Wheels When Who Wants Them: Assessing Social Equity and Access Implications of Carsharing in NYC

Carsharing operations such as Zipcar have grown in popularity in the last two decades, and provide a case study for examining transportation equity. These programs provide a vehicle to rent by the hour or day usually based on an hourly fee and an annual membership fee. The service provides a transportation alternative that could reduce economic and environmental costs of car use, and increase access -- ultimately creating a more sustainable transportation network. However, as with many transportation investments, it is unclear whether these benefits are actually accruing to those with the most limited transport options. Governments subsidize carsharing operations through free parking for shared vehicles; New York City has even altered its zoning code to promote carsharing and encourages the system through PlaNYC 2030. Public subsidization provides the impetus for analyzing private carshare providers through a social justice framework. This thesis will examine whether the distribution of Zipcars (the largest carsharing operator in NYC) is socially equitable, and whether carsharing could potentially increase transport equity through alternative carshare models. The study uses mixed methods including spatial and statistical analysis of carshare density to determine if shared vehicles are correlated with equity variables, controlling for feasibility indicators. This research also includes an intercept survey to determine the barriers and potential of carsharing for non-work trips. The results indicate that shared vehicle density is most closely related to low car ownership, high level of alternative commuters, and high level of education; and that both spatial and corporate barriers exclude segments of the public from participating in the service. Expanding the opportunity to access carsharing through community-based innovations and government intervention could create a more equitable and sustainable transportation system

Resilience Programming for Occupational Therapy Students: A Mixed-Methods Exploration

Occupational therapy students and practitioners experience high levels of stress due to classroom and professional demands which can lead to burnout. Resilience is found as a protective factor against stress and burnout. Resilience can be defined as the different ways systems work together to achieve better results than expected, after experiencing adversity. Concepts related to resilience include social connection, self-efficacy, and mindfulness. Research done on resilience programming for students has been shown to support students in navigating the hardships of college. Resilience programming has been found to be effective for occupational therapists in the workplace during high work demands. However, there is very little existing research done on resilience programming for occupational therapy students. This research study investigated a resilience program for OT students at Dominican University of California and specifically aimed to explore the perceived value, utilization, and impact of the programming. This study utilized a mixed-methods explanatory design consisting of an online survey and semi- structured interviews. Results from the survey showed that students found co-curricular resources most valuable, with curricular being second, and passive programming being third. Results from the survey showed that curricular programming was the most utilized, then passive programming, and third was co-curricular programming. In the interviews, students cited social connection in their responses as to why resilience programming was valuable. Barriers to participation included lack of accessibility due to academic workloads, commuting to events, student work schedules, and funding. This research provides valuable insights for other OT programs to develop resilience initiatives and the role of resilience in preparing students for future careers

Exploration of a Novel Approach to Measure Brain Smudging in Dancers

Objective Obtain baseline accuracy measurements of right/left discrimination in actively performing dancers without performance-inhibiting injuries. Purpose Gather data that can be used in future studies to expand understanding of brain smudging in dancers. Methods This study is a prognostic cohort study. This study will involve participant use of a simple iPad application to do the left and right discrimination test that is suggested to give information on brain reorganization, or brain smudging Research Problem The specific physical, mental, and emotional demands of dancers’ careers put constant strain on their bodies to perform at the level required and can lead to injury or a higher risk for reinjury. 1,2,3,4Traditional interventions often do not address central consequences of injury on the body, such as motor cortex reorganization, or brain smudging. 5,6The degree of brain smudging that occurs in injured dancers is currently unknown. Ability to discriminate between right and left sides of the body has been proposed as a means of measuring this smudging.7,8,9,1 Results Mean accuracies out of 100 were as follows: right hand was 62.73 (n=22, SD=23.53), left hand was 61.36 (n=22, SD=16.99), right foot was 94.09 (n=22,SD=11.41), and left foot was 91.82 (n=22, SD=14.02). Conclusions The heavier workload that is typically placed on the lower extremities relative to the upper extremities may explain some of the lower accuracy in the hands in this population. 1,2 Further research is needed to establish scores in those with current injuries and determine whether those scores are predictive of future injury

Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Cascade Inhibitors: How Mutations Can Result in Therapy Resistance and How to Overcome Resistance

The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Integral components of these pathways, Ras, B-Raf, PI3K, and PTEN are also activated/inactivated by mutations. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of these pathways can contribute to chemotherapeutic drug resistance, proliferation of cancer initiating cells (CICs) and premature aging. This review will evaluate more recently described potential uses of MEK, PI3K, Akt and mTOR inhibitors in the proliferation of malignant cells, suppression of CICs, cellular senescence and prevention of aging. Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways play key roles in the regulation of normal and malignant cell growth. Inhibitors targeting these pathways have many potential uses from suppression of cancer, proliferative diseases as well as aging

A strategy for constructing aneuploid yeast strains by transient nondisjunction of a target chromosome

<p>Abstract</p> <p>Background</p> <p>Most methods for constructing aneuploid yeast strains that have gained a specific chromosome rely on spontaneous failures of cell division fidelity. In <it>Saccharomyces cerevisiae</it>, extra chromosomes can be obtained when errors in meiosis or mitosis lead to nondisjunction, or when nuclear breakdown occurs in heterokaryons. We describe a strategy for constructing N+1 disomes that does not require such spontaneous failures. The method combines two well-characterized genetic tools: a conditional centromere that transiently blocks disjunction of one specific chromosome, and a duplication marker assay that identifies disomes among daughter cells. To test the strategy, we targeted chromosomes III, IV, and VI for duplication.</p> <p>Results</p> <p>The centromere of each chromosome was replaced by a centromere that can be blocked by growth in galactose, and <it>ura3::HIS3</it>, a duplication marker. Transient exposure to galactose induced the appearance of colonies carrying duplicated markers for chromosomes III or IV, but not VI. Microarray-based comparative genomic hybridization (CGH) confirmed that disomic strains carrying extra chromosome III or IV were generated. Chromosome VI contains several genes that are known to be deleterious when overexpressed, including the beta-tubulin gene <it>TUB2</it>. To test whether a tubulin stoichiometry imbalance is necessary for the apparent lethality caused by an extra chromosome VI, we supplied the parent strain with extra copies of the alpha-tubulin gene <it>TUB1</it>, then induced nondisjunction. Galactose-dependent chromosome VI disomes were produced, as revealed by CGH. Some chromosome VI disomes also carried extra, unselected copies of additional chromosomes.</p> <p>Conclusion</p> <p>This method causes efficient nondisjunction of a targeted chromosome and allows resulting disomic cells to be identified and maintained. We used the method to test the role of tubulin imbalance in the apparent lethality of disomic chromosome VI. Our results indicate that a tubulin imbalance is necessary for disomic VI lethality, but it may not be the only dosage-dependent effect.</p

Abstract 1224: A patient derived xenograft (PDX) platform for development of next generation KIT kinase inhibitors in imatinib-resistant gastrointestinal stromal tumors (GIST)

Abstract Despite best efforts in the treatment of gastrointestinal stromal tumors (GIST), patients continue to face a poor prognosis. That said, introduction of imatinib into clinical practice has vastly improved outcomes for KIT positive patients. However, as with many kinases, resistance has developed into a clinical dilemma, rendering the drug ineffective. A number of resistance mutations have previously been identified including the well known D816 activating mutation. To overcome this challenge, we have established a set of GIST patient derived xenograft models to recapitulate the original patient tumor, including genetics of resistance. In this work, we show four primary GIST samples which were selected based on mutational and clinical profile. PDX models were developed in immunocompromised mice and were further characterized by immunohistochemistry, additional sequencing and pharmacological efficacy. We then evaluated the efficacy of chemotherapeutic agents in these models. We describe imatinib resistance mutations, and demonstrate in vivo efficacy of dasatinib over imatinib in the resistant GIST PDX model. Take together, this data validates these GIST PDX models as a novel platform for the evaluation of new drug candidates to better delay and circumvent resistance now found in the clinic. Citation Format: Chelsea Mullins, Jill Ricono, Patrick Carson, Gaston Habets, Rafe Shellooe, Hoa Nguyen, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair. A patient derived xenograft (PDX) platform for development of next generation KIT kinase inhibitors in imatinib-resistant gastrointestinal stromal tumors (GIST). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1224. doi:10.1158/1538-7445.AM2014-1224</jats:p

Abstract PR06: Integrated epigenomic profiling reveals widespread demethylation in melanoma and reveals CSF-1 Receptor as an aberrant regulator of malignant growth and invasion

Abstract Epigenetic changes in cancer are thought to contribute to regulation of tumor invasion and metastasis, but this previously has not been studied at a genome wide level in melanoma. We analyzed the methylome of 44 cases of malignant melanoma with the HELP (HpaII tiny fragment enriched by LM-PCR) assay and compared it with healthy melanocyte controls. We observed widespread demethylation in malignant melanoma, preferentially outside of CpG islands. The epigenomic loss of methylation was independent of mutational status of BRAF, RAS and Kit. Comparison of primary and metastatic lesions demonstrated that demethylation occurs early during carcinogenesis with very few additional alterations in advanced tumors. Parallel transcriptomic analysis revealed many known and novel oncogenic pathways that were aberrantly expressed and regulated by loss of DNA methylation. Strikingly, the colony stimulating factor-1 receptor (CSF1R, c-fms) was aberrantly expressed and hypomethylated in nearly all cases. CSF1R is a transmembrane tyrosine kinase receptor that predominantly regulates macrophages, osteoclasts, and microglia, but is known to sometimes be aberrantly expressed by malignant cells in Hodgkins lymphoma. The expression of CSF1R on malignant melanocytes was validated by immunohistochemical analysis of primary tumors. In several melanoma cell lines (A2058, WM-266-4, SK-MEL-2, M14c#5) we found through PCR sequencing of the cDNA 5′ untranslated region that the CSF1R can be expressed through an aberrant promoter, as has been described for Hodgkin lymphoma. A custom Taqman assay was developed for this unique transcript, and then used to detect the transcript in 4 of 40 samples in a panel of melanoma biopsies, suggesting that aberrant CSF1R expression in melanoma is not uncommon. Expression of CSF1R protein in the cell lines was confirmed by FACS using anti-CD115 antibodies, and by Western blot using antibodies directed to the C-terminus. Expression of the ligand CSF-1 was also found in the melanoma cells by both ELISA and Taqman assays. Inhibition of in vitro cell growth by PLX3397, a clinically relevant small molecule inhibitor of CSF1R kinase, could be observed in 3D cell culture, indicating that under some conditions an autocrine stimulation of growth occurs. shRNA mediated knockdown of CSF1R also demonstrated decreased colony size and increased apoptosis in 3D culture conditions. The invasiveness of melanoma cells was decreased after treatment with PLX3397 or anti-CSF1 antibodies, suggesting a role for melanoma cancer cell expression of CSF1R in metastasis. Since three of cell lines possess an oncogenic BRAF mutation, co-inhibition of CSF1R and BRAF was tested and resulted in synergistic blockade of cell growth in vitro and A2058 xenograft growth in vivo. The CSF1R inhibitor, PLX3397, is under investigation in clinical trials for breast, glioma, and other cancers, and these data present a preclinical rationale for its study in malignant melanoma. This abstract is also being presented as Poster A06. Citation Format: Orsolya Giricz, Yongkai Mo, Caroline Hu, Kimberly Dahlman, Sanchari Bhattacharyya, Hoa Nguyen, Bernice Matusow, Tushar Bhagat, Yiting Yu, Rafe Shellooe, Elizabeth Burton, Gaston Habets, John Greally, Kenny Paraic, Jeffrey Sosman, Gideon Bollag, Brian West, Amit Verma. Integrated epigenomic profiling reveals widespread demethylation in melanoma and reveals CSF-1 Receptor as an aberrant regulator of malignant growth and invasion. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr PR06.</jats:p

Abstract 3332: Aberrant expression of CSF1R in melanoma is driven through an endogenous viral promoter and it contributes to malignant growth and the acquisition of resistance against BRAF inhibition

Abstract Epigenetic changes in cancer are thought to contribute to regulation of invasion and metastasis. To study this at a genome-wide level in melanoma we analyzed the methylome of 44 cases of malignant melanoma. We saw widespread demethylation in melanoma occurring preferentially outside of CpG islands. Comparison of primary and metastatic lesions showed demethylation occurs early during carcinogenesis with few additional alterations in advanced tumors. The colony stimulating factor-1 receptor was aberrantly expressed and hypomethylated in nearly all cases. The expression of CSF1R was validated by IHC on primary tumors and by qPCR and Western blotting in BRAF mutant and WT cell lines. CSF1R can be aberrantly expressed via an upstream LTR element in Hodgkin’s lymphoma. After analyzing our patient samples and the cell lines, we have found this aberrant transcript may be the dominant form in melanoma as well. Expression of one of its ligands IL34 was also shown in the cell lines by both ELISA and qPCR pointing to a potential autocrine regulatory loop. The effects of a small molecule inhibitor, PLX3397 as well as shRNA-mediated knockdown of the receptor were investigated in 2D and 3D cell culture. We saw inhibition of cell growth, smaller colony size, increased apoptosis and decreased invasiveness - suggesting a functional role for CSF1R in melanoma. Treatment of melanoma with small molecule inhibitors of BRAF V600E is effective for a time, but resistance invariably develops. The feedback activation of EGFR, BRAF amplification, BRAF splice variants and others are known to aid in the acquisition of resistance and the rebound activation of the MAPK-pathway. We are suggesting a role for CSF1R in this process. In Western experiments, the rebound of phospho-ERK after BRAF inhibitor treatment was accelerated with the addition of CSF1R ligands, or delayed with PLX3397, also attenuating AKT phosphorylation. Melanoma cells stably expressing shRNA against CSF1R recapitulated the effects of the inhibitor. Assaying the cells at different time points during a long-term V600E inhibitory experiment, we saw increasing levels of the transcription factor RUNX1, followed by increasing levels of IL34 and of the receptor, as well as its maturation, evidenced by the appearance of the high MW form. Utilizing shRNA-mediated knockdown of RUNX1 resulted in lower levels of the CSF1R and IL34 transcripts and delayed the rebound. Analysis of primary RNA-Seq data showed an increase in RUNX1, CSF1R and IL34 expression in resistant tumors. Co-inhibition of CSF1R and BRAF was also tested and resulted in synergistic blockade of cell growth in vitro and xenograft growth in vivo. The CSF1R inhibitor, PLX3397 is currently in clinical trials for glioblastoma, prostate, breast cancers and other cancers. These data present a preclinical rationale for its study in malignant melanoma. Citation Format: Orsolya Giricz, Yongkai Mo, Caroline Y. Hu, Yiting Yu, Kith Pradhan, Matthias Bartenstein, Nandini Ramachandra, Veronika Polishchuck, Kimberly B. Dahlman, Tushar Bhagat, Hoa Nguyen, Bernice Matusow, Rafe Shellooe, Elizabeth Burton, Paraic Kenny, John Greally, Jeffrey Sosman, Gideon Bollag, Brian West, Amit Verma. Aberrant expression of CSF1R in melanoma is driven through an endogenous viral promoter and it contributes to malignant growth and the acquisition of resistance against BRAF inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3332. doi:10.1158/1538-7445.AM2017-3332</jats:p