuploidy, particularly chromosome arm 8q gains, an adverse prognostic factor. Genetic ancestry was associated with similar tumor alterations as self-reported race, but also with modifiable cancer risk factors. Community-level average income was associated with chr8q gains after adjusting for race and ancestry.

Conclusions:

Tumor genomics differed by race even after accounting for clinical characteristics. Equalizing access to care may not fully eliminate such differences. Therapies for alterations more common in racial minorities are needed. Tumor genomic differences should not be assumed to be entirely due to germline genetics.
Neoadjuvant and Adjuvant Nivolumab and Lirilumab in Patients with Recurrent, Resectable Squamous Cell Carcinoma of the Head and Neck
Authors: Hanna Glenn J. , O'Neill Anne , Shin Kee-Young , Wong Kristine , Jo Vickie Y. , Quinn Charles T. , Cutler Jennifer M. , Flynn Michelle , Lizotte Patrick H. , Annino Donald J. , Goguen Laura A. , Kass Jason I. , Rettig Eleni M. , Sethi Rosh K.V. , Lorch Jochen H. , Schoenfeld Jonathan D. , Margalit Danielle N. , Tishler Roy B. , Everett Peter C. , Desai Anupam M. , Cavanaugh Megan E. , Paweletz Cloud P. , Egloff Ann Marie , Uppaluri Ravindra , Haddad Robert I.
Published: October 2021

Purpose:

Surgery often represents the best chance for disease control in locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We investigated dual immune-checkpoint inhibition [anti–PD-1, nivolumab (N), and anti-KIR, lirilumab (L)] before and after salvage surgery to improve disease-free survival (DFS).

Patients and Methods:

In this phase II study, patients received N (240 mg) + L (240 mg) 7 to 21 days before surgery, followed by six cycles of adjuvant N + L. Primary endpoint was 1-year DFS; secondary endpoints were safety, pre-op radiologic response, and overall survival (OS). Correlatives included tumor sequencing, PD-L1 scoring, and immunoprofiling.

Results:

Among 28 patients, the median age was 66, 86% were smokers; primary site: 9 oral cavity, 9 oropharynx, and 10 larynx/hypopharynx; 96% had prior radiation. There were no delays to surgery. Grade 3+ adverse events: 11%. At the time of surgery, 96% had stable disease radiologically, one had progression. Pathologic response to N + L was observed in 43% (12/28): 4/28 (14%) major (tumor viability, TV ≤ 10%) and 8/28 (29%) partial (TV ≤ 50%). PD-L1 combined positive score (CPS) at surgery was similar regardless of pathologic response (P = 0.71). Thirteen (46%) recurred (loco-regional = 10, distant = 3). Five of 28 (18%) had positive margins, 4 later recurred. At median follow-up of 22.8 months, 1-year DFS was 55.2% (95% CI, 34.8–71.7) and 1-year OS was 85.7% (95% CI, 66.3–94.4). Two-year DFS and OS were 64% and 80% among pathologic responders.

Conclusions:

(Neo)adjuvant N + L was well tolerated, with a 43% pathologic response rate. We observed favorable DFS and excellent 2-year OS among high-risk, previously treated patients exhibiting a pathologic response. Further evaluation of this strategy is warranted.
Targeting CD99 Compromises the Oncogenic Effects of the Chimera EWS–FLI1 by Inducing Reexpression of Zyxin and Inhibition of GLI1 Activity
Authors: Balestra Tommaso , Manara Maria Cristina , Laginestra Maria Antonella , Pasello Michela , De Feo Alessandra , Bassi Cristian , Guerzoni Clara , Landuzzi Lorena , Lollini Pier-Luigi , Donati Davide Maria , Negrini Massimo , Magnani Mauro , Scotlandi Katia
Published: October 2021

Ewing sarcoma, a highly aggressive pediatric tumor, is driven by EWS–FLI1, an oncogenic transcription factor that remodels the tumor genetic landscape. Epigenetic mechanisms play a pivotal role in Ewing sarcoma pathogenesis, and the therapeutic value of compounds targeting epigenetic pathways is being identified in preclinical models. Here, we showed that modulation of CD99, a cell surface molecule highly expressed in Ewing sarcoma cells, may alter transcriptional dysregulation in Ewing sarcoma through control of the zyxin–GLI1 axis. Zyxin is transcriptionally repressed, but GLI1 expression is maintained by EWS–FLI1. We demonstrated that targeting CD99 with antibodies, including the human diabody C7, or genetically inhibiting CD99 is sufficient to increase zyxin expression and induce its dynamic nuclear accumulation. Nuclear zyxin functionally affects GLI1, inhibiting targets such as NKX2–2, cyclin D1, and PTCH1 and upregulating GAS1, a tumor suppressor protein negatively regulated by SHH/GLI1 signaling. We used a battery of functional assays to demonstrate (i) the relationship between CD99/zyxin and tumor cell growth/migration and (ii) how CD99 deprivation from the Ewing sarcoma cell surface is sufficient to specifically affect the expression of some crucial EWS–FLI1 targets, both in vitro and in vivo, even in the presence of EWS–FLI1. This article reveals that the CD99/zyxin/GLI1 axis is promising therapeutic target for reducing Ewing sarcoma malignancy.
Distinct Characteristics of Sweet’s Syndrome of the Scrotum Caused by All-trans Retinoic Acid in a Patient with Acute Promyelocytic Leukemia
Authors: Imataki Osamu , Yoshida Shunsuke , Kaji Tomohiro , Kida Jun-ichiro , Kubo Hiroyuki , Uemura Makiko , Fujita Haruyuki , Kadowaki Norimitsu
Published: October 2021

Induction therapy with all-trans retinoic acid (ATRA) is effective for acute promyelocytic leukemia (APL). ATRA induces neutrophil differentiation and its associated side effects. The differentiation syndrome is the most characterized ATRA-induced adverse effect. Sweet’s syndrome, also known as neutrophilic dermatosis, is another form of ATRA-associated disease characterized by neutrophil infiltrating erythema that develops with fever. This is a case of a 34-year-old Japanese man diagnosed with APL. At the onset, the patient did not have skin involvement of APL cells. He was treated with ATRA and induction chemotherapy with idarubicin and cytarabine. Scrotal skin rash occurred at day 14, which developed into scrotal ulceration up to day 28 even after eliminating APL cells in his peripheral blood. Sweet’s syndrome is a pathological diagnosis of scrotal skin ulceration representing neutrophil infiltration. The infiltrating neutrophils showed PML-RARα rearrangement. The patient was diagnosed with ATRA-associated Sweet’s syndrome with skin ulcer. His cutaneous lesion did not respond to intravenous prednisolone therapy; thereby, ATRA was discontinued. After the cessation of ATRA, the skin lesion improved in the next week. We confirmed he achieved a complete response after induction chemotherapy. In our observation, ATRA-associated Sweet’s syndrome is characterized by the following clinical manifestations: preferable occurrence in the scrota, tend to progress into skin ulcer, and pathogenicity associated with PML-RARα-positive matured neutrophils. The etiology, pathogenesis, and risk factors of ATRA-associated scrotal ulceration were discussed in the literature review.
The Proliferating and Malignant Proliferating Trichilemmal Cyst: An Anatomo-Clinical Study of Three Cases
Authors: Benslimane Kamal Ibtissam , Hali Fouzia , Marnissi Farida , Chiheb Soumiya
Published: October 2021

Background: The proliferating and malignant proliferating trichilemmal cysts (MPTC) are rare adnexal tumors. We report 3 cases through which we will detail the anatomo-clinical characteristics of these tumors. Cases: Two patients, 60 and 56 years old, consulted for multiple scalp nodules, one of which had changed with the appearance of a central ulceration. The removal of the remaining scalp nodules was in favor of PTCs. The third patient presented with an ulcerative lesion occupying the vertex. Skin biopsy found trichilemmal-type keratinization associated with areas of necrosis concluding with a MPTC. Discussion: The PTC is a transitional form between the trichilemmal cyst (TC) and the MPTC. The increase in the size of a TC and ulceration are sufficient signals to suspect this evolution.
Identifying High-Risk Triple-Negative Breast Cancer Patients by Molecular Subtyping
Authors: Hartung Carolin , Porsch Martin , Stückrath Kathrin , Kaufhold Sandy , Staege Martin S. , Hanf Volker , Lantzsch Tilmann , Uleer Christoph , Peschel Susanne , John Jutta , Pöhler Marleen , Weigert Edith , Buchmann Jörg , Bürrig Karl-Friedrich , Schüler Kathleen , Bethmann Daniel , Große Ivo , Kantelhardt Eva Johanna , Thomssen Christoph , Vetter Martina
Published: October 2021

Introduction: Triple-negative breast cancer (TNBC) is considered the most aggressive type of breast cancer (BC) with limited options for therapy. TNBC is a heterogeneous disease and tumors have been classified into TNBC subtypes using gene expression profiling to distinguish basal-like 1, basal-like 2, immunomodulatory, mesenchymal, mesenchymal stem-like, luminal androgen receptor (LAR), and one nonclassifiable group (called unstable). Objectives: The aim of this study was to verify the clinical relevance of molecular subtyping of TNBCs to improve the individual indication of systemic therapy. Patients and Methods: Molecular subtyping was performed in 124 (82%) of 152 TNBC tumors that were obtained from a prospective, multicenter cohort including 1,270 histopathologically confirmed invasive, nonmetastatic BCs (NCT 01592825). Treatment was guideline-based. TNBC subtypes were correlated with recurrence-free interval (RFI) and overall survival (OS) after 5 years of observation. Results: Using PAM50 analysis, 87% of the tumors were typed as basal with an inferior clinical outcome compared to patients with nonbasal tumors. Using the TNBCtype-6 classifier, we identified 23 (15%) of TNBCs as LAR subtype. After standard adjuvant or neoadjuvant chemotherapy, patients with LAR subtype showed the most events for 5-year RFI (66.7 vs. 80.6%) and the poorest probability of 5-year OS (60.0 vs. 84.4%) compared to patients with non-LAR disease (RFI: adjusted hazard ratio [aHR] = 1.87, 95% confidence interval [CI] 0.69–5.05, p = 0.211; OS: aHR = 2.74, 95% CI 1.06–7.10, p = 0.037). Conclusion: Molecular analysis and subtyping of TNBC may be relevant to identify patients with LAR subtype. These cancers seem to be less sensitive to conventional chemotherapy, and new treatment options, including androgen receptor-blocking agents and immune checkpoint inhibitors, have to be explored.
Blood Product Supply for a Helicopter Emergency Medical Service
Authors: Selleng Kathleen , Baschin Marcel , Henkel Berthold , Jenichen Gregor , Thies Karl-Christian , Rudolph Marcus , Reifferscheid Florian , Braun Jörg , Hannich Malte , Winter Theresa , Hahnenkamp Klaus , Greinacher Andreas
Published: October 2021

Background: Long patient transport times to trauma centers are a well-known problem in sparsely populated regions with a low hospital density. Transfusion of red blood cell concentrates (RBC) and plasma improves outcome of trauma patients with severe bleeding. Helicopter emergency services (HEMS) are frequently employed to provide early advanced medical care and to reduce time to hospital admission. Supplying HEMS with blood products allows prehospital transfusion and may help to prevent exsanguination or prolonged hemorrhagic shock. We have investigated the maintenance of blood product quality under air transport conditions and the logistical steps to introduce a HEMS blood depot into routine practice. Methods: A risk analysis was performed and a validation plan developed. A special, commercially available transport container for blood products was identified. Maintenance of temperature conditions between 2 and 6°C in the box were monitored at ambient temperatures up to 35°C over 48 h. Quality of blood products before and after helicopter air transport were evaluated including (1) for RBCs: hemoglobin, hematocrit, hemolysis rate; (2) for thawed plasma: aPTT, INR, single clotting factor activities. The logistics for blood supply of the regional HEMS were developed by the transfusion service of the Greifswald University Hospital in collaboration with the in-hospital transport team, the HEMS team, and the HEMS operator. Results: The transport container maintained a temperature below 6°C up to 36 h at 35°C ambient temperature. Vibration during helicopter operation did not impair quality of RBC and thawed plasma. To provide blood products for HEMS at least two transport containers and an additional set of cooling tiles is needed as the cooling tiles need a special temperature priming over 20 h. The two boxes were used at alternate days. To reduce wastage, RBCs and thawed plasmas were exchanged every fourth day and reintegrated into the blood bank inventory for further in-hospital use. Conclusions: Supplying HEMS with RBCs and plasma is feasible. Helicopter transport has no negative impact on blood product quality. The logistic challenges require close collaboration between the HEMS team and the blood transfusion service.
Features of Pathobiology and Clinical Translation of Approved Treatments for Coronavirus Disease 2019
Authors: Fallah Ali , Razavi Nikoo Hadi , Abbasi Hamidreza , Mohammad-Hasani Azadeh , Hosseinzadeh Colagar Abasalt , Khosravi Ayyoob
Published: October 2021

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is currently the most important etiological agent of acute respiratory distress syndrome (ARDS) with millions of infections and deaths in the last 2 years worldwide. Several reasons and parameters are responsible for the difficult management of coronavirus disease-2019 (COVID-19) patients; the first is virus behavioral factors such as high transmission rate, and the different molecular and cellular mechanisms of pathogenesis remain a matter of controversy, which is another factor. Summary: In the present review, we attempted to explain about features of SARS-COV-2, particularly focusing on the various aspects of pathogenesis and treatment strategies. Key Messages: We note evidence for the understanding of the precise molecular and cellular mechanisms of SARS-CoV-2 pathogenesis, which can help design the appropriate drug or vaccine. Additionally, and importantly, we reported the updated issues associated with the history and development of treatment strategies such as, drugs, vaccines, and other medications that have been approved or under consideration in clinics and markets worldwide.
Subject Clitics in Microcontact: A Case Study from Heritage Friulian in Argentina and Brazil
Authors: Frasson Alberto , D’Alessandro Roberta , van Osch Brechje
Published: October 2021

In this paper we present data from first generation immigrants (G1) and second and third generation heritage speakers of Friulian, a Rhaeto-Romance language spoken in North-Eastern Italy and also found in Argentina and Brazil. The target phenomenon is subject clitics (SCL s). We show that SCL s in heritage Friulian are in a process of being reanalyzed from being agreement markers to pronouns. While SCL s are obligatory in Friulian as spoken in Italy, they are often dropped in heritage Friulian in Argentina and Brazil; this phenomenon, we argue, needs to be interpreted as the drop of pronominal subjects, and not of agreement-like SCL s. We also demonstrate that the use of SCL s (reanalyzed as pronominal subjects) is conditioned both by grammatical factors (it happens more in some grammatical persons than in others) and by discourse factors (they are used more in the case of a continuation topic than in other topicalization contexts). This means that in heritage Friulian, discourse constraints on the expression of subjects are not being lost or weakened; in fact, against the general grammaticalization trend of pronominal forms, new discourse constraints are introduced.