An Interview with APPLE Lecture Speaker Professor Alister Cumming

On April 11, 2014, the TESOL/AL Web Journal (represented by Rongchan Lin, Yuna Seong, and Catherine Box) had the opportunity to sit down with Professor Alister Cumming, guest speaker for the 2014 Applied Linguistics & Language Education (APPLE) Lecture Series, hosted annually by the TESOL/Applied Linguistics Programs at Teachers College, Columbia University. Professor Cumming was kind enough to take the time, during a very busy day, to speak about his research, his work on assessing writing, his thoughts on dynamic assessment, and his advice for new scholars working in the TESOL/AL fields. Professor Cumming is professor in the Centre for Educational Research on Languages and Literacies (CERLL) at the Ontario Institute for Studies in Education, University of Toronto. His research and teaching focus on writing in second languages, language assessment, language program evaluation and policies, and research methods. His most recent books include Adolescent Literacies in a Multicultural Context (2012, Routledge), A Synthesis of Research on Second Language Writing in English (with Ilona Leki & Tony Silva, 2008, Routledge), and Goals for Academic Writing (2006, John Bejamins). Professor Cumming is currently the Executive Director of Language Learning, a journal he edited in the 1990s. For the past five years he has chaired the TOEFL Committee of Examiners at Educational Testing Service in Princeton. He received his PhD from the University of Toronto in 1988, MA and BA from the University of British Columbia in 1979 and 1975 respectively, and an honorary doctorate from the University of Copenhagen in 2009. From 2014 to 2017 he will hold a Changjiang Scholarship at Beijing Foreign Studies University. We thank Professor Cumming for his participation in a lively interview. We also thank Fred Tsutagawa for videotaping and Dr. Kirby Grabowski for coordinating the APPLE Lecture Series Interview

The Deafness-Associated Mitochondrial DNA Mutation at Position 7445, Which Affects tRNASer(UCN) Precursor Processing, Has Long-Range Effects on NADH Dehydrogenase Subunit ND6 Gene Expression

The pathogenetic mechanism of the deafness-associated mitochondrial DNA (mtDNA) T7445C mutation has been investigated in several lymphoblastoid cell lines from members of a New Zealand pedigree exhibiting the mutation in homoplasmic form and from control individuals. We show here that the mutation flanks the 3' end of the tRNASer(UCN) gene sequence and affects the rate but not the sites of processing of the tRNA precursor. This causes an average reduction of ~70% in the tRNASer(UCN) level and a decrease of ~45% in protein synthesis rate in the cell lines analyzed. The data show a sharp threshold in the capacity of tRNASer(UCN) to support the wild-type protein synthesis rate, which corresponds to ~40% of the control level of this tRNA. Strikingly, a 7445 mutation-associated marked reduction has been observed in the level of the mRNA for the NADH dehydrogenase (complex I) ND6 subunit gene, which is located ~7 kbp upstream and is cotranscribed with the tRNASer(UCN) gene, with strong evidence pointing to a mechanistic link with the tRNA precursor processing defect. Such reduction significantly affects the rate of synthesis of the ND6 subunit and plays a determinant role in the deafness-associated respiratory phenotype of the mutant cell lines. In particular, it accounts for their specific, very significant decrease in glutamate- or malate-dependent O2 consumption. Furthermore, several homoplasmic mtDNA mutations affecting subunits of NADH dehydrogenase may play a synergistic role in the establishment of the respiratory phenotype of the mutant cells

Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy.

Activating mutations in FLT3 confer poor prognosis for individuals with acute myeloid leukemia (AML). Clinically active investigational FLT3 inhibitors can achieve complete remissions but their utility has been hampered by acquired resistance and myelosuppression attributed to a 'synthetic lethal toxicity' arising from simultaneous inhibition of FLT3 and KIT. We report a novel chemical strategy for selective FLT3 inhibition while avoiding KIT inhibition with the staurosporine analog, Star 27. Star 27 maintains potency against FLT3 in proliferation assays of FLT3-transformed cells compared with KIT-transformed cells, shows no toxicity towards normal human hematopoiesis at concentrations that inhibit primary FLT3-mutant AML blast growth, and is active against mutations that confer resistance to clinical inhibitors. As a more complete understanding of kinase networks emerges, it may be possible to define anti-targets such as KIT in the case of AML to allow improved kinase inhibitor design of clinical agents with enhanced efficacy and reduced toxicity

The Global Lake Ecological Observatory Network (GLEON): the evolution of grassroots network science

Nine years later, with over 380 members from 40 countries, and 50 publications to its credit, GLEON is growing at a rapid pace and pushing the boundaries of the practice of network science. GLEON is really three networks: a network of lakes, data, and peopl

Predicting Bone Mechanical Properties of Cancellous Bone from DXA, MRI, and Fractal Dimensional Measurements

This project was aimed at making predictions of bone mechanical properties from non-invasive DXA and MRI measurements. Given the bone mechanical properties, stress calculations can be made to compare normal bone stresses to the stresses developed in exercise countermeasures against bone loss during space flight. These calculations in turn will be used to assess whether mechanical factors can explain bone loss in space. In this study we assessed the use of T2(sup *) MRI imaging, DXA, and fractal dimensional analysis to predict strength and stiffness in cancellous bone

Genetic and epigenetic profiling of BRCA1/2 in ovarian tumors reveals additive diagnostic yield and evidence of a genomic BRCA1/2 DNA methylation signature

Poly-ADP-ribose-polymerase inhibitor (PARPi) treatment is indicated for advanced-stage ovarian tumors with BRCA1/2 deficiency. The “BRCAness” status is thought to be attributed to a tumor phenotype associated with a specific epigenomic DNA methylation profile. Here, we examined the diagnostic impact of combined BRCA1/2 sequence, copy number, and promoter DNA methylation analysis, and evaluated whether genomic DNA methylation patterns can predict the BRCAness in ovarian tumors. DNA sequencing of 172 human tissue samples of advanced-stage ovarian adenocarcinoma identified 36 samples with a clinically significant tier 1/2 sequence variants (point mutations and in/dels) and 9 samples with a CNV causing a loss of function in BRCA1/2. DNA methylation analysis of the promoter of BRCA1/2 identified promoter hypermethylation of BRCA1 in two mutation-negative samples. Computational modeling of genome-wide methylation markers, measured using Infinium EPIC arrays, resulted in a total accuracy of 0.75, sensitivity: 0.83, specificity: 0.64, positive predictive value: 0.76, negative predictive value: 0.74, and area under the receiver’s operating curve (AUC): 0.77, in classifying tumors harboring a BRCA1/2 defect from the rest. These findings indicate that the assessment of CNV and promoter DNA methylation in BRCA1/2 increases the cumulative diagnostic yield by 10%, compared with the 20% yield achieved by sequence variant analysis alone. Genomic DNA methylation data can partially predict BRCAness in ovarian tumors; however, further investigation in expanded BRCA1/2 cohorts is needed, and the effect of other double strand DNA repair gene defects in these tumors warrants further investigations

Overcoming myelosuppression due to synthetic lethal toxicity for FLT3-targeted acute myeloid leukemia therapy

Activating mutations in FLT3 confer poor prognosis for individuals with acute myeloid leukemia (AML). Clinically active investigational FLT3 inhibitors can achieve complete remissions but their utility has been hampered by acquired resistance and myelosuppression attributed to a 'synthetic lethal toxicity' arising from simultaneous inhibition of FLT3 and KIT. We report a novel chemical strategy for selective FLT3 inhibition while avoiding KIT inhibition with the staurosporine analog, Star 27. Star 27 maintains potency against FLT3 in proliferation assays of FLT3-transformed cells compared with KIT-transformed cells, shows no toxicity towards normal human hematopoiesis at concentrations that inhibit primary FLT3-mutant AML blast growth, and is active against mutations that confer resistance to clinical inhibitors. As a more complete understanding of kinase networks emerges, it may be possible to define anti-targets such as KIT in the case of AML to allow improved kinase inhibitor design of clinical agents with enhanced efficacy and reduced toxicity.published_or_final_versio

A Spatially Resolved Inner Hole in the Disk around GM Aurigae

We present 0.3 arcsec resolution observations of the disk around GM Aurigae with the Submillimeter Array (SMA) at a wavelength of 860 um and with the Plateau de Bure Interferometer at a wavelength of 1.3 mm. These observations probe the distribution of disk material on spatial scales commensurate with the size of the inner hole predicted by models of the spectral energy distribution. The data clearly indicate a sharp decrease in millimeter optical depth at the disk center, consistent with a deficit of material at distances less than ~20 AU from the star. We refine the accretion disk model of Calvet et al. (2005) based on the unresolved spectral energy distribution (SED) and demonstrate that it reproduces well the spatially resolved millimeter continuum data at both available wavelengths. We also present complementary SMA observations of CO J=3-2 and J=2-1 emission from the disk at 2" resolution. The observed CO morphology is consistent with the continuum model prediction, with two significant deviations: (1) the emission displays a larger CO J=3-2/J=2-1 line ratio than predicted, which may indicate additional heating of gas in the upper disk layers; and (2) the position angle of the kinematic rotation pattern differs by 11 +/- 2 degrees from that measured at smaller scales from the dust continuum, which may indicate the presence of a warp. We note that photoevaporation, grain growth, and binarity are unlikely mechanisms for inducing the observed sharp decrease in opacity or surface density at the disk center. The inner hole plausibly results from the dynamical influence of a planet on the disk material. Warping induced by a planet could also potentially explain the difference in position angle between the continuum and CO data sets.Comment: 12 pages, 6 figures, accepted for publication in Ap

Perspectives of Zambian Clinical Oncology Trainees in the MD Anderson and Zambia Virtual Clinical Research Training Program (MOZART)

BACKGROUND: African countries are underrepresented in cancer research, partly because of a lack of structured curricula on clinical research during medical education. To address this need, the MD Anderson and Zambia Virtual Clinical Research Training Program (MOZART) was developed jointly by MD Anderson Cancer Center (MDA) and the Cancer Diseases Hospital in Zambia (CDH) for Zambian clinical oncology trainees. We explored participant perspectives to provide insight for implementation of similar efforts. MATERIALS AND METHODS: The MD Anderson and Zambia Virtual Clinical Research Training Program consisted of weekly virtual lectures and support of Zambian-led research protocols through longitudinal mentorship groups that included CDH faculty and MDA peer and faculty mentors. Participants were contacted via email to take part in semi-structured interviews, which were conducted via teleconference and audio-recorded, transcribed, and coded. Emergent themes were extracted and are presented with representative verbatim quotations. RESULTS: Thirteen of the 14 (93%) trainees were interviewed. Emergent themes included (1) participants having diverse educational backgrounds but limited exposure to clinical research, (2) importance of cancer research specific to a resource-constrained setting, (3) complementary roles of peer mentors and local and international faculty mentors, (4) positive impact on clinical research skills but importance of a longitudinal program and early exposure to clinical research, and (5) challenges with executing research protocols. CONCLUSION: To our knowledge, this is the first qualitative study of African clinical oncology trainees participating in a virtual clinical research training program. The lessons learned from semi-structured interviews with participants in MOZART provided valuable insights that can inform the development of similar clinical research training efforts and scale-up

Performance of Epigenetic Markers SEPT9 and ALX4 in Plasma for Detection of Colorectal Precancerous Lesions

BACKGROUND: Screening for colorectal cancer (CRC) has shown to reduce cancer-related mortality, however, acceptance and compliance to current programmes are poor. Developing new, more acceptable non-invasive tests for the detection of cancerous and precancerous colorectal lesions would not only allow preselection of individuals for colonoscopy, but may also prevent cancer by removal of precancerous lesions. METHODS: Plasma from 128 individuals (cohort I - exploratory study: 73 cases / 55 controls) was used to test the performance of a single marker, SEPT9, using a real-time quantitative PCR assay. To validate performance of SEPT9, plasma of 76 individuals (cohort II - validation study: 54 cases / 22 controls) was assessed. Additionally, improvement of predictive capability considering SEPT9 and additionally ALX4 methylation was investigated within these patients. RESULTS: In both cohorts combined, methylation of SEPT9 was observed in 9% of controls (3/33), 29% of patients with colorectal precancerous lesions (27/94) and 73% of colorectal cancer patients (24/33). The presence of both SEPT9 and ALX4 markers was analysed in cohort II and was observed in 5% of controls (1/22) and 37% of patients with polyps (18/49). Interestingly, also 3/5 (60%) patients with colorectal cancer were tested positive by the two marker panel in plasma. CONCLUSIONS: While these data confirm the detection rate of SEPT9 as a biomarker for colorectal cancer, they also show that methylated DNA from advanced precancerous colorectal lesions can be detected using a panel of two DNA methylation markers, ALX4 and SEPT9. If confirmed in larger studies these data indicate that screening for colorectal precancerous lesions with a blood-based test may be as feasible as screening for invasive cancer