Publications by authors named "M J Rubio"

1,496 Publications

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Thrombolysis by PLAT/tPA increases serum free IGF1 leading to a decrease of deleterious autophagy following brain ischemia.

Autophagy 2021 Sep 14:1-21. Epub 2021 Sep 14.

Physiopathology and Imaging of Neurological Disorders (PhIND), Institute Blood and Brain @Caen-Normandie ([email protected]), GIP Cyceron, Normandy University, UNICAEN, INSERM, UMR-S U1237, Caen, France.

Cerebral ischemia is a pathology involving a cascade of cellular mechanisms, leading to the deregulation of proteostasis, including macroautophagy/autophagy, and finally to neuronal death. If it is now accepted that cerebral ischemia induces autophagy, the effect of thrombolysis/energy recovery on proteostasis remains unknown. Here, we investigated the effect of thrombolysis by PLAT/tPA (plasminogen activator, tissue) on autophagy and neuronal death. In two models of hypoxia reperfusion and an model of thromboembolic stroke with thrombolysis by PLAT/tPA, we found that ischemia enhances neuronal deleterious autophagy. Interestingly, PLAT/tPA decreases autophagy to mediate neuroprotection by modulating the PI3K-AKT-MTOR pathways both and . We identified IGF1R (insulin-like growth factor I receptor; a tyrosine kinase receptor) as the effective receptor and showed and in human stroke patients and that PLAT/tPA is able to degrade IGFBP3 (insulin-like growth factor binding protein 3) to increase IGF1 (insulin-like growth factor 1) bioavailability and thus IGF1R activation. AKT/protein kinase B: thymoma viral proto-oncogene 1; EGFR: epidermal growth factor receptor; Hx: hypoxia; IGF1: insulin-like growth factor 1; IGF1R: insulin-like growth factor I receptor; IGFBP3: insulin-like growth factor binding protein 3; Ka: Kainate; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK/ERK: mitogen-activated protein kinase; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OGD: oxygen and glucose deprivation; OGD: oxygen and glucose deprivation + reoxygentation; PepA: pepstatin A1; PI3K: phosphoinositide 3-kinase; PLAT/tPA: plasminogen activator, tissue; PPP: picropodophyllin; SCH77: SCH772984; ULK1: unc-51 like kinase 1; Wort: wortmannin.
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http://dx.doi.org/10.1080/15548627.2021.1973339DOI Listing
September 2021

Improved outcome in children compared to adolescents and young adults after allogeneic hematopoietic stem cell transplant for acute myeloid leukemia: a retrospective study from the Francophone Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC).

J Cancer Res Clin Oncol 2021 Sep 4. Epub 2021 Sep 4.

Department of Haematology, Hôpital de Haute-Pierre, 67200, Strasbourg, France.

Background: There are currently few data on the outcome of acute myeloid leukemia (AML) in adolescents after allogeneic HSCT. The aim of this study is to describe the outcome and its specific risk factors for children, adolescents and young adults after a first allogeneic HSCT for AML.

Methods: In this retrospective study, we compared the outcome of AML patients receiving a first allogeneic HSCT between 2005 and 2017 according to their age at transplantation's time: children (< 15 years, n = 564), adolescent and post-adolescent (APA) patients (15-25 years, n = 647) and young adults (26-40 years; n = 1434).

Results: With a median follow-up of 4.37 years (min-max 0.18-14.73 years), the probability of 2-year overall survival (OS) was 71.4% in children, 61.1% in APA patients and 62.9% in young adults (p = 0.0009 for intergroup difference). Both relapse and non-relapse mortality (NRM) Cumulative Incidence (CI) estimated at 2 years were different between the age groups (30.8% for children, 35.2% for APA patients and 29.4% for young adults-p = 0.0254, and 7.0% for children, 10.6% for APA patients and 14.2% for young adults, p < 0.0001; respectively). Whilst there was no difference between the three groups for grade I to IV acute GVHD CI at 3 months, the chronic GVHD CI at 2 years was higher in APA patients and young adults (31.4% and 36.4%, respectively) in comparison to the children (17.5%) (p < 0.0001). In multivariable analysis, factors associated with death were AML cytogenetics (HR1.73 [1.29-2.32] for intermediate risk 1, HR 1.50 [1.13-2.01] for intermediate risk 2, HR 2.22 [1.70-2.89] for high cytogenetics risk compared to low risk), use of TBI ≥ 8 Grays (HR 1.33 [1.09-1.61]), disease status at transplant (HR 1.40 [1.10-1.78] for second Complete Remission (CR), HR 2.26 [1.02-4.98] for third CR and HR 3.07 [2.44-3.85] for active disease, compared to first CR), graft source (HR 1.26 [1.05-1.50] for Peripheral Blood Stem Cells compared to Bone Marrow) and donor age (HR 1.01 (1-1.02] by increase of 1 year).

Conclusion: Age is an independent risk factor for NRM and extensive chronic GVHD. This study suggests that APA patients with AML could be beneficially treated with a chemotherapy-based MAC regimen and bone marrow as a stem cells source.
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http://dx.doi.org/10.1007/s00432-021-03761-wDOI Listing
September 2021

Outcomes of Young Patients With Alcoholic Cirrhosis After First Hospitalization for Cirrhosis: A Carilion Clinic Experience.

Cureus 2021 Jul 28;13(7):e16695. Epub 2021 Jul 28.

Gastroenterology and Hepatology, Virginia Tech Carilion School of Medicine, Roanoke, USA.

Background  Alcoholic cirrhosis though uncommon in young patients is being reported more frequently and related mortality is also increasing.  Study aim  To evaluate risk factors associated with mortality among young patients (<40 years) with alcoholic cirrhosis and older patients (> 40 years old) after their first hospitalization in a tertiary referral academic center.  Methods Carilion clinic's electronic medical record (EPIC) was queried to identify all alcoholic patients hospitalized for the first time with either a new diagnosis of alcoholic cirrhosis or a prior diagnosis of this from 2008 to 2016 with follow-up through June 2018. Information on demographics, comorbidities, lab values, procedures, and mortality was extracted. The cumulative risks of long-term mortality after the first hospitalization were estimated using Kaplan-Meier curves and compared between the two groups; those < 40 years of age and those > 40 years of age. Demographic data, lab values, and comorbidities associated with cirrhosis were assessed using multivariable Cox proportional hazard analysis to determine risk factors associated with long-term mortality.  Results We identified 65 young patients out of a total of 325 patients admitted for the first time for alcoholic cirrhosis (mean age: 34.6 ± 4.7 yrs, 72.3% males, 74.4% current alcohol users, 52.3% current smokers, 12.6% current illicit drugs users). The one, three, and five-year cumulative mortality after the first hospitalization was 21.1 %, 31.1%, and 49.7% respectively. The median survival for young patients was longer as compared to the older patients (p<0.001); likely related to high early mortality in older patients who had many other comorbidities. On multivariate Cox proportional hazard analysis, increased age [hazard ratio (HR) 1.03; 95% confidence interval (CI), 1.01-1.05], neutrophils-to-lymphocytes ratio (NLR) at first hospital discharge (HR 1.02; 95% CI, 1.01-1.04), the presence of encephalopathy (HR, 1.93; 95% CI, 1.06-3.55), and initial MELD (model for end-stage liver disease) score (HR, 1.13; 95% CI, 1.08-1.19) were associated with increased risk of mortality. Though the majority of patients endorsed current alcohol and tobacco use before the admission, it was not significantly associated with mortality.  Conclusions  Five-year cumulative mortality for patients < 40 years of age with alcoholic cirrhosis after their first hospitalization is 49.7%. Old age, most recent NLR, hepatic encephalopathy, and MELD score on admission were associated with increased late mortality.
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http://dx.doi.org/10.7759/cureus.16695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397324PMC
July 2021

On Behalf of the SFGM-TC: Retrospective Comparison of Reduced and Higher Intensity Conditioning for High-Risk Myelodysplastic Syndrome Treated With Allogeneic Stem-Cell Transplantation.

Clin Lymphoma Myeloma Leuk 2021 Jul 31. Epub 2021 Jul 31.

Hematology department, CHRU Nancy, F-54000, Nancy, France. Electronic address:

Background: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) remains the best curative option for high-risk myelodysplastic syndrome . We retrospectively compared patient outcomes after allo-HSCT according to the intensity of the conditioning regimen.

Patients And Methods: Three conditioning regimens were compared in 427 patients allografted for high-risk myelodysplastic syndrome: reduced-intensity conditioning (RIC), fludarabine (150-160 mg/m) and busulfan (6.4 mg/kg); sequential FLAMSA-RIC, fludarabine, amsacrine, and aracytine followed by RIC; and myeloablative with reduced toxicity (RTC), fludarabine and busulfan (9.6 mg/kg or 12.8 mg/kg).

Results: The patients in the 3 conditioning groups were different in regards to the number of treatment lines (P< .001), percentage of blasts in bone marrow (P< .001), and disease status at transplantation (P< .001). No significant differences in outcomes (overall survival, progression-free survival, nonrelapse mortality, relapse incidence, and graft versus host disease relapse-free survival) were observed between the 3 groups. Using propensity score analysis to overcome baseline imbalances, we compared 70 patients receiving FLAMSA-RIC to 260 patients receiving RIC, and compared 83 patients receiving RTC to 252 patients receiving RIC. The only factor influencing overall and progression-free survival was cytogenetic risk at transplantation. After the covariate adjustment using propensity score to reduce baseline imbalances, the only factor influencing overall and progression-free survival was still cytogenetic risk at transplantation.

Conclusion: Overall survival appears to be similar with the 3 conditioning regimens. The only factor influencing survival is cytogenetic risk at transplantation, suggesting that new promising drugs in the conditioning and/or early interventions after transplantation are needed to improve outcomes in these patients.
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http://dx.doi.org/10.1016/j.clml.2021.07.027DOI Listing
July 2021

Role of inflammation in alcohol-related brain abnormalities: a translational study.

Brain Commun 2021 16;3(3):fcab154. Epub 2021 Jul 16.

Normandie Univ, UNICAEN, PSL Université Paris, EPHE, INSERM, U1077, CHU de Caen, GIP Cyceron, Neuropsychologie et Imagerie de la Mémoire Humaine, 14000 Caen, France.

Brain abnormalities observed in alcohol use disorder are highly heterogeneous in nature and severity, possibly because chronic alcohol consumption also affects peripheral organs leading to comorbidities that can result in exacerbated brain alterations. Despite numerous studies focussing on the effects of alcohol on the brain or liver, few studies have simultaneously examined liver function and brain damage in alcohol use disorder, and even fewer investigated the relationship between them except in hepatic encephalopathy. And yet, liver dysfunction may be a risk factor for the development of alcohol-related neuropsychological deficits and brain damage well before the development of liver cirrhosis, and potentially through inflammatory responses. The use of animal models enables a better understanding of the pathophysiological mechanisms underlying liver-brain relationships in alcohol use disorder, and more particularly of the inflammatory response at the tissue, cerebral and hepatic levels. The objective of this translational study was to investigate, both in alcohol use disorder patients and in a validated animal model of alcohol use disorder, the links between peripheral inflammation, liver damage and brain alterations. To do this, we conducted an neuroimaging examination and biological measures to evaluate brain volumes, liver fibrosis and peripheral cytokines in alcohol use disorder patients. In selectively bred Sardinian alcohol-preferring rats, we carried out neuroimaging examination and immunohistochemistry to evaluate brain and liver inflammatory responses after chronic (50 consecutive weeks) alcohol drinking. In recently abstinent and non-cirrhotic alcohol use disorder patients, the score of liver fibrosis positively correlated with subcortical regions volumes (especially in right and left putamen) and level of circulating proinflammatory cytokines. In Sardinian alcohol-preferring rats, we found macrostructural brain damage and microstructural white matter abnormalities similar to those found in alcohol use disorder patients. In addition, in agreement with the results of peripheral inflammation observed in the patients, we revealed, in Sardinian alcohol-preferring rats, inflammatory responses in the brain and liver were caused by chronic alcohol consumption. Since the liver is the main source of cytokines in the human body, these results suggest a relationship between liver dysfunction and brain damage in alcohol use disorder patients, even in the absence of major liver disease. These findings encourage considering new therapeutic strategies aiming at treating peripheral organs to limit alcohol-related brain damage.
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http://dx.doi.org/10.1093/braincomms/fcab154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361421PMC
July 2021
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