Avoiding Degeneracies in Ordinal Unfolding Using Kemeny-Equivalent Dissimilarities for Two-Way Two-Mode Preference Rank Data.

In this paper a simple but effective procedure to avoid degeneracies in ordinal Unfolding for preference rank data based on the Kemeny distance is proposed. Considering Unfolding as a particular MDS procedure with missing within-set proximities, unknown proximities are first estimated using correlations related to the Kemeny distance, and then the complete proximity matrix is analyzed in a standard MDS framework. A simulation study shows that our proposal is able to both recover the order of the preferences and reproduce the position of both rankings and objects in a geometrical space. Several applications on real data sets show that our procedure returns non-degenerate Unfolding solutions.

Genetic Evolution of Glioblastoma Stem-Like Cells From Primary to Recurrent Tumor.

Glioblastoma (GBM) is a lethal tumor that displays remarkable genetic heterogeneity. It is also known that GBM contains a cell hierarchy driven by GBM stem-like cells (GSCs), responsible for tumor generation, therapeutic resistance, and relapse. An important and still open issue is whether phylogenetically related GSCs can be found in matched primary and recurrent GBMs, and reflect tumor genetic evolution under therapeutic pressure. To address this, we analyzed the mutational profile of GSCs isolated from either human primary GBMs (primary GSCs) or their matched tumors recurring after surgery and chemoradiotherapy (recurrent GSCs). We found that recurrent GSCs can accumulate temozolomide-related mutations over primary GSCs, following both linear and branched patterns. In the latter case, primary and recurrent GSCs share a common set of lesions, but also harbor distinctive mutations indicating that primary and recurrent GSCs derive from a putative common ancestor GSC by divergent genetic evolution. Interestingly, TP53 mutations distinctive of recurrent GSCs were detectable at low frequency in the corresponding primary tumors and likely marked pre-existent subclones that evolved under therapeutic pressure and expanded in the relapsing tumor. Consistently, recurrent GSCs displayed in vitro greater therapeutic resistance than primary GSCs. Overall, these data indicate that (a) phylogenetically related GSCs are found in matched primary and recurrent GBMs and (b) recurrent GSCs likely pre-exist in the untreated primary tumor and are both mutagenized and positively selected by chemoradiotherapy. Stem Cells 2017;35:2218-2228.

Mathematical Modeling of the Gastrointestinal System for Preliminary Drug Absorption Assessment.

The objective of this study is to demonstrate the potential of a multicompartmental mathematical model to simulate the activity of the gastrointestinal system after the intake of drugs, with a limited number of parameters. The gastrointestinal system is divided into five compartments, modeled as both continuous systems with discrete events (stomach and duodenum) and systems with delay (jejunum, ileum, and colon). The dissolution of the drug tablet occurs in the stomach and is described through the Noyes-Whitney equation, with pH dependence expressed through the Henderson-Hasselbach relationship. The boluses resulting from duodenal activity enter the jejunum, ileum, and colon compartments, where drug absorption takes place as blood flows countercurrent. The model includes only three parameters with assigned physiological meanings. It was tested and validated using data from in vivo experiments. Specifically, the model was tested with the concentration profiles of nine different drugs and validated using data from two drugs with varying initial concentrations. Overall, the outputs of the model are in good agreement with experimental data, particularly with regard to the time of peak concentration. The primary sources of discrepancy were identified in the concentration decay. The model's main strength is its relatively low computational cost, making it a potentially excellent tool for in silico assessment and prediction of drug adsorption in the intestine.

Mathematical Modeling of Vedolizumab Treatment's Effect on Microbiota and Intestinal Permeability in Inflammatory Bowel Disease Patients.

Growing evidence suggests that impaired gut permeability and gut microbiota alterations are involved in the pathogenesis of Inflammatory Bowel Diseases (IBDs), which include Ulcerative Colitis (UC) and Crohn's Disease (CD). Vedolizumab is an anti-α4ß7 antibody approved for IBD treatment, used as the first treatment or second-line therapy when the first line results in inadequate effectiveness. The aim of this study is to develop a mathematical model capable of describing the pathophysiological mechanisms of Vedolizumab treatment in IBD patients. In particular, the relationship between drug concentration in the blood, colonic mucosal permeability and fecal microbiota composition was investigated and modeled to detect and predict trends in order to support and tailor Vedolizumab therapies. To pursue this aim, clinical data from a pilot study on a cluster of 11 IBD patients were analyzed. Enrolled patients underwent colonoscopy in three phases (before (t0), after 24 weeks of (t1) and after 52 weeks of (t2 ) Vedolizumab treatment) to collect mucosal biopsies for transepithelial electrical resistance (TEER) evaluation (permeability to ions), intestinal permeability measurement and histological analysis. Moreover, fecal samples were collected for the intestinal microbiota analysis at the three time points. The collected data were compared to those of 11 healthy subjects at t0, who underwent colonoscopy for screening surveillance, and used to implement a three-compartmental mathematical model (comprising central blood, peripheral blood and the intestine). The latter extends previous evidence from the literature, based on the regression of experimental data, to link drug concentration in the peripheral blood compartment with Roseburia abundance and intestinal permeability. The clinical data showed that Vedolizumab treatment leads to an increase in TEER and a reduction in intestinal permeability to a paracellular probe, improving tissue inflammation status. Microbiota analysis showed increasing values of Roseburia, albeit not statistically significant. This trend was adequately reproduced by the mathematical model, which offers a useful tool to describe the pathophysiological effects of Vedolizumab therapy on colonic mucosal permeability and fecal microbiota composition. The model's satisfactory predictive capabilities and simplicity shed light on the relationship between the drug, the microbiota and permeability and allow for its straightforward extension to diverse therapeutic conditions.

Differences in views of schizophrenia during medical education: a comparative study of 1st versus 5th-6th year Italian medical students.

PURPOSE: This study explored medical students' causal explanations and views of schizophrenia, and whether they changed during medical education. METHOD: The survey was carried out on medical students of the Second University of Naples, Italy, who attended their first-year and their fifth- or sixth-year of lessons. The 381 who accepted were asked to read a case-vignette describing a person who met the ICD-10 criteria for schizophrenia and then fill in the Opinions on mental illness Questionnaire. RESULTS: The most frequently cited causes were psychological traumas (60%) and stress (56%), followed by misuse of street drugs (47%), and heredity (42%). 28% of students stated that persons with the disorder could be well again, and 28% that they were unpredictable. Labeling the case as "schizophrenia" and naming heredity among the causes were associated with pessimism about recovery and higher perception of social distance. First-year students more frequently reported psychological traumas among the causes (76 vs. 45%), and less frequently heredity (35 vs. 81%) and stress (42 vs. 69%), and they perceived less social distance from the "schizophrenics" than fifth/sixth-year students. In particular, 18% percent of first-year versus 38% of fifth/sixth-year students believed that these persons were kept at a distance by the other, and 45 versus 57% felt frightened by persons with the condition. CONCLUSIONS: These results indicate a need to include education on stigma and recovery in schizophrenia in the training of medical students.

The Bradley-Terry Regression Trunk approach for Modeling Preference Data with Small Trees.

This paper introduces the Bradley-Terry regression trunk model, a novel probabilistic approach for the analysis of preference data expressed through paired comparison rankings. In some cases, it may be reasonable to assume that the preferences expressed by individuals depend on their characteristics. Within the framework of tree-based partitioning, we specify a tree-based model estimating the joint effects of subject-specific covariates over and above their main effects. We, therefore, combine a tree-based model and the log-linear Bradley-Terry model using the outcome of the comparisons as response variable. The proposed model provides a solution to discover interaction effects when no a-priori hypotheses are available. It produces a small tree, called trunk, that represents a fair compromise between a simple interpretation of the interaction effects and an easy to read partition of judges based on their characteristics and the preferences they have expressed. We present an application on a real dataset following two different approaches, and a simulation study to test the model's performance. Simulations showed that the quality of the model performance increases when the number of rankings and objects increases. In addition, the performance is considerably amplified when the judges' characteristics have a high impact on their choices.

Coexisting cancer stem cells with heterogeneous gene amplifications, transcriptional profiles, and malignancy are isolated from single glioblastomas.

Glioblastoma (GBM) is known as an intractable, highly heterogeneous tumor encompassing multiple subclones, each supported by a distinct glioblastoma stem cell (GSC). The contribution of GSC genetic and transcriptional heterogeneity to tumor subclonal properties is debated. In this study, we describe the systematic derivation, propagation, and characterization of multiple distinct GSCs from single, treatment-naive GBMs (GSC families). The tumorigenic potential of each GSC better correlates with its transcriptional profile than its genetic make-up, with classical GSCs being inherently more aggressive and mesenchymal more dependent on exogenous growth factors across multiple GBMs. These GSCs can segregate and recapitulate different histopathological aspects of the same GBM, as shown in a paradigmatic tumor with two histopathologically distinct components, including a conventional GBM and a more aggressive primitive neuronal component. This study provides a resource for investigating how GSCs with distinct genetic and/or phenotypic features contribute to individual GBM heterogeneity and malignant escalation.

MicroRNA 483-3p overexpression unleashes invasive growth of metastatic colorectal cancer via NDRG1 downregulation and ensuing activation of the ERBB3/AKT axis.

In colorectal cancer, the mechanisms underlying tumor aggressiveness require further elucidation. Taking advantage of a large panel of human metastatic colorectal cancer xenografts and matched stem-like cell cultures (m-colospheres), here we show that the overexpression of microRNA 483-3p (miRNA-483-3p; also known as MIR-483-3p), encoded by a frequently amplified gene locus, confers an aggressive phenotype. In m-colospheres, endogenous or ectopic miRNA-483-3p overexpression increased proliferative response, invasiveness, stem cell frequency, and resistance to differentiation. Transcriptomic analyses and functional validation found that miRNA-483-3p directly targets NDRG1, known as a metastasis suppressor involved in EGFR family downregulation. Mechanistically, miRNA-483-3p overexpression induced the signaling pathway triggered by ERBB3, including AKT and GSK3ß, and led to the activation of transcription factors regulating epithelial-mesenchymal transition (EMT). Consistently, treatment with selective anti-ERBB3 antibodies counteracted the invasive growth of miRNA-483-3p-overexpressing m-colospheres. In human colorectal tumors, miRNA-483-3p expression inversely correlated with NDRG1 and directly correlated with EMT transcription factor expression and poor prognosis. These results unveil a previously unrecognized link between miRNA-483-3p, NDRG1, and ERBB3-AKT signaling that can directly support colorectal cancer invasion and is amenable to therapeutic targeting.

The unusual first sign of presentation of renal cell carcinoma: a rare case report.

Background: Renal cell carcinoma (RCC) usually is characterized by a slow pattern of growth, although with an unpredictable evolution and metastatic potential, favored by its extensive vascularity and related high angioinvasive profile. The most common sites of metastases from kidney cancer are lung, lymph nodes, bone and liver; whereas orbital metastases are very uncommon. In more than 25% of cases, orbital metastases are the first manifestation of a primary tumor of unknown origin. The clinical features of orbital metastases from kidney cancer are non-specific and could divert attention from the real problem. Case Description: In this article, we describe the case of a 72-year-old male patient reporting a painful mass on the right orbit, with exophthalmos and ptosis, as the first and unique signs of a previously undetected advanced RCC. Due to the clinical conditions, the patient underwent palliative radiation therapy delivered to the orbital lesion with the scope to relieve pain; subsequently started systemic therapy with pazopanib at the dose of 800 mg daily. Unfortunately, he did not achieve any benefit from systemic therapy, his conditions progressively worsened, and he finally passed away after four months of treatment due to rapid disease progression. Conclusions: Despite its rarity, differential diagnosis of an orbital lesion should always consider the possibility of metastasis from RCC, performing an appropriate radiological evaluation.

ERBB3 overexpression due to miR-205 inactivation confers sensitivity to FGF, metabolic activation, and liability to ERBB3 targeting in glioblastoma.

In glioblastoma (GBM), the most frequent and lethal brain tumor, therapies suppressing recurrently altered signaling pathways failed to extend survival. However, in patient subsets, specific genetic lesions can confer sensitivity to targeted agents. By exploiting an integrated model based on patient-derived stem-like cells, faithfully recapitulating the original GBMs in vitro and in vivo, here, we identify a human GBM subset (∼9% of all GBMs) characterized by ERBB3 overexpression and nuclear accumulation. ERBB3 overexpression is driven by inheritable promoter methylation or post-transcriptional silencing of the oncosuppressor miR-205 and sustains the malignant phenotype. Overexpressed ERBB3 behaves as a specific signaling platform for fibroblast growth factor receptor (FGFR), driving PI3K/AKT/mTOR pathway hyperactivation, and overall metabolic upregulation. As a result, ERBB3 inhibition by specific antibodies is lethal for GBM stem-like cells and xenotransplants. These findings highlight a subset of patients eligible for ERBB3-targeted therapy.

Cancer of unknown primary stem-like cells model multi-organ metastasis and unveil liability to MEK inhibition.

Cancers of unknown primary (CUPs), featuring metastatic dissemination in the absence of a primary tumor, are a biological enigma and a fatal disease. We propose that CUPs are a distinct, yet unrecognized, pathological entity originating from stem-like cells endowed with peculiar and shared properties. These cells can be isolated in vitro (agnospheres) and propagated in vivo by serial transplantation, displaying high tumorigenicity. After subcutaneous engraftment, agnospheres recapitulate the CUP phenotype, by spontaneously and quickly disseminating, and forming widespread established metastases. Regardless of different genetic backgrounds, agnospheres invariably display cell-autonomous proliferation and self-renewal, mostly relying on unrestrained activation of the MAP kinase/MYC axis, which confers sensitivity to MEK inhibitors in vitro and in vivo. Such sensitivity is associated with a transcriptomic signature predicting that more than 70% of CUP patients could be eligible to MEK inhibition. These data shed light on CUP biology and unveil an opportunity for therapeutic intervention.

Ovariectomy Impairs Socio-Cognitive Functions in Dogs.

Recent studies have underlined the effect of ovariectomy on the spatial cognition of female dogs, with ovariectomized dogs showing a clear preference for an egocentric rather than an allocentric navigation strategy whereas intact females did not show preferences. Intact females had better performances than gonadectomized females in solving a learning task in a maze. Ovariectomy also affects socio-cognitive abilities, reducing the dog's level of attention on the owner. We tested dogs (Canis lupus familiaris) in the object choice task paradigm to assess whether an ovariectomy could impair females' ability to follow human signals. Forty pet dogs (18 intact females (IF) and 22 gonadectomized females (GF)) were tested in the object choice task paradigm using the human proximal pointing gesture. For the analysis, the frequency of correct, wrong and no-choices was collected; moreover, the latency of the correct choices was also considered. The IF group followed the pointing gestures more often than the GF group and with a lower latency, whereas a significantly higher no-choice frequency was recorded for the GF group. These results show a detrimental effect of ovariectomy on dogs' socio-cognitive skills related to the responsiveness to human pointing gestures.

Vaccination knowledge and acceptability among pregnant women in Italy.

The aims of this survey were to ascertain pregnant women's level of knowledge and acceptability on the vaccinations and to identify their associations with several characteristics. A cross-sectional study was performed from December 2017 through March 2018 in the geographic area of Naples, Italy. The study used two stages cluster sampling method for selection and recruitment of participants. Data were collected through face-to-face interviews with pregnant women present at the Obstetrics outpatient clinic of the selected hospitals. A total of 358 respondents agreed to be interviewed out of the 405 pregnant women selected. One-fourth knew at least one of the vaccinations recommended during pregnancy and only 2.8% correctly identified all of these. Women who had received information about the vaccinations during pregnancy from general practitioners or gynecologists or other sources and those with at least one child were more likely to know at least one of the recommended vaccinations, whereas women with middle school education were less knowledgeable. None of the women had received tetanus, diphtheria, and acellular pertussis vaccine and only 1.4% the seasonal influenza vaccination. Only 27.9% reported a positive willingness to receive all the recommended vaccinations during pregnancy. Pregnant women would be willing to get all recommended vaccinations if they had at least one child and if they needed additional information, whereas the willingness was significantly lower among women who had reported high school as the highest level of education, who were in the second trimester of pregnancy, and who felt that the recommended vaccines administered during pregnancy were less dangerous for them and for the unborn child. This study suggests important focus points to be taking into account for informing and for implementing education activities on the benefits regarding vaccinations in order to increase the level of knowledge and the uptake in pregnant women.

A Recursive Partitioning Method for the Prediction of Preference Rankings Based Upon Kemeny Distances.

Preference rankings usually depend on the characteristics of both the individuals judging a set of objects and the objects being judged. This topic has been handled in the literature with log-linear representations of the generalized Bradley-Terry model and, recently, with distance-based tree models for rankings. A limitation of these approaches is that they only work with full rankings or with a pre-specified pattern governing the presence of ties, and/or they are based on quite strict distributional assumptions. To overcome these limitations, we propose a new prediction tree method for ranking data that is totally distribution-free. It combines Kemeny's axiomatic approach to define a unique distance between rankings with the CART approach to find a stable prediction tree. Furthermore, our method is not limited by any particular design of the pattern of ties. The method is evaluated in an extensive full-factorial Monte Carlo study with a new simulation design.

MET inhibition overcomes radiation resistance of glioblastoma stem-like cells.

Glioblastoma (GBM) contains stem-like cells (GSCs) known to be resistant to ionizing radiation and thus responsible for therapeutic failure and rapidly lethal tumor recurrence. It is known that GSC radioresistance relies on efficient activation of the DNA damage response, but the mechanisms linking this response with the stem status are still unclear. Here, we show that the MET receptor kinase, a functional marker of GSCs, is specifically expressed in a subset of radioresistant GSCs and overexpressed in human GBM recurring after radiotherapy. We elucidate that MET promotes GSC radioresistance through a novel mechanism, relying on AKT activity and leading to (i) sustained activation of Aurora kinase A, ATM kinase, and the downstream effectors of DNA repair, and (ii) phosphorylation and cytoplasmic retention of p21, which is associated with anti-apoptotic functions. We show that MET pharmacological inhibition causes DNA damage accumulation in irradiated GSCs and their depletion in vitro and in GBMs generated by GSC xenotransplantation. Preclinical evidence is thus provided that MET inhibitors can radiosensitize tumors and convert GSC-positive selection, induced by radiotherapy, into GSC eradication.

"Social dangerousness and incurability in schizophrenia": results of an educational intervention for medical and psychology students.

This study explored the influence of an educational intervention addressing common prejudices and scientific evidence about schizophrenia on medical and psychology students' views of this disorder. The intervention--consisting in two three-hour lessons with an interval of a week between--was run at first for medical students and then for psychology students. Participants' views of schizophrenia were assessed at baseline vs. at post intervention by matched questionnaires. At medical school, participation was voluntary and also included a six-month online re-assessment, while at psychology school, participation was mandatory. A total of 211 students attended the educational initiative. At post intervention assessment, students more frequently mentioned psychosocial causes of schizophrenia, and more firmly believed that recovery in schizophrenia is possible and that persons with this disorder are not unpredictable and dangerous vs. their baseline assessment. The online six-month assessment confirmed favourable changes in medical students' views found at post intervention. These results confirm that an educational intervention including personal experiences and scientific evidence can be successful in reducing students' prejudices toward persons with schizophrenia.

Analysis of powered two-wheeler crashes in Italy by classification trees and rules discovery.

Aim of the study was the analysis of powered two-wheeler (PTW) crashes in Italy in order to detect interdependence as well as dissimilarities among crash characteristics and provide insights for the development of safety improvement strategies focused on PTWs. At this aim, data mining techniques were used to analyze the data relative to the 254,575 crashes involving PTWs occurred in Italy in the period 2006-2008. Classification trees analysis and rules discovery were performed. Tree-based methods are non-linear and non-parametric data mining tools for supervised classification and regression problems. They do not require a priori probabilistic knowledge about the phenomena under studying and consider conditional interactions among input data. Rules discovery is the identification of sets of items (i.e., crash patterns) that occur together in a given event (i.e., a crash in our study) more often than they would if they were independent of each other. Thus, the method can detect interdependence among crash characteristics. Due to the large number of patterns considered, both methods suffer from an extreme risk of finding patterns that appear due to chance alone. To overcome this problem, in our study we randomly split the sample data in two data sets and used well-established statistical practices to evaluate the statistical significance of the results. Both the classification trees and the rules discovery were effective in providing meaningful insights about PTW crash characteristics and their interdependencies. Even though in several cases different crash characteristics were highlighted, the results of the two the analysis methods were never contradictory. Furthermore, most of the findings of this study were consistent with the results of previous studies which used different analytical techniques, such as probabilistic models of crash injury severity. Basing on the analysis results, engineering countermeasures and policy initiatives to reduce PTW injuries and fatalities were singled out. The simultaneous use of classification trees and association discovery must not, however, be seen as an attempt to supplant other techniques, but as a complementary method which can be integrated into other safety analyses.

The MET oncogene is a functional marker of a glioblastoma stem cell subtype.

The existence of treatment-resistant cancer stem cells contributes to the aggressive phenotype of glioblastoma. However, the molecular alterations that drive stem cell proliferation in these tumors remain unknown. In this study, we found that expression of the MET oncogene was associated with neurospheres expressing the gene signature of mesenchymal and proneural subtypes of glioblastoma. Met expression was almost absent from neurospheres expressing the signature of the classical subtype and was mutually exclusive with amplification and expression of the EGF receptor (EGFR) gene. Met-positive and Met-negative neurospheres displayed distinct growth factor requirements, differentiated along divergent pathways, and generated tumors with distinctive features. The Met(high) subpopulation within Met-pos neurospheres displayed clonogenic potential and long-term self-renewal ability in vitro and enhanced growth kinetics in vivo. In Met(high) cells, the Met ligand HGF further sustained proliferation, clonogenicity, expression of self-renewal markers, migration, and invasion in vitro. Together, our findings suggest that Met is a functional marker of glioblastoma stem cells and a candidate target for identification and therapy of a subset of glioblastomas.

Simulator evaluation of drivers' speed, deceleration and lateral position at rural intersections in relation to different perceptual cues.

Aim of the study was to investigate, by means of a driving simulator experiment, drivers' behaviour in terms of speed, deceleration, and lateral position on major approaches of rural intersections in relation to different perceptual cues. In the experiment, ten different design conditions with and without speed-reducing treatments along the approach to the intersection were tested. Twenty-three drivers drove a test route two times and data from the second drive were used for comparison. The order of the ten design conditions was counterbalanced for all the drivers to minimize the presentation order effect. Three different data analysis techniques were used: (a) cluster analysis of speed and lateral position data, (b) statistical tests of speed and lateral position data, and (c) categorical analysis of deceleration behaviour patterns. The most effective treatments were the dragon teeth markings (based on the principle of optical road narrowing), the colored intersection area (based on the principle of intersection highlighting), and the raised median island (based on the principle of physical road narrowing). These measures, in comparison to the base intersection, produced: (1) a significant speed reduction starting from 250 m before the intersection in the range between 13 and 23 km/h, (2) a significant change in the deceleration behaviour with a reduction in the proportion of drivers which did not decelerate, and (3) a shift away from the intersection of the deceleration beginning. Given the significant effects on drivers' behaviour, the dragon teeth markings, the colored intersection area, and the raised median island are strongly recommended for real world implementation.