Data literacy in genome research.

With an ever increasing amount of research data available, it becomes constantly more important to possess data literacy skills to benefit from this valuable resource. An integrative course was developed to teach students the fundamentals of data literacy through an engaging genome sequencing project. Each cohort of students performed planning of the experiment, DNA extraction, nanopore sequencing, genome sequence assembly, prediction of genes in the assembled sequence, and assignment of functional annotation terms to predicted genes. Students learned how to communicate science through writing a protocol in the form of a scientific paper, providing comments during a peer-review process, and presenting their findings as part of an international symposium. Many students enjoyed the opportunity to own a project and to work towards a meaningful objective.

COVID-19 Vaccination Intentions: The Theory of Planned Behavior, Optimistic Bias, and Anticipated Regret.

High vaccination rates within the general population are essential for overcoming the current COVID-19 pandemic. The aim of the present study was to investigate intentions to receive a COVID-19 vaccine as well as the predictors of such intentions. A representative sample of the Norwegian population (N = 1,003, 49.5% females, Mage = 47.9, SD = 17.1) filled in an online questionnaire assessing the components of the Theory of planned behavior (attitudes, subjective norms, and perceived behavioral control), as well as optimistic bias and anticipated regret. Results showed that a majority (61.6%) of participants intend to get vaccinated. Regression analysis revealed that intentions were predicted by positive attitudes toward vaccination (ß = 0.31, p < 0.001), subjective norms in favor of vaccination in one's family (ß = 0.23, p < 0.001), perceived behavioral control (ß = 0.09, p < 0.001), and by anticipated net regret (ß = 0.32, p < 0.001), explaining 69% (f 2 = 2.23) of the variance in intentions. Optimistic bias did not predict intentions.

Dual EGFR-VEGF Pathway Inhibition: A Promising Strategy for Patients With EGFR-Mutant NSCLC.

The VEGF pathway has been recognized as a key mediator of angiogenesis to support tumorigenesis. Multiple therapeutic agents targeting VEGF and VEGF receptors have been developed and approved for use in NSCLCs. Preclinical studies have found that the VEGF and EGFR pathways share common downstream signaling, and these pathways can function exclusively of one another during oncogenesis. In EGFR-mutant NSCLCs, up-regulated EGFR signaling increases VEGF through hypoxia-independent mechanisms, and elevated VEGF, in turn, contributes to the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs). In clinical trials, the addition of anti-VEGF therapy to EGFR TKIs considerably improved clinical outcomes. In recently reported large randomized studies, the addition of bevacizumab or ramucirumab to EGFR TKIs substantially improved progression-free survival in patients with TKI-naive EGFR-mutant NSCLC. This article reviews the preclinical and clinical data supporting dual inhibition of EGFR and VEGF in EGFR-mutant NSCLC as a way to improve patient outcomes.

I Can See Clearly Now: Episodic Future Thinking and Imaginability in Perceptions of Climate-Related Risk Events.

Climate change is statistical, abstract and difficult to comprehend directly. Imagining a specific, personal episode where you experience consequences of climate change in the future (episodic future thinking) may bring climate change closer, thus increasing the perceived risk of climate-related risk events. We conducted an experiment to test whether episodic future thinking increased the perceived risk of climate-related risk events and climate change in general, as compared to thinking about the future in a general, abstract manner (semantic future thinking). We also tested whether this effect is moderated by how easy it is to imagine the specific climate-related risk event initially. Participants were randomly assigned to an episodic future thinking-condition or a semantic future thinking-condition, and two of the risk events in each condition were related to flooding (difficult to imagine) and two were related to extreme temperature (easy to imagine). The results show no main effect of episodic future thinking on perceived risk, and no interaction effect with imaginability. Contrary to expectations and earlier research, this suggests that episodic future thinking may not influence risk perception.

Exploratory analysis of front-line therapies in REVEL: a randomised phase 3 study of ramucirumab plus docetaxel versus docetaxel for the treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy.

INTRODUCTION: Non-small-cell lung cancer (NSCLC) is a heterogeneous disease. Front-line therapy may affect responses to subsequent treatment regimens, thus influencing second-line therapy decision making. In the randomised phase 3 REVEL study, second-line ramucirumab plus docetaxel (ram+doc) versus docetaxel (doc) improved survival of patients with metastatic NSCLC. We explore efficacy, safety and quality-of-life (QoL) in REVEL based on front-line therapy. METHODS: Patients were grouped by specific front-line therapy received. Overall survival (OS), progression-free survival (PFS), objective response rate, safety and QoL were assessed descriptively. Kaplan-Meier estimation and Cox proportional hazards modelling were used; frequencies reported in percentages. RESULTS: Baseline characteristics of 1253 patients were generally well balanced between treatment arms within each front-line therapy subgroup. For patients with non-squamous disease (n=912), induction therapies included platinum-based chemotherapy plus a taxane (n=227; 25%) or pemetrexed (n=449; 49%), with (n=172; 19%) or without bevacizumab. For patients with squamous disease (n=328), induction therapies included platinum-based chemotherapy plus gemcitabine (n=176; 54%) or a taxane (n=69; 21%). A highly selected subgroup (n=127; 14%) received pemetrexed continuation maintenance therapy. Ram+doc improved median OS and PFS versus doc across front-line therapy subgroups, as reflected by HRs ranging from 0.78 to 0.91 and 0.66 to 0.92, respectively, similar to results in the overall intention-to-treat cohort (HRs: 0.86 and 0.76, respectively). High-grade treatment-emergent adverse events of special interest (including neutropenia, febrile neutropenia, leucopenia and hypertension) were generally higher in ram+doc-treated patients relative to doc-treated patients regardless of front-line therapy. No clear differences in safety or QoL were seen across front-line therapy subgroups; outcomes were consistent with those reported in the overall intention-to-treat cohort. CONCLUSIONS: Results of this exploratory analysis suggest that second-line ram+doc may be effective regardless of prior treatment with platinum-based chemotherapy plus a taxane, pemetrexed, gemcitabine or bevacizumab. Overall, ram+doc is clinically beneficial across a wide range of patients with metastatic NSCLC who have progressed after various front-line therapies. TRIAL REGISTRATION NUMBER: NCT01168973.

Generation of focal mutations and large genomic deletions in the pancreas using inducible in vivo genome editing.

Beyond the nearly uniform presence of KRAS mutations, pancreatic cancer is increasingly recognized as a heterogeneous disease. Preclinical in vivo model systems exist, but with the advent of precision oncology, murine models with enhanced genetic flexibility are needed to functionally annotate genetic alterations found in the human malignancy. Here, we describe the generation of focal gene disruptions and large chromosomal deletions via inducible and pancreas-specific expression of Cas9 in adult mice. Experimental mice are derived on demand directly from genetically engineered embryonic stem cells, without the need for further intercrossing. To provide initial validation of our approach, we show that disruption of the E3 ubiquitin ligase Rnf43 accelerates KrasG12D-dependent tumourigenesis. Moreover, we demonstrate that this system can be used to rapidly interrogate the impact of complex cancer-associated alleles through the generation of a previously unstudied 1.2 megabase deletion surrounding the CDKN2A and CDKN2B tumour suppressors. Thus, our approach is capable of reproducibly generating biallelic and precise loss of large chromosomal fragments that, in conjunction with mutant Kras, leads to development of pancreatic ductal adenocarcinoma with full penetrance.

Potent Antitumor Activity of Liposomal Irinotecan in an Organoid- and CRISPR-Cas9-Based Murine Model of Gallbladder Cancer.

Gallbladder cancer is associated with a dismal prognosis, and accurate in vivo models will be elemental to improve our understanding of this deadly disease and develop better treatment options. We have generated a transplantation-based murine model for gallbladder cancer that histologically mimics the human disease, including the development of distant metastasis. Murine gallbladder-derived organoids are genetically modified by either retroviral transduction or transfection with CRISPR/Cas9 encoding plasmids, thereby allowing the rapid generation of complex cancer genotypes. We characterize the model in the presence of two of the most frequent oncogenic drivers-Kras and ERBB2-and provide evidence that the tumor histology is highly dependent on the driver oncogene. Further, we demonstrate the utility of the model for the preclinical assessment of novel therapeutic approaches by showing that liposomal Irinotecan (Nal-IRI) is retained in tumor cells and significantly prolongs the survival of gallbladder cancer-bearing mice compared to conventional irinotecan.

Complexity and Simplification in Understanding Travel Preferences Among Tourists.

Travel preferences are complex phenomena, and thus cumbersome to deal with in full width in diagnostic and strategic planning processes. The aim of the present investigation was to explore to what extent individual preferences can be simplified into structures, and if tourists can be grouped into preference clusters that are viable and practically applicable for tourism planning. Building on prior studies that have validated survey instruments designed to measure different tourist role orientations, we used a factor analytical approach to develop a simplified structure of individual preferences, and a standard clustering technique for grouping tourists into preference clusters. Further analyses indicated that preference clusters based on reduced factor preference-data are to some extent related to context-specific valuations, perceptions, and revisit intentions; however, the magnitude of differences between groups was rather small. Overall findings provide reason to suggest that the identified preference clusters are insufficient when it comes to explaining variability in which aspects tourists emphasize as part of their vacation. Possible managerial implications and methodological limitations of the present investigation are noted.

A Terrible Future: Episodic Future Thinking and the Perceived Risk of Terrorism.

Terrorism is a salient risk source in 21st century life and may deter tourists from visiting certain destinations. How people perceive the risk of a future terror attack abroad, and thus their traveling decisions, may be influenced by whether they think about the future in specific and personal terms (episodic future thinking) or in more general, abstract terms (semantic future thinking). In a pre-registered experiment (N = 277) we explored the potential impact of episodic future thinking on the perceived risk of terror attacks abroad. Participants were randomly assigned to one of four conditions: (1) An episodic future thinking-condition, where participants were asked to imagine a specific, terror-related personal episode that might occur in the future while traveling abroad; (2) a semantic future thinking-condition, where participants were asked to think more abstractly about terror events that might occur in the future; (3) an episodic counterfactual thinking-condition, where participants were asked to imagine a specific, terror-related personal episode that might have occurred in the past while traveling abroad and (4) a passive control condition. Participants indicated their perceived risk of six different future terror attacks occurring abroad. The manipulation checks suggest that the experimental manipulations functioned as intended. Contrary to the central hypothesis of the study, there were no differences in the perceived risk of terror attacks between the conditions. These results run counter to previous research and do not support the idea that how people think about the future influences their perceived risk of future dramatic events. Potential limitations and implications are discussed.

What Makes Tourist Experiences Interesting.

Traditional tourist role theory implies that tourists are either novelty seekers or familiarity seekers, while the interaction-hypothesis-of-inherent-interest predicts that interestingness is maximal when novel and familiar elements simultaneously are present in the experience. This paper tests these conflicting theoretical perspectives in three large surveys. In Study 1 (N = 1,029), both novelty and familiarity seeking tourists were asked about how interesting it would be for them to meet tourists from their home country (familiar) or from a foreign country (unfamiliar), either at home (familiar) or abroad (unfamiliar). Study 2 (N = 760) asked tourists to indicate the interestingness of well-known (familiar) and unknown (unfamiliar) sights at home (familiar) and abroad (unfamiliar) in familiarity seekers and novelty seekers alike. Study 3 (N = 1,526) was a field experiment were tourists rated interestingness of familiar and unfamiliar attractions in familiar and unfamiliar surroundings for either themselves or for other tourists. Results show that perceived interestingness of tourist experiences depends on a combination of familiarity and novelty, for both familiarity seekers and novelty seekers. These results therefore are supportive of the interaction-hypothesis-of-inherent-interest; seemingly cognitive factors are better predictors of interestingness of tourist experiences than personality is.

Murine Liver Organoids as a Genetically Flexible System to Study Liver Cancer In Vivo and In Vitro.

The rising incidence of cholangiocarcinoma (CCA) coupled with a low 5-year survival rate that remains below 10% delineates the urgent need for more effective treatment strategies. Although several recent studies provided detailed information on the genetic landscape of this fatal malignancy, versatile model systems to functionally dissect the immediate clinical relevance of the identified genetic alterations are still missing. To enhance our understanding of CCA pathophysiology and facilitate rapid functional annotation of putative CCA driver and tumor maintenance genes, we developed a tractable murine CCA model by combining the cyclization recombination (Cre)-lox system, RNA interference, and clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) technology with liver organoids, followed by subsequent transplantation into immunocompetent, syngeneic mice. Histologically, resulting tumors displayed cytokeratin 19-positive ductal structures surrounded by a desmoplastic stroma-hallmark features of human CCAs. Despite their initial biliary phenotype in vitro, organoids retained the plasticity to induce a broader differentiation spectrum of primary liver cancers following transplantation into recipient mice, depending on their genetic context. Thus, the organoid system combines the advantage of using nontransformed, premalignant cells to recapitulate liver tumorigenesis as a multistep process, with the advantage of a reproducible and expandable cell culture system that abrogates the need for recurrent isolations of primary cells. Conclusion: Genetically modified liver organoids are able to transform into histologically accurate CCAs. Depending on the oncogenic context, they are also able to give rise to liver cancers that show features of hepatocellular carcinomas. The model can be used to functionally explore candidate cancer genes of primary liver cancers in immunocompetent animals and evaluate novel treatment regimens.

Flux and permanence of risk perceptions: Tourists' perception of the relative and absolute risk for various destinations.

The present investigation is a cross-sectional, multi-national, quantitative, and quasi-experimental comparison of tourists' risk perceptions regarding different destinations throughout the past decade. Over 10,000 tourists to Norway from 89 different countries filled in a questionnaire rating the perceived risk for various destinations. Data were collected during 2004, 2010, 2011, 2012, 2013 and 2015 and allow for a comparison of perceived risk across time, place and nationality. Results show that while absolute risk judgments for different destinations fluctuate somewhat over the years, relative risk judgments remain constant. Findings also reveal a "home-is-safer-then-abroad-bias" with tourists consistently perceiving their home country among the safest destinations. The current investigation is rare because it looks at more than one destination at a time. Insights gained from the present findings diverge from what would have been concluded from employing case studies, that is, looking at one destination at a time.

Feedback activation of neurofibromin terminates growth factor-induced Ras activation.

BACKGROUND: Growth factors induce a characteristically short-lived Ras activation in cells emerging from quiescence. Extensive work has shown that transient as opposed to sustained Ras activation is critical for the induction of mitogenic programs. Mitogen-induced accumulation of active Ras-GTP results from increased nucleotide exchange driven by the nucleotide exchange factor Sos. In contrast, the mechanism accounting for signal termination and prompt restoration of basal Ras-GTP levels is unclear, but has been inferred to involve feedback inhibition of Sos. Remarkably, how GTP-hydrolase activating proteins (GAPs) participate in controlling the rise and fall of Ras-GTP levels is unknown. RESULTS: Monitoring nucleotide exchange of Ras in permeabilized cells we find, unexpectedly, that the decline of growth factor-induced Ras-GTP levels proceeds in the presence of unabated high nucleotide exchange, pointing to GAP activation as a major mechanism of signal termination. Experiments with non-hydrolysable GTP analogues and mathematical modeling confirmed and rationalized the presence of high GAP activity as Ras-GTP levels decline in a background of high nucleotide exchange. Using pharmacological and genetic approaches we document a raised activity of the neurofibromatosis type I tumor suppressor Ras-GAP neurofibromin and an involvement of Rsk1 and Rsk2 in the down-regulation of Ras-GTP levels. CONCLUSIONS: Our findings show that, in addition to feedback inhibition of Sos, feedback stimulation of the RasGAP neurofibromin enforces termination of the Ras signal in the context of growth-factor signaling. These findings ascribe a precise role to neurofibromin in growth factor-dependent control of Ras activity and illustrate how, by engaging Ras-GAP activity, mitogen-challenged cells play safe to ensure a timely termination of the Ras signal irrespectively of the reigning rate of nucleotide exchange.

Sumoylation of HDAC2 promotes NF-κB-dependent gene expression.

The transcription factor nuclear factor-κB (NF-κB) is crucial for the maintenance of homeostasis. It is incompletely understood how nuclear NF-κB and the crosstalk of NF-κB with other transcription factors are controlled. Here, we demonstrate that the epigenetic regulator histone deacetylase 2 (HDAC2) activates NF-κB in transformed and primary cells. This function depends on both, the catalytic activity and an intact HDAC2 sumoylation motif. Several mechanisms account for the induction of NF-κB through HDAC2. The expression of wild-type HDAC2 can increase the nuclear presence of NF-κB. In addition, the ribosomal S6 kinase 1 (RSK1) and the tumor suppressor p53 contribute to the regulation of NF-κB by HDAC2. Moreover, TP53 mRNA expression is positively regulated by wild-type HDAC2 but not by sumoylation-deficient HDAC2. Thus, sumoylation of HDAC2 integrates NF-κB signaling involving p53 and RSK1. Since HDAC2-dependent NF-κB activity protects colon cancer cells from genotoxic stress, our data also suggest that high HDAC2 levels, which are frequently found in tumors, are linked to chemoresistance. Accordingly, inhibitors of NF-κB and of the NF-κB/p53-regulated anti-apoptotic protein survivin significantly sensitize colon carcinoma cells expressing wild-type HDAC2 to apoptosis induced by the genotoxin doxorubicin. Hence, the HDAC2-dependent signaling node we describe here may offer an interesting therapeutic option.

Worry and its correlates onboard cruise ships.

The present study examined job-specific worry, as well as possible predictors of such worry, namely job-specific self-efficacy and supervisor dispositionism. 133 non-supervising crew members at different departments onboard upmarket cruise ships filled in a questionnaire during one of their journeys. Findings show that employees report moderate amounts of job-specific worry and the galley crew reports significantly greater amounts of worry than the other departments. Results also indicate that cruise ship crews worry somewhat more than workers in the land based service sector. Furthermore it was found that supervisor dispositionism, i.e. supervisors with fixed mindsets, was related to greater amounts of worry among the crew. Surprisingly, job-specific self-efficacy was unrelated to job-specific worry.

Affective and cognitive attitudes, uncertainty avoidance and intention to obtain genetic testing: an extension of the Theory of Planned Behaviour.

To ensure successful implementation of genetic screening and counselling according to patients best interests, the attitudes and motives of the public are important to consider. The aim of this study was to apply a theoretical framework in order to investigate which individual and disease characteristics might facilitate the uptake of genetic testing. A questionnaire using an extended version of the Theory of Planned Behaviour was developed to assess the predictive value of affective and cognitive expected outcomes, subjective norms, perceived control and uncertainty avoidance on the intention to undergo genetic testing. In addition to these individual characteristics, the predictive power of two disease characteristics was investigated by systematically varying the diseases fatality and penetrance (i.e. the probability of getting ill in case one is a mutation carrier). This resulted in four versions of the questionnaire which was mailed to a random sample of 2400 Norwegians. Results showed genetic test interest to be quite high, and to vary depending on the characteristics of the disease, with participants preferring tests for highly penetrant diseases. The most important individual predictor was uncertainty avoidance.

Confidentiality versus duty to inform--an empirical study on attitudes towards the handling of genetic information.

We set out to investigate whether potential relatives want to be informed about the existence of hereditary conditions within their family and under which conditions they want healthcare providers to breach confidentiality to inform them. We hypothesized that the willingness to be informed about a hereditary condition in the family would be influenced by characteristics of the disease and by individual characteristics. Surveys were administered to a Norwegian random sample (N = 2,400) to a Swedish random sample (N = 1,200), and to a Norwegian student sample (n = 607). Eight different disease scenarios were constructed, systematically varying three disease characteristics: fatality, penetrance, and availability of treatment. Results show that a majority of participants wished to be informed about the existence of a hereditary disease within their family. The desire to be informed and the acceptability of breaches of confidentiality were predicted by the treatability of the disease, uncertainty avoidance, and age, but not by self-efficacy or worry.

The natural inverse agonist agouti-related protein induces arrestin-mediated endocytosis of melanocortin-3 and -4 receptors.

Agouti-related protein (Agrp), one of the two naturally occurring inverse agonists known to inhibit G protein-coupled receptor activity, regulates energy expenditure by decreasing basal and blocking agonist-promoted melanocortin receptor (MCR) signaling. Here we report that, in addition to its inverse agonistic activities, Agrp exhibits agonistic properties on the endocytosis pathway of melanocortin receptors. Sustained exposure of human embryonic kidney 293 cells to Agrp induced endocytosis of the MC3R or the MC4R. The extent and kinetics of Agrp-promoted MCR endocytosis were similar to the endocytosis induced by melanocortins. Using the bioluminescence resonance energy transfer technique, we further showed that after binding of Agrp both MCRs interacted with beta-arrestins. In line with this observation, in COS-7 cells co-expression of beta-arrestins enhanced Agrp-induced MCR endocytosis, whereas in human embryonic kidney 293 cells co-transfection of beta-arrestin-specific small interference RNAs diminished Agrp-promoted endocytosis. This new regulatory mechanism was likewise detectable in a cell line derived from murine hypothalamic neurons endogenously expressing MC4R, pointing to the physiological relevance of Agrp-promoted receptor endocytosis. In conclusion, we demonstrated that Agrp does not solely act by directly blocking MCR signaling but also by reducing the amount of MCR molecules accessible to melanocortins at the cell surface. This beta-arrestin-dependent mechanism reveals a new aspect of MCR signaling in particular and refines the concept of G protein-coupled receptor antagonism in general.