"Look for the Union Label": A History of the ILGWU's Iconic Jingle 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. Here, we show that human MM cell lines (HMCLs) rely on glycolysis for proliferation and survival. She then traveled to Denver to work with media logistics for the Democratic National Convention. The Cancer Within Modern Medicine Part 1 & 2 | SGT Report ); 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.). [12], Edith and Harold were divorced in December 1921. 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. It will be her second year to participate in the walk, and she hopes to raise even more money than she did last year, when her team took top fundraising honors in the individuals category. She joined Chi Omega sorority and was an Associated Student Government (ASG) representative. A heterogeneous response to 2-DG (half maximal effective concentrations [EC50s] ranging from 0.9 mM to >100 mM) was observed, which did not differ significantly between the BCL subtypes, although it is noteworthy that MM1.S (an HMCL) and Namalwa (a BLCL) showed a marked resistance (EC50 >100 mM) (Figure1B & supplemental Figure1B). 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. Her Texarkana doctor recommended that she go to UAMS in Little Rock for treatment. These results indicate that AKT signaling is required to restrain the FOXO-dependent suppression of many key metabolic enzymes in MM cells. "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. All univariate P values were reported regardless of significance. doi: https://doi.org/10.1182/bloodadvances.2022007383. It's sad to know how brainwashed breast cancer awareness is about chemotherapy, radiation, and surgery. In high school, Lavender was very involved in "almost every activity," she says. HOPE AGAINST HOPE | WORD AND PRAYER | 27-04-2023 - Facebook Editha McCormick (19031904), who also died young. Despite the availability of high-resolution structures, the discovery of allosteric modulators remains challenging due to the dynamic nature of GPCRs in native membranes. Together, these results show that AKT crucially regulates the metabolic functioning of MM cells by controlling the activity of FOXO. Conflict-of-interest disclosure: The authors declare no competing financial interests. 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. Timeline: American Foundations and the History of Public Health For Lavender, staying positive is key to dealing with cancer and all of life's challenges. These alterations may result in metabolic dependencies that can be exploited for therapeutic purposes. 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). "[17] She was also said to be interested in astrology and to celebrate Christmas on December 15. EDITH ROCKEFELLER TO GET $8,419,032", "J.D. 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). 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 D. Rockefeller is also the son of the founder of the pharmaceutical industry in the US. Here is a quote from John D. Rockefeller that sums up his vision for America: "I don't want a nation of thinkers. I had sat in it many times. For Lavender, 52, a colorectal cancer survivor, participating is part of her mission to encourage people to get screened for colorectal cancer. John Rockefeller: How he took control over Modern Medicine These results suggest that AKT signaling might be a determinant of metabolic adaptability in MM cells. 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. "It was a wonderful experience being on the 'Hill,'" she says. Her father, on the other hand, was more serious and disciplined as he worked hard at his law practice. This document may not be reprinted without the express written permission of Northwest Arkansas Newspapers LLC. Edith later explained that her donation was motivated by a fascination with animal psychology. 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). designed the study and wrote the manuscript; T.A.B. When evidence began to emerge that petroleum based medicine was causing cancer, Rockefeller founded the American Cancer Society, through which he suppressed that information. She then went to UAMS, where she says the care she received saved her life. Experimental details are provided in the supplemental Materials and Methods. "[14] Over the next few years, Edith and Harold frequently found themselves in court in lawsuits over the divorce agreement.[15]. Also, basal respiration and spare respiratory capacity were similar in the primary MM cells and HMCLs. 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. Financials & Governance | American Cancer Society 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. 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). 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. What the super-rich really did during World War II - MSN 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. In addition, AKT kinase activity regulated mitochondrial respiration in MM (Figure2C, supplemental Figure2E-F). Upon graduation, he moved his family to Texarkana, where he joined a local law firm. 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. 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. [13] He was given custody of their youngest daughter Mathilde so that she could marry Max Oser, a Swiss riding instructor. CI, confidence interval; B2M, beta2-microglobulin; Hb, hemoglobin; HR, hazard ratio; ISS, International Staging System; LDH, lactate dehydrogenase. Basal ECAR values from the Seahorse XF glycolysis stress test are depicted, and means SEM are shown (ttest,n=5-6 measurements). (B) Multivariate analysis of subgroups (n= 525) for OS. Texarkana is actually two cities -- one in Texas and one in Arkansas -- divided by the Texas-Arkansas state line. GEP data were obtained using samples from patients with MM who were at baseline and were undergoing total therapy 2 (TT2) or TT3 protocols.22 The clinical course for the patients showing high expression of these FOXO-repressed metabolic genes was characterized by a highly inferior OS (P< .0001). 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. 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. 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. 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). All rights reserved. At Christmas, she and her family, which included a younger sister and brother, would carol throughout the neighborhood. CTRL, control; ES, enrichment score; FDR, false discovery rate; KEGG, Kyoto Encyclopedia of Genes and Genomes; KO, knockout; NES, normalized enrichment score. 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. LE analysis provided the genes that contributed most prominently to the core enrichment of multiple gene sets associated with glycolysis, the TCA cycle, and OXPHOS (supplemental Table1). 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. Z-score values are depicted, ranging from3 (blue) indicating low expression to 3 (red) indicating high expression. David Dubinsky, the president of the ILGWU, stands to his left, holding a pair of scissors. When no longer able to generate sufficient ATP from glycolysis, OXPHOS is increased, although not sufficiently to maintain a similar proliferation rate and viability. 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). A Brief History of American Pharma: From Snake Oil to Big Money In September 2012, Lavender was on her way home to Little Rock from the 2012 Democratic National Convention in Charlotte, N.C., when she began feeling ill. She had coordinated travel plans for Biden and his family and had stayed up all night making sure everyone made flights back home. P-values were determined with Wald 2 test in Cox regression analysis. Laurance received many honors for his efforts on behalf of the environment and cancer research and treatment. (PBMNCs and purified Bcellswere obtained from 3 healthy donors). ); 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. I was his first wife. She was born in Fayetteville in 1970 while her father, Bill Lavender, was finishing law school at the University of Arkansas. How Rockefeller Founded Modern Medicine and Eliminated Natural Cures After a business trip in September 2012, however, she knew something was wrong. (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. Her friend won. On spring breaks, her father would join them for excursions to Disneyland and snow skiing. John Rockefeller and modern medicine: Abraham Flexner was born in 1866 in Louisville, Kentucky. She and her husband Harold Fowler McCormick were prominent in Chicago society, supporting many causes, including the city's first opera company. 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. In 1927, she was mentioned in a newspaper article about Chicago's wealthy unmarried, divorced, and widowed wealthy women. We have previously shown that AKT regulates the stability of the antiapoptotic Myeloid-cell leukemia 1 (MCL-1) protein, which is essential for the survival of MM cells.18 Consequently, HMCLs overexpressing MCL-1 were resistant to AKT inhibitorinduced cell death.18 However, MCL-1 overexpression did not prevent reduced glycolysis induced by MK2206 treatment, indicating that the effects of AKT inhibition on glycolysis were not related to the induction of apoptosis (supplemental Figure2C). ", Copyright 2023, Northwest Arkansas Newspapers LLC. How John D. Rockefeller Influenced Modern Medicine We developed a strategy to covalently tether drug fragments adjacent to allosteric sites in GPCRs to enhance . Edith Rockefeller McCormick (August 31, 1872 August 25, 1932) was an American socialite, daughter of Standard Oil co-founder John D. Rockefeller. 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. Please read our Terms of Use or contact us. To continue their mission today, Shah says the RF must "directly confront climate change". "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.". Guikema, Department of Pathology, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; e-mail: [email protected]. 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. 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. Most recently, Lavender has been involved with the "Be a Part of the Cure Walk" hosted by the UAMS Winthrop P. Rockefeller Cancer Institute. Undaunted, her team countered by putting attention-grabbing balloons on her friend's homemade signs. It was the beginning of the wireless telecommunications industry, and Alltel was poised to be a big player. On her first trip to Iowa in September 2007, she thought she would only be there a few days and packed accordingly. 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. Seahorse extracellular flux (XF) metabolic profiling experiments were performed according to the manufacturers protocols. Her mother would take them on trips in the summer while her father stayed home to work. "It was a great place to grow up." Part II: The Rockefeller and Rothschild Empires, the Freemasons, and 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. We passed out Clinton buttons and stickers." 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. She was the fourth daughter of schoolteacher Laura Celestia "Cettie" Spelman (18391915) and Standard Oil co-founder John Davison Rockefeller. For the TCA cycle a >1.2-fold (FOXO-dependent) decrease in gene expression is indicated. 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. "I'm most grateful to have grown up in my family and in Texarkana," Lavender says. (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). "It was a fabulous environment that day," Lavender says, noting that more than 1,000 people participated in 2022. 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. As a prospect, the therapeutic exploitation of these aspects of FOXO may guide the development of novel treatments for MM. Oftentimes, younger patients don't get timely diagnoses because doctors don't think they are old enough to have colorectal cancer, 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. 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. 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. 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). Tera Futrell Kesterson of Nashville in Howard County, who met Lavender in college as Chi Omega sorority sisters, says Lavender is a "great friend" to many and inspired others with her courage, especially during her recovery from colorectal cancer. Biography: John D. Rockefeller, Senior | American Experience | PBS LME-1 cells showed low OCR when only glucose was present, in contrast to MM1.S (supplemental Figure2G). American Cancer Society - 1913 . They would go to the beach, to the Smoky Mountains, to Disney World, Cape Canaveral and more. Her mother would play piano and they would all sing. Enrichment plots for Reactome glycolysis, KEGG TCA cycle, and GSEA Hallmark_oxidative_phosphorylation gene sets are shown. However, the therapeutic targeting of metabolic enzymes may not be straightforward, given the many redundancies within and between metabolic pathways and the lack of truly specific inhibitors/therapeutic agents. She and her husband Harold Fowler McCormick were prominent in Chicago society, supporting many causes, including the citys first opera company. Now it seems that another iconic American institution has turned its back on the Sussexes: The Rockefeller family. provided theoretical and technical input and supervised the metabolic profiling experiments; M.S., C.J.M.v.N., and J.E.J.G. (B) Half maximal effective concentrations (EC50) of 2-DG for cell death in HMCLs and BCLs after 3 days of treatment. Also, tours of the MammoVan, UAMS' mobile mammography unit, will be offered. 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. [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. Margaret Sanger - Wikipedia That support was vital, she adds. (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).
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