Heme catabolism by tumor-associated macrophages controls metastasis formation.

Although the pathological significance of tumor-associated macrophage (TAM) heterogeneity is still poorly understood, TAM reprogramming is viewed as a promising anticancer therapy. Here we show that a distinct subset of TAMs (F4/80hiCD115hiC3aRhiCD88hi), endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1), plays a critical role in shaping a prometastatic tumor microenvironment favoring immunosuppression, angiogenesis and epithelial-to-mesenchymal transition. This population originates from F4/80+HO-1+ bone marrow (BM) precursors, accumulates in the blood of tumor bearers and preferentially localizes at the invasive margin through a mechanism dependent on the activation of Nrf2 and coordinated by the NF-κB1-CSF1R-C3aR axis. Inhibition of F4/80+HO-1+ TAM recruitment or myeloid-specific deletion of HO-1 blocks metastasis formation and improves anticancer immunotherapy. Relative expression of HO-1 in peripheral monocyte subsets, as well as in tumor lesions, discriminates survival among metastatic melanoma patients. Overall, these results identify a distinct cancer-induced HO-1+ myeloid subgroup as a new antimetastatic target and prognostic blood marker.

The categorical use of a continuous time representation.

The abstract concept of time is mentally represented as a spatially oriented line, with the past associated with the left space and the future associated with the right. Although the line is supposed to be continuous, most available evidence is also consistent with a categorical representation that only discriminates between past and future. The aim of the present study was to test the continuous or categorical nature of the mental timeline. Italian participants judged the temporal reference of 20 temporal expressions by pressing keys on either the left or the right. In Experiment 1 (N = 32), all words were presented at the center of the screen. In Experiment 2 (N = 32), each word was presented on the screen in a central, left, or right position. In Experiment 3 (N = 32), all text was mirror-reversed. In all experiments, participants were asked to place the 20 temporal expressions on a 10-cm line. The results showed a clear Spatial-TEmporal Association of Response Codes (STEARC) effect which did not vary in strength depending on the location of the temporal expressions on the line. However, there was also a clear Distance effect: latencies were slower for words that were closer to the present than further away. We conclude that the mental timeline is a continuous representation that can be used in a categorical way when an explicit past vs. future discrimination is required by the task.

Multilevel Hidden Markov Models for Behavioral Data: A Hawk-and-Dove Experiment.

Motivated by the analysis of behavioral data taken from an economic experiment based on the Hawk-and-Dove game, this article describes a multilevel hidden Markov model, that includes covariates, autoregression, and endogenous initial conditions under a unified framework. The data at hand are affected by multiple sources of latent heterogeneity, due to multilevel unobserved factors that operate in conjunction with observed covariates at all the levels of the data hierarchy. We fit a multilevel logistic regression model for repeated measurements of player behaviors, nested within groups of interacting players. The model integrates discrete random effects at the group level and Markovian sequences of discrete random effects at the player level. Parameters are estimated by a computationally feasible expectation-maximization algorithm. We model the probability of playing the Hawk strategy, which implies fighting aggressively for controlling an asset, and test the role played by initial possession, property, and other player-specific characteristics in driving hawkish behaviors. The results from our study suggest that crucial factors in determining hawkish behavior are both the way possession is achieved - which depends on our treatment manipulation- and possession itself. Furthermore, a clear time-dependence is observed in the data at the player level as accounted for by the Markovian random effects.

Is Cadmium Toxicity Tissue-Specific? Toxicogenomics Studies Reveal Common and Specific Pathways in Pulmonary, Hepatic, and Neuronal Cell Models.

Several harmful modifications in different tissues-organs, leading to relevant diseases (e.g., liver and lung diseases, neurodegeneration) are reported after exposure to cadmium (Cd), a wide environmental contaminant. This arises the question whether any common molecular signatures and/or Cd-induced modifications might represent the building block in initiating or contributing to address the cells towards different pathological conditions. To unravel possible mechanisms of Cd tissue-specificity, we have analyzed transcriptomics data from cell models representative of three major Cd targets: pulmonary (A549), hepatic (HepG2), and neuronal (SH-SY-5Y) cells. Further, we compared common features to identify any non-specific molecular signatures. The functional analysis of dysregulated genes (gene ontology and KEGG) shows GO terms related to metabolic processes significantly enriched only in HepG2 cells. GO terms in common in the three cell models are related to metal ions stress response and detoxification processes. Results from KEGG analysis show that only one specific pathway is dysregulated in a significant way in all cell models: the mineral absorption pathway. Our data clearly indicate how the molecular mimicry of Cd and its ability to cause a general metal ions dyshomeostasis represent the initial common feature leading to different molecular signatures and alterations, possibly responsible for different pathological conditions.

A three-gene signature based on MYC, BCL-2 and NFKBIA improves risk stratification in diffuse large B-cell lymphoma.

Recent randomized trials focused on gene expression-based determination of the cell of origin in diffuse large B-cell lymphoma could not show significant improvements by adding novel agents to standard chemoimmunotherapy. The aim of this study was the identification of a gene signature able to refine current prognostication algorithms and applicable to clinical practice. Here we used a targeted gene expression profiling panel combining the Lymph2Cx signature for cell of origin classification with additional targets including MYC, BCL-2 and NFKBIA, in 186 patients from 2 randomized trials (discovery cohort) (NCT00355199 and NCT00499018). Data were validated in 3 independent series (2 large public datasets and a real-life cohort). By integrating the cell of origin, MYC/BCL-2 double expressor status and NFKBIA expression, we defined a 3-gene signature combining MYC, BCL-2 and NFKBIA (MBN-signature), which outperformed the MYC/BCL-2 double expressor status in multivariate analysis, and allowed further risk stratification within the germinal center B-cell/unclassified subset. The high-risk (MBN Sig-high) subgroup identified the vast majority of double hit cases and a significant fraction of Activated B-Cell-derived diffuse large B-cell lymphomas. These results were validated in 3 independent series including a cohort from the REMoDL-B trial, where, in an exploratory ad hoc analysis, the addition of bortezomib in the MBN Sig-high subgroup provided a progression free survival advantage compared with standard chemoimmunotherapy. These data indicate that a simple 3-gene signature based on MYC, BCL-2 and NFKBIA could refine the prognostic stratification in diffuse large B-cell lymphoma, and might be the basis for future precision-therapy approaches.

In vitro human cord blood platelet lysate characterisation with potential application in wound healing.

Platelets contain abundant growth factors and cytokines that have a positive influence on the migration and proliferation of different cell types by modulating its physiopathological processes. As it is known that human umbilical cord blood platelet lysate (UCB-PL) contains a supraphysiological concentration of growth factors, in the present study, we investigated its effectiveness in wound-healing processes. Human UCB-PL was obtained by the freeze/thaw of platelet concentrate (1.1 × 109 platelets/L), and its effect was evaluated on human or mouse endothelial cells, monocytes, fibroblasts, and keratinocytes in different concentrations. Human UCB-PL was observed to have high levels of pro-angiogenic growth factor than peripheral blood platelet-rich plasma. Among the cell lines, different concentrations of human UCB-PL were necessary to influence their viability and proliferation. For L929 cells, 5% of total volume was necessary, while for human umbilical vein endothelial cell, it was 10%. Cell migration on monocytes was increased with respect to the positive control, and scratch closure on keratinocytes was increased with respect to serum-free medium with only 10% of human UCB-PL. We concluded that the human UCB-PL may be useful to produce a large amount of standard platelet concentrates sufficient for several clinical-scale expansions avoiding inter-individual variability, which can also be used as a functional tool for clinical regenerative application for wound healing.

Theory of mind and joint action in Parkinson's disease.

It has been suggested that the Theory of Mind (ToM) may rely on more basic processes of social cognition, such as action control (e.g., joint action), even if little is known about this relationship. The relationship between ToM and joint action can be studied in patients with Parkinson's disease (PD), because they are characterized not only by a deficit in ToM (and in its cognitive and affective subcomponents) but also by a deficit in the inhibition of competing responses. Sixty PD patients and 60 matched healthy controls (HCs) performed a go/no-go Flanker task in both joint and individual conditions. Cognitive (Advanced Test or AT) and affective (Emotion Attribution Task or EAT) ToM also were measured. Thirty-five PD patients and matched HCs also performed the standard Flanker task, as a control measure. In patients, only individuals with high AT scores exhibited a joint Flanker effect, whereas in HCs the joint effect was found irrespectively of AT score. Patients with low EAT scores showed a greater interference effect than patients with high scores, whereas the opposite pattern was found for HCs. In regression analysis AT and EAT scores predicted the Flanker effect in the joint condition only. In the standard task, both groups showed a Flanker effect. The role of different fronto-striatal circuits, especially in PD patients, could explain the different involvement of cognitive and affective ToM in joint tasks. The Flanker effect is discussed considering the referential coding account and the attention-focus account as possible candidates to explain joint action effects.

Influence of time-of-day on joint Navon effect.

The shared attention theory suggests that people devote greater cognitive resources to those features co-attended simultaneously with others, determining better performance in several types of tasks. When co-actors performed a go/no-go Navon task attending different features of target letters, the performance was impaired, reflecting a joint Navon effect (the representation of a co-actor's attentional focus made it more difficult to select and apply one's own focus of attention), probably due to asynchronous co-attention with a decrease in cognitive resources involved. Researches in chronobiology and chronopsychology demonstrated that not only selective attention (involved in a Navon task), but also cognitive resources have a daily fluctuations, mainly paralleling the circadian rhythm of body temperature (i.e. increasing values from the morning to evening with a subsequent decline in the night). The study was conducted to assess whether the presence of joint attention, as measured by the joint Navon effect, was influenced by the time-of-day. Sixteen pairs of participants sitting next to each other were required to respond to the identity letters in a go/no-go Navon task twice: in the morning (09:00-10:00) and early afternoon (13:00-14:00). The results showed a joint Navon effect in the morning session only, suggesting that joint attention was affected by the time-of-day effect on cognitive resources.

Synchrony effect on joint attention.

Research on joint attention has demonstrated that individuals are sensitive to a coactor's attentional relation to jointly attended stimuli. Within a chronobiological approach, a study was conducted to assess whether the presence of joint attention, as measured by the joint Navon effect, was influenced by the synchrony effect. Pairs of participants sitting next to each other were required to respond to the identity letters in a go/no-go Navon task. The joint Navon task was performed by morning, intermediate and evening types (81 pairs) at different times of day (09:00-10:00; 13:00-14:00; 17:00-18:00). The joint Navon effect on task performance was highlighted at the optimal time of day (in the morning for morning types, in the early afternoon for intermediate types and in the evening for evening types), but it disappeared or decreased at the non-optimal time of day, with the exception of evening types. The results demonstrated that joint attention was affected by the synchrony effect.

Finger counting habit and spatial-numerical association in children and adults.

Sensory-motor experiences are known to build up concrete and abstract concepts during the lifespan. The present study aimed to test how finger counting habits (right-hand vs. left-hand starters) could influence the spatial-numerical representation in number-to-position (explicit) and digit-string bisection (implicit) tasks. The subjects were Italian primary school children (N=184, from the first to the fifth year) and adults (N=42). No general preference for right- or left-starting in the finger counting was found. In the explicit task, right- or left-starting did not affect performance. In the implicit task, the right-hand starters shifted from the left to the right space when bisecting small and large numbers respectively, while the left-hand starters shifted from the right to the left space with higher leftward bias for large numbers. The finger configuration in Italian children and adults influences the spatial-numerical representation, but only when implicit number processing is required by the task.

Loss of function of Ribonuclease T2, an ancient and phylogenetically conserved RNase, plays a crucial role in ovarian tumorigenesis.

In recent years, the role played by the stromal microenvironment has been given growing attention in order to achieve a full understanding of cancer initiation and progression. Because cancer is a tissue-based disease, the integrity of tissue architecture is a major constraint toward cancer growth. Indeed, a large contribution of the natural resistance to cancer stems from stromal microenvironment components, the dysregulation of which can facilitate cancer occurrence. For instance, recent experimental evidence has highlighted the involvement of stromal cells in ovarian carcinogenesis, as epitomized by ovarian xenografts obtained by a double KO of the murine Dicer and Pten genes. Likewise, we reported the role of an ancient extracellular RNase, called Ribonuclease T2 (RNASET2), within the ovarian stromal microenvironment. Indeed, hyperexpression of RNASET2 is able to control tumorigenesis by recruiting macrophages (mostly of the anticancer M1 subtype) at the tumor sites. We present biological data obtained by RNASET2 silencing in the poorly tumorigenetic and highly RNASET2-expressing human OVCAR3 cell line. RNASET2 knockdown was shown to stimulate in vivo tumor growth early after microinjection of OVCAR3 cells in nude mice. Moreover, we have investigated by molecular profiling the in vivo expression signature of human and mouse cell xenografts and disclosed the activation of pathways related to activation of the innate immune response and modulation of ECM components. Finally, we provide evidence for a role of RNASET2 in triggering an in vitro chemotactic response in macrophages. These results further highlight the critical role played by the microenvironment in RNASET2-mediated ovarian tumor suppression, which could eventually contribute to better clarify the pathogenesis of this disease.

24-h actigraphic monitoring of motor activity, sleeping and eating behaviors in underweight, normal weight, overweight and obese children.

PURPOSE: Within a chronobiological perspective, the present study aimed to describe 24 h of sleep-wake cycle, motor activity, and food intake patterns in different body mass index (BMI) categories of children through 7 days of actigraphic recording. METHODS: Height and weight were objectively measured for BMI calculation in a sample of 115 Italian primary schoolchildren (10.21 ± 0.48 years, 62.61 % females). According to BMI values, 2.60 % were underweight, 61.70 % were of normal weight, 29.60 % were overweight and 6.10 % were obese. Participants wore a wrist actigraph continuously for 7 days to record motor activity and describe sleep-wake patterns. In addition, participants were requested to push the event-marker button of the actigraph each time they consumed food to describe their circadian eating patterns. RESULTS: BMI group differences were found for sleep quantity (i.e. midpoint of sleep and amplitude), while sleep quality, 24-h motor activity and food intake patterns were similar between groups. Regression analyses showed that BMI was negatively predicted by sleep duration on schooldays. BMI was also predicted by motor activity and by food intake frequencies recorded at particular times of day during schooldays and at the weekend. CONCLUSIONS: The circadian perspective seems to provide promising insight into childhood obesity, but this aspect needs to be further explored.

Circadian typology and the Alternative Five-Factor Model of personality.

Two studies were carried out to explore the relationship between circadian typology and the Alternative Five-Factor Model of personality. In the first study, 379 participants (232 females) were administered the reduced version of the Morningness-Eveningness Questionnaire and the Zuckerman-Kuhlman Personality Questionnaire. Evening types reported higher impulsive sensation-seeking scores than morning and intermediate types, whereas morning types scored higher than evening types on activity factor. In the second study, the association between morningness and activity personality factor was verified through the objective-actigraphic monitoring of the rest-activity cycle. Actigraphy allowed us to operationalise both circadian typology, through the computing of midpoint of sleep (early values, expressed in hours and minutes, correspond to an advanced phase of the sleep/wake cycle), and activity factor by the means of motor activity recording. Fifty-one individuals (30 females) wore an actigraph on the nondominant wrist continuously for 1 week. A negative correlation was observed between midpoint of sleep and mean diurnal motor activity, demonstrating that an early phase of the sleep/wake cycle (i.e. morningness preference) was related to higher diurnal motor activity. Assessed both subjectively and objectively, the results of both studies highlight a significant relationship between morningness and activity personality factor.

Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages: similarities and differences.

The molecular repertoire of macrophages in health and disease can provide novel biomarkers for diagnosis, prognosis, and treatment. Th2-IL-4­activated macrophages (M2) have been associated with important diseases in mice, yet no specific markers are available for their detection in human tissues. Although mouse models are widely used for macrophage research, translation to the human can be problematic and the human macrophage system remains poorly described. In the present study, we analyzed and compared the transcriptome and proteome of human and murine macrophages under resting conditions (M0) and after IL-4 activation (M2). We provide a resource for tools enabling macrophage detection in human tissues by identifying a set of 87 macrophage-related genes. Furthermore, we extend current understanding of M2 activation in different species and identify Transglutaminase 2 as a conserved M2 marker that is highly expressed by human macrophages and monocytes in the prototypic Th2 pathology asthma.

The consensus sleep diary: quantitative criteria for primary insomnia diagnosis.

OBJECTIVE: The aim of the study was to put forward quantitative criteria for the Consensus Sleep Diary, to differentiate people with insomnia from normal sleepers. METHODS: In this retrospective study, we analyzed 295 sleep diaries of patients with primary insomnia (43% were male, ages ranging between 17 and 76 years) collected in two clinical centers for insomnia and 536 sleep diaries of normal sleepers (47% were male, ages ranging between 15 and 82 years). We considered the following sleep parameters: time in bed, sleep onset latency, total sleep time, wake after sleep onset, sleep efficiency, number of awakenings, terminal wakefulness, and subjective feeling of rest. Using the Youden index, we calculated the quantitative criteria that performed best for each sleep parameter. Finally, we created receiver operating characteristic curves to test the accuracy of each identified criterion. RESULTS: Individuals with insomnia significantly differed from controls on all sleep indices (p < .001). Differentiation between individuals with insomnia from controls was optimal for terminal wakefulness (>15 minutes, area under the curve [AUC] = 0.83), wake after sleep onset (cutoff >20 minutes, AUC = 0.81), total sleep time (<390 minutes, AUC = 0.80), and particularly sleep efficiency (<87.5%, AUC = 0.92, sensitivity = 0.80, specificity = 0.90). Time in bed was the least differentiating variable (<500 minutes, AUC = 0.57). CONCLUSIONS: The quantitative criteria of the sleep diary in this study agree with the few available data in the literature. This confirms that the sleep diary could be a useful screening tool for assessing patients with primary insomnia.

Effects of dawn simulation on attentional performance in adolescents.

PURPOSE: This study aimed at examining the effects of 2 weeks of dawn simulation on attentional performance in adolescents. METHODS: On the whole, 56 adolescents (24 females and 32 males) took part to the study, with a mean age of 17.68 ± 0.97 years (age ranging between 15 and 20 years). Each adolescent was requested to participate for 5 consecutive weeks and the research design included the baseline and two counterbalanced conditions, dawn simulator and control (no dawn simulator). Attentional performance of adolescents was measured through the attention network test (ANT) that allowed assessing the efficiency of three separable attentional networks, namely alerting, orienting and executive. Overall, participants performed the ANT three times (i.e., one time for each condition), while sleep quality, sleep duration and sleep timing were concurrently monitored by means of actigraphy and were treated as potential confounders. RESULTS: The only improvement of the attentional performance attributable to the use of dawn simulator was observed for the efficiency of alerting network (45.97 ± 32.76 ms) that significantly increased in comparison to the baseline (31.57 ± 26.97 ms) (p < 0.05). On the contrary, the sleep quality, sleep quantity and sleep timing did not significantly change. CONCLUSION: These results show for the first time that, controlling for sleep quality, sleep duration and sleep timing, the use of dawn simulator across 2 weeks is able to determine an alerting effect in adolescents.

Remember to do: insomnia versus control groups in a prospective memory task.

Primary insomnia is characterized by difficulty in falling asleep and/or remaining asleep, by early morning awakening and/or nonrestorative sleep, and resultant daytime dysfunction in the absence of specific physical, mental, or substance-related causes. However, the studies on daytime cognitive functioning of insomnia patients report inconclusive results. This retrospective study aimed to compare the performance of insomnia patients (N = 54) to that of controls (N = 113) in a naturalistic prospective memory task. Task performance was defined by the percentage of times the event-marker button of an actigraph was pressed, at lights-off time and at wake-up time. The performance pattern in the prospective memory task was similar in both groups. In addition, the task was performed better at lights-off time than at wake-up time regardless of group. Post-hoc subgroup analysis showed that there were more insomnia patients who performed the task perfectly (i.e., 100%) than controls. Performance at wake-up time was significantly correlated to objective sleep quality (i.e., sleep efficiency) only in insomnia patients.

Microenvironmental control of malignancy exerted by RNASET2, a widely conserved extracellular RNase.

A recent body of evidence indicates an active role for stromal (mis)-regulation in the progression of neoplasias. Within this conceptual framework, genes belonging to the growing but still poorly characterized class of tumor antagonizing/malignancy suppressor genes (TAG/MSG) seem to play a crucial role in the regulation of the cross-talk between stromal and epithelial cells by controlling malignant growth in vivo without affecting any cancer-related phenotype in vitro. Here, we have functionally characterized the human RNASET2 gene, which encodes the first human member of the widespread Rh/T2/S family of extracellular RNases and was recently found to be down-regulated at the transcript level in several primary ovarian tumors or cell lines and in melanoma cell lines. Although we could not detect any activity for RNASET2 in several functional in vitro assays, a remarkable control of ovarian tumorigenesis could be detected in vivo. Moreover, the control of ovarian tumorigenesis mediated by this unique tumor suppressor gene occurs through modification of the cellular microenvironment and the induction of immunocompetent cells of the monocyte/macrophage lineage. Taken together, the data presented in this work strongly indicate RNASET2 as a previously unexplored member of the growing family of tumor-antagonizing genes.