bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical Activity for Executive Function and Activities of Daily Living in AD Patients: A Systematic Review and Meta-Analysis
Authors: Zhu Lin , Li Long , Wang Lin , Jin Xiaohu , Zhang Huajiang
Published: December 2020

Objectives: The present study aimed to systematically analyze the effects of physical activity on executive function, working memory, cognitive flexibility, and activities of daily living (ADLs) in Alzheimer's disease (AD) patients and to provide a scientific evidence-based exercise prescription.

Methods: Both Chinese and English databases (PubMed, Web of Science, the Cochrane Library, EMBASE, VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure, and Wanfang) were used as sources of data to search for randomized controlled trials (RCTs) published between January 1980 and December 2019 relating to the effects of physical activity on executive function, working memory, cognitive flexibility, and ADL issues in AD patients. Sixteen eligible RCTs were ultimately included in the meta-analysis.

Results: Physical activity had significant benefits on executive function [standard mean difference (SMD) = 0.42, 95% confidence interval (CI) 0.22–0.62, p < 0.05], working memory (SMD = 0.28, 95% CI 0.11–0.45, p < 0.05), cognitive flexibility (SMD = 0.23, 95% CI −0.02 to 0.47, p < 0.01), and ADLs (SMD = 0.68, 95% CI 0.19–1.16, p < 0.05) among AD patients. Subgroup analysis indicated that, for executive function issues, more than 60 min per session for 16 weeks of moderate-to-high-intensity dual-task exercises or multimodal exercise had a greater effect on AD patients. For working memory and cognitive flexibility issues, 60–90 min of moderate-intensity dual-task exercises 1–4 times/week was more effective. For ADL issues, 30–90 min of multimodal exercise at 60–79% of maximal heart rate (MHR) 3–4 times/week had a greater effect on AD patients.

Conclusions: Physical activity was found to lead to significant improvements in executive function, working memory, cognitive flexibility, and ADLs in AD patients and can be used as an effective method for clinical exercise intervention in these patients. However, more objective, scientific, and effective RCTs are needed to confirm this conclusion.
Psychological Mediators of the Association Between Childhood Emotional Abuse and Depression: A Systematic Review
Authors: Li Elizabeth Tianyu , Luyten Patrick , Midgley Nick
Published: December 2020

Background: A number of existing meta-analyses and narrative reviews have already addressed the relation between childhood adversity and depression, yet none of them has examined the specific link between emotional abuse and depression highlighted by previous research. It is no longer appropriate to regard childhood maltreatment as a unitary concept when considering its effects on subsequent depression; instead, subtypes of childhood maltreatment need to be scrutinized separately. This review addresses this significant gap by critically evaluating empirical studies examining psychological mediators of the relationship between childhood emotional abuse and subsequent depression.

Methods: A systematic search of nine electronic databases was conducted to identify eligible studies published in English between January 1980 and January 2020. Given the heterogeneous outcomes of eligible studies and the inconsistent reporting of indirect effects, a narrative synthesis, rather than a quantitative meta-analysis, was conducted. An appraisal of methodological quality was also included.

Results: We identified 34 papers, comprising 18,529 adults and 3,434 adolescents, including 888 clinical participants. Our synthesis suggests that studies on mediators in the emotional abuse–depression link have focused on five clusters of intervening variables: early maladaptive schemas, cognitive-personality variables, emotion dysregulation, interpersonal styles, and stressful negative events. Only 11 studies identified the unique contribution of emotional abuse to depression by controlling for other forms of childhood maltreatment.

Conclusions: Our findings support several routes with relative consistency (e.g., early maladaptive schemas, hopelessness, negative cognitive styles, brooding rumination, overall emotion dysregulation). Because psychological mediators function as a complex interrelated system, controlling for the interrelation between them is important. The evidence for the purported mediating role of the factors identified in this review should be considered with caution given the relative dearth of large-scale, adequately powered longitudinal studies. This review proposes a comprehensive multilevel theoretical framework as a basis for future research.
Computational Psychiatry Research Map (CPSYMAP): A New Database for Visualizing Research Papers
Authors: Kato Ayaka , Kunisato Yoshihiko , Katahira Kentaro , Okimura Tsukasa , Yamashita Yuichi
Published: December 2020

The field of computational psychiatry is growing in prominence along with recent advances in computational neuroscience, machine learning, and the cumulative scientific understanding of psychiatric disorders. Computational approaches based on cutting-edge technologies and high-dimensional data are expected to provide an understanding of psychiatric disorders with integrating the notions of psychology and neuroscience, and to contribute to clinical practices. However, the multidisciplinary nature of this field seems to limit the development of computational psychiatry studies. Computational psychiatry combines knowledge from neuroscience, psychiatry, and computation; thus, there is an emerging need for a platform to integrate and coordinate these perspectives. In this study, we developed a new database for visualizing research papers as a two-dimensional “map” called the Computational Psychiatry Research Map (CPSYMAP). This map shows the distribution of papers along neuroscientific, psychiatric, and computational dimensions to enable anyone to find niche research and deepen their understanding ofthe field.
Altered Reward Processing System in Internet Gaming Disorder
Authors: Raiha Syeda , Yang Guochun , Wang Lingxiao , Dai Weine , Wu Haiyan , Meng Guangteng , Zhong Bowei , Liu Xun
Published: December 2020

Converging evidence indicates that addiction involves impairment in reward processing systems. However, the patterns of dysfunction in different stages of reward processing in internet gaming addiction remain unclear. In previous studies, individuals with internet gaming disorder were found to be impulsive and risk taking, but there is no general consensus on the relation between impulsivity and risk-taking tendencies in these individuals. The current study explored behavioral and electrophysiological responses associated with different stages of reward processing among individuals with internet gaming disorders (IGDs) with a delayed discounting task and simple gambling tasks. Compared to the healthy control (HC) group, the IGD group discounted delays more steeply and made more risky choices, irrespective of the outcome. As for the event-related potential (ERP) results, during the reward anticipation stage, IGDs had the same stimulus-preceding negativity (SPN) for both large and small choices, whereas HCs exhibited a higher SPN in large vs. small choices. During the outcome evaluation stage, IGDs exhibited a blunted feedback-related negativity for losses vs. gains. The results indicate impairment across different stages of reward processing among IGDs. Moreover, we found negative correlation between impulsivity indexed by BIS-11 and reward sensitivity indexed by SPN amplitude during anticipation stage only, indicating different neural mechanisms at different stages of reward processing. The current study helps to elucidate the behavioral and neural mechanisms of reward processing in internet gaming addiction.
Aggressive and Disruptive Behavior Among Psychiatric Patients With Major Depressive Disorder, Schizophrenia, or Alcohol Dependency and the Effect of Depression and Self-Esteem on Aggression
Authors: Fritz Michael , Shenar Riad , Cardenas-Morales Lizbeth , Jäger Markus , Streb Judith , Dudeck Manuela , Franke Irina
Published: December 2020

Aggressive and disruptive behavior in inpatient settings poses a serious challenge for clinical staff and fellow patients. Hence, the aim of this study was to identify different aspects of aggressive and disruptive behavior in the context of an aberrant self-esteem or clinically manifested depression as potentially influencing factors. We collected self-reported data from 282 psychiatric patients [ICD-10 diagnoses for alcohol dependency, schizophrenia or major depressive disorder (MDD)] and compared it to healthy norm groups. As expected, all three patient groups scored higher in the aggression questionnaires than the norm group. Specifically, patients with MDD exhibited significantly higher externally directed aggression, reactive aggression, and irritability compared to controls. Patients with schizophrenia displayed higher irritability, while all three groups showed distinctly higher self-aggressiveness than healthy persons. We found a lower inhibition of aggression in alcohol dependent subjects compared to both the patient groups and the norm sample. Yet, the higher the self-esteem among alcohol dependent and MDD patients, the lower were their aggression scores; similarly, a lower self-esteem among patients diagnosed with schizophrenia resulted in heighten self-aggressiveness. Thus, our data suggests that therapeutic interventions for strengthening self-esteem in patients with a diagnosis of MDD, alcohol dependency or schizophrenia could reduce certain aspects of aggressive behavior. Therefore, it seems conceivable that strengthening self-esteem in psychiatric patients could contribute to the prevention of violence in clinical practice.
Efficacy and Safety of Botulinum Toxin vs. Placebo in Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Qian Huan , Shao Fangjie , Lenahan Cameron , Shao Anwen , Li Yingjun
Published: December 2020

Background: Major depressive disorder (MDD) is a serious mental disorder that represents a substantial public health problem. Several trials have been undertaken to investigate the role of botulinum toxin type A (BTX-A) in the treatment of MDD, but the conclusions were controversial. To examine the efficacy and safety of BTX-A vs. placebo on patients with a clinical diagnosis of MDD, we conducted this systematic review and meta-analysis.

Methods: A systematic search was conducted for all relevant randomized controlled trials (RCTs) in PubMed and Web of Science from inception to June 17, 2020. All published studies that investigated the efficacy and safety of BTX-A injections on patients with a clinical diagnosis of MDD were included. The overall effect size was summarized using a random-effects meta-analysis model. The primary outcomes of the present meta-analysis were the changes in depressive rating scale at week 6 after BTX-A injection compared with placebo. The safety of BTX-A injections also was assessed.

Results: Five RCTs with a total of 417 participants (189 patients in the BTX-A group, 228 patients in placebo group) were eligible in this meta-analysis. The results indicated an overall positive effect of BTX-A injections for reducing the depressive symptoms of patients with MDD (Hedges' g, −0.82; 95% CI, −1.38 to −0.27) with large effect size. Differences are likely explained by the dose of BTX-As and the gender of the participants. Our findings also highlighted that BTX-A injections were generally well-tolerated, with only mild and temporary adverse events reported.

Conclusions: The present meta-analysis provides evidence that BTX-A injections are associated with a statistically significant improvement in depressive symptoms. BTX-A injections are generally safe and may provide a new, alternative option for the treatment of depression.
The Legacy of Sickness Behaviors
Authors: Kelley Keith W. , Kent Stephen
Published: December 2020

Systemic infections of all types lead to a syndrome known as sickness behaviors. Changes in the behavior of febrile humans and animals formed the original basis for this concept. Body temperature is behaviorally regulated in both endotherms and ectotherms. However, infections cause other changes in body functions, including sleep disruption, anorexia, cognitive and memory deficits and disorientation. The brain mediates this entire cluster of symptoms, even though most major infections occur outside the brain. The true importance of sickness behaviors is not the numerous discoveries of symptoms that affect all of us when we get sick. Instead, the legacy of 30 years of research in sickness behaviors is that it established the physiologic importance of reciprocal communication systems between the immune system and the brain. This conceptual advance remains in its infancy.
Ecosystem Impacts and Productive Capacity of a Multi-Species Pastured Livestock System
Authors: Rowntree Jason E. , Stanley Paige L. , Maciel Isabella C. F. , Thorbecke Mariko , Rosenzweig Steven T. , Hancock Dennis W. , Guzman Aidee , Raven Matt R.
Published: December 2020

Regenerative agriculture is a newly codified approach to agriculture that emphasizes reducing reliance on exogeneous inputs, as well as restoring and enhancing ecosystem services such as soil carbon (C) sequestration. These regenerative agriculture principles suggest that modern livestock systems can be redesigned to better capitalize on animals' ecological niche as biological up cyclers and may be necessary to fully regenerate some landscapes. One example is a multispecies pasture rotation (MSPR) system, which symbiotically stacks multiple animal production enterprises (i.e., chickens, cattle, sheep, and pigs) on one landscape. We conducted a whole-farm life cycle assessment (LCA) of an MSPR in the southeastern United States that was originally converted from degraded cropland. We compared the production outputs, greenhouse gas (GHG) emissions, land footprints, and soil health outcomes to a conventional, commodity (COM) production system of each respective species. Our 20-year MSPR chronosequence of soil C and other soil health indicators shows dramatic improvement since establishment, sequestering an average of 2.29 Mg C ha−1 yr−1. Incorporation of soil C sequestration into the LCA reduced net GHG emissions of the MSPR by 80%, resulting in a footprint 66% lower than COM. However, when comparing required land between the two systems for food production, MSPR required 2.5 times more land when compared to COM. Thus, while our model indicates that MSPR can simultaneously produce protein while regenerating land, a considerably greater land area is needed when compared to COM. Our results present an important yet paradoxical conclusion on land and food production balance. Should society prioritize an input-intensive, COM system that produces more food from a smaller yet degrading land base? Or, alternatively, should systems such as MSPR that produce less food on a larger, but more ecologically functional landscape be more highly prioritized? These complexities must be considered in the global debate of agricultural practice and land. Our results indicate MSPRs are a useful model for alternative livestock production systems with improved environmental outcomes, but in this study may present considerable land-use tradeoffs.
A Mapping Study of Veterinary Literature on Perceptions and Attitudes of Female Canine Spaying
Authors: Fausak Erik Davis
Published: December 2020

This is a mapping study conducted to evaluate the characteristics of where content that engages in perspectives or attitudes on female dog spaying is published. Three databases, CAB Direct, PubMed, and Scopus, were systematically searched. There were 84 out of 642 papers identified and screened for relevance on attitudes or perceptions on female canine spaying. These 84 articles were then examined for recurring authors, institutional representation, and publisher information. Additionally, information regarding the population being addressed, veterinarian or client, was noted with most literature addressing the veterinary perspective. Many important articles were published in a wide array of journals from many countries, which suggests the importance of not only browsing journals but also searching for relevant literature in databases like CAB Abstracts and MEDLINE.
Multidrug Resistance in Enterococci Isolated From Wild Pampas Foxes (Lycalopex gymnocercus) and Geoffroy's Cats (Leopardus geoffroyi) in the Brazilian Pampa Biome
Authors: Oliveira de Araujo Gabriella , Huff Rosana , Favarini Marina Ochoa , Mann Michele Bertoni , Peters Felipe Bortolotto , Frazzon Jeverson , Guedes Frazzon Ana Paula
Published: December 2020

Enterococci are ubiquitous microorganisms present in various environments and within the gastrointestinal tracts of humans and other animals. Notably, fecal enterococci are suitable indicators for monitoring antimicrobial resistance dissemination. Resistant bacterial strains recovered from the fecal samples of wild animals can highlight important aspects of environmental disturbances. In this report, we investigated antimicrobial susceptibility as well as resistance and virulence genes in fecal enterococci isolated from wild Pampas foxes (Lycalopex gymnocercus) (n = 5) and Geoffroy's cats (Leopardus geoffroyi) (n = 4) in the Brazilian Pampa biome. Enterococci were isolated from eight out of nine fecal samples and Enterococcus faecalis was identified in both animals. However, E. faecium and E. durans were only detected in Pampas foxes, while E. hirae was only detected in Geoffroy's cats. Antimicrobial susceptibility analysis showed resistance to rifampicin (94%), erythromycin (72.6%), ciprofloxacin/norfloxacin (40%), streptomycin (38%), and tetracycline (26%). The high frequency of multidrug-resistant enterococci (66%) isolated in this study is a matter of concern since these are wild animals with no history of therapeutic antibiotic exposure. The tetM/tetL and msrC/ermB genes were detected in most tetracycline- and erythromycin-resistant enterococci, respectively. The gelE, ace, agg, esp, and clyA virulence genes were also detected in enterococci. In conclusion, our data suggest that habitat fragmentation and anthropogenic activities in the Pampa biome may contribute to high frequencies of multidrug-resistant enterococci in the gut communities of wild Pampas foxes and Geoffroy's cats. To the best of the authors' knowledge, this is the first report of antimicrobial-resistant enterococci in the Pampa biome.
A Hybrid Metaheuristic Algorithm for the Efficient Placement of UAVs
Authors: Fernandez Stephanie Alvarez , Carvalho Marcelo M. , Silva Daniel G.
Published: December 2020

This work addresses the problem of using Unmanned Aerial Vehicles (UAV) to deploy a wireless aerial relay communications infrastructure for stations scattered on the ground. In our problem, every station in the network must be assigned to a single UAV, which is responsible for handling all data transfer on behalf of the stations that are assigned to it. Consequently, the placement of UAVs is key to achieving both network coverage and the maximization of the aggregate link capacities between UAVs and stations, and among the UAVs themselves. Because the complexity of this problem increases significantly with the number of stations to cover, for a given fixed number p of available UAVs, we model it as a single allocation p-hub median optimization problem, and we propose a hybrid metaheuristic algorithm to solve it. A series of numerical experiments illustrate the efficiency of the proposed algorithm against traditional optimization tools, which achieves high-quality results in very short time intervals, thus making it an attractive solution for real-world application scenarios.
Introduction to the Special Issue: Assessing the Environmental Adaptation of Wildlife and Production Animals: Applications of Physiological Indices and Welfare Assessment Tools
Authors: Narayan Edward
Published: December 2020

Wild animals under human care as well as domesticated farm production animals are often exposed to environmental changes (e [...]
Gastrointestinal Strongyles Egg Excretion in Relation to Age, Gender, and Management of Horses in Italy
Authors: Scala Antonio , Tamponi Claudia , Sanna Giuliana , Predieri Giulio , Dessì Giorgia , Sedda Giampietro , Buono Francesco , Cappai Maria Grazia , Veneziano Vincenzo , Varcasia Antonio
Published: December 2020

Current equine helminth control strategies play a key role in strongyle epidemiology and anthelmintic resistance and have led to the recommendation for new treatment plans, which include diagnostic and efficacy surveillance. Assessing the equine strongyle distribution patterns would thus be useful and this study describes the strongyle prevalence in the equine population in Italy through coprological analysis and coproculture. In addition, individual data on each animal were collected in order to identify risk factors associated with strongyle egg shedding. Of the total number of stables investigated, 86.4% were found to have at least one positive animal and a 39.5% prevalence of strongyle egg shedding with a mean eggs per gram (EPG) of 245. A total of 80% of the total recorded EPG was shed from 12.8% of positive horses, thus confirming the need for new targeted intervention strategies. Significant differences in parasite prevalence were found based on season, sex, geographical distribution, management and rearing system, and breed. Significantly lower EPG values were found in horses that had received anthelmintic treatment, and macrocyclic lactones (MLs) were the most effective. Lastly, although large strongyles are more pathogenic, horses in Italy are mainly burdened by small strongyles, which pose an important animal health risk requiring continuous parasitological monitoring.
Quillaja saponaria (Molina) Extracts Inhibits In Vitro Piscirickettsia salmonis Infections
Authors: Cañon-Jones Hernán , Cortes Hernán , Castillo-Ruiz Mario , Schlotterbeck Trinidad , San Martín Ricardo
Published: December 2020

P. salmonis infections are the cause of major bacterial disease in salmonids in Chile, and the reason for using more antibiotics compared to other salmon-producing countries. Vaccination and antibiotics have not been efficient and new approaches are needed. The safety of Quillaja saponaria extracts was measured by cytotoxicity using flow cytometry of cytopathic and death of fish cell cultures and efficacy was assessed using in vitro infection models with pathogenic P. salmonis. Cytotoxicity was low and control of in vitro infections was achieved with all products, with protection of over 90%. Minimum inhibitory concentrations were much higher than those in the infection using cell cultures. These results suggest a dual mechanism of action where less purified extracts with a combination of saponin and non-saponin components simultaneously decrease P. salmonis infection while protecting cell lines, rather than exerting a direct antimicrobial effect. Quillaja saponins controlled in vitro infections with P. salmonis and could be considered good candidates for a new, safe and sustainable method of controlling fish bacterial infectious diseases.
Effects of Ozone Treatment on Personal Protective Equipment Contaminated with SARS-CoV-2
Authors: Clavo Bernardino , Córdoba-Lanús Elizabeth , Rodríguez-Esparragón Francisco , Cazorla-Rivero Sara E. , García-Pérez Omar , Piñero José E. , Villar Jesús , Blanco Angeles , Torres-Ascensión Cristina , Martín-Barrasa José L. , González-Martin Jesús M. , Serrano-Aguilar Pedro , Lorenzo-Morales Jacob
Published: December 2020

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing profound health, economic, and social problems worldwide. Management of personal protective equipment (PPE) and its potential limited availability have created concerns about the increased risks for healthcare professionals at hospitals and nursing homes. Ozone is a powerful oxidant agent. The objectives of this study were to examine the effects of ozone treatment on PPE contaminated with SARS-CoV-2, and to explore whether relative humidity could modify those effects. Methods: PPE contaminated by heat-inactivated SARS-CoV-2 were treated with different ozone concentrations, exposure times, and relative humidity conditions. SARS-CoV-2 gene amplification was assessed by real-time polymerase chain reaction. Results: There was no amplification of SARS-CoV-2 in PPE after the following ozone exposures: 30 s at 10,000 ppm (20 g/m3), 5 min at 4000 ppm, and 10 min at 2000 ppm. At lower ozone concentrations, 4–12 ppm (0.008–0.024 g/m3), the effects were highly dependent on the relative humidity conditions. Conclusions: Oxidative stress induced by ozone exposure eliminated heat-inactivated SARS-CoV-2 in different PPE components under appropriate exposure times, ozone concentrations, and relative humidity conditions. These findings could have implications in decreasing the risk of contamination associated with personal protective equipment management and in increasing its availability. Further research in the original SARS-CoV-2 strain is guaranteed.
Anti-Inflammatory Flavonolignans from Triticum aestivum Linn. Hull
Authors: Han Ah-Reum , Kil Yun-Seo , Hong Min Jeong , Park Jisu , Park Hyeon Hwa , Jin Chang Hyun , Nam Joo-Won , Kim Jin-Baek
Published: December 2020

Wheat (Triticum aestivum Linn.; Poaceae) is a very common and important food grain and ranks second in total cereal crop production. A large amount of wheat hull is produced after threshing that, as the non-food part of wheat, is agro-waste, accounting for 15~20% of the wheat. This study aimed at biologically and phytochemically investigating wheat hull for its valorization as a by-product. In our ongoing search for natural product-derived anti-inflammatory agents, T. aestivum hull was evaluated for its nitric oxide (NO) production inhibition in lipopolysaccharide (LPS)-activated RAW 264.7 cells, and the phytochemical investigation of the ethyl acetate fraction showing inhibitory effect led to the isolation of a flavone (1) and seven flavonolignans (2–8). Compounds 2–8 have not yet been isolated from Triticum species. All compounds were evaluated for their LPS-induced NO production inhibition, and 1, 2, 4, 6, and 8 exhibited inhibitory effects with IC50 values ranging from 24.14 to 58.95 μM. These results suggest the potential of using T. aestivum hull as a source for producing anti-inflammatory components, enhancing its valorization as a by-product.
Tackling Pseudomonas aeruginosa Virulence by Mulinane-Like Diterpenoids from Azorella atacamensis
Authors: Azuama Onyedikachi Cecil , Ortiz Sergio , Quirós-Guerrero Luis , Bouffartigues Emeline , Tortuel Damien , Maillot Olivier , Feuilloley Marc , Cornelis Pierre , Lesouhaitier Olivier , Grougnet Raphaël , Boutefnouchet Sabrina , Wolfender Jean-Luc , Chevalier Sylvie , Tahrioui Ali
Published: December 2020

Pseudomonas aeruginosa is an important multidrug-resistant human pathogen by dint of its high intrinsic, acquired, and adaptive resistance mechanisms, causing great concern for immune-compromised individuals and public health. Additionally, P. aeruginosa resilience lies in the production of a myriad of virulence factors, which are known to be tightly regulated by the quorum sensing (QS) system. Anti-virulence therapy has been adopted as an innovative alternative approach to circumvent bacterial antibiotic resistance. Since plants are known repositories of natural phytochemicals, herein, we explored the anti-virulence potential of Azorella atacamensis, a medicinal plant from the Taira Atacama community (Calama, Chile), against P. aeruginosa. Interestingly, A. atacamensis extract (AaE) conferred a significant protection for human lung cells and Caenorhabditis elegans nematodes towards P. aeruginosa pathogenicity. The production of key virulence factors was decreased upon AaE exposure without affecting P. aeruginosa growth. In addition, AaE was able to decrease QS-molecules production. Furthermore, metabolite profiling of AaE and its derived fractions achieved by combination of a molecular network and in silico annotation allowed the putative identification of fourteen diterpenoids bearing a mulinane-like skeleton. Remarkably, this unique interesting group of diterpenoids seems to be responsible for the interference with virulence factors as well as on the perturbation of membrane homeostasis of P. aeruginosa. Hence, there was a significant increase in membrane stiffness, which appears to be modulated by the cell wall stress response ECFσ SigX, an extracytoplasmic function sigma factor involved in membrane homeostasis as well as P. aeruginosa virulence.
Pembrolizumab as Consolidation Strategy in Patients with Multiple Myeloma: Results of the GEM-Pembresid Clinical Trial
Authors: Puig Noemí , Corchete-Sánchez Luis A. , Pérez-Morán José J. , Dávila Julio , Paíno Teresa , de la Rubia Javier , Oriol Albert , Martín-Sánchez Jesús , de Arriba Felipe , Bladé Joan , Blanchard María-Jesús , González-Calle Verónica , García-Sanz Ramón , Paiva Bruno , Lahuerta Juan-José , San-Miguel Jesús F. , Mateos María-Victoria , Ocio Enrique M.
Published: December 2020

PD1 expression in CD4+ and CD8+ T cells is increased after treatment in multiple myeloma patients with persistent disease. The GEM-Pembresid trial analyzed the efficacy and safety of pembrolizumab as consolidation in patients achieving at least very good partial response but with persistent measurable disease after first- or second-line treatment. Moreover, the characteristics of the immune system were investigated to identify potential biomarkers of response to pembrolizumab. One out of the 17 evaluable patients showed a decrease in the amount of M-protein, although a potential late effect of high-dose melphalan could not be ruled out. Fourteen adverse events were considered related to pembrolizumab, two of which (G3 diarrhea and G2 pneumonitis) prompted treatment discontinuation and all resolving without sequelae. Interestingly, pembrolizumab induced a decrease in the percentage of NK cells at cycle 3, due to the reduction of the circulating and adaptive subsets (0.615 vs. 0.43, p = 0.007; 1.12 vs. 0.86, p = 0.02). In the early progressors, a significantly lower expression of PD1 in CD8+ effector memory T cells (MFI 1327 vs. 926, p = 0.03) was observed. In conclusion, pembrolizumab used as consolidation monotherapy shows an acceptable toxicity profile but did not improve responses in this MM patient population. The trial was registered at clinicaltrials.gov with identifier NCT02636010 and with EUDRACT number 2015-003359-23.
NRF2 Regulation by Noncoding RNAs in Cancers: The Present Knowledge and the Way Forward
Authors: Fabrizio Federico Pio , Sparaneo Angelo , Muscarella Lucia Anna
Published: December 2020

Nuclear factor erythroid 2-related factor 2 (NRF2) is the key transcription factor triggered by oxidative stress that moves in cells of the antioxidant response element (ARE)-antioxidant gene network against reactive oxygen species (ROS) cellular damage. In tumors, the NRF2 pathway represents one of the most intriguing pathways that promotes chemo- and radioresistance of neoplastic cells and its activity is regulated by genetic and epigenetic mechanisms; some of these being poorly investigated in cancer. The noncoding RNA (ncRNA) network is governed by microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) and modulates a variety of cellular mechanisms linked to cancer onset and progression, both at transcriptional and post-transcriptional levels. In recent years, the scientific findings about the effects of ncRNA landscape variations on NRF2 machines are rapidly increasing and need to be continuously updated. Here, we review the latest knowledge about the link between NRF2 and ncRNA networks in cancer, thus focusing on their potential translational significance as key tumor biomarkers.
Untargeted Metabolomic Characterization of Ovarian Tumors
Authors: Liu Xiaona , Liu Gang , Chen Lihua , Liu Fei , Zhang Xiaozhe , Liu Dan , Liu Xinxin , Cheng Xi , Liu Lei
Published: December 2020

Diagnosis of ovarian cancer is difficult due to the lack of clinical symptoms and effective screening algorithms. In this study, we aim to develop models for ovarian cancer diagnosis by detecting metabolites in urine and plasma samples. Ultra-high-performance liquid chromatography and quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) in positive ion mode was used for metabolome quantification in 235 urine samples and 331 plasma samples. Then, Urine and plasma metabolomic profiles were analyzed by univariate and multivariate statistics. Four groups of samples: normal control, benign, borderline and malignant ovarian tumors were enrolled in this study. A total of 1330 features and 1302 features were detected from urine and plasma samples respectively. Based on two urine putative metabolites, five plasma putative metabolites and five urine putative metabolites, three models for distinguishing normal-ovarian tumors, benign-malignant (borderline + malignant) and borderline-malignant ovarian tumors were developed respectively. The AUC (Area Under Curve) values were 0.987, 0876 and 0.943 in discovery set and 0.984, 0.896 and 0.836 in validation set for three models. Specially, the diagnostic model based on 5 plasma putative metabolites had better early-stage diagnosis performance than CA125 alone. The AUC values of the model were 0.847 and 0.988 in discovery and validation set respectively. Our results showed that normal and ovarian tumors have unique metabolic signature in urine and plasma samples, which shed light on the ovarian cancer diagnosis and classification.
Tumour Dissemination in Multiple Myeloma Disease Progression and Relapse: A Potential Therapeutic Target in High-Risk Myeloma
Authors: Zeissig Mara N. , Zannettino Andrew C. W. , Vandyke Kate
Published: December 2020

Multiple myeloma (MM) is a plasma cell (PC) malignancy characterised by the presence of MM PCs at multiple sites throughout the bone marrow. Increased numbers of peripheral blood MM PCs are associated with rapid disease progression, shorter time to relapse and are a feature of advanced disease. In this review, the current understanding of the process of MM PC dissemination and the extrinsic and intrinsic factors potentially driving it are addressed through analysis of patient-derived MM PCs and MM cell lines as well as mouse models of homing and dissemination. In addition, we discuss how patient cytogenetic subgroups that present with highly disseminated disease, such as t(4;14), t(14;16) and t(14;20), suggest that intrinsic properties of MM PC influence their ability to disseminate. Finally, we discuss the possibility of using therapeutic targeting of tumour dissemination to slow disease progression and prevent overt relapse.
Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma
Authors: Maillard Maud , Chevreau Christine , Le Louedec Félicien , Cassou Manon , Delmas Caroline , Gourdain Laure , Blay Jean-Yves , Cupissol Didier , Bompas Emmanuelle , Italiano Antoine , Isambert Nicolas , Delcambre-Lair Corinne , Penel Nicolas , Bertucci François , Guillemet Cécile , Plenecassagnes Julien , Foulon Stéphanie , Chatelut Étienne , Le Cesne Axel , Thomas Fabienne
Published: December 2020

Hepatotoxicity is an important concern for nearly 40% of the patients treated with trabectedin for advanced soft tissue sarcoma (ASTS). The mechanisms underlying these liver damages have not yet been elucidated but they have been suggested to be related to the production of reactive metabolites. The aim of this pharmacogenetic study was to identify genetic variants of pharmacokinetic genes such as CYP450 and ABC drug transporters that could impair the trabectedin metabolism in hepatocytes. Sixty-three patients with ASTS from the TSAR clinical trial (NCT02672527) were genotyped by next-generation sequencing for 11 genes, and genotype–toxicity association analyses were performed with R package SNPassoc. Among the results, ABCC2 c.1249A allele (rs2273697) and ABCG2 intron variant c.-15994T (rs7699188) were associated with an increased risk of severe cytolysis, whereas ABCC2 c.3563A allele had a protective effect, as well as ABCB1 variants rs2032582 and rs1128503 (p-value < 0.05). Furthermore, CYP3A5*1 rs776746 (c.6986A > G) increased the risk of severe overall hepatotoxicity (p = 0.012, odds ratio (OR) = 5.75), suggesting the implication of metabolites in the hepatotoxicity. However, these results did not remain significant after multiple analysis correction. These findings need to be validated on larger cohorts of patients, with mechanistic studies potentially being able to validate the functional consequences of these variants.
Efficacy of the CDK7 Inhibitor on EMT-Associated Resistance to 3rd Generation EGFR-TKIs in Non-Small Cell Lung Cancer Cell Lines
Authors: Ji Wonjun , Choi Yun Jung , Kang Myoung-Hee , Sung Ki Jung , Kim Dong Ha , Jung Sangyong , Choi Chang-Min , Lee Jae Cheol , Rho Jin Kyung
Published: December 2020

Epithelial to mesenchymal transition (EMT) is associated with resistance during EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. Here, we investigated whether EMT is associated with acquired resistance to 3rd generation EGFR-TKIs, and we explored the effects of cyclin-dependent kinase 7 (CDK7) inhibitors on EMT-mediated EGFR-TKIs resistance in non-small cell lung cancer (NSCLC). We established 3rd generation EGFR-TKI resistant cell lines (H1975/WR and H1975/OR) via repeated exposure to WZ4002 and osimertinib. The two resistant cell lines showed phenotypic changes to a spindle-cell shape, had a reduction of epithelial marker proteins, an induction of vimentin expression, and enhanced cellular mobility. The EMT-related resistant cells had higher sensitivity to THZ1 than the parental cells, although THZ1 treatment did not inhibit EGFR activity. This phenomenon was also observed in TGF-β1 induced EMT cell lines. THZ1 treatment induced G2/M cell cycle arrest and apoptosis in all of the cell lines. In addition, THZ1 treatment led to drug-tolerant, EMT-related resistant cells, and these THZ1-tolerant cells partially recovered their sensitivity to 3rd generation EGFR-TKIs. Taken together, EMT was associated with acquired resistance to 3rd generation EGFR-TKIs, and CDK7 inhibitors could potentially be used as a therapeutic strategy to overcome EMT associated EGFR-TKI resistance in NSCLC.
The Role of Mitochondrial Fat Oxidation in Cancer Cell Proliferation and Survival
Authors: De Oliveira Matheus Pinto , Liesa Marc
Published: December 2020

Tumors remodel their metabolism to support anabolic processes needed for replication, as well as to survive nutrient scarcity and oxidative stress imposed by their changing environment. In most healthy tissues, the shift from anabolism to catabolism results in decreased glycolysis and elevated fatty acid oxidation (FAO). This change in the nutrient selected for oxidation is regulated by the glucose-fatty acid cycle, also known as the Randle cycle. Briefly, this cycle consists of a decrease in glycolysis caused by increased mitochondrial FAO in muscle as a result of elevated extracellular fatty acid availability. Closing the cycle, increased glycolysis in response to elevated extracellular glucose availability causes a decrease in mitochondrial FAO. This competition between glycolysis and FAO and its relationship with anabolism and catabolism is conserved in some cancers. Accordingly, decreasing glycolysis to lactate, even by diverting pyruvate to mitochondria, can stop proliferation. Moreover, colorectal cancer cells can effectively shift to FAO to survive both glucose restriction and increases in oxidative stress at the expense of decreasing anabolism. However, a subset of B-cell lymphomas and other cancers require a concurrent increase in mitochondrial FAO and glycolysis to support anabolism and proliferation, thus escaping the competing nature of the Randle cycle. How mitochondria are remodeled in these FAO-dependent lymphomas to preferably oxidize fat, while concurrently sustaining high glycolysis and increasing de novo fatty acid synthesis is unclear. Here, we review studies focusing on the role of mitochondrial FAO and mitochondrial-driven lipid synthesis in cancer proliferation and survival, specifically in colorectal cancer and lymphomas. We conclude that a specific metabolic liability of these FAO-dependent cancers could be a unique remodeling of mitochondrial function that licenses elevated FAO concurrent to high glycolysis and fatty acid synthesis. In addition, blocking this mitochondrial remodeling could selectively stop growth of tumors that shifted to mitochondrial FAO to survive oxidative stress and nutrient scarcity.
Tolerant/Persister Cancer Cells and the Path to Resistance to Targeted Therapy
Authors: Swayden Mirna , Chhouri Houssein , Anouar Youssef , Grumolato Luca
Published: December 2020

The capacity of cancer to adapt to treatment and evolve is a major limitation for targeted therapies. While the role of new acquired mutations is well-established, recent findings indicate that resistance can also arise from subpopulations of tolerant/persister cells that survive in the presence of the treatment. Different processes contribute to the emergence of these cells, including pathway rebound through the release of negative feedback loops, transcriptional rewiring mediated by chromatin remodeling and autocrine/paracrine communication among tumor cells and within the tumor microenvironment. In this review, we discuss the non-genetic mechanisms that eventually result in cancer resistance to targeted therapies, with a special focus on those involving changes in gene expression.
TRPM Channels in Human Diseases
Authors: Jimenez Ivanka , Prado Yolanda , Marchant Felipe , Otero Carolina , Eltit Felipe , Cabello-Verrugio Claudio , Cerda Oscar , Simon Felipe
Published: December 2020

The transient receptor potential melastatin (TRPM) subfamily belongs to the TRP cation channels family. Since the first cloning of TRPM1 in 1989, tremendous progress has been made in identifying novel members of the TRPM subfamily and their functions. The TRPM subfamily is composed of eight members consisting of four six-transmembrane domain subunits, resulting in homomeric or heteromeric channels. From a structural point of view, based on the homology sequence of the coiled-coil in the C-terminus, the eight TRPM members are clustered into four groups: TRPM1/M3, M2/M8, M4/M5 and M6/M7. TRPM subfamily members have been involved in several physiological functions. However, they are also linked to diverse pathophysiological human processes. Alterations in the expression and function of TRPM subfamily ion channels might generate several human diseases including cardiovascular and neurodegenerative alterations, organ dysfunction, cancer and many other channelopathies. These effects position them as remarkable putative targets for novel diagnostic strategies, drug design and therapeutic approaches. Here, we review the current knowledge about the main characteristics of all members of the TRPM family, focusing on their actions in human diseases.
Isotope Effect in the Translation-Invariant Bipolaron Theory of High-Temperature Superconductivity
Authors: Lakhno Victor D.
Published: December 2020

It is shown that the translation-invariant bipolaron theory of superconductivity can explain the dependence of the isotope coefficient in high-temperature superconductors on the critical temperature of a superconducting transition: in the case of strong electron–phonon interaction, the isotope coefficient is low when doping is optimal and high when it is weak. It is demonstrated that in the case of London penetration depth, the absolute value of the isotope coefficient behaves in the opposite way. A conclusion of the great role of non-adiabaticity in the case of weak doping is made. The criteria for d-wave phonon input into the isotope effect is established.
The Effect of Intensity Fluctuations on Sequential X-ray Photon Correlation Spectroscopy at the X-ray Free Electron Laser Facilities
Authors: Cao Yue , Sheyfer Dina , Jiang Zhang , Maddali Siddharth , You Hoydoo , Wang Bi-Xia , Ye Zuo-Guang , Dufresne Eric M. , Zhou Hua , Stephenson G. Brian , Hruszkewycz Stephan O.
Published: December 2020

How materials evolve at thermal equilibrium and under external excitations at small length and time scales is crucial to the understanding and control of material properties. X-ray photon correlation spectroscopy (XPCS) at X-ray free electron laser (XFEL) facilities can in principle capture dynamics of materials that are substantially faster than a millisecond. However, the analysis and interpretation of XPCS data is hindered by the strongly fluctuating X-ray intensity from XFELs. Here we examine the impact of pulse-to-pulse intensity fluctuations on sequential XPCS analysis. We show that the conventional XPCS analysis can still faithfully capture the characteristic time scales, but with substantial decrease in the signal-to-noise ratio of the g2 function and increase in the uncertainties of the extracted time constants. We also demonstrate protocols for improving the signal-to-noise ratio and reducing the uncertainties.
Visual Speech Recognition with Lightweight Psychologically Motivated Gabor Features
Authors: Zhang Xuejie , Xu Yan , Abel Andrew K. , Smith Leslie S. , Watt Roger , Hussain Amir , Gao Chengxiang
Published: December 2020

Extraction of relevant lip features is of continuing interest in the visual speech domain. Using end-to-end feature extraction can produce good results, but at the cost of the results being difficult for humans to comprehend and relate to. We present a new, lightweight feature extraction approach, motivated by human-centric glimpse-based psychological research into facial barcodes, and demonstrate that these simple, easy to extract 3D geometric features (produced using Gabor-based image patches), can successfully be used for speech recognition with LSTM-based machine learning. This approach can successfully extract low dimensionality lip parameters with a minimum of processing. One key difference between using these Gabor-based features and using other features such as traditional DCT, or the current fashion for CNN features is that these are human-centric features that can be visualised and analysed by humans. This means that it is easier to explain and visualise the results. They can also be used for reliable speech recognition, as demonstrated using the Grid corpus. Results for overlapping speakers using our lightweight system gave a recognition rate of over 82%, which compares well to less explainable features in the literature.
Correction: Young Sik, K. Partial Derivative Approach to the Integral Transform for the Function Space in the Banach Algebra. Entropy 2020, 22, 1047
Authors: Sik Kim Young
Published: December 2020

In the original article [...]