Gene Editing and Genotoxicity: Targeting the Off-Targets

Gene editing technologies show great promise for application to human disease as a result of rapid developments in targeting tools notably based on ZFN, TALEN, and CRISPR-Cas systems. Precise modification of a DNA sequence is now possible in mature human somatic cells including stem and progenitor cells with increasing degrees of efficiency. At the same time new technologies are required to evaluate their safety and genotoxicity before widespread clinical application can be confidently implemented. A number of methodologies have now been developed in an attempt to predict expected and unexpected modifications occurring during gene editing. This review surveys the techniques currently available as state of the art, highlighting benefits and limitations, and discusses approaches that may achieve sufficient accuracy and predictability for application in clinical settings

Facing the Emotional Barriers to Colorectal Cancer Screening. The Roles of Reappraisal and Situation Selection

Background Disgust, embarrassment, and fear can hinder the attendance of colorectal cancer (CRC) screening. However, individuals can respond to these emotions differently. The present study tested whether reappraising a negative stimulus versus avoiding a negative stimulus is associated with age; whether these two emotion regulation strategies (reappraisal and situation selection) moderate the effects of disgust, embarrassment and fear on CRC screening intention; and the efficacy of a message based on participants' preferred emotion regulation strategy.Methods We recruited 483 Italian participants (aged 40-84 years) through snowball sampling. Participants were randomly assigned to one of four conditions differing for a message promoting CRC screening with an affective lever, a cognitive lever, both levers or none. Key variables included emotion regulation strategies, emotional barriers and intention to get screened.Results The preference for reappraisal over situation selection increased with age. Reappraisal neutralized the effect of disgust on CRC screening intention. The combined message with both affective and cognitive levers increased CRC screening intention (b = 0.27, beta = 0.11, SE = 0.13 p = .049), whereas reading the message based only on the affective (b = 0.16, beta = 0.06, SE = 0.14 p = .258) or the cognitive (b = 0.22, beta = 0.09, SE = 0.14 p = .107) lever was not effective.Conclusions Communication campaigns should support the activation of a reappraisal strategy of emotion control, and messages promoting CRC screening should highlight both the instrumental (i.e., early detection) and affective (i.e., peace of mind) benefits of attendance

Continental accretion and incremental deformation in the thermochronologic evolution of the Lesser Caucasus

Apatite fission-track analysis and thermochronologic statistical modeling of Precambrian\u2013Oligocene plutonic and metamorphic rocks from the Lesser Caucasus resolve two discrete cooling episodes. Cooling occurred during incremental crustal shortening due to obduction and continental accretion along the margins of the northern branch of the Neotethys. (1) The thermochronometric record of a Late Cretaceous (Turonian\u2013Maastrichtian) cooling/exhumation event, coeval to widespread ophiolite obduction, is still present only in a relatively small area of the upper plate of the Amasia-Sevan-Akera (ASA) suture zone, i.e. the suture marking the final closure of the northern Neotethys during the Paleogene. Such area has not been affected by significant later exhumation. (2) Rapid cooling/exhumation occurred in the Early-Middle Miocene in both the lower and upper plates of the ASA suture zone, obscuring previous thermochronologic signatures over most of the study area. Miocene contractional reactivation of the ASA suture zone occurred contemporaneously with the main phase of shortening and exhumation along the Bitlis suture zone marking the closure of the southern branch of the Neotethys and the ensuing Arabia-Eurasia collision. Miocene collisional stress from the Bitlis suture zone was transmitted northward across the Anatolian hinterland, which was left relatively undeformed, and focused along preexisting structural discontinuities such as the eastern Pontides and the ASA suture zone

Histopathology of vasculitis

The range of pathologies that are related to primitive vasculitis is broad, complex and not as typical as we would expect. Clinicians should be aware that several forms of primitive and systemic vasculitis, regardless of the size of the affected vessel, may exhibit identical histological alterations. This observation has important clinical implications as it means that cases of vasculitis do not correspond clinically and histologically. Thus, while histology remains the diagnostic gold standard, it can be used only as part of the most complete clinical assessment possible. Another point worth of the clinician’s attention is that vasculitis histology changes over time, as do disease evolution and activity, even without considering the masking effects of treatment and the possibility of sampling error due to the patchy occurrence of vasculitis. The purpose of this review is to identify the most common forms of vasculitis in clinical practice, and to provide guidance to the clinician on the pathology of the vessels

When a Politician Disappoints: The Role of Gender Stereotypical Expectations in Post-Scandal Judgment

This study examines how evaluations of male and female politicians are worsened by corruption scandals that disappoint expectations of honesty. Participants evaluated a fictitious politician before and after watching a video about a corruption scandal involving that politician. The manipulated variables were the politician’s sex and whether they shared participants’ political affiliations. Results showed that a female politician affiliated with the participants’ preferred party was the most damaged by the scandal because she had the highest expectations of honesty placed upon her

A Pragmatics-based Model for Narrative Dialogue Generation

We describe a method and a proof of concept which allow the generation of rich and engaging dialogues between virtual characters from a formalised plot description. The structure of the dialogue generated borrows from inferential pragmatics, following the Geneva Model of discourse analysis, in order to provide realistic interaction between characters in the narrative. At a higher level, this discourse is organised following heuristics borrowed from narratology theory in order to elicit emotions linked to dramatic tension and thus favour narrative engagement. Besides enriching narrative generation systems embedded within simulation applications, our work also has the potential to be adapted to support engaging interactive dialogues between users and virtual conversational agents in narrative systems

Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease in the emergency department: early predictors of in-hospital outcome

The applications of early non-invasive ventilation (NIV) are nowadays expanding in the Emergency Department (ED) for the treatment of different types and etiologies of acute respiratory failure (ARF) Emergency physicians (EP) often face the challenge of predicting short-term outcomes for patients with ARF in the E

A modified vimentin histological score helps recognize pulmonary sarcomatoid carcinoma in small biopsy samples

Background: As pulmonary sarcomatoid carcinomas (PSCs) are life-threatening tumors, an improvement in their recognition in small-sized tumor samples is clinically warranted. Materials and Methods: Preoperative biopsy samples and paired surgical specimens from 20 pleomorphic carcinomas, two pulmonary blastomas and one carcinosarcoma (training set) were studied for vimentin immunohistochemistry. A modified vimentin histologic score (M-VHS) was devised by multiplying three independently assessed parameters, i.e. the percentage of positive cells (from 0 to 5+, by quintiles), the intensity of immunostaining (low=1 vs. strong=2) and the distribution pattern within the cytoplasm (partial=1 vs. diffuse=2), so ranging from 0 to 20. Forty-eight consecutive and independent cases of non-small cell lung carcinoma (NSCLC), including two additional cases of PSC, were used as control groups (validation set). Results: No differences in M-VHS were found between biopsies and surgical specimens of PSC, thus confirming the occurrence of stable epithelial mesenchymal transition (EMT) and hence the specific diagnosis of PSC. All types of PSC shared the same M-VHS. The M-VHS of 46 conventional NSCLC was by far lower (p<0.0001), whereas two additional cases of PSC showed the same results as the training set. Poorly differentiated NSCLC with marked pleomorphism but not stable EMT did not exhibit significantly increased M-VHS values. Conclusion: M-VHS helped in morphological analysis to render more definite diagnoses on small biopsies of PSC