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在小鼠模式中探討破傷風類毒素結合治療性癌症疫苗GVAX對抗子宮頸癌的機制

為了解決uh-50xt100的問題，作者Donia Alson 這樣論述：

Table of ContentsRecommendation Letter from the Thesis AdvisorThesis/Dissertation Oral Defense Committee CertificateAcknowledgement …………………………………………………… iiiAbstract ..…………………………………………………………….. iv Table of contents …………………………………………………….. viList of Figures ……………………………………………………….. ixChapter 1:

Introduction ……………………………………………… 11.1 Cancer and Immune System …………………………………….. 11.2 Cancer Immunotherapy ………………………………………... 21.2.1 Immune Checkpoint Inhibitors …………………………….. 31.2.2 Adoptive T cell Therapy …………………………………… 41.3 Cervical Cancer and HPV ……………………………………... 51.3.1 HPV Genome ………

………………………………………. 61.3.2 HPV Subtypes …………………………………………….. 91.3.3 HPV Viral Oncogenes ……………………………………… 91.3.4 HPV Infectious Cycle ………………………………………. 111.3.5 HPV Associated Cancer …………………………………… 121.3.6 HPV Vaccines……………………………………………….. 131.4 GVAX and GM-CSF …………………………………………… 141.4.1 Codon-Modif

ied GM-CSF ………………………………….. 151.4.2 GM-CSF and Cancer………………………………………… 161.4.3 Anti-tumor mechanism of GM-CSF ………………………… 171.4.4 GM-CSF Monotherapy………………………………………. 181.5 Tetanus Toxoid and Immune Response ………………………… 191.6 Research Rational ………………………………………………. 201.7 Specific Aims …………………………………………………

. 211.7.1 Experimental Design …………………………………….. 23Chapter 2: Materials and Methods – I ……………………………… 242.1.1 Mice …………………………………………………………. 242.1.2 Cell Lines...……………………………………………………. 242.1.3 Tumor Model and Vaccination ……………………………… 252.1.4 Spleen Weight Index and Splenocyte Proliferation …………. 2

52.1.5 Cytokine Secretion Measurement with ELISA ……………… 262.1.6 Flow Cytometric Analysis of Immune Cells ………………… 262.1.7 In-Vivo Cytotoxicity Assay ……………………………….272.1.8 Statistical Analysis …………………………………………... 27Materials and Methods – II2.2.1 Mice ………………………………………………………….. 282.2.2 Cell Line

s ……………………………………………………. 282.2.3 Cytokine Secretion Measurement with ELISA ........................ 292.2.4 Tumor Model and Vaccination ……………………………… 292.2.5 Flow Cytometric Analysis ………………………………….. 292.2.6 Statistical Analysis …………………………………………… 30Chapter 3: Results – I3.1.1 Higher level of GM-CSF

secretion by TC-1/cGM-CSF stable cell line …………………………………………………………………… 313.1.2 Vaccination with tetanus toxoid and TC-1/cGM-CSF induced enhanced splenocyte proliferation …………………………………… 313.1.3 Increased levels of Th1 and Th2 cytokines in the group of mice vaccinated with combination vaccination ……………

……………… 323.1.4 Higher percentage of memory T cells generation after combination vaccination of tetanus and TC-1/cGM-CSF ……………………..…. 333.1.5 Generation of cytotoxic effector T cells in-vivo after combination vaccination with tetanus toxoid and TC-1/cGM-CSF ………….......... 343.1.6 Combination v

accination with tetanus toxoid and TC-1/cGM-CSF vaccine induced enhanced immunosurveillance and effectively inhibits tumorigenesis in vivo............................................................................. 35Results – II3.2.1 TC-1 cells transfected with LV-cGM-CSF(Lentiviral) (TC-1/cGM-CS

F) expressed increased levels of GM-CSF compared with that of TC-1 cells transfected with LV-wtGM-CSF (TC-1/wtGM-CSF)……..…….. 363.2.2 Mice vaccinated with three doses of irradiated TC-1/cGM-CSF induce enhanced immunosurveillance compared with that of mice vaccinated for TC-1 tumor with one dose and

five doses…………..….. 373.2.3 Generation of antigen-specific IFN-γ (Interferon-γ) producing CD8+ and CD4+ T cells …………………………………………………....… 383.2.4 A higher percentage of B220+ NK1.1+ interferon-producing killer dendritic cells (IKDCs) were produced in mice vaccinated with three doses of irradiated TC-

1/cGM-CSF vaccine compared with that of mice vaccinated with one dose and five doses of irradiated TC-1/cGM-CSF vaccine………………………………………………………………… 39Chapter 4: Discussion …………………………………………………. 41Figures ………………………………………………………………… 49References …………………………………………………………….. 62List of Figures - IFig. 1. Incr

eased levels of GM-CSF secretion by TC-1 cells containing codon-modified GM-CSF ………………………………………...….. 49Fig. 2. Enhanced splenocyte proliferation after combination vaccination ……………………………………………………………………..….. 50Fig. 3. Combination of tetanus toxoid and TC-1/cGM-CSF vaccination enhances the level o

f Th1 and Th2 cytokine secretion …………..….. 51Fig. 4. Combination vaccination increase the percentage of CD8+CD44+ memory T cell lymphocyte in the spleen ……………………….…. . 52Fig. 5. Combination vaccination increase the percentage of CD4+CD44+ and CD8+CD44+ memory T cell lymphocyte infiltration in t

he tumor …………………………………………………………………….…. 53Fig. 6. Effects of combination vaccination on the generation E7-specific CTL in C56BL/6 mice …………………………………………….… 54Fig. 7. Combination vaccination with tetanus toxoid and TC-1/cGM-CSF can effectively inhibit tumor growth ………………………………. 55List of Fi

gures – IIFig 8. Increased levels of GM-CSF production by TC-1 cells containing codon-modified GM-CSF……………………………………………... 56Fig 9. Tumor vaccination three-times with cGM-CSF can efficiently inhibit tumor growth compared to five-time vaccination…………..….. 57Fig 10. Vaccination three-times with cGM-CS

F generates a higher IFN-γ secreting CD8+ T and CD4+ T cell response compared to five-times….. 59Fig 11. Vaccination three-times with irradiated TC-1/cGM-CSF vaccine generates a higher percentage of IKDCs compared to vaccination five-times……………………………………………………………………. 61

蛋白質合成和蛋白酶體降解作用之正調控賦予非典型橫紋肌樣瘤對蛋白酶體抑製劑萬科(Bortezomib)之敏應性

為了解決uh-50xt100的問題，作者Tran Minh Huy 這樣論述：

Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Non-specific and traditional cytotoxicity treatments offer low disease control rates and cause some long-term neurocognitive sequelae in young children, highlighting the urge

ncy of targeted therapies. The primary genetic aberration in ATRTs is the loss of SMARCB1 or very rarely SMARCA4 genes. One consequence of the SMARCB1 depletion is the upregulation of MYC signaling pathway. ATRTs comprise of three distinct molecular subgroups, including ATRT-SHH, ATRT-TYR, and ATRT-

MYC. ATRT-MYC is driven by the MYC oncogene, which directly controls the intracellular protein synthesis rate. The Food and Drug Administration approved proteasome inhibitor bortezomib (BTZ) as a primary treatment for multiple myeloma. This study aimed at determining whether the upregulation of prot

ein synthesis and proteasome degradation in ATRTs, particularly in the MYC subgroup, increases tumor cell sensitivity to BTZ.We performed differential gene expression and gene set enrichment analysis on matched primary and recurrent patient-derived xenograft (PDX) samples from an infant with ATRT. T

he expressions of proteasome-encoding genes were compared among this paired model as well as between the 24 human ATRT samples and normal brain tissues. The antitumor effect of BTZ was evaluated in three human ATRT-MYC cell lines (PDX-derived tumor cell line Re1-P6, BT-12, and CHLA-266), two human A

TRT-SHH cell lines (CHLA-02 and CHLA-04), and in the orthotopic xenograft models of Re1-P6 cell.Concomitant upregulation of the Myc pathway, protein synthesis, and proteasome degradation were identified in recurrent ATRTs. Additionally, we found that the proteasome-encoding genes were highly express

ed in ATRTs compared with in normal brain tissues, correlated with the malignancy of tumor cells, and were essential for tumor cell survival. BTZ inhibited proliferation and induced apoptosis through the accumulation of p53 in three human ATRT-MYC cell lines. Additionally, ATRT-SHH cell lines were a

lso sensitive to a clinically achievable concentration of BTZ, but less sensitive than ATRT-MYC. Furthermore, BTZ inhibited tumor growth and prolonged the survival of ATRT-MYC orthotopic xenograft mice.Our findings suggest that BTZ may be a promising targeted therapy for ATRTs, particularly ATRT-MYC

. Together, these preclinical data provided a substantial background for conducting future clinical trials of BTZ in ATRTs.