bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radiological appearance of coal mine dust lung diseases in Australian workers
Authors: McBean Rhiannon , Newbigin Katrina , Dickinson Shannan , Edwards Robert 
Published: October 2018

SummaryCoal Mine Dust Lung Disease (CMDLD) encompasses a spectrum of lung diseases caused by prolonged exposure to coal mine dust. This review presents high‐resolution computed tomography (HRCT) images from men diagnosed with a CMDLD since the resurgence of these diseases in Queensland in 2015.
Effects of serial phlebotomy on vascular endothelial function: Results of a prospective double‐blind randomized study
Authors: Jelani Qurat‐ul‐ain , Harchandani Bhisham , Cable Ritchard G. , Guo Yu , Zhong Hua , Hilbert Timothy , Newman Jonathan D. , Katz Stuart D. 
Published: October 2018

SummaryIntroductionBlood donation has been proposed as a potential therapy to reduce risk of cardiovascular disease, but the effects of phlebotomy on vascular function in human subjects have not been well characterized.AimsWe conducted a prospective randomized double‐blind study to determine the effects of serial phlebotomy on vascular endothelial function in the brachial artery. Eighty‐four iron‐replete, non‐anemic subjects were randomly assigned to one of three study treatment groups: (a) four serial phlebotomy procedures each followed by intravenous infusion of placebo normal saline; (b) four serial phlebotomy procedures each followed by intravenous infusion to replete lost iron; and (c) four serial sham phlebotomy procedures each followed by intravenous infusion of placebo normal saline. Assigned phlebotomy procedures were conducted at 56‐day intervals. We measured brachial artery reactivity (BAR, %) in response to transient oxidative stress induced by oral methionine with high‐resolution duplex ultrasound imaging before and one week after the fourth study phlebotomy.ResultsBefore phlebotomy, oral methionine decreased BAR by −2.04% (95% CI −2.58%, −1.50%), P < 0.001) with no significant difference between groups (P = 0.42). After phlebotomy, the BAR response to oral methionine did not significantly change between groups (P = 0.53). Brachial artery nitroglycerin‐mediated dilation did not change in response to phlebotomy.ConclusionsFour serial phlebotomy procedures over six months with or without intravenous iron supplementation did not alter vascular endothelial function in the brachial artery when compared with sham phlebotomy.
A survey of patients’ perceptions about, and their experiences of, root canal treatment
Authors: Chandraweera Lahiru , Goh Kelly , Lai‐Tong Julia , Newby Janni , Abbott Paul 
Published: October 2018

AbstractRoot canal treatment (RCT) is widely perceived to be a painful procedure. There is a lack of data regarding patients’ perceptions of RCT within the Australian population. The aims of this pilot study were to investigate the perception of adult Australian patients within the Perth Metropolitan area and to identify how this changes following treatment. Effects of demographic factors on anxiety and pain experience were also explored. Sixty‐nine patients were surveyed, of which 28 (41%) completed both pre‐ and post‐treatment surveys. Modified Visual Analogue scales and multiple choice questions identified patient concerns, nervousness and anticipated or experienced pain. Cost (55%) and pain (51%) were the greatest pre‐treatment concerns. No expectation of pain was reported by 7% of patients, while 28% reported experiencing no pain during the course of treatment. Results suggest that anticipated pain is greater than pain experienced, and that after the treatment, anxiety for future RCT was significantly reduced.
The Developing Regorafenib Eye drops for neovascular Age‐related Macular degeneration (DREAM) study: an open‐label phase II trial
Authors: Joussen Antonia M. , Wolf Sebastian , Kaiser Peter K. , Boyer David , Schmelter Thomas , Sandbrink Rupert , Zeitz Oliver , Deeg Gesa , Richter Annett , Zimmermann Torsten , Hoechel Joachim , Buetehorn Ulf , Schmitt Walter , Stemper Brigitte , Boettger Michael K. 
Published: October 2018

AimsThis programme investigated topical regorafenib, a multikinase inhibitor, in patients with neovascular age‐related macular degeneration (nAMD).MethodsTopical regorafenib was investigated in an open‐label, phase IIa/b study in which patients with choroidal neovascularization (CNV) secondary to nAMD received regorafenib (25 μl, 30 mg ml–1) three times a day for 12 weeks. The primary endpoint of the phase II/a/b study was mean change in best‐corrected visual acuity (BCVA) from baseline to weeks 4 and 12.ResultsIn nAMD patients (N = 51), mean changes in BCVA were +1.2 [90% confidence interval (CI) –0.61, 2.97] and −2.4 (90% CI −4.18, −0.54) letters at weeks 4 and 12, respectively. Ocular treatment‐emergent adverse events (TEAEs) (study eye) were reported in 21 patients by week 12. There was one serious ocular TEAE (visual acuity reduced) that was not drug related. Twenty patients required rescue (intravitreal ranibizumab).ConclusionsThe programme was terminated after phase IIa ended because efficacy was lower than with current nAMD treatments. According to elaborate post hoc analyses, the most likely reason was insufficient exposure in the target compartment (back of the eye).
How the CIOMS guidelines contribute to fair inclusion of pregnant women in research
Authors: van der Graaf Rieke , van der Zande Indira S. E. , van Delden Johannes J. M. 
Published: October 2018

AbstractAs early as 2002, CIOMS stated that pregnant women should be presumed eligible for participation in research. Despite this position and calls of other well‐recognized organizations, the health needs of pregnant women in research remain grossly under‐researched. Although the presumption of eligibility remains unchanged, the revision of the 2002 CIOMS International ethical guidelines for biomedical research involving human subjects involved a substantive rewrite of the guidance on research with pregnant women and related guidelines, such as those on fair inclusion and vulnerability. However, close reading of the guidelines reveals morally relevant different approaches to fair inclusion of pregnant women and other under‐represented groups, such as children and incompetents. Where CIOMS sets out that children and adolescents must be included unless a good scientific reason justifies their exclusion, no such claim of having to justify exclusion appears in the guideline on pregnant women. Instead, CIOMS claims that research relevant to pregnant women’s health needs must be promoted. This paper analyses how and to what extent the guideline on pregnant women differs from other guidance on fair inclusion in the document. Accordingly, the paper evaluates to what extent the current phrasing may contribute to fair inclusion of pregnant women in research. We will conclude that a system change towards a learning health system is essential to break down the status quo of knowledge generation in the field of medication use during pregnancy and argue that the CIOMS guidelines allow for this system change.
The epistemic and ethical onus of ‘One Health’
Authors: Beever Jonathan , Morar Nicolae 
Published: October 2018

AbstractThis paper argues that the practical reach and ethical impact of the One Health paradigm is conditional on satisfactorily distinguishing between interconnected and interdependent factors among human, non‐human, and environmental health. Interconnection does not entail interdependence. Offering examples of interconnections and interdependence in the context of existing One Health literature, we demonstrate that the conversations about One Health do not yet sufficiently differentiate between those concepts. They tend to either ignore such distinctions or embrace bioethically untenable positions. We conclude that careful conceptual differentiation can prevent One Health stakeholders either from over‐reaching or under‐reaching the practical and ethical boundaries of this developing paradigm.
The German debate on male circumcision and Habermas’ model of post‐secularity
Authors: Greve Jens 
Published: October 2018

AbstractThis paper considers Habermas’ model of a post‐secular political order in the light of the debate on male circumcision that arose in Germany after a court ruled that male circumcision was an unjustifiable act of bodily harm. Central to this model is the idea that religious reasons can only become effective in central legal institutions when they are translated into secular reasons. My paper demonstrates that there are two distinguishable readings of this proviso. On the one hand, there is a broad reading according to which it is only necessary to reach a conclusion that is in line with the democratic principle stating that all citizens can be regarded as co‐legislators even if non‐generalizable value orientations might then shape the interpretation of fundamental rights (in the case of circumcision, the right to bodily integrity). On the other hand, a truly secular (narrow) reading would avoid the inclusion of non‐generalizable value orientations. The debate on circumcision demonstrates that these two interpretations lead to different and conflicting modes of justification. The broad reading allows for a justification of male circumcision, whereas the narrow reading makes such a justification unlikely. In addition, the filtering function of the proviso is weakened in a broad reading.
Endothelial NOS: perspective and recent developments
Authors: Garcia Victor , Sessa William C 
Published: October 2018

Endothelial NOS (eNOS), and its product NO, are vital components of the control of vasomotor function and cardiovascular homeostasis. In the present review, we will take a deep dive into eNOS enzymology, function and mechanisms regulating endothelial NO. The mechanisms regulating eNOS and NO synthesis discussed here include alterations to transcriptional, post‐translational modifications and protein–protein regulations. Also, we will discuss the phenotypes associated with various eNOS mutants and the consequences of a disrupted eNOS/NO cascade, highlighting the importance of eNOS function and vascular homeostasis.Linked ArticlesThis article is part of a themed section on Nitric Oxide 20 Years from the 1998 Nobel Prize. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.2/issuetoc
Metabolism of sulfur compounds in homocystinurias
Authors: Kožich Viktor , Ditrói Tamás , Sokolová Jitka , Křížková Michaela , Krijt Jakub , Ješina Pavel , Nagy Peter 
Published: October 2018

Background and PurposeHomocystinurias are rare genetic defects characterized by altered fluxes of sulfur compounds including homocysteine and cysteine. We explored whether the severely perturbed sulfur amino acid metabolism in patients with homocystinurias affects the metabolism of hydrogen sulfide.Experimental ApproachWe studied 10 treated patients with a block in the conversion of homocysteine to cysteine due to cystathionine β‐synthase deficiency (CBSD) and six treated patients with remethylation defects (RMD) and an enhanced flux of sulfur metabolites via transsulfuration. Control groups for CBSD and RMD patients consisted of 22 patients with phenylketonuria on a low‐protein diet and of 12 healthy controls respectively. Plasma and urine concentrations of selected sulfur compounds were analysed by HPLC and LC–MS/MS.Key ResultsPatients with CBSD exhibited plasma concentrations of monobromobimane‐detected sulfide similar to appropriate controls. Urinary homolanthionine and thiosulfate in CBSD were increased significantly 1.9 and 3 times suggesting higher hydrogen sulfide synthesis by γ‐cystathionase and detoxification respectively. Surprisingly, patients with RMD had significantly lower plasma sulfide levels (53 and 64% of controls) with lower sulfite concentrations, and higher taurine and thiosulfate levels suggesting enhanced cysteine oxidation and hydrogen sulfide catabolism respectively.Conclusion and ImplicationsThe results from this study suggest that severe inherited defects in sulfur amino acid metabolism may be accompanied by only moderately perturbed hydrogen sulfide metabolism and lends support to the hypothesis that enzymes in the transsulfuration pathway may not be the major contributors to the endogenous hydrogen sulfide pool.Linked ArticlesThis article is part of a themed section on Chemical Biology of Reactive Sulfur Species. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.4/issuetoc
The affinity, intrinsic activity and selectivity of a structurally novel EP2 receptor agonist at human prostanoid receptors
Authors: Coleman R A , Woodrooffe A J , Clark K L , Toris C B , Fan S , Wang J W , Woodward D F 
Published: October 2018

Background and PurposeProstanoid EP2 receptor agonists exhibit several activities including ocular hypotension, tocolysis and anti‐inflammatory activity. This report describes the affinity and selectivity of a structurally novel, non‐prostanoid EP2 receptor agonist, PGN‐9856, and its therapeutic potential.Experimental ApproachThe pharmacology of a series of non‐prostanoid EP2 receptor agonists was determined according to functional and radioligand binding studies, mostly using human recombinant prostanoid receptor transfectants. The selectivity of PGN‐9856, as the preferred compound, was subsequently determined by using a diverse variety of non‐prostanoid target proteins. The therapeutic potential of PGN‐9856 was addressed by determining its activity in relevant primate cell, tissue and disease models.Key ResultsPGN‐9856 was a selective and high affinity (pKi ≥ 8.3) ligand at human recombinant EP2 receptors. In addition to high affinity binding, it was a potent and full EP2 receptor agonist with a high level of selectivity at EP1, EP3, EP4, DP, FP, IP and TP receptors. In cells overexpressing human recombinant EP2 receptors, PGN‐9856 displayed a potency (pEC50≥ 8.5) and a maximal response (increase in cAMP) comparable to that of the endogenous agonist PGE2. PGN‐9856 exhibited no appreciable affinity (up 10 μM) for a range of 53 other receptors, ion channels and enzymes. Finally, PGN‐9856 exhibited tocolytic, anti‐inflammatory and long‐acting ocular hypotensive properties consistent with its potent EP2 receptor agonist properties.Conclusions and ImplicationsPGN‐9856 is a potent, selective and efficacious prostanoid EP2 receptor agonist with diverse potential therapeutic applications: tocolytic, anti‐inflammatory and notably anti‐glaucoma.
The Earlier the Better? Pausing for Thought …
Authors: Maughan Barbara , Barker Edward D. 
Published: October 2018

Is earlier intervention always superior? Using two complementary forms of meta‐analysis, Gardner and colleagues find no support for the “earlier is better” hypothesis in outcomes of parenting programs for child behavior problems across the 2–11 year age range. This commentary explores possible methodological and substantive reasons for the pattern of their findings. We need additional careful analyses of this kind, assessing age variations in intervention effects across broader age ranges, and in other developmental domains, for strong tests of the “earlier is better” hypothesis. At this stage, however, Gardner et al.'s findings give us some pause for thought.
Spin in articles about minimally invasive transanal total mesorectal excision: an assessment of the current literature
Authors: Patel S. V. , Zhang L. , Elsolh B. , Yu D. , Chadi S. A. 
Published: October 2018

AbstractAimMinimally invasive transanal total mesorectal excision (TaTME) is a new approach for treating rectal cancer. ‘Spin’ can be defined as ‘reporting strategies to highlight that the experimental treatment is beneficial’ despite limitations in study design. The aim of this study was to assess spin within publications about TaTME.Method
EMBASE and MEDLINE (2009–2017) were searched for publications assessing TaTME in rectal cancer. All papers published between 2009 and 2017 were eligible for inclusion. Study titles and abstracts were assessed for evidence of spin, as previously defined.ResultsA total of 1202 studies were identified through our search, and 73 were included. The majority were case series (n = 48, 66%). A total of 55 publications (75%) had evidence of spin within at least one domain. The most common type of spin was claiming safety without describing how this was defined or tested (56%). Other strategies included claiming superiority without support (33%) and reporting nonsignificance as equivalence (42%). We did not find that year of publication (P = 0.61), study design (P = 0.60), number of patients (P = 0.85) or declared conflict of interest (P = 0.43) were associated with spin.ConclusionWe have shown that spin is common within studies assessing TaTME for rectal cancer. Despite a lack of support from study results, in the majority of studies authors concluded that TaTME is safe for use in rectal cancer. Readers of study abstracts describing new techniques need to be cautious about accepting the authors’ conclusions, especially in case series and observational studies.
The Influence of Globally Ungrammatical Local Syntactic Constraints on Real‐Time Sentence Comprehension: Evidence From the Visual World Paradigm and Reading
Authors: Kamide Yuki , Kukona Anuenue 
Published: October 2018

AbstractWe investigated the influence of globally ungrammatical local syntactic constraints on sentence comprehension, as well as the corresponding activation of global and local representations. In Experiment 1, participants viewed visual scenes with objects like a carousel and motorbike while hearing sentences with noun phrase (NP) or verb phrase (VP) modifiers like “The girl who likes the man (from London/very much) will ride the carousel.” In both cases, “girl” and “ride” predicted carousel as the direct object; however, the locally coherent combination “the man from London will ride…” in NP cases alternatively predicted motorbike. During “ride,” local constraints, although ruled out by the global constraints, influenced prediction as strongly as global constraints: While motorbike was fixated less than carousel in VP cases, it was fixated as much as carousel in NP cases. In Experiment 2, these local constraints likewise slowed reading times. We discuss implications for theories of sentence processing.
Resveratrol enhances the chemotherapeutic response and reverses the stemness induced by gemcitabine in pancreatic cancer cells via targeting SREBP1
Authors: Zhou Cancan , Qian Weikun , Ma Jiguang , Cheng Liang , Jiang Zhengdong , Yan Bin , Li Jie , Duan Wanxing , Sun Liankang , Cao Junyu , Wang Fengfei , Wu Erxi , Wu Zheng , Ma Qingyong , Li Xuqi 
Published: October 2018

AbstractObjectivesGemcitabine is a standard treatment for advanced pancreatic cancer patients but can cause chemoresistance during treatment. The chemoresistant cells have features of cancer stem cells (CSCs). Resveratrol has been reported to overcome the resistance induced by gemcitabine. However, the mechanism by which resveratrol enhances chemosensitivity remains elusive. Here, we explored the mechanism by which resveratrol enhanced chemosensitivity and the role of sterol regulatory element binding protein 1 (SREBP1) in gemcitabine‐induced stemness.Materials and methodsThe pancreatic cancer cell lines MiaPaCa‐2 and Panc‐1 were treated under different conditions. Methyl thiazolyl tetrazolium and colony formation assays were performed to evaluate effects on proliferation. Flow cytometry was conducted to detect apoptosis. Oil red O staining was performed to examine lipid synthesis. The sphere formation assay was applied to investigate the stemness of cancer cells. Immunohistochemistry was performed on tumour tissue obtained from treated KPC mice.ResultsResveratrol enhanced the sensitivity of gemcitabine and inhibited lipid synthesis via SREBP1. Knockdown of SREBP1 limited the sphere formation ability and suppressed the expression of CSC markers. Furthermore, suppression of SREBP1 induced by resveratrol reversed the gemcitabine‐induced stemness. These results were validated in a KPC mouse model.ConclusionsOur data provide evidence that resveratrol reverses the stemness induced by gemcitabine by targeting SREBP1 both in vitro and in vivo. Thus, resveratrol can be an effective chemotherapy sensitizer, and SREBP1 may be a rational therapeutic target.
The Nedd8‐activating enzyme inhibitor MLN4924 (TAK‐924/Pevonedistat) induces apoptosis via c‐Myc‐Noxa axis in head and neck squamous cell carcinoma
Authors: Zhang Wenjuan , Liang Yupei , Li Lihui , Wang Xiaofang , Yan Zi , Dong Changsheng , Zeng Mu‐Sheng , Zhong Qian , Liu Xue‐Kui , Yu Jinha , Sun Shuyang , Liu Xiaojun , Kang Jihui , Zhao Hu , Jeong Lak Shin , Zhang Yanmei , Jia Lijun 
Published: October 2018

AbstractObjectivesThe present study aimed to reveal expression status of the neddylation enzymes in HNSCC and to elucidate the anticancer efficacy and the underlying mechanisms of inhibiting neddylation pathway.Materials and methodsThe expression levels of neddylation enzymes were estimated by Western blotting in human HNSCC specimens and bioinformatics analysis of the cancer genome atlas (TCGA) database. Cell apoptosis was evaluated by Annexin V fluorescein isothiocyanate/propidium iodide (Annexin V‐FITC/PI) stain and fluorescence‐activated cell sorting (FACS). Small interfering RNA (siRNA) and the CRISPR‐Cas9 system were used to elucidate the underlying molecular mechanism of MLN4924‐induced HNSCC apoptosis.ResultsExpression levels of NAE1 and UBC12 were prominently higher in HNSCC tissues than that in normal tissues. Inactivation of the neddylation pathway significantly inhibited malignant phenotypes of HNSCC cells. Mechanistic studies revealed that MLN4924 induced the accumulation of CRL ligase substrate c‐Myc that transcriptionally activated pro‐apoptotic protein Noxa, which triggered apoptosis in HNSCC.ConclusionsThese findings determined the over‐expression levels of neddylation enzymes in HNSCC and revealed novel mechanisms underlying neddylation inhibition induced growth suppression in HNSCC cells, which provided preclinical evidence for further clinical evaluation of neddylation inhibitors (eg, MLN4924) for the treatment of HNSCC.
Golgi protein 73 and its diagnostic value in liver diseases
Authors: Xia Yanyan , Zhang Yuanying , Shen Mengjiao , Xu Hongpan , Li Zhiyang , He Nongyue 
Published: October 2018

AbstractGolgi protein 73 (GP73, also referred to as Golph 2) with 400 amino acids is a 73 kDa transmembrane glycoprotein typically found in the cis‐Golg complex. It is primarily expressed in epithelial cells, which has been found upregulated in hepatocytes in patients suffering from both viral and non‐viral liver diseases. GP73 has drawn increasing attention for its potential application in the diagnosis of liver diseases such as hepatitis, liver cirrhosis and liver cancer. Herein, we reviewed the discovery history of GP73 and summarized studies by many groups around the world, aiming at understanding its structure, expression, function, detection methods and the relationship between GP73 and liver diseases in various settings.