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AT-101 downregulates BCL2 and MCL1 and potentiates the cytotoxic effects of lenalidomide and dexamethasone in preclinical models of multiple myeloma and Waldenström macroglobulinaemia.
[waldenström macroglobulinemia]
Multiple
myeloma
,
the
second
most
common
haematological
malignancy
in
the
U
.
S
.
,
is
currently
incurable
.
Disruption
of
the
intrinsic
apoptotic
pathway
by
BCL
2
and
MCL
1
upregulation
is
observed
in
>
80
%
of
myeloma
cases
and
is
associated
with
an
aggressive
clinical
course
.
Remarkably
,
there
is
no
approved
drug
with
the
ability
to
target
BCL
2
or
MCL
1
.
Thus
,
we
investigated
the
anti-tumour
effects
of
a
pan-
BCL
2
inhibitor
,
AT-
101
,
which
has
high
binding
specificity
for
BCL
2
and
MCL
1
in
preclinical
models
of
plasma
cell
cancers
(
Multiple
myeloma
and
Waldenström
macroglobulinaemia
)
.
Gene
expression
and
immunoblot
analysis
of
six
plasma
cell
cancer
models
showed
upregulation
of
BCL
2
family
members
.
AT-
101
was
able
to
downregulate
BCL
2
and
MCL
1
in
all
plasma
cell
cancer
models
and
induced
apoptotic
cell
death
in
a
caspase-dependent
manner
by
altering
mitochondrial
membrane
permeability
.
This
cytotoxic
effect
and
BCL
2
downregulation
were
further
potentiated
when
AT-
101
was
combined
with
lenalidomide
/
dexamethasone
(
LDA
)
.
NanoString
nCounter
mRNA
quantification
and
Ingenuity
Pathways
Analysis
revealed
differential
changes
in
the
CCNA
2
,
FRZB
,
FYN
,
IRF
1
,
PTPN
11
genes
in
LDA
-treated
cells
.
In
summary
,
we
describe
for
the
first
time
the
cellular
and
molecular
events
associated
with
the
use
of
AT-
101
in
combination
with
lenalidomide
/
dexamethasone
in
preclinical
models
of
plasma
cell
malignancy
.
Diseases
Validation
Diseases presenting
"first time"
symptom
achondroplasia
acute rheumatic fever
adrenal incidentaloma
adrenomyeloneuropathy
alpha-thalassemia
aniridia
aromatase deficiency
canavan disease
carcinoma of the gallbladder
cholangiocarcinoma
classical phenylketonuria
congenital adrenal hyperplasia
congenital toxoplasmosis
cowden syndrome
cushing syndrome
cutaneous mastocytosis
dedifferentiated liposarcoma
dentin dysplasia
dentinogenesis imperfecta
dracunculiasis
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
erdheim-chester disease
erythropoietic protoporphyria
esophageal adenocarcinoma
esophageal carcinoma
esophageal squamous cell carcinoma
fabry disease
familial mediterranean fever
gm1 gangliosidosis
harlequin ichthyosis
heparin-induced thrombocytopenia
hirschsprung disease
hodgkin lymphoma, classical
holt-oram syndrome
hydrocephalus with stenosis of the aqueduct of sylvius
junctional epidermolysis bullosa
kabuki syndrome
kallmann syndrome
liposarcoma
locked-in syndrome
lymphangioleiomyomatosis
malignant atrophic papulosis
megacystis-microcolon-intestinal hypoperistalsis syndrome
monosomy 21
neuralgic amyotrophy
oculocutaneous albinism
oligodontia
omenn syndrome
oral submucous fibrosis
papillon-lefèvre syndrome
pendred syndrome
phenylketonuria
primary effusion lymphoma
primary hyperoxaluria type 1
severe combined immunodeficiency
sneddon syndrome
triple a syndrome
trochlear dysplasia
von hippel-lindau disease
waldenström macroglobulinemia
well-differentiated liposarcoma
werner syndrome
wiskott-aldrich syndrome
wolf-hirschhorn syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
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