It was the beginning of the wireless telecommunications industry, and Alltel was poised to be a big player. (PBMNCs and purified Bcellswere obtained from 3 healthy donors). GSEA enrichment plots are shown, interrogating Reactome for glycolysis, KEGG for TCA cycle, and GSEA for Hallmark_oxidative_phosphorylation gene sets. To test this, the effects of the hexokinase inhibitor 2-deoxy-D-glucose (2-DG) on the survival of BCLs were determined. NEW ARTICLE: Rockefeller Foundation's New Focus on Climate Change Moreover, we show that the FOXO-dependent repression of metabolic genes predicts superior overall survival (OS) in a large cohort of patients with MM. On Saturday, Betsy Lavender will lead a team in the "Be a Part of the Cure Walk" hosted by the University of Arkansas for Medical Sciences' Winthrop P. Rockefeller Cancer Institute in Little Rock . Last year, the walk raised about $250,000. This notion, in combination with our finding that MM cells display limited metabolic adaptability suggests that the FOXO-dependent regulation of metabolic features may represent an attractive therapeutic Achilles heel. [20][21] She and two of her children, John and Editha, are buried in Graceland Cemetery in Chicago. "It was the change and not knowing what was going to happen dealing with what was thrown at you and making the best way out of it.". Furthermore, we demonstrated that AKT signaling is of crucial importance for glycolysis and mitochondrial respiration in MM cells. Multiple myeloma (MM) is a malignancy characterized by the clonal expansion of plasma cells in the bone marrow. Also, basal respiration and spare respiratory capacity were similar in the primary MM cells and HMCLs. In high school, Lavender was very involved in "almost every activity," she says. In this month of breast cancer awareness, it is sad to see people being brainwashed about chemotherapy, radiation and surgery. Still, she thrived in the unpredictable, always-on lifestyle. FOXO represses the expression of metabolic genes in MM cells. Enrichment plots for Reactome glycolysis, KEGG TCA cycle, and GSEA Hallmark_oxidative_phosphorylation gene sets are shown. "[16] She followed up in Time magazine by stating "My interest in reincarnation is of many years' standing. She was born in Fayetteville in 1970 while her father, Bill Lavender, was finishing law school at the University of Arkansas. Upon graduation from college, Lavender moved to Little Rock to work for Alltel's wireless company in customer service. 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. -actin served as a loading control. To continue their mission today, Shah says the RF must "directly confront climate change". "The Rockefeller Women." John D. Rockefeller was born July 8, 1839, in Richford, New York, about midway between Binghamton and Ithaca. The American Medical Association (AMA) was founded in 1847, and by the late 1800's it had heavy financial involvement by Rockefeller. All univariate P values were reported regardless of significance. Of note, galactose is oxidized to pyruvate, yielding all glycolysis intermediates, thus indicating that it is unlikely that cell death is caused by the lack of glycolysis-derived metabolites required for anabolic processes.30. "I'm most grateful to have grown up in my family and in Texarkana," Lavender says. 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. 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). In 1912, they hired prominent architect Charles A. Platt to build a mansion on their large country estate, located directly on Lake Michigan in Lake Forest, Illinois, which they named Villa Turicum, and which had extensive architecturally landscaped gardens. By the turn on the 20th century, he controlled 90% of all oil refineries in the U.S. through his oil company, Standard Oil, which was later on broken up to become Chevron, Exxon, Mobil etc. Cancer Society Executive Resigns Amid Upset Over Corporate Partnerships That support was vital, she adds. To determine the functional metabolic features of HMCLs in comparison with other mature malignant B-cell lines (BCLs), normal activated human peripheral blood mononuclear cells (PBMNCs), and activated purified B cells, glycolysis and mitochondrial stress tests were performed. For the TCA cycle a >1.2-fold (FOXO-dependent) decrease in gene expression is indicated. (A) Immunoblot analysis of HK2 and PKM2 expression in LME-1, MM1.S, and XG-3 Cas9-CTRL clones CTRL and FOXO KO clones (FOXO1 for LME-1, and FOXO3 for MM1.S and XG-3) treated overnight with 2.5 M MK2206 or left untreated. Phosphorylation of AKT at Ser473, which marks its activation, slightly increased upon treatment with DCA in 2 out of 3 galactose-adapted HMCLs. 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. Patient material was obtained according to the ethical standards of our institutional medical ethical committee, as well as in agreement with the 1975 declaration of Helsinki, as revised in1983. 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. Blood Adv 2023; 7 (9): 16971712. There, she had the strong family support she had known since childhood. EDITH ROCKEFELLER TO GET $8,419,032", "J.D. This suggests that HMCLs, BCLs, activated PBMNCs, and normal B cells have comparable energetic demands under basal conditions. Means SEM of OCR values are depicted (n= 5 measurements for each clone) and Seahorse XF injections are shown: oligomycin (=A), FCCP (=B), rotenone and antimycin A (=C). Harold Fowler McCormick Jr. (18981973), who married Anne Urquhart Brown "Fifi" (, Muriel McCormick (19031959), who married Elisha Dyer Hubbard (1878-1936), a nephew of. Cell lines, cell culture conditions, and details on reagents are provided in the supplemental Materials and Methods. Protein expression of the glycolysis rate-limiting enzyme HK2 was decreased upon MK2206 treatment, whereas the effects on pyruvate kinase M2 (PKM2) were modest (Figure2A). She then went to UAMS, where she says the care she received saved her life. She attributes her good outcome to the doctors, especially her surgeon, Dr. Jason Mizell, and her oncologist, Dr. Sam Makhoul (now at CARTI), nurses and other staff who helped in her recovery. Laurance S. Rockefeller, 1910-2004 | Rockefeller Archive Center 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. We demonstrate that active FOXO diminished glycolysis and mitochondrial respiration in MM cell lines, and that the expression of glycolysis- and TCA cyclerelated genes in patients with MM negatively correlates with the transcriptional activity of FOXO. 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. John D. Rockefeller (1839-1937), founder of the Standard Oil Company, became one of the world's wealthiest men and a major philanthropist. "I don't need her to convince me, but there could not be a better ambassador for UAMS. Laurance received many honors for his efforts on behalf of the environment and cancer research and treatment. Although novel treatment strategies have improved the prognosis and outcome of MM, most patients eventually relapse and become refractory to further treatment. She joined Chi Omega sorority and was an Associated Student Government (ASG) representative. Rockefeller was allegedly instrumental in financially supporting the American Society for the Control of Cancer (the predecessor of the American Cancer Society) founded in 1913 by a small group of doctors and laypeople. OCR decreased upon AKT inhibition in the presence of pyruvate as the sole carbon source, indicating that AKT directly regulates mitochondrial respiration. Most well-known for his career in big oil and the petroleum sector, Rockefeller, at the time of his death, was estimated to be worth 300 to 400 billion dollars making him the "richest man in modern history." Like many people though of the time, his influence on medicine has had detrimental long-term negative effects on society as a whole. Edith later explained that her donation was motivated by a fascination with animal psychology. 10 Things You May Not Know About John D. Rockefeller - History They saw the sights, Lavender says, but her small crew of interns stayed busy with work. [12], Edith and Harold were divorced in December 1921. 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. Multiple myeloma (MM) is a malignancy characterized by the clonal expansion of plasma cells in the bone marrow. [22], Harold McCormick and Edith Rockefeller, 1895, "MYSTERY OF CHICAGO'S 110 UNWED MILLION-HEIRESSES" Youngstown Vindicator, June 5, 1927, "MRS. M'CORMICK SAYS TUTANKHAMEN WED HER", The Hartford Courant, Mar 1, 1923. p. 22, "WOMEN TO UNITE TO DISPLAY RECORDS OF ACHIEVEMENT OF MODERN ENTERPRISE", Lawrence Daily Journal-World, Feb. 19, 1925 at p. 9, "MRS. McCORMICK'S CAREER. UAMS says the economic impact on Arkansas could be $72 million, with 1,500 new jobs created over five years. [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. She was educated at home by private tutors and, unlike other women of means at the time, did not attend finishing school.[1]. (D) Schematic representation of the glycolysis metabolic pathway and the TCA cycle. Undaunted, her team countered by putting attention-grabbing balloons on her friend's homemade signs. "We would go to different countries.". 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). The 5.5-year survival rate was 54% in the LE glycolysis high group (n= 137) vs 71% in the LE glycolysis low group (n= 639). They later moved to Chicago. We raise nearly all of our money through private individual donations, which helps to . Edith and her father had an often stormy relationship, where her extravagance would often conflict with his frugality. Margaret Higgins Sanger (born Margaret Louise Higgins; September 14, 1879 - September 6, 1966), also known as Margaret Sanger Slee, was an American birth control activist, sex educator, writer, and nurse.Sanger popularized the term "birth control", opened the first birth control clinic in the United States, and established organizations that evolved into the Planned Parenthood Federation of . -actin served as a loading control. At the time of her death, her estate, through the Edith Rockefeller McCormick Trust set up by her father in 1923, consisted mostly of real estate and no longer held much Standard Oil stock. "We left on a Saturday morning and drove all day," she recalls. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Edith Rockefeller McCormick - Wikipedia "So during Colon Cancer Month [March], I'm a beast about promoting screenings. John Rockefeller: How he took control over Modern Medicine -actin served as a loading control. In addition, we show that the LE glycolysis, LE TCA, and LE OXPHOS gene sets are significantly enriched in MMPCs from newly diagnosed patients (Figure5B) and patients with refractory/relapsed MM in comparison with those having healthy donor plasma cells, but not in those with monoclonal gammopathy of undetermined significance. The married couple spent their first two years living in Council Bluffs, Iowa, where Harold managed a branch of his father's business. All rights reserved. I want a nation of workers." For the LE TCA and LE OXPHOS high groups (n= 178 and n= 170, respectively), the 5.5-year survival rate was 57% vs for the LE TCA and LE OXPHOS low groups, it was 71% (n= 598 and n= 606, respectively) (Figure5A). During the race for ASG president, Lavender says, her friend's opponent had more money and used it to make professional yard signs. American spin-off organizations associated with these Rockefeller-supported programs include the American Eugenics Society (synonymous with Rockefeller's Population Council) and the Human Genome Project). 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. 1.8K views, 91 likes, 68 loves, 461 comments, 162 shares, Facebook Watch Videos from Stop the Rot Sack the Lot: Live chat with Guru and Cazz "I love it to this day," she says. 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. designed the study and wrote the manuscript; T.A.B. She called her parents to say she wanted to come home to Texarkana to see a doctor. According to the American Cancer Society, screening can often find colorectal cancer early, before it has spread, making it easier to treat. Bioorthogonal Tethering Enhances Drug Fragment Affinity for G Protein Most recently, Lavender has been involved with the "Be a Part of the Cure Walk" hosted by the UAMS Winthrop P. Rockefeller Cancer Institute. Numbers of patients at risk are tabulated below. AKT regulates glycolysis and OXPHOS in a FOXO-dependent fashion in MM cells. This was the pivotal moment when the AMA was no longer about the medicine and the physicians, it became America's most profitable LOBBY group. His father, William Avery . Replacing glucose with galactose resulted in a significant increase in cell death in several HMCLs (LME-1, XG-3, and RPMI-8226), suggesting that these cell lines are unable to generate sufficient ATP from OXPHOS, thus indicating defective mitochondrial respiration and limited metabolic adaptability. In addition, AKT kinase activity regulated mitochondrial respiration in MM (Figure2C, supplemental Figure2E-F). 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. She also studied astrology and reincarnation. Her longtime friend Keisha Merritt of Bentonville can attest to Lavender's persistence. HIGH PROFILE: Betsy Lavender is determined to be 'Part of the Cure' by 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. The oxidation of galactose to pyruvate by glycolysis yields no netATP, forcing cells to rely on mitochondrial respiration for ATPgeneration, which is characterized by an increased OCR (Figure1D).30,31 Galactose caused a significant decrease in the ECAR/OCR ratio in all HMCLs tested, indicating that HMCLs can switch to OXPHOS when forced to do so (Figure1E). They lived on the Arkansas side, which she calls the "good side" of Texarkana. [2] Together, Harold and Edith were the parents of five children, three of whom survived to adulthood: A famous story about McCormick involves an evening in 1901 during a party. Experimental details are provided in the supplemental Materials and Methods. [13] He was given custody of their youngest daughter Mathilde so that she could marry Max Oser, a Swiss riding instructor. 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. He lived until 1959. In agreement, the glycolytic rate of primary MM cells was lower than that of HMCLs, perhaps explained by the low invitro proliferative capacity of primary cells. She was a member of both the Young Democrats group and the Teenage Republicans. [8] After extended analysis and intense study, Edith became a Jungian analyst, with a full-time practice of more than fifty patients. Classification of patients with MM according to several metabolism-associated gene sets revealed that the FOXO-dependent repression of these genes confers a favorable prognosis. She knew something was wrong, so she planned to drive to Texarkana to see a doctor her family knew. Financials & Governance. provided theoretical and technical input and supervised the metabolic profiling experiments; M.S., C.J.M.v.N., and J.E.J.G. Datasets from the HMCLs LME-1, MM1.S, and XG-3 were combined for GSEA. We passed out Clinton buttons and stickers." 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. ROCKEFELLER JR. This study was supported by a grant from the Dutch Cancer Society (KWF) (AMC 2018-11597) (J.E.J.G. ", Copyright 2023, Northwest Arkansas Newspapers LLC. In addition to the walk, there will be drawings, games, entertainment and retail booths. To continue their mission today, Shah says the RF must "directly confront climate change." Mathilde and Max were married in London in April 1923. Despite the known role of AKT in modulating cellular metabolism, little is known about the downstream factors of AKT that control the metabolic adaptability of MM cells. David M. Rubenstein, cofounder of one of the world's largest investment firms, has spent years interviewing the greatest investors in the world to discover the time-tested principles, hard-earned wisdom, and indispensable tools that guide their practice. Similar effects of DCA treatment were observed in other cancer types, such as non-small cell lung cancer cells38 and breast cancer cells.39 Our results indicate that the reliance of MM cells on glycolysis for proliferation and survival is not related to an intrinsic inability to perform OXPHOS because MM cells are able to switch to OXPHOS when cultured in the presence of galactose instead of glucose. 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. News arrived that Edith and Harold's elder son, John Rockefeller McCormick, had died of scarlet fever. I had sat in it many times. 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. Her Texarkana doctor recommended that she go to UAMS in Little Rock for treatment. Kayla is a scion of the ubiquitous dynasty, which is one of America's most. . John D Rockefeller Founded Modern Medicine And American Cancer Society "Look for the Union Label": A History of the ILGWU's Iconic Jingle FDR, ES, NES, and P-value are depicted in the plots. Enzymes (purple boxes), metabolites, and conversions (arrows) are indicated. The American Cancer Society invests hundreds of millions of dollars every year to fight cancer on a global scale and has earned the public trust by demonstrating a history of careful and proven financial stewardship for over a century. Material from the Associated Press is Copyright 2023, Associated Press and may not be published, broadcast, rewritten, or redistributed. Together, these results show that AKT crucially regulates the metabolic functioning of MM cells by controlling the activity of FOXO. "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. In order to disseminate Jung's ideas, Edith paid to have his writings translated into English. Edith was born on August 31, 1872 at her parents' home in Cleveland, Ohio. 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. The American Cancer Society (ACS) is a nationwide voluntary health organization dedicated to eliminating cancer.Established in 1913, the society is organized into six geographical regions of both medical and lay volunteers operating in more than 250 Regional offices throughout the United States. [9] From February 1918 until October 1919, she provided James Joyce with a monthly benefaction. Correspondence: Jeroen E.J. Its global headquarters is located in the American Cancer Society Center in Atlanta, Georgia. [6], As wealthy socialites, with two family fortunes available, the McCormicks were prominent in Chicago social and cultural circles, donating large amounts of money and time to causes. This document may not be reprinted without the express written permission of Northwest Arkansas Newspapers LLC. Contribution: T.A.B., G.d.W., and J.E.J.G. Heiress Kayla Rockefeller says Meghan Markle is 'controversial' ); grants or awards from the US Department of Defense, National Cancer Institute (R01 CA236814) (DoD; CA180190), the Myeloma Crowd Research Initiative award, and the Riney Family Multiple Myeloma Research Program Fund (F.Z. Furthermore, we provide evidence that AKT sustains glycolysis and OXPHOS in MM by restricting FOXO. "She never wallowed in it," Kesterson says. Immunoblotting was performed as previously described.18 The antibodies used in this study are listed in the supplemental Materials and Methods. 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. Conflict-of-interest disclosure: The authors declare no competing financial interests. (E) OCR/ECAR ratios of HMCLs cultured for 4 days in a glucose-containing medium or in a galactose-containing, glucose-free medium. How Rockefeller founded modern medicine and killed natural cures SAID RICHES HURT CHILDREN Harold F. McCormick, Ex-Husband, Has Received $30,000 a Year Since Divorce. 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. (A) Kaplan-Meier univariate analysis for the OS of k-means clusteringdefined groups of patients with MM (776 patients in total). American Cancer Society Fact Sheet In 2006, the campaign bug struck again when Lavender was invited to a local fundraiser for Hillary Clinton, who was running for re-election to the U.S. Senate. To continue their mission today, Shah says the RF must "directly confront climate change". 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. Second, these LE gene sets were used to partition patients with MM into 2 groups using k-means clustering, representing high or low expression of LE FOXOrepressed genes from glycolysis-, the TCA cycle or OXPHOS-associated gene sets. (F) Immunoblot analysis of total and phosphorylated (Ser473) AKT, total and phosphorylated (Thr24) FOXO1, and total and phosphorylated (Thr32) FOXO3 in the HMCLs LME-1, LP-1, and XG-1 cells cultured for 20 hours with or without 25 mM DCA or in a galactose-containing, glucose-free medium. John Rockefeller and modern medicine: Abraham Flexner was born in 1866 in Louisville, Kentucky. The role of FOXO downstream of AKT in MM cells was further substantiated by the FOXO-dependent decrease of HK2 protein expression and a modest decrease in PKM2 expression (Figure4A). "It's not just awareness for the patient to do their screenings," she says. She says Lavender reminds her regularly to get screened, noting that colorectal cancer disproportionately affects the Black community. Longtime friends are not surprised at Lavender's dedication to colorectal cancer awareness and prevention. Indict World Economic Forum on Twitter: "https://youtube.com/watch?v The official, Dr . Rockefellers later relocated the U . 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.