Miracle-dz/UniFAR-FTUs huggingface dataset:
Synergistic action of the novel HSP90 inhibitor NVP‐AUY922 with histone deacetylase inhibitors, melphalan, or doxorubicin in multiple myeloma

Heat shock protein 90 (HSP90) is a promising target for tumor therapy. The novel HSP90 inhibitor NVP‐AUY922 has preclinical activity in multiple myeloma, however, little is known about effective combination partners to design clinical studies. Multiple myeloma cell lines, OPM‐2, RPMI‐8226, U‐266, LP‐1, MM1.S, and primary myeloma cells were exposed to NVP‐AUY922 and one of the combination partners histone deacetylase inhibitor NVP‐LBH589, suberoylanilide hydroxamic acid (SAHA), melphalan, or doxorubicin, either simultaneously or in sequential patterns. Effects on cell proliferation and apoptosis were determined. Synergistic effects were evaluated using the method of Chou and Talalay. Combined sequential incubation with NVP‐AUY922 and SAHA showed that best synergistic effects were achieved with 24 h preincubation with SAHA followed by another 48 h of combination treatment. Combination of NVP‐AUY922 with SAHA, NVP‐LBH589, melphalan, or doxorubicin resulted in synergistic inhibition of viability, with strong synergy (combination index < 0.3) in the case of melphalan. Importantly, resistance of the RPMI‐8226 cell line and relative resistance of some primary myeloma cells against NVP‐AUY922 could be overcome by combination treatment. These data show impressive synergistic action of the novel HSP90 inhibitor NVP‐AUY922 with melphalan, doxorubicin, NVP‐LBH589, and SAHA in multiple myeloma and build the frame work for clinical trials.
The historical present in Spanish and semantic/pragmatic structure

The historical present (HP) is the use of the present tense to refer to past events, usually as part of a narrative. Most work on this topic has dealt with the functions of English HP, mainly within the context of tense switching in conversational narrative. Relatively little work focuses exclusively on HP in Spanish, and most of it deals with the function of HP in conversational narratives. There is a gap in the literature regarding the specific interaction between the semantics and pragmatics involved in the use of HP, especially with respect to the formal representation of this interaction. In order to fill this gap, this paper analyzes the use of HP within the Parallel Architecture framework (Jackendoff 2002) and examines the implications for the semantic/pragmatic structure. Language samples produced by native speakers of Spanish and data from a large Spanish corpus are used as part of the basis for analysis. The present study also explores how the use of the preterite and imperfect in narrative in the past parallels the use of the simple present and the present progressive in narrative within the present timeframe, and shows how this can also be fruitfully analyzed employing the Parallel Architecture. The result is an original model that extends the formal apparatus of the Parallel Architecture to an area where it has not been applied before, the interface between semantics and narrative structure.
Benzene exposure and hematopoietic mortality: A long-term epidemiologic risk assessment.

BACKGROUND Previous studies of a cohort of rubber hydrochloride workers indicated an association between benzene exposure and excess mortality from leukemia and multiple myeloma. To determine whether risks remain elevated with increasing time since plant shutdown, we extended follow-up from 1981 through 1996. MATERIALS AND METHODS We evaluated risk using standardized mortality ratios (SMR) and generalized Cox proportional hazards regression models. RESULTS Five new leukemia cases were observed in benzene-exposed white males, but the summary SMR for this group declined from 3.37 (95% CI = 1.54-6.41) to 2.56 (95% CI = 1.43-4.22). In regression models, cumulative exposure was significantly associated with elevated relative risks for leukemia mortality. Four new multiple myeloma deaths occurred, three of which were in workers judged to be unexposed. CONCLUSIONS These findings reaffirm the leukemogenic effects of benzene exposure and suggest that excess risk diminishes with time.
A Reliability Study of the Universal Goniometer, Fluid Goniometer, and Electrogoniometer for the Measurement of Ankle Dorsiflexion

This study investigated the reliability of three goniometers, the universal, fluid, and electro-goniometers, in the measurement of ankle dorsiflexion. Intra- and interobserver reliability were assessed using 10 healthy volunteers and five observers. A standardized ankle position was used to measure full range of active dorsiflexion. Intraobserver reliability was assessed using one observer over two successive occasions. Interobserver reliability was assessed among five observers over five separate occasions. A one-factor analysis of variance to examine intraobserver reliability demonstrated no significant difference between each of the devices on the two occasions. A multifactorial analysis of variance demonstrated significant differences among observers and again among devices (P < 0.001). Secondary analysis for interdevice reliability demonstrated significant differences among the three devices (p<0.1). The study suggests that each device cannot be used reliably among observers or be used interchangeably, and clinical judgment based on angular changes of less than 10° are invalid if rigid protocols are not followed.
The Impact of Subsidized Health Insurance on the Poor in Colombia: Evaluating the Case of Medellín

Este trabalho utiliza modelos de dados binarios e de contagem com uma variavel indicadora endogena para avaliar o efeito do programa de saude em Medellin (Colombia). Encontrou-se um impacto significativo do programa subsidiado, que abrange principalmente a populacao pobre, sobre o uso de assistencia medica preventiva e de internacao, o que pode ter um impacto negativo sobre as situacoes financeiras do programa. Especificamente, estimativas econometricas da utilizacao de cuidados de saude indicam que ha selecao e risco moral. Esses fatos sugerem que o programa pode melhorar sua cobertura se forem criados mecanismos para diminuir o efeito de risco moral individual.
Export market location decision and performance

Purpose – Drawing on the resource-based view and network theory, the purpose of this paper is to investigate the role of external networks (ENs) and absorptive capacity (AC) in export market location decision of emerging economy firms (EEFs) and the performance implication of this decision. Design/methodology/approach – This study employs structural equation modeling to test three hypotheses: first, ENs influence an EEF manager's propensity to enter culturally/psychically distant markets for exports. Distant markets are more likely to be chosen by managers of firms with abundant ENs. Second, AC moderates this network-market location relationship. Third, superior performance results from the fit between managers’ propensity to enter a market and firms’ levels of ENs and AC. Findings – An analysis of 196 Chinese exporting firms supports the hypotheses. Research limitations/implications – Though the theoretical discussion is general, the empirical context is specific to Chinese export manufacturers. Replicat.
Russian Multinationals: From Regional Supremacy to Global Lead

1. The Internationalisation of the Russian Economy 2. Multinational Genesis 3. Exporting from Russia: The Oil and Gas Industry 4. Establishing Partnerships: High Tech Sector 5. Opening Subsidiaries: Banking Industry 6. FDI from Russia: Metallurgy Sector 7. Acquiring the Customer: Telecom Industry 8. Born to Global Business 9. Strategy Emphasis: Stake of Government or Power of Brand? 10. Boundaries of Russian MNEs. Conclusion: Whither Multinationals?
Binding of Transmissible Gastroenteritis Coronavirus to Cell Surface Sialoglycoproteins

ABSTRACT The surface glycoprotein S of transmissible gastroenteritis virus (TGEV) has two binding activities. (i) Binding to porcine aminopeptidase N (pAPN) is essential for the initiation of infection. (ii) Binding to sialic acid residues on glycoproteins is dispensable for the infection of cultured cells but is required for enteropathogenicity. By comparing parental TGEV with mutant viruses deficient in the sialic acid binding activity, we determined the contributions of both binding activities to the attachment of TGEV to cultured cells. In the presence of a functional sialic acid binding activity, the amount of virus bound to two different porcine cell lines was increased sixfold compared to the binding of the mutant viruses. The attachment of parental virus was reduced to levels observed with the mutants when sialic acid containing inhibitors was present or when the cells were pretreated with neuraminidase. In virus overlay binding assays with immobilized cell surface proteins, the mutant virus only recognized pAPN. In addition, the parental virus bound to a high-molecular-mass sialoglycoprotein. The recognition of pAPN was sensitive to reducing conditions and was not dependent on sialic acid residues. On the other hand, binding to the sialic acid residues of the high-molecular-mass glycoprotein was observed regardless of whether the cellular proteins had been separated under reducing or nonreducing conditions. We propose that binding to a surface sialoglycoprotein is required for TGEV as a primary attachment site to initiate infection of intestinal cells. This concept is discussed in the context of other viruses that use two different receptors to infect cells.
Immunohistochemical analysis of tumor antigen saturation following injection of monoclonal antibody G250.

Clinical tumor targeting studies with monoclonal antibody (mAb) G250 showed excellent targeting of primary renal cell carcinomas (RCC). However, tumor uptake decreased at higher mAb G250 doses, suggesting saturation of the G250 antigenic determinants. In this immunohistochemical study we investigated the saturability of G250 antigen sites after i.v. administration of mAb G250 at various protein doses in nude mice with RCC xenografts. Five groups of mice received five different protein doses (1, 3, 10, 30 or 100 micrograms) of murine mAb G250. Three days post injection mice were killed and the tumors were removed. Free G250 antigen sites, i.e., not targeted by the i.v. injected murine mAb G250 were determined by immunohistochemical staining with chimeric mAb G250. Distinct staining of the G250 antigen was observed only at the 1 and 3 micrograms dose whereas G250 antigen staining at higher doses was virtually negative. The results of this study indicate that saturation of antigen occurs at relatively low doses of i.v. administered mAb G250. Apparently, all antigenic determinants present on the RCC tumor cells were targeted, while previous preclinical studies suggested that i.v. administration of mAb G250 only saturated the accessible antigen sites.
A fitness trade-off between local competition and dispersal in Vibrio cholerae biofilms

Bacteria commonly grow in densely populated surface-bound communities, termed biofilms, where they gain benefits including superior access to nutrients and resistance to environmental insults. The secretion of extracellular polymeric substances (EPS), which bind bacterial collectives together, is ubiquitously associated with biofilm formation. It is generally assumed that EPS secretion is a cooperative phenotype that benefits all neighboring cells, but in fact little is known about the competitive and evolutionary dynamics of EPS production. By studying Vibrio cholerae biofilms in microfluidic devices, we show that EPS-producing cells selectively benefit their clonemates and gain a dramatic advantage in competition against an isogenic EPS-deficient strain. However, this advantage carries an ecological cost beyond the energetic requirement for EPS production: EPS-producing cells are impaired for dispersal to new locations. Our study establishes that a fundamental tradeoff between local competition and dispersal exists among bacteria. Furthermore, this tradeoff can be governed by a single phenotype.
A Double‐Blind, Placebo‐Controlled, Ascending‐Dose Evaluation of the Pharmacokinetics and Tolerability of Modafinil Tablets in Healthy Male Volunteers

A randomized, double‐blind, placebo‐controlled, ascending‐dose study was conducted to evaluate the pharmacokinetic and safety profiles of increasing modafinil doses (200 mg, 400 mg, 600 mg, 800 mg) administered orally over a 7‐day period in normal healthy male volunteers. Eight subjects (six modafinil; two placebo) were randomized to each of the four dose groups. Modafinil or a placebo was administered once daily for 7 days. Serial blood samples were obtained following administration of the day 1 and day 7 doses for characterization of pharmacokinetics, and trough samples were obtained prior to dosing on days 2 through 6 to assess the time to reach the steady state. Pharmacokinetic parameters were calculated using noncompartmental methods. Modafinil steady state was reached after three daily doses. Modafinil pharmacokinetics were dose and time independent over the range of 200 mg to 800 mg. Steady‐state pharmacokinetics of modafinil were characterized by a rapid oral absorption rate, a low plasma clearance of ∼50 mL/min, a volume of distribution of ∼0.8 L/kg, and a long half‐life of ∼15 hr. Modafinil was primarily eliminated by metabolism. Modafinil acid was the major urinary metabolite. Stereospecific pharmacokinetics of modafinil were demonstrated. The d‐modafinil enantiomer was eliminated at a threefold faster rate than l‐modafinil. Modafinil 200 mg, 400 mg, and 600 mg doses were generally well tolerated. The modafinil 800 mg dose panel was discontinued after 3 days of treatment due to the observation of increased blood pressure and pulse rate. The safety data from this study suggest that the maximum tolerable single daily oral modafinil dose, without titration, may be 600 mg.
Use of sonography in the evaluation of the gastroesophageal junction

To demonstrate the gastroesophageal junction with a real‐time, transabdominal sonography through the window of left lobe of liver, the normal sonographic pattern and the thickness of the wall of abdominal esophagus were determined. The detection rate of the normal pattern in 30 control subjects was 93%, the normal thickness of the wall being 3.8 ± 1.2 mm (range 2 mm to 5 mm). In 7 patients with severe acute esophageal inflammation, the thickness was 7.6 ± 2.1 mm (range 5 mm to 10 mm). In 6 patients with an invading lesion in the gastroesophageal junction due to malignancy, the thickness of the wall was more than 10 mm in each case. This preliminary study indicates that the sonographic detection of gastroesophageal junction through the liver window can be included in routine abdominal sonography. An increased thickness of the wall needs further study to find the cause of the thickening. © 1996 John Wiley & Sons, Inc.
A Validated Framework for Measuring Interface Support for Interactive Information Seeking

In this paper we present the validation of an evaluation framework that models the support provided by search systems for different types of user and their expected types of seeking behavior. Factors determining the types of users include previous knowledge and goals. After an overview is presented, the framework is validated in two ways. First, the novel integration of the two existing information-seeking models used in the framework is validated by the correlation of multiple expert and novice analysis. Second, the framework is validated against the results produced by two separated user studies. Further, the refinements made by the first validation technique are shown to increase the accuracy of the framework through the second technique. The successful validation process has shown that the framework can identify both strong and weak areas of search interface design in only a few hours. The results produced can be used to either revise and strengthen designs or inform the structure of a user study.
Does Technology Present a New Way of Learning?

This reflective essay suggests certain precepts that should be effective in the design of instruction and its evaluation, particularly if advanced or experimental technology is involved. The arguments are based on the assumption that human learning is a biological process that, when reduced to its essentials, is the product of evolution and does not change even as study habits do. The emphasis here is on the aspects of learning that are common to all humans and less on personal preferences for kinds of content or study methods. A brief review of the biological basis of learning is followed by some speculative suggestions on the use of technology and the outcomes of any pedagogy that are of timeless importance.
Modelling the interplay of environment, economy and resources in Marine Protected Areas. A case study in Southern Italy

In order to improve environmental management and policy making based on the principles of sustainable development it is necessary to explore both ecological and economic dynamics interacting in human-dominated ecosystems. A way to perform such an integrated assessment is provided by the Emergy Synthesis method that allows to account for mass, energy and money flows supporting a given ecosystem. In this paper Geographical Information System and Emergy Synthesis methods were combined to model the interplay of environment, economy, and resources in the Site of Community Interest named Parco Marino di S. Maria di Castellabate and located in Southern Italy. The GIS allowed to organize and explore data dealing with several environmental features while the emergy modelling and accounting provided a characterization of the energy metabolism of the study area. The solar transformity of the net primary production of the marine system resulted in 4.86·10 4 seJ Joule -1 . The emergy cost for fish and mollusk (two of the main products of the fishing sector) resulted in 1.05·10 7 seJ Joule -1 and 2.43·10 7 seJ Joule -1 , respectively. These emergy-based indicators provided information about the environmental performance of the marine ecosystem and its fishing economic sector by relating the input emergy invested into the processes with the generated outputs. The solar transformities calculated in this case study (one of the first ever performed in Italy by adopting this methodological approach) will provide a benchmark for future comparison with similar marine systems in Italy and abroad. In conclusion, the combined use of GIS and Emergy Synthesis methods resulted a promising approach able to provide a deeper understanding of human-managed ecosystems and their dynamics.
How Do Regulation and Deregulation of Audit Fees Influence Audit Quality?: Empirical Evidence from Japan

The Japanese Institute of Certified Public Accountants (JICPA) formerly issued a standard audit fees table in accordance with the Certified Public Accountants Law. This table was intended to serve as a reference for the determination of audit fees, but in practice, the standard fees were applied frequently as substantive upper limits. The table was criticized and blamed for low fees and, thus, inefficient audit services. In response to this criticism, the Certified Public Accountants Law was amended in 2004, and the JICPA discontinued the issuance of the table, and audit fee pricing was no longer quasi-regulated in Japan. In this work, we examine the effects of (de)regulation on audit quality in this institutional setting. We specifically investigate the effects of low audit fees on audit quality prior to deregulation and the effects of higher fees on audit quality after deregulation. We use the accrual quality measure of Dechow and Dichev to capture audit quality. The results show that high fees, not low fees, correlate with poor accrual quality during the period of regulation and accrual quality decreases when audit fees increase after implementing deregulation.
International advertising strategy: the standardisation question in manager studies

Purpose – This paper's objectives are firstly to systematically analyse patterns of research in international advertising standardisation (IAS) conducted among managers and secondly to suggest fruitful paths for future research in this area.Design/methodology/approach – Content analysis of academic papers published in major marketing, advertising and international business journals.Findings – Results show that overall future research would benefit from a unified definition of and measurement procedures for advertising standardisation as only these can ensure the advancement of knowledge in the field. Additionally, more research is needed in order to further explore process issues in advertising standardisation, especially a newly proposed perspective related to the implementation process of the standardisation decision. Finally, an interesting avenue for future research relates to the study of the subjectivity involved in the standardisation decision.Research limitations/implications – As with all literat.
Chewing rates among domestic dog breeds

SUMMARY The mammalian masticatory rhythm is produced by a brainstem timing network. The rhythm is relatively fixed within individual animals but scales allometrically with body mass (Mb) across species. It has been hypothesized that sensory feedback and feed-forward adjust the rhythm to match the jaw's natural resonance frequency, with allometric scaling being an observable consequence. However, studies performed with adult animals show that the rhythm is not affected by jaw mass manipulations, indicating that either developmental or evolutionary mechanisms are required for allometry to become manifest. The present study was performed to tease out the relative effects of development versus natural selection on chewing rate allometry. Thirty-one dog breeds and 31 mass-matched non-domestic mammalian species with a range in Mb from ∼2 kg to 50 kg were studied. Results demonstrated that the chewing rhythm did not scale with Mb among dog breeds (R=0.299, P>0.10) or with jaw length (Lj) (R=0.328, P>0.05). However, there was a significant relationship between the chewing rhythm and Mb among the non-domestic mammals (R=0.634, P<0.001). These results indicate that scaling is not necessary in the adult animal. We conclude that the central timing network and related sensorimotor systems may be necessary for rhythm generation but they do not explain the 1/3rd to 1/4th allometric scaling observed among adult mammals. The rhythm of the timing network is either adjusted to the physical parameters of the jaw system during early development only, is genetically determined independently of the jaw system or is uniquely hard-wired among dogs and laboratory rodents.
Measuring and Managing Operational Risks in Financial Institutions: Tools, Techniques, and other Resources

Acknowledgments Preface BACKGROUND Introduction Basic Concepts Models of Operational Risk AN OPERATIONAL RISK MANAGEMENT METHODOLOGY Developing Objectives for Risk Management Identifying the Risks Estimating Potential Losses: Data Estimating Potential Losses: Loss Distributions Analyzing Risks RISK MANAGEMENT ACTIONS Risk Avoidance and Factor Management Loss Prediction Loss Prevention Loss Control Loss Reduction and Contingency Management Risk Financing OPERATIONAL RISK MANAGEMENT IN PRACTICE Monitoring and Reporting Operational Risks Risk-based Capital Appendix A: A Glossary of Operational Risk Appendix B: Operational Risk Management Software and Services Bibliography Index