Three
distinct
pharmacological
corrector
types
(I,
II,
III)
with
different
binding
sites
and
additive
behavior
only
partially
rescue
the
F508del-cystic
fibrosis
transmembrane
conductance
regulator
(CFTR)
folding
trafficking
defect
observed
in
cystic
fibrosis.
We
describe
uniquely
effective,
macrocyclic
CFTR
correctors
that
were
to
known
types,
exerting
a
complementary
“type
IV”
mechanism.
Macrocycles
achieved
wild-type–like
efficiency
of
F508del-CFTR
at
endoplasmic
reticulum
normalized
currents
reconstituted
patient-derived
bronchial
epithelium.
Using
photo-activatable
macrocycles,
docking
studies
site-directed
mutagenesis
highly
probable
site
pose
for
type
IV
was
identified
cavity
between
lasso
helix-1
(Lh1)
membrane
spanning
domain
(MSD)-1,
from
sites.
Since
fragments
Lh1
until
MSD2
responded
correctors,
these
likely
promote
cotranslational
assembly
Lh1,
MSD1,
MSD2.
Previously
corrector-resistant
mutants
also
robustly
rescued,
suggesting
substantial
therapeutic
potential
correctors.
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(3), С. 1933 - 1933
Опубликована: Фев. 5, 2024
The
respiratory
mucus,
a
viscoelastic
gel,
effectuates
primary
line
of
the
airway
defense
when
operated
by
mucociliary
clearance.
In
chronic
diseases
(CRDs),
such
as
asthma,
obstructive
pulmonary
disease
(COPD),
and
cystic
fibrosis
(CF),
mucus
is
overproduced
its
solid
content
augments,
changing
structure
properties
determining
derangement
essential
mechanisms
against
opportunistic
microbial
(virus
bacteria)
pathogens.
This
ensues
in
damaging
airways,
leading
to
vicious
cycle
obstruction
infection
responsible
for
harsh
clinical
evolution
these
CRDs.
Here,
we
review
features
normal
pathological
(i.e.,
sputum
CF,
COPD,
asthma),
i.e.,
mucin
content,
(mesh
size),
micro/macro-rheology,
pH,
osmotic
pressure,
ending
with
awareness
that
biomarkers
(mucins,
inflammatory
proteins
peptides,
metabolites)
might
serve
indicate
acute
exacerbation
response
therapies.
There
are
some
indications
old
novel
treatments
may
change
structure,
properties,
biomarker
sputum;
however,
wealth
work
still
needed
embrace
measures
correlates
severity
association
(or
even
substitutes
of)
functional
tests.
American Journal of Respiratory and Critical Care Medicine,
Год журнала:
2024,
Номер
209(11), С. 1338 - 1350
Опубликована: Янв. 23, 2024
Pharmacological
improvement
of
cystic
fibrosis
transmembrane
conductance
regulator
(CFTR)
function
with
elexacaftor/tezacaftor/ivacaftor
(ETI)
provides
unprecedented
improvements
in
lung
and
other
clinical
outcomes
patients
(CF).
However,
ETI
effects
on
impaired
mucosal
homeostasis
host
defense
at
the
molecular
cellular
levels
airways
CF
remain
unknown.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Март 23, 2024
Abstract
The
dense
O
-glycosylation
of
mucins
plays
an
important
role
in
the
defensive
properties
mucus
hydrogel.
Aberrant
glycosylation
is
often
correlated
with
inflammation
and
pathology
such
as
COPD,
cancer,
Crohn’s
disease.
inherent
complexity
glycans
diversity
-core
structure
constitute
fundamental
challenges
for
analysis
mucin-type
-glycans.
Due
to
coexistence
multiple
isomers,
multidimensional
workflows
LC-MS
are
required.
To
separate
highly
polar
carbohydrates,
porous
graphitized
carbon
used
a
stationary
phase.
However,
time-consuming
lack
reproducibility.
Here
we
present
rapid
alternative
separating
identifying
-glycans
released
from
based
on
trapped
ion
mobility
mass
spectrometry.
Compared
established
LC-MS,
acquisition
time
reduced
hour
two
minutes.
test
validity,
developed
workflow
was
applied
sputum
samples
cystic
fibrosis
patients
map
features
associated
European Respiratory Journal,
Год журнала:
2024,
Номер
64(3), С. 2400004 - 2400004
Опубликована: Июнь 20, 2024
Background
We
recently
demonstrated
that
elexacaftor/tezacaftor/ivacaftor
(ETI)
improves
the
lung
clearance
index
(LCI)
and
abnormalities
in
morphology
detected
by
magnetic
resonance
imaging
(MRI)
adolescent
adult
patients
with
cystic
fibrosis
(CF).
However,
real-world
data
on
effect
of
ETI
these
sensitive
outcomes
structure
function
school-age
children
CF
have
not
been
reported.
The
aim
this
study
was
therefore
to
examine
LCI
MRI
score
aged
6–11
years
one
or
two
F508del
alleles.
Methods
This
prospective,
observational,
multicentre,
post-approval
assessed
longitudinal
up
12
months
before
3
after
initiation
ETI.
Results
A
total
107
including
40
heterozygous
for
a
minimal
mutation
(F/MF)
67
homozygous
(F/F)
were
enrolled
study.
Treatment
improved
median
(interquartile
range
(IQR))
F/MF
(−1.0
(−2.0–
−0.1);
p<0.01)
F/F
(−0.8
(−1.9–
−0.2);
p<0.001)
from
onwards.
Further,
(IQR)
global
(−4.0
(−9.0–0.0);
(−3.5
(−7.3–
−0.8);
p<0.001).
Conclusions
early
ventilation
at
least
allele
setting.
Our
results
support
reduce
even
prevent
disease
progression
CF.
European Respiratory Review,
Год журнала:
2024,
Номер
33(171), С. 230178 - 230178
Опубликована: Янв. 31, 2024
is
the
most
commonly
isolated
pathogen
in
bronchiectasis
and
associated
with
worse
outcomes.
Eradication
treatment
recommended
by
guidelines,
but
evidence
base
limited.
The
expected
success
rate
of
eradication
clinical
practice
not
known.
European Respiratory Journal,
Год журнала:
2024,
Номер
63(3), С. 2301794 - 2301794
Опубликована: Фев. 8, 2024
Background
This
study
sought
to
evaluate
the
impact
of
elexacaftor/tezacaftor/ivacaftor
(ETI)
on
lung
structural
abnormalities
in
adults
with
cystic
fibrosis
(awCF)
a
specific
focus
reversal
bronchial
dilatations.
Methods
Chest
computed
tomography
(CT)
scans
performed
prior
and
12
months
after
initiation
ETI
were
visually
reviewed
for
possible
AwCF
without
dilatations
(the
latter
served
as
controls,
three
controls
per
case)
selected.
Visual
Brody
score,
arterial
diameters,
volume
measured
CT.
Results
Reversal
was
found
12/235
(5%)
awCF
treated
ETI.
36
further
analysed
(male
56%,
mean±
sd
age
31.6±8.5
years,
F508del/F508del
CFTR
54%
mean
forced
expiratory
1
s
58.8±22.3%
predicted).
The
score
improved
overall
from
79.4±29.8
54.8±32.3
(p<0.001).
confirmed
by
decrease
lumen
diameter
cases
3.9±0.9
3.2±1.1
mm
(p<0.001),
whereas
it
increased
(from
3.5±1.1
3.6±1.2
mm;
p=0.002).
occurred
cylindrical
(not
varicose
or
saccular)
Lung
volumes
decreased
−6.6±10.7%
but
+2.3±9.6%
(p=0.007).
Conclusions
Although
are
generally
considered
irreversible,
associated
reversal,
which
limited
dilatation
subtype,
small
subset
awCF.
Initiating
earlier
life
may
reverse
early
