Comprehensive analysis of T cell leukemia signals reveals heterogeneity in the PI3 kinase-Akt pathway and limitations of PI3 kinase inhibitors as monotherapy.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer. Poly-chemotherapy with cytotoxic and genotoxic drugs causes substantial toxicity and more specific therapies targeting the underlying molecular lesions are highly desired. Perturbed Ras signaling is prevalent in T-ALL and occurs via oncogenic RAS mutations or through overexpression of the Ras activator RasGRP1 in ~65% of T-ALL patients. Effective small molecule inhibitors for either target do not currently exist. Genetic and biochemical evidence link phosphoinositide 3-kinase (PI3K) signals to T-ALL, PI3Ks are activated by Ras-dependent and Ras-independent mechanisms, and potent PI3K inhibitors exist. Here we performed comprehensive analyses of PI3K-Akt signaling in T-ALL with a focus on class I PI3K. We developed a multiplex, multiparameter flow cytometry platform with pan- and isoform-specific PI3K inhibitors. We find that pan-PI3K and PI3K γ-specific inhibitors effectively block basal and cytokine-induced PI3K-Akt signals. Despite such inhibition, GDC0941 (pan-PI3K) or AS-605240 (PI3Kγ-specific) as single agents did not efficiently induce death in T-ALL cell lines. Combination of GDC0941 with AS-605240, maximally targeting all p110 isoforms, exhibited potent synergistic activity for clonal T-ALL lines in vitro, which motivated us to perform preclinical trials in mice. In contrast to clonal T-ALL lines, we used a T-ALL cancer model that recapitulates the multi-step pathogenesis and inter- and intra-tumoral genetic heterogeneity, a hallmark of advanced human cancers. We found that the combination of GDC0941 with AS-605240 fails in such trials. Our results reveal that PI3K inhibitors are a promising avenue for molecular therapy in T-ALL, but predict the requirement for methods that can resolve biochemical signals in heterogeneous cell populations so that combination therapy can be designed in a rational manner

Empowering Responsible Online Gambling by Real-time Persuasive Information Systems

Online gambling, unlike other mediums of problem- atic and addictive behaviours, such as tobacco and alcohol, offers unprecedented opportunities for building information systems that are able to monitor and understand a user’s behaviour in real-time and adapt persuasive messages and interactions that would fit their personal profile and usage context. Online gambling industry usually provides Application Programming Interfaces (APIs) meant mainly to enable third-party applications to network with their gambling services and enhance a user’s gambling experience. In this industrial practice and experience paper, we advocate that such API’s can also be used to retrieve gamblers’ online data, such as browsing and betting history, promotions and available offers and use it to build more intel- ligent and proactive responsible gambling information systems. We report on our industrial experience in this field and make the argument that data available for persuasive marketing and usability should, under specific usage conditions, also be made available for responsible gambling information systems. This principle would provide equal opportunities for both directions. We discuss the psychological foundations of our proposed solution and the risks and challenges typically found when building such a software-assisted intervention, persuasion and emotion regulation technology. We also shed light on its potential implications from the perspectives of social corporate responsibility and data protection. We finally propose a conceptual architecture to demonstrate our vision and explain how it can be implemented. In the wider context, the paper is meant to provide insights on building behavioural awareness and regulation information systems in relation to problematic digital media usage

Enabling Responsible Online Gambling by Real-time Persuasive Technologies

Online gambling, unlike other offline addiction forms, provides unprecedented opportunities for monitoring users’ behaviour in real-time, along with the ability to adapt persuasive interactions and messages that would match the gamblers usage and personal context. Online gambling industry usually offers Application Programming Interfaces (APIs) that are mainly intended to allow third-party applications to interact with their services and enhance user’s experience. In this paper, we claim that such API’s can also be utilised to retrieve gamblers’ online data, such as browsing and betting history and other available offers, and use it to build more proactive and intelligent responsible gambling systems. We report on our experience in this field and make the argument that the available data for persuasive marketing and usability should, under certain usage conditions, also be made available for responsible online gambling services. We discuss the psychological foundations of our proposed approach and the risks and challenges typically resulted when building such a software-assisted intervention, persuasion and emotion regulation technology. We also explain the potential impact of corporate social responsibility and data protection prospects. Furthermore, we explore the required principles that should be followed by the gambling industry for enabling responsible online gambling. We finally propose a conceptual architecture to show our vision and explain how it can be implemented. In the broader context, the paper is intended to provide insights on building behavioural awareness and regulation information systems related to problematic digital media usage. Keywords: Persuasive technologies, responsible online gambling, gambling data availability, corporate social responsibility

A Signature of Maternal Anti-Fetal Rejection in Spontaneous Preterm Birth: Chronic Chorioamnionitis, Anti-Human Leukocyte Antigen Antibodies, and C4d

Chronic chorioamnionitis is found in more than one-third of spontaneous preterm births. Chronic chorioamnionitis and villitis of unknown etiology represent maternal anti-fetal cellular rejection. Antibody-mediated rejection is another type of transplantation rejection. We investigated whether there was evidence for antibody-mediated rejection against the fetus in spontaneous preterm birth.This cross-sectional study included women with (1) normal pregnancy and term delivery (n = 140) and (2) spontaneous preterm delivery (n = 140). We analyzed maternal and fetal sera for panel-reactive anti-HLA class I and class II antibodies, and determined C4d deposition on umbilical vein endothelium by immunohistochemistry. Maternal anti-HLA class I seropositivity in spontaneous preterm births was higher than in normal term births (48.6% vs. 32.1%, p = 0.005). Chronic chorioamnionitis was associated with a higher maternal anti-HLA class I seropositivity (p<0.01), significant in preterm and term birth. Villitis of unknown etiology was associated with increased maternal and fetal anti-HLA class I and II seropositivity (p<0.05, for each). Fetal anti-HLA seropositivity was closely related to maternal anti-HLA seropositivity in both groups (p<0.01, for each). C4d deposition on umbilical vein endothelium was more frequent in preterm labor than term labor (77.1% vs. 11.4%, p<0.001). Logistic regression analysis revealed that chronic chorioamnionitis (OR = 6.10, 95% CI 1.29–28.83), maternal anti-HLA class I seropositivity (OR = 5.90, 95% CI 1.60–21.83), and C4d deposition on umbilical vein endothelium (OR = 36.19, 95% CI 11.42–114.66) were associated with preterm labor and delivery.A major subset of spontaneous preterm births has a signature of maternal anti-fetal cellular and antibody-mediated rejections with links to fetal graft-versus-host disease and alloimmune reactions

Local effect of progesterone infusion into ovarian artery on activin A and inhibin alpha-subunit secretion during the middle luteal phase in gilts

The present study was undertaken to elucidate whether an increased, but physiological, amount of progesterone (P4) supplied to the porcine corpus luteum affects luteal secretion of activin A and inhibin a-subunit (Inha) in freely moving gilts. On day 9 of the estrous cycle (EC), both ovarian arteries and both ovarian veins of gilts (n=5) were cannulated. Progesterone was infused into the right ovarian arteries in gilts on days 10, 11 and 12 of the EC at a rate adequate to its physiological retrograde transfer found during the middle luteal phase of the EC. The P4 infusion rate was 0.62 μg/min (day 10), 2x0.62 μg/min (day 11) and 3x0.62 μg/min (day 12). The left ovarian arteries were infused with saline (control). Blood samples were collected from both ovarian veins on days 10-12 of the EC before and after P4 or saline infusion. The mean plasma activin A level in the ovarian vein ipsilateral to the P4-infused ovary was higher (PcO.OOOl) on days 10-12 of the EC than this found in the contralateral ovarian vein. The level of activin A in the ovarian vein ipsilataral to the infusion of P4 was higher on days 11 (PcO.Ol) and 12 (P0.05) than this found in the contralateral ovarian vein. The results of the present study indicate that a local elevation of P4 concentration in blood supplying the ovary during the middle luteal phase of the porcine EC affects ovarian secretion of activin A. The effect of P4 on the secretion of activin A suggested the existence of a short regulatory loop of a positive feedback between P4 being retrogradely transferred into the ovary and the secretion of this peptide

The influence of steroids on noradrenaline-mediated contractile reactivity of the superficial nasal and facial veins in cycling gilts

The nasal venous blood may be directed through the facial vein into the systemic circulation or through the frontal vein into the venous cavernous sinus of the perihypophyseal vascular complex, where hormones and pheromones permeate from the venous blood into the arterial blood supplying the brain and hypophysis. The present study was designed to determine the effect of noradrenaline (NA) on the tension of the nasal, frontal and facial veins of cycling gilts, and influence of ovarian steroid hormones on NA-mediated contractile reactivity. Additionally, the enzyme dopamine-β-hydroxylase catalysing the conversion of dopamine to noradrenaline (DβH) was immunolocalized in these vessels. Among three studied veins, the frontal proximal vein, that fulfill a key role in the supply of the nasal venous blood into the venous cavernous sinus, reacted to NA most strongly (P<0.001) and this reaction was weaker in the periestrous period than in luteal phase (P<0.001). Inversely, the reaction to NA of the facial proximal vein, that carry blood to the peripheral circulation, was stronger in the periestrous period than in luteal phase (P<0.05). P4, E2 and T significantly lowered NA-mediated tension of the frontal proximal vein during the periestrous period (P<0.001), while in the luteal phase P4 might antagonize relaxing effect of E2 to this vessel. The result suggests that supply of the nasal venous blood into the venous cavernous sinus is greater during the periestrous period than during the luteal phase. DβH was clearly expressed in the muscular layer of the isolated superficial nasal and facial veins of gilts in both studied stages of the estrous cycle. We suggest that the reactivity of the superficial veins of the nose and face to NA combined with the previously demonstrated reactivity of these veins to steroid ovarian hormones and male steroid pheromones may regulate the access of priming pheromone androstenol (resorebed in the nasal cavity) to the brain of gilts during periestrous period via humoral local destination transfer