Miracle-dz/UniFAR-FTUs huggingface dataset:
A potential role for nilotinib in KIT-mutated melanoma

Introduction: The advent of effective immunotherapy and targeted therapy, such as ipilimumab (anti-CTLA-4 monoclonal antibody) and vemurafenib (BRAF inhibitor), are changing the treatment paradigm for metastatic melanoma. One of the most readily recognized targets in metastatic melanoma is the oncogenic ‘driver' mutations KIT, which is thought to be an important driver mutation in up to 3% of melanomas. Areas covered: We review the current state of development of KIT-targeted agents in melanoma with KIT mutations. The pharmacokinetic and pharmacodynamic profiles of nilotinib are presented, as well its safety clinical activity data. Finally, we present the knowledge learned from the experience of nilotinib in chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST) to guide its development for melanoma. Expert opinion: Given its favorable safety and efficacy profile in CML and imatinib-resistant GISTs, nilotinib, a second-generation tyrosine kinase inhibitor with greater potency than imatinib, emerges as a promising agent in the treatment of metastatic melanoma harboring the KIT mutation and warrants clinical investigation in this setting.
Bivariate Whole Genome Linkage Analyses for Total Body Lean Mass and BMD

A genome‐wide bivariate analysis was conducted for TBLM and BMD at the spine and hip in a large white sample. We found some QTLs shared by TBLM and BMD in the entire sample and the sex‐specific subgroups, and QTLs with potential pleiotropy were disclosed.
IN PURSUIT OF UNDERSTANDING MARKUPS IN RESTAURANT SERVICES PRICES

Measuring markups in restaurant services is a difficult task. Although the sales price is observed, cost of the product served is unobserved. In this study, we employ an intuitive framework and focus specifically on markups on soft drinks. We analyze the determinants of markup on soft drinks in restaurants over 2006–2014. Results suggest that current demand conditions (net minimum wage, output gap), major cost items (food and energy prices, exchange rate) and economic uncertainty (exchange rate volatility) significantly affect markups. This strategy enables the detection of relevant factors which may not be possible to detect in other settings.
Trends in Environmental Governance: Evidence from Seventeen Countries and Sundry Reflections Thereon

This book examines how different countries define and address environmental issues, specifically in relation to intergovernmental relations: the creation of institutions, the assignment of powers, and the success of alternative solutions. It also investigates whether a systemic view of the environment has influenced the policy-making process. The broad perspective adopted includes a detailed analysis of seventeen countries in six continents by scholars from a range of disciplines – economics, political science, environmental science and law – thus producing novel material that moves away from the conventional treatment of decentralisation and the environment in economic literature.
The Association Between Benzodiazepine Use and Depression Outcomes in Older Veterans

Benzodiazepines (BZDs) are commonly prescribed to older adults with depression, but it is unknown whether they improve antidepressant (AD) adherence or depressive symptoms. We followed 297 older veterans diagnosed with depression and provided a new AD medication prospectively for 4 months. Data include validated self-report measures and VA pharmacy records. At initial assessment, 20.5% of participants were prescribed a BZD. Those with a BZD prescription at baseline were significantly more likely than those without to have a personality disorder, schizophrenia spectrum disorder, or other anxiety disorder, and higher depressive symptom and anxiety symptom scale scores on average. In adjusted regressions, BZD use was not significantly associated with AD adherence, any improvement in depressive symptoms, or a 50% reduction in depressive symptoms. Our results suggest BZD use concurrent with AD treatment does not significantly improve depressive outcomes in older veterans.
Phase Correction Following a Perturbation in Sensorimotor Synchronization Depends on Sensory Information

Abstract In models of sensorimotor synchronization, it is generally assumed that phase correction occurs in response to information about sensorimotor asynchrony or relative phase. Without such feedback, a phase perturbation in the motor activity should not be followed by phase correction. Alternatively, internally generated temporal expectations could provide a basis for phase correction in the absence of feedback. To test those hypotheses, the author conducted an experiment in which participants (N = 8) tapped their finger in synchrony with isochronous auditory sequences containing a single shifted event onset, after which there could be a gap of up to 3 missing events. Participants were instructed to not react to the shifted event and to continue tapping regularly during any gap. The shifted event caused an involuntary phase shift of the following tap. The shift was corrected if the sequence continued, but during a gap, the shift persisted without correction. Those results confirm that sensory feedback is necessary for phase correction to occur.
Enhanced ethanol intake in preweanling rats following exposure to ethanol in a nursing context.

Several studies have confirmed that diet selection patterns of adult rats are at least partially established as a result of early experiences with food-related stimuli present in the milk of a lactating female (e.g., Capretta & Rawls, 1974; Galef & Clark, 1972; Galef & Henderson 1972). The present experiments were designed to investigate whether preweanling rats would similarly modify their acceptance of an ethanol solution following exposure to this cue in a nursing context. In Experiment 1, 8-, 12-, and 16-day-old rats were given ethanol, delivered intraorally in compound with milk, while given the opportunity to suckle an anesthetized dam. Subsequent testing revealed that 12- and 16-day-old subjects evidenced enhanced intake of the ethanol relative to controls, while 8-day-olds did not. Finally, the oldest (16 days of age) subjects also expressed a conditioned aversion to the milk when tested 24 hr after conditioning and ethanol-ingestion testing. Experiment 2 demonstrated that the critical factor for ethanol conditioning was the opportunity to suckle, rather than the simultaneous presence of milk. Finally, the aversion to milk observed in Experiment 1 was shown to have resulted from long-delay learning, due to the ingestion of a sufficient dose of ethanol during testing to serve as an aversive unconditioned stimulus (Exp. 3).
Singular moduli for real quadratic fields: A rigid analytic approach

A rigid meromorphic cocycle is a class in the rst cohomology of the discrete group Γ := SL2(Z[1/p]) with values in the multiplicative group of non-zero rigid meromorphic functions on the p-adic upper half plane Hp := P1(Cp) − P1(Qp). Such a class can be evaluated at the real quadratic irrationalities in Hp, which are referred to as “RM points”. Rigid meromorphic cocycles can be envisaged as the real quadratic counterparts of Borcherds’ singular theta lis: their zeroes and poles are contained in a nite union of Γ-orbits of RM points, and their RM values are conjectured to lie in ring class elds of real quadratic elds. ese RM values enjoy striking parallels with the CM values of modular functions on SL2(Z)\H: in particular they seem to factor just like the dierences of classical singular moduli, as described by Gross and Zagier. A fast algorithm for computing rigid meromorphic cocycles to high p-adic accuracy leads to convincing numerical evidence for the algebraicity and factorisation of the resulting singular moduli for real quadratic elds.
Can Indonesia’s Fiscal Policy be Sustained, with Exploding Debt?

The debate over debt issues always becomes hot potatoes to be discussed. Recent data in debt position which accounted for 1.977,71 trillion IDR onDecember31st2012 has made a thousand eyes looking at The Central Government and questioning whether Indonesia should continue to rely on debt for development financing, and whether its debt level is dangerous for fiscal sustainability or not. This paper analyzes debt sustainability by using Natural Debt Limit (NDL) approach introduced by Mendoza-Oveido. In order to examine how the Indonesian government reacts to changes in its debt position, this paper estimates fiscal reaction functions using an econometric approach, namely Vector Error Correction Model (VECM). The result shows that: (i) natural debt limit for Indonesia is 32,3% over GDP; (ii) since 1992 the central government has run a sustainable fiscal policy, by reducing the primary deficit or increasing the surplus in response towards rising debt. Indonesia has a space to utilize more debt, but in a good manner (well-managed) especially aimed for productive and priority spending such as for infrastructure and education.
The relationship between music therapy goals, health goals and education goals in a transition school for adolescents with mental health needs

This exegesis explores the relationship between music therapy goals, health goals and education goals in a transition school for adolescents with mental health needs. Secondary analysis of data uncovered language and goals from the schools Individual Education Plans and Individual Therapeutic Plans. The language and goals from each plan were compared and set against language and goals derived from student music therapist’s music therapy goals. The research showed that although goals set by teachers and therapists in the school addressed different areas of education and health, they were in fact linked. The team worked collaboratively to support students to reach health and education goals. Music therapy supported both health and education goals in the school context. This study presents a community perspective on education and health goals in a school context. Adolescents may need support from teachers and therapists to reach education and health goals in New Zealand schools.
A controlled study of ranitidine for the prevention of recurrent hemorrhage from duodenal ulcer

BACKGROUND Hemorrhage is the most common complication of duodenal ulcer disease, but there is little information about the effectiveness and safety of long-term maintenance therapy with histamine H2-receptor blockers. METHODS We conducted a double-blind study in patients with endoscopically documented hemorrhage from duodenal ulcers. Patients were randomly assigned to maintenance therapy with ranitidine (150 mg at night) or placebo and were followed for up to three years. Endoscopy was performed at base line (to document that the ulcers had healed), at exit from the study, and when a patient had persistent ulcer symptoms unrelieved by antacids or had gastrointestinal bleeding. Symptomatic relapses without bleeding were treated with ranitidine; if the ulcer healed within eight weeks, the patient resumed taking the assigned study medication. RESULTS The two groups were similar at entry, which usually occurred about three months after the index hemorrhage. After a mean follow-up of 61 weeks, 3 of the 32 patients treated with ranitidine had recurrent hemorrhage, as compared with 12 of the 33 given placebo (P < 0.05). Half the episodes of recurrent bleeding were asymptomatic. One patient in the ranitidine group withdrew from the study because of asymptomatic thrombocytopenia during the first month. CONCLUSIONS For patients whose duodenal ulcers heal after severe hemorrhage, long-term maintenance therapy with ranitidine is safe and reduces the risk of recurrent bleeding.
People Prefer System 2 Nudges (Kind Of)

In the United States, the United Kingdom, Australia, and many other nations, those involved in law and policy have been exploring choice-preserving approaches, or “nudges,” informed by behavioral science and with the purpose of promoting important public policy goals, such as improved health and safety. But there is a large and insufficiently explored difference between System 1 nudges, which target or benefit from automatic processing, and System 2 nudges, which target or benefit from deliberative processing. Graphic warnings and default rules are System 1 nudges; statistical information and factual disclosures are System 2 nudges. On philosophical grounds, it might seem tempting to prefer System 2 nudges, on the assumption that they show greater respect for individual dignity and promote individual agency. A nationally representative survey in the United States finds evidence that in important contexts, majorities do indeed prefer System 2 nudges. At the same time, that preference is not fixed and firm. If people are asked to assume that the System 1 nudge is significantly more effective, then large numbers of them will move in its direction. In a range of contexts, Republicans, Democrats, and independents show surprisingly similar responses. The survey findings, and an accompanying normative analysis, offer lessons for those involved in law and policy who are choosing between System 1 nudges and System 2 nudges.
Evidence for expression of early myeloid antigens in mature, non‐blast myeloid cells in myelodysplasia

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders with frequent cytogenetic abnormalities. They can arise de novo or be related to therapy. Although blasts in MDS have been studied extensively, there is little information available on the mature, non‐blast myeloid cells (NBMCs). We used a retrospective case‐control study design. NBMC populations in MDS (48 cases) and in tumor‐free control (12 cases) bone marrow samples were analyzed using multiparameter flow cytometry for mean side scatter (SSC) channel number and for expression of aberrant cell surface antigens. MDS cases were stratified on the basis of cytogenetic abnormalities. We report that NBMCs in MDS with normal karyotype expressed significantly higher HLA‐DR than controls (P = 0.034). NBMCs in MDS cases with cytogenetic abnormalities and with ≥5% marrow blasts, compared with controls, had significantly higher CD34 and higher HLA‐DR but lower CD10 and lower SSC mean channel number. CD34 expression in NBMCs was significantly greater in therapy‐related MDS compared with de novo MDS ( P = 0.01), although the presence of cytogenetic abnormalities was not different ( P > 0.05). These data suggest that bone marrow, mature, NBMCs have phenotypic changes in MDS that are not seen in normal controls. Am. J. Hematol. 74:9–16, 2003. © 2003 Wiley‐Liss, Inc.
Erythromycin vs metoclopramide for facilitating gastric emptying and tolerance to intragastric nutrition in critically ill patients.

BACKGROUND The purpose of this study is to evaluate erythromycin vs metoclopramide for facilitating gastric emptying and tolerance to intragastric enteral nutrition (EN). METHODS Twenty critically ill patients with a gastric residual >150 mL while receiving EN were randomized to receive 4 intravenous doses of erythromycin 250 mg or metoclopramide 10 mg, each administered every 6 hours. Acetaminophen 975 mg was administered enterally at baseline and after the fourth dose. Acetaminophen peak plasma concentration (Cmax), concentration at 60 minutes (C(60)), time to Cmax (Tmax), and area under the concentration-time curve from 0 to 60 minutes (AUC(0-60)) were determined. Residual volumes and feeding rates were recorded. RESULTS Compared with baseline, erythromycin increased Cmax (9.5 +/- 6.1 mg/L to 17.7 +/- 11.9 mg/L, P < .01), C(60) (5.4 +/- 3.5 mg/L to 12.9 +/- 7.6 mg/L, P < .01), and AUC(0-60) (3.5 +/- 3.0 mg.h/L to 12.5 +/- 8.7 mg.h/L, P < .01), while metoclopramide increased only AUC(0-60) (4.4 +/- 2.8 mg.h/L to 9.5 +/- 3.8 mg.hr/L, P < .05). Neither agent significantly reduced Tmax. Both erythromycin and metoclopramide reduced residual volumes (122 +/- 48 mL to 36 +/- 48 mL, P < .01, and 103 +/- 88 mL to 21 +/- 23 mL, P < .05, respectively) and allowed increased feeding rates (17 +/- 23 mL/h to 45 +/- 21 mL/h, P < .05, and 14 +/- 17 mL/h to 44 +/- 22 mL/h, P < .05, respectively). CONCLUSIONS Both agents facilitate tolerance to intragastric EN, but erythromycin may be more effective than metoclopramide for enhancing gastric motility.
Scutellarin‐Induced Apoptosis in HepG2 Hepatocellular Carcinoma Cells Via a STAT3 Pathway

Liver cancers remain one main reason for the mortality in patients with tumors. Up to now, however, the effective drugs to treat liver cancers are limited. The aim of this study was to study whether Scutellarin which was widely found in many medicinal plants can exert an inhibitory role in HepG2 hepatocellular carcinoma cell lines, and to explore its molecular mechanisms. The MTT assay showed that Scutellarin markedly inhibited the proliferation of HepG2 cells in a concentration‐ and time‐dependent manner. Moreover, Scutellarin‐treated cells exhibited typical apoptotic appearance by staining assay. Also, Scutellarin‐treated HepG2 cells exhibited the reduction of ROS production, compared with untreated HepG2 cells. Western blot analysis displayed that STAT3 protein was obviously decreased in Scutellarin‐treated HepG2 cells. Furthermore, STAT3 transcriptional targets Bcl‐XL and Mcl‐1 were also downregulated in HepG2 cells treated by Scutellarin. In summary, we found that Scutellarin was able to inhibit the proliferation and induce the apoptosis of HepG2 cells via a STAT3 signal pathway, which provided evident support for developing Scutellarin as an alternative treatment for liver cancer. Copyright © 2012 John Wiley & Sons, Ltd.
The Importance of Old, Traditionally Managed
Orchards for Breeding Birds in
the Agricultural Landscape

The purpose of this study was to characterise the breeding birds of an old, extensively managed apple orchard and its influence on the biodiversity of the agricultural landscape in central Poland. What distinguishes old orchards from other habitats is the very high density of birds and the simplified species composition. The assemblages of birds are governed by an orchard’s age and the diversity of the habitats surrounding it. The non-use of chemicals in a traditional orchard was not found to limit the composition of bird species. Ten species nested in the orchard. The bird species and brood success were determined for 68 completed nests.
Analysis of Specific Immunoglobulin G Subclass Antibodies for Serological Diagnosis of Echinococcosis by a Standard Enzyme-Linked Immunosorbent Assay

ABSTRACT The potential roles of specific antibodies of the different immunoglobulin G (IgG) subclasses in the serological diagnosis of cystic echinococcosis (CE) and alveolar echinococcosis (AE) were investigated by an enzyme-linked immunosorbent assay based on hydatid fluid as antigen. Specific antibodies of subclass 1 were found to be of major importance. In sera collected at the time of diagnosis (i.e., before any therapeutic intervention was initiated) they could be demonstrated in 14 of 15 sera from patients with CE and in all 12 sera from patients with AE. The most discriminatory and the most specific antibodies found in this study belonged to IgG subclass 4. Only one false-positive reaction was observed with 253 sera from healthy volunteers, and no cross-reactions occurred in 80 sera from patients with different parasitic infections. Specific IgG4 antibodies could be demonstrated in 61.0 to 66.7% (CE) or 47.6 to 66.7% (AE) of the cases. Antibody levels of IgG subclass 2 were elevated only moderately, and subclass 3 antibodies were detected in a few cases only. In addition, nonspecific reactions in sera of healthy volunteers or patients with other parasitic infections could partially be attributed to antibodies of subclasses 2 and 3.
Specificity of human anti‐variable heavy (VH) chain autoantibodies and impact on the design and clinical testing of a VH domain antibody antagonist of tumour necrosis factor‐α receptor 1

During clinical trials of a tumour necrosis factor (TNF)‐R1 domain antibody (dAb™) antagonist (GSK1995057), infusion reactions consistent with cytokine release were observed in healthy subjects with high levels of a novel, pre‐existing human anti‐VH (HAVH) autoantibody. In the presence of HAVH autoantibodies, GSK1995057 induced cytokine release in vitro due to binding of HAVH autoantibodies to a framework region of the dAb. The epitope on GSK1995057 was characterized and dAbs with reduced binding to HAVH autoantibodies were generated; pharmacological comparability was determined in human in‐vitro systems and in‐vivo animal experiments. A Phase I clinical trial was conducted to investigate the safety and tolerability of the modified dAb (GSK2862277). A significant reduction in HAVH binding was achieved by adding a single alanine residue at the C‐terminus to create GSK2862277. Screening a pool of healthy donors demonstrated a reduced frequency of pre‐existing autoantibodies from 51% to 7%; in all other respects, GSK2862277 and the parent dAb were comparable. In the Phase I trial, GSK2862277 was well tolerated by both the inhaled and intravenous routes. One subject experienced a mild infusion reaction with cytokine release following intravenous dosing. Subsequently, this subject was found to have high levels of a novel pre‐existing antibody specific to the extended C‐terminus of GSK2862277. Despite the reduced binding of GSK2862277 to pre‐existing HAVH autoantibodies, adverse effects associated with the presence of a novel pre‐existing antibody response specific to the modified dAb framework were identified and highlight the challenge of developing biological antagonists to this class of receptor.
Recruitment and Mobilisation for the Islamist Militant Movement in Europe

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Úrokový transmisní mechanismus a řízení úrokové marže bank v kontextu dezinflační politiky České národní banky

The paper analyzes the relationship between interest rate transmission mechanism and bank's management of interest rate risk during the disinflation monetary policy in the Czech Republic in 1999-2006. In theoretical part, main determinants of short-run and long-run equilibrium of client interest rates are discussed (market power, duration of credits and deposits, pricing mechanism, credit risk, operation efficiency). Using the error correction model, sensitivity of credit and deposit interest rates on market interest rates is tested. It is found out that in the short equilibrium client interest rates changes follow dynamics of CNB repo rate, the sensitivity of credit and deposit interest rates differs and banks face up the pressure on interest margin. The cointegration analysis confirms change of equilibrium interest rate margin in the long-run and supports hypothesis of consistency between Czech National Bank monetary policy and its expected outcomes by banks.