Enzymes (purple boxes), metabolites, and conversions (arrows) are indicated. 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. However, when glucose is present, glycolysis remains the major source of ATP production for HMCLs, as is evident from their limited glycolytic reserve. "[17] She was also said to be interested in astrology and to celebrate Christmas on December 15. "She is literally living proof that screening saves lives. 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. Previous works by us and others have shown that AKT plays a pivotal role in the survival and growth of MM cells.13-18 We recently showed that AKT restrains the tumor-suppressive functions of forkhead box O (FOXO) transcription factors (TFs) in MM.18 Importantly, AKT is a central node in the phosphatidylinositol 3-kinase (PI3K)/AKT/mechanistic target of rapamycin pathway that connects proliferation, survival, and cellular metabolism and drives glycolysis.19,20 Activation of AKT is common in cancer, either by activating mutations or by growth factors provided by the tumor microenvironment. 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). Texarkana is actually two cities -- one in Texas and one in Arkansas -- divided by the Texas-Arkansas state line. -actin served as a loading control. [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. In 1913 JDR established the Rockefeller Foundation to "promote the well-being of mankind throughout the world." In keeping with this broad commitment, the foundation has given important global assistance to public health, medical education, improved food production, scientific advancement, social research, and the arts. 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. These results confirm that FOXO suppresses the expression of genes involved in metabolic pathways in patients with MM (Figure3E). supervised the study; and all authors read and approved the final manuscript. MM cells are characterized by the high expression of lactate dehydrogenase,35-37 which catalyzes the conversion of pyruvate into lactate instead of into acetyl-CoA. Lavender would spend 14 years at Alltel, moving up to a position where she worked on the development of Alltel's national wireless footprint with a partnership that put Alltel stores in Walmart stores across the nation. In 1930, Edith had a growth removed from her breast and died of cancer two years later on August 25, 1932,[19] surrounded by her family. Univariate and multivariate Cox regression analysis of OS in the TT2 and TT3 cohort of patients with MM. 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. The increased glycolytic rate seems counterintuitive because glycolysis yields far less ATP per glucose molecule than that in mitochondrial respiration. As for cancer, the American Cancer Society was founded by Rockefeller himself in 1913. 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 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. They lived on the Arkansas side, which she calls the "good side" of Texarkana. Edith and her father had an often stormy relationship, where her extravagance would often conflict with his frugality. 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. 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. 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. In addition to the walk, there will be drawings, games, entertainment and retail booths. I want a nation of workers." 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. Undaunted, her team countered by putting attention-grabbing balloons on her friend's homemade signs. "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.". (A) Kaplan-Meier univariate analysis for the OS of k-means clusteringdefined groups of patients with MM (776 patients in total). In addition, AKT kinase activity regulated mitochondrial respiration in MM (Figure2C, supplemental Figure2E-F). 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. The article noted that she was "glad to be rid of the gay Harold McCormick, but hasn't succeeded in convincing her friends she will never marry again. 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). 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). Basal ECAR values from the Seahorse XF glycolysis stress test are depicted, and means SEM are shown (ttest,n=5-6 measurements). 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). (B) Half maximal effective concentrations (EC50) of 2-DG for cell death in HMCLs and BCLs after 3 days of treatment. This result is surprising because it was previously shown that a shorter (36 kDa) MCL-1 isoform is required for normal mitochondrial bioenergetics in mouse embryonic fibroblasts.54 However, it is unlikely that the overexpression of the shorter MCL-1 isoform would rescue mitochondrial respiration because we found many OXPHOS-associated genes decreased in a FOXO-dependent fashion upon AKT inhibition. ROCKEFELLER JR. His father, William Avery . She was the fourth daughter of schoolteacher Laura Celestia "Cettie" Spelman (18391915) and Standard Oil co-founder John Davison Rockefeller. By establishing the China Medical Board in 1914 and purchasing the Union Medical College from the London Missionary Society in 1915, the Foundation took its first steps toward that goal. [12], Edith and Harold were divorced in December 1921. Correspondence: Jeroen E.J. On spring breaks, her father would join them for excursions to Disneyland and snow skiing. She joined Chi Omega sorority and was an Associated Student Government (ASG) representative. 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. To further assess metabolic adaptability, HMCLs were cultured for 4 days in a medium in which glucose was replaced with galactose. "She just kept moving forward and kept educating people, and every time we have someone we know get cancer, Betsy's the first one there to guide them through that initial diagnosis.". The American Cancer Society suggests that people with average risk for colorectal cancer should get screened starting at age 45. She was born in Fayetteville in 1970 while her father, Bill Lavender, was finishing law school at the University of Arkansas. Numbers of patients at risk are tabulated below. They would go to the beach, to the Smoky Mountains, to Disney World, Cape Canaveral and more. Black Americans are about 20% more likely to get colorectal cancer and about 40% more likely to die from it than other ethnic groups. The first International Congress in Human Genetics to convene after WWII was held in Copenhagen in 1956. John D. Rockefeller is also the son of the founder of the pharmaceutical industry in the US. Rather, a subpopulation of cells displayed an increased glucose uptake, perhaps because of feedback regulation (supplemental Figure2D). (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). Lavender's experience would be positive as well. According to the American Cancer Society, screening can often find colorectal cancer early, before it has spread, making it easier to treat. Meanwhile, Harold married Ganna Walska, a Polish opera singer in August 1922, becoming her fourth husband. "It was a fabulous environment that day," Lavender says, noting that more than 1,000 people participated in 2022. She would continue her practice after her return to America, attracting many socialite patients from around the United States. 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. 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. Ile Ife, Nigeria | 29 views, 5 likes, 0 loves, 0 comments, 0 shares, Facebook Watch Videos from Spokesman Sanctuary Of Hope: Join us this evening at 4:30 pm WAT onsite or online for a powerful. Flexner is considered the 'father' of modern medical education. SAID RICHES HURT CHILDREN Harold F. McCormick, Ex-Husband, Has Received $30,000 a Year Since Divorce. I drive everybody crazy.". 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 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. 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. Sheila Yount Special to the Democrat-Gazette 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. Kayla is a scion of the ubiquitous dynasty, which is one of America's most. To continue their mission today, Shah says the RF must "directly confront climate change". The GraphPad Prism software package was used for statistical analyses (GraphPad Software, La Jolla, CA). "I felt comfortable.". Bar graphs (right panels) depict basal respiration values, and means SEM are shown (one-way ANOVA, with Bonferroni multiple comparison test, P< .0001, P< .001, P< .01, P< .05; ns= not significant. Nevertheless, the glycolytic reserve of the primary MM cells was limited and similar to that observed in the HMCLs. Our results demonstrate that the expression of several key metabolic genes involved in glycolysis, the tricarboxylic acid (TCA) cycle, and OXPHOS are repressed by FOXO TFs. [11] She returned to America in 1921 after an eightyear stay. Longtime friends are not surprised at Lavender's dedication to colorectal cancer awareness and prevention. Edith Rockefeller McCormick (August 31, 1872 August 25, 1932) was an American socialite, daughter of Standard Oil co-founder John D. Rockefeller. Activation of PI3K/AKT signaling is an established oncogenic feature of MM cells, sustaining several antiapoptotic and proliferative pathways. "[14] Over the next few years, Edith and Harold frequently found themselves in court in lawsuits over the divorce agreement.[15]. When evidence began to emerge that petroleum based medicine was causing cancer, Rockefeller founded the American Cancer Society, through which he suppressed that information. That support was vital, she adds. (D) Fold change of ECAR, basal respiration, maximum respiration, and spare respiratory capacity (OCR) from a Seahorse XF mitochondrial stress test in HMCLs treated with DCA (25 mM for 20 hours) or cultured for 4 days in a galactose-containing medium (11.1 mM, no glucose). In 1913, America's first billionaire endowed the Rockefeller Foundation, which had the ambitious goal "to promote the well-being of mankind throughout the world." The foundation contributed to. Lavender was 42 when she was diagnosed. In agreement, the phosphorylation of FOXO1 (Thr24) and FOXO3 (Thr32), which mark their inactivation, followed a similar pattern (Figure1F). "So during Colon Cancer Month [March], I'm a beast about promoting screenings. Expression of FOXO-repressed metabolic genes predicts poor survival in patients with MM. "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." After a business trip in September 2012, however, she knew something was wrong. [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. In the summers, she says, they went swimming, set up Kool-Aid stands and played wiffleball. To continue their mission today, Shah says the RF must "directly confront climate change". Traveling was another favorite activity of the Lavender family, she says. "[16] She followed up in Time magazine by stating "My interest in reincarnation is of many years' standing. Her brother was John Davison Rockefeller Jr. (18741960). ", Copyright 2023, Northwest Arkansas Newspapers LLC. 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). 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). Edith Rockefeller McCormick (August 31, 1872 - August 25, 1932) was an American socialite, daughter of Standard Oil co-founder John D. Rockefeller . 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). Rockefeller then took control of the American Medical Association and began offering grants to top medical schools under the mandate that only his approved curriculum be taught. Neither these AP materials nor any portion thereof may be stored in a computer except for personal and noncommercial use. All rights reserved. After being treated for depression by Jung, she became a successful Jungian psycho-analyst herself. and G.d.W performed the experiments and analyses; R.J.B. This document may not be reprinted without the express written permission of Northwest Arkansas Newspapers LLC. Furthermore, we provide evidence that AKT sustains glycolysis and OXPHOS in MM by restricting FOXO. Financials & Governance. These results indicate that increased pyruvate conversion does not directly boost the TCA cycle and OXPHOS but may improve the mitochondrial fitness in most HMCLs. John D. Rockefeller, Sr. Rockefeller Archive Center. EDITH ROCKEFELLER TO GET $8,419,032", "J.D. 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). She called her parents to say she wanted to come home to Texarkana to see a doctor. John D. Rockefeller (1839-1937), founder of the Standard Oil Company, became one of the world's wealthiest men and a major philanthropist. (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. She also took on a new role to raise awareness of colorectal cancer and promote screening for the disease. "UAMS is Arkansas' cancer center," Lavender says, adding that she encourages Arkansans with cancer to consider UAMS for treatment. 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. "I've gotten a [regular] colonoscopy since I was 10 years old," Merritt says. 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. Furthermore, AKT inhibition significantly decreased glycolysis, which required functional FOXO expression (Figure4B). It was shown previously that AKT has a direct effect on metabolism by phosphorylating several metabolic enzymes, such as HK2,47 ACLY,48 and phosphofructokinase.49 Although this may also occur in MM cells, our results suggest that this is not the major mode of action by which AKT regulates the metabolic features of MM cells. 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. After dinner, where they met Clinton and his wife, Hillary, they got back on the charter bus and headed home. 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. Together, these results show that AKT crucially regulates the metabolic functioning of MM cells by controlling the activity of FOXO. "Having that many people there, it was just incredible.". John D. Rockefeller was born July 8, 1839, in Richford, New York, about midway between Binghamton and Ithaca. Interestingly, the spare respiratory capacity and the maximum respiration increased in the majority of the HMCLs (5 out of 6) (Figure1D). In agreement, we found that the FOXO-mediated repression of key metabolic genes is lost in MM plasma cells in comparison with plasma cells from healthy donors, patients with monoclonal gammopathy of undetermined significance, and patients with smoldering MM, suggesting that the progressive loss of FOXO-dependent gene regulation accompanies the malignant transformation of plasma cells. SHE TESTIFIES IN COURT He Is Absent and Makes No Defense, Although Represented by Counsel. Original data are available on request from the corresponding author, Jeroen E. J. Guikema (j.e.guikema@amsterdamumc.nl). Her three elder sisters were Elizabeth (Bessie) (18661906), Alice (18691870), and Alta (18711962). To continue their mission today, Shah says the RF must "directly confront climate change". She is especially interested in raising awareness. designed the study and wrote the manuscript; T.A.B. They later moved to Chicago. Offsetting these medical advances, World War I killed 16.6 million people, including 6.8 million civilians. HR (diamond symbols) and 95% CI (lines) are indicated. This suggests that AKT is the pivotal kinase that crucially regulates both glycolysis and mitochondrial respiration in MM. 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. CTRL, control; ES, enrichment score; FDR, false discovery rate; KEGG, Kyoto Encyclopedia of Genes and Genomes; KO, knockout; NES, normalized enrichment score.