bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Strong Synergy Between the Thiopeptide Bacteriocin Micrococcin P1 and Rifampicin Against MRSA in a Murine Skin Infection Model
Authors: Ovchinnikov Kirill V. , Kranjec Christian , Telke Amar , Kjos Morten , Thorstensen Tage , Scherer Siegfried , Carlsen Harald , Diep Dzung B. 
Published: July 2021

Antibiotic-resistant bacterial pathogens have become a serious threat worldwide. One of these pathogens is methicillin-resistant Staphylococcus aureus (MRSA), a major cause of skin and soft tissue infections. In this study we identified a strain of Staphylococcus equorum producing a substance with high antimicrobial activity against many Gram-positive bacteria, including MRSA. By mass spectrometry and whole genome sequencing the antimicrobial substance was identified as the thiopeptide bacteriocin micrococcin P1 (MP1). Based on its properties we developed a one-step purification protocol resulting in high yield (15 mg/L) and high purity (98%) of MP1. For shorter incubation times (5-7 h) MP1 was very potent against MRSA but the inhibitory effect was overshadowed by resistance development during longer incubation time (24h or more). To overcome this problem a synergy study was performed with a number of commercially available antibiotics. Among the antibiotics tested, the combination of MP1 and rifampicin gave the best synergistic effect, with MIC values 25 and 60 times lower than for the individual drugs, respectively. To assess the therapeutic potential of the MP1-rifampicin combination, we used a murine skin infection model based on the use of the multidrug-resistant luciferase-tagged MRSA strain Xen31. As expected, neither of the single antimicrobials (MP1 or rifampicin) could eradicate Xen31 from the wounds. By contrary, the MP1-rifampicin combination was efficient not only to eradicate but also to prevent the recurrence of Xen31 infection. Furthermore, compared to fucidin cream, which is commonly used in skin infection treatments, MP1-rifampicin combination was superior in terms of preventing resistance development. Our results show that combining MP1, and probably other thiopeptides, with antibiotics can be a promising strategy to treat SSTIs caused by MRSA and likely many other Gram-positive bacteria.
Superiority of Formalin-Fixed Paraffin-Embedded Brain Tissue for in vitro Assessment of Progressive Supranuclear Palsy Tau Pathology With [18F]PI-2620
Authors: Willroider Marie , Roeber Sigrun , Horn Anja K. E. , Arzberger Thomas , Scheifele Maximilian , Respondek Gesine , Sabri Osama , Barthel Henryk , Patt Marianne , Mishchenko Olena , Schildan Andreas , Mueller André , Koglin Norman , Stephens Andrew , Levin Johannes , Höglinger Günter U. , Bartenstein Peter , Herms Jochen , Brendel Matthias , Beyer Leonie 
Published: July 2021

Objectives: Autoradiography on brain tissue is used to validate binding targets of newly discovered radiotracers. The purpose of this study was to correlate quantification of autoradiography signal using the novel next-generation tau positron emission tomography (PET) radiotracer [18F]PI-2620 with immunohistochemically determined tau-protein load in both formalin-fixed paraffin-embedded (FFPE) and frozen tissue samples of patients with Alzheimer's disease (AD) and Progressive Supranuclear Palsy (PSP).Methods: We applied [18F]PI-2620 autoradiography to postmortem cortical brain samples of six patients with AD, five patients with PSP and five healthy controls, respectively. Binding intensity was compared between both tissue types and different disease entities. Autoradiography signal quantification (CWMR = cortex to white matter ratio) was correlated with the immunohistochemically assessed tau load (AT8-staining, %-area) for FFPE and frozen tissue samples in the different disease entities.Results: In AD tissue, relative cortical tracer binding was higher in frozen samples when compared to FFPE samples (CWMRfrozen vs. CWMRFFPE: 2.5-fold, p &lt; 0.001), whereas the opposite was observed in PSP tissue (CWMRfrozen vs. CWMRFFPE: 0.8-fold, p = 0.004). In FFPE samples, [18F]PI-2620 autoradiography tracer binding and immunohistochemical tau load correlated significantly for both PSP (R = 0.641, p &lt; 0.001) and AD tissue (R = 0.435, p = 0.016), indicating a high agreement of relative tracer binding with underlying pathology. In frozen tissue, the correlation between autoradiography and immunohistochemistry was only present in AD (R = 0.417, p = 0.014) but not in PSP tissue (R = −0.115, p = n.s.).Conclusion: Our head-to-head comparison indicates that FFPE samples show superiority over frozen samples for autoradiography assessment of PSP tau pathology by [18F]PI-2620. The [18F]PI-2620 autoradiography signal in FFPE samples reflects AT8 positive tau in samples of both PSP and AD patients.
Construction of an Immune-Related Six-lncRNA Signature to Predict the Outcomes, Immune Cell Infiltration, and Immunotherapy Response in Patients With Hepatocellular Carcinoma
Authors: Zhou Pengcheng , Lu Yuhua , Zhang Yewei , Wang Lei 
Published: July 2021

BackgroundHepatocellular carcinoma (HCC) is one of the world’s most lethal malignant tumors with a poor prognosis. Growing evidence has been demonstrating that immune-related long non-coding RNAs (lncRNAs) are relevant to the tumor microenvironment (TME) and can help assess the effects of immunotherapy and evaluate one’s prognosis. This study aims to identify an immune-related lncRNA signature for the prospective assessment of the immunotherapy and prognosis in HCC.MethodWe downloaded HCC RNA-seq data and clinical information from The Cancer Genome Atlas (TCGA) project database. We first used ESTIMATE to evaluate the TME. Then, we conducted a cox regression analysis to construct a prognostic signature and the riskScore. We then applied the univariate Cox regression, multivariate Cox regression, principal components analysis (PCA), receiver operating characteristic (ROC) curve, and stratification analyses to confirm our previous assessments. Afterward, we employed a gene set enrichment analysis (GSEA) to explore the biological processes and pathways. Besides, we used CIBERSORT to estimate the abundance of tumor-infiltrating immune cells (TIICs). Furthermore, we investigated the relationship between the immune-related lncRNA signature and immune checkpoint genes. Finally, we used the quantitative real-time polymerase chain reaction (qRT-PCR) assays to demonstrate the expression of the six lncRNAs.ResultsWe identified six immune-related lncRNAs — MSC-AS1, AC145207.5, SNHG3, AL365203.2, AL031985.3, NRAV — which show the ability to stratify patients into high-risk and low-risk groups with significantly different survival rates. The univariate Cox regression, multivariate Cox regression, ROC, and stratification analyses confirmed that the immune-related six-lncRNA signature was a novel independent prognostic factor in HCC patients. The high-risk group and low-risk group illustrated contrasting distributions in PCA. The GSEA suggested that the immune-related six-lncRNA signature was involved in the immune-related biological processes and pathways. Besides, the immune-related six-lncRNA signature was associated with the infiltration of immune cells. Furthermore, it was linked with the expression of critical immune genes and could predict immunotherapy’s clinical response. Finally, the qRT-PCR demonstrated that the six lncRNAs were significantly differentially expressed in HCC cell lines and normal hepatic cell lines.ConclusionIn summary, we identified an immune-related six-lncRNA signature that can predict the outcomes, immune cell infiltration, and immunotherapy response in patients with hepatocellular carcinoma.
Systematic Review and Meta-Analysis of Renin–Angiotensin–Aldosterone System Blocker Effects on the Development of Cardiovascular Disease in Patients With Chronic Kidney Disease
Authors: Yanai Katsunori , Ishibashi Kenichi , Morishita Yoshiyuki 
Published: July 2021

Background: Cardiovascular events are one of the most serious complications that increase the risk of mortality and morbidity in pre-dialysis and on-dialysis chronic kidney disease (CKD) patients. Activation of the renin–angiotensin–aldosterone system (RAAS) is considered to contribute to the development of cardiovascular events in these populations. Therefore, several kinds of RAAS blockers have been frequently prescribed to prevent cardiovascular events in patients with CKD; however, their effectiveness remains controversial. This systematic review focuses on whether RAAS blockers prevent cardiovascular events in patients with CKD.Method: PubMed were searched to retrieve reference lists of eligible trials and related reviews. Randomized prospective controlled trials that investigated the effects on cardiovascular events in CKD patients that were published in English from 2010 to 2020 were included.Results: Among 167 identified studies, 11 eligible studies (n = 8,322 subjects) were included in the meta-analysis. The meta-analysis showed that RAAS blockers significantly reduced cardiovascular events in on-dialysis patients with CKD [three studies; odds ratio (OR), 0.52; 95% confidence interval (CI), 0.36 to 0.74; p = 0.0003], but there was no significant difference in pre-dialysis patients with CKD because of the heterogeneity in each study (eight studies). We also investigated the effects of each kind of RAAS blocker on cardiovascular events in CKD patients. Among the RAAS blockers, mineralocorticoid receptor antagonists significantly decreased cardiovascular events in pre-dialysis or on-dialysis patients with CKD (four studies; OR, 0.60; 95%CI, 0.50 to 0.73, p &lt; 0.0001). However, angiotensin receptor blockers did not show significant effects (four studies; OR, 0.65; 95%CI, 0.42 to 1.01; p = 0.0529). The effects of angiotensin converting enzyme inhibitors and direct renin inhibitors on cardiovascular events in patients with CKD could not be analyzed because there were too few studies.Conclusion: Mineralocorticoid receptor antagonists may decrease cardiovascular events in pre-dialysis or on-dialysis patients with CKD.
Evidence That Tumor Microenvironment Initiates Epithelial-To-Mesenchymal Transition and Calebin A can Suppress it in Colorectal Cancer Cells
Authors: Buhrmann Constanze , Brockmueller Aranka , Harsha Choudhary , Kunnumakkara Ajaikumar B. , Kubatka Peter , Aggarwal Bharat B. , Shakibaei Mehdi 
Published: July 2021

Background: Tumor microenvironment (TME) has a pivotal impact on tumor progression, and epithelial-mesenchymal transition (EMT) is an extremely crucial initial event in the metastatic process in colorectal cancer (CRC) that is not yet fully understood. Calebin A (an ingredient in Curcuma longa) has been shown to repress CRC tumor growth. However, whether Calebin A is able to abrogate TME-induced EMT in CRC was investigated based on the underlying pathways.Methods: CRC cell lines (HCT116, RKO) were exposed with Calebin A and/or a FAK inhibitor, cytochalasin D (CD) to investigate the action of Calebin A in TME-induced EMT-related tumor progression.Results: TME induced viability, proliferation, and increased invasiveness in 3D-alginate CRC cultures. In addition, TME stimulated stabilization of the master EMT-related transcription factor (Slug), which was accompanied by changes in the expression patterns of EMT-associated biomarkers. Moreover, TME resulted in stimulation of NF-κB, TGF-β1, and FAK signaling pathways. However, these effects were dramatically reduced by Calebin A, comparable to FAK inhibitor or CD. Finally, TME induced a functional association between NF-κB and Slug, suggesting that a synergistic interaction between the two transcription factors is required for initiation of EMT and tumor cell invasion, whereas Calebin A strongly inhibited this binding and subsequent CRC cell migration.Conclusion: We propose for the first time that Calebin A modulates TME-induced EMT in CRC cells, at least partially through the NF-κB/Slug axis, TGF-β1, and FAK signaling. Thus, Calebin A appears to be a potential agent for the prevention and management of CRC.
Prolonged Right Ventricular Outflow Tract Endocardial Activation Duration and Presence of Deceleration Zones in Patients With Idiopathic Premature Ventricular Contractions. Association With Low Voltage Areas
Authors: Parreira Leonor , Carmo Pedro , Marinheiro Rita , Mesquita Dinis , Farinha José , Esteves Ana , Amador Pedro , Ferreira António , Fonseca Marta , Caria Rui , Adragao Pedro 
Published: July 2021

Background and AimsThe wavefront propagation velocity in the myocardium with fibrosis is characterized by the presence of deceleration zones and late activated zones, that are absent in the normal myocardium. Our aim was to study the right ventricular outflow tract (RVOT) endocardial activation duration in sinus rhythm, and assess the presence of deceleration zones, in patients with premature ventricular contractions (PVCs) and in controls.MethodsWe studied 29 patients with idiopathic PVCs from the outflow tract, subjected to catheter ablation that had an activation and voltage map of the RVOT in sinus rhythm. A control group of 15 patients without PVCs that underwent ablation of supraventricular arrhythmias was also studied. RVOT endocardial activation duration and number of 10 ms isochrones across the RVOT were assessed. Propagation speed was calculated at the zone with the higher number of isochrones per cm radius. Deceleration zones were defined as zones with &gt;3 isochrones within 1 cm radius. Low voltage areas were defined as areas with local electrogram with amplitude &lt;1.5 mV.ResultsThe two groups did not differ in relation to age, gender or number of points in the map. RVOT endocardial activation duration and number of 10 ms isochrones were higher in the PVC group; 56 (41–66) ms vs. 39 (35–41) ms, p = 0.001 and 5 (4–8) vs. 4 (4–5), p = 0.001. Presence of deceleration zones and low voltage areas were more frequent in the PVC group; 20 (69%) vs. 0 (0%), p &lt; 0.0001 and 21 (72%) vs. 0 (0%), p &lt; 0.0001. The wavefront propagation speed was significantly lower in patients with PVCs than in the control group, 0.35 (0.27–0.40) vs. 0.63 (0.56–0.66) m/s, p &lt; 0.0001. Patients with low voltage areas had longer activation duration 60 (52–67) vs. 36 (32–40) ms, p &lt; 0.0001, more deceleration zones, 20 (95%) vs. 0 (0%), p &lt; 0.0001, and lower wavefront propagation speed, 0.30 (0.26–0.36) vs. 0.54 (0.36–0.66) m/s, p = 0.002, than patients without low voltage areas.ConclusionRight ventricular outflow tract endocardial activation duration was longer, propagation speed was lower and deceleration zones were more frequent in patients with PVCs than in controls and were associated with the presence of low voltage areas.
The Psychological Impact of the Coronavirus Disease 2019 Pandemic on Pregnant Women in China
Authors: Zheng Zheng , Zhang Ruoxi , Liu Tao , Cheng Pei , Zhou Yanhong , Lu Weicong , Xu Guiyun , So Kwok-Fai , Lin Kangguang 
Published: July 2021

Background: The coronavirus disease 2019 (COVID-19) pandemic has been reported to have negative psychological impact on mental health. Nonetheless, there are few studies investigating the impacts on pregnant women. This study investigated the psychological impact of COVID-19 pandemic on pregnant women, and the associated risk factors that moderated this impact.Methods and Materials: A total of 2,798 pregnant participants were recruited from the Guangzhou Women and Children's Medical Center. The Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7) and Insomnia Severity Index (ISI) were used to assess depression, generalized anxiety disorder and insomnia, respectively, during and before the COVID-19 pandemic. The Impact of Event Scale-Revised (IES-R) was used to assess psychological stress during the COVID-19 pandemic.Results: During the COVID-19 pandemic, over one third of pregnant participants reported mild depression, around 20% experienced mild generalized anxiety, about one third reported problems with sleeping, and more than 15% felt mild psychological stress. The occurrence of psychological problems was significantly higher during the COVID-19 pandemic when compared to before the outbreak. The previously described pattern that pregnant women in the first trimester are more likely to report depression, and those in the third trimester are more likely to report insomnia and psychological stress, was also recognized in our study population. Mental health issues existing before the outbreak were risk factors, while family support was a protective factor in the occurrence of the measured mental health problems during the COVID-19 pandemic.Conclusion: Our data suggest pregnant women's mental health is inevitably affected during the COVID-19 pandemic. Pregnant women in the first and third trimester and those who experienced mental issues before the outbreak may be particularly affected.
Victims of the Terrorist Attacks in Belgium and Professional Mental Health Aid Barriers: A Qualitative Study
Authors: Van Overmeire Roel , Muysewinkel Emilie , Van Keer Rose-Lima , Vesentini Lara , Bilsen Johan 
Published: July 2021

Introduction: Terrorist attacks can cause short and long-term stress-reactions, anxiety, and depression among those exposed. Sometimes, professional mental health aid, meaning all types of professional psychotherapy, would be appropriate, but victims often delay or never access mental health aid, even up to a decade after the initial event. Little is known about the barriers terrorist-victims encounter when they try to access professional mental health aid.Method: Using a qualitative design, 27 people exposed to the 22/03/2016 terrorist attack in Belgium were interviewed using half-structured, in-depth interviews, on their experiences with professional mental health aid. A reflexive thematic analysis was employed.Results: Five main barriers for professional mental health aid seeking by victims were found. First, their perception of a lack of expertise of mental health aid professionals. Second, the lack of incentives to overcome their uncertainty to contact a professional. Third, social barriers: people did not feel supported by their social network, feared stigma, or trusted that the support of their social network would be enough to get them through any difficulties. Fourth, a lack of mental health literacy, which seems to be needed to recognize the mental health issues they are facing. Finally, there are financial barriers. The cost of therapy is often too high to begin or continue therapy.Conclusions: This study showed that the barriers for seeking professional mental health aid are diverse and not easily overcome. More mental health promotion is needed, so that there is a societal awareness of possible consequences of being exposed to terrorist attacks, which might result in less stigma, and a quicker realization of possible harmful stress reactions due to a disaster.
Study Protocol—Coping With the Pandemics: What Works Best to Reduce Anxiety and Depressive Symptoms
Authors: Fortea Lydia , Solanes Aleix , Pomarol-Clotet Edith , Garcia-Leon Maria Angeles , Fortea Adriana , Torrent Carla , Varo Cristina , Bonnin C. Mar , Montejo Laura , Alonso Jordi , Carmona Susana , Soldevila-Matías Pau , Alustiza Irene , Arbós Daniel , Hidalgo-Mazzei Diego , Grande Iria , Vieta Eduard , Fullana Miquel Àngel , Radua Joaquim 
Published: July 2021

Background: The coronavirus disease 2019 (COVID-19) pandemic and lockdown might increase anxiety and depressive symptoms in most individuals. Health bodies recommend several coping behaviors to protect against such symptoms, but evidence on the relationship between these behaviors and symptoms mostly comes from cross-sectional studies in convenience samples. We will conduct a prospective longitudinal study of the associations between coping behaviors and subsequent anxiety and depressive symptoms during the COVID-19 pandemic in a representative sample of the Spanish general adult population.Methods: We will recruit 1,000 adult participants from all autonomous communities of Spain and with sex, age, and urbanicity distributions similar to those of their populations and assess anxiety and depressive symptoms and coping behaviors using fortnightly questionnaires and real-time methods (ecological momentary assessments) for 1 year. The fortnightly questionnaires will inquire about anxiety and depressive symptoms [General Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9)] and the frequency of 10 potential coping behaviors (e.g., follow a routine) during the past 2 weeks. In addition, we will collect several variables that could confound or moderate these associations. These will include subjective well-being [International Positive and Negative Affect Schedule Short Form (I-PANAS-SF) and Satisfaction with Life Scale (SWLS)], obsessive-compulsive symptoms [Obsessive Compulsive Inventory-Revised (OCI-R)], personality and emotional intelligence [International Personality Item Pool (IPIP) and Trait Emotional Intelligence Questionnaire Short Form (TEIQue-SF)], sociodemographic factors (e.g., work status, housing-built environment), and COVID-19 pandemic-related variables (e.g., hospitalizations or limitations in social gatherings). Finally, to analyze the primary relationship between coping behaviors and subsequent anxiety and depressive symptoms, we will use autoregressive moving average (ARMA) models.Discussion: Based on the study results, we will develop evidence-based, clear, and specific recommendations on coping behaviors during the COVID-19 pandemic and lockdown. Such suggestions might eventually help health bodies or individuals to manage current or future pandemics.
Safety and Preliminary Efficacy of Lorcaserin for Cocaine Use Disorder: A Phase I Randomized Clinical Trial
Authors: Johns Sade E. , Keyser-Marcus Lori , Abbate Antonio , Boone Edward , Van Tassell Benjamin , Cunningham Kathryn A. , Anastasio Noelle C. , Poklis Justin L. , Ramey Tatiana , Moeller F. Gerard 
Published: July 2021

Background and Objectives: Preclinical studies show serotonin (5-HT) 5-HT2C receptor (5-HT2CR) agonists reduce cocaine-seeking and cocaine intake. This study examined safety of the 5-HT2CR agonist lorcaserin administered with cocaine in participants with cocaine use disorder (CocUD). Secondarily, subjective response to cocaine and choice of cocaine vs. money were examined.Methods: A double-blind, randomized, placebo-controlled trial of 25 inpatient non-treatment seeking participants with CocUD. Participants were randomized to either lorcaserin (n = 17) or placebo (n = 8). Primary outcome measures included cardiovascular measures and plasma cocaine levels. Secondary measures of subjective response to cocaine were assessed using a visual analog scale (VAS) and cocaine vs. money progressive ratio choice sessions.Results: Thirteen randomized participants were included in the final analysis. No serious or unexpected adverse events were related to lorcaserin. There were no significant interactions between cocaine and lorcaserin on cardiovascular measures, plasma cocaine, or subjective ratings. After multiple comparisons correction, cocaine significantly increased blood pressure, heart rate, and QTc. Lorcaserin significantly decreased VAS ratings of “feel irritable,” “feel hungry,” and “I am craving.” For the cocaine vs. money choice procedure, there was a significant interaction between choice (cocaine vs. money) and lorcaserin. Participants treated with lorcaserin were more likely to choose cocaine.Discussion and Conclusions: This study showed safety of lorcaserin administered with cocaine but lack of efficacy to reduce the reinforcing effects of cocaine.Scientific Significance: This study is the first to show a disconnect between effects of 5-HT2CR agonists on craving and cocaine choice in human cocaine users.