17 research outputs found
Clinical and Neuropsychological Correlates of Prefrailty Syndrome
Physical frailty is closely associated with cognitive impairment. We aim to investigate the neuropsychological profiles of prefrail and non-frail dementia-free community-dwelling older adults using a comprehensive neuropsychological evaluation, and to examine the association between specific frailty criteria and clinical and neuropsychological scores. Participants completed a comprehensive standardized neuropsychological evaluation (covering cognitive domains such as memory, executive functions, language and attention), and frailty assessment. Frailty was assessed according to biological criteria: unintentional weight loss, exhaustion, low physical activity, slowness, and weakness. The sample comprised 60 dementia-free community-dwelling adults, aged 65 years or older (range 65-89 years; 60.0% women). Forty-two participants were classified as robust (no frailty criteria present), and 18 as prefrail (1 or 2 frailty criteria present). We explored neurocognitive differences between the groups and examined the association between specific criteria of frailty phenotype and clinical and neuropsychological outcomes with bivariate tests and multivariate models. Prefrail participants showed poorer cognitive performance than non-frail participants in both memory and non-memory cognitive domains. However, delayed episodic memory was the only cognitive subdomain that remained significant after controlling for age, gender, and educational level. Gait speed was significantly associated with general cognitive performance, immediate memory, and processing speed, while grip strength was associated with visual episodic memory and visuoconstructive abilities. Both gait speed and grip strength were negatively associated with depressive scores. Our results suggest that prefrailty is associated with cognitive dysfunction. The fact that specific cognitive domains may be susceptible to subclinical states of physical frailty may have important clinical implications. Indeed, early detection of specific cognitive dysfunctions may allow opportunities for reversibility
Detailed Characterization of Mesenchymal Stem/Stromal Cells from a Large Cohort of AML Patients Demonstrates a Definitive Link to Treatment Outcomes
Altres ajuts: Health Canada's Genomics Research and Development Initiative Phase VI (H4080-144541-2014-2019); Obra Social La Caixa-Fundació Josep Carreras and the Generalitat de Catalunya (SGR330); Asociación Española Contra el Cáncer (AECC-CI-2015)Bone marrow mesenchymal stem/stromal cells (BM-MSCs) are key components of the hematopoietic niche thought to have a direct role in leukemia pathogenesis. BM-MSCs from patients with acute myeloid leukemia (AML) have been poorly characterized due to disease heterogeneity. We report a functional, genetic, and immunological characterization of BM-MSC cultures from 46 AML patients, stratified by molecular/cytogenetics into low-risk (LR), intermediate-risk (IR), and high-risk (HR) subgroups. Stable MSC cultures were successfully established and characterized from 40 of 46 AML patients irrespective of the risk subgroup. AML-derived BM-MSCs never harbored tumor-specific cytogenetic/molecular alterations present in blasts, but displayed higher clonogenic potential than healthy donor (HD)-derived BM-MSCs. Although HD- and AML-derived BM-MSCs equally provided chemoprotection to AML cells in vitro, AML-derived BM-MSCs were more immunosuppressive/anti-inflammatory, enhanced suppression of lymphocyte proliferation, and diminished secretion of pro-inflammatory cytokines. Multivariate analysis revealed that the level of interleukin-10 produced by AML-derived BM-MSCs as an independent prognostic factor negatively affected overall survival. Collectively our data show that AML-derived BM-MSCs are not tumor related, but display functional differences contributing to therapy resistance and disease evolution. In this article, Díaz de la Guardia and colleagues report a functional, genetic, and immunological characterization of BM-MSC cultures from 46 AML patients, stratified by molecular/cytogenetics into low-risk (LR), intermediate-risk (IR), and high-risk (HR) subgroups. BM-MSCs never harbored tumor-specific cytogenetic/molecular alterations present in blasts, and IL-10 produced by AML-derived BM-MSCs is an independent prognostic factor negatively impacting on overall survival
Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications
Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations.This work was supported by the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Health (FIS; PI16/00425 and PI19/00321), Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER, 06/07/0036), IIS-FJD BioBank (PT13/0010/0012), Comunidad de Madrid (CAM, RAREGenomics Project, B2017/BMD-3721), European Regional Development Fund (FEDER), the Organización Nacional de Ciegos Españoles (ONCE), Fundación Ramón Areces, Fundación Conchita Rábago and the University Chair UAM-IIS-FJD of Genomic Medicine. Irene Perea-Romero is supported by a PhD fellowship from the predoctoral Program from ISCIII (FI17/00192). Ionut F. Iancu is supported by a grant from the Comunidad de Madrid (CAM, PEJ-2017-AI/BMD7256). Marta del Pozo-Valero is supported by a PhD grant from the Fundación Conchita Rábago. Berta Almoguera is supported by a Juan Rodes program from ISCIII (JR17/00020). Pablo Minguez is supported by a Miguel Servet program from ISCIII (CP16/00116). Marta Corton is supported by a Miguel Servet program from ISCIII (CPII17/00006). The funders played no role in study design, data collection, data analysis, manuscript preparation and/or publication decisions
IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q-AML
Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory
or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk
between AML cells and the BM stroma is a major mechanism underlying therapy resistance in AML.
Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in
hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma. Whether IMiDs may improve the efficacy of current standard treatment
in AML remains understudied. Here, we have exploited in vitro and in vivo preclinical AML models to
analyze whether IMiDs potentiate the efficacy of AraC/Idarubicin-based standard AML chemotherapy by
interfering with the BM stroma-mediated chemoresistance. We report that IMiDs do not exert cytotoxic
effects on either non-del5q/5q- AML cells nor BM-MSCs, but they enhance the immunomodulatory
properties of BM-MSCs. When combined with AraC/Idarubicin, IMiDs fail to circumvent BM stromamediated resistance of non-del5q/5q- AML cells in vitro and in vivo but induce robust extramedullary
mobilization of AML cells. When administered as a single agent, lenalidomide specifically mobilizes nondel5q/5q- AML cells, but not healthy CD34+ cells, to peripheral blood (PB) through specific downregulation of CXCR4 in AML blasts. Global gene expression profiling supports a migratory/mobilization
gene signature in lenalidomide-treated non-del5q/5q- AML blasts but not in CD34+ cells. Collectively,
IMiDs mobilize non-del5q/5q- AML blasts to PB through CXCR4 downregulation, but fail to potentiate
AraC/Idarubicin activity in preclinical models of non-del5q/5q- AML
Robust In Vitro and In Vivo Immunosuppressive and Anti-inflammatory Properties of Inducible Caspase-9-mediated Apoptotic Mesenchymal Stromal/Stem Cell
Mesenchymal stromal stem/cells (MSC) therapies are clinically used in a wide range of disorders based on their robust HLA-independent immunosuppressive and anti-inflammatory properties. However, the mechanisms underlying MSC therapeutic activity remain elusive as demonstrated by the unpredictable therapeutic efficacy of MSC infusions reported in multiple clinical trials. A seminal recent study showed that infused MSCs are actively induced to undergo apoptosis by recipient cytotoxic T cells, a mechanism that triggers in vivo recipient-induced immunomodulation by such apoptotic MSCs, and the need for such recipient cytotoxic cell activity could be replaced by the administration of ex vivo-generated apoptotic MSCs. Moreover, the use of MSC-derived extracellular vesicles (MSC-EVs) is being actively explored as a cell-free therapeutic alternative over the parental MSCs. We hypothesized that the introduction of a "suicide gene" switch into MSCs may offer on-demand in vivo apoptosis of transplanted MSCs. Here, we prompted to investigate the utility of the iCasp9/AP1903 suicide gene system in inducing apoptosis of MSCs. iCasp9/AP1903-induced apoptotic MSCs (MSCiCasp9+) were tested in vitro and in in vivo models of acute colitis. Our data show a very similar and robust immunosuppressive and anti-inflammatory properties of both "parental" alive MSCGFP+ cells and apoptotic MSCiCasp9+ cells in vitro and in vivo regardless of whether apoptosis was induced in vivo or in vitro before administering MSCiCasp9+ lysates. This development of an efficient iCasp9 switch may potentiate the safety of MSC-based therapies in the case of an adverse event and, will also circumvent current logistic technical limitations and biological uncertainties associated to MSC-EVs
IL17 functions through the novel REG3β-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) offers an optimal model for discovering "druggable" molecular pathways that participate in inflammation-associated cancer development. Chronic pancreatitis, a common prolonged inflammatory disease, behaves as a well-known premalignant condition that contributes to PDAC development. Although the mechanisms underlying the pancreatitis-to-cancer transition remain to be fully elucidated, emerging evidence supports the hypothesis that the actions of proinflammatory mediators on cells harboring Kras mutations promote neoplastic transformation. Recent elegant studies demonstrated that the IL17 pathway mediates this phenomenon and can be targeted with antibodies, but the downstream mechanisms by which IL17 functions during this transition are currently unclear. In this study, we demonstrate that IL17 induces the expression of REG3β, a wellknown mediator of pancreatitis, during acinar-to-ductal metaplasia and in early pancreatic intraepithelial neoplasia (PanIN) lesions. Furthermore, we found that REG3β promotes cell growth and decreases sensitivity to cell death through activation of the gp130-JAK2-STAT3-dependent pathway. Genetic inactivation of REG3β in the context of oncogenic Kras-driven PDAC resulted in reduced PanIN formation, an effect that could be rescued by administration of exogenous REG3β. Taken together, our findings provide mechanistic insight into the pathways underlying inflammation-associated pancreatic cancer, revealing a dual and contextual pathophysiologic role for REG3β during pancreatitis and PDAC initiation.Fil: Loncle, Celine. Centre de Recherche en Cancerologie de Marseille; FranciaFil: Bonjoch, Laia. Instituto de Investigación Biomédica de Barcelona.; EspañaFil: Folch Puy, Emma. Instituto de Investigación Biomédica de Barcelona.; EspañaFil: Lopez Millan, Maria Belen. Centre de Recherche en Cancerologie de Marseille; FranciaFil: Lac, Sophie. Centre de Recherche en Cancerologie de Marseille; FranciaFil: Molejon, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centre de Recherche en Cancerologie de Marseille; FranciaFil: Chuluyan, Hector Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Centre de Recherche en Cancerologie de Marseille; FranciaFil: Cordelier, Pierre. Centre de Recherche sur le Cancer de Toulouse; FranciaFil: Dubus, Pierre. Université de Bordeaux; FranciaFil: Lomberk, Gwen. Mayo Clinic Cancer Center; Estados UnidosFil: Urrutia, Raul. Mayo Clinic Cancer Center; Estados UnidosFil: Closa, Daniel. Instituto de Investigación Biomédica de Barcelona.; EspañaFil: Iovanna, Juan Lucio. Centre de Recherche en Cancerologie de Marseille; Franci
Engraftment characterization of risk-stratified AML in NSGS mice
The authors thank Paola Romecin and Virginia Rodriguez-Cortez
for technical assistance.
This work was supported by the Spanish Ministry of Economy
and Competitiveness (SAF2016-80481R, PID2019-108160RBI00),
the Obra Social La Caixa (LCF/PR/HR19/52160011), Interreg
V-A programme (POCTEFA) 2014-2020 (grant PROTEOblood
EFA360/19), Health Canada (H4080-144541), and
Deutsche Josep Carreras Leukämie Stiftung (P.M.). Additional
funding was provided by Consejería de Salud y Familia (PI-
0119-2019) (R.D.d.l.G.), Health Institute Carlos III (ISCIII/FEDER, PI17/01028) and Asociación Española Contra el Cáncer (C.B.),
Health Institute Carlos III/FEDER (CPII17/00032) (V.R.-M.), and
Fundación Hay Esperanza (E.A.). CERCA/Generalitat de Catalunya
and Fundación Josep Carreras-Obra Social la Caixa provided
institutional support. B.L.-M. was supported by a Lady Tata Memorial
Trust International Award and Asociación Española Contra el
Cáncer (INVES20011LÓPE). O.M. and T.V.-H. were supported
by Asociación Española Contra el Cáncer (INVES211226MOLI)
and a Marie Sklodowska Curie Fellowship (792923), respectively.
P.M. is an investigator in the Spanish Cell Therapy Network.Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Disease
heterogeneity is well documented, and patient stratification determines treatment
decisions. Patient-derived xenografts (PDXs) from risk-stratified AML are crucial for
studying AML biology and testing novel therapeutics. Despite recent advances in PDX
modeling of AML, reproducible engraftment of human AML is primarily limited to high-risk
(HR) cases, with inconsistent or very protracted engraftment observed for favorable-risk
(FR) and intermediate-risk (IR) patients. We used NSGS mice to characterize the engraftment
robustness/kinetics of 28 AML patient samples grouped according to molecular/
cytogenetic classification and assessed whether the orthotopic coadministration of patientmatched
bone marrow mesenchymal stromal cells (BM MSCs) improves AML engraftment.
PDX event-free survival correlated well with the predictable prognosis of risk-stratified
AML patients. The majority (85-94%) of the mice were engrafted in bone marrow (BM)
independently of the risk group, although HR AML patients showed engraftment levels that
were significantly superior to those of FR or IR AML patients. Importantly, the engraftment
levels observed in NSGS mice by week 6 remained stable over time. Serial transplantation
and long-term culture-initiating cell (LTC-IC) assays revealed long-term engraftment limited
to HR AML patients, fitter leukemia-initiating cells (LICs) in HR AML samples, and the
presence of AML LICs in the CD342 leukemic fraction, regardless of the risk group. Finally,
orthotopic coadministration of patient-matched BM MSCs and AML cells was dispensable
for BM engraftment levels but favored peripheralization of engrafted AML cells. This
comprehensive characterization of human AML engraftment in NSGS mice offers a
valuable platform for in vivo testing of targeted therapies in risk-stratified AML patient
samples.Spanish Ministry of Economy
and Competitiveness (SAF2016-80481R, PID2019-108160RBI00)Obra Social La Caixa (LCF/PR/HR19/52160011)Interreg
V-A programme (POCTEFA) 2014-2020 (grant PROTEOblood
EFA360/19)Health Canada (H4080-144541)Deutsche Josep Carreras Leukämie StiftungConsejer ıa de Salud y Familia (PI-
0119-2019)Health Institute Carlos III (ISCIII/FEDER, PI17/01028)Asociación Española Contra el CáncerHealth Institute Carlos III/FEDER (CPII17/00032)Fundación Hay EsperanzaCERCA/Generalitat de CatalunyaFundació Josep Carreras-Obra Social la CaixaLady Tata Memorial
Trust International AwardAsociación Española Contra el
Cáncer (INVES20011LÓPE)Asociación Española Contra el Cáncer (INVES211226MOLI)Marie Sklodowska Curie Fellowship (792923
IL17 Functions through the Novel REG3β–JAK2–STAT3 Inflammatory Pathway to Promote the Transition from Chronic Pancreatitis to Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) offers an optimal model for discovering “druggable” molecular pathways that participate in inflammation-associated cancer development. Chronic pancreatitis, a common prolonged inflammatory disease, behaves as a well-known premalignant condition that contributes to PDAC development. Although the mechanisms underlying the pancreatitis-to-cancer transition remain to be fully elucidated, emerging evidence supports the hypothesis that the actions of proinflammatory mediators on cells harboring Kras mutations promote neoplastic transformation. Recent elegant studies demonstrated that the IL-17 pathway mediates this phenomenon and can be targeted with antibodies, but the downstream mechanisms by which IL-17 functions during this transition are currently unclear. In this study, we demonstrate that IL-17 induces the expression of REG3β, a well-known mediator of pancreatitis, during acinar-to-ductal metaplasia and in early PanIN lesions. Furthermore, we found that REG3β promotes cell growth and decreases sensitivity to cell death through activation of the gp130-JAK2-STAT3-dependent pathway. Genetic inactivation of REG3β in the context of oncogenic Kras-driven PDAC resulted in reduced PanIN formation, an effect that could be rescued by administration of exogenous REG3β. Taken together, our findings provide mechanistic insight into the pathways underlying inflammation-associated pancreatic cancer, revealing a dual and contextual pathophysiological role for REG3β during pancreatitis and PDAC initiation
Engraftment characterization of risk-stratified AML in NSGS mice
International audienceKey Points- PDXs from risk-stratified AML samples are crucial for studying AML biology and testing novel therapeutics.- We characterize human AML engraftment in NSGS mice, offering a valuable platform for in vivo testing of targeted therapies.Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Disease heterogeneity is well documented, and patient stratification determines treatment decisions. Patient-derived xenografts (PDXs) from risk-stratified AML are crucial for studying AML biology and testing novel therapeutics. Despite recent advances in PDX modeling of AML, reproducible engraftment of human AML is primarily limited to high-risk (HR) cases, with inconsistent or very protracted engraftment observed for favorable-risk (FR) and intermediate-risk (IR) patients. We used NSGS mice to characterize the engraftment robustness/kinetics of 28 AML patient samples grouped according to molecular/cytogenetic classification and assessed whether the orthotopic coadministration of patient-matched bone marrow mesenchymal stromal cells (BM MSCs) improves AML engraftment. PDX event-free survival correlated well with the predictable prognosis of risk-stratified AML patients. The majority (85-94%) of the mice were engrafted in bone marrow (BM) independently of the risk group, although HR AML patients showed engraftment levels that were significantly superior to those of FR or IR AML patients. Importantly, the engraftment levels observed in NSGS mice by week 6 remained stable over time. Serial transplantation and long-term culture-initiating cell (LTC-IC) assays revealed long-term engraftment limited to HR AML patients, fitter leukemia-initiating cells (LICs) in HR AML samples, and the presence of AML LICs in the CD34− leukemic fraction, regardless of the risk group. Finally, orthotopic coadministration of patient-matched BM MSCs and AML cells was dispensable for BM engraftment levels but favored peripheralization of engrafted AML cells. This comprehensive characterization of human AML engraftment in NSGS mice offers a valuable platform for in vivo testing of targeted therapies in risk-stratified AML patient sample