Régulation de la synthétase des acides gras par l'insuline et la T3 : mise en évidence de l'action génomique et non génomique de la T3

La synthétase des acides gras (FAS) est une enzyme clef de la lipogenèse hépatique responsable de la synthèse des acides gras saturés à longue chaîne. Cette enzyme est régulée au niveau transcriptionel par les nutriments et les hormones. Ainsi, le glucose, l'insuline et la T3 augmentent son activité alors que les acides gras à moyennes chînes (MCFAs), les acides gras poly-insaturés (PUFAs) et le glucagon la diminuent. Dans des cellules hépatiques, nous avons mis en évidence que la T3 et l'insuline étaient capables d'activer de façon synergique l'activité enzymatique et le niveau d'expression des ARNm de la FAS (14 fois). L'analyse du promoteur a permis de démontrer que cette activation était aussi transcriptionnelle. Par la suite l'élément de réponse à la T3 (TRE) a été localisé dans la région promotrice du gène FAS. Ce TRE fixe un hétérodimère TR/RXR en absence d'hormone et cette fixation est augmentée en présence d'insuline et/ou de T3. L'utilisation de H7, un inhibiteur général des serines/thréonines kinases, nous a permis de mettre en évidence que des mécanismes de phosphorylation sont impliqués dans la régulation transcriptionelle de la FAS par ces deux hormones. En fait, nous avons démontré que la voie de signalisation cellulaire PI3-Kinase/\ud ERK1/2-MAPK est impliquée dans la régulation de la FAS par la T3 via le TRE. De plus, nous avons aussi mis en évidence un effet de l'insuline sur ce TRE qui impliquerait la même voie de signalisation ainsi qu'une voie qui pourrait aussi impliquer Akt. Les mêmes effets non génomiques de la T3 et de l'insuline sont aussi observés au niveau d'un TRE consensus de type DR4. En conclusion, nos résultats suggèrent que la T3 régule la transcription par un mécanisme d'action à la fois génomique et non génomique impliquant la voie PI3-Kinse/MAPK et que l'insuline est aussi capable de cibler ce TRE par des voies de signalisation spécifiques. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : FAS, T3, Insuline, PI3-Kinase, Erk1/2-MAPK

Impact of comprehensive geriatric assessment on survival, function, and nutritional status in elderly patients with head and neck cancer: protocol for a multicentre randomised controlled trial (EGeSOR)

BACKGROUND: Survival is poorer in elderly patients with head and neck squamous cell carcinomas [HNSCCs] than in younger patients. Possible explanations include a contribution of co-morbidities to mortality, frequent refusal of standard therapy, and the use of suboptimal treatments due to concern about toxicities. The Comprehensive Geriatric Assessment [CGA] is a multidimensional assessment of general health that can help to customise treatment and follow-up plans. The CGA has been proven effective in several health settings but has not been evaluated in randomised studies of patients with cancer. Our aim here was to assess the impact of the CGA on overall survival, function, and nutritional status of elderly patients with HNSCC. METHODS/DESIGN: EGeSOR is an open-label, multicentre, randomised, controlled, parallel-group trial in patients aged 70 years or older and receiving standard care for HNSCC. The intervention includes four components: the CGA conducted by a geriatrician before cancer treatment, participation of the same geriatrician in cancer treatment selection, a standardised geriatric therapeutic intervention designed by the same geriatrician; and geriatric follow-up for 24 months. The primary endpoint, assessed after 6 months, is a composite criterion including death, functional impairment [Activities of Daily Living score decrease ≥2], and weight loss ≥10%. Secondary endpoints include progression-free survival, unscheduled admissions, quality of life, treatment toxicities, costs, and completion of the planned cancer treatment. A centralised online system is used to perform 1:1 randomisation with a minimisation algorithm for centre, age, T and N stages, and tumour site [oral, oropharyngeal, hypopharyngeal, or laryngeal]. The estimated sample size is 704 patients, who are being recruited by 14 centres in 9 French cities. DISCUSSION: EGeSOR is the first randomised trial of the CGA in elderly cancer patients. We expect the CGA to have direct clinical benefits on the management of elderly patients with HNSCC. If this expectation is fulfilled, the trial may lead to modifications of the management model for elderly patients with cancer. TRIAL REGISTRATION: Trial registration: NCT0202506

Interleukin-17A expression in patients presenting with nasal polyposis

Sinonasal polyposis (SNP) is a chronic inflammatory pathology of the nasal/paranasal cavities which affects from 1%-4% of the population. Although polyps seem to be a manifestation of chronic inflammation of nasal/paranasal sinus mucosa in both allergic and non-allergic subjects, the pathogenesis of nasal polyposis remains unknown. Interleukin-17A (IL-17A) is a key inflammatory cytokine in many disorders. Little attention has been paid to the role of IL-17A in chronic inflammatory disorders.OBJECTIVE:To investigate the expression of IL-17A in the SNP and verify if this expression is a marker of good or bad prognosis.METHOD:Prospective study with 25 patients presenting with SNP were subjected to the immunohistochemistry technique. After a skin prick test, all patients were divided into atopic and nonatopic groups, and asthmatic or non-asthmatic.RESULTS:The IL-17A expression was observed in both atopic and nonatopic patients. The numbers of IL-17A positive cells were greater in nasal polyps of atopic patients than nonatopic (p = 0.0128).CONCLUSION:These results indicate that IL-17A may play an important role in the pathology of SNP. Considering the inflammatory properties of IL-17A, this study suggests that it could increase susceptibility to atopy and asthma.Polipose nasossinusal (PNS) é uma afecção inflamatória crônica das cavidades nasais/paranasais que afeta 1%-4% da população. Pólipos parecem ser uma manifestação inflamatória crônica da mucosa do seio nasal/paranasal em indivíduos alérgicos e não alérgicos; porém, a patogênese da PNS permanece desconhecida. A interleucina-17A (IL-17A) é uma citocina chave em muitas doenças inflamatórias. Pouca atenção tem sido dada ao papel da IL-17A em distúrbios inflamatórios crônicos.OBJETIVO:Investigar a expressão da IL-17A na PNS e verificar se ela é um marcador de bom ou mau prognóstico.MÉTODO:Estudo prospectivo de 25 pacientes com PNS foram submetidas à técnica de imuno-histoquímica. Após realizarem teste cutâneo, todos os pacientes foram divididos em grupos atópicos e não atópicos e classificados em asmáticos ou não asmáticos.RESULTADOS:A expressão de IL-17A foi observada nos pacientes atópicos e não atópicos; porém, o número de células positivas com IL-17A foi maior nos pólipos nasais de pacientes atópicos que nos não atópicos (p = 0,0128).CONCLUSÃO:Os resultados indicam que a IL-17A pode desempenhar papel importante na patologia da PNS. Considerando as propriedades inflamatórias da IL-17A, este estudo sugere que a IL-17A pode aumentar a susceptibilidade a atopia e asma.Universidade Federal de GoiasUniversidade Estadual de GoiasPontificia Universidade Catolica de GoiasUniversidade Federal de São Paulo (UNIFESP)UNIFESPSciEL

Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: Results of the ELITA/EF-CLIF collaborative study (ECLIS)

BACKGROUND AND AIMS: Liver transplantation (LT) has been proposed to be an effective salvage therapy even for the sickest patients with acute-on-chronic liver failure (ACLF). This large collaborative study was designed to address the current clinical practice and outcomes of ACLF patients wait listed (WL) for LT in Europe. METHODS: Retrospective study including 308 consecutive ACLF patients, listed in 20 centres across 8 European countries, from January 2018 to June 2019. RESULTS: 2677 patients received a LT, 1216 (45.4%) for decompensated cirrhosis (DC). Of these, 234 (19.2%) had ACLF at LT: ACLF-1, 58 (4.8%); ACLF-2, 78 (6.4%); and ACLF-3, 98 (8.1%). Wide variations were observed amongst countries: France and Germany had high rates of ACLF-2/3 (27-41%); Italy, Switzerland, Poland and Netherlands had medium rates (9-15%); and United Kingdom and Spain had low rates (3-5%) (p 4 mmol/L (HR 3.14, 95% CI 1.37-7.19), recent infection from multi-drug resistant organisms (HR 3.67, 95% CI 1.63-8.28), and renal replacement therapy (HR 2.74, 95% CI 1.37-5.51) were independent predictors of post-LT mortality. During the same period, 74 patients with ACLF died on the WL. In an intention-to-treat analysis, one-year survival of ACLF patients on the LT WL was 73% for ACLF-1 or -2 and 50% for ACLF-3. CONCLUSION: The results reveal wide variations in listing patients with ACLF in Europe despite favorable post-LT survival. Risk factors for mortality were identified, allowing a more precise prognostic assessment of ACLF patients for potential LT. LAY SUMMARY: Acute on chronic liver failure (ACLF) is a severe clinical condition for which liver transplantation is an effective therapeutic option. This study has demonstrated that in Europe, referral and access to liver transplantation (LT) for patients with ACLF needs to be harmonized to avoid inequities. Post-LT survival for patients with ACLF was >80% after 1 year and some factors have been identified for selecting patients with favorable outcomes

Safety and efficacy of protease inhibitors to treat hepatitis C after liver transplantation: A multicenter experience

Background & Aims: Protease inhibitors (PI) with peginterferon/ ribavirin have significantly improved SVR rates in HCV G1 patients. Their use to treat HCV recurrence after liver transplantation (LT) is a challenge. Methods: This cohort study included 37 liver transplant recipients (male, 92%, age 57 ± 11 years), treated with boceprevir (n = 18) or telaprevir (n = 19). The indication for therapy was HCV recurrence (fibrosis stage PF2 (n = 31, 83%) or fibrosing cholestatic hepatitis (n = 6, 16%). Results: Eighteen patients were treatment-naive, five were relapsers and fourteen were non-responders to dual therapy after LT. Twenty-two patients received cyclosporine and fifteen tacrolimus. After 12 weeks of PI therapy, a complete virological response was obtained in 89% of patients treated with boceprevir, and 58% with telaprevir (p = 0.06). The end of treatment virological response rate was 72% (13/18) in the boceprevir group and 40% (4/10) in the telaprevir group (p = 0.125). A sustained virological response 12 weeks after treatment discontinuation was observed in 20% (1/5) and 71% (5/7) of patients in the telaprevir and boceprevir groups, respectively (p = 0.24). Treatment was discontinued in sixteen patients (treatment failures (n = 11), adverse events (n = 5)). Infections occurred in ten patients (27%), with three fatal outcomes (8%). The most common adverse effect was anemia (n = 34, 92%), treated with erythropoietin and/ or a ribavirin dose reduction; thirteen patients (35%) received red blood cell transfusions. The cyclosporine dose was reduced by 1.8 ± 1.1-fold and 3.4 ± 1.0-fold with boceprevir and telaprevir, respectively. The tacrolimus dose was reduced by 5.2 ± 1.5-fold with boceprevir and 23.8 ± 18.2-fold with telaprevir. Conclusions: Our results suggest that triple therapy is effective in LT recipients, particularly those experiencing a severe recurrence. The occurrence of anemia and drug-drug interactions, and the risk of infections require close monitoring.

Early liver transplantation for severe alcohol-related hepatitis not responding to medical treatment: a prospective controlled study

peer reviewedBackground: Early liver transplantation for severe alcohol-related hepatitis is an emerging treatment option. We aimed to assess the risk of alcohol relapse 2 years after early liver transplantation for alcohol-related hepatitis compared with liver transplantation for alcohol-related cirrhosis after at least 6 months of abstinence. Methods: We conducted a multicentre, non-randomised, non-inferiority, controlled study in 19 French and Belgian hospitals. All participants were aged 18 years or older. There were three groups of patients recruited prospectively: patients with severe alcohol-related hepatitis who did not respond to medical treatment and were eligible for early liver transplantation according to a new selection scoring system based on social and addiction items that can be quantified in points (early transplantation group); patients with alcohol-related cirrhosis listed for liver transplantation after at least 6 months of abstinence (standard transplantation group); patients with severe alcohol-related hepatitis not responding to medical treatment not eligible for early liver transplantation according to the selection score (not eligible for early transplantation group), this group did not enter any further liver transplantation processes. We also defined a historical control group of patients with severe alcohol-related hepatitis unresponsive to medical therapy and non-transplanted. The primary outcome was the non-inferiority of 2-year rate of alcohol relapse after transplantation in the early transplantation group compared with the standard transplantation group using the alcohol timeline follow back (TLFB) method and a prespecified non-inferiority margin of 10%. Secondary outcomes were the pattern of alcohol relapse, 2-year survival rate post-transplant in the early transplantation group compared with the standard transplantation group, and 2-year overall survival in the early transplantation group compared with patients in the not eligible for early transplantation group and historical controls. This trial is registered with ClinicalTrials.gov, NCT01756794. Findings: Between Dec 5, 2012, and June 30, 2016, we included 149 patients with severe alcohol-related hepatitis: 102 in the early transplantation group and 47 in the not eligible for early transplantation group. 129 patients were included in the standard transplantation group. 68 patients in the early transplantation group and 93 patients in the standard transplantation group received a liver transplant. 23 (34%) patients relapsed in the early transplantation group, and 23 (25%) patients relapsed in the standard transplantation group; therefore, the non-inferiority of early transplantation versus standard transplantation was not demonstrated (absolute difference 9·1% [95% CI –∞ to 21·1]; p=0·45). The 2-year rate of high alcohol intake was greater in the early transplantation group than the standard transplantation group (absolute difference 16·7% [95% CI 5·8–27·6]) The time spent drinking alcohol was not different between the two groups (standardised difference 0·24 [95% CI −0·07 to 0·55]), but the time spent drinking a large quantity of alcohol was higher in the early transplantation group than the standard transplantation group (standardised difference 0·50 [95% CI 0·17–0·82]). 2-year post-transplant survival was similar between the early transplantation group and the standard transplantation group (hazard ratio [HR] 0·87 [95% CI 0·33–2·26]); 2-year overall survival was higher in the early transplantation group than the not eligible for early transplantation group and historical controls (HR 0·27 [95% CI 0·16–0·47] and 0·21 [0·13–0·32]). Interpretation: We cannot conclude non-inferiority in terms of rate of alcohol relapse post-transplant between early liver transplantation and standard transplantation. High alcohol intake is more frequent after early liver transplantation. This prospective controlled study confirms the important survival benefit related to early liver transplantation for severe alcohol-related hepatitis; and this study provides objective data on survival and alcohol relapse to tailor the management of patients with severe alcohol-related hepatitis. Funding: The present study has been granted by the French Ministry of Health—Programme Hospitalier de Recherche Clinique 2010

Tilings of a Domain on a Hexagon Mesh with Balanced 3-Tiles

In this article, we study the question of tilings on a hexagon mesh with balanced 3-tiles. This problem has been studied by Conway and Lagarias in [CL90], by studying the tiling groups, in fact a group containing the tiling-groups, and their Cayley graphs. We will use two different approaches. The first one is based on matchings in bipartite graphs, which in this case are in correspondance with tilings of domains by lozenges, and thus can be efficiently studied, using Thurston's algorithm (see [Thu90]). The second one is based on a color and balancing approach of Thurston's algorithm, exposed in [Fou96]

Tilings of a Domain on a Hexagon Mesh with Balanced 3-Tiles

In this article, we study the question of tilings on a hexagon mesh with balanced 3-tiles. This problem has been studied by Conway and Lagarias in [CL90], by studying the tiling groups, in fact a group containing the tiling-groups, and their Cayley graphs. We will use two different approaches. The first one is based on matchings in bipartite graphs, which in this case are in correspondance with tilings of domains by lozenges, and thus can be efficiently studied, using Thurston’s algorithm. (See [Thu90]). The second one is based on a color and balancing approach of Thurston’s algorithm, exposed in [Fou96]

Tabagisme de la femme enceinte (rôle du médecin généraliste)

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