Gene expression analysis of glioblastomas identifies the major molecular basis for the prognostic benefit of younger age

<p>Abstract</p> <p>Background</p> <p>Glioblastomas are the most common primary brain tumour in adults. While the prognosis for patients is poor, gene expression profiling has detected signatures that can sub-classify GBMs relative to histopathology and clinical variables. One category of GBM defined by a gene expression signature is termed ProNeural (PN), and has substantially longer patient survival relative to other gene expression-based subtypes of GBMs. Age of onset is a major predictor of the length of patient survival where younger patients survive longer than older patients. The reason for this survival advantage has not been clear.</p> <p>Methods</p> <p>We collected 267 GBM CEL files and normalized them relative to other microarrays of the same Affymetrix platform. 377 probesets on U133A and U133 Plus 2.0 arrays were used in a gene voting strategy with 177 probesets of matching genes on older U95Av2 arrays. Kaplan-Meier curves and Cox proportional hazard analyses were applied in distinguishing survival differences between expression subtypes and age.</p> <p>Results</p> <p>This meta-analysis of published data in addition to new data confirms the existence of four distinct GBM expression-signatures. Further, patients with PN subtype GBMs had longer survival, as expected. However, the age of the patient at diagnosis is not predictive of survival time when controlled for the PN subtype.</p> <p>Conclusion</p> <p>The survival benefit of younger age is nullified when patients are stratified by gene expression group. Thus, the main cause of the age effect in GBMs is the more frequent occurrence of PN GBMs in younger patients relative to older patients.</p

Perfusion and diffusion MRI signatures in histologic and genetic subtypes of WHO grade II–III diffuse gliomas

The value of perfusion and diffusion-weighted MRI in differentiating histological subtypes according to the 2007 WHO glioma classification scheme (i.e. astrocytoma vs. oligodendroglioma) and genetic subtypes according to the 2016 WHO reclassification (e.g. 1p/19q co-deletion and IDH1 mutation status) in WHO grade II and III diffuse gliomas remains controversial. In the current study, we describe unique perfusion and diffusion MR signatures between histological and genetic glioma subtypes. Sixty-five patients with 2007 histological designations (astrocytomas and oligodendrogliomas), 1p/19q status (+ = intact/- = co-deleted), and IDH1 mutation status (MUT/WT) were included in this study. In all patients, median relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) were estimated within T2 hyperintense lesions. Bootstrap hypothesis testing was used to compare subpopulations of gliomas, separated by WHO grade and 2007 or 2016 glioma classification schemes. A multivariable logistic regression model was also used to differentiate between 1p19q+ and 1p19q- WHO II-III gliomas. Neither rCBV nor ADC differed significantly between histological subtypes of pure astrocytomas and pure oligodendrogliomas. ADC was significantly different between molecular subtypes (p = 0.0016), particularly between IDHWT and IDHMUT/1p19q+ (p = 0.0013). IDHMUT/1p19q+ grade III gliomas had higher median ADC; IDHWT grade III gliomas had higher rCBV with lower ADC; and IDHMUT/1p19q- had intermediate rCBV and ADC values, similar to their grade II counterparts. A multivariable logistic regression model was able to differentiate between IDHWT and IDHMUT WHO II and III gliomas with an AUC of 0.84 (p &lt; 0.0001, 74% sensitivity, 79% specificity). Within IDHMUT WHO II-III gliomas, a separate multivariable logistic regression model was able to differentiate between 1p19q+ and 1p19q- WHO II-III gliomas with an AUC of 0.80 (p = 0.0015, 64% sensitivity, 82% specificity). ADC better differentiated between genetic subtypes of gliomas according to the 2016 WHO guidelines compared to the classification scheme outlined in the 2007 WHO guidelines based on histological features of the tissue. Results suggest a combination of rCBV, ADC, T2 hyperintense volume, and presence of contrast enhancement together may aid in non-invasively identifying genetic subtypes of diffuse gliomas

Moral Cognition: Explaining the Gender Difference in Antisocial Behavior

Males’ greater propensity for antisocial (i.e., externalizing) behavior has been well documented. Because males and females generally have evidenced negligible differences in moral judgment stage, we investigated whether the gender discrepancy in antisocial behavior might be attributable to gender differences in other moral cognitive variables, specifically, moral self-relevance and self-serving cognitive distortion. The sample included 88 male and 105 female college students aged 16 to 19 years. In multiple regression analyses, moral judgment and moral self-relevance correlated negatively, and self-serving cognitive distortion correlated positively with antisocial behavior. Path analysis revealed that mature moral judgment and higher moral self-relevance were associated with lower levels of self-serving cognitive distortion, which partially mediated the relationship between those variables and antisocial behavior. Relationships among the moral cognitive variables and antisocial behavior did not vary by gender. Although the genders did not differ in moral judgment stage, females evidenced greater moral self-relevance, less self-serving cognitive distortion, and less antisocial behavior. The implications of these findings for moral developmental theory and the treatment of antisocial behavior are discussed

Gene expression analysis of glioblastomas identifies the major molecular basis for the prognostic benefit of younger age.

BackgroundGlioblastomas are the most common primary brain tumour in adults. While the prognosis for patients is poor, gene expression profiling has detected signatures that can sub-classify GBMs relative to histopathology and clinical variables. One category of GBM defined by a gene expression signature is termed ProNeural (PN), and has substantially longer patient survival relative to other gene expression-based subtypes of GBMs. Age of onset is a major predictor of the length of patient survival where younger patients survive longer than older patients. The reason for this survival advantage has not been clear.MethodsWe collected 267 GBM CEL files and normalized them relative to other microarrays of the same Affymetrix platform. 377 probesets on U133A and U133 Plus 2.0 arrays were used in a gene voting strategy with 177 probesets of matching genes on older U95Av2 arrays. Kaplan-Meier curves and Cox proportional hazard analyses were applied in distinguishing survival differences between expression subtypes and age.ResultsThis meta-analysis of published data in addition to new data confirms the existence of four distinct GBM expression-signatures. Further, patients with PN subtype GBMs had longer survival, as expected. However, the age of the patient at diagnosis is not predictive of survival time when controlled for the PN subtype.ConclusionThe survival benefit of younger age is nullified when patients are stratified by gene expression group. Thus, the main cause of the age effect in GBMs is the more frequent occurrence of PN GBMs in younger patients relative to older patients

The effects of prosocial video games on prosocial behaviours: evidence from correlational, longitudinal, and experimental studies

Abstract Although dozens of studies have documented a relation between violent video games and aggressive behaviors, very little attention has been paid to potential effects of prosocial games. Theoretically, games in which game characters help and support each other in nonviolent ways should increase both short-term and long-term prosocial behaviors. We report three studies conducted in three countries with three age groups to test this hypothesis. In the correlational study, Singaporean middle-school students who played more prosocial games behaved more prosocially. In the two longitudinal samples of Japanese children and adolescents, prosocial game play predicted later increases in prosocial behavior. In the experimental study, U.S. undergraduates randomly assigned to play prosocial games behaved more prosocially toward another student. These similar results across different methodologies, ages, and cultures provide robust evidence a prosocial game content effect, and provide support for the General Learning Model. Keywords NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript industry&apos;s several years ago, and surpassed the music industry &apos;s in 2008&apos;s in (Reuters, 2007. In a nationally representative sample of U.S. teens, 99% of boys and 94% of girls played video games Many researchers have addressed potential positive and negative effects of playing various types of video games. Most research has focused on deleterious effects of violent games (e.g., Gentile and his colleagues To date, a majority of the research has focused on game content, especially violent content. Much of this research has been guided by the General Aggression Model, from which violent game play is predicted to increase aggressive thoughts, feelings, and behaviors in the short term, and to reinforce aggressive scripts, perceptual schemata, aggressive attitudes, and aggression desensitization in the long term Prosocial behaviors can be defined at several levels If these short-term effects are practiced repeatedly, then several long-term effects could result, including changes to (1) pre-cognitive and cognitive constructs, such as perception and expectation schemata, beliefs, scripts, (2) cognitive-emotional constructs, such as attitudes and stereotypes, and (3) affective traits, such as conditioned emotional responses (e.g., equating playing violent games with &quot;fun&quot;) and affective traits like empathy or trait hostility. These potential long-term effects are shown in STUDY 1 Study 1 was a cross-sectional correlational study of video game habits and prosocial behaviors with Singaporean secondary school children. We hypothesized a positive association between amount of time spent playing prosocial video games and the amount of prosocial behavior, even when controlling for other factors related to prosocial behavior. Methods Participants-We surveyed 727 Singaporean secondary school children (N = 446 S1--7 th grade equivalent; N = 281 S2--8 th grade equivalent; mean age 13.0 years, SD = 0.79). Because two of the six participating schools were boys&apos; schools, the sample is 73% male. Seventy-five percent classified themselves as ethnic Chinese, 15% as ethnic Malay, 7% as ethnic Indian, and 3% as other ethnicities, representative of Singapore. All participants were treated in accordance with the ethical guidelines appropriate to the culture and the participating schools. Procedures-Data were collected at the schools from March -May, 2007. Average participation rate was 94% (range 91% -99%). We measured both video game habits and prosocial behaviors. The various surveys were administered in counterbalanced orders. To measure prosocial and violent game exposure, participants listed their three favorite games, estimated the number of hours per week spent playing each game, and rated how often players help others in the game, and how often players hurt or kill others in the game. Prosocial and violent content of each game were multiplied by the amount of time playing that game, and averaged across the three named games Although this is a standard approach to measuring violent video game exposure (e.g., We included several measures of prosocial behavior. Helping Behavior was assessed using a 11-item subscale from the Prosocial Orientation Questionnaire (POQ) (e.g., &quot;I would spend time and money to help those in need;&quot; Cheung, Ma &amp; Shek, 1998, α = .72). Cooperation and Sharing was measured using a 7-item subscale from the same scale (e.g., &quot;I feel happy In general, it is OK to hit other people;&quot; Huesmann, Guerra, 1997; α = .94). Hostile Attribution Bias was measured using 6 stories describing ambiguous provocative situations (e.g., someone breaks your watch). Respondents select an explanation for the event (e.g., he did it to be mean; Results and Discussion Prosocial and Aggressive Behaviors and Traits-Each prosocial behavior or trait was regressed onto prosocial game exposure after controlling for sex, age, violent game exposure, and weekly amount of time spent playing video games. As predicted, prosocial game exposure was positively related to prosocial behaviors and traits (see Aggressive Cognition-Our learning theory of game content effects suggests that prosocial game exposure might be a negative predictor of aggression-related variables as well as a positive predictor of prosocial behaviors and traits. As a test of discriminant validity, the identical hierarchical regression analyses were conducted predicting children&apos;s approval of aggression and their hostile attribution biases The results from Study 1 are consistent with the hypothesis that exposure to prosocial video games increases prosocial behavior. However, a causal interpretation based solely on these results would be inappropriate, because either variable might precede the other (or some uncontrolled third variable might be related to both). Nonetheless, the fact that the general learning model passed this opportunity for falsification is important, as is the fact that alternative (i.e., non-causal) explanations involving time and exposure to violent content were contradicted. STUDY 2 In Study 2 we more directly tested the hypothesis that habitual playing of prosocial video games would increase prosocial behavior assessed months later. In each of two separate samples, Japanese children&apos;s video game habits and prosocial behaviors were assessed twice with a three to four month time span between the two assessments. Structural equation analyses were conducted simultaneously on the two correlation matrices from these samples. We hypothesized that exposure to prosocial video games would predict subsequent prosocial behavior. Procedures-Participants completed surveys in their school classrooms. Prosocial video game exposure was assessed by asking participants to rate how frequently in the previous month they had played video games with two types of prosocial scenes [scenes in which characters help troubled persons, and scenes where friendships or affections between parent(s) and child(ren) are shown] on scales ranging from 1 (not at all) to 5 (very often). Prosocial behavior was assessed by asking participants to rate how often in the previous month they had done each of four helpful or prosocial behaviors (e.g., &quot;I helped a person who was in trouble&quot;; α = .75) using the same 5-point rating scales. Results and Discussion LISREL 8.5 was used to test competing models using maximum likelihood procedures. We began with a structural equation model in which prosocial gaming and prosocial behavior at Time 1 were correlated with each other and predicted prosocial gaming and prosocial behavior at Time 2, which also were allowed to correlate with each other. In addition, sex was included as a predictor of prosocial gaming and prosocial behavior at both time periods. When we allowed the predictive links between sex and the other four factors to differ between the two samples, the model fit very well, χ 2 (11) = 6.68, p &gt; .80, RMSEA = .00, NFI = .995 (see STUDY 3 Study 3 used an experiment designed to test the short-term causal hypothesis that playing prosocial video games would increase prosocial behavior in the immediate situation, whereas playing matched violent games would increase aggressive behavior. Neutral video games were also included in the design as a control. To increase generalizability, two games of each type were used; all were rated E (appropriate for everyone) by the Entertainment Software Ratings Board. After playing one type of video game for 20 minutes, participants completed a task where they could either help or harm another participant. Prosocial games were expected to increase helpful, prosocial behavior, whereas violent games were expected to increase unhelpful, aggressive behavior. Methods Participants-Participants were 161 college students (64 men, 95 women, 1 unidentified; mean age = 19.2 years, SD = 1.8) who received course credit in exchange for their voluntary participation. All participants were treated in accordance with the American Psychological Association&apos;s guidelines on the ethical treatment of participants. Next, participants assigned their partner 11 tangram puzzles to complete. Tangram puzzles are based on seven differently shaped pieces (e.g., small square, large triangle) used to form a specified outlined shape. Outlines that require more shapes (6 or 7 pieces) are harder and more time consuming than those requiring fewer shapes. Participants could choose from 30 puzzles: 10 easy, 10 medium, and 10 hard. Participants were told that if their partner completed at least 10 of the 11 puzzles within 10 minutes, the partner would win a $10 gift certificate. Participants could help their partner by assigning easy puzzles, or hurt their partner by assigning difficult puzzles. Participants were encouraged to select from multiple difficulty levels. Because they had to choose 11 puzzles, and there were only 10 of each difficulty level, participants necessarily had to use at least 2 of the difficulty levels. Participants then completed a video game evaluation questionnaire Participants also completed the 29-item Buss-Perry Aggression Questionnaire (Buss &amp; Perry, 1992) as a measure of trait aggressiveness. Participants indicated agreement with statements (e.g., &quot;If somebody hits me, I hit back&quot;) using a five-point scale (1= &quot;Extremely uncharacteristic of me&quot;, 5= &quot;Extremely characteristic of me&quot;), alpha = 0.92. Finally, participants were probed for suspicion (with multiple open-ended questions to see if participants realized that the video game and the tangram task were related), thanked, and dismissed. Nine participants expressed some suspicion about the study, but the results were NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript the same regardless of whether we kept or deleted these nine participants, so we kept their data. Results and Discussion Helping and Hurting Scores-Participants chose the tangrams mostly from the medium category (M medium = 4.30), followed by the easy category (M easy = 3.85), followed by the hard category (M hard = 2.85). &quot;Helping&quot; was defined as the number of &quot;easy&quot; puzzles chosen by participants for their partners. &quot;Hurting&quot; was defined as the number of &quot;hard&quot; puzzles chosen. Of course, once one knows the helping and hurting scores of any participant, one also knows the number of medium difficulty choices. Thus, the number of medium difficulty choices is wholly redundant, and therefore was not analyzed. 1 Preliminary Analyses-Preliminary analyses revealed no significant effects of participant sex or of the &quot;fun&quot; covariate on helping and hurting behavior, so they were dropped from final analyses. The game &quot;difficulty&quot; covariate yielded one marginally significant effect, so it was kept in the main analyses of puzzle choice behavior. 2 Main Analyses-A 3 (game type: prosocial, neutral, or violent) x 2 (behavior type: helping or hurting) analysis of covariance was conducted with game difficulty and trait aggression as covariates. 3 There was a main effect of behavior type, F(1, 155) = 9.47, p &lt; . 005, d = .49. As we&apos;ve already seen, participants chose more easy than difficult puzzles (Ms = 3.92 &amp; 2.79). More importantly, the game type by behavior type interaction was significant, F(2, 155) = 5.26, p &lt; .01 (see 3 Preliminary analyses demonstrated that trait aggression was marginally significant when predicting helping behavior, whereas trait prosocial behavior was not significantly related to helping or hurting behavior (lowest p = .48). The results did not change regardless of whether both or neither were included in the analyses. 4 The trait aggression x behavior type interaction approached statistical significance, F(1, 155) = 3.23, p &lt; .10. Trait aggression was negatively related to helping, b = -0.46, p &lt; .08, r = .14, and slightly positively related to hurting, b = 0.38, p &lt; .25, r = .13. predicting helping and hurting behavior towards their partner. It is interesting to note that across the six games, these two types of content were essentially uncorrelated with each other (r = -.07). In other words, across these six games the amount of prosocial and violent content were largely orthogonal. A 2 (game content: prosocial or violent) x 2 (behavior type: helping or hurting) analysis of covariance was conducted with game difficulty and trait aggression as covariates. By including both types of game content simultaneously in the regression model, we tested for the unique effect of each content dimension while controlling for the other. Preliminary analyses yielded no hint of a 2-way game content interaction, so that term was dropped. There was a significant behavior type by violent content interaction, and a marginally significant behavior type by prosocial content interaction, Fs GENERAL DISCUSSION As we have discussed elsewhere The present studies satisfy all of these criteria. The experimental study using U.S. university undergraduates demonstrated a short-term causal impact of playing prosocial games on helpful behavior (and of playing violent games on hurtful behavior). Short-term experiments like this are especially important for at least two reasons: (a) they provide a strong case for causality; (b) they reveal underlying processes likely to influence long-term effects. The correlational study using Singaporean junior high schoolers demonstrated the predicted associations among video game habits and &quot;real world&quot; prosocial and antisocial behaviors and traits. Such correlational studies are important because: (a) they provide an opportunity for a theoretical model to fail; (b) they allow tests of the predicted association with longterm consequential behavioral patterns and traits; and (c) they allow tests of some plausible alternative explanations. The longitudinal study using Japanese children and adolescents demonstrated effects of earlier prosocial game play habits on later prosocial behavior. Such studies allow strong causal inferences, primarily by ruling out many alternative explanations that rely on individual differences in trait aggressiveness and in interests that exist at the first assessment time period; they also allow testing of the theoretical model with consequential real-world outcome measures. The bi-directionality of the present longitudinal results also demonstrates that the often-asked chicken and egg question is overly simplistic. These data suggest that playing prosocial games tends to increase prosocial behavior tendencies, and that prosocial tendencies tend to lead to selection of prosocial games. This clearly has implications for the parallel argument about violent media and aggression Overall, these results provide support for both the short-term and long-term predictions of the General Learning Model. Specifically, in the short-term players&apos; behaviors were predicted by the prosocial and violent content of the games they played. In the long-term, players with high prosocial game exposure had higher prosocial traits and behaviors. Study 1 also provides additional information about the relations between prosocial and aggressive effects of prosocial and violent games. As noted earlier, prosocial and aggressive behavior are not simply opposite behaviors. The cross-sectional correlations between violent game play and prosocial behaviors and traits were not always significant. Prosocial game play was significantly positively related to all four measured prosocial behaviors and traits (and negatively related to aggressive cognition), whereas violent game play was significantly negatively related to helping behavior and empathy (and was positively related to aggressive cognition). We do not know from the results of this one study why violent game play was not significantly related to sharing and cooperation or emotional awareness, but it does suggest that game content is most likely to have specific rather than broad effects. One possible reason is that some violent games require cooperation and others do not. We further speculate that violent game play can be related to empathy but not to emotional awareness because many violent games require the player to see others&apos; emotions (e.g., begging for mercy), but to then ignore them. Thus, players can be aware of others&apos; (and their own) emotions without showing empathy. Future research is needed to test these speculations

The effects of prosocial video games on prosocial behaviors: International evidence from correlational, longitudinal, and experimental studies

Although dozens of studies have documented a relationship between violent video games and aggressive behaviors, very little attention has been paid to potential effects of prosocial games. Theoretically, games in which game characters help and support each other in nonviolent ways should increase both short-term and long-term prosocial behaviors. We report three studies conducted in three countries with three age groups to test this hypothesis. In the correlational study, Singaporean middle-school students who played more prosocial games behaved more prosocially. In the two longitudinal samples of Japanese children and adolescents, prosocial game play predicted later increases in prosocial behavior. In the experimental study, U.S. undergraduates randomly assigned to play prosocial games behaved more prosocially toward another student. These similar results across different methodologies, ages, and cultures provide robust evidence of a prosocial game content effect, and they provide support for the General Learning Model. © 2009 by the Society for Personality and Social Psychology, Inc