Remote Opportunities: A Rethinking and Retooling

Abstract Introducing technology as a sustainable means of creating, connecting, and collaborating reveals the need to carefully consider subtle aspects of deployment strategies and support in remote regions. In order to comprehensively address both cultural and technical issues for educational infrastructure, we consider two elements to be key: (1) a staged deployment approach, involving both educators and community members, coupled with (2) uniquely designed collaborative Integrated Development Environments (IDEs) to aid constructivism. This paper presents our current experience with these elements in the context of a pilot project for aboriginal communities on the west coast of British Columbia. Currently, these local communities have been working alongside our group for a staged deployment of programs throughout southern Vancouver Island. In our next phase we will be extending this to more remote regions in the north island and coastal regions. By building on a philosophy of CommunityDriven Initiatives for Technology (C-DIT), we hope to secure community involvement in the development and testing of necessary tool support. These tools specifically target IDEs for the development of programming skills, and support our long term goal to help secondary and postsecondary level students appreciate both the process and the art of programming

Investigating studio-based learning in a course on game design

Jobs in the computing field demand communication and teamwork skills in addition to programming skills. Focus at the undergraduate level needs to be shifted towards developing these collaborative skills to enable a more smooth transition into employment in industry. The University of Victoria is in its second year of offering a course on game design. In the first offering, new activities were introduced to address issues identified by recent studies on university graduates entering industry. We focused on integrating cooperative learning, group orientation, and peer review activities into the game design process. The course attracted students across multiple disciplines, and an analysis indicated increased student interest in pursuing a computer science degree. Unfortunately, the same pre- and post-surveys suggested that our collaborative activities may have resulted in a decrease in student interest regarding course work and in pursuing studies in game design. In this paper we report on how we used a studio-based pedagogical approach to restructure the peer review activities in our course. In our previous offering, students received peer feedback only on their final game presentation. In our latest offering, we integrated peer review activities into every step of the game development process, allowing students to refine their ideas while progressing through a game project. A quantitative analysis informs us that our refined peer review activities were successful in increasing student presentation confidence, sense of community, and excitement towards their course projects

Viewing Progress in Non-photorealistic Rendering through Heinlein’s Lens

The field of non-photorealistic rendering is reaching a mature state. In its infancy, researchers explored the mimicry of methods and tools used by traditional artists to generate works of art, through techniques like watercolor or oil painting simulations. As the field has moved past mimicry, ideas from artists and artistic techniques have been adapted and altered for performance in the media of computer graphics, creating algorithmic aesthetics such as generative art or the automatic composition of objects in a scene, as well as abstraction in rendering and geometry. With these two initial stages of non-photorealistic rendering well established, the field must find new territory to cover. In this paper, we provide a high level overview of the past and current state of non-photorealistic rendering and call to arms the community to create the areas of research that make computation of non-photorealistic rendering generate never before realized results

Personalized Approach to Treatment of Acute Myeloid Leukemia Using a High-Throughput Chemosensitivity Assay

Most patients with acute myeloid leukemia either relapse or fail to respond to initial therapy. Moreover, each patient’s AML contains multiple mutations that although varying from one population to another, are unique to that individual, prompting development of individualized approaches to AML therapy. We have devised a high-throughput sensitivity assay for 160 drugs; 45 are FDA approved and 115 are investigational, representing multiple mechanisms of action and signaling pathways. 30 primary patient blood marrow samples and 15 acute leukemia cell lines have been analyzed. Peripheral blood blasts from individual patients were thawed, viable cells isolated and purified to \u3e80% using magnetic bead separations. In vitro chemotherapy cytotoxicity testing is performed in a 384 well high throughput format, with eight concentrations of each drug. The output is cell survival assessed via a luminescent detection method after a 4-day incubation with various drugs. Fitted curves (idbs XLfit) were derived from plots of survival versus drug concentrations used in the study. Leukemia cells are tested adherent to coated plates to mimic adhesion in the bone marrow microenvironment, a property that confers drug resistance. The assay exhibits excellent reproducibility from independently thawed samples from the same patients, with a Spearman correlation coefficient of 0.9 (p=1.6 X 10-141). Gene expression microarrays were also performed for the same 30 patients. Our assay of the 30 patients revealed that there were over 50 drugs that exhibited cytotoxicity in at least some patients. There was wide variation in the drug sensitivity patterns exhibited by the patient blasts samples, and each was unique. Notably, all patient samples were susceptible to several drugs with IC50s in the range that might predict clinical response. For patients who achieved complete remission, we showed statistically significant association with in vitro cytotoxicity in response to 7 drugs that are commonly employed to treat AML, including mitoxantrone (p=0.002 for 0.1 µM, p=0.01 for 0.3 µM), clofarabine (p=0.0009 for 0.1 µM, p=0.003 for 0.3 µM, p=0.007 for 1µM), daunorubicin (p=003 for 0.1 µM, p=0.005 for 0.3 µM), etoposide (p=0.02 at for 0.1 µM, p=0.01 for 0.3 µM, p=0.01 for 1 µM), and fludarabine (p=0.05 for 0.3 µM, p=0.002 for 1 µM). In addition, we used a multivariate statistical method to identify drug combinations that are effective in predicting the complete remission of AML patients. In particular, we found that the in vitro cytotoxicity data of a combination of three drugs (BAY 11-7085, TPCA-1, ON 01910.Na) are more predictive of the complete remission of patients compared to using each of these drugs individually (i.e. 91.2% accuracy compared to 84.8%, 84.2%, 79.1% respectively). We also performed linear regression analyses to study the relationship between in vitro cytotoxicity in the high throughput screen of each drug versus the patients’ clinical features (including complete remission, having received the tested drug, new diagnosis vs. relapse status, age, gender, bilirubin, albumin, lactate dehydrogenase, white blood count, platelet count, blast, absolute neutrophil count, % bone marrow blasts, hemoglobin, fibrinogen, cytogenetics risk category). The following patients’ clinical features showed significant correlations with the in vitro cytotoxicity of our assays in selected drugs: complete remission for mitoxantrone (p= 0.04 for 0.3 µM), flavoperidol (p= 0.02 0.1 µM), and fludarabine (p= 0.01 0.3 µM, p=0.02 for 1 µM); drug the patient received for clofarabine (p= 0.03 for 0.3 µM, p=0.007 for 1 µM); new diagnosis vs. relapse for clofarabine (p= p= 0.02 for 0.3 µM, p=0.006 for 1 µM). This assay serves as the basis for a new clinical trial (ClinicalTrials.gov Identifier: NCT01872819) now open to enrollment for “personalized” leukemia therapy, for which patients with refractory AML are assigned drugs based on the results of this test. This new personalized approach to individualized therapy for refractory AML may provide novel drugs to patients and new insights into leukemia drug resistance

Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results of the MRC AML12 trial.

Purpose. To optimize treatment for younger patients with acute myeloid leukemia and high-risk myelodysplastic syndrome by comparing induction options and the number of consolidation courses and whether consolidation should include transplantation. Patients and Methods. We randomly assigned 1,658 patients younger than age 60 years to receive mitoxantrone/cytarabine/etoposide versus cytarabine/daunorubicin/etoposide and subsequently 1,193 patients to daunorubicin/cytarabine/thioguanine (DAT) where the cytarabine dose was standard (S-DAT) versus double the standard dose (H-DAT). Patients in this randomization were randomly assigned to all-trans-retinoic acid or not. In consolidation, 992 patients were randomly assigned between a total of four courses versus five courses, and 324 patients who were not good risk were randomly assigned to transplantation or chemotherapy as the final course. Results. Complete remission (CR) was achieved in 74% of patients and CR without recovery was achieved in an additional 11%; overall survival (OS) at 8 years was 38%. No differences in CR, relapse-free survival, relapse, or OS were seen between any of the induction randomizations except for a reduction in relapse risk (RR) on the mitoxantrone arm, which was offset by increased myelosuppression and deaths in CR. The addition of a fifth course did not improve OS and may be detrimental in older patients. Although transplantation reduced RR, it did not improve OS for the intermediate-risk group but was probably of benefit in high-risk patients. Conclusion. Several chemotherapy schedules achieved similar remission rates and OS. Four courses of chemotherapy are adequate, but the addition of transplantation as a final course does not improve OS. New agents are required to enhance conventional chemotherapy

Toward Individualized Therapy: Correlation of Mutation Analysis With in Vitro High Throughput Drug Sensitivity Testing in New Diagnosis and Relapsed Acute Myeloid Leukemia

Introduction: Whole genome sequencing has demonstrated tremendous heterogeneity in the mutations and chromosomal translocations associated with acute myeloid leukemia (AML), and there are several correlates with prognosis, yet we remain quite limited in our ability to predict specific chemotherapy drug sensitivity based on genomics with the exception of a few selected mutations or translocations, such as FLT3 -ITD or PML-RARA. One third of new diagnosis patients and over half of relapsed patients will not respond to initial chemotherapy regimens that incur appreciable toxicity and result in prolonged hospitalization. We therefore seek to define molecular information that might better predict response to conventional or novel therapies. Methods: MyAML™ uses next generation sequencing (NGS) to analyze the 3\u27 and 5\u27 UTR and exonic regions of 194 genes and potential genomic breakpoints within known somatic gene fusion breakpoints known to be associated with AML. Fragmented genomic DNA (~3.4Mb) is captured with a customized probe design, and sequenced with 300bp paired end reads on an Illumina MiSeq instrument to an average depth of coverage \u3e1000x. Using a custom bioinformatics pipeline, MyInformatics™, single nucleotide variants (SNVs), insertion/deletions (indels), inversions and translocations are identified, annotated, characterized, and allelic frequencies calculated. Commonly associated variants in dbSNP and 1000 genomes may be eliminated, as well as variants with allele frequencies less than 5%. High throughput drug sensitivity testing was performed against a panel of 160 drugs, of which 56 are FDA approved and 104 are investigational. De-identified samples from 12 patients with de novo AML and 12 patients with relapsed AML were analyzed. For 2 patient samples, Duplex Sequencing was also performed to detect sub-clonal mutations below the detection limit of conventional NGS. Pearson and Spearman correlations were performed between all possible pairs of genes containing missense or indel mutations and the in vitro cytotoxicity response across the same set of 24 patients. Results: From the 24 patient samples analyzed to date, an average of 129 missense mutations were identified in each sample with an allelic frequency \u3e5%. Of these, an average of over 21 missense variants were observed in COSMIC and less than 3 were novel (not in dbSNP). These samples also contained an average of over 12 coding indels (~5 frameshift and 7 inframe indels per sample). In addition, MyAML™ identified 3 samples with inv(16) and 6 samples with translocations, including the cryptic NUP98-NSD1 t(5;11) that was not detected by karyotyping. For 2 of the samples, Duplex Sequencing was performed at a depth of at least 6000X, and an accuracy of 10-7, and showed concordance of some of the mutations, with each method identifying additional mutations not observed by the other, an expected finding, as each method targeted distinct regions, and Duplex Sequencing had a greater depth of coverage. Fourteen genes were observed to exhibit at least one indel with a frameshift at frequency greater than 5% in more than one patient. In order to identify significantly associated drugs and genes containing indel mutations, we computed Pearson and Spearman correlations between drugs and these 14 genes across 24 patients. The correlation analyses revealed significant associations (p= 0.006 to 0.04) between indel mutations in three genes and chemosensitivity to drugs commonly used in AML such as cladribine, clofarabine, cytarabine, daunorubicin, etoposide, fludarabine and mitoxantrone. Similarly, significant associations (p\u3c0.05) were identified between missense mutations in 5 genes and chemosensitivity to these drugs. Conclusion: Personalized data derived from a targeted genomic assay and in vitro chemotherapy sensitivity testing of individual patient AML samples will likely lead to innovation in treatment, identification of novel targeted agents, and improved outcomes in AML. Disclosures Xie: Invivoscribe: Employment. Carson: Genection: Employment. Patay: Genection: Employment