Whereas in patients with smoldering MM, only the LE OXPHOS gene set was significantly enriched (supplemental Figure4A-C). The first International Congress in Human Genetics to convene after WWII was held in Copenhagen in 1956. We demonstrated that FOXO was an absolute requirement for the effects of AKT inhibition, suggesting that AKT regulates metabolism in MM, predominantly at the transcriptional level. Established in 1913, the foundation used the Rockefeller family wealth to ostensibly promote "public health" by funding mass vaccination campaigns and the founding of public health authorities around the world. April 30, 2023 at 7:30 a.m. Betsy Lavender at the Winthrop Rockefeller Cancer Institute at UAMS. I want a nation of workers." To continue their mission today, Shah says the RF must "directly confront climate change." And she found out the hard way. All rights reserved. She was educated at home by private tutors and, unlike other women of means at the time, did not attend finishing school.[1]. Nonetheless, the aberrantly activated MYC-dependent gene expression is still subject to auxiliary regulation, in which PI3K/AKT signaling plays a pivotal role.44,45 However, the expression of MYC was significantly different in patients with MM classified as FOXO high (low AKT activity) vs those classified as FOXO low (high AKT activity) (supplemental Figure5). Edith Rockefeller McCormick (August 31, 1872 August 25, 1932) was an American socialite, daughter of Standard Oil co-founder John D. Rockefeller. [20][21] She and two of her children, John and Editha, are buried in Graceland Cemetery in Chicago. Lavender's experience would be positive as well. In addition to the walk, there will be drawings, games, entertainment and retail booths. SPEEDING TO ILL SISTER; Financier, Despite Attack of Shingles, Is on Way to Chicago to See Mrs. Edith McCormick", "J.D. (B) GSEA in Cas9-CTRL HMCL clones treated overnight with 2.5 M MK2206 (CTRL+MK) vs the combination of untreated CTRL clones and FOXO KO clones, either treated overnight with 2.5 M MK2206 or left untreated (REST). There, she had the strong family support she had known since childhood. Gene expression profile (GEP) dataset E-TABM-113822 was obtained from the ArrayExpress archive, and datasets GSE6477,23 GSE2658,24,25 and GSE12094118 were obtained from the NCBI Gene Expression Omnibus database. ); and the Translational Research Institute (TRI) and grant KL2 TR003108 through the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) (T.C.A.). "It was the campaign part that was the fun part for me," she says. But in recent years, there has been a rise in early-onset colorectal cancer, which refers to cases that occur before age 45. FOXO represses the expression of metabolic genes in MM cells. AKT was shown to regulate the expression of metabolic genes, primarily by controlling FOXO TFs.20,32 Previously, we defined a gene set that became repressed by FOXO upon AKT inhibition in MM cells (shared FOXOrepressed).18 GSEA indicated that the expression of these genes was enriched in MM cells (n= 75) in comparison with healthy donor plasma cells (n= 15),23 suggesting that FOXO is less active in MM cells (Figure3A). Multiple myeloma (MM) is a malignancy characterized by the clonal expansion of plasma cells in the bone marrow. "Sometimes, I think it was better than any drug they could have given me," she says. Her father had surgery there, and the experience was good. Born into modest circumstances in upstate New York, he. She was quoted as saying, "I married King Tutankhamen when I was only sixteen years old. Here, we show that human MM cell lines (HMCLs) rely on glycolysis for proliferation and survival. Blood Adv 2023; 7 (9): 16971712. OCR values from the Seahorse XF mitochondrial stress test are depicted, and means SEM are shown (t-test, n= 5-6 measurements).ttest,P< .05; MMPC, primary MM plasma cells. GSEA enrichment plots are shown, interrogating Reactome for glycolysis, KEGG for TCA cycle, and GSEA for Hallmark_oxidative_phosphorylation gene sets. doi: https://doi.org/10.1182/bloodadvances.2022007383. As for cancer, oh yeah, the American Cancer Society was founded by none other than Rockefeller in 1913. "It was coming here and feeling supported, and there wasn't a time that I have ever been scared.". That was good news for Lavender because she was already familiar with UAMS. [10] In 1919 McCormick donated land she had received from her father as a wedding gift to the Forest Preserve of Cook County, to be developed as a zoological garden, later to become Chicago's Brookfield Zoo. Moreover, the FOXO-dependent repression of glycolysis- and TCA-associated genes correlates with a favorable prognosis in a large cohort of patients with MM. WASHINGTON A top official of the American Cancer Society has resigned in part because of concern over some of the organization's fund-raising partnerships. We raise nearly all of our money through private individual donations, which helps to . Sheila Yount Special to the Democrat-Gazette The R2 genomics analysis and visualization platform (http://r2.amc.nl) was used for k-means clustering based on the GEP data and survival analysis using the Kaplan-Meier method. The AP will not be held liable for any delays, inaccuracies, errors or omissions therefrom or in the transmission or delivery of all or any part thereof or for any damages arising from any of the foregoing. Similarly, the expression of genes associated with most steps of the TCA cycle were downregulated (>1.2-fold) in a FOXO-dependent fashion upon AKT inhibition in at least 2 HMCLs, whereas the expression of ATP citrate lyase decreased in all 3 HMCLs (Figure3D). AKT prevents the metabolic shutdown of multiple myeloma cells by restricting FOXO. Gates open and registration begins at 6:30 p.m. By helping with projects such as the walk, Lavender is doing her part to help build momentum for UAMS as it prepares to apply for the NCI Designation from the National Cancer Institute. She remained prominent after her divorce from McCormick and helped sponsor and organize several "Women's World Fairs" celebrating female achievement in the 1920s. Undaunted, her team countered by putting attention-grabbing balloons on her friend's homemade signs. "I felt comfortable.". He lived until 1959. In line with this, we showed that treatment with the purported glycolysis inhibitor 2-DG resulted in the variable induction of cell death in HMCLs and BCLs, which was not related to their glycolytic or respiratory capacity. Upon graduation from college, Lavender moved to Little Rock to work for Alltel's wireless company in customer service. She was very tired, naturally, but it was more than that. This year, she is already at work on raising money and recruiting a team of walkers for the third annual walk, which starts at 8:30 a.m. Saturday at War Memorial Stadium in Little Rock. This experiment further indicated that glutamine can be used by HMCLs to fuel OXPHOS, which requires AKT activity. Expression of FOXO-repressed metabolic genes predicts poor survival in patients with MM. The increased reliance of cancer cells on glycolysis is often associated with decreased mitochondrial respiration, suggesting that aerobic glycolysis occurs at the expense of oxidative phosphorylation (OXPHOS).4 However, many tumors exhibit increased glycolysis and OXPHOS.7-9. It was not held thereafter. "I'm most grateful to have grown up in my family and in Texarkana," Lavender says. To her surprise, she didn't return home to Little Rock until Dec. 13, and then for only a short stay, and had to miss Christmas with her family. "So during Colon Cancer Month [March], I'm a beast about promoting screenings. Our data suggest that repression of FOXO by AKT is essential to sustain glycolysis and the TCA cycle activity in MM cells and, as such, predicts patient survival. Most HMCLs show an increased expression of the MYC proto-oncogene because of chromosomal rearrangements and/or mutations.42 An aberrant MYC expression is a major determinant of the metabolic phenotype of MM cells,35 and may drive glycolysis because it directly activates the expression of almost all glycolysis genes.43 Correspondingly, the glycolytic reserve was comparably low in BLCLs that represent archetypal MYC-driven lymphomas. and G.d.W performed the experiments and analyses; R.J.B. Cell numbers and specific cell death were determined by 7-aminoactinomycin D staining (BioLegend, San Diego, CA) and calculated as published previously.18 Experimental details for the glucose uptake assay are provided in the supplemental Materials and Methods. (C) Linear regression analysis of the glycolytic reserve values (x-axis) vs the EC50 values for 2-DG (y-axis) in HMCLs and BCLs. However, our results suggest that acetyl-CoA is not limiting for OXPHOS in MM cells because an increased acetyl-CoA formation caused by DCA treatment did not boost basal mitochondrial respiration. Please read our Terms of Use or contact us. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. For Lavender, 52, a colorectal cancer survivor, participating is part of her mission to encourage people to get screened for colorectal cancer. Our results suggest that the expression of a subset of metabolic genes is an important output parameter of AKT signaling, which crucially impacts the malignant behavior of MM cells and represents an independent adverse feature. These effects appear to be cell/tissue contextspecific because several studies report the opposite, showing that FOXO expression is actually required for glucose metabolism and the TCA cycle in neural and intestinal stem cells.50,51 In agreement with our data, it was shown that FOXO3a antagonized MYC and repressed genes involved in the mitochondrial respiration in colon cancer cells52 and in glycolysis in melanoma cells.53. To exclude the possibility that a perturbed AKT signaling indirectly affected mitochondrial respiration because of its effect on glycolysis, the OCR was determined in LME-1 and MM1.S, with either glucose, pyruvate, or glutamine present in the Seahorse medium as a single carbon source. ROCKEFELLER JR. From hectic politics to the unexpected peril of colorectal cancer, Lavender just laces up her shoes and deals with whatever life throws at her. In accordance, despite their high rate of glycolysis, it was shown that MM cells also use OXPHOS because a combined treatment with the mitochondrial respiratory complex I inhibitor, metformin, and the glucose uptake inhibitor, ritonavir, synergized to induce death in MM cells.10 The rewiring of metabolic pathways and the flexibility to utilize different substrates are closely linked to recurrent genetic aberrations that characterize MM.11 In addition to fulfilling increased energy demands, several reports described changes in metabolism that lead to drug resistance in refractory MM.11,12 However, the key molecular factors that determine dynamic metabolic changes in MM cells have not been studied in detail. She's had this special experience there, and she loves to share it with everyone.". Texarkana is actually two cities -- one in Texas and one in Arkansas -- divided by the Texas-Arkansas state line. She joined Chi Omega sorority and was an Associated Student Government (ASG) representative. FDR, ES, NES, and P-value are shown in the plots. Furthermore, AKT inhibition significantly decreased glycolysis, which required functional FOXO expression (Figure4B). Most genes involved in glycolysis and the TCA cycle significantly downregulated in a FOXO-dependent manner after AKT inhibition (Figure3C). Z-score values are depicted, ranging from3 (blue) indicating low expression to 3 (red) indicating high expression. "[17] She was also said to be interested in astrology and to celebrate Christmas on December 15. Conflict-of-interest disclosure: The authors declare no competing financial interests. "It's not just awareness for the patient to do their screenings," she says. In MM, AKT activation is primarily caused by growth factors in the bone marrow and the sporadic loss of phosphatase and tensin homolog expression.17,21. G protein-coupled receptors (GPCRs) modulate diverse cellular signaling pathways and are important drug targets. For Lavender, 52, a colorectal cancer survivor, participating is part of her mission to encourage people to get screened for colorectal cancer. FDR, ES, NES, and P-value are depicted in the plots. Mary Rockefeller, the wife of New York State Governor Nelson Rockefeller, sews the first of the new union labels onto a garment, January 15, 1959. As a prospect, the therapeutic exploitation of these aspects of FOXO may guide the development of novel treatments for MM. Edith and her father had an often stormy relationship, where her extravagance would often conflict with his frugality. Participants can choose to do a 1K or 5K route (both are wheelchair and stroller accessible). "[14] Over the next few years, Edith and Harold frequently found themselves in court in lawsuits over the divorce agreement.[15]. . She was on student council and attended Girls' State and the Governor's School, a summer program then held at Hendrix College. They later moved to Chicago. "I think attitude probably was most important to me," she says, adding that it is important never to give up and "to make the best of everything. Together, these results show that AKT crucially regulates the metabolic functioning of MM cells by controlling the activity of FOXO. Enrichment plots for Reactome glycolysis, KEGG TCA cycle, and GSEA Hallmark_oxidative_phosphorylation gene sets are shown. Bair, Deirdre, "Jung - A Biography" London: Time-Warner Books UK, 2004, This page was last edited on 28 April 2023, at 05:29. "UAMS is Arkansas' cancer center," Lavender says, adding that she encourages Arkansans with cancer to consider UAMS for treatment. Importantly, our results suggest that the effects of AKT inhibition on metabolism are uncoupled from its effect on MM survival, as overexpression of the full length (40 kDa) antiapoptotic protein MCL-1 prevented AKT inhibitorinduced cell death but did not rescue glycolysis or OXPHOS activity. These results suggest that AKT kinase activity exerts its oncogenic function in MM by driving glycolysis and the TCA cycle, which is associated with aggressive disease. They would also make fudge and cookies to deliver to the neighbors, and they regularly visited nursing homes where her family and another local family would entertain the residents. (B) Seahorse XF glycolysis stress test profiles of CTRL clones (left panels, n= 2), and FOXO knockout clones (middle panels, n= 2) treated for 20 hours with 2.5 M MK2206 (red lines) or left untreated (blue lines). Means of 3 to 6 measurements are shown, andvalues are normalized to the untreated control condition and depicted as a dotted line (one-sample t test). Established in 1913, the foundation used the Rockefeller family wealth to ostensibly promote "public health" by funding mass vaccination campaigns and the founding of public health authorities around the world. (B) Basal glycolysis in HMCLs and MMPCs (n= 2 patients) treated with 2.5 M MK2206 (blue bars) for 20 hours or untreated (red bars). And she returned to working on campaigns when a friend ran for student body president. (B) Half maximal effective concentrations (EC50) of 2-DG for cell death in HMCLs and BCLs after 3 days of treatment. They lived on the Arkansas side, which she calls the "good side" of Texarkana. "My mother was a stay-at-home mom, but she was always involved in things," Lavender says, adding that her mother was "always the fun mom." Functionally, AKT inhibition resulted in a significant decrease in ECAR in most HMCLs (6 out of 8) and in primary MM cells from 2 newly diagnosed patients (Figure2B and supplemental Figure2A-B). After a business trip in September 2012, however, she knew something was wrong. A biographer of her father, however, makes it clear that this could not have been true: at the time of her son's death, Edith was with him at the family estate, Kykuit, at Pocantico Hills, New York. "I remembered that I loved everything at UAMS then," she says. Univariate analysis showed that LE glycolysis (high), LE TCA (high), and LE OXPHOS (high) represent adverse features for OS (hazard ratios 1.6-1.7) in conjunction with other well-known adverse factors (Figure6A). CI, confidence interval; B2M, beta2-microglobulin; Hb, hemoglobin; HR, hazard ratio; ISS, International Staging System; LDH, lactate dehydrogenase. In 1925, she and other wealthy Chicago women including Miss Helen M. Bennett, Mrs. John V. Farwell, Mrs. Silas Strawn, Mrs. John Alden Carpenter, Mrs. B.F. Langworthy, Mrs. Florence Fifer Bohrer, and Mrs. Medill McCormick sponsored an international exposition to celebrate the progress and achievements of American women The first Woman's World's Fair, which was held at the American Exposition Palace on Lake Michigan in April 1925, and was held again each year in Chicago in April or May from 1926 to 1928. Nonetheless, DCA increased the maximum respiration rate in MM cells, indicating an increased influx of pyruvate into the mitochondria and improved usage of mitochondrial respiration. News arrived that Edith and Harold's elder son, John Rockefeller McCormick, had died of scarlet fever. The married couple spent their first two years living in Council Bluffs, Iowa, where Harold managed a branch of his father's business. AKT inhibition suppresses glycolysis and OXPHOS in MM cells. Primary plasma cells from newly diagnosed patients with MM (n=2) and with a plasmacytosis of mononuclear cells being >80% were isolated as detailed in the supplemental Materials and Methods and as described previously.18 Primary MM cells were cultured overnight in supplemented Iscove modified Dulbecco medium with 10% fetal calf serum and 1 ng/mL interleukin-6 before experiments. That's for another blog post but here is a quote from John D. Rockefeller that summarizes his vision for . Most recently, Lavender has been involved with the "Be a Part of the Cure Walk" hosted by the UAMS Winthrop P. Rockefeller Cancer Institute. From this we conclude that AKT-mediated negative regulation of FOXO licenses the expression of glycolysis- and TCA-associated genes in MM but not in premalignant plasma cell disorders, most likely reflecting higher energetic demands due to the increased proliferation of MM cells. That support was vital, she adds. "[18] Newspaper articles mention organizing troubles that caused it to be cancelled in 1929. UAMS says the economic impact on Arkansas could be $72 million, with 1,500 new jobs created over five years. However, this resulted in reduced proliferation and cell death in several HMCLs, suggesting that the ATP generated from mitochondrial respiration is not sufficient to meet the metabolic demands of MM cells. No striking differences in the extracellular acidification rates (ECARs) or basal oxygen consumption rates (OCRs) were observed, indicating similar basal glycolysis and OXPHOS activity (Figure1A, supplemental Figure1A). designed the study and wrote the manuscript; T.A.B. (PBMNCs and purified Bcellswere obtained from 3 healthy donors). She knew something was wrong, so she planned to drive to Texarkana to see a doctor her family knew. Multiple myeloma (MM) plasma cells show increased glycolysis and oxidative phosphorylation (OXPHOS), which are characteristics associated with recurrent genetic aberrations that drive the proliferation and survival of MM cells. Last year, the walk raised about $250,000. "I've gotten a [regular] colonoscopy since I was 10 years old," Merritt says. "Anything that is thrown at me doesn't rattle me.". (Arkansas Democrat-Gazette/Cary Jenkins). (D) Schematic representation of the glycolysis metabolic pathway and the TCA cycle. [1] Edith helped fund the juvenile probation program of Chicago's pioneering Juvenile Court system when it was revealed that, although legislation set up the system, there was no provision to fund the probation officers. Established in 1913, the foundation used the Rockefeller family wealth to ostensibly promote "public health" by funding mass vaccination campaigns and the founding of public health authorities around the world. They saw the sights, Lavender says, but her small crew of interns stayed busy with work. She was the fourth daughter of schoolteacher Laura Celestia "Cettie" Spelman (18391915) and Standard Oil co-founder John Davison Rockefeller. The American Medical Association (AMA) was founded in 1847, and by the late 1800's it had heavy financial involvement by Rockefeller.

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