Edith Rockefeller McCormick (August 31, 1872 August 25, 1932) was an American socialite, daughter of Standard Oil co-founder John D. Rockefeller. Here, we show that human MM cell lines (HMCLs) rely on glycolysis for proliferation and survival. Her Texarkana doctor recommended that she go to UAMS in Little Rock for treatment. The American Cancer Society, Inc., is a 501 (c) (3) nonprofit corporation governed by a single Board of Directors that is responsible for setting policy, establishing long-term goals, monitoring general operations, and approving the organizational outcomes and allocation of resources. It was the beginning of the wireless telecommunications industry, and Alltel was poised to be a big player. To continue their mission today, Shah says the RF must "directly confront climate change." 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. 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. Search for other works by this author on: Metabolic signature identifies novel targets for drug resistance in multiple myeloma, Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib, On respiratory impairment in cancer cells, An HK2 antisense oligonucleotide induces synthetic lethality in HK1-HK2+ multiple myeloma, Cyclin D1 targets hexokinase 2 to control aerobic glycolysis in myeloma cells, Metabolic heterogeneity in human lung tumors, The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type, Targeting the metabolic plasticity of multiple myeloma with FDA-approved ritonavir and metformin, Bortezomib resistance in multiple myeloma is associated with increased serine synthesis, Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells, The AKT kinase is activated in multiple myeloma tumor cells, Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma, The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: roles in cytokine-dependent survival and proliferative responses, PI3-K/AKT/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells, Loss of PTEN expression leading to high Akt activation in human multiple myelomas, AKT signaling restrains tumor suppressive functions of FOXO transcription factors and GSK3 kinase in multiple myeloma, Is Akt the Warburg kinase?-Akt-energy metabolism interactions and oncogenesis, The PI3K-AKT network at the interface of oncogenic signalling and cancer metabolism, Analysis of PTEN deletions and mutations in multiple myeloma, Pharmacogenomics of bortezomib test-dosing identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk feature in myeloma treated with Total Therapy 3, Molecular dissection of hyperdiploid multiple myeloma by gene expression profiling, Prognostic value of cyclin D2 mRNA expression in newly diagnosed multiple myeloma treated with high-dose chemotherapy and tandem autologous stem cell transplantations, Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation, Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles, Mitochondrial spare respiratory capacity: Mechanisms, regulation, and significance in non-transformed and cancer cells, Under normoxia, 2-deoxy-D-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylation, Dichloroacetate enhances apoptotic cell death via oxidative damage and attenuates lactate production in metformin-treated breast cancer cells, Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants, Galactose enhances oxidative metabolism and reveals mitochondrial dysfunction in human primary muscle cells, The role of FOXO in the regulation of metabolism, Avalidated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1, TP53 deletion is not an adverse feature in multiple myeloma treated with total therapy 3, Metabolic effects of recurrent genetic aberrations in multiple myeloma, Lactate dehydrogenase production and release in a newly established human myeloma cell line, Lactate, a putative survival factor for myeloma cells, is incorporated by myeloma cells through monocarboxylate transporters 1, Dichloroacetic acid (DCA) synergizes with the SIRT2 inhibitor Sirtinol and AGK2 to enhance anti-tumor efficacy in non-small cell lung cancer, Dichloroacetate and PX-478 exhibit strong synergistic effects in a various number of cancer cell lines, Catabolic efficiency of aerobic glycolysis: the Warburg effect revisited, Perturbational profiling of a cell-line model of tumorigenesis by using metabolic measurements, Characterization of MYC translocations in multiple myeloma cell lines, Regulation of cancer cell metabolism: oncogenic MYC in the drivers seat, Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1, Myc-induced proliferation and transformation require Akt-mediated phosphorylation of FoxO proteins, Akt stimulates aerobic glycolysis in cancer cells, Hexokinase-II positively regulates glucose starvation induced autophagy through TORC1 inhibition, The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes, Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis, FoxO3 coordinates metabolic pathways to maintain redox balance in neural stem cells, Mitochondria define intestinal stem cell differentiation downstream of a FOXO/notch axis, FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression, FOXO3a-SIRT6 axis suppresses aerobic glycolysis in melanoma, Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration, 2023 by The American Society of Hematology. ROCKEFELLER JR. GREETS DYING SISTER; Mrs. Edith McCormick Has Relapse in the Night, but Soon Rallies", "MRS. McCORMICK'S ESTATE; Once Estimated at $40,000,000 -- Great Losses Since Crash of 1929", Edith Rockefeller McCormick Trust records, https://en.wikipedia.org/w/index.php?title=Edith_Rockefeller_McCormick&oldid=1152097548, John Rockefeller McCormick (18971901), who died young from. On November 26, 1895, she married Harold Fowler McCormick from Chicago, a son of Nancy Fowler and Cyrus Hall McCormick, the inventor of the mechanical reaper. In order to disseminate Jung's ideas, Edith paid to have his writings translated into English. His father, William Avery . As one of the wealthiest and most influential families in North America in the last 200 years, headed up by patriarch John D. Rockefeller I (pictured), the Rockefellers played an integral role in . News arrived that Edith and Harold's elder son, John Rockefeller McCormick, had died of scarlet fever. Furthermore, we demonstrated that AKT signaling is of crucial importance for glycolysis and mitochondrial respiration in MM cells. Its global headquarters is located in the American Cancer Society Center in Atlanta, Georgia. That support was vital, she adds. Rather, a subpopulation of cells displayed an increased glucose uptake, perhaps because of feedback regulation (supplemental Figure2D). Notably, there was no correlation between 2-DG sensitivity and metabolic function in the cell lines tested (Figure1C and supplemental Figure1C), suggesting that 2-DGdependent cell death involves a different mechanism, such as the induction of endoplasmic reticulum stress through the inhibition of N-glycosylation, as previously described.28. Furthermore, we provide evidence that AKT sustains glycolysis and OXPHOS in MM by restricting FOXO. Metabolic alterations are important cancer-associated features that allow cancer cell transformation and survival under stress conditions. She then traveled to Denver to work with media logistics for the Democratic National Convention. Means SEM are shown (paired t test, n= 3-5 measurements). They would go to the beach, to the Smoky Mountains, to Disney World, Cape Canaveral and more. After a business trip in September 2012, however, she knew something was wrong. He lived until 1959. AKT regulates glycolysis and OXPHOS in a FOXO-dependent fashion in MM cells. The increased glycolytic rate seems counterintuitive because glycolysis yields far less ATP per glucose molecule than that in mitochondrial respiration. Similar to other cancer types, MM cells predominantly fulfill their energetic demands via glycolysis,2,3 a phenomenon known as the Warburg effect.4 In agreement, it was shown that the glycolysis rate-limiting enzyme, hexokinase II (HK2), is highly expressed in MM and is associated with poor prognosis.2,5,6. After being treated for depression by Jung, she became a successful Jungian psycho-analyst herself. She was educated at home by private tutors and, unlike other women of means at the time, did not attend finishing school.[1]. 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. Sterling Drug, Inc., the largest holding company in the Rockefeller Drug Empire and its 68 subsidiaries, showed profits in 1961 of $23,463,719 after taxes, on net assets of $43,108,106 - a 54% profit. After dinner, where they met Clinton and his wife, Hillary, they got back on the charter bus and headed home. Blood Adv 2023; 7 (9): 16971712. ALIMONY NOT MENTIONEDUnderstanding Is That Both WillContinue to Aid GrandOpera Lavishly", "EDITH ROCKEFELLER TO GET $8,419,032; Accounting Suit Reveals That Her Father Suggested She Give It to Charity. "Anything that is thrown at me doesn't rattle me.". In that respect, (combinatorial) targeting of signaling pathways that regulate metabolic plasticity may be a preferred approach, placing the AKT kinase in the limelight again, where the prevention of feedback regulation and/or activation of salvage pathways will be key for a successful therapeutic modality. Associated Press text, photo, graphic, audio and/or video material shall not be published, broadcast, rewritten for broadcast or publication or redistributed directly or indirectly in any medium. And she found out the hard way. "She has a way of just making people's lives better," Merritt says. Licensed under, Copyright 2023 by American Society of Hematology, Supplemental Materials and Methods, Reference, Table, and Figures, https://doi.org/10.1182/bloodadvances.2022007383, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0). ); 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.). Neither these AP materials nor any portion thereof may be stored in a computer except for personal and noncommercial use. "We had gone to almost every state by the time I graduated high school," she says, adding that after high school she and her mother and sister traveled even more. It was rumored that when this was whispered to her at the dinner table, she proceeded to merely nod her head and allowed the party to continue without incident. Patients were clustered based on the FOXO-regulated LE gene sets; LE glycolysis, LE TCA cycle, or LE OXPHOS, which were derived by combining the LE genes from GSEAs performed for several glycolysis, TCA cycle, or OXPHOS gene sets (Supplemental Table1). Then in 2007, Lavender helped with another fundraiser for Hillary, this time as part of her first presidential bid. After recovering, she moved back to Fayetteville, where she had always hoped to return, and began focusing on fundraising projects. 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. This document may not be reprinted without the express written permission of Northwest Arkansas Newspapers LLC. Means SEM of ECAR values are depicted (n= 5 measurements for each clone) and Seahorse XF injections are shown: glucose (=A), oligomycin (=B), 2-DG (=C). Oftentimes, younger patients don't get timely diagnoses because doctors don't think they are old enough to have colorectal cancer, she says. (B) Multivariate analysis of subgroups (n= 525) for OS. She was a member of both the Young Democrats group and the Teenage Republicans. The GraphPad Prism software package was used for statistical analyses (GraphPad Software, La Jolla, CA). The Rockefeller Foundation (RF) entered China with an ambitious goal: to build modern medical schools in both Beijing and Shanghai. Laurance received many honors for his efforts on behalf of the environment and cancer research and treatment. American Cancer Society - 1913 . Although novel treatment strategies have improved the prognosis and outcome of MM, most patients eventually relapse and become refractory to further treatment. "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." Timon A. Bloedjes, Guus de Wilde, Gerarda H. Khan, Timothy C. Ashby, John D. Shaughnessy, Fenghuang Zhan, Riekelt H. Houtkooper, Richard J. Bende, Carel J. M. van Noesel, Marcel Spaargaren, Jeroen E. J. Guikema; AKT supports the metabolic fitness of multiple myeloma cells byrestricting FOXO activity. These alterations may result in metabolic dependencies that can be exploited for therapeutic purposes. Offsetting these medical advances, World War I killed 16.6 million people, including 6.8 million civilians. Univariate and multivariate Cox regression analysis of OS in the TT2 and TT3 cohort of patients with MM. To further investigate the role of AKT signaling in the metabolic features of MM cells, HMCLs were treated with the allosteric AKT inhibitor MK2206. "Sometimes, I think it was better than any drug they could have given me," she says. Her longtime friend Keisha Merritt of Bentonville can attest to Lavender's persistence. The plan fell through for undisclosed reasons in December 1922. 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. John Rockefeller and modern medicine: Abraham Flexner was born in 1866 in Louisville, Kentucky. (NWA Media). SHE TESTIFIES IN COURT He Is Absent and Makes No Defense, Although Represented by Counsel. The effects of AKT inhibition on the OCRs were similar in MCL-1 overexpressing MM cells and the control cells, indicating that survival and mitochondrial respiration are independently regulated by AKT (supplemental Figure2H). (B) Half maximal effective concentrations (EC50) of 2-DG for cell death in HMCLs and BCLs after 3 days of treatment. UAMS started the walk in 2021 to honor patients with all forms of cancer and raise money for cancer research. Her three elder sisters were Elizabeth (Bessie) (18661906), Alice (18691870), and Alta (18711962). We raise nearly all of our money through private individual donations, which helps to . Couric invited Lavender to attend the Stand Up to Cancer telethon in Los Angeles, which Couric had co-founded to raise money for cancer research. Although novel treatment strategies have improved the prognosis and outcome of MM, most patients eventually relapse and become refractory to further treatment.1 Cancer cells are characterized by metabolic alterations, which are driven by oncogenes. To explore whether these findings also apply to patients with MM, a large GEP dataset comprising 542 patients with MM was partitioned into 2 groups representing either high (n= 387) or low (n= 155) FOXO activity, based on the expression of the shared FOXOrepressed gene set.18 GSEA showed that patients with MM with low FOXO activity were significantly enriched (FDR <0.25) for glycolysis, TCA cycle, and OXPHOS-associated gene sets in comparison with those with high FOXO activity. Lavender's experience would be positive as well. Moreover, AKT kinase is a major driver of glycolysis, stimulating the switch from mitochondrial respiration to aerobic glycolysis.46, Our results show that metabolic modulation by DCA and galactose adaptation resulted in the activation of AKT in MM cells and a concomitant FOXO inactivation, suggesting that altered metabolic demands are relayed into the PI3K/AKT signaling pathway, likely representing feedback regulation. Still, she thrived in the unpredictable, always-on lifestyle. "I felt comfortable.". (C) Heatmaps showing (z-score transformed) expression of Reactome glycolysis genes (upper panels) and KEGG_TCA cycle genes (lower panels) in LME-1 CTRL clones and LME-1 FOXO1-knockout (FOXO1-/-) clones (left panels), MM1.S CTRL clones and FOXO3-KO (FOXO3-/-) (middle panels), and XG-3 CTRL clones and FOXO3-KO clones (right panels) that were treated overnight with 2.5 M MK2206 or left untreated. 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). (A) Seahorse XF real-time metabolic profiling of HMCLs (red symbols) and BCLs (blue, green, yellow, and light blue symbols), CpG-activated PBMNCs and purified human peripheral blood B cells (pink symbols). She called her parents to say she wanted to come home to Texarkana to see a doctor. Then, during her senior year, she caught the political bug big-time when she joined a group of students on a whirlwind trip to Iowa to support Clinton's campaign for president. As for cancer, the American Cancer Society was founded by Rockefeller himself in 1913. 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. "We got there, and it was snowing. They saw the sights, Lavender says, but her small crew of interns stayed busy with work. She is especially interested in raising awareness. Despite the availability of high-resolution structures, the discovery of allosteric modulators remains challenging due to the dynamic nature of GPCRs in native membranes. and G.d.W performed the experiments and analyses; R.J.B. (B) GSEA enrichment plots show enrichment of the FOXO-regulated LE glycolysis, LE TCA cycle, and LE OXPHOS gene sets (supplemental Table1) in MM plasma cells from newly diagnosed patients (MMPCs, n= 75) compared with plasma cells from healthy donors (n= 15). On spring breaks, her father would join them for excursions to Disneyland and snow skiing. Black Americans are about 20% more likely to get colorectal cancer and about 40% more likely to die from it than other ethnic groups. Nov. 5, 2018. "I remembered that I loved everything at UAMS then," she says. Original data are available on request from the corresponding author, Jeroen E. J. Guikema (j.e.guikema@amsterdamumc.nl). 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. "It was the campaign part that was the fun part for me," she says. provided theoretical and technical input and supervised the metabolic profiling experiments; M.S., C.J.M.v.N., and J.E.J.G. 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. supervised the study; and all authors read and approved the final manuscript. The Board is composed entirely of volunteers from the . I had sat in it many times. MM cells show restricted glycolytic reserve and heterogeneous metabolic flexibility. 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. To determine the metabolic adaptability, HMCLs were treated with dichloroacetate (DCA), which increases the activity of the pyruvate dehydrogenase complex and leads to to decreased production of lactate and increased decarboxylation of pyruvate to acetyl coenzyme A (acetyl-CoA), resulting in a shift of pyruvate toward mitochondrial metabolism.3,29 Phosphorylation of pyruvate dehydrogenase wasreduced upon DCA treatment, verifying on-target activity (supplemental Figure1D). Here, we demonstrate that negative regulation of the forkhead box O (FOXO) transcription factors (TFs) by AKT is crucial to prevent the metabolic shutdown in MM cells, thus contributing to their metabolic adaptability. We have previously shown that prosurvival AKT signaling in MM critically depends on the inhibition of FOXO TFs, resulting in the stabilization of the antiapoptotic MCL-1 protein.18 Here, we show that the expression of key metabolic genes in MM is also regulated by AKT signaling that restrains FOXO-dependent gene repression. | Notably, the expression of glucose-6-phosphate isomerase, aldolase (ALDOA, ALDOB, and ALDOC), and PKM reduced most prominently (>1.5-fold) in all 3 tested HMCLs, whereas the majority of the other genes involved in glycolysis were significantly downregulated in at least 1 of the HMCLs studied (Figure3D). Meanwhile, Harold married Ganna Walska, a Polish opera singer in August 1922, becoming her fourth husband. In addition, regular screening can prevent colorectal cancer by allowing doctors to find and remove polyps before they turn into cancer. After radiation, chemotherapy and surgery at UAMS, Lavender spent time recuperating in Texarkana at her family home. Rockefellers later relocated the U . EDITH ROCKEFELLER TO GET $8,419,032", "J.D. To investigate the effects of FOXO activation on the expression of genes involved in metabolism, gene expression data obtained from FOXO1- (LME-1) or FOXO3- (MM1.S and XG-3) deficient clones treated with MK2206 were investigated. This is further substantiated by our GEP results showing that AKT inhibition resulted in the FOXO-dependent decreased expression of metabolic genes and gene sets. All univariate P values were reported regardless of significance. "I don't need her to convince me, but there could not be a better ambassador for UAMS. One-way ANOVA with Bonferroni multiple comparisons test P< .05, P< .01; One-sample t test P< .05, P< .01; paired t test, P< .05; ANOVA, analysis of variance; ns, not significant; SEM, standard error of the mean. -actin served as a loading control. For Lavender, 52, a colorectal cancer survivor, participating is part of her mission to encourage people to get screened for colorectal cancer. 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). [11] She returned to America in 1921 after an eightyear stay. and G.H.K. CTRL, control; ES, enrichment score; FDR, false discovery rate; KEGG, Kyoto Encyclopedia of Genes and Genomes; KO, knockout; NES, normalized enrichment score. Glycolysis, TCA cycle, and OXPHOS gene sets significantly depleted in MK2206-treated control clones in comparison with FOXO-deficient and untreated clones (Figure3B, supplemental Figure3A-C). Moreover, glucose uptake did not decrease upon AKT inhibition, as shown by the 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2-deoxyglucose uptake assay. SAID RICHES HURT CHILDREN Harold F. McCormick, Ex-Husband, Has Received $30,000 a Year Since Divorce. The first International Congress in Human Genetics to convene after WWII was held in Copenhagen in 1956. Most recently, Lavender has been involved with the "Be a Part of the Cure Walk" hosted by the UAMS Winthrop P. Rockefeller Cancer Institute. 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. "It was a wonderful experience being on the 'Hill,'" she says. ", Copyright 2023, Northwest Arkansas Newspapers LLC. Edith later explained that her donation was motivated by a fascination with animal psychology. 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. In February 1923, she received some minor press for claiming to be the reincarnation of the wife of King Tutankhamen, whose tomb had just been explored and was a popular topic. 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. The overall conclusion here, and of our previous work,18 is that metabolism, proliferation, and survival of MM cells critically converge on the tumor-suppressive function of FOXO, which is actively restrained by AKT signaling. Activation of PI3K/AKT signaling is an established oncogenic feature of MM cells, sustaining several antiapoptotic and proliferative pathways. 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.
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