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Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.

Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.

BackgroundMalignant pleural effusions (MPE) are a frequent cause of dyspnea and discomfort at the end of cancer patients' lives. The tunneled indwelling pleural catheter (TIPC) was approved by the FDA in 1997 and has been investigated as a treatment for MPE.ObjectiveTo systematically review published data on the efficacy and safety of the TIPC for treatment of MPE.DesignWe searched the MEDLINE, EMBASE, and ISI Web of Science databases to identify studies published through October 2009 that reported outcomes in adult patients with MPE treated with a TIPC. Data were aggregated using summary statistics when outcomes were described in the same way among multiple primary studies.Main measuresSymptomatic improvement and complications associated with use of the TIPC.Key resultsNineteen studies with a total of 1,370 patients met criteria for inclusion in the review. Only one randomized study directly compared the TIPC with the current gold standard treatment, pleurodesis. All other studies were case series. Symptomatic improvement was reported in 628/657 patients (95.6%). Quality of life measurements were infrequently reported. Spontaneous pleurodesis occurred in 430/943 patients (45.6%). Serious complications were rare and included empyema in 33/1168 patients (2.8%), pneumothorax requiring a chest tube in 3/51 (5.9%), and unspecified pneumothorax in 17/439 (3.9%). Minor complications included cellulitis in 32/935 (3.4%), obstruction/clogging in 33/895 (3.7%) and unspecified malfunction of the catheter in 11/121 (9.1%). The use of the TIPC was without complication in 517/591 patients (87.5%).ConclusionsBased on low-quality evidence in the form of case series, the TIPC may improve symptoms for patients with MPE and does not appear to be associated with major complications. Prospective randomized studies comparing the TIPC to pleurodesis are needed before the TIPC can be definitively recommended as a first-line treatment of MPE.

The purpose of this research was to examine the effects of instruction on students' generation of questions when reading multiple documents. Participants were 151 undergraduate students who were randomly assigned to one of two conditions: a treatment condition that received question generation instruction and a control condition that did not receive question generation instruction. All participants read four primary-source documents and were asked to generate up to 10 questions based on those documents. Results indicate that students generated significantly fewer higher-order integration questions without instructional support. These results are replicated with an alternative document set to demonstrate that the effects found were not due to the specific historical topic.

Background: We tested the effects of an intervention on the learning of introductory thermodynamics principles. This intervention, OEM-Thermo, is designed to prompt the cognitive operations of meaningful learning: organization, elaboration, and monitoring. We also sought evidence to show that execution of these operations was associated with learning gains and that cognitive operations are influenced by different intervention exercises. Purpose/Hypothesis: Study 1: Students who complete OEM-Thermo will gain more conceptual knowledge than students who complete traditional problems. Study 2: First, elaboration and monitoring contribute to learning with OEM-Thermo. Second, students engage in elaboration and monitoring at a higher rate when answering elaboration questions than when completing matrix exercises. Design/Method: Study 1: A two-group, pre- and post-test experimental design tested OEM-Thermo effectiveness. Study 2: A one-group, pre- and post-test design where participants thought aloud while completing OEM-Thermo tested deep and surface reasoning as well as the frequency of elaboration and monitoring events. Results: Study 1: A significant interaction between test time (pre- and post-test) and condition shows that OEM-Thermo promoted development of conceptual reasoning more effectively than did traditional homework problems. Study 2: Significant partial correlations were found between post-test scores on one of two deep reasoning categories and the frequency of elaboration and monitoring events in the think-aloud protocols. Differences were also found in the rate of elaboration across intervention exercises. Conclusions: An intervention that includes tasks designed to stimulate the cognitive operations of meaningful learning improves students' conceptual reasoning.

DSM-IV-TR defines four subtypes of bipolar disorder (BP): bipolar I, bipolar II, cyclothymic disorder and bipolar not otherwise specified (NOS). However, cyclothymic disorder in children is rarely researched, or often subsumed in an "NOS" category. The present study tests the replicability of findings from an earlier study, and expands on the criterion validity of cyclothymic disorder in youth. Using the Robins and Guze (1970) framework we examined the validity of cyclothymic disorder as a subtype of BP. Using a youth (ages 5-17) outpatient clinical sample (N = 894), participants with cyclothymic disorder (n = 53) were compared to participants with other BP spectrum disorders (n = 399) and to participants with non-bipolar disorders (n = 442). Analyses tested differences in youth with cyclothymic disorder and bipolar disorder not otherwise specified who do, and those who do not, have a parent with BP. Compared to youth with non-bipolar disorders, youth with cyclothymic disorder had higher irritability (p less than 0.001), more comorbidity (p less than 0.001), greater sleep disturbance (p less than 0.005), and were more likely to have a family history of BP (p less than 0.001). Cyclothymic disorder was associated with a younger age of onset compared to depression (p less than 0.001) and bipolar II (p = 0.05). Parental BP status was not significantly associated with any variables. Results support that cyclothymic disorder belongs on the bipolar spectrum. Epidemiological studies indicate that cyclothymic disorder is not uncommon and involves significant impairment. Failing to differentiate between cyclothymic disorder and bipolar NOS limits our knowledge about a significant proportion of cases of bipolarity.

This study examined the effect of different anatomic representations on student learning in a human anatomy class studying the muscular system. Specifically, we examined the efficacy of using dissected cats (with and without handouts) compared with clay sculpting of human structures. Ten undergraduate laboratory sections were assigned to three treatment groups: cat dissection only, cat dissection with handouts, and human clay sculpting with handouts. Exams included higher-order questions that presented novel anatomic images and scenarios that the students did not practice in class. The higher-order anatomy exam questions varied the degree to which students in the different treatments had to transform the anatomic representation studied during laboratory activities to match the representation used in the exam questions. In this respect, exam questions manipulated the similarity between the surface features of the anatomic representations used in the classroom versus the exam. When identifying anatomic structures presented in a photograph or diagram, student performance improved significantly when transformation demands decreased, i.e., students in the human clay sculpting treatment group performed best on human anatomy questions and students in the cat dissection treatment group performed better on cat anatomy questions (independent of the use of handouts). There were similar, but nonsignificant, trends when students were asked functional anatomy questions presented in human and cat contexts. On survey questions designed to measure student attitudes about dissection versus nonanimal alternatives, students typically preferred the method used in their treatment group, suggesting that student preference is too fluid to factor into curricular decisions. When designing curricula, instructors must choose anatomic representations that support their course goals. Human representations are most effective when teaching the human muscular system. (Contains 4 tables, 1 footnote and 4 figures.)

The importance of emergent literacy skills as a foundation for proficient reading has led to the development of interventions to teach these skills. These interventions are particularly important for children from disadvantaged homes because they often lack the home literacy experiences necessary for building foundational literacy skills prior to school entry. While previous interventions have been successful in developing literacy skills, noticeably absent has been instruction to develop comprehension. In this study, teachers explicitly taught the narrative structure to kindergarten and first grade children in high poverty schools to increase their comprehension of children's literature. Instruction was delivered as children listened to stories during daily story time. The findings indicate that children who learned story structures recalled more ideas from new stories and answered more questions about structural elements of those stories (e.g., who is the main character?). The results suggest that teachers can deliver effective comprehension instruction to emergent and beginning readers in the context of listening comprehension activities. (Contains 6 tables.)

The goal of this project was to develop and test the efficacy of a research-based early reading program that provided integrated reading instruction in kindergarten through 2nd grade. The Reading and Integrated Literacy Strategies (RAILS) program provided integrated instruction in word reading, vocabulary development, and comprehension to students in regular and self-contained special education classes in 2 schools serving low-income populations. Teachers provided explicit instruction in the alphabetic principle, phonemic analysis, word reading, vocabulary development, listening comprehension, and reading comprehension. Classes were organized so students received 2 periods of reading instruction daily, a longer morning period of instruction and a shorter afternoon review of instruction. The students in the RAILS program had significantly higher performance on standardized reading and language achievement tests, as well as on individually administered tests of phonemic awareness and reading fluency. The implications for research-based instructional practice that integrates instruction in word reading, vocabulary, and comprehension are discussed. (Contains 5 tables.)

A language-levels model was used to analyze written narratives. The results have implications for instruction and for documenting change in the story-writing performance of students with and without special needs in the area of written language development. This study was based on stories written at midyear by 277 students (224 typical learners and 53 children with special difficulty in the area of written language) across grade levels one through five. Measures that differentiated students by grade level and special difficulty are reported by language level. Discourse-level measures were total words, total T-units, and story scores. Sentence-level measures were sentence codes (simple or complex, correct or incorrect), mean length of T-unit, and number and types of conjunctions. Word-level measures were number of different words and proportions of words spelled correctly. Gender differences were found for productivity measures in favor of females; no differences were found when comparing stories written by African American and Caucasian students. (Contains 5 tables.)

Purpose: This article reviews the construct of alexithymia and its relationship to language impairment. Method: The article includes a review of the literature on emotional competence, trauma effects, alexithymia, and language impairment; summarizes tools to assess alexithymia; and provides an intervention framework. Implications: Understanding the relationship of emotional competence and language impairment may provide a new perspective for speech-language pathologists who are serving children with language and socioemotional impairments.

Learner-generated drawing is a strategy that can improve learning from expository text. In this paper, a model of drawing construction is proposed and the experimental design tests hypotheses derived from this model. Fourth and sixth grade participants used drawing under three experimental conditions with two conditions including varying degrees of support. On a problem solving posttest, both supported drawing groups scored higher than the non-drawing Control group. Although the grade by condition interaction was not significant, there was a strong trend in this direction. When sixth grade participants were considered independently, participants in the most supported drawing condition also obtained higher problem solving scores than those who drew without support. There were no significant condition effects for fourth grade nor were there any significant effects on a multiple-choice recognition posttest. Results were consistent with hypotheses and are discussed in light of the proposed theoretical framework.

This article describes how partnerships among general and special education teachers and speech-language pathologists operate within a writing lab approach to enhance curriculum-based language instruction and intervention for students with and without disabilities. Areas discussed include (a) gaining invitations into the classroom, (b) establishing a routine through collaborative planning, (c) creating opportunities to address individual goals, and (d) negotiating theoretical perspectives and partner roles. The classroom- and curriculum-based but individualized nature of the approach is illustrated with probe data, and intervention goals and techniques for 2 boys, 1 from mid-second through third-grade and 1 within his fourth-grade year.