A structured population model of clonal selection in acute leukemias with multiple maturation stages

Funding: TS and AM-C were supported by research funding from the German Research Foundation DFG (SFB 873; subproject B08). TL gratefully acknowledges support from the Heidelberg Graduate School (HGS).Recent progress in genetic techniques has shed light on the complex co-evolution of malignant cell clones in leukemias. However, several aspects of clonal selection still remain unclear. In this paper, we present a multi-compartmental continuously structured population model of selection dynamics in acute leukemias, which consists of a system of coupled integro-differential equations. Our model can be analysed in a more efficient way than classical models formulated in terms of ordinary differential equations. Exploiting the analytical tractability of this model, we investigate how clonal selection is shaped by the self-renewal fraction and the proliferation rate of leukemic cells at different maturation stages. We integrate analytical results with numerical solutions of a calibrated version of the model based on real patient data. In summary, our mathematical results formalise the biological notion that clonal selection is driven by the self-renewal fraction of leukemic stem cells and the clones that possess the highest value of this parameter are ultimately selected. Moreover, we demonstrate that the self-renewal fraction and the proliferation rate of non-stem cells do not have a substantial impact on clonal selection. Taken together, our results indicate that interclonal variability in the self-renewal fraction of leukemic stem cells provides the necessary substrate for clonal selection to act upon.PostprintPeer reviewe

Men, Women, and Economic Changes: Social Representations of the Economic Crisis

The current economic crisis has been a new and unexpected phenomenon; it is part of the capitalist banking and economic system that has been known until 2008. The crisis has led to banks, states, international institutions, as well as common people, changing profoundly their representations about the economy. In this scenario, some questions arise: how do men and women of different social status face the complex and unknown phenomenon of the economic crisis? Do gender and social status justify the different meanings attributed to the crisis, to its causes and its consequences? When confronted with an external threat like the economic crisis, people draw on social representations to provide meaning to that unfamiliar situation. Through media and interpersonal communication, social groups produce naive theories that improve familiarity with an unexpected and distressing phenomenon. In order to analyze these lay theories elaborated though daily economic thinking and acting, this research has been conducted using Social Representation Theory and its methodological approaches. This theory, in fact, contributes to our understanding of the societal process of sense making when an unexperienced external shock affects society. It offers a way to understand economic phenomena’s impact on social groups. Social representations (SRs) serve the purpose of making the unfamiliar become familiar, and the unusual become usual, as well as to provide orientation in times of change. In this sense, in this article, social representations theory is used to examine the role of gender and educational status in the production of representations of the crisis. Presented findings came from a survey carried out in Southern Italy (N = 120) revealing status and gender differences in the ways people define the crisis and cope with it. Participants were asked to order the first most important five statements and the first least important statements, among a list of 15 (according to the rule of a multiple of 3) to code every item with a score of 1 (less characteristic), 3 (more characteristic), or 2 (not chosen). Every Questionnaire of Characterization was created starting from social descriptions and explanations of the crisis, identified in a previous study. They covered every sub-dimension of the content (complementary to the structure) of the social representation of the crisis, such as: cognitive-evaluative aspects about the representation’s structure (central and peripheral elements); descriptive-defining aspects of the representation; informative sources and interaction networks; level of involvement/implication with the object; relationship between representation and social practices; perceptions, attributions and categorizations (causes, responsibilities, duration/evolution, solutions, positive implications, the EU’s role). In this paper, we will only consider the answers related to the following dimensions: crisis definitions, strategies to tackle the crisis and social practices related to the crisis. The analysis of the data was carried out primarily using Multiple Correspondence Analysis (MCA). In this analysis, in order to uncover the objectification and anchoring processes, we considered the interaction of status and gender as an illustrative variable. These findings were further substantiated with the use of Discriminant analysis. The social anchoring of social representations of the economic crisis is influenced by gender and social status. Nevertheless, the difference in status modifies the stereotypical dimensions, also coherently with predictions derived from gender role theory about the reduction of the impact of gender stereotypes when men and women occupy similar social positions. On the one hand, high-status participants defined the crisis in more abstract terms than low-status participants. On the other hand, high-status men hold a more proactive style of coping with the crisis than other participants, especially women. The discussion focuses on the role of social representations theory in understanding the relationships between gender, status and economic behavior, providing insights into how gender equality might be improved

Men, Women, and Economic Changes: Social Representations of the Economic Crisis

The current economic crisis has been a new and unexpected phenomenon; it is part of the capitalist banking and economic system that has been known until 2008. The crisis has led to banks, states, international institutions, as well as common people, changing profoundly their representations about the economy. In this scenario, some questions arise: how do men and women of different social status face the complex and unknown phenomenon of the economic crisis? Do gender and social status justify the different meanings attributed to the crisis, to its causes and its consequences? When confronted with an external threat like the economic crisis, people draw on social representations to provide meaning to that unfamiliar situation. Through media and interpersonal communication, social groups produce naive theories that improve familiarity with an unexpected and distressing phenomenon. In order to analyze these lay theories elaborated though daily economic thinking and acting, this research has been conducted using Social Representation Theory and its methodological approaches. This theory, in fact, contributes to our understanding of the societal process of sense making when an unexperienced external shock affects society. It offers a way to understand economic phenomena’s impact on social groups. Social representations (SRs) serve the purpose of making the unfamiliar become familiar, and the unusual become usual, as well as to provide orientation in times of change. In this sense, in this article, social representations theory is used to examine the role of gender and educational status in the production of representations of the crisis. Presented findings came from a survey carried out in Southern Italy (N = 120) revealing status and gender differences in the ways people define the crisis and cope with it. Participants were asked to order the first most important five statements and the first least important statements, among a list of 15 (according to the rule of a multiple of 3) to code every item with a score of 1 (less characteristic), 3 (more characteristic), or 2 (not chosen). Every Questionnaire of Characterization was created starting from social descriptions and explanations of the crisis, identified in a previous study. They covered every sub-dimension of the content (complementary to the structure) of the social representation of the crisis, such as: cognitive-evaluative aspects about the representation’s structure (central and peripheral elements); descriptive-defining aspects of the representation; informative sources and interaction networks; level of involvement/implication with the object; relationship between representation and social practices; perceptions, attributions and categorizations (causes, responsibilities, duration/evolution, solutions, positive implications, the EU’s role). In this paper, we will only consider the answers related to the following dimensions: crisis definitions, strategies to tackle the crisis and social practices related to the crisis. The analysis of the data was carried out primarily using Multiple Correspondence Analysis (MCA). In this analysis, in order to uncover the objectification and anchoring processes, we considered the interaction of status and gender as an illustrative variable. These findings were further substantiated with the use of Discriminant analysis. The social anchoring of social representations of the economic crisis is influenced by gender and social status. Nevertheless, the difference in status modifies the stereotypical dimensions, also coherently with predictions derived from gender role theory about the reduction of the impact of gender stereotypes when men and women occupy similar social positions. On the one hand, high-status participants defined the crisis in more abstract terms than low-status participants. On the other hand, high-status men hold a more proactive style of coping with the crisis than other participants, especially women. The discussion focuses on the role of social representations theory in understanding the relationships between gender, status and economic behavior, providing insights into how gender equality might be improved

Le « patrimoine du quotidien », enjeu renouvelé pour les urbanistes européens

La sensibilité au patrimoine s’est développée dans nos sociétés. En conséquence, les dispositifs de protection et de mise en valeur du patrimoine se sont multipliés. Après avoir visé la protection stricte d’ensembles urbains remarquables, nous sommes passés à des dispositifs de mise en valeur de tissus urbains plus modestes, témoins d’un passé et d’une identité locale. Travailler ce patrimoine du quotidien appelle une transformation des méthodes de l’urbanisme. Le présent article montre la complémentarité des dispositifs de protection français et prend appui sur le cas troyen pour illustrer leur mise en œuvre. Il montre ensuite les questions que cette patrimonialisation de l’urbanisme pose aux villes européennes.Our societies have become more and more aware of the importance of safeguarding their heritage. Heritage policies have expanded, going from the museification of outstanding urban sites to the wise management of landscapes representative of local identities and cultures. As a consequence, methods of urban planning change. The present paper shows the complementarity heritage protection and management in the French system. It uses the case of Troyes to show how heritage protection is being implemented and included in territorial marketing strategies. Finally, it addresses some key issues that European cities are facing when performing heritage policies

Allogeneic mesenchymal stromal cells overexpressing mutant human Hypoxia-inducible factor 1-α (HIF1-α) in an ovine model of acute myocardial infarction

Background-Bone marrow mesenchymal stromal cells (BMMSCs) are cardioprotective in acute myocardial infarction (AMI) because of release of paracrine angiogenic and prosurvival factors. Hypoxia-inducible factor 1-α (HIF1-α), rapidly degraded during normoxia, is stabilized during ischemia and upregulates various cardioprotective genes. We hypothesized that BMMSCs engineered to overexpress mutant, oxygen-resistant HIF1-α would confer greater cardioprotection than nontransfected BMMSCs in sheep with AMI. Methods and Results-Allogeneic BMMSCs transfected with a minicircle vector encoding mutant HIF1-α (BMMSC-HIF) were injected in the peri-infarct of sheep (n=6) undergoing coronary occlusion. Over 2 months, infarct volume measured by cardiac magnetic resonance (CMR) imaging decreased by 71.7±1.3% (P < 0.001), and left ventricular (LV) percent ejection fraction (%EF) increased near 2-fold (P < 0.001) in the presence of markedly decreased end-systolic volume. Sheep receiving nontransfected BMMSCs (BMMSC; n=6) displayed less infarct size limitation and percent LVEF improvement, whereas in placebo-treated animals (n=6), neither parameters changed over time. HIF1-α-transfected BMMSCs (BMMSC-HIF) induced angio-/arteriogenesis and decreased apoptosis by HIF1-mediated overexpression of erythropoietin, inducible nitrous oxide synthase, vascular endothelial growth factor, and angiopoietin-1. Cell tracking using paramagnetic iron nanoparticles in 12 additional sheep revealed enhanced long-term retention of BMMSC-HIF. Conclusions-Intramyocardial delivery of BMMSC-HIF reduced infarct size and improved LV systolic performance compared to BMMSC, attributed to increased neovascularization and cardioprotective effects induced by HIF1-mediated overexpression of paracrine factors and enhanced retention of injected cells. Given the safety of the minicircle vector and the feasibility of BMMSCs for allogeneic application, this treatment may be potentially useful in the clinic.Fil: Hnatiuk, Anna. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Ong, Sang-Ging. Stanford University School of Medicine; Estados UnidosFil: Olea, Fernanda Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Locatelli, Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Riegler, Johannes. Stanford University School of Medicine; Estados UnidosFil: Lee, Won Hee. Stanford University School of Medicine; Estados UnidosFil: Jen, Cheng Hao. University of London; Reino UnidoFil: De Lorenzi, Andrea. Fundación Favaloro; ArgentinaFil: Giménez, Carlos Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; ArgentinaFil: Laguens, Rubén. Universidad Favaloro; ArgentinaFil: Wu, Joseph C.. Stanford University School of Medicine; Estados UnidosFil: Crottogini, Alberto José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Medicina Traslacional, Trasplante y Bioingeniería. Fundación Favaloro. Instituto de Medicina Traslacional, Trasplante y Bioingeniería; Argentin

Discrete and continuum phenotype-structured models for the evolution of cancer cell populations under chemotherapy

Funding: German Research Foundation DFG (SFB 873; subproject B08) (T.S. and A.M.-C); Heidelberg Graduate School (T.L.).We present a stochastic individual-based model for the phenotypic evolution of cancer cell populations under chemotherapy. In particular, we consider the case of combination cancer therapy whereby a chemotherapeutic agent is administered as the primary treatment and an epigenetic drug is used as an adjuvant treatment. The cell population is structured by the expression level of a gene that controls cell proliferation and chemoresistance. In order to obtain an analytical description of evolutionary dynamics, we formally derive a deterministic continuum counterpart of this discrete model, which is given by a nonlocal parabolic equation for the cell population density function. Integrating computational simulations of the individual-based model with analysis of the corresponding continuum model, we perform a complete exploration of the model parameter space. We show that harsher environmental conditions and higher probabilities of spontaneous epimutation can lead to more effective chemotherapy, and we demonstrate the existence of an inverse relationship between the efficacy of the epigenetic drug and the probability of spontaneous epimutation. Taken together, the outcomes of the model provide theoretical ground for the development of anticancer protocols that use lower concentrations of chemotherapeutic agents in combination with epigenetic drugs capable of promoting the re-expression of epigenetically regulated genes.PostprintPeer reviewe

Clinical, genetic, and pathological features of male pseudohermaphroditism in dog

Male pseudohermaphroditism is a sex differentiation disorder in which the gonads are testes and the genital ducts are incompletely masculinized. An 8 years old dog with normal male karyotype was referred for examination of external genitalia abnormalities. Adjacent to the vulva subcutaneous undescended testes were observed. The histology of the gonads revealed a Leydig and Sertoli cell neoplasia. The contemporaneous presence of testicular tissue, vulva, male karyotype were compatible with a male pseudohermaphrodite (MPH) condition

Immigrati di seconda generazione in Toscana: valutazione sperimentale di un modello teorico

The following article is part of the discussion about immigration, and it takes into specific consideration the integration phenomenon of the so-called “second generations” of young immigrants. Supported by a research performed throughout the High School Institutes in the Region of Tuscany, this study is aimed at evaluating the trustworthiness and factorial reliability of the assessment model, which has been used to produce the questionnaire administered to the students. In order to assess the reliability and factorial structure of our measurement scales, as well as to better define the role of several theoretical factors (Integration, Relationship with School, Socialization in Groups and Values / Prejudices) assumed for the assessment of the degree of integration between foreign and Italian students, the data analysis was carried out through the use of Structural Equation Modeling. This kind of an approach allows us not only to reduce a certain theoretical complexity, but also to identify and formalize causative relationships between the variables, through the analysis of indexes related to the adaptive effectiveness of data in the model. The outcomes obtained from this study support not only the factorial reliability of the tool – as well as the effectiveness of measurement scales for several factors (INT, RS, VP, SG) – but they also confirm the leading role played by school in producing positive processes for the integration of new generations of immigrants.Lo studio qui presentato spende il proprio interesse alla riflessione sulle tematiche dell’immigrazione ed in particolare dell’integrazione delle c.d. “seconde generazioni”. Partendo da una ricerca svolta negli istituti di istruzione secondaria superiore della Regione Toscana, la ricerca si propone di valutare l’attendibilità e l’affidabilità fattoriale del modello di analisi utilizzato per la costruzione questionario somministrato agli studenti. Al fine di verificare la fedeltà e la struttura fattoriale delle scale di misura utilizzate ed il ruolo dei diversi fattori teorici ipotizzati (Integrazione, Rapporto con la scuola, Socializzazione nei gruppi e Valori/Pregiudizi) nella valutazione del grado di integrazione tra studenti stranieri e studenti italiani, l’analisi dei dati è stata condotta attraverso l’uso dei modelli di equazioni strutturali.Tale approccio consente la riduzione della complessità teorica, l'identificazione e la formalizzazione dei nessi causali tra le variabili attraverso l’analisi degli indici relativi alla bontà di adattamento dei dati al modello.I risultati ottenuti, oltre all’affidabilità fattoriale dello strumento e alla bontà delle scale riferite ai diversi fattori (INT, RS, VP, SG), hanno confermato il ruolo primario dell’istituzione scolastica nella costruzione di processi favorevoli all’integrazione delle nuove generazioni di immigrat

Victimization and sentimental relationships during COVID-19 pandemic : Vittimizzazione e relazioni sentimentali durante la pandemia da COVID-19

Covid-19 pandemic has been hard for all of us. Isolation and social distancing, particularly, have damage the quality of interpersonal relationships. Starting from these considerations the authors questioned what is the impact of the sanitary emergency on the sentimental relationships. Considering that this aspect was already present in the scientific literatures, the authors have narrowed it down to victimization which had not yet appeared in these terms.So, the aim of this study is to evaluate, inside the adult population, if the couples sentimental relationships are different between victimized and not. At last was evaluated if the anxiety, depression and stress moderate the relationship with the victimization.La pandemia da Covid-19 ha messo ognuno di noi a dura prova. L’isolamento e il distanziamento sociale, in particolar modo, hanno minato la qualità delle relazioni interpersonali. Partendo da queste considerazioni gli autori si sono interrogati rispetto a quale potesse essere stato l’impatto dell’emergenza sanitaria sulla qualità delle relazioni sentimentali. Dato che questo aspetto era già presente a vari livelli della letteratura scientifica gli autori hanno ristretto il loro campo di considerazione al fenomeno della vittimizzazione che ancora non era comparsa in questi termini. Quindi l’obiettivo principale dello studio risulta essere quello di valutare, all’interno della popolazione adulta, se le relazioni sentimentali di coppia sono diverse fra soggetti vittimizzati e non vittimizzati. Infine è stato valutato se i sintomi di ansia, depressione e stress fungono da moderatori fra relazione e vittimizzazione

Targeting the Endothelin-1 Receptors Curtails Tumor Growth and Angiogenesis in Multiple Myeloma

The endothelin-1 (ET-1) receptors were recently found to mediate pro-survival functions in multiple myeloma (MM) cells in response to autocrine ET-1. This study investigated the effectiveness of macitentan, a dual ET-1 receptor antagonist, in MM treatment, and the mechanisms underlying its activities. Macitentan affected significantly MM cell (RPMI-8226, U266, KMS-12-PE) survival and pro-angiogenic cytokine release by down-modulating ET-1-activated MAPK/ERK and HIF-1 alpha pathways, respectively. HIF-1 alpha silencing abrogated the ET-1 mediated induction of genes encoding for pro-angiogenic cytokines such as VEGF-A, IL-8, Adrenomedullin, and ET-1 itself. Upon exposure to macitentan, MM cells cultured in the presence of the hypoxia-mimetic agent CoCl2, exogenous ET-1, or CoCl2 plus ET-1, down-regulated HIF-1 alpha and the transcription and release of downstream pro-angiogenic cytokines. Consistently, macitentan limited significantly the basal pro-angiogenic activity of RPMI-8226 cells in chorioallantoic membrane assay. In xenograft mouse models, established by injecting NOG mice either via intra-caudal vein with U266 or subcutaneously with RPMI-8226 cells, macitentan reduced effectively the number of MM cells infiltrating bone marrow, and the size and microvascular density of subcutaneous MM tumors. ET-1 receptors targeting by macitentan represents an effective anti-proliferative and anti-angiogenic therapeutic approach in preclinical settings of MM