2011/10/6–7 Rehearsal
2011/10/29–30 Scientific Review/Site Visit
2012/2/17–18 PI Retreat
Review Member:
鄭院士、龔院士、楊院士、劉院士、閻校長、洪院士、院長、王副院長
PI 23 RA/postdoc 20
Director Chang JY
Drug discoverypast 3-yr publication
HuR bind to HIF1a mRNA stablization (inhibited by MPT0B098)
MPT0B098 decreased cytoplams translocation of HuR
MPT0B292 HDAC6 inhibitor
HDAC6 acetylates a-tubulin
Ca2+ influx STIMI Ac actin
What is the effect of actin acetylation upon STIM1 activation?
nticancer efficacy of PLGA-30
MGMT modulates therapeutic efficacy of platinum drugs with radiation and its clinical significance
2012-02 補遺:
- Cheng Gung 70–80% OrCa patients have betel quid habit, radiotherapy is okay; chemotherapy (cisplatin + EGFR inhibitor or taxol)
- Auro Kinae Inhibitor (a multi-target kinase at 100 nM range)
Dr. Liu KJ
Chronic inflammation
Tumorigenesis Metastasi
Animal model of oral cancer:
4-NQO 200 ug/ml drinkimg water 16 wks
8-9 wks leukoplakia & erythoplakia
bacteria clump
4-NQO+arecolin 500 ug/ml
10 ug/20 ul PMA
CCL2 (MCP1)->Th0 to Th2 change
comdition medium from OSCC cells stimulates the prodiuction of IL6 IL10 VEGF
IL6 JAK STAT3
by by macrophage
VPA decreases IL23 production
IL23 -> Th17 precursor celldifferentiation into pathogenic Th17 cells.
N-linked glycoprotein THBS1
acute and chronic inflammation thrombospondin 1 a chemoacctrant
HLA-G glycoprotein
ENO1 Ab is reversely correlated with cancer metasta
Dr Lee CH
BEX1 and LDOC1
the reduced expressions of BEX1 and LODC1 was primarily due to promoter
methylation
Dr. Shia SG
40 patient pairs
30 overexpressed 52 downregulated
2 clusters
X chromosome
14q32.
mi 329 410 411 in EG-3 imprinting
gene were hypermethylated
wnt-7b is overexpressed in OSCC
cMYC is the end product of wnt-7b that is a ligand of WNT pathway
GAS6 and AXL
MMP2 (miR 1237),MMP14(miR 663) and MMP9 (miR 483 3P).
292 and integrin and focal formation
Dr Chen YW
miR 99a is downregulated in OSCC cells, suppresses cell growth and migration,
ectopic miR99a inhibit cell proliferation and cell migration and invasion
miR99a targets to IGFR1 but not to mTOR
IGF downregulates miR99a
EMT
p16 Ink4a in cell migration
reintroduction of p16 into MM189 enhances cll migration.
p16 is shuttlimg between nucleus and cytoplasma
Increased Cdc42 and Rac1 GTPase activity in p16-mediated migration
Kuo CC
Nrf2/ARE mediated defense mechanism
Nrf2 is a molecular target for chemoprevention
Discovery of Nrf2 activator
4-KPR is a Nrf2 activatorvia AKT pathway
Nrf2 is a precancerous marker of lung cancer and and oral tumorigenesi.
Chang SM
Genetic factor and risk factor
prospective 1000 persons
causal SNP and Tag SNP
Enthanol Metabolism Pathway
ADH1B rs1229984
Retinoid acid pathway
simialr to ehtnal metabolism pathway
prosglandin pathway
HPV assay kit
Allen Lee
Cdc7/Dbf4 in S phase check point
repliction stress
JBMC 2011 Vol 3 p4
Nature 2000 pretty DDR figure
Dbf4 is phosphorylated by ATM/ATR pathways. which is importat for mediating the intra-S checkpoint.
Dbf4 is accumulated on chromatin and is independent of Dbf4 phosphorylation.
S539 antibody
The kinase activity of Dbf4 is important for stablizing replication fork
Increased Cdc7 activity increased recovery from failed replication fork.
Overexpression of Cdc7 in OSCC cells, is a prognosis marker for OSCC.
72 genes were invilved in orca
80% clincial samples have VIII variants
ovexpression of SIK3 in ovarian cancer
Chang KY
PI3K/mTOR dual inhibitor BT226
Aberrant EGFR in Head and Neck Cancer
Lacking effective drug in recurrent tumors
Cetuximab EGFR MoAb 2008 NEJM
overexpression of EGFR in 28%
High prevalence of EGFRviii IHC
Increased activation of AKT in 57-81% patients.
A novel PI3K mTOR dual inhibitor BGT226 impede cell growth via autophagy but not apoptosis Cell arrets in G0 G1
Clinical Cancer Research
Chang IS
false discovery rate
q-value
ROC is old way, New method uses predictiveness PPV NPV
parsimony
lung ADC
Prediction of Methylation bases
Cox model with
Shi NY
The role of tumor associaed antigen in tumor formation
enhancementof atitumor activity
Serological identification of ovarian cancer tumor associayed peptides
OVTA1/SIK3 overexpressed in 53.3% ovarian caners
SIK3 is involved in G1 S transition
downregulation of p21 by SIK/3 can be rescued by P2 showing that Src is a target of SIK3.
SIK3 is a specific marker for ovarian cancer
KO SIK3 causes reproduction defect in both male and female
Tumor associated antigen in lung cancer ENO1 promotes cell migration
ENOI attrnuates macrophage fumction in immune surveillance
Prevention effect of ENO1 adjuvant on tumor growth
Therapeutic of ENO1 vaccine
Chen LT
Pancreatic cancer
Gemcitabine + CCRT
KLF10 KO mice glucose intolerace
microenvironment (macrophage)
stem cell (prof Hong and Prof Li )
biomarker KLF10
Chlorangiocarcinoma
HER2 amplificantion 30%
expression array of 60 samples
SNU1196 cell line
Randomilized phase II clinical trial
phase I clinical trial in NCKUH
GIST
c-KIT analysis
multi mutation in cKIT
HSP90 inhibitor AUY922
FASN helps cKIT translocation
HDAC6 and HSP90/GSK3 are required for cKIT maturation
X
Chuang SE
miR34a AXL
at RNA level,-> AXL->inhibits JNK->elk1->inhibits miR34a
AXL is targeted by 34a,449a,449c
AXL kinase activity is required for negative autoregulation feedback
AXL downregulates ELK1 via JNK, ELK1 upregulates AXL via miR34a
ELK1 is a miR34A promoter repressor
AXL and ROS
overexpressed AXL increase ROS production
NAC and catalase decreased AXL mediated cell migration
both intra an extra domains are required for AXL med migration
ROS induced AXL phosphorylation by other kinases
AXL overexpression prolongs AKT
akt1 but not akt2 is involved in the ROS enhanced AXL mediated cell migration
Tsai KC
Establish tissuemimetic models and orthotopic tumorigenesis and human in mice glandular tissue modelsdissesceting transcriptional chances by microarray
CEL A gene expression profile (28 genes )prdicts differentiation is a favor marker for prognosis eg
34 gene signatur for PrCA eg ABCG1 PDCD4 and KLF6
Radiation stimulates stromal cells
chemotherapy induces premature senescence in carcinomaassociated fibroblast in breast cancer.
Chemotherapy induces stromal cells secreting ccl1 2 5 6 etc via CXCR2
Nuclear co repressor 2 N-CoR2
downregulation of N-CoR2 promotes mammary branching morphorgenesis in vivo.
Ch’ang HJ
Pancreatic cancer chemotherapy and Radio therapy plus chemotherapy
Hepatocellular carcinoma
Bone marrow enhances intesstinal strom cell proliferation and protects cell from radiation through paracrone mechanism
Fusion between bone marrow and intestinal stromal cells contributes to intestine fibroblasis after radiation.
Shear stres in regulating radiation sensitivity of tumor cells . Shear flow contributes to radiosensitivity of caner cells through Fak
KLF10 in pancreatic cancer TGFb1 induced early gene 1
high KLF10 is with good prognosis
Chang WS
# Cysteine Cathepsin B (CTSS)
JAMA 306 p1113 serum CTSS and logentivity
Compound 6r
look for inhibitors do not inhibit CTSS L
CCL RJW 58
RJW58 inhibits CCTS S mediated fibronectin degradation
RJW58 inhibits pancreatic cell migradation but CTSS S is not overexpressed in PANC1S
RJW 58/CTSS S inhibition induces autophagy in cells
Huang TS
Roles of secreted HSP90a in macrophage associated inflammation in PDAC
In mouse model only kRAS mutation is sufficient for development of PANIN lesion
Ascinar to ADM
M1 or M2 polarized macrophages
CD163+ cells is asociated wth stage of cancer
HSP90a
serum HSP90a level is elevated in patients of various cancers
GdCl3
GdCl3 decreases M2 macrophage formation
eases CD163pos cells
and HSP90a serum level
ITGAm CD11b
macrophage induces HSP90a secretion from PDAC cells
the promoter region of IL10 CD163 CD204contain NFKB binding sites
HSP90a ->TLR4->NFKB->IL10 CD163 CD204 ->polarized M2 macrophage
connexin 43 and 26 were also downregulated by HSP90a and EMT is formed.
Shiah HS
noval function of mTOR
Effect od RAD001 plus CPT on cancer cells
2.5mg per day
anti HBV before RAS001 admistration
HONE1/CPT30 resistant Tpo1 mutation and decreased
KB/KB100 XRCC1 increases,sensitive to PARPi
A2780/ Top1 double mutation
Lamividine plus mTOR inhibitor in Treating virus postive HCC
mTOR inhibits preS1 promoter expression
Activation of mTOR enhanced YY1 expression and nuclear localization
Recruitment of HDAC1 by YY1 mediated preS1 repression via mTOR.
mTOR inhibitor behaves like PARP1 inhibitor
considering the application of mTOR inhibitor and CPT
Synthetic lethality eg BRCA1+PARP1
reduction of ATP pool
synthetic inhibitors of DNA damaging drug and PARPi
HER2 was overexpressed in HONE1
HER2 and Cisplatin
HER2 AKT FOXO signaling pathway.
Chen JY
NEjM 1234
LMP1 induces GI in NPC cells
Suggestion EBV reactivation contributes to the carcinogeness of NPC
Ecurrent EBV reactivations in NPC cells.
Environmental factor
MMNG
(2012/2/18 補遺: NPC 1,500/year in Taiwan, among these, 600–700 are late stage and recurrence are easily in these patients after chemoradiotherapy. Thus, we ant to help these patients from recurrence (recurrent rate : 50% in 5-yr).
MNNG -> ROS ->
600 mg ~ 4 cups of tea / day