136 research outputs found
‘De l’élitisme lexical au style familier : la rhétorique d’Emmanuel Macron’
Le Président Macron joue sur les différences de registres linguistiques en s'adaptant à son auditoire. S'agit-il d'une stratégie de communication ou d'un instrument linguistique? La rhétorique de Macron est-elle comparable à celle de ses prédecesseurs? Dans cet article, nous chercherons, dans un premier temps, à considérer ce qu’est ‘la langue politique’, qui l’utilise, et à quelles fins et nous tâcherons tout particulièrement de décrypter, aux prémices de la guerre en Ukraine, le discours de Macron vers l’Elysée en nous intéressant aux notions de langue de bois et de ‘parler-vrai’
Insights into the mechanism of a G-quadruplex-unwinding DEAH-box helicase.
The unwinding of nucleic acid secondary structures within cells is crucial to maintain genomic integrity and prevent abortive transcription and translation initiation. DHX36, also known as RHAU or G4R1, is a DEAH-box ATP-dependent helicase highly specific for DNA and RNA G-quadruplexes (G4s). A fundamental mechanistic understanding of the interaction between helicases and their G4 substrates is important to elucidate G4 biology and pave the way toward G4-targeted therapies. Here we analyze how the thermodynamic stability of G4 substrates affects binding and unwinding by DHX36. We modulated the stability of the G4 substrates by varying the sequence and the number of G-tetrads and by using small, G4-stabilizing molecules. We found an inverse correlation between the thermodynamic stability of the G4 substrates and rates of unwinding by DHX36. In stark contrast, the ATPase activity of the helicase was largely independent of substrate stability pointing toward a decoupling mechanism akin to what has been observed for many double-stranded DEAD-box RNA helicases. Our study provides the first evidence that DHX36 uses a local, non-processive mechanism to unwind G4 substrates, reminiscent of that of eukaryotic initiation factor 4A (eIF4A) on double-stranded substrates.Cancer Research UK and ERC (Balasubramanian group); Cambridge Trust studentship (to M.C.C.); Intramural Program of the National Heart, Lung and Blood Institute, NIH; ALS on the Berkeley Center for Structural Biology beamlines, US National Institutes of Health (NIH); NIH Oxford Cambridge Scholars Program [to M.C.C.]. Funding for open access charge: University of Cambridge.This is the final published version. The article was originally published in Nucleic Acids Research, 2015, Vol. 43, No. 4 2223–2231, doi: 10.1093/nar/gkv051
Addition of adult-to-adult living donation to liver transplant programs improves survival but at an increased cost
Using outcomes data from the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, we performed a cost-effectiveness analysis exploring the costs and benefits of living donor liver transplantation (LDLT). A multistage Markov decision analysis model was developed with treatment, including medical management only (strategy 1), waiting list with possible deceased donor liver transplantation (DDLT; strategy 2), and waiting list with possible LDLT or DDLT (strategy 3) over 10 years. Decompensated cirrhosis with medical management offered survival of 2.0 quality-adjusted life years (QALYs) while costing an average of 151,613, and waiting list with possible DDLT or LDLT offered 4.9-QALY survival and a mean cost of 35,976 over strategy 1, whereas strategy 3 produced an ICER of 47,693 more per QALY than strategy 1. Both DDLT and LDLT were cost-effective compared to medical management of cirrhosis over our 10-year study period. The addition of LDLT to a standard waiting list DDLT program is effective at improving recipient survival and preventing waiting list deaths but at a greater cost. Liver Transpl 15:148–162, 2009. © 2009 AASLD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/61905/1/21671_ftp.pd
Heparanase contributes to pancreatic carcinoma progression through insulin-dependent glucose uptake
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor, which is highly resistant to existing therapies and characterized by one of the lowest survival rates known for solid cancers. Among the reasons for this poor prognosis are unique pathophysiological features of PDAC, such as dense extracellular matrix [ECM] creating barriers to drug delivery, as well as systemically-deregulated glucose metabolism manifested by diabetic conditions (i.e., hyperinsulinemia/hyperglycemia) occurring in the majority of PDAC patients. Moreover, in addition to systemically deregulated glucose homeostasis, intracellular metabolic pathways in PDAC are rewired toward increased glucose uptake/anabolic metabolism by the tumor cells. While the role of oncogene-driven programs in governing these processes is actively studied, mechanisms linking metabolic dysregulation and ECM enzymatic remodeling to PDAC progression/therapy resistance are less appreciated. The aim of the current study was to investigate the action of heparanase (the predominant mammalian enzyme that degrades heparan sulfate glycosaminoglycan in the ECM), as a molecular link between the diabetic state and the intracellular metabolic rewiring in PDAC pathogenesis. Here we show that in PDAC elevated levels of heparanase, coupled with diabetic conditions typical for PDAC patients, promote growth and chemotherapy resistance of pancreatic carcinoma by favoring insulin receptor signaling and GLUT4-mediated glucose uptake into tumor cells. Collectively, our findings underscore previously unknown mechanism through which heparanase acts at the interface of systemic and intracellular metabolic alterations in PDAC and attest the enzyme as an important and potentially modifiable contributor to the chemo-resistance of pancreatic tumors
Managing expectations, rights, and duties in large-scale genomics initiatives: a European comparison
This article reports on the findings of an international workshop organised by the UK-France Genomics and Ethics Network (UK-FR GENE) in 2021. They focus specifically on how collection, storage and sharing of genomic data may pose challenges to established principles and values such as trust, confidentiality, and privacy in countries that have implemented, or are about to implement, large-scale national genomic initiatives. These challenges impact the relationships between patients/citizens and medicine/science, and on each party’s rights and duties towards each other. Our geographic scope of comparative analysis includes initiatives underway in England (Genomics England), France (Plan France Médecine Génomique) and Germany (German Human Genome-Phenome Archive). We discuss existing as well as future challenges raised by large-scale health data collection and management in each country. We conclude that the prospects of improving individualised patient healthcare as well as contributing to the scientific and research prosperity of any given nation engaged in health data collection, storage and processing are undeniable. However, we also attempt to demonstrate that biomedical data requires careful management, and transparent and accountable governance structures that are clearly communicated to patients/participants and citizens. Furthermore, when third parties partake as stakeholders, transparent consent protocols relative to data access and use come centre stage, and patient benefits must clearly outweigh commercial interests. Finally, any cross-border data transfer needs to be carefully managed to address incoherencies between regional, national, and supranational regulations and recommendations
Implementation of Vascularized Composite Allografts in the United States: Recommendations From the ASTS VCA Ad Hoc Committee and the Executive Committee
Like all other areas of transplantation, vascularized composite allografts (VCA) has the capacity to transform the lives of patients, for the better or for the worse. It is this duality that mandates VCA be performed in centers prepared for the intricacies accompanying other transplant procedures. Similarly, the complexities of VCA require that the procedures be driven by surgeons and physicians with experience in the multidisciplinary management of immunocompromised postsurgical patients. Furthermore, the grafts should be considered as organs rather than tissues from a regulatory and a biological standpoint. The ASTS supports the field of VCA and has demonstrated its support and leadership by actively formulating a strategy for its systematic development. The goal of this document is to provide a framework for the prospective, thoughtful realization of VCA in the United States from the American Society of Transplant Surgeons (ASTS) perspective.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79113/1/j.1600-6143.2010.03374.x.pd
Laboratory test results after living liver donation in the adult-to-adult living donor liver transplantation cohort study
Information on the long-term health of living liver donors is incomplete. Because changes in standard laboratory tests may reflect the underlying health of donors, results before and after donation were examined in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). A2ALL followed 487 living liver donors who donated at 9 US transplant centers between 1998 and 2009. The aminotransferase [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] and alkaline phosphatase (AP) activities, bilirubin, international normalized ratio (INR), albumin, white blood cell count (WBC), hemoglobin (HGB), platelet count, ferritin, serum creatinine (SCR), and blood urea nitrogen (BUN) were measured at the evaluation and after donation (1 week, 1 month, 3 months, 1 year, and yearly thereafter). Repeated measures models were used to estimate median laboratory values at each time point and to test for differences between values at the evaluation (baseline) and postdonation time points. Platelet counts were significantly decreased at every time point in comparison with the baseline, and at 3 years, they were 19% lower. Approximately 10% of donors had a platelet count < 150 × 1000/mm 3 2 to 3 years post-donation. Donors with a platelet count ≤ 150 × 1000/mm 3 at 1 year had significantly lower mean platelet counts (189 ± 32 × 1000/mm 3 ) versus the remainder of the cohort (267 ± 56 × 1000/mm 3 , P < 0.0001) at the evaluation. Statistically significant differences compared to the evaluation values were noted for AST, AP, INR, and albumin through the first year, although most measurements were in the normal range. The median values for WBC, HGB, ferritin, albumin, SCR, BUN, and INR were not substantially outside the normal range at any time point. In conclusion, after 3 months, most laboratory values return to normal among right hepatic lobe liver donors, with a slower return to baseline levels for AST, AP, INR, and albumin. Persistently decreased platelet counts warrant further investigation. Liver Transpl, 2011. © 2011 AASLD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83476/1/22246_ftp.pd
Rapid biolayer interferometry measurements of urinary CXCL9 to detect cellular infiltrates noninvasively after kidney transplantation
Introduction: measuring the chemokine CXCL9 in urine by enzyme-linked immunosorbent assay (ELISA) can diagnose acute cellular rejection (ACR) noninvasively after kidney transplantation, but the required 12- to 24-hour turnaround time is not ideal for rapid, clinical decision-making. Methods: we developed a biolayer interferometry (BLI)−based assay to rapidly measure urinary CXCL9 in 200 pg/ml in subjects with ACR and ≤100 pg/ml in subjects with stable kidney function without cellular infiltrates. In samples obtained after treatment for ACR, BLI CXCL9 measurements detected biopsy-proven intragraft infiltrates despite treatment-induced reduction in serum creatinine. Discussion: together, our proof-of-principle results demonstrate that BLI-based urinary CXCL9 detection has potential as a point-of-care noninvasive biomarker to diagnose and guide therapy for ACR in kidney transplantation recipients
Urinary-Cell mRNA Profile and Acute Cellular Rejection in Kidney Allografts
Background—The standard test for the diagnosis of acute rejection in kidney transplants is the renal biopsy. Noninvasive tests would be preferable.
Methods—We prospectively collected 4300 urine specimens from 485 kidney-graft recipients from day 3 through month 12 after transplantation. Messenger RNA (mRNA) levels were measured in urinary cells and correlated with allograft-rejection status with the use of logistic regression.
Results—A three-gene signature of 18S ribosomal (rRNA)–normalized measures of CD3ε mRNA and interferon-inducible protein 10 (IP-10) mRNA, and 18S rRNA discriminated between biopsy specimens showing acute cellular rejection and those not showing rejection (area under the curve [AUC], 0.85; 95% confidence interval [CI], 0.78 to 0.91; P<0.001 by receiver-operatingcharacteristic curve analysis). The cross-validation estimate of the AUC was 0.83 by bootstrap resampling, and the Hosmer–Lemeshow test indicated good fit (P = 0.77). In an externalvalidation data set, the AUC was 0.74 (95% CI, 0.61 to 0.86; P<0.001) and did not differ significantly from the AUC in our primary data set (P = 0.13). The signature distinguished acute cellular rejection from acute antibody-mediated rejection and borderline rejection (AUC, 0.78; 95% CI, 0.68 to 0.89; P<0.001). It also distinguished patients who received anti–interleukin-2 receptor antibodies from those who received T-cell–depleting antibodies (P<0.001) and was diagnostic of acute cellular rejection in both groups. Urinary tract infection did not affect the signature (P = 0.69). The average trajectory of the signature in repeated urine samples remained below the diagnostic threshold for acute cellular rejection in the group of patients with no rejection, but in the group with rejection, there was a sharp rise during the weeks before the biopsy showing rejection (P<0.001).
Conclusions—A molecular signature of CD3ε mRNA, IP-10 mRNA, and 18S rRNA levels in urinary cells appears to be diagnostic and prognostic of acute cellular rejection in kidney allografts
Recurrence after cure in cranial dural arteriovenous fistulas:a collaborative effort by the Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR)
OBJECTIVE Cranial dural arteriovenous fistulas (dAVFs) are often treated with endovascular therapy, but occasionally a multimodality approach including surgery and/or radiosurgery is utilized. Recurrence after an initial angiographic cure has been reported, with estimated rates ranging from 2% to 14.3%, but few risk factors have been identified. The objective of this study was to identify risk factors associated with recurrence of dAVF after putative cure. METHODS The Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR) data were retrospectively reviewed. All patients with angiographic cure after treatment and subsequent angiographic follow-up were included. The primary outcome was recurrence, with risk factor analysis. Secondary outcomes included clinical outcomes, morbidity, and mortality associated with recurrence. Risk factor analysis was performed comparing the group of patients who experienced recurrence with those with durable cure (regardless of multiple recurrences). Time-to-event analysis was performed using all collective recurrence events (multiple per patients in some cases). RESULTS Of the 1077 patients included in the primary CONDOR data set, 457 met inclusion criteria. A total of 32 patients (7%) experienced 34 events of recurrence at a mean of 368.7 days (median 192 days). The recurrence rate was 4.5% overall. Kaplan-Meier analysis predicted long-term recurrence rates approaching 11% at 3 years. Grade III dAVFs treated with endovascular therapy were statistically significantly more likely to experience recurrence than those treated surgically (13.3% vs 0%, p = 0.0001). Tentorial location, cortical venous drainage, and deep cerebral venous drainage were all risk factors for recurrence. Endovascular intervention and radiosurgery were associated with recurrence. Six recurrences were symptomatic, including 2 with hemorrhage, 3 with nonhemorrhagic neurological deficit, and 1 with progressive flow-related symptoms (decreased vision). CONCLUSIONS Recurrence of dAVFs after putative cure can occur after endovascular treatment. Risk factors include tentorial location, cortical venous drainage, and deep cerebral drainage. Multimodality therapy can be used to achieve cure after recurrence. A delayed long-term angiographic evaluation (at least 1 year from cure) may be warranted, especially in cases with risk factors for recurrence
- …