bluuebunny/crossref_metadata_2025_split huggingface dataset:
25B‐NBOMe, a novel N‐2‐methoxybenzyl‐phenethylamine (NBOMe) derivative, may induce rewarding and reinforcing effects via a dopaminergic mechanism: Evidence of abuse potential
Authors: Custodio Raly James Perez , Sayson Leandro Val , Botanas Chrislean Jun , Abiero Arvie , You Kyung Yi , Kim Mikyung , Lee Hyun Jun , Yoo Sung Yeun , Lee Kun Won , Lee Yong Sup , Seo Joung‐Wook , Ryu In Soo , Kim Hee Jin , Cheong Jae Hoon 
Published: November 2019

AbstractAn increasing number of N‐2‐methoxybenzyl‐phenethylamine (NBOMe) derivatives are being misused worldwide, including the potent hallucinogen 2‐(4‐bromo‐2,5‐dimethoxyphenyl)‐N‐(2‐methoxybenzyl)ethanamine (25B‐NBOMe). However, the number of studies characterizing the abuse potential and psychopharmacological properties of 25B‐NBOMe is limited; thus, we examined its rewarding and reinforcing effects using conditioned place preference (CPP) and self‐administration (SA) tests. Pretreatment with SCH23390 (SCH), Haloperidol (HAL), and ketanserin (KS), antagonists of dopamine D1 (DRD1), dopamine D2 (DRD2), and serotonin 2A (5‐HT2A receptor) receptors, respectively, was utilized during a CPP test to investigate the involvement of the dopaminergic and serotonergic systems in 25B‐NBOMe‐mediated effects. We also examined the effects of 25B‐NBOMe on the expression of dopamine‐related proteins in the nucleus accumbens (NAcc) and ventral tegmental area (VTA). Then, we measured the dopamine level, phosphorylated CREB (p‐CREB), deltaFosB (ΔFosB), and brain‐derived neurotrophic factor (BDNF) in the NAcc. In addition, we explored the involvement of 5‐HT2A receptors in the 25B‐NBOMe‐induced head twitch response (HTR). We also examined the effects of 25B‐NBOMe on brain wave activity using electroencephalography. 25B‐NBOMe elicited CPP and SA. SCH and HAL blocked 25B‐NBOMe‐induced CPP, whereas KS did not. Moreover, 25B‐NBOMe altered the DRD1, DRD2, and dopamine transporter expression and increased dopamine levels. It also induced changes in p‐CREB, ΔFosB, and BDNF expression. 25B‐NBOMe induced HTR and increased 5‐HT2A receptor mRNA levels, effects inhibited by KS. Furthermore, 25B‐NBOMe altered delta and gamma wave activity, which was normalized by SCH and HAL. These findings show that 25B‐NBOMe may induce rewarding and reinforcing effects via a dopaminergic mechanism, suggesting its abuse potential.
Microbial risk factors for treatment failure of pivmecillinam in community‐acquired urinary tract infections caused by ESBL‐producing Escherichia coli
Authors: Syre Heidi , Hetland Marit Andrea Klokkhammer , Bernhoff Eva , Bollestad Marianne , Grude Nils , Simonsen Gunnar Skov , Löhr Iren Høyland 
Published: November 2019

The aim of this study was to identify microbial risk factors for treatment failure of pivmecillinam in community‐acquired urinary tract infections (ca‐UTIs) caused by ESBL‐producing Escherichia coli. Eighty‐nine ESBL‐producing E. coli isolated from women suffering from ca‐UTIs were included. The susceptibilities to mecillinam were determined using MIC gradient strip. Whole genome sequencing was performed on a MiSeq platform, and genome assembly was performed using SPAdes v3.11.0. Neither mecillinam MICs nor ESBL genotypes were associated with treatment outcome of patients treated with pivmecillinam. Specific STs, however, showed significant differences in treatment outcome. Patients infected with ST131 were more likely to experience treatment failure compared to patients infected with non‐ST131 (p 0.02) when adjusted for pivmecillinam dose, mecillinam MIC and severity of infection. Patients infected with ST69 were more often successfully treated compared to patients infected with non‐ST69 (p 0.04). Patients infected with blaCTX‐M‐15 ST131 strains were more likely to experience treatment failure than those infected with non‐blaCTX‐M‐15 ST131 strains (p 0.02). The results suggest that specific STs are associated with the clinical efficacy of pivmecillinam. Further studies with a larger number of strains, including a larger number of mecillinam resistant strains, are needed to confirm these results.
Results of phase 2 trials exploring the safety and efficacy of omiganan in patients with human papillomavirus‐induced genital lesions
Authors: Rijsbergen Melanie , Rijneveld Rianne , Todd Marina , Feiss Gary L. , Kouwenhoven Stijn T.P. , Quint Koen D. , van Alewijk Dirk C.J.G. , de Koning Maurits N.C. , Klaassen Erica S. , Burggraaf Jacobus , Rissmann Robert , van Poelgeest Mariëtte I.E. 
Published: November 2019

AimsTo assess safety and tolerability and explore pharmacodynamics and efficacy of omiganan in external anogenital warts (AGW) and vulvar high‐grade squamous intraepithelial lesions (HSIL).MethodsTwo randomized controlled trials in patients with external AGW and vulvar HSIL were conducted. Patients received topical omiganan 2.5% or placebo gel once daily for 12 weeks with a follow‐up of 12 weeks. Safety and tolerability were monitored and pharmacodynamics and clinical efficacy of omiganan were assessed by analysing lesion count, size and viral load. Self‐reported pain, itch and quality of life were assessed by an electronic diary and questionnaire.ResultsTwenty‐four AGW and 12 vulvar HSIL patients were enrolled. All patients had a high treatment adherence (99%). No serious adverse events occurred and all adverse events (n = 27) were mild, transient and self‐limiting. The treatment groups were not different in terms of safety and tolerability, lesion count and size, and patient‐reported outcomes pain, itch and quality of life. Human papillomavirus load significantly reduced after 12 weeks of treatment with omiganan compared to placebo (–96.6%; 95% confidence interval –99.9 to –7.4%; P = .045) in AGW patients only.ConclusionTopical omiganan appears to be safe in patients with AGW and vulvar HSIL and reduced human papillomavirus load after 12 weeks of treatment in AGW patients.
Modelling pharmacokinetics and pharmacodynamics of the selective S1P1 receptor modulator cenerimod in healthy subjects and systemic lupus erythematosus patients
Authors: Lott Dominik , Juif Pierre‐Eric , Dingemanse Jasper , Krause Andreas 
Published: November 2019

AimsAssessment of time to attain steady state as well as drug accumulation following long‐term treatment with the selective sphingosine‐1‐phosphate 1 receptor modulator cenerimod and prediction of the incidence of low total lymphocyte (LY) counts. Differences in pharmacokinetics and pharmacodynamics based on demographic characteristics and between healthy subjects and systemic lupus erythematosus (SLE) patients were to be identified.MethodsData from 4 Phase I studies and 1 Phase II study were pooled to develop a population pharmacokinetic/pharmacodynamic model describing cenerimod concentration and its effect on LY count. Simulations addressed the objectives.ResultsSimulations of 365 days of treatment indicated a time to steady state of 49 days and changes in exposure of 15% beyond 35 days. For a dose of 2 mg, the predicted incidences of LY counts below 0.5 and 0.2 × 109 cells/L were 18.2 and 0.6% for healthy subjects and 25.9 and 1.0% for SLE patients, respectively. Incidence increased with higher dose and lower baseline LY counts. For body weights of 50 and 100 kg compared to 75 kg, exposure was predicted to change by +37% and −20%, respectively.ConclusionLong‐term cenerimod administration is not expected to result in exposure and LY count reduction substantially different from results of completed studies. Low LY counts are predicted to occur more frequently in SLE patients compared to healthy subjects. Dose individualization based on the model is not considered necessary. Model‐based simulations enable benefit–risk evaluations, supporting planning of late‐phase clinical studies and scientific exchange with health authorities.
Eosinophil cytolysis on Immunoglobulin G is associated with microtubule formation and suppression of rho‐associated protein kinase signalling
Authors: Esnault Stephane , Leet Jonathan P. , Johansson Mats W. , Barretto Karina T. , Fichtinger Paul S. , Fogerty Frances J. , Bernau Ksenija , Mathur Sameer K. , Mosher Deane F. , Sandbo Nathan , Jarjour Nizar N. 
Published: November 2019

AbstractBackgroundThe presence of eosinophils in the airway is associated with asthma severity and risk of exacerbations. Cell‐free eosinophil granules are found in tissues in eosinophilic diseases, including asthma. This suggests that eosinophils have lysed and released cellular content, likely harming tissues.ObjectiveThe present study explores the mechanism of CD32‐ and αMß2 integrin‐dependent eosinophil cytolysis of IL3‐primed blood eosinophils seeded on heat‐aggregated immunoglobulin G (HA‐IgG).MethodsCytoskeletal events and signalling pathways potentially involved in cytolysis were assessed using inhibitors. The level of activation of the identified events and pathways involved in cytolysis was measured. In addition, the links between these identified pathways and changes in degranulation (exocytosis) and adhesion were analysed.ResultsCytolysis of IL3‐primed eosinophils was dependent on the production of reactive oxygen species (ROS) and downstream phosphorylation of p‐38 MAPK. In addition, formation of microtubule (MT) arrays was necessary for cytolysis and was accompanied by changes in MT dynamics as measured by phosphorylation status of stathmin and microtubule‐associated protein 4 (MAP4), the latter of which was regulated by ROS production. Reduced ROCK signalling preceded cytolysis, which was associated with eosinophil adhesion and reduced migration.Conclusion and Clinical RelevanceIn this CD32‐ and αMß2 integrin‐dependent adhesion model, lysing eosinophils exhibit reduced migration and ROCK signalling, as well as both MT dynamic changes and p‐38 phosphorylation downstream of ROS production. We propose that interfering with these pathways would modulate eosinophil cytolysis and subsequent eosinophil‐driven tissue damage.
What do we know about the cytological features of pure intraductal carcinomas of the salivary glands?
Authors: Palicelli Andrea 
Published: November 2019

AbstractObjectiveIntraductal carcinomas (IDCs) are rare, poorly characterised salivary gland tumours. The cytological features of IDCs are even less known. In this paper, a systematic literature review of pure IDCs (without stromal invasion, not associated with other histotypes) of low‐grade (LG‐IDCs) and high‐grade (HG‐IDCs) was performed.MethodsThe bibliographic research included multiple databases (PubMed, Scopus, Web of Science). Mild‐moderate nuclear atypia favoured LG‐IDCs, severe atypia favoured HG‐IDCs.ResultsPreoperative fine‐needle aspiration cytology (FNAC) was performed in 13/94 published cases (14%): 10 parotid; two oral; one submandibular. All the cases were histologically LG‐IDCs, except two parotid IDCs. FNAC results included: negative for malignancy (three of 13 cases, 23%); tumour of uncertain malignant potential (seven of 13, 54%); malignancy (three of 13, 23%). The ductal component was identified in two cases; mucoepidermoid carcinoma was suggested in two additional cases. The grade was underestimated on FNAC evaluation in one HG‐IDC as focal high‐grade features were present on subsequent histological examination. The cases diagnosed as malignant tumours or describing intermediate atypia resulted in LG‐IDCs on subsequent histology. Occasional mitoses were described only in one HG‐IDC; this feature may have not been considered in the remaining published cases.ConclusionsFNAC and clinico‐pathological correlation are important aids for clinicians and pathologists. FNAC could assist surgery even if an accurate diagnosis is sometimes impossible. Discrepancy in grading the nuclear atypia between the FNAC material and the resected specimen can occur, sometimes being unavoidable. Further studies are needed to better characterise this rare tumour.
KCNQ1OT1 promotes migration and inhibits apoptosis by modulating miR‐185‐5p/Rab14 axis in oral squamous cell carcinoma
Authors: Bao Qiyan , Liao Xiangling , Li Rongyin , Ding Nan 
Published: November 2019

AbstractLong non‐coding RNAs (lncRNAs) play essential roles in the regulation of gene transcription in carcinogenesis and metastasis via interacting with microRNA. In this study, we explored the expressions and functions of lncRNA KCNQ1OT1 and miR‐185‐5p in oral squamous cell carcinoma (OSCC) cells. KCNQ1OT1 expression in OSCC tissues and cells was examined by qRT‐PCR. Small interfering RNAs against KCNQ1OT1 (si‐ KCNQ1OT1) were used to knockdown KCNQ1OT1 in OSCC cells. Cell function was assessed by wound healing assay, transwell assay, and apoptosis detection. The binding region between KCNQ1OT1 and miR‐185‐5p was confirmed by luciferase assays. MiR‐185‐5p expression was measured by qRT‐PCR. Rab14 was confirmed as a downstream target gene of miR‐185‐5p by measuring luciferase activities. The protein level of Rab14 in OSCC cells transfected with miR‐185‐5p or si‐KCNQ1OT1 was determined by Western blot. The OSCC cell function and Rab14 expression after co‐transfection of si‐KCNQ1OT1 and miR‐185‐5p inhibitor were also examined. KCNQ1OT1 was upregulated in OSCC tissues and cells. KCNQ1OT1 silencing suppressed OSCC cell malignancy and downregulated miR‐185‐5p level, which showed upregulated expression in OSCC samples. Rab14 as a target gene of miR‐185‐5p was highly expressed in OSCC. KCNQ1OT1 knockdown impaired the invasion capability of OSCC cells, promoted apoptosis, and suppressed Rab14 expression. The inhibition of miR‐185‐5p in KCNQ1OT1 silencing cells reversed the suppression of Rab14 and restored the cancerous growth of OSCC cells. These results indicated that KCNQ1OT1 promoted OSCC tumorigenesis via the modulation of miR‐185‐5p/Rab14 axis, which may serve as a therapeutic target for the treatment of OSCC.
The Brief 10‐Item Community Assessment of Psychic Experiences‐Positive Scale (Brief CAPE‐P10): Initial psychometric properties, gender measurement invariance and mean differences among Nigerian adolescents
Authors: Aloba Olutayo , Opakunle Tolulope 
Published: November 2019

AbstractAimThe aim of this study was to evaluate the Community Assessment of Psychic Experiences—Positive Scale (CAPE‐P) for its psychometric properties in terms of its reliability and validity, in addition to its factor structure and gender measurement invariance among Nigerian adolescents (n = 1336, Mage = 15.15).MethodsThe sample consisted of 606 (45.4%) males, who completed the 20‐items CAPE‐P in addition to the Positive and Negative Suicide Ideation Inventory (PANSI), the Hospital Anxiety and Depression Scale (HADS) and the Rosenberg Self‐Esteem Scale (RSES). We compared 11 a priori models of the CAPE‐P with the aim of identifying the one with the best fit indices applying Confirmatory Factor Analysis (CFA). Gender measurement invariance was examined with nested multiple‐group confirmatory factor analysis (MGCFA).ResultsAll the 11 a priori models had poor fit indices. An examination of the scale's 20 items revealed that 10 items had poor correlation with the overall scale. The remaining 10 items which we labelled as the Brief CAPE—P10 were subjected to CFA which yielded a 3‐factor model (Bizarre Experiences‐5 items, Delusional Ideation‐3 items and Perceptual Anomalies‐2 items) with satisfactory fit indices (CFI = 0.961, SRMR = 0.0376, RMSEA = 0.062/90% CI = 0.052‐0.069).The validity and reliability of the Brief CAPE—P10 and its subscales were modestly satisfactory. MGCFA affirmed the configural, metric and scalar gender invariance of the 3‐factor Brief CAPE‐P10.ConclusionsThe Brief CAPE—P10 is a promising instrument for the evaluation of PLEs among Nigerian adolescents.
Mean growth rate when rare is not a reliable metric for persistence of species
Authors: Pande Jayant , Fung Tak , Chisholm Ryan , Shnerb Nadav M. 
Published: November 2019

AbstractThe coexistence of many species within ecological communities poses a long‐standing theoretical puzzle. Modern coexistence theory (MCT) and related techniques explore this phenomenon by examining the chance of a species population growing from rarity in the presence of all other species. The mean growth rate when rare, , is used in MCT as a metric that measures persistence properties (like invasibility or time to extinction) of a population. Here we critique this reliance on and show that it fails to capture the effect of temporal random abundance variations on persistence properties. The problem becomes particularly severe when an increase in the amplitude of stochastic temporal environmental variations leads to an increase in , since at the same time it enhances random abundance fluctuations and the two effects are inherently intertwined. In this case, the chance of invasion and the mean extinction time of a population may even go down as increases.
P‐glycoprotein: a role in the export of amyloid‐β in Alzheimer's disease?
Authors: Chai Amanda B. , Leung Gavin K. F. , Callaghan Richard , Gelissen Ingrid C. 
Published: November 2019

The accumulation of amyloid‐β (Aβ) peptides is a key histopathological feature of the Alzheimer's brain. Defective clearance mechanisms result in toxic levels of soluble Aβ40 and Aβ42 oligomers, leading to impaired synaptic function, neurodegeneration and cognitive decline. Growing evidence points to the involvement of P‐glycoprotein (P‐gp or ABCB1), an ATP‐binding cassette transporter highly expressed on the luminal side of the blood–brain barrier, in facilitating the clearance of Aβ from the brain. In this review, we summarise evidence from human, animal and in vitro studies examining the contribution of P‐gp to Aβ clearance, and discuss the potential for P‐gp as a novel pharmacological target in Alzheimer's disease (AD). P‐gp expression and activity in the brain are inversely correlated with ageing, Aβ deposition and AD. Moreover, Aβ itself has been found to compromise the expression of P‐gp, thereby exacerbating Aβ deposition and disease. Despite decades of research, the pathophysiology of AD remains elusive. Understanding the normal versus impaired processing and clearance mechanisms affecting Aβ peptides will assist the development of more effective therapeutic agents to combat this progressive neurodegenerative condition that continues to devastate millions of patients globally.
Comparison between the Identification of Seniors at Risk and Triage Risk Screening Tool in predicting mortality of older adults visiting the emergency department: Results from Indonesia
Authors: Rizka Aulia , Harimurti Kuntjoro , Pitoyo Ceva W , Koesnoe Sukamto 
Published: November 2019

AimAmong others, the Identification of Seniors at Risk (ISAR) and Triage Risk Screening Tool (TRST) are widely used screening instruments for risk stratification of older adults visiting the emergency department (ED). In developing countries, such as Indonesia, older patients often present with acute and severe conditions, leading to a high mortality rate, in which the performance of these two instruments have not been studied. This study aimed to measure the performance of the ISAR and TRST to predict 1‐ and 3‐month mortality in older patients visiting the ED in Indonesia.MethodsThis was a prospective cohort study of older patients consecutively visiting the ED of Cipto Mangunkusumo Hospital, a national referral hospital in Jakarta, Indonesia, from January to July 2017. The area of under the curve (AUC) of the ISAR and TRST in predicting 1‐ and 3‐month mortality was measured.ResultsOf 771 participants, 400 (52.8%) were men. The 1 month‐mortality incidence was 22.8% (95% CI 21.3–24.8), and 3‐month mortality was 31.2% (95% CI 29.3–33.8). For 1‐month mortality, the ISAR showed AN AUC of 0.62 (95% CI 0.57–0.68), whereas the TRST showed an AUC of 0.58 (95% CI 0.52–0.64). For 3‐month mortality, the ISAR showed an AUC of 0.60 (95% CI 0.54–0.65), whereas the TRST showed an AUC of 0.57 (95% CI 0.51–0.62).ConclusionsBoth instruments showed moderate predictive ability, but the ISAR showed better performance in predicting 1‐ and 3‐month mortality of older patients visiting the ED in Indonesia. Geriatr Gerontol Int 2020; 20: 47–51.
Low‐temperature synthesis of tungsten diboride powders via a simple molten salt route
Authors: Ma Ke , Xue Xiangxin , Cao Xiaozhou 
Published: November 2019

AbstractWB2 powders were successfully prepared at 1000°C using NaCl–KCl salts as molten salts. Compared to the conventional solid‐state reaction, the introduction of NaCl–KCl salts decreased the synthesis temperature of WB2 phase, which was related to the faster diffusion rate of particles in the liquid state than in the solid‐state. The effect of reaction temperature, time, and the amount of molten salts on the synthesis of WB2 were studied in detail. The template formation mechanism was considered to have played an essential part in the synthesis process. Transmission electron microscope analysis showed that the as‐synthesized WB2 powders exhibited a hexagonal crystal structure. Furthermore, the oxidation protective performance of as‐synthesized WB2 powders was investigated by TG‐DSC measurement.
TRIM21 controls Toll‐like receptor 2 responses in bone‐marrow‐derived macrophages
Authors: Sjöstrand Maria , Carow Berit , Nyberg William A. , Covacu Ruxandra , Rottenberg Martin E. , Espinosa Alexander 
Published: November 2019

SummaryTRIM21 is an interferon‐stimulated E3 ligase that controls the activity of pattern‐recognition signaling via ubiquitination of interferon regulatory factors and DDX41. Previous studies on the role of TRIM21 in innate immune responses have yielded contradictory results, suggesting that the role of TRIM21 is cell specific. Here, we report that bone‐marrow‐derived macrophages (BMDMs) generated from Trim21−/− mice have reduced expression of mature macrophage markers. Reflecting their reduced differentiation in response to macrophage colony‐stimulating factor (M‐CSF), Trim21−/− BMDMs had decreased expression of M‐CSF signature genes. Although Trim21−/− BMDMs responded normally to Toll‐like receptor 9 (TLR9) activation, they produced lower levels of pro‐inflammatory cytokines in response to the TLR2 agonist PAM3CSK4. In line with this, the response to infection with the Bacillus Calmette–Guérin strain of Mycobacterium bovis was also diminished in Trim21−/− BMDMs. Our results indicate that TRIM21 controls responses to TLR2 agonists.
Understanding and measuring human B‐cell tolerance and its breakdown in autoimmune disease
Authors: Cashman Kevin S. , Jenks Scott A. , Woodruff Matthew C. , Tomar Deepak , Tipton Christopher M. , Scharer Christopher D. , Eun‐Hyung Lee F. , Boss Jeremy M. , Sanz Iñaki 
Published: November 2019

AbstractThe maintenance of immunological tolerance of B lymphocytes is a complex and critical process that must be implemented as to avoid the detrimental development of autoreactivity and possible autoimmunity. Murine models have been invaluable to elucidate many of the key components in B‐cell tolerance; however, translation to human homeostatic and pathogenic immune states can be difficult to assess. Functional autoreactive, flow cytometric, and single‐cell cloning assays have proven to be critical in deciphering breaks in B‐cell tolerance within autoimmunity; however, newer approaches to assess human B‐cell tolerance may prove to be vital in the further exploration of underlying tolerance defects. In this review, we supply a comprehensive overview of human immune tolerance checkpoints with associated mechanisms of enforcement, and highlight current and future methodologies which are likely to benefit future studies into the mechanisms that become defective in human autoimmune conditions.