bluuebunny/crossref_metadata_2025 huggingface dataset:
Circ-ZFR Promotes Progression of Bladder Cancer by Upregulating WNT5A Via Sponging miR-545 and miR-1270
Authors: Luo Liping , Miao Pingping , Ming Yao , Tao Jie , Shen Hongchun
Published: April 2021

Background

Bladder cancer is one of the most common cancers all over the world. CircZFR is a circular RNA and has been implicated in tumor generation and invasion. However, the exact role of circZFR in the development of bladder cancer (BCa) remains unknown. This study aimed to investigate the function of circZFR in BCa, and further to probe into the association between circ-ZFR, miR-545/miR-1270 and WNT5A.

Methods

The expression of circZFR in BCa was quantified by qRT-PCR and was positively correlated with the prognosis of BCa patients. Next, the stable knockdown of circZFR BCa cell lines was established and the resulting capacities of proliferation, migration and invasion were measured. The association of circZFR with miR-1270/miR-545 was predicted by circinteractome prediction, and was confirmed by luciferase assay as well as RNA pull down assay. Furthermore, miRNA inhibitors, WNT5A overexpression and Pearson correlation analysis were used to examine the relationship between circZFR, miR-1270/miR-545 and WNT5A.

Results

The expression of CircZFR was up-regulated both in BCa tissues and in BCa cell lines, and was positively correlated with patient survival rates. Blocking of circZFR’s expression by RNA inhibitors suppressed the proliferation, migration and invasion of BCa cells both in vitro and in vivo. On the other hand, overexpression of target miRNA supported that circZFR directly interact with miR-545 and miR-1270. Moreover, we demonstrated that circZFR promotes the progression of BCa by upregulating WNT5A’s expression via sponging miR-545 and miR-1270.

Conclusions

CircZFR promotes the proliferation, migration and invasion of BCa cells by upregulating WNT5A signaling pathway via sponging miR-545 and miR-1270. These results provide new insights into the molecular mechanism of circZFR in BCa progression, and more important, a novel target for BCa clinical treatment.
The Role of Gut Barrier Dysfunction and Microbiome Dysbiosis in Colorectal Cancer Development
Authors: Genua Flavia , Raghunathan Vedhika , Jenab Mazda , Gallagher William M. , Hughes David J.
Published: April 2021

Accumulating evidence indicates that breakdown of the+ protective mucosal barrier of the gut plays a role in colorectal cancer (CRC) development. Inflammation and oxidative stress in the colonic epithelium are thought to be involved in colorectal carcinogenesis and the breakdown of the integrity of the colonic barrier may increase the exposure of colonocytes to toxins from the colonic milieu, enhancing inflammatory processes and release of Reactive Oxygen Species (ROS). The aetiological importance of the gut microbiome and its composition – influenced by consumption of processed meats, red meats and alcoholic drinks, smoking, physical inactivity, obesity - in CRC development is also increasingly being recognized. The gut microbiome has diverse roles, such as in nutrient metabolism and immune modulation. However, microbial encroachment towards the colonic epithelium may promote inflammation and oxidative stress and even translocation of species across the colonic lumen. Recent research suggests that factors that modify the above mechanisms, e.g., obesity and Western diet, also alter gut microbiota, degrade the integrity of the gut protective barrier, and expose colonocytes to toxins. However, it remains unclear how obesity, lifestyle and metabolic factors contribute to gut-barrier integrity, leading to metabolic disturbance, colonocyte damage, and potentially to CRC development. This review will discuss the interactive roles of gut-barrier dysfunction, microbiome dysbiosis, and exposure to endogenous toxins as another mechanism in CRC development, and how biomarkers of colonic mucosal barrier function may provide avenues for disease, prevention and detection.
Delayed Response After Confirmed Progression (DR) and Other Unique Immunotherapy-Related Treatment Concepts in Cutaneous Squamous Cell Carcinoma
Authors: Lim Annette M. , Cavanagh Karda , Hicks Rodney J. , McLean Luke , Goh Michelle S. , Webb Angela , Rischin Danny
Published: April 2021

Non-melanoma skin cancers are one of the most common cancers diagnosed worldwide, with the highest incidence in Australia and New Zealand. Systemic treatment of locally advanced and metastatic cutaneous squamous cell carcinomas has been revolutionized by immune checkpoint inhibition with PD-1 blockade. We highlight treatment issues distinct to the management of the disease including expansion of the traditional concept of pseudoprogression and describe delayed responses after immune-specific response criteria confirmed progressive disease with and without clinical deterioration. We term this phenomenon “delayed response after confirmed progression (DR)”. We also discuss the common development of second primary tumors, heterogeneous disease responses, and expanding clinical boundaries for immunotherapy use.
Case Reports: Management Challenges in Pediatric Germ Cell Tumors
Authors: Carr Sophie , Safavi Arash , Skarsgard Erik D.
Published: April 2021

Germ cell tumors in infants are most frequently extragonadal, benign, and amenable to surgical resection. An unusual feature of germ cell tumors is the potential coexistence of malignant with benign disease which makes it possible for patients with incompletely resected tumors to experience either a benign or malignant recurrence. A challenge to postoperative surveillance is the interpretation of serum alpha fetoprotein, a marker of malignancy, that is physiologically elevated during the first year of life. A rare subset of germ cell tumors occur in the retroperitoneum. Although the vast majority are benign, these tumors are often large and distort normal anatomy, and may demonstrate local invasiveness that increases risk of resection. The intent of these reports is to caution readers about these unusual features of germ cell tumors of infancy.
Alpha-1 Antitrypsin Deficiency: Home Therapy
Authors: Annunziata Anna , Lanza Maurizia , Coppola Antonietta , Andreozzi Paolo , Spinelli Sara , Fiorentino Giuseppe
Published: April 2021

While available in only a few countries, home therapy is a possible strategy for the treatment of alpha-1 antitrypsin deficiency. We want to describe our experience in the management of human alpha-1 antitrypsin using home care intravenous augmentation therapy during this emergency period caused by SARS-CoV2 infection. We assessed the safety of the home treatment and the quality of life of patients enrolled in the program.
Corynoxine Protects Dopaminergic Neurons Through Inducing Autophagy and Diminishing Neuroinflammation in Rotenone-Induced Animal Models of Parkinson’s Disease
Authors: Chen Leilei , Huang Yujv , Yu Xing , Lu Jiahong , Jia Wenting , Song Juxian , Liu Liangfeng , Wang Youcui , Huang Yingyu , Xie Junxia , Li Min
Published: April 2021

Recent studies have shown that impairment of autophagy is related to the pathogenesis of Parkinson’s disease (PD), and small molecular autophagy enhancers are suggested to be potential drug candidates against PD. Previous studies identified corynoxine (Cory), an oxindole alkaloid isolated from the Chinese herbal medicine Uncaria rhynchophylla (Miq.) Jacks, as a new autophagy enhancer that promoted the degradation of α-synuclein in a PD cell model. In this study, two different rotenone-induced animal models of PD, one involving the systemic administration of rotenone at a low dosage in mice and the other involving the infusion of rotenone stereotaxically into the substantia nigra pars compacta (SNpc) of rats, were employed to evaluate the neuroprotective effects of Cory. Cory was shown to exhibit neuroprotective effects in the two rotenone-induced models of PD by improving motor dysfunction, preventing tyrosine hydroxylase (TH)-positive neuronal loss, decreasing α-synuclein aggregates through the mechanistic target of the rapamycin (mTOR) pathway, and diminishing neuroinflammation. These results provide preclinical experimental evidence supporting the development of Cory into a potential delivery system for the treatment of PD.
A New Chalcone Derivative C49 Reverses Doxorubicin Resistance in MCF-7/DOX Cells by Inhibiting P-Glycoprotein Expression
Authors: Wang Ting , Dong Jingjing , Yuan Xu , Wen Haotian , Wu Linguangjin , Liu Jianwen , Sui Hua , Deng Wanli
Published: April 2021

Objective: C49 is a chalcone derivative. The aim of the current study is to illuminate the efficacy of C49 in reversing multidrug resistance (MDR) in MCF-7/DOX cells and its underlying molecular mechanism.

Methods: The cytotoxic effects of C49 on MCF-7/DOX cells were evaluated by MTT assay using different concentration (0–250 μmol/L) of C49. Cell proliferation was evaluated by colony formation assay. Cell death was examined by morphological analysis using Hoechst 33,258 staining. Flow cytometry and immunofluorescence were utilized to evaluate the intracellular accumulation of doxorubicin (DOX) and cell apoptosis. The differentially expressed genns between MCF-7 and MCF-7/DOX cells were analyzed by GEO database. The expression of PI3K/Akt pathway proteins were assessed by Western blot The activities of C49 combined with DOX was evaluated via xenograft tumor model in female BALB/c nude mice.

Results: C49 inhibited the growth of MCF-7 cells (IC50 = 59.82 ± 2.10 μmol/L) and MCF-7/DOX cells (IC50 = 65.69 ± 8.11 μmol/L) with dosage-dependent and enhanced the cellular accumulation of DOX in MCF-7/DOX cells. The combination of C49 and DOX inhibited cell proliferation and promoted cell apoptosis. MCF-7/DOX cells regained drug sensibility with the combination treatment through inhibiting the expression of P-gp, p-PI3K and p-Akt proteins. Meanwhile, C49 significantly increased the anticancer efficacy of DOX in vivo.

Conclusion: C49 combined with DOX restored DOX sensitivity in MCF-7/DOX cells through inhibiting P-gp protein.
Methanolic Extract of Lysimachia Candida Lindl. Prevents High-Fat High-Fructose-Induced Fatty Liver in Rats: Understanding the Molecular Mechanism Through Untargeted Metabolomics Study
Authors: Kamboj Parul , Sarkar Soumalya , Gupta Sonu Kumar , Bisht Neema , Kumari Deepika , Alam Md. Jahangir , Barge Sagar , Kashyap Bhaswati , Deka Barsha , Bharadwaj Simanta , Rahman Seydur , Dutta Partha Pratim , Borah Jagat C. , Talukdar Narayan Chandra , Banerjee Sanjay K. , Kumar Yashwant
Published: April 2021

Fatty liver is one of the most common metabolic syndrome affecting the global population. Presently, limited treatment modalities with symptomatic approach are available for alleviating fatty liver. Traditional and herbal treatment modalities have shown evidence to improve the disease pathology. In the present research work, evaluation of a selected medicinal plant Lysimachia candida Lindl. was carried out to investigate its beneficial effects on fatty liver disease in rats. Male Sprague Dawley (SD) rats were fed with high-fat high-fructose diet to induce fatty liver phenotypes. After induction for 15 weeks, methanolic extract of Lysimachia candida Lindl. (250 mg/kg b. w. p. o.) was administrated to the rats daily for the next 17 weeks. Blood samples were collected at different time points to analyze fasting blood glucose levels and relevant biochemical parameters important for the assessment of metabolic disease phenotypes. Liquid chromatography-mass spectrometry (LC-MS) based metabolomics was done to study the dynamics of metabolic changes in the serum during disease progression and how the medicinally important plant extract treatment reversed the metabolic diseases. Multivariate data analysis approaches have been employed to understand the metabolome changes and disease pathology. This study has identified the interplay of some metabolic pathways that alter the disease progression and their reversal after administration of the plant extract. Different group of metabolites mainly bile acids, fatty acids, carnitines, and their derivatives were found to be altered in the diseased rats. However, all the metabolites identified between control and disease groups are mainly related to lipid metabolism. The results depict that the treatment with the above-mentioned plant extract improves the regulation of aberrant lipid metabolism, and reverses the metabolic syndrome phenotype. Therefore, the present study reveals the potential mechanism of the herbal extract to prevent metabolic syndrome in rats.
Ambipolar Behavior of Ge-Intercalated Graphene: Interfacial Dynamics and Possible Applications
Authors: Zakharov A. A.
Published: April 2021

For the realization of graphene-based electronic and optic devices, the functionalization of this material becomes essential. Graphene doping through intercalation and tuning the chemical potential is one among other promising concepts. Intercalation of germanium is particularly interesting in view of its ambipolar doping behavior. Both p- and n-type doped graphene and their doping levels were identified by x-ray photoelectron emission microscopy (XPEEM), low-energy electron microscopy (LEEM), and angle-resolved photoemission microspectroscopy (μ-ARPES). The absolute amount of intercalated Ge was determined to be roughly 1 ML and 2 MLs for n- and p-phases, respectively. For the samples in the present study, we utilized the transition from 2 ML to 1 ML Ge via a mix phase after a high temperature annealing. Concrete implementation of mutual distribution of p- and n-phases depends on the temperature, mobility of Ge atoms in the second intercalated layer, and cooling/heating protocol, and can be nicely followed live in low-energy electron microscope (LEEM) during heating/cooling below 500°C. The process has a significant temperature hysteresis, which is an indication of the first-order phase transition. The enhanced Ge diffusion in the second layer can be suitable for tailoring ultrashort junction lengths so that pseudo-spin mismatch can be used in future electronic concepts. Another application can utilize the negative relative refractive index at the p–n boundary and can find possible applications in focusing electron optics.
Whitefly Network Analysis Reveals Gene Modules Involved in Host Plant Selection, Development and Evolution
Authors: Tian Jiahui , Zhan Haixia , Dewer Youssef , Zhang Biyun , Qu Cheng , Luo Chen , Li Fengqi , Yang Shiyong
Published: April 2021

Whiteflies are Hemipterans that typically feed on the undersides of plant leaves. They cause severe damage by direct feeding as well as transmitting plant viruses to a wide range of plants. However, it remains largely unknown which genes play a key role in development and host selection. In this study, weighted gene co-expression network analysis was applied to construct gene co-expression networks in whitefly. Nineteen gene co-expression modules were detected from 15560 expressed genes of whitefly. Combined with the transcriptome data of salivary glands and midgut, we identified three gene co-expression modules related to host plant selection. These three modules contain genes related to host-plant recognition, such as detoxification genes, chemosensory genes and some salivary gland-associated genes. Results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses elucidated the following pathways involved in these modules: lysosome, metabolic and detoxification pathways. The modules related to the development contain two co-expression modules; moreover, the genes were annotated to the development of chitin-based cuticle. This analysis provides a basis for future functional analysis of genes involved in host-plant recognition.
The Neurophysiological Processing of Music in Children: A Systematic Review With Narrative Synthesis and Considerations for Clinical Practice in Music Therapy
Authors: Bower Janeen , Magee Wendy L. , Catroppa Cathy , Baker Felicity Anne
Published: April 2021

Introduction: Evidence supporting the use of music interventions to maximize arousal and awareness in adults presenting with a disorder of consciousness continues to grow. However, the brain of a child is not simply a small adult brain, and therefore adult theories are not directly translatable to the pediatric population. The present study aims to synthesize brain imaging data about the neural processing of music in children aged 0-18 years, to form a theoretical basis for music interventions with children presenting with a disorder of consciousness following acquired brain injury.

Methods: We conducted a systematic review with narrative synthesis utilizing an adaptation of the methodology developed by Popay and colleagues. Following the development of the narrative that answered the central question “what does brain imaging data reveal about the receptive processing of music in children?”, discussion was centered around the clinical implications of music therapy with children following acquired brain injury.

Results: The narrative synthesis included 46 studies that utilized EEG, MEG, fMRI, and fNIRS scanning techniques in children aged 0-18 years. From birth, musical stimuli elicit distinct but immature electrical responses, with components of the auditory evoked response having longer latencies and variable amplitudes compared to their adult counterparts. Hemodynamic responses are observed throughout cortical and subcortical structures however cortical immaturity impacts musical processing and the localization of function in infants and young children. The processing of complex musical stimuli continues to mature into late adolescence.

Conclusion: While the ability to process fundamental musical elements is present from birth, infants and children process music more slowly and utilize different cortical areas compared to adults. Brain injury in childhood occurs in a period of rapid development and the ability to process music following brain injury will likely depend on pre-morbid musical processing. Further, a significant brain injury may disrupt the developmental trajectory of complex music processing. However, complex music processing may emerge earlier than comparative language processing, and occur throughout a more global circuitry.
Test Preparation in Figural Matrices Tests: Focus on the Difficult Rules
Authors: Krautter Kai , Lehmann Jessica , Kleinort Eva , Koch Marco , Spinath Frank M. , Becker Nicolas
Published: April 2021

It is well documented that training the rules employed in figural matrices tests enhances test performance. Previous studies only compare experimental conditions in which all or no rules were trained and therefore ignore the particular influence of knowledge about the easy and difficult rules. With the current study, we wanted to provide some first insights into this topic. Respondents were assigned to four groups that received training for no rules, only the easy rules, only the difficult rules, or for all rules. The results show that a training only for the difficult rules was more effective than the other trainings. This applies also to performance in the easy rules that were actually not part of the training. A possible explanation for this finding is a facilitation of the solution process that is primarily driven by knowledge about the difficult rules. In conclusion, our results demonstrate that taking differences between the rules into account may provide a deeper understanding of the effects of trainings for figural matrices tests.
Adaptive Social Factors and Precompetitive Anxiety in Elite Sport
Authors: Pineda-Espejel Heriberto Antonio , Alarcón Edgar , Morquecho-Sánchez Raquel , Morales-Sánchez Verónica , Gadea-Cavazos Erika
Published: April 2021

Grounded in achievement goal theory and self-determination theory, the aim of this study was to analyze the motivational determinants of precompetitive anxiety in the sports context, considering the horizontal motivational sequence: adaptive social factors (task-involving climate, autonomy support style), competence need, types of motivation (autonomous motivation, controlled motivation, amotivation), and consequences (precompetitive anxiety and self-confidence). This study was also conducted in order to analyze the mediating role of the need for competition and motivational regulations on social factors and consequences. The sample consisted of 217 athletes of both sexes engaged in elite sport, who answered a series of questionnaires to measure study variables to develop an analysis of the structural equation model. The results showed that both the task-involving climate and autonomy support were associated with competence need, and competence need was associated with autonomous motivation in a positive way and with controlled motivation and amotivation in a negative way. On the other hand, autonomous motivation was positively associated with self-confidence, while amotivation was positively related to somatic and cognitive anxiety before a competition. Furthermore, there was a total mediation of competence need and autonomous motivation between task climate and self-confidence. In conclusion, these social factors favor self-confidence, and besides, these climates disfavor anxiety before a sport competition.
The Role of Socio-Demographic Factors in the Coverage of Breast Cancer Screening: Insights From a Quantile Regression Analysis
Authors: Ding Lilu , Jidkova Svetlana , Greuter Marcel J. W. , Van Herck Koen , Goossens Mathieu , De Schutter Harlinde , Martens Patrick , Van Hal Guido , de Bock Geertruida H.
Published: April 2021

Background: In Flanders, breast cancer (BC) screening is performed in a population-based breast cancer screening program (BCSP), as well as in an opportunistic setting. Women with different socio-demographic characteristics are not equally covered by BC screening.

Objective: To evaluate the role of socio-demographic characteristics on the lowest 10th and highest 90th quantile levels of BC screening coverage.

Methods: The 2017 neighborhood-level coverage rates of 8,690 neighborhoods with women aged 50–69 and eligible for BCSP and opportunistic screening were linked to socio-demographic data. The association between socio-demographic characteristics and the coverage rates of BCSP and opportunistic screening was evaluated per quantile of coverage using multivariable quantile regression models, with specific attention to the lowest 10th and highest 90th quantiles.

Results: The median coverage in the BCSP was 50%, 33.5% in the 10th quantile, and 64.5% in the 90th quantile. The median coverage of the opportunistic screening was 12, 4.2, and 24.8% in the 10th and 90th quantile, respectively. A lower coverage of BCSP was found in neighborhoods with more foreign residents and larger average household size, which were considered indicators for a lower socioeconomic status (SES). However, a higher average personal annual income, which was considered an indicator for a higher SES, was also found in neighborhoods with lower coverage of BCSP. For these neighborhoods, that have a relatively low and high SES, the negative association between the percentage of foreign residents, average household size, and average personal annual income and the coverage in the BCSP had the smallest regression coefficient and 95% confidence interval (CI) values were −0.75 (95% CI: −0.85, −0.65), −13.59 (95% CI: −15.81, −11.37), and −1.05 (95% CI: −1.18, −0.92), respectively, for the 10th quantile. The neighborhoods with higher coverage of opportunistic screening had a relatively higher average personal annual income, with the largest regression coefficient of 1.72 (95% CI: 1.59, 1.85) for the 90th quantile.

Conclusions: Women from relatively low and high SES neighborhoods tend to participate less in the BCSP, whereas women with a relatively high SES tend to participate more in opportunistic screening. For women from low SES neighborhoods, tailored interventions are needed to improve the coverage of BCSP.
The Development of Overtrust: An Empirical Simulation and Psychological Analysis in the Context of Human–Robot Interaction
Authors: Ullrich Daniel , Butz Andreas , Diefenbach Sarah
Published: April 2021

With impressive developments in human–robot interaction it may seem that technology can do anything. Especially in the domain of social robots which suggest to be much more than programmed machines because of their anthropomorphic shape, people may overtrust the robot's actual capabilities and its reliability. This presents a serious problem, especially when personal well-being might be at stake. Hence, insights about the development and influencing factors of overtrust in robots may form an important basis for countermeasures and sensible design decisions. An empirical study [N= 110] explored the development of overtrust using the example of a pet feeding robot. A 2 × 2 experimental design and repeated measurements contrasted the effect of one's own experience, skill demonstration, and reputation through experience reports of others. The experiment was realized in a video environment where the participants had to imagine they were going on a four-week safari trip and leaving their beloved cat at home, making use of a pet feeding robot. Every day, the participants had to make a choice: go to a day safari without calling options (risk and reward) or make a boring car trip to another village to check if the feeding was successful and activate an emergency call if not (safe and no reward). In parallel to cases of overtrust in other domains (e.g., autopilot), the feeding robot performed flawlessly most of the time until in the fourth week; it performed faultily on three consecutive days, resulting in the cat's death if the participants had decided to go for the day safari on these days. As expected, with repeated positive experience about the robot's reliability on feeding the cat, trust levels rapidly increased and the number of control calls decreased. Compared to one's own experience, skill demonstration and reputation were largely neglected or only had a temporary effect. We integrate these findings in a conceptual model of (over)trust over time and connect these to related psychological concepts such as positivism, instant rewards, inappropriate generalization, wishful thinking, dissonance theory, and social concepts from human–human interaction. Limitations of the present study as well as implications for robot design and future research are discussed.
Chronic Exposure to Continuous Brightness or Darkness Modulates Immune Responses and Ameliorates the Antioxidant Enzyme System in Male Rats
Authors: Moustafa Amira
Published: April 2021

Circadian rhythms are considered vital regulators of immune functions. This study aims to elucidate the effects of chronic circadian disruption on immune functions, clock genes expression, and antioxidant enzymes levels in lymphoid tissues. Adult male Sprague-Dawley rats were subjected to a normal light/dark cycle or either continuous light (LL) or continuous dark (DD) for 8 weeks. The results demonstrated (1) significant decreases in the circulating levels of interleukin 1β, interleukin 6 and tumor necrosis factor alpha (TNF-α) and significant increases in the levels of interleukin 10, interleukin 12, C-reactive protein (CRP) and corticosterone in both LL and DD groups; (2) upregulation in mRNA expression of core clock genes Cry1, Cry2, Per1, Per2, and Per3 in the spleen of the DD group and downregulation in Cry1 and Cry2 genes in the LL group; (3) elevation of total antioxidant capacity (TAC), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), nitric oxide (NO) and the lipid peroxidation marker malondialdehyde (MDA) in the spleen, lymph node and bone marrow of both the LL and DD groups and decreases in the levels of the same markers in the thymus of the LL group; (4) decreased numbers of CD4+ and CD8+ cells in lymphoid tissues of both the LL and the DD groups; (5) reduced platelets count and suppressed immunoglobulin (IgM, IgE) in the LL and DD groups with marked erythropenia and leukocytosis in the DD group. Taken together, circadian misalignment leads to hematological disruptions, dysregulation of clock genes, and inflammatory mediators, which further enhances the antioxidant enzyme system that is crucial for an organism's adaptation to stresses.
Clinicopathological Significance of Estrogen Receptor β and Estrogen Synthesizing/Metabolizing Enzymes in Urothelial Carcinoma of Urinary Bladder
Authors: Sato Naomi , Ise Kazue , Hata Shuko , Yamashita Shinichi , Ito Akihiro , Sasano Hironobu , Nakamura Yasuhiro
Published: April 2021

Sex-specific differences in the incidence of urinary bladder carcinomas are well known, and the possible involvement of sex steroids has been proposed. We previously reported the association of the loss of androgen receptors and androgen-producing enzymes with tumor progression of urinary bladder cancer patients. Clinically, the selective estrogen receptor modulators (SERMs) were reported to suppress the progression of these tumors but the status of estrogen receptors (ERs) has not been well studied in patients with bladder urinary cancer. Moreover, not only ERs but also estrogen-related enzymes, such as aromatase, steroid sulfatase (STS), and estrogen sulfotransferase (EST), have been reported in the biological/clinical behavior of various hormone-dependent carcinomas but not studied in urinary bladder carcinoma. Therefore, in this study, we immunolocalized ERs as well as estrogen metabolizing enzymes in urinary bladder carcinoma and performed immunoblotting and cell proliferation assays using the bladder urothelial carcinoma cell line, T24. The results revealed that the loss of STS and aromatase was significantly correlated with advanced stages of the carcinoma. In vitro studies also revealed that T24 cell proliferation rates were significantly ameliorated after treatment with estradiol or diarylpropionitrile (DPN). EST and aromatase were also significantly correlated with the nuclear grade of the carcinoma. The results of our present study, for the first time, demonstrated that biologically active estrogens that bind to ERs could suppress tumor progression and the inactive ones could promote its progression and the potential clinical utility of SERM treatment in selective patients with urinary bladder carcinoma.
Seismic Evaluation and Methods of Rehabilitation of Old Masonry Buildings in the Bay of Kotor (Montenegro)
Authors: Tomanović Dušan , Marković Ljubo , Gadžić Nebojša , Rajković Irena , Aleksić Julija , Tomanović Tijana
Published: April 2021

Old load-bearing masonry buildings exist all around the world. The cultural and architectural heritage value of these buildings and the consciousness of public opinion have led to a need for safeguarding and preservation policies for these architecturally valued buildings and urban aggregates. This paper provides the information on the constructive and structural details of the old buildings dating from the 12th to 19th century in the Bay of Kotor and discusses their seismic and dynamic behaviour, identifying structural fragilities and consequently their vulnerability. One factor that significantly influences the seismic vulnerability is the quality of workmanship, which has, in conjunction with the lack of maintenance of the buildings, increased the seismic vulnerability of heritage masonry buildings in general. Masonry constructions represent an important part of Montenegrin Architectural Heritage. The existing heritage masonry buildings in the Bay of Kotor suffered major earthquakes with repairs ranging from minor repairs to partial rebuilding. No degree of seismic resistance to any potentially severe shaking levels has been determined for the surviving buildings. The lack of strategies, policies and actions by the institutions responsible for this domain in the course of the second half of the 20th century drove these buildings to the state of serious degradation. The adoption of intrusive and inadequate rehabilitation and conservation practices, using new materials and construction techniques on structural and nonstructural elements, has strayed away from traditional knowledge and practices. The main objective of this research is understanding the whole building process that underpins a historical construction, and building techniques and other methods applied in building the architectural and engineering structures constituting the present Historical Heritage in Montenegro.
The Fungicide Chlorothalonil Changes the Amphibian Skin Microbiome: A Potential Factor Disrupting a Host Disease-Protective Trait
Authors: Jiménez Randall R. , Alvarado Gilbert , Ruepert Clemens , Ballestero Erick , Sommer Simone
Published: April 2021

The skin microbiome is an important part of amphibian immune defenses and protects against pathogens such as the chytrid fungus Batrachochytrium dendrobatidis (Bd), which causes the skin disease chytridiomycosis. Alteration of the microbiome by anthropogenic factors, like pesticides, can impact this protective trait, disrupting its functionality. Chlorothalonil is a widely used fungicide that has been recognized as having an impact on amphibians, but so far, no studies have investigated its effects on amphibian microbial communities. In the present study, we used the amphibian Lithobates vibicarius from the montane forest of Costa Rica, which now appears to persist despite ongoing Bd-exposure, as an experimental model organism. We used 16S rRNA amplicon sequencing to investigate the effect of chlorothalonil on tadpoles’ skin microbiome. We found that exposure to chlorothalonil changes bacterial community composition, with more significant changes at a higher concentration. We also found that a larger number of bacteria were reduced on tadpoles’ skin when exposed to the higher concentration of chlorothalonil. We detected four presumed Bd-inhibitory bacteria being suppressed on tadpoles exposed to the fungicide. Our results suggest that exposure to a widely used fungicide could be impacting host-associated bacterial communities, potentially disrupting an amphibian protective trait against pathogens.
The Evolution of Molybdenum Dependent Nitrogenase in Cyanobacteria
Authors: Watanabe Tomoaki , Horiike Tokumasa
Published: April 2021

Nitrogen fixation plays a crucial role in the nitrogen cycle by helping to convert nitrogen into a form usable by other organisms. Bacteria capable of fixing nitrogen are found in six phyla including Cyanobacteria. Molybdenum dependent nitrogenase (nif) genes are thought to share a single origin as they have homologs in various phyla. However, diazotrophic bacteria have a mosaic distribution within the cyanobacterial lineage. Therefore, the aim of this study was to determine the cause of this mosaic distribution. We identified nif gene operon structures in the genomes of 85 of the 179 cyanobacterial strains for which whole genome sequences were available. Four nif operons were conserved in each diazotroph Cyanobacterium, although there were some gene translocations and insertions. Phylogenetic inference of these genes did not reveal horizontal gene transfer from outside the phylum Cyanobacteria. These results support the hypothesis that the mosaic distribution of diazotrophic bacteria in the cyanobacterial lineage is the result of the independent loss of nif genes inherited from common cyanobacterial ancestors in each lineage.
Non-Coding RNAs as Biomarkers of Tumor Progression and Metastatic Spread in Epithelial Ovarian Cancer
Authors: Seborova Karolina , Vaclavikova Radka , Rob Lukas , Soucek Pavel , Vodicka Pavel
Published: April 2021

Ovarian cancer is one of the most common causes of death among gynecological malignancies. Molecular changes occurring in the primary tumor lead to metastatic spread into the peritoneum and the formation of distant metastases. Identification of these changes helps to reveal the nature of metastases development and decipher early biomarkers of prognosis and disease progression. Comparing differences in gene expression profiles between primary tumors and metastases, together with disclosing their epigenetic regulation, provides interesting associations with progression and metastasizing. Regulatory elements from the non-coding RNA families such as microRNAs and long non-coding RNAs seem to participate in these processes and represent potential molecular biomarkers of patient prognosis. Progress in therapy individualization and its proper targeting also rely upon a better understanding of interactions among the above-listed factors. This review aims to summarize currently available findings of microRNAs and long non-coding RNAs linked with tumor progression and metastatic process in ovarian cancer. These biomolecules provide promising tools for monitoring the patient’s response to treatment, and further they serve as potential therapeutic targets of this deadly disease.
Using Exome Sequencing to Improve Prediction of FOLFIRINOX First Efficacy for Pancreatic Adenocarcinoma
Authors: Lecuelle Julie , Aarnink Anne , Tharin Zoé , Truntzer Caroline , Ghiringhelli François
Published: April 2021

Purpose: The first line treatment of advanced pancreatic ductal adenocarcinoma cancer (PDAC) comprises a FOLFIRINOX regimen for most patients with good performance status. However, no biomarker to predict efficacy is currently available. We investigated whether exome sequencing could be used to predict progression-free and overall survival in patients undergoing FOLFIRINOX for PDAC. Methods: In this single-center observational study, we included 78 patients with advanced PDAC who underwent somatic and germline exome analyses during first line therapy with FOLFIRINOX or gemcitabine. Exome-derived variables associated with outcome were then used in Cox regression models to generate a composite biomarker. Results: Performance status, tumor stage, liver metastasis, and lung metastasis were retained to generate a prognostic clinical score associated with overall and progression-free survival. Clonality, ploidy, and copy number variant (CNV) signatures 1 and 5, as well as gene variants in the calcium, non-homologous end-joining (NHEJ), and spliceosome pathways, were retained to generate a genomic prognostic score. The addition of genomic score improved the prediction of prognosis compared to the clinical score alone. Conclusions: This study underlines that structural and pathway genomic features could be used to predict FOLFIRINOX survival in patients with advanced PDAC.
Sensitivity and Resistance of Oncogenic RAS-Driven Tumors to Dual MEK and ERK Inhibition
Authors: Catalano Antonella , Adlesic Mojca , Kaltenbacher Thorsten , Klar Rhena F. U. , Albers Joachim , Seidel Philipp , Brandt Laura P. , Hejhal Tomas , Busenhart Philipp , Röhner Niklas , Zodel Kyra , Fritsch Kornelia , Wild Peter J. , Duyster Justus , Fritsch Ralph , Brummer Tilman , Frew Ian J.
Published: April 2021

Oncogenic mutations in RAS family genes arise frequently in metastatic human cancers. Here we developed new mouse and cellular models of oncogenic HrasG12V-driven undifferentiated pleomorphic sarcoma metastasis and of KrasG12D-driven pancreatic ductal adenocarcinoma metastasis. Through analyses of these cells and of human oncogenic KRAS-, NRAS- and BRAF-driven cancer cell lines we identified that resistance to single MEK inhibitor and ERK inhibitor treatments arise rapidly but combination therapy completely blocks the emergence of resistance. The prior evolution of resistance to either single agent frequently leads to resistance to dual treatment. Dual MEK inhibitor plus ERK inhibitor therapy shows anti-tumor efficacy in an HrasG12V-driven autochthonous sarcoma model but features of drug resistance in vivo were also evident. Array-based kinome activity profiling revealed an absence of common patterns of signaling rewiring in single or double MEK and ERK inhibitor resistant cells, showing that the development of resistance to downstream signaling inhibition in oncogenic RAS-driven tumors represents a heterogeneous process. Nonetheless, in some single and double MEK and ERK inhibitor resistant cell lines we identified newly acquired drug sensitivities. These may represent additional therapeutic targets in oncogenic RAS-driven tumors and provide general proof-of-principle that therapeutic vulnerabilities of drug resistant cells can be identified.
Analysis of TERT Isoforms across TCGA, GTEx and CCLE Datasets
Authors: Subasri Mathushan , Shooshtari Parisa , Watson Andrew J. , Betts Dean H.
Published: April 2021

Reactivation of the multi-subunit ribonucleoprotein telomerase is the primary telomere maintenance mechanism in cancer, but it is rate-limited by the enzymatic component, telomerase reverse transcriptase (TERT). While regulatory in nature, TERT alternative splice variant/isoform regulation and functions are not fully elucidated and are further complicated by their highly diverse expression and nature. Our primary objective was to characterize TERT isoform expression across 7887 neoplastic and 2099 normal tissue samples using The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression Project (GTEx), respectively. We confirmed the global overexpression and splicing shift towards full-length TERT in neoplastic tissue. Stratifying by tissue type we found uncharacteristic TERT expression in normal brain tissue subtypes. Stratifying by tumor-specific subtypes, we detailed TERT expression differences potentially regulated by subtype-specific molecular characteristics. Focusing on β-deletion splicing regulation, we found the NOVA1 trans-acting factor to mediate alternative splicing in a cancer-dependent manner. Of relevance to future tissue-specific studies, we clustered cancer cell lines with tumors from related origin based on TERT isoform expression patterns. Taken together, our work has reinforced the need for tissue and tumour-specific TERT investigations, provided avenues to do so, and brought to light the current technical limitations of bioinformatic analyses of TERT isoform expression.
Mechanism of the Mg3Bi2 Phase Formation in Pb-Free Aluminum 6xxx Alloy with Bismuth Addition
Authors: Rečnik Simon , Bizjak Milan , Medved Jožef , Cvahte Peter , Karpe Blaž , Nagode Aleš
Published: April 2021

In the present work, free-cutting aluminum alloy AA6026 with 1.1 wt.% bismuth addition was fabricated by different melt preparation methods in order to investigate whether the melt preparation route affects the solidification sequence and thus has an influence on the machinability of the alloy. All experiments were designed to simulate variable industrial conditions: addition of bismuth in an induction melting furnace, addition of bismuth in an electric resistance holding furnace, addition of bismuth together with grain refiner, effect of holding time and melt temperature before casting. Detailed thermodynamic analyses (DSC, Thermo-Calc) and microstructural characterization (SEM-EDS, XRD) have been performed to explain the solidification sequence, microstructure development and especially formation of the intermetallic Mg3Bi2 phase.
Cancer, Clinical Trials, and Canada: Our Contribution to Worldwide Randomized Controlled Trials
Authors: Sharma Shubham , Wells J. Connor , Hopman Wilma M. , Del Paggio Joseph C. , Gyawali Bishal , Hammad Nazik , Hay Annette E. , Booth Christopher M.
Published: April 2021

Canada has a long tradition of leading practice-changing clinical trials in oncology. Here, we describe methodology, results, and interpretation of oncology RCTs with Canadian involvement compared to RCTs from other high-income countries (HICs). A literature search identified all RCTs evaluating anti-cancer therapies published 2014–2017. RCTs were classified based on the country affiliation of first authors. The study cohort included 636 HIC-led RCTs; 155 (24%) had Canadian authors. Three-quarters (112/155, 72%) of Canadian RCTs were conducted in the palliative setting, compared to two thirds (299/481, 62%) of RCTs from other HICs (p = 0.022). Canadian RCTs were more likely than those from other HICs to be supported by industry (85% vs. 69%, p < 0.001). The proportion of positive Canadian trials that met the ESMO-MCBS threshold for substantial clinical benefit was comparable to RCTs without Canadian authors (29% vs. 32%, p = 0.137). Thirteen percent (20/155) of all Canadian trials were affiliated with the Canadian Cancer Trials Group (CCTG). Canada plays a meaningful role in the global cancer research ecosystem but is overly reliant on industry support. The very low proportion of trials that identify a new treatment with substantial clinical benefit is worrisome. A renewed investment in cancer clinical trials is needed in Canada.
Single Neuronal Dynamical System in Self-Feedbacked Hopfield Networks and Its Application in Image Encryption
Authors: Xu Xitong , Chen Shengbo
Published: April 2021

Image encryption is a confidential strategy to keep the information in digital images from being leaked. Due to excellent chaotic dynamic behavior, self-feedbacked Hopfield networks have been used to design image ciphers. However, Self-feedbacked Hopfield networks have complex structures, large computational amount and fixed parameters; these properties limit the application of them. In this paper, a single neuronal dynamical system in self-feedbacked Hopfield network is unveiled. The discrete form of single neuronal dynamical system is derived from a self-feedbacked Hopfield network. Chaotic performance evaluation indicates that the system has good complexity, high sensitivity, and a large chaotic parameter range. The system is also incorporated into a framework to improve its chaotic performance. The result shows the system is well adapted to this type of framework, which means that there is a lot of room for improvement in the system. To investigate its applications in image encryption, an image encryption scheme is then designed. Simulation results and security analysis indicate that the proposed scheme is highly resistant to various attacks and competitive with some exiting schemes.
On a Variational Definition for the Jensen-Shannon Symmetrization of Distances Based on the Information Radius
Authors: Nielsen Frank
Published: April 2021

We generalize the Jensen-Shannon divergence and the Jensen-Shannon diversity index by considering a variational definition with respect to a generic mean, thereby extending the notion of Sibson’s information radius. The variational definition applies to any arbitrary distance and yields a new way to define a Jensen-Shannon symmetrization of distances. When the variational optimization is further constrained to belong to prescribed families of probability measures, we get relative Jensen-Shannon divergences and their equivalent Jensen-Shannon symmetrizations of distances that generalize the concept of information projections. Finally, we touch upon applications of these variational Jensen-Shannon divergences and diversity indices to clustering and quantization tasks of probability measures, including statistical mixtures.
Simulation Model to Analyze the Consequences of DC Faults in MMC-Based HVDC Stations
Authors: Guedon Davin , Ladoux Philippe , Sanchez Sébastien , Cornet Sébastien
Published: April 2021

The global development of high-voltage direct-current (HVDC) systems in fields such as renewable energy sources, interconnection of asynchronous grids or power transmission over great distances, is unquestionably important. Though widely used, the modular multilevel converter with half-bridge cells is sensitive to DC pole-to-pole faults and the time-response of the protections is critical. Reliability and availability are paramount: circuit-breakers must minimize the effects of any fault on the converter, while ensuring rapid restart. This paper focuses on the modelling aspects to analyse the behaviour of HVDC stations during DC pole-to-pole faults, using either AC or DC circuit-breakers, with different parameters. The proposed model can represent the main issues met by the converter cells during DC faults, such as semiconductor overcurrents and overvoltages, allowing a proper design of the cells.