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. (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). Still, she thrived in the unpredictable, always-on lifestyle. At Christmas, she and her family, which included a younger sister and brother, would carol throughout the neighborhood. Traveling was another favorite activity of the Lavender family, she says. [8] After extended analysis and intense study, Edith became a Jungian analyst, with a full-time practice of more than fifty patients. Within days of Harold's remarriage, Edith announced plans to marry Edward Krenn, a 28 year old Austrian architect. And the fact that she's willing to scream it from the mountaintops makes me love her even more.". 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. 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. She then traveled to Denver to work with media logistics for the Democratic National Convention. 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. 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. For Lavender, 52, a colorectal cancer survivor, participating is part of her mission to encourage people to get screened for colorectal cancer. "I'm most grateful to have grown up in my family and in Texarkana," Lavender says. provided theoretical and technical input and supervised the metabolic profiling experiments; M.S., C.J.M.v.N., and J.E.J.G. 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. Here is a quote from John D. Rockefeller that sums up his vision for America: "I don't want a nation of thinkers. This implies that most glucose is converted into lactate and cannot be used for the TCA cycle, suggesting that other carbon sources fuel OXPHOS in MM. The AP will not be held liable for any delays, inaccuracies, errors or omissions therefrom or in the transmission or delivery of all or any part thereof or for any damages arising from any of the foregoing. FOXO represses the expression of metabolic genes in MM cells. 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). ROCKEFELLER JR. 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). "That was a lot of fun," she says, adding that it was the first time she was involved in developing strategy for a political race. This experiment further indicated that glutamine can be used by HMCLs to fuel OXPHOS, which requires AKT activity. 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. 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). Cell lines, cell culture conditions, and details on reagents are provided in the supplemental Materials and Methods. CTRL, control; ES, enrichment score; FDR, false discovery rate; KEGG, Kyoto Encyclopedia of Genes and Genomes; KO, knockout; NES, normalized enrichment score. To continue their mission today, Shah says the RF must "directly confront climate change". That was good news for Lavender because she was already familiar with UAMS. "I felt comfortable.". 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. Guikema, Department of Pathology, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands; e-mail: j.e.guikema@amsterdamumc.nl. (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. Furthermore, we provide evidence that AKT sustains glycolysis and OXPHOS in MM by restricting FOXO. For several years, he ran a college prep school in his home town of Louisville. She is especially interested in raising awareness. and G.d.W performed the experiments and analyses; R.J.B. 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. ", Copyright 2023, Northwest Arkansas Newspapers LLC. 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). P-values were determined with Wald 2 test in Cox regression analysis. 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. "[16] She followed up in Time magazine by stating "My interest in reincarnation is of many years' standing. Multiple myeloma (MM) is a malignancy characterized by the clonal expansion of plasma cells in the bone marrow. . Among them are the Alfred P. Sloan, Jr. Memorial Award from the American Cancer Society (1969), the Medal of Freedom (1969), the Congressional Gold Medal (1991), and the Lady Bird Johnson Conservation Award for Lifetime Achievement (1997). Stasz, Clarice. 1 Cancer cells are characterized by metabolic alterations, which are driven by oncogenes. 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). Laurance received many honors for his efforts on behalf of the environment and cancer research and treatment. Whereas in patients with smoldering MM, only the LE OXPHOS gene set was significantly enriched (supplemental Figure4A-C). 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. They saw the sights, Lavender says, but her small crew of interns stayed busy with work. 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. They would go to the beach, to the Smoky Mountains, to Disney World, Cape Canaveral and more. "It was coming here and feeling supported, and there wasn't a time that I have ever been scared.". Her friend won. Activation of PI3K/AKT signaling is an established oncogenic feature of MM cells, sustaining several antiapoptotic and proliferative pathways. "I had no reason to believe I was sick," she says. . 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. CI, confidence interval; B2M, beta2-microglobulin; Hb, hemoglobin; HR, hazard ratio; ISS, International Staging System; LDH, lactate dehydrogenase. 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. 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). Correspondence: Jeroen E.J. Editha McCormick (19031904), who also died young. As for cancer, oh yeah, the American Cancer Society was founded by none other than Rockefeller in 1913. "We would go to different countries.". 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. (A) Kaplan-Meier univariate analysis for the OS of k-means clusteringdefined groups of patients with MM (776 patients in total). Most recently, Lavender has been involved with the "Be a Part of the Cure Walk" hosted by the UAMS Winthrop P. Rockefeller Cancer Institute. "[17] She was also said to be interested in astrology and to celebrate Christmas on December 15. 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. After Hillary Clinton's campaign ended before the 2008 Democratic Convention in Denver, Lavender went on a trip to Africa where the Clinton Foundation had several programs. 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. Similarly, the normalized spare respiratory capacity of HMCLs was similar to that of other BCLs, demonstrating that HMCLs and BCLs do not differ with regard to mitochondrial adaptability.27 However, both HMCLs and Burkitt lymphoma cell lines (BLCLs) showed very limited normalized glycolytic reserve (Figure1A). Moreover, proliferation was decreased in all HMCLs tested (supplemental Figure1E), indicating that insufficient ATP is generated through mitochondrial respiration. 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. He lived until 1959. [7], In 1913, she travelled to Zurich to be treated for depression by Carl Gustav Jung, and contributed generously to the Zrich Psychological Society. I was his first wife. And she found out the hard way. In this month of breast cancer awareness, it is sad to see people being brainwashed about chemotherapy, radiation and surgery. ; Her Leadership of Chicago Society Unchallenged to the End", "Fowler McCormick Dies at 74; ExChairman of Harvester", "MRS. MAX OSER DIES ON COAST; Granddaughter of the Late John D. Rockefeller, Sister of Fowfer McCormick ", "MRS. OSER GOES TO MOTHER; Rides in Twentieth Century to Bedside of Mrs. McCormick", "The Aryan Christ: The Secret Life of Carl Jung - ResearchGate", "A Quirky Visionary: Edith Rockefeller McCormick Reigned as Queen of Chicago's Elite", "MRS. H.F. M'CORMICK BACK AFTER 8 YEARS; Rockefeller's Daughter Denies Planning Divorce Action Against International Harvester Head. 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. She and her husband Harold Fowler McCormick were prominent in Chicago society, supporting many causes, including the citys first opera company. 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. 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. 01 May 2023 02:14:13 . 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. She remained prominent after her divorce from McCormick and helped sponsor and organize several "Women's World Fairs" celebrating female achievement in the 1920s. 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). When evidence began to emerge that petroleum based medicine was causing cancer, Rockefeller founded the American Cancer Society, through which he suppressed that information. GSEA enrichment plots are shown, interrogating Reactome for glycolysis, KEGG for TCA cycle, and GSEA for Hallmark_oxidative_phosphorylation gene sets. FDR, ES, NES, and P-value are shown in the plots. She says Lavender reminds her regularly to get screened, noting that colorectal cancer disproportionately affects the Black community. [13] He was given custody of their youngest daughter Mathilde so that she could marry Max Oser, a Swiss riding instructor. 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. 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. Enrichment plots for Reactome glycolysis, KEGG TCA cycle, and GSEA Hallmark_oxidative_phosphorylation gene sets are shown. "The Rockefeller Women." Senator Herbert Lehman looks over her right shoulder, while Governor Rockefeller stands over her left shoulder. SHE TESTIFIES IN COURT He Is Absent and Makes No Defense, Although Represented by Counsel. John D. Rockefeller (1839-1937), founder of the Standard Oil Company, became one of the world's wealthiest men and a major philanthropist. She would continue her practice after her return to America, attracting many socialite patients from around the United States. These results indicate that AKT signaling is required to restrain the FOXO-dependent suppression of many key metabolic enzymes in MM cells. She is especially interested in raising awareness of early onset colorectal cancer, which occurs in people under age 45 and is on the rise. Lavender was 42 when she was diagnosed. 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. (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). -actin served as a loading control. As expected, ECAR decreased upon DCA treatment, confirming reduced lactate production, whereas basal respiration was generally not increased in HMCLs. [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. Rockefellers later relocated the U . I had sat in it many times. 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. Mean values of 3 individual experiments are depicted. Phosphorylation of AKT at Ser473, which marks its activation, slightly increased upon treatment with DCA in 2 out of 3 galactose-adapted HMCLs. The official, Dr . [9] From February 1918 until October 1919, she provided James Joyce with a monthly benefaction. 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). She joined Chi Omega sorority and was an Associated Student Government (ASG) representative. Sheila Yount Special to the Democrat-Gazette "Anything that is thrown at me doesn't rattle me.". Mean values for basal glycolysis andnormalized glycolytic reserve (percentage of basal glycolysis) based on ECAR and mean values for basal respiration and normalized spare respiratory capacity(percentage of basal respiration) based on OCR are depicted (one-way ANOVA with Bonferroni multiple comparisons test; HMCLs vs BCLs, n= 5 measurements. She was born in Fayetteville in 1970 while her father, Bill Lavender, was finishing law school at the University of Arkansas. 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. UAMS started the walk in 2021 to honor patients with all forms of cancer and raise money for cancer research. The protein kinase B/AKT acts as a central node in cellular metabolism and is constitutively active in MM cells. 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. 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. Upon graduation, he moved his family to Texarkana, where he joined a local law firm. As a prospect, the therapeutic exploitation of these aspects of FOXO may guide the development of novel treatments for MM. "We got there, and it was snowing. NONE OF FAMILY ON SHIP $50,000 Fee Reported for Psychoanalyst Who Will See Herto Chicago Home", "MRS. H. F. M'CORMICK OBTAINS DIVORCE IN FIFTY MINUTES; John D. Rockefeller's Daughter Gains Decree for Desertion, Which Husband Admits. It was the beginning of the wireless telecommunications industry, and Alltel was poised to be a big player. 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. [20][21] She and two of her children, John and Editha, are buried in Graceland Cemetery in Chicago. (C) Basal respiration and spare respiratory capacity in HMCLs and MMPCs (n= 2 patients) treated with 2.5 M MK2206 (blue bars) or untreated(red bars) for 20 hours. She accepted and soon found herself in the fast-paced, sometimes chaotic, world of a presidential campaign. Undaunted, her team countered by putting attention-grabbing balloons on her friend's homemade signs.
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