did rockefeller found the american cancer society

1 Cancer cells are characterized by metabolic alterations, which are driven by oncogenes. 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). Bair, Deirdre, "Jung - A Biography" London: Time-Warner Books UK, 2004, This page was last edited on 28 April 2023, at 05:29. 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. She was a member of both the Young Democrats group and the Teenage Republicans. Despite the availability of high-resolution structures, the discovery of allosteric modulators remains challenging due to the dynamic nature of GPCRs in native membranes. 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. Also, basal respiration and spare respiratory capacity were similar in the primary MM cells and HMCLs. She is especially interested in raising awareness. For the glycolysis pathway, red, blue, and yellow symbols indicate >1.5-fold (FOXO-dependent) decrease in gene expression in LME-1, MM1.S, and XG-3, respectively. 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). At Christmas, she and her family, which included a younger sister and brother, would carol throughout the neighborhood. "[18] Newspaper articles mention organizing troubles that caused it to be cancelled in 1929. (B) Multivariate analysis of subgroups (n= 525) for OS. Lavender's experience would be positive as well. 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. UAMS says the economic impact on Arkansas could be $72 million, with 1,500 new jobs created over five years. "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.". He was also a "big, big" Razorback fan, she says, a passion she shares with him. However, at high glucose uptake rates, the activation of glycolysis and decreased mitochondrial respiration results in more ATP production due to a more efficient cytoplasmic solvent capacity.40 Rapidly proliferating cells are characterized by a high glucose uptake capacity,41 which may explain the glycolytic phenotype of HMCLs. FDR, ES, NES, and P-value are depicted in the plots. She was educated at home by private tutors and, unlike other women of means at the time, did not attend finishing school.[1]. 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. After dinner, where they met Clinton and his wife, Hillary, they got back on the charter bus and headed home. According to the UAMS website, the "NCI Designation is a highly competitive assessment process during which cancer centers must demonstrate outstanding depth and breadth of high-quality cancer research and treatment." John D. Rockefeller is also the son of the founder of the pharmaceutical industry in the US. During aerobic glycolysis, glucose is converted to pyruvate and subsequently to acetyl-CoA to fuel the TCA cycle and OXPHOS. 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. Then in 2007, Lavender helped with another fundraiser for Hillary, this time as part of her first presidential bid. 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. "[14] Over the next few years, Edith and Harold frequently found themselves in court in lawsuits over the divorce agreement.[15]. FDR, ES, NES, and P-value are shown in the plots. "I don't need her to convince me, but there could not be a better ambassador for UAMS. 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. 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). As for cancer, the American Cancer Society was founded by Rockefeller himself in 1913. Bar graphs (right panels) depict basal glycolysis values, means SEM are shown (one-way ANOVA, with Bonferroni multiple comparison test). Original data are available on request from the corresponding author, Jeroen E. J. Guikema (j.e.guikema@amsterdamumc.nl). 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. When evidence began to emerge that petroleum based medicine was causing cancer, Rockefeller founded the American Cancer Society, through which he suppressed that information. (A) Immunoblot analysis of HK2 and PKM2 in LME-1, MM1.S, and LP-1 HMCLs treated overnight with 2.5 M MK2206 AKT inhibitor or left untreated. Her Texarkana doctor recommended that she go to UAMS in Little Rock for treatment. 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. All univariate P values were reported regardless of significance. 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. (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). ); 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. During the race for ASG president, Lavender says, her friend's opponent had more money and used it to make professional yard signs. AKT regulates glycolysis and OXPHOS in a FOXO-dependent fashion in MM cells. "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.". John D. Rockefeller (1839-1937), founder of the Standard Oil Company, became one of the world's wealthiest men and a major philanthropist. ROCKEFELLER JR. News arrived that Edith and Harold's elder son, John Rockefeller McCormick, had died of scarlet fever. Lavender had early-onset colorectal cancer. (A) GSEA in MMPCs from newly diagnosed patients with MM (n= 75) vs bone marrow plasma cells obtained from healthy donors (n= 15) showing that the shared FOXOrepressed gene set is enriched in MMPCs, indicating lower FOXO activity in these cells. 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. SPEEDING TO ILL SISTER; Financier, Despite Attack of Shingles, Is on Way to Chicago to See Mrs. Edith McCormick", "J.D. "UAMS is Arkansas' cancer center," Lavender says, adding that she encourages Arkansans with cancer to consider UAMS for treatment. 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. 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. "It was a wonderful experience being on the 'Hill,'" she says. "We would go to different countries.". (Arkansas Democrat-Gazette/Cary Jenkins). The plan fell through for undisclosed reasons in December 1922. 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). "I'm most grateful to have grown up in my family and in Texarkana," Lavender says. -actin served as a loading control. 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. [20][21] She and two of her children, John and Editha, are buried in Graceland Cemetery in Chicago. "It's not just awareness for the patient to do their screenings," she says. In high school, Lavender was very involved in "almost every activity," she says. A year later, she and her husband established the John McCormick Institution of Infectious Diseases in Chicago, a source of funding for the researchers who later isolated the bacterium responsible for the disease. 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). 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. Its global headquarters is located in the American Cancer Society Center in Atlanta, Georgia. Moreover, proliferation was decreased in all HMCLs tested (supplemental Figure1E), indicating that insufficient ATP is generated through mitochondrial respiration. In 2016, Lavender caught the attention of Katie Couric, the former co-anchor of NBC's Today Show, who led a national colorectal cancer awareness campaign in the late 1990s after her husband, Jay Monahan, died from the disease at age 42. To continue their mission today, Shah says the RF must "directly confront climate change". [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. Edith began support of the Art Institute in 1909 as a charter member and supported it with monetary contributions and loans from her extensive personal art collection. 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. Experimental details are provided in the supplemental Materials and Methods. UAMS started the walk in 2021 to honor patients with all forms of cancer and raise money for cancer research. Multiple myeloma (MM) is a malignancy characterized by the clonal expansion of plasma cells in the bone marrow. It all starts with John D. Rockefeller (1839 - 1937) who was an oil magnate, a robber baron, America's first billionaire, and a natural-born monopolist. 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. 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. Moreover, our results suggest that AKT signaling sustains OXPHOS independently of its effects on glycolysis because AKT inhibition still decreased mitochondrial respiration when pyruvate was present as the sole carbon source, thereby obviating the need for pyruvate provided by glycolysis. (B) Half maximal effective concentrations (EC50) of 2-DG for cell death in HMCLs and BCLs after 3 days of treatment. This experiment further indicated that glutamine can be used by HMCLs to fuel OXPHOS, which requires AKT activity. They lived on the Arkansas side, which she calls the "good side" of Texarkana. As expected, ECAR decreased upon DCA treatment, confirming reduced lactate production, whereas basal respiration was generally not increased in HMCLs. 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. Texarkana is actually two cities -- one in Texas and one in Arkansas -- divided by the Texas-Arkansas state line. G protein-coupled receptors (GPCRs) modulate diverse cellular signaling pathways and are important drug targets. ROCKEFELLER JR. GREETS DYING SISTER; Mrs. Edith McCormick Has Relapse in the Night, but Soon Rallies", "MRS. McCORMICK'S ESTATE; Once Estimated at $40,000,000 -- Great Losses Since Crash of 1929", Edith Rockefeller McCormick Trust records, https://en.wikipedia.org/w/index.php?title=Edith_Rockefeller_McCormick&oldid=1152097548, John Rockefeller McCormick (18971901), who died young from. (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). CI, confidence interval; B2M, beta2-microglobulin; Hb, hemoglobin; HR, hazard ratio; ISS, International Staging System; LDH, lactate dehydrogenase. The American Society for the Control of Cancer (the forerunner of the American Cancer Society) was established with the aid of John D. Rockefeller, and the first X-ray machine was put into use. This document may not be reprinted without the express written permission of Northwest Arkansas Newspapers LLC. Longtime friends are not surprised at Lavender's dedication to colorectal cancer awareness and prevention. [12], Edith and Harold were divorced in December 1921. Rather, a subpopulation of cells displayed an increased glucose uptake, perhaps because of feedback regulation (supplemental Figure2D). -actin served as a loading control. She called her parents to say she wanted to come home to Texarkana to see a doctor. Please read our Terms of Use or contact us. Nov. 5, 2018. Mr. Rockefeller founded the American Cancer Society for which he surpressed that information. When evidence began to emerge that petroleum based medicine was causing cancer, Rockefeller founded the American Cancer Society, through which he suppressed that information. And she returned to working on campaigns when a friend ran for student body president. SHE TESTIFIES IN COURT He Is Absent and Makes No Defense, Although Represented by Counsel. 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. 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. David Dubinsky, the president of the ILGWU, stands to his left, holding a pair of scissors. 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. Enrichment plots for Reactome glycolysis, KEGG TCA cycle, and GSEA Hallmark_oxidative_phosphorylation gene sets are shown. The increased glycolytic rate seems counterintuitive because glycolysis yields far less ATP per glucose molecule than that in mitochondrial respiration. 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. 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. 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. Interestingly, our findings could be extended to patients with MM and have important prognostic implications. 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. She accepted and soon found herself in the fast-paced, sometimes chaotic, world of a presidential campaign. Edith was born on August 31, 1872 at her parents' home in Cleveland, Ohio. Nevertheless, the glycolytic reserve of the primary MM cells was limited and similar to that observed in the HMCLs. "Betsy Lavender has been such a tireless warrior and powerful voice about the importance of early detection for colon cancer," Couric says. Here, we show that human MM cell lines (HMCLs) rely on glycolysis for proliferation and survival. 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. The Board is composed entirely of volunteers from the . Mean values of 3 individual experiments are depicted. Her three elder sisters were Elizabeth (Bessie) (18661906), Alice (18691870), and Alta (18711962). 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). The gene set enrichment analysis (GSEA) software (http://www.broad.mit.edu/gsea)26 and the Molecular Signature Database were used for GSEAs and leading edge (LE) analyses. 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). New York: St. Martin's Press, 1995. [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. I drive everybody crazy.". | (C) Linear regression analysis of the glycolytic reserve values (x-axis) vs the EC50 values for 2-DG (y-axis) in HMCLs and BCLs. [13] He was given custody of their youngest daughter Mathilde so that she could marry Max Oser, a Swiss riding instructor. 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. (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). 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. 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. John D. Rockefeller, Sr. Rockefeller Archive Center. "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. Interestingly, the spare respiratory capacity and the maximum respiration increased in the majority of the HMCLs (5 out of 6) (Figure1D). For Lavender, 52, a colorectal cancer survivor, participating is part of her mission to encourage people to get screened for colorectal cancer. 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).
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