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Addressing the Hippo in the Room: Investigating the Mechanism of YAP/TAZ as a Treatment Target in Clear Cell Renal Cell Carcinoma
No full textPh.D.Clear Cell Renal Cell Carcinoma (ccRCC) is the most common subtype of kidney neoplasms characterized by a near universal inactivation of the von Hippel-Lindau (VHL) tumor suppressor protein. Targeted therapies that inhibit the unfettered transcriptional signaling of Hypoxia-inducible Factor 2ɑ (HIF2ɑ) transcription factor and its downstream pro-angiogenic effectors, consequential to VHL loss, has undoubtedly improved patient survival. Despite these improvements, a substantial fraction of patients with advanced ccRCC experience upfront or acquired resistance to presently available treatment options, warranting the investigation into adjunct therapies capable of improving efficacy and response duration to existing treatments. Assessing tumor copy number alteration, methylation, and expression data from large ccRCC patient cohorts, we demonstrate that dysregulation of the Hippo tumor suppressor pathway occurs commonly in ccRCC, correlates with increased YAP/TAZ target gene expression, and is associated with worse overall survival in treatment naïve patients. In addition, we showed that high YAP/TAZ gene signature is associated with poor treatment response to therapies that target HIF2ɑ-VEGF signaling. In vivo efficacy studies with a first-in-class TEAD palmitoylation inhibitor or YAP/TAZ-targeted shRNAs showed both forms of YAP/TAZ silencing substantially delays the development of acquired resistance to a clinical HIF2ɑ inhibitor in a ccRCC xenograft model sensitive to HIF2ɑ inhibition. Moreover, the TEAD inhibitor also exhibited profound single agent anti-tumor efficacy in a patient-derived ccRCC xenograft model of upfront resistance to HIF2ɑ-targeted treatments. By combining ATAC-seq, BRB-seq and Cut&Tag analysis, we assessed the chromatin binding and gene regulation of YAP and HIF2ɑ, and unveiled that these two proteins are co-recruited to AP-1 sites through interactions with the AP-1 transcription factors. YAP/TAZ, HIF2ɑ and JUN are dependent on each other to maintain their expression, and function cooperatively to promote the expression of highly expressed transcription factors and other important oncogenes. Our findings not only revealed the therapeutic potentials of adjunct YAP/TAZ-based therapies in the treatment of advanced ccRCC, but also revealed novel mechanistic insights into the dynamic interactions among YAP, HIF2ɑ and AP-1 proteins that could be further exploited to improve treatment for ccRCC
A Hidden Economic Growth Engine? The Impact of Second-Generation Immigrants in the U.S.
No full textPh.D.This project studies the causal impact of second-generation immigrants (US-born with at least one foreign-born parent) in the United States on real per-worker GDP using county-level data from 2001 to 2021. My analysis shows that an increase in the second-generation immigrant shares on average increases real per-worker GDP. First-generation immigrants, on the other hand, do not have a significant impact on GDP. The GDP effect of second-generation immigrants varies depending on their skill levels. The high-skilled second-generation immigrants have their impact driven by STEM workers' contribution to technological innovation, while the low-skilled group's influence on local growth is strengthened in counties with more college-graduated non-second-generation workers. These patterns that I observe also vary for high- and low-skilled second-generation immigrants from different countries of origin
Book Review: Fiction, Philosophy, and the Ideal of Conversation, by Erin Elizabeth Greer. Edinburgh: Edinburgh University Press, 2024, 234 p., ISBN 9781399520218
No full textReview of - Fiction, Philosophy, and the Ideal of Conversation, by Erin Elizabeth Greer. Edinburgh: Edinburgh University Press, 2024, 234 p., ISBN 9781399520218https://doi.org/10.57928/mr7z-fm4
Measuring soft power in international relations - UNESCO international education historical data
No full textCommunications Culture and Technology ProgramMeasuring soft power in international relations by Irene S. Wu, Ph.D. (Lynne Reinner, 2024)
The Soft Power Rubric tracks changes in the volume and direction of interactions that people have with foreigners. Three elements are direct people-to-people interactions: emigrating, studying abroad, and traveling abroad. The fourth element is a mediated interaction: watching foreign movies. Emigration reflects a person’s ultimate integration in a foreign society, permanently moving family and home to another country. Studying abroad reflects a person’s serious interest and commitment to understanding another society by spending substantial financial resources and formative time in a foreign country. Visiting a foreign country reflects a short-term interest in a foreign society. Watching a movie expresses an interest or curiosity about another country.
For UNESCO international education data from 1960–1990 and UN Population Division migration data from 1960–1980, which are primarily available in printed statistical books, I have made digital versions available at Digital Georgetown (library.georgetown.edu/digitalgeorgetown), the university’s digital repository.
International Education: United Nations Educational, Scientific, and Cultural Organization (UNESCO)
• 1963–1999. UNESCO Statistical Yearbooks. Bibliographic information available at unevoc.unesco.org/home/UNESCO+Publications
• 1999 onward. See number and rates of international mobile students, inbound internationally mobile students by country of origin. Data- base available at data.uis.unesco.org
International Migrant Stock: United Nations Population Division
• 1960, 1970, 1980: United Nations Demographic Yearbook. 1977 and 1989 yearbooks feature migration data. Digitally scanned yearbooks available for download at unstats.un.org/unsd/demographic-social /products/dyb/index.cshtml#overview
• 1990 onward available at www.un.org/development/desa/pd/content /international-migrant-stoc
The Role of Conventional Counterforce in NATO Strategy: Historical Precedents and Present Opportunities
No full textAssociation Between Breast Cancer Treatment Type and Health Related Quality of Life
No full textM.S.More women are surviving breast cancer with many women reporting health-related quality of life is implicated in breast cancer survivorship. Many studies have been done to understand the predictors of health-related quality of life. Other studies have found that health related quality of life in breast cancer survivors and the prevalence of fear of cancer recurrence is negatively associated. In this study, it is hypothesized that treatment type received, and health-related quality of life are associated. If an association is found between health-related quality of life, fear of cancer recurrence will be tested to see if it acts as a mediator on this association. It is hypothesized that fear of cancer recurrence acts as a mediator on the association between treatment and health related quality of life. When testing for the association between treatment types and health-related quality of life subscales, no associations were found. There were no associations found between treatments and fear of cancer recurrence. Due to this, fear of cancer recurrence was not tested as a mediator. Demographic variables income (p=0.0392), age (p=0.0153), and menopausal status (p=0.0086) found associations with social well-being. This was untrue when adjusting for all variables. In In the future, this association should be studied on a larger sample size, there is a possibility of a lower power causing the inability to detect an association.
Carbon-Fluorine Bond Functionalization with Organometallic Reagents
No full textPh.D.Fluorinated organic compounds receive considerable attention and are frequently used in numerous chemical development projects across the chemical and life sciences. A large, structurally diverse pool of alkyl fluorides is nowadays available but the notorious thermodynamic stability and chemical inertness of the C(sp3)-F bond continues to limit synthetic applications that trail far behind the widely accepted utility of other alkyl halides. A methodology for broadly useful cross-coupling of alkyl fluorides with organozinc compounds was developed, featuring short-lived ion-pairing zincate cluster intermediates primed for fast C-C bond formation. This approach overcomes long-standing limitations of organometallic C(sp2)-C(sp3) cross-coupling methodology, and it is mechanistically different from previously reported radical reactions between organozinc compounds and alkyl halides. The C(sp3)-F bond functionalization method presented herein expands the currently restricted synthetic space of challenging unactivated primary, secondary and tertiary C(sp3)-F bonds but it is also applicable to benzylic, propargylic and acyl fluorides. A large variety of functional groups and sterically demanding substrates are tolerated, which sets the stage for unprecedented synthetic opportunities that recognize alkyl fluorides as attractive starting materials for practical carbon-carbon bond formation and late-stage functionalization.
Another methodology for practical and high-yielding functionalization of the C-F bond,
at temperatures as low as -78 °C, in short reaction times and with unprecedented chemoselectivity was developed. Smooth C(sp3)-F bond cleavage using fluorophilic organoaluminum compounds under cryogenic conditions together with fast nucleophile transfer of intermediate ate complexes forge carbon-carbon bonds with non-activated primary, secondary and tertiary alkyl fluorides. This approach is highly selective toward C(sp3)-F bond functionalization whereas many other functional groups including chlorides, bromides and iodides are perfectly tolerated, a fundamental reversal of long standing alkyl halide reactivity trend presumptions.
In addition, we have found a rare sequence of C-F bond activation and C-C bond cleavage with 4-fluoropiperidines and organoaluminum reagents resulting in the formation of unsaturated tertiary amines. This reaction gives excellent yields at room temperature without by-product formation. X-ray crystallographic analysis of cationic reaction intermediates gave a unique snapshot of the ring-opening process. Intermediate isolation and chemical trapping/control experiments points to a stepwise C-F cleavage, ring opening, and nucleophile delivery sequence