Immune resistance of Multiple Myeloma : the role of the microenvironment

Immunotherapeutic strategies in Multiple Myeloma are under development. In this thesis we present a new perspective in optimizing immunotherapy in Multiple Myeloma patient. We propose that currently, immunotherapy is limited in efficacy through interactions of Multiple Myeloma cells with the bone marrow microenvironment. This phenomenon was previously only acknowledged as a mechanism of drug resistance. To modulate resistance it is essential to further elucidate these mechanisms. We describe the presence of immune resistance of myeloma cells in the presence of cells of the bone marrow microenvironment and introduce cell adhesion mediated immune resistance (CAM-IR). Furthermore a rational combination of molecularly targeted and immunologic strategy is provided. Next, it is shown that CAM-IR is not restricted to T cell therapy only, but also applicable to antibody therapy. Furthermore we focused on another mechanism of immune escape induced by the microenvironment and show that lysis of myeloma cell by CD4-T cells can be hampered by microenvironment-induced autophagy of myeloma cells. Also Notch is investigated as being one of the targets responsible for the interaction between bone marrow and myeloma cells and thus a possible mechanism for induction of resistance and as a consequence a rational target for therapy. Finally, we investigated targetable mutations in extramedullary myeloma and compared these with the lesions in the bone marrow aiming to identify novel therapeutic targets. In this study we did not identify the mechanisms behind the growth outside the bone marrow, nor the therapy resistance but did demonstrate a high incidence of RAS mutations. Finally the general discussion is mainly focused on future perspectives on how to improve immunotherapy by interfering with the interactions between myeloma cells and the microenvironment and/ or resistance to apoptosis of myeloma cells; suggestions are provided for rational combinations of immunotherapy and targeted therapies

Immune resistance of Multiple Myeloma : the role of the microenvironment

Immunotherapeutic strategies in Multiple Myeloma are under development. In this thesis we present a new perspective in optimizing immunotherapy in Multiple Myeloma patient. We propose that currently, immunotherapy is limited in efficacy through interactions of Multiple Myeloma cells with the bone marrow microenvironment. This phenomenon was previously only acknowledged as a mechanism of drug resistance. To modulate resistance it is essential to further elucidate these mechanisms. We describe the presence of immune resistance of myeloma cells in the presence of cells of the bone marrow microenvironment and introduce cell adhesion mediated immune resistance (CAM-IR). Furthermore a rational combination of molecularly targeted and immunologic strategy is provided. Next, it is shown that CAM-IR is not restricted to T cell therapy only, but also applicable to antibody therapy. Furthermore we focused on another mechanism of immune escape induced by the microenvironment and show that lysis of myeloma cell by CD4-T cells can be hampered by microenvironment-induced autophagy of myeloma cells. Also Notch is investigated as being one of the targets responsible for the interaction between bone marrow and myeloma cells and thus a possible mechanism for induction of resistance and as a consequence a rational target for therapy. Finally, we investigated targetable mutations in extramedullary myeloma and compared these with the lesions in the bone marrow aiming to identify novel therapeutic targets. In this study we did not identify the mechanisms behind the growth outside the bone marrow, nor the therapy resistance but did demonstrate a high incidence of RAS mutations. Finally the general discussion is mainly focused on future perspectives on how to improve immunotherapy by interfering with the interactions between myeloma cells and the microenvironment and/ or resistance to apoptosis of myeloma cells; suggestions are provided for rational combinations of immunotherapy and targeted therapies

Is visuospatial hemineglect longitudinally associated with postural imbalance in the postacute phase of stroke?

15%. RESULTS: Visuospatial hemineglect was significantly associated with BBS and FAC. The relation between hemineglect and both BBS and FAC was confounded by severity of paresis of the lower limb. After controlling for severity of paresis, hemineglect remained independently associated with BBS, whereas the association with FAC lost significance. CONCLUSION: Visuospatial hemineglect is an independent covariate that is longitudinally associated with postural imbalance after stroke. These findings suggest that hemineglect is an important factor for controlling static and dynamic standing balance during the first months poststrok

HAMK Kaupallisten tapahtumien liiketoimintamalli

Tämän opinnäytetyön toimeksiantajana toimii Hämeen ammattikorkeakoulun Työelämän lähipalvelut. Opinnäytetyön tavoitteena oli määritellä Työelämän lähipalveluiden kaupallisten tapahtumien liiketoimintamalli. Liiketoimintamallin tavoitteena on toimia kaupallisten tapahtumien tuotantoprosessin tukena. Liiketoimintamalli havainnollistetaan Business Model Canvas-työkalua hyväksi käyttäen. Työn teoriaosuus koostuu liiketoimintamallista, liiketoimintamallin rakentamisesta ja tapahtumatuotannosta. Liiketoimintamallin teoriaa avataan käyttäen Business Model Canvas-työkalun kokonaisuuksia hyväksi käyttäen. Työhön on tehty teemahaastattelu, jossa haastateltiin kolmea henkilöä jotka toimivat tapahtumatuotannon asiantuntijoina. Haastattelun avulla selvitettiin Työelämän lähipalveluiden kaupallisten tapahtumien nykytilannetta ja tulevaisuuden mahdollisuuksia. Haastattelun tulokset on huomioitu liiketoimintamallia rakentaessa. Opinnäytetyön tuloksena on syntynyt kaupallisten tapahtumien liiketoi-mintamalli. Liiketoimintamalli havainnollistaa kaupallisten tapahtumien asiakaskuntaa, myyntiä, tapahtumatuotantoa ja kustannustehokasta ajattelua. Opinnäytetyön loppuun on koottu kehitysehdotukset. Kehitysehdotuksissa käydään läpi kokonaisuuksia, jotka saattaisivat parantaa kaupallisten tapahtumien tuotantoprosessia.This thesis was commissioned by the Business Services of Häme Univer-sity of Applied Sciences. The subject of this thesis was to make a business model of the commercial events of the Business Services. The business model is made to be part of the commercial events’ production process. The business model is illustrated by using the Business Model Canvas tool. The theoretical part of the thesis deals with the parts of the business model, how to build a business model and the event production. The business model itself is opened by using the Business Model Canvas tool. The thesis uses a qualitative research method. The study was made by in-terviewing three professional event organizers. The point of the interview was to clarify the current status of the Business services’ commercial events and the possibilities of the future. The results of the interviews were used when creating the actual business model. As the result of this thesis, the business model was created for the Business Services. The business model elaborates customer markets, sales, event production and cost-efficiency approach of commercial events. The final part of the thesis compiles the development points, which could help the production process of the commercial events