The novel ATP-competitive inhibitor of the MET hepatocyte growth factor receptor EMD1214063 displays inhibitory activity against selected MET-mutated variants

The receptor tyrosine kinase MET is a prime target in clinical oncology due to its aberrant activation and involvement in the pathogenesis of a broad spectrum of malignancies. Similar to other targeted kinases, primary and secondary mutations seem to represent an important resistance mechanism to MET inhibitors. Here, we report the biologic activity of a novel MET inhibitor, EMD1214063, on cells that ectopically express the mutated MET variants M1268T, Y1248H, H1112Y, L1213V, H1112L, V1110I, V1206L, and V1238I. Our results demonstrate a dose-dependent decrease in MET autophosphorylation in response to EMD1214063 in five out of the eight cell lines (IC50 2-43nM). Blockade of MET by EMD1214063 was accompanied by a reduced activation of downstream effectors in cells expressing EMD1214063-sensitive mutants. In all sensitive mutant-expressing lines, EMD1214063 altered cell cycle distribution, primarily with an increase in G1 phase. EMD1214063 strongly influenced MET-driven biological functions, such as cellular morphology, MET-dependent cell motility and anchorage-independent growth. To assess the in vivo efficacy of EMD1214063, we used a xenograft tumor model in immunocompromised mice bearing NIH3T3 cells expressing sensitive and resistant MET mutated variants. Animals were randomized for the treatment with EMD1214063 (50mg/kg/day) or vehicle only. Remarkably, five days of EMD1214063 treatment resulted in a complete regression of the sensitive H1112L-derived tumors, while tumor growth remained unaffected in mice with L1213V tumors and in vehicle-treated animals. Collectively, the current data identifies EMD1214063 as a potent MET small molecule inhibitor with selective activity towards mutated MET variants.

The Swiss-Austrian Alliance for Mountain Research

Switzerland and Austria are committed to addressing sustainable mountain development in Europe through a joint effort. In June 2013, more than 140 researchers as well as representatives of the 2 countries' funding ministries participated in the “Mountain Days” event in Mittersill, Austria, thereby marking the official launch of the Swiss-Austrian Alliance. The resulting Mittersill Commitment Paper highlights 8 research areas and calls for international cooperation between mountain researchers, institutions, and governments.

The Effects of Density, Spatial Pattern, and Competitive Symmetry on Size Variation in Simulated Plant Populations

Patterns of size inequality in crowded plant populations are often taken to be indicative of the degree of size asymmetry of competition, but recent research suggests that some of the patterns attributed to size‐asymmetric competition could be due to spatial structure. To investigate the theoretical relationships between plant density, spatial pattern, and competitive size asymmetry in determining size variation in crowded plant populations, we developed a spatially explicit, individual‐based plant competition model based on overlapping zones of influence. The zone of influence of each plant is modeled as a circle, growing in two dimensions, and is allometrically related to plant biomass. The area of the circle represents resources potentially available to the plant, and plants compete for resources in areas in which they overlap. The size asymmetry of competition is reflected in the rules for dividing up the overlapping areas. Theoretical plant populations were grown in random and in perfectly uniform spatial patterns at four densities under size‐asymmetric and size‐symmetric competition. Both spatial pattern and size asymmetry contributed to size variation, but their relative importance varied greatly over density and over time. Early in stand development, spatial pattern was more important than the symmetry of competition in determining the degree of size variation within the population, but after plants grew and competition intensified, the size asymmetry of competition became a much more important source of size variation. Size variability was slightly higher at higher densities when competition was symmetric and plants were distributed nonuniformly in space. In a uniform spatial pattern, size variation increased with density only when competition was size asymmetric. Our results suggest that when competition is size asymmetric and intense, it will be more important in generating size variation than is local variation in density. Our results and the available data are consistent with the hypothesis that high levels of size inequality commonly observed within crowded plant populations are largely due to size‐asymmetric competition, not to variation in local density.

From Theory to Practice: Improving the Impact of Health Services Research.

BACKGROUND: While significant strides have been made in health research, the incorporation of research evidence into healthcare decision-making has been marginal. The purpose of this paper is to provide an overview of how the utility of health services research can be improved through the use of theory. Integrating theory into health services research can improve research methodology and encourage stronger collaboration with decision-makers. DISCUSSION: Recognizing the importance of theory calls for new expectations in the practice of health services research. These include: the formation of interdisciplinary research teams; broadening the training for those who will practice health services research; and supportive organizational conditions that promote collaboration between researchers and decision makers. Further, funding bodies can provide a significant role in guiding and supporting the use of theory in the practice of health services research. SUMMARY: Institutions and researchers should incorporate the use of theory if health services research is to fulfill its potential for improving the delivery of health care.

The Texas driver responsibility program: A preliminary analysis of the impact on impaired driving and trauma system funding

Objective. In 2003, the State of Texas instituted the Driver Responsibility Program (TDRP), a program consisting of a driving infraction point system coupled with a series of graded fines and annual surcharges for specific traffic violations such as driving while intoxicated (DWI). Approximately half of the revenues generated are earmarked to be disbursed to the state's trauma system to cover uncompensated trauma care costs. This study examined initial program implementation, the impact of trauma system funding, and initial impact on impaired driving knowledge, attitudes and behaviors. A model for targeted media campaigns to improve the program's deterrence effects was developed. ^ Methods. Data from two independent driver survey samples (conducted in 1999 and 2005), department of public safety records, state health department data and a state auditor's report were used to evaluate the program's initial implementation, impact and outcome with respect to drivers' impaired driving knowledge, attitudes and behavior (based on constructs of social cognitive theory) and hospital uncompensated trauma care funding. Survey results were used to develop a regression model of high risk drivers who should be targeted to improve program outcome with respect to deterring impaired driving. ^ Results. Low driver compliance with fee payment (28%) and program implementation problems were associated with lower surcharge revenues in the first two years ($59.5 million versus $525 million predicted). Program revenue distribution to trauma hospitals was associated with a 16% increase in designated trauma centers. Survey data demonstrated that only 28% of drivers are aware of the TDRP and that there has been no initial impact on impaired driving behavior. Logistical regression modeling suggested that target media campaigns highlighting the likelihood of DWI detection by law enforcement and the increased surcharges associated with the TDRP are required to deter impaired driving. ^ Conclusions. Although the TDRP raised nearly $60 million in surcharge revenue for the Texas trauma system over the first two years, this study did not find evidence of a change in impaired driving knowledge, attitudes or behaviors from 1999 to 2005. Further research is required to measure whether the program is associated with decreased alcohol-related traffic fatalities. ^

Barriers to cross-border research projects: A prelude to improving professional collaborations between the United States and Mexico

Study objective. This was a secondary data analysis of a study designed and executed in two phases in order to investigate several questions: Why aren't more investigators conducting successful cross-border research on human health issues? What are the barriers to conducting this research? What interventions might facilitate cross-border research? ^ Methods. Key informant interviews and focus groups were used in Phase One, and structured questionnaires in Phase Two. A multi-question survey was created based on the findings of focus groups and distributed to a wider circle of researchers and academics for completion. The data was entered and analyzed using SPSS software. ^ Setting. El Paso, TX located on the U.S-Mexico Border. ^ Participants. Individuals from local academic institutions and the State Department of Health. ^ Results. From the transcribed data of the focus groups, eight major themes emerged: Political Barriers, Language/Cultural Barriers, Differing Goals, Geographic Issues, Legal Barriers, Technology/Material Issues, Financial Barriers, and Trust Issues. Using these themes, the questionnaire was created. ^ The response rate for the questionnaires was 47%. The largest obstacles revealed by this study were identifying a funding source for the project (47% agreeing or strongly agreeing), difficulties paying a foreign counterpart (33% agreeing or strongly agreeing) and administrative changes in Mexico (31% agreeing or strongly agreeing). ^ Conclusions. Many U.S. investigators interested in cross-border research have been discouraged in their efforts by varying barriers. The majority of respondents in the survey felt financial issues and changes in Mexican governments were the most significant obstacles. While some of these barriers can be overcome simply by collaboration among motivated groups, other barriers may be more difficult to remove. Although more evaluation of this research question is warranted, the information obtained through this study is sufficient to support creation of a Cross-Border Research Resource Manual to be used by individuals interested in conducting research with Mexico. ^

Federal regulation of human embryonic stem cell research

President George W. Bush's 2001 statement, which laid out guidelines for research that uses human embryonic stem cells to qualify for federal funding, intends to prevent new embryonic stem cell lines from being developed, by prohibiting the federal funding of research that uses embryonic stem cell lines other than those that existed at the time of the policy's inception and were approved by the National Institutes of Health. This policy raises questions of medical and technological ethics and the governments' role in making decisions regarding the advancement of science based on moral and political opinions. Federal stem cell usage policy directly affects scientific research efforts that are currently on the path to understanding the mechanisms of cell differentiation and could potentially offer answers and therapies for disabilities and many chronic diseases. By reviewing the current literature on the background information on human embryonic stem cells, including what they are, where they come from, how they are used for research purposes, and the ethical controversy surrounding their use, I have researched and reported the impact of the 2001 policy on medical research. ^ Both those who support the current policy on human embryonic stem cell research and those who are advocates for policy change have relevant arguments and varying opinions on human embryonic stem cell usage itself. The ethical implication of how embryonic stem cells are obtained has led to fierce debate. This paper presents many arguments for and against hESC research in addition to the policy governing their use. This analysis concludes that the current policy on federal funding of human embryonic stem cell research should be revised to allow research using new stem lines to be eligible for federal funding under specific guidelines. Supporting evidence for this recommendation is provided.^

Perceptions of institutional support of community -based participatory research within prevention research centers

The Institute of Medicine (IOM) report on the future of health care states that the focus on health needs to shift to the management and prevention of chronic illnesses and that academic health centers (AHCs) should play an active role in this process through community partnerships (IOM, 2002). Grant funding from the National Institutes of Health and the creation of the Centers for Disease Control and Prevention (CDC) Prevention Research Centers (PRC) across the county represent a transition toward more proactively seeking out community partnerships to better design and disseminate health promotion programs (Green, 2001). ^ The focus of the PRCs is to conduct rigorous, community-based, prevention research, to seek outcomes applicable to public health programs and policies. The PRCs work is to create and foster partnerships among public health and community organizations, to address health promotion and disease prevention issues (CDC, 2003). ^ The W.K. Kellogg Foundation defines CBPR as "a collaborative approach to research that equitably involves all partners in the research process and recognizes the unique strengths that each brings. CBPR begins with a research topic of importance to the community with the aim of combining knowledge and action for social change to improve community health." ^ In 1995, CDC asked the IOM to review the PRC program to examine the extent to which the program is providing the public health community with strategies to address public health problems in disease prevention and health promotion (IOM, 1997). No comprehensive evaluation n of the individual PRCs had ever been done (IOM, 1997). ^ The CDC was interested in understanding how it could better support the PRC program through improved management and oversight to influence the program's success. The CDC only represents one of the entities that influence the success of a PRC. Another key entity to consider is the support of and influence of the Schools of Public Health in which the PRCs reside. Using evaluation criteria similar to those that were developed by the IOM, this study examined how aspects of structural capacity of the Schools of Public Health in which the PRCs reside are perceived to influence PRC community-based research activities. ^

Review of Research on Speech Technology: Main Contributions From Spanish Research Groups

In the last two decades, there has been an important increase in research on speech technology in Spain, mainly due to a higher level of funding from European, Spanish and local institutions and also due to a growing interest in these technologies for developing new services and applications. This paper provides a review of the main areas of speech technology addressed by research groups in Spain, their main contributions in the recent years and the main focus of interest these days. This description is classified in five main areas: audio processing including speech, speaker characterization, speech and language processing, text to speech conversion and spoken language applications. This paper also introduces the Spanish Network of Speech Technologies (RTTH. Red Temática en Tecnologías del Habla) as the research network that includes almost all the researchers working in this area, presenting some figures, its objectives and its main activities developed in the last years.

EvAAL: Evaluating AAL Systems through Competitive Benchmarking

Owing to the complexity of Ambient Assisted Living (AAL) systems and platforms, the evaluation of AAL solutions is a complex task that will challenge researchers for years to come. However, the analysis and comparison of proposed solutions is paramount to enable us to assess research results in this area. We have thus organized an international contest called EvAAL: Evaluating AAL Systems through Competitive Benchmarking. Its aims are to raise interest within the research and developer communities in the multidisciplinary research fields enabling AAL, and to create benchmarks for the evaluation and comparison of AAL systems.

Differences and Relationship Between Standard and Specific Throwing Test in Handball According to the Competitive and Professional Level

The present study analyzed the differences in distance throwing with heavy and light medicine ball and throwing velocity between handball players of different competitive and professional level. Likewise, the relationship between the three throwing test of progressive specificity was analyzed: throwing with heavy medicinal ball (TH), throwing with light medicinal ball (TL) and throwing velocity (TV). For this purpose, sixty-five professional (P), semiprofessional (S) and non-professional (N) players were evaluated. El presente estudio analizó las diferencias en la distancia de lanzamiento realizado con balón medicinal pesado y ligero y en la velocidad de lanzamiento entre jugadores de balonmano de diferente nivel competitivo y profesional. Igualmente, la relación entre los tres test de lanzamiento, de progresiva especificidad, fue analizado: lanzamiento con balón medicinal pesado (TH), lanzamiento con balón medicinal ligero (TL) y velocidad de lanzamiento (TV). Para ello, sesenta y cinco jugadores profesionales (P), semi-profesionales (S) y no-profesionales (N) fueron evaluados.

Toward a planning model for the peruvian university system as a competitive strategy.

University education in Peru is based on models of teacher-centered teaching and a conception of knowledge which is closed and static and under the dominance of an information model now overwhelmed by multiple factors hastened by international change. The worlds most prestigious universities have chosen cultural diversity as a sign of quality and are hence interested in the mobility of teachers and students through exchange and cooperation with foreign educational institutions. These universities respond more effectively to pressure from the international business sector, better satisfy training demands, introduce new information and communication technologies into education and research and have improved administration and management structures. While there is progress, the university system in Peru is a planning model defined "as a discipline that seeks to respond to the needs of an organization defined by new cultural and social models" (A. Cazorla, et al 2007).This paper studies the non-Euclidean thinking of planning and development of John Friedmann (2001). Based on the four domains of social practice, it proposes a planning model for Peruvian universities that meets international requirements.

SONIA REGINA PRADO

A dissertação teve como objetivo principal estudar como uma Instituição de Ensino Superior Privada (IES) atuante no Brasil tem crescido pós Lei de Diretrizes e Bases (LDB) de 1996 até 2015, por meio da análise do curso de bacharelado em Administração de Empresas, nas modalidades: presencial, EAD e Flex (semipresencial). Para este fim, foi realizada uma pesquisa exploratória, de caráter qualitativo baseada no método do estudo de caso. Para coleta de evidências foram analisados relatórios corporativos (Annual Report, Relatórios Internos e outros documentos), entrevistas baseadas em roteiro semiestruturado com gestores da IES privada e observações. Dentre os principais achados, verificou-se que as principais estratégicas de crescimento da IES privada estudada se basearam em fusões e aquisições de outras IES, abertura de novos polos de EAD, na abertura de novas unidades próprias, bem como em inovações em várias dimensões da organização. Os programas governamentais de financiamento aos alunos também são fortes contribuintes para este crescimento, como o Fundo de Financiamento ao Estudante do Ensino Superior (FIES) e o Programa Universidade para Todos (Prouni). Com essa nova realidade, o ensino superior privado recebeu incentivo e facilitação para o seu crescimento, a um ritmo acelerado. Consequentemente pode-se concluir que a IES privada estudada adotou as seguintes estratégias de crescimento: Expansão orgânica com fusões/ aquisições de Instituições menores, com desenvolvimento de planos para todos os campi Brasil; Greenfield (por meio de solicitação de autorização de novas unidades e/ou cursos) em cidades sem possibilidades de aquisições/fusões, e aumentando o número de vagas/ matriculas nas unidades já existentes, aderiu aos programas do governo e também cuidou da evasão por meio de: Seguro educacional; gestão preparada para atender necessidades do discente; Sistema de Ensino com currículos integrados nacionalmente; Intercâmbio de alunos e professores entre as diversas unidades em todas as regiões do país e padronização dos processos.

Greetings: 50 years of Atomic Bomb Casualty Commission–Radiation Effects Research Foundation studies

The Atomic Bomb Casualty Commission was established in Hiroshima in 1947 and in Nagasaki in 1948 under the auspices of the U.S. National Academy of Sciences to initiate a long-term and comprehensive epidemiological and genetic study of the atomic bomb survivors. It was replaced in 1975 by the Radiation Effects Research Foundation which is a nonprofit Japanese foundation binationally managed and supported with equal funding by the governments of Japan and the United States. Thanks to the cooperation of the survivors and the contributions of a multitude of scientists, these studies flourish to this day in what must be the most successful long-term research collaboration between the two countries. Although these studies are necessarily limited to the effects of acute, whole-body, mixed gamma-neutron radiation from the atom bombs, their comprehensiveness and duration make them the most definitive descriptions of the late effects of radiation in humans. For this reason, the entire world relies heavily on these data to set radiation standards. As vital as the study results are, they still represent primarily the effects of radiation on older survivors. Another decade or two should correct this deficiency and allow us to measure definitively the human risk of heritable mutation from radiation. We look to the worldwide radiation and risk community as well as to the survivors who have contributed so much to what has been done already to accomplish this goal.

Trends and patterns in research and development expenditures in the United States

This paper is a review of recent trends in United States expenditures on research and development (R&D). Real expenditures by both the government and the private sector increased rapidly between the mid-1970s and the mid-1980s, and have since leveled off. This is true of both overall expenditures and expenditures on basic research, as well as funding of academic research. Preliminary estimates indicate that about $170 billion was spent on R&D in the United States in 1995, with ≈60% of that funding coming from the private sector and about 35% from the federal government. In comparison to other countries, we have historically spent more on R&D relative to our economy than other advanced economies, but this advantage appears to be disappearing. If defense-related R&D is excluded, our expenditures relative to the size of the economy are considerably smaller than those of other similar economies.