bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of CYP3A5 in Modulating Androgen Receptor Signaling and Its Relevance to African American Men with Prostate Cancer
Authors: Gorjala Priyatham , Kittles Rick A. , Goodman Jr. Oscar B. , Mitra Ranjana
Published: April 2020

Androgen receptor signaling is crucial for prostate cancer growth and is positively regulated in part by intratumoral CYP3A5. As African American (AA) men often carry the wild type CYP3A5 and express high levels of CYP3A5 protein, we blocked the wild type CYP3A5 in AA origin prostate cancer cells and tested its effect on androgen receptor signaling. q-PCR based profiler assay identified several AR regulated genes known to regulate AR nuclear translocation, cell cycle progression, and cell growth. CYP3A5 processes several commonly prescribed drugs and many of these are CYP3A5 inducers or inhibitors. In this study, we test the effect of these commonly prescribed CYP3A5 inducers/inhibitors on AR signaling. The results show that the CYP3A5 inducers promoted AR nuclear translocation, downstream signaling, and cell growth, whereas CYP3A5 inhibitors abrogated them. The observed changes in AR activity is specific to alterations in CYP3A5 activity as the effects are reduced in the CYP3A5 knockout background. Both the inducers tested demonstrated increased cell growth of prostate cancer cells, whereas the inhibitors showed reduced cell growth. Further, characterization and utilization of the observation that CYP3A5 inducers and inhibitors alter AR signaling may provide guidance to physicians prescribing CYP3A5 modulating drugs to treat comorbidities in elderly patients undergoing ADT, particularly AA.
Interferon Alpha Therapy Increases Pro-Thrombotic Biomarkers in Patients with Myeloproliferative Neoplasms
Authors: Faille Dorothée , Lamrani Lamia , Loyau Stéphane , Huisse Marie-Geneviève , Bourrienne Marie-Charlotte , Alkhaier Sawsaneh , Cassinat Bruno , Boulaftali Yacine , Debus Jérôme , Jandrot-Perrus Martine , Chomienne Christine , Dosquet Christine , Ajzenberg Nadine
Published: April 2020

Myeloproliferative neoplasms (MPN) are associated with an increased risk of arterial and venous thrombosis. Pegylated-interferon alpha (IFN) and hydroxyurea (HU) are commonly used to treat MPN, but their effect on hemostasis has not yet been studied. The aim of our study was to determine whether IFN and HU impact the biological hemostatic profile of MPN patients by studying markers of endothelial, platelet, and coagulation activation. A total of 85 patients (50 polycythemia vera and 35 essential thrombocythemia) were included: 28 treated with IFN, 35 with HU, and 22 with no cytoreductive drug (non-treated, NT). Von Willebrand factor, shear-induced platelet aggregation, factor VIII coagulant activity (FVIII:C), fibrinogen, and thrombin generation with and without exogenous thrombomodulin were significantly higher in IFN-treated patients compared to NT patients, while protein S anticoagulant activity was lower. In 10 patients in whom IFN therapy was discontinued, these hemostatic biomarkers returned to the values observed in NT patients, strongly suggesting an impact of IFN therapy on endothelial and coagulation activation. Overall, our study shows that treatment with IFN is associated with significant and reversible effects on the biological hemostatic profile of MPN patients. Whether they could be associated with an increased thrombotic risk remains to be determined in further randomized clinical studies.
Effect of Baseline Characteristics on Cabazitaxel Treatment Duration in Patients with Metastatic Castration-Resistant Prostate Cancer: A Post Hoc Analysis of the Compassionate Use/Expanded Access Programs and CAPRISTANA Registry
Authors: Malik Zafar , Di Lorenzo Giuseppe , Pichler Angelika , De Giorgi Ugo , Hitier Simon , Ecstein-Fraisse Evelyne , Ozatilgan Ayse , Carles Joan
Published: April 2020

We examined factors that may impact cabazitaxel treatment duration in a real-life setting in a compassionate use program, expanded access program, and prospective observational study in metastatic castration-resistant prostate cancer (mCRPC). Patients with mCRPC previously treated with docetaxel (N = 1621) received cabazitaxel 25 mg/m2 intravenously every 3 weeks until disease progression, death, unacceptable toxicity or physician/patient decision. The median number of cabazitaxel cycles was six (range, 1–49); 708 patients (43.7%) received >6 cycles. Patients receiving >6 cycles tended to have a better Eastern Cooperative Oncology Group performance status of 0–1 (p = 0.0017 for ≤6 vs. >6 cycles). Overall, 348 patients (21.5%) were ≥75 years of age; 139 (39.9%) received >6 cycles. The main reason for discontinuation was disease progression; however, in patients receiving 1–2 cycles, the main reason for discontinuation was adverse events. Only 52 patients (3.2%) progressed during cycles 1–2. Cabazitaxel was well tolerated in these studies, which included some elderly and frail patients, offering clinicians an important treatment option in the management of mCRPC. Proactive management of adverse events may allow patients to receive a higher number of cabazitaxel cycles and derive greater benefit.
Erbb4 Is Required for Cerebellar Development and Malignant Phenotype of Medulloblastoma
Authors: Aldaregia Juncal , Errarte Peio , Olazagoitia-Garmendia Ane , Gimeno Marian , Uriz Jose Javier , Gershon Timothy R. , Garcia Idoia , Matheu Ander
Published: April 2020

Medulloblastoma is the most common and malignant pediatric brain tumor in childhood. It originates from dysregulation of cerebellar development, due to an excessive proliferation of cerebellar granule neuron precursor cells (CGNPs). The underlying molecular mechanisms, except for the role of SHH and WNT pathways, remain largely unknown. ERBB4 is a tyrosine kinase receptor whose activity in cancer is tissue dependent. In this study, we characterized the role of ERBB4 during cerebellum development and medulloblastoma progression paying particular interests to its role in CGNPs and medulloblastoma stem cells (MBSCs). Our results show that ERBB4 is expressed in the CGNPs during cerebellum development where it plays a critical role in migration, apoptosis and differentiation. Similarly, it is enriched in the population of MBSCs, where also controls those critical processes, as well as self-renewal and tumor initiation for medulloblastoma progression. These results are translated to clinical samples where high levels of ERBB4 correlate with poor outcome in Group 4 and all medulloblastomas groups. Transcriptomic analysis identified critical processes and pathways altered in cells with knock-down of ERBB4. These results highlight the impact and underlying mechanisms of ERBB4 in critical processes during cerebellum development and medulloblastoma.
Impact of Use of Gastric-Acid Suppressants and Oral Anti-Cancer Agents on Survival Outcomes: A Systematic Review and Meta-Analysis
Authors: Indini Alice , Petrelli Fausto , Tomasello Gianluca , Rijavec Erika , Facciorusso Antonio , Grossi Francesco , Ghidini Michele
Published: April 2020

We performed a systematic review and meta-analysis to evaluate the role of gastric acid suppressant use on outcomes of tyrosine kinase inhibitors (TKIs) and oral chemotherapy. We identified all research evaluating the effect of GAS (gastric acid suppressants) use on patients receiving oral chemotherapy or TKIs for solid tumors. The pooled hazard ratios (HRs) and 95% confidence interval (95%CI) for overall survival (OS) and progression-free survival (PFS) were calculated with a fixed-effects or a random effects model. The study population included n = 16 retrospective studies and 372,418 patients. The series concerned gastrointestinal tract tumors (n = 5 studies), renal cell carcinomas (RCC, n = 3 studies), non-small cell lung cancers (NSCLC, n = 5 studies), and soft tissue sarcomas or mixed histologies solid tumors in n = 3 studies. The pooled HRs for OS and PFS were 1.31 (95%CI: 1.20–1.43; p < 0.01) and 1.3 (95%CI 1.07–1.57; p < 0.01) for GAS and no GAS users, respectively. Only studies of EGFR (epidermal growth factor receptor) mutated NSCLC patients receiving TKIs and those with colorectal cancer receiving oral chemotherapy showed a significant correlation between GAS and poor survival. Our study supports the evidence of a possible negative impact of concomitant GAS therapy on survival outcomes of patients receiving oral anti-cancer drugs.
Public Adverse Event Data Insights into the Safety of Pembrolizumab in Melanoma Patients
Authors: Schaefer Anne , Sachpekidis Christos , Diella Francesca , Doerks Anja , Kratz Anne-Sophie , Meisel Christian , Jackson David B. , Soldatos Theodoros G.
Published: April 2020

Immune checkpoint inhibition represents an important therapeutic option for advanced melanoma patients. Results from clinical studies have shown that treatment with the PD-1 inhibitors Pembrolizumab and Nivolumab provides improved response and survival rates. Moreover, combining Nivolumab with the CTLA-4 inhibitor Ipilimumab is superior to the respective monotherapies. However, use of these immunotherapies is frequently associated with, sometimes life-threatening, immune-related adverse events. Thus, more evidence-based studies are required to characterize the underlying mechanisms, towards more effective clinical management and treatment monitoring. Our study examines two sets of public adverse event data coming from FAERS and VigiBase, each with more than two thousand melanoma patients treated with Pembrolizumab. Standard disproportionality metrics are utilized to characterize the safety of Pembrolizumab and its reaction profile is compared to those of the widely used Ipilimumab and Nivolumab based on melanoma cases that report only one of them. Our results confirm known toxicological considerations for their related and distinct side-effect profiles and highlight specific immune-related adverse reactions. Our retrospective computational analysis includes more patients than examined in other studies and relies on evidence coming from public pharmacovigilance data that contain safety reports from clinical and controlled studies as well as reports of suspected adverse events coming from real-world post-marketing setting. Despite these informative insights, more prospective studies are necessary to fully characterize the efficacy of these agents.
Weekends-Off Lenvatinib for Unresectable Hepatocellular Carcinoma Improves Therapeutic Response and Tolerability Toward Adverse Events
Authors: Iwamoto Hideki , Suzuki Hiroyuki , Shimose Shigeo , Niizeki Takashi , Nakano Masahito , Shirono Tomotake , Okamura Shusuke , Noda Yu , Kamachi Naoki , Nakamura Toru , Masuda Atsutaka , Sakaue Takahiko , Tanaka Toshimitsu , Nakano Dan , Sakai Miwa , Yamaguchi Taizo , Kuromatsu Ryoko , Koga Hironori , Torimura Takuji
Published: April 2020

Background: Although lenvatinib has become the standard therapy for hepatocellular carcinoma (HCC), the high incidence rate of adverse events (AEs) is an issue. This study aimed to clarify the AEs of lenvatinib and the therapeutic impact of five days-on/two days-off administration (i.e., weekends-off strategy) for lenvatinib. Methods: We retrospectively assessed the therapeutic effects and AEs of 135 patients treated with lenvatinib, and the improvement of tolerability and therapeutic efficacy of 30 patients treated with the weekends-off strategy. We also evaluated lenvatinib-induced vascular changes in tumors and healthy organs using a mouse hepatoma model. Results: The incidence rates of any grade and grade ≥ 3 AEs were 82.1% and 49.6%. Fatigue was the most important AE since it resulted in dose reduction and discontinuation. Of the 30 patients who received weekends-off lenvatinib, 66.7% tolerated the AEs. Although 80.8% of the patients showed progression after dose reduction, the therapeutic response improved in 61.5% of the patients by weekends-off lenvatinib. Notably, weekends-off administration significantly prolonged the administration period and survival (p < 0.001 and p < 0.05). The mouse hepatoma model showed that weekends-off administration contributed to recovery of vascularity in the organs. Conclusion: Weekends-off administration of lenvatinib was useful to recover the therapeutic response and tolerability toward AEs.
Gonadotroph Tumors Show Subtype Differences that Might Have Implications for Therapy
Authors: Ilie Mirela Diana , Vasiljevic Alexandre , Louvet Camille , Jouanneau Emmanuel , Raverot Gérald
Published: April 2020

Gonadotroph tumors, although frequent, are poorly studied and understood, being usually included in the larger nonfunctioning pituitary neuroendocrine tumors (PitNETs) group. Moreover, in comparison to the other types of PitNETs, no established medical treatment is currently available for gonadotroph tumors. Here, we performed a retrospective study and analyzed the clinicopathological characteristics of 98 gonadotroph tumors operated in a single large pituitary center. Although being larger in men (p = 0.01), the aggressiveness of gonadotroph tumors did not appear to be sex-related. LH tumors were rare (4/98) and exclusively encountered in men. Somatostatin receptor type 5 (SST5) was absent in all analyzed tumors. The immunoreactive score (IRS) of somatostatin receptor type 2 (SST2) and of estrogen receptor alpha (ERα) was associated with the histological subtype (p = 0.01 and p = 0.02). IRS ERα correlated moderately with IRS SST2 in all (rho = 0.44, adjusted p-value = 0.0001) and in male (rho = 0.51, adjusted p-value = 0.0002) patients, and with follicle-stimulating hormone (FSH) percentage in all (rho = 0.40, adjusted p-value = 0.0005) and in female (rho = 0.58, adjusted p-value = 0.004) patients. In conclusion, gonadotroph tumors exhibit histological characteristics pinpointing the existence of several subtypes. Their heterogeneity warrants further investigations and may have to be taken into account when studying these tumors and investigating treatment options.
Correlation of PKM2 and CD44 Protein Expression with Poor Prognosis in Platinum-Treated Epithelial Ovarian Cancer: A Retrospective Study
Authors: Papadaki Chara , Manolakou Stavroula , Lagoudaki Eleni , Pontikakis Spyros , Ierodiakonou Despo , Vogiatzoglou Konstantinos , Messaritakis Ippokratis , Trypaki Maria , Giannikaki Linda , Sfakianaki Maria , Kalykaki Antonia , Mavroudis Dimitrios , Tzardi Maria , Souglakos John
Published: April 2020

CD44, a surface marker for cancer stem cells, interacts with PKM2, a key regulator of aerobic glycolysis, and enhances the glycolytic phenotype of cancer cells leading to antioxidant protection and macromolecules’ synthesis. To clarify the clinical importance of this “cross-talk” as a mechanism of drug resistance, we assessed the expression both of PKM2 and of CD44 in cancer cells of patients with epithelial ovarian cancer (EOC) treated with platinum-based treatment. One hundred and seventy-one patients with EOC were assessed for PKM2mRNA expression and PKM2 and CD44 proteins detection. Associations with progression-free survival (PFS) and overall survival (OS) were assessed with Kaplan–Meier and adjusted Cox regression models. PKM2mRNA and protein as well as CD44 protein were detectable in the majority of patients. Positive correlation between PKM2 and CD44 protein expression was observed (Spearman rho = 0.2, p = 0.015). When we used the median to group patients into high versus low expression, high PKM2mRNA and protein levels were significantly associated with lower progression-free survival (PFS; p = 0.003 and p = 0.002, respectively) and shorter overall survival (OS; p ≤ 0.001 and p = 0.001, respectively). However, high CD44 protein expression was significantly correlated only with shorter OS (p = 0.004). Moreover, patients with both high PKM2 and CD44 protein levels experienced shorter PFS and OS (p = 0.007 and p = 0.003, respectively) compared to patients with low expression of both proteins. Finally, higher PKM2mRNA and protein expression as well as CD44 protein expression (HR: 2.16; HR: 1.82; HR: 1.01, respectively) were independent prognostic factors for decreased median OS (mOS), whereas only PKM2 protein expression (HR: 1.95) was an independent prognostic factor for decreased median PFS (mPFS). In conclusion, PKM2 expression is a negative prognostic factor in EOC patients, but the interaction between CD44 and PKM2 that may be implicated in EOC platinum-resistance needs further investigation.
Epigenetic Research in Stem Cell Bioengineering—Anti-Cancer Therapy, Regenerative and Reconstructive Medicine in Human Clinical Trials
Authors: Dompe Claudia , Janowicz Krzysztof , Hutchings Greg , Moncrieff Lisa , Jankowski Maurycy , Nawrocki Mariusz J. , Józkowiak Małgorzata , Mozdziak Paul , Petitte Jim , Shibli Jamil A. , Dyszkiewicz-Konwińska Marta , Bruska Małgorzata , Piotrowska-Kempisty Hanna , Kempisty Bartosz , Nowicki Michał
Published: April 2020

The epigenome denotes all the information related to gene expression that is not contained in the DNA sequence but rather results from chemical changes to histones and DNA. Epigenetic modifications act in a cooperative way towards the regulation of gene expression, working at the transcriptional or post-transcriptional level, and play a key role in the determination of phenotypic variations in cells containing the same genotype. Epigenetic modifications are important considerations in relation to anti-cancer therapy and regenerative/reconstructive medicine. Moreover, a range of clinical trials have been performed, exploiting the potential of epigenetics in stem cell engineering towards application in disease treatments and diagnostics. Epigenetic studies will most likely be the basis of future cancer therapies, as epigenetic modifications play major roles in tumour formation, malignancy and metastasis. In fact, a large number of currently designed or tested clinical approaches, based on compounds regulating epigenetic pathways in various types of tumours, employ these mechanisms in stem cell bioengineering.
ZnO@TiO2 Core/Shell Nanowire Arrays with Different Thickness of TiO2 Shell for Dye-Sensitized Solar Cells
Authors: Liu Liqing , Wang Hui , Wang Dehao , Li Yongtao , He Xuemin , Zhang Hongguang , Shen Jianping
Published: April 2020

The ZnO@TiO2 core/shell nanowire arrays with different thicknesses of the TiO2 shell were synthesized, through depositing TiO2 on the ZnO nanowire arrays using the pulsed laser deposition process. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images show that these core/shell nanowires were homogeneously coated with TiO2 nanoparticles with high crystallinity, appearing to be a rather rough surface compared to pure ZnO nanowires. The efficiency of ZnO@TiO2 core/shell structure-based dye-sensitized solar cells (DSSCs) was improved compared with pure ZnO nanowires. This is mainly attributed to the enlarged internal surface area of the core/shell structures, which increases dye adsorption on the anode to improve the light harvest. In addition, the energy barrier which formed at the interface between ZnO and TiO2 promoted the charge separation and suppressed the carrier recombination. Furthermore, the efficiency of DSSCs was further improved by increasing the thickness of the TiO2 shell. This work shows an efficient method to achieve high power conversion efficiency in core/shell nanowire-based DSSCs.
Species Richness, Ecology, and Prediction of Orchids in Central Europe: Local-Scale Study
Authors: Hrivnák Matúš , Slezák Michal , Galvánek Dobromil , Vlčko Jaroslav , Belanová Eva , Rízová Veronika , Senko Dušan , Hrivnák Richard
Published: April 2020

Orchids are one of the most species-rich families in the world, and many species are under threat in numerous countries. Biodiversity research focusing on the relationship between the richness of orchid species and ecological factors was performed across the Cerová vrchovina Mts (Western Carpathians) testing impact of 26 explanatory variables. We aimed to determine the main ecological predictors controlling species richness and to predict potential species richness patterns. Altogether, 19 orchid species were found in the studied area, with Cephalanthera damasonium and Epipactis microphylla being the most common. Four environmental predictors (minimal longitude, carbonate-containing sediments, maximal yearly solar irradiation, and agricultural land) had statistically significant effects on orchid richness following regression analysis. Predictive models for the nine most frequent species using MaxEnt software showed (i) that land cover and geological substrate had the highest contribution to the explained variance in the models and (ii) strong potential for occurrence of given orchids in several poorly mapped parts of the studied area.
Productivity-Index Behavior for a Horizontal Well Intercepted by Multiple Finite-Conductivity Fractures Considering Nonlinear Flow Mechanisms under Steady-State Condition
Authors: Cao Maojun , Xiao Hong , Wang Caizhi
Published: April 2020

In this paper, a mathematical model is proposed to investigate the effect of nonlinear flow mechanisms on productivity-index (PI) behavior in hydraulically fractured reservoirs during steady-state condition. This approach focuses on the fact that PI approaches a constant value at a certain time, indicating the beginning of steady state. In this model, the reservoirs are considered as an elliptical-shaped drainage with constant-pressure boundary, which is depleted by a multiple-fractured horizontal well (MFHW), and various nonlinear flow mechanisms, such as the non-Darcy flow effect and pressure-dependency effect, control flow patterns in the hydraulic fractures. Then, an exact algorithm of solving the resulting nonlinear equations is developed to obtain the PI of MFHW using a semi-analytical approach. Next, type curves are generated to investigate the influences of flow mechanisms and fracture properties on PI. The most interesting points in this study are the following: (1) PI is determined by the properties of MHFW (i.e., dimensions and configuration), the reservoir geometry, and flow mechanism; (2) PI is deteriorated by non-Darcy flow caused by inertial forces; and (3) PI is reduced under the influence of pressure sensitivity caused by the degradation of dynamic conductivity. Generally, this study provides a significant insight into understanding the factors affecting the productivity of a MFHW with nonlinear flow mechanisms.
Radial Growth Adaptability to Drought in Different Age Groups of Picea schrenkiana Fisch. & C.A. Mey in the Tianshan Mountains of Northwestern China
Authors: Jiao Liang , Liu Xiaoping , Wang Shengjie , Chen Ke
Published: April 2020

Forest ecosystems are strongly impacted by extreme climate, and the age effects of radial growth under drought can provide profound understanding of the adaptation strategy of a tree species to climate change. Schrenk spruce (Picea schrenkiana Fisch. & C.A. Mey) trees of three age groups (young, middle-aged, and old) were collected to establish the tree-ring width chronologies in the eastern Tianshan Mountains of northwestern China. Meanwhile, we analyzed and compared the response and resistance disparities of radial growth to drought in trees of different age groups. The results showed that (1) drought stress caused by increasing temperatures was the main factor limiting the radial growth of Schrenk spruce, (2) the old and young trees were more susceptible to drought stress than the middle-aged trees, as suggested by the responses of Schrenk spruce trees and based on the SPEI (standardized precipitation evapotranspiration index), and (3) the difference of the resistance indexes (resistance, recovery, resilience, and relative resilience) of three age groups to drought supported that the resistance values were in the order middle age > young age > old age, but the recovery, resilience, and relative resilience values were in the order old age > young age > middle age. These results will provide a basis for the ecological restoration and scientific management of dominant coniferous tree species of different age groups in the sub-alpine forest ecosystems of the arid regions under climate change scenarios.
Impact of Invasive Tree Species on Natural Regeneration Species Composition, Diversity, and Density
Authors: Dyderski Marcin K. , Jagodziński Andrzej M.
Published: April 2020

Invasive tree species decrease ecosystem resilience with negative impacts on natural regeneration. The influence of alien tree species on ecosystems is unevenly recognized and does not always account for different habitat specificity. We assessed the impacts of the three most frequent invasive tree species in European forests: Prunus serotina Ehrh., Quercus rubra L., and Robinia pseudoacacia L. on natural regeneration diversity, species composition, and density. We hypothesized that invaded forest types, in comparison with non-invaded, will differ in terms of species composition, will have lower taxonomic, functional, and phylogenetic diversity of natural regeneration, and will have lower densities of native tree species. We used a set of 189 study plots (200 m2) in a systematic design, established in various forest types in Wielkopolski National Park (West Poland). We analyzed impacts of forest type, accounting for soil C:N ratio, soil pH, and light availability on natural regeneration (woody species up to 0.5 m height) species composition, diversity, and density. We found an overlap of species composition among invaded and non-invaded forests and low impacts of invasive species on taxonomic diversity and functional richness. We found no impacts on phylogenetic diversity and other functional diversity components. In contrast, we found that the natural regeneration of forest-forming tree species reached lower densities in invaded than non-invaded forest types. However, sub-canopy and shrub species reached higher densities in invaded than non-invaded forest types. We confirmed that invasive tree species affect natural regeneration by decreasing the regeneration density of native tree species (in eight of nine tree species studied), species composition homogenization, and supporting natural regeneration of sub-canopy and shrub species. Therefore, the restoration of invaded forests requires eradication of invasive tree species to decrease propagule pressure and to stop decreases in the abundance of native tree species’ natural regeneration.
Comparative Plastome Analyses and Phylogenetic Applications of the Acer Section Platanoidea
Authors: Yu Tao , Gao Jian , Huang Bing-Hong , Dayananda Buddhi , Ma Wen-Bao , Zhang Yu-Yang , Liao Pei-Chun , Li Jun-Qing
Published: April 2020

The Acer L. (Sapindaceae) is one of the most diverse and widespread genera in the Northern Hemisphere. Section Platanoidea harbours high genetic and morphological diversity and shows the phylogenetic conflict between A. catalpifolium and A. amplum. Chloroplast (cp) genome sequencing is efficient for the enhancement of the understanding of phylogenetic relationships and taxonomic revision. Here, we report complete cp genomes of five species of Acer sect. Platanoidea. The length of Acer sect. Platanoidea cp genomes ranged from 156,262 bp to 157,349 bp and detected the structural variation in the inverted repeats (IRs) boundaries. By conducting a sliding window analysis, we found that five relatively high variable regions (trnH-psbA, psbN-trnD, psaA-ycf3, petA-psbJ and ndhA intron) had a high potential for developing effective genetic markers. Moreover, with an addition of eight plastomes collected from GenBank, we displayed a robust phylogenetic tree of the Acer sect. Platanoidea, with high resolutions for nearly all identified nodes, suggests a promising opportunity to resolve infrasectional relationships of the most species-rich section Platanoidea of Acer.
Heat Treatment of Pine Wood: Possible Effect of Impregnation with Silver Nanosuspension
Authors: Taghiyari Hamid R. , Bayani Siavash , Militz Holger , Papadopoulos Antonios N.
Published: April 2020

The scope of the present work was to study the effects of heat treatment (at different mild temperatures) on the physicomechanical properties of pine wood, and to find out if impregnation with nanosilver may have any potential influence on the impact of heat treatment. Impregnation of wood with a 400-ppm silver nanosuspension was carried out under an initial vacuum pressure of 0.07 MPa, followed by a pressure of 0.25 MPa for thirty minutes, before heat treatment. Heat treatment was carried out under hot air at three relatively mild temperatures, 145, 165, and 185 °C. Results showed improvement of some properties in heat-treated wood at 145 °C. This was indicative of the improving impact caused by hornification and irreversible hydrogen bonding in the course of water movements due to heat treatment; significant fluctuations in the intensities of FTIR spectra bands at 1750–1500 cm−1 were corroborating evidence of chemical alterations in hemicellulose polymer. The high mass loss at temperature 185 °C, and the extreme thermal degradation thereof, overcame the improving effects of hornification and formation of irreversible hydrogen bonds, consequently mechanical properties decreased significantly. Interaction of different elements involved made it hard to predict properties in specimens modified at 165 °C. Impregnation of specimens with nanosilver suspension resulted in significant increase of mass loss in specimens heat-treated at 185 °C, and significant fluctuations in properties of specimens heat-treated at 145 °C.
Eutypella parasitica and Other Frequently Isolated Fungi in Wood of Dead Branches of Young Sycamore Maple (Acer pseudoplatanus) in Slovenia
Authors: Brglez Ana , Piškur Barbara , Ogris Nikica
Published: April 2020

Eutypella parasitica R.W. Davidson and R.C. Lorenz is the causative agent of Eutypella canker of maple, a destructive disease of maples in Europe and North America. The fungus E. parasitica infects the trunk through a branch stub or bark wound. Because the fungal community may have an impact on infection and colonization by E. parasitica, the composition of fungi colonizing wood of dead branches of sycamore maple (Acer pseudoplatanus L.) was investigated in five sampling sites in Slovenia. Forty samples from each sampling site were collected between the November 2017 and March 2018 period. Isolations were made from the wood in the outer part of dead branches and from discoloured wood in the trunk that originated from a dead branch. Pure cultures were divided into morphotypes, and one representative culture per morphotype was selected for further molecular identification. From a total of 2700 cultured subsamples, 1744 fungal cultures were obtained, which were grouped into 212 morphotypes. The investigated samples were colonized by a broad spectrum of fungi. The most frequently isolated species were Eutypa maura (Fr.) Sacc., Eutypa sp. Tul. and C. Tul., Fusarium avenaceum (Fr.) Sacc., Neocucurbitaria acerina Wanas., Camporesi, E.B.G. Jones and K.D. Hyde and E. parasitica. In this study, we distinguished species diversity and the fungal community. There were no significant differences in the diversity of fungal species between the five sampling sites, and branch thickness did not prove to be a statistically significant factor in fungal species diversity. Nevertheless, relatively low Jaccard similarity index values suggested possible differences in the fungal communities from different sampling sites. This was confirmed by an analysis of similarities, which showed that the isolated fungal community distinctly differed between the five sampling sites and between the different isolation sources. Eutypella parasitica was isolated from all five investigated sampling sites, although Eutypella cankers were observed in only three sampling sites, indicating the possibility of asymptomatic infection.
Publishing Anonymized Set-Valued Data via Disassociation towards Analysis
Authors: Awad Nancy , Couchot Jean-Francois , Al Bouna Bechara , Philippe Laurent
Published: April 2020

Data publishing is a challenging task for privacy preservation constraints. To ensure privacy, many anonymization techniques have been proposed. They differ in terms of the mathematical properties they verify and in terms of the functional objectives expected. Disassociation is one of the techniques that aim at anonymizing of set-valued datasets (e.g., discrete locations, search and shopping items) while guaranteeing the confidentiality property known as k m -anonymity. Disassociation separates the items of an itemset in vertical chunks to create ambiguity in the original associations. In a previous work, we defined a new ant-based clustering algorithm for the disassociation technique to preserve some items associated together, called utility rules, throughout the anonymization process, for accurate analysis. In this paper, we examine the disassociated dataset in terms of knowledge extraction. To make data analysis easy on top of the anonymized dataset, we define neighbor datasets or in other terms datasets that are the result of a probabilistic re-association process. To assess the neighborhood notion set-valued datasets are formalized into trees and a tree edit distance (TED) is directly applied between these neighbors. Finally, we prove the faithfulness of the neighbors to knowledge extraction for future analysis, in the experiments.
Aggregated Indices in Website Quality Assessment
Authors: Król Karol , Zdonek Dariusz
Published: April 2020

Website users have increasingly high expectations regarding website quality, starting from performance and ending up with the content. This article provides a list and characteristics of selected website quality indices and testing applications that are available free of charge. Aggregated website quality indices were characterised based on a review of various source materials, including the academic literature and Internet materials. Aggregated website quality indices are usually developed with a less specialised user (customer) searching for descriptive information in mind. Their presentation is focused on aesthetic sensations. Most frequently, their values are expressed in points or percent. Many of these indices appear to be of little substantive value, as they present approximate, estimated values. These indices, however, are of great marketing value instead. Specific (“single”) indices are of a specialised nature. They are more difficult to interpret and address the subtle aspects of website and web application functioning. They offer great value to designers and software developers. They indicate critical spots which affect the website quality. Most of them are expressed precisely, often up to two or three decimal places, in specific units. Algorithmic tests for website quality, whose results are presented using indices, enable a reduction in the cost intensiveness of tests as well as an increase in their number and frequency, as the tests are repetitive and their number is not limited. What is more, they allow the results to be compared.
DeepDiver: Diving into Abysmal Depth of the Binary for Hunting Deeply Hidden Software Vulnerabilities
Authors: Rustamov Fayozbek , Kim Juhwan , Yun JooBeom
Published: April 2020

Fuzz testing is a simple automated software testing approach that discovers software vulnerabilities at a high level of performance by using randomly generated seeds. However, it is restrained by coverage and thus, there are chances of finding bugs entrenched in the deep execution paths of the program. To eliminate these limitations in mutational fuzzers, patching-based fuzzers and hybrid fuzzers have been proposed as groundbreaking advancements which combine two software testing approaches. Despite those methods having demonstrated high performance across different benchmarks such as DARPA CGC programs, they still present deficiencies in their ability to analyze deeper code branches and in bypassing the roadblocks checks (magic bytes, checksums) in real-world programs. In this research, we design DeepDiver, a novel transformational hybrid fuzzing tool that explores deeply hidden software vulnerabilities. Our approach tackles limitations exhibited by existing hybrid fuzzing frameworks, by negating roadblock checks (RC) in the program. By negating the RCs, the hybrid fuzzer can explore new execution paths to trigger bugs that are hidden in the abysmal depths of the binary. We combine AFL++ and concolic execution engine and leveraged the trace analyzer approach to construct the tree for each input to detect RCs. To demonstrate the efficiency of DeepDiver, we tested it with the LAVA-M dataset and eight large real-world programs. Overall, DeepDiver outperformed existing software testing tools, including the patching-based fuzzer and state-of-the-art hybrid fuzzing techniques. On average, DeepDiver discovered vulnerabilities 32.2% and 41.6% faster than QSYM and AFLFast respectively, and it accomplished in-depth code coverage.
Game Theoretic Modeling of Infectious Disease Transmission with Delayed Emergence of Symptoms
Authors: Soltanolkottabi Marzieh , Ben-Arieh David , Wu Chih-Hang
Published: April 2020

Modeling the spread of infectious diseases and social responses is one method that can help public health policy makers improve the control of epidemic outbreaks and make better decisions about vaccination costs, the number of mandatory vaccinations, or investment in media efforts to inform the public of disease threats. Incubation period—the period when an individual has been exposed to a disease and could be infectious but is not yet aware of it—is one factor that can affect an epidemic outbreak, and considering it when modeling outbreaks can improve model accuracy. A change in outbreak activity can occur from the time a person becomes infected until they become aware of infection when they can transmit the disease but their social group considers them a susceptible individual and not an infectious one. This study evaluates the effect of this delay between the time of infection of an individual and the time of diagnosis of the infection (incubation period) in an epidemic outbreak. This study investigates the social dynamics of vaccination and transmission in such epidemic outbreaks, using a model of the public goods game.
Innovating Computational Biology and Intelligent Medicine: ICIBM 2019 Special Issue
Authors: Guo Yan , Ning Xia , Mathé Ewy , Wang Kai , Li Lang , Zhang Chi , Zhao Zhongming
Published: April 2020

The International Association for Intelligent Biology and Medicine (IAIBM) is a nonprofit organization that promotes intelligent biology and medical science. It hosts an annual International Conference on Intelligent Biology and Medicine (ICIBM), which was established in 2012. The ICIBM 2019 was held from 9 to 11 June 2019 in Columbus, Ohio, USA. Out of the 105 original research manuscripts submitted to the conference, 18 were selected for publication in a Special Issue in Genes. The topics of the selected manuscripts cover a wide range of current topics in biomedical research including cancer informatics, transcriptomic, computational algorithms, visualization and tools, deep learning, and microbiome research. In this editorial, we briefly introduce each of the manuscripts and discuss their contribution to the advance of science and technology.
Interindividual Variability of Apixaban Plasma Concentrations: Influence of Clinical and Genetic Factors in a Real-Life Cohort of Atrial Fibrillation Patients
Authors: Roşian Adela-Nicoleta , Roşian Ştefan Horia , Kiss Bela , Ştefan Maria Georgia , Trifa Adrian Pavel , Ober Camelia Diana , Anchidin Ovidiu , Buzoianu Anca Dana
Published: April 2020

(1) Background: Prescribing apixaban for stroke prevention has significantly increased in patients with non-valvular atrial fibrillation (NVAF). The ABCB1 genotype can influence apixaban absorption and bioavailability. The aim of the present study was to assess the factors that influence apixaban’s plasma level and to establish if a certain relationship has clinical relevance. (2) Methods: Fifty-three NVAF patients were treated with 5 mg apixaban twice/day (70.0 years, range: 65–77, 60.4% men). Trough and peak plasma concentrations of apixaban were determined by liquid chromatography-tandem mass-spectrometry (LC-MS/MS), and ABCB1 genotyping was performed. (3) Results: Apixaban plasma concentrations varied considerably. They were higher in women than in men (311.2 ng/dL vs. 252.2 ng/dL; p = 0.05) and were lower in patients with heart failure (149.4 ng/dL vs. 304.5 ng/dL; p < 0.01). Creatinine clearance was inversely correlated with the apixaban plasma level (Spearman correlation: r = −0.365; p = 0.007 for trough concentrations). No statistically significant differences between the genotypic groups of ABCB1 rs1045642 and ABCB1 rs4148738 were found in the trough or peak apixaban plasma concentrations. (4) Conclusions: Pharmacokinetic parameters are influenced by several clinical factors of which renal function is the major determinant. Plasma concentrations measured in women had higher values than those measured in men, and heart failure was associated with decreased plasma levels of apixaban.
Special Issue: Genetics of Biodegradation and Bioremediation
Authors: Santero Eduardo , Díaz Eduardo
Published: April 2020

Many different biodegradation pathways, both aerobic and anaerobic, have already been characterised, and the phylogenetic relationships among catabolic genes within the different types of pathways have been studied. However, new biodegradation activities and their coding genes are continuously being reported, including those involved in the catabolism of emerging contaminants or those generally regarded as non-biodegradable. Gene regulation is also an important issue for the efficient biodegradation of contaminants. Specific induction by the substrate and over-imposed global regulatory networks adjust the expression of the biodegradation genes to the bacterial physiological needs. New biodegradation pathways can be assembled in a particular strain or in a bacterial consortium by recruiting biodegradation genes from different origins through horizontal gene transfer. The abundance and diversity of biodegradation genes, analysed by either genomic or metagenomic approaches, constitute valuable indicators of the biodegradation potential of a particular environmental niche. This knowledge paves the way to systems metabolic engineering approaches to valorise biowaste for the production of value-added products.
Genetics and Epigenetics of Atopic Dermatitis: An Updated Systematic Review
Authors: Martin Maria J , Estravís Miguel , García-Sánchez Asunción , Dávila Ignacio , Isidoro-García María , Sanz Catalina
Published: April 2020

Background: Atopic dermatitis is a common inflammatory skin disorder that affects up to 15–20% of the population and is characterized by recurrent eczematous lesions with intense itching. As a heterogeneous disease, multiple factors have been suggested to explain the nature of atopic dermatitis (AD), and its high prevalence makes it necessary to periodically compile and update the new information available. In this systematic review, the focus is set at the genetic and epigenetic studies carried out in the last years. Methods: A systematic literature review was conducted in three scientific publication databases (PubMed, Cochrane Library, and Scopus). The search was restricted to publications indexed from July 2016 to December 2019, and keywords related to atopic dermatitis genetics and epigenetics were used. Results: A total of 73 original papers met the inclusion criteria established, including 9 epigenetic studies. A total of 62 genes and 5 intergenic regions were described as associated with AD. Conclusion: Filaggrin (FLG) polymorphisms are confirmed as key genetic determinants for AD development, but also epigenetic regulation and other genes with functions mainly related to the immune system and extracellular matrix, reinforcing the notion of skin homeostasis breakage in AD.
A Novel Cosegregating DCTN1 Splice Site Variant in a Family with Bipolar Disorder May Hold the Key to Understanding the Etiology
Authors: Hallen André , Cooper Arthur J. L.
Published: April 2020

A novel cosegregating splice site variant in the Dynactin-1 (DCTN1) gene was discovered by Next Generation Sequencing (NGS) in a family with a history of bipolar disorder (BD) and major depressive diagnosis (MDD). Psychiatric illness in this family follows an autosomal dominant pattern. DCTN1 codes for the largest dynactin subunit, namely p150Glued, which plays an essential role in retrograde axonal transport and in neuronal autophagy. A GT→TT transversion in the DCTN1 gene, uncovered in the present work, is predicted to disrupt the invariant canonical splice donor site IVS22 + 1G > T and result in intron retention and a premature termination codon (PTC). Thus, this splice site variant is predicted to trigger RNA nonsense-mediated decay (NMD) and/or result in a C-terminal truncated p150Glued protein (ct-p150Glued), thereby negatively impacting retrograde axonal transport and neuronal autophagy. BD prophylactic medications, and most antipsychotics and antidepressants, are known to enhance neuronal autophagy. This variant is analogous to the dominant-negative GLUED Gl1 mutation in Drosophila, which is responsible for a neurodegenerative phenotype. The newly identified variant may reflect an autosomal dominant cause of psychiatric pathology in this affected family. Factors that affect alternative splicing of the DCTN1 gene, leading to NMD and/or ct-p150Glued, may be of fundamental importance in contributing to our understanding of the etiology of BD as well as MDD.
A Study of Gene Expression Changes in Human Spinal and Oculomotor Neurons; Identifying Potential Links to Sporadic ALS
Authors: Patel Aayan N. , Mathew Dennis
Published: April 2020

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes compromised function of motor neurons and neuronal death. However, oculomotor neurons are largely spared from disease symptoms. The underlying causes for sporadic ALS as well as for the resistance of oculomotor neurons to disease symptoms remain poorly understood. In this bioinformatic-analysis, we compared the gene expression profiles of spinal and oculomotor tissue samples from control individuals and sporadic ALS patients. We show that the genes GAD2 and GABRE (involved in GABA signaling), and CALB1 (involved in intracellular Ca2+ ion buffering) are downregulated in the spinal tissues of ALS patients, but their endogenous levels are higher in oculomotor tissues relative to the spinal tissues. Our results suggest that the downregulation of these genes and processes in spinal tissues are related to sporadic ALS disease progression and their upregulation in oculomotor neurons confer upon them resistance to ALS symptoms. These results build upon prevailing models of excitotoxicity that are relevant to sporadic ALS disease progression and point out unique opportunities for better understanding the progression of neurodegenerative properties associated with sporadic ALS.