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  1. Article: A locally optimised machine learning approach to early prognostication of long-term neurological outcomes after out-of-hospital cardiac arrest.

    Pey, Vincent / Doumard, Emmanuel / Komorowski, Matthieu / Rouget, Antoine / Delmas, Clément / Vardon-Bounes, Fanny / Poette, Michaël / Ratineau, Valentin / Dray, Cédric / Ader, Isabelle / Minville, Vincent

    Digital health

    2024  Volume 10, Page(s) 20552076241234746

    Abstract: Background: Out-of-hospital cardiac arrest (OHCA) represents a major burden for society and health care, with an average incidence in adults of 67 to 170 cases per 100,000 person-years in Europe and in-hospital survival rates of less than 10%. Patients ... ...

    Abstract Background: Out-of-hospital cardiac arrest (OHCA) represents a major burden for society and health care, with an average incidence in adults of 67 to 170 cases per 100,000 person-years in Europe and in-hospital survival rates of less than 10%. Patients and practitioners would benefit from a prognostication tool for long-term good neurological outcomes.
    Objective: We aim to develop a machine learning (ML) pipeline on a local database to classify patients according to their neurological outcomes and identify prognostic features.
    Methods: We collected clinical and biological data consecutively from 595 patients who presented OHCA and were routed to a single regional cardiac arrest centre in the south of France. We applied recursive feature elimination and ML analyses to identify the main features associated with a good neurological outcome, defined as a Cerebral Performance Category score less than or equal to 2 at six months post-OHCA.
    Results: We identified 12 variables 24 h after admission, capable of predicting a six-month good neurological outcome. The best model (extreme gradient boosting) achieved an AUC of 0.96 and an accuracy of 0.92 in the test cohort.
    Conclusion: We demonstrated that it is possible to build accurate, locally optimised prediction and prognostication scores using datasets of limited size and breadth. We proposed and shared a generic machine-learning pipeline which allows external teams to replicate the approach locally.
    Language English
    Publishing date 2024-04-15
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2819396-9
    ISSN 2055-2076
    ISSN 2055-2076
    DOI 10.1177/20552076241234746
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Integrative Multimodal Metabolomics to Early Predict Cognitive Decline Among Amyloid Positive Community-Dwelling Older Adults.

    Tremblay-Franco, Marie / Canlet, Cécile / Carriere, Audrey / Nakhle, Jean / Galinier, Anne / Portais, Jean-Charles / Yart, Armelle / Dray, Cédric / Lu, Wan-Hsuan / Bertrand Michel, Justine / Guyonnet, Sophie / Rolland, Yves / Vellas, Bruno / Delrieu, Julien / Barreto, Philippe de Souto / Pénicaud, Luc / Casteilla, Louis / Ader, Isabelle

    The journals of gerontology. Series A, Biological sciences and medical sciences

    2024  Volume 79, Issue 5

    Abstract: Alzheimer's disease is strongly linked to metabolic abnormalities. We aimed to distinguish amyloid-positive people who progressed to cognitive decline from those who remained cognitively intact. We performed untargeted metabolomics of blood samples from ... ...

    Abstract Alzheimer's disease is strongly linked to metabolic abnormalities. We aimed to distinguish amyloid-positive people who progressed to cognitive decline from those who remained cognitively intact. We performed untargeted metabolomics of blood samples from amyloid-positive individuals, before any sign of cognitive decline, to distinguish individuals who progressed to cognitive decline from those who remained cognitively intact. A plasma-derived metabolite signature was developed from Supercritical Fluid chromatography coupled with high-resolution mass spectrometry (SFC-HRMS) and nuclear magnetic resonance (NMR) metabolomics. The 2 metabolomics data sets were analyzed by Data Integration Analysis for Biomarker discovery using Latent approaches for Omics studies (DIABLO), to identify a minimum set of metabolites that could describe cognitive decline status. NMR or SFC-HRMS data alone cannot predict cognitive decline. However, among the 320 metabolites identified, a statistical method that integrated the 2 data sets enabled the identification of a minimal signature of 9 metabolites (3-hydroxybutyrate, citrate, succinate, acetone, methionine, glucose, serine, sphingomyelin d18:1/C26:0 and triglyceride C48:3) with a statistically significant ability to predict cognitive decline more than 3 years before decline. This metabolic fingerprint obtained during this exploratory study may help to predict amyloid-positive individuals who will develop cognitive decline. Due to the high prevalence of brain amyloid-positivity in older adults, identifying adults who will have cognitive decline will enable the development of personalized and early interventions.
    MeSH term(s) Humans ; Aged ; Independent Living ; Alzheimer Disease/metabolism ; Amyloid/metabolism ; Cognitive Dysfunction/metabolism ; Brain/metabolism ; Metabolomics ; Amyloidogenic Proteins ; Amyloid beta-Peptides/metabolism ; Biomarkers
    Chemical Substances Amyloid ; Amyloidogenic Proteins ; Amyloid beta-Peptides ; Biomarkers
    Language English
    Publishing date 2024-03-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1223643-3
    ISSN 1758-535X ; 1079-5006
    ISSN (online) 1758-535X
    ISSN 1079-5006
    DOI 10.1093/gerona/glae077
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Periostin Plasma Levels and Changes on Physical and Cognitive Capacities in Community-Dwelling Older Adults.

    Sánchez-Sánchez, Juan Luis / Ader, Isabelle / Jeanson, Yannick / Planat-Benard, Valérie / Vellas, Bruno / Casteilla, Louis / de Souto-Barreto, Philipe

    The journals of gerontology. Series A, Biological sciences and medical sciences

    2022  Volume 78, Issue 3, Page(s) 424–432

    Abstract: Periostin, involved in extracellular matrix development and support, has been shown to be elevated in senescent tissues and fibrotic states, transversal signatures of aging. We aimed to explore associations between plasma periostin and physical and ... ...

    Abstract Periostin, involved in extracellular matrix development and support, has been shown to be elevated in senescent tissues and fibrotic states, transversal signatures of aging. We aimed to explore associations between plasma periostin and physical and cognitive capacity evolution among older adults. Our hypothesis was that higher levels of plasma periostin will be associated with worse physical and mental capacities along time. Analyses included 1 096 participants (mean age = 75.3 years ± 4.4; 63.9% women) from the Multidomain Alzheimer Preventive Trial. Periostin levels (pg/mL) were measured in plasma collected at year 1. Periostin was used in continuous variable, and as a dichotomous variable highest quartile (POSTN+) versus lowest 3 quartiles (POSTN-) were used. Outcomes were measured annually over 4 years and included: gait speed (GS), short physical performance battery (SPPB) score, 5-times sit-to-stand test (5-STS), and handgrip strength (HS) as physical and cognitive composite z-score (CCS) and the Mini-Mental State Examination (MMSE) as cognitive endpoints. Plasma periostin as a continuous variable was associated with the worsening of physical and cognitive capacities over 4 years of follow-up, specifically the SPPB score, the 5-STS, and CCS in full-adjusted models. POSTN+ was associated with worse evolution in the physical (GS: [β = -0.057, 95% confidence interval (CI) = -0.101, -0.013], SPPB score [β = -0.736, 95% CI = -1.091, -0.381], 5-STS [β = 1.681, 95% CI = 0.801, 2.561]) as well as cognitive (CCS [β = -0.215, 95% CI = -0.335, -0.094]) domains compared to POSTN- group. No association was found with HS or the MMSE score. Our study showed for the first time that increased plasma periostin levels were associated with declines in both physical and cognitive capacities in older adults over a 4-year follow-up. Further research is needed to evaluate whether periostin might be used as a predictive biomarker of functional decline at an older age.
    MeSH term(s) Aged ; Female ; Humans ; Male ; Aging/psychology ; Alzheimer Disease ; Cognition ; Cognitive Dysfunction ; Hand Strength ; Independent Living
    Chemical Substances POSTN protein, human
    Language English
    Publishing date 2022-11-14
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1223643-3
    ISSN 1758-535X ; 1079-5006
    ISSN (online) 1758-535X
    ISSN 1079-5006
    DOI 10.1093/gerona/glac226
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Explainable machine learning framework to predict personalized physiological aging.

    Bernard, David / Doumard, Emmanuel / Ader, Isabelle / Kemoun, Philippe / Pagès, Jean-Christophe / Galinier, Anne / Cussat-Blanc, Sylvain / Furger, Felix / Ferrucci, Luigi / Aligon, Julien / Delpierre, Cyrille / Pénicaud, Luc / Monsarrat, Paul / Casteilla, Louis

    Aging cell

    2023  Volume 22, Issue 8, Page(s) e13872

    Abstract: Attaining personalized healthy aging requires accurate monitoring of physiological changes and identifying subclinical markers that predict accelerated or delayed aging. Classic biostatistical methods most rely on supervised variables to estimate ... ...

    Abstract Attaining personalized healthy aging requires accurate monitoring of physiological changes and identifying subclinical markers that predict accelerated or delayed aging. Classic biostatistical methods most rely on supervised variables to estimate physiological aging and do not capture the full complexity of inter-parameter interactions. Machine learning (ML) is promising, but its black box nature eludes direct understanding, substantially limiting physician confidence and clinical usage. Using a broad population dataset from the National Health and Nutrition Examination Survey (NHANES) study including routine biological variables and after selection of XGBoost as the most appropriate algorithm, we created an innovative explainable ML framework to determine a Personalized physiological age (PPA). PPA predicted both chronic disease and mortality independently of chronological age. Twenty-six variables were sufficient to predict PPA. Using SHapley Additive exPlanations (SHAP), we implemented a precise quantitative associated metric for each variable explaining physiological (i.e., accelerated or delayed) deviations from age-specific normative data. Among the variables, glycated hemoglobin (HbA1c) displays a major relative weight in the estimation of PPA. Finally, clustering profiles of identical contextualized explanations reveal different aging trajectories opening opportunities to specific clinical follow-up. These data show that PPA is a robust, quantitative and explainable ML-based metric that monitors personalized health status. Our approach also provides a complete framework applicable to different datasets or variables, allowing precision physiological age estimation.
    MeSH term(s) Nutrition Surveys ; Algorithms ; Health Status ; Machine Learning
    Language English
    Publishing date 2023-06-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2113083-8
    ISSN 1474-9726 ; 1474-9718
    ISSN (online) 1474-9726
    ISSN 1474-9718
    DOI 10.1111/acel.13872
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Long-term use of liposomal nebulized amikacin and tedizolid for the treatment of disseminated nocardiosis after allogeneic hematopoietic stem cell transplantation.

    Soueges, Sarah / Triffault-Fillit, Claire / Roux, Sandrine / Labussière-Wallet, Hélène / Lebeaux, David / Dumitrescu, Oana / Morelec, Isabelle / Hodille, Elisabeth / Ader, Florence

    European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology

    2021  Volume 40, Issue 9, Page(s) 2033–2036

    Abstract: Nocardiosis is a life-threatening opportunistic infection in immunocompromised patients. Herein, we present successful adjunctive use of liposomal nebulized amikacin and tedizolid in a recipient of allogeneic hematopoietic stem cell transplantation ... ...

    Abstract Nocardiosis is a life-threatening opportunistic infection in immunocompromised patients. Herein, we present successful adjunctive use of liposomal nebulized amikacin and tedizolid in a recipient of allogeneic hematopoietic stem cell transplantation infected with Nocardia nova complex who presented multiple complications to conventional therapeutic options.
    MeSH term(s) Amikacin/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Immunosuppressive Agents/adverse effects ; Liposomes/administration & dosage ; Liposomes/chemistry ; Liposomes/therapeutic use ; Male ; Middle Aged ; Nebulizers and Vaporizers ; Nocardia/drug effects ; Nocardia Infections/diagnosis ; Nocardia Infections/drug therapy ; Oxazolidinones/pharmacology ; Tetrazoles/pharmacology ; Time Factors
    Chemical Substances Anti-Bacterial Agents ; Immunosuppressive Agents ; Liposomes ; Oxazolidinones ; Tetrazoles ; Amikacin (84319SGC3C) ; tedizolid (97HLQ82NGL)
    Language English
    Publishing date 2021-03-10
    Publishing country Germany
    Document type Case Reports ; Journal Article
    ZDB-ID 603155-9
    ISSN 1435-4373 ; 0934-9723 ; 0722-2211
    ISSN (online) 1435-4373
    ISSN 0934-9723 ; 0722-2211
    DOI 10.1007/s10096-021-04186-6
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  6. Article: Lactate Fluxes and Plasticity of Adipose Tissues: A Redox Perspective.

    Lagarde, Damien / Jeanson, Yannick / Portais, Jean-Charles / Galinier, Anne / Ader, Isabelle / Casteilla, Louis / Carrière, Audrey

    Frontiers in physiology

    2021  Volume 12, Page(s) 689747

    Abstract: Lactate, a metabolite produced when the glycolytic flux exceeds mitochondrial oxidative capacities, is now viewed as a critical regulator of metabolism by acting as both a carbon and electron carrier and a signaling molecule between cells and tissues. In ...

    Abstract Lactate, a metabolite produced when the glycolytic flux exceeds mitochondrial oxidative capacities, is now viewed as a critical regulator of metabolism by acting as both a carbon and electron carrier and a signaling molecule between cells and tissues. In recent years, increasing evidence report its key role in white, beige, and brown adipose tissue biology, and highlights new mechanisms by which lactate participates in the maintenance of whole-body energy homeostasis. Lactate displays a wide range of biological effects in adipose cells not only through its binding to the membrane receptor but also through its transport and the subsequent effect on intracellular metabolism notably on redox balance. This study explores how lactate regulates adipocyte metabolism and plasticity by balancing intracellular redox state and by regulating specific signaling pathways. We also emphasized the contribution of adipose tissues to the regulation of systemic lactate metabolism, their roles in redox homeostasis, and related putative physiopathological repercussions associated with their decline in metabolic diseases and aging.
    Language English
    Publishing date 2021-06-30
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2021.689747
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  7. Article ; Online: FTY720 (Fingolimod) Inhibits HIF1 and HIF2 Signaling, Promotes Vascular Remodeling, and Chemosensitizes in Renal Cell Carcinoma Animal Model.

    Gstalder, Cécile / Ader, Isabelle / Cuvillier, Olivier

    Molecular cancer therapeutics

    2016  Volume 15, Issue 10, Page(s) 2465–2474

    Abstract: Clear cell renal cell carcinoma (ccRCC) is characterized by intratumoral hypoxia and chemoresistance. The hypoxia-inducible factors HIF1α and HIF2α play a crucial role in ccRCC initiation and progression. We previously identified the sphingosine kinase 1/ ...

    Abstract Clear cell renal cell carcinoma (ccRCC) is characterized by intratumoral hypoxia and chemoresistance. The hypoxia-inducible factors HIF1α and HIF2α play a crucial role in ccRCC initiation and progression. We previously identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) pathway as a new modulator of HIF1α and HIF2α under hypoxia in various cancer cell models. Here, we report that FTY720, an inhibitor of the S1P signaling pathway, inhibits both HIF1α and HIF2α accumulation in several human cancer cell lines. In a ccRCC heterotopic xenograft model, we show that FTY720 transiently decreases HIF1α and HIF2α intratumoral level and modifies tumor vessel architecture within 5 days of treatment, suggesting a vascular normalization. In mice bearing subcutaneous ccRCC tumor, FTY720 and a gemcitabine-based chemotherapy alone display a limited effect, whereas, in combination, there is a significant effect on tumor size without toxicity. Noteworthy, administration of FTY720 for 5 days before chemotherapy is not associated with a more effective tumor control, suggesting a mode of action mainly independent of the vascular remodeling. In conclusion, these findings demonstrate that FTY720 could successfully sensitize ccRCC to chemotherapy and establish this molecule as a potent therapeutic agent for ccRCC treatment, independently of drug scheduling. Mol Cancer Ther; 15(10); 2465-74. ©2016 AACR.
    MeSH term(s) Animals ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Carcinoma, Renal Cell/drug therapy ; Carcinoma, Renal Cell/genetics ; Carcinoma, Renal Cell/metabolism ; Carcinoma, Renal Cell/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Disease Models, Animal ; Drug Resistance, Neoplasm ; Female ; Fingolimod Hydrochloride/pharmacology ; Gene Expression ; Humans ; Hypoxia/genetics ; Hypoxia/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Lysophospholipids ; Mice ; Neovascularization, Pathologic/drug therapy ; Neovascularization, Pathologic/metabolism ; Oxygen Consumption ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Receptors, Lysosphingolipid/metabolism ; Signal Transduction/drug effects ; Sphingosine/analogs & derivatives ; Vascular Endothelial Growth Factor A/biosynthesis ; Vascular Remodeling/drug effects ; Xenograft Model Antitumor Assays
    Chemical Substances Antineoplastic Agents ; Basic Helix-Loop-Helix Transcription Factors ; HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; Lysophospholipids ; Receptors, Lysosphingolipid ; Vascular Endothelial Growth Factor A ; endothelial PAS domain-containing protein 1 (1B37H0967P) ; sphingosine 1-phosphate (26993-30-6) ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; sphingosine kinase (EC 2.7.1.-) ; Fingolimod Hydrochloride (G926EC510T) ; Sphingosine (NGZ37HRE42)
    Language English
    Publishing date 2016-08-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-16-0167
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: The emerging roles of lactate as a redox substrate and signaling molecule in adipose tissues.

    Carrière, Audrey / Lagarde, Damien / Jeanson, Yannick / Portais, Jean-Charles / Galinier, Anne / Ader, Isabelle / Casteilla, Louis

    Journal of physiology and biochemistry

    2020  Volume 76, Issue 2, Page(s) 241–250

    Abstract: Thermogenic (brown and beige) adipose tissues improve glucose and lipid homeostasis and therefore represent putative targets to cure obesity and related metabolic diseases including type II diabetes. Beside decades of research and the very well-described ...

    Abstract Thermogenic (brown and beige) adipose tissues improve glucose and lipid homeostasis and therefore represent putative targets to cure obesity and related metabolic diseases including type II diabetes. Beside decades of research and the very well-described role of noradrenergic signaling, mechanisms underlying adipocytes plasticity and activation of thermogenic adipose tissues remain incompletely understood. Recent studies show that metabolites such as lactate control the oxidative capacity of thermogenic adipose tissues. Long time viewed as a metabolic waste product, lactate is now considered as an important metabolic substrate largely feeding the oxidative metabolism of many tissues, acting as a signaling molecule and as an inter-cellular and inter-tissular redox carrier. In this review, we provide an overview of the recent findings highlighting the importance of lactate in adipose tissues, from its production to its role as a browning inducer and its metabolic links with brown adipose tissue. We also discuss additional function(s) than thermogenesis ensured by brown and beige adipose tissues, i.e., their ability to dissipate high redox pressure and oxidative stress thanks to the activity of the uncoupling protein-1, helping to maintain tissue and whole organism redox homeostasis and integrity.
    MeSH term(s) Adipose Tissue, Beige/cytology ; Adipose Tissue, Beige/metabolism ; Adipose Tissue, Brown/cytology ; Adipose Tissue, Brown/metabolism ; Animals ; Energy Metabolism ; Humans ; Lactic Acid/metabolism ; Oxidation-Reduction ; Oxidative Stress ; Thermogenesis ; Uncoupling Protein 1/metabolism
    Chemical Substances UCP1 protein, human ; Uncoupling Protein 1 ; Lactic Acid (33X04XA5AT)
    Language English
    Publishing date 2020-01-02
    Publishing country Spain
    Document type Journal Article ; Review
    ZDB-ID 1325104-1
    ISSN 1877-8755 ; 0034-9402 ; 1138-7548
    ISSN (online) 1877-8755
    ISSN 0034-9402 ; 1138-7548
    DOI 10.1007/s13105-019-00723-2
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  9. Article ; Online: CD36 Drives Metastasis and Relapse in Acute Myeloid Leukemia.

    Farge, Thomas / Nakhle, Jean / Lagarde, Damien / Cognet, Guillaume / Polley, Nathaniel / Castellano, Rémy / Nicolau, Marie-Laure / Bosc, Claudie / Sabatier, Marie / Sahal, Ambrine / Saland, Estelle / Jeanson, Yannick / Guiraud, Nathan / Boet, Emeline / Bergoglio, Camille / Gotanègre, Mathilde / Mouchel, Pierre-Luc / Stuani, Lucille / Larrue, Clément /
    Sallese, Marie / De Mas, Véronique / Moro, Cedric / Dray, Cédric / Collette, Yves / Raymond-Letron, Isabelle / Ader, Isabelle / Récher, Christian / Sarry, Jean-Emmanuel / Cabon, Florence / Vergez, François / Carrière, Audrey

    Cancer research

    2023  Volume 83, Issue 17, Page(s) 2824–2838

    Abstract: Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in hematologic malignancies suggests that it could also play a role in drug resistance and ... ...

    Abstract Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in hematologic malignancies suggests that it could also play a role in drug resistance and relapse in acute myeloid leukemia (AML). In a cohort of 1,273 AML patients, we uncovered that the multifunctional scavenger receptor CD36 was positively associated with extramedullary dissemination of leukemic blasts, increased risk of relapse after intensive chemotherapy, and reduced event-free and overall survival. CD36 was dispensable for lipid uptake but fostered blast migration through its binding with thrombospondin-1. CD36-expressing blasts, which were largely enriched after chemotherapy, exhibited a senescent-like phenotype while maintaining their migratory ability. In xenograft mouse models, CD36 inhibition reduced metastasis of blasts and prolonged survival of chemotherapy-treated mice. These results pave the way for the development of CD36 as an independent marker of poor prognosis in AML patients and a promising actionable target to improve the outcome of patients.
    Significance: CD36 promotes blast migration and extramedullary disease in acute myeloid leukemia and represents a critical target that can be exploited for clinical prognosis and patient treatment.
    MeSH term(s) Humans ; Animals ; Mice ; Leukemia, Myeloid, Acute/pathology ; Treatment Outcome ; Prognosis ; Recurrence ; Blast Crisis/pathology ; Chronic Disease
    Language English
    Publishing date 2023-06-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-22-3682
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  10. Article ; Online: Hypoxia-inducible factors and sphingosine 1-phosphate signaling.

    Cuvillier, Olivier / Ader, Isabelle

    Anti-cancer agents in medicinal chemistry

    2011  Volume 11, Issue 9, Page(s) 854–862

    Abstract: Hypoxia, defined as reduced tissue oxygen concentration, is a characteristic of solid tumors and is an indicator of unfavorable diagnosis in patients. At the cellular level, the adaptation to hypoxia is under the control of two related transcription ... ...

    Abstract Hypoxia, defined as reduced tissue oxygen concentration, is a characteristic of solid tumors and is an indicator of unfavorable diagnosis in patients. At the cellular level, the adaptation to hypoxia is under the control of two related transcription factors, HIF-1α and HIF-2α (Hypoxia-Inducible Factor), which activate expression of genes promoting angiogenesis, metastasis, increased tumor growth and resistance to treatments. A role for HIF-1α and HIF-2α is also emerging in hematologic malignancies such as lymphoma and l eukemia. Recent studies have identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) signaling pathway - which elicits various cellular processes including cell proliferation, cell survival or angiogenesis - as a new regulator of HIF-1α or HIF-2α activity. This review will consider how targeting the SphK1/S1P signaling could represent an attractive strategy for therapeutic intervention in cancer.
    MeSH term(s) Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Hematologic Neoplasms/drug therapy ; Hematologic Neoplasms/metabolism ; Humans ; Hypoxia-Inducible Factor 1/metabolism ; Lysophospholipids/metabolism ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; Signal Transduction/drug effects ; Sphingosine/analogs & derivatives ; Sphingosine/metabolism
    Chemical Substances Antineoplastic Agents ; Basic Helix-Loop-Helix Transcription Factors ; Hypoxia-Inducible Factor 1 ; Lysophospholipids ; endothelial PAS domain-containing protein 1 (1B37H0967P) ; sphingosine 1-phosphate (26993-30-6) ; Phosphotransferases (Alcohol Group Acceptor) (EC 2.7.1.-) ; sphingosine kinase (EC 2.7.1.-) ; Sphingosine (NGZ37HRE42)
    Language English
    Publishing date 2011-06-25
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2217610-X
    ISSN 1875-5992 ; 1871-5206
    ISSN (online) 1875-5992
    ISSN 1871-5206
    DOI 10.2174/187152011797655050
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