Miracle-dz/UniFAR-FTUs huggingface dataset:
Safety and Pharmacokinetics of Motesanib in Combination with Panitumumab and Gemcitabine-Cisplatin in Patients with Advanced Cancer

Purpose. The aim of this study was to assess the safety and tolerability of motesanib (an orally administered small-molecule antagonist of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and Kit) when administered in combination with panitumumab, gemcitabine, and cisplatin. Methods. This was an open-label, multicenter phase 1b study in patients with advanced solid tumors with an ECOG performance status ≤1 and for whom a gemcitabine/cisplatin regimen was indicated. Patients received motesanib (0 mg [control], 50 mg once daily [QD], 75 mg QD, 100 mg QD, 125 mg QD, or 75 mg twice daily [BID]) with panitumumab (9 mg/kg), gemcitabine (1250 mg/m2) and cisplatin (75 mg/m2) in 21-day cycles. The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Results. Forty-one patients were enrolled and received treatment (including 8 control patients). One of eight patients in the 50 mg QD cohort and 5/11 patients in the 125 mg QD cohort experienced DLTs. The maximum tolerated dose was established as 100 mg QD. Among patients who received motesanib (n = 33), 29 had motesanib-related adverse events. Fourteen patients had serious motesanib-related events. Ten patients had motesanib-related venous thromboembolic events and three had motesanib-related arterial thromboembolic events, two of which were considered serious. One patient had a complete response and nine had partial responses as their best objective response. Conclusions. The combination of motesanib, panitumumab, and gemcitabine/cisplatin could not be administered consistently and, at the described doses and schedule, may be intolerable. However, encouraging antitumor activity was noted in some cases.
Frequency of Ring Separations from the Loop Current in the Gulf of Mexico: A Revised Estimate

The most energetic events in the circulation of the Gulf of Mexico are the separation of large anticyclonic rings from the Loop Current. Building on previous work, the authors examine all the apparent rings since July 1973. This new dataset includes the satellite altimetry since 1992, providing a set of 34 consecutive ring formations. The primary advantage of altimetry is that the data remain available in the summer. One finding is that the ambiguity of whether or not a ring has separated is reduced, but not eliminated; the uncertainty with which separation ‘‘events’’ can be specified remains approximately 4 weeks, even with nearly continuous data. Primary peaks in the distribution of separation intervals are found at 6 and 11 months with a smaller peak at 9 months. If the spectrum is smoothed heavily enough, a peak in the distribution can be formed nearer 12 months, but this near-annual peak is a result more of the smoothing than of the data.
On the Mechanism(s) of Membrane Permeability Transition in Liver Mitochondria of Lamprey, Lampetra fluviatilis L.: Insights from Cadmium

Previously we have shown that opening of the mitochondrial permeability transition pore in its low conductance state is the case in hepatocytes of the Baltic lamprey (Lampetra fluviatilis L.) during reversible metabolic depression taking place in the period of its prespawning migration when the exogenous feeding is switched off. The depression is observed in the last year of the lamprey life cycle and is conditioned by reversible mitochondrial dysfunction (mitochondrial uncoupling in winter and coupling in spring). To further elucidate the mechanism(s) of induction of the mitochondrial permeability transition pore in the lamprey liver, we used Cd2+ and Ca2+ plus Pi as the pore inducers. We found that Ca2+ plus Pi induced the high-amplitude swelling of the isolated “winter” mitochondria both in isotonic sucrose and ammonium nitrate medium while both low and high Cd2+ did not produce the mitochondrial swelling in these media. Low Cd2+ enhanced the inhibition of basal respiration rate of the “winter” mitochondria energized by NAD-dependent substrates whereas the same concentrations of the heavy metal evoked its partial stimulation on FAD-dependent substrates. The above changes produced by Cd2+ or Ca2+ plus Pi in the “winter” mitochondria were only weakly (if so) sensitive to cyclosporine A (a potent pharmacological desensitizer of the nonselective pore) added alone and they were not sensitive to dithiothreitol (a dithiol reducing agent). Under monitoring of the transmembrane potential of the “spring” lamprey liver mitochondria, we revealed that Cd2+ produced its decrease on both types of the respiratory substrates used that was strongly hampered by cyclosporine A, and the membrane potential was partially restored by dithiothreitol. The effects of different membrane permeability modulators on the lamprey liver mitochondria function and the seasonal changes in their action are discussed.
Globalization and Sovereignty

Globalization represents the reality that we live in a time when the walls of sovereignty are no protection against the movements of capital, labor, information and ideas—nor can they provide effective protection against harm and damage.1 This declaration by Judge Rosalyn Higgins, the former President of the International Court of Justice, represents the conventional wisdom about the future of global governance. Many view globalization as a reality that will erode or even eliminate the sovereignty of nation-states. The typical account points to at least three ways that globalization has affected sovereignty. First, the rise of international trade and capital markets has interfered with the ability of nation-states to control their domestic economies.2 Second, nation-states have responded by delegating authority to international organizations.3 Third, a “new” international law, generated in part by these organizations, has placed limitations on the independent conduct of domestic policies.4
The cultural environment of international business

This book provides comprehensive coverage of international business relationships, and goes further to explain how deeply these relationships are affected by cultural differences, such as religious beliefs, values, education, social strata and politics. The third edition reflects recent changes in the global business environment. Real-world examples show how major corporations have dealt successfully with cultural differences, and provide readers with guidelines for understanding and managing relationships between organizations from different cultures.
Media coverage of international climate negotiations: assessing the ethical dimension of the global debate

This study explores the mediatisation of political challenges involved in addressing climate change, in particular relation to the United Nations framework in place to tackle the issue. Climate change is one of the most urgent issues of our time and extensive international collaboration is required in order to deal with it appropriately. Due to the nature of climate change, this thesis argues that ethical considerations should be at the core of public debates. Addressing climate change will require the implementation of drastic and often expensive measures, which might be particularly challenging to ‘western’ way of life. The media provides a crucial forum for debating the challenges climate change poses to our societies. This thesis examines how the issue is represented in the television and print media in three European countries: the United Kingdom, Denmark and the Faroe Islands during two global conferences on climate change,COP15 and COP16. This is backed up by examination of the ideal role of the media within liberal democracies and how such a role can be used as a benchmark against which to measure coverage. The thesis applies an ethical lens to the three different national media and their treatment of climate change to explore how the issue is made meaningful to the public. It examines the prominence of different ethical arguments – divided into cosmopolitan and communitarian positions - within public debates on climate change. It develops a comprehensive framework that identifies the key issues in the debate over climate change, and how ethical positions figure within them. Through the application of this analytical framework, this thesis seeks to shed light on the overall quality of public debate on the main issues around climate change in the respective countries. It also considers the extent to which media coverage in the United Kingdom, Denmark and the Faroe Islands could represent an emerging transnational public sphere on climate change. These questions are addressed through a quantitative and qualitative content analysis of climate change coverage. The approach deployed means that the study is able to examine in a systematic fashion how values underpin the debate on climate change in the respective countries. This thesis also brings a much needed comparative dimension to the analysis of media coverage of climate change. The findings demonstrate that political ideology plays a stronger role in shaping coverage in the UK context, whilst its role is less significant in Denmark and the Faroe Islands. The analysis also identifies some strong similarities in coverage across the countries, both with respect to the quantity of coverage, the topics and values emphasised. In addition, the thesis concludes that coverage across the three countries could indicate an emerging transnational public sphere on climate change.
Spatial interactive visualization on small screen

The amount of data stored in personal digital devices increases rapidly as their memory capacities increase. These devices are usually equipped with relatively small displays, which makes presenting the information a challenge. We set out to explore the spatial design space for small screen user interfaces by incorporating additional dimensions into the visual representation, and investigate techniques that may be used to display more information at once. We focus on interactive visualization, with a document manager as a target application. We present the design factors and a simulated application running on a desktop computer. We also report a formative usability study with promising results.
Accumulation of Misfolded SOD1 in Dorsal Root Ganglion Degenerating Proprioceptive Sensory Neurons of Transgenic Mice with Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease affecting upper and lower motoneurons (MNs). Although the motor phenotype is a hallmark for ALS, there is increasing evidence that systems other than the efferent MN system can be involved. Mutations of superoxide dismutase 1 (SOD1) gene cause a proportion of familial forms of this disease. Misfolding and aggregation of mutant SOD1 exert neurotoxicity in a noncell autonomous manner, as evidenced in studies using transgenic mouse models. Here, we used the SOD1G93A mouse model for ALS to detect, by means of conformational-specific anti-SOD1 antibodies, whether misfolded SOD1-mediated neurotoxicity extended to neuronal types other than MNs. We report that large dorsal root ganglion (DRG) proprioceptive neurons accumulate misfolded SOD1 and suffer a degenerative process involving the inflammatory recruitment of macrophagic cells. Degenerating sensory axons were also detected in association with activated microglial cells in the spinal cord dorsal horn of diseased animals. As large proprioceptive DRG neurons project monosynaptically to ventral horn MNs, we hypothesise that a prion-like mechanism may be responsible for the transsynaptic propagation of SOD1 misfolding from ventral horn MNs to DRG sensory neurons.
Leukocyte-Dependent Responses of the Microvasculature to Chronic Angiotensin II Exposure

Angiotensin II (Ang II) contributes to the pathogenesis of hypertension and other cardiovascular diseases. Ang II induces a pro-oxidative, proinflammatory, and prothrombogenic phenotype in vascular endothelial cells. Although the peptide promotes the recruitment of leukocytes and platelets and induces oxidative stress in the microvasculature, it remains unclear whether and how the blood cell recruitment is linked to the production of reactive oxygen species. In this study, we addressed the contributions of Ang II type 1 receptors (AT1r) and gp91phox to the recruitment of leukocytes and platelets and reactive oxygen species production in venules during chronic (2-week) infusion of Ang II in wild-type (WT) and mutant mice. Intravital video microscopy was used to measure the adhesion and emigration of leukocytes, the adhesion of fluorescently labeled platelets, and dihydrorhodamine oxidation (a measure of oxidative stress) in cremaster muscle postcapillary venules. In WT mice, Ang II infusion induced a time-dependent increase in the adhesion of leukocytes and platelets and enhanced reactive oxygen species production in venules. These changes in blood cell adhesion and reactive oxygen species production were not observed in AT1r−/− mice, AT1r−/− bone marrow chimeras (blood cells deficient in AT1r), gp91phox−/− mice, gp91phox−/− chimeras (blood cells or endothelial cells deficient in gp91phox), and in WT mice rendered granulocytopenic via intraperitoneal injection of antimouse granulocyte receptor 1 antibody. Thrombocytopenic WT mice (platelets depleted by intraperitoneal injection of rabbit antimouse thrombocyte antiserum) responded similar to WT mice. These findings implicate leukocyte-associated AT1r and gp91phox in the induction of the pro-oxidative, proinflammatory, and prothrombogenic phenotype assumed by microvessels that is chronically exposed to elevated Ang II.
Resveratrol Improved Flow-Mediated Outward Arterial Remodeling in Ovariectomized Rats with Hypertrophic Effect at High Dose

Objectives Chronic increases in blood flow in resistance arteries induce outward remodeling associated with increased wall thickness and endothelium-mediated dilatation. This remodeling is essential for collateral arteries growth following occlusion of a large artery. As estrogens have a major role in this remodeling, we hypothesized that resveratrol, described as possessing phytoestrogen properties, could improve remodeling in ovariectomized rats. Methods Blood flow was increased in vivo in mesenteric arteries after ligation of adjacent arteries in 3-month old ovariectomized rats treated with resveratrol (5 or 37.5 mg/kg per day: RESV5 or RESV37.5) or vehicle. After 2 weeks arterial structure and function were measured in vitro in high flow (HF) and normal flow (NF) arteries isolated from each rat. Results Arterial diameter was greater in HF than in NF arteries in ovariectomized rats treated with RESV5 or RESV37.5, not in vehicle-treated rats. In mice lacking estrogen receptor alpha diameter was equivalent in HF and NF arteries whereas in mice treated with RESV5 diameter was greater in HF than in NF vessels. A compensatory increase in wall thickness and a greater phenylephrine-mediated contraction were observed in HF arteries. This was more pronounced in HF arteries from RESV37.5-treated rats. ERK1/2 phosphorylation, involved in hypertrophy and contraction, were higher in RESV37.5-treated rats than in RESV5- and vehicle-treated rats. Endothelium-dependent relaxation was greater in HF than in NF arteries in RESV5-treated rats only. In HF arteries from RESV37.5-treated rats relaxation was increased by superoxide reduction and markers of oxidative stress (p67phox, GP91phox) were higher than in the 2 other groups. Conclusion Resveratrol improved flow-mediated outward remodeling in ovariectomized rats thus providing a potential therapeutic tool in menopause-associated ischemic disorders. This effect seems independent of the estrogen receptor alpha. Nevertheless, caution should be taken with high doses inducing excessive contractility and hypertrophy in association with oxidative stress in HF arteries.
Interleukin-1β Accelerates the Onset of Stroke in Stroke-Prone Spontaneously Hypertensive Rats

High blood levels of inflammatory biomarkers and immune cells in stroke lesions have been recognized as results of stroke. However, recent studies have suggested that inflammation occurs prior to stroke onset. In this study, we aimed to clarify the role of inflammation in stroke onset among stroke-prone spontaneously hypertensive rats (SHRSP). At 4 weeks of age (before stroke onset), the plasma level of IL-1β was significantly higher in SHRSP (153.0 ± 49.7 pg/ml) than in Wistar Kyoto rats (WKY) (7.7 ± 3.4 pg/ml, P < 0.001 versus SHRSP) or spontaneously hypertensive rats (SHR) (28.0 ± 9.1 pg/ml, P < 0.001 versus SHRSP) (n = 6 per strain). Stimulated IL-1β signal was also observed in cerebrovascular endothelial cells of SHRSP. Gene expressions of IL-1β, IL-1 receptors, caspase-1, and downstream genes (MCP-1 and ICAM-1), which associated with immune cell recruitment, were significantly greater in SHRSP than in WKY or SHR, coincident with greater NFκB protein levels in SHRSP compared to WKY or SHR. In addition, continuous administration of IL-1β (2 μg/day) using an osmotic pump slightly increased the incidence of stroke in SHR (P = 0.046) and significantly accelerated the onset of stroke in SHRSP (P = 0.006) compared to each control (n = 10 per group). These results suggest that a stimulated IL-1β signal might be a cause of stroke onset when concomitant with severe hypertension.
Dividend Policy Decisions

Although firms have been distributing dividends to their shareholders for four centuries (Baskin, 1988), the motivation for this corporate policy is under debate in the academic community. In an early paper, Black (1976, p. 5) coined the term the “dividends puzzle” to illustrate the poor understanding of dividend payment policy: “The harder we look at the dividend picture, the more it seems like a puzzle, with pieces that just don’t fit together. ” Over the years, dozens of theories have attempted to explain the dividends phenomenon with no consensus reached. Many of the theories view agents as rational and dividends either serve as an efficient way to resolve agency problems or as a signaling device to mitigate information asymmetry problems. Allen and Michaely (2003), Frankfurter and Wood (2006), Baker (2009), and DeAngelo, DeAngelo, and Skinner (2009) provide excellent reviews of these theories and the related empirical facts. After reviewing the literature, Allen and Michaely (2003) and Frankfurter and Wood (2006) conclude that theories based on agency or signaling are not consistent with the empirical evidence and that the question of why firms distribute dividends remains a puzzle. DeAngelo et al., however, reach a different conclusion and argue that asymmetric information could provide an explanation for the dividends phenomenon. This chapter reviews the main stylized facts about dividends and examines the behavioral theories that attempt to explain the evidence. Given the focus on the behavioral perspective, this chapter reexamines and reclassifies some of the empirical facts that previous researchers have used to support rational theories. As such, it does not replace the many surveys written about dividends over the years (e.g., Allen and Michaely, 2003; DeAngelo et al., 2009). Rather, this chapter tries to assess whether the empirical evidence is consistent with a departure from rational behavior on the part of investors or managers. The role of behavioral finance in explaining the existence of dividends is debated as a matter of academic dispute. Miller (1986) presents a traditional argument against behavioral finance by contending that behavioral theories may be able to explain the micro-behavior of agents, but that rational theories should suffice to explain the aggregate behavior of firms. Frankfurter and Lane (1992) and Frankfurter and Wood (2006) emphasize the normative aspects of dividend payments
Enhanced Food Anticipatory Activity Associated with Enhanced Activation of Extrahypothalamic Neural Pathways in Serotonin2C Receptor Null Mutant Mice

The ability to entrain circadian rhythms to food availability is important for survival. Food-entrained circadian rhythms are characterized by increased locomotor activity in anticipation of food availability (food anticipatory activity). However, the molecular components and neural circuitry underlying the regulation of food anticipatory activity remain unclear. Here we show that serotonin2C receptor (5-HT2CR) null mutant mice subjected to a daytime restricted feeding schedule exhibit enhanced food anticipatory activity compared to wild-type littermates, without phenotypic differences in the impact of restricted feeding on food consumption, body weight loss, or blood glucose levels. Moreover, we show that the enhanced food anticipatory activity in 5-HT2CR null mutant mice develops independent of external light cues and persists during two days of total food deprivation, indicating that food anticipatory activity in 5-HT2CR null mutant mice reflects the locomotor output of a food-entrainable oscillator. Whereas restricted feeding induces c-fos expression to a similar extent in hypothalamic nuclei of wild-type and null mutant animals, it produces enhanced expression in the nucleus accumbens and other extrahypothalamic regions of null mutant mice relative to wild-type subjects. These data suggest that 5-HT2CRs gate food anticipatory activity through mechanisms involving extrahypothalamic neural pathways.
Production , Manufacturing and Logistics Would a risk-averse newsvendor order less at a higher selling price ?

We model a risk-averse newsvendor’s decision-making behavior with some commonly used classes of utility functions within the expected utility theory (EUT) framework. Under fairly general conditions of EUT, we show that a risk-averse newsvendor will order less than an arbitrarily small quantity as selling price gets larger if price is higher than a threshold value, i.e., the optimal order quantity decreases as the selling price increases. 2008 Elsevier B.V. All rights reserved.
Stakeholder Actions and Their Impact on the Organizational Cultures of Two Tobacco Companies

We link the behaviors of executives and lawyers in two tobacco companies, in defending their tobacco products to the actions of stakeholders (e.g., the U.S. Government and Congress, medical researchers, consumers, public-health organizations, tobacco-control advocates, and insiders who have spoken out). Included in our analysis, which is based on publicly available documents spanning over a period of almost six decades, are critical incidents in which moral disengagement tactics were applied in the decision-making process. We infer that the disengagement tactics applied by tobacco decision makers are indicative of what Schein and other organizational scientists describe as organizational culture. We equate the critical incidents to the espoused beliefs and values and underlying assumptions which comprise organizational culture and explain that the cultures of these two tobacco companies are not consistent with the stakeholder theory of management. We conclude that the critical incidents we analyze were immoral and the representatives were indeed accountable for these behaviors. From an organizational change perspective, we discuss how analyzing these critical incidents can serve to assess the extent to which an organizational culture is ethical. Furthermore, these critical incidents can be fed back to organizational decision makers and can then be used to initiate organizational changes.