Comparison of adenoma miss rate and adenoma detection rate between conventional colonoscopy and colonoscopy with second generation distal attachment cuff: a multicenter, randomized, back-to-back trial.

BACKGROUND AND AIMS: Endocuff VisionTM has been designed to enhance mucosal visualization thereby improving detection of (pre-)malignant colorectal lesions. This multicenter, international, back-to-back, randomized colonoscopy trial compared adenoma detection rate (ADR) and adenoma miss rate (AMR) between Endocuff Vision-assisted colonoscopy (EVC) and conventional colonoscopy (CC). METHODS: Patients aged 40-75 years referred for non-immunochemical fecal occult blood test-based screening, surveillance, or diagnostic colonoscopy were included at ten hospitals and randomized into four groups: Group 1; 2xCC, Group 2; CC followed by EVC, Group 3; EVC followed CC and Group 4; 2xEVC. Primary outcomes included ADR and AMR. RESULTS: A total of 717 patients were randomized of which 661 patients (92.2%) had one and 646 (90.1%) patients had two completed back-to-back colonoscopies. EVC did not significantly improve ADR compared to CC (41.1% [95%-CI;36.1-46.3] versus 35.5% [95%-CI;30.7-40.6], respectively, P=0.125), but EVC did reduced AMR by 11.7% (29.6% [95%-CI;23.6-36.5] versus 17.9% [95%-CI;12.5-23.5], respectively, P=0.049). AMR of 2xCC compared to 2xEVC was also not significantly different (25.9% [95%-CI;19.3-33.9] versus 18.8% [95%-CI;13.9-24.8], respectively, P=0.172). Only 3.7% of the polyps missed during the first procedures had advanced pathologic features. Factors affecting risk of missing adenomas were age (P=0.002), Boston Bowel Preparation Scale (P=0.008) and region where colonoscopy was performed (P<0.001). CONCLUSIONS: Our trial shows that EVC reduces the risk of missing adenomas but does not lead to a significant improved ADR. Remarkably, 25% of adenomas are still missed during conventional colonoscopies, which is not different from miss rates reported 25 years ago; reassuringly, advanced features were only found in 3.7% of these missed lesions. TRAIL REGISTRATION NUMBER: NCT03418948.

Proteomics Analysis Revealed the Importance of Inflammation-Mediated Downstream Pathways and the Protective Role of Curcumin in Bleomycin-Induced Pulmonary Fibrosis in C57BL/6 Mice.

Bleomycin (BLM)-induced pulmonary fibrosis is characterized by inflammation in the alveoli, subsequent deposition of extracellular matrix (ECM) and myofibroblasts, and an impaired fibrinolytic system. Here, we describe major hematological changes, the IL-17A-mediated p53-fibrinolytic pathway, and the high throughput hits of liquid chromatography-mass spectrometry (LC-MS) analysis during the progression of pulmonary fibrosis and the therapeutic potential of curcumin against disease progression. C57BL/6 mice were exposed to BLM, followed by curcumin intervention after 24 and 48 h. Mice were sacrificed after 7 days to validate the hematological parameters, molecular pathways, and proteomics. Various techniques such as western blotting, immunofluorescence, reverse transcriptase polymerase chain reaction (RT-PCR), hematoxylin and eosin staining, Masson's trichrome staining, and immunohistochemistry were used to validate the proposed theory. LC-MS analysis was performed using a Q-Orbitrap mass spectrometer. The Schrödinger approach was used to perform the in silico molecular docking studies. BLM-exposed mice exhibited gradual weight loss and altered lung morphology; however, these were reversed by curcumin treatment. Significant changes in the hematological parameters confirmed the severity of BLM exposure in the mice, and expression of IL-17A-mediated p53-fibrinolytic system components and alveolar epithelial cell (AEC) apoptosis further confirmed the pathophysiology of pulmonary fibrosis. Differentially expressed proteins were characterized and mapped using the proteomics approach. A strong interaction of curcumin is observed with p53, uPA, and PAI-I proteins. The key role of IL-17A-mediated inflammation in the impairment of the p53-fibrinolytic system and AEC apoptosis was confirmed during BLM-induced pulmonary fibrosis. Therapeutic efficacy of curcumin exhibited a protective role against the progression of pulmonary fibrosis, which promises potent therapeutic modality to target the IL-17A-mediated p53-fibrinolytic system during pulmonary fibrosis.

Proteogenomic examination of esophageal squamous cell carcinoma (ESCC): new lines of inquiry.

Introduction: Esophageal squamous cell carcinoma (ESCC), a histopathologic subtype of esophageal cancer is a major cause of cancer-related morbidity and mortality worldwide. This is primarily because patients are diagnosed at an advanced stage by the time symptoms appear. The genomics and mass spectrometry-based proteomics continue to provide important leads toward biomarker discovery for ESCC. However, such leads are yet to be translated into clinical utilities. Areas covered: We gathered information pertaining to proteomics and proteogenomics efforts in ESCC from the literature search until 2020. An overview of omics approaches to discover the candidate biomarkers for ESCC were highlighted. We present a summary of recent investigations of alterations in the level of gene and protein expression observed in biological samples including body fluids, tissue/biopsy and in vitro-based models. Expert opinion: A large number of protein-based biomarkers and therapeutic targets are being used in cancer therapy. Several candidates are being developed as diagnostics and prognostics for the management of cancers. High-resolution proteomic and proteogenomic approaches offer an efficient way to identify additional candidate biomarkers for diagnosis, monitoring of disease progression, prediction of response to chemo and radiotherapy. Some of these biomarkers can also be developed as therapeutic targets.

Split-dose preparation for colonoscopy increases adenoma detection rate: a randomised controlled trial in an organised screening programme.

OBJECTIVE: Although a split regimen of bowel preparation has been associated with higher levels of bowel cleansing, it is still uncertain whether it has a favourable effect on the adenoma detection rate (ADR). The present study was aimed at evaluating whether a split regimen was superior to the traditional 'full-dose, day-before' regimen in terms of ADR. DESIGN: In a multicentre, randomised, endoscopist-blinded study, 50-69-year-old subjects undergoing first colonoscopy after positive-faecal immunochemical test within an organised colorectal cancer organised screening programmes were 1:1 randomised to receive low-volume 2-L polyethylene glycol (PEG)-ascorbate solution in a 'split-dose' (Split-Dose Group, SDG) or 'day-before' regimen (Day-Before Group, DBG). The primary endpoint was the proportion of subjects with at least one adenoma. Secondary endpoints were the detection rates of advanced adenomas and serrated lesions at per-patient analysis and the total number of lesions. RESULTS: 690 subjects were included in the study. At per-patient analysis, the proportion of subjects with at least one adenoma was significantly higher in the SDG than in the DBG (183/345, 53.0% vs 141/345, 40.9%, relative risk (RR) 1.22, 95% CI 1.03 to 1.46); corresponding figures for advanced adenomas were 26.4% (91/345) versus 20.0% (69/345, RR 1.35, 95% CI 1.06 to 1.73). At per-polyp analysis, the total numbers of both adenomas and advanced adenomas per subject were significantly higher in the SDG (1.15 vs 0.8, p <0.001; 0.36 vs 0.22, p<0.001). CONCLUSIONS: In an organised screening setting, the adoption of a split regimen resulted into a higher detection rate of clinically relevant neoplastic lesions, thus improving the effectiveness of colonoscopy. Based on such evidence, the adoption of a split regimen for colonoscopy should be strongly recommended. CLINICAL TRIAL REGISTRATION NUMBER: NCT02178033.

Efficacy and safety of endoscopic resection of large colorectal polyps: a systematic review and meta-analysis.

OBJECTIVE: To assess the efficacy and safety of endoscopic resection of large colorectal polyps. DESIGN: Relevant publications were identified in MEDLINE/EMBASE/Cochrane Central Register for the period 1966-2014. Studies in which ≥20 mm colorectal neoplastic lesions were treated with endoscopic resection were included. Rates of postendoscopic resection surgery due to non-curative resection or adverse events, as well as the rates of complete endoscopic removal, invasive cancer, adverse events, recurrence and mortality, were extracted. Study quality was ascertained according to Newcastle-Ottawa Scale. Forest plot was produced based on random effect models. I2 statistic was used to describe the variation across studies due to heterogeneity. Meta-regression analysis was also performed. RESULTS: 50 studies including 6442 patients and 6779 large polyps were included in the analyses. Overall, 503 out of 6442 patients (pooled rate: 8%, 95% CI 7% to 10%, I2=78.6%) underwent surgery due to non-curative endoscopic resection, and 31/6442 (pooled rate: 1%, 95% CI 0.7% to 1.4%, I2=0%) to adverse events. Invasive cancer at histology, non-curative endoscopic resection, synchronous lesions and recurrence accounted for 58%, 28%, 2.2% and 5.9% of all the surgeries, respectively. Endoscopic perforation occurred in 96/6595 (1.5%, 95% CI 1.2% to 1.7%) polyps, while bleeding in 423/6474 (6.5%, 95% CI 5.9% to 7.1%). Overall, 5334 patients entered in surveillance, 502/5836 (8.6%, 95% CI 7.9% to 9.3%) being lost at follow-up. Endoscopic recurrence was detected in 735/5334 patients (13.8%, 95% CI 12.9% to 14.7%), being an invasive cancer in 14/5334 (0.3%, 95% CI 0.1% to 0.4%). Endoscopic treatment was successful in 664/735 cases (90.3%, 95% CI 88.2% to 92.5%). Mortality related with management of large polyps was reported in 5/6278 cases (0.08%, 95% CI 0.01% to 0.15%). CONCLUSIONS: Endoscopic resection of large polyps appeared to be an extremely effective and safe intervention. However, an adequate endoscopic surveillance is necessary for its long-term efficacy.

The economic impact of multiple sclerosis in Australia in 2010.

BACKGROUND: Multiple sclerosis (MS) has a major impact on health and is a substantial burden on patients and society. We estimated the annual costs of MS in Australia from individual and societal perspectives using data from the Australian MS Longitudinal Study (AMSLS) and prevalence figures from 2010. METHODS: Direct and indirect costs were estimated from a subsample of 712 AMSLS subjects who completed baseline and follow-up economic impact surveys. All costs are in 2010 Australian dollars (AUD). RESULTS: Annual costs per person with MS were AUD48,945 (95% CI: 45,138 to 52,752). Total costs were AUD1.042 (0.9707 to 1.1227) billion based on a prevalence of 21,283. The largest component was indirect costs due to loss of productivity (48%). Costs increased with increasing disability: AUD36,369, AUD58,890 and AUD65,305 per patient per year for mild, moderate and severe disability, respectively. Total costs of MS to Australian society have increased 58% between 2005 and 2010. CONCLUSIONS: This study confirms that MS imposes a substantial burden on Australian society, particularly impacting on productivity. The burden increases with worsening disability associated with the disease. Investment in interventions that slow progression, as well as resources, services and environments that assist people with MS to retain employment, is supported.

Assessing possible selection bias in a national voluntary MS longitudinal study in Australia.

BACKGROUND: Surveying volunteer members of a multiple sclerosis registry is a very cost-effective way of assessing the impact of the disease on life outcomes. However, whether the data from such a study can be generalised to the whole population of persons living with MS in a country or region is unclear. METHODS: Here we compare the demographic and disease characteristics of participants in one such study, the Australian Multiple Sclerosis Longitudinal Study (AMSLS), with two well-characterised MS prevalence studies with near-complete ascertainment of MS in their study regions. RESULTS: Although some differences were found, these largely represented the effects of geography (sex ratios) and local factors (national immunomodulatory therapy prescribing requirements), and the cohorts were otherwise comparable. Overall, despite comprising only 12-16% of MS cases in Australia, the AMSLS is highly representative of the MS population. CONCLUSIONS: Therefore with some minor caveats, the AMSLS data can be generalised to the whole Australasian MS population. Volunteer disease registries such as this can be highly representative and provide an excellent convenience sample when studying rare conditions such as MS.

A comprehensive network map of IL-17A signaling pathway.

Interleukin-17A (IL-17A) is one of the member of IL-17 family consisting of other five members (IL-17B to IL-17F). The Gamma delta (γδ) T cells and T helper 17 (Th17) cells are the major producers of IL-17A. Aberrant signaling by IL-17A has been implicated in the pathogenesis of several autoimmune diseases including idiopathic pulmonary fibrosis, acute lung injury, chronic airway diseases, and cancer. Activation of the IL-17A/IL-17 receptor A (IL-17RA) system regulates phosphoinositide 3-kinase/AKT serine/threonine kinase/mammalian target of rapamycin (PI3K/AKT/mTOR), mitogen-activated protein kinases (MAPKs) and activation of nuclear factor-κB (NF-κB) mediated signaling pathways. The IL-17RA activation orchestrates multiple downstream signaling cascades resulting in the release of pro-inflammatory cytokines such as interleukins (IL)-1ß, IL-6, and IL-8, chemokines (C-X-C motif) and promotes neutrophil-mediated immune response. Considering the biomedical importance of IL-17A, we developed a pathway resource of signaling events mediated by IL-17A/IL-17RA in this study. The curation of literature data pertaining to the IL-17A system was performed manually by the NetPath criteria. Using data mined from the published literature, we describe an integrated pathway reaction map of IL-17A/IL-17RA consisting of 114 proteins and 68 reactions. That includes detailed information on IL-17A/IL-17RA mediated signaling events of 9 activation/inhibition events, 17 catalysis events, 3 molecular association events, 68 gene regulation events, 109 protein expression events, and 6 protein translocation events. The IL-17A signaling pathway map data is made freely accessible through the WikiPathways Database ( https://www.wikipathways.org/index.php/Pathway : WP5242).

A network map of discoidin domain receptor 1(DDR1)-mediated signaling in pathological conditions.

Discoidin domain receptor 1 (DDR1) is one of the receptors that belong to a family of non-integrin collagen receptors. In common, DDR1 is predominantly found in epithelial and smooth muscle cells and its mainly involved in organogenesis during embryonic development. However, it's also overexpressed in several pathological conditions, including cancer and inflammation. The DDR1 is reported in numerous cancers, including breast, prostate, pancreatic, bladder, lung, liver, pituitary, colorectal, skin, gastric, glioblastoma, and inflammation. DDR1 activates through the collagen I, IV, IGF-1/IGF1R, and IGF2/IR, regulating downstream signaling molecules such as MAPKs, PI3K/Akt, and NF-kB in diseases. Despite its biomedical importance, there is a lack of consolidated network map of the DDR1 signaling pathway, which prompted us for curation of literature data pertaining to the DDR1 system following the NetPath criteria. We present here the compiled pathway map comprises 39 activation/inhibition events, 17 catalysis events, 22 molecular associations, 65 gene regulation events, 35 types of protein expression, and two protein translocation events. The detailed DDR1 signaling pathway map is made freely accessible through the WikiPathways Database ( https://www.wikipathways.org/index.php/ Pathway: https://www.wikipathways.org/index.php/Pathway:WP5288 ).

The multiple sclerosis work difficulties questionnaire.

BACKGROUND: A better understanding of the workplace difficulties experienced by people with multiple sclerosis (PwMS) may be critical to developing appropriate vocational and rehabilitative programs. OBJECTIVE: We aimed to assess the factor structure, internal consistency and validity of the new Multiple Sclerosis Work Difficulties Questionnaire (MSWDQ). METHODS: Work difficulty items were developed and reviewed by a panel of experts. Using the MSWDQ, cross-sectional self-report data of work difficulties were obtained in addition to employment status and MS disease information, in a community-based sample of 189 PwMS. RESULTS: Exploratory Maximum Likelihood Factor Analysis on the draft questionnaire yielded 50 items measuring 12 factors. Subscale internal consistencies ranged from 0.74 to 0.92, indicating adequate to excellent internal consistency reliability. The MSWDQ explained 40% of the variance in reduced work hours since diagnosis, 40% of the variance in expectations about withdrawing from work, 34% of the variance in expectations about reducing work hours, and 39% of the variance in expectations about changing type of work due to MS. CONCLUSION: The MSWDQ is a valid and internally reliable measure of workplace difficulties in PwMS. Physical difficulties, as well as cognitive and psychological difficulties were important predictors of workplace outcomes and expectations about future employment.

Endoscopist-directed propofol administration versus anesthesiologist assistance for colorectal cancer screening: a cost-effectiveness analysis.

BACKGROUND: Propofol for colonoscopy is largely administered by anesthesiologists or anesthesiology nurses in the United States (US) and Europe. Endoscopist-directed administration of propofol (EDP) by nonanesthesiologists has recently been proposed, with potential savings of anesthetist reimbursement costs. We aimed to assess potential EDP-related benefit in a screening setting. METHODS: In a Markov model the total number of screening and follow-up colonoscopies in a cohort of 100 000 US subjects were estimated. Anesthetist-assisted colonoscopy was compared with an EDP strategy. Model outputs were projected onto the 50 - 80-year-old US population, assuming 27 % as the current uptake for colonoscopy screening. Anesthetist costs were estimated using the mean reimbursement for the corresponding Medicare code (≥ 65-year-olds) and from commercial insurance information (50 - 64-year-olds). The proportion of colonoscopies with anesthesiologist assistance was estimated from the Medicare database. Mean nurse salary was used to estimate the cost of a 2-week EDP training. The absolute number of US endoscopists was estimated by inflating by 33 % the number of board-certified gastroenterologists. No EDP mortality was assumed in the reference scenario, and 0.0008 % mortality in the sensitivity analysis. US census data were adopted. Analogous inputs were used for France to assess EDP-related benefit in a European country. RESULTS: EDP training for 17 166 nurses (one for each US endoscopist) showed a cost of $ 47 million. Cost estimates for anesthesiologist assistance for colonoscopy were $ 95 (Medicare) and $ 450 (non-Medicare commercial insurance), with 34.8 % of colonoscopies requiring anesthesiologist assistance. US implementation of an EDP policy showed a 10-year saving of $ 3.2 billion (Monte Carlo analysis 5 - 95 % percentiles $ 2.7 - $ 11.9 billion). In the sensitivity analysis, assuming 50 % of colonoscopies were anesthetist-assisted showed an EDP benefit of $ 4.6 billion. Assuming a 0.0008 % mortality rate, the incremental cost - effectiveness of anesthetist-assisted colonoscopy versus an EDP policy was $ 1.5 million per life-year gained, supporting EDP as the optimal choice. A 31-fold increase of EDP-related mortality or a 17-fold cost reduction for anesthetist-assisted colonoscopy was required for EDP to become not cost-effective in this scenario. Implementation of an EDP policy in France, within a guaiac-fecal occult blood test (g-FOBT) screening program, was estimated to save € 0.8 billion in 10 years. CONCLUSIONS: The absolute economic benefit of EDP implementation in a screening setting is probably substantial with 10-year savings of $3.2 billion in the US and €0.8 billion in France. The impact of an eventual EDP-related mortality on EDP cost - effectiveness seems marginal. The huge economic and medical resources entailed by anesthetist-assisted colonoscopy could be more efficiently invested in other clinical fields.

Colon capsule endoscopy: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.

PillCam colon capsule endoscopy (CCE) is an innovative noninvasive, and painless ingestible capsule technique that allows exploration of the colon without the need for sedation and gas insufflation. Although it is already available in European and other countries, the clinical indications for CCE as well as the reporting and work-up of detected findings have not yet been standardized. The aim of this evidence-based and consensus-based guideline, commissioned by the European Society of Gastrointestinal Endoscopy (ESGE) is to furnish healthcare providers with a comprehensive framework for potential implementation of this technique in a clinical setting.

A network map of apelin-mediated signaling.

The apelin receptor (APLNR) is a class A (rhodopsin-like) G-protein coupled receptor with a wide distribution throughout the human body. Activation of the apelin/APLNR system regulates AMPK/PI3K/AKT/mTOR and RAF/ERK1/2 mediated signaling pathways. APLNR activation orchestrates several downstream signaling cascades, which play diverse roles in physiological effects, including effects upon vasoconstriction, heart muscle contractility, energy metabolism regulation, and fluid homeostasis angiogenesis. We consolidated a network map of the APLNR signaling map owing to its biomedical importance. The curation of literature data pertaining to the APLNR system was performed manually by the NetPath criteria. The described apelin receptor signaling map comprises 35 activation/inhibition events, 38 catalysis events, 4 molecular associations, 62 gene regulation events, 113 protein expression types, and 4 protein translocation events. The APLNR signaling pathway map data is made freely accessible through the WikiPathways Database ( https://www.wikipathways.org/index.php/Pathway:WP5067 ).

The network map of urotensin-II mediated signaling pathway in physiological and pathological conditions.

Urotensin-II is a polypeptide ligand with neurohormone-like activity. It mediates downstream signaling pathways through G-protein-coupled receptor 14 (GPR14) also known as urotensin receptor (UTR). Urotensin-II is the most potent endogenous vasoconstrictor in mammals, promoting cardiovascular remodelling, cardiac fibrosis, and cardiomyocyte hypertrophy. It is also involved in other physiological and pathological activities, including neurosecretory effects, insulin resistance, atherosclerosis, kidney disease, and carcinogenic effects. Moreover, it is a notable player in the process of inflammatory injury, which leads to the development of inflammatory diseases. Urotensin-II/UTR expression stimulates the accumulation of monocytes and macrophages, which promote the adhesion molecules expression, chemokines activation and release of inflammatory cytokines at inflammatory injury sites. Therefore, urotensin-II turns out to be an important therapeutic target for the treatment options and management of associated diseases. The main downstream signaling pathways mediated through this urotensin-II /UTR system are RhoA/ROCK, MAPKs and PI3K/AKT. Due to the importance of urotensin-II systems in biomedicine, we consolidated a network map of urotensin-II /UTR signaling. The described signaling map comprises 33 activation/inhibition events, 31 catalysis events, 15 molecular associations, 40 gene regulation events, 60 types of protein expression, and 11 protein translocation events. The urotensin-II signaling pathway map is made freely accessible through the WikiPathways Database ( https://www.wikipathways.org/index.php/Pathway:WP5158 ). The availability of comprehensive urotensin-II signaling in the public resource will help understand the regulation and function of this pathway in normal and pathological conditions. We believe this resource will provide a platform to the scientific community in facilitating the identification of novel therapeutic drug targets for diseases associated with urotensin-II signaling.

The network map of Elabela signaling pathway in physiological and pathological conditions.

Elabela (ELA; also called Apela and Toddler) is one of the recently discovered ligand among the two endogenous peptide ligands (Apelin and Elabela) of the apelin receptor (APLNR, also known as APJ). Elabela-induced signaling plays a crucial role in diverse biological processes, including formation of the embryonic cardiovascular system and early placental development by reducing the chances of occurrence of preeclampsia during pregnancy. It also plays the major role in the renoprotection by reducing kidney injury and the inflammatory response and regulation of gene expression associated with heart failure and fibrosis. Elabela may be processed into different active peptides, each of which binds to APLNR and predominantly activates the signals through PI3K/AKT pathway. Owing to its biomedical importance, we developed a consolidated signaling map of Elabela, in accordance with the NetPath criteria. The presented Elabela signaling map comprises 12 activation/inhibition events, 15 catalysis events, 1 molecular association, 34 gene regulation events and 32 protein expression events. The Elabela signaling pathway map is freely made available through the WikiPathways Database ( https://www.wikipathways.org/index.php/Pathway:WP5100 ).

A modular map of Bradykinin-mediated inflammatory signaling network.

Bradykinin, a member of the kallikrein-kinin system (KKS), is associated with an inflammatory response pathway with diverse vascular permeability functions, including thrombosis and blood coagulation. In majority, bradykinin signals through Bradykinin Receptor B2 (B2R). B2R is a G protein-coupled receptor (GPCR) coupled to G protein family such as Gαqs, Gαq/Gα11, Gαi1, and Gß1γ2. B2R stimulation leads to the activation of a signaling cascade of downstream molecules such as phospholipases, protein kinase C, Ras/Raf-1/MAPK, and PI3K/AKT and secondary messengers such as inositol-1,4,5-trisphosphate, diacylglycerol and Ca2+ ions. These secondary messengers modulate the production of nitric oxide or prostaglandins. Bradykinin-mediated signaling is implicated in inflammation, chronic pain, vasculopathy, neuropathy, obesity, diabetes, and cancer. Despite the biomedical importance of bradykinin, a resource of bradykinin-mediated signaling pathway is currently not available. Here, we developed a pathway resource of signaling events mediated by bradykinin. By employing data mining strategies in the published literature, we describe an integrated pathway reaction map of bradykinin consisting of 233 reactions. Bradykinin signaling pathway events included 25 enzyme catalysis reactions, 12 translocations, 83 activation/inhibition reactions, 11 molecular associations, 45 protein expression and 57 gene regulation events. The pathway map is made publicly available on the WikiPathways Database with the ID URL: https://www.wikipathways.org/index.php/Pathway:WP5132 . The bradykinin-mediated signaling pathway map will facilitate the identification of novel candidates as therapeutic targets for diseases associated with dysregulated bradykinin signaling.

A multi-cellular molecular signaling and functional network map of C-C motif chemokine ligand 18 (CCL18): a chemokine with immunosuppressive and pro-tumor functions.

The C-C Motif Chemokine Ligand 18 (CCL18) is a beta-chemokine sub-family member with immunomodulatory functions in primates. CCL18-dependent migration and epithelial-to-mesenchymal transition of oral squamous cell carcinoma, squamous cell carcinoma of head and neck, breast cancer, hepatocellular carcinoma, non-small cell lung carcinoma, ovarian cancer, pancreatic ductal carcinoma and bladder cancer cells are well-established. In the tumor niche, tumor-associated macrophages produce CCL18 and its overexpression is correlated with reduced patient survival in multiple cancers. Although multiple receptors including C-C chemokine receptor type 3 (CCR3), type 6 (CCR6), type 8 (CCR8) and G-protein coupled estrogen receptor (GPER1) are reported for CCL18, the Phosphatidylinositol Transfer Protein, Membrane-Associated 3 (PITPNM3) receptor is currently considered as its predominant receptor. Characterization of the molecular events and check points associated with the immunosuppressive and cancer progression support functions induced by CCL18 for their potential towards therapeutic applications is an area of active research. Hence, in this study, we assembled 917 signaling events reported to be induced by CCL18 through their studied receptors in diverse cell types as an integrated knowledgebase for reference, data integration and gene-set enrichment analysis of global transcriptomic and/or proteomics datasets.

A grading scale to evaluate colon cleansing for the PillCam COLON capsule: a reliability study.

BACKGROUND AND STUDY AIMS: The PillCam COLON capsule (Given Imaging, Ltd., Yoqneam, Israel) is an emerging technology for colon visualization. The aim of this prospective study was to assess the interobserver agreement of a new grading scale to evaluate colon cleansing for capsule use. PATIENTS AND METHODS: Healthy volunteers underwent colon preparation and ingested a PillCam COLON capsule. A RAPID 5 (Given Imaging, Ltd.) video was generated and de-identified, and the colon was divided into five segments. Two cleanliness grading scales were compared: a 2-point scale (adequate and inadequate) and a 4-point grading scale (poor, fair, good, and excellent). For assessment of interobserver variability, two experienced gastroenterologists independently rated the cleansing level for each colon segment and for the entire video. Investigators participated in a calibration session prior to reading the study videos. RESULTS: A total of 40 individuals (aged 40 - 74 years) completed the study. A total of 196 colon video segments were evaluated. Per segment, κ values for the 2-point and 4-point scales were 0.754 and 0.619, respectively, representing good interobserver agreement. For the overall grade of the 40 videos, κ values for the 2-point and 4-point scales were 0.647 and 0.44, respectively. CONCLUSIONS: This new cleanliness grading scale showed good interobserver agreement and may be used with the PillCam COLON capsule to assess preparation quality.

A quantitative assessment of the risks and cost savings of forgoing histologic examination of diminutive polyps.

BACKGROUND AND AIMS: Endoscopic prediction of polyp histology is rapidly improving to the point where it may not be necessary to submit all polyps for formal histologic assessment. This study aimed to quantify the expected costs and outcomes of removing diminutive polyps without subsequent pathologic assessment. METHODS: Cross-sectional analysis of a colonoscopy database for polyp histology; decision models that quantify effects on guideline-recommended surveillance and subsequent costs and consequences. The database was composed of consecutive colonoscopies from 1999 to 2004 at a single-institution tertiary care center. Patients were those found to have at least one diminutive polyp removed during colonoscopy, irrespective of indication. The main outcome measurements include up-front cost savings resulting from forgoing pathologic assessment; frequency and cost of incorrect surveillance intervals based on errors in histologic assessment; number needed to harm (NNH) for perforation and/or interval cancer. RESULTS: Incorrect surveillance intervals were recommended in 1.9% of cases when tissue was submitted for pathologic assessment and 11.8% of cases when it was not. Based on the annual volume of colonoscopy in the US, the annual up-front cost savings of forgoing the pathologic assessment would exceed a billion dollars. An upper estimate on the downstream costs and consequences of forgoing pathology suggests that less than 10% of the up-front savings would be offset and the NNH exceeds 11000. CONCLUSION: Endoscopic diagnosis of polyp histology during colonoscopy and forgoing pathologic examination would result in substantial up-front cost savings. Downstream consequences of the resulting incorrect surveillance intervals appear to be negligible.