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Journal articles on the topic "Harmon Foundation, inc"
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Lac, V., L. Verhoef, R. Aguirre-Hernandez, T. M. Nazeran, B. Tessier-Cloutier, T. Praetorius, N. L. Orr, et al. "Iatrogenic endometriosis harbors somatic cancer-driver mutations." Human Reproduction 34, no. 1 (November 14, 2018): 69–78. http://dx.doi.org/10.1093/humrep/dey332.
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Abstract STUDY QUESTION Does incisional endometriosis (IE) harbor somatic cancer-driver mutations? SUMMARY ANSWER We found that approximately one-quarter of IE cases harbor somatic-cancer mutations, which commonly affect components of the MAPK/RAS or PI3K-Akt-mTor signaling pathways. WHAT IS KNOWN ALREADY Despite the classification of endometriosis as a benign gynecological disease, it shares key features with cancers such as resistance to apoptosis and stimulation of angiogenesis and is well-established as the precursor of clear cell and endometrioid ovarian carcinomas. Our group has recently shown that deep infiltrating endometriosis (DE), a form of endometriosis that rarely undergoes malignant transformation, harbors recurrent somatic mutations. STUDY DESIGN, SIZE, DURATION In a retrospective study comparing iatrogenically induced and endogenously occurring forms of endometriosis unlikely to progress to cancer, we examined endometriosis specimens from 40 women with IE and 36 women with DE. Specimens were collected between 2004 and 2017 from five hospital sites in either Canada, Germany or the Netherlands. IE and DE cohorts were age-matched and all women presented with histologically typical endometriosis without known history of malignancy. PARTICIPANTS/MATERIALS, SETTING, METHODS Archival tissue specimens containing endometriotic lesions were macrodissected and/or laser-capture microdissected to enrich endometriotic stroma and epithelium and a hypersensitive cancer hotspot sequencing panel was used to assess for presence of somatic mutations. Mutations were subsequently validated using droplet digital PCR. PTEN and ARID1A immunohistochemistry (IHC) were performed as surrogates for somatic events resulting in functional loss of respective proteins. MAIN RESULTS AND THE ROLE OF CHANCE Overall, we detected somatic cancer-driver events in 11 of 40 (27.5%) IE cases and 13 of 36 (36.1%) DE cases, including hotspot mutations in KRAS, ERBB2, PIK3CA and CTNNB1. Heterogeneous PTEN loss occurred at similar rates in IE and DE (7/40 vs 5/36, respectively), whereas ARID1A loss only occurred in a single case of DE. While rates of detectable somatic cancer-driver events between IE and DE are not statistically significant (P > 0.05), KRAS activating mutations were more prevalent in DE. LIMITATIONS, REASONS FOR CAUTION Detection of somatic cancer-driver events were limited to hotspots analyzed in our panel-based sequencing assay and loss of protein expression by IHC from archival tissue. Whole genome or exome sequencing, or epigenetic analysis may uncover additional somatic alterations. Moreover, because of the descriptive nature of this study, the functional roles of identified mutations within the context of endometriosis remain unclear and causality cannot be established. WIDER IMPLICATIONS OF THE FINDINGS The alterations we report may be important in driving the growth and survival of endometriosis in ectopic regions of the body. Given the frequency of mutation in surgically displaced endometrium (IE), examination of similar somatic events in eutopic endometrium, as well as clinically annotated cases of other forms of endometriosis, in particular endometriomas that are most commonly linked to malignancy, is warranted. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by a Canadian Cancer Society Impact Grant [701603, PI Huntsman], Canadian Institutes of Health Research Transitional Open Operating Grant [MOP-142273, PI Yong], the Canadian Institutes of Health Research Foundation Grant [FDN-154290, PI Huntsman], the Canadian Institutes of Health Research Project Grant [PJT-156084, PIs Yong and Anglesio], and the Janet D. Cottrelle Foundation through the BC Cancer Foundation [PI Huntsman]. D.G. Huntsman is a co-founder and shareholder of Contextual Genomics Inc., a for profit company that provides clinical reporting to assist in cancer patient treatment. R. Aguirre-Hernandez, J. Khattra and L.M. Prentice have a patent MOLECULAR QUALITY ASSURANCE METHODS FOR USE IN SEQUENCING pending and are current (or former) employees of Contextual Genomics Inc. The remaining authors have no competing interests to declare. TRIAL REGISTRATION NUMBER Not applicable.
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Hadi, Syamsul. "Lasem: Harmoni dan Kontestasi Masyarakat Bineka." ISLAM NUSANTARA: Journal for Study of Islamic History and Culture 1, no. 1 (July 30, 2020): 163–208. http://dx.doi.org/10.47776/islamnusantara.v1i1.49.
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This article aims to explain how the contestation of social spaces in the lives of the plural society at Lasem it processes dynamically. It is a pattern of space contestation that leads to the affirmation and strengthening of identity or a pattern that leads to the fusion of identities. As a consequence, the first pattern creates social friction or conflict. On the contrary, the second pattern is directed towards acculturation and assimilation of culture which can strengthen social harmony. The important finding of this research is that it can be known the real issue, so that problems related to all parties can be found a solution as well as a resolution. This research also proves that social mechanism preparedness is considered urgent to prevent negative excesses (negative things) from the space contestation. So the space contestation that occurs dynamically proves that the plural society in Lasem has found a valuable experience, namely social resilience in facing all possible emergence of social disintegration.Keywords: contestation, space, social mechanisms and an plural society
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Oxnard, Geoffrey R., Jennifer C. Heng, Irene R. Rainville, Suzanne Eleanor Dahlberg, Alicia L. Sable-Hunt, Georgia L. Wiesner, Kelly A. Taylor, David Michael Jackman, Pasi A. Janne, and Judy Ellen Garber. "Investigating hereditary risk from T790M (inherit): A prospective multicentered study of risk associated with germ-line EGFR T790M." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): TPS1606. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.tps1606.
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TPS1606 Background: The EGFR T790M mutation, commonly associated with acquired resistance to EGFR kinase inhibitors, has also been seen as a germline mutation in association with familial lung cancer. In collaboration with the Addario Lung Cancer Medical Institute (www.ALCMI.net), we initiated a prospective trial to identify patients and families carrying germline EGFR mutations in order to characterize their cancer risk. Preliminary data: In a prior study (Oxnard et al, JTO, 2012), it was found that patients with lung cancers found to harbor EGFRT790M at diagnosis have a 50% chance of carrying an underlying germline T790M mutation. This suggests that study of patients known to carry T790M in their cancer will enrich for a germline event that otherwise is too rare to study prospectively. Subject eligibility: Three cohorts are eligible: (1) Patients with a cancer (lung or other) harboring EGFR T790M on tumor genotyping; lung cancers that acquire EGFR T790M only after treatment are ineligible. (2) First-degree relatives of patients carrying a germline EGFR mutation. (3) Patients already known to carry a germline EGFRmutation on prior testing. Subjects are referred to cohort 1 based upon routine genotyping results from commercial laboratories (e.g. Response Genetics Inc., Los Angeles, CA). Methods: Subjects may present at a participating cancer center or may participate remotely through a study website (www.Dana-Farber.org/T790Mstudy). Eligible patients submit a saliva and/or blood specimen for central testing in a CLIA lab. After counseling, patients carrying germline EGFR mutations have the option of inviting first-degree relatives to participate. Genetic counseling is coordinated at the participating center or offered over the phone. Chest CT scans are collected from germline carriers and analyzed centrally to study nodule characteristics. Patients are clinically followed for 2 years. At time of submission, 6 subjects have enrolled from 3 different families and 4 different US states. (NCT01754025) Funding: Supported by grants from the Conquer Cancer Foundation of ASCO and the Bonnie J. Addario Lung Cancer Foundation. Clinical trial information: NCT01754025.
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Pourebrahim, Rasoul, Rafael Heinz Montoya, Zoe Alaniz, Lauren B. Ostermann, Hung Alex Luong, Joseph D. Khoury, and Michael Andreeff. "Mdm2 Loss of Heterozygosity Cooperates with Mutant p53 in Acute Myeloid Leukemia." Blood 136, Supplement 1 (November 5, 2020): 20–21. http://dx.doi.org/10.1182/blood-2020-142523.
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TP53 mutations are observed in 5 to10% of de novo AML cases with dismal disease prognosis and response to therapy. We found that MDM2 loss of heterozygosity (MDM2 LOH) in AML was always concomitant with TP53 missense mutations (log2 odds ratio>3, p<.001), and not TP53 deletions or truncations whereas in lymphomas, MDM2 LOH and TP53 mutations were mutually exclusive. To understand the functional association of MDM2 LOH and TP53 mutation in AML, we generated a conditional somatic Trp53 mutant AML mouse by combining a Trp53R172H mutation with Mdm2 haploinsufficiency in hematopoietic cells using Vav-cre transgenic mice combined with RosamTmG (mTmG) allele as tracing reporter. The conditional mutant Trp53 allele used in this study harbored a R172H mutation downstream of a wildtype Trp53 cDNA flanked by loxP sites (Trp53wm-R172H) so that the expression of the wildtype Trp53 was preserved before the recombination. Mouse cohorts were generated to harbor one Trp53wm-R172H allele and a Trp53fl or were homozygous for the floxed Trp53 allele (Trp53fl/fl). The expression of Cre in hematopoietic stem cells resulted in heterozygous deletion of Mdm2 and conversion of WT Trp53 to Trp53R172, which corresponds to TP53R175H, one of the most frequent mutations in AML. Mice with somatic Trp53 mutation died due to lymphoma, however, Mdm2 haploinsufficient mice combined with Trp53 mutation succumbed to AML. The disease was immunophenotypically and histologically characterized as AML based on the bone marrow histopathology and expression of Cd11b and Ly6A on the surface of leukemic cells. Immunohistopathology of bone marrow and spleen of MdmLOH p53Mut showed a highly proliferative AML characterized by strong nuclear expression of Ki67 and mutant p53 in the bone marrow of mice. Together, our data identifies Mdm2 LOH to be essential for malignant transformation of p53 mutant myeloid lineage leading to AML development. Disclosures Andreeff: Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Amgen: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees.
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Nishida, Yuki, Rafael Heinz Montoya, Kiyomi Morita, Tomoyuki Tanaka, Feng Wang, Koichi Takahashi, Jo Ishizawa, et al. "Clonal Expansion of Mutant p53 Clones By MDM2 Inhibition in Acute Myeloid Leukemias." Blood 136, Supplement 1 (November 5, 2020): 27–28. http://dx.doi.org/10.1182/blood-2020-142794.
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MDM2 inhibition by small molecules as a means of restoring p53 function has shown clinical activity against acute myeloid leukemia (AML) (Andreeff, Clin Cancer Res 2015). However, we and others have found increased variant allele frequencies (VAFs) of TP53 mutations in AML cells after treatment with MDM2 inhibitors, either as monotherapy or in combination with other agents (Daver ASH 2019), which suggests that MDM2 inhibition selects preexisting clones or generates de novo clones with TP53 mutations. We performed a long-term culture of AML cells (MOLM-13, an AML cell line with wild-type p53 and FLT3-ITD) treated with increasing concentrations of an MDM2 inhibitor idasanutlin (up to 320 nM, less than 10% concentration of Cmax) (Selleck). We obtained MDM2 inhibitor-resistant (R) AML cells after 96 days of the drug exposure and found that the resistant cells harbor hotspot TP53 p.R248W (R248W) mutation. We next isolated single cell clones from MOLM-13 R cells by limiting dilution, and obtained twelve subclones (subclones #1-12 in order of development). All clones carried the same R248W mutation. To determine clonal patterns of these cells, we performed single cell DNA sequencing (scDNAseq) of MOLM-13 parental, R and subclone #1 and #2 (SC1 and SC2) cells using the MissionBio Tapestry system covering 125 amplicons of 19 genes frequently mutated in AML. scDNAseq identified FLT3-ITD mutations in all cells analyzed, as expected. In the parental cells we identified only 0.02% cells (1/ 5,240) with the identical R248W mutation found in MOLM-13 R cells. MOLM-13 R cells had only 0.6% of wild-type TP53 cells, 51% carrying R248W only, and 43% R248W/R213* mutation (R248W/R213*). SC1 and SC2 cells had 1% and 99% of R248W and R248W/R213* clones, respectively (Fig.1). Seven other mutations were detected by scDNAseq. Results suggest that MDM2 inhibition can accelerate the selection of TP53-mutant AML cells in vitro. Of note, the parental cells had remained mostly p53 wild-type, where the subclone with mutant R248W did not have a growth advantage over other cells. Next we analyzed patient samples enrolled in the phase 1 clinical trial (NCT02319369) for the MDM2 inhibitor milademetan (DS-3032b; Daiichi-Sankyo) in relapsed/refractory AML or high-risk MDS patients. Fifty seven patients were treated with single agent milademetan in the study. All but one patient had wild-type TP53 as determined by NGS at baseline. One patient (1.8%) had a TP53 p.R213* mutation at baseline with VAF of 91%. Four patients (7%) developed different TP53 mutations (R248Q, R248W, P250fs, V122fs and V274L), with increasing VAFs that were not detected at baseline to 19% average, ranging from 11% to 28% post treatment, One patient (anonymized ID 1001-1005) developed both, R248Q and R248W mutations, detected at cycle 2 day1 (C2D1, day 29). The pre-existing R213* mutation detected in one patient persisted with increased VAF after treatment (91% to 100%). To detect p53 mutations with higher sensitivity than NGS, we performed droplet digital PCR (ddPCR) for R248W/Q and R273H in samples from two patients. ddPCR detected 0.46% and 0.62% of R248Q and R248W mutations, respectively, at baseline, which were not detected by NGS, with increased VAFs of 18.2 and 27.6% at C2D1, respectively. ddPCR detected additional R273H mutations with VAFs of 0.08% and 0.18% at baseline, and 2.2% and 2.6% in these patients at C2D1, respectively. Conclusion: Data suggest that MDM2 inhibition selects rare AML subpopulations with TP53 mutations and careful monitoring of patients treated with MDM2 inhibitors with sensitive methods to detect TP53 mutant clones is warranted. This finding also points to the need to develop strategies to prevent/suppress these clones early on. Disclosures Kumar: Daiichi-Sankyo Inc.: Current Employment. Patel:Daiichi-Sankyo Inc.: Current Employment. Dos Santos:Daiichi Sankyo, Inc.: Current Employment. DiNardo:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; ImmuneOnc: Honoraria; Calithera: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Jazz: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Syros: Honoraria. Andreeff:Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding.
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Soria, Jean-Charles, Jordi Rodon Ahnert, Raanan Berger, Wilson H. Miller, Irene Brana, Yohann Loriot, Tariq I. Mughal, et al. "WINTHER: An international study to select rational therapeutics based on the analysis of matched tumor and normal biopsies in subjects with advanced malignancies." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): TPS11625. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps11625.
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TPS11625 Background: Today, personalized cancer medicine implies matching the patient’s tumor genomic characteristics with molecularly and immune targeted agents. Although there are an increasing number of DNA aberrations that can now be matched to a cognate therapy, some patients do not display such druggable oncogene drivers. Methods: WINTHER is an open non-randomized study involving 6 cancer centers in France, Spain, Israel, Canada and USA applying genomic and also transcriptomic assays to guide treatment decisions. The novelty of the WINTHER approach lies in the use of tumor and matched normal tissue biopsies together and an algorithm for predicting efficacy of therapies. The aim is to provide a rational therapeutic choice for all of the patients enrolled in the study whether or not they harbor actionable DNA alterations. The study endpoint is the comparison of the progression-free-survival (PFS) under the WINTHER selected therapy to the PFS of the last therapeutic line. Patients included have refractory metastatic cancer of any histological type, with at least one prior therapeutic regimen and performance status of 0 to 1. Patients who have received a matched treatment based on a molecular anomaly as their immediate prior therapy were excluded. After consent, patients undergo a tumor and histologically-matched normal tissue biopsy. Extracted DNA and RNA of both tumor and normal from frozen tissues at the local center under common standard operating procedures are sent to centralized laboratories for omics investigations. DNA is investigated at Foundation Medicine Inc. and RNA at Gustave Roussy using Agilent technology. For RNA, the WINTHER algorithm is applied on the differential RNA expression data between tumor and normal tissues and establishes the list of drugs with the presumed higher score of efficacy for each patient. Patients with actionable genomic events enter in ARM A, and patients without any druggable anomaly of the DNA enter in ARM B and are treated using the WINTHER algorithm RNA-based treatment decision tool. To date, the trial has recruited 303 patients. Clinical trial information: NCT01856296.
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Heyman, Benjamin, Michael Y. Choi, Emanuela M. Ghia, George F. Widhopf II, Minya Pu, Emily Pittman, Karen Messer, Catriona Jamieson, and Thomas J. Kipps. "Cirmtuzumab Consolidation for Treatment of Patients with Detectable CLL on Venetoclax." Blood 136, Supplement 1 (November 5, 2020): 13. http://dx.doi.org/10.1182/blood-2020-134711.
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Background: Venetoclax (Ven)-based regimens are highly effective in treating patients with chronic lymphocytic leukemia (CLL), effecting clearance of detectable minimal residual disease (MRD) in many patients after just 1 year of therapy. Approximately, 30% of patients fail to clear detectable MRD within this time period and risk developing, progressive disease (PD) despite continued Ven therapy. Moreover, these patients have a relatively short progression free survival (PFS) after stopping fixed-duration therapy. Therefore, development of consolidation strategies to eradicate detectable MRD and/or to mitigate the risk of PD in patients who fail to clear MRD after 1 year of Ven-based therapy is of vital clinical importance. In particular, patients who fail to clear MRD after 1 year of Ven-based therapy harbor CLL cells with high-level expression of ROR1, an oncoembryonic protein expressed by a broad array of incurable malignancies. Patients who are refractory to MRD-clearance on Ven-based therapies have gene-expression signatures reflective of high-level ROR1-signaling, which can be inhibited by the anti-ROR1 mAb, Cirmtuzumab (Choi et al., Cell Stem Cell. 2018; 22: 951-959). Prior studies demonstrated that Cirmtuzumab and Ven have at least additive activity in promoting cytotoxicity of CLL cells in vitro (Rassenti et al. PNAS. 2017;114(40):10731-10736). As such, cirmtuzumab may be an effective consolidation strategy for patients who fail to clear MRD following completing 1 year of Ven-based therapy. Study Design and Methods: Study Design: We initiated a single center, phase 2 Simon's two-stage-designed study to determine the efficacy of Cirmtuzumab plus Ven combination therapy in patients who fail to clear detectable MRD (defined as > 0.01% of the blood mononuclear cells, as assessed by flow cytometry) after ≥1 year of Ven-based therapy (NCT04501939). Enrolled patients will receive cirmtuzumab at 600 mg IV, q14 days for 2 doses and then monthly thereafter. Patients will continue oral Ven at 400mg daily and be monitored for safety and PD. Following 6 months of Cirmtuzumab + Ven, patients will be assessed for MRD in the blood. At the discretion of the treating physician, patients may continue combination treatment for up to one year (Figure 1). Major Eligibility Criteria: Patients must have a diagnosis of CLL with detectable MRD after having received ≥ 12 months of Ven-based treatment . Patients will be excluded from the study if they have an uncontrolled medical co-morbidity, which compromises their capacity to complete the study, or if they are receiving treatment for CLL with agents other than Ven. End Points: The primary end-point of the proposed study is clearance of detectable MRD in the blood after 6 months of cirmtuzumab + Ven therapy. Secondary end-points include safety and time to next CLL treatment. Exploratory end-points include changes in gene expression in leukemia cells, including analysis of archival pre-Ven treatment samples, when available. Statistical Methods: We used a Simon's two-stage minimax design at 5% significance level to test the scientific hypothesis that 6 cycles of cirmtuzumab + Ven will achieve undetectable MRD (a 'response') in more than 5% of patients, against the null hypothesis of less than a 5% response rate. In the first stage, we plan to accrue 12 patients. If none of these patients respond at 6 months, the study will close. Otherwise, we will accrue an additional 4 patients for a total of 16 patients. If three or more patients respond, the primary endpoint of the trial will have been met, demonstrating an MRD clearance rate greater than 5%. The trial is designed to have 80% power to provide such evidence at the 5% significance level if the true rate of clearance of MRD is 25% or greater. Disclosures Heyman: Oncternal Therapeutics, INC: Research Funding. Choi:Pharmacyclics/Abbvie: Research Funding; Genentech: Consultancy. Jamieson:Forty Seven Inc: Patents & Royalties; Bristol-Myers Squibb: Other. Kipps:Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VelosBio: Research Funding; Oncternal Therapeutics, Inc.: Other: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory, Research Funding; Celgene: Honoraria, Research Funding; Ascerta/AstraZeneca, Celgene, Genentech/F. Hoffmann-La Roche, Gilead, Janssen, Loxo Oncology, Octernal Therapeutics, Pharmacyclics/AbbVie, TG Therapeutics, VelosBio, and Verastem: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics/ AbbVie, Breast Cancer Research Foundation, MD Anderson Cancer Center, Oncternal Therapeutics, Inc., Specialized Center of Research (SCOR) - The Leukemia and Lymphoma Society (LLS), California Institute for Regenerative Medicine (CIRM): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.
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O'Shaughnessy, Joyce, Corinne Ramos, Phil Stephens, Nicholas N. Hoke, Norma Alonzo Palma, Maren K. Levin, Marina Horiates, Christine E. Horak, and Kai Wang. "Association of PIK3CA mutation with response (ExRx) to cetuximab (C) in metastatic (met) triple-negative breast cancer (TNBC)." Journal of Clinical Oncology 33, no. 28_suppl (October 1, 2015): 151. http://dx.doi.org/10.1200/jco.2015.33.28_suppl.151.
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151 Background: 10 to 17% of TNBCs harbor PIK3CA mutations (TCGA Nature 490:61, 2012; Khambata-Ford S. ASCO 2010, abst 1056). Here we report clinical history and molecular findings for a TNBC patient with loss of mutant PIK3CA in a C-refractory metastasis that was present in her primary BC, who has had an ExRx to C. Methods: Following IRB-approved informed consent, targeted NGS was performed on the pt’s FFPE primary TNBC and on a C-refractory recurrent lung metastasis at a CLIA-certified laboratory (Foundation Medicine) to characterize all classes of genomic alterations across 287 cancer-related genes. RPPA was performed at a CLIA-certified laboratory (Theranostics Health) where immunostaining with 24 antibodies was directed against HER1/2/3 pathway proteins and AR. Results: 37 yo woman presented in 2006 with grade 3 primary TNBC, infraclavicular LNs and lung metastases at 33 weeks gestation. There was no response to preop doxorubicin/cyclophosphamide and following delivery of a healthy baby, she was treated with irinotecan, carboplatin, and C (#NCT00248287) and had near complete response (CR) in her lungs and pathologic CR in breast. In 2008, after 20 mos on C, chest CT showed a new lung met which was resected and she remains disease-free on C alone. NGS: Primary BC: PIK3CA C420R, TP53 mutations, MCL1 amplification (amp), and RAD51D germline mutation; C-refractory lung met: TP53, MLL2 mutations, MCL1, MYC, KDM5A, CCNE1 amp and RAD51D germline mutation (loss of PIK3CAmutation confirmed). RPPA: Primary BC: p-AR S650 (3+); p-ERK (2+), and HER1, p-HER1, p-HER3, p-AKT, p-S6, p-4EBP1 (1+); C-refractory lung met: loss of p-ERK; p-HER1, p-4EBP1 (2+), and p-AR, p-AKT, p-mTOR (1+). PTEN: Primary BC: 60% cells positive by IHC MAb 6H2.1 (Cascade Biosciences). Conclusions: The pt’s ExRx to C was dependent on presence of PIK3CA mutation which was lost in the C-refractory lung met. Loss of RAD51D function may also have contributed (Liping L. Ca Res 68:9141, 2008). High p-AR expression did not preclude response to C. Activating PIK3CA mutations induce an EGFR/ERK paracrine signaling axis in TNBCs (Young CD. Mol Cell Proteomics 2015). A prospective trial of EGFR inhibition in PIK3CA-mutant TNBC is warranted.
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Di Liberto, Maurizio, Yang Hu, Xiangao Huang, Christina Y. Lee, Kevin Wang, Nancy L. Bartlett, LeAnn Ridling, et al. "Composite Copy Number Variation in CDK4, CDKN2A and RB1 Predisposes Mantle Cell Lymphoma to Expansion of PD1+ Tumor Cells and Resistance to CDK4/6 Inhibitor Therapy as Revealed by Integrative Longitudinal scRNA-seq." Blood 134, Supplement_1 (November 13, 2019): 1492. http://dx.doi.org/10.1182/blood-2019-130944.
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Mantle cell lymphoma (MCL) is incurable due to the development of drug resistance. MCL cells proliferate without constraint on disease progression, fueled by aberrant cyclin D1 expression due to (11;14)(q13;q32) chromosomal translocation and dysregulation of CDK4 (CDK6 is silenced) that accelerate cell cycle progression through G1. Previously, we demonstrated that selective inhibition of CDK4/6 with palbociclib leads to prolonged early G1 arrest that sensitizes MCL cells to partner drugs including the BTK inhibitor ibrutinib. In our phase I clinical trial of palbociclib + ibrutinib (PALIBR) in recurrent MCL, complete response (CR) was achieved in 10/28 patients with only 5/19 responding patients progressing in 5 years. CDK4/6 inhibition thus appears to prolong and deepen the clinical response to ibrutinib. To determine the tumor-intrinsic mechanism that discriminate sensitivity from resistance to PALIBR, we performed integrative analysis of longitudinal whole exome- and whole transcriptome- sequencing (WES/WTS) of MCL cells isolated from the tissue and peripheral blood of patients before, during therapy and on progression. To reveal tumor heterogeneity, clonal evolution, and the tumor-immune interaction during the clinical response, we undertook single cell RNA-sequencing (scRNA-seq) of the corresponding peripheral blood mononuclear cells (PBMCs) in conjunction with flow cytometry. Integrative WES/WTS analysis demonstrated that CR (n=8) was achieved despite copy number gain of CDK4, BCL6 or MYC, or hemizygous deletion (h-del) of RB1, CDKN2A (encoding CDK4/6 inhibitor p16), ATM or TP53. However, composite CDK4 gain + CDKN2A and RB1 h-del, coupled with ATM or TP53 h-del before treatment was associated with loss of cell cycle control in 3 of 4 evaluable primary resistant patients, on progression at cycle 5 after a transient CR (Pt 18) and cycle 30 after a durable partial response (PR) (Pt 2). The other PR patients harbor various copy number variations (CNV) but not the resistance composite CNV. Thus, by perturbing the stoichiometry of CDK4/p16/Rb, composite CNV of CDK4, CDKN2A and RB1 predisposes MCL to resistance to dual CDK4/6 and BTK inhibition. scRNA-seq analysis further revealed 5 transcriptionally distinct MCL clusters (cyclin D1+CD19+) in PBMCs of treatment-naïve patients (n=4) as well as PBMCs, bone marrow and tissue samples of recurrent MCL patients before PALIBR. Cluster 3 (mC3) and cluster 4 (mC4) were absent in PBMCs of normal subjects (n=4) but expanded with disease progression. mC3 was enriched for a cytokine signaling, interferon and inflammatory response signature and mC4 was enriched for a cell cycle signature. Unexpectedly, PDCD1 was expressed in MCL cells in all patients before PALIBR, modestly in mC3 in responding patients and strongly in both mC3 and mC4 in primary resistant patients. Loss of MCL cells in a durable CR (Pt 17) correlated with marked expansion of CD8+ T cells, whereas re-emergence of PDCD1- expressing mC3 and mC4 on progression after a durable PR (Pt 11) or CR (Pt 25) was preceded by loss of CD8+T cells (Lee et al Abstract # 122322). Flow cytometry confirmed that PD-1 was expressed on the surface of MCL cells. WTS of purified MCL cells further revealed that PDCD1 was regulated by the cell cycle, being repressed in MCL cells by palbociclib alone in patients responding to a separate sequential palbociclib-bortezomib therapy and elevated in mC3 on progression after a durable PR. In summary, we have demonstrated, for the first time, that composite gain of CDK4 and hemizygous deletion of CDKN2A and RB1, but not each alone, predisposes MCL to resistance to dual CDK4/6 and BTK inhibition, and identified the resistant MCL clusters. The discovery of PD-1 expression in MCL cells suggests the existence of a clinically relevant tumor-intrinsic program that impinges on immunomodulation. A failure to curb the expansion of PD-1+ MCL clusters may fuel resistance by restricting cytotoxic T cell expansion. Conversely, repressing PD-1 expression in MCL cells and eliminating MCL cells in G1 arrest induced by CDK4/6 inhibition may augment ibrutinib's antitumor immunity by favoring T cell expansion. As the first integrative analysis of longitudinal scRNA-seq, WES and WTS in the context of clinical response to CDK4/6 inhibitor therapy in human cancer, our study provides new insights into tumor-intrinsic and -extrinsic mechanisms for targeting CDK4/6 in cancer. Disclosures Bartlett: Merck: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Genenetech: Research Funding; Gilead: Research Funding; Immune Design: Research Funding; Pfizer: Research Funding; Millenium: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding. Maddocks:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; BMS: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding. Park:Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Seattle Genetics: Research Funding, Speakers Bureau; G1 Therapeutics: Consultancy; Teva: Consultancy, Research Funding; Gilead: Speakers Bureau. Ruan:Juno: Consultancy; Kite: Consultancy; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie company: Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Galluzzi:Inzen: Consultancy; Luke Heller TECPR2 Foundation: Consultancy; Astra Zeneca: Consultancy; OmniSEQ: Consultancy, Membership on an entity's Board of Directors or advisory committees. Leonard:Sutro Biopharma: Consultancy; Bayer Corporation: Consultancy; AstraZeneca: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Bayer Corporation: Consultancy; MorphoSys: Consultancy; Karyopharm Therapeutics: Consultancy; Miltenyi: Consultancy; Akcea Therapeutics: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Merck: Consultancy; Akcea Therapeutics: Consultancy; Gilead: Consultancy; Sutro Biopharma: Consultancy; BeiGene: Consultancy; MorphoSys: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Karyopharm Therapeutics: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Nordic Nanovector: Consultancy; ADC Therapeutics: Consultancy; Sandoz: Consultancy; BeiGene: Consultancy; Sandoz: Consultancy; Gilead: Consultancy; ADC Therapeutics: Consultancy; Nordic Nanovector: Consultancy; Merck: Consultancy; Miltenyi: Consultancy. Martin:Janssen: Consultancy; Teneobio: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; I-MAB: Consultancy; Sandoz: Consultancy. OffLabel Disclosure: Palbociclib is a CDK4/6 inhibitor FDA-approved for breat cancer treatment. It was used off-label in combination with ibrutinib in a phase I clinical trial in patients with relapsed/refractory mantle cell lymphoma.
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Mahal, Brandon Arvin Virgil, Liangliang Zhang, Mohamed Alshalalfa, Ryon Graf, Hanna Tukachinsky, Richard S. P. Huang, Kimberly McGregor, Alexa Betzig Schrock, and Jeffrey Michael Venstrom. "Molecular, immunologic, and clinicodemographic landscape of MYC-amplified (MYCamp) advanced prostate cancer (PCa)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 5041. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.5041.
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5041 Background: The MYC oncogene is one of the most commonly amplified genes in PCa, contributes to androgen independent growth, and is potentially targetable. We sought to define the molecular, immunologic, and clinicodemographic landscape of MYCamp in advanced PCa to better understand progression and establish rationale for personalized treatments and combinations. Methods: Hybrid capture-based comprehensive genomic profiling (CGP) was performed on tumor samples from predominantly advanced PCa samples. MYCamp was defined as copy number (CN) ≥6. PD-L1 IHC was performed using Dako 22C3. A subset of patients (pts) with advanced PCa were selected from the Flatiron Health- Foundation Medicine (FM) clinicogenomic database (CGDB), a nationwide de-identified EHR-derived clinical DB linked to FM CGP data for pts treated from 01/2011-12/2020. The de-identified data originated from approximately 280 US cancer clinics (̃800 sites of care). Results: The genomic profiles of 12,528 tissue samples from unique PCa pts (including hormone sensitive and castrate resistant) were evaluated. MYCamp was detected in 10.6%, with a median MYC CN of 8. Median age was 67 years (67 for MYCwt versus 68 for MYCamp). MYCamp occurred at a higher frequency in men with African (N = 190/1,473, 12.9%) versus European (N = 996/9,796, 10.2%) ancestry (P = 0.002), was more frequent in metastatic biopsy sites vs primary (15.7% vs 6.2%, P < 0.001), and was most common in liver mets (20.2%). MYCamp CN > 15 was enriched for PD-L1 positivity (26.1%) compared with MYCwt (9.8%) or MYCamp CN 6-15 (11.5%) (CN > 15 vs wt P = 0.025). In pts with MYCamp vs MYCwt PCa AR, RAD21, PTEN, CCND1, ZNF703, FGF19, FGFR1, and FGF3 each had significantly higher rates of CN changes (all p < 0.001); TP53 mutation was also more common with MYCamp (47.5% vs 39.7%, P < 0.001). MYCamp tumors were less likely to harbor microsatellite instability vs MYCwt (0.8% vs 2.4%, P < 0.001) and had higher tumor mutational burden (median 2.6 vs 1.7 mut/Mb, P < 0.001). In liquid samples with evidence of circulating tumor DNA (compositive tumor fraction [cTF] > 0) from PCa pts MYCamp was detected in 2.0% (28/1,402), and in 4.5% (20/445) with cTF > 20%. Among evaluable PCa pts in the CGDB, (67 MYCamp and 658 MYCwt) MYCamp did not significantly impact treatment decisions, with the majority receiving novel hormone therapies (35.8% MYCamp vs. 31.5% MYCwt) or chemotherapy containing regimens (37.3% MYCamp vs. 27.7% MYCwt) as first therapy after CGP report. Conclusions: Herein, we report the largest analysis to date of molecular, immunologic, and clinicodemographic features of MYCamp advanced PCa. These findings suggest that MYCamp defines a biologically distinct subset of PCa pts for whom personalized combination treatments utilizing targeted and/or immunotherapies may be effective. Independent cohorts are needed to validate these findings.
Books on the topic "Harmon Foundation, inc"
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J, Wright Beryl, Driskell David C, Newark Museum, Gibbes Museum of Art (Charleston, S.C.), and Chicago Public Library. Cultural Center., eds. Against the odds: African-American artists and the Harmon Foundation. Newark, N.J: Newark Museum, 1989.
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California. Legislature. Senate. Committee on Governmental Organization. Transcript of proceedings: Informational hearing on problems relating to the commercial fishing industry and economic development in the Los Angeles harbor area : Los Angeles Harbor Department board room, 425 S. Palos Verdes Street, San Pedro, California, September 26, 1986. [Sacramento, Calif.]: The Committee, 1986.
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United States. General Accounting Office. Accounting and Information Management Division. Federally chartered corporation: Review of the financial statement audit reports of the National Fallen Firefighters Foundation for years 1993-1997. Washington, D.C. (P.O. Box 37050, Washington, D.C. 20013): The Office, 1998.
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United States. General Accounting Office. Accounting and Information Management Division. Federally chartered corporation: Review of the financial statement audit reports for the Vietnam Veterans of America, Inc., for fiscal years 1998 and 1999. Washington, D.C. (P.O. Box 37050, Washington, D.C. 20013): The Division, 2000.
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United States. General Accounting Office. Accounting and Information Management Division. Federally chartered corporation: Review of the financial statement audit reports for the Vietnam Veterans of America, Inc., for fiscal years 1998 and 1999. Washington, D.C. (P.O. Box 37050, Washington, D.C. 20013): The Office, 2000.
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United States. General Accounting Office. Accounting and Information Management Division. Federally chartered corporation: Review of the financial statement audit reports for the Pearl Harbor Survivors Association for fiscal years 1998 and 1999. Washington, D.C. (P.O. Box 37050, Washington, D.C. 20013): The Office, 2000.
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United States. General Accounting Office. Accounting and Information Management Division. Federally chartered corporation: Review of the financial statement audit reports for the Pearl Harbor Survivors Association for fiscal years 1998 and 1999. Washington, D.C. (P.O. Box 37050, Washington, D.C. 20013): The Division, 2000.
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United States. General Accounting Office. Accounting and Information Management Division. Federally chartered corporation: Review of the financial statement audit report for the National Society Daughters of the American Colonists for fiscal year 1999. Washington, D.C. (P.O. Box 37050, Washington, D.C. 20013): The Division, 2000.
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Division, United States General Accounting Office Accounting and Information Management. Federally chartered corporation: Review of the financial statement audit report for the Aviation Hall of Fame for 1997 and 1998. Washington, D.C. (P.O. Box 37050, Washington, D.C. 20013): The Division, 2000.
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United States. General Accounting Office. Accounting and Information Management Division. Federally chartered corporation: Review of the financial statement audit report for the Non Commissioned Officers Association of the United States of America, Incorporated, for 1997 and 1998. Washington, D.C. (P.O. Box 37050, Washington, D.C. 20013): The Division, 2000.
Find full textBook chapters on the topic "Harmon Foundation, inc"
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Barbancho, Ana M., Isabel Barbancho, Lorenzo J. Tardón, and Emilio Molina. "Foundations of Harmony." In SpringerBriefs in Electrical and Computer Engineering, 3–16. New York, NY: Springer New York, 2013. http://dx.doi.org/10.1007/978-1-4614-7476-0_2.
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Marassi, Massimo. "An Insight into the Foundations of Eco-Phenomenology." In Eco-Phenomenology: Life, Human Life, Post-Human Life in the Harmony of the Cosmos, 69–77. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-77516-6_7.
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"Digital Harbor Foundation." In American Perspectives on Learning Communities and Opportunities in the Maker Movement, 102–29. IGI Global, 2019. http://dx.doi.org/10.4018/978-1-5225-8310-3.ch005.
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If not for stolen computers, the Digital Harbor Foundation may have been a very different learning environment, focused on computer technology more than making. As it turned out, the staff in the 5,000-square-foot space works with students from around the Baltimore area to develop their skills in technology and making. Several students from the space have been invited to the White House to showcase their knowledge and projects. Learning communities are developed intentionally through physical seating arrangements and layout of the learning spaces, and through the course material. In the middle and high school room, all students complete a 14-week basic maker course to familiarize them with the machines and processes of making. The space follows a “pay-what-you-can” model for all courses and materials used for the projects. A separate Nano Lab caters to younger students in 3rd to 5th grades. Digital Harbor Foundation believes in building students' problem-solving abilities and ability to self-direct their learning. This chapter explores the Digital Harbor Foundation.
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"Mathematical Foundations of Aesthetics." In Advances in Religious and Cultural Studies, 120–56. IGI Global, 2020. http://dx.doi.org/10.4018/978-1-7998-1702-4.ch005.
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Mathematical methods were used to prove the principle of aesthetics. It was pointed out that the least action principle is the fundamental law of harmonious beauty. This chapter establishes a variational equation of the beauty of harmony, with the left side of the equation being the least action principle, which represents energy efficiency and time efficiency, while the right side refers to harmony and beauty, namely the beauty of harmony. The mathematical symbol linking the two sides suggests that physics, philosophy, and aesthetics are unified in a harmonious and organic way. Its beauty lies in the fact that the two sides of the equation are not only symmetric, congruous, orderly, and succinct, but also in the fact that it has a very beautiful look.
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Lohar, Hareram, Anirban Mitra, and Sarmila Sahoo. "Effect of Boundary Conditions and Taper Patterns on Geometrically Nonlinear Frequency Response of Axially Graded Beams on Elastic Foundation." In Handbook of Research on Advancements in Manufacturing, Materials, and Mechanical Engineering, 110–40. IGI Global, 2021. http://dx.doi.org/10.4018/978-1-7998-4939-1.ch006.
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Forced vibration analysis is performed on a tapered axially functionally graded beam resting on elastic foundation under externally applied harmonic excitations to present the effect of boundary conditions and taper patterns on the frequency response. The elastic foundation is modelled in the present analysis as Winkler foundation. A displacement based semi-analytical method is adopted for mathematical formulation and the derivation of governing equations is carried out following Hamilton's principle. Von Karman nonlinear strain-displacement relation employed to incorporate geometric nonlinearity. Broyden method is adopted to solve the nonlinear set of equations. Frequency response curves are plotted in non-dimensional frequency-amplitude plane to represent nonlinear forced vibration characteristic of the system. New benchmark results are also provided for different combination of system parameters (i.e., excitation amplitudes, foundation stiffness values, material models, taper patterns, and flexural boundary conditions). Operational deflection shapes (ODS) are also presented.
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Ekong, Obot Uko. "Religion, Culture, and Educational Development in Nigeria." In Handbook of Research on the Impact of Culture in Conflict Prevention and Peacebuilding, 213–33. IGI Global, 2020. http://dx.doi.org/10.4018/978-1-7998-2574-6.ch013.
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Various religions teach their adherents to imbibe and live out sound, moral, and ethical values that go a long way to create harmony in the human society, which is necessary for societal development. Religion cannot be practiced successfully without the teachings of its core ideas, principles, scriptural truths, etc. to its adherents. This study is hinged on the fact that the three religious traditions as practice in Nigeria have affected the way of lives of the people, thus giving Nigeria a unique religious identity. Religion, therefore, cannot thrive in any society without the culture of the people and that of the religion mixing. Every religion is borne out of a culture of the people. The study is an attempt to reveal that religious culture and tradition laid the foundation of educational development in Nigeria, for example, the establishment of mission schools and the development of Nigerian indigenous language.
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Bayly, Brian. "One Phase and Two Components." In Chemical Change in Deforming Materials. Oxford University Press, 1993. http://dx.doi.org/10.1093/oso/9780195067644.003.0021.
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The purpose of this chapter is to bring chemical variation into the examples discussed. Equation (12.7) shows a material's change of dimension as the sum of two effects, change of shape and diffusive mass transfer, but it describes only changes driven by unequal stress components. Equation (12.8) suggests that the same form continues to be applicable when potential gradients exist for reasons that are not stress-related, but the suggestion is not followed up and Chapter 13 is entirely concerned with effects of stress. We now go back to the harmonic variation in Figure 11.6 and ask: supposing that both the radial compression and the composition fluctuate along the x-direction, what material movements will result? An answer to this seemingly simple and fundamental question was produced rather recently, by G. B. Stephenson, whose work provides the foundation for this chapter. At once we have to give up the idea of a continuum and turn to a material containing countable numbers of atoms.
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Fant, Clyde E., and Mitchell G. Reddish. "Crete." In A Guide to Biblical Sites in Greece and Turkey. Oxford University Press, 2003. http://dx.doi.org/10.1093/oso/9780195139174.003.0015.
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Crete is the largest and most southerly of all the Greek islands. It is also one of the most visited, due to both its beauty and its famous ancient sites. By far the best-known of these attractions is the spectacular Palace of Knossos, reconstructed over a period of thirty-five years by its discoverer, Sir Arthur Evans, who put more than a million dollars of his own money into the work. Scholars have criticized his reconstruction as a fanciful and not altogether accurate representation of the original, but millions of tourists delight in being able to see more at an ancient site than foundations, scattered stones, and a few columns. But Knossos is not the only dramatic ruin of antiquity on the island. Gortyna and Phaistos should not be missed, and for Christians the harbor of Kaloi Limenes (called Fair Havens in the New Testament) is a place of importance in the life of the Apostle Paul. Likewise, the Basilica of St. Titus at Gortyna commemorates the ministry of Titus, a Greek convert who was a disciple of Paul (Gal 2:3), as described in the New Testament book of Titus. Furthermore, Iraklion possesses an archaeological museum second only to the National Museum in Athens. The only site on Crete mentioned in the Bible, though Crete itself was said to be the place of the ministry of Titus (Titus 1:5), is the harbor of Kaloi Limenes (Good Harbor), referred to in the Book of Acts as Fair Havens (Acts 27: 8). After two thousand years, the site is known by the same name today. Even in New Testament times the place was distinguished only as the harbor for the nearby city of Lasea, a flourishing commercial city in the Roman period. Today the tranquil bay in its remote location harbors nothing more than sunbathers who visit its beaches to enjoy the beautiful waters of the Mediterranean. The site can be reached best by automobile, or by taking a bus from Iraklion to Moires/Mires.
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Polyak, Ilya. "Digital Filters." In Computational Statistics in Climatology. Oxford University Press, 1996. http://dx.doi.org/10.1093/oso/9780195099997.003.0003.
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In this chapter, several systems of digital filters are presented. The first system consists of regressive smoothing filters, which are a direct consequence of the least squares polynomial approximation to equally spaced observations. Descriptions of some particular univariate cases of these filters have been published and applied (see, for example, Anderson, 1971; Berezin and Zhidkov, 1965; Kendall and Stuart, 1963; Lanczos, 1956), but the study presented in this chapter is more general, more elaborate in detail, and more fully illustrated. It gives exhaustive information about classical smoothing, differentiating, one- and two-dimensional filtering schemes with their representation in the spaces of time, lags, and frequencies. The results are presented in the form of algorithms, which can be directly used for software development as well as for theoretical analysis of their accuracy in the design of an experiment. The second system consists of harmonic filters, which are a direct consequence of a Fourier approximation of the observations. These filters are widely used in the spectral and correlation analysis of time series. The foundation for developing regressive filters is the least squares polynomial approximation (of equally spaced observations), a principal notion that will be considered briefly.
Conference papers on the topic "Harmon Foundation, inc"
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Bhattiprolu, Udbhau, Anil K. Bajaj, and Patricia Davies. "Effect of Axial Load on the Response of Beams on Nonlinear Viscoelastic Unilateral Foundations." In ASME 2014 International Design Engineering Technical Conferences and Computers and Information in Engineering Conference. American Society of Mechanical Engineers, 2014. http://dx.doi.org/10.1115/detc2014-35347.
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Flexible polyurethane foams used for cushioning in the furniture and automotive industries serve as foundations and exhibit complex nonlinear viscoelastic behavior. To design systems that incorporate these materials, it is important to model their mechanical behavior and then to predict the dynamic response of such systems. The example of a pinned-pinned beam interacting with a nonlinear viscoelastic foundation is the focus of the present study. The foundation can either react in compression as well as tension (bilateral), or react only in compression (unilateral). In the latter case, the contact regions between the beam and the foundation are not known a priori, and thus the coefficients of the modal equations obtained in a Galerkin approximation solution approach, are functions of the solution as well. It is therefore computationally expensive to predict the dynamic and steady-state response of these structures to static and harmonic loads. For polynomial-type nonlinearities, it is possible to speed up the computation time by using a convolution method to evaluate integral terms in the model. Also, if only the steady-state response is of interest, direct-time integration can be replaced by incremental harmonic balance to make the frequency response predictions more efficient. The effect of axial load and the influence of various parameters e.g., loading configuration, excitation amplitude, linear and nonlinear stiffness, on the response of the beam on unilateral and bilateral foundations are studied.
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Kartik, V., and J. A. Wickert. "Vibration and Guiding of Moving Media With Edge Weave Imperfections." In ASME 2005 International Design Engineering Technical Conferences and Computers and Information in Engineering Conference. ASMEDC, 2005. http://dx.doi.org/10.1115/detc2005-84502.
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This paper examines the steady-state forced vibration of a moving medium that is guided by a partial elastic foundation, and where geometric imperfections on the medium’s edge act as an excitation source. Such a system is of technical interest in the areas of web handling and magnetic tape transport where externally-pressurized air bearing guides are sometimes used to control lateral position. The axially-moving strip is modeled here as a string that is guided by elastic foundation segments and that is subjected to traveling wave excitation as the edge imperfections interact with the foundations. The equation of motion for this “moving medium and moving load” system incorporates a skew-symmetric Coriolis acceleration component that arises from convection. The governing equation is cast in the state-space form, with one symmetric and one skew-symmetric operator, as is characteristic of gyroscopic systems. Through modal analysis, the forced response of the system is obtained to the complex harmonic excitation associated with the interaction between the edge weave and the guides. Parameter studies are presented in the transport speed, foundation stiffness, guide placement, guide width, and imperfection wavelength. Of potential technological application, for a given wavelength of the edge imperfection, it is possible to reduce the medium’s vibration at a certain location by judiciously selecting the locations and spans of the foundation segments.
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Froio, Diego, Roberto Moioli, and Egidio Rizzi. "NUMERICAL DYNAMIC ANALYSIS OF BEAMS ON NONLINEAR ELASTIC FOUNDATIONS UNDER HARMONIC MOVING LOAD." In VII European Congress on Computational Methods in Applied Sciences and Engineering. Athens: Institute of Structural Analysis and Antiseismic Research School of Civil Engineering National Technical University of Athens (NTUA) Greece, 2016. http://dx.doi.org/10.7712/100016.2149.7515.
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Takahashi, Kazuo, and Hisaaki Furutani. "Vibration, Buckling and Dynamic Stability of a Non-Uniform Cantilever Plate With Thermal Gradient Resting on a Pasternak Foundation." In ASME 1995 Design Engineering Technical Conferences collocated with the ASME 1995 15th International Computers in Engineering Conference and the ASME 1995 9th Annual Engineering Database Symposium. American Society of Mechanical Engineers, 1995. http://dx.doi.org/10.1115/detc1995-0282.
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Abstract The dynamic stability of a non-uniform rectangular cantilever plate on a Pasternak foundation under the action of a pulsating inplane load is reported in this paper. The small deflection theory of the thin plate is used Hamilton’s principle is used to derive the time variables while the dynamic stability is solved by the harmonic balance method. Natural frequencies and buckling properties are presented at first. Then, regions of instability which contain simple parametric resonances and combination resonances are discussed for various parameters of a Pasternak foundation, non-uniform cross section and thermal gradient.
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Demeio, L., G. Lancioni, and S. Lenci. "Resonances in an Infinitely Long Cable on a Tensionless Non-Smooth Foundation: A Numerical Analysis." In ASME 2011 International Design Engineering Technical Conferences and Computers and Information in Engineering Conference. ASMEDC, 2011. http://dx.doi.org/10.1115/detc2011-47890.
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When a semi-infinite cable resting on a bed of unilateral springs is subjected to a harmonic excitation, the motion of the touch-down-point (TDP), i.e., the point which separates the detached part of the cable from the laid part, and which is assumed to be unique in this paper, exhibits interesting resonant phenomena. These phenomena are studied numerically by means of a self-made finite element (FEM) code, and the effects of the non-linearity of the problem, such as, e.g., the bending of the resonance curves and the secondary resonances, are investigated in detail.
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Bhattiprolu, Udbhau, Patricia Davies, and Anil K. Bajaj. "Response of a Beam on Nonlinear Viscoelastic Unilateral Foundation and Numerical Challenges." In ASME 2011 International Design Engineering Technical Conferences and Computers and Information in Engineering Conference. ASMEDC, 2011. http://dx.doi.org/10.1115/detc2011-48776.
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Nonlinear viscoelastic behavior is a characteristic of many engineering materials and also biological tissue, yet it is difficult to develop dynamic models of systems that include these materials and are able to predict system behavior over a wide range of excitations. This research is focused on a specific example system in the form of a pinned-pinned beam interacting with polyurethane foam. Two cases are considered: (1) the beam and foam are glued so that they are always in contact and the foam can undergo both stretching and compression, and (2) the beam and foam are not glued so that the contact region changes with beam motion, and the foam only reacts in compression. Static as well as dynamic forces act on the beam and the Galerkin method is used to derive modal amplitude equations for the beam on polyurethane foundation. In the second case, determination of the loss of contact points is integrated into the solution procedure through a constraint relation. The static responses for both cases are examined as a function of the foam nonlinearity and loading conditions, and three and five mode solutions are compared. The steady state response of the system subject to static and harmonic loads is studied by using numerical integration techniques. Numerical challenges and the accuracy of this approach are discussed. Frequency responses are generated for a range of foam nonlinearities and loading conditions.
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Nusirat, Timour M. A., and M. N. Hamdan. "Static and Dynamic Response of a Beam on a Winkler Elastic Foundation." In ASME 2005 International Design Engineering Technical Conferences and Computers and Information in Engineering Conference. ASMEDC, 2005. http://dx.doi.org/10.1115/detc2005-84384.
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This paper is concerned with analysis of dynamic behavior of an Euler-Bernoulli beam resting on an elastic foundation. The beam is assumed to be subjected to a uniformly distributed lateral static load, have an initial quarter-sine shape deflection. At one end, the beam is assumed to be restrained by a pin, while at the other end, the beam is assumed to be restrained by a torsional and a translational linear spring. The beam is modeled by a nonlinear partial differential equation where the nonlinearity enters the governing equation through the beam axial force. In the static case, because of a unique feature of governing equation, the analysis was carried out using the theory of linear differential equations, but takes into account the effect of actual deflection on the induced axial thrust. In the dynamic case, stability analysis of the beam is carried out by calculating the nonlinear frequencies of free vibration of the beam about its static equilibrium configuration. The assumed mode method is used to discretize and find an equivalent nonlinear initial value problem. Then the harmonic balance is used to obtain an approximate solution to the nonlinear oscillator described by the equivalent initial value problem. The analyses of results were carried out for a selected range of values of the system parameters: foundation elastic stiffness, lateral load, and maximum beam edge deflection. In the static case the results are presented as characteristic curves showing the variation of the beam static deflection and associated bending moment distribution with each of the above system parameters. In the dynamic case, the presented characteristic curves show the variation of the nonlinear natural frequency corresponding to the first and the second modes over a range of each of the above system parameters.
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Sinopoli, Anna, and Alessio Ageno. "Stability Analysis of a Free-Standing Block With Friction on a Moving Foundation." In ASME 2001 International Design Engineering Technical Conferences and Computers and Information in Engineering Conference. American Society of Mechanical Engineers, 2001. http://dx.doi.org/10.1115/detc2001/vib-21510.
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Abstract The problem analyzed here concerns the dynamic response of a bidimensional polygonal rigid body simply supported on a harmonically moving rigid ground. The immediate scientific purpose of the paper is to obtain and analyze the dynamic response by using a variational formulation, recently proposed by one of the authors [1], where the dynamics is described as a differential inclusion. This formulation allows us to determine the instantaneous accelerations of the system by means of a mechanical model with friction and unilateral constraints, which does not reduce the degrees of freedom or impose an “a priori” choice of the mechanism activated during the motion. By treating the friction coefficient as a stability parameter, it has been possible to obtain different kind of responses, ranging from rocking to sliding-rocking, and compare them with those obtained in the literature. Sliding-rocking motions obtained so far have exhibited not only harmonic but also interesting and more complex behaviors with chaotic features. The search for theoretical and numerical instruments able to identify and classify these more complex motions was first performed in the case of rocking, characterized by a smaller number of degrees of freedom. A technique was then implemented for calculating Lyapunov’s exponents also during the time intervals of the impacts. The introduction and evaluation of these exponents can also permit us to perform the stability analysis with respect to overturning, by limiting the analysis and evaluation to the first impact that the system undergoes by starting at rest: in fact, large values of Lyapunov’s exponents before the first impact are connected with overturning during the motion which follows. This circumstance can make it easier to carry out the stability analysis with respect to overturning, as a function of the amplitude and frequency of the excitation.
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Zhang, Wei, Wenhua Hu, Dongxing Cao, and Xiaofeng Yang. "Nonlinear Analysis of a Z-Shaped Planar Beam." In ASME 2014 International Design Engineering Technical Conferences and Computers and Information in Engineering Conference. American Society of Mechanical Engineers, 2014. http://dx.doi.org/10.1115/detc2014-34109.
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In this paper, a z-shaped planar inextensible beam with harmonic foundation excitations is considered. The linear frequencies and modes of the beam with various folding angles are obtained through analytical formulations, and validated by numerical simulations. The continuous system is truncated into a system of ordinary differential equations with quadratic nonlinear terms by using the Galerkin method based on the modes obtained under a special folding angle, which may bring about modal interactions. The nonlinearities of the system are researched under the combined resonances, such as primary and internal resonances.
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Natslavas, Sotirios, and Petros Tratskas. "Prediction and Elimination of Subharmonic Resonances in Mechanical Systems With Nonlinear Foundations." In ASME 1995 Design Engineering Technical Conferences collocated with the ASME 1995 15th International Computers in Engineering Conference and the ASME 1995 9th Annual Engineering Database Symposium. American Society of Mechanical Engineers, 1995. http://dx.doi.org/10.1115/detc1995-0290.
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Abstract In the first part of this work an analysis is presented on the dynamics of a two degree of freedom nonlinear mechanical oscillator. The model consists of a rigid body which rests on a foundation with nonlinear stiffness. This body can exhibit both vertical and rocking motions, which are coupled through the nonlinearities only. In the present study, attention is focused on the response of the system under external harmonic excitation of the vertical translation only, leading to conditions of subharmonic resonance of order three. Also, the model parameters are chosen so that its two linear natural frequencies are almost identical (1:1 internal resonance). For this case, the method of multiple time scales is first applied and a set of four coupled odes is derived, governing the amplitudes and phases of approximate motions of the system. Then, determination of approximate periodic steady state response of the oscillator is reduced to solving a set of four nonlinear algebraic equations. It is shown that besides linear and nonlinear single-mode response, two-mode response is also possible, due to the internal resonance. In addition, the stability of the various single- and two-mode periodic responses of the system is analyzed. In the last part of the work, the analytical findings are verified and complemented by numerical results. The main interest lies on identifying the effect of system parameters on the existence and stability of the predicted motions. The results of this study reveal patterns of appearance of these motions, which provide valuable help in the efforts to eliminate them. Finally, direct integration of the original equations of motion reveals the existence of other more complex motions, which coexist with the analytically predicted motions within the frequency ranges of interest.