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Joop Jansen and colleagues show that myelodysplastic syndromes frequently harbor somatic mutations in TET2 . Analysis of lineage markers suggests that TET2 mutations are early events contributing to malignant transformation. Myelodysplastic syndromes (MDS) represent a heterogeneous group of neoplastic hematopoietic disorders 1 . Several recurrent chromosomal aberrations have been associated with MDS, but the genes affected have remained largely unknown. To identify relevant genetic lesions involved in the pathogenesis of MDS, we conducted SNP array–based genomic profiling and genomic sequencing in 102 individuals with MDS and identified acquired deletions and missense and nonsense mutations in the TET2 gene in 26% of these individuals. Using allele-specific assays, we detected TET2 mutations in most of the bone marrow cells (median 96%). In addition, the mutations were encountered in various lineages of differentiation including CD34 + progenitor cells, suggesting that TET2 mutations occur early during disease evolution. In healthy tissues, TET2 expression was shown to be elevated in hematopoietic cells with highest expression in granulocytes, in line with a function in myelopoiesis. We conclude that TET2 is the most frequently mutated gene in MDS known so far.

In response to demands for public accountability and improved teaching and learning, institutions are recognizing the need to strengthen their faculty development programs. Central to strengthening faculty development programs is increasing faculty participation in these programs. This mixed-method study examined the motivation of full and part-time faculty to seek development, obstacles to attending, as well as preferred formats across four institutions. Results indicate that full-time faculty seek more development than part-time faculty across institutions. At some institutions, the preferred format of faculty development contributed to differences among the types of faculty. Despite efforts to offer short workshops and faculty development online, in this study full time faculty tended not to value short workshops or online activities and instead preferred such things as books, videos, or even attending retreats. The results of this study suggest that faculty developers should begin thinking differently about the types and the frequency of faculty development.

Every year thousands of overweight and obese people in the United States join weight loss programs such as Weight Watchers in an effort to become healthier and feel more attractive. Weight Watchers has increased its program focus on physical activity as a critical part of weight loss. Initiating a consistent physical activity routine, however, is generally one of the last behavior changes made by program members, despite its proven role in weight loss maintenance. Using self-determination theory as a framework, the purpose of this study was to examine how perceptions of fulfillment of three psychological needs (i.e. competence, autonomy, and relatedness), affected the motivation and physical activity patterns of five female Lifetime members of Weight Watchers, with the goal of exploring ways to facilitate motivation for physical activity in weight loss programs. The level of self-regulated motivation was also examined. Participants completed a Psychological Need Satisfaction in Exercise Questionnaire, kept written exercise logs, and participated in an in depth interview. Perceived need satisfaction for competence and autonomy facilitated participation in physical activity, but perceived relatedness was a key to overall psychological need satisfaction. Family, mind/body connections, and structure emerged as factors that served to enhance or constrain need satisfaction, and ultimately as either catalysts promoting need satisfaction or barriers to activity. Four participants mentioned guilt, an introjected externally-regulated motivation, as one motive for engaging in activity, but all five mentioned better health as a more internally-regulated motivation for their activity behaviors. Only one participant made comments that could be classified as indicative of intrinsic motivation for physical activity. The findings suggest that for weight loss programs to help their members lose weight, and keep it off, participation in physical activity should be introduced in a way that motivates the members to incorporate it into their daily routines. Stressing improved health and fitness as a valued outcome of regular participation in physical activity and encouraging individuals to identify ways to satisfy the psychological need of relatedness through family support and structure are strategies that emerged in this study as having the potential to facilitate long term behavior change.

The responses of 250 faculty members to questions about \"good\" teaching were analyzed by gender as well as by rank and discipline. Interesting differences between the responses of the female and male professors emerged from the analyses, although overall there were relatively few gender-related ones.

We assessed the prognostic impact of TET2 mutations and mRNA expression in a prospective cohort of 357 adult AML patients < 60 years of age enrolled in the European Organization For Research and Treatment of Cancer (EORTC)/Gruppo Italiano Malattie Ematologiche dell’ Adulto (GIMEMA) AML-12 06991 clinical trial. In addition the co-occurrence with other genetic defects and the functional consequences of TET2 mutations were investigated. TET2 mutations occurred in 7.6 % of the patients and were an independent marker of poor prognosis ( p  = 0.024). TET2 and IDH1 / 2 mutations strongly associated with aberrations in the DNA methyltransferase DNMT3A . Functional studies confirmed previous work that neither nonsense truncations, nor missense TET2 mutations, induced 5-hydroxymethylcytosine formation. In addition, we now show that mutant TET2 forms did not act in a dominant negative manner when co-expressed with the wild-type protein. Finally, as loss-of-function TET2 mutations predicted poor outcome, we questioned whether low TET2 mRNA expression in cases of AML without TET2 mutations would affect overall survival. Notably, also AML patients with low TET2 mRNA expression levels showed inferior overall survival.

The most imperative issues for ovarian carcinoma patients, due to high relapse rates against mainstay therapies, is to identify new molecular targets and develop novel therapeutics. This dissertation aims to address both of these issues by (1) defining the role, regulation and mechanism of Rho Guanine Nucleotide Dissociation Inhibitor 2 (RhoGDI2) in ovarian carcinoma and (2) testing nitric oxide (NO)-releasing nanoparticles as a potential targeted therapy for ovarian carcinoma. For the first part of my thesis, I demonstrated that RhoGDI2 protein expression is elevated in ovarian carcinoma cell lines and knockdown of RhoGDI2 in HeyA8 ovarian carcinoma cells results in increased Matrigel invasion and tail-vein lung metastasis of HeyA8 cells. RhoGDI2 associates primarily with Rac1 in HeyA8 cells and knockdown of RhoGDI2 decreases Rac1 activity and translocates Rac1 from the cytosol to membrane protrusions. Mechanistically, the phosphorylation of the MKK3/6/p38/JNK components of a key pathway downstream of Rac1, which is known to be important for ovarian cancer metastasis, decreased following RhoGDI2 knockdown in HeyA8 cells. My results suggest that RhoGDI2 overexpression contributes to the metastatic phenotype of ovarian carcinoma cells, although the exact mechanism responsible remains to be uncovered. For the second part of my thesis, I determined anti-tumor efficacy of NO-releasing silica nanoparticles against ovarian carcinoma cells. The NO-releasing nanoparticles display enhanced growth inhibition against ovarian tumor cells when compared to both control nanoparticles and a previously developed NO donor drug, PYRRO/NO. Confocal msicroscopy analysis revealed that fluorescently-labeled nanoparticles entered the cytosol of the cell, released NO, and localized to late endosomes and lysosomes. Additionally, we observed that nanoparticle efficacy against normal versus transformed ovarian cells depended on their size. Our study demonstrates the first application of nanoparticle-derived NO as an antitumor therapy. Collectively, my studies validated RhoGDI2 as a metastasis suppressor in ovarian carcinoma and supported the anti-tumor efficacy of nanoparticle delivery of NO.

The improvement of teaching is a constant need in colleges and universities, but commitment, resources, and strategies devoted to the task rise and fall from time to time and place to place. To test the proposition that competent teachers are made, not born, the author examined approaches to teaching taken by twelve outstanding instructors. The results suggest the promise of persistent, individual effort based on reflective practice and incremental improvement.