309 results on '"Gerson SL"'
Search Results
2. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH)
- Author
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Koç, ON, Day, J, Nieder, M, Gerson, SL, Lazarus, HM, and Krivit, W
- Published
- 2002
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3. CD34+ selection of hematopoietic blood cell collections and autotransplantation in lymphoma: overnight storage of cells at 4°C does not affect outcome
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Lazarus, HM, Pecora, AL, Shea, TC, Koç, ON, White, JM, Gabriel, DA, Cooper, BW, Gerson, SL, Krieger, M, and Sing, AP
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- 2000
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4. Autologous CD34+ cell transplantation for patients with advanced lymphoma: effects of overnight storage on peripheral blood progenitor cell enrichment and engraftment
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Koç, ON, Gerson, SL, Phillips, GL, Cooper, BW, Kutteh, L, Van Zant, G, Reece, DE, Fox, RM, Schupp, JE, Tainer, N, and Lazarus, HM
- Published
- 1998
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5. Erythroid burst-forming units (BFU-E) predict hematopoietic recovery after peripheral blood progenitor cell transplantation in patients with advanced breast cancer
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Cooper, BW, Mackay, W, Gerson, SL, and Lazarus, HM
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- 1997
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6. REPAIR OF O6METHYLGUANINE DNA ADDUCTS IN THE LIVER AND KIDNEY OF TRANSGENIC MICE EXPRESSING THE BACTERIAL O6ALKYLGUANINE-DNA ALKYLTRANSFERASE
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GERSON, SL, primary, DUMENCO, LL, additional, NORTON, K, additional, ARCE, C, additional, and JOHNSON, K, additional
- Published
- 1991
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7. Human CD34+ hematopoietic progenitors have low, cytokine-unresponsive O6-alkylguanine-DNA alkyltransferase and are sensitive to O6- benzylguanine plus BCNU
- Author
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Gerson, SL, primary, Phillips, W, additional, Kastan, M, additional, Dumenco, LL, additional, and Donovan, C, additional
- Published
- 1996
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8. An unusual case of autoimmune hemolytic anemia with reticulocytopenia, erythroid dysplasia, and an IgG2 autoanti-U
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Roush, GR, primary, Rosenthal, NS, additional, Gerson, SL, additional, Toy, EM, additional, McCarthy, P, additional, Hirschler, NV, additional, and Yomtovian, R, additional
- Published
- 1996
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9. Retroviral transduction and expression of the human alkyltransferase cDNA provides nitrosourea resistance to hematopoietic cells
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Allay, JA, primary, Dumenco, LL, additional, Koc, ON, additional, Liu, L, additional, and Gerson, SL, additional
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- 1995
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10. Phase I clinical trial of O6-benzylguanine and topical carmustine in the treatment of cutaneous T-cell lymphoma, mycosis fungoides type.
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Apisarnthanarax N, Wood GS, Stevens SR, Carlson S, Chan DV, Liu L, Szabo SK, Fu P, Gilliam AC, Gerson SL, Remick SC, and Cooper KD
- Published
- 2012
11. Fetal liver hematopoietic stem cells as a target for in utero retroviral gene transfer
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Clapp, DW, primary, Dumenco, LL, additional, Hatzoglou, M, additional, and Gerson, SL, additional
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- 1991
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12. Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for relapsed non-Hodgkin's lymphoma: blood and bone marrow progenitor growth studies. A phase II Eastern Cooperative Oncology Group Trial
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Lazarus, HM, primary, Andersen, J, additional, Chen, MG, additional, Variakojis, D, additional, Mansour, EG, additional, Oette, D, additional, Arce, CA, additional, Oken, MM, additional, and Gerson, SL, additional
- Published
- 1991
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13. Hematopoietic stem cell gene therapy of murine protoporphyria by methylguanine-DNA-methyltransferase-mediated in vivo drug selection.
- Author
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Richard, E, Robert, E, Cario-André, M, Ged, C, Géronimi, F, Gerson, SL, de Verneuil, H, and Moreau-Gaudry, F
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HEMATOPOIETIC stem cells ,GENE therapy ,TRANSGENE expression ,GENETIC vectors ,GENETIC transformation ,GENETIC engineering - Abstract
Erythropoietic protoporphyria (EPP) is an inherited defect of the ferrochelatase (FECH) gene characterized by the accumulation of toxic protoporphyrin in the liver and bone marrow resulting in severe skin photosensitivity. We previously described successful gene therapy of an animal model of the disease with erythroid-specific lent/viral vectors in the absence of preselection of corrected cells. However, the high-level of gene transfer obtained in mice is not translatable to large animal models and humans if there is no selective advantage for genetically modified hematopoietic stem cells (HSC5) in vivo. We used bicistronic SIN-lentiviral vectors coexpressing EGFP or FECH and the G156A-mutated O
6 -methylguanine-DNA -methyltransferase (MGMT) gene, which allowed efficient in vivo selection of transduced HSCs after O6 -benzylguanine and BCNU treatment. We demonstrate for the first time that the correction and in vivo expansion of deficient transduced HSC population can be obtained by this dual gene therapy, resulting in a progressive increase of normal RBCs in EPP mice and a complete correction of skin photosensitivity. Finally, we developed a novel bipromoter SIN-lentiviral vector with a constitutive expression of MGMT gene to allow the selection of HSCs and with an erythroid-specific expression of the FECH therapeutic gene. [ABSTRACT FROM AUTHOR]- Published
- 2004
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14. Unsuccessful Reexposure to Clozapine
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Frances R. Frankenburg, Gerson Sl, and Stormberg D
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Psychiatry and Mental health ,business.industry ,Anesthesia ,medicine ,Pharmacology (medical) ,business ,Clozapine ,medicine.drug - Published
- 1994
15. Reduced lung tumorigenesis in human methylguanine DNA-methyltransferase transgenic mice achieved by expression of transgene within the target cell.
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Liu, L, Qin, X, and Gerson, SL
- Abstract
Human methylguanine-DNA methyltransferase (MGMT) transgenic mice expressing high levels of O6-alkylguanine-DNA alkyltransferase (AGT) in lung were crossbred to A/J mice that are susceptible to pulmonary adenoma to study the impact of O6-methylguanine (O6mG)-DNA adduct repair on NNK-induced lung tumorigenesis. Expression of the chimeric human MGMT transgene in lung was identified by northern and western blot analysis, immunohistochemistry assay and enzymatic assay. AGT activity was 17.6 ± 3.2 versus 1.2 ± 0.4 fmol/μg DNA in lung of MGMT transgenic mice compared with non-transgenic mice. Immunohistochemical staining with anti-human AGT antibody showed that human AGT was expressed throughout the lung. However, some epithelial cells of bronchi and alveoli did not stain for human AGT, suggesting that the human MGMT transgene expression was heterogeneous. After 100 mg/kg NNK i.p. injection in MGMT transgenic mice, lung AGT activity remained much higher and levels of lung O6mG-DNA adducts in MGMT transgenic mice were lower than those of non-transgenic mice. In the tumorigenesis study, mice received 100 mg/kg NNK at 6 weeks of age and were killed 44 weeks later. Ten of 17 MGMT transgenic mice compared with 16 of 17 non-transgenic mice had lung tumors, P < 0.05. MGMT transgenic mice had lower multiplicity and smaller sized lung tumors than non-transgenic mice. Moreover, a reduction in the frequency of K-ras mutations in lung tumors was found in MGMT transgenic mice (6.7 versus 50% in non-transgenic mice). These results indicate that high levels of AGT expressed in mouse lung reduce lung tissue susceptibility to NNK-induced tumorigenesis due to increased repair capacity for O6-mG, subsequently, decreased mutational activation of K-ras oncogene. Heterogeneity in the level of AGT expressed in different lung cell populations or other forms of carcinogenic DNA damage caused by NNK may explain the residual incidence of lung tumors in MGMT transgenic mice. [ABSTRACT FROM PUBLISHER]
- Published
- 1999
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16. Release of granulocyte-specific colony-stimulating activity by human bone marrow exposed to phorbol esters
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Gerson, SL and Cooper, RA
- Abstract
Granulocyte-macrophage colony growth depends on the presence of colony- stimulating activity (CSA). Phorbol esters induce concentration- dependent colony formation in the absence of exogenous CSA. We questioned whether phorbol esters mimicked the action of CSA by directly stimulating colony growth, or whether phorbol esters acted indirectly by inducing marrow cells to release CSA. First, after incubating human bone marrow cells with phorbol 12,13-dibutyrate (PDB) for 3 days, we separated PDB from the protein peak of the conditioned medium by Sephadex G-10 gel filtration and tested this peak for the presence of CSA. When diluted 1:10 in the agar colony assay, this material induced 133 +/- 15 colonies/10(5) bone marrow cells. Second, to determine whether bone marrow cells required the continued presence of PDB in order to release CSA, PDB was removed from bone marrow cells by washing, and these cells were reincubated in fresh medium in the absence of PDB. CSA was found in the medium of these cultures; its release was maximal after preincubation of bone marrow cells with 5 X 10(-8) M PDB for 3 days, followed by incubation for 3 days in the absence of PDB. This CSA stimulated granulopoiesis out of proportion to monocytopoiesis, with 85% +/- 17% of the colonies being granulocytic (as indicated by histochemical staining for chloroacetate esterase), and 12% +/- 3% being monocytic (as indicated by nonspecific esterase). Inhibitors of monocyte colony formation, including PGE1, were not present in the medium that contained this CSA. These studies demonstrate that normal human bone marrow cells exposed to PDB release CSA and that this CSA selectively stimulates granulopoiesis in vitro.
- Published
- 1984
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17. Modulation of nitrosourea resistance in myeloid leukemias
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Gerson, SL and Trey, JE
- Abstract
Drug resistance in myeloid leukemias may be mediated by an increased capacity to repair chemotherapy-induced DNA damage. Some tumor cell lines that are resistant to nitrosoureas contain the DNA repair protein O6-alkylguanine-DNA alkyltransferase (alkyltransferase). This protects cells by removing cytotoxic, nitrosourea-induced O6-alkylguanine adducts. We measured the level of alkyltransferase activity in myeloid leukemic cells freshly obtained from patients to determine whether the alkyltransferase was an important factor in nitrosourea resistance in these cells and whether inactivation of this protein could sensitize leukemic cells to nitrosoureas. Myeloid leukemic cells from patients with acute nonlymphocytic leukemia and chronic myelogenous leukemia had higher levels of alkyltransferase than did myeloid precursors from normal donors (P less than .01). This difference did not appear to be due to the state of differentiation of the leukemic or normal cells. To show that this repair protein mediated nitrosourea resistance in leukemic cells, cells were treated with the modified base O6- methylguanine to selectively and irreversibly inactivate the alkyltransferase and then exposed to 1,3-bis (2-chloroethyl)-1- nitrosourea (BCNU). An 18-hour incubation in 0.5 mmol/L O6- methylguanine caused an 87% +/- 3.6% decrease in alkyltransferase activity in leukemic cells and a 73% +/- 8.6% decrease in normal myeloid precursors. After treatment with O6-methylguanine, clonogenic leukemic cells from ten different donors became much more sensitive to BCNU, with a decrease in the dose needed to reduce colony survival by 50% (LD50) of 6.3 +/- 1.4-fold. A lesser effect was seen on CFU-GM, BFU- E, and CFU-GEM where the LD50 decreased two- to threefold. These studies show that nitrosourea resistance in myeloid leukemic cells can be abrogated by inactivation of the DNA repair protein O6-alkylguanine- DNA alkyltransferase. This method of biochemical modulation of DNA repair will sensitize leukemic cells to nitrosoureas in vitro and has the potential of increasing the therapeutic index of nitrosoureas in this disease.
- Published
- 1988
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18. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors.
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Laughlin MJ, Barker J, Bambach B, Koc ON, Rizzieri DA, Wagner JE, Gerson SL, Lazarus HM, Cairo M, Stevens CE, Rubinstein P, and Kurtzberg J
- Published
- 2001
19. Clozapine alone versus clozapine and risperidone for refractory schizophrenia.
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Grass G, Hellmich M, Leweke FM, Meltzer HY, Yagcioglu AEA, Akdede BBK, Gerson SL, Honer WG, Thornton AE, MacEwan GW, and Davis JM
- Published
- 2006
20. Combined HDAC8 and checkpoint kinase inhibition induces tumor-selective synthetic lethality in preclinical models.
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Chang TY, Yan Y, Yu ZY, Rathore M, Lee NZ, Tseng HJ, Cheng LH, Huang WJ, Zhang W, Chan ER, Qing Y, Kang ML, Wang R, Tsai KK, Pink JJ, Harte WE, Gerson SL, and Lee SB
- Abstract
The elevated level of replication stress is an intrinsic characteristic of cancer cells. Targeting the mechanisms that maintain genome stability to further increase replication stress and thus induce severe genome instability has become a promising approach for cancer treatment. Here, we identify histone deacetylase 8 (HDAC8) as a drug target whose inactivation synergizes with the inhibition of checkpoint kinases to elicit substantial replication stress and compromise genome integrity selectively in cancer cells. We showed that simultaneous inhibition of HDAC8 and checkpoint kinases led to extensive replication fork collapse, irreversible cell-cycle arrest, and synergistic vulnerability in various cancer cells. The efficacy of the combination treatment was further validated in patient tumor-derived organoid (PDO) and xenograft mouse (PDX) models, providing important insights into patient-specific drug responses. Our data revealed that HDAC8 activity was essential for reducing the acetylation level of structural maintenance of chromosomes protein 3 (SMC3) ahead of replication forks and preventing R loop formation. HDAC8 inactivation resulted in slowed fork progression and checkpoint kinase activation. Our findings indicate that HDAC8 guards the integrity of the replicating genome, and the cancer-specific synthetic lethality between HDAC8 and checkpoint kinases provides a promising replication stress-targeting strategy for treating a broad range of cancers.
- Published
- 2024
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21. Impact of age, antiretroviral therapy, and cancer on epigenetic aging in people living with HIV.
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Qing Y, Chan R, Fu P, Cullen J, Miron A, Jacobson JM, Pink J, and Gerson SL
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- Humans, Aging genetics, Epigenesis, Genetic, Aging, Premature genetics, Aging, Premature complications, HIV Infections complications, HIV Infections drug therapy, HIV Infections epidemiology, Neoplasms drug therapy, Neoplasms epidemiology, Neoplasms genetics
- Abstract
Background: Premature aging has been identified as a global risk factor for cancer. Causes of premature aging are multifactorial, including inflammation, infection, chronic stress, and lifestyle factors., Method: We evaluated whether premature aging in people living with HIV (PLWH) was associated with antiretroviral therapy (ART) or the diagnosis of cancer. We used well-established DNA methylation patterns to assess premature aging, using Horvath et al., in individuals with HIV located in Cleveland, Ohio and compared these to standardized datasets of US historical blood samples. Some of the PLWH developed cancer over time., Results: We found that DNA methylation analysis identified accelerated aging in PLWH whereas ART therapy mitigated the advancement of DNA methylation age. A variety of cancers were observed in this population, but a cancer diagnosis was not significantly associated with more advanced DNA methylation age., Conclusion: We find that the age acceleration detected in PLWH is mitigated by ART therapy and is not further accelerated by a diagnosis of cancer., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2023
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22. 15-PGDH regulates hematopoietic and gastrointestinal fitness during aging.
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Ho WJ, Smith JNP, Park YS, Hadiono M, Christo K, Jogasuria A, Zhang Y, Broncano AV, Kasturi L, Dawson DM, Gerson SL, Markowitz SD, and Desai AB
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- Aging genetics, Animals, Dinoprostone metabolism, Mice, Hydroxyprostaglandin Dehydrogenases genetics
- Abstract
Emerging evidence implicates the eicosanoid molecule prostaglandin E2 (PGE2) in conferring a regenerative phenotype to multiple organ systems following tissue injury. As aging is in part characterized by loss of tissue stem cells' regenerative capacity, we tested the hypothesis that the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) contributes to the diminished organ fitness of aged mice. Here we demonstrate that genetic loss of 15-PGDH (Hpgd) confers a protective effect on aging of murine hematopoietic and gastrointestinal (GI) tissues. Aged mice lacking 15-PGDH display increased hematopoietic output as assessed by peripheral blood cell counts, bone marrow and splenic stem cell compartments, and accelerated post-transplantation recovery compared to their WT counterparts. Loss of Hpgd expression also resulted in enhanced GI fitness and reduced local inflammation in response to colitis. Together these results suggest that 15-PGDH negatively regulates aged tissue regeneration, and that 15-PGDH inhibition may be a viable therapeutic strategy to ameliorate age-associated loss of organ fitness., Competing Interests: The authors (A. Desai, S.L. Gerson, and S.D. Markowitz) hold patents relating to use of 15-PGDH inhibitors in bone marrow transplantation that have been licensed to Rodeo Therapeutics (acquired by Amgen). Drs. Markowitz and Gerson are founders of Rodeo Therapeutics, and Drs. Markowitz, Gerson, and Desai are consultants to Rodeo Therapeutics. Conflicts of interest are managed according to institutional guidelines and oversight by Case Western Reserve University. No conflict of interest pertains to any of the remaining authors. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
- Published
- 2022
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23. Identification of a Cancer-Predisposing Germline POT1 p.Ile49Metfs*7 Variant by Targeted Sequencing of a Splenic Marginal Zone Lymphoma.
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Jajosky AN, Mitchell AL, Akgul M, Shetty S, Yoest JM, Gerson SL, Sadri N, and Oduro KA Jr
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- Aged, Humans, Male, Shelterin Complex, Telomere, Telomere-Binding Proteins genetics, Glioma, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Lymphoma, Non-Hodgkin, Melanoma genetics
- Abstract
Germline disruptive variants in Protection of Telomeres 1 ( POT1 ) predispose to a wide variety of cancers, including melanoma, chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, myeloproliferative neoplasms, and glioma. We report the first case of splenic marginal zone lymphoma (SMZL) arising in a patient with a germline POT1 variant: a 65-year-old male with an extensive history of cancer, including melanoma and papillary thyroid carcinoma, who presented with circulating atypical lymphocytosis. Bone marrow biopsy revealed 20% involvement by a CD5
- CD10- B-cell lymphoma that was difficult to classify. During the clinical workup of his low-grade lymphoma, targeted next-generation sequencing (NGS) identified POT1 p.I49Mfs*7 (NM_015450:c. 147delT) at a variant allele frequency (VAF) of 51%. NGS of skin fibroblasts confirmed the POT1 variant was germline. This likely pathogenic POT1 loss-of-function variant has only been reported once before as a germline variant in a patient with glioma and likely represents one of the most deleterious germline POT1 variants ever linked to familial cancer. The spectrum of cancers associated with germline pathogenic POT1 variants (i.e., autosomal dominant POT1 tumor predisposition syndrome) should potentially be expanded to include SMZL, a disease often associated with the loss of chromosome 7q: the location of the POT1 genetic locus (7q31.33).- Published
- 2022
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24. Adding Base-Excision Repair Inhibitor TRC102 to Standard Pemetrexed-Platinum-Radiation in Patients with Advanced Nonsquamous Non-Small Cell Lung Cancer: Results of a Phase I Trial.
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Biswas T, Dowlati A, Kunos CA, Pink JJ, Oleinick NL, Malik S, Fu P, Cao S, Bruno DS, Bajor DL, Patel M, Gerson SL, and Machtay M
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cisplatin, DNA Repair, Glutamates adverse effects, Guanine adverse effects, Humans, Pemetrexed adverse effects, Platinum therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung radiotherapy, Lung Neoplasms drug therapy
- Abstract
Purpose: TRC102, a small-molecule base-excision repair inhibitor, potentiates the cytotoxicity of pemetrexed and reverses resistance by binding to chemotherapy-induced abasic sites in DNA. We conducted a phase I clinical trial combining pemetrexed and TRC102 with cisplatin-radiation in stage III nonsquamous non-small cell lung cancer (NS-NSCLC)., Patients and Methods: Fifteen patients were enrolled from 2015 to 2019. The primary objective was to determine the dose-limiting toxicity and maximum tolerated dose of TRC102 in combination with pemetrexed, cisplatin, and radiotherapy. Secondary objectives were to assess toxicity, tumor response, and progression-free survival at 6 months. Based on our preclinical experiments, pemetrexed-TRC102 was given on day 1, and cisplatin/radiotherapy was initiated on day 3. This schedule was duplicated in the second cycle. After completion, two additional cycles of pemetrexed-cisplatin were given. Toxicities were assessed using NCI CTACAE versions 4/5., Results: The median age was 69 years (45-79) with the median follow-up of 25.7 months (range, 7.9-47.4). No dose-limiting toxicities and no grade 5 toxicity were seen. Hematologic and gastrointestinal toxicities were the most common side effects. No clinical radiation pneumonitis was seen. Of 15 evaluable patients, three had complete response (20%), and 12 had partial response (80%). The 6-month progression-free survival was 80%, and the 2-year overall survival was 83%., Conclusions: Pemetrexed-TRC102 combined with cisplatin/radiotherapy in NS-NSCLC is safe and well tolerated. The recommended phase II dose is 200 mg TRC102 along with cisplatin-pemetrexed. No additional safety signal was seen beyond the expected CRT risks. A phase II trial, integrating post-CRT immunotherapy with this aggressive DNA-damaging regimen, is warranted., (©2021 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2022
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25. An effective human uracil-DNA glycosylase inhibitor targets the open pre-catalytic active site conformation.
- Author
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Nguyen MT, Moiani D, Ahmed Z, Arvai AS, Namjoshi S, Shin DS, Fedorov Y, Selvik EJ, Jones DE, Pink J, Yan Y, Laverty DJ, Nagel ZD, Tainer JA, and Gerson SL
- Subjects
- Catalytic Domain, Cytidine Deaminase, DNA Damage, Humans, Minor Histocompatibility Antigens, Uracil, DNA Repair, Uracil-DNA Glycosidase genetics, Uracil-DNA Glycosidase metabolism
- Abstract
Human uracil DNA-glycosylase (UDG) is the prototypic and first identified DNA glycosylase with a vital role in removing deaminated cytosine and incorporated uracil and 5-fluorouracil (5-FU) from DNA. UDG depletion sensitizes cells to high APOBEC3B deaminase and to pemetrexed (PEM) and floxuridine (5-FdU), which are toxic to tumor cells through incorporation of uracil and 5-FU into DNA. To identify small-molecule UDG inhibitors for pre-clinical evaluation, we optimized biochemical screening of a selected diversity collection of >3,000 small-molecules. We found aurintricarboxylic acid (ATA) as an inhibitor of purified UDG at an initial calculated IC
50 < 100 nM. Subsequent enzymatic assays confirmed effective ATA inhibition but with an IC50 of 700 nM and showed direct binding to the human UDG with a KD of <700 nM. ATA displays preferential, dose-dependent binding to purified human UDG compared to human 8-oxoguanine DNA glycosylase. ATA did not bind uracil-containing DNA at these concentrations. Yet, combined crystal structure and in silico docking results unveil ATA interactions with the DNA binding channel and uracil-binding pocket in an open, destabilized UDG conformation. Biologically relevant ATA inhibition of UDG was measured in cell lysates from human DLD1 colon cancer cells and in MCF-7 breast cancer cells using a host cell reactivation assay. Collective findings provide proof-of-principle for development of an ATA-based chemotype and "door stopper" strategy targeting inhibitor binding to a destabilized, open pre-catalytic glycosylase conformation that prevents active site closing for functional DNA binding and nucleotide flipping needed to excise altered bases in DNA., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2021
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26. 15-PGDH inhibition activates the splenic niche to promote hematopoietic regeneration.
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Smith JN, Dawson DM, Christo KF, Jogasuria AP, Cameron MJ, Antczak MI, Ready JM, Gerson SL, Markowitz SD, and Desai AB
- Subjects
- Animals, Bone Marrow Cells cytology, Female, Gene Expression Profiling, Mice, Mice, Inbred C57BL, Spleen enzymology, Spleen metabolism, Bone Marrow Cells drug effects, Enzyme Inhibitors pharmacology, Hematopoiesis, Extramedullary drug effects, Hydroxyprostaglandin Dehydrogenases antagonists & inhibitors, Regeneration, Spleen drug effects
- Abstract
The splenic microenvironment regulates hematopoietic stem and progenitor cell (HSPC) function, particularly during demand-adapted hematopoiesis; however, practical strategies to enhance splenic support of transplanted HSPCs have proved elusive. We have previously demonstrated that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using the small molecule (+)SW033291 (PGDHi), increases BM prostaglandin E2 (PGE2) levels, expands HSPC numbers, and accelerates hematologic reconstitution after BM transplantation (BMT) in mice. Here we demonstrate that the splenic microenvironment, specifically 15-PGDH high-expressing macrophages, megakaryocytes (MKs), and mast cells (MCs), regulates steady-state hematopoiesis and potentiates recovery after BMT. Notably, PGDHi-induced neutrophil, platelet, and HSPC recovery were highly attenuated in splenectomized mice. PGDHi induced nonpathologic splenic extramedullary hematopoiesis at steady state, and pretransplant PGDHi enhanced the homing of transplanted cells to the spleen. 15-PGDH enzymatic activity localized specifically to macrophages, MK lineage cells, and MCs, identifying these cell types as likely coordinating the impact of PGDHi on splenic HSPCs. These findings suggest that 15-PGDH expression marks HSC niche cell types that regulate hematopoietic regeneration. Therefore, PGDHi provides a well-tolerated strategy to therapeutically target multiple HSC niches, promote hematopoietic regeneration, and improve clinical outcomes of BMT.
- Published
- 2021
- Full Text
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27. Status of Cancer Care at Network Sites of the Nation's Academic Cancer Centers.
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Gerson SL, Shaw K, Harrison LB, Holcombe RF, Hutchins L, Lee CB, Loehrer PJ, Mulkerin D, Purcell WT, Teston L, Weiner LM, and Weiner GJ
- Subjects
- Certification, Electronic Health Records, Humans, Surveys and Questionnaires, United States, Neoplasms epidemiology, Neoplasms therapy, Patient Navigation, Physicians
- Abstract
Background: Cancer care coordination across major academic medical centers and their networks is evolving rapidly, but the spectrum of organizational efforts has not been described. We conducted a mixed-methods survey of leading cancer centers and their networks to document care coordination and identify opportunities to improve geographically dispersed care., Methods: A mixed-methods survey was sent to 91 cancer centers in the United States and Canada. We analyzed the number and locations of network sites; access to electronic medical records (EMRs); clinical research support and participation at networks; use of patient navigators, care paths, and quality measures; and physician workforce. Responses were collected via Qualtrics software between September 2017 and December 2018., Results: Of the 69 responding cancer centers, 74% were NCI-designated. Eighty-seven percent of respondents were part of a matrix health system, and 13% were freestanding. Fifty-six reported having network sites. Forty-three respondents use navigators for disease-specific populations, and 24 use them for all patients. Thirty-five respondents use ≥1 types of care path. Fifty-seven percent of networks had complete, integrated access to their main center's EMRs. Thirty-nine respondents said the main center provides funding for clinical research at networks, with 22 reporting the main center provides all funding. Thirty-five said the main center provided pharmacy support at the networks, with 15 indicating the main center provides 100% pharmacy support. Certification program participation varied extensively across networks., Conclusions: The data show academic cancer centers have extensive involvement in network cancer care, often extending into rural communities. Coordinating care through improved clinical trial access and greater use of patient navigation, care paths, coordinated EMRs, and quality measures is likely to improve patient outcomes. Although it is premature to draw firm conclusions, the survey results are appropriate for mapping next steps and data queries.
- Published
- 2021
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28. Socioeconomic Factors and Survival of Multiple Myeloma Patients.
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Chamoun K, Firoozmand A, Caimi P, Fu P, Cao S, Otegbeye F, Metheny L, Patel S, Gerson SL, Boughan K, De Lima M, and Malek E
- Abstract
Background: Outcome of Multiple Myeloma (MM) patients has improved as the result of the introduction of novel medications and use of autologous hematopoietic cell transplantation. However, this improvement comes at the expense of increased financial burden. It is largely unknown if socioeconomic factors influence MM survival., Methods: We used the National Cancer Database, a database that houses data on 70% of cancer patients in the US, to evaluate the effect of socioeconomic factors on the survival of 117,926 MM patients diagnosed between 2005 and 2014., Results: Patients aged ≥65 years who were privately insured lived longer than patients with Medicare (42 months vs. 31 months, respectively, p < 0.0001). Treatment in academic institutions led to better survival (HR: 1.49, 95% CI: 1.39, 1.59). Younger age, fewer comorbidities, treatment in academic centers, and living in a higher median income area were significantly associated with improved survival. After adjusting for confounders, survival of Medicare patients was similar to those with private insurance. However, the hazard of death remained higher for patients with Medicaid (HR: 1.59, 95% CI: 1.36, 1.87) or without insurance (HR: 1.62, 95% CI: 1.32, 1.99), compared to privately insured patients., Conclusion: Economic factors and treatment facility type play an important role in the survival of MM patients.
- Published
- 2021
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29. Phase I clinical trial of temozolomide and methoxyamine (TRC-102), an inhibitor of base excision repair, in patients with advanced solid tumors.
- Author
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Eads JR, Krishnamurthi SS, Saltzman J, Bokar JA, Savvides P, Meropol NJ, Gibbons J, Koon H, Sharma N, Rogers L, Pink JJ, Xu Y, Beumer JH, Riendeau J, Fu P, Gerson SL, and Dowlati A
- Subjects
- Adult, Aged, Antineoplastic Agents, Alkylating administration & dosage, Antineoplastic Agents, Alkylating adverse effects, Antineoplastic Agents, Alkylating pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Area Under Curve, DNA Repair drug effects, Dose-Response Relationship, Drug, Drug Synergism, Female, Half-Life, Humans, Hydroxylamines administration & dosage, Hydroxylamines adverse effects, Hydroxylamines pharmacokinetics, Male, Maximum Tolerated Dose, Metabolic Clearance Rate, Middle Aged, Temozolomide adverse effects, Temozolomide pharmacokinetics, Antineoplastic Agents, Alkylating therapeutic use, Hydroxylamines therapeutic use, Neoplasms drug therapy, Temozolomide therapeutic use
- Abstract
Temozolomide (TMZ) generates DNA adducts that are repaired by direct DNA and base excision repair mechanisms. Methoxyamine (MX, TRC-102) potentiates TMZ activity by binding to apurinic and apyrimidinic (AP) sites after removal of N
3 -methyladenine and N7 -methylguanine, inhibiting site recognition of AP endonuclease. We conducted a phase I trial to determine the maximum tolerated dose and dose-limiting toxicities (DLTs) of intravenous MX when given with oral TMZ. Patients with advanced solid tumors and progression on standard treatment were enrolled to a standard 3 + 3 dose escalation trial assessing escalating doses of TMZ and MX. Tumor response was assessed per RECIST and adverse events (AEs) by CTCAEv3. Pharmacokinetics (PK) of MX and COMET assays on peripheral blood mononuclear cells were performed. 38 patients were enrolled-median age 59.5 years (38-76), mean number of cycles 2.9 [1-13]. No DLTs were observed. Cycle 1 grade 3 AEs included fatigue, lymphopenia, anemia, INR, leukopenia, neutropenia, allergic reaction, constipation, psychosis and paranoia. Cycle 2-13 grade 4 AEs included thrombocytopenia and confusion. A partial response was seen in 1 patient with a pancreatic neuroendocrine tumor (PNET) and six additional patients, each with different tumor types, demonstrated prolonged stable disease. MX PK was linear with dose and was not affected by concomitant TMZ. TMZ 200 mg/m2 daily × 5 may be safely administered with MX 150 mg/m2 intravenously once on day 1 with minimal toxicity. Further studies assessing this drug combination in select tumor types where temozolomide has activity may be warranted.- Published
- 2021
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30. Myeloid Krüppel-like factor 2 is a critical regulator of metabolic inflammation.
- Author
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Sweet DR, Vasudevan NT, Fan L, Booth CE, Keerthy KS, Liao X, Vinayachandran V, Takami Y, Tugal D, Sharma N, Chan ER, Zhang L, Qing Y, Gerson SL, Fu C, Wynshaw-Boris A, Sangwung P, Nayak L, Holvoet P, Matoba K, Lu Y, Zhou G, and Jain MK
- Subjects
- Animals, Central Nervous System immunology, Diet, High-Fat adverse effects, Eating, Humans, Inflammation, Insulin Resistance, Kruppel-Like Transcription Factors genetics, Male, Metabolic Diseases genetics, Metabolic Diseases metabolism, Metabolic Diseases physiopathology, Mice, Mice, Knockout, Obesity etiology, Obesity genetics, Obesity physiopathology, Peripheral Nervous System immunology, Kruppel-Like Transcription Factors immunology, Metabolic Diseases immunology, Myeloid Cells immunology, Obesity immunology
- Abstract
Substantial evidence implicates crosstalk between metabolic tissues and the immune system in the inception and progression of obesity. However, molecular regulators that orchestrate metaflammation both centrally and peripherally remains incompletely understood. Here, we identify myeloid Krüppel-like factor 2 (KLF2) as an essential regulator of obesity and its sequelae. In mice and humans, consumption of a fatty diet downregulates myeloid KLF2 levels. Under basal conditions, myeloid-specific KLF2 knockout mice (K2KO) exhibit increased feeding and weight gain. High-fat diet (HFD) feeding further exacerbates the K2KO metabolic disease phenotype. Mechanistically, loss of myeloid KLF2 increases metaflammation in peripheral and central tissues. A combination of pair-feeding, bone marrow-transplant, and microglial ablation implicate central and peripheral contributions to K2KO-induced metabolic dysfunction observed. Finally, overexpression of myeloid KLF2 protects mice from HFD-induced obesity and insulin resistance. Together, these data establish myeloid KLF2 as a nodal regulator of central and peripheral metabolic inflammation in homeostasis and disease.
- Published
- 2020
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31. Protons and High-Linear Energy Transfer Radiation Induce Genetically Similar Lymphomas With High Penetrance in a Mouse Model of the Aging Human Hematopoietic System.
- Author
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Patel R, Zhang L, Desai A, Hoenerhoff MJ, Kennedy LH, Radivoyevitch T, La Tessa C, Gerson SL, and Welford SM
- Subjects
- Aging, Animals, DNA Mismatch Repair, Disease Models, Animal, Female, Gene Expression Profiling, Hematopoietic System physiology, Humans, Lymphoma pathology, Male, Mice, MutL Protein Homolog 1 genetics, Neoplasms, Radiation-Induced pathology, Penetrance, Radiation Exposure adverse effects, Sequence Analysis, RNA methods, Space Flight, Whole-Body Irradiation adverse effects, Whole-Body Irradiation methods, Hematopoietic System radiation effects, Linear Energy Transfer, Lymphoma genetics, MutL Protein Homolog 1 deficiency, Neoplasms, Radiation-Induced genetics, Protons adverse effects, Silicon adverse effects
- Abstract
Purpose: Humans are exposed to charged particles in different scenarios. The use of protons and high-linear energy transfer (LET) in cancer treatment is steadily growing. In outer space, astronauts will be exposed to a mixed radiation field composed of both protons and heavy ions, in particularly the long-term space missions outside of earth's magnetosphere. Thus, understanding the radiobiology and transforming potential of these types of ionizing radiation are of paramount importance., Methods and Materials: We examined the effect of 10 or 100 cGy of whole-body doses of protons or
28 Si ions on the hematopoietic system of a genetic model of aging based on recent studies that showed selective loss of the MLH1 protein in human hematopoietic stems with age., Results: We found that Mlh1 deficient animals are highly prone to develop lymphomas when exposed to either low doses of protons or28 Si ions. The lymphomas that develop are genetically indistinguishable, in spite of different types of damage elicited by low- and high-LET radiation. RNA sequencing analyses reveal similar gene expression patterns, similar numbers of altered genes, similar numbers of single nucleotide variants and insertions and deletions, and similar activation of known leukemogenic loci., Conclusions: Although the incidence of malignancy is related to radiation quality, and increased due to loss of Mlh1, the phenotype of the tumors is independent of LET., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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32. Inhibition of 15-PGDH Protects Mice from Immune-Mediated Bone Marrow Failure.
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Smith JNP, Otegbeye F, Jogasuria AP, Christo KF, Antczak MI, Ready JM, Gerson SL, Markowitz SD, and Desai AB
- Subjects
- Animals, Bone Marrow Transplantation, Humans, Hydroxyprostaglandin Dehydrogenases, Mice, Anemia, Aplastic drug therapy, Hematopoietic Stem Cell Transplantation
- Abstract
Aplastic anemia (AA) is a human immune-mediated bone marrow failure syndrome that is treated by stem cell transplantation for patients who have a matched related donor and by immunosuppressive therapy (IST) for those who do not. Responses to IST are variable, with patients still at risk for prolonged neutropenia, transfusion dependence, immune suppression, and severe opportunistic infections. Therefore, additional therapies are needed to accelerate hematologic recovery in patients receiving front-line IST. We have shown that inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) with the small molecule SW033291 (PGDHi) increases bone marrow (BM) prostaglandin E2 levels, expands hematopoietic stem cell (HSC) numbers, and accelerates hematologic reconstitution following murine BM transplantation. We now report that in a murine model of immune-mediated BM failure, PGDHi therapy mitigated cytopenias, increased BM HSC and progenitor cell numbers, and significantly extended survival compared with vehicle-treated mice. PGDHi protection was not immune-mediated, as serum IFN-γ levels and BM CD8
+ T lymphocyte frequencies were not impacted. Moreover, dual administration of PGDHi plus low-dose IST enhanced total white blood cell, neutrophil, and platelet recovery, achieving responses similar to those seen with maximal-dose IST with lower toxicity. Taken together, these data demonstrate that PGDHi can complement IST to accelerate hematologic recovery and reduce morbidity in severe AA., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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33. Mlh1 deficiency increases the risk of hematopoietic malignancy after simulated space radiation exposure.
- Author
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Patel R, Zhang L, Desai A, Hoenerhoff MJ, Kennedy LH, Radivoyevitch T, Ban Y, Chen XS, Gerson SL, and Welford SM
- Subjects
- Animals, Biomarkers, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic radiation effects, Disease Models, Animal, Disease Susceptibility, Female, Heterozygote, Humans, INDEL Mutation, Immunohistochemistry, Incidence, Male, Mice, Mice, Knockout, Microsatellite Instability, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Exome Sequencing, Environmental Exposure adverse effects, Hematologic Neoplasms etiology, MutL Protein Homolog 1 deficiency, Radiation Exposure adverse effects
- Abstract
Cancer-causing genome instability is a major concern during space travel due to exposure of astronauts to potent sources of high-linear energy transfer (LET) ionizing radiation. Hematopoietic stem cells (HSCs) are particularly susceptible to genotoxic stress, and accumulation of damage can lead to HSC dysfunction and oncogenesis. Our group recently demonstrated that aging human HSCs accumulate microsatellite instability coincident with loss of MLH1, a DNA Mismatch Repair (MMR) protein, which could reasonably predispose to radiation-induced HSC malignancies. Therefore, in an effort to reduce risk uncertainty for cancer development during deep space travel, we employed an Mlh1
+/- mouse model to study the effects high-LET56 Fe ion space-like radiation. Irradiated Mlh1+/- mice showed a significantly higher incidence of lymphomagenesis with56 Fe ions compared to γ-rays and unirradiated mice, and malignancy correlated with increased MSI in the tumors. In addition, whole-exome sequencing analysis revealed high SNVs and INDELs in lymphomas being driven by loss of Mlh1 and frequently mutated genes had a strong correlation with human leukemias. Therefore, the data suggest that age-related MMR deficiencies could lead to HSC malignancies after space radiation, and that countermeasure strategies will be required to adequately protect the astronaut population on the journey to Mars.- Published
- 2019
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34. Immune Signatures Associated With Clonal Isotype Switch After Autologous Stem Cell Transplantation for Multiple Myeloma.
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Ye R, Kundrapu S, Gerson SL, Driscoll JJ, Beck R, Ali N, Landgren O, VanHeeckeren W, Luo G, Kroger N, Caimi P, De Lima M, and Malek E
- Subjects
- Adult, Aged, B-Lymphocytes immunology, B-Lymphocytes metabolism, Dose-Response Relationship, Drug, Female, Humans, Immunoglobulin Isotypes genetics, Immunoglobulin Isotypes immunology, Immunoglobulin Isotypes metabolism, Male, Middle Aged, Multiple Myeloma immunology, Multiple Myeloma mortality, Postoperative Period, Prognosis, Progression-Free Survival, Retrospective Studies, Standard of Care, Transplantation Conditioning methods, Transplantation, Autologous, Tumor Microenvironment immunology, Hematopoietic Stem Cell Transplantation, Immune Reconstitution immunology, Immunoglobulin Class Switching immunology, Multiple Myeloma therapy, Myeloablative Agonists administration & dosage
- Abstract
Background: High-dose chemotherapy and autologous stem cell transplantation (ASCT) are integral components of the overall treatment for patients with multiple myeloma (MM) aged ≤ 65 years. The emergence of oligoclonal immunoglobulin bands (ie, immunoglobulins differing from those originally identified at diagnosis [termed clonal isotype switch (CIS)]) has been reported in patients with MM after high-dose chemotherapy followed by autologous stem cell transplantation. However, the clinical relevance and the correlation with immune reconstitution remains unclear., Patients and Methods: Patients with MM who had undergone ASCT from 2007 to 2016 were included in the present study. The percentage of natural killer cells, B-cells, and T-cells was measured using flow cytometry in pre- and post-ASCT bone marrow samples. CIS was defined as the appearance of a new serum monoclonal spike on serum protein electrophoresis and immunofixation that differed from original heavy or light chain detected at diagnosis., Results: A retrospective analysis of 177 patients with MM who had undergone ASCT detected CIS in 39 (22%). CIS after ASCT correlated with improved progression-free survival (52.2 vs. 36.6 months; P = .21) and overall survival (75.1 vs. 65.4 months; P = .021). Patients with a relapse had an isotype that differed from a CIS, confirming the benign nature of this phenomenon. CIS was also associated with lower CD8 T-cell percentages and a greater CD4/CD8 ratio (2.8 vs. 0.2; P = .001) compared with patients who did not demonstrate a CIS, suggestive of more profound T-cell immune reconstitution in this group., Conclusion: Taken together, our data have demonstrated that a CIS is a benign phenomenon and correlates with a reduced disease burden and enriched immune repertoire beyond the B-cell compartment., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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35. Gold Nanoparticle-Based Fluorescent Theranostics for Real-Time Image-Guided Assessment of DNA Damage and Repair.
- Author
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Srinivasan SS, Seenivasan R, Condie A, Gerson SL, Wang Y, and Burda C
- Subjects
- Cell Line, Tumor, Humans, Molecular Structure, DNA Damage physiology, DNA Repair physiology, Gold chemistry, Metal Nanoparticles chemistry, Theranostic Nanomedicine methods
- Abstract
Chemotherapeutic dosing, is largely based on the tolerance levels of toxicity today. Molecular imaging strategies can be leveraged to quantify DNA cytotoxicity and thereby serve as a theranostic tool to improve the efficacy of treatments. Methoxyamine-modified cyanine-7 (Cy7MX) is a molecular probe which binds to apurinic/apyrimidinic (AP)-sites, inhibiting DNA-repair mechanisms implicated by cytotoxic chemotherapies. Herein, we loaded (Cy7MX) onto polyethylene glycol-coated gold nanoparticles (AuNP) to selectively and stably deliver the molecular probe intravenously to tumors. We optimized the properties of Cy7MX-loaded AuNPs using optical spectroscopy and tested the delivery mechanism and binding affinity using the DLD1 colon cancer cell line in vitro. A 10:1 ratio of Cy7MX-AuNPs demonstrated a strong AP site-specific binding and the cumulative release profile demonstrated 97% release within 12 min from a polar to a nonpolar environment. We further demonstrated targeted delivery using imaging and biodistribution studies in vivo in an xenografted mouse model. This work lays a foundation for the development of real-time molecular imaging techniques that are poised to yield quantitative measures of the efficacy and temporal profile of cytotoxic chemotherapies., Competing Interests: The authors declare no conflict of interest.
- Published
- 2019
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36. Concise Reviews: Cancer Stem Cell Targeted Therapies: Toward Clinical Success.
- Author
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Desai A, Yan Y, and Gerson SL
- Subjects
- Drug Resistance, Neoplasm, Epigenomics methods, Humans, Immunotherapy methods, Signal Transduction physiology, Neoplastic Stem Cells cytology
- Abstract
Cancer stem cells (CSCs) are a subpopulation of cells within tumors that possess the stem cell characteristics of self-renewal, quiescence, differentiation, and the ability to recapitulate the parental tumor when transplanted into a host. CSCs are correlated with poor clinical outcome due to their contribution to chemotherapy resistance and metastasis. Multiple cell surface and enzymatic markers have been characterized to identify CSCs within a heterogeneous tumor, and here we summarize ongoing preclinical and clinical efforts to therapeutically target these cells and improve patient outcomes. Stem Cells Translational Medicine 2019;8:75-81., (© 2018 The Authors. Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)
- Published
- 2019
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37. High UDG and BRCA1 expression is associated with adverse outcome in patients with pemetrexed treated non-small cell lung Cancer.
- Author
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Hashemi Sadraei N, Feng Y, Du L, Fu P, Haque S, Dowlati A, Gollamudi J, Pennell NA, Mekhail T, Avril S, Farver C, Gerson SL, and Sharma N
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor metabolism, Carcinoma, Non-Small-Cell Lung diagnosis, Carcinoma, Non-Small-Cell Lung metabolism, Female, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Lung Neoplasms diagnosis, Lung Neoplasms metabolism, Male, Middle Aged, Pemetrexed administration & dosage, Retrospective Studies, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, BRCA1 Protein biosynthesis, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy, Uracil-DNA Glycosidase biosynthesis
- Abstract
Objective: The antifolate chemotherapy agent pemetrexed has been widely used to treat non-small-cell-lung-cancer (NSCLC), but there is no clinically validated biomarker to select patients likely to respond. The aim of this study was to assess two proteins involved in DNA repair mechanisms, uracil DNA glycosylase (UDG) and BRCA1 as potential prognostic biomarkers in NSCLC patients treated with pemetrexed-based chemotherapy., Material and Methods: Formalin-fixed-paraffin-embedded tumor specimens from 119 patients with advanced NSCLC treated with pemetrexed between 2004 and 2011 were retrospectively analyzed. Expression of UDG, BRCA1, and known prognostic factors ALK, TTF-1, thymidylate synthase and folylpolyglutamate synthase was assessed by immunohistochemistry using H-SCORE (product of percent stained cells and intensity of expression). Progression-free (PFS) and overall survival (OS) served as reference endpoint., Results: Most NSCLC tumor samples had UDG positivity in at least 5% of tumor cells and 34% samples had more than 50% positive tumor cells. Using the median expression value as threshold, high UDG expression (H-SCORE≥75) was significantly associated with shorter median PFS (3-year PFS 7% vs. 37%, p = 0.045) and a trend for shorter OS (3-year OS 15% vs 42%, p = 0.066) compared to patients with low UDG. In multivariable Cox analysis, the association between high UDG and shorter PFS was close to statistically significant (p = 0.08) at a significance level of 0.05 after controlling for age, gender, ALK- and TTF1-status with hazard ratio of 2.1. Grouping patients according to combined UDG and BRCA1 expression, patients with a profile of UDG
high /BRCA1high had the shortest PFS and OS compared to all other patient groups (p = 0.007 and 0.02, respectively)., Conclusion: Our results demonstrate an important prognostic role for high UDG expression in pemetrexed-treated NSCLC patients, in addition to its previously reported role in pemetrexed cytotoxicity. High UDG expression was predictive of shorter PFS and OS, and patients with a combined profile of UDGhigh /BRCA1high had the poorest outcome following pemetrexed treatment., (Copyright © 2018. Published by Elsevier B.V.)- Published
- 2018
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38. MMR Deficiency Does Not Sensitize or Compromise the Function of Hematopoietic Stem Cells to Low and High LET Radiation.
- Author
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Patel R, Qing Y, Kennedy L, Yan Y, Pink J, Aguila B, Desai A, Gerson SL, and Welford SM
- Subjects
- Animals, Blood Cell Count, Bone Marrow Cells cytology, Bone Marrow Cells metabolism, Bone Marrow Cells radiation effects, Cell Proliferation radiation effects, Female, Hematopoiesis radiation effects, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells radiation effects, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, MutL Protein Homolog 1 deficiency, MutL Protein Homolog 1 genetics, Radiation Dosage, DNA Mismatch Repair radiation effects, Gamma Rays, Hematopoietic Stem Cells metabolism
- Abstract
One of the major health concerns on long-duration space missions will be radiation exposure to the astronauts. Outside the earth's magnetosphere, astronauts will be exposed to galactic cosmic rays (GCR) and solar particle events that are principally composed of protons and He, Ca, O, Ne, Si, Ca, and Fe nuclei. Protons are by far the most common species, but the higher atomic number particles are thought to be more damaging to biological systems. Evaluation and amelioration of risks from GCR exposure will be important for deep space travel. The hematopoietic system is one of the most radiation-sensitive organ systems, and is highly dependent on functional DNA repair pathways for survival. Recent results from our group have demonstrated an acquired deficiency in mismatch repair (MMR) in human hematopoietic stem cells (HSCs) with age due to functional loss of the MLH1 protein, suggesting an additional risk to astronauts who may have significant numbers of MMR deficient HSCs at the time of space travel. In the present study, we investigated the effects gamma radiation, proton radiation, and
56 Fe radiation on HSC function in Mlh1+/+ and Mlh1-/- marrow from mice in a variety of assays and have determined that while cosmic radiation is a major risk to the hematopoietic system, there is no dependence on MMR capacity. Stem Cells Translational Medicine 2018;7:513-520., (© 2018 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)- Published
- 2018
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39. A second-generation 15-PGDH inhibitor promotes bone marrow transplant recovery independently of age, transplant dose and granulocyte colony-stimulating factor support.
- Author
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Desai A, Zhang Y, Park Y, Dawson DM, Larusch GA, Kasturi L, Wald D, Ready JM, Gerson SL, and Markowitz SD
- Subjects
- Adult, Age Factors, Animals, Bone Marrow Transplantation, Female, Hematopoietic Stem Cell Transplantation, Heterografts, Humans, Male, Mice, Antineoplastic Agents pharmacology, Enzyme Inhibitors pharmacology, Graft Survival drug effects, Granulocyte Colony-Stimulating Factor pharmacology, Hydroxyprostaglandin Dehydrogenases antagonists & inhibitors
- Abstract
Hematopoietic stem cell transplantation following myeloablative chemotherapy is a curative treatment for many hematopoietic malignancies. However, profound granulocytopenia during the interval between transplantation and marrow recovery exposes recipients to risks of fatal infection, a significant source of transplant-associated morbidity and mortality. We have previously described the discovery of a small molecule, SW033291, that potently inhibits the prostaglandin degrading enzyme 15-PGDH, increases bone marrow prostaglandin E2, and accelerates hematopoietic recovery following murine transplant. Here we describe the efficacy of (+)-SW209415, a second-generation 15-PGDH inhibitor, in an expanded range of models relevant to human transplantation. (+)-SW209415 is 10,000-fold more soluble, providing the potential for intravenous delivery, while maintaining potency in inhibiting 15-PGDH, increasing in vivo prostaglandin E2, and accelerating hematopoietic regeneration following transplantation. In additional models, (+)-SW209415: (i) demonstrated synergy with granulocyte colony-stimulating factor, the current standard of care; (ii) maintained efficacy as transplant cell dose was escalated; (iii) maintained efficacy when transplant donors and recipients were aged; and (iv) potentiated homing in xenotransplants using human hematopoietic stem cells. (+)-SW209415 showed no adverse effects, no potentiation of in vivo growth of human myeloma and leukemia xenografts, and, on chronic high-dose administration, no toxicity as assessed by weight, blood counts and serum chemistry. These studies provide independent chemical confirmation of the activity of 15-PGDH inhibitors in potentiating hematopoietic recovery, extend the range of models in which inhibiting 15-PGDH demonstrates activity, allay concerns regarding potential for adverse effects from increasing prostaglandin E2, and thereby, advance 15-PGDH as a therapeutic target for potentiating hematopoietic stem cell transplantation., (Copyright © 2018 Ferrata Storti Foundation.)
- Published
- 2018
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40. Advances in therapeutic targeting of the DNA damage response in cancer.
- Author
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Desai A, Yan Y, and Gerson SL
- Subjects
- Antineoplastic Agents pharmacology, DNA metabolism, Humans, Antineoplastic Agents therapeutic use, DNA Repair drug effects, Neoplasms drug therapy
- Abstract
The DNA damage response (DDR) is a series of pathways and processes required to repair lesions to DNA. These pathways range from repairing strand breaks to the double helix, damaged bases formed after oxidation or deamination, inaccurate DNA replication resulting in mispaired base alignment, intrastrand crosslinks that trigger cell death, and a plethora of other genomic insults. The DDR is believed to be a critical component of radio and chemoresistance in many cancers as well, with the tumor's ability to repair therapy induced damage being an important tool used to survive traditional chemotherapeutic agents. Here we summarize advances made in specifically targeting DDR proteins in cancer therapy and project on the potential breakthroughs and pitfalls to arise as the field progresses., (Copyright © 2018. Published by Elsevier B.V.)
- Published
- 2018
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41. Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy.
- Author
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Liao X, Shen Y, Zhang R, Sugi K, Vasudevan NT, Alaiti MA, Sweet DR, Zhou L, Qing Y, Gerson SL, Fu C, Wynshaw-Boris A, Hu R, Schwartz MA, Fujioka H, Richardson B, Cameron MJ, Hayashi H, Stamler JS, and Jain MK
- Subjects
- Animals, Cardiomegaly immunology, Cardiomegaly metabolism, Cardiomyopathies immunology, Cardiomyopathies metabolism, Cells, Cultured, Heart Failure immunology, Heart Failure metabolism, Kruppel-Like Factor 4, Macrophages immunology, Macrophages metabolism, Mice, Myocardium immunology, Myocardium metabolism, Pressure, Cardiomegaly pathology, Cardiomyopathies pathology, Heart Failure pathology, Kruppel-Like Transcription Factors metabolism, Macrophages pathology, Myocardium pathology
- Abstract
Nonischemic cardiomyopathy (NICM) resulting from long-standing hypertension, valvular disease, and genetic mutations is a major cause of heart failure worldwide. Recent observations suggest that myeloid cells can impact cardiac function, but the role of tissue-intrinsic vs. tissue-extrinsic myeloid cells in NICM remains poorly understood. Here, we show that cardiac resident macrophage proliferation occurs within the first week following pressure overload hypertrophy (POH; a model of heart failure) and is requisite for the heart's adaptive response. Mechanistically, we identify Kruppel-like factor 4 (KLF4) as a key transcription factor that regulates cardiac resident macrophage proliferation and angiogenic activities. Finally, we show that blood-borne macrophages recruited in late-phase POH are detrimental, and that blockade of their infiltration improves myocardial angiogenesis and preserves cardiac function. These observations demonstrate previously unappreciated temporal and spatial roles for resident and nonresident macrophages in the development of heart failure., Competing Interests: Conflict of interest statement: X.L. and M.K.J. have a patent application (serial no. 62/644,792).
- Published
- 2018
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42. Pilot trial of intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis.
- Author
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Cohen JA, Imrey PB, Planchon SM, Bermel RA, Fisher E, Fox RJ, Bar-Or A, Sharp SL, Skaramagas TT, Jagodnik P, Karafa M, Morrison S, Reese Koc J, Gerson SL, and Lazarus HM
- Subjects
- Adolescent, Adult, Disease Progression, Female, Hematopoietic Stem Cell Transplantation methods, Humans, Male, Middle Aged, Multiple Sclerosis, Chronic Progressive drug therapy, Transplantation, Autologous methods, Young Adult, Mesenchymal Stem Cell Transplantation methods, Mesenchymal Stem Cells cytology, Multiple Sclerosis drug therapy, Multiple Sclerosis, Relapsing-Remitting drug therapy
- Abstract
Background: Mesenchymal stem cells (MSCs) exhibit immunomodulatory, tissue-protective, and repair-promoting properties in vitro and in animals. Clinical trials in several human conditions support the safety and efficacy of MSC transplantation. Published experience in multiple sclerosis (MS) is modest., Objective: To assess feasibility, safety, and tolerability and explore efficacy of autologous MSC transplantation in MS., Methods: Participants with relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS), Expanded Disability Status Scale score 3.0-6.5, disease activity or progression in the prior 2 years, and optic nerve involvement were enrolled. Bone-marrow-derived MSCs were culture-expanded and then cryopreserved. After confirming fulfillment of release criteria, 1-2 × 10
6 MSCs/kg were thawed and administered IV., Results: In all, 24 of 26 screened patients were infused: 16 women and 8 men, 10 RRMS and 14 SPMS, mean age 46.5, mean Expanded Disability Status Scale score 5.2, 25% with gadolinium-enhancing magnetic resonance imaging (MRI) lesions. Mean cell dosage (requiring 1-3 passages) was 1.9 × 106 MSCs/kg (range, 1.5-2.0) with post-thaw viability uniformly ⩾95%. Cell infusion was tolerated well without treatment-related severe or serious adverse events, or evidence of disease activation., Conclusion: Autologous MSC transplantation in MS appears feasible, safe, and well tolerated. Future trials to assess efficacy more definitively are warranted.- Published
- 2018
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43. Patient Access to Academic Cancer Centers.
- Author
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Gerson SL and Jensen RA
- Subjects
- Humans, Academic Medical Centers, Health Services Accessibility
- Published
- 2018
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44. Loss of Uracil DNA Glycosylase Selectively Resensitizes p53-Mutant and -Deficient Cells to 5-FdU.
- Author
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Yan Y, Qing Y, Pink JJ, and Gerson SL
- Subjects
- Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Deoxyuridine pharmacology, Drug Resistance, Neoplasm drug effects, Drug Synergism, Gene Knockdown Techniques methods, Gene Knockout Techniques, HCT116 Cells, Humans, Neoplasms drug therapy, Pemetrexed pharmacology, Tumor Suppressor Protein p53 antagonists & inhibitors, Deoxyuridine analogs & derivatives, Mutation, Neoplasms genetics, RNA, Small Interfering pharmacology, Tumor Suppressor Protein p53 genetics, Uracil-DNA Glycosidase deficiency
- Abstract
Thymidylate synthase (TS) inhibitors including fluoropyrimidines [e.g., 5-Fluorouracil (5-FU) and 5-Fluorodeoxyuridine (5-FdU, floxuridine)] and antifolates (e.g., pemetrexed) are widely used against solid tumors. Previously, we reported that shRNA-mediated knockdown (KD) of uracil DNA glycosylase (UDG) sensitized cancer cells to 5-FdU. Because p53 has also been shown as a critical determinant of the sensitivity to TS inhibitors, we further interrogated 5-FdU cytotoxicity after UDG depletion with regard to p53 status. By analyzing a panel of human cancer cells with known p53 status, it was determined that p53-mutated or -deficient cells are highly resistant to 5-FdU. UDG depletion resensitizes 5-FdU in p53-mutant and -deficient cells, whereas p53 wild-type (WT) cells are not affected under similar conditions. Utilizing paired HCT116 p53 WT and p53 knockout (KO) cells, it was shown that loss of p53 improves cell survival after 5-FdU, and UDG depletion only significantly sensitizes p53 KO cells. This sensitization can also be recapitulated by UDG depletion in cells with p53 KD by shRNAs. In addition, sensitization is also observed with pemetrexed in p53 KO cells, but not with 5-FU, most likely due to RNA incorporation. Importantly, in p53 WT cells, the apoptosis pathway induced by 5-FdU is activated independent of UDG status. However, in p53 KO cells, apoptosis is compromised in UDG-expressing cells, but dramatically elevated in UDG-depleted cells. Collectively, these results provide evidence that loss of UDG catalyzes significant cell death signals only in cancer cells mutant or deficient in p53. Implications: This study reveals that UDG depletion restores sensitivity to TS inhibitors and has chemotherapeutic potential in the context of mutant or deficient p53. Mol Cancer Res; 16(2); 212-21. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2018
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45. Long-Term Deficits in Behavior Performances Caused by Low- and High-Linear Energy Transfer Radiation.
- Author
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Patel R, Arakawa H, Radivoyevitch T, Gerson SL, and Welford SM
- Subjects
- Animals, Hydrogen, Iron, Male, Mice, Mice, Inbred C57BL, Radiation Injuries, Experimental etiology, Rotarod Performance Test, Silicon, Time Factors, Anxiety etiology, Exploratory Behavior radiation effects, Gamma Rays adverse effects, Linear Energy Transfer, Maze Learning radiation effects, Memory Disorders etiology, Protons adverse effects, Psychomotor Performance radiation effects, Radiation Injuries, Experimental psychology, Recognition, Psychology radiation effects
- Abstract
Efforts to protect astronauts from harmful galactic cosmic radiation (GCR) require a better understanding of the effects of GCR on human health. In particular, little is known about the lasting effects of GCR on the central nervous system (CNS), which may lead to behavior performance deficits. Previous studies have shown that high-linear energy transfer (LET) radiation in rodents leads to short-term declines in a variety of behavior tests. However, the lasting impact of low-, medium- and high-LET radiation on behavior are not fully defined. Therefore, in this study C57BL/6 male mice were irradiated with 100 or 250 cGy of γ rays (LET ∼0.3 KeV/μm), 10 or 100 cGy of
1 H at 1,000 MeV/n (LET ∼0.2 KeV/μm),28 Si at 300 MeV/n (LET ∼69 KeV/μm) or56 Fe at 600 MeV/n (LET of ∼180 KeV/μm), and behavior metrics were collected at 5 and 9 months postirradiation to analyze differences among radiation qualities and doses. A significant dose effect was observed on recognition memory and activity levels measured 9 months postirradiation, regardless of radiation source. In contrast, we observed that each ion species had a distinct effect on anxiety, motor coordination and spatial memory at extended time points. Although28 Si and56 Fe are both regarded as high-LET particles, they were shown to have different detrimental effects on behavior. In summary, our findings suggest that GCR not only affects the CNS in the short term, but also has lasting damaging effects on the CNS that can cause sustained declines in behavior performance.- Published
- 2017
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46. New Opportunities and Challenges to Defeat Cancer Stem Cells.
- Author
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Ramos EK, Hoffmann AD, Gerson SL, and Liu H
- Subjects
- Cell Differentiation genetics, Drug Resistance, Neoplasm genetics, Humans, Neoplasms pathology, Signal Transduction genetics, Carcinogenesis genetics, Neoplasms genetics, Neoplastic Stem Cells pathology
- Abstract
Cancer stem cells (CSCs) are a subpopulation of cancer cells that are capable of self-renewal, proliferation, differentiation, plastic adaptation, and immune regulation, thereby mediating tumorigenesis, metastasis, and therapy resistance. CSCs are associated with cancer progression and clinical outcome in cancer patients. Successful targeting of CSCs will therefore be necessary to eradicate and cure cancer. Functional regulators of stem cell (stemness) signaling pathways in human cancers have brought new opportunities to target CSCs and reframe cancer-targeting strategies in clinical settings. However, challenges remain due to a lack of complete understanding of CSC plasticity/heterogeneity and the limited efficacy of individual stemness inhibitors in cancer treatment. In this article we review CSC signaling pathways and the current state of CSC-targeting therapeutics in combinatory treatments in clinical trials., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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47. New Advances and Challenges of Targeting Cancer Stem Cells.
- Author
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Dashzeveg NK, Taftaf R, Ramos EK, Torre-Healy L, Chumakova A, Silver DJ, Alban TJ, Sinyuk M, Thiagarajan PS, Jarrar AM, Turaga SM, Saygin C, Mulkearns-Hubert E, Hitomi M, Rich JN, Gerson SL, Lathia JD, and Liu H
- Subjects
- Animals, Epigenesis, Genetic, Humans, Neoplasms drug therapy, Neoplasms genetics, Neoplastic Stem Cells drug effects, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm drug effects, Neoplasms pathology, Neoplastic Stem Cells pathology, Tumor Microenvironment drug effects
- Abstract
The second International Cancer Stem Cell Conference in Cleveland, Ohio, on September 20-23, 2016, convened 330 attendees from academic, industrial, and clinical organizations. It featured a debate on the concepts and challenges of the cancer stem cells (CSC) as well as CSC-centered scientific sessions on clinical trials, genetics and epigenetics, tumor microenvironment, immune suppression, metastasis, therapeutic resistance, and emerging novel concepts. The conference hosted 35 renowned speakers, 100 posters, 20 short talks, and a preconference workshop. The reported advances of CSC research and therapies fostered new collaborations across national and international borders, and inspired the next generation's young scientists. Cancer Res; 77(19); 5222-7. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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48. Phase I clinical trial of the base excision repair inhibitor methoxyamine in combination with fludarabine for patients with advanced hematologic malignancies.
- Author
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Caimi PF, Cooper BW, William BM, Dowlati A, Barr PM, Fu P, Pink J, Xu Y, Lazarus HM, de Lima M, and Gerson SL
- Abstract
Purpose: We determined the safety, pharmacokinetics, pharmacodynamics and recommended phase II dose of the base excision repair blocker methoxyamine combined with fludarabine., Materials and Methods: This was a phase I study with intravenous fludarabine (25 mg/m
2 , days 1-5), and methoxyamine (15 mg/m2 -120 mg/m2 , once). A maximum of six cycles were given. Adult patients with relapsed/refractory hematologic malignancies, excluding acute myeloid leukemia, were eligible., Results: Twenty patients were treated; diagnoses included CLL/SLL ( n = 10), follicular lymphoma ( n = 3), DLBCL ( n = 3), mantle cell lymphoma ( n = 1), anaplastic large cell lymphoma ( n = 1) and plasma cell myeloma ( n = 2). No DLTs were observed and dose escalation reached the maximum planned dose. Hematologic toxicity was frequent; most common grade 3-4 toxicities were lymphopenia (70%), neutropenia (60%), leukopenia (50%) and anemia (40%). Four patients achieved a partial remission and 8 achieved stable disease. The drug combination resulted in increased DNA damage measured with the Comet assay., Conclusions: Methoxyamine combined with fludarabine was safe and well tolerated. Hematologic toxicity was comparable to single agent fludarabine. Activity appears to correlate with increased levels of DNA damage. Further studies will examine use of this combination of as part conditioning regimens of stem cell transplant and use of methoxyamine as fludarabine dose-sparing agent., Competing Interests: CONFLICTS OF INTEREST SLG holds patents under Case Western Reserve University for the use of methoxyamine, is compensated for service on the Scientific Advisory Board for Tracon, holds shares, and has a royalty and milestone interest through Case Western Reserve University for Methoxyamine (TRC-102). All other authors have no relevant conflicts of interest to disclose.- Published
- 2017
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49. Mismatch repair deficient hematopoietic stem cells are preleukemic stem cells.
- Author
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Qing Y and Gerson SL
- Subjects
- Animals, Bone Marrow Transplantation, Disease Models, Animal, Hematopoietic Stem Cells metabolism, Lymphoma genetics, Lymphoma metabolism, Mice, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, T-Lymphocytes cytology, T-Lymphocytes pathology, Thymus Neoplasms genetics, Thymus Neoplasms metabolism, Tumor Microenvironment, Hematopoietic Stem Cells cytology, Lymphoma pathology, MutS Homolog 2 Protein deficiency, Thymus Neoplasms pathology
- Abstract
Whereas transformation events in hematopoietic malignancies may occur at different developmental stages, the initial mutation originates in hematopoietic stem cells (HSCs), creating a preleukemic stem cell (PLSC). Subsequent mutations at either stem cell or progenitor cell levels transform the PLSC into lymphoma/leukemia initiating cells (LIC). Thymic lymphomas have been thought to develop from developing thymocytes. T cell progenitors are generated from HSCs in the bone marrow (BM), but maturation and proliferation of T cells as well as T-lymphomagenesis depends on both regulatory mechanisms and microenvironment within the thymus. We studied PLSC linked to thymic lymphomas. In this study, we use MSH2-/- mice as a model to investigate the existence of PLSC and the evolution of PLSC to LIC. Following BM transplantation, we found that MSH2-/- BM cells from young mice are able to fully reconstitute multiple hematopoietic lineages of lethally irradiated wild-type recipients. However, all recipients developed thymic lymphomas within three and four months post transplantation. Transplantation of different fractions of BM cells or thymocytes from young health MSH2-/- mice showed that an HSC enriched fraction always reconstituted hematopoiesis followed by lymphoma development. In addition, lymphomas did not occur in thymectomized recipients of MSH2-/- BM. These results suggest that HSCs with DNA repair defects such as MSH2-/- are PLSCs because they retain hematopoietic function, but also carry an obligate lymphomagenic potential within their T-cell progeny that is dependent on the thymic microenvironment.
- Published
- 2017
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50. Splenic marginal zone lymphoma: excellent outcomes in 64 patients treated in the rituximab era.
- Author
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Starr AG, Caimi PF, Fu P, Massoud MR, Meyerson H, Hsi ED, Mansur DB, Cherian S, Cooper BW, De Lima MJG, Lazarus HM, Gerson SL, Jagadeesh D, Smith MR, Dean RM, Pohlman BL, Hill BT, and William BM
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Cohort Studies, Combined Modality Therapy, Female, Follow-Up Studies, Humans, Kaplan-Meier Estimate, Lymphoma, B-Cell, Marginal Zone diagnosis, Male, Middle Aged, Neoplasm Metastasis, Neoplasm Staging, Odds Ratio, Prognosis, Splenic Neoplasms diagnosis, Treatment Outcome, Antineoplastic Agents therapeutic use, Lymphoma, B-Cell, Marginal Zone drug therapy, Lymphoma, B-Cell, Marginal Zone mortality, Rituximab therapeutic use, Splenic Neoplasms drug therapy, Splenic Neoplasms mortality
- Abstract
Objectives and Methods: Splenic marginal zone lymphoma (SMZL) is a rare non-Hodgkin lymphoma. We sought to identify prognostic factors and define outcomes in a cohort of 64 patients with SMZL who were treated at two large academic medical centers in North America in the rituximab era., Results: Over a median follow-up of 37.8 (range 6-167.1) months, Kaplan-Meier estimate of median OS was 156.3 months and median PFS was 52.9 months. On univariate analysis, baseline hemoglobin <12 g/dl was associated with inferior OS (p = 0.045). High-risk FLIPI score was associated with inferior PFS when compared with intermediate/low risk (p = 0.05) and marginally significant with regard to OS (p = 0.056). Splenectomy was not predictive of OS or PFS (p = 0.563 and 0.937, respectively). Transformation to diffuse large B-cell lymphoma occurred in four (6.3%) patients during the observation period. OS was comparable to contemporaneous cohorts of patients with extranodal and nodal marginal lymphomas and FLIPI score was highly predictive for inferior PFS and OS when all three cohorts were analyzed together., Conclusion: Outcomes of SMZL, in our series, were excellent, with a median OS of >13 years. Low hemoglobin and high-risk FLIPI were associated with inferior outcomes.
- Published
- 2017
- Full Text
- View/download PDF
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