| 1. |
- Smati, S., et al.
(författare)
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Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target
- 2022
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Ingår i: Gut. - : BMJ Publishing Group. - 0017-5749 .- 1468-3288. ; 71:4, s. 807-821
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans. Different models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver. The different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα. These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target. NCT02390232.
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| 2. |
- Pradere, P., et al.
(författare)
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Lung transplantation for scleroderma lung disease: An international, multicenter, observational cohort study
- 2018
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Ingår i: Journal of Heart and Lung Transplantation. - : Elsevier BV. - 1053-2498. ; 37:7, s. 903-911
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Due to its multisystemic nature, scleroderma is considered a relative contraindication to lung transplantation at many centers. However, recent studies suggest similar post-transplant outcomes in patients with scleroderma compared to those with other causes of interstitial lung disease (ILD). Furthermore, it remains unknown whether scleroderma-associated pulmonary arterial hypertension (PAH) influences post-transplant outcomes. Our objective in this study was to assess the indications, survival, and prognostic factors of lung or heart lung transplantation for scleroderma lung disease. METHODS: We retrospectively reviewed the data of 90 patients with scleroderma who underwent lung or heart lung transplantation between 1993 and 2016 at 14 European centers. International criteria were used to diagnose scleroderma. Pulmonary hypertension (PH) was diagnosed during right heart catheterization based on international guidelines. RESULTS: Survival rates after 1, 3, and 5 years were 81%, 68%, and 61%, respectively. By univariate analysis, borderline-significant associations with poorer survival were found for female gender (hazard ratio 2.11; 95% confidence interval [CI] 0.99 to 4.50; p = 0.05) and PAH as the reason for transplantation (hazard ratio 1.90; 95% CI 0.96 to 3.92; p = 0.06). When both these factors were present in combination, the risk of death was 3-fold that in males without PAH. The clinical and histologic presentation resembled veno-occlusive disease in 75% of patients with PAH. CONCLUSIONS: Post-transplant survival rates and freedom from chronic lung allograft dysfunction in patients with scleroderma were similar to those in patients with other reasons for lung transplantation. Female sex and PAH in combination was associated with lower survival. (C) 2018 International Society for Heart and Lung Transplantation. All rights reserved.
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| 3. |
- Rouprêt, Morgan, et al.
(författare)
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European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma : 2023 Update
- 2023
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838. ; 84:1, s. 49-64
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Forskningsöversikt (refereegranskat)abstract
- Context: The European Association of Urology (EAU) guidelines panel on upper urinary tract urothelial carcinoma (UTUC) has updated the guidelines to aid clinicians in evidence-based management of UTUC. Objective: To provide an overview of the EAU guidelines on UTUC as an aid to clinicians. Evidence acquisition: The recommendations provided in these guidelines are based on a review of the literature via a systematic search of the PubMed, Ovid, EMBASE, and Cochrane databases. Data were searched using the following keywords: urinary tract cancer, urothelial carcinomas, renal pelvis, ureter, bladder cancer, chemotherapy, ureteroscopy, nephroureterectomy, neoplasm, (neo)adjuvant treatment, instillation, recurrence, risk factors, metastatic, immunotherapy, and survival. The results were assessed by a panel of experts. Evidence synthesis: Even though data are accruing, for many areas there is still insufficient high-level evidence to provide strong recommendations. Patient stratification on the basis of histology and clinical examination (including imaging) and assessment of patients at risk of Lynch syndrome will aid management. Kidney-sparing management should be offered as a primary treatment option to patients with low-risk UTUC and two functional kidneys. In particular, for patients with high-risk or metastatic UTUC, new treatment options have become available. In high-risk UTUC, platinum-based chemotherapy after radical nephroureterectomy, and adjuvant nivolumab for unfit or patients who decline chemotherapy, are options. For metastatic disease, gemcitabine/carboplatin chemotherapy is recommended as first-line treatment for cisplatin-ineligible patients. Patients with PD-1/PD-L1–positive tumours should be offered a checkpoint inhibitor (pembrolizumab or atezolizumab). Conclusions: These guidelines contain information on the management of individual patients according to the current best evidence. Urologists should take into account the specific clinical characteristics of each patient when determining the optimal treatment regimen according to the risk stratification of these tumours. Patient summary: Cancer of the upper urinary tract is rare, but because 60% of these tumours are invasive at diagnosis, timely and appropriate diagnosis is most important. A number of known risk factors exist.
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