Setsuko K Chambers
- Professor, Obstetrics and Gynecology
- Professor, Obstetrics and Gynecology (Banner)
- Professor, Medicine
- Professor, Cancer Biology - GIDP
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1. CSF-1 and its role in neoplastic progression and metastasis of ovarian cancer; the role of RNA binding proteins and miRNAs in regulation of CSF-1 expression.2. Androgens and neoplastic transformation of normal ovarian surface epithelium.3. The c-fms proto-oncogene and breast cancer invasiveness and bone metastasis; mechanism of regulation of c-fms expression novel c-fms RNA binding proteins and miRNAs.
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- Hoyer, P. B., Rice, P. F., Howard, C. C., Koevary, J. W., Dominguez Cooks, J. P., Hutchens, G. V., Chambers, S. K., Craig, Z. R., Connolly, D. C., & Barton, J. K. (2019). Comparison of Reproductive Function in Female Transgenic and Wildtype C57BL/6 Mice. Comparative medicine, 69(1), 16-21.More infoTransgenic (TAg) mice express the oncogenic virus SV40 in Mullerian epithelial cells. Female TAg mice spontaneously develop epithelial ovarian carcinoma, the most common type of ovarian cancer in women. Female TAg mice are infertile, but the reason has not been determined. We therefore investigated whether female TAg mice undergo puberty, demonstrate follicular development, maintain regular cycles, and ovulate. Ovarian cancers in women commonly develop after menopause. The occupational chemical 4-vinylcyclohexene diepoxide (VCD) accelerates follicle degeneration in the ovaries of rats and mice, causing early ovarian failure. We therefore used VCD dosing of mice to develop an animal model for menopause. The purpose of this study was to characterize reproductive parameters in female TAg mice and to investigate whether the onset of ovarian failure due VCD dosing differed between female TAg and WT C57BL/6 mice. As in WT female mice, TAg female mice underwent puberty (vaginal opening) and developed cyclicity in patterns that were similar between the groups. Vehicle-only TAg mice had fewer ovulations (numbers of corpora lutea) than WT animals. VCD exposure delayed the onset of puberty (day of first estrus) in TAg as compared with WT mice. Morphologic evaluation of ovaries revealed many more degenerating follicles in TAg mice than WT mice, and more VCD-dosed TAg mice were in ovarian failure than VCD-dosed WT mice. These results suggest that despite showing similar onset of sexual maturation, TAg mice have increased follicular degeneration and fewer ovulations than WT. These features may contribute to the inability of female TAg mice to reproduce.
- Pandey, R., Woo, H. H., Varghese, F., Zhou, M., & Chambers, S. K. (2019). Circulating miRNA Profiling of Women at High Risk for Ovarian Cancer. Translational oncology, 12(5), 714-725.More infoSurvival of epithelial ovarian cancer patients remains poor without significant change over many decades. There is a need to better identify women at high risk (HR) for ovarian cancer. We propose that miRNA dysregulation may play critical roles in the early stages of ovarian cancer development. Circulating miRNAs may represent an important biomarker in this context, and miRNA profiling of serum in women at HR compared to those at low risk (LR) may give insights in tumor initiation pathways. There is also rationale for a specific focus on regulation of the androgen and its related hypoxia pathways in tumor initiation. We hypothesized that subsets of these pathway related miRNAs may be downregulated in the HR state. Serum from four HR and five LR women were sequenced and analyzed for 2083 miRNAs. We found 137 miRNAs dysregulated between the HR and LR groups, of which 36 miRNAs were overexpressed in HR and the vast majority (101 miRNAs or 74%) downregulated in the HR, when compared to LR serum. mRNA targets for the differentially expressed miRNAs were analyzed from three different miRNA-mRNA interaction resources. Functional association analysis of hypoxia and androgen pathway mRNA targets of dysregulated miRNAs in HR serum revealed that all but one of the miRNAs that target 52 hypoxia genes were downregulated in HR compared to LR serum. Androgen pathway analysis also had a similar expression pattern where all but one of the miRNAs that target these 135 identified genes were downregulated in HR serum. Overall, there were 91 differentially expressed miRNA-mRNA pairings in the hypoxia analysis. In the androgen-related analysis, overall, there were 429 differentially expressed miRNA-mRNA pairs. Our pilot study suggests that almost all miRNAs that are conserved and/or validated are downregulated in the HR compared to LR serum. This study, which requires validation, suggests that, via miRNA dysregulation, involvement of both hypoxia and its related androgen pathways may contribute to the HR state. This pilot study is the first report to our knowledge that studies circulating miRNA profiling of HR and LR women.
- Woo, H. H., & Chambers, S. K. (2019). Human ALKBH3-induced mA demethylation increases the CSF-1 mRNA stability in breast and ovarian cancer cells. Biochimica et biophysica acta. Gene regulatory mechanisms, 1862(1), 35-46.More infoIn ovarian and breast cancers, the actions of the cytokine CSF-1 lead to poor prognosis. CSF-1 expression can be regulated post-transcriptionally. RNA methylation is another layer of posttranscriptional regulation. The methylation of N atom of adenine (mA) results in a conformational change of RNA which regulates translational efficiency. Our study indicates that the mA is also involved in the CSF-1 mRNA decay. The alteration of ALKBH3 expression, an mA demethylase, regulates the CSF-1 mRNA stability. Demethylation of mA by ALKBH3 increases the half-life of CSF-1 mRNA without affecting the translation efficiency. The mA in CSF-1 mRNA is mapped in the 5'UTR near the translation initiation site. YTHDF2, a known mA reader which interacts with the CCR4-NOT deadenylation complex, is not the reader of mA-containing CSF-1 mRNA. Overexpression of ALKBH3 increases CSF-1 expression and the degree of cancer cell invasiveness without affecting cell proliferation or migration. Collectively, we showed that CSF-1 mRNA decay can be regulated at an epigenetic level, and that alteration of the N‑methylation status leads to phenotypic changes in cancer cell behavior.
- Fader, A. N., Roque, D. M., Siegel, E., Buza, N., Hui, P., Abdelghany, O., Chambers, S. K., Secord, A. A., Havrilesky, L., O'Malley, D. M., Backes, F., Nevadunsky, N., Edraki, B., Pikaart, D., Lowery, W., ElSahwi, K. S., Celano, P., Bellone, S., Azodi, M., , Litkouhi, B., et al. (2018). Randomized Phase II Trial of Carboplatin-Paclitaxel Versus Carboplatin-Paclitaxel-Trastuzumab in Uterine Serous Carcinomas That Overexpress Human Epidermal Growth Factor Receptor 2/neu. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 36(20), 2044-2051.More infoPurpose Uterine serous carcinoma is a rare, aggressive variant of endometrial cancer. Trastuzumab is a humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2)/neu, a receptor overexpressed in 30% of uterine serous carcinoma. This multicenter, randomized phase II trial compared carboplatin-paclitaxel with and without trastuzumab in patients with advanced or recurrent uterine serous carcinoma who overexpress HER2/neu. Methods Eligible patients had primary stage III or IV or recurrent HER2/neu-positive disease. Participants were randomly assigned to receive carboplatin-paclitaxel (control arm) for six cycles with or without intravenous trastuzumab (experimental arm) until progression or unacceptable toxicity. The primary end point was progression-free survival, which was assessed for differences between treatment arms via one-sided log-rank tests. Results From August 2011 to March 2017, 61 patients were randomly assigned. Forty progression-free survival-related events occurred among 58 evaluable participants. Among all patients, median progression-free survival was 8.0 months (control) versus 12.6 months (experimental; P = .005; hazard ratio [HR], 0.44; 90% CI, 0.26 to 0.76). Similarly, median progression-free survival was 9.3 (control) versus 17.9 (experimental) months among 41 patients with stage III or IV disease undergoing primary treatment ( P = .013; HR, 0.40; 90% CI, 0.20 to 0.80) and 6.0 (control) versus 9.2 months (experimental), respectively, among 17 patients with recurrent disease ( P = .003; HR, 0.14; 90% CI, 0.04 to 0.53). Toxicity was not different between treatment arms, and no unexpected safety signals emerged. Conclusion Addition of trastuzumab to carboplatin-paclitaxel was well tolerated and increased progression-free survival. These encouraging results deserve further investigation to determine their impact on overall survival in patients with advanced or recurrent uterine serous carcinoma who overexpress HER2/neu.
- Lin, K. K., Harrell, M. I., Oza, A. M., Oaknin, A., Ray-Coquard, I., Tinker, A. V., Helman, E., Radke, M. R., Say, C., Vo, L. T., Mann, E., Isaacson, J. D., Maloney, L., O'Malley, D. M., Chambers, S. K., Kaufmann, S. H., Scott, C. L., Konecny, G. E., Coleman, R. L., , Sun, J. X., et al. (2018). BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. Cancer discovery.
- Woo, H. H., Lee, S. C., Gibson, S. J., & Chambers, S. K. (2017). Expression of the cytoplasmic nucleolin for post-transcriptional regulation of macrophage colony-stimulating factor mRNA in ovarian and breast cancer cells. Biochimica et biophysica acta, 1860(3), 337-348.More infoThe formation of the mRNP complex is a critical component of translational regulation and mRNA decay. Both the 5' and 3'UTRs of CSF-1 mRNA are involved in post-transcriptional regulation. In CSF-1 mRNA, a small hairpin loop structure is predicted to form at the extreme 5' end (2-21nt) of the 5'UTR. Nucleolin binds the hairpin loop structure in the 5'UTR of CSF-1 mRNA and enhances translation, while removal of this hairpin loop nucleolin binding element dramatically represses translation. Thus in CSF-1 mRNA, the hairpin loop nucleolin binding element is critical for translational regulation. In addition, nucleolin interacts with the 3'UTR of CSF-1 mRNA and facilitates the miRISC formation which results in poly (A) tail shortening. The overexpression of nucleolin increases the association of CSF-1 mRNA containing short poly (A)n≤26, with polyribosomes. Nucleolin both forms an mRNP complex with the eIF4G and CSF-1 mRNA, and is co-localized with the eIF4G in the cytoplasm further supporting nucleolin's role in translational regulation. The distinct foci formation of nucleolin in the cytoplasm of ovarian and breast cancer cells implicates the translational promoting role of nucleolin in these cancers.
- Chen, H., Klein, R., Arnold, S., Chambers, S., & Zheng, W. (2016). Cytologic studies of the fallopian tube in patients undergoing salpingo-oophorectomy. Cancer cell international, 16, 78.More infoMounting evidence suggests the fallopian tube as the origin for ovarian high grade serous carcinoma (HGSC). We attempted to identify the tubal cytological features that allow us to distinguish malignant from benign conditions.
- Jones, K. M., Randtke, E. A., Yoshimaru, E. S., Howison, C. M., Chalasani, P., Klein, R. R., Chambers, S. K., Kuo, P. H., & Pagel, M. D. (2016). Clinical Translation of Tumor Acidosis Measurements with AcidoCEST MRI. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging.More infoWe optimized acido-chemical exchange saturation transfer (acidoCEST) magnetic resonance imaging (MRI), a method that measures extracellular pH (pHe), and translated this method to the radiology clinic to evaluate tumor acidosis.
- Sinharay, S., Randtke, E. A., Jones, K. M., Howison, C. M., Chambers, S. K., Kobayashi, H., & Pagel, M. D. (2016). Noninvasive detection of enzyme activity in tumor models of human ovarian cancer using catalyCEST MRI. Magnetic resonance in medicine.More infoWe proposed to detect the in vivo enzyme activity of γ-glutamyl transferase (GGT) within mouse models of human ovarian cancers using catalyCEST MRI with a diamagnetic CEST agent.
- Tate, T. H., Baggett, B., Rice, P. F., Koevary, J. W., Orsinger, G. V., Nymeyer, A. C., Welge, W. A., Saboda, K., Roe, D. J., Hatch, K. D., Chambers, S. K., Utzinger, U., & Barton, J. K. (2016). Multispectral fluorescence imaging of human ovarian and fallopian tube tissue for early-stage cancer detection. Journal of biomedical optics, 21(5), 56005.
- Wang, X., Li, L., Cragun, J. M., Chambers, S. K., Hatch, K. D., & Zheng, W. (2016). Assessment of the Role of Intraoperative Frozen Section in Guiding Surgical Staging for Endometrial Cancer. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society, 26(5), 918-23.More infoThe aim of this study was to assess the role of intraoperative frozen section (FS) in guiding decision making for surgical staging of endometrioid endometrial cancer (EC).
- Wang, Y., Wang, Y., Zhang, Z., Park, J. Y., Guo, D., Liao, H., Yi, X., Zheng, Y., Zhang, D., Chambers, S. K., & Zheng, W. (2016). Mechanism of progestin resistance in endometrial precancer/cancer through Nrf2-AKR1C1 pathway. Oncotarget, 7(9), 10363-72.More infoProgestin resistance is a main obstacle for endometrial precancer/cancer conservative therapy. Therefore, biomarkers to predict progestin resistance and studies to gain a more detailed understanding of the mechanism are needed. The antioxidant Nrf2-AKR1C1 signal pathway exerts chemopreventive activity. However whether it plays a role in progestin resistance has not been explored. In this study, elevated levels of AKR1C1 and Nrf2 were found in progestin-resistant endometrial epithelia, but not in responsive endometrial glands. Exogenous overexpression of Nrf2/AKR1C1 resulted in progestin resistance. Inversely, silencing of Nrf2 or AKR1C1 rendered endometrial cancer cells more susceptible to progestin treatment. Moreover, medroxyprogesterone acetate withdrawal resulted in suppression of Nrf2/AKR1C1 expression accompanied by a reduction of cellular proliferative activity. In addition, brusatol and metformin overcame progestin resistance by down-regulating Nrf2/AKR1C1 expression. Our findings suggest that overexpression of Nrf2 and AKR1C1 in endometrial precancer/cancer may be part of the molecular mechanisms underlying progestin resistance. If validated in a larger cohort, overexpression of Nrf2 and AKR1C1 may prove to be useful biomarkers to predict progestin resistance. Targeting the Nrf2/AKR1C1 pathway may represent a new therapeutic strategy for treatment of endometrial hyperplasia/cancer.
- Jeffery, J. J., Lux, K., Vogel, J. S., Herrera, W. D., Greco, S., Woo, H. H., AbuShahin, N., Pagel, M. D., & Chambers, S. K. (2014). Autocrine inhibition of the c-fms proto-oncogene reduces breast cancer bone metastasis assessed with in vivo dual-modality imaging. Experimental biology and medicine (Maywood, N.J.), 239(4), 404-13.More infoBreast cancer cells preferentially home to the bone microenvironment, which provides a unique niche with a network of multiple bidirectional communications between host and tumor, promoting survival and growth of bone metastases. In the bone microenvironment, the c-fms proto-oncogene that encodes for the CSF-1 receptor, along with CSF-1, serves as one critical cytokine/receptor pair, functioning in paracrine and autocrine fashion. Previous studies concentrated on the effect of inhibition of host (mouse) c-fms on bone metastasis, with resulting decrease in osteolysis and bone metastases as a paracrine effect. In this report, we assessed the role of c-fms inhibition within the tumor cells (autocrine effect) in the early establishment of breast cancer cells in bone and the effects of this early c-fms inhibition on subsequent bone metastases and destruction. This study exploited a multidisciplinary approach by employing two non-invasive, in vivo imaging methods to assess the progression of bone metastases and bone destruction, in addition to ex vivo analyses using RT-PCR and histopathology. Using a mouse model of bone homing human breast cancer cells, we showed that an early one-time application of anti-human c-fms antibody delayed growth of bone metastases and bone destruction for at least 31 days as quantitatively measured by bioluminescence imaging and computed tomography, compared to controls. Thus, neutralizing human c-fms in the breast cancer cell alone decreases extent of subsequent bone metastasis formation and osteolysis. Furthermore, we are the first to show that anti-c-fms antibodies can impact early establishment of breast cancer cells in bone.
- Woo, H. H., Baker, T., Laszlo, C., & Chambers, S. K. (2013). Nucleolin mediates microRNA-directed CSF-1 mRNA deadenylation but increases translation of CSF-1 mRNA. Molecular & cellular proteomics : MCP, 12(6), 1661-77.More infoCSF-1 mRNA 3'UTR contains multiple unique motifs, including a common microRNA (miRNA) target in close proximity to a noncanonical G-quadruplex and AU-rich elements (AREs). Using a luciferase reporter system fused to CSF-1 mRNA 3'UTR, disruption of the miRNA target region, G-quadruplex, and AREs together dramatically increased reporter RNA levels, suggesting important roles for these cis-acting regulatory elements in the down-regulation of CSF-1 mRNA. We find that nucleolin, which binds both G-quadruplex and AREs, enhances deadenylation of CSF-1 mRNA, promoting CSF-1 mRNA decay, while having the capacity to increase translation of CSF-1 mRNA. Through interaction with the CSF-1 3'UTR miRNA common target, we find that miR-130a and miR-301a inhibit CSF-1 expression by enhancing mRNA decay. Silencing of nucleolin prevents the miRNA-directed mRNA decay, indicating a requirement for nucleolin in miRNA activity on CSF-1 mRNA. Downstream effects followed by miR-130a and miR-301a inhibition of directed cellular motility of ovarian cancer cells were found to be dependent on nucleolin. The paradoxical effects of nucleolin on miRNA-directed CSF-1 mRNA deadenylation and on translational activation were explored further. The nucleolin protein contains four acidic stretches, four RNA recognition motifs (RRMs), and nine RGG repeats. All three domains in nucleolin regulate CSF-1 mRNA and protein levels. RRMs increase CSF-1 mRNA, whereas the acidic and RGG domains decrease CSF-1 protein levels. This suggests that nucleolin has the capacity to differentially regulate both CSF-1 RNA and protein levels. Our finding that nucleolin interacts with Ago2 indirectly via RNA and with poly(A)-binding protein C (PABPC) directly suggests a nucleolin-Ago2-PABPC complex formation on mRNA. This complex is in keeping with our suggestion that nucleolin may work with PABPC as a double-edged sword on both mRNA deadenylation and translational activation. Our findings underscore the complexity of nucleolin's actions on CSF-1 mRNA and describe the dependence of miR-130a- and miR-301a-directed CSF-1 mRNA decay and inhibition of ovarian cancer cell motility on nucleolin.
- Woo, H. H., László, C. F., Greco, S., & Chambers, S. K. (2012). Regulation of colony stimulating factor-1 expression and ovarian cancer cell behavior in vitro by miR-128 and miR-152. Molecular cancer, 11, 58.More infoColony stimulating factor-1 (CSF-1) plays an important role in ovarian cancer biology and as a prognostic factor in ovarian cancer. Elevated levels of CSF-1 promote progression of ovarian cancer, by binding to CSF-1R (the tyrosine kinase receptor encoded by c-fms proto-oncogene).Post-transcriptional regulation of CSF-1 mRNA by its 3' untranslated region (3'UTR) has been studied previously. Several cis-acting elements in 3'UTR are involved in post-transcriptional regulation of CSF-1 mRNA. These include conserved protein-binding motifs as well as miRNA targets. miRNAs are 21-23nt single strand RNA which bind the complementary sequences in mRNAs, suppressing translation and enhancing mRNA degradation.
- Toy, E. P., Lamb, T., Azodi, M., Roy, W. J., Woo, H. H., & Chambers, S. K. (2011). Inhibition of the c-fms proto-oncogene autocrine loop and tumor phenotype in glucocorticoid stimulated human breast carcinoma cells. Breast cancer research and treatment, 129(2), 411-9.More infoThe c-fms proto-oncogene encoded CSF-1 receptor and its ligand represent a feedback loop, which in a paracrine manner, is well known to promote spread of breast cancers. The role of the autocrine feedback loop in promotion of breast tumor behavior, in particular in vitro, is less well understood. The physiologic stimulation of c-fms expression by glucocorticoids (GCs) in vitro and in vivo magnifies the tumor promoting effect seen in these cells from activated c-fms signaling by CSF-1. Targeted molecular therapy against c-fms could therefore abrogate both complementary feedback loops. Using breast cancer cells endogenously co-expressing receptor and ligand, we used complementary approaches to inhibit c-fms expression and function within this autocrine pathway in the context of GC stimulation. Silencing RNA (shRNA), antisense oligonucleotide therapy (AON), and inhibition of c-fms signaling, were all used to quantitate inhibition of GC-stimulated adhesion, motility, and invasion of human breast cancer cells in vitro. shRNA to c-fms downregulated GC-stimulated c-fms mRNA by fourfold over controls, correlating with over twofold reduction in cellular invasiveness. AON therapy was also able to inhibit GC stimulation of c-fms mRNA, and resulted in threefold less invasiveness and 1.5 to 2-fold reductions in adhesion and motility. Finally, the small-molecule c-fms inhibitor Ki20227 was able to decrease in a dose-response manner, breast cancer cell invasion by up to fourfold. Inhibition of this receptor/ligand pair may have clinical utility in inhibition of the autocrine as well as the known paracrine interactions in breast cancer, thus further supporting use of targeted therapies in this disease.
- Woo, H. H., Yi, X., Lamb, T., Menzl, I., Baker, T., Shapiro, D. J., & Chambers, S. K. (2011). Posttranscriptional suppression of proto-oncogene c-fms expression by vigilin in breast cancer. Molecular and cellular biology, 31(1), 215-25.More infocis-acting elements found in 3'-untranslated regions (UTRs) are regulatory signals determining mRNA stability and translational efficiency. By binding a novel non-AU-rich 69-nucleotide (nt) c-fms 3' UTR sequence, we previously identified HuR as a promoter of c-fms proto-oncogene mRNA. We now identify the 69-nt c-fms mRNA 3' UTR sequence as a cellular vigilin target through which vigilin inhibits the expression of c-fms mRNA and protein. Altering association of either vigilin or HuR with c-fms mRNA in vivo reciprocally affected mRNA association with the other protein. Mechanistic studies show that vigilin decreased c-fms mRNA stability. Furthermore, vigilin inhibited c-fms translation. Vigilin suppresses while HuR encourages cellular motility and invasion of breast cancer cells. In summary, we identified a competition for binding the 69-nt sequence, through which vigilin and HuR exert opposing effects on c-fms expression, suggesting a role for vigilin in suppression of breast cancer progression.
- Woo, H. H., Zhou, Y., Yi, X., David, C. L., Zheng, W., Gilmore-Hebert, M., Kluger, H. M., Ulukus, E. C., Baker, T., Stoffer, J. B., & Chambers, S. K. (2009). Regulation of non-AU-rich element containing c-fms proto-oncogene expression by HuR in breast cancer. Oncogene, 28(9), 1176-86.More infoThe role of RNA-binding proteins in cancer biology is recognized increasingly. The nucleocytoplasmic shuttling and AU-rich RNA-binding protein HuR stabilizes several cancer-related target mRNAs. The proto-oncogene c-fms, whose 3'untranslated region (3'UTR) is not AU-rich, is associated with poor prognosis in breast cancer. Using a large breast-cancer tissue array (N=670), we found nuclear HuR expression to be associated with nodal metastasis and independently with poor survival (P=0.03, RR 1.45), as well as to be co-expressed with c-fms in the breast tumors (P=0.0007). We described c-fms mRNA as a direct target of HuR in vivo, and that HuR bound specifically to a 69-nt region containing 'CUU' motifs in 3'UTR c-fms RNA. Overexpressing or silencing HuR significantly up- or down-regulated c-fms RNA expression, respectively. We also found that known glucocorticoid stimulation of c-fms RNA and protein is largely dependent on the presence of HuR. HuR, by binding to the 69-nt wild type, but not mutant, c-fms sequence can regulate reporter gene expression post-transcriptionally. We are the first to describe that HuR can regulate gene expression by binding non-AU-rich sequences in 3'UTR c-fms RNA. Collectively, our findings suggest that HuR plays a supportive role for c-fms in breast cancer progression by binding a 69-nt element in its 3'UTR, thus regulating its expression.
- Chambers, S. K. (2018, November). BRCA reversion mutations in circulating tumor DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma.. EORTC-NCI-AACR, 2018 Triple Meeeting, Dublin Ireland. Dublin, Ireland: EORTC-NCI-AACR.
- Pandey, R., Woo, H., Varghese, F., Zhou, M., & Chambers, S. K. (2018, September). Circulating miRNA profiling of women at high risk for ovarian cancer (POSTER/ABSTRACT). UACC Scientific Retreat.