A first-in-human study of AMG 208, an oral MET inhibitor, in adult patients with advanced solid tumors.

BackgroundThis first-in-human study evaluated AMG 208, a small-molecule MET inhibitor, in patients with advanced solid tumors.MethodsThree to nine patients were enrolled into one of seven AMG 208 dose cohorts (25, 50, 100, 150, 200, 300, and 400 mg). Patients received AMG 208 orally on days 1 and days 4-28 once daily. The primary objectives were to evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of AMG 208.ResultsFifty-four patients were enrolled. Six dose-limiting toxicities were observed: grade 3 increased aspartate aminotransferase (200 mg), grade 3 thrombocytopenia (200 mg), grade 4 acute myocardial infarction (300 mg), grade 3 prolonged QT (300 mg), and two cases of grade 3 hypertension (400 mg). The MTD was not reached. The most frequent grade ≥3 treatment-related adverse event was anemia (n = 3) followed by hypertension, prolonged QT, and thrombocytopenia (two patients each). AMG 208 exposure increased linearly with dose; mean plasma half-life estimates were 21.4-68.7 hours. One complete response (prostate cancer) and three partial responses (two in prostate cancer, one in kidney cancer) were observed.ConclusionsIn this study, AMG 208 had manageable toxicities and showed evidence of antitumor activity, particularly in prostate cancer

Radiation effects in the environment

Although the Navajo possess substantial resource wealth-coal, gas, uranium, water-this potential wealth has been translated into limited permanent economic or political power. In fact, wealth or potential for wealth has often made the Navajo the victims of more powerful interests greedy for the assets under limited Navajo control. The primary focus for this education workshop on the radiation effects in the environment is to provide a forum where scientists from the nuclear science and technology community can share their knowledge toward the advancement and diffusion of nuclear science and technology issues for the Navajo public. The scientists will make an attempt to consider the following basic questions; what is science; what is mathematics; what is nuclear radiation? Seven papers are included in this report: Navajo view of radiation; Nuclear energy, national security and international stability; ABC`s of nuclear science; Nuclear medicine: 100 years in the making; Radon in the environment; Bicarbonate leaching of uranium; and Computational methods for subsurface flow and transport. The proceedings of this workshop will be used as a valuable reference materials in future workshops and K-14 classrooms in Navajo communities that need to improve basic understanding of nuclear science and technology issues. Results of the Begay-Stevens research has revealed the existence of strange and mysterious concepts in the Navajo Language of nature. With these research results Begay and Stevens prepared a lecture entitled The Physics of Laser Fusion in the Navajo language. This lecture has been delivered in numerous Navajo schools, and in universities and colleges in the US, Canada, and Alaska

Serotonin and corticosterone rhythms in mice exposed to cigarette smoke and in patients with COPD:implication for COPD-associated neuropathogenesis

The circadian timing system controls daily rhythms of physiology and behavior, and disruption of clock function can trigger stressful life events. Daily exposure to cigarette smoke (CS) can lead to alteration in diverse biological and physiological processes. Smoking is associated with mood disorders, including depression and anxiety. Patients with chronic obstructive pulmonary disease (COPD) have abnormal circadian rhythms, reflected by daily changes in respiratory symptoms and lung function. Corticosterone (CORT) is an adrenal steroid that plays a considerable role in stress and anti-inflammatory responses. Serotonin (5-hydroxytryptamine; 5HT) is a neurohormone, which plays a role in sleep/wake regulation and affective disorders. Secretion of stress hormones (CORT and 5HT) is under the control of the circadian clock in the suprachiasmatic nucleus. Since smoking is a contributing factor in the development of COPD, we hypothesize that CS can affect circadian rhythms of CORT and 5HT secretion leading to sleep and mood disorders in smokers and patients with COPD. We measured the daily rhythms of plasma CORT and 5HT in mice following acute (3 d), sub-chronic (10 d) or chronic (6 mo) CS exposure and in plasma from non-smokers, smokers and patients with COPD. Acute and chronic CS exposure affected both the timing (peak phase) and amplitude of the daily rhythm of plasma CORT and 5HT in mice. Acute CS appeared to have subtle time-dependent effects on CORT levels but more pronounced effects on 5HT. As compared with CORT, plasma 5HT was slightly elevated in smokers but was reduced in patients with COPD. Thus, the effects of CS on plasma 5HT were consistent between mice and patients with COPD. Together, these data reveal a significant impact of CS exposure on rhythms of stress hormone secretion and subsequent detrimental effects on cognitive function, depression-like behavior, mood/anxiety and sleep quality in smokers and patients with COPD

Measuring Risk Attitudes Controlling for Personality Traits*

Abstract: This study measures risk attitudes using two paid experiments: the Holt and Laury (2002) procedure and a variation of the game show Deal or No Deal. The participants also completed a series of personality questionnaires developed in the psychology literature including the risk domains of Weber, Blais, and Betz (2002). As in previous studies risk attitudes vary within subjects across elicitation methods. However, this variation can be explained by individual personality traits. Specifically, subjects behave as though the Holt and Laury task is an investment decision while the Deal or No Deal task is a gambling decision

The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation

Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines IL-25 and IL-33. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after IL-25 stimulation. Neuromedin U (NMU), the ligand of NMUR1, activated ILC2s in vitro, and in vivo co-administration of NMU with IL-25 strongly amplified allergic inflammation. Loss of NMU-NMUR1 signalling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo. Thus, NMUR1 signalling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces

Incipient Social Groups: An Analysis via In-Vivo Behavioral Tracking

Social psychology is fundamentally the study of individuals in groups, yet there remain basic unanswered questions about group formation, structure, and change. We argue that the problem is methodological. Until recently, there was no way to track who was interacting with whom with anything approximating valid resolution and scale. In the current study we describe a new method that applies recent advances in image-based tracking to study incipient group formation and evolution with experimental precision and control. In this method, which we term "in vivo behavioral tracking," we track individuals' movements with a high definition video camera mounted atop a large field laboratory. We report results of an initial study that quantifies the composition, structure, and size of the incipient groups. We also apply in-vivo spatial tracking to study participants' tendency to cooperate as a function of their embeddedness in those crowds. We find that participants form groups of seven on average, are more likely to approach others of similar attractiveness and (to a lesser extent) gender, and that participants' gender and attractiveness are both associated with their proximity to the spatial center of groups (such that women and attractive individuals are more likely than men and unattractive individuals to end up in the center of their groups). Furthermore, participants' proximity to others early in the study predicted the effort they exerted in a subsequent cooperative task, suggesting that submergence in a crowd may predict social loafing. We conclude that in vivo behavioral tracking is a uniquely powerful new tool for answering longstanding, fundamental questions about group dynamics

Wage inequality, segregation by skill and the price of capital in an assignment model

Some pieces of empirical evidence suggest that in the U.S., over the last few decades, (i) wage inequality between-plants has risen much more than wage inequality within-plants and (ii) there has been an increase in the segregation of workers by skill into separate plants. This paper presents a frictionless assignment model in which these two features can be explained simultaneously as the result of the decline in the relative price of capital. Additional implications of the model regarding the skill premium and the dispersion in labor productivity across plants are also consistent with the empirical evidence. [resumen de autor

Can we learn from the pathogenetic strategies of group A hemolytic streptococci how tissues are injured and organs fail in post-infectious and inflammatory sequelae?

The purpose of this review-hypothesis is to discuss the literature which had proposed the concept that the mechanisms by which infectious and inflammatory processes induce cell and tissue injury, in vivo, might paradoxically involve a deleterious synergistic ‘cross-talk’, among microbial- and host-derived pro-inflammatory agonists. This argument is based on studies of the mechanisms of tissue damage caused by catalase-negative group A hemolytic streptococci and also on a large body of evidence describing synergistic interactions among a multiplicity of agonists leading to cell and tissue damage in inflammatory and infectious processes. A very rapid cell damage (necrosis), accompanied by the release of large amounts of arachidonic acid and metabolites, could be induced when subtoxic amounts of oxidants (superoxide, oxidants generated by xanthine-xanthine oxidase, HOCl, NO), synergized with subtoxic amounts of a large series of membrane-perforating agents (streptococcal and other bacterial-derived hemolysins, phospholipases A 2 and C, lysophosphatides, cationic proteins, fatty acids, xenobiotics, the attack complex of complement and certain cytokines). Subtoxic amounts of proteinases (elastase, cathepsin G, plasmin, trypsin) very dramatically further enhanced cell damage induced by combinations between oxidants and the membrane perforators. Thus, irrespective of the source of agonists, whether derived from microorganisms or from the hosts, a triad comprised of an oxidant, a membrane perforator, and a proteinase constitutes a potent cytolytic cocktail the activity of which may be further enhanced by certain cytokines. The role played by non-biodegradable microbial cell wall components (lipopolysaccharide, lipoteichoic acid, peptidoglycan) released following polycation- and antibiotic-induced bacteriolysis in the activation of macrophages to release oxidants, cytolytic cytokines and NO is also discussed in relation to the pathophysiology of granulomatous inflammation and sepsis. The recent failures to prevent septic shock by the administration of only single antagonists is disconcerting. It suggests, however, that since tissue damage in post-infectious syndromes is caused by synergistic interactions among a multiplicity of agents, only cocktails of appropriate antagonists, if administered at the early phase of infection and to patients at high risk, might prevent the development of post-infectious syndromes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72535/1/j.1574-695X.1999.tb01357.x.pd