2,385 research outputs found
JNK inhibition sensitises hepatocellular carcinoma cells but not normal hepatocytes to the TNF-related apoptosis-inducing ligand.
Background: cJun terminal kinase (JNK) is constitutively
activated in most hepatocellular carcinomas (HCCs), yet
its exact role in carcinogenesis remains controversial.
While tumour necrosis factor (TNF)-related apoptosisinducing
ligand (TRAIL) is known as a major mediator of
acquired immune tumour surveillance, and is currently
being tested in clinical trials as a novel cancer therapy,
the resistance of many tumours to TRAIL and concerns
about its toxicity in vivo represent obstacles to its clinical
application. In this study we investigated whether JNK
activity in HCC could contribute to the resistance to
apoptosis in these tumours.
Methods: The effect of JNK/Jun inhibition on receptormediated
apoptosis was analysed by pharmacological
inhibition or RNA interference in cancer cells and nontumour
cells isolated from human liver or transgenic mice
lacking a phosphorylation site for Jun.
Results: JNK inhibition caused cell cycle arrest,
enhanced caspase recruitment, and greatly sensitised
HCC cells but not normal hepatocytes to TRAIL. TRAILinduced
activation of JNK could be effectively interrupted
by administration of the JNK inhibitor SP600125.
Conclusions: Expression and TRAIL-dependent feedback
activation of JNK likely represent a mechanism by which
cancer cells escape TRAIL-mediated tumour surveillance.
JNK inhibition might represent a novel strategy for
specifically sensitising HCC cells to TRAIL thus opening
promising therapeutic perspectives for safe and effective
use of TRAIL in cancer treatment
Multiview video representations for quality-scalable navigation
Interactive multiview video (IMV) applications offer to users the freedom of selecting their preferred viewpoint. Usually, in these systems texture and depth maps of captured views are available at the user side, as they permit the rendering of intermediate virtual views. However, the virtual views' quality depends on the distance to the available views used as references and on their quality, which is generally constrained by the heterogeneous capabilities of the users. In this context, this work proposes an IMV scalable system, where views are optimally organized in layers, each one offering an incremental improvement in the interactive navigation quality. We propose a distortion model for the rendered virtual views and an algorithm that selects the optimal views' subset per layer. Simulation results show the efficiency of the proposed distortion model, and that the careful choice of reference cameras permits to have a graceful quality degradation for clients with limited capabilities
Direct versus indirect treatment for preschool children who stutter: The RESTART randomized trial
Objective Stuttering is a common childhood disorder. There is limited high quality evidence regarding options for best treatment. The aim of the study was to compare the effectiveness of direct treatment with indirect treatment in preschool children who stutter. Methods In this multicenter randomized controlled trial with an 18 month follow-up, preschool children who stutter who were referred for treatment were randomized to direct treatment (Lidcombe Program; n = 99) or indirect treatment (RESTART-DCM treatment; n = 100). Main inclusion criteria were age 3-6 years, ≥ 3% syllables stuttered (%SS), and time since onset ≥ 6 months. The primary outcome was the percentage of non-stuttering children at 18 months. Secondary outcomes included stuttering frequency (%SS), stuttering severity ratings by the parents and therapist, severity rating by the child, health-related quality of life, emotional and behavioral problems, and speech attitude. Results Percentage of non-stuttering children for direct treatment was 76.5% (65/85) versus 71.4% (65/91) for indirect treatment (Odds Ratio (OR), 0.6; 95% CI, 0.1-2.4, p = .42). At 3 months, children treated by direct treatment showed a greater decline in %SS (significant interaction time x therapy: β = -1.89; t(282.82) = -2.807, p = .005). At 18 months, stuttering frequency was 1.2% (SD 2.1) for direct treatment and 1.5% (SD 2.1) for indirect treatment. Direct treatment had slightly better scores on most other secondary outcome measures, but no differences between treatment approaches were significant. Conclusions Direct treatment decreased stuttering more quickly during the first three months of treatment. At 18 months, however, clinical outcomes for direct and indirect treatment were comparable. These results imply that at 18 months post treatment onset, both treatments are roughly equal in treating developmental stuttering in ways that surpass expectations of natural recovery. Follow-up data are needed to confirm these findings in the longer term
Tivantinib (ARQ 197) affects the apoptotic and proliferative machinery downstream of c-MET: role of Mcl-1, Bcl-xl and Cyclin B1
Wolfram Syndrome (Diabetes Insipidus, Diabetes, Optic Atrophy, and Deafness): Clinical and genetic study
OBJECTIVE—Wolfram syndrome is an autosomal recessive neurodegenerative disorder characterized by diabetes insipidus, diabetes (nonautoimmune), optic atrophy, and deafness (a set of conditions referred to as DIDMOAD). The WFS1 gene is located on the short arm of chromosome 4. Wolfram syndrome prevalence is 1 in 770,000 live births, with a 1 in 354 carrier frequency
Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke
Background
Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared
the efficacy and safety of two antiplatelet regimens — aspirin plus extendedrelease
dipyridamole (ASA–ERDP) versus clopidogrel.
Methods
In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive
25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive
75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke.
The secondary outcome was a composite of stroke, myocardial infarction, or death
from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075),
followed by superiority testing, was planned.
Results
A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke
occurred in 916 patients (9.0%) receiving ASA–ERDP and in 898 patients (8.8%) receiving
clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The
secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for
ASA–ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events
among ASA–ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365
[3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage
(hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major
hemorrhagic event was similar in the two groups (1194 ASA–ERDP recipients [11.7%],
vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11).
Conclusions
The trial did not meet the predefined criteria for noninferiority but showed similar rates
of recurrent stroke with ASA–ERDP and with clopidogrel. There is no evidence that either
of the two treatments was superior to the other in the prevention of recurrent
stroke. (ClinicalTrials.gov number, NCT00153062.
Economic factors influencing zoonotic disease dynamics: demand for poultry meat and seasonal transmission of avian influenza in Vietnam
While climate is often presented as a key factor influencing the seasonality of diseases, the importance of anthropogenic factors is less commonly evaluated. Using a combination of methods-wavelet analysis, economic analysis, statistical and disease transmission modelling-we aimed to explore the influence of climatic and economic factors on the seasonality of H5N1 Highly Pathogenic Avian Influenza in the domestic poultry population of Vietnam. We found that while climatic variables are associated with seasonal variation in the incidence of avian influenza outbreaks in the North of the country, this is not the case in the Centre and the South. In contrast, temporal patterns of H5N1 incidence are similar across these 3 regions: periods of high H5N1 incidence coincide with Lunar New Year festival, occurring in January-February, in the 3 climatic regions for 5 out of the 8 study years. Yet, daily poultry meat consumption drastically increases during Lunar New Year festival throughout the country. To meet this rise in demand, poultry production and trade are expected to peak around the festival period, promoting viral spread, which we demonstrated using a stochastic disease transmission model. This study illustrates the way in which economic factors may influence the dynamics of livestock pathogens
Microencapsulated islet allografts in diabetic NOD mice and nonhuman primates
OBJECTIVE: Our goal was to assess the efficacy of encapsulated allogeneic islets transplanted in diabetic NOD mice and streptozotocin (STZ)-diabetic nonhuman primates (NHPs).MATERIALS AND METHODS: Murine or NHP islets were microencapsulated and transplanted in non-immunosuppressed mice or NHPs given clinically-acceptable immunosuppressive regimens, respectively. Two NHPs were treated with autologous mesenchymal stem cells (MSCs) and peri-transplant oxygen therapy. Different transplant sites (intraperitoneal [i.p.], omental pouch, omental surface, and bursa omentalis) were tested in separate NHPs. Graft function was monitored by exogenous insulin requirements, fasting blood glucose levels, glucose tolerance tests, percent hemoglobin A1c (% HbA1c), and C-peptide levels. In vitro assessment of grafts included histology, immunohistochemistry, and viability staining; host immune responses were characterized by flow cytometry and cytokine/chemokine multiplex ELISAS.RESULTS: Microencapsulated islet allografts functioned long-term i.p. in diabetic NOD mice without immunosuppression, but for a relatively short time in immunosuppressed NHPs. In the NHPs, encapsulated allo-islets initially reduced hyperglycemia, decreased exogenous insulin requirements, elevated C-peptide levels, and lowered % HbA1c in plasma, but graft function diminished with time, regardless of transplant site. At necropsy, microcapsules were intact and non-fibrotic, but many islets exhibited volume loss, central necrosis and endogenous markers of hypoxia. Animals receiving supplemental oxygen and autologous MSCs showed improved graft function for a longer post-transplant period. In diabetic NHPs and mice, cell-free microcapsules did not elicit a fibrotic response.CONCLUSIONS: The evidence suggested that hypoxia was a major factor for damage to encapsulated islets in vivo. To achieve long-term function, new approaches must be developed to increase the oxygen supply to microencapsulated islets and/or identify donor insulin-secreting cells which can tolerate hypoxia.</p
The novel mTOR inhibitor RAD001 (Everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells
Background/Aim: Tumors exhibiting constitutively activated PI(3) K/Akt/mTOR signaling are hypersensitive to mTOR inhibitors such as RAD001 (everolimus) which is presently being investigated in clinical phase II trials in various tumor entities, including neuroendocrine tumors (NETs). However, no preclinical data about the effects of RAD001 on NET cells have been published. In this study, we aimed to evaluate the effects of RAD001 on BON cells, a human pancreatic NET cell line that exhibits constitutively activated PI(3) K/Akt/mTOR signaling. Methods: BON cells were treated with different concentrations of RAD001 to analyze its effect on cell growth using proliferation assays. Apoptosis was examined by Western blot analysis of caspase-3/PARP cleavage and by FACS analysis of DNA fragmentation. Results: RAD001 potently inhibited BON cell growth in a dose-dependent manner which was dependent on the serum concentration in the medium. RAD001-induced growth inhibition involved G0/G1-phase arrest as well as induction of apoptosis. Conclusion: In summary, our data demonstrate antiproliferative and apoptotic effects of RAD001 in NET cells in vitro supporting its clinical use in current phase II trials in NET patients. Copyright (c) 2007 S. Karger AG, Basel
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