Jehanno, Charly; Percevault, Frederic; Boujrad, Noureddine; Goff, Pascale Le; Fontaine, Coralie; Arnal, Jean-Francois; Primig, Michael; Pakdel, Farzad; Michel, Denis; Metivier, Raphael; Flouriot, Gilles Nuclear translocation of MRTFA in MCF7 breast cancer cells shifts ER
alpha nuclear/genomic to extra-nuclear/non genomic actions Article de journal Dans: MOLECULAR AND CELLULAR ENDOCRINOLOGY, vol. 530, 2021, ISSN: 0303-7207. @article{ISI:000653627900006,
title = {Nuclear translocation of MRTFA in MCF7 breast cancer cells shifts ER
alpha nuclear/genomic to extra-nuclear/non genomic actions},
author = {Charly Jehanno and Frederic Percevault and Noureddine Boujrad and Pascale Le Goff and Coralie Fontaine and Jean-Francois Arnal and Michael Primig and Farzad Pakdel and Denis Michel and Raphael Metivier and Gilles Flouriot},
doi = {10.1016/j.mce.2021.111282},
issn = {0303-7207},
year = {2021},
date = {2021-06-01},
journal = {MOLECULAR AND CELLULAR ENDOCRINOLOGY},
volume = {530},
abstract = {The Myocardin-related transcription factor A [MRTFA, also known as
Megakaryoblastic Leukemia 1 (MKL1))] is a major actor in the epithelial
to mesenchymal transition (EMT). We have previously shown that
activation and nuclear accumulation of MRTFA mediate endocrine
resistance of estrogen receptor alpha (ER alpha) positive breast cancers
by initiating a partial transition from luminal to basal-like phenotype
and impairing ER alpha cistrome and transcriptome. In the present study,
we deepen our understanding of the mechanism by monitoring functional
changes in the receptor's activity. We demonstrate that MRTFA nuclear
accumulation down-regulates the expression of the unliganded (Apo-)ER
alpha and causes a redistribution of the protein localization from its
normal nuclear place to the entire cell volume. This phenomenon is
accompanied by a shift in Apo-ER alpha monomer/dimer ratio towards the
monomeric state, leading to significant functional consequences on ER
alpha activities. In particular, the association of Apo-ER alpha with
chromatin is drastically decreased, and the remaining ER alpha binding
sites are substantially less enriched in ERE motifs than in control
conditions. Monitored by proximity Ligation Assay, ER alpha interactions
with P160 family coactivators are partly impacted when MRTFA accumulates
in the nucleus, and those with SMRT and NCOR1 corepressors are
abolished. Finally, ER alpha interactions with kinases such as c-src and
PI3K are increased, thereby enhancing MAP Kinase and AKT activities. In
conclusion, the activation and nuclear accumulation of MRTFA in ER alpha
positive breast cancer cells remodels both ER alpha location and
functions by shifting its activity from nuclear genome regulation to
extra-nuclear non-genomic signaling.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The Myocardin-related transcription factor A [MRTFA, also known as
Megakaryoblastic Leukemia 1 (MKL1))] is a major actor in the epithelial
to mesenchymal transition (EMT). We have previously shown that
activation and nuclear accumulation of MRTFA mediate endocrine
resistance of estrogen receptor alpha (ER alpha) positive breast cancers
by initiating a partial transition from luminal to basal-like phenotype
and impairing ER alpha cistrome and transcriptome. In the present study,
we deepen our understanding of the mechanism by monitoring functional
changes in the receptor's activity. We demonstrate that MRTFA nuclear
accumulation down-regulates the expression of the unliganded (Apo-)ER
alpha and causes a redistribution of the protein localization from its
normal nuclear place to the entire cell volume. This phenomenon is
accompanied by a shift in Apo-ER alpha monomer/dimer ratio towards the
monomeric state, leading to significant functional consequences on ER
alpha activities. In particular, the association of Apo-ER alpha with
chromatin is drastically decreased, and the remaining ER alpha binding
sites are substantially less enriched in ERE motifs than in control
conditions. Monitored by proximity Ligation Assay, ER alpha interactions
with P160 family coactivators are partly impacted when MRTFA accumulates
in the nucleus, and those with SMRT and NCOR1 corepressors are
abolished. Finally, ER alpha interactions with kinases such as c-src and
PI3K are increased, thereby enhancing MAP Kinase and AKT activities. In
conclusion, the activation and nuclear accumulation of MRTFA in ER alpha
positive breast cancer cells remodels both ER alpha location and
functions by shifting its activity from nuclear genome regulation to
extra-nuclear non-genomic signaling. |
Richalet, Jean-Paul; Pillard, Fabien; Moal, David Le; Riviere, Daniel; Oriol, Philippe; Poussel, Mathias; Chenuel, Bruno; Doutreleau, Stephane; Verges, Samuel; Demanez, Sophie; Vergnion, Michel; Boulet, Jean-Michel; Douard, Herve; Dupre, Maryse; Mesland, Olivier; Remetter, Romain; Lonsdorfer-Wolf, Evelyne; Frey, Alain; Vilcoq, Louis; Jaffuel, Anne Nedelec; Debeaumont, David; Duperrex, Guy; Lecoq, Francois; Hedon, Christophe; Hayot, Maurice; Giardini, Guido; Lhuissier, Francois J Validation of a Score for the Detection of Subjects with High Risk for
Severe High-Altitude Illness Article de journal Dans: MEDICINE AND SCIENCE IN SPORTS AND EXERCISE, vol. 53, no. 6, p. 1294-1302, 2021, ISSN: 0195-9131. @article{ISI:000650003400022,
title = {Validation of a Score for the Detection of Subjects with High Risk for
Severe High-Altitude Illness},
author = {Jean-Paul Richalet and Fabien Pillard and David Le Moal and Daniel Riviere and Philippe Oriol and Mathias Poussel and Bruno Chenuel and Stephane Doutreleau and Samuel Verges and Sophie Demanez and Michel Vergnion and Jean-Michel Boulet and Herve Douard and Maryse Dupre and Olivier Mesland and Romain Remetter and Evelyne Lonsdorfer-Wolf and Alain Frey and Louis Vilcoq and Anne Nedelec Jaffuel and David Debeaumont and Guy Duperrex and Francois Lecoq and Christophe Hedon and Maurice Hayot and Guido Giardini and Francois J Lhuissier},
doi = {10.1249/MSS.0000000000002586},
issn = {0195-9131},
year = {2021},
date = {2021-06-01},
journal = {MEDICINE AND SCIENCE IN SPORTS AND EXERCISE},
volume = {53},
number = {6},
pages = {1294-1302},
abstract = {Purpose
A decision tree based on a clinicophysiological score (severe
high-altitude illness (SHAI) score) has been developed to detect
subjects susceptible to SHAI. We aimed to validate this decision tree,
to rationalize the prescription of acetazolamide (ACZ), and to specify
the rule for a progressive acclimatization. Methods
Data were obtained from 641 subjects in 15 European medical centers
before and during a sojourn at high altitude. Depending on the value of
the SHAI score, advice was given and ACZ was eventually prescribed. The
outcome was the occurrence of SHAI at high altitude as a function of the
SHAI score, ACZ prescription, and use and fulfillment of the
acclimatization rule. Results
The occurrence of SHAI was 22.6%, similar to what was observed 18 yr
before (23.7%), whereas life-threatening forms of SHAI (high-altitude pulmonary and cerebral edema) were less frequent (2.6%-0.8%},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Purpose
A decision tree based on a clinicophysiological score (severe
high-altitude illness (SHAI) score) has been developed to detect
subjects susceptible to SHAI. We aimed to validate this decision tree,
to rationalize the prescription of acetazolamide (ACZ), and to specify
the rule for a progressive acclimatization. Methods
Data were obtained from 641 subjects in 15 European medical centers
before and during a sojourn at high altitude. Depending on the value of
the SHAI score, advice was given and ACZ was eventually prescribed. The
outcome was the occurrence of SHAI at high altitude as a function of the
SHAI score, ACZ prescription, and use and fulfillment of the
acclimatization rule. Results
The occurrence of SHAI was 22.6%, similar to what was observed 18 yr
before (23.7%), whereas life-threatening forms of SHAI (high-altitude pulmonary and cerebral edema) were less frequent (2.6%-0.8% |
Anquetil, Typhaine; Solinhac, Romain; Jaffre, Aude; Chicanne, Gaetan; Viaud, Julien; Darcourt, Jean; Orset, Cyrille; Geuss, Eva; Kleinschnitz, Christoph; Vanhaesebroeck, Bart; Vivien, Denis; Hnia, Karim; Larrue, Vincent; Payrastre, Bernard; Gratacap, Marie-Pierre PI3KC2 beta inactivation stabilizes VE-cadherin junctions and preserves
vascular integrity Article de journal Dans: EMBO REPORTS, vol. 22, no. 6, 2021, ISSN: 1469-221X. @article{ISI:000641611600001,
title = {PI3KC2 beta inactivation stabilizes VE-cadherin junctions and preserves
vascular integrity},
author = {Typhaine Anquetil and Romain Solinhac and Aude Jaffre and Gaetan Chicanne and Julien Viaud and Jean Darcourt and Cyrille Orset and Eva Geuss and Christoph Kleinschnitz and Bart Vanhaesebroeck and Denis Vivien and Karim Hnia and Vincent Larrue and Bernard Payrastre and Marie-Pierre Gratacap},
doi = {10.15252/embr.202051299, Early Access Date = APR 2021},
issn = {1469-221X},
year = {2021},
date = {2021-06-01},
journal = {EMBO REPORTS},
volume = {22},
number = {6},
abstract = {Endothelium protection is critical, because of the impact of vascular
leakage and edema on pathological conditions such as brain ischemia.
Whereas deficiency of class II phosphoinositide 3-kinase alpha (PI3KC2
alpha) results in an increase in vascular permeability, we uncover a
crucial role of the beta isoform (PI3KC2 beta) in the loss of
endothelial barrier integrity following injury. Here, we studied the
role of PI3KC2 beta in endothelial permeability and endosomal
trafficking in vitro and in vivo in ischemic stroke. Mice with inactive
PI3KC2 beta showed protection against vascular permeability, edema,
cerebral infarction, and deleterious inflammatory response. Loss of
PI3KC2 beta in human cerebral microvascular endothelial cells stabilized
homotypic cell-cell junctions by increasing Rab11-dependent VE-cadherin
recycling. These results identify PI3KC2 beta as a potential new
therapeutic target to prevent aggravating lesions following ischemic
stroke.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Endothelium protection is critical, because of the impact of vascular
leakage and edema on pathological conditions such as brain ischemia.
Whereas deficiency of class II phosphoinositide 3-kinase alpha (PI3KC2
alpha) results in an increase in vascular permeability, we uncover a
crucial role of the beta isoform (PI3KC2 beta) in the loss of
endothelial barrier integrity following injury. Here, we studied the
role of PI3KC2 beta in endothelial permeability and endosomal
trafficking in vitro and in vivo in ischemic stroke. Mice with inactive
PI3KC2 beta showed protection against vascular permeability, edema,
cerebral infarction, and deleterious inflammatory response. Loss of
PI3KC2 beta in human cerebral microvascular endothelial cells stabilized
homotypic cell-cell junctions by increasing Rab11-dependent VE-cadherin
recycling. These results identify PI3KC2 beta as a potential new
therapeutic target to prevent aggravating lesions following ischemic
stroke. |
Gallez, Anne; Blacher, Silvia; Maquoi, Erik; Konradowski, Erika; Joiret, Marc; Primac, Irina; Gerard, Celine; Taziaux, Melanie; Houtman, Rene; Geris, Liesbet; Lenfant, Francoise; Marangoni, Elisabetta; Sounni, Nor Eddine; Foidart, Jean-Michel; Noel, Agnes; Pequeux, Christel Estetrol Combined to Progestogen for Menopause or Contraception
Indication Is Neutral on Breast Cancer Article de journal Dans: CANCERS, vol. 13, no. 10, 2021. @article{ISI:000654668500001,
title = {Estetrol Combined to Progestogen for Menopause or Contraception
Indication Is Neutral on Breast Cancer},
author = {Anne Gallez and Silvia Blacher and Erik Maquoi and Erika Konradowski and Marc Joiret and Irina Primac and Celine Gerard and Melanie Taziaux and Rene Houtman and Liesbet Geris and Francoise Lenfant and Elisabetta Marangoni and Nor Eddine Sounni and Jean-Michel Foidart and Agnes Noel and Christel Pequeux},
doi = {10.3390/cancers13102486},
year = {2021},
date = {2021-05-01},
journal = {CANCERS},
volume = {13},
number = {10},
abstract = {Simple Summary
Hormonal treatments, especially those used to treat menopause symptoms
are known to increase breast cancer risk. It is thus necessary to
identify new formulations with a better benefit/risk profile. The aim of
this translational study was to evaluate the breast cancer risk
associated with a combination of a natural estrogen named estetrol, with
progestogens such as natural progesterone and drospirenone. Since the
assessment of breast cancer risk in patients during drug development is
not possible given the requirement of long-term studies in large
populations, this study provides new evidence that a therapeutic dose of
estetrol for menopause treatment or contraception, combined with
progesterone or drospirenone, may provide a better benefit/risk profile
toward breast cancer risk compared to the hormonal treatments currently
available for patients.
Given the unequivocal benefits of menopause hormone therapies (MHT) and
combined oral contraceptives (COC), there is a clinical need for new
formulations devoid of any risk of breast cancer promotion. Accumulating
data from preclinical and clinical studies support that estetrol (E4) is
a promising natural estrogen for MHT and COC. Nevertheless, we report
here that E4 remains active on the endometrium, even under a dose that
is neutral on breast cancer growth and lung metastasis dissemination.
This implies that a progestogen should be combined with E4 to protect
the endometrium of non-hysterectomized women from hyperplasia and
cancer. Through in vivo observations and transcriptomic analyses, our
work provides evidence that combining a progestogen to E4 is neutral on
breast cancer growth and dissemination, with very limited
transcriptional impact. The assessment of breast cancer risk in patients
during the development of new MHT or COC is not possible given the
requirement of long-term studies in large populations. This
translational preclinical research provides new evidence that a
therapeutic dose of E4 for MHT or COC, combined with progesterone or
drospirenone, may provide a better benefit/risk profile towards breast
cancer risk compared to hormonal treatments currently available for
patients.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Simple Summary
Hormonal treatments, especially those used to treat menopause symptoms
are known to increase breast cancer risk. It is thus necessary to
identify new formulations with a better benefit/risk profile. The aim of
this translational study was to evaluate the breast cancer risk
associated with a combination of a natural estrogen named estetrol, with
progestogens such as natural progesterone and drospirenone. Since the
assessment of breast cancer risk in patients during drug development is
not possible given the requirement of long-term studies in large
populations, this study provides new evidence that a therapeutic dose of
estetrol for menopause treatment or contraception, combined with
progesterone or drospirenone, may provide a better benefit/risk profile
toward breast cancer risk compared to the hormonal treatments currently
available for patients.
Given the unequivocal benefits of menopause hormone therapies (MHT) and
combined oral contraceptives (COC), there is a clinical need for new
formulations devoid of any risk of breast cancer promotion. Accumulating
data from preclinical and clinical studies support that estetrol (E4) is
a promising natural estrogen for MHT and COC. Nevertheless, we report
here that E4 remains active on the endometrium, even under a dose that
is neutral on breast cancer growth and lung metastasis dissemination.
This implies that a progestogen should be combined with E4 to protect
the endometrium of non-hysterectomized women from hyperplasia and
cancer. Through in vivo observations and transcriptomic analyses, our
work provides evidence that combining a progestogen to E4 is neutral on
breast cancer growth and dissemination, with very limited
transcriptional impact. The assessment of breast cancer risk in patients
during the development of new MHT or COC is not possible given the
requirement of long-term studies in large populations. This
translational preclinical research provides new evidence that a
therapeutic dose of E4 for MHT or COC, combined with progesterone or
drospirenone, may provide a better benefit/risk profile towards breast
cancer risk compared to hormonal treatments currently available for
patients. |
Tremollieres, F; Chabbert-Buffet, N; Plu-Bureau, G; Rousset-Jablonski, C; Lecerf, J-M; Duclos, M; Pouilles, J-M; Gosset, A; Boutet, G; Hocke, C; Maris, E; Hugon-Rodin, J; Maitrot-Mantelet, L; Robin, G; Andre, G; Hamdaoui, N; Mathelin, C; Lopes, P; Graesslin, O; Fritel, X Postmenopausal women management: CNGOF and GEMVi clinical practice
guidelines (Short version) Article de journal Dans: GYNECOLOGIE OBSTETRIQUE FERTILITE & SENOLOGIE, vol. 49, no. 5, p. 305-317, 2021, ISSN: 2468-7197. @article{ISI:000653091300001,
title = {Postmenopausal women management: CNGOF and GEMVi clinical practice
guidelines (Short version)},
author = {F Tremollieres and N Chabbert-Buffet and G Plu-Bureau and C Rousset-Jablonski and J-M Lecerf and M Duclos and J-M Pouilles and A Gosset and G Boutet and C Hocke and E Maris and J Hugon-Rodin and L Maitrot-Mantelet and G Robin and G Andre and N Hamdaoui and C Mathelin and P Lopes and O Graesslin and X Fritel},
doi = {10.1016/j.gofs.2021.03.010},
issn = {2468-7197},
year = {2021},
date = {2021-05-01},
journal = {GYNECOLOGIE OBSTETRIQUE FERTILITE & SENOLOGIE},
volume = {49},
number = {5},
pages = {305-317},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Gosset, A; Robin, G; Letombe, B; Pouilles, J-M; Tremollieres, F Menopause hormone treatment. Postmenopausal women management : CNGOF and
GEMVi clinical practice guidelines Article de journal Dans: GYNECOLOGIE OBSTETRIQUE FERTILITE & SENOLOGIE, vol. 49, no. 5, p. 358-372, 2021, ISSN: 2468-7197. @article{ISI:000653091300006,
title = {Menopause hormone treatment. Postmenopausal women management : CNGOF and
GEMVi clinical practice guidelines},
author = {A Gosset and G Robin and B Letombe and J-M Pouilles and F Tremollieres},
doi = {10.1016/j.gofs.2021.03.019},
issn = {2468-7197},
year = {2021},
date = {2021-05-01},
journal = {GYNECOLOGIE OBSTETRIQUE FERTILITE & SENOLOGIE},
volume = {49},
number = {5},
pages = {358-372},
abstract = {Menopause Hormonal Treatment (MHT) was initially developed to correct
the climacteric symptoms induced by postmenopausal estrogen deficiency.
In non-hysterectomized women, MHT combines estrogens and a progestogen,
the latter opposing the negative impact of estrogen on endometrial
proliferation. In France, and contrary to the USA and Northern European
countries, MHT mainly combines 1713-estradiol, which is the
physiological estrogen produced by the ovary, and progesterone or its
derivative, dihydrogesterone. France has been a pioneer in the
development of cutaneous administration routes (gel or transdermal
patch) for estradiol, allowing better metabolic tolerance and a
reduction of the risk of venous thromboembolism compared to the oral
route. The choice of the doses as well as the treatment regimen is
underpinned by tolerance as well as acceptance and compliance. The risk
of breast cancer, which is one of the main risks of MHT, is higher with
estro-progestogen combinations than with estrogens alone ; the
preferential use of progesterone or dihydrogesterone being likely to
limit the excess risk of breast cancer associated with MHT at least for
duration of treatment of less than 5 to 7 years. The question of the
optimal duration of MHT remains an issue and must take into account the
initial indication of treatment as well as the benefit-risk balance,
which is specific to each woman. Continuation of MHT is conditioned by
the benefit-risk balance, which must be evaluated regularly, but also by
the evolution of symptoms when MHT is stopped as well as
menopause-related health risks or induced by MHT. After stopping MHT, it
is necessary to maintain a medical follow-up to be adapted to the
clinical situation of each woman and in particular, her cardiovascular
and gynecological risk factors. (C) 2021 Elsevier Masson SAS. All rights
reserved.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Menopause Hormonal Treatment (MHT) was initially developed to correct
the climacteric symptoms induced by postmenopausal estrogen deficiency.
In non-hysterectomized women, MHT combines estrogens and a progestogen,
the latter opposing the negative impact of estrogen on endometrial
proliferation. In France, and contrary to the USA and Northern European
countries, MHT mainly combines 1713-estradiol, which is the
physiological estrogen produced by the ovary, and progesterone or its
derivative, dihydrogesterone. France has been a pioneer in the
development of cutaneous administration routes (gel or transdermal
patch) for estradiol, allowing better metabolic tolerance and a
reduction of the risk of venous thromboembolism compared to the oral
route. The choice of the doses as well as the treatment regimen is
underpinned by tolerance as well as acceptance and compliance. The risk
of breast cancer, which is one of the main risks of MHT, is higher with
estro-progestogen combinations than with estrogens alone ; the
preferential use of progesterone or dihydrogesterone being likely to
limit the excess risk of breast cancer associated with MHT at least for
duration of treatment of less than 5 to 7 years. The question of the
optimal duration of MHT remains an issue and must take into account the
initial indication of treatment as well as the benefit-risk balance,
which is specific to each woman. Continuation of MHT is conditioned by
the benefit-risk balance, which must be evaluated regularly, but also by
the evolution of symptoms when MHT is stopped as well as
menopause-related health risks or induced by MHT. After stopping MHT, it
is necessary to maintain a medical follow-up to be adapted to the
clinical situation of each woman and in particular, her cardiovascular
and gynecological risk factors. (C) 2021 Elsevier Masson SAS. All rights
reserved. |
Pouilles, J-M; Gosset, A; Tremollieres, F Menopause, menopause hormone therapy and osteoporosis. Postmenopausal
women management : CNGOF and GEMVi clinical practice guidelines Article de journal Dans: GYNECOLOGIE OBSTETRIQUE FERTILITE & SENOLOGIE, vol. 49, no. 5, p. 420-437, 2021, ISSN: 2468-7197. @article{ISI:000653091300010,
title = {Menopause, menopause hormone therapy and osteoporosis. Postmenopausal
women management : CNGOF and GEMVi clinical practice guidelines},
author = {J-M Pouilles and A Gosset and F Tremollieres},
doi = {10.1016/j.gofs.2021.03.015},
issn = {2468-7197},
year = {2021},
date = {2021-05-01},
journal = {GYNECOLOGIE OBSTETRIQUE FERTILITE & SENOLOGIE},
volume = {49},
number = {5},
pages = {420-437},
abstract = {Postmenopausal osteoporosis is a frequent clinical condition, which
affects nearly 1 in 3 women. Estrogen deficiency leads to rapid bone
loss, which is maximal within the first years after the menopause
transition and can be prevented by menopause hormone therapy (MHT).
Assessment of the individual risk of osteoporosis is primarily based on
the measurement of bone mineral density (BMD) at the spine and femur by
DXA. Clinical risk factors (CRFs) for fractures taken either alone or in
combination in the FRAX score were shown not to reliably predict
fractures and/or osteoporosis (as defined by a T-score <-2.5) in early
postmenopausal women. If DXA measurement is indicated in all women with
CRFs for fractures, it can be proposed on a case-by-case basis, when
knowledge of BMD is likely to condition the management of women at the
beginning of menopause, particularly the benefit-risk balance of MHT.
MHT prevents both bone loss and degradation of the bone
microarchitecture in early menopause. It significantly reduces the risk
of fracture at all bone sites by 20 to 40% regardless of basal level of
risk with an estrogen-dependent dose-effect. Given the inter-individual
variability in bone response, individual monitoring of the bone effect
of MHT is warranted when prescribed for the prevention of osteoporosis.
This monitoring is based on repeated measurement of lumbar and femoral
BMD (on the same DXA measurement system) after 2 years of MHT, the
response criterion being no significant bone loss. Discontinuation of
treatment is associated with a resumption of transient bone loss
although there is a large variability in the rate of bone loss among
women. Basically, there is a return to the level of fracture risk
comparable to that of in untreated woman of the same age within 2 to 5
years. Therefore, when MHT is prescribed for the prevention of
osteoporosis in women with an increased risk at the beginning of
menopause, measurement of BMD is recommended when MHT is stopped in
order to consider further management of the risk of fracture whenever
necessary (with possibly another antiosteoporotic treatment). (C) 2021
Elsevier Masson SAS. All rights reserved.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Postmenopausal osteoporosis is a frequent clinical condition, which
affects nearly 1 in 3 women. Estrogen deficiency leads to rapid bone
loss, which is maximal within the first years after the menopause
transition and can be prevented by menopause hormone therapy (MHT).
Assessment of the individual risk of osteoporosis is primarily based on
the measurement of bone mineral density (BMD) at the spine and femur by
DXA. Clinical risk factors (CRFs) for fractures taken either alone or in
combination in the FRAX score were shown not to reliably predict
fractures and/or osteoporosis (as defined by a T-score <-2.5) in early
postmenopausal women. If DXA measurement is indicated in all women with
CRFs for fractures, it can be proposed on a case-by-case basis, when
knowledge of BMD is likely to condition the management of women at the
beginning of menopause, particularly the benefit-risk balance of MHT.
MHT prevents both bone loss and degradation of the bone
microarchitecture in early menopause. It significantly reduces the risk
of fracture at all bone sites by 20 to 40% regardless of basal level of
risk with an estrogen-dependent dose-effect. Given the inter-individual
variability in bone response, individual monitoring of the bone effect
of MHT is warranted when prescribed for the prevention of osteoporosis.
This monitoring is based on repeated measurement of lumbar and femoral
BMD (on the same DXA measurement system) after 2 years of MHT, the
response criterion being no significant bone loss. Discontinuation of
treatment is associated with a resumption of transient bone loss
although there is a large variability in the rate of bone loss among
women. Basically, there is a return to the level of fracture risk
comparable to that of in untreated woman of the same age within 2 to 5
years. Therefore, when MHT is prescribed for the prevention of
osteoporosis in women with an increased risk at the beginning of
menopause, measurement of BMD is recommended when MHT is stopped in
order to consider further management of the risk of fracture whenever
necessary (with possibly another antiosteoporotic treatment). (C) 2021
Elsevier Masson SAS. All rights reserved. |
Montfort, Anne; Bertrand, Florie; Rochotte, Julia; Gilhodes, Julia; Filleron, Thomas; Milhes, Jean; Dufau, Carine; Imbert, Caroline; Riond, Joelle; Tosolini, Marie; Clarke, Christopher J; Dufour, Florent; Constantinescu, Andrei A; Junior, Nilton De Franca; Garcia, Virginie; Record, Michel; Cordelier, Pierre; Brousset, Pierre; Rochaix, Philippe; Silvente-Poirot, Sandrine; Therville, Nicole; Andrieu-Abadie, Nathalie; Levade, Thierry; Hannun, Yusuf A; Benoist, Herve; Meyer, Nicolas; Micheau, Olivier; Colacios, Celine; Segui, Bruno Neutral Sphingomyelinase 2 Heightens Anti-Melanoma Immune Responses and
Anti-PD-1 Therapy Efficacy Article de journal Dans: CANCER IMMUNOLOGY RESEARCH, vol. 9, no. 5, p. 568-582, 2021, ISSN: 2326-6066. @article{ISI:000647314900009,
title = {Neutral Sphingomyelinase 2 Heightens Anti-Melanoma Immune Responses and
Anti-PD-1 Therapy Efficacy},
author = {Anne Montfort and Florie Bertrand and Julia Rochotte and Julia Gilhodes and Thomas Filleron and Jean Milhes and Carine Dufau and Caroline Imbert and Joelle Riond and Marie Tosolini and Christopher J Clarke and Florent Dufour and Andrei A Constantinescu and Nilton De Franca Junior and Virginie Garcia and Michel Record and Pierre Cordelier and Pierre Brousset and Philippe Rochaix and Sandrine Silvente-Poirot and Nicole Therville and Nathalie Andrieu-Abadie and Thierry Levade and Yusuf A Hannun and Herve Benoist and Nicolas Meyer and Olivier Micheau and Celine Colacios and Bruno Segui},
doi = {10.1158/2326-6066.CIR-20-0342},
issn = {2326-6066},
year = {2021},
date = {2021-05-01},
journal = {CANCER IMMUNOLOGY RESEARCH},
volume = {9},
number = {5},
pages = {568-582},
abstract = {Dysregulation of lipid metabolism affects the behavior of cancer cells,
but how this happens is not completely understood. Neutral
sphingomyelinase 2 (nSMase2), encoded by SMPD3, catalyzes the breakdown
of sphingomyelin to produce the anti-oncometabolite ceramide. We found
that this enzyme was often downregulated in human metastatic melanoma,
likely contributing to immune escape. Overexpression of nSMase2 in mouse
melanoma reduced tumor growth in syngeneic wild-type but not
CD8-deficient mice. In wild-type mice, nSMase2-overexpressing tumors
showed accumulation of both ceramide and CD8(+) tumor-infiltrating
lymphocytes, and this was associated with increased level of transcripts
encoding IFN gamma and CXCL9. Overexpressing the catalytically inactive
nSMase2 failed to alter tumor growth, indicating that the deleterious
effect nSMase2 has on melanoma growth depends on its enzymatic activity.
In vitro, small extracellular vesicles from melanoma cells
overexpressing wild-type nSMase2 augmented the expression of IL12,
CXCL9, and CCL19 by bone marrow-derived dendritic cells, suggesting that
melanoma nSMase2 triggers T helper 1 (Th1) polarization in the earliest
stages of the immune response. Most importantly, overexpression of
wild-type nSMase2 increased anti-PD-1 efficacy in murine models of
melanoma and breast cancer, and this was associated with an enhanced Th1
response. Therefore, increasing SMPD3 expression in melanoma may serve
as an original therapeutic strategy to potentiate Th1 polarization and
CD8(+) T-cell-dependent immune responses and overcome resistance to
anti-PD-1.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Dysregulation of lipid metabolism affects the behavior of cancer cells,
but how this happens is not completely understood. Neutral
sphingomyelinase 2 (nSMase2), encoded by SMPD3, catalyzes the breakdown
of sphingomyelin to produce the anti-oncometabolite ceramide. We found
that this enzyme was often downregulated in human metastatic melanoma,
likely contributing to immune escape. Overexpression of nSMase2 in mouse
melanoma reduced tumor growth in syngeneic wild-type but not
CD8-deficient mice. In wild-type mice, nSMase2-overexpressing tumors
showed accumulation of both ceramide and CD8(+) tumor-infiltrating
lymphocytes, and this was associated with increased level of transcripts
encoding IFN gamma and CXCL9. Overexpressing the catalytically inactive
nSMase2 failed to alter tumor growth, indicating that the deleterious
effect nSMase2 has on melanoma growth depends on its enzymatic activity.
In vitro, small extracellular vesicles from melanoma cells
overexpressing wild-type nSMase2 augmented the expression of IL12,
CXCL9, and CCL19 by bone marrow-derived dendritic cells, suggesting that
melanoma nSMase2 triggers T helper 1 (Th1) polarization in the earliest
stages of the immune response. Most importantly, overexpression of
wild-type nSMase2 increased anti-PD-1 efficacy in murine models of
melanoma and breast cancer, and this was associated with an enhanced Th1
response. Therefore, increasing SMPD3 expression in melanoma may serve
as an original therapeutic strategy to potentiate Th1 polarization and
CD8(+) T-cell-dependent immune responses and overcome resistance to
anti-PD-1. |
Guerby, Paul; Tasta, Oriane; Swiader, Audrey; Pont, Frederic; Bujold, Emmanuel; Parant, Olivier; Vayssiere, Christophe; Salvayre, Robert; Negre-Salvayre, Anne Role of oxidative stress in the dysfunction of the placental endothelial
nitric oxide synthase in preeclampsia Article de journal Dans: REDOX BIOLOGY, vol. 40, 2021, ISSN: 2213-2317. @article{ISI:000621105900003,
title = {Role of oxidative stress in the dysfunction of the placental endothelial
nitric oxide synthase in preeclampsia},
author = {Paul Guerby and Oriane Tasta and Audrey Swiader and Frederic Pont and Emmanuel Bujold and Olivier Parant and Christophe Vayssiere and Robert Salvayre and Anne Negre-Salvayre},
doi = {10.1016/j.redox.2021.101861},
issn = {2213-2317},
year = {2021},
date = {2021-04-01},
journal = {REDOX BIOLOGY},
volume = {40},
abstract = {Preeclampsia (PE) is a multifactorial pregnancy disease, characterized
by new-onset gestational hypertension with (or without) proteinuria or
end-organ failure, exclusively observed in humans. It is a leading cause
of maternal morbidity affecting 3-7% of pregnant women worldwide. PE
pathophysiology could result from abnormal placentation due to a
defective trophoblastic invasion and an impaired remodeling of uterine
spiral arteries, leading to a poor adaptation of utero-placental
circulation. This would be associated with hypoxia/reoxygenation
phenomena, oxygen gradient fluctuations, altered antioxidant capacity,
oxidative stress, and reduced nitric oxide (NO) bioavailability. This
results in part from the reaction of NO with the radical anion
superoxide (O-2(center dot-)), which produces peroxynitrite ONOO-, a
powerful pro-oxidant and inflammatory agent. Another mechanism is the
progressive inhibition of the placental endothelial nitric oxide
synthase (eNOS) by oxidative stress, which results in eNOS uncoupling
via several events such as a depletion of the eNOS substrate Larginine
due to increased arginase activity, an oxidation of the eNOS cofactor
tetrahydrobiopterin (BH4), or eNOS post-translational modifications (for
instance by S-glutathionylation). The uncoupling of eNOS triggers a
switch of its activity from a NO-producing enzyme to a NADPH
oxidase-like system generating O-2(center dot-), thereby potentiating
ROS production and oxidative stress. Moreover, in PE placentas, eNOS
could be post-translationally modified by lipid peroxidation-derived
aldehydes such as 4-oxononenal (ONE) a highly bioreactive agent, able to
inhibit eNOS activity and NO production. This review summarizes the
dysfunction of placental eNOS evoked by oxidative stress and lipid
peroxidation products, and the potential consequences on PE
pathogenesis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Preeclampsia (PE) is a multifactorial pregnancy disease, characterized
by new-onset gestational hypertension with (or without) proteinuria or
end-organ failure, exclusively observed in humans. It is a leading cause
of maternal morbidity affecting 3-7% of pregnant women worldwide. PE
pathophysiology could result from abnormal placentation due to a
defective trophoblastic invasion and an impaired remodeling of uterine
spiral arteries, leading to a poor adaptation of utero-placental
circulation. This would be associated with hypoxia/reoxygenation
phenomena, oxygen gradient fluctuations, altered antioxidant capacity,
oxidative stress, and reduced nitric oxide (NO) bioavailability. This
results in part from the reaction of NO with the radical anion
superoxide (O-2(center dot-)), which produces peroxynitrite ONOO-, a
powerful pro-oxidant and inflammatory agent. Another mechanism is the
progressive inhibition of the placental endothelial nitric oxide
synthase (eNOS) by oxidative stress, which results in eNOS uncoupling
via several events such as a depletion of the eNOS substrate Larginine
due to increased arginase activity, an oxidation of the eNOS cofactor
tetrahydrobiopterin (BH4), or eNOS post-translational modifications (for
instance by S-glutathionylation). The uncoupling of eNOS triggers a
switch of its activity from a NO-producing enzyme to a NADPH
oxidase-like system generating O-2(center dot-), thereby potentiating
ROS production and oxidative stress. Moreover, in PE placentas, eNOS
could be post-translationally modified by lipid peroxidation-derived
aldehydes such as 4-oxononenal (ONE) a highly bioreactive agent, able to
inhibit eNOS activity and NO production. This review summarizes the
dysfunction of placental eNOS evoked by oxidative stress and lipid
peroxidation products, and the potential consequences on PE
pathogenesis. |
Martinelli, Ilenia; Timotin, Andrei; Moreno-Corchado, Paula; Marsal, Dimitri; Kramar, Solomiia; Loy, Halina; Joffre, Carine; Boal, Frederic; Tronchere, Helene; Kunduzova, Oksana Galanin promotes autophagy and alleviates apoptosis in the hypertrophied
heart through FoxO1 pathway Article de journal Dans: REDOX BIOLOGY, vol. 40, 2021, ISSN: 2213-2317. @article{ISI:000621104800004,
title = {Galanin promotes autophagy and alleviates apoptosis in the hypertrophied
heart through FoxO1 pathway},
author = {Ilenia Martinelli and Andrei Timotin and Paula Moreno-Corchado and Dimitri Marsal and Solomiia Kramar and Halina Loy and Carine Joffre and Frederic Boal and Helene Tronchere and Oksana Kunduzova},
doi = {10.1016/j.redox.2021.101866},
issn = {2213-2317},
year = {2021},
date = {2021-04-01},
journal = {REDOX BIOLOGY},
volume = {40},
abstract = {Autophagy and apoptosis are powerful regulators of multiple facets of
cellular metabolism and homeostasis. Here, we uncover that galanin, a
pleiotropic peptide, regulates cardiac autophagy and deactivates
apoptotic cell death through the Forkhead box protein O1 (FoxO1)
pathway. In hypertrophied heart, galanin promotes autophagy and
metabolic shift from fatty acid (FA) to glucose oxidation and preserves
mitochondrial integrity. In cardiomyoblasts, galanin triggers
autophagosome formation and alleviates hypertrophy, apoptotic cell
death, and mitochondrial stress. Mechanistically, galanin dictates cell
autophagic and anti-apoptotic phenotypes through FoxO1 pathway.
Together, these findings uncover a previously unknown role for galanin
in the regulation of cardiac autophagy and provide new insights into the
molecular mechanisms supporting cell survival in the hypertrophic
reprogramming of the heart.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Autophagy and apoptosis are powerful regulators of multiple facets of
cellular metabolism and homeostasis. Here, we uncover that galanin, a
pleiotropic peptide, regulates cardiac autophagy and deactivates
apoptotic cell death through the Forkhead box protein O1 (FoxO1)
pathway. In hypertrophied heart, galanin promotes autophagy and
metabolic shift from fatty acid (FA) to glucose oxidation and preserves
mitochondrial integrity. In cardiomyoblasts, galanin triggers
autophagosome formation and alleviates hypertrophy, apoptotic cell
death, and mitochondrial stress. Mechanistically, galanin dictates cell
autophagic and anti-apoptotic phenotypes through FoxO1 pathway.
Together, these findings uncover a previously unknown role for galanin
in the regulation of cardiac autophagy and provide new insights into the
molecular mechanisms supporting cell survival in the hypertrophic
reprogramming of the heart. |
Labaste, Francois; Rey, Valentin; Gonzalez, Helene; Marcheix, Bertrand; Fourcade, Olivier; Minville, Vincent AnaConDa Device: Solution to Perform Cardiac Surgery Without Intravenous
Anesthetic During the Corona Virus Disease 2019 Pandemic Article de journal Dans: JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA, vol. 35, no. 4, p. 1267-1268, 2021, ISSN: 1053-0770. @article{ISI:000623262300050,
title = {AnaConDa Device: Solution to Perform Cardiac Surgery Without Intravenous
Anesthetic During the Corona Virus Disease 2019 Pandemic},
author = {Francois Labaste and Valentin Rey and Helene Gonzalez and Bertrand Marcheix and Olivier Fourcade and Vincent Minville},
doi = {10.1053/j.jvca.2020.09.121},
issn = {1053-0770},
year = {2021},
date = {2021-04-01},
journal = {JOURNAL OF CARDIOTHORACIC AND VASCULAR ANESTHESIA},
volume = {35},
number = {4},
pages = {1267-1268},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
Briand, Francois; Maupoint, Julie; Brousseau, Emmanuel; Breyner, Natalia; Bouchet, Melanie; Costard, Clement; Leste-Lasserre, Thierry; Petitjean, Mathieu; Chen, Li; Chabrat, Audrey; Richard, Virgile; Burcelin, Remy; Dubroca, Caroline; Sulpice, Thierry Elafibranor improves diet-induced nonalcoholic steatohepatitis
associated with heart failure with preserved ejection fraction in Golden
Syrian hamsters Article de journal Dans: METABOLISM-CLINICAL AND EXPERIMENTAL, vol. 117, 2021, ISSN: 0026-0495. @article{ISI:000632688100008,
title = {Elafibranor improves diet-induced nonalcoholic steatohepatitis
associated with heart failure with preserved ejection fraction in Golden
Syrian hamsters},
author = {Francois Briand and Julie Maupoint and Emmanuel Brousseau and Natalia Breyner and Melanie Bouchet and Clement Costard and Thierry Leste-Lasserre and Mathieu Petitjean and Li Chen and Audrey Chabrat and Virgile Richard and Remy Burcelin and Caroline Dubroca and Thierry Sulpice},
doi = {10.1016/j.metabol.2021.154707},
issn = {0026-0495},
year = {2021},
date = {2021-04-01},
journal = {METABOLISM-CLINICAL AND EXPERIMENTAL},
volume = {117},
abstract = {Background: Cardiovascular disease is the leading cause of deaths in
nonalcoholic steatohepatitis (NASH) patients. Mouse models, while widely
used for drug development, do not fully replicate human NASH nor
integrate the associated cardiac dysfunction, i.e. heart failure with
preserved ejection fraction (HFpEF). To overcome these limitations, we
established a nutritional hamster model developing both NASH and HFpEF.
We then evaluated the effects of the dual peroxisome proliferator
activated receptor alpha/delta agonist elafibranor developed for the
treatment of NASH patients.
Methods: Male Golden Syrian hamsters were fed for 10 to 20 weeks with a
free choice diet, which presents hamsters with a choice between control
chow diet with normal drinking water or a high fat/high cholesterol diet
with 10% fructose enriched drinking water. Biochemistry, histology and
echocardiography analysis were performed to characterize NASH and HFpEF.
Once the model was validated, elafibranor was evaluated at 15 mg/kg/day
orally QD for 5 weeks.
Results: Hamsters fed a free choice diet for up to 20 weeks developed
NASH, including hepatocyte ballooning (as confirmed with cytokeratin-18
immunostaining), bridging fibrosis, and a severe diastolic dysfunction
with restrictive profile, but preserved ejection fraction. Elafibranor
resolved NASH, with significant reduction in ballooning and fibrosis
scores, and improved diastolic dysfunction with significant reduction in
E/A and E/E ` ratios. Conclusion: Our data demonstrate that the free
choice diet induced NASH hamster model replicates the human phenotype
and will be useful for validating novel drug candidates for the
treatment of NASH and associated HFpEF.
(c) 2021 The Authors. Published by Elsevier Inc. This is an open access
article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Background: Cardiovascular disease is the leading cause of deaths in
nonalcoholic steatohepatitis (NASH) patients. Mouse models, while widely
used for drug development, do not fully replicate human NASH nor
integrate the associated cardiac dysfunction, i.e. heart failure with
preserved ejection fraction (HFpEF). To overcome these limitations, we
established a nutritional hamster model developing both NASH and HFpEF.
We then evaluated the effects of the dual peroxisome proliferator
activated receptor alpha/delta agonist elafibranor developed for the
treatment of NASH patients.
Methods: Male Golden Syrian hamsters were fed for 10 to 20 weeks with a
free choice diet, which presents hamsters with a choice between control
chow diet with normal drinking water or a high fat/high cholesterol diet
with 10% fructose enriched drinking water. Biochemistry, histology and
echocardiography analysis were performed to characterize NASH and HFpEF.
Once the model was validated, elafibranor was evaluated at 15 mg/kg/day
orally QD for 5 weeks.
Results: Hamsters fed a free choice diet for up to 20 weeks developed
NASH, including hepatocyte ballooning (as confirmed with cytokeratin-18
immunostaining), bridging fibrosis, and a severe diastolic dysfunction
with restrictive profile, but preserved ejection fraction. Elafibranor
resolved NASH, with significant reduction in ballooning and fibrosis
scores, and improved diastolic dysfunction with significant reduction in
E/A and E/E ` ratios. Conclusion: Our data demonstrate that the free
choice diet induced NASH hamster model replicates the human phenotype
and will be useful for validating novel drug candidates for the
treatment of NASH and associated HFpEF.
(c) 2021 The Authors. Published by Elsevier Inc. This is an open access
article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/). |
Vlahou, Antonia; Hallinan, Dara; Apweiler, Rolf; Argiles, Angel; Beige, Joachim; Benigni, Ariela; Bischoff, Rainer; Black, Peter C; Boehm, Franziska; Ceraline, Jocelyn; Chrousos, George P; Delles, Christian; Evenepoel, Pieter; Fridolin, Ivo; Glorieux, Griet; van Gool, Alain J; Heidegger, Isabel; Ioannidis, John P A; Jankowski, Joachim; Jankowski, Vera; Jeronimo, Carmen; Kamat, Ashish M; Masereeuw, Rosalinde; Mayer, Gert; Mischak, Harald; Ortiz, Alberto; Remuzzi, Giuseppe; Rossing, Peter; Schanstra, Joost P; Schmitz-Draeger, Bernd J; Spasovski, Goce; Staessen, Jan A; Stamatialis, Dimitrios; Stenvinkel, Peter; Wanner, Christoph; Williams, Stephen B; Zannad, Faiez; Zoccali, Carmine; Vanholder, Raymond Data Sharing Under the General Data Protection Regulation Time to
Harmonize Law and Research Ethics? Article de journal Dans: HYPERTENSION, vol. 77, no. 4, p. 1029-1035, 2021, ISSN: 0194-911X. @article{ISI:000639315900007,
title = {Data Sharing Under the General Data Protection Regulation Time to
Harmonize Law and Research Ethics?},
author = {Antonia Vlahou and Dara Hallinan and Rolf Apweiler and Angel Argiles and Joachim Beige and Ariela Benigni and Rainer Bischoff and Peter C Black and Franziska Boehm and Jocelyn Ceraline and George P Chrousos and Christian Delles and Pieter Evenepoel and Ivo Fridolin and Griet Glorieux and Alain J van Gool and Isabel Heidegger and John P A Ioannidis and Joachim Jankowski and Vera Jankowski and Carmen Jeronimo and Ashish M Kamat and Rosalinde Masereeuw and Gert Mayer and Harald Mischak and Alberto Ortiz and Giuseppe Remuzzi and Peter Rossing and Joost P Schanstra and Bernd J Schmitz-Draeger and Goce Spasovski and Jan A Staessen and Dimitrios Stamatialis and Peter Stenvinkel and Christoph Wanner and Stephen B Williams and Faiez Zannad and Carmine Zoccali and Raymond Vanholder},
doi = {10.1161/HYPERTENSIONAHA.120.16340},
issn = {0194-911X},
year = {2021},
date = {2021-04-01},
journal = {HYPERTENSION},
volume = {77},
number = {4},
pages = {1029-1035},
abstract = {The General Data Protection Regulation (GDPR) became binding law in the
European Union Member States in 2018, as a step toward harmonizing
personal data protection legislation in the European Union. The
Regulation governs almost all types of personal data processing, hence,
also, those pertaining to biomedical research. The purpose of this
article is to highlight the main practical issues related to data and
biological sample sharing that biomedical researchers face regularly,
and to specify how these are addressed in the context of GDPR, after
consulting with ethics/legal experts. We identify areas in which
clarifications of the GDPR are needed, particularly those related to
consent requirements by study participants. Amendments should target the
following: (1) restricting exceptions based on national laws and
increasing harmonization, (2) confirming the concept of broad consent,
and (3) defining a roadmap for secondary use of data. These changes will
be achieved by acknowledged learned societies in the field taking the
lead in preparing a document giving guidance for the optimal
interpretation of the GDPR, which will be finalized following a period
of commenting by a broad multistakeholder audience. In parallel,
promoting engagement and education of the public in the relevant issues
(such as different consent types or residual risk for
re-identification), on both local/national and international levels, is
considered critical for advancement. We hope that this article will open
this broad discussion involving all major stakeholders, toward
optimizing the GDPR and allowing a harmonized transnational research
approach.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The General Data Protection Regulation (GDPR) became binding law in the
European Union Member States in 2018, as a step toward harmonizing
personal data protection legislation in the European Union. The
Regulation governs almost all types of personal data processing, hence,
also, those pertaining to biomedical research. The purpose of this
article is to highlight the main practical issues related to data and
biological sample sharing that biomedical researchers face regularly,
and to specify how these are addressed in the context of GDPR, after
consulting with ethics/legal experts. We identify areas in which
clarifications of the GDPR are needed, particularly those related to
consent requirements by study participants. Amendments should target the
following: (1) restricting exceptions based on national laws and
increasing harmonization, (2) confirming the concept of broad consent,
and (3) defining a roadmap for secondary use of data. These changes will
be achieved by acknowledged learned societies in the field taking the
lead in preparing a document giving guidance for the optimal
interpretation of the GDPR, which will be finalized following a period
of commenting by a broad multistakeholder audience. In parallel,
promoting engagement and education of the public in the relevant issues
(such as different consent types or residual risk for
re-identification), on both local/national and international levels, is
considered critical for advancement. We hope that this article will open
this broad discussion involving all major stakeholders, toward
optimizing the GDPR and allowing a harmonized transnational research
approach. |
Gouyou, Baptiste; Ongaro, Tiziano; Cazzamalli, Samuele; Luca, Roberto De; Kerschenmeyer, Anne; Valet, Philippe; Villa, Alessandra; Neri, Dario; Matasci, Mattia Antibody-based delivery of interleukin-9 to neovascular structures:
Therapeutic evaluation in cancer and arthritis Article de journal Dans: EXPERIMENTAL BIOLOGY AND MEDICINE, vol. 246, no. 8, p. 940-951, 2021, ISSN: 1535-3702. @article{ISI:000637074600007,
title = {Antibody-based delivery of interleukin-9 to neovascular structures:
Therapeutic evaluation in cancer and arthritis},
author = {Baptiste Gouyou and Tiziano Ongaro and Samuele Cazzamalli and Roberto De Luca and Anne Kerschenmeyer and Philippe Valet and Alessandra Villa and Dario Neri and Mattia Matasci},
doi = {10.1177/1535370220981578},
issn = {1535-3702},
year = {2021},
date = {2021-04-01},
journal = {EXPERIMENTAL BIOLOGY AND MEDICINE},
volume = {246},
number = {8},
pages = {940-951},
abstract = {Interleukin-9 is a cytokine with multiple functions, including the
ability to activate group 2 innate lymphoid cells, which has been
postulated to be therapeutically active in mouse models of arthritis.
Similarly, interleukin-9 has been suggested to play an important role in
tumor immunity. Here, we describe the cloning, expression, and
characterization of three fusion proteins based on murine interleukin-9
and the F8 antibody, specific to the alternatively spliced EDA domain of
fibronectin. EDA is strongly expressed in cancer and in various
arthritic conditions, while being undetectable in the majority of
healthy organs. Interleukin-9-based fusion proteins with an irrelevant
antibody specific to hen egg lysozyme served as negative control in our
study. The fusion proteins were characterized by quantitative
biodistribution analysis in tumor-bearing mice using radioiodinated
protein preparations. The highest tumor uptake and best tumor:organ
ratios were observed for a format, in which the interleukin-9 moiety was
flanked by two units of the F8 antibody in single-chain Fv format.
Biological activity of interleukin-9 was retained when the payload was
fused to antibodies. However, the targeted delivery of interleukin-9 to
the disease site resulted in a modest anti-tumor activity in three
different murine models of cancer (K1735M2, CT26, and F9), while no
therapeutic benefit was observed in a collagen induced model of
arthritis. Collectively, these results confirm the possibility to
deliver interleukin-9 to the site of disease but cast doubts about the
alleged therapeutic activity of this cytokine in cancer and arthritis,
which has been postulated in previous publications.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Interleukin-9 is a cytokine with multiple functions, including the
ability to activate group 2 innate lymphoid cells, which has been
postulated to be therapeutically active in mouse models of arthritis.
Similarly, interleukin-9 has been suggested to play an important role in
tumor immunity. Here, we describe the cloning, expression, and
characterization of three fusion proteins based on murine interleukin-9
and the F8 antibody, specific to the alternatively spliced EDA domain of
fibronectin. EDA is strongly expressed in cancer and in various
arthritic conditions, while being undetectable in the majority of
healthy organs. Interleukin-9-based fusion proteins with an irrelevant
antibody specific to hen egg lysozyme served as negative control in our
study. The fusion proteins were characterized by quantitative
biodistribution analysis in tumor-bearing mice using radioiodinated
protein preparations. The highest tumor uptake and best tumor:organ
ratios were observed for a format, in which the interleukin-9 moiety was
flanked by two units of the F8 antibody in single-chain Fv format.
Biological activity of interleukin-9 was retained when the payload was
fused to antibodies. However, the targeted delivery of interleukin-9 to
the disease site resulted in a modest anti-tumor activity in three
different murine models of cancer (K1735M2, CT26, and F9), while no
therapeutic benefit was observed in a collagen induced model of
arthritis. Collectively, these results confirm the possibility to
deliver interleukin-9 to the site of disease but cast doubts about the
alleged therapeutic activity of this cytokine in cancer and arthritis,
which has been postulated in previous publications. |
Gouin, Anna; Ribes, David; Colombat, Magali; Chauveau, Dominique; Prevot, Gregoire; Lairez, Olivier; Pugnet, Gregory; Fremeaux-Bacchi, Veronique; Huart, Antoine; Belliere, Julie; Faguer, Stanislas Role of C5 inhibition in Idiopathic Inflammatory Myopathies and
Scleroderma Renal Crisis-Induced Thrombotic Microangiopathies Article de journal Dans: KIDNEY INTERNATIONAL REPORTS, vol. 6, no. 4, p. 1015-1021, 2021, ISSN: 2468-0249. @article{ISI:000639562600017,
title = {Role of C5 inhibition in Idiopathic Inflammatory Myopathies and
Scleroderma Renal Crisis-Induced Thrombotic Microangiopathies},
author = {Anna Gouin and David Ribes and Magali Colombat and Dominique Chauveau and Gregoire Prevot and Olivier Lairez and Gregory Pugnet and Veronique Fremeaux-Bacchi and Antoine Huart and Julie Belliere and Stanislas Faguer},
doi = {10.1016/j.ekir.2021.01.021},
issn = {2468-0249},
year = {2021},
date = {2021-04-01},
journal = {KIDNEY INTERNATIONAL REPORTS},
volume = {6},
number = {4},
pages = {1015-1021},
abstract = {Introduction: Connective tissue diseases, including systemic sclerosis
and idiopathic inflammatory myopathies (IIMs), are a very rare cause of
thrombotic microangiopathies (TMAs). Whether dysregulation of the
complement pathways underlies these secondary forms of TMA and may be
targeted by complement blocking agents remains elusive.
Methods: Kidney pathology and outcomes of 18 critically ill patients with TMA related to inflammatory myopathy flare-up (IIM},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Introduction: Connective tissue diseases, including systemic sclerosis
and idiopathic inflammatory myopathies (IIMs), are a very rare cause of
thrombotic microangiopathies (TMAs). Whether dysregulation of the
complement pathways underlies these secondary forms of TMA and may be
targeted by complement blocking agents remains elusive.
Methods: Kidney pathology and outcomes of 18 critically ill patients with TMA related to inflammatory myopathy flare-up (IIM |
Gauckler, Philipp; Shin, Jae Il; Alberici, Federico; Audard, Vincent; Bruchfeld, Annette; Busch, Martin; Cheung, Chee Kay; Crnogorac, Matija; Delbarba, Elisa; Eller, Kathrin; Faguer, Stanislas; Galesic, Kresimir; Griffin, Sian; van den Hoogen, Martijn W F; Hruskova, Zdenka; Jeyabalan, Anushya; Karras, Alexandre; King, Catherine; Kohli, Harbir Singh; Mayer, Gert; Maas, Rutger; Muto, Masahiro; Moiseev, Sergey; Odler, Balazs; Pepper, Ruth J; Quintana, Luis F; Radhakrishnan, Jai; Ramachandran, Raja; Salama, Alan D; Schonermarck, Ulf; Segelmark, Marten; Smith, Lee; Tesar, Vladimir; Wetzels, Jack; Willcocks, Lisa; Windpessl, Martin; Zand, Ladan; Zonozi, Reza; Kronbichler, Andreas; Grp, RITERM Study Rituximab in Membranous Nephropathy Article de journal Dans: KIDNEY INTERNATIONAL REPORTS, vol. 6, no. 4, p. 881-893, 2021, ISSN: 2468-0249. @article{ISI:000639562600005,
title = {Rituximab in Membranous Nephropathy},
author = {Philipp Gauckler and Jae Il Shin and Federico Alberici and Vincent Audard and Annette Bruchfeld and Martin Busch and Chee Kay Cheung and Matija Crnogorac and Elisa Delbarba and Kathrin Eller and Stanislas Faguer and Kresimir Galesic and Sian Griffin and Martijn W F van den Hoogen and Zdenka Hruskova and Anushya Jeyabalan and Alexandre Karras and Catherine King and Harbir Singh Kohli and Gert Mayer and Rutger Maas and Masahiro Muto and Sergey Moiseev and Balazs Odler and Ruth J Pepper and Luis F Quintana and Jai Radhakrishnan and Raja Ramachandran and Alan D Salama and Ulf Schonermarck and Marten Segelmark and Lee Smith and Vladimir Tesar and Jack Wetzels and Lisa Willcocks and Martin Windpessl and Ladan Zand and Reza Zonozi and Andreas Kronbichler and RITERM Study Grp},
doi = {10.1016/j.ekir.2020.12.035},
issn = {2468-0249},
year = {2021},
date = {2021-04-01},
journal = {KIDNEY INTERNATIONAL REPORTS},
volume = {6},
number = {4},
pages = {881-893},
abstract = {Membranous nephropathy (MN) is the most common cause of primary
nephrotic syndrome among adults. The identification of phospholipase A2
receptor (PLA2R) as target antigen in most patients changed the
management of MN dramatically, and provided a rationale for B-cell
depleting agents such as rituximab. The efficacy of rituximab in
inducing remission has been investigated in several studies, including 3
randomized controlled trials, in which complete and partial remission of
proteinuria was achieved in approximately two-thirds of treated
patients. Due to its favorable safety profile, rituximab is now
considered a first-line treatment option for MN, especially in patients
at moderate and high risk of deterioration in kidney function. However,
questions remain about how to best use rituximab, including the optimal
dosing regimen, a potential need for maintenance therapy, and assessment
of long-term safety and efficacy outcomes. In this review, we provide an
overview of the current literature and discuss both strengths and
limitations of ``the new standard.''},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Membranous nephropathy (MN) is the most common cause of primary
nephrotic syndrome among adults. The identification of phospholipase A2
receptor (PLA2R) as target antigen in most patients changed the
management of MN dramatically, and provided a rationale for B-cell
depleting agents such as rituximab. The efficacy of rituximab in
inducing remission has been investigated in several studies, including 3
randomized controlled trials, in which complete and partial remission of
proteinuria was achieved in approximately two-thirds of treated
patients. Due to its favorable safety profile, rituximab is now
considered a first-line treatment option for MN, especially in patients
at moderate and high risk of deterioration in kidney function. However,
questions remain about how to best use rituximab, including the optimal
dosing regimen, a potential need for maintenance therapy, and assessment
of long-term safety and efficacy outcomes. In this review, we provide an
overview of the current literature and discuss both strengths and
limitations of ``the new standard.'' |
Salhi, Sofiane; Ribes, David; Faguer, Stanislas Complement C5 inhibition reverses bleomycin-induced thrombotic
microangiopathy Article de journal Dans: CLINICAL KIDNEY JOURNAL, vol. 14, no. 4, p. 1275-1276, 2021, ISSN: 2048-8505. @article{ISI:000642298600029,
title = {Complement C5 inhibition reverses bleomycin-induced thrombotic
microangiopathy},
author = {Sofiane Salhi and David Ribes and Stanislas Faguer},
doi = {10.1093/ckj/sfaa101},
issn = {2048-8505},
year = {2021},
date = {2021-04-01},
journal = {CLINICAL KIDNEY JOURNAL},
volume = {14},
number = {4},
pages = {1275-1276},
abstract = {Whether C5 blocking may improve the outcomes of patients developing
chemotherapy-induced thrombotic microangiopathy (TMA) remains elusive.
Lung fibrosis is a well-known complication of bleomycin, whereas TMA5
are very rare (<20 cases described). Here, we report an exceptional case
of a male patient that developed acute respiratory distress syndrome and
TMA following administration of bleomycin, cisplatin and etoposide .
Refractoriness to plasma exchanges prompted us to use eculizumab as
salvage therapy. Eculizumab led to complete remission of the TMA before
Day 2. However, the patient progressed towards refractory respiratory
failure, suggesting that pathophysiological mechanisms of
bleomycin-induced lung fibrosis and TMA differ.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Whether C5 blocking may improve the outcomes of patients developing
chemotherapy-induced thrombotic microangiopathy (TMA) remains elusive.
Lung fibrosis is a well-known complication of bleomycin, whereas TMA5
are very rare (<20 cases described). Here, we report an exceptional case
of a male patient that developed acute respiratory distress syndrome and
TMA following administration of bleomycin, cisplatin and etoposide .
Refractoriness to plasma exchanges prompted us to use eculizumab as
salvage therapy. Eculizumab led to complete remission of the TMA before
Day 2. However, the patient progressed towards refractory respiratory
failure, suggesting that pathophysiological mechanisms of
bleomycin-induced lung fibrosis and TMA differ. |
Gosset, Anna; Escanes, Claire; Pouilles, Jean-Michel; Vidal, Fabien; Gac, Yann Tanguy Le; Plu-Bureau, Genevieve; Tremollieres, Florence A Bone mineral density in women with deep infiltrating endometriosis who
have undergone early bilateral oophorectomy Article de journal Dans: MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY, vol. 28, no. 3, p. 300-306, 2021, ISSN: 1072-3714. @article{ISI:000618022400010,
title = {Bone mineral density in women with deep infiltrating endometriosis who
have undergone early bilateral oophorectomy},
author = {Anna Gosset and Claire Escanes and Jean-Michel Pouilles and Fabien Vidal and Yann Tanguy Le Gac and Genevieve Plu-Bureau and Florence A Tremollieres},
doi = {10.1097/GME.0000000000001696},
issn = {1072-3714},
year = {2021},
date = {2021-03-01},
journal = {MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY},
volume = {28},
number = {3},
pages = {300-306},
abstract = {Objective: To study bone mineral density (BMD) in women with and without
pelvic deep infiltrating endometriosis (DIE) who underwent early
bilateral oophorectomy (BO). Methods: A case-control study was performed
in 83 women who underwent early BO before the age of 45 years, 31 for
DIE and 52 for another clinical condition. All the women answered a
standardized computer-assisted questionnaire to record their clinical
and historical data and were medically examined. Lumbar spine and
femoral neck BMDs were measured by dual-energy X-ray absorptiometry
after early BO. Simultaneously, serum calcium, intact parathyroid,
25-hydroxyvitamin D, and cross-linked C-telopeptide were also measured.
Unadjusted and adjusted odds ratios (with 95% confidence intervals
[CI]) for endometriosis were calculated using logistic regression.
Results: The mean lumbar spine and femoral neck BMDs were significantly
higher in women who underwent early BO for DIE than in those who
underwent early BO for another clinical condition. After adjusting for
age at BMD measurement, years since menopause, age at menarche and body
mass index, odds ratio for endometriosis associated with a 1-SD increase
in lumbar spine and femoral neck BMD was 2.59 (95% CI: 1.45-4.62) and
2.16 (95% CI: 1.23-3.81), respectively. Conclusion: Higher lumbar spine
and femoral neck BMDs are associated with an increase in the likelihood
of pelvic DIE in women who underwent early BO. This might be expected to
the extent that endometriosis is itself associated with enhanced
estrogen status, although further studies are needed to confirm such a
hypothesis. These findings suggest that BMD measurement could contribute
to the hormonal management of surgical menopause in women with DIE.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Objective: To study bone mineral density (BMD) in women with and without
pelvic deep infiltrating endometriosis (DIE) who underwent early
bilateral oophorectomy (BO). Methods: A case-control study was performed
in 83 women who underwent early BO before the age of 45 years, 31 for
DIE and 52 for another clinical condition. All the women answered a
standardized computer-assisted questionnaire to record their clinical
and historical data and were medically examined. Lumbar spine and
femoral neck BMDs were measured by dual-energy X-ray absorptiometry
after early BO. Simultaneously, serum calcium, intact parathyroid,
25-hydroxyvitamin D, and cross-linked C-telopeptide were also measured.
Unadjusted and adjusted odds ratios (with 95% confidence intervals
[CI]) for endometriosis were calculated using logistic regression.
Results: The mean lumbar spine and femoral neck BMDs were significantly
higher in women who underwent early BO for DIE than in those who
underwent early BO for another clinical condition. After adjusting for
age at BMD measurement, years since menopause, age at menarche and body
mass index, odds ratio for endometriosis associated with a 1-SD increase
in lumbar spine and femoral neck BMD was 2.59 (95% CI: 1.45-4.62) and
2.16 (95% CI: 1.23-3.81), respectively. Conclusion: Higher lumbar spine
and femoral neck BMDs are associated with an increase in the likelihood
of pelvic DIE in women who underwent early BO. This might be expected to
the extent that endometriosis is itself associated with enhanced
estrogen status, although further studies are needed to confirm such a
hypothesis. These findings suggest that BMD measurement could contribute
to the hormonal management of surgical menopause in women with DIE. |
Egot, Marion; Lasne, Dominique; Poirault-Chassac, Sonia; Mirault, Tristan; Pidard, Dominique; Dreano, Elise; Elie, Caroline; Gandrille, Sophie; Marchelli, Aurore; Baruch, Dominique; Rendu, John; Faure, Julien; Flaujac, Claire; Gratacap, Marie-Pierre; Sie, Pierre; Gaussem, Pascale; Salomon, Remi; Baujat, Genevieve; Bachelot-Loza, Christilla Role of oculocerebrorenal syndrome of Lowe (OCRL) protein in
megakaryocyte maturation, platelet production and functions: a study in
patients with Lowe syndrome Article de journal Dans: BRITISH JOURNAL OF HAEMATOLOGY, vol. 192, no. 5, p. 909-921, 2021, ISSN: 0007-1048. @article{ISI:000613753600001,
title = {Role of oculocerebrorenal syndrome of Lowe (OCRL) protein in
megakaryocyte maturation, platelet production and functions: a study in
patients with Lowe syndrome},
author = {Marion Egot and Dominique Lasne and Sonia Poirault-Chassac and Tristan Mirault and Dominique Pidard and Elise Dreano and Caroline Elie and Sophie Gandrille and Aurore Marchelli and Dominique Baruch and John Rendu and Julien Faure and Claire Flaujac and Marie-Pierre Gratacap and Pierre Sie and Pascale Gaussem and Remi Salomon and Genevieve Baujat and Christilla Bachelot-Loza},
doi = {10.1111/bjh.17346, Early Access Date = FEB 2021},
issn = {0007-1048},
year = {2021},
date = {2021-03-01},
journal = {BRITISH JOURNAL OF HAEMATOLOGY},
volume = {192},
number = {5},
pages = {909-921},
abstract = {Lowe syndrome (LS) is an oculocerebrorenal syndrome of Lowe (OCRL1)
genetic disorder resulting in a defect of the OCRL protein, a
phosphatidylinositol-4,5-bisphosphate 5-phosphatase containing various
domains including a Rho GTPase-activating protein (RhoGAP) homology
domain catalytically inactive. We previously reported surgery-associated
bleeding in patients with LS, suggestive of platelet dysfunction,
accompanied with a mild thrombocytopenia in several patients. To
decipher the role of OCRL in platelet functions and in megakaryocyte
(MK) maturation, we conducted a case-control study on 15 patients with
LS (NCT01314560). While all had a drastically reduced expression of
OCRL, this deficiency did not affect platelet aggregability, but
resulted in delayed thrombus formation on collagen under flow
conditions, defective platelet spreading on fibrinogen and impaired clot
retraction. We evidenced alterations of the myosin light chain
phosphorylation (P-MLC), with defective Rac1 activity and, inversely,
elevated active RhoA. Altered cytoskeleton dynamics was also observed in
cultured patient MKs showing deficient proplatelet extension with
increased P-MLC that was confirmed using control MKs transfected with
OCRL-specific small interfering(si)RNA (siOCRL). Patients with LS also
had an increased proportion of circulating barbell-shaped proplatelets.
Our present study establishes that a deficiency of the OCRL protein
results in a defective actomyosin cytoskeleton reorganisation in both
MKs and platelets, altering both thrombopoiesis and some platelet
responses to activation necessary to ensure haemostasis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Lowe syndrome (LS) is an oculocerebrorenal syndrome of Lowe (OCRL1)
genetic disorder resulting in a defect of the OCRL protein, a
phosphatidylinositol-4,5-bisphosphate 5-phosphatase containing various
domains including a Rho GTPase-activating protein (RhoGAP) homology
domain catalytically inactive. We previously reported surgery-associated
bleeding in patients with LS, suggestive of platelet dysfunction,
accompanied with a mild thrombocytopenia in several patients. To
decipher the role of OCRL in platelet functions and in megakaryocyte
(MK) maturation, we conducted a case-control study on 15 patients with
LS (NCT01314560). While all had a drastically reduced expression of
OCRL, this deficiency did not affect platelet aggregability, but
resulted in delayed thrombus formation on collagen under flow
conditions, defective platelet spreading on fibrinogen and impaired clot
retraction. We evidenced alterations of the myosin light chain
phosphorylation (P-MLC), with defective Rac1 activity and, inversely,
elevated active RhoA. Altered cytoskeleton dynamics was also observed in
cultured patient MKs showing deficient proplatelet extension with
increased P-MLC that was confirmed using control MKs transfected with
OCRL-specific small interfering(si)RNA (siOCRL). Patients with LS also
had an increased proportion of circulating barbell-shaped proplatelets.
Our present study establishes that a deficiency of the OCRL protein
results in a defective actomyosin cytoskeleton reorganisation in both
MKs and platelets, altering both thrombopoiesis and some platelet
responses to activation necessary to ensure haemostasis. |
Swiader, Audrey; Camare, Caroline; Guerby, Paul; Salvayre, Robert; Negre-Salvayre, Anne 4-Hydroxynonenal Contributes to Fibroblast Senescence in Skin Photoaging
Evoked by UV-A Radiation Article de journal Dans: ANTIOXIDANTS, vol. 10, no. 3, 2021. @article{ISI:000633337900001,
title = {4-Hydroxynonenal Contributes to Fibroblast Senescence in Skin Photoaging
Evoked by UV-A Radiation},
author = {Audrey Swiader and Caroline Camare and Paul Guerby and Robert Salvayre and Anne Negre-Salvayre},
doi = {10.3390/antiox10030365},
year = {2021},
date = {2021-03-01},
journal = {ANTIOXIDANTS},
volume = {10},
number = {3},
abstract = {Solar ultraviolet A (UV-A) radiation promotes a huge variety of damages
on connective tissues and dermal fibroblasts, including cellular
senescence, a major contributor of skin photoaging. The mechanisms of
skin photoaging evoked by UV-A partly involve the generation of reactive
oxygen species and lipid peroxidation. We previously reported that
4-hydroxynonenal (HNE), a lipid peroxidation-derived aldehyde, forms
adducts on elastin in the skins of UV-A irradiated hairless mice,
possibly contributing to actinic elastosis. In the present study, we
investigated whether and how HNE promotes fibroblast senescence in skin
photoaging. Dermal fibroblasts of skins from UV-A-exposed hairless mice
exhibited an increased number of gamma H2AX foci characteristic of cell
senescence, together with an accumulation of HNE adducts partly
colocalizing with the cytoskeletal protein vimentin. Murine fibroblasts
exposed to UV-A radiation (two cycles of 15 J/cm(2)), or HNE (30 mu M, 4
h), exhibited senescence patterns characterized by an increased gamma
H2AX foci expression, an accumulation of acetylated proteins, and a
decreased expression of the sirtuin SIRT1. HNE adducts were detected on
vimentin in cultured fibroblasts irradiated by UV-A or incubated with
HNE. The HNE scavenger carnosine prevented both vimentin modification
and fibroblast senescence evoked by HNE in vitro and in the skins of
UV-A-exposed mice. Altogether, these data emphasize the role of HNE and
lipid peroxidation-derived aldehydes in fibroblast senescence, and
confirm the protective effect of carnosine in skin photoaging.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Solar ultraviolet A (UV-A) radiation promotes a huge variety of damages
on connective tissues and dermal fibroblasts, including cellular
senescence, a major contributor of skin photoaging. The mechanisms of
skin photoaging evoked by UV-A partly involve the generation of reactive
oxygen species and lipid peroxidation. We previously reported that
4-hydroxynonenal (HNE), a lipid peroxidation-derived aldehyde, forms
adducts on elastin in the skins of UV-A irradiated hairless mice,
possibly contributing to actinic elastosis. In the present study, we
investigated whether and how HNE promotes fibroblast senescence in skin
photoaging. Dermal fibroblasts of skins from UV-A-exposed hairless mice
exhibited an increased number of gamma H2AX foci characteristic of cell
senescence, together with an accumulation of HNE adducts partly
colocalizing with the cytoskeletal protein vimentin. Murine fibroblasts
exposed to UV-A radiation (two cycles of 15 J/cm(2)), or HNE (30 mu M, 4
h), exhibited senescence patterns characterized by an increased gamma
H2AX foci expression, an accumulation of acetylated proteins, and a
decreased expression of the sirtuin SIRT1. HNE adducts were detected on
vimentin in cultured fibroblasts irradiated by UV-A or incubated with
HNE. The HNE scavenger carnosine prevented both vimentin modification
and fibroblast senescence evoked by HNE in vitro and in the skins of
UV-A-exposed mice. Altogether, these data emphasize the role of HNE and
lipid peroxidation-derived aldehydes in fibroblast senescence, and
confirm the protective effect of carnosine in skin photoaging. |