bluuebunny/crossref_metadata_2025_split huggingface dataset:
Internationalisation theory and Born Globals
Authors: Wadeson Nigel 
Published: April 2020

PurposeIt has been claimed that Born Globals are incompatible with the Uppsala model, which is based on the firm having a maximum tolerable risk level. This assumption was used to explain observed incremental commitments, with further commitments being made as experiential learning reduces the level of risk faced. This study aims to show that adding a consideration of the role of expected value, including the effects of resource constraints, can reconcile the Born Global and internationalisation process literatures.Design/methodology/approachThe theoretical arguments are supported by mathematical modelling of a firm pursuing expected value based on subjective beliefs.FindingsWhile the effects of risk and expected value coincide when firms limit their downside risks by taking an incremental approach to commitments, other factors impacting on expected value can shift the balance of incentives towards earlier and more rapid internationalisation. For instance, some firms are specialised and have high costs of R&D, and so need to achieve early and rapid growth but face small home markets. While resource constraints can lead a firm to expand for some time in its home market before internationalising, the effect can be reversed in the case of the finance constraint for some firms.Originality/valueThe study shows how Born Global and internationalisation process literatures can be reconciled through a consideration of the effects of expected value on internationalisation decisions. It also provides a novel theoretical analysis of Born Globals.
Severe pyrexia from nivolumab‐resistant advanced melanoma after successful combined therapy with encorafenib plus binimetinib
Authors: Amagai Ryo , Fujimura Taku , Kambayashi Yumi , Sato Yota , Tanita Kayo , Ohuchi Kentaro , Hashimoto Akira , Aiba Setsuya 
Published: April 2020

AbstractVarious serious adverse events (AE) have been reported to occur at a high rate in patients treated with BRAF plus mitogen‐activated protein kinase kinase (MEK) inhibitor combination therapy, but their subtypes differ among the BRAF/MEK inhibitors. Pyrexia or a spike of fever are well‐known AE of BRAF inhibitors, with or without MEK inhibitors, and have been reported to have a high incidence after dabrafenib/trametinib, but not after encorafenib/binimetinib. In this report, we describe three cases of severe pyrexia in nivolumab‐resistant advanced melanoma after successful combined therapy with encorafenib plus binimetinib. Interestingly, in all cases, the serum levels of soluble CD163 C‐X‐C motif chemokine (CXCL)9, CXCL10 and CXCL11, which are known biomarkers for adult‐onset Still’s disease (AOSD), increased in parallel with the development of pyrexia. Our present cases suggest that pyrexia caused by BRAF/MEK inhibitors may possess a similar pathophysiology as that of AOSD.
Metabolic mechanism of colistin resistance and its reverting in Vibrio alginolyticus
Authors: Li Lu , Su Yu‐bin , Peng Bo , Peng Xuan‐xian , Li Hui 
Published: April 2020

SummaryColistin is a last‐line antibiotic against Gram‐negative multidrug‐resistant bacteria, but the increased resistance poses a huge challenge to this drug. However, the mechanisms underlying such resistance are largely unexplored. The present study first identified the mutations of two genes encoding AceF subunit of pyruvate dehydrogenase (PDH) and TetR family transcriptional regulator in colistin‐resistant Vibrio alginolyticus (VA‐RCT) through genome sequencing. Then, gas chromatography‐mass spectroscopy‐based metabolomics was adopted to investigate metabolic responses since PDH plays a role in central carbon metabolism. Colistin resistance was associated with the reduction of the central carbon metabolism and energy metabolism, featuring the alteration of the pyruvate cycle, a recently characterized energy‐producing cycle. Metabolites in the pyruvate cycle reprogramed colistin‐resistant metabolome to colistin‐sensitive metabolome, resulting in increased gene expression, enzyme activity or protein abundance of the cycle and sodium‐translocating nicotinamide adenine dinucleotide‐ubiquinone oxidoreductase. This reprogramming promoted the production of the proton motive force that enhances the binding between colistin and lipid A in lipopolysaccharide. Moreover, this metabolic approach was effective against VA‐RCT in vitro and in vivo as well as other clinical isolates. These findings reveal a previously unknown mechanism of colistin resistance and develop a metabolome‐reprogramming approach to promote colistin efficiency to combat with colistin‐resistant bacteria.
The efficacy and safety of ramucirumab plus docetaxel in older patients with advanced non‐small cell lung cancer
Authors: Sakaguchi Tadashi , Furuya Naoki , Ito Kentaro , Hida Naoya , Morikawa Kei , Komase Yuko , Inoue Takeo , Hataji Osamu , Mineshita Masamichi 
Published: April 2020

AbstractBackgroundRamucirumab plus docetaxel (RAM+DOC) is expected to prolong survival in patients with advanced non‐small cell lung cancer (NSCLC); however, the efficacy and safety for older patients remains unknown. The objective of this study was to evaluate the efficacy and safety of RAM+DOC in patients 75 years and older.MethodsWe retrospectively reviewed consecutive patients with advanced NSCLC who had received RAM+DOC treatment at three institutions. We compared the efficacy and safety in patients 75 years and older to those under 75 years of age.ResultsA total of 114 patients were identified. The median progression‐free survival, time to treatment failure and overall survival was 3.6 (95% CI: 0.4–6.7), 3.1 (95% CI: 2.4–3.9) and 11.2 months (95% CI: 5.6–16.8) in the older group (N = 23), and 4.2 (95% CI: 3.3–5.0), 3.4 (95% CI: 3.3–5.0) and 12.2 months (95% CI: 9.1–15.4) in the younger group (N = 91), respectively. Survival curves were similar for each group, while the objective response rate was 30.4% (95% CI: 13.2–52.9%) in older patients and 35.2% (95% CI, 25.4–45.9%) for the younger group. A total of 22 older patients (95.7%) and 73 (80.2%) younger patients received primary prophylactic pegylated‐granulocyte‐colony stimulating factor (PEG‐G‐CSF). Four older patients (17.3%) and 14 younger patients (15.3%) discontinued RAM+DOC due to adverse events.ConclusionsRAM+DOC is expected to be efficacious and tolerable in older patients when supported with prophylactic PEG‐G‐CSF therapy.Key pointsSignificant findings of the study・PFS, OS, and ORR in older patients were similar to those under 75 years of age.・Safety of RAM+DOC was well tolerated in older patients with prophylactic PEG‐G‐CSF.・Prophylactic PEG‐G‐CSF with RAM+DOC may contribute to better efficacy.What this study adds・This study suggests that RAM+DOC with prophylactic PEG‐G‐CSF is expected to be a useful option in older patients with advanced NSCLC.
MicroRNA‐125b as a tumor suppressor by targeting MMP11 in breast cancer
Authors: Wang Yanan , Wei Yaning , Fan Xiangyu , Zhang Pei , Wang Pan , Cheng Shujie , Zhang Jinku 
Published: April 2020

BackgroundBreast cancer is a common type of tumor in women worldwide. MicroRNAs have been identified as regulators in many human cancers. The aim of this study was therefore to investigate the functional role of miR‐125b in regulating breast cancer progression.MethodsWe used the StarBase database to investigate the expression of miRNA‐125b in breast cancer and adjacent normal tissues. MMP11 3′‐UTR construct and luciferase reporter assays was performed for target genes. Cell proliferation was evaluated by CCK‐8 and colony formation assay. The migration and invasion were assessed by transwell assay.ResultsLuciferase reporter assays showed miRNA‐125b directly targeted MMP11. miRNA‐125b by transfection with its mimic in breast cancer cells significantly suppressed breast cancer cell proliferation and migration. Western blot revealed that overexpression of miRNA‐125b substantially reduced MMP11 protein expression. We used the UALCAN database to investigate the expression of MMP11 in human breast cancer and adjacent normal tissues. In addition, we found that miRNA‐125b spoiled MMP11 induced breast cancer cell proliferation and migration promotion effect.ConclusionsmiRNA‐125b mimic inhibited proliferation, migration, and invasion of breast cancer cells through targeting MMP11 protein.
miR‐181a regulates p62/SQSTM1, parkin, and protein DJ‐1 promoting mitochondrial dynamics in skeletal muscle aging
Authors: Goljanek‐Whysall Katarzyna , Soriano‐Arroquia Ana , McCormick Rachel , Chinda Caroline , McDonagh Brian 
Published: April 2020

AbstractOne of the key mechanisms underlying skeletal muscle functional deterioration during aging is disrupted mitochondrial dynamics. Regulation of mitochondrial dynamics is essential to maintain a healthy mitochondrial population and prevent the accumulation of damaged mitochondria; however, the regulatory mechanisms are poorly understood. We demonstrated loss of mitochondrial content and disrupted mitochondrial dynamics in muscle during aging concomitant with dysregulation of miR‐181a target interactions. Using functional approaches and mito‐QC assay, we have established that miR‐181a is an endogenous regulator of mitochondrial dynamics through concerted regulation of Park2, p62/SQSTM1, and DJ‐1 in vitro. Downregulation of miR‐181a with age was associated with an accumulation of autophagy‐related proteins and abnormal mitochondria. Restoring miR‐181a levels in old mice prevented accumulation of p62, DJ‐1, and PARK2, and improved mitochondrial quality and muscle function. These results provide physiological evidence for the potential of microRNA‐based interventions for age‐related muscle atrophy and of wider significance for diseases with disrupted mitochondrial dynamics.
Nuclear envelope dysfunction and its contribution to the aging process
Authors: Martins Filipa , Sousa Jéssica , Pereira Cátia D. , da Cruz e Silva Odete A. B. , Rebelo Sandra 
Published: April 2020

AbstractThe nuclear envelope (NE) is the central organizing unit of the eukaryotic cell serving as a genome protective barrier and mechanotransduction interface between the cytoplasm and the nucleus. The NE is mainly composed of a nuclear lamina and a double membrane connected at specific points where the nuclear pore complexes (NPCs) form. Physiological aging might be generically defined as a functional decline across lifespan observed from the cellular to organismal level. Therefore, during aging and premature aging, several cellular alterations occur, including nuclear‐specific changes, particularly, altered nuclear transport, increased genomic instability induced by DNA damage, and telomere attrition. Here, we highlight and discuss proteins associated with nuclear transport dysfunction induced by aging, particularly nucleoporins, nuclear transport factors, and lamins. Moreover, changes in the structure of chromatin and consequent heterochromatin rearrangement upon aging are discussed. These alterations correlate with NE dysfunction, particularly lamins’ alterations. Finally, telomere attrition is addressed and correlated with altered levels of nuclear lamins and nuclear lamina‐associated proteins. Overall, the identification of molecular mechanisms underlying NE dysfunction, including upstream and downstream events, which have yet to be unraveled, will be determinant not only to our understanding of several pathologies, but as here discussed, in the aging process.
Nicotine abolishes memory‐related synaptic strengthening and promotes synaptic depression in the neurogenic dentate gyrus of miR‐132/212 knockout mice
Authors: Stojanovic Tamara , Benes Hannah , Awad Amena , Bormann Daniel , Monje Francisco J. 
Published: April 2020

AbstractMicro‐RNAs (miRNAs) are highly evolutionarily conserved short‐length/noncoding RNA molecules that modulate a wide range of cellular functions in many cell types by regulating the expression of a variety of targeted genes. miRNAs have also recently emerged as key regulators of neuronal genes mediating the effects of psychostimulant drugs and memory‐related neuroplasticity processes. Smoking is a predominant addictive behaviour associated with millions of deaths worldwide, and nicotine is a potent natural psychoactive agonist of cholinergic receptors, highly abundant in cigarettes. The influence of miRNAs modulation on cholinergic signalling in the nervous system remains however poorly explored. Using miRNA knockout mice and biochemical, electrophysiological and pharmacological approaches, we examined the effects of miR‐132/212 gene disruption on the levels of hippocampal nicotinic acetylcholine receptors, total ERK and phosphorylated ERK (pERK) and MeCP2 protein levels, and studied the impact of nicotine stimulation on hippocampal synaptic transmission and synaptic depression and strengthening. miR‐132/212 deletion significantly altered α7‐nAChR and pERK protein levels, but not total ERK or MeCP2, and resulted in both exacerbated synaptic depression and virtually abolished memory‐related synaptic strengthening upon nicotine stimulation. These observations reveal a functional miRNAs/nicotinergic signalling interplay critical for nicotinic‐receptor expression and neuroplasticity in brain structures relevant for drug addiction and learning and memory functions.
Accuracy of sonographic estimation of weight in fetuses with abdominal wall defects
Authors: Spaulding Portia , Edwards Andrew , Coombs Peter , Davies‐Tuck Miranda , Robinson Alice 
Published: April 2020

BackgroundAccurate estimation of fetal weight is essential in guiding management of fetuses with abdominal wall defects (AWDs), as growth restriction is an important predictor of perinatal morbidity and mortality. Several sonographic formulae are available involving multiple biometric parameters, but abdominal circumference measurements may underestimate weight in fetuses with AWDs. No formula has yet shown superior accuracy.AimsThe objectives of this study were to evaluate, in fetuses with gastroschisis and omphalocoele, the accuracy of a sonographic estimated fetal weight (EFW) formula proposed by Siemer and colleagues, specifically for use in fetuses with AWDs compared to the commonly used Hadlock IV formula in estimating fetal weight, and detecting small for gestational age (SGA) fetuses.Materials and MethodsA retrospective cohort of 113 fetuses with AWDs was identified from an Australian teaching hospital over 13 years. Pregnancy data and sonographic fetal biometry parameters were obtained. The accuracy of each formula in predicting birthweight was compared using Bland–Altman limits of agreement, and the intraclass correlation coefficient between EFW and actual birthweight. Performance of each formula in detecting SGA fetuses was determined.ResultsThe Siemer and Hadlock formulae have similar accuracies for predicting birthweight in fetuses with AWDs. The Hadlock formula has a higher detection rate for SGA < 10th centile and < 3rd centile compared to the Seimer formula (84% vs 68% and 83% vs 67% respectively), albeit with a higher false‐positive rate.ConclusionThere is no clear clinical advantage in using the Siemer formula, which is specifically designed for fetuses with AWDs, over the Hadlock formula to estimate weight in fetuses with AWDs.
Open mesh removal combined with laparoscopic totally extraperitoneal inguinal hernia repair: A case report of a novel surgical technique for chronic postoperative inguinal pain
Authors: Kojima Shigehiro , Sakamoto Tsuguo , Yajima Kazuhito , Ogawa Fumihiro 
Published: April 2020

AbstractA 74‐year‐old man presented for surgical treatment to alleviate chronic post‐herniorrhaphy inguinal pain. Physical and imaging examinations suggested that his pain was due to his ilioinguinal nerve being entrapped by a meshoma composed of bilayer mesh and plug mesh. The patient strongly desired mesh removal, although it appeared challenging because of adhesion of the meshes from the previous herniorrhaphies. Anticipating technical difficulty, we performed laparoscopic totally extraperitoneal repair followed by open mesh removal. Thus, the risk of damaging the peritoneum and visceral organs during open mesh removal was eliminated because the peritoneum had already been separated from the pathogenic mesh during the laparoscopic repair. The patient's chronic pain was drastically relieved. Combination surgery may therefore be a safe and useful technique in select patients with chronic postoperative inguinal pain. This approach could also prevent hernia recurrence.
Evaluation of influence of milk urea nitrogen on reproductive performance in smallholder dairy farms
Authors: Kananub S , Pechkerd P , VanLeeuwen J , Stryhn H , Arunvipas P 
Published: April 2020

ObjectiveThe aim of this study was to determine the relationship between milk urea nitrogen (MUN) and reproductive performance in dairy cows in western Thailand.DesignAll cows calving from November 2014 to April 2015 were included in the study, a total of 486 cows from 47 farms. Each cow had milk constituents and MUN tested monthly up to confirmed conception or until the 8th month after parturition. Each farm had a dietary assessment completed. Cox proportional hazard models with shared frailty were used to determine associations of conception rate.ResultsCows became pregnant increasingly quickly over time, except during 100–150 days of lactation. A change in MUN from 12.5 to 13.5 mg/dL on the closet day to breeding was associated with a 5% decrease in conception. Milk protein was negatively associated with hazard of conception, whereas milk lactose and dietary protein:energy ratio had positive associations with conception rate. Breeding season was also significant; the highest conception rate was observed in cows inseminated during winter, whereas insemination during the humid rainy season resulted in the lowest conception rates. The farm random effect in the model was strongly significant.ConclusionDetrimental effects of higher MUN on rate of conception were identified. The rate of conception was positively associated with protein:energy ratio in the study. Therefore, good nutritional management leading to positive energy balance should benefit conception rates.
Efficient screening of predictive biomarkers for individual treatment selection
Authors: Sugasawa Shonosuke , Noma Hisashi 
Published: April 2020

AbstractThe development of molecular diagnostic tools to achieve individualized medicine requires identifying predictive biomarkers associated with subgroups of individuals who might receive beneficial or harmful effects from different available treatments. However, due to the large number of candidate biomarkers in the large‐scale genetic and molecular studies, and complex relationships among clinical outcome, biomarkers, and treatments, the ordinary statistical tests for the interactions between treatments and covariates have difficulties from their limited statistical powers. In this paper, we propose an efficient method for detecting predictive biomarkers. We employ weighted loss functions of Chenet al. to directly estimate individual treatment scores and propose synthetic posterior inference for effect sizes of biomarkers. We develop an empirical Bayes approach, namely, we estimate unknown hyperparameters in the prior distribution based on data. We then provide efficient screening methods for the candidate biomarkers via optimal discovery procedure with adequate control of false discovery rate. The proposed method is demonstrated in simulation studies and an application to a breast cancer clinical study in which the proposed method was shown to detect the much larger numbers of significant biomarkers than existing standard methods.
Factors associated with development and distribution of granular/fuzzy astrocytes in neurodegenerative diseases
Authors: Miki Tomoko , Yokota Osamu , Haraguchi Takashi , Ishizu Hideki , Hasegawa Masato , Ishihara Takeshi , Ueno Shu‐ichi , Takenoshita Shintaro , Terada Seishi , Yamada Norihito 
Published: April 2020

AbstractGranular/fuzzy astrocytes (GFAs), a subtype of “aging‐related tau astrogliopathy,” are noted in cases bearing various neurodegenerative diseases. However, the pathogenic significance of GFAs remains unclear. We immunohistochemically examined the frontal cortex, caudate nucleus, putamen and amygdala in 105 cases composed of argyrophilic grain disease cases (AGD, N = 26), and progressive supranuclear palsy (PSP, N = 10), Alzheimer’s disease (AD, N = 20) and primary age‐related tauopathy cases (PART, N = 18) lacking AGD, as well as 31 cases bearing other various neurodegenerative diseases to clarify (i) the distribution patterns of GFAs in AGD, and PSP, AD and PART lacking AGD, (ii) the impacts of major pathological factors and age on GFA formation and (iii) immunohistochemical features useful to understand the formation process of GFAs. In AGD cases, GFAs consistently occurred in the amygdala (100%), followed by the putamen (69.2%) and caudate nucleus and frontal cortex (57.7%, respectively). In PSP cases without AGD, GFAs were almost consistently noted in all regions examined (90–100%). In AD cases without AGD, GFAs were less frequent, developing preferably in the putamen (35.0%) and caudate nucleus (30.0%). PART cases without AGD had GFAs most frequently in the amygdala (35.3%), being more similar to AGD than to AD cases. Ordered logistic regression analyses using all cases demonstrated that the strongest independent factor of GFA formation in the frontal cortex and striatum was the diagnosis of PSP, while that in the amygdala was AGD. The age was not significantly associated with GFA formation in any region. In GFAs in AGD cases, phosphorylation and conformational change of tau, Gallyas‐positive glial threads indistinguishable from those in tufted astrocytes, and the activation of autophagy occurred sequentially. Given these findings, AGD, PSP, AD and PART cases may show distinct distributions of GFAs, which may provide clues to predict the underlying processes of primary tauopathies.
Impacts of habitat on butterfly dispersal in tropical forests, parks and grassland patches embedded in an urban landscape
Authors: Jain Anuj , Chan Simon Kee Mun , Vlasanek Petr , Webb Edward L. 
Published: April 2020

AbstractDispersal distances of 17 species of butterflies in tropical Singapore were significantly greater in forest than in urban habitat. Butterflies in urban plots frequently moved within suitable habitat (park/grassland) patches but rarely crossed non‐habitat patches suggesting potential isolation and a need for urban corridors.
Synergistic effect of the inhibitors of RAF/MEK and AXL on KRAS‐mutated ovarian cancer cells with high AXL expression
Authors: Umemura Shiori , Sowa Yoshihiro , Iizumi Yosuke , Kitawaki Jo , Sakai Toshiyuki 
Published: April 2020

AbstractKRAS mutation is frequently seen in a subtype of ovarian cancer categorized as type 1. The KRAS‐MAPK pathway, which is closely involved in type 1 cancer progression, is under the regulation of receptor tyrosine kinases (RTKs). AXL, one of the RTKs, has been reported to be overexpressed in ovarian cancer and contributes to the poor prognosis. However, there is no useful target‐based agent against such gene profiles. We examined the combined effect of the dual RAF/MEK inhibitor CH5126766 and AXL inhibitor R428 on the growth of ovarian cancer HEY‐T30 and OVCAR‐5 cell lines, both of which bear KRAS mutation and express AXL at a high level, using the WST‐8 assay and the colony formation assay. The synergistic effect of the combination was evaluated by the combination index. The apoptotic cells were analyzed by flow cytometry. The expression of apoptotic proteins and the phosphorylation of MAPK and AKT pathway proteins were investigated by western blotting. We found that CH5126766 and R428 suppressed the phosphorylation of ERK and AKT, respectively, and their combination synergistically inhibited the growth of both cell lines with enhancement of apoptosis accompanied by the Bim upregulation. Combined treatment with CH5126766 and R428 is expected as the novel therapeutic option for KRAS‐mutated ovarian cancer with high expression of AXL.