Antibodies targeting hepatoma-derived growth factor as a novel strategy in treating lung cancer.

Hepatoma-derived growth factor (HDGF) is overexpressed in lung cancer and the overexpression correlates with aggressive biological behaviors and poor clinical outcomes. We developed anti-HDGF monoclonal antibodies and tested their antitumor activity in lung cancer xenograft models. We also determined biological effects in tumors treated with the antibody alone or in combination with bevacizumab/avastin (an anti-vascular endothelial growth factor antibody) and/or gemcitabine (a chemotherapeutic agent). We found the anti-HDGF was effective to inhibit tumor growth in non-small cell lung cancer xenograft models. In the A549 model, compared with control IgG, tumor growth was substantially inhibited in animals treated with anti-HDGF antibodies, particularly HDGF-C1 (P = 0.002) and HDGF-H3 (P = 0.005). When HDGF-H3 was combined with either bevacizumab or gemcitabine, we observed enhanced tumor growth inhibition, particularly when the three agents were used together. HDGF-H3-treated tumors exhibited significant reduction of microvessel density with a pattern distinctive from the microvessel reduction pattern observed in bevacizumab-treated tumors. HDGF-H3-treated but not bevacizumab-treated tumors also showed a significant increase of apoptosis. Interestingly, many of the apoptotic cells in HDGF-H3-treated tumors are stroma cells, suggesting that the mechanism of the antitumor activity is, at least in part, through disrupting formation of tumor-stroma structures. Our results show that HDGF is a novel therapeutic target for lung cancer and can be effectively targeted by an antibody-based approach.

Generation of a murine hepatic angiosarcoma cell line and reproducible mouse tumor model

Hepatic angiosarcoma (AS) is a rare and highly aggressive tumor of endothelial origin with dismal prognosis. Studies of the molecular biology of AS and treatment options are limited as animal models are rare. We have previously shown that inducible knockout of Notch1 in mice leads to spontaneous formation of hepatic AS. The aims of this study were to: (1) establish and characterize a cell line derived from this murine AS, (2) identify molecular pathways involved in the pathogenesis and potential therapeutic targets, and (3) generate a tumor transplantation model. AS cells retained specific endothelial properties such as tube formation activity, as well as expression of CD31 and Von Willebrand factor. However, electron microscopy analysis revealed signs of dedifferentiation with loss of fenestrae and loss of contact inhibition. Microarray and pathway analysis showed substantial changes in gene expression and revealed activation of the Myc pathway. Exposing the AS cells to sorafenib reduced migration, filopodia dynamics, and cell proliferation but did not induce apoptosis. In addition, sorafenib suppressed ERK phosphorylation and expression of cyclin D2. Injection of AS cells into NOD/SCID mice resulted in formation of undifferentiated tumors, confirming the tumorigenic potential of these cells. In summary, we established and characterized a murine model of spontaneous AS formation and hepatic AS cell lines as a useful in vitro tool. Our data demonstrate antitumor activity of sorafenib in AS cells with potent inhibition of migration, filopodia formation, and cell proliferation, supporting further evaluation of sorafenib as a novel treatment strategy. In addition, AS cell transplantation provides a subcutaneous tumor model useful for in vivo preclinical drug testing.Laboratory Investigation advance online publication, 24 November 2014; doi:10.1038/labinvest.2014.141.

A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3.

Mutations of STAT3 underlie the autosomal dominant form of hyperimmunoglobulin E syndrome (HIES). STAT3 has critical roles in immune cells and thus, hematopoietic stem cell transplantation (HSCT), might be a reasonable therapeutic strategy in this disease. However, STAT3 also has critical functions in nonhematopoietic cells and dissecting the protean roles of STAT3 is limited by the lethality associated with germline deletion of Stat3. Thus, predicting the efficacy of HSCT for HIES is difficult. To begin to dissect the importance of STAT3 in hematopoietic and nonhematopoietic cells as it relates to HIES, we generated a mouse model of this disease. We found that these transgenic mice recapitulate multiple aspects of HIES, including elevated serum IgE and failure to generate Th17 cells. We found that these mice were susceptible to bacterial infection that was partially corrected by HSCT using wild-type bone marrow, emphasizing the role played by the epithelium in the pathophysiology of HIES.

Mechanical restoration and failure analyses of a hydrogel and scaffold composite strategy for annulus fibrosus repair

Unrepaired defects in the annulus fibrosus of intervertebral disks are associated with degeneration and persistent back pain. A clinical need exists for a disk repair strategy that can seal annular defects, be easily delivered during surgical procedures, and restore biomechanics with low risk of herniation. Multiple annulus repair strategies were developed using poly(trimethylene carbonate) scaffolds optimized for cell delivery, polyurethane membranes designed to prevent herniation, and fibrin-genipin adhesive tuned to annulus fibrosus shear properties. This three-part study evaluated repair strategies for biomechanical restoration, herniation risk and failure mode in torsion, bending and compression at physiological and hyper-physiological loads using a bovine injury model. Fibrin-genipin hydrogel restored some torsional stiffness, bending ROM and disk height loss, with negligible herniation risk and failure was observed histologically at the fibrin-genipin mid-substance following rigorous loading. Scaffold-based repairs partially restored biomechanics, but had high herniation risk even when stabilized with sutured membranes and failure was observed histologically at the interface between scaffold and fibrin-genipin adhesive. Fibrin-genipin was the simplest annulus fibrosus repair solution evaluated that involved an easily deliverable adhesive that filled irregularly-shaped annular defects and partially restored disk biomechanics with low herniation risk, suggesting further evaluation for disk repair may be warranted. Statement of significance Lower back pain is the leading cause of global disability and commonly caused by defects and failure of intervertebral disk tissues resulting in herniation and compression of adjacent nerves. Annulus fibrosus repair materials and techniques have not been successful due to the challenging mechanical and chemical microenvironment and the needs to restore biomechanical behaviors and promote healing with negligible herniation risk while being delivered during surgical procedures. This work addressed this challenging biomaterial and clinical problem using novel materials including an adhesive hydrogel, a scaffold capable of cell delivery, and a membrane to prevent herniation. Composite repair strategies were evaluated and optimized in quantitative three-part study that rigorously evaluated disk repair and provided a framework for evaluating alternate repair techniques.

Refining the vulnerability model of low self-esteem and depression: Disentangling the effects of genuine self-esteem and narcissism

A growing body of research supports the vulnerability model of low self-esteem and depression, which states that low self-esteem is a risk factor for depression. The goal of the present research was to refine the vulnerability model, by testing whether the self-esteem effect is truly due to a lack of genuine self-esteem or due to a lack of narcissistic self-enhancement. For the analyses, we used data from 6 longitudinal studies consisting of 2,717 individuals. In each study, we tested the prospective effects of self-esteem and narcissism on depression both separately for each construct and mutually controlling the constructs for each other (i.e., a strategy that informs about effects of genuine self-esteem and pure narcissism), and then meta-analytically aggregated the findings. The results indicated that the effect of low self-esteem holds when narcissism is controlled for (uncontrolled effect = -.26, controlled effect = -.27). In contrast, the effect of narcissism was close to zero when self-esteem was controlled for (uncontrolled effect = -.06, controlled effect = .01). Moreover, the analyses suggested that the self-esteem effect is linear across the continuum from low to high self-esteem (i.e., the effect was not weaker at very high levels of self-esteem). Finally, self-esteem and narcissism did not interact in their effect on depression; that is, individuals with high self-esteem have a lower risk for developing depression, regardless of whether or not they are narcissistic. The findings have significant theoretical implications because they strengthen the vulnerability model of low self-esteem and depression.

From metaphor to practice in the crafting of strategy

The editors of Strategy as Practice, Johnson, Langley, Melin and Whittington, illustrate theoretical perspectives and alternative methodologies of 'strategy as practice' research by reflecting and commenting on selected 'classic' research papers such as Buergi, Jacobs and Roos' "From metaphor to practice in the crafting of strategy". Their paper explores how the link between the hand and the mind might be exploited in the making of strategy. Using Mintzberg's image of a potter, Buergi et al. develop a three-level theoretical schema, progressing from the physiological to the psychological to the social to trace the consequences of the hand-mind link. They discuss their model in view of an indicative case of managers from a large telecommunications firm experimenting with a process for strategy making in which they actively use their hands to construct representations of their organization and its environment.

Development of a Novel Rabies Simulation Model for Application in a Non-endemic Environment.

Domestic dog rabies is an endemic disease in large parts of the developing world and also epidemic in previously free regions. For example, it continues to spread in eastern Indonesia and currently threatens adjacent rabies-free regions with high densities of free-roaming dogs, including remote northern Australia. Mathematical and simulation disease models are useful tools to provide insights on the most effective control strategies and to inform policy decisions. Existing rabies models typically focus on long-term control programs in endemic countries. However, simulation models describing the dog rabies incursion scenario in regions where rabies is still exotic are lacking. We here describe such a stochastic, spatially explicit rabies simulation model that is based on individual dog information collected in two remote regions in northern Australia. Illustrative simulations produced plausible results with epidemic characteristics expected for rabies outbreaks in disease free regions (mean R0 1.7, epidemic peak 97 days post-incursion, vaccination as the most effective response strategy). Systematic sensitivity analysis identified that model outcomes were most sensitive to seven of the 30 model parameters tested. This model is suitable for exploring rabies spread and control before an incursion in populations of largely free-roaming dogs that live close together with their owners. It can be used for ad-hoc contingency or response planning prior to and shortly after incursion of dog rabies in previously free regions. One challenge that remains is model parameterisation, particularly how dogs' roaming and contacts and biting behaviours change following a rabies incursion in a previously rabies free population.

Revisiting the ISN Flow Parameters, using a variable IBEX pointing strategy

The Interstellar Boundary Explorer (IBEX) has observed the interstellar neutral (ISN) gas flow over the past 6 yr during winter/spring when the Earth's motion opposes the ISN flow. Since IBEX observes the interstellar atom trajectories near their perihelion, we can use an analytical model based upon orbital mechanics to determine the interstellar parameters. Interstellar flow latitude, velocity, and temperature are coupled to the flow longitude and are restricted by the IBEX observations to a narrow tube in this parameter space. In our original analysis we found that pointing the spacecraft spin axis slightly out of the ecliptic plane significantly influences the ISN flow vector determination. Introducing the spacecraft spin axis tilt into the analytical model has shown that IBEX observations with various spin axis tilt orientations can substantially reduce the range of acceptable solutions to the ISN flow parameters as a function of flow longitude. The IBEX operations team pointed the IBEX spin axis almost exactly within the ecliptic plane during the 2012-2014 seasons, and about 5° below the ecliptic for half of the 2014 season. In its current implementation the analytical model describes the ISN flow most precisely for the spin axis orientation exactly in the ecliptic. This analysis refines the derived ISN flow parameters with a possible reconciliation between velocity vectors found with IBEX and Ulysses, resulting in a flow longitude lambda∞ = 74.°5 ± 1.°7 and latitude beta∞ = -5.°2 ± 0.°3, but at a substantially higher ISN temperature than previously reported.

Tribalism as a Minimax-Regret Strategy: Evidence from Voting in the 2007 Kenyan Elections

Although many studies find that voting in Africa approximates an ethnic census in that voting is primarily along ethnic lines, hardly any of the studies have sought to explain ethnic voting following a rational choice framework. Using data of voter opinions from a survey conducted two weeks before the December 2007 Kenyan elections, we find that the expected benefits associated with a win by each of the presidential candidates varied significantly across voters from different ethnic groups. We hypothesize that decision to participate in the elections was influenced by the expected benefits as per the minimax-regret voting model. We test the predictions of this model using data of voter turnout in the December 2007 elections and find that turnout across ethnic groups varied systematically with expected benefits. The results suggest that individuals participated in the elections primarily to avoid the maximum regret should a candidate from another ethnic group win. The results therefore offer credence to the minimax regret model as proposed by Ferejohn and Fiorina (1974) and refute the Downsian expected utility model.

Homeless access to dental health care: Creation of a dental service model

This project involved developing a model for planning a dental emergency treatment center that could function as an embedded component of a shelter for the homeless population. The dental services provided by such a clinic should include treatment for tooth pain, dental caries or cavities, chipped or broken teeth, broken partials, abscessed teeth, emergency cleanings, periodontal disease or gum disease and fillings. These are the dental services that are most often sought by homeless people in hospital emergency rooms.^ The underlying assumption for this project was that the oral health needs of the homeless community can most effectively be addressed by implementing small dental clinics in existing facilities that provide shelter and other services for this population. The model described in this project identifies oral health care services that would be provided by the clinic, facility (physical plant) requirements and associated infrastructure to operate an embedded dental clinic, methods for obtaining funding, strategies of recruiting dental professionals to staff the facility, and methods to assess the outcomes of the embedded clinic strategy. As an example, this project describes a strategy for developing such an embedded clinic at San Antonio Metropolitan Ministries SAMM shelter based on recommendations from community health care leaders, managers of homeless shelters, members of the homeless community and dental professionals^

STUDYING AGGREGATE FORMATION BY AMYOTROPHIC LATERAL SCLEROSIS-ASSOCIATED MUTANT SOD1 PROTEIN IN DROSOPHILA MODEL

A common pathological hallmark of most neurodegenerative disorders is the presence of protein aggregates in the brain. Understanding the regulation of aggregate formation is thus important for elucidating disease pathogenic mechanisms and finding effective preventive avenues and cures. Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a selective neurodegenerative disorder predominantly affecting motor neurons. The majority of ALS cases are sporadic, however, mutations in superoxide dismutase 1 (SOD1) are responsible for about 20% of familial ALS (fALS). Mutated SOD1 proteins are prone to misfold and form protein aggregates, thus representing a good candidate for studying aggregate formation. The long-term goal of this project is to identify regulators of aggregate formation by mutant SOD1 and other ALS-associated disease proteins. The specific aim of this thesis project is to assess the possibility of using the well-established Drosophila model system to study aggregation by human SOD1 (hSOD1) mutants. To this end, using wild type and the three mutant hSOD1 (A4V, G85R and G93A) most commonly found among fALS, I have generated 16 different SOD1 constructs containing either eGFP or mCherry in-frame fluorescent reporters, established and tested both cell- and animal-based Drosophila hSOD1 models. The experimental strategy allows for clear visualization of ectopic hSOD1 expression as well as versatile co-expression schemes to fully investigate protein aggregation specifically by mutant hSOD1. I have performed pilot cell-transfection experiments and verified induced expression of hSOD1 proteins. Using several tissue- or cell type-specific Gal4 lines, I have confirmed the proper expression of hSOD1 from established transgenic fly lines. Interestingly, in both Drosophila S2 cells and different fly tissues including the eye and motor neurons, robust aggregate formation by either wild type or mutant hSOD1 proteins was not observed. These preliminary observations suggest that Drosophila might not be a good experimental organism to study aggregation and toxicity of mutant hSOD1 protein. Nevertheless this preliminary conclusion implies the potential existence of a potent protective mechanism against mutant hSOD1 aggregation and toxicity in Drosophila. Thus, results from my SOD1-ALS project in Drosophila will help future studies on how to best employ this classic model organism to study ALS and other human brain degenerative diseases.

Territorial quality and sustainable development : Indicators of performance in the context of a model for participatory rural tourism certification

El turismo rural ha sido incorporado por pequeños establecimientos agropecuarios del partido de Cnel. Suárez, provincia de Buenos Aires, Argentina, como actividad alternativa para mejorar la calidad de vida de sus miembros y superar situaciones de crisis agravadas por la marginalidad productiva del SO bonaerense, región a la que pertenecen. Bajo el programa Cambio Rural del INTA (Instituto Nacional de Tecnología Agropecuaria) conforman el Grupo 'Cortaderas II', junto a otros emprendedores interesados en valorar el medio rural. Han avanzado en el proceso de reconocimiento de su identidad y puesta en valor de recursos específicos con anclaje en el territorio. Esta identidad comienza a apreciarse internamente, a raíz de la dinámica grupal lograda y la incipiente articulación con otros actores para la construcción de un partenariado público y privado que genere sinergias y contribuya al desarrollo sustentable del territorio. Sin embargo, aún no es claramente percibida por el turista, cada vez más exigente. Por lo tanto, el presente trabajo persigue proponer indicadores para evaluar el desempeño de un Sistema de Gestión de Calidad con enfoque territorial que, adaptando el modelo europeo 'Marca de Calidad Territorial', sustente una estrategia comercial de diferenciación del servicio y simultáneamente, mida el progreso hacia una mejor calidad de vida y fortalecimiento de vínculos con la cultura local y el entorno físico-natural en el marco del desarrollo sustentable. La investigación se plantea para la micro escala, ya que se trata de un estudio de caso, relevándose información primaria mediante observación directa y entrevistas semi-estructuradas, complementada con información secundaria diagnóstica utilizada por INTA. Las características del grupo y su dinámica de funcionamiento bajo el programa Cambio Rural revelan que es posible adoptar un proceso de certificación participativa propuesto para cuatro pilares de la calidad: de Bienes y Servicios, Institucional, Social y Ambiental. El modelo se integra con indicadores de evaluación de desempeño, agrupados en áreas clave para cada una de las dimensiones de la sustentabilidad, que contemplan el paisaje y la gestión de los recursos naturales; el impacto económico de la actividad, la calidad de la oferta y satisfacción del turista; así como las relaciones sociales internas y los vínculos con otros actores del territorio. Principalmente se encontraron fortalezas en la búsqueda de partenariados y debilidades en aspectos de comunicación y promoción. Se considera que este sistema de herramientas de gestión sustentable permitiría superar las dificultades de una certificación individual, pudiendo aplicarse a emprendimientos con otra ubicación geográfica

Territorial quality and sustainable development : Indicators of performance in the context of a model for participatory rural tourism certification

El turismo rural ha sido incorporado por pequeños establecimientos agropecuarios del partido de Cnel. Suárez, provincia de Buenos Aires, Argentina, como actividad alternativa para mejorar la calidad de vida de sus miembros y superar situaciones de crisis agravadas por la marginalidad productiva del SO bonaerense, región a la que pertenecen. Bajo el programa Cambio Rural del INTA (Instituto Nacional de Tecnología Agropecuaria) conforman el Grupo 'Cortaderas II', junto a otros emprendedores interesados en valorar el medio rural. Han avanzado en el proceso de reconocimiento de su identidad y puesta en valor de recursos específicos con anclaje en el territorio. Esta identidad comienza a apreciarse internamente, a raíz de la dinámica grupal lograda y la incipiente articulación con otros actores para la construcción de un partenariado público y privado que genere sinergias y contribuya al desarrollo sustentable del territorio. Sin embargo, aún no es claramente percibida por el turista, cada vez más exigente. Por lo tanto, el presente trabajo persigue proponer indicadores para evaluar el desempeño de un Sistema de Gestión de Calidad con enfoque territorial que, adaptando el modelo europeo 'Marca de Calidad Territorial', sustente una estrategia comercial de diferenciación del servicio y simultáneamente, mida el progreso hacia una mejor calidad de vida y fortalecimiento de vínculos con la cultura local y el entorno físico-natural en el marco del desarrollo sustentable. La investigación se plantea para la micro escala, ya que se trata de un estudio de caso, relevándose información primaria mediante observación directa y entrevistas semi-estructuradas, complementada con información secundaria diagnóstica utilizada por INTA. Las características del grupo y su dinámica de funcionamiento bajo el programa Cambio Rural revelan que es posible adoptar un proceso de certificación participativa propuesto para cuatro pilares de la calidad: de Bienes y Servicios, Institucional, Social y Ambiental. El modelo se integra con indicadores de evaluación de desempeño, agrupados en áreas clave para cada una de las dimensiones de la sustentabilidad, que contemplan el paisaje y la gestión de los recursos naturales; el impacto económico de la actividad, la calidad de la oferta y satisfacción del turista; así como las relaciones sociales internas y los vínculos con otros actores del territorio. Principalmente se encontraron fortalezas en la búsqueda de partenariados y debilidades en aspectos de comunicación y promoción. Se considera que este sistema de herramientas de gestión sustentable permitiría superar las dificultades de una certificación individual, pudiendo aplicarse a emprendimientos con otra ubicación geográfica

Territorial quality and sustainable development : Indicators of performance in the context of a model for participatory rural tourism certification

El turismo rural ha sido incorporado por pequeños establecimientos agropecuarios del partido de Cnel. Suárez, provincia de Buenos Aires, Argentina, como actividad alternativa para mejorar la calidad de vida de sus miembros y superar situaciones de crisis agravadas por la marginalidad productiva del SO bonaerense, región a la que pertenecen. Bajo el programa Cambio Rural del INTA (Instituto Nacional de Tecnología Agropecuaria) conforman el Grupo 'Cortaderas II', junto a otros emprendedores interesados en valorar el medio rural. Han avanzado en el proceso de reconocimiento de su identidad y puesta en valor de recursos específicos con anclaje en el territorio. Esta identidad comienza a apreciarse internamente, a raíz de la dinámica grupal lograda y la incipiente articulación con otros actores para la construcción de un partenariado público y privado que genere sinergias y contribuya al desarrollo sustentable del territorio. Sin embargo, aún no es claramente percibida por el turista, cada vez más exigente. Por lo tanto, el presente trabajo persigue proponer indicadores para evaluar el desempeño de un Sistema de Gestión de Calidad con enfoque territorial que, adaptando el modelo europeo 'Marca de Calidad Territorial', sustente una estrategia comercial de diferenciación del servicio y simultáneamente, mida el progreso hacia una mejor calidad de vida y fortalecimiento de vínculos con la cultura local y el entorno físico-natural en el marco del desarrollo sustentable. La investigación se plantea para la micro escala, ya que se trata de un estudio de caso, relevándose información primaria mediante observación directa y entrevistas semi-estructuradas, complementada con información secundaria diagnóstica utilizada por INTA. Las características del grupo y su dinámica de funcionamiento bajo el programa Cambio Rural revelan que es posible adoptar un proceso de certificación participativa propuesto para cuatro pilares de la calidad: de Bienes y Servicios, Institucional, Social y Ambiental. El modelo se integra con indicadores de evaluación de desempeño, agrupados en áreas clave para cada una de las dimensiones de la sustentabilidad, que contemplan el paisaje y la gestión de los recursos naturales; el impacto económico de la actividad, la calidad de la oferta y satisfacción del turista; así como las relaciones sociales internas y los vínculos con otros actores del territorio. Principalmente se encontraron fortalezas en la búsqueda de partenariados y debilidades en aspectos de comunicación y promoción. Se considera que este sistema de herramientas de gestión sustentable permitiría superar las dificultades de una certificación individual, pudiendo aplicarse a emprendimientos con otra ubicación geográfica

Prioritization of Policies: A Prototype Model of a Flowchart Method

This paper builds a prototype model of how to prioritize policies by using a flowchart. We presented the following six steps to decide priorities of policies: Step 1 is to attain the social subsistence level (primary education, health care, and food sufficiency); Step 2 is to attain macroeconomic stability; Step 3 is to liberalize the economy by structural adjustment programs; Step 4 is capacity building specific to a growth strategy by facilitating sufficient infrastructure (physical infrastructure and institutions); Step 5 is to initiate a growth strategy; and Step 6 is to narrow income inequalities. We illustrated the effectiveness of our "flowchart method" in case studies of Morocco, Laos, Vietnam, and China. The first priority of reforms in Morocco was given to social sectors of primary education and health care, particularly in the rural areas at Step 1. Laos should not put much emphasis on growth strategy before educational reform, attainment of macroeconomic stability, and institutional capacity building at Steps 1, 2, and 3. Vietnam can focus on reforming the state-run enterprises and developing the stock markets at Step 5 of growth strategies. We found that we should apply our flowchart method to China not nation-wide but province-wide.