the role of tyrosine kinase inhibitors in the treatment of all

... generates binding sites for proteins containing Src homology-2 (SH2) and protein tyrosine- binding (PTB) domains4 Two families of tyrosine kinases exist within cells They are the receptor tyrosine kinases ... Introduction……………………………………………………………… 1.1 Tyrosine kinases and their signaling pathways…………………………… 1.2 The role of tyrosine kinases in cancer……………………………………… 1.3 Tyrosine kinase inhibitors as therapeutic agents in cancer………………… ... transmission1; The proteins that perform tyrosine phosphorylation are the tyrosine kinases These kinases are enzymes that catalyze the transfer of the γ phosphate of adenosine triphosphate (ATP) to tyrosine...

Ngày tải lên: 10/09/2015, 09:04

... of tyrosine kinase inhibitors 110 5.3.2 Potential effect of enzyme inducer/inhibitor on pharmacokinetics of tyrosine kinase inhibitors 113 5.3.3 Effect of tyrosine kinase inhibitors ... _ Summary The advent of molecular targeted therapy in the late 1990s marks a major breakthrough in the fight against cancer The critical role of tyrosine kinases in the control of cancer phenotypes, ... 6.5 Overcoming tyrosine kinase inhibitors- induced hepatotoxicity 160 6.5.1 Switching tyrosine kinase inhibitors 161 6.5.2 Alternative dosing 161 6.5.3 Reversibility of toxicities...

Ngày tải lên: 09/09/2015, 08:14

... rh 84 rof SBP ni esorcus %03 ni detcetorpoyrc neht dna C ta thginrevo evitaxif emas siht ni dexif-tsop erew seussiT desu erew ,2.7 Hp ,SBP M 1.0 ni edyhedlamrofarap %4 evitaxif yb dewollof ,)2.7Hp ... epotipe na sezingocer dna seidobitna lanolcylop deifirup ytiniffa si ydobitna yramirp sihT )ASU ,zurC atnaS( 001 : detulid ,nilubolgonummi AkrT-itna tibbar htiw C ta rh 84-42 rof detabucni erew ... ,rotceV( seidobitna tibbar itna yradnoces detalynitoib htiw C ta thginrevo detabucni dna ,)spets gniwollof eht fo hcae neewteb demrofrep saw erudecorp hsaw emas( TR ta hcae nim 01 ,SBP ni semit dehsaw...

Ngày tải lên: 07/08/2014, 18:21

... protein Syk includes two tandem SH2 domains and a tyrosine kinase domain Interdomain A is between the two SH2 domains, and interdomain B is between the tyrosine kinase domain and C-terminal SH2 ... Syk involved in the function of additional cells? What other kinases or non -kinase molecules are targeted by the available Syk inhibitors? Can medicinal chemistry enable the development of inhibitors ... synthesis Eicosanoid synthesis Figure FcεR crosslinking by allergen involves spleen tyrosine kinase (Syk)-mediated signaling transduction Allergen binding to IgE bound to FcεR on mast cell initiates...

Ngày tải lên: 12/08/2014, 15:22

... study, in the analysis of the patient cohorts, in the statistical analysis and in the writing of the manuscript BD initiated, planned and supervised the study, participated in the analysis of data ... potentially also be due to increased shedding of Mer receptors from the monocyte/macrophage surface resulting in decreased surface expression of Mer Whether any of these mechanisms are involved in the ... activation of the intracellular kinase domain of Mer The presence of fluid phase sMer in the extra-cellular space can compete with cell bound Mer acting as a decoy receptor and, thereby, result in defective...

Ngày tải lên: 12/08/2014, 15:23

... fibroblasts lacking p15INK4b are resistant to the growth-inhibitory effects of gefitinib As the level of p15INK4b is increased by MEK inhibitors, but not by Akt inhibitors, the induction of Fig The cell-cycle ... protein Activation of cyclin–CDK complexes is counterbalanced by CDK inhibitors, including those of the kinase inhibitor proteins (KIP) family and the INK4 family (Fig 3) The KIP family consists of ... p57KIP2; and the INK4 family consists of p15INK4b, p16INK4a, p18INK4c and p19INK4d AG1478, which, like gefitinib and erlotinib, acts as a specific inhibitor of the EGFR tyrosine kinase, has been...

Ngày tải lên: 16/02/2014, 09:20

... 2) initiated our interest in the role of NK cells in the development of nasal polyps and chronic sinusitis The aim of our study is to investigate the involvement of NK cells in the chronic inflammation ... polyp group, there were seven Chinese, two Malays, three Indians and one Philippino In the chronic sinusitis group, there were one Indian and eight Chinese In the allergic rhinitis group, there were ... difference in the NK cell numbers in the inflamed sinus mucosa, and in the middle turbinate of allergic rhinitis and controls Z values and the P values of Mann-Whitney test are shown in Table 51...

Ngày tải lên: 16/09/2015, 17:13

... turbinate but not in the sinus mucosa 12 (60%) of the sinusitis patients had a high mast cell score in the inflamed sinus mucosa (66.7%) of these patients had high mast cell infiltration in the ... by the National Medical Research Council of Singapore and the institutional review board of the Medical Faculty of the National University of Singapore Table Patient groups in the study of inflammatory ... important roles in the persistence of mucosal inflammation and in inducing nasal airway remodeling IV There may be ethnic based differences controlling cell patterns involved in the chronic inflammation...

Ngày tải lên: 16/09/2015, 17:13

... and chronic sinusitis 2.8 Discussion 2.8.1 The role of inflammatory cells in the pathogenesis of nasal polyps 2.8.2 The role of inflammatory cells in the pathogenesis of chronic sinusitis 2.8.3 ... Chapter The involvement of Trichophyton rubrum in the pathogenesis of nasal polyps and chronic sinusitis 5.1 Role of fungi in the pathogenesis of nasal polyps and chronic sinusitis 5.1.1 Incidence of ... Generally speaking, sinusitis is inflammation of paranasal sinuses Because of the high frequency of coexistence of inflammation of the nasal cavity, it has also been suggested that the term “rhinosinusitis”...

Ngày tải lên: 16/09/2015, 17:14

... change Within the linear range of the assay (~5-25μg/mL), the more protein present, the more the Coomassie Blue binds changing the absorbance of the sample After getting cell lysates from the CHO ... of Human SPHK Inhibitors components in the samples, which are then separated in the TLC plate The plate was run in the chamber until the solvent front reached 2cm from the top of the plate, then ... was not in the final list and not being tested further, is mainly because the yield of compound 2a3 is really low (~7%) Therefore, obtaining compound 3a3 requied a large amount of the starting material-Garner’s...

Ngày tải lên: 11/09/2015, 16:06

... Staining 3.1.3.1 Alizarin Red S Staining Alizarin Red S staining is widely used to evaluate the calcium-rich deposits generated by cells In this study, the staining was used to detect the mineralization ... shown in Figure 3.4D In this type of AD-MSCs, the presence of 0.5μM of DMS increased the staining in both 14 days and 28 days culture as compared with the osteogenic-induced sample without inhibitors ... (NanoDrop ND-1000) All of the 55°C incubation period stated above could vary, based on the estimated amount of processing DNA Copies of the 72 Chapter Roles of SPHK Inhibitors in Human BM- and...

Ngày tải lên: 11/09/2015, 16:06

... days, then fixed and stained with Alizarin Red S The Alizarin Red S Staining quantification results are shown in Figure 4.11 Alizarin Red Staining quantification of human BM-MSCs cultured in different ... Cultured in Different Conditions The osteogenic differentiation was chosen in this part of the study as a “proof-ofprinciple” strategy to investigate whether human BM- and AD- MSCs, cultured in S1Psupplemented ... 128 Chapter Role of S1P in human BM- and AD- MSCs proliferation 4.2.2.2 BSA effect on the MSCs growth Since S1P was prepared in 0.1% FAF-BSA, the largest amount of the BSA used in all experiments...

Ngày tải lên: 11/09/2015, 16:06

... tissue increases (Jaiswal et al., 2000) It also suggests the potential for the use of SPHK inhibitors in preconditioning stem cells before transplanting them into the body, by committing stem ... work, including in vivo work, needs to be done to fully validate the potential for SPHK inhibitors in adult-stem cell differentiation In the final part of my research project (Chapter 4), the bioactive ... Future Work being one of the most potent and specific SPHK1 inhibitors (chapter 2), DMS was continuously used as a reference inhibitor It is interesting to note that CP6 and DMS affected the osteogenic...

Ngày tải lên: 11/09/2015, 16:06

... et al (1998) “N,N-Dimethylsphingosine Is a Potent Competitive Inhibitor of Sphingosine Kinase but Not of Protein Kinase C: Modulation of Cellular Levels of Sphingosine 1-Phosphate and Ceramide.” ... “Characterization of N, N-dimethyl-derythro-sphingosine-induced apoptosis and signaling in U937 cells: independence of sphingosine kinase inhibition.” Prostaglandins & Other Lipid Mediators 86(1-4):18-25 Kimura, ... (1994) "The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signaling." Cell 77(3): 325-8 Kono, K., Tanaka, M., et al (2000a) “B-535a, b and c, new sphingosine kinase inhibitors, ...

Ngày tải lên: 11/09/2015, 16:06

... increasing need for more MSCs is one of the main motivations of the present study, in particular, in studying the role of S1P in adult stem cell proliferation Another major motivation is the pressing ... activation, while HDL could inhibit all of these, by inhibiting the SPHK activity triggered by TNFα These findings suggested an atherogenic role for SPHK activation Interestingly, Nofer et al (2004) reported ... include using SPHK inhibitors to inhibit endogenous SPHK directly, or inhibiting the phosphorylated product S1P directly One of the successful attempts of inhibiting S1P is the development of the monoclonal...

Ngày tải lên: 11/09/2015, 16:06

... with PH domains to the membrane where they are activated These proteins include protein serine-threonine kinases (Akt and phosphoinositidedependent kinase (PDK1)), protein tyrosine kinases (Btk ... pathway in human fibroblasts (Morel et al., 2002) and in hypertensive rats (Kobayashi et al., 2003) 1.3 Inhibitors of the Tyrosine kinase signaling cascade 1.3.1 Protein tyrosine kinases inhibitors ... specifically inhibit the activity of certain major kinases such as tyrosine kinases, MAPKs and PI3Ks can be used for the control of airway inflammation Therefore, the objectives of my thesis project...

Ngày tải lên: 15/09/2015, 22:09

... 22 1.2 Tyrosine kinase signaling cascade 1.2.1 Protein tyrosine kinases (PTKs) 25 25 iii 1.2.1.1 Role of PTK signaling cascade in allergic inflammation 1.2.2 Mitogen-activated protein kinase (MAPK) ... Inhibitors of the tyrosine kinase signaling cascade 38 1.3.1 Protein tyrosine kinase inhibitors 38 1.3.2 MAPK kinase inhibitors 40 1.3.3 PI3K inhibitors 43 1.4 Animal models of asthma 45 RATIONALE ... 1.2.2.2 Role of MAPK cascade in allergic inflammation 31 1.2.3 Phosphoinositide kinase (PI3K) 33 1.2.3.1 PI3K cascade 33 1.2.3.2 Role of PI3K cascade in allergic inflammation 37 1.3 Inhibitors of the...

Ngày tải lên: 16/09/2015, 17:11

... Protein targeting to the microsomes requires the cotranslational insertion of the newly synthesized protein into the microsomal membrane, where the N-terminal hydrophobic signal sequence of the ... signal, as in the case of CYP1A1 [4]; and (b) PKA- or protein kinase C-mediated phosphorylation of nascent chains either at the N-terminus (Ser128 or Ser129) or the C-terminus, which promotes the mitochondrial ... localization of intact CYP2E1 in yeast cells Because of the existing ambiguity in the literature on the nature and extent of CYP2E1 import into mitochondria, we first established the relative purity of...

Ngày tải lên: 18/02/2014, 16:20

... date The rarity of PAL in bacteria may be explained by the infrequency of phenylpropanoids in these species The bacterial PALs seem to be involved in biosynthesis of the antibiotics enterocin by ... is involved in the biosynthesis of the photoactive yellow protein chromophore of these bacteria The two recently discovered aminomutases, the phenylalanine 2,3-aminomutase (PAM) involved in taxol ... analysis of the possible role of C-terminal multi-helix domain in this process Investigation of bacterial PAL structures As Table shows, there is a substantial similarity between the members of the...

Ngày tải lên: 07/03/2014, 12:20

... using peptides containing single tyrosines show that Lck is capable of phosphorylating all six of the tyrosines without being tethered to the substrate via such phosphotyrosine–SH2 domain interactions ... arising in the order of phosphorylation of the subsequent tyrosines in the whole cTCRf chain in vitro, relative to the single -tyrosine- containing peptides, may well be due to the presence of an ... located on the intact protein Therefore, determination of the kinetics of phosphorylation of these peptides allows the order of phosphorylation of the six TCRf ITAM tyrosines, by the PTK Lck,...

Ngày tải lên: 08/03/2014, 02:20