bluuebunny/crossref_metadata_2025 huggingface dataset:
The Global Durum Wheat Panel (GDP): An International Platform to Identify and Exchange Beneficial Alleles
Authors: Mazzucotelli Elisabetta , Sciara Giuseppe , Mastrangelo Anna M. , Desiderio Francesca , Xu Steven S. , Faris Justin , Hayden Matthew J. , Tricker Penny J. , Ozkan Hakan , Echenique Viviana , Steffenson Brian J. , Knox Ron , Niane Abdoul A. , Udupa Sripada M. , Longin Friedrich C. H. , Marone Daniela , Petruzzino Giuseppe , Corneti Simona , Ormanbekova Danara , Pozniak Curtis , Roncallo Pablo F. , Mather Diane , Able Jason A. , Amri Ahmed , Braun Hans , Ammar Karim , Baum Michael , Cattivelli Luigi , Maccaferri Marco , Tuberosa Roberto , Bassi Filippo M.
Published: December 2020

Representative, broad and diverse collections are a primary resource to dissect genetic diversity and meet pre-breeding and breeding goals through the identification of beneficial alleles for target traits. From 2,500 tetraploid wheat accessions obtained through an international collaborative effort, a Global Durum wheat Panel (GDP) of 1,011 genotypes was assembled that captured 94–97% of the original diversity. The GDP consists of a wide representation ofTriticum turgidumssp.durummodern germplasm and landraces, along with a selection of emmer and primitive tetraploid wheats to maximize diversity. GDP accessions were genotyped using the wheat iSelect 90K SNP array. Among modern durum accessions, breeding programs from Italy, France and Central Asia provided the highest level of genetic diversity, with only a moderate decrease in genetic diversity observed across nearly 50 years of breeding (1970–2018). Further, the breeding programs from Europe had the largest sets of unique alleles. LD was lower in the landraces (0.4 Mbp) than in modern germplasm (1.8 Mbp) atr2= 0.5.ADMIXTUREanalysis of modern germplasm defined a minimum of 13 distinct genetic clusters (k), which could be traced to the breeding program of origin. Chromosome regions putatively subjected to strong selection pressure were identified from fixation index (Fst) and diversity reduction index (DRI) metrics in pairwise comparisons among decades of release and breeding programs. Clusters of putative selection sweeps (PSW) were identified as co-localized with major loci controlling phenology (PpdandVrn), plant height (Rht) and quality (gliadins and glutenins), underlining the role of the corresponding genes as driving elements in modern breeding. Public seed availability and deep genetic characterization of the GDP make this collection a unique and ideal resource to identify and map useful genetic diversity at loci of interest to any breeding program.
Competencies for a Healthy Physically Active Lifestyle: Second-Order Analysis and Multidimensional Scaling
Authors: Carl Johannes , Sudeck Gorden , Pfeifer Klaus
Published: December 2020

The physical activity-related health competence (PAHCO) model assumes that individuals require movement competence, control competence, and self-regulation competence to lead a healthy, physically active lifestyle. Although previous research has already established some measurement factors (n = 8) of the three dimensions, no attempts have so far been made to statistically aggregate them on the sub-competence level. Therefore, the goal of the present study was to test two additional factors for PAHCO and subsequently model the second-order structure with two samples from the fields of rehabilitation and prevention. We conducted two questionnaire surveys with persons with multiple sclerosis (n = 475) and teaching students undergoing a basic qualification course in physical education (n = 502). After performing exploratory items analysis, we used second-order confirmatory factor analysis (CFA) and multidimensional scaling to investigate whether the scales could be bundled in accordance with the PAHCO model. The CFAs with 10 factors (42 items) demonstrated a good model fit. In contrast, the second-order analysis with a simple loading structure on the three sub-competencies revealed an unacceptable model fit. Instead, a second-order model variant was preferred [comparative fit index (CFI) = 0.926, root mean square error of approximation (RMSEA) = 0.048, standardized root mean square residual (SRMR) = 0.065] in which body awareness and self-efficacy had theory-conform cross-loadings. The results of multidimensional scaling (two-dimensional solution) were in line with the extracted second-order structure. The present results suggested that the extension of the measurement instrument to 10 first-order factors was psychometrically justified for the two populations. The results from the second-order analyses provided the basis for the creation of sum scores, representing manifest indicators of movement competence, control competence, and self-regulation competence. Future studies are needed that cross-validate the extended measurement model with other populations and that relate the sub-competencies of PAHCO to indicators of health-enhancing physical activity.
Effect of Coronavirus Disease 2019 (COVID-19) on Elite Spanish Student-Athletes’ Perception of the Dual Career
Authors: Abenza-Cano Lucia , Leiva-Arcas Alejandro , Vaquero-Cristóbal Raquel , García-Roca Juan Alfonso , Meroño Lourdes , Sánchez-Pato Antonio
Published: December 2020

The aim of the present research was to assess elite student-athletes’ perception of the dual career during the lockdown caused by the coronavirus disease 2019 (COVID-19) pandemic, compared with a group of elite student-athletes who could develop their dual career under normal conditions. A total of 150 elite athletes who were also undergraduate or postgraduate students self-completed the “Perceptions of dual career student-athletes (ESTPORT)” questionnaire. From them, 78 did it during the mandatory lockdown period due to the state of emergency caused by COVID-19 (COVID-19 group) and 72 completed it in the previous year to Rio 2016 Olympic Games (control group). The COVID-19 group was found to spend a significantly higher number of hours per week studying, while no significant differences were observed between groups in any training time variable. Student-athletes of the COVID-19 group showed better perception of whether their sport career could help them cope with their academic career and better general perception of remote learning and the use of tasks and videoconferencing as learning support tools. A lower percentage of athletes of the COVID-19 group than of the control group wished to continue with their sport career once they finished their studies. To conclude, student-athletes of the COVID-19 group show adaptations with regard to the organization of their studies and the importance they give to them and to the services provided by dual-career programs, compared with student-athletes from an ordinary pre-Olympic year. In general, student-athletes’ perception of the dual career is very positive.
The Association Between Adolescent Residential Mobility and Adult Social Anxiety, BDNF and Amygdala-Orbitofrontal Functional Connectivity in Young Adults With Higher Education
Authors: Hasler Gregor , Haynes Melanie , Müller Sabrina Theresia , Tuura Ruth , Ritter Christopher , Buchmann Andreas
Published: December 2020

Background: Large-scale epidemiological studies demonstrate that house moves during adolescence lead to an increase in anxiety and stress-sensitivity that persists into adulthood. As such, it might be expected that moves during adolescence have strong negative and long-lasting effects on the brain. We hypothesized that moves during adolescence impair fear circuit maturation, as measured by the connectivity between amygdala and orbitofrontal cortex, and expression of brain-derived neurotrophic factor (BDNF).

Methods: We examined young adults with middle and high economic status recruited from the community using clinical interviews, self-report questionnaires, functional magnetic resonance imaging during an emotional faces task and during a 10 min rest phase, and serum BDNF serum concentration.

Results: Out of 234 young adults, 164 did not move between ages 10 and 16 (i.e., moves with change of school), 50 moved once, and 20 moved twice or more than twice. We found relationships between adolescent moving frequency and social avoidance (pcorr = 0.012), right amygdala-orbitofrontal cortex connectivity (pcorr = 0.016) and low serum BDNF concentrations in young adulthood (pcorr = 0.012). Perceived social status of the mother partly mitigated the effects of moving on social avoidance and BDNF in adulthood.

Conclusions: This study confirms previous reports on the negative and persistent effects of residential mobility during adolescence on mental health. It suggests that these effects are mediated by impairments in fear circuit maturation. Finally, it encourages research into protecting factors of moving during adolescents such as the perceived social status of the mother.
Impact of Baseline Characteristics on the Effectiveness of Disorder-Specific Cognitive Behavioral Analysis System of Psychotherapy (CBASP) and Supportive Psychotherapy in Outpatient Treatment for Persistent Depressive Disorder
Authors: Serbanescu Ilinca , Backenstrass Matthias , Drost Sarah , Weber Bernd , Walter Henrik , Klein Jan Philipp , Zobel Ingo , Hautzinger Martin , Meister Ramona , Härter Martin , Schramm Elisabeth , Schoepf Dieter
Published: December 2020

Importance: In the treatment of persistent depressive disorder (PDD), disorder-specific Cognitive Behavioral Analysis System of Psychotherapy (CBASP) has been shown to be superior to Supportive Psychotherapy (SP) in outpatients. It remains to clear which subgroups of patients benefit equally and differentially from both psychotherapies.

Objective: To identify those patient-level baseline characteristics that predict a comparable treatment effectiveness of CBASP and SP and those that moderate the differential effectiveness of CBASP compared to SP.

Design, setting and participants: In this analysis of a 48-week multicenter randomized clinical trial comparing CBASP to SP in adult antidepressant-free outpatients with early-onset PDD, we evaluated baseline variables from the following domains as potential predictors and moderators of treatment effectiveness: socio-demography, clinical status, psychosocial and global functioning, life quality, interpersonal problems, childhood trauma, treatment history, preference for psychotherapy, and treatment expectancy.

Interventions: A 48-week treatment program with 32 sessions of either CBASP or SP.

Main outcomes and measures: Depression severity measured by the 24-item Hamilton Rating Scale for Depression (HRSD-24) at week 48.

Results: From N = 268 randomized outpatients, N = 209 completed the 48-week treatment program. CBASP completers had significantly lower post-treatment HRSD-24 scores than SP completers (meanCBASP=13.96, sdCBASP= 9.56; meanSP= 16.69, sdSP= 9.87; p = 0.04). A poor response to both therapies was predicted by higher baseline levels of clinician-rated depression, elevated suicidality, comorbid anxiety, lower social functioning, higher social inhibition, moderate-to-severe early emotional or sexual abuse, no preference for psychotherapy, and the history of at least one previous inpatient treatment. Moderator analyses revealed that patients with higher baseline levels of self-rated depression, comorbidity of at least one Axis-I disorder, self-reported moderate-to-severe early emotional or physical neglect, or at least one previous antidepressant treatment, had a significantly lower post-treatment depression severity with CBASP compared to SP (all p < 0.05).

Conclusions and relevance: A complex multifactorial interaction between severe symptoms of depression, suicidality, and traumatic childhood experiences characterized by abuse, social inhibition, and anxiety may represent the basis of non-response to psychotherapy in patients with early onset PDD. Specific psychotherapy with CBASP might, however, be more effective and recommendable for a variety of particularly burdened patients compared to SP.
Seasonal Pattern of Prevalence and Excretion of Eggs of Baylisascaris transfuga in the Brown Bear (Ursus arctos)
Authors: Molnár Ladislav , Königová Alžbeta , Major Peter , Vasilková Zuzana , Tomková Martina , Várady Marián
Published: December 2020

The seasonal dynamics of the prevalence, abundance, and mean intensity of egg excretion by the nematode parasite Baylisascaris transfuga in the European brown bear (Ursus arctos) were monitored relative to environmental factors (mean temperature, humidity, and temperature) over three years. The prevalence, abundance, and mean intensity of egg excretion tended to increase from spring to autumn throughout the monitoring period. The seasonal prevalence (84.2–90.6%), abundance (470.2–545.3 eggs per gramme (EPG) of faeces), mean intensity of excretion (558.3–602.1 EPG), and number of eggs (1150 EPG) were highest in autumn. The prevalence of eggs (up to 48.5%), abundance (37.8–60.6 EPG), and mean intensity of excretion (94.4–125.0 EPG) were high in winter, despite the period of hibernation. The seasonal dynamics of B. transfuga abundance in bears, the mean temperature between spring and autumn, and the seasonal trend of increase in intensity of egg excretion with temperature from winter to summer were interrelated. Abundance differed significantly between winter and autumn, spring and autumn, and summer and autumn (p < 0.0001) in all years and between spring and summer in 2016 (p < 0.005), 2017 (p < 0.05). B. transfuga abundance differed significantly between the seasons over the three years only in spring (p ≤ 0.0001).
Quantifying the Economic Impact of Bovine Tuberculosis on Livestock Farms in South-Western Spain
Authors: Pérez-Morote Rosario , Pontones-Rosa Carolina , Gortázar-Schmidt Christian , Muñoz-Cardona Álvaro Ignacio
Published: December 2020

Pasture-based livestock farming generates income in regions with limited resources and is key to biodiversity conservation. However, costs derived from fighting disease can make the difference between profit and loss, eventually compromising farm survival. Animal TB (TB), a chronic infection of cattle and other domestic and wild hosts, is one of the primary limitations of beef cattle farming in some parts of Europe. When an animal tests positive for TB, a loss of profit is caused in the farm, which is due mainly to the animal’s slaughter, replacement of the slaughtered animal and the need to immobilize the rest of the herd. We estimated the economic impact in terms of loss of profit as a result of incremental costs and forgone incomes. We show that farms with a larger number of heads are more capable of dealing with the loss of profit caused by the disease. The quantification of the loss of profit contributes to the ongoing debate on the co-sharing of TB costs between government and farmers. The compensation farmers receive from the public administration to mitigate the economic effects of the disease control interventions is only intended to balance the loss due to slaughter of the infected cattle, being the loss of profit a more global concept.
Cornelian Cherry Pulp Has Beneficial Impact on Dyslipidemia and Reduced Bone Quality in Zucker Diabetic Fatty Rats
Authors: Omelka Radoslav , Blahova Jana , Kovacova Veronika , Babikova Martina , Mondockova Vladimira , Kalafova Anna , Capcarova Marcela , Martiniakova Monika
Published: December 2020

Cornelian cherry (Cornus mas L.) is a medicinal plant with a range of biological features. It is often used as a nutritional supplement in the treatment of diabetes mellitus. Our study was aimed to first investigate the effects of Cornelian cherry pulp on bone quality parameters in Zucker diabetic fatty (ZDF) rats. Moreover, lipid-lowering properties of this fruit were also evaluated. Adult rats (n = 28) were assigned into four groups of seven individuals each: L group (non-diabetic lean rats), C group (diabetic obese rats), and E1 and E2 groups (diabetic obese rats receiving 500 and 1000 mg/kg body weight of Cornelian cherry pulp, respectively, for 10 weeks). Significantly lower levels of triglyceride, total cholesterol and alkaline phosphatase activity were determined in the E2 group versus the C group. A higher dose of Cornus mas also had a beneficial impact on femoral weight, cortical bone thickness, relative volume of trabecular bone and trabecular thickness. We observed elevated density of Haversian systems and accelerated periosteal bone apposition in both treated groups (E1 and E2). Our results clearly demonstrate that Cornelian cherry pulp has a favorable effect on lipid disorder and impaired bone quality consistent with type 2 diabetes mellitus in a suitable animal model.
Concurrent Validity of Equine Joint Range of Motion Measurement: A Novel Digital Goniometer versus Universal Goniometer
Authors: Bergh Anna , Lauridsen Nicole Gandre , Hesbach Amie Lamoreaux
Published: December 2020

Goniometry is the measurement of joint angles with a conventional universal goniometer (UG) or a digital goniometer (DG). The UG is validated for use in dogs and cats. However, it demands both of the user’s hands when measuring. To avoid this, a novel type of DG has been developed, simplifying measurement by offering single-hand usage. The objective of this study is to examine the concurrent validity of the DG. The study consists of measurement with the DG and UG for flexion of the carpus and fetlock on ten horses, and with the DG in flexion and neutral positioning of the fetlock on a sedated horse and corresponding radiographs, intra- and inter-tester reliability and a survey on user-friendliness. The data were analyzed with ANOVA and intraclass correlation coefficient (ICC), with a significance of p < 0.05. The study showed significant differences in range of motion for the carpus and fetlock joint, a 2–3° difference comparing measurements on a sedated horse with corresponding radiographs, a “fair” to “excellent” inter-tester reliability and a “fair” to “almost perfect” intra-tester reliability, and the DG was easier to use than the UG. In conclusion, the novel DG may serve as a simple tool for measuring joint motion in equine rehabilitation patients.
Milk Production and Energetic Metabolism of Heat-Stressed Dairy Goats Supplemented with Propylene Glycol
Authors: Hamzaoui Soufiane , Caja Gerardo , Such Xavier , Albanell Elena , Salama Ahmed A. K.
Published: December 2020

Heat-stressed dairy animals increase their reliance on glucose. This elevated glucose demand is partially met by increasing the conversion of glucogenic amino acids (AA) in the liver. Propylene glycol (PG) is a glucogenic precursor and was not tested in dairy goats under thermoneutral (TN) and heat stress (HS) conditions simultaneously. We hypothesize that if HS-goats are fed with PG, they would get more glucose and consequently spare more glucogenic AA for milk protein synthesis rather than gluconeogenesis. Eight multiparous dairy goats (40.8 ± 1.1 kg body weight; 84 ± 1 days in milk) were used in a replicated 4 × 4 Latin square design of 4 periods; 21 d each (14 d adaptation, 5 d for measurements, and 2 d of transition). Goats were allocated to one of 4 treatments in a 2 × 2 factorial arrangement. Factors were control (CO) without PG or 5% of PG, and thermoneutral (TN; 15 to 20 °C) or heat stress (HS; 12 h/d at 37 °C and 12 h/d at 30 °C) conditions. Feed intake, rectal temperature, respiratory rate, milk yield, milk composition, and blood metabolites were measured. Compared to TN, HS goats had lower (p < 0.01) feed intake (–34%), fat-corrected milk (–15%), and milk fat (–15%). Heat-stressed goats also tended (p < 0.10) to produce milk with lower protein (–11%) and lactose (–4%) contents. Propylene glycol increased blood glucose (+7%; p < 0.05), blood insulin (+37%; p < 0.10), and body weight gain (+68%; p < 0.05), but decreased feed intake (–9%; p < 0.10) and milk fat content (–23%; p < 0.01). Furthermore, blood non-esterified fatty acids (–49%) and β-hydroxybutyrate (–32%) decreased (p < 0.05) by PG. In conclusion, supplementation of heat-stressed dairy goats with propylene glycol caused milk fat depression syndrome, but reduced body weight loss that is typically observed under HS conditions. Supplementation with lower doses of PG would avoid the reduced feed intake and milk fat depression, but this should be tested.
Rapid Multianalyte Microfluidic Homogeneous Immunoassay on Electrokinetically Driven Beads
Authors: Thiriet Pierre-Emmanuel , Medagoda Danashi , Porro Gloria , Guiducci Carlotta
Published: December 2020

The simplicity of homogeneous immunoassays makes them suitable for diagnostics of acute conditions. Indeed, the absence of washing steps reduces the binding reaction duration and favors a rapid and compact device, a critical asset for patients experiencing life-threatening diseases. In order to maximize analytical performance, standard systems employed in clinical laboratories rely largely on the use of high surface-to-volume ratio suspended moieties, such as microbeads, which provide at the same time a fast and efficient collection of analytes from the sample and controlled aggregation of collected material for improved readout. Here, we introduce an integrated microfluidic system that can perform analyte detection on antibody-decorated beads and their accumulation in confined regions within 15 min. We employed the system to the concomitant analysis of clinical concentrations of Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Cystatin C in serum, two acute kidney injury (AKI) biomarkers. To this end, high-aspect-ratio, three-dimensional electrodes were integrated within a microfluidic channel to impart a controlled trajectory to antibody-decorated microbeads through the application of dielectrophoretic (DEP) forces. Beads were efficiently retained against the fluid flow of reagents, granting an efficient on-chip analyte-to-bead binding. Electrokinetic forces specific to the beads’ size were generated in the same channel, leading differently decorated beads to different readout regions of the chip. Therefore, this microfluidic multianalyte immunoassay was demonstrated as a powerful tool for the rapid detection of acute life-threatening conditions.
An Integrated Organizational System for Project Source Selection in the Major Iranian Construction Companies
Authors: Faraji Amir , Rashidi Maria , Sorooshnia Ehsan
Published: December 2020

Studies show that procurement management and its processes strongly affect project success in the construction industry, because the project-oriented organizations in the construction industry prefer to buy goods and services from outside the project team and benefit from outsourcing. Hence, these organizations are continually facing different levels of procurement processes, and the establishment of a robust outsourcing system is crucial for success of their projects and development of their businesses. On the other hand, the housing projects are considered a significant sector of the construction industry in terms of the number of projects and the impact on the national economy. Traditionally, the key sources in conventional housing projects are the general contractors, the consultants and the suppliers. In this study, essential elements of an organizational system have been investigated by expert opinions and through the Delphi method, and all effective aspects of the source selection problem have been identified and integrated. Based on the research findings, procurement of housing construction projects should be organized in three organizational levels: development of the long list, preparation of the short list and selection of the most appropriate source by focusing on four main elements of the source identification method, criteria definition, evaluation arrangement and assessment model.
Circulating IL-13 Is Associated with De Novo Development of HCC in HCV-Infected Patients Responding to Direct-Acting Antivirals
Authors: Macek Jílková Zuzana , Seigneurin Arnaud , Coppard Celine , Ouaguia Laurissa , Aspord Caroline , Marche Patrice N. , Leroy Vincent , Decaens Thomas
Published: December 2020

Direct-acting antivirals (DAAs) are highly effective in targeting hepatitis C virus (HCV) infections, but the incidence of HCV-related hepatocellular carcinoma (HCC) remains still high. In this study, we investigated a cohort of HCV-infected patients treated with DAAs who were followed up for 4 years after sustained virological response (SVR) achievement. Patients who developed de novo HCC following DAA treatment were compared to matched controls who did not develop HCC. These control patients were selected based on DAA treatment, sex, age, fibrosis status, and platelet counts. We evaluated serum levels of 30 immune mediators before, during, at the end of, and three months after DAA treatment using Luminex technology. We identified the immune factors associated with de novo HCC occurrence following DAA treatment. Specifically, interleukin (IL)-4 and IL-13 levels were significantly higher before start of the DAA treatment in the serum of patients who later developed HCC than in controls and stayed higher at each subsequent time point. Least absolute shrinkage and selection operator (LASSO) regression revealed IL-13 as the only strong factor associated with HCC development in this cohort of HCV patients. The difference was observed already at baseline of DAA treatment, which confirms the existence of a specific immune profile in these patients who later develop HCC.
Convergent Evolution by Cancer and Viruses in Evading the NKG2D Immune Response
Authors: Baugh Richard , Khalique Hena , Seymour Leonard W.
Published: December 2020

The natural killer group 2 member D (NKG2D) receptor and its family of NKG2D ligands (NKG2DLs) are key components in the innate immune system, triggering NK, γδ and CD8+ T cell-mediated immune responses. While surface NKG2DL are rarely found on healthy cells, expression is significantly increased in response to various types of cellular stress, viral infection, and tumour cell transformation. In order to evade immune-mediated cytotoxicity, both pathogenic viruses and cancer cells have evolved various mechanisms of subverting immune defences and preventing NKG2DL expression. Comparisons of the mechanisms employed following virus infection or malignant transformation reveal a pattern of converging evolution at many of the key regulatory steps involved in NKG2DL expression and subsequent immune responses. Exploring ways to target these shared steps in virus- and cancer-mediated immune evasion may provide new mechanistic insights and therapeutic opportunities, for example, using oncolytic virotherapy to re-engage the innate immune system towards cancer cells.
APC Mutations Are Not Confined to Hotspot Regions in Early-Onset Colorectal Cancer
Authors: Aitchison Alan , Hakkaart Christopher , Day Robert C. , Morrin Helen R. , Frizelle Frank A. , Keenan Jacqueline I.
Published: December 2020

While overall colorectal cancer (CRC) cases have been declining worldwide there has been an increase in the incidence of the disease among patients under 50 years of age. Mutation of the APC gene is a common early event in CRC but is reported at lower rates in early-onset colorectal cancer (EOCRC) than in older patients. Here we investigate the APC mutation status of a cohort of EOCRC patients in New Zealand using a novel sequencing approach targeting regions of the gene encompassing the vast majority of known APC mutations. Using this strategy we find a higher rate (72%) of APC mutation than previously reported in EOCRC with mutations being spread throughout the gene rather than clustered in hotspots as seen with sporadic mutations in older patients. The rate of mutations falling within hotspots was similar to those previously seen in EOCRC and as such our study has implications for sequencing strategies for EOCRC patients. Overall there were low rates of both loss of heterozygosity and microsatellite instability whereas a relatively high rate (40%) of APC promoter methylation was found, possibly reflecting increasing exposure of young people to pro-oncogenic lifestyle factors.
Premature MicroRNA-Based Therapeutic: A “One-Two Punch” against Cancers
Authors: Chen Luyue , Huang Kai , Yi Kaikai , Huang Yanlin , Tian Xinhua , Kang Chunsheng
Published: December 2020

Up-to-date knowledge regarding the biogenesis and functioning of microRNAs (miRNAs) has provided a much more comprehensive and concrete view of miRNA biology than anyone ever expected. Diverse genetic origins and biogenesis pathways leading to functional miRNAs converge on the synthesis of ≈21-nucleotide RNA duplex, almost all of which are processed from long premature sequences in a DICER- and/or DROSHA-dependent manner. Formerly, it was assumed that one mature strand of the duplex is preferentially selected for entry into the silencing complex, and the paired passenger strands (miRNA*) are subjected to degradation. However, given the consolidated evidence of substantial regulatory activity of miRNA* species, currently, this preconception has been overturned. Here, we see the caveat and opportunity toward exogenously manipulating the expression of premature miRNA, leading to simultaneous upregulation or downregulation of dual regulatory strands due to altered expressions. The caveat is the overlooked miRNA* interference while manipulating the expression of a target miRNA at the premature stage, wherein lies the opportunity. If the dual strands of a pre-miRNA function synergistically, the overlooked miRNA* interference may inversely optimize the therapeutic performance. Insightfully, targeting the premature miRNAs may serve as the “one-two punch” against diseases, especially cancers, and this has been discussed in detail in this review.
Germline Genetic Variants of the Renin-Angiotensin System, Hypoxia and Angiogenesis in Non-Small Cell Lung Cancer Progression: Discovery and Validation Studies
Authors: Catarata Maria Joana , Medeiros Rui , Oliveira Maria José , Pêgo Alice , Frade João Gonçalo , Martins Maria Fátima , Robalo Cordeiro Carlos Robalo , Herth Felix J F , Thomas Michael , Kriegsmann Mark , Meister Michael , Schneider Marc A , Muley Thomas , Ribeiro Ricardo
Published: December 2020

Introduction: The renin–angiotensin system (RAS) is involved in cell proliferation, immunoinflammatory response, hypoxia and angiogenesis, which are critical biological processes in lung cancer. Our aim was to study the association of putatively functional genetic polymorphisms in genes coding for proteins involved in RAS, hypoxia and angiogenesis with non-small cell lung cancer (NSCLC) prognosis. Methods: Genotyping of 52 germline variants from genes of the RAS and hypoxic/angiogenic factors/receptors was performed using MassARRAY iPLEX Gold in a retrospective cohort (n = 167) of advanced NSCLC patients. Validation of the resulting genetic markers was conducted in an independent group (n = 190), matched by clinicopathological characteristics. Results: Multivariate analysis on the discovery set revealed that MME rs701109 C carriers were protected from disease progression in comparison with homozygous T (hazard ratio (HR) = 0.5, 95% confidence interval (CI) = 0.2–0.8, p = 0.010). Homozygous A and T genotypes for KDR rs1870377 were at increased risk for disease progression and death compared to heterozygous (HR = 1.7, 95% CI = 1.2–2.5, p = 0.005 and HR = 2.1, 95% CI = 1.2–3.4, p = 0.006, respectively). Carriers of homozygous genotypes for ACE2 rs908004 presented increased risk for disease progression, only in the subgroup of patients without tumour actionable driver mutations (HR = 2.9, 95% CI = 1.3–6.3, p = 0.010). Importantly, the association of homozygous genotypes in MME rs701109 with risk for disease progression was confirmed after multivariate analysis in the validation set. Conclusion: This study provides evidence that MME polymorphism, which encodes neprilysin, may modulate progression-free survival in advanced NSCLC. Present genetic variation findings will foster basic, translational, and clinical research on their role in NSCLC.
Circulating miRNAs as Tumor Biomarkers: A Preface to the Special Issue
Authors: Markou Athina N.
Published: December 2020

Nowadays, therapeutic strategies in cancer are subsequently defined according to the molecular profile of the tissue [...]
3′RNA Sequencing Accurately Classifies Formalin-Fixed Paraffin-Embedded Uterine Leiomyomas
Authors: Mehine Miika , Khamaiseh Sara , Ahvenainen Terhi , Heikkinen Tuomas , Äyräväinen Anna , Pakarinen Päivi , Härkki Päivi , Pasanen Annukka , Bützow Ralf , Vahteristo Pia
Published: December 2020

Uterine leiomyomas are benign smooth muscle tumors occurring in 70% of women of reproductive age. The majority of leiomyomas harbor one of three well-established genetic changes: a hotspot mutation in MED12, overexpression of HMGA2, or biallelic loss of FH. The majority of studies have classified leiomyomas by complex and costly methods, such as whole-genome sequencing, or by combining multiple traditional methods, such as immunohistochemistry and Sanger sequencing. The type of specimens and the amount of resources available often determine the choice. A more universal, cost-effective, and scalable method for classifying leiomyomas is needed. The aim of this study was to evaluate whether RNA sequencing can accurately classify formalin-fixed paraffin-embedded (FFPE) leiomyomas. We performed 3′RNA sequencing with 44 leiomyoma and 5 myometrium FFPE samples, revealing that the samples clustered according to the mutation status of MED12, HMGA2, and FH. Furthermore, we confirmed each subtype in a publicly available fresh frozen dataset. These results indicate that a targeted 3′RNA sequencing panel could serve as a cost-effective and robust tool for stratifying both fresh frozen and FFPE leiomyomas. This study also highlights 3′RNA sequencing as a promising method for studying the abundance of unexploited tissue material that is routinely stored in hospital archives.
Ouabain and Digoxin Activate the Proteasome and the Degradation of the ERα in Cells Modeling Primary and Metastatic Breast Cancer
Authors: Busonero Claudia , Leone Stefano , Bianchi Fabrizio , Maspero Elena , Fiocchetti Marco , Palumbo Orazio , Cipolletti Manuela , Bartoloni Stefania , Acconcia Filippo
Published: December 2020

Estrogen receptor α expressing breast cancers (BC) are classically treated with endocrine therapy. Prolonged endocrine therapy often results in a metastatic disease (MBC), for which a standardized effective therapy is still lacking. Thus, new drugs are required for primary and metastatic BC treatment. Here, we report that the Food and Drug Administration (FDA)-approved drugs, ouabain and digoxin, induce ERα degradation and prevent proliferation in cells modeling primary and metastatic BC. Ouabain and digoxin activate the cellular proteasome, instigating ERα degradation, which causes the inhibition of 17β-estradiol signaling, induces the cell cycle blockade in the G2 phase, and triggers apoptosis. Remarkably, these effects are independent of the inhibition of the Na/K pump. The antiproliferative effects of ouabain and digoxin occur also in diverse cancer models (i.e., tumor spheroids and xenografts). Additionally, gene profiling analysis reveals that these drugs downregulate the expression of genes related to endocrine therapy resistance. Therefore, ouabain and digoxin behave as ‘anti-estrogen’-like drugs, and are appealing candidates for the treatment of primary and metastatic BCs.
Establishment and Characterization of Patient-Derived Xenografts (PDXs) of Different Histology from Malignant Pleural Mesothelioma Patients
Authors: Affatato Roberta , Mendogni Paolo , Del Gobbo Alessandro , Ferrero Stefano , Ricci Francesca , Broggini Massimo , Rosso Lorenzo
Published: December 2020

Background: Malignant pleural mesothelioma (MPM) is a very aggressive tumor originating from mesothelial cells. Although several etiological factors were reported to contribute to MPM onset, environmental exposure to asbestos is certainly a major risk factor. The latency between asbestos (or asbestos-like fibers) exposure and MPM onset is very long. MPM continues to be a tumor with poor prognosis despite the introduction of new therapies including immunotherapy. One of the major problems is the low number of preclinical models able to recapitulate the features of human tumors. This impacts the possible discovery of new treatments and combinations. Methods: In this work, we aimed to generate patient-derived xenografts (PDXs) from MPM patients covering the three major histotypes (epithelioid, sarcomatoid, and mixed) occurring in the clinic. To do this, we obtained fresh tumors from biopsies or pleurectomies, and samples were subcutaneously implanted in immunodeficient mice within 24 h. Results: We successfully isolated different PDXs and particularly concentrated our efforts on three covering the three histotypes. The tumors that grew in mice compared well histologically with the tumors of origin, and showed stable growth in mice and a low response to cisplatin, as was observed in the clinic. Conclusions: These models are helpful in testing new drugs and combinations that, if successful, could rapidly translate to the clinical setting.
Delayed Postoperative Hyponatremia Following Endoscopic Transsphenoidal Surgery for Non-Adenomatous Parasellar Tumors
Authors: Hasegawa Hirotaka , Shin Masahiro , Makita Noriko , Shinya Yuki , Kondo Kenji , Saito Nobuhito
Published: December 2020

Little is known about delayed postoperative hyponatremia (DPH) accompanied with transsphenoidal surgery for non-adenomatous skull base tumors (NASBTs). Consecutive data on 30 patients with parasellar NASBT was retrospectively reviewed with detailed analyses on perioperative serial sodium levels. Serological DPH (sodium ≤ 135 mmol/L) was observed in eight (27%), with four (13%) of them being symptomatic. DPH developed on postoperative day 7–12 where the mean sodium levels were 134 mmol/L (a mean of 7 mmol/L drop from the baseline) in asymptomatic and 125 mmol/L (a mean of 17.5 mmol/L drop from the baseline) in symptomatic DPH. Serological DPH was accompanied with “weight loss and hemoconcentration (cerebral salt wasting type)” in four (50%), “weight gain and hemodilution (syndrome of inappropriate antidiuretic hormone secretion type)” in three (38%), and no significant weight change in one. Intraoperative extradural retraction of the pituitary gland was the only significant factor for serological DPH (p = 0.035; odds ratio, 12.25 (95% confidence interval, 1.27–118.36)). DPH should be recognized as one of the significant postsurgical complications associated with TSS for NASBTs. Although the underlying mechanism is still controversial, intraoperative extradural compression of the pituitary gland and subsequent dysregulation of the hypothalamo-hypophyseal axis may be responsible.
High Expression of NRF2 Is Associated with Increased Tumor-Infiltrating Lymphocytes and Cancer Immunity in ER-Positive/HER2-Negative Breast Cancer
Authors: Oshi Masanori , Angarita Fernando A. , Tokumaru Yoshihisa , Yan Li , Matsuyama Ryusei , Endo Itaru , Takabe Kazuaki
Published: December 2020

Nuclear factor erythroid 2-related factor 2 (NRF2) is a key modifier in breast cancer. It is unclear whether NRF2 suppresses or promotes breast cancer progression. We studied the clinical relevance of NRF2 expression by conducting in silico analyses in 5443 breast cancer patients from several large patient cohorts (METABRIC, GSE96058, GSE25066, GSE20194, and GSE75688). NRF2 expression was significantly associated with better survival, low Nottingham pathological grade, and ER-positive/HER2-negative and triple negative breast cancer (TNBC). High NRF2 ER-positive/HER2-negative breast cancer enriched inflammation- and immune-related gene sets by GSEA. NRF2 expression was elevated in immune, stromal, and cancer cells. High NRF2 tumors were associated with high infiltration of immune cells (CD8+, CD4+, and dendritic cells (DC)) and stromal cells (adipocyte, fibroblasts, and keratinocytes), and with low fraction of Th1 cells. NRF2 expression significantly correlated with area under the curve (AUC) of several drug response in multiple ER-positive breast cancer cell lines, however, there was no significant association between NRF2 and pathologic complete response (pCR) rate after neoadjuvant chemotherapy in human samples. Finally, high NRF2 breast cancer was associated with high expression of immune checkpoint molecules. In conclusion, NRF2 expression was associated with enhanced tumor-infiltrating lymphocytes in ER-positive/HER2-negative breast cancer.
Proteomic Resistance Biomarkers for PI3K Inhibitor in Triple Negative Breast Cancer Patient-Derived Xenograft Models
Authors: Guo Zhanfang , Primeau Tina , Luo Jingqin , Zhang Cynthia , Sun Hua , Hoog Jeremy , Gao Feng , Huang Shixia , Edwards Dean P. , Davies Sherri R. , Aft Rebecca , Ding Li , Ellis Matthew J. , Li Shunqiang , Ma Cynthia X.
Published: December 2020

PI3K pathway activation is frequently observed in triple negative breast cancer (TNBC). However, single agent PI3K inhibitors have shown limited anti-tumor activity. To investigate biomarkers of response and resistance mechanisms, we tested 17 TNBC patient-derived xenograft (PDX) models representing diverse genomic backgrounds and varying degrees of PI3K pathway signaling activities for their tumor growth response to the pan-PI3K inhibitor, BKM120. Baseline and post-treatment PDX tumors were subjected to reverse phase protein array (RPPA) to identify protein markers associated with tumor growth response. While BKM120 consistently reduced PI3K pathway activity, as demonstrated by reduced levels of phosphorylated AKT, percentage tumor growth inhibition (%TGI) ranged from 35% in the least sensitive to 84% in the most sensitive model. Several biomarkers showed significant association with resistance, including elevated baseline levels of growth factor receptors (EGFR, pHER3 Y1197), PI3Kp85 regulatory subunit, anti-apoptotic protein BclXL, EMT (Vimentin, MMP9, IntegrinaV), NFKB pathway (IkappaB, RANKL), and intracellular signaling molecules including Caveolin, CBP, and KLF4, as well as treatment-induced increases in the levels of phosphorylated forms of Aurora kinases. Interestingly, increased AKT phosphorylation or PTEN loss at baseline were not significantly correlated to %TGI. These results provide important insights into biomarker development for PI3K inhibitors in TNBC.
Obesity Epidemic—The Underestimated Risk of Endometrial Cancer
Authors: Kiesel Ludwig , Eichbaum Christine , Baumeier Ariane , Eichbaum Michael
Published: December 2020

Endometrial cancer (EC) is the most frequently observed malignant gynecologic disease in developed countries. There is a strong association between the established risk factor obesity and the incidence of EC. Furthermore, the rate of women with a body mass index (BMI) > 30 kg/m2 is increasing worldwide, correspondingly leading to a higher prevalence of EC. Understanding the adipose tissue as an endocrine organ, elementary pathophysiological pathways of tumorigenesis have been revealed. This includes the fundamental role of hyperglycemia, insulin resistance, and hyperestrogenemia, as well as interactions with a chronic proinflammatory microenvironment. Therapeutic options potentially include metformin or bariatric surgery. Moreover, changes in individual lifestyle such as weight reduction, physical activity, and an awareness of healthy nutrition are effective in preventing the disease.
Adipocyte-Derived Leptin Promotes PAI-1-Mediated Breast Cancer Metastasis in a STAT3/miR-34a Dependent Manner
Authors: Li Si-Jing , Wei Xiao-Hui , Zhan Xiao-Man , He Jin-Yong , Zeng Yu-Qi , Tian Xue-Mei , Yuan Sheng-Tao , Sun Li
Published: December 2020

The crosstalk between cancer cells and adipocytes is critical for breast cancer progression. However, the molecular mechanisms underlying these interactions have not been fully characterized. In the present study, plasminogen activator inhibitor-1 (PAI-1) was found to be a critical effector of the metastatic behavior of breast cancer cells upon adipocyte coculture. Loss-of-function studies indicated that silencing PAI-1 suppressed cancer cell migration. Furthermore, we found that PAI-1 was closely related to the epithelial-mesenchymal transition (EMT) process in breast cancer patients. A loss-of-function study and a mammary orthotopic implantation metastasis model showed that PAI-1 promoted breast cancer metastasis by affecting the EMT process. In addition, we revealed that leptin/OBR mediated the regulation of PAI-1 through the interactions between adipocytes and breast cancer cells. Mechanistically, we elucidated that leptin/OBR further activated STAT3 to promote PAI-1 expression via miR-34a–dependent and miR-34a–independent mechanisms in breast cancer cells. In conclusion, our study suggests that targeting PAI-1 and interfering with its upstream regulators may benefit breast cancer patients.
Entacapone Treatment Modulates Hippocampal Proteins Related to Synaptic Vehicle Trafficking
Authors: Yoo Dae Young , Jung Hyo Young , Kim Woosuk , Hahn Kyu Ri , Kwon Hyun Jung , Nam Sung Min , Chung Jin Young , Yoon Yeo Sung , Kim Dae Won , Hwang In Koo
Published: December 2020

Entacapone, a reversible inhibitor of catechol-O-methyl transferase, is used for patients in Parkinson’s disease because it increases the bioavailability and effectiveness of levodopa. In the present study, we observed that entacapone increases novel object recognition and neuroblasts in the hippocampus. In the present study, two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry were performed to compare the abundance profiles of proteins expressed in the hippocampus after entacapone treatment in mice. Results of 2-DE, MALDI-TOF mass spectrometry, and subsequent proteomic analysis revealed an altered protein expression profile in the hippocampus after entacapone treatment. Based on proteomic analysis, 556 spots were paired during the image analysis of 2-DE gels and 76 proteins were significantly changed more than two-fold among identified proteins. Proteomic analysis indicated that treatment with entacapone induced expressional changes in proteins involved in synaptic transmission, cellular processes, cellular signaling, the regulation of cytoskeletal structure, energy metabolism, and various subcellular enzymatic reactions. In particular, entacapone significantly increased proteins related to synaptic trafficking and plasticity, such as dynamin 1, synapsin I, and Munc18-1. Immunohistochemical staining showed the localization of the proteins, and western blot confirmed the significant increases in dynamin I (203.5% of control) in the hippocampus as well as synapsin I (254.0% of control) and Munc18-1 (167.1% of control) in the synaptic vesicle fraction of hippocampus after entacapone treatment. These results suggest that entacapone can enhance hippocampal synaptic trafficking and plasticity against various neurological diseases related to hippocampal dysfunction.