bluuebunny/crossref_metadata_2025 huggingface dataset:
Complement Overactivation and Consumption Predicts In-Hospital Mortality in SARS-CoV-2 Infection
Authors: Sinkovits György , Mező Blanka , Réti Marienn , Müller Veronika , Iványi Zsolt , Gál János , Gopcsa László , Reményi Péter , Szathmáry Beáta , Lakatos Botond , Szlávik János , Bobek Ilona , Prohászka Zita Z. , Förhécz Zsolt , Csuka Dorottya , Hurler Lisa , Kajdácsi Erika , Cervenak László , Kiszel Petra , Masszi Tamás , Vályi-Nagy István , Prohászka Zoltán
Published: March 2021

Objectives

Uncontrolled thromboinflammation plays an important role in the pathogenesis of coronavirus disease (COVID-19) caused by SARS-CoV-2 virus. Complement was implicated as key contributor to this process, therefore we hypothesized that markers of the complement profile, indicative for the activation state of the system, may be related to the severity and mortality of COVID-19.

Methods

In this prospective cohort study samples of 102 hospitalized and 26 outpatients with PCR-confirmed COVID-19 were analyzed. Primary outcome was in-hospital, COVID-19 related mortality, and secondary outcome was COVID-19 severity as assessed by the WHO ordinal scale. Complement activity of alternative and classical pathways, its factors, regulators, and activation products were measured by hemolytic titration, turbidimetry, or enzyme-immunoassays. Clinical covariates and markers of inflammation were extracted from hospital records.

Results

Increased complement activation was characteristic for hospitalized COVID-19 patients. Complement activation was significantly associated with markers of inflammation, such as interleukin-6, C-reactive protein, and ferritin. Twenty-five patients died during hospital stay due to COVID-19 related illness. Patients with uncontrolled complement activation leading to consumption of C3 and decrease of complement activity were more likely to die, than those who had complement activation without consumption. Cox models identified anaphylatoxin C3a, and C3 overactivation and consumption (ratio of C3a/C3) as predictors of in-hospital mortality [HR of 3.63 (1.55–8.45, 95% CI) and 6.1 (2.1–17.8), respectively].

Conclusion

Increased complement activation is associated with advanced disease severity of COVID-19. Patients with SARS-CoV-2 infection are more likely to die when the disease is accompanied by overactivation and consumption of C3. These results may provide observational evidence and further support to studies on complement inhibitory drugs for the treatment of COVID-19.
How the Signaling Crosstalk of B Cell Receptor (BCR) and Co-Receptors Regulates Antibody Class Switch Recombination: A New Perspective of Checkpoints of BCR Signaling
Authors: Chen Zhangguo , Wang Jing H.
Published: March 2021

Mature B cells express B cell antigen receptor (BCR), toll-like receptors (TLR) and TNF family receptors including CD40 and B-cell activating factor receptor (BAFFR). These receptors transduce cellular signals to govern the physiological and pathological processes in B cells including B cell development and differentiation, survival, proliferation, and antibody-mediated immune responses as well as autoimmune diseases and B cell lymphomagenesis. Effective antibody-mediated immune responses require class switch recombination (CSR), a somatic DNA recombination event occurring at the immunoglobulin heavy chain (Igh) gene locus. Mature B cells initially express IgM as their BCR, and CSR enables the B cells to switch from expressing IgM to expressing different classes of antibodies including IgG, IgA or IgE that exhibit distinct effector functions. Here, we briefly review recent findings about how the signaling crosstalk of the BCR with TLRs, CD40 and BAFFR regulates CSR, antibody-mediate immune responses, and B cell anergy.
Species-Specific Variations in the Metabolomic Profiles of Acropora hyacinthus and Acropora millepora Mask Acute Temperature Stress Effects in Adult Coral Colonies
Authors: Sweet Michael , Bulling Mark , Varshavi Dorsa , Lloyd Gavin R. , Jankevics Andris , Najdekr Lukáš , Weber Ralf J. M. , Viant Mark R. , Craggs Jamie
Published: March 2021

Coral reefs are suffering unprecedented declines in health state on a global scale. Some have suggested that human assisted evolution or assisted gene flow may now be necessary to effectively restore reefs and pre-condition them for future climate change. An understanding of the key metabolic processes in corals, including under stressed conditions, would greatly facilitate the effective application of such interventions. To date, however, there has been little research on corals at this level, particularly regarding studies of the metabolome of Scleractinian corals. Here, the metabolomic profiles [measured using 1H nuclear magnetic resonance spectroscopy (1H NMR) and ultra-high-performance liquid chromatography-mass spectrometry (LC-MS)] of two dominant reef building corals, Acropora hyacinthus and A. millepora, from two distinct geographical locations (Australia and Singapore) were characterized. We assessed how an acute temperature stress (an increase of 3.25°C ± 0.28 from ambient control levels over 8 days), shifted the corals’ baseline metabolomic profiles. Regardless of the profiling method utilized, metabolomic signatures of coral colonies were significantly distinct between coral species, a result supporting previous work. However, this strong species-specific metabolomic signature appeared to mask any changes resulting from the acute heat stress. On closer examination, we were able to discriminate between control and temperature stressed groups using a partial least squares discriminant analysis classification model (PLSDA). However, in all cases “late” components needed to be selected (i.e., 7 and 8 instead of 1 and 2), suggesting any treatment effect was small, relative to other sources of variation. This highlights the importance of pre-characterizing the coral colony metabolomes, and of factoring that knowledge into any experimental design that seeks to understand the apparently subtle metabolic effects of acute heat stress on adult corals. Further research is therefore needed to decouple these apparent individual and species-level metabolomic responses to climate change in corals.
Glider-Based Estimates of Meso-Zooplankton Biomass Density: A Fisheries Case Study on Antarctic Krill (Euphausia superba) Around the Northern Antarctic Peninsula
Authors: Reiss Christian S. , Cossio Anthony M. , Walsh Jennifer , Cutter George R. , Watters George M.
Published: March 2021

We compare estimates of krill density derived from gliders to those from contemporaneous and previous ship-based surveys. Our comparisons cover several temporal and spatial scales within two strata around the northern Antarctic Peninsula (off Cape Shirreff on the north side of Livingston Island and in the Bransfield Strait). Our objective is to explore the feasibility of using gliders to supplement or replace vessel-based surveys of fishery resources. We deployed two long-duration Slocum G3 gliders manufactured by Teledyne Webb Research (TWR), each equipped with a suite of oceanographic sensors and a three-frequency (38, 67.5, and 125 kHz, each single-beam) Acoustic Zooplankton Fish Profiler. We used the acoustic data collected by these gliders to estimate biomass densities (g⋅m–2) of Antarctic krill (Euphausia superba). The two gliders were, respectively, deployed for 82 and 88 days from mid-December 2018 through mid-March 2019. Off Cape Shirreff, glider-based densities estimated from two repeat small-scale surveys during mid-December and January were 110.6 and 55.7 g⋅m–2, respectively. In Bransfield Strait, the glider-based estimate of biomass density was 106.7 g⋅m–2 during December–January. Contemporaneous ship-based estimates of biomass density, from a multi-ship broad-scale krill survey (Macaulay et al., 2019) restricted to the areas sampled by the gliders, were 84.6 g⋅m–2 off Cape Shirreff and 79.7 g⋅m–2 in Bransfield Strait during January. We compared two alternative krill-delineation algorithms (dB differencing and SHAPES); differences between biomass densities estimated by applying these algorithms were small and ranged between 4 and 7%. Alternative methods of sampling krill length-frequency distributions (LFDs) (nets or predator diets), which are required to convert acoustic energy to biomass density, also influenced the glider-based results. In Bransfield Strait, net-based estimates of biomass density were 6% less than those based on predator diets. Off Cape Shirreff the biomass density of krill estimated from a net-based LFD was 20% greater than that based on predator diets. Development of a variance estimator for glider-based biomass surveys is ongoing, but our results demonstrate that fisheries surveys using acoustically-equipped gliders are feasible, can provide density estimates to inform management, and may be conducted at lower cost than ship surveys in some cases.
Dissemination of blaNDM–1 Gene Among Several Klebsiella pneumoniae Sequence Types in Mexico Associated With Horizontal Transfer Mediated by IncF-Like Plasmids
Authors: Toledano-Tableros José Eduardo , Gayosso-Vázquez Catalina , Jarillo-Quijada Ma Dolores , Fernández-Vázquez José Luis , Morfin-Otero Rayo , Rodríguez-Noriega Eduardo , Giono-Cerezo Silvia , Gutkind Gabriel , Di Conza José , Santos-Preciado José Ignacio , Alcántar-Curiel María Dolores
Published: March 2021

Nosocomial infections caused by multidrug-resistant (MDR) Klebsiella pneumoniae are a major health problem worldwide. The aim of this study was to describe NDM-1-producing K. pneumoniae strains causing bacteremia in a tertiary referral hospital in Mexico. MDR K. pneumoniae isolates were screened by polymerase chain reaction for the presence of resistance genes. In resistant isolates, plasmids were identified and conjugation assays were performed. Clonal diversity and the sequence types were determined by pulsed-field gel electrophoresis and multilocus sequence typing. A total of 80 K. pneumoniae isolates were collected from patients with bacteremia over a 1-year period. These isolates showed a level of resistance of 59% (47/80) to aztreonam, 56–60% (45–48/80) to cephalosporins, 54% (43/80) to colistin and 12.5% (10/80) to carbapenems. The carbapenem resistant isolates were blaNDM–1 carriers and negative for blaKPC, blaNDM, blaIMP, blaVIM and blaOXA–48–like carbapenemases genes. Conjugative plasmids IncFIIA and IncF group with sizes of 82–195 kbp were carriers of blaNDM–1, blaCTX–M–15, blaTEM–1, aac(6′)-Ib and/or aac(3′)-IIa. Clonal variability and nine different multilocus sequence types were detected (ST661, ST683, ST1395, ST2706, ST252, ST1198, ST690, ST1535, and ST3368) for the first time in the isolates carrying blaNDM–1 in Mexico. This study demonstrates that blaNDM–1 has remained within this hospital in recent years and suggests that it is currently the most prevalent carbapenemase among K. pneumoniae MDR strains causing bacteremia in Mexico. The horizontal transfer of blaNDM–1 gene through IncF-like plasmids among different clones demonstrates the dissemination pathway of antimicrobial resistance and underscore the need for strong and urgent joint measures to control the spread of NDM-1 carbapenemase in the hospital.
Genomic Metrics Applied to Rhizobiales (Hyphomicrobiales): Species Reclassification, Identification of Unauthentic Genomes and False Type Strains
Authors: Volpiano Camila Gazolla , Sant’Anna Fernando Hayashi , Ambrosini Adriana , de São José Jackson Freitas Brilhante , Beneduzi Anelise , Whitman William B. , de Souza Emanuel Maltempi , Lisboa Bruno Brito , Vargas Luciano Kayser , Passaglia Luciane Maria Pereira
Published: March 2021

Taxonomic decisions within the order Rhizobiales have relied heavily on the interpretations of highly conserved 16S rRNA sequences and DNA–DNA hybridizations (DDH). Currently, bacterial species are defined as including strains that present 95–96% of average nucleotide identity (ANI) and 70% of digital DDH (dDDH). Thus, ANI values from 520 genome sequences of type strains from species of Rhizobiales order were computed. From the resulting 270,400 comparisons, a ≥95% cut-off was used to extract high identity genome clusters through enumerating maximal cliques. Coupling this graph-based approach with dDDH from clusters of interest, it was found that: (i) there are synonymy between Aminobacter lissarensis and Aminobacter carboxidus, Aurantimonas manganoxydans and Aurantimonas coralicida, “Bartonella mastomydis,” and Bartonella elizabethae, Chelativorans oligotrophicus, and Chelativorans multitrophicus, Rhizobium azibense, and Rhizobium gallicum, Rhizobium fabae, and Rhizobium pisi, and Rhodoplanes piscinae and Rhodoplanes serenus; (ii) Chelatobacter heintzii is not a synonym of Aminobacter aminovorans; (iii) “Bartonella vinsonii” subsp. arupensis and “B. vinsonii” subsp. berkhoffii represent members of different species; (iv) the genome accessions GCF_003024615.1 (“Mesorhizobium loti LMG 6125T”), GCF_003024595.1 (“Mesorhizobium plurifarium LMG 11892T”), GCF_003096615.1 (“Methylobacterium organophilum DSM 760T”), and GCF_000373025.1 (“R. gallicum R-602 spT”) are not from the genuine type strains used for the respective species descriptions; and v) “Xanthobacter autotrophicus” Py2 and “Aminobacter aminovorans” KCTC 2477T represent cases of misuse of the term “type strain”. Aminobacter heintzii comb. nov. and the reclassification of Aminobacter ciceronei as A. heintzii is also proposed. To facilitate the downstream analysis of large ANI matrices, we introduce here ProKlust (“Prokaryotic Clusters”), an R package that uses a graph-based approach to obtain, filter, and visualize clusters on identity/similarity matrices, with settable cut-off points and the possibility of multiple matrices entries.
Pathogenic and Virulence Factor Detection on Viable but Non-culturable Methicillin-Resistant Staphylococcus aureus
Authors: Jiang Hua , Wang Kan , Yan Muxia , Ye Qian , Lin Xiaojing , Chen Ling , Ye Yanrui , Zhang Li , Liu Junyan , Huang Tengyi
Published: March 2021

Food safety and foodborne infections and diseases have been a leading hotspot in public health, and methicillin-resistant Staphylococcus aureus (MRSA) has been recently documented to be an important foodborne pathogen, in addition to its recognition to be a leading clinical pathogen for some decades. Standard identification for MRSA has been commonly performed in both clinical settings and food routine detection; however, most of such so-called “standards,” “guidelines,” or “gold standards” are incapable of detecting viable but non-culturable (VBNC) cells. In this study, two major types of staphylococcal food poisoning (SFP), staphylococcal enterotoxins A (sea) and staphylococcal enterotoxins B (seb), as well as the panton-valentine leucocidin (pvl) genes, were selected to develop a cross-priming amplification (CPA) method. Limit of detection (LOD) of CPA for sea, seb, and pvl was 75, 107.5, and 85 ng/μl, indicating that the analytical sensitivity of CPA is significantly higher than that of conventional PCR. In addition, a rapid VBNC cells detection method, designated as PMA-CPA, was developed and further applied. PMA-CPA showed significant advantages when compared with PCR assays, in terms of rapidity, sensitivity, specificity, and accuracy. Compared with conventional VBNC confirmation methods, the PMA-CPA showed 100% accordance, which had demonstrated that the PMA-CPA assays were capable of detecting different toxins in MRSA in VBNC state. In conclusion, three CPA assays were developed on three important toxins for MRSA, and in combination with PMA, the PMA-CPA assay was capable of detecting virulent gene expression in MRSA in the VBNC state. Also, the above assays were further applied to real samples. As concluded, the PMA-CPA assay developed in this study was capable of detecting MRSA toxins in the VBNC state, representing first time the detection of toxins in the VBNC state.
Current Trends on Role of Biological Treatment in Integrated Treatment Technologies of Textile Wastewater
Authors: Ceretta Maria Belen , Nercessian Débora , Wolski Erika A.
Published: March 2021

Wastewater discharge is a matter of concern as it is the primary source of water pollution. Consequently, wastewater treatment plays a key role in reducing the negative impact that wastewater discharge produce into the environment. Particularly, the effluents produced by textile industry are composed of high concentration of hazardous compounds such as dyes, as well as having high levels of chemical and biological oxygen demand, suspended solids, variable pH, and high concentration of salt. Main efforts have been focused on the development of methods consuming less water or reusing it, and also on the development of dyes with a better fixation capacity. However, the problem of how to treat these harmful effluents is still pending. Different treatment technologies have been developed, such as coagulation-flocculation, adsorption, membrane filtration, reverse osmosis, advanced oxidation, and biological processes (activated sludge, anaerobic-aerobic treatment, and membrane bioreactor). Concerning to biological treatments, even though they are considered as the most environmentally friendly and economic methods, their industrial application is still uncertain. On the one hand, this is due to the costs of treatment plants installation and, on the other, to the fact that most of the studies are carried out with simulated or diluted effluents that do not represent what really happens in the industries. Integrated treatment technologies by combining the efficiency two or more methodologies used to be more efficient for the decontamination of textile wastewater, than treatments used separately. The elimination of hazardous compounds had been reported using combination of physical, chemical, and biological processes. On this way, as degradation products can sometimes be even more toxic than the parent compounds, effluent toxicity assessment is an essential feature in the development of these alternatives. This article provides a critical view on the state of art of biological treatment, the degree of advancement and the prospects for their application, also discussing the concept of integrated treatment and the importance of including toxicity assays to reach an integral approach to wastewater treatment.
Comparison of Current Methods for Signal Peptide Prediction in Phytoplasmas
Authors: Garcion Christophe , Béven Laure , Foissac Xavier
Published: March 2021

Although phytoplasma studies are still hampered by the lack of axenic cultivation methods, the availability of genome sequences allowed dramatic advances in the characterization of the virulence mechanisms deployed by phytoplasmas, and highlighted the detection of signal peptides as a crucial step to identify effectors secreted by phytoplasmas. However, various signal peptide prediction methods have been used to mine phytoplasma genomes, and no general evaluation of these methods is available so far for phytoplasma sequences. In this work, we compared the prediction performance of SignalP versions 3.0, 4.0, 4.1, 5.0 and Phobius on several sequence datasets originating from all deposited phytoplasma sequences. SignalP 4.1 with specific parameters showed the most exhaustive and consistent prediction ability. However, the configuration of SignalP 4.1 for increased sensitivity induced a much higher rate of false positives on transmembrane domains located at N-terminus. Moreover, sensitive signal peptide predictions could similarly be achieved by the transmembrane domain prediction ability of TMHMM and Phobius, due to the relatedness between signal peptides and transmembrane regions. Beyond the results presented herein, the datasets assembled in this study form a valuable benchmark to compare and evaluate signal peptide predictors in a field where experimental evidence of secretion is scarce. Additionally, this study illustrates the utility of comparative genomics to strengthen confidence in bioinformatic predictions.
IRE1α-XBP1 Affects the Mitochondrial Function of Aβ25–35-Treated SH-SY5Y Cells by Regulating Mitochondria-Associated Endoplasmic Reticulum Membranes
Authors: Chu Bingcong , Li Maoyu , Cao Xi , Li Rulong , Jin Suqin , Yang Hui , Xu Linlin , Wang Ping , Bi Jianzhong
Published: March 2021

Background: Neurotoxicity induced by the amyloid beta (Aβ) peptide is one of the most important pathological mechanisms of Alzheimer's disease (AD). Activation of the adaptive IRE1α-XBP1 pathway contributes to the pathogenesis of AD, making it a potential target for AD therapeutics. However, the mechanism of IRE1α-XBP1 pathway involvement in AD is unclear. We, therefore, investigated the effect of the IRE1α-XBP1 axis in an in vitro AD model and explored its potential mechanism.

Methods: The human neuroblastoma cell line, SH-SY5Y, was used. Cells were treated with Aβ25–35, with or without 4μ8c, an inhibitor of IRE1α. Cells were collected and analyzed by Western blotting, quantitative real-time PCR, electron microscopy, fluorescence microscopy, calcium imaging, and other biochemical assays.

Results: Aβ-exposed SH-SY5Y cells showed an increased expression of XBP1s and p-IRE1α. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and calcium imaging analysis showed that the IRE1α inhibitor, 4μ8c, reduced Aβ-induced cytotoxicity. Increased levels of ATP, restoration of mitochondrial membrane potential, and decreased production of mitochondrial reactive oxygen species after Aβ treatment in the presence of 4μ8c showed that inhibiting the IRE1α-XBP1 axis effectively mitigated Aβ-induced mitochondrial dysfunction in SH-SY5Y cells. Furthermore, Aβ treatment increased the expression and interaction of IP3R, Grp75, and vdac1 and led to an increased endoplasmic reticulum (ER)–mitochondria association, malfunction of mitochondria-associated ER-membranes (MAMs), and mitochondrial dysfunction. These deficits were rescued by inhibiting the IRE1α-XBP1 axis.

Conclusion: These findings demonstrate that Aβ peptide induces the activation of the IRE1α-XBP1 axis, which may aggravate cytotoxicity and mitochondrial impairment in SH-SY5Y cells by targeting MAMs. Inhibition of the IRE1α-XBP1 axis provides the protection against Aβ-induced injury in SH-SY5Y cells and may, therefore, be a new treatment strategy.
Intrinsically Photosensitive Retinal Ganglion Cells of the Human Retina
Authors: Mure Ludovic S.
Published: March 2021

Light profoundly affects our mental and physical health. In particular, light, when not delivered at the appropriate time, may have detrimental effects. In mammals, light is perceived not only by rods and cones but also by a subset of retinal ganglion cells that express the photopigment melanopsin that renders them intrinsically photosensitive (ipRGCs). ipRGCs participate in contrast detection and play critical roles in non-image-forming vision, a set of light responses that include circadian entrainment, pupillary light reflex (PLR), and the modulation of sleep/alertness, and mood. ipRGCs are also found in the human retina, and their response to light has been characterized indirectly through the suppression of nocturnal melatonin and PLR. However, until recently, human ipRGCs had rarely been investigated directly. This gap is progressively being filled as, over the last years, an increasing number of studies provided descriptions of their morphology, responses to light, and gene expression. Here, I review the progress in our knowledge of human ipRGCs, in particular, the different morphological and functional subtypes described so far and how they match the murine subtypes. I also highlight questions that remain to be addressed. Investigating ipRGCs is critical as these few cells play a major role in our well-being. Additionally, as ipRGCs display increased vulnerability or resilience to certain disorders compared to conventional RGCs, a deeper knowledge of their function could help identify therapeutic approaches or develop diagnostic tools. Overall, a better understanding of how light is perceived by the human eye will help deliver precise light usage recommendations and implement light-based therapeutic interventions to improve cognitive performance, mood, and life quality.
Case Report: A Novel Mutation in the Mitochondrial MT-ND5 Gene Is Associated With Leber Hereditary Optic Neuropathy (LHON)
Authors: Engvall Martin , Kawasaki Aki , Carelli Valerio , Wibom Rolf , Bruhn Helene , Lesko Nicole , Schober Florian A. , Wredenberg Anna , Wedell Anna , Träisk Frank
Published: March 2021

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease causing severe bilateral visual loss, typically in young adults. The disorder is commonly caused by one of three primary point mutations in mitochondrial DNA, but a number of other rare mutations causing or associated with the clinical syndrome of LHON have been reported. The mutations in LHON are almost exclusively located in genes encoding subunits of complex I in the mitochondrial respiratory chain. Here we report two patients, a mother and her son, with the typical LHON phenotype. Genetic investigations for the three common mutations were negative, instead we found a new and previously unreported mutation in mitochondrial DNA. This homoplasmic mutation, m.13345G>A, is located in the MT-ND5 gene, encoding a core subunit in complex I in the mitochondrial respiratory chain. Investigation of the patients mitochondrial respiratory chain in muscle found a mild defect in the combined activity of complex I+III. In the literature six other mutations in the MT-ND5 gene have been associated with LHON and by this report a new putative mutation in the MT-ND5 can be added.
Temporal Binding in Multisensory and Motor-Sensory Contexts: Toward a Unified Model
Authors: Jagini Kishore Kumar
Published: March 2021

Our senses receive a manifold of sensory signals at any given moment in our daily lives. For a coherent and unified representation of information and precise motor control, our brain needs to temporally bind the signals emanating from a common causal event and segregate others. Traditionally, different mechanisms were proposed for the temporal binding phenomenon in multisensory and motor-sensory contexts. This paper reviews the literature on the temporal binding phenomenon in both multisensory and motor-sensory contexts and suggests future research directions for advancing the field. Moreover, by critically evaluating the recent literature, this paper suggests that common computational principles are responsible for the temporal binding in multisensory and motor-sensory contexts. These computational principles are grounded in the Bayesian framework of uncertainty reduction rooted in the Helmholtzian idea of unconscious causal inference.
Long Multi-Stage Training for a Motor-Impaired User in a BCI Competition
Authors: Turi Federica , Clerc Maureen , Papadopoulo Théodore
Published: March 2021

In a Mental Imagery Brain-Computer Interface the user has to perform a specific mental task that generates electroencephalography (EEG) components, which can be translated in commands to control a BCI system. The development of a high-performance MI-BCI requires a long training, lasting several weeks or months, in order to improve the ability of the user to manage his/her mental tasks. This works aims to present the design of a MI-BCI combining mental imaginary and cognitive tasks for a severely motor impaired user, involved in the BCI race of the Cybathlon event, a competition of people with severe motor disability. In the BCI-race, the user becomes a pilot in a virtual race game against up to three other pilots, in which each pilot has to control his/her virtual car by his/her mental tasks. We present all the procedures followed to realize an effective MI-BCI, from the user's first contact with a BCI technology to actually controlling a video-game through her EEG. We defined a multi-stage user-centered training protocol in order to successfully control a BCI, even in a stressful situation, such as that of a competition. We put a specific focus on the human aspects that influenced the long training phase of the system and the participation to the competition.
Agonal Factors Distort Gene-Expression Patterns in Human Postmortem Brains
Authors: Dai Jiacheng , Chen Yu , Dai Rujia , Jiang Yi , Tian Jianghua , Liu Sihan , Xu Meng , Li Miao , Zhou Jiaqi , Liu Chunyu , Chen Chao
Published: March 2021

Agonal factors, the conditions that occur just prior to death, can impact the molecular quality of postmortem brains, influencing gene expression results. Our study used gene expression data of 262 samples from ROSMAP with the detailed terminal state recorded for each donor, such as fever, infection, and unconsciousness. Fever and infection were the primary contributors to brain gene expression changes, brain cell-type-specific gene expression, and cell proportion changes. Furthermore, we also found that previous studies of gene expression in postmortem brains were confounded by agonal factors. Therefore, correction for agonal factors is important in the step of data preprocessing. Our analyses revealed fever and infection contributing to gene expression changes in postmortem brains and emphasized the necessity of study designs that document and account for agonal factors.
Medial Parabrachial Nucleus Is Essential in Controlling Wakefulness in Rats
Authors: Xu Qi , Wang Dian-Ru , Dong Hui , Chen Li , Lu Jun , Lazarus Michael , Cherasse Yoan , Chen Gui-Hai , Qu Wei-Min , Huang Zhi-Li
Published: March 2021

Activation of the parabrachial nucleus (PB) in the brainstem induced wakefulness in rats, suggesting which is an important nucleus that controls arousal. However, the sub-regions of PB in regulating sleep-wake cycle is still unclear. Here, we employ chemogenetics and optogenetics strategies and find that activation of the medial part of PB (MPB), but not the lateral part, induces continuous wakefulness for 10 h without sleep rebound in neither sleep amount nor the power spectra. Optogenetic activation of glutamatergic MPB neurons in sleeping rats immediately wake rats mediated by the basal forebrain (BF) and lateral hypothalamus (LH), but not the ventral medial thalamus. Most importantly, chemogenetic inhibition of PB neurons decreases wakefulness for 10 h. Conclusively, these findings indicate that the glutamatergic MPB neurons are essential in controlling wakefulness, and that MPB-BF and MPB-LH pathways are the major neuronal circuits.
Systematic Literature Review and Meta-Analysis of the Relationship Between Polyunsaturated and Trans Fatty Acids During Pregnancy and Offspring Weight Development
Authors: Ren Xuan , Vilhjálmsdóttir Birgitta Lind , Rohde Jeanett Friis , Walker Karen Christina , Runstedt Suzanne Elizabeth , Lauritzen Lotte , Heitmann Berit Lilienthal , Specht Ina Olmer
Published: March 2021

Eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and trans fatty acids (TFAs) may have an impact on offspring weight development. We conducted a systematic review and meta-analysis according to PRISMA guidelines to evaluate whether levels of these fatty acids during pregnancy influenced offspring weight development. Randomized controlled trials (RCTs) with DHA and/or EPA supplementation or cohort studies, which examined levels of DHA, EPA, or TFAs in maternal or neonatal blood samples and recorded offspring weight, were included. Overall, 27 RCTs and 14 observational studies were identified. The results showed that DHA and/or EPA supplementation doses >650 mg/day resulted in slightly higher birth weight (MD 87.5 g, 95% CI 52.3–122.6, n = 3,831) and combined BMI and BMI z score at 5–10 years (SMD 0.11, 95% CI 0.04–0.18, n = 3,220). These results were rated as moderate quality. Results from the observational studies were generally inconsistent. High TFA levels during pregnancy seemed to be associated with lower birth weight. Finally, this review and meta-analysis supports a relationship between high maternal or neonatal DHA and/or EPA levels and higher offspring birth weight and weight in childhood. More high-quality long-term studies are still needed.
Pegylated Liposomal Doxorubicin in Vindesine-Based and Bortezomib-Based Regimens for Patients With Newly Diagnosed Multiple Myeloma: A Retrospective Study of Efficacy and Safety
Authors: Zhai Yujia , Yuan Dai , Ge Xueling , Hu Shunfeng , Li Peipei , Fang Xiaosheng , Li Ying , Zhou Xiangxiang , Wang Xin
Published: March 2021

Purpose

Although pegylated liposomal doxorubicin (PLD) has been approved in combination with bortezomib for relapsed/refractory multiple myeloma (MM), the antitumor efficacy and tolerability of PLD in different regimens for patients with newly diagnosed MM (NDMM) have not been fully defined.

Methods

A total of 249 NDMM patients diagnosed between January 2008 and October 2019 were included in this retrospective study. Among them, 112 patients received vindesine-based chemotherapy (35 vDD and 77 vAD) and 137 received bortezomib-based chemotherapy (58 VDD and 79 VD).

Results

In bortezomib-containing regimens, the complete response rate (48.3 vs. 30.4%, p = 0.033) and very good partial response or better rate (74.1 vs. 57.0%, p = 0.038) of VDD were significantly higher than those of VD subgroup. While no superior survival was found between VDD and VD subgroup. In vindesine-containing regimens, no statistical significance was identified between vDD and vAD in terms of response rate and survival. The occurrence rates of all cardiac AEs were similar between VDD and VD.

Conclusions

The vDD regimen was similar with vAD in the aspect of response rate, survival, and toxicity in NDMM patients. The addition of PLD to VD brought deeper response without increased toxicity, while no superior survival was found.
TAM-ing the CIA—Tumor-Associated Macrophages and Their Potential Role in Unintended Side Effects of Therapeutics for Cancer-Induced Anemia
Authors: Weiler Stefan , Nairz Manfred
Published: March 2021

Cancer-induced anemia (CIA) is a common consequence of neoplasia and has a multifactorial pathophysiology. The immune response and tumor treatment, both intended to primarily target malignant cells, also affect erythropoiesis in the bone marrow. In parallel, immune activation inevitably induces the iron-regulatory hormone hepcidin to direct iron fluxes away from erythroid progenitors and into compartments of the mononuclear phagocyte system. Moreover, many inflammatory mediators inhibit the synthesis of erythropoietin, which is essential for stimulation and differentiation of erythroid progenitor cells to mature cells ready for release into the blood stream. These pathophysiological hallmarks of CIA imply that the bone marrow is not only deprived of iron as nutrient but also of erythropoietin as central growth factor for erythropoiesis. Tumor-associated macrophages (TAM) are present in the tumor microenvironment and display altered immune and iron phenotypes. On the one hand, their functions are altered by adjacent tumor cells so that they promote rather than inhibit the growth of malignant cells. As consequences, TAM may deliver iron to tumor cells and produce reduced amounts of cytotoxic mediators. Furthermore, their ability to stimulate adaptive anti-tumor immune responses is severely compromised. On the other hand, TAM are potential off-targets of therapeutic interventions against CIA. Red blood cell transfusions, intravenous iron preparations, erythropoiesis-stimulating agents and novel treatment options for CIA may interfere with TAM function and thus exhibit secondary effects on the underlying malignancy. In this Hypothesis and Theory, we summarize the pathophysiological hallmarks, clinical implications and treatment strategies for CIA. Focusing on TAM, we speculate on the potential intended and unintended effects that therapeutic options for CIA may have on the innate immune response and, consequently, on the course of the underlying malignancy.
Cancer Associated Fibroblasts Promote Renal Cancer Progression Through a TDO/Kyn/AhR Dependent Signaling Pathway
Authors: Chen Li-bo , Zhu Shun-ping , Liu Tian-pei , Zhao Heng , Chen Ping-feng , Duan You-jun , Hu Rong
Published: March 2021

Cancer associated fibroblasts (CAFs) play crucial roles in cancer development, however, the specific mechanisms of CAFs associated renal cancer progression remain poorly understood. Our study observed enriched CAFs in high degree malignant tumor tissues from renal cancer patients. These CAFs isolated from tumor tissues are prone to facilitate drugs resistance and promote tumor progression in vitro and in vivo. Mechanistically, CAFs up-regulated tryptophan 2, 3-dioxygenase (TDO) expression, resulting in enhanced secretion of kynurenine (Kyn). Kyn produced from CAFs could up-regulated the expression of aromatic hydrocarbon receptor (AhR), eventually resulting in the AKT and STAT3 signaling pathways activation. Inhibition of AKT signal prevented cancer cells proliferation, while inhibition of the STAT3 signal reverted drugs resistance and cancer migration induced by kynurenine. Application of AhR inhibitor DMF could efficiently suppress distant metastasis of renal cancer cells, and improve anticancer effects of sorafenib (Sor)/sunitinib (Sun), which described a promising therapeutic strategy for clinical renal cancer.
Dasatinib in the Management of Pediatric Patients With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Authors: Cerchione Claudio , Locatelli Franco , Martinelli Giovanni
Published: March 2021

Acute leukemia is the most common cancer in childhood; in particular, acute lymphoblastic leukemia (ALL) represents roughly up to 80% of all cases of acute leukemias in children. Survival of children with ALL has dramatically improved over the last few decades, and is now over 90% (versus 40% of adult patients) in developed countries, except for in infants (i.e., children < 1 year), where no significant improvement was registered. Philadelphia positive ALL (Ph+ALL) accounts for around 3% of cases of childhood ALL, its incidence increasing with patient’s age. Before the era of tyrosine-kinase inhibitors (TKIs), pediatric Ph+ALL showed a worse prognosis in comparison to other forms of ALL, and was managed with intensive chemotherapy, followed, whenever possible, by allogenic hematopoietic stem cell transplantation (HSCT) in first morphological complete remission. TKIs have revolutionized the current clinical approach, which involves combinations of imatinib plus standard chemotherapy that can abrogate the negative prognostic impact conferred by the presence of BCR/ABL1 rearrangement, resulting in the probability of event-free survival (EFS) being significantly better than that recorded in the pre-TKI era. Long-term follow-up confirms these data, questioning the role of a real advantage offered by HSCT over intensive chemotherapy plus TKI in all Ph+ALL pediatric patients. Imatinib was the first generation TKI and the prototype of targeted therapy, but over the years second- (dasatinib, nilotinib, bosutinib) and third-generation (ponatinib) TKIs showed a capacity to overcome resistance to imatinib in Ph+ hematological neoplasms. Given the effectiveness of the first-in-class TKI, imatinib, also the second-generation TKI dasatinib was incorporated in the treatment regimens of Ph+ALL. In this manuscript, we will discuss the role of this drug in pediatric Ph+ALL, analyzing the available data published to date.
Prognostic Value of an Immunohistochemical Signature in Patients With Bladder Cancer Undergoing Radical Cystectomy
Authors: Wu Jie , Wen Jun-Miao , Wang Yu-Chen , Luo Wen-Jie , Wang Qi-Feng , Lv Hong , Dai Bo , Ye Ding-Wei , Su Heng-Chuan , Zhu Yi-Ping
Published: March 2021

Background

This study aimed to assess the prognostic value of various diagnostic immunohistochemical (IHC) markers and develop an IHC-based classifier to predict the disease-free survival (DFS) of patients with bladder cancer undergoing radical cystectomy.

Methods

IHC was performed on tumor specimens from 366 patients with transitional cell bladder cancer. The least absolute shrinkage and selection operator (LASSO) Cox regression model was used to develop a multi-marker classifier for predicting DFS of patients with bladder cancer. The Kaplan–Meier estimate was performed to assess DFS, and unadjusted and adjusted Cox regression models were used to identify independent risk factors to predict DFS of patients with bladder cancer.

Results

Based on the LASSO Cox regression model, nine prognostic markers were identified in the training cohort. Patients were stratified into low- and high-risk groups using the IHC-based classifier. In the training cohort, the 10-year DFS was significantly better in low-risk patients (71%) compared with high-risk patients (18%) (p < 0.001); in the validation cohort, the 10-year DFS was 86% for the low-risk group and 20% for the high-risk group (p < 0.001). Multivariable Cox regression analyses showed that the high-risk group based on the classifier was associated with poorer DFS adjusted by clinicopathological characteristics. Finally, a nomogram comprising the classifier and clinicopathological factors was developed for clinical application.

Conclusion

The nine-IHC-based classifier is a reliable prognostic tool, which can eventually guide clinical decision making regarding treatment strategy and follow-up scheduling of bladder cancer.
WEE1 Inhibition in Combination With Targeted Agents and Standard Chemotherapy in Preclinical Models of Pancreatic Ductal Adenocarcinoma
Authors: Hartman Sarah J. , Bagby Stacey M. , Yacob Betelehem W. , Simmons Dennis M. , MacBeth Morgan , Lieu Christopher H. , Davis S. Lindsey , Leal Alexis D. , Tentler John J. , Diamond Jennifer R. , Eckhardt S. Gail , Messersmith Wells A. , Pitts Todd M.
Published: March 2021

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with high incidences of p53 mutations. AZD1775 (adavosertib, previously MK-1775) is a small molecule WEE1 inhibitor that abrogates the G2M checkpoint and can potentially synergize with DNA damaging therapies commonly used in PDAC treatment. The purpose of this study was to identify combination partners for AZD1775, including standard chemotherapy or targeted agents, in PDAC preclinical models. Low powered preliminary screens demonstrated that two of the four PDX models responded better to the combinations of AZD1775 with irinotecan or capecitabine than to either single agent. Following the screens, two full powered PDAC PDX models of differing p53 status were tested with the combinations of AZD1775 and irinotecan or capecitabine. The combinations of AZD1775 and SN38 or 5-FU were also tested on PDAC cell lines. Cellular proliferation was measured using an IncuCyte Live Cell Imager and apoptosis was measured using a Caspase-Glo 3/7 assay. Flow cytometry was conducted to measure alterations in cell cycle distribution. Western blot analysis was used to determine the effects of the drug combinations on downstream effectors. In PDX models with mutated p53 status, there was significant tumor growth inhibition from the combination of AZD1775 with irinotecan or capecitabine (P ≤ 0.03), while PDX models with wild type p53 did not show anti-tumor synergy from the same combinations (P ≥ 0.08). The combination of AZD1775 with SN38 or 5-FU significantly decreased proliferation in all PDAC cell lines, and enhanced apoptosis in multiple cell lines. Cell cycle distribution was disrupted from the combination of AZD1775 with SN38 or 5-FU which was recorded as G2M arrest and decreased G1 phase. AZD1775 inhibited phospho-CDC2 and increased the expression of γH2AX that was either maintained or enhanced after combination with SN38 or 5-FU. The combination of AZD1775 with irinotecan/SN38 or capecitabine/5-FU showed anti-tumor effects in vivo and in vitro in PDAC models. These results support further investigation for these combination strategies to enhance outcomes for PDAC patients.
Integrative Pan-Cancer Analysis Reveals Decreased Melatonergic Gene Expression in Carcinogenesis and RORA as a Prognostic Marker for Hepatocellular Carcinoma
Authors: Zou Yi , Sun Huaqin , Guo Yating , Shi Yidan , Jiang Zhiyu , Huang Jingxuan , Li Li , Jiang Fengle , Lin Zeman , Wu Junling , Zhou Ruixiang , Liu Yuncai , Ao Lu
Published: March 2021

Background

Melatonin has been shown to play a protective role in the development and progression of cancer. However, the relationship between alterations in the melatonergic microenvironment and cancer development has remained unclear.

Methods

We performed a comprehensive investigation on 12 melatonergic genes and their relevance to cancer occurrence, progression and survival by integrating multi-omics data from microarray analysis and RNA sequencing across 11 cancer types. Specifically, the 12 melatonergic genes that we investigated, which reflect the melatonergic microenvironment, included three membrane receptor genes, three nuclear receptor genes, two intracellular receptor genes, one synthetic gene, and three metabolic genes.

Results

Widely coherent underexpression of nuclear receptor genes, intracellular receptor genes, and metabolic genes was observed in cancerous samples from multiple cancer types compared to that in normal samples. Furthermore, genomic and/or epigenetic alterations partially contributed to these abnormal expression patterns in cancerous samples. Moreover, the majority of melatonergic genes had significant prognostic effects in predicting overall survival. Nevertheless, few corresponding alterations in expression were observed during cancer progression, and alterations in expression patterns varied greatly across cancer types. However, the association of melatonergic genes with one specific cancer type, hepatocellular carcinoma, identified RORA as a tumor suppressor and a prognostic marker for patients with hepatocellular carcinoma.

Conclusions

Overall, our study revealed decreased melatonergic gene expression in various cancers, which may help to better elucidate the relationship between melatonin and cancer development. Taken together, our findings highlight the potential prognostic significance of melatonergic genes in various cancers.
Colony Stimulating Factor 1 Receptor in Acute Myeloid Leukemia
Authors: Sletta Kristine Yttersian , Castells Oriol , Gjertsen Bjørn Tore
Published: March 2021

Acute myeloid leukemia (AML) is an aggressive heterogeneous blood cancer derived from hematopoietic stem cells. Tumor-stromal interactions in AML are of importance for disease development and therapy resistance, and bone marrow stroma seem like an attractive therapeutic target. Of particular interest is colony stimulating factor 1 receptor (CSF1R, M-CSFR, c-FMS, CD115) and its role in regulating plasticity of tumor-associated macrophages. We discuss first the potential of CSF1R-targeted therapy as an attractive concept with regards to the tumor microenvironment in the bone marrow niche. A second therapy approach, supported by preclinical research, also suggests that CSF1R-targeted therapy may increase the beneficial effect of conventional and novel therapeutics. Experimental evidence positioning inhibitors of CSF1R as treatment should, together with data from preclinical and early phase clinical trials, facilitate translation and clinical development of CSF1R-targeted therapy for AML.