bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bad News Withholding and Stock Price Crash Risk of Banks
Authors: Jung Taejin , Kim Natalie Kyung Won , Kim Young Jun , Na Hyun Jong 
Published: December 2019

AbstractUsing US banks’ quarterly data from 1995 to 2014, this study examines the mechanism by which delayed expected loss recognition (DELR) affects the stock price crash risk of banks. We first show that greater DELR is positively associated with a subsequent crash in stock price. We then find that this association is only present when bank managers have more discretion in concealing bad news, which is proxied by the high proportion of heterogeneous loans. These findings provide policy implications for bank regulators regarding the importance of specific loan types and time horizons when monitoring the accounting treatment of banks.
Beyond “Intent‐to‐treat” and “Per protocol”: Improving assessment of treatment effects in clinical trials through the specification of an estimand
Authors: Pétavy Frank , Guizzaro Lorenzo , Antunes dos Reis Inês , Teerenstra Steven , Roes Kit C.B. 
Published: December 2019

There is a key problem in randomised clinical trials as outcomes can be distorted due to informative post‐randomisation events. This is inadequately addressed by the use of traditional intention‐to‐treat or per protocol analysis sets and often either ignored or wrongly labelled as missing data. As a consequence, the treatment effects of interest in a clinical trial are not well defined and their estimates might be misinterpreted.The estimand framework should help all those planning, conducting and analysing clinical trials as well as those interpreting the results to better define, estimate and understand the treatment effects of interest.This framework is described in the addendum to ICH E9 and addresses precisely this problem. It is relevant for regulatory drug trials and academic‐run trials, as well as for trials of nonpharmacological interventions.
The effects of anti‐VEGF and kinin B1 receptor blockade on retinal inflammation in laser‐induced choroidal neovascularization
Authors: Hachana Soumaya , Fontaine Olivier , Sapieha Przemyslaw , Lesk Mark , Couture Réjean , Vaucher Elvire 
Published: December 2019

Background and PurposeAge‐related macular degeneration (AMD) is a complex neurodegenerative disease treated by anti‐VEGF intravitreal injections. As inflammation is potentially involved in retinal degeneration, the pro‐inflammatory kallikrein–kinin system is a possible alternative pharmacological target. Here, we investigated the effects of anti‐VEGF and anti‐B1 receptor treatments on the inflammatory mechanisms in a rat model of choroidal neovascularization (CNV).Experimental ApproachImmediately after laser‐induced CNV, Long–Evans rats were treated by eye‐drop application of a B1 receptor antagonist (R‐954) or by intravitreal injection of B1 receptor siRNA or anti‐VEGF antibodies. Effects of treatments on gene expression of inflammatory mediators, CNV lesion regression and integrity of the blood‐retinal barrier was measured 10 days later in the retina. B1 receptor and VEGF‐R2 cellular localization was assessed.Key ResultsThe three treatments significantly inhibited the CNV‐induced retinal changes. Anti‐VEGF and R‐954 decreased CNV‐induced up‐regulation of B1 and B2 receptors, TNF‐α, and ICAM‐1. Anti‐VEGF additionally reversed up‐regulation of VEGF‐A, VEGF‐R2, HIF‐1α, CCL2 and VCAM‐1, whereas R‐954 inhibited gene expression of IL‐1β and COX‐2. Enhanced retinal vascular permeability was abolished by anti‐VEGF and reduced by R‐954 and B1 receptor siRNA treatments. Leukocyte adhesion was impaired by anti‐VEGF and B1 receptor inhibition. B1 receptors were found on astrocytes and endothelial cells.Conclusion and ImplicationsB1 receptor and VEGF pathways were both involved in retinal inflammation and damage in laser‐induced CNV. The non‐invasive, self‐administration of B1 receptor antagonists on the surface of the cornea by eye drops might be an important asset for the treatment of AMD.
Donecopride, a Swiss army knife with potential against Alzheimer's disease
Authors: Rochais Christophe , Lecoutey Cédric , Hamidouche Katia , Giannoni Patrizia , Gaven Florence , Cem Eleazere , Mignani Serge , Baranger Kevin , Freret Thomas , Bockaert Joël , Rivera Santiago , Boulouard Michel , Dallemagne Patrick , Claeysen Sylvie 
Published: December 2019

Background and PurposeWe recently identified donecopride as a pleiotropic compound able to inhibit AChE and to activate 5‐HT4 receptors. Here, we have assessed the potential therapeutic effects of donecopride in treating Alzheimer's disease (AD).Experimental ApproachWe used two in vivo animal models of AD, transgenic 5XFAD mice and mice exposed to soluble amyloid‐β peptides and, in vitro, primary cultures of rat hippocampal neurons. Pro‐cognitive and anti‐amnesic effects were evaluated with novel object recognition, Y‐maze, and Morris water maze tests. Amyloid load in mouse brain was measured ex vivo and effects of soluble amyloid‐β peptides on neuronal survival and neurite formation determined in vitro.Key ResultsIn vivo, chronic (3 months) administration of donecopride displayed potent anti‐amnesic properties in the two mouse models of AD, preserving learning capacities, including working and long‐term spatial memories. These behavioural effects were accompanied by decreased amyloid aggregation in the brain of 5XFAD mice and, in cultures of rat hippocampal neurons, reduced tau hyperphosphorylation. In vitro, donecopride increased survival in neuronal cultures exposed to soluble amyloid‐β peptides, improved the neurite network and provided neurotrophic benefits, expressed as the formation of new synapses.Conclusions and ImplicationsDonecopride acts like a Swiss army knife, exhibiting a range of sustainable symptomatic therapeutic effects and potential disease‐modifying effects in models of AD. Clinical trials with this promising drug candidate will soon be undertaken to confirm its therapeutic potential in humans.
Modeling Neoadjuvant chemotherapy resistance in vitro increased NRP‐1 and HER2 expression and converted MCF7 breast cancer subtype
Authors: Al‐Zeheimi Noura , Adham Sirin A. 
Published: December 2019

Background and PurposePatients with locally advanced breast cancer usually receive third‐generation neoadjuvant chemotherapy (NAC). Although NAC treatment improved the overall survival, patients' response varies, some acquire resistance and others exhibit a conversion in their breast cancer molecular subtype. We aimed to identify the molecular changes involved in NAC resistance attempting to find new therapeutic targets in different breast cancer subtypes.Experimental ApproachWe modelled NAC treatments used in clinical practice and generated resistant cell lines in vitro. The resistant cells were generated by consecutive treatment with four cycles of doxorubicin (adriamycin)/cyclophosphamide (4xAC) followed by an additional four cycles of paclitaxel (4xAC + 4xPAC).Key ResultsOur data revealed distinct mechanisms of resistance depending on breast cancer subtype and drugs used. MDA‐MB‐231 cells resistant to 4xAC + 4xPAC activated neuropilin‐1/TNC/integrin β3/FAK/NF‐κBp65 axis and displayed a decrease in breast cancer resistance protein (BCRP/ABCB2). However, MCF7 cells resistant to 4xAC treatments induced HER2 expression, which converted MCF7 subtype from luminal A to luminal B HER2 type, up‐regulated neuropilin‐1, oestrogen receptor‐α, and EGFR, and activated PI3K/Akt/NF‐κBp65 axis. However, MCF7 cells resistant to 4xAC + 4xPAC exhibited down‐regulation of the survival axis and up‐regulated BCRP/ABCG2. Co‐immunoprecipitation demonstrated a novel interaction between HER2 and neuropilin‐1 driving the resistance features.Conclusions and ImplicationsThe concurrent increase in neuropilin‐1 and HER2 upon resistance and the inverse relationship between neuropilin‐1 and BCRP/ABCG2 suggest that, in addition to HER2, neuropilin‐1 status should be assessed in patients undergoing NAC, and as a potential drug target for refractory breast cancer.
Eucalyptol alleviates inflammation and pain responses in a mouse model of gout arthritis
Authors: Yin Chengyu , Liu Boyu , Wang Ping , Li Xiaojie , Li Yuanyuan , Zheng Xiaoli , Tai Yan , Wang Chuan , Liu Boyi 
Published: December 2019

Background and PurposeGout arthritis, which is provoked by monosodium urate (MSU) crystal accumulation in the joint and periarticular tissues, induces severe pain and affects quality of life of the patients. Eucalyptol (1,8‐cineol), the principal component in the essential oils of eucalyptus leaves, is known to possess anti‐inflammatory and analgesic properties. We aimed to examine the therapeutic effects of eucalyptol on gout arthritis and related mechanisms.Experimental ApproachA mouse model of gout arthritis was established via MSU injection into the ankle joint. Ankle oedema, mechanical allodynia, neutrophil infiltration, oxidative stress, NLRP3 inflammasome, and TRPV1 expression were examined.Key ResultsEucalyptol attenuated MSU‐induced mechanical allodynia and ankle oedema in dose‐dependently, with effectiveness similar to indomethacin. Eucalyptol reduced inflammatory cell infiltrations in ankle tissues. Eucalyptol inhibited NLRP3 inflammasome activation and pro‐inflammatory cytokine production induced by MSU in ankle tissues in vivo. Eucalyptol reduced oxidative stress induced by MSU in RAW264.7 cells in vitro as well as in ankle tissues in vivo, indicated by an increase in activities of antioxidant enzymes and reduction of ROS. Eucalyptol attenuated MSU‐induced up‐regulation of TRPV1 expression in ankle tissues and dorsal root ganglion neurons innervating the ankle. The in vivo effects of eucalyptol on ankle oedema, mechanical allodynia, NLRP3 inflammasome, IL‐1β, and TRPV1 expression were mimicked by treating MSU‐injected mice with antioxidants.Conclusion and ImplicationsEucalyptol alleviates MSU‐induced pain and inflammation via mechanisms possibly involving anti‐oxidative effect. Eucalyptol and other antioxidants may represent promising therapeutic options for gout arthritis.
MicroRNA‐493‐5p‐mediated repression of the MYCN oncogene inhibits hepatic cancer cell growth and invasion
Authors: Yasukawa Ken , Liew Lee Chuen , Hagiwara Keitaro , Hironaka‐Mitsuhashi Ai , Qin Xian‐Yang , Furutani Yutaka , Tanaka Yasuhito , Nakagama Hitoshi , Kojima Soichi , Kato Takashi , Ochiya Takahiro , Gailhouste Luc 
Published: December 2019

AbstractPrimary hepatic tumors mainly include hepatocellular carcinoma (HCC), which is one of the most frequent causes of cancer‐related deaths worldwide. Thus far, HCC prognosis has remained extremely poor given the lack of effective treatments. Numerous studies have described the roles played by microRNAs (miRNAs) in cancer progression and the potential of these small noncoding RNAs for diagnostic or therapeutic applications. The current consensus supports the idea that direct repression of a wide range of oncogenes by a single key miRNA could critically affect the malignant properties of cancer cells in a synergistic manner. In this study, we aimed to investigate the oncogenes controlled by miR‐493‐5p, a major tumor suppressor miRNA that inactivates miR‐483‐3p oncomir in hepatic cancer cells. Using global gene expression analysis, we highlighted a set of candidate genes potentially regulated by miR‐493‐5p. In particular, the canonical MYCN protooncogene (MYCN) appeared to be an attractive target of miR‐493‐5p given its significant inhibition through 3′‐UTR targeting in miR‐493‐5p‐rescued HCC cells. We showed that MYCN was overexpressed in liver cancer cell lines and clinical samples from HCC patients. Notably, MYCN expression levels were inversely correlated with miR‐493‐5p in tumor tissues. We confirmed that MYCN knockdown mimicked the anticancer effect of miR‐493‐5p by inhibiting HCC cell growth and invasion, whereas MYCN rescue hindered miR‐493‐5p activity. In summary, miR‐493‐5p is a pivotal miRNA that modulates various oncogenes after its reexpression in liver cancer cells, suggesting that tumor suppressor miRNAs with a large spectrum of action could provide valuable tools for miRNA replacement therapies.
Quality of life, treatment satisfaction, and adherence to treatment in patients with vesicular hand eczema: A cross‐sectional study
Authors: Politiek Klaziena , Ofenloch Robert F. , Angelino Marius J. , van den Hoed Ewoud , Schuttelaar Marie L. A. 
Published: December 2019

AbstractBackgroundRecurrent vesicular hand eczema frequently has a chronic course and needs long‐term treatment.ObjectivesTo evaluate health‐related quality of life (HRQoL), treatment satisfaction, and adherence in patients with vesicular hand eczema.MethodsPatients using one main treatment for at least three months were included. Data on HRQoL (Quality of Life in Hand Eczema Questionnaire [QOLHEQ]), treatment satisfaction (Treatment Satisfaction Questionnaire for Medication, version II), and treatment adherence (4‐item Morisky Medication Adherence Scale) were collected. Univariate and multivariate regression analysis were used to predict variables associated with HRQoL.ResultsHRQoL was moderately impaired, with the highest impact in the QOLHEQ subdomain symptoms. Female sex, more severe hand eczema, and lower treatment satisfaction were associated with more impairment in HRQoL. Patients with severe/very severe hand eczema had significant lower “global satisfaction” scores compared with the other severity groups. The “global satisfaction” and treatment adherence in patients using systemic treatment were significantly higher compared with those with only topical treatment.ConclusionsIn patients with vesicular hand eczema disease severity affects both HRQoL and treatment satisfaction. Systemic treatment of severe hand eczema could improve the severity and as a result also HRQoL, treatment satisfaction, and medication adherence.
Correlatıon of neutrophyle/lymphocyte ratio and pulmonary parameters with optic coherence tomography findings in stable chronic obstructive pulmonary disease
Authors: Ozer Pinar Altiaylik , Ogan Nalan 
Published: December 2019

AbstractIntroductionTo examine the correlation of pulmonary functions and neutrophyle/lymphocyte ratio (NLR) with optic coherence tomography findings in stable chronic obstructive pulmonary disease (COPD).MethodsFifty‐five COPD (110 eyes) and 48 control cases (96 eyes) were enrolled. COPD patients were grouped as Group 1 (mild‐moderate) and Group 2 (severe) according to GOLD classification. Subfoveal choroidal thickness (SFCT), ganglion cell‐inner plexiform layer (GCIP) and retinal nerve fiber layer (RNFL) analysis by SD‐OCT were performed in follow up. NLR was calculated by blood cell count.ResultsInferior RNFL and average GCIP of COPD were lower than control during the initial and sixth month examination (P = .002, P < .001, respectively). Average RNFL and SFCT were lower in COPD patients in sixth month examination (P = .020, P = .015, respectively). Average, temporal, inferior, nasal RNFL and SFCT in sixth month examination were significantly lower in severe COPD (P < .05 for all), but average GCIP were similar (P = .015). Disease duration, Modified Medical Research Council (mMRC) and attacks/year showed significant negative correlations, whereas forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC) showed significant positive correlations with OCT values. NLR was significantly higher in COPD cases compared to control (P < .001) and had a negative correlation with GCIP values.ConclusionChronic obstructive pulmonary disease severity is shown to have a negative effect on OCT measurements. SD‐OCT can reflect severity of inflammation, and suggested to be used in follow up of COPD cases. NLR may have a role to predict the ganglion cell damage in COPD patients.
Incorporating wildlife connectivity into forest plan revision under the United States Forest Service's 2012 planning rule
Authors: Williamson Matthew A. , Creech Tyler G. , Carnwath Gunnar , Dixon Beverly , Kelly Virginia 
Published: December 2019

AbstractThe United States Forest Service promulgated new planning regulations under the National Forest Management Act in 2012 (i.e., the Planning Rule). These new regulations include the first requirements in U.S. public land management history for National Forests to evaluate, protect, and/or restore ecological connectivity as they revise their land management plans. Data and resource limitations make single‐species, functional connectivity analyses for the myriad species that occur within the 78 million ha the Forest Service manages implausible. We describe an approach that relies on freely available data and generic species, virtual species whose profile consists of ecological requirements designed to reflect the needs of a group of real species, to address the new Planning Rule requirements. We present high‐resolution connectivity estimates for 10 different generic species across a 379,000 ha study area centered on the Custer Gallatin National Forest (CGNF) in Montana and South Dakota under two different movement models. We identify locations important for connectivity for multiple species and characterize the role of the CGNF for regional connectivity. Our results informed the Plan Revision process on the CGNF and could be readily exported to other National Forests currently or planning to revise their land management plans under the new Planning Rule.
Characteristics and prognostic significance of incidentally detected cancer cells in uterine specimens of patients with pelvic high‐grade serous carcinoma
Authors: Ushigusa Takeshi , Yoshida Hiroshi , Kuno Ikumi , Kojima Naoki , Ishikawa Mitsuya , Kato Tomoyasu 
Published: December 2019

AbstractObjectiveCases of pelvic high‐grade serous carcinoma (HGSC) with incidentally detected cancer cells (ICCs) in endometrial and/or cervicovaginal cytology have been reported. This study aimed to clarify the incidence and characteristics of pelvic HGSC with ICCs and to determine whether ICCs have a negative prognostic impact.MethodsPatients with ovarian/tubal/peritoneal HGSC who underwent pre‐treatment uterine (endometrial/cervicovaginal) cytology or biopsy between January 2007 and May 2017 were included. We reviewed the frequencies of ICCs and compared the clinicopathological features and survival outcome between the ICC‐positive and ICC‐negative groups.ResultsOf the 160 patients evaluated, 69 (43.2%) had positive ICCs in at least one uterine specimen. There were no significant differences in clinicopathological characteristics, such as age, FIGO stage, serum CA125 level, ascites, and tubal lesion, between the two groups. Moreover, ICCs had no significant survival impact on progression‐free survival or overall survival.ConclusionOur study showed a high rate of pelvic HGSC with ICCs in pre‐treatment uterine specimens. The ICCs per se had no negative impact on survival outcomes of pelvic HGSC. Furthermore, uterine biopsy and cytology can be useful and less‐invasive methods to obtain tubo‐ovarian/peritoneal cancer cells before treatment.
A risk‐prediction model for en bloc resection failure or perforation during endoscopic submucosal dissection of colorectal neoplasms
Authors: Imai Kenichiro , Hotta Kinichi , Ito Sayo , Yamaguchi Yuichiro , Kishida Yoshihiro , Yabuuchi Yohei , Yoshida Masao , Kawata Noboru , Tanaka Masaki , Kakushima Naomi , Takizawa Kohei , Ishiwatari Hirotoshi , Matsubayashi Hiroyuki , Mori Keita , Ono Hiroyuki 
Published: December 2019

ObjectivesTechnical difficulties in colorectal endoscopic submucosal dissections (ESD) result in en bloc resection failure or perforation. This study aimed to develop and validate a risk score for predicting en bloc resection failure or perforation in ESD of colorectal neoplasms.MethodsThis single‐center observational study included 1133 colorectal neoplasms treated with ESD in a Japanese tertiary cancer center. With a derivation set (n = 716), we performed multiple logistic regression to identify significant risk factors for en bloc resection failure or perforation. Based on odds ratios, we developed a risk score, ranging from 0 to 10: 0–1 ‘low risk’ (LR); 2–4 ‘moderate risk’ (MR); and 5–10 ‘high risk’ (HR). An independent validation set comprised prospectively enrolled subjects (n = 417) that underwent ESDs from January 2014 to August 2016. The performance of the risk score for predicting en bloc resection failure or perforation for each risk tier was evaluated.ResultsThe baseline incidences of en bloc resection failure or perforation were 14.5% and 5.5% in the derivation and validation sets, respectively. We identified the following significant risk factors: endoscopist experience, tumor location, morphology, scope operability, underlying fold, and fold convergence. In the validation set, the incidences of en bloc resection failure or perforation were 0% in the LR tier (n = 62; 14.8%), 2.3% in the MR tier (n = 293; 70.4%), and 25.8% in the HR tier (n = 62; 14.8%) (P < 0.001, Cochran‐Armitage trend test).ConclusionsA risk scoring system, which was developed and prospectively validated, can successfully estimate the incidence of en bloc resection failure or perforation.
Assessing prophylactic use and clinical outcomes in hemophilia A patients treated with rVIII‐SingleChain and other common rFVIII products in Germany
Authors: Olivieri Martin , Sommerer Patrick , Maro Geraldine , Yan Songkai 
Published: December 2019

AbstractObjectiveTo evaluate real‐world outcomes with rVIII‐SingleChain and other commonly used recombinant FVIII (rFVIII) products.MethodsHemophilia treatment centers in Germany (n = 21) contributed patient chart data. Inclusion criteria were prophylactic treatment with one of five rFVIII products for ≥8 weeks.ResultsMale patients (n = 225) were included: rVIII‐SingleChain (n = 40), rFVIIIFc (n = 47), octocog alfa (rFVIII; n = 58), octocog alfa (BAY 81‐8973; n = 40), or moroctocog alfa (n = 40). In patients with severe disease (n = 76), 66.6%, 70.0%, 20.0%, 7.7%, and 27.3% were dosed ≤2×/week, respectively. Irrespective of dosing frequency, mean annualized bleed rates (ABRs)/annualized spontaneous bleed rates (AsBRs) were 0.3/0.1, 0.8/0.4, 1.1/0.5, 1.5/0.8, and 1.4/0.6, and mean FVIII consumption (IU/kg/week) was 83.2, 97.2, 92.5, 104.0, and 102.1, respectively. Results for all patients were similar. Of the patients on prophylaxis with prior therapy and after switching to rVIII‐SingleChain (n = 21), mean ABR/AsBRs were 0.7/0.3 and 0.2/0.0, respectively. After switching to rVIII‐SingleChain, mean FVIII consumption reduced (109.4 vs 74.5 IU/kg/week), and percentage of patients dosed ≤2×/week increased (0% to 71.4%).ConclusionsrVIII‐SingleChain prophylaxis provides excellent bleeding protection, with potentially lowest factor consumption among the products assessed. Patients who switched to rVIII‐SingleChain prophylaxis reduced dosing frequency and consumption compared with prior treatment, with similar or potentially lower bleeding rates.