bluuebunny/crossref_metadata_2025 huggingface dataset:
Could Gnomoniopsis castaneae Be Used as a Biological Control Agent against Insect Pests?
Authors: Mantzoukas Spiridon , Lagogiannis Ioannis , Ntoukas Aristeidis , Tziros George T. , Poulas Konstantinos , Eliopoulos Panagiotis A. , Avtzis Dimitrios Ν.
Published: April 2021

Gnomoniopsis castaneae is the cause of the chestnut brown rot but has been also regarded as an important mortality factor for the chestnut gall wasp Dryocosmus kuriphilus. The question to whether G. castaneae could serve as a natural biocontrol agent against insect pests is investigated in the present study. We used three serious insect pests as experimental model insects: Plodia interpuctella and Trogoderma granarium, which are important pests of stored products, and Myzus persicae, a cosmopolitan, serious pest of annual and perennial crop plants. Although chemical pesticides represent effective control means, they are also related to several environmental and health risks. In search for alternative pest management methods, scientific interest has been focused, inter alia, on the use of entomopathogenic fungi. While Isaria fumosorosea has long been recognized as an effective control agent against several pests, G.castaneae has been very little studied. The present study examined whether and to what extent G. castaneae and I. fumosorosea exhibit insecticidal activity against fourth-instar larvae of P. interpunctella and T. granarium and adults of M. persicae. Mortality was examined in interrelation with dosage and time exposure intervals. Both fungi exhibited pesticidal action. However, G. castaneae induced noteworthy mortality only at very high doses. In general, we concluded that G. castaneae failed to cause high insect pathogenicity at normal doses and may not be an efficient biocontrol agent compared with other entomopathogens. On the other hand, our study reiterates the pathogenic potential of I. fumosorosea. More studies are needed to further our insight into the potential of EF species as a component of IPM.
The Oxidative Process of Acarbose, Maysin, and Luteolin with Maltase-Glucoamylase: Molecular Docking and Molecular Dynamics Study
Authors: Landeros-Martínez Linda-Lucila , Gutiérrez-Méndez Néstor , Palomares-Báez Juan Pedro , Sánchez-Bojorge Nora-Aydeé , Flores-De los Ríos Juan Pablo , Piñón-Castillo Hilda Amelia , Chávez-Rojo Marco Antonio , Rodríguez-Valdez Luz-María
Published: April 2021

Type 2 diabetes mellitus has been classified as the epidemic of the XXI century, making it a global health challenge. Currently, the commonly used treatment for this disease is acarbose, however, the high cost of this medicine has motivated the search for new alternatives. In this work, the maysin, a characteristic flavonoid from maize inflorescences, and its aglycon version, luteolin, are proposed as acarbose substitutes. For this, a theoretical comparative analysis was conducted on the molecular interactions of acarbose, maysin, and luteolin with human maltase-glucoamylase (NtMGAM), as well as their oxidative process. The binding energies in the active site of NtMGAM with acarbose, maysin, and luteolin molecules were predicted using a molecular docking approach applying the Lamarckian genetic algorithm method. Theoretical chemical reactivity parameters such as chemical hardness (η) and chemical potential (µ) of the acarbose, maysin, and luteolin molecules, as well as of the amino acids involved in the active site, were calculated using the electronic structure method called Density Functional Theory (DFT), employing the M06 meta-GGA functional in combination with the 6-31G(d) basis set. Furthermore, a possible oxidative process has been proposed from quantum-chemical calculations of the electronic charge transfer values (ΔN), between the amino acids of the active site and the acarbose, maysin, and luteolin. Molecular docking predictions were complemented with molecular dynamics simulations. Hence, it was demonstrated that the solvation of the protein affects the affinity order between NtMGAM and ligands.
EGR2, IGF1 and IL6 Expression Are Elevated in the Intervertebral Disc of Patients Suffering from Diffuse Idiopathic Skeletal Hyperostosis (DISH) Compared to Degenerative or Trauma Discs
Authors: Gantenbein Benjamin , May Rahel D. , Bermudez-Lekerika Paola , Oswald Katharina A. C. , Benneker Lorin M. , Albers Christoph E.
Published: April 2021

Diffuse idiopathic skeletal hyperostosis (DISH) is characterised by ectopic ossification along the anterior spine and the outer intervertebral discs (IVD). However, the centre of the IVD, i.e., the nucleus pulposus, always remains unaffected, which could be due to the inhibition of the bone morphogenetic protein (BMP) pathway. In this study, we investigated the transcriptome for the BMP pathway of DISH-IVD cells versus disc cells of traumatic or degenerative discs. The disc cells originated from nucleus pulposus (NP), annulus fibrosus (AF) and from cartilaginous endplate (CEP) tissue. Here, ninety genes of the transforming growth factor β-BMP signalling pathway were screened by qPCR. Furthermore, the protein expression of genes of interest was further investigated by immune-staining and semi-quantitative microscopy. IVDs of three DISH patients were tested against three control patients (same disc level and similar age). Early Growth Response 2 (EGR2) and Interleukin 6 (IL6) were both significantly up-regulated in DISH-IVD cells compared to controls (12.8 ± 7.6-fold and 54.0 ± 46.5-fold, respectively, means ± SEM). Furthermore, Insulin-like Growth Factor 1 (IGF1) tended to be up-regulated in DISH-IVD donors, i.e., 174.13 ± 120.6-fold. IGF1 was already known as a serum marker for DISH and other rheumatoid diseases and is confirmed here to play a possible key role in DISH-IVD.
Bilateral Patella Cartilage Debridement and Exercise Rehabilitation for Chondromalacia and Plica Syndrome: A Case Report
Authors: Park Jihong , Kim Jingoo , Ko Bongseong
Published: April 2021

A 41-year-old active (exercising >600 min per week) male without a surgical history complained of nine years of intermittent bilateral anterior knee pain after physical activity. He was diagnosed with bilateral chondromalacia (grade IV chondrosis) with plica syndrome, for which he underwent bilateral patella cartilage debridement with medial plica excision (additional removal of lateral retinaculum in the right knee). The patient then performed 12 weeks of an aggressive postoperative rehabilitation program. Each rehabilitation session consisted of disinhibitory modalities (sensory level of transcutaneous electrical stimulation and cryotherapy: focal knee joint cooling and cold-water immersion) and voluntary exercises (aerobic, resistance, and flexibility). During rehabilitation, pain perception, knee joint skin temperature and circumference, and functional outcome measures (Kujala anterior knee pain scale, International Knee Documentation Committee Score, and lower-extremity functional scale) were also recorded. While the patient’s pathology and surgical intervention were not extreme, progressions in the rehabilitation components and functional outcome measures in this clinical case could be used as a future reference for postoperative interventions. Additionally, surgery-induced inflammation seemed to last for four weeks.
Priority Pricing for Efficient Resource Usage of Mobile Internet Access
Authors: Cho Sung-woo
Published: April 2021

Radio-frequency spectrum resources are finite and scarce, but their demand is increasing exponentially every year. Therefore, wireless network resources are too expensive to be wasted. To avoid waste, pricing techniques can efficiently control resource usage and manage user needs in networks. This study focuses on QoS-aware pricing for usage-based mobile Internet access charging. Specifically, I propose a heuristic algorithm for priority pricing with multiple service levels. The proposed algorithm is built on top of the existing equilibrium analysis methods. While being extensively studied for optimal price selection, the equilibrium methods make a few unrealistic assumptions, and so my methods adjust the solutions of the equilibrium methods to account for distortions that the real world creates. The evaluation results indicate that multiple equilibrium prices may exist, and the proposed scheme produces a pricing plan that is substantially more effective than existing equilibrium methods.
Fault-Tolerant Active Disturbance Rejection Control of Plant Protection of Unmanned Aerial Vehicles Based on a Spatio-Temporal RBF Neural Network
Authors: Hua Lianghao , Zhang Jianfeng , Li Dejie , Xi Xiaobo
Published: April 2021

This paper presents a fault-tolerant flight control method for a multi-rotor UAV under actuator failure and external wind disturbances. The control method is based on an active disturbance rejection controller (ADRC) and spatio-temporal radial basis function neural networks, which can be used to achieve the stable control of the system when the parameters of the UAV mathematical model change. Firstly, an active disturbance rejection controller with an optimized parameter design is designed for rthe obust control of a multi-rotor vehicle. Secondly, a spatio-temporal radial basis function neural network with a new adaptive kernel is designed. In addition, the output of the novel radial basis function neural network is used to estimate fusion parameters containing actuator faults and model uncertainties and, consequently, to design an active fault-tolerant controller for a multi-rotor vehicle. Finally, fault injection experiments are carried out with the Qball-X4 quadrotor UAV as a specific research object, and the experimental results show the effectiveness of the proposed self-tolerant, fault-tolerant control method.
Served on a Plate: Engraved Sources of San Diego de Alcalá’s ‘Miraculous Meal’ for the Franciscans of Santiago, Chile (ca. 1710)
Authors: Burdick Catherine
Published: April 2021

There exists a consensus in academic literature regarding the centrality of engraved prototypes for the production of colonial paintings in the Spanish Americas. In Peru, these artistic models were written into legal contracts between painters and clients. An examination of the notarial contracts produced in Cusco from 1650 to 1700 suggests that prototypes in a variety of formats were not only central to artistic professional practice, but that adherence to their images may have provided one motive for entering into such agreements. This study leans upon the centrality of Flemish print sources to confirm the attribution of a partial canvas at the Pinacoteca Universidad de Concepción, Chile as an episode of the series on the life of Diego de Alcalá (c. 1710) in Santiago, Chile. Commissioned from Cusco by the Franciscans of Santiago, the status of the hagiographic cycle as the most extensive ever produced on the subject of this missionary saint dictates that a multiplicity of sources was necessary for its creation. By identifying two engravings that served as its models, this study recovers the subject of this painting as a miracle that sustained Diego during an arduous journey.
C-Band SAR Winds for Tropical Cyclone Monitoring and Forecast in the South-West Indian Ocean
Authors: Duong Quoc-Phi , Langlade Sébastien , Payan Christophe , Husson Romain , Mouche Alexis , Malardel Sylvie
Published: April 2021

Tropical cyclone (TC) monitoring and forecast in the South West Indian Ocean (SWIO) basin remain challenging, notably because of the lack of direct observations. During the 2018–2019 cyclone season, S-1 Sentinel SAR images were acquired, as part of the ReNovRisk-Cyclone research program, giving access to unprecedented detailed TC wind structure description without wind speed limitation. This paper assesses the quality of these data and the impact of their assimilation for TC forecasts. SAR observations are compared with analyses from a convection-permitting, limited area model AROME OI 3D-Var and with wind products used for operational TC monitoring. Their bias depends on the angle of incidence of the radar and the observation error is larger for extreme wind speed. The impact of SAR assimilation in AROME OI 3D-Var is assessed through two case studies. In the TC GELENA case, it leads to a better TC positioning and an improved representation of inner and outer vortex structures. The TC intensity reduction in the analysis propagates through subsequent analyses and it has an impact on forecasts for around 12 h. In the TC IDAI case, the 3D-Var does not manage to reproduce TC intensity captured by SAR. In both cases, the modification of the initial conditions has little influence on the intensification rate of the model forecasts. Sensitivity tests show that these results are robust to different observation errors and thinning.
Artifact-Free Single Image Defogging
Authors: Graffieti Gabriele , Maltoni Davide
Published: April 2021

In this paper, we present a novel defogging technique, named CurL-Defog, with the aim of minimizing the insertion of artifacts while maintaining good contrast restoration and visibility enhancement. Many learning-based defogging approaches rely on paired data, where fog is artificially added to clear images; this usually provides good results on mildly fogged images but is not effective for difficult cases. On the other hand, the models trained with real data can produce visually impressive results, but unwanted artifacts are often present. We propose a curriculum learning strategy and an enhanced CycleGAN model to reduce the number of produced artifacts, where both synthetic and real data are used in the training procedure. We also introduce a new metric, called HArD (Hazy Artifact Detector), to numerically quantify the number of artifacts in the defogged images, thus avoiding the tedious and subjective manual inspection of the results. HArD is then combined with other defogging indicators to produce a solid metric that is not deceived by the presence of artifacts. The proposed approach compares favorably with state-of-the-art techniques on both real and synthetic datasets.
Trees in Positive Entropy Subshifts
Authors: Salo Ville
Published: April 2021

I give a simple proof for the fact that positive entropy subshifts contain infinite binary trees where branching happens synchronously in each branch, and that the branching times form a set with positive lower asymptotic density.
Perception of Aqueous Ethanol Binary Mixtures Containing Alcohol-Relevant Taste and Chemesthetic Stimuli
Authors: Thibodeau Margaret , Pickering Gary
Published: April 2021

Ethanol is a complex stimulus that elicits multiple gustatory and chemesthetic sensations. Alcoholic beverages also contain other tastants that impact flavour. Here, we sought to characterize the binary interactions between ethanol and four stimuli representing the dominant orosensations elicited in alcoholic beverages: fructose (sweet), quinine (bitter), tartaric acid (sour) and aluminium sulphate (astringent). Female participants were screened for thermal taste status to determine whether the heightened orosensory responsiveness of thermal tasters (n = 21–22) compared to thermal non-tasters (n = 13–15) extends to these binary mixtures. Participants rated the intensity of five orosensations in binary solutions of ethanol (5%, 13%, 23%) and a tastant (low, medium, high). For each tastant, 3-way ANOVAs determined which factors impacted orosensory ratings. Burning/tingling increased as ethanol concentration increased in all four binary mixture types and was not impacted by the concentration of other stimuli. In contrast, bitterness increased with ethanol concentration, and decreased with increasing fructose concentration. Sourness tended to be reduced as ethanol concentration increased, although astringency intensity decreased with increasing concentration of fructose. Overall, thermal tasters tended to be more responsive than thermal non-tasters. These results provide insights into how the taste and chemesthetic profiles of alcoholic beverages across a wide range of ethanol concentrations can be manipulated by changing their composition.
The Unfolded Protein Response: An Overview
Authors: Read Adam , Schröder Martin
Published: April 2021

The unfolded protein response is the mechanism by which cells control endoplasmic reticulum (ER) protein homeostasis. Under normal conditions, the UPR is not activated; however, under certain stresses, such as hypoxia or altered glycosylation, the UPR can be activated due to an accumulation of unfolded proteins. The activation of the UPR involves three signaling pathways, IRE1, PERK and ATF6, which all play vital roles in returning protein homeostasis to levels seen in non-stressed cells. IRE1 is the best studied of the three pathways, as it is the only pathway present in Saccharomyces cerevisiae. This pathway involves spliceosome independent splicing of HAC1 or XBP1 in yeast and mammalians cells, respectively. PERK limits protein synthesis, therefore reducing the number of new proteins requiring folding. ATF6 is translocated and proteolytically cleaved, releasing a NH2 domain fragment which is transported to the nucleus and which affects gene expression. If the UPR is unsuccessful at reducing the load of unfolded proteins in the ER and the UPR signals remain activated, this can lead to programmed cell death.
Effectiveness of N-Acetylcysteine in the Treatment of Renal Deterioration Caused by Long-Term Exposure to Bisphenol A
Authors: Kobroob Anongporn , Peerapanyasut Wachirasek , Kumfu Sirinart , Chattipakorn Nipon , Wongmekiat Orawan
Published: April 2021

Human health hazards caused by bisphenol A (BPA), a precursor for epoxy resins and polycarbonate-based plastics, are well documented and are closely associated with mitochondrial impairment and oxidative imbalance. This study aimed to assess the therapeutic efficacy of N-acetylcysteine (NAC) on renal deterioration caused by long-term BPA exposure and examine the signaling transduction pathway involved. Male Wistar rats were given vehicle or BPA orally for 12 weeks then the BPA-treated group was subdivided to receive vehicle or NAC concurrently with BPA for a further 4 weeks, while the vehicle-treated normal control group continued to receive vehicle through to the end of experiment. Proteinuria, azotemia, glomerular filtration reduction and histopathological abnormalities caused by chronic BPA exposure were significantly reduced following NAC therapy. NAC also diminished nitric oxide and lipid peroxidation but enhanced renal glutathione levels, and counteracted BPA-induced mitochondrial swelling, increased mitochondrial reactive oxygen species production, and the loss of mitochondrial membrane potential. The benefit of NAC was related to the modulation of signaling proteins in the AMPK-SIRT3-SOD2 axis. The present study shows the potential of NAC to restore mitochondrial integrity and oxidative balance after long-term BPA exposure, and suggests that NAC therapy is an effective approach to tackle renal deterioration in this condition.
Olfactory Perception in Relation to the Physicochemical Odor Space
Authors: Bierling Antonie Louise , Croy Ilona , Hummel Thomas , Cuniberti Gianaurelio , Croy Alexander
Published: April 2021

A growing body of research aims at solving what is often referred to as the stimulus-percept problem in olfactory perception. Although computational efforts have made it possible to predict perceptual impressions from the physicochemical space of odors, studies with large psychophysical datasets from non-experts remain scarce. Following previous approaches, we developed a physicochemical odor space using 4094 molecular descriptors of 1389 odor molecules. For 20 of these odors, we examined associations with perceived pleasantness, intensity, odor quality and detection threshold, obtained from a dataset of 2000 naïve participants. Our results show significant differences in perceptual ratings, and we were able to replicate previous findings on the association between perceptual ratings and the first dimensions of the physicochemical odor space. However, the present analyses also revealed striking interindividual variations in perceived pleasantness and intensity. Additionally, interactions between pleasantness, intensity, and olfactory and trigeminal qualitative dimensions were found. To conclude, our results support previous findings on the relation between structure and perception on the group level in our sample of non-expert raters. In the challenging task to relate olfactory stimulus and percept, the physicochemical odor space can serve as a reliable and helpful tool to structure the high-dimensional space of olfactory stimuli. Nevertheless, human olfactory perception in the individual is not an analytic process of molecule detection alone, but is part of a holistic integration of multisensory inputs, context and experience.
Crosstalk between 17β-Estradiol and TGF-β Signaling Modulates Glioblastoma Progression
Authors: Hernández-Vega Ana M. , Camacho-Arroyo Ignacio
Published: April 2021

Epithelial–mesenchymal transition (EMT) is an essential mechanism contributing to glioblastoma multiforme (GBM) progression, the most common and malignant brain tumor. EMT is induced by signaling pathways that crosstalk and regulate an intricate regulatory network of transcription factors. It has been shown that downstream components of 17β-estradiol (E2) and transforming growth factor β (TGF-β) signaling pathways crosstalk in estrogen-sensitive tumors. However, little is known about the interaction between the E2 and TGF-β signaling components in brain tumors. We have investigated the relationship between E2 and TGF-β signaling pathways and their effects on EMT induction in human GBM-derived cells. Here, we showed that E2 and TGF-β negatively regulated the expression of estrogen receptor α (ER-α) and Smad2/3. TGF-β induced Smad2 phosphorylation and its subsequent nuclear translocation, which E2 inhibited. Both TGF-β and E2 induced cellular processes related to EMT, such as morphological changes, actin filament reorganization, and mesenchymal markers (N-cadherin and vimentin) expression. Interestingly, we found that the co-treatment of E2 and TGF-β blocked EMT activation. Our results suggest that E2 and TGF-β signaling pathways interact through ER-α and Smad2/3 mediators in cells derived from human GBM and inhibit EMT activation induced by both factors alone.
Attention and Default Mode Network Assessments of Meditation Experience during Active Cognition and Rest
Authors: Devaney Kathryn , Levin Emily , Tripathi Vaibhav , Higgins James , Lazar Sara , Somers David
Published: April 2021

Meditation experience has previously been shown to improve performance on behavioral assessments of attention, but the neural bases of this improvement are unknown. Two prominent, strongly competing networks exist in the human cortex: a dorsal attention network, that is activated during focused attention, and a default mode network, that is suppressed during attentionally demanding tasks. Prior studies suggest that strong anti-correlations between these networks indicate good brain health. In addition, a third network, a ventral attention network, serves as a “circuit-breaker” that transiently disrupts and redirects focused attention to permit salient stimuli to capture attention. Here, we used functional magnetic resonance imaging to contrast cortical network activation between experienced focused attention Vipassana meditators and matched controls. Participants performed two attention tasks during scanning: a sustained attention task and an attention-capture task. Meditators demonstrated increased magnitude of differential activation in the dorsal attention vs. default mode network in a sustained attention task, relative to controls. In contrast, there were no evident attention network differences between meditators and controls in an attentional reorienting paradigm. A resting state functional connectivity analysis revealed a greater magnitude of anticorrelation between dorsal attention and default mode networks in the meditators as compared to both our local control group and a n = 168 Human Connectome Project dataset. These results demonstrate, with both task- and rest-based fMRI data, increased stability in sustained attention processes without an associated attentional capture cost in meditators. Task and resting-state results, which revealed stronger anticorrelations between dorsal attention and default mode networks in experienced mediators than in controls, are consistent with a brain health benefit of long-term meditation practice.
Tablet Use Affects Preschoolers’ Executive Function: fNIRS Evidence from the Dimensional Change Card Sort Task
Authors: Li Hui , Wu Dandan , Yang Jinfeng , Luo Jiutong , Xie Sha , Chang Chunqi
Published: April 2021

This study aims to examine the impact of heavy use of tablets on preschoolers’ executive function during the Dimensional Change Card Sort (DCCS) task using the functional near-infrared spectroscopy (fNIRS). Altogether, 38 Chinese preschoolers (Mage = 5.0 years, SD = 0.69 years, 17 girls) completed the tasks before the COVID-19 lockdown. Eight children never used tablets, while 16 children were diagnosed as the ‘heavy-user’. The results indicated that: (1) the ‘non-user’ outperformed the ‘heavy-user’ with a significantly higher correct rate in the DCCS task; (2) the two groups differed significantly in the activation of the prefrontal cortex (BA 9): the ‘non-user’ pattern is normal and healthy, whereas the ‘heavy-user’ pattern is not normal and needs further exploration.
A Virtual Kitchen Protocol to Measure Everyday Memory Functioning for Meal Preparation
Authors: Barnett Michael D. , Childers Lucas G. , Parsons Thomas D.
Published: April 2021

In this study, we developed the Virtual Kitchen Protocol (VKP), a virtual reality-based measure of everyday memory functioning for meal preparation tasks. We investigated the construct validity of the VKP by comparing the performance of young adults (n = 41) and older adults without (n = 52) and with (n = 7) a neurocognitive diagnosis, as well as by examining correlations with standardized measures of verbal and visual memory. The results show that young adults had higher recall than older adults and that the VKP was sensitive to neurocognitive impairment among older adults. The VKP demonstrated moderate to high correlations with other memory tests. These results support the construct validity of the VKP and suggest that it holds promise as a virtual reality-based measure of memory for meal preparation tasks.
Many Voices in a Choir: Tumor-Induced Neurogenesis and Neuronal Driven Alternative Splicing Sound Like Suspects in Tumor Growth and Dissemination
Authors: Dlamini Zodwa , Mathabe Kgomotso , Padayachy Llewellyn , Marima Rahaba , Evangelou George , Syrigos Konstantinos N. , Bianchi Arianna , Lolas Georgios , Hull Rodney
Published: April 2021

During development, as tissues expand and grow, they require circulatory, lymphatic, and nervous system expansion for proper function and support. Similarly, as tumors arise and develop, they also require the expansion of these systems to support them. While the contribution of blood and lymphatic systems to the development and progression of cancer is well known and is targeted with anticancer drugs, the contribution of the nervous system is less well studied and understood. Recent studies have shown that the interaction between neurons and a tumor are bilateral and promote metastasis on one hand, and the formation of new nerve structures (neoneurogenesis) on the other. Substances such as neurotransmitters and neurotrophins being the main actors in such interplay, it seems reasonable to expect that alternative splicing and the different populations of protein isoforms can affect tumor-derived neurogenesis. Here, we report the different, documented ways in which neurons contribute to the development and progression of cancer and investigate what is currently known regarding cancer-neuronal interaction in several specific cancer types. Furthermore, we discuss the incidence of alternative splicing that have been identified as playing a role in tumor-induced neoneurogenesis, cancer development and progression. Several examples of changes in alternative splicing that give rise to different isoforms in nerve tissue that support cancer progression, growth and development have also been investigated. Finally, we discuss the potential of our knowledge in alternative splicing to improve tumor diagnosis and treatment.
Discordance of KRAS Mutational Status between Primary Tumors and Liver Metastases in Colorectal Cancer: Impact on Long-Term Survival Following Radical Resection
Authors: Ardito Francesco , Razionale Francesco , Salvatore Lisa , Cenci Tonia , Vellone Maria , Basso Michele , Panettieri Elena , Calegari Maria Alessandra , Tortora Giampaolo , Martini Maurizio , Giuliante Felice
Published: April 2021

If KRAS mutation status of primary colorectal tumor is representative of corresponding colorectal liver metastases (CRLM) mutational pattern, is controversial. Several studies have reported different rates of KRAS discordance, ranging from 4 to 32%. Aim of this study is to assess the incidence of discordance and its impact on overall survival (OS) in a homogenous group of patients. KRAS mutation status was evaluated in 107 patients resected for both primary colorectal tumor and corresponding CRLM at the same institution, between 2007 and 2018. Discordance rate was 15.9%. Its incidence varied according to the time interval between the two mutation analyses (p = 0.025; Pearson correlation = 0.2) and it was significantly higher during the first 6 months from the time of primary tumor evaluation. On multivariable analysis, type of discordance (wild-type in primary tumor, mutation in CRLM) was the strongest predictor of poor OS (p < 0.001). At multivariable logistic regression analysis, the number of CRLM >3 was an independent risk factor for the risk of KRAS discordance associated with the worst prognosis (OR = 4.600; p = 0.047). Results of our study suggested that, in the era of precision medicine, possibility of KRAS discordance should be taken into account within multidisciplinary management of patients with metastatic colorectal cancer.
Local Recurrence in Young Women with Breast Cancer: Breast Conserving Therapy vs. Mastectomy Alone
Authors: Nguyen Dang Van , Kim Sang-Won , Oh Young-Taek , Noh O Kyu , Jung Yongsik , Chun Mison , Yoon Dae Sung
Published: April 2021

We compared the cumulative incidence of local recurrence in young patients (≤40 years) with breast cancer between breast conserving therapy (BCT) and mastectomy alone. Among 428 women with early-stage breast cancer who were treated between 2001 and 2012, 311 underwent BCT and 117 underwent mastectomy alone. Adjuvant systemic treatments were administered to 409 patients (95.6%). We compared the cumulative incidence of LR and survival rates between two groups. During a median follow-up period of 91 months, the 10-year cumulative incidence of LR was 9.3% (median interval of 36.5 months from surgery). Patients treated with BCT tended to have a higher risk for local recurrence (11.1% for BCT vs. 4.1% for mastectomy alone, p = 0.078). All patients with isolated LR after BCT (n = 23) underwent salvage mastectomy followed by systemic treatments. The 5-year distant metastasis-free survival and overall survival of patients with isolated LR after BCT were 44.2% and 82.2%, respectively. The BCT group exhibited an approximately 2.5-fold higher risk of LR than mastectomy alone group. Patients with isolated LR after BCT showed poor prognosis despite undergoing aggressive salvage treatments. The development of novel treatments should be investigated to reduce LR for improving prognosis and preserving cosmetic outcomes in young women.
Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis
Authors: Baltanás Fernando C. , Mucientes-Valdivieso Cynthia , Lorenzo-Martín L. Francisco , Fernández-Parejo Natalia , García-Navas Rósula , Segrelles Carmen , Calzada Nuria , Fuentes-Mateos Rocío , Paramio Jesús M. , Bustelo Xosé R. , Santos Eugenio
Published: April 2021

Prior reports showed the critical requirement of Sos1 for epithelial carcinogenesis, but the specific functionalities of the homologous Sos1 and Sos2 GEFs in skin homeostasis and tumorigenesis remain unclear. Here, we characterize specific mechanistic roles played by Sos1 or Sos2 in primary mouse keratinocytes (a prevalent skin cell lineage) under different experimental conditions. Functional analyses of actively growing primary keratinocytes of relevant genotypes—WT, Sos1-KO, Sos2-KO, and Sos1/2-DKO—revealed a prevalent role of Sos1 regarding transcriptional regulation and control of RAS activation and mechanistic overlapping of Sos1 and Sos2 regarding cell proliferation and survival, with dominant contribution of Sos1 to the RAS-ERK axis and Sos2 to the RAS-PI3K/AKT axis. Sos1/2-DKO keratinocytes could not grow under 3D culture conditions, but single Sos1-KO and Sos2-KO keratinocytes were able to form pseudoepidermis structures that showed disorganized layer structure, reduced proliferation, and increased apoptosis in comparison with WT 3D cultures. Remarkably, analysis of the skin of both newborn and adult Sos2-KO mice uncovered a significant reduction of the population of stem cells located in hair follicles. These data confirm that Sos1 and Sos2 play specific, cell-autonomous functions in primary keratinocytes and reveal a novel, essential role of Sos2 in control of epidermal stem cell homeostasis.
Germline Genetics of Prostate Cancer: Prevalence of Risk Variants and Clinical Implications for Disease Management
Authors: Doan David K. , Schmidt Keith T. , Chau Cindy H. , Figg William D.
Published: April 2021

Prostate cancer has entered into the era of precision medicine with the recent approvals of targeted therapeutics (olaparib and rucaparib). The presence of germline mutations has important hereditary cancer implications for patients with prostate cancer, and germline testing is increasingly important in cancer screening, risk assessment, and the overall treatment and management of the disease. In this review, we discuss germline variants associated with inherited predisposition, prostate cancer risk and outcomes. We review recommendations for germline testing, available testing platforms, genetic counseling as well as discuss the therapeutic implications of germline variants relevant to prostate cancer treatments. Understanding the role of germline (heritable) mutations that affect prostate cancer biology and risk as well as the subsequent effect of these alterations on potential therapies is critical as the treatment paradigm shifts towards precision medicine. Furthermore, enhancing patient education tactics and healthcare system infrastructure is essential for the utilization of relevant predictive biomarkers and the improvement of clinical outcomes of patients with prostate cancer or at high risk of developing the disease.
Validation of CIP2A as a Biomarker of Subsequent Disease Progression and Treatment Failure in Chronic Myeloid Leukaemia
Authors: Clark Richard E. , Basabrain Ammar A. , Austin Gemma M. , Holcroft Alison K. , Loaiza Sandra , Apperley Jane F. , Law Christopher , Scott Laura , Parry Alexandra D. , Bonnett Laura , Lucas Claire M.
Published: April 2021

Background: It would be clinically useful to prospectively identify the risk of disease progression in chronic myeloid leukaemia (CML). Overexpression of cancerous inhibitor of protein phosphatase 2A (PP2A) (CIP2A) protein is an adverse prognostic indicator in many cancers. Methods: We examined CIP2A protein levels in diagnostic samples from the SPIRIT2 trial in 172 unselected patients, of whom 90 received imatinib and 82 dasatinib as first-line treatment. Results: High CIP2A levels correlated with inferior progression-free survival (p = 0.04) and with worse freedom from progression (p = 0.03), and these effects were confined to dasatinib recipients. High CIP2A levels were associated with a six-fold higher five-year treatment failure rate than low CIP2A levels (41% vs. 7.5%; p = 0.0002), in both imatinib (45% vs. 11%; p = 0.02) and dasatinib recipients (36% vs. 4%; p = 0.007). Imatinib recipients with low CIP2A levels had a greater risk of treatment failure (p = 0.0008). CIP2A levels were independent of Sokal, Hasford, EUTOS (EUropean Treatment and Outcome Study), or EUTOS long-term survival scores (ELTS) or the presence of major route cytogenetic abnormalities. No association was seen between CIP2A levels and time to molecular response or the levels of the CIP2A-related proteins PP2A, SET, SET binding protein 1 (SETBP1), or AKT. Conclusions: These data confirm that high diagnostic CIP2A levels correlate with subsequent disease progression and treatment failure. CIP2A is a simple diagnostic biomarker that may be useful in planning treatment strategies.
The Impact of DNMT3A Status on NPM1 MRD Predictive Value and Survival in Elderly AML Patients Treated Intensively
Authors: Heiblig Maël , Duployez Nicolas , Marceau Alice , Lebon Delphine , Goursaud Laure , Plantier Isabelle , Stalnikiewich Laure , Cambier Nathalie , Balsat Marie , Fossard Gaëlle , Labussière-Wallet Hélène , Barraco Fiorenza , Ducastelle-Lepretre Sophie , Sujobert Pierre , Huet Sarah , Hayette Sandrine , Ghesquières Hervé , Thomas Xavier , Preudhomme Claude
Published: April 2021

Minimal residual disease (MRD) is now a powerful surrogate marker to assess the response to chemotherapy in acute myeloid leukemia (AML). DNMT3A mutation has been associated with adverse outcomes. In this study, we aimed to investigate the impact of DNMT3A status on NPM1 MRD predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1-mutated AML in two French institutions were analyzed retrospectively. DNMT3A status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. Only 20.4% of FLT3-ITD patients reached ≥ 4log MRD1 reduction compared to 47.5% in FLT3wt cases. A 4log reduction of NPM1 MRD was associated with a better outcome, even in FLT3-ITD mutated patients, independent of the allelic ratio. DNMT3A negative patients who reached a 4log reduction had a superior outcome to those who did not (HR = 0.23; p < 0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and LFS in DNMT3Amut patients. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3A also identifies a subgroup of patients at high risk of relapse.
Cytostatic Drug 6-Mercaptopurine Degradation on Pilot Scale Reactors by Advanced Oxidation Processes: UV-C/H2O2 and UV-C/TiO2/H2O2 Kinetics
Authors: González-Burciaga Luis A. , García-Prieto Juan C. , García-Roig Manuel , Lares-Asef Ismael , Núñez-Núñez Cynthia M. , Proal-Nájera José B.
Published: April 2021

6-Mercaptopurine (6-MP) is a commonly used cytostatic agent, which represents a particular hazard for the environment because of its low biodegradability. In order to degrade 6-MP, four processes were applied: Photolysis (UV-C), photocatalysis (UV-C/TiO2), and their combination with H2O2, by adding 3 mM H2O2/L (UV-C/H2O2 and UV-C/TiO2/H2O2 processes). Each process was performed with variable initial pH (3.5, 7.0, and 9.5). Pilot scale reactors were used, using UV-C lamps as radiation source. Kinetic calculations for the first 20 min of reaction show that H2O2 addition is of great importance: in UV-C experiments, highest k was reached under pH 3.5, k = 0.0094 min−1, while under UV-C/H2O2, k = 0.1071 min−1 was reached under the same initial pH; similar behavior was observed for photocatalysis, as k values of 0.0335 and 0.1387 min−1 were calculated for UV-C/TiO2 and UV-C/TiO2/H2O2 processes, respectively, also under acidic conditions. Degradation percentages here reported for UV-C/H2O2 and UV-C/TiO2/H2O2 processes are above 90% for all tested pH values. Ecotoxicity analysis of samples taken at 60 min in the photolysis and photocatalysis processes, suggests that contaminant degradation by-products present higher toxicity than the original compound.
A Study on the Effect of Different Ball Milling Methods on the NH3-SCR Activity of Aluminum-Laden Bayan Obo Tailings
Authors: Bai Xinrui , Lin Jiawei , Chen Zedong , Hou Limin , Wu Wenfei
Published: April 2021

Rich in Fe, Ce, Mn, Si and other elements which have good catalytic activity, Bayan Obo rare-earth tailings are naturally advantaged as the carrier of denitrification catalysts. In this paper, pseudo boehmite (γ-Al2O3) was mixed with Bayan Obo tailings using different ball milling methods for modification to prepare NH3-SCR catalysts. The effect of different mixing methods on the SCR denitrification activity at a low temperature was investigated and the prepared catalysts were characterized by X-ray diffraction (XRD), scanning electron microscope (SEM), temperature programed desorption (NH3-TPD), temperature programed reduction (H2-TPR) and other means. The conversion rate of NOx at 250–350 °C was above 80% and the highest conversion rate of NOx of 90% was achieved at 300 °C. SEM and XRD revealed that the tailings modified by pseudo boehmite (γ-Al2O3) using the ordinary ball milling method have loose structure and good dispersion of active substances, and specific surface area (BET) analysis shows that the tailings have the maximum specific surface area and pore volume. However, over grinding and secondary spheronization were observed in the tailings modified by pseudo boehmite (γ-Al2O3) using high energy ball milling method, leading to the decrease of specific surface area and pore volume, poor dispersion of active substances, and ultimately low denitrification rate.
Hepatic Wnt1 Inducible Signaling Pathway Protein 1 (WISP-1/CCN4) Associates with Markers of Liver Fibrosis in Severe Obesity
Authors: Pivovarova-Ramich Olga , Loske Jennifer , Hornemann Silke , Markova Mariya , Seebeck Nicole , Rosenthal Anke , Klauschen Frederick , Castro José , Buschow René , Grune Tilman , Lange Volker , Rudovich Natalia , Ouwens D.
Published: April 2021

Liver fibrosis is a critical complication of obesity-induced fatty liver disease. Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4), a novel adipokine associated with visceral obesity and insulin resistance, also contributes to lung and kidney fibrosis. The aim of the present study was to investigate the role of CCN4 in liver fibrosis in severe obesity. For this, human liver biopsies were collected from 35 severely obese humans (BMI 42.5 ± 0.7 kg/m2, age 46.7 ± 1.8 y, 25.7% males) during bariatric surgery and examined for the expression of CCN4, fibrosis, and inflammation markers. Hepatic stellate LX-2 cells were treated with human recombinant CCN4 alone or in combination with LPS or transforming growth factor beta (TGF-β) and examined for fibrosis and inflammation markers. CCN4 mRNA expression in the liver positively correlated with BMI and expression of fibrosis markers COL1A1, COL3A1, COL6A1, αSMA, TGFB1, extracellular matrix turnover enzymes TIMP1 and MMP9, and the inflammatory marker ITGAX/CD11c. In LX-2 cells, the exposure to recombinant CCN4 caused dose-dependent induction of MMP9 and MCP1. CCN4 potentiated the TGF-β-mediated induction of COL3A1, TIMP1, and MCP1 but showed no interaction with LPS treatment. Our results suggest a potential contribution of CCN4 to the early pathogenesis of obesity-associated liver fibrosis.
1,3,4-Thiadiazoles Effectively Inhibit Proliferation of Toxoplasma gondii
Authors: Węglińska Lidia , Bekier Adrian , Dzitko Katarzyna , Pacholczyk-Sienicka Barbara , Albrecht Łukasz , Plech Tomasz , Paneth Piotr , Paneth Agata
Published: April 2021

Congenital and acquired toxoplasmosis caused by the food- and water-born parasite Toxoplasma gondii (T. gondii) is one of the most prevalent zoonotic infection of global importance. T. gondii is an obligate intracellular parasite with limited capacity for extracellular survival, thus a successful, efficient and robust host cell invasion process is crucial for its survival, proliferation and transmission. In this study, we screened a series of novel 1,3,4-thiadiazole-2-halophenylamines functionalized at the C5 position with the imidazole ring (1b–12b) for their effects on T. gondii host cell invasion and proliferation. To achieve this goal, these compounds were initially subjected to in vitro assays to assess their cytotoxicity on human fibroblasts and then antiparasitic efficacy. Results showed that all of them compare favorably to control drugs sulfadiazine and trimethoprim in terms of T. gondii growth inhibition (IC50) and selectivity toward the parasite, expressed as selectivity index (SI). Subsequently, the most potent of them with meta-fluoro 2b, meta-chloro 5b, meta-bromo 8b, meta-iodo 11b and para-iodo 12b substitution were tested for their efficacy in inhibition of tachyzoites invasion and subsequent proliferation by direct action on established intracellular infection. All the compounds significantly inhibited the parasite invasion and intracellular proliferation via direct action on both tachyzoites and parasitophorous vacuoles formation. The most effective was para-iodo derivative 12b that caused reduction in the percentage of infected host cells by 44% and number of tachyzoites per vacuole by 93% compared to non-treated host cells. Collectively, these studies indicate that 1,3,4-thiadiazoles 1b–12b, especially 12b with IC50 of 4.70 µg/mL and SI of 20.89, could be considered as early hit compounds for future design and synthesis of anti-Toxoplasma agents that effectively and selectively block the invasion and subsequent proliferation of T. gondii into host cells.
Manifestations of Age on Autophagy, Mitophagy and Lysosomes in Skeletal Muscle
Authors: Triolo Matthew , Hood David A.
Published: April 2021

Sarcopenia is the loss of both muscle mass and function with age. Although the molecular underpinnings of sarcopenia are not fully understood, numerous pathways are implicated, including autophagy, in which defective cargo is selectively identified and degraded at the lysosome. The specific tagging and degradation of mitochondria is termed mitophagy, a process important for the maintenance of an organelle pool that functions efficiently in energy production and with relatively low reactive oxygen species production. Emerging data, yet insufficient, have implicated various steps in this pathway as potential contributors to the aging muscle atrophy phenotype. Included in this is the lysosome, the end-stage organelle possessing a host of proteolytic and degradative enzymes, and a function devoted to the hydrolysis and breakdown of defective molecular complexes and organelles. This review provides a summary of our current understanding of how the autophagy-lysosome system is regulated in aging muscle, highlighting specific areas where knowledge gaps exist. Characterization of the autophagy pathway with a particular focus on the lysosome will undoubtedly pave the way for the development of novel therapeutic strategies to combat age-related muscle loss.