| 1. |
- Sodergren, Erica, et al.
(författare)
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The genome of the sea urchin Strongylocentrotus purpuratus.
- 2006
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 314:5801, s. 941-52
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Tidskriftsartikel (refereegranskat)abstract
- We report the sequence and analysis of the 814-megabase genome of the sea urchin Strongylocentrotus purpuratus, a model for developmental and systems biology. The sequencing strategy combined whole-genome shotgun and bacterial artificial chromosome (BAC) sequences. This use of BAC clones, aided by a pooling strategy, overcame difficulties associated with high heterozygosity of the genome. The genome encodes about 23,300 genes, including many previously thought to be vertebrate innovations or known only outside the deuterostomes. This echinoderm genome provides an evolutionary outgroup for the chordates and yields insights into the evolution of deuterostomes.
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| 2. |
- Beumer, B. R., et al.
(författare)
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Impact of muscle mass on survival of patients with hepatocellular carcinoma after liver transplantation beyond the Milan criteria
- 2022
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Ingår i: Journal of Cachexia, Sarcopenia and Muscle. - : Wiley. - 2190-5991 .- 2190-6009. ; 13:5, s. 2373-2382
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Tidskriftsartikel (refereegranskat)abstract
- Background: Access to the liver transplant waitlist for patients with hepatocellular carcinoma (HCC) depends on tumour presentation, biology, and response to treatments. The Milan Criteria (MC) represent the benchmark for expanded criteria that incorporate additional prognostic factors. The purpose of this study was to determine the added value of skeletal muscle index (SMI) in HCC patients beyond the MC. Method: Patients with HCC that were transplanted beyond the MC were included in this retrospective multicentre study. SMI was quantified using the Computed Tomography (CT) within 3months prior to transplantation. Cox regression models were used to identify predictors of overall survival (OS). The discriminative performance of SMI extended Metroticket 2.0 and AFP models was also assessed. Results: Out of 889 patients transplanted outside the MC, 528 had a CT scan within 3months prior to liver transplantation (LT), of whom 176 (33%) were classified as sarcopenic. The median time between assessment of the SMI and LT was 1.8months (IQR: 0.77–2.67). The median follow-up period was 5.1 95% CI [4.7–5.5] years, with a total of 177 recorded deaths from any cause. In a linear regression model with SMI as the dependent variable, only male gender (8.55 95% CI [6.51–10.59], P<0.001) and body mass index (0.74 95% CI [0.59–0.89], P<0.001) were significant. Univariable survival analysis of patients with sarcopenia versus patients without sarcopenia showed a significant difference in OS (HR 1.44 95% CI [1.07−1.94], P=0.018). Also the SMI was significant (HR 0.98 95% CI [0.96–0.99], P=0.014). The survival difference between the lowest SMI quartile versus the highest SMI quartile was significant (log-rank: P=0.005) with 5year OS of 57% and 71%, respectively. Data from 423 patients, describing 139 deaths, was used for multivariate analysis. Both sarcopenia (HR 1.45 95% CI [1.02−2.05], P=0.036) and SMI were (HR 0.98 95% CI [0.95–0.99], P=0.035) significant. On the survival scale this translates to a 5year OS difference of 11% between sarcopenia and no sarcopenia. Whereas for SMI, this translates to a survival difference of 8% between first and third quartiles for both genders. Conclusions: Overall, we can conclude that higher muscle mass contributes to a better long-term survival. However, for individual patients, low muscle mass should not be considered an absolute contra-indication for LT as its discriminatory performance was limited.
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| 3. |
- Jevnikar, Z., et al.
(författare)
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Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation
- 2019
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 143:2, s. 577-590
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Tidskriftsartikel (refereegranskat)abstract
- Background: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. Objective: We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. Methods: An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. Results: Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1 beta, IL-8, and IL-1 beta. Conclusions: Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.
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| 4. |
- Efe, C., et al.
(författare)
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Efficacy and Safety of Mycophenolate Mofetil and Tacrolimus as Second-line Therapy for Patients With Autoimmune Hepatitis
- 2017
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Ingår i: Clinical Gastroenterology and Hepatology. - : Elsevier BV. - 1542-3565 .- 1542-7714. ; 15:12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Predniso(lo) ne, alone or in combination with azathioprine, is the standard-of-care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH. METHODS: We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6-190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second-line therapy as a result of side effects of predniso(lo) ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC. RESULTS: There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal. CONCLUSIONS: Long-term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.
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| 5. |
- Efe, C., et al.
(författare)
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Extrahepatic autoimmune diseases in primary biliary cholangitis: Prevalence and significance for clinical presentation and disease outcome
- 2021
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Ingår i: Journal of Gastroenterology and Hepatology. - : Wiley. - 0815-9319 .- 1440-1746. ; 36:4, s. 936-942
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aim The prevalence and clinical significance of extrahepatic autoimmune diseases (EHAIDs) have not been evaluated in a large cohort of primary biliary cholangitis (PBC). Methods The medical records of 1554 patients with PBC from 20 international centers were retrospectively reviewed. Development of decompensated cirrhosis (ascites, variceal bleeding, and/or hepatic encephalopathy) and hepatocellular carcinoma were considered clinical endpoints. Results A total of 35 different EHAIDs were diagnosed in 440 (28.3%) patients with PBC. Patients with EHAIDs were more often female (92.5%vs86.1%,P < 0.001) and seropositive for anti-mitochondrial antibodies (88%vs84%,P = 0.05) and antinuclear antibodies and/or smooth muscle antibodies (53.8%vs43.6%,P = 0.005). At presentation, patients with EHAIDs had significantly lower levels of alkaline phosphatase (1.76vs1.98 x upper limit of normal [ULN],P = 0.006), aspartate aminotransferase (1.29vs1.50 x ULN,P < 0.001), and total bilirubin (0.53vs0.58 x ULN,P = 0.002). Patients with EHAIDs and without EHAIDs had similar rates of GLOBE high-risk status (12.3%vs16.1%,P = 0.07) and Paris II response (71.4%vs69.4%,P = 0.59). Overall, event-free survival was not different in patients with and without EHAIDs (90.8%vs90.7%,P = 0.53, log rank). Coexistence of each autoimmune thyroid diseases (10.6%), Sjogren disease (8.3%), systemic sclerosis (2.9%), rheumatoid arthritis (2.7%), systemic lupus erythematosus (1.7%), celiac disease (1.7%), psoriasis (1.5%), and inflammatory bowel diseases (1.3%) did not influence the outcome. Conclusions Our study confirms that EHAIDs are frequently diagnosed in patients with PBC. The presence of EHAIDs may influence the clinical phenotype of PBC at presentation but has no impact on PBC outcome.
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| 6. |
- Karwen, T., et al.
(författare)
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Platelet-derived lipids promote insulin secretion of pancreatic beta cells
- 2023
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Ingår i: Embo Molecular Medicine. - 1757-4676. ; 15:9
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Tidskriftsartikel (refereegranskat)abstract
- Hyperreactive platelets are commonly observed in diabetic patients indicating a potential link between glucose homeostasis and platelet reactivity. This raises the possibility that platelets may play a role in the regulation of metabolism. Pancreatic beta cells are the central regulators of systemic glucose homeostasis. Here, we show that factor(s) derived from beta cells stimulate platelet activity and platelets selectively localize to the vascular endothelium of pancreatic islets. Both depletion of platelets and ablation of major platelet adhesion or activation pathways consistently resulted in impaired glucose tolerance and decreased circulating insulin levels. Furthermore, we found platelet-derived lipid classes to promote insulin secretion and identified 20-Hydroxyeicosatetraenoic acid (20-HETE) as the main factor promoting beta cells function. Finally, we demonstrate that the levels of platelet-derived 20-HETE decline with age and that this parallels with reduced impact of platelets on beta cell function. Our findings identify an unexpected function of platelets in the regulation of insulin secretion and glucose metabolism, which promotes metabolic fitness in young individuals.
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| 7. |
- Efe, C., et al.
(författare)
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Validation of Risk Scoring Systems in Ursodeoxycholic Acid-Treated Patients With Primary Biliary Cholangitis
- 2019
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Ingår i: American Journal of Gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 0002-9270 .- 1572-0241. ; 114:7, s. 1101-1108
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Risk stratification based on biochemical variables is a useful tool for monitoring ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC). Several UDCA response criteria and scoring systems have been proposed for risk prediction in PBC, but these have not been validated in large external cohorts. METHODS: We performed a study on data of 1746 UDCA-treated patients with PBC from 25 centers in Europe, United States, and Canada. The prognostic performance of the risk scoring systems (GLOBE and UK-PBC) and the UDCA response criteria (Barcelona, Paris I, Paris II, Rotterdam, and Toronto) were evaluated. We regarded cirrhosis-related complications (ascites, variceal bleeding, and/or hepatic encephalopathy) as clinical end points. RESULTS: A total of 171 patients reached a clinical end point during a median 7 years (range 1-16 years) of follow-up. The 5-, 10- and 15-year adverse outcome-free survivals were 95%, 85%, and 77%. The GLOBE and UK-PBC scores predicted cirrhosis-related complications better than the UDCA response criteria. The hazard ratio (HR) for a 1 standard deviation increase was HR 5.05 (95% confidence interval (CI): 4.43-5.74, P < 0.001) for the GLOBE score and HR 3.39 (95% CI: 3.10-3.72, P < 0.001) for the UK-PBC score. Overall, the GLOBE and UK-PBC risk scores showed similar and excellent prognostic performance (C-statistic, 0.93; 95% CI: 0.91%-95% vs 0.94; 95% CI: 0.91%-0.96%). DISCUSSION: In our international, multicenter PBC cohort, the GLOBE and UK-PBC risk scoring systems were good predictors of future cirrhosis-related complications.
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| 8. |
- Lynch, Kate D, et al.
(författare)
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Effects of Vedolizumab in Patients with Primary Sclerosing Cholangitis and Inflammatory Bowel Diseases.
- 2020
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Ingår i: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. - : Elsevier BV. - 1542-7714. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Gut-homing lymphocytes that express the integrin α4β7 and CCR9 might contribute to development of primary sclerosing cholangitis (PSC). Vedolizumab, which blocks the integrin α4β7, is used to treat patients with inflammatory bowel diseases (IBD), but there are few data on its efficacy in patients with PSC. We investigated the effects of vedolizumab in a large international cohort of patients with PSC and IBD.We collected data from European and North American centers participating in the International PSC Study Group from patients with PSC and IBD who received at least 3 doses of vedolizumab (n= 102; median vedolizumab treatment duration, 412 days). Demographic and clinical data were collected from baseline and during the follow-up period (until liver transplantation, death, or 56 days after the final vedolizumab infusion). We analyzed overall changes in biochemical features of liver and proportions of patients with reductions in serum levels of alkaline phosphatase (ALP) of 20% or more, from baseline through last follow-up evaluation. Other endpoints included response of IBD to treatment (improved, unchanged, or worsened, judged by the treating clinician, as well as endoscopic score) and liver-related outcomes.In the entire cohort, the median serum level of ALP increased from 1.54-fold the upper limit of normal at baseline to 1.64-fold the upper limit of normal at the last follow-up examination (P= .018); serum levels of transaminases and bilirubin also increased by a small amount between baseline and the last follow-up examination. Serum levels of ALP decreased by 20% or more in 21 patients (20.6%); only the presence of cirrhosis (odds ratio, 4.48; P= .019) was independently associated with this outcome. Of patients with available endoscopic data, 56.8% had a response of IBD to treatment. Liver-related events occurred in 21 patients (20.6%), including bacterial cholangitis, cirrhosis decompensation, or transplantation.In an analysis of patients with PSC and IBD in an international study group, we found no evidence for a biochemical response to vedolizumab, although serum level of ALP decreased by 20% or more in a subset of patients. Vedolizumab appears to be well tolerated and the overall response of IBD was the same as expected for patients without PSC.
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