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Article: Pharmacological Inhibition of Oncogenic STAT3 and STAT5 Signaling in Hematopoietic Cancers.

Brachet-Botineau, Marie / Polomski, Marion / Neubauer, Heidi A / Juen, Ludovic / Hédou, Damien / Viaud-Massuard, Marie-Claude / Prié, Gildas / Gouilleux, Fabrice

Cancers

2020 Volume 12, Issue 1

Abstract: Signal Transducer and Activator of Transcription (STAT) 3 and 5 are important effectors of cellular transformation, and aberrant STAT3 and STAT5 signaling have been demonstrated in hematopoietic cancers. STAT3 and STAT5 are common targets for different ... ...

Abstract	Signal Transducer and Activator of Transcription (STAT) 3 and 5 are important effectors of cellular transformation, and aberrant STAT3 and STAT5 signaling have been demonstrated in hematopoietic cancers. STAT3 and STAT5 are common targets for different tyrosine kinase oncogenes (TKOs). In addition, STAT3 and STAT5 proteins were shown to contain activating mutations in some rare but aggressive leukemias/lymphomas. Both proteins also contribute to drug resistance in hematopoietic malignancies and are now well recognized as major targets in cancer treatment. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations during the last decade. This review summarizes the current knowledge of oncogenic STAT3 and STAT5 functions in hematopoietic cancers as well as advances in preclinical and clinical development of pharmacological inhibitors.
Language	English
Publishing date	2020-01-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12010240
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Article ; Online: Evaluation of Alternative Diagnostic Follow-up Intervals for Lung Reporting and Data System Criteria on the Effectiveness of Lung Cancer Screening.

Bastani, Mehrad / Toumazis, Iakovos / Hedou', Julien / Leung, Ann / Plevritis, Sylvia K

Journal of the American College of Radiology : JACR

2021 Volume 18, Issue 12, Page(s) 1614–1623

Abstract: Purpose: The ACR developed the Lung CT Screening Reporting and Data System (Lung-RADS) to standardize the diagnostic follow-up of suspicious screening findings. A retrospective analysis showed that Lung-RADS would have reduced the false-positive rate in ...

Abstract	Purpose: The ACR developed the Lung CT Screening Reporting and Data System (Lung-RADS) to standardize the diagnostic follow-up of suspicious screening findings. A retrospective analysis showed that Lung-RADS would have reduced the false-positive rate in the National Lung Screening Trial, but the optimal timing of follow-up examinations has not been established. In this study, we assess the effectiveness of alternative diagnostic follow-up intervals on lung cancer screening. Methods: We used the Lung Cancer Outcome Simulator to estimate population-level outcomes of alternative diagnostic follow-up intervals for Lung-RADS categories 3 and 4A. The Lung Cancer Outcome Simulator is a microsimulation model developed within the Cancer Intervention and Surveillance Modeling Network Consortium to evaluate outcomes of national screening guidelines. Here, among the evaluated outcomes are percentage of mortality reduction, screens performed, lung cancer deaths averted, screen-detected cases, and average number of screens and follow-ups per death averted. Results: The recommended 3-month follow-up interval for Lung-RADS category 4A is optimal. However, for Lung-RADS category 3, a 5-month, instead of the recommended 6-month, follow-up interval yielded a higher mortality reduction (0.08% for men versus 0.05% for women), and a higher number of deaths averted (36 versus 27), a higher number of screen-detected cases (13 versus 7), and a lower number of combined low-dose CTs and diagnostic follow-ups per death avoided (8 versus 5), per one million general population. Sensitivity analysis of nodule progression threshold verifies a higher mortality reduction with a 1-month earlier follow-up for Lung-RADS 3. Conclusions: One-month earlier diagnostic follow-ups for individuals with Lung-RADS category 3 nodules may result in a higher mortality reduction and warrants further investigation.
MeSH term(s)	Early Detection of Cancer ; Female ; Follow-Up Studies ; Humans ; Lung ; Lung Neoplasms/diagnostic imaging ; Male ; Retrospective Studies ; Tomography, X-Ray Computed
Language	English
Publishing date	2021-08-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2274861-1
ISSN	1558-349X ; 1546-1440
ISSN (online)	1558-349X
ISSN	1546-1440
DOI	10.1016/j.jacr.2021.08.001
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Article ; Online: Comment on 'Cutaneous manifestations in COVID-19: a first perspective' by Recalcati S.

Hedou, M / Carsuzaa, F / Chary, E / Hainaut, E / Cazenave-Roblot, F / Masson Regnault, M

Journal of the European Academy of Dermatology and Venereology : JEADV

2020 Volume 34, Issue 7, Page(s) e299–e300

MeSH term(s)	Betacoronavirus ; COVID-19 ; Coronavirus Infections ; Humans ; Pandemics ; Pneumonia, Viral ; SARS-CoV-2 ; Skin Diseases/virology
Keywords	covid19
Language	English
Publishing date	2020-04-19
Publishing country	England
Document type	Letter ; Comment
ZDB-ID	1128828-0
ISSN	1468-3083 ; 0926-9959
ISSN (online)	1468-3083
ISSN	0926-9959
DOI	10.1111/jdv.16519
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Article ; Online: Discovery of sparse, reliable omic biomarkers with Stabl.

Hédou, Julien / Marić, Ivana / Bellan, Grégoire / Einhaus, Jakob / Gaudillière, Dyani K / Ladant, Francois-Xavier / Verdonk, Franck / Stelzer, Ina A / Feyaerts, Dorien / Tsai, Amy S / Ganio, Edward A / Sabayev, Maximilian / Gillard, Joshua / Amar, Jonas / Cambriel, Amelie / Oskotsky, Tomiko T / Roldan, Alennie / Golob, Jonathan L / Sirota, Marina /

Bonham, Thomas A / Sato, Masaki / Diop, Maïgane / Durand, Xavier / Angst, Martin S / Stevenson, David K / Aghaeepour, Nima / Montanari, Andrea / Gaudillière, Brice

Nature biotechnology

2024

Abstract: Adoption of high-content omic technologies in clinical studies, coupled with computational methods, has yielded an abundance of candidate biomarkers. However, translating such findings into bona fide clinical biomarkers remains challenging. To facilitate ...

Abstract	Adoption of high-content omic technologies in clinical studies, coupled with computational methods, has yielded an abundance of candidate biomarkers. However, translating such findings into bona fide clinical biomarkers remains challenging. To facilitate this process, we introduce Stabl, a general machine learning method that identifies a sparse, reliable set of biomarkers by integrating noise injection and a data-driven signal-to-noise threshold into multivariable predictive modeling. Evaluation of Stabl on synthetic datasets and five independent clinical studies demonstrates improved biomarker sparsity and reliability compared to commonly used sparsity-promoting regularization methods while maintaining predictive performance; it distills datasets containing 1,400-35,000 features down to 4-34 candidate biomarkers. Stabl extends to multi-omic integration tasks, enabling biological interpretation of complex predictive models, as it hones in on a shortlist of proteomic, metabolomic and cytometric events predicting labor onset, microbial biomarkers of pre-term birth and a pre-operative immune signature of post-surgical infections. Stabl is available at https://github.com/gregbellan/Stabl .
Language	English
Publishing date	2024-01-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	1311932-1
ISSN	1546-1696 ; 1087-0156
ISSN (online)	1546-1696
ISSN	1087-0156
DOI	10.1038/s41587-023-02033-x
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Zs.A 2167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Stabl: sparse and reliable biomarker discovery in predictive modeling of high-dimensional omic data.

Research square

2023

Abstract: High-content omic technologies coupled with sparsity-promoting regularization methods (SRM) have transformed the biomarker discovery process. However, the translation of computational results into a clinical use-case scenario remains challenging. A rate- ... ...

Abstract	High-content omic technologies coupled with sparsity-promoting regularization methods (SRM) have transformed the biomarker discovery process. However, the translation of computational results into a clinical use-case scenario remains challenging. A rate-limiting step is the rigorous selection of reliable biomarker candidates among a host of biological features included in multivariate models. We propose Stabl, a machine learning framework that unifies the biomarker discovery process with multivariate predictive modeling of clinical outcomes by selecting a sparse and reliable set of biomarkers. Evaluation of Stabl on synthetic datasets and four independent clinical studies demonstrates improved biomarker sparsity and reliability compared to commonly used SRMs at similar predictive performance. Stabl readily extends to double- and triple-omics integration tasks and identifies a sparser and more reliable set of biomarkers than those selected by state-of-the-art early- and late-fusion SRMs, thereby facilitating the biological interpretation and clinical translation of complex multi-omic predictive models. The complete package for Stabl is available online at https://github.com/gregbellan/Stabl.
Language	English
Publishing date	2023-02-28
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-2609859/v1
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Article ; Online: Proteomic biomarkers of Kleine-Levin syndrome.

Hédou, Julien / Cederberg, Katie L / Ambati, Aditya / Lin, Ling / Farber, Neal / Dauvilliers, Yves / Quadri, Mohammed / Bourgin, Patrice / Plazzi, Giuseppe / Andlauer, Olivier / Hong, Seung-Chul / Huang, Yu-Shu / Leu-Semenescu, Smaranda / Arnulf, Isabelle / Taheri, Shahrad / Mignot, Emmanuel

Sleep

2022 Volume 45, Issue 9

Abstract: Study objectives: Kleine-Levin syndrome (KLS) is characterized by relapsing-remitting episodes of hypersomnia, cognitive impairment, and behavioral disturbances. We quantified cerebrospinal fluid (CSF) and serum proteins in KLS cases and controls.: ... ...

Abstract	Study objectives: Kleine-Levin syndrome (KLS) is characterized by relapsing-remitting episodes of hypersomnia, cognitive impairment, and behavioral disturbances. We quantified cerebrospinal fluid (CSF) and serum proteins in KLS cases and controls. Methods: SomaScan was used to profile 1133 CSF proteins in 30 KLS cases and 134 controls, while 1109 serum proteins were profiled in serum from 26 cases and 65 controls. CSF and serum proteins were both measured in seven cases. Univariate and multivariate analyses were used to find differentially expressed proteins (DEPs). Pathway and tissue enrichment analyses (TEAs) were performed on DEPs. Results: Univariate analyses found 28 and 141 proteins differentially expressed in CSF and serum, respectively (false discovery rate <0.1%). Upregulated CSF proteins included IL-34, IL-27, TGF-b, IGF-1, and osteonectin, while DKK4 and vWF were downregulated. Pathway analyses revealed microglial alterations and disrupted blood-brain barrier permeability. Serum profiles show upregulation of Src-family kinases (SFKs), proteins implicated in cellular growth, motility, and activation. TEA analysis of up- and downregulated proteins revealed changes in brain proteins (p < 6 × 10-5), notably from the pons, medulla, and midbrain. A multivariate machine-learning classifier performed robustly, achieving a receiver operating curve area under the curve of 0.90 (95% confidence interval [CI] = 0.78-1.0, p = 0.0006) in CSF and 1.0 (95% CI = 1.0-1.0, p = 0.0002) in serum in validation cohorts, with some commonality across tissues, as the model trained on serum sample also discriminated CSF samples of controls versus KLS cases. Conclusions: Our study identifies proteomic KLS biomarkers with diagnostic potential and provides insight into biological mechanisms that will guide future research in KLS.
MeSH term(s)	Biomarkers ; Cognitive Dysfunction ; Disorders of Excessive Somnolence ; Humans ; Kleine-Levin Syndrome ; Proteomics
Chemical Substances	Biomarkers
Language	English
Publishing date	2022-07-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	424441-2
ISSN	1550-9109 ; 0161-8105
ISSN (online)	1550-9109
ISSN	0161-8105
DOI	10.1093/sleep/zsac097
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Article ; Online: Human immune system adaptations to simulated microgravity revealed by single-cell mass cytometry.

Spatz, J M / Fulford, M Hughes / Tsai, A / Gaudilliere, D / Hedou, J / Ganio, E / Angst, M / Aghaeepour, N / Gaudilliere, Brice

Scientific reports

2021 Volume 11, Issue 1, Page(s) 11872

Abstract: Exposure to microgravity (µG) during space flights produces a state of immunosuppression, leading to increased viral shedding, which could interfere with long term missions. However, the cellular mechanisms that underlie the immunosuppressive effects of ... ...

Abstract	Exposure to microgravity (µG) during space flights produces a state of immunosuppression, leading to increased viral shedding, which could interfere with long term missions. However, the cellular mechanisms that underlie the immunosuppressive effects of µG are ill-defined. A deep understanding of human immune adaptations to µG is a necessary first step to design data-driven interventions aimed at preserving astronauts' immune defense during short- and long-term spaceflights. We employed a high-dimensional mass cytometry approach to characterize over 250 cell-specific functional responses in 18 innate and adaptive immune cell subsets exposed to 1G or simulated (s)µG using the Rotating Wall Vessel. A statistically stringent elastic net method produced a multivariate model that accurately stratified immune responses observed in 1G and sµG (p value 2E-4, cross-validation). Aspects of our analysis resonated with prior knowledge of human immune adaptations to µG, including the dampening of Natural Killer, CD4
MeSH term(s)	Adaptation, Physiological/genetics ; Adaptation, Physiological/immunology ; Adult ; Flow Cytometry/methods ; Humans ; Immune System/cytology ; Immune System/immunology ; Immune System/metabolism ; Middle Aged ; RNA, Messenger/genetics ; RNA, Messenger/immunology ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/genetics ; Signal Transduction/immunology ; Single-Cell Analysis/methods ; Space Flight/methods ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Transcriptome/immunology ; Weightlessness Simulation ; Young Adult
Chemical Substances	RNA, Messenger
Language	English
Publishing date	2021-06-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-90458-2
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Article: Proteostasis During Cerebral Ischemia.

Thiebaut, Audrey M / Hedou, Elodie / Marciniak, Stefan J / Vivien, Denis / Roussel, Benoit D

Frontiers in neuroscience

2019 Volume 13, Page(s) 637

Abstract: Cerebral ischemia is a complex pathology involving a cascade of cellular mechanisms, which deregulate proteostasis and lead to neuronal death. Proteostasis refers to the equilibrium between protein synthesis, folding, transport, and protein degradation. ... ...

Abstract	Cerebral ischemia is a complex pathology involving a cascade of cellular mechanisms, which deregulate proteostasis and lead to neuronal death. Proteostasis refers to the equilibrium between protein synthesis, folding, transport, and protein degradation. Within the brain proteostasis plays key roles in learning and memory by controlling protein synthesis and degradation. Two important pathways are implicated in the regulation of proteostasis: the unfolded protein response (UPR) and macroautophagy (called hereafter autophagy). Both are necessary for cell survival, however, their over-activation in duration or intensity can lead to cell death. Moreover, UPR and autophagy can activate and potentiate each other to worsen the issue of cerebral ischemia. A better understanding of autophagy and ER stress will allow the development of therapeutic strategies for stroke, both at the acute phase and during recovery. This review summarizes the latest therapeutic advances implicating ER stress or autophagy in cerebral ischemia. We argue that the processes governing proteostasis should be considered together in stroke, rather than focusing either on ER stress or autophagy in isolation.
Language	English
Publishing date	2019-06-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2019.00637
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Article ; Online: Proteomic Biomarkers of the Apnea Hypopnea Index and Obstructive Sleep Apnea: Insights into the Pathophysiology of Presence, Severity, and Treatment Response.

Cederberg, Katie L J / Hanif, Umaer / Peris Sempere, Vicente / Hédou, Julien / Leary, Eileen B / Schneider, Logan D / Lin, Ling / Zhang, Jing / Morse, Anne M / Blackman, Adam / Schweitzer, Paula K / Kotagal, Suresh / Bogan, Richard / Kushida, Clete A / Ju, Yo-El S / Petousi, Nayia / Turnbull, Chris D / Mignot, Emmanuel / The Stages Cohort Investigator Group

International journal of molecular sciences

2022 Volume 23, Issue 14

Abstract: Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and ... ...

Abstract	Obstructive sleep apnea (OSA), a disease associated with excessive sleepiness and increased cardiovascular risk, affects an estimated 1 billion people worldwide. The present study examined proteomic biomarkers indicative of presence, severity, and treatment response in OSA. Participants (n = 1391) of the Stanford Technology Analytics and Genomics in Sleep study had blood collected and completed an overnight polysomnography for scoring the apnea−hypopnea index (AHI). A highly multiplexed aptamer-based array (SomaScan) was used to quantify 5000 proteins in all plasma samples. Two separate intervention-based cohorts with sleep apnea (n = 41) provided samples pre- and post-continuous/positive airway pressure (CPAP/PAP). Multivariate analyses identified 84 proteins (47 positively, 37 negatively) associated with AHI after correction for multiple testing. Of the top 15 features from a machine learning classifier for AHI ≥ 15 vs. AHI < 15 (Area Under the Curve (AUC) = 0.74), 8 were significant markers of both AHI and OSA from multivariate analyses. Exploration of pre- and post-intervention analysis identified 5 of the 84 proteins to be significantly decreased following CPAP/PAP treatment, with pathways involving endothelial function, blood coagulation, and inflammatory response. The present study identified PAI-1, tPA, and sE-Selectin as key biomarkers and suggests that endothelial dysfunction and increased coagulopathy are important consequences of OSA, which may explain the association with cardiovascular disease and stroke.
MeSH term(s)	Biomarkers ; Continuous Positive Airway Pressure ; Humans ; Polysomnography ; Proteomics ; Sleep Apnea, Obstructive/complications ; Sleep Apnea, Obstructive/diagnosis ; Sleep Apnea, Obstructive/therapy
Chemical Substances	Biomarkers
Language	English
Publishing date	2022-07-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23147983
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Article: An immune signature of postoperative cognitive decline in elderly patients.

bioRxiv : the preprint server for biology

2024

Abstract: Postoperative cognitive decline (POCD) is the predominant complication affecting elderly patients following major surgery, yet its prediction and prevention remain challenging. Understanding biological processes underlying the pathogenesis of POCD is ... ...

Abstract	Postoperative cognitive decline (POCD) is the predominant complication affecting elderly patients following major surgery, yet its prediction and prevention remain challenging. Understanding biological processes underlying the pathogenesis of POCD is essential for identifying mechanistic biomarkers to advance diagnostics and therapeutics. This longitudinal study involving 26 elderly patients undergoing orthopedic surgery aimed to characterize the impact of peripheral immune cell responses to surgical trauma on POCD. Trajectory analyses of single-cell mass cytometry data highlighted early JAK/STAT signaling exacerbation and diminished MyD88 signaling post-surgery in patients who developed POCD. Further analyses integrating single-cell and plasma proteomic data collected before surgery with clinical variables yielded a sparse predictive model that accurately identified patients who would develop POCD (AUC = 0.80). The resulting POCD immune signature included one plasma protein and ten immune cell features, offering a concise list of biomarker candidates for developing point-of-care prognostic tests to personalize perioperative management of at-risk patients. The code and the data are documented and available at https://github.com/gregbellan/POCD . Teaser: Modeling immune cell responses and plasma proteomic data predicts postoperative cognitive decline.
Language	English
Publishing date	2024-03-05
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.02.582845
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