bluuebunny/crossref_metadata_2025 huggingface dataset:
A Middleware-Based Approach for Multi-Scale Mobility Simulation
Authors: Boulet Xavier , Zargayouna Mahdi , Scemama Gérard , Leurent Fabien
Published: January 2021

Modeling and simulation play an important role in transportation networks analysis. In the literature, authors have proposed many traffic and mobility simulations, with different features and corresponding to different contexts and objectives. They notably consider different scales of simulations. The scales refer to the represented entities, as well as to the space and the time representation of the transportation environment. However, we often need to represent different scales in the same simulation, for instance to represent a neighborhood interacting with a wider region. In this paper, we advocate for the reuse of existing simulations to build a new multi-scale simulation. To do so, we propose a middleware model to couple independent mobility simulations, working at different scales. We consider all the necessary processing and workflow to allow for a coherent orchestration of these simulations. We also propose a prototype implementation of the middleware. The results show that such a middleware is capable of creating a new multi-scale mobility simulation from existing ones, while minimizing the incoherence between them. They also suggest that, to have a maximal benefit from the middleware, existing mobility simulation platforms should allow for an external control of the simulations, allowing for executing a time step several times if necessary.
A Continuous Statistical Phasing Framework for the Analysis of Forensic Mitochondrial DNA Mixtures
Authors: Smart Utpal , Cihlar Jennifer Churchill , Mandape Sammed N. , Muenzler Melissa , King Jonathan L. , Budowle Bruce , Woerner August E.
Published: January 2021

Despite the benefits of quantitative data generated by massively parallel sequencing, resolving mitotypes from mixtures occurring in certain ratios remains challenging. In this study, a bioinformatic mixture deconvolution method centered on population-based phasing was developed and validated. The method was first tested on 270 in silico two-person mixtures varying in mixture proportions. An assortment of external reference panels containing information on haplotypic variation (from similar and different haplogroups) was leveraged to assess the effect of panel composition on phasing accuracy. Building on these simulations, mitochondrial genomes from the Human Mitochondrial DataBase were sourced to populate the panels and key parameter values were identified by deconvolving an additional 7290 in silico two-person mixtures. Finally, employing an optimized reference panel and phasing parameters, the approach was validated with in vitro two-person mixtures with differing proportions. Deconvolution was most accurate when the haplotypes in the mixture were similar to haplotypes present in the reference panel and when the mixture ratios were neither highly imbalanced nor subequal (e.g., 4:1). Overall, errors in haplotype estimation were largely bounded by the accuracy of the mixture’s genotype results. The proposed framework is the first available approach that automates the reconstruction of complete individual mitotypes from mixtures, even in ratios that have traditionally been considered problematic.
The Utilization of Protective Face Masks among Polish Healthcare Workers during COVID-19 Pandemic: Do We Pass the Exam?
Authors: Reszke Radomir , Matusiak Łukasz , Krajewski Piotr K. , Szepietowska Marta , Białynicki-Birula Rafał , Szepietowski Jacek C.
Published: January 2021

Relevant personal protective measures during the COVID-19 pandemic include face masks, possibly decreasing the risk of infection among the general population and healthcare workers (HCW) if utilized properly. The aim of the study was to assess whether different Polish HCW utilize face masks according to the 2020 World Health Organization guidance (WHO) criteria. This cross-sectional study included 1156 respondents who participated in an internet survey evaluating mask-related behaviors. All the WHO criteria were complied with by 1.4% of participants, regardless of medical profession, specialty or place of employment. HCW mostly adhered to criterion 1 (C1; strict covering of the face and mouth with the mask; 90.8%), C4 (washing/disinfecting the hands after touching/taking off the mask; 49%) and C3 (taking off the mask properly without touching the anterior surface; 43.4%), whereas C2 (avoidance of touching the mask with hands) was complied with least commonly (6.8%). HCW with mask-induced itch (31.6%) complied to C2 less often (odds ratio 0.53; p = 0.01). The study reveals that Polish HCW rarely adhere to all the 2020 WHO guidance criteria on the use of masks, whereas the adherence to particular criteria is variable and may be associated with the presence of skin-related conditions and other factors. Better compliance with the recommendations in the future is necessary to increase personal safety of HCW and prevent the transmission of SARS-CoV-2.
The Effect of a Personalized Oral Health Education Program on Periodontal Health in an At-Risk Population: A Randomized Controlled Trial
Authors: Almabadi Eman S. , Bauman Adrian , Akhter Rahena , Gugusheff Jessica , Van Buskirk Joseph , Sankey Michelle , Palmer Janet E. , Kavanagh David J. , Seymour Gregory J. , Cullinan Mary P. , Eberhard Joerg
Published: January 2021

While periodontal disease is associated with many risk factors, socioeconomically disadvantaged communities experience the highest disease burden. The aim of this study was to evaluate the effectiveness of a personalized oral health education program, in combination with routine dental treatment, in participants from a low socioeconomic community. We used a randomized, controlled, examiner-blinded clinical trial. A total of 579 participants (aged 18–60 years) were randomly grouped: the intervention group (n = 292) received a personalized oral health education program in combination with routine dental care and the control group (n = 287) received routine dental care. All participants were assessed for improvement in oral health care behaviors, dental plaque, and periodontal status at baseline, 12 months, and 24 months. We found a significant drop (p < 0.001) in the plaque indices, Periodontal Probing Depths (PPD) and Bleeding on Probing (BOP) between baseline and the 12-month follow-up for both groups. For BOP, the number of sites positive was significantly different between baseline and the 24-month follow-up (p = 0.037). No differences were found between the two groups for any evaluated clinical outcome. The personalized oral health education program used in the current study did not appear to add significant improvement to clinical outcomes of periodontal health compared with routine restorative dental care per se.
Analysis of the Different Approaches Adopted in the Italian Regions to Care for Patients Affected by COVID-19
Authors: Pecoraro Fabrizio , Luzi Daniela , Clemente Fabrizio
Published: January 2021

As the Italian health system is regionally based, COVID-19 emergency actions are based on a general lockdown imposed by national authority and then management at local level by 21 regional authorities. Therefore, the pandemic response plan developed by each region led to different approaches. The aim of this paper is to analyze whether differences in patient management may have influenced the local course of the epidemic. The analysis on the 21 Italian regions considers the strategies adopted in terms of hospitalization, treatment in the ICU and at home. Moreover, an in-depth analysis was carried out on: Lombardia, which adopted a hospitalization approach; Veneto, which tended to confine patients at home; and Emilia Romagna, which adopted a mixed hospitalization-home based approach. The majority of regions implemented a home-based approach, while the hospital approach was followed in three regions (Lombardia, Piemonte, and Lazio), mainly limited to the first period of the outbreak. All regions in the later phases tended to reduce hospitalization, preferring to confine patients at home. This comparison, highlighting the different phases of the pandemic, outlined that the adoption of home-based practices contributed to limiting infection rates among patients and health professionals as well as decreasing the number of deaths.
Gender Differences in the Relationships among Metabolic Syndrome and Various Obesity-Related Indices with Nonalcoholic Fatty Liver Disease in a Taiwanese Population
Authors: Lin I-Ting , Lee Mei-Yueh , Wang Chih-Wen , Wu Da-Wei , Chen Szu-Chia
Published: January 2021

The incidence of nonalcoholic fatty liver disease(NAFLD) is increasing worldwide, and it is strongly associated with metabolic syndrome (MetS) and some obesity-related indices. However, few studies have investigated gender differences in these associations. The aim of this study was to investigate associations among MetS and various obesity-related indices with NAFLD, and also look at gender differences in these associations. We enrolled participants who completed a health survey in southern Taiwan. MetS was defined according to the Adult Treatment Panel III for Asians, and the following obesity-related indices were calculated: body mass index (BMI), waist-to-height ratio (WHtR), waist–hip ratio (WHR), lipid accumulation product (LAP), body roundness index (BRI), conicity index (CI), visceral adiposity index (VAI), body adiposity index (BAI), abdominal volume index (AVI), triglyceride-glucose (TyG) index, and hepatic steatosis index (HSI). NAFLD was diagnosed when hepatic steatosis was noted on a liver ultrasound. A total of 1969 (764 men and 1205 women) participants were enrolled. Multivariable analysis showed that both male and female participants with MetS, high BMI, high WHtR, high WHR, high LAP, high BRI, high CI, high VAI, high BAI, high AVI, high TyG index, and high HSI were significantly associated with NAFLD. In addition, the interactions between MetS and gender, WHR and gender, LAP and gender, and TyG index and gender on NAFLD were statistically significant. Among these obesity-related indices, HSI and LAP had the greatest area under the curve in both men and women. Furthermore, stepwise increases in the number of MetS components and the values of indices corresponding to the severity of NAFLD were noted. In conclusion, our results demonstrated significant relationships between MetS and obesity-related indices with NAFLD, and also stepwise increases in the number of MetS components and the values of indices with the severity of NAFLD. MetS, WHR, LAP, and TyG index were associated with NAFLD more obviously in women than in men.
The Role of the Clinical Exercise Physiologist in Reducing the Burden of Chronic Disease in New Zealand
Authors: Pearce Amy , Longhurst Glynis
Published: January 2021

Clinical exercise physiologists (CEPs) specialize in managing long-term, non-communicable health conditions using scientific rehabilitative exercise prescription, which alleviates the burden of these conditions on health care systems. This is evident, particularly in Australia (AUS), where they are registered as health care workers. CEPs have been shown to reduce the physical burden of long-term conditions on populations and the economic load that these place on national health departments. This article aims to evidence the effectiveness of CEPs in Noncommunicable Disease (NCD) rehabilitation, the cost-effectiveness of supervised exercise prescription for various NCDs by CEPs in AUS, and related cost-effectiveness New Zealand (NZ) burden of disease. This article highlights the important role NZ. CEPs can play in reducing chronic disease cost if given the same opportunities as Australian CEPs within NZ’s health care system.
Comorbidity of Geo-Helminthes among Malaria Outpatients of the Health Facilities in Ethiopia: Systematic Review and Meta-Analysis
Authors: Boltena Minyahil Tadesse , El-Khatib Ziad , Sahlemichael Kebede Abraham , Asamoah Benedict Oppong , Tadesse Boltena Andualem , Yeshambaw Melese , Biru Mulatu
Published: January 2021

Background: Coinfection of malaria and intestinal helminths affects one third of the global population, largely among communities with severe poverty. The spread of these parasitic infections overlays in several epidemiological locations and the host shows different outcomes. This systematic review and meta-analysis determine the pooled prevalence of malaria and intestinal helminthiases coinfections among malaria suspected patients in Ethiopia. Methods: Primary studies published in English language were retrieved using appropriate search terms on Google Scholar, PubMed/MEDLINE, CINHAL, Scopus, and Embase. The Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) was used for critical appraisal of studies. A pooled statistical meta-analysis was conducted using STATA Version 14.0 software. The heterogeneity and publication bias were assessed using the I2 statistics and Egger’s test, respectively. Duval and Tweedie’s nonparametric trim and fill analysis using the random-effect analysis. The Random effects model was used to estimate the summary prevalence of comorbidity of malaria and soil transmitted helminthiases and the corresponding 95% confidence intervals (CI). The review protocol has registered in PROSPERO number CRD42019144803. Results: We identified ten studies (n = 6633 participants) in this study. The overall pooled result showed 13% of the ambulatory patients infected by malaria and intestinal helminths concurrently in Ethiopia. The pooled prevalence of Plasmodium falciparum and Plasmodium vivax, and mixed infections were 12, 30, and 6%, respectively. The most common intestinal helminth parasites detected were Hookworm, Ascaris lumbricoides, and Tirchuris trichiura. Conclusions: The comorbidity of malaria and intestinal helminths causes lower hemoglobin level leading to maternal anemia, preterm delivery, and still birth in pregnant women and lactating mother. School-aged children and neonates coinfected by plasmodium species and soil transmitted helminths develop cognitive impairment, protein energy malnutrition, low birth weight, small for gestational age, and gross motor delay. The Ministry of Health of Ethiopia and its international partners working on malaria elimination programs should give more emphasis to the effect of the interface of malaria and soil transmitted helminths, which calls for an integrated disease control and prevention.
Incidence and Risk Factors of 30-Day Surgical Site Infection after Primary Total Joint Arthroplasty in a Middle-Income Country: A Single-Center Experience
Authors: Marusic Vuk , Markovic-Denic Ljiljana , Djuric Olivera , Cirkovic Andja , Nikolic Vladimir , Dubljanin-Raspopovic Emilija , Kadija Marko
Published: January 2021

The data about the incidence and risk factors for surgical site infections (SSIs) following total joint arthroplasty (TJA) in middle-income countries are still scant. The aim of this study was to assess the incidence and risk factors associated with 30-day SSIs following total hip arthroplasty (THA) and total knee arthroplasty (TKA). The study was conducted at the Clinic for Orthopedic Surgery and Traumatology, Clinical Center of Serbia (CCS) in Belgrade, from May 2016 to April 2018. All patients undergoing THA or TKA were followed throughout hospitalization until day 30 after discharge. Of the 1073 admitted patients, 459 had THA and 230 had TKA. The incidence rate of surgical site infections (SSIs) among the patients who underwent THA was 5.4%, which is 3.8 per 1000 postoperative patient-days, while the rate among those who had TKA was 4.8%, i.e., 3.4 per 1000 postoperative patient-days. Out of the 36 SSIs, 15 were deep and 21 were superficial incisional ones. Among the variables examined, the independent risk factors for SSIs after THA were the American Society of Anesthesiologists (ASA) score > 2 (RR = 3.17; 95% CI—1.26–8.02), smoking (RR = 3.14; 95% CI—1.26–7.82) and peripheral vascular disease (PVD) (RR = 6.09; 95% CI—2.35–15.77), and after TKA, only PVD (RR = 3.87; 95% CI—1.09–13.76) was the risk factor. Incidence rates of SSIs after arthroplasty are higher compared to reports from developed countries. Therefore, it is necessary to enhance infection prevention and control measures with strict control of modifiable risk factors.
Psychological Wellbeing in Physical Education and School Sports: A Systematic Review
Authors: Piñeiro-Cossio Javier , Fernández-Martínez Antonio , Nuviala Alberto , Pérez-Ordás Raquel
Published: January 2021

Mental health in children and adolescents has become an increasingly important topic in recent years. It is against this backdrop that physical education and school sports play an important role in promoting psychological wellbeing. The aim of this review was to analyse interventions for improving psychological wellbeing in this area. To this end, a literature review was conducted using four databases (WOS, SPORTDiscus, SCOPUS and ERIC) and the following keywords: psychological wellbeing, physical education, and school sports. Twenty-one articles met the inclusion criteria. The results showed that interventions varied greatly in terms of duration and used a wide range of strategies (conventional and non-conventional sports, physical activity, games, etc.) for promoting psychological wellbeing, primarily among secondary school students. There was a lack of consensus as to the conceptualisation of the construct of psychological wellbeing, resulting in a variety of tools and methods for assessing it. Some studies also suggested a link between psychological wellbeing and other variables, such as basic psychological needs and self-determination. Finally, this study provides a definition of psychological wellbeing through physical activity based on our findings.
Validity of the Polar V800 Monitor for Assessing Heart Rate Variability in Elderly Adults under Mental Stress and Dual Task Conditions
Authors: Huang Chang-Jing , Chan Hsiao-Lung , Chang Ya-Ju , Chen Shu-Mei , Hsu Miao-Ju
Published: January 2021

Background: Aging may result in autonomic nervous dysfunction. Heart rate variability (HRV) is a non-invasive method to measure autonomic nervous activities. Many studies have shown that HRV contributes to the risk assessment of diseases. A Polar V800 heart rate monitor is a wearable device that measures R-R intervals, but has only been validated in younger adults under limited testing conditions. There is no validation of the V800 under mental stress or in dual task testing conditions. Therefore, this study investigated the validity of the Polar V800 heart rate monitor for assessing R-R intervals and evaluated if there were differences on HRV parameters under different situations in community-dwelling elderly adults. Methods: Forty community-dwelling elderly adults were recruited. Heart rates were recorded via electrocardiogram (ECG) and the V800 under sitting, during an arithmetic test, during a naming test, a self-selected walking velocity test (SSWV), and dual tasks (SSWV performing mental arithmetic test and SSWV performing naming test). Indices of time and frequency domains of HRV were calculated afterwards. The intra-class correlation coefficient (ICC) analysis and effect size were calculated to examine the concurrent validity between the V800 and the ECG. Results: All HRV indices from the V800 were highly correlated with the ECG under all tested conditions (ICC = 0.995–1.000, p < 0.001) and the effect size of bias was small (<0.1). Conclusion: Overall, the V800 has good validity on the assessment of HRV in community-dwelling elderly adults during sitting, mental arithmetic test, naming test, SSWV, and dual tasks.
The Direct and Indirect Relationships of Environmental, Interpersonal and Personal Factors with High School Students Physical Activity: An Ecological Approach
Authors: Mieziene Brigita , Emeljanovas Arunas , Tilindiene Ilona , Tumynaite Laura , Trinkuniene Laima , Kawachi Ichiro
Published: January 2021

Background: Across countries, young people are not sufficiently physically active. The evidence confirms that beyond demographic and individual agents, individuals participate within their social and physical environment. The ecological model enables a search for the modifiable factors in specific populations, as it allows consideration of factors affecting individuals’ lives on different levels, as well as considering the interplay of those factors. The aim of this study was to examine the complex interconnections among environmental, social capital and motivational factors at different levels, within an ecological model for high school students’ moderate-to-vigorous physical activity during their leisure time. Methods: This cross-sectional population-based study included 1285 students from 14 to 18 years old, with a mean age of 16.14 ± 1.22. Physical activity, neighborhood physical activity recourses, neighborhood safety, social capital, physical activity motivation and sociodemographic factors were evaluated. Logistic regression, mediation and moderation analyses were performed predicting moderate-to-vigorous physical activity during leisure time. Results: In the final multivariate logistic regression model, greater social participation (OR 1.03 [1.01–1.05]), higher relative autonomy index (OR 1.11 [1.06–1.15]) and male gender (OR 1.71 [1.13–2.57]) directly predicted meeting MVPA recommendations. Any significant moderation effects (p > 0.05) of environmental characteristics were not found for the relationship between social capital, motivational factors and moderate-to-vigorous physical activity. The evidence of positive indirect mediation effects was found in all five models for social capital components as all CIs for its βs do not contain 0, though standardized effect sizes were between 0.02 and 0.07, indicating small effect sizes. Conclusion: These findings provide support for the presence of some direct and indirect pathways from social capital to moderate-to-vigorous physical activity. Future intervention strategies should focus on strengthening physical activity motivation by encouraging the development of social network and social participation as well as family, neighborhood and school social capital within the framework of the ecological model.
Severe Suicidality in Athletes with Chronic Traumatic Encephalopathy: A Case Series and Overview on Putative Ethiopathogenetic Mechanisms
Authors: Costanza Alessandra , Radomska Michalina , Zenga Francesco , Amerio Andrea , Aguglia Andrea , Serafini Gianluca , Amore Mario , Berardelli Isabella , Ojio Yasutaka , Nguyen Khoa D.
Published: January 2021

Chronic traumatic encephalopathy (CTE) results from repetitive brain injuries and is a common neurotraumatic sequela in contact sports. CTE is often accompanied by neuropsychiatric symptoms, which could escalate to suicidal ideation (SI) and suicidal behaviour (SB). Nevertheless, fairly limited emphasis about the association between suicidality and CTE exists in medical literature. Here, we report two cases of retired professional athletes in high contact sports (boxing and ice hockey) who have developed similar clinical trajectories characterized by progressive neuropsychiatric symptoms compatible with a CTE diagnosis and subsequent SB in its severe forms (medical serious suicide attempt (SA) and completed suicide). In addition to the description of outlining clinical, neuropsychological, neuroimaging, and differential diagnosis elements related to these cases, we also hypothesized some mechanisms that might augment the suicide risk in CTE. They include those related to neurobiological (neuroanatomic/neuroinflammatory) dysfunctions as well as those pertaining to psychiatry and psychosocial maladaptation to neurotraumas and retirement from professional competitive activity. Findings described here can provide clinical pictures to improve the identification of patients with CTE and also potential mechanistic insights to refine the knowledge of eventual severe SB development, which might enable its earlier prevention.
Eustachian Tube Function Assessment after Radiofrequency Turbinate Reduction in Atopic and Non-Atopic Patients
Authors: Martines Francesco , Dispenza Francesco , Sireci Federico , Gallina Salvatore , Salvago Pietro
Published: January 2021

(1) Background: Inferior turbinates’ hypertrophy is often associated with Eustachian tube dysfunction (ETD); radiofrequency turbinate reduction (RTR) may provide a long-term improvement of nasal obstruction and ETD-related symptoms. (2) Aim: The study aimed to compare ETD in atopic and non-atopic patients before and after RTR and to investigate the correlation between tympanometry and Eustachian Tube Dysfunction Questionnaire-7 (ETDQ-7). (3) Methods: Ninety-seven patients, ranging from 33 to 68 years old, were screened by skin tests and divided into atopic (G1) and non-atopic (G2). Eustachian tube function (ETF) was evaluated through tympanometry, William’s test and ETDQ-7. (4) Results: A moderate to severe subjective ETDQ-7 was found in the 35.42% of G1 and in the 22.45% of G2 patients before RTR. William’s test resulted normal in 141 ears (72.68%), partially impaired in 15 (7.73%), and grossly impaired in 38 (19.59%) before surgery. A grossly ETD was evidenced in the 19.59% of cases before surgery and decreased to 6.18% after surgery with a significant difference among atopic patients (p < 0.001). (5) Conclusion: RTR may be considered a treatment option in patients suffering from ETD and inferior turbinates’ hypertrophy; RTR reduced the percentage of grossly impaired ET function (p < 0.001). ETDQ-7 and William’s test may represent valuable tools to assess ET function before and after surgery.
TGFβ-1 Induced Cross-Linking of the Extracellular Matrix of Primary Human Dermal Fibroblasts
Authors: Semkova Mariya E. , Hsuan J. Justin
Published: January 2021

Excessive cross-linking is a major factor in the resistance to the remodelling of the extracellular matrix (ECM) during fibrotic progression. The role of TGFβ signalling in impairing ECM remodelling has been demonstrated in various fibrotic models. We hypothesised that increased ECM cross-linking by TGFβ contributes to skin fibrosis in Systemic Sclerosis (SSc). Proteomics was used to identify cross-linking enzymes in the ECM of primary human dermal fibroblasts, and to compare their levels following treatment with TGFβ-1. A significant upregulation and enrichment of lysyl-oxidase-like 1, 2 and 4 and transglutaminase 2 were found. Western blotting confirmed the upregulation of lysyl hydroxylase 2 in the ECM. Increased transglutaminase activity in TGFβ-1 treated ECM was revealed from a cell-based assay. We employed a mass spectrometry-based method to identify alterations in the ECM cross-linking pattern caused by TGFβ-1. Cross-linking sites were identified in collagens I and V, fibrinogen and fibronectin. One cross-linking site in fibrinogen alpha was found only in TGFβ-treated samples. In conclusion, we have mapped novel cross-links between ECM proteins and demonstrated that activation of TGFβ signalling in cultured dermal fibroblasts upregulates multiple cross-linking enzymes in the ECM.
Inflammatory Bowel Disease: New Insights into the Interplay between Environmental Factors and PPARγ
Authors: Caioni Giulia , Viscido Angelo , d’Angelo Michele , Panella Gloria , Castelli Vanessa , Merola Carmine , Frieri Giuseppe , Latella Giovanni , Cimini Annamaria , Benedetti Elisabetta
Published: January 2021

The pathophysiological processes of inflammatory bowel diseases (IBDs), i.e., Crohn’s disease (CD) and ulcerative colitis (UC), are still not completely understood. The exact etiology remains unknown, but it is well established that the pathogenesis of the inflammatory lesions is due to a dysregulation of the gut immune system resulting in over-production of pro-inflammatory cytokines. Increasing evidence underlines the involvement of both environmental and genetic factors. Regarding the environment, the microbiota seems to play a crucial role. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that exert pleiotropic effects on glucose homeostasis, lipid metabolism, inflammatory/immune processes, cell proliferation, and fibrosis. Furthermore, PPARs modulate interactions with several environmental factors, including microbiota. A significantly impaired PPARγ expression was observed in UC patients’ colonic epithelial cells, suggesting that the disruption of PPARγ signaling may represent a critical step of the IBD pathogenesis. This paper will focus on the role of PPARγ in the interaction between environmental factors and IBD, and it will analyze the most suitable in vitro and in vivo models available to better study these relationships.
Molecular Mechanisms of DUBs Regulation in Signaling and Disease
Authors: Li Ying , Reverter David
Published: January 2021

The large family of deubiquitinating enzymes (DUBs) are involved in the regulation of a plethora of processes carried out inside the cell by protein ubiquitination. Ubiquitination is a basic pathway responsible for the correct protein homeostasis in the cell, which could regulate the fate of proteins through the ubiquitin–proteasome system (UPS). In this review we will focus on recent advances on the molecular mechanisms and specificities found for some types of DUBs enzymes, highlighting illustrative examples in which the regulatory mechanism for DUBs has been understood in depth at the molecular level by structural biology. DUB proteases are responsible for cleavage and regulation of the multiple types of ubiquitin linkages that can be synthesized inside the cell, known as the ubiquitin-code, which are tightly connected to specific substrate functions. We will display some strategies carried out by members of different DUB families to provide specificity on the cleavage of particular ubiquitin linkages. Finally, we will also discuss recent progress made for the development of drug compounds targeting DUB proteases, which are usually correlated to the progress of many pathologies such as cancer and neurodegenerative diseases.
Role of HMOX1 Promoter Genetic Variants in Chemoresistance and Chemotherapy Induced Neutropenia in Children with Acute Lymphoblastic Leukemia
Authors: Bukowska-Strakova Karolina , Włodek Joanna , Pitera Ewelina , Kozakowska Magdalena , Konturek-Cieśla Anna , Cieśla Maciej , Gońka Monika , Nowak Witold , Wieczorek Aleksandra , Pawińska-Wąsikowska Katarzyna , Józkowicz Alicja , Siedlar Maciej
Published: January 2021

Whilst the survival rates of childhood acute lymphoblastic leukemia (ALL) have increased remarkably over the last decades, the therapy resistance and toxicity are still the major causes of treatment failure. It was shown that overexpression of heme oxygenase-1 (HO-1) promotes proliferation and chemoresistance of cancer cells. In humans, the HO-1 gene (HMOX1) expression is modulated by two polymorphisms in the promoter region: (GT)n-length polymorphism and single-nucleotide polymorphism (SNP) A(−413)T, with short GT repeat sequences and 413-A variants linked to an increased HO-1 inducibility. We found that the short alleles are significantly more frequent in ALL patients in comparison to the control group, and that their presence may be associated with a higher risk of treatment failure, reflecting the role of HO-1 in chemoresistance. We also observed that the presence of short alleles may predispose to develop chemotherapy-induced neutropenia. In case of SNP, the 413-T variant co-segregated with short or long alleles, while 413-A almost selectively co-segregated with long alleles, hence it is not possible to determine if SNPs are actually of phenotypic significance. Our results suggest that HO-1 can be a potential target to overcome the treatment failure in ALL patients.
Recent Advancement in Atypical Lipomatous Tumor Research
Authors: Mashima Emi , Sawada Yu , Nakamura Motonobu
Published: January 2021

After Evans and colleagues identified the lipomatous tumor with a well-differentiated liposarcoma in a subcutaneous location or within a muscle layer, namely, atypical lipomatous tumor (ALT), this malignancy has been investigated to clarify the characteristics of clinical behavior and genomic changes. As one of the important issues for clinicians, it is a hot topic of how to distinguish ALT from benign lipoma in the clinical aspect. Recent studies revealed novel findings to clarify the risk factor for the diagnosis of ALT and molecular targets for the treatment of ALT. Clinical characteristics of superficial-type ALT well reflect the subcutaneous location of the tumor and are slightly different compared to deep-type ALT, such as tumor size. In addition, there has been a recent discovery of novel findings in ALT-related genes, namely, HMG2A (high mobility group protein 2a), YEATS4 (YEATS domain containing 4), and CPM (Carboxypeptidase M). Recent updates on treatment for advanced ALT are well developed including immunotherapy and conducting clinical trials. Finally, this review introduces one of the hot topics of ALT research focused on epigenetic changes: their attention in recent updates on clinical characteristics and the novel discovery of related genes, treatment, and epigenetic modifications in atypical lipomatous tumors.
Legacy and Emerging Per- and Polyfluoroalkyl Substances: Analytical Techniques, Environmental Fate, and Health Effects
Authors: Brase Richard A. , Mullin Elizabeth J. , Spink David C.
Published: January 2021

Due to their unique chemical properties, per- and polyfluoroalkyl substances (PFAS) have been used extensively as industrial surfactants and processing aids. While several types of PFAS have been voluntarily phased out by their manufacturers, these chemicals continue to be of ecological and public health concern due to their persistence in the environment and their presence in living organisms. Moreover, while the compounds referred to as “legacy” PFAS remain in the environment, alternative compounds have emerged as replacements for their legacy predecessors and are now detected in numerous matrices. In this review, we discuss the historical uses of PFAS, recent advances in analytical techniques for analysis of these compounds, and the fate of PFAS in the environment. In addition, we evaluate current biomonitoring studies of human exposure to legacy and emerging PFAS and examine the associations of PFAS exposure with human health impacts, including cancer- and non-cancer-related outcomes. Special focus is given to short-chain perfluoroalkyl acids (PFAAs) and ether-substituted, polyfluoroalkyl alternatives including hexafluoropropylene oxide dimer acid (HFPO-DA; tradename GenX), 4,8-dioxa-3H-perfluorononanoic acid (DONA), and 6:2 chlorinated polyfluoroethersulfonic acid (6:2 Cl-PFESA; tradename F-53B).
p38 Signalling Pathway
Authors: Sanz-Ezquerro Juan José , Cuenda Ana
Published: January 2021

p38 Mitogen activated protein kinases (p38MAPK) are a highly evolutionary conserved group of protein kinases, which are central for cell adaptation to environmental changes as well as for immune response, inflammation, tissue regeneration, and tumour formation [...]
Preventive Effect of Canstatin against Ventricular Arrhythmia Induced by Ischemia/Reperfusion Injury: A Pilot Study
Authors: Sugiyama Akira , Shimizu Yurie , Okada Muneyoshi , Otani Kosuke , Yamawaki Hideyuki
Published: January 2021

Ventricular arrhythmia induced by ischemia/reperfusion (I/R) injury is a clinical problem in reperfusion therapies for acute myocardial infarction. Ca2+ overload through reactive oxygen species (ROS) production is a major cause for I/R-induced arrhythmia. We previously demonstrated that canstatin, a C-terminal fragment of type IV collagen α2 chain, regulated Ca2+ handling in rat heart. In this study, we aimed to clarify the effects of canstatin on I/R-induced ventricular arrhythmia in rats. Male Wistar rats were subjected to I/R injury by ligating the left anterior descending artery followed by reperfusion. Ventricular arrhythmia (ventricular tachycardia and ventricular fibrillation) was recorded by electrocardiogram. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity and ROS production in neonatal rat cardiomyocytes (NRCMs) stimulated with oxygen glucose deprivation/reperfusion (OGD/R) were measured by lucigenin assay and 2′,7′-dichlorodihydrofluorescein diacetate staining, respectively. The H2O2-induced intracellular Ca2+ ([Ca2+]i) rise in NRCMs was measured by a fluorescent Ca2+ indicator. Canstatin (20 µg/kg) inhibited I/R-induced ventricular arrhythmia in rats. Canstatin (250 ng/mL) inhibited OGD/R-induced NOX activation and ROS production and suppressed the H2O2-induced [Ca2+]i rise in NRCMs. We for the first time demonstrated that canstatin exerts a preventive effect against I/R-induced ventricular arrhythmia, perhaps in part through the suppression of ROS production and the subsequent [Ca2+]i rise.
Selenium Compounds as Novel Potential Anticancer Agents
Authors: Radomska Dominika , Czarnomysy Robert , Radomski Dominik , Bielawski Krzysztof
Published: January 2021

The high number of new cancer incidences and the associated mortality continue to be alarming, leading to the search for new therapies that would be more effective and less burdensome for patients. As there is evidence that Se compounds can have chemopreventive activity, studies have begun to establish whether these compounds can also affect already existing cancers. This review aims to discuss the different classes of Se-containing compounds, both organic and inorganic, natural and synthetic, and the mechanisms and molecular targets of their anticancer activity. The chemical classes discussed in this paper include inorganic (selenite, selenate) and organic compounds, such as diselenides, selenides, selenoesters, methylseleninic acid, 1,2-benzisoselenazole-3[2H]-one and selenophene-based derivatives, as well as selenoamino acids and Selol.
Novel Short-Chain Quinones to Treat Vision Loss in a Rat Model of Diabetic Retinopathy
Authors: Daniel Abraham , Premilovac Dino , Foa Lisa , Feng Zikai , Shah Krupali , Zhang Qianyi , Woolley Krystel L. , Bye Nicole , Smith Jason A. , Gueven Nuri
Published: January 2021

Diabetic retinopathy (DR), one of the leading causes of blindness, is mainly diagnosed based on the vascular pathology of the disease. Current treatment options largely focus on this aspect with mostly insufficient therapeutic long-term efficacy. Mounting evidence implicates mitochondrial dysfunction and oxidative stress in the central etiology of DR. Consequently, drug candidates that aim at normalizing mitochondrial function could be an attractive therapeutic approach. This study compared the mitoprotective compounds, idebenone and elamipretide, side-by-side against two novel short-chain quinones (SCQs) in a rat model of DR. The model effectively mimicked type 2 diabetes over 21 weeks. During this period, visual acuity was monitored by measuring optokinetic response (OKR). Vision loss occurred 5–8 weeks after the onset of hyperglycemia. After 10 weeks of hyperglycemia, visual function was reduced by 65%. From this point, the right eyes of the animals were topically treated once daily with the test compounds. The left, untreated eye served as an internal control. Only three weeks of topical treatment significantly restored vision from 35% to 58–80%, while visual acuity of the non-treated eyes continued to deteriorate. Interestingly, the two novel SCQs restored visual acuity better than idebenone or elamipretide. This was also reflected by protection of retinal pathology against oxidative damage, retinal ganglion cell loss, reactive gliosis, vascular leakage, and retinal thinning. Overall, mitoprotective and, in particular, SCQ-based compounds have the potential to be developed into effective and fast-acting drug candidates against DR.
Targeted Nanoparticles Harboring Jasmine-Oil-Entrapped Paclitaxel for Elimination of Lung Cancer Cells
Authors: Engelberg Shira , Lin Yuexi , Assaraf Yehuda G. , Livney Yoav D.
Published: January 2021

Selectively targeted drug delivery systems are preferable chemotherapeutic platforms, as they specifically deliver the drug cargo into tumor cells, while minimizing untoward toxic effects. However, these delivery systems suffer from insufficient encapsulation efficiency (EE), encapsulation capacity (EC), and premature drug release. Herein, we coencapsulated paclitaxel (PTX) and Jasmine oil (JO) within PEG-PCL nanoparticles (NPs), with an average diameter < 50 nm, selectively targeted to non-small cell lung cancer (NSCLC) cells, via S15-aptamer (APT) decoration. JO was selected as an “adhesive” oily core to enhance PTX entrapment, as JO and PTX share similar hydrophobicity and terpenoid structure. JO markedly enhanced EE of PTX from 23% to 87.8% and EC from 35 ± 6 to 74 ± 8 µg PTX/mg PEG-PCL. JO also markedly increased the residual amount of PTX after 69 h, from 18.3% to 65%. Moreover, PTX cytotoxicity against human NSCLC A549 cells was significantly enhanced due to the co-encapsulation with JO; the IC50 value for PTX encapsulated within JO-containing APT-NPs was 20-fold lower than that for APT-NPs lacking JO. Remarkably, JO-containing APT-NPs displayed a 6-fold more potent cell-killing, relatively to the free-drug. Collectively, these findings reveal a marked synergistic contribution of JO to the cytotoxic activity of APT-NP-based systems, for targeted PTX delivery against NSCLC, which may be readily applied to various hydrophobic chemotherapeutics.
DNA Methylation Analysis Identifies Patterns in Progressive Glioma Grades to Predict Patient Survival
Authors: Weng Jingyin , Salazar Nicole
Published: January 2021

DNA methylation is an epigenetic change to the genome that impacts gene activities without modification to the DNA sequence. Alteration in the methylation pattern is a naturally occurring event throughout the human life cycle which may result in the development of diseases such as cancer. In this study, we analyzed methylation data from The Cancer Genome Atlas, under the Lower-Grade Glioma (LGG) and Glioblastoma Multiforme (GBM) projects, to identify methylation markers that exhibit unique changes in DNA methylation pattern along with tumor grade progression, to predict patient survival. We found ten glioma grade-associated Cytosine-phosphate-Guanine (CpG) sites that targeted four genes (SMOC1, KCNA4, SLC25A21, and UPP1) and the methylation pattern is strongly associated with glioma specific molecular alterations, primarily isocitrate dehydrogenase (IDH) mutation and chromosome 1p/19q codeletion. The ten CpG sites collectively distinguished a cohort of diffuse glioma patients with remarkably poor survival probability. Our study highlights genes (KCNA4 and SLC25A21) that were not previously associated with gliomas to have contributed to the poorer patient outcome. These CpG sites can aid glioma tumor progression monitoring and serve as prognostic markers to identify patients diagnosed with less aggressive and malignant gliomas that exhibit similar survival probability to GBM patients.
Alteration of Pituitary Tumor Transforming Gene 1 by MicroRNA-186 and 655 Regulates Invasion Ability of Human Oral Squamous Cell Carcinoma
Authors: Lee Sang Shin , Choi Jong Ho , Lim Seung Mook , Kim Gi Jin , Lee Suk Keun , Jeon Yoon Kyung
Published: January 2021

Background: Pituitary tumor-transforming gene 1 (PTTG1) was recently shown to be involved in the progression as well as the metastasis of cancers. However, their expression and function in the invasion of oral squamous cell carcinoma (SCC) remain unclear. Methods: The expressions of PTTG1 and PTTG1-targeted miRNA in oral SCC cell lines and their invasion capability depended on PTTG1 expression were analyzed by quantitative RT-PCR, Western blots, the transwell insert system and Zymography. Results: Invasion abilities were decreased in oral SCC cells treated with siRNA-PTTG1. When PTTG1 were downregulated in oral SCC cells treated with microRNA-186 and -655 inhibited their invasion abilities via MMP-9 activity. Conclusions: These results indicate that alteration of expression of PTTG1 in oral SCC cells by newly identified microRNA-186 and -655 can regulate invasion activity. Therefore, these data offer new insights into further understanding PTTG1 function in oral SCC and should provide new strategies for diagnostic markers for oral SCC.
Hedgehog Signaling in Colorectal Cancer: All in the Stroma?
Authors: Geyer Natalie , Gerling Marco
Published: January 2021

Hedgehog (Hh) signaling regulates intestinal development and homeostasis. The role of Hh signaling in cancer has been studied for many years; however, its role in colorectal cancer (CRC) remains controversial. It has become increasingly clear that the “canonical” Hh pathway, in which ligand binding to the receptor PTCH1 initiates a signaling cascade that culminates in the activation of the GLI transcription factors, is mainly organized in a paracrine manner, both in the healthy colon and in CRC. Such canonical Hh signals largely act as tumor suppressors. In addition, stromal Hh signaling has complex immunomodulatory effects in the intestine with a potential impact on carcinogenesis. In contrast, non-canonical Hh activation may have tumor-promoting roles in a subset of CRC tumor cells. In this review, we attempt to summarize the current knowledge of the Hh pathway in CRC, with a focus on the tumor-suppressive role of canonical Hh signaling in the stroma. Despite discouraging results from clinical trials using Hh inhibitors in CRC and other solid cancers, we argue that a more granular understanding of Hh signaling might allow the exploitation of this key morphogenic pathway for cancer therapy in the future.
Molecular S = 2 High-Spin, S = 0 Low-Spin and S = 0 ⇄ 2 Spin-Transition/-Crossover Nickel(II)-Bis(nitroxide) Coordination Compounds
Authors: Ishida Takayuki , Ito Saki , Homma Yuta , Kyoden Yukiya
Published: January 2021

Heterospin systems have a great advantage in frontier orbital engineering since they utilize a wide diversity of paramagnetic chromophores and almost infinite combinations and mutual geometries. Strong exchange couplings are expected in 3d–2p heterospin compounds, where the nitroxide (aminoxyl) oxygen atom has a direct coordination bond with a nickel(II) ion. Complex formation of nickel(II) salts and tert-butyl 2-pyridyl nitroxides afforded a discrete 2p–3d–2p triad. Ferromagnetic coupling is favored when the magnetic orbitals, nickel(II) dσ and radical π*, are arranged in a strictly orthogonal fashion, namely, a planar coordination structure is characterized. In contrast, a severe twist around the coordination bond gives an orbital overlap, resulting in antiferromagnetic coupling. Non-chelatable nitroxide ligands are available for highly twisted and practically diamagnetic complexes. Here, the Ni–O–N–Csp2 torsion (dihedral) angle is supposed to be a useful metric to describe the nickel ion dislocated out of the radical π* nodal plane. Spin-transition complexes exhibited a planar coordination structure in a high-temperature phase and a nonplanar structure in a low-temperature phase. The gradual spin transition is described as a spin equilibrium obeying the van’t Hoff law. Density functional theory calculation indicates that the energy level crossing of the high- and low-spin states. The optimized structures of diamagnetic and high-spin states well agreed with the experimental large and small torsions, respectively. The novel mechanism of the present spin transition lies in the ferro-/antiferromagnetic coupling switch. The entropy-driven mechanism is plausible after combining the results of the related copper(II)-nitroxide compounds. Attention must be paid to the coupling parameter J as a variable of temperature in the magnetic analysis of such spin-transition materials. For future work, the exchange coupling may be tuned by chemical modification and external stimulus, because it has been clarified that the parameter is sensitive to the coordination structure and actually varies from 2J/kB = +400 K to −1400 K.