bluuebunny/crossref_metadata_2025_split huggingface dataset:
CEO inside debt and investment‐cash flow sensitivity
Authors: Han Jianlei , Pan Zheyao 
Published: January 2015

AbstractThis paper provides a new explanation for investment‐cash flow sensitivity from the perspective of CEO inside debt holdings. We examine the effect of CEO pensions and deferred compensation (inside debt) on investment‐cash flow sensitivity for a sample of U.S. manufacturing firms from 2006 to 2012. We find that the firms with higher relative CEO leverage ratios (CEO's debt/equity ratio scaled by the firm's debt/equity ratio) generate higher investment‐cash flow sensitivity. Moreover, one standard deviation increase in the logarithm of the relative CEO leverage ratio enlarges investment‐cash flow sensitivity by 50 per cent. This positive relationship still holds even after we take account of endogeneity and financial constraints.
Adenosine 2A receptors modulate reward behaviours for methamphetamine
Authors: Chesworth Rose , Brown Robyn M. , Kim Jee Hyun , Ledent Catherine , Lawrence Andrew J. 
Published: January 2015

AbstractAddiction to methamphetamine (METH) is a global health problem for which there are no approved pharmacotherapies. The adenosine 2A (A2A) receptor presents a potential therapeutic target for METH abuse due to its modulatory effects on striatal dopamine and glutamate transmission. Notably, A2A receptor signalling has been implicated in the rewarding effects of alcohol, cocaine and opiates; yet, the role of this receptor in METH consumption and seeking is essentially unknown. Therefore, the current study used A2A knockout (KO) mice to assess the role of A2A in behaviours relevant to METH addiction. METH conditioned place preference was absent in A2A KO mice compared with wild‐type (WT) littermates. Repeated METH treatment produced locomotor sensitization in both genotypes; however, sensitization was attenuated in A2A KO mice in a dose‐related manner. METH intravenous self‐administration was intact in A2A KO mice over a range of doses and schedules of reinforcement. However, the motivation to self‐administer was reduced in A2A KO mice. Regression analysis further supported the observation that the motivation to self‐administer METH was reduced in A2A KO mice even when self‐administration was similar to WT mice. Sucrose self‐administration was also reduced in A2A KO mice but only at higher schedules of reinforcement. Collectively, these data suggest that A2A signalling is critically required to integrate rewarding and motivational properties of both METH and natural rewards.
Addressing Population‐Specific Multiple Testing Burdens in Genetic Association Studies
Authors: Sobota Rafal S. , Shriner Daniel , Kodaman Nuri , Goodloe Robert , Zheng Wei , Gao Yu‐Tang , Edwards Todd L. , Amos Christopher I. , Williams Scott M. 
Published: January 2015

SummaryThe number of effectively independent tests performed in genome‐wide association studies (GWAS) varies by population, making a universal P‐value threshold inappropriate. We estimated the number of independent SNPs in Phase 3 HapMap samples by: (1) the LD‐pruning function in PLINK, and (2) an autocorrelation‐based approach. Autocorrelation was also used to estimate the number of independent SNPs in whole genome sequences from 1000 Genomes. Both approaches yielded consistent estimates of numbers of independent SNPs, which were used to calculate new population‐specific thresholds for genome‐wide significance. African populations had the most stringent thresholds (1.49 × 10−7 for YRI at r2 = 0.3), East Asian populations the least (3.75 × 10−7 for JPT at r2 = 0.3). We also assessed how using population‐specific significance thresholds compared to using a single multiple testing threshold at the conventional 5 × 10−8 cutoff. Applied to a previously published GWAS of melanoma in Caucasians, our approach identified two additional genes, both previously associated with the phenotype. In a Chinese breast cancer GWAS, our approach identified 48 additional genes, 19 of which were in or near genes previously associated with the phenotype. We conclude that the conventional genome‐wide significance threshold generates an excess of Type 2 errors, particularly in GWAS performed on more recently founded populations.
De Novo Mutations in the BMPR2 Gene in Patients with Heritable Pulmonary Arterial Hypertension
Authors: Momose Yuichi , Aimi Yuki , Hirayama Tomomi , Kataoka Masaharu , Ono Masae , Yoshino Hideaki , Satoh Toru , Gamou Shinobu 
Published: January 2015

SummaryA substantial proportion of patients with pulmonary arterial hypertension (PAH) have mutations in the Bone Morphogenetic Protein Receptor type‐2 (BMPR2) gene. PAH due to BMPR2 mutations is inherited as an autosomal dominant trait with several unique features, including a wide variety of mutations, reduced penetrance, a skewed gender ratio, variable expressivity and genetic anticipation. To address the genetic background of these unique features of BMPR2 mutation, we conducted a systematic analysis of 15 PAH families with BMPR2 mutation. The exonic protein coding sequence of BMPR2 was amplified by polymerase chain reaction and the products were sequenced directly to detect point mutations in BMPR2. Parental identification was carried out to confirm the parental relationship using multiplex 15 loci analysis. Combining mutation detection in family members with parental identification, we described three cases of de novo mutation in the BMPR2 gene by different modes in a PAH family. These de novo mutations may account for the wide variety of mutations in BMPR2. Taken together with the juvenile onset of the disease, there is possibly some balance of de novo mutations and untransmittable mutations which keeps the frequency of PAH low in the general population.
A randomized phase I clinical study of cis‐urocanic acid eye drops in healthy adult subjects
Authors: Jauhonen Hanna‐Mari , Kari Eeva , Pylkkänen Liisa , Poutanen Jutta , Laihia Jarmo , Kaarniranta Kai , Leino Lasse 
Published: January 2015

AbstractPurposeTo evaluate safety, ocular tolerability and pharmacokinetics of 0.5% and 2.5% cis‐urocanic acid (cis‐UCA) eye drops.MethodsIn this phase I, double‐blinded, placebo‐controlled trial, 37 healthy volunteers were randomized to three treatment arms: 0.5% cis‐UCA (12 subjects), 2.5% cis‐UCA (12 subjects) and placebo eye drops (13 subjects). In the first part, the subjects were dosed topically on a randomized eye with one drop three times at 7 ± 1 hr intervals during 1 day. In the second part, the subjects self‐administered three daily drops at 7 ± 1 hr intervals on both eyes for 14 days. Physical examination of the eyes was performed seven times during the study. Tolerability of cis‐UCA was assessed by ocular comfort rating questionnaire. Pharmacokinetic blood and urine samples were analysed under good laboratory practice (GLP).ResultsAll subjects completed both parts of the study. There were no significant adverse events (AEs). The most common treatment‐related ocular AE was eye irritation (62.2% of subjects). Cis‐UCA concentrations in plasma remained below the limit of quantification (0.195 μg/ml) in all but two subjects. The fraction of the administered drug excreted into urine over the total collection period ranged from 3.2% to 61.6% of the last dose and from 1.1% to 20.5% of the daily dose.ConclusionsTopical ocular administration of cis‐UCA solution is safe and apart from mild‐ and short‐lasting eye irritation after administration well tolerated in healthy adult subjects. Topical ocular dosing leads to transient systemic exposure to cis‐UCA that does not cause systemic AEs.
Intra‐ and intermale variability of mature sperm traits analysed in two brackish water populations of the pipefish Syngnathus abaster (Syngnathidae)
Authors: Piras Francesca , Biagi Francesca , Floris Antonello , Farina Vittorio , Zedda Marco , Franzoi Piero , Carcupino Marcella 
Published: January 2015

AbstractSperm cells are highly diversified in animals, and considerable research effort has focused on variation in sperm morphology among species. Surprisingly, little is known about intraspecific variation in sperm morphology. We analysed within‐ and between‐male variation in mature sperm traits in two brackish water populations of the pipefish Syngnathus abaster. Four morphometric parameters, such as the width and length of the head (including nucleus, and midpiece), length of flagellum and total sperm length were taken into account. The differences in all morphometric parameters analysed between populations were not statistically significant. Moreover, the multidimensional scaling analysis shows that (i) the two populations seem to be indistinguishable based on their spermatozoa and (ii) there is not polymorphism, being sperm not distinguishable into discrete classes both within a single male and between males of each populations. The latter datum does not seem to support the presence of polymorphic sperm in syngnathids. Both populations, however, exhibit a high variation in all sperm traits, both among individual sperm within an ejaculate and among males within each population. The relationship between sperm traits variability and the low selection pressure determined by the absence of postcopulatory sexual selection (i.e. absence of sperm competition) is discussed.
Physiologically based pharmacokinetic model for 6‐mercpatopurine: exploring the role of genetic polymorphism in TPMT enzyme activity
Authors: Ogungbenro Kayode , Aarons Leon ,   the CRESim & Epi‐CRESim Project Groups
Published: January 2015

AimsTo extend the physiologically based pharmacokinetic (PBPK) model developed for 6‐mercaptopurine to account for intracellular metabolism and to explore the role of genetic polymorphism in the TPMT enzyme on the pharmacokinetics of 6‐mercaptopurine.MethodsThe developed PBPK model was extended for 6‐mercaptopurine to account for intracellular metabolism and genetic polymorphism in TPMT activity. System and drug specific parameters were obtained from the literature or estimated using plasma or intracellular red blood cell concentrations of 6‐mercaptopurine and its metabolites. Age‐dependent changes in parameters were implemented for scaling, and variability was also introduced for simulation. The model was validated using published data.ResultsThe model was extended successfully. Parameter estimation and model predictions were satisfactory. Prediction of intracellular red blood cell concentrations of 6‐thioguanine nucleotide for different TPMT phenotypes (in a clinical study that compared conventional and individualized dosing) showed results that were consistent with observed values and reported incidence of haematopoietic toxicity. Following conventional dosing, the predicted mean concentrations for homozygous and heterozygous variants, respectively, were about 10 times and two times the levels for wild‐type. However, following individualized dosing, the mean concentration was around the same level for the three phenotypes despite different doses.ConclusionsThe developed PBPK model has been extended for 6‐mercaptopurine and can be used to predict plasma 6‐mercaptopurine and tissue concentration of 6‐mercaptopurine, 6‐thioguanine nucleotide and 6‐methylmercaptopurine ribonucleotide in adults and children. Predictions of reported data from clinical studies showed satisfactory results. The model may help to improve 6‐mercaptopurine dosing, achieve better clinical outcome and reduce toxicity.
Therapeutic phlebotomy is safe in children with sickle cell anaemia and can be effective treatment for transfusional iron overload
Authors: Aygun Banu , Mortier Nicole A. , Kesler Karen , Lockhart Alexandre , Schultz William H. , Cohen Alan R. , Alvarez Ofelia , Rogers Zora R. , Kwiatkowski Janet L. , Miller Scott T. , Sylvestre Pamela , Iyer Rathi , Lane Peter A. , Ware Russell E. ,   the Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) Trial Investigators
Published: January 2015

SummarySerial phlebotomy was performed on sixty children with sickle cell anaemia, stroke and transfusional iron overload randomized to hydroxycarbamide in the Stroke With Transfusions Changing to Hydroxyurea trial. There were 927 phlebotomy procedures with only 33 adverse events, all of which were grade 2. Among 23 children completing 30 months of study treatment, the net iron balance was favourable (−8·7 mg Fe/kg) with significant decrease in ferritin, although liver iron concentration remained unchanged. Therapeutic phlebotomy was safe and well‐tolerated, with net iron removal in most children who completed 30 months of protocol‐directed treatment.
RUNX3 promoter hypermethylation is frequent in leukaemia cell lines and associated with acute myeloid leukaemia inv(16) subtype
Authors: Estécio Marcos R. H. , Maddipoti Sirisha , Bueso‐Ramos Carlos , DiNardo Courtney D. , Yang Hui , Wei Yue , Kondo Kimie , Fang Zhihong , Stevenson William , Chang Kun‐Sang , Pierce Sherry A. , Bohannan Zachary , Borthakur Gautam , Kantarjian Hagop , Garcia‐Manero Guillermo 
Published: January 2015

SummaryCorrelative and functional studies support the involvement of the RUNX gene family in haematological malignancies. To elucidate the role of epigenetics in RUNX inactivation, we evaluated promoter DNA methylation of RUNX1, 2, and 3 in 23 leukaemia cell lines and samples from acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) and myelodysplatic syndromes (MDS) patients. RUNX1 and RUNX2 gene promoters were mostly unmethylated in cell lines and clinical samples. Hypermethylation of RUNX3 was frequent among cell lines (74%) and highly variable among patient samples, with clear association to cytogenetic status. High frequency of RUNX3 hypermethylation (85% of the 20 studied cases) was found in AML patients with inv(16)(p13.1q22) compared to other AML subtypes (31% of the other 49 cases). RUNX3 hypermethylation was also frequent in ALL (100% of the six cases) but low in MDS (21%). In support of a functional role, hypermethylation of RUNX3 was correlated with low levels of protein, and treatment of cell lines with the DNA demethylating agent, decitabine, resulted in mRNA re‐expression. Furthermore, relapse‐free survival of non‐inv(16)(p13.1q22) AML patients without RUNX3 methylation was significantly better (P = 0·016) than that of methylated cases. These results suggest that RUNX3 silencing is an important event in inv(16)(p13.1q22) leukaemias.
Clinical outcomes of a novel therapeutic vaccine with Tax peptide‐pulsed dendritic cells for adult T cell leukaemia/lymphoma in a pilot study
Authors: Suehiro Youko , Hasegawa Atsuhiko , Iino Tadafumi , Sasada Amane , Watanabe Nobukazu , Matsuoka Masao , Takamori Ayako , Tanosaki Ryuji , Utsunomiya Atae , Choi Ilseung , Fukuda Tetsuya , Miura Osamu , Takaishi Shigeo , Teshima Takanori , Akashi Koichi , Kannagi Mari , Uike Naokuni , Okamura Jun 
Published: January 2015

SummaryAdult T cell leukaemia/lymphoma (ATL) is a human T cell leukaemia virus type‐I (HTLV‐I)‐infected T cell malignancy with poor prognosis. We herein developed a novel therapeutic vaccine designed to augment an HTLV‐I Tax‐specific cytotoxic T lymphocyte (CTL) response that has been implicated in anti‐ATL effects, and conducted a pilot study to investigate its safety and efficacy. Three previously treated ATL patients, classified as intermediate‐ to high‐risk, were subcutaneously administered with the vaccine, consisting of autologous dendritic cells (DCs) pulsed with Tax peptides corresponding to the CTL epitopes. In all patients, the performance status improved after vaccination without severe adverse events, and Tax‐specific CTL responses were observed with peaks at 16–20 weeks. Two patients achieved partial remission in the first 8 weeks, one of whom later achieved complete remission, maintaining their remission status without any additional chemotherapy 24 and 19 months after vaccination, respectively. The third patient, whose tumour cells lacked the ability to express Tax at biopsy, obtained stable disease in the first 8 weeks and later developed slowly progressive disease although additional therapy was not required for 14 months. The clinical outcomes of this pilot study indicate that the Tax peptide‐pulsed DC vaccine is a safe and promising immunotherapy for ATL.
Clinical significance of estrogen receptor β in breast and prostate cancer from biological aspects
Authors: Omoto Yoko , Iwase Hirotaka 
Published: January 2015

Breast and prostate cancers are among the most common of all cancers. They are referred to as hormone‐dependent cancers, because estrogen and androgen are involved in their development and growth. The effects of these hormones are mediated by their respective receptors, estrogen receptor (ER) α and androgen receptor. Around 18 years ago, a second ER, ERβ, which has a very similar structure to ERα, was discovered. Its function has been investigated using a variety of methods and biological systems, leading to our present understanding that ERβ can interact with or inhibit ERα and androgen receptor function directly and/or indirectly, suppress cell growth, and influence responsiveness to endocrine therapy. In order to apply the “inhibition of cell growth” function to cancer treatment, several specific ERβ agonists have been synthesized and are being tested for effectiveness in cancer treatment. We need to keep our eyes on ERβ.
Enriching the isotopic toolbox for migratory connectivity analysis: a new approach for migratory species breeding in remote or unexplored areas
Authors: Pekarsky Sasha , Angert Alon , Haese Barbara , Werner Martin , Hobson Keith A. , Nathan Ran 
Published: January 2015

AbstractAimWe examined three potential enhancements of the stable isotope technique for elucidating migratory connectivity in birds inhabiting poorly studied areas, illustrated for Eurasian cranes (Grus grus) that overwinter in and migrate through Israel. First, we examined the use of oxygen stable isotopes (δ18O), seldom applied for this purpose. Second, we examined the relationship between ambient water δ18O and hydrogen stable isotope (δ2H) values derived from various models, to determine the geographical origins of migrants. Third, we introduced the use of probabilistic distribution modelling to refine the assignment to origin of migrants lacking detailed distribution maps.LocationFeather samples were collected in the Hula Valley (northern Israel) and across the species breeding range in north Eurasia.MethodsWe analysed δ18O and δ2H in primary and secondary flight feathers using standard mass spectrometry. The maximum entropy (maxent) model was used to map the probability surface of potential breeding areas, as a Bayesian prior for assigning Hula Valley cranes to potential breeding grounds.ResultsWe found that δ18O was suitable and informative. The soil water isoscape performed better for δ18O while precipitation isoscape was preferable for δ2H. The maxent‐based probability surface largely refined assignments. Overall, most (>85%) cranes were assigned to the area west of the Ural Mountains, but for two individuals, most of the assigned area (>90%) was farther east, suggesting, for the first time, that Eurasian cranes may undertake the North Asia–Middle East (and perhaps Africa) migration flyway.Main conclusionsOur results call for broader use of δ18O in migratory connectivity studies and for application of probabilistic distribution modelling. We also encourage investigation of factors determining δ18O and δ2H integration into animal tissues. The proposed framework may help improve our understanding of migratory connectivity of species inhabiting previously unexplored areas and thus contribute to the development of efficient conservation plans.
Echo Doppler Estimation of Pulmonary Capillary Wedge Pressure in Patients with Severe Aortic Stenosis
Authors: Biner Simon , Topilsky Yan , Banai Shmuel , Steinvil Arie , Arbel Yaron , Siegel Robert James , Beigel Roy , Keren Gad , Finkelstein Ariel 
Published: January 2015

BackgroundTranscatheter aortic valve replacement (TAVR) has become a treatment option for patients with severe aortic stenosis (AS) and high surgical risk. Assessment of symptoms in these patients is challenging because of advanced age, comorbidities, and limited physical activity. Noninvasive quantification of pulmonary capillary wedge pressure (PCWP) in candidates for TAVR may be helpful for risk stratification. The objective of the study was to create a model for estimation of PCWP by echo Doppler in patients with severe AS.Methods and ResultsData from 80 patients with severe AS referred for TAVR were used to develop an echo Doppler model for predicting PCWP. Its performance was evaluated in the test cohort of 33 patients who had invasive and noninvasive evaluation. No single echo Doppler parameter estimated PCWP accurately. In the retrospective analysis, the multilinear regression provided an accurate estimate of PCWP (r2 = 0.74). The model included, in order of importance (all P < 0.05), the ratio of early transmitral velocity (E) to annular velocity (E’), the left ventricular ejection fraction, and the velocity time integral of tricuspid regurgitation signal. In the prospective cohort of patients with severe AS, the model demonstrated good predictive ability of PCWP (r = 0.77, P < 0.01).ConclusionIn patients with severe AS, noninvasive estimation of PCWP is possible by integration of two‐dimensional, spectral, and tissue Doppler variables.
Long‐range seasonal migration in insects: mechanisms, evolutionary drivers and ecological consequences
Authors: Chapman Jason W. , Reynolds Don R. , Wilson Kenneth 
Published: January 2015

AbstractMyriad tiny insect species take to the air to engage in windborne migration, but entomology also has its ‘charismatic megafauna’ of butterflies, large moths, dragonflies and locusts. The spectacular migrations of large day‐flying insects have long fascinated humankind, and since the advent of radar entomology much has been revealed about high‐altitude night‐time insect migrations. Over the last decade, there have been significant advances in insect migration research, which we review here. In particular, we highlight: (1) notable improvements in our understanding of lepidopteran navigation strategies, including the hitherto unsuspected capabilities of high‐altitude migrants to select favourable winds and orientate adaptively, (2) progress in unravelling the neuronal mechanisms underlying sun compass orientation and in identifying the genetic complex underpinning key traits associated with migration behaviour and performance in the monarch butterfly, and (3) improvements in our knowledge of the multifaceted interactions between disease agents and insect migrants, in terms of direct effects on migration success and pathogen spread, and indirect effects on the evolution of migratory systems. We conclude by highlighting the progress that can be made through inter‐phyla comparisons, and identify future research areas that will enhance our understanding of insect migration strategies within an eco‐evolutionary perspective.