The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis.
Gut. 2015 Mar 24;
Authors: Ling H, Pickard K, Ivan C, Isella C, Ikuo M, Mitter R, Spizzo R, Bullock MD, Braicu C, Pileczki V, Vincent K, Pichler M, Stiegelbauer V, Hoefler G, Almeida MI, Hsiao A, Zhang X, Primrose JN, Packham GK, Liu K, Bojja K, Gafà R, Xiao L, Rossi S, Song JH, Vannini I, Fanini F, Kopetz S, Zweidler-McKay P, Wang X, Ionescu C, Irimie A, Fabbri M, Lanza G, Hamilton SR, Berindan-Neagoe I, Medico E, Mirnezami AH, Calin GA, Nicoloso MS
OBJECTIVE: MicroRNA (miRNA) expression profile can be used as prognostic marker for human cancers. We aim to explore the significance of miRNAs in colorectal cancer (CRC) metastasis.
DESIGN: We performed miRNA microarrays using primary CRC tissues from patients with and without metastasis, and validated selected candidates in 85 CRC samples by quantitative real-time PCR (qRT-PCR). We tested metastatic activity of selected miRNAs and identified miRNA targets by prediction algorithms, qRT-PCR, western blot and luciferase assays. Clinical outcomes were analysed in six sets of CRC cases (n=449), including The Cancer Genome Atlas (TCGA) consortium and correlated with miR-224 status. We used the Kaplan-Meier method and log-rank test to assess the difference in survival between patients with low or high levels of miR-224 expression.
RESULTS: MiR-224 expression increases consistently with tumour burden and microsatellite stable status, and miR-224 enhances CRC metastasis in vitro and in vivo. We identified SMAD4 as a miR-224 target and observed negative correlation (Spearman Rs=-0.44, p<0.0001) between SMAD4 and miR-224 expression in clinical samples. Patients with high miR-224 levels display shorter overall survival in multiple CRC cohorts (p=0.0259, 0.0137, 0.0207, 0.0181, 0.0331 and 0.0037, respectively), and shorter metastasis-free survival (HR 6.51, 95% CI 1.97 to 21.51, p=0.0008). In the TCGA set, combined analysis of miR-224 with SMAD4 expression enhanced correlation with survival (HR 4.12, 95% CI 1.1 to 15.41, p=0.0175).
CONCLUSIONS: MiR-224 promotes CRC metastasis, at least in part, through the regulation of SMAD4. MiR-224 expression in primary CRC, alone or combined with its targets, may have prognostic value for survival of patients with CRC.
PMID: 25804630 [PubMed - as supplied by publisher]
Effectiveness, training and quality assurance of colonoscopy screening for colorectal cancer.
Gut. 2015 Mar 24;
Authors: Robertson DJ, Kaminski MF, Bretthauer M
Screening for colorectal cancer has been proven to be effective in reducing colorectal cancer incidence and mortality. While the precise benefit of screening exclusively by colonoscopy is not yet known, unarguably, the exam is central to the success of any screening programme. The test affords the opportunity to detect and resect neoplasia across the entire large bowel and is the definitive examination when other screening tests are positive. However, colonoscopy is invasive and often requires sedation as well as extensive bowel preparation, all of which puts the patient at risk. Furthermore, the test can technically be demanding and, unarguably, there is variation in how it is performed. This variation in performance has now been definitively linked to important outcome measures. For example, interval cancers are more common in low adenoma detectors as compared with high adenoma detectors. This review outlines the most current thinking regarding the effectiveness of colonoscopy as a screening tool. It also outlines key concepts to optimise its performance through robust quality assurance programmes and high-quality training.
PMID: 25804631 [PubMed - as supplied by publisher]
Failure of interleukin 13 blockade in ulcerative colitis.
Gut. 2015 Mar 24;
Authors: Tilg H, Kaser A
PMID: 25804632 [PubMed - as supplied by publisher]
An independent validation of the mortality score for the short-term prognostic prediction in patients with chronic HCV infection and advanced liver disease.
Gut. 2015 Mar 24;
Authors: Giannini EG, Savarino V
PMID: 25804633 [PubMed - as supplied by publisher]
Liver transplantation for hepatocellular carcinoma beyond the Milan criteria.
Gut. 2015 Mar 24;
Authors: Xu X, Lu D, Ling Q, Wei X, Wu J, Zhou L, Yan S, Wu L, Geng L, Ke Q, Gao F, Tu Z, Wang W, Zhang M, Shen Y, Xie H, Jiang W, Wang H, Zheng S
OBJECTIVE: Liver transplantation is an optimal radical therapy for selected patients with hepatocellular carcinoma. The stringent organ allocation system driven by the Milan criteria has been challenged by alternative sets of expanded criteria. Careful analysis is needed to prove that the Milan criteria can be expanded safely and effectively.
DESIGN: This study collectively reviewed 6012 patients of hepatocellular carcinoma from the China Liver Transplant Registry. Expanded criteria were evaluated to characterise an optimised expansion with acceptable outcomes beyond the Milan criteria.
RESULTS: Compared with the Milan criteria, Valencia, University of California, San Francisco, University Clinic of Navarra and Hangzhou criteria provided an expansion of 12.4%, 16.3%, 19.6%, and 51.5%, respectively. The post-transplant survivals of patients fulfilling the expanded criteria were comparable to that of the Milan criteria. The analysis of net reclassification improvement and area under the receiver operating characteristic curves showed an excellent efficiency in recurrence prediction for the expanded criteria compared with the Milan criteria. In patients exceeding Milan but fulfilling the Hangzhou criteria (N=1352), α-fetoprotein (AFP) >100 ng/mL and tumour burden>8 cm were the only two independent prognostic factors (p<0.001). Accordingly, the Hangzhou criteria were stratified as type A (tumour burden ≤8 cm, or tumour burden >8 cm but AFP≤100 ng/mL) and type B (tumour burden >8 cm but AFP between 100 and 400 ng/mL). Type A showed significantly higher 5-year tumour-free survival rates compared with type B (p<0.001).
CONCLUSIONS: The Milan criteria can be expanded safely and effectively. The prognostic stratification system based on the Hangzhou criteria serves as a hierarchy of transplant candidates for hepatocellular carcinoma.
PMID: 25804634 [PubMed - as supplied by publisher]
Exploring the underlying structure of mental disorders: cross-diagnostic differences and similarities from a network perspective using both a top-down and a bottom-up approach.
Psychol Med. 2015 Mar 25;:1-13
Authors: Wigman JT, van Os J, Borsboom D, Wardenaar KJ, Epskamp S, Klippel A, MERGE, Viechtbauer W, Myin-Germeys I, Wichers M
BACKGROUND: It has been suggested that the structure of psychopathology is best described as a complex network of components that interact in dynamic ways. The goal of the present paper was to examine the concept of psychopathology from a network perspective, combining complementary top-down and bottom-up approaches using momentary assessment techniques.
METHOD: A pooled Experience Sampling Method (ESM) dataset of three groups (individuals with a diagnosis of depression, psychotic disorder or no diagnosis) was used (pooled N = 599). The top-down approach explored the network structure of mental states across different diagnostic categories. For this purpose, networks of five momentary mental states (‘cheerful’, ‘content’, ‘down’, ‘insecure’ and ‘suspicious’) were compared between the three groups. The complementary bottom-up approach used principal component analysis to explore whether empirically derived network structures yield meaningful higher order clusters.
RESULTS: Individuals with a clinical diagnosis had more strongly connected moment-to-moment network structures, especially the depressed group. This group also showed more interconnections specifically between positive and negative mental states than the psychotic group. In the bottom-up approach, all possible connections between mental states were clustered into seven main components that together captured the main characteristics of the network dynamics.
CONCLUSIONS: Our combination of (i) comparing network structure of mental states across three diagnostically different groups and (ii) searching for trans-diagnostic network components across all pooled individuals showed that these two approaches yield different, complementary perspectives in the field of psychopathology. The network paradigm therefore may be useful to map transdiagnostic processes.
PMID: 25804221 [PubMed - as supplied by publisher]
Evidence that the presence of psychosis in non-psychotic disorder is environment-dependent and mediated by severity of non-psychotic psychopathology.
Psychol Med. 2015 Mar 25;:1-13
Authors: Guloksuz S, van Nierop M, Lieb R, van Winkel R, Wittchen HU, van Os J
BACKGROUND: Evidence suggests that in affective, non-psychotic disorders: (i) environmental exposures increase risk of subthreshold psychotic experiences (PEs) and strengthen connectivity between domains of affective and subthreshold psychotic psychopathology; and (ii) PEs are a marker of illness severity.
METHOD: In 3021 adolescents from the Early Developmental Stages of Psychopathology cohort, we tested whether the association between PEs and presence of DSM-IV mood disorder (MD)/obsessive-compulsive disorder (OCD) would be moderated by risk factors for psychosis (cannabis use, childhood trauma and urbanicity), using the interaction contrast ratio (ICR) method. Furthermore, we analysed whether the interaction between environment and PEs was mediated by non-psychotic psychopathology.
RESULTS: The association between PEs and MD/OCD was moderated by urbanicity (ICR = 2.46, p = 0.005), cannabis use (ICR = 3.76, p = 0.010) and, suggestively, trauma (ICR = 1.91, p = 0.063). Exposure to more than one environmental risk factor increased the likelihood of co-expression of PEs in a dose-response fashion. Moderating effects of environmental exposures were largely mediated by the severity of general non-psychotic psychopathology (percentage explained 56-68%, all p < 0.001). Within individuals with MD/OCD, the association between PEs and help-seeking behaviour, as an index of severity, was moderated by trauma (ICR = 1.87, p = 0.009) and urbanicity (ICR = 1.48, p = 0.005), but not by cannabis use.
CONCLUSIONS: In non-psychotic disorder, environmental factors increase the likelihood of psychosis admixture and help-seeking behaviour through an increase in general psychopathology. The findings are compatible with a relational model of psychopathology in which more severe clinical states are the result of environment-induced disturbances spreading through a psychopathology network.
PMID: 25804288 [PubMed - as supplied by publisher]
A pragmatic randomized controlled trial to evaluate the effectiveness of a facilitated exercise intervention as a treatment for postnatal depression: the PAM-PeRS trial.
Psychol Med. 2015 Mar 25;:1-13
Authors: Daley AJ, Blamey RV, Jolly K, Roalfe AK, Turner KM, Coleman S, McGuinness M, Jones I, Sharp DJ, MacArthur C
BACKGROUND: Postnatal depression affects about 10-15% of women in the year after giving birth. Many women and healthcare professionals would like an effective and accessible non-pharmacological treatment for postnatal depression.
METHOD: Women who fulfilled the International Classification of Diseases (ICD)-10 criteria for major depression in the first 6 months postnatally were randomized to receive usual care plus a facilitated exercise intervention or usual care only. The intervention involved two face-to-face consultations and two telephone support calls with a physical activity facilitator over 6 months to support participants to engage in regular exercise. The primary outcome was symptoms of depression using the Edinburgh Postnatal Depression Scale (EPDS) at 6 months post-randomization. Secondary outcomes included EPDS score as a binary variable (recovered and improved) at 6 and 12 months post-randomization.
RESULTS: A total of 146 women were potentially eligible and 94 were randomized. Of these, 34% reported thoughts of self-harming at baseline. After adjusting for baseline EPDS, analyses revealed a -2.04 mean difference in EPDS score, favouring the exercise group [95% confidence interval (CI) -4.11 to 0.03, p = 0.05]. When also adjusting for pre-specified demographic variables the effect was larger and statistically significant (mean difference = -2.26, 95% CI -4.36 to -0.16, p = 0.03). Based on EPDS score a larger proportion of the intervention group was recovered (46.5% v. 23.8%, p = 0.03) compared with usual care at 6 months follow-up.
CONCLUSIONS: This trial shows that an exercise intervention that involved encouragement to exercise and to seek out social support to exercise may be an effective treatment for women with postnatal depression, including those with thoughts of self-harming.
PMID: 25804297 [PubMed - as supplied by publisher]
Life satisfaction and mental health problems (18 to 35 years).
Psychol Med. 2015 Mar 25;:1-10
Authors: Fergusson DM, McLeod GF, Horwood LJ, Swain NR, Chapple S, Poulton R
BACKGROUND: Previous research has found that mental health is strongly associated with life satisfaction. In this study we examine associations between mental health problems and life satisfaction in a birth cohort studied from 18 to 35 years.
METHOD: Data were gathered during the Christchurch Health and Development Study, which is a longitudinal study of a birth cohort of 1265 children, born in Christchurch, New Zealand, in 1977. Assessments of psychiatric disorder (major depression, anxiety disorder, suicidality, alcohol dependence and illicit substance dependence) using DSM diagnostic criteria and life satisfaction were obtained at 18, 21, 25, 30 and 35 years.
RESULTS: Significant associations (p < 0.01) were found between repeated measures of life satisfaction and the psychiatric disorders major depression, anxiety disorder, suicidality, alcohol dependence and substance dependence. After adjustment for non-observed sources of confounding by fixed effects, statistically significant associations (p < 0.05) remained between life satisfaction and major depression, anxiety disorder, suicidality and substance dependence. Overall, those reporting three or more mental health disorders had mean life satisfaction scores that were nearly 0.60 standard deviations below those without mental health problems. A structural equation model examined the direction of causation between life satisfaction and mental health problems. Statistically significant (p < 0.05) reciprocal associations were found between life satisfaction and mental health problems.
CONCLUSIONS: After adjustment for confounding, robust and reciprocal associations were found between mental health problems and life satisfaction. Overall, this study showed evidence that life satisfaction influences mental disorder, and that mental disorder influences life satisfaction.
PMID: 25804325 [PubMed - as supplied by publisher]
Altered mesocorticolimbic functional connectivity in psychotic disorder: an analysis of proxy genetic and environmental effects.
Psychol Med. 2015 Mar 25;:1-13
Authors: Peeters SC, Gronenschild EH, van de Ven V, Habets P, Goebel R, van Os J, Marcelis M, for Genetic Risk and Outcome of Psychosis (G.R.O.U.P.)
BACKGROUND: Altered dopaminergic neurotransmission in the mesocorticolimbic (MCL) system may mediate psychotic symptoms. In addition, pharmacological dopaminergic manipulation may coincide with altered functional connectivity (fc) ‘in rest’. We set out to test whether MCL-fc is conditional on (familial risk for) psychotic disorder and/or interactions with environmental exposures.
METHOD: Resting-state functional magnetic resonance imaging data were obtained from 63 patients with psychotic disorder, 73 non-psychotic siblings of patients with psychotic disorder and 59 healthy controls. With the nucleus accumbens (NAcc) as seed region, fc within the MCL system was estimated. Regression analyses adjusting for a priori hypothesized confounders were used to assess group differences in MCL connectivity as well as gene (group) × environmental exposure interactions (G × E) (i.e. to cannabis, developmental trauma and urbanicity).
RESULTS: Compared with controls, patients and siblings had decreased fc between the right NAcc seed and the right orbitofrontal cortex (OFC) as well as the left middle cingulate cortex (MCC). Siblings showed decreased connectivity between the NAcc seed and lentiform nucleus compared with patients and controls. In addition, patients had decreased left NAcc connectivity compared with siblings in the left middle frontal gyrus. There was no evidence for a significant interaction between group and the three environmental exposures in the model of MCL-fc.
CONCLUSIONS: Reduced NAcc-OFC/MCC connectivity was seen in patients and siblings, suggesting that altered OFC connectivity and MCC connectivity are vulnerability markers for psychotic disorder. Differential exposure to environmental risk factors did not make an impact on the association between familial risk and MCL connectivity.
PMID: 25804977 [PubMed - as supplied by publisher]