Epithelial mesenchymal transition and tumor budding in aggressive colorectal cancer: Tumor budding as oncotarget

Epithelial mesenchymal transition (EMT) is proposed as a critical mechanism for the acquisition of malignant phenotypes by epithelial cells. In colorectal cancer, tumor cells having undergone EMT are histologically represented by the presence of tumor buds defined as single cells or small clusters of de-differentiated tumor cells at the invasive front. Tumor budding is not a static, histological feature rather it represents a snap-shot of a dynamic process undertaken by an aggressive tumor with the potential to disseminate and metastasize. Strong, consistent evidence shows that tumor budding is a predictor of lymph node metastasis, distant metastatic disease, local recurrence, worse overall and disease-free survival time and an independent prognostic factor. Moreover, the International Union against Cancer (UICC) recognizes tumor budding as a highly relevant, additional prognostic parameter. The aim of this review is to summarize the evidence supporting the implementation of tumor budding into diagnostic pathology and patient management and additionally to illustrate its worthiness as a potential therapeutic target

Fermionic state discrimination by local operations and classical communication

We consider the problem of local operations and classical communication (LOCC) discrimination between two bipartite pure states of fermionic systems. We show that, contrary to the case of quantum systems, for fermionic systems it is generally not possible to achieve the ideal state discrimination performances through LOCC measurements. On the other hand, we show that an ancillary system made of two fermionic modes in a maximally entangled state is a sufficient additional resource to attain the ideal performances via LOCC measurements. The stability of the ideal results is studied when the probability of preparation of the two states is perturbed, and a tight bound on the discrimination error is derived.Comment: 8 pages, 1 figur

Value of staining intensity in the interpretation of immunohistochemistry for tumor markers in colorectal cancer

The purpose of this study was to determine whether staining intensity in conjunction with the percentage of positive tumor cells should be used as an indicator of protein expression detected by immunohistochemistry. A tissue microarray of 1,197 colorectal cancers was immunostained for p53, Her2/neu, epidermal growth factor receptor (EGFR), adenomatosis polyposis coli (APC), and β-catenin. Immunoreactivity was described by the percentage of positive tumor cells (percent positivity) and by the staining intensity (weak, moderate, strong). The interobserver reproducibility of both was evaluated by two pathologists. The association of T stage, N stage, tumor grade, vascular invasion, and survival with percent positivity, staining intensity, and the combination of both was assessed. In univariate analysis, protein expression assessed by percent positivity resulted in 11 significant associations between the proteins and clinico-pathological features. Eight of these 11 were also demonstrated using only the degree of staining intensity. However, more than half of the associations identified by percent positivity alone were lost when staining intensity was also analyzed in combination with the percentage of positive tumor cells. A scoring method based on percent positivity, rather than on staining intensity, for p53, Her2/neu, EGFR, APC, and β-catenin is reproducible and appears to be sufficient for establishing associations of the selected tumor markers with most clinico-pathological feature

Time-driven activity-based costing for capturing the complexity of healthcare processes: the case of deep vein thrombosis and leg ulcers

Time-driven activity-based costing (TDABC) is suggested to assess costs within the value-based healthcare approach, but there is a paucity of applications in chronic diseases such as deep vein thrombosis (DVT) and leg ulcers. In this context, we applied TDABC in a cost-effectiveness analysis comparing venous stenting to compression ± anticoagulation (standard of care—SOC) from both hospital and societal perspectives in Italy. TDABC was applied to both treatments to assess costs that were included in a cost-effectiveness model. Clinical inputs were retrieved from the literature and integrated with real-world data. The Incremental Cost Utility Ratio (ICUR) of stenting compared to SOC was EUR 10,270/QALY and EUR 8962/QALY for hospital and societal perspectives, respectively. The mean cost per patient for venous stenting of EUR 5082 was higher than the Diagnosis-Related Group (DRG) reimbursement (EUR 4742). For SOC, an ulcer healing in 3 months costs EUR 1892, of which EUR 302 (16%) is borne by the patient versus a reimbursement of EUR 1132. TDABC showed that venous stenting may be cost-effective compared with SOC but that reimbursement rates may not completely cover the real costs, which are partially sustained by the patients. A more efficient policy for covering the real costs may be beneficial for both clinical centers and patients

Characterization of CDKN2A(p16) methylation and impact in colorectal cancer: systematic analysis using pyrosequencing

Background The aim of this study is to analyse CDKN2A methylation using pyrosequencing on a large cohort of colorectal cancers and corresponding non-neoplastic tissues. In a second step, the effect of methylation on clinical outcome is addressed. Methods Primary colorectal cancers and matched non-neoplastic tissues from 432 patients underwent CDKN2A methylation analysis by pyrosequencing (PyroMarkQ96). Methylation was then related to clinical outcome, microsatellite instability (MSI), and BRAF and KRAS mutation. Different amplification conditions (35 to 50 PCR cycles) using a range of 0-100% methylated DNA were tested. Results Background methylation was at most 10% with ≥35 PCR cycles. Correlation of observed and expected values was high, even at low methylation levels (0.02%, 0.6%, 2%). Accuracy of detection was optimal with 45 PCR cycles. Methylation in normal mucosa ranged from 0 to >90% in some cases. Based on the maximum value of 10% background, positivity was defined as a ≥20% difference in methylation between tumor and normal tissue, which occurred in 87 cases. CDKN2A methylation positivity was associated with MSI (p = 0.025), BRAF mutation (p < 0.0001), higher tumor grade (p < 0.0001), mucinous histology (p = 0.0209) but not with KRAS mutation. CDKN2A methylation had an independent adverse effect (p = 0.0058) on prognosis. Conclusion The non-negligible CDKN2A methylation of normal colorectal mucosa may confound the assessment of tumor-specific hypermethylation, suggesting that corresponding non-neoplastic tissue should be used as a control. CDKN2A methylation is robustly detected by pyrosequencing, even at low levels, suggesting that this unfavorable prognostic biomarker warrants investigation in prospective studies

Cell line derived xenograft mouse models are a suitable in vivo model for studying tumor budding in colorectal cancer

Tumor budding (TB) is an important prognostic parameter in colorectal cancer (CRC) and associated with metastasis. However, the mechanisms of TB have not been fully elucidated and a major limitation is the absence of in vivo models. Here, we determine the suitability of human cell line derived xenografts (CDX) as models of TB in CRC. Pan-cytokeratin (CK)-stained next-generation Tissue Microarrays (ngTMA) of two CDX models (HT-29, n = 12 and HCT-8, n = 8) and human CRC (n = 27 high-grade and 25 low-grade budding tumors, each) were evaluated for TB. Immunohistochemistry for E-cadherin, β-catenin, Ki-67, ZEB1, and TWIST1 was performed. HT-29 and HCT-8 were predominantly high-grade and no/low-grade TB tumors, respectively. TB counts in the tumor center (intratumoral budding, ITB) were significantly higher in HT-29 CDX tumors compared to human CRC (p = 0.0099). No difference was found in TB counts at the invasion front (peritumoral budding, PTB; p=0.07). ITB and PTB were strongly correlated (r = 0.438 and r = 0.62 in CDX and human CRC, respectively). Immunohistochemistry profiles were comparable in CDX and human CRC tissues. TB in the CDX mouse models is phenotypically similar to human CRCs and highlights comparable protein profiles. The HT-29 CDX could be a suitable model for the in vivo assessment of TB.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Numerical investigation on the effects of bore reduction in a high performance turbocharged GDI engine. 3D investigation of knock tendency

Abstract Downsizing is a must for current high performance turbocharged SI engines. This is often achieved through the reduction of cylinder number, while keeping constant unit displacement and increasing boost pressure. However, the ensuing higher loads strongly increases the risk of abnormal combustion and thermo-mechanical failures. An alternative path to downsizing is the reduction of cylinder bore: this approach is more expensive, requiring a brand new design of the combustion system, but it also provides some advantages. The goal of the present paper is to explore the potential of bore reduction for achieving a challenging downsizing target, while preserving the engine knock safety margins. A current V8 GDI turbocharged sporting engine is taken as a reference, and a preliminary CFD-3D analysis is carried out in order to define the most suitable bore-to-stroke ratio. On this basis, bore is reduced by 11% at constant stroke, thus obtaining a reduction of about 20% on the engine displacement. In order to achieve the same peak power target, both engine boost and spark advance are adjusted until the knock safety margin of the original engine is met. 3D CFD tools, accurately calibrated on the reference engine, are used to address engine design and the calibration of the operating parameters

New insights into the genesis of the Miocene collapse structures of the island of Gozo (Malta, central Mediterranean Sea)

The large palaeosinkholes located in the NW of Gozo (central Mediterranean Sea, Malta) offer excellent exposures that provide information on the geometry and kinematics of large karst-related collapse structures. Detailed geological analysis of these peculiar palaeosinkholes indicates that deep-seated evaporite dissolution is the most feasible hypothesis to explain their formation, according to the following evidence. (1) Several structures have been formed by progressive foundering of cylindrical blocks with limited internal deformation as revealed by the synsedimentary subsidence recorded by their Miocene sedimentary fill. This subsidence mechanism is more compatible with interstratal dissolution of evaporites than karstification and cave development in limestone formations. (2) The dimensions and deformation style of the palaeosinkholes are similar to those of other collapse structures related to deep-seated dissolution of salt-bearing evaporites. (3) The arcuate monocline associated with some of these collapse structures is also a characteristic feature of subsidence related to dissolution of evaporites. However, no major evaporite formations have been documented so far in the subsurface of the Malta Platform

Machine learning-based Sr isoscape of southern Sardinia: A tool for bio-geographic studies at the Phoenician-Punic site of Nora

Since prehistoric times, the island of Sardinia—in the western Mediterranean—has played a leading role in the dynamics of human population and mobility, in the circulation of raw materials and artefacts, idioms and customs, of technologies and ideas that have enriched the biological, linguistic and cultural heritage of local groups. For the Phoenician and Punic periods (from the 9th to the 3rd centuries BCE), the ancient site of Nora—in southern Sardinia—represents an emblematic case in the study of migratory phenomena that occurred on the Island from the Iron Age until the Roman conquest. Despite the importance of exploring (and characterising) such movements from a wider bio-cultural perspective, the application of bio-geochemical tools for geographical provenance to the ancient skeletal populations of Sardinia is yet scarce. The present work is the first step towards filling this gap with the development of the first isoscape of southern Sardinia using new bioavailable Sr isotope data and a machine-learning approach. From a geolithological point of view, Sardinia is rather heterogeneous and requires detailed studies to correctly assess the distribution of the isotopic signature of bioavailable Sr. The random forest model employed here to construct the Sr isoscape uses several external environmental and geological variables. The most important predictors are related to age and bedrock type, with additional input from local soil properties. A 10-fold cross-validation gives a mean square error of 0.0008 and an R-squared of 0.81, so the model correctly predicts the 87Sr/86Sr ratio of unknown areas. By using a Bayesian provenance assignment workflow, we tested the isoscape here produced to determine the geographic origin and the mobility of archaeological and modern fauna collected from the Phoenician-Punic site of Nora and the surrounding Pula Plain. Our results indicate that archaeological sheep and goats (87Sr/86Sr &lt; 0.7090) are compatible with areas close to Nora and Pula Plain, in agreement with archaeological evidence of pastoralism in those areas. Modern wild and domesticated fauna (87Sr/86Sr &gt; 0.7090) show compatibility with several natural and anthropogenic locations in southern Sardinia, as expected based on modern species distribution data. Finally, we discuss the large Sr isotopic variability of the Nora baseline, where human mobility studies of human cremated and inhumed individuals are currently underway