Outcome for Children and Young Adults With T-Cell ALL and Induction Failure in Contemporary Trials.

PURPOSE: Historically, patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission at the end of induction (EOI) have had poor long-term survival. The goal of this study was to examine the efficacy of contemporary therapy, including allogeneic hematopoietic stem cell transplantation (HSCT) in first remission (CR1). METHODS: Induction failure (IF) was defined as the persistence of at least 5% bone marrow (BM) lymphoblasts and/or extramedullary disease after 4-6 weeks of induction chemotherapy. Disease features and clinical outcomes were reported in 325 of 6,167 (5%) patients age 21 years and younger treated in 14 cooperative study groups between 2000 and 2018. RESULTS: With a median follow-up period of 6.4 years (range, 0.3-17.9 years), the 10-year overall survival (OS) was 54.7% (SE = 2.9), which is significantly higher than the 27.6% (SE = 2.9) observed in the historical cohort from 1985 to 2000. There was no significant impact of sex, age, white blood cell count, central nervous system disease status, T-cell maturity, or BM disease burden at EOI on OS. Postinduction complete remission (CR) was achieved in 93% of patients with 10-year OS of 59.6% (SE = 3.1%) and disease-free survival (DFS) of 56.3% (SE = 3.1%). Among the patients who achieved CR, 72% underwent HSCT and their 10-year DFS (with a 190-day landmark) was significantly better than nontransplanted patients (63.8% [SE = 3.6] v 45.5% [SE = 7.1]; P = .005), with OS of 66.2% (SE = 3.6) versus 50.8% (SE = 6.8); P = .10, respectively. CONCLUSION: Outcomes for patients age 21 years and younger with T-ALL and IF have improved in the contemporary treatment era with a DFS benefit among those undergoing HSCT in CR1. However, outcomes still lag considerably behind those who achieve remission at EOI, warranting investigation of new treatment approaches.

Trajectory of Anxiety Related to Radiation Therapy Mask Immobilization and Treatment Delivery in Head and Neck Cancer and Radiation Therapists' Ability to Detect This Anxiety.

Purpose: Receiving radiation therapy treatment with an immobilization mask is a source of anxiety in people with head and neck cancer (HNC). This study aimed to document the trajectory of situational anxiety during HNC treatment delivery and explore radiation therapists' (RTs') ability to identify it. Methods and Materials: Participants with HNC commencing radiation therapy completed the state-trait anxiety inventory at their mask-making session, and once each week immediately before and after their radiation treatment. Treating RTs independently rated their perception of participant's anxiety at the same time points. Participant- and RT-rated anxiety scores were calculated at each time point together with the proportion of participants reporting clinically significant anxiety (state-trait anxiety inventory ≥ 40). Intraclass correlations were calculated to assess concordance between participant- and RT-ratings. Results: Sixty-five participants and 16 RTs took part in this study. Participants were classified into 1 of 5 trajectory groups: stable high (16%), increasing (19%), decreasing (27%), fluctuating (19%), and no anxiety (19%). Nearly half (43%) of participants reported clinically significant anxiety before their mask-making session, and between 30% and 43% across trajectories reported significant anxiety immediately before treatments. Intraclass correlation values indicated poor agreement between participant- and RT-ratings. Conclusions: Situational anxiety is prevalent in people receiving HNC radiation therapy with mask immobilization. RTs did not reliably capture patients' situational anxiety. There is no single best time point to provide intervention, suggesting people should be screened for anxiety regularly throughout their treatment. Resources and education should also be available to improve RT skills in providing psychosocial support.

JAK3 mutations and mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia.

Resistance to mitochondrial apoptosis predicts inferior treatment outcomes in patients with diverse tumor types, including T-cell acute lymphoblastic leukemia (T-ALL). However, the genetic basis for variability in this mitochondrial apoptotic phenotype is poorly understood, preventing its rational therapeutic targeting. Using BH3 profiling and exon sequencing analysis of childhood T-ALL clinical specimens, we found that mitochondrial apoptosis resistance was most strongly associated with activating mutations of JAK3. Mutant JAK3 directly repressed apoptosis in leukemia cells, because its inhibition with mechanistically distinct pharmacologic inhibitors resulted in reversal of mitochondrial apoptotic blockade. Inhibition of JAK3 led to loss of MEK, ERK and BCL2 phosphorylation, and BH3 profiling revealed that JAK3-mutant primary T-ALL patient samples were characterized by a dependence on BCL2. Treatment of JAK3-mutant T-ALL cells with the JAK3 inhibitor tofacitinib in combination with a spectrum of conventional chemotherapeutics revealed synergy with glucocorticoids, in vitro and in vivo. These findings thus provide key insights into the molecular genetics of mitochondrial apoptosis resistance in childhood T-ALL, and a compelling rationale for a clinical trial of JAK3 inhibitors in combination with glucocorticoids for patients with JAK3-mutant T-ALL.

Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001.

BACKGROUND/OBJECTIVES: While outcomes for pediatric T-cell acute lymphoblastic leukemia (T-ALL) are favorable, there are few widely accepted prognostic factors, limiting the ability to risk stratify therapy. DESIGN/METHODS: Dana-Farber Cancer Institute (DFCI) Protocols 05-001 and 11-001 enrolled pediatric patients with newly diagnosed B- or T-ALL from 2005 to 2011 and from 2012 to 2015, respectively. Protocol therapy was nearly identical for patients with T-ALL (N = 123), who were all initially assigned to the high-risk arm. End-induction minimal residual disease (MRD) was assessed by reverse transcription polymerase chain reaction (RT-PCR) or next-generation sequencing (NGS), but was not used to modify postinduction therapy. Early T-cell precursor (ETP) status was determined by flow cytometry. Cases with sufficient diagnostic DNA were retrospectively evaluated by targeted NGS of known genetic drivers of T-ALL, including Notch, PI3K, and Ras pathway genes. RESULTS: The 5-year event-free survival (EFS) and overall survival (OS) for patients with T-ALL was 81% (95% CI, 73-87%) and 90% (95% CI, 83-94%), respectively. ETP phenotype was associated with failure to achieve complete remission, but not with inferior OS. Low end-induction MRD (<10-4 ) was associated with superior disease-free survival (DFS). Pathogenic mutations of the PI3K pathway were mutually exclusive of ETP phenotype and were associated with inferior 5-year DFS and OS. CONCLUSIONS: Together, our findings demonstrate that ETP phenotype, end-induction MRD, and PI3K pathway mutation status are prognostically relevant in pediatric T-ALL and should be considered for risk classification in future trials. DFCI Protocols 05-001 and 11-001 are registered at www.clinicaltrials.gov as NCT00165087 and NCT01574274, respectively.

Molecular basis of ETV6-mediated predisposition to childhood acute lymphoblastic leukemia.

There is growing evidence supporting an inherited basis for susceptibility to acute lymphoblastic leukemia (ALL) in children. In particular, we and others reported recurrent germline ETV6 variants linked to ALL risk, which collectively represent a novel leukemia predisposition syndrome. To understand the influence of ETV6 variation on ALL pathogenesis, we comprehensively characterized a cohort of 32 childhood leukemia cases arising from this rare syndrome. Of 34 nonsynonymous germline ETV6 variants in ALL, we identified 22 variants with impaired transcription repressor activity, loss of DNA binding, and altered nuclear localization. Missense variants retained dimerization with wild-type ETV6 with potentially dominant-negative effects. Whole-transcriptome and whole-genome sequencing of this cohort of leukemia cases revealed a profound influence of germline ETV6 variants on leukemia transcriptional landscape, with distinct ALL subsets invoking unique patterns of somatic cooperating mutations. 70% of ALL cases with damaging germline ETV6 variants exhibited hyperdiploid karyotype with characteristic recurrent mutations in NRAS, KRAS, and PTPN11. In contrast, the remaining 30% cases had a diploid leukemia genome and an exceedingly high frequency of somatic copy-number loss of PAX5 and ETV6, with a gene expression pattern that strikingly mirrored that of ALL with somatic ETV6-RUNX1 fusion. Two ETV6 germline variants gave rise to both acute myeloid leukemia and ALL, with lineage-specific genetic lesions in the leukemia genomes. ETV6 variants compromise its tumor suppressor activity in vitro with specific molecular targets identified by assay for transposase-accessible chromatin sequencing profiling. ETV6-mediated ALL predisposition exemplifies the intricate interactions between inherited and acquired genomic variations in leukemia pathogenesis.

Unmasking Anxiety: A Qualitative Investigation of Health Professionals; Perspectives of Mask Anxiety in Head and Neck Cancer.

BACKGROUND: To ensure precision of treatment, patients requiring radiation therapy for treatment of head and neck cancer (HNC) are stabilized using a fitted thermoplastic immobilization mask. Despite evidence that many patients experience significant anxiety when restrained in the mask, there is a lack of proven interventions to prevent or manage mask-related anxiety. The Promoting Action on Research Implementation in Health Services implementation framework promotes consideration of context and culture when developing interventions to ensure successful implementation if proven effective. Health professionals (HPs) play a crucial role in the management of patients' psychological concerns, yet no studies have explored their perspectives of mask anxiety and how it should be managed. The aim of this study, therefore, was to elicit and analyse HPs' perspectives of mask anxiety, using the Promoting Action on Research Implementation in Health Services framework, to guide the development of implementation-ready interventions to reduce mask anxiety. METHODS: Semistructured interviews were conducted with 20 HPs involved in the care of HNC patients, including radiation oncologists, radiation therapists, nurses, and psychologists, from nine hospitals in NSW, Australia. Framework analysis methods were used. RESULTS: Participants were on average 40 years old (range, 27-56), the majority were female (75%), and they had worked from 1 to 22 years with HNC patients. Six emergent themes were identified: (1) Mask anxiety is a significant problem but is easily missed; (2) Context matters; (3) Trust is critical; (4) Choice and control facilitate adjustment; (5) Psychological strategies are valued; and (6) Culture matters. Subgroup analysis also highlighted differences in perspectives between specialties. CONCLUSIONS: Participants identified key principles underlying successful intervention. Two significant barriers to mask-anxiety intervention were identified: (1) a lack of empirical evidence surrounding its prevalence and predictors and (2) contextual and systematic hurdles making the health system potentially unresponsive to change. These data suggest a need for further descriptive studies and careful development of interventions which will address these hurdles.

Exploring head and neck cancer patients' experiences with radiation therapy immobilisation masks: A qualitative study.

OBJECTIVE: Head and neck cancer (HNC) patients commonly undergo radiation therapy requiring immobilisation by a mask. Some find the mask distressing, and this can disrupt treatment sessions. This study aimed to explore the patient experience of immobilisation masks in the Australian and New Zealand (ANZ) context, to guide possible intervention. METHODS: Semi-structured interviews were conducted with HNC patients who had completed radiation therapy, recruited via hospitals and social media. Interviews continued until data saturation; then, three further interviews were conducted for member-checking purposes. Qualitative methodology with thematic analysis was used to identify themes in the data. RESULTS: Twenty HNC survivors participated in interviews, and seven themes were identified: information received by participants, potential predictors of mask anxiety, participant reactions to the mask, trajectories of mask anxiety, supportive behaviour and communication of health professionals, coping with the mask, and thoughts and feelings about the mask. CONCLUSIONS: Participant experiences of the immobilisation mask were diverse. The findings fit with Lazarus and Folkman's (Stress, appraisal, and coping. New York, NY: Springer Pub. Co) transactional model of stress and coping, as participants appeared to make cognitive appraisals of the mask and their coping abilities throughout treatment, resulting in varied levels of mask-related distress. Complex intervention is recommended to reduce mask anxiety in HNC patients across ANZ.

Fanconi-BRCA pathway mutations in childhood T-cell acute lymphoblastic leukemia.

BRCA2 (also known as FANCD1) is a core component of the Fanconi pathway and suppresses transformation of immature T-cells in mice. However, the contribution of Fanconi-BRCA pathway deficiency to human T-cell acute lymphoblastic leukemia (T-ALL) remains undefined. We identified point mutations in 9 (23%) of 40 human T-ALL cases analyzed, with variant allele fractions consistent with heterozygous mutations early in tumor evolution. Two of these mutations were present in remission bone marrow specimens, suggesting germline alterations. BRCA2 was the most commonly mutated gene. The identified Fanconi-BRCA mutations encode hypomorphic or null alleles, as evidenced by their inability to fully rescue Fanconi-deficient cells from chromosome breakage, cytotoxicity and/or G2/M arrest upon treatment with DNA cross-linking agents. Disabling the tumor suppressor activity of the Fanconi-BRCA pathway is generally thought to require biallelic gene mutations. However, all mutations identified were monoallelic, and most cases appeared to retain expression of the wild-type allele. Using isogenic T-ALL cells, we found that BRCA2 haploinsufficiency induces selective hypersensitivity to ATR inhibition, in vitro and in vivo. These findings implicate Fanconi-BRCA pathway haploinsufficiency in the molecular pathogenesis of T-ALL, and provide a therapeutic rationale for inhibition of ATR or other druggable effectors of homologous recombination.

Prohibitin is a prognostic marker and therapeutic target to block chemotherapy resistance in Wilms' tumor.

Wilms' tumor is the most common type of childhood kidney cancer. To improve risk stratification and identify novel therapeutic targets for patients with Wilms' tumor, we used high-resolution mass spectrometry proteomics to identify urine tumor markers associated with Wilms' tumor relapse. We determined the urine proteomes at diagnosis of 49 patients with Wilms' tumor, non-Wilms' tumor renal tumors, and age-matched controls, leading to the quantitation of 6520 urine proteins. Supervised analysis revealed specific urine markers of renal rhabdoid tumors, kidney clear cell sarcomas, renal cell carcinomas as well as those detected in patients with cured and relapsed Wilms' tumor. In particular, urine prohibitin was significantly elevated at diagnosis in patients with relapsed as compared with cured Wilms' tumor. In a validation cohort of 139 patients, a specific urine prohibitin ELISA demonstrated that prohibitin concentrations greater than 998 ng/mL at diagnosis were significantly associated with ultimate Wilms' tumor relapse. Immunohistochemical analysis revealed that prohibitin was highly expressed in primary Wilms' tumor specimens and associated with disease stage. Using functional genetic experiments, we found that prohibitin was required for the growth and survival of Wilms' tumor cells. Overexpression of prohibitin was sufficient to block intrinsic mitochondrial apoptosis and to cause resistance to diverse chemotherapy drugs, at least in part by dysregulating factors that control apoptotic cytochrome c release from mitochondrial cristae. Thus, urine prohibitin may improve therapy stratification, noninvasive monitoring of treatment response, and early disease detection. In addition, therapeutic targeting of chemotherapy resistance induced by prohibitin dysregulation may offer improved therapies for patients with Wilms' and other relapsed or refractory tumors.

PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia.

The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondrial apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (EZH2, EED, or SUZ12) were associated with mitochondrial apoptosis resistance. In T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action. PRC2 loss induced apoptosis resistance via transcriptional up-regulation of the LIM domain transcription factor CRIP2 and downstream up-regulation of the mitochondrial chaperone TRAP1 These findings demonstrate the importance of mitochondrial apoptotic priming as a prognostic factor in T-ALL and implicate mitochondrial chaperone function as a molecular determinant of chemotherapy response.

Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease.

Genomic DNA transposition induced by human PGBD5.

Transposons are mobile genetic elements that are found in nearly all organisms, including humans. Mobilization of DNA transposons by transposase enzymes can cause genomic rearrangements, but our knowledge of human genes derived from transposases is limited. In this study, we find that the protein encoded by human PGBD5, the most evolutionarily conserved transposable element-derived gene in vertebrates, can induce stereotypical cut-and-paste DNA transposition in human cells. Genomic integration activity of PGBD5 requires distinct aspartic acid residues in its transposase domain, and specific DNA sequences containing inverted terminal repeats with similarity to piggyBac transposons. DNA transposition catalyzed by PGBD5 in human cells occurs genome-wide, with precise transposon excision and preference for insertion at TTAA sites. The apparent conservation of DNA transposition activity by PGBD5 suggests that genomic remodeling contributes to its biological function.

Use of the Wii Gaming System for Balance Rehabilitation: Establishing Parameters for Healthy Individuals.

OBJECTIVE: This study was designed to establish balance parameters for the Nintendo(®) (Redmond, WA) "Wii Fit™" Balance Board system with three common games, in a sample of healthy adults, and to evaluate the balance measurement reproducibility with separation by age. SUBJECTS AND METHODS: This was a prospective, multivariate analysis of variance, cohort study design. Seventy-five participants who satisfied all inclusion criteria and completed an informed consent were enrolled. Participants were grouped into age ranges: 21-35 years (n=24), 36-50 years (n=24), and 51-65 years (n=27). Each participant completed the following games three consecutive times, in a randomized order, during one session: "Balance Bubble" (BB) for distance and duration, "Tight Rope" (TR) for distance and duration, and "Center of Balance" (COB) on the left and right sides. RESULTS: COB distributed weight was fairly symmetrical across all subjects and trials; therefore, no influence was assumed on or interaction with other "Wii Fit" measurements. Homogeneity of variance statistics indicated the assumption of distribution normality of the dependent variables (rates) were tenable. The multivariate analysis of variance included dependent variables BB and TR rates (distance divided by duration to complete) with age group and trials as the independent variables. The BB rate was statistically significant (F=4.725, P<0.005), but not the TR rate. The youngest group's BB rate was significantly larger than those of the other two groups. CONCLUSIONS: "Wii Fit" can discriminate among age groups across trials. The results show promise as a viable tool to measure balance and distance across time (speed) and center of balance distribution.

Pregait balance rehabilitation in acute stroke patients.

Rehabilitation interventions designed to enhance balance control in individuals with acute stroke are quite limited. The goal was to develop and assess a technique of early pregait balance training involving the use of a combination of force platform visual feedback and the unweighting system in individuals with recent stroke. A total of 28 individuals with acute stroke were randomly divided into the experimental and control groups: individuals included in the experimental group received 1 week of treatment on the basis of retraining balance utilizing visual biofeedback (Balance Master) while provided with a body weight support harness system, whereas the individuals in the control group received conventional treatment. Both the groups undertook identical tests (Fugl-Meyer Balance test, Functional Independence Measure test for gait, and Fugl-Meyer lower extremity assessment) before the start of treatment and after its completion. Individuals in the experimental group showed larger gains as seen in the increased scores of the Fugl-Meyer Balance test and the Functional Independence Measure test for gait as compared with the control group. The outcome of the study provides a basis for future investigations of the applicability of the intervention in early balance rehabilitation of individuals with neurological disorders.

Reticulate evolutionary history of a complex group of grasses: phylogeny of Elymus StStHH allotetraploids based on three nuclear genes.

BACKGROUND: Elymus (Poaceae) is a large genus of polyploid species in the wheat tribe Triticeae. It is polyphyletic, exhibiting many distinct allopolyploid genome combinations, and its history might be further complicated by introgression and lineage sorting. We focus on a subset of Elymus species with a tetraploid genome complement derived from Pseudoroegneria (genome St) and Hordeum (H). We confirm the species' allopolyploidy, identify possible genome donors, and pinpoint instances of apparent introgression or incomplete lineage sorting. METHODOLOGY/PRINCIPAL FINDINGS: We sequenced portions of three unlinked nuclear genes-phosphoenolpyruvate carboxylase, beta-amylase, and granule-bound starch synthase I-from 27 individuals, representing 14 Eurasian and North American StStHHElymus species. Elymus sequences were combined with existing data from monogenomic representatives of the tribe, and gene trees were estimated separately for each data set using maximum likelihood. Trees were examined for evidence of allopolyploidy and additional reticulate patterns. All trees confirm the StStHH genome configuration of the Elymus species. They suggest that the StStHH group originated in North America, and do not support separate North American and European origins. Our results point to North American Pseudoroegneria and Hordeum species as potential genome donors to Elymus. Diploid P. spicata is a prospective St-genome donor, though conflict among trees involving P. spicata and the Eurasian P. strigosa suggests either introgression of GBSSI sequences from P. strigosa into North American Elymus and Pseudoroegneria, or incomplete lineage sorting of ancestral GBSSI polymorphism. Diploid H. californicum and/or allotetraploid H. jubatum are possible H-genome donors; direct involvement of an allotetraploid Hordeum species would simultaneously introduce two distinct H genomes to Elymus, consistent with some of the relationships among H-genome sequences in Hordeum and Elymus. CONCLUSIONS/SIGNIFICANCE: Comparisons among molecular phylogenetic trees confirm allopolyploidy, identify potential genome donors, and highlight cases of apparent introgression or incomplete lineage sorting. The complicated history of this group emphasizes an inherent problem with interpreting conflicts among bifurcating trees-identifying introgression and determining its direction depend on which tree is chosen as a starting point of comparison. In spite of difficulties with interpretation, differences among gene trees allow us to identify reticulate species and develop hypotheses about underlying evolutionary processes.

Phylogenetic relationships and reticulation among Asian Elymus (Poaceae) allotetraploids: analyses of three nuclear gene trees.

This phylogenetic study focuses on a subset of the species in Elymus-specifically, the endemic Asian tetraploids presumed to combine the St genome from Pseudoroegneria with the Y genome from an unknown donor. The primary goals were to (1) determine whether the St and Y genomes are derived from phylogenetically distinct donors; (2) identify the closest relative, and potentially the likely donor, of the Y genome; and (3) interpret variation among StStYY species in terms of multiple origins and/or introgression. The goals were addressed using phylogenetic analyses of sequences from three low-copy nuclear genes: phosphoenolpyruvate carboxylase, beta-amylase, and granule-bound starch synthase I. Data sets include 16 StStYY individuals representing nine species, along with a broad sample of representatives from most of the monogenomic (i.e., non-allopolyploid) genera in the tribe. To briefly summarize the results: (1) the data clearly support an allopolyploid origin for the Asian tetraploids, involving two distinct donors; (2) the Y genome was contributed by a single donor, or multiple closely-related donors; (3) the phylogenetic position of the ElymusY genome varies among the three trees and its position is not strongly supported, so the identity of the donor remains a mystery; and (4) conflicts among the gene trees with regard to the St-genome sequences suggest introgression involving both Elymus and Pseudoroegneria.

Bead-based profiling of tyrosine kinase phosphorylation identifies SRC as a potential target for glioblastoma therapy.

The aberrant activation of tyrosine kinases represents an important oncogenic mechanism, and yet the majority of such events remain undiscovered. Here we describe a bead-based method for detecting phosphorylation of both wild-type and mutant tyrosine kinases in a multiplexed, high-throughput and low-cost manner. With the aim of establishing a tyrosine kinase-activation catalog, we used this method to profile 130 human cancer lines. Follow-up experiments on the finding that SRC is frequently phosphorylated in glioblastoma cell lines showed that SRC is also activated in primary glioblastoma patient samples and that the SRC inhibitor dasatinib (Sprycel) inhibits viability and cell migration in vitro and tumor growth in vivo. Testing of dasatinib-resistant tyrosine kinase alleles confirmed that SRC is indeed the relevant target of dasatinib, which inhibits many tyrosine kinases. These studies establish the feasibility of tyrosine kinome-wide phosphorylation profiling and point to SRC as a possible therapeutic target in glioblastoma.

Building a local agenda for dissemination of research into practice.

Across North America and in other parts of the world, there has been a growing recognition that a large gap exists between public health knowledge generated through scientific discovery and its application in individual, community, organizational, and policy innovation. An academic-funder partnership sought to identify potential actions to improve the translation of public health research to practice in Missouri. Concept mapping, a structured conceptualization process, was used to develop information to support a local action planning effort to improve research translation to practice in Missouri. Nine conceptual clusters emerged: (1) provide education and training; (2) enhance capacity; (3) change incentives and accountability; (4) shift funding toward community needs; (5) support practice-based research; (6) engage and collaborate with the community; (7) share knowledge; (8) engage influentials; and (9) sustain momentum; action plans were drafted to address priorities in each cluster. The project connected the ideas of a wide-ranging set of stakeholders, identified areas of high-level agreement among stakeholders, and supported shared agenda setting.