Exploiting proteasome function in senescence-associated proteotoxicity as target principle in lymphoma therapy

Chemotherapien verursachen DNA-Schäden in Krebszellen, was zur Apoptose der meisten Zellen führt. Die überlebenden Zellen können in eine Therapie-induzierte Seneszenz (TIS) eintreten, die zum Zellzyklusarrest führt. Zellen in TIS weisen einen Seneszenz-assoziierten sekretorischen Phänotyp (SASP) auf – eine erhöhte Proteinproduktion, die proteotoxischen Stress bedingt. Verbliebene seneszente Zellen könnten jedoch wieder in den Zellzyklus eintreten und ihr SASP kann entzündungsfördernd wirken. Da seneszente Zellen besonders auf Proteinabbau angewiesen sind, um eine zu hohe Proteotoxizität zu vermeiden, zielten wir auf Proteindegradierungswege mit einer sekundären Therapie ab, um TIS Zellen zu eliminieren. Mittels Bcl2-überexprimierender Lymphome aus dem transgenen Eμ-myc Maus-Modell, die nach Chemotherapie in Seneszenz eintreten, und des Vergleichs mit Lymphomen, die aufgrund einer genetischen Läsion nicht seneszent werden können. identifizierten wir eine verringerte proteasomale Aktivität in TIS, die mit Kennzeichen von proteotoxischem Stress korrelierte. Dabei hängt die daraus folgende Empfindlichkeit von TIS Zellen für proteasomale Hemmung von NF-κB regulierter SASP Produktion ab. Die Kombination aus proteasomaler Hemmung durch Bortezomib und einem Autophagieblocker zeigte einen additiven Effekt auf den Zelltod von TIS Zellen. Diese Ergebnisse konnten in vivo anhand verbesserten Überlebens durch TIS-nachfolgende Sekundärtherapie von mit Lymphomen inokulierten Mäusen bestätigt werden. Schließlich konnte das Prinzip der Seneszenz-spezifischen Beseitigung von Tumorzellen unter Einsatz von Bortezomib in zwei humanen Lymphomzelllinien untermauert werden. Diese Ergebnisse zeigen, dass seneszente Zellen auf eine intakte Proteinabbau-Maschinerie angewiesen sind und auf Veränderungen in proteasomaler Aktivität empfindlich reagieren. Diese Angreifbarkeit könnte in einer neuartigen, synthetisch lethalen Strategie ausgenutzt werden, um maligne Zellen effektiv zu eliminieren.Chemotherapy causes DNA damage in cancer cells, causing apoptosis in most, but not all cells. Surviving cells can undergo therapy-induced senescence (TIS), an emergency mechanism that arrests the cell cycle. Cells in TIS exhibit a senescence-associated secretory phenotype (SASP) - a massive increase in protein production leading to proteotoxic stress. Sustained senescent cells might reenter the cell cycle, and their SASP can stimulate dangerous inflammation. Aiming to eliminate remaining TIS cells, we reasoned that they need to reduce their excessive protein burden and avoid proteotoxicity and we therefore targeted protein degradation pathways with a secondary treatment. Using Bcl2-overexpressing lymphomas from the Eμ-myc mouse transgenic model, which become senescent after chemotherapy, and comparing them to lymphomas that do not become senescent due to a genetic impairment, we found reduced proteasomal activity in TIS, correlating to hallmarks of proteotoxic stress, such as accumulation of protein aggregates and oxidized proteins. The consequential sensitivity of TIS cells to proteasome inhibition was dependent on NF-κB governed SASP production. Very significantly, combining proteasome inhibition by bortezomib with autophagy inhibition had an additive effect on susceptibility to rapid death after TIS. These findings were confirmed by in vivo treatments improving survival of mice carrying lymphomas that had been treated into TIS. Lastly, the senescent-specific clearance of cells by bortezomib following TIS induction was confirmed using two human, lymphoid cell lines, supporting the proof-of-principle. This study suggests that senescent cells are highly dependent on protein disposal and are hypersensitive to changes in proteasome activity. This vulnerability might be exploited in a novel synthetic lethality strategy to fully eliminate malignant cells

Business Service Firms and Market Share

Traditional thinking suggests that profitability is linearly dependent upon market share, an assumption not carefully tested/or services. This assumption is examined in this study for business services in light of the apparent opportunity in this sector for entrepreneurs. Cross-sectional data from secondary sources suggest that a V-shaped relationship may be a better description of variation up to nine times average firm size in this sector. This interpretation of results is important to the strategy of small business managers became it relates to the plans they might make in growing their businesses. Normative recommendations promise improvements/or firms entering the critical intermediate share stage. These include focusing on revenue per employee as an objective, developing professional management assistance, formal projectfication of work (thus utilizing "virtual organizations'), and paying a11ention to organization while growing

Lineamientos de ecología humana para preservar el matrimonio y la familia desde la perspectiva de Juan Pablo II

Entendemos como “hábitat natural” el ambiente o espacio que cuenta con las condiciones físicas y biológicas mínimas requeridas para la supervivencia de una especie. Si un determinado hábitat se ve alterado o vulnerado por algún agente externo o interno, la especie que lo habita corre el riesgo de extinguirse. Así como todas las especies en nuestro planeta, el ser humano, también tiene la necesidad de contar con un hábitat ecológico natural adecuado, que le permita vivir conforme a su condición de persona. Este hábitat natural está dado por la familia, en razón a que ésta representa un papel imprescindible en la vida de cada individuo y se constituye como estructura fundamental de la ecología humana. En este sentido, es que se torna necesario contar con lineamientos, de ecología humana que permitan preservar a la familia de fundación matrimonial como hábitat natural del ser humano. Para el desarrollo de la presente investigación hemos establecido como objetivo general, presentar una propuesta de lineamientos de ecología humana desde la perspectiva de Juan Pablo II, que permita preservar el matrimonio y la familia como hábitat natural del ser humano; y como objetivos específicos: Argumentar la importancia de la familia como hábitat natural para el desarrollo de la persona humana de acuerdo a su dignidad y singularidad; identificar los agentes contaminantes que afectan la familia como hábitat natural para el desarrollo pleno de la persona humana y finalmente identificar políticas y lineamientos de ecología humana para preservar el matrimonio y la familia. La técnica de investigación utilizada corresponde al tipo cualitativo (análisis documental), mediante la observación indirecta y fichaje, se utilizaron fichas de contenido (textuales y paráfrasis), el procedimiento desarrollado siguió los criterios de rigor ético, basados en la verdad de la registración y ética de la publicación, así como los criterios de rigor científico, como son: credibilidad, confirmabilidad y aplicabilidad, lo que nos permitió obtener conclusiones centradas en el objeto de investigación, así como, presentar una propuesta de lineamientos de ecología humana para preservar el matrimonio y la familia desde la perspectiva de Juan Pablo II, que permitan al Estado, a la sociedad y a las familias mismas, un desarrollo óptimo integral y su propio fortalecimiento en favor de la sociedad y de la humanidad

Primärvårdens resurser, styrning och organisation : En jämförelse av villkor och förhållanden i Danmark, Norge, Nederländerna och Storbritannien

Myndigheten för vård- och omsorgsanalys (Vårdanalys) har vänt sig till professor Anders Anell vid Lunds universitet för att genomföra fallstudier av primärvården i fyra länder: Danmark, Norge, Nederländerna och Storbritannien. Denna promemoria är hans redovisning av arbetet och är ett underlag till Vårdanalys rapport En primär angelägenhet. Kunskapsunderlag för en stärkt primärvård med patienten i centrum (Rapport 2017:3)

Information, Switching Costs, and Consumer Choice : Evidence from Two Randomized Field Experiments in Swedish Primary Health Care

Consumers of services that are financed by a third party, such as publicly financed health care or firm-sponsored health plans, are often allowed to freely choose provider. The rationale is that consumer choice may improve the matching of consumers and providers and spur quality competition. Such improvements are contingent on consumers having access to comparative information about providers and acting on this information when making their choice. However, in the presence of information frictions and switching costs, consumers may have limited ability to find suitable providers. We use two large-scale randomized field experiments in primary health care to examine if the choice of provider is affected when consumers receive comparative information by postal mail and small costs associated with switching are reduced. The first experiment targeted a subset of the general population in the Swedish region Skåane, and the second targeted new residents in the region, who should have less prior information and lower switching costs. In both cases, the propensity to switch provider increased significantly after the intervention. The effects were larger for new residents than for the general population, and were driven by individuals living reasonably close to alternative providers

Visualizing Volkekunde: Photography in the Mainstream and Dissident Tradition of Afrikaner Ethnology, 1920-2013

Magister Artium - MAThis mini-thesis explores the role of photography in the mainstream and dissident tradition of Afrikaner ethnology (volkekunde) from the time of its establishment at Stellenbosch University in the 1920s through to its development at Pretoria University in the 1950s to 1970s, to its period of decline in the era of dissidence from the 1970s to the 2010s. I use a biographical approach, tracing the career biographies and photographic portfolios of three volkekundiges: the German-trained government ethnologist Nicolaas J. van Warmelo; little known dissident volkekundige Frans Hendrik Boot (1939-2010) who founded the Volkekunde Department at the University of the Western Cape in 1972 and for whom fieldwork photography was an expression of his humanist digression from the racialised mainstream volkekunde tradition; and Cornelis Seakle “Kees” van der Waal (1949-) whose ‘Long Walk from Volkekunde to Anthropology’ has been textually demonstrated but also takes on visual expressions in his use of photography. My thesis seeks to demonstrate that photography and visuality was important in displaying the different traditions of volkekunde. The central argument in this thesis postulates that fieldwork photographs, read in relation to the ethnographers intellectual focus offers us insight into an individual’s orientation. Furthermore this thesis explores the degree of a photographers technicality and aesthetics skil