This document discusses next generation epigenetic profiling using methylation-based biomarkers. It provides an overview of epigenetics and methylation in oncology. It then discusses MDxHealth's next-generation epigenetic biomarkers and methylation-based companion diagnostics. As an example, it summarizes research on MGMT promoter methylation predicting benefit from DNA-alkylating chemotherapy in glioblastoma patients.
Epigenetic silencing of MGMT (O6-methylguanine DNA methyltransferase) gene in...arman170701
O6–methylgunine-DNA methyltransferace (MGMT) is a DNA binding protein that is involved in repairing mutations.
MGMT gene - a tumor suppressor gene that codes MGMT (O6-methylguanine DNA methyltransferase) protein.
The MGMT protein removes mutagenic methyl groups from guanines through the methyltransferase activity.
Epigenetic silencing of MGMT (O6-methylguanine DNA methyltransferase) gene in...arman170701
O6–methylgunine-DNA methyltransferace (MGMT) is a DNA binding protein that is involved in repairing mutations.
MGMT gene - a tumor suppressor gene that codes MGMT (O6-methylguanine DNA methyltransferase) protein.
The MGMT protein removes mutagenic methyl groups from guanines through the methyltransferase activity.
I received a PhD in April of 2007 from the Schultz Lab at the Scripps Research Institute in La Jolla, CA. Here is a PowerPoint presentation of my primary work - a use of functional genomics tools to probe cellular disease problems, notably in cancer models.
Decades of cancer research including comprehensive molecular profiling combined with the
development of a broad array of targeted therapies have created the opportunity to transform
cancer care in the near future by implementing precision oncology based approaches. An
important element of this system is the widespread availability of robust and cost-effective
multivariate profiling methods in order to characterize relevant cancer associated molecular
alterations.
Current commercially available multivariate profiling methods vary dramatically with regard to
the number of cancer genes interrogated. Given that many large scale and detailed molecular
profiling studies have been completed, the landscape of somatic alterations in solid tumors is
reasonably well-known. Furthermore, the specific gene variants that are relevant to application
of targeted therapies are also a matter of record. Therefore, we set out to define the number of
relevant cancer genes for precision oncology research based on the currently available
empirical evidence.
genetic variations and its role in health/ pharmacologysrivani mandaloju
Here is the reference for the above topic. I have collected the maximum information that i got from the internet. If any one need the complete information comment here.
Kinases belong to the family of phosphotransferases and play critical roles in the process known as phosphorylation in which a phosphorylated substrate and ADP are produced.
https://www.creative-biogene.com/products/kinase-stable-cell-lines.html
Molecular mechanisms of action and potential biomarkers of growth inhibition ...Enrique Moreno Gonzalez
Molecular targeted therapy has emerged as a promising treatment of Hepatocellular carcinoma (HCC). One potential target is the Src family Kinase (SFK). C-Src, a non-receptor tyrosine kinase is a critical link of multiple signal pathways that regulate proliferation, invasion, survival, metastasis, and angiogenesis. In this study, we evaluated the effects of a novel SFK inhibitor, dasatinib (BMS-354825), on SFK/FAK/p130CAS, PI3K/PTEN/Akt/mTOR, Ras/Raf/MAPK and Stats pathways in 9 HCC cell lines.
I received a PhD in April of 2007 from the Schultz Lab at the Scripps Research Institute in La Jolla, CA. Here is a PowerPoint presentation of my primary work - a use of functional genomics tools to probe cellular disease problems, notably in cancer models.
Decades of cancer research including comprehensive molecular profiling combined with the
development of a broad array of targeted therapies have created the opportunity to transform
cancer care in the near future by implementing precision oncology based approaches. An
important element of this system is the widespread availability of robust and cost-effective
multivariate profiling methods in order to characterize relevant cancer associated molecular
alterations.
Current commercially available multivariate profiling methods vary dramatically with regard to
the number of cancer genes interrogated. Given that many large scale and detailed molecular
profiling studies have been completed, the landscape of somatic alterations in solid tumors is
reasonably well-known. Furthermore, the specific gene variants that are relevant to application
of targeted therapies are also a matter of record. Therefore, we set out to define the number of
relevant cancer genes for precision oncology research based on the currently available
empirical evidence.
genetic variations and its role in health/ pharmacologysrivani mandaloju
Here is the reference for the above topic. I have collected the maximum information that i got from the internet. If any one need the complete information comment here.
Kinases belong to the family of phosphotransferases and play critical roles in the process known as phosphorylation in which a phosphorylated substrate and ADP are produced.
https://www.creative-biogene.com/products/kinase-stable-cell-lines.html
Molecular mechanisms of action and potential biomarkers of growth inhibition ...Enrique Moreno Gonzalez
Molecular targeted therapy has emerged as a promising treatment of Hepatocellular carcinoma (HCC). One potential target is the Src family Kinase (SFK). C-Src, a non-receptor tyrosine kinase is a critical link of multiple signal pathways that regulate proliferation, invasion, survival, metastasis, and angiogenesis. In this study, we evaluated the effects of a novel SFK inhibitor, dasatinib (BMS-354825), on SFK/FAK/p130CAS, PI3K/PTEN/Akt/mTOR, Ras/Raf/MAPK and Stats pathways in 9 HCC cell lines.
The Matrix metalloproteinase-9 is involved in several pathologies. Its strong presence in ocular pathologies explains our interest for its genetic variation in cataract, glaucoma and retinoblastoma in Senegal. MMP9 is highly polymorphic with cataract and glaucoma. 77 mutations were noted with 21 haplotypes for the entire population. The haplotype diversity Hd is 0.831 and the nucleotide diversity Pi is 0.016; k = 17.395. The polymorphism of the Matrix metalloproteinase-9 gene is associated with all three diseases and SNP 3918249 is found in both cataract and glaucoma.
Next-Generation Sequencing Clinical Research Milestones InfographicQIAGEN
DNA mutations have been implicated in several diseases, particularly cancer. NGS presents an ideal technology to efficiently profile the multitude of mutations in a high throughput manner. In 2001 the first draft of human genome was published. Since then many major milestones have been reached. Do you know when PIK3CA was identified in colon cancer? When was Olaparib for ovarian cancer treatment? This infographic traces the major clinical research milestones starting from the first draft of the human genome.
Clinical molecular diagnostics for drug guidanceNikesh Shah
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2. Identify the utility of these diagnostic approaches with some examples
3. Be aware of the challenges that exist in implementing these tools as part of the routine clinical decision making process, especially in resource limited settings
Unit 8 - Information and Communication Technology (Paper I).pdfThiyagu K
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Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
How to Make a Field invisible in Odoo 17Celine George
It is possible to hide or invisible some fields in odoo. Commonly using “invisible” attribute in the field definition to invisible the fields. This slide will show how to make a field invisible in odoo 17.
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Acetabularia acetabulum is a single-celled green alga that in its vegetative state is morphologically differentiated into a basal rhizoid and an axially elongated stalk, which bears whorls of branching hairs. The single diploid nucleus resides in the rhizoid.
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For more information, visit-www.vavaclasses.com
A Strategic Approach: GenAI in EducationPeter Windle
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
6. Historically,
Cancer
Was
Considered
to
be
Driven
Mostly
by
Gene,c
Changes
GENETIC
§ Muta*ons
in
p53
Example:
Replica,on
errors
§ Ac*va*ng
muta*ons
in
RAS
§ Muta*ons
or
amplifica*ons
of
the
X
X
Altered
DNA
sequence
Altered
DNA/mRNA/proteins
HER-‐2
gene
§ Chromosomal
transloca*ons
in
Oncogenesis
myeloid
cells
and
the
genera*on
of
the
BCR-‐ABL
fusion
protein
Tumor
7. Epigene,c
Changes
are
Important
in
Causing
Cancer
GENETIC
EPIGENETIC
Example:
Chroma,n
modifica,on
errors
Example:
Replica,on
errors
X
X
Altered
DNA
sequence
Altered
DNA/mRNA/proteins
Altered
chroma,n
structure
Oncogenesis
Altered
levels
of
mRNA/proteins
Tumor
8. Example
of
Methyla,on
vs
Muta,on:
Colon
&
Breast
Cancer
120
100
80
Dx
60
40
CDx
20
0
Methylated
Mutated
Source:
Schuebel
et
al
2007
76-100 51-75
21-50
1-20
9. MGMT Biology
O6 Methyl-Guanine
Methyl Transferase
Essential DNA Repair Enzyme
Removes alkyl groups from damaged
guanine bases
Healthy
individual:
-‐
MGMT
is
an
essen*al
DNA
repair
enzyme
Loss
of
MGMT
ac*vity
makes
individuals
suscep*ble
to
DNA
damage
and
prone
to
tumor
development
Glioblastoma
pa,ent
on
alkylator
chemotherapy:
-‐
Pa*ents
with
MGMT
promoter
methyla*on
show
have
longer
PFS
and
OS
with
the
use
of
alkyla*ng
agents
as
chemotherapy
10. MGMT Promoter
Methylation Predicts
Benefit form DNA-Alkylating Chemotherapy
Post-hoc subgroup analysis of Temozolomide Clinical trial with primary
glioblastoma patients show benefit for patients with MGMT promoter methylation
25
Median
Overall
Survival
21.7 months
20
15
plus
temozolomide
12.7 months
radiotherapy
10
radiotherapy
5
0
Non-Methylated
MGMT Gene
Methylated
MGMT Gene
Adapted
from
Hegi
et
al.
NEJM
2005
352(10):1036-‐8.
Study
with
207
pa*ents
11. Clinical
Valida,on
of
MDxHealth
assay
RTOG
0525
Study
§ MGMT
was
measured
prospec*vely
in
the
RTOG
0525
study
§ MGMT
used
to
balance
the
arms
of
the
study
as
there
is
an
advantage
to
overall
survival
and
progression
free
survival
being
MGMT
methyla*on
§ Physicans
goal
in
this
study
was
to
compare
current
temozolomide
schedule
(Arm
1)
vs
a
dose-‐dense
administra*on
of
temozolomide(Arm2).
§ The
dose
dense
schedule
was
hypothesized
as
being
able
to
overcome
the
unmethylated
MGMT
tumors
by
overwhelming
the
tumor
with
alkyla*on.
§ The
dose
dense
schedule
did
not
work.
12. Outcomes
by
MGMT
Status-‐
MDxHealth
Assay
100
Dead Total
162
244
Methylated
Unmethylated 433
516
p (2-sided) =< 0.0001
HR (95% CI) =1.74 (1.45, 2.08)
75
Progression-free Survival (%)
Overall Survival (%)
100
50
25
0
0
Patients at Risk
Methy
244
Unmethy 516
12
24
36
Months after Randomization
168
104
37
295
106
28
48
6
6
Dead Total
202
244
Methylated
Unmethylated 486
516
p (2-sided) =< 0.0001
HR (95% CI) =1.63 (1.38, 1.92)
75
50
25
0
0
Patients at Risk
Methy
244
Unmethy 516
12
24
36
Months after Randomization
99
55
19
108
40
14
48
3
4
However
the
study
did
show
that
the
MDxHealth
assay
was
able
to
show
the
benefit
to
OS
and
PFS
with
the
MGMT
methylated
cohort.
Confiden*al
ASCO
2011,
Mark
R.
Gilbert,
MD
12
13. Overview
Epigene,cs
–
Introduc*on
–
Methyla*on
&
Oncology
–
Biomarkers
MDxHealth
– NEXT-‐GENera*on
Epigene*c
Biomarkers
Can
we
rediscover
MGMT
?
What
does
the
epigenome
look
like
?
27. GCATCGTGACTAGCGACTGATCGATGGATGCTAGCAT
25%
50%
25%
GCATCGTGACTAGCGACTGATCGATGGATGCTAGCAT
GCATCGTGACTAGCGACTGATCGATGGATGCTAGCAT
Dense
methylated
needed
for
transcrip*onal
silencing
Are
there
alleles
with
all
three
posi4ons
methylated
?
28. Deep
Sequencing
unmethylated
alleles
methylated
alleles
less
methyla*on
more
methyla*on
GCATCGTGACTTACGACTGATCGATGGATGCTAGCAT!
42. Epi-‐health:
comprehensive
epigene,c
profiling
§ Key
genes
– For
all
know
epigene*c
genes
– For
all
important
gene
classes
(CT
genes,
immune-‐response)
47. Epi-‐health:
comprehensive
epigene,c
profiling
§ Key
genes
– For
all
know
epigene*c
genes
– For
all
important
gene
classes
(CT
genes,
immune-‐response)
§ Key
regions
– Iden*fied
by
mining
epigenomes
50. Epi-‐health:
comprehensive
epigene,c
profiling
§ Key
genes
– For
all
know
epigene*c
genes
– For
all
important
gene
classes
(CT
genes,
immune-‐response)
§ Key
regions
– Iden*fied
by
mining
epigenomes
§ Approach
– Acceptable
amounts
of
clinical
material
– TAT/cost
§ Analysis
– Ac*onable
interpreta*on
– Get
gene*c
data
as
a
bonus
51. Molecular
Unifica,on
E
P
I
Whole-genome
Bisulphite seq
G
E
N
E
T
I
C
Whole-genome
sequencing
Enrichment seq
(MBD, RRBS)
Probes
(450-27K)
Ultra
Deep
Enrichment
Targeted Panels
Enrichment seq
(Exome)
Enrichment
Targeted Panels
Deep
Seq
bp
Full genome
109
108
RUO
107
106
105
104
103
Sequencing
102
101
1
Clinical