Background & Aims Subtle inter-patient genetic variation and environmental factors combine to determine disease progression in non-alcoholic fatty liver disease (NAFLD). Carriage of the PNPLA3 ...rs738409 c.444C >G minor allele (encoding the I148M variant) has been robustly associated with advanced NAFLD. Although most hepatocellular carcinoma (HCC) is related to chronic viral hepatitis or alcoholic liver disease, the incidence of NAFLD-related HCC is increasing. We examined whether rs738409 C >G was associated with HCC-risk in patients with NAFLD. Methods PNPLA3 rs738409 genotype was determined by allelic discrimination in 100 European Caucasians with NAFLD-related HCC and 275 controls with histologically characterised NAFLD. Results Genotype frequencies were significantly different between NAFLD-HCC cases (CC = 28, CG = 43, GG = 29) and NAFLD-controls (CC = 125, CG = 117, GG = 33) ( p = 0.0001). In multivariate analysis adjusted for age, gender, diabetes, BMI, and presence of cirrhosis, carriage of each copy of the rs738409 minor (G) allele conferred an additive risk for HCC (adjusted OR 2.26 95% CI 1.23–4.14, p = 0.0082), with GG homozygotes exhibiting a 5-fold 1.47–17.29, p = 0.01 increased risk over CC. When compared to the UK general population (1958 British Birth Cohort, n = 1476), the risk-effect was more pronounced (GC vs. CC: unadjusted OR 2.52 1.55–4.10, p = 0.0002; GG vs. CC: OR 12.19 6.89–21.58, p <0.0001). Conclusions Carriage of the PNPLA3 rs738409 C >G polymorphism is not only associated with greater risk of progressive steatohepatitis and fibrosis but also of HCC. If validated, these findings suggest that PNPLA3 genotyping has the potential to contribute to multi-factorial patient-risk stratification, identifying those to whom HCC surveillance may be targeted.
Death receptors as targets in cancer Micheau, O; Shirley, S; Dufour, F
British journal of pharmacology,
August 2013, Letnik:
169, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Anti‐tumour therapies based on the use pro‐apoptotic receptor agonists, including TNF‐related apoptosis‐inducing ligand (TRAIL) or monoclonal antibodies targeting TRAIL‐R1 or TRAIL‐R2, have been ...disappointing so far, despite clear evidence of clinical activity and lack of adverse events for the vast majority of these compounds, whether combined or not with conventional or targeted anti‐cancer therapies. This brief review aims at discussing the possible reasons for the lack of apparent success of these therapeutic approaches and at providing hints in order to rationally design optimal protocols based on our current understanding of TRAIL signalling regulation or resistance for future clinical trials.
Linked Articles
This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue‐8
Sorafenib (S), a multitargeted tyrosine kinase inhibitor, is the standard of care for first-line systemic treatment of advanced hepatocellular carcinoma (HCC). Everolimus (E) is a potent inhibitor of ...mTOR, a pathway frequently activated in HCC. Preclinical data suggest that the combination S + E has additive effects compared with single-agent S.
Patients with unresectable or metastatic HCC and Child-Pugh ≤7 liver dysfunction were randomized to receive daily S 800 mg alone or with E 5 mg until progression or unacceptable toxicity. The primary end point was progression-free survival at 12 weeks (PFS12). The secondary end points included response rate, PFS, time to progression (TTP), overall survival (OS), duration of disease stabilization (DDS), safety, and quality-of-life (QoL) assessments.
A total of 106 patients were randomized: 46 patients received S and 60 patients received S + E. Ninety-three patients were assessable for the primary end point and 105 patients for the safety analysis. The PFS12 rate was 70% 95% confidence interval (CI) 54–83 and 68% (95% CI 53–81) in patients randomized to S and S + E, respectively. The RECIST (mRECIST) response rate was 0% (23%) in the S arm and 10% (35%) in the S + E arm. Median PFS (6.6 versus 5.7 months), TTP (7.6 versus 6.3 months), DDS (6.7 versus 6.7 months), and OS (10 versus 12 months) were similar in the S and S + E arms, respectively. Grade 3/4 adverse events occurred in 72% and 86% of patients in arm S and arm S + E, respectively. Patients had similar QoL scores over time, except for a greater worsening in physical well-being and mood in the arm S + E.
No evidence was found that S + E improves the efficacy compared with S alone. Combining 5 mg E with full-dose S is feasible, but more toxic than S alone. Further testing of this drug combination in molecularly unselected HCCs appears unwarranted.
NCT01005199.
Women experiencing homelessness (WEH) are a marginalized group who often lack support services, leading them to adopt alternative survival strategies that leave them at risk of being victimized and ...becoming involved with the justice-system. To better understand this problem, we analyzed the adaptive strategies Canadian WEH use to survive. Comparing the life histories of WEH who turned to criminal activities (n = 4) with WEH who demonstrated prosocial resilience (n = 4) makes it possible to identify protective and risk factors for criminal behavior and to propose adaptive strategies that can be used to support these women to adopt a prosocial lifestyle. The results provide a framework for understanding the needs of WEH, filling a gap that results from the focus on men needs in most scientific literature and by many resources, and suggesting that meeting those needs may reduce the likelihood that WEH will become involved with the justice-system.
Summary
In order to accurately assess the burden of hepatitis C (HCV) and develop effective interventions, we must understand the magnitude and trends of mortality related to the disease. In the ...United States, HCV‐related mortality is continuously increasing. We have no comparable data for Switzerland and other European countries, although a modelling study predicted a similar increase. We analysed time trends (1 January 1995‐31 December 2014) in HCV‐specific mortality rates in the Swiss general population using the death registry of the Swiss Federal Statistical Office (SFSO). We compared HCV‐related mortality to HIV‐related and hepatitis B (HBV)‐related mortality. To determine potential under‐reporting in HCV‐related mortality, we probabilistically linked the SFSO data to persons who died in the Swiss Hepatitis C Cohort Study (SCCS). SFSO data showed that HCV‐related mortality more than doubled between 1995 and 2003, but has since stabilized at ~2.5/100 000 person‐years. Since 2000, HCV‐related mortality has been higher than HIV‐related mortality and was about fivefold higher in 2014. HBV‐related mortality remained low at ~0.5/100 000 person‐years. Of 4556 persons in the SCCS, 421 have died and 86.2% could be linked to the death registry. According to the SCCS, 133 deaths were HCV‐related. HCV was not mentioned on the SFSO death certificate of 45% of these (n = 60/133). In conclusion, HCV‐related mortality remained constant, possibly because quality of care was high, or because of under‐reporting or because mortality has not yet increased. However, HCV‐related mortality is now much higher than HIV‐ and HBV‐related mortality, and under‐reporting was common.
•We propose a Bayesian inversion method combining adaptive Polynomial Chaos Kriging and a Structural Reliability Method.•An active-learning scheme is proposed in order to enrich the surrogate models ...in informative zones.•The method is illustrated on three Bayesian inverse problems with different complexity and dimensionality.•The method enables to efficiently sample from posteriors distributions for a limited amount of model calls.
In this paper, we propose a Bayesian inversion approach combining adaptive Polynomial Chaos Kriging (PCK) surrogate models and a rare event estimation method called Subset Simulation (SuS). It is based on the recently introduced Bayesian Updating with Structural reliability (BUS) framework that enables to reformulate the classical Bayesian inference into a rare event estimation problem. In this context, the SuS method aims at drawing samples from the posterior distribution as well as estimating the model evidence, which is usually computationally intractable when considering classical MCMC approaches. The proposed approach involves the construction of a PCK surrogate model which provides both global and local approximations of the likelihood function, through the combination of Polynomial Chaos and Kriging surrogates. Furthermore, we propose an adaptive scheme for enriching the PCK surrogate throughout the SuS sampling procedure, in order to improve its accuracy near informative regions. The applicability and the efficiency of the proposed approach are assessed through several cases studies with increasing complexity. Results highlight that the proposed approach enables to accurately approximating posteriors with a limited amount of full model calls, even in the case of multi-modal posteriors, which are usually difficult to sample when using classical MCMC algorithms.
•Effect of water temperature on concrete dams displacement.•How to include the dam thickness profile in statistical modelling?•Improvements of statistical modellings to increase their capacities of ...prediction.•Use of numerical mock-up for virtual case generation.•Separating effect of thermal boundary conditions on dam displacements.
Several factors are acting on concrete dams and affect dam displacements: hydrostatic load, thermal effect and irreversible phenomena (creep, swelling …). The different influences need to be quantified for the analysis of monitoring measurements. In most statistical models for the dam behavior analysis, the thermal effect which is often the main contributor to the total displacement is introduced only by means of the dam temperatures. Recently Tatin et al. (2015) have introduced a global gradient across the dam of the temperature bringing an additional bending effect. However, the thermal gradient may be very different, even with opposite sign, from the top to the bottom depending on seasons.
In this paper, a statistical model accounting for the water temperature profile is proposed. In this original statistical model, the dam is discretized along its height in n layers on which both mean and gradient of the dam temperature are computed for the evaluation of the thermal effect. It implies 2·n new explicative variables for the statistical model yielding a reduced dispersion of the residuals. However, statistical compensation occurs from one layer to the next leading to unrealistic influence functions along the height of the dam. In order to reduce this effect, the statistical problem is constrained by imposing a polynomial approximation of influence functions. The parameters of the polynomial may be estimated either beforehand by means of the dam numerical model or directly by the statistical process. The number of additional degrees of freedom of the statistical process is thus reduced but can still describe the effects of both profiles of the water temperature and the dam thickness on dam displacements. For the model construction and validation, an arch dam is modelled by means of the finite element method and serves as a virtual case study. Although results show only a slight reduced residual dispersion, physical meaning of the model to the intermediate quantities is increased.
Epithelial-to-mesenchymal transition (EMT) promotes cell motility, which is important for the metastasis of malignant cells, and blocks CD95-mediated apoptotic signaling triggered by immune cells and ...chemotherapeutic regimens. CD95L, the cognate ligand of CD95, can be cleaved by metalloproteases and released as a soluble molecule (cl-CD95L). Unlike transmembrane CD95L, cl-CD95L does not induce apoptosis but triggers cell motility. Electron paramagnetic resonance was used to show that EMT and cl-CD95L treatment both led to augmentation of plasma membrane fluidity that was instrumental in inducing cell migration. Compaction of the plasma membrane is modulated, among other factors, by the ratio of certain lipids such as sphingolipids in the membrane. An integrative analysis of gene expression in NCI tumor cell lines revealed that expression of ceramide synthase-6 (CerS6) decreased during EMT. Furthermore, pharmacological and genetic approaches established that modulation of CerS6 expression/activity in cancer cells altered the level of C16-ceramide, which in turn influenced plasma membrane fluidity and cell motility. Therefore, this study identifies CerS6 as a novel EMT-regulated gene that has a pivotal role in the regulation of cell migration.
Serious juvenile offenders present high recidivism rates. Much research focus on the processes of desistance from crime in adult populations. However, much less is known about the processes of ...desistance of adolescents. This scoping review aimed to map available knowledge regarding processes of desistance from crime among serious juvenile offenders. Twenty-six quantitative and qualitative studies were analysed. Results indicate that individual, relational, and structural factors can either facilitate or hinder adolescents' attempts to move away from crime. During this transitional period, the role of case workers in assisting desistance appears to be essential.
A better understanding of how adolescent offenders come to move away from crime is essential to develop more humane and effective practices.
Social workers can play a key role in assisting offenders to identify their strengths and goals for the future in order to help them gradually retake control of their life and become the person they aspire to be.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hepatocellular carcinoma (HCC) is a common cause of cancer‐related death. Sorafenib prolongs survival of patients with advanced disease and is approved for the systemic treatment of unresectable HCC. ...It possesses antiangiogenic and antiproliferative properties by way of inhibition of the receptor tyrosine kinases vascular endothelial growth factor receptor 2 (VEGFR‐2) and platelet‐derived growth factor receptor‐beta 1/2 (PDGFR‐β) and the kinase RAF. Sorafenib represents a candidate compound for adjuvant therapy in HCC patients. The aim of our study was to investigate whether sorafenib affects liver regeneration. C57BL6 mice received sorafenib orally at 30 mg/kg/day or its vehicle either for 14 days until the day before hepatectomy or starting the day after surgery or both. Animals were sacrificed 24, 72, and 120 hours after hepatectomy. Liver regeneration was calculated as a percent of initial liver weight. Bromodeoxyuridine (BrdU) incorporation and phospho‐extracellular signal‐regulated kinase (pERK1/2) were determined by immunohistochemistry on liver sections. VEGF‐A, PDGF‐BB, and hepatocyte growth factor (HGF) levels were measured in liver tissue homogenates. Histological analysis of scar tissue was performed. Treatment stopped 1 day before surgery had no impact on liver regeneration. Continuous sorafenib treatment and treatment started 1 day after surgery had statistically significant effects on liver regeneration at 120 hours compared to vehicle‐treated control animals (72% ± 12 versus control 88% ± 15 and 70% ± 13 versus control 86% ± 5 at 120 hours, both P ≤ 0.02). BrdU incorporation showed decreased numbers of positive nuclei in both groups receiving sorafenib after surgery. Phospho‐ERK levels were reduced in sorafenib‐treated animals. An increase of VEGF‐A levels was observed in mice receiving sorafenib. Wound‐healing complications were observed in animals receiving sorafenib after surgery and confirmed on histological sections. Conclusion: This preclinical study shows that sorafenib did not impact on liver regeneration when ceased before surgery; however, administration after hepatectomy affected late liver regeneration. (HEPATOLOGY 2011;53:577‐586)
PDF
