bluuebunny/crossref_metadata_2025 huggingface dataset:
The Outcome of Critically Ill COVID-19 Patients Is Linked to Thromboinflammation Dominated by the Kallikrein/Kinin System
Authors: Lipcsey Miklós , Persson Barbro , Eriksson Oskar , Blom Anna M. , Fromell Karin , Hultström Michael , Huber-Lang Markus , Ekdahl Kristina N. , Frithiof Robert , Nilsson Bo
Published: February 2021

An important manifestation of severe COVID-19 is the ARDS-like lung injury that is associated with vascular endothelialitis, thrombosis, and angiogenesis. The intravascular innate immune system (IIIS), including the complement, contact, coagulation, and fibrinolysis systems, which is crucial for recognizing and eliminating microorganisms and debris in the body, is likely to be involved in the pathogenesis of COVID-19 ARDS. Biomarkers for IIIS activation were studied in the first 66 patients with COVID-19 admitted to the ICU in Uppsala University Hospital, both cross-sectionally on day 1 and in 19 patients longitudinally for up to a month, in a prospective study. IIIS analyses were compared with biochemical parameters and clinical outcome and survival. Blood cascade systems activation leading to an overreactive conjunct thromboinflammation was demonstrated, reflected in consumption of individual cascade system components, e.g., FXII, prekallikrein, and high molecular weight kininogen and in increased levels of activation products, e.g., C4d, C3a, C3d,g, sC5b-9, TAT, and D-dimer. Strong associations were found between the blood cascade systems and organ damage, illness severity scores, and survival. We show that critically ill COVID-19 patients display a conjunct activation of the IIIS that is linked to organ damage of the lung, heart, kidneys, and death. We present evidence that the complement and in particular the kallikrein/kinin system is strongly activated and that both systems are prognostic markers of the outcome of the patients suggesting their role in driving the inflammation. Already licensed kallikrein/kinin inhibitors are potential drugs for treatment of critically ill patients with COVID-19.
Evasion of Immunological Memory by S. aureus Infection: Implications for Vaccine Design
Authors: Teymournejad Omid , Montgomery Christopher P.
Published: February 2021

RecurrentS. aureusinfections are common, suggesting that natural immune responses are not protective. All candidate vaccines tested thus far have failed to protect againstS. aureusinfections, highlighting an urgent need to better understand the mechanisms by which the bacterium interacts with the host immune system to evade or prevent protective immunity. Although there is evidence in murine models that both cellular and humoral immune responses are important for protection againstS. aureus, human studies suggest that T cells are critical in determining susceptibility to infection. This review will use an “anatomic” approach to systematically outline the steps necessary in generating a T cell-mediated immune response againstS. aureus. Through the processes of bacterial uptake by antigen presenting cells, processing and presentation of antigens to T cells, and differentiation and proliferation of memory and effector T cell subsets, the ability ofS. aureusto evade or inhibit each step of the T-cell mediated response will be reviewed. We hypothesize that these interactions result in the redirection of immune responses away from protective antigens, thereby precluding the establishment of “natural” memory and potentially inhibiting the efficacy of vaccination. It is anticipated that this approach will reveal important implications for future design of vaccines to prevent these infections.
Risk Assessment of Cadmium, Lead, and Mercury on Human Health in Relation to the Consumption of Farmed Sea Bass in Italy: A Meta-Analytical Approach
Authors: Di Bella Calogero , Calagna Antonino , Cammilleri Gaetano , Schembri Pietro , Lo Monaco Daniela , Ciprì Valentina , Battaglia Luisa , Barbera Giuseppe , Ferrantelli Vincenzo , Sadok Saloua , Tliba Ines , Lo Dico Gianluigi Maria , Allegro Rosalinda
Published: February 2021

A risk assessment, related to the consumption of farmed sea bass, was carried out by meta-analysis, taking into account the concentration of trace metals (Cd, Pb, Hg) reported in the literature, the estimated weekly intake (EWI), the provisional tolerable weekly intake (PTWI), and the target hazard quotient (THQ). The concentrations of Cd, Pb, and Hg in farmed sea bass marketed in Sicily (Southern Italy) were also assessed by inductively coupled plasma mass spectrometry (ICP-MS) and atomic absorption spectroscopy (AAS) to have screening data for the comparison with literature results. In any case, the results obtained by meta-analysis and by screening were lower than the pre-established legal limits for each metal. The meta-analysis results showed very low levels of Cd (0.031 μg g–1 w.w.), Pb (0.110 μg g–1 w.w.), and Hg (0.023 μg g–1 w.w.). The EWI estimation confirmed safety limits for human health (0.004, 0.015, and 0.003 μg kg–1 for Cd, Pb, and Hg, respectively). Even the THQ demonstrated that farmed sea bass represent a secure food for humans (0.0006, 0.0005, and 0.0048 for Cd, Pb, and Hg, respectively). The comparison with our screening data showed a significant difference only for the Pb levels (p < 0.05). The results obtained were compared with the same indexes relative to other food types (meat, cereals, vegetables, etc.). The EWI and THQ calculated were always lower than same indexes relative to other food types considered.
The Self-Healing Performance of Carbon-Based Nanomaterials Modified Asphalt Binders Based on Molecular Dynamics Simulations
Authors: Gong Yan , Xu Jian , Yan Er-hu , Cai Jun-hua
Published: February 2021

In this study, the molecular dynamics simulation was used to explore the effects of carbon-based nanomaterials as binder modifiers on self-healing capability of asphalt binder and to investigate the microscopic self-healing process of modified asphalt binders under different temperature. An asphalt average molecular structure model of PEN70 asphalt binder was constructed firstly. Further, three kinds of carbon-based nanomaterials were added at three different percentages ranging from 0.5 to 1.5% to the base binder to study their effects on the self-healing capability, including two carbon nanotubes (CNT1 and CNT2) and graphene nanoflakes. Combining with the three-dimensional (3D) microcrack model to simulate the asphalt self-healing process, the density analysis, relative concentration analysis along OZ direction, and mean square displacement analysis were performed to investigate the temperature sensitive self-healing characters. Results showed that the additions of CNTs were effective in enhancing the self-healing efficiency of the plain asphalt binder. By adding 0.5% CNT1 and 0.5% CNT2, about 652% and 230% of the mean square displacement of plain asphalt binder were enhanced at the optimal temperatures. However, the use of graphene nanoflakes as an asphalt modifier did not provide any noticeable changes on the self-healing efficiency. It can be found that the self-healing capability of the asphalt was closely related to the temperature. For base asphalt, the self-healing effect became especially high at the phase transition temperature range, while, for the modified asphalt, the enhancement of the self-healing capability at the low phase transition temperature (15°C) became negligible. In general, the optimal healing temperature range of the CNTs modified asphalt binders is determined as 45–55°C and the optimal dosage of the CNTs is about 0.5% over the total weight of the asphalt binder. Considering the effect of carbon-based nanomaterials on the self-healing properties, the recommended carbon-based nanomaterials modifier is CNT1 with the aspect ratio of 1.81.
Metformin Use Is Associated With a Lower Incidence of Hospitalization for Atrial Fibrillation in Patients With Type 2 Diabetes Mellitus
Authors: Tseng Chin-Hsiao
Published: February 2021

Background: The effect of metformin on the risk of atrial fibrillation (AF) requires confirmation. This retrospective cohort study compared the incidence of hospitalization for AF in ever and never users of metformin.

Methods: Patients with newly diagnosed type 2 diabetes mellitus during 1999–2005 were enrolled from Taiwan's National Health Insurance database. Analyses were conducted in both an unmatched cohort of 173,398 ever users and 21,666 never users and in a propensity score-matched cohort of 21,662 pairs of ever and never users. They were free from a diagnosis of AF before January 1, 2006 and were followed up until December 31, 2011. Hazard ratios were estimated by Cox regression incorporated with the inverse probability of treatment weighting using the propensity score.

Results: A total of 303 ever users and 86 never users in the unmatched cohort and 56 ever users and 86 never users in the matched cohort developed hospitalization for AF during follow-up. The respective incidence rates were 37.72 and 92.45 per 100,000 person-years in the unmatched cohort and were 56.98 and 92.46 per 100,000 person-years in the matched cohort. The hazard ratio for ever vs. never users was 0.405 (95% confidence interval: 0.319–0.515) in the unmatched cohort and 0.617 (0.441–0.864) in the matched cohort. Hazard ratios for the tertiles of cumulative duration of metformin therapy vs. never users showed a dose-response effect. The findings were consistent in sensitivity analyses.

Conclusion: Metformin use is associated with a lower risk of hospitalization for AF in patients with type 2 diabetes mellitus.
Understanding COVID-19 in Wuhan From the Perspective of Cold-Dampness: Clinical Evidences and Mechanisms
Authors: Zheng Yujiao , Jin De , Lin Jiaran , Zhang Yuehong , Tian Jiaxing , Lian Fengmei , Tong Xiaolin
Published: February 2021

Traditional Chinese medicine (TCM) has played a significant role in the treatment of coronavirus disease 2019 (COVID-19) in Wuhan City. During the epidemic, Academician Tong Xiaolin suggested a close association of COVID-19 with cold-dampness, an etiological factor in TCM, by summarizing the characteristics of the COVID-19 patients in Wuhan. and the theory of Cold-dampness Plague was proposed. Based on the Cold-dampness Plague theory, a series of TCM drugs, such as Huoxiang Zhengqi Dropping Pills, Lianhua Qingwen Granules Hanshiyi Formula, and Tongzhi Granule were developed for the different stages, namely mild, moderate, severe, recovery, of the COVID-19. In addition, clinical evidences were obtained through randomized clinical trials or retrospective cohort studies. The Anti-SARS-CoV-2 mechanism of the TCM prescriptions were then summarized from the four aspects: targeting the ACE2 and 3CLPro, targeting cytokines, targeting acute immune responses to SARS-CoV-2, and targeting pulmonary fibrosis. Despite the clinical efficacy and therapeutic pharmacology speculation, more studies such as large-scale randomized clinical trials, cell and animal experiments are needed to further verify the theory of the Cold-dampness Plague in COVID-19 patients.
Modeling Cell Selectivity of Antimicrobial Peptides: How Is the Selectivity Influenced by Intracellular Peptide Uptake and Cell Density
Authors: Schefter Bethany R. , Nourbakhsh Shokoofeh , Taheri-Araghi Sattar , Ha Bae-Yeun
Published: February 2021

Antimicrobial peptides (AMPs) are known to attack bacteria selectively over their host cells. Many attempts have been made to use them as a template for designing peptide antibiotics for fighting drug-resistant bacteria. A central concept in this endeavor is “peptide selectivity,” which measures the “quality” of peptides. However, the relevance of selectivity measurements has often been obscured by the cell-density dependence of the selectivity. For instance, the selectivity can be overestimated if the cell density is larger for the host cell. Furthermore, recent experimental studies suggest that peptide trapping in target bacteria magnifies the cell-density dependence of peptide activity. Here, we propose a biophysical model for peptide activity and selectivity, which assists with the correct interpretation of selectivity measurements. The resulting model shows how cell density and peptide trapping in cells influence peptide activity and selectivity: while these effects can alter the selectivity by more than an order of magnitude, peptide trapping works in favor of host cells at high host-cell densities. It can be used to correct selectivity overestimates.
Comparative Transcriptomics and RNA-Seq-Based Bulked Segregant Analysis Reveals Genomic Basis Underlying Cronartium ribicola vcr2 Virulence
Authors: Liu Jun-Jun , Sniezko Richard A. , Zamany Arezoo , Williams Holly , Omendja Kangakola , Kegley Angelia , Savin Douglas P.
Published: February 2021

Breeding programs of five-needle pines have documented both major gene resistance (MGR) and quantitative disease resistance (QDR) to Cronartium ribicola (Cri), a non-native, invasive fungal pathogen causing white pine blister rust (WPBR). WPBR is one of the most deadly forest diseases in North America. However, Cri virulent pathotypes have evolved and can successfully infect and kill trees carrying resistance (R) genes, including vcr2 that overcomes MGR conferred by the western white pine (WWP, Pinus monticola) R gene (Cr2). In the absence of a reference genome, the present study generated a vcr2 reference transcriptome, consisting of about 20,000 transcripts with 1,014 being predicted to encode secreted proteins (SPs). Comparative profiling of transcriptomes and secretomes revealed vcr2 was significantly enriched for several gene ontology (GO) terms relating to oxidation-reduction processes and detoxification, suggesting that multiple molecular mechanisms contribute to pathogenicity of the vcr2 pathotype for its overcoming Cr2. RNA-seq-based bulked segregant analysis (BSR-Seq) revealed genome-wide DNA variations, including about 65,617 single nucleotide polymorphism (SNP) loci in 7,749 polymorphic genes shared by vcr2 and avirulent (Avcr2) pathotypes. An examination of the distribution of minor allele frequency (MAF) uncovered a high level of genomic divergence between vcr2 and Avcr2 pathotypes. By integration of extreme-phenotypic genome-wide association (XP-GWAS) analysis and allele frequency directional difference (AFDD) mapping, we identified a set of vcr2-associated SNPs within functional genes, involved in fungal virulence and other molecular functions. These included six SPs that were top candidate effectors with putative activities of reticuline oxidase, proteins with common in several fungal extracellular membrane (CFEM) domain or ferritin-like domain, polysaccharide lyase, rds1p-like stress responsive protein, and two Cri-specific proteins without annotation. Candidate effectors and vcr2-associated genes provide valuable resources for further deciphering molecular mechanisms of virulence and pathogenicity by functional analysis and the subsequent development of diagnostic tools for monitoring the virulence landscape in the WPBR pathosystems.
A Novel Salmonella Periplasmic Protein Controlling Cell Wall Homeostasis and Virulence
Authors: Cestero Juan J. , Castanheira Sónia , Pucciarelli M. Graciela , García-del Portillo Francisco
Published: February 2021

Horizontal gene transfer has shaped the evolution ofSalmonella entericaas pathogen. Some functions acquired by this mechanism include enzymes involved in peptidoglycan (PG) synthesis and remodeling. Here, we report a novel serovar Typhimurium protein that is absent in non-pathogenic bacteria and bears a LprI functional domain, first reported in aMycobacterium tuberculosislipoprotein conferring lysozyme resistance. Based on the presence of such domain, we hypothesized a role of thisS.Typhimurium protein in PG metabolism. This protein, which we named ScwA forSalmonellacellwall-related regulator-A, controls positively the levels of the murein lytic transglycosylase MltD. In addition, the levels of other enzymes that cleave bonds in the PG lattice were affected in a mutant lacking ScwA, including a soluble lytic tranglycosylase (Slt), the amidase AmiC, and a few endo- and carboxypeptidases (NlpC, PBP4, and AmpH). ThescwAgene has lower G+C content than the genomic average (43.1 vs. 52.2%), supporting acquisition by horizontal transfer. ScwA is located in the periplasm, stabilized by two disulfide bridges, produced preferentially in stationary phase and down-regulated following entry of the pathogen into eukaryotic cells. ScwA deficiency, however, results in a hypervirulent phenotype in the murine typhoid model. Based on these findings, we conclude that ScwA may be exploited byS.Typhimurium to ensure cell envelope homeostasis along the infection and to prevent host overt damage. This role could be accomplished by controlling the production or stability of a reduced number of peptidoglycan hydrolases whose activities result in the release of PG fragments.
Structural Network Efficiency Predicts Resilience to Cognitive Decline in Elderly at Risk for Alzheimer’s Disease
Authors: Fischer Florian U. , Wolf Dominik , Tüscher Oliver , Fellgiebel Andreas ,   on behalf of Alzheimer’s Disease Neuroimaging Initiative
Published: February 2021

Introduction: Functional imaging studies have demonstrated the recruitment of additional neural resources as a possible mechanism to compensate for age and Alzheimer’s disease (AD)-related cerebral pathology, the efficacy of which is potentially modulated by underlying structural network connectivity. Additionally, structural network efficiency (SNE) is associated with intelligence across the lifespan, which is a known factor for resilience to cognitive decline. We hypothesized that SNE may be a surrogate of the physiological basis of resilience to cognitive decline in elderly persons without dementia and with age- and AD-related cerebral pathology.Methods: We included 85 cognitively normal elderly subjects or mild cognitive impairment (MCI) patients submitted to baseline diffusion imaging, liquor specimens, amyloid-PET and longitudinal cognitive assessments. SNE was calculated from baseline MRI scans using fiber tractography and graph theory. Mixed linear effects models were estimated to investigate the association of higher resilience to cognitive decline with higher SNE and the modulation of this association by increased cerebral amyloid, liquor tau or WMHV. Results: For the majority of cognitive outcome measures, higher SNE was associated with higher resilience to cognitive decline (p-values: 0.011–0.039). Additionally, subjects with higher SNE showed more resilience to cognitive decline at higher cerebral amyloid burden (p-values: <0.001–0.036) and lower tau levels (p-values: 0.002–0.015).Conclusion: These results suggest that SNE to some extent may quantify the physiological basis of resilience to cognitive decline most effective at the earliest stages of AD, namely at increased amyloid burden and before increased tauopathy.
The Absence of the Transient Receptor Potential Vanilloid 1 Directly Impacts on the Expression and Localization of the Endocannabinoid System in the Mouse Hippocampus
Authors: Egaña-Huguet Jon , Bonilla-Del Río Itziar , Gómez-Urquijo Sonia M. , Mimenza Amaia , Saumell-Esnaola Miquel , Borrega-Roman Leire , García del Caño Gontzal , Sallés Joan , Puente Nagore , Gerrikagoitia Inmaculada , Elezgarai Izaskun , Grandes Pedro
Published: February 2021

The transient receptor potential vanilloid 1 (TRPV1) is a non-selective ligand-gated cation channel involved in synaptic transmission, plasticity, and brain pathology. In the hippocampal dentate gyrus, TRPV1 localizes to dendritic spines and dendrites postsynaptic to excitatory synapses in the molecular layer (ML). At these same synapses, the cannabinoid CB1 receptor (CB1R) activated by exogenous and endogenous cannabinoids localizes to the presynaptic terminals. Hence, as both receptors are activated by endogenous anandamide, co-localize, and mediate long-term depression of the excitatory synaptic transmission at the medial perforant path (MPP) excitatory synapses though by different mechanisms, it is plausible that they might be exerting a reciprocal influence from their opposite synaptic sites. In this anatomical scenario, we tested whether the absence of TRPV1 affects the endocannabinoid system. The results obtained using biochemical techniques and immunoelectron microscopy in a mouse with the genetic deletion of TRPV1 show that the expression and localization of components of the endocannabinoid system, included CB1R, change upon the constitutive absence of TRPV1. Thus, the expression of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) drastically increased in TRPV1−/− whole homogenates. Furthermore, CB1R and MAGL decreased and the cannabinoid receptor interacting protein 1a (CRIP1a) increased in TRPV1−/− synaptosomes. Also, CB1R positive excitatory terminals increased, the number of excitatory terminals decreased, and CB1R particles dropped significantly in inhibitory terminals in the dentate ML of TRPV1−/− mice. In the outer 2/3 ML of the TRPV1−/− mutants, the proportion of CB1R particles decreased in dendrites, and increased in excitatory terminals and astrocytes. In the inner 1/3 ML, the proportion of labeling increased in excitatory terminals, neuronal mitochondria, and dendrites. Altogether, these observations indicate the existence of compensatory changes in the endocannabinoid system upon TRPV1 removal, and endorse the importance of the potential functional adaptations derived from the lack of TRPV1 in the mouse brain.
An Australian State-Based Cohort Study of Autoimmune Encephalitis Cases Detailing Clinical Presentation, Investigation Results, and Response to Therapy
Authors: Swayne Andrew , Warren Nicola , Prain Kerri , Gillis David , O'Gorman Cullen , Tsang Benjamin K-T. , Muller Claire , Broadley Simon , Adam Robert J. , McCombe Pamela , Wong Richard C. , Blum Stefan
Published: February 2021

Introduction: Autoimmune encephalitis is a disorder associated with antibodies directed against central nervous system proteins with variable clinical features. This study aims to add to knowledge of the disease by reporting the details of a cohort of patients with autoimmune encephalitis in Queensland, Australia.

Methodology: We surveyed patients with autoimmune encephalitis diagnosed and managed through public hospitals in Queensland, Australia between 2010 and the end of 2019. Cases were identified via case detection through a centralized diagnostic neuroimmunology laboratory (Division of Immunology, HSQ Pathology Queensland Central Laboratory, Brisbane, Queensland, Australia) and a survey of neurologists. Data including demographic details, clinical presentation, investigation results, treatments including immune therapy and outcomes was collected.

Results: Sixty cases of antibody positive autoimmune encephalitis were identified. Twenty-eight were of anti-NMDA-receptor encephalitis with other cases associated with antibodies against LGi1, Caspr2, glycine receptor, DPPX, GABAB receptor, IgLON5, GFAP, and SOX1. The number of diagnosed cases, especially of anti-NMDA-receptor encephalitis has markedly increased over the period 2017 to 2019. Clinical presentations were marked by heterogeneous symptom complexes and prolonged hospital admissions. Imaging studies were largely normal or non-specific. There was a response to immune therapy and a low mortality rate. Most cases affected by this disorder were left with ongoing symptoms associated with mild disability.

Conclusion: Autoimmune encephalitis in Queensland, Australia is an increasingly common but complex clinical entity marked by heterogeneous presentations, response to immune therapy and outcome results marked by low mortality and incomplete recovery.
Neurologic Manifestations of the World Health Organization's List of Pandemic and Epidemic Diseases
Authors: McEntire Caleb R. S. , Song Kun-Wei , McInnis Robert P. , Rhee John Y. , Young Michael , Williams Erika , Wibecan Leah L. , Nolan Neal , Nagy Amanda M. , Gluckstein Jeffrey , Mukerji Shibani S. , Mateen Farrah J.
Published: February 2021

The World Health Organization (WHO) monitors the spread of diseases globally and maintains a list of diseases with epidemic or pandemic potential. Currently listed diseases include Chikungunya, cholera, Crimean-Congo hemorrhagic fever, Ebola virus disease, Hendra virus infection, influenza, Lassa fever, Marburg virus disease,Neisseria meningitis, MERS-CoV, monkeypox, Nipah virus infection, novel coronavirus (COVID-19), plague, Rift Valley fever, SARS, smallpox, tularemia, yellow fever, and Zika virus disease. The associated pathogens are increasingly important on the global stage. The majority of these diseases have neurological manifestations. Those with less frequent neurological manifestations may also have important consequences. This is highlighted now in particular through the ongoing COVID-19 pandemic and reinforces that pathogens with the potential to spread rapidly and widely, in spite of concerted global efforts, may affect the nervous system. We searched the scientific literature, dating from 1934 to August 2020, to compile data on the cause, epidemiology, clinical presentation, neuroimaging features, and treatment of each of the diseases of epidemic or pandemic potential as viewed through a neurologist's lens. We included articles with an abstract or full text in English in this topical and scoping review. Diseases with epidemic and pandemic potential can be spread directly from human to human, animal to human, via mosquitoes or other insects, or via environmental contamination. Manifestations include central neurologic conditions (meningitis, encephalitis, intraparenchymal hemorrhage, seizures), peripheral and cranial nerve syndromes (sensory neuropathy, sensorineural hearing loss, ophthalmoplegia), post-infectious syndromes (acute inflammatory polyneuropathy), and congenital syndromes (fetal microcephaly), among others. Some diseases have not been well-characterized from a neurological standpoint, but all have at least scattered case reports of neurological features. Some of the diseases have curative treatments available while in other cases, supportive care remains the only management option. Regardless of the pathogen, prompt, and aggressive measures to control the spread of these agents are the most important factors in lowering the overall morbidity and mortality they can cause.
The Association Between Metabolic Disturbance and Cognitive Impairments in Early-Stage Schizophrenia
Authors: Peng Xing-Jie , Hei Gang-Rui , Li Ran-Ran , Yang Ye , Liu Chen-Chen , Xiao Jing-Mei , Long Yu-Jun , Shao Ping , Huang Jing , Zhao Jing-Ping , Wu Ren-Rong
Published: February 2021

Background: Cognitive impairment is one of the core symptoms of schizophrenia, which is considered to be significantly correlated to prognosis. In recent years, many studies have suggested that metabolic disorders could be related to a higher risk of cognitive defects in a general setting. However, there has been limited evidence on the association between metabolism and cognitive function in patients with early-stage schizophrenia.

Methods: In this study, we recruited 172 patients with early-stage schizophrenia. Relevant metabolic parameters were examined and cognitive function was evaluated by using the MATRICS Consensus Cognitive Battery (MCCB) to investigate the relationship between metabolic disorder and cognitive impairment.

Results: Generally, the prevalence of cognitive impairment among patients in our study was 84.7% (144/170), which was much higher than that in the general population. Compared with the general Chinese setting, the study population presented a higher proportion of metabolic disturbance. Patients who had metabolic disturbance showed no significant differences on cognitive function compared with the other patients. Correlation analysis showed that metabolic status was significantly correlated with cognitive function as assessed by the cognitive domain scores (p < 0.05), while such association was not found in further multiple regression analysis.

Conclusions: Therefore, there may be no association between metabolic disorder and cognitive impairment in patients with early-stage schizophrenia.

Trial Registration: Clinicaltrials.gov, NCT02880462. Registered August 26, 2016.
Using EEG Alpha States to Understand Learning During Alpha Neurofeedback Training for Chronic Pain
Authors: Patel Kajal , Henshaw James , Sutherland Heather , Taylor Jason R. , Casson Alexander J. , Lopez-Diaz Karen , Brown Christopher A. , Jones Anthony K. P. , Sivan Manoj , Trujillo-Barreto Nelson J.
Published: February 2021

Objective

Alpha-neurofeedback (α-NFB) is a novel therapy which trains individuals to volitionally increase their alpha power to improve pain. Learning during NFB is commonly measured using static parameters such as mean alpha power. Considering the biphasic nature of alpha rhythm (high and low alpha), dynamic parameters describing the time spent by individuals in high alpha state and the pattern of transitioning between states might be more useful. Here, we quantify the changes during α-NFB for chronic pain in terms of dynamic changes in alpha states.

Methods

Four chronic pain and four healthy participants received five NFB sessions designed to increase frontal alpha power. Changes in pain resilience were measured using visual analogue scale (VAS) during repeated cold-pressor tests (CPT). Changes in alpha state static and dynamic parameters such as fractional occupancy (time in high alpha state), dwell time (length of high alpha state) and transition probability (probability of moving from low to high alpha state) were analyzed using Friedman’s Test and correlated with changes in pain scores using Pearson’s correlation.

Results

There was no significant change in mean frontal alpha power during NFB. There was a trend of an increase in fractional occupancy, mean dwell duration and transition probability of high alpha state over the five sessions in chronic pain patients only. Significant correlations were observed between change in pain scores and fractional occupancy (r = −0.45, p = 0.03), mean dwell time (r = -0.48, p = 0.04) and transition probability from a low to high state (r = -0.47, p = 0.03) in chronic pain patients but not in healthy participants.

Conclusion

There is a differential effect between patients and healthy participants in terms of correlation between change in pain scores and alpha state parameters. Parameters providing a more precise description of the alpha power dynamics than the mean may help understand the therapeutic effect of neurofeedback on chronic pain.
Alcohol Intake Is Associated With Elevated Serum Levels of Selenium and Selenoprotein P in Humans
Authors: Isobe Yuki , Asakura Hiroki , Tsujiguchi Hiromasa , Kannon Takayuki , Takayama Hiroaki , Takeshita Yumie , Ishii Kiyo-aki , Kanamori Takehiro , Hara Akinori , Yamashita Tatsuya , Tajima Atsushi , Kaneko Shuichi , Nakamura Hiroyuki , Takamura Toshinari
Published: February 2021

Selenoprotein P is a hepatokine with antioxidative properties that eliminate a physiologic burst of reactive oxygen species required for intracellular signal transduction. Serum levels of selenoprotein P are elevated during aging and in people with type 2 diabetes, non-alcoholic fatty liver disease, and hepatitis C. However, how serum levels of full-length selenoprotein P are regulated largely remains unknown, especially in the general population. To understand the significance of serum selenoprotein P levels in the general population, we evaluated intrinsic and environmental factors associated with serum levels of full-length selenoprotein P in 1,183 subjects participating in the Shika-health checkup cohort. Serum levels of selenium were positively correlated with liver enzymes and alcohol intake and negatively correlated with body mass index. Serum levels of selenoprotein P were positively correlated with age, liver enzymes, and alcohol intake. In multiple regression analyses, alcohol intake was positively correlated with serum levels of both selenium and selenoprotein P independently of age, gender, liver enzymes, and fatty liver on ultrasonography. In conclusion, alcohol intake is associated with elevated serum levels of selenium and selenoprotein P independently of liver enzyme levels and liver fat in the general population. Moderate alcohol intake may exert beneficial or harmful effects on health, at least partly by upregulating selenoprotein P. These findings increase our understanding of alcohol-mediated redox regulation and form the basis for the adoption of appropriate drinking guidelines.
Remodeling of Tumor Immune Microenvironment by Oncolytic Viruses
Authors: Zhang Bin , Wang Xilei , Cheng Ping
Published: February 2021

Oncolytic viruses (OVs) are potential antitumor agents with unique therapeutic mechanisms. They possess the ability of direct oncolysis and the induction of antitumor immunity. OV can be genetically engineered to potentiate antitumor efficacy by remodeling the tumor immune microenvironment. The present mini review mainly describes the effect of OVs on remodeling of the tumor immune microenvironment and explores the mechanism of regulation of the host immune system and the promotion of the immune cells to destroy carcinoma cells by OVs. Furthermore, this article focuses on the utilization of OVs as vectors for the delivery of immunomodulatory cytokines or antibodies.
Establishment and Characterization of an Irinotecan-Resistant Human Colon Cancer Cell Line
Authors: Wu Zhuo-Xun , Yang Yuqi , Zeng Leli , Patel Harsh , Bo Letao , Lin Lusheng , Chen Zhe-Sheng
Published: February 2021

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Irinotecan is widely used as a chemotherapeutic drug to treat CRC. However, the mechanisms of acquired resistance to irinotecan in CRC remain inconclusive. In the present study, we established a novel irinotecan-resistant human colon cell line to investigate the underlying mechanism(s) of irinotecan resistance, particularly the overexpression of ABC transporters. The irinotecan-resistant S1-IR20 cell line was established by exposing irinotecan to human S1 colon cancer cells. MTT cytotoxicity assay was carried out to determine the drug resistance profile of S1-IR20 cells. The drug-resistant cells showed about 47-fold resistance to irinotecan and cross-resistance to ABCG2 substrates in comparison with S1 cells. By Western blot analysis, S1-IR20 cells showed significant increase of ABCG2, but not ABCB1 or ABCC1 in protein expression level as compared to that of parental S1 cells. The immunofluorescence assay showed that the overexpressed ABCG2 transporter is localized on the cell membrane of S1-IR20 cells, suggesting an active efflux function of the ABCG2 transporter. This finding was further confirmed by reversal studies that inhibiting efflux function of ABCG2 was able to completely abolish drug resistance to irinotecan as well as other ABCG2 substrates in S1-IR20 cells. In conclusion, our work established an in vitro model of irinotecan resistance in CRC and suggested ABCG2 overexpression as one of the underlying mechanisms of acquired resistance to irinotecan. This novel resistant cell line may enable future studies to overcome drug resistance in vitro and improve CRC treatment in vivo.
Post-Operative Accelerated-Hypofractionated Chemoradiation With Volumetric Modulated Arc Therapy and Simultaneous Integrated Boost in Glioblastoma: A Phase I Study (ISIDE-BT-2)
Authors: Ferro Marica , Ferro Milena , Macchia Gabriella , Cilla Savino , Buwenge Milly , Re Alessia , Romano Carmela , Boccardi Mariangela , Picardi Vincenzo , Cammelli Silvia , Cucci Eleonora , Mignogna Samantha , Di Lullo Liberato , Valentini Vincenzo , Morganti Alessio Giuseppe , Deodato Francesco
Published: February 2021

Background

Glioblastoma Multiforme (GBM) is the most common primary brain cancer and one of the most lethal tumors. Theoretically, modern radiotherapy (RT) techniques allow dose-escalation due to the reduced irradiation of healthy tissues. This study aimed to define the adjuvant maximum tolerated dose (MTD) using volumetric modulated arc RT with simultaneous integrated boost (VMAT-SIB) plus standard dose temozolomide (TMZ) in GBM.

Methods

A Phase I clinical trial was performed in operated GBM patients using VMAT-SIB technique with progressively increased total dose. RT was delivered in 25 fractions (5 weeks) to two planning target volumes (PTVs) defined by adding a 5-mm margin to the clinical target volumes (CTVs). The CTV1 was the tumor bed plus the MRI enhancing residual lesion with 10-mm margin. The CTV2 was the CTV1 plus 20-mm margin. Only PTV1 dose was escalated (planned dose levels: 72.5, 75, 77.5, 80, 82.5, 85 Gy), while PTV2 dose remained unchanged (45 Gy/1.8 Gy). Concurrent and sequential TMZ was prescribed according to the EORTC/NCIC protocol. Dose-limiting toxicities (DLTs) were defined as any G ≥ 3 non-hematological acute toxicity or any G ≥ 4 acute hematological toxicities (RTOG scale) or any G ≥ 2 late toxicities (RTOG-EORTC scale).

Results

Thirty-seven patients (M/F: 21/16; median age: 59 years; median follow-up: 12 months) were enrolled and treated as follows: 6 patients (72.5 Gy), 10 patients (75 Gy), 10 patients (77.5 Gy), 9 patients (80 Gy), 2 patients (82.5 Gy), and 0 patients (85 Gy). Eleven patients (29.7%) had G1-2 acute neurological toxicity, while 3 patients (8.1%) showed G ≥ 3 acute neurological toxicities at 77.5 Gy, 80 Gy, and 82.5 Gy levels, respectively. Since two DLTs (G3 neurological: 1 patient and G5 hematological toxicity: 1 patient) were observed at 82.5 Gy level, the trial was closed and the 80 Gy dose-level was defined as the MTD. Two asymptomatic histologically proven radionecrosis were recorded.

Conclusions

According to the results of this Phase I trial, 80 Gy in 25 fractions accelerated hypofractionated RT is the MTD using VMAT-SIB plus standard dose TMZ in resected GBM.
Simultaneous Integrated Boost Intensity-Modulated Radiation Therapy Can Benefit the Locally Advanced Rectal Cancer Patients With Clinically Positive Lateral Pelvic Lymph Node
Authors: Li Shuai , Zhang Yangzi , Yu Yang , Zhu Xianggao , Geng Jianhao , Teng Huajing , Wang Zhilong , Sun Tingting , Wang Lin , Wang Hongzhi , Li Yongheng , Wu Aiwen , Cai Yong , Wang Weihu
Published: February 2021

Background and Purpose

The optimal treatment modality for clinically positive lateral pelvic lymph node (LPLN) from locally advanced rectal cancer (LARC) is unknown. Thus, we aimed to analyze the optimal radiotherapy dose for clinically positive LPLN from LARC.

Materials and Methods

We retrospectively evaluated distal LARC (i.e., within 8 cm from the anal verge) patients with clinically positive LPLN (i.e., ≥7 mm in the short axis). They were divided into two groups based on whether or not they received simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT)–based chemoradiotherapy. The total radiotherapy dose on LPLN were 56-60Gy for SIB-IMRT group and 41.8Gy for non-SIB-IMRT group. The clinical parameters and regrowth rate of LPLN were then compared between the two groups.

Results

A total of 151 patients were evaluated, and 83 and 68 patients were classified to the SIB-IMRT and non-SIB-IMRT group, respectively. The median follow-up period was 22.6 months, and the 2-year LPLN regrowth rate was significantly different between the SIB-IMRT group and the non-SIB-IMRT group (0% vs 10.8%, P=0.024). Further, SIB-IMRT yielded a significantly lower 2-year LPLN regrowth rate in patients whose LPLN measured ≥8 mm in the short axis (0% vs. 15.9%, P=0.019) or ≥10 mm in the long axis (0% vs. 17.6%, P=0.024) compared to patients who were in non-SIB-IMRT group. Meanwhile, there was no significant difference in grade II radiation-related toxicity (30.1% vs. 39.1%, P=0.217) and surgical complications (21.8% vs. 12.2%, P=0.198) between the two groups.

Conclusion

SIB-IMRT–based neoadjuvant chemoradiotherapy is beneficial for eliminating clinically positive LPLN from LARC without increasing the incidence of radiotherapy-related toxicity and surgical complications, and patients with larger LPLN may gain benefit from this technique.
TIM-3 as a Prognostic Marker and a Potential Immunotherapy Target in Human Malignant Tumors: A Meta-Analysis and Bioinformatics Validation
Authors: Zang Kui , Hui Liangliang , Wang Min , Huang Ying , Zhu Xingxing , Yao Bin
Published: February 2021

Background

As a novel immune checkpoint molecular, T-cell immunoglobulin mucin 3 (TIM-3) is emerging as a therapeutic target for cancer immunotherapy. However, the predictive role of TIM-3 in cancer remains largely undetermined. This study was designed to investigate the role of TIM-3 in cancer.

Methods

Publications were searched using multiple databases. The hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. To further confirm the prognostic effect of TIM-3, The Cancer Genome Atlas (TCGA) data were applied. Functional analysis of TIM-3 was also investigated.

Results

28 studies with 7284 patients with malignant tumors were identified. Based on multivariate Cox regression analysis, TIM-3 was an independent prognostic indicator for poor overall survival (OS) (HR= 1.54, 95% CI = 1.19-1.98, P = 0.001). However, TIM-3 was not correlated with cancer-specific survival and disease-free survival (DFS). Particularly, TIM-3 showed a worse prognosis in non-small cell lung carcinoma and gastric cancer; but it showed a favorable prognosis in breast cancer. Functional analysis showed that TIM-3 was closely correlated with immune responses such as T-cell activation and natural killer cell-mediated cytotoxicity. Moreover, TIM-3 expression was found to be related to worse OS in 9491 TCGA patients (HR = 1.2, P < 0.001), but was not associated with DFS.

Conclusions

TIM-3 was an independent prognostic factor. Meanwhile, TIM-3 played a crucial role in tumor immune responses. This supports TIM-3 as a promising target for cancer immunotherapy.
Survival After Combining Stereotactic Body Radiation Therapy and Tyrosine Kinase Inhibitors in Patients With Metastatic Renal Cell Carcinoma
Authors: Liu Yang , Zhang Zhiling , Han Hui , Guo Shengjie , Liu Zhuowei , Liu Mengzhong , Zhou Fangjian , Dong Pei , He Liru
Published: February 2021

Background

Stereotactic body radiation therapy (SBRT) and tyrosine kinase inhibitors (TKIs) are effective treatments for metastatic renal cell carcinoma, but data on combining these two modalities are scarce. We aimed to investigate the survival outcomes of SBRT plus TKIs.

Methods

Data of patients treated with TKIs from December 2007 to June 2019 were collected. Patients received SBRT plus TKIs (TKI + SBRT group) or TKIs alone (TKI alone group). Local control (LC), time to change of systemic therapy (TTS), and overall survival (OS) were assessed.

Results

A total of 190 patients were included, and 85 patients received TKI + SBRT. The 2-year LC rate was 92.8%. The median OS in the TKI + SBRT group was significantly longer than that of the TKI alone group (63.2 vs 29.8 months; P < 0.001). In multivariate analysis, IMDC intermediate (HR 1.96; 95% CI 1.10–3.48; P = 0.022) and poor risk (HR 2.43; 95% CI 1.25–4.75; P = 0.009), oligometastasis (HR 0.41; 95% CI 0.26–0.65; P < 0.001), and the addition of SBRT (HR 0.48; 95% CI 0.31–0.75; P = 0.001) were prognostic factors for OS. Patients with oligometastasis (P = 0.009) and those with IMDC favorable (P = 0.044) or intermediate (P = 0.002) risk had significantly longer OS with TKI + SBRT. The median TTS were 21.5, 6.4, and 9.0 months in patients receiving SBRT before first-line TKI failure, SBRT after first-line TKI failure, and first-line TKI alone (P < 0.001). Five patients (5.9%) experienced SBRT-related grade 3 toxicities.

Conclusions

Combining SBRT with TKIs is tolerable and associated with longer OS in selected patients, such as those with oligometastasis and favorable or intermediate risk.
Clinical Implications of Inflammation in Acute Myeloid Leukemia
Authors: Récher Christian
Published: February 2021

Recent advances in the description of the tumor microenvironment of acute myeloid leukemia, including the comprehensive analysis of the leukemic stem cell niche and clonal evolution, indicate that inflammation may play a major role in many aspects of acute myeloid leukemia (AML) such as disease progression, chemoresistance, and myelosuppression. Studies on the mechanisms of resistance to chemotherapy or tyrosine kinase inhibitors along with high-throughput drug screening have underpinned the potential role of glucocorticoids in this disease classically described as steroid-resistant in contrast to acute lymphoblastic leukemia. Moreover, some mutated oncogenes such as RUNX1, NPM1, or SRSF2 transcriptionally modulate cell state in a manner that primes leukemic cells for glucocorticoid sensitivity. In clinical practice, inflammatory markers such as serum ferritin or IL-6 have a strong prognostic impact and may directly affect disease progression, whereas interesting preliminary data suggested that dexamethasone may improve the outcome for AML patients with a high white blood cell count, which paves the way to develop prospective clinical trials that evaluate the role of glucocorticoids in AML.
Biological Activities of Snowdrop (Galanthus spp., Family Amaryllidaceae)
Authors: Kong Chee Kei , Low Liang Ee , Siew Wei Sheng , Yap Wei-Hsum , Khaw Kooi-Yeong , Ming Long Chiau , Mocan Andrei , Goh Bey-Hing , Goh Poh Hui
Published: February 2021

Snowdrop is an iconic early spring flowering plant of the genusGalanthus(Amaryllidaceae).Galanthusspecies (Galanthusspp.) are economically important plants as ornaments. Galanthus spp has gained significance scientific and commercial interest due to the discovery of Galanthamine as symptomatic treatment drug for Alzhiermer disease. This review aims to discuss the bioactivities ofGalanthusspp including anticholinesterase, antimicrobial, antioxidant and anticancer potential of the extracts and chemical constituents ofGalanthusspp. This review highlights thatGalanthusspp. as the exciting sources for drug discovery and nutraceutical development.
Gastrodin Inhibits Virus Infection by Promoting the Production of Type I Interferon
Authors: Zhou Yunlian , Li Mengyao , Lv Tingyi , Huang Meixia , Cheng Beilei , Zhang Yuanyuan , Zhu Jie
Published: February 2021

Type I interferon (IFN-I) plays a critical role in the antiviral immune response. However, viruses have developed different strategies to suppress the production of IFN-I for its own escape and amplification. Therefore, promoting the production of IFN-I is an effective strategy against virus infection. Gastrodin (GTD), a phenolic glucoside extracted from Gastrodia elata Blume, has been reported to play a protective role in some central nervous system -related diseases and is beneficial for the recovery of diseases by inhibiting inflammation. However, the effect of GTD on virus infection is largely unknown. Here we found GTD treatment increased the survival rate of mice infected with vesicular stomatitis virus (VSV) or herpes simplex virus-1 (HSV-1). The production of IFN-I was increased in GTD-treated mice or macrophages compared to the control group, during virus infection. Furthermore, the activation of interferon regulatory factor 3 (IRF3) was promoted by GTD in macrophages upon VSV and HSV-1 infection. Our results demonstrated that GTD could inhibit the VSV and HSV-1 infection by promoting the production of IFN-I in macrophages and might provide an effective strategy against virus infection.