Ebf1 or Pax5 haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia

STAT5 is abnormally activated in patients with acute lymphoblastic leukemia, and increased STAT5 activation synergizes with PAX5 and EBF1 to induce disease

Development of a market entry and marketing strategy for Germany : internationalization of the portuguese swimwear startup Turquesa Beach

Turquesa Beach an early startup for premium children swimwear wants to expand internationally to Germany. It sought the help from the master consulting project to analyze the swimwear market, assess the costs of entering, find the right marketing and entry strategy. The literature review analyzed the current state of the academic world on internationalization of new ventures and how networks affect the internationalization process. This is followed by current findings of researchers on digital marketing and the best practices. The analysis part characterizes the German swimwear market, compares different entry and marketing strategies. Based on the findings and the assessment of the firm, recommendations were drawn on how Turquesa Beach should proceed with its internationalization to Germany.A Turquesa Beach é uma start-up de fatos-de-banho premium para crianças que pretende expandir internacionalmente para a Alemanha. A empresa procurou a ajuda do consultor de forma a analisar o mercado de fatos-de-banho, calcular os custos de entrada e ainda encontrar as melhores estratégias de marketing para entrar no mercado. A revisão de literatura analisou os atuais pontos de vista do mundo académico em relação à internacionalização de start-ups, assim como possíveis ações que afetam o processo de internacionalização. De seguida, as conclusões e estratégias seguidas pelos autores dos artigos são apresentadas, particularmente tendo em conta marketing digital. No seguinte capítulo, é conduzida uma análise que caracteriza o mercado alemão, assim como diversos modos de entrada e estratégias de marketing são comparados. No último capítulo, de acordo com toda a análise previamente feita, conclusões e recomendações em relação à entrada da Turquesa Beach no mercado alemão serão escritas

Gentherapie der septischen Granulomatose : Chancen und Risiken ; der Weg zur erfolgreichen Therapie einer angeborenen Immundefizienz

Im Jahre 2004 sind am Universitätsklinikum Frankfurt zwei Patienten mit X-CGD gentherapeutisch behandelt worden. Nach einer initialen Phase mit Nachweis ausreichender Mengen Oxidase-positiver Zellen im Blut der Patienten und einer deutlichen klinischen Besserung vorbestehender Infektionsherde kam es zu einem Verlust der Transgenexpression durch epigenetische Veränderungen des viralen Promotors. Ferner entwickelte sich durch Insertionsmutagenese eine klonale Expansion in der Hämatopoese und schließlich ein myelodysplastisches Syndrom mit Monosomie 7 bei beiden Patienten. In der Zusammenschau mit anderen Gentherapiestudien zur X-CGD zeigt sich, dass bislang ein langanhaltendes Engraftment funktionierender genkorrigierter Zellen nur im Zusammenhang mit einer Insertionsmutagenese beobachtet wurde. Zukünftige gentherapeutische Strategien zur Behandlung der X-CGD müssen das Risiko einer Insertionsmutagenese minimieren und gleichzeitig die Effektivität des Engraftments genkorrigierter Zellen steigern. Dies soll durch den Einsatz von SIN-Vektoren sowie einer Intensivierung der Konditionierung der Patienten erreicht werden

Gene Therapy of Chronic Granulomatous Disease: The Engraftment Dilemma

The potential of gene therapy as a curative treatment for monogenetic disorders has been clearly demonstrated in a series of recent Phase I/II clinical trials. Among primary immunodeficiencies, gene transfer into hematopoietic stem (HSC)/progenitor cells has resulted in the long-term correction of immune and metabolic defects in treated patients. In most cases, successes were augmented by a recognized biological selection for successfully treated cells in vivo, perhaps even to some extent at the HSC level. In contrast, similar achievements have not turned into reality for immunodeficiencies in which gene-transduced cells lack selective advantages in vivo. This is the case for chronic granulomatous disease (CGD), a primary immunodeficiency, characterized by deficient antimicrobial activity in phagocytic cells. Several attempts to correct CGD by gene transfer in combination with bone marrow conditioning have resulted in low-level long-term engraftment and transient clinical benefits despite high levels of gene marking and high numbers of reinfused cells. This review summarizes the data from clinical trials for CGD and provides some insights into treatment options that may lead to a successful application of gene therapy for CGD

High Efficiency Gene Correction in Hematopoietic Cells by Donor-Template-Free CRISPR/Cas9 Genome Editing

The CRISPR/Cas9 prokaryotic adaptive immune system and its swift repurposing for genome editing enables modification of any prespecified genomic sequence with unprecedented accuracy and efficiency, including targeted gene repair. We used the CRISPR/Cas9 system for targeted repair of patient-specific point mutations in the Cytochrome b-245 heavy chain gene (CYBB), whose inactivation causes chronic granulomatous disease (XCGD)—a life-threatening immunodeficiency disorder characterized by the inability of neutrophils and macrophages to produce microbicidal reactive oxygen species (ROS). We show that frameshift mutations can be effectively repaired in hematopoietic cells by non-integrating lentiviral vectors carrying RNA-guided Cas9 endonucleases (RGNs). Because about 25% of most inherited blood disorders are caused by frameshift mutations, our results suggest that up to a quarter of all patients suffering from monogenic blood disorders could benefit from gene therapy employing personalized, donor template-free RGNs