changes in protein profiles in bortezomib applied multiple myeloma ...

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Obesity is the most common known risk factor for MM. Being overweight or obese increases a person’s risk of developing MM according to a study carried out by the American Cancer Society (ACS, 2011). Other plasma cell diseases are also important risk factor for people, because these people most prone to get caught to MM. There is a crucial information related to plasma cells and MM. It must be noted that uncontrolled plasma cell growth is not always correspond to MM. Besides, there are two plasma cell related diseases like MM. One of them is monoclonal gammopathy of undetermined significance (MGUS). In this diseases, similar to MM, abnormal plasma cells produce excess amounts of antibody protein. However, these cells do not form an actual tumor or mass and do not cause any of the other problems seen in MM. The most distinction between MGUS and MM is that MGUS does not give rise to weak bones and anemia. Scientists who have studied the genes of the plasma cells in patients with MGUS found that the genetic background of these cells resembles myeloma plasma cells more than it resembles normal plasma cells. This finding suggests that these cells are principally malignant, and people with MGUS can go on to develop MM (Weiss and Kuehl, 2010). Another type of abnormal plasma cell growth disease is solitary or isolated plasmacytoma. It differs from MM with regards to number of tumor. Patients with this disease have only one tumor rather than multiple tumors in different locations as in multiple myeloma. Most often, a solitary plasmacytoma develops in a bone, but it is also rarely found in other tissues. When it begins in other tissues (such as the lungs), it is called an extramedullary plasmacytoma. As many people with a solitary plasmacytoma will develop multiple myeloma (Di Micco and Di Micco, 2005). 1.2.4. Signs and Symptoms of MM The bone marrow microenvironment has a key role in both bone destructive and tumor growth process in MM (Roodman, 2009). There are two major kinds of bone cells that basically work together to keep bones healthy and strong. One of them is osteoblasts that are responsible for laying down new bones and the other one is osteoclasts which break down worn or dying bones. These cells take part in the bone tissue. The main function of osteoblasts are both bone matrix synthesis and regulation 11
of the mineralizations by adjusting the calcium-phosphorus balance. The most characteristic morphological features of osteoclasts are their curved cell edges and finger-shaped cell membrane protrusions. These features makes it easy to form bone resorption (the destruction of bones from metabolism by melting physiologically). function. These two types of cells are controlled various growth factors and they are in balance in the bone tissues of healthy individuals. However, this situation is somewhat differ in patients with MM. Because myeloma cells change the balance between osteoblasts (formation of new bones) and osteoclasts (destruction of old bones) in favor of osteoclasts by producing certain growth factors. While dickkopil, interleukin-3 (IL-3) and interleukin-7 (IL-7) which are the growth factors secreted by myeloma cells are inhibiting the functions of osteoblast cells, macrophage inflammatory protein and interleukin-3 (IL-3) activate the role osteoclast cells either directly or indirectly (Terpos and Dimopoulos, 2005; Silvestris et al., 2007; Terpos, 2008) (Figure 1.6). Another important molecule in bone metabolism, RANKL (Receptor Activator for Nuclear Factor KB Ligand), plays also a role to activate the osteoclasts (Edwards et al., 2008). In addition to all of these, myeloma cells encourage the bone marrow stromal cells to the production of interleukin-6 (IL-6), interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) to increase osteoclast formation and tumor growth (Sirohi and Powles, 2004; Terpos, 2008; Roodman, 2009). These interleukins activates multiple pathways that protect myeloma cells from apoptosis (Zaidi and Vesole, 2001; Bommert et al., 2006). Figure 1.6. Tumor-micro Environmental Interactions in MM (Source: Roodman, 2009) 12
Page 1 and 2: CHANGES IN PROTEIN PROFILES IN BORT
Page 3 and 4: ACKNOWLEDGEMENTS First of all, with
Page 5 and 6: ÖZET BORTEZOMĠB UYGULANAN MULTĠP
Page 7 and 8: 2.1.4.1.2. Two-Dimensional Gel Elec
Page 9 and 10: LIST OF FIGURES Figure Page Figure
Page 11 and 12: LIST OF TABLES Table Page Table 1.1
Page 13 and 14: When normal cells in the body begin
Page 15 and 16: Figure 1.2. Development of Cancer S
Page 17 and 18: the myeloma cells does not help fig
Page 19 and 20: A rare form of MM called Nonsecreto
Page 21: 1.2.3. Risk Factors for MM A risk f
Page 25 and 26: To measure the levels of red cells,
Page 27 and 28: The levels of blood urea nitrogen (
Page 29 and 30: By using the system introduced by D
Page 31 and 32: 1.2.7.2. Biology of The Proteasome
Page 33 and 34: Figure 1.10. Ubiquitin-Proteasome P
Page 35 and 36: Figure 1.12. Effect of Bortezomib o
Page 37 and 38: encompasses the investigation of pr
Page 39 and 40: of modification. Ubiquitin is a sma
Page 41 and 42: the given cells. On the other hand,
Page 43 and 44: is-acrylamide (N,N'-methylene-bisac
Page 45 and 46: 2.1.4.2. Detection of Protein Spots
Page 47 and 48: ange of 600-2500 Da. This is the id
Page 49 and 50: ions resolved by the mass analyzer
Page 51 and 52: 2.1.4.5.2. Mass Analyzers Figure 2.
Page 53 and 54: There is no doubt that different ma
Page 55 and 56: mask low-quantity proteins that may
Page 57 and 58: 3.1. Materials 3.1.1. Medias CHAPTE
Page 59 and 60: 3.2.5. Cell Proliferation Assay Ant
Page 61 and 62: After 72 hour incubation period at
Page 63 and 64: eceptors of the Tumor Necrosis Fact
Page 65 and 66: The preparation of stock BSA Standa
Page 67 and 68: 3.2.6.3. Detection of the Loss of M
Page 69 and 70: centrifugation, the supernatant was
Page 71 and 72: selected symmetrically to load the
Page 73 and 74:
approximately 35 ml, the volume of
Page 75 and 76:
After electrophoresis was finished,
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7 Day Two: Reduction, Alkylation, a
Page 79 and 80:
CHAPTER 4 RESULTS AND DISCUSSION 4.
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% Changes in Cytoplasmic/Mitochondr
Page 83 and 84:
Table 4.1. Magnified Segments of Di
Page 85 and 86:
Table 4.1. Magnified Segments of Di
Page 87 and 88:
After labeling, black and red color
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78 7 8 Y2S Y3S Table 4.2. Results o
Page 91 and 92:
80 12 S4Ca Table 4.2. Results of Di
Page 93 and 94:
82 27 Y5S Table 4.2. Results of Dif
Page 95 and 96:
Spot 4, Ubiquitin-conjugating enzym
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is a transcriptional repressor, but
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activity and loss of mitochondrial
Page 101 and 102:
distributed, but correlate with nat
Page 103 and 104:
DeMartino, G. N. and Slaughter, C.
Page 105 and 106:
proteomic analyses of a systematica
Page 107 and 108:
Mahindraa, A., Hideshimab, T. and A
Page 109 and 110:
Richardson, P. G., Hideshima, T. an
Page 111 and 112:
Terpos, E. 2008. Bortezomib Directl
Page 113 and 114:
A.1. RPMI-1640 Growth Medium APPEND
Page 115 and 116:
Table B.1. Chemicals and Reagents U
Page 117 and 118:
B.4.3. Standard Curve for BSA Table
Page 119 and 120:
Urea (8M) 4.8 g CHAPS (%2) 0.2 g DT
Page 121 and 122:
E. F. G. STOCK REAGENT PREPARATION
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