Small and flat adenomas are known to carry a high miss-rate during standard white-light endoscopy. Increased detection rate may be achieved by molecular fluorescence endoscopy with targeted ...near-infrared (NIR) fluorescent tracers. The aim of this study was to validate vascular endothelial growth factor A (VEGF-A) and epidermal growth factor receptor (EGFR)-targeted fluorescent tracers during ex vivo colonoscopy with an NIR endoscopy platform.
VEGF-A and EGFR expression was determined by immunohistochemistry on a large subset of human colorectal tissue samples--48 sessile serrated adenomas/polyps, 70 sporadic high-grade dysplastic adenomas, and 19 hyperplastic polyps--and tissue derived from patients with Lynch syndrome--78 low-grade dysplastic adenomas, 57 high-grade dysplastic adenomas, and 31 colon cancer samples. To perform an ex vivo colonoscopy procedure, 14 mice with small intraperitoneal EGFR-positive HCT116(luc) tumors received intravenous bevacizumab-800CW (anti-VEGF-A), cetuximab-800CW (anti-EGFR), control tracer IgG-800CW, or sodium chloride. Three days later, 8 resected HCT116(luc) tumors (2-5 mm) were stitched into 1 freshly resected human colon specimen and followed by an ex vivo molecular fluorescence colonoscopy procedure.
Immunohistochemistry showed high VEGF-A expression in 79%-96% and high EGFR expression in 51%-69% of the colorectal lesions. Both targets were significantly overexpressed in the colorectal lesions, compared with the adjacent normal colon crypts. During ex vivo molecular fluorescence endoscopy, all tumors could clearly be delineated for both bevacizumab-800CW and cetuximab-800CW tracers. Specific tumor uptake was confirmed with fluorescent microscopy showing, respectively, stromal and cell membrane fluorescence.
VEGF-A is a promising target for molecular fluorescence endoscopy because it showed a high protein expression, especially in sessile serrated adenomas/polyps and Lynch syndrome. We demonstrated the feasibility to visualize small tumors in real time during colonoscopy using a NIR fluorescence endoscopy platform, providing the endoscopist a wide-field red-flag technique for adenoma detection. Clinical studies are currently being performed in order to provide in-human evaluation of our approach.
Abstract NOD1/CARD4 and NOD2/CARD15 are members of Nod-like receptor family. They are located in cytosol, bind bacterial and viral ligands and play a key role in realization of innate and adaptive ...immune response, apoptosis, autophagy, and reactive oxygen species generation. Polymorphisms in NOD1/CARD4 and NOD2/CARD15 genes may shift balance between pro- and anti-inflammatory cytokines, modulating the risk of infection, chronic inflammation and cancer. NOD1/CARD4 and NOD2/CARD15 gene polymorphisms may be associated with altered risk of gastric, colorectal, breast, ovarian, prostate, testicular, lung, laryngeal, liver, gallbladder, biliary tract, pancreatic, small bowel, kidney, urinary bladder cancer, skin cancer, nonthyroid endocrine tumors, lymphoma and leukemia. The short list of such polymorphisms perspective for oncogenomic investigations may include rs2006847, rs2066845, rs2066844, rs2066842, ND(1)+32656, rs2075820 whereas rs104895493, rs104895476, rs104895475, rs104895474, rs104895473, rs104895472, rs104895462, rs104895461, rs104895460, rs104895438, rs5743291, rs5743260, rs2076756, rs2066843, Pro371Thr, Ala794Pro, Gln908His, rs72551113, rs72551107, rs6958571, rs2907749, rs2907748, rs2075822, rs2075819, rs2075818 may be added to the extended list. Reasons of discrepancies between different studies include confounding host genetic, bacterial, or environmental factors modulating penetrance of variant allele and affecting risk of condition increasing cancer risk, different bacterial impact in aetiology of such conditions, differences in sample size, clinicopathological characteristics, diagnostics, stratification, genotyping methods, and chance.
Remote electronic voting (REV) as technology is gradually taking root in the political practice in Russia. As the technology is legally and chronologically new, it is both interesting and necessary ...to explain its implementation, as well as to identify the technological basis of the REV and, therefore, questions about the potential illegal use of this technology. This study aims at identifying the elements of the analysis of the implementation and legitimation of REV in cities and villages across Russia. The research is based on qualitative sociological and general logical methods: in general, the author uses the dialectical-materialistic approach, as well as the tools of comparative politics. A series of expert interviews were conducted in 10 regions of Russia. The results of the study showed that the Central Election Commission of the Russian Federation, the regional election commissions of the subjects of the Russian Federation, as well as regional and municipal authorities where the REV is being held, are at this stage looking for specific technologies to legitimize electronic voting. These practices will differ not only when comparing different regions, but also, most often, within one subject. One of the most significant differences will be noticeable with the introduction of REV in highly urbanized massifs and rural areas. Urban areas are characterized by the wide usage of political technologies to attract voters to electronic voting and legitimize it. Significantly larger budgets are invested in propaganda materials, including large, printed products (billboards, advertising at bus stops, and public transport). The idea of electronic voting is being promoted in social networks, mainly through VK, Telegram, Odnoklassniki, and WhatsApp. The rural areas, meanwhile, are characterized by activities aimed at personal contact with the voters and the use of informal connections. At the same time, today messages in social networks also reach rural residents, although most often it is not a purposeful activity, but a background capture of the audience. Concerning the improvement of the technological basis and the expansion of the geography of the REV, we can further elaborate on its legitimization and implementation, including in the context of the issues identified in this study.
The impact of socioeconomic disparities on surgical outcome in the absence of healthcare inequality remains unclear. Therefore, we set out to determine the association between socioeconomic status ...(SES), reflected by household income, and overall survival after surgery in the Dutch setting of equal access and provision of care. Additionally, we aim to assess whether SES is associated with cause-specific survival and major 30-day complications.
Patients undergoing surgery between March 2005 and December 2006 in a general teaching hospital in the Netherlands were prospectively included. Adjusted logistic and cox regression analyses were used to assess the independent association of SES-quantified by gross household income-with major 30-day complications and long-term postoperative survival.
A total of 3929 patients were included, with a median follow-up of 6.3 years. Low household income was associated with worse survival in continuous analysis (HR: 1.05 per 10.000 euro decrease in income, 95% CI: 1.01-1.10) and in income quartile analysis (HR: 1.58, 95% CI: 1.08-2.31, first i.e. lowest quartile relative to the fourth quartile). Similarly, low income patients were at higher risk of cardiovascular death (HR: 1.26 per 10.000 decrease in income, 95% CI: 1.07-1.48, first income quartile: HR: 3.10, 95% CI: 1.04-9.22). Household income was not independently associated with cancer-related mortality and major 30-day complications.
Low SES, quantified by gross household income, is associated with increased overall and cardiovascular mortality risks among surgical patients. Considering the equality of care provided by this study setting, the associated survival hazards can be attributed to patient and provider factors, rather than disparities in healthcare. Increased physician awareness of SES as a risk factor in preoperative decision-making and focus on improving established SES-related risk factors may improve surgical outcome of low SES patients.
Testing assumptions proposed by Frenzel’s reciprocal model of teacher emotions (e.g.,
Frenzel, 2014
), this study explored relations between teachers’ appraisals concerning the attainment and ...importance of their teaching goals, and their emotions. Specifically, we addressed teachers’ goals of high student performance, motivation, discipline, and high-quality teacher–student relationship and three key discrete emotions, namely, enjoyment, anger, and anxiety, during teaching. We had 244 secondary school teachers (70.1% female) self-report their goal attainment and importance appraisals and emotional experiences with respect to up to three different classes they currently taught. Results from single- and two-level multivariate multiple regression analyses largely supported the relevance of the goal attainment appraisals for teachers’ emotions both on the between-person and the within-person level. Goal importance appraisals proved to be of secondary relevance. On the between-person level, those teachers who positively appraised the attainment of motivation, discipline, and teacher–student relationship quality proved to report more enjoyment and less anxiety and anger. On the within-person level, teachers reported enjoying teaching those classes more, which they perceived as better performing, more motivated and disciplined, and with whom they had a better relationship. Anger and anxiety were negatively linked to appraisals pertaining to the attainment of discipline and teacher–student relationship quality. Across both analysis perspectives, teacher–student relationship quality attainment showed particularly strong links with all three emotions. Because teachers’ subjective evaluations regarding student behaviors were shown to be highly relevant for their emotions, we conclude that teachers could be supported in modifying their emotional experiences through cognitive reappraisal. Interventions targeting teachers’ relationships with students, and their cognitive judgments thereof, seem particularly promising.
In solid tumors, angiogenesis occurs in the setting of a defective vasculature and impaired lymphatic drainage that is associated with increased vascular permeability and enhanced tumor permeability. ...These universal aspects of the tumor microenvironment can have a marked influence on intratumoral drug delivery that may often be underappreciated. In this study, we investigated the effect of blood vessel normalization in tumors by the antiangiogenic drug bevacizumab on antibody uptake by tumors. In mouse xenograft models of human ovarian and esophageal cancer (SKOV-3 and OE19), we evaluated antibody uptake in tumors by positron emission tomographic imaging 24 and 144 hours after injection of (89)Zr-trastuzumab (SKOV-3 and OE19), (89)Zr-bevacizumab (SKOV-3), or (89)Zr-IgG (SKOV-3) before or after treatment with bevacizumab. Intratumor distribution was assessed by fluorescence microscopy along with mean vessel density (MVD) and vessel normalization. Notably, bevacizumab treatment decreased tumor uptake and intratumoral accumulation compared with baseline in the tumor models relative to controls. Bevacizumab treatment also reduced MVD in tumors and increased vessel pericyte coverage. These findings are clinically important, suggesting caution in designing combinatorial trials with therapeutic antibodies due to a possible reduction in tumoral accumulation that may be caused by bevacizumab cotreatment.
The role of endoscopy in inflammatory bowel disease Shergill, Amandeep K., MD; Lightdale, Jenifer R., MD, MPH; Bruining, David H., MD ...
Gastrointestinal endoscopy,
05/2015, Letnik:
81, Številka:
5
Journal Article
The main cause of cancer-related mortality, metastasis, is a complex, multi-step process. The extracellular matrix (ECM) component of solid tumors has been implicated in metastatic progression; ...however, the ECM exists as a complex macromolecular substrate and it is unclear how its molecular composition promotes cancer progression. ECM homeostasis is regulated by various secreted proteins including cross-linkers (e.g., lysyl oxidases and transglutaminases), modifying enzymes (e.g., sulfatases and extracellular kinases), proteases (e.g., matrix metalloproteinases, heparanase, and cathepsins) and protease inhibitors (e.g., tissue inhibitors of metalloproteinases, cystatins, and serpins); each of which can alter the structural, mechanical, and biochemical properties of the ECM. Emerging evidence indicates that altered ECM regulator activity in cancer triggers pathological ECM remodeling facilitating metastatic dissemination making ECM regulators potential targets for cancer therapy. In this review, we summarize and critically discuss the existing literature on the role of ECM regulators in cancer metastasis.
Intratumour heterogeneity is a major cause of treatment failure in cancer. We present in-depth analyses combining transcriptomic and genomic profiling with ultra-deep targeted sequencing of ...multiregional biopsies in 10 patients with neuroblastoma, a devastating childhood tumour. We observe high spatial and temporal heterogeneity in somatic mutations and somatic copy-number alterations which are reflected on the transcriptomic level. Mutations in some druggable target genes including ALK and FGFR1 are heterogeneous at diagnosis and/or relapse, raising the issue whether current target prioritization and molecular risk stratification procedures in single biopsies are sufficiently reliable for therapy decisions. The genetic heterogeneity in gene mutations and chromosome aberrations observed in deep analyses from patient courses suggest clonal evolution before treatment and under treatment pressure, and support early emergence of metastatic clones and ongoing chromosomal instability during disease evolution. We report continuous clonal evolution on mutational and copy number levels in neuroblastoma, and detail its implications for therapy selection, risk stratification and therapy resistance.
Microvascular injury (MVI) after coronary ischemia-reperfusion is associated with high morbidity and mortality. Both ischemia and reperfusion are involved in MVI, but to what degree these phases ...contribute is unknown. Understanding the etiology is essential for the development of new potential therapies.
Rats were divided into 3 groups receiving either 30 minutes ischemia, 90 minutes ischemia or 30 minutes ischemia followed by 60 minutes reperfusion. Subsequently hearts were ex-vivo perfused in a Langendorff-model. Fluorescence and electron microscopy was used for analysis of capillary density, vascular permeability and ultrastructure. Most MVI was observed after 30 minutes ischemia followed by 60 minutes reperfusion. In comparison to the 30' and 90' ischemia group, wall thickness decreased (207.0±74 vs 407.8±75 and 407.5±71, p = 0.02). Endothelial nuclei in the 30'-60' group showed irreversible damage and decreased chromatin density variation (50.5±9.4, 35.4±7.1 and 23.7±3.8, p = 0.03). Cell junction density was lowest in the 30'-60' group (0.15±0.02 vs 2.5±0.6 and 1.8±0.7, p<0.01). Microsphere extravasation was increased in both the 90' ischemia and 30'-60' group.
Ischemia alone for 90 minutes induces mild morphological changes to the coronary microcirculation, with increased vascular permeability. Ischemia for 30 minutes, followed by 60 minutes of reperfusion, induces massive MVI. This shows the direct consequences of reperfusion on the coronary microcirculation. These data imply that a therapeutic window exists to protect the microcirculation directly upon coronary revascularization.
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