110 research outputs found

    Therapist telephone-delivered CBT and web-based CBT compared with treatment as usual in refractory irritable bowel syndrome: the ACTIB three-arm RCT

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    Background: Irritable bowel syndrome (IBS) affects 10–22% of people in the UK. Abdominal pain, bloating and altered bowel habits affect quality of life and can lead to time off work. Current treatment relies on a positive diagnosis, reassurance, lifestyle advice and drug therapies, but many people suffer ongoing symptoms. Cognitive–behavioural therapy (CBT) is recommended in guidelines for patients with ongoing symptoms but its availability is limited. Objectives: To determine the clinical effectiveness and cost-effectiveness of therapist telephone-delivered CBT (TCBT) and web-based CBT (WCBT) with minimal therapist support compared with treatment as usual (TAU) in refractory IBS. Design: This was a three-arm randomised controlled trial. Setting: This trial took place in UK primary and secondary care. Participants: Adults with refractory IBS (clinically significant symptoms for 12 months despite first-line therapies) were recruited from 74 general practices and three gastroenterology centres from May 2014 to March 2016. Interventions: TCBT – patient CBT self-management manual, six 60-minute telephone sessions over 9 weeks and two 60-minute booster sessions at 4 and 8 months (8 hours’ therapist time). WCBT – interactive, tailored web-based CBT, three 30-minute telephone sessions over 9 weeks and two 30-minute boosters at 4 and 8 months (2.5 hours’ therapist time). Main outcome measures: Primary outcomes – IBS symptom severity score (IBS SSS) and Work and Social Adjustment Scale (WSAS) at 12 months. Cost-effectiveness [quality-adjusted life-years (QALYs) and health-care costs]. Results: In total, 558 out of 1452 patients (38.4%) screened for eligibility were recruited – 186 were randomised to TCBT, 185 were randomised to WCBT and 187 were randomised to TAU. The mean baseline Irritable Bowel Syndrome Symptom Severity Score (IBS SSS) was 265.0. An intention-to-treat analysis with multiple imputation was carried out at 12 months; IBS SSS were 61.6 points lower in the TCBT arm [95% confidence interval (CI) 89.5 to 33.8; p < 0.001] and 35.2 points lower in the WCBT arm (95% CI 57.8 to 12.6; p = 0.002) than in the TAU arm (IBS SSS of 205.6). The mean WSAS score at 12 months was 10.8 in the TAU arm, 3.5 points lower in the TCBT arm (95% CI 5.1 to 1.9; p < 0.001) and 3.0 points lower in the WCBT arm (95% CI 4.6 to 1.3; p = 0.001). For the secondary outcomes, the Subject’s Global Assessment showed an improvement in symptoms at 12 months (responders) in 84.8% of the TCBT arm compared with 41.7% of the TAU arm [odds ratio (OR) 6.1, 95% CI 2.5 to 15.0; p < 0.001] and 75.0% of the WCBT arm (OR 3.6, 95% CI 2.0 to 6.3; p < 0.001). Patient enablement was 78.3% (responders) for TCBT, 23.5% for TAU (OR 9.3, 95% CI 4.5 to 19.3; p < 0.001) and 54.8% for WCBT (OR 3.5, 95% CI 2.0 to 5.9; p < 0.001). Adverse events were similar between the trial arms. The incremental cost-effectiveness ratio (ICER) (QALY) for TCBT versus TAU was £22,284 and for WCBT versus TAU was £7724. Cost-effectiveness reduced after imputation for missing values. Qualitative findings highlighted that, in the CBT arms, there was increased capacity to cope with symptoms, negative emotions and challenges of daily life. Therapist input was important in supporting WCBT. Conclusions: In this large, rigorously conducted RCT, both CBT arms showed significant improvements in IBS outcomes compared with TAU. WCBT had lower costs per QALY than TCBT. Sustained improvements in IBS symptoms are possible at an acceptable cost. Suggested future research work is longer-term follow-up and research to translate these findings into usual clinical practice. Future work: Longer-term follow-up and research to translate these findings into usual clinical practice is needed

    Specific sequences within arginine–glycine-rich domains affect mRNA-binding protein function

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    The discovery of roles for arginine methylation in intracellular transport and mRNA splicing has focused attention on the methylated arginine–glycine (RG)-rich domains found in many eukaryotic RNA-binding proteins. Sequence similarity among these highly repetitive RG domains, combined with interactions between RG-rich proteins, raises the question of whether these regions are general interaction motifs or whether there is specificity within these domains. Using the essential Saccharomyces cerevisiae mRNA-binding protein Npl3 (ScNpl3) as a model system, we first tested the importance of the RG domain for protein function. While Npl3 lacking the RG domain could not support growth of cells lacking Npl3, surprisingly, expression of the RG domain alone supported partial growth of these cells. To address the specificity of this domain, we created chimeric forms of ScNpl3 with RG-rich domains of S. cerevisiae nucleolar proteins, Gar1 and Nop1 (ScGar1, ScNop1), or of the Candida albicans Npl3 ortholog (CaNpl3). Whereas the CaNpl3 RG chimeric protein retained nearly wild-type function in S. cerevisiae, the ScGar1 and ScNop1 RG domains significantly reduced Npl3 function and self-association, indicating RG domain specificity. Nuclear localization of Npl3 also requires specific RG sequences, yet heterologous RG domains allow similar modulation of Npl3 transport by arginine methylation

    Optimization of Energy-Consuming Pathways towards Rapid Growth in HPV-Transformed Cells

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    Cancer is a complex, multi-step process characterized by misregulated signal transduction and altered metabolism. Cancer cells divide faster than normal cells and their growth rates have been reported to correlate with increased metabolic flux during cell transformation. Here we report on progressive changes in essential elements of the biochemical network, in an in vitro model of transformation, consisting of primary human keratinocytes, human keratinocytes immortalized by human papillomavirus 16 (HPV16) and passaged repeatedly in vitro, and the extensively-passaged cells subsequently treated with the carcinogen benzo[a]pyrene. We monitored changes in cell growth, cell size and energy metabolism. The more transformed cells were smaller and divided faster, but the cellular energy flux was unchanged. During cell transformation the protein synthesis network contracted, as shown by the reduction in key cap-dependent translation factors. Moreover, there was a progressive shift towards internal ribosome entry site (IRES)-dependent translation. The switch from cap to IRES-dependent translation correlated with progressive activation of c-Src, an activator of AMP-activated protein kinase (AMPK), which controls energy-consuming processes, including protein translation. As cellular protein synthesis is a major energy-consuming process, we propose that the reduction in cell size and protein amount provide energy required for cell survival and proliferation. The cap to IRES-dependent switch seems to be part of a gradual optimization of energy-consuming mechanisms that redirects cellular processes to enhance cell growth, in the course of transformation

    The Caenorhabditis elegans HNF4α Homolog, NHR-31, Mediates Excretory Tube Growth and Function through Coordinate Regulation of the Vacuolar ATPase

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    Nuclear receptors of the Hepatocyte Nuclear Factor-4 (HNF4) subtype have been linked to a host of developmental and metabolic functions in animals ranging from worms to humans; however, the full spectrum of physiological activities carried out by this nuclear receptor subfamily is far from established. We have found that the Caenorhabditis elegans nuclear receptor NHR-31, a homolog of mammalian HNF4 receptors, is required for controlling the growth and function of the nematode excretory cell, a multi-branched tubular cell that acts as the C. elegans renal system. Larval specific RNAi knockdown of nhr-31 led to significant structural abnormalities along the length of the excretory cell canal, including numerous regions of uncontrolled growth at sites near to and distant from the cell nucleus. nhr-31 RNAi animals were sensitive to acute challenge with ionic stress, implying that the osmoregulatory function of the excretory cell was also compromised. Gene expression profiling revealed a surprisingly specific role for nhr-31 in the control of multiple genes that encode subunits of the vacuolar ATPase (vATPase). RNAi of these vATPase genes resulted in excretory cell defects similar to those observed in nhr-31 RNAi animals, demonstrating that the influence of nhr-31 on excretory cell growth is mediated, at least in part, through coordinate regulation of the vATPase. Sequence analysis revealed a stunning enrichment of HNF4α type binding sites in the promoters of both C. elegans and mouse vATPase genes, arguing that coordinate regulation of the vATPase by HNF4 receptors is likely to be conserved in mammals. Our study establishes a new pathway for regulation of excretory cell growth and reveals a novel role for HNF4-type nuclear receptors in the development and function of a renal system

    Identification and validation of the pathways and functions regulated by the orphan nuclear receptor, ROR alpha1, in skeletal muscle

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    The retinoic acid receptor-related orphan receptor (ROR) alpha has been demonstrated to regulate lipid metabolism. We were interested in the RORα1 dependent physiological functions in skeletal muscle. This major mass organ accounts for ∼40% of the total body mass and significant levels of lipid catabolism, glucose disposal and energy expenditure. We utilized the strategy of targeted muscle-specific expression of a truncated (dominant negative) RORα1ΔDE in transgenic mice to investigate RORα1 signaling in this tissue. Expression profiling and pathway analysis indicated that RORα influenced genes involved in: (i) lipid and carbohydrate metabolism, cardiovascular and metabolic disease; (ii) LXR nuclear receptor signaling and (iii) Akt and AMPK signaling. This analysis was validated by quantitative PCR analysis using TaqMan low-density arrays, coupled to statistical analysis (with Empirical Bayes and Benjamini–Hochberg). Moreover, westerns and metabolic profiling were utilized to validate the genes, proteins and pathways (lipogenic, Akt, AMPK and fatty acid oxidation) involved in the regulation of metabolism by RORα1. The identified genes and pathways were in concordance with the demonstration of hyperglycemia, glucose intolerance, attenuated insulin-stimulated phosphorylation of Akt and impaired glucose uptake in the transgenic heterozygous Tg-RORα1ΔDE animals. In conclusion, we propose that RORα1 is involved in regulating the Akt2-AMPK signaling pathways in the context of lipid homeostasis in skeletal muscle

    Dehydrocostuslactone Suppresses Angiogenesis In Vitro and In Vivo through Inhibition of Akt/GSK-3β and mTOR Signaling Pathways

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    The traditional Chinese medicine component dehydrocostuslactone (DHC) isolated from Saussurea costus (Falc.) Lipschitz, has been shown to have anti-cancer activity. Angiogenesis is an essential process in the growth and progression of cancer. In this study, we demonstrated, for the first time, the anti-angiogenic mechanism of action of DHC to be via the induction of cell cycle progression at the G0/G1 phase due to abrogation of the Akt/glycogen synthase kinase-3β (GSK-3β)/cyclin D1 and mTOR signaling pathway. First, we demonstrated that DHC has an anti-angiogenic effect in the matrigel-plug nude mice model and an inhibitory effect on human umbilical vein endothelial cell (HUVEC) proliferation and capillary-like tube formation in vitro. DHC caused G0/G1 cell cycle arrest, which was associated with the down-regulation of cyclin D1 expression, leading to the suppression of retinoblastoma protein phosphorylation and subsequent inhibition of cyclin A and cdk2 expression. With respect to the molecular mechanisms underlying the DHC-induced cyclin D1 down-regulation, this study demonstrated that DHC significantly inhibits Akt expression, resulting in the suppression of GSK-3β phosphorylation and mTOR expression. These effects are capable of regulating cyclin D1 degradation, but they were significantly reversed by constitutively active myristoylated (myr)-Akt. Furthermore, the abrogation of tube formation induced by DHC was also reversed by overexpression of Akt. And the co-treatment with LiCl and DHC significantly reversed the growth inhibition induced by DHC. Taken together, our study has identified Akt/GSK-3β and mTOR as important targets of DHC and has thus highlighted its potential application in angiogenesis-related diseases, such as cancer

    Ablation of TSC2 Enhances Insulin Secretion by Increasing the Number of Mitochondria through Activation of mTORC1

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    ) mice. The present study examines the effects of TSC2 ablation on insulin secretion from pancreatic beta cells. mice and TSC2 knockdown insulin 1 (INS-1) insulinoma cells treated with small interfering ribonucleic acid were used to investigate insulin secretion, ATP content and the expression of mitochondrial genes. mice exhibit hyperinsulinemia due to an increase in the number of mitochondria as well as enlargement of individual beta cells via activation of mTORC1.Activation of mTORC1 by TSC2 ablation increases mitochondrial biogenesis and enhances insulin secretion from pancreatic beta cells
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