Patients' & Healthcare Professionals' Values Regarding True- & False-Positive Diagnosis when Colorectal Cancer Screening by CT Colonography: Discrete Choice Experiment

Purpose

To establish the relative weighting given by patients and healthcare professionals to gains in diagnostic sensitivity versus loss of specificity when using CT colonography (CTC) for colorectal cancer screening.

Materials and Methods

Following ethical approval and informed consent, 75 patients and 50 healthcare professionals undertook a discrete choice experiment in which they chose between “standard” CTC and “enhanced” CTC that raised diagnostic sensitivity 10% for either cancer or polyps in exchange for varying levels of specificity. We established the relative increase in false-positive diagnoses participants traded for an increase in true-positive diagnoses.

Results

Data from 122 participants were analysed. There were 30 (25%) non-traders for the cancer scenario and 20 (16%) for the polyp scenario. For cancer, the 10% gain in sensitivity was traded up to a median 45% (IQR 25 to >85) drop in specificity, equating to 2250 (IQR 1250 to >4250) additional false-positives per additional true-positive cancer, at 0.2% prevalence. For polyps, the figure was 15% (IQR 7.5 to 55), equating to 6 (IQR 3 to 22) additional false-positives per additional true-positive polyp, at 25% prevalence. Tipping points were significantly higher for patients than professionals for both cancer (85 vs 25, p<0.001) and polyps (55 vs 15, p<0.001). Patients were willing to pay significantly more for increased sensitivity for cancer (p = 0.021).

Conclusion

When screening for colorectal cancer, patients and professionals believe gains in true-positive diagnoses are worth much more than the negative consequences of a corresponding rise in false-positives. Evaluation of screening tests should account for this.     

Synthesis of Coral-Like Tantalum Oxide Films via Anodization in Mixed Organic-Inorganic Electrolytes

We report a simple method to fabricate nano-porous tantalum oxide films via anodization with Ta foils as the anode at room temperature. A mixture of ethylene glycol, phosphoric acid, NH₄F and H₂O was used as the electrolyte where the nano-porous tantalum oxide could be synthesized by anodizing a tantalum foil for 1 h at 20 V in a two–electrode configuration. The as-prepared porous film exhibited a continuous, uniform and coral-like morphology. The diameters of pores ranged from 30 nm to 50 nm. The pores interlaced each other and the depth was about 150 nm. After calcination, the as-synthesized amorphous tantalum oxide could be crystallized to the orthorhombic crystal system. As observed in photocatalytic experiments, the coral-like tantalum oxide exhibited a higher photocatalytic activity for the degradation of phenol than that with a compact surface morphology, and the elimination rate of phenol increased by 66.7%.     

Proliferation of Colorectal Cancer Is Promoted by Two Signaling Transduction Expression Patterns: ErbB2/ErbB3/AKT and MET/ErbB3/MAPK

One of the recent breakthroughs in cancer research is the identification of activating mutations in various receptor tyrosine kinase(RTK) pathways in many cancers including colorectal cancer(CRC). We hypothesize that, alternative to mutations, overexpression of various oncogenic RTKs may also underpin CRC pathogenesis, and different RTK may couple with distinct downstream signaling pathways in different subtypes of human CRC. By immunohistochemistry, we show here that RTK members ErbB2, ErbB3 and c-Met were in deed differentially overexpressed in colorectal cancer patient samples leading to constitutive activation of RTK signaling pathways. Using ErbB2 specific inhibitor Lapatinib and c-Met specific inhibitor PHA-665752, we further demonstrated that this constitutive activation of RTK signaling is necessary for the survival of colorectal cancer cells. Furthermore, we show that RTK overexpression pattern dictates the use of downstream AKT and/or MAPK pathways. Our data are important additions to current oncogenic mutation models, and further explain the clinical variation in therapeutic responses of colorectal cancer. Our findings advocate for more personalized therapy tailored to individual patients based on their type of RTK expression in addition to their mutation status.     

Inhibition of Human Neutrophil Elastase by Pentacyclic Triterpenes

Scope

Inhibiting human neutrophil elastase (HNE) is a promising strategy for treating inflammatory lung diseases, such as H1N1 and SARS virus infections. The use of sivelestat, the only clinically registered synthesized HNE inhibitor, is largely limited by its risk of organ toxicity because it irreversibly inhibits HNE. Therefore, potent reversible HNE inhibitors are promising alternatives to sivelestat.

Methods and Results

An in vitro HNE inhibition assay was employed to screen a series of triterpenes. Six pentacyclic triterpenes, but not tetracyclic triterpenes, significantly inhibited HNE. Of these pentacyclic triterpenes, ursolic acid exhibited the highest inhibitory potency (IC₅₀ = 5.51 µM). The HNE inhibitory activity of ursolic acid was further verified using a mouse model of acute smoke-induced lung inflammation. The results of nuclear magnetic resonance and HNE inhibition kinetic analysis showed that the pentacyclic triterpenes competitively and reversibly inhibited HNE. Molecular docking experiments indicated that the molecular scaffold, 28-COOH, and a double bond at an appropriate location in the pentacyclic triterpenes are important for their inhibitory activity.

Conclusion

Our results provide insights into the effects of pentacyclic triterpenes on lung inflammatory actions through reversible inhibition of HNE activity.     

Modified McKeown Minimally Invasive Esophagectomy for Esophageal Cancer: A 5-Year Retrospective Study of 142 Patients in a Single Institution

Background

To achieve decreased invasiveness and lower morbidity, minimally invasive esophagectomy (MIE) was introduced in 1997 for localized esophageal cancer. The combined thoracoscopic-laparoscopic esophagectomy (left neck anastomosis, defined as the McKeown MIE procedure) has been performed since 2007 at our institution. From 2007 to 2011, our institution subsequently evolved as a high-volume MIE center in China. We aim to share our experience with MIE, and have evaluated the outcomes of 142 patients.

Methods

We retrospectively reviewed 142 consecutive patients who had presented with esophageal cancer undergoing McKeown MIE from July 2007 to December 2011. The procedure, surgical outcomes, disease-free and overall survival of these cases were assessed.

Results

The average total procedure time was 270.5±28.1 min. The median operation time for thoracoscopy was 81.5±14.6 min and for laparoscopy was 63.8±9.1 min. The average blood loss associated with thoracoscopy was 123.8±39.2 ml, and for laparoscopic procedures was 49.9±14.3 ml. The median number of lymph nodes retrieved was 22.8. The 30 day mortality rate was 0.7%. Major surgical complications occurred in 24.6% and major non-surgical complications occurred in 18.3% of these patients. The median DFS and OS were 36.0±2.6 months and 43.0±3.4 months respectively.

Conclusions

Surgical and oncological outcomes following McKeown MIE for esophageal cancer were acceptable and comparable with those of open-McKeown esophagectomy. The procedure was both feasible and safe – properties that can be consolidated by experience.     

Association of TLR2 and TLR4 Polymorphisms with Risk of Cancer: A Meta-Analysis

Backgrounds

The activation of Toll-like receptors (TLRs) may be an important event in the immune evasion of tumor cell. Recently, numerous studies have investigated the associations between TLR2 −196 to −174 del and two SNPs of TLR4 (rs4986790 and rs4986791) and the susceptibility to different types of cancer; however, the results remain conflicting. The aim of this study was to assess the association between TLR2 and TLR4 polymorphisms and cancer risk in a meta-analysis with eligible published studies.

Methodology/Principle Findings

A dataset composed of 14627 cases and 17438 controls from 34 publications were included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and three SNPs of TLRs (TLR2 −196 to −174 del, TLR4 rs4986790 and rs4986791). The results showed that all of these three polymorphisms were significantly associated with the increased cancer risk (dominant model: OR = 1.64, 95% CI: 1.04–2.60 for TLR2 −196 to −174 del; OR = 1.19, 95% CI: 1.01–1.41 for TLR4 rs4986790; and OR = 1.47, 95% CI: 1.120–1.80 for TLR4 rs4986791; respectively). In stratified analysis, we found the effect of TLR2 −196 to −174 del on cancer risk remained significant in the subgroup of Caucasians and South Asians, but not in East Asians. However, the association between rs4986791 and cancer risk was significant in both South Asians and East Asians, but not in Caucasians. Furthermore, the association between rs4986790 and cancer risk was statistically significant in digestive cancers (dominant model: OR = 1.76, 95% CI: 1.13–2.73) and female-specific cancers (dominant model: OR = 1.50, 95% CI: 1.16–1.94). However, no significant association with risk of digestive system cancers was observed for TLR2 −196 to −174 del and TLR4 rs4986791.

Conclusions/Significance

This meta-analysis presented additional evidence for the association between TLR2 and TLR4 polymorphisms and cancer risk. Further well-designed investigations with large sample sizes are required to confirm this conclusion.     

A Functional Variant rs1820453 in YAP1 and Breast Cancer Risk in Chinese Population

Background

To investigate the association between rs1820453 which located in the promoter region of yes-associated protein 1 (YAP1) gene and breast cancer (BC) risk.

Method and Findings

We conducted a hospital-based case-control study including a total of 480 BC cases and 545 cancer-free controls in Chinese population. Then the expression quantitative trait locus (e-QTL) analysis was performed to explore the possible function of rs1820453 to the YAP1 gene expression. The association between rs1820453 and BC risk was significantly identified with the odds ratio (OR) was 1.27 (95 % confidence interval (CI) =1.03-1.57) under allelic model when adjusted by age and menopausal status. In addition, the correlation analysis of rs1820453 and YAP1 expression level found that this variant was significantly associated with the gene expression in Chinese population. When compared with level of mRNA expression of the AA genotype (6.011±0.046), the mRNA expression level in CC genotype (5.903±0.026) was statistically lower (P=0.024).

Conclusion

The results from this study suggested that rs1820453 A>C change may affect the gene expression and contribute to the risk of developing BC in Chinese population though larger sample-size studies along with functional experiments were anticipated to warrant the results.     

Molecular Phylogeny of the Butterfly Genus Polytremis (Hesperiidae,Hesperiinae, Baorini) in China

Background

The genus Polytremis, restricted to the continental part of the southeastern Palaearctic and northern Oriental regions, is one of the largest and most diverse lineages of the tribe Baorini. Previous studies on the genus were focused mainly on morphological classification and identification of new species. Due to the lack of effective and homologous traits of morphology, there were many challenges in the traditional classification. In this report, we reconstruct the phylogeny to provide a solid framework for these studies and to test the traditional limits and relationships of taxa.

Methodology and Principal Findings

We sequenced a mitochondrial and three nuclear gene fragments, coupled with an evaluation of traditional morphological characters, to determine the phylogenetic relationships for a total of 15 species representing all major species groups of the Polytremis genus in China, and to elucidate their taxonomic status.

Conclusions and Significance

Analysis of mitochrondial and nuclear DNA showed considerable congruent phylogenetic signal in topology at the inter-species level. We found strong support for the monophyly of Polytremis and some clades were recognized with morphological data. Thus, the COI sequence in our study could be used as a DNA barcode to identify almost all members of the genus. However, incongruences of phylogenetic analyses occurred: in contrast to the phylogenetic trees of mitochondrial COI, it was not possible for nuclear rDNA to discriminate P. gotama from P. caerulescens, suggesting a possible recent separation of these two species. Additionally, P. theca was the only species with a greater intra-specific genetic distance compared to some inter-specific genetic distances in this study and some problems associated with the cryptic diversity of the species are discussed. The results of this study will helpful to reveal the causes of the high degree of diversity of butterflies, and possibly other groups of insects in China.     

Alternative Immunomodulatory Strategies for Xenotransplantation: CD80/CD86-CTLA4 Pathway-Modified Immature Dendritic Cells Promote Xenograft Survival

Background

Xenotransplantation is a promising approach to circumventing the current organ shortage. However, T-cell-dependent anti-xenoresponses are a major challenge to successful xenografts. Given the advantages of the use of CTLA4-Ig in the survival of allografts, the purpose of the study was to investigate the therapeutic potential of CTLA4-IgG4 modified immature dendritic cells (imDCs) in the prevention of islets xenograft rejection.

Methods

CTLA4-IgG4 was constructed by the fusion of the extracellular regions of porcine CTLA4 to human the hIgG4 Fc region. The imDCs were induced and cultured from porcine peripheral blood mononuclear cells (PBMC). The CTLA4-IgG4 modified imDCs were delivered via the portal vein to the liver of diabetic mice (insulin-dependent diabetes mellitus) before islet xenografting, and mCTLA4-Ig was administered intravenously after xenotransplantation.

Results

The xenograft survival of mice receiving unmodified imDCs was approximately 30 days. However, following administration of CTLA4-IgG4 modified imDCs before grafting and mCTLA4-Ig after grafting, xenografts survived for more than 100 days. Flow cytometric analysis showed that the CD4⁺CD25⁺Foxp3⁺ Treg population was increased in spleens. The efficacy of donor CTLA4-IgG4 modified imDCs correlated partially with the amplification of Tregs.

Conclusions

These results confirm that selective inhibition of the direct and indirect pathways of T-cell activation by donor CTLA4-IgG4 modified imDCs and receptor CTLA4-Ig is a highly effective strategy to promote survival of xenografts.