bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thick Concepts and Moral Revisionism in Plato’s Gorgias: Arguing About Something There Can Be No Argument About
Authors: Brüllmann Philipp 
Published: November 2019

Abstract
David Furley has suggested that we think of Callicles’ immoralism as attacking a thick concept. I take up this suggestion and apply it to the argument of Plato’s Gorgias more generally. I show that the discussion between Socrates, Gorgias and Polus, which prepares the ground for Callicles, is precisely addressing the thickness of the concept of justice: it reveals that this concept is both descriptive and evaluative and that formulating a revisionist position about justice is therefore extremely difficult. Callicles’ strategy is best read as a response to this difficulty, which sets the stage for Socrates’ revisionist account of justice.
Aristotle and the Origins of Evil
Authors: Müller Jozef 
Published: November 2019

Abstract
Why do human beings, on Aristotle’s view, have an innate tendency to badness, that is, to developing desires that go beyond and against their natural needs? Given Aristotle’s teleological assumptions (including the thesis that nature does nothing in vain), such tendency should not be present. I argue that the culprit is to be found in the workings of rationality, in particular in the (necessary) presence of theoretical reason. As theoretical reason requires that human beings have unlimited non-rational desires for the fine (to kalon), it also gives rise to a tendency to form unlimited non-rational desires for other things.
The Virtual Hand Illusion in Obesity: Dissociation Between Multisensory Interactions Supporting Illusory Experience and Self-Location Recalibration
Authors: Tagini Sofia , Scarpina Federica , Bruni Francesca , Scacchi Massimo , Mauro Alessandro , Zampini Massimiliano 
Published: November 2019

Abstract
The Rubber Hand Illusion (RHI) is used widely to investigate the multisensory integration mechanisms that support bodily self-consciousness and, more specifically, body ownership and self-location. It has been reported that individuals affected by obesity show anomalous multisensory integration processes. We propose that these obesity-induced changes could lead to an unusual susceptibility to the RHI and anomalous bodily self-experience. To test this hypothesis, we administered a modified version of the RHI (using a picture of the participant’s hand) to individuals affected by obesity and participants with a healthy weight. During synchronous and asynchronous stimulation, we compared the subjective experience of the illusion (using a questionnaire) and the effect of the illusion on self-location (i.e., proprioceptive drift). In accordance with the illusion phenomenology, both groups had a comparable subjective illusory experience after the synchronous stimulation. Nevertheless, individuals affected by obesity showed less recalibration of self-location than healthy weight participants. In light of a recent interpretation of the multisensory integration mechanisms that underpin the RHI, our findings suggest that in obesity visuo-tactile integration supporting the subjective experience of the illusion is preserved, whereas visuo-proprioceptive integration for self-location is reduced.
<p><strong>Bryoflora Salvadorensis 3. An updated checklist and new records of Pottiaceae for El Salvador</strong></p>
Authors: BÚCARO ROSA DELIA , SOLLMAN PHILIP , STECH MICHAEL 
Published: November 2019

An updated list of the taxa of the moss family Pottiaceae recorded for El Salvador is presented, based on literature reports and own investigations. At present, 20 genera of Pottiaceae are known from El Salvador, of which four (Barbula, Scopelophila, Trichostomum, Weissia) are reported as new for the country. Eight species and two varieties are reported as new for El Salvador: Barbula orizabensis, Bryoerythrophyllum ferruginascens, B. inaequalifolium, Chionoloma tenuirostre, Didymodon acutus var. icmadophilus, Hyophila nymaniana, Leptodontium viticulosoides var. viticulosoides, Scopelophila cataractae, Trichostomum brachydontium, and Weissia jamaicensis, increasing the total number of species to 35. Information on the distribution, main substrate types, and approximate elevational range in Mesoamerica as well as the general distribution are provided for all taxa.
An Intuitive Metric to Quantify and Communicate Tropical Cyclone Rainfall Hazard
Authors: Bosma Christopher D. , Wright Daniel B. , Nguyen Phu , Kossin James P. , Herndon Derrick C. , Shepherd J. Marshall 
Published: November 2019

AbstractRecent tropical cyclones (TCs) have highlighted the hazards that TC rainfall poses to human life and property. These hazards are not adequately conveyed by the commonly used Saffir–Simpson scale. Additionally, while recurrence intervals (or, their inverse, annual exceedance probabilities) are sometimes used in the popular media to convey the magnitude and likelihood of extreme rainfall and floods, these concepts are often misunderstood by the public and have important statistical limitations. We introduce an alternative metric—the extreme rain multiplier (ERM), which expresses TC rainfall as a multiple of the climatologically derived 2-yr rainfall value. ERM allows individuals to connect (“anchor,” in cognitive psychology terms) the magnitude of a TC rainfall event to the magnitude of rain events that are more typically experienced in their area. A retrospective analysis of ERM values for TCs from 1948 to 2017 demonstrates the utility of the metric as a hazard quantification and communication tool. Hurricane Harvey (2017) had the highest ERM value during this period, underlining the storm’s extreme nature. ERM correctly identifies damaging historical TC rainfall events that would have been classified as “weak” using wind-based metrics. The analysis also reveals that the distribution of ERM maxima is similar throughout the eastern and southern United States, allowing for both the accurate identification of locally extreme rainfall events and the development of regional-scale (rather than local-scale) recurrence interval estimates for extreme TC rainfall. Last, an analysis of precipitation forecast data for Hurricane Florence (2018) demonstrates ERM’s ability to characterize Florence’s extreme rainfall hazard in the days preceding landfall.
Sex-Specific Associations Between Area-Level Poverty and Cardiometabolic Dysfunction Among US Adolescents
Authors: Williams Andrew D. , Shenassa Edmond D. 
Published: November 2019

Objective: Cardiometabolic disease is the leading cause of mortality in the United States. Cardiometabolic function during adolescence predicts future cardiometabolic disease, yet few studies have examined early determinants of cardiometabolic function. Informed by evidence of sex differences in the prevalence and severity of cardiometabolic disorders and evidence of sexual dimorphism in the stress response, we examined sex differences in the association between living in poverty and cardiometabolic function during adolescence, a precursor of later cardiometabolic disorders. Methods: We linked data from 10 415 adolescents aged 12-19 in the National Health and Nutrition Examination Survey (1999-2012) with US Census–tract data on area-level poverty (percentage of the population living in poverty, grouped into quartiles). We parameterized cardiometabolic dysfunction by summing the z scores of 6 cardiometabolic biomarkers, grouped into quintiles. Hierarchical ordinal models estimated associations. Results: Compared with residents in low-poverty areas, residents in high-poverty areas had elevated odds of cardiometabolic dysfunction (highest quartile of poverty odds ratio [OR] = 1.27; 95% confidence interval [CI], 1.08-1.50). This association was more pronounced among boys than girls (highest quartile of poverty for boys: OR = 1.36; 95% CI, 1.10-1.70; highest quartile of poverty for girls: OR = 1.17; 95% CI, 0.94-1.47). Conclusion: Our study supports the existence of sex-specific associations. These results highlight the potential for community-based programs, such as housing assistance, to improve population health.
Online training improves medical students’ ability to recognise when a person is dying: The ORaClES randomised controlled trial
Authors: White Nicola , Oostendorp Linda JM , Tomlinson Christopher , Yardley Sarah , Ricciardi Federico , Gökalp Hülya , Minton Ollie , Boland Jason W , Clark Ben , Harries Priscilla , Stone Patrick 
Published: November 2019

Background: Recognising dying is a key clinical skill for doctors, yet there is little training. Aim: To assess the effectiveness of an online training resource designed to enhance medical students’ ability to recognise dying. Design: Online multicentre double-blind randomised controlled trial (NCT03360812). The training resource for the intervention group was developed from a group of expert palliative care doctors’ weightings of various signs/symptoms to recognise dying. The control group received no training. Setting/participants: Participants were senior UK medical students. They reviewed 92 patient summaries and provided a probability of death within 72 hours (0% certain survival – 100% certain death) pre, post, and 2 weeks after the training. Primary outcome: (1) Mean Absolute Difference (MAD) score between participants’ and the experts’ scores, immediately post intervention. Secondary outcomes: (2) weight attributed to each factor, (3) learning effect and (4) level of expertise (Cochran–Weiss–Shanteau (CWS)). Results: Out of 168 participants, 135 completed the trial (80%); 66 received the intervention (49%). After using the training resource, the intervention group had better agreement with the experts in their survival estimates ( δMAD = −3.43, 95% CI −0.11 to −0.34, p = <0.001) and weighting of clinical factors. There was no learning effect of the MAD scores at the 2-week time point ( δMAD = 1.50, 95% CI −0.87 to 3.86, p = 0.21). At the 2-week time point, the intervention group was statistically more expert in their decision-making versus controls (intervention CWS = 146.04 (SD 140.21), control CWS = 110.75 (SD 104.05); p = 0.01). Conclusion: The online training resource proved effective in altering the decision-making of medical students to agree more with expert decision-making.
Penile Invasive Squamous Cell Carcinoma: Analysis of Incidence, Mortality Trends, and Geographic Distribution in Canada
Authors: Lagacé François , Ghazawi Feras M. , Le Michelle , Savin Evgeny , Zubarev Andrei , Powell Mathieu , Moreau Linda , Sasseville Denis , Popa Ioana , Litvinov Ivan V. 
Published: November 2019

Background Penile invasive squamous cell carcinoma (SCC) is a rare disease with several known risk factors. However, few studies have assessed its incidence, mortality, and temporal trends. Objective Our objectives are to analyze the epidemiology of penile SCC in Canada and to examine patient distribution with this cancer across Canada in order to elucidate population risk factors. Methods Three independent cancer registries were used to retrospectively analyze demographic data from Canadian men diagnosed with penile invasive SCC between 1992 and 2010. The Canadian Census of Population was used to calculate incidence and mortality rates at the province and Forward Sortation Area levels. Results The overall age-adjusted incidence rate was 6.08 cases per million males. Four provinces with statistically significantly higher incidence rates were identified. The national crude incidence rates increased linearly between 1992 and 2010, whereas the age-adjusted incidence rates showed no significant increase during this time period. The overall age-adjusted mortality rate was 1.88 deaths per million males per year. The province of Saskatchewan had significantly higher mortality rates. There was no increase in crude or age-adjusted mortality rates between 1992 and 2010. There was a significant positive correlation between incidence rates and obesity, Caucasian ethnicity, and lower socioeconomic status. Conclusion This study was able to establish geographic variation for this malignancy at the provincial level. Although there are many established risk factors for penile SCC, our results suggest that the increase in crude incidence rates observed is largely due to the aging population.
Activating TP53 by Dual Inhibition of MDMX and MDM2
Authors: Steidl Ulrich G. 
Published: November 2019

TP53 is often inactivated by mutations or other mechanisms in human cancers. Recent work has demonstrated that its endogenous inhibitor MDMX (or MDM4) is frequently overexpressed in patients with hematologic malignancies including AML, lymphoid malignancies, as well as other cancers. Pharmacological disruption of the interactions of TP53 with both its endogenous inhibitors (MDMX and MDM2) has long been sought after as an attractive strategy to restore p53-dependent tumor suppressor activity. However, selective targeting of this pathway has previously been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX. More recently, pharmacological dual targeting of MDMX/MDM2 has become feasible through stapled peptides and is currently being tested in clinical trials. This presentation will discuss such MDMX/MDM2 dual-targeting strategies as well as new insights into MDMX-mediated mechanisms of tumor progression at the stem cell level, which have emerged from recent studies.

Disclosures
Steidl: Aileron Therapeutics: Consultancy, Research Funding; Stelexis Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Scientific Co-Founder; Pieries Pharmaceuticals: Consultancy; Celgene: Consultancy; BayerHealthcare: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding.
MCL1 Inhibitors in Multiple Myeloma
Authors: Vanderkerken Karin , De Veirman Kim , Maes Ken , Menu Eline , De Bruyne Elke 
Published: November 2019

Apoptosis plays a key role, not only in normal homeostasis but also in protection against genomic instability. Protection against apoptosis is a hallmark of cancer and is mainly regulated by the overexpression of anti-apoptotic proteins such as Bcl-2, Bcl-Xl or Mcl-1. This results in increased survival of the tumor cells and resistance to therapy.
This presentation will focus on MCL-1 (myeloid cell leukemia 1), its expression and its role as potential target in multiple myeloma (MM). MCL1 gene regions are one the most amplified gene regions in several human cancers and Mcl-1 activity is often associated with therapy resistance and relapse. Mcl-1 binds to and sequesters the pro-apoptotic BH3 proteins, thereby preventing apoptosis.
Mcl-1 is overexpressed on MM cells from newly diagnosed patients compared to normal plasma cells and in MM cells at relapse. This overexpression is furthermore associated with a shorter survival of these patients. Increased Mcl-1 expression can result either from genetic lesions or by induction through interaction with the bone marrow microenvironment. Its expression is correlated with the molecular heterogeneity of the myeloma patients; while the CCDN1 group has high BCL2 and low MCL-1 expression; the MMSET and MAF group has high MCL-1 and low BCL2 expression. Unlike Bcl-2 and Bcl-Xl, Mcl-1 has a large unstructured aminoterminus and its activity is mainly dependent on posttranslational modifications. The bone marrow microenvironment, by producing high levels of interleukin 6, also induces the upregulation of Mcl-1. Furthermore, our group recently demonstrated that not only stromal cells in the bone marrow microenvironment, but also MDSC (myeloid derived suppressor cells) induce survival of MM cells by increasing Mcl-1 levels through the AMPK pathway.
As such, these data suggest the potential therapeutic benefit of targeting Mcl-1 in MM patients. Developing the first-generation inhibitors appeared to be challenging, especially in view of the occurrence of unwanted off target effects. Recent preclinical data with new, selective Mcl-1 inhibitors show promising anti-tumor effects both in vitro and in in vivo myeloma models, either alone or in combination with the Bcl-2 selective inhibitor, venetoclax, especially as it was demonstrated that high levels of MCL-1 are associated with venetoclax resistance in MM. In addition, it was also shown that proteasome inhibition can trigger Mcl-1 accumulation, further pointing to the importance of Mcl-1 inhibition. Induction of NOXA, as an inhibitor of Mcl-1, is also suggested as a therapeutic option, especially in combinations with other drugs.
Clinically, following preclinical results, several new Mcl-1 inhibitors have entered phase I trials. Most of them are still recruiting patients, and as such too early to have results.

Disclosures
No relevant conflicts of interest to declare.
Genetic Engineering in Hematopoietic Stem Cells for Gene Therapy of Hemoglobinopathies
Authors: Ferrari Giuliana 
Published: November 2019

Beta-thalassemia and sickle cell disease (SCD) are congenital anemias caused by mutations in the beta-globin gene, resulting in either reduced/absent production of globin chains or abnormal hemoglobin structure. At present, the definitive cure is represented by allogeneic hematopoietic stem cell transplantation, with a probability to find a well-matched donor of <25%.
Experimental gene therapy for hemoglobinopathies is based on transplantation of autologous hematopoietic stem cells genetically modified to express therapeutic hemoglobin levels. Approaches to genetically modify HSCs for treatment of hemoglobinopathies include: 1) the addition of globin genes by lentiviral vectors and 2) gene editing by nucleases to reactivate fetal hemoglobin either through inhibition of repressors or by reproducing mutations associated with high fetal hemoglobin levels.
The outcomes of early clinical trials are showing the safety and potential efficacy, as well as the hurdles still limiting a general application.Current challenges and improved strategies will be presented and discussed.

Disclosures
No relevant conflicts of interest to declare.

OffLabel Disclosure:
Plerixafor
Developmental Biology of the Blood System
Authors: Speck Nancy , Zhu Qin , Gao Peng , Tober Joanna , Bennett Laura , Chen Changya , Uzun Yasin , Li Yan , Tan Kai 
Published: November 2019

Hematopoietic stem and progenitor cells (HSPCs) in the bone marrow are derived from a small population of hemogenic endothelial (HE) cells located in the yolk sac and major caudal arteries of the mammalian embryo. HE cells undergo an endothelial to hematopoietic cell transition, giving rise to HSPCs that accumulate in intra-arterial clusters before colonizing the fetal liver. To examine the molecular transitions between endothelial cells, HE, and intra-arterial cluster cells, and the heterogeneity of HSPCs within the intra-arterial clusters, we profiled ~40,000 cells from the caudal arteries (dorsal aorta, umbilical, vitelline) of embryonic day 9.5 to 11.5 mouse embryos by single-cell RNA sequencing (scRNA-seq) and single-cell chromatin accessibility sequencing (scATAC-Seq). A continuous developmental trajectory leads from endothelial cells to intra-arterial cluster cells, with identifiable intermediate stages between endothelial cells and HE. The intermediate endothelial stages most proximal to HE are characterized by elevated expression of genes regulated by GATA and SOX transcription factors. Developmental bottlenecks separate endothelial cells from HE cells, with the efficiency of transit through one of the last bottleneck regulated by RUNX1 dosage. Distinct developmental trajectories within intra-arterial cluster cells result in two populations of CD45+HSPCs; an initial wave of multi-lineage committed progenitors followed by precursors of hematopoietic stem cells (pre-HSCs). These and other insights gained from single cell analyses of HSPC formation from arterial endothelium will be presented.

Disclosures
No relevant conflicts of interest to declare.
Post-Treatment FDG-Avid Splenic Lesions in DLBCL: Clinical and Radiographic Characteristics for Risk Assessment
Authors: Nachmias Boaz , Godefroy Geremy , Ganzel Chezi , Goldschmidt Neta , Rozenbach Eyal , Bar-Shalom Rachel , Libster Diana , Vainstein Vladimir 
Published: November 2019

PET-CT has been widely incorporated in the treatment of diffuse large B cell lymphoma (DLBCL) and Hodgkin's lymphoma (HD) both for staging at diagnosis and for evaluation of response to therapy. Residual FDG-avid lesions at the end of treatment (EOT) are often due to infectious or inflammatory process and not due to refractory lymphoma. Nonetheless, such lesions prompt diagnostic and therapeutic interventions. In the present study, we evaluate clinical and radiological characteristics of patients with EOT FDG-avid splenic lesions in hope to provide better tools to discern false from true lesions.
The study cohort included patients with DLBCL or HD who had residual EOT FDG-avid splenic lesion with no evidence of active disease in other sites. Patients were concluded as false positive or true positive according to pathological results or long-term follow-up. Clinical and PET-CT characteristics were compared between the two groups.
Our cohort included 9 patients with DLBCL and 2 with HD, of which 6 patients were determined to have false positive lesions and 5 true positive.
Comparing metabolic volume (MV) ratio between EOT to interim (EOT/interim) tests showed a marked difference between false positive and true positive lesions (0.5 vs 3.6, p= 0.02). Notably, comparing EOT to diagnosis (EOT/Dx) MV showed a similar trend that did not reach statistical significance, highlighting MV EOT/interim ratio as a parameter with higher discriminative ability. EOT SUVmax was also significantly different between false positive and true positive (7 vs. 19, p=0.02). A MV EOT/interim ratio >3 has a 75% sensitivity and 100% specificity for the true positive group. Other clinical and PET-CT characteristics were not found to statistically differ between the groups.
To date, this is the first report showing predictive ability of PET-CT characteristics to discern true from false positive residual FDG-avid splenic lesions. Our cohort is of small numbers, nonetheless, EOT/interim MV shows a clear opposite ratio with a decrease in the false positive compared to an increase in the true positive groups. We suggest EOT/interim MV ratio might be a tool to identify patients at low risk of refractory disease allowing non-invasive surveillance. Further larger studies will be needed to validate the role MV EOT/interim ratio as a tool to discriminate residual disease from false positive FDG-avid lesions.

Disclosures
No relevant conflicts of interest to declare.