Factors associated with dropout from treatment for eating disorders: a comprehensive literature review

<p>Abstract</p> <p>Background</p> <p>Dropout (DO) is common in the treatment of eating disorders (EDs), but the reasons for this phenomenon remain unclear. This study is an extensive review of the literature regarding DO predictors in EDs.</p> <p>Methods</p> <p>All papers in PubMed, PsycINFO and Cochrane Library (1980-2009) were considered. Methodological issues and detailed results were analysed for each paper. After selection according to inclusion criteria, 26 studies were reviewed.</p> <p>Results</p> <p>The dropout rates ranged from 20.2% to 51% (inpatient) and from 29% to 73% (outpatient). Predictors of dropout were inconsistent due to methodological flaws and limited sample sizes. There is no evidence that baseline ED clinical severity, psychiatric comorbidity or treatment issues affect dropout. The most consistent predictor is the binge-purging subtype of anorexia nervosa. Good evidence exists that two psychological traits (high maturity fear and impulsivity) and two personality dimensions (low self-directedness, low cooperativeness) are related to dropout.</p> <p>Conclusion</p> <p>Implications for clinical practice and areas for further research are discussed. Particularly, these results highlight the need for a shared definition of dropout in the treatment of eating disorders for both inpatient and outpatient settings. Moreover, the assessment of personality dimensions (impulse control, self-efficacy, maturity fear and others) as liability factors for dropout seems an important issue for creating specific strategies to reduce the dropout phenomenon in eating disorders.</p

Suppression of microRNA-31 increases sensitivity to 5-FU at an early stage, and affects cell migration and invasion in HCT-116 colon cancer cells

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) are endogenously expressed noncoding RNAs with important biological and pathological functions. Although several studies have shown that microRNA-31 (miR-31) is obviously up-regulated in colorectal cancer (CRC), there is no study on the functional roles of miR-31 in CRC.</p> <p>Methods</p> <p>Anti-miR™ miRNA 31 inhibitor (anti-miR-31) is a sequence-specific and chemically modified oligonucleotide to specifically target and knockdown miR-31 molecule. The effect of anti-miR-31 transfection was investigated by real-time PCR. HCT-116^p53+/+and HCT-116^p53-/-colon cancer cells were treated by anti-miR-31 with or without 5-fluorouracil (5-FU), cell proliferation was determined by MTT assay; apoptosis was detected by DAPI staining; cell cycle was evaluated by flow cytometry; colony formation, migration and invasion assays were performed to investigate the effect of suppression of miR-31 on the cell lines.</p> <p>Results</p> <p>Real-time PCR results showed that anti-miR-31 was efficiently introduced into the cells and reduced miR-31 levels to 44.1% in HCT-116^p53+/+and 67.8% in HCT-116^p53-/-cell line (<it>p </it>= 0.042 and 0.046). MTT results showed that anti-miR-31 alone had no effect on the proliferation of HCT-116^p53+/+or HCT-116^p53-/-. However, when combined with 5-FU, anti-miR-31 inhibited the proliferation of the two cell lines as early as 24 h after exposure to 5-FU (<it>p </it>= 0.038 and 0.044). Suppression of miR-31 caused a reduction of the migratory cells by nearly 50% compared with the negative control in both HCT-116^p53+/+and HCT-116^p53-/-(<it>p </it>= 0.040 and 0.001). The invasive ability of the cells were increased by 8-fold in HCT-116^p53+/+and 2-fold in HCT-116^p53-/-(<it>p </it>= 0.045 and 0.009). Suppression of miR-31 had no effect on cell cycle and colony formation (<it>p </it>> 0.05).</p> <p>Conclusions</p> <p>Suppression of miR-31 increases sensitivity to 5-FU at an early stage, and affects cell migration and invasion in HCT-116 colon cancer cells.</p

Circulating tumour cells demonstrate an altered response to hypoxia and an aggressive phenotype

BACKGROUND: Tumours contain hypoxic regions that select for an aggressive cell phenotype; tumour hypoxia induces metastasis-associated genes. Treatment refractory patients with metastatic cancer show increased numbers of circulating tumour cells (CTCs), which are also associated with disease progression. The aim of this study was to examine the as yet unknown relationship between hypoxia and CTCs. METHODS: We generated human MDA-MB-231 orthotopic xenografts and, using a new technology, isolated viable human CTCs from murine blood. The CTCs and parental MDA-MB-231 cells were incubated at 21 and 0.2% (hypoxia) oxygen, respectively. Colony formation was assayed and levels of hypoxia- and anoxia-inducible factors were measured. Xenografts generated from CTCs and parental cells were compared. RESULTS: MDA-MB-231 xenografts used to generate CTCs were hypoxic, expressing hypoxia factors: hypoxia-inducible factor1 alpha (HIF1alpha) and glucose transporter protein type 1 (GLUT1), and anoxia-induced factors: activating transcription factor 3 and 4 (ATF3 and ATF4). Parental MDA-MB-231 cells induced ATF3 in hypoxia, whereas CTCs expressed it constitutively. Asparagine synthetase (ASNS) expression was also higher in CTCs. Hypoxia induced ATF4 and the HIF1alpha target gene apelin in CTCs, but not in parental cells. Hypoxia induced lower levels of carbonic anhydrase IX (CAIX), GLUT1 and BCL2/adenovirus E1B 19-KD protein-interacting protein 3 (BNIP3) proteins in CTCs than in parental cells, supporting an altered hypoxia response. In chronic hypoxia, CTCs demonstrated greater colony formation than parental cells. Xenografts generated from CTCs were larger and heavier, and metastasised faster than MDA-MB-231 xenografts. CONCLUSION: CTCs show an altered hypoxia response and an enhanced aggressive phenotype in vitro and in vivo

Neuropilin-2 Mediated β-Catenin Signaling and Survival in Human Gastro-Intestinal Cancer Cell Lines

NRP-2 is a high-affinity kinase-deficient receptor for ligands belonging to the class 3 semaphorin and vascular endothelial growth factor families. NRP-2 has been detected on the surface of several types of human cancer cells, but its expression and function in gastrointestinal (GI) cancer cells remains to be determined. We sought to determine the function of NRP-2 in mediating downstream signals regulating the growth and survival of human gastrointestinal cancer cells. In human gastric cancer specimens, NRP-2 expression was detected in tumor tissues but not in adjacent normal mucosa. In CNDT 2.5 cells, shRNA mediated knockdown NRP-2 expression led to decreased migration and invasion in vitro (p<0.01). Focused gene-array analysis demonstrated that loss of NRP-2 reduced the expression of a critical metastasis mediator gene, S100A4. Steady-state levels and function of β-catenin, a known regulator of S100A4, were also decreased in the shNRP-2 clones. Furthermore, knockdown of NRP-2 sensitized CNDT 2.5 cells in vitro to 5FU toxicity. This effect was associated with activation of caspases 3 and 7, cleavage of PARP, and downregulation of Bcl-2. In vivo growth of CNDT 2.5 cells in the livers of nude mice was significantly decreased in the shNRP-2 group (p<0.05). Intraperitoneal administration of NRP-2 siRNA-DOPC decreased the tumor burden in mice (p = 0.01). Collectively, our results demonstrate that tumor cell–derived NRP-2 mediates critical survival signaling in gastrointestinal cancer cells

Hypoxia Regulates BMP4 Expression in the Murine Spleen during the Recovery from Acute Anemia

Bone marrow erythropoiesis is primarily homeostatic, producing new erythrocytes at a constant rate. However at times of acute anemia, new erythrocytes must be rapidly produced much faster than bone marrow steady state erythropoiesis. At these times stress erythropoiesis predominates. Stress erythropoiesis occurs in the fetal liver during embryogenesis and in the adult spleen and liver. In adult mice, stress erythropoiesis utilizes a specialized population of stress erythroid progenitors that are resident in the spleen. In response to acute anemia, these progenitors rapidly expand and differentiate in response to three signals, BMP4, SCF and hypoxia. In absence of acute anemic stress, two of these signals, BMP4 and hypoxia, are not present and the pathway is not active. The initiating event in the activation of this pathway is the up-regulation of BMP4 expression in the spleen.In this paper we analyze the regulation of BMP4 expression in the spleen by hypoxia. Using stromal cell lines, we establish a role for hypoxia transcription factor HIFs (Hypoxia Inducible Factors) in the transcription of BMP4. We identified putative Hypoxia Responsive Elements (HREs) in the BMP4 gene using bioinformatics. Analysis of these elements showed that in vivo, Hif2alpha binds two cis regulatory sites in the BMP4 gene, which regulate BMP4 expression during the recovery from acute anemia.These data show that hypoxia plays a key role in initiating the BMP4 dependent stress erythropoiesis pathway by regulating BMP4 expression

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Chronic Myeloid Leukemia Stem Cell Biology

Leukemia progression and relapse is fueled by leukemia stem cells (LSC) that are resistant to current treatments. In the progression of chronic myeloid leukemia (CML), blast crisis progenitors are capable of adopting more primitive but deregulated stem cell features with acquired resistance to targeted therapies. This in turn promotes LSC behavior characterized by aberrant self-renewal, differentiation, and survival capacity. Multiple reports suggest that cell cycle alterations, activation of critical signaling pathways, aberrant microenvironmental cues from the hematopoietic niche, and aberrant epigenetic events and deregulation of RNA processing may facilitate the enhanced survival and malignant transformation of CML progenitors. Here we review the molecular evolution of CML LSC that promotes CML progression and relapse. Recent advances in these areas have identified novel targets that represent important avenues for future therapeutic approaches aimed at selectively eradicating the LSC population while sparing normal hematopoietic progenitors in patients suffering from chronic myeloid malignancies

Cytoplasmic location of factor-inhibiting hypoxia-inducible factor is associated with an enhanced hypoxic response and a shorter survival in invasive breast cancer

INTRODUCTION: Hypoxia-inducible factor (HIF)-1alpha levels in invasive breast carcinoma have been shown to be an adverse prognostic indicator. Cellular HIF-1alpha activity is regulated by factor-inhibiting hypoxia-inducible factor 1 (FIH-1). In hypoxia, FIH-1 hydroxylation of Asn803 within the C-terminal transactivation domain does not occur and HIF-1alpha forms a fully active transcriptional complex. The present study investigates the role of FIH-1 in invasive breast carcinoma and its correlation with hypoxia. METHODS: Microarrayed tissue cores from 295 invasive carcinomas were stained for FIH-1, for HIF-1alpha and for carbonic anhydrase 9. FIH-1 expression was correlated with standard clinicopathological parameters and with the expression of the surrogate hypoxic markers HIF-1alpha and carbonic anhydrase 9. RESULTS: FIH-1 was positive in 239/295 (81%) tumours, 42/295 (14%) exclusively in the nucleus and 54/295 (18%) exclusively in the cytoplasm. Exclusive nuclear FIH-1 expression was significantly inversely associated with tumour grade (P = 0.02) and risk of recurrence (P = 0.04), whereas exclusive cytoplasmic FIH-1 was significantly positively associated with tumour grade (P = 0.004) and carbonic anhydrase 9 expression (P = 0.02). Patients with tumours that excluded FIH-1 from the nucleus had a significantly shorter survival compared with those with exclusive nuclear expression (P = 0.02). Cytoplasmic FIH-1 expression was also an independent poor prognostic factor for disease-free survival. CONCLUSION: FIH-1 is widely expressed in invasive breast carcinoma. As with other HIF regulators, its association between cellular compartmentalization and the hypoxic response and survival suggests that tumour regulation of FIH-1 is an additional important mechanism for HIF pathway activation

Modeling early recovery of physical function following hip and knee arthroplasty

BACKGROUND: Information on early recovery after arthroplasty is needed to help benchmark progress and make appropriate decisions concerning patient rehabilitation needs. The purpose of this study was to model early recovery of physical function in patients undergoing total hip (THA) and knee (TKA) arthroplasty, using physical performance and self-report measures. METHODS: A sample of convenience of 152 subjects completed testing, of which 69 (mean age: 66.77 ± 8.23 years) underwent THA and 83 (mean age: 60.25 ± 11.19 years) TKA. Postoperatively, patients were treated using standardized care pathways and rehabilitation protocols. Using a repeated measures design, patients were assessed at multiple time points over the first four postoperative months. Outcome measures included the Lower Extremity Function Scale (LEFS), the physical function subscale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC PF), the 6 minute walk test (6 MWT), timed up and go test (TUG) and a timed stair test (ST). Average recovery curves for each of the measures were characterized using hierarchical linear modeling. Predictors of recovery were sequentially modeled after validation of the basic developmental models. RESULTS: Slopes of recovery were greater in the first 6 to 9 weeks with a second-degree polynomial growth term (weeks squared) providing a reasonable fit for the data over the study interval. Different patterns of recovery were observed between the self-report measures of physical function and the performance measures. In contrast to the models for the WOMAC PF and the LEFS, site of arthroplasty was a significant predictor (p = 0.001) in all of the physical performance measure models with the patients post TKA initially demonstrating higher function. Site of arthroplasty (p = 0.025) also predicted the rate of change for patients post THA and between 9 to 11 weeks after surgery, the THA group surpassed the function of the patients post TKA. CONCLUSION: Knowledge about the predicted growth curves will assist clinicians in referencing patient progress, and determining the critical time points for measuring change. The study has contributed further evidence to highlight the benefit of using physical performance measures to learn about the patients' actual level of disability

Examination of Apoptosis Signaling in Pancreatic Cancer by Computational Signal Transduction Analysis

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains an important cause of cancer death. Changes in apoptosis signaling in pancreatic cancer result in chemotherapy resistance and aggressive growth and metastasizing. The aim of this study was to characterize the apoptosis pathway in pancreatic cancer computationally by evaluation of experimental data from high-throughput technologies and public data bases. Therefore, gene expression analysis of microdissected pancreatic tumor tissue was implemented in a model of the apoptosis pathway obtained by computational protein interaction prediction. METHODOLOGY/PRINCIPAL FINDINGS: Apoptosis pathway related genes were assembled from electronic databases. To assess expression of these genes we constructed a virtual subarray from a whole genome analysis from microdissected native tumor tissue. To obtain a model of the apoptosis pathway, interactions of members of the apoptosis pathway were analysed using public databases and computational prediction of protein interactions. Gene expression data were implemented in the apoptosis pathway model. 19 genes were found differentially expressed and 12 genes had an already known pathophysiological role in PDAC, such as Survivin/BIRC5, BNIP3 and TNF-R1. Furthermore we validated differential expression of IL1R2 and Livin/BIRC7 by RT-PCR and immunohistochemistry. Implementation of the gene expression data in the apoptosis pathway map suggested two higher level defects of the pathway at the level of cell death receptors and within the intrinsic signaling cascade consistent with references on apoptosis in PDAC. Protein interaction prediction further showed possible new interactions between the single pathway members, which demonstrate the complexity of the apoptosis pathway. CONCLUSIONS/SIGNIFICANCE: Our data shows that by computational evaluation of public accessible data an acceptable virtual image of the apoptosis pathway might be given. By this approach we could identify two higher level defects of the apoptosis pathway in PDAC. We could further for the first time identify IL1R2 as possible candidate gene in PDAC